Effect of empagliflozin on cardiac energetics in volume overload-induced heart failure in rats
V Farkasova, T Kiss, K Ferenczyova, K Ferenczyova, U DulovaAbstract
Background/Introduction
Sodium-glucose co-transporter 2 (SGLT-2) inhibitors are the newest class of antidiabetic drugs. Recently, clinical trials reported the cardiovascular benefits of empagliflozin, an SGLT-2 inhibitor, by significantly decreasing the incidence of hospitalization associated with HF and cardiovascular-cause death rate in diabetic patients with CVD and in HF patients. In addition, SGLT2 inhibitors - empagliflozin exert cardioprotective effects in animal models of acute MI, independent of improved glycaemic control – presumably through alteration of myocardial metabolism to favour ketone oxidation—an energetically efficient substrate.
Purpose
This study aims to investigate whether pharmacological treatment with an SGLT2 inhibitor- empagliflozin (EMPA)- directly affects cardiac energetics in volume overload-induced HF in rats. The further goal is to determine the effect of EMPA treatment on cardiac structure and function in volume overload-induced HF.
Methods
Chronic HF due to volume overload was induced by creating an aortocaval fistula (ACF) between the vena cava and the abdominal aorta in male Wistar rats of age 6 months. EMPA (10mg/kg/day) was administered in tap water 2 weeks before and 5 weeks after ACF induction. Animals underwent echocardiographic examination before ACF induction and at the end of EMPA treatment. Western Blot analysis was performed on frozen heart tissue to assess protein levels of distinct energy substrates and their metabolic pathways.
Results
Our findings indicate the development of eccentric hypertrophy, accompanied by a significantly decreased ejection fraction in ACF rats compared to SHAM-operated controls. EMPA administration prevented the drop in ejection fraction in ACF animals. Interestingly, the examination of the metabolic pathways of different energy substrates showed increased utilisation ability for ketone body oxidation (increased OXCT1 and stable BDH1 levels) in EMPA-treated ACF rats compared to non-treated counterparts. On the other hand, our results designate reduced fatty acid utilisation in EMPA-treated ACF rats (decreased CD36 and CPT1/2), suggesting reduced uptake and accumulation of cardiotoxic lipids within the myocardium.
Conclusions
Empagliflozin treatment successfully suppressed the development of hypertrophy and prevented the development of systolic dysfunction in the volume overload-induced HF model in rats. Our findings indicate that EMPA favours the ketone utilization in the rat heart, thereby improving function and energetics in failing hearts due to volume overload.