vents under the sea can supply that, but that does not mean that it is the beginning of all ... Cucumber is almost entirely water but has structure. So, perhaps .... corpses of prehistoric creatures (fossils) constitute the fuels like coal, oil and gas that ...... interpretation. If you take the three types of calcium antagonists nifedipine,.
1
Wrong notions about the heart
Mark Noble
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" " " Copyright © 2014 Mark Noble.
All rights reserved. No part of this book may be reproduced, stored, or transmitted by any means— whether auditory, graphic, mechanical, or electronic—without written permission of both publisher and author, except in the case of brief excerpts used in critical articles and reviews. Unauthorized reproduction of any part of this work is illegal and is punishable by law.
The information, ideas, and suggestions in this book are not intended as a substitute for professional medical advice. Before following any suggestions contained in this book, you should consult your personal physician. Neither the author nor the publisher shall be liable or responsible for any loss or damage allegedly arising as a consequence of your use or application of any information or suggestions in this book.
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Contents
" Preface:
Why did I write this book?
Introduction:
Facts, theorems, theories and absurdities.
Chapter 1:
The cells of your body — control by membrane or gel?
Chapter 2:
False theory: don’t eat salt; it will put your blood
pressure up; it will kill you. NOT SO
Chapter 3:
Command of contraction of the heart by calcium but how?
Chapter 4:
False theory: the micromuscles in muscle
Chapter 5:
False notions of the heart: preload, afterload,
Vmax, etc
Chapter 6:
Franck versus Starling, and Emax -true or false?
Chapter 7:
Heart attack: what is being attacked? Heart failure: what has failed?
Chapter 8:
The heart delivers a series of dollops of blood flow with each beat, interspersed with zero blood flow, but the body needs a steady blood flow!
Chapter 9:
Arteries are living things, and become diseased
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Chapter 10:
The great cholesterol myth
Chapter 11:
What is so special about coronaries? And a silly
debate!
Chapter 12:
Drugs for the heart - and a Bloody Mess
Chapter 13:
I’m so worried about my blood pressure. Why? My
care team are so worried about my blood pressure
Why?
Chapter 14:
Stress, fight, flight and fright - and you can’t beat a
beta block!
Chapter 15:
What diet should I eat if I am obese or diabetic?
What diet should I eat if
I’m normal?
Chapter 16:
You are not joking Mr Feynman: Where medicine
went wrong
Bibliography
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" "
Preface
Why did I write this book?
1.
The usual misrepresentation of science and medicine by the media.
2.
The actions taken by Government on the basis of false theories leading to policies such as depriving normal people of essential elements of their food, such as salt and fat.
3.
The hypocrisy of Government in proclaiming that their policies are helping the health of the people, when there is evidence that some of those policies harm the health of the people.
4.
The failure of those with a public voice to point out that theories cannot
be proved, only disproved.
5.
A peer review system that is prejudiced in such a way that work supporting popular theories are favoured for funding and publication, even though theories can only be disproved, not proved. Dissent and discordant voices have difficulty to be heard.
6.
That medical education and practice now follow “labels” and “protocols” which treat the average patient, not the individual.
7.
The structure of the hospital training system for physicians and surgeons leading to the risk of creating incompetent consultants.
8.
The incorrect interpretation of results of analytical statistics.
9.
The double standards of people concerned about animal welfare.
In short, that policy, regulation, social political correctness (PC), ideology and hypocrisy govern much of science and medicine rather than common sense.
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Fewer and fewer people vote. Fewer and fewer people have faith in religion, the police and the medical profession. More and more people say, “The world has gone mad” — Why? — because the controllers of the world lack common sense.
The same applies to a lot of modern medicine. As my field of research and medicine has been in the cardiovascular system, I have illustrated my theme by describing instances of conflicting theories about aspects of cardiology, and how the sway of false theories has caused problems. Some of these controversies are mainly of my own intellectual interest, but others have a serious impact on public health.
As Richard Feynman once stated— “Reality is more important than public relations. You cannot cheat nature”.
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Introduction
Facts, Theorems, Theories and Absurdities
" This book is intended to explain to intelligent non-medical people the various disagreements about how the heart and circulation works that I have encountered in my career. In this introduction, I point out that all the the things that we think we know about in bioscience, are in the form of theories, which are, by definition, capable of disproof and are therefore potentially falsehoods. Maybe, after my explanations, the reader may think that some of these ideas might well be more false than others!
The idea that I write about controversies in cardiovascular science and medicine arose from frustration at the popularisation of certain theories that have become so “fashionable” as a result of inappropriate preaching of them in the media — newspapers, TV etc. People are changing their lives under the influence of these popular theories.
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Sometimes the theory concerned is compatible with some real scientific data, and their adoption into ordinary peoples lifestyle appear just now to be beneficial, e.g., that smoking is detrimental to health and should be avoided. Other theories are associated with very little compatible evidence, and other evidence which strongly challenges the validity of the theories, for example that the normal population should starve itself of salt and fat, an action very likely to be detrimental to health.
The worst crime of the TV reporter is when he or she says “Scientists believe that so and so...”. If the scientists did indeed say that to the reporter then they are not scientists but charlatans. The verb “to believe” is totally banned from the scientific thought process. If the non scientist tries to check for himself about such things in the scientific literature, he is more likely to come to false rather than true conclusions. Acceptance by scientific journals of submitted pieces of research are strongly biased toward some theories by two factors:
“Positive” interpretations (compatible with popular theory) are preferred over “negative” skeptical ones.
Papers are judged by “peer” reviewers who often turn out to be so-called “experts”, who are really very strong supporters of the popular theory. To support a theory is a fundamentally non–scientific attitude.
Facts, Theorems, Laws, Theories and Statistics.
Fact: These are the basis of all advancements that can be made in knowledge and are what they are. For instance, the fact that there are 60 seconds in one minute.
Theorem: A theorem is the result of a deduction, worked out in pure mathematics and logic.
Theory: A hypothesis, or prediction about a process, in applied mathematics, physics, chemistry and biomedicine. A theory cannot be proved but may become a law, for instance Newton’s Laws.
Law: A theory that has resisted all attempts to disprove it. All data is consistent with the theory being true, but only under certain conditions.
Statistics: Statistics has two meanings: raw data and the analysis of data. Analysing data can show a possible trend, relationship or problem. All analysis of data is probabilistic, it never shows a link between sets of data.
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" Nothing can be proved with statistics.
" I like to discuss these matters with colleagues in both medical and non medical scientific fields in order to try and clarify my mind amongst the vast number of supposed “discoveries” being thrown at us daily.
Philosopher: “There have been many proofs of mathematical relationships; these are called theorems, for example, the law of Pythagorus.”
Prof: “I regard the science of physics and chemistry as a single subject. (‘All science is either physics or stamp collecting’ – Ernest Rutherford, Nobel Prize winner for Chemistry (1908)). We have a mixture of relationships that can be proved and some that have not been proved, and are therefore theories, not theorems (e.g., the big bang theory). In biology, we only have theories, and we have been taught by Carl Popper that all theories can be disproved. The correct scientific method to increase knowledge is to endeavour always to try and disprove theories.”
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" Philosopher: “Someone has to think up the theories in the first place.”
Prof: “Yes, Feynman said that you start with a guess, then work out the consequences of your guess, then test that, and if experimental results are not as predicted, you have to scrap the theory however clever you think it is.”
Philosopher: “We could avoid a lot of unnecessary work by using a maxim of mathematics, ‘Is this answer reasonable?’. If not, that pathway in the exercise can be set aside as absurd, a number of theorems have been proved using this process, the process of logic. An absurdity in the practice of logic is a process that enables a particular possibility to be excluded by the use of common sense.”
Prof: “What we think we know in bioscience are facts and measurements — data, also confusingly called ‘statistics’, established and confirmed by observation or experiment. The joy in the BBC programme, ‘The Joy of Statistics’ is the joy that so much data is available. However, that programme confirmed the maxim that evidence based on statistical manipulation of data (analytical statistics) cannot prove theories, only disprove them.”
Surgeon: “Most important for us are the facts of anatomy that can now be determined for each individual by modern imaging techniques, particularly to help us surgeons assess diseased organs and know what to expect when we operate.”
Philosopher: “Facts differ from theorems; the latter are derived from a sequence of logical steps.”
Prof: “Facts in biology are obtained from correct observations, raising the problem of whether a supposed fact really is a fact or comes from a flawed observation. Our theories need to take into account reliable facts.” Even the more precise science such as mechanics involve measurements which all have an uncertainty, expressed by the ± sign. In biomedical science we also have further uncertainty as no result is identical on repetition, so that this variation also has to be accounted for as a ± (‘A result without uncertainty is meaningless’ — Walter Lewin).
Prof: “That there are 60 seconds in a minute is a fact, but measurement of time always has some uncertainty. Hence the need for ever more accurate clocks such as Harrison’s chronometer. Even timing formula one cars qualifying times to one hundredth of a second does not exclude the possibility of different times measured in milliseconds (ms — one thousandth of a second). Current atomic clocks loose one second every billion years or so”.
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Philosopher, “Isaac Asimov, in his ‘The Relativity of Wrong’ (see Asimov in Bibliography) quotes a correspondent of his who argued that with passing centuries, thoughts about the universe were changed, for instance a flat earth displaced by a spherical earth, then replaced by an oblate spheroid; an earth centred universe replaced by a sun centred one, etc. From this he argued that each century’s different view showed that our ideas about the universe must always be wrong. Asimov countered with the argument that each idea was less wrong than that in the previous century and therefore we are less wrong than we have ever been”.
Surgeon: “An example of a reliable fact is that blood circulates around the body. Philosophers prior to the 17th century thought that blood ebbed and flowed in the arteries and veins. They could easily have disproved this by doing a simple observation. They only needed to be at a battle (there were plenty of those at the time) to see that a wound severing an artery caused blood to continuously flow out in high pressure squirts.”
Prof: “Don’t you surgeons just love to see the gore!”
Surgeon: “I have to confess that it was a physician, the great royal physician William Harvey in the 17th century, that pointed out these and many other aspects, such as the function of valves in heart and blood vessels, leading to the establishment of the circulation of blood as a fact.”
Prof: “Yes, this must be adhered to in any theory we may form (or postulate) in the science of the cardiovascular system.”
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Philosopher: “Although all theories in biology are capable of disproof, some are weird enough for us to say that they are very improbable and therefore very likely to be disproved. Others have so much evidence with which they are compatible that we can say that they are very probable. Or, to put it more correctly, the probability that they can be disproved is very low.”
Prof: “In the case of Darwin’s theory of evolution by natural selection, the probability of disproof is so minute that I shall use it for the time being as if it were a fact. This is because evolution by human selection is a fact — we breed plants and animals to provide the best food, we even genetically modify organisms and produce clones. Also natural selection has been observed in wildlife, by Darwin and by many others since. We are presently observing in Scotland the displacement of red squirrels by grey squirrels by natural selection, only hindered by human intervention.”
You cannot prove anything with analytical statistics
Prof: “In biological research we use the word ‘probability’ very much in the
branch of mathematics that we use most, namely statistics.”
Philosopher: “The most important fact about statistics is that it is impossible to prove anything with statistics, contrary to popular belief, because when we say that a result is statistically significant, we should be saying that the probability of the result being wrong is less than 5%.”
" " " " " " " " " " Statistician: “A correlation between two factors depends on the choice of
factors thought to be correlated. One (the dependent variable) has to be thought to depend on the other (the independent variable). Visually, this is 13
presented as a graph with a vertical axis representing the dependent variable (y axis or ordinate) and a horizontal axis representing the independent variable (x axis or abscissa). Perfect correlation is obtained if you plot the same variables on both axes, when all the points lie exactly on a straight line.”
Prof: “If you plot different biological variables on the axes, e.g., height of a population versus shoe size, the points are scattered. Statistical correlation analysis will show a significant correlation, but that does not mean that a person’s height is caused by his or her shoe size. It probably means that both are caused by the extent of bone growth. But time and again, the progenitors of false theories argue from such correlations, for example, when cholesterol lowering drugs (statins) are given to people, there is a correlation between survival and cholesterol. This is not because the improved survival is caused by the lower cholesterol. It is a false hypothesis to say that the improved survival is caused by the lower cholesterol, in that it does not apply to all patients. The correlation arises because statins reduce arterial disease regardless of cholesterol level, but they also independently lower cholesterol, so a positive correlation will be obtained that does not mean any dependency of one variable upon the other.”
Statistician: “Even if one thinks one has found a meaningful statistical correlation between, say, a clinical problem in a population and a potential cause, say, smoking, this only applies to an average person in the population. The difference between a datum from an individual observation and the average varies with such individual observation and is analysed in statistics as a variance. Often the variance, the amount of the problem not related to the independent variable or average, is larger than that which is, for instance, tall individuals with small shoe size, short people with large shoe size (or foot size in the case of Hobbits). Nevertheless there is a considerable amount of bad medicine that is due to applying to individual patients that which applies only to the average patient.”
Philosopher: “One has to accept that biomedical results are imprecise, plagued with natural biological variation. Then there is the tendency of research workers to try and obtain data that support a hypothesis, rather than trying to disprove it. Thus, it is not surprising that there is so much bad biological and medical science.”
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Conclusions from the debate
Facts are as they are and are vital for correct medical and surgical treatments of disease.
Theorems are the only deductions that can be proved and that only by process of pure mathematics or logic. This is not possible in science, although there are various derived formulas and laws that are not theorems as they rely on a theory.
Laws and theories are predictions about how things work in nature; both can be disproved. Laws have resisted disproof within the practical conditions of human experiment. Theories are still capable of disproof through the processes of human scientific endeavour, endeavour that should always be directed at disproof, especially in the most inexact of sciences — biomedical science.
Statistics, other than mere data collection, is a process of applied mathematics that examines the possibilities and probabilities of chance associations versus meaningful association. Too many false conclusions arise from this process, particularly in biomedical science. Proof is impossible by statistical analysis.
My role as a teacher
I do not think that my job as a teacher is to stand in front of a bunch of students and tell them about facts. They can get their facts from books. I see my role as that of a biomedical philosopher trying to impart understanding of mechanisms (as far as that is possible in medicine). This is analogous to a ‘master’ in conversation with a ‘disciple’, as follows. (If only one-to-one teaching was possible more often in biomedical courses!)
Disciple: “Do you equate logic with common sense?”
Master: “They are related but not the same. The most logical thing in the world is the workings of a computer, logic being essentially mathematical. Many people use computers in a way that is the antithesis of common sense.”
Disciple: “Do you equate common sense with intelligence?”
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Master: “There is a correlation for the simple reason that to exert common sense, or indeed logical thinking, one needs a good functioning brain. However, there are plenty of examples of intelligent people doing crazy things. Now, what do you want to know about biological science?”
Disciple: “What is the difference between a theory or hypothesis and a Law, e.g., Starling’s Law.”
Master: “A theory in science cannot be proved, but can be claimed to be a Law when all attempts to disprove it fail, e.g., Newton’s Laws of motion. However, laws only apply under specified conditions; Newton’s Laws do not work at very small scales, very high speeds or in strong gravitational fields. There are problems with calling Starling’s heart muscle theory a law, but if we called it a hypothesis, it would be confused with his other hypothesis about fluid transport in the microcirculation!
Disciple: “Okay. You accept Darwin’s theory of evolution, but how do you think life began?”
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Master: “While it is possible to regard Darwin’s theory as extremely unlikely to be disproved, that is certainly not the case when it comes to a theory of the way life began on earth; we do not know, and even the creationists might be less ridiculous if they focused on this subject.”
Disciple: “You must have some speculations, knowing you.”
Master: “We do have some definite clues, of which the most obvious is the necessity of water for life. Thoughts about this subject do have some relevance to the way I think we should think about some problems in cardiovascular science. If we assume that the ever changing earth’s crust is full of physics/ chemistry, and has an atmosphere, it seems reasonable to postulate that before life on earth, the earth had surface water, clouds and rain.”
Disciple: “You mean life started as rain?”
" Master: “Water can be incorporated into life if there is an energy source. Hot
vents under the sea can supply that, but that does not mean that it is the beginning of all life. Certainly the dominant forms of life on the earth surface derive their energy directly or indirectly from the sun. We can be sure that cloud water can develop separation of electric charge causing lightning (Lightning however does not always require water, as evidenced 17
by lightning from volcanic ash clouds and lightning storms on Venus and Saturn)”.
Disciple: “What happens in water on the Earth’s surface then?”
Master: “As a liquid, water has structure having two hydrogen atoms bound to an oxygen atom by electrostatic bonds. If we confine our speculation to liquid water, as opposed to solid or gaseous water (vapour and steam), other molecules will mix with water and change the structure. Some of these mixtures are capable of generating other forms of energy from photons derived from the sun, a process called photosynthesis”.
Disciple, “You mean impure water and light produces electricity and that is essential for life to begin?”
Master, “This seems to me to be the fundamental process for the early life that led to the vast majority of life forms on the earth’s surface today. Remember that water is full of electric charge; it is two protons attached to an oxygen radicle that has two negative charges.
Disciple: “What else is needed for life to begin?”
Master: “Everything in the universe, except possibly gravity, is quantum electromagnetism, including life. A number of elements in the rich mixture of earth’s chemistry must be included in theories on the start of life. Elements like hydrogen, oxygen, carbon, nitrogen, sodium, potassium and phosphorus. Such involvement has led to the popular theory that the first living thing evolved near under water volcanic vents, fuelled by energy from the earth and not dependent on photons from the sun. This cannot account for most life forms on the earth’s surface which depend ultimately on photons from the sun, for instance, plankton which fixes the energy from light by photosynthesis and feeds the oceans. Take the earth’s dominant animal, man. He either eats plants (a vegetarian) which fixes light energy by photosynthesis, or he eats an animal that has eaten plants directly or sometimes through a complex food chain, starting with an animal that eats plants. There are exceptions, for instance some bacteria, viruses and fungi which have other energy sources than light.”
Disciple: “What else is necessary for life on the surface?”
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Master: “I suggest that life forms are based on collections of structured water in the form of gels.”
Disciple: “You mean that life is a jelly?”
Master: “Yes. This is an oversimplification; water behaves in many different ways depending on the distribution of charges.
So, if you want to read up on this, try Pollack’s two books listed in the bibliography. The most familiar non-solid, non-liquid, non-gas structured water that we experience is when gelatine is dissolved in warm water and allowed to cool, and we obtain jelly. Jelly is water, but not liquid or solid or vapour or gas. Cucumber is almost entirely water but has structure. So, perhaps, the first life form occurred when some other chemical of the earth’s crust caused a little water to form a blob of gel (this is not my idea — it was proposed by Ling and elaborated by Jerry Pollack - see bibliography). Assuming then that we had a little lump of gel with chemicals within, and that, like the clouds, photon energy was converted to electron energy within what we must now call a ‘cell’, we have an organism within which energy might be used for various functions that are characteristic of life forms”.
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Disciple: “What is organic?”
Master: “The first and most obvious use of energy to promote intracellular chemistry is the acquisition of carbon. Carbon, having a valency of 4 means that it can form molecules with carbon chains (for more information on molecules, try the Periodic Table of Videos from the University of Nottingham)”.
The bonds that are not occupied by other carbon atoms are linked to hydrogen (hydrocarbons), or hydrogen and oxygen (carbohydrates and fats) or hydrogen oxygen and nitrogen (amino acids, peptides, proteins) or countless other elements.
The production of carbohydrates such as sugar using the energy from sunlight is called photosynthesis. There are innumerable other molecules made up of these long carbon chains linked to other elements, so that their accumulation by unicellular lumps of gel confer the characteristic of growth. Such unicellular organisms divide into two smaller cells which then grow on — reproduction!”
Disciple: “So you think a primitive organism, little more than a lump of jelly, can photosynthesise?”
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Master: “There can be no consensus about this, obviously as we have no relevant data, so we can all have our theories. I subscribe to the gel theory.
I find it’s difficult to imagine life getting going without that. Chlorophyll is not a prerequisite for photosynthesis; photosynthesis is the process I am imagining as being primary conversion of light energy to chemical energy. Later, I imagine an early revolution in evolution might have been when, within one of these lumps of gel, chlorophyll was synthesised to produce something like algae; chlorophyll vastly accelerates the process of photosynthesis, and the consequent production of food. The presence of chlorophyll in what was to become the plant kingdom made the fixing of light energy (photons) much more efficient in that carbon dioxide (plentiful in the atmosphere at that time) was combined with water to produce carbohydrate and oxygen. Thus, food (fuel that can be burned to provide energy) was available to these organisms and the atmosphere became enriched with oxygen which is necessary for the burning of food and fuel. Not only plants, but the animal kingdom could evolve by ‘eating’ plant produced carbohydrate and burning it with the oxygen available (the process of cellular respiration) to fire the development of animal organisms.”
Disciple: “What happened next?”
Master: “Possibly, amino acids that contain nitrogen and form long chains of proteins, enabled cells to bind electrons, an essential step if organisms are to do anything”.
Disciple: “But reproduction was limited to simple cell division?”
Master: “Yes, for a time, but at one stage nucleoproteins emerged including DNA, which clusters in the nucleus in the middle of the cell. This has the property of encoding the characteristic of the organism, which can be transmitted to the offspring, and so the establishment of a species. Biological variation was much enhanced with the development of sexual reproduction, enabling the sharing of DNA between two organisms in forming the offspring. Sexual reproduction may cause more biological variation than the occasional mutation (spontaneous change in DNA).”
Disciple: “How did these primitive organism start moving?”
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Master: “An example of primitive utilisation of energy is the development of intracellular (one should perhaps say intragellular) proteins that change shape when the electric field patterns change with a change in protein molecules, that is, a change in energy status. Thus in such a cell, something like an amoeba, the gel can change its shape and engulf other material within it, thus increasing the acquisition of food. We all have such cells within our bodies, phagocytes and macrophages, which ‘eat up’ dead or damaged tissue.”
Disciple: “How did we end up as multicellular organisms?”
Master: “I suppose these unicellular organisms amalgamated into multicellular ones, and the specialisation of cells within the multicellular organism became a possibility.”
Disciple: “You mean specialised into your beloved cardiovascular system?”
Master: “Yes, particularly the evolution of cells specialising in movement, or more specifically contraction, including contraction of heart muscle, of which the circulatory pump is constructed.”
Disciple: “I would have thought that a heart pumping must need a lot of energy.”
Master: “The general picture is of energy on the life-dominated earth coming from photons coming from the sun. More such energy could be obtained if there were different atmospheric and magnetic conditions in the earth’s environment, but then the earth might be too hot or cold for ideal life development. Life converts light energy to food, which is stored chemical energy. Life then breaks down stored chemical energy to fuel the organisms’ functions accompanied by heat production. Ultimately the energy acquired by Life from the sun is transmitted out to space as heat. The concept of the steady state, or equilibrium, is that on average energy in must equal energy out. Similarly, if a person wants to be in equilibrium, say, constant mass, energy in must equal energy out; any imbalance will result in weight gain or loss.”
Why is the heart mostly water?
22
Master: “Estimation of the dry contents of heart tissue vary but it is about 190 grammes per thousand grammes, i.e., 19%. So the heart is 81% water!. Yet is seems quite solid. That is because the great majority of water in tissue is structured.
" " " " " " " " " " It is now possible to study this structured water by the modern technique of nuclear magnetic resonance imaging (MRI). An MRI imager emits a strong oscillating magnetic field which makes the water protons oscillate (resonate) in different ways according to their role within the local environment; recording this in relation to space gives you these extremely useful images of the body interior. The way the water is structured depends upon its molecular contents, and this in turn determines its mechanical properties. The reason why the heart is mostly water is the reason why most living tissue is mostly water, it’s the way the structured water interacts with the molecular contents that presumably determines the function contributing to the life of the organism.”
Conclusion
In this book I discuss controversies, by which I mean conflicting theories and improbable theories pertinent to an understanding of the cardiovascular system. It is very easy for the scientifically trained person, 23
with all his or her expertise in understanding the complex language, jargon, of science, to misinterpret data and mislead the layman. Yet there is no lack of common sense in such non scientists, and the thought process that I think is not used sufficiently in biological research is the use of logic. Mathematicians are able to dismiss some results if they are illogical, and by doing so can get from a false path of thinking to on one which fulfils all the requirements of the formulation of a theorem — the ability to say “QED” (Quod erat demonstrandum, literally “what was to be demonstrated”). That theorems are not possible in science is no reason not to use the process of logic, particularly in the vital process of disproving theories (however much so–called support they may have from statistical data). I am sure that the layman can appreciate such a process. In this book I have tried to avoid details that are not pertinent to the basic logical differences between theories, and to put the various cases in as simple terms as possible to enable the people to perhaps appreciate the potential pitfalls of the material they are being fed by the so called scientific reporting of the media. Once upon a time, it was accepted that the world is flat, but now we can say that that is a crackpot theory, so we need to eradicate present theories that we think are crackpot.
Some of the following chapters deal with theories about the basic functions of the circulation, and whether the conflicting ideas are right or wrong is not going to affect the lives of people; they are just of scientific interest. However, when it comes to theories about disease or disease prevention, these may lead to changes in life style advocated or implemented by government. Some of these so called public health measures are based on theories that are clearly wrong and will lead to worse health of the population than would be the case if ignored. If some such theories are false, then it is likely that so are a lot more.
I have tried to make each chapter as far as possible independent of the others so that you, the reader, can pick any of the subjects that particularly interests you.
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" " CHAPTER 1
The cells of your body — control by membrane or gel?
" " Theory 1 (Gel theory): The interior of a mammalian cell is determined by the gel matrix, the essential function of cell membrane is protective and controlling.
"
25
Theory 2 (Membrane theory): The interior of a mammalian cell is determined by constituent proteins of the cell membrane.
The cellular composition in the gel theory depends on the protein matrix, which binds potassium ions (K+) and ATP (see below); this explains why the main positive ion (cation) in cells is K+.
In the membrane theory the cellular composition depends on membrane protein activity. Thus the predominance of K+ inside the cells results from active pumping of Na+ out and K+ in by the Na+/K+ATPase, or “sodium pump” or I prefer the gel theory because Ling showed that K+ was still the predominant intracellular ion after stripping the cell membrane off. Certainly, I find that poisoning the N+/K+ATPase does not abolish the in/ out ion difference completely, only slightly.
Similarly the difference in electrical potential according to gel theory is that the protein matrix of the gel binds electrons, so that the electrical potential difference is not abolished by stripping the cell membrane, only reduced. The Na+/K+exchanger (3 Na+ out for 2 K+ in) contributes a minor adjustable contribution to cell potential and has a number of other important functions in the body.
26
Roles of cell membrane and gel interior
The muscle cells of the heart (myocardium) convert (chemical) food energy into mechanical energy required to pump blood around the body.
How do we get to a cell like this from the slow moving blob of gel described in the introduction?
The first requirement is a vastly greater store of chemical energy. At some time in evolution, a primitive unicellular organism developed, by chance, peptides (chains of amino acids containing nitrogen atoms as well as carbon chains, hydrogen and oxygen) that incorporated phosphorus to form phosphates. One of these, adenosine triphosphate (ATP), transfers energy to metabolic processes.
This system provided those organisms acquiring it with a great evolutionary advantage. In cells, there are specialised intracellular organelles, called mitochondria, that generate ATP from the burning of food derivatives (carbohydrate or fat) and oxygen, and produce carbon dioxide. Some theorists have thought that maybe primitive unicellular organisms amalgamated with some kind of bacterium–like organism that possessed these phosphate generating properties, and that that one of these organisms became the mitochondrion. I cannot imagine whether it will ever be possible to work out the probability of this theory being disproved (see introduction).
Cell Membrane
Some unicellular organisms do not have a cell membrane (e.g., viruses), but a new problem arises when an organism living in an aqueous medium uses the phosphate-based chemical energy system, due to the fact that the external medium - water in the case of unicellular organisms and extracellular fluid in multicellular organisms - contains calcium ions.
Calcium ions entering the cell react with phosphate to produce insoluble calcium phosphate and react with the carbon dioxide produced by mitochondria to produce calcium carbonate (chalk). Thus the cell “turns to stone” and dies as a result. All the chalk cliffs of the world are the remains of millions of such chalky dead, but once living, creatures. Life on earth has now changed the atmosphere and even the geology from that which 27
would have existed without the contribution of life. (The accumulated corpses of prehistoric creatures (fossils) constitute the fuels like coal, oil and gas that we burn so carelessly to alter the biosphere even more as the result of human activity).
Cell membrane according to gel theory
Clearly the calcium entry problem resulted in a limitation in the amount of energy-rich phosphate that could be tolerated. At some time in evolution cells synthesised fats (lipids) and laid them over the surface of the cell which became a protection against calcium ion entry. Fats (lipids) are not very soluble and form the electrical insulating system of life. In most cells, e.g., myocardial (heart muscle) cells, the lipids of the surface membrane are arranged as a bilayer, with long carbon chains of the lipid units in apposition in the the middle of the “sandwich”. In the resting state, ions cannot penetrate this space between the two layers, and calcium ions are excluded. The calcium ion concentration inside a resting myocardial cell is one ten thousandth of the concentration in the fluid surrounding the cell (extracellular fluid) and in the blood plasma! In this theory the cell membrane protects the interior from calcification. The proteins within the cell membrane are responsible for signalling, i.e., sending the cell messages as to what to do, e.g., contract.
The cell, in the simple situation described above, is impervious to external influence; how can the cell be “told” what is required of it? The evolutionary answer to this was possibly to take natural selection advantage of peppering the outside surface of the cell membrane with various proteins. Some of these are “receptors”, i.e., a protein that reacts with an applied chemical in such a way as to trigger chemical reactions within the cell. Some of these proteins make possible the entry of specific ions in a controlled manner, i.e., in sufficiently small quantities that the mitochondrial energy production is not impaired, but sufficient to trigger a chemical reaction within the cell. This applies particularly to entry of calcium ions, Ca++ required to trigger contraction.
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This chapter continues with an attempt to discuss cell electricity.
A Lesson in Heart Muscle Cell Electronics
Prof, “What are you trying to do here lassie?”
Student, “Checking that I can pass a current through this circuit”.
Prof, “How?”
Student, “By using this ammeter to measure the current passing through the circuit from the positive to the negative pole of this battery”.
Prof, “Wrong. You are measuring the flow of electrons through the circuit from the negative to the positive pole”.
Student, “Then what is going from the positive to the negative pole?”.
Prof, “Nothing, some say, ‘holes’! The whole hole problem arises because the chaps who discovered electricity arbitrarily gave the most positive thing in the universe a negative charge. They should have called the charge positive!”
Student, “I have now checked the circuit and am now going to record currents between the inside and outside of a nerve fibre. I am recording the 29
resting voltage and it is registering -80millivolts inside relative to the outside”.
Prof, “OK, now what happens when you make it 0mV, that is, remove the polarisation?”
Student,”I record a very rapid inward current”.
Prof, “Yes, but what is happening at molecular level?”
Student, “Sodium ions with a positive charge (Na+) are flowing into the cell through the sodium channel”.
Prof, “Why do you say that?”
Student, “Hodgkin and Huxley said so”.
Prof, “Well you are wrong. You have recorded a very rapid flow of electrons out of the cell”.
Student, “But Hodgkin and Huxley found that it depended on Na+”.
Prof, “Have you ever tried to pass an electric current through de-ionised water?”
Student, “No, but I suppose I would not be able to do so”.
Prof, “With great difficulty. For the current to pass easily, that is, to allow electrons to flow fast, one needs a good conducting medium, like a copper wire, not a plastic one. So, how are you going to pass a current through water?”.
Student, “Dissolve salts in it?”
Prof, “Yes. If you use common table salt (sodium chloride, NaCl), what do you end up with in the water?”
Student, “Freely moving sodium ions with a positive electric charge (Na+) and freely moving chloride ions with a negative charge (Cl-)”.
Prof, “Splendid. So Hodgkin and Huxley found that Na+ needed to be present so that the medium through which the electrons flow out of the cell upon depolarisation is conductive”.
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Student, “Are you trying to tell me that the great Hodgkin and Huxley were wrong!?
Prof, “They were great. I knew them both and nicer people you could not imagine. There is nothing wrong with the measurements; it is the interpretation that might be wrong”.
Student, “What heresy are you going to try and trap me into next?”
Prof, “What do you record during repolarisation?”.
Student, “I record a very rapid outward current”
Prof, “Yes, but what is happening at molecular level”.
Student, “Potassium ions with a positive charge (K+) are flowing out of the cell through the potassium channel”.
Prof, “Why do you say that?”.
Student, “Hodgkin and Huxley said so”.
Prof, “Well, you are wrong. You have recorded a very rapid flow of electrons into the cell”.
Student, “But Hodgkin and Huxley found that it depended on the presence of potassium ions (K+)”.
Prof, “Well now that I have explained what I think happens during depolarisation, perhaps you could hazard a guess as to what I think happens during repolarisation.
Student, “I suppose you will say that, as K+ is the predominant positive ion (cation) inside the cell, it provides the necessary conductivity of the medium to allow the electrons to flow”.
Prof, “Well done. In your clinical modules, have you done neurology and seen patients having recordings made from their nerves (electroneurograph, ENG) or from their muscles (electromyograph, EMG)?”
Student, “Trains of spikes”
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Prof, “That’s right. Each spike reflects a very rapid flow of electrons out of the cell followed by a very rapid flow of electrons into the cell”.
Student, “Why does that happen?”
Prof, “In the body, things are quite different from the lab. Nerve impulses travel along the fibre, so what you have at any particular point is the arrival of a depolarisation wave from the proximal direction, which short circuits your local bit of the fibre. It is followed almost immediately by a wave of repolarisation that restores the status quo”.
Student, “But you’re supposed to be teaching me about the heart!”
Prof, “OK, so what happens in the clinic when you record from the chest?”
Student, “An electrocardiogram (ECG)”.
Prof, “Yes, but strictly speaking, it should be called an electrocardiograph, but we will compromise by just calling it an ECG! Does that look like an ENG”.
Student, “Not at all; there is an initial “P” wave from the atria (upper thin walled chambers of the heart), then a rapid “QRS” wave from the ventricles (lower thick walled pumping chambers), and then another “T” wave also from the ventricles”.
Prof, “Quite right, let us stick to the QRS and T waves. What is happening there?”
Student, “With the QRS, the ventricles are depolarising; with the T wave the ventricles are repolarising”.
Prof, “What is the time interval between the QRS and the T waves?”.
Student, “It varies a bit but by about 400ms (milliseconds).
Prof, “Can you explain that on the basis of what happens in a nerve?”
Student, “No”.
Prof, “OK. So lets do the experiment; replace that nerve fibre in your setup with a ventricular heart muscle cell. Do you start with -80mV inside again?”
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Student, “Yes”.
Prof, “So now what are you going to do?”
Student, “Apply 0mV for 400ms?”
Prof, “Yes, go ahead. What currents do you record?”
Student, “A very fast initial inward current, followed by a slower inward current”.
Prof, “Do you think the initial fast inward current could share the same mechanism as the one in the nerve fibre?”
Student, “Yes”.
Prof, “How do you interpret that?”
Student, “According to my text book, it is a rapid influx of sodium ions, but I suppose you are going to try and persuade me that it is merely as outrush of electrons!”
Prof, “I am indeed. I do not need to repeat the argument. The whole problem arises because physiologists think that there must be something positive going in the direction of the current, and forget that a current going, by convention, in one direction, is, in fact, a flow of electrons in the opposite direction”.
Student, “You mean they should have put a plus on the electron and a minus on cations?”
Prof, “Yes”.
Student, “We women were ahead of you males on making sure we had a + on our female signs”.
Prof, “I concede that you are the positive gender, otherwise you might not be getting this unpaid extra help with your studies from me!! So stop diverting me, What do you record next?”.
Student, “Then I record a slow inward current, and my text book says that this is caused by sodium ions (Na+) and calcium ions (Ca++), going into 33
the cell through sodium and calcium channels. I suppose you do not believe that either!”
Prof, “Never use the verb ‘to believe’ in science. We have theories, but they can all potentially be disproved. If you do not try to disprove theories, you will never make progress in science”.
Student, “But I do not want to make progress in science; I want to make sick people well!”
Prof, “Good. Then I hope you think that you can do that. But that is philosophy, not science! Now let’s get back to this slow inward current. You claim that holding the cell at zero voltage, you have recorded a current. When do you record current in an electrical circuit?”
Student, “When there is a potential difference. Oh, that means when there is a voltage!”
Prof, “Precisely, but there is no voltage for 400ms here. How on earth can there be a current?”
Student, “I suppose you think my ammeter is NBG!”
Prof, “No, the measurement is correct, but the odd behaviour is to do with the cell membrane”.
Student, “So you do believe in the sodium and calcium channels!”
Prof, “Certainly not. Do not use the verb ‘to believe’”.
Student, “But I have seen papers showing these channels (also called ‘gates’) opening and closing”.
Prof, “Oh you have have you; what a pity. What was the experimental setup”.
Student, “Electrodes across isolated cell membrane”.
Prof, “What relevance has a recording from a torn off bit of membrane got to do with an understanding of how an intact cell works?”
Student, “Well, it shows that these gates are there”.
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Prof, “Unfortunately, you have not heard that, when you remove the membrane from this apparatus, and go on recording, the gates are still there in the absence of the cell membrane!!!!”.
Student, “Gosh. Really!”.
Prof, “Yes, really. So you stick to your whole cell experiment and your slow inward current which does exist”.
Student, “Well, what do you mean when you say the cell membrane is involved? ”
Prof, “What is the structure of the cell membrane?”
Student, “A lipid (fat) bilayer. Two sheets of lipid molecules with their tails going towards each other in the middle between the two layers”.
Prof, “Let’s go back to the polarised state. What is the potential difference across the cell membrane?”
Student, “80mV”
Prof, “What is the thickness of the cell membrane?”
Student, “8nm (nanometres, one thousandth of a micrometer (μm), which is one thousandth of a millimeter (mm))”
Prof, “Then the electric field force across the membrane is 80mV divided by 8nm”.
Student, “10mV per nm”
Prof, “10,000mV per μm”
Student, “10volts per μm”
Prof, “10,000volts per mm. That is a huge huge electric field. What effect will that have on the membrane?”
Student, !
Prof, “The core of the membrane excludes ions. No ions can flow either way across the membrane”.
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Student, “Except when it depolarises and the gates open?”
Prof, “Good Lord NO. When the voltage goes to zero, the electric field disappears and ions are more free to diffuse through the membrane, not that much, because lipid is rather non-conductive, but this diffusion is electrically neutral as in a bath of salt water”.
Student, “So, how do you think the slow inward current arises?”.
Prof, “In the membrane, there are various proteins floating about. One of these, combined in a complex way with certain lipid molecules, have the extraordinary property of exchanging across the membrane a calcium ion (Ca++) with two positive charges for three sodium ions (Na+) having a net positive charge of three positive. Because of this imbalance, the exchanger (called Na+/Ca++ exchanger) generates a current, positive in the Na+ direction (into the cell). This current is part of what you have recorded. The exchanger can work in both directions, rather like a revolving door, depending on the concentration of Ca++ and the potential difference across the membrane”.
Student, “But surely Ca++ is going into the cell, not out”.
Prof, “I have personal data suggesting that no calcium enters the ventricular muscle cells for at least the first 100ms of depolarisation, but this is a story for later. However, it is certainly true that Ca++ enters during 400ms of depolarisation. We will not discuss that and the ‘calcium current’ now but in the next lesson (Chapter 3). In the meantime, do you know anything about the Ca++ transient?”
Student. “No”.
Prof, “It comes in a later learning module, but its relevance here is that some clever chaps have shown that the Ca++ concentration inside the cell rises rapidly after depolarisation and then fades before the muscle reaches peak contraction. This internal Ca++ drives the exchanger, therefore the late inward current, therefore the delay of repolarisation by about 400ms”.
Student, “Wow, how fascinating. Is it really true?”
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Prof, “Possibly not, but it’s a nice idea. Now how about repolarisation; what do you think happens then”.
Student, “I suppose I dare not say it results from an outward K+ current”.
Prof, “That is the answer your examiners will expect, but I think it’s a similar thing to what happens in the nerve, for the same reasons”.
Rhythm, arrhythmia and the pacemakers
Prof: I was so distracted by this gorgeous girl that we ran out of time allocated for the lesson. I did not have time to ask her where the travelling wave of depolarisation-repolarisation came from.
Her textbook would tell her that it starts in specialised cells up in the atrium (called the SA or sino-atrial node), travels across the walls of the atria and at the junction of the atria with the ventricles, meets a sheet of insulating material. The only way through is via another node (called the AV or atrio-ventricular node) leading to a specialised bundle of transmission cells. This mechanism has a delay that allows the atria, then the ventricles to be activated sequentially. Finally more specialised transmission fibres conduct the signal to the inner surface of the ventricular cavities from whence it spreads to all of the ventricular muscle.
Where her textbook will mislead her, in my opinion, is the description of the pacemaker cells in the SA node that start the whole thing off. If you put these cells in the kind of apparatus my student was using in the lesson, one finds that the resting voltage is less than -80mV, say about -60mV and that between activations, it drifts to even less, say to about -40mV. There is a threshold in these cells which then, at about this voltage (it varies from cell to cell), fires an action potential to activate the cell. (An action potential is the voltage recording during natural unstimulated depolarisationrepolarisation). The cell that has the fastest frequency of activations triggers all other cardiac cells and determines your pulse rate (heart rate), about 70 beats/minute at rest.
Of course, the electrophysiologists have then manipulated the voltage in the experiment to see what currents are flowing, and as you might expect, between activations there is an inward current, called a pacemaker current. Equally predictably this inward current is interpreted as an inward 37
movement of positive charges, but these clever chaps were unable to nail the positive ion responsible. So they called it the “funny current”!
If you have taken in the main import of the lesson, you will know immediately that I think this is a spontaneous outflow of electrons. The gel theory of animal cell biology recognises that the avidity with which intracellular proteins bind electrons will vary with the different electric field patterns resulting from the different protein networks of different cells. So, all I have to do is postulate that the electron binding by proteins in SA cells is weaker than in, say, ventricular muscle cells, and so they leak out. The inward current, I suggest, is possibly an outward flow of electrons, not an inward flow of “funny” positive ions!
Clinical cardiac electrocardiography.
Some patients come into hospital because their hearts are not beating properly. Sometimes it’s going too fast because a wrong pacemaker has taken over. Sometimes it’s going too slow because some part of the conducting system isn’t working. Sometimes there’s a break in the atrioventricular insulation sheet, etc.
The picture shows what happens nowadays.
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One of the pleasurable challenges in my early days as a cardiologist was to make the diagnosis merely by looking at the surface ECG. In those days, all one could do was try various drugs and hope you could get control of the situation that way.
Cardiologists can now put wires from peripheral veins up into the heart and record the electronic situation in the various parts of the heart to give them a very detailed diagnosis. Then they can sometimes cure the problem, e.g., by burning out an unwanted aberrant pacemaker or blocking off an aberrant pathway. Nature’s pacemaker failures can be treated by implanting a man-made electronic pacemaker somewhere convenient in the body, connected by wires to the appropriate spot in the heart. Another implanted device connected by wires can detect the occurrence of a disordered rhythm and administer a shock to restart the heart.
You may be surprised to learn that I totally approve of this development of cardiology, which is indeed, a triumph of modern medicine. I am not an iconoclast about everything!
False theories of interpretation of the electrocardiogram
1. Why is the T wave positive?
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Prof, “ECG recordings show a T wave, a positive wave that occurs with ventricular repolarisation. As the direction of the currents during repolarisation are opposite to those of depolarisation, why is the T wave not negative?”.
Student, “Sometimes it is negative and that tells me that I need to attend to the probably inadequate supply of blood to the heart”.
Prof, “Very good doctor, but the very best doctors also understand the basic science underlying what they are observing, not just go through a ‘see that, do this’ rule of thumb”.
Student. “I suppose you are one of the best as they made you a Professor. Why don’t you just tell me”.
Prof, “The explanation, presently put forward for this, recognises the fact that the action potentials travel first through specialised cells called Purkinje fibres that are on the inside of the ventricular cavities (the endocardium), so that the endocardial muscle depolarises first while the muscle on the outside (epicardium) is still polarised. Thus there is an electrical potential difference between inner muscle at near zero volts and outer muscle still at -80mV, and it is that which is recorded on the surface of the body as a positive potential difference (voltage.) This voltage is positive if the recording electrode is in the right place and is a negative voltage with the recording electrode opposite. Outer muscle repolarises before inner muscle, so that, once again there is polarised epicardium and depolarised endocardium. So once again there is an electrical potential difference between inner (near zero volts) and outer muscle (repolarised back to 80mV), and it is that which is recorded on the surface of the body as a positive potential difference. The electrons in both cases are traveling from the outside to the inside, which registers as a positive voltage.
How do you record lead I?”
Student, “Left arm with reference to the right arm except when the heart is on the right side of the chest instead of the left (dextrocardia). Ha! I caught you out there Professor!”
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Prof, “Yes, just remember in the exam to check that haven’t tried to trick you by getting you to examine the heart in a case of dextrocardia! Now explain for the normal case”
Student, “Why don’t you just tell me.”
Prof, “Left arm lead gives a positive QRS complex and a positive T wave because the Purkinje fibres connect first with the tip (apex) of the heart where the muscle depolarises before and repolarises after the muscle at the equator (base) to which the Purkinje fibres spread later. The T wave is smaller because the slower downstroke of the action potential causes less difference in electrical potential”.
Student, “2. Why is the P wave, that occurs with atrial depolarisation, not followed by a voltage at the time of atrial repolarisation?”
Prof, “That is because the atrial action potential has no pronounced plateau”.
Student, “You mean it has a triangular shape?”
Prof, “Yes, it declines steadily after depolarisation and there are only very small potential differences during this phase in the thin walled atria; these do not show up on a surface ECG”.
Student, “I read that the delay between the P wave and the QRS is important in determining the delay between atrial and ventricular contractions that ensures the most efficient final blood filling phase of the ventricular cavities”.
Prof, “Quite right”. 3. The mechanism of ST elevation in myocardial infarction type heart attack.
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Prof, “What does this ECG show?”
Student, “STEMI”
Prof, “What does that mean?”
Student, “ST elevation myocardial infarction”. Prof, “What is the cause?”
Student, “Patients with coronary artery disease are subject to the occurrence of clotting (thrombosis) in these arteries which supply blood to the heart muscle. The myocardium deprived of blood (ischaemic) starts to deteriorate (myocardial infarction), the patients get chest pain, call for medical aid and an ECG is recorded. In the acute phase of such an incident, the voltage between the QRS complex and the T wave may be higher than the baseline between beats. This is called ST elevation and is more serious than when no such elevation is recorded, and has been categorised as STEMI (ST elevation myocardial infarction). This patient needs an immediate angioplasty if possible”.
Prof, “Full marks, but the very best doctors also understand the basic science underlying what they are observing, not just go through a ‘see that, do this’ rule of thumb. So how does this ST elevation arise?”
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Student, “Does that matter? I have made the diagnosis and I am concentrating on getting the patient to a hospital catheter laboratory where they can open up the artery and put in a stent. I have read in a textbook that it is a current of injury”.
Prof, “A very old textbook I hope. You are recording voltages, not currents. In addition, during the ST interval, all ventricular muscle, whether ischaemic or not, is depolarised at a voltage around zero. The apparent ST elevation all turns out to be caused by the fact that you are recording a negative voltage between beats. The diastolic voltage is normally zero because all the muscle is at -80mV, no potential differences. When some muscle becomes ischaemic the hold of the proteins on electrons weakens, so that the resting membrane potential drops, perhaps to -40mV. There is then a potential difference in diastole, in the polarised state, with electrons tending to flow from the healthy -80mV muscle to the ischaemic -40mV muscle, i.e., a negative potential difference”.
Student, “Are you suggesting that this is to do with the relaxed state and not the pumping phase?”
Prof, “Yes indeed. ST elevation is not an abnormal positive systolic (activated period) voltage at all; one is observing a negative diastolic voltage. Ha, I’ve caught you out this time!”
Student,” In spite of that, STEMI still seems to be the description universally used clinically”.
Prof, “OK, OK, OK. So do I, but it’s not good science!”
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" CHAPTER 2
False theory: don’t eat salt; it will put your blood pressure up; it will kill you. NOT SO
If you have not read the previous chapter, you may not know about sodium. Sodium ion is sodium with a positive electric charge, written Na+. A positive charge is like the charge on the positive pole of your car battery before you switch the power on. An ion with a positive charge is called a cation. An ion with a negative charge is called an anion, such as chloride ion, written Cl-. When an anion and a cation come together by electrostatic attraction, a salt is formed. There are many salts, but the combination of sodium and chloride, sodium chloride, written NaCl, is called “salt”, i.e., table salt, cooking salt, sea salt. Salt is the source of sodium in the body.
" 44
If the inflow increases in a salt water reservoir (pictured), the outflow also increases and the level of salt water remains constant; it’s the same in the body.
BUT IF SOMEONE BLOCKS OFF THE INFLOW, THE LEVEL GOES DOWN - THAT’S WHAT HAPPENS TO YOUR BODY SALT LEVEL IF YOU STOP EATING IT.
45
The next picture shows a chap eating more salt than he needs, but he merely pees out the excess.
How about a common sense approach.
The previous chapter told us that many cells in the body rely on an electrical signal to trigger their action. All cells in the body that have fluid around them which is a modified salt solution, sodium chloride being the main salt; if the sodium concentration goes down, the cells cannot work properly. The sodium concentration goes down if one does not have enough salt in the diet. So insufficient salt in the diet is harmful because the body’s cells cannot work properly.
INSUFFICIENT SALT IN THE DIET IS HARMFUL
Nerve cells are the source of thought and of messages to the other cells of the body. The passage of the message from nerve cell to other cells in the form of waves of internal negative charge to no charge (depolarisation wave, action potential) depends on Na+.
" " If I did restrict my salt intake, would not my brain, muscles, heart, gut, blood vessels be in trouble?
46
" " 47
The activation of your muscle when you move happens because of depolarisation waves along the muscles. These depend on Na+. The heart also is told when to beat by action potentials. These depend on Na+. There is muscle - so called smooth muscle - in your gut and the walls of your blood vessels. These are activated by action potentials. These depend on Na+.
Knowing all this, does it make sense to deprive your body of Na+?
If you a normal human, the answer must surely be, “NO”
You have just disproved the theory in the title, “Eating salt will put your blood pressure up; it will kill you”, by the use of logic. If something is necessary for your bodily health, do not deprive yourself of it - that’s common sense.
There is increasing concern about the harmful effects of the universal adoption of low salt diet by the normal population, as advocated by medical authorities and governments. Low salt diet can lead to reduced concentration of Na+ in blood and extracellular fluid (hyponatraemia), particularly in the elderly, chronic sick and those with kidneys unable to retain sodium.
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THERE ARE INCREASING NUMBERS OF PEOPLE ADMITTED TO HOSPITAL BECAUSE OF HYPONATRAEMIA
Of particular concern is the possibility of brain damage, mental illness and the development of Alzheimer’s disease. The latest research population study reports increased mortality amongst people taking low salt diets.
IS IT DANGEROUS TO EAT MORE SALT THAN I NEED?
If you eat too much salt all at once, you will be sick and vomit most of it out. If, over time, you eat more salt than your body needs, your kidneys, if normal, will get rid of the excess in the urine. Only if your kidneys have a defect, will salt accumulate in the body and cause problems.
The “salt causes hypertension” propaganda.
The theory that salt ingestion causes hypertension (high blood pressure) is so fashionable that all sorts of laymen, doctors, experts and authorities, even governments are telling you to stop eating salt. The basis of the theory is that, if a group of people go on a low salt diet, their average blood pressure goes down a little bit. To extrapolate from this to prescribe salt restriction for the entire population is the antithesis of science; it is bad science, bad medicine.
" 49
The theory was completely disproved many years ago, in the good old days of academic medical research, by doctors at the MRC Blood Pressure Research Group in Glasgow. In those days, it was quite OK to give people tiny amounts of radioactive tracer substances. In this case it was radioactive sodium ions (Na+).
Nowadays, what with “health and safety” and taboos about radioactivity, it is very difficult to do this. It is quite all right to give large quantities of
radioactivity to treat cancer, whereas the amount of radioactive sodium we used to use for investigating problems was very much less than that of a chest X-ray, (but we happily go on doing them!). The Na+ tracer is diluted in all the fluid that surrounds the cells of the tissues of the body, which has a high concentration of essential Na+, and the Na+ present in much lower concentration within cells. So by taking a blood sample when everything is equilibrated and measuring the Na+ radioactivity in the sample, one can calculate the total exchangeable Na+ of the body. If the high blood pressure in hypertensive patients is caused by excess sodium in the body, the total exchangeable Na+ in hypertensive patients must be higher than normal.
It is not - it is exactly the same as the total exchangeable Na+ in normal people.
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" And, when salt has been deliberately loaded in excess amount into normal people, their BP does not go up. I wish there was an equivalent to QED which we use when we prove a theorem (see introduction), that could be applied when a theory like the “salt causes hypertension” theory is definitively disproved!
The latest lunacy of the bird-brained human race - salt deprivation for birds!
" " " " " " " " " " " " " " " " " " But you may say,
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“What about all the data that correlated blood pressure with salt intake”?
I told you in the introduction that you cannot prove anything with statistics, and statistics is all this correlation depends upon.
" What happened was that a large number of people had their Blood Pressure (BP) measured and their salt intake measured. Then BP was plotted against salt intake and the data points were all over the place. Nevertheless, statistical analysis showed that there was a correlation between the two variables. Yes indeed, but the probability of correlation (significance) increases as a function of the number of subjects included in the
analysis. Thus, the greater the number studied, the more likely that a significant correlation will emerge. The correct interpretation of such a significant result is to say “there seems to be some people in this population who might be affected by the independent variable (salt intake)”. It does not mean that the dependent variable (in this case BP) is caused by the independent variable. The real message is that there is a minority of subjects in whom the independent variable might be having an effect, but in the vast majority, no such dependence is apparent. The statistical jargon for this is that the variance of BP not related to salt intake is much 52
greater than the variance that is so related. This result cries out for the following interpretation: mixed up with the majority of people for whom salt intake has no effect on BP, there must be a small minority who are salt sensitive.
Who are they? The most recent population study, measuring BP and urinary sodium output, confined its subjects to normal European white people (PC name; Caucasians). There was no correlation between the two measurements. So there must have been some other ethnic group mixed in with Caucasians in the previous studies. As most of those studies come from America, the most obvious possibility is that some black people (PC name, Afro–Caribbean) were included amongst the subjects.
" " " " " " " " " " " " " " " " " 53
It turns out that there is a minority of Afro–Caribbean people who are salt sensitive. It is not difficult to imagine that these people, adapted in long past generations to a very hot climate, have developed both a lot of melanin in the skin (protection against the sun’s destructive rays) but also an adaptation to excessive sweating. Sweat contains salt, and therefore, if there is inadequate salt available from the diet, it is an advantage to have kidneys which retain sodium.
Strains of humans who have this adaptation will retain salt to their disadvantage if they move to an area where there is plentiful salt. These people can be detected by measuring the concentration of the hormone renin in their blood which is abnormally low. In addition, the previous sample population could have contained people with abnormal kidneys due to past disease, such as an infection, sometimes painful - see cartoon -
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but have forgotten about it. Salt will not accumulate if your kidney function is normal.
Why does sodium not accumulate in the body from ingestion of salt surplus to requirements?
The answer to this is that the kidneys have an exquisite mechanism that enables any excess sodium to be excreted in the urine. That is why, in the absence of excessive sweating, the easiest way to assess a normal person’s salt intake is to measure the amount of sodium being put out in the urine. So, for a normal person with normal kidneys, there is no need to worry about the amount of salt in the diet and the cooking; any excess will simply be dumped when you pee. The level in the body stays the same, just like the level of salt water in our seaside pool (second cartoon of this chapter).
Disease conditions that cause sodium retention
Of these the most obvious to the reader should be kidney conditions.
If this is normal, and nothing else is discovered which could cause hypertension, then there is no need to restrict salt intake. Salt restriction is not a good way to treat hypertension; the drop in BP achieved is very small.
The correct action, adopted by most doctors, is to lower the BP with drugs of which there are many that are effective. Many people who undergo such treatment complain of feeling worse because their brain has been used to a high pressure and has to adapt over a period of months to the new normal 55
pressure. The majority of Caucasian hypertensive patients in the developed world have the “insulin resistance syndrome” or “metabolic syndrome”, a triad of hypertension, type 2 diabetes and obesity, although many do not have all three characteristics. The logical way to combat this is dietary calorie reduction if overweight and carbohydrate reduction in any case (carbohydrates break down in the body to sugars including glucose, which puts too much strain on the glucose regulating function of the pancreas, so that it may fail).
Other disease conditions that cause sodium retention are those of the liver and gut via a reduction in the blood of the protein albumin, and respiratory disease. It is also a secondary effect of heart failure. All these conditions need to be properly analysed in each individual patient and treated according to the cause. In these circumstances the doctors may, but only rarely, advise salt restriction. The clue to the presence of sodium retention is swelling of the ankles - called oedema. If the sodium retention is extreme, there may be swelling of the belly due to fluid there, or difficult breathing due to fluid in the lungs. Lower limb oedema is the most common site because of the effect of gravity in an upright mammal. In 1966, it was still possible to study patients like this with the radioactive sodium method for measuring total exchangeable Na+ (see above). That this method is valid for the disproof of the salt causes hypertension theory, is shown by the ease with which abnormally high total exchangeable Na+ is detected with this method. In 1966, I published a paper in the Lancet about such a patient in whom, as day by day he was treated by a diuretic (drug to make the kidneys pee out sodium), the total exchangeable Na+ came down to normal. It got published because this was a lung problem, and in those days, oedema in respiratory cases was not fully understood.
Needless to say, people with ordinary hypertension do not develop oedema, i.e., they do not have fluid retention until they are treated. If they are treated with calcium antagonists (see Chapter 3), they may then develop oedema at the same time that their BP is being brought down! What’s that all about? The drug acts by relaxing the smooth muscle in the tiny vessels (called arterioles or resistance vessels) that control how much blood goes to the organs of the body. So the BP is brought down by leaking more blood into the microcirculation (increase of pressure in capillaries, the smallest blood vessels in the tissues), excess fluid is then pushed into the tissues. As this is not sodium retention, the correct treatment is not a 56
diuretic drug but elastic compression of the lower limb. However, if you are hypertensive, you may find your doctor prescribing a diuretic for you. This is sometimes necessary, not because excess salt loss in the urine (which is what a diuretic does) is any better treatment than salt restriction, but because a diuretic can enhance the BP lowering effect of another drug you are taking that tackles the hormone angiotensin (a hormone that puts BP up).
Drug treatment of hypertension is the only safe way to protect patients from the bad effects of high BP, not salt deprivation.
" " "
57
CHAPTER 3
Command of contraction of the heart by calcium - but how?
" Prof, “What are you doing here today. I am too tired to teach. I have been campaigning all day against the low salt diet which deprives the body of the essential sodium ions (Na+).
Student, “Hodgkin and Huxley would approve of that!” Prof, “That’s good, but I do not have to teach you today”
Student, “You do, according to the college”
Prof, “I’m only honorary - that means they don’t pay me. Therefore I don’t have to teach you, especially as you have plastered your face with makeup”
Student, “Oh yes you do - and I wanted to look my best for you!”.
Prof, “Bah. OK for today, but then I resign from this cruel college. What am I
supposed to be teaching about today”.
58
Student, “The calcium system of the heart”.
Prof, “Well I haven’t prepared for that, so you had better just tell me what you have learned in your reading”.
Student, “In the nineteenth century, Ringer showed that heart muscle placed in a medium lacking calcium ions (Ca++) stopped beating, but it did beat again when calcium was restored (it had been kept alive by the other constituents of the medium). Therefore, Ca++ is necessary for contraction. It is now universally agreed that Ca++ reacts with the contractile proteins to switch on contraction. Surely you’re not iconoclastic enough to deny that?”
Prof, “Don’t be sarcastic. Go on”
Student, “There is an internal store of calcium within the endoplasmic reticulum (a membranous intracellular organelle), in this case called sarcoplasmic reticulum (SR) because it is within the contracting units of muscle called sarcomeres (about 2μm long)”.
Prof, “How does that work?”
Student, “There is a Ca++-activated ATPase system in the SR membrane which
actively pumps Ca++ into the SR lumen to keep the Ca++ concentration very low between beats”.
Prof, “And don’t forget that between beats the polarised cell membrane prevents any Ca++ diffusing into the cell, and Ca++ entry is still restricted during depolarisation by the low solubility of the lipid cell membrane (you have to dissolve the lipid off with a detergent to remove that barrier). Extracellular Ca++ concentration is about 1.5 millimolar (mM), whereas intracellular Ca++ concentration ten thousand times lower in the polarised state.
Student, “Another part of the SR is at the end of the sarcomeres and is called the terminal cysternae. Upon depolarisation of the cell, the cysternae release the calcium within as Ca++, and this goes to the contractile filaments to produce the heart beat”.
Prof, “Yes, and with Ca++ indicators it has been possible to observe the wave of Ca++ flowing from the ends of the sarcomeres to the centre where 59
the contractile action is. What triggers the release of Ca++ from the cysternae?”
Student, “Invaginations of the cell membrane to the ends of the sarcomeres brings a source of extracellular space close to the intracellular terminal cysternae”.
Prof, “Excellent!”
Student, “Extracellular Ca++ enters the heart cell (myocyte) through the calcium channel upon depolarisation and...”
Prof, “People who refer to a calcium channel are thinking of some sort of weird tunnel made of protein poking through both bilayers of the sarcolemma; Ca++ is allowed through this tunnel but not smaller ions like Na+!”
60
Student, “I suppose that sticks in your gullet?”
Prof, “Yes, but I think there is a case to be made for a specialised Ca++ entry mechanism responsible for a current carried by Na+ and Ca++. I ignored this in your previous lesson for the sake of simplicity, but we will have to tackle it today, but later.
Student, “This Ca++ reacts with the cysternae to cause Ca++ release from the
cysternae; the process is called Ca++-induced Ca++ release”.
Prof, “Would you not expect the calcium to be released anyway upon loss of the 80mV potential difference, as is thought to happen in skeletal muscle”.
Student, “Skeletal muscle only has a very brief action potential, whereas heart has an action potential of about 400ms with a plateau during which positive
ions flow through the sodium and calcium channels”.
Prof, “No. I explained to you last time that the so-called sodium current is an outflow of electrons responsible for the sharp upstroke of the action potential. The plateau that follows is associated with some inflow of Na+ and Ca++ and an inward current. The current that maintains depolarisation to the end of the plateau is possibly produced by the Na+/ Ca++ exchanger (Ca++ going OUT in exchange for 3Na+ going in)”. This is facilitated by a protein called NCX in the cell membrane and is sensitive to both membrane potential and Ca++ and Na+ concentration gradients.
Student,“So you don’t believe in a calcium inward current or Ca++- induced Ca++ release?”
Prof, “I told you the verb ‘to believe’ was banned in science. Anyway, I do not think much of the calcium tunnel idea for reasons given in the last lesson. I’m prepared to accept Ca++ induced Ca++ release as a possibility for the time being”.
Student, “Where does the inducing Ca++ come from?”.
Prof, “Excellent question. What most people seem to ignore is the work of Glenn Langer at UCLA.
61
He demonstrated that there is calcium bound to the inner leaflet of the cell membrane (plasmalemma, or sarcolemma in muscle). It is also true that the inner leaflet of the plasmalemma contains lipid molecules with negative charges, called anionic phospholipids; there are none in the outer leaflet of healthy cells. I told you that the field force in the membrane is huge and excludes all ions. What other ions might it exclude apart from calcium ions?”.
Student, “You said, ‘all ions’”
62
Prof, “Yes, and that includes hydrogen ions (H+). Do you know any other way of reducing H+ activity from a medium?”
Student, “Make it very alkaline?”
Prof, “So Langer simulated polarised sarcolemma by putting some into a very alkaline medium and measuring how much Ca++ bound to it (using radioactive Ca++ tracer). How do you think he simulated depolarisation?”
Student, “Titrated in acid to bring the pH down to neutral pH7?”
Prof, “And what do you think happened?”
Student, “The Ca++ dissociated phospholipids? ”
from
the
sarcolemmal
anionic
Prof, “Brilliant - maybe you’re a better student than I thought when I saw all that makeup on your face!”
Student, “Why is that so important?”
Prof, “It should come off like the sarcolemmal Ca++. In real intact myocytes, there is Ca++ bound to the inner leaflet of the sarcolemma because the effective pH of the membrane in the polarised state is highly
alkaline (H+, i.e., protons excluded). With depolarisation, the effective pH drops immediately and all that bound Ca++ is released. Now, which calcium do you think will reach the cysternae first, Ca++ released from the sarcolemma, which is already inside the cell, or some external calcium trying to struggle though a sort of tunnel in the membrane called a calcium channel?”
Student, “The Ca++ that is already inside the cell”.
Prof, “Of course. You and I think it is obvious, but, remember, it is still only a theory, and all theories can be disproved”.
Student, “But Ca++ does enter the cell during depolarisation surely?”
Prof. “Yes, we need to go into that. First though, let us consider the possible role of released sub-sarcolemmal Ca++ on the action potential.”
Student. “Ah, now we are coming to the calcium current”.
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Prof, “Not quite. You see that, in our previous discussion (Chapter 1), we talked all the time about current - inward currents and outward currents. That was because we made your experiment dependent on you, the experimenter, manipulating the cell potential, holding it at a depolarised value for a time and measuring the resultant currents. But that is quite artificial. In real life, the changes in cell potential - the action potential - occur naturally, that is, the changes in voltage occur naturally. So really, you have to think about why, the initial inward current (rapid outflow of electrons, generated by the incoming spreading wave of depolarisation) is followed by a maintained depolarisation before the Na+/Ca++ exchange kicks in with the onset of the calcium transient”.
Student. “As you said we have been considering the effect of Ca++ released from the sarcolemma, I suppose you mean that this causes the initial part of the action potential plateau?”
Prof. “Why do you think that I might consider that to be a possible theory?”
Student. “Because of all those released positive charges on the Ca++ released from the sarcolemma?”
Prof. “Do you think that such an idea is the madness of a mad iconoclastic Professor?”
Student. “Well, no, it seems reasonable, but you have no evidence for it”.
Prof. “No, getting evidence for a thing like this is very difficult, but you should not be thinking of doing experiments to obtain evidence for the idea; you should be thinking about obtaining evidence that disproves it”.
Student. “So we could postulate that there is a Ca++ dependent voltage following the initial fast (“sodium current”) that maintains the action potential initially, and that the final phase of the plateau is dependent on the Na+/Ca++ exchanger”.
Prof. “That scheme does not allow for any Ca++ to enter the cell during the action potential”.
Student, “But you said no Ca++ entered the cell, at least after about 100ms from the initial depolarisation”.
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Prof. “But we know Ca++ enters at some time during depolarisation because, if you prolong the duration of that depolarisation with your voltage clamp equipment you will demonstrate that extra Ca++ entered, was mopped up by the SR and released as an increment in the Ca++ transient of the following beat. I can see that I will have to explain the evidence I claimed to have for that effect, but I am tired and need a break and a cup of tea. And also it is necessary to fill you in on the relationship between the amount of Ca++ released from the cysternae to the interval between beats. That is a future learning objective, so I cannot expect you to have read it up, but maybe with some caffeine you will be able to keep your brain going while I tell you the essentials”.
Student, “You mean the force-frequency relationship of calcium accumulation through more frequent beating”.
Prof, “No. No, that’s not the way to think about it. Listen while I drink my tea”.
Mechanical restitution
If after a steady state of regular beats, say at 60 beats/minute (interval between beats 1 second) you apply a premature stimulus, the resulting calcium release and force of contraction is absent or weak, then, as the interval to the premature stimulus is progressively prolonged, the amount of force elicited gets progressively greater. The theory is that the weakness of a premature beat results from inadequate time for SR calcium (taken up by the Ca++-activated ATPase of the previous beat) to reach the terminal cysternae. This redistribution to the terminal cysternae only starts with repolarisation of the cell and is much slower than diffusion. This was demonstrated using a voltage clamp to delay the time of repolarisation. This phenomenon, called mechanical restitution, was delayed by exactly the same time. It has therefore been postulated that the Ca++ handling involved in mechanical restitution is achieved by re-establishment of the intracellular diastolic electric field patterns.
Post–extrasystolic potentiation
If, in this experiment, one follows the premature beat with an interval of one second, the following beat is stronger than the previous steady state beats, thus, it is potentiated by the extrasystole. These data can be fitted to 65
the theory above concerning compartmentalisation of the SR. The Ca++ that was taken up by the uptake compartment around the contractile filaments, but could not be released in the premature beat, is an extra amount of Ca++ for release after a further second, over and above that which is available for release during steady state beats.
Post-tachycardia potentiation
It is possible to achieve even greater potentiation if one puts in a whole train of premature beats, say, after a steady state at 60 beats/minute (one second intervals) pacing the myocardium at a high rate - say 150 beats a minute (400ms intervals) - and then going back to one second intervals. The first beat after one second is greatly potentiated. This is called post tachycardia potentiation (tachycardia means fast heart rate). During the tachycardia, the first beat is weakest and they become progressively stronger as the tachycardia continues”.
Rude interjection from listening student, “I told you it was calcium accumulation from more opportunities to come in through the calcium channel because of more channel openings during the more frequent action potentials”.
Prof, “SHUT UP, I am coming to the ‘channel openings’ question later”.
Student, “Do you agree that such calcium accumulation during the tachycardia is compatible with the increasing Ca++ transient and consequent increase in force of contraction?”
Prof, “Only when considered from the starting point of incomplete mechanical restitution. During such a run of tachycardia when the muscle is in the depolarised state for longer, sodium will also accumulate in the cells, and the observation that this switches on the Na+/K+ ATPase (sodium pump) suggests that this augmenting method of expelling excess intracellular Na+ is required for dealing with fast heart rates. With a switch back to pacing at 60 beats per minute, the beat after the first 1 second interval is greatly potentiated, reflecting the higher intracellular Ca++ that has accumulated during the tachycardia. Subsequent beats at 60 per minute show a beat to beat exponential decline to the initial steady state.
" 66
Post prolonged depolarisation potentiation
Another way of greater potentiation other than the save effect can only be done in an isolated strip of myocardium subjected to voltage clamp. In Chapter 1, this was described as a method of holding the membrane potential in the depolarised condition for as long as desired by the experimenter in order to measure currents. If one holds the membrane depolarised for longer than occurs in an action potential, Ca++ will continue to enter the cells until the clamp is removed, as evidenced by a failure of relaxation to be complete. A normal depolarisation elicited after full mechanical restitution after the end of the clamp is now greatly potentiated, when Ca++ entry during prolonged depolarisation taken up by the SR Ca++ ATPase, reaches the Ca++ release compartment.
Ca++ recirculation
The implication from the foregoing is that Ca++ taken up by the SR during relaxation is recirculated to be released again on the following beat. So how much goes out and how much recirculates? The idea of measuring the “recirculated fraction”, like most of these ideas emanates from Bjorn Wohlfart. Beats potentiated by the foregoing methods are followed by further but less potentiated beats in an exponential beat to beat decay. Consequently, if one plots the Ca++ transient amplitude or force of the second potentiated beat against the Ca++ transient amplitude or force of the first potentiated beat, one obtains a straight line with an intercept on the Y axis; the slope of the line is the recirculated fraction of activator. So if the slope is 0.65, it means that 65% of the calcium released with the potentiated beat was recirculated to the cysternae for release on the second potentiated beat; 35% of the calcium released on the second potentiated beat came into the cell from the exterior during the action potential of the first potentiated beat. Both the 35% coming in and the 65% recirculating decline exponentially from beat to beat until the actual amount coming in (35% of steady state calcium transient) equals the amount going out between beats via the Na/Ca++ exchanger and/or a sarcolemmal Ca pump if such exists. Then you have a steady state of equal strength beats”.
Rude interjection from listening student, “Gosh, that is very neat and simple. Now, can you explain why you think that no calcium enters during the first part of the action potential”.
67
Prof, “OK, but it’s only a theory. I am giving you, as your student project an attempt to disprove the theory, and a prospect of publishing the results”.
Student, “Oh. That’s exciting”.
Prof, “You set up a voltage clamp experiment. You apply a steady train of 400ms voltage clamp depolarisations at one second intervals”.
Student, “then a test depolarisation after different preceding intervals to find out how long it takes for full mechanical restitution?”
Prof, “Then you apply a steady train of voltage clamps with runs like this: polarised (P) 650ms, depolarised (D) 350ms, P650, D350, P650, D350 etc until you have a steady state from beat to beat in each run of force or Ca++ transient. I prefer you to use a muscle strip rather than an isolated myocyte because myocytes are difficult to potentiate enough for our purpose.
Student, “I don’t think I can manage Ca++ transient measurement in that case”.
Prof, “OK, measure force, that’s simple”.
Student. “But the relationship between force and calcium transient is not linear”.
Prof. “No but they go up and down together, so you will not be misled qualitatively. Now you programme your clamp controller to vary the depolarised times of single intervals. Now you measure the recirculated fraction”.
Student, “Ah, yes, I need two fully restituted intervals so that I can measure the decay of potentiation”.
Prof, “Right, you use that interval prior to all test beats. You will need varying degrees of potentiation prior to those, so just repeat after another steady state with one P at 600ms/D at 400ms, then repeat after another steady state with one D at P550/D450, and so on. One at 750/250 if it responds. Make sure that the last D before the two test depolarisations are the Ds, not the Ps. Now you plot all the second potentiated beat amplitudes (force F2) against the corresponding first potentiated beat amplitudes (force F1, both allowed full mechanical restitution) and calculated the slope. Suppose it is 0.65.
68
Student, “I’m still not sure what you’re getting at”
Prof, “Ca++ can only come in during depolarisation, the Ds, to be mopped up by the SR; the longer the duration of the D, the more Ca++ will come in”.
Student, “Even though the Na+/Ca++ exchanger is in the Ca++ out mode?”.
Prof. “Yes, (by the way the lipoprotein mediator of the exchanger is now called the NCX; its a protein-lipid complex in the cell membrane. We still have to discuss the Ca++ inflow during the action potential). The calcium not recirculated also increases as you increase the duration of the D. So you now multiply the amplitude of all the first potentiated beats by 0.35, and plot that against the duration of the last preceding variable D clamp”.
Student, “So 35% of F1 will increase with longer depolarisation of the preceding D because of more time for calcium to come in”.
Prof, “That would be predicted if the amount coming, dependent on the time to come in, is recirculated to the first test beat.”
Prof, “If, say, there is a positive X intercept, it means that there is a dead time after initial depolarisation before Ca++ enters during the action potential”.
Student, “Hey, this could be great fun”.
Prof, “The proper attitude is to hope there will be no intercept and you have disproved my theory”.
Student, “Is it fair having variable P durations in the initial train, rather than a constant P interval and just variable D durations?”
Prof, “Mm, good thought. Maybe you should do it both ways; we will find something new either way, but I’m not sure what the difference in results (if they are different) between the two methods might be”.
Student, “Now that I have done that and written up the results, you must give me a distinction in physiology and now tell me what I really want to know - how does all this help me look after patients?”
69
Prof, “OK, this has gone on too long, but as a reward, I’ll answer that question, but do not interrupt. You can ask questions at the end”
Arrhythmias
When you start working as a doctor, which will be in a hospital, you will see patients admitted in distress, even in heart failure because their heart rhythm is wrong. A very common one is atrial fibrillation (AF) in which the rhythm is totally irregular and too fast. When you examine such a patient, always listen with a stethoscope when feeling the pulse, or look at the ECG when feeling the pulse. That is because some heart beats are so weak they cannot even produce a pulse.
I have been disturbed to hear of recent cases where only the pulse rate is charted. Always insist that the apex rate recorded with stethoscope or, preferably the ECG ventricular rate is charted as well as the peripheral pulse rate. Those weak beats follow short intervals; stronger beats follow longer intervals. It used to be taught that there is inadequate filling of the heart with blood during diastole with short intervals and more time for filling with the longer intervals, so that changes in beat strength were explained by the application of Starling’s Law (that is a future learning objective - the strength of the beat depends on the initial length of the muscle fibres).
That is true, but you now know that a short interval causes incomplete mechanical restitution, that beats after longer intervals following a short one are potentiated, and that potentiation takes time to decay, i.e., the amount of Ca++ released on each beat varies, i.e., the contractility varies each beat. I had to do an experiment to demonstrate that.
These patients often need a cardiac catheterisation to determine the underlying disease causing the AF. So when this was happening, we introduced a catheter that measures the pressure and volume of the left ventricle which pumps blood to the body. The arterial (aortic) pressure during the heart beats varied little from beat to beat, so that, if there was no variation of contractility beat to beat, the volume at the end of the beat would be constant. It wasn’t. It was all over the place. Contractility did vary from beat to beat.
70
Now you know, from this lesson, that a lot of short intervals will mean inefficient weak contractions, an excessive amount of Ca++ activated SR ATPase energy consumption, an excessive number of contractile protein, Ca++ activated ATPase energy consumption, excessive membrane Na+/ K+ sodium pump ATP consumption, and cellular Ca++ accumulation due to the high frequency of action potentials. These are all bad aspects of all fast arrhythmias (tachyarrhythmias). Your treatment must reduce the apex heart rate.
Prof, “Any questions?”
Student, “But I want to know what to do”.
Prof, “If the AF is of recent commencement, you may be able to switch the patient back to normal rhythm by putting a DC shock from a defibrillator through the chest at the moment of the QRS wave of the ECG. However, if AF is well established, it is probably better to settle the rhythm down with drugs and also take the mechanical strain off the atrial walls before applying the shock wave. The pharmacologists will tell you about what drugs. It is not very controversial, so I cannot exert my iconoclastic mind over it”.
Student. “You’ve explained your theory about no Ca++ entry in the first 100 ms and about Ca++ going out by the Na+/Ca++ exchanger, but I want to know how Ca++ comes in”.
Prof. “As I said before, there is evidence compatible with the idea of some of the inward current during depolarisation being carried by Na+ and Ca++ by a mechanism with a preference for Ca++ that has led to the Ca++ tunnel idea. If the sarcolemma were to become totally permeable because it is depolarised, all ions would mix in both directions along their concentration gradients. The concentration of Ca++ outside the cell is 10,000 times the concentration inside, so a very brief period of such free mixing will let plenty of Ca++ in and lead to death of the cell. I conclude that the sarcolemmal barrier to Ca++ entry must therefore be largely maintained during the action potential, and think this could be because the sarcolemmal lipids are insoluble. To make the sarcolemma completely permeable, one has to bathe it in a detergent to dissolve out the lipids. Have you ever looked at a brain?”
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Student. “Yes”.
Prof, “What does it look like?”
Student, “A great lump of fat”.
Prof. “Yes, the point I am getting at is that fat is the insulating material that
enables excitable tissues to have become controllable. The brain cannot work without insulation to prevent short circuits. The cell membrane consists of fat: so, even when the huge electric field disappears with depolarisation, the membrane still limits ionic and charge penetration enough to permit some specialised function”.
Student. “I thought that it had been shown that the calcium channel is inhibited by calcium channel blockers”.
Prof. “The inward current is inhibited by so-called calcium antagonist drugs, the main evidence consistent with a specialised calcium entry mechanism. I do not like arguing from data obtained with artificial man- made substances, and there is something odd about the conventional interpretation. If you take the three types of calcium antagonists nifedipine, diltiazem and verapamil, one finds that they bind to three different proteins on the outer surface of the cell. All three cannot be THE calcium tunnel. That doesn’t stop some tunnel enthusiasts isolating the protein to which nifedipine binds and calling the result “isolated calcium channels”.
My idea is that there may indeed be specialised areas in the sarcolemma that account for the observations. The cell membrane is a dynamic structure and in the outer leaflet, there are various proteins swimming about. There are many different proteins some of which are receptors taking part in physiological processes like the response to adrenaline, and some of which are doing other things. Suppose that sometimes the calcium antagonist binding proteins in the outer leaflet become aligned with an anionic phospholipid like phosphatydyl serine in the inner leaflet; let us also suppose that these proteins allow that spot in the outer membrane to be soluble, perhaps displacing the neutral phospholipids. Upon depolarisation that spot on the sarcolemma becomes permeable to ions at exactly the same spot as the Ca++ is released from its binding to the two negative charges of the phosphatydyl serine. Everything then depends on the new distribution of charge and the ion concentration gradients in that 72
microsite, which we don’t know. Ca++ might go out (in addition to the exit via the Na+/Ca++ exchanger), while a little Na+ might come in (inward concentration gradient much less than for Ca++), then Ca++ would come in as soon as the concentration on the inside of the microsite falls due to diffusion away. This could account for the maintained action potential plateau attributed to the “calcium current”. As the Ca++ transient increases following SR release, the Na+/Ca++ exchanger will be switched on more in the Ca++ out direction and be responsible for the the final part of the maintained plateau of the action potential. This inward Na+/Ca++ current will decline with the Ca++ transient until repolarisation is triggered”.
Student. “This idea of yours is quite disappointing from the point of view of your pride in being an iconoclast!”
Prof. “Yes this amounts to acceptance of a calcium channel, but not a channel through a tunnel within a transmembrane protein. Even an iconoclast needs to recognise all possibilities when it comes to theories; however to please you, here is a more iconoclastic idea.”
Student. “I hope its a fun idea”.
Prof. “I can see no reason why Ca++ entry during depolarisation could not be electrically neutral. Suppose we have a moderate increase in the conductivity of the sarcolemma once it has lost its trans-membrane electric field force. That would allow positively charged ions to diffuse each way across the membrane if of equal charge, e.g., Ca++ in while two K+ go out, both along their concentration gradients”.
Student. “I have been wondering about something in my experiment in which I create progressively longer depolarisation clamps. The changes obviously are all taking place in the latter part of the depolarisation when we think Ca++ is actually going out through the Na+/Ca++ exchanger, and yet the fact of the progressively higher potentiation of the following beat can only be interpreted by an increase inward Ca++ at the same time during the latter part of the depolarisation. This seems to be a very odd situation”.
Prof. “Well, why can’t we have Ca++ going out by the exchanger to maintain the depolarisation, while, at the same time Ca++ is diffusing in neutrally because two K+s are going out!”
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Student. “I don’t know”
Prof. “Nor do I!”
Student, “You’re the Prof; you should know everything.”
Prof. “Any Prof who thinks that should be sacked!”
Student. “What is the relevance of all this to practical medicine?”
Prof, “First, we do not call calcium antagonist drugs ‘calcium channel blockers’ so we do not kid ourselves that we a shutting off tunnels. Second, as there is evidence that some arrhythmias are caused by calcium overload of some myocytes, it makes sense to see if these arrhythmias are inhibited by calcium antagonist drugs that presumably restrict Ca++ entry. Third, as cardiac cell death follows from extreme Ca++ overload, it makes sense that in some situations, calcium antagonism protects myocardium from damage. Fourth, since an increase of contractility is usually mediated by an increase in Ca++ release from the SR, it makes sense not to treat damaged hearts and heart failure with drugs that increase contractility, for instance, don’t give adrenaline to a damaged or failing heart”.
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" Interlude
Prof, “Is beat to beat decay of potentiation exponential of biexponential?”
We think that the decay of potentiation is exponential decay because there is a fixed recirculated fraction of Ca++ by the SR. Supposing the SR uptake mechanism were to become saturated, i.e., the amount of Ca++ to be sucked up overloads the Ca++-activated SR uptake mechanism (Ca++ATPase) so that less Ca++ is recirculated. Could that be demonstrated?
The voltage clamp method of causing potentiation can produce very large potentiation indeed, far above anything in real life. When the decay of such excessive potentiation is studied, is it still exponential or is it biexponential with a lower recirculated fraction at very high contractility levels? Rapid expulsion of intracellular calcium from the cell would then proceed at maximum under the pressure of the very high intracellular Ca++ concentration via the Na+/Ca++ exchanger.
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To test this hypothesis, all you need to do is record some decays in the beats following a very long preceding clamp that produces huge potentiation of the first potentiated beat. This work will have no impact on human health or disease that you seem to be only interested in, but it would be pleasing, from an interest point of view, if you were to try and disprove the theory.
Student, “Please summarise for me your current ideas about the ion and electrical cycle of heart muscle”.
Prof, “OK but don’t put this as an exam answer! And remember that I am probably going to be shown to be wrong. The action potential initial spike happens because a travelling wave of depolarisation along the muscle short circuits the cell membrane so that there is an outrush of electrons into the extracellular conducting medium (mainly sodium salts). Consequent release of calcium from the inner layer of the cell membrane enables a small amount of inflow of positive ions, sodium and, after a delay, calcium. This is the “calcium current”, or, preferably, slow inward current, causing a maintained depolarisation. The release of calcium from the inner layer of the cell membrane also causes release of intracellular Ca++ from the SR, which, in turn causes contraction. With depolarisation and raised intracellular Ca++, the Na+/Ca++ reverses from the Ca++ outward mode in the polarised state to cause a perpetuated inward current, 3Na+ in, Ca++ out, prolonging the depolarisation further, as the calcium transient reaches its peak. During depolarisation there is inward movement Ca++ in an electrically neutral manner, which augments calcium recirculated by the SR, and this produces a larger calcium transient and force of contraction of the following beat. Repolarisation, is when the travelling wave of that passes along the muscle, and is achieved by an inflow of electrons with K+ salts providing the intracellular conductive medium. Recirculation is triggered by repolarisation.
If you do become interested in this subject, you can access a book that Tony Seed and I published in which we collected articles from some of the real experts in this field (The Interval-Force Relationship of the Heart: Cambridge University Press 1992 ISBN 0 521 40022 8 - see Bibliography).
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CHAPTER 4
False theory: the micromuscles in muscle
Prof, “Hey, I only withheld my resignation so that I can examine that girl who came the last two times; now I’m presented with a strapping male”.
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Student with a posh voice, “She’s too busy doing the project you set her”.
Prof, “But she can’t afford to lose my valuable tutorials”.
Student, “She says that if she listens to any more of your revolutionary ideas, she will fail the examination”.
Prof, “I must see if I can pass her and fail all the rest of you churning out conventional rubbish”.
Student, “That drawing on your desk is crazy. All accept one of the rowers are just catching crabs because you have stupidly asked them to put their oars into slots and the slots arn’t aligned”.
Prof, “This is my model of the micromuscle theory of muscle contraction”. Student, “I must report you to the Dean; you should be certified and put in a looney bin”.
Prof, “You may change your mind after I have given you a masterclass in logical thought. In the last lesson with the girl, she agreed that calcium ions (Ca++) trigger contraction; now we consider how contraction happens. The contractile proteins of most importance are myosin and actin; both are polymerised proteins that form filaments. Myosin molecules have a stem and a head, the latter being an ATPase switched on by Ca++; they form a filament within sarcomeres, the contractile units (there are strings of sarcomeres in series along the long axis of the muscle cell). When they form a filament, it is in two parts going towards the ends of the sarcomere from the middle. Thus, in the middle there are only stems, and as one goes away from the middle, there are heads sticking out from the filament”.
Student, “Are they your rowers, and they are trying pull along this rail or ratchet or whatever you think it is?”
Prof, “Yes. Do you know anything about rowing”. Student, in posh voice, “I’m a double rowing blue!”
Prof, “Oh, for which University?” Student, “Oxford and Cambridge.”
Prof, “I support Oxford in the Boat Race, so you will have to be my opponent today, supporting Cambridge”.
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Student, “Well I’m sure all the scientists at Cambridge would say that your model of muscle contraction is rubbish”.
Prof, “Ah! But it is not a model of my theory, it is my model of their theory!”
Student, “Those chaps at Cambridge would not have a theory as crazy as that!”
Prof, “Oh, but they do, and the chaps at Oxford also subscribe to that theory”.
Student, “Are you telling me that you think all those geniuses at Oxford and Cambridge have the wrong theory?”
Prof, “In smooth muscle (e.g., in vessel walls and gut), the contractile filaments are not strictly ordered within the intra-sarcomere space, so that when one looks at it down a microscope, there is no pattern — it looks “smooth”. In heart and skeletal muscle, the ‘thick’ (i.e., thicker than actin filaments) myosin filaments are in the centre of each sarcomere, so that, if the sarcomeres are 2μm long (1 micrometer, 1μm = one thousandth of a millimetre), they occupy the central 1.6μm. So, if one looks at the strings of sarcomeres lying alongside one another, the thick filaments form a dark band across the muscle 1.6μm wide, alternating with a paler band 0.8μm wide where there are only thin filaments of actin”.
Student, “Ah, you’re talking about the sliding filament mechanism of striated muscle that is in all the text books. Don’t tell me you do not believe in that!”
Prof, “It’s a theory and can be disproved; therefore the verb “to believe” is banned. The observation is that the dark (thick filament myosin) bands stay the same width during shortening of the muscle, while the light (thin filament actin) bands are the only bands that narrow. This is interpreted as constant length thin filaments sliding between constant length thick filaments. Some researchers claim that the dark bands do contract”.
Student, “I’ve heard that you are an iconoclast, so I suppose you support the heretical view that the myosin filaments contract”.
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Prof, “I have an open mind about that, but for the time being I prefer to accept the sliding filament because the myosin heads which stick out every 14.3 nanometres (nm) along the thick filament remain that distance apart during shortening. The thin filaments run from the disc that separates each sarcomere from the next in the string (the Z disc) towards the centre of the sarcomeres. They are 1μm long, so that in a 2μm long sarcomere, they just meet in the middle; in a sarcomere of 2.4μm length, the tips will be 0.4μm apart. Thus, the thin filaments are thought to slide inwards between the thick filaments.
Student, “Then you’ve made a mistake in your model where you have the oars at intervals of 43nm”.
Prof, “I’ve only illustrated one plane. From one myosin head to the next is 14.3nm but at 60 degrees to the plane of the picture, as determined by the helical structure of the filament (a twisting structure like knitting wool composed of several strands). The next is at 120 degrees and the next at 180 degrees, but that one will be in the same plane so it goes in the diagram after 43nm”.
Cross bridge theory - I call it micro-muscle theory!
Prof, “Some physiologists thought that there would be a thin filament opposite each head, and that during contraction, these heads would grab the thin filaments and pull them towards the centre of the sarcomere, thus achieving contraction. This was called “cross bridge” theory, i.e., the heads were bridging across the space between the two types of filament. For me, a bridge is something that allows one to cross an otherwise impassible obstacle. The heads in cross bridge theory are not doing that, they are acting as micro-muscles able to attach mechanically to the thin filaments and pull them along”.
Student, “Why have you got the oars going into slits?”.
Prof, “Because the theory postulates that the interaction is between the myosin heads and the active sites along the thin filament where there are other proteins called troponins”.
Student, “There’s a test we do for patients with suspected myocardial infarction called troponin I”.
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Prof, “When the cell membrane is damaged enough, proteins like troponins will leak out and appear in the blood. I was involved in establishing the worth of the test but using troponin T, not troponin I”.
Student, “Are you saying that these bunches of troponins along the thin filament are 39nm apart?”
Prof, “Yes, they are”.
Student, “In that case, I do not see how the thing can possibly work”.
Prof, “Nor can I, but there are more objections. If you put thin filaments in an experimental bath of the appropriate liquid that is the same composition as the cell interior, with plenty of ATP, then add some myosin heads, the heads float around in the bath and do not attach to the troponin complexes. Now if you do the experiment again and leave out any ATP, the myosin heads all attach to the troponin complexes resulting in what is called “decorated” actin”.
Student, “I thought there was always a lot of ATP in cells; it’s the provider of the energy energy requiring cellular processes”.
Prof, “Correct. Rowers must be brighter students than those rugger buggers”.
Student, “Some of my rugger pals are quite bright!”.
Prof, “Can you think of a situation in which ATP disappears from the cells? ”.
Student, “Yes. Death”.
Prof, “Yes, and what happens after death?”.
Student, “Rigor mortis”.
Prof, “Yes, after a time interval during which the body consumes all its ATP and the energy rich P from its back-up store, creatine phosphate (hence a delay in onset of rigor), being unable to produce any more ATP”.
Student, “Rigor mortis is due to attachment of myosin heads to troponins on the thin filament?”
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Prof, “I think so”.
Student, “Then surely that cannot happen in living muscle?”
Prof, “That’s what I think”.
Student, “I had another thought. Since these postulated cross connections are in the transverse plane, surely all they will do is pull the thin filaments sideways towards the thick filaments! We rowers know that a lot of our energy is wasted in producing a sideways force towards the boat that is opposed by the fact that the oars are rigid”.
Prof, “Ah! said these proposers of the theory, the cross bridges are at an angle pointing towards the Z discs, so they will pull the thin filaments towards the centre”.
Student, “But what about the parallelogram of forces, i.e., the fact that a force exerted at an angle acts as two forces, one straight along and the other across at right angles?
Prof, “Well, say the proposers, the heads are really like piano hammers (see Tom and Jerry in the Cat Concerto) with the stem exactly aligned with the filaments and the heads pulling by just rotating in the longitudinal axis!”
Student, “That sounds a bit far fetched to me”.
Prof, “One reason that the theory was popular was the following experiment. If you study a skeletal muscle fibre in the laboratory, one can hold the ends tight so that the activated fibre cannot shorten, but produces force in stead. If one stimulates it at 2.2μm sarcomere length, a force is recorded (isometric force). Next time, the fibre is stimulated at 2.4μm; during the intervening time the relaxed fibre has been stretched to achieve this. The force recorded this time is less than at 2.2μm. Indeed in this type of experiment the isometric force recorded declines linearly with decreasing overlap of thick and thin filaments, i.e., with the number of micro–muscles in apposition to the thin filaments”.
Student, “Hey presto QED?”
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Prof, “I am afraid not. As pointed out in the introduction of the book I’m writing, a correlation (in this case between force and filament overlap) does not necessarily mean cause and effect. This relationship became known as the descending limb of the force-sarcomere length relation (below 2.0μm sarcomere length, force goes up with length - an ascending limb)”.
Student, “Just a moment. My interest is heart muscle, which has an almost identical arrangement of filaments and myosin heads, and yet there is no descending limb! What’s more, the working range of heart muscle sarcomeres is 1.8 - 2.2 μm sarcomere length, where there is double overlap of thin filaments. Do the thin filaments smash into each other? If not, why has this seemingly crazy arrangement evolved?”
Prof, “Good, I too am mainly interested in heart muscle. A clue can be obtained by looking at the transverse arrangements of filaments in insect flight muscle, a much faster and more frequently contracting muscle than skeletal or heart muscle. This muscle operates with double the number of thin filaments, and they take different positions in the cross section”.
Student, “I can imagine you could strengthen the muscle or make it faster by having more micro–muscles, but doubling the number of thin filaments does not do that; only doubling the number of thick filaments would do that? Or, if the micro–muscles are aligned from the thick filaments towards the thin filaments in the skeletal muscle single overlap state, they cannot be aligned correctly in the double overlap state in which the heart works best? There is something screwy about all this!”
Prof, “Once doubt about the micro-muscle theory has begun to creep into the consciousness, one starts to think that there must be something wrong with the descending limb of skeletal muscle experiment or its interpretation. Stimulation of skeletal muscle can be arranged so that the contraction is prolonged at a more or less level force (a ‘tetanus’). So, let’s stimulate a tetanus at 2.3μm sarcomere length, and then increase the sarcomere length to 2.4μm by stretching the fibre while its contracting, not when its relaxed”.
Student, “Surely, with fewer micro–muscles in apposition to the thin filaments, the force must fall?”
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Prof, “No, it increases. Perhaps the descending limb is due to something quite different from the number of micro–muscles, maybe if you start from rest at a longer length less Ca++ reaches the myosin ATPase that determines the force. Or maybe not. Anyway, the descending limb argument could no longer be accepted as relevant evidence”.
Student, “With more modern techniques such as diffraction of electromagnetic waves, it should be possible to obtain more detailed evidence of structure”.
Prof, “It turns out that the thin filament is more complicated than I have indicated so far. There are other proteins in it than actin. For instance the protein tropomyosin is threaded around it along its length. Part of the troponin complex binds Ca++. ‘There you are’ say the micro– musclologists, ‘that’s the active site on the thin filament to which the micro–muscles attach and then pull’. Wait a moment; the interval between these active sites on the thin filaments is 39nm, but the interval between myosin heads in the same transverse angular orientation is 43nm, so as you observed at the beginning, they are all going to be mutually out of alignment with each other leading to a chaotic result. This evidence helps towards disproof of the theory”.
Student, “I think the evidence about attachment only when ATP is absent is the stronger argument; therefore in life there can be no attachment because there is always lots of ATP in living tissue”.
Prof, “‘Ah no’ they say, ‘there must be a brief moment of ATP exclusion during the attachment’. At this point, I have to give up. Contraction occurs because of activation of the myosin head with Ca++ and ATP”.
There must be some other way.
Student, “Suppose we were to think how we would design an instrument to pull a rod along a straight line with no sideways force or movement, something like what happens to a thin filament. I imagine that we would use a rod made of magnetisable material and set up an electromagnet, so that when the voltage supply to the electromagnet is changed appropriately, the magnetic field established would pull the rod straight into the electromagnet”.
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Prof, “It is not surprising that there exists a theory of muscle contraction that
proposes something just like that, i.e., that the thin filaments are pulled towards the centre of the sarcomere by a magnetic force. You might think that that is rather far fetched, but surely it is not as far fetched as micro– muscles; after all, the whole universe is quantum electromagnetism; all life is quantum electromagnetism. Why should one say that contraction in muscle is not electromagnetism?”
Electric field synthesis
Prof, “Another approach is to go back to basics as outlined in the introduction of this course - the cell is a gel with a protein matrix, in structured water, not liquid, and with electrons and positive ions, mostly potassium ions (K+), bound to the proteins. That concept enabled us to get some idea of what is involved in the generation of action potentials (Chapter 1), and some idea of how contraction might be switched on after an action potential (Chapter 3). Both of these functions are mediated by electrical changes, so why not contraction itself? The late Tatsuo Iwazumi thought about the arrangement of the filaments in cross section, and wondered why such changes in position of thin filaments would occur, as in flight muscle and double thin filament overlap. This led him to map out the electrical field forces in the three dimensional matrix which is the sarcomere, and to propose that the position of thin filaments was determined by the shape of the electrical potential energy wall in the transverse plane”.
Student, “Could he do that for the extra thin filaments in insect flight muscle?
Prof, “Yes, and for situations where a thin filament is missing. Iwazumi then postulated that the cross projections of the thick filament could
reach the adjacent thick filament (a real cross bridge!), and supposed that there could be a difference in charge between the two ends of the cross projection, in which case there would be an important contribution to the electric field map in the transverse plane”.
Student, “This is interesting. Can I have a look at these electric field maps?”
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Prof, “Yes, they are in his PhD thesis (see Bibliography); I have an electronic copy that I can give you if you are interested. As I was saying, he also observed some cases in which an element was missing, e.g., filament missing in a transverse section. You should not be surprised that such a thing could happen because all elements of the body are constantly undergoing change. Damaged elements are cleaned up and got rid of and are rebuilt”.
Student, “Rather like the constant deterioration and need for restoration of the Forth rail bridge”.
Prof, “This latest painting of the bridge is supposed to last 20 years, so no work is being done on it now, and they are going to let people go up the structure in a lift”.
Student, “Scotland scraping more barrels to attract tourists now there is hardly any heavy industry?”
Prof, “No doubt. So the atoms and molecules in the contractile filaments are constantly being rebuilt. The missing thin filament led to a shift in the position of the adjacent thin filaments consistent with the change in the electric field map caused by the absence of the charge on a missing thin filament. Tatsuo also realised that the whole matrix was very stable, whereas micro-muscle arrays are intrinsically unstable”.
Student, “You mean the sideways forces they create”.
Prof, “In addition, when one half sarcomere has more micro–muscles than the opposite half sarcomere, which is bound to happen quite often, the thick filaments will be pulled to one end or other of the sarcomere up to the Z discs”.
Student, “So there is a need to find a basis for both lateral and longitudinal stability1”.
Prof, “Tatsuo looked at electron micrographs of muscle and realised the possibility of an optical illusion in longitudinal sections. He could see cross projections from the thick filament apparently going across to a thin filament (straight across, not at an angle), and what could have been another one going from the same point on that filament to the next adjacent 86
thick filament. This would be compatible with two micro-muscles latching on to the same point on the thin filament, but was also compatible with the possibility that the cross projection went behind or in front of the thin filament, directly to the next thick filament”.
Student, “That could imply an arrangement of thick filaments with cross projections arrayed towards the adjacent thick filament whose own cross projection would be the other way”.
Prof, “He then went on to postulate that there might be a difference in charge between the proximal end of the cross projection abutting upon the thick filament itself, and the distal end near, but not touching the next thick filament. Any such arrangement would mean the creation of an electric field along the cross projection in the transverse plane”.
Student, “What happens when one goes along the shaft of the thick filament to the next myosin head, 14.3nm away? The transverse cross projection-generated electric field is oriented at 60 degrees to the first, and the next one is at 120 degrees and the third one at 180 degrees, i.e., one would have a transverse column of electric fields that twist around the longitudinal axis in a helical manner reflecting the helical structure of the thick filament”.
Student, “A physical equivalent to a helically rotating electric field would be if a rod is kept in a stable position by a series of discs with slots oriented at different angles”.
Prof, “Yes, and the importance of the helical arrangement of the field is the effect on the thin filaments. According to this scheme, there is only one position within the field that is compatible with the filament positioning longitudinally straight through all three helically oriented transverse fields, and it is that that secures lateral stability of the protein matrix”.
Student, “Did he also solve the longitudinal instability problem?”
Prof, “What you call ‘his solution’ may be wrong. Iwazumi’s hypothesis concerning the source of longitudinal stability was based on the fact that the M disc connects the thick filaments crosswise in the centre of the sarcomere, and on each side of this line there is an area bare of myosin heads; there are only myosin shafts. When all the different positions of the 87
tips of the thin filaments from which the force exerted is calculated, he obtained a curved relationship of force versus position with the minimum in the centre of the sarcomere and the maxima at the ends of the thick filaments. This ensures longitudinal stability, so that the thick filaments are kept in the middle of the sarcomere. Longitudinal stability was achieved in this theoretical approach by calculating the force acting on the thin filament, which from an electric point of view is the equivalent of a dielectric rod in which charge separation occurs in an electric field”.
Student, “All this elaborate business about stability seems very boring; I want to know how the thing contracts.
Is there an electrical equivalent of an electromagnet pulling a ferromagnetic rod?”
Prof, “Yes. When a dielectric rod is placed in relation to charged plates so that the tip is within the electric field but the other end is outside that field, the rod is pulled with a force that depends on the electrical properties of the rod and the medium surrounding it. If the actin filament acted like such a dielectric, it is conceivable that a similar mechanism might apply in muscle”.
Student, “The conductivity of the medium must be very low, and the field force very high. Now, I can trash the theory by pointing out that intracellular medium is full of salts and therefore any such electric field as proposed would, in effect, be shorted out”.
Prof, “Yes, but it is not like the same constituents in free watery solution; we are dealing with structured water in a gel. Even so the electrical conductivity is not low enough to allow the high voltage required - maybe as much as 1.5 volts!
Student, “And what structure is going to develop such a voltage around the tip of the thin filament?”
Prof, “The lateral stability, even in resting muscle in Iwazumi’s scheme depends on the cross projections extending beyond the thin filaments and carrying a difference in charge between the ends (see previous discussion). When the Ca++ concentration increases to trigger contraction, there is a conformational change in the myosin head, as detected by X-ray 88
diffraction techniques; that means that the head moves and changes shape”.
Student, “I thought this was evidence in favour of the heads moving to the thin filament and attaching to it”.
Prof, “Iwazumi interpreted this as a shape change that involves the exposure of a higher charge difference between the ends of the cross projections”.
Student, “But still, why does this increased charge difference not short out?”
Prof, “In chapter 1, I pointed out that the very high electric field density across the resting cell membrane produced an exclusion of ions, making the membrane extremely impermeable, for instance, to Ca++. Thus the increased electrical potential difference between the ends of the cross projections in Iwazumi’s theory would exclude ions from the area, thus reducing greatly its conductivity”.
Student, “So, if an increased voltage between the tip of the cross projection and the thick filament end creates an electric field that excludes ions from the gel within the field, as the cross projection extends beyond it towards the next thick filament, the force generated acts on the tip of the thin filament, and if the ends of the sarcomere are fixed by the experimenter, will be held within the field exerting force”.
Prof, “Yes and if the sarcomere length is not constrained, the tip of the thin filament will pass on through a row of such ‘batteries’ spaced at 14.3nm intervals along the thick filament”.
Adaptation of different types of muscle to required function.
Prof, “The orderliness of the contractile filament arrays differs in different types of muscle. I have already alluded to the disorderliness of the array in smooth muscle such that stripes are not apparent as in cardiac and skeletal muscle. The differences roughly correlate with different speed requirements. Smooth muscle does not have to contract very fast; there is a reasonable amount of time available for a section of gut to contract as the peristaltic wave passes. Vascular muscle has some time in which it can adapt to stimuli linked to changed requirements. Another “smooth” aspect of 89
smooth muscle is that it is often required to contract all the time, so that it has what is called resting “tone”. The smooth muscle in the walls of blood vessels do this, such as in arteries, so that when more blood has to pass through, the smooth muscle relaxes. By contrast, cardiac muscle has to contract and relax more frequently than once per second, perhaps for a century.
A much more orderly array of contractile filaments allows a greater speed of the cycle, but there is still some disorder. The ATP requirements of such constant activity with no possibility of rest are associated with muscle that is packed with mitochondria, the ATP producing organelle. The fast 90
skeletal muscle of the frog leg is another case. It needs to contract extremely fast to enable the frog to leap, but it does not have to do it too frequently. This type of muscle has more orderliness of its contractile filament array than cardiac muscle, and together with the ease of dissecting out single fibres, it is a favourite for muscle researchers to study.
Yet more orderliness is apparent in the filament arrays in insect flight muscle, whose function is to oscillate the insect wing at high frequency. With double the number of thin filaments, the whole array is held together more strictly. The mechanics of the wing and attachment to the muscle are such that there is a resonant frequency of the whole arrangement.
When the tips of the thin filaments are pulled into the electric field, the mechanical reaction as the wing moves is to pull the tips out again, and this movement in and out continues as a harmonic oscillation for as long as Ca++ and ATP are present at the myosin heads.
This is unlike cardiac muscle which has to remove Ca++ to achieve a complete relaxation between beats. Insect muscle therefore requires much less chemical energy consumption than skeletal and cardiac muscle according to Iwazumi’s theory - a very efficient mechanism.
" In conclusion, there are presently many theories about how muscle contracts, and we do not know which one might be nearest the truth, but I am confident that the micro-muscle theory must be wrong, and would guess that the answer is some kind of electromagnetic mechanism”.
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" " CHAPTER 5
False notions of the heart:
preload, afterload, Vmax, etc
" Prof, “What’s all this?”
Bruisers, “Our rowing pal told us you thought rugger players were dim”.
Prof, “Yes, but he told me some of them were quite bright”.
Bruisers, “We are the bright rugger chaps”.
Prof, “What are you rugger buggers doing here”.
Bruisers, “You’re teaching us the next lesson”.
Prof, “Oh no, I only postponed my resignation so that I could examine that really bright girl who is doing a scientific project”.
Bruisers, “Yeah, she’s busy with that, so we’re taking her place”.
Prof, “Did she tell you what she is measuring?
Bruisers, “Yeah - something about isometric force. What the F is isometric force?”
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Prof, “In what position do you pay rugby?”
Bruiser 1, “Hooker”.
Bruiser 2, “I’m a wing three-quarter; I’m fast”
Prof, “You shouldn’t play fast with hookers, you might contract AIDS”.
Bruiser 1, “We don’t play ladies’ rugby; we’re men. I’m the chap in the middle of the front row of the scrum”.
Prof, “OK, you’re having a scrum, but your opponent scrum is as good as you, so when you start pushing each other, there is no movement”.
Bruiser 1, “Yeah, so what?”
Prof, “That is P0”.
Bruiser, “I can’t pee in the scrum with the chap behind grabbing my goollies!”
" Prof, “Sorry, I mean that it is isometric force. Your muscles are exerting maximum force, but your muscles cannot move”.
Bruiser 1, “Ah but we’re the best; we soon start moving the Bs backwards”.
Prof, “When that happens, are your muscles exerting more or less force? ”
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Bruiser 1, “Less, I guess”.
Prof, “Perhaps there is a thinking brain in that monstrous body of yours. Yes, when the muscles shorten they exert less force”.
Prof, to Bruiser 2, “How fast can you run the 100 metres?”
Bruiser 2, “12 seconds”.
"
Prof, “Pretty good. Did you do that carrying a rugger ball?”
Bruiser 2, “No, carrying a rugger ball I take 12.5 seconds”.
Prof, “Speed isn’t everything in rugby. What’s your 100 metres time carrying the heavy medicine ball that your trainer should surely make you carry?”
Bruiser 2, “13 seconds”.
Prof, “So what is your velocity, first unloaded and then carrying the medicine ball?”
Bruiser, “What do you mean, velocity?”
Prof, “Speed in a specific straight line direction. Would you say that, the heavier the load the slower you can run, and that if you switch to the front row and are in a locked scrum, you are slowed to zero speed but at maximum load?”.
Bruiser. “I guess so.”
Prof. “So there is an inverse relationship between the force and velocity of muscle - the force-velocity curve.”
Bruisers, “Eh!”
Prof. “If you are numerate enough to plot a graph of velocity (on the upright or Y axis) against force (on the horizontal or X axis), the line joining the points will go down in a curve from the maximum velocity at zero force to the maximum force at zero velocity”.
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Bruiser 2. “Are you accusing me of being innumerate?”
Prof. “We’ll see. What is the equation for a hyperbola?”.
Bruiser 2. “Eh!”.
Prof. “So much for your numeracy!”
Bruiser 2. “Does this hyperbolic stuff matter”.
Prof. “Perhaps not to you, but I want to teach you a lesson in literacy!”
Bruisers. “Are you accusing us of being illiterate?”
Prof. “We’ll see. What does your coach tell you about how to improve your rugby playing?”
Bruiser 1, “‘There are certain parameters within the training schedule that you must achieve’”
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Prof. “So, what is the definition of the word ‘parameter’?”
Bruiser 1. “Something achievable?”
Prof. “NO. Let’s go back to the force-velocity curve of muscle. What are the
parameters of that curve?”
Bruisers. “Force and velocity.”
Prof to reader, “Skip this bit if you are allergic to mathematics.
Prof. “COMPLETELY WRONG! The curve finally levels out to constant velocity on the force axis at a force of “-a” and levels out to constant force on the velocity axis at a velocity of “-b”. Velocity(V) and force (F) are the variables, related to one another through the Hill equation
(F+a)(V+b) = (Fo +a)b
in which V0, F0, a and b are parameters.
Also
(F0 - F)b = V(F +a).
Bruiser 1. “You said P0 was isometric force, not F0.”
Prof. “They are used interchangeably. Anyway, I am trying to guide you towards the actual subject of this lesson. I wonder whether we will ever get there with you two! So tell me, if a and b are the parameters of the force velocity curve, what are force and velocity?”
Bruiser 2. “The measureables?”.
Prof. “Sensible idea - a pity there is no such word. No, they are called the variables, because they vary as you go along the curve. Your speed on the wing varies depending on what load you are carrying. So do not get overweight and do not play after a heavy meal; and you might go a bit faster if you emptied your bowels and bladder first!”
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Bruiser 1. “You seem to have a fixation about P. You should see a psychiatrist”.
Prof. “I think I will do straight away in order to recover from the effect you two are having on me! But remember this, ‘IN YOUR READING, IF YOU COME ACROSS THE WORD PARAMETER, YOU WILL OFTEN WORK OUT THAT THEY MEAN VARIABLE’. To himself, muttering, ‘Some of these so-called experts are illiterate!’”
Prof. “I need a cup of tea, so I am calling an interlude, and letting you have some basics before the next topic.
Force, calcium ions and initial muscle length
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In chapters 2 and 4, the contraction of heart muscle was described in the condition of fixed ends, so that the muscle could not shorten, and therefore developed force (F0).
By putting a strip of cardiac muscle into a solution with low Ca++ concentration simulating the intracellular concentration and varying it, together with a detergent to make the cell membrane permeable (even the depolarised cell membrane has low permeability, being made of fat), and by changing the sarcomere length by stretching the muscle to a varying extent, one can measure the isometric force produced by each combination of Ca++ concentration and sarcomere length, both of which increase force.
When force is increased as a result of an increase in Ca++ concentration at a given sarcomere length, it is called as increase in “contractility”.
When force is increased at a given Ca++ concentration by an increase in sarcomere length it is called “the application of Starling’s Law”.
Starling stated that the energy of contraction was a function of the initial fibre length. The question is, “How do you measure energy of contraction?” Later, we will discuss whether his measurements were appropriate, but already, Otto Franck had performed an experiment with an isometric frog heart, showing that the pressure generated (analogous to force) increased with increased ventricular stretch. For a long time, there was no clear explanation of the mechanism; then there was an experiment which showed that increased sarcomere length shifts the force versus Ca++ concentration to the left, i.e., it increases the sensitivity of the contractile filaments to Ca++. In that experiment, the cell membrane was bypassed due to chemical “skinning”, but in intact strips of heart muscle using a dye to measure the Ca++ transient, it was shown that the first beat at a longer initial length was associated with the same amplitude of Ca++ release, (that is, same amplitude of the calcium transient) but increased isometric force. So, the sensitivity of the contractile mechanism to Ca++ was increased. How that change is brought about is a matter for speculation but it is possible that the troponin complex on the thin filament is involved. However, as there is this Starling Law effect, the importance of keeping initial muscle length constant in the type of study described in Chapter 3, will be evident”.
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Bruisers, “We thought Starlings Law was about cardiac output being determined by atrial pressure”.
Prof. “Thanks boys; I needed that tea. If so, it is derived in a complicated way from the force-sarcomere length relationship that I have just shown you. So first things first, how would you go about recording the force velocity curve of heart muscle?”
Bruiser 2. “Put different loads on it and measure how fast it shortens at the different loads?”
Prof. “Yes. That’s how I started but when one performs such an experiment on whole cardiac muscle strips, the force-velocity curves are distorted by all sorts of intruding factors, causing controversy”.
Bruisers. “Did you resolve them?”
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" " Prof. “Fortunately, it eventually became possible to record and control sarcomere length in Henk ter Keurs’s laboratory using light diffraction”.
Bruiser 1. “What’s that?”
Prof. “If you pass an electromagnetic wave such as a monochromatic light laser through a grid, like striated skeletal or cardiac muscle, and shine the emerging beam, light, on to a recording device, one sees, and can measure the distance between what are called diffraction bands. As the grid spacing gets narrower, the diffraction bands move away from each other. Then one applies the appropriate formula to calculate the sarcomere length on line”.
Bruiser 2. “So you could measure sarcomere shortening velocity, but how about force?”
Prof. “Fortunately the sarcomeres are arranged in series, so the force of the muscle divided by the cross sectional area of the sarcomeres give you the sarcomere force. The only deviation from a hyperbolic relationship between velocity and force occurred near F0, where the curve dipped towards the force axis reaching a measured F0 that was less than predicted by the hyperbola”.
Bruiser 2. “Perhaps there was some stretching of the attachments?”
Prof. “There was indeed, but we simultaneously stretch the muscle to keep the measured sarcomere length from shortening”.
Bruiser 2. “So why was the F0 less than it should have been?”
Prof. “This could be attributed to the fact that the measurements were made during a muscle twitch, in which more time is required to reach maximum force, so the measured value falls short of what it would have reached if the active state had lasted longer. When sarcomere force velocity curves were measured with different initial sarcomere lengths, V0 was found not to change, whereas F0 increased; V0 could increase if contractility was altered”.
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Bruiser 2, “The doctors on the ward keep talking about
Preload and afterload”
Prof. “Have you read up any of the earlier stuff on force-velocity curves using whole muscle measurements?”
Bruisers. “No, should we have done?”
Prof. “Not unless you wanted know where ‘preload and afterload’ came from”.
Bruiser “Well that does come up in clinical cardiology books”.
Prof. “The old method to measure force-velocity was to control the initial length of the muscle by hanging it vertical and tying a weight to the bottom; this was called the preload. Increasing preload caused an increase in initial muscle length and thus increased isometric force. There was great enthusiasm for applying this basic approach to clinical cardiology understanding the mechanical function of the heart better”.
Bruiser 1. “Cardiologists even now talk about cardiac preload and afterload dependence”.
Prof. “This is ridiculous because, as long ago as the sixties, preloading of muscle had been abandoned. In any case, what is the preload of the heart?”
Bruiser 2. “Load is measured in the same units as force, whether total force or force per unit cross-sectional area of muscle (stress); it is also sometimes called tension, although that strictly means force per length, which does not apply to muscle mechanics”.
Prof. “Well, well. You must have done physics at advanced level.”
Bruiser, “How do you think I got to Oxford?”
Prof, “I assumed it was that posh voice of yours, but perhaps you were quite bright?”
Bruiser 2, “Yes, that’s how I got my scholarships.”
Prof, “Apologies, I suppose some posh voices are more capable than the usual fops.”
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Anyway, unfortunately for this antiquated experimental method, the left ventricle (to which this concept is usually applied) is not a straight strip of muscle; it is a complex three dimensional structure with varying muscle thickness over its wall. In order to change the initial fibre length to test Starling’s Law, one needs to change the volume of the ventricle just before it contracts at the end of filling. But you cannot call this preload because volume is in ml, not mN. People also called the pressure in the left atrium or at the end of diastole in the ventricle the preload. If there is anything in the intact heart similar to the preload, it is the force in the ventricular wall at the end of filling. Nobody measures that, although some try to calculate it.”
Bruiser, “So, typical for you, you are de-bunking preload.”
Prof. “As a clinical variable, yes. Going back to these early crude experiments, in order to allow the muscle to shorten, so that velocity of shortening could be measured, they attached another load that only became applied to the muscle once it began to shorten. This was called an afterload”.
Bruiser 2. “How does applying a load after the contraction help?”
Prof. “It doesn’t of course; logically it is a duringload. The afterload concept applied to the intact heart is even more absurd than preload. First of all, when the muscle started to relax, it was still carrying the afterload, so it gave way by lengthening. Eventually the afterload was dumped where it started and the poor muscle was able to relax force”.
(In the intact heart, soon after the start of relaxation, the aortic valve closes, allowing the force in the muscle to fall immediately. Only when relaxation is complete do the muscle fibres lengthen again allowing filling).
Bruisers. “Are you going to put even more shit on this concept?”
Prof. “No rugger field language please. The application of a duringload meant that the load and force of the muscle was constant during systole. It is absolutely certain that the force in the wall of the left ventricle declines during shortening”.
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Bruiser 2. “But is it not a useful concept clinically to assess the heart’s load?”
Prof. “The people who talk about afterload in patients and afterload dependence are actually talking about blood pressure (BP). But the left ventricle is not opposed to BP, but to left ventricular pressure”.
Bruiser 2. “But systolic ventricular pressure is dependent of systolic blood pressure”.
Prof. “True, but the force in the wall of the left ventricle depends not only on the pressure within, but also on the size and shape of the cavity. So, when you increase the ‘preload’, you are actually increasing the afterload by increasing the volume and radii of curvature (there are different degrees of curvature, i.e., more than one radius of curvature). So preload dependence is actually afterload dependence, an afterload that cannot be measured (it is duringload anyway). Again, I wish there was an equivalent to QED for disproof of theories. The preload - afterload idea is complete nonsense. Perhaps I could call it anti-QED?!”
Bruiser, “They also used to talk about Vmax. I suppose you will debunk that!”
Prof, “I already have!”
Worst of all - Vmax!
This last nonsense also came out of isolated heart muscle experiments. The idea was to measure the equivalent of V0 in patients as an index of ‘contractility’”.
Bruiser 2. “That sounds very sensible as you say V0 increases with contractility and not with increased fibre length”.
Prof. “But you cannot measure V0 in an intact patient. So they reasoned like this: If you suddenly release one end of a contracting muscle the end recoils as if it was a spring.
If you oscillate the length of a contracting muscle the force oscillates with a much greater peak to peak change than in the muscle when it is resting. All this led to a concept that muscle consisted of a contractile element 103
attached to a spring like element called the series elastic element. Thus in an isometric contraction, the contractile element was supposed to shorten and stretch the series elastic element.”
Bruiser 2. “Didn’t Prof Harris at the National Heart Institute sneeringly call it the ‘Lady Cerise Elastic’?”
Prof. “Yes. He did not like cardiac mechanics, but he was quite right to poor scorn because the mechanics boys went on to reason that during the rise of isometric force, the rate of rise of force increase (called dF/ dt) was made up of a rate of decrease in contractile element length (dl/ dt), also equal to the rate of increase of series elastic element length, and the elastic relationship of the series 2elastic element (dF/dl).
The picture shows how they thought of a contractile element (CE) shortening a spring (series elastic element, SE) during an isometric contraction A. The spring-like characteristic is shown by releasing the lower end at the arrow?.
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Bruiser 1. “That sounds like calculus. I have not studied calculus”.
Prof. “Confessing to be not numerate now are you?”
Bruiser 1. “I can count, and I want to know the contractility of a patient’s heart”.
Prof. “Why?”
Bruiser 1. “I intend to become a cardiac surgeon”.
Prof. “Poor patients! Well, dx/dy means the slope at an instant (tangent) of the relationship between x and y. By means of some unjustifiable assumptions (never mind about them), the proposers came up with the solution that Vmax, the V0 of the cardiac muscle in the intact heart, was equal to maximum dP/dt/P, where dP/dt is the instantaneous rate of increase of left ventricular pressure, and P is the left ventricular pressure itself ”.
Bruiser. 2 “Sounds swell to me”.
Prof. “You - a heart surgeon! Nothing can describe the almost hysterical enthusiasm that greeted this supposedly ground breaking advance. I remember how many of the leading centres with clinical cardiac catheterisation theatres installed the new electronic dP/dt/P modules in the haemodynamic recording sets.”
Bruiser 1, “This seems to be very interesting”.
Prof. “The problem is, ‘what is the correct P?’ Is it the ‘developed pressure’, the pressure above the value at the end of diastole? That difference in pressure starts at zero, so Vmax starts at infinity!”
Bruiser 1. “Whoops! How can a muscle shorten at a speed of infinity?”
Prof. “AntiQED! So the only other possible P in this approach is to use the “absolute pressure”. The pressure in the left ventricle at end- diastole is certainly higher than at the beginning of the filling phase. The pressure rises as the ventricle fills. The relevant pressure is therefore the difference in pressure between the inside and the outside of the ventricular wall, that is between the intra-ventricular pressure and the pressure within the pericardial cavity, the other side of the ventricular wall”.
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Bruiser 1. “Should be easy enough to put a manometer tube into the pericardium”.
Prof. “One would have to open the chest to measure that, and we are not going to do that in the catheter lab!”.
Bruiser 1. “I could just make a keyhole incision between ribs and pass a pressure transducer into the pleural cavity. Or perhaps we could persuade the patient to swallow a pressure transducer into his/her oesophagus as a possible way of measuring the outside pressure of the heart?!”
Prof. “That’s how to become unpopular with your patients!”
Bruiser 2. “Is measuring Vmax really worth such unpleasantness for the patient? Such attempts would be unethical because each of these potential pressure measurements themselves require a reference pressure, which, traditionally, is to take zero pressure as existing at the mid chest level”.
Prof. “Suppose the doctor or nurse or technician, responsible for eyeballing from the side of a patient lying on the theatre table, estimates it a little too high; the Vmax readout will be a little low (remember, Vmax = [dP/ dt/P]max). Suppose the doctor or nurse or technician responsible for eyeballing from the side of a patient lying on the theatre table estimates it a little too low? Vmax is now higher in the same patient heart. anti-antiQED!!”
Prof. “The coup de grace for this notion comes in two devastating blows (let’s order some champagne!).
Bruisers, “Yes, we need alcohol to be heros of cardiac surgery.”
One of the characteristics of hearts in cardiac patients is that the contraction of the left ventricle is often not synchronous, e.g., a defect in the conduction system such as an aberrant electrical pathway, or a non contractile segment from myocardial infarction, results in part of the ventricle contracting out of phase. You are not then estimating contractility, but asynchronicity.
Going back to muscle strips, both Jerry Pollack and I independently showed that the elastic properties of contracting cardiac muscle resided in 106
the contractile system itself, not in a series elastic element. This had also been shown for skeletal muscle by the great Sir AF Huxley. If there is no series elastic element, then there can be no possibility of a Vmax measurement in the patient heart. Anti-anti-anti-QED. Since I pointed out the fallacy of the whole thing in the worlds’s leading cardiology journal, Circulation, Vmax has never been mentioned again!”
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CHAPTER 6
Franck versus Starling, and
Emax -true or false?
Prof, “Not you two too rugger buggers again!”
Bruiser 1, “Sorry Prof, you were so brilliant, we would like to hear the rest of the story”.
Prof, “What do you think of my exposition of the mechanics of cardiac muscle? ”
Bruiser, “We want you to apply it to the intact human”.
Prof, “Why?”
Bruisers, “We are going to be heart surgeons”.
Prof, “Oh no, so you said - poor patients”.
Bruiser 2, “It seems to be much more common sense, not to try and understand heart mechanics on the basis of single strips of muscle, but to start with the whole heart itself”.
Prof, “In the previous session, we were reminded that, before Starling, Franck had shown that isovolumic pressure development in a frog heart increased as starting volume was increased, reflecting isometric force increasing with initial fibre length. Force and pressure are not Starling’s
‘energy of contraction’, but an increase in either is associated with more chemical energy and oxygen consumption”.
Bruiser 1, “Good, now you’re getting down to the conventional stuff we need to know”.
Prof, “You may not think so when I tell you that my next sub-heading is
Starling measured the wrong thing!”
Starling rigged up the heart so that it ejected blood into a Starling resistor. The idea was to hold BP constant; the contraption did not achieve that 108
perfectly, but we can ignore that. He then measured how much blood was pumped by the heart. At each beat an amount came out called the stroke volume, measured in units of volume (ml).
Over the number of beats that took place in a minute (depending on the heart rate), we measure the cardiac output in ml/min. Starling found that when he increased the starting volume of the left ventricle, the stroke volume increased. But that is not evidence of an increase in energy of contraction because it turns out that, at the end of a heart beat, there is always some blood left behind (the residual volume). At a given pressure in the ventricle, the residual volume is always the same; the heart contracts down to the same residual volume regardless of starting volume. All Starling actually observed is the greater amount of blood volume that comes out of the heart from a larger starting volume, i.e., starting volume minus residual volume equals stroke volume!”
Bruiser 2, “So we need to measure not the cardiac output but the mechanical energy output?”
Prof, “We can multiply the stroke volume by the ventricular pressure, which gives the stroke work, and if we multiply that again by the heart rate, we get the mechanical power output per minute”.
Bruiser 2, “I think we’re getting near to energy output”.
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Prof, “It’s all very well if you can keep the BP constant as Starling (nearly) did, but if you measure this at the normal working level in an intact mammal, both an increase and a decrease in BP causes the stoke work and minute power to decrease. These variables are pressure sensitive; as pressure increases, stroke work and power go up to a maximum and then decrease back to zero at the isovolumic (no blood allowed to be ejected) pressure. Thus, this is not the correct way to do the Starling experiment. You must also remember that the heart puts out a lot of heat energy; not even the heart can be 100% efficient - its more like 40%”.
Hefner to the rescue
Prof, “I once had the privilege of working for a short time in the lab of Lloyd Hefner in Birmingham, Alabama. He was a somewhat underrated but excellent physiologist of whom I had the greatest respect. He continuously measured the left ventricular pressure and volume, and had them recorded on an XY chart; any change of volume moved the recording pen horizontally on the recording paper, and simultaneously any change of pressure moved the pen vertically up (described by ter Keurs - see Bibliography).
As the heart contracted isovolumically prior to the opening of the aortic (left ventricular outlet) valve, the pen moved upwards vertically.
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" The aortic valve then opened, and the pen moved to the left (indicating blood coming out) and a little bit up and down with pressure change during ejection. Then the aortic valve shut and the pen moved vertically down. Then the heart started filling between beats and the pen moved right to the starting point, with a small movement up vertically. During the cardiac cycle the pressure-volume point has gone round a roughly rectangular loop.
Bruiser 2, “How does that tell us how to look at Starling’s Law?”
Prof, “He changed the starting point, e.g., increased the starting volume and/or the pressure, so that a whole series of cardiac cycle loops were inscribed. Now the important concept; all the top left points (end-systolic points) of the loops joined up gave a smooth curve up and to the right. Now, when one records, over the same range of volume, the pressure generated isovolumically, the peak pressures at the various volumes overlie the end-systolic points almost exactly. Thus, the envelope of the end-systolic pressure-volume points are the same as the Franck curve. After that, the end-systolic pressure-volume curve became, for me, the “Franck-Starling Relationship”, displacing “Starling’s Law”. Now we have a decent definition in the whole heart of the dependence of the mechanics on initial fibre length, represented by end-systolic volume.
Bruiser 2, “What happens if we increase ‘contractility’?”.
Prof, “We find that the end-systolic pressure-volume curve has shifted up and to the left”.
Bruiser 1, “What about Emax?”
Application to patients
Prof, “These end-systolic relationships are useful in studying patient problems; it was with this method that we were able to confirm that contractility changes from beat to beat in atrial fibrillation (see Chapter 3). It is fortunate that catheters (fine tubes) are available, to make these measurements, that can be introduced into the left ventricle from a limb. In order to obtain a series of loops, one presses on the veins draining back to 111
the heart and then releases them. The left ventricular volume goes down and up with this manoeuver and there are changes in pressure as well”.
Bruiser 2, “Are those end-systolic pressure-volume relationships straight?”
Prof, “Fundamentally not. There was a school of thought that stated that this was always a straight line and that the lines at higher contractility had a steeper slope and went through the same point on the volume axis”
Bruiser 2, “What was the point of that?”.
Prof, “They then postulated that contractility could be described by a single variable - the slope of the end-systolic pressure-volume line, Emax. E stands for elastance, meaning stiffness, having units of pressure/ volume. Emax is the maximum elastance of the ventricle which occurs at endsystole”.
Bruiser 2, “That seems a nice simplification”.
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Prof, “Unfortunately, the end-systolic pressure-volume relationship is usually not straight. It was not straight in Hefner’s experiments; I checked for myself that the Franck experiment in a mammalian heart gave a definitely curvilinear relationship between isovolumic pressure and volume”.
Bruiser 2, “So you think that assuming that the line is always straight is dangerous?”
Prof, “Yes, because then people start deriving Emax from just two endsystolic points without checking whether the relationship is straight or not. It is not necessary to make the line straight; what’s wrong with recording the truth?”
Bruiser 1,
“Can you say anything good about Emax
Prof, “Well, there is something to be thought about with regard to the concept. If we imagine a line which is fairly flat at end-diastole and becomes progressively steeper until it reaches a maximum stiffness slope at Emax. All these slopes are being reached sequentially with time as the heart contracts”.
Bruiser 1, “Is the stiffness (elastance) of the heart increasing during contraction?”
Prof, “Yes. A chap called Templeton studied a heart that was forced to contract with a volume that oscillated around a fixed average value; the oscillations of volume had a constant amplitude. The amplitude of the accompanying oscillations of pressure increased in proportion to the increase in average pressure during systole, just as, in a muscle strip, fixed amplitude oscillation of length provokes increasing amplitude oscillations of force during contraction”.
Bruiser, “So the heart does get stiffer with contraction?”
Prof, “Yes, now remember that in the previous lesson, I indicated that Jerry and I had showed that this increased stiffness was in the contractile apparatus itself and not in a series elastic element as previously proposed. So I think it is quite exciting to imagine that, when we do P-V loops, we 113
may be recording an intrinsic property of the contractile system. Of course, this elastic behaviour is probably not linear any more than the end-systolic pressure volume relationship is linear.”
Bruiser 1,
“What about dP/dt?”
Prof, “If one has a high frequency response pressure measuring device in the left ventricle, it is easy to pass the electronic pressure signal though a differentiator circuit which then reads out the rate of change of pressure with time. When the peak of this signal LVdP/dtmax occurs before the aortic valve opens, it has been used by some as an index of contractility, for instance, in showing an increase with post-extrasystolic potentiation (Chapter 3)”.
Bruiser 2, “I have read that some authorities claim that dP/dt is “preload dependent”, by which they mean that LVdP/dtmax increases with increased filling”.
Prof, “However, I found that in patients, there is no difference in LVdP/ dtmax between the head up tilt position and the head down tilt position, which increases filling”.
Prof to Reader, “Skip this bit if you are allergic to mathematics”.
(The resolution of this dispute is found by taking Hefner’s equation for ventricular wall force. The force he considered was that between the two halves of the heart above and below its equator, which is the left ventricular pressure (P) multiplied by the cross sectional area of the left ventricular cavity at the equator (a), i.e., F = Pa. Using calculus we derive
dF/dt = a.dP/dt + P.da/dt
In the isovolumic contraction phase, a is not changing, so da/dt and Pda/ dt both equal 0
dF/dt = a.dP/dt,
or dP/dt = (dF/dt)/a
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From this one can predict how LVdP/dtmax varies with increase initial fibre length, which increases a.
Bruiser 1, “That’s calculus, you can’t expect me to follow that!”
Prof, “dF/dt increases with a in accordance with the Franck-Starling relationship, but the increasing value of the denominator, a, will decrease dP/dt in accordance with the equation above”.
Bruiser 1, “So you think that dP/dt goes up and down with increased filling?”
Prof, “Yes, when I checked this while measuring the isolvolumic pressurevolume curve, I also recorded LVdP/dtmax and found that with increasing end-diastolic volume, this variable increased at first, then levelled out, then started to decline, as predicted by the equation. It turns out that, if the heart is well below its normal volume, as when the chest is open, LVdP/dtmax increases with volume. In the normal situation with intact chest, LVdP/ dtmax does not change much with volume”.
LaPlace and ventricular wall force
Prof, “Hefner’s equation is a specific modification of the general Law of LaPlace which states that in hollow objects the force in the wall is a function of the pressure within and the radius of curvature.
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Bruiser 1, “In my old physics lesson, some buffer tried to get me to work out something like this in a soap bubble - never could make head or tail of it!”
Prof, “The law doesn’t just apply to a sphere. Consider the pointy bit at the bottom of a love heart as an exaggeration of the tip of the left ventricle where the internal radius of curvature of the apex is much less than that at the equator. That means that the wall force at the apex is less than at the equator.
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Bruiser 2, “Is that why the heart has developed a thicker wall at the equator than at the base?”
Prof, “Yes, so that the the force per muscle fibre is the same everywhere. Various versions of the LaPlace equation have been applied depending on which geometric model of the heart’s shape one assumes. However they all predict a higher wall force for a given pressure with an increase in left ventricular volume and consequent increase in radii of curvature, in other words different parts of the heart are ‘curvier’ than others - with smaller radius of curvature”.
Bruiser 2, “My textbook says that the heart is controlled by homeometric autoregulation; what’s that all about”.
False concepts: Homeometric autoregulation, the Anrep effect
Prof, “In a previous lesson, I mentioned that, when recording Ca++ transients in cardiac muscle strips, the first beat after an increase in initial fibre length showed no change in the amplitude of the Ca++ signal. However the following beats showed a gradual further increase in Ca++ amplitude and force of contraction. Early workers using preparations similar to Starling’s found a similar effect after increasing left ventricular filling. They also found that if one increased the aortic pressure, there was a gradual increase in contractility at the higher level of load. Repeating these experiments in an intact mammal (that became possible with the availability of catheter tip pressure probes) has failed to show either of these effects. One presumes that they are a result of the unphysiological state of the preparations used”.
Bruiser 1,
“But how well does the heart pump?”
Prof, “You would be quite right to claim that all of the foregoing attempts at characterising cardiac mechanics are always harking back to variables akin to those obtained in muscle strips. But the heart is a pump, so how would you characterise a man-made pump?”
Bruiser 1, “Have we got to understand engineering as well as medicine?”
Prof, “Yes, if you want to understand haemodynamics. Engineers plot the average pressure during a pump cycle against the output; this is called a 117
pump function curve. This approach goes against the grain with a lot of cardiologists, because the left ventricular pressure is near zero during diastole, so the average pressure is much lower than average BP!”
Bruiser 2, “Yes, surely one should be plotting peak left ventricular pressure against cardiac output!”
Prof, “No, and the pump function curve shows that, while an increase in filling enhances both variables, an increase in contractility only increases the pressure generating ability, not the ability to put out more blood”.
Bruiser 1, “Seems daft, why don’t we just measure power output?”
Prof, “Ah! Another interesting observation using the pump function curve is that, under normal circumstances and normal BP, the left ventricle acts at a point on the pump function curve where power output is optimal”.
Bruiser 1, “There you are then!”
Prof, “It’s not so simple. Power (pressure times flow) rises to this maximum and then declines as one goes along the curve”.
Bruiser 1, “How can this help my patients?”
Prof, “By making you think about the subject correctly. It is difficult to use pump function curves in patients because, when one changes pressure, one also changes end-diastolic volume, so the pump function curve is a fine concept, but impracticable for patient work”.
Bruiser 2, “What happens during exercise?”
Prof, “You may wonder why, according to this approach, an increase in contractility as occurs with exercise (accompanied by some adrenaline surge) fails to increase cardiac output, when we know that cardiac output does increase on exercise. The answer to this is that the resistance of the peripheral system to cardiac outflow drops considerably during exercise, so that the whole cardiovascular system attains a new balance”.
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CHAPTER 7
Heart attack: what is being attacked?
Heart failure: what has failed?
" Prof, “I was going to hand in my resignation today, but as you have returned to me, I won’t!”
Gorgeous girl Student, “Yes, I have completed the project you gave me”.
Prof, “And did you disprove my hypothesis?”
Student, “No!”
Prof, “So it is still possible that Ca++ does not enter ventricular muscle cells during the first approximately 100ms?”
Student, “Yes, I thought you would be pleased”.
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Prof, “No, obviously I will have to think of some other way of disproving it!”
Student, “Now I demand you teach me some clinical medicine - about heart attacks”
Heart Attack
Prof, “‘Heart attack’ is a meaningless term, because it gives no clue as to the patient’s problem other than that it is sudden (acute)”.
Student, “I thought it referred to a coronary”.
Prof, “If somebody collapses, it might mean no more than a simple faint, or it might be a break in the conducting system (Chapter 1). It might be the sudden onset of atrial fibrillation (Chapter 3). These all are usually accompanied by disturbed consciousness, but there is still some sort of pulse”.
Student, “And if there is no pulse?”
Cardiac Arrest
Prof, “That situation is much more serious; it is possible that the patient has ventricular fibrillation - a situation in which the electrical system in the ventricular muscle goes haywire and it looks like a bag of worms, because there is no coordinated contraction”.
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Student, “How will I know that? What must I do?”
Prof, “The patient immediately needs someone with a defibrillator who knows how to use it! Make sure you do know what to do. Practice on dummies. Make sure the Airway is clear, Breathe the patient mouth to mouth until you can get a tube into the windpipe, and maintain some Circulation if possible by chest compression ‘cardiac massage’”.
Student, “How do I react if the collapse is associated with chest pain?”
Prof, “The patient can’t tell you if unconscious, but a witness may be able to tell you. A severe central chest pain suggests that the flow of blood to the heart muscle is reduced, in which case, the problem is either a form of angina (they have varying degrees of severity) or a myocardial infarction (Chapter 1) in which the blood supply is completely cut off”.
Student, “A myocardial infarction is a coronary thrombosis.”
Prof, “A myocardial infarction is heart muscle deprived of blood supply. The thrombosis (clot) in the coronary artery is the cause of the cutting off of the blood supply”.
Student, “What else can that be confused with?”
Prof, “It may be nothing to do with the heart; the main artery leading out of the left ventricle, the aorta, may be damaged or may rupture. Acid may have gone backwards from the stomach into the gullet, and so on. So do not be fobbed off with ‘heart attack’; ask for the actual diagnosis”.
Prof, “All you students nagging me makes me feel tired. I reckon my heart has beat about 40 million times! Surely it must be getting tired and ready to stop. When the heart stops, we do not call it heart failure, we call it cardiac arrest. In a young person, it may be worth while to get the heart started up again, but when it has already beat 40 million times? Debatable.
There is a speculative theory that the slower the heart beats, the longer the mammal will live. Rats and mice who have very fast heart rates do not live long; humans, whose heart rate is much lower, live much longer! There must be a flaw in that somewhere1”.
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Heart failure
Student, “So what do you call heart failure?”
Prof, “When we talk about heart failure, we actually mean a failing heart in a living patient - it has a weak beat. This seems a fairly simple concept, but there has been a huge amount written and debated about it”.
Student, “What do you mean by heart failure?”
Prof, “Take the different definitions of heart failure. One such definition is that the heart is not able to deliver enough blood for the metabolic needs of the body. This can be detected by finding less oxygen than there should be in mixed venous blood coming back to the heart from the body. But this can happen for other reasons than something wrong with the heart, say, haemorrhage”.
Student, “How do I get a sample of blood coming back to the heart from the body?”
Prof, “Float a catheter from a vein through the right heart into the pulmonary artery. It is a reasonable measurement in an acute situation, but it is hardly convenient in patients with chronic heart failure to catheterise the pulmonary artery to obtain mixed venous blood for analysis of oxygen content”.
Student, “I think it is most important that I know what to do in acute heart failure”.
Acute left ventricular failure
Prof, “If this happens to the left ventricle within a short time frame, say, following a large myocardial infarction, blood is not cleared into the periphery and accumulates in the heart and lungs, and may even cause frothy pink sputum to come out of the lungs. The patient will be gasping for breath”.
Student, “Sounds as if I would have to take desperate measures”.
Prof, “Yes, this is a very tricky situation, and may need very specialised treatment, perhaps putting a catheter mounted pumping device into the 122
aorta (this is called aortic counter-pulsation), or even bypassing the heart and lungs with an external pump oxygenator”.
Student, “Couldn’t I just give a shot of adrenaline?”
Prof, “I’d rather you didn’t; do you like flogging a dying horse? I have found in some intensive care units an obsession with low BP (heart unable to maintain normal BP)”.
Student, “I thought monitoring the BP was very important”.
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Prof, “True, and the treatment team would be right to be concerned with this in other conditions, but it seems inappropriate to me in heart disease because, the lower the BP, the less the strain on the weak heart. Pushing the BP up willy nilly in such a case is likely to make the situation worse”.
Student, “How low would you let the BP go?”
" Prof, “As long as the patient is conscious, the BP is high enough to keep the vital brain perfused. The kidneys may not have a high enough perfusion pressure but there are ways of opening the kidneys up. The aim is to tide the patients over until compensatory mechanisms come into play that can mitigate the situation”.
Student, “There’s a legend around the medical school that you were once
Locked in a coffin!”
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Prof, “I’ll tell you about it while I have a cup of tea”.
Student, “How can you drink so much tea without wetting yourself?”
Prof, “Mind your manners. Of purely academic interest is the observation that patients with acute left ventricular failure sometime wheeze when you listen to the lungs.
Prof, “I thought it would be interesting to find out whether the resistance of the bronchial tubes was abnormally high to account for this; after all, this
situation used to be called ‘cardiac asthma’! Asthma is assessed by getting the patient to blow into a tube as fast and as far as possible; a patient with acute left ventricular failure cannot do that! It is a very poor test anyway because it depends on how much effort the patient is prepared to put into it. Airway resistance itself can be measured using a ‘body box’ (proper name body plethysmograph). This is like a sedan chair, but it is sealed airtight while the subject breathes in and out of a tube. I was trying this out in the early days, acting as the subject in the box. My colleague sealed me inside, then realised he was supposed to be giving a lecture and rushed off to deliver. All I could do was bang on the walls of my upright coffin and shout. The head of the department happened to come along before starting his ward round and thought he ought to see what noise was disturbing my 125
colleague’s lecture; he was dragged out of his lecture to release me! Phew!”
Student, “So that was the source of the legend, the coffin being the body
plethysmograph?”
Prof, “You got it. It was apparent that it would be hopeless to expect a patient with acute left ventricular failure to go into the box! Years later I mastered a much superior method of measuring airway resistance. While the patients breathed slowly through a nice wide tube, oscillations of a volume of air were applied and the oscillations of pressure measured, from which, knowing the resistance of the tube, airway resistance could be continuously calculated and displayed. Unfortunately, circumstances were such that I never got the opportunity to apply this method to patients in left ventricular failure. I think the airway resistance probably does go up, but I do not know the mechanism. It goes up in chronic heart failure when there is body fluid retention and structural changes in the lungs”.
Student, “Thanks for the yarn. Now tell me about
Chronic left ventricular failure”
Prof, “If the patient survives an acute phase, or if the heart failure comes on more gradually, what are the compensatory mechanisms that allow the patients to live a reasonable life on treatment? One of the mechanisms produced by natural selection is the reaction of the kidneys to haemorrhage, namely to retain sodium, which takes water with it.
The fluid retention helps to top up the blood loss. In heart failure there is no blood loss, but the kidney reaction is similar, so the body starts to retain sodium, resulting in body swelling (oedema). The logical approach is to get rid of the excess fluid with diuretics (drugs which make the kidneys pass more urine) and then examine the heart. What compensatory mechanisms would have taken place in the heart itself?”
Student, “A compensatory increase in contractility?”
Prof, “Have you read the lessons you made me give to those bruising rugger buggers?”
Student, “Yes, I read your hand outs”.
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Prof, “Then imagine the following sequence of events:- (1) the left ventricle is not able to eject a normal stroke volume (2) that means that the residual (end-systolic) volume increases (the end-systolic pressure-volume curve (Chapter 6) is shifted down and to the right). (3) the left ventricle fills as much as before, so the end-diastolic volume increases. (4) the Franck-Starling mechanism and the pump function curve shift to restore the stroke volume to normal. (5) the end-diastolic volume is now chronically bigger than normal (6) the left ventricle “remodels”, i.e., slowly changes to the situation of a bigger heart”.
Student, “Are you telling me that to diagnose heart failure, all I have to do is measure heart size?”
Prof, “Yes, as long as there is no valvular or congenital abnormal heart anatomy to account for it. My logical sequence allows you to realise that the diagnosis of heart failure depends on measuring the heart size. In my 127
youth, we did this by examining the chest and maybe looking at a chest X radiograph, but nowadays it is very much simpler”.
Student, “We can do an echocardiogram?”
Prof, “You got it. But it should really be called an echocardiograph. It is now possible to obtain very accurate measurements of the dimensions of the heart chambers, thickness of the left ventricular wall, and a number of other useful measurements”.
Student, “What about MRI?”
Prof, “The most accurate pictures and measurements are made with nuclear magnetic resonance imaging (MRI), but the very strong magnetic fields used preclude any loose metal entering the scanner, such as recent joint replacements, some pacemakers”.
Student, “I think they’re getting round that problem somehow”.
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Prof, “I hope so. So, if the end-diastolic diameter is above normal and there is no other defect to account for it, we may diagnose chronic left ventricular failure”.
Student, “Having done that, can I give drugs to strengthen the heart?”
Prof, “No. Treatment for this improved enormously when it was realised that one should not try and beef the heart up with drugs to improve contractility, but one should slow the heart if it is beating too frequently, maintain a low resistance to the ejection of blood into the arteries, and suppress the hormonal and renal changes that are appropriate for blood loss, but not for heart failure”.
Student,
“How can heart failure be diastolic?”
Prof, “Pretty crazy to say that the heart is failing when it is relaxed! It is indeed a poor name. The problem is that some patients’ hearts do not fill adequately between beats”.
Student, “What would you call it then?”
Prof, “We used to have a much better name for this, namely constrictive cardiac failure. When tuberculosis was common, the pericardium, a sac that surrounds the heart, would sometimes get diseased and harden into a rock-like structure due to calcium deposition; this prevented the heart from filling adequately. A similar picture arises when the heart muscle itself becomes diseased in such a way that it is very stiff when relaxed (diastolic stiffness, not to be confused with the stiffness of contraction)”.
Student, “How does this cause heart failure?”
Prof, “If the disease mainly affects the left ventricle, the patient is sensitive to minor changes in fluid balance and tips in and out of acute episodes of breathlessness due to damning back of blood into the lungs. If the right ventricle is involved, one sees a very high pressure in the veins (with a characteristic wave pattern) and liver engorgement”.
Student, “Doctors on the ward talk about a
Right heart failure”.
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Prof, “When, in the right side of the heart (which pumps blood from the veins into the lungs via the pulmonary artery), the sequence of events is similar leading to enlargement of the right ventricle, sometimes causing back flow through the in and out valves”.
Student, “This cannot be as common as the use of the term on the wards”.
Prof, “There is a habit of over diagnosing right failure due to the fact that venous pressure is raised”.
Student, “How do I tell that?”
Prof, “Get the patient leaning back at 45o, see and feel where the collar bone and muscles bulge, and ignore the prominent superficial vein that comes from the side (external jugular vein). In the area between the two muscles you can feel the deep arterial pulse coming from the carotid artery. The internal jugular vein is alongside, but you have to look for venous pressure type double flick.
However, venous pressure is also raised by fluid retention. Therefore the correct procedure is to get rid of the excess fluid with diuretics. If the high venous pressure is caused by fluid retention it will fall to normal (you wont see the double flick), before all oedema (Chapter 2) has gone”.
Student, “And what if it really is right heart failure?”
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Prof, “If right ventricular failure is present, the venous pressure will remain high after removal of oedema. In any case, at that stage, one can confirm or deny the diagnosis with echocardiography”.
Student, “And how do I treat it?”
Prof, “Right heart failure is difficult to treat, especially if it is caused by a high resistance to the passage of blood through the lungs (pulmonary hypertension); there are national centres that specialise in this.
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CHAPTER 8
The heart delivers a series of dollops of blood flow with each beat, interspersed with zero blood flow, but the body needs a steady blood flow!
Student, “I read somewhere that you were an expert in haemodynamics. What
does that mean?”
Prof, “The first problem is that the heart is made of muscle that has to contract and relax, so the blood comes out in dollops during systole (contraction) and none comes out in diastole (relaxation). But that is not what the body needs; the body need a steady inflow of blood”.
Prof, “If you measure the blood flow and pressure as blood comes out into the aorta of a human, (using catheter tip sensors inserted from a peripheral artery) you find a pulse of flow in systole and no flow in diastole, but if you measure the aortic pressure, there is a change from systole to diastole, but the pressure goes nowhere near zero in diastole. If you stick a body 132
organ with a resistance on to that pressure source, the flow will be reasonably steady into the organ throughout the cardiac cycle - abracadabra!!”
Student, “What is the magic?”
Prof, “Nature’s design of the arterial tree. To recap, the flow out of the left ventricle all occurs during contraction (systole); between systoles (diastole) there is no flow. Blood flows out for a brief period during systole, and is zero during the rest of the cycle. The organs and tissues of the body need a steady flow and have a high resistance. The flow in the organs of the body depend on the perfusion pressure (blood pressure - BP, aortic or arterial pressure - AP)) and the resistance of the organ blood vessels. In the aorta (main big artery out of the left ventricle), the arterial pressure (AP) does not drop to zero like the outflow, so a reasonably steady perfusion pressure is maintained. The difference between the totally intermittent flow into the arterial system (AF) and the pressure (AP) is a vital function of the arteries.
Windkessel
This problem is similar to that in early fire engines that consisted of a plunger pump, like a big bicycle pump. You push the plunger down and water comes out; you withdraw the plunger for the next stroke and no 133
water comes out. This is not much good for putting out a fire, for which one needs a steady flow of water.
So, they put an elastic balloon between the pumping cylinder and a resistance between the balloon and the nozzle to cause a high pressure. When the plunger is forced down some of the water is taken up by the elastic balloon, and when the plunger is withdrawn, the balloon recoils and continues to force water out. This arrangement was called a ‘Windkessel’”.
Student, “But there isn’t a balloon in the body!
Prof, “A simple model of how this is achieved is to say that the elastic properties of the arteries comprise a Windkessel”.
It is true that the aorta and large arteries near the heart are elastic and that as one goes down the arterial tree, the arteries get less elastic (stiffer) and contain more active smooth muscle in the walls. It is also true that when the arteries near the heart get stiffer with disease, the ‘Windkessel function’ is reduced; there is a greater difference between the highest 134
(systolic) aortic pressure and the lowest (diastolic) pressure (the difference between the two is called the pulse pressure)”.
Student, “So the aorta is the balloon!”
Prof, “It is not that simple. A side issue is that in the second part of systole, aortic pressure is higher than left ventricular pressure although the blood flow is still forward. Previous to this discovery as a result of more accurate pressure recording, physiologists thought that the ventricular pressure must be higher than aortic pressure throughout ejection, but they could not measure these pressures accurately when relying on pressure transmission through connecting tubes which distort the waveforms. The difference was that I was able to put high frequency response pressure probes right into the aorta and left ventricle themselves”.
Student, “So you were just using an improvement in technology to show that your research rivals were wrong!”
Prof, “That was not my motivation! The point is that the left ventricular outflow tract and the aorta are wide open and have almost no resistance. A similar observation along a short length of aorta was that as blood accelerates from zero to peak flow the pressure nearest the heart is higher than one downstream, and that this reverses when flow decelerates from peak back to zero, so that the more distant pressure from the heart is then higher. So in the presence of negligible resistance along the wide arterial tubes, the main phenomenon affecting flow is the inertia and momentum of the blood; the pressure gradient is in the direction of acceleration and deceleration. This very low resistance applies to the large arteries; once the artery reaches the organ it is supplying, there is a great increase in branching until one reaches very small vessels called resistance vessels or arterioles. Almost the entire drop in average pressure over the cardiac cycle, between blood leaving and coming back to the heart resides in these arterioles”.
Student, “So what is the peripheral resistance?”
Prof, “The total resistance of the circulation, dependent on these resistance vessels, is the average blood pressure (approximately the diastolic pressure plus one third of the pulse pressure) divided by the average flow (cardiac output). One should subtract venous pressure from the average BP, but 135
venous pressure is normally very low. This is akin to Ohm’s law in electricity, which says that an electrical resistance is equal to the potential difference (voltage) divided by the current”.
Student, “What if it’s not a DC circuit?”
Prof, “The arterial system is nothing like the balloon on the fire engine pump. The arteries branch in order to reach the various organs. The arteries are not rigid, otherwise there would be no Windkessel effect, but behave like an electrical circuit that has capacitors and inductance coils”.
Student, So what do you measure?”
Prof, “We had a lot of fun doing mathematics on the flow and aortic pressure traces. The results told us what would happen if we replaced the left ventricle with a sinusoidally oscillating pump at various frequencies”.
Student, “Was there a pulsatile resistance then?”
Prof, “No, because the pressure and flow sine waves were out of phase. The ratio of pressure amplitudes to flow amplitudes and the lag or otherwise between them, is called impedance and showed that these values were very small compared with the peripheral resistance. At heart rate and a few multiples of heart rate frequency the relationship was like that of a capacitance (flow leading pressure) and this became less so with higher frequencies at which there was little difference in phase; this could account for the Windkessel-like behaviour”.
Student, “Was this your classic paper solving the problem?”
Prof, “No. It is still not that simple. If you connect a pump to a long tube with a closed end, there are reflections from the end which arrive back at the source as a pressure wave. As the arterial system ends in a high resistance at the arterioles, there is a somewhat similar situation to that of a closed ended tube”.
Student, “You can have reflected light but surely blood does not reflect!”
Prof, “No, but sound does, which are pressure waves. I had the great good fortune during my time as a physiologist in having a collaboration in Amsterdam (Gerard van den Bos, Nico Westerhof and Gijs Elzinga) with whom I was able to join in many of their fun experiments”.
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Student, “Between boat trips on the canals and visits to the art museums, I suppose!”
Prof, “Of course. But my friends were able (on this occasion without my participation) to calculate the reflected waves that came back from the periphery to the heart. The aortic pressure turns out to be the sum of a forward going wave plus a backward reflected wave. The flow wave turns out to be the sum of a forward wave, with the same wave shape as the pressure forward wave, minus the backward wave. This backward wave is the same shape as the pressure backward wave but upside down. When the peripheral resistance is increased (vasoconstriction) the reflected waves are larger, so an upward hump appears on the aortic pressure wave after the time necessary for the wave to reach the periphery and come back. At the same time there is a downward dip in the flow wave. When the peripheral resistance is reduced (vasodilation) the backward wave is smaller and the pressure and flow waveforms are much more similar to each other, resulting in a higher pulse pressure at lower average pressure”.
Student, “Sounds as if vasodilatation is better for the heart than vasoconstriction.”
Prof, “Excellent. That’s one reason why, in the last lesson we decided not to flog the heart with adrenalin which causes vasoconstriction, but actually to vasodilate the periphery as much as possible!”
Student, “How big is this backward pressure wave problem?”
Prof, “The surprising thing is that these reflections are so small as to not make that much difference to the work output of the heart. If one does a similar measurement and analysis on a peripheral artery, the reflected wave is much bigger, so somehow the reflected wave is diminished as it travels back. Possibly, when a reflected wave comes back to a branching point in the ‘wrong’ direction, it is reflected back again towards the periphery to a certain extent, so that the reflected waves get ‘bottled up’ downstream! The pulse pressure (systolic minus diastolic) gets larger as one goes towards the periphery (the pulse pressure when you have BP measured in your arm is higher than the pulse pressure in the aorta), because the arteries get stiffer as one goes from the heart to the periphery”.
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Student, “And the pulse pressure is bigger in elderly people with stiffer arteries”.
Prof, “Exactly!”
Student, “So what you’re saying is that the arterial system as a buffer between an intermittent pump and the need for steady perfusion pressure for the body organs is complicated?”
Prof, “It is a compromise with plus points and minus points. The plus points are the Windkessel function to steady pressure and the minimal reflected wave at the heart. The minus point is that the pulsatility of the pressure at the periphery (where it needs to be minimal) is not reduced as much as it is in the aorta”.
" Student, “Is this the same as the wave velocity that people seem to measure a lot in patients?”
Prof, “No, that pulse wave travels much faster along the walls of the arteries than the speed of the blood flow. As one goes towards the periphery, the gradual change in composition of the artery (stiffer because less elastic tissue and more smooth muscle) towards stiffer, less elastic walls causes the pulse wave velocity to increase and the pulse amplitude to increase”.
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CHAPTER 9
Arteries are living things,
and become diseased
Student, “That’s not very exciting - all those tube mechanics and maths. How
do arteries get atheroma?”
Prof, “There is a lot of chemical action going on in the walls of blood vessels. All blood vessels contain smooth muscle in their walls. Smooth muscle differs from skeletal muscle and cardiac muscle in that it does not completely contract and then completely relax, so it does not have the same ordered arrays of thick and thin filaments”.
Student, “I learned that it is normally contracted to a certain extent all the time and you chaps call this ‘tone’, or ‘basal tone’”.
Prof, “Yes, then under the influence of some stimuli, it contracts more, and under other circumstances it contracts less. These stimuli vary in different kinds of vessels, namely arteries, arterioles, veins and lung vessels”.
Student, “Is the arrangement the same in all blood vessels?”
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Prof, “No, I told you last time how the biggest arteries near the heart had the most elastic tissue, that behave in a passive way and contributes to the Windkessel effect. There is some smooth muscle in the aortic wall, but the amount increases as one goes towards the arteries that feed into the body organs”.
Student, “Why?”
Prof, “When we come to an artery that feeds blood to an organ or tissue (‘conduit artery’), the way that the smooth muscle behaves is very important”.
Student, “You mean in leading to atheroma?”
Prof, “It is certainly important to remember that these conduit arteries are the main site of the common arterial disease, called atheroma, atherosclerosis or atherothrombosis. The disease affects the arteries to the heart muscle (coronary arteries) causing coronary heart disease, the arteries to the brain, causing stokes, and the arteries to the legs causing intermittent claudication and peripheral gangrene”.
Student, “A pretty large part of medical practice!”
Prof, “First you should know something about how arteries work normally. A characteristic of smooth muscle is that, if it is stretched, it contracts more; this is called the ‘myogenic response’. Thus if the blood pressure (BP) goes up, exposing the conduit artery to a stretch, the smooth muscle contracts more to resist the stretch”.
Student, “You mean we do not want an arterial blow-out if the BP goes up!”.
Prof, “Quite. Another characteristic of smooth muscle is that, when the rate of stretch increases, it contracts more. This had, until recently, only been demonstrated for the smooth muscle in the portal vein that goes from the gut to the liver, and in the smooth muscle in arterioles (small arteries that control the blood flow to organs by controlling resistance), and shown to be of modest amplitude. My colleagues in Cork (Hazim Markos and Therese Ruane O’Hora) and I decided to see how much of this effect was present in the iliac artery, a conduit artery”.
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Student, “Why?”
Prof, “Because the stretch with each systole is considerable and can be assessed by measuring the changes in diameter with the cardiac cycle, using an ultrasound method”.
Student, “So what happened when you changes the rate of stretch?”
Prof, “The first thing we did was to decide that it was much easier to hold diameter constant and measure the changes in pressure (average pressure up = smooth muscle contracting more, average pressure down = smooth muscle contracting less) than to try and keep the pressure constant and measure changes in diameter”.
Student, “I suppose that’s fair enough”.
" Prof, “The next thing we did was to occlude the artery beyond the bit where we had our measuring devices. This meant that our section of artery 141
was exposed to the same average and pulsatile pressure as before, but with no flow through. There was little change in average pressure. Next we occluded the artery above the bit where we had our measuring devices. So now, the pulsatility was cut off, and the average pressure at the same diameter plummeted very rapidly. We estimated that about half of the tone of the artery could be attributed to pulsatility; the rate of increase of stretch,
with only half attributable to the steady stretch. This is a much greater dependence on pulsatility than has been described for other blood vessels”.
Student, “I suppose that gave you another publication for your collection, but I don’t see the connection to atheroma!”
Prof, “OK, but you also need to know about the chemistry of arteries. When an organ increases its activity, say skeletal muscle upon exercise, the resistance vessels of that organ dilate due to relaxation of the tone in the arteriolar walls. There is then an increased organ blood flow due to Ohm’s Law (flow = pressure/resistance). The cross sectional area of the feeding artery is now not optimal for the increased flow.”
Student, “That’s awkward! What did you invent to deal with that”.
Prof, “Tried to go on observing nature faithfully - why don’t you try it after doing that nice project!”
Student, “Sorry - I’ll get you some more tea”.
Prof, “Thanks, you forgot last time. Faster flow to the organ causes higher speed (velocity in a strait line) which in turn causes higher force between the blood and the arterial wall (called ‘shear stress’)”.
Student, “I suppose you think I cause you shear stress!”
Prof, “You do indeed! And sheer stress! The artery dilates (smooth muscle relaxation), thus reducing the shear stress. That is higher flow at a lower speed than before the artery got wider. This reaction is called “flow mediated dilatation”; it should more properly be called “shear stress mediated dilatation”.
Student, “This still isn’t chemistry. How does this come about?” Prof, “Patience lassie, plenty of chemistry coming up!”
Student, “Oooh, what a treat!”.
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Prof, “Smooth muscle relaxes when its membrane potential increases (hyperpolarisation) and contracts when the membrane potential decreases (partial depolarisation). An early idea was that when the arterioles relaxed to allow increased flow, the hyperpolarisation of the smooth muscle was conducted electrically upwards to the feeding artery”.
Student, “Through what wires?”
Prof, “No wires required, we are talking about electrically excitable tissue. Our
Cork collaboration was able to show that this hyperpolarisation wave did not reach the iliac artery”.
Student, “Are you ever going to get on to the chemistry?”
Prof, “There are a number of chemicals produced in the body that influence vascular smooth muscle. In particular, those which cause relaxation mostly do so via the generation of nitric oxide (NO)”.
Student, “Yes there’s an awful lot of that in the books, but it seems far fetched. Surely nitric oxide is a toxic gas?”
Prof, “Yes but it disappears rapidly once it’s produced in the cells. It comes, has an effect, and then disappears very quickly, for instance by being cleared by haemoglobin, the red pigment in blood”.
Enter, the vascular endothelium
Prof, “Between the smooth muscle and the blood, there is a layer of extremely metabolically active cells called endothelial cells. It turns out that substances that dilate blood vessels, like acetylcholine and bradykinin that are produced in the body, act upon receptors in these endothelial cell that switch on a reaction. An enzyme, NO synthase causes splitting of the amino acid L-arginine with release of NO; the NO diffuses to and acts upon the smooth muscle to relax it, and cause vasodilatation”.
Student, “Is shear stress mediated arterial dilatation mediated by NO?”
Prof, “Yes, because, when we block the action of NO synthase, the shear stress mediated arterial dilatation completely disappears!”
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Enter, the endothelial glycocalyx
Student, “Then the question is, “How does increased shear stress at the arterial wall trigger the endothelial cell to produce NO?”
Prof, “There are two contending theories, but first you need to know about a relatively recent discovery. There is yet another layer between the endothelium and the blood. This is not cellular but is a half micrometre thick layer of gel”.
Student, “Don’t tell me your about to go back on to your gel hobby horse!”
Prof, “Gel theory is quite respectable you know. One theory says that the endothelial cell surface detects the change in shear stress; the other says that the gel layer (the glycocalyx) detects the change in shear stress and transmits it to the endothelial cell”.
Student, “But it must do so by shifting the cell membrane somehow; I’m sure glycocalyx doesn’t produce NO”.
Prof, “Quite right. The first of these theories is a sort of fall back position after disproof of the second theory, but such disproof is lacking. The gel contains a glycoprotein (protein with bound glucose molecules) called hyaluronan, and this can be disrupted by applying the enzyme hyaluronidase. The cell surface sensing theory predicts that shear stress 144
mediated dilatation should survive such treatment, but it does not; it is abolished”.
Student, “Still one could argue that the hyaluronidase might have attacked the intercellular “glue” of the endothelium”.
Prof, “Quite right; well done. The gel structure is supported by glycoproteins, proteins with bound glucose. Supposing we change the amount of glucose binding (glycosylation) by applying a high glucose concentration to the glycocalyx?”
Student, “That sounds like a fun experiment”.
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Prof, “We did this and inhibited, in some cases abolished, shear stress mediated dilatation! The glucose we used was dextro-(D)-glucose. The glucose molecule has a mirror image version. D-glucose turns polarised light to the right. L-glucose turns polarised light to the left. Only Dglucose is biologically active”.
Student, “So, if the abolition of shear stress mediated dilatation by high Dglucose had been due to a non-specific effect, L-glucose would also abolish it”.
Prof, “Yes, you’re coming on. It had no effect. So, at the moment the glycocalyx theory of shear stress mediated dilatation holds sway, awaiting challenge”.
Student, “Stop prevaricating and tell me
Why do arteries become diseased?”
Prof, “All you students starting a presentation begin with ‘Arterial disease is the greatest cause of serious illness and death in the developed world. The usual cause is a process called variously atheroma, atherosclerosis or atherothrombosis. Atheroma indicates that there are cheesy-like lesions that project into the lumena of the arteries. Atheroscerosis indicates that the arterial walls become harder (less elasticity, less changeable tone). Atherothrombosis indicates that thrombosis (clotting) contributes to the process. There is no doubt that thrombosis is involved at a late stage’”.
Student, “So, is there anything wrong with that?”
Prof, “Depends on the audience. If you’re talking to doctors it’s stating the obvious. I should think most laymen know this also”.
Student, “You are a stinker to please!”
Prof, “Coronary arterial (arteries supplying the heart muscle itself) thrombosis is the cause of myocardial infarction and unstable angina”.
Rude interruption by student, “Now who’s stating the obvious!”
Prof, “Thrombosis in the arteries to the head cause thrombotic stroke. Thrombosis in the arteries to the legs cause acute gangrene, etc”.
Student, “More stating the obvious!”
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Prof, “However, people unfortunate enough to suffer from haemophilia (an inherited condition in which clotting does not occur properly) do not develop the disease!”
Student, “What. Really!”
Prof, “leading to the theory that thrombosis is a necessary component of development of the atheroma lesions”.
Student, “Oh, I hadn’t heard that one before. There are many theories about the cause of the disease”.
Prof, “which I will take up in the next tutorial, but if the glycocalyx theory of shear stress mediated dilatation holds sway it leads to a new theory of atheroma causation”.
Student, “Has this got to do with the theory that the disease is delayed or prevented by moderate exercise on the part of the subject?”
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Prof, “Exercise increases the flow speed of blood round the circulation and therefore the shear stress at the arterial walls, causing the endothelium to produce more NO. Ignarro, who won the Nobel prize showed that NO inhibited the process of atheroma, so we are tempted to suggest a theory that atheroma starts from a lack of NO production by arterial endothelium”.
Student, “I like that; so NO is not so toxic after all - quite beneficial?”
Prof, “Compatible with such an idea is the fact that the sites within the arterial tree, where atheroma is most likely to develop, are those with the lowest shear rates. If the glycocalyx is indeed the trigger for shear rate dependent NO production, it would place the glycocalyx in the forefront of the process of protection against disease!”
Student, “I suppose that’s another of your theories that you’ve published?” Prof, “Yes, to give an opportunity to others to try and disprove it!”
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Student, “Does this glucose experiment explain why diabetics get more atheroma than normals?”
Prof, “Possibly. Sugar diabetes (diabetes mellitus), literally translated from latin as sweet diabetes, was so called to distinguish it from diabetes insipidus. The old physicians recognised diabetes as a condition in which patients passed excessive amounts of urine and had to drink a lot of water to compensate. To make the diagnosis between sweet and insipid diabetes, they tasted the urine to find out whether it was sweet or not!” Student, “I hope I don’t have to do that.” Prof, “No, you’re spoilt nowadays, you just have to dip a stick into the urine specimens; we simply measure the amount of glucose in the urine and blood using a chemical reaction. Diabetes insipidus is uncommon and is due to a fault in the pituitary gland”.
Student, “I’m aware that in diabetes mellitus (all too common) the concentration of glucose in the blood is too high”.
Prof, “Yes and that in diabetes mellitus, atherothrombosis is much more common than in normal people as you already said. Restricting the progression of atherothrombosis depends on strict control of blood glucose concentration with diet and drugs. When glucose is high, there is greater glycosylation of glycocalyx glycoproteins and therefore less NO production by arterial endothelium. Coincidence or cause and effect?
" " " " " " " "
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CHAPTER 10
The great cholesterol myth
150
Prof, “Hello Freda, I haven’t seen you for ages”. Freda, “I always do my weekly shop at this time”. Prof, “You mean before the booze department opens at 10?” Freda, “That’s right, it’s quieter now and booze is bad for you anyway!” Prof, “That is an extraordinary trolley you’re using. What’s that contraption underneath?”
Freda, “It’s a resistance, so that I have to push harder to move the trolley, so I get more exercise and that’s good for you!”
Prof, “You could get more exercise by returning to my Scottish Country Dancing class”.
Freda, “Oh! I’m much too busy with work and the kids, ye ken”. Prof, “Is that why you’re worried about your health?” Freda, “No it’s because my cholesterol is high”. Prof, “Then you haven’t heard about the great cholesterol myth?” Freda, “What!”
Prof, “This was the title of a recent published article in which the author attacked the false theory that heart disease is caused by cholesterol, and attacked the present obsession for measuring cholesterol and abstaining from eating fat”.
Freda, “Oh, but I’m sure fat must be bad for you, ye ken”.
Prof, “Judging from what you’ve got in your trolley, you obviously believe that, but cholesterol refers to a whole group of lipids (fats) combined with protein - lipoproteins. Most of the cholesterols in your blood are manufactured within the body and are not the same as the cholesterols you eat, so the particular mix of cholesterols in your blood are primarily determined by the genes you inherit from your parents. It so happens that there are families in whom there is an abnormally great amount of one of these cholesterols and are free of cardiovascular disease. Freda, “Surely not. I’ve heard of families with high cholesterol and they all get disease at a young age”.
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Prof, “Not all such families. The presumption is that that particular lipoprotein in their disease-free case is protective against arterial disease it is a ‘good’ cholesterol. Getting your total cholesterol measured does not tell you whether it is mostly good cholesterol that is high, and that trying to lower it will cause harm”.
Freda, “But most cholesterol is bad for you, ye ken”.
Prof, “There are other families in whom there is an abnormally great amount of one of these cholesterols and the family members tend to suffer arterial disease (atheroma) at a young age. The presumption is that that various particular lipoproteins in such families (familial hyperlipidaemia) are a risk factor for arterial disease - it is a ‘bad’ cholesterol”.
Freda, “So I don’t know whether my cholesterol is good or bad?”
Prof, “You got it. Many years ago, a study called “Framington” measured total cholesterol in a huge number of people and found that those with high ‘cholesterol’, i.e., mixed total cholesterol, later developed more atheromatous disease than those with normal levels. It was also known that many arterial lesions contained a lot of cholesterol. This is where the false theory that cholesterol causes arterial disease began”.
False interpretation of statistical data.
Freda, “I thought they showed that people with high cholesterol had more heart disease”.
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Prof, “Let’s go into the cafe and I’ll explain over a cup of tea”. Freda, “Coffee for me please”.
Prof, “These people made the same mistake as those who created the ‘salt causes hypertension’ false theory (Chapter 2). Inevitably mixed up in a huge population of apparently normal people as studied in Framington, there will be people who have the misfortune to have too much ‘bad’ cholesterol”.
Freda, “What’s that doodling your doing?”
Prof, “This is to give you an idea of the enormous scatter in this kind of exercise - all these dots all over the place when you relate outcome to total cholesterol. This will appear as a statistically significant correlation in the process of statistical analysis, indicated by the line I’ve drawn through the dots, so they concluded quite incorrectly that cholesterol was causative in the disease”.
Freda, “But there a lot of dots!”
Prof, “Yes that’s part of the trouble. If they had studied a smaller population, they would not have found the correlation, in other words, in most people, cholesterol is not causative. If they had worked out the amount of variation due to cholesterol, they would have found that it was much smaller than the variation not due to cholesterol, in other words, in most people, cholesterol is not causative”.
Freda, “How can you be sure about that?”
Prof, “What does the epidemic tell us?”
Freda, “How would I know?”
Prof, “Strictly speaking one cannot be 100% certain about anything in medicine, but the correct way to approach this is to look at the epidemic of heart disease, as the author of the cholesterol myth article did”.
Freda, “Arn’t epidemics about infections?”
Prof, “Yes they wax and wane with the prevalence of the germ, and coronary disease waxed and waned. Arterial disease was not a great health 153
problem in the nineteenth century, possibly because people were killed at a younger age by infections. During the twentieth century when, in the developed countries, infection control (age of antibiotics) was achieved, an epidemic of arterial disease developed peaking at about three quarters of the way through that century. Since then, the prevalence of the disease has declined in the developed countries while increasing in the developing countries”.
Freda, “Because people stopped eating fat?”
Prof, “No cholesterol levels were constant throughout the waxing and waning of the disease, and so could not be the cause, and as I told you before, your cholesterol does not reflect how much fat you eat”.
Freda, “So your looking for a germs a cause?”
Prof, “That’s a possibility, but what did wax and wane in parallel with coronary disease was smoking and industrial pollution. One must look at what risk factors could increase and decline in a similar way, allowing for the lag in time between exposure to the risk factor and the development of the disease. No such increase followed by decline of cholesterol occurred and cholesterol levels are not increasing in the populations of the developing countries where heart disease is increasing”. Freda, “So you think we should just stop smoking and pollution?”
Prof, “Yes. We’re making progress with stopping smoking but pollution from all the diesel we burn is still a problem. If one was to conclude from this that these two factors were causative, control of arterial disease might be achieved by stopping smoking and pollution. In stark contrast to the cholesterol myth, taking these measures is pretty well guaranteed to be harmless”.
Freda, “So, if that doesn’t work you’re going to look for a virus or something?”
Prof, “Yes. As we shall see, trying to reduce cholesterol can be harmful. Again, like all theories, there is no certainty about these proposals. An alternative theory is that arterial disease is caused by an infection. Some organisms that were suspected of this do not seem to be possible as a cause, but there are plenty of unknown infectious organisms, especially viruses; the current fall in prevalence of arterial disease in the developed countries could be attributed to the acquisition of immunity to the 154
organism. The current increasing prevalence of arterial disease in the developing countries can be attributed, according to these various theories, to increasing smoking, increasing industrial pollution or lack of immunity to the organism”.
Prof, “What does studying patients with coronary artery disease tell us?”
Freda, “You seem to know a lot about all this!”
Prof, “Yes, coronary disease was increasing to its peak during my time as a hospital doctor and I ended up in charge of a coronary care unit and was able to ask the question, ‘What correlations are there between various factors that can be measured in the blood as soon as the patient arrives (and before specific treatment) and their subsequent clinical course?”
Freda, “Presumably you measured cholesterol!” Prof, ‘Yes. It is already established that, after a patient has had a coronary episode (myocardial infarction or unstable angina (STEMI or non-STEMI, see chapter 1), they are more likely to have a further episode in the following five years than subjects of the same age that have not had such an episode”.
Freda, “Were you able to find out what happened to all these patients after they left hospital?”
Prof, “Yes. When we followed our patients for four years, we found that patients who had had an episode before their admission to us, were more at risk in the next four years than those who had not”.
Freda, “That makes sense”.
Prof, “Another factor that predicted a less good outcome on follow up was the level of a protein in the blood (troponin T) that leaks from dead and dying heart muscle cells, so that the rise in concentration following admission indicated the amount of myocardial damage, in other words, the outlook is not so good if you have a large infarct rather than a small one”.
Freda, “But what about supposed causative factors like cholesterol?”
Prof, “Although we excluded from our analysis patients with diabetes, we measured the insulin resistance of the patients, high insulin resistance being a forerunner of sugar diabetes (type 2 diabetes mellitus, sweet 155
diabetes). There was a higher incidence of recurrent coronary episodes in such patients in the following 4 years”.
Freda, “I was aware that diabetics got more heart disease”.
Prof, “We also measured a notoriously “bad” cholesterol called lipoprotein(a) (Lp(a)). There was a higher incidence of recurrent coronary episodes in patients with high levels of Lp(a) in the following 4 years”.
Freda, “What about my high cholesterol?” Prof, “We also measured ‘cholesterol’, i.e., the total mixture of total cholesterols that you can get measured in the high street. Most of our patients admitted with a coronary episode had normal levels! There was no correlation between total cholesterol and subsequent clinical events!”
Why is lowering cholesterol harmful - diet
Freda, “Surely you were not serious implying that lowering cholesterol is harmful!”
Prof, “Just because a few “bad” cholesterols, if present in the blood at a higher concentration than average, can sometimes be associated with premature arterial disease, there is no logical reason to eat a low fat diet. Eating cholesterol is harmless; most of the cholesterol in your blood is manufactured in the body and is controlled by your genes, not your diet”.
Freda, I don’t like the idea of eating fat”.
Prof, “The ethnic Inuits used to be called eskimos and lived mainly on seal blubber, seal meat and oily (fatty) fish - a high fat diet. They rarely developed arterial disease, so, high fat diet is healthy.
Fat is very necessary for the body to work. All living, active cells in the body have membranes around them (cell membranes) which are made of fat - the so-called lipid bilayer. The brain, nerves, muscles, heart, blood vessels, gut etc are all collections of electrically excitable cells that depend for function on their cell membranes.”
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Prof, “Natural selection (or if you insist, God) designed that the best possible diet should be available for mammalian babies - breast milk, a high fat diet, in other words, high fat diet is healthy. It is generally thought (though without proof) that Mediterranean populations have less arterial disease than North Europeans or Americans because of the healthy nature of the Mediterranean diet. That diet is rich in olive oil, so, high fat diet is healthy”.
Freda, “Can you prove it?”
Prof, “No, in science we try to disprove theories. In order to show that fat is bad for you, one would need to take a whole lot of identical twins (clones would be even better!) and, from birth, feed one of each twin with a normal diet and the other of each twin with a low fat diet, and then measure their respective clinical courses over their life spans. If I had to 157
guess what would happen, I would say that the normal fat diet subjects would have normal lives with only the average history of illness, while the low fat diet twins would have, in addition, a higher incidence of autism and, if you could live long enough to follow them to old age, a higher incidence of Alzheimer’s”.
Freda, “Oh dear, I have wondered if my boy is becoming autistic”. Prof, “I can guarantee nothing, but if I were you I would throw away all that skimmed milk in your shopping basket and give him gold top. Look, I’ve drawn you a brain. Have you ever seen a brain?”
" " " " " " " " " " Freda, “Ugh no” Prof, “What colour have I used?” Freda, “Yellow” Prof, “Why do you think brains are yellow?” Freda, “I know what you’re trying to make me say - fat”.
Prof, “Yes. Without fat the brain cannot work properly. I think I was fortunate going to school during the war and soon after. Every child was given a quarter of a pint of whole fat milk to drink every day - very healthy!”
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Freda, “But no proof!”
Prof, “No. Needless to say, no trial has ever been done in identical twins, nor is it likely to be performed. Nor has a double blind, cross over trial of margarine versus butter. In the absence of any valid evidence that fat in the diet is bad for you, in the presence of evidence that fat may be good for you, and with the unknown effects of fat deprivation on the brain, let us please stick to butter, stop skimming milk, eat old-fashioned natural foods and not eat mucked about stuff (processed foods etc) - I think most of the stuff in your shopping trolley is stuff I wouldn’t touch”.
Freda, “What’s wrong with processed food?”
" " " " " " " " " " " " " " " " " Prof, “The other potentially harmful aspect of low fat diet is the type of foodstuff that is substituted for the fat in low fat foods - maybe I could preach to you about that sometime!
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Prof, “And now some people must have been listening to me, as this article in the Daily Express seems to confirm. 40 years to be vindicated. Fortunately, I have kept to my high fat diet all that time!
"
Freda, “Maybe I should try some nice fatty food”.
Prof, “Butter, cream”.
Why is lowering cholesterol harmful - drugs”
Freda, “Our doctor put my husband on a statin for his high cholesterol”.
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Prof, “If he definitely has coronary disease, that is the correct thing to do, but watch out for side effects”.
Freda, “Oh, what should I look for?”
Prof, “The cholesterol myth madness has got to the stage where healthy people are urged to take so-called lipid lowering drugs because they have a highish total (mixed good and bad) cholesterol. The main drugs to do this are the statins. Here is another example of misuse of statistical correlation. If one takes a whole lot of patients with arterial disease and treats them with a statin, their cholesterol level goes down, and the disease is arrested (or even regresses in some studies)”.
Freda, “That’s a good thing surely”.
Prof, “Yes but there is the erroneous conclusion that the arrest of the disease is brought about by the lowering of the cholesterol. NOT SO. Statins have a number of effects. One is to lower cholesterol, another is to leach cholesterol out of tissue, another is to suppress inflamed tissue. The arresting of atheroma is caused by the 2nd and 3rd effect, not the first. The statin leaches the cholesterol out of the atheromatous lesions that are fatty (some are not), and suppresses the inflammation that exists in the lesions. Therefore the rationale for treating patients with statins is when the lesions are life threatening, regardless of the cholesterol level, which will often be normal or low”.
Freda, “What are the side effects I have to watch for in my husband?” Prof, “The statins also leach lipoproteins out of cell membranes. Cell membranes are essential for normal function in electrically excitable tissues like nerve, muscle and heart. What is going to happen when lipoproteins are leached out of ‘the little grey cells of Poirot’ (and his!)? Depression? - a known side effect. Alzheimer’s? What is going to happen when the fat which insulates the nerve circuits of the body is depleted? Short circuits? What is going to happen when lipoprotein is leached out of the cell membranes of your muscles? We know that - it is muscle pain. I remember one case of a patient whose cholesterol had been lowered with such fanatical over-enthusiasm that most of her muscles died and the dead products completely clogged the kidneys so that the whole of her died death due to a doctor’s treatment is called ‘iatrogenic’, perhaps it should be called ‘killergenic’!
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Then there is
Independent analysis
There has been publication of many surveys that suggest that nearly everybody should be treated with statin drugs to lower cholesterol levels. There is always the suspicion, that such surveys, which mainly benefit pharmaceutical companies that sell statin drugs, are in some way biased. The Cochrane reviews have a high reputation for being unbiased. Several of them concluded that there was no convincing link between hypertension and ingested salt (see Chapter 2)”.
Freda, “What does the Cochrane review on statins for normal people have to say?”
Prof, “I‘ve got a print out of what I think they say - you can have it and read it and see what your husband thinks of it”.
Here is a summary of the document given for Freda’s husband to peruse.
The new Cochrane review (2011) has provoked controversy by concluding that there is not enough evidence to recommend the widespread use of statins in the primary prevention of heart disease. The authors of the Cochrane analysis, led by London School of Hygiene and Tropical Medicine, UK (a renowned school of population medical statistics) questioned the benefit of statins in primary prevention (in healthy people) and suggested that the previous data showing benefit may have been biased by industry-funded studies.
The Cochrane authors reviewed data from 14 trials involving 34,272 patients. Outcomes in patients given statins were compared with outcomes in patients given placebos or usual care. Although results suggested that deaths were reduced on statins, the researchers say the effect is not large enough to justify the cost/effort and risk of adverse effects. The review differed from others done in primary prevention (normal people free of coronary disease) in that it looked at just those at low risk, limiting the studies included to just those with populations where 20% 10-year risk), “it is likely that the benefits of statins are greater than potential short-term harms, although long-term effects (over decades) remain unknown.” They conclude: “Any decision to use statins for primary prevention should be made cautiously and in the light of an assessment of the patient’s overall cardiovascular risk profile. Widespread use of statins in people at low risk of cardiovascular events below a 1% annual all-cause mortality risk or an annual CVD event rate of below 2% observed in the control groups in the trials considered here-is not supported by the existing evidence.”
Critics of the review say the only argument against using statins in lowrisk people is economic. “The absolute benefits of statin therapy become very small when used among people at low absolute risk, so it is important that the costs of such treatment are considered when weighing how widely 163
statins should be used. That is a government decision.” But why should the government decide that a normal individual should be exposed to damaging side effects to muscles, nerves and brain? Apparently it has decided to go along with the universal statin policy, in spite of the Cochrane Review, but the advice of the National Institute for Clinical Excellence [NICE], which currently recommends that statins should be used for people with a CHD risk below 20% over 10 years is totally contrary to the Cochrane conclusions that are totally opposite to this. So much for supposed ‘authorities.’ The man or woman in the street might therefore think. “I had better not take drugs, but change my lifestyle”. A separate Cochrane review looked at the use of “healthy heart programs” that use counselling and educational methods to encourage people to reduce their risks for developing heart disease. These risk factors were assumed to include high cholesterol, excessive salt intake, high blood pressure, excess weight, a high fat diet, smoking, diabetes, and a sedentary lifestyle. They reviewed 55 trials that aimed to reduce more than one risk factor in people without evidence of cardiovascular disease.
Results showed that after a median duration of 12 months of follow-up, multiple risk-factor intervention was associated with small reductions in risk factors, including blood pressure, cholesterol, and smoking, but had little or no impact on the risk of coronary heart disease mortality or morbidity. They conclude: “The methods of attempting behaviour change in the general population are limited and do not appear to be effective. Different approaches to behaviour change are needed and should be tested empirically before being widely promoted, particularly in developing countries where cardiovascular disease rates are rising.”
Prof, “One might suppose that legislating for smoke-free public spaces, redesigning public spaces to improve exercise, and getting rid of diesel exhaust, might prove generally effective and can be cost-saving and harmless interventions.
THERE IS NO JUSTIFICATION FOR STATIN TREATMENT IN PEOPLE WHO DO NOT HAVE LIFE THREATENING ARTERIAL DISEASE. DO NOT GIVE HEALTHY PEOPLE DRUG SIDE EFFECTS.
Particularly discouraging is the distress caused to old people being encouraged by their doctors to go on statins because of high mixed good 164
and bad cholesterol. Take my own case at age nearly 80 years. If I accepted my GP’s advice, I could expect to derive benefit from the treatment when I am aged 120. I have no ambition to rival Methusalah, so, in the meantime, I WOULD RATHER NOT JEOPARDISE MY MARBLES!
Freda, “Are you sure you have not already lost them?”
Prof, “But this is an important question? What is more important, to preserve the heart or to preserve the brain? Can there be any doubt? The heart is a mere blood pump. The brain is the seat of the personality and of the soul. I have no doubt about that, even though I am a cardiologist!”
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CHAPTER 11
What is so special about coronaries? And a silly debate!
Prof, “OK you want to be heart surgeons, you should know about
The blood supply to the heart
Bruiser, “The heart is a muscle which converts chemical energy into mechanical energy as discussed before, in this case pumping blood around the body to supply all the organs with fuel and oxygen. So the heart also needs a blood supply to carry fuel and oxygen for the contracting heart muscle. The coronary arteries arise from just outside the exit of the left ventricle, just beyond the aortic valve that stops blood going back into the left ventricle when it relaxes between beats”.
Prof, “Always?”
Bruiser, “These arteries run and branch on the surface; some unfortunate people are born with some heart muscle bridging over an artery which occludes it”.
Prof, “OK, describe the rest”.
Bruiser, “When the branch gets to where it has to supply blood, it dives down from the surface into the muscle”.
Prof, “This can cause a difficulty. When the heart contracts it occludes all those little branches within the muscle. So, what is special about the 166
coronary arteries, is that blood flow stops when the heart contracts (systole) and flows forwards when the heart relaxes (diastole)”.
Bruiser, “We can stop the heart when we operate so that blood can flow through all the time!”
Prof, “Quite so. But in real life, the flow carrying the precious fuel and oxygen depends on the diastolic pressure, whereas in other organs it depends on the average pressure over the cardiac cycle”. One consequence of this is that the distance, from the artery on the outside to the bits of muscle at various depths within the muscle, matters”.
Bruiser, “The muscle on the inside next to the cavity has the most precarious blood supply - this part of the muscle is called subendocardium; the supply gets progressively less precarious as one tracks back to the feed artery on the surface”.
Prof, “Another problem arises if the heart beats faster, because this means that the heart needs more fuel and oxygen, but the duration of diastole gets
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much shorter than the shortening of the duration of systole, so there is less time for blood supply when the need is increased”.
Bruiser, “In the condition called angina pectoris, there is a narrowing of the feed artery, so that the diastolic pressure at the point where it plunges into the depth of the muscle is less than the diastolic pressure at the aorta, the sub-endocardium does not get enough blood when the heart rate goes up and the patients get a pain in the chest. This acts as a warning to the patient to stop doing whatever it was that put the heart rate up, e.g., exercise, and to spray some glyceryl trinitrate (GTN spray) on to the tongue; this dilates the veins, reducing the work of the heart and therefore reducing the amount of fuel and oxygen required”.
Prof, “A most physicianly account. I’m glad you did not say the GTN was to dilate the coronary arteries, because a diseased section of coronary artery can hardly be expected to dilate”.
Bruiser, “This situation led to the idea that under-perfusion of the subendocardium and angina occurred when there was a change in the balance of supply and demand; a lowering of supply (say, a narrowing of the coronary artery) and/or an increase in demand (say, higher heart rate, higher systolic blood pressure)”.
" " " " " " " " " " " " 168
Prof, “I was once asked at the last minute to speak in a debate. This was a cardiologists’ club where they liked to have formal debates as conducted in the House of Commons with a motion supported by two speakers, and a counter-motion supported by two other speakers. I did not know the club existed; the chairman for whom I had worked in the past contacted me to say that the second speaker of the opposition had been unable to participate at the last minute and would I take his place? Ever ready to take on a challenge, I agreed. The session turned out to be a question, “What is more important in the heart - supply or demand?” The proposers of the motion argued that supply was more important, and I had to second the counter-motion that demand was more important! You will say, ‘What a silly debate’ - and you would be right”.
Bruiser, “In coronary disease the fundamental problem is a narrowing of one or more coronary arteries which limits supply. Obviously the thing to do is to get rid of the narrowing. This can be done very successfully by heart surgeons, but cardiologists nowadays like to do it by sticking tubes called catheters down the affected coronary artery and blowing up a balloon inside to crack the narrowing (we call it a stenosis) open. Then they put a stent inside the artery to stop in bunging up again”.
Prof, “Ah, you don’t like physicians stealing your work, but don’t blame me, I never got into the angioplasty racket! There is one big disadvantage of this which I will tackle in the next lesson”.
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Bruiser, “I don’t see how you possibly have been able to make out that demand was more important than removing the stenosis”.
Prof, “In order to make a game of trying to argue for demand being more important, I presented the pressure-flow diagram of the coronary circulation. If you control the pressure of blood in the coronary arteries, starting from zero pressure, the flow goes up steeply to a certain level after which it hardly goes up at all; there is rather flat diagram where pressure is going up and flow goes up much more slowly.
The mechanism whereby flow is maintained almost constant is called autoregulation. Eventually autoregulation breaks down at very high pressure well above the normal level of BP. Now if one increases demand by increasing heart rate, the flow rate during the autoregulatory pressure range goes up more or less parallel to the first curve. However the pressure at the low end, at which autoregulation cuts in, is higher than in the original run. In the case of a coronary stenosis, the narrowing does not matter if there is no pressure drop across it.
Bruiser, “Isn’t there a cardiologist whose always trumpeting about the need to measure the pressure gradient across stenoses?”
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Prof, “Yes, quite right too. It is unfortunate that this measurement is not made in patients as much as it should be; cardiologists tend to treat a narrowing as such rather than test whether it is critical or not”.
Bruiser, “You mean that when I become a heart surgeon, cardiologists will ask me to bypass narrowed coronary arteries that do not need to be bypassed?!”
Prof, “That’s exactly what I mean. It’s not the anatomy that matters, it’s the function. Returning to the pressure-flow diagram, the pressure that matters is that beyond the stenosis, which is lower than normal if there is a pressure drop. Now if we increase demand, that pressure can end up below that necessary to achieve autoregulation and we get demand related subendocardial ischaemia (not enough blood)”.
Bruiser, “A much more interesting question than that posed by the silly supply-demand debate is, ‘What is the mechanism by which parallel autoregulation curves are obtained with different demand levels?’”
Prof, “Essentially what is happening as the pressure increases is a constriction of the downstream resistance vessels that restricts the increase in flow, while the parallel shift upwards in flow with increased demand is a dilatation of the resistance vessels”.
Bruiser, “By what agency is the resistance controlled?”
Prof, “There is a controversy about this. When muscles like heart contract, they consume fuel and oxygen, and produce waste products. For instance, oxygen is combined with carbon in the energy transfer process to produce carbon dioxide, adenosine is produced from the breakdown of ATP, potassium leaks from cells, if the oxygen supply gets low, lactic acid is produced. All these agents are vasodilators. The popular theory was that one of these dilators (adenosine being the favourite) also controlled the resistance vessels”.
Bruiser, “Yes, I seem to remember from my physiology lessons that adenosine controlled coronary blood flow”.
Prof, “Trust a budding surgeon to remember something about physiology that is probably wrong!”
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Bruiser, “OK Professor Iconoclast, what’s your idea?”
Prof, “An alternative theory for the control in the heart is that it is via the concentration of oxygen around the resistance vessels; higher oxygen constricts resistance vessels. When pressure increases, more oxygen is dissolved in the fluid around these vessels, so they constrict; when demand increases less oxygen is dissolved in the fluid around these vessels, so they dilate”.
Bruiser, “Why do you prefer that theory?”
Prof, “When we wrote out the mathematical equations for an oxygen control versus a waste product control, the former predicted the measured results better”.
Bruiser, “You prefer a theory that gives you the neatest maths!”
Prof, “Yes, maths is an exact exercise, medicine is just a lot theories that cannot be proved but can be disproved. Measuring the oxygen in the fluid around the resistance vessels in a beating heart in situ is almost impossible, but we did get quite a close correlation between the resistance of the coronary vessels and the oxygen in the blood draining the heart in the cardiac veins”.
Bruiser, “So what!”
Prof, “All this proves nothing; we just have theories and they are fun and stimulating from an academic standpoint”.
Bruiser, “OK, if you think demand is so important, how do you measure it?”
Prof, “Another conflict of theories that has gone on, throughout my career right up to the present time, is the debate about what mechanical or haemodynamic measurement or combination of measurements determines demand”.
Bruiser, “Well you haven’t defined demand yet”.
Prof, “By demand, we mean the energy consumption of the heart as evidenced from one or other of ATP consumption, oxygen consumption, carbon dioxide production and work plus heat production. One popular 172
idea was that energy consumption was determined by the “area” within the pressure-volume diagram of the cardiac cycle plus the area under the Emax line (see Chapter 6). This cannot be correct because it completely ignores the heat production by the heart burning fuel and oxygen. One reason that these various theories fail is that many authors ignore the “activation” energy requirement as measured by Colin Gibbs in Australia. This is the energy required for the electrical activity and calcium cycling (see Chapters 1 & 3)”.
Bruiser, “This is all too academic to be of practical use in assessing patients.”
Prof, “Although you may be indifferent to this whole subject because it is purely academic, it is nevertheless relevant to understanding what goes on when a patient gets angina pectoris, that is, demand mediated heart pain”.
Bruiser, “Oh I think I understand that. The patients exercise and get chest pain”.
Prof, “OK but suppose we think about what happens other than more heart work when the heart rate increases. There will be more relaxations per minute and relaxation is achieved through the sarcoplasmic reticular ATPase (Chapter 3). As heart rate progressively increases, there is more and more activation of the Na+/K+ATPase. So these two components of activation energy utilisation will not increase linearly with heart rate, but will follow an upward curvilinear relationship. The main mechanical component that correlates with energy consumption is force of contraction; this requires knowledge of wall force in the intact heart but, (discussed in Chapter 6), this cannot be measured and varies in various parts of the left ventricle. Then there is is going to be a great non-linearity in the relationship between energy consumption and force if it is true that energy consumption in the latter part of systole is much less than in the first half!”
Bruiser, “You’re making it all too complicated”.
Prof, “Then there is the complication that it appears that an increase in contractility (Chapter 6) puts an extra demand upon energy consumption that is greater than the mere relationship to force - remember all that extra intracellular Ca++ that is circulating in the myocardial cells. It is therefore 173
not surprising that my authority on this subject (Colin Gibbs) still cannot reckon with all these factors”.
Bruiser, “Why do patients with angina have a variable threshold for chest pain?”
Prof, “Presumably because sometimes one of the factors may be dominant in one circumstance and another in a different circumstance. All this uncertainty justifies cardiologists in not measuring oxygen consumption and heat production in patients; that would require measurement of coronary blood flow, arterial and mixed venous oxygen content and multiple temperature measurements!”
Bruiser, “And how would that help a patient with angina pectoris when the treatment would still be to reduce demand as much as possible with ßblockers (Chapter 14), antihypertensives and venodilators (that dilate veins to reduce the heart’s load). I would like to hear more about
Unnecessary angioplasty”
Prof, “I mentioned before that a stenosis can be stretched open by a catheter balloon (angioplasty) followed by a stent to keep the artery open, but that cardiologists tend not to measure the pressure gradient. There are other ways of investigating whether a stenosis matters, that is, whether it is critical in preventing supply; these are also ignored even though large studies have now shown poor correlation between stenoses critical to supply and narrowing as seen on a coronary angiogram (an X-radiograph with the lumen of the coronary arteries shown up). The significance of this is that a large number of angioplasties (an expensive procedure with risk), need not have been performed. This is especially disadvantageous if only one of the coronary arteries is involved, because, having an angioplasty, the patient needs not go on to dangerous anti-thrombotic drugs (see Chapter 12)”.
Bruiser, “I must be careful when I am a heart surgeon to avoid being accused of unnecessary bypasses in order to make more money from the fees!”
Prof, “Yes, it is possible that the situation is worse in private practice where doing an angioplasty earns a considerable fee. This is probably not a 174
factor in Europe, but in the USA at the time of writing, two American cardiologists have been put in jail for performing unnecessary angioplasties”.
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CHAPTER 12
Drugs for the heart - and a Bloody Mess
" The dosing problem
Prof, Hello Bert, is that a very precious plant you’re watering?”
Gardener, “I’m not watering, I’m killing. This is Japanese knotweed, I must get rid of it”.
Prof, “When you make up weedkiller solution, how do you know whether it will be effective?”
Gardener, “The effectiveness of the mixture depends on the concentration of
weedkiller. I also know that to obtain the right concentration, I have to have both the right amount of chemical in the bucket and the right amount of water, because concentration equals the amount of chemical - say in 176
grams - divided by the volume - say in litres - of water in which it is dissolved, the concentration in this case being in units of grams per litre”.
Prof, “You’re obviously a fully trained gardener!”
Gardener, “When I was a lad the chemist used to make up medicines for me on the same principle, but now all I get is pills”.
Prof, “But the effectiveness of a drug does depend upon its concentration. If one gives 75mg (milligrams) of a drug to a patient whose volume is 75 litres, the effect is going to be that of a concentration of 1mg/litre. If you give 75mg of the drug to a patient whose volume is 150 litres, the effect is going to be that of a concentration of half a mg per litre”.
Gardener, “So I should have a bigger pill than a tiddler?”
Prof, “You got it. I am angry that pills are not of different sizes to suit different size patients”.
Gardener, “Some weeds are more sensitive to weedkiller than others. So, depending on what weed you want to kill, one needs a lower concentration to kill sensitive weeds and a higher concentration to kill tough resistant weeds like this terrible Japanese knotweed”.
Prof, “The same applies to drugs. If you give 75mg of the drug to a patient who is sensitive to its effects, the effect will be more like that of a higher concentration, say, 2mg/litre in a 75 litre patient. If you give 75mg to patient who is insensitive to its effects, the effect will be more like that of a lower concentration, say, a quarter of a mg/litre in a 150 litre patient”.
Gardener, “Don’t see much of that in the chemists”.
Prof, “Unfortunately. If you give 75mg of the drug to every patient, regardless of their size or sensitivity to the drug, there can be no possible control of the concentration. Some patients will be inadequately dosed because of too low a concentration; others will be dangerously poisoned by too high a concentration. YET THIS IS PRECISELY WHAT HAPPENS!
A specific case - clots in veins, lung vessels and heart chambers
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Gardener, “I’m on warfarin because I had an episode of dicky heart rhythm”.
Prof, “In diseases of the blood vessels, we are often fighting against blood clots that cause trouble. Clots in veins, clots in the heart chambers as in your case, clots in lung vessels, clots in arteries. You are fortunate to be on warfarin, because that is the one drug for which the dose is adjusted to get the right effect as judged by blood tests”.
" Gardener, “Yes, I only have to have a blood test once a month now”.
Prod, “Pretty stable. Clotting is the normal mechanism that has developed to restrict bleeding from wounds. During evolution, mammals had to fight each other constantly to maintain their lives and the survival of their species. In the case of humans, survival might mean living to the age of forty if you were lucky; living to the age of 80 would have been exceedingly rare”.
Gardener, “That’s coming to me soon. The youngsters nowadays don’t want to be gardeners”.
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Prof, “Quite, but during human evolution you would probably die before this and not have to deal with clots forming inside the body as in mostly middle aged and elderly people. To treat such people now, we have to inhibit clotting with drugs; that means they will bleed more easily. So we have to carefully balance the amount of anti-clotting drugs we give and the risk of excessive bleeding”.
Gardener, “Yes, hence the blood tests”.
Prof, “You seem interested in this hobby horse of mine. Consider the first three examples clots in veins, heart chambers and lung vessels. These happen in a different way to clots in arteries. They are what we call fibrinrich whereas clots in arteries are platelet-rich, but do not worry about this, only about the fact that different drugs are suitable for veins, heart chambers and lung vessels as against arteries”.
Gardener, “O hope I don’t have dicky arteries!”.
Prof, “For many years, your kind of clots have been successfully controlled with warfarin. If you are put on warfarin, you have to have regular blood tests to check whether the dose you are taking is having the right effect due to the right concentration. The test - called an INR checks on whether the concentration is too low (clots still forming), too high (excessive bleeding) or just right”.
Gardener, “Why don’t they do this for other drugs for clots?”
Prof, “This procedure is unpopular with health services and patients because it takes time, trouble and money to maintain, but is the correct procedure - it makes sure the patients are at the right drug concentration. Experience has shown that the sensitivity changes, requiring changes in dosage; there is an interaction with alcohol and other drugs”.
Gardener, “Yes, I’ve been told to keep my alcohol consumption always the same”.
Prof, “Right. Because of the time, trouble and money involved in warfarin treatment blood testing and dose adjustment, the drug industry has for some years been foolishly promising health services anti-clot drugs that could be simply administered as a single dose to everybody! Had they never heard about the importance of drug concentration? Had they never 179
heard of the need to balance anti-clot activity versus excessive bleeding? Apparently not; such drugs have now been produced and released for patient use. It does not require much intelligence to understand your weed killer analogy. It was entirely predictable that report after report is appearing now of bleeding complications in the use of these new drugs!”
Gardener, “That sounds irresponsible to me”.
Prof, “It sure is. Now consider the fourth example - clots in arteries. Arterial disease, in which clotting (thrombosis) is the end stage, is the most common disease afflicting people in the developed world. Most “heart attacks” (see Chapter 7) occur because of clot (thrombus) forming in the coronary arteries which feed the heart muscle. The cut off of blood supply causes chest pain.
Gardener, “A friend of mine was told he had a heart attack even when he had no chest pain but they put him on a clot buster drug”.
Prof, “Was he diabetic?”
Gardener, “Yes”.
Prof, “Some patients with diabetes have lost the nerves from the heart that carry the pain message. The heart muscle supplied by that clotted artery dies (myocardial infarction), leaving a weak heart. Lesser degrees of thrombosis cause angina of various degrees - stable, unstable, crescendo etc”.
Gardener, “Different patterns of chest pain”.
Prof, “All the lesser degrees of coronary thrombosis above need treatment with drugs that inhibit the thrombosis. The patient whose coronary artery is completely blocked with thrombus and those with critical narrowing of the lumen of the artery need to have the blockage removed as quickly as possible before the heart muscle dies”.
Gardener, “With that clot busting drug”.
Prof, “The modern method of choice is to pass a catheter into the affected artery, open it up and insert a stent to keep it open”.
Gardener, “That sounds rather drastic”.
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"
Prof, “Yes, and unfortunately, stents cause thrombosis! So all these patients need to on an anti-thrombotic drug (for the rest of their lives).
Gardener, “That’s all very well if the patients can be got quickly to an unoccupied catheter laboratory, but supposing you live in Orkney and the nearest catheter laboratory is in Aberdeen!”
Prof, “Then we need to revert to an older method of clearing the blockage, that of injecting a clot dissolving drug (clot buster) called a thrombolytic. (A great advantage of injected drugs is that one can vary the amount in the syringe according to body weight). But thrombolytic drugs cause more thrombosis, so one also has to put these patients on an long term antithrombotic drug and, as there is a continuing risk of future thrombosis, that also has to be continued for life”.
Gardener, “With warfarin?”
Prof, “The first attempt to control arterial thrombosis was to use a warfarin like drug and then warfarin itself. When I was a newly qualified doctor, all the patients who had had a myocardial infarction were taking warfarin and attending anti-coagulant clinics”.
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Gardener, “With so many coronary patients that must have been a lot of work for you!”
Prof, “Yes, the opinion then developed that this did not have much effect in preventing coronary thrombosis, and the practice was stopped. More recent analyses of what happened actually showed that there was a definite though small diminution in thrombosis. The reality was that the practice was stopped because of the time, trouble and money involved in warfarin treatment; blood testing and dose adjustment”.
Gardener, “But you did say this was not suited to thrombosis in arteries”.
Prof, “Yes, unlike thrombosis in veins, lung vessels and heart chambers, thrombosis in the coronary artery is initiated mainly by blood platelets; these are little cells in the blood that bind to surfaces other than the artery lining and start the thrombosis off. Therefore it was logical to replace warfarin with a drug that inhibited platelets - anti-platelet drugs”.
Gardener, “I have been advised to take a mini-aspirin to ward off possible coronaries”.
Prof, Yes, the most used anti-platelet drug is aspirin, a very old and cheap drug, but there is no clear evidence about the correct dose. That is not a straightforward matter with aspirin, so most patients get given 75mg willy nilly! Needless to say, some patients are aspirin resistant and some small patients have trouble with bleeding on this dose”
Gardener, “You’re always hearing about new wonder drugs on the telly”.
Prof, “The drug industry responded to the incomplete success of aspirin by developing anti-platelet drugs that work through a different “receptor”. Receptors are proteins on the surface of cells (including (including platelets) to which natural body substances bind to have their effect. Such interactions can be blocked by drugs targeted at those receptors”.
Gardener, “How does aspirin work?”
"
Prof, “Aspirin works by blocking the pathway by which thromboxane activates platelets. Another ubiquitous substance in the body is ADP produced by the breakdown of ATP when chemical energy is converted to 182
another form of energy (- see Chapter 1). There is a receptor on platelets which reacts with ADP and activates the platelets to initiate thrombosis”.
"
Prof, “Aspirin works by blocking the pathway by which thromboxane activates platelets. Another ubiquitous substance in the body is ADP produced by the breakdown of ATP when chemical energy is converted to another form of energy (see Chapter 1). There is a receptor on platelets which reacts with ADP and activates the platelets to initiate thrombosis”.
Gardener, “Can you block that effect?”
Prof, “Yes, but drugs which do this inhibit thrombosis and cause bleeding; the most commonly used is called clopidogrel. But then what happens they give everybody 75mg! Even though it is known that people are of different sizes and that there is conclusive documentation of different sensitivities!”
Gardener, “Drug companies, it seems are not as intelligent as gardeners!”
Prof, “Quite so. They ignore the fact that the stopping of the thrombosis, like all drug effects (responses) depends upon the Drug Concentration. 183
Therefore a fixed dose will produce higher concentrations that cause bleeding in small patients, while producing lower concentrations in large people who are then inadequately treated. Getting the correct concentration from the fixed dose tablet is therefore a matter of pure chance!”
Gardener, “That sounds irresponsible to me”.
Prof, “Then there is the problem that not all people of a given size are the same. Some are more sensitive than average to the drug and have bleeding; others are less sensitive to the drug and are inadequately treated!”
Gardener, “Should not the patients be tested for sensitivity?”
Prof, “Of course, but it’s not straightforward and costs too much time and effort!”
Gardener, “That sounds irresponsible to me”.
Story from a grief stricken friend
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Prof, “Here’s a story. My friend, a sweet little lady, was attending a public function when afflicted with chest pain and faintness. An ambulance was called, the paramedics recorded an ECG and tried to radio it to the local cardiologist who was not available. The MC of the function happened to be a retired cardiologist, who diagnosed ST elevation myocardial infarction, the sort of heart attack caused by blockage of a coronary artery with clot, leading to death of the heart muscle. He persuaded the paramedics to administer a clot busting thrombolytic drug immediately before taking the patient to hospital. This was effective; the ST elevation resolved, the hospital cardiologist was able to put in a stent to keep the culprit coronary artery open, but also started the patient on a tablet called clopidogrel. A few weeks later she died of a “stroke”. No post mortem was performed to find out what kind of stroke. The same dose of clopidogrel (which inhibits clotting but causes bleeding) was given to this little lady that is given to big men. Should the dose not have been reduced according to body weight? I am convinced she died of brain bleeding caused by clopidogrel, i.e., by the treatment for the coronary thrombosis. Her appearance in the records will no doubt be recorded as a cardiological success, as the later admission was to a stroke unit, so I doubt if the cardiology department knew about it. Her death will not be a contribution to the number of recorded bleeding complications of clopidogrel”.
Gardener, “What a tragedy. What else can you do?”
"
Prof, “Well, there are
"
The ultimate anti-platelet drugs
"
These are called IIb/IIIa antagonists or antibodies.
"
Gardener, “What a funny name!”
Prof, “I’ll explain. When platelets are activated they form a layer, called the haemostatic layer, that rapidly seals off the injured tissue. They do this by binding to a protein in the blood called fibrinogen, which becomes a sticky layer. This vital anti-bleeding mechanism comes about by the reaction of the IIb/IIIa receptor on the platelet with the dissolved fibrinogen in the blood. So those intelligent prophets of the drug industry deduced, “If we block the IIb/IIIa receptor, that will certainly cause a lot of 185
bleeding - it has to be the most potent anti-platelet agent ever! So it is, but it also has, as one would predict, an even worse tendency to bleeding complications than the the other anti-platelet drugs”.
"
Gardener, “Surely they wouldn’t put people on that for life!”
"
Prof, “Fortunately, this has been appreciated and no one hopefully is given such a drug long term; it should only be used in a catheter laboratory for emergency situations.
" Gardener,
" “What a bloody mess”.
" Is there a solution?”
"
Prof, “Yes, we should prevent thrombosis with a drug that does not cause bleeding at all; then it would not matter if the concentration was higher than it need be.
"
Gardener, “Wonderful; is there such a drug?”
"
Prof, “Yes, I have demonstrated how it works”.
"
Gardener, “Why has it not been made available to patients?”
"
Prof, “It would take a lot of money for that to happen - it’s called drug development costs”.
"
Gardener, “But surely a drug company with it could make a lot of profit!”
"
Prof, “Yes, but the drug companies are not interested, possibly because, if successful, the market for all the existing anti-platelet drugs would disappear!”
"
Gardener, “That’s a disgrace!”
"
Prof, “Yes, so we have to go on putting up with A BLOODY MESS”
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A STORY FROM ANOTHER FRIEND
How protocol and routine caused agony.
The background to this is that when I was working in the 1970s in a general hospital, the orthopaedic surgeons had taken up the new procedure of hip replacement for patients with osteoarthritis affecting these joints. The patients were elderly, sometimes frail, sometimes overweight. I found myself, as consultant physician, being requested to attend some of these patients who were complaining or demonstrating one or more of leg pain, leg swelling, chest pain or breathing difficulty. It seemed to me that what we were seeing were episodes of venous thrombosis (clots in veins) and pulmonary embolus (venous clot coming loose and lodging in the lungs). Other doctors in other hospitals were coming to the same conclusion, stimulating research that showed that when radioactive fibrinogen is injected into the bed-bound patients, some radioactivity became fixed in the legs. This is because, when a clot forms in a vein, fibrinogen (soluble) is turned into fibrin (insoluble).
I started recommending anti-coagulation, although the surgeons declined this advice as they did not want bleeding. Other surgeons in other hospitals were not so shy and anticoagulation became accepted as the correct postoperative treatment to prevent and treat post-operative venous thrombosis. This was managed reasonably safely by titrating each patient’s warfarin dose against the INR test (see above).
A number of changes in medical, surgical and hospital administrative practice have occurred in the intervening decades:
1.
An alliance between orthopaedic surgeons and the physiotherapists has established that the best results of joint replacement are obtained by rapid mobilisation and exercises. One tries to get the patient out of bed the day after the operation and the patient is urged to bend and stretch the joint, and contract the muscles to achieve this.
2. More joints than just hips are replaced, e.g., knees, shoulders. My friend was to have a knee replacement. 3. Many clinical conditions are characterised by inflammation of the tissues, which become painful, hot and swollen; the pain is excacerbated by movement of the tissue, e.g., by contracting inflamed muscle. The inflammation can be controlled by cortisone187
like drugs, called steroids, or by chemically synthesised drugs called non-steroids anti-inflammatory drugs (NSAIDs). An early drug of the latter type is called ibuprofen, and none of the similar fancy “me too” drugs developed by the pharmaceutical industry have been as good. So, relief from painful inflammation can be obtained with ibuprofen.
4. The realisation that an ageing population has a high amount of arterial disease has led to many patients needing joint replacement also needing regular dosage with aspirin to prevent arterial thrombosis. Aspirin, being an anti-platelet drug, causes bleeding (see above). Therefore, sensibly, the surgeons request that patients stop their aspirin one week before the operation. 5. The pharmaceutical companies have conned the hospitals into the idea that their new anti-coagulants do not need to be titrated for each patient - just give them all the same dose (I have gone into the error of this in this chapter). 6.
The main big district general hospitals (DGHs) have run into difficulties owing to the swamping of their accident and emergency departments (A/E) with patients unable to obtain medical care acutely by other services. Therefore many patients who were due for planned joint replacement had their beds cancelled at the last minute.
The health authority where my friend lived had solved problem 6 very sensibly by providing for planned care in a secondary hospital with no A&E commitments. So, my friend and his surgeon could find a date convenient to both of them for him to come into the secondary hospital (the hospital for “elective” treatment) on a booked day, knowing that it would all happen as planned unless my friend suffered some unforeseen misfortune; that did not happen.
The problem for this system is that only the main DGH has the facilities to deal with very ill and complicated patients. So, if such patients require hip replacement, they have to come into the main hospital willy nilly. So, my friend goes to a pre-assessment clinic where they decide that he is fit enough, and can go into the planned care route to the elective hospital. Now we come to my friends story, as he obediently follows that hospital’s “protocol”; that is a routine set of procedures and drug treatments applied to all joint replacement patients. 188
THE STORY According to the protocol, my friend stops his aspirin a week before the day of the operation and stops his ibuprofen and alcohol two days before that day, arrives on the day and undergoes a successful knee replacement operation. In the absence of aspirin and the presence of a tourniquet tightened around the thigh, the surgeon has the best conditions possible from the point of view of operative bleeding, and can do a first class job.
My friend is returned to the ward. The nurses stand him up during the night when he wants to pass urine. Several hours after the operation, one of the modern non-titrated anticoagulants is injected, to be followed by daily tablets for a week. Next morning, and each day following, the physiotherapist arrives and makes him contract his leg muscles, and bend and stretch his operated knee. This causes agony; he just cannot do it. At least he can spend most time during the days in a chair, but has to walk about as well, and walk to the loo. This is managed OK, but the physiotherapy exercises continue to cause agony, and his wound bleeds.
What I think was wrong
The first critical question is, “Why was his ibuprofen stopped?” It was because published studies have shown that bleeding with the anticoagulant they used is made worse by ibuprofen; therefore stop the ibuprofen. “NO”, I SAY, “STOP THE ANTICOAGULANT”. Why?
1. I know from my own, and from many others experience, that movement pain from tissue, inflamed in this case by the trauma of the surgery, is much reduced if one is taking an NSAID. Ibuprofen is much more effective in this circumstance than mere pain killers like paracetamol and codeine, which my friend was given in stead, or even morphine. (He was able to inject himself with this in the immediate post-operative period, and oral morphine was also available after that). 2. The result of the replacement is much improved with successful
physiotherapy, so the physiotherapy should be done under NSAID treatment. 3.
The indication for anti-coagulation, i.e., the reason for using it, is a bed-bound patient in whom stagnation of venous blood can occur. 189
But my friend is not bed-bound; he is being actively mobilised, and he is also moving his feet and legs all the time to keep the venous blood flowing fast, and he is also wearing compression stockings to compress the veins and keep the amount of blood in them minimal. There is no longer an indication for anti-coagulation.
This sort of thing is happening more and more as treatments, that were perfectly effective and logical in past circumstances, are combined into a rigid protocol and routine for all patients, without thought for common sense and the needs of the individual.
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CHAPTER 13
I’m so worried about my blood pressure. Why? My care team are so worried about my blood pressure. Why?
Freda, “Fancy seeing you in here again. Won’t your wife be worried, you chatting me up so often, y’ken?”
Prof, “She likes me to do the booze shopping and she’s always meeting my Scottish country dancing ladies who say they enjoyed a chat with me in the supermarket!”
Freda, “Well you can talk to me about my blood pressure (BP). I’m very worried about my blood pressure, y’ken”.
Prof, “We have, to add to the cholesterol mythical madness, the obsession with
blood pressure (BP) madness. The first question is
191
Is my blood pressure too low?”
Freda, “How would I know”.
" " " " " " " " Prof, “If you are able to ask this question, the answer is, ‘No, you must be conscious to ask such a question, so there is enough perfusion pressure to keep your brain functioning, and that, should, perhaps, be your major consideration’. If you are not conscious, then your care team do need to do something to restore your brain’s perfusion pressure before you lose brain function”.
Freda, “Can you tell me
When to do something about low BP, and when not to”.
Prof, “It all depends on whether the low BP is because flow of blood from the heart is low, (BP = flow times resistance); or whether the BP is low because of a low resistance. The latter, without going into detail is generally due to various types of ‘shock’”.
Freda, “But I’m all right even when I am in shock. You shock me often enough!”
Prof, “Do not worry unless you have symptoms such as faintness. You have the great advantage that your heart is under less strain and stress than average”.
Freda, Is fainting due to low BP?”
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Prof, “Yes, a faint occurs when the vagus nerve goes hyperactive and slows the heart rate right down. The important thing to do then is lie the fainting person flat or preferably head down to get blood back to the brain”.
Freda, “What happens when the heart fails?”
Prof, “As a cardiologist, I am more concerned with situations of acute depression of the heart’s ability to pump, such as acute damage to the heart causing low flow output. Unfortunately, I have sometimes (only sometimes) been involved in disputes with intensive care teams about this problem”.
Freda, “Surely they know what they’re doing, y’ken!”
Prof, “I have come across reactions in intensive care units, in which the obsession with BP results in the staff raising the BP with vasoconstrictor
193
drugs which increase resistance (BP = flow times resistance). This will inevitably increase the load on the damaged heart, and will therefore do the patient a disservice. If the patient is conscious, there is no need for intervention, except when the patient’s kidneys show signs of packing up, in which case one can ease the kidney situation by administering a renal dilator (dopamine), or even by using haemodialysis or haemofiltration to take over kidney function temporarily”. Freda, “Surely you don’t want to wreck a patient’s kidneys!”
Prof, “The fundamental objective in this situation is to lower the load on the heart. There are two ways of doing this. I can use old fashioned conservative care which was the only possibility when I was a young doctor, or I can insert an “aortic balloon pump” into the aorta, synchronised to the electrocardiogram (ECG) so that systolic BP when the heart was pumping was reduced, while the diastolic pressure, which is the perfusion pressure for the heart was increased; and the aortic valve being closed, no load on the heart. Or I can establish bypass of the heart with cardiopulmonary bypass, pumping blood with an external machine from the veins into the arteries in order to rest the heart completely from its normal pumping function”.
Is my BP too high?
Freda, “Golly! But a friend of mine went into hospital for an op and they sent her home because her BP was up. High BP seems to be the biggest problem”
Prof, “Yes. A frequently encountered situation as a very senior physician not expected to be first on call for such emergencies, is to be asked before a surgical operation. ‘This patient has been shown to be hypertensive’, or ‘This patient has a history of heart disease’. ‘Should we proceed?’ These referrals make me annoyed because it is a surgical decision whether the procedure is high priority or not”.
Freda, “You mean if it has to be done, it has to be done whatever!”
Prof, “Exactly. Privately, I think that if the operation is removal of varicose veins, I would not advocate surgery anyway (but that will not bring me favour with the surgical fraternity). On the other hand, if it is an emergency, or a high priority procedure, one must obviously advise a goahead, even though this should be a surgical, and not a medical decision”.
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Freda, “But if you say go ahead when the patients has a dicky heart, you could end up in trouble, y’ken”
Prof, “So, I invariably recommended, in the case of patients with cardiovascular abnormalities of any sort, that the BP, during and after the operation, should be kept as low as possible with an infusion of GTN (glyceryl trinitrate is the substance in angina inhalers that lowers the BP and relieves the heart and the symptoms by reducing the heart load)”.
Freda, “I thought it relaxed the coronaries”
Prof, “So do some doctors, but never mind. As long as the patient remained conscious, the GTN reduced the load on the heart caused by the operational stress”.
Freda, “Is that what they did?”
Prof, “Needless to say, (my medical professorial status none the less), my advice was invariably ignored because it did not conform with recovery ward protocol, of which illogical abomination, more anon”.
Freda, “These considerations do not cover the situation where my GP, on a routine visit says that your BP is low”.
Prof, “In this “chronic” scenario (not urgent), there is probably nothing to be gained by detailed investigation, but these should be embarked upon if there is any worry upon the part of your doctor, about an underlying condition needing specialist consideration, such as glandular insufficiency”.
Freda, “In my case the GP says,
My blood Pressure is too high?”
Prof, “A much more frequently posed question.
You will often be told so, even when it is not! In the UK, people are called in by their doctors to have their BP measured, because the government foolishly pay them extra to do it - to achieve a so-called ‘target’”.
Freda, “That’s because our benevolent government want us all to be healthy, y’ken”.
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Prof, “Politicians always make things worse. It is difficult to conceive of a better way to make normal people think they are hypertensive and start worrying about it!”
Freda, “The practice nurse measured mine using using a cuff and stethoscope”.
Prof, “The cuff should be inflated until the pulse below disappears, then the cuff pressure should be allowed allowed to drop slowly, the systolic BP being the cuff pressure that just obliterates the pulse”.
" Freda, “So you don’t approve using a stethoscope?”
Prof, “Its all there is for the diastolic (between beats) pressure without using an automatic method”.
Freda, “I’ve seen these machines on sale in chemists” Prof, “They are not all reliable. There are all sorts of problems with cuffs; they may be not long enough, they may be too wide or too narrow, the 196
velcro grip may slip, so, the standard cuff does not fit the individual arm. Cuffs are mostly unsatisfactory on short fat arms now that the old fashioned long thin ones have gone out of fashion. For a short fat arm, probably better to use a wrist cuff”.
" " " " " " " " " " " " " " " " " " Freda, “I saw some quite complicated ones in hospital when I visited a friend there”.
Prof, “There are much better techniques than using the stethoscope, such as noting the pressure in the cuff when blood starts to flow into the arm below, using a flowmeter. Another reasonable technique is to note the pressure in the cuff when the pulse below the cuff reappears. All these 197
techniques measure the systolic pressure that occurs when the heart contracts”.
Freda, “The nurse said my diastolic pressure was too high”.
Prof, “The pressure drops to the diastolic (the minimum between heart beats); here one uses the stethoscope to note the cuff pressure at which the sounds disappear. Unfortunately, this method of determining the diastolic pressure is unreliable”.
Freda, “So how can you get a really accurate measurement?”
Prof, “The only completely accurate method is to stick a needle in the artery and connect it to an electronic manometer (pressure recording device), but one is not going to do that routinely!”
Freda, “So I don’t need to worry”. Prof, “I’m not sure because I’m not your doctor and they won’t let me practice any more because they say I’m too old! A quite different problem is the fact that worry puts the blood pressure up. If the first few readings are high, so that hypertension is on the cards, it can stay up, because the fact that the measurement is to be made causes worry”.
Freda, “How do you find out what it is when I’m not worried?”
Prof, “There’s an answer to that because BP also fluctuates greatly during the day and night, being lowest during sleep. Therefore hypertension 198
should not be diagnosed unless the average pressure during 24 hours is raised. This is done by applying an automatic cuff inflating and deflating device and measuring and recording the BP electronically. It happens that when a patient has undergone this procedure, even more than once, with normal results, they still get treated for hypertension at the GP clinic because spot measurements are high!”
" " " " " " " " " " " " " " " " " Freda, “You mean that I should demand one of these average measurements, and if it’s normal, stop going for a nurse measurement”.
Prof, “You got it! The tendency for BP to be higher in clinics than at home has been called “white coat hypertension”. That was when doctors wore 199
white coats with a laundered surface next to the patients. Now they wear their ordinary clothes, the cleanliness of which is unknown!”.
Freda, “These casually dressed doctors nowadays do not command any respect”. Prof, “Quite right. Anyway, the epidemiologists did studies on patients with white coat hypertension and claimed that it resulted in hypertension related clinical problems”.
Freda, “So if I’ve got white coat hypertension, I should be treated?”
Prof, “That result was because the subjects studied contained a subset that developed true hypertension, but that does not justify treating the majority who are normal. I came across an estimate recently that one third of the population of the Unites States of America had hypertension!”
Freda, “What should happen if I have true hypertension?”
Prof, “I had the instruction to assess a foreign country’s project to have a nationwide campaign to greatly improve hypertension by non-drug measures, such as low salt (wrong - see chapter 2), exercise, etc. The external committee, of which I was a member, stopped the project on ethical grounds, because it would involve denying hypertensive patients drug treatment known to be effective. It would also have been wrong to subject people, who might have had normal average BP, to such measures on the basis of high spot measures”.
Freda, “Well you did some good then with your ideas!”
Prof, “The fact that hypertension is over diagnosed, and that normal people get treated for it who should be sent away as normal if the average BP is normal, should not blind one to the fact that true hypertension (diagnosed by high 24 hour average BP) is a serious threat to health that should be treated thoroughly. The most important aspect is to find out if there is a cause such as a structural, kidney or hormonal cause, because if so, that cause should be treated first”.
Freda, “They never did any other investigations after they said my BP was too high”.
Prof, “Not even dipping a diagnostic paper strip into your urine?
" 200
But the tests should be done. Often, all these tests are negative, giving the patient the label, “essential hypertension” - there is nothing essential about it. Some AfroCarribean patients are salt retainers (see Chapter 2) and need diuretic (salt removing) treatment. More common in the developed countries is an excessive action of the renin-angiotensin- aldosterone hormonal system, for which there are effective drugs”. Freda, “I have a friend who says her BP became too high because she was obese.
Prof, “Hypertension is often one of a trio of conditions, together with obesity and diabetes mellitus, which constitute the syndrome called, ‘insulin resistance’ although now the name ‘metabolic syndrome’ is more in fashion”. Freda, “I’m not sure the term metabolic syndrome means anything”.
Prof, “A silly term - every cell in the body has metabolism doing every function. They’re not all affected in insulin resistance. I prefer the concept of insulin resistance because it holds out the hope of diagnosing insulin resistance in people who have not yet developed hypertension, obesity or diabetes”.
201
" " " " " " " " " " " " " " " " " " " Freda, “With a blood glucose test?”
Prof, “More than that. This is done by multiplying the blood glucose concentration by the blood insulin concentration and finding the product raised. When we did this in patients admitted to a coronary care unit in West London who were not diabetic, those with high glucose times insulin had a worse outcome over the following 4 years”.
Freda, “Sounds straight forward”. 202
" " " " " " " " " " " " " " " " " Prof, “Yet I am told that our health authority refuse to do insulin measurements in people suspected of being insulin resistant. I suppose they think it’s too expensive. So much for governments thinking they are helping population health by getting everybody’s BP measured!”
Freda, “Why isn’t this scandal exposed?”
Prof, “Surely you know from the news that scandals are exposed decades after they have occurred. Many of such patients in West London were of Asian ethnic origin, in which population, insulin resistance and coronary disease seems to be more common than in Caucasian subjects. I suggest that such patients need to adopt a diet similar to that for patients with type 2 diabetes. Maybe you’d like me to chat to you about that sometime?”
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Freda, “Yes, you’re getting me interested in these things, and I might pick up hints that would help the kids”.
Prof, “Did your doctor feel your femoral pulse in your groin?”
" Freda, “No, why would he do that?”
Prof, “To compare with the pulse in your right arm. If the femoral pulse is weaker than that in your arm, you could have hypertension due to coarctation, a narrowing of the main artery, the aorta.”
Freda, “Gosh!” Prof, “Did your doctor look into your eyes with an instrument?” Freda, “No, why would he do that?”
204
Prof, “To see the blood vessels at the back of the eye. One can tell from that whether there is established hypertension, and if the discs in the back of the eye are swollen, one should get the patient into hospital for very rapid control of the blood pressure.”
" "
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CHAPTER 14
Stress, fight, flight and fright - and
you can’t beat a beta block!
206
" Prof, “There used to be a need to fight; some people still fight. You have to imagine that you are an evolving hominid. Your food, apart from wild fruit and vegetables depends on you killing another animal (or even a human if your tribe has a cannibal tradition) for food if you do not have access to fish; you are a hunter gatherer”. Student, “A hunter gatherer’s life must have been stressful”.
Prof, “Indeed. It involved fighting animals and other men, and in the case that your opponent is much stronger, fleeing. The reaction of the body to this has been called “fight and flight reaction”. the “defence reaction” and “acute stress”. I call it the fight, flight and fright reaction”.
Student, “A defence centre sounds like something like Faslane” (a nuclear defence station on the Firth of Clyde).
Prof, “The, ‘Defence centre’ in the brain sets off a lot of body changes, of which one is activation of the sympathetic nerve system and another is release of adrenaline into the blood”.
Student, “How can that help defend the person?”
Prof, “The sympathetic nerves act on tissue by releasing nor-adrenaline from the ends of these nerves. Adrenaline and nor-adrenaline increase the heart rate, blood pressure and breathing; these effects increase the capability to extreme exertion”.
Student, “They say that about racing drivers although they’re only sitting in a car.”
Prof, “They have to be very fit and tough. One finds motor racing drivers, athletes and other performers actually appreciating this reaction”.
Student, “It still doesn’t seem worthwhile to have all that stress”.
Prof, “In the fighting situation, you also have the advantage that adrenaline and nor-adrenaline activate platelets in which the pro- thrombotic action is enhanced - useful for the enhanced consequent stopping of bleeding if a wound is sustained in a fight”.
" 207
" Student,“Hopefully, we no longer need to fight (if you are not a soldier) what then?”
Prof, “In modern life, the reaction can be triggered by acute bouts of anger or anxiety; the activation of platelets in these circumstances may account for the apparent correlation of heart attacks due to coronary thrombosis with episodes of acute stress; the activation of platelets leading to a situation in which platelet rich arterial thrombosis is more likely to occur than in restful circumstances”.
Student, “From this point of view, one can regard the fight flight and fright reaction as a disadvantage to most humans in a modern, city based, developed country, a situation far removed from that of the hunter gatherers in the distant past of human evolution”.
Prof, “Fair enough. Nowadays, an excessive reaction of this type is described as a ‘panic attack’ that can sometimes lead to an emergency hospital admission due to muscle spasm. What started as a normal stress 208
reaction itself causes further stress, so the patient enters a ‘viscous circle’ more properly called a positive feedback”.
Student, “Why muscle spasms?”
Prof, “They result from the reduced carbon dioxide (CO2) in the blood consequent upon the over-breathing. This can be relieved by making the patient rebreathe their own expired air so that CO2 re-accumulates”.
Student, “Reduced CO2 also makes the blood alkaline which constricts the coronary arteries - bad news if the patient also has coronary disease”.
Prof, “Well done; perhaps I can persuade you to take up physiology?”
Student, “No way; I want to treat patients”.
Prof, “The study of long continued (chronic) or frequent intermittent stress is difficult and cannot lead to convincing evidence of its role in cardiovascular dysfunction, simply because chronic stress cannot be accurately measured, particularly as modern society stress often has a putative psychological cause”.
Student, “I suppose you don’t think psychology is a proper science?”
Prof, “Hard to get hard data is how I describe it”’
Student, “But you’re still trying to talk about stress, which is psychology”
Prof, “It’s difficult to measure but how much doubt do you have that chronic disease itself is associated with chronic stress?”.
Student, “Not much”
Prof, “You only have to sit in a clinic and hear a patient telling you how worried they are. But we do have more data on the most common disease to do this in my field - heart failure”.
Student, “What’s the evidence?”
Prof, “Hormonal abnormalities. It is noteworthy that treatment of heart failure has been greatly improved since doctors began treating the associated chronic stress as well as the heart problem itself. Another point that is compatible with the idea of chronic stress as a cause of bodily 209
dysfunction is that treatment of the hormonal imbalance also prolongs life”.
Student, “So there is
The need to treat chronic stress?”
" Prof, “The first target of such treatment is to try and block out the effects of excessive adrenaline and sympathetic nerve activation”.
Student, “Like beater-blockers?”
Prof, “Yes. Beta, not beater! Many years ago, snooker players were banned from taking ‘beta blockers’ to eliminate the tremor of acute stress”.
Student, “What really is a beta (ß) blocker?”
Prof, “It is a ß-adrenergic receptor antagonist. There are two different types of reaction of cells to the exposure of cell surface receptors to adrenaline, arbitrarily called alpha and beta (it is actually more complicated than that)”. Student, “I found the pharmacology course on this very confusing”.
Prof, “Quite. Drug development results in artificial chemicals that can either stimulate or block these effects differentially. Alpha-1 blockers 210
prevent the effect of adrenaline and nor-adrenaline (catecholamines) on peripheral resistance, namely oppose constriction of resistance vessels in response to catecholamines”. Student, “Do they block platelet thrombosis?”
Prof, “No, alpha-2 blockers prevent the effect of catecholamines on platelets”.
Student, “But this is not going to treat the anxiety”.
Prof, “No. Beta-1 blockers prevent the effect of catecholamines on heart rate and contractility. Beta-2 blockers prevent the effect of catecholamines on relaxation of resistance vessels that are alpha blocked and relaxation of the airways”.
Student, “So you use these in heart failure?” Prof, “Yes”.
Student, “Why are they used in hypertension even in the absence of stress?”
Prof, “Of these, only beta-1 (e.g., bisoprolol) and alpha-1 (e.g., doxazocin) are commonly used clinically. Alpha-1 blockade is used for some hypertensive patients in whom adrenergically (adrenaline, and noradrenaline from the sympathetic nerves) mediated peripheral vasoconstriction is suspected to be a contribution to the high BP. 211
Surprisingly ß-blockers have been used much more extensively in hypertension, despite the apparent illogicality of such an approach as considered from a knowledge of the basic effects of adrenaline and noradrenaline and their antagonists”.
Student, “Maybe empiricism is more useful for practical medicine than all your theoretical stuff”.
Prof, “I prefer to try and understand the fundamentals underlying a treatment. Beta-2 blockade is undesirable as it can lead to constriction of the airways, particularly in patients with asthma. Beta-1 blockers have beneficial effects in slowing too fast a heart rate and higher than necessary strength of heart contraction in a weakened heart”.
Student, “Surely clinical trials are more important than theory?”
Prof, “Clinical trials showed that patients who suffered from angina benefited from beta-1 blockade in that they could walk much further before chest pain set in, presumably by increasing the length of time before reaching a critical heart rate and myocardial oxygen consumption”.
Student, “I suppose they might protect the heart attack heart?”
Prof, “Yes, beta-1 blockade was then tried out in patients who had suffered a myocardial infarction; this treatment was found to improve subsequent outcome. However, the state of the heart when first applying the treatment may be a contraindication, namely in the presence of acute heart failure as a result of the myocardial infarction, with a chest radiograph looking something like -”.
212
Student, “You mean a failing heart cannot stand having the effect of adrenaline blocked?”
Prof, “An acutely failing heart, yes. For some time after that we taught that beta blockers should not be given to patients with heart failure. Most of the trials of treatment for heart failure were using heart stimulants. It turned out that recovery from an acute situation was improved by such drugs, but that when applied to patients with chronic heart failure, subsequent mortality increased!” Student, “I would have thought that stimulating a failing heart would be a good thing”.
Prof, “You’d think so but we use
Beta blockade in heart failure
Many years ago I was looking after a patient with chronic heart failure whose clinical condition remained fragile after we had removed excess fluid from the body. An outstanding characteristic of this patient’s condition was the excessively fast heart rate. It seemed to me that the 213
reduced total diastolic time, during which coronary blood flow to the heart muscle is possible, might be critically insufficient. At that time, the only drugs available for slowing heart rate were the beta blockers. So I tried this patient out on a beta blocker - a highly heretical thing to do in those days. Slowly the heart rate did slow and the heart failure improved, as evidenced by reduced heart size on the chest radiograph. My interpretation of this is that the chronic heart failure had caused a chronic stress reaction leading to excessive catecholamine release and beta-1 induced high heart rate; this was reversed by the drug”.
" Prof, “The chest radiograph in chronic heart failure like her’s shows the heart size increased but less water in the lungs than is the case with acute heart failure as seen in the previous picture.
Student, “If the standard precept of, ‘do not give beta block to heart failure’ was really true, you might have killed her!”
Prof, “I know, but sometimes you have to take risks to find better ways of treating patients”.
Student, “And then get sued!?”
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Prof, “Yes, it did not happen on this occasion because the patient felt well enough to leave hospital and she did live longer than was predicted. Some time later, clinical trials of heart failure showed that life was prolonged by beta blocker treatment. This signalled a change in the philosophy of chronic heart failure treatment. No longer did we try to stimulate the heart; in stead we tried to block the other hormonal effects of chronic stress; ACE inhibitors to block the high renin and angiotensin levels, spironolactone to block the high aldosterone levels”.
Student, “And beta blockade?” Prof, “Yes, although now there are drugs that slow the heart without blocking adrenaline, if that is desired, say, in an asthmatic patient intolerant of beta blockers”. Student, “Does a stressful life give me heart disease?” Prof, “We do not know; this is not a question that can be tackled in a scientific manner. How does one define a stressful life anyway? A hectic professional life, or just a hard working life can be regarded by those who pursue them as stressful, but such people are usually in the top socioeconomic part of modern society with the lowest incidence of heart disease, whereas heart disease is most common in the lowest socioeconomic class - unskilled workers and unemployed. It is up to everyone to speculate on what all this could mean”.
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CHAPTER 15
What diet should I eat if I am
obese or diabetic? What diet
should I eat if I’m normal?
" Prof, “Obese and diabetic people develop more coronary disease than normals”.
Woman, “Why am I obese and thus risk becoming diabetic?”
Obesity
Prof, “Obesity occurs after a time in which the calorie (energy) intake in the diet exceeds the calorie (energy) output of the body as achieved by exercise and the generation of body heat. The answer to the question above is, ‘If you cannot increase your calorie output, you must eat fewer calories - that essentially means, eat less’”.
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Woman, “But I do my work and don’t eat that much. I have a friend who is very slim and eats much more than I do!” Prof, “Bad luck, but you would survive a food shortage better than she!” Woman, “But this is Europe, not Africa”. Prof, “Better to be fat in Europe than starving in Africa”. Woman, “So what do I do?”
Prof, “Unfortunately, obesity occurs commonly in people with insulin resistance, although they may by no means be considered gluttonous; other people on an identical diet may never become obese (lucky blighters!)”.
Woman, “So am I one of these insulin resistance people?”
Prof, “You need to get someone to measure your fasting insulin and glucose levels before I can tell you that, and I might also have to do a glucose tolerance test”.
Woman, “If I am, is it inherited?”.
Prof, “One wonders whether the genetic nature of people with insulin resistance has evolved over the centuries in response to frequent famine conditions, in which eating less than normal will not reduce such folk to death by starvation nearly as quickly as normals”.
Woman, “What can I do about it?”
Prof, “If you are an insulin resistant obese person, you must, in addition to reducing calorie intake mainly reduce sugar and carbohydrate intake. Such action is incompatible with eating so-called ‘healthy (low fat) food’, because such foods are often stuffed full of sugar and carbohydrate”.
Woman, “I know I should not eat sugary things like sweets, as I picked up from the Daily Telegraph”.
Prof, “Yes, but the carbohydrate in bread, chips, potatoes and so on break down to sugars in your gut, so it’s not just a question of avoiding sugar, it’s a question of avoiding too much total carbohydrate plus sugar. Woman, “Food labels should help with that”.
217
Prof, “A pernicious habit has grown up to label foods with ‘so much’ carbohydrate of which 5 (or so) % is sugar. This is done presumably to deceive the housewife into thinking that carbohydrate is not relevant. However, carbohydrates are broken down into sugars in the gut. So it is the total carbohydrate as well as sugar that must be reduced”.
" Woman, “So - I must not eat food with a high total carbohydrate content”.
Prof, “You got it - it is a misconception to think that if you are fat, you should not eat fat; most obese people have ingested an excess of carbohydrate, which the body has converted to fat and stored”. Woman, “Will I lose weight on this low carbohydrate diet?”
Prof, “Only if the total calorie intake is less than the energy you burn up during exercise including your normal activities”.
Woman, “I thought the trouble with fast food was the fat”.
218
Prof, “No, mainly the carbohydrate. The present generation seems to be addicted to ‘fast food’. The problem with burgers is not fat in the meat (there isn’t much fat in it), it is the bun and the chips. Pizzas are mainly bread with other little bits added. One must reduce or avoid potatoes, chips, bread, cakes, puddings, sugary drinks. Even root vegetable, peas and beans, and fruit should not be eaten excessively by insulin resistant persons”.
"
Low fat yoghurt usually has more sugar and carbohydrate than full fat yoghurt. 219
Woman, “So I can have my meat and veg?”
Prof, “By reducing carbohydrate, it is less necessary to reduce the amount of fresh meat, fish, free range eggs, dairy produce, and one can almost allow any amount of green leaves. Such diet has the advantage of satisfying appetite more effectively than high carbohydrate foods”.
" " " " " " " " " " " " " " " " Woman, “What about my infant son?”
Prof, “Nature provided babies with the perfect food high fat milk. Babies should be weaned on the mashed up mixture of fresh meat, fish, free range eggs, and dairy produce, and not be given sweet drinks (or food containing wheat to which they may become allergic and develop gluten intolerance the best cereal is oats)”. Breast Milk is Good High Fat Food
220
Woman, “But my friends give those drinks to their kids to avoid them having the fat in milk”.
Prof, “I would be afraid that that might retard the development of their brains!”
Woman, “Are you sure?”
Low fat implies high carbohydrate
Prof, “No, but I do not like the risk. Full fat milk is the food designed by nature for babies”.
Woman, “If I’m going to become diabetic, you’d better tell me more about it”.
" " 221
Diabetes mellitus
Prof, “Diabetes means excessive production of urine, but this can result from a hormonal insufficiency when there is no sugar in the urine (diabetes insipidus - insipid polyuria).
Woman, “Sometimes I think it is called ‘sugar diabetes’”
Prof, “Yes discovered when doctors tasted the urine and found it was sweet”.
" " " " " " " " " " " " " " " " " " " " Woman, “Disgusting!”
222
Prof, “We call it diabetes mellitus meaning sweet diabetes because there is glucose in the urine. There are two types of diabetes mellitus, namely type 1 and type 2. It is recommended that one think of these as two different diseases. Type 1 is due to insufficient production of insulin by the pancreatic gland, perhaps following an inflammatory disease of the pancreas (the internal organ that manufactures insulin, the controlling hormone for blood sugar). Type 2 diabetes is an exaggeration of insulin resistance to the extent that the pancreas becomes overloaded”.
" "
Woman, “How did they discover this pancreas thing?”
Prof, “Removed the pancreas from dogs and they got type 1 diabetes.”
223
Woman, “That’s terrible, I disapprove of experimenting on animals - its too cruel”.
Prof, “If that had not been done, all type 1 diabetics would die, as used to be the case before we produced insulin from pigs’ pancreases to treat type 1 diabetes. The animals are treated humanely.”
Woman, “I wouldn’t like to have pigs’ insulin”.
Prof, “You won’t have to; we now have human insulin produced by bacteria - a wonder of modern medicine. I suppose you don’t think that is cruelty to bacteria?”
Woman, “All right. So, if I become diabetic it will be the type 2 type?” Prof, “You got it! Much more likely than you developing type 1.” Woman, “Should I go to a dietician?” Prof, “That’s a bit of a lottery. It is of much annoyance to me that many dieticians and nurses give the same advice to patients with the two types of diabetes”.
Woman, “Why?”
Prof, “The advice is that, as vascular disease is the main cause of poor health in diabetes, and the false theory still holds sway that such disease is caused by cholesterol, plus the false theory that cholesterol has to be lowered by eating low fat diets, both types of diabetic are being disasterously advised by some ‘experts’ to reduce fat intake! Then their carbohydrate intake is too high and they have to take more drugs to control their blood sugar”
Woman, “But surely it’s cholesterol that attacks the arteries, not sugar?’
Prof, “Glucose definitely attacks arteries, and fructose (the other half of table sugar) causes high blood pressure. Only some fats attack arteries”.
Woman, “At any rate, I’m glad I’m not heading for
Type 1 diabetes
Prof, “Not unless you are unfortunate enough to contract pancreatitis - let’s hope you don’t! The insufficiency of insulin production in such patients is made up by injections of insulin”.
224
Woman, “Do they have to have your low carbohydrate diet?”
Prof, “Not necessarily. The key to successful diet is that there must be average intake of carbohydrate that matches the average amount of injected insulin, and both have to be matched to the calorie output of the patient. If any of these factors which determine the blood glucose is changed, the patient will either develop too high a blood glucose in one direction, or too low (can cause loss of consciousness) in the other direction”. Woman, “How can the poor patients tell whether they are in this balance of yours?”
Prof, “Blood glucose needs to be measured frequently to guide the treatment. From this. it should be clear that there can be no general recommendation about diet - it has to be titrated to each individual patient”. Woman, “But you still think your low carbohydrate diet should be a ‘general
225
recommendation’ for Type 2 diabetes?” Prof, “This is the diabetes that is one of the triad of conditions that define insulin resistance or ‘metabolic syndrome’. The dietary advice is therefore the same as I gave you for non-obese insulin resistant subjects only more so. Every effort should be made to control blood glucose by limiting carbohydrate ingestion so that as little as possible drug treatment for high blood glucose concentration is required, usually metformin”. Woman, “My neighbour says she eats her cakes and just takes more metformin to compensate”
Prof, “Reasonable if you are elderly and just want to enjoy the rest of your life, but not if you are younger and have family responsibilities”. Woman, “Why is low blood glucose so important?”
Prof, “I think it is because of reduced arterial endothelial nitric oxide production when the blood glucose concentration is high, but that is a theory that may eventually be proved false. Woman, “You mentioned a “Fructose problem”
" " " " " " " " " " " " 226
" Prof, “It has now been shown that high blood fructose concentration dilates arteries, so that the shear stress levels are reduced, and low shear stress predisposes to atherothrombosis. In addition, high blood fructose constricts resistance vessels, causing high blood pressure, and compounding the pro-disease influence of fructose. So continuing with high blood fructose concentration can be contributing to the acceleration of this disease”.
Woman, “Where is the fructose in food?”
Prof, “Ordinary sugar is sucrose which is a combination of a glucose molecule with fructose molecule. High fructose levels have been found in diabetic patients and is an additional cause for concern. Indeed nondiabetic but carbohydrate sensitive subjects show high fructose as well as glucose levels following eating sucrose. Even more worrying is the widespread use of high fructose corn syrup in many manufactured foods and free fructose sweetener. It is a great mistake to imagine that, because high fructose concentration does not affect arterial endothelial nitric oxide production, it is OK to eat a lot of it”.
Woman, “You mean all those cereals made from maize?”
Prof, “That’s right, and the syrup from maize. The high fructose levels that have been found in diabetic patients indicates that these patients continue to ingest more sucrose, high fructose corn syrup and free fructose sweetener than is appropriate in this condition. In the USA, the ingestion of high fructose corn syrup associated with a decrease in sucrose ingestion produced speculation that the effects of free fructose and fructose derived from sucrose might be different. However, there is no evidence for this in experiments designed to elucidate such a difference. A wide range of adverse metabolic effects of hyperfructosaemia (high fructose levels in the blood) have been described in humans associated with the obesity epidemic”.
Woman, “You worry me so much; I wish I had not got you on to all this gloom. What sort of effects?”.
Prof, “They include disordered fat distribution, fat deposition in the liver and skeletal muscle, impaired glucose control and insulin resistance, altered uric acid and mineral metabolism, and hypertension”.
227
Woman, “Heavens!”
Prof, “The administration of fructose to animals and humans increases blood pressure and the development of metabolic syndrome, so it looks as if high fructose ingestion may be causing insulin resistance (metabolic syndrome). These changes occur independently of caloric intake because of the effect of fructose on cell energy depletion and uric acid generation. Fructose ingestion may also be a risk factor for kidney disease that includes glomerular hypertension, renal inflammation, and tubulointerstitial injury in animals. It has been suggested by an expert in this field that excessive fructose intake should be considered an environmental toxin with major health implications. The highly palatable foods of high-energy content and large amounts of high- fructose sweeteners are thought by other authorities to contribute to the obesity epidemic and insulin resistance”.
Woman, “Stop, stop, this is terrible”.
Prof, “Don’t worry too much - it’s all theory and may be wrong. We doctors worry about it because an experimental high-fructose diet given to humans has been shown to significantly increased fasting blood glucose concentration, so it looks as if high fructose ingestion may be causing diabetes mellitus”.
Woman,
“My husband has a sweet tooth and you are
telling me that I cannot have sugar.
How on earth can I satisfy my husband’s sweet tooth if sugar is so bad; he hates saccharine”.
Prof, “My wife sweetens deserts with sucralose, and a lot of restaurants now provide this as a non-sugar sweetener in yellow packets. I cannot tell the difference in taste from sugar, so maybe your husband will find the same. The main drawback is that if you try and make jam with it, it wont set (Common brand names of sucralose based sweeteners are Splenda, Sukrana, SucraPlus, Candys, Cukren and Nevella)”. The recent scare caused by feeding sucralose to rats is based on unsound evidence which should not apply to the sweetening of food. 228
"
" Woman, “How do you know it’s safer than sugar?”
Prof, “I don’t. One has to wait and see whether any problems emerge in the future. The recent scare caused by feeding sucralose to rats is based on unsound evidence which should not apply to the sweetening of food”.
Woman, “At least, if I continue using sugar, I’m using something natural”.
Prof, “No you’re not. Sugar is a refined product, a processed food, and not a real natural food like milk, meat, fish, fruit and vegetables”.
Woman, “But some canned food is very convenient”. Prof,
“Always look at the label
229
That would be the advice if only food labelling was honest! One wants to know whether sucrose, fructose or corn syrup have been used in the manufacture of the foodstuff, and those foods could then be avoided much more important than avoiding contaminating horse meat in processed foods, which is harmless (the horse meat, not the processing!). Perhaps the simplest way is to avoid manufactured food and stick to fresh natural food?”
" " " " " " " " " " " " " " " " " "
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CHAPTER 16
You are not joking Mr Feynman: Where medicine went wrong
" Prof, “Richard Feynman was a nuclear physisist who worked on the atomic bomb in America at the end of the second world war, who subsequently won the Nobel Prize for work on quantum physics. In the book, ‘Surely you’re joking Mr Feynman’, he attacks bad science. Some of his comments are worth quoting verbatim, because they apply equally well to some of the bad science and bad medicine that I have discussed. An example is ‘even today I meet lots of people who sooner or later get me into a conversation about UFOs, or astrology, or some form of mysticism, expanded consciousness, new types of awareness, ESP, and so forth. And I’ve concluded that it’s not a scientific world’”.
Student, “I think I see what he means”.
231
Prof, “Here’s another quote, ‘One time I sat down in a natural hot spring bath where there was a beautiful girl sitting with a guy who didn’t seem to know her.
" Right away I began thinking, ‘Gee! How am 1 gonna get started talking to this beautiful nude babe?’ I’m trying to figure out what to say, when the guy says to her, ‘I’m, uh, studying massage. Could I practice on you?’ ‘Sure,’ she says. They get out of the bath and she lies down on a massage table nearby. I think to myself, ‘What a nifty line! I can never think of anything like that!’ He starts to rub her big toe. ‘I think I feel it,’ he says. ‘I feel a kind of dent - is that the pituitary?’ I blurt out,‘You’re a helluva long way from the pituitary, man!’ They looked at me, horrified - I had blown my cover - and said,‘It’s reflexology!’ I quickly closed my eyes and appeared to be meditating’. Then Feynman began to think, what other nonsense is there that people believe”
Student, “I don’t think the girl is that beautiful”. 232
Prof, “Compared with yourself you mean!” Student, “Be careful”.
Prof, “Prof Ioannides and his team at Stanford University examined 49 of the most highly regarded medical findings in the last decade or so and found that between a third and a half of them were wrong or highly exaggerated”. Student, “If I can’t trust the published medical literature, how can I get things right?”
" " " " " " " " " " " " " " " " " " " " 233
Prof, “Check whether the main author is plugging his pet theory too much.”
Student, “Like you and you jelly theory”. Prof. “It’s not MY theory, and I said it could be disproved. Conan Doyle, the inventor of Sherlock Holmes, the famous fictional detective, says, about forensic science, something very similar to Feynman, ‘It is a capital mistake if one insensibly begins to twist facts to suit a theory.’” Student, “What can I teach students when I become more senior?”
Prof, “Always point out the uncertainties”. Feynman has some damning comments on ideas of education, which also apply to current medical education. He complains about how what’s taught keeps changing and asks,‘How do they know that their method should work?’”
Student, “How do you think we medical students should be taught?”
Prof, “I think that medical students need to be taught basic mammalian science and research methods, and then be attached as apprentices to masters of their specialty, who can show them how to approach each patient as an individual, with a unique medical problem or combination of problems, and to treat each patient as a research project, working things out from the first principles, in which they should have previously been immersed. That does not happen nowadays - it is fashionable to plunge students straight away into dealing with patients, with diagnosis and treatment reduced to applying labels for which there are ‘protocols’. This is bad medicine; protocols are all based on the average patient, not the individual”.
Student, “What else did Feynman have to say?”
Prof, “He says, ‘I think ordinary people with common sense ideas are intimidated by pseudoscience. A teacher who has some good idea of how to teach her children to read is forced by the school system to do it some other way - or is even fooled by the school system into thinking that her method is not necessarily a good one. Or a parent of bad boys, after disciplining them in one way or another, feels guilty for the rest of her life because she didn’t do ‘the right thing,’ according to the experts”.
Student, “There certainly was a discipline problem in the school I went to!” 234
Prof, “Yes, it’s very common. Fortunately, you must have been sensible enough not to let it deflect you from your studies”.
Student, “Going back to bad science, of which bad medicine, in your view, is an example, does Feynman say anything about that?”. Prof, “He says, ‘So we really ought to look into theories that don’t work, and science that isn’t science. For example, if you’re doing an experiment, you should report everything that you think might make it invalid - not only what you think is right about it: other causes that could possibly explain your results’; and, ‘The idea is to try to give all of the information to help others to judge the value of your contribution; not just the information that leads to judgment in one particular direction or another’.
He goes on to describe publications that ignore evidence that the authors are studying an artifact”.
" " 235
Scientific Integrity
Feynman says, “The first principle is that you must not fool yourself - and you are the easiest person to fool. So you have to be very careful about that. After you’ve not fooled yourself, it’s easy not to fool other scientists. You just have to be honest in a conventional way after that. We’ve learned from experience that the truth will out. Other experimenters will repeat your experiment and find out whether you were wrong or right. Nature’s phenomena will agree or they’ll disagree with your theory. And, although you may gain some temporary fame and excitement, you will not gain a good reputation as a scientist if you haven’t tried to be very careful in this kind of work. And it’s this type of integrity, this kind of care not to fool yourself, that is missing to a large extent in much of research”.
" " " " " " " " " " " " " " " " 236
Student, “Does Feynman have anything to say about lay people trying to understand medicine?”
Prof, “Feynman insists that one should not fool the layman when talking as a scientist. ‘I am not trying to tell you what to do about cheating on your wife, or fooling your girlfriend, or something like that, when you’re not trying to be a scientist, but just trying to be an ordinary human being. We’ll leave those problems up to you and your rabbi. I’m talking about a specific, extra type of integrity, that is bending over backwards to show how you’re maybe wrong, that you ought to have when acting as a scientist. And this is our responsibility as scientists, certainly to other scientists, and I think to laymen. One example of the principle is this: If you’ve made up your mind to test a theory, or you want to explain some idea, you should always decide to publish it whichever way it comes out. If we only publish results of a certain kind, we can make the argument look good. We must publish both kinds of results’”.
Student, “Does he have anything to say about targets?”
Prof, “He also criticises certain types of government advice. Who advised the government to subsidise the current excessive search for hypertension? So that the voters think the government is looking after them? Who endorses such a policy? Drug companies producing anti- hypertensive drugs? Or doctors who get paid extra for reaching ‘targets’ in hypertension set by government. The same applies to the policy about cholesterol control. And who do the governments consult? Very likely a so-called ‘expert’ who has pontificated about how these controls would improve health; then a grateful government can say the same and the voters are conned. Feynmen says, ‘You’re being used. If your answer happens to come out in the direction the government or the politicians like, they can use it as an argument in their favour; if it comes out the other way, they don’t publish it at all. That’s not giving scientific advice’”.
Student, “I came across a book called Where medicine went wrong
How can you teach medicine if it is wrong?”
Prof, “This is the title of a book by Bruce West that explores how the idea of an average value has been misapplied to medical phenomena, distorted understanding and led to flawed medical decisions. 237
West points out that the capricious nature of physiological systems is commonly made conceptually manageable by smoothing over fluctuations and thinking in terms of averages, whereas, actually, it is variations in such aspects as heart rate, breathing and walking that are much more susceptible to the early influence of disease than are averages”. Student, “Is he talking about variations between individuals or about variations with time - like diurnal rhythms?”
Prof, “Both. West maintains that through new insights into the science of complexity, traditional physiology should be replaced with fractal physiology, in which variability is more indicative of health than is an average. It may be useful to quote from the late Stephen Jay Gould’s book Full House on the errant nature of averages, ‘our culture encodes a strong bias either to neglect or ignore variation. We tend to focus instead on measures of central tendency, and as a result we make some terrible mistakes, often with considerable practical import?’”
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I have presented, in the present book, some glaring examples of this kind of bad medicine, e.g., the fallacious conclusion that all hypertension is caused by salt ingestion (Chapter 2) so that every normal person is urged to eat a low salt diet, the fallacious conclusion that all arterial disease is caused by cholesterol (Chapter 10) so that every normal person is urged to eat a low fat diet, or even take cholesterol lowering drugs with side effects. In both cases, the average of measurements in large populations was influenced by the presence in those populations of small subsets of subjects in whom there was an influence of salt on blood pressure, or a particular lipoprotein on arterial disease. I point out that, in those analyses, there was much more variability not due to salt and cholesterol than to those variables, so that the greater salt/ cholesterol, non dependent variability, is what should have been applied to normal people. By applying the average to everybody, in stead of only to the affected subset of subjects, we have made, according to West, “terrible mistakes with considerable practical import” and, “distorted understanding leading to flawed medical decisions”
Where the NHS went wrong
When I first qualified (1960) and started working in hospitals, the NHS was a relatively young institution, and it was immediately obvious to me that it was a marvellous concept. One did not have to consider whether the patients could afford fees, because I worked for a straight salary. That also meant that I was never tempted to offer unnecessary tests or treatments. All of this led to a moral attitude that I might not have had had I been working as a private physician.
The hospital’s decision making was achieved by a committee of the consultant physicians and surgeons. The hospital secretary was in attendance and his job was to enable the decisions of the doctors to be carried out. All this was spoilt because of interference from politicians. Successive governments of all political colour tried to win votes by improving the NHS. This led to regular changes in the organisation, good hospitals being closed, the transfer of authority from doctors to chief executives, the introduction of purchasers and providers, the patient’s charter, targets, waiting list management, bed management, etc, all run and documented by managers and who can blame them if they cooked the data to look favourable to them. After all. they are not trained scientists following the example of Feynman. To implement each change required the employment of lay managers, each manager required a PA, each PA 239
demanded a secretary, i.e., gross Parkinson’s Lawism. Each change in the system and each proliferation of managers caused a downturn in the morale of the front line workers (doctors, nurses, paramedics etc). This huge unnecessary expenditure took place in an era of increasingly powerful investigative tools (CAT scanning, nuclear medicine, MRI, endoscopy, etc) further escalating the cost of the NHS and leading to furtive “rationing”.
We should restore the NHS to the way it was run in 1960 and spend much more money on good medicine and much less on management. You will say I’m an old fogey. True, but I think I have quite a lot of reasons to be a GRUMPY OLD MAN.
Conclusion on medical science
I can do no better than to quote Feynman again, this time his advice to research workers, “So I have just one wish for you - the good luck to be somewhere where you are free to maintain the kind of integrity I have described, and where you do not feel forced by a need to maintain your position in the organization, or financial support, or so on, to lose your integrity. May you have that freedom”.
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Westerhof N, Stergiopulos N, Noble MIM (2011). Snapshots of Hemodynamics. Second Edition Springer Dordrecht
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