Etiology of Hypertrophic Obstructive Cardiomyopathy
Hypertrophic obstructive cardiomyopathy is primarily a genetic disease caused by autosomal dominant mutations in genes encoding cardiac sarcomere proteins, with 30-60% of patients having an identifiable pathogenic variant. 1
Genetic Etiology
Primary Sarcomeric Mutations
The two most common causative genes are MYH7 (beta-myosin heavy chain) and MYBPC3 (myosin-binding protein C), which together account for 70% of all genetically-positive cases. 1, 2
Eight sarcomere genes are definitively established as causative: beta-myosin heavy chain, myosin-binding protein C, cardiac troponin T (TNNT2), cardiac troponin I (TNNI3), alpha-tropomyosin (TPM1), actin (ACTC1), regulatory light chain (MYL2), and essential light chain (MYL3). 1
Each of these non-MYH7/MYBPC3 genes accounts for only 1-5% of variant-positive patients individually. 1
Over 1,500 distinct variants have been identified across these genes, with most being "private" mutations unique to individual families. 1
Inheritance Pattern
HCM follows autosomal dominant inheritance, meaning each offspring of an affected parent has a 50% chance of inheriting the pathogenic variant. 1
A single mutation in one allele is sufficient to cause disease, though 5% of patients carry two mutations in the same or different genes. 1
The age at which disease manifests is highly variable even among family members carrying the same variant. 1
Non-Genetic and Unexplained Cases
A substantial 40-70% of HCM patients have no identifiable genetic cause, with up to 40% having no affected family members ("non-familial" HCM), suggesting other pathophysiologic mechanisms contribute to disease expression. 1
Genetic testing identifies pathogenic mutations in approximately 60-70% of patients with positive family history but only 10-50% of those without family history. 1
These observations indicate that novel mechanisms beyond sarcomere mutations may be responsible for phenotypic expression in genetically-unexplained cases. 1
Metabolic and Syndromic Causes
Metabolic Disorders
Anderson-Fabry disease is the most common metabolic cause in adults, with prevalence of 0.5-1% in patients older than 35-40 years. 2
PRKAG2 mutations account for approximately 1% of cases, while Danon disease has reported prevalence of 0.7-2.7%. 2
Metabolic disorders represent a greater proportion of HCM in children and adolescents compared to adults. 2
Syndromic Associations
Ras/MAPK pathway mutations are the most common syndromic causes, including Noonan syndrome, LEOPARD syndrome, Costello syndrome, and cardiofaciocutaneous syndrome. 2
Friedreich's ataxia is the most common neuromuscular disease associated with HCM. 2
Other Secondary Causes
Infants of diabetic mothers can develop transient ventricular hypertrophy due to maternal hyperglycemia's direct pathophysiologic effect on the fetal myocardium. 2, 3
Cardiac amyloidosis causes progressive myocardial thickening through three main types: light chain (AL) amyloidosis, hereditary transthyretin (TTR)-related amyloidosis, and wild-type (senile) TTR amyloidosis. 2
Pheochromocytoma and acromegaly are associated with left ventricular hypertrophy in adults. 2
Pathophysiologic Mechanisms
Mutant sarcomere genes trigger myocardial changes leading to hypertrophy and fibrosis, ultimately resulting in a small, stiff ventricle with impaired systolic and diastolic performance despite preserved ejection fraction. 1
The precise mechanisms by which sarcomere variants produce the clinical phenotype remain incompletely elucidated. 1
Diverse disease features including abnormal intramural coronary arteries causing small vessel ischemia, elongated mitral valve leaflets, and congenital anomalies of the sub-mitral valve apparatus appear to have no direct association with sarcomere variants, suggesting additional pathophysiologic pathways. 1
Clinical Implications for Diagnosis
The clinical diagnosis requires demonstrating left ventricular hypertrophy (≥15 mm maximal end-diastolic wall thickness in adults) in the absence of another cardiac, systemic, or metabolic disease capable of producing the observed magnitude of hypertrophy. 1
More limited hypertrophy (13-14 mm) can be diagnostic when present in family members of HCM patients or in conjunction with a positive genetic test. 1
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. 2