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BackgroundCardiovascular disease (CVD) is more frequent among people with HIV (PWH) and may relate to traditional and nontraditional factors, including inflammation and immune activation. A critical need exists to develop effective strategies to prevent CVD in this population.MethodsThe Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) (A5332) is a prospective, randomized, placebo-controlled trial of a statin strategy for the primary prevention of major adverse cardiovascular events (MACE) in PWH with low to moderate traditional risk. At least 7,500 PWH, 40-75 years of age, on stable antiretroviral therapy, will be randomized to pitavastatin calcium (4 mg/d) or identical placebo and followed for up to 8 years. Participants are enrolled based on the 2013 American College of Cardiology (ACC)/American Heart Association (AHA) atherosclerotic cardiovascular disease (ASCVD) risk score and low-density lipoprotein cholesterol (LDL-C) level with a goal to identify a low- to moderate-risk population who might benefit from a pharmacologic CVD prevention strategy. Potential participants with a risk score ≤ 15% were eligible based on decreasing LDL-C thresholds for increasing risk score >7.5% (LDL-C 7,500 participants at approximately 120 sites across 11 countries, generating a diverse and representative population of PWH to investigate the primary objective of the trial.ConclusionsREPRIEVE is the first trial investigating a primary CVD prevention strategy in PWH. REPRIEVE will inform the field of the efficacy and safety of a statin strategy among HIV-infected participants on antiretroviral therapy and provide critical information on CVD mechanisms and non-CVD events in PWH.

BACKGROUND. Activation of the NLRP3 inflammasome is associated with metabolic dysfunction, and intermittent fasting has been shown to improve clinical presentation of NLRP3 inflammasome-linked diseases. As mitochondrial perturbations, which function as a damage-associated molecular pattern, exacerbate NLRP3 inflammasome activation, we investigated whether fasting blunts inflammasome activation via sirtuin-mediated augmentation of mitochondrial integrity. METHODS. We performed a clinical study of 19 healthy volunteers. Each subject underwent a 24-hour fast and then was fed a fixed-calorie meal. Blood was drawn during the fasted and fed states and analyzed for NRLP3 inflammasome activation. We enrolled an additional group of 8 healthy volunteers to assess the effects of the sirtuin activator, nicotinamide riboside, on NLRP3 inflammasome activation. RESULTS. In the fasting/refeeding study, individuals showed less NLRP3 inflammasome activation in the fasted state compared with that in refed conditions. In a human macrophage line, depletion of the mitochondrial-enriched sirtuin deacetylase SIRT3 increased NLRP3 inflammasome activation in association with excessive mitochondrial ROS production. Furthermore, genetic and pharmacologic SIRT3 activation blunted NLRP3 activity in parallel with enhanced mitochondrial function in cultured cells and in leukocytes extracted from healthy volunteers and from refed individuals but not in those collected during fasting. CONCLUSIONS. Together, our data indicate that nutrient levels regulate the NLRP3 inflammasome, in part through SIRT3mediated mitochondrial homeostatic control. Moreover, these results suggest that deacetylase-dependent inflammasome attenuation may be amenable to targeting in human disease. TRIAL REGISTRATION. ClinicalTrials.gov NCT02122575 and NCT00442195. FUNDING. Division of Intramural Research, NHLBI of the NIH., Introduction Sterile inflammation linked to obesity is mediated in part by the NLRP3 (Nod-like receptor family protein 3) inflammasome (1). The activation of this program, as a component of the [...]

Skeletal muscle mitochondrial dysfunction is hypothesized to contribute to the pathophysiology of insulin resistance and Type 2 diabetes. Whether thiazolidinedione therapy enhances skeletal muscle mitochondrial function as a component of its insulin-sensitizing effect is unknown. To test this, we evaluated skeletal muscle mitochondria and exercise capacity in Type 2 diabetic subjects with otherwise normal cardiopulmonary function in response to rosiglitazone therapy. Twenty-three subjects were treated for 12 wk and underwent pre- and post-therapy metabolic stress testing and skeletal muscle biopsies. Rosiglitazone significantly ameliorated fasting glucose, insulin, and free fatty acid levels but did not augment the subjects' maximal oxygen consumption ([Vo.sub.2max]) or their skeletal muscle mitochondrial copy number. The baseline [Vo.sub.2max] correlated strongly with muscle mitochondrial copy number (r = 0.56, P = 0.018, n = 17) and inversely with the duration of diabetes (r = -0.67, P = 0.004, n = 23). Despite the global lack of effect of rosiglitazone-mediated insulin sensitization on skeletal muscle mitochondria, subjects with the most preserved functional capacity demonstrated some plasticity in their mitochondria biology as evidenced by an upregulation of electron transfer chain proteins and in citrate synthase activity. This study demonstrates that the augmentation of skeletal muscle mitochondrial electron transfer chain content and/or bioenergetics is not a prerequisite for rosiglitazone-mediated improved insulin sensitivity. Moreover, in diabetic subjects, [Vo.sub.2max] reflects the duration of diabetes and skeletal muscle mitochondrial content. It remains to be determined whether longer-term insulin sensitization therapy with rosiglitazone will augment skeletal muscle mitochondrial bioenergetics in those diabetic subjects with relatively preserved basal aerobic capacity. exercise capacity; citrate synthase activity; peroxisome proliferator-activated receptor-[gamma] agonist

Study is presented to determine the relationship between N-Terminal pro-brain natriuretic peptide (NT-proBNP) levels and severity of pulmonary hypertension and prospective mortality in patients with sickle cell disease (SCD). Results suggest that a high NT-proBNP level is associated with pulmonary hypertension and is a major risk factor for patients dying of SCD.

Insulin resistance is a risk factor for atherosclerosis and is associated with hyperinsulinemia, abnormal lipid profile, and hypertension. Whether hyperinsulinemia affects vascular function independent of insulin resistance or other metabolic risk factors is unknown. This investigation aimed to assess the effects of hyperinsulinemia on endothelial function in subjects with a spectrum of insulin sensitivity and lipid profile. Endothelium-dependent (flow-mediated dilation, FMD) and -independent (nitroglycerin) responses of the brachial artery were studied by high-resolution ultrasound before and during hyperinsulinemia (euglycemic clamp) in 25 normoglycemic, normotensive subjects. Participants were divided into an insulin-sensitive and an insulin-resistant subgroup based on their sensitivity index values, with a cutoff of 8, and into a normal-cholesterol and a high-cholesterol subgroup based on their total cholesterol levels, with a cutoff of 5.2 mmol/l (200 mg/dl). In the whole population, FMD was lower during hyperinsulinemia compared with baseline (2.3 [+ or -] 0.6% vs. 6 [+ or -] 0.6%; P < 0.001). Resting FMD was lower in the insulin-resistant subgroup compared with the insulin-sensitive subgroup (4.2 [+ or -] 0.9% vs. 7.4 [+ or -] 0.8%; P = 0.014) and in the high-cholesterol subjects compared with the normal-cholesterol subjects (4.4 [+ or -] 0.7% vs. 8 [+ or -] 0.7%; P = 0.002). Hyperinsulinemia decreased FMD in both the insulin-sensitive (from 7.4 [+ or -] 0.8% to 3.6 [+ or -] 0.4%; P < 0.001) and insulin-resistant (from 4.2% to 1.22%; P = 0.012) subgroups and in both the normal-cholesterol (from 8 [+ or -] 0.7% to 3.9 [+ or -] 0.4%; P < 0.001) and high-cholesterol (from 4.4 [+ or -] 0.7% to 1.1 [+ or -] 0.8%; P = 0.01) participants. Acute hyperinsulinemia impairs conduit vessel endothelial function independent of insulin sensitivity and lipid profile. Insulin may trigger endothelial dysfunction and promote atherosclerosis. hyperinsulinemia; endothelial function; cholesterol; metabolic syndrome

Nitrite anions comprise the largest vascular storage pool of nitric oxide (NO), provided that physiological mechanisms exist to reduce nitrite to NO. We evaluated the vasodilator properties and mechanisms for bioactivation of nitrite in the human forearm. Nitrite infusions of 36 and 0.36 [mu]mol/min into the forearm brachial artery resulted in supra- and near-physiologic intravascular nitrite concentrations, respectively, and increased forearm blood flow before and during exercise, with or without NO synthase inhibition. Nitrite infusions were associated with rapid formation of erythrocyte iron-nitrosylated hemoglobin and, to a lesser extent, S-nitroso-hemoglobin. NO-modified hemoglobin formation was inversely proportional to oxyhemoglobin saturation. Vasodilation of rat aortic rings and formation of both NO gas and NO-modified hemoglobin resulted from the nitrite reductase activity of deoxyhemoglobin and deoxygenated erythrocytes. This finding links tissue hypoxia, hemoglobin allostery and nitrite bioactivation. These results suggest that nitrite represents a major bioavailable pool of NO, and describe a new physiological function for hemoglobin as a nitrite reductase, potentially contributing to hypoxic vasodilation., Author(s): Kenyatta Cosby [1]; Kristine S Partovi [2]; Jack H Crawford [3]; Rakesh P Patel [3]; Christopher D Reiter [2, 4]; Sabrina Martyr [2, 4]; Benjamin K Yang [2]; Myron [...]

Hydroxyurea treatment for patients with sickle cell disease can lower their mortality rate by as much as 40%, according to a study of 299 patients. Patients who developed acute chest syndrome or vaso-occlusive events had higher mortality rates than those who did not. Hydroxyurea increases blood levels of fetal hemoglobin, which partly compensates for the abnormal hemoglobin that causes sickle cell disease.

An increase in the number of endothelial progenitor cells in blood may be a sign that damage to blood vessels is being repaired. In a study of 45 men with risk factors for cardiovascular disease, those who had high amounts of endothelial progenitor cells had a lower risk for cardiovascular disease as determined by their Framingham Risk Score. Cardiovascular disease is believed to start from an injury to blood vessels.

Estrogen appears to lower blood levels of plasminogen-activator inhibitor type 1 (PAI-1), which could account for its ability to reduce a woman's risk of cardiovascular disease. PAI-1 inhibits the breakdown of blood clots, a process called fibrinolysis. Researchers measured PAI-1 in blood samples from 50 women who were on estrogen replacement therapy. Thirty women were taking oral estrogen and 20 were using an estradiol patch. Oral estrogen reduced PAI-1 levels by 50% and also increased fibrinolysis, as measured by chemicals produced during fibrinolysis. The estradiol patch had no effect on PAI-1 levels.

Patients with coronary artery disease who also are infected with cytomegalovirus may be less likely to benefit from angioplasty and atherectomy. These two techniques are used to remove plaque from inside the artery, but the plaque often returns. Researchers tested 75 patients with coronary artery disease for cytomegalovirus infection before surgery. Forty-nine tested positive and almost half had recurring plaque six months after surgery compared to only 8% of those who tested negative.

Imipramine, a drug used to treat chronic pain may be more effective than clonidine in reducing symptoms of chest pain in patients with structurally normal hearts and normal coronary angiograms. Sixty patients with a history of chest pain received either imipramine, clonidine or a placebo. All the patients receiving imipramine indicated they experienced chest pain about one-half as often as before treatment. Seventy-five percent of the other two groups reported less frequent pain. The use of imipramine did not seem to have any adverse effects on the functioning of the patients' hearts, even over a follow-up period of two years. Three possible causes of their chest pain were described as psychiatric illness, esophageal dysfunction, and coronary microvascular dysfunction. Chest pain in most of the patients was made worse by the administration of right ventricular electrical stimulation or infusion of adenosine.