Diastolic dysfunction and abnormalities of the microcirculation in type 2 diabetes

Abstract

Diabetic cardiomyopathy is an increasingly recognized entity. The pathogenic factors that may contribute to its development, especially the earliest changes of diastolic dysfunction (DD), have not been clearly defined. Microvessel dysfunction and upregulation of profibrotic growth factors have been described as possible causes. The aim of this study was therefore to determine whether microvascular dysfunction and/or upregulation of the profibrotic connective tissue growth factor (CTGF) are associated with subclinical DD in subjects with type 2 diabetes. Forty subjects with type 2 diabetes and 20 age-matched non-diabetic controls, all of whom had no clinical evidence of ischaemic heart disease, cardiac failure or echo evidence of systolic ventricular dysfunction, were recruited. Microvascular function was measured by laser Doppler velocimetry, with examination of endothelium-dependent increase in blood flow following iontophoresis of acetylcholine (ACh) and endothelium-independent increase in blood flow in response to the nitric oxide donor sodium nitroprusside (SNP). CTGF levels were determined by Western immunoblotting. DD determined on the basis of traditional echocardiographic criteria was similar in diabetic subjects compared with controls (28 vs. 20%, p = 0.5). Using left ventricular myocardial tissue Doppler-based indices for DD, the E/E' and the E'/A' ratios (where E is the flow related to early ventricular filling and E' and A' are early and late diastolic velocities, respectively) in diabetic subjects revealed evidence of more DD than controls (p = 0.046 and p = 0.007 respectively) . Comparing controls with no DD by conventional echocardiographic criteria (Group I), diabetes and no DD (Group II) and diabetes with DD (Group III), there was a significant trend in reduction of both endothelium-dependent (ACh fold change; p = 0.04) and endothelium-independent (SNP fold change; p = 0.0004) blood flow across the groups. The ACh and SNP responses, however, were not correlated significantly with quartiles of the E/E' ratio or the E'/A' ratio. CTGF plasma levels did not differ across the groups and CTGF did not correlate with parameters of microvascular function. This study indicates that while there is a significant association between DD and measures of microvascular function, the relationship between endothelial dysfunction, CTGF and subtle measures of DD is not strong. Other factors are therefore likely to play an important role in the early pathogenesis of subclinical cardiac DD in type 2 diabetes.