The adverse long-term effects of diabetes mellitus have been well described and involve many organ systems. While diabetes management has largely focused on control of hyperglycemia, the presence of abnormalities of angiogenesis may cause or contribute to many of the clinical manifestations of diabetes. When compared with non-diabetic subjects, diabetics demonstrate vascular abnormalities of the retina, kidneys, and fetus. Diabetics have impaired wound healing, increased risk of rejection of transplanted organs, and impaired formation of coronary collaterals. In each of these conditions, and possibly in diabetic neuropathy as well, abnormalities of angiogenesis can be implicated in the pathogenesis. A perplexing feature of the aberrant angiogenesis is that excessive and insufficient angiogenesis can occur in different organs in the same individual. In this review, the clinical features, molecular mechanisms, and potential therapeutic options of abnormal angiogenesis in diabetes will be reviewed.

Erythropoietin is a hypoxia-induced hormone that is essential for normal erythropoiesis. The production of recombinant human erythropoietin (rHuEpo) has revolutionized the treatment of anemia associated with chronic renal failure and chemotherapy, and has been used as prophylaxis to prevent anemia after surgery. The erythropoietin receptor is widely distributed in the cardiovascular system, including endothelial cells, smooth muscle cells and cardiomyocytes. Epo has potentially beneficial effects on the endothelium including anti-apoptotic, mitogenic and angiogenic activities. On the other hand, some reports suggest that rHuEpo may have pro-thrombotic or platelet-activating effects. Hypertension develops in 20-30% of renal patients treated with rHuEpo. Many patients with heart failure have anemia. Despite some potential adverse effects, early studies in heart failure patients with anemia suggest that rHuEpo therapy is safe and effective in reducing left ventricular hypertrophy, enhancing exercise performance and increasing ejection fraction. Further studies are warranted to define the role of rHuEpo in chronic heart failure and other cardiovascular settings.

Objective: To summarize the structure, function, and regulation of matrix metalloproteinases (MMPs) and to review the literature to date on their potential role in the pathogenesis of acute coronary syndromes. Methods: A recursive strategy starting with a Medline Search for primary articles in the last decade, followed by identification of additional articles of interest among the cited literature in the primary articles, followed by identification of additional articles of interest cited in the secondary articles. Results: MMPs play a central role in many fundamental processes in human health and disease. In vitro evidence suggests that MMP activity may facilitate atherosclerosis, plaque destabilization, and platelet aggregation. Limited evidence from clinical studies supports a role of MMPs in the development of acute coronary syndromes. Conclusions: MMP activity likely contributes to the development of acute coronary syndromes and may be an important therapeutic target for future drug development.

Abstract-Altered expression and functional responses to cardiac ␤ 3 -adrenergic receptors (ARs) may contribute to progressive cardiac dysfunction in heart failure (CHF). We compared myocyte ␤ 3 -AR mRNA and protein levels and myocyte contractile, [Ca 2ϩ ] i transient, and Ca 2ϩ current (I Ca,L ) responses to BRL-37344 (BRL, 10 Ϫ8 mol/L), a selective ␤ 3 -AR agonist, in 9 instrumented dogs before and after pacing-induced CHF. Myocytes were isolated from left ventricular myocardium biopsy tissues. Using reverse transcription-polymerase chain reaction, we detected ␤ 3 -AR mRNA from myocyte total RNA in each animal. Using a cloned canine ␤ 3 -AR cDNA probe and myocyte poly A ϩ RNA, we detected a single band about 3.4 kb in normal and CHF myocytes. ␤ 3 -AR protein was detected by Western blot. ␤ 3 -AR mRNA and protein levels were significantly greater in CHF myocytes than in normal myocytes. Importantly, these changes were associated with enhanced ␤ 3 -AR-mediated negative modulation on myocyte contractile response and [Ca 2ϩ ] i regulation. Compared with normal myocytes, CHF myocytes had much greater decreases in the velocity of shortening and relengthening with BRL accompanied by larger reductions in the peak systolic [Ca 2ϩ ] i transient and I Ca,L . These responses were not modified by pretreating myocytes with metoprolol (a ␤ 1 -AR antagonist) or nadolol (a ␤ 1 -and ␤ 2 -AR antagonist), but were nearly prevented by bupranolol or L-748,337 (␤ 3 -AR antagonists). We conclude that in dogs with pacing-induced CHF, ␤ 3 -AR gene expression and protein levels are upregulated, and the functional response to ␤ 3 -AR stimulation is increased. This may contribute to progression of cardiac dysfunction in CHF.

Background-No therapy has been shown to improve survival in heart failure (HF) with a normal ejection fraction (EF).There are plausible reasons to hypothesize that statins may be of benefit in HF with a normal EF. Methods and Results-We evaluated 137 patients with HF and an EF Ն0.50. The effect of treatment received at study entry on survival was determined. During a follow-up of 21Ϯ12 months, 20 deaths were observed. Treatment with an ACE inhibitor or receptor blocker, ␤-blocker, or calcium blocker had no significant effect on survival.