Relationship of extracellular matrix regulation, collagen turnover and renin angiotensin system activity with myocardial function in patients with type 2 diabetes mellitus

Abstract

Background: Patients with type 2 diabetes mellitus (T2DM) have impaired myocardial function, one of the proposed pathologic is expansion and change in composition of extracellular matrix (ECM) of the heart, but the underlying mechanism is unclear. Purpose: The aim of the present study was to evaluate the relationship of ECM regulation, collagen turnover and the renin angiotensin system (RAS) with myocardial dysfunction in T2DM patients. Methods: A total of 123 patients (62 female, 60.8±8.8 years) with T2DM and no evidence of underlying coronary artery disease were recruited. All patients underwent resting and exercise echocardiography. Resting echocardiography was analyzed by conventional parameters, E/E' ratio (left ventricular filling pressure) and speckle tracking derived global longitudinal strain (GLS). Exercise echocardiography parameters included diastolic function reserve index (DFRI) and stress GLS. Plasma concentration of ECM turnover, including matrix metalloproteinase-1 (MMP-1), tissue inhibitor of MMP-1 (TIMP-1), procollagen propeptides (amino-terminal propeptide of type I and type III procollagen [PINP and PIIINP]) and RAS activity (PRA, angiotensin II and aldosterone) were also measured. Results: Diastolic dysfunction was diagnosed in 75 (61%) patients: they had a higher plasma level of TIMP-1 (135.2±44.8 vs 153.3±46.1ng.ml-1, P=0.03) and PIIINP (7.7±3.9 vs 9.4±4.9 ng.ml-1, p<0.05) than those with no diastolic dysfunction. Plasma TIMP-1 level was positively associated with left ventricular E/E' and GLS both at rest (r=0.27, P<0.01; r=0.25, P=0.01) and during stress (r=0.23, P=0.01; r=0.25, P=0.01) and negatively with DFRI (r=−0.21, P=0.02). After multivariate adjustment, TIMP-1 level remained significantly associated with E/E' at rest [B=2.71, 95% confidence interval (CI) = 0.27–5.16, P=0.03] and at stress (B=2.96, 95% CI = 0.92–5.01, P=0.01), as well as DFRI (B=−0.45, 95% CI = −0.85–0.05, P=0.03). The procollagen propeptides and RAS activity showed no association with either echocardiography parameter. Conclusions: In patients with T2DM, TIMP-1, an ECM regulator, is independently associated with myocardial diastolic dysfunction both at rest and during stress. Measures that could reduce TIMP-1, such as statin therapy, may reduce myocardial dysfunction in these patients.