Background: Mitral regurgitation (MR) is a major contributor for heart failure (HF) and atrial fibrillation. Despite the advancement of MR surgeries, an effective medical therapy to mitigate MR progression is lacking. Sodium glucose cotransporter 2 inhibitors, a new class of antidiabetic drugs, has shown measurable benefits in reduction of HF hospitalization and cardiovascular mortality but the mechanism is unclear. We hypothesized that dapagliflozin (DAPA), a sodium glucose cotransporter 2 inhibitor, can improve cardiac hemodynamics in MR‐induced HF. Methods and Results: Using a novel, mini‐invasive technique, we established a MR model in rats, in which MR induced left heart dilatation and functional decline. Half of the rats were randomized to be administered with DAPA at 10 mg/kg per day for 6 weeks. After evaluation of electrocardiography and echocardiography, hemodynamic studies were performed, followed by postmortem tissue analyses. Results showed that DAPA partially rescued MR‐induced impairment including partial restoration of left ventricular ejection fraction and end‐systolic pressure volume relationship. Despite no significant changes in electrocardiography at rest, rats treated with DAPA exhibited lower inducibility and decreased duration of pacing‐induced atrial fibrillation. DAPA also significantly attenuated cardiac fibrosis, cardiac expression of apoptosis, and endoplasmic reticulum stress‐associated proteins. Conclusions: DAPA was able to suppress cardiac fibrosis and endoplasmic reticulum stress and improve hemodynamics in an MR‐induced HF rat model. The demonstrated DAPA effect on the heart and its association with key molecular contributors in eliciting its cardio‐protective function, provides a plausible point of DAPA as a potential strategy for MR‐induced HF.

Dapagliflozin (DAPA), a sodium–glucose cotransporter 2 inhibitor, is approved for treatments of patients with diabetes. The DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) trial disclosed DAPA’s benefits in symptomatic heart failure, but the underlying mechanism remains largely unknown. In this longitudinal and prospective study, we investigated changes of left ventricular functions including speckle tracking in patients with diabetes who were free from symptomatic heart failure post–DAPA treatment. Using a rat model with streptozotocin-induced diabetes, we measured the effects of DAPA on myocardial function. In patients with diabetes, following 6 months of DAPA treatment, despite no significant changes in left ventricular ejection fraction, the diastolic function and longitudinal strain improved. Likewise, compared with control, the diabetic rat heart developed pronounced fibrosis and a decline in strain and overall hemodynamics, all of which were mitigated by DAPA treatment. In contrast, despite insulin exerting a glucose-lowering effect, it failed to improve myocardial function and fibrosis. In our in vitro study, under high glucose cardiomyocytes showed significant activations of apoptosis, reactive oxygen species, and endoplasmic reticulum (ER) stress–associated proteins, which were attenuated by the coincubation of DAPA. Mechanistically, DAPA suppressed ER stress, reduced myocardial fibrosis, and improved overall function. The results can lead to further improvement in management of left ventricular function in patients with diabetes.

Objective Varicose veins (VVs) are common and although considered benign may cause morbidity. However, the association between VV severity and cardiovascular and mortality risks remains unknown. The aim of this study was to investigate the factors associated with overall mortality in patients with VV. Methods A total of 4644 patients with newly diagnosed VV between 1999 and 2013 were identified from Taiwan’s National Health Insurance Database. VV severity was classified from grade 1 to 3 according to the presentation of ulcers or inflammation. Moreover, 9497, 2541 and 5722 age-matched, sex-matched and chronic cardiovascular risk factor-matched controls, as assessed based on propensity score, were separately selected for three grading VV groups. Enrolled patients were analysed using conditional Cox proportional hazards regression analysis to estimate risk of mortality and major adverse cardiovascular events (MACEs) in the VV and control groups. Results Most patients with VV were free from systemic disease. However, compared with matched controls, patients with VV showed a 1.37 times increased risk of mortality (95% CI 1.19 to 1.57; p<0.0001). Compared with matched controls, older (age ≧65 years) (adjusted HR: 1.38; 95% CI 1.17 to 1.62; p=0.0001) and male patients with VV (adjusted HR 1.41; 95% CI 1.18 to 1.68; p=0.0001) showed increased risk of mortality. Furthermore, compared with controls, patients with VV showed 2.05 times greater risk of MACE. Compared with matched controls, population at grade 3 increased 1.83 times risk of mortality and 2.04 to 38.42 times risk of heart failure, acute coronary syndrome, ischaemic stroke and venous thromboembolism. Conclusions This nationwide cohort study demonstrated that patients with VV are at a risk of cardiovascular events and mortality. Our findings suggest that presence of VV warrants close attention in terms of prognosis and treatment.

Coronavirus disease 2019 (COVID-19) is a pandemic infection caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). COVID-19 significantly affects multiple systems including the cardiovascular system. Most importantly, in addition to the direct injury from the virus per se, the subsequent cytokine storm, an overproduction of immune cells and their activating compounds, causes devastating damage. To date, emerging anti-SARS-CoV-2 treatments are warranted to control epidemics. Several candidate drugs have been screened and are currently under investigation. These primarily include antiviral regimens and immunomodulatory regimens. However, beyond the anti-SARS-CoV-2 effects, these drugs may also have risks to the cardiovascular system, especially altering cardiac conduction. Herein, we review the cardiovascular risks of potential anti-COVID-19 drugs.

Esaxerenone (ESAX; CS-3150, Minnebro^®) is known to be a newly non-steroidal mineralocorticoid receptor (MR) antagonist. However, its modulatory actions on different types of ionic currents in electrically excitable cells remain largely unanswered. The present investigations were undertaken to explore the possible perturbations of ESAX on the transient, late and persistent components of voltage-gated Na⁺ current (I_Na) identified from pituitary GH₃ or MMQ cells. GH₃-cell exposure to ESAX depressed the transient and late components of I_Na with varying potencies. The IC₅₀ value of ESAX required for its differential reduction in peak or late I_Na in GH₃ cells was estimated to be 13.2 or 3.2 μM, respectively. The steady-state activation curve of peak I_Na remained unchanged during exposure to ESAX; however, recovery of peak I_Na block was prolonged in the presence 3 μM ESAX. In continued presence of aldosterone (10 μM), further addition of 3 μM ESAX remained effective at inhibiting I_Na. ESAX (3 μM) potently reversed Tef-induced augmentation of I_Na. By using isosceles-triangular ramp pulse with varying durations, the amplitude of persistent I_Na measured at high or low threshold was enhanced by the presence of tefluthrin (Tef), in combination with the appearance of the figure-of-eight hysteretic loop; moreover, hysteretic strength of the current was attenuated by subsequent addition of ESAX. Likewise, in MMQ lactotrophs, the addition of ESAX also effectively decreased the peak amplitude of I_Na along with the increased current inactivation rate. Taken together, the present results provide a noticeable yet unidentified finding disclosing that, apart from its antagonistic effect on MR receptor, ESAX may directly and concertedly modify the amplitude, gating properties and hysteresis of I_Na in electrically excitable cells.