Cardiomyopathy: From Basics to Clinical Management

What Is Cardiomyopathy?

• Primary cardiomyopathies - predominantly involve the heart muscle (genetic, mixed, or acquired)
• Secondary cardiomyopathies - heart muscle involvement as part of a systemic disease

Source: Goldman-Cecil Medicine, Fuster and Hurst's The Heart 15e, Harrison's Principles 22e

Classification by Pathophysiology

1. Dilated Cardiomyopathy (DCM)

Definition

Causes

• Autosomal dominant inheritance is the predominant pattern

• 50 genes implicated; most common are mutations in titin (TTN) - accounting for ~25% of familial cases

• Also: beta-myosin heavy chain (MYH7), cardiac troponin T, alpha-myosin heavy chain
• The mutations primarily cause loss of function in cytoskeletal or sarcomere proteins (contrast with HCM which is gain-of-function)
• X-linked: mutations in dystrophin (as in Duchenne/Becker muscular dystrophy)

• Infectious myocarditis (viral - coxsackievirus B, parvovirus B19, adenovirus)
• Alcohol - toxic effect of alcohol and acetaldehyde on myocardium
• Chemotherapy (e.g., doxorubicin/anthracyclines)
• Peripartum/pregnancy
• Radiation therapy
• Nutritional deficiencies (thiamine, selenium)
• Iron overload (hemochromatosis)
• Cocaine, tachycardia-mediated, sarcoidosis

Pathophysiology

• Reduced stroke volume and cardiac output
• Elevated filling pressures → pulmonary congestion
• Ventricular dilation promotes dispersion of depolarization/repolarization → risk of ventricular arrhythmias and sudden death

Clinical Features

• Progressive dyspnea (exertional, then at rest)
• Fatigue, reduced exercise tolerance
• Signs of heart failure: S3 gallop, displaced apex beat, peripheral edema, elevated JVP
• Mitral/tricuspid regurgitation due to annular dilation
• Embolic events (mural thrombus in dilated ventricle)

Investigations

• Echo: Dilated LV with globally reduced EF, wall motion abnormality
• ECG: Left bundle branch block, non-specific ST changes, arrhythmias
• BNP/NT-proBNP: Elevated, reflects wall stress
• Genetics: TTN mutation screening in familial cases

2. Hypertrophic Cardiomyopathy (HCM)

Definition

Echocardiogram of HCM

Echocardiogram of HCM: asymmetric hypertrophy of the septum compared to the lateral wall of the LV. The mitral valve (MV) is moving anteriorly toward the hypertrophied septum in systole (SAM - systolic anterior motion). LA is enlarged. - Harrison's Principles 22e

Genetics

• ~40-50% have a sarcomere gene variant; ~80% of those involve MYH7 (beta-myosin heavy chain) or MYBPC3 (myosin-binding protein C)

• 1500 genetic variants identified across >9 genes

• Autosomal dominant, but with age-dependent and incomplete penetrance
• The hypertrophic phenotype is rarely present at birth; usually develops in adolescence/young adulthood
• The mutations cause a gain of function at the sarcomere level - enhanced calcium sensitivity, maximal force generation, and ATPase activity - leading to abnormal energetics and impaired relaxation

Histology of HCM

HCM histology: disarrayed myocyte architecture with swirling and branching fibers. Myocyte nuclei vary markedly in size. Interstitial fibrosis is present. - Harrison's Principles 22e

Pathophysiology

• Diastolic dysfunction is the primary problem - the stiff, hypertrophied LV cannot relax properly, impairing filling
• LVOT obstruction is present in ~30% at rest and can be provoked by exercise in another ~30%
• Obstruction mechanism: drag forces push the anteriorly displaced anterior mitral leaflet into the hypertrophied septum during systole (SAM - systolic anterior motion) → outflow tract narrowing + posteriorly directed mitral regurgitation
• Conditions that reduce preload (dehydration) or afterload (vasodilators) worsen obstruction
• The classic murmur: harsh, late-peaking systolic ejection murmur at the LLSB, increased by Valsalva and standing (decreased ventricular volume worsens obstruction), decreased by squatting

Clinical Features

• Exertional dyspnea, angina, syncope (especially with exertion)
• Sudden cardiac death (most feared, especially in young athletes)
• Palpitations (AF, VT)
• Family history in ~50%
• Risk of sudden death increases ~1% per year

HCM vs. Athlete's Heart

3. Restrictive Cardiomyopathy (RCM)

Definition

Causes

• Infiltrative: Amyloidosis (AL or ATTR type - most important), sarcoidosis
• Storage diseases: Hemochromatosis (iron overload), Fabry disease, glycogen storage diseases
• Fibrotic: Post-radiation fibrosis, post-cardiac surgery, hypereosinophilic syndrome
• Endomyocardial fibrosis (EMF): A tropical disease causing obliteration of ventricular apices
• Löeffler endocarditis: Eosinophilic infiltration

Key: Cardiac Amyloidosis

Clinical Features

• Dyspnea, fatigue, peripheral edema
• Elevated JVP with Kussmaul's sign (JVP rises on inspiration, opposite to normal)
• S3 and S4 gallop
• Right heart failure may be prominent
• Must be distinguished from constrictive pericarditis (both cause diastolic restriction)

4. Arrhythmogenic (Right Ventricular) Cardiomyopathy (ARVC)

• Right-sided heart failure
• Ventricular arrhythmias with LBBB morphology (originating from RV)
• Syncope and sudden cardiac death
• ECG: epsilon wave (a small notch after the QRS in V1-V3), T-wave inversions in right precordial leads
• Caused by mutations in desmosomal proteins (plakophilin-2 most common, desmoplakin, desmoglein-2)
• ICD implantation recommended for high-risk patients

Comparing All Four Types: Summary Table

Approach to Diagnosis

1. History: Family history of SCD, heart failure, symptoms (dyspnea, syncope, palpitations)
2. Physical exam: Murmurs, S3/S4, signs of heart failure
3. ECG: LBBB in DCM; LVH + deep T inversions in HCM; epsilon wave in ARVC; low voltage + pseudo-infarct in amyloid
4. Echocardiography: First-line imaging - defines anatomy, EF, wall motion, LVOT gradient
5. Cardiac MRI: Gold standard for tissue characterization (fibrosis by late gadolinium enhancement, fatty infiltration in ARVC)
6. Genetic testing: Recommended in familial disease; guides family screening
7. Endomyocardial biopsy: For suspected infiltrative disease (amyloid, sarcoid, myocarditis)
8. Lab: BNP, troponin, iron studies, TTR gene sequencing

General Treatment Principles

DCM / Heart Failure with Reduced EF

1. ACE inhibitors / ARBs / ARNi (sacubitril-valsartan) - reduce afterload and remodeling
2. Beta-blockers (carvedilol, metoprolol succinate, bisoprolol) - reduce heart rate, improve remodeling
3. Mineralocorticoid receptor antagonists (spironolactone, eplerenone) - reduce fibrosis
4. SGLT2 inhibitors (dapagliflozin, empagliflozin) - reduce hospitalizations and mortality

HCM

• Avoid vasodilators, diuretics (worsen obstruction)
• Beta-blockers or calcium channel blockers (verapamil) for symptoms
• Disopyramide for refractory LVOT obstruction
• Mavacamten (cardiac myosin inhibitor) - new targeted therapy, reduces LVOT gradient
• Septal reduction therapy (surgical myectomy or alcohol septal ablation) for severely symptomatic obstruction
• ICD implantation for high-risk patients (SCD risk factors: wall thickness ≥30 mm, VT, family history of SCD, syncope)

RCM

• Treat the underlying cause (chelation for hemochromatosis, steroids for sarcoid)
• Diuretics cautiously (preload-dependent filling)
• Heart transplantation for end-stage disease

ARVC

• ICD (primary prevention in high-risk)
• Beta-blockers, sotalol, amiodarone for arrhythmia suppression
• Avoid intense competitive sports
• Catheter ablation for refractory VT

Myocarditis and Its Link to DCM

Key Points to Remember

• Cardiomyopathy = intrinsic heart muscle disease - not from ischemia, valve disease, or hypertension
• DCM: dilated + weak pump (systolic failure); most common type
• HCM: thick + stiff (diastolic failure, outflow obstruction); #1 cause of sudden death in young athletes
• RCM: stiff + non-compliant (filling problem); least common; think amyloid
• ARVC: fibro-fatty RV replacement; arrhythmia and SCD in young adults
• Genetics plays a central role in all four types - family screening is mandatory
• Echocardiogram is first-line; cardiac MRI for tissue characterization