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.

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.

Association of systemic inflammation with posttraumatic stress disorder after a myocardial infarction.

Background: Adverse mental health conditions including depression, posttraumatic stress disorder (PTSD), and anxiety are prevalent among patients who survive myocardial infarctions (MI) and are associated with adverse outcomes. The mechanisms underlying these associations, however, are not well understood. Inflammatory pathways may mediate the cardiovascular outcomes of patients with mental health disorders. We examined the bidirectional association between PTSD symptoms and inflammatory biomarkers in a young/middle-aged post MI population. We further examined how this association may differ between women and men as well as between Black and non-Black individuals. Methods: Participants included individuals with early onset MI between the ages 25 and 60. Mental health scores for depression, PTSD, perceived stress, and anxiety as well as inflammatory biomarkers, interleukin-6 (IL-6) and high sensitivity C-reactive protein (hsCRP), were collected at baseline and at six-month follow up. We examined the bidirectional changes in mental health symptoms and inflammatory biomarkers between baseline and follow-up. Results: Among 244 patients in the study (mean age: 50.8, 48.4% female, 64.3% Black), the geometric means for IL-6 level and hsCRP at rest were 1.7 pg/mL and 2.76 mg/L, respectively. Mental health scores at baseline did not consistently predict changes in inflammatory biomarkers at follow-up. However, baseline levels of both IL-6 and hsCRP were robustly associated with an increase in re-experiencing PTSD symptoms at 6 months: in adjusted linear mixed models, there was a 1.58-point increase in re-experiencing PTSD symptoms per unit of baseline hsCRP (p = 0.01) and 2.59-point increase per unit of baseline IL-6 (p = 0.02). Once the analysis was stratified by race, the association was only noted in Black individuals. Baseline inflammation was not associated with change in any of the other mental health symptom scores. Conclusion: Markers of inflammation are associated with an increase in post-event PTSD symptoms in younger or middle-aged patients who experienced an MI, especially Black patients. These results suggest a mechanistic link between inflammation and the development of PTSD among individuals with cardiovascular disease.

Mental Stress-Induced Change in Plasma Stromal Cell-Derived Factor-1 and Adverse Cardiovascular Outcomes: A Cohort Study.

Background: Acute psychological stress can provoke mental stress-induced myocardial ischemia (MSIMI) in coronary artery disease (CAD). Stromal cell-derived factor 1 (SDF1) is released in response to hypoxia, and higher levels of SDF1 are associated with adverse outcomes. We examined whether an increase in SDF1 level in response to mental stress predicts adverse outcomes in CAD patients. Methods: A total of 554 patients with stable CAD (mean age 63 years; 76% male; 26% Black) underwent standardized mental stress testing. Plasma SDF1 levels were measured at rest and 90 minutes after mental stress, and MSIMI was evaluated by 99mTc-sestamibi perfusion imaging. Participants were followed for 5 years for the primary endpoint of composite of death and myocardial infarction (MI) and the secondary endpoint of composite of death, MI, and heart failure hospitalization. Cox hazard models were used to assess the association between SDF1 change and incident adverse events. Results: Mean (standard deviation) SDF1 change with mental stress was +56.0 (230) pg/mL. During follow-up, a rise of 1 standard deviation in SDF1 with mental stress was associated with a 32% higher risk for the primary endpoint of death and MI (95% confidence interval, 6%-64%), independent of the resting SDF1 level, demographic and clinical risk factors, and presence of ischemia. A rise of 1 standard deviation in SDF1 was associated with a 33% (95% confidence interval, 11%-59%) increase in the risk for the secondary endpoint, independent of the resting SDF1 level, demographic, and clinical risk factors and presence of ischemia. Conclusions: An increase in SDF1 level in response to mental stress is associated with a higher risk of adverse events in stable CAD, independent of MSIMI.

Contexte: Un stress psychologique aigu peut provoquer une ischémie myocardique induite par le stress mental chez les patients atteints d'une coronaropathie. Le facteur dérivé des cellules stromales de type 1 (SDF1) est libéré en réponse à une hypoxie, et des taux accrus de SDF1 sont associés à des résultats défavorables. Nous avons examiné si une élévation des taux de SDF1 en réponse à un stress mental permettait de prévoir la survenue de résultats défavorables chez des patients atteints d'une coronaropathie. Méthodologie: Au total, 554 patients présentant une coronaropathie stable (âge moyen de 63 ans; 76 % d'hommes; 26 % de patients de race noire) ont subi une évaluation standardisée du stress mental. Les taux plasmatiques de SDF1 ont été mesurés au repos et 90 minutes après un stress mental, et l'ischémie myocardique induite par le stress mental a été évaluée par imagerie avec injection de Tc-99m sestamibi. Les participants ont fait l'objet d'un suivi pendant cinq ans afin de surveiller la survenue des événements constituant le paramètre d'évaluation principal composé (décès et infarctus du myocarde [IM]) et le paramètre d'évaluation secondaire composé (décès, IM et hospitalisation en raison d'une insuffisance cardiaque). Des modèles de Cox ont été utilisés pour évaluer le lien entre la modification des taux de SDF1 et les événements indésirables susceptibles de survenir. Résultats: La variation moyenne du taux de SDF1 (écart-type) associée au stress mental a été de +56,0 (230) pg/ml. Pendant le suivi, une augmentation de 1 écart-type du taux de SDF1 en raison du stress mental a été associée à un risque 32 % plus élevé de survenue de l'un des événements constituant le paramètre d'évaluation principal (décès et IM) [intervalle de confiance [IC] à 95 % : 6 % à 64 %], indépendamment du taux de SDF1 au repos, des caractéristiques démographiques, des facteurs de risque clinique et de la présence d'une ischémie. Une augmentation de 1 écart-type du taux de SDF1 a été associée à un risque 33 % plus élevé (IC à 95 % : 11 % à 59 %) de survenue de l'un des événements constituant le paramètre d'évaluation secondaire, indépendamment du taux de SDF1 au repos, des caractéristiques démographiques, des facteurs de risque clinique et de la présence d'une ischémie. Conclusions: Une augmentation du taux de SDF1 en réponse à un stress mental est associée à une augmentation du risque d'événements indésirables chez les patients atteints d'une coronaropathie stable, indépendamment de la présence d'une ischémie myocardique induite par le stress mental.

Association between symptoms of psychological distress and cognitive functioning among adults with coronary artery disease.

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.

Soluble Urokinase-Type Plasminogen Activator Receptor and High-Sensitivity Troponin Levels Predict Outcomes in Nonobstructive Coronary Artery Disease.

Background Multiple biomarkers have been independently and additively associated with major adverse cardiovascular events in patients with coronary artery disease. We investigated the prognostic value of suPAR (soluble urokinase-type plasminogen activator receptor) and hsTnI (high-sensitivity troponin I) levels in symptomatic patients with no obstructive coronary artery disease. We hypothesized that high levels of these biomarkers will be associated with the risk of future adverse outcomes. Methods and Results Plasma levels of suPAR and hsTnI were measured in 556 symptomatic patients with no obstructive coronary artery disease. A biomarker risk score was calculated by counting the number of biomarkers above the median in this cohort (suPAR>2523 pg/mL and hsTnI>2.7 pg/mL). Survival analyses were performed with models adjusted for traditional risk factors. All-cause death and major adverse cardiovascular events (cardiovascular death, myocardial infarction, stroke, and heart failure) served as clinical outcomes over a median follow-up of 6.2 years. Mean age was 57±10 years, 49% of the cohort patients were female, and 68% had a positive stress test. High suPAR and hsTnI levels were independent predictors of all-cause death (hazard ratio=3.2 [95% CI, 1.8-5.7] and 1.3 [95% CI, 1.0-1.7], respectively; both P<0.04) and major adverse cardiovascular events (hazard ratio=2.7 [95% CI, 1.4-5.4] and 1.5 [95% CI, 1.2-2.0], respectively; both P<0.002). Compared with a biomarker risk score of 0, biomarker risk scores of 1 and 2 were associated with 19- and 14-fold increased risk of death and development of major adverse cardiovascular events, respectively. Conclusions Among symptomatic patients with no obstructive coronary artery disease, higher levels of suPAR and hsTnI were independently and additively associated with an increased risk of adverse events. Whether modification of these biomarkers will improve risk in these patients needs further investigation.

Neural Correlates of Stress and Abdominal Obesity in Patients With Coronary Artery Disease.

OBJECTIVE: This study aimed to investigate the relationship between waist circumference as a measure of abdominal obesity and brain responses to stress among patients with coronary artery disease (CAD). METHODS: Patients with CAD (N = 151) underwent acute mental stress tasks in conjunction with high-resolution positron emission tomography and radiolabeled water imaging of the brain. Brain responses to mental stress were correlated with waist circumference. RESULTS: Waist circumference was positively correlated with increased activation in the right and left frontal lobes (ß values ranging from 2.81 to 3.75 in the paracentral, medial, and superior gyri), left temporal lobe, left hippocampal, left amygdala, left uncus, and left anterior and posterior cingulate gyri (ß values ranging from 2.93 to 3.55). Waist circumference was also negatively associated with the left and right parietal lobes, right superior temporal gyrus, and right insula and precuneus (ß values ranging from 2.82 to 5.20). CONCLUSION: Increased brain activation in the brain regions involved in the stress response and autonomic regulation of the cardiovascular system during psychological stress may underlie stress-induced overeating and abdominal obesity in patients with CAD.