Hemodynamic Reactivity to Mental Stress and Cognitive Function in Coronary Artery Disease.

OBJECTIVE: People with coronary artery disease (CAD) are at higher risk of cognitive impairment than those without CAD. Psychological stress is a risk factor for both conditions and assessing the hemodynamic reactivity to mental stress could explain the link between stress and cognitive function. METHODS: Individuals with stable CAD from two prospective cohort studies were included. All individuals underwent acute mental stress testing, as well as conventional stress testing. Cognitive function was assessed both at baseline and at a 2-year follow-up. The rate-pressure product (RPP) was calculated as the mean systolic blood pressure times the mean heart rate at rest. RPP reactivity was defined as the maximum RPP during standardized mental stress test minus the RPP at rest. RESULTS: After multivariable adjustment, every standard deviation decrease in RPP reactivity with mental stress was associated with slower completion of Trail-A and Trail-B in both cohorts (13% and 11% in cohort 1, and 15% and 16% in cohort 2, respectively, p for all <0.01). After a 2-year follow-up period, every standard deviation decrease in RPP reactivity with mental stress was associated with a 8%, and 9% slower completion of Trail-A and Trail-B, respectively (p for all <0.01). There was no significant association between RPP reactivity with conventional stress testing and any of the cognitive tests. CONCLUSION: In the CAD population, a blunted hemodynamic response to mental stress is associated with slower visuomotor processing and worse executive function at baseline and with greater decline in these abilities over time.

Heart Rate Variability, Deceleration Capacity of Heart Rate, and Death: A Veteran Twins Study.

BACKGROUND: Autonomic function can be measured noninvasively using heart rate variability (HRV), which indexes overall sympathovagal balance. Deceleration capacity (DC) of heart rate is a more specific metric of vagal modulation. Higher values of these measures have been associated with reduced mortality risk primarily in patients with cardiovascular disease, but their significance in community samples is less clear. METHODS AND RESULTS: This prospective twin study followed 501 members from the VET (Vietnam Era Twin) registry. At baseline, frequency domain HRV and DC were measured from 24-hour Holter ECGs. During an average 12-year follow-up, all-cause death was assessed via the National Death Index. Multivariable Cox frailty models with random effect for twin pair were used to examine the hazard ratios of death per 1-SD increase in log-transformed autonomic metrics. Both in the overall sample and comparing twins within pairs, higher values of low-frequency HRV and DC were significantly associated with lower hazards of all-cause death. In within-pair analysis, after adjusting for baseline factors, there was a 22% and 27% lower hazard of death per 1-SD increment in low-frequency HRV and DC, respectively. Higher low-frequency HRV and DC, measured during both daytime and nighttime, were associated with decreased hazard of death, but daytime measures showed numerically stronger associations. Results did not substantially vary by zygosity. CONCLUSIONS: Autonomic inflexibility, and especially vagal withdrawal, are important mechanistic pathways of general mortality risk, independent of familial and genetic factors.

Psychological Distress and the Risk of Adverse Cardiovascular Outcomes in Patients With Coronary Heart Disease.

BACKGROUND: Psychological distress is a recognized risk factor in patients with coronary heart disease (CHD), but its clinical significance is unclear. OBJECTIVES: The purpose of this study was to determine if an index of psychological distress is independently associated with adverse outcomes and significantly contributes to risk prediction. METHODS: Pooled analysis of 2 prospective cohort studies of patients with stable CHD (N = 891). A psychological distress score was constructed using measures of depression, anxiety, anger, perceived stress, and post-traumatic stress disorder, measured at baseline. The study endpoint included cardiovascular death or first or recurrent nonfatal myocardial infarction or hospitalization for heart failure at 5.9 years. RESULTS: In both cohorts, first and recurrent events occurred more often among those in the highest tertile of distress score than those in the lowest tertile. After combining the 2 cohorts, compared with the lowest tertile, the hazards ratio for having a distress score in the highest tertile was 2.27 (95% CI: 1.69-3.06), and for the middle tertile, it was 1.52 (95% CI: 1.10-2.08). Adjustment for demographics and clinical risk factors only slightly weakened the associations. When the distress score was added to a traditional clinical risk model, C-statistic, net reclassification index, and integrative discrimination index all significantly improved. CONCLUSIONS: Among patients with CHD, a composite measure of psychological distress was significantly associated with an increased risk of adverse events and significantly improved risk prediction.

Acute psychological stress-induced progenitor cell mobilization and cardiovascular events.

OBJECTIVE: Certain brain activation responses to psychological stress are associated with worse outcomes in CVD patients. We hypothesized that elevated acute psychological stress, manifesting as greater activity within neural centers for emotional regulation, mobilizes CPC from the bone marrow to the peripheral blood and predicts future cardiovascular events. METHODS: In 427 patients with stable CAD undergoing a laboratory-based mental stress (MS) test, CPCs were enumerated using flow cytometry as CD34-expressing mononuclear cells (CD34+) before and 45 min after stress. Changes in brain regional blood flow with MS were measured using high resolution-positron emission tomography (HR-PET). Association between the change in CPC with MS and the risk of cardiovascular death or myocardial infarction (MI) during a 5-year follow-up period was analyzed. RESULTS: MS increased CPC counts by a mean of 150 [630] cells/mL (15%), P < 0.001. Greater limbic lobe activity, indicative of activation of emotion-regulating centers, was associated with greater CPC mobilization (P < 0.005). Using Fine and Gray models after adjustment for demographioc, clinical risk factors and medications use, greater CPC mobilization was associated with a higher adjusted risk of adverse events; a rise of 1000 cells/mL was associated with a 50% higher risk of cardiovascular death/MI [hazards ratio, 1.5, 95% confidence interval, 1.1-2.2). CONCLUSION: Greater limbic lobe activity, brain areas involved in emotional regulation, is associated with MS-induced CPC mobilization. This mobilization isindependently associated with cardiovascular events. These findings provide novel insights into mechanisms through which psychological stressors modulate cardiovascular risk.

Association Between Symptoms of Chronic Psychological Distress and Myocardial Ischemia Induced by Mental Stress in Patients With Coronary Artery Disease.

Background Mental stress-induced myocardial ischemia is a frequent phenomenon in patients with coronary artery disease and is associated with a greater risk of future cardiovascular events. The association between chronic symptoms of psychological distress and mental stress-induced ischemia is not clear. Methods and Results We used a composite score of psychological distress derived from symptoms of depression, posttraumatic stress disorder, anxiety, anger, and perceived general stress. Participants underwent myocardial perfusion imaging with both mental (public speaking task) and conventional (exercise or pharmacological) stress testing. Overall, 142 (15.9%) patients experienced mental stress-induced myocardial ischemia. After adjusting for demographic factors, medical history, and medication use, patients in the highest tertile of psychological distress score had 35% higher odds of having mental stress-induced ischemia compared to those in the lowest tertile (odds ratio [OR], 1.35 [95% CI, 1.06-2.22]). Stratified analyses showed that the association between psychological distress score and mental stress-induced myocardial ischemia was significantly associated only within the subgroup of patients with a prior myocardial infraction, with patients with a prior myocardial infarction in the highest tertile having a 93% higher odds of developing myocardial ischemia with mental stress (95% CI, 1.07-3.60). There was no significant association between psychological distress and conventional stress-induced ischemia (OR, 1.19 [95% CI, 0.87-1.63]). Conclusions Among patients with a history of myocardial infarction, a higher level of psychosocial distress is associated with mental stress-induced myocardial ischemia but not with ischemia induced by a conventional stress test.

Hemodynamic Reactivity to Mental Stress in Patients With Coronary Artery Disease.

Importance: The clinical significance of hemodynamic reactivity to mental stress in the population with coronary artery disease (CAD) is unclear. Objective: To investigate the association between hemodynamic reactivity to mental stress and the risk of adverse cardiovascular events in patients with stable CAD. Design, Setting, and Participants: This cohort study included individuals with stable CAD from 2 prospective studies from a university-based hospital network: the Mental Stress Ischemia Prognosis Study (MIPS) and the Myocardial Infarction and Mental Stress Study 2 (MIMS2). Participants were enrolled between June 2011 and March 2016 and followed up for a median of 6.0 (IQR, 5.6-6.0) years in MIPS and 4.6 (IQR, 3.8-5.3) years in MIMS2. Data were analyzed from December 1, 2022, to February 15, 2023. Exposures: The rate-pressure product (RPP) was calculated as the mean systolic blood pressure times the mean heart rate at rest. Rate-pressure product reactivity was calculated as the maximum RPP during a standardized mental stress test minus the RPP at rest. Main Outcomes and Measures: The primary outcome was a composite of cardiovascular death or nonfatal myocardial infarction. The secondary end point additionally included hospitalizations for heart failure. Results: From the total of 938 individuals from the pooled cohort (mean [SD] age, 60.2 [10.1] years; 611 [65.1%] men), 631 participated in MIPS and 307 in MIMS2. A total of 373 individuals (39.8%) were Black, 519 (55.3%) were White, and 46 (4.9%) were of unknown race or ethnicity. The RPP increased by a mean (SD) of 77.1% (23.1%) during mental stress (mean [SD] absolute change, 5651 [2878]). For every SD decrease in RPP reactivity with mental stress, the adjusted hazard ratios for the primary and secondary end points were 1.30 (95% CI, 1.04-1.72) and 1.30 (95% CI, 1.06-1.56), respectively, in MIPS and 1.41 (95% CI, 1.06-1.97) and 1.21 (95% CI, 1.02-1.60), respectively, in MIMS2. In the pooled sample, when RPP reactivity to mental stress was added to a model including traditional clinical risk characteristics, model discrimination for adverse events improved (increase in C statistic of 5% for the primary end point; P = .009). Conclusions and Relevance: In this cohort study of individuals with stable CAD, a blunted cardiovascular reactivity to mental stress was associated with adverse outcomes. Future studies are needed to assess the clinical utility of mental stress reactivity testing in this population.

Transcutaneous vagal nerve stimulation modulates stress-induced plasma ghrelin levels: A double-blind, randomized, sham-controlled trial.

BACKGROUND: Transcutaneous cervical vagus nerve stimulation (tcVNS) has emerged as a potential treatment strategy for patients with stress-related psychiatric disorders. Ghrelin is a hormone that has been postulated to be a biomarker of stress. While the mechanisms of action of tcVNS are unclear, we hypothesized that tcVNS reduces the levels of ghrelin in response to stress. METHODS: Using a randomized double-blind approach, we studied the effects of tcVNS on ghrelin levels in individuals with a history of exposure to traumatic stress. Participants received either sham (n = 29) or active tcVNS (n = 26) after exposure to acute personalized traumatic script stress and mental stress challenges (public speech, mental arithmetic) over a three day period. RESULTS: There were no significant differences in the levels of ghrelin between the tcVNS and sham stimulation groups at either baseline or in the absence of trauma scripts. However, tcVNS in conjunction with personalized traumatic scripts resulted in lower ghrelin levels compared to the sham stimulation group (265.2 ± 143.6 pg/ml vs 478.7 ± 349.2 pg/ml, P = 0.01). Additionally, after completing the public speaking and mental arithmetic tests, ghrelin levels were found to be lower in the group receiving tcVNS compared to the sham group (293.3 ± 102.4 pg/ml vs 540.3 ± 203.9 pg/ml, P = 0.009). LIMITATIONS: Timing of ghrelin measurements, and stimulation of only left vagus nerve. CONCLUSION: tcVNS decreases ghrelin levels in response to various stressful stimuli. These findings are consistent with a growing literature that tcVNS modulates hormonal and autonomic responses to stress.

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

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

Sex Differences in Vascular Response to Mental Stress and Adverse Cardiovascular Events Among Patients With Ischemic Heart Disease.

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.

Circulating progenitor cells and outcomes in patients with coronary artery disease.

BACKGROUND: Low quantities of circulating progenitor cells (CPCs), specifically CD34+ populations, reflect impairment of intrinsic regenerative capacity. This study investigates the relationship between subsets of CPCs and adverse outcomes. METHODS: 1366 individuals undergoing angiography for evaluation of coronary artery disease (CAD) were enrolled into the Emory Cardiovascular Biobank. Flow cytometry identified CPCs as CD45med blood mononuclear cells expressing the CD34 epitope, with further enumeration of hematopoietic CPCs as CD133+/CXCR4+ cells and endothelial CPCs as vascular endothelial growth factor receptor-2 (VEGFR2+) cells. Adjusted Cox or Fine and Gray's sub-distribution hazard regression models analyzed the relationship between CPCs and 1) all-cause death and 2) a composite of cardiovascular death and non-fatal myocardial infarction (MI). RESULTS: Over a median 3.1-year follow-up period (IQR 1.3-4.9), there were 221 (16.6%) all-cause deaths and 172 (12.9%) cardiovascular deaths/MIs. Hematopoietic CPCs were highly correlated, and the CD34+/CXCR4+ subset was the best independent predictor. Lower counts (≤median) of CD34+/CXCR4+ and CD34+/VEGFR2+ cells independently predicted all-cause mortality (HR 1.46 [95% CI 1.06-2.01], p = 0.02 and 1.59 [95% CI 1.15-2.18], p = 0.004) and cardiovascular death/MI (HR 1.50 [95% CI 1.04-2.17], p = 0.03 and 1.47 [95% CI 1.01-2.03], p = 0.04). A combination of low CD34+/CXCR4+ and CD34+/VEGFR2+ CPCs predicted all-cause death (HR 2.1, 95% CI 1.4-3.0; p = 0.0002) and cardiovascular death/MI (HR 2.0, 95% CI 1.3-3.2; p = 0.002) compared to those with both lineages above the cut-offs. CONCLUSIONS: Lower levels of hematopoietic and endothelial CPCs indicate diminished endogenous regenerative capacity and independently correlate with greater mortality and cardiovascular risk in patients with CAD.

The association between baseline circulating progenitor cells and vascular function: The role of aging and risk factors.

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 <0.05) for both vascular measures. Among younger subjects (< 48 years), CPC counts were higher in those with risk factors and vascular function was better in those with higher compared to those with lower CPC counts (p for all < 0.0l). In contrast, in older participants, CPCs were not higher in those with risk factors, and vascular function was worse compared to the younger age group. A lower CPC count at baseline was an independent predictor of worsening vascular function during 2-year follow-up. 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.

Gender Disparities Between Neighborhood Social Vulnerability and Psychological Distress Among Patients with Heart Disease.

Background: Psychological 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. Materials and Methods: We studied 286 patients with heart disease recruited from Emory-based hospitals in the Myocardial Infarction and Mental Stress 2 Study (n = 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. Results: The 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; p = 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. Conclusion: Neighborhood social vulnerability may be a psychosocial stressor that potentiates women's susceptibility to adverse psychological and cardiovascular health.

Local intramuscular transplantation of autologous bone marrow mononuclear cells for critical lower limb ischaemia.

BACKGROUND: Peripheral arterial disease is a major health problem, and in about 1% to 2% of patients, the disease progresses to critical limb ischaemia (CLI), also known as critical limb-threatening ischaemia. In a substantial number of individuals with CLI, no effective treatment options other than amputation are available, with around a quarter of these patients requiring a major amputation during the following year. This is the second update of a review first published in 2011. OBJECTIVES: To evaluate the benefits and harms of local intramuscular transplantation of autologous adult bone marrow mononuclear cells (BMMNCs) as a treatment for CLI. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was 8 November 2021. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) of CLI in which participants were randomly allocated to intramuscular administration of autologous adult BMMNCs or control (either no intervention, conventional conservative therapy, or placebo). DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes of interest were all-cause mortality, pain, and amputation. Our secondary outcomes were angiographic analysis, ankle-brachial index (ABI), pain-free walking distance, side effects and complications. We assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS: We included four RCTs involving a total of 176 participants with a clinical diagnosis of CLI. Participants were randomised to receive either intramuscular cell implantation of BMMNCs or control. The control arms varied between studies, and included conventional therapy, diluted autologous peripheral blood, and saline. There was no clear evidence of an effect on mortality related to the administration of BMMNCs compared to control (risk ratio (RR) 1.00, 95% confidence interval (CI) 0.15 to 6.63; 3 studies, 123 participants; very low-certainty evidence). All trials assessed changes in pain severity, but the trials used different forms of pain assessment tools, so we were unable to pool data. Three studies individually reported that no differences in pain reduction were observed between the BMMNC and control groups. One study reported that reduction in rest pain was greater in the BMMNC group compared to the control group (very low-certainty evidence). All four trials reported the rate of amputation at the end of the study period. We are uncertain if amputations were reduced in the BMMNC group compared to the control group, as a possible small effect (RR 0.52, 95% CI 0.27 to 0.99; 4 studies, 176 participants; very low-certainty evidence) was lost after undertaking sensitivity analysis (RR 0.52, 95% CI 0.19 to 1.39; 2 studies, 89 participants). None of the included studies reported any angiographic analysis. Ankle-brachial index was reported differently by each study, so we were not able to pool the data. Three studies reported no changes between groups, and one study reported greater improvement in ABI (as haemodynamic improvement) in the BMMNC group compared to the control group (very low-certainty evidence). One study reported pain-free walking distance, finding no clear difference between BMMNC and control groups (low-certainty evidence). We pooled the data for side effects reported during the follow-up, and this did not show any clear difference between BMMNC and control groups (RR 2.13, 95% CI 0.50 to 8.97; 4 studies, 176 participants; very low-certainty evidence). We downgraded the certainty of the evidence due to the concerns about risk of bias, imprecision, and inconsistency. AUTHORS' CONCLUSIONS: We identified a small number of studies that met our inclusion criteria, and these differed in the controls they used and how they measured important outcomes. Limited data from these trials provide very low- to low-certainty evidence, and we are unable to draw conclusions to support the use of local intramuscular transplantation of BMMNC for improving clinical outcomes in people with CLI. Evidence from larger RCTs is needed in order to provide adequate statistical power to assess the role of this procedure.

Neural correlates of stress and leucocyte telomere length in patients with coronary artery disease.

BACKGROUND: Accelerated biological aging, as indicated by telomere shortening, is associated with CAD pathogenesis. In a cross-sectional study, we investigated neural correlates of acute psychological stress and short telomeres in patients with CAD. METHODS: Individuals with CAD (N = 168) underwent a validated mental stress protocol including public speaking and mental arithmetic. Imaging of the brain with [O-15] water and high-resolution positron emission tomography (HR-PET) was performed during mental stress and control conditions. Blood flow during stressful tasks (average of speech and arithmetic) and control tasks were assessed. Telomere length in peripheral leucocytes was measured by quantitative polymerase chain reaction and expressed as Telomere/Single Copy Gene (T/S) ratio. Voxel-wise regression models were constructed to assess the association between brain areas and activity during rest and mental stress after adjustments for demographic factors and clinical characteristics. RESULTS: The mean (SD) age of the sample was 62 (8) years, and 69% were men. Increased activation with mental stress in the lingual gyrus, cerebellum and superior and inferior frontal gyri were associated with reduced telomere length; 1.6 higher voxel activation of these areas was associated with 0.1 T/S-units reduction in telomere length (P < 0.005). Additionally, during neutral counting and speaking tasks, brain activity in the precentral, middle and superior frontal and middle temporal gyri was inversely associated with telomere length. Results remained consistent after adjustment for demographic and clinical risk factors. CONCLUSION: Increased stress-induced activity in brain areas mediating the stress response was associated with shortened telomere length in CAD patients.

Associations Between Inflammation, Cardiovascular Regenerative Capacity, and Cardiovascular Events: A Cohort Study.

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<0.001). Using linear regression, IL-6 and high-sensitivity CRP levels declined by -0.59 (95% CI, -0.90 to -0.20) pg/mL and -0.13 (-0.28 to 0.01) mg/L per 1 log higher CPC counts after adjustment for the demographic and clinical variables, as well as medications. Using Cox models adjusted for these risk factors, a rise in 1 pg/mL of IL-6 was associated with a 11% (95% CI, 9-13) greater risk of death/myocardial infarction. We found that the change in IL6 level partly (by 40%) mediated the higher risk of adverse events among those with low CPC counts. 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.

Racial Disparities in Adverse Cardiovascular Outcomes After a Myocardial Infarction in Young or Middle-Aged Patients.

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) <61 years old hospitalized for confirmed type 1 MI at Emory-affiliated hospitals and followed them for 5 years. We used Cox proportional-hazard models to estimate the association of race with a composite end point of recurrent MI, stroke, heart failure, or cardiovascular death after adjusting for demographic, socioeceonomic status, psychological, and clinical risk factors. The mean age was 50 years, and 50% were women. Compared with non-Black patients, Black patients had lower socioeconomic status and more clinical and psychosocial risk factors but less angiographic coronary artery disease. The 5-year incidence of cardiovascular events was higher in Black (35%) compared to non-Black patients (19%): hazard ratio (HR) 2.1, 95% CI, 1.3 to 3.6. Adjustment for socioeconomic status weakened the association (HR 1.3, 95% CI, 0.8-2.4) more than adjustment for clinical and psychological risk factors. A lower income explained 46% of the race-related disparity in outcome. 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.

Everyday Discrimination and Mental Stress-Induced Myocardial Ischemia.

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.

Neurobiological Pathways Linking Acute Mental Stress to Impairments in Executive Function in Individuals with Coronary Artery Disease.

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.

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

[Figure: see text].