Lifetime trauma exposure and prospective cardiovascular events and all-cause mortality: findings from the Heart and Soul Study.

OBJECTIVE: Little is known about the effect of cumulative psychological trauma on health outcomes in patients with cardiovascular disease. The objective of this study was to prospectively examine the association between lifetime trauma exposure and recurrent cardiovascular events or all-cause mortality in patients with existing cardiovascular disease. METHODS: A total of 1021 men and women with cardiovascular disease were recruited in 2000 to 2002 and followed annually. Trauma history and psychiatric comorbidities were assessed at baseline using the Computerized Diagnostic Interview Schedule for DSM-IV. Health behaviors were assessed using standardized questionnaires. Outcome data were collected annually, and all medical records were reviewed by two independent, blinded physician adjudicators. We used Cox proportional hazards models to evaluate the association between lifetime trauma exposure and the composite outcome of cardiovascular events and all-cause mortality. RESULTS: During an average of 7.5 years of follow-up, there were 503 cardiovascular events and deaths. Compared with the 251 participants in the lowest trauma exposure quartile, the 256 participants in the highest exposure quartile had a 38% greater risk of adverse outcomes (hazard ratio = 1.38, 95% confidence interval = 1.06-1.81), adjusted for age, sex, race, income, education, depression, posttraumatic stress disorder, generalized anxiety disorder, smoking, physical inactivity, and illicit drug abuse. CONCLUSIONS: Cumulative exposure to psychological trauma was associated with an increased risk of recurrent cardiovascular events and mortality, independent of psychiatric comorbidities and health behaviors. These data add to a growing literature showing enduring effects of repeated trauma exposure on health that are independent of trauma-related psychiatric disorders such as depression and posttraumatic stress disorder.

Hostility, health behaviors, and risk of recurrent events in patients with stable coronary heart disease: findings from the Heart and Soul Study.

BACKGROUND: Hostility is a significant predictor of mortality and cardiovascular events in patients with coronary heart disease (CHD), but the mechanisms that explain this association are not well understood. The purpose of this study was to evaluate potential mechanisms of association between hostility and adverse cardiovascular outcomes. METHODS AND RESULTS: We prospectively examined the association between self-reported hostility and secondary events (myocardial infarction, heart failure, stroke, transient ischemic attack, and death) in 1022 outpatients with stable CHD from the Heart and Soul Study. Baseline hostility was assessed using the 8-item Cynical Distrust scale. Cox proportional hazard models were used to determine the extent to which candidate biological and behavioral mediators changed the strength of association between hostility and secondary events. During an average follow-up time of 7.4 ± 2.7 years, the age-adjusted annual rate of secondary events was 9.5% among subjects in the highest quartile of hostility and 5.7% among subjects in the lowest quartile (age-adjusted hazard ratio [HR]: 1.68, 95% confidence interval [CI]: 1.30 to 2.17; P < 0.0001). After adjustment for cardiovascular risk factors, participants with hostility scores in the highest quartile had a 58% greater risk of secondary events than those in the lowest quartile (HR: 1.58, 95% CI: 1.19 to 2.09; P = 0.001). This association was mildly attenuated after adjustment for C-reactive protein (HR: 1.41, 95% CI, 1.06 to 1.87; P = 0.02) and no longer significant after further adjustment for smoking and physical inactivity (HR: 1.25, 95% CI: 0.94 to 1.67; P = 0.13). CONCLUSIONS: Hostility was a significant predictor of secondary events in this sample of outpatients with baseline stable CHD. Much of this association was moderated by poor health behaviors, specifically physical inactivity and smoking.

Alcohol consumption and 5-year change in left atrial volume among patients with coronary heart disease: results from the Heart and Soul study.

BACKGROUND: Heavy alcohol consumption is a risk factor for developing atrial fibrillation, but whether chronic alcohol use affects left atrial volume is unknown. We evaluated the association of self-reported alcohol consumption with 5-year change in left atrial volume among patients with coronary heart disease (CHD). METHODS: We studied 601 participants with stable CHD who underwent 2-dimensional echocardiography at baseline (2000-2002) and after 5 years of follow-up (2005-2007). Alcohol consumption was determined at baseline with the use of the Alcohol Use Disorders Identification Test consumption questions (AUDIT-C), with a standard cutoff point of ≥3 used to define at-risk drinking. We used logistic regression to evaluate the association of baseline alcohol use with 5-year increase in left atrial end-systolic volume index (defined as being in the highest tertile of percent change). RESULTS: After adjustment for covariates, each standard deviation (2.4-point) increase in AUDIT-C score was associated with a 24% greater odds of experiencing a 5-year increase in left atrial volume index (adjusted odds ratio [OR] 1.24, 95% confidence interval [CI] 1.04-1.48; P = .02). Compared with the 369 participants who had AUDIT-C scores of <3, the 171 participants with scores of 3-5 had a 51% greater odds (OR 1.51, 95% CI, 1.11-2.25) and the 61 participants with scores of >5 a 98% greater odds (OR 1.98, 95% CI, 1.10-3.56) of experiencing a 5-year increase in left atrial volume index. CONCLUSIONS: In patients with CHD, heavier alcohol consumption is associated with a 5-year increase in left atrial volume. Whether greater left atrial volume contributes to the increased risk of atrial fibrillation associated with alcohol use deserves further study.

Depressive symptoms and white blood cell count in coronary heart disease patients: prospective findings from the Heart and Soul Study.

BACKGROUND: Depression has been associated with elevated white blood cell (WBC) count - indicative of systemic inflammation - in cross-sectional studies, but no longitudinal study has evaluated whether depressive symptoms predict subsequent WBC count or vice versa. We sought to evaluate the bidirectional association between depressive symptoms and WBC count in patients with coronary heart disease (CHD). METHODS: Depressive symptoms were assessed at baseline and annually during 5 consecutive years of follow-up in 667 outpatients with stable CHD from the Heart and Soul Study. The presence of significant depressive symptoms was defined as a score of ≥10 on the Patient Health Questionnaire (PHQ-9) at one or more assessments. WBC count was measured in blood samples collected at baseline and after 5 years of follow-up. RESULTS: Of the 667 participants, 443 (66%) had no depressive symptoms (PHQ-9<10), 86 (13%) had depressive symptoms (PHQ-9≥10) at 1 assessment, and 138 (21%) had depressive symptoms at 2 or more annual assessments. Across the three groups, participants with recurrent depressive symptoms had higher WBC levels after 5 years of follow-up (p<.001). This relationship was essentially unchanged after adjustment for demographics, traditional cardiovascular risk factors, cardiac disease severity, inflammatory cytokine levels, and health behaviors (p=.009). Baseline WBC count was not associated with subsequent depressive symptoms (p=.18). CONCLUSIONS: Depressive symptoms independently predicted higher subsequent WBC count in patients with stable CHD, but baseline WBC count did not predict subsequent depressive symptoms. These findings support a unidirectional relationship in which depression is a risk-factor for inflammation.

Mitral annular calcium, inducible myocardial ischemia, and cardiovascular events in outpatients with coronary heart disease (from the Heart and Soul Study).

We sought to determine whether mitral annular calcium (MAC) is associated with inducible myocardial ischemia and adverse cardiovascular outcomes in ambulatory patients with coronary artery disease (CAD). MAC is associated with cardiovascular disease (CVD) in the general population, but its association with CVD outcomes in patients with CAD has not been evaluated. We examined the association of MAC with inducible ischemia and subsequent cardiovascular events in 1,020 ambulatory patients with CAD who were enrolled in the Heart and Soul Study. We used logistic regression to determine the association of MAC with inducible ischemia and Cox proportional hazards models to determine the association with CVD events (myocardial infarction, heart failure, stroke, transient ischemic attack or death). Models were adjusted for age, gender, race, smoking, history of heart failure, blood pressure, high-density lipoprotein, and estimated glomerular filtration rate. Of the 1,020 participants 192 (19%) had MAC. Participants with MAC were more likely than those without MAC to have inducible ischemia (adjusted odds ratio 2.06, 95% confidence interval 1.41 to 3.01, p = 0.0002). During an average of 6.26 ± 2.11 years of follow-up, there were 310 deaths, 161 hospitalizations for heart failure, 118 myocardial infarctions, and 55 cerebrovascular events. MAC was associated with an increased rate of cardiovascular events (adjusted hazard ratio 1.39, 95% confidence interval 1.08 to 1.79, p = 0.01). In conclusion, we found that MAC was associated with inducible ischemia and subsequent CVD events in ambulatory patients with CAD. MAC may indicate a high atherosclerotic burden and identify patients at increased risk for adverse cardiovascular outcomes.

Adiponectin is associated with increased mortality and heart failure in patients with stable ischemic heart disease: data from the Heart and Soul Study.

OBJECTIVE: Serum adiponectin protects against incident ischemic heart disease (IHD). However, in patients with existing IHD, higher adiponectin levels are paradoxically associated with worse outcomes. We investigated this paradox by evaluating the relationship between adiponectin and cardiovascular events in patients with existing IHD. METHODS: We measured total serum adiponectin and cardiac disease severity by stress echocardiography in 981 outpatients with stable IHD who were recruited for the Heart and Soul Study between September 2000 and December 2002. Subsequent heart failure hospitalizations, myocardial infarction, and death were recorded. RESULTS: During an average of 7.1 years of follow-up, patients with adiponectin levels in the highest quartile were more likely than those in the lowest quartile to be hospitalized for heart failure (23% vs. 13%; demographics-adjusted hazard ratio (HR) 1.63, 95% confidence interval (CI) 1.04-2.56, p=0.03) or die (49% vs. 31%; HR 1.67, 95% CI 1.24-2.26, p<0.008), but not more likely to have a myocardial infarction (12% vs. 17%; HR 0.64, 95% CI 0.38-1.06, p=0.08). The combined outcome of myocardial infarction, heart failure, or death occurred in 56% (136/245) of participants in the highest quartile of adiponectin vs. 38% (94/246) of participants in the lowest quartile (HR 1.54, 95% CI 1.31-2.21, p<0.002). Adjustment for left ventricular ejection fraction, diastolic dysfunction, inducible ischemia, C-reactive protein, and NT-proBNP attenuated the association between higher adiponectin and increased risk of subsequent events (HR 1.43, 95% CI 0.98-2.09, p=0.06). CONCLUSIONS: Higher concentrations of adiponectin were associated with heart failure and mortality among patients with existing IHD.

Physical fitness and telomere length in patients with coronary heart disease: findings from the Heart and Soul Study.

BACKGROUND: Short telomere length (TL) is an independent predictor of mortality in patients with coronary heart disease (CHD). However, the relationship between physical fitness and TL has not been explored in these patients. METHODS: In a cross sectional study of 944 outpatients with stable CHD, we performed exercise treadmill testing, assessed self-reported physical activity, and measured leukocyte TL using a quantitative PCR assay. We used generalized linear models to calculate mean TL (T/S ratio), and logistic regression models to compare the proportion of patients with short TL (defined as the lowest quartile), among participants with low, medium and high physical fitness, based on metabolic equivalent tasks achieved (METs). RESULTS: 229 participants had low physical fitness (<5 METS), 334 had moderate physical fitness (5-7 METS), and 381 had high physical fitness (>7 METS). Mean ± T/S ratio ranged from 0.86±0.21 (5349±3781 base pairs) in those with low physical fitness to 0.95±0.23 (5566±3829 base pairs) in those with high physical fitness (p<.001). This association remained strong after adjustment for numerous patient characteristics, including measures of cardiac disease severity and physical inactivity (p = 0.005). Compared with participants with high physical fitness, those with low physical fitness had 2-fold greater odds of having TL in the lowest quartile (OR 2.39, 95% CI 1.60-3.55; p<.001). This association was similar after multivariable adjustment (OR 1.94, 95%CI, 1.18-3.20; p = 0.009). Self-reported physical inactivity was associated with shorter TL in unadjusted analyses, but not after multivariable adjustment. CONCLUSIONS: We found that worse objectively-assessed physical fitness is associated with shorter leukocyte telomere length in patients with CHD. The clinical implications of this association deserve further study.

The CHADS2 score predicts ischemic stroke in the absence of atrial fibrillation among subjects with coronary heart disease: data from the Heart and Soul Study.

BACKGROUND: We sought to evaluate the prognostic performance of the CHADS(2) score for prediction of ischemic stroke/transient ischemic attack (TIA) in subjects with coronary heart disease (CHD) without atrial fibrillation (AF). METHODS: In 916 nonanticoagulated outpatients with stable CHD and no AF by baseline electrocardiogram, we calculated CHADS(2) scores (congestive heart failure, hypertension, age ≥75 years, diabetes [1 point each], and prior stroke or TIA [2 points]). The primary outcome was time to ischemic stroke or TIA over a mean follow-up of 6.4 ± 2.3 years. RESULTS: Over 5,821 person-years of follow-up, 40 subjects had an ischemic stroke/TIA (rate 0.69/100 person-years, 95% CI 0.50-0.94). Compared with subjects with low (0-1) CHADS(2) scores, those with intermediate (2-3) and high (4-6) CHADS(2) scores had an increased rate of stroke/TIA, even after adjustment for age, tobacco, antiplatelet therapy, statins, and angiotensin inhibitors (CHADS(2) score 2-3: HR 2.4, 95% CI 1.1-5.3, P = .03; CHADS(2) score 4-6: HR 4.0, 95% CI 1.5-10.6, P = .006). Model discrimination (c-statistic = 0.65) was comparable with CHADS(2) model fit in published AF-only cohorts. CONCLUSIONS: The CHADS(2) score predicts ischemic stroke/TIA in subjects with stable CHD and no baseline AF. The event rate in non-AF subjects with high CHADS(2) scores (5-6) was comparable with published rates in AF patients with moderate CHADS(2) scores (1-2), a population known to derive benefit from stroke prevention therapies. These findings should inform efforts to determine whether stroke prevention therapies or screening for silent AF may benefit subjects with stable CHD and high CHADS(2) scores.

Accuracy and prognostic value of American Heart Association: recommended depression screening in patients with coronary heart disease: data from the Heart and Soul Study.

BACKGROUND- In 2008, the American Heart Association (AHA) recommended a 2-step screening method, consisting of the 2-item Patient Health Questionnaire (PHQ-2) followed by the 9-item Patient Health Questionnaire (PHQ-9), for identifying depression in cardiovascular patients. The accuracy and prognostic value of this screening method have not been evaluated. METHODS AND RESULTS- We administered the 2-step AHA-recommended screening algorithm to 1024 patients with stable coronary heart disease and calculated sensitivity and specificity against a gold standard interview for major depressive disorder. Subsequent cardiovascular events (myocardial infarction, stroke, transient ischemic attack, heart failure, or death) were determined during a mean of 6.27 ± 2.11 years of follow-up. The AHA-recommended screening method had high specificity (0.91; 95% confidence interval, 0.89 to 0.93) but low sensitivity (0.52; 95% confidence interval, 0.46 to 0.59) for a diagnosis of major depressive disorder. Participants who screened positive on the AHA depression protocol had a 55% greater risk of events than those who screened negative (age-adjusted hazard ratio, 1.55; 95% confidence interval, 1.21 to 1.97; P=0.0005). After adjustment for age, sex, body mass index, history of myocardial infarction, hypertension, diabetes, heart failure, and high-density lipoprotein levels, screening positive remained associated with a 41% greater rate of cardiovascular events (hazard ratio, 1.41; 95% confidence interval, 1.10 to 1.81; P=0.008). CONCLUSIONS- Among outpatients with stable coronary heart disease, the AHA-recommended depression screening protocol is highly specific for depression and identifies patients at risk for adverse cardiovascular outcomes.

First-degree atrioventricular block is associated with heart failure and death in persons with stable coronary artery disease: data from the Heart and Soul Study.

AIMS: First-degree atrioventricular block (AVB) has traditionally been considered a benign electrocardiographic finding in healthy individuals. However, the clinical significance of first-degree AVB has not been evaluated in patients with stable coronary heart disease. We investigated whether first-degree AVB is associated with heart failure (HF) and mortality in a prospective cohort study of outpatients with stable coronary artery disease (CAD). METHODS AND RESULTS: We measured the P-R interval in 938 patients with stable CAD and classified them into those with (P-R interval ≥ 220 ms) and without (P-R interval <220 ms) first-degree AVB. Hazard ratios (HRs) and 95% confidence intervals were calculated for HF hospitalization and all-cause mortality. During 5 years of follow-up, there were 123 hospitalizations for HF and 285 deaths. Compared with patients who had normal atrioventricular conduction, those with first-degree AVB were at increased risk for HF hospitalization (age-adjusted HR 2.33: 95% CI 1.49-3.65; P= 0.0002), mortality [age-adjusted HR 1.58; 95% CI (1.13-2.20); P = 0.008], cardiovascular (CV) mortality [age-adjusted HR 2.33; 95% CI (1.28-4.22); P= 0.005], and the combined endpoint of HF hospitalization or CV mortality (age-adjusted HR 2.43: 95% CI 1.64-3.61; P ≤ 0.0001). These associations persisted after multivariable adjustment for heart rate, medication use, ischaemic burden, and QRS duration. Adjustment for left ventricular systolic and diastolic function partially attenuated the effect, but first-degree AVB remained associated with the combined endpoint of HF or CV death (HR 1.61, CI 1.02-2.54; P= 0.04). CONCLUSION: In a large cohort of patients with stable coronary artery disease, first-degree AVB is associated with HF and death.

Relation of concentric remodeling to adverse outcomes in patients with stable coronary artery disease (from the Heart and Soul Study).

Concentric remodeling (CR) is defined as increased left ventricular (LV) wall thickness with normal total LV mass. When encountered in populations with hypertension or patients undergoing aortic valve replacement, some studies have shown that CR predicts cardiovascular (CV) events and stroke. To expand our understanding of the prognostic implications of this common echocardiographic finding, we examined the association of CR and adverse CV events in ambulatory patients with coronary artery disease (CAD). We tested the hypothesis that finding CR on echocardiogram in ambulatory CAD independently predicts heart failure hospitalizations and CV death. Transthoracic echocardiograms were recorded in 973 participants from the Heart and Soul Study. Participants were divided into 4 groups: normal, CR, concentric LV hypertrophy, and eccentric LV hypertrophy. CV events were determined by 2 independent adjudicators and these were analyzed by Cox proportional hazards models. After mean 4.9 ± 1.5 years of follow-up, adverse outcomes occurred more frequently in those with concentric and eccentric LV hypertrophy but not in those with CR. After multivariate adjustment, concentric and eccentric LV hypertrophies were associated with increased risk of death and heart failure hospitalization, whereas CR was not. In conclusion, our hypothesis was not supported because CR was not associated with adverse CV events in our cohort of patients with stable CAD.

Relation of whole blood n-3 fatty acid levels to exercise parameters in patients with stable coronary artery disease (from the heart and soul study).

Dietary intake of n-3 polyunsaturated fatty acids is associated with a lower incidence of cardiovascular events. Mechanisms underlying this association are poorly understood but may include beneficial effects on physical conditioning and vagal tone. We investigated the association of n-3 fatty acid levels to exercise parameters in 992 subjects with stable coronary artery disease. Cross-sectional associations of heart rate recovery time, treadmill exercise capacity, and exercise time with docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) levels were evaluated in multivariable linear and logistic regression models adjusted for demographics, cardiovascular risk factors, co-morbidities, self-reported physical activity, medication use, and left ventricular function. After multivariable adjustment, n-3 fatty acid levels (DHA + EPA) were strongly associated with heart rate recovery (beta 2.1, p = 0.003), exercise capacity (beta 0.8, p <0.0001), and exercise time (beta 0.9, p <0.0001). Increasing levels of (DHA + EPA) were also associated with decreased risk of impaired heart rate recovery (odds ratio 0.8, p = 0.004) and exercise time (odds ratio 0.7, p = 0.01) and trended toward significance for exercise capacity (odds ratio 0.8, p = 0.07). These associations were not modified by demographics, body mass index, smoking, co-morbid conditions, statin use, or ß-blocker use (p for interaction >0.1 for all comparisons). In conclusion, an independent association exists between n-3 fatty acid levels and important exercise parameters in patients with stable coronary artery disease. These findings support the hypothesis that n-3 fatty acids may increase vagal tone and physical conditioning.

Left ventricular outflow tract and pulmonary artery stroke distances independently predict heart failure hospitalization and mortality: the Heart and Soul Study.

BACKGROUND: Stroke distance of the left ventricular outflow tract (LVOT) or pulmonary artery (PA) is readily measurable by Doppler echocardiography. Stroke distance, calculated by the velocity time integral, expresses the average linear distance traveled by red blood cells during systole. We hypothesized that reduced stroke distance predicts heart failure (HF) hospitalization or mortality among ambulatory adults with stable coronary artery disease. METHODS: We compared stroke distances by lowest quartile among 990 participants in the Heart and Soul Study. We calculated hazard ratios (HRs) for events adjusted for clinical and echocardiographic parameters. RESULTS: At 5.9 ± 1.9-year follow-up, there were 154 HF hospitalizations and 271 all-cause deaths. Among 254 participants with LVOT stroke distance in the lowest quartile (≤ 18 cm), 24% developed HF hospitalization, compared with 10% of those with higher stroke distance (HR 2.7; CI, 2.0-3.8; P < .0001). This association remained after adjustment for multiple variables including medical history, heart rate, blood pressure, and left ventricular ejection fraction (HR 1.8; CI, 1.1-3.0; P = .02). Both LVOT stroke distance ≤ 18 cm and PA stroke distance ≤ 17 cm were independently associated with the combined end point of HF hospitalization and mortality (HR 1.4; CI, 1.1-1.9; P = .02). CONCLUSION: Reduced stroke distance predicts HF hospitalization and mortality independent of clinical and other echocardiographic parameters among ambulatory adults with coronary artery disease.

Prognostic value of electrocardiographic detection of unrecognized myocardial infarction in persons with stable coronary artery disease: data from the Heart and Soul Study.

Unrecognized myocardial infarction (MI) carries a poor prognosis in the general population, but its prognostic value is less clear in high-risk patients. We sought to determine whether Q waves on electrocardiogram (ECG), suggestive of unrecognized MI, predict cardiovascular events in patients with stable coronary artery disease (CAD), but without a prior history of MI. We studied 462 patients enrolled in the Heart and Soul Study with stable CAD but without a prior history of MI. All patients had baseline ECGs. The baseline prevalence of unrecognized myocardial infarction was 36%. After a mean of 6.3 years of follow-up, there were a total of 141 cardiovascular events. The presence of Q waves in any ECG lead territory predicted cardiovascular events before (unadjusted HR 1.41, 95% CI 1.01-1.97) and after adjustment for demographics, medical history, diastolic function, and ejection fraction (HR 1.55, 95% CI 1.06-2.26). This association was partly attenuated after adjustment for the presence of inducible ischemia at baseline (HR 1.43, 95% CI 0.96-2.12). When specific territories were analyzed separately, Q waves in anterior leads were predictive of cardiovascular events in both unadjusted and adjusted models (adjusted HR 1.85, 95% CI 1.14-3.00), and this association was partly attenuated after adjustment for inducible ischemia. In conclusion, in patients with CAD but no history of prior MI, the presence of any Q waves or anterior Q waves alone is independently predictive of adverse cardiovascular events.

Association of resistin with heart failure and mortality in patients with stable coronary heart disease: data from the heart and soul study.

BACKGROUND: Resistin is a pro-inflammatory signaling molecule that is thought to contribute to atherosclerosis. We sought to evaluate whether resistin is predictive of worse cardiovascular outcomes among ambulatory patients with stable coronary heart disease (CHD). METHODS AND RESULTS: We measured baseline serum resistin in 980 participants with documented CHD. After a mean follow-up of 6.1 (range, 0.1 to 9.0) years, 358 (36.5%) were hospitalized for myocardial infarction or heart failure or had died. As compared with participants who had resistin levels in the lowest quartile, those with resistin levels in the highest quartile were at an increased risk of heart failure (hazard ratio [HR], 2.06; 95% confidence interval [CI], 1.26-3.39) and death (HR, 1.56; 95% CI, 1.11-2.18), adjusted for age, sex, and race. Further adjustments for obesity, hypertension, insulin resistance, dyslipidemia, and renal dysfunction eliminated these associations. Resistin levels were not associated with an increased risk of non-fatal myocardial infarction (unadjusted HR, 1.18; 95% CI, 0.68-2.05). CONCLUSIONS: Elevated serum resistin is associated with higher rates of mortality and hospitalization for heart failure. However, this appears to be explained by the association of resistin with traditional measures of cardiovascular risk. Thus, serum resistin does not add prognostic information among high-risk persons with established CHD.

Association of low leptin with cardiovascular events and mortality in patients with stable coronary artery disease: the Heart and Soul Study.

OBJECTIVE: Leptin is an adipokine with both protective and harmful effects on the cardiovascular (CV) system. Prior studies evaluating the association between leptin and CV outcomes have yielded conflicting results. Thus, we sought to investigate the relationship between leptin and CV events and mortality in patients with chronic stable coronary artery disease (CAD). METHODS: We performed a prospective cohort study of 981 outpatients with stable CAD. Leptin levels were measured in fasting venous samples at baseline. We used proportional hazards models to evaluate the association of baseline leptin with subsequent CV events (myocardial infarction, stroke, transient ischemic attack) and death. RESULTS: During a mean follow-up of 6.2±2.1 years, there were 304 deaths, 112 myocardial infarctions, and 52 strokes/TIAs. In models adjusted for age, sex, and race, low leptin was associated with a 30% increased risk of the combined outcome (HR 1.30, CI 1.05-1.59, p=0.01). After further adjustment for obesity, traditional CV risk factors and biomarkers, low leptin remained associated with a 37% increased risk of events (HR 1.37, CI 1.06-1.76, p=0.02). CONCLUSIONS: Low leptin is associated with increased CV events and mortality in patients with stable coronary artery disease. This association is independent of known factors affecting leptin levels, including gender and obesity.

Resistin, exercise capacity, and inducible ischemia in patients with stable coronary heart disease: data from the Heart and Soul study.

OBJECTIVE: Resistin is an adipocytokine involved in insulin resistance, inflammation, and atherosclerosis. Its role in the development and progression of coronary heart disease (CHD) is not yet well-characterized. We performed a cross-sectional study to evaluate the association between serum resistin levels, exercise capacity, and exercise-induced cardiac ischemia among patients with stable CHD. METHODS AND RESULTS: We measured serum resistin concentrations and determined treadmill exercise capacity and inducible ischemia by stress echocardiography in 899 outpatients with documented CHD. Of these, 215 (24%) had poor exercise capacity (<5 metabolic equivalent tasks), and 217 (24%) had inducible ischemia. As compared with participants who had resistin levels in the lowest quartile, those with resistin levels in the highest quartile were more likely to have poor exercise capacity (33% versus 16%, odds ratio [OR] 2.68, P<0.0001) and inducible ischemia (30% versus 17%, OR 2.08, P=0.001). Both associations remained robust after adjusting for numerous clinical risk factors, metabolic variables, and markers of insulin resistance (poor exercise capacity adjusted OR 1.73, P=0.04; inducible ischemia adjusted OR 1.82, P=0.01). However, further adjustments for C-reactive protein, interleukin-6, and tumor necrosis factor-α eliminated the association with poor exercise capacity (adjusted OR 1.50, P=0.14) and substantially weakened the association with inducible ischemia (adjusted OR 1.72, P=0.03). CONCLUSIONS: Elevated serum resistin is associated with poor exercise capacity and exercise-induced cardiac ischemia in patients with stable coronary disease. Adjustment for inflammatory markers attenuated these associations, suggesting a possible role for resistin in inflammation and CHD pathophysiology.

A functional polymorphism in renalase (Glu37Asp) is associated with cardiac hypertrophy, dysfunction, and ischemia: data from the heart and soul study.

BACKGROUND: Renalase is a soluble enzyme that metabolizes circulating catecholamines. A common missense polymorphism in the flavin-adenine dinucleotide-binding domain of human renalase (Glu37Asp) has recently been described. The association of this polymorphism with cardiac structure, function, and ischemia has not previously been reported. METHODS: We genotyped the rs2296545 single-nucleotide polymorphism (Glu37Asp) in 590 Caucasian individuals and performed resting and stress echocardiography. Logistic regression was used to examine the associations of the Glu37Asp polymorphism (C allele) with cardiac hypertrophy (LV mass>100 g/m2), systolic dysfunction (LVEF<50%), diastolic dysfunction, poor treadmill exercise capacity (METS<5) and inducible ischemia. RESULTS: Compared with the 406 participants who had GG or CG genotypes, the 184 participants with the CC genotype had increased odds of left ventricular hypertrophy (OR = 1.43; 95% CI 0.99-2.06), systolic dysfunction (OR = 1.72; 95% CI 1.01-2.94), diastolic dysfunction (OR = 1.75; 95% CI 1.05-2.93), poor exercise capacity (OR = 1.61; 95% CI 1.05-2.47), and inducible ischemia (OR = 1.49, 95% CI 0.99-2.24). The Glu37Asp (CC genotype) caused a 24-fold decrease in affinity for NADH and a 2.3-fold reduction in maximal renalase enzymatic activity. CONCLUSIONS: A functional missense polymorphism in renalase (Glu37Asp) is associated with cardiac hypertrophy, ventricular dysfunction, poor exercise capacity, and inducible ischemia in persons with stable coronary artery disease. Further studies investigating the therapeutic implications of this polymorphism should be considered.

Differential associations between specific depressive symptoms and cardiovascular prognosis in patients with stable coronary heart disease.

OBJECTIVES: The purpose of this research was to evaluate the relationship between cognitive and somatic depressive symptoms and cardiovascular prognosis. BACKGROUND: Depression in patients with stable coronary heart disease (CHD) is associated with poor cardiac prognosis. Whether certain depressive symptoms are more cardiotoxic than others is unknown. METHODS: In the Heart and Soul Study, 1,019 patients with stable CHD were assessed using the Patient Health Questionnaire to determine the presence of the 9 depressive symptoms included in the Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition. The mean age of the patients was 67 years, and 82% were men. A comparison was made on a new cardiovascular event (myocardial infarction, stroke, transient ischemic attack, or congestive heart failure) or death (mean follow-up duration 6.1 +/- 2.0 years) on the basis of cognitive and somatic sum scores and for patients with or without each of those specific depressive symptoms. Demographic characteristics, cardiac risk factors, and cardiac medications were controlled for. RESULTS: After adjustment for demographic data and cardiac risk factors, each somatic symptom was associated with 14% greater risk for events (hazard ratio [HR]: 1.14; 95% confidence interval [CI]: 1.05 to 1.24; p = 0.002). Fatigue (HR: 1.34; 95% CI: 1.07 to 1.67; p = 0.01), appetite problems (HR: 1.46; 95% CI: 1.12 to 1.91; p = 0.005), and sleeping difficulties (HR: 1.26; 95% CI: 1.00 to 1.58; p = 0.05) were most strongly predictive of cardiovascular events. In contrast, cognitive symptoms (HR: 1.08; 95% CI: 0.99 to 1.17; p = 0.09) were not significantly associated with cardiovascular events. CONCLUSIONS: In patients with stable CHD, somatic symptoms of depression were more strongly predictive of cardiovascular events than cognitive symptoms, although the CIs surrounding these estimates had substantial overlap. These findings are highly consistent with those of previous studies. Further research is needed to understand the pathophysiological processes by which somatic depressive symptoms contribute to prognosis in patients with CHD.

Association of blood pressure and heart rate response during exercise with cardiovascular events in the Heart and Soul Study.

BACKGROUND: We sought to evaluate the association of blood pressure and heart rate response during exercise with myocardial infarction (MI), heart failure, stroke, transient ischemic attack (TIA) and death in ambulatory adults with coronary artery disease. METHODS: A study population of 937 patients with stable coronary artery disease underwent treadmill exercise stress testing and was followed for 5 years. Participants were divided into quartiles based on peak SBP change, peak SBP and heart rate. We used multivariable Cox proportional hazards models to evaluate the association of change in SBP and heart rate with subsequent cardiovascular events. RESULTS: The participants with SBP increases in the highest quartile had a decreased rate of hospitalization for heart failure [hazard ratio 0.38, 95% confidence interval (CI), 0.21-0.7; P = 0.002], MI (hazard ratio 0.3, 95% CI 0.15-0.58; P = 0.0004), stroke or TIA (hazard ratio 0.39, 95% CI 0.15-0.98; P = 0.04), and all cause mortality (hazard ratio 0.5, 95% CI 0.33-0.76; P = 0.001). After adjusting for age, history of MI and HTN, use of ß blockers, statins and calcium channel blockers, resting heart rate, and SBP, participants with SBP change in the highest quartile remained at lowest risk of MI (hazard ratio 0.31, 95% CI 0.15-0.66, P = 0.002), hospitalization for heart failure (hazard ratio 0.46, 95% CI 0.22-0.97, P = 0.04) and death (hazard ratio 0.52, 95% CI 0.32-0.86, P = 0.01). This association was largely explained by greater exercise capacity in those with the highest SBP change. Change in heart rate had a similar association with cardiovascular events. CONCLUSION: In ambulatory patients with coronary artery disease, the group with the greatest blood pressure and heart rate increase had the lowest risk of MI, heart failure, stroke or TIA and death. These findings support the notion that a robust blood pressure response predicts favorable outcomes.