Longitudinal associations between self-reported experiences of discrimination and depressive symptoms in young women and men post- myocardial infarction.

Objectives: Research suggests that following a myocardial infarction (MI), women under the age of 60 have more elevated depressive symptoms and adverse outcomes than similarly aged men. Identifying risk factors that contribute to gender differences in depressive symptoms among this group may be critical to the development of psychosocial interventions. Experiences of discrimination may be an important correlate of depressive symptoms in this group; however, studies of this relationship have largely been cross-sectional and focused on healthy populations. This study examines longitudinal associations among gender, discrimination, and depressive symptoms in a young post-MI cohort. Methods: Participants were 313 adults from the Myocardial Infarction and Mental Stress Ischemia Study 2 of young (≤60 yrs) post-MI patients. At baseline and 6 month follow-up, depressive symptoms were measured with the Beck Depression Inventory-II and discrimination was assessed with the 10-item version Everyday Discrimination scale. Linear regression models were used to assess the longitudinal association between reports of discrimination and depressive symptoms adjusted for sociodemographic characteristics, psychosocial factors and health status indicators and tested for gender differences. Results: The mean age was 51.2, 49.6% were women, and 69.5% were African-American. Although the discrimination-by-gender interaction was marginally significant (p=.09) in the fully adjusted model, findings suggest that the association between changes in reports of discrimination and depressive symptoms over time may be more pronounced for women (ß=.61, standard error=.15, p<.001) than men (ß=.27, standard error=.13, p=.033). Conclusion: Our findings suggest that discrimination is a risk factor for depressive symptoms in young post-MI populations over time.

Psychological Distress and Subsequent Cardiovascular Events in Individuals With Coronary Artery Disease.

Background Higher symptom levels of a variety of measures of emotional distress have been associated with cardiovascular disease ( CVD ), especially among women. Here, our goal was to investigate the association between a composite measure of psychological distress and incident cardiovascular events. Methods and Results In a prospective cohort study, we assessed 662 individuals (28% women; 30% blacks) with stable coronary artery disease. 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) as a predictor of an adjudicated composite end point of adverse events (cardiovascular death, myocardial infarction, stroke, heart failure, or unstable angina). During a mean follow-up of 2.8 years, 120 (18%) subjects developed CVD events. In the overall population, there was no association between the psychological distress measure and CVD events, but there was a sex-based interaction ( P=0.004). In women, higher psychological distress was associated with a higher incidence of CVD events; each SD increase in the composite score of psychological distress was associated with 1.44 times adjusted hazard of CVD events (95% CI, 1.09-1.92). No such association was found in men. Conclusions Among patients with coronary artery disease, higher psychological distress is associated with future cardiovascular events in women only.

Comparison of autonomic stress reactivity in young healthy versus aging subjects with heart disease.

BACKGROUND: The autonomic response to acute emotional stress can be highly variable, and pathological responses are associated with increased risk of adverse cardiovascular events. We evaluated the autonomic response to stress reactivity of young healthy subjects and aging subjects with coronary artery disease to understand how the autonomic stress response differs with aging. METHODS: Physiologic reactivity to arithmetic stress in a cohort of 25 young, healthy subjects (< 30 years) and another cohort of 25 older subjects (> 55 years) with CAD was evaluated using electrocardiography, impedance cardiography, and arterial pressure recordings. Stress-related changes in the pre-ejection period (PEP), which measures sympathetic activity, and high frequency heart rate variability (HF HRV), which measures parasympathetic activity, were analyzed as primary outcomes. RESULTS: Mental stress reduced PEP in both groups (p<0.01), although the decrease was 50% greater in the healthy group. Mean HF HRV decreased significantly in the aging group only (p = 0.01). DISCUSSION: PEP decreases with stress regardless of health and age status, implying increased sympathetic function. Its decline with stress may be attenuated in CAD. The HF HRV (parasympathetic) stress reactivity is more variable and attenuated in younger individuals; perhaps this is related to a protective parasympathetic reflex. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02657382.

The Relation of Psychosocial Distress With Myocardial Perfusion and Stress-Induced Myocardial Ischemia.

OBJECTIVE: Mental stress-induced myocardial ischemia is a frequent phenomenon in patients with coronary artery disease (CAD). The link between an integrated measure of chronic psychosocial distress and mental stress-induced myocardial ischemia, and whether it differs by sex, has not been examined before. METHODS: We used latent class analysis to derive a composite measure of psychosocial distress integrating scales of depression, posttraumatic stress, anxiety, anger, hostility, and perceived stress in 665 individuals with stable CAD. Participants underwent myocardial perfusion imaging with mental stress and perfusion defects were quantified at rest (summed rest score), with mental stress (summed stress score), and their difference (summed difference score), the latter being an index of inducible ischemia. RESULTS: The M (SD) age was 63 (9) years, and 185 (28%) were women. Latent class analysis characterized the study sample into four distinct classes of incremental psychosocial distress. In women, class 4 (highest distress) had an adjusted 4.0-point higher summed rest score (95% confidence interval = 0.2-7.7) as compared with class 1 (lowest distress), whereas no difference was observed in men (-0.87 points, 95% confidence interval = -3.74 to 1.99, p = .04 for interaction). There was no association between the psychosocial distress latent variable and summed difference score in either women or men. CONCLUSIONS: Among patients with CAD, a higher level of psychosocial distress is not associated with mental stress ischemia, but it is associated with more resting (fixed) perfusion abnormalities in women only, as well as with blunted hemodynamic response to mental stress in both men and women.

Brain correlates of stress-induced peripheral vasoconstriction in patients with cardiovascular disease.

The influence of acute psychological stress on cardiovascular disease is an emerging public health concern. Identification of brain mechanisms underlying this may aid in the discovery of possible treatments. Acute psychological stress may induce arteriolar vasoconstriction and reduce blood flow to vital organs. We hypothesized that functional changes in brain regions involved with memory and autonomic/emotional regulation are implicated in the vasoconstrictive stress response, including the medial prefrontal cortex (anterior cingulate), insula, and dorsolateral prefrontal cortex. Subjects with a history of coronary artery disease (N = 59) underwent measurement of microvascular vasomotor tone with the EndoPAT device and O-15 positron emission tomography (PET) imaging of the brain during exposure to mental stress and control conditions. The peripheral arterial tonometry (PAT) ratio was calculated as the mean peripheral vasomotor tone during stress divided by the mean tone during rest. Whole brain contrasts were performed between groups above and below the median PAT ratio, and significant contrasts were defined with cutoff p < 0.005. Stress-induced peripheral vasoconstriction (below median PAT ratio) was associated with increased stress activation in insula and parietal cortex, and decreased activation in the medial prefrontal cortex with stress tasks compared to control tasks. These findings demonstrate that stress-induced vasoreactivity is associated with changes in brain responses to stress in areas involved in emotion and autonomic regulation. These findings have important implications on possible treatments for mental stress-induced vascular toxicity.

Sex-Specific Association Between Coronary Artery Disease Severity and Myocardial Ischemia Induced by Mental Stress.

OBJECTIVE: It is unclear whether mental stress-induced myocardial ischemia (MSIMI) is related to obstructive coronary artery disease (CAD). We examined this question and contrasted results with ischemia induced by conventional stress testing (CSIMI). Because women are more susceptible to ischemia without coronary obstruction than men, we examined sex differences. METHODS: We studied 276 patients 61 years and younger with recent myocardial infarction. CAD severity was quantified using the log-transformed Gensini Score (lnGS) and the Sullivan Stenosis Score. Patients underwent myocardial perfusion imaging with mental stress (public speaking) and conventional (exercise or pharmacological) stress testing. MSIMI and CSIMI were defined as a new or worsening perfusion defect. RESULTS: The prevalence of MSIMI was 15% in men and 20% in women. The median GS for patients with MSIMI was 65.0 in men and 28.5 in women. In logistic regression models adjusted for demographic and cardiovascular risk factors, CAD severity was associated with CSIMI in the full sample (odds ratio [OR] = 1.49, 95% [CI], 1.14-1.95, per 1-unit increase in lnGS), with no significant difference by sex. Although CAD severity was not associated with MSIMI in the entire sample, results differed by sex. CAD severity was associated with MSIMI among men (OR = 1.95, 95% CI, 1.13-3.36, per 1-unit increase in lnGS), but not among women (OR = 1.02, 95% CI, 0.74-1.42, p = .042 for interaction). Analysis using Sullivan Stenosis Score yielded similar results. CONCLUSIONS: Findings suggest that CAD severity is related to MSIMI in men but not women. MSIMI in women may therefore be driven by alternative mechanisms such as coronary microvascular disease.

Posttraumatic stress disorder is associated with enhanced interleukin-6 response to mental stress in subjects with a recent myocardial infarction.

BACKGROUND: Posttraumatic Stress Disorder (PTSD) is prevalent among patients who survived an acute coronary syndrome, and is associated with adverse outcomes, but the mechanisms underlying these associations are unclear. Individuals with PTSD have enhanced sensitivity of the noradrenergic system to stress which may lead to immune activation. We hypothesized that survivors of a myocardial infarction (MI) who have PTSD would show an enhanced inflammatory response to acute psychological stress compared to those without PTSD. METHODS: Individuals with a verified history of MI within 8 months and a clinical diagnosis of current PTSD underwent a mental stress speech task. Inflammatory biomarkers including interleukin-6 (IL-6), high-sensitivity C reactive protein (HsCRP), matrix metallopeptidase 9 (MMP-9), intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1 and monocyte chemoattractant protein (MCP)-1 were measured at rest and 90 min after mental stress. RESULTS: Among 271 patients in the study (mean age 51 ±â€¯7 years, 50% female, 60% African-American), the prevalence of PTSD was 12%. Mental stress resulted in a significant increase in IL-6, but the increase was more marked in patients with PTSD (126% increase) than those without (63% increase) (p = 0.001). MCP-1 showed a modest increase with stress which was similar in patients with PTSD (9% increase) and without PTSD (6% increase) (p = 0.35). CRP did not increase with stress in either group. CONCLUSION: MI patients with current PTSD exhibit enhanced IL-6 response to psychosocial stress, suggesting a mechanistic link between PTSD and adverse cardiovascular outcomes as well as other diseases associated with inflammation.

Neighborhood poverty and hemodynamic, neuroendocrine, and immune response to acute stress among patients with coronary artery disease.

Living in neighborhoods characterized by poverty may act as a chronic stressor that results in physiological dysregulation of the sympathetic nervous system. No previous study has assessed neighborhood poverty with hemodynamic, neuroendocrine, and immune reactivity to stress. We used data from 632 patients with coronary artery disease. Patients' residential addresses were geocoded and merged with poverty data from the 2010 American Community Survey at the census-tract level. A z-transformation was calculated to classify census tracts (neighborhoods) as either having 'high' or 'low' poverty. Systolic blood pressure, diastolic blood pressure, heart rate, rate-pressure product, epinephrine, interleukin-6, and high-sensitivity C-reactive protein were measured before and after a public speaking stress task. Multilevel models were used for repeated measures and accounting for individuals nested within census tracts. Adjusted models included demographics, lifestyle and medical risk factors, and medication use. Another set of models included propensity scores weighted by the inverse probability of neighborhood status for sex, age, race, and individual-level income. The mean age was 63 years and 173 were women. After adjusting for potential confounders, participants living in high (vs. low) poverty neighborhoods had similar hemodynamic values at rest and lower values during mental stress for systolic blood pressure (157 mmHg vs. 161 mmHg; p = 0.07), heart rate (75 beats/min vs. 78 beats/min; p = 0.02) and rate-pressure product (11839 mmHg x beat/min vs 12579 mmHg x beat/min; p = 0.01). P-values for neighborhood poverty-by-time interactions were <0.05. Results were similar in the propensity weighted models. There were no significant differences in inflammatory and epinephrine responses to mental stress based on neighborhood poverty status. A blunted hemodynamic response to mental stress was observed among participants living in high poverty neighborhoods. Future studies should explore whether neighborhood poverty and blunted hemodynamic response to stress translate into differences in long-term cardiovascular outcomes.

Young Women With Coronary Artery Disease Exhibit Higher Concentrations of Interleukin-6 at Baseline and in Response to Mental Stress.

Background Young women with coronary artery disease ( CAD ), a group with high psychosocial burden, were previously shown to have higher levels of interleukin-6 ( IL -6) compared with men of similar age. We sought to examine IL -6 response to acute stress in CAD patients across sex and age, and contrast results to healthy controls and other biomarkers known to increase with mental stress (monocyte chemoattractant protein-1 and matrix metallopeptidase-9) and known limited stress-reactivity (high-sensitivity C-reactive protein). Methods and Results Inflammatory biomarkers were measured at rest and 90 minutes after mental stress (speech task) among 819 patients with CAD and 89 healthy controls. Repeated-measures models were used to investigate age (continuous) and sex differences across time, before and after adjusting for demographics, CAD risk factors, depressive symptoms, medication use, and CAD severity. Among patients with CAD , the mean age was 60 years (range, 25-79) and 31% were women. Younger women with CAD had significantly higher concentrations of IL -6 at rest, 90 minutes after mental stress, as well as a higher response to stress, compared with similarly aged men ( P<0.05 for sex by age interactions). In contrast, IL -6 increased with age, and there were no sex differences in IL -6 levels or response to stress among controls. Inflammatory responses to stress for high-sensitivity C-reactive protein, monocyte chemoattractant protein-1, and matrix metallopeptidase-9 among CAD patients were similar in women and men. Conclusions IL -6 response to mental stress are higher in young women with CAD than men of similar age.

Use of High-Sensitivity Cardiac Troponin for the Exclusion of Inducible Myocardial Ischemia: A Cohort Study.

Background: Many patients with coronary artery disease (CAD) are routinely referred for surveillance stress testing despite recommendations against it. Objective: To determine whether low levels of resting high-sensitivity cardiac troponin I (hs-cTnI) can identify persons without inducible myocardial ischemia. Design: Observational study. Setting: A university-affiliated hospital network. Patients: Persons with stable CAD: 589 in the derivation group and 118 in the validation cohort. Measurements: Presence of inducible myocardial ischemia was determined by myocardial perfusion imaging with technetium-99m single-photon emission computed tomography during either treadmill or pharmacologic stress testing. Resting plasma hs-cTnI was measured within 1 week of the stress test, and the negative predictive value (NPV) for inducible ischemia was calculated. The derivation cohort was followed for 3 years for incident cardiovascular death and myocardial infarction. Results: In the derivation cohort, 10 of 101 patients with an hs-cTnI level below 2.5 pg/mL had inducible myocardial ischemia (NPV, 90% [95% CI, 83% to 95%]) and 3 of 101 had inducible ischemia involving at least 10% of the myocardium (NPV, 97% [CI, 92% to 99%]). In the validation cohort, 4 of 32 patients with an hs-cTnI level below 2.5 pg/mL had inducible ischemia (NPV, 88% [CI, 71% to 96%]) and 2 of 32 had ischemia of 10% or greater (NPV, 94% [CI, 79% to 99%]). After a median follow-up of 3 years in the derivation cohort, no adverse events occurred in patients with an hs-cTnI level below 2.5 pg/mL, compared with 33 (7%) cardiovascular deaths or incident myocardial infarctions among those with an hs-cTnI level of 2.5 pg/mL or greater. Limitation: The data may not be applicable to a population without known CAD or to persons with unstable angina, and the modest sample sizes warrant further validation in a larger cohort. Conclusion: Very low hs-cTnI levels may be useful in excluding inducible myocardial ischemia in patients with stable CAD. Primary Funding Source: National Institutes of Health.

Coronary and Peripheral Vasomotor Responses to Mental Stress.

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.

Brain Correlates of Mental Stress-Induced Myocardial Ischemia.

OBJECTIVE: Coronary artery disease (CAD) is a major cause of morbidity and mortality, and despite important advances in our understanding of this disorder, the underlying mechanisms remain under investigation. Recently, increased attention has been placed on the role of behavioral factors such as emotional stress on CAD risk. Brain areas involved in memory and the stress response, including medial prefrontal cortex, insula, and parietal cortex, also have outputs to the peripheral cardiovascular system. The purpose of this study was to assess the effects of mental stress on brain and cardiac function in patients with CAD. METHODS: CAD patients (N = 170) underwent cardiac imaging with [Tc-99m] sestamibi single-photon emission tomography at rest and during a public speaking mental stress task. On another day, they underwent imaging of the brain with [O-15] water positron emission tomography (PET) during mental stress (arithmetic and public speaking) and control conditions. RESULTS: Patients with mental stress-induced myocardial ischemia showed increased activation with stress in anterior cingulate, inferior frontal gyrus, and parietal cortex (p < .005). This was seen with both arithmetic stress and public speaking stress. Arithmetic stress was additionally associated with left insula activation, and public speaking with right pre/postcentral gyrus and middle temporal gyrus activation (p < .005). CONCLUSIONS: These findings suggest that mental stress-induced myocardial ischemia is associated with activation in brain areas involved in the stress response and autonomic regulation of the cardiovascular system. Altered brain reactivity to stress could possibly represent a mechanism through which stress leads to increased risk of CAD-related morbidity and mortality.

Mental Stress-Induced-Myocardial Ischemia in Young Patients With Recent Myocardial Infarction: Sex Differences and Mechanisms.

BACKGROUND: Mental stress-induced myocardial ischemia (MSIMI) is frequent in patients with coronary artery disease and is associated with worse prognosis. Young women with a previous myocardial infarction (MI), a group with unexplained higher mortality than men of comparable age, have shown elevated rates of MSIMI, but the mechanisms are unknown. METHODS: We studied 306 patients (150 women and 156 men) ≤61 years of age who were hospitalized for MI in the previous 8 months and 112 community controls (58 women and 54 men) frequency matched for sex and age to the patients with MI. Endothelium-dependent flow-mediated dilation and microvascular reactivity (reactive hyperemia index) were measured at rest and 30 minutes after mental stress. The digital vasomotor response to mental stress was assessed using peripheral arterial tonometry. Patients received 99mTc-sestamibi myocardial perfusion imaging at rest, with mental (speech task) and conventional (exercise/pharmacological) stress. RESULTS: The mean age of the sample was 50 years (range, 22-61). In the MI group but not among controls, women had a more adverse socioeconomic and psychosocial profile than men. There were no sex differences in cardiovascular risk factors, and among patients with MI, clinical severity tended to be lower in women. Women in both groups showed a higher peripheral arterial tonometry ratio during mental stress but a lower reactive hyperemia index after mental stress, indicating enhanced microvascular dysfunction after stress. There were no sex differences in flow-mediated dilation changes with mental stress. The rate of MSIMI was twice as high in women as in men (22% versus 11%, P=0.009), and ischemia with conventional stress was similarly elevated (31% versus 16%, P=0.002). Psychosocial and clinical risk factors did not explain sex differences in inducible ischemia. Although vascular responses to mental stress (peripheral arterial tonometry ratio and reactive hyperemia index) also did not explain sex differences in MSIMI, they were predictive of MSIMI in women only. CONCLUSIONS: Young women after MI have a 2-fold likelihood of developing MSIMI compared with men and a similar increase in conventional stress ischemia. Microvascular dysfunction and peripheral vasoconstriction with mental stress are implicated in MSIMI among women but not among men, perhaps reflecting women's proclivity toward ischemia because of microcirculatory abnormalities.

Association Between High-Sensitivity Cardiac Troponin Levels and Myocardial Ischemia During Mental Stress and Conventional Stress.

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.

Sex Differences in Hemodynamic and Microvascular Mechanisms of Myocardial Ischemia Induced by Mental Stress.

OBJECTIVE: To investigate sex-specific vascular mechanisms for mental stress-induced myocardial ischemia (MSIMI). APPROACH AND RESULTS: Baseline data from a prospective cohort study of 678 patients with coronary artery disease underwent myocardial perfusion imaging before and during a public speaking stressor. The rate-pressure product response was calculated as the difference between the maximum value during the speech minus the minimum value during rest. Peripheral vasoconstriction by peripheral arterial tonometry was calculated as the ratio of pulse wave amplitude during the speech over the resting baseline; ratios <1 indicate a vasoconstrictive response. MSIMI was defined as percent of left ventricle that was ischemic and as a dichotomous variable. Men (but not women) with MSIMI had a higher rate-pressure product response than those without MSIMI (6500 versus 4800 mm Hg bpm), whereas women (but not men) with MSIMI had a significantly lower peripheral arterial tonometry ratio than those without MSIMI (0.5 versus 0.8). In adjusted linear regression, each 1000-U increase in rate-pressure product response was associated with 0.32% (95% confidence interval, 0.22-0.42) increase in inducible ischemia among men, whereas each 0.10-U decrease in peripheral arterial tonometry ratio was associated with 0.23% (95% confidence interval, 0.11-0.35) increase in inducible myocardial ischemia among women. Results were independent of conventional stress-induced myocardial ischemia. CONCLUSIONS: Women and men have distinct cardiovascular reactivity mechanisms for MSIMI. For women, stress-induced peripheral vasoconstriction with mental stress, and not increased hemodynamic workload, is associated with MSIMI, whereas for men, it is the opposite. Future studies should examine these pathways on long-term outcomes.

Chest Pain and Mental Stress-Induced Myocardial Ischemia: Sex Differences.

BACKGROUND: Mental stress-induced myocardial ischemia is a frequent phenomenon in patients with coronary artery disease. Women with coronary artery disease tend to have more mental stress-induced myocardial ischemia and more chest pain/anginal symptoms than men, but whether the association between mental stress-induced myocardial ischemia and angina burden differs in women and men is unknown. METHODS: This was a cross-sectional study with experimental manipulation of 950 individuals with stable coronary artery disease. Chest pain/angina frequency in the previous 4 weeks was assessed with the Seattle Angina Questionnaire's angina-frequency subscale. Mental stress-induced myocardial ischemia was assessed with myocardial perfusion imaging during mental stress (standardized public speaking task). Presence of mental stress-induced myocardial ischemia was based on expert readers and established criteria. A conventional (exercise or pharmacologic) stress test was used as a control condition. RESULTS: Overall, 338 individuals (37%) reported angina; 112 (12%) developed mental stress-induced myocardial ischemia, and 256 (29%) developed conventional stress ischemia. Women who reported angina had almost double the probability to develop mental stress-induced myocardial ischemia (19% vs 10%, adjusted prevalence rate ratio, 1.90; 95% confidence interval, 1.04-3.46), whereas there was no such difference in men (11% vs 11%, adjusted prevalence rate ratio, 1.09; 95% confidence interval, 0.66-1.82). No association was found between angina symptoms and conventional stress ischemia for women or men. Results for ischemia as a continuous variable were similar. CONCLUSIONS: In women, but not in men, anginal symptoms may be a marker of vulnerability toward ischemia induced by psychologic stress. These results highlight the psychosocial origins of angina in women and may have important implications for the management and prognosis of women with angina.

Myocardial Ischemia and Mobilization of Circulating Progenitor Cells.

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.

Inflammatory response to mental stress and mental stress induced myocardial ischemia.

BACKGROUND: Mental stress-induced myocardial ischemia (MSIMI) is associated with increased risk of adverse cardiovascular outcomes, yet the underlying mechanisms are not well understood. We measured the inflammatory response to acute laboratory mental stress in patients with coronary artery disease (CAD) and its association with MSIMI. We hypothesized that patients with MSIMI would have a higher inflammatory response to mental stress in comparison to those without ischemia. METHODS: Patients with stable CAD underwent 99mTc sestamibi myocardial perfusion imaging during mental stress testing using a public speaking stressor. MSIMI was determined as impaired myocardial perfusion using a 17-segment model. Inflammatory markers including interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), matrix metallopeptidase 9 (MMP-9) and high-sensitivity C reactive protein (hsCRP) were measured at rest and 90 min after mental stress. Results were validated in an independent sample of 228 post-myocardial infarction patients. RESULTS: Of 607 patients analyzed in this study, (mean age 63 ±â€¯9 years, 76% male), 99 (16.3%) developed MSIMI. Mental stress resulted in a significant increase in IL-6, MCP-1, and MMP-9 (all p <0.0001), but not hsCRP. However, the changes in these markers were similar in those with and without MSIMI. Neither resting levels of these biomarkers, nor their changes with mental stress were significantly associated with MSIMI. Results in the replication sample were similar. CONCLUSION: Mental stress is associated with acute increases in several inflammatory markers. However, neither the baseline inflammatory status nor the magnitude of the inflammatory response to mental stress over 90 min were significantly associated with MSIMI.

The association between acute mental stress and abnormal left atrial electrophysiology.

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. PTFV1 was defined as the duration (milliseconds) times the value of the depth (µV) of the downward deflection (terminal portion) of the P-wave in lead V1 measured on digital electrocardiograms (ECG). Electrocardiographic left atrial abnormality was defined as PTFV1 ≤ -4000 µV*ms. Mean PTFV1 values 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, PTFV1 became 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.