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

Cardiomyopathy is the leading cause of morbidity and mortality among all complications of type 2 diabetes (T2D) and obese patients. Diabetic cardiomyopathy (DC) is characterized by changes in cardiac morphology with declines in both systolic and diastolic functions. 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. Age-matched male ZDSD and SD rats 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. ZDSD rats developed hypertension from age of 18 weeks with blood pressure significantly higher than controls. At resting state, ZDSD rats showed biphasic changes in left ventricular posterior wall thickness and cavity volume. Concomitantly, both ejection fraction (EF) and transmitral E/A ratio of LV declined at 34 weeks old. Upon treatment with dobutamine, ZDSD lost cardiac contractility. Therefore, ZDSD rats may serve as a suitable preclinical model to study potential therapeutic approaches to treat cardiomyopathy with presence of metabolic syndromes.