Cardiomyopathies (Dilated, Hypertrophic, Restrictive)

1. Introduction and Conceptual Framework

A. The Cardiomyopathy Paradigm

• Cardiomyopathies are heterogeneous myocardial diseases with mechanical or electrical dysfunction
• Defined by inappropriate ventricular hypertrophy or dilatation without loading conditions
• Often genetic but may be acquired across lifespan
• Major substrate for heart failure and sudden cardiac death
• Occur independent of coronary artery disease, hypertension, or valvular disease
• Advanced approach integrates hemodynamic phenotyping with etiological precision
• Key distinction: intrinsic myocardial disease versus secondary adaptive remodeling
• Pressure–volume relationships clarify phenotype overlap
• Wall stress governed by Laplace’s Law explains progression
• Cellular energetics determine long-term myocardial viability

B. The Fourth Universal Definition of Myocardial Infarction in Cardiomyopathy

• Cardiac troponin elevation common in non-ischemic cardiomyopathies
• Misinterpretation represents frequent diagnostic and testing error
• Framework distinguishes myocardial injury from infarction

1. Differentiation of Myocardial Injury vs. Infarction

• Myocardial injury defined by troponin above $99^{th}$ percentile URL
• Troponin elevation alone does not indicate infarction
• Chronic Myocardial Injury:
  • Stable, persistently elevated troponin levels
  • Seen in advanced dilated cardiomyopathy and amyloidosis
  • Mechanisms include apoptosis, turnover, and membrane leakage
• Acute Myocardial Injury:
  • Dynamic rise and/or fall of troponin values
  • Occurs during acute heart failure decompensation
  • Mediated by transient wall stress, not ischemia

2. Type 2 Myocardial Infarction (Myocardial Infarction Type 2 [MI])

• Most cardiomyopathy troponin elevations represent injury, not MI
• Type 2 MI requires objective ischemia plus troponin rise/fall
• Ischemia evidence includes symptoms, ECG changes, or imaging loss
• Caused by oxygen supply–demand mismatch
• Unrelated to acute coronary thrombosis
• Hypertrophic cardiomyopathy with tachyarrhythmia illustrates mechanism
• High myocardial mass increases oxygen demand
• Shortened diastole reduces subendocardial perfusion
• Results in genuine necrosis without plaque rupture

2. Hypertrophic Cardiomyopathy (HCM)

A. Definition and Epidemiology

• Most common inherited cardiovascular disease
• Clinically overt prevalence approximately $1:500$
• Genotype-positive prevalence approaches $1:200$
• Defined by left ventricular hypertrophy without abnormal loading conditions
• Characterized by often asymmetric septal hypertrophy
• Diagnostic Thresholds:
  • Adults: end-diastolic wall thickness $\ge 15$ mm
  • With genotype or family history: $\ge 13$ mm

B. Pathophysiology and Genetics

1. Sarcomere Mutations and Energetics

• Autosomal dominant disorder of sarcomeric proteins
• Mutations cause molecular gain-of-function
• High-Yield Associations:
  • MYBPC3 (Myosin-binding protein C): most common mutation
  • MYH7 (Beta-myosin heavy chain): earlier onset, severe hypertrophy
• Energy Starvation Hypothesis:
  • Normal myosin enters super-relaxed state conserving ATP
  • Mutations destabilize super-relaxed state
  • Myosin remains actin-ready during diastole
  • Causes hypercontractility with excessive ATP consumption
  • Leads to metabolic ischemia and fibrosis

2. Histopathology

• Pathognomonic feature is myocyte disarray
• Myocytes arranged in chaotic, whorled patterns
• Distinct from parallel alignment in hypertensive hypertrophy
• Replacement fibrosis and intramural coronary dysplasia present
• Architecture predisposes to re-entrant ventricular arrhythmias
• Major substrate for sudden cardiac death

3. Hemodynamics of Obstruction (Hypertrophic Obstructive Cardiomyopathy [HOCM])

• Approximately $70%$ exhibit LVOT obstruction
• Obstruction may be resting or provoked
• Anatomical Substrate:
  • Septal hypertrophy plus mitral apparatus abnormalities
• Systolic Anterior Motion (SAM):
  • High-velocity LVOT flow initiates leaflet displacement
  • Flow drag is dominant initiating force
• Double Effect of SAM:
  1. LVOT obstruction causing late-peaking systolic gradient
  2. Mitral regurgitation with posteriorly directed jet

C. Clinical Presentation and Vignette Cues

1. Symptomatology

• Dyspnea most common presenting symptom
• Driven by diastolic dysfunction and elevated LVEDP
• Angina occurs without epicardial coronary disease
• Caused by oxygen demand–supply mismatch
• Syncope represents critical prognostic red flag
  • Exertional syncope suggests obstruction or arrhythmia
  • Post-exertional syncope due to preload drop and vasodilation

2. Physical Examination: The Dynamic Murmur

• Harsh crescendo–decrescendo systolic murmur
• Best heard at left lower sternal border and apex
• Does not radiate to carotids
• Murmur intensity inversely proportional to LV volume
• Smaller LV cavity increases SAM and obstruction
• Larger LV cavity relieves obstruction

• Memory anchor: Less LV volume produces louder murmur

D. Diagnostic Evaluation and Risk Stratification

1. Multimodality Imaging

• Echocardiography: primary diagnostic modality
  • ASH, SAM, mid-systolic aortic closure
  • LVOT gradient $\ge 30$ mmHg indicates obstruction
  • LVOT gradient $\ge 50$ mmHg defines severe obstruction
• Cardiac Magnetic Resonance (CMR):
  • Late gadolinium enhancement reflects fibrosis
  • LGE $\ge 15%$ predicts sudden death risk
  • Detects apical aneurysms accurately

2. Sudden Cardiac Death Risk Stratification

• ICD decisions based on major risk factors
• Major Risk Factors:
  1. Family history of sudden cardiac death $\le 50$ years
  2. Maximal wall thickness $\ge 30$ mm
  3. Recent or exertional unexplained syncope
  4. Apical aneurysm of any size
  5. LVEF $< 50%$ indicating end-stage disease
• Risk modifiers include NSVT and extensive LGE

E. Management Principles

1. Pharmacotherapy for Symptom Management

• Goal is obstruction relief and diastolic filling improvement
• First-Line: Non-vasodilating beta-blockers
• Second-Line: Non-dihydropyridine calcium channel blockers
• Refractory Symptoms: Disopyramide

2. Disease-Specific Therapy: Cardiac Myosin Inhibitors

• Mavacamten reduces hypercontractility
• Stabilizes myosin super-relaxed state
• Indicated for symptomatic obstructive HCM
• Requires LVEF monitoring and REMS protocol

3. Septal Reduction Therapy

• Indicated for NYHA III–IV with gradient $\ge 50$ mmHg
• Surgical myectomy preferred in young or massive septum
• Alcohol septal ablation for high surgical risk

4. Lifestyle, Athletics, and Pregnancy

• Low-to-moderate exercise encouraged
• Competitive sports require expert evaluation
• Beta-blockers continued in pregnancy
• DOACs contraindicated

3. Dilated Cardiomyopathy (DCM)

A. Definition and Diagnosis

• LV dilation with systolic dysfunction
• Defined by LVEF $<50%$
• Exclude coronary artery disease mandatorily

B. Etiology-Specific Management

• Alcohol-associated cardiomyopathy
• Peripartum cardiomyopathy
• Chagas cardiomyopathy
• Chemotherapy-induced cardiomyopathy
• Genetic dilated cardiomyopathy (TTN)

C. Guideline-Directed Medical Therapy (GDMT)

Four Pillars of HFrEF

1. ARNI (Sacubitril–Valsartan)
2. Evidence-based beta-blockers
3. Mineralocorticoid receptor antagonists
4. SGLT2 inhibitors

D. Advanced Heart Failure: The Referral Trigger

• Stage D HF requires early referral

4. Restrictive Cardiomyopathy (RCM) and Differential

A. RCM vs. Constrictive Pericarditis

• Both present with preserved EF and right HF
• RCM is myocardial disease
• CP is pericardial disease
• Systolic function declines late → transplant-stage disease

1. Shared Features

• Kussmaul’s sign
• Square root sign

2. Ventricular Interdependence

• CP shows discordant pressures
• RCM shows concordant pressures

B. Cardiac Amyloidosis

• AL amyloidosis is medical emergency
• ATTR amyloidosis increasingly treatable

C. Other Causes of RCM

• Sarcoidosis
• Hemochromatosis
• Loeffler’s endocarditis

5. Conclusion: The Master Framework

• HCM requires dynamic gradient assessment and SCD prevention
• DCM demands etiologic exclusion before idiopathic labeling
• RCM mandates exclusion of constrictive pericarditis
• Amyloidosis recognition is now core competency

6. Quick-Recap: High-Yield Associations Table