There are few data on angiographic coronary artery anatomy in patients whose coronary artery disease progresses to myocardial infarction. In this retrospective analysis, progression of coronary artery disease between two cardiac catheterization procedures is described in 38 patients: 23 patients (Group I) who had a myocardial infarction between the two studies and 15 patients (Group II) who presented with one or more new total occlusions at the second study without sustaining an intervening infarction. In Group I the median percent stenosis on the initial angiogram of the artery related to the infarct at restudy was significantly less than the median percent stenosis of lesions that subsequently were the site of a new total occlusion in Group II (48 versus 73.5%, p less than 0.05). In the infarct-related artery in Group I, only 5 (22%) of 23 lesions were initially greater than 70%, whereas in Group II, 11 (61%) of 18 lesions that progressed to total occlusion were initially greater than 70% (p less than 0.01). In Group I, patients who developed a Q wave infarction had less severe narrowing at initial angiography in the subsequent infarct-related artery (34%) than did patients who developed a non-Q wave infarction (80%) (p less than 0.05). Univariate and multivariate analysis of angiographic and clinical characteristics present at initial angiography in Group I revealed proximal lesion location as the only significant predictor of evolution of lesions greater than or equal to 50% to infarction. This retrospective study suggests that myocardial infarction frequently develops from previously nonsevere lesions.(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract-Heme oxygenase-1 (HO-1) is a stress protein that has been suggested to participate in defense mechanisms against agents that may induce oxidative injury, such as heme and inflammatory molecules. Incubation of endothelial cells in a high-glucose (33 mmol/L) medium for 7 days resulted in a decrease of HO activity by 34% and a decrease in HO-1 and HO-2 proteins compared with cells exposed to low glucose (5 mmol/L) (PϽ0.05) or cells exposed to mannitol (33 mmol/L). Overexpression of HO-1 was coupled with an increase in HO activity and carbon monoxide synthesis, decreased cellular heme, and acceleration in all phases of the cell cycle (PϽ0.001). Key Words: cell cycle Ⅲ oxidative stress Ⅲ superoxide anion production Ⅲ gene transfer Ⅲ heme oxygenase E xposure of endothelial cells to elevated glucose levels causes glucose oxidation, resulting in the generation of excess reactive oxygen species (ROS) in endothelial cells. A reduction in antioxidant reserves has been attributed to endothelial cell dysfunction in diabetes, even in patients with well-controlled glucose levels. 1-3 Hyperglycemia-mediated local formation of ROS is considered to be the major contributing factor to endothelial dysfunction, including abnormalities in cell cycling 1,4,5 and delayed replication, and these abnormalities can be reversed by antioxidant agents 6,7 and an increased expression of antioxidant enzymes. 8 Du et al 9 have demonstrated that hyperglycemia stimulates the induction of apoptosis in endothelial cells by a mechanism that involves the generation of ROS and superoxide anion formation. Moreover, high glucose conditions facilitated the susceptibility of various serum proteins to oxidation, which contributes to the inhibition of endothelial cell proliferation. 10 Wolf et al 11 have reported that high glucose stimulates mitogen-activated protein kinase, which was associated with an enhancement in p27 Kip1 protein and growth arrest.We have previously shown that overexpression of the human heme oxygenase-1 (HO-1) gene in rabbit and rat endothelial cells renders the cells resistant to oxidative stress-causing agents 12 and enhances cell growth 13,14 and angiogenesis, 15 which highlights the important metabolic and cytoprotective role of the HO-1 gene. 12,15-17 Inhibition of HO activity has been shown to exacerbate the inflammatory response in the arterial wall in animal models of atherosclerosis model. 18 HO-1 is expressed, under basal conditions, at low levels in endothelial cells 12,15,19,20 and can be induced in these cells in response to oxidants, including heme, H 2 O 2 , and tumor necrosis factor. [21][22][23] It is conceivable, then, that upregulation of HO activity could function to attenuate the glucosemediated inhibition of cell-cycle progression.The objectives of this study were to determine the effects of glucose on HO activity and the expression of HO-1 and HO-2 proteins and DNA distribution and to examine the role of heme metabolism by HO on cell-cycle progression. We also examined the effect of overexpression and un...

Heme oxygenase (HO) plays a critical role in the regulation of cellular oxidative stress. The effects of the reactive oxygen species scavenger ebselen and the HO inducers cobalt protoporphyrin and stannous chloride (SnCl 2 ) on HO protein levels and activity, indices of oxidative stress, and the progression of diabetes were examined in the Zucker rat model of type 2 diabetes. The onset of diabetes coincided with an increase in HO-1 protein levels and a paradoxical decrease in HO activity, which was restored by administration of ebselen. Up-regulation of HO-1 expressed in the early development of diabetes produced a decrease in oxidative/nitrosative stress as manifested by decreased levels of 3-nitrotyrosine, superoxide, and cellular heme content. This was accompanied by a decrease in endothelial cell sloughing and reduced blood pressure. Increased HO activity was also associated with a significant increase in the antiapoptotic signaling molecules Bcl-xl and phosphorylation of p38-mitogen-activated protein kinase but no significant increases in Bcl-2 or BAD proteins. In conclusion, 3-nitrotyrosine, cellular heme, and superoxide, promoters of vascular damage, are reduced by HO-1 induction, thereby preserving vascular integrity and protecting cardiac function involving an increase in antiapoptotic proteins.

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Myocarditis was diagnosed by endomyocardial biopsy in 34 patients with otherwise unexplained heart failure. On the basis of both clinical and histologic findings these patients were divided into three groups. Seven patients had acute myocarditis (mean age, 20 years; mean ejection fraction, 22 per cent) characterized by an interstitial inflammatory infiltrate and extensive, acute cell damage. Five of these patients died after a mean duration of illness of eight weeks. Eighteen patients had rapidly progressive myocarditis (mean age, 35 years; mean ejection fraction, 19 per cent) characterized by patchy acute and healing cell damage and fibrosis; 17 of them died after a mean duration of illness of 23 months. Nine patients had chronic myocarditis (mean age, 31 years; mean ejection fraction, 31 per cent) characterized by focal inflammation and cell damage. All nine were alive after a mean follow-up period of 39 months. In four of these nine, clinical and hemodynamic improvement occurred after one month of immunosuppressive therapy. Our study suggests that a clinically useful classification of myocarditis can be accomplished by endomyocardial biopsy.

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Aims/hypothesis: Patients with diabetes mellitus are well known to be at high risk for vascular disease. Circulating endothelial cells (CECs) have been reported to be an ex vivo indicator of vascular injury. We investigated the presence of CECs in the peripheral blood of 25 patients with diabetes mellitus and in nine nondiabetic control donors. Methods: Endothelial cells were isolated from peripheral blood with anti-CD-146-coated immunomagnetic Dynabeads, and were stained with acridine orange dye and counted by fluorescence microscopy. The cells were also stained for von Willebrand factor and Ulex europaeus lectin 1. Results: Patients with diabetes mellitus had an elevated number of CECs (mean 69±30 cells/ml, range 35-126) compared with healthy controls (mean 10±5 cells/ml, range 3-18) (p<0.001). The increase in CECs did not correlate with the levels of HbA 1 c. Circulating endothelial cell numbers were elevated regardless of glucose levels, suggesting that, even with control of glucose levels, there is increased endothelial cell sloughing. Conclusions: Our study suggests that the higher number of CECs in patients with type 2 diabetes may reflect ongoing vascular injury that is not directly dependent on glucose control.

the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Study GroupBackground-In the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial, an initial strategy of coronary revascularization and optimal medical treatment (REV) compared with an initial optimal medical treatment with the option of subsequent revascularization (MED) did not reduce all-cause mortality or the composite of cardiovascular death, myocardial infarction, and stroke in patients with type 2 diabetes mellitus and stable ischemic heart disease. In the same population, we tested whether the REV strategy was superior to the MED strategy in preventing worsening and new angina and subsequent coronary revascularizations. Methods and Results-Among the 2364 men and women (mean age, 62.4 years) with type 2 diabetes mellitus, documented coronary artery disease, and myocardial ischemia, 1191 were randomized to the MED and 1173 to the REV strategy preselected in the percutaneous coronary intervention (796) and coronary artery bypass graft (377) strata. Compared with the MED strategy, the REV strategy at the 3-year follow-up had a lower rate of worsening angina (8% versus 13%; PϽ0.001), new angina (37% versus 51%; Pϭ0.001), and subsequent coronary revascularizations (18% versus 33%; PϽ0.001) and a higher rate of angina-free status (66% versus 58%; Pϭ0.003). The coronary artery bypass graft stratum patients were at higher risk than those in the percutaneous coronary intervention stratum, and had the greatest benefits from REV. Conclusions-In these patients, the REV strategy reduced the occurrence of worsening angina, new angina, and subsequent coronary revascularizations more than the MED strategy. The symptomatic benefits were observed particularly for high-risk patients. Clinical Trial Registration-URL: http://www.ClinicalTrials.gov. Unique identifier: NCT00006305.