Abstract
BackgroundAlthough the clinical outcome of acute myocardial infarction (AMI) in patients with type 2 diabetes mellitus (T2DM) is well established to be worse than for non-diabetic patients, the reasons for this remain unclear. We hypothesized that this may be related to impairment of bone marrow-derived endothelial progenitor cells (EPCs) mobilization.Methodology/Principal FindingsWe observed short term bone marrow EPCs mobilization and long term clinical outcomes in 62 AMI patients with or without T2DM and investigated EPCs levels as well as bone marrow pathway changes in a rat model of diabetes after AMI. Patients with T2DM exhibited a delay (peak time diabetics vs. non-diabetics: day 7 vs. day 5) and a decrease in EPCs mobilization (diabetics vs. non-diabetics: 285±56/106 mononuclear cells (MNCs) vs. 431±88/106 MNCs, p<0.05) within one month after AMI. Plasma levels of VEGF and SDF-1α as well as of hsCRP were higher in T2DM patients. Over a mean of 2.26 years follow-up, T2DM patients exhibited a pronounced decrease in LVEF as well as an increase in clinical events. Glucose (HR 2.01, 95% CI 1.42–2.85, p = 0.008), first day EPC (HR 0.974, 95% CI 0.952–0.997, p = 0.02) and seven day EPCs (HR 0.966, 95% CI 0.945–0.988, p = 0.003) were independent prognostic variables for cardiovascular mortality. In a diabetic rat model of AMI, decreased circulating EPCs was accompanied by lower expression of phospho-Akt, phospho-eNOS, HIF, MMP-9 and MMP-9 activity in the bone marrow as well as impaired cardiac function, angiogenesis and increased left ventricle remodeling.Conclusions/SignificanceBone marrow EPCs mobilization is delayed and reduced in diabetes, with impaired HIF/p-Akt/p-eNOS/MMP-9 signaling. This is likely to contribute to the deterioration in cardiac function and worsened clinical outcome seen in patients with T2DM.
Highlights
Clinical outcomes of acute myocardial infarction (AMI) in patients with type 2 diabetes mellitus (T2DM) is well established to be worse than non-diabetic patients [1,2], the reasons for this remain unclear
In a rat model of diabetes, we investigated whether reduced hypoxia induced factor (HIF)/vascular endothelial growth factor (VEGF)/Akt/ eNOS/MMP-9 signaling in the bone marrow may underlie impaired endothelial progenitor cells (EPCs) mobilization in response to AMI as compared to control rats
Clinical outcome post-AMI was worse in patients with T2DM than in non-diabetic patients [27]
Summary
Clinical outcomes of acute myocardial infarction (AMI) in patients with type 2 diabetes mellitus (T2DM) is well established to be worse than non-diabetic patients [1,2], the reasons for this remain unclear. It has been shown that patients following AMI exhibited increased mobilization of endothelial progenitor cells (EPCs) from the bone marrow [3]. The clinical outcome of acute myocardial infarction (AMI) in patients with type 2 diabetes mellitus (T2DM) is well established to be worse than for non-diabetic patients, the reasons for this remain unclear. We hypothesized that this may be related to impairment of bone marrow-derived endothelial progenitor cells (EPCs) mobilization
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