Abstract 15180: Myeloid Differentiation Factor 2 Inhibitor Improves Left Ventricular Function And Heart Rate Variability Via Attenuating Cardiac Mitochondrial Dysfunction In Pre-diabetic Rats

Introduction: Systemic inflammation is known as a key mediator of left ventricular (LV) dysfunction in pre-diabetic models including obese-insulin resistance. In obese rats, lipopolysaccharide activates myeloid differentiation factor 2 (MD2)/toll-like receptor 4 complex, leading to systemic inflammation. Previously, MD2 inhibitor L6H21 (20 mg/kg) was shown to effectively reduce systemic inflammation in obese mice. However, its potential benefits on the heart and the underlying mechanisms in pre-diabetic obese-insulin resistant rats are unknown. Hypothesis: L6H21 exerts cardiometabolic protection in pre-diabetic rats by improving LV function and heart rate variability (HRV) via reducing cardiac mitochondrial dysfunction. Methods: Male Wistar rats were fed either a normal diet (n=8) or high-fat diet (HFD, n=40) for 12 weeks. In HFD group, rats were divided into 5 groups (n=8/group): 1) vehicle (1% Na-carboxymethyl cellulose), 2) metformin (300 mg/kg, positive control), 3-5) L6H21 at 10, 20, and 40 mg/kg. After 4 weeks of treatments, LV function and HRV were examined. Heart tissue was assessed for mitochondrial function. Results: Pre-diabetic rats had impaired glucose tolerance, depressed HRV, and decreased LV ejection fraction (LVEF), indicating cardiac autonomic imbalance and LV dysfunction. Cardiac mitochondrial dysfunction was also observed, shown by increased mitochondrial ROS levels, mitochondrial depolarization, and mitochondrial swelling. Although L6H21 at 20 and 40 mg/kg improved insulin sensitivity, cardiac autonomic balance, LV function, and mitochondrial function, L6H21 at 40 mg/kg exerted the highest cardioprotective effects, compared to metformin, in pre-diabetic rats by restoring LV function, HRV, and cardiac mitochondrial function (Fig) . Conclusions: L6H21 exerted cardiometabolic protection in pre-diabetic rats by improving insulin sensitivity and cardiac mitochondrial function, leading to restoring LV function.