Dapagliflozin reduces the vulnerability of rats with pulmonary arterial hypertension-induced right heart failure to ventricular arrhythmia by restoring calcium handling

Cardiovascular Diabetology

卷:21

Research

Xiaoling Su¹  Gang Wu²  Shaobo Shi²  Bo Cui²  He Huang²  Congxin Huang²  Min Yan²  Zhixing Fan²  Wei Zhang²  Tao Liu²  Yanhong Tang²  Jinchun Wu³  Rong Chang⁴  Feng Xiong⁵  Roddy Hiram⁵ 

[1] Department of Cardiology, Qinghai Provincial People’s Hospital, No.2 Gong He Road, 810007, Xining, People’s Republic of China;

[2] Department of Cardiology, Renmin Hospital of Wuhan University, No. 238 Jiefang Road, 430060, Wuhan, People’s Republic of China;Cardiovascular Research Institute, Wuhan University, 238 Jiefang Road, 430060, Wuhan, People’s Republic of China;Hubei Key Laboratory of Cardiology, 238 Jiefang Road, 430060, Wuhan, People’s Republic of China;

[3] Department of Cardiology, Renmin Hospital of Wuhan University, No. 238 Jiefang Road, 430060, Wuhan, People’s Republic of China;Cardiovascular Research Institute, Wuhan University, 238 Jiefang Road, 430060, Wuhan, People’s Republic of China;Hubei Key Laboratory of Cardiology, 238 Jiefang Road, 430060, Wuhan, People’s Republic of China;Department of Cardiology, Qinghai Provincial People’s Hospital, No.2 Gong He Road, 810007, Xining, People’s Republic of China;

[4] Department of Cardiology, Shenzhen Longhua District Central Hospital, The Affiliated Central Hospital of Shenzhen Longhua District, Guangdong Medical University, No. 187 Guanlan Road, Longhua District, 518109, Shenzhen, China;

[5] Department of Medicine, Faculty of Medicine, Montreal Heart Institute (MHI), Université de Montréal, Montreal, QC, Canada;

关键词: Dapagliflozin;    Ventricular arrhythmias;    Calcium handling;    Right heart failure;    Pulmonary arterial hypertension;    Monocrotaline;   

DOI  :  10.1186/s12933-022-01614-5

 received in 2022-02-22, accepted in 2022-09-01,  发布年份 2022

来源: Springer

【 摘 要 】

BackgroundMalignant ventricular arrhythmia (VA) is a major contributor to sudden cardiac death (SCD) in patients with pulmonary arterial hypertension (PAH)-induced right heart failure (RHF). Recently, dapagliflozin (DAPA), a sodium/glucose cotransporter-2 inhibitor (SGLT2i), has been found to exhibit cardioprotective effects in patients with left ventricular systolic dysfunction. In this study, we examined the effects of DAPA on VA vulnerability in a rat model of PAH-induced RHF.MethodsRats randomly received monocrotaline (MCT, 60 mg/kg) or vehicle via a single intraperitoneal injection. A day later, MCT-injected rats were randomly treated with placebo, low-dose DAPA (1 mg/kg/day), or high-dose (3 mg/kg/day) DAPA orally for 35 days. Echocardiographic analysis, haemodynamic experiments, and histological assessments were subsequently performed to confirm the presence of PAH-induced RHF. Right ventricle (RV) expression of calcium (Ca2+) handling proteins were detected via Western blotting. RV expression of connexin 43 (Cx43) was determined via immunohistochemical staining. An optical mapping study was performed to assess the electrophysiological characteristics in isolated hearts. Cellular Ca2+ imaging from RV cardiomyocytes (RVCMs) was recorded using Fura-2 AM or Fluo-4 AM.ResultsHigh-dose DAPA treatment attenuated RV structural remodelling, improved RV function, alleviated Cx43 remodelling, increased the conduction velocity, restored the expression of key Ca2+ handling proteins, increased the threshold for Ca2+ and action potential duration (APD) alternans, decreased susceptibility to spatially discordant APD alternans and spontaneous Ca2+ events, promoted cellular Ca2+ handling, and reduced VA vulnerability in PAH-induced RHF rats. Low-dose DAPA treatment also showed antiarrhythmic effects in hearts with PAH-induced RHF, although with a lower level of efficacy.ConclusionDAPA administration reduced VA vulnerability in rats with PAH-induced RHF by improving RVCM Ca2+ handling.

【 授权许可】

CC BY   
© The Author(s) 2022

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