Individual and Joint Associations of High-Sensitivity Troponin I and High-Sensitivity Troponin T with Cardiac Phenotypes and Outcomes in the General Population: An Analysis From the Dallas Heart Study.

BACKGROUND: High-sensitivity troponin I (hs-cTnI) and T (hs-cTnT) provide complementary information regarding cardiovascular disease risk. The explanation for their distinct risk profiles is incompletely understood. METHODS AND RESULTS: hs-cTnI and hs-cTnT were measured in Dallas Heart Study participants. Associations of hs-cTnI and hs-cTnT with demographics and phenotypes were assessed using linear regression. Associations with incident heart failure, atherosclerotic cardiovascular disease, global cardiovascular disease, and cardiovascular and all-cause mortality were assessed using Cox models. Among 3276 participants (56% women, 50% Black persons, median age 43 years), the correlation between hs-cTnI and hs-cTnT was modest (Spearman rho=0.35). Variables associated with hs-cTnI but not hs-cTnT included hypertension, higher body mass index and total cholesterol, and lower high-density lipoprotein and cholesterol efflux capacity. Older age, male sex, and diabetes were positively associated, and smoking was negatively associated, with hs-cTnT but not hs-cTnI. Hs-cTnI and hs-cTnT were associated with heart failure (hazard ratio [HR] per SD log hs-cTnI 1.53 [95% CI, 1.30-1.81] and HR per SD log hs-cTnT 1.65 [95% CI, 1.40-1.95]), global cardiovascular disease (HR, 1.22 [95% CI, 1.10-1.34] and HR, 1.27 [95% CI, 1.15-1.32]), and all-cause mortality (HR, 1.12 [95% CI, 1.01-1.25], and HR, 1.17 [95% CI, 1.06-1.29]). After adjustment for N-terminal pro-B-type natriuretic peptide and the alternative troponin, both remained associated with heart failure (HR per SD log hs-cTnI 1.32 [95% CI, 1.1-1.58] and HR per log hs-cTnT 1.27 [95% CI, 1.06-1.51]). CONCLUSIONS: Hs-cTnI and hs-cTnT are modestly correlated, demonstrate differential associations with cardiac and metabolic phenotypes, and provide complementary information regarding heart failure risk.

HDL-C and apolipoprotein A-I are independently associated with skeletal muscle mitochondrial function in healthy humans.

Prior animal and cell studies have demonstrated a direct role of high-density lipoprotein (HDL) and apolipoprotein A-I (ApoA-I) in enhancing skeletal muscle mitochondrial function and exercise capacity. However, the relevance of these animal and cell investigations in humans remains unknown. Therefore, a cross-sectional study was conducted in 48 adults (67% female, 8% Black participants, age 39 ± 15.4 yr old) to characterize the associations between HDL measures, ApoA-I, and muscle mitochondrial function. Forearm muscle oxygen recovery time (tau) from postexercise recovery kinetics was used to assess skeletal muscle mitochondrial function. Lipoprotein measures were assessed by nuclear magnetic resonance. HDL efflux capacity was assessed using J774 macrophages, radiolabeled cholesterol, and apolipoprotein B-depleted plasma both with and without added cyclic adenosine monophosphate. In univariate analyses, faster skeletal muscle oxygen recovery time (lower tau) was significantly associated with higher levels of HDL cholesterol (HDL-C), ApoA-I, and larger mean HDL size, but not HDL cholesterol efflux capacity. Slower recovery time (higher tau) was positively associated with body mass index (BMI) and fasting plasma glucose (FPG). In multivariable linear regression analyses, higher levels of HDL-C and ApoA-I, as well as larger HDL size, were independently associated with faster skeletal muscle oxygen recovery times that persisted after adjusting for BMI and FPG (all P < 0.05). In conclusion, higher levels of HDL-C, ApoA-I, and larger mean HDL size were independently associated with enhanced skeletal muscle mitochondrial function in healthy humans.NEW & NOTEWORTHY Our study provides the first direct evidence supporting the beneficial role of HDL-C and ApoA-I on enhanced skeletal muscle mitochondrial function in healthy young to middle-aged humans without cardiometabolic disease.

Dyslipidemia and cardiovascular disease among childhood cancer survivors: a St. Jude Lifetime Cohort report.

BACKGROUND: Childhood cancer survivors have increased risk of dyslipidemia and atherosclerotic cardiovascular disease (CVD). The aim of this study was to evaluate the prevalence and associated cardiovascular risks of specific lipid abnormalities among childhood cancer survivors. METHODS: Comprehensive lipid panel measurements were obtained from 4115 5-year survivors, with 3406 (mean age at evaluation = 35.2 years, SD = 10.4 years) not having previous dyslipidemia diagnosis, as well as 624 age, sex, and race and ethnicity matched community controls. RESULTS: Previously undiagnosed dyslipidemia with abnormal low-density lipoprotein (LDL) cholesterol (>160 mg/dL), non-high density lipoprotein (HDL) cholesterol (>190 mg/dL), HDL cholesterol (<40 mg/dL for men, <50 mg/dL for women), and triglycerides (>150 mg/dL) were identified in 4%, 6%, 30%, and 17%, respectively. Survivors without previous dyslipidemia diagnosis had higher LDL cholesterol and non-HDL cholesterol and lower HDL cholesterol than community controls. Cranial radiotherapy (relative risk [RR] = 2.2, 95% confidence interval [CI] = 1.6 to 3.0 for non-HDL cholesterol) and total body irradiation for hematopoietic cell transplantation (RR = 6.7, 95% CI = 3.5 to 13.0 for non-HDL cholesterol; RR = 9.9, 95% CI = 6.0 to 16.3 for triglycerides) were associated with greater risk of dyslipidemia. Diagnoses of low HDL cholesterol (hazard ratio [HR] = 2.9, 95% CI = 1.8 to 4.7) and elevated triglycerides (HR = 3.1, 95% CI = 1.9 to 5.1) were associated with increased risk for myocardial infarction, and diagnoses of high LDL cholesterol (HR = 2.2, 95% CI = 1.3 to 3.7), high non-HDL cholesterol (HR = 2.2, 95% CI = 1.3 to 3.7), low HDL cholesterol (HR = 3.9, 95% CI = 2.8 to 5.4), and elevated triglycerides (HR = 3.8, 95% CI = 2.7 to 5.5) were associated with increased risk for cardiomyopathy. CONCLUSIONS: Previously undiagnosed dyslipidemia among childhood cancer survivors was associated with increased risk for myocardial infarction and cardiomyopathy. Comprehensive dyslipidemia evaluation and treatment are needed to reduce cardiovascular morbidity in this population.

Soluble Fms-like tyrosine kinase-1 (sFlt-1) is associated with subclinical and clinical atherosclerotic cardiovascular disease: The Dallas Heart Study.

BACKGROUND AND AIMS: Soluble Fms-like tyrosine kinase-1 (sFlt-1) plays a role in angiogenesis, atherogenesis, and preeclampsia. The relationship of sFlt-1 with markers of subclinical atherosclerosis and future atherosclerotic cardiovascular disease (ASCVD) events in a generally healthy population is unknown. METHODS: Participants in the Dallas Heart Study with sFlt-1 measured were included (n = 3292). Abdominal aortic atherosclerosis was measured by MRI and coronary artery calcium (CAC) by CT. The cohort was also followed for subsequent ASCVD events (CV death, MI, stroke, unstable angina, revascularization). Multivariable linear and logistic regression analyses and Cox regression analyses were performed adjusting for demographics and traditional cardiac risk factors. RESULTS: sFlt-1 levels were higher in older individuals, males, and African Americans, and tracked with most traditional risk factors. sFlt-1 was significantly associated with higher prevalence of aortic plaque [OR 1.33 (95% CI 1.02-1.73)], greater abdominal aortic wall thickness (p<0.01) and aortic plaque area (p<0.02) but no difference in coronary artery calcification. There were 322 ASCVD events over 12 years of follow-up. Higher sFlt-1 levels associated with increased ASCVD events in unadjusted (16.1% vs. 8.9%, p<0.001, quartile 4 vs. quartile 1) and adjusted analyses (HR 1.58 [1.14-2.18], p<0.01, quartile 4 vs. quartile 1). Findings were unchanged when analyzing sFlt-1 as a continuous variable or when excluding those with a history of ASCVD. CONCLUSIONS: In a population-based cohort, sFlt-1 is associated with measures of subclinical aortic atherosclerosis and clinical ASCVD events. Future studies are warranted on the therapeutic potential of targeting sFlt-1 for atherosclerotic disease.

Molecular Patterns of Extreme and Persistent Cholesterol Efflux Capacity.

Objective: Cholesterol efflux capacity (CEC), the ability of extracellular acceptors to pick-up cholesterol from macrophages, is a clinically relevant cardiovascular biomarker. CEC is inversely associated with incident atherosclerotic cardiovascular disease events. However, CEC is only modestly associated with HDL-C (high-density lipoprotein cholesterol) levels, which may explain the failure of HDL-C raising therapies to improve atherosclerotic cardiovascular disease outcomes. Determinants of variation in CEC are not well understood. Thus, we sought to establish whether extreme high and low CEC is a robust persistent phenotype and to characterize associations with cholesterol, protein, and phospholipids across the particle size distribution. Approach and Results: CEC was previously measured in 2924 participants enrolled in the Dallas Heart Study, a multi-ethnic population-based study from 2000 to 2002. We prospectively recruited those who were below the 10th and above 90th percentile of CEC. Our study revealed that extreme low and high CEC are persistent, robust phenotypes after 15 years of follow-up. Using size exclusion chromatography, CEC to fractionated plasma depleted of apolipoprotein B (fraction-specific CEC) demonstrated significant differences in CEC patterns between persistent high and low efflux groups. Fraction-specific CEC was correlated with fraction-specific total phospholipid but not apolipoprotein A-I, cholesterol, or total protein. These correlations varied across the size distribution and differed among persistent high versus low efflux groups. Conclusions: Extreme high and low CEC are persistent and robust phenotypes. CEC patterns in fractionated plasma reveal marked variation across the size distribution. Future studies are warranted to determine specific molecular species linked to CEC in a size-specific manner.

HDL in the 21st Century: A Multifunctional Roadmap for Future HDL Research.

Low high-density lipoprotein cholesterol (HDL-C) characterizes an atherogenic dyslipidemia that reflects adverse lifestyle choices, impaired metabolism, and increased cardiovascular risk. Low HDL-C is also associated with increased risk of inflammatory disorders, malignancy, diabetes, and other diseases. This epidemiologic evidence has not translated to raising HDL-C as a viable therapeutic target, partly because HDL-C does not reflect high-density lipoprotein (HDL) function. Mendelian randomization analyses that have found no evidence of a causal relationship between HDL-C levels and cardiovascular risk have decreased interest in increasing HDL-C levels as a therapeutic target. HDLs comprise distinct subpopulations of particles of varying size, charge, and composition that have several dynamic and context-dependent functions, especially with respect to acute and chronic inflammatory states. These functions include reverse cholesterol transport, inhibition of inflammation and oxidation, and antidiabetic properties. HDLs can be anti-inflammatory (which may protect against atherosclerosis and diabetes) and proinflammatory (which may help clear pathogens in sepsis). The molecular regulation of HDLs is complex, as evidenced by their association with multiple proteins, as well as bioactive lipids and noncoding RNAs. Clinical investigations of HDL biomarkers (HDL-C, HDL particle number, and apolipoprotein A through I) have revealed nonlinear relationships with cardiovascular outcomes, differential relationships by sex and ethnicity, and differential patterns with coronary versus noncoronary events. Novel HDL markers may also have relevance for heart failure, cancer, and diabetes. HDL function markers (namely, cholesterol efflux capacity) are associated with coronary disease, but they remain research tools. Therapeutics that manipulate aspects of HDL metabolism remain the holy grail. None has proven to be successful, but most have targeted HDL-C, not metrics of HDL function. Future therapeutic strategies should focus on optimizing HDL function in the right patients at the optimal time in their disease course. We provide a framework to help the research and clinical communities, as well as funding agencies and stakeholders, obtain insights into current thinking on these topics, and what we predict will be an exciting future for research and development on HDLs.

Effect of Anacetrapib on Cholesterol Efflux Capacity: A Substudy of the DEFINE Trial.

Background Anacetrapib is the only cholesteryl ester transfer protein inhibitor proven to reduce coronary heart disease (CHD). However, its effects on reverse cholesterol transport have not been fully elucidated. Macrophage cholesterol efflux (CEC), the initial step of reverse cholesterol transport, is inversely associated with CHD and may be affected by sex as well as haptoglobin copy number variants among patients with diabetes mellitus. We investigated the effect of anacetrapib on CEC and whether this effect is modified by sex, diabetes mellitus, and haptoglobin polymorphism. Methods and Results A total of 574 participants with CHD were included from the DEFINE (Determining the Efficacy and Tolerability of CETP Inhibition With Anacetrapib) trial. CEC was measured at baseline and 24-week follow-up using J774 macrophages, boron dipyrromethene difluoride-labeled cholesterol, and apolipoprotein B-depleted plasma. Haptoglobin copy number variant was determined using an ELISA assay. Anacetrapib increased CEC, adjusted for baseline CEC, risk factors, and changes in lipids/apolipoproteins (standard ß, 0.23; 95% CI, 0.05-0.41). This CEC-raising effect was seen only in men (P interaction=0.002); no effect modification was seen by diabetes mellitus status. Among patients with diabetes mellitus, anacetrapib increased CEC in those with the normal 1-1 haptoglobin genotype (standard ß, 0.42; 95% CI, 0.16-0.69) but not the dysfunctional 2-1/2-2 genotypes (P interaction=0.02). Conclusions Among patients with CHD, anacetrapib at a dose linked to improved CHD outcomes significantly increased CEC independent of changes in high-density lipoprotein cholesterol or other lipids, with effect modification by sex and a novel pharmacogenomic interaction by haptoglobin genotype, suggesting a putative mechanism for reduced risk requiring validation.

An Association Between the Inflammatory Biomarker GlycA and Depressive Symptom Severity.

OBJECTIVE: The underlying mechanisms of depression remain unclear; however, current literature suggests a relationship between inflammation and depression. The association between the inflammatory biomarker high-sensitivity C-reactive protein (hs-CRP) and depression has been previously investigated, but the relationship between GlycA, a novel spectroscopic inflammatory biomarker, and depression does not appear to have been examined. METHODS: Data were obtained from The Dallas Heart Study (DHS, conducted between 2000 and 2002), which consisted of a large community-based sample of Dallas County residents (N = 3,033). Depressive symptom severity was assessed with the Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR). It was hypothesized that the serum GlycA level would be a statistically significant predictor of QIDS-SR scores after control for demographic covariates. Multiple linear regression was used to assess the relationship between GlycA level and QIDS-SR scores. The role of hs-CRP in predicting QIDS-SR scores was also explored. RESULTS: GlycA level was a statistically significant positive predictor of QIDS-SR score (ß = .053, P = .038) with control for sex, age, antidepressant use, ethnicity, smoking status, drinking status, body mass index, and years of education. In a subset of adults with moderate-to-severe depression, GlycA level was not associated with QIDS-SR scores. Additionally, hs-CRP level was not a statistically significant predictor of QIDS-SR scores. CONCLUSIONS: This study found a positive association between the inflammatory biomarker GlycA, but not hs-CRP, and depressive symptom severity in a large multiethnic and multiracial community-based sample. Thus, these results provide the first indication that GlycA may be a potentially useful novel biomarker of depression.

Dynamic Forecasts of Survival for Patients Living With Destination Left Ventricular Assist Devices: Insights From INTERMACS.

Background Left ventricular assist devices (LVADs) improve outcomes in patients with end-stage heart failure and are increasingly implanted for destination therapy. We describe dynamic estimates of event-free survival with conditional survival probabilities in a destination therapy LVAD population. Methods and Results We studied 8245 adult patients in INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) implanted with a continuous-flow destination therapy LVAD. The composite primary end point was death, device exchange or removal, or heart transplantation. Conditional survival probabilities were calculated and stratified by implantation characteristics and nonfatal adverse events experienced within the first year after implant. Probabilities of surviving an additional 1 to 3 years were numerically higher after longer prior event-free survival. INTERMACS profile 1, extracorporeal membrane oxygenation support, prior or concomitant surgery, and dialysis within 48 hours of implantation were associated with significantly lower event-free survival in the first year but did not impact event-free survival beyond then. For patients who experienced a nonfatal adverse event within the first year, subsequent 1-year conditional survival was lower than in the absence of that event for stroke (65% [95% CI, 57%-73%] versus 75% [95% CI, 73%-77%]; P<0.001), device-related infection (64% [95% CI 57%-71%] versus 76% [95% CI, 74%-78%]; P<0.001), and pump thrombosis or malfunction (64% [95% CI, 57%-70%] versus 76% [95% CI, 74%-78%]; P<0.001). Conclusions Conditional survival in patients with destination therapy LVADs improves over time, even for patients with unfavorable implantation characteristics. However, LVAD-related complications including stroke, device-related infection, and pump thrombosis or malfunction have an enduring negative influence on dynamic estimates of long-term prognosis.

Racial Differences in Cardiovascular Biomarkers in the General Population.

Background The incidence and clinical manifestations of cardiovascular disease (CVD) differ between blacks and whites. Biomarkers that reflect important pathophysiological pathways may provide a window to allow deeper understanding of racial differences in CVD. Methods and Results The study included 2635 white and black participants from the Dallas Heart Study who were free from existing CVD. Cross-sectional associations between race and 32 biomarkers were evaluated using multivariable linear regression adjusting for age, traditional CVD risk factors, imaging measures of body composition, renal function, insulin resistance, left ventricular mass, and socioeconomic factors. In fully adjusted models, black women had higher lipoprotein(a), leptin, d-dimer, osteoprotegerin, antinuclear antibody, homoarginine, suppression of tumorigenicity-2, and urinary microalbumin, and lower adiponectin, soluble receptor for advanced glycation end products and N-terminal pro-B-type natriuretic peptide versus white women. Black men had higher lipoprotein(a), leptin, d-dimer, high-sensitivity C-reactive protein, antinuclear antibody, symmetrical dimethylarginine, homoarginine, high-sensitivity cardiac troponin T, suppression of tumorigenicity-2, and lower adiponectin, soluble receptor for advanced glycation end products, and N-terminal pro-B-type natriuretic peptide versus white men. Adjustment for biomarkers that were associated with higher CVD risk, and that differed between blacks and whites, attenuated the risk for CVD events in black women (unadjusted hazard ratio 2.05, 95% CI 1.32, 3.17 and adjusted hazard ratio 1.15, 95% CI 0.69, 1.92) and black men (unadjusted hazard ratio 2.39, 95% CI 1.64, 3.46, and adjusted hazard ratio 1.21, 95% CI 0.76, 1.95). Conclusions Significant racial differences were seen in biomarkers reflecting lipids, adipokines, and biomarkers of endothelial function, inflammation, myocyte injury, and neurohormonal stress, which may contribute to racial differences in the development and complications of CVD.

Association of the serum myeloperoxidase/high-density lipoprotein particle ratio and incident cardiovascular events in a multi-ethnic population: Observations from the Dallas Heart Study.

BACKGROUND AND AIMS: Myeloperoxidase (MPO), a product of systemic inflammation, promotes oxidation of lipoproteins; whereas, high-density lipoprotein (HDL) exerts anti-oxidative effects in part via paraoxonase-1 (PON1). MPO induces dysfunctional HDL particles; however, the interaction of circulating levels of these measures in cardiovascular disease (CVD) has not been studied in humans. We tested whether serum levels of MPO indexed to HDL particle concentration (MPO/HDLp) are associated with increased CVD risk in a large multiethnic population sample, free of CVD at baseline. METHODS: Levels of MPO, HDL-C, and HDL particle concentration (HDLp) by NMR were measured at baseline in 2924 adults free of CVD. The associations of MPO/HDLp with incident ASCVD (first non-fatal myocardial infarction, non-fatal stroke, coronary revascularization, or CVD death) and total CVD were assessed in Cox proportional-hazards models adjusted for traditional risk factors. The median follow-up period was 9.4 years. RESULTS: Adjusted for sex and race/ethnicity, MPO/HDLp was associated directly with body mass index, smoking status, high-sensitivity C-reactive protein, and interleukin 18, and inversely with age, HDL-C levels, HDL size, and PON1 arylesterase activity, but not with cholesterol efflux. In fully adjusted models, the highest versus lowest quartile of MPO/HDLp was associated with a 74% increase in incident ASCVD (aHR, 1.74, 95% CI 1.12-2.70) and a 91% increase in total incident CVD (aHR, 1.91, 95% CI 1.27-2.85). CONCLUSIONS: Increased MPO indexed to HDL particle concentration (MPO/HDLp) at baseline is associated with increased risk of incident CVD events in a population initially free of CVD over the 9.4 year period.

Sex-Based Differences in Cardiometabolic Biomarkers.

BACKGROUND: Few data are available comparing cardiovascular disease (CVD) biomarker profiles between women and men in the general population. We analyzed sex-based differences in multiple biomarkers reflecting distinct pathophysiological pathways, accounting for differences between women and men in CVD risk factors, body composition, and cardiac morphology. METHODS: A cross-sectional analysis was performed using data from the Dallas Heart Study, a multiethnic population-based study. Associations between sex and 30 distinct biomarkers representative of 6 pathophysiological categories were evaluated using multivariable linear regression adjusting for age, race, traditional CVD risk factors, kidney function, insulin resistance, MRI and dual-energy x-ray absorptiometry measures of body composition and fat distribution, and left ventricular mass. RESULTS: After excluding participants with CVD, the study population included 3439 individuals, mean age 43 years, 56% women, and 52% black. Significant sex-based differences were seen in multiple categories of biomarkers, including lipids, adipokines, and biomarkers of inflammation, endothelial dysfunction, myocyte injury and stress, and kidney function. In fully adjusted models, women had higher levels of high-density lipoprotein cholesterol and high-density lipoprotein particle concentration, leptin, d-dimer, homoarginine, and N-terminal pro B-type natriuretic peptide, and lower levels of low-density lipoprotein cholesterol, adiponectin, lipoprotein-associated phospholipase A2 mass and activity, monocyte chemoattractant protein-1, soluble endothelial cell adhesion molecule, symmetrical dimethylarginine, asymmetrical dimethylarginine, high-sensitivity troponin T, and cystatin C. CONCLUSIONS: Biomarker profiles differ significantly between women and men in the general population. Sex differences were most apparent for biomarkers of adiposity, endothelial dysfunction, inflammatory cell recruitment, and cardiac stress and injury. Future studies are needed to characterize whether pathophysiological processes delineated by these biomarkers contribute to sex-based differences in the development and complications of CVD.

HDL Cholesterol Efflux Capacity: Cardiovascular Risk Factor and Potential Therapeutic Target.

Low high-density lipoprotein cholesterol (HDL-C) levels are associated with incident cardiovascular events; however, many therapies targeting increases in HDL-C have failed to show consistent clinical benefit. Thus, focus has recently shifted toward measuring high-density lipoprotein (HDL) function. HDL is the key mediator of reverse cholesterol transport, the process of cholesterol extraction from foam cells, and eventual excretion into the biliary system. Cholesterol efflux from peripheral macrophages to HDL particles has been associated with atherosclerosis in both animals and humans. We review the mechanism of cholesterol efflux and the emerging evidence on the association between cholesterol efflux capacity and cardiovascular disease in human studies. We also focus on the completed and ongoing trials of novel therapies targeting different aspects of HDL cholesterol efflux.

High-Density Lipoprotein Function Measurement in Human Studies: Focus on Cholesterol Efflux Capacity.

A low plasma level of high-density lipoprotein (HDL) cholesterol (HDL-C) is a major risk factor for the development of atherosclerotic cardiovascular disease (ASCVD). However, several observations have highlighted the shortcomings of using cholesterol content as the sole reflection of HDL metabolism. In particular, several large randomized controlled trials of extended release niacin and cholesteryl-ester transfer protein (CETP) inhibitors on background statin therapy have failed to show improvement in ASCVD outcomes despite significant increases in HDL-C. Reverse cholesterol transport (RCT) is the principal HDL function that impacts macrophage foam cell formation and other functions such as endothelial activation of endothelial nitric oxide synthase, monocyte adhesion, and platelet aggregation. Cholesterol efflux from macrophages to plasma/serum reflects the first critical step of RCT and is considered a key anti-atherosclerotic function of HDL. Whether this function is operative in humans remains to be seen, but recent studies assessing cholesterol efflux in humans suggest that the cholesterol efflux capacity (CEC) of human plasma or serum is a potent marker of ASCVD risk. This review describes the methodology of measuring CEC ex vivo from human samples and the findings to date linking CEC to human disease. Studies to date confirm that CEC can be reliably measured using stored human blood samples as cholesterol acceptors and suggest that CEC may be a promising new biomarker for atherosclerotic and metabolic diseases. Further studies are needed to standardize measurements and clarify the role CEC may play in predicting risk of developing disease and response to therapies.

The relationship of body mass and fat distribution with incident hypertension: observations from the Dallas Heart Study.

BACKGROUND: Obesity has been linked to the development of hypertension, but whether total adiposity or site-specific fat accumulation underpins this relationship is unclear. OBJECTIVES: This study sought to determine the relationship between adipose tissue distribution and incident hypertension. METHODS: Normotensive participants enrolled in the Dallas Heart Study were followed for a median of 7 years for the development of hypertension (systolic blood pressure [SBP] ≥140 mm Hg, diastolic blood pressure ≥90 mm Hg, or initiation of blood pressure medications). Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) was quantified by magnetic resonance imaging and proton-spectroscopic imaging, and lower body fat (LBF) was imaged by dual-energy x-ray absorptiometry. Multivariable relative risk regression was performed to test the association between individual fat depots and incident hypertension, adjusting for age, sex, race/ethnicity, diabetes, smoking, SBP, and body mass index (BMI). RESULTS: Among 903 participants (median age, 40 years; 57% women; 60% nonwhite; median BMI 27.5 kg/m(2)), 230 (25%) developed incident hypertension. In multivariable analyses, higher BMI was significantly associated with incident hypertension (relative risk: 1.24; 95% confidence interval: 1.12 to 1.36, per 1-SD increase). However, when VAT, SAT, and LBF were added to the model, only VAT remained independently associated with incident hypertension (relative risk: 1.22; 95% confidence interval: 1.06 to 1.39, per 1-SD increase). CONCLUSIONS: Increased visceral adiposity, but not total or subcutaneous adiposity, was robustly associated with incident hypertension. Additional studies will be needed to elucidate the mechanisms behind this association.

Coronary artery calcification and family history of myocardial infarction in the Dallas heart study.

OBJECTIVES: This study aimed to investigate the independent and joint associations between family history of myocardial infarction (FH) and coronary artery calcification (CAC) with incident coronary heart disease (CHD). BACKGROUND: FH and CAC are associated with each other and with incident CHD. It is not known whether FH retains its predictive value after CAC results are accounted for. METHODS: Among 2,390 participants without cardiovascular disease enrolled in the Dallas Heart Study, we assessed FH (myocardial infarction in a first-degree relative) and prevalent CAC by electron-beam computed tomography. The primary outcome, a composite of CHD-related death, myocardial infarction, and percutaneous or surgical coronary revascularization, was assessed over a mean follow-up of 8.0 ± 1.2 years. The individual and joint associations with the CHD composite outcome were determined for FH and CAC. RESULTS: The mean age of the population was 44 ± 9 years; 32% had FH and 47% had a CAC score of 0. In multivariate models adjusted for traditional risk factors, FH was independently associated with CHD (adjusted hazard ratio: 2.6; 95% confidence interval: 1.6 to 4.2; p < 0.001). Further adjustment for prevalent CAC did not diminish this association (adjusted hazard ratio: 2.6; 95% confidence interval: 1.6 to 4.2; p < 0.001). FH and CAC were additive: CHD event rates in those with both FH and CAC were 8.8% vs. 3.3% in those with prevalent CAC alone (p < 0.001). CHD rates were 1.9% in those with FH alone compared with 0.4% in those with neither FH nor CAC (p < 0.017). Among subjects without CAC, FH characterized a group with a more unfavorable cardiometabolic profile. CONCLUSIONS: FH provided prognostic information that was independent of and additive to CAC. Among those with CAC, FH identified subjects at particularly high short-term risk, and, among those without it, selected a group with an adverse risk-factor profile.

Discordant effects of rosiglitazone on novel inflammatory biomarkers.

BACKGROUND: Although rosiglitazone favorably affects myriad intermediate markers of atherosclerosis, it appears to increase myocardial infarction (MI) risk. We analyzed the effects of rosiglitazone on a panel of 8 novel circulating biomarkers, 4 of which are independently associated with atherosclerosis: lymphotoxin ß receptor, peptidoglycan recognition protein 1, chemokine ligand 23, and soluble receptor for advanced glycation end products (sRAGE) as well as on high-sensitivity C-reactive protein (hs-CRP). METHODS: Blood samples were analyzed at baseline and after 6 months of study treatment from subjects with type 2 diabetes with or at high risk for coronary artery disease in a randomized trial comparing rosiglitazone versus placebo. RESULTS: Data from 111 subjects (rosiglitazone 55, placebo 56) were analyzed. Mean age was 56 years, 41% were women, and 66% were nonwhite. Compared with baseline values, rosiglitazone adversely affected levels of lymphotoxin ß receptor (1.7 vs 2.4 ng/mL, P = .002), peptidoglycan recognition protein 1 (29.0 vs 30.1 ng/mL, P = .01), and chemokine ligand 23 (0.76 vs 0.84 ng/mL, P = .02) and favorably affected levels of sRAGE (inversely associated with atherosclerosis, 1.1 vs 1.4 ng/mL, P = .003) and hs-CRP (0.42 vs 0.31 ng/mL, P = .02); no changes were observed with rosiglitazone in the other biomarkers. In the placebo group, change was observed only for sRAGE (1.0 vs 1.1 ng/mL, P = .046). CONCLUSION: Rosiglitazone adversely affected 3 novel biomarkers and favorably affected a fourth previously associated with atherosclerosis while improving hs-CRP, as has previously been shown. Whether these complex effects on circulating inflammatory biomarkers contribute to the signal of increased MI risk with rosiglitazone and whether pioglitazone has similar effects warrant further investigation.

Association of chronic lung disease with treatments and outcomes patients with acute myocardial infarction.

BACKGROUND: Although chronic lung disease (CLD) is common among patients with myocardial infarction (MI), little is known about the influence of CLD on patient management and outcomes following MI. METHODS: Using the National Cardiovascular Data Registry's ACTION Registry-GWTG, demographics, clinical characteristics, treatments, processes of care, and in-hospital adverse events after acute MI were compared between patients with (n = 22,624) and without (n = 136,266) CLD. Multivariable adjustment was performed to determine the independent association of CLD with treatments and adverse events. RESULTS: CLD (17.0% of non-ST-elevation MI [NSTEMI] and 10.1% of ST-elevation MI [STEMI] patients) was associated with older age, female sex, and a greater burden of comorbidities. Among NSTEMI patients, those with CLD were less likely to undergo cardiac catheterization, percutaneous coronary intervention, and coronary artery bypass graft compared to those without; in contrast, no differences were seen in invasive therapies for STEMI patients with or without CLD. Multivariable-adjusted risk of major bleeding was significantly increased in CLD patients with NSTEMI (13.0% vs 8.1%, OR(adj) = 1.27, 95% CI = 1.20-1.34, P < .001) and STEMI (16.0% vs 10.5%, OR(adj) = 1.19, 95% CI = 1.10-1.29, P < .001). In NSTEMI, CLD was associated with a higher risk of inhospital mortality (OR(adj) = 1.21, 95% CI = 1.11-1.33); in STEMI no association between CLD and mortality was seen (OR(adj) = 1.05, 95% CI = 0.95-1.17). CONCLUSIONS: CLD is common among patients with MI and is independently associated with an increased risk for major bleeding. In NSTEMI, CLD is also associated with receiving less revascularization and with increased in-hospital mortality. Special attention should be given to this high-risk subgroup for the prevention and management of complications after MI.

Association of growth differentiation factor-15 with coronary atherosclerosis and mortality in a young, multiethnic population: observations from the Dallas Heart Study.

BACKGROUND: Growth differentiation factor 15 (GDF-15) is produced by cardiomyocytes and atherosclerotic lesions under stress conditions. Although higher circulating GDF-15 concentrations are associated with mortality across a spectrum of cardiovascular conditions, the relationship of GDF-15 with atherosclerosis and mortality in the general population remains undefined. METHODS: We measured plasma GDF-15 in 3219 participants of the Dallas Heart Study, a population sample of adults ages 30-65 years (55% women, 49% black). GDF-15 was analyzed in prespecified categories (<1200; 1200-1799; and ≥1800 ng/L) and continuously. End points included prevalent coronary artery calcium (CAC>10 Agatston units), increased CAC (CAC≥100 Agatston units) by electron beam computed tomography, and mortality through a median 7.3 years of follow-up (120 deaths, 48 cardiovascular deaths). RESULTS: Increasing GDF-15 associated with older age, black race, hypertension, diabetes, smoking, left ventricular (LV) mass/body surface area, and worse renal function (P<0.0001 for each). In multivariable models adjusted for traditional risk factors, renal function, and LV mass/body surface area, GDF-15≥1800 ng/L was associated with CAC>10 (odds ratio 2.1; 95% CI 1.2-3.7; P=0.01), CAC≥100 (odds ratio 2.6; 95% CI 1.4-4.9; P=0.002), all-cause mortality (hazard ratio 3.5; 95% CI 2.1-5.9, P<0.0001), and cardiovascular mortality (hazard ratio 2.5; 95% CI 1.1-5.8, P=0.03). Adding log GDF-15 to fully adjusted models modestly improved the c statistic (P=0.025), the integrated discrimination index (0.028; P<0.0001) and the category-less net reclassification index (0.42; P=0.002). These findings remained significant with further adjustment for high-sensitivity C-reactive protein, N-terminal pro-B-type natriuretic peptide, and cardiac troponin T. CONCLUSIONS: GDF-15 is independently associated with subclinical coronary atherosclerosis and mortality, and its potential role for risk stratification in the general population merits further evaluation.

Interactions between smoking, pulmonary surfactant protein B, and atherosclerosis in the general population: the Dallas Heart Study.

OBJECTIVE: Pulmonary surfactant protein B (SP-B), an alveolar protein normally detectable at only very low concentrations in blood, circulates at higher levels among smokers and those with alveolar injury and inflammation. We hypothesized that SP-B may serve as a marker of the vascular effects of smoking and would thus be associated with subclinical measures of atherosclerosis. METHODS AND RESULTS: Plasma levels of SP-B were measured in 3294 subjects, ages 30 to 65, enrolled in the Dallas Heart Study, a probability-based population sample of Dallas County adults. Coronary artery calcium (CAC) was measured by computed tomography and abdominal aortic plaque (AP) by magnetic resonance imaging. The cohort comprised 29% current and 17% former smokers. The overall prevalence of CAC was 22%, and that of AP was 39%. Median SP-B levels were 5-fold higher among current versus never smokers (P<0.0001) and were significantly correlated with estimated pack-years smoked (Spearman ρ=0.35, P<0.0001). Increasing levels of SP-B also associated with other traditional cardiac risk factors and higher levels of inflammatory biomarkers. In univariable analyses, increasing SP-B quartiles associated with higher prevalence of both CAC and AP (P(trend)<0.0001 for each). In multivariable analyses adjusting for traditional cardiovascular risk factors, SP-B remained associated with AP (OR 1.87 for the 4th versus 1st quartiles, 95% confidence interval 1.39 to 2.51; P<0.0001) but not CAC. An interaction was observed between SP-B, smoking status, and AP (P(interaction)=0.01), such that SP-B associated with AP in current smokers (adjusted OR 2.15 for the 4th versus 1st quartile, 95% confidence interval 1.26 to 3.67; P=0.005) but not in former or never smokers. CONCLUSIONS: Circulating levels of SP-B increase with greater smoking burden and independently associate with abdominal AP among current smokers. Our findings support further investigation of the role of SP-B as a marker of the vascular effects of smoking.