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To evaluate the effect of metformin therapy on coronary endothelial function and major adverse cardiac events (MACE) in patients with prediabetes with stable angina and nonobstructive coronary stenosis (NOCS). RESEARCH DESIGN AND METHODS Metformin therapy may be needed to reduce coronary heart disease risk in patients with prediabetes. A total of 258 propensity score-matched (PSM) patients with stable angina undergoing coronary angiography were enrolled in the study. Data from 86 PSM subjects with normoglycemia (NG), 86 PSM subjects with prediabetes (pre-DM), and 86 PSM subjects with prediabetes treated with metformin (pre-DM metformin) were analyzed. During coronary angiography, NOCS was categorized by luminal stenosis <40% and fractional flow reserve >0.80. In addition, we assessed the endothelial function, measuring coronary artery diameter of left anterior descending coronary (LAD) at baseline and after the infusion of acetylcholine, by means of an intracoronary Doppler guide wire. MACE, as cardiac death, myocardial infarction, and heart failure, was evaluated at 24 months of follow-up. RESULTS At baseline, NG patients had a lower percentage of LAD endothelial dysfunction compared with pre-DM patients (P < 0.05). The pre-DM patients had a higher percentage of endothelial LAD dysfunction as compared with the pre-DM metformin patients (P < 0.05). At the 24th month of follow-up, MACE was higher in pre-DM versus NG (P < 0.05). In pre-DM metformin patients, MACE was lower compared with pre-DM patients (P < 0.05). CONCLUSIONS Metformin therapy may reduce the high risk of cardiovascular events in pre-DM patients by reducing coronary endothelial dysfunction.

This article is available online at http://www.jlr.org tural basis of the progression from well-compensated hypertrophy to HF is still largely unknown in MS patients. Emerging evidence suggests that inherited and acquired cardiomyopathies, such as impaired glucose tolerance and diabetes, are associated with marked intracellular lipid accumulation in the heart ( 2, 3 ). In the normal body, most triglyceride is stored in adipocytes; the amount of triglyceride stored in nonadipocyte tissues (liver, and myocardium) is minimal and very tightly regulated. However, several-fold increased cardiomyocyte triglyceride stores are observed in animal models of obesity and diabetes ( 4 ). This lipid accumulation may contribute to cardiomyocyte death by nonoxidative and oxidative ( 5 ) metabolic pathways and to HF. Even in humans, myocardial lipid content was recently reported to increase with the degree of adiposity and contribute to cardiac dysfunction ( 6 ), suggesting that myocardial lipid content may be a biomarker and putative therapeutic target for cardiac disease in patients with MS.Genes involved in lipid metabolism are nutritionally regulated at the transcriptional level in a coordinated fashion ( 7 ). Sterol-regulatory element binding protein (SREBP)-1c is a transcription factor that controls lipogenesis and is induced during overnutrition to facilitate the conversion of glucose to fatty acids and triglycerides for the storage of excess energy ( 8 ). Uncontrolled activation of nuclear SREBP-1c in the liver can cause hepatosteatosis Metabolic syndrome (MS) is strongly associated with left ventricular (LV) hypertrophy and cardiac function derangements that lead to heart failure (HF) ( 1 ). The struc-

OBJECTIVE -Stress hyperglycemia has been associated with increased mortality in patients with myocardial infarction (MI). We examined the association between plasma glucose levels, circulating inflammatory markers, T-cell activation, and functional cardiac outcome in patients with first MI. RESEARCH DESIGN AND METHODS -Echocardiographic parameters, circulating levels of interleukin-18 (IL-18), C-reactive protein (CPR), and the percent of CD16-CD56, CD4/CD8, CD152, and HLA-DR expression were investigated in 108 patients with acute MI on admission to the emergency ward.RESULTS -Our review found that 31 new hyperglycemic patients (glycemia Ն7 mmol/l) had higher infarct segment length (P Ͻ 0.05) and myocardial performance index (P Ͻ 0.02) and reduced transmitral Doppler flow (P Ͻ 0.05), pulmonary flow analysis (P Ͻ 0.02), and ejection fraction (P Ͻ 0.05) compared with 36 hyperglycemic diabetic patients and 41 normoglycemic patients. Plasma IL-18 and CRP were higher in the hyperglycemic than in the normoglycemic patients (P Ͻ 0.005), with the highest values in patients with new hyperglycemia (P Ͻ 0.05). Hyperglycemic patients had a higher percent of CD16ϩ/CD56ϩ cells and CD4/CD8 ratio (P Ͻ 0.01), whereas they had lower CD152 expression (which has a negative regulatory function in T-cell activation) compared with normoglycemic patients (P Ͻ 0.001).CONCLUSIONS -During MI, hyperglycemia is associated with increased levels of inflammatory markers, enhanced expression of cytotoxic T-cells, and reduced expression of T-cells, which are implicated in limiting the immune process. An increased inflammatory immune process seems a likely mechanism linking acute hyperglycemia to poor cardiac outcome in MI patients. Diabetes Care 26:3129 -3135, 2003A n unusually high prevalence of glycosuria in nondiabetic patients who have acute myocardial infarction (MI) was noted as early as 1931 (1). Stress hyperglycemia after MI is associated with an increased risk of in-hospital mortality in patients with and without diabetes (2). Moreover, a positive association between hyperglycemia at the time of the event and subsequent mortality from MI has been reported (3). Although the mechanisms underlying this association are not fully understood, evidence that the use of insulin to lower glucose concentrations decreases mortality in diabetic patients who have MI (4) suggests that hyperglycemia is not simply an epiphenomenon of a stress response. Consequently, hyperglycemia at the time of MI may be an important and potentially modifiable risk factor for poor outcome.A growing body of evidence suggests that MI is associated with local and systemic inflammation (5). Cell activation, which is mediated to some extent by immune mechanisms, is an important component of inflammatory reaction (6). Atherosclerotic plaques contain large numbers of activated T-cells, suggesting that immune mechanisms are important factors in the pathogenesis of the atherosclerotic background (6). Indeed, inflammatory cells infiltrate nearly all plaques, and culprit lesions of...

Inadequate angiogenic response to ischemia in diabetic myocardium could result in poor collateral formation. Because hypoxia-inducible factor (HIF)-1␣ is a transcriptional activator of vascular endothelial growth factor (VEGF) and is critical for initiating angiogenic responses to hypoxia, we investigated the expression of HIF-1␣ and VEGF in specimens of human heart tissue to elucidate the molecular responses to myocardial ischemia in diabetic patients during unstable angina. Moreover, accumulation of a marker of protein nitration nitrotyrosine, as well as the superoxide anion (O 2 ؊ ) levels and inducible nitric oxide synthase (iNOS), were evaluated. Ventricular biopsy specimens from 15 type 2 diabetic and 14 nondiabetic patients presenting with unstable angina (ischemic group) and from 20 patients (11 type 2 diabetic and 9 nondiabetic patients) who underwent coronary bypass surgery without angina within the preceding 10 days (control group) were collected during coronary bypass surgery. Nondiabetic patients had higher HIF-1␣ and VEGF expressions compared with diabetic patients (P < 0.001). As compared with nondiabetic specimens, diabetic specimens showed higher levels of both iNOS mRNA and protein levels (P < 0.001) associated with the highest tissue levels of nitrotyrosine and O 2 ؊ (P < 0.001). Diabetes is associated with increased myocardial tissue levels of iNOS, O 2 ؊ , and nitrotyrosine and reduced expression of myocardial angiogenesis factors during ischemia. Diabetes