PDF(Pubmed)
Abstract：
Pathogenic variants in MYH7 and MYBPC3 account for the majority of hypertrophic cardiomyopathy (HCM). Targeted drugs like myosin ATPase inhibitors have not been evaluated in children. We generate patient and variant-corrected iPSC-cardiomyocytes (CMs) from pediatric HCM patients harboring single variants in MYH7 (V606M; R453C), MYBPC3 (G148R) or digenic variants (MYBPC3 P955fs, TNNI3 A157V). We also generate CMs harboring MYBPC3 mono- and biallelic variants using CRISPR editing of a healthy control. Compared with isogenic and healthy controls, variant-positive CMs show sarcomere disorganization, higher contractility, calcium transients, and ATPase activity. However, only MYH7 and biallelic MYBPC3 variant-positive CMs show stronger myosin-actin binding. Targeted myosin ATPase inhibitors show complete rescue of the phenotype in variant-positive CMs and in cardiac Biowires to mirror isogenic controls. The response is superior to verapamil or metoprolol. Myosin inhibitors can be effective in genotypically diverse HCM highlighting the need for myosin inhibitor drug trials in pediatric HCM.
摘要：
MYH7和MYBPC3的致病变体占肥厚型心肌病（HCM）的大多数。尚未在儿童中评估诸如肌球蛋白ATPase抑制剂之类的靶向药物。我们从MYH7（V606M;R453C）中携带单个变体的儿科HCM患者中产生患者和变异校正的iPSC心肌细胞（CM），MYBPC3（G148R）或双基因变体（MYBPC3P955fs，TNNI3A157V）。我们还使用健康对照的CRISPR编辑生成包含MYBPC3单等位基因和双等位基因变体的CM。与同基因和健康对照相比，变异阳性CM显示肌节解体，更高的收缩性，钙瞬变，和ATP酶活性。然而,只有MYH7和双等位基因MYBPC3变体阳性CM显示更强的肌球蛋白-肌动蛋白结合。靶向肌球蛋白ATP酶抑制剂显示完全挽救了变异阳性CM和心脏Biowires中的表型，以反映等基因对照。反应优于维拉帕米或美托洛尔。肌球蛋白抑制剂在基因型不同的HCM中可以有效，这凸显了对小儿HCM中肌球蛋白抑制剂药物试验的需求。
