Genetics of Hypertrophic Cardiomyopathy

Introduction

Hypertrophic cardiomyopathy (HCM) is among the most studied genetic cardiovascular disorders. It is characterized by abnormal thickening (hypertrophy) of the left ventricular myocardium, occurring in the absence of other conditions that could explain hypertrophy, such as systemic hypertension or valvular aortic stenosis. Since its first descriptions in the mid-20th century, HCM has transitioned from being considered a rare curiosity to one of the most common inherited heart diseases, affecting approximately 1 in 200–500 individuals worldwide.

What makes HCM especially intriguing is its genetic foundation and highly variable clinical expression. Some individuals remain asymptomatic throughout life, while others develop progressive heart failure, arrhythmias, or sudden cardiac death (SCD), often at a young age. The interplay between genetic mutations, molecular pathways, and mechanical consequences drives the disease process.

This article provides a comprehensive exploration of the genetics of HCM and its pathophysiology, covering the major gene mutations, inheritance patterns, molecular mechanisms, and how these genetic changes translate into structural and functional alterations of the heart.

Genetic Basis of Hypertrophic Cardiomyopathy

Inheritance Pattern

HCM follows an autosomal dominant inheritance with variable penetrance. This means that:

A single copy of the defective gene is sufficient to predispose to disease.
Not all carriers exhibit clinical manifestations due to incomplete penetrance.
The severity of hypertrophy and clinical course vary even within the same family.

Major Genes Involved in HCM

HCM is fundamentally a disease of the sarcomere, the contractile unit of cardiac muscle. More than 11 core genes encoding sarcomeric proteins are implicated, with two accounting for the majority of cases:

MYH7 (β-myosin heavy chain)
- One of the first identified genes in HCM.
- Mutations alter cross-bridge cycling kinetics, increasing energy cost of contraction.
- Typically associated with severe hypertrophy and earlier onset.
MYBPC3 (myosin-binding protein C)
- The most commonly mutated gene in HCM.
- Truncating mutations lead to haploinsufficiency and abnormal sarcomere assembly.
- Often associated with later-onset, milder hypertrophy but significant risk of heart failure.

Other important genes include:

TNNT2 (cardiac troponin T) – linked with increased risk of arrhythmias and sudden death, sometimes with minimal hypertrophy.
TNNI3 (cardiac troponin I) – associated with variable hypertrophy and restrictive physiology.
TPM1 (α-tropomyosin) – rare, but associated with severe outcomes.
ACTC1 (cardiac actin) – involved in sarcomere integrity.
MYL2 and MYL3 (regulatory and essential myosin light chains) – contribute to altered contractility.

Collectively, these genes underscore the concept that HCM is a disease of sarcomeric dysfunction.

Genetic Heterogeneity and Modifiers

While sarcomeric mutations explain the majority of cases, several additional layers of complexity exist:

Non-sarcomeric genes: In rare syndromic forms (e.g., PRKAG2 mutation causing glycogen storage cardiomyopathy, or LAMP2 mutation in Danon disease), hypertrophy mimics HCM.
Modifier genes: Variations in other loci may influence severity, progression, and risk of complications.
Epigenetics and environment: Lifestyle, exercise, hypertension, and metabolic status can modify disease expression.

Molecular Pathophysiology of HCM

The genetic defects in HCM translate into molecular abnormalities that disrupt normal cardiac physiology.

1. Sarcomeric Dysfunction

Mutations alter the interaction of actin and myosin filaments.
Some mutations increase the calcium sensitivity of myofilaments, leading to hypercontractility.
Others increase the energetic cost of contraction, exhausting ATP reserves and impairing relaxation.

2. Impaired Energy Metabolism

HCM is often described as an “energy-starved” heart.
Increased ATP consumption during contraction is not matched by adequate production, leading to energetic inefficiency.
This contributes to diastolic dysfunction and triggers maladaptive signaling pathways.

3. Myocyte Hypertrophy

To compensate for altered force generation, myocytes enlarge.
This hypertrophy leads to increased wall thickness and abnormal geometry of the LV.
However, hypertrophy is often asymmetric, affecting the interventricular septum more prominently.

4. Fibrosis and Extracellular Matrix Remodeling

Chronic stress activates fibroblasts and promotes deposition of collagen.
Fibrosis stiffens the ventricle and disrupts electrical conduction pathways.
This substrate is central to the development of arrhythmias.

5. Abnormal Calcium Handling

Genetic mutations disrupt normal calcium cycling between the sarcoplasmic reticulum and cytoplasm.
Excess calcium prolongs contraction and delays relaxation.
Calcium overload also predisposes to arrhythmogenic activity.

Morphological Features of HCM

Left Ventricular Hypertrophy (LVH)

The hallmark of HCM is unexplained LV hypertrophy, most often asymmetric.
Septal hypertrophy can obstruct the left ventricular outflow tract (LVOT).
Wall thickness >15 mm is typically diagnostic in adults.

Myocyte Disarray

Histological hallmark of HCM: myofiber disarray where cardiac muscle cells lose their parallel alignment.
Disarray promotes arrhythmogenesis by creating conduction heterogeneity.

Interstitial and Replacement Fibrosis

Seen on histology and cardiac MRI with late gadolinium enhancement.
Correlates with arrhythmic risk and adverse outcomes.

Clinical Pathophysiology of HCM

Genetic and molecular defects translate into a variety of clinical consequences.

1. Diastolic Dysfunction

Stiff, hypertrophied ventricles impair filling during diastole.
Elevated LV filling pressures cause symptoms like dyspnea and exercise intolerance.

2. Left Ventricular Outflow Tract (LVOT) Obstruction

Hypertrophied septum and systolic anterior motion (SAM) of the mitral valve obstruct blood flow.
Dynamic obstruction worsens with exercise or reduced preload.
Leads to syncope, angina, and heart failure symptoms.

3. Microvascular Ischemia

Hypertrophy increases oxygen demand while capillary density fails to keep up.
Small-vessel disease and fibrosis further reduce coronary flow reserve.
Patients often experience angina even without epicardial coronary artery disease.

4. Arrhythmias

Atrial fibrillation is common due to elevated atrial pressures and fibrosis.
Ventricular arrhythmias are a major cause of sudden cardiac death, particularly in young athletes.

5. Progression to Heart Failure

Some patients evolve from hyperdynamic LV function to dilated, end-stage HCM with systolic dysfunction.
This phenotype overlaps with dilated cardiomyopathy.

Genetics and Risk Stratification in HCM

Sudden Cardiac Death (SCD) Risk

SCD is a feared complication, often occurring in young individuals.
Genetic variants (especially in TNNT2) increase arrhythmogenic potential.
Risk factors: family history of SCD, massive hypertrophy (>30 mm), syncope, abnormal blood pressure response, nonsustained VT.

Role of Genetic Testing

Helps confirm diagnosis in borderline cases.
Enables cascade screening in families.
Identifies high-risk mutations.
Guides counseling on lifestyle, exercise, and ICD implantation.

Advances in Genetic Research

Next-Generation Sequencing (NGS)

Has broadened the spectrum of known mutations.
Enables rapid and cost-effective screening of multiple genes.

Polygenic Risk Scores

Researchers are exploring whether cumulative effects of multiple small genetic variations influence disease severity.

Epigenetics and Non-Coding RNAs

MicroRNAs and other regulatory RNAs play roles in hypertrophy, fibrosis, and arrhythmogenesis.
These are emerging therapeutic targets.

Therapeutic Implications

Current Therapies (Symptom Control)

Beta-blockers and calcium channel blockers: Improve diastolic filling and reduce LVOT gradients.
Disopyramide: Used in obstructive HCM to reduce contractility.
Anticoagulation: Indicated in AF to prevent stroke.

Invasive and Device Therapies

Septal myectomy: Surgical removal of part of the hypertrophied septum.
Alcohol septal ablation: Catheter-based alternative.
Implantable cardioverter-defibrillators (ICDs): Prevent SCD in high-risk patients.

Emerging Targeted Therapies

Mavacamten (a myosin inhibitor): Reduces hypercontractility and improves symptoms in obstructive HCM.
Gene therapy: Still in experimental stages, aimed at correcting underlying mutations.

Future Directions

Precision medicine: Tailoring therapies based on specific mutations and molecular signatures.
Early detection: Screening of at-risk individuals before phenotype develops.
Preventive therapy: Using drugs like myosin inhibitors in genotype-positive/phenotype-negative individuals.
Regenerative approaches: Stem cell therapy to replace fibrotic tissue.