Ian J. Neeland

HDL cholesterol efflux capacity and incident cardiovascular events

BACKGROUND It is unclear whether high-density lipoprotein (HDL) cholesterol concentration plays a causal role in atherosclerosis. A more important factor may be HDL cholesterol efflux capacity, the ability of HDL to accept cholesterol from macrophages, which is a key step in reverse cholesterol transport. We investigated the epidemiology of cholesterol efflux capacity and its association with incident atherosclerotic cardiovascular disease outcomes in a large, multiethnic population cohort. METHODS We measured HDL cholesterol level, HDL particle concentration, and cholesterol efflux capacity at baseline in 2924 adults free from cardiovascular disease who were participants in the Dallas Heart Study, a probability-based population sample. The primary end point was atherosclerotic cardiovascular disease, defined as a first nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization or death from cardiovascular causes. The median follow-up period was 9.4 years. RESULTS In contrast to HDL cholesterol level, which was associated with multiple traditional risk factors and metabolic variables, cholesterol efflux capacity had minimal association with these factors. Baseline HDL cholesterol level was not associated with cardiovascular events in an adjusted analysis (hazard ratio, 1.08; 95% confidence interval [CI], 0.59 to 1.99). In a fully adjusted model that included traditional risk factors, HDL cholesterol level, and HDL particle concentration, there was a 67% reduction in cardiovascular risk in the highest quartile of cholesterol efflux capacity versus the lowest quartile (hazard ratio, 0.33; 95% CI, 0.19 to 0.55). Adding cholesterol efflux capacity to traditional risk factors was associated with improvement in discrimination and reclassification indexes. CONCLUSIONS Cholesterol efflux capacity, a new biomarker that characterizes a key step in reverse cholesterol transport, was inversely associated with the incidence of cardiovascular events in a population-based cohort. (Funded by the Donald W. Reynolds Foundation and others.).

Associations of visceral and abdominal subcutaneous adipose tissue with markers of cardiac and metabolic risk in obese adults.

Objective: Visceral (VAT) and abdominal subcutaneous (SAT) adipose tissues contribute to obesity but may have different metabolic and atherosclerosis risk profiles. We sought to determine the associations of abdominal VAT and SAT mass with markers of cardiac and metabolic risk in a large, multiethnic, population‐based cohort of obese adults.

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.

Biomarkers of Chronic Cardiac Injury and Hemodynamic Stress Identify a Malignant Phenotype of Left Ventricular Hypertrophy in the General Population

OBJECTIVES The goal of this study was to determine if biomarkers of subclinical myocardial injury and hemodynamic stress identify asymptomatic individuals with left ventricular hypertrophy (LVH) at higher risk for heart failure (HF) and death. BACKGROUND The interaction between LVH, low but detectable cardiac troponin T (cTnT), and elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) on cardiovascular (CV) outcomes in the general population is unknown. METHODS Participants in the Dallas Heart Study without clinical HF, LV dysfunction, or chronic kidney disease underwent measurement of LV mass by magnetic resonance imaging (MRI), cTnT by highly sensitive assay, and NT-proBNP analysis (n = 2,413). Subjects were stratified according to LVH and by detectable cTnT (≥3 pg/ml) and increased NT-proBNP (>75th age- and sex-specific percentile) levels. For each analysis, participants were categorized into groups based on the presence (+) or absence (-) of LVH and biomarker levels above (+) or below (-) the predefined threshold. RESULTS Nine percent of participants were LVH+, 25% cTnT+, and 24% NT-proBNP+. Those LVH+ and cTnT+ and/or NT-proBNP+ (n = 144) were older and more likely to be male, with a greater risk factor burden and more severe LVH compared with those who were LVH+ biomarker- (p < 0.01 for each). The cumulative incidence of HF or CV death over 8 years among LVH+ cTnT+ was 21% versus 1% (LVH- cTnT-), 4% (LVH- cTnT+), and 6% (LVH+ cTnT-) (p < 0.0001). The interactions between LVH and cTnT (p(interaction) = 0.0005) and LVH and NT-proBNP (p(interaction) = 0.014) were highly significant. Individuals who were LVH+ and either cTnT+ or NT-proBNP+ remained at >4-fold higher risk for HF or CV death after multivariable adjustment for CV risk factors, renal function, and LV mass compared with those who were LVH- biomarker-. CONCLUSIONS Minimal elevations in biomarkers of subclinical cardiac injury and hemodynamic stress modify the association of LVH with adverse outcomes, identifying a malignant subphenotype of LVH with high risk for progression to HF and CV death.

Coronary angiographic scoring systems: an evaluation of their equivalence and validity.

BACKGROUND Multiple scoring systems have been devised to quantify angiographic coronary artery disease (CAD) burden, but it is unclear how these scores relate to each other and which scores are most accurate. The aim of this study was to compare coronary angiographic scoring systems (1) with each other and (2) with intravascular ultrasound (IVUS)-derived plaque burden in a population undergoing angiographic evaluation for CAD. METHODS Coronary angiographic data from 3600 patients were scored using 10 commonly used angiographic scoring systems and interscore correlations were calculated. In a subset of 50 patients, plaque burden and plaque area in the left anterior descending coronary artery were quantified using IVUS and correlated with angiographic scores. RESULTS All angiographic scores correlated with each other (range for Spearman coefficient [ρ] 0.79-0.98, P < .0001); the 2 most widely used scores, Gensini and CASS-70, had a ρ = 0.90 (P < .0001). All scores correlated significantly with average plaque burden and plaque area by IVUS (range ρ 0.56-0.78, P < .0001 and 0.43-0.62, P < .01, respectively). The CASS-50 score had the strongest correlation (ρ 0.78 and 0.62, P < .0001) and the Duke Jeopardy score the weakest correlation (ρ 0.56 and 0.43, P < .01) with plaque burden and area, respectively. CONCLUSIONS Angiographic scoring systems are strongly correlated with each other and with atherosclerotic plaque burden. Scoring systems therefore appear to be a valid estimate of CAD plaque burden.

Higher Natriuretic Peptide Levels Associate With a Favorable Adipose Tissue Distribution Profile

OBJECTIVES The goal of this study was to investigate the association between natriuretic peptides and body fat distribution in a multiethnic cohort. BACKGROUND Natriuretic peptides stimulate lipolysis, reduce weight gain, and promote adipocyte browning in animal models, but data are lacking in humans. METHODS A total of 2,619 participants without heart failure in the Dallas Heart Study underwent measurements of 1) B-type natriuretic peptide (BNP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP); and 2) body fat distribution by dual energy x-ray absorptiometry and magnetic resonance imaging. Cross-sectional associations of natriuretic peptides with adiposity phenotypes were examined after adjustment for age, sex, race, comorbidities, and body mass index. RESULTS Median BNP and NT-proBNP levels in the study cohort (mean age 44 years; 56% women, 48% African Americans, 32% obese) were 3.0 and 28.1 pg/ml, respectively. Natriuretic peptide levels above the median were associated with a more favorable body fat profile and less insulin resistance, including lower visceral fat, liver fat, and homeostasis model assessment of insulin resistance index, and increased lower body fat and higher adiponectin (p < 0.05 for each). In multivariable analyses, NT-proBNP remained inversely associated with visceral fat (beta coefficient = -0.08; p < 0.0001) and liver fat (beta coefficient = -0.14; p < 0.0001) and positively associated with lower body fat (beta coefficient = 0.07; p < 0.0001) independent of age, sex, race, and obesity status; findings were similar with BNP. Adjustment for body composition, homeostasis model assessment of insulin resistance index, circulating androgens, and adipocytokines did not attenuate the associations. CONCLUSIONS Higher natriuretic peptide levels were independently associated with a favorable adiposity profile, characterized by decreased visceral and liver fat and increased lower body fat, suggesting a link between the heart and adipose tissue distribution mediated through natriuretic peptides.

Relation of regional fat distribution to left ventricular structure and function.

Background— The relation of body fat distribution to left ventricular (LV) structure and function is poorly defined. Methods and Results— A total of 2710 participants without heart failure or LV dysfunction in the Dallas Heart Study underwent dual energy x-ray absorptiometry and MRI assessment of fat distribution, LV morphology, and hemodynamics. Cross-sectional associations of fat distribution with LV structure and function were examined after adjustment for age, sex, race, comorbidities, and lean mass. Mean age was 44 years with 55% women; 48% blacks; and 44% obese. After multivariable adjustment, visceral adipose tissue was associated with concentric remodeling characterized by lower LV end-diastolic volume (&bgr;=−0.21), higher concentricity (&bgr;=0.20), and wall thickness (&bgr;=0.09; P<0.0001 for all). In contrast, lower body subcutaneous fat was associated with higher LV end-diastolic volume (&bgr;=0.48), reduced concentricity (&bgr;=−0.50), and wall thickness (&bgr;=−0.28, P<0.0001 for all). Visceral adipose tissue was also associated with lower cardiac output (&bgr;=−0.10, P<0.05) and higher systemic vascular resistance (&bgr;=0.08, P<0.05), whereas lower body subcutaneous fat associated with higher cardiac output (&bgr;=0.20, P<0.0001) and lower systemic vascular resistance (&bgr;=−0.18, P<0.0001). Abdominal subcutaneous fat showed weaker associations with concentric remodeling and was not associated with hemodynamics. Among the subset of obese participants, visceral adipose tissue, but not abdominal subcutaneous fat, was significantly associated with concentric remodeling. Conclusions— Visceral adipose tissue, a marker of central adiposity, was independently associated with concentric LV remodeling and adverse hemodynamics. In contrast, lower body subcutaneous fat was associated with eccentric remodeling. The impact of body fat distribution on heart failure risk requires prospective study.

Evolving considerations in the management of patients with left bundle branch block and suspected myocardial infarction

Patients with a suspected acute coronary syndrome and left bundle branch block (LBBB) present a unique diagnostic and therapeutic challenge to the clinician. Although current guidelines recommend that patients with new or presumed new LBBB undergo early reperfusion therapy, data suggest that only a minority of patients with LBBB are ultimately diagnosed with acute myocardial infarction, regardless of LBBB chronicity, and that a significant proportion of patients will not have an occluded culprit artery at cardiac catheterization. The current treatment approach exposes a significant proportion of patients to the risks of fibrinolytic therapy without the likelihood of significant benefit and leads to increased rates of false-positive cardiac catheterization laboratory activation, unnecessary risks, and costs. Therefore, alternative strategies to those for patients with ST-segment elevation myocardial infarction are needed to guide selection of appropriate patients with a suspected acute coronary syndrome and LBBB for urgent reperfusion therapy. In this article, we describe the evolving epidemiology of LBBB in acute coronary syndromes and discuss controversies related to current clinical practice. We propose a more judicious diagnostic approach among clinically stable patients with LBBB who do not have electrocardiographic findings highly specific for ST-segment elevation myocardial infarction.

Sex and Age Differences in the Association of Depression With Obstructive Coronary Artery Disease and Adverse Cardiovascular Events

Background Young women with coronary heart disease have high rates of depression and a higher risk of adverse events than men of similar age. Whether depression has a higher prognostic value in this group than in men and older women is not known. Our objective was to assess whether depression in young women is associated with higher risk of coronary artery disease (CAD) and adverse outcomes compared with similarly aged men and older women. Methods and Results We examined 3237 patients undergoing coronary angiography for evaluation of CAD and followed them for 2.9 years (median). Depressive symptoms were assessed with the Patient Health Questionnaire (PHQ)‐9, and CAD burden was dichotomized based on its presence or absence. After multivariable adjustment for CAD risk factors, depressive symptoms predicted CAD presence in women aged ≤55 years (odds ratio=1.07 95% confidence interval [CI] 1.02 to 1.13 per 1 point increase in PHQ‐9 score), but not in men aged ≤55 years or women aged >55 years. Depressive symptoms also predicted increased risk of death in women aged ≤55 years (adjusted hazard ratio=1.07, 95% CI 1.02 to 1.14, per 1 point increase in PHQ‐9 score), but not in men aged ≤55 years and women aged >55 years, with P=0.02 for the depression‐sex interaction and P=0.02 for depression‐sex‐age interaction. Conclusions Among patients with suspected or established CAD, depressive symptoms are associated with increased risk of death, particularly in young women. This group may be especially vulnerable to the adverse cardiovascular effects of depression.

Body fat distribution and incident cardiovascular disease in obese adults

Emerging evidence suggests that significant heterogeneity exists in the cardiometabolic risk associated with excess body fat in obese individuals (1). We investigated the associations of novel imaging markers of adiposity, including visceral adipose tissue (VAT) and abdominal subcutaneous adipose tissue (SAT) by magnetic resonance imaging, lower body subcutaneous adipose tissue (LBAT) by dual-energy x-ray absorptiometry, and liver fat by magnetic resonance spectroscopy, with the risk for cardiovascular disease (CVD) events in a multiethnic cohort of obese adults.