Racial differences in baroreflex function: Implications for the cardiovascular conundrum.

Study objective: African Americans (AAs) show early signs of vascular dysfunction paired with elevated blood pressure (BP) and total peripheral resistance (TPR), which is thought to underlie their increased rates of cardiovascular health complications relative to European Americans (EAs). AAs paradoxically have higher cardiac vagal tone, indexed by heart rate variability (HRV), which is cardio-protective. This paradox has been termed the Cardiovascular Conundrum. The physiological mechanism underlying this phenomenon is not well understood. We examined race differences in baroreflex function, which might be an important mechanism underlying the Cardiovascular Conundrum. Design: Participants completed a 5-minute baseline period where resting cardiac metrics were assessed. Setting: Laboratory. Participants: 130 college-aged individuals (54 women, 57 AAs). Main outcome measures: Baroreflex function was indexed as baroreflex sensitivity (BRS; the magnitude of changes in cardiovascular activity in accordance with BP changes) and effectiveness (BEI; the ratio of BP changes that elicit changes in cardiovascular activity) in the cardiac, vascular, and myocardial limbs. Results and conclusions: Results showed AAs to have higher HRV and cardiac BRS in comparison to EAs, suggesting the baroreflex is more sensitive to correcting the heart period for changes in BP among AAs compared to EAs. However, AAs showed lower vascular BEI relative to EAs, suggesting less effective control of TPR. In sum, lower BEI in the vascular branch might be an important mechanism underlying the Cardiovascular Conundrum (i.e., higher HRV and BP) and by extension, health disparities in cardiovascular diseases between AAs and EAs.

Mice with endothelial cell-selective adhesion molecule deficiency develop coronary microvascular rarefaction and left ventricle diastolic dysfunction.

Endothelial cell-selective adhesion molecule (ESAM) regulates inflammatory cell adhesion and transmigration and promotes angiogenesis. Here, we examined the role of ESAM in cardiac vascularization, inflammatory cell infiltration, and left ventricle (LV) diastolic function under basal and hemodynamic stress conditions. We employed mice with homozygous genetic deletion of ESAM (ESAM-/- ) and also performed uninephrectomy and aldosterone infusion (UNX-Aldo) to induce volume and pressure overload. Using echocardiography, we found that ESAM-/- mice display no change in systolic function. However, they develop LV diastolic dysfunction, as indicated by a significantly reduced E/A ratio (E = early, A = late mitral inflow peak velocities), increased E/e' ratio, isovolumic relaxation time (IVRT), and E wave deceleration time. An unbiased automated tracing and 3D reconstruction of coronary vasculature revealed that ESAM-/- mice had reduced coronary vascular density. Arteries of ESAM-/- mice exhibited impaired endothelial sprouting and in cultured endothelial cells siRNA-mediated ESAM knockdown reduced tube formation. Changes in ESAM-/- mice were accompanied by elevated myocardial inflammatory cytokine and myeloperoxidase-positive neutrophil levels. Furthermore, UNX-Aldo procedure in wild type mice induced LV diastolic dysfunction, which was accompanied by significantly increased serum ESAM levels. When compared to wild types, ESAM-/- mice with UNX-Aldo displayed worsening of LV diastolic function, as indicated by increased IVRT and pulmonary edema. Thus, we propose that ESAM plays a mechanistic role in proper myocardial vascularization and the maintenance of LV diastolic function under basal and hemodynamic stress conditions.

Aortic pressure-only wave separation analysis in adolescents: accuracy and associations with left ventricular mass index.

Early-life exposure to high blood pressure (BP) is associated with cardiovascular target organ damage but not all BP-related risk is attributable to systolic and diastolic BP alone. In adolescence, aortic wave separation (WS) parameters are associated with increased left ventricular mass index (LVMI) but this approach is limited by the requirement for aortic flow measurements. Several methods for estimating the aortic flow waveform from pressure waveforms have emerged, but their accuracy and associations with LVMI have never been tested in adolescents, which was the aim of our study. Carotid pressure waveforms were acquired by tonometry from 58 adolescents (age 16 ± 1.5 years, 59% female). Measured (aortic) flow and LVMI were acquired via 2D echocardiography. Three pressure-only approximations of aortic flow were synthesized, including triangular, excess, and individualized-physiologic flow. A 4th aortic flow (average flow) was approximated from the average of all 58 measured flow waveforms. Forward (Pf) and backward (Pb) pressure and reflection magnitude (Rm) were derived from WS analysis. The individualized-physiologic flow produced the best approximations of Pf (mean difference ± SD, -0.15 ± 2.38 mmHg), Pb (0.14 ± 0.25 mmHg), and Rm (0.01 ± 0.02 mmHg). Pf derived using measured, individualized-physiologic, and average flow, was similarly associated with LVMI adjusting for age, brachial systolic BP, cardiac output, and BMI (P ≤ 0.03 all). Pb derived using all flow waveforms was associated with LVMI and all associations yielded similar effect estimates. Of the estimated flow waveforms, individualized-physiologic flow yielded the best approximation of WS parameters and may provide important physiological and clinical insight among adolescents.

Commentary: Cancer Survivorship and Subclinical Myocardial Damage.

The rate of cardiovascular disease among cancer survivors is higher than in the general population. This difference is due to traditional cardiovascular disease (CVD) risk factors and also to the cardiotoxicity of cancer treatment. In a population-based cohort study of 3,512 men and women who were free of CVD at visit 5 of a large, community-based cohort study, Florido et al. (Am J Epidemiol. 2019;188(12):2188-2195) evaluated the association of cancer survivorship with subclinical myocardial damage, as assessed by elevated high-sensitivity cardiac troponin T (hs-cTnT). Cancer survivors had significantly higher odds of elevated hs-cTnT (odds ratio = 1.26, 95% confidence interval: 1.03, 1.53). Results were similar for survivors of non-sex-related and colorectal cancers. There was no association between survivorship from breast and prostate cancers and elevated hs-cTnT. The findings of Florido et al. indicate that survivors of some cancers might be more likely to have elevated hs-cTnT than patients without prior cancer. These findings have important implications because identifying cancer survivors who have elevated CVD risk is of paramount importance in order to prevent CVD manifestations such as heart attack, congestive heart failure, or stroke. Additional research is needed to clarify the associations of elevated hs-cTnT levels among survivors of specific cancer sites, stage at diagnosis, and histologic types.

Decreased heritability and emergence of novel genetic effects on pulse wave velocity from youth to young adulthood.

Increased arterial stiffness measured by pulse wave velocity (PWV) is an important parameter in the assessment of cardiovascular risk. Our previous longitudinal study has demonstrated that carotid-distal PWV showed reasonable stability throughout youth and young adulthood. This stability might be driven by genetic factors that are expressed consistently over time. We aimed to illustrate the relative contributions of genetic and environmental factors to the stability of carotid-distal PWV from youth to young adulthood. We also examined potential ethnic differences. For this purpose, carotid-distal PWV was measured twice in 497 European American (EA) and African American (AA) twins, with an average interval time of 3 years. Twin modelling on PWV showed that heritability decreased over time (62-35%), with the nonshared environmental influences becoming larger. There was no correlation between the nonshared environmental factors on PWV measured at visit 1 and visit 2, with the phenotypic tracking correlation (r = 0.32) completely explained by shared genetic factors over time. Novel genetic influences were identified accounting for a significant part of the variance (19%) at the second measurement occasion. There was no evidence for ethnic differences. In summary, novel genetic effects appear during development into young adulthood and account for a considerable part of the variation in PWV. Environmental influences become larger with age for PWV.

Higher cardiac vagal activity predicts lower peripheral resistance 6 years later in European but not African Americans.

African American (AA) individuals are at a greater risk for the development of cardiovascular complications, such as hypertension, compared with European Americans (EAs). Higher vagally mediated heart rate variability (HRV) is typically associated with lower blood pressure (BP) and total peripheral resistance (TPR). However, research has yet to examine the differential impact of HRV on longitudinal hemodynamic activity between AAs and EAs. We sought to rectify this in a sample of 385 normotensive youths (207 AAs, 178 EAs; mean age 23.16 ± 2.9 yr). Individuals participated in two laboratory evaluations spanning approximately 6 yr. Bioimpedance was used to assess HRV at time 1 and cardiac output at both time 1 and time 2. Mean arterial pressure (MAP) was measured at both time points via an automated BP machine. TPR was calculated as MAP divided by cardiac output. Results showed AAs to have higher BP and higher TPR at time 2 compared with EAs, independent of several important covariates. Also, higher HRV at time 1 significantly predicted both lower TPR and BP at time 2 among EAs only; these associations were attenuated and not significant in AAs. HRV did not significantly predict cardiac output at time 2 in the full sample or split by ethnicity. Our findings highlight that AAs show TPR mediated long-term increases in BP irrespective of resting HRV, providing a physiological pathway linking AAs with a greater risk for mortality and morbidity from hypertension and potentially other cardiovascular disease.NEW & NEWSWORTHY African Americans and European Americans differ in hemodynamics underlying long-term blood pressure regulation. Over 6 yr, African Americans show total peripheral resistance-mediated increases in blood pressure compared with European Americans. Higher heart rate variability predicts lower blood pressure and total peripheral resistance 6 yr later in European Americans but not African Americans.

Rapid decline of resting heart rate trajectories from childhood to young adulthood is paradoxically associated with increased cardiac mass.

BACKGROUND: Little is known about the varied resting heart rate (RHR) trajectory patterns from childhood to young adulthood and their clinical significance. We aim to identify RHR trajectories from childhood to young adulthood, and to determine their relationship with left ventricular mass (LVM) index. METHODS: RHR was measured up to 15 times over a 21-year period in 759 participants from childhood to young adulthood. LVM was measured using echocardiography and was normalised to body surface area to obtain LVM index in 546 participants. RESULTS: Using latent class models, three trajectory groups in RHR from childhood to young adulthood were identified, including high-decreasing group (HDG), moderate-decreasing group (MDG), and low-decreasing group (LDG). We found that trajectory of RHR was a significant predictor of LVM index with faster decrease of RHR associated with higher levels of total peripheral resistance (P for trend <0.001) and LVM index (P for trend <0.001). Compared to the LDG, individuals in the HDG showed higher LVM index (ß = 6.08, p < 0.001). In addition, the interactions between race and RHR trajectories for LVM index was significant (p < 0.05). CONCLUSION: Our findings show an association between RHR trajectories from childhood to young adulthood with cardiac mass, suggesting that monitoring RHR may help identify subpopulation at high cardiovascular risk.

Effects of Race, Cardiac Mass, and Cardiac Load on Myocardial Function Trajectories from Childhood to Young Adulthood: The Augusta Heart Study.

Background The overall goal of this longitudinal study was to determine if the Black population has decreased myocardial function, which has the potential to lead to the early development of congestive heart failure, compared with the White population. Methods and Results A total of 673 subjects were evaluated over a period of 30 years including similar percentages of Black and White participants. Left ventricular systolic function was probed using the midwall fractional shortening (MFS). A longitudinal analysis of the MFS using a mixed effect growth curve model was performed. Black participants had greater body mass index, higher blood pressure readings, and greater left ventricular mass compared with White participants (all P<0.01). Black participants had a 0.54% decrease of MFS compared with White participants. As age increased by 1 year, MFS increased by 0.05%. As left ventricular mass increased by 1 g, MFS decreased by 0.01%. As circumferential end systolic stress increased by 1 unit, MFS decreased by 0.04%. The MFS trajectories for race differed from early age to young adulthood. Conclusions Changes in myocardial function mirror the race-dependent variations in blood pressure, afterload, and cardiac mass, suggesting that myocardial function depression occurs early in childhood in populations at high cardiovascular risk such as Black participants.

Ethnic and sex differences in the longitudinal association between heart rate variability and blood pressure.

PURPOSE: Elevated blood pressure is a risk factor for increased cardiovascular morbidity and mortality. Decreased vagally-mediated heart rate variability has previously been prospectively linked with increased blood pressure; however, to date, no such prospective data exist regarding this relationship among Blacks. MATERIALS AND METHODS: We examined this association in 387 normotensive young adults (mean age, 23 years, 52% female, 54% Black) who participated in two laboratory evaluations spanning approximately six years. Blood pressure was measured at both timepoints with a non-invasive oscillometric device and heart rate variability was assessed via bio-impedance. RESULTS: In the total sample, heart rate variability significantly predicted systolic (p = .022) and diastolic (p < .001) blood pressure increases six years into the future. However, this pattern varied as a function of ethnicity and sex with the effect of heart rate variability on Time 2 systolic blood pressure only significant among White males (p = .007). Heart rate variability was also predictive of Time 2 diastolic blood pressure in White males (p = .038) as well as among both White (p = .032) and Black (p = .015) females, but was not related to blood pressure among Black males. CONCLUSION: We report for the first time significant ethnic and sex differences in the prospective relationship between heart rate variability and blood pressure change. These findings may give clues as to the underlying mechanisms that are involved in the well-known health disparities in blood pressure and hypertension-related cardiovascular diseases.

α-Adrenergic receptor blockade attenuates pressor response during mental stress in young black adults.

Black individuals exhibit increased blood pressure (BP) responses to sympathetic stimulation that are associated with an increased risk of hypertension (HTN). We tested the hypothesis that α1 -adrenergic blockade inhibits the increased BP response during and after 45-min stress in young normotensive Black adults, which may be mediated, in part, by dampened vasoconstriction and decreased renal sodium retention. Utilizing a double-masked randomized, crossover study design, 51 normotensive Black adults (31 ± 8 yr) were treated with either a placebo or 1 mg/day of prazosin for 1 week. On the final day of each treatment, hemodynamic measures and urinary sodium excretion (UNaV) were collected before (Rest), during (Stress) and after (Recovery) 45 min of mental stress induced via a competitive video game task. During the Stress period, diastolic BP and total peripheral resistance (TPR) were significantly lower with prazosin compared to placebo (p < .05 for both). Similarly, we observed lower systolic BP, diastolic BP, and TPR during the Recovery period with prazosin versus placebo (p < .05 for both). There was no effect of prazosin on stress-associated UNaV. The change in systolic BP from Rest to Recovery was positively associated with the change in TPR with both treatments (p < .05 for both). In summary, prazosin treatment dampened BP reactivity to 45-min mental stress and lowered post-stress BP over the recovery period, which was linked to reduce TPR in young normotensive Black adults. These results suggest that α1 -adrenergic receptor activity may contribute to BP responses and delayed BP recovery to prolonged mental stress through increased vasoconstriction in Black adults.

Impaired vasodilation in pregnant African Americans: Preliminary evidence of potential antecedents and consequences.

Significant health disparities exist between African Americans (AA) and European Americans (EA) in hypertension and hypertension-related disorders. Evidence suggests that this is due to impaired vasodilation in AAs. Pregnancy is a potent systemic vasodilatory state. However, differences in vasodilation between AAs and EAs have not been investigated in pregnancy. We sought to examine the effects of pregnancy on vasodilation in AA and EA women and how this might be related to discrimination and low birth weight in their offspring. Hemodynamics [blood pressure (MAP), cardiac output (CO), total peripheral resistance (TPR)] and heart rate variability (HF-HRV) were examined at baseline in 40 pregnant AAs (n = 20) and EAs (n = 20) and matched nonpregnant women (n = 40). The Experiences of Discrimination scale and birth weight were also measured in the offspring of the pregnant participants. Whereas pregnancy was associated with decreased MAP independent of race, AAs showed impaired vasodilation independent of pregnancy status as indicated by greater TPR despite greater HF-HRV. In AAs, but not EAs, reports of fewer incidences of discrimination were associated with greater TPR. Finally, the HF-HRV of EA mothers was inversely related to the birth weight of their offspring but was uncorrelated in AAs. We report novel evidence of impaired vasodilation to an endogenous vasodilatory stimulus in AAs. Higher TPR was related to discrimination in AAs and higher HF-HRV was related to low birth weight in EAs. These findings have implications for understanding the intergenerational transmission of impaired vasodilation in AAs.

High-Mobility Group Box-1 Is Associated With Obesity, Inflammation, and Subclinical Cardiovascular Risk Among Young Adults: A Longitudinal Cohort Study.

OBJECTIVE: We aimed to characterize circulating HMGB1 (high-mobility group box-1) levels, one of the better-characterized damage-associated molecular patterns, with respect to age, sex, and race in the general population, and investigate the longitudinal associations of HMGB1 with inflammatory markers, obesity, and preclinical markers of cardiovascular disease. Approach and Results: The analyses included 489 participants (50% Blacks, aged 24.6±3.3 years at the first visit) with up to 4 follow-up visits (1149 samples) over a maximum of 8.5 years. Systolic blood pressure, diastolic blood pressure, carotid-femoral pulse wave velocity, and carotid intima-media thickness together with plasma HMGB1, hs-CRP (high-sensitivity C-reactive protein), IFN-γ (interferon-γ), IL-6 (interleukin-6), IL-10 (interleukin-10), and TNF-α (tumor necrosis factor-α) were measured at each visit. At baseline, plasma HMGB1 concentrations were higher in Blacks compared with Whites (3.86 versus 3.20 ng/mL, P<0.001), and in females compared with males (3.75 versus 3.30 ng/mL, P=0.005). HMGB1 concentrations increased with age (P=0.007), and higher levels of obesity measures (P<0.001). Without adjustment for age, sex, race, and body mass index, HMGB1 concentrations were positively associated with hs-CRP, IL-6, TNF-α, systolic blood pressure, diastolic blood pressure, and carotid-femoral pulse wave velocity (P<0.05) but not IL-10, IFN-γ or carotid intima-media thickness. After covariate adjustments, the associations of HMGB1 with hs-CRP, and carotid-femoral pulse wave velocity remained statistically significant (P<0.05). CONCLUSIONS: This study demonstrates the age, sex, and race differences in circulating HMGB1. The increasing circulating concentrations of HMGB1 with age suggest a potential role of HMGB1 in the pathogenesis of chronic low-grade inflammation, obesity, and subclinical cardiovascular disease risk.

Cardiovascular Disease among Breast Cancer Survivors.

BACKGROUND: Among breast cancer survivors age > 50 years, deaths due to cardiovascular disease account for 35% of non-cancer related deaths. The increases in cardiovascular disease among breast cancer survivors is due to the cardiotoxic effects of breast cancer treatment and to overlapping risk factors for breast cancer and cardiovascular disease. METHODS: We conducted a study of a sample of 164 breast cancer patients in order to examine the frequency of cardiovascular disease. The overall objective was to examine the frequency of high blood pressure, myocardial infarction, cardiomyopathy, congestive heart failure, stroke, and venous thrombosis/thromboembolism among women who have been diagnosed with stage I-IV breast cancer and who had completed primary therapy for the disease. Data were collected by postal survey and abstraction of electronic medical records. RESULTS: A high percentage of the women (62.8%) had a reported history of high blood pressure. Fifty percent of the women had a reported history of high cholesterol. About 8.3% of the women were current smokers and 36.0% were former smokers. About 23.8% of the women had a reported history of diabetes. About 4.9% of the women had a reported history of congestive heart failure and 6.1% had a history of stroke. DISCUSSION: Additional studies are needed of cardiovascular risk factors and adverse cardiovascular events among breast cancer survivors. Of particular concern is whether patients with hypertension, hypercholesterolemia, and diabetes are receiving appropriate therapy to reduce their cardiovascular risk and prevent morbidity and mortality from adverse cardiovascular events.

Ethnic Differences in Resting Total Peripheral Resistance: A Systematic Review and Meta-Analysis.

OBJECTIVE: Decades of research suggest that there may be important ethnic differences in the hemodynamic mechanisms that co-determine arterial blood pressure, the primary diagnostic index of hypertension. In general, studies have observed that, compared with European Americans (EAs), African Americans (AAs) exhibit higher total peripheral resistance (TPR), an important summative index of peripheral vascular constriction. In contrast, EAs have been reliably shown to exhibit greater cardiac output (CO), which is directly linked to left ventricle and overall cardiac blood flow. We have previously proposed that elevated basal TPR, in particular, represents one component of the cardiovascular conundrum, characterized, paradoxically, by elevated resting heart rate variability among AAs relative to EAs. The present meta-analysis and systematic review of the literature sought to extend this previous work by establishing the magnitude of the empirically implied ethnic differences in resting TPR and CO. METHODS: A search of the literature yielded 140 abstracts on differences in TPR between AAs and EAs; 40 were included. Sample sizes, means, and standard deviations for baseline TPR with samples that included EAs and AAs were collected, and Hedges g was computed. RESULTS: Findings indicated that AAs had higher baseline TPR than did EAs (Hedges g = 0.307, SE = 0.043, confidence interval= 0.224 to 0.391, p < .001). In addition, EAs had higher resting CO than did AAs (Hedges g = -0.214, SE = 0.056, confidence interval = -0.324 to -0.104, p < .001). CONCLUSIONS: We discuss the present findings in the context of the role of elevated TPR in the deleterious effects of high blood pressure specifically for AAs.

Adenosine kinase inhibition enhances microvascular dilator function and improves left ventricle diastolic dysfunction.

OBJECTIVE: Inhibition of adenosine kinase (ADK), via augmenting endogenous adenosine levels exerts cardiovascular protection. We tested the hypothesis that ADK inhibition improves microvascular dilator and left ventricle (LV) contractile function under metabolic or hemodynamic stress. METHODS AND RESULTS: In Obese diabetic Zucker fatty/spontaneously hypertensive heart failure F1 hybrid rats, treatment with the selective ADK inhibitor, ABT-702 (1.5 mg/kg, intraperitoneal injections for 8-week) restored acetylcholine-, sodium nitroprusside-, and adenosine-induced dilations in isolated coronary arterioles, an effect that was accompanied by normalized end-diastolic pressure (in mm Hg, Lean: 3.4 ± 0.6, Obese: 17.6 ± 4.2, Obese + ABT: 6.6 ± 1.4) and LV relaxation constant, Tau (in ms, Lean: 6.9 ± 1.5, Obese: 13.9 ± 1.7, Obese + ABT: 6.0 ± 1.1). Mice with vascular endothelium selective ADK deletion (ADKVEC KO) exhibited an enhanced dilation to acetylcholine in isolated gracilis muscle (lgEC50 WT: -8.2 ± 0.1, ADKVEC KO: -8.8 ± 0.1, P < .05) and mesenteric arterioles (lgEC50 WT: -7.4 ± 0.2, ADKVEC KO: -8.1 ± 1.2, P < .05) when compared to wild-type (WT) mice, whereas relaxation of the femoral artery and aorta (lgEC50 WT: -7.03 ± 0.6, ADKVEC KO: -7.05 ± 0.8) was similar in the two groups. Wild-type mice progressively developed LV systolic and diastolic dysfunction when they underwent transverse aortic constriction surgery, whereas ADKVEC -KO mice displayed a lesser degree in decline of LV function. CONCLUSIONS: Our results indicate that ADK inhibition selectively enhances microvascular vasodilator function, whereby it improves LV perfusion and LV contractile function under metabolic and hemodynamic stress.

Cigarette smoking related DNA methylation in peripheral leukocytes and cardiovascular risk in young adults.

There is strong evidence linking changes in DNA methylation with cigarette smoking, and smoking has long been associated with cardiovascular disease; however not many studies have investigated the effects of smoking related DNA methylation changes on cardiovascular risk, especially in young adults. We explored this relationship in 480 African American and European American men and women aged 27.3 ±â€¯3.5. Out of the DNA methylation data obtained from Illumina 450 k in peripheral leukocytes, 62 CpG sites that have been associated with smoking in multiple studies were selected. Of these, 48 were significantly related to smoking within our population. These CpG sites were then used to predict 2 subclinical markers of cardiovascular health: carotid intima media thickness and left ventricular mass (LVM). There was a significant association (FDR < 0.05) between LVM and 13 of these CpG sites. We constructed a DNA methylation score using these CpG sites and found a significant association between this score and LVM (p < 0.01). Mediation test showed that 36.5% of the effect of smoking on LVM could be explained by this methylation score. Our data suggests that, in young adult populations, cigarette smoking related DNA methylation changes are already associated with changes in subclinical markers of cardiovascular health.

Exercise effects on arterial stiffness and heart health in children with excess weight: The SMART RCT.

INTRODUCTION: Childhood obesity and inactivity are associated with cardiovascular risk. Evidence is limited for exercise effects on arterial health in children. METHODS: One hundred and seventy-five inactive children with overweight or obesity (8-11 years, ≥85th percentile BMI, 61% female, 87% Black, 73% with obesity) were randomized to an 8-month daily after-school aerobic exercise program (40 min/day, n = 90) or a sedentary control condition (n = 85). Carotid-femoral pulse wave velocity (PWV, primary outcome, arterial stiffness), fitness, adiposity, blood pressure (BP), glucose, insulin resistance, lipids, and C-reactive protein were measured at baseline and posttest (8 months). Adiposity, fitness, and BP were measured again at follow-up, 8-12 months later. Intent-to-treat analyses were conducted using mixed models. RESULTS: The study had 89% retention, with attendance of 59% in exercise and 64% in the control condition, and vigorous exercise participation (average heart rate 161 ± 7 beats/min). Compared with controls, the exercise group had twice the improvement in fitness (VÈ®2 peak, 2.7 (95% CI 1.8, 3.6) vs. 1.3 (0.4, 2.3) mL/kg/min) and adiposity (-1.8 (-2.4, -1.1) vs. -0.8 (-1.5, -0.1)%), each p = 0.04, and a large improvement in HDL-cholesterol (0.13 (0.075, 0.186) vs. -0.028 (-0.083, 0.023) mmol/L, p < 0.0001). There was no group × time effect on other outcomes at 8 months, or on any outcomes at follow-up. The change in PWV at 8 months correlated with changes in insulin and insulin resistance (both r = 0.32), diastolic BP (r = 0.24), BMI (r = 0.22), and adiposity (r = 0.18). CONCLUSIONS: Eight months of aerobic exercise training improved fitness, adiposity, and HDL-cholesterol levels, but did not reduce arterial stiffness in children with excess weight. PWV improved as a function of insulin resistance, BP, BMI, and adiposity. Weight loss may be required to improve arterial stiffness. Exercise benefits waned after discontinuing the program.

Adenosine Kinase Inhibition Augments Conducted Vasodilation and Prevents Left Ventricle Diastolic Dysfunction in Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is often manifested as impaired cardiovascular reserve. We sought to determine if conducted vasodilation, which coordinates microvascular resistance longitudinally to match tissue metabolic demand, becomes compromised in HFpEF. We hypothesized that the metabolic vasodilator adenosine facilitates and that inhibition of ADK (adenosine kinase) augments conducted vasodilation for a more efficient myocardial perfusion and improved left ventricle (LV) diastolic function in HFpEF. METHODS AND RESULTS: We assessed conducted vasodilation in obese ZSF1 rats that develop LV diastolic dysfunction and is used to model human HFpEF. Additionally, conducted vasodilation was measured in arterioles isolated from the right atrial appendages of patients with HFpEF. We found a markedly reduced conducted vasodilation both in obese ZSF1 rats and in patients with HFpEF. Impaired conducted vasodilation was accompanied by increased vascular ADK expression. Isolated rat and human arterioles incubated with adenosine (10 nmol/L) or ADK inhibitor ABT-702 (0.1 µmol/L) both displayed augmented conducted vasodilation. Treatment of obese ZSF1 rats with ABT-702 (1.5 mg/kg, IP for 8 weeks) prevented LV diastolic dysfunction, and in a crossover design augmented conducted vasodilation and improved LV diastolic function. ABT-702 treated obese ZSF1 rats exhibited reduced expression of myocardial carbonic anhydrase 9 and collagen, surrogate markers of myocardial hypoxia. CONCLUSIONS: Upregulation of vascular ADK mitigates adenosine-facilitated conducted vasodilation in obese ZSF1 rats and in patients with HFpEF. We propose that pharmacological inhibition of ADK could be beneficial for therapeutic augmentation of conducted vasodilation, thereby improving tissue perfusion and LV diastolic function in HFpEF.

Angiotensin II receptor blocker attenuates stress pressor response in young adult African Americans.

African Americans (AAs) are susceptible to hypertension (HTN) and its associated organ damage leading to adverse cardiovascular (CV) outcomes. Psychological stress is proposed to contribute to the development of HTN; however, the potential role of the renin-angiotensin system (RAS) in stress-related HTN in AAs is largely unknown. In this study, we tested the hypothesis that activation of RAS is a potential contributing factor for altered CV responses to stress, and suppression of angiotensin II (Ang II) activity will improve hemodynamic responses to a prolonged mental stressor in healthy young AAs. Utilizing a double-blind, randomized, crossover study design, 132 normotensive AAs (25 ± 7 years) were treated with either a placebo (PLC) or 150 mg/d irbesartan (an Ang II type 1 receptor blocker; ARB) for 1 week. On the final day of each treatment, hemodynamic measures and urinary sodium excretion (UNaV) were collected before, during and after a 45 minute-mental stress. The magnitude of stress-induced increase in blood pressure with ARB was blunted and delayed compared to PLC. Systolic blood pressure at the end of recovery on ARB was significantly lower compared to either PLC (110 ± 13 vs 117 ± 12 mm Hg respectively; P < 0.001) or the prestress level on ARB (P = 0.02). ARB treatment reduced overall vasoconstriction and improved poststress UNaV. ARB attenuated blood pressure responses to mental stress and improved the poststress BP recovery process which were partly linked to reduced overall vasoconstriction and improved stress-induced UNaV in young adult AAs prior to the development of disease conditions. These results suggest that treatment approaches that inhibit RAS action could have significant relevance to potentially lower susceptibility to stress responses and eventually the premature development of HTN in AAs.

Ethnic Differences in Nighttime Melatonin and Nighttime Blood Pressure: A Study in European Americans and African Americans.

BACKGROUND: Ethnic differences in nighttime blood pressure (BP) have long been documented with African Americans (AAs) having higher BP than European Americans (EAs). At present, lower nighttime melatonin, a key regulator of circadian rhythms, has been associated with higher nighttime BP levels in EAs. This study sought to test the hypothesis that AAs have lower nighttime melatonin secretion compared with EAs. We also determined if this ethnic difference in melatonin could partially explain the ethnic difference in nighttime BP. METHODS: A total of 150 young adults (71 AA; 46% females; mean age: 27.7 years) enrolled in the Georgia Stress and Heart study provided an overnight urine sample for the measurement of 6-sulfatoxymelatonin, a major metabolite of melatonin. Urine melatonin excretion (UME) was calculated as the ratio between 6-sulfatoxymelatonin concentration and creatinine concentration. Twenty-four-hour ambulatory BP was assessed and nighttime systolic BP (SBP) was used as a major index of BP regulation. RESULTS: After adjustment of age, sex, body mass index, and smoking, AAs had significantly lower UME (P = 0.002) and higher nighttime SBP than EAs (P = 0.036). Lower UME was significantly associated with higher nighttime SBP and this relationship did not depend on ethnicity. The ethnicity difference in nighttime SBP was significantly attenuated after adding UME into the model (P = 0.163). CONCLUSION: This study is the first to document the ethnic difference in nighttime melatonin excretion, demonstrating that AAs have lower melatonin secretion compared with EAs. Furthermore, the ethnic difference in nighttime melatonin can partially account for the established ethnic difference in nighttime SBP.