Abstract 3536: Diabetes Mellitus Accelerates Left Ventricular Diastolic Dysfunction through Activation of Renin-Angiotensin System in Hypertensive Rats
Diabetes mellitus (DM) is a major risk factor of heart failure, independent of coronary artery disease or hypertension (HT). We have previously demonstrated that DM is an independent prognostic factor in patients with diastolic heart failure in our cohort study; however, the detailed mechanisms of DM-induced diastolic dysfunction remain to be fully elucidated. In this study, we made 5 different groups of Dahl salt-sensitive hypertensive rats that were treated for 10 weeks as follows; a low-salt (0.5% NaCl) diet (control), a high-salt (5% NaCl) diet (HT), a low-salt diet with streptozotocin (STZ) injection (30 mg/kg, IP) (DM), a high-salt diet with STZ injection (HT + DM), and a high-salt diet with STZ treated with an angiotensin receptor blocker, olmesartan (sub-depressor dose, 1 mg/kg/day, PO) (olmesartan) (n=12–20 each). After the 10-week treatment, as compared with the control group, cardiac diastolic dysfunction with preserved systolic function was noted in the HT group and more prominently in the HT + DM group (E/A, 1.2±0.4, 1.6±0.4 and 2.7±0.5, P<0.05; tau, 18±1, 17±2 and 13±1 msec, P<0.05), associated with enhanced cardiac fibrosis (%fibrosis area, 2.6±0.9, 1.7±0.8 and 1.0±0.4, P<0.05). By contrast, the extent of HT and myocardial hypertrophy was comparable between the HT and HT + DM groups. Myocardial expressions of collagen III, transforming growth factor-β2, and angiotensin-converting enzyme (ACE) and myocardial oxidative stress (evaluated by 4-hydroxy-2-nonenal-modified protein) were mostly enhanced in the HT + DM group. Importantly, there was a positive correlation between the extent of diastolic dysfunction (tau) and that of myocardial ACE expression (n=28, R=0.46, P<0.05). The inhibition of renin-angiotensin system (RAS) with olmesartan significantly ameliorated all these cardiac abnormalities induced by DM and HT, independent of the changes in blood pressure. These results indicate that DM accelerates diastolic dysfunction in hypertensive heart disease (HHD) through RAS activation with subsequent inflammatory and oxidative stresses and myocardial fibrosis, suggesting the therapeutic importance of RAS inhibition for the treatment of HHD, especially when complicated with DM.