Alteration in Left Ventricular Diastolic Filling and Accumulation of Myocardial Collagen at Insulin-Resistant Prediabetic Stage of a Type II Diabetic Rat Model

Abstract

Background-Considerable controversy exists regarding impairment of cardiac function in diabetes mellitus (DM). We investigated the serial changes in left ventricular (LV) histopathology and LV filling dynamics in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, which have been established as an animal model of type II DM. Methods and Results-In 54 OLETF and 54 non-DM rats, body weight, blood pressure, heart rate, and transmitral pulsed Doppler examinations were performed from 5 to 47 weeks of age. An oral glucose tolerance test was performed at 10, 20, and 30 weeks of age. The hearts were excised for histopathology, including immunohistochemistry and histomorphometry of collagen, and measurement of hydroxyproline at baseline and each stage of developing DM. In the prediabetic stage (15 weeks of age), in which fast blood glucose remained normal, OLETF rats manifested mild obesity, postprandial hyperglycemia, and hyperinsulinemia, and early diastolic transmitral inflow exhibited prolonged deceleration time (OLETF, 59Ϯ10 ms versus non-DM, 49Ϯ8 ms, PϽ0.01) and low peak velocity (OLETF, 73Ϯ11 cm/s versus non-DM, 88Ϯ11 cm/s, PϽ0.01). Histopathology revealed extracellular fibrosis and abundant transforming growth factor-␤ 1 receptor II in LV myocytes of OLETF rats. At 15 weeks of age, the ratio of collagen area/visual field of LV wall in OLETF rats (8.3Ϯ1.3%) was larger than that in non-DM rats (4.9Ϯ1.8%, PϽ0.0001), and the collagen content/dry tissue weight ratio of heart was significantly higher in OLETF (2.0Ϯ0.5 mg/g) than non-DM (1.3Ϯ0.2 mg/g, PϽ0.01) rats.

Alteration in haemodynamics and pathological changes in the cardiovascular system during the development of Type 2 diabetes mellitus in OLETF rats

“…Relaxation abnormality in the diabetic heart has been found in clinical studies as well as experimental investigations [28,29]. Another study [30] recently reported that an increase of interstitial collagen and diastolic filling abnormalities appeared in the pre-diabetic stage in OLETF rats. However, in the diabetic stage at 47 weeks of age, the amount of interstitial collagen and LV diastolic function in OLETF rats was not different from LETO rats.In contrast, no collagen accumulation in the extracellular matrix of the heart or LVEDP and LVDd abnormalities were found in this study.…”

Relationships between Echocardiographic Findings, Pulse Wave Velocity, and Carotid Atherosclerosis in Type 2 Diabetic Patients

“…Another explanation is that histological changes in the left ventricular and aortic wall in diabetic patients may contribute to the correlation between left ventricular diastolic function and aortic stiffness. Several studies of diabetic cardiomyopathy have demonstrated an accumulation of myocardial collagen leading to interstitial and perivascular fibrosis, which correlate with left ventricular early diastolic and systolic dysfunction (3,30). In addition, there have been some reports that collagen accumulation may contribute to aortic wall stiffness in the type 2 diabetic rat model, which would accelerate the aging process in the aortic wall (31,32).…”

Effects of combined olmesartan and pravastatin on glucose intolerance and cardiovascular remodeling in a metabolic-syndrome model

“…At 30 weeks of age, blood was sampled from the right jugular vein after an overnight fast and the oral glucose (2 g kg À1 body weight) tolerance test (OGTT) was applied as described elsewhere. 10,11,17 Then, all the rats were killed after administering deep anesthesia with i.p. sodium pentobarbital (50 mg kg À1 ), and the heart, aorta and epididymal WAT were excised.…”

“…24 This strain manifests obesity, elevated BP, insulin resistance and dyslipidemia, and thus well serves as a model of metabolic syndrome. 10,11 We and others showed the consequences of such metabolic abnormalities, including impaired coronary-vasodilatory function 19 and left ventricular-diastolic dysfunction, 17 which were attributable to impaired nitric oxide/superoxide balance and enhanced expression of redox-sensitive prolifero-inflammatory cytokines. 10,11,17 The decreased cardiac content of DHFR and increased superoxide production in the aortic wall shown in this study adds new evidence for the accentuated oxidative stress in this model.…”