What are the causes of hypertrophic cardiomyopathy?

Causes of Hypertrophic Cardiomyopathy

The majority (up to 60%) of hypertrophic cardiomyopathy in adolescents and adults is caused by autosomal dominant mutations in cardiac sarcomere protein genes, with beta-myosin heavy chain (MYH7) and myosin-binding protein C (MYBPC3) accounting for most cases. 1

Primary Genetic Causes

Sarcomere Protein Gene Mutations (Most Common)

• Sarcomere mutations account for 50-60% of all HCM cases in adolescents and adults, representing the predominant etiology 1

• The two most frequently mutated genes are:

  • Beta-myosin heavy chain (MYH7) 1
  • Myosin-binding protein C (MYBPC3) 1

• Less commonly affected sarcomere genes include:

  • Cardiac troponin I (TNNI3) 1
  • Cardiac troponin T (TNNT2) 1
  • Tropomyosin alpha-1 chain (TPM1) 1
  • Myosin light chain 3 (MYL3) 1
  • Alpha-actin 1
  • Regulatory and essential myosin light chains 1

• Over 1,400 different mutations have been identified across at least 8-10 sarcomere genes, with most being missense mutations causing single amino acid substitutions 1, 2

• Patients with sarcomere mutations typically present earlier, have more severe hypertrophy, greater microvascular dysfunction, more myocardial fibrosis, and higher prevalence of family history of HCM and sudden cardiac death compared to those without mutations 1

Metabolic Disorders (5-10% of Adult Cases)

Glycogen Storage Diseases

• Anderson-Fabry disease is the most common metabolic cause in adults, with prevalence of 0.5-1% in patients older than 35-40 years 1
• PRKAG2 mutations (encoding AMP-activated protein kinase gamma-2 regulatory subunit) account for approximately 1% of cases 1
• Danon disease (LAMP-2 mutations) has reported prevalence of 0.7-2.7% 1
• Pompe disease 1
• Most metabolic disorders are inherited as autosomal recessive traits, though some are X-linked 1
• Metabolic disorders account for a greater proportion of HCM in children and adolescents compared to adults 1

Mitochondrial Cardiomyopathies

• Caused by mutations in nuclear or mitochondrial DNA affecting respiratory chain protein complexes 1
• Transmitted through multiple inheritance patterns: autosomal dominant, autosomal recessive, X-linked, and maternally inherited 1
• Clinical presentation varies widely in age of onset and severity of organ involvement 1

Neuromuscular Diseases

• Friedreich's ataxia is the most common neuromuscular disease associated with HCM 1
• Other rare associations include:
  • Certain muscular dystrophies 1
  • Congenital skeletal myopathies (e.g., nemaline myopathy) 1
  • FHL-1 gene mutations causing muscle weakness and contractures 1
  • Desmin gene mutations (typically cause dilated/restrictive cardiomyopathy but can present as HCM with AV block) 1

Malformation Syndromes

• Ras/MAPK pathway mutations are the most common syndromic causes 1
• Specific syndromes include:
  • Noonan syndrome (most common, often diagnosed in childhood but milder forms may escape early detection) 1
  • LEOPARD syndrome 1
  • Costello syndrome 1
  • Cardiofaciocutaneous syndrome 1

Infiltrative Diseases

Cardiac Amyloidosis

• Causes progressive thickening of left and right ventricular myocardium, interatrial septum, and AV valves 1
• Three main types:
  • Light chain (AL) amyloidosis 1
  • Hereditary transthyretin (TTR)-related amyloidosis 1
  • Wild-type (senile) TTR amyloidosis (predominantly affects heart and carpal tunnel ligament) 1

Acute Myocarditis

• Myocardial edema and cellular infiltration can transiently mimic HCM, though usually accompanied by other clinical and laboratory findings 1

Endocrine Disorders

• Infants of diabetic mothers can develop transient ventricular hypertrophy even with good maternal diabetic control during pregnancy 1, 3
• Pheochromocytoma is associated with left ventricular hypertrophy in adults 1
• Acromegaly causes LVH that usually resolves with treatment of the underlying endocrine disorder 1

Drug-Induced Causes

• Tacrolimus 1
• Hydroxychloroquine 1
• Steroids 1

Unknown Etiology

• Approximately 25-30% of HCM cases remain genetically unexplained despite comprehensive genetic testing 1
• This percentage is higher (40-50%) in patients without a positive family history 1

Important Clinical Pitfalls

• In older patients with both LV hypertrophy and systemic hypertension, distinguishing coexistent HCM from hypertensive heart disease requires identification of diagnostic sarcomere mutations, marked LV thickness ≥25 mm, and/or LVOT obstruction with systolic anterior motion 1
• Metabolic and infiltrative storage disorders in infants, children, and young adults can clinically mimic sarcomeric HCM and require specific testing to differentiate 1
• The term "HCM" should be reserved for cases where disease is confined to the heart with sarcomere mutations or unresolved genotype; syndromic presentations should be termed as "[Syndrome name] with LV hypertrophy" rather than "[Syndrome name] hypertrophic cardiomyopathy" 1