BACKGROUND Approximately 10% of hypertrophic cardiomyopathy (HCM) patients have left ventricular systolic dysfunction (end-stage HCM) leading to severe heart-failure; however, risk stratification to identify patients at risk of progressing to end-stage HCM remains insufficient. OBJECTIVES In this study, the authors sought to elucidate whether the coexistence of other cardiovascular disease (CVD)-related variants is associated with progression to end-stage HCM in patients with HCM harboring pathogenic or likely pathogenic (P/LP) sarcomeric variants. METHODS The authors performed genetic analysis of 83 CVD-related genes in HCM patients from a Japanese multicenter cohort. P/LP variants in 8 major sarcomeric genes (MYBPC3, MYH7, TNNT2, TNNI3, TPM1, MYL2, MYL3, and ACTC1) definitive for HCM were defined as "sarcomeric variants." In addition, P/LP variants associated with other CVDs, such as dilated cardiomyopathy and arrhythmogenic cardiomyopathy, were referred to as "other CVD-related variants." RESULTS Among 394 HCM patients, 139 carried P/LP sarcomeric variants: 11 (7.9%) carried other CVD-related variants, 6 (4.3%) multiple sarcomeric variants, and 122 (87.8%) single sarcomeric variants. In a multivariable Cox regression analysis, presence of multiple sarcomeric variants (adjusted HR [aHR]: 3.35 [95% CI: 1.25-8.95]; P = 0.016) and coexistence of other CVD-related variants (aHR: 2.80 [95% CI: 1.16-6.78]; P = 0.022) were independently associated with progression to end-stage HCM. Coexisting other CVD-related variants were also associated with heart failure events (aHR: 2.75 [95% CI: 1.27-5.94]; P = 0.010). CONCLUSIONS Approximately 8% of sarcomeric HCM patients carried other CVD-related variants, which were associated with progression to end-stage HCM and heart failure events. Comprehensive surveillance of CVD-related variants within sarcomeric HCM patients contributes to risk stratification and understanding of mechanisms underlying end-stage HCM.

中文翻译：

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多种非肥厚性心肌病相关遗传变异与肥厚性心肌病患者预后的关联。


背景 大约 10% 的肥厚型心肌病 (HCM) 患者存在左心室收缩功能障碍（终末期 HCM），导致严重心力衰竭；然而，用于识别有进展为终末期 HCM 风险的患者的风险分层仍然不够。目的 在这项研究中，作者试图阐明其他心血管疾病 (CVD) 相关变异的共存是否与携带致病性或可能致病 (P/LP) 肌节变异的 HCM 患者进展为终末期 HCM 相关。方法 作者对来自日本多中心队列的 HCM 患者的 83 个 CVD 相关基因进行了遗传分析。 HCM 的 8 个主要肌节基因（MYBPC3、MYH7、TNNT2、TNNI3、TPM1、MYL2、MYL3 和 ACTC1）中的 P/LP 变异被定义为“肌节变异”。此外，与其他CVD相关的P/LP变异，例如扩张型心肌病和致心律失常性心肌病，被称为“其他CVD相关变异”。结果 在 394 名 HCM 患者中，139 名携带 P/LP 肌节变异：11 名（7.9%）携带其他 CVD 相关变异，6 名（4.3%）携带多种肌节变异，122 名（87.8%）携带单一肌节变异。在多变量 Cox 回归分析中，存在多种肌节变异（调整后的 HR [aHR]：3.35 [95% CI：1.25-8.95]；P = 0.016）和其他 CVD 相关变异的共存（aHR：2.80 [95% CI]） ：1.16-6.78]；P = 0.022）与进展为终末期 HCM 独立相关。共存的其他 CVD 相关变异也与心力衰竭事件相关（aHR：2.75 [95% CI：1.27-5.94]；P = 0.010）。 结论 大约 8% 的肌节 HCM 患者携带其他 CVD 相关变异，这些变异与进展为终末期 HCM 和心力衰竭事件相关。对肌节 HCM 患者中 CVD 相关变异的全面监测有助于风险分层和了解终末期 HCM 的潜在机制。