Cardiomyopathy Unit, Careggi University Hospital, Florence, Italy (M.B., C.F.).
Department of Cardiology, Policlinico Casilino, Rome, Italy (E.F.).
Circ Genom Precis Med. 2023 Aug;16(4):363-371. doi: 10.1161/CIRCGEN.122.003832. Epub 2023 Jul 6.
The 2 sarcomere genes most commonly associated with hypertrophic cardiomyopathy (HCM), MYBPC3 (myosin-binding protein C3) and MYH7 (β-myosin heavy chain), are indistinguishable at presentation, and genotype-phenotype correlations have been elusive. Based on molecular and pathophysiological differences, however, it is plausible to hypothesize a different behavior in myocardial performance, impacting lifetime changes in left ventricular (LV) function.
We reviewed the initial and final echocardiograms of 402 consecutive HCM patients with pathogenic or likely pathogenic MYBPC3 (n=251) or MYH7 (n=151) mutations, followed over 9±8 years.
At presentation, MYBPC3 patients were less frequently obstructive (15% versus 26%; =0.005) and had lower LV ejection fraction compared with MYH7 (66±8% versus 68±8%, respectively; =0.03). Both HCM patients harboring MYBPC3 and MYH7 mutations exhibited a small but significant decline in LV systolic function during follow-up; however, new onset of severe LV systolic dysfunction (LV ejection fraction, <50%) was greater among MYBPC3 patients (15% versus 5% among MYH7; =0.013). Prevalence of grade II/III diastolic dysfunction at final evaluation was comparable between MYBPC3 and MYH7 patients (=0.509). In a Cox multivariable analysis, MYBPC3-positive status (hazard ratio, 2.53 [95% CI, 1.09-5.82]; =0.029), age (hazard ratio, 1.03 [95% CI, 1.00-1.06]; =0.027), and atrial fibrillation (hazard ratio, 2.39 [95% CI, 1.14-5.05]; =0.020) were independent predictors of severe systolic dysfunction. No statistically significant differences occurred with regard to incidence of atrial fibrillation, heart failure, appropriate implanted cardioverter defibrillator shock, or cardiovascular death.
MYBPC3-related HCM showed increased long-term prevalence of systolic dysfunction compared with MYH7, in spite of similar outcome. Such observations suggest different pathophysiology of clinical progression in the 2 subsets and may prove relevant for understanding of genotype-phenotype correlations in HCM.
与肥厚型心肌病（HCM）关系最密切的 2 个肌节基因是 MYBPC3（肌球蛋白结合蛋白 C3）和 MYH7（β-肌球蛋白重链），在表现上无法区分，且基因型-表型相关性难以捉摸。然而，基于分子和病理生理学的差异，可以合理假设心肌功能的表现不同，从而影响左心室（LV）功能的终生变化。
我们回顾了 402 例连续的 HCM 患者的初始和最终超声心动图，这些患者携带致病性或可能致病性的 MYBPC3（n=251）或 MYH7（n=151）突变，并进行了 9±8 年的随访。
在表现上，与 MYH7 相比，MYBPC3 患者发生梗阻的频率较低（15% vs. 26%；=0.005），左心室射血分数也较低（66±8% vs. 68±8%；=0.03）。携带 MYBPC3 和 MYH7 突变的 HCM 患者在随访期间均出现了轻微但有统计学意义的左心室收缩功能下降；然而，MYBPC3 患者新发严重左心室收缩功能障碍（左心室射血分数<50%）的发生率更高（15% vs. MYH7 中的 5%；=0.013）。在最终评估时，MYBPC3 和 MYH7 患者的 II/III 级舒张功能障碍发生率相当（=0.509）。在 Cox 多变量分析中，MYBPC3 阳性状态（危险比，2.53[95%置信区间，1.09-5.82]；=0.029）、年龄（危险比，1.03[95%置信区间，1.00-1.06]；=0.027）和心房颤动（危险比，2.39[95%置信区间，1.14-5.05]；=0.020）是严重收缩功能障碍的独立预测因素。在心房颤动、心力衰竭、适当的植入式心脏复律除颤器电击或心血管死亡方面，未出现统计学上显著差异。
尽管结局相似，但与 MYH7 相比，MYBPC3 相关的 HCM 显示出更高的长期收缩功能障碍发生率。这些观察结果表明，在这两个亚组中，临床进展的病理生理学不同，这可能有助于理解 HCM 的基因型-表型相关性。
