Empagliflozin treatment prevented oxidative stress, macrophage infiltration, pro-inflammatory and pro-fibrotic responses in the left ventricle of isoprenaline-induced Takotsubo-like syndrome in rats

Abstract Introduction Takotsubo Syndrome (TTS) is an acute heart failure (HF) syndrome induced by both emotional and physical stressors involving a surge of catecholamines and apical ballooning. Currently, there is no specific treatment for TTS. Sodium-glucose cotransporter2 inhibitors (SGLT2i) showed major cardiovascular protective effects in patients with HF independent of glycemic control. SGLT2i have also been shown to have anti-inflammatory and anti-oxidant effects, and to improve the endothelial function in experimental models of cardiac disease. However, a possible protective role of SGLT2i in TTS is unclear. Thus, this study evaluated the effect of SGLT2i on isoprenaline-induced TTS-like syndrome in rats, and determined the underlying mechanism. Methods 32 female Sprague-Dawley rats (10 weeks old) were divided into 4 groups: control, empagliflozin (30 mg/kg/day provided in the diet for 2 weeks), isoprenaline (Iso, 100 mg/kg, i.p.) to induce a TTS-like syndrome, and Iso plus empagliflozin (IE group). After 6 h of Iso injection, echocardiography was performed to determine left ventricular (LV) ejection fraction (EF) by area and heart rate (HR). At day 3, rats were sacrificed, main mesenteric artery and microvessels were collected for vascular reactivity studies, and LV was divided into base and apex to study mRNA expression levels using RT-qPCR, macrophage infiltration by in situ CD68 immunofluorescence staining, and oxidative stress using dihydroethidium. Results The injection of Iso to rats caused at 6 h an increased LVEF and HR in the Iso and the IE groups as compared to their corresponding controls. The HR response was significantly smaller in the IE group compared to Iso group whereas LVEF was similar. In addition, in mesenteric microvessels but not the main mesenteric artery, Iso group showed significant decreased relaxations to acetylcholine and increased contractile responses to phenylephrine in intact rings both of which were not observed in the IE group. Hearts showed significantly increased mRNA levels of IL-1β, TNF-α, NOX2, VCAM-1, MMP-9, TGF-β1 and collagen-1, oxidative stress levels and CD68 staining in the apex compared to the base in the ISO group, all of which were significantly reduced in IE group. Conclusions The present findings indicate that ISO injection caused in the LV elevated levels of oxidative stress, macrophage infiltration, pro-inflammatory, pro-remodeling and pro-fibrosis responses that were more pronounced in the apex compared to the base, and also endothelial dysfunction in the systemic microcirculation, all of which were significantly prevented by the empagliflozin treatment. They further suggest that SGLT2 appears as an interesting target in TTS.