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1.  Better Population Health Through Behavior Change in Adults A Call to Action 
Circulation  2013;128(19):2169-2176.
PMCID: PMC4074536  PMID: 24100544
AHA Scientific Statements; behavior; population health; prevention
2.  Are there Race-Dependent Endothelial Cell Responses to Exercise? 
African Americans have endothelial dysfunction which likely contributes to their high prevalence of hypertension. Endothelial cell responses to stimuli could play a role in the development of endothelial dysfunction and hypertension. High physiological levels of vascular laminar shear stress can profoundly alter endothelial cell phenotype. It is not known whether there are race-dependent endothelial cell responses to laminar shear stress.
PMCID: PMC3577070  PMID: 23262464
Endothelial cell; shear stress; exercise; African American; oxidative stress; inflammation
3.  Incorporating Diffusion-Weighted Magnetic Resonance Imaging into an Observation Unit Transient Ischemic Attack Pathway 
The Neurohospitalist  2014;4(2):66-73.
Background and Purpose:
National guidelines advocate for early, aggressive transient ischemic attack (TIA) evaluations and recommend diffusion-weighted magnetic resonance imaging (MRI) for brain imaging. The purpose of this study is to examine clinician compliance, the yield of MRI, and patient-centered clinical outcomes following implementation of an emergency department observation unit (EDOU) clinical pathway incorporating routine MRI into the acute evaluation of patients with TIA.
This is a prospective observational study of patients with TIA admitted from the ED. Patients with low-risk TIA were transferred to an EDOU for diagnostic testing including MRI; high-risk patients were directed to hospital admission. Clinical variables, diagnostic tests, and treatment were recorded for all patients. The primary clinical outcome was the rate of stroke or recurrent TIA, determined through telephone follow-up and medical record review at 7 and 30 days.
A total of 116 patients with TIA were enrolled. In all, 92 (79.3%) patients were transferred to the EDOU, of whom 69 (59.5%) were discharged without hospitalization. Compliance with the EDOU pathway was 83 (91.2%) of 92. Magnetic resonance imaging demonstrated acute infarct in 16 (15.7%) of 102 patients. Stroke (n = 2) or TIA (n = 3) occurred in 5 patients with TIA (4.3%, 95% confidence interval: 1.6%-10.0%) within 30 days; no strokes occurred after discharge.
Implementation of a TIA clinical pathway incorporating MRI effectively encouraged guideline-compliant diagnostic testing; however, patient-important outcomes appear similar to diagnostic protocols without routine MRI. Further study is needed to assess the benefits and costs associated with routinely incorporating MRI into TIA evaluation.
PMCID: PMC3975796  PMID: 24707334
outcomes; techniques; imaging; techniques; ischemic attack; transient; cerebrovascular disorders; stroke and cerebrovascular disease; clinical specialty
4.  Mitochondrial DNA Diversity in Indigenous Populations of the Southern Extent of Siberia, and the Origins of Native American Haplogroups 
Annals of human genetics  2005;69(0 1):67-89.
In search of the ancestors of Native American mitochondrial DNA (mtDNA) haplogroups, we analyzed the mtDNA of 531 individuals from nine indigenous populations in Siberia. All mtDNAs were subjected to high-resolution RFLP analysis, sequencing of the control-region hypervariable segment I (HVS-I), and surveyed for additional polymorphic markers in the coding region. Furthermore, the mtDNAs selected according to haplogroup/subhaplogroup status were completely sequenced. Phylogenetic analyses of the resulting data, combined with those from previously published Siberian arctic and sub-arctic populations, revealed that remnants of the ancient Siberian gene pool are still evident in Siberian populations, suggesting that the founding haplotypes of the Native American A–D branches originated in different parts of Siberia. Thus, lineage A complete sequences revealed in the Mansi of the Lower Ob and the Ket of the Lower Yenisei belong to A1, suggesting that A1 mtDNAs occasionally found in the remnants of hunting-gathering populations of northwestern and northern Siberia belonged to a common gene pool of the Siberian progenitors of Paleoindians. Moreover, lineage B1, which is the most closely related to the American B2, occurred in the Tubalar and Tuvan inhabiting the territory between the upper reaches of the Ob River in the west, to the Upper Yenisei region in the east. Finally, the sequence variants of haplogroups C and D, which are most similar to Native American C1 and D1, were detected in the Ulchi of the Lower Amur. Overall, our data suggest that the immediate ancestors of the Siberian/Beringian migrants who gave rise to ancient (pre-Clovis) Paleoindians have a common origin with aboriginal people of the area now designated the Altai-Sayan Upland, as well as the Lower Amur/Sea of Okhotsk region.
PMCID: PMC3905771  PMID: 15638829
mtDNA variation; native Siberians; Native Americans
5.  Inpatient capsule endoscopy leads to frequent incomplete small bowel examinations 
AIM: To examine the predictive factors of capsule endoscopy (CE) completion rate (CECR) including the effect of inpatient and outpatient status.
METHODS: We identified 355 consecutive patients who completed CE at Rush University Medical Center between March 2003 and October 2005. Subjects for CE had either nothing by mouth or clear liquids for the afternoon and evening of the day before the procedure. CE exams were reviewed by two physicians who were unaware of the study hypotheses. After retrospective analysis, 21 cases were excluded due to capsule malfunction, prior gastric surgery, endoscopic capsule placement or insufficient data. Of the remaining 334 exams [264 out-patient (OP), 70 in-patient (IP)], CE indications, findings, location of the patients [IP vs OP and intensive care unit (ICU) vs general medical floor (GMF)] and gastrointestinal transit times were analyzed. Statistical analysis was completed using SPSS version 17 (Chicago, IL). Chi-square, t test or fisher exact-tests were used as appropriate. Multivariate logistic regression analysis was used to identify variables associated with incomplete CE exams.
RESULTS: The mean age for the entire study population was 54.7 years. Sixty-one percent of the study population was female, and gender was not different between IPs vs OPs (P = 0.07). The overall incomplete CECR was 14% in our study. Overt obscure gastrointestinal bleeding (OGB) was significantly more common for the IP CE (P = 0.0001), while abdominal pain and assessment of IBD were more frequent indications for the OP CE exams (P = 0.002 and P = 0.01, respectively). Occult OGB was the most common indication and arteriovenous malformations were the most common finding both in the IPs and OPs. The capsule did not enter the small bowel (SB) in 6/70 IPs and 8/264 OPs (P = 0.04). The capsule never reached the cecum in 31.4% (22/70) of IP vs 9.5% (25/ 264) of OP examinations (P < 0.001). The mean gastric transit time (GTT) was delayed in IPs compared to OPs, 98.5 ± 139.5 min vs 60.4 ± 92.6 min (P = 0.008). Minimal SB transit time was significantly prolonged in the IP compared to the OP setting [IP = 275.1 ± 111.6 min vs OP = 244.0 ± 104.3 min (P = 0.037)]. CECR was also significantly higher in the subgroup of patients with OGB who had OP vs IP exams (95% vs 80% respectively, P = 0.001). The proportion of patients with incomplete exams was higher in the ICU (n = 7/13, 54%) as compared to the GMF (n = 15/57, 26%) (P = 0.05). There was only a single permanent SB retention case which was secondary to a previously unknown SB stricture, and the remaining incomplete SB exams were due to slow transit. Medications which affect gastrointestinal system motility were tested both individually and also in aggregate in univariate analysis in hospitalized patients (ICU and GMF) and were not predictive of incomplete capsule passage (P > 0.05). Patient location (IP vs OP) and GTT were independent predictors of incomplete CE exams (P < 0.001 and P = 0.008, respectively).
CONCLUSION: Incomplete CE is a multifactorial problem. Patient location and related factors such as severity of illness and sedentary status may contribute to incomplete exams.
PMCID: PMC3460331  PMID: 23049213
Capsule endoscopy; Completion rate; Inpatient; Outpatient; Hospitalization
6.  Endothelial-dependent Flow-mediated Dilation in African-Americans with Masked-Hypertension 
American journal of hypertension  2011;24(10):1102-1107.
Office-blood pressure (BP) measurements alone overlook a significant number of individuals with masked-hypertension (office-BP: 120/80 -139/89 mmHg & 24-hr ambulatory BP monitoring, ABPM: daytime >135/85 mmHg or nighttime >120/70 mmHg). Diminished endothelial function contributes to the pathogenesis of hypertension. To better understand the pathophysiology involved in the increased cardiovascular disease (CVD) risk associated with masked-hypertension, we estimated the occurrence, assessed the endothelial function, compared plasma levels of inflammatory markers, white blood cell count, tumor necrosis factor-α and high sensitivity C-reactive protein (hsCRP) and examined the possible relationship between endothelial function and inflammatory markers in apparently healthy prehypertensive (office-BP: 120/80-139/89 mmHg) African-Americans.
50 African-Americans who were sedentary, non-diabetic, non-smoking, devoid of CVD were recruited. Office-BP was measured according to JNC-7 guidelines to identify prehypertensives in whom ABPM was then assessed. Fasting plasma samples were assayed for inflammatory markers. Brachial artery flow-mediated dilation at rest and during reactive hyperemia was measured in a subset of prehypertensives.
Subjects in the masked-hypertension sub-group had a higher hsCRP (P=0.04) and diminished endothelial function (P=0.03) compared to the true-prehypertensive sub-group (office-BP: 120/80-139/89 mmHg & ABPM: daytime <135/85 mmHg or nighttime <120/70 mmHg). Regression analysis showed that endothelial function was inversely related to hsCRP amongst the masked-hypertensive sub-group (R2=0.160; P=0.04).
Masked-hypertension was identified in 58% of African-Americans which suggests that a masking phenomenon may exist in a sub-group of prehypertensives who also seem to have a diminished endothelial function that could be mediated by an elevated subclinical inflammation leading to the increased CVD.
PMCID: PMC3711226  PMID: 21677701
Masked Hypertension; Prehypertension; Endothelial Dysfunction; Flow-mediated Dilation; high sensitivity C-Reactive protein; African-Americans
7.  Endothelial Activation Microparticles and Inflammation Status Improve with Exercise Training in African Americans 
African Americans have the highest prevalence of hypertension in the world which may emanate from their predisposition to heightened endothelial inflammation. The purpose of this study was to determine the effects of a 6-month aerobic exercise training (AEXT) intervention on the inflammatory biomarkers interleukin-10 (IL-10), interleukin-6 (IL-6), and endothelial microparticle (EMP) CD62E+ and endothelial function assessed by flow-mediated dilation (FMD) in African Americans. A secondary purpose was to evaluate whether changes in IL-10, IL-6, or CD62E+ EMPs predicted the change in FMD following the 6-month AEXT intervention. A pre-post design was employed with baseline evaluation including office blood pressure, FMD, fasting blood sampling, and graded exercise testing. Participants engaged in 6 months of AEXT. Following the AEXT intervention, all baseline tests were repeated. FMD significantly increased, CD62E+ EMPs and IL-6 significantly decreased, and IL-10 increased but not significantly following AEXT. Changes in inflammatory biomarkers did not significantly predict the change in FMD. The change in VO2 max significantly predicted the change in IL-10. Based on these results, AEXT may be a viable, nonpharmacological method to improve inflammation status and endothelial function and thereby contribute to risk reduction for cardiovascular disease in African Americans.
PMCID: PMC3652180  PMID: 23691280
8.  Racial differences in tumor necrosis factor-α-induced endothelial microparticles and interleukin-6 production 
African Americans (AA) tend to have heightened systemic inflammation and endothelial dysfunction. Endothelial microparticles (EMP) are released from activated/apoptotic endothelial cells (EC) when stimulated by inflammation. The purpose of our study was to assess EMP responses to inflammatory cytokine (TNF-α) and antioxidant (superoxide dismutase, SOD) conditions in human umbilical vein ECs (HUVECs) obtained from AA and Caucasians. EMPs were measured under four conditions: control (basal), TNF-α, SOD, and TNF-α + SOD. Culture supernatant was collected for EMP analysis by flow cytometry and IL-6 assay by ELISA. IL-6 protein expression was assessed by Western blot. AA HUVECs had greater EMP levels under the TNF-α condition compared to the Caucasian HUVECs (6.8 ± 1.1 vs 4.7% ± 0.4%, P = 0.04). The EMP level increased by 89% from basal levels in the AA HUVECs under the TNF-α condition (P = 0.01) compared to an 8% increase in the Caucasian HUVECs (P = 0.70). Compared to the EMP level under the TNF-α condition, the EMP level in the AA HUVECs was lower under the SOD only condition (2.9% ± 0.3%, P = 0.005) and under the TNF-α + SOD condition (2.1% ± 0.4%, P = 0.001). Basal IL-6 concentrations were 56.1 ± 8.8 pg/mL/μg in the AA and 30.9 ± 14.9 pg/mL/μg in the Caucasian HUVECs (P = 0.17), while basal IL-6 protein expression was significantly greater (P < 0.05) in the AA HUVECs. These preliminary observational results suggest that AA HUVECs may be more susceptible to the injurious effects of the proinflammatory cytokine, TNF-α.
Video abstract
PMCID: PMC3180509  PMID: 21966220
endothelium; inflammation; endothelial microparticles; African Americans
Journal of human hypertension  2013;27(11):671-677.
The purpose of this study was to investigate the association of visit-to-visit and 24-h BP variability with markers of endothelial injury and vascular function. We recruited 72 African Americans who were non-diabetic, non-smoking, and free of cardiovascular and renal disease. Office BP was measured at three visits and 24-h ambulatory BP monitoring was conducted to measure visit-to-visit and 24-h BP variability, respectively. The 5-min time-course of brachial artery flow-mediated dilation and nitroglycerin-mediated dilation were assessed as measures of endothelial and smooth muscle function. Fasted blood samples were analyzed for circulating endothelial microparticles. Significantly lower CD31+CD42− endothelial microparticles were found in participants with high visit-to-visit SBP variability or high 24-h DBP variability. Participants with high visit-to-visit DBP variability had significantly lower flow-mediated dilation and higher nitroglycerin-mediated dilation at multiple time-points. When analyzed as continuous variables, 24-h mean arterial pressure variability was inversely associated with CD62+ endothelial microparticles; visit-to-visit DBP variability was inversely associated with flow-mediated dilation normalized by smooth muscle function and was positively associated with nitroglycerin-mediated dilation; and 24-h DBP variability was positively associated with nitroglycerin-mediated dilation. All associations were independent of age, gender, BMI, and mean BP. In conclusion, in this cohort of African Americans visit-to-visit and 24-h BP variability were associated with measures of endothelial injury, endothelial function, and smooth muscle function. These results suggest that BP variability may influence the pathogenesis of cardiovascular disease, in part, through influences on vascular health.
PMCID: PMC3745784  PMID: 23615389
Blood pressure variability; endothelial function; endothelial microparticles; smooth muscle function; blood pressure; ambulatory blood pressure monitoring
10.  Racial differences in oxidative stress and inflammation: in vitro and in vivo 
African American race is an independent risk factor for enhanced oxidative stress and inflammation. We sought to examine whether oxidative stress and inflammatory markers that are typically measured in human also differ by race in cell culture. We compared levels between African American and Caucasian young adults and then separately in human umbilical vein endothelial cells (HUVECs) from both races. We found heightened oxidative stress and inflammation in the African Americans both in vitro and in vivo. African American HUVECs showed higher nitric oxide (NO) levels (10.8±0.4 vs 8.8±0.7umol/L/mg, P=0.03), IL-6 levels (61.7±4.2 vs 23.9±9.0pg/mg, P=0.02), and lower superoxide dismutase activity (15.6±3.3 vs. 25.4±2.8U/mg, P=0.04), and also higher protein expression (p<0.05) of NADPH oxidase subunit p47phox, isoforms NOX2 and NOX4, endothelial nitric oxide synthase, inducible NOS, as well as IL-6. African American adults had higher plasma protein carbonyls (1.1±0.1 vs 0.8±0.1nmol/mg, P=0.01) and antioxidant capacity (2.3±0.2 vs 1.1±0.3mM, P=0.01). This preliminary translational data demonstrates a racial difference in HUVECs much like that in humans, but should be interpreted with caution given its preliminary nature. It is known that racial differences exist in how humans respond to development and progression of disease, therefore these data suggest that ethnicity of cell model may be important to consider with in vitro clinical research.
PMCID: PMC3077905  PMID: 21348953
African American; NADPH oxidase; HUVECs
11.  Prehypertensive African-American Women Have Preserved Nitric Oxide and Renal Function but High Cardiovascular Risk 
Kidney & Blood Pressure Research  2010;33(4):282-290.
African-Americans, in particular women, exhibit disproportionate levels of hypertension, inflammation, and oxidative stress compared to other ethnic groups. The relationship between prehypertension, renal function, inflammation, and oxidative stress was examined.
Twenty-eight African-American women (53.5 ± 1.1 years) followed an AHA diet and then underwent 24-hour ambulatory BP (ABP) monitoring. Urinary albumin (uAlb), serum and urinary creatinine, glomerular filtration rate (GFR), 24-hour urinary Na+ excretion, plasma superoxide dismutase, total antioxidant capacity (TAC), urinary (uNOx) and plasma (pNOx) nitric oxide levels, and high-sensitivity C-reactive protein (hsCRP) were measured.
When the group was divided by average 24-hour ABP into optimal and nonoptimal groups, a significant difference existed between the groups for uNOx (p = 0.001; nonoptimal: 933.5 ± 140.4, optimal: 425.0 ± 52.6 μmol/gCr), and for hsCRP (p = 0.018, nonoptimal: 3.9 ± 0.7, optimal: 1.9 ± 0.6 mg/l). Significant inverse relationships existed between hsCRP and uNOx and between uAlb and pNOx in the non-optimal group, between GFR and pNOx in the entire group, and positive association existed between TAC and uNOx in the optimal group.
These results suggest that in African-American women as BP levels rise toward hypertension, the NO/NOS balance may be associated with renal function, and may have implications for CV risk based on their hsCRP levels.
PMCID: PMC3214938  PMID: 20628261
Pre-hypertension; Nitric oxide; High-sensitivity C-reactive protein; African-Americans
12.  Racial differences in the responses to shear stress in human umbilical vein endothelial cells 
African American ethnicity is an independent risk factor for exaggerated oxidative stress, which is related to inflammation, hypertension, and cardiovascular disease. Recently, we reported that in vitro oxidative stress and inflammation levels differ between African American and Caucasian human umbilical vein endothelial cells (HUVECs), African American HUVECs having higher levels of both. However, it remains to be shown whether the cells would respond differently to external stimuli.
We used a cone and plate viscometer to apply laminar shear stress (LSS) as an aerobic exercise mimetic to compare the responses by race. HUVECs were exposed to static conditions (no LSS), low LSS (5 dyne/cm2), and moderate LSS (20 dyne/cm2).
It was found that African American HUVECs had higher levels of oxidative stress under static conditions, and when LSS was applied protein expression levels (NADPH oxidase NOX2, NOX4 and p47phox subunits, eNOS, SOD2, and catalase) and biomarkers (NO, SOD, and total antioxidant capacity) were modulated to similar levels between race.
African American HUVECs may be more responsive to LSS stimulus indicating that aerobic exercise prescriptions may be valuable for this population since the potential exists for large in vivo improvements in oxidative stress levels along the endothelial layer in response to increased shear flow.
PMCID: PMC3141915  PMID: 21796257
shear stress; African American; NADPH oxidase; HUVECs; oxidative stress
High blood pressure (BP) levels in African Americans elicit vascular inflammation resulting in vascular remodeling. BP variability (BPV) correlates with target organ damage. We aimed to investigate the relationship between inflammatory markers and BPV in African Americans.
36 African Americans underwent 24-hr ambulatory BP monitoring (ABPM). BPV was calculated using the average real variability (ARV) index. Fasting blood samples were assayed for high sensitivity C-reactive protein (hs-CRP), tumor necrosis factor-alpha (TNF-α) and white blood cell (WBC) count.
Significant association between hs-CRP and 24-hr systolic variability (r = 0.50; p = 0.012) and awake systolic variability (r = 0.45; p =0.02) was identified after adjusting for age, BMI and 24-hr mean BP. ABPM variables were compared between the hs-CRP tertile groups. In Post-hoc analysis, there was a significant difference in 24-hr and awake periods for both systolic and diastolic variability among the groups. TNF-α and WBC count showed no associations with ABPM variables.
hs-CRP is associated with systolic variability and higher levels of hs-CRP are related with greater BPV. Higher inflammatory status influences wider fluctuations in systolic BP which in turn could facilitate early progression to target organ damage independent of absolute BP levelsin African Americans.
PMCID: PMC2945908  PMID: 20885987
Blood pressure variability; high sensitivity C-reactive protein; African Americans; tumor necrosis factor-alpha; white blood cells; inflammation
14.  Racial Differences in the Time-Course Oxidative Stress Responses to Acute Exercise 
African Americans have disproportionate levels of cardiovascular disease and oxidative stress. The purpose of our study was to examine racial differences between African American and Caucasian adults in time-course oxidative stress responses to a treadmill test. After a 12-hr fast, 18 participants (9 of each ethnic group; 21 ± 0.4 yrs) completed a submaximal treadmill test and underwent serial blood draws: Pre, Post (within 2 min), 30, 60, and 120 min after exercise. At each time-point, superoxide dismutase (SOD, U/mL), total antioxidant capacity (TAC, mM), protein carbonyls (PC, nmol/mg), and thiobarbituric acid-reactive substance (TBARs, μmol/L) were measured. We found no difference between groups for blood pressure, BMI, or exercise capacity (as measured by volume of oxygen consumed, VO2 max). African Americans had significantly (p < 0.05) higher SOD (Pre: 5.45 ± 0.4 vs. 3.69 ± 0.69; 60 min: 8.99 ± 0.7 vs. 4.23 ± 0.6; 120 min: 9.69 ± 1.6 vs. 3.52 ± 0.7), TAC (Pre: 2.31 ± 0.25 vs. 1.16 ± 0.3; Post: 2.39 ± 0.2 vs. 1.34 ± 0.2; 30 min: 2.29 ± 0.2 vs. 1.09 ± 0.2), and PC (Pre: 1.09 ± 0.1 vs. 0.82 ± 0.1; Post: 1.14 ± 0.1 vs. 0.81 ± 0.1; 30 min: 1.13 ± 0.1 vs. 0.85 ± 0.1; 60 min: 1.06 ± 0.1 vs. 0.81 ± 0.05), but not TBARs. Between groups, only SOD exhibited a different time-course response: levels for African Americans rose steadily throughout the 120 min, while levels for Caucasians peaked at 30 min and by 120 min had returned to pre-exercise levels. Race had a greater effect on oxidative stress responses than submaximal exercise did. African Americans had significantly higher TAC, SOD, and PC levels compared to Caucasians.
PMCID: PMC3118095  PMID: 21691463
African Americans; Sub-maximal Exercise; Antioxidants; Nitric Oxide; Superoxide Dismutase; Total Antioxidant Capacity
15.  Clinical Risk Factors Demonstrate an Age-dependent Relationship with Oxidative Stress Biomarkers in African Americans 
Ethnicity & disease  2010;20(4):403-408.
To examine the interaction of oxidative stress biomarkers with age, and also factors that influence oxidative stress such as body mass index (BMI) and fitness in a population of individuals with established higher risk of cardiovascular disease, African Americans.
Blood samples were obtained from healthy college-age and middle-age to older African Americans. Participants underwent a graded exercise test. Superoxide dismutase (SOD) activity, total antioxidant capacity and thiobarbituric acid reactive substances (TBARS) levels were measured.
TBARS levels were significantly (P=.001) lower in young participants relative to middle-age to older participants. SOD activity was significantly (P=.001) lower in middle-age to older participants with low fitness relative to participants with normal fitness, and lower (P=.04) in middle-age to older participants that were overweight relative to normal weight participants.
In a healthy middle-age to older population of African Americans, BMI and fitness are crucial for maintaining a healthy endothelium.
PMCID: PMC3103990  PMID: 21305829
Aging; Oxidative Stress; African Americans; Fitness; BMI
17.  Increased Nitric Oxide and Attenuated Diastolic Blood Pressure Variability in African Americans with Mildly Impaired Renal Function 
We investigated the relationship between renal function, blood pressure variability (BPV), and nitric oxide (NO) in a group of African Americans with normal or mildly impaired renal function. 24-hour ambulatory blood pressure monitoring was performed, NO measured, and glomerular filtration rate (GFR) calculated in 38 African Americans. Participants were categorized as having normal (GFR > 90 mL/min per 1.73 m2) or mildly impaired (GFR 60–89 mL/min per 1.73 m2) renal function. Diastolic BPV was significantly lower in the mildly impaired renal function group. Regression analyses revealed a significant positive association between GFR and diastolic BPV for the entire study group. Plasma NO levels were significantly higher in the mildly impaired renal function group and negatively correlated with diastolic BPV. In conclusion, diastolic BPV was reduced in African Americans with mildly impaired renal function, which may be the result of increased NO production. These results conflict with previous findings in diseased and nonblack populations and could provide rationale for studying BPV early in the disease state when BP-buffering mechanisms are still preserved.
PMCID: PMC3025367  PMID: 21274440
18.  Plasma Nitrate/Nitrite Levels are Unchanged after Long-Term Aerobic Exercise Training in Older Adults 
Reduced nitric oxide (NO) production and bioactivity is a major contributor to endothelial dysfunction. Animal data suggests that improvements in endothelial function in response to aerobic exercise training may depend on the duration of the training program. However, no studies have examined changes in NO (as assessed by the major NO metabolites, nitrate and nitrite, NOx) after long-term training in humans. In addition, aging may impair the ability of the vasculature to increase NO with exercise. Thus, we determined whether 24 weeks of aerobic exercise training increases plasma NOx levels in sedentary older adults. We also examined changes in forearm blood flow (FBF) at rest and during reactive hyperemia as a measure of vasomotor function. Plasma NOx levels were measured in 82 men and women using a modified Griess assay. FBF was assessed in a subset of individuals (n=15) using venous occlusion plethysmography. After 24 weeks of exercise training, there were significant improvements in maximum oxygen consumption, HDL cholesterol, triglycerides, and body fat. Changes in plasma NOx levels ranged from −14.83 to +16.69 μmol/L; however, the mean change overall was not significant (−0.33±6.30 μmol/L, p=0.64). Changes in plasma NOx levels were not associated with age, gender, race, HDL cholesterol, triglycerides, body weight, body fat, or maximal oxygen consumption. There were also no significant changes in basal FBF, peak FBF, hyperemic response, total hyperemic flow, or minimum forearm vascular resistance with exercise training. In conclusion, improvements in plasma NOx levels and FBF are not evident after long-term training in older adults.
PMCID: PMC2796424  PMID: 19825427
exercise training; nitric oxide; forearm blood flow; aging
19.  Independent and combined influence of AGTR1 variants and aerobic exercise on oxidative stress in hypertensives 
Blood pressure  2009;18(4):204-212.
Angiotensin II (AngII), via the AngII type 1 receptor (AT1R), contributes to oxidative stress. Aerobic exercise training (AEXT) reduces the risk of cardiovascular (CV) disease, presumably by reducing the grade of oxidative stress. We investigated the independent and combined influence of the AGTR1 A1166C and −825 T/A polymorphisms on oxidative stress and plasma AngII responses to AEXT in pre- and stage 1 hypertensives. Urinary 8-iso-PGF2α significantly increased with AEXT (p=0.002); however, there were no significant changes in superoxide dismutase activity or AngII levels. There was a significant difference in the change in AngII levels with AEXT between A1166C genotype groups (p=0.04) resulting in a significant interactive effect of the A1166C polymorphism and AEXT on the change in AngII (p<0.05). Only the TT genotype group of the −825 T/A polymorphism had a significant reduction in plasma AngII (p=0.02). Risk allele analysis revealed a significant reduction in plasma AngII (p=0.04) and a significant increase in urinary 8-iso-PGF2α (p=0.01) with AEXT in individuals with two risk alleles only. Our findings suggest that variation in the AGTR1 gene is associated with differential changes in plasma AngII but not oxidative stress.
PMCID: PMC2922402  PMID: 19593696
AGTR1; angiotensin II; exercise; isoprostanes; oxidative stress
20.  The relationship of oxidative stress and cholesterol with dipping status before and after aerobic exercise training 
Blood pressure  2009;18(4):171-179.
The purpose of this study was to examine the effects of aerobic exercise training (AEXT) on dipping status in pre-hypertensive and stage-1 hypertensive individuals. A secondary purpose was to evaluate whether AEXT alters oxidative stress and endothelial biomarkers correlated to dipping status.
Twenty-three subjects underwent 24-h ambulatory blood pressure monitoring at baseline and after 6 months of AEXT. AEXT consisted of training at 70% VO2max 3 days/week for 6 months. Total cholesterol, high-density lipoprotein-cholesterol, low-density lipoprotein (LDL)-cholesterol, oxidized LDL (ox-LDL), triglycerides, urinary and plasma nitric oxide end-products, superoxide dismutase and 8-iso-PGF2α were measured before and after AEXT. Statistically, ANOVA and linear regression were used.
Before and after AEXT, there were no significant differences between dippers and non-dippers in any of the biomarkers except for total cholesterol following AEXT. In a sub-analysis following AEXT, 14 subjects retained their original dipping status, five subjects changed from dippers to non-dippers and four subjects changed from non-dippers to dippers. Significant differences existed between these groups in changes in total and LDL-cholesterol, ox-LDL, 8-iso-PGF2α and % Dip.
Changes in cholesterol levels but not oxidative stress or endothelial biomarkers were related to changes in BP variables following AEXT in dippers and non-dippers.
PMCID: PMC2922419  PMID: 19544106
Aerobic exercise; ambulatory blood pressure monitoring; dipper; non-dipper; hypertension; oxidative stress
21.  Exercise Training, NADPH Oxidase p22phox Gene Polymorphisms, and Hypertension 
Oxidative stress that is mediated through NADPH oxidase activity plays a role in the pathology of hypertension, and aerobic exercise training reduces NADPH oxidase activity. The involvement of genetic variation in the p22phox (CYBA) subunit genes in individual oxidative stress responses to aerobic exercise training has yet to be examined in Pre and Stage 1 hypertensives.
Ninety-four sedentary Pre and Stage 1 hypertensive adults underwent 6 months of aerobic exercise training at a level of 70% V̇O2max to determine whether the CYBA polymorphisms, C242T and A640G, were associated with changes in urinary 8-iso-prostaglandin F2α (8-iso-PGF2α), urinary nitric oxide metabolites (NOx), and plasma total antioxidant capacity (TAC).
Demographic and subject characteristics were similar among genotype groups for both polymorphisms. At baseline, a significant (P = 0.03) difference among the C2424T genotype groups in 8-iso-PGF2α levels was detected, with the TT homozygotes having the lowest levels and the CC homozygotes having the highest levels. However, no differences were found at baseline between the A640G genotype groups. After 6 months of aerobic exercise training, there was a significant increase in V̇O2max (P < 0.0001) in the entire study population. In addition, there were significant increases in both urinary 8-iso-PGF2α (P = 0.002) and plasma TAC (P = 0.03) levels and a significant decrease in endogenous urinary NOx (P < 0.0001). Overall, aerobic exercise training elicited no significant differences among genotype groups in either CYBA variant for any of the oxidative stress variables.
We found that compared with CYBA polymorphisms C242T and A640G, it was aerobic exercise training that had the greatest influence on the selected biomarkers; furthermore, our results suggest that the C242T CYBA variant influences baseline levels of urinary 8-iso-PGF2α but not the aerobic exercise-induced responses.
PMCID: PMC2871250  PMID: 19516159
22.  The effect of a quantitative resuscitation strategy on mortality in patients with sepsis: A meta-analysis* 
Critical care medicine  2008;36(10):2734-2739.
Quantitative resuscitation consists of structured cardiovascular intervention targeting predefined hemodynamic end points. We sought to measure the treatment effect of quantitative resuscitation on mortality from sepsis.
Data Sources
We conducted a systematic review of the Cochrane Library, MEDLINE, EMBASE, CINAHL, conference proceedings, clinical practice guidelines, and other sources using a comprehensive strategy.
Study Selection
We identified randomized control trials comparing quantitative resuscitation with standard resuscitation in adult patients who were diagnosed with sepsis using standard criteria. The primary outcome variable was mortality.
Data Abstraction
Three authors independently extracted data and assessed study quality using standardized instruments; consensus was reached by conference. Preplanned subgroup analysis required studies to be categorized based on early (at the time of diagnosis) vs. late resuscitation implementation. We used the chi-square test and I2 to assess for statistical heterogeneity (p < 0.10, I2 > 25%). The primary analysis was based on the random effects model to produce pooled odds ratios with 95% confidence intervals.
The search yielded 29 potential publications; nine studies were included in the final analysis, providing a sample of 1001 patients. The combined results demonstrate a decrease in mortality (odds ratio 0.64, 95% confidence interval 0.43–0.96); however, there was statistically significant heterogeneity (p = 0.07, I2 = 45%). Among the early quantitative resuscitation studies (n = 6) there was minimal heterogeneity (p = 0.40, I2 = 2.4%) and a significant decrease in mortality (odds ratio 0.50, 95% confidence interval 0.37–0.69). The late quantitative resuscitation studies (n = 3) demonstrated no significant effect on mortality (odds ratio 1.16, 95% confidence interval 0.60–2.22).
This meta-analysis found that applying an early quantitative resuscitation strategy to patients with sepsis imparts a significant reduction in mortality.
PMCID: PMC2737059  PMID: 18766093
sepsis; septic shock; mortality; resuscitation; meta-analysis
23.  Variation in the Lectin-like Oxidized LDL Receptor 1 (LOX-1) Gene Is Associated With Plasma Soluble LOX-1 Levels 
Experimental physiology  2008;93(9):1085-1090.
The lectin-like ox-LDL receptor 1 (LOX-1) expressed on vascular cells plays a major role in atherogenesis by internalizing and degrading oxidized LDL. LOX-1 can be cleaved from the cell surface and released as soluble LOX-1 (sLOX-1), and elevated sLOX-1 levels may be indicative of atherosclerotic plaque instability. We examined associations between the LOX-1 3′UTR-C/T and G501C polymorphisms and plasma sLOX-1 levels in 97 healthy older men and women. The frequencies for the 3′UTR-T and 501C alleles were 46% and 10%, respectively. Plasma sLOX-1 levels were significantly higher in the 3′UTR CC genotype group compared to both the CT (p=0.02) and TT (p=0.002) genotype groups. Plasma sLOX-1 were also significantly higher in the 501GC genotype group compared to the GG genotype group (p=0.004). In univariate analyses, sLOX-1 levels were significantly associated with both the 3′UTR-C/T and G501 C polymorphisms. These associations remained significant after adjusting for age, gender, race, and BMI. In conclusion, variation in the LOX-1 gene is associated with plasma sLOX-1 levels in older men and women.
PMCID: PMC2652129  PMID: 18469066
receptor; cardiovascular; gene expression
24.  Differential aerobic exercise-induced changes in plasma aldosterone between African Americans and Caucasians 
Experimental physiology  2007;92(5):871-879.
Aldosterone influences the kidney’s regulation of blood pressure (BP), but aldosterone can contribute to the pathogenesis of hypertension. Blood pressure is reduced with aerobic exercise training (AEX), but the extent to which plasma aldosterone (PA) levels change is unclear. The purpose of this study was to determine whether 6 months of AEX changed PA levels, 24 h sodium (Na+) excretion and BP in prehypertensive and hypertensive subjects and whether these changes differed according to ethnicity. The study was performed in the Kinesiology Department at the University of Maryland, College Park, and 35 (22 Caucasian; 13 African American) sedentary prehypertensive and hypertensive subjects completed 6 months of AEX. Blood samples were collected under fasting and supine conditions, and PA was measured by radioimmunoassay. In total population aerobic exercise training increased maximal oxygen consumption (24 ± 0.8 versus 28 ± 1 ml kg−1 min−1, P < 0.001) and decreased PA levels (97 ± 11 versus 72 ± 6 pg ml−1, P = 0.01), body mass index (28 ± 0.5 versus 28 ± 0.5 kg m−2, P = 0.004) and weight (85 ± 2 versus 83 ± 2 kg, P = 0.003). Aerobic exercise training decreased PA levels (from 119 ± 16 to 81 ± 7 pg ml−1, P = 0.02) in the Caucasians but there was no change in BP or Na+ excretion. African American participants had no significant changes in PA levels, BP and Na+ excretion. Plasma aldosterone levels were 47% lower at baseline (P = 0.01) and 30% lower after AEX (P = 0.04) in African American participants compared with Caucasians. Baseline (P = 0.08) and final PA levels (P = 0.17) did not differ between the two groups after accounting for baseline and final intra-abdominal fat, respectively. The reduction in PA levels with AEX appeared to be driven by the change in PA levels in Caucasian participants. Fat distribution contributed to the ethnic differences in PA levels.
PMCID: PMC2729146  PMID: 17483200
25.  NFKB1 promoter variation implicates shear-induced NOS3 gene expression and endothelial function in prehypertensives and stage I hypertensives 
In endothelial cells, NF-κB is an important intracellular signaling molecule by which changes in wall shear stress are transduced into the nucleus to initiate downstream endothelial nitric oxide synthase (NOS3) gene expression. We investigated whether NF-κ light-chain gene enhancer in B cells 1 (NFKB1) promoter polymorphism (−94NFKB1 I/D, where I is the insertion allele and D is the deletion allele) was associated with 1) NOS3 gene expression in endothelial cells under physiological levels of unidirectional laminar shear stress (LSS) and 2) endothelial function in prehypertensive and stage I hypertensive individuals before and after a 6-mo supervised endurance exercise intervention. Competitive EMSAs revealed that proteins present in the nuclei of endothelial cells preferentially bound to the I allele NFKB1 promoter compared with the D allele. Reporter gene assays showed that the I allele promoter had significantly higher activity than the D allele. In agreement with these observations, homozygous II genotype cells had higher p50 expression levels than homozygous DD genotype cells. Cells with the homozygous II genotype showed a greater increase in NOS3 protein expression than did homozygous DD genotype cells under LSS. Functional experiments on volunteers confirmed higher baseline reactive hyperemic forearm blood flow, and, furthermore, the subgroup analysis revealed that DD homozygotes were significantly less prevalent in the exercise responder group compared with II and ID genotypes. We conclude that the −94NFKB1 I/D promoter variation contributes to the modulation of vascular function and adaptability to exercise-induced flow shear stress, most likely due to differences in NFKB1 gene transactivity.
PMCID: PMC2614625  PMID: 17644577
nuclear factor-κ light-chain gene enhancer in B cells 1; nitric oxide synthase 3; shear stress

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