Zucker Diabetic Sprague Dawley (ZDSD) Rat, A Spontaneously Diabetic Rat Model Develops Cardiac Dysfunction and Compromised Cardiac Reserve

Abstract

1. Abstract 1.1. <span lang=EN-AU style=font-size:10.0pt; font-family: times= new= roman,serif=>Introduction: Diabetic Cardiomyopathy (DC) is the leading cause of morbidity and mortality among all complications of Type 2 Diabetes (T2D) and obese patients. It is characterized by an initial cardiac hypertrophy followed by declines in cardiac functions, which ultimately leads to heart failure. No rodent models fully captured phenotypes of DC. The Zucker Diabetic Sprague Dawley (ZDSD) rat, a new generation of T2D rat model with intact leptin signaling features with slow onset of diabetes, obesity and dyslipidemia, 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. 1.2. <span lang=EN-AU style=font-size:10.0pt; font-family: times= new= roman,serif=>Methods: Age matched male ZDSD and SD rats were monitored for blood pressure and cardiac function using Echocardiography. Animals were also challenged with 1 mg/kg dobutamine for the assessment of cardiac reserve. 1.3. <span lang=EN-AU style=font-size:10.0pt; font-family: times= new= roman,serif=>Results: ZDSD rats developed hypertension from age of 18 weeks with both systolic and diastolic blood pressure significantly higher than controls. Their Left Ventricular (LV) functions were compromised along with changes in cardiac morphology. At resting state, ZDSD rats showed thickening of LV posterior wall from age of 18 to 22 weeks after which cardiac walls became thinner with larger LV cavity volume. Both Ejection Fraction (EF) and transmitral E/A ratio of LV declined at 34 weeks old. Upon treatment with dobutamine, ZDSD rats had much lower EF and Fractional Shorterning (FS) compared to SD rats, suggesting the loss of contractility and cardiac reserve of the animals. 1.4. <span lang=EN-AU style=font-size:10.0pt; font-family: times= new= roman,serif=>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. 2. Keywords: Cardiomyopathy; Diabetes; Echocardiography; Obesity; Ultrasound