期刊
CARDIOVASCULAR RESEARCH
卷 109, 期 1, 页码 162-173出版社
OXFORD UNIV PRESS
DOI: 10.1093/cvr/cvv248
关键词
Renin-angiotensin system; Sudden; Cardiac; Arrhythmia; Electrical remodelling
资金
- Japan Society for the Promotion of Science [23390210, 24659386, 22590810, 24591095, 25893090, 2213610, 23126511, 25126712, 21229013]
- Japanese Ministry of Health, Labor and Welfare
- Japan Foundation for Applied Enzymology
- UBE Foundation
- Ichiro Kanehara Foundation
- Takeda Science Foundation
- Hoh-ansha Foundation
- Novartis Pharma AG
- SENSHIN Medical Research Foundation
- Grants-in-Aid for Scientific Research [24591095, 23390210, 15K09078, 26293187, 25293182, 24659386, 21229013, 23126511, 25893090, 22590810, 26670400, 15K19377] Funding Source: KAKEN
Aims The progression of pathological left ventricular remodelling leads to cardiac dysfunction and contributes to the occurrence of malignant arrhythmias and sudden cardiac death. The underlying molecular mechanisms remain unclear, however. Our aim was to examine the role of the renin-angiotensin system (RAS) in the mechanism underlying arrhythmogenic cardiac remodelling using a transgenic mouse expressing a cardiac-specific dominant-negative form of neuron-restrictive silencer factor (dnNRSF-Tg). This mouse model exhibits progressive cardiac dysfunction leading to lethal arrhythmias. Methods and results Subcutaneous administration of aliskiren, a direct renin inhibitor, significantly suppressed the progression of pathological cardiac remodelling and improved survival among dnNRSF-Tg mice while reducing arrhythmogenicity. Genetic deletion of the angiotensin type 1a receptor (AT1aR) similarly suppressed cardiac remodelling and sudden death. In optical mapping analyses, spontaneous ventricular tachycardia (VT) and fibrillation (VF) initiated by breakthrough-type excitations originating from focal activation sites and maintained by functional re-entry were observed in dnNRSF-Tg hearts. Under constant pacing, dnNRSF-Tg hearts exhibited markedly slowed conduction velocity, which likely contributes to the arrhythmogenic substrate. Aliskiren treatment increased conduction velocity and reduced the incidence of sustained VT. These effects were associated with suppression of cardiac fibrosis and restoration of connexin 43 expression in dnNRSF-Tg ventricles. Conclusion Renin inhibition or genetic deletion of AT1aR suppresses pathological cardiac remodelling that leads to the generation of substrates maintaining VT/VF and reduces the occurrence of sudden death in dnNRSF-Tg mice. These findings demonstrate the significant contribution of RAS activation to the progression of arrhythmogenic substrates.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据