Next Generation of Spontaneous Diabetic Model of ZDSD Rats with Intact Leptin Signaling Develop Cardiac Dysfunction and Compromised Cardiac Reserve

Abstract

Introduction: Cardiomyopathy is the leading cause of morbidity and mortality among all complications of type 2 diabetic (T2D) and obese patients. Diabetic cardiomyopathy (DC) is characterized by an initial cardiac hypertrophy followed by thinning of the cardiac walls with declines in both systolic and diastolic functions, which ultimately leads to heart failure. No rodent models fully captured phenotypes of DC. The ZDSD rat, a new generation of T2D rat model with intact leptin signaling features with slow onset of diabetes and obesity, which closely mimics the development of the disease in patients. Here we sought to evaluate the cardiac function during the development of metabolic syndromes in ZDSD rats. Methods: 12 male ZDSD rats and age-matched SD controls were monitored for blood pressure, glucose, and cardiac function using echocardiography. Animals were also challenged with 1 mg/kg dobutamine for the assessment of cardiac reserve. Results: ZDSD rats developed hypertension from age of 18 weeks. Their left ventricular (LV) functions were compromised along with changes in cardiac morphology. At resting state, ZDSD rats showed LV hypertrophy from age of 18 to 22 weeks after which cardiac walls became thinner with larger LV volume. At 34 weeks old, both ejection fraction (EF) and transmitral E/A ratio declined. Upon treatment with dobutamine for 5 minutes, SD rats reached almost 98% EF, while the values of ZDSD were 91% at 30 and 34 weeks old, suggesting the loss of LV contractility the animals. Conclusion: ZDSD rats which carry multiple dysmetabolic phenotypes are spontaneously hypertensive with reduction in LV function and cardiac reserve which resembles ultrasonic symptoms of diabetic cardiomyopathy patients. Therefore, ZDSD rats may serve as a suitable preclinical model to study potential therapeutic approaches to treat cardiomyopathy with presence of metabolic syndromes. Disclosure G. Sun: None. G. Zhang: None. Y. Wang: None.