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.
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.To investigate whether therapy with granulocyte-macrophage colony-stimulating factor (GM-CSF) improves exercise capacity in patients with intermittent claudication.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.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.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.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.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.clinicaltrials.gov Identifier: NCT01041417.
Endothelial dysfunction is more prevalent in African Americans ( AAs ) compared with whites. The authors hypothesized that nebivolol, a selective β 1 ‐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 <.001). Similarly, there was a contribution of NO to exercise‐induced vasodilation during nebivolol but not during metoprolol treatment. There were significantly greater contributions of NO and EDHF to resting vasodilator tone and of NO to exercise‐induced vasodilation with nebivolol compared with metoprolol in AA s with hypertension.
Background: Unlike traditional beta-blockers, nebivolol activates nitric oxide (NO) release via partial agonist activity at beta-2/3 receptors. We hypothesized that this property of nebivolol compared to metoprolol would improve oxidative stress (OS) and mobilize progenitor cells (PCs) that are known to be enhanced by NO, and ultimately contribute to improved vascular health. Methods: Thirty-two hypertensive subjects (age 54±10 years, 57% male, 83% African American) were randomized in a double-blind, cross-over study to receive either nebivolol or metoprolol for 3 months each. Of the 32 subjects randomized, 30 subjects successfully completed the trial. Two subjects did not complete the study due to serious adverse events. Nebivolol was titrated from 5mg to 20mg daily (mean 12mg) and metoprolol XL from 50mg to 200mg daily (mean 123mg). All other hypertensive therapy was kept constant. Measurements were made at baseline and on each drug after 3 and 6 months. OS was estimated from plasma levels of glutathione that reflects increased oxidative stress at lower levels. Circulating PCs were measured using flow cytometry for CD34+ and CD34+/CD133+ positive cells in mononuclear cell pools (CD45med). Arterial stiffness was measured as pulse wave velocity and augmentation index using the Sphygmacor device. Results: Compared to baseline, both nebivolol and metoprolol significantly and equally lowered systolic and diastolic BP (p<0.01). Nebivolol, but not metoprolol significantly increased the glutathione level (from 1.08 to 1.50μM; p=0.04). Both nebivolol and metoprolol significantly increased circulating numbers of CD34+/CD133+ PCs compared to baseline by 28% and 18%, respectively (p=0.02, for both). Neither nebivolol nor metoprolol significantly changed indices of arterial stiffness. Conclusion: Beta adrenergic antagonists increase circulating levels of PCs indicating improved regenerative capacity. Nebivolol, but not metoprolol, reduces oxidative stress, measured as plasma glutathione. The lack of translation of these effects on arterial stiffness may be secondary to the short duration of therapy in a treated population.
Background: Depression has been linked to cardiovascular disease (CVD) risk, and multiple mechanisms are likely implicated. Although depression was previously associated with endothelial dysfunction, limited data are available on whether it also influences arterial stiffening.
Methods: We administered the Beck Depression Inventory II (BDI-II) to 595 community participants without a previous history of CVD (mean age 51±9 years, 62% female) enrolled in the Morehouse-Emory Partnership to Eliminate Cardiovascular Health Disparities (META-Health) study. BDI-II scores of ≥14 indicated presence of depressive symptoms. Central augmentation index (CAIx), a composite measure of arterial wave reflections and stiffness, and pulse wave velocity (PWV) were estimated using applanation tonometry (SphygmoCor, AtCor Medical).
Results: Participants with depressive symptoms had higher CAIx (adjusted for heart rate) compared to those without depressive symptoms (49.1±11.1 vs. 46.8±11.2%, p=0.02). There was no difference in PWV between the groups. After adjusting for age, race, smoking, hypertension, diabetes, body mass index, mean arterial pressure, glucose, and lipid profile, the total BDI-II score remained a significant predictor of higher CAIx in men (β=0.172, p=0.002), but not women (β=0.006, p=0.9). The p-value for gender X BDI-II score interaction was not significant (p=0.1).
Conclusions: Depressive symptoms are associated with increased arterial wave reflections in men. Further research is needed to define this association, and what the role of gender-based differences might be.
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.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.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.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.
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.
Background Clinical and animal studies indicate that transfusions of older stored red blood cells ( RBC s) impair clinical outcomes as compared to fresh RBC transfusions. It has been suggested that this effect is due to inhibition of nitric oxide ( NO )‐mediated vasodilation after transfusion of older RBC units. However, to date this effect has not been identified in human transfusion recipients. Study Design and Methods Forty‐three hospitalized patients with transfusion orders were randomly assigned to receive either fresh (<14 days) or older stored (>21 days) RBC units. Before transfusion, and at selected time points after the start of transfusion, endothelial function was assessed using noninvasive flow‐mediated dilation assays. Results After transfusion of older RBC units, there was a significant reduction in NO ‐mediated vasodilation at 24 hours after transfusion (p = 0.045), while fresh RBC transfusions had no effect (p = 0.231). Conclusions This study suggests for the first time a significant inhibitory effect of transfused RBC units stored more than 21 days on NO ‐mediated vasodilation in anemic hospitalized patients. This finding lends further support to the hypothesis that deranged NO signaling mediates adverse clinical effects of older RBC transfusions. Future investigations will be necessary to address possible confounding factors and confirm these results.
