Dapagliflozin Improves Cardiac Hemodynamics and Mitigates Arrhythmogenesis in Mitral Regurgitation-Induced Myocardial Dysfunction.

Abstract

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.

• Authors: Yu-Wen Lin, Chin-Yu Chen, Jhih-Yuan Shih, Bor-Chih Cheng, Ching-Ping Chang, Mao-Tsun Lin, Chung-Han Ho, Zhih-Cherng Chen, Sudeshna Fisch, Wei-Ting Chang
• Journal: Journal of the American Heart Association (J Am Heart Assoc) Vol. 10 Issue 7 Pg. e019274 (04 06 2021) ISSN: 2047-9980 [Electronic] England
• PMID: 33749310 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Benzhydryl Compounds
• Glucosides
• Sodium-Glucose Transporter 2 Inhibitors
• dapagliflozin

Topics

• Animals
• Arrhythmias, Cardiac (drug therapy, etiology, physiopathology)
• Benzhydryl Compounds (pharmacology)
• Disease Models, Animal
• Glucosides (pharmacology)
• Hemodynamics (drug effects, physiology)
• Male
• Mitral Valve Insufficiency (complications, physiopathology)
• Rats
• Rats, Sprague-Dawley
• Sodium-Glucose Transporter 2 Inhibitors (pharmacology)