Heart Failure & Cardiomyopathies (HFrEF, HFpEF, GDMT)

Heart Failure with Reduced Ejection Fraction (HFrEF, LVEF <=40%) is characterized by systolic contractile failure and eccentric hypertrophy (sarcomeres added in series), resulting in a dilated, compliant left ventricular cavity with thinned walls (classic after anterior MI, viral myocarditis, dilated cardiomyopathy, or chronic aortic/mitral regurgitation) and a pathognomonic S3 ventricular filling gallop. Conversely, Heart Failure with Preserved Ejection Fraction (HFpEF, LVEF >=50%) is driven by impaired ventricular relaxation/compliance and concentric hypertrophy (sarcomeres added in parallel from chronic systemic hypertension or aortic stenosis) or infiltrative stiffening (transthyretin/AL cardiac amyloidosis, hemochromatosis), producing a thick-walled, small-chambered ventricle with a loud S4 atrial gallop.

Cardiomyocyte stretching from elevated ventricular end-diastolic wall stress triggers cleavage of proBNP into biologically active B-type natriuretic peptide (BNP) and biologically inert N-terminal proBNP (NT-proBNP). BNP binds guanylyl cyclase-A receptors to increase intracellular cGMP, inducing afferent arteriolar dilation, efferent arteriolar constriction (increasing GFR), inhibition of renin/aldosterone secretion, and natriuresis. On board vignettes, remember two crucial diagnostic caveats: (1) obesity falsely lowers BNP levels (adipocytes express natriuretic peptide clearance receptors [NPR-C]), and (2) patients taking sacubitril-valsartan (ARNI) have pharmacologically elevated BNP (since sacubitril inhibits neprilysin degradation of BNP), so NT-proBNP (which is not a neprilysin substrate) must be ordered to monitor heart failure progression on ARNI therapy.

A perennial board distinction separates medications that reduce mortality and reverse remodeling in HFrEF—the four foundational GDMT pillars (ARNI/ACEi/ARB, beta-blockers [carvedilol, metoprolol succinate, bisoprolol], mineralocorticoid receptor antagonists [spironolactone, eplerenone], and SGLT2 inhibitors [dapagliflozin, empagliflozin]), plus hydralazine-isosorbide dinitrate in self-identified Black patients with persistent NYHA III–IV symptoms and ivabradine (I_f funny channel blocker) if sinus HR remains >=70 bpm on maximal beta-blocker—from medications that only improve symptoms/hospitalizations without reducing mortality: loop diuretics (furosemide, bumetanide, torsemide) and digoxin (Na+/K+-ATPase inhibitor). Conversely, non-dihydropyridine calcium channel blockers (verapamil, diltiazem), thiazolidinediones (pioglitazone), and NSAIDs worsen heart failure and are contraindicated in HFrEF.

Patients hospitalized with Acute Decompensated Heart Failure (ADHF) are stratified at the bedside along two axes: congestion ('Wet' vs. 'Dry')—assessed by jugular venous distension, orthopnea, bendopnea, pulmonary rales, hepatomegaly, and peripheral edema—and perfusion ('Warm' vs. 'Cold')—assessed by extremity temperature, pulse pressure (narrow if <25% of SBP), mentation, urine output, and serum lactate. Over 80% of ADHF admissions are 'Warm and Wet' (Profile B) and respond rapidly to intravenous loop diuretics (dosed at 1 to 2.5 times their home oral dose) plus intravenous nitroglycerin or sodium nitroprusside if severely hypertensive, alongside non-invasive positive pressure ventilation (BiPAP) to reduce left ventricular transmural afterload and preload.

When a patient presents in Profile C ('Cold and Wet' cardiogenic shock) with hypotension, cool mottled extremities, lactic acidosis, and oliguria, home beta-blockers and ACEi/ARNIs must be temporarily held, and perfusion is restored using an intravenous inotrope (dobutamine [beta-1 agonist] or milrinone [PDE-3 inhibitor]) combined with norepinephrine if mean arterial pressure is <65 mmHg (note: milrinone causes potent peripheral and pulmonary vasodilation and skips the beta-1 receptor, making it preferred in patients on chronic beta-blockers, though it requires dose reduction in renal failure). In contrast, if a patient is 'Warm and Wet' without shock or severe bradycardia, home oral beta-blockers should be continued during hospitalization rather than abruptly stopped, avoiding rebound sympathetic tachyarrhythmias.

According to the Frank-Starling relationship, increasing ventricular preload (end-diastolic volume) stretches cardiac myocytes, optimizing actin-myosin cross-bridge overlap and increasing stroke volume. In HFrEF, impaired myocardial contractility flattens the Frank-Starling curve and decreases the slope of the End-Systolic Pressure-Volume Relationship (ESPVR). Consequently, for any given end-diastolic volume, stroke volume is severely reduced, shifting the entire pressure-volume loop to the right with a markedly elevated end-systolic volume (ESV). In HFpEF, the ESPVR slope remains normal, but impaired active Lusitropic relaxation (SERCA2a dysfunction) and myocardial fibrosis steepen the End-Diastolic Pressure-Volume Relationship (EDPVR), causing steep rises in LVEDP and pulmonary venous congestion despite normal chamber volumes.

A drop in cardiac output unloads carotid sinus baroreceptors and decreases renal afferent arteriolar perfusion, triggering three neurohormonal axes: (1) Sympathetic Nervous System (SNS) activation releases norepinephrine, initially supporting heart rate and contractility via beta-1 receptors while increasing afterload via alpha-1 vasoconstriction, but chronically inducing myocyte apoptosis and beta-1 receptor downregulation; (2) Renin-Angiotensin-Aldosterone System (RAAS) activation generates Angiotensin II (increasing efferent arteriolar tone and systemic afterload) and Aldosterone (driving distal nephron Na⁺/H₂O retention and myocardial fibroblast collagen deposition); and (3) ANP and BNP release from stretched atrial and ventricular myocytes, which activate guanylyl cyclase (increasing cGMP) to promote natriuresis and vasodilation. BNP < 100 pg/mL (or NT-proBNP < 300 pg/mL) rules out acute heart failure as the cause of dyspnea (note: obesity falsely lowers BNP levels).

Board vignettes require distinguishing unidirectional structural staging from fluctuating symptom severity. The ACC/AHA Stages (A through D) progress in only one direction: Stage A (at risk: HTN, DM, CAD, cardiotoxic chemotherapy without structural disease), Stage B (pre-heart failure: structural disease such as reduced LVEF, LV hypertrophy, or prior MI without ever having symptoms), Stage C (structural heart disease with prior or current HF symptoms), and Stage D (refractory end-stage HF requiring inotropes, LVAD, or transplant). In contrast, the NYHA Functional Class (I–IV) shifts dynamically with diuresis: Class I (no limitation during ordinary activity), Class II (slight limitation; dyspnea with moderate exertion), Class III (marked limitation; dyspnea with minimal daily activity), and Class IV (symptoms at rest).

Sacubitril inhibits neprilysin, the neutral endopeptidase responsible for degrading active B-type Natriuretic Peptide (BNP), atrial natriuretic peptide (ANP), and bradykinin. Because active BNP is a direct substrate of neprilysin, initiating sacubitril-valsartan pharmacologically elevates circulating serum BNP concentrations even as the patient's ventricular wall stress improves. However, the inactive N-terminal prohormone cleavage fragment, NT-proBNP, is not a substrate of neprilysin and is cleared renally. Therefore, in patients treated with an ARNI, clinicians must order NT-proBNP (which accurately decreases with successful decongestion) rather than BNP to monitor heart failure trajectory.

Unlike beta-blockers or non-dihydropyridine calcium channel blockers, ivabradine lowers heart rate without any negative inotropic (contractility) or lusitropic effects. It selectively blocks hyperpolarization-activated cyclic nucleotide-gated (HCN / I_f 'funny' channels) within the sinoatrial node, prolonging phase 4 slow diastolic depolarization. On board examinations, ivabradine is indicated only when a patient meets all four criteria: (1) symptomatic HFrEF with LVEF ≤ 35%, (2) taking maximally tolerated doses of an evidence-based beta-blocker (or contraindicated), (3) in normal sinus rhythm (it is ineffective in atrial fibrillation because the SA node does not drive the rhythm), and (4) resting heart rate ≥ 70 bpm.

For patients with worsening HFrEF following a recent hospitalization despite quadruple therapy, vericiguat (an oral soluble guanylyl cyclase stimulator that enhances cGMP production independently of nitric oxide) reduces repeat heart failure hospitalizations. When digoxin is used as a low-dose adjunct (target serum trough 0.5–0.9 ng/mL), clinicians must watch for cholinergic nausea/vomiting, visual xanthopsia (yellow-green halos), and arrhythmias (premature ventricular contractions, paroxysmal atrial tachycardia with AV block, or bidirectional ventricular tachycardia). Precipitants include renal insufficiency, hypokalemia, and P-glycoprotein inhibitors (amiodarone, verapamil, quinidine, macrolides). Definitive treatment is anti-digoxin Fab fragments (Digibind) plus potassium/magnesium repletion.

In acute cardiogenic pulmonary edema ('Warm and Wet'), immediate application of Non-Invasive Positive Pressure Ventilation (CPAP or BiPAP) decreases both intubation rates and mortality. Positive intrathoracic pressure mechanically splints open flooded alveoli, decreases venous return (reducing RV and LV preload), and decreases transmural left ventricular systolic wall stress (reducing LV afterload). Simultaneously, IV loop diuretics (furosemide, bumetanide, or torsemide) are administered at a dose 1 to 2.5 times the patient's total daily home oral dose. IV furosemide relieves dyspnea within 15 minutes via prostaglandin-mediated venodilation before natriuresis peaks at 30–60 minutes. If diuretic resistance occurs due to distal convoluted tubule hypertrophy, add a thiazide-like diuretic (IV chlorothiazide or oral metolazone) for sequential nephron blockade.

When a patient presents in 'Cold and Wet' cardiogenic shock (CI < 2.2 L/min/m² with end-organ hypoperfusion), home beta-blockers must be held and positive inotropes initiated to restore forward cardiac output. Dobutamine is a synthetic catecholamine predominantly stimulating beta-1 adrenergic receptors (increasing adenylyl cyclase and intracellular cAMP) with mild beta-2 peripheral vasodilation. Milrinone is a phosphodiesterase-3 (PDE-3) inhibitor that prevents cAMP degradation in both cardiac myocytes (increasing inotropy) and vascular smooth muscle (causing potent pulmonary and systemic arterial vasodilation— an 'inodilator'). Because milrinone bypasses the beta-1 receptor, milrinone is preferred in patients on chronic high-dose beta-blockers; however, it is renally cleared and causes more systemic hypotension than dobutamine.

Patients who develop sudden-onset flash pulmonary edema over minutes in the setting of severe systemic hypertension (SBP > 180–200 mmHg) typically suffer from acute afterload mismatch rather than total body hypervolemia. Common underlying etiologies include bilateral renal artery stenosis (Pickering syndrome), severe HFpEF, or acute mitral regurgitation. In these patients, high-dose IV nitroglycerin (venodilator at low doses, arteriolar dilator at high doses) or IV sodium nitroprusside (balanced arterial and venous nitric oxide donor) plus BiPAP rapidly unloads LV afterload and resolves pulmonary edema much faster than loop diuretics alone.

In Hypertrophic Obstructive Cardiomyopathy (HOCM), dynamic left ventricular outflow tract (LVOT) obstruction is caused by the hypertrophied interventricular septum and the Venturi/drag effect pulling the anterior mitral leaflet into the outflow tract (Systolic Anterior Motion, or SAM). Unlike fixed valvular aortic stenosis, the HOCM murmur increases in intensity with maneuvers that decrease LV cavity volume (preload or afterload)—including the Valsalva maneuver (strain phase), standing abruptly from a squatting position, or amyl nitrite inhalation—because a smaller LV chamber brings the septum and anterior mitral leaflet closer together. Conversely, squatting, passive leg raise, and sustained isometric handgrip increase LV volume and soften the murmur. Mavacamten (a cardiac myosin ATPase inhibitor) reduces actin-myosin cross-bridge hypercontractility. An ICD is implanted if the patient has prior cardiac arrest/sustained VT, family history of sudden cardiac death, unexplained syncope, massive LV wall thickness ≥ 30 mm, or LV apical aneurysm.

Both Restrictive Cardiomyopathy (RCM) and Constrictive Pericarditis present with right-sided heart failure, preserved ejection fraction, elevated JVP with a prominent y-descent, Kussmaul sign (paradoxical rise in JVP on inspiration), and a 'dip-and-plateau' (square root sign) on ventricular pressure tracings. However, Constrictive Pericarditis (post-tuberculosis, post-cardiac surgery, mediastinal radiation, viral pericarditis) displays a pericardial knock in early diastole, pericardial calcification on chest CT/X-ray, ventricular interdependence (inspiratory septal bounce/shift to the left), and normal BNP levels because the rigid pericardial shell prevents myocardial stretch. RCM displays an S₃/S₄ gallop, markedly elevated BNP, low-voltage ECG with thick walls on Echo (in amyloidosis), and Concordance of RV/LV systolic pressures during respiration.

Device therapy is evaluated after a patient has received at least 3 months of optimal 4-pillar GDMT (and is > 40 days post-MI / > 90 days post-revascularization). A primary prevention ICD is indicated to prevent sudden arrhythmic death in patients with LVEF ≤ 35% and NYHA Class II or III symptoms (or LVEF ≤ 30% with NYHA Class I ischemic cardiomyopathy) who have an expected survival > 1 year. Cardiac Resynchronization Therapy (CRT / biventricular pacing) paces both the right ventricle and the lateral left ventricle (via the coronary sinus) to restore synchronous ventricular contraction and reduce functional mitral regurgitation. CRT is strongly indicated in patients with LVEF ≤ 35%, Sinus Rhythm, Left Bundle Branch Block (LBBB) morphology, and QRS duration ≥ 150 ms with NYHA Class II–IV symptoms.