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

Abstract

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. Rats in the experimental group were intraperitoneally injected with a single dose of 60mg/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 4weeks, whereas rats in the rest of subgroups were given sterile drinking water. After 4weeks, 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±0.53ms, vs. 14.43±0.57ms in CTL; 14.00±0.65ms in CTL+DAPA; 14.57±0.65ms in MCT+DAPA; P<0.05), RR interval (171.60±1.48ms, vs. 163.10±1.10ms in CTL; 163.30±1.19ms in CTL+DAPA; 163.10±1.50ms in MCT+DAPA; P<0.05), Tpeak-Tend interval (65.93±2.55ms, vs. 49.55±1.71ms in CTL; 48.27±3.08ms in CTL+DAPA; P<0.05), and corrected QT interval (200.90±2.40ms, vs. 160.00±0.82ms in CTL; 160.40±1.36ms in CTL+DAPA; 176.6±1.57ms in MCT+DAPA; P<0.01) were significantly prolonged in the MCT group after 4weeks, whereas P-wave amplitude (0.07±0.0011mV, vs. 0.14±0.0009mV in CTL; 0.14±0.0011mV in CTL+DAPA; 0.08±0.0047mV in MCT+DAPA; P<0.05) and T-wave amplitude (0.04±0.002mV, vs. 0.13±0.003mV in CTL; 0.13±0.003mV in CTL+DAPA; P<0.01) were decreased, and atrial 90% action potential duration (47.50±0.93ms, vs. 59.13±2.1ms in CTL; 59.75±1.13ms in CTL+DAPA; 60.63±1.07ms in MCT+DAPA; P<0.01) and effective refractory periods (41.14±0.88ms, vs. 62.86±0.99ms in CTL; 63.14±0.67ms in CTL+DAPA; 54.86±0.70ms 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±22.90s, vs. 0±0s in CTL; 0.24±0.76s in CTL+DAPA; 5.08±7.92s 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. Dapagliflozin reduces pulmonary vascular damage and right heart dysfunction, as well as the susceptibility to AF in RHD rats.