Introduction to Heart Failure

Systems Physiology II Sam Dudley, MD, PhD Associate Professor of Medicine and Physiology Office: VA room 2A167 Tel: 404-329-4626 Email: [email protected]

Overview of the CV system • Purposes – – – –

Distribute metabolites and O2 Collect wastes and CO2 Thermoregulation Hormone distribution

• Components – – – –

Heart – the driving force Arteries – distribution channels Veins - collection channels Capillaries – exchange points

Parallel and series design

RA LA RV LV Organ 1 Organ 2 Organ 3

• A given volume of blood passes through a single organ • Blood entering an organ has uniform composition • Perfusion pressure is the same for each organ • Blood flow to each organ can be controlled independently

Cardiac anatomy

•

•

The myocardial syncytium – All atrial cells are coupled, all ventricular cells are coupled, the AV node links the two – Connections between cells are known as intercalated disks Electrical activation leads to contraction (EC coupling)

Cardiac cellular anatomy • Basic unit is a sarcomere (Z line to Z line) – Think filaments of myosin in the A band – Thin filaments of actin in the I band

• Sarcoplasmic reticulum – Holds Ca2+ – Forms cisternae – Approximation to T tubules (sacrolemmal invaginations) known as a dyad

Review of Cardiac Electrophysiology

2+ Ca

induced

2+ Ca

release

Ca2+ K+ Na+

Ca2+ SARCOLEMMA

ATP

Ca2+

ATP

RyR2

Ca2+

Ca2+

RyR2

SARCOPLASMIC RETICULUM

ATP

Ca2+

SARCOMERE

• •

Ca2+ enters from sacrolemmal Ca2+ channels, diffuses to the SR Ca2+ release channel (ryanodine receptor), and causes a large Ca2+ release. SR Ca2+ release raises intracellular Ca2+ from 10-7 M to 10-5 M, enough to cause Ca2+ binding to troponin, displacing tropomyosin, causing actin-myosin cross bridge cycling

Sliding filaments

Length-tension (Frank-Starling Effect) •

•

•

•

Length of a fiber determines force generation The major determinate of length in the heart is chamber volume The ascending limb results from lengthdependent changes in EC coupling The descending limb derives mostly from the number of thick and thin filament cross bridge interactions

Pressure-volume loops • Determinants of cardiac output (stroke volume x heart rate) – Preload or ventricular end diastolic volume – Afterload or Aortic pressure – Contractility or modulation of active force generation (ESPVR, inotropy) – Ventricular compliance (EDPVR, lusitropy) – Heart rate

ESV= end systolic volume; EDV = end-diastolic volume; SV = stroke volume

Myocardial work • Most myocardial work is potential work

W = ∫ PdV • Myocardial O2 consumption is a function of myocardial wall tension, contractility, and heart rate • The law of Laplace:

T = Pr/ 2 where T is tension, P is pressure, and r is the radius. – Larger ventricles have higher wall tension and O2 utilization to produce the same pressure as smaller ones

The Idea of Heart Failure

RH

LH

• Vasoconstriction • Fluid retention Right heart failure

Left heart failure

The Effect of Heart Failure ESPVR Pressure (mm Hg)

120

↓Inotropy Acute HF

80

Chronic HF

40

EDPVR

0 40

80 120 Volume (mL)

Conceptualizing Treatment for Heart Failure ESPVR changes by • ↑ inotropy • ↓ afterload

Pressure (mm Hg)

120 80 40

EDPVR

0 40

80 120 Volume (mL)

Coupling the heart and vasculature Cardiac function curve Vascular function curve

CO =

Pms − Pra R(1 + cv / ca )

Where Pms, Pra, R, cv, and ca are the mean systemic pressure, right atria pressure, total peripheral resistance, arterial and venous capacitance, respectively.

Normal equilibrium

The Vicious Cycle of Heart Failure Injury • Cell death • Apoptosis • Fetal gene activation • Inflammation Systolic dysfunction Hypertrophy Energy Starvation Increased Load

Neurohormonal activation • RAAS, SNS, ET, AVP, bradykinin

Epidemiology of HF in the US Patients in US (millions)

10.0 10

• Incidence: about 550,000 new cases each year1

8 6 4

• 4.9 million patients1; estimated 10 million in 20372

4.8

• Prevalence is 2% in persons aged 40 to 59 years, progressively increasing to 10% for those aged 70 years and older3

3.5

2 0

1991

2001

2037

Year 1. American Heart Association. Heart and Stroke Statistics2003 Update. 2. Croft JB et al. J Am Geriatr Soc 1997;45:270–75. 3. National Heart, Lung, and Blood Institute. Congestive Heart Failure Data Fact Sheet. Available at: http://www.nhlbi.nih.gov/health/public/heart/other/CHF.htm

• 52,000 deaths each year1 • Sudden cardiac death is 6 to 9 times higher in the heart failure population1

Etiology of Heart Failure

Diagnosis Modalities • • • • • • • •

Physical examination Chest X ray Echocardiography Bioimpedance MRI CT (Electron beam and Multidetector-row) Nuclear scintigraphy Cardiac catheterization

Chest X ray

• • • • •

No temporal information No quantification Requires radiation No valvular/coronary information Two dimensional

Echocardiography

Limitations to Echocardiography • Two dimensional • Views limited by anatomy • Image quality frequently poor – Improved signal to noise ratios – Improved contrast

• • • •

Limited quantitative information Need better contrast agents for flow Need higher resolution images Acoustic shadowing

Magnetic Resonance

• • • • • •

Need for more rapid acquisition Breathing artifacts Better contrast agents Higher spatial resolution Thinner slices 3D Reconstruction

Complications of Heart Failure • Progressive pump dysfunction – End organ underperfusion – Pulmonary and systemic congestion

• Sudden death

Options for Pump Dysfunction When Medications Fail • Left ventricular reconstruction/left ventricular resection • Biventricular pacing (BiV) • Left ventricular assist devices (LVAD) • Cell/tissue replacement therapy • Cardiac transplant

Biventricular pacing

Problems with BiV Pacing • • • •

Not all people benefit Technical insertion failures Not all people have wide QRS Optimum intervals and pacing sites unknown • Diaphragmatic pacing • Frequent premature beats alter timing

LVADs • • • •

•

Pulsatile vs. nonpulsatile Centrifugal, axial flow, pneumatic pumps Extracorporeal (short term) vs. implantable (longer term) Bleeding, hemolysis, DIC, embolism (air or thrombotic), battery life, bulk, mechanical failure, cost, infection, surgery Valvular/coronary disease/arrhythmias/con-genital defects limit use

Cardiac Cell Transplantation

Cell replacement therapy

Unresolved issues • Arrhythmogenicity – – –

• Best source of cells

Automaticity Slow Conduction/Reentry Triggered activity

• Immunogenicity • Mechanism of improved function – contraction, remodeling

• How does cell therapy compare to engineered replacement tissue?

– adult, fetal, embryonic, tissue, species, differentiated, undifferentiated

• Best route of application – injection, mobilization, IC, IV

• • •

Timing of application How does homing occur? Which types of cells are necessary?

Cardiac transplantation • • • • • •

Limited donors Infection Rejection Renal failure Tumors Accelerated Vascular Disease

Sudden Death in HF

Risk Predictors for Sudden Death • • • • • • • •

Left ventricular dysfunction Frequent premature ventricular contractions Nonsustained ventricular tachycardia Inducible ventricular tachycardia on programmed electrical stimulation Abnormal signal averaged ECG (presence of late potentials) Reduced heart rate variability Presence of T wave alternans Increased QT segment dispersion

Finding (Mapping) Arrhythmias • Contact vs. noncontact • Baskets vs. single electrodes • No integration of mapping and imaging • Difficulty interpreting activation patterns and electrograms • Cannot measure full thickness of myocardium • Map resolution/accurate anatomical display

Implanted Cardiac Defibrillators (ICDs) • • • •

• • • •

Battery life Inappropriate shocks Limited event recording Infection/bleeding/perforation/unstable leads/pneumothorax/erosion Lead failure/dislodgement Pain Incessant VT/VF EM interference

ICD in action

Future Challenges for the Bioengineer • Develop cellular/nanotechnology solutions – Will require more knowledge of pathogenesis

• Implement tissue engineering solutions • Improve biomedical imaging – More noninvasive solutions – Integrate with therapy – Molecular imaging

• Need better bioinformatics risk predictive models

References 1. Katz A.M., Physiology of the Heart, Lippincott Williams & Wilkins, New York, 2001. 2. Berne and Levy, Cardiovascular Physiology, 7th Edition, Mosby, St. Louis, 1996.