Background: Atrial fibrillation is commonly associated with dilated pulmonary veins. Stretch has been shown to have mechano-electrical effects. Objective: To investigate whether stretch can increase the arrhythmogenic activity of the pulmonary veins. Methods: The transmembrane action potentials were recorded from rabbit pulmonary veins before and after stretch (100 and 300 mg). Gadolinium and streptomycin (stretch-activated ion channel blockers) were each perfused into the pulmonary veins under a 300-mg stretch. Results: Stretch (0, 100 and 300 mg) force dependently increased the incidence of spontaneous activity (22%, 48% and 83%; p<0.05), mean (standard deviation (SD)) firing rates of spontaneous activity (1.7 (0.2), 2.1 (0.3) and 3 (0.2) Hz; p<0.05) and incidence of early post-depolarisations (9%, 26% and 61%; p<0.05) and delayed post-depolarisations (0%, 4% and 30%; p<0.05) in 23 pulmonary veins. In the seven preparations with spontaneous activity after the 300-mg stretch, gadolinium (1, 3 and 10 μmol/l) decreased the incidence of spontaneous activity by 43%, 29% and 14%, respectively (p<0.05), and decreased the firing rate from 2.9 (0.1) Hz to 0.8 (0.4), 0.3 (0.1) and 0.1 (0.1) Hz, respectively (p<0.05). Streptomycin (10 and 40 μmol/l) decreased the incidence of spontaneous activity by 71% and 29%, respectively (p<0.05), and decreased the firing rate from 2.9 (0.1) Hz to 1.6 (0.4) and 0.5 (0.3) Hz, respectively (p<0.05). Conclusion: Stretch is an important factor in the electrical activity of the pulmonary vein. Stretch-induced arrhythmogenic activity of the pulmonary vein may contribute to the genesis of atrial fibrillation.

Diabetes mellitus (DM) has significant effects on cardiac calcium (Ca²⁺) and sodium (Na⁺) regulation. Clinical studies have shown that empagliflozin (Jardiance™) has cardiovascular benefits, however the mechanisms have not been fully elucidated. This study aimed to investigate whether empagliflozin modulates cardiac electrical activity as well as Ca²⁺/Na⁺ homeostasis in DM cardiomyopathy. Electrocardiography, echocardiography, whole-cell patch-clamp, confocal microscopic examinations, and Western blot, were performed in the ventricular myocytes of control and streptozotocin-induced DM rats, with or without empagliflozin (10 mg/kg for 4 weeks). The results showed that the control and empagliflozin-treated DM rats had smaller left ventricular end-diastolic diameters and shorter QT intervals than the DM rats. In addition, the prolonged action potential duration in the DM rats was attenuated in the empagliflozin-treated DM rats. Moreover, the DM rats had smaller sarcoplasmic reticular Ca²⁺ contents, intracellular Ca²⁺ transients, L-type Ca²⁺, reverse mode Na⁺-Ca²⁺exchanger currents, lower protein expressions of sarcoplasmic reticulum ATPase, ryanodine receptor 2 (RyR2), but higher protein expressions of phosphorylated RyR2 at serine 2808 than the control and empagliflozin-treated DM rats. The incidence and frequency of Ca²⁺ sparks, cytosolic and mitochondrial reactive oxygen species, and late Na⁺ current and Na⁺/hydrogen-exchanger currents were greater in the DM rats than in the control and empagliflozin-treated DM rats. Empagliflozin significantly changed Ca²⁺ regulation, late Na⁺ and Na⁺/hydrogen-exchanger currents and electrophysiological characteristics in DM cardiomyopathy, which may contribute to its cardioprotective benefits in DM patients.

Diabetic cardiomyopathy is a major complication of diabetes mellitus (DM). Currently, effective treatments for diabetic cardiomyopathy are limited. The pathophysiology of diabetic cardiomyopathy is complex, whereas mitochondrial dysfunction plays a vital role in the genesis of diabetic cardiomyopathy. Metabolic regulation targeting mitochondrial dysfunction is expected to be a reasonable strategy for treating diabetic cardiomyopathy. Peroxisome proliferator-activated receptors (PPARs) are master executors in regulating glucose and lipid homeostasis and also modulate mitochondrial function. However, synthetic PPAR agonists used for treating hyperlipidemia and DM have shown controversial effects on cardiovascular regulation. This article reviews our updated understanding of the beneficial and detrimental effects of PPARs on mitochondria in diabetic hearts.