We tested the hypothesis that angiotensin II-induced hypertension is associated with an increase in vascular и

We performed a meta-analysis of 14 genome-wide association studies of coronary artery disease (CAD) comprising 22,233 cases and 64,762 controls of European descent, followed by genotyping of top association signals in 60,738 additional individuals. This genomic analysis identified 13 novel loci harboring one or more SNPs that were associated with CAD at P<5×10−8 and confirmed the association of 10 of 12 previously reported CAD loci. The 13 novel loci displayed risk allele frequencies ranging from 0.13 to 0.91 and were associated with a 6 to 17 percent increase in the risk of CAD per allele. Notably, only three of the novel loci displayed significant association with traditional CAD risk factors, while the majority lie in gene regions not previously implicated in the pathogenesis of CAD. Finally, five of the novel CAD risk loci appear to have pleiotropic effects, showing strong association with various other human diseases or traits.

Abstract-Nitric oxide (NO·) is an important protective molecule in the vasculature, and endothelial NO· synthase (eNOS) is responsible for most of the vascular NO· produced. A functional eNOS oxidizes its substrate L-arginine to L-citrulline and NO·. This normal function of eNOS requires dimerization of the enzyme, the presence of the substrate L-arginine, and the essential cofactor (6R)- ⅐Ϫ production by eNOS (referred to as eNOS uncoupling). This transformation of eNOS from a protective enzyme to a contributor to oxidative stress has been observed in several in vitro models, in animal models of cardiovascular diseases, and in patients with cardiovascular risk factors. In many cases, supplementation with BH 4 has been shown to correct eNOS dysfunction in animal models and patients. In addition, folic acid and infusions of vitamin C are able to restore eNOS functionality, most probably by enhancing BH 4 levels as well. However, many of us unintentionally mistreat our endothelial cells. We expose them to risk factors such as cigarette smoke, high blood pressure, high glucose, or high lipids. Despite this abuse, our endothelium bears with us for some time, tries to maintain NO· production, and preserves vascular protection. However, the risk factors lead to excess production of superoxide (O 2 ⅐Ϫ ; ie, they produce oxidative stress). O 2 ⅐Ϫ reacts with NO· to form peroxynitrite, and vascular protection slowly vanishes. But that is only the beginning of the calamity. Our eNOS now enters into a vicious biochemical cycle. It changes its enzymology, starts making peroxynitrite (ONOO Ϫ ) itself, and eventually becomes an enzyme that generates only O 2 ⅐Ϫ . This brief review discusses how and when this happens and how it may be prevented. Vascular Protection by eNOS-Derived NO·eNOS, the predominant NOS isoform in the vasculature, is responsible for most of the NO· produced in this tissue. 1 Vascular NO· dilates all types of blood vessels by stimulating soluble guanylyl cyclase and increasing cyclic guanosine monophosphate (cGMP) in smooth muscle cells. 1 NO· released toward the vascular lumen is a potent inhibitor of platelet aggregation and adhesion. NO· also can inhibit leukocyte adhesion to the vessel wall either by interfering with the ability of the leukocyte adhesion molecule CD11/ CD18 to form an adhesive bond with the endothelial cell surface or by suppressing CD11/CD18 expression on leukocytes. White cell adherence is an early event in the development of atherosclerosis; therefore, NO· may protect against the onset of atherogenesis. Furthermore, NO· has been shown to inhibit DNA synthesis, mitogenesis, and proliferation of vascular smooth muscle cells. The inhibition of platelet aggregation and adhesion protects smooth muscle from exposure to platelet-derived growth factor(s). Therefore, NO· also prevents a later step in atherogenesis, fibrous plaque formation. Based on the combination of those effects, endothelial NO· probably represents the most important antiatherogenic defense principle in the vasculature...

Background Endothelial function is impaired in coronary artery disease and may contribute to its clinical manifestations. Increased oxidative stress has been linked to impaired endothelial function in atherosclerosis and may play a role in the pathogenesis of cardiovascular events. This study was designed to determine whether endothelial dysfunction and vascular oxidative stress have prognostic impact on cardiovascular event rates in patients with coronary artery disease. Methods and Results Endothelium-dependent and -independent vasodilation was determined in 281 patients with documented coronary artery disease by measuring forearm blood flow responses to acetylcholine and sodium nitroprusside using venous occlusion plethysmography. The effect of the coadministration of vitamin C (24 mg/min) was assessed in a subgroup of 179 patients. Cardiovascular events, including death from cardiovascular causes, myocardial infarction, ischemic stroke, coronary angioplasty, and coronary or peripheral bypass operation, were studied during a mean follow-up period of 4.5 years. Patients experiencing cardiovascular events (n=91) had lower vasodilator responses to acetylcholine ( P <0.001) and sodium nitroprusside ( P <0.05), but greater benefit from vitamin C ( P <0.01). The Cox proportional regression analysis for conventional risk factors demonstrated that blunted acetylcholine-induced vasodilation ( P =0.001), the effect of vitamin C ( P =0.001), and age ( P =0.016) remained independent predictors of cardiovascular events. Conclusions Endothelial dysfunction and increased vascular oxidative stress predict the risk of cardiovascular events in patients with coronary artery disease. These data support the concept that oxidative stress may contribute not only to endothelial dysfunction but also to coronary artery disease activity.

BackgroundWhile loneliness has been regarded as a risk to mental and physical health, there is a lack of current community data covering a broad age range. This study used a large and representative German adult sample to investigate loneliness.MethodsBaseline data of the Gutenberg Health Study (GHS) collected between April 2007 and April 2012 (N = 15,010; 35–74 years), were analyzed. Recruitment for the community-based, prospective, observational cohort study was performed in equal strata for gender, residence and age decades. Measures were provided by self-report and interview. Loneliness was used as a predictor for distress (depression, generalized anxiety, and suicidal ideation) in logistic regression analyses adjusting for sociodemographic variables and mental distress.ResultsA total of 10.5% of participants reported some degree of loneliness (4.9% slight, 3.9% moderate and 1.7% severely distressed by loneliness). Loneliness declined across age groups. Loneliness was stronger in women, in participants without a partner, and in those living alone and without children. Controlling for demographic variables and other sources of distress loneliness was associated with depression (OR = 1.91), generalized anxiety (OR = 1.21) and suicidal ideation (OR = 1.35). Lonely participants also smoked more and visited physicians more frequently.ConclusionsThe findings support the view that loneliness poses a significant health problem for a sizeable part of the population with increased risks in terms of distress (depression, anxiety), suicidal ideation, health behavior and health care utilization.