Worse clinical outcomes in acute myocardial infarction patients with type 2 diabetes mellitus: relevance to impaired endothelial progenitor cells mobilization - PubMed (original) (raw)

Worse clinical outcomes in acute myocardial infarction patients with type 2 diabetes mellitus: relevance to impaired endothelial progenitor cells mobilization

Lin Ling et al. PLoS One. 2012.

Abstract

Background: Although 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 findings: We 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/significance: Bone 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.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. EPCs mobilization following AMI was impaired in diabetics.

(A) Mobilization of EPCs in non-diabetics and diabetics at different time points post-AMI (*p<0.05 vs. non-diabetics). (B) Three step analysis by flow cytometry to quantify the CD45−/low/CD34+/CD133+/KDR+ EPCs at peak time (non-diabetic: day 5; diabetics: day 7).

Figure 2. Plasma VEGF, SDF-1α and hsCRP were increased in patients with T2DM post-AMI.

Plasma concentrations of (A) VEGF, (B) SDF-1α and (C) hsCRP were assessed by enzyme-linked immunosorbent assay at different time points post-AMI in non-diabetics and diabetics (*p<0.05 vs. non-diabetic patients).

Figure 3. Cardiac function in diabetics and non-diabetics patients with AMI.

Baseline echocardiography measurements were taken while hospitalized for AMI. Compared with non-diabetic patients, T2DM patients showed a increased left atrial diameter at baseline and decreased ejection fraction after 2.26 years follow up. (A) Systolic ejection fraction. (*p<0.05 vs. non-diabetic patients at follow up). (B) left ventricular end-diastolic diameter. (C) left atrial diameter. (*p<0.05 vs. non-diabetic patients at baseline). (D) inter-ventricular septal thickness at diastole. (E) left ventricular posterior wall thickness.

Figure 4. Decreased survival in diabetics during follow up and negative effect of diabetics after AMI.

(A) Cumulative survival curve of the two groups at follow up. T2DM patients showed decreased survival rate after AMI. (B) The negative effect of T2DM on clinical outcomes post-AMI.

Figure 5. EPCs mobilization in rats post-AMI.

(A) Mobilization of EPCs after myocardial infarction in rats at different time time points post-AMI (*p<0.05 vs. non-diabetic rats). (B) Flow cytometry analysis of the CD34+/c-Kit+ EPCs at peak time.

Figure 6. Bone marrow signalling impairment in diabetic rats post-AMI.

Proteins expression in bone marrow at days 0, 1, 3, 7 after myocardial infarction were measured by western blot. (A) HIF (B) VEGF (C) phospho-Akt to Akt (D) phospho-eNOS to eNOS (E) MMP-9 (F) MMP-9 activity measured by gelatin zymography (*p<0.05 vs. non-diabetic rats).

Figure 7. Echocardiography showed deceased cardiac function in diabetic rats four weeks after AMI.

(A) Systolic function index ejection fraction (*p<0.05 vs. non-diabetic rats). (B) Systolic function index percent fractional shortening (*p<0.05 vs. non-diabetic rats). (C) Left ventricle end-diastolic diameter (*p<0.05 vs. non-diabetic rats). (D) Left ventricle end-systolic diameter (*p<0.05 vs. non-diabetic rats). (E) The inter-ventricular septal thickness at diastole. (F) Left ventricle posterior wall thickness.

Figure 8. Cardiac morphology showed increased remodelling in diabetic rats.

(A) Infarct myocardium stained with hematoxylin-eosin (*p<0.05 vs. non-diabetic rats). (B) Masson’s trichrome staining showed the fibrosis area (*p<0.05 vs. non-diabetic rats). (C) vWF immuno-histochemistry of micro-vessels (*p<0.05 vs. non-diabetic rats). (D) HIF immuno-histochemistry staining of the myocardium (*p<0.05 vs. non-diabetic rats).

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Worse clinical outcomes in acute myocardial infarction patients with type 2 diabetes mellitus: relevance to impaired endothelial progenitor cells mobilization - PubMed (original) (raw)