6.2 Heart Failure & Cardiomyopathies

Heart failure (HF) represents a clinical syndrome characterized by cardinal symptoms (breathlessness, fatigue, ankle swelling) and objective structural or functional cardiac abnormalities. For MRCP(UK) Part 1, candidates must master the diagnostic thresholds for natriuretic peptides, evidence-based pharmacology across the ejection fraction spectrum, device indications, and the distinct phenotypes of inherited and acquired cardiomyopathies.

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1. Classification & Diagnostic Evaluation of Heart Failure

Universal Definition & Ejection Fraction Categories

The international consensus defines heart failure according to left ventricular ejection fraction (LVEF):

• HFrEF (Heart Failure with reduced Ejection Fraction): $\text{LVEF} \le 40%$. Characterized by ventricular dilatation, progressive eccentric remodelling, and marked activation of the sympathetic and renin-angiotensin-aldosterone systems (RAAS).
• HFmrEF (Heart Failure with mildly reduced Ejection Fraction): $\text{LVEF } 41\text{–}49%$. Shares phenotypic traits with both HFrEF and HFpEF; post-hoc analyses show significant benefit from HFrEF neurohormonal therapies.
• HFpEF (Heart Failure with preserved Ejection Fraction): $\text{LVEF} \ge 50%$. Characterized by impaired diastolic relaxation, increased passive myocardial stiffness, left ventricular hypertrophy (LVH), and left atrial hypertension.

Natriuretic Peptides: Diagnostic Thresholds & Caveats

Myocytes release B-type natriuretic peptide (BNP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in response to increased myocardial wall stretch and transmural pressure.

• NICE Referral Pathways:
  • $\text{NT-proBNP} > 2000\text{ pg/mL}$ ($> 236\text{ pmol/L}$): Urgent specialist clinical assessment and transthoracic echocardiography (TTE) within 2 weeks.
  • $\text{NT-proBNP } 400\text{–}2000\text{ pg/mL}$ ($47\text{–}236\text{ pmol/L}$): Specialist assessment and TTE within 6 weeks.
  • $\text{NT-proBNP} < 400\text{ pg/mL}$ ($< 47\text{ pmol/L}$): Heart failure is highly unlikely (negative predictive value $> 95%$). Consider alternative diagnoses.
• Clinical Confounders:
  • Elevated Levels: Advanced age ($> 75$ years), female sex, renal impairment (reduced glomerular clearance), atrial fibrillation (continuous atrial stretch), pulmonary embolism, sepsis, severe COPD.
  • Depressed Levels: Obesity ($\text{BMI} \ge 30\text{ kg/m}^2$) reduces circulating natriuretic peptide levels by approximately $30\text{–}50%$ due to upregulation of clearance receptors (NPR-C) and blunted cardiac peptide synthesis.

Echocardiographic Diastolic Function Assessment

Diastolic dysfunction underpins HFpEF and is evaluated via transmitral pulsed-wave and tissue Doppler imaging:

• Mitral Inflow E/A Ratio: Ratio of peak velocity of early passive filling ($E$ wave) to late atrial contraction ($A$ wave). Normal is $1.0\text{–}2.0$. Grade I (impaired relaxation): $E/A < 0.8$; Grade II (pseudonormal): $E/A\ 0.8\text{–}2.0$; Grade III (restrictive filling): $E/A > 2.0$ with deceleration time $< 140\text{ ms}$.
• $E/e'$ Ratio: Ratio of mitral inflow $E$ velocity to early diastolic mitral annular tissue velocity ($e'$). An average $E/e' > 14$ is a robust surrogate for elevated left ventricular end-diastolic pressure (LVEDP) and pulmonary capillary wedge pressure ($> 15\text{ mmHg}$).
• Left Atrial Volume Index (LAVI): $\text{LAVI} > 34\text{ mL/m}^2$ reflects chronic exposure to elevated left ventricular filling pressures.

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2. Guideline-Directed Medical Therapy (GDMT): The Four Pillars of HFrEF

All patients with HFrEF should be rapidly uptitrated onto the "four pillars" of guideline-directed medical therapy, each proven in landmark clinical trials to independently reduce all-cause mortality, cardiovascular death, and heart failure hospitalizations.

MRCP Exam Pearl: Diuretics: Loop diuretics (furosemide, bumetanide) and thiazides provide essential symptomatic decongestion and preload reduction, but have never been shown to reduce mortality. Always use the lowest dose required to maintain euvolaemia.

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3. Secondary Pharmacotherapy & Device Indications

Second-Line Pharmacotherapy

• Ivabradine: Selective inhibitor of hyperpolarization-activated cyclic nucleotide-gated ($I_f$) funny channels in the sinoatrial node, slowing heart rate without negative inotropy. Indications: HFrEF ($\text{LVEF} \le 35%$) in sinus rhythm with resting heart rate $\ge 70\text{ bpm}$ despite maximal tolerated beta-blocker therapy (SHIFT trial). Contraindicated in atrial fibrillation.
• Hydralazine + Isosorbide Dinitrate (H-ISDN): Arteriolar vasodilator plus venodilator / nitric oxide donor. Indications: Self-identified Black/African-Caribbean patients with persistent NYHA class III–IV symptoms despite optimal 4-pillar GDMT (A-HeFT trial), or patients intolerant to ARNI/ACEi/ARB due to renal dysfunction or severe hyperkalaemia.
• Vericiguat: Direct stimulator of soluble guanylate cyclase (sGC), augmenting cyclic GMP signaling. Indicated in high-risk HFrEF with recent worsening heart failure hospitalization or elevated natriuretic peptides despite GDMT (VICTORIA trial).
• Digoxin: Inhibits myocardial $\text{Na}^+/\text{K}^+$-ATPase. Reduces heart failure hospitalizations without altering overall mortality (DIG trial). Narrow therapeutic range ($0.5\text{–}0.9\text{ ng/mL}$); hypokalaemia precipitates life-threatening digoxin toxicity.

Device Therapies: ICD & CRT

• Implantable Cardioverter-Defibrillator (ICD):
  • Primary Prevention: Indicated for patients with $\text{LVEF} \le 35%$ after at least 3 months of optimal medical therapy, NYHA functional class II–III, and good functional status with life expectancy $> 1\text{ year}$. In ischaemic cardiomyopathy, ICD implantation must be delayed until at least 40 days post-infarction to exclude recovery.
• Cardiac Resynchronisation Therapy (CRT):
  • Delivers biventricular pacing via leads in the right atrium, right ventricle, and coronary sinus (pacing the left ventricular lateral wall) to eliminate ventricular dyssynchrony.
  • Indications (NICE / ESC): $\text{LVEF} \le 35%$, NYHA class II–IV despite optimal medical therapy, in sinus rhythm with $\text{QRS duration} \ge 130\text{ ms}$ with LBBB morphology (greatest benefit seen when $\text{QRS} \ge 150\text{ ms}$). CRT-D incorporates defibrillator capability, whereas CRT-P provides resynchronisation pacing alone.

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4. Cardiomyopathies: Inherited & Secondary Myocardial Diseases

Hypertrophic Cardiomyopathy (HCM)

• Genetics & Histopathology: Autosomal dominant inheritance with incomplete penetrance. Caused by missense mutations in sarcomeric contractile proteins, predominantly $\beta$-myosin heavy chain ($MYH7$, ~35%) and myosin-binding protein C ($MYBPC3$, ~35%). Histopathology reveals marked myocyte hypertrophy, interstitial fibrosis, and characteristic myocyte disarray (loss of parallel myofibrillar architecture).
• Pathophysiology: Asymmetric septal hypertrophy (ASH; ratio of septal to posterior wall thickness $> 1.3$) creates high-velocity systolic ejection, pulling the anterior mitral leaflet into the left ventricular outflow tract (Systolic Anterior Motion [SAM] via the Venturi effect and flow drag). This causes dynamic LVOT obstruction and eccentric mitral regurgitation.
• Auscultation & Dynamic Maneuvers: Harsh crescendo-decrescendo ejection systolic murmur best heard at the lower left sternal border:
  • Intensified by: Decreased preload or decreased afterload (Valsalva strain, standing, vasodilators, nitrates), which shrink LV cavity dimensions and narrow the outflow tract.
  • Softened by: Increased preload or increased afterload (squatting, handgrip, passive leg raising), which expand LV dimensions.
• Pharmacotherapy & Contraindications: First-line agents are non-vasodilating beta-blockers (bisoprolol, atenolol) or rate-limiting calcium channel blockers (verapamil) to prolong diastole and enhance filling. Mavacamten (cardiac myosin ATPase inhibitor) is licensed for symptomatic obstructive HCM. Strictly contraindicated: Nitrates, ACE inhibitors, dihydropyridine CCBs, and digoxin (exacerbate the dynamic LVOT gradient).
• Sudden Cardiac Death (SCD) Risk Stratification: Risk factors include massive LV hypertrophy (maximal wall thickness $\ge 30\text{ mm}$), unexplained syncope, non-sustained VT on ambulatory Holter, family history of premature SCD, extensive late gadolinium enhancement ($\text{LGE} > 15%$) on CMR, and apical LV aneurysm. High-risk patients require primary prevention ICD.

Dilated Cardiomyopathy (DCM)

• Etiology: Familial/genetic in up to 40% (mutations in titin [$TTN$] in 25%, lamin A/C [$LMNA$] associated with high risk of conduction block and malignant arrhythmias). Acquired causes: viral myocarditis (coxsackie B, parvovirus B19), toxic (chronic alcohol abuse, anthracyclines [doxorubicin], trastuzumab), autoimmune, and peripartum cardiomyopathy.
• Echocardiography: Left ventricular dilation with spherical remodelling, eccentric hypertrophy, and diffuse global hypokinesis resulting in severe systolic impairment. Management follows standard HFrEF 4-pillar GDMT and primary prevention ICD.

Restrictive Cardiomyopathy (RCM) & Cardiac Amyloidosis

• Pathophysiology: Rigid, non-compliant ventricular myocardium causing severe diastolic filling impairment with normal or near-normal systolic function and preserved ventricular wall thickness (or pseudohypertrophy).
• Cardiac Amyloidosis: Infiltration of insoluble fibrillar amyloid deposits:
  • AL (Light-Chain) Amyloidosis: Clonal plasma cell dyscrasia producing monoclonal kappa or lambda light chains. Rapidly progressive heart failure, macroglossia, periorbital purpura.
  • ATTR (Transthyretin) Amyloidosis: Wild-type (senile, typically men $> 70$ years) or hereditary (mutations in the $TTR$ gene). Associated with bilateral carpal tunnel syndrome, spinal stenosis, and biceps tendon rupture years prior to cardiac diagnosis.
  • Diagnostic Signatures:
    • ECG: Low voltage QRS complexes across limb leads paradoxical to marked ventricular wall thickening on echocardiography ("voltage-mass discordance").
    • Echocardiography: Granular, sparkling ground-glass myocardial appearance, biatrial enlargement, and longitudinal strain showing apical sparing ("cherry-on-top" pattern).
    • Cardiac MRI: Diffuse global subendocardial or transmural late gadolinium enhancement with abnormal myocardial nulling kinetics.
    • Technetium-99m DPD / PYP Scintigraphy: Intense Grade 2 or 3 cardiac tracer uptake confirms ATTR amyloidosis non-invasively, eliminating the need for endomyocardial biopsy if serum and urine clonal light chains are negative. Tafamidis stabilizes the transthyretin tetramer, improving survival in ATTR.
  • Biopsy: Demonstrates Congo red staining with pathognomonic apple-green birefringence under polarized light.

Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC)

• Pathophysiology: Autosomal dominant mutations in desmosomal proteins (plakophilin-2 [$PKP2$], desmoplakin, plakoglobin [Naxos disease with woolly hair and palmoplantar keratoderma]). Mechanical stress detaches myocytes, leading to fibrofatty replacement of the right ventricular free wall within the "triangle of dysplasia" (RV inflow, apex, and outflow tract).
• Clinical & ECG Findings: Palpitations, syncope, and ventricular tachycardia with LBBB morphology and superior axis (arising from the RV free wall). Resting 12-lead ECG demonstrates:
  1. Epsilon wave: Pathognomonic distinct low-amplitude deflection or notch at the terminal end of the QRS complex in leads V1–V3 (present in ~30%).
  2. T-wave inversion in leads V1–V3 in individuals $> 14$ years of age (in the absence of complete RBBB).
  3. Prolonged S-wave upstroke ($\ge 55\text{ ms}$) in V1–V3.
• Management: Competitive athletics and endurance sports are strictly prohibited (accelerates disease progression). First-line therapy includes beta-blockers and early ICD implantation for high-risk patients.