Racial Differences in Mental Stress-Induced Transient Endothelial Dysfunction and Its Association With Cardiovascular Outcomes.

OBJECTIVE: This study aimed to investigate differences in transient endothelial dysfunction (TED) with mental stress in Black and non-Black individuals with coronary heart disease (CHD), and their potential impact on cardiovascular outcomes. METHODS: We examined 812 patients with stable CHD between June 2011 and March 2016 and followed through February 2020 at a university-affiliated hospital network. Flow-mediated vasodilation (FMD) was assessed before and 30 minutes after mental stress. TED was defined as a lower poststress FMD than prestress FMD. We compared prestress FMD, post-stress FMD, and TED between Black and non-Black participants. In both groups, we examined the association of TED with an adjudicated composite end point of cardiovascular death or nonfatal myocardial infarction (first and recurring events) after adjusting for demographic, clinical, and socioeconomic factors. RESULTS: Prestress FMD was lower in Black than non-Black participants (3.7 [2.8] versus 4.9 [3.8], p < .001) and significantly declined with mental stress in both groups. TED occurred more often in Black (76%) than non-Black patients (67%; multivariable-adjusted odds ratio = 1.6, 95% confidence interval = 1.5-1.7). Over a median (interquartile range) follow-up period of 75 (65-82) months, 142 (18%) patients experienced either cardiovascular death or nonfatal myocardial infarction. Black participants had a 41.9% higher risk of the study outcome than non-Black participants (95% confidence interval = 1.01-1.95). TED with mental stress explained 69% of this excess risk. CONCLUSIONS: Among CHD patients, Black individuals are more likely than non-Black individuals to develop endothelial dysfunction with mental stress, which in turn explains a substantial portion of their excess risk of adverse events.

Impaired Peripheral Microvascular Function and Risk of Major Adverse Cardiovascular Events in Patients With Coronary Artery Disease.

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Relation of High-sensitivity Cardiac Troponin I Elevation With Exercise to Major Adverse Cardiovascular Events in Patients With Coronary Artery Disease.

High sensitive cardiac troponin I (hs-cTnI) increases with inducible myocardial ischemia in patients with coronary artery disease (CAD). We aimed to assess if the change in hs-cTnI levels with exercise stress testing is associated with major adverse cardiac events (MACE). A cohort of 365 (age 62 ± 9 years, 77% men) patients with stable CAD underwent 99mTc sestamibi myocardial perfusion imaging with treadmill testing. Plasma hs-cTnI level was measured at rest and at 45 min after stress. Multivariable Fine & Gray's subdistribution hazards models were used to determine the association between the change in hs-cTnI and MACE, a composite end point of cardiovascular death, myocardial infarction, and unstable angina requiring revascularization. During a median follow-up of 3 years, 39 (11%) patients experienced MACE. After adjustment, for each two-fold increment in hs-cTnI with stress, there was a 2.2 (95% confidence interval 1.3-3.6)-fold increase in the hazard for MACE. Presence of both a high resting hs-cTnI level (>median) and ≥ 20% stress-induced hs-cTnI elevation was associated with the highest incidence of MACE (subdistribution hazards models 4.6, 95% confidence interval 1.6 to 13.0) compared with low levels of both. Risk discrimination statistics significantly improved after addition of resting and change in hs-cTnI levels to a model including traditional risk factors and inducible ischemia (0.67 to 0.71). Conversely, adding inducible ischemia by SPECT did not significantly improve the C-statistic from a model including traditional risk factors, baseline and change in hs-cTnI (0.70 to 0.71). In stable CAD patients, higher resting levels and elevation of hs-cTnI with exercise are predictors of adverse cardiovascular outcomes beyond traditional cardiovascular risk factors and presence of inducible ischemia.

Ethnic differences in subclinical vascular function in South Asians, Whites, and African Americans in the United States.

BACKGROUND: South Asians are a high-risk ethnic group for cardiovascular disease despite having lower levels of conventional cardiovascular risk factors such as obesity and smoking. Ethnic differences in pulse wave reflections, arterial stiffness, and subclinical atherosclerosis as measured using augmentation index (AIX), pulse wave velocity (PWV), and carotid intima-media thickness (CIMT) may reflect some of this excess risk. METHODS: We conducted a cross-sectional analysis of pooled data from three community-based sources in Atlanta, Georgia, USA. Data on 530 South Asians collected from local health fairs was compared with data on 507 White and 192 African Americans from the Emory Predictive Health Initiative and 351 White and 382 African Americans from the Morehouse and Emory Team up to Eliminate Health Disparities Study. RESULTS: Linear regression models adjusted for age, sex, smoking, MAP, fasting glucose, TC, HDL-C, creatinine, and body mass index were used to assess the relationship between ethnicity and vascular function measures. In fully adjusted models, South Asians had higher heart rate corrected AIX as compared with Whites and African Americans (by 5.47%, p < 0.01 and 3.50%, p < 0.01; respectively), but lower PWV (by 0.51 m/s, p < 0.01 and 0.72 m/s, p < 0.01; respectively) and lower CIMT (by 0.02 mm p = 0.03 and 0.04 mm p < 0.01; respectively). CONCLUSIONS: Systemic pulse wave reflections, independent of other risk factors, are higher in South Asians as compared with Whites and African Americans. Future research is needed to determine whether higher AIX explains the increased cardiovascular risk among South Asians.

Race and Gender Differences in the Association Between Experiences of Everyday Discrimination and Arterial Stiffness Among Patients With Coronary Heart Disease.

BACKGROUND: Self-reported experiences of discrimination have been linked to indices of cardiovascular disease. However, most studies have focused on healthy populations. Thus, we examined the association between experiences of everyday discrimination and arterial stiffness among patients with a history of myocardial infarction (MI). PURPOSE: We hypothesized that higher reports of discrimination would be associated with greater arterial stiffness and that associations would be more pronounced among Black women, in particular, relative to other race-gender groups, using an "intersectionality" perspective. METHODS: Data were from 313 participants (49.2% female, mean age: 50.8 years) who were 6 months post-MI in the Myocardial Infarction and Mental Stress 2 study. Data were collected via self-reported questionnaires, medical chart review, and a clinic visit during which arterial stiffness was measured noninvasively using pulse wave velocity. RESULTS: Reports of discrimination were highest in Black men and women and arterial stiffness was greatest in Black and White women. After adjustment for demographics and relevant clinical variables, discrimination was not associated with arterial stiffness in the overall study sample. However, discrimination was associated with increased arterial stiffness among Black women but not White women, White men, or Black men. CONCLUSIONS: Despite no apparent association between discrimination and arterial stiffness in the overall study sample, further stratification revealed an association among Black women but not other race-gender groups. These data not only support the utility of an intersectionality lens but also suggest the importance of implementing psychosocial interventions and coping strategies focused on discrimination into the care of clinically ill Black women.

Association of Transient Endothelial Dysfunction Induced by Mental Stress With Major Adverse Cardiovascular Events in Men and Women With Coronary Artery Disease.

Importance: Acute mental stress can result in transient endothelial dysfunction, but the prognostic relevance of this phenomenon is unknown. Objective: To determine the association between mental stress-induced impairment in endothelium-dependent relaxation as assessed by brachial artery flow-mediated vasodilation and adverse cardiovascular outcomes among individuals with stable coronary artery disease. Design, Setting, and Participants: This cohort study was conducted at a university-affiliated hospital network between June 2011 and August 2014. A cohort of individuals with stable coronary artery disease were included. Data analysis took place from November 2018 to May 2019. Exposures: Study participants were subjected to a laboratory mental stress task (public speaking). Main Outcomes and Measures: Flow-mediated vasodilation was measured before and 30 minutes after a public-speaking mental stress task. We examined the association of the rest (prestress), poststress, and δ flow-mediated vasodilation (poststress minus prestress levels) with an adjudicated composite end point of adverse events, including cardiovascular death, myocardial infarction, unstable angina leading to revascularization, and heart failure hospitalization, after adjusting for sociodemographic factors, medical history, and depression. Results: A total of 569 patients were included (mean [SD] age, 62.6 [9.3] years; 420 men [73.8%]). Flow-mediated vasodilation decreased from a mean (SD) of 4.8% (3.7%) before mental stress to 3.9% (3.6%) after mental stress (a 23% reduction; P < .001), and 360 participants (63.3%) developed transient endothelial dysfunction (a decrease in flow-mediated vasodilation). During a median (interquartile range) follow-up period of 3.0 (2.9-3.1) years, 74 patients experienced a major adverse cardiovascular event. The presence of transient endothelial dysfunction with mental stress was associated with a 78% increase (subdistribution hazard ratio [sHR], 1.78 [95% CI, 1.15-2.76]) in the incidence of major adverse cardiovascular event. Both the δ flow-mediated vasodilation (sHR, 1.15 [95% CI, 1.03-1.27] for each 1% decline) and poststress flow-mediated vasodilation (sHR, 1.14 [95% CI, 1.04-1.24] for each 1% decline) were associated with major adverse cardiovascular event. Risk discrimination statistics demonstrated a significant model improvement after addition of either poststress flow-mediated vasodilation (change in the area under the curve, 0.05 [95% CI, 0.01-0.09]) or prestress plus δ flow-mediated vasodilation (change in the area under the curve, 0.04 [95% CI, 0.00-0.08]) compared with conventional risk factors. Conclusions and Relevance: In this study, transient endothelial dysfunction with mental stress was associated with adverse cardiovascular outcomes in patients with coronary artery disease. Endothelial responses to stress represent a possible mechanism through which psychological stress may affect outcomes in patients with coronary artery disease.

Hemodynamic, catecholamine, vasomotor and vascular responses: Determinants of myocardial ischemia during mental stress.

AIMS: Mental stress-induced myocardial ischemia (MSIMI) in patients with coronary artery disease (CAD) is associated with adverse cardiovascular outcomes. We aim to assess hemodynamic, neuro-hormonal, endothelial, vasomotor and vascular predictors of MSIMI. METHODS AND RESULTS: We subjected 660 patients with stable CAD to 99mTc sestamibi myocardial perfusion imaging at rest, with mental (speech task) and with conventional (exercise/pharmacological) stress. Endothelium-dependent flow-mediated dilation (FMD), microvascular reactivity [reactive hyperemia index (RHI)] and arterial stiffness [pulse wave velocity (PWV)] were measured at rest and 30-min after mental stress. The digital microvascular vasomotor response during mental stress was assessed using peripheral arterial tonometry (PAT). A total of 106(16.1%) patients had MSIMI. Mental stress was accompanied by significant increases in rate-pressure-product (heart rate x systolic blood pressure; RPP), epinephrine levels and PWV, and significant decreases in FMD and PAT ratio denoting microvascular constriction. In comparison to those with no MSIMI, patients with MSIMI had higher hemodynamic and digital vasoconstrictive responses (p<0.05 for both), but did not differ in epinephrine, endothelial or macrovascular responses. Only presence of ischemia during conventional stress (OR of 7.1, 95%CI of 4.2, 11.9), high hemodynamic response (OR for RPP response≥vs

Endothelial Dysfunction is Associated with Occult Coronary Artery Disease Detected by Positron Emission Tomography.

OBJECTIVE: Silent myocardial ischemia is common in asymptomatic subjects without a prior history of coronary artery disease (CAD) and is associated with increased morbidity and mortality. Our objective was to determine whether endothelial dysfunction is associated with silent myocardial ischemia and whether the association is independent of genetic and familial factors. MATERIAL AND METHODS: We examined 416 male monozygotic and dizygotic twins aged 47 to 63 years, free of symptomatic CAD. Subclinical ischemia was diagnosed by [13N] ammonia positron emission tomography at rest and after adenosine stress. Endothelial function was measured by flow-mediated dilation (FMD) of the brachial artery. Generalized estimating equations were used for analysis. RESULTS: Fixed perfusion defects were found in 24 (6%) twins and reversible perfusion defects in 90 (22%) twins, indicating subclinical ischemia. There was an inverse correlation between FMD and the reversible perfusion defect score (r = - 0.14, p=0.01) but not the fixed defect score (r= -0.017, p=0.73). From the lowest to the highest quartile of FMD, the prevalence of reversible defects decreased 28% to 14%, p=0.008. In multivariable analysis, reversible defects were significantly associated with each quartile of decreasing FMD (OR =1.3; 95% 1.1, 2.5). In 54 twin pairs discordant for endothelial dysfunction (FMD ≤ 7% dilation from baseline), twins with endothelial dysfunction had 9% higher likelihood of having perfusion defects than their co-twins without endothelial dysfunction (p=0.041). CONCLUSIONS: Endothelial dysfunction is independently associated with silent ischemia and this association is not confounded by genetic or other shared familial factors.

The differential effect of statins on oxidative stress and endothelial function: atorvastatin versus pravastatin.

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

Vitamin D status is associated with arterial stiffness and vascular dysfunction in healthy humans.

OBJECTIVES: The primary objective of this study was to elucidate mechanisms underlying the link between vitamin D status and cardiovascular disease by exploring the relationship between 25-hydroxyvitamin D (25-OH D), an established marker of vitamin D status, and vascular function in healthy adults. BACKGROUND: Mechanisms underlying vitamin D deficiency-mediated increased risk of cardiovascular disease remain unknown. Vitamin D influences endothelial and smooth muscle cell function, mediates inflammation, and modulates the renin-angiotensin-aldosterone axis. We investigated the relationship between vitamin D status and vascular function in humans, with the hypothesis that vitamin D insufficiency will be associated with increased arterial stiffness and abnormal vascular function. METHODS: We measured serum 25-OH D in 554 subjects. Endothelial function was assessed as brachial artery flow-mediated dilation, and microvascular function was assessed as digital reactive hyperemia index. Carotid-femoral pulse wave velocity and radial tonometry-derived central augmentation index and subendocardial viability ratio were measured to assess arterial stiffness. RESULTS: Mean 25-OH D was 31.8 ± 14 ng/ml. After adjustment for age, sex, race, body mass index, total cholesterol, low-density lipoprotein, triglycerides, C-reactive protein, and medication use, 25-OH D remained independently associated with flow-mediated vasodilation (ß = 0.1, p = 0.03), reactive hyperemia index (ß = 0.23, p < 0.001), pulse wave velocity (ß = -0.09, p = 0.04), augmentation index (ß = -0.11, p = 0.03), and subendocardial viability ratio (ß = 0.18, p = 0.001). In 42 subjects with vitamin D insufficiency, normalization of 25-OH D at 6 months was associated with increases in reactive hyperemia index (0.38 ± 0.14, p = 0.009) and subendocardial viability ratio (7.7 ± 3.1, p = 0.04), and a decrease in mean arterial pressure (4.6 ± 2.3 mm Hg, p = 0.02). CONCLUSIONS: Vitamin D insufficiency is associated with increased arterial stiffness and endothelial dysfunction in the conductance and resistance blood vessels in humans, irrespective of traditional risk burden. Our findings provide impetus for larger trials to assess the effects of vitamin D therapy in cardiovascular disease.