Heart Failure — Systolic and Diastolic

Systolic Heart Failure (HFrEF)

• Myocardial necrosis from acute myocardial infarction results in irreversible loss of contractile mass; progressive post-MI remodeling with left ventricular dilatation increases wall stress according to the Law of Laplace (wall stress = pressure × radius/2 × wall thickness)
• Cardiomyocyte apoptosis and autophagy driven by oxidative stress, calcium overload, and activation of pro-apoptotic signaling cascades
• Impaired calcium handling with sarcoplasmic reticulum calcium-ATPase (SERCA2a) dysfunction and increased phospholamban inhibition, prolonging diastolic calcium reuptake
• Altered sarcomeric protein expression with shift from V1 to V3 myosin heavy chain isoforms reducing contractility; reduced expression of Z-disk proteins compromising structural integrity

Neurohormonal activation in response to reduced cardiac output

• Renin-Angiotensin-Aldosterone System (RAAS) activation through decreased renal perfusion pressure triggers angiotensinogen→angiotensin II production, causing systemic and renal vasoconstriction, sodium/water retention, and myocardial fibrosis via AT1 receptor signaling
• Sympathetic nervous system hyperactivation increases norepinephrine release, enhancing contractility initially but ultimately promoting cardiomyocyte apoptosis, arrhythmias, and increased myocardial oxygen demand
• Natriuretic peptide system upregulation (BNP and NT-proBNP) represents a compensatory but ultimately insufficient counterregulatory mechanism
• Inflammatory cytokine cascade with increased TNF-α, IL-1, and IL-6 promoting oxidative stress and myocardial remodeling

Progressive ventricular remodeling

• Eccentric hypertrophy with lengthening of individual myocytes, chamber dilatation, and thinning of the ventricular wall
• Extracellular matrix degradation from matrix metalloproteinase (MMP) activation, particularly MMP-2 and MMP-9, disrupting the collagen scaffold
• Collagen deposition and fibrosis with replacement of contractile tissue by non-contractile fibrous tissue, further reducing ejection fraction

Diastolic Heart Failure (HFpEF)

Impaired relaxation and increased stiffness

• Prolonged isovolumetric relaxation time from delayed myocardial calcium reuptake and slow cross-bridge cycling reduces early ventricular filling
• Increased chamber stiffness from excessive collagen deposition in the interstitium, altered titin (a giant elastic protein) isoform expression with increased stiffness variants, and cardiomyocyte hypertrophy
• Increased passive stiffness reflecting altered left ventricular geometry (concentric hypertrophy) with increased relative wall thickness
• Abnormal myocardial relaxation from impaired SERCA2a function, altered calcium sensitivity, and reduced ATP availability in hypertrophied myocytes

Functional hemodynamic consequences

• Left ventricular filling becomes pressure-dependent requiring elevated diastolic pressures to achieve adequate ventricular filling, manifesting as elevated pulmonary capillary wedge pressure and pulmonary congestion at normal or near-normal end-diastolic volumes
• Atrial dysfunction with impaired contractility reduces the atrial contribution to ventricular filling (normally 20-30% of total), exacerbating hemodynamic compromise particularly in atrial fibrillation
• Right ventricular involvement from systemic hypertension and pulmonary hypertension secondary to elevated left-sided pressures

Major Causes of Systolic Heart Failure

• Acute transmural MI with loss of contractile mass
• Chronic ischemic cardiomyopathy from repeated infarctions or hibernating myocardium
• Ischemic mitral regurgitation from papillary muscle rupture or geometric distortion

• Genetic causes: autosomal dominant (dystrophin, lamin A/C, β-myosin heavy chain), autosomal recessive, and X-linked mutations
• Viral myocarditis (enterovirus, adenovirus, HCV) with post-viral cardiomyopathy
• Peripartum cardiomyopathy in pregnancy or early postpartum period

• Chronic aortic regurgitation with volume overload
• Mitral regurgitation (organic or functional) from LV dilatation
• Aortic stenosis causing LV hypertrophy progressing to systolic dysfunction

Myocarditis and infiltrative diseases

• Acute viral myocarditis (fulminant vs. non-fulminant)
• Autoimmune myocarditis (lupus, giant cell myocarditis)
• Sarcoidosis with granulomatous infiltration
• Amyloidosis (light chain or transthyretin)
• Hemochromatosis with iron deposition in myocardium

Toxic cardiomyopathies

• Chemotherapy: anthracyclines (dose-dependent), trastuzumab, tyrosine kinase inhibitors, checkpoint inhibitors
• Alcohol: chronic ethanol directly damages myocytes, interferes with thiamine metabolism
• Cocaine and amphetamines from sympathomimetic effects and oxidative stress

High-output states with chronic hemodynamic burden

• Severe anemia
• Thyrotoxicosis
• Arteriovenous fistula
• Chronic pulmonary hypertension

Major Causes of Diastolic Heart Failure (HFpEF)

• Systemic hypertension causing concentric LV hypertrophy
• Pulmonary hypertension (any etiology) with RV dilatation and septal shift

Left ventricular hypertrophy

• Aortic stenosis (chronic pressure overload)
• Hypertrophic cardiomyopathy (sarcomeric protein mutations)

Restrictive physiology

• Restrictive cardiomyopathy (infiltrative or idiopathic)
• Constrictive pericarditis (fibrosis limiting ventricular expansion)
• Cardiac tamponade

• Loss of atrial contractile function reduces ventricular filling
• May trigger or worsen HFpEF presentation

Coronary microvascular dysfunction

• Endothelial dysfunction reducing nitric oxide availability
• Associated with diabetes, chronic kidney disease, hypertension

Metabolic and systemic conditions

• Diabetes mellitus (independent of hypertension)
• Obesity with diastolic dysfunction
• Chronic kidney disease
• Chronic obstructive pulmonary disease

Universal Risk Factors for Both Phenotypes

• Age >65 years
• Diabetes mellitus
• Hypertension
• Obesity (BMI >30)
• Chronic kidney disease (reduced GFR, electrolyte disturbance)
• Prior myocardial infarction
• Smoking
• Atrial fibrillation

Cardinal Symptoms

• Exertional dyspnea disproportionate to exertion level, improving with rest
• Orthopnea (dyspnea when supine) from redistribution of blood from legs to lungs when recumbent
• Paroxysmal nocturnal dyspnea (PND) with abrupt awakening 2-3 hours after sleep onset, often with accessory muscle use
• Dyspnea at rest indicating decompensated HF with pulmonary edema

Fatigue and exercise intolerance

• Decreased cardiac output limiting muscle perfusion and oxygen delivery
• Peripheral vasoconstriction (peripheral hypoperfusion syndrome) with cold extremities
• Right ventricular dysfunction with hepatic congestion causing early satiety

Fluid retention symptoms

• Peripheral edema (bilateral, dependent, pitting) from elevated systemic venous pressure and sodium/water retention
• Abdominal distension and discomfort from hepatomegaly and ascites
• Nocturia from nocturnal reabsorption of peripheral edema when supine, mobilizing fluid volume

Physical Examination Findings

Vital signs and general appearance

• Tachycardia from sympathetic activation; resting HR >100 bpm indicates worse prognosis
• Hypotension or narrow pulse pressure in decompensated HF or cardiogenic shock
• Tachypnea with respiratory rate >20-24 breaths/min reflecting pulmonary congestion
• Cachexia in advanced HF from increased metabolic rate, TNF-α, and poor intake

Jugular venous pressure (JVP) assessment

• Elevated JVP >4 cm H₂O (normal 2-8 cm H₂O) indicating right atrial pressure elevation
• Prominent hepatojugular reflux with further JVP rise on abdominal compression (abdominojugular test) confirming elevated right atrial pressure
• Prominent S wave in JVD without prominent X descent suggests tricuspid regurgitation
• Absent Y descent suggests restrictive physiology

Cardiac auscultation

• S3 gallop (ventricular gallop) at low frequencies (best heard with bell at apex in supine position), representing rapid early diastolic filling against a stiff ventricle; highly specific for systolic HF when present
• S4 gallop from forceful atrial contraction against a stiff LV (as in diastolic HF, hypertrophic cardiomyopathy); absent in atrial fibrillation
• Holosystolic (pansystolic) murmur at apex radiating to axilla from mitral regurgitation (may be functional from LV dilatation)
• Displaced apical impulse laterally (>5-6 cm from midclavicular line) and inferiorly from LV dilatation
• Diminished S2 from prolonged LV ejection time (decreased A2-P2 interval)

Pulmonary examination

• Bibasilar crackles (rales) from pulmonary edema with alveolar filling by transudative fluid; may become absent in chronic decompensation with elevated pulmonary vascular resistance
• Dullness to percussion and decreased breath sounds at bases from pleural effusions (often right-sided, but can be bilateral)
• Wheezing (cardiac asthma) from bronchospasm secondary to pulmonary edema

Hepatic findings

• Hepatomegaly from hepatic venous congestion; tender to palpation (positive hepatic tenderness)
• Hepatojugular reflux as noted above
• Ascites in advanced right heart failure with markedly elevated venous pressure

Extremity findings

• Peripheral edema (pitting) present in dependent areas (ankles if ambulating, sacrum if bedridden)
• Cold extremities from peripheral vasoconstriction and decreased cardiac output
• Cyanosis (central) from pulmonary edema; peripheral cyanosis from poor perfusion
• Clubbing (rare, suggests underlying cardiopulmonary disease like cyanotic heart disease)

Spectrum of Clinical Presentations

Acute decompensated heart failure (ADHF)

• Flash pulmonary edema with acute respiratory distress
• Cardiogenic shock with evidence of hypoperfusion (altered mental status, oliguria, cool extremities)
• Hypertensive emergency with markedly elevated BP worsening pulmonary edema

Chronic compensated HF

• Stable on optimal medical therapy with only mild dyspnea on exertion
• May have residual symptoms limiting activity tolerance

Right heart failure (cor pulmonale)

• Elevated JVP, hepatomegaly, ascites, peripheral edema
• May present without significant pulmonary edema if left heart is spared
• Dyspnea may be less prominent than signs of venous congestion

Initial Clinical Assessment

Natriuretic Peptide Biomarkers

B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP)

• Mechanism: Released from ventricular myocytes in response to increased wall stretch and neurohormonal activation
• Cutoff values for HF diagnosis:
• BNP <100 pg/mL or NT-proBNP <125 pg/mL effectively rules out HF with high negative predictive value (>95%)
• BNP 100-500 pg/mL or NT-proBNP 125-900 pg/mL represent gray zone requiring further evaluation
• BNP >500 pg/mL or NT-proBNP >900 pg/mL support HF diagnosis but lack specificity
• Elevated in: HF (both systolic and diastolic), acute coronary syndrome, pulmonary embolism, sepsis, renal failure, atrial fibrillation, advanced age, obesity
• Falsely low in: Obesity (higher BMI dilutes the peptide), early stages of HF (especially acute), acute mitral regurgitation
• Clinical utility: Most useful in acute dyspnea to differentiate HF from non-cardiac causes (pneumonia, asthma, pulmonary embolism); guides risk stratification and prognosis; NT-proBNP superior to BNP in renal failure due to better stability

High-sensitivity troponin (hs-cTn)

• Elevation indicates myocardial injury from infarction, myocarditis, sepsis, renal failure, or HF
• Prognostic marker in HF; elevated levels correlate with increased mortality

Laboratory Studies

Comprehensive metabolic panel

• Serum creatinine and GFR: Assess renal function; worsening GFR may indicate cardiorenal syndrome
• Electrolytes (Na, K, Cl): Hyponatremia (<135 mEq/L) indicates worse prognosis; hyperkalemia relative to GFR limits ACE inhibitor/ARB/MRA use
• BUN: Elevated BUN-to-creatinine ratio (>20:1) suggests prerenal azotemia from hypoperfusion
• Liver function tests: Elevated transaminases and bilirubin from hepatic congestion; prolonged PT from impaired synthetic function

Complete blood count

• Anemia worsens HF symptoms and prognosis; assess for underlying causes
• Leukocytosis may indicate acute decompensation or superimposed infection

Lipid panel

• Baseline assessment for coronary disease risk

Thyroid-stimulating hormone (TSH)

• Rule out thyroid dysfunction (hyperthyroidism causing high-output HF, hypothyroidism as reversible cause)

Urinalysis

• Assess proteinuria and hematuria (renal disease association)

Electrocardiography

Systolic HF characteristic findings

• Reduced QRS voltage from

Acute decompensated HF (stabilise first)

• Oxygen/noninvasive positive-pressure ventilation: reduces preload and work of breathing in flash pulmonary edema.
• IV loop diuretic (furosemide): first-line for congestion; inhibits the Na-K-2Cl cotransporter. ACC/AHA/HFSA 2022 recommends IV rather than oral dosing in decompensation because gut wall edema impairs absorption.
• IV vasodilator (nitroglycerin): adjunct when blood pressure is adequate, especially hypertensive sympathetic crashing acute pulmonary edema.
• Inotropes/mechanical support: dobutamine or milrinone only for cardiogenic shock or end-organ hypoperfusion; they increase mortality if used routinely. Escalate to IABP/Impella/VA-ECMO as a bridge.

Chronic HFrEF — the four pillars of GDMT (ACC/AHA/HFSA 2022)

• ARNI (sacubitril/valsartan), or ACEI/ARB if ARNI unaffordable: blocks RAAS and augments natriuretic peptides.
• Beta blocker: only carvedilol, metoprolol succinate, or bisoprolol have mortality data; start when euvolemic, never during acute decompensation.
• MRA (spironolactone, eplerenone): blocks aldosterone-driven fibrosis; monitor K⁺ and creatinine.
• SGLT2 inhibitor (dapagliflozin, empagliflozin): benefit is independent of diabetes.

Add-on and second-line

• Loop diuretics: symptom control only, no mortality benefit.
• Hydralazine + isosorbide dinitrate: added for self-identified Black patients with persistent NYHA III–IV symptoms.
• Ivabradine (sinus rhythm, HR ≥70 on maximally tolerated beta blocker), vericiguat, digoxin (reduces hospitalisation, not mortality).

Device and surgical therapy

• ICD for LVEF ≤35%, NYHA II–III, after ≥3 months of GDMT and ≥40 days post-MI.
• CRT for LVEF ≤35% with LBBB and wide QRS.
• LVAD or transplant for stage D disease.

Complications of the disease

• Sudden cardiac death: scar and fibrosis create reentry; the arrest rhythm is ventricular fibrillation or pulseless VT. Emergency — immediate defibrillation; this is the rationale for prophylactic ICD.
• Atrial fibrillation: atrial stretch from elevated filling pressures; loss of atrial kick precipitates abrupt decompensation, especially in HFpEF where filling is pressure-dependent.
• Acute cardiogenic pulmonary edema / cardiogenic shock: emergencies signalled by hypoxemia with diffuse crackles, or hypotension with cool extremities, oliguria, and rising lactate.
• Cardiorenal syndrome: renal venous congestion plus low forward flow; signalled by rising creatinine during decongestion.
• Congestive hepatopathy/cardiac cirrhosis: chronic hepatic venous congestion; tender hepatomegaly, elevated bilirubin and transaminases, ascites.
• LV mural thrombus and systemic embolism: stasis in a dilated, akinetic ventricle (classically post-anterior MI apical aneurysm).
• Cardiac cachexia and iron deficiency: cytokine-driven catabolism; both independently predict mortality.

Complications of therapy

• Hyperkalemia (ACEI/ARB/ARNI plus MRA): aldosterone blockade impairs distal K⁺ secretion. Peaked T waves or a widening QRS is an emergency — IV calcium first.
• Angioedema (ACEI, ARNI): bradykinin accumulation; airway compromise is an emergency. Never overlap ARNI with an ACEI.
• Symptomatic hypotension and AKI from over-diuresis or rapid uptitration.
• Diuretic effects: hypokalemia, hypomagnesemia, contraction alkalosis, hyperuricemia/gout, ototoxicity with rapid IV loop infusion.
• Digoxin toxicity: nausea, yellow-green visual halos, and arrhythmia (classically atrial tachycardia with block); precipitated by hypokalemia and renal failure — give digoxin immune Fab.
• Spironolactone: gynecomastia from androgen-receptor antagonism — switch to eplerenone.
• SGLT2 inhibitors: genital mycotic infection, volume depletion, and euglycemic diabetic ketoacidosis.
• ICD: inappropriate shocks, lead infection/endocarditis.

• The four pillars are non-negotiable: HFrEF GDMT is ARNI (or ACEI/ARB) + beta blocker + MRA + SGLT2 inhibitor. A stem listing only three and asking for the missing agent is nearly always testing the SGLT2 inhibitor.
• S3 vs S4: an S3 gallop points to a dilated, volume-overloaded ventricle (HFrEF); an S4 reflects a stiff, hypertrophied ventricle (HFpEF, HCM) and cannot exist in atrial fibrillation.
• Best next step in undifferentiated acute dyspnea: BNP/NT-proBNP plus echocardiography. A low natriuretic peptide essentially excludes HF; echo assigns the phenotype and drives therapy.
• Sacubitril interferes with BNP, not NT-proBNP: neprilysin inhibition blocks BNP degradation, so BNP rises on ARNI while NT-proBNP (not a neprilysin substrate) falls. Use NT-proBNP to follow these patients.
• The 36-hour washout: switching from an ACEI to sacubitril/valsartan requires a 36-hour gap — overlapping bradykinin effects cause angioedema.
• Distractor to avoid: do not start or uptitrate a beta blocker in a patient who is acutely decompensated or in cardiogenic shock; the negative inotropy worsens output. Beta blockers are started once euvolemic.
• Distractor to avoid: verapamil and diltiazem are contraindicated in HFrEF. Amlodipine and felodipine are the safe calcium channel blockers if one is needed for hypertension or angina.
• Mortality vs symptoms: loop diuretics and digoxin improve symptoms and reduce hospitalisation but do not reduce mortality — a favorite trap.
• ICD timing: reassess LVEF after ≥3 months of optimal GDMT and wait ≥40 days after MI; many ventricles recover, and early implantation shows no survival benefit (ACC/AHA/HFSA 2022).
• The classic association: hydralazine plus isosorbide dinitrate is added for self-identified Black patients with persistent NYHA III–IV symptoms despite full GDMT.