Sotagliflozin Enhances Left Ventricular Function and Myocardial Perfusion in Chronic Myocardial Ischemia Through
Kelsey C Muir1,2, Christopher Stone1,2, Riya Reddy2
1Department of Surgery, Division of Cardiothoracic Surgery, Warren Alpert Medical School, Brown University, Providence, RI (K.C.M., C.S., M.K., D.D.H., M.R.A., F.W.S.).
Insights
Sotagliflozin improves heart function in ischemic heart disease by reducing fibrosis and enhancing blood flow. This dual SGLT1/2 inhibitor shows potential as a novel cardioprotective therapy.
Area of Science:
- Cardiology
- Pharmacology
- Biochemistry
Background:
- Ischemic heart disease (IHD) is a leading global cause of death, often leaving patients with persistent symptoms.
- Current treatments for IHD have limitations, necessitating novel therapeutic approaches.
- Sotagliflozin, a dual inhibitor of sodium-glucose cotransporter 1 and 2 (SGLT1/2), has demonstrated cardiovascular benefits.
Purpose of the Study:
- To investigate the direct myocardial benefits of sotagliflozin in a preclinical model of ischemic heart disease.
- To determine if sotagliflozin exerts cardioprotective effects independent of comorbid conditions.
- To elucidate the cellular and molecular mechanisms underlying sotagliflozin's effects on the ischemic myocardium.
Main Methods:
- Yorkshire swine underwent surgical induction of ischemic heart disease via ameroid constrictor placement.
- Following ischemia induction, swine were randomized to receive sotagliflozin or a placebo for 5 weeks.
- Cardiac function was assessed using pressure-volume loops, myocardial perfusion was measured by microsphere injection, and tissue analysis included histology and immunoblotting.
Main Results:
- Sotagliflozin treatment significantly improved ejection fraction, cardiac output, and stroke work.
- A notable increase in absolute blood flow to the ischemic myocardium was observed in the sotagliflozin group.
- Sotagliflozin administration reduced myocardial fibrosis and nitrosative stress, with associated molecular changes indicating improved nitric oxide signaling and metabolic shifts.
Conclusions:
- Sotagliflozin treatment enhanced left ventricular function, myocardial perfusion, and diastolic relaxation in a swine model of ischemic heart disease.
- These improvements are likely mediated by reduced nitrosative stress and fibrosis, enhanced nitric oxide signaling, and favorable metabolic alterations.
- The findings suggest sotagliflozin holds promise as a cardioprotective agent for patients with ischemic heart disease, potentially offering benefits beyond existing therapies.
Background:
Ischemic heart disease is the leading cause of mortality and human suffering globally. It often leaves patients with residual symptomatic burden despite current optimized procedural and medical options. Sotagliflozin, a dual SGLT1/2 (sodium-glucose cotransporter 1 and 2) inhibitor, has emerged for its clinically evident ischemic cardiovascular benefits. We hypothesize that sotagliflozin treatment exerts direct myocardial benefits in ischemic heart disease, independent of comorbid conditions.
Methods:
Yorkshire swine (n=22) underwent placement of an ameroid constrictor around the left circumflex coronary artery. Following a 2-week period in which the ameroid gradually closes, swine (n=18) were randomized to receive either 400 mg daily sotagliflozin (n=8) or no drug (n=10) for 5 weeks. Afterwards, swine underwent terminal harvest to acquire cardiac functional data with pressure-volume loops, myocardial perfusion by microsphere injection, and ventricular sectioning. To investigate the cellular and tissue-level impact of therapy, histology, immunoblotting, and high-throughput techniques were performed.
Results:
Sotagliflozin swine had improved ejection fraction, cardiac output, and stroke work compared with no drug (P<0.05) and a reduction in tau (P=0.04). Absolute blood flow to the ischemic myocardium was increased in the sotagliflozin group (P=0.03). Sotagliflozin swine had a reduction in 3-nitrotyrosine and trichrome staining, representing decreased reactive nitrogen species and myocardial fibrosis (P=0.03 for both). Molecularly, sotagliflozin swine demonstrated increased expression of endothelial nitric oxide synthase and superoxide dismutase 3 (P=0.02, P=0.04; respectively), with upregulated arginine metabolism, protein kinase A/cyclic adenosine monophosphate signaling, as well as glycolysis, fatty acid oxidation, and citric acid cycle.
Conclusions:
Sotagliflozin treatment improved left ventricular function, myocardial perfusion, and diastolic relaxation, likely through reduced nitrosative stress and myocardial fibrosis, improved nitric oxide coupling, enhanced insulin signaling, and favorable metabolic shifts. This study suggests a potential role for sotagliflozin as a cardioprotective therapy in patients with ischemic heart disease beyond current treatment strategies.
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