Heart Failure - I Pathophysiology Dr Hanan ALBackr 3/11/1429(1/11/2008)

REMEMBER LEFT VENTRICULAR FAILURE IS A TRUE LIFE THREATENING EMERGENCY

Overview Cardiac failure: heart unable to pump blood at a rate required by tissues Caused by: Myocardial death Myocardial death Myocyte dysfunction Myocyte dysfunction Ventricular remodeling Ventricular remodeling Abnormal energy utilization Abnormal energy utilization Ischemia Ischemia Neurohormonal disturbances Neurohormonal disturbances

Coronary artery disease--chronic Coronary artery disease--chronic HTN--both HTN--both Valvular heart disease (especially aorta and mitral disease)-- chronic Valvular heart disease (especially aorta and mitral disease)-- chronic Infections--acute Infections--acute Dysrhythmias--acute Dysrhythmias--acute Alcohol--chronic MI--acute Diabetes—chronic

Etiology— Acute MI— Inferior MI Inferior MI Pulmonary disease COPD, fibrosis, HTN COPD, fibrosis, HTN Cardiac disease involving the left or both ventricles Results from LVF Pathophysiology— Decreased right-sided cardiac output or increased pulmonary vascular resistance  increased right vent. Pressures. As pressures rise, this  increased pressure in the right atrium and venous system Higher right atrium pressures  JVP

Marked JVD Marked JVD Clear chest Clear chest Hypotension Hypotension Marked peripheral edema Marked peripheral edema Ascites, hepatomegaly Ascites, hepatomegaly Poor exercise tolerance Poor exercise tolerance The first three are for an inferior MI, describe cardiac tamponade. The first three are for an inferior MI, describe cardiac tamponade. Often will be on Lasix, Digoxin, Have chronic pump failure

Jugular Venous Distention—not directly related to LVF. Jugular Venous Distention—not directly related to LVF. Comes from back pressure building from right heart into venous circulation Vital Signs— Vital Signs— Significant increase in sympathetic discharge to compensate. BP—elevated Pulse rate—elevated to compensate for decreased stroke volume. Respirations—rapid and labored

Neurohormonal system Neurohormonal system Renin-angiotensin-aldosterone system Renin-angiotensin-aldosterone system Ventricular hypertrophy Ventricular hypertrophy

compensatory mechanisms Atrial underfilling Atrial underfilling Renin-Angiotensin-Aldosterone System Renin-Angiotensin-Aldosterone System Sympathetic system Sympathetic system Natriuretic peptides Natriuretic peptides

Background Heart failure pathophysiology Index event Index event Compensatory mechanisms Compensatory mechanisms Maladaptive mechanisms Maladaptive mechanisms

Body-Fluid Volume Renal Na and water excretion Dependent on arterial circulation Dependent on arterial circulation Cardiac output and peripheral resistance Cardiac output and peripheral resistance Decrease in circulation leads to arterial underfilling Decreased effective circulating volume Decreased effective circulating volume Neurohormonal reflexes are triggered

Arterial Underfilling Causes and consequences Counter-regulation

Arterial Underfilling Mechanoreceptors Sense arterial filling Sense arterial filling Regulate body-fluid volume Regulate body-fluid volume LV, carotid sinus, aortic arch, renal afferents LV, carotid sinus, aortic arch, renal afferents Decreased activation leads to Increase sympathetic outflow Increase sympathetic outflow RAAS activation RAAS activation ADH release and thirst activation ADH release and thirst activation

High vs Low Output Failure Majority of HF is low output High output failure Beriberi, thyrotoxicosis, AV fistula, pregnancy etc. Beriberi, thyrotoxicosis, AV fistula, pregnancy etc. Arterial underfilling results from arterial vasodilation Arterial underfilling results from arterial vasodilation

Arterial Underfilling

Sympathetic Nervous System Increased sympathetic tone leads to Increased myocardial contractility Increased myocardial contractility Tachycardia Tachycardia Arterial vasoconstriction  high afterload Arterial vasoconstriction  high afterload Venoconstriction  high preload Venoconstriction  high preload

Sympathetic NS & Frank-Starling In HF, generalized adrenergic activation Reduction in NE stores and beta-R density

Sympathetic NS

Previously, beta-blockade thought to be contraindicated Now, one of the principal treatments CIBIS II (bisoprolol, NYHA III-IV) CIBIS II (bisoprolol, NYHA III-IV) MERIT-HF (metoprolol, NYHA II-IV) MERIT-HF (metoprolol, NYHA II-IV) COPERNICUS (carvedilol, NYHA III-IV) COPERNICUS (carvedilol, NYHA III-IV)

Renin Angiotensin Aldosterone

Renin-Angiotensin-Aldosterone RAAS increased Degree of increase plasma renin prognostic Degree of increase plasma renin prognostic Mild HF May have near normal renin/aldosterone May have near normal renin/aldosterone Inappropriate given high extracellular volume Inappropriate given high extracellular volume Severe HF High plasma renin and aldosterone High plasma renin and aldosterone

RAAS Aldosterone activity more persistent in HF In normal person – high mineralocorticoid Initially increases volume 1.5-2L Initially increases volume 1.5-2L Renal Na retention then plateaus Renal Na retention then plateaus Usually no detectable edema Usually no detectable edema Plateau does not occur in HF

RAAS

Angiotensin II Increases aldosterone secretion Increases proximal Na reabsorption Vasoconstriction of renal arterioles Stimulates central thirst May also have mitogenic effect on myocytes Decrease in capillary network relative to myocardium Decrease in capillary network relative to myocardium

Arginine Vasopressin Leads to edema and hyponatremia Ominous prognostic indicator Nonosmostic release of ADH Carotid baroreceptor activation Carotid baroreceptor activation V2-receptors: upregulates aquaporins in CD V1-receptors: in vascular smooth ms; contributes to cardiac dysfxn

Natriuretic Peptides Atrial natriuretic peptide Synthesized in atria > ventricles Synthesized in atria > ventricles Released into circulation during atrial distention Released into circulation during atrial distention Increased in HF as atrial pressures rise Increased in HF as atrial pressures rise Brain natriuretic peptide Synthesized primarily in ventricles Synthesized primarily in ventricles Increased in early LV dysfxn Increased in early LV dysfxn

Natriuretic Peptides Atrial NP and BNP Causes renal efferent V/C and afferent V/D Causes renal efferent V/C and afferent V/D GFR rises GFR rises Decreases Na reabsorption in CD Decreases Na reabsorption in CD Inhibits secretion of renin and aldosterone Inhibits secretion of renin and aldosterone In HF, develop resistance to natriuretic effect Down-regulation of receptors Down-regulation of receptors Increased degradation of peptides by endopeptidase Increased degradation of peptides by endopeptidase

RAAS vs Natriuretic Peptides

Endothelial Hormones Prostacyclin and PG E Autocrine hormones in glomerular afferents: V/D Autocrine hormones in glomerular afferents: V/D Stimulated by Angiotenin II, NE Stimulated by Angiotenin II, NE Counterbalance neurohormone-induced V/C Counterbalance neurohormone-induced V/C Nitric oxide Potent V/D Potent V/D NO synthase blunted in HF NO synthase blunted in HFEndothelin Potent V/C Potent V/C Increased in HF  poor prognostic indicator Increased in HF  poor prognostic indicator

Summary of Effects

Chronic Myocardial Remodeling

Remodeling Pressure Overload Increase in systolic wall stress Parallel replication of myofibrils Thickening of myocytes Small increase in number of myocytes Volume Overload Increase in diastolic wall stress Replication of sarcomeres in series Elongation of myoctytes Ventricular dilatation

Stages of Cardiac Hypertrophy

Laplace’s Law

Transition to HF Stress on ventricle Acute adaptive compensatory mechanisms Acute adaptive compensatory mechanisms Hemodynamic overload severe / prolonged Contractility depressed Contractility depressed Depressed intramural myocardial shortening Depressed intramural myocardial shortening

Molecular Mechanisms

Myocyte loss Causes decreased contractile fxn Causes decreased contractile fxn 1.Necrosis Occurs with O2 / energy deprivation Occurs with O2 / energy deprivation Loss of membrane integrity Loss of membrane integrity Influx of extracellular fluid  cellular disruption Influx of extracellular fluid  cellular disruption

Molecular Mechanisms 2.Apoptosis Programmed cell death Energy-dependent process Involution of myocyte  phagocytosis by neighbouring cell Increasing evidence of role in HF Catecholamines, A II, NO, cytokines, mechanical strain

Summary Pathophysiology based on compensatory mechanisms becoming maladaptive Key players: Atrial underfilling Atrial underfilling Renin-Angiotensin-Aldosterone System Renin-Angiotensin-Aldosterone System Sympathetic system Sympathetic system Natriuretic peptides Natriuretic peptides Leads to chronic remodelling via apoptosis and necrosis

In conclusion, congestive heart failure is often assumed to be a disease when in fact it is a syndrome caused by multiple disorders.