Physiology of Heart Failure

Heart Failure

• Heart failure evokes three major compensatory mechanisms to enhance cardiac output:
  • Increased sympathetic activity
  • Activation of the renin-angiotensin-aldosterone system
  • Activation of natriuretic peptides

Compensatory Mechanisms

• Increased sympathetic activity:
  • Baroreceptors sense a decrease in blood pressure and activate the sympathetic nervous system
  • Stimulation of β-adrenergic receptors results in an increased heart rate and a greater force of contraction
  • Vasoconstriction enhances venous return and increases cardiac preload
  • An increase in preload increases stroke volume, which in turn increases cardiac output

Activation of the Renin-Angiotensin-Aldosterone System

• A fall in cardiac output (COP) decreases blood flow to the kidney, prompting the release of renin
• Release of renin results in increased formation of angiotensin II and aldosterone
• Increased peripheral resistance (afterload) and retention of sodium and water
• Increased volume returns to the heart, increasing cardiac preload

Activation of Natriuretic Peptides

• Increase in preload also increases the release of natriuretic peptides
• Natriuretic peptides (atrial, B-type, and C-type) have differing roles in heart failure
• Atrial and B-type natriuretic peptides are the most important
• Activation of natriuretic peptides results in:
  • Vasodilation
  • Natriuresis
  • Inhibition of renin and aldosterone release
  • Reduction in myocardial fibrosis

Pharmacological Treatment

• Digoxin:
  • Increases the force of contraction (inotropic effect)
  • Long half-life of 30-40 hours
  • Eliminated by the kidney, requiring dose adjustment in renal dysfunction
  • Common adverse reactions: anorexia, nausea, vomiting, blurred vision, and cardiac arrhythmias
  • Toxicity can be managed by discontinuing digoxin, determining serum potassium levels, and replenishing potassium if necessary

β-Adrenergic Agonists

• β-Adrenergic agonists (dobutamine and dopamine):
  • Cause positive inotropic effects and vasodilation
  • Increase intracellular cAMP, leading to the activation of protein kinase
  • Protein kinase phosphorylates slow calcium channels, increasing entry of calcium ions into the myocardial cells and enhancing contraction

Phosphodiesterase Inhibitors

• Milrinone:
  • Increases the intracellular concentration of cAMP
  • Results in an increase in intracellular calcium and cardiac contractility

Angiotensin Receptor-Neprilysin Inhibitor

• Sacubitril/valsartan:
  • Combines the actions of an angiotensin receptor blocker (ARB) with neprilysin inhibition
  • Inhibition of neprilysin results in increased concentration of vasoactive peptides, leading to:
    • Natriuresis
    • Diuresis
    • Vasodilation
    • Inhibition of fibrosis
  • Decreases afterload, preload, and myocardial fibrosis
  • Improves survival and symptoms of heart failure compared to therapy with an ACE inhibitor

Hyperpolarization-Activated Cyclic Nucleotide-Gated Channel Blocker

• Ivabradine:
  • Selectively slows the If current in the SA node, reducing heart rate
  • Does not reduce contractility, AV conduction, ventricular repolarization, or blood pressure
  • Used in heart failure with reduced ejection fraction (HFrEF) to improve symptoms in patients who are in sinus rhythm with a heart rate above 70 beats per minute and are on optimized HF pharmacotherapy