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Objectives: The aim of this study was to investigate the association between resting myocardial function as assessed by tissue Doppler myocardial velocities and the propensity to develop mental stress-induced ischemia (MSIMI)., Background: Tissue Doppler myocardial velocities detect preclinical cardiac dysfunction and clinical outcomes in a range of conditions. However, little is known about the interrelationship between myocardial velocities and the propensity to develop MSIMI compared with exercise stress-induced myocardial ischemia., Methods: Resting annular myocardial tissue Doppler velocities were obtained in 225 patients with known coronary heart disease who were subjected to both conventional exercise stress testing as well as a battery of 3 mental stress tests. Diastolic early (e') and late (a') as well as systolic (s') velocities were obtained, and the eas index, an integrated measure of myocardial velocities, was calculated as e'/(a' × s'). MSIMI was defined as: 1) the development or worsening of regional wall motion abnormality; 2) a reduction in left ventricular ejection fraction ≥ 8%; and/or 3) ischemic ST-segment changes during 1 or more of the 3 mental stress tests., Results: A total of 98 of 225 patients (43.7%) exhibited MSIMI. Patients developing MSIMI had significantly lower s' (7.0 ± 1.7 vs. 7.5 ± 1.2, p = 0.016) and a' (8.9 ± 1.8 vs. 10.0 ± 1.9, p < 0.001) at baseline, whereas e' did not differ (6.5 ± 1.7 vs. 6.5 ± 1.8, p = 0.85). Furthermore, the eas index was significantly higher (0.11 ± 0.04 vs. 0.09 ± 0.03, p < 0.0001). The eas index remained significantly associated with the propensity to develop MSIMI (odds ratio per 0.05-U increase: 1.85; 95% confidence interval: 1.21 to 2.82; p = 0.004) after adjustment for resting left ventricular ejection fraction, resting wall motion index score, sex, and social circumstances of living. There was no association between resting eas index and exercise stress-induced myocardial ischemia., Conclusions: MSIMI but not exercise stress-induced myocardial ischemia is independently associated with resting abnormalities in myocardial systolic and late diastolic velocities as well as the integrated measure of the eas index in patients with known coronary artery disease. (Responses of Myocardial Ischemia to Escitalopram Treatment [REMIT]; NCT00574847)., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to examine the associations between depressive symptoms and mental stress-induced myocardial ischemia (MSIMI) in patients with coronary heart disease (CHD)., Methods: Adult patients with documented CHD were recruited for baseline mental stress and exercise stress screening testing as a part of the enrollment process of the Responses of Myocardial Ischemia to Escitalopram Treatment trial. Patients were administered the Beck Depression Inventory II and the Center for Epidemiologic Studies Depression Scale. After a 24-48-hour β-blocker withdrawal, participants completed three mental stress tests followed by a treadmill exercise test. Ischemia was defined as a) any development or worsening of any wall motion abnormality and b) reduction of left ventricular ejection fraction at least 8% by transthoracic echocardiography and/or ischemic ST-segment change by electrocardiography during stress testing. MSIMI was considered present when ischemia occurred in at least one mental test. Data were analyzed using logistic regression adjusting for age, sex, and resting left ventricular ejection fraction., Results: One hundred twenty-five (44.2%) of 283 patients were found to have MSIMI, and 93 (32.9%) had ESIMI. Unadjusted analysis showed that Beck Depression Inventory II scores were positively associated with the probability of MSIMI (odds ratio = 0.1.30: 95% confidence interval = 1.06-1.60, p = .013) and number of MSIMI-positive tasks (all p < .005). These associations were still significant after adjustment for covariates (p values <.05)., Conclusions: In patients with CHD, depressive symptoms were associated with a higher probability of MSIMI. These observations may enhance our understanding of the mechanisms contributing to the association of depressive symptoms to future cardiovascular events. Trial Registration Clinicaltrials.gov identifier: NCT00574847.

Importance: Mental stress can induce myocardial ischemia and also has been implicated in triggering cardiac events. However, pharmacological interventions aimed at reducing mental stress-induced myocardial ischemia (MSIMI) have not been well studied., Objective: To examine the effects of 6 weeks of escitalopram treatment vs placebo on MSIMI and other psychological stress-related biophysiological and emotional parameters., Design, Setting, and Participants: The REMIT (Responses of Mental Stress Induced Myocardial Ischemia to Escitalopram Treatment) study, a randomized, double-blind, placebo-controlled trial of patients with clinically stable coronary heart disease and laboratory-diagnosed MSIMI. Enrollment occurred from July 24, 2007, through August 24, 2011, at a tertiary medical center., Interventions: Eligible participants were randomized 1:1 to receive escitalopram (dose began at 5 mg/d, with titration to 20 mg/d in 3 weeks) or placebo over 6 weeks., Main Outcomes and Measures: Occurrence of MSIMI, defined as development or worsening of regional wall motion abnormality; left ventricular ejection fraction reduction of 8% or more; and/or horizontal or down-sloping ST-segment depression of 1 mm or more in 2 or more leads, lasting for 3 or more consecutive beats, during 1 or more of 3 mental stressor tasks., Results: Of 127 participants randomized to receive escitalopram (n = 64) or placebo (n = 63), 112 (88.2%) completed end point assessments (n = 56 in each group). At the end of 6 weeks, more patients taking escitalopram (34.2% [95% CI, 25.4%-43.0%]) had absence of MSIMI during the 3 mental stressor tasks compared with patients taking placebo (17.5% [95% CI, 10.4%-24.5%]), based on the unadjusted multiple imputation model for intention-to-treat analysis. A significant difference favoring escitalopram was observed (odds ratio, 2.62 [95% CI, 1.06-6.44]). Rates of exercise-induced ischemia were slightly lower at 6 weeks in the escitalopram group (45.8% [95% CI, 36.6%-55.0%]) than in patients receiving placebo (52.5% [95% CI, 43.3%-61.8%]), but this difference was not statistically significant (adjusted odds ratio; 1.24 [95% CI, 0.60-2.58]; P = .56)., Conclusions and Relevance: Among patients with stable coronary heart disease and baseline MSIMI, 6 weeks of escitalopram, compared with placebo, resulted in a lower rate of MSIMI. There was no statistically significant difference in exercise-induced ischemia. Replication of these results in multicenter settings and investigations of other medications for reducing MSIMI are needed., Trial Registration: clinicaltrials.gov Identifier: NCT00574847.

Objectives: The goal of this study was to evaluate the prevalence and clinical characteristics of mental stress-induced myocardial ischemia., Background: Mental stress-induced myocardial ischemia is prevalent and a risk factor for poor prognosis in patients with coronary heart disease, but past studies mainly studied patients with exercise-induced myocardial ischemia., Methods: Eligible patients with clinically stable coronary heart disease, regardless of exercise stress testing status, underwent a battery of 3 mental stress tests followed by a treadmill test. Stress-induced ischemia, assessed by echocardiography and electrocardiography, was defined as: 1) development or worsening of regional wall motion abnormality; 2) left ventricular ejection fraction reduction ≥ 8%; and/or 3) horizontal or downsloping ST-segment depression ≥ 1 mm in 2 or more leads lasting for ≥ 3 consecutive beats during at least 1 mental test or during the exercise test., Results: Mental stress-induced ischemia occurred in 43.45%, whereas exercise-induced ischemia occurred in 33.79% (p = 0.002) of the study population (N = 310). Women (odds ratio [OR]: 1.88), patients who were not married (OR: 1.99), and patients who lived alone (OR: 2.24) were more likely to have mental stress-induced ischemia (all p < 0.05). Multivariate analysis showed that compared with married men or men living with someone, unmarried men (OR: 2.57) and married women (OR: 3.18), or living alone (male OR: 2.25 and female OR: 2.72, respectively) had higher risk for mental stress-induced ischemia (all p < 0.05)., Conclusions: Mental stress-induced ischemia is more common than exercise-induced ischemia in patients with clinically stable coronary heart disease. Women, unmarried men, and individuals living alone are at higher risk for mental stress-induced ischemia. (Responses of Myocardial Ischemia to Escitalopram Treatment [REMIT]; NCT00574847)., (Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

This study examined the effects of exercise and stress management training on clinical outcomes and medical expenditures over a 5-year follow-up period in 94 male patients with established coronary artery disease (CAD) and evidence of ambulatory or mental stress-induced myocardial ischemia. Patients were randomly assigned to 4 months of aerobic exercise 3 times per week or to a 1.5-hour weekly class on stress management; patients who lived too far from Duke to participate in the weekly treatments formed the usual care control group. Follow-up was performed at the end of treatment and annually thereafter for 5 years. Stress management was associated with a significant reduction in clinical CAD events relative to usual care over each of the first 2 years of follow-up and after 5 years. Economic analyses revealed that stress management was associated with lower medical costs than usual care and exercise in the first 2 years, and that the cumulative cost over 5 years was also lower for stress management relative to usual care. These results suggest that there may be clinical and economic benefit to offering the type of preventive stress management and exercise interventions provided to patients with myocardial ischemia. Moreover, these findings suggest that the financial benefits that accrue from an appropriately targeted intervention may be substantial and immediate.

Background: The purpose of the current study was to determine whether survival after revascularization (coronary artery bypass grafting or percutaneous transluminal coronary angioplasty) is influenced by the extent of electrocardiographic (ECG) evidence of previous myocardial infarction (MI) in patients with ischemic cardiomyopathy by use of the 50-criteria, 31-point Selvester QRS scoring system., Methods: Patients with ischemic cardiomyopathy documented by a left ventricular ejection fraction (LVEF) < or =30% undergoing coronary angiography between January 1984 and July 1996, with no acute MI within the last 30 days, follow-up through 1996, and > or =75% occlusion in at least 1 major coronary artery at catheterization were included. These patients were subdivided on the basis of subsequent treatment: revascularization or no revascularization. The complete Selvester QRS system was applied to each patient's ECG and the subgroups were further subdivided by QRS score., Results: The 141 patients receiving revascularization had better survival at 5 years compared with the 298 patients receiving no revascularization (adjusted 5-year survival rate 73% vs 47%, P =.0001). No significant treatment differences were observed for low (< or =3 points) versus high (>3 points) QRS levels in either of the 2 treatment groups (revascularized patients: P =.215, patients without revascularization: P =.126) between the 2 treatment groups. Although all patients had LVEF < or =30%, only 8% of patients had QRS scores >10 points, the level that would be expected if the decrease in LVEF could be attributed entirely to infarcted myocardium., Conclusions: Hibernating myocardium may contribute significantly to the decreased function in patients with ischemic cardiomyopathy, and the QRS score cannot be used as an independent predictor of survival in those patients with a marked decrease in LVEF but small to moderate infarct sizes.

The authors examined whether facial expressions of emotion would predict changes in heart function. One hundred fifteen male patients with coronary artery disease underwent the Type A Structured Interview, during which time measures of transient myocardial ischemia (wall motion abnormality and left ventricular ejection fraction) were obtained. Facial behavior exhibited during the ischemia measurement period was videotaped and later coded by using the Facial Action Coding System (P. Ekman & W. V. Friesen, 1978). Those participants who exhibited ischemia showed significantly more anger expressions and nonenjoyment smiles than nonischemics. Cook-Medley Hostility scores did not vary with ischemic status. The findings have implications for understanding how anger and hostility differentially influence coronary heart disease risk.

Major depression is a common comorbidity associated with ischemic heart disease (IHD). There is growing evidence that psychological stress in general and depression in particular predispose to cardiovascular disease. Persons who have mental stress during daily life are at twice the risk of myocardial ischemia, and patients with post-myocardial infarction depression have higher mortality rates than nondepressed controls. These data suggest a psychophysiologic mechanism underlying the vulnerability of depressed patients to IHD. Clinical studies have demonstrated that depression is associated with a much higher risk of both cardiovascular morbidity and mortality, which could be caused by platelet activation. Physicians should maintain a heightened level of clinical suspicion for depression and depressive disorders in persons with IHD, particularly those individuals who are recovering from an acute ischemic event, such as myocardial infarction. Furthermore, depression may complicate the recovery of IHD, but in most cases depression can be effectively treated with antidepressant agents.

Background: It has been reported that selectins participate in the pathogenesis of acute coronary syndromes by modulating platelet-leukocyte-endothelium interactions. Elevated P-selectin level also has been observed in the clinical setting of myocardial ischemia and reperfusion; however, its utility in differentiating cardiac from noncardiac origins of chest pain is unknown., Methods and Results: Soluble and platelet fractions of P-selectin were measured for 122 patients with chest pain and 14 healthy persons acting as controls. Patients with a cardiac problem (unstable angina, congestive heart failure, acute myocardial infarction) had significantly elevated levels of soluble P-selectin (156.0 +/- 58.8 ng/mL, P =.002) and platelet-bound P-selectin (11.7% +/- 6.4% positive cells, P =.013) compared with the P-selectin profile among controls (102.6 +/- 29.0 ng/mL, 4.1% +/- 1.2% positivity) and among patients with noncardiac chest pain (114.7 +/- 36.6 ng/mL, 5.7% +/- 2.9% positivity). With a cutpoint of 10% positivity for membrane and 120 ng/mL for soluble P-selectin, the sensitivities were 0.442 and 0. 558, and the specificities were 0.915 and 0.553., Conclusions: When a patient arrives in the emergency department, measurement of membrane P-selectin may serve as an additional diagnostic tool to detect heightened platelet activity, which is most prevalent among patients with a cardiac origin of chest pain. However, low sensitivity limits the utility of the P-selectin profile alone in suitably differentiating acute coronary syndromes within the overall population of patients with chest pain.

Unlabelled: We evaluated the effect of aprotinin, administered before the onset of acute regional myocardial ischemia, on reversible contractile dysfunction induced by ischemia and reperfusion in pentobarbital-anesthetized dogs. Animals were randomized to receive either aprotinin 30,000 kallikrein inactivator units (KIU)/kg and 7000 KIU x kg(-1) x hr(-1) (n = 8) or equivalent volumes of 0.9% sodium chloride (n = 7) IV 60 min before a 15-min interruption of circumflex coronary artery blood flow and then reperfusion. There were no intra- or intergroup differences in hemodynamic variables or regional myocardial mechanics (sonomicrometry) before onset of ischemia. Immediately before reperfusion, systolic dysfunction characterized by significantly decreased percent systolic shortening was present in the circumflex coronary artery area of both study groups. After reestablishment of perfusion, aprotinin animals had preserved percent systolic shortening whereas saline animals exhibited regional systolic dysfunction. Regional myocardial contractility as assessed by the slope Mw of the preload recruitable stroke work relation was preserved during reperfusion in animals who received aprotinin but depressed in the control group. We conclude that functional recovery from myocardial ischemia-reperfusion injury at normothermia is improved by IV administration of aprotinin before the onset of acute regional myocardial ischemia in physiologically intact dogs., Implications: Administration of clinically relevant doses of aprotinin IV before the onset of regional myocardial ischemia, in contrast to control conditions, preserved regional systolic function and contractility at baseline values after reestablishment of myocardial perfusion in dogs.

Background: Previous studies have demonstrated that myocardial ischemia can be elicited by mental stress in the laboratory and during daily life and that ischemia induced by mental stress is associated with an increased risk for future cardiac events in patients with coronary artery disease., Objectives: To examine the extent to which ischemia induced by mental stress can be modified by exercise stress management, and to evaluate the impact of these interventions on clinical outcomes., Methods: One hundred seven patients with coronary artery disease and ischemia documented during mental stress testing or ambulatory electrocardiographic monitoring were randomly assigned to a 4-month program of exercise or stress management training. Patients living at a distance from the facility formed a nonrandom, usual care comparison group. Myocardial ischemia was reassessed following treatment, and patients were contacted annually for as long as 5 years to document cardiac events, including death, nonfatal myocardial infarction, and cardiac revascularization procedures., Results: Twenty-two patients (21%) experienced at least 1 cardiac event during a mean (+/- SD) follow-up period of 38 +/- 17 months. Stress management was associated with a relative risk of 0.26 compared with controls. The relative risk for the exercise group also was lower than that of controls, but the effect did not reach statistical significance. Stress management also was associated with reduced ischemia induced by mental stress and ambulatory ischemia., Conclusion: These data suggest that behavioral interventions offer additional benefit over and above usual medical care in cardiac patients with evidence of myocardial ischemia.

Objective: To determine the relative risk of myocardial ischemia triggered by specific emotions during daily life., Design and Setting: Relative risk was calculated by the recently developed case-crossover method, in which the frequency of a presumed trigger during nonischemic, or control, hours is compared with the trigger's frequency during ischemic, or case, hours. Outpatients at Duke University Medical Center, Durham, NC, underwent 48 hours of ambulatory electrocardiographic (ECG) monitoring with concurrent self-report measures of activities and emotions. Occurrences of negative emotions in the hour before the onset of myocardial ischemia were compared with their usual frequency based on all hours in which ischemia did not occur., Subjects: From a sample of 132 patients with coronary artery disease and recent evidence of exercise-induced ischemia who underwent 48 hours of ambulatory ECG monitoring, 58 patients exhibited ambulatory ischemia and were included in the analysis., Outcome Measures: Myocardial ischemia during 48-hour ECG monitoring was defined as horizontal or downsloping ST-segment depression of 1 mm (0.1 mV) or more for 1 minute or longer compared with resting baseline. The ECG data were cross-tabulated with subjects' concurrent diary ratings of 3 negative emotions-tension, sadness, and frustration-and 2 positive emotions-happiness and feeling in contro-on a 5-point scale of intensity., Results: The unadjusted relative risk of occurrence of myocardial ischemia in the hour following high levels of negative emotions was 3.0 (95% confidence interval [CI], 1.5-5.9; P<.01) for tension, 2.9 (95% CI, 1.0-8.0; P<.05) for sadness, and 2.6 (95% CI, 1.3-5.1; P<.01) for frustration. The corresponding risk ratios adjusted for physical activity and time of day were 2.2 (95% CI, 1.1 -4.5; P<.05) for tension, 2.2 (95% CI, 0.7-6.4; P=.16) for sadness, and 2.2 (95% CI, 1.1-4.3; P<.05) for frustration., Conclusions: Mental stress during daily life, including reported feelings of tension, frustration, and sadness, can more than double the risk of myocardial ischemia in the subsequent hour. The clinical significance of mental stress-induced ischemia during daily life needs to be further evaluated.

Objective: To assess the clinical significance of mental stress-induced myocardial ischemia in patients with coronary artery disease (CAD)., Design and Setting: Cohort study in outpatients in a tertiary care teaching hospital assessed at baseline and followed up for up to 5 years., Subjects: A total of 126 volunteer patients (112 men, 14 women; mean age, 59 years) with documented CAD and exercise-induced myocardial ischemia., Outcome Measures: Patients underwent baseline mental stress and exercise testing using radionuclide ventriculography and 48-hour Holter monitoring. Patients were subsequently contacted by mailed questionnaires or telephone to document cardiac events, including death, nonfatal myocardial infarction, and cardiac revascularization procedures. Logistic regression and Cox proportional hazards models were used to examine the prognostic value of the ischemic measures after adjusting for such potential confounding factors as age, baseline left ventricular ejection fraction (LVEF), and history of myocardial infarction., Results: Twenty-eight patients (22%) experienced at least 1 cardiac event. Baseline mental stress-induced ischemia was associated with significantly higher rates of subsequent cardiac events (odds ratio, 2.8; 95% confidence interval [CI], 1.0-7.7; P < .05). The LVEF change during mental stress was significantly related to event-free survival (risk ratio [RR], 2.4; 95% CI, 1.12-5.14; P = .02), controlling for age, history of prior myocardial infarction, and baseline LVEF. This relationship remained significant after controlling for electrocardiogram (ECG)-defined ischemia during exercise (RR, 2.2; 95% CI, 1.01-4.81; P < .05). The RR for ECG-defined ischemia during exercise testing was 1.9 (95% CI, 0.95-3.96; P = .07) and the RR for ambulatory ECG ischemia was 0.75 (95% CI, 0.35-1.64; P = .47)., Conclusions: The presence of mental stress-induced ischemia is associated with significantly higher rates of subsequent fatal and nonfatal cardiac events, independent of age, baseline LVEF, and previous myocardial infarction, and predicted events over and above exercise-induced ischemia. These data suggest that the relationship between psychological stress and adverse cardiac events may be mediated by the occurrence of myocardial ischemia.

Purpose: To examine the relationship between physical fitness and transient myocardial ischemia (TMI) in the laboratory and during daily life, in a sample of coronary patients with a recent positive exercise test., Methods: 47 patients with coronary disease (CAD) participated in laboratory mental and exercise stress testing and 48-hour outpatient Holter monitoring after being withdrawn from ant-ischemic medications. During laboratory testing, left ventricular performance was assessed by radionuclide ventriculography. Physical fitness was assessed by measurement of oxygen consumption during symptom-limited exercise treadmill testing., Results: Higher physical fitness subjects were less likely to exhibit wall-motion abnormalities in response to mental stress (P < .05), and to exercise stress (P < .05) testing. They also had smaller decreases in left ventricular ejection fraction (LVEF) in response to mental stress than less fit subjects (P .056), and exhibited a mean increase in LVEF during exercise, compared to the less fit subjects who exhibited a decrease in LVEF (P < .02). Moreover, higher fit subjects exhibited fewer episodes of TMI (P < .04), for a shorter duration (P < .04), and less total ischemic burden (P < .04) during Holter monitoring., Conclusion: These findings suggest that within a population of CAD patients, higher levels of physical fitness are associated with less TMI assessed in the laboratory and during routine activities of daily living.

To compare the efficacy of 3-channel ambulatory electrocardiographic monitoring (Holter monitoring) with 2-channel Holter monitoring in the detection of transient myocardial ischemia (TMI), channels CM2, CM5, and modified II were studied. Sixty patients with documented coronary artery disease underwent 48-hour Holter monitoring during their normal daily life, followed by exercise stress testing in the laboratory monitored by means of radionuclide ventriculography and standard 12-lead electrocardiography. Analysis revealed that 3-channel Holter monitoring identified 24 patients with a total of 205 TMI episodes and a total ischemic burden of 371.00 mV-min. By itself, CM2 would have detected only 3 patients (13% of the TMI population), 6 TMI episodes (3% of the total TMI episodes), and a 2.4 mV-min ischemic burden (0.7% of the total ischemic burden). Modified II alone would have identified 17 patients (71% of the TMI population), 160 TMI episodes (78% of the total TMI episodes), and 307.24 mV-min of the ischemic burden (82% of the total ischemic burden). The combination of CM5/modified II identified 23 patients (96% of the TMI population), 201 TMI episodes (98% of the total TMI episodes), and 370.44 mV-min of the ischemic burden (98% of the total ischemic burden). These findings suggest that the electrode placement is more important than the absolute number of channels in the detection of TMI by Holter monitoring.