Abstract
BackgroundHeart failure with preserved ejection fraction (HFpEF) is a difficult disease with high morbidity and mortality rates and lacks an effective treatment. Here, we report the therapeutic effect of dapagliflozin, a sodium-glucose cotransporter 2 inhibitor (SGLT2i), on hypertension + hyperlipidemia-induced HFpEF in a pig model.MethodsHFpEF pigs were established by infusing a combination of deoxycorticosterone acetate (DOCA) and angiotensin II (Ang II), and Western diet (WD) feeding for 18 weeks. In the 9th week, half of the HFpEF pigs were randomly assigned to receive additional dapagliflozin treatment (10 mg/day) by oral gavage daily for the next 9 weeks. Blood pressure, lipid levels, echocardiography and cardiac hemodynamics for cardiac structural and functional changes, as well as epinephrine and norepinephrine concentrations in the plasma and tissues were measured. After sacrifice, cardiac fibrosis, the distribution of tyrosine hydroxylase (TH), inflammatory factors (IL-6 and TNF-α) and NO-cGMP-PKG pathway activity in the cardiovascular system were also determined.ResultsBlood pressure, total cholesterol (TC), triglyceride (TG) and low-density lipoprotein (LDL) were markedly increased in HFpEF pigs, but only blood pressure was significantly decreased after 9 weeks of dapagliflozin treatment. By echocardiographic and hemodynamic assessment, dapagliflozin significantly attenuated heart concentric remodeling in HFpEF pigs, but failed to improve diastolic function and compliance with the left ventricle (LV). In the dapagliflozin treatment group, TH expression and norepinephrine concentration in the aorta were strongly mitigated compared to that in the HFpEF group. Moreover, inflammatory cytokines such as IL-6 and TNF-α in aortic tissue were markedly elevated in HFpEF pigs and inhibited by dapagliflozin. Furthermore, the reduced expression of eNOS and the PKG-1 protein and the cGMP content in the aortas of HFpEF pigs were significantly restored after 9 weeks of dapagliflozin treatment.Conclusion9 weeks of dapagliflozin treatment decreases hypertension and reverses LV concentric remodeling in HFpEF pigs partly by restraining sympathetic tone in the aorta, leading to inhibition of the inflammatory response and NO-cGMP-PKG pathway activation.
Highlights
Heart failure with preserved ejection fraction (HFpEF) is a difficult disease with high morbidity and mortality rates and lacks an effective treatment
Effects of dapagliflozin on cardiovascular biochemical indicators in pigs As shown in Table 1, a significant difference in pig body weight was observed between the HFpEF and DAPA groups, both of which were significantly greater than that in the Normal group at the 18th week
At the 18th week, total cholesterol (TC), low-density lipoprotein (LDL) and TG were markedly elevated in the HFpEF group when compared to the Normal group, and no significant difference was found after 9 weeks of dapagliflozin treatment
Summary
Heart failure with preserved ejection fraction (HFpEF) is a difficult disease with high morbidity and mortality rates and lacks an effective treatment. We report the therapeutic effect of dapagliflozin, a sodiumglucose cotransporter 2 inhibitor (SGLT2i), on hypertension + hyperlipidemia-induced HFpEF in a pig model. HF with preserved ejection fraction (HFpEF) accounts for up to 40–60% of all HF cases, which has become an urgent health problem with high morbidity and mortality [3, 4]. Previous studies have suggested that the inflammatory response and a deficient NO-cGMP-PKG signaling pathway in the myocardium are involved in the LV diastolic dysfunction of HFpEF [8,9,10]. Novel strategies to improve blood pressure, hyperlipidemia, the inflammatory response or the NO-cGMP-PKG signaling pathway may offer a therapeutic benefit to the cardiac function of HFpEF
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