OBJECTIVE:We studied responses to acute mental stress in individuals with stable coronary artery disease (CAD) with and without heart failure with reduced ejection fraction (HFrEF). METHODS:Individuals with stable CAD ( N = 313, 45 with HFrEF) underwent a laboratory-based mental stress. HFrEF was defined as an ejection fraction of <40%. Hemodynamic reactivity and vasoconstriction during mental stress were evaluated using changes in systolic blood pressure and peripheral arterial tonometry, respectively. Immune function was assessed by measuring changes in interleukin-6 (IL-6) and circulating progenitor cell counts enumerated using flow cytometry of CD34-expressing mononuclear cells before and 90 minutes after mental stress. RESULTS:During the mental stress testing, patients in the HFrEF exhibited a smaller (blunted) increase in systolic blood pressure compared with the non HFrEF group (30.4 ± 14.1 vs 41.9 ± 16.1 mm Hg, p < .001), greater vasoconstriction (PAT ratio 0.69 ± 0.30 vs 0.83 ± 0.40, p = .02), a larger increase in IL-6 levels (0.91 ± 0.11 vs 0.42 ± 0.14 pg/mL, p = .01), and larger increases in circulating progenitor cell counts (0.68 ± 0.12 vs 0.22 ± 0.11 cell/L, p = .009). After adjustment for demographic and traditional risk factors, each of these 4 maladaptive stress responses remained independently associated with the presence of HFrEF. CONCLUSIONS:Among individuals with stable CAD, the presence of HFrEF was independently associated with a blunted systolic blood pressure response, greater vasoconstriction, increased inflammation, and enhanced progenitor cell mobilization with mental stress, a response that is associated with adverse long-term outcomes.

Introduction: Air pollution is recognized as an important environmental risk factor for cardiovascular risk, but how combined measures of air pollution contribute to this risk and potential disparities need further investigation. Hypothesis: Patients with a recent myocardial infarction (MI) living in neighborhoods with higher rankings for a composite measure of air pollution would have a greater risk of major adverse cardiovascular events (MACE). Methods: We studied 281 patients recruited from Emory-based hospitals in the Myocardial Infarction and Mental Stress 2 (MIMS2) Study. Participants’ residential addresses were geocoded and a composite measure of air pollution at the census-tract level was calculated by the Centers for Disease Control and Prevention as part of their environmental justice index for: 1) ozone; 2) particulate matter with a diameter of 2.5 microns or less; 3) diesel particulate matter; and 4) air toxics for cancer risk. An overall score for air pollution is based on percentile ranks (0-100%) with higher values indicating greater burden of air pollution. Participants were prospectively followed for 5 years from their initial baseline visit and MACE was defined as a composite index of cardiovascular death and first/recurring events of myocardial infarction and hospitalizations for heart failure. Cox proportional hazards models were used to estimate the regression parameters accounting for clustering of recurrent events and individuals within census-tracts. Hazard ratios were estimated per 10-unit increase in percentile ranking for air pollution. Results: The mean age of the sample was 51 years (range: 26-61); 50% were women and 67% African American. During a median follow-up of 4.3 years, there were 151 adverse cardiovascular events (first and repeated). In models adjusted for sex, race, age, education, cardiovascular risk factors, and MI severity indicators, each 10-unit increase in percentile ranking for air pollution was associated with 64% greater risk of MACE (HR: 1.64, 95% CI: 1.18, 2.29; p = 0.003) among women, but not among men (HR: 1.01; 95% CI: 0.81, 1.26; p = 0.95 (sex interaction: p = 0.01). There were no significant interactions by race. Conclusions: A composite measure of air pollution is associated with cardiovascular risk only among women with heart disease. Future studies should further explore this increased risk among women and potential biological mechanisms.

BACKGROUND:Acute psychological stress may induce physiological changes predisposing individuals to adverse health outcomes through hemodynamic and vascular effects. We studied the association between the aggregated stress-induced changes in hemodynamic and vascular function tests with adverse cardiovascular outcomes in patients with coronary artery disease, after adjusting for sociodemographic and clinical factors. METHODS AND RESULTS:Individuals with stable coronary artery disease from 2 prospective cohort studies were studied. Hemodynamic reactivity, changes in endothelial function, and vasoconstriction during mental stress were evaluated using changes in rate-pressure product, brachial artery flow-mediated vasodilation, and peripheral arterial tonometry, respectively. A cardiovascular reactivity risk score was calculated by allotting 0 to 3 points for each quartile of increasing abnormality for each of the 3 reactivity responses and summing the quartile points from the MIPS (Mental Stress Ischemia Prognosis Study) to yield a cardiovascular reactivity risk score ranging from 0 to 9. The outcome was a composite of cardiovascular death, nonfatal myocardial infarction, and heart failure hospitalizations during follow-up. A total of 629 participants were included. After adjustment for demographic and traditional risk factors, a blunted hemodynamic response, a greater decrease in flow-mediated vasodilation, and a greater degree of peripheral vasoconstriction to mental stress were all independently associated with a higher risk of adverse outcomes in both cohorts. By adding the cardiovascular reactivity risk score, the C-statistic increased significantly by 10% (P<0.001). CONCLUSIONS:Among individuals with stable coronary artery disease, a risk score derived from cardiovascular reactivity to mental stress was predictive of adverse cardiovascular outcomes beyond traditional cardiovascular risk factors.

Mild cognitive impairment and Alzheimer's disease contribute to cognitive decline in the aging population, affecting 10–20% of adults ≥60 years and 50 million individuals globally, respectively. Chronic inflammation is implicated in their pathogenesis, but relationships remain unclear. This study examined longitudinal associations between inflammatory biomarkers and cognition in 4228 English Longitudinal Study of Aging participants over two- and ten-year follow-ups. Mixed-effects models evaluated C-reactive protein, ferritin, fibrinogen, and white blood cell count in relation to memory, executive function, processing speed, and overall cognition. The results indicated cumulative inflammation-related cognitive decline in adults aged ≥75 years.

Background:Heart failure (HF) is a common complication in individuals with coronary artery disease (CAD). Autonomic effects of psychological stress may play an important, under-recognized role in this relationship. We hypothesized that stress-induced autonomic dysfunction, measured by change in low-frequency heart rate variability (HRV) during mental stress challenge, associates with increased HF risk. Methods:We examined 662 participants with stable CAD and no known diagnosis of HF who underwent mental stress challenge via a standardized speaking task in conjunction with Holter monitoring. We evaluated HRV in 5-minute windows and examined its change from rest to stress as our primary exposure. Repeated events Cox proportional hazard models were used to examine incident and recurrent acute HF in the outpatient and inpatient setting. Results:The mean age was 58 years, 35 % were women, and 43 % self-identified as Black. In models adjusted for age, sex, race, comorbidities, ejection fraction, and resting low-frequency HRV, each standard deviation decrease (negative change) in low-frequency HRV change from rest to stress was associated with an increased risk of incident and recurrent acute HF (HR 1.39 [95 % CI 1.02-1.90], p = 0.035) over a median follow-up of 5.7 years. These estimates for HF risk were higher than those of resting HRV. Conclusion:Greater decreases in low-frequency HRV change during acute mental stress challenge independently associate with higher risks of future HF development in individuals with stable CAD and had stronger effect sizes than resting HRV alone, highlighting an important role of stress autonomic pathways in the pathogenesis of HF.

BACKGROUND:Posttraumatic stress disorder (PTSD) is associated with maladaptive dysregulation of stress response systems, which could lead to an increased risk of heart failure. We investigated whether PTSD was independently associated with first and recurrent heart failure hospitalizations in the setting of coronary artery disease.METHODS:Individuals with stable coronary artery disease and without heart failure at baseline were enrolled in 2 parallel prospective cohort studies in metropolitan Atlanta, GA. Participants underwent a structured clinical interview to assess their lifetime history of PTSD. Current PTSD symptoms were assessed using the PTSD symptom checklist. Participants were followed up for a median time of 4.9 years. The primary end point was first or recurrent hospitalization for heart failure. Secondary end points included cardiovascular death and nonfatal myocardial infarction with and without hospitalization for heart failure. Survival analysis for repeated events was used to assess the association of PTSD with adverse events.RESULTS:We studied 736 individuals with a mean age of 60 +/- 10 years; 36% were Black, and 35% were women. In total, 69 (9.4%) patients met the criteria for PTSD. Having a PTSD diagnosis was associated with the primary end point of first or recurrent heart failure hospitalizations, with a hazard ratio of 4.4 (95% CI, 2.6-7.3). The results were minimally attenuated after adjusting for demographic and clinical factors (hazard ratio, 3.7 [95% CI, 2.1-6.3]). Similarly, a 10-point increase in the PTSD symptom checklist score was associated with a 30% (95% CI, 10%-50%) increase in heart failure hospitalizations. PTSD was not associated with an end point of cardiovascular death or nonfatal myocardial infarction, which excluded hospitalizations due to heart failure.CONCLUSIONS:Among patients with coronary artery disease, PTSD is associated with incident and recurrent heart failure hospitalizations. Future research is needed to investigate whether PTSD management can reduce the risk of heart failure.

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.

Aims The mechanisms linking acute psychological stress to cardiovascular disease (CVD) mortality are incompletely understood. We studied the relationship of electrocardiographic measures of autonomic dysfunction during acute mental stress provocation and CVD death.Methods and results In a pooled cohort of 765 participants with stable CVD from two related studies, we collected Holter data during standardized laboratory-based mental stress testing with a speech task and followed them for events. We assessed autonomic function using low-frequency (LF) heart rate variability (HRV) in 5-min intervals before, during, and after stress induction, and specifically examined changes from rest to stress. We employed cause-specific survival models to examine its association with CVD and all-cause mortality, controlling for demographic and CVD risk factors. The mean (SD) age was 58 (10) years, 35% were women, and 44% self-identified as Black. After a median follow-up of 5.6 years, 37 (5%) died from CVD causes. A stress-induced LF HRV decrease (67% of sample), vs. increase, was associated with a hazard ratio (HR) of 3.48 (95% confidence interval-3.25, 3.73) for CVD mortality. Low rest LF HRV (bottom quartile) was also independently associated with CVD mortality, HR = 1.75 (1.58, 1.94), vs. normal rest LF HRV (upper three quartiles). The combination of stress-induced LF HRV decrease and low rest LF HRV was associated with HR = 5.73 (5.33, 6.15) vs. the normal stress/rest LF HRV reference. We found similar results with HF HRV.Conclusion Stress-induced LF HRV decrease and low rest LF HRV are both independently and additively associated with a higher CVD mortality risk. Additional research is needed to assess whether targeting autonomic dysfunction may improve CVD outcomes.

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:A total of 779 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 <.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 <.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.

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.

The multiple pathogenetic mechanisms underlying Alzheimer's disease (AD) remain a subject of intense ongoing research. An estimated 10% to 20% of people over 60 years live with mild cognitive impairment (MCI), and 10% to 15% of those with MCI will progress to clinical dementia within a year. 1 Yaffe K Petersen RC Lindquist K Kramer J Miller B. Subtype of mild cognitive impairment and progression to dementia and death. Dement Geriatr Cogn Disord. 2006; 22: 312-319 Crossref PubMed Scopus (247) Google Scholar Although the hallmark of cardiovascular disease (CVD) is vascular dysfunction, and CVD shares numerous risk factors with AD, the complex interplay between vascular dysfunction and AD needs to be further clarified. 2 Attems J Jellinger KA. The overlap between vascular disease and Alzheimer's disease—lessons from pathology. BMC Med. 2014; 12: 206 Crossref PubMed Scopus (479) Google Scholar

BackgroundMental 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 ResultsWe 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]).ConclusionsAmong 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.

Aims:The mechanisms linking acute psychological stress to cardiovascular disease (CVD) mortality are incompletely understood. We studied the relationship of electrocardiographic measures of autonomic dysfunction during acute mental stress provocation and CVD death. Methods and results:In a pooled cohort of 765 participants with stable CVD from two related studies, we collected Holter data during standardized laboratory-based mental stress testing with a speech task and followed them for events. We assessed autonomic function using low-frequency (LF) heart rate variability (HRV) in 5-min intervals before, during, and after stress induction, and specifically examined changes from rest to stress. We employed cause-specific survival models to examine its association with CVD and all-cause mortality, controlling for demographic and CVD risk factors. The mean (SD) age was 58 (10) years, 35% were women, and 44% self-identified as Black. After a median follow-up of 5.6 years, 37 (5%) died from CVD causes. A stress-induced LF HRV decrease (67% of sample), vs. increase, was associated with a hazard ratio (HR) of 3.48 (95% confidence interval-3.25, 3.73) for CVD mortality. Low rest LF HRV (bottom quartile) was also independently associated with CVD mortality, HR = 1.75 (1.58, 1.94), vs. normal rest LF HRV (upper three quartiles). The combination of stress-induced LF HRV decrease and low rest LF HRV was associated with HR = 5.73 (5.33, 6.15) vs. the normal stress/rest LF HRV reference. We found similar results with HF HRV. Conclusion:Stress-induced LF HRV decrease and low rest LF HRV are both independently and additively associated with a higher CVD mortality risk. Additional research is needed to assess whether targeting autonomic dysfunction may improve CVD outcomes.

Background: An established link exists between acute mental stress and the development of transient endothelial dysfunction (TED) as assessed by brachial artery flow-mediated vasodilation (FMD). Black individuals have a high burden of cardiovascular (CV) risk factors and social disadvantages, which may result in adverse vascular responses to stress. We investigated differences in TED with mental stress in Black and non-Black individuals with coronary artery disease (CAD), and whether TED is associated with CV outcomes in both groups. Methods: We enrolled 812 patients with stable CAD between June 2011 and March 2016 and followed them through February 2020. Study participants were subjected to a public-speaking mental stress task and FMD (derived from % vasodilation with brachial artery hyperemia testing) was assessed by ultrasound before and 30 minutes after mental stress. TED was defined as a lower post-stress FMD than pre-stress FMD. We compared pre-stress FMD, post-stress FMD, and TED between Black and non-Black participants. In both groups, we examined the association of TED with an adjudicated composite end point of CV death and myocardial infarction (MI) after adjusting for demographic, clinical, and socioeconomic factors. Both first and recurring events were counted and multivariable models for repeated events were used for analysis. Results: The mean (SD) age was 59 (10) years, and 328 (40%) were Black. Pre-stress FMD was lower in Black than non-Black participants [3.7 (2.8) vs. 4.9 (3.8) p<0.001], and significantly declined with mental stress in both groups. TED occurred more often in Black (76%) than non-Black patients (67%), age- and sex-adjusted OR, 1.6, 95% CI, 1.4-1.7). Race related differences in TED persisted after adjustment for demographic factors, CAD risk factors and medications (Black vs. non-Black OR, 1.6, 95% CI, 1.5-1.7). After further adjusting for socioeconomic indicators (education, income, and employment status), TED remained elevated in Black patients (OR, 1.4 (95% CI, 1.3-1.6). Over a median (interquartile range) follow-up period of 75 (65-82) months, 142 (18%) patients had at least one event. Development of TED with mental stress was associated with an increased risk for the study outcome both in Black (age- and sex-adjusted HR, 3.0; 95% CI, 1.3-6.8) and non-Black participants (HR, 1.7, 95% CI, 0.96-3.0), p=0.26 for interaction. Adjustment for demographic, clinical and socioeconomic factors did not diminish these associations. Conclusions: Among CAD patients, Black individuals are more likely than non-Black individuals to develop endothelial dysfunction with mental stress, which in turn is associated with an increased risk of adverse cardiovascular events. Endothelial dysfunction in response to psychological stress may represent an important mechanism for the disproportionate risk of adverse CV outcomes in Black patients.

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.

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 mono-nuclear 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.

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.

Introduction: Cardiovascular disease (CVD) and Alzheimer’s Dementia (AD) share numerous risk factors, with vascular dysfunction a common underlying mechanism. Individuals with mild cognitive impairment (MCI) have a high likelihood of developing AD in their lifetime. The link between microvascular dysfunction (MVD) and AD has yet to be fully established. Hypothesis: We examined the contribution of MVD to MCI with the hypothesis that Black Americans, who have a higher prevalence of MVD, will have higher rates of MCI. Methods: Participants >50 years with MCI or with normal cognition (NC) were enrolled for neuropsychological and microvascular function testing using peripheral arterial tonometry. Microvascular function was measured as the reactive hyperemia index (RHI) and calculated as the ratio of the post- to pre-occlusion pulse volume in the fingertip (EndoPAT). Multivariate analyses, adjusting for demographic and CVD risk factors associated with MCI, evaluated the relationship between RHI and MCI in Black and White participants. Causal mediation analysis, using the Monte Carlo approach, was performed to investigate whether the effect of RHI on MCI was mediated through plausible mediators, including risk factors. Results: Of 152 participants (NC=104, MCI=48), 41.4% were Black and 33.6% male. Participants with MCI were more likely to be Black (58.3% vs 33.7%%, p=0.007) and have lower RHI (1.93 vs 2.27, p=0.004) compared to NC. RHI was an independent predictor of MCI with a 96% adjusted greater odds of MCI per unit reduction in RHI. Black race remained an independent predictor of MCI (OR 2.90, 95% CI [1.16, 7.56]). RHI was lower in Black compared to White participants (1.86 vs 2.37, p<0.001). There was no heterogeneity in the impact of RHI on MCI. In a casual mediation analysis, MCI was mediated via RHI more in Black than in White participants (proportion mediated 24.2% vs 18.4%, p=0.034) after multivariate adjustment. Conclusions: Peripheral MVD, measured as RHI, was independently associated with MCI. Furthermore, Black participants exhibited lower RHI levels, a higher prevalence of MCI, and potentially mediated MCI through RHI to a greater extent compared to their White counterparts.