Background. Diabetic cardiomyopathy, evolving into heart failure, dramatically affects patients morbidity and mortality. Cardiac magnetic resonance (CMR) is the gold standard to assess cardiac remodeling. Aim. The aim of this study was to follow the long-term progression of diabetic cardiomyopathy by CMR. A secondary outcome was to highlight changes of circulating miRNAs and relative targets. Methods and Results. A longitudinal 5-years prospective study was undertaken in 71 subjects: all diabetic men completing the a registered trial (NCT number anonimized) and 20 non-diabetic matched controls. CMR with tagging was performed at baseline and after 4.6±0.2 years in 51/59 of enrolled diabetic men (age 64.6 ± 8.15 years). A significant increase in ventricular mass (∆LVMi= 13.47±29.66 g/m2; p=0.014) and a borderline increase in end-diastolic volume (∆EDVi= 5.16±14.71 ml/m2; p=0.056) was found at follow-up time point in diabetic men. Circumferential strain worsened (∆σ=1.52 ± 3.85%; p=0.033) without significant changes in torsion (∆θ=0.24 ±4.04°; p=0.737) revealing a loss of the adaptive uncoupling between strain and torsion. Contraction dynamics showed a significant decrease in time to systolic peak (∆TtP= -35.18±28.81 ms; p=0.000) and in early diastolic recoil rate (∆RR=-20.01±19.07 s-1; p=0.000). Cardiac performance and metabolic control were preserved. Micro-array analysis documented up-regulation of circulating hsa-miR-122-5p, hsa-miR-193a-5p, hsa-miR-4707-5p, hsa-miR-4749-3p, and down-regulation of hsa-miR-3148, miR-3149, miR-32-3p, miR-595, but only the longitudinal change of hsa-miR-122-5p, hsa-miR-3148 and miR-595 correlated with CMR. Target-scan predicted metalloproteinases (MMP2, MMP16) and their regulators (TIMP1) as converging targets in network analysis. Using Db/Db mouse model we confirmed that miR-122-5p expression is associated with diabetic cardiomiopathy and that cardiac tissue can be considered its main source. In vitro analysis showed that MMP2 is a direct hsa-miR-122-5p target and its expression is altered in diabetic endothelial cells model. Moreover, we found that hsa-miR-122-5p overexpression affects extracellular matrix genes likely through MMP2 modulation. Conclusion. Within five years, independently from glycemic control, increasing cardiac hypertrophy is associated with a progressive impairment in strain, exhaustion of the compensatory role of torsion and changes in viscoelastic contraction dynamics that are paralleled by specific changes in circulating miRNA targeting the extracellular matrix.
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