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Rationale: Despite direct immediate intervention and therapy, ST-segment–elevation myocardial infarction (STEMI) victims remain at risk for infarct expansion, heart failure, reinfarction, repeat revascularization, and death. Objective: To evaluate the safety and bioactivity of autologous CD34+ cell (CLBS10) intracoronary infusion in patients with left ventricular dysfunction post STEMI. Methods and Results: Patients who underwent successful stenting for STEMI and had left ventricular dysfunction (ejection fraction≤48%) ≥4 days poststent were eligible for enrollment. Subjects (N=161) underwent mini bone marrow harvest and were randomized 1:1 to receive (1) autologous CD34+ cells (minimum 10 mol/L±20% cells; N=78) or (2) diluent alone (N=83), via intracoronary infusion. The primary safety end point was adverse events, serious adverse events, and major adverse cardiac event. The primary efficacy end point was change in resting myocardial perfusion over 6 months. No differences in myocardial perfusion or adverse events were observed between the control and treatment groups, although increased perfusion was observed within each group from baseline to 6 months ( P P =0.05). At 1 year, 3.6% (N=3) and 0% deaths were observed in the control and treatment group, respectively. Conclusions: This PreSERVE-AMI (Phase 2, randomized, double-blind, placebo-controlled trial) represents the largest study of cell-based therapy for STEMI completed in the United States and provides evidence supporting safety and potential efficacy in patients with left ventricular dysfunction post STEMI who are at risk for death and major morbidity. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01495364.

Endothelial dysfunction is more prevalent in African Americans (AAs) compared with whites. The authors hypothesized that nebivolol, a selective β1 -antagonist that stimulates nitric oxide (NO), will improve endothelial function in AAs with hypertension when compared with metoprolol. In a double-blind, randomized, crossover study, 19 AA hypertensive patients were randomized to a 12-week treatment period with either nebivolol 10 mg or metoprolol succinate 100 mg daily. Forearm blood flow (FBF) was measured using plethysmography at rest and after intra-arterial infusion of acetylcholine and sodium nitroprusside to estimate endothelium-dependent and independent vasodilation, respectively. Physiologic vasodilation was assessed during hand-grip exercise. Measurements were repeated after NO blockade with L-N(G) -monomethylarginine (L-NMMA) and after inhibition of endothelium-derived hyperpolarizing factor (EDHF) with tetraethylammonium chloride (TEA). NO blockade with L-NMMA produced a trend toward greater vasoconstriction during nebivolol compared with metoprolol treatment (21% vs 12% reduction in FBF, P=.06, respectively). This difference was more significant after combined administration of L-NMMA and TEA (P

Background— Cross-sectional studies demonstrated ethnic and gender differences in ambulatory blood pressure patterns, but little is known about the longitudinal development of these differences. Methods and Results— Twenty-four-hour ambulatory blood pressure was measured up to 12 times (5 times on average) over a 15-year period in 312 African Americans (AAs) and 351 European Americans aged 7 to 30 years. Multivariate individual growth curves across age were created for daytime and nighttime blood pressure jointly. For both daytime and nighttime systolic blood pressure (SBP), AAs and males had higher levels ( P P P P Conclusions— We observed significant ethnic and gender differences in longitudinal trajectories of ambulatory blood pressure in youth and young adults. The blunted nocturnal decline and its exacerbation with age in AAs corroborate and extend findings of cross-sectional studies.

The sympathetic nervous system (SNS) is the first line of defense in the response to environmental stress through its regulation of second-to-second changes in blood pressure (BP). Both the activity of the SNS and the therapeutic responses to SNS agonists and antagonists are known to be highly variable in the population. Small changes caused by single nucleotide polymorphisms (SNPs) of SNS genes may have considerable impact on SNS function and individualized hypertension treatment. In this review, we first describe the physiology of the SNS and its influence on cardiovascular and renal mechanisms of BP regulation. A thorough review of the role of genetic variability of various SNS genes in relation to the development of BP and essential hypertension (EH) follows. Given the vast number of SNS components, evaluations of multiple SNPs from multiple SNS genes are necessary for future association studies of BP and EH. One way to surpass the limitations and inconsistencies of previous association studies is to use a gene-based approach also referred to as indirect association, which takes all common variation within a candidate gene into account. In order to determine how SNS genes are differentially expressed or silenced, activated or inactivated against various environmental backgrounds, it is important to assess not only environmental and lifestyle risk factors such as diet, climate, chronic stress, but also personality characteristics such as hostility and coping styles. Uncovering relevant gene-gene and geneenvironment interactions within the SNS cascade will not only enable early detection of EH risk but will also aid in the treatment of hypertensives through both non-pharmacological and pharmacological means.

Unlike traditional beta receptor antagonists, nebivolol activates nitric oxide. We hypothesized that therapy with nebivolol compared with metoprolol would improve arterial stiffness, increase levels of circulating progenitor cells (PC), and decrease oxidative stress (OS). In a randomized, double–blind, cross–over study, 30 hypertensive subjects received either once daily nebivolol or metoprolol succinate for 3 months each. Pulse wave velocity and augmentation index were measured using tonometry. Flow cytometry was used to measure circulating PC. OS was measured as plasma aminothiols. Measurements were performed at baseline, and repeated at 3 and 6 months. No significant differences were present between the levels of OS, arterial stiffness, and PC numbers during treatment with metoprolol compared with nebivolol. In subgroup analyses of beta–blocker naive subjects (n = 19), nebivolol reduced pulse wave velocity significantly compared with metoprolol (−1.4 ± 1.9 vs. −0.1 ± 2.2; P = .005). Both nebivolol and metoprolol increased circulating levels of CD34+/CD133 + PC similarly ( P = .05), suggesting improved regenerative capacity.

Background Compared with whites, black A mericans suffer from a disproportionate burden of cardiovascular disease ( CVD ). We hypothesized that racial differences in the prevalence of CVD could be attributed, in part, to impaired vascular function in blacks after adjustment for differences in risk factor burden. Methods and Results We assessed vascular function in 385 black and 470 white subjects (mean age, 48±11 years; 45% male). Using digital pulse amplitude tonometry (Endo PAT ) we estimated the reactive hyperemia index ( RHI ), a measure of microvascular endothelial function, and peripheral augmentation index ( PAT ‐ AI x). Central augmentation index ( C ‐ AI x) and pulse‐wave velocity ( PWV ) were measured as indices of wave reflections and arterial stiffness, respectively, using applanation tonometry (Sphygmocor). Compared with whites, blacks had lower RHI (2.1±0.6 versus 2.3±0.6, P PAT ‐ AI x (20.4±21.5 versus 17.0±22.4, P =0.01) and CAI x (20.8±12.3 versus 17.5±13.3, P =0.001), and greater arterial stiffness, measured as PWV (7.4±1.6 versus 7.1±1.6 m/s, P =0.001). After adjustment for traditional CVD risk factors, black race remained a significant predictor of lower RHI and higher PAT ‐ AI x and CAI x (all P PWV in men ( P =0.01). Furthermore, these associations persisted in a subgroup analysis of “healthy” individuals free of CVD risk factors. Conclusion Black race is associated with impaired microvascular vasodilatory function, and greater large arterial wave reflections and stiffness. Because impairment in these vascular indices may be associated with worse long‐term outcomes, they may represent underlying mechanisms for the increased CVD risk in blacks.

Background The functional impairment caused by peripheral arterial disease (PAD) is difficult to evaluate objectively and quantitatively. Current methods used to assess the efficacy of therapeutic interventions in patients with PAD are limited by variability and changes representing the placebo effect. Recently, Gadolinium-enhanced first-pass (FP) MRI has emerged as a new method to assess perfusion in peripheral muscles at peak exercise. We seek to demonstrate that calf muscle perfusion index measured with FP MRI at peak exercise correlates with treadmill exercise measures of ischemia in patients with PAD.

ST elevation myocardial infarction (STEMI) is associated with an increased risk for congestive heart failure and long-term mortality despite the widespread use of thrombolysis and catheter-based revascularization. The need for improved post-STEMI therapies has led to a surge of novel therapeutics, especially regenerative approaches using autologous mononuclear cells. Indeed, the past decade has been marked by a number of human trials studying the safety and efficacy of progenitor cell delivery in the post-STEMI setting. While a variety of cell types and delivery techniques have been utilized, directed therapy to the infarct-related artery has been the most widely used approach. From over 1300 subjects randomized in these studies, there is sufficient evidence to conclude that cell therapy after STEMI is uniformly safe, while the efficacy of this intervention for improving outcomes is less clear. Recent meta-analyses have highlighted the importance of both timing of cell delivery, as well as the type, quantity, and mobility of delivered cells as determinants of response. Here, we show the case in which higher doses of CD34+cells, which are more potent in terms of their migratory capacity, offer the best hope for preserving cardiac function following STEMI.

Although we have demonstrated a link between metabolic syndrome (MetS) and increased arterial stiffness, the relationship between varying definitions of MetS and arterial stiffness, particularly across ethnic groups, remains unclear. Compared to Adult Treatment Panel (ATP) III criteria, which appear

Activation of diverse pathophysiologic processes that include thrombotic, inflammatory, and immune pathways contribute to plaque rupture and adverse outcomes in CAD. We hypothesized that an aggregate biomarker risk score comprised of C-reactive protein (CRP), fibrin degradation products (FDP)

OBJECTIVES The purpose of this study was to examine how variation in the beta-2 adrenergic receptor gene (ADRB2), in combination with the moderating influences of race, body mass index (BMI), and anger expression style (anger-in, anger-out), affects blood pressure (BP) at rest and in response to acute laboratory stress. METHODS Four hundred fifty adolescents (mean age = 18.5 +/- 2.7 years; 228 [124 males] whites and 222 [110 males] blacks completed two stressors (video game challenge, forehead cold pressor). Hemodynamic measures were taken before, during, and after each stressor. Stressors were separated by a 20-minute rest period. RESULTS Frequency of detrimental haplotype (Gly16/Glu27) carrier status was greater among whites than blacks (p < .05). A significant three-way interaction among haplotype, BMI, and race for resting systolic blood pressure (SBP) found the highest BP level to be among high BMI carriers, but only for whites. A separate three-way interaction was found to be significant for haplotype, anger-in and race such that high anger-in carriers showed the highest level of resting SBP (p < .05) and total peripheral resistance (TPR) (p < .05) and the greatest TPR reactivity to the cold pressor task (p < .01). Post hoc analyses revealed these interactions with anger-in were only present among blacks. No significant interactions with anger-out for either ethnic group were observed. CONCLUSIONS This study demonstrates modulating influences of BMI and anger expression styles on ADRB2 gene associations with hemodynamic function at rest and in response to laboratory stress. These findings support the hypothesis that consideration of gene-environment interactions may better characterize the role of ADRB2 variation in the development of stress-induced essential hypertension.

Background: Ineffective anger expression has been associated with essential hypertension (EH) and with blood pressure (BP) reactivity to stress. The ET-1/Lys198Asn polymorphism has been associated with increased resting BP and exaggerated vasoconstrictive mediated BP reactivity. African Americans (AAs) are at particular risk for development of EH, report greater anger difficulties, and exhibit greater vasoconstrictive reactivity than their European American (EA) counterparts.Purpose: The objective is to investigate a gene-environment model of stress reactivity in which anger expression, particularly in combination with ET-1 T allele carrier status and AA ethnicity, would be associated with the greatest vasoconstrictive reactivity in response to a behavioral stressor.Methods: One hundred ninety-one AA and 197 EA normotensive young adults (Mage=18.8±2.5 years) participated in the study. Total peripheral resistance index (TPRI) reactivity was assessed during a 10-min video game challenge. Anger expression was measured using Spielberger’s Anger Expression Scale.Results: A multiple regression model with TPRI reactivity as the dependent variable revealed a three-way interaction effect for anger management (i.e., AM=anger control minus anger out scores), ethnicity, and ET-1 polymorphism. Specifically, AA carriers of the ET-1 polymorphism with poor AM skills exhibited the greatest TPRI reactivity.Conclusions: Individuals with a genetic predisposition for exaggerated vasoconstriction who also display low AM skills may be at particular risk for development of stress-induced EH. Such individuals may particularly benefit from anger management training.

Studies on the associations between the nitric oxide synthase gene (NOS3) Glu298Asp polymorphism and hypertension status or blood pressure (BP) levels have had inconsistent results. Potential moderating influences of ethnicity, sex, and obesity on the effects of the NOS3 polymorphism have not been examined. We evaluated the influence of these factors on associations between the NOS3 polymorphism, nitric oxide metabolites (NOx), and hemodynamics at rest and during stress. Subjects were 235 African American (AA) and 262 European American (EA) young adults (18.5±2.6 years). Hemodynamic measurements and blood samples for NOx assays were taken before and after a competitive video game challenge. Glu298Asp polymorphism was detected by polymerase chain reaction–restriction enzyme digestion assay. A regression model was built using genotypes, ethnicity, sex, and obesity (body mass index >85th percentile) and their interactions controlling for age; 20.1% of AAs and 49.8% of EAs were carriers of the Asp allele. AAs, regardless of obesity status, exhibited high diastolic blood pressure (DBP) reactivity unless they were nonobese and noncarriers of the Asp allele. EAs exhibited lower DBP reactivity unless they were obese Asp allele carriers. AA nonobese carriers exhibited the greatest total peripheral resistance reactivity. Obese Asp allele carriers exhibited the greatest increases in cardiac output and the greatest decrease in NOx to the stressor. Results indicate the importance of examining impact of BP control-related genetic polymorphisms within the context of moderating factors such as adiposity and ethnicity.

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.

✓ A case of esthesioneuroblastoma (olfactory neuroblastoma) is reported. Its onset was that of an intracranial tumor, and it subsequently recurred four times. At autopsy, 4 years and 8 months after the onset of symptoms, metastases were found in the cerebrospinal pathways and visceral organs. The literature on this relatively rare neoplasm is reviewed with special reference to the unusual clinical presentation and biological behavior of the tumor.

The Graf/Pen sonic digitilizer facilitates routine application of neuroradiologic measurements during film interpretation. The Vlahovitch and Probst measurements were performed 23 times faster with this device than manually. The Graf/Pen computer combination shows great potential in the rapid quantitative analysis of both carotid and vertebral angiograms.