107 - Experimental Model of Type 2 Diabetic Cardiomyopathy: A State of cGMP Deficiency

Abstract

Introduction: Patients with type 2 diabetes mellitus (DM) are predisposed to long term cardiovascular complications, including development of myocardial dysfunction and heart failure. Despite the high prevalence of diabetic cardiomyopathy, characterized by diastolic dysfunction independent of coronary artery disease and thought to be related to metabolic derangements and protein alterations, not much is known regarding the genesis and treatment of this condition. The development of an experimental type 2 diabetes mellitus animal model can help to better understand pathophysiology and mechanisms of diabetic cardiomyopathy. Methods: Genetically designated Zucker diabetic ZDFO rats and Zucker lean non-diabetic ZDFL rats (ten each) were maintained on Purina 5008 diet from 13 to 32 weeks of age. Echocardiography with strain imaging was performed, and vital signs and blood work were obtained from the rats at the beginning and end of the study. Echocardiography was used to assess left ventricular (LV) structure and function. At the end of 32 weeks, rats were anesthetized and arterial blood was collected from carotid artery. Cardiac tissues were harvested for histological analysis and sections stained with Picrosirius Red to assess for fibrosis. Results: The development of diabetes was confirmed by HbA1c measurements (diabetic rats 12.7 ± 0.2 vs nondiabetic rats 5.1 ± 0.1%, P < .01). There was no difference in LV ejection fraction between the diabetic rats as compared to nondiabetic controls (78.1 ± 0.6 vs 78.0 ± 0.7%, P = .87). However, there was evidence of diastolic dysfunction with longitudinal strain imaging. Early diastolic strain demonstrated a trend for difference in the diabetic group from 13 to 32 weeks (−10.9 ± 0.6 to −9.6 ± 0.7, P = .16) that is not seen in the nondiabetic group (−11.1 ± 0.5 to −11.6 ± 0.9, P = .98). The diabetic vs nondiabetic rats had increased mean arterial pressures at 32 weeks (106 ± 4 vs 95 ± 2 mmHg, P = .01). LV mass indexed to rat body weight was increased in the diabetic vs nondiabetic rats (2.34 ± 0.36 vs 2.06 ± 0.03 mg/g, P < .01). Upon tissue histological examination, there was greater LV interstitial (21.6 ± 3 vs 10.8 ± 1%, P = .01) and perivascular (25.8 ± 3 vs 14.8 ± 1%, P < .01) fibrosis. The diabetic vs nondiabetic rats had decreased plasma cGMP at 32 weeks (2.8 ± 0.7 vs 8.9 ± 1.7 pmol/ml, P = .01) and no difference in plasma BNP (24.6 ± 5.5 vs 18.4 ± 2.6 pg/ml, P = .76). Conclusion: In this genetically designated Zucker type 2 diabetes mellitus rat model, we demonstrated that there is development of cardiac hypertrophy, fibrosis and diastolic dysfunction, along with a cGMP deficiency state. Future studies using these diabetic animal models can help better elucidate the pathophysiology of diabetic cardiomyopathy and development of novel therapeutic options.