MYH7 (Beta-Myosin Heavy Chain)
Details
MYH7 encodes the β-myosin heavy chain, the predominant myosin isoform in adult ventricular and slow-twitch skeletal muscle. It is the most commonly implicated gene in hypertrophic cardiomyopathy (HCM) and one of the top genes harboring disease-associated variants in patients with early-onset atrial fibrillation.
Key Facts
- HCM association: MYH7 missense variants are the most common cause of HCM after MYBPC3 (~25–40% of identified mutations), producing a gain-of-function sarcomeric effect that results in myocyte disarray, hypertrophy, and diastolic dysfunction. HCM from MYH7 variants carries a significantly higher risk of AF than HCM from other sarcomeric gene variants.
- High-risk SCD mutations: Five MYH7 mutations are considered "high-risk" for SCD based on multiple studies: R403Q, R453C, G716R, R719W (MYH7); TNNT2-R92W is also in this high-risk group. Patients carrying these mutations have a significantly higher incidence of SCD. (sources/HCM-VA-FCVMed-2022)
- Ion channel mechanism: MYH7-R442G hiPSC-CMs confirmed electrophysiological changes similar to adult HCM myocytes: prolonged APD50/APD90, ↑Ca²⁺ current, ↑INaL, K⁺ current abnormality. See concepts/Ion-Channel-Remodeling-in-HCM. (sources/HCM-VA-FCVMed-2022)
- Early-onset AF: In 1293 patients with early-onset AF who underwent WGS, MYH7 was the second most prevalent gene with P/LP variants: 18 participants (13% of all disease-associated variants). Median age at AF diagnosis was 48 years (IQR 29–53). (sources/eoaf-jama-2021)
- Syndrome assignment: MYH7 variants in this cohort were classified under the HCM category, consistent with evidence that HCM patients have high rates of AF (~28.8%) compared with inherited arrhythmia patients (~8.2%). (sources/eoaf-jama-2021)
- Mechanism: The leading hypothesis is that MYH7-associated hypertrophy and diastolic dysfunction create atrial pressure and volume overload over time, promoting atrial remodeling and fibrosis that precipitates AF. Alternatively, early-onset AF may predate overt ventricular hypertrophy and represent primary atrial involvement.
- Atrial fibrosis substrate in AF ablation: MYH7 variant–positive HCM patients undergoing AF ablation have significantly more LA low-voltage areas than gene-negative HCM controls (normal voltage 89.9% vs. 94.3%; intermediate scar 5.54% vs. 3.07%; dense scar 4.55% vs. 2.61%), despite similar LA pressures. MYH7 patients show a specific predilection for dense scar in lateral LA regions — the clinical significance of which remains uncertain. (sources/MYBPC3-MYH7-JACCEP-2024, rating: medium)
- AF ablation outcomes: Freedom from AF at 12 months in MYH7 variant–positive HCM (83.3%) was not significantly different from controls (73.3%; P=0.92); cumulative freedom at last follow-up was 66.7%. More procedures were needed in the combined gene-positive cohort compared with gene-negative controls (mean 1.67 vs. 1.20; P=0.03). (sources/MYBPC3-MYH7-JACCEP-2024)
Contradictions / Open Questions
- Five high-risk SCD mutations — historical cohort data vs. contemporary risk context: R403Q, R453C, G716R, and R719W are labeled "high-risk" SCD mutations based on studies predating routine ICD implantation and contemporary medical therapy. In the current ICD era, the attributable excess mortality of these genotypes over other sarcomere mutations may be lower than historical data suggest. HCM Risk-SCD, which does not incorporate genotype, is the guideline-endorsed risk tool — creating tension between genotype-informed historical risk labeling and validated calculator-based current practice. (sources/HCM-VA-FCVMed-2022)
- MYH7 → AF mechanism: secondary to hypertrophy vs. primary atrial involvement: The predominant hypothesis is that MYH7-associated ventricular hypertrophy and diastolic dysfunction drives atrial pressure overload and structural remodeling, precipitating AF over time. Alternatively, early-onset AF may precede overt hypertrophy and represent primary atrial myosin dysfunction. The two mechanisms predict different timelines and different responses to HCM-specific therapies (e.g., mavacamten targeting LVOTO may not prevent AF if the mechanism is primarily atrial). A 2024 single-center ablation study found that MYH7/MYBPC3-positive patients had greater LA fibrosis than gene-negative HCM despite similar LA pressures, supporting primary atrial myopathy as an independent mechanism. (sources/eoaf-jama-2021, sources/MYBPC3-MYH7-JACCEP-2024)
- High-risk MYH7 genotype vs. HCM Risk-SCD calculator — unresolved integration: Current HCM guidelines recommend the HCM Risk-SCD calculator for ICD decisions and do not assign additional ICD indication based solely on high-risk MYH7 genotype. Yet the historical high-risk label persists in the literature. This creates a prescribing gap: clinicians may implant ICDs for R403Q carriers below the 6% calculator threshold — a practice not supported by current guidelines but with a historical preclinical rationale. (sources/HCM-VA-FCVMed-2022)
Connections
- Related to concepts/Early-Onset-Atrial-Fibrillation
- Related to concepts/Genetic-Testing-in-AF
- Related to entities/Atrial-Fibrillation
- Related to entities/MYH6
- Related to entities/HCM
- Related to entities/MYBPC3
- Related to concepts/Ion-Channel-Remodeling-in-HCM
- Related to concepts/HCM-Risk-SCD
- Related to concepts/Atrial-Myopathy-in-HCM
- Related to concepts/Catheter-Ablation-AF