In hypertrophic cardiomyopathy (HCM), sarcomeric mutations most commonly affect myosin heavy chain (MYH7) or myosin binding protein C (MYBPC3). How do gain-of-function sarcomeric mutations cause the characteristic diastolic dysfunction and fibrosis in HCM?
- A Mutant sarcomeres have decreased ATP hydrolysis, impairing cross-bridge detachment and causing persistent contractile activation (hypercontractility); the resulting elevated myocardial energetic demand leads to myocyte death, reactive fibrosis, and stiffness that impairs relaxation (diastole) ✓
- B Sarcomeric mutations impair Z-disk assembly, leading to titin-dependent mechanosensing failure and NFAT pathway activation driving concentric hypertrophy
- C MYH7 mutations directly activate TGF-β1 secretion from cardiomyocytes, causing interstitial fibrosis independent of hypertrophy
- D Gain-of-function mutations in MYBPC3 activate the PI3K-AKT pathway in fibroblasts, causing primary fibrosis before hypertrophy
Explanation
Most HCM-causing sarcomeric mutations (MYH7 R403Q, MYBPC3 truncation mutations) are gain-of-function: they increase the duty ratio of myosin cross-bridges (fraction of time myosin is strongly bound to actin), shifting the sarcomere toward a hypercontractile state with impaired cross-bridge detachment. This requires more ATP per contraction cycle, creating energetic stress in subendocardial regions. Ischemia-reperfusion cycles and metabolic stress activate TGF-β signaling, leading to myocyte disarray and interstitial fibrosis. The resultant stiff, fibrotic myocardium cannot relax normally, causing diastolic dysfunction despite preserved or even hyperdynamic systolic function.
Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.