Heart Failure - Overview for Medical Students

Definition

• Robbins Pathologic Basis of Disease - affects >6.5 million in the US (~2% of population), ~50% mortality within 5 years of diagnosis
• Textbook of Family Medicine 9e - preferred over the older term "congestive heart failure" because pulmonary congestion is not always present

Types of Heart Failure

By Ejection Fraction (most important classification)

By Side

By Onset

• Acute HF - sudden decompensation (e.g. acute MI, flash pulmonary oedema)
• Chronic HF - gradual progression with compensatory mechanisms

By Output

• Low-output HF - most common; heart cannot generate adequate CO
• High-output HF - paradoxically elevated CO but still cannot meet excessive demand (causes: thyrotoxicosis, Paget disease, anaemia, AV fistulae, beriberi)

Compensatory Mechanisms (Initially Helpful, Ultimately Harmful)

1. Frank-Starling mechanism - increased filling volumes stretch myocytes, increasing actin-myosin cross-bridge formation for a more forceful contraction. This is short-term effective but chronic volume overload causes dilation and failure.
2. Neurohumoral activation:
   • SNS: Norepinephrine release - increases HR, contractility, and vascular resistance
   • RAAS: Renin-Ang II-aldosterone axis - promotes salt/water retention, vasoconstriction
   • ANP/BNP: Released by stretched atria/ventricles as a counter-regulatory response - promotes diuresis and vasodilation
3. Cardiac hypertrophy / LV remodeling - the heart increases myocyte mass to handle increased wall stress. Over time this leads to adverse remodeling: dilation, fibrosis, and progressive dysfunction.

Pathophysiology: The Neurohormonal Model

• Angiotensin II promotes cardiomyocyte apoptosis, hypertrophy, and ventricular fibrosis; stimulates aldosterone secretion
• Aldosterone "escapes" ACE inhibitor suppression over time, independently promoting adverse remodeling (explains the need for MRA therapy)
• Catecholamines downregulate adrenergic receptors, cause Ca²⁺ overload in myocytes, increase O₂ consumption, and trigger arrhythmias
• Endothelin-1 (from dysfunctional endothelium) causes vasoconstriction
• Inflammatory cytokines (TNF-α, IL-6) further worsen endothelial function
• MMPs (matrix metalloproteinases) promote cardiac fibrosis and collagen deposition
• Metabolic shift - from fatty acid oxidation to glycolysis (less efficient)

Common Causes (by type)

• Ischaemic heart disease / MI (most common)
• Dilated cardiomyopathy
• Hypertension (long-standing)
• Valvular disease (aortic regurgitation, mitral regurgitation)
• Myocarditis

• Hypertension (LV hypertrophy)
• Obesity / metabolic syndrome
• Diabetes mellitus
• Constrictive pericarditis
• Amyloidosis
• Hypertrophic cardiomyopathy

Forward vs. Backward Failure

Key Exam Points

• HF ≠ cardiomegaly, and it ≠ always = pulmonary congestion
• BNP/NT-proBNP is elevated in both HFrEF and HFpEF - useful biomarker for diagnosis and prognosis
• The ejection fraction is the single most important prognostic and management-guiding parameter
• LV remodeling is reversible with appropriate therapy
• Aldosterone "escape" justifies MRA (spironolactone/eplerenone) even with ACE-I or ARB use
• Right HF most commonly results from left HF - not primary right-sided disease

Pharmacological Treatments in Heart Failure

The "Fantastic Four" - Disease-Modifying Drugs for HFrEF (Mortality Benefit)

1. ARNI (Angiotensin Receptor-Neprilysin Inhibitor)

• Sacubitril inhibits neprilysin - the enzyme that degrades natriuretic peptides (ANP, BNP), bradykinin, and adrenomedullin. This increases circulating natriuretic peptides → vasodilation, natriuresis, anti-fibrotic, anti-hypertrophic effects.
• Valsartan (ARB) blocks AT₁ receptors → reduces vasoconstriction, aldosterone secretion, and adverse remodeling.
• The ARB component is used (not ACE-I) because both neprilysin and ACE-I break down bradykinin; combining them risks dangerous angioedema.

• Never combine with ACE inhibitor
• Require a 36-hour washout after stopping ACE-I before starting
• Contraindicated if history of angioedema

2. Beta-Blockers

• HF is characterized by chronic SNS hyperactivation: excess norepinephrine causes myocyte hypertrophy, apoptosis, Ca²⁺ overload, arrhythmias, increased afterload, and receptor downregulation.
• Beta-blockers counteract these effects: reduce HR (an independent prognostic factor), decrease myocardial O₂ demand, prevent arrhythmias, and allow adrenergic receptor upregulation over time.
• Long-term use improves EF (reverse remodeling) - paradoxically, despite initially reducing contractility.

3. MRA - Mineralocorticoid Receptor Antagonists

• Aldosterone promotes Na⁺/water retention, K⁺/Mg²⁺ loss, sympathetic activation, parasympathetic inhibition, myocardial and vascular fibrosis, and baroreceptor dysfunction - all deleterious in HF.
• Aldosterone "escapes" ACE-I/ARB therapy (chymase can still generate angiotensin II, and aldosterone is also regulated by plasma Na⁺/K⁺ levels) → MRA blockade is needed on top of RAAS blockade.
• MRAs are K⁺-sparing diuretics at the aldosterone-sensitive distal tubule/collecting duct, but their main HF benefit is anti-fibrotic and anti-remodeling.

4. SGLT2 Inhibitors

• Inhibit sodium-glucose co-transporter 2 (SGLT2) in the renal proximal tubule → increased urinary glucose AND sodium excretion + osmotic diuresis.
• Additional effects: increased hematocrit, reduced long-term GFR decline, modest BP reduction.
• Exact cardioprotective mechanism in HF is not fully established but extends beyond glycemic control - effective regardless of diabetes status.
• Mitigate MRA-induced hyperkalemia.

Symptom-Relieving Drugs (Do NOT reduce mortality alone)

5. Diuretics

• Loop diuretics: Furosemide, torsemide, bumetanide (most potent)
• Thiazides: Metolazone (used synergistically in resistant oedema)

• Loop diuretics: Inhibit the Na⁺-K⁺-2Cl⁻ symporter in the thick ascending limb of the loop of Henle → block up to 15% of filtrate reabsorption → powerful natriuresis and diuresis.
• Thiazides: Inhibit Na⁺-Cl⁻ co-transporter in the distal convoluted tubule.
• Move patients to lower filling pressures along the ventricular function curve - relieves congestion.
• Do NOT give to patients without congestion (activates RAAS, worsens neurohormonal state).

Second-Line / Adjunctive Agents

6. Hydralazine + Isosorbide Dinitrate (H-ISDN)

• Hydralazine: Arteriolar vasodilator → reduces afterload
• Isosorbide dinitrate: Venodilator → reduces preload
• Together they reduce both pre- and afterload and may inhibit oxidative stress.
• Use: When ACE-I/ARB/ARNI are not tolerated (e.g., renal failure, hypotension, angioedema). Also specifically recommended for Black patients with HFrEF already on standard therapy (A-HeFT trial showed additive mortality benefit in this population).

7. Ivabradine

• Selectively blocks the If (funny) current (HCN channels) in the SA node → reduces heart rate without affecting myocardial contractility or blood pressure.
• Used when: resting HR ≥70 bpm in sinus rhythm despite maximal tolerated beta-blocker dose (or where beta-blockers are contraindicated).

8. Vericiguat

• Stimulates soluble guanylate cyclase (sGC) → increases cGMP → activates protein kinase G → vascular and cardiac muscle relaxation.
• Also inhibits pathological fibrosis and hypertrophy.
• For patients who remain symptomatic after recent hospitalization for HF worsening, despite full neurohormonal blockade.
• Reduces HF hospitalization but not all-cause mortality.
• Avoid with PDE5 inhibitors (risk of severe hypotension).

9. Digoxin

• Inhibits Na⁺/K⁺-ATPase → increases intracellular Na⁺ → reduces Na⁺-Ca²⁺ exchanger activity → increases intracellular Ca²⁺ → positive inotropy.
• Also enhances parasympathetic tone and inhibits renin release.
• In AF with HF: rate control benefit.
• DIG trial: reduced hospitalizations but no mortality benefit.
• Narrow therapeutic window. Risk of toxicity (bradycardia, heart block, nausea, visual disturbances). Target digoxin level: 0.5-0.9 ng/mL.

Summary Table

High-Yield Exam Points

• ARNI + beta-blocker + MRA + SGLT2i = the "four pillars" of HFrEF - all recommended together
• ARNI preferred over ACE-I/ARB as first-line neurohormonal blockade
• ACE-I + neprilysin inhibitor is FORBIDDEN (angioedema risk) - 36 h washout required when switching ACE-I → ARNI
• Aldosterone escape justifies MRA despite already using ACE-I/ARB
• Spironolactone gynecomastia → switch to eplerenone
• SGLT2i benefit is DM-independent in HFrEF
• Digoxin - no mortality benefit; useful for symptom control and rate control in AF
• Beta-blockers improve EF over time (reverse remodeling) - don't judge beta-blocker efficacy by short-term contractility changes
• Do not start beta-blockers during acute decompensation
• Hydralazine/ISDN - specifically beneficial in Black patients and those intolerant of RAAS blockers