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Background: South Asians are a high-risk ethnic group for cardiovascular disease despite having lower levels of conventional cardiovascular risk factors such as obesity and smoking. Ethnic differences in pulse wave reflections, arterial stiffness, and subclinical atherosclerosis as measured using augmentation index (AIX), pulse wave velocity (PWV), and carotid intima-media thickness (CIMT) may reflect some of this excess risk. Methods: We conducted a cross-sectional analysis of pooled data from three community-based sources in Atlanta, Georgia, USA. Data on 530 South Asians collected from local health fairs was compared with data on 507 White and 192 African Americans from the Emory Predictive Health Initiative and 351 White and 382 African Americans from the Morehouse and Emory Team up to Eliminate Health Disparities Study. Results: Linear regression models adjusted for age, sex, smoking, MAP, fasting glucose, TC, HDL-C, creatinine, and body mass index were used to assess the relationship between ethnicity and vascular function measures. In fully adjusted models, South Asians had higher heart rate corrected AIX as compared with Whites and African Americans (by 5.47%, p

Background: African Americans (AA) are more likely to develop Alzheimer’s disease (AD) than Caucasians (CC). Dietary modification may have the potential to reduce the risk of developing AD. Objective: The objective of this study is to investigate the relationship between Southern and Prudent diet patterns and cognitive performance in individuals at risk for developing AD. Design: Cross-sectional observational study. Participants: Sixty-six cognitively normal AA and CC individuals aged 46-77 years with a parental history of AD were enrolled. Measurements: Participants completed a Food Frequency questionnaire, cognitive function testing, which consisted of 8 neuropsychological tests, and cardiovascular risk factor assessments, including evaluation of microvascular and macrovascular function and ambulatory blood pressure monitoring. Results: Results revealed a relationship between the Southern diet and worse cognitive performance among AAs. AAs who consumed pies, mashed potatoes, tea, and sugar drinks showed worse cognitive performance (p

Rationale: Peripheral arterial disease (PAD) is a clinical manifestation of extracoronary atherosclerosis. Despite sharing the same risk factors, only 20% to 30% of patients with coronary artery disease (CAD) develop PAD. Decline in the number of bone marrow–derived circulating progenitor cells (PCs) is thought to contribute to the pathogenesis of atherosclerosis. Whether specific changes in PCs differentiate patients with both PAD and CAD from those with CAD alone is unknown. Objective: Determine whether differences exist in PCs counts of CAD patients with and without known PAD. Methods and Results: 1497 patients (mean age: 65 years; 62% men) with known CAD were identified in the Emory Cardiovascular Biobank. Presence of PAD (n=308) was determined by history, review of medical records, or imaging and was classified as carotid (53%), lower extremity (41%), upper extremity (3%), and aortic disease (33%). Circulating PCs were enumerated by flow cytometry. Patients with CAD and PAD had significantly lower PC counts compared with those with only CAD. In multivariable analysis, a 50% decrease in cluster of differentiation 34 (CD34+) or CD34+/vascular endothelial growth factor receptor-2 (VEGFR2+) counts was associated with a 31% ( P =0.032) and 183% ( P =0.002) increase in the odds of having PAD, respectively. CD34+ and CD34+/VEGFR2+ counts significantly improved risk prediction metrics for prevalent PAD. Low CD34+/VEGFR2+ counts were associated with a 1.40-fold (95% confidence interval, 1.03–1.91) and a 1.64-fold (95% confidence interval, 1.07–2.50) increases in the risk of mortality and PAD-related events, respectively. Conclusions: PAD is associated with low CD34+ and CD34+/VEGFR2+ PC counts. Whether low PC counts are useful in screening for PAD needs to be investigated.

Background The 2015–2020 Dietary Guidelines for Americans recommend a Mediterranean-type diet as one of three healthful eating patterns. However, only one previous trial has evaluated the effects of a Mediterranean diet intervention in a US sample population. Methods To address this gap, we conducted a pilot, non-blinded, 8-week randomized controlled trial on the comparative efficacy of consumption of a Mediterranean diet or a diet supplemented with fish oil, walnuts, and grape juice versus controls. Participants (overweight or obese US adults; 73% female and mean age 51 years) were randomly assigned to one of three groups: (1) Mediterranean diet; (2) habitual high-fat American-type diet supplemented with fish oil, walnuts, and grape juice; or (3) habitual high-fat American-type diet (controls). Intent-to-treat analysis of within-subject differences (Student’s paired t-test or Wilcoxon sign ranks test) and between-subject differences (mixed-effects models with a group-by-time interaction term, adjusted for baseline health outcome) was conducted. Results Participants in the Mediterranean diet arm (n = 11) had significantly greater weight loss despite no significant change in total caloric intake, and lower plasma cystine, indicative of decreased oxidative stress, compared to controls (n = 9) at both 4 and 8 weeks. Compared to controls, they also had significantly lower total cholesterol and low-density lipoprotein cholesterol levels at 4 weeks. Participants in the supplement arm (n = 10) had significantly lower adiponectin levels compared to controls at 4 weeks. No significant improvements in endothelial function or inflammatory biomarkers were observed in either intervention group compared to controls. Conclusion These results suggest that adopting a dietary pattern reflecting a Mediterranean diet improves weight and cardio-metabolic health among overweight or obese US adults, and may be more beneficial than supplementing habitual American diets with fish oil, walnuts, and grape juice. Trial registration ClinicalTrials.gov NCT00166088. Registered 14 September 2005.

American-style football (ASF) participation rates in the United States are highest among high school (HS) athletes. This study sought to compare the cardiovascular response to HS versus collegiate ASF participation.The ASF participants (HS, n = 61; collegiate, n = 87) were studied at preseason and postseason time points with echocardiography and applanation tonometry. Primary outcome variables included: left ventricular (LV) mass index, LV diastolic function (early relaxation velocity [E']), and arterial stiffness (pulse wave velocity [PWV]).High school (17.1 ± 0.4 yr) and collegiate ASF participants (18 ± 0.4 yr) experienced similar LV hypertrophy (ΔLV mass HS = 10.5 ± 10 vs collegiate = 11.2 ± 13.6 g·m, P = 0.97). Among HS participants, increases in LV mass were associated with stable diastolic tissue velocities (ΔE' = -0.3 ± 2.9 cm·s, P = 0.40) and vascular function (ΔPWV = -0.1 ± 0.6 m·s, P = 0.13). In contrast, collegiate participants demonstrated a higher burden of concentric LV hypertrophy (21/87, 24% vs 7/61, 11%, P = 0.026) with concomitant reductions in diastolic tissue velocities (ΔE': -2.0 ± 2.7 cm·s, P0.001) and increased arterial stiffness (ΔPWV: Δ0.2 ± 0.6 m·s, P = 0.003), changes that were influenced by linemen who had the highest post-season weight (124 ± 10 kg) and systolic blood pressure ([SBP], 138.8 ± 11 mm Hg). In multivariable analyses adjusting for age and ethnicity, body mass was an independent predictor of post-season PWV (β estimate = 0.01, P = 0.04) and E' (β estimate = -0.04, P = 0.05), whereas SBP was an independent predictor of postseason LV mass index (β estimate = 0.18, P = 0.01) and PWV (β estimate = 0.01, P = 0.007).The transition from HS to college represents an important physiologic temporal data point after which differential ASF cardiovascular phenotypes manifest. Future work aimed to clarify underlying mechanisms, and the long-term clinical implications of these findings is warranted.

Background— Free radical scavengers have failed to improve patient outcomes, promoting the concept that clinically important oxidative stress may be mediated by alternative mechanisms. We sought to examine the association of emerging aminothiol markers of nonf ree radical mediated oxidative stress with clinical outcomes. Methods and Results— Plasma levels of reduced (cyst ei ne and glutathione) and oxidized (cyst i ne and glutathione disulphide) aminothiols were quantified by high performance liquid chromatography in 1411 patients undergoing coronary angiography (mean age 63 years, male 66%). All patients were followed for a mean of 4.7±2.1 years for the primary outcome of all-cause death (n=247). Levels of cystine (oxidized) and glutathione (reduced) were associated with risk of death ( P +1 SD and Conclusions— A high burden of oxidative stress, quantified by the plasma aminothiols, cystine, glutathione, and their ratio, is associated with mortality in patients with coronary artery disease, a finding that is independent of and additive to the inflammatory burden. Importantly, these data support the emerging role of nonfree radical biology in driving clinically important oxidative stress.

The pooled cohort Atherosclerotic Cardiovascular Disease (ASCVD) risk calculator is designed to improve cardiovascular risk estimation compared with the Framingham Risk Score, particularly in blacks. Although the ASCVD risk score better predicts mortality and incident cardiovascular disease in blacks, less is known about its performance for subclinical vascular disease measures, including arterial stiffness and carotid intima-media thickness. We sought to determine if the ASCVD risk score better identifies subclinical vascular disease in blacks compared with the Framingham risk score. We calculated both the Framingham and ASCVD cohort risk scores in 1,231 subjects (mean age 53 years, 59% female, 37% black) without known cardiovascular disease and measured the extent of arterial stiffness, as determined by pulse wave velocity (PWV), central pulse pressure (CPP), and central augmentation index (CAIx), and subclinical atherosclerosis, as determined by carotid-IMT (C-IMT). Compared with whites, blacks had higher CAIx (23.9 ± 10.2 vs 22.1 ± 9.6%, p = 0.004), CPP (36.4 ± 10.5 vs 34.9 ± 9.8 mmHg, p = 0.014), PWV (7.6 ± 1.5 vs 7.3 ± 1.3 m/s, p = 0.004), and C-IMT (0.67 ± 0.10 vs 0.65 ± 0.10 mm, p = 0.005). In a multivariable analysis including race and Framingham risk score, race remained an independent predictor of all measures of subclinical vascular disease; however, models with race and the ASCVD risk score showed that race was not an independent predictor of subclinical vascular disease. In conclusion, greater subclinical vascular disease in blacks was not estimated by the Framingham risk score. The new ASCVD risk score provided a better estimate of racial differences in vascular function and structure.

This study sought to determine the cardiovascular physiologic correlates of sleep-disordered breathing (SDB) in American-style football (ASF) participants using echocardiography, vascular applanation tonometry, and peripheral arterial tonometry. Forty collegiate ASF participants were analyzed at pre- and postseason time points with echocardiography and vascular applanation tonometry. WatchPAT (inclusive of peripheral arterial tonometry) used to assess for SDB was then performed at the postseason time point. Twenty-two of 40 (55%) ASF participants demonstrated SDB with an apnea-hypopnea index (pAHI) ≥5. ASF participants with SDB were larger (109 ± 20 vs 92 ± 14 kg, p = 0.004) and more likely linemen position players (83% vs 50%, p = 0.03). Compared with those without SDB, ASF participants with SDB demonstrated relative impairments in left ventricular diastolic and vascular function as reflected by lower lateral e' (14 ± 3 vs 17 ± 3 cm/s, p = 0.007) and septal e' (11 ± 2 vs 13 ± 2 cm/s, p = 0.009) tissue velocities and higher pulse wave velocity (5.4 ± 0.9 vs 4.8 ± 0.5 m/s, p = 0.02). In the total cohort, there were significant positive correlations between pAHI and pulse wave velocity (r = 0.42, p = 0.008) and inverse correlations between pAHI and the averaged e' tissue velocities (r = -0.42, p = 0.01). In conclusion, SDB is highly prevalent in youthful collegiate ASF participants and associated with relative impairments in cardiac and vascular function. Targeted efforts to identify youthful populations with SDB, including ASF participants, and implement SDB treatment algorithms, represent important future clinical directives.

Chronic kidney disease (CKD) patients have exercise intolerance associated with increased cardiovascular mortality. Previous studies demonstrate that blood pressure (BP) and sympathetic nerve responses to handgrip exercise are exaggerated in CKD. These patients also have decreased nitric oxide (NO) bioavailability and endothelial dysfunction, which could potentially lead to an impaired ability to vasodilate during exercise. We hypothesized that CKD patients have exaggerated BP responses during maximal whole body exercise and that endothelial dysfunction correlates with greater exercise pressor responses in these patients. Brachial artery flow-mediated dilation (FMD) was assessed before maximal treadmill exercise in 56 participants: 38 CKD (56.7 ± 1.2 yr old, 38 men) and 21 controls (52.8 ± 1.8 yr old, 20 men). During maximal treadmill exercise, the slope-of-rise in systolic BP (+10.32 vs. +7.75 mmHg/stage, P < 0.001), mean arterial pressure (+3.50 vs. +2.63 mmHg/stage, P = 0.004), and heart rate (+11.87 vs. +10.69 beats·min−1·stage−1, P = 0.031) was significantly greater in CKD compared with controls. Baseline FMD was significantly lower in CKD (2.76 ± 0.42% vs. 5.84 ± 0.97%, P = 0.008). Lower FMD values were significantly associated with a higher slope-of-rise in systolic BP (+11.05 vs. 8.71 mmHg/stage, P = 0.003) during exercise in CKD, as well as poorer exercise capacity measured as peak oxygen uptake (V̇o2peak; 19.47 ± 1.47 vs. 24.57 ± 1.51 ml·min−1·kg−1, P < 0.001). These findings demonstrate that low FMD in CKD correlates with augmented BP responses during exercise and lower V̇o2peak, suggesting that endothelial dysfunction may contribute to exaggerated exercise pressor responses and poor exercise capacity in CKD patients.

Free radical scavengers have failed to improve patient outcomes, promoting the concept that clinically important oxidative stress may be mediated by alternative mechanisms. We sought to examine the association of emerging aminothiol markers of nonfree radical mediated oxidative stress with clinical outcomes.Plasma levels of reduced (cysteine and glutathione) and oxidized (cystine and glutathione disulphide) aminothiols were quantified by high performance liquid chromatography in 1411 patients undergoing coronary angiography (mean age 63 years, male 66%). All patients were followed for a mean of 4.7 ± 2.1 years for the primary outcome of all-cause death (n=247). Levels of cystine (oxidized) and glutathione (reduced) were associated with risk of death (P0.001 both) before and after adjustment for covariates. High cystine and low glutathione levels (+1 SD and-1 SD, respectively) were associated with higher mortality (adjusted hazard ratio [HR], 1.63; 95% confidence interval [CI], 1.19-2.21; HR, 2.19; 95% CI, 1.50-3.19; respectively) compared with those outside these thresholds. Furthermore, the ratio of cystine/glutathione was also significantly associated with mortality (adjusted HR, 1.92; 95% CI, 1.39-2.64) and was independent of and additive to high-sensitivity C-reactive protein level. Similar associations were found for other outcomes of cardiovascular death and combined death and myocardial infarction.A high burden of oxidative stress, quantified by the plasma aminothiols, cystine, glutathione, and their ratio, is associated with mortality in patients with coronary artery disease, a finding that is independent of and additive to the inflammatory burden. Importantly, these data support the emerging role of nonfree radical biology in driving clinically important oxidative stress.

Background— Genome-wide association studies have identified multiple variants associating with coronary artery disease (CAD) and myocardial infarction (MI). Whether a combined genetic risk score (GRS) is associated with prevalent and incident MI in high-risk subjects remains to be established. Methods and Results— In subjects undergoing cardiac catheterization (n=2597), we identified cases with a history of MI onset at age P P value of P =0.11). Finally, during a median 2.5-year follow-up, only a nonsignificant trend was noted between the GRS and incident events, which was also not significant in the replication cohort. Conclusions— A GRS of 11 CAD/MI variants is associated with prevalent MI but not near-term incident adverse events in 2 independent angiographic cohorts. These findings have implications for understanding the clinical use of genetic risk scores for secondary as opposed to primary risk prediction.

a Division of Cardiology, Emory University School of Medicine, Atlanta, GA, United States b Division of Pulmonary Medicine, Emory University School of Medicine, Atlanta, GA, United States c Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, GA, United States d Department of Dermatology, Atlanta VA Medical Center and Emory University School of Medicine, Atlanta, GA, United States e Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, United States

Statins have been proposed to exert pleiotropic benefits that extend beyond that predicted by cholesterol reduction (1,2), even though some analyses argue against the existence of such non-cholesterol related effects in preventing adverse cardiovascular events (3). A meta-regression analysis of data from statin and non-statin clinical treatment trials has shown that the changes in LDL cholesterol levels alone are sufficient to account for the decrease in cardiovascular events (3). However, at the cellular level, statins have potent anti-inflammatory and other beneficial effects on immune, endothelial and smooth muscle cells (2). At the molecular level, these HMG CoA reductase inhibitors not only decrease cholesterol synthesis but also inhibit the isoprenylation and activation of important intracellular signaling proteins such as RhoA and Ras that can affect pathogenesis (1,2). These disparate basic and clinical observations indicate a need for further translational investigations to improve our understanding of statin treatment effects. In this regard, the identification of biomarkers that provide additional information about the therapeutic activities of statins may be helpful. Various cellular elements and signaling pathways contribute to atherosclerosis, but circulating inflammatory cells play a pivotal role in the initiation and final manifestation of disease (4,5). Recent work examining the transcriptional profiles of blood cells in patients with coronary artery disease provide insights into cardiovascular pathogenesis supporting the potential clinical utility of such investigations (6-8). We previously reported that the mononuclear cell mRNA level of the Finkel-Biskis-Jinkins Osteosarcoma (FOS) gene, a transcription factor essential for monocyte differentiation into macrophages (9), was correlated with the severity of atherosclerosis (10). The localization of FOS to macrophages and smooth muscle cells in plaques and its importance in calcification suggest that it may also play a direct role in atherosclerosis (10-12). Based on the known transcriptional regulation of FOS through a cholesterol-independent pathway (13), we hypothesized that blood FOS levels will be sensitive to statin treatment independent of LDL cholesterol levels and in a dose dependent manner. The following translational study was designed to determine whether FOS expression in blood can serve as a statin treatment response marker that could then be evaluated further with regard to clinical application given, for example, the questions about the pleiotropic effects of statins.

Tetrahydrobiopterin (BH(4)) is a cofactor for the nitric oxide (NO) synthase enzymes, such that its insufficiency results in uncoupling of the enzyme, leading to release of superoxide rather than NO in disease states, including hypertension. We hypothesized that oral BH(4) will reduce arterial blood pressure (BP) and improve endothelial function in hypertensive subjects. Oral BH(4) was given to subjects with poorly controlled hypertension (BP135/85 mm Hg) and weekly measurements of BP and endothelial function made. In Study 1, 5 or 10 mg kg(-1) day(-1) of BH(4) (n=8) was administered orally for 8 weeks, and in Study 2, 200 and 400 mg of BH(4) (n=16) was given in divided doses for 4 weeks. Study 1: significant reductions in systolic (P=0.005) and mean BP (P=0.01) were observed with both doses of BH(4). Systolic BP was 15+/-15 mm Hg (P=0.04) lower after 5 weeks and persisted for the 8-week study period. Study 2: subjects given 400 mg BH(4) had decreased systolic (P=0.03) and mean BP (P=0.04), with a peak decline of 16+/-19 mm Hg (P=0.04) at 3 weeks. BP returned to baseline 4 weeks after discontinuation. Significant improvement in endothelial function was observed in Study 1 subjects and those receiving 400 mg BH(4). There was no significant change in subjects given the 200 mg dose. This pilot investigation indicates that oral BH(4) at a daily dose of 400 mg or higher has a significant and sustained antihypertensive effect in subjects with poorly controlled hypertension, an effect that is associated with improved endothelial NO bioavailability.

BACKGROUND: Truncal obesity is associated with metabolic syndrome and cardiovascular risk. Although vascular health is influenced by weight, it is not known whether changes in fat distribution modulate arterial function. OBJECTIVE: We assessed how changes in truncal (android) fat at one year affect arterial stiffness and endothelial function. METHODS: We recruited 711 healthy volunteers (235 males, age 48±11) into the Emory Predictive Health Study; 498 returned at one year. Measurements included anthropometric and chemistry panels, fat mass using dual-energy X-ray absorptiometry, arterial stiffness indices [pulse wave velocity (PWV), augmentation index (AIx), and subendocardial viability ratio (SEVR)] (Sphygmocor), flow-mediated dilation (FMD) and reactive hyperemia index (RHI, Endo-PAT). RESULTS: At baseline, measures of body mass correlated with PWV, AIx, SEVR, and FMD. A multivariable analysis including body mass index (BMI) and traditional risk factors, BMI remained an independent predictor of PWV, AIx, SEVR, and FMD. In a model including BMI and measures of fat distribution, android fat remained an independent predictor of PWV (β= .31, p= .004), AIx (β = .24, p= .008), and SEVR (β = −.41, p

Chronic kidney disease (CKD) is characterized by overactivation of the sympathetic nervous system (SNS) that contributes to cardiovascular risk. Decreased nitric oxide (NO) bioavailability is a major factor contributing to SNS overactivity in CKD, since reduced neuronal NO leads to increased central SNS activity. Tetrahydrobiopterin (BH4) is an essential cofactor for nitric oxide synthase that increases NO bioavailability in experimental models of CKD. We conducted a randomized, double-blinded, placebo-controlled trial testing the benefits of oral sapropterin dihydrochloride (6R-BH4, a synthetic form of BH4) in CKD. 36 patients with CKD and hypertension were randomized to 12 wk of 1) 200 mg 6R-BH4 twice daily + 1 mg folic acid once daily; vs. 2) placebo + folic acid. The primary endpoint was a change in resting muscle sympathetic nerve activity (MSNA). Secondary endpoints included arterial stiffness using pulse wave velocity (PWV) and augmentation index (AIx), endothelial function using brachial artery flow-mediated dilation and endothelial progenitor cells, endothelium-independent vasodilatation (EID), microalbuminuria, and blood pressure. We observed a significant reduction in MSNA after 12 wk of 6R-BH4 (−7.5 ± 2.1 bursts/min vs. +3.2 ± 1.3 bursts/min; P = 0.003). We also observed a significant improvement in AIx (by −5.8 ± 2.0% vs. +1.8 ± 1.7 in the placebo group, P = 0.007). EID increased significantly (by +2.0 ± 0.59%; P = 0.004) in the 6R-BH4 group, but there was no change in endothelial function. There was a trend toward a reduction in diastolic blood pressure by −4 ± 3 mmHg at 12 wk with 6R-BH4 ( P = 0.055). 6R-BH4 treatment may have beneficial effects on SNS activity and central pulse wave reflections in hypertensive patients with CKD.

BACKGROUND: A low testosterone level in men is associated with increased adiposity, insulin resistance, and dyslipidemia. Whether low testosterone level is associated with arterial stiffness and endothelial and microvascular dysfunction remains unknown and was investigated in this study. METHODS: Serum testosterone was measured in 237 healthy men aged 50 years (SD 12). Endothelial and microvascular function were assessed as brachial artery flow-mediated dilation (FMD) and digital reactive hyperemia index (RHI), respectively. Arterial stiffness was evaluated by tonometry-derived pulse wave velocity (PWV) and central augmentation index (AIX). RESULTS: Mean total testosterone level was 16.3 nmol/L(SD 6.11) and 25% of subjects had low levels (

Chronic kidney disease (CKD) is characterized by chronic overactivation of the sympathetic nervous system (SNS) that contributes to increased blood pressure and cardiovascular risk. One contributing factor to SNS overactivation in this population is decreased nitric oxide (NO) bioavailability. Tetrahydrobiopterin (BH4) is a necessary cofactor for endothelial nitric oxide synthase (eNOS) that has been shown to increase NO bioavailability in experimental models of CKD. We conducted a randomized, double-masked, placebo-controlled trial testing the potential benefits of oral BH4 treatment on SNS activity in CKD patients. 36 patients with CKD and hypertension were randomized to 12 weeks of: 1) 200mg BH4 twice daily + 1mg folic acid once daily; versus 2) matching placebo twice daily + 1mg folic acid once daily. The primary endpoint was change in muscle sympathetic nerve activity (MSNA) assessed via microneurography. Secondary endpoints included ambulatory and clinic blood pressures, endothelial function via bra...

Transfusion of storage–aged (aged) packed red blood cells (pRBCs) is associated with worse outcomes, but the underlying mechanisms remain unknown. We tested endothelial nitric oxide (NO) bioavailability during transfusion of aged and fresh pRBCs with the hypothesis that aged pRBCs will impair

Heritable factors play a key role in the development of coronary heart disease.1 Early unbiased genome-wide approaches have led to the identification of more than a dozen novel risk loci for myocardial infarction (MI) in predominantly Caucasian cohorts.2–8 Many loci have replicated in large cohorts, yet of these only four appear to have a mechanistically relevant basis through lipid metabolism pathways (1p13, 1p32, 19p13, 6q26).9,10 The remaining loci span genomic regions that as yet have no clearly defined mechanism to explain MI risk. Valuable insights into the functions of these variants may be gleaned by studying their effects on related or intermediate phenotypes which may be causal in the pathway to developing MI. This is best illustrated by the initial association of 1p13 with MI and then with the intermediate phenotype of lipid levels, with subsequent functional studies identifying its role in cellular cholesterol transport through the sortillin protein.11 Another intermediate phenotype of interest in vascular disease is abnormal pressure wave reflection within the arterial tree. Abnormalities in these arterial tree properties occur due to complex composite changes in parameters such as arterial stiffness and vasomotor tone, ultimately leading to increased left ventricular after-load and cardiovascular events such as myocardial ischemia, MI, and stroke.12–15 We therefore investigated the association of variants at eight MI risk loci, whose mechanisms of action are currently unknown, with noninvasively derived pulse wave analysis (PWA) indexes including the magnitude and timing of reflected arterial pressure waveforms in two separate Caucasian populations. The first consisting of very healthy subjects, free of confounding risk factors to enable an assessment of direct genetic risk and the second, an unselected community-based population that allowed determination of genetic effects in the context of common risk factors. We hypothesized that some or all of these markers would demonstrate association with indexes of adverse arterial wave reflection.

Background Atherogenic risk in subjects with metabolic syndrome is partly mediated by increased oxidative stress and subsequent endothelial dysfunction. Clinical trials have demonstrated differences in outcomes between subjects receiving lipophilic statins (atorvastatin) compared with hydrophilic statins (pravastatin). However, whether these findings are attributable to differences in the doses administered or to nonlipid-lowering pleiotropic effects of statins on oxidative stress and vascular function remains unknown. We hypothesized that equipotent doses of these two statins will have divergent effects on markers of oxidative stress and endothelial function. Methods Thirty-six subjects with hyperlipidemia and metabolic syndrome and/or diabetes were randomized in a double-blind manner to either pravastatin 80 mg or atorvastatin 10 mg daily. Oxidative stress (dROMs assay that measures lipid hydroperoxides, plasma thiobarbituric acid reactive substances [TBARS], and aminothiol levels) and brachial artery flow-mediated dilation (FMD) were measured at baseline and after 12 weeks of statin therapy. Results Statin therapy reduced serum low-density lipoprotein cholesterol levels equally in both groups. Atorvastatin therapy was associated with a significant reduction in TBARS ( P = .006) and dROMs levels ( P = .02), which was not observed in subjects treated with pravastatin. Endothelial function improved with statin therapy ( P = .02), but there was no difference between the statin groups. Conclusion In hyperlipidemic subjects with metabolic syndrome, atorvastatin is associated with a greater reduction in lipid markers of oxidation compared with pravastatin. Whether these effects are responsible for the outcome differences in trials comparing these agents needs further investigation.

Left ventricular dyssynchrony is an adverse consequence of ST-elevation myocardial infarction (STEMI) and bears an unfavorable prognosis. Mechanical dyssynchrony as measured by phase analysis from gated single photon emission computed tomography (GSPECT) correlates well with other imaging methods of assessing dyssynchrony but has not been studied in STEMI. We hypothesized that systolic dyssynchrony as measured by GSPECT would correlate with adverse remodeling after STEMI. In 28 subjects suffering STEMI, GSPECT with technetium-99m sestamibi was performed immediately after presentation (day 5) and remotely (6 months). Parameters of left ventricular dyssynchrony (QRS width, histogram bandwidth (HBW) and phase standard deviation (PSD)) were measured from GSPECT using the Emory Cardiac Toolbox. Left ventricular volumes, ejection fraction (LVEF) and infarct size were also assessed. After successful primary percutaneous coronary intervention to the infarct-related artery, subjects had an LVEF of 46.4% ± 11% and a resting perfusion defect of 27.4% ± 16% at baseline. Baseline QRS width was normal (91.5 ± 17.5 ms). Subjects with STEMI had dyssynchrony compared with a cohort of 22 normal subjects (age 57.2 ± 10.6 years

Background The objective of the study was to determine whether the effects of infarct-related artery (IRA) infusion of autologous bone marrow–derived CD34 + cells after ST elevation myocardial infarction (STEMI) are dependent on the dose (quantity and mobility) of the cells infused. Beneficial effects of IRA infusion of mononuclear cells after STEMI have been inconsistent, possibly because of differences in timing, cell type, quantity, and mobility of infused cells. Methods Patients were randomized to bone marrow harvest (n = 16) or control (n = 15). At a median of 8.3 days after coronary stenting for STEMI, CD34 + cells were infused via the IRA at 3 dose levels (5, 10, and 15 × 10 6 ) in cohorts of 5 patients each. Baseline and follow-up imaging and ex vivo CD34 + cell mobility were performed. Results Cell harvest and infusion were safe. Quantitative rest hypoperfusion score measured by single-photon emission computed tomography improved at 6 months in the ≥10 million cohorts compared with controls (−256 vs +14, P = .02). There was a trend toward improved ejection fraction at 6 months (+4.5%) in the ≥10 million cohorts compared with no change in the controls and 5 million cohort (+0.7%). Improved perfusion and infarct size reduction correlated with the quantity and mobility of the infused CD34 + cells. Conclusions The effects of CD34 + cell IRA infusion during the repair phase after STEMI are dose dependent and, at a threshold dose of 10 million CD34 + cells, associated with a significant improvement in perfusion that may limit deterioration in cardiac function (IRA infusion of CD34 + cells in patients with acute myocardial infarction [AMR-01] NCT00313339).

Studies investigating endothelial progenitor cell levels and cardiovascular (CVD) risk and outcomes have yielded contradictory information based on the assays employed. Culture assays of early ``angiogenic” endothelial cells differ from the late outgrowth ``proliferative” ones. We hypothesized that the number of colonies, representing the circulating pool of endothelial precursors, will be significantly stimulated by the presence of CVD and risk factors (RF). Methods We performed an ``intermediate” duration assay where peripheral blood mononuclear cells were cultured on fibronectin plates for 7 days and the number of colonies with endothelial-type cells at their periphery were counted by the same technician in all subjects. We sampled 420 subjects who either: were healthy and free of RF (n = 36, age = 47 ± 10), had metabolic syndrome, overt diabetes, or increased carotid thickness (n = 131, age = 59 ± 10), had coronary artery disease (n = 206, age = 61 ± 10), or peripheral vascular disease (n = 45, age = 64 ± 8). Results Endothelial precursor colony counts were lowest in the healthy subjects, higher in patients with RF, and highest in those with CVD (Figure ). These differences persisted after correcting for age. Conclusion Our data unequivocally demonstrates that the numbers of cultured endothelial colonies, utilizing an intermediate duration assay, are stimulated by the presence of risk factors, sub-clinical disease and overt CVD. This illustrates the presence of a reparative or compensatory regenerative response by endothelial progenitors to vascular injury. Whether an inadequate repair response is associated with increased risk needs to be further studied.

The dendritic cell (DC) possesses the ability to stimulate both T helper 1 (Th1) and Th2 responses depending on activation stimuli. Although it is known that chemically or genetically modified DC can be used therapeutically to steer immune responses towards either Th1 or Th2, cellular therapy with ex vivo manipulated DC is clinically difficult. Here we demonstrate a novel method of switching immune responses from Th1 to Th2 through in vivo immune modulation by administration of siRNA. We demonstrate that siRNA targeting of the IL-12p35 gene leads to a Th2 bias in vitro through an IL-10 dependent mechanism. In vivo administration of siRNA admixed with the oil-based contrast agent lipiodol in the presence of antigen and adjuvant induced a deviation in recall response to reduced production of IFN-γ and augmented IL-4 response using either KLH or ovalbumin. This simple method of in vivo modification of immune response possesses therapeutic potential in Th1-mediated diseases such as multiple sclerosis and autoimmune diabetes.

mportance Many patients with peripheral artery disease (PAD) have walking impairment despite therapy. Experimental studies in animals demonstrate improved perfusion in ischemic hind limb after mobilization of bone marrow progenitor cells (PCs), but whether this is effective in patients with PAD is unknown. Objective To investigate whether therapy with granulocyte-macrophage colony-stimulating factor (GM-CSF) improves exercise capacity in patients with intermittent claudication. Design, Setting, and Participants In a phase 2 double-blind, placebo-controlled study, 159 patients (median [SD] age, 64 [8] years; 87% male, 37% with diabetes) with intermittent claudication were enrolled at medical centers affiliated with Emory University in Atlanta, Georgia, between January 2010 and July 2012. Interventions Participants were randomized (1:1) to received 4 weeks of subcutaneous injections of GM-CSF (leukine), 500 µg/day 3 times a week, or placebo. Both groups were encouraged to walk to claudication daily. Main Outcomes and Measures The primary outcome was peak treadmill walking time (PWT) at 3 months. Secondary outcomes were PWT at 6 months and changes in circulating PC levels, ankle brachial index (ABI), and walking impairment questionnaire (WIQ) and 36-item Short-Form Health Survey (SF-36) scores. Results Of the 159 patients randomized, 80 were assigned to the GM-CSF group. The mean (SD) PWT at 3 months increased in the GM-CSF group from 296 (151) seconds to 405 (248) seconds (mean change, 109 seconds [95% CI, 67 to 151]) and in the placebo group from 308 (161) seconds to 376 (182) seconds (change of 56 seconds [95% CI, 14 to 98]), but this difference was not significant (mean difference in change in PWT, 53 seconds [95% CI, -6 to 112], P?=?.08). At 3 months, compared with placebo, GM-CSF improved the physical functioning subscore of the SF-36 questionnaire by 11.4 (95% CI, 6.7 to 16.1) vs 4.8 (95% CI, -0.1 to 9.6), with a mean difference in change for GM-CSF vs placebo of 7.5 (95% CI, 1.0 to 14.0; P?=?.03). Similarly, the distance score of the WIQ improved by 12.5 (95% CI, 6.4 to 18.7) vs 4.8 (95% CI, -0.2 to 9.8) with GM-CSF compared with placebo (mean difference in change, 7.9 [95% CI, 0.2 to 15.7], P?=?.047). There were no significant differences in the ABI, WIQ distance and speed scores, claudication onset time, or mental or physical component scores of the SF-36 between the groups. Conclusions and Relevance Therapy with GM-CSF 3 times a week did not improve treadmill walking performance at the 3-month follow-up. The improvements in some secondary outcomes with GM-CSF suggest that it may warrant further study in patients with claudication. Trial Registration clinicaltrials.gov Identifier: NCT01041417 Peripheral artery disease (PAD) affects more than 8 million individuals in the United States.1- 3 Although exercise, smoking cessation, antiplatelet therapy, cilostazol, statins, and revascularization are used to treat PAD, men and women with PAD have significantly greater functional impairment and faster functional decline than those without PAD.1,4- 7 Stem and progenitor cell (PC) therapy that promotes neoangiogenesis is an emerging treatment modality in PAD. Progenitor cells, particularly those of endothelial origin, are involved in vascular repair and regeneration.8 They originate primarily but not exclusively from the bone marrow, differentiate into endothelial and other vascular cells, and contribute to neovascularization during tissue repair by direct and paracrine mechanisms.8,9 Endogenous, pharmacologically stimulated, and exogenous PCs contribute to reendothelialization and neovascularization. Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulate mobilization of hematopoietic and other PCs from the bone marrow.10,11 In the murine hind limb ischemia model, GM-CSF administered by injection or by plasmid transfer augments circulating levels of PCs, increases capillary density, and promotes arteriogenesis.12 Granulocyte-macrophage colony-stimulating factor also augments neoendothelialization of denuded arteries and promotes proliferation, differentiation, and survival of hematopoietic cells, monocytes, and macrophages.9,10,13,14 Based on the observations of improved neovascularization in experimental models with GM-CSF,9 and some equivocal clinical trials,15- 17 we previously completed a phase 1 dose-escalation trial in patients with claudication, which demonstrated the safety of GM-CSF and its ability to mobilize PCs into the circulation. Additionally, we observed a strong trend toward an improvement in exercise duration after 3 months of treatment.18 In this larger phase 2 study, we tested the hypothesis that GM-CSF administration in patients with symptomatic PAD would improve walking performance. In exploratory analyses, we assessed the safety of GM-CSF for patients with claudication.

Background Transfusion of storage-aged (aged) packed red blood cells (pRBCs) is associated with worse outcomes, but the underlying mechanisms remain unknown. We measured plasma nitrite (NO2) levels and tested brachial vascular reactivity during transfusion of aged and fresh pRBCs with the hypothesis that aged pRBCs will impair NO2 and endothelial function. Methods Forty-four hospital inpatients (aged 59 ± 14 years, 46% female) receiving cross-matched pRBC transfusions for clinical indications were randomized to receive either fresh (aged 21 days, n = 24). NO2 was measured via high-performance liquid chromatography and vascular endothelial function was assessed using flow-mediated dilation (FMD) of the brachial artery before, during, and following (1 and 24 h) transfusion. Data were analyzed using a linear mixed effects model. Results There were no differences in demographics, CVD risk factors, known CVD, amount of pRBC transfused, or baseline NO2 or FMD between groups. The mean (±SD) age of pRBC units was 9.1 ± 3.1 days and 29.8 ± 5.7 days in the fresh and aged groups, respectively. Patients receiving fresh blood had a 0.191 ± 0.438 and 0.069 ± 0.242 μM increase in NO2 at 1 and 24 h after transfusion, respectively, whereas, patients receiving aged blood experienced a 0.055 ± 0.227 and 0.079 ± 0.226 μM decrease in NO2 at 1 and 24 h representing a difference in NO2 response between fresh and aged blood, p = 0.027 and p = 0.052 at 1 and 24 h, respectively (Panel A). Patients receiving fresh pRBCs had no significant change in FMD. However, FMD significantly decreased by 2.4% (p = 0.037) 24 h after transfusion of aged pRBCs (Panel B). Summary and conclusions Transfusion of aged, but not fresh blood is associated with decreased plasma NO2 and FMD response within 24 h of transfusion. Aged transfusion-induced endothelial dysfunction may contribute to poor outcomes associated with blood transfusion. Strategies to improve NO bioactivity in transfusion need to be further investigated. Disclosure Nothing to disclose.