The combination of ipragliflozin and losartan preserves cardiac function in a rat experimental autoimmune myocarditis model

Abstract Introduction Myocarditis is an inflammatory disease that arises from infectious and non-infectious causes, often resulting in severe cardiac dysfunction. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have demonstrated efficacy in treating heart failure, even in patients without diabetes, largely due to their pleiotropic anti-inflammatory and haemodynamic effects. However, the cardioprotective and renoprotective effects of SGLT2i monotherapy or its combination with an angiotensin II receptor blocker (ARB) in myocarditis remain unexplored. Purpose This study aimed to evaluate the effects of the SGLT2i ipragliflozin on cardiac and renal function in the acute phase of experimental autoimmune myocarditis (EAM) in rats, with or without the ARB losartan. Methods Myocarditis was induced in Lewis rats via subcutaneous administration of porcine cardiac myosin in the hindfoot (Figure 1). The rats were then randomized into four groups (n=12 per group) and received one of the following treatments through their diet for 28 days: vehicle (EAM group), ipragliflozin 0.04% (IPRA group), losartan 0.05% (LOS group), or a combination of ipragliflozin and losartan (IPRA+LOS group). Blood pressure, transthoracic echocardiogram (ECHO), blood tests, and urine parameters were determined at the end of the study. Histological myocardial inflammation and immunohistochemical analysis of macrophages and T-helper cell infiltration and glomerulosclerosis scores, were assessed. Results Combination therapy significantly improved cardiac function compared to the EAM group, whereas monotherapy with ipragliflozin or losartan alone had a lesser effect. ECHO showed higher left ventricular fractional shortening (44.3 ± 5.8% vs 31.5 ± 5.3%, p0.05) and ejection fraction (74.4 ± 6.6% vs 58.1 ± 8.4%, p0.05). The increase in the left ventricular end-systolic dimension was also attenuated by combination therapy (3.36 ± 0.65mm vs 4.29 ± 0.6mm, p0.05). Notably, only combination therapy significantly attenuated the increase in heart weight and lung weight to tibia length ratio (figure 2). The heart weight to tibia length ratio positively correlated with the inflammation score (r=0.624, p0.005), and combination therapy resulted in the lowest inflammatory scores among the treated groups. This was accompanied by a decreased accumulation of macrophages but not T-helper cells. On the other hand, glomerulosclerosis scores remained unchanged in this model. Ipragliflozin with or without losartan significantly increased 24-hour sodium and glucose excretion without significant changes to creatinine clearance and albumin-to-creatinine ratio compared to the EAM Group. Conclusion The combination of ipragliflozin and losartan improved cardiac function in the acute phase of myocarditis. The observed trend towards reduced inflammation warrants further investigation and the need to explore the detailed mechanisms for the treatment of myocarditis with SGLT2i and ARB.