Background:Arrhythmogenic right ventricular cardiomyopathy type 5 (ARVC5) is an inherited cardiac disease with complete penetrance and an aggressive clinical course caused by mutations in TMEM43 (transmembrane protein 43). There is no cure for ARVC5 and palliative treatment is started once the phenotype is present. A transgenic mouse model of ARVC5 expressing human TMEM43-S358L (TMEM43mut) recapitulates the human disease, enabling the exploration of preventive treatments. The aim of this study is to determine whether preventive treatment with heart failure drugs (β-blockers, ACE [angiotensin-converting enzyme] inhibitors, mineralocorticoid-receptor antagonists) improves the disease course of ARVC5 in TMEM43mut mice.Methods:TMEM43mut male/female mice were treated with metoprolol (β-blockers), enalapril (ACE inhibitor), spironolactone (mineralocorticoid-receptor antagonist), ACE inhibitor + mineralocorticoid-receptor antagonist, ACE inhibitor + mineralocorticoid-receptor antagonist + β-blockers or left untreated. Drugs were initiated at 3 weeks of age, before ARVC5 phenotype, and serial ECG and echocardiograms were performed.Results:TMEM43mut mice treated with enalapril showed a significantly increased median survival compared with untreated mice (26 versus 21 weeks; P=0.003). Enalapril-treated mice also exhibited increased left ventricular ejection fraction at 4 months compared with controls (37.0% versus 24.9%; P=0.004), shorter QRS duration and reduced left ventricle fibrosis. Combined regimens including enalapril also showed positive effects. Metoprolol decreased QRS voltage prematurely and resulted in a nonsignificant decrease in left ventricular ejection fraction compared with untreated TMEM43mut mice.Conclusions:Preventive enalapril-based regimens reduced fibrosis, improved ECG, echocardiographic parameters and survival of ARVC5 mice. Early metoprolol did not show positive effects and caused premature ECG abnormalities. Our findings pave the way to consider prophylactic enalapril in asymptomatic ARVC5 genetic carriers.

中文翻译：

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使用依那普利进行早期预防治疗可改善心律失常性右心室心肌病 5 型小鼠的心脏功能并延缓其死亡率

背景：致心律失常性右心室心肌病 5 型 (ARVC5) 是一种遗传性心脏病，具有完全外显率和由TMEM43突变引起的侵袭性临床病程(跨膜蛋白43)。ARVC5 无法治愈，一旦出现表型就开始姑息治疗。表达人类 TMEM43-S358L (TMEM43mut) 的 ARVC5 转基因小鼠模型概括了人类疾病，从而探索了预防性治疗方法。本研究的目的是确定用心力衰竭药物（β-受体阻滞剂、ACE [血管紧张素转换酶]抑制剂、盐皮质激素受体拮抗剂）进行预防性治疗是否能改善 TMEM43mut 小鼠中 ARVC5 的病程。方法：TMEM43mut 雄性/雌性小鼠用美托洛尔（β-受体阻滞剂）、依那普利（ACE 抑制剂）、螺内酯（盐皮质激素受体拮抗剂）、ACE 抑制剂 + 盐皮质激素受体拮抗剂、ACE 抑制剂 + 盐皮质激素受体拮抗剂 + β-受体阻滞剂治疗或不治疗。P = 0.003）。与对照组相比，依那普利治疗的小鼠在 4 个月时还表现出左心室射血分数增加（37.0% 对 24.9%；P = 0.004）、更短的 QRS 持续时间和减少的左心室纤维化。包括依那普利在内的联合方案也显示出积极的效果。与未治疗的 TMEM43mut 小鼠相比，美托洛尔过早降低 QRS 电压并导致左心室射血分数无显着降低。结论：基于预防性依那普利的方案减少了纤维化，改善了心电图、超声心动图参数和 ARVC5 小鼠的存活率。早期的美托洛尔没有表现出积极的作用并导致过早的心电图异常。我们的研究结果为考虑在无症状的 ARVC5 基因携带者中预防性使用依那普利铺平了道路。