Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain (F.D., L.L., M.L.-O., M.V.-O., L.P.-B., M.R., E.B.-A., E.L.-P.).
Heart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain (F.D., A.B., E.G.-L., J.S.-C., P.G.-P.).
Circ Heart Fail. 2021 Sep;14(9):e007616. doi: 10.1161/CIRCHEARTFAILURE.120.007616. Epub 2021 Aug 20.
Arrhythmogenic right ventricular cardiomyopathy type 5 (ARVC5) is an inherited cardiac disease with complete penetrance and an aggressive clinical course caused by mutations in (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.
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.
TMEM43mut mice treated with enalapril showed a significantly increased median survival compared with untreated mice (26 versus 21 weeks; =0.003). Enalapril-treated mice also exhibited increased left ventricular ejection fraction at 4 months compared with controls (37.0% versus 24.9%; =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.
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.
致心律失常性右室心肌病 5 型（ARVC5）是一种遗传性心脏病，完全外显，由跨膜蛋白 43 基因突变引起，临床病程进展迅速。目前尚无 ARVC5 的治愈方法，一旦出现表型，就开始进行姑息治疗。表达人类 TMEM43-S358L（TMEM43mut）的 ARVC5 转基因小鼠模型再现了人类疾病，使预防性治疗的探索成为可能。本研究旨在确定预防性使用心力衰竭药物（β受体阻滞剂、血管紧张素转换酶抑制剂、盐皮质激素受体拮抗剂）是否能改善 TMEM43mut 小鼠的 ARVC5 病程。
TMEM43mut 雄性/雌性小鼠接受美托洛尔（β受体阻滞剂）、依那普利（血管紧张素转换酶抑制剂）、螺内酯（盐皮质激素受体拮抗剂）、血管紧张素转换酶抑制剂+盐皮质激素受体拮抗剂、血管紧张素转换酶抑制剂+盐皮质激素受体拮抗剂+β受体阻滞剂或未治疗。药物在 ARVC5 表型出现前的 3 周开始使用，定期进行心电图和超声心动图检查。
与未治疗的小鼠相比，接受依那普利治疗的 TMEM43mut 小鼠的中位生存期显著延长（26 周 vs. 21 周；=0.003）。与对照组相比，依那普利治疗的小鼠在 4 个月时的左心室射血分数也增加（37.0% vs. 24.9%；=0.004），QRS 时限缩短，左心室纤维化减少。包括依那普利在内的联合方案也显示出积极的效果。美托洛尔过早降低 QRS 电压，导致与未治疗的 TMEM43mut 小鼠相比，左心室射血分数无显著降低。
基于依那普利的预防方案减少了纤维化，改善了 ARVC5 小鼠的心电图、超声心动图参数和生存率。早期使用美托洛尔没有显示出积极的效果，反而导致了过早的心电图异常。我们的研究结果为考虑在无症状的 ARVC5 遗传携带者中预防性使用依那普利铺平了道路。
