Heart Failure I Pathophysiology

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Heart Failure - I Pathophysiology

• Dr Hanan ALBackr
• 3/11/1429
• (1/11/2008)

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Overview

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

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compensatory mechanisms

• Atrial underfilling
• Renin-Angiotensin-Aldosterone System
• Sympathetic system
• Natriuretic peptides

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Background

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

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Body-Fluid Volume

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

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Arterial Underfilling

• Causes and consequences
• Counter-regulation

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Arterial Underfilling

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

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High vs Low Output Failure

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

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Arterial Underfilling
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Sympathetic Nervous System

• Increased sympathetic tone leads to
• Increased myocardial contractility
• Tachycardia
• Arterial vasoconstriction ? high afterload
• Venoconstriction ? high preload

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Sympathetic NS Frank-Starling

• In HF, generalized adrenergic activation
• Reduction in NE stores and beta-R density

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Sympathetic NS
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Sympathetic NS

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

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Renin Angiotensin Aldosterone
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Renin-Angiotensin-Aldosterone

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

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RAAS

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

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RAAS
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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

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Arginine Vasopressin

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

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Natriuretic Peptides

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

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Natriuretic Peptides

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

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RAAS vs Natriuretic Peptides
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Endothelial Hormones

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

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Summary of Effects
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Chronic Myocardial Remodeling
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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

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Stages of Cardiac Hypertrophy
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Laplaces Law
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Transition to HF

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

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Molecular Mechanisms
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Molecular Mechanisms

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

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Molecular Mechanisms

• 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

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Summary

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