Dapagliflozin Reduces the Vulnerability of Rats with Pulmonary Arterial Hypertension-induced Right Heart Failure to Ventricular Arrhythmia by Restoring Calcium Handling

Overview

Journal Cardiovasc Diabetol

Publisher Biomed Central

Specialties Cardiology & Vascular Diseases
Endocrinology

Date 2022 Sep 28

PMID 36171554

Authors

Jinchun Wu

Tao Liu

Shaobo Shi

Zhixing Fan

Roddy Hiram

Feng Xiong

Bo Cui

Xiaoling Su

Rong Chang

Wei Zhang

Min Yan

Yanhong Tang

He Huang

Gang Wu

Congxin Huang

Affiliations

Soon will be listed here.

Abstract

Background: Malignant 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.

Methods: Rats 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 (Ca) 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 Ca imaging from RV cardiomyocytes (RVCMs) was recorded using Fura-2 AM or Fluo-4 AM.

Results: High-dose DAPA treatment attenuated RV structural remodelling, improved RV function, alleviated Cx43 remodelling, increased the conduction velocity, restored the expression of key Ca handling proteins, increased the threshold for Ca and action potential duration (APD) alternans, decreased susceptibility to spatially discordant APD alternans and spontaneous Ca events, promoted cellular Ca 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.

Conclusion: DAPA administration reduced VA vulnerability in rats with PAH-induced RHF by improving RVCM Ca handling.

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