Alteration in left ventricular diastolic filling and accumulation of myocardial collagen at insulin-resistant prediabetic stage of a type II diabetic rat model

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, 59 +/- 10 ms versus non-DM, 49 +/- 8 ms, P<0.01) and low peak velocity (OLETF, 73 +/- 11 cm/s versus non-DM, 88 +/- 11 cm/s, P<0.01). Histopathology revealed extracellular fibrosis and abundant transforming growth factor-beta(1) receptor LI in LV myocytes of OLETF rats. At 15 weeks of age, the ratio of collagen area/visual field of LV wall in OLETF rats (8.3 +/- 1.3%) was larger than that in non-DM rats (4.9 +/- 1.8%, P<0.0001), and the collagen content/dry tissue weight ratio of heart was significantly higher in OLETF (2.0 +/- 0.5 mg/g) than non-DM (1.3 +/- 0.2 mg/g, P<0.01) rats. Conclusions-A metabolic abnormality present in the prestage of type IT DM may produce LV fibrosis and alteration in cardiac function.