Prognosis After Change in Left Ventricular Ejection Fraction During Mental Stress Testing in Patients With Stable Coronary Artery Disease
Article Outline
Previous studies of patients with stable coronary artery disease have demonstrated that decreases in the left ventricular ejection fraction (LVEF) during acute mental stress are predictive of adverse clinical outcomes. The aim of the present study was to examine the prospective relation of mental stress on clinical outcomes in a sample of 138 patients with stable coronary artery disease. Patients underwent mental stress testing and were followed for a median of 5.9 years to assess the occurrence of the combined end point of myocardial infarction or all-cause mortality. There were 32 events (17 nonfatal myocardial infarctions and 15 deaths) over the follow-up period. Of the 26 patients who exhibited myocardial ischemia during mental stress testing, 11 (42%) sustained subsequent clinical events, compared to 21 of the 112 patients (19%) who showed no mental stress–induced ischemia. LVEF change during mental stress was also related to the clinical events in a graded, continuous fashion, with each 4% decrease from the LVEF at rest associated with an adjusted hazard ratio of 1.7, (95% confidence interval 1.1 to 2.6, p = 0.011). In conclusion, reductions in the LVEF during mental stress are prospectively associated with adverse clinical outcomes.
A decrease in the left ventricular ejection fraction (LVEF) during mental stress (LVEF-MS) has been shown to identify patients at increased risk for adverse clinical events1, 2, 3, 4 among those with documented coronary artery disease (CAD). Previously, we showed that reductions in the LVEF in response to mental stress were associated with an increased likelihood of subsequent clinical events, but these events were primarily revascularization procedures.1 Because revascularization procedures may not always reflect extraclinical factors as well as disease progression,5 we reexamined this association using “hard” end points of all-cause death and myocardial infarction (MI) in a sample of patients with stable CAD.
Methods
Data were available from baseline assessments of 138 of 144 patients with documented CAD who participated in a clinical trial of exercise and behavioral stress management.6 To participate in the trial, patients had to have documented CAD (by previous MI, coronary artery bypass graft surgery, coronary angioplasty, and/or ≥75% stenosis in ≥1 major coronary artery) and a positive results on treadmill exercise testing within the previous year. Informed consent was obtained for all participants, and the study protocol was approved by the Institutional Review Board at Duke University Medical Center.
Unless medically contraindicated, patients were briefly withdrawn from anti-ischemic medications (e.g., β blockers, calcium channel blockers, and long-acting nitrates) ≥48 hours before testing; the medication washout period was ≥5 half-lives of the anti-ischemic medication. Twenty-eight patients were unable to be withdrawn from their medications and were tested on their usual doses of anti-ischemic medications. After a 40-minute rest period, mental stress testing was performed, in which patients were presented with 2 mental stress tasks, public speaking and mirror trace, in counterbalanced order. The speaking stressor required participants to give a speech on a controversial current events topic after 1 minute of preparation. The mirror trace stressor required participants to outline the shape of a star from its reflection in a mirror. Each task lasted 5 minutes, with a 10-minute rest period between each stressor. These tasks have been used in previous work and have been found to elicit ischemia in vulnerable patients.7
To determine the presence of myocardial ischemia, R-wave-synchronized, gated equilibrium radionuclide ventriculography using Paragon PBR software (Medasys, Inc., Ann Arbor, Michigan) was performed before and during each stressor at 20 frames/cardiac cycle using a gamma camera (Siemens Gammasonics, Inc., Des Plaines, Illinois) equipped with a sodium iodide crystal and an all-purpose collimator. Images were obtained after the labeling of autologous red blood cells with technetium-99m pertechnetate using the in vivo technique.8 Imaging was conducted during the last 2 minutes of the rest period, the first minute of speech preparation, and at 2 and 4 minutes for the speaking and mirror trace stressors with the camera in the left anterior oblique view. The LVEF was determined using the PBR software.
We defined LVEF-MS as the change from the LVEF at rest, averaged across the speaking and trace tasks. We also classified patients who had reductions in the LVEF of ≥5% (e.g., from 55% during rest to an average of ≤50% during the tasks) as exhibiting mental stress–induced myocardial ischemia. Participants were assessed for clinical events 4 months after testing and annually thereafter through a combination of telephone and mail contact with participants, examination of medical records, and public sources of vital statistics. The primary outcome was the combined end point of all-cause mortality or MI.
We used multivariate Cox proportional-hazards models9 to estimate the hazard associated with LVEF-MS, adjusting for age, gender, history of MI, and LVEF at rest. LVEF-MS was modeled as a continuous variable and scaled such that the resulting hazard ratio (HR) represented the change in hazard for every 4% (the interquartile range of LVEF-MS) reduction in LVEF-MS. The LVEF at rest and age also were modeled as continuous variables scaled to their interquartile ranges (14% and 15 years, respectively). We examined the association between the continuous LVEF-MS measure and the end point for possible nonlinearity using a flexible nonparametric curve-fitting algorithm.10, 11 We also conducted a number of sensitivity analyses, adjusting for further potential confounders, including revascularization procedures that occurred during follow-up (modeled as a time-varying covariate). In addition, we evaluated whether the relation between LVEF-MS and the combined end point differed for patients who were tapered off their cardiac medications during the mental stress testing and those who were still taking their medications by testing an interaction term for LVEF-MS by medication status (on vs off medication) in the Cox model. Finally, we reestimated the primary Cox models for the separate end points of death and MI.
Results
One hundred thirty-eight participants (98%) had adequate radionuclide ventriculographic studies during mental stress testing. The average age of the sample was 62 years, with most being white men. Twenty-six patients (19%) of the sample exhibited mental stress–induced ischemia. Patients with mental stress–induced ischemia were more likely to belong to ethnic minorities, to report histories of diabetes, and to have lower serum high-density lipoprotein levels at the time of testing compared to the nonischemic patients (Table 1). The median follow-up time was 5.9 years (interquartile range 4.8 to 7.2 years, range 35 days to 8.8 years). There were 18 deaths and 17 nonfatal MIs. Of the 18 deaths, 4 were known to be related to cardiac causes, 2 were known to be noncardiac, and 12 were of unknown causes. In 3 cases, death was preceded by MI, so the initial MI rather than death was used as the outcome. Thus, 32 unique events (15 deaths and 17 MIs) were available for analysis.
Table 1. Characteristics of patients with and without mental stress–induced myocardial ischemia (n = 138)
| Variable | No Ischemia | Ischemia | All Participants | p Value (Ischemia vs No Ischemia)⁎ |
|---|---|---|---|---|
| (n = 112) | (n = 26) | (n = 138) | ||
| Age (years) | 62.5 (55.8to71.2) | 60.0(51.2to69.0) | 62.0(55.0to70.0) | 0.471 |
| Men | 79(71%) | 17(65%) | 96(70%) | 0.607 |
| Ethnicity | 0.030† | |||
| African America | 17(15%) | 8(31%) | 25(18%) | |
| Caucasian | 91(81%) | 15(58%) | 106(77%) | |
| Other ethnicity | 4(4%) | 3(12%) | 7(5%) | |
| Education | 0.391† | |||
| High school or less | 32(29%) | 7(27%) | 39(28%) | |
| Some college | 39(35%) | 6(23%) | 45(33%) | |
| College or more | 41(37%) | 13(50%) | 54(39%) | |
| Body mass index (kg/m2) | 28.4(25.8to32.3) | 30.1(25.5to32.4) | 28.9(25.7to32.3) | 0.584 |
| Hypertension | 60(54%) | 15(58%) | 75(54%) | 0.704 |
| Diabetes mellitus | 21(19%) | 10(38%) | 31(22%) | 0.030 |
| Current smokers | 14(12%) | 3(12%) | 17(12%) | 0.893 |
| Quit smoking | 72(64%) | 15(58%) | 87(63%) | 0.530 |
| Past myocardial reinfarction | 63(56%) | 15(58%) | 78(57%) | 0.894 |
| Past revascularization | 50(45%) | 12(46%) | 62(45%) | 0.889 |
| Total cholesterol (mg/dl) | 180(160to205) | 183(166to197) | 180(161to201) | 0.819 |
| Low-density lipoprotein (mg/dl) | 97(87,124) | 114(88,125) | 98(87,125) | 0.539 |
| High-density lipoprotein (mg/dl) | 45(39.54) | 40(35.47) | 44(38.52) | 0.016 |
| Triglycerides (mg/dl) | 141(102to211) | 138(100to166) | 140(102to210) | 0.888 |
| β blockade | 81(72%) | 18(72%) | 99(72%) | 0.974 |
| Nitrates | 34(30%) | 8(23%) | 42(31%) | 0.872 |
| Calcium channel blockade | 25(22%) | 5(20%) | 30(22%) | 0.800 |
| Anticoagulants | 102(91%) | 22(85%) | 124(90%) | 0.326 |
| Statins | 87(78%) | 20(77%) | 107(78%) | 0.934 |
| LVEF at rest (%) | 57.5(51.0to66.2) | 56.2(51.1to63.0) | 57.2(51.0to64.9) | 0.729 |
| Reduction in LVEF during mental stress (%) | −0.75(−2.25to0.75) | −6.50(−7.19to−5.56) | −1.50(−3.50to0.50) | <0.001 |
| Medication during testing | 21(19%) | 7(27%) | 28(20%) | 0.351 |
⁎Wilcoxon's test was used for continuous variables, and Pearson's chi-square test was used for categorical variables. |
†From global test of all categories. |
Among the 26 patients who exhibited mental stress–induced ischemia, 42% (n = 11) sustained clinical events during the follow-up period, compared with 19% (n = 21) of the 112 patients who showed no ischemia. Figure 1 shows the unadjusted Kaplan-Meier curves for patients with and without mental stress–induced ischemia. The log-rank test comparing the 2 curves was statistically significant (p = 0.020). Turning to the Cox regression results, LVEF-MS was significantly associated with the time to the combined end point (see Table 2), adjusting for age, gender, previous MI, and the LVEF at rest. We found no evidence that the association between LVEF-MS and the combined end point was nonlinear (p = 0.485).
Figure 1.
Kaplan-Meier curves comparing patients with myocardial ischemia (LVEF decrease ≥5%) and those without myocardial ischemia (LVEF decrease <5%) during mental stress. The log-rank test was statistically significant (p = 0.012).
Table 2. Cox regression results predicting time to combined end point of death (n = 15) or nonfatal myocardial infarction (n = 17)
| Factor | Scale Value for Predictor | HR (95% CI) | p Value |
|---|---|---|---|
| Age | 15 | 1.1(0.6–1.9) | 0.718 |
| Previous MI | Yes vs no | 1.1(0.5–2.4) | 0.824 |
| LVEF at rest | 14 | 1.0(0.6–1.6) | 0.820 |
| Reduction in LVEF during mental stress | 4 | 1.7(1.1–2.6) | 0.011 |
Adjusting for revascularization procedures (as a time-varying covariate), diabetes, high-density lipoprotein, and ethnic minority status in the primary Cox model did not materially alter the estimate for LVEF-MS (HR 1.8, 95% confidence interval [CI] 1.1 to 2.9, p = 0.012). We also observed no evidence that the relation between LVEF-MS and the end point differed by medication status during the mental stress testing (p = 0.637). Considering only the 17 MIs as the end point (censoring deceased patients at the time of death), the estimate for LVEF-MS remained similar to that in the primary analysis (HR 1.8, 95% CI 1.02 to 3.2, p = 0.043). Using only the 18 deaths (including the 3 patients who had died after MIs) as the end point, the HR for change in LVEF-MS was attenuated (HR 1.6), and the CI contained 1.0 (95% CI 0.84 to 2.9, p = 0.159). When we removed the 3 deceased patients with known MIs from the analysis of deaths only, the HR was further attenuated, and the CI became wider (HR 1.5, 95% CI 0.8 to 2.9, p = 0.221).
Discussion
Our finding of an association between clinical events and change in the LVEF during mental stress is consistent with several previous studies using a variety of methodologies to evaluate mental stress–induced changes in left ventricular function,1, 2, 3, 4 supporting the robustness of the association across a relatively broad population of patients with stable CAD. In the present sample, the HR for every 4% decrease in LVEF during mental stress was 1.7, which is consistent with our previous study, in which the adjusted HR was about 1.5 for every 4% reduction in the LVEF during mental stress.1 We also found that the hazard estimate for LVEF-MS remained relatively unchanged after adjustment for a number of additional covariates and also when examining MI and all-cause mortality as a separate end point. The association of LVEF-MS with all-cause mortality alone was somewhat weaker, especially after the 3 overlapping MI cases were removed from among the deaths. This latter finding suggests that the inclusion of non-cardiac-related death may have attenuated the association in the primary analysis of the combined end point. Sensitivity analyses also indicated that the present finding is unlikely explained by confounding baseline differences between patients with and without ischemic responses. We also found that although the conventional binary definition of ischemia during mental stress was related to the risk for an event, the continuous measures of LVEF change was also associated with clinical events. Indeed, given the relatively few patients (19%) with responses that met the definition of mental stress–induced ischemia, the association between LVEF change and prognosis was driven to a large extent by patients who did not have decreases in the LVEF of ≥5%. We observed a similar continuous linear association in our previous study.1 Because LVEF changes with stress may reflect hemodynamic responses that are not due to myocardial ischemia, other mechanisms may contribute to the relation between LVEF change and subsequent cardiovascular events.
Despite the important diagnostic and prognostic utility of mental stress ischemia, the mechanisms underlying its occurrence are not well understood. Because mental stress typically elicits marked hemodynamic adjustments, including increased blood pressure and heart rate, as well as cardiac contractility, it results in increased myocardial oxygen demand.12 Unlike normal coronary arteries, atherosclerotic vessels are prone to constrict rather than dilate, and constriction of the coronary arteries leads to reduced myocardial oxygen supply.13 Myocardial ischemia is understood to be the manifestation of a myocardial oxygen supply-demand imbalance.14 On the demand side, we have previously shown that mental stress–induced ischemia was associated with increases in systolic blood pressure and the rate–pressure product but not with increased heart rate.7 We also observed that mental stress–induced ischemia was associated with elevated diastolic blood pressure and suggested that ischemia may be caused by reduced myocardial oxygen supply.7 Indeed, increased systemic vascular resistance during mental stress was linked to myocardial ischemia in the Psychophysiological Investigations of Myocardial Ischemia (PIMI) study,15 and increased systemic vascular resistance may be considered a manifestation of arterial vasoconstriction and represent a marker of coronary vasoconstriction. Our previous work has shown that mental stress–induced increases in systemic vascular resistance are associated with vascular endothelial dysfunction, as indexed by low flow-mediated dilation (FMD).16 Indeed, the occurrence of mental stress–induced myocardial ischemia has been found to be associated with impaired FMD in postmenopausal women with angina.17 Acute mental stress may also result in unfavorable transient alterations in endothelial function. Ghiadoni et al18 found that exposure to a laboratory-based, simulated public speaking stressor resulted in transiently impaired FMD (decreasing from 5% at rest to 2.8% after stress) in 10 healthy, middle-aged men. Gottdiener et al19 also documented that mental stress, associated with laboratory anger recall and mental arithmetic stressors, impaired FMD in a study sample composed of 38 men and women. Findings of mental stress–related impairment of FMD have been replicated in several additional studies, which have used a variety of laboratory-based mental stressors, including mental arithmetic,20 psychomotor reaction time tasks,21 and cold pressors.22, 23 Therefore, mental stress ischemia may be a manifestation of increased myocardial demand, combined with impaired vascular regulation that may transiently compromise myocardial oxygen supply and increase vulnerability to adverse cardiac events.
References
- . Mental stress–induced myocardial ischemia and cardiac events. JAMA. 1996;275:1651–1656
- . Prognostic implications of mental stress-induced silent left ventricular dysfunction in patients with stable angina pectoris. Am J Cardiol. 1995;76:31–35
- . Mental stress-induced ischemia and all-cause mortality in patients with coronary artery disease: results from the psychophysiological investigations of myocardial ischemia study. Circulation. 2002;105:1780–1784
- . Prognostic value of mental stress testing in coronary artery disease. Am J Cardiol. 1999;84:1292–1297
- . Determinants of the use of coronary angiography and revascularization after thrombolysis for acute myocardial infarction. N Engl J Med. 1996;335:1198–1205
- . Effects of exercise and stress management training on markers of cardiovascular risk in patients with ischemic heart disease: a randomized controlled trial. JAMA. 2005;293:1626–1634
- . Mental stress-induced ischemia in the laboratory and ambulatory ischemia during daily life (Association and hemodynamic features). Circulation. 1995;92:2102–2108
- . Cardiovascular system. In: Metler FA, Guiberteau MJ editor. Essentials of Nuclear Imaging. Orlando: Grune & Stratton; 1986;p. 151–152
- . Regression models and life tables. J R Stat Soc Series B Stat Methodol. 1972;34:187–220
- . Regression Modeling Strategies: With Applications to Linear Modeling, Logistic Regression, and Survival Analysis. In: New York: Springer; 2001;p. 568
- . Additive Splines in Statistics (Proceedings of the Statistical Computing Section). Washington, DC: American Statistical Association; 1985;
- . Hemodynamic responses during psychological stress: implications for studying disease processes. Int J Behav Med. 1995;2:193–218
- . Sympathetically mediated effects of mental stress on the cardiac microcirculation of patients with coronary artery disease. Am J Cardiol. 1995;76:125–130
- . Changing concepts in the pathophysiology of myocardial ischemia. Am J Cardiol. 1989;64(suppl):3F–9F
- . Ischemic, hemodynamic, and neurohormonal responses to mental and exercise stress: experience from the Psychophysiological Investigations of Myocardial Ischemia study (PIMI). Circulation. 1996;94:2402–2409
- . Endothelial function and hemodynamic responses during mental stress. Psychosom Med. 1999;61:365–370
- . Mental stress-induced myocardial ischemia in women with angina and normal coronary angiograms. J Nucl Cardiol. 2006;13:507–513
- . Mental stress induces transient endothelial dysfunction in humans. Circulation. 2000;102:2473–2478
- . Effects of mental stress on flow-mediated brachial arterial dilation and influence of behavioral factors and hypercholesterolemia in subjects without cardiovascular disease. Am J Cardiol. 2003;92:687–691
- . Hypnotic modulation of flow-mediated endothelial response to mental stress. Int J Psychophysiol. 2005;55:221–227
- . Mental stress induces prolonged endothelial dysfunction via endothelin-A receptors. Circulation. 2002;105:2817–2820
- . Modulation of pain-induced endothelial dysfunction by hypnotisability. Pain. 2005;116:181–186
- . The effects of mental stress and the cold pressure test on flow-mediated vasodilation. Blood Press. 2002;11:22–27
This study was supported by Grants HL59672 and M01-RR-30 from the National Institutes of Health, Bethesda, Maryland.
PII: S0002-9149(09)02212-7
doi:10.1016/j.amjcard.2009.08.647
© 2010 Elsevier Inc. All rights reserved.
