Health & body · 2022
Can make dangerous heart rhythms less likely in rats with pulmonary hypertension and right heart failure?
Yes—in rats with -induced right heart failure, dapagliflozin reduced vulnerability to ventricular arrhythmias. High-dose treatment improved right-heart function and calcium handling; low-dose treatment also had antiarrhythmic effects, but was less effective.
Details
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). Dapagliflozin (DAPA), a sodium/glucose cotransporter-2 inhibitor (SGLT2i), has recently been found to have cardioprotective effects in patients with left ventricular systolic dysfunction. This study examined whether DAPA affects vulnerability to VA in a rat model of PAH-induced RHF.
In this randomized animal experiment, rats received either monocrotaline (MCT, 60 mg/kg) or vehicle through a single intraperitoneal injection. One day later, MCT-injected rats were randomly assigned to oral placebo, low-dose DAPA (1 mg/kg/day), or high-dose DAPA (3 mg/kg/day) for 35 days.
Researchers then used echocardiographic analysis, haemodynamic experiments, and histological assessments to confirm PAH-induced RHF. They measured right ventricular (RV) expression of calcium (Ca²⁺)-handling proteins by Western blotting and RV expression of connexin 43 (Cx43) by immunohistochemical staining. Optical mapping assessed electrophysiological characteristics in isolated hearts. Cellular Ca²⁺ imaging in RV cardiomyocytes (RVCMs) used Fura-2 AM or Fluo-4 AM.
High-dose DAPA attenuated RV structural remodelling, improved RV function, alleviated Cx43 remodelling, increased conduction velocity, and restored expression of key Ca²⁺-handling proteins. It also increased the threshold for Ca²⁺ alternans and action potential duration (APD) alternans, decreased susceptibility to spatially discordant APD alternans and spontaneous Ca²⁺ events, improved cellular Ca²⁺ handling, and reduced VA vulnerability in rats with PAH-induced RHF.
Low-dose DAPA also showed antiarrhythmic effects in hearts with PAH-induced RHF, but with lower efficacy than high-dose treatment. The authors concluded that DAPA reduced VA vulnerability in these rats by improving Ca²⁺ handling in RV cardiomyocytes.
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