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.

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.

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.

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.

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 ± 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.

Objectives: Depression is an adverse prognostic factor after an acute myocardial infarction (MI), and an increased propensity toward emotionally-driven myocardial ischemia may play a role. We aimed to examine the association between depressive symptoms and mental stress-induced myocardial ischemia in young survivors of an MI. Methods: We studied 98 patients (49 women and 49 men) age 38-60 years who were hospitalized for acute MI in the previous 6 months. Patients underwent myocardial perfusion imaging at rest, after mental stress (speech task), and after exercise or pharmacological stress. A summed difference score (SDS), obtained with observer-independent software, was used to quantify myocardial ischemia under both stress conditions. The Beck Depression Inventory-II (BDI-II) was used to measure depressive symptoms, which were analyzed as overall score, and as separate somatic and cognitive depressive symptom scores. Results: There was a significant positive association between depressive symptoms and SDS with mental stress, denoting more ischemia. After adjustment for demographic and lifestyle factors, disease severity and medications, each incremental depressive symptom was associated with 0.14 points higher SDS. When somatic and cognitive depressive symptoms were examined separately, both somatic [β = 0.17, 95% CI: (0.04, 0.30), p = 0.01] and cognitive symptoms [β = 0.31, 95% CI: (0.07, 0.56), p = 0.01] were significantly associated with mental stress-induced ischemia. Depressive symptoms were not associated with ischemia induced by exercise or pharmacological stress. Conclusion: Among young post-MI patients, higher levels of both cognitive and somatic depressive symptoms are associated with a higher propensity to develop myocardial ischemia with mental stress, but not with physical (exercise or pharmacological) stress.

Objective: Patients with rheumatoid arthritis (RA) have increased coronary atherosclerosis possibly related to increased prevalence of visceral adiposity, insulin resistance, and metabolic syndrome. Epicardial adipose tissue (EAT), a type of visceral fat, may contribute to cardiometabolic risk. The aim of this study was to measure EAT volume in patients with RA and determine its relationship with cardiometabolic risk markers and coronary artery calcium. Methods: EAT volume and coronary artery calcium score were measured by noncontrast cardiac computed tomography and compared in RA patients (n = 162) and controls (n = 89). The relationships between EAT volume and markers of cardiometabolic risk in RA were examined with adjustment for age, race, and sex. Results: Among RA patients, EAT volume was positively associated with interleukin-6 (P = 0.03), triglycerides (P = 0.004), hypertension (P = 0.01), homeostatic model of insulin resistance (HOMA) (P < 0.001), smoking history (P = 0.04), and homocysteine level (P = 0.001), and negatively associated with high-density lipoprotein (P = 0.005). With further adjustment for waist circumference (a measure of visceral obesity), EAT volume remained independently associated with triglycerides, HOMA, current smoking, and homocysteine level (all P < 0.05). EAT volume was not associated with corticosteroid use or coronary artery calcium score. Patients with metabolic syndrome had significantly greater EAT volume (P < 0.001) and each increase in metabolic syndrome criteria was associated, on average, with a 20% increase (95% confidence interval 14-26%) in EAT volume (P < 0.001). Conclusion: EAT volume is associated with metabolic syndrome and cardiometabolic risk factors, including insulin resistance, triglycerides, current smoking, and homocysteine levels, but not with coronary artery calcium in RA patients.

Introduction: Major depression is associated with an increased risk for and mortality from coronary artery disease (CAD), however the mechanisms by which this occurs are not clear. Depression, which is linked to stress, is associated with changes in brain areas involved in memory and the stress response, and it is likely that these regions play an important role in this increased risk. This study assessed the effects of stress on brain and cardiac function in patients with CAD with and without depression. Methods: CAD patients with (N = 17) and without (N = 21) major depression based on the Structured Clinical Interview for DSM-IV (DSM-IV) and/or a Hamilton Depression Scale score of nine or greater underwent imaging of the brain with high resolution positron emission tomography (HR-PET) and [O-15] water and imaging of the heart with single photon emission tomography (SPECT) and [Tc-99 m] sestamibi during mental stress (mental arithmetic) and control conditions. Results: Patients with CAD and major depression showed increased parietal cortex activation and a relative failure of medial prefrontal/anterior cingulate activation during mental stress compared to CAD patients without depression. Depressed CAD patients with stress-induced myocardial ischemia, however, when compared to depressed CAD patients without showed increased activation in rostral portions of the anterior cingulate. Conclusions: These findings are consistent with a role for brain areas implicated in stress and depression in the mechanism of increased risk for CAD morbidity and mortality in CAD patients with the diagnosis of major depression.