Introduction: Hemodynamic responses to mental stress (MS) have been associated with adverse CV outcomes. We investigated if hemodynamic responses during laboratory MS testing are predictive of outcomes. Hypothesis: Lower rate pressure product (RPP) changes during MS testing are predictive of adverse CV events. Methods: Patients recruited into the Mental Stress Ischemia Prognosis Study and Myocardial Infarction and Mental Stress Study 2 studies underwent MS testing with a standardized public speaking stressor and followed for incident CV death, MI rates (primary endpoint) and heart failure hospitalizations (secondary endpoint). Maximum changes in the RPP during MS were calculated. A generalized linear mixed model determined predictors of RPP change, and Prentice, Williams, Peterson model gap time approach was used for analysis of recurrent events after adjustment for demographic and clinical variables. Results: In 919 patients (mean 59.6 years; 65.6% men), the median change in RPP was 5,112 mmHg x beats/minute (IQR, 3,666 - 7,120). Patients with lower RPP changes (<median) during MS were more likely to have a lower resting RPP, be male, and have a history of smoking, obesity, and heart failure. Serum epinephrine levels (22.5 ± 37.3 pg/mL; p<0.001) increased after MS and correlated with RPP changes (r = 0.32; p < 0.001). During a mean follow-up of 4.6 years, there were 135 CV death and MI events (3.2/100 patient-years) and 279 events including HF hospitalizations (6.7 events/100 patient-years). After adjusting for the baseline RPP, demographics, clinical factors, and medication, patients with lower change in RPP during MS had higher primary [HR, 1.7 (95% CI, 1.1 - 2.5); p = 0.009] and secondary events [HR, 1.5 (95% CI, 1.1 - 2.0); p = 0.006]. Conclusions: A reduced change in RPP during MS is independently associated with worse outcomes in patients with CAD. Whether hemodynamic reactivity during MS can be clinically used to identify residual risk needs further evaluation.

Background Early life trauma has been associated with increased cardiovascular risk, but the arrhythmic implications are unclear. We hypothesized that in patients with coronary artery disease, early life trauma predicts increased arrhythmic risk during mental stress, measured by elevated microvolt T‐wave alternans (TWA), a measure of repolarization heterogeneity and sudden cardiac death risk. Methods and Results In a cohort with stable coronary artery disease (NCT04123197), we examined early life trauma with the Early Trauma Inventory Self Report‐Short Form. Participants underwent a laboratory‐based mental stress speech task with Holter monitoring, as well as a structured psychiatric interview. We measured TWA during rest, mental stress, and recovery with ambulatory electrocardiographic monitoring. We adjusted for sociodemographic factors, cardiac history, psychiatric comorbidity, and hemodynamic stress reactivity with multivariable linear regression models. We examined 320 participants with noise‐ and arrhythmia‐free ECGs. The mean (SD) age was 63.8 (8.7) years, 27% were women, and 27% reported significant childhood trauma (Early Trauma Inventory Self Report‐Short Form ≥10). High childhood trauma was associated with a multivariable‐adjusted 17% increase in TWA ( P =0.04) during stress, and each unit increase in the Early Trauma Inventory Self Report‐Short Form total score was associated with a 1.7% higher stress TWA ( P =0.02). The largest effect sizes were found with the emotional trauma subtype. Conclusions In a cohort with stable coronary artery disease, early life trauma, and in particular emotional trauma, is associated with increased TWA, a marker of increased arrhythmic risk, during mental stress. This association suggests that early trauma exposures may affect long‐term sudden cardiac death risk during emotional triggers, although more studies are warranted.

BACKGROUND:Short-duration exposure to ambient particulate matter (PM) air pollution is associated with cardiac autonomic dysfunction and prolonged ventricular repolarization. However, associations with sub-chronic exposures to coarser particulates are relatively poorly characterized as are molecular mechanisms underlying their potential relationships with cardiovascular disease. MATERIALS AND METHODS:We estimated associations between monthly mean concentrations of PM < 10 μm and 2.5-10 μm in diameter (PM10; PM2.5-10) with time-domain measures of heart rate variability (HRV) and QT interval duration (QT) among U.S. women and men in the Women's Health Initiative and Atherosclerosis Risk in Communities Study (nHRV = 82,107; nQT = 76,711). Then we examined mediation of the PM-HRV and PM-QT associations by DNA methylation (DNAm) at three Cytosine-phosphate-Guanine (CpG) sites (cg19004594, cg24102420, cg12124767) with known sensitivity to monthly mean PM concentrations in a subset of the participants (nHRV = 7,169; nQT = 6,895). After multiply imputing missing PM, electrocardiographic and covariable data, we estimated associations using attrition-weighted, linear, mixed, longitudinal models adjusting for sociodemographic, behavioral, meteorological, and clinical characteristics. We assessed mediation by estimating the proportions of PM-HRV and PM-QT associations mediated by DNAm. RESULTS:We found little evidence of PM-HRV association, PM-QT association, or mediation by DNAm. CONCLUSIONS:The findings suggest that among racially/ethnically and environmentally diverse U.S. populations, sub-chronic exposures to coarser particulates may not exert appreciable, epigenetically mediated effects on cardiac autonomic function or ventricular repolarization. Further investigation in better-powered studies is warranted, with additional focus on shorter duration exposures to finer particulates and non-electrocardiographic outcomes among relatively susceptible populations.

Acute psychological stress can provoke mental stress (MS)-induced myocardial ischemia (MSIMI) in coronary artery disease (CAD). Stromal cell-derived factor 1 alpha (SDF1) is released in response to hypoxia, and higher levels of SDF1 are associated with adverse outcomes. We examined whether change in

OBJECTIVES This study sought to investigate whether patients with mental stress-induced myocardial ischemia will have high resting and post-mental stress high-sensitivity cardiac troponin I (hs-cTnI). BACKGROUND Hs-cTnI is a marker of myocardial necrosis, and its elevated levels are associated with adverse outcomes. Hs-cTnI levels may increase with exercise in patients with coronary artery disease. Mental stress-induced myocardial ischemia is also linked to adverse outcomes. METHODS In this study, 587 patients with stable coronary artery disease underwent technetium Tc 99m sestamibi-single-photon emission tomography myocardial perfusion imaging during mental stress testing using a public speaking task and during conventional (pharmacological/exercise) stress testing as a control condition. Ischemia was defined as new/worsening impairment in myocardial perfusion using a 17-segment model. RESULTS The median hs-cTnI resting level was 4.3 (interquartile range [IQR]: 2.9 to 7.3) pg/ml. Overall, 16% and 34.8% of patients developed myocardial ischemia during mental and conventional stress, respectively. Compared with those without ischemia, median resting hs-cTnI levels were higher in patients who developed ischemia either during mental stress (5.9 [IQR: 3.9 to 8.3] pg/ml vs. 4.1 [IQR: 2.7 to 7.0] pg/ml; p < 0.001) or during conventional stress (5.4 [IQR: 3.9 to 9.3] pg/ml vs. 3.9 [IQR: 2.5 to 6.5] pg/ml; p < 0.001). Patients with high hs-cTnI (cutoff of 4.6 pg/ml for men and 3.9 pg/ml for women) had greater odds of developing mental (odds ratio [OR]: 2.4; 95% confidence interval [CI]: 1.5 to 3.9; p < 0.001) and conventional (OR: 2.4; 95% CI: 1.7 to 3.4; p < 0.001) stress-induced ischemia. Although there was a significant increase in 45-min post-treadmill exercise hs-cTnI levels in those who developed ischemia, there was no significant increase after mental or pharmacological stress test. CONCLUSIONS In patients with coronary artery disease, myocardial ischemia during either mental stress or conventional stress is associated with higher resting levels of hs-cTnI. This suggests that hs-cTnI elevation is an indicator of chronic ischemic burden experienced during everyday life. Whether elevated hs-cTnI levels are an indicator of adverse prognosis beyond inducible ischemia or whether it is amenable to intervention requires further investigation. (c) 2018 Published by Elsevier on behalf of the American College of Cardiology Foundation.

BackgroundThe response of progenitor cells (PCs) to transient myocardial ischemia in patients with coronary artery disease remains unknown. We aimed to investigate the PC response to exercise‐induced myocardial ischemia (ExMI) and compare it to flow mismatch during pharmacological stress testing. Methods and ResultsA total of 356 patients with stable coronary artery disease underwent 99mTc‐sestamibi myocardial perfusion imaging during exercise (69%) or pharmacological stress (31%). CD34+ and CD34+/chemokine (C‐X‐C motif) receptor 4 PCs were enumerated by flow cytometry. Change in PC count was compared between patients with and without myocardial ischemia using linear regression models. Vascular endothelial growth factor and stromal‐derived factor‐1α were quantified. Mean age was 63±9 years; 76% were men. The incidence of ExMI was 31% and 41% during exercise and pharmacological stress testing, respectively. Patients with ExMI had a significant decrease in CD34+/chemokine (C‐X‐C motif) receptor 4 (−18%, P=0.01) after stress that was inversely correlated with the magnitude of ischemia (r=−0.19, P=0.003). In contrast, patients without ExMI had an increase in CD34+/chemokine (C‐X‐C motif) receptor 4 (14.7%, P=0.02), and those undergoing pharmacological stress had no change. Plasma vascular endothelial growth factor levels increased (15%, P<0.001) in all patients undergoing exercise stress testing regardless of ischemia. However, the change in stromal‐derived factor‐1α level correlated inversely with the change in PC counts in those with ExMI (P=0.03), suggesting a greater decrease in PCs in those with a greater change in stromal‐derived factor‐1α level with exercise. ConclusionsExMI is associated with a significant decrease in circulating levels of CD34+/chemokine (C‐X‐C motif) receptor 4 PCs, likely attributable, at least in part, to stromal‐derived factor‐1α–mediated homing of PCs to the ischemic myocardium. The physiologic consequences of this uptake of PCs and their therapeutic implications need further investigation.

Background Coronary microvascular dysfunction may contribute to myocardial ischemia during mental stress ( MS ). However, the role of coronary epicardial and microvascular function in regulating coronary blood flow ( CBF ) responses during MS remains understudied. We hypothesized that coronary vasomotion during MS is dependent on the coronary microvascular endothelial function and will be reflected in the peripheral microvascular circulation. Methods and Results In 38 patients aged 59±8 years undergoing coronary angiography, endothelium‐dependent and endothelium‐independent coronary epicardial and microvascular responses were measured using intracoronary acetylcholine and nitroprusside, respectively, and after MS induced by mental arithmetic testing. Peripheral microvascular tone during MS was measured using peripheral arterial tonometry (Itamar Inc, Caesarea, Israel) as the ratio of digital pulse wave amplitude compared to rest (peripheral arterial tonometry ratio). MS increased the rate‐pressure product by 22% (±23%) and constricted epicardial coronary arteries by −5.9% (−10.5%, −2.6%) (median [interquartile range]), P =0.001, without changing CBF . Acetylcholine increased CBF by 38.5% (8.1%, 91.3%), P =0.001, without epicardial coronary diameter change (0.1% [−10.9%, 8.2%], P =not significant). The MS ‐induced CBF response correlated with endothelium‐dependent CBF changes with acetylcholine ( r =0.38, P =0.03) but not with the response to nitroprusside. The peripheral arterial tonometry ratio also correlated with the demand‐adjusted change in CBF during MS ( r =−0.60, P =0.004), indicating similarity between the microcirculatory responses to MS in the coronary and peripheral microcirculation. Conclusions The coronary microvascular response to MS is determined by endothelium‐dependent, but not endothelium‐independent, coronary microvascular function. Moreover, the coronary microvascular responses to MS are reflected in the peripheral microvascular circulation.

Background: Mental stress induced myocardial ischemia (MSIMI) is linked to increased risk of adverse cardiovascular outcomes, but its mechanisms are thought to be different from those of conventional stress-induced ischemia (CSIMI). Specifically, whether MSIMI is associated with more severe underlying obstructive coronary artery disease (CAD) is unclear. We investigated the association between angiographically-defined CAD severity and both MSIMI and CSIMI with a hypothesis that, CAD severity will be linked to CSIMI, but not MSIMI. Methods: A total of 273 patients with stable CAD, aged 51±7 years, 49% female, who survived a myocardial infarction (MI) within the past 8 months (median 167±52 days) were enrolled in the Myocardial Infarction and Mental Stress 2 (MIMS-2) study. The coronary angiogram performed during the index MI hospitalization was used to assess CAD severity. Coronary artery obstruction was assessed by counting the number of diseased vessels with 70% stenosis (DV70%) and using the Gensini Score (GS) after correcting for revascularized vessels. Patients underwent 99mTc sestamibi myocardial perfusion imaging during mental stress, using a public speaking task, and during conventional stress test, using exercise or pharmacological stress. MSIMI and CSIMI were defined as a new or worsening impairment in myocardial perfusion using a 17-segment model. Results: A total of 68 (26%) patients developed CSIMI, while 46 (17%) developed MSIMI. Median DV70% and GS were 0 (0-1), and 3 (0-12), respectively. Using logistic regression models, and after adjustment for age, gender, hypertension, hyperlipidemia and diabetes, obstructive CAD was associated with increased risk of CSIMI [OR(95%CI) of 1.54 (1.02 - 2.31) for DV70% and 1.25 (1.03-1.53), for GS], but not MSIMI [OR(95%CI) of 0.93 (0.56 - 1.53) for DV70%, and 0.94 (0.75-1.18) for GS]. Conclusion: Although CSIMI is linked to underlying coronary obstruction, MSIMI is independent of CAD severity among post- MI patients. Other mechanisms are likely responsible for MSIMI post MI.

Background: Circulating progenitor cells (CPCs) are involved in vascular repair and regeneration. Low levels of CPCs in patients with CAD have been linked to adverse cardiovascular outcomes. The response of CPCs to transient myocardial ischemia in patients with CAD has not been studied before. We aimed to investigate the CPC response to exercise provoked myocardial ischemia (demand ischemia), and compare it to myocardial ischemia detected during pharmacological stress test (flow mismatch). Methods: 570 patients with stable CAD underwent 99mTc sestamibi myocardial perfusion imaging during exercise (69%), or pharmacological stress (31%). myocardial ischemia was defined as a new or worsening impairment in myocardial perfusion using a 17-segment model. CD34+ CPCs were enumerated by flow cytometry at rest and 30 min after stress testing. The change in CPC count was compared between patients with and without myocardial ischemia using mixed linear models. Results: Mean age was 63±9 years, 76% males, 36% with previous myocardial infarction. The incidence of myocardial ischemia was 31% and 41% during exercise and pharmacological stress test, respectively. No difference was observed in resting CPC between patients undergoing exercise vs pharmacological stress test, nor between patients with or without myocardial ischemia. However, patients who developed myocardial ischemia during exercise stress had a significant decrease in CPC with stress in comparison to those without myocardial ischemia (-12% vs 4%, respectively, p=0.006). Furthermore, the change in CPCs was inversely correlated with the magnitude of myocardial ischemia (R=-0.13, p=0.023), suggesting a greater CPC reduction with larger ischemic burden. These findings remained significant even after adjustment for age, gender, race, BMI, previous myocardial infarction, resting levels of CPCs and hematocrit change with stress. No difference was observed in CPC response to pharmacological stress test (change of -1% vs 3%, for patients with and without myocardial ischemia, respectively, p=0.96). Conclusion: Exercise stress-induced myocardial ischemia is associated with a decrease in CPC counts, likely due to increased homing of stem cells to the ischemic myocardium. Whether the extent of CPC uptake has prognostic implication, or whether the CPC response can be altered with intervention needs further investigation.

Introduction: Stress tests are routinely used for the detection of reversible myocardial ischemia. We determined the relationship between resting high sensitivity cardiac troponin I (hs-cTnI) levels and stress-induced myocardial ischemia (SMI) in patients with known coronary artery disease (CAD). Hypothesis: Patients with low hs-cTnI levels will not have reversible ischemia during stress. Methods: A discovery cohort of 581 patients and a validation cohort of 103 patients with stable CAD underwent 99mTc-SPECT myocardial perfusion imaging during treadmill exercise or pharmacologic stress testing and had pre-stress hs-cTnI levels measured (Abbott Labs). SMI was defined as a new or worsening impairment in myocardial perfusion using a 17-segment model. Sensitivity, specificity, and negative predictive value (NPV) were calculated. Results: The 34.9% of patients who developed SMI in the discovery cohort had higher hs-cTnI levels (5.4 [3.9-9.2] vs 3.9 [2.5-6.5] pg/mL, p<0.001). Low resting levels of hs-cTnI had a...

Introduction: Mental stress-induced myocardial ischemia (MSIMI) is a common phenomenon in patients with coronary heart disease (CHD) and an emerging prognostic factor. Women with CHD tend to have m...

Introduction: Mental stress-induced myocardial ischemia (MSIMI) has been linked to adverse cardiovascular outcomes in patients with stable CAD. However, the underlying mechanisms are not well understood. We aimed to study vasomotor, hemodynamic and hormonal responses to mental stress (MS) and their relationships with MSIMI. Methods: 660 patients with stable CAD underwent 99mTc sestamibi myocardial perfusion imaging before, and during a public speaking stressor. Hemodynamic parameters (heart rate, BP, rate-pressure product [RPP]), circulating catecholamines, and peripheral arterial tonometry (PAT, Itamar Inc.) were measured at rest, during, and after MS. MSIMI was defined as myocardial perfusion impairment with MS. Results: Participant age was 63±9; 72% male. Overall, 102 (16.1%) patients developed MSIMI. During MS, there was a significant increase in heart rate, BP, RPP and epinephrine, but not norepinephrine levels. The mean PAT ratio, measured as a ratio of the lowest pulse wave amplitude during the speaking task to the final three minutes of pulse wave amplitude during rest, was 0.7 ± 0.3 indicating vasoconstriction with MS. Patients with MSIMI had a greater hemodynamic response (Figure) and a lower PAT ratio (0.6±0.3 vs 0.7±0.3, p=0.008), in comparison to those with no ischemia. After adjustment for age, CAD risk factors and beta blocker use, both higher hemodynamic response (change in RPP≥median) and more vasoconstriction (PAT ratio Conclusion: A greater hemodynamic response and peripheral vasoconstriction are associated with MSIMI, indicating that both increased myocardial demand and potentially coronary vasoconstriction contribute to this phenomenon.

OBJECTIVES:There are conflicting reports on the role of cholesterol as an adverse prognostic predictor in patients with heart failure (HF). This study aimed to examine the impact of low levels of low-density lipoprotein cholesterol (LDL-c) on cardiac mortality in a cohort of elderly patients with moderate and severe HF. METHODS:Chronic HF patients from the HF Unit at the Tel-Aviv Medical Center (n = 212, 77% males) with an average NYHA classification of 2.8, a mean age of 76.9 ± 7.3 years (range 66-91) and a mean follow-up of 3.7 years were consecutively enrolled. The cohort was divided into tertiles according to LDL-c levels: LDL <90 mg/dl (group 1), LDL 90-115 mg/dl (group 2) and LDL >115 mg/dl (group 3). RESULTS:The Cox regression analysis revealed that group 3 patients had the best outcome (p = 0.01 vs. groups 2 and 3), with 58% of them surviving longer than 50 months compared to 34% in group 1. The same trend was seen in the group of patients suffering from ischemic cardiomyopathy and in patients who were treated by statins (p = 0.04). CONCLUSION:Low LDL-c levels are associated with a reduced survival in elderly patients with clinically controlled moderate and severe HF.

Background Mental stress–induced myocardial ischemia (MSIMI) is associated with adverse prognosis in patients with coronary artery disease (CAD), yet the mechanisms underlying this phenomenon remain unclear. We hypothesized that compared with exercise/pharmacological stress–induced myocardial ischemia (PSIMI) that is secondary to the atherosclerotic burden of CAD, MSIMI is primarily due to vasomotor changes. Methods and Results Patients with angiographically documented CAD underwent 99mTc‐sestamibi myocardial perfusion imaging at rest and following both mental and physical stress testing, performed on separate days. The severity and extent of CAD were quantified using the Gensini and Sullivan scores. Peripheral arterial tonometry (Itamar Inc) was used to assess the digital microvascular tone during mental stress as a ratio of pulse wave amplitude during speech compared with baseline. Measurements were made in a discovery sample (n=225) and verified in a replication sample (n=159). In the pooled (n=384) sample, CAD severity and extent scores were not significantly different between those with and without MSIMI, whereas they were greater in those with compared with those without PSIMI (P<0.04 for all). The peripheral arterial tonometry ratio was lower in those with compared with those without MSIMI (0.55±0.36 versus 0.76±0.52, P=0.009). In a multivariable analysis, the peripheral arterial tonometry ratio was the only independent predictor of MSIMI (P=0.009), whereas angiographic severity and extent of CAD independently predicted PSIMI. Conclusions The degree of digital microvascular constriction, and not the angiographic burden of CAD, is associated with MSIMI. Varying causes of MSIMI compared with PSIMI may require different therapeutic interventions that require further study.

Mental stress (MS) provokes myocardial ischemia in many patients with coronary artery disease (CAD). Arterial stiffness and endothelial dysfunction are important determinants of cardiovascular risk. We investigated the effect of MS on endothelial function and arterial stiffness, with the hypothesis

Introduction: Evidence supports gender-specific pathophysiological differences in the presentation and risk profile of cardiovascular disease, and microvascular disease has been proposed as a mecha...

Background: Mental Stress Induced Myocardial Ischemia (MSI) portends a worse prognosis in patients with CAD. Exaggerated cardiovascular reactivity to mental stress has been suggested as a possible ...