Background Progression of atherosclerosis is associated with a greater risk for adverse outcomes. Angiotensin II plays a key role in the pathogenesis and progression of atherosclerosis. We aimed to investigate the effects of angiotensin II type-1 receptor blockade with Valsartan on carotid wall atherosclerosis, with the hypothesis that Valsartan will reduce progression of atherosclerosis. Methods Subjects (n = 120) with carotid intima-media thickness >0.65 mm by ultrasound were randomized (2:1) in a double-blind manner to receive either Valsartan or placebo for 2 years. Bilateral T2-weighted black-blood carotid magnetic resonance imaging was performed at baseline, 12 and 24 months. Changes in the carotid bulb vessel wall area and wall thickness were primary endpoints. Secondary endpoints included changes in carotid plaque thickness, plasma levels of aminothiols, C-reactive protein, fibrinogen, and endothelium-dependent and -independent vascular function. Results Over 2 years, the carotid bulb vessel wall area decreased with Valsartan (-6.7, 95% CI [-11.6, -1.9] mm2) but not with placebo (3.4, 95% CI [-2.8, 9.6] mm2), P =.01 between groups. Similarly, mean wall thickness decreased with Valsartan (-0.18, 95% CI [-0.30, -0.06] mm), but not with placebo (0.08, 95% CI [-0.07, 0.23] mm), P =.009 between groups. Furthermore, plaque thickness decreased with Valsartan (-0.35, 95% CI [-0.63, -0.08] mm) but was unchanged with placebo (+0.28, 95% CI [-0.11, 0.69] mm), P =.01 between groups. These findings were unaffected by statin therapy or changes in blood pressure. Notably, there were significant improvements in the aminothiol cysteineglutathione disulfide, and trends to improvements in fibrinogen levels and endothelium-independent vascular function. Conclusions In subjects with carotid wall thickening, angiotensin II type-1 receptor blockade was associated with regression in carotid atherosclerosis. Whether these effects translate into improved outcomes in subjects with subclinical atherosclerosis warrants investigation.

Purpose: Neighborhood environment is increasingly recognized as an important determinant of cardiovascular health (CVH) among Black adults. Most research to date has focused on negative aspects of the neighborhood environment, with little attention being paid to the specific positive features, in particular the social environment, that promote cardiovascular resilience among Black adults.We examined whether better neighborhood physical and social characteristics are associated with ideal CVH among Black adults, as measured by Life's Simple 7 (LS7) scores. Methods: We recruited 392 Black adults (age 53 ± 10 years, 39% men) without known CV disease living in Atlanta, GA. Seven neighborhood domains were assessed via questionnaire: asthetic quality, walking environment, safety, food access, social cohesion, activity with neighbors, and violence. CVH was determined by LS7 scores calculated from measured blood pressure; glucose; cholesterol; body mass index (BMI); and self-reported exercise, diet, and smoking, and categorized into poor (0–8), intermediate (9–10), and ideal (11–14). Multinomial logistic regression was used to examine the association between neighborhood characteristics and the odds of intermediate/ideal CVH categories compared with poor CVH after adjustment for age, gender, household income, education, marital status, and employment status. Results: Better scores in the neighborhood domains of social cohesion and activity with neighbors were significantly associated with higher adjusted odds of ideal LS7 scores (OR 2.02, 95% CI [1.36–3.01] and 1.71 [1.20–2.45] per 1 standard deviation [SD] increase in respective scores). These associations were stronger for both social cohesion (OR 2.61, 95% CI [1.48–4.61] vs. 1.40 [0.82–2.40]) and activity with neighbors (OR 1.82, 95% CI [1.15–2.86] vs. 1.53 [0.84–2.78]) in Black women than men. Specifically, better scores in social cohesion were associated with higher odds of ideal CVH in exercise (OR 1.73 [1.16–2.59]), diet (OR 1.90 [1.11–3.26]), and BMI (OR 1.52 [1.09–2.09]); better scores in activity with neighbors were also similarly associated with higher odds of ideal CVH in exercise (OR 1.48 [1.00–2.19]), diet (OR 2.15 [1.23–3.77]), and BMI (OR 1.45 [1.07–1.98]; per 1 SD in respective scores). Conclusions: More desirable neighborhood characteristics, particularly social cohesion and activity with neighbors, were associated with better CVH among Black adults.

Background: Chronic kidney disease (CKD) patients have exercise intolerance and exaggerated blood pressure reactivity during exercise that are mediated by sympathetic nervous system (SNS) overactivation and decreased nitric oxide (NO) bioavailability. The activation of the renin-angiotensin system (RAS) increases SNS activation and reduces NO synthesis, and prior studies suggest that RAS blockade attenuates declines in physical function. We hypothesized that RAS inhibitor (RASi) use is associated with higher exercise capacity mediated by decreased SNS activity and increased NO-dependent endothelial function in CKD. Method: In 35 CKD patients (57 ± 7 years) and 20 controls (CONs) (53 ± 8 years), we measured exercise capacity (peak oxygen consumption [VO2peak]), muscle sympathetic nervous activity (MSNA), and flow-mediated dilation (FMD) for NO-dependent endothelial function. Results: CKD patients treated with RASi (CKD + RASi, n = 25) had greater VO2peak than CKD patients not treated with RASi (CKD no RASi, n = 10), but lower VO2peak than CONs (23.3 ± 5.8 vs. 16.4 ± 2.9, p = 0.007; vs. 30.0 ± 7.7, p = 0.016 mL/min/kg, respectively). CKD + RASi had lower resting MSNA and greater FMD than CKD no RASi. Compared to CONs, CKD + RASi had similar MSNA but lower FMD. VO2peak was positively associated with FMD (r = 0.417, p = 0.038) and was predicted by the combination of FMD and RASi status (r2 = 0.344, p = 0.01) and MSNA and RASi status (r2 = 0.575, p = 0.040) in CKD patients. Conclusion: In summary, CKD patients with RASi have higher exercise capacity than those not on RASi. Higher exercise capacity in the RASi-treated group was associated with lower resting SNS activity and higher NO-dependent vascular endothelial function.

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Although multiple culture assays have been designed to identify “endothelial progenitor cells” (EPCs), the phenotype of cells grown in culture often remains undefined. We sought to define and characterize the pro-angiogenic cell population within human peripheral blood mononuclear cells. Mononuclear cells were isolated from peripheral blood and grown under angiogenic conditions for 7 days. Formed colonies (CFU-As) were identified and analyzed for proliferation, mRNA and surface antigen expression, tube-forming ability and chromosomal content. Colonies were composed of a heterogeneous group of cells expressing the leukocyte antigens CD45, CD14, and CD3, as well as the endothelial proteins vascular endothelial (VE) cadherin, von Willebrand's Factor (vWF), CD31 and endothelial nitric oxide synthase (eNOS). Colony cells expressed increased levels of pro-angiogenic growth factors, and they formed tubes in Matrigel. In comparison with colonies from the CFU-Hill assay, our assay resulted in a greater number of colonies (19±9 vs. 13±7; p<0.0001) with a substantial number of cells expressing an endothelial phenotype (20.2±7.4% vs. 2.2±1.2% expressing eNOS, p=0006). Chromosomal analysis indicated the colony cells were bone marrow-derived. We, therefore, describe a colony forming unit assay that measures bone marrow-derived circulating mononuclear cells with the capacity to proliferate and mature into proangiogenic leukocytic and endothelial-like cells. This assay, therefore, reflects circulating, bone marrow-derived pro-angiogenic activity.

Background Obstructive sleep apnea (OSA) has been associated with incidence of cardiovascular disease and with nocturnal angina, but evidence of a link with coronary atherosclerosis and myocardial ischemia is limited and previous studies may have been affected by selection bias or unmeasured confounding factors. Methods We performed overnight polysomnography in 178 older male twins. The Apnea/Hypopnea Index (AHI) was calculated to assess OSA from the overnight sleep evaluation. AHI ≥15 was used as indicator of moderate/severe OSA. The following day, twins underwent myocardial perfusion imaging with [82Rb]-chloride positron emission tomography. Quantitative and semiquantitative measures of myocardial perfusion and absolute myocardial blood flow were obtained. Results The mean age was 68 years and 40% of the sample had an AHI≥15, which indicates moderate to severe OSA. Abnormal myocardial perfusion, both with stress and at rest, was more common in twins with elevated AHI. After adjusting for clinical, lifestyle and behavioral factors, and previous history of cardiovascular disease, twins with AHI ≥15 had 3.6 higher odds (95% CI, 1.5–8.9) of an abnormal total severity score, defined as a score ≥100, and for each 5-point increment in AHI, the odds of abnormality increased by 20% (95% CI, 7%-34%). Twin pairs where both twins had OSA exhibited the greatest risk. There were no differences in measures of ischemia and absolute myocardial blood flow and flow reserve by AHI status. Conclusions OSA is associated with myocardial perfusion abnormalities that suggest prior subclinical myocardial scarring or infarction. Early environmental factors that affect both twins equally may play a role and should be further explored.

Expression quantitative trait locus (eQTL) detection has emerged as an important tool for unraveling of the relationship between genetic risk factors and disease or clinical phenotypes. Most studies use single marker linear regression to discover primary signals, followed by sequential conditional modeling to detect secondary genetic variants affecting gene expression. However, this approach assumes that functional variants are sparsely distributed and that close linkage between them has little impact on estimation of their precise location and the magnitude of effects. We describe a series of simulation studies designed to evaluate the impact of linkage disequilibrium (LD) on the fine mapping of causal variants with typical eQTL effect sizes. In the presence of multisite regulation, even though between 80 and 90% of modeled eSNPs associate with normally distributed traits, up to 10% of all secondary signals could be statistical artifacts, and at least 5% but up to one-quarter of credible intervals of SNPs within r 2 > 0.8 of the peak may not even include a causal site. The Bayesian methods eCAVIAR and DAP (Deterministic Approximation of Posteriors) provide only modest improvement in resolution. Given the strong empirical evidence that gene expression is commonly regulated by more than one variant, we conclude that the fine mapping of causal variants needs to be adjusted for multisite influences, as conditional estimates can be highly biased by interference among linked sites, but ultimately experimental verification of individual effects is needed. Presumably similar conclusions apply not just to eQTL mapping, but to multisite influences on fine mapping of most types of quantitative trait.

Background Individuals with posttraumatic stress disorder (PTSD) are more likely to present with metabolic diseases such as type-2 diabetes mellitus (T2DM), and cardiovascular dysfunction has been implicated in this link. These diseases disproportionately affect women and individuals exposed to chronic environmental stressors (e.g., community violence, poverty). We examined associations among PTSD, cardiovascular indices, and metabolic function in highly trauma-exposed Black women with T2DM. Methods Participants (N = 80) were recruited for a follow-up study of stress and T2DM as part of the Grady Trauma Project. PTSD symptoms were assessed with the Clinician Administered PTSD Scale (CAPS-IV). Cardiovascular indices included heart rate (HR), blood pressure (BP), respiratory sinus arrhythmia (RSA), and endothelial function (assessed via flow-mediated dilation; FMD). An oral glucose tolerance test was used as an indicator of metabolic function. Results Of the cardiovascular indices, only FMD was significantly associated with PTSD symptoms (CAPS Avoidance symptoms; β = −0.37, p = .042), and glucose tolerance (β = −0.44, p = .019), controlling for age and body mass index. The association between FMD and PTSD Avoidance was moderated by RSA such that the effect of FMD was only significant at low levels of RSA (simple slopes β = −0.87, p = .004). Conclusions Our results indicate that endothelial function is significantly related to PTSD and glucose tolerance, over and above other cardiovascular measures (HR, BP, RSA). Further, our results suggest that low RSA may be a risk factor for the link between poor endothelial function and PTSD in women with T2DM.

OBJECTIVE: Coronary heart disease is a leading cause of death and disability. Although psychological stress has been identified as an important potential contributor, mechanisms by which stress increases risk of heart disease and mortality are not fully understood. The purpose of this study was to assess mechanisms by which stress acts through the brain and heart to confer increased CHD risk. METHODS: Coronary Heart Disease patients (N=10) underwent cardiac imaging with [Tc-99m] sestamibi single photon emission tomography at rest and during a public speaking mental stress task. Patients returned for a second day and underwent positron emission tomography imaging of the brain, heart, bone marrow, aorta (indicating inflammation) and subcutaneous adipose tissue, after injection of [18F]2-fluoro-2-deoxyglucose for assessment of glucose uptake followed mental stress. Patients with (N=4) and without (N=6) mental stress-induced myocardial ischemia were compared for glucose uptake in brain, heart, adipose tissue and aorta with mental stress. RESULTS: Patients with mental stress-induced ischemia showed a pattern of increased uptake in the heart, medial prefrontal cortex, and adipose tissue with stress. In the heart disease group as a whole, activity increase with stress in the medial prefrontal brain and amygdala correlated with stress-induced increases in spleen (r=0.69, p=0.038; and r=0.69, p=0.04 respectfully). Stress-induced frontal lobe increased uptake correlated with stress-induced aorta uptake (r=0.71, p=0.016). Activity in insula and medial prefrontal cortex was correlated with post-stress activity in bone marrow and adipose tissue. Activity in other brain areas not implicated in stress did not show similar correlations. Increases in medial prefrontal activity with stress correlated with increased cardiac glucose uptake with stress, suggestive of myocardial ischemia (r=0.85, p=0.004). CONCLUSIONS: These findings suggest a link between brain response to stress in key areas mediating emotion and peripheral organs involved in inflammation and hematopoietic activity, as well as myocardial ischemia, in Coronary Heart Disease patients.

BACKGROUND: Extremes of wall shear stress (WSS) have been associated with plaque progression and transformation, which has raised interest in the clinical assessment of WSS. We hypothesized that calculated coronary WSS is predicted only partially by luminal geometry and that WSS is related to plaque composition. METHODS AND RESULTS: Twenty-seven patients with coronary artery disease underwent virtual histology intravascular ultrasound and Doppler velocity measurement for computational fluid dynamics modeling for WSS calculation in each virtual histology intravascular ultrasound segment (N=3581 segments). We assessed the association of WSS with plaque burden and distribution and with plaque composition. WSS remained relatively constant across the lower 3 quartiles of plaque burden (P=0.08) but increased in the highest quartile of plaque burden (P<0.001). Segments distal to lesions or within bifurcations were more likely to have low WSS (P<0.001). However, the majority of segments distal to lesions (80%) and within bifurcations (89%) did not exhibit low WSS. After adjustment for plaque burden, there was a negative association between WSS and percent necrotic core and calcium. For every 10 dynes/cm(2) increase in WSS, percent necrotic core decreased by 17% (P=0.01), and percent dense calcium decreased by 17% (P<0.001). There was no significant association between WSS and percent of fibrous or fibrofatty plaque components (P=NS). CONCLUSIONS: IN PATIENTS WITH CORONARY ARTERY DISEASE: (1) Luminal geometry predicts calculated WSS only partially, which suggests that detailed computational techniques must be used to calculate WSS. (2) Low WSS is associated with plaque necrotic core and calcium, independent of plaque burden, which suggests a link between WSS and coronary plaque phenotype. (J Am Heart Assoc. 2012;1:e002543 doi: 10.1161/JAHA.112.002543.).