Heart Failure Mechanisms and Treatments

Heart Failure Pharmacology

• Heart failure (HF) is the inability of the heart to pump sufficient blood due to impaired filling and/or ejection capabilities.
• Major causes include ischemic heart disease, hypertension, valvular disorders, arrhythmias, cardiomyopathies, and sometimes certain anticancer drugs like doxorubicin or severe anemia.
• Chronic activation of the sympathetic nervous system (SNS) and renin-angiotensin-aldosterone system (RAAS) leads to cardiac remodeling, characterized by myocyte loss, hypertrophy, and fibrosis, ultimately decreasing heart function.
• Initial myocardial insult decreases cardiac output and/or mean arterial pressure leading to increased wall stress.
• Compensatory mechanisms include increased sympathetic activity, RAAS activation, and natriuretic peptides.
  • Increased sympathetic activity leads to increased heart rate and contraction strength, raising preload, and workload on the heart.
• RAAS activation reduces renal blood flow, leading to renin release, angiotensin II and aldosterone production. Results in vasoconstriction, sodium & water retention, and elevated blood volume and fluid accumulation.
• Natriuretic peptides lead to vasodilation and natriuresis (sodium in urine), reducing fluid overload symptoms.

Heart Failure Symptoms

• Common symptoms include: shortness of breath, coughing, tiredness, fluid buildup around lungs (pulmonary edema), abdomen swelling (ascites), and swelling in ankles and legs (pitting edema)

Pharmacologic Treatment of HF

• Drug classes target different aspects of HF physiology to improve outcomes.
  • Reducing preload and afterload improves cardiac output.
  • Increasing myocardial contractility.

Angiotensin-Converting Enzyme (ACE) Inhibitors

• Decrease vascular resistance and venous tone, lowering afterload and preload.
• Improves cardiac output and counteracts angiotensin II-mediated effects
• Recommended for all HFrEF patients to reduce mortality and morbidity. Start at low doses.
• Most are prodrugs, activated in the liver.
• Half-life ranges from 2-12 hours.
• Adverse effects include postural hypotension, renal insufficiency, hyperkalemia, cough (due to bradykinin), and angioedema.
• Potassium and creatinine monitoring is vital.

Angiotensin Receptor Blockers (ARBs)

• Block angiotensin II receptors.
• Produce similar effects to ACE inhibitors, but without raising bradykinin, reducing cough and angioedema risk.
• Alternative to ACE inhibitors for patients who cannot tolerate them.
• Typically given once daily, highly plasma-bound, and some with first-pass metabolism into an active metabolite.
• Adverse effects are similar to ACE inhibitors, but with lower risk of cough and angioedema.

Mineralocorticoid Receptor Antagonists (MRAs)

• Inhibit aldosterone, reducing sodium retention and cardiac remodeling
• Decreases mortality.
• Indicated for symptomatic HFrEF patients, especially post-myocardial infarction.
• High risk of hyperkalemia.
• Can have endocrine side effects such as gynecomastia.

Angiotensin Receptor-Neprilysin Inhibitors (ARNIs)

• Combine angiotensin receptor blockade (ARB) with neprilysin inhibition, increasing natriuretic peptides. Reducing Angiotensin II's harmful effects and decreasing afterload, preload, and myocardial fibrosis.
• Recommeded as a replacement for ACE inhibitors in symptomatic HFrEF patients on optimal therapy.
• Higher risk of hypotension, not recommended for patients with a history of angioedema.

Beta-Blockers

• Mitigate harmful SNS activation and prevent norepinephrine-induced cardiac remodeling.
• Some Beta-Blockers are non-selective, also containing a-blocking and antioxidant properties.
• Recommended for chronic HFrEF and some HFpEF patients needing heart rate control.
• Gradual dose increase vital to avoid adverse effects.
• Potential for worsening HF symptoms initially, but gradual dosing helps.

Diuretics

• Primarily loop diuretics like furosemide reduce plasma volume and preload, improving symptoms of fluid overload.
• Primarily used in fluid-overloaded HF patients.
• Adverse effects include dehydration, hyponatremia, and hypokalemia, requiring regular electrolyte monitoring.

Hyperpolarization-activated cyclic nucleotide-gated channel blockers (HCN channel blockers)

• Ivabradine selectively slows the If current in the SA node, reducing heart rate without affecting contractility, AV conduction, ventricular repolarization, or blood pressure.
• Used in HFrEF for patients with a heart rate above 70 bpm who are on optimized therapy, especially if beta-blockers are not tolerated.
• Adverse effects include bradycardia, and in some cases, atrial fibrillation risk. May cause luminous phenomena (e.g., brightness or halos) due to eye channel inhibition.

Vaso- and Venodilators

• Venous dilators (eg., nitrates, nitroprusside) reduce preload.
• Arterial dilators (eg., hydralazine) reduce afterload.
• Useful for patients who can't tolerate ACE inhibitors or ARBs, or need additional vasodilation support.
• Potential adverse effects include headache, dizziness, and drug-induced lupus erythematosus (hydralazine).

Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitors

• Reduce plasma volume through glucosuria and natriuresis, consequently lowering preload & afterload.
• May prevent cardiac fibrosis.
• SGLT2 inhibitors like dapagliflozin reduce HF hospitalizations and mortality in HFrEF patients.
• Adverse effects include volume depletion, renal issues, and urogenital infections. Additional monitoring needed for hypoglycemia if used with insulin or sulfonylureas.

Inotropic Drugs

• Increase cardiac contractility via enhanced intracellular calcium.
• Typically reserved for acute, severe HF due to association with increased mortality in long-term use.
• Examples include digitalis glycosides, phosphodiesterase inhibitors, and beta-adrenergic agonists.

Digitalis Glycosides

• Inhibit Na+/K+ ATPase, increasing calcium and contractility; improve symptomatic HFrEF and atrial fibrillation.
• Low serum digoxin concentration (0.5-0.9 ng/mL) typically beneficial in HFrEF.
• Primarily excreted by the kidneys, requiring dosage adjustments in renal dysfunction.
• Has a narrow therapeutic range, requiring careful dosing and monitoring.
• Initial signs of toxicity include anorexia, nausea, vomiting, blurred vision, or yellow vision.
• Decreased serum potassium levels (hypokalemia) increase risk of digoxin toxicity.
• Use with caution with other drugs that slow AV conduction (e.g., beta-blockers, verapamil, diltiazem).

Phosphodiesterase Inhibitors

• Milrinone increases intracellular calcium and therefore contractility via phosphodiesterase inhibition and increase intracellular cAMP level.
• Usually used for short-term treatment of acute decompensated HF with low cardiac output.
• Can also reduce pulmonary vasculature resistance, beneficial for treating acute pulmonary hypertension and right heart failure.

β-Adrenergic Agonists

• Improve cardiac performance by causing positive inotropic effects and vasodilation (Dobutamine).
• Increased calcium ion entry into myocardial cells enhances contraction.
• Typically administered intravenously.
• Used primarily in short-term treatment of acute decompensated HF.

Soluble Guanylate Cyclase Stimulators (Vericiguat)

• Directly stimulates sGC and sensitizes it to endogenous NO.
• Increases cGMP, improves left ventricular compliance and reduces inflammation and prevents hypertrophy and fibrosis.
• Contraindicated in pregnancy and breastfeeding, avoided with nitrates or phosphodiesterase inhibitors due to increased hypotension.

Acute vs. Chronic HF Management

• Chronic HF: Managed through lifestyle modifications and optimized drug combinations. Emphasizes RAAS and SNS inhibitors depending on subtype (HFpEF or HFrEF).
• Acute Decompensated HF: Treatment involves inotropes and IV vasodilators for rapid stabilization. Drugs known to worsen HF, such as NSAIDs, should be avoided.