Departments of 1Clinical Pharmacology and 2Cardiology, Ninewells Hospital and Medical School,. University of Dundee, Dundee DD1 9SY, UK. Keywords: ...
Journal of Human Hypertension (1998) 12, 3–5 1998 Stockton Press. All rights reserved 0950-9240/98 $12.00
COMMENTARY
Abnormal heart rate variability and/or late potentials in hypertensive left ventricular hypertrophy: are they chickens, eggs or an omelette? RJ MacFadyen1,2 and SD Pringle2 Departments of 1Clinical Pharmacology and 2Cardiology, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, UK
Keywords: surrogate endpoints; autonomic tone; heart rate variability; signal averaged electrocardiography; hypertensive heart disease; pathophysiological mediators; type II error
Background Surrogate markers are common in cardiology and represent a measurement which has a direct or indirect relationship to patient outcomes. Their individual clinical usefulness depends on statistical sensitivity, specificity, reproducibility and importantly a demonstrable pathophysiological relationship to cardiac events.1 Surrogate measurements are increasingly used as alternatives to measuring clinical outcome most notably when trying to identify potentially modifiable risk factors for cardiovascular events. In hypertension these have the advantage of short term, often point, measurement and a potential saving of countless patient years of observation waiting for the occurrence of definitive events such as death, myocardial infarction or stroke. However, the value of any surrogate marker is only as good as its accuracy, clinical relevance and direct applicability to the end-point in question. In this regard blood pressure and left ventricular hypertrophy (LVH) are widely accepted as excellent surrogate markers of cardiovascular risk.2,3 Hypertensive patients are classically regarded as asymptomatic individuals awaiting the onset of an excess of atherosclerotic vascular events such as stroke; myocardial infarction; arrhythmia or peripheral vascular disease. The likelihood of these events is indicated by poor blood pressure control and attenuated to a greater or lesser extent by successful blood pressure lowering therapy. Echocardiographic ventricular hypertrophy is established to be a major multiplicative risk factor within the hypertensive population for obstructive coronary disease; ventricular
Correspondence: Robert J MacFadyen, University of Dundee, Ninewells Hospital, Dundee DD1 9SY, UK Received and accepted 9 September 1997
arrhythmia and sudden death and is independent of current blood pressure. Within clinical cardiac research there has been considerable interest in the use of several electrocardiographic surrogate markers to stratify future events in a variety of patient groups. Several of these have been applied to asymptomatic patients with hypertension and this issue of the Journal of Human Hypertension contains another example looking at hypertensive ventricular hypertrophy. Interpretation of this type of study is complex as widely varying results have already been documented. At the heart of this lies confusion over the sensitivity, specificity and physiological interpretation of different electrocardiographic surrogate markers and patient factors which influence their documented values. Heart rate variability There has been great clinical interest and applied research in recent years on the variability of the beat-to-beat RR interval as an index of autonomic tone in intact man. While there is good agreement about the reflection of parasympathetic tone4 in this parameter the ability to map the sympathetic nervous system or sympathovagal balance in this way is more controversial.5 A variety of mathematical expressions have been used to refine the impact of the autonomic nervous system on this time interval. The basic division of time domain or frequency domain analysis appears to make little qualitative difference to an analysis although the quantitative picture may alter.6 Exactly what HRV represents in physiological terms is the matter of debate. Few would suggest it has no relationship to autonomic tone yet it is clear that the respiratory cycle; pathophysiology and many
Heart rate variability and/or late potentials in hypertensive LVH RJ MacFadyen and SD Pringle
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cardiovascular drug treatments have powerful effects on its interpretation.7 The literature abounds with studies examining the impact of risk factors on HRV in many previous studies.8 Signal averaged ECG There are strong similarities between the research application of HRV with studies of the utility of the signal averaged electrocardiogram. Signal averaging is a simple yet impressive technique widely studied in the 1980s. It is based on amplification and averaging of repetitive normal ventricular complexes to identify alterations in depolarisation and repolarisation like HRV using a time and/or frequency domain analysis. Consensus has recognised the utility of such measurements in the prediction of arrhythmogenic substrate in patients after myocardial infarction in particular, although a host of other patient groups have been examined.9 There is no agreement that SAECG has any role in the assessment of patients with hypertension either with or without LVH prior to index cardiac infarction. As with HRV there are many studies on the impact of drug therapy on this parameter although with this technology most concentrate specifically on the effects of anti-arrhythmic drug treatment.10 Surrogate markers as chickens or eggs? With many surrogate markers in cardiovascular medicine major difficulties arise where investigators legitimately imply pathophysiological significance to the statistical correlation derived in their studies. This is not at all unreasonable. For example with respect to HRV analysis its suggested correlation to the activity of the autonomic nervous system makes a link to a critically important control system in physiology and pathophysiology. With respect to SAECG late potentials then an abnormal myocardial substrate after infarction is a logical and basic element in the development of arrhythmia. Yet the many caveats in interpretation can generate a less than convincing picture across the range of published studies. Importantly in this type of extrapolation we should not forget those observations which go unpublished for reasons of ‘non-conformity’ or otherwise. In hypertensive patients the sympathetic nervous system is the subject of vast amounts of both cellular, animal and clinical research.11 Despite this the precise role of the overall autonomic nervous system in the initiation or amplification of hypertension in individual patients remains remarkably obscure. Whether hypertensive ventricular hypertrophy drives, or is a response to arterial hypertension remains obscure.12 Within this it is a very legitimate area for study to examine surrogate markers for their role in the genesis of the various patterns of ventricular hypertrophy in hypertensive patients prior to the emergence of symptomatic coronary disease or infarction. The key question is, what can we expect of HRV and/or SAECG technology to add either to the pathophysiology of hypertensive LVH
or the prognostic assessment of individual patients with this complication of arterial hypertension? In this issue of the Journal Franchi and colleagues compare a relatively small group of essential hypertensive patients in sinus rhythm to a group of normals. They highlight the need for further research in this important area and yet also illustrate the dangers of this form of linked observational analysis. The pathophysiological mechanisms responsible for ECG findings and interrelationships need to be further investigated. What is the way forward? This is a difficult time in clinically-based research where technological development is proceeding dramatically and to a degree in an uncontrolled manner. The danger of proceeding without reference to clinical practice or physiological mechanisms using technically well characterised yet physiologically obscure observations should be obvious. Practising physicians and cardiologists largely appreciate the qualitative risk of LVH and many appreciate its quantitative population risk too. Further qualitative work on this relationship is largely redundant and examination of the associations between secondary markers are unrewarding to elucidate either mechanisms or predict outcomes. Importantly patients must be studied in the absence of prior drug therapy to obtain meaningful physiological relationships, and the lack of sensitivity of uncontrolled or unmatched observations must be rigorously avoided. There are many parallels in the clinical research of surrogate electrocardiographic parameters in hypertensive patients with the failures of uncontrolled drug studies or experimental animal work to have a meaningful impact on the management of human hypertension. If electrocardiographic surrogate markers are to become clinically useful then they must be applied to well designed clinical trials with clearly defined end points in a more analytical way. There are ideal opportunities to do this either in longitudinal studies of patients who will develop hypertension; eg, those with a variety of pre-hypertensive states or more fruitfully the offspring of hypertensive parents within genetically well characterised population samples.13 In this setting surrogates of autonomic tone, cardiac structure or function studied serially along with the heart and vascular resistance may reveal new clues as to whether hypertensive heart disease is a primary or secondary phenomenon. Using this form of analyses it may be possible to distinguish the eggs from the chickens and avoid making a theoretical omelette out of what might simply be a series of inter linked clinical observations.
References 1 Coats AJS. Reproducibility in cardiology. Eur Heart J 1995; 16: 149–150. 2 Maseri A, Cianflone D, Pasceri V, Crea F. The risk and cost-effective individual patient management: the challenge of a new generation of clinical trials. Cardiovasc Drugs Ther 1997; 10: 751–758.
Heart rate variability and/or late potentials in hypertensive LVH RJ MacFadyen and SD Pringle
3 Liao YL et al. Prediction of mortality risk by different methods of indexation for left ventricular mass. J Am Coll Cardiol 1997; 29: 641–647. 4 Nolan J et al. Measurement of parasympathetic activity from 24 hour ambulatory elecetrocardiograms and its reproducibility and sensitivity in normal subjects, patients with symptomatic myocardial ischemia, and patients with diabetes mellitus. Am J Cardiol 1996; 77: 154 –158. 5 Adamopoulos S et al. Comparison of different methods for assessing sympathovagal balance in chronic congestive heart failure secondary to coronary artery disease. Am J Cardiol 1992; 70: 1576–1582. 6 Karemaker JM. HRV Heart rate variability: Why do spectral analysis? Heart 1997; 77: 99–101. 7 Tuininga YS et al. Heart rate variability in left ventricular dysfunction and heart failure: effects and implications of drug treatment. Br Heart J 1994; 72: 509–513.
8 Tsuji H et al. Impact of reduced heart rate variability on risk for cardiac events: the Framingham Heart Study. Circulation 1996; 11: 2850–2855. 9 Cain ME et al. Signal averaged electrocardiography. J Am Coll Cardiol 1996; 27: 238–249. 10 Hall PAX, Atwood JE, Myers J, Froelicher VF. The signal averaged surface electrocardiogram and the identification of late potentials. Prog Cardiovasc Dis 1989; 31: 295–317. 11 Osborn JW. The sympathetic nervous system and longterm regulation of arterial pressure: what are the critical questions? Clin Exp Pharmacol Physiol 1997; 24: 68–71. 12 Post WS, Larson MG, Levy D. Impact of left ventricular structure on the incidence of hypertension. Circulation 1994; 90: 179–185. 13 Voss A et al. Familial and genetic influences on heart rate variability. J Electrocardiography 1996; 29: 154 – 160.
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