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.

Our study was conducted using the UK Biobank data with 227,951 women and thus includes proportionately far fewer women compared to 5.7 million cohort studied by Yang et al1. Our data also agree with observations in the South Korean cohort that the nadir of risk in women was in the 80–100mg/dL subset of high-density lipoprotein cholesterol (HDL-C) levels. The number of women with HDL-C > 100 mg/dL (n=3074, 1.3% of women) and the number of all-cause deaths (n=89) and cardiovascular death events (n=15) in this subset were also small. Although we did not have sufficient power to demonstrate statistically higher risk in this subset, in comparison with the women with HDL-C levels between 80 and 99 mg/dL, the U-shaped association was observed at the extremely high HDL-C levels, where risk appears to be higher, using both the continuous data analysis in Figure 1 and categorical analysis in Figure 2. For example, the fully adjusted hazard ratio for cardiovascular death in the subset of women with HDL-C > 100 mg/dL was 1.14 (0.65, 2.00), p=0.7, compared to women with HDL-C levels between 80 and 99 mg/dL. In this regard, our findings agree with the observations by Yang et al.

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.

Rationale: Circulating progenitor cells (CPCs) mobilize in response to ischemic injury, but their predictive value remains unknown in acute coronary syndrome (ACS). Objective: We aimed to investigate the number of CPCs in ACS compared with those with stable coronary artery disease (CAD), relationship between bone marrow PCs and CPCs, and whether CPC counts predict mortality in patients with ACS. Methods and Results: In 2028 patients, 346 had unstable angina, 183 had an acute myocardial infarction (AMI), and the remaining 1499 patients had stable CAD. Patients with ACS were followed for the primary end point of all-cause death. CPCs were enumerated by flow cytometry as mononuclear cells expressing a combination of CD34+, CD133+, vascular endothelial growth factor receptor 2+, or chemokine (C-X-C motif) receptor 4+. CPC counts were higher in subjects with AMI compared those with stable CAD even after adjustment for age, sex, race, body mass index, renal function, hypertension, diabetes mellitus, hyperlipidemia, and smoking; CD34+, CD34+/CD133+, CD34+/CXCR4+, and CD34+/VEGFR2+ CPC counts were 19%, 25%, 28%, and 142% higher in those with AMI, respectively, compared with stable CAD. There were strong correlations between the concentrations of CPCs and the PC counts in bone marrow aspirates in 20 patients with AMI. During a 2 (interquartile range, 1.31-2.86)-year follow-up period of 529 patients with ACS, 12.4% died. In Cox regression models adjusted for age, sex, body mass index, heart failure history, estimated glomerular filtration rate, and AMI, subjects with low CD34+ cell counts had a 2.46-fold (95% confidence interval, 1.18-5.13) increase in all-cause mortality, P=0.01. CD34+/CD133+ and CD34+/CXCR4+, but not CD34+/VEGFR2+ PC counts, had similar associations with mortality. Results were validated in a separate cohort of 238 patients with ACS. Conclusions: CPC levels are significantly higher in patients after an AMI compared with those with stable CAD and reflect bone marrow PC content. Among patients with ACS, a lower number of hematopoietic-enriched CPCs are associated with a higher mortality.

Background: Acute stress may trigger atrial fibrillation (AF), but the underlying mechanisms are unclear. We examined if acute mental stress results in abnormal left atrial electrophysiology as detected by more negative deflection of P-wave terminal force in lead V1(PTFV1), a well-known marker of AF risk. Methods and results: We examined this hypothesis in 422 patients (mean age = 56 ± 10 years; 61% men; 44% white) with stable coronary heart disease who underwent mental (speech task) stress testing. PTFV1was defined as the duration (milliseconds) times the value of the depth (μV) of the downward deflection (terminal portion) of the P-wave in lead V1measured on digital electrocardiograms (ECG). Electrocardiographic left atrial abnormality was defined as PTFV1≤ −4000 μV*ms. Mean PTFV1values during stress and recovery were compared with rest. The percentage of participants who developed left atrial abnormality during stress and recovery was compared with the percentage at rest. Compared with rest, PTFV1became more negative during mental stress (mean change = −348, 95% CI = [−515, −182]; P < 0.001) and no change was observed at recovery (mean change = 12, 95%CI = [−148, 172]; P = 0.89). A larger percentage of participants showed left atrial abnormality on ECGs obtained at stress (n = 163, 39%) and recovery (n = 142, 34%) compared with rest (n = 127, 30%). Conclusion: Acute mental stress alters left atrial electrophysiology, suggesting that stressful situations promote adverse transient electrical changes to provide the necessary substrate for AF.

Background Circulating NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels, a well-known indicator of atrial wall stress and remodeling, inversely correlate with body mass index. Both are strongly predictive of atrial fibrillation (AF). Their potential interaction in relation to incident AF, however, has not been explored. Methods and Results In total, 9556 participants of the ARIC (Atherosclerosis Risk in Communities) study who had 2 measurements of NT-proBNP and no baseline AF or heart failure were followed from 1996 to 1998 through 2016 for the occurrence of incident AF. Participants were categorized as obese (body mass index ≥30) and nonobese (body mass index <30) and by NT-proBNP levels (using the median of 68.2 pg/mL as the cutoff). Over a median follow-up of 18.3 years, we identified 1806 incident cases of AF. Analysis using multivariable Cox regression models showed that obese participants with high NT-proBNP levels at visit 4 had a higher adjusted risk of incident AF (hazard ratio: 3.64; 95% CI, 3.15-4.22) compared with nonobese individuals with low NT-proBNP levels. The association of obesity with AF risk was not modified by NT-proBNP levels (P=0.46 for interaction). Increasing BNP among participants from 1990-1992 to 1996-1998 was associated with increased AF risk. After further adjustment for clinical risk factors and medications, results were similar. Conclusions Individuals who had both elevated body mass index and NT-proBNP and were free of clinically recognized heart failure were at higher risk of AF development. Those who experienced an increase in NT-proBNP levels between visits 2 and 4 were at higher risk of AF.

Patients with coronary artery disease and renal insufficiency (RI) (estimated glomerular filtration rate <60 ml/min/1.73 m2) are at an increased risk of cardiovascular events. The contribution of regenerative capacity, measured as circulating progenitor cell (CPC) counts, to this increased risk is unclear. CPCs were enumerated as cluster of differentiation (CD) 45med+ mononuclear cells expressing CD34+, CD133+, CXCR4+ (chemokine [C-X-C motif] receptor 4), and VEGF2R+ (vascular endothelial growth factor receptor 2) epitopes in 1,281 subjects with coronary artery disease (35% with RI). Patients with RI and low (<median) hematopoietic CPCs (CD34+, CD34+/CD133+, and CD34+/CXCR4+) were at an increased risk of cardiovascular death or myocardial infarction events (hazard ratios: 1.75 to 1.80) during 3.5-year follow-up, while those with RI and high CPCs (>median) were at a similar risk as those without RI.

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.

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.

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.