Arginase Inhibition Improves Endothelial Function in Patients With Coronary Artery Disease and Type 2 Diabetes Mellitus Results of a Randomized, Double-Blind, Placebo-Controlled Trial to Circulation Editors’ Picks Most Read Articles in Coronary Heart Disease

Summary: Vascular complications associated with type 2 diabetes mellitus are a widespread clinical problem. The mechanism behind these complications is far from understood, and specific treatment is lacking. Endothelial dysfunction with reduced bioavailability of nitric oxide has been suggested to be of importance for development of ath-erosclerosis and diabetic vascular complications. Emerging evidence suggests that increased activity and the expression of arginase via the metabolism of L-arginine, which is a substrate for both arginase and nitric oxide synthase, may result in reduced levels of arginine available for nitric oxide production and hence endothelial dysfunction. In the current study, we demonstrate that patients with coronary artery disease with and without diabetes mellitus have impaired endothelial function in comparison with age-matched control subjects. Further-more, we show that inhibition of arginase activity in the forearm of patients with diabetes mellitus and coronary artery disease markedly improves endothelial function. The improvement in endothelial function is more pronounced in patients with coronary artery disease and diabetes mellitus than in those with coronary artery disease alone. The beneficial effect of arginase inhibition is completely dependent on the increased bioavailability of nitric oxide. These novel observations suggest that arginase activity is a key factor for endothelial dysfunction in patients with coronary artery disease, in particular, among those with diabetes mellitus, by regulating the bioavailability of nitric oxide. Our findings suggest that arginase inhibition could be an effective pharmacological intervention to improve the vascular function in these patients. Conclusions: Arginase inhibition markedly improves endothelial function in patients with CAD and type 2 diabetes mellitus suggesting that increased arginase activity is a key factor in the development of endothelial dysfunction. 1 on-pump coronary artery bypass graft surgery, the American College of Cardiology/American Heart Association guidelines recommend the use of volatile anesthetics as beneficial in hemodynamically stable patients at cardiovascular risk undergoing noncardiac surgery (class IIa recommendation). In the present randomized, controlled trial, anesthesia maintenance with sevoflurane compared with propofol did not reduce the incidence of perioperative myocardial ischemia in patients with coronary artery disease or at risk for it undergoing major noncardiac surgery. In addition, the data did not suggest any effect of sevoflurane on postoperative N-terminal prohormone of brain natriuretic peptide release or on major adverse cardiac events at 12 months. These results are in agreement with observational data and data generated in a small randomized trial. This growing evidence questions the recommendation to preferentially use volatile anesthetics in noncardiac surgical patients at cardiac risk. Conclusions: Compared with propofol, sevoflurane did not reduce the incidence of myocardial ischemia in high-risk patients undergoing major noncardiac surgery. The sevoflurane and propofol groups did not differ in postoperative NT-proBNP release, major adverse cardiac events at 1 year, or delirium. 2 on maximally tolerated lipid-lowering therapy LDL-C >2.6 mmol/L (100 mg/dL). The phase 2, double-blind, placebo-controlled trial randomized 124 patients (41 placebo, 83 mipomersen) to weekly subcutaneous mipomersen 200 mg or placebo (2:1) for 26 weeks. The primary end point was percent change in LDL-C from baseline at week 28. Safety assessments included adverse events, laboratory tests, and MRI assessment of hepatic fat. Mean LDL-C decreased 28.0% with mipomersen compared with a 5.2% with placebo ( P <0.001), and 45.1% Mipomersen P <0.001) apolipoprotein B (−26.3%) and lipoprotein(a) (−21.1%) compared with placebo. More frequent and severe injection site reactions occurred with mipomersen, and 5 mipomersen-treated patients (6%) 2 consecutive alanine aminotransferase levels ≥ 3 times the upper limit of normal at least 7 days apart; none were associated with significant bilirubin increases. Hepatic fat content increased a median of 4.9% with mipomersen versus 0.4% with placebo ( P <0.001). The clinical implications of such increases in hepatic fat and transaminase elevations are unclear and must be elucidated in longer-term studies. We conclude that mipomersen is effective to further reduce apolipoprotein B–containing lipoproteins, including LDL and lipoprotein(a), in patients with heterozygous familial hypercholesterolemia with coronary artery disease on statins and other lipid-lowering therapy. Mipomersen is an effective therapy to further reduce apolipoprotein B–containing lipoproteins, including LDL and lipoprotein(a), in HeFH patients with coronary artery disease on statins and other lipid-lowering therapy. The significance of hepatic fat and transaminase increases remains uncertain at this time. study examined the potential roles of high blood cholesterol and the cholesterol metabolite 27-hydroxycholesterol (an endogenous selective estrogen receptor antagonist) in increasing the risk of coronary heart disease caused by menopausal hormone therapy. The findings indicate that higher levels of low-density lipoprotein cholesterol, but not 27-hydroxycholesterol, were related to risk of coronary heart disease and that low-density lipoprotein cholesterol, but not 27-hydroxycholesterol, further increased the risk of coronary heart disease in women exposed to menopausal hormone therapy. The risk of coronary heart disease resulting from menopausal hormone therapy begins to increase at a low-density lipoprotein cholesterol level of ≈ 3.36 mmol/L (130 mg/dL). Screening women for low-density lipoprotein cholesterol levels could be helpful in mak-ing a decision about whether to recommend menopausal hormone therapy. Conclusions: This study found that 27OHC does not independently increase the risk of CHD, does not modify the increased risk of CHD resulting from MHT, and does not mediate the interaction of LDLC with MHT. Measuring blood lipids may aid in counseling individual women about initiating MHT and cardiovascular risk mitigation. Summary: The majority of acute coronary syndrome events are the result of sudden luminal thrombosis, with 55% to 60% caused by plaque rupture, 30% to 35% resulting from plaque erosion, and a small portion due to a calcified nodule. In the present analysis using 3-vessel intravascular ultrasound and virtual histology imaging and comprehensive follow-up data from Providing Regional Observations to Study Predictors of Events in the Coronary Tree (PROSPECT), we describe the frequency of incidentally detected calcified nodules and the angiographic appearance, intravascular ultrasound and virtual histology intravascular ultrasound features, and natural history of patients whose arteries contain ≥ 1 calcified nodules. The incidence of calcified nodule was 17% per artery and 30% per patient. Two or more calcified nodules were detected in 48 coronary arteries (3%) in 76 patients (12%). The calcified nodules were located <40 mm from the ostium of the coronary artery in 85% of left anterior descending arteries and 86% of left circumflex arteries, whereas calcified nodules within the right coronary arteries were evenly and more distally dis-tributed, similar to other vulnerable plaque types. Patients with calcified nodules were significantly older and had more plaque volume, more thick-cap fibroatheroma, but fewer events at follow-up that could be attributed to their calcified nodules. Therefore, although a culprit calcified nodule has been reported by 1 pathology group to be a cause (albeit rarely) of coronary thrombosis, incidentally detected nonculprit calcified nodules appear to be more benign and do not often lead to thrombosis as suggested by the low event rate in the present study. Conclusions: Calcified nodules in untreated nonculprit coronary segments in patients with acute coronary syndromes were more preva-lent than previously recognized. Although their distribution mirrored the origin of most thrombotic events, calcified nodules caused fewer major adverse events during 3 years of follow-up. Summary: Coronary plaques progresses in a highly individual man-ner. Identification of early stages of high-risk plaque may enable development of preemptive strategies to alter the natural history of high-risk plaque and avert adverse cardiac events. The purposes of the PREDICTION Study were to determine the role of local vascular characteristics on coronary plaque progression in humans and to relate plaque changes to clinical events. Five hundred six patients with an acute coronary syndrome treated with a percutaneous coronary intervention were enrolled. Vascular profiling using coronary angiography and intravascular ultrasound was used to reconstruct the artery and calculate endothelial shear stress and plaque/remodeling characteristics in vivo. Each reconstructed artery was divided into sequential 3-mm segments for serial analysis. Three-vessel vascular profiling was performed at baseline and in a subset of 374 patients 6 to 10 months later to assess plaque natural history. Clinical fol-low-up was performed at 1 year. Symptomatic clinical events were infrequent. Increase in plaque area at follow-up was predicted by baseline large plaque burden; decrease in lumen area was independently predicted by baseline large plaque burden and low endothelial shear stress. Large plaque size and low endothelial shear stress independently predicted increased plaque burden and worsening of luminal obstructions treated with a percutaneous coronary intervention at follow-up. Large plaque burden and low local endothelial shear stress provide independent and additive prediction to identify plaques that develop progressive enlargement and lumen narrowing. These observations may justify prospective, randomized t