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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.

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.

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.

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.

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.

Background: Chronic kidney disease (CKD) patients have exercise intolerance and exaggerated blood pressure reactivity during exercise that are mediated by sympathetic nervous system (SNS) overactivation and decreased nitric oxide (NO) bioavailability. The activation of the renin-angiotensin system (RAS) increases SNS activation and reduces NO synthesis, and prior studies suggest that RAS blockade attenuates declines in physical function. We hypothesized that RAS inhibitor (RASi) use is associated with higher exercise capacity mediated by decreased SNS activity and increased NO-dependent endothelial function in CKD. Method: In 35 CKD patients (57 ± 7 years) and 20 controls (CONs) (53 ± 8 years), we measured exercise capacity (peak oxygen consumption [VO2peak]), muscle sympathetic nervous activity (MSNA), and flow-mediated dilation (FMD) for NO-dependent endothelial function. Results: CKD patients treated with RASi (CKD + RASi, n = 25) had greater VO2peak than CKD patients not treated with RASi (CKD no RASi, n = 10), but lower VO2peak than CONs (23.3 ± 5.8 vs. 16.4 ± 2.9, p = 0.007; vs. 30.0 ± 7.7, p = 0.016 mL/min/kg, respectively). CKD + RASi had lower resting MSNA and greater FMD than CKD no RASi. Compared to CONs, CKD + RASi had similar MSNA but lower FMD. VO2peak was positively associated with FMD (r = 0.417, p = 0.038) and was predicted by the combination of FMD and RASi status (r2 = 0.344, p = 0.01) and MSNA and RASi status (r2 = 0.575, p = 0.040) in CKD patients. Conclusion: In summary, CKD patients with RASi have higher exercise capacity than those not on RASi. Higher exercise capacity in the RASi-treated group was associated with lower resting SNS activity and higher NO-dependent vascular endothelial function.

The electronic health records (EHR) infrastructure offers a tremendous resource for identifying controls who match the characteristics of study participants in a single-arm trial. The objectives are to (1) demonstrate the feasibility of curating a synthetic control group for an existing study cohort through EHR data extraction and (2) evaluate the effect of a lifestyle intervention on selected cardiovascular health metrics. A total of 711 university employees were recruited between 2008 and 2012 to participate in a health partner intervention to improve cardiovascular health and were followed for five years. Data of nearly 8000 eligible subjects were extracted from the EHR to create a synthetic control cohort during the same study period. To minimize confounding, crude comparison, exact matching, propensity score matching, and doubly robust estimation were used to compare the selected cardiovascular health metrics at 1 and 5 years of follow-up. Blood pressure and body mass index improved in the intervention group compared to the EHR synthetic controls. The findings of changes in lipid measurements were somewhat unexpected. When analyzing the subgroup without lipid-lowering medications, the intervention group exhibited better control of cholesterol levels over time than did our synthetic controls. Some measurements in the EHR system may be more robust for synthetic selection than others. EHR synthetic controls can provide an alternative to estimate intervention effects appropriately in single-arm studies for these measurements.

Background Black patients tend to develop coronary artery disease at a younger age than other groups. Previous data on racial disparities in outcomes of myocardial infarction (MI) have been inconsistent and limited to older populations. Our objective was to investigate racial differences in the outcome of MI among young and middle‐aged patients and the role played by socioeconomic, psychosocial, and clinical differences. Methods and Results We studied 313 participants (65% non‐Hispanic Black) Conclusions Among young and middle‐aged adult survivors of an MI, Black patients have a 2‐fold higher risk of adverse outcomes, which is largely driven by upstream socioeconomic factors rather than downstream psychological and clinical risk factors.

BACKGROUND: Acute kidney injury is common, with a major effect on morbidity and health care utilization. Soluble urokinase plasminogen activator receptor (suPAR) is a signaling glycoprotein thought to be involved in the pathogenesis of kidney disease. We investigated whether a high level of suPAR predisposed patients to acute kidney injury in multiple clinical contexts, and we used experimental models to identify mechanisms by which suPAR acts and to assess it as a therapeutic target. METHODS: We measured plasma levels of suPAR preprocedurally in patients who underwent coronary angiography and patients who underwent cardiac surgery and at the time of admission to the intensive care unit in critically ill patients. We assessed the risk of acute kidney injury at 7 days as the primary outcome and acute kidney injury or death at 90 days as a secondary outcome, according to quartile of suPAR level. In experimental studies, we used a monoclonal antibody to urokinase plasminogen activator receptor (uPAR) as a therapeutic strategy to attenuate acute kidney injury in transgenic mice receiving contrast material. We also assessed cellular bioenergetics and generation of reactive oxygen species in human kidney proximal tubular (HK-2) cells that were exposed to recombinant suPAR. RESULTS: The suPAR level was assessed in 3827 patients who were undergoing coronary angiography, 250 who were undergoing cardiac surgery, and 692 who were critically ill. Acute kidney injury developed in 318 patients (8%) who had undergone coronary angiography. The highest suPAR quartile (vs. the lowest) had an adjusted odds ratio of 2.66 (95% confidence interval [CI], 1.77 to 3.99) for acute kidney injury and 2.29 (95% CI, 1.71 to 3.06) for acute kidney injury or death at 90 days. Findings were similar in the surgical and critically ill cohorts. The suPAR-overexpressing mice that were given contrast material had greater functional and histologic evidence of acute kidney injury than wild-type mice. The suPAR-treated HK-2 cells showed heightened energetic demand and mitochondrial superoxide generation. Pretreatment with a uPAR monoclonal antibody attenuated kidney injury in suPAR-overexpressing mice and normalized bioenergetic changes in HK-2 cells. CONCLUSIONS: High suPAR levels were associated with acute kidney injury in various clinical and experimental contexts. (Funded by the National Institutes of Health and others.)

Major depression is a highly prevalent condition, affecting approximately 10% of the population. It is also a growing global problem, and has been consistently associated with increased risk of coronary heart disease (CHD). It is therefore not surprising that depression is highly comorbid with CHD, being two to three times more common among patients with CHD than in the general population. The prevalence of depression is 15–30% in patients with CHD, and is approximately twice as high in women than men, especially affecting young women in the aftermath of acute myocardial infarction (MI). Depression as a risk factor for CHD has been characterized from mild depressive symptoms to a clinical diagnosis of major depression. As defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), clinical depression, or major depression, is characterized by depressed mood or anhedonia (loss of interest or pleasure) for at least 2 weeks accompanied by significant functional impairment and additional somatic or cognitive symptoms. Most epidemiological studies of depression and incidence of CHD have used depressive symptom scales, and have frequently demonstrated a dose–response pattern, with higher levels of depressive symptoms being associated with higher risk. The exact mechanisms linking depression to increased CHD risk are complex and multifactorial, and still incompletely understood. Although adverse lifestyle behaviours and traditional CHD risk factors, such as smoking and sedentary lifestyle, largely contribute to the risk, they do not explain it entirely. In CHD patients, depression is also associated with severity of functional impairment, lower adherence to therapy and lower participation in cardiac rehabilitation. Whether and to what extent these factors explain the relationship between depression and CHD deserves future study. The present paper summarizes key aspects in our current knowledge linking depression and CHD within the intersecting fields of neuroscience, cardiovascular physiology, and behavioural medicine, with the objective of bringing attention to this area and stimulating interdisciplinary research, clinical awareness, and improved care.

Rationale: Excessive vasoconstriction in response to mental stress may be a potential mechanism by which acute psychological stress leads to adverse cardiac events. Objectives: We investigated whether excessive digital vasoconstriction during acute mental stress predicts adverse cardiovascular outcomes among patients with coronary artery disease. Methods and Results: Five hundred forty-nine patients with stable coronary artery disease (age 63±9, 76% male, 29% black) underwent mental stress testing with a standardized public speaking stressor and followed prospectively for cardiovascular end points. Digital pulse wave amplitude was continuously measured using peripheral artery tonometry (PAT, Itamar Inc). Stress/rest PAT ratio (sPAT) of pulse wave amplitude during mental stress/baseline was calculated and dichotomized by the median value into low and high sPAT ratio groups. Upon 3-year follow-up, Fine and Gray’s subdistribution hazard ratios were used to examine the association between sPAT ratio and the composite end point of cardiovascular death, myocardial infarction, revascularization, and hospitalization for heart failure. The median sPAT ratio was 0.68 (interquartile range, 0.48–0.88), indicating 32% vasoconstriction with mental stress. Men were more likely to have low sPAT ratio than women (odds ratio, 1.79; P =0.007) while those on β-blockers were less likely to have low sPAT ratio (odds ratio, 0.52; P =0.003). After adjusting for demographic and cardiovascular risk factors, medications, and rate-pressure product change during mental stress, those with low sPAT ratio were at significantly higher risk of adverse outcomes (subdistribution hazard ratio, 1.77 [95% CI, 1.12–2.80]). Conclusions: Greater peripheral vasoconstriction with mental stress, denoted by a low sPAT ratio, is associated with a higher risk of adverse cardiovascular outcomes in patients with coronary artery disease.

Objectives To determine the frequency of obstructive sleep apnea (OSA), insomnia, restless legs, and other sleep symptoms in patients with cardiovascular disease and the association of these sleep disorders with quantitative cardiovascular measures. Methods Study design was a cross-sectional survey and retrospective chart review. A questionnaire containing validated sleep symptoms was distributed to 202 patients with cardiovascular disease at a tertiary referral cardiology clinic. Following a focused review of these patients' medical charts, their questionnaire responses were examined for associations with clinical cardiovascular parameters. Results Twenty-one percent of patients reported a prior diagnosis of OSA. A total of 115 patients (60%) had at least one additional sleep symptom. Clinically significant insomnia was significantly associated with heart disease (relative risk [RR] = 1.5, confidence interval [CI] = 1.1 to 2.1), prior myocardial infarction or cerebrovascular accident (RR = 2.1, CI = 1.2 to 3.6), and heart failure (RR = 2.2, CI = 1.3 to 3.8). Left ventricular ejection fraction was significantly associated with insomnia by Insomnia Severity Index (β = -0.52, CI = -0.89 to -0.13). Conclusion The frequency of OSA in patients in this tertiary cardiology clinic was higher than the general population in the United States, with the majority of patients experiencing at least one sleep symptom. Insomnia symptoms were shown to be associated with multiple cardiovascular measures, including left ventricular ejection fraction. These findings imply an interwoven relationship between cardiovascular and sleep symptoms as captured by validated sleep questionnaires. Level of evidence IV Laryngoscope, 130:1595-1602, 2020.

BACKGROUND: Early childhood trauma is known to independently increase adverse outcome risk in coronary artery disease (CAD) patients, although the neurological correlates are not well understood. The purpose of this study was to examine whether early childhood trauma alters neural responses to acute mental stress in CAD patients. METHODS: Participants (n = 152) with CAD underwent brain imaging with High Resolution Positron Emission Tomography and radiolabeled water during control (verbal counting, neutral speaking) and mental stress (mental arithmetic, public speaking). Traumatic events in childhood were assessed with the Early Trauma Inventory (ETI-SR-SF) and participants were separated by presence (ETI+) or absence (ETI−) of early childhood trauma. Brain activity during mental stress was compared between ETI+ and ETI−. RESULTS: Compared to ETI−, ETI+ experienced greater (p < 0.005) activations during mental stress within the left anterior cingulate, left occipital lobe, bilateral frontal lobe and deactivations (p < 0.005) within the left insula, left parahippocampal gyrus, right dorsal anterior cingulate, bilateral cerebellum, bilateral fusiform gyrus, left inferior temporal gyrus, right occipital lobe, and right parietal lobe. Significant (p < 0.005) positive correlations between brain activation and ETI-SR-SF scores were observed within the left hippocampus, bilateral frontal lobe, left occipital cuneus, right parietal precuneus, and bilateral temporal lobe. LIMITATIONS: Results in non-CAD samples may differ and ETI may be subject to recall bias. CONCLUSION: Early childhood trauma exacerbated activations in stress-responsive limbic and cognitive brain areas with direct and indirect connections to the heart, potentially contributing to adverse outcomes in CAD patients.

Objectives— Coronary endothelial dysfunction is a precursor of atherosclerosis and adverse outcomes. Whether endothelial dysfunction is a localized or generalized phenomenon in humans remains uncertain. We simultaneously measured femoral and coronary vascular function with the hypothesis that peripheral vascular endothelial function will be reflective of coronary endothelial function. Approach and Results— Eighty-five subjects underwent coronary angiography for evaluation of chest pain or abnormal stress tests. Endothelium-dependent and -independent vascular function were measured using intracoronary and intrafemoral infusions of acetylcholine and sodium nitroprusside, respectively. Coronary flow reserve was assessed using intracoronary adenosine infusion. Flow velocity was measured in each circulation using a Doppler wire (FloWire, EndoSonics). Coronary vascular resistance and femoral vascular resistance were calculated as mean arterial pressure (mm Hg)/coronary blood flow (mL/min) and mean arterial pressure (mm Hg)/femoral average peak velocity (cm/s), respectively. Mean age was 53±11 years, 37% were female, 44% had hypertension, 12% had diabetes mellitus, and 38% had obstructive coronary artery disease. There was a correlation between the change in femoral vascular resistance with acetylcholine and acetylcholine-mediated changes in both the coronary vascular resistance ( r =0.27; P =0.014) and in the epicardial coronary artery diameter ( r =−0.25; P =0.021), indicating that subjects with normal endothelial function in the femoral circulation had normal endothelial function in the coronary epicardial and microcirculation and vice versa. The coronary vasodilator response to adenosine also correlated with the femoral vasodilatation with acetylcholine ( r =0.4; P =0.0002). There was no correlation between the coronary and femoral responses to sodium nitroprusside. Conclusions— Endothelial functional changes in the peripheral and coronary circulations were modestly correlated. Thus, peripheral microvascular endothelial function reflects endothelium-dependent coronary epicardial and microvascular function and the coronary flow reserve. Visual Overview— An online visual overview is available for this article.

Objective Mental stress-induced myocardial ischemia is a frequent phenomenon in patients with coronary artery disease (CAD). The link between an integrated measure of chronic psychosocial distress and mental stress-induced myocardial ischemia, and whether it differs by sex, has not been examined before. Methods We used latent class analysis to derive a composite measure of psychosocial distress integrating scales of depression, posttraumatic stress, anxiety, anger, hostility, and perceived stress in 665 individuals with stable CAD. Participants underwent myocardial perfusion imaging with mental stress and perfusion defects were quantified at rest (summed rest score), with mental stress (summed stress score), and their difference (summed difference score), the latter being an index of inducible ischemia. Results The M (SD) age was 63 (9) years, and 185 (28%) were women. Latent class analysis characterized the study sample into four distinct classes of incremental psychosocial distress. In women, class 4 (highest distress) had an adjusted 4.0-point higher summed rest score (95% confidence interval = 0.2-7.7) as compared with class 1 (lowest distress), whereas no difference was observed in men (-0.87 points, 95% confidence interval = -3.74 to 1.99, p = .04 for interaction). There was no association between the psychosocial distress latent variable and summed difference score in either women or men. Conclusions Among patients with CAD, a higher level of psychosocial distress is not associated with mental stress ischemia, but it is associated with more resting (fixed) perfusion abnormalities in women only, as well as with blunted hemodynamic response to mental stress in both men and women.

Background:Early trauma (general, emotional, physical, and sexual abuse before age 18 years) has been associated with both cardiovascular disease risk and lifestyle-related risk factors for cardiovascular disease, including smoking, obesity, and physical inactivity. Despite higher prevalence, the association between early trauma and cardiovascular health (CVH) has been understudied in Black Americans, especially those from low-income backgrounds, who may be doubly vulnerable. Therefore, we investigated the association between early trauma and CVH, particularly among low-income Black Americans.Methods:We recruited 457 Black adults (age 53±10, 38% male) without known cardiovascular disease from the Atlanta, GA, metropolitan area using personalized, community-based recruitment methods. The Early Trauma Inventory was administered to assess overall early traumatic life experiences which include physical, sexual, emotional abuse, and general trauma. Our primary outcome was the American Heart Association Life’s Simple 7, which is a set of 7 CVH metrics, including 4 lifestyle-related factors (smoking, body mass index, physical activity, and diet) and three physiologically measured health factors (blood pressure, total blood cholesterol, and blood glucose). We used linear regression models adjusting for age, sex, socioeconomic status, and depression to test the association between early trauma and CVH and tested the early trauma by household income (Results:Higher levels of early trauma were associated with lower Life’s Simple 7 scores (β, −0.05 [95% CI, −0.09 to −0.01],P=0.02, per 1 unit increase in the Early Trauma Inventory score) among lower, but not higher, income Black participants (Pvalue for interaction=0.04). Subtypes of early trauma linked to Life’s Simple 7 were general trauma, emotional abuse, and sexual abuse. Exploratory analyses demonstrated that early trauma was only associated with the body mass index and smoking components of Life’s Simple 7.Conclusions:Early trauma, including general trauma, emotional abuse, and sexual abuse, may be associated with worse CVH among low-, but not higher-income Black adults.

BACKGROUND Several monogenic causes for isolated dystonia have been identified, but they collectively account for only a small proportion of cases. Two genome-wide association studies have reported a few potential dystonia risk loci; but conclusions have been limited by small sample sizes, partial coverage of genetic variants, or poor reproducibility. OBJECTIVE To identify robust genetic variants and loci in a large multicenter cervical dystonia cohort using a genome-wide approach. METHODS We performed a genome-wide association study using cervical dystonia samples from the Dystonia Coalition. Logistic and linear regressions, including age, sex, and population structure as covariates, were employed to assess variant- and gene-based genetic associations with disease status and age at onset. We also performed a replication study for an identified genome-wide significant signal. RESULTS After quality control, 919 cervical dystonia patients compared with 1491 controls of European ancestry were included in the analyses. We identified one genome-wide significant variant (rs2219975, chromosome 3, upstream of COL8A1, P-value 3.04 × 10-8 ). The association was not replicated in a newly genotyped sample of 473 cervical dystonia cases and 481 controls. Gene-based analysis identified DENND1A to be significantly associated with cervical dystonia (P-value 1.23 × 10-6 ). One low-frequency variant was associated with lower age-at-onset (16.4 ± 2.9 years, P-value = 3.07 × 10-8 , minor allele frequency = 0.01), located within the GABBR2 gene on chromosome 9 (rs147331823). CONCLUSION The genetic underpinnings of cervical dystonia are complex and likely consist of multiple distinct variants of small effect sizes. Larger sample sizes may be needed to provide sufficient statistical power to address the presumably multi-genic etiology of cervical dystonia. © 2021 International Parkinson and Movement Disorder Society.

ObjectiveTo simultaneously examine multiple individual-level neighbourhood perceptions and psychosocial characteristics and their relationships with cardiovascular health (CVH) among blacks.DesignCross-sectional study.SettingSubjects were recruited between 2016 and 2018 via convenience sampling.Participants385 Black men and women, age 30–70 living in the Atlanta metropolitan area (Georgia, USA).Primary outcome measureIndividual’s CVH was summarised as a composite score using American Heart Association’s Life’s Simple 7 (LS7) metrics.MethodsWe implemented unsupervised learning (k-means) and supervised learning (Bayesian Dirichlet process clustering) to identify clusters based on 11 self-reported neighbourhood perception and psychosocial characteristics. We also performed principal component analysis to summarise neighbourhood perceptions and psychosocial variables and assess their associations with LS7 scores.ResultsK-means and Bayesian clustering resulted in 4 and 5 clusters, respectively. Based on the posterior distributions, higher LS7 scores were associated with better neighbourhood perceptions and psychosocial characteristics, including neighbourhood safety, social cohesion, activities with neighbours, environmental mastery, purpose in life, resilient coping and no depression. Taken together, the first principal components of neighbourhood perceptions and psychosocial characteristics were associated with an increase of 0.07 (95% CI −0.17 to 0.31) and 0.31 (95% CI 0.06 to 0.55) in LS7 score, respectively, after accounting for age, sex, household income and education level.ConclusionBoth neighbourhood perception and psychosocial domains were related to CVH, but individual psychosocial characteristics appeared to contribute to CVH most. Approaches that acknowledge the importance of factors in both domains may prove most beneficial for enhancing resilience and promoting CVH among black communities.

The link between posttraumatic stress disorder (PTSD) and ischemic heart disease remains elusive owing to a shortage of longitudinal studies with a clinical diagnosis of PTSD and objective measures of cardiac compromise.We performed positron emission tomography in 275 twins who participated in two examinations approximately 12 years apart. At both visits, we obtained a clinical diagnosis of PTSD, which was classified as long-standing (both visit 1 and visit 2), late onset (only visit 2), and no PTSD (no PTSD at both visits). With positron emission tomography, we assessed myocardial flow reserve (MFR), which, in absence of significant coronary stenoses, indexes coronary microvascular function. We compared positron emission tomography data at visit 2 across the three categories of longitudinally assessed PTSD and examined changes between the two visits.Overall, 80% of the twins had no or minimal obstructive coronary disease. Yet, MFR was depressed in twins with PTSD and was progressively lower across groups with no PTSD (2.13), late-onset PTSD (1.97), and long-standing PTSD (1.93) (p = .01). A low MFR (a ratio2.0) was present in 40% of the twins without PTSD, in 56% of those with late-onset PTSD, and in 72% of those with long-standing PTSD (p.001). Associations persisted in multivariable analysis, when examining changes in MFR between visit 1 and visit 2, and within twin pairs. Results were similar by zygosity.Longitudinally, PTSD is associated with reduced coronary microcirculatory function and greater deterioration over time. The association is especially noted among twins with chronic, long-standing PTSD and is not confounded by shared environmental or genetic factors.

BackgroundThe COVID-19 pandemic adversely affected the socially vulnerable and minority communities in the U.S. initially, but the temporal trends during the year-long pandemic remain unknown.ObjectiveWe examined the temporal association between the county-level Social Vulnerability Index (SVI), a percentile-based measure of social vulnerability to disasters, its subcomponents and race/ethnic composition with COVID-19 incidence and mortality in the U.S. in the year starting in March 2020.MethodsCounties (n=3091) with ≥ 50 COVID-19 cases by March 6th, 2021 were included in the study. Associations between SVI (and its subcomponents) and county level racial composition with the incidence and death per capita were assessed by fitting a negative-binomial mixed-effects model. This model was also used to examine potential time varying associations between weekly number of cases/deaths and SVI or racial composition. Data was adjusted for percentage of population aged ≥65 years, state level testing rate, comorbidities using the average Hierarchical Condition Category (HCC) score, and environmental factors including average fine particulate matter (PM2.5), temperature and precipitation.ResultsHigher SVI, indicative of greater social vulnerability, was independently associated with higher COVID-19 incidence (adjusted incidence rate ratio [IRR] per-10 percentile increase:1.02, (95% CI 1.02, 1.03, pConclusionExcept for the winter “third wave” when majority White communities had the highest incidence of cases, counties with greater social vulnerability and proportionately higher minority populations, experienced worse COVID-19 outcomes.Article Summary/Strengths & LimitationsExamined full 12 months of county-level data in the US delineating the temporal trends in the association between social vulnerability index and COVID-19 outcomesInvestigated COVID-19 outcomes in predominantly Black and Hispanic communities in comparison to White communities in the USAnalysis is ecological, descriptive, and on the county-level rather than on an individual levelAnalysis adjusted for confounders including county level age ≥ 65, comorbidities, and environmental factorsAnalysis limited to the US

Introduction: Psychological stress disorders are twice as prevalent in women with ischemic heart disease compared to their male counterparts. The disproportionate psychological health experience of these women is not well understood. Neighborhood social factors may help to explain disparities in psychological risk by sex. Hypothesis: We hypothesized that in patients with a recent myocardial infarction, living in neighborhoods with higher social vulnerability would be associated with greater psychological distress. We also hypothesized that this association would be moderated by sex, with a greater association among women than men. Methods: We studied 286 patients with heart disease recruited from Emory-based hospitals in the Myocardial Infarction and Mental Stress 2 Study. We used the social vulnerability index (SVI) developed by the Centers for Disease Control and Prevention to rank patients’ census tracks on 14 social factors, including unemployment, lack of vehicle access, and crowded housing, which are further grouped into four themes: socioeconomic status; household composition; minority status and language; and housing and transportation. Census tracts received a percentile ranking (0-100%), overall and for each theme, with higher values indicating greater social vulnerability. We calculated a global measure of psychological distress by ranking each participant on each of six symptom scales (depression, post-traumatic stress disorder, anxiety, anger, hostility, and perceived stress) and then taking an average of all ranks. Multilevel linear regression models were used to account for individuals nested within census tracts. Beta coefficients for mean ranks in psychological distress scores were estimated per 10-unit increase in SVI percentile ranking. Results: The mean age of the sample was 51 years (range: 26-61); 49% were women and 66% African American. Women in higher SVI census tracts had greater psychological distress scores. After adjusting for demographics (age, race, individual-level education and income), lifestyle and medical risk factors, and anti-depressant use, there were significant differences by sex (SVI-by-sex-interaction = 0.01) such that each 10 unit increase in SVI percentile ranking was associated with 4.09 (95% CI: 0.02, 8.08; p = 0.05) unit increase in mean scores for psychological distress among women only. These associations were driven by the SVI themes of lower socioeconomic status and poorer access to housing and transportation. There were no significant interactions by race. Conclusions: We show for the first time that neighborhood social vulnerability is associated with psychological distress among women with heart disease. These findings support the role of contextual influences of the neighborhood environment on the mental health of high-risk women, independent of individual-level measures of income and education.

Background: Excessive peripheral microvascular constriction during acute psychological stress, measured using peripheral arterial tonometry reflects similar changes in coronary blood flow.The ratio of digital pulse wave amplitude during stress compared to rest (sPAT) is used to estimate the degree of microvascular response to stress. Hypothesis: We hypothesized that genetic factors contribute to the degree of microvascular constriction during mental stress and that excessive vasoconstriction is associated with adverse cardiovascular outcomes. Methods: A total of 580 stable CAD subjects of European and African ancestries from two prospective cohort studies underwent mental stress testing with a standardized public speaking stressor. Digital pulse wave amplitude was continuously measured using PAT and the stress/rest PAT ratio (sPAT) of pulse wave amplitude during mental stress/baseline was calculated. Genotyping was performed using Illumina’s Multi-Ethnic Genotyping Array platform and imputed to the 1000 Genome reference panel. Ethnicity-specific genome-wide association studies (GWAS) of sPAT were conducted using linear regression of additive genetic mode adjusted for age, sex and population stratification in both cohorts. A trans-ethnic meta-analysis integrated the GWAS results from four sub-cohorts. Upon 5-year follow-up, Fine and Gray’s sub-distribution hazard ratios (sHR) were used to examine the association between sPAT ratio (> vs=< median) and the composite endpoint of cardiovascular death, myocardial infarction, revascularization, and hospitalization for heart failure. Results: Mean age was 63±9; 65% male, 35% African American. We identified three SNPs in linkage disequilibrium on chr7:111,666,943 T>C (rs6466396); chr7: 111,668,622 T>G (rs876170); chr7: 111,668,623 T>G (rs876169) that were associated with greater sPAT ratio by means of 0.13, 0.12 and 0.10, ( P = 1.42E-08). The sPAT-associated locus was within DOCK4 gene which encodes Dedicator of Cytokinesis 4, an essential protein for angiogenesis and brain development, and a known locus for obesity. After adjusting for demographic and cardiovascular risk factors, medications, and rate-pressure product change during mental stress, those with low sPAT ratio were at significantly higher risk of adverse outcomes (sHR 1.8 [95% CI 1.1 - 2.8]). Conclusion: We have identified a genetic basis for stress-induced vasomotion. Presence of allele C (rs6466396) is associated with increased vasoconstriction during mental stress, and thus may predispose CAD patients to a higher risk for adverse cardiovascular outcomes with stressful exposure.

Introduction: Mental stress-induced myocardial ischemia (MSI) is a risk marker for adverse outcomes among coronary artery disease (CAD) that is more prevalent among patients with posttraumatic stress disorder (PTSD). Hypothesis: CAD patients with PTSD who develop MSI experience a higher risk of adverse cardiovascular events compared with those who do not develop MSI. Methods: We studied 995 individuals with stable CAD who participated in two contemporary cohort studies with similar protocols, the Mental Stress Ischemia Prognosis Study (MIPS), and the Myocardial Infarction and Mental Stress Study (MIMS). Provocation of myocardial ischemia with a standardized mental stress test (speech task) was assessed with single-photon emission computed tomography. PTSD was assessed with the structured clinical interviews for DSM-IV. Participants were categorized into four groups based on their MSI and PTSD status. The primary endpoint was a composite outcome of cardiovascular death or nonfatal myocardial infarction (MI), stroke, or heart failure hospitalization. Cox regression models were used to investigate the interaction of PTSD and MSI on the study endpoint in the two samples pooled with meta-analysis. Results: In total, 603 participants in MIPS and 392 in MIMS were included. MSI occurred in 16% of the patients in MIPS and 17% in MIMS. Over a 5-year median follow-up, there were 126 outcome events in MIPS and 117 in MIMS. In Cox regression models with adjustment for demographic and clinical risk factors, participants with both MSI and PTSD had a higher risk for the study endpoint, compared to those with neither. In contrast, participants with PTSD or MSI but not both were not at a higher risk ( p interaction=0.01). Separate analyses in the two studies were consistent. Conclusions: There is a synergistic association of PTSD and MSI on adverse outcomes in CAD patients. These findings support the confluence of chronic mental health vulnerability with acute stress responses in defining elevated risk in CAD patients.patients.

Title: Net Worth, Debt Stress, and Ambulatory Blood Pressure in African American Women Author Names: Telisa Spikes, RN, PHD, Raphiel Murden, MS, Izraelle McKinnon, MPH, Miriam Van Dyke, PhD, Samantha Bromfield, PhD, Renee Moore, PhD, Bianca Booker, MA, Frederic Rahbari-Oskoui MD, Arshed Quyyumi, MD, Viola Vaccarino, MD, PhD, Tené T. Lewis, PhD Background: Low socioeconomic status (SES) is an established predictor of higher cardiovascular disease (CVD) incidence and mortality. Research suggests that neither higher education nor income have been consistently associated with lower CVD risk or outcomes in African Americans (AAs). Net worth and debt stress are two underexamined indices of SES that may be more important for CVD risk, especially in AAs, due to attenuated returns of traditional indicators of SES on health, and the high rates of debt in this group. Objective: To examine the associations of net worth and debt stress, independent of education and income, with ambulatory blood pressure (ABP) in AA women. Methods: Participants were AA women (n=422), mean age 37±4.2 years from various sociodemographic backgrounds recruited from a large metropolitan southeastern region. Net worth was measured using a single item (“Suppose you and others in your household were to sell all of your major possessions including your home, turn all of your investments and other assets into cash, and pay off all of your debts. Would you have something left over, break even, or be in debt?”) with three response categories, left over , break-even , and debt . Debt stress was measured using the four-item Debt Stress Index (e.g. “Overall, how often do you worry about the total amount you and your spouse/partner owe in overall debt?”). ABP was assessed over 48 hours. Multiple linear regression was used to evaluate associations between SES indicators and continuous ABP outcomes adjusting for age, education, income, BMI, BP meds, and depressive symptoms. Results: Overall, 48% of the cohort was categorized as having a positive (“left over”) net worth, while 30% and 22% were categorized as having a neutral (“break-even”), and negative (“debt”) net worth, respectively. Compared to the positive net worth group, negative net worth was associated with higher daytime (ß=5.2; CI: 2.44-8.05 ) and nighttime systolic blood pressure (SBP) (ß=5.3; CI: 2.59-8.06 ) in unadjusted analyses. Findings remained significant for both daytime (ß=4.3; CI:1.38-7.24 ) and nighttime (ß=4.1; CI:1.26-6.90 ) SBP in fully adjusted models. There were no significant unadjusted or fully-adjusted associations between debt stress and daytime, or nighttime SBP. Discussion: Negative net worth was associated with a 4.3 mm Hg higher daytime, and 4.1 mm Hg nighttime SBP independent of education and income. Future research is needed to determine the prospective impact of net worth on long-term CVD risk in AA women.

Introduction: Poor quality neighborhoods are independent risk factors for cardiovascular disease (CVD) but are understudied in Blacks, who face large CVD health disparities. Arterial stiffness (AS) precedes development of hypertension and adverse CVD events but the effect of neighborhood on AS among Blacks remain unknown. Objective: We compared the association between neighborhood environment and AS among Blacks in Jackson, MS and Atlanta, GA. Methods: We studied 1592 Blacks (age 58 ± 10, 38% male) living in Jackson, MS from the Jackson Heart Study (JHS) and 451 Blacks (age 53 ± 10, 39% male) living in Atlanta, GA from the Morehouse/Emory 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. AS was measured as pulse wave velocity (PWV) using MRI 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 AS, 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 (Fig). Conclusion: Neighborhood social characteristics show an independent association with vascular health of Blacks, findings that were reproducible in two distinct American cities.

Introduction Perceived and actual access to healthy foods may differ in urban areas, particularly among Black people. We assessed the effect of objective and perceived neighborhood food access on self-reported cardiovascular disease (CVD) among Black people living in areas of high risk and low risk for the disease in Atlanta, Georgia. We hypothesized that perceived and objective food access would independently predict self-reported CVD. Methods We used survey data from the Morehouse-Emory Cardiovascular (MECA) Center for Health Equity Study. Study participants consisted of 1,402 Black adults, aged 35 to 64, residing in urban Atlanta census tracts with high rates or low rates of CVD. We assessed perceived neighborhood healthy food access by self-reported selection and quality of produce and low-fat food options. We assessed objective food access by the 2015 US Department of Agriculture Food Access Research Atlas. Low access was defined as census tracts with at least 500 people living more than 1 mile from a large food retailer. Self-reported CVD included related conditions and/or procedures. We used multilevel logistic models adjusted for demographic characteristics to examine the association between objective and perceived food access and self-reported CVD. Results Overall, self-reported CVD was not significant for perceived (odds ratio = 0.87; 95% CI, 0.59-1.29) or objective (odds ratio = 0.74; 95% CI, 0.48-1.12) healthy food access. Similar results were obtained among adults living in areas with higher-than-expected rates of CVD. Conclusion Results of this study suggest the odds for self-reported CVD events were not significantly affected by perceived or objective access to healthy foods.

Aims Inflammation plays an important role in cardiovascular disease (CVD) development. The NOD-like receptor protein-3 (NLRP3) inflammasome contributes to the development of atherosclerosis in animal models. Components of the NLRP3 inflammasome pathway such as interleukin-1β can therapeutically be targeted. Associations of genetically determined inflammasome-mediated systemic inflammation with CVD and mortality in humans are unknown. Methods and results We explored the association of genetic NLRP3 variants with prevalent CVD and cardiovascular mortality in 538 167 subjects on the individual participant level in an explorative gene-centric approach without performing multiple testing. Functional relevance of single-nucleotide polymorphisms on NLRP3 inflammasome activation has been evaluated in monocyte-enriched peripheral blood mononuclear cells (PBMCs). Genetic analyses identified the highly prevalent (minor allele frequency 39.9%) intronic NLRP3 variant rs10754555 to affect NLRP3 gene expression. rs10754555 carriers showed significantly higher C-reactive protein and serum amyloid A plasma levels. Carriers of the G allele showed higher NLRP3 inflammasome activation in isolated human PBMCs. In carriers of the rs10754555 variant, the prevalence of coronary artery disease was significantly higher as compared to non-carriers with a significant interaction between rs10754555 and age. Importantly, rs10754555 carriers had significantly higher risk for cardiovascular mortality during follow-up. Inflammasome inducers (e.g. urate, triglycerides, apolipoprotein C3) modulated the association between rs10754555 and mortality. Conclusion The NLRP3 intronic variant rs10754555 is associated with increased systemic inflammation, inflammasome activation, prevalent coronary artery disease, and mortality. This study provides evidence for a substantial role of genetically driven systemic inflammation in CVD and highlights the NLRP3 inflammasome as a therapeutic target.

Supplemental Digital Content is available in the text., Objective: The underlying pathobiology of the paradoxical relationship between obesity and adverse outcomes in coronary artery disease (CAD) is unclear. Our objective was to determine the association between obesity and circulating progenitor cell (CPC) counts—a measure of intrinsic regenerative capacity—in asymptomatic individuals and patients with CAD and its impact on the obesity paradox. Approach and Results: CPCs were enumerated by flow cytometry as CD45med+ cells expressing CD34+, CD133+, and CXCR4+ epitopes in 672 asymptomatic individuals (50 years of age; 28% obese) and 1277 patients with CAD (66 years of age; 39% obese). The association between obesity and CPCs was analyzed using linear regression models. The association of obesity and CPCs with cardiovascular death/myocardial infarction events over 3.5-year follow-up in patients with CAD was studied using Cox models. Obesity was independently associated with 16% to 34% higher CPC counts (CD34+, CD34+/CD133+, and CD34+/CXCR4+) in asymptomatic individuals. This association was not attenuated by systemic inflammation, insulin resistance, or secretion but partly attenuated by cardiorespiratory fitness and body composition. In patients with CAD, obesity was associated with 8% to 12% higher CPC counts and 30% lower risk of adverse outcomes. Compared with nonobese patients, only obese patients with high CPC counts (CD34+ cells ≥median, 1806 cells/mL) were at a lower risk (hazard ratio, 0.52 [95% CI, 0.31–0.88]), whereas those with low counts (

Cardiovascular disease (CVD) is the number one killer of adults in the U.S., with marked ethnic/racial disparities in prevalence, risk factors, associated health behaviors, and death rates. In this study, we recruited and randomized Blacks with poor cardiovascular health in the Atlanta Metro area to receive an intervention comparing two approaches to engagement with a behavioral intervention technology for CVD. Generalized Linear Mixed Models results from a 6-month intervention indicate that 53% of all participants experienced a statistical improvement in Life’s Simple 7 (LS7), 54% in BMI, 61% in blood glucose, and 53% in systolic blood pressure. Females demonstrated a statistically significant improvement in BMI and diastolic blood pressure and a reduction in self-reported physical activity. We found no significant differences in changes in LS7 or their constituent parts but found strong evidence that health coaches can help improve overall LS7 in participants living in at-risk neighborhoods. In terms of clinical significance, our result indicates that improvements in LS7 correspond to a 7% lifetime reduction of incident CVD. Our findings suggest that technology-enabled self-management can be effective for managing selected CVD risk factors among Blacks.

Aims While most patients with myocardial infarction (MI) have underlying coronary atherosclerosis, not all patients with coronary artery disease (CAD) develop MI. We sought to address the hypothesis that some of the genetic factors which establish atherosclerosis may be distinct from those that predispose to vulnerable plaques and thrombus formation. Methods and results We carried out a genome-wide association study for MI in the UK Biobank (n∼472 000), followed by a meta-analysis with summary statistics from the CARDIoGRAMplusC4D Consortium (n∼167 000). Multiple independent replication analyses and functional approaches were used to prioritize loci and evaluate positional candidate genes. Eight novel regions were identified for MI at the genome wide significance level, of which effect sizes at six loci were more robust for MI than for CAD without the presence of MI. Confirmatory evidence for association of a locus on chromosome 1p21.3 harbouring choline-like transporter 3 (SLC44A3) with MI in the context of CAD, but not with coronary atherosclerosis itself, was obtained in Biobank Japan (n∼165 000) and 16 independent angiography-based cohorts (n∼27 000). Follow-up analyses did not reveal association of the SLC44A3 locus with CAD risk factors, biomarkers of coagulation, other thrombotic diseases, or plasma levels of a broad array of metabolites, including choline, trimethylamine N-oxide, and betaine. However, aortic expression of SLC44A3 was increased in carriers of the MI risk allele at chromosome 1p21.3, increased in ischaemic (vs. non-diseased) coronary arteries, up-regulated in human aortic endothelial cells treated with interleukin-1β (vs. vehicle), and associated with smooth muscle cell migration in vitro. Conclusions A large-scale analysis comprising ∼831 000 subjects revealed novel genetic determinants of MI and implicated SLC44A3 in the pathophysiology of vulnerable plaques.

Background: The genomic structure that contributes to the risk of coronary artery disease (CAD) can be evaluated as a risk score of multiple variants. However, sex differences have not been fully examined in applications of genetic risk score (GRS) of CAD. Methods: Using data from the UK Biobank, we constructed a CAD-GRS based on all known loci, 3 mediating trait-based (blood pressure, lipids, and body mass index) subscores, and a genome-wide polygenic risk score based on 1.1 million variants. The differences in genetic associations with prevalent and incident CAD between men and women were investigated among 317 509 unrelated individuals of the European ancestry. We also assessed interactions with sex for 161 individual loci included in the comprehensive GRS. Results: For both prevalent and incident CAD, the associations of comprehensive and genome-wide GRSs were stronger among men than women. Using a score of 161 loci, we observed a 2.4× higher risk for incident CAD comparing men with high genetic risk to men with low genetic risk but an 80% greater risk comparing women with high genetic risk to women with low genetic risk (interaction P =0.002). Of the 3 subscores, the blood pressure–associated subscore exhibited sex differences (interaction P =0.0004 per SD increase in subscore). Analysis of individual variants identified a novel gene-sex interaction at locus 21q22.11 . Conclusions: Sexual differences in genetic predisposition should be considered in future studies of CAD, and GRSs should not be assumed to perform equally well in men and women.

Background Several polygenic risk scores (PRS) have been developed for cardiovascular risk prediction, but the additive value of including PRS together with conventional risk factors for risk prediction is questionable. This study assesses the clinical utility of including four PRS generated from 194, 46K, 1.5M, and 6M SNPs, along with conventional risk factors, to predict risk of ischemic heart disease (IHD), myocardial infarction (MI), and first MI event on or before age 50 (early MI). Methods A cross-validated logistic regression (LR) algorithm was trained either on ~ 440K European ancestry individuals from the UK Biobank (UKB), or the full UKB population, including as features different combinations of conventional established-at-birth risk factors (ancestry, sex) and risk factors that are non-fixed over an individual’s lifespan (age, BMI, hypertension, hyperlipidemia, diabetes, smoking, family history), with and without also including PRS. The algorithm was trained separately with IHD, MI, and early MI as prediction labels. Results When LR was trained using risk factors established-at-birth, adding the four PRS significantly improved the area under the curve (AUC) for IHD (0.62 to 0.67) and MI (0.67 to 0.73), as well as for early MI (0.70 to 0.79). When LR was trained using all risk factors, adding the four PRS only resulted in a significantly higher disease prevalence in the 98th and 99th percentiles of both the IHD and MI scores. Conclusions PRS improve cardiovascular risk stratification early in life when knowledge of later-life risk factors is unavailable. However, by middle age, when many risk factors are known, the improvement attributed to PRS is marginal for the general population.

Greater psychological distress is associated with cognitive impairment in healthy adults. Whether such associations also exist in patients with coronary artery disease (CAD) is uncertain. We assessed cognitive function in 496 individuals with CAD using the verbal and visual memory subtests of the Wechsler Memory Scale and executive functioning measured by the Trail Making Test Parts A and B. We used a composite score of psychological distress derived through summation of Z-transformed psychological distress symptom scales (depression, posttraumatic stress, anxiety, anger, hostility and perceived stress) and scores for each individual psychological scale. Multivariable linear regression models were used to determine the association between memory scores (as outcomes) and the psychological distress scores (both composite score and individual scales). After adjusting for demographic and cardiovascular risk factors, a higher psychological distress score was independently associated with worse memory and executive functioning. Each standard deviation increase in psychological distress score was associated with 3% (95% confidence interval [CI], 1%-5%) to 5% (95% CI, 3-7%) worse cognitive performance (higher Trail A and Trail B, and lower verbal and visual memory scores). Among individuals with CAD, a higher level of psychological distress is independently associated with worse cognitive performance. These findings suggest that psychological risk factors play a role in cognitive trajectories of persons with CAD.

Background:Microvascular dysfunction is known to play a key role in patients with angina and nonobstructive coronary artery disease. We investigated the impact of ranolazine among patients with angina and nonobstructive coronary artery disease.Methods:In this randomized, double-blinded, placebo-controlled pilot trial, 26 patients with angina once weekly or more, abnormal stress test, and nonobstructive coronary artery disease (0.80) were randomized 1:1 to ranolazine or placebo for 12 weeks. Primary end point was ΔSeattle Angina Questionnaire (SAQ) angina frequency score. Baseline and 3 months follow-up SAQ, Duke Activity Status Index scores along with invasive fractional flow reserve, coronary flow reserve (CFR), hyperemic myocardial resistance, and cardiopulmonary exercise testing measurements were performed.Results:No significant differences in ΔSAQ angina frequency scores (P=0.53) or Duke Activity Status Index (P=0.76) were observed between ranolazine versus placebo, although patients on ranolazine had lesser improvement in SAQ physical limitation scores (P=0.02) compared with placebo at 3 months. There were no significant differences in ΔCFR or Δhyperemic myocardial resistance between ranolazine and placebo groups. Patients treated with ranolazine, compared with placebo, had no significant improvement in maximum rate of oxygen consumption measured during incremental exercise (VO2max) and peak metabolic equivalents of task. Interestingly, in the ranolazine group, patients with baseline CFRP=0.02).Conclusions:Ranolazine did not demonstrate improvement in SAQ angina frequency score, invasive microvascular function, or peak metabolic equivalent compared with placebo at 3 months.Registration:URL:https://www.clinicaltrials.gov. Unique identifier: NCT02147067.

Introduction: Impaired vascular function in blacks contributes to a higher risk of heart failure (HF) compared to other race/ethnicities. Hypothesis: Black patients with HF with reduced ejection fraction (HFrEF) will have worse digital microvascular function measured using peripheral arterial tonometry (PAT). High resolution metabolomics profiling will identify novel biomarkers of vascular function. Methods: PAT was used to estimate the reactive hyperemia index (RHI) in blacks and whites with HFrEF (N=154, age: 53.7 ± 13.0 yrs, 48.7% female, 61.0% black) and healthy controls (N=200, age: 43.2 ± 14.0 yrs, 47.0% female, 27.0% black). Linear regression was used to determine if race was associated with RHI after adjustment for traditional CV risk factors. High-resolution plasma metabolomics profiling and pathway analysis, followed by metabolite confirmation with mass spectrometry were used to derive a metabolomics score (MS) from metabolites that were significantly associated with RHI, different between blacks and whites, and attenuated the association of black race with RHI. Results: Black subjects were younger in both the HFrEF and control cohorts. Blacks with HFrEF were more likely to have nonischemic HF and hypertension, more likely to be on hydralazine-nitrates and diuretics. RHI was lower in blacks than whites both in subjects with HFrEF (1.8 ± 0.5 vs. 2.0 ± 0.5, P=0.02) and in healthy controls (2.1 ± 0.5 vs. 2.4 ± 0.5, P=0.003). Black race was independently associated with lower RHI (adjusted β=-0.221, P=0.03). MS comprising metabolites representative of cardiac cachexia (3-Methyl-Histidine, L-Histidine, Creatinine), vascular collagen turnover (4-hydroxyproline), purine metabolism and oxidative stress (uric acid) attenuated the association of black race with RHI by 49.8%. Conclusion: Integration of vascular phenotyping with metabolomic profiling reveals a novel MS that attenuates the association of black race with impaired microvascular function.

Introduction: Arterial stiffness is a precursor for 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 Blacks remain unknown. We examined whether physical activity levels were associated with arterial stiffness among Blacks in two independent cohorts. Methods: In the Morehouse-Emory Cardiovascular (MECA) Center for Health Equity, 458 Black adults (age 53 ± 10, 39% male) without known CVD living in Atlanta, GA were recruited. Arterial stiffness was measured as pulse wave velocity (PWV) using applanation tonometry (Sphygmocor Inc). Total and domain specific physical activity (work, active living, household, and sport/exercise) were assessed by self-report using the Jackson Heart Study Physical Activity Questionnaire. Multiple linear regression models were used to investigate differences after adjusting for age, gender, blood pressure, diabetes, and smoking. Change in the Framingham Risk Score (FRS) was tested as a potential mediator. Findings were validated in the Emory-Morehouse Partnership to Reduce Cardiovascular Health Disparities (META-Health) --another independent cohort of Black adults (n=60, age 50 ± 10, 25% male). Results: Lower arterial stiffness was associated with higher self-reported levels of sport/exercise (Beta = -0.54 [-1.03, -0.05], p=0.03, highest versus lowest quartile), but not work, active living, household-related physical activities, or the overall physical activity scores. 26.9% of this improvement appeared to be mediated through changes in FRS factors. These findings were confirmed in an independent group of Blacks in META-Health where higher levels of sport/exercise remained associated with lower arterial stiffness (Beta = -1.46 [-2.80, -0.12], p=0.03, highest versus lowest quartile). Conclusion: Higher sport/exercise related physical activity is associated with lower arterial stiffness in Blacks, an association that is only partially attributable to a lower traditional CVD risk factor burden.