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The field of coronary plaque analysis is advancing including more quantitative analysis of coronary artery diseases such as plaque burden, high-risk plaque features, computed tomography-derived fractional flow reserve, and radiomics. Although these biomarkers have shown great promise for the diagnosis and prognosis of cardiac patients in a research setting, many of these advanced analyses are labour and time intensive and therefore hard to implement in daily clinical practice. Artificial intelligence (AI) is playing an increasing role in supporting the quantification of these new biomarkers. AI offers the opportunity to increase efficiency, reduce human error and reader variability and to increase the accuracy of diagnosis and prognosis by automating many processing and supporting clinicians in their decision-making. With the use of AI these novel analysis approaches for coronary artery disease can be made feasible for clinical practice without increasing cost and workload and potentially improve patient care.

Endothelin-1 A receptors (ETARs) have been shown to reduce endothelial function independently and through increased production of superoxide. We show that independent ETAR inhibition increases microvascular endothelial function in non-Hispanic Black young adults. However, administration of a superoxide dismutase mimetic alone and in combination with ETAR inhibition had no effect on microvascular endothelial function suggesting that, in the cutaneous microvasculature, the negative effects of ETAR in non-Hispanic Black young adults are independent of superoxide production.

biBackground:/i/bPsychological stress disorders are twice as prevalent in women with ischemic heart disease compared to men. The disproportionate psychological health experience of these women is not well understood. The objective of this study was to examine whether neighborhood social factors are associated with disparities in psychological health by gender.biMaterials and Methods:/i/bWe studied 286 patients with heart disease recruited from Emory-based hospitals in the Myocardial Infarction and Mental Stress 2 Study (in/i = 286). A global measure of psychological distress was calculated by taking an average of ranks across symptom scales for depression, post-traumatic stress disorder, anxiety, anger, and perceived stress. The social vulnerability index (SVI) was developed by the Centers for Disease Control and Prevention and was used to rank patients' census tracks on 14 social factors. Beta coefficients for mean ranks in psychological distress scores were estimated per 10-unit increase in SVI percentile ranking using multilevel regression models.biResults:/i/bThe mean age of the sample was 51 years, 49% were women, and 66% African American. After adjusting for demographics, cardiovascular risk factors, and antidepressant use, each 10-unit increase in SVI percentile ranking was associated with 4.65 (95% CI: 0.61-8.69;ip/i = 0.02) unit increase in mean scores for psychological distress among women only (SVI-by-gender-interaction = 0.01). These associations were driven by the SVI themes of lower socioeconomic status and poorer access to housing and transportation.biConclusion:/i/bNeighborhood social vulnerability may be a psychosocial stressor that potentiates women's susceptibility to adverse psychological and cardiovascular health.

Metabolomics identifies molecular products produced in response to numerous stimuli, including both adaptive (includes exercise training) and disease processes. We analyzed a longitudinal cohort of American-style football (ASF) athletes, who reliably acquire maladaptive cardiovascular (CV) phenotypes during competitive training, with high-resolution metabolomics to determine whether metabolomics can discriminate exercise-induced CV adaptations from early CV pathology.Matched discovery ( n = 42) and validation ( n = 40) multicenter cohorts of collegiate freshman ASF athletes were studied with longitudinal echocardiography, applanation tonometry, and high-resolution metabolomics. Liquid chromatography-mass spectrometry identified metabolites that changed ( P0.05, false discovery rate0.2) over the season. Metabolites demonstrating similar changes in both cohorts were further analyzed in linear and mixed-effects models to identify those associated with left ventricular mass, tissue-Doppler myocardial E ' velocity (diastolic function), and arterial function (pulse wave velocity).In both cohorts, 20 common metabolites changed similarly across the season. Metabolites reflective of favorable CV health included an increase in arginine and decreases in hypoxanthine and saturated fatty acids (heptadecanoate, arachidic acid, stearate, and hydroxydecanoate). In contrast, metabolic perturbations of increased lysine and pipecolate, reflective of adverse CV health, were also observed. Adjusting for player position, race, height, and changes in systolic blood pressure, weight, and pulse wave velocity, increased lysine ( β = 0.018, P = 0.02) and pipecolate ( β = 0.018, P = 0.02) were associated with increased left ventricular mass index. In addition, increased lysine ( β = -0.049, P = 0.01) and pipecolate ( β = -0.052, P = 0.008) were also associated with lower E ' (reduced diastolic function).ASF athletes seem to develop metabolomic changes reflective of both favorable CV health and early CV maladaptive phenotypes. Whether metabolomics can discriminate early pathologic CV transformations among athletes is a warranted future research direction.

Background: Microvascular measures of vascular dysfunction during acute mental stress may be important determinants of major adverse cardiovascular events (MACE), especially among younger and middle-aged women survivors of an acute myocardial infarction. Methods: In the MIMS2 study (Myocardial Infarction and Mental Stress 2), individuals who had been hospitalized for a myocardial infarction in the past 8 months were prospectively followed for 5 years. MACE was defined as a composite index of cardiovascular death and first/recurring events for nonfatal myocardial infarction and hospitalizations for heart failure. Reactive hyperemia index and flow-mediated dilation were used to measure microvascular and endothelial function, respectively, before and 30 minutes after a public-speaking mental stress task. Survival models for recurrent events were used to examine the association between vascular response to stress (difference between poststress and resting values) and MACE. Reactive hyperemia index and flow-mediated dilation were standardized in analyses. Results: Of 263 patients (the mean age was 51 years; range, 25–61), 48% were women, and 65% were Black. During a median follow-up of 4.3 years, 64 patients had 141 adverse cardiovascular events (first and repeated). Worse microvascular response to stress (for each SD decrease in the reactive hyperemia index) was associated with 50% greater risk of MACE (hazard ratio, 1.50 [95% CI, 1.05–2.13]; P =0.03) among women only (sex interaction: P =0.03). Worse transient endothelial dysfunction in response to stress (for each SD decrease in flow-mediated dilation) was associated with a 35% greater risk of MACE (hazard ratio, 1.35 [95% CI, 1.07–1.71]; P =0.01), and the association was similar in women and men. Conclusions: Peripheral microvascular dysfunction with mental stress was associated with adverse events among women but not men. In contrast, endothelial dysfunction was similarly related to MACE among both men and women. These results suggest a female-specific mechanism linking psychological stress to adverse outcomes.

Introduction: Microvascular dysfunction during acute mental stress may be an important determinant of major adverse cardiovascular outcomes (MACE) especially among middle-aged women survivors of an acute myocardial infarction (MI). Hypothesis: There are sex differences in the association between microvascular dysfunction and MACE. Methods: The Myocardial Infarction and Mental Stress Study 2 enrolled individuals who had been hospitalized for an MI in the past 8 months at the age of 60 years or younger, with an oversampling of women. Reactive hyperemia index (RHI) was used to measure digital microvascular function before and 30 minutes after a public-speaking mental stress task. This assessment was contrasted with macrovascular endothelial function at the brachial artery through flow-mediated dilation (FMD). Participants were followed for 5-years, and MACE was defined as a composite of cardiovascular death, first/recurring events for nonfatal MI, and hospitalizations for heart failure. Cox proportional hazards models were used to examine vascular response to stress (difference between post-stress and resting values) and MACE adjusting for demographics, clinical risk factors, medications, psychological factors, and mental stress ischemia. Lower RHI and FMD values are indicative of greater microvascular and endothelial dysfunction, respectively. Results: Of 263 participants, the mean age was 51 years and 48% were women. There were 64 patients with 141 adverse cardiovascular events (first and repeated). In the overall sample, there was no significant association between microvascular response to stress and MACE, but there was a significant interaction with sex (p = 0.03). Each standard deviation decrease in RHI response to stress was associated with 50% greater risk of MACE (HR: 1.50, 95% CI: 1.05, 2.13) among women only, while no association was observed in men (HR 0.93, 95% CI: 0.69, 1.26). Transient endothelial dysfunction in response to stress (for each standard deviation decrease in FMD) was associated with 35% greater risk of MACE (HR: 1.35; 95% CI: 1.07, 1.71), and was similar in women and men. Conclusions: Peripheral microvascular dysfunction with mental stress is associated with MACE among women but not among men. In contrast, brachial artery endothelial dysfunction is similarly related to MACE among both men and women. These results suggest that microvascular dysfunction is a female-specific mechanism linking psychological stress to adverse outcomes.

Introduction: Current guidelines recommend ≥2 servings of fish/week for the prevention of atherosclerotic cardiovascular disease (ASCVD). However, a recent large meta-analysis suggested that the benefit may exist only for persons with a prior ASCVD event. Whether coronary artery calcium (CAC) can help to identify individuals who are likely to benefit from habitual fish consumption is unknown. Hypothesis: CAC will stratify persons who may and may not benefit from habitual fish consumption. Methods: There were 4977 participants in the Multi-Ethnic Study of Atherosclerosis who reported their frequency of fish intake and underwent CAC scanning at Visit 1. Adjusted Cox proportional hazards regression models stratified by the presence/absence of CAC assessed the association between fish intake and incident ASCVD over a median follow-up of 15.7 years. Results: The mean age was 61 years old, 53% were women, 26% were Black, and 49% of participants had prevalent CAC. A similar proportion of individuals reported consuming ≥2 servings of fish/week for those with CAC=0 and CAC >0 (35% versus 33%, p=0.12). The absolute ASCVD event rate for those with 0 (Figure 1). Each additional serving of fish/week was associated with a 9% lower risk of ASCVD for participants with CAC=0 (HR=0.91, 95% CI: 0.83-0.99) whereas there was no significant association for persons with CAC >0 (HR=1.03, 95% CI: 0.99-1.07). Conclusions: A higher amount of fish consumption was associated with a lower risk of incident ASCVD for participants with CAC=0, but not those with CAC >0, although the absolute ASCVD event rate was low for persons with CAC=0 regardless of fish consumption frequency.

Introduction: Poor quality neighborhood environments are independent risk factors for cardiovascular disease (CVD) but are understudied in Black adults, who face large CVD health disparities. Arterial stiffness, a marker of early vascular aging, precedes development of hypertension and adverse CVD events but the effect of neighborhood on arterial stiffness among Black adults remains unknown. Objective: We compared the association between neighborhood environment and arterial stiffness among Black adults in Jackson, MS and Atlanta, GA. Methods: We studied 1582 Black adults (mean age 53 ± 10, 35% male) living in Jackson, MS from the Jackson Heart Study (JHS) and 451 Black adults (mean age 53 ± 10, 39% male) living in Atlanta, GA from the Morehouse-Emory Cardiovascular Center for Health Equity (MECA) study, without known CVD. Neighborhood problems (includes measures of aesthetic quality, walking environment, food access), social cohesion (includes activity with neighbors), and violence/safety were assessed using validated questionnaires. Arterial stiffness was measured as pulse wave velocity (PWV) using magnetic resonance imaging in JHS and as PWV and augmentation index (AIx) using applanation tonometry (SphygmoCor, Inc.) in MECA. Multivariable linear regression models were used to examine the association between neighborhood characteristics and arterial stiffness, adjusting for potential confounders. Results: Improved social characteristics, measured as social cohesion in JHS (β = −0.32 [−0.63, −0.02], p = 0.04) and activity with neighbors (β = −0.23 [−0.40, −0.05], p = 0.01) in MECA, were associated with lower PWV in both cohorts and lower AIx (β = −1.74 [−2.92, − 0.56], p = 0.004) in MECA, after adjustment for CVD risk factors and income. Additionally, in MECA, better food access (β = −1.18 [−2.35, − 0.01], p = 0.05) was associated with lower AIx and, in JHS, lower neighborhood problems (β = −0.33 [−0.64, − 0.02], p = 0.04) and lower violence (β = −0.30 [−0.61, 0.002], p = 0.05) were associated with lower PWV. Conclusion: Neighborhood social characteristics show an independent association with the vascular health of Black adults, findings that were reproducible in two distinct American cities.

Objective: Circulating progenitor cells possess immune modulatory properties and might mitigate inflammation that is characteristic of patients with coronary artery disease. We hypothesized that patients with fewer circulating progenitor cells (CPCs) will have higher inflammatory markers and worse outcomes. Approach and Results: Patients with stable coronary artery disease were enrolled in a prospective study enumerating CPCs as CD (cluster of differentiation)-34–expressing mononuclear cells (CD34+) and inflammation as levels of IL (interleukin)-6 and high-sensitivity CRP (C-reactive protein) levels. Patients were followed for 5 years for the end points of death and myocardial infarction with repeat inflammatory biomarkers measured after a median of 2 years. In the entire cohort of 392 patients, IL-6 and high-sensitivity CRP levels remained unchanged (0.3±2.4 pg/mL and 0.1±1.0 mg/L; P =0.45) after 2 years. CPC counts (log-transformed) were inversely correlated with the change in IL-6 levels (r, −0.17; P Conclusions: Reduced cardiovascular regenerative capacity is independently associated with progressive inflammation in patients with coronary artery disease that in turn is associated with poor outcomes. Graphic Abstract: A graphic abstract is available for this article.

Arterial stiffness is a precursor for the development of hypertension and premature cardiovascular disease (CVD). Physical activity has been associated with lower arterial stiffness among largely White populations, but the types of activity required and whether these findings apply to Black adults remain unknown. We examined whether physical activity levels were associated with arterial stiffness among Black adults in two independent cohorts. In the Morehouse-Emory Cardiovascular (MECA) Center for Health Equity, 378 Black adults (age 52.8 ± 10.3, 39.7% male) without known CVD living in Atlanta, GA were recruited. Arterial stiffness was measured as pulse wave velocity (PWV). Total and domain-specific physical activity were assessed by self-report. Multiple linear regression models were used to investigate differences across physical activity levels after adjusting for age, sex, CVD risk factors, and socioeconomic status. Findings were validated in an independent cohort of Black adults ( n = 55, age 50.4 ± 9.2, 23.6% male). After adjustment for covariates, lower arterial stiffness was associated with higher self-reported levels of sport/exercise (6.92 ± 1.13 vs 7.75 ± 1.14, p < 0.001, highest vs lowest quartile) and home/life activities (7.34 ± 1.24 vs 7.73 ± 1.07, p = 0.04, highest vs lowest quartile), but not work, active living, or the overall physical activity scores. These findings were replicated in the independent cohort where higher levels of sport/exercise remained associated with lower arterial stiffness (6.66 ± 0.57 vs 8.21 ± 0.66, p < 0.001, highest vs lowest quartile). Higher levels of sport/exercise and home/life-related physical activities (in comparison to occupational physical activity) are associated with lower arterial stiffness in Black adults.

Background: To investigate the cross-sectional and longitudinal relationships between vascular function and circulating progenitor cell (CPC) counts with respect to aging and exposure to risk factors. Methods: In 797 adult participants, CPCs were enumerated by flow cytometry as CD45med mononuclear cells expressing CD34 epitope and its subsets co-expressing CD133, and chemokine C-X-C motif receptor 4 (CXCR4+). Arterial stiffness was evaluated by tonometry-derived pulse wave velocity (PWV) and microvascular function was assessed as digital reactive hyperemia index (RHI). Results: In cross-sectional analyses, for every doubling in CD34+ cell counts, PWV was 15% higher and RHI was 9% lower, after adjusting for baseline characteristics and risk factors ( p for all < 0.01). There were significant CPC-by-age-by-risk factor interactions ( p Conclusion: A higher CPC count in the presence of risk factors is associated with better vascular function among younger individuals. There is no increase in CPC count with risk factors in older individuals who have worse vascular function. Moreover, a higher CPC count is associated with less vascular dysfunction with aging.

ObjectivesAmerican-style football (ASF) athletes are at risk for the development of concentric left ventricular hypertrophy (C-LVH), an established cardiovascular risk factor in the general population. We sought to address whether black race is associated with acquired C-LVH in collegiate ASF athletes.MethodsCollegiate ASF athletes from two National Collegiate Athletic Association Division-I programmes were recruited as freshmen between 2014 and 2019 and analysed over 3 years. Demographics (neighbourhood family income) and repeated clinical characteristics and echocardiography were recorded longitudinally at multiple timepoints. A mixed-modelling approach was performed to evaluate acquired C-LVH in black versus white athletes controlling for playing position (linemen (LM) and non-linemen (NLM)), family income, body weight and blood pressure.ResultsAt baseline, black athletes (N=124) were more often NLM (72% vs 54%, p=0.005) and had lower median neighbourhood family income ($54 119 vs $63 146, p=0.006) compared with white athletes (N=125). While both black and white LM demonstrated similar increases in C-LVH over time, among NLM acquired C-LVH was more common in black versus white athletes (postseason year-1: N=14/89 (16%) vs N=2/68 (3%); postseason year-2: N=9/50 (18%) vs N=2/32 (6%); postseason year-3: N=8/33 (24%) vs N=1/13 (8%), p=0.005 change over time). In stratified models, black race was associated with acquired C-LVH in NLM (OR: 3.70, 95% CI 1.12 to 12.21, p=0.03) and LM was associated with acquired C-LVH in white athletes (OR: 3.40, 95% CI 1.03 to 11.27, p=0.048).ConclusionsIndependent of family income and changes in weight and blood pressure, black race was associated with acquired C-LVH among collegiate ASF NLM and LM was associated with acquired C-LVH in white athletes.

The influence of psychological stress on the physiology of the cardiovascular system, and on the etiology and outcomes of cardiovascular disease (CVD) has been the object of intense investigation. As a whole, current knowledge points to a “brain-heart axis” that is especially important in individuals with pre-existing CVD. The use of acute psychological stress provocation in the laboratory has been useful to clarify the effects of psychological stress on cardiovascular physiology, immune function, vascular reactivity, myocardial ischemia, neurobiology and cardiovascular outcomes. An emerging paradigm is that dynamic perturbations of physiological and molecular pathways during stress or negative emotions are important in influencing cardiovascular outcomes, and that some patient subgroups, such as women, patients with an early-onset myocardial infarction, and patients with adverse psychosocial exposures, may be at especially high risk for these effects. This review summarizes recent knowledge on mind-body connections in CVD among cardiac patients and highlights important pathways of risk which could become the object of future intervention efforts. As a whole, this research suggests that an integrated study of mind and body is necessary to fully understand the determinants and consequences of CVD.

Objective Mental stress-induced myocardial ischemia (MSIMI), a transient myocardial ischemic response to mental stress, is associated with poorer outcomes among patients with coronary heart disease and is more likely to occur among women. However, predictors of MSIMI are not well explored. The current study investigated the association between experiences of everyday discrimination and MSIMI among patients with recent myocardial ischemia and contrasted the results with conventional stress-induced myocardial ischemia (CSIMI). We examined sex differences in associations. Methods We studied 295 post-MI patients (145 women, 150 men). Provocation of myocardial ischemia with mental stress (speech task) and conventional stress (exercise or pharmacologic) was assessed by myocardial perfusion imaging. Frequency of exposure to everyday discrimination was assessed via questionnaire using the Everyday Discrimination Scale (EDS). Results The mean age was 51 years in both women and men, and the EDS score ranged from 10 to 38 (mean [standard deviation] = 17 [6] years). After multivariable analysis, each standard deviation increase in the EDS score (more frequent exposure) was associated with an increased odds of MSIMI (odds ratio [OR] = 1.57 [1.10-2.23]). The EDS score was not associated with CSIMI (OR = 0.86 [0.64-1.17]). Women demonstrated a twofold increase (OR = 1.96 [1.13-3.38], p = .02) in the adjusted odds of MSIMI, with each standard deviation increase in the EDS score compared with a 1.4-fold increase (OR = 1.40 [0.80-2.44], p = .24) among men; however, interaction was not statistically significant. Conclusions Among post-MI patients, everyday discrimination was positively associated with occurrence of MSIMI, but not with CSIMI; associations were more pronounced among women.

Previous studies have shown reduced cardiovascular risk with increasing high-density lipoprotein cholesterol (HDL-C) levels. However, recent data in the general population have shown increased risk of adverse outcomes at very high concentrations of HDL-C. Thus, we aimed to study the gender-specific relation between very high HDL-C levels (80,100 mg/100 ml) and adverse cardiovascular outcomes and the genetic basis in the general population enrolled in the United Kingdom Biobank. A total of 415,416 participants enrolled in the United Kingdom Biobank without coronary artery disease were included in this prospective cohort study, with a median follow-up of 9 years. A high HDL-C level80 mg/100 ml was associated with increased risk of all-cause death (Hazard ratio [HR] 1.11, confidence interval [CI] 1.03 to 1.20, p = 0.005) and cardiovascular death (HR 1.24, CI 1.05 to 1.46, p = 0.01) after adjustment for age, gender, race, body mass index, hypertension, smoking, triglycerides, LDL-C, stroke history, heart attack history, diabetes, eGFR, and frequent alcohol use (defined as ≥3 times/week) using Cox proportional hazard and Fine and Gray's subdistribution hazard models, respectively. In gender-stratified analyses, such associations were only observed in men (all-cause death HR 1.79, CI 1.59 to 2.02, p0.0001; cardiovascular death HR 1.92, CI 1.52 to 2.42, p0.0001), but not in women (all-cause death HR 0.97, CI 0.88 to 1.06, p = 0.50; cardiovascular death HR 1.04, CI 0.83 to 1.31, p = 0.70). The findings persisted after adjusting for the genetic risk score comprised of known HDL-C-associated single nucleotide polymorphisms. Very high HDL-C levels are associated with an increased risk of all-cause death and cardiovascular death among men but not in women in the general population free of coronary artery disease.

Background: Increased arterial stiffness is associated with adverse cardiovascular outcomes. We studied the sex-specific impact of angiotensin antagonists on vascular function in hypertension with the hypothesis that their effects on arterial stiffness may be variable in men and women. Methods: In 141 hypertensive participants with mild cognitive impairment (age 65.9±7.7, 57% female), candesartan (up to 32 mg, n=77) or lisinopril (up to 40 mg, n=64) were administered to achieve blood pressure Results: Blood pressure reduction was similar among candesartan and lisinopril groups. Compared with candesartan, lisinopril therapy resulted in lower pulse wave velocity (0.5±0.8 versus −0.7±0.4 m/s, respectively; P =0.003) and central pulse pressure (−1±3 versus −7±4 mm Hg; P =0.03) after 1 year. There was a significant interaction by sex whereby the improvements in pulse wave velocity and central pulse pressure with lisinopril compared with candesartan were only observed in women. In contrast, there was greater improvement in augmentation index with candesartan compared with lisinopril (−4±7% versus −1.5±8%; P =0.05), with no sex differences. Conclusions: Despite equipotent antihypertensive effects, lisinopril was more effective than candesartan at lowering arterial stiffness in women. In contrast, candesartan was more effective than lisinopril in improving pulse wave reflections in both sexes. These findings demonstrate differential sex-specific effects of renin-angiotensin system antagonists on arterial function in hypertension that may contribute to long-term cardiovascular and neurocognitive outcomes in this population.

Background: The COVID-19 pandemic has disproportionately affected low-income and racial/ethnic minority populations in the United States. However, it is unknown whether hospitalized patients with COVID-19 from socially vulnerable communities experience higher rates of death and/or major adverse cardiovascular events (MACEs). Thus, we evaluated the association between county-level social vulnerability and in-hospital mortality and MACE in a national cohort of hospitalized COVID-19 patients. Methods: Our study population included patients with COVID-19 in the American Heart Association COVID-19 Cardiovascular Disease Registry across 107 US hospitals between January 14, 2020 to November 30, 2020. The Social Vulnerability Index (SVI), a composite measure of community vulnerability developed by Centers for Disease Control and Prevention, was used to classify the county-level social vulnerability of patients’ place of residence. We fit a hierarchical logistic regression model with hospital-level random intercepts to evaluate the association of SVI with in-hospital mortality and MACE. Results: Among 16 939 hospitalized COVID-19 patients in the registry, 5065 (29.9%) resided in the most vulnerable communities (highest national quartile of SVI). Compared with those in the lowest quartile of SVI, patients in the highest quartile were younger (age 60.2 versus 62.3 years) and more likely to be Black adults (36.7% versus 12.2%) and Medicaid-insured (31.1% versus 23.0%). After adjustment for demographics (age, sex, race/ethnicity) and insurance status, the highest quartile of SVI (compared with the lowest) was associated with higher likelihood of in-hospital mortality (OR, 1.25 [1.03–1.53]; P =0.03) and MACE (OR, 1.26 [95% CI, 1.05–1.50]; P =0.01). These findings were not attenuated after accounting for clinical comorbidities and acuity of illness on admission. Conclusions: Patients hospitalized with COVID-19 residing in more socially vulnerable communities experienced higher rates of in-hospital mortality and MACE, independent of race, ethnicity, and several clinical factors. Clinical and health system strategies are needed to improve health outcomes for socially vulnerable patients.

BackgroundApolipoprotein A1 (ApoA1) is the principal protein component of high-density lipoprotein (HDL). Although low HDL cholesterol (HDL-C) levels are known to be associated with greater cardiovascular risk, recent studies have also shown heightened mortality risk at very high HDL-C levels.AimsTo investigate the sex-specific association between elevated ApoA1 levels and adverse outcomes, and their genetic basis.MethodsA prospective cohort study of United Kingdom Biobank participants without coronary artery disease at enrollment was performed. The primary exposure was serum ApoA1 levels. The primary and secondary outcome measures were cardiovascular and all-cause death, respectively.ResultsIn 402 783 participants followed for a median of 12.1 years, there was a U-shaped relationship between ApoA1 levels and both cardiovascular as well as all-cause mortality, after adjustment for traditional cardiovascular risk factors. Individuals in the highest decile of ApoA1 levels (1.91–2.50 g/L) demonstrated higher cardiovascular (HR 1.21, 95% CI 1.07–1.37, P < 0.0022) and all-cause mortality (HR 1.14, 95% CI 1.07–1.21, P < 0.0001) compared with those within the lowest risk eighth decile (1.67–1.75 g/L). The U-shaped relationship was present in both sexes, though more pronounced in men. Sensitivity analyses showed that cardiovascular mortality rates were higher in those with greater alcohol intake (P < 0.004). Adjustment for polygenic variation associated with higher ApoA1 levels did not attenuate the effect of very high ApoA1 levels on mortality. In the sub-group with very elevated HDL-C levels (> 80 mg/dL in men, > 100 mg/dL in women), there was no association between ApoA1 levels and mortality.ConclusionBoth very low and very elevated ApoA1 levels are associated with higher cardiovascular and all-cause mortality.

Background: Individuals with coronary artery disease (CAD) have worse executive function compared to the general population but the mechanisms are unknown. Objective: To investigate the role of acute mental stress (MS) on the executive function of patients with CAD. Methods: Participants with stable CAD underwent acute MS testing with simultaneous peripheral vascular function measurements and brain imaging using high resolution-positron emission tomography. Digital pulse wave amplitude was continuously measured using peripheral artery tonometry (PAT, Itamar Inc). Stress/rest PAT ratio (sPAT) of pulse wave amplitude during MS/baseline was calculated as a measure of microvascular constriction during MS. Plasma levels of catecholamine and interleukin-6 were assessed at baseline and after MS. Executive function was assessed both at baseline and at 2 years follow-up using the Trail Making Test parts A and B. Results: We studied 389 individuals with brain data available for 148 participants. Of this population follow-up cognitive assessments were performed in 226 individuals (121 with brain imaging). After multivariable adjustment for baseline demographics, risk factors, and medication use, a lower sPAT, indicating greater vasoconstriction, a higher inferior frontal lobe activation with MS, and increases in norepinephrine and IL-6 levels with MS were all independently associated with greater time to complete Trail B test.-38.4pt Conclusion: In response to acute MS, greater peripheral vasoconstriction, higher inferior frontal lobe brain activation, and increases in the levels of norepinephrine and IL-6 are associated with worse executive function.

We tested the hypothesis that inducible nitric oxide synthase (iNOS) contributes to reduced nitric oxide (NO)-dependent vasodilation in non-Hispanic Blacks and prehypertensive non-Hispanic Whites. Twenty Black and twenty White participants (10 normotensive, 10 prehypertensive per group; n = 40 total) participated in this study. Participants were instrumented with two microdialysis fibers, and each site was randomized as control (lactated Ringer) or iNOS inhibition (0.1 mM 1400W). Laser-Doppler flow probes and local heaters were used to measure skin blood flow and heat the skin to induce vasodilation, respectively. Each site was heated from 33°C to 39°C (rate: 0.1°C/s). Once a plateau was established, 20 mM nitro-l-arginine methyl ester (l-NAME), a nonspecific NOS inhibitor, was infused at each site to quantify NO-dependent vasodilation. At control sites, %NO-dependent vasodilation was reduced in prehypertensive Whites (47 ± 10%NO) and in both normotensive and prehypertensive Blacks (39 ± 9%NO and 28 ± 5%NO, respectively) relative to normotensive Whites (73 ± 8%NO; P < 0.0001 for all comparisons). Compared with respective control sites, iNOS inhibition increased NO-dependent vasodilation in prehypertensive Whites (68 ± 8%NO) and in both normotensive and prehypertensive Blacks (78 ± 8%NO and 55 ± 6%NO, respectively; P < 0.0001 for all comparisons). We failed to find an effect for normotensive Whites (77 ± 7%NO). After iNOS inhibition, %NO-dependent vasodilation was similar between normotensive Whites, prehypertensive Whites, and normotensive Blacks. Inhibition of iNOS increased NO-dependent vasodilation to a lesser extent in prehypertensive Blacks. These data suggest that iNOS contributes to reduced NO-dependent vasodilation in prehypertension and in Black participants. NEW & NOTEWORTHY Inducible nitric oxide synthase (iNOS) is typically upregulated in conditions of increased oxidative stress and may have detrimental effects on the vasculature. Endothelial nitric oxide (NO), which is cardioprotective, is reduced in prehypertensive non-Hispanic Whites and in non-Hispanic Blacks. We found that inhibition of iNOS can increase endothelial NO-dependent vasodilation in prehypertensive White participants and in both normotensive and prehypertensive Black participants.

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.

Introduction Sleepiness in obstructive sleep apnoea is associated with cardiovascular risk; however, the biological mechanisms are not known. This study explored whether those with subjective sleepiness have increased plasma tumour necrosis factor-related protein 1 (C1qTNF1), a novel adipose-derived hormone (adipokine), and 24-h ambulatory blood pressure (ABP) compared to those without sleepiness in newly diagnosed, treatment-naïve participants with obstructive sleep apnoea. Methods Overall, 94 participants were included in the analysis. Participants completed the Epworth Sleepiness Scale (ESS), 24-h ABP was monitored, and plasma C1qTNF1 was measured. Sleepy participants were defined as ESS≥10 and nonsleepy as ESS, Excessive sleepiness experienced by treatment-naïve patients with obstructive sleep apnoea is associated with inflammation, higher daily systolic ambulatory blood pressure and higher 24 h mean arterial pressure https://bit.ly/3goeqGD

BACKGROUND Patients without obstructive coronary artery disease (CAD) may have epicardial or microvascular dysfunction. The purpose of this study was to characterize patterns of epicardial and microvascular dysfunction in men and women with stable and unstable angina undergoing functional coronary angiography to inform medical therapy. METHODS 163 symptomatic patients with ≤50% diameter stenosis and fractional flow reserve (FFR) > 0.8 underwent endothelium-dependent epicardial and microvascular function after intracoronary acetylcholine (10-4 M, 81 mcg over 3 minutes). Endothelium-independent function was assessed using coronary flow reserve (CFR) and hyperemic microvascular resistance (HMR) after intravenous adenosine (140 ug/kg/min). Coronary microvascular dysfunction (CMD) was defined as CFR

Background:Psychological stress is a risk factor for major adverse cardiovascular events (MACE) in individuals with coronary artery disease. Certain brain regions that control both emotional states and cardiac physiology may be involved in this relationship. The rostromedial prefrontal cortex (rmPFC) is an important brain region that processes stress and regulates immune and autonomic functions. Changes in rmPFC activity with emotional stress (reactivity) may be informative of future risk for MACE.Methods:Participants with stable coronary artery disease underwent acute mental stress testing using a series of standardized speech/arithmetic stressors and simultaneous brain imaging with high-resolution positron emission tomography brain imaging. We defined high rmPFC activation as a difference between stress and control scans greater than the median value for the entire cohort. Interleukin-6 levels 90 minutes after stress, and high-frequency heart rate variability during stress were also assessed. We defined MACE as a composite of cardiovascular death, myocardial infarction, unstable angina with revascularization, and heart failure hospitalization.Results:We studied 148 subjects (69% male) with mean±SD age of 62±8 years. After adjustment for baseline demographics, risk factors, and baseline levels of interleukin-6 and high-frequency heart rate variability, higher rmPFC stress reactivity was independently associated with higher interleukin-6 and lower high-frequency heart rate variability with stress. During a median follow-up of 3 years, 34 subjects (21.3%) experienced a MACE. Each increase of 1 SD in rmPFC activation with mental stress was associated with a 21% increase risk of MACE (hazard ratio, 1.21 [95% CI, 1.08–1.37]). Stress-induced interleukin-6 and high-frequency heart rate variability explained 15.5% and 32.5% of the relationship between rmPFC reactivity and MACE, respectively. Addition of rmPFC reactivity to conventional risk factors improved risk reclassification for MACE prediction, and C-statistic improved from 0.71 to 0.76 (P=0.03).Conclusions:Greater rmPFC stress reactivity is associated with incident MACE. Immune and autonomic responses to mental stress may play a contributory role.

Highlights •Patients with CAD and renal insufficiency (eGFR •CPC counts, an index of endogenous vascular regenerative capacity, may help stratify risk in patients with CAD and renal insufficiency. •Renal insufficiency is associated with lower CPC counts in old, but not young, patients with established CAD. •The increased risk of adverse outcomes with CAD and renal insufficiency is limited to patients with low, but not high, CPC counts.

INTRODUCTION Nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with adverse cardiovascular outcomes and reportedly overused in American-style football (ASF). However, assessment of ASF NSAID use in the context of cardiovascular risk has not been performed. We sought to characterize NSAID use patterns and the association with cardiovascular risk in a diverse cohort of high school and collegiate ASF athletes. METHODS A total of 226 ASF athletes, 60 endurance athletes, and 63 nonathletic controls were studied pre- and postseason with echocardiography, vascular applanation tonometry, and clinical data assessment. Qualitative NSAID use throughout the season was recorded at postseason. RESULTS ASF athletes gained weight (Δ0.86 ± 3.9 kg, P < 0.001), increased systolic blood pressure (SBP, Δ3.1 ± 12 mm Hg, P < 0.001) and pulse wave velocity (Δ0.2 ± 0.6 m·s, P < 0.001), and decreased E' (Δ-1.4 ± 2.8 cm·s, P < 0.001) across one athletic season. Seventy-seven percent (n = 173) of ASF athletes reported that sport-specific NSAID use began in middle school. ASF NSAID use was more frequent with "weekly" (n = 42.19%) and "daily" (n = 32.14%) use compared with endurance athletes (P < 0.001) and controls (P = 0.02). ASF NSAID use increased in parallel with postseason SBP and weights. "Daily" ASF NSAID users demonstrated the highest postseason SBP (137 ± 13 vs 128 ± 13 mm Hg, P = 0.002) and weight (109.0 ± 18.6 vs 95.8 ± 20.5 kg, P = 0.002) compared with "never/rare" users. Adjusting for player position, SBP, pulse wave velocity, and E', increased weight (odds ratio = 1.04, 95% confidence interval = 1.0-1.08, P = 0.037) was associated with more frequent NSAID use. CONCLUSIONS Habitual NSAID use commonly begins during adolescence, before full physical maturation, and is associated with cardiovascular risk, particularly increased weight, in ASF athletes. NSAID use frequency should be considered when risk stratifying high-risk ASF athletes.

The national burden of cardiovascular disease (CVD) continues to impose significant risk of morbidity, mortality and increased costs. While traditional risk factors have been well-established, the evolving role of non-traditional risk factors, including socioeconomic and psychosocial factors, is increasingly being recognized. Several studies have acknowledged an association between marital status and the presence of CVD and its associated adverse outcomes. Across multiple U.S. and international cohorts, patients who are unmarried, including those who are divorced, separated, widowed, or never married, have an increased rate of adverse cardiovascular events when compared to their married counterparts. Some studies suggest that marriage may have a more protective role for men compared to women. Furthermore, dissatisfaction in a marriage and marriage quality have significant impact on cardiovascular risk. Psychosocial and socioeconomic factors, as well as other acute stressors, may contribute to the association between marital status and CVD outcomes, but the underlying mechanisms are not completely clear. Further investigation is required to identify potential targets for intervention and to determine whether more aggressive targeting of standard anti-atherosclerotic therapies can favorably impact CVD risk in unmarried patients.

The health of African Americans has been largely described in terms of deficits, disease and death. Little attention has been histori­cally given to the fact that African Americans as a population show the sustained ability to survive an evolving array of social, eco­nomic and environmental adversities that date back to more than a century before the founding of the United States. While these inequities have indeed taken (and continue to take) a devastating toll, there is also wide heterogeneity in outcomes, suggesting the existence of substantial individual and col­lective resilience among African Americans.This Perspective aims to stimulate discus­sion and research that explores resilience in a population in which “overcoming” and “bouncing back” from adversities (ranging from minor incidents to legally ordained, chronic and horrific oppression) has been a requirement for survival. Rigorous scientific exploration of Black resilience may yield important insights into the phenomenon of human resilience that transcend race. Ethn Dis. 2020;30(2):365-368; doi:10.18865/ ed.30.2.365

BACKGROUND: As the population of adults with congenital heart disease (CHD) grows, cardiologists continue to encounter patients with complex anatomies that challenge the standard treatment of care. Single ventricle Fontan palliated patients are the most complex within CHD, with a high morbidity and mortality burden. Factors driving this early demise are largely unknown. METHODS AND RESULTS: We analyzed biomarker expression in 44 stable Fontan outpatients (29.2 ± 10.7 years, 68.2% female) seen in the outpatient Emory Adult Congenital Heart Center and compared them to 32 age, gender and race matched controls. In comparison to controls, Fontan patients had elevated levels of multiple cytokines within the inflammatory pathway including Tumor Necrosis Factor-α (TNF-α) (p

BackgroundSelf-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).PurposeWe 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.MethodsData 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.ResultsReports 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.ConclusionsDespite 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.

Introduction: Young and middle-aged women with ischemic heart disease are a high-risk group for morbidity and mortality particularly after a myocardial infarction (MI). This group exhibits higher concentrations of the inflammatory cytokine interleukin-6 (IL-6) at baseline and in response to mental stress compared to men. The reasons for these differences are unknown; however, sex hormones may play a role. While testosterone has been shown to have anti-inflammatory effects among men; the role of testosterone on inflammatory cytokines among women has been understudied, and no research has examined the influence of testosterone on IL-6 response to stress. Hypothesis: Among young and middle-aged patients with a recent MI, higher concentrations of testosterone have anti-inflammatory effects among men at baseline and in response to mental stress; but are associated with greater inflammation among women. Methods: We studied 269 patients 61 years old or younger who were hospitalized for a MI in the previous 8 months. We measured plasma IL-6 (pg/mL) before and 90 minutes after mental stress (speech task). Inflammatory response was defined as the difference between IL-6 levels 90-minutes post mental stress and resting values. Serum free testosterone (pg/mL) was measured before mental stress. Differences across sex and time were examined with mixed models for repeated measures after natural log-transformation of IL-6. Results: The mean age was 51 years (range: 26-61); 48% were women and 64% African American. Mean values of free testosterone among men and women were 12.6 pg/mL (range: 0.9-29.0) and 1.8 pg/mL (range: 0.3-15.6), respectively. After adjusting for demographic factors (age, race, income), lifestyle and medical history (BMI, hypertension, diabetes, depression) and medication use, the association of testosterone with the IL-6 response to stress differed by sex (p for testosterone-by-sex-by-time interaction = 0.06). Among men, higher levels of testosterone were associated with lower concentrations of IL-6 at rest (β = -0.04; p = Conclusions: Among young and middle-aged survivors of a recent MI, higher concentrations of free testosterone are associated with lower inflammation among men, but with an opposite trend of higher inflammation among women.

Background: Existing literature suggests that atrial fibrillation (AF) can lead to coronary artery disease (CAD). However, little information exists regarding the association between AF and CAD severity. Methods: We conducted cross-sectional and prospective analyses of 7819 participants in the Emory Cardiovascular Biobank (EmCAB). EmCAB recruits patients undergoing cardiac catheterization at three Emory Healthcare hospitals in the Atlanta area. At enrollment, data on AF history and four CAD severity measurements were collected: presence of ≥70% coronary stenosis, presence of ≥50% coronary stenosis, number of vessels with ≥50% coronary stenosis, and the Gensini score. To minimize the effect of missing covariates, multiple imputation by chained equation (MICE) was employed. In the imputed dataset, linear, logistic, and Poisson models were used to examine the association between the different measurements and AF history. During follow-up, the occurrence of incident MI, fatal MI, and all-cause death were obtained as primary endpoints, and Cox regression models were used to examine the association of AF history with each endpoint. Results: At baseline, the prevalence of AF history was 8.5%. Among patients with and without AF history respectively, the prevalence of ≥50% stenosis was 72% and 76%, and of ≥70% stenosis was 65% and 70%, respectively. AF patients and non-AF patients had similar numbers of vessels with ≥50% stenosis on average (1.7, vs. 1.8) and a median Gensini score (10.0 vs. 10.5). No association was found between AF and the presence of ≥50% and ≥70% stenosis, and numbers of vessels with ≥50% stenosis. AF was associated with 3.32 (95% CI -7.20, 0.57) points lower Gensini score after multivariable adjustment (demographic and clinical factors). In the longitudinal analysis, there was no evidence of an association between AF and nonfatal MI, fatal MI, and any MI. The risk of all-cause mortality among AF patients was 1.66 times (95% CI 1.37, 2.01) that among non-AF patients in the unadjusted model and was strongly attenuated after adjustment for demographic and clinical factors (HR: 1.26, 95% CI 1.03, 1.53). Conclusion: In the EmCAB, AF was associated with all-cause mortality but not with CAD severity.

Background: An established link exists between acute mental stress and the development of transient endothelial dysfunction (TED) as assessed by brachial artery flow-mediated vasodilation (FMD). Black individuals have a high burden of cardiovascular (CV) risk factors and social disadvantages, which may result in adverse vascular responses to stress. We investigated differences in TED with mental stress in Black and non-Black individuals with coronary artery disease (CAD), and whether TED is associated with CV outcomes in both groups. Methods: We enrolled 812 patients with stable CAD between June 2011 and March 2016 and followed them through February 2020. Study participants were subjected to a public-speaking mental stress task and FMD (derived from % vasodilation with brachial artery hyperemia testing) was assessed by ultrasound before and 30 minutes after mental stress. TED was defined as a lower post-stress FMD than pre-stress FMD. We compared pre-stress 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 CV death and myocardial infarction (MI) after adjusting for demographic, clinical, and socioeconomic factors. Both first and recurring events were counted and multivariable models for repeated events were used for analysis. Results: The mean (SD) age was 59 (10) years, and 328 (40%) were Black. Pre-stress FMD was lower in Black than non-Black participants [3.7 (2.8) vs. 4.9 (3.8) p Conclusions: Among CAD patients, Black individuals are more likely than non-Black individuals to develop endothelial dysfunction with mental stress, which in turn is associated with an increased risk of adverse cardiovascular events. Endothelial dysfunction in response to psychological stress may represent an important mechanism for the disproportionate risk of adverse CV outcomes in Black patients.

Introduction: Mental stress-induced myocardial ischemia (MSI) is a marker of future cardiovascular events. The underlying biochemical mechanisms of this cardiovascular condition are poorly understood. Our objective was to use metabolic profiling to identify biochemical changes associated with mental stress (MS) in patients with stable coronary artery disease (CAD) and investigate differential pathways that are involved in MSI. Methods: A total of 110 Individuals with stable CAD who participated in the Mental Stress Ischemia Prognosis Study (MIPS) underwent a standardized mental stress to provoke of myocardial ischemia, detected with single-photon emission tomography. Plasma samples were obtained before and after MS at 45 and 90 minutes and metabolomic profiling was performed using liquid chromatography/mass spectrometry using a confirmed 500 compounds. Metabolomic features and pathways associated with ischemia using metabolome-wide association studies and Mummichog, respectively. Results: The sample involved a subset case-control for (MSI+ vs MSI-). At 45 minutes and 90 minutes, there were significant stress-induced changes in several compounds. There was a significant upregulation of metabolites associated with lipid signaling et ( p = 0.025, Inosine diphosphate). A comparison between the MSI+ and MS- groups showed differential upregulation of DNA methylation metabolites ( p = .036, 5-Methylcytosine hydrochloride) at 45 minutes and microbiome-related metabolites at 90 minutes (P=0.041, N, N-dimethyl-1,4-phenylenediamine). Pathway analyses were consistent with the aforementioned findings. Conclusion: Upregulation of metabolic pathways involved in DNA methylation and microbial metabolism is differentially associated with MSI. These findings provide novel mechanistic insights into the association between acute mental stress and myocardial ischemia as a marker for cardiovascular vulnerability in patients with CAD