What causes apical hypertrophic cardiomyopathy?

Causes of Apical Hypertrophic Cardiomyopathy

Primary Genetic Causes

Apical hypertrophic cardiomyopathy (AHCM) is primarily caused by mutations in cardiac sarcomere protein genes, with the most common being mutations in beta-myosin heavy chain (MYH7) and myosin-binding protein C (MYBPC3). 1 These genetic mutations account for the majority of AHCM cases, which is a rare variant of hypertrophic cardiomyopathy characterized by hypertrophy predominantly affecting the apex of the left ventricle.

The genetic basis of AHCM follows the same pattern as other forms of HCM:

• Sarcomere protein mutations - Account for 60-70% of cases with a positive family history and 10-50% of cases without a family history 1
• Inheritance pattern - Predominantly autosomal dominant, meaning each child of an affected individual has a 50% chance of inheriting the disease 1
• Genetic heterogeneity - At least 8 definitive genes can cause HCM, including:
  • Beta-myosin heavy chain (MYH7)
  • Myosin-binding protein C (MYBPC3)
  • Troponin T (TNNT2)
  • Troponin I (TNNI3)
  • Alpha tropomyosin (TPM1)
  • Actin (ACTC)
  • Regulatory light chain (MYL2)
  • Essential light chain (MYL3) 1

While AHCM is frequently sporadic, autosomal dominant inheritance has been reported in some families 2. The specific distribution of hypertrophy to the apex appears to be related to particular genetic variants, though the exact genotype-phenotype correlations remain under investigation.

Secondary Causes and Phenocopies

Several conditions can mimic or cause apical hypertrophic cardiomyopathy:

1. Metabolic disorders:

   • Anderson-Fabry disease (X-linked lysosomal storage disorder)
   • Glycogen storage diseases (e.g., PRKAG2 mutations, Danon disease)
   • Other lysosomal storage diseases 1

2. Neuromuscular diseases:

   • Friedreich's ataxia
   • Muscular dystrophies
   • Congenital skeletal myopathies 1

3. Malformation syndromes:

   • Noonan syndrome
   • LEOPARD syndrome
   • Costello syndrome 1

4. Infiltrative/inflammatory conditions:

   • Cardiac amyloidosis (AL and TTR types)
   • Acute myocarditis (transient hypertrophy) 1

5. Endocrine disorders:

   • Pheochromocytoma
   • Acromegaly
   • Transient ventricular hypertrophy in infants of diabetic mothers 1

6. Drug-induced causes:

   • Anabolic steroids
   • Tacrolimus
   • Hydroxychloroquine 1

Pathophysiological Mechanisms

The development of AHCM involves several pathophysiological processes:

1. Primary sarcomere dysfunction - Mutations lead to abnormal contractile proteins that affect sarcomere function

2. Myocyte disarray - Characteristic histopathological finding showing disorganized arrangement of cardiac muscle cells 1

3. Myocardial fibrosis - Progressive scarring that contributes to ventricular dysfunction

4. Microvascular dysfunction - Impaired coronary blood flow reserve leading to myocardial ischemia 1

5. Phenotypic expression modifiers - Environmental factors and modifier genes influence the severity and distribution of hypertrophy 1

Clinical Presentation and Complications

AHCM can present with various clinical manifestations:

• Asymptomatic (incidental finding)
• Chest pain
• Palpitations
• Dyspnea
• Syncope
• Atrial fibrillation
• Myocardial infarction
• Embolic events
• Ventricular fibrillation
• Congestive heart failure 2

The classic electrocardiographic finding in AHCM is giant negative T-waves in the precordial leads, which helps distinguish it from other forms of HCM 2, 3.

Diagnostic Considerations

AHCM may mimic other conditions affecting the left ventricular apex:

• LV apical cardiac tumors
• LV apical thrombus
• Isolated ventricular non-compaction
• Endomyocardial fibrosis
• Coronary artery disease 2

Important Clinical Pearls

1. AHCM has a higher prevalence in Japanese populations (approximately 15% of all HCM cases) compared to Western populations (approximately 3% of HCM cases) 3

2. The presence of multiple mutations in the same patient (found in about 5% of HCM cases) is associated with more severe disease expression 1

3. Genetic testing is essential for definitive diagnosis and family screening, but may not identify the causative mutation in all cases 1

4. Regular cardiac evaluation is recommended for first-degree relatives of AHCM patients, especially when genetic status is unknown 1

5. While AHCM generally has a more favorable prognosis than other forms of HCM, patients still require monitoring for arrhythmias and progression to heart failure 3