Dapagliflozin reduces pulmonary vascular damage and susceptibility to atrial fibrillation in right heart disease

Abstract

Aims: Sodium-glucose cotransporter 2 inhibitors (SGLT2is) have made considerable progress in the field of heart failure, but their application in arrhythmia remains to be in-depth. Right heart disease (RHD) often leads to right heart dysfunction and is associated with atrial fibrillation (AF). Here, we explored the possible electrophysiologic effect of dapagliflozin (a type of SGLT2is) in the development of AF in rats with RHD. Methods and results: Rats in the experimental group were intraperitoneally injected with a single dose of 60 mg/kg monocrotaline (MCT group, n = 32) on the first day of the experiment, whereas rats in the control group were injected with vehicle (CTL group, n = 32). Rats in the treatment subgroup were treated with dapagliflozin solution orally (MCT + DAPA and CTL + DAPA groups) for a total of 4 weeks, whereas rats in the rest of subgroups were given sterile drinking water. After 4 weeks, echocardiography demonstrated that MCT group rats developed obvious pulmonary arterial hypertension and right heart dysfunction. In addition, there were also obvious inflammatory infiltration, fibrosis, and muscularization in right atrial and pulmonary arteries. The P-wave duration (17.00 ± 0.53 ms, vs. 14.43 ± 0.57 ms in CTL; 14.00 ± 0.65 ms in CTL + DAPA; 14.57 ± 0.65 ms in MCT + DAPA; P < 0.05), RR interval (171.60 ± 1.48 ms, vs. 163.10 ± 1.10 ms in CTL; 163.30 ± 1.19 ms in CTL + DAPA; 163.10 ± 1.50 ms in MCT + DAPA; P < 0.05), Tpeak-Tend interval (65.93 ± 2.55 ms, vs. 49.55 ± 1.71 ms in CTL; 48.27 ± 3.08 ms in CTL + DAPA; P < 0.05), and corrected QT interval (200.90 ± 2.40 ms, vs. 160.00 ± 0.82 ms in CTL; 160.40 ± 1.36 ms in CTL + DAPA; 176.6 ± 1.57 ms in MCT + DAPA; P < 0.01) were significantly prolonged in the MCT group after 4 weeks, whereas P-wave amplitude (0.07 ± 0.0011 mV, vs. 0.14 ± 0.0009 mV in CTL; 0.14 ± 0.0011 mV in CTL + DAPA; 0.08 ± 0.0047 mV in MCT + DAPA; P < 0.05) and T-wave amplitude (0.04 ± 0.002 mV, vs. 0.13 ± 0.003 mV in CTL; 0.13 ± 0.003 mV in CTL + DAPA; P < 0.01) were decreased, and atrial 90% action potential duration (47.50 ± 0.93 ms, vs. 59.13 ± 2.1 ms in CTL; 59.75 ± 1.13 ms in CTL + DAPA; 60.63 ± 1.07 ms in MCT + DAPA; P < 0.01) and effective refractory periods (41.14 ± 0.88 ms, vs. 62.86 ± 0.99 ms in CTL; 63.14 ± 0.67 ms in CTL + DAPA; 54.86 ± 0.70 ms in MCT + DAPA; P < 0.01) were shortened. Importantly, the inducibility rate (80%, vs. 0% in CTL; 10% in CTL + DAPA; 40% in MCT + DAPA; P < 0.05) and duration of AF (30.85 ± 22.90 s, vs. 0 ± 0 s in CTL; 0.24 ± 0.76 s in CTL + DAPA; 5.08 ± 7.92 s in MCT + DAPA; P < 0.05) were significantly increased, whereas the expression levels of cardiac ion channels and calcium-handling proteins such as potassium/calcium channels and calmodulin were decreased. Mechanistically, ‘NACHT, LRR, and PYD domain-containing protein 3’ inflammasome-related pathway was significantly activated in the MCT group. Nevertheless, in the MCT + DAPA group, the above abnormalities were significantly improved. Conclusions: Dapagliflozin reduces pulmonary vascular damage and right heart dysfunction, as well as the susceptibility to AF in RHD rats.