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Background: The prognostic value of the 6-minute walk test (6MWT) in patients with stable coronary heart disease is unknown. We sought to determine whether the 6MWT predicted cardiovascular events in ambulatory patients with coronary heart disease., Methods: We measured 6MWT distance and treadmill exercise capacity in 556 outpatients with stable coronary heart disease from September 11, 2000, through December 20, 2002. Participants were followed up for a median of 8.0 years for cardiovascular events (heart failure, myocardial infarction, and death)., Results: Cardiovascular events occurred in 218 of 556 participants (39.2%). Patients in the lowest quartile of 6MWT distance (87-419 m) had 4 times the rate of events as those in the highest quartile (544-837 m) (unadjusted hazard ratio, 4.29; 95% CI, 2.83-6.53; P < .001). Each SD decrease in 6MWT distance (104 m) was associated with a 55% higher rate of cardiovascular events (age-adjusted hazard ratio, 1.55; 95% CI, 1.35-1.78). After adjustment for traditional risk factors and cardiac disease severity measures (ejection fraction, inducible ischemia, diastolic dysfunction, amino-terminal portion of the prohormone of brain-type natriuretic peptide, and C-reactive protein), each SD decrease in 6MWT was associated with a 30% higher rate of cardiovascular events (hazard ratio, 1.30; 95% CI, 1.10-1.53). When added to traditional risk factors, the 6MWT resulted in category-free net reclassification improvement of 39% (95% CI, 19%-60%). The discriminative ability of the 6MWT was similar to that of treadmill exercise capacity for predicting cardiovascular events (C statistics both 0.72; P = .29)., Conclusions: Distance walked on the 6MWT predicted cardiovascular events in patients with stable coronary heart disease. The addition of a simple 6MWT to traditional risk factors improved risk prediction and was comparable with treadmill exercise capacity.

Context: Anxiety is common in patients with coronary heart disease (CHD), but studies examining the effect of anxiety on cardiovascular prognosis and the role of potential mediators have yielded inconsistent results., Objectives: To evaluate the effect of generalized anxiety disorder (GAD) on subsequent cardiovascular events and the extent to which this association is explained by cardiac disease severity and potential behavioral or biological mediators., Design: Prospective cohort study (Heart and Soul Study)., Setting: Participants were recruited between September 11, 2000, and December 20, 2002, from 12 outpatient clinics in the San Francisco Bay Area and were followed up until March 18, 2009., Participants: One thousand fifteen outpatients with stable CHD followed up for a mean (SD) of 5.6 (1.8) years., Main Outcome Measures: We determined the presence of GAD using the Diagnostic Interview Schedule. Proportional hazards models were used to evaluate the association of GAD with subsequent cardiovascular events and the extent to which this association was explained by potential confounders and mediators., Results: A total of 371 cardiovascular events occurred during 5711 person-years of follow-up. The age-adjusted annual rate of cardiovascular events was 9.6% in the 106 participants with GAD and 6.6% in the 909 participants without GAD (P = .03). After adjustment for demographic characteristics, comorbid conditions (including major depressive disorder), cardiac disease severity, and medication use, GAD remained associated with a 62% higher rate of cardiovascular events (hazard ratio, 1.62; 95% confidence interval, 1.11-2.37; P = .01). Additional adjustment for a variety of potential behavioral and biological mediators had little effect on this association (hazard ratio, 1.74; 95% confidence interval, 1.13-2.67; P = .01)., Conclusions: In outpatients with CHD, a robust association between GAD and cardiovascular events was found that could not be explained by disease severity, health behaviors, or biological mediators. How GAD leads to poor cardiovascular outcomes deserves further study.

Context: Posttraumatic stress disorder (PTSD) is increasingly recognized as a cause of substantial disability. In addition to its tremendous mental health burden, PTSD has been associated with worse physical health status and an increased risk of cardiovascular disease., Objective: To determine whether PTSD is associated with cardiovascular health status in patients with heart disease and whether this association is independent of cardiac function., Design: Cross-sectional study., Setting: The Heart and Soul Study, a prospective cohort study of psychological factors and health outcomes in adults with stable cardiovascular disease., Participants: One thousand twenty-two men and women with coronary heart disease., Main Outcome Measures: Posttraumatic stress disorder was assessed using the Computerized Diagnostic Interview Schedule for DSM-IV. Cardiac function was measured using left ventricular ejection fraction, treadmill exercise capacity, and inducible ischemia on stress echocardiography. Disease-specific health status was assessed using the symptom burden, physical limitation, and quality of life subscales of the Seattle Angina Questionnaire. We used ordinal logistic regression to evaluate the association of PTSD with health status, adjusted for objective measures of cardiac function., Results: Of the 1022 participants, 95 (9%) had current PTSD. Participants with current PTSD were more likely to report at least mild symptom burden (57% vs 36%), mild physical limitation (59% vs 44%), and mildly diminished quality of life (62% vs 35%) (all P < or = .001). When adjusted for cardiovascular risk factors and objective measures of cardiac function, PTSD remained independently associated with greater symptom burden (odds ratio, 1.9; 95% confidence interval, 1.2-2.9; P = .004); greater physical limitation (odds ratio, 2.2; 95% confidence interval, 1.4-3.6; P = .001); and worse quality of life (odds ratio, 2.5; 95% confidence interval, 1.6-3.9; P < .001). Results were similar after excluding participants with depression., Conclusions: Among patients with heart disease, PTSD is more strongly associated with patient-reported cardiovascular health status than objective measures of cardiac function. Future studies should explore whether assessing and treating PTSD symptoms can improve function and quality of life in patients with heart disease.

Background: Current guidelines do not recommend routine cardiac stress testing in patients with stable coronary heart disease (CHD) unless they report symptoms of angina. Our objective was to compare the prognosis of self-reported angina symptoms, inducible ischemia, or both in patients with stable CHD., Methods: We measured self-reported angina by questionnaire and inducible ischemia using treadmill stress echocardiography in 937 outpatients with stable CHD. We used Cox proportional hazard models, adjusted for traditional cardiovascular risk factors, to evaluate the independent association of angina and inducible ischemia with CHD events (myocardial infarction or CHD death) during a mean of 3.9 years of follow-up., Results: Of the study participants, 129 (14%) had angina alone, 188 (20%) had inducible ischemia alone, and 40 (4%) had both angina and ischemia. Recurrent CHD events occurred in 7% of participants without angina or inducible ischemia, 10% of those with angina alone, 21% of those with inducible ischemia alone, and 23% of those with both angina and inducible ischemia (P < .001). The presence of angina alone was not associated with recurrent CHD events (adjusted hazard ratio, 1.4; 95% confidence interval, 0.7-2.9) (P = .31). However, the presence of inducible ischemia without self-reported angina strongly predicted recurrent CHD events (adjusted hazard ratio, 2.2; 95% CI, 1.4-3.5) (P = .005)., Conclusions: We found that 24% of patients with stable CHD had inducible ischemia, and more than 80% of these patients did not report angina. The presence of inducible ischemia without self-reported angina is associated with a greater than 2-fold increased rate of recurrent CHD events.

Background: Nonadherence to physician treatment recommendations is an increasingly recognized cause of adverse outcomes and increased health care costs, particularly among patients with cardiovascular disease. Whether patient self-report can provide an accurate assessment of medication adherence in outpatients with stable coronary heart disease is unknown., Methods: We prospectively evaluated the risk of cardiovascular events associated with self-reported medication nonadherence in 1015 outpatients with established coronary heart disease from the Heart and Soul Study. We asked participants a single question: "In the past month, how often did you take your medications as the doctor prescribed?" Nonadherence was defined as taking medications as prescribed 75% of the time or less. Cardiovascular events (coronary heart disease death, myocardial infarction, or stroke) were identified by review of medical records during 3.9 years of follow-up. We used Cox proportional hazards analysis to determine the risk of adverse cardiovascular events associated with self-reported medication nonadherence., Results: Of the 1015 participants, 83 (8.2%) reported nonadherence to their medications, and 146 (14.4%) developed cardiovascular events. Nonadherent participants were more likely than adherent participants to develop cardiovascular events during 3.9 years of follow-up (22.9% vs 13.8%, P = .03). Self-reported nonadherence remained independently predictive of adverse cardiovascular events after adjusting for baseline cardiac disease severity, traditional risk factors, and depressive symptoms (hazards ratio, 2.3; 95% confidence interval, 1.3-4.3; P = .006)., Conclusions: In outpatients with stable coronary heart disease, self-reported medication nonadherence is associated with a greater than 2-fold increased rate of subsequent cardiovascular events. A single question about medication adherence may be a simple and effective method to identify patients at higher risk for adverse cardiovascular events.

Background: N-terminal pro-B-type natriuretic peptide (NT-proBNP) testing is useful for diagnosing acute decompensated heart failure. Whether NT-proBNP can be used to detect ventricular dysfunction in patients with stable coronary heart disease (CHD) and no history of heart failure is unknown., Methods: We measured NT-proBNP levels and performed transthoracic echocardiography in 815 participants from the Heart and Soul Study, who had stable CHD and no history of heart failure. We hypothesized that NT-proBNP concentrations lower than 100 pg/mL would rule out ventricular dysfunction and concentrations higher than 500 pg/mL would identify ventricular dysfunction. We calculated sensitivities, specificities, likelihood ratios, and areas under the receiver operating characteristic curves for NT-proBNP as a case-finding instrument for systolic and diastolic dysfunction., Results: Of the 815 participants with no history of heart failure, 68 (8%) had systolic dysfunction defined as a left ventricular ejection fraction of 50% or lower. Of the 730 participants for whom the presence or absence of diastolic dysfunction could be determined, 78 (11%) had diastolic dysfunction defined as a pseudonormal or restrictive filling pattern. The overall area under the receiver operating characteristic curve for detecting systolic or diastolic dysfunction was 0.78 (95% confidence interval, 0.74-0.82). Likelihood ratios were 0.28 for NT-proBNP concentrations lower than 100 pg/mL, 0.95 for concentrations between 100 and 500 pg/mL, and 4.1 for concentrations higher than 500 pg/mL. A test result lower than 100 pg/mL reduced the probability of ventricular dysfunction from a pretest probability of 18% to a posttest probability of 6%. A test result higher than 500 pg/mL increased the probability of ventricular dysfunction from a pretest probability of 18% to a posttest probability of 47%. A test result between 100 and 500 pg/mL did not change the probability of ventricular dysfunction., Conclusion: In patients with stable CHD and no history of heart failure, NT-proBNP levels lower than 100 pg/mL effectively rule out ventricular dysfunction, with a negative likelihood ratio of 0.28.

Background: Depression leads to adverse outcomes in patients with coronary heart disease (CHD). Medication nonadherence is a potential mechanism for the increased risk of CHD events associated with depression, but it is not known whether depression is associated with medication nonadherence in outpatients with stable CHD., Methods: We examined the association between current major depression (assessed using the Diagnostic Interview Schedule) and self-reported medication adherence in a cross-sectional study of 940 outpatients with stable CHD., Results: A total of 204 participants (22%) had major depression. Twenty-eight (14%) of 204 depressed participants reported not taking their medications as prescribed compared with 40 (5%) of 736 nondepressed participants (odds ratio [OR], 2.8; 95% confidence interval [CI], 1.7-4.7; P<.001). Twice as many depressed participants as nondepressed participants (18% vs 9%) reported forgetting to take their medications (OR, 2.4; 95% CI, 1.6-3.8; P<.001). Nine percent of depressed participants and 4% of nondepressed participants reported deciding to skip their medications (OR, 2.2; 95% CI, 1.2-4.2; P = .01). The relationship between depression and nonadherence persisted after adjustment for potential confounding variables, including age, ethnicity, education, social support, and measures of cardiac disease severity (OR, 2.2; 95% CI, 1.2-3.9; P = .009 for not taking medications as prescribed)., Conclusions: Depression is associated with medication nonadherence in outpatients with CHD. Medication nonadherence may contribute to adverse cardiovascular outcomes in depressed patients.

Context: Depression is associated with low heart rate variability (HRV) in patients following myocardial infarction, suggesting that alterations in the autonomic nervous system may contribute to the adverse cardiac outcomes associated with depression. Whether depression is associated with low HRV in patients with stable coronary heart disease (CHD) is not known., Objective: To examine the association between major depression and 24-hour HRV in patients with stable CHD., Design, Setting, and Participants: Cross-sectional study of 873 outpatients with stable CHD recruited from outpatient clinics in the San Francisco Bay Area, California., Main Outcome Measures: Major depression was assessed using the Computerized National Institute of Mental Health Diagnostic Interview Schedule. Heart rate variability was measured by 24-hour ambulatory electrocardiography., Results: A total of 195 participants (22%) had major depression. Overall, we observed no association between depression and HRV as measured by time domain or frequency domain variables. Mean HRV was similar in participants with and without depression (all P values >.10), and participants with depression were no more likely than those without depression to have low HRV (all P values >.10)., Conclusions: We found no evidence of an association between depression and HRV in 873 outpatients with stable CHD. These findings raise questions about the potential role of HRV in the association between depression and cardiovascular disease.

Background: Use of central nervous system (CNS) active medications may increase the risk for fractures. Prior studies are limited by incomplete control of confounders., Methods: To determine whether use of CNS active medications, including benzodiazepines, antidepressants, anticonvulsants, and narcotics, increases fracture risk in elderly, community-dwelling women, we examined use of these 4 categories of medications in a cohort of 8127 older women and followed the participants prospectively for incident nonspine fractures, including hip fractures. Current use of CNS active medications was assessed by interview with verification of use from containers between 1992 and 1994 and between 1995 and 1996. Use was coded as a time-dependent variable. Incident nonspine fractures occurring after the initial medication assessment until May 31, 1999, were confirmed by radiographic reports., Results: During an average follow-up of 4.8 years, 1256 women (15%) experienced at least one nonspine fracture, including 288 (4%) with first hip fractures. Compared with nonusers, women taking narcotics (multivariate hazard ratio [HR], 1.40; 95% confidence interval [CI], 1.06-1.83) and those taking antidepressants (multivariate HR, 1.25; 95% CI, 0.99-1.58) had increases in the risks for any nonspine fractures. Women taking tricyclic antidepressants and those using selective serotonin reuptake inhibitors (SSRIs) had similar fracture rates. There were no independent associations between benzodiazepine use or anticonvulsant use and risk for nonspine fracture. Women taking antidepressants compared with nonusers had a 1.7-fold increase in the risk for hip fracture (multivariate HR, 1.65; 95% CI, 1.05-2.57). We did not observe independent associations between use of any of the other 3 classes of CNS active medications and risk of hip fracture., Conclusions: Community-dwelling older women taking narcotics have an increased risk for any nonspine fracture, and those taking antidepressants have a greater risk for nonspine fractures, including hip fracture. Rates of fracture were similar in women taking tricyclic antidepressants and those using SSRIs. Benzodiazepine use and anticonvulsant use were not independently associated with an increased risk of nonspine fractures, including hip fracture.

Background: Previous studies have suggested an association between depression and low socioeconomic status, but few have empirically examined the effect of depressive symptoms on income and employment over time., Objective: To determine whether depressive symptoms are associated with subsequent unemployment or loss of family income., Methods: We performed a prospective cohort study of 5115 adults aged 18 to 30 years. These participants included approximately equal numbers of African Americans and whites and men and women from 4 cities in the United States who completed the 1990-1991 examination of the Coronary Artery Risk Development in Young Adults (CARDIA) study. For this analysis, we included 2334 participants who were employed full or part time and who reported an annual family income of $25 000 or more. Participants completed the Center for Epidemiologic Studies Depression Scale and were considered to have depressive symptoms if they scored 16 or higher on the 60-point scale. We evaluated self-reported unemployment and annual family income during 5 years of follow-up., Results: Thirty-three percent (118/354) of participants with depressive symptoms (Center for Epidemiologic Studies Depression Scale score >/=16) in 1990-1991 and 21% (335/1581) of participants without substantial depressive symptoms (Center for Epidemiologic Studies Depression Scale score <16) reported new unemployment during the subsequent 5 years (odds ratio, 1.9; 95% confidence interval, 1.4-2.4; P<.001). This association remained strong after adjusting for potential confounding variables, including marital status, education, history of unemployment, current part-time (vs full-time) employment, and cigarette smoking (odds ratio, 1.6; 95% confidence interval, 1.2-2.0; P =.001). Seventeen percent (62/371) of participants with depressive symptoms and 7% (113/1631) of participants without substantial depressive symptoms in 1990-1991 reported that their family income had decreased below $25 000 by 1995-1996 (odds ratio, 2.7; 95% confidence interval, 1.9-3.8; P<.001). This association also remained strong after adjusting for potential confounding variables (odds ratio, 1.9; 95% confidence interval, 1.3-2.7; P<.001)., Conclusions: Depressive symptoms are associated with subsequent unemployment and loss of family income among working young adults. Socioeconomic indicators, such as income and employment, should be considered in evaluating the potential benefits of treatment for patients with depressive symptoms.

Background: Results of previous studies have suggested that involvement in religious activities may be associated with lower rates of smoking. We sought to determine whether frequent attendance at religious services is associated with less smoking among young adults., Methods: This prospective cohort study of 4569 adults aged 20 to 32 years included approximately equal numbers of blacks and whites and men and women from 4 cities in the United States who attended the 1987/1988 examination of the Coronary Artery Risk Development in Young Adults (CARDIA) study. Frequency of attendance at religious services and denominational affiliation were determined by self-report questionnaire in 1987/1988. Cigarette smoking was determined by interview at this time and again 3 years later., Results: Of 4544 participants who completed the tobacco questionnaire in 1987/1988, 34% (891/2598) who attended religious services less than once per month or never and 23% (451/1946) who attended religious services at least once per month reported current smoking (odds ratio [OR], 1.7; 95% confidence interval [CI], 1.5-2.0; P<.001). This association between less frequent attendance at religious services and current smoking was found in most denominations and remained significant after adjusting for potential confounding variables (OR, 1.5; 95% CI, 1.3-1.8; P<.001). During 3-year follow-up, nonsmokers who reported little or no religious involvement had an increased risk of smoking initiation (adjusted OR, 1.9; 95% CI, 1.3-2.7; P<.001)., Conclusions: Young adults who attend religious services have lower rates of current and subsequent cigarette smoking. The potential health benefits associated with religious involvement deserve further study.

Background: Previous studies have suggested that depression is associated with falls and with low bone density, but it is not known whether depression leads to an increased risk of fracture., Subjects and Methods: We conducted a prospective cohort study in elderly white women who were recruited from population-based listings in the United States. At a second visit (1988-1990), 7414 participants completed the 15-item Geriatric Depression Scale and were considered depressed if they reported 6 or more symptoms of depression. We measured bone mineral density (BMD) in the spine and hip using dual energy x-ray absorptiometry at the second visit, and asked participants about incident falls (yes/no) at 4 follow-up visits. Nonvertebral fractures were ascertained for an average of 6 years following the depression measure, and verified radiologically. We determined incident vertebral fractures by comparing lateral spine films obtained at the first visit (1986-1988) with repeat films obtained an average of 3.7 years later (1991-1992)., Results: The prevalence of depression (Geriatric Depression Scale score > or = 6) was 6.3% (467/7414). We found no difference in mean BMD of the hip and lumbar spine in women with depression compared with those without depression. Women with depression were more likely to experience subsequent falls than women without depression (70% vs 59%; age-adjusted odds ratio [OR], 1.6; 95% confidence interval [CI], 1.3-1.9; P<.001), an association that persisted after adjusting for potential confounding variables (OR, 1.4; 95% CI, 1.1-1.8; P=.004). Women with depression had a 40% (age-adjusted hazard ratio [HR], 1.4; 95% CI, 1.2-1.7; P<.001) increased rate of nonvertebral fracture (124 fractures in 3805 woman-years of follow-up) compared with women without depression (1367 fractures in 59 503 woman-years of follow-up). This association remained strong after adjusting for potential confounding variables, including medication use and neuromuscular function (HR, 1.3; 95% CI, 1.1-1.6; P=.008). Further adjustment for subsequent falls appeared to explain part of this association (HR, 1.2; 95% CI, 1.0-1.5; P = .06). Women with depression were also more likely to suffer vertebral fractures than women without depression, adjusting for history of vertebral fracture, history of falling, arthritis, diabetes, steroid use, estrogen use, supplemental calcium use, cognitive function, and hip BMD (OR, 2.1; 95% CI, 1.4-3.2; P<.001)., Conclusions: Depression is a significant risk factor for fracture in older women. The greater frequency of falls among individuals with depression partially explains this finding. Other mechanisms responsible for the association between depression and fracture remain to be determined.

Background: Major depression is associated with increased mortality, but it is not known whether patients who report depressive symptoms have greater mortality., Subjects and Methods: We performed a prospective cohort study of 7518 white women 67 years of age or older who were recruited from population-based listings in Baltimore, Md, Minneapolis, Minn, Portland, Ore, and the Monongahela Valley, Pa. Participants completed the Geriatric Depression Scale (short form) and were considered depressed if they reported 6 or more of 15 possible symptoms of depression. Women were followed up for an average of 6 years. If a participant died, we obtained a copy of the official death certificate and hospital records, if available, and used International Classification of Diseases, Ninth Revision, codes to classify death attributable to cardiovascular, cancer, or noncancer, noncardiovascular cause., Results: Mortality during 7-year follow-up varied from 7% in women with no depressive symptoms to 17% in those with 3 to 5 symptoms to 24% in those with 6 or more symptoms of depression (P<.001). Of 473 women (6.3%) with 6 or more depressive symptoms at baseline, 24% died (111 deaths in 2610 woman-years of follow-up) compared with 11% of women who reported 5 or fewer symptoms of depression (760 deaths in 41 460 woman-years of follow-up) (P<.001). Women with 6 or more depressive symptoms had a 2-fold increased risk of death (age-adjusted hazard ratio [HR], 2.14; 95% confidence interval [CI], 1.75-2.61; P<.001) compared with those who had 5 or fewer depressive symptoms. This association remained strong after adjusting for potential confounding variables, including history of myocardial infarction, stroke, diabetes mellitus, hypertension, chronic obstructive pulmonary disease, smoking, perceived health, and cognitive function (HR, 1.47; 95% CI, 1.14-1.88; P=.003). Depressive symptoms were associated with an increased adjusted risk of death from cardiovascular diseases (HR, 1.8; 95% CI, 1.2-2.5; P= .003), and non-cancer, noncardiovascular diseases (HR, 1.8; 95% CI, 1.2-2.7; P = .01), but were not associated with deaths from cancer (HR, 1.0; 95% CI, 0.6-1.7; P=.93)., Conclusions: Depressive symptoms are a significant risk factor for cardiovascular and noncancer, noncardiovascular mortality but not cancer mortality in older women. Whether depressive symptoms are a marker for, or a cause of, life-threatening conditions remains to be determined.