Search

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.

Supplemental Digital Content is available in the text., Background: High-density lipoprotein (HDL) cholesterol concentration (HDL-C) is an established atheroprotective marker, in particular for coronary artery disease; however, HDL particle concentration (HDL-P) may better predict risk. The associations of HDL-C and HDL-P with ischemic stroke and myocardial infarction (MI) among women and Blacks have not been well studied. We hypothesized that HDL-P would consistently be associated with MI and stroke among women and Blacks compared with HDL-C. Methods: We analyzed individual-level participant data in a pooled cohort of 4 large population studies without baseline atherosclerotic cardiovascular disease: DHS (Dallas Heart Study; n=2535), ARIC (Atherosclerosis Risk in Communities; n=1595), MESA (Multi-Ethnic Study of Atherosclerosis; n=6632), and PREVEND (Prevention of Renal and Vascular Endstage Disease; n=5022). HDL markers were analyzed in adjusted Cox proportional hazard models for MI and ischemic stroke. Results: In the overall population (n=15 784), HDL-P was inversely associated with the combined outcome of MI and ischemic stroke, adjusted for cardiometabolic risk factors (hazard ratio [HR] for quartile 4 [Q4] versus quartile 1 [Q1], 0.64 [95% CI, 0.52–0.78]), as was HDL-C (HR for Q4 versus Q1, 0.76 [95% CI, 0.61–0.94]). Adjustment for HDL-C did not attenuate the inverse relationship between HDL-P and atherosclerotic cardiovascular disease, whereas adjustment for HDL-P attenuated all associations between HDL-C and events. HDL-P was inversely associated with the individual end points of MI and ischemic stroke in the overall population, including in women. HDL-P was inversely associated with MI among White participants but not among Black participants (HR for Q4 versus Q1 for Whites, 0.49 [95% CI, 0.35–0.69]; for Blacks, 1.22 [95% CI, 0.76–1.98]; Pinteraction=0.001). Similarly, HDL-C was inversely associated with MI among White participants (HR for Q4 versus Q1, 0.53 [95% CI, 0.36–0.78]) but had a weak direct association with MI among Black participants (HR for Q4 versus Q1, 1.75 [95% CI, 1.08–2.83]; Pinteraction

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 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 even further. 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 anti-diabetic properties. HDLs can be anti-inflammatory, which may protect against atherosclerosis and diabetes, as well as pro-inflammatory, which may help clear pathogens in sepsis. In addition, the molecular regulation of HDLs is complex, as evidenced by their association with multiple proteins, as well as bioactive lipids and non-coding RNAs. Clinical investigations of HDL biomarkers (HDL-C, HDL particle number, and apolipoprotein A-I) have revealed non-linear relationships with cardiovascular outcomes, differential relationships by sex and ethnicity, and differential patterns with coronary versus non-coronary 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 remain research tools thus far. Ultimately, therapeutics that manipulate aspects of HDL metabolism remain the holy grail. None thus far have 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 here 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.

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 β, 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 β, 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.

Introduction: The Friedewald equation (F-LDL-C) and the Martin-Hopkins algorithm (MH-LDL-C) estimate direct LDL-C from a standard lipid panel. Discordant LDL-C estimates by the two methods may carry significant clinical implications. We evaluated the clinical variables associated with discordant LDL-C estimates and the association of discordance with risk of incident atherosclerotic cardiovascular disease (ASCVD) in the Dallas Heart Study (DHS), a multi-ethnic, population based prospective cohort. Methods: We estimated F-LDL-C and MH-LDL-C in 2824 DHS participants (42% male; mean age 43.5 years) with TG ≤ 400 mg/dL, who were not on baseline lipid lowering therapy and were free of prior ASCVD. We divided the cohort into quintiles of LDL-C discordance (MH-LDL-C minus F-LDL-C, in mg/dL) and assessed associations with ASCVD risk factors. We evaluated associations between discordance and incident ASCVD by sequentially adjusted Cox regression models, and we generated restricted cubic spline plots of discordance and hazard for ASCVD. Results: There were 228 ASCVD events over a median of 12.3 years. Clinical characteristics across discordance quintiles are shown in the Table . After adjustment for traditional ASCVD risk factors, there was a linear association between higher LDL-C discordance and increased risk of ASCVD events ( Figure ) with the highest hazard in Quintile 5 (HR 1.5, 95% CI 1.1 - 2.0). Conclusions: Discordant LDL-C estimates were largely associated with male sex, White and Hispanic races, and characteristics of the metabolic syndrome. Individuals in the highest quintile of discordant LDL-C estimates, with MH-LDL-C > F-LDL-C, had greater risk for incident ASCVD.

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 P P 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.

Background Elevated lipoprotein(a) (Lp[a]) and family history (FHx) of coronary heart disease (CHD) are individually associated with cardiovascular risk, and Lp(a) is commonly measured in those with FHx. Objectives The aim of this study was to determine independent and joint associations of Lp(a) and FHx with atherosclerotic cardiovascular disease (ASCVD) and CHD among asymptomatic subjects. Methods Plasma Lp(a) was measured and FHx was ascertained in 2 cohorts. Elevated Lp(a) was defined as the highest race-specific quintile. Independent and joint associations of Lp(a) and FHx with cardiovascular risk were determined using Cox regression models adjusted for cardiovascular risk factors. Results Among 12,149 ARIC (Atherosclerosis Risk In Communities) participants (54 years, 56% women, 23% black, 44% with FHx), 3,114 ASCVD events were observed during 21 years of follow-up. FHx and elevated Lp(a) were independently associated with ASCVD (hazard ratio [HR]: 1.17; 95% confidence interval [CI]: 1.09 to 1.26, and HR: 1.25; 95% CI: 1.12 to 1.40, respectively), and no Lp(a)-by-FHx interaction was noted (p = 0.75). Compared with subjects without FHx and nonelevated Lp(a), those with either elevated Lp(a) or FHx were at a higher ASCVD risk, while those with both had the highest risk (HR: 1.43; 95% CI: 1.27 to 1.62). Similar findings were observed for CHD risk in ARIC, in analyses stratified by premature FHx, and in an independent cohort, the DHS (Dallas Heart Study). Presence of both elevated Lp(a) and FHx resulted in greater improvement in ASCVD and CHD risk reclassification and discrimination indexes than either marker alone. Conclusions Elevated plasma Lp(a) and FHx have independent and additive joint associations with cardiovascular risk and may be useful concurrently for guiding primary prevention therapy decisions.

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 (β = .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.

Background: The associations of low-density lipoprotein cholesterol (LDL-C) with cardiovascular disease (CVD) and coronary heart disease mortality in an exclusively low estimated 10-year risk group are not well delineated. We sought to determine the long-term associations of various LDL-C and non–high-density lipoprotein cholesterol (HDL-C) thresholds and CVD and coronary heart disease mortality in a large, low 10-year risk cohort. Methods: The study sample included participants of the CCLS (Cooper Center Longitudinal Study) without a history of CVD or diabetes mellitus and defined as low risk ( Results: In 36 375 participants (72% men, median age 42) followed for a median of 26.8 years, 1086 CVD and 598 coronary heart disease deaths occurred. Compared with LDL-C Conclusions: In a low 10-year risk cohort with long-term follow-up, LDL-C and non–HDL-C ≥160 mg/dL were independently associated with a 50% to 80% increased relative risk of CVD mortality. These findings may have implications for future cholesterol treatment paradigms.

High-density lipoproteins (HDL) have been known since the 1960s to be associated with protection from atherosclerotic cardiovascular disease. However, the mechanisms of this protection are unclear. The extent to which HDL per se vs other correlated metabolic factors may mitigate atherosclerosis has been seriously questioned. In fact, new epidemiologic studies have found that in some clinical settings, very high HDL cholesterol levels correlate with increased atherosclerotic risk. Most importantly, over the past 2 decades, randomized clinical trials targeting HDL have failed to reproduce the usual epidemiologic inverse relation of HDL cholesterol to atherosclerotic events. In this roundtable discussion, we bring together 3 expert investigators working in the HDL field to elucidate questions of HDL function. One area of agreement is that reverse cholesterol transport remains a primary hypothesis for an anti-atherogenic role of HDL. Bioassays that measure cholesterol efflux capacity of HDL (or of apolipoprotein [apo] B-depleted plasma) have emerged as potentially accurate surrogates for reverse cholesterol transport. ApoA-I is the major functional apoprotein of HDL, but apoE- and apoC-III-containing subpopulations of HDL may have significant roles. Anti- and pro-inflammatory functions of various HDL particles, as well as the role of oxidative and other modifications, are gaining attention.

Objective— Measures of HDL (high-density lipoprotein) function are associated with cardiovascular disease. However, the effects of regular exercise on these measures is largely unknown. Thus, we examined the effects of different doses of exercise on 3 measures of HDL function in 2 randomized clinical exercise trials. Approach and Results— Radiolabeled and boron dipyrromethene difluoride–labeled cholesterol efflux capacity and HDL-apoA-I (apolipoprotein A-I) exchange were assessed before and after 6 months of exercise training in 2 cohorts: STRRIDE-PD (Studies of Targeted Risk Reduction Interventions through Defined Exercise, in individuals with Pre-Diabetes; n=106) and E-MECHANIC (Examination of Mechanisms of exercise-induced weight compensation; n=90). STRRIDE-PD participants completed 1 of 4 exercise interventions differing in amount and intensity. E-MECHANIC participants were randomized into 1 of 2 exercise groups (8 or 20 kcal/kg per week) or a control group. HDL-C significantly increased in the high-amount/vigorous-intensity group (3±5 mg/dL; P =0.02) of STRRIDE-PD, whereas no changes in HDL-C were observed in E-MECHANIC. In STRRIDE-PD, global radiolabeled efflux capacity significantly increased 6.2% (SEM, 0.06) in the high-amount/vigorous-intensity group compared with all other STRRIDE-PD groups (range, −2.4 to −8.4%; SEM, 0.06). In E-MECHANIC, non-ABCA1 (ATP-binding cassette transporter A1) radiolabeled efflux significantly increased 5.7% (95% CI, 1.2–10.2%) in the 20 kcal/kg per week group compared with the control group, with no change in the 8 kcal/kg per week group (2.6%; 95% CI, −1.4 to 6.7%). This association was attenuated when adjusting for change in HDL-C. Exercise training did not affect BODIPY-labeled cholesterol efflux capacity or HDL-apoA-I exchange in either study. Conclusions— Regular prolonged vigorous exercise improves some but not all measures of HDL function. Future studies are warranted to investigate whether the effects of exercise on cardiovascular disease are mediated in part by improving HDL function. Clinical Trial Registration— URL: https://www.clinicaltrials.gov . Unique identifiers: NCT00962962 and NCT01264406.

When high density lipoprotein cholesterol (HDL-C) was identified as a protective factor in atherosclerotic cardiovascular disease (ASCVD), the inverse relationship between HDL-C and ASCVD was thought to be linear (1).

Background Cell adhesion molecules are key regulators of atherosclerotic plaque development, but circulating levels of soluble fragments, such as intercellular adhesion molecule (sICAM-1) and vascular cell adhesion molecule (sVCAM-1), have yielded conflicting associations with atherosclerotic cardiovascular disease (ASCVD). Endothelial cell-selective adhesion molecule (ESAM) is expressed exclusively in platelets and endothelial cells, and soluble ESAM (sESAM) levels have been associated with prevalent subclinical atherosclerosis. We therefore hypothesized that sESAM would be associated with incident ASCVD. Methods sESAM, sICAM-1, and sVCAM-1 were measured in 2,442 participants without CVD in the Dallas Heart Study, a probability-based population sample aged 30-65 years enrolled between 2000 and 2002. ASCVD was defined as first myocardial infarction, stroke, coronary revascularization, or CV death. A total of 162 ASCVD events were analyzed over 10.4 years. Results Increasing sESAM was associated with ASCVD, independent of risk factors (HR Q4 vs Q1: 2.7, 95% CI 1.6-4.6). Serial adjustment for renal function, sICAM-1, VCAM-1, and prevalent coronary calcium did not attenuate these associations. Continuous ESAM demonstrated similar findings (HR 1.31, 95% CI 1.2-1.4). Addition of sESAM to traditional risk factors improved discrimination and reclassification (delta c-index: P = .009; integrated-discrimination-improvement index P = .001; net reclassification index = 0.42, 95% CI 0.15-0.68). Neither sICAM-1 nor sVCAM-1 was independently associated with ASCVD. Conclusions sESAM but not sICAM-1 or sVCAM-1 levels are associated with incident ASCVD. Further studies are warranted to investigate the role of sESAM in ASCVD.

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.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.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).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.

Background: Obesity-related hypertension is a common disorder, and attempts to combat the underlying obesity are often unsuccessful. We previously revealed that mice globally deficient in the inhibitory immunoglobulin G (IgG) receptor FcγRIIB are protected from obesity-induced hypertension. However, how FcγRIIB participates is unknown. Studies were designed to determine if alterations in IgG contribute to the pathogenesis of obesity-induced hypertension. Methods: Involvement of IgG was studied using IgG μ heavy chain–null mice deficient in mature B cells and by IgG transfer. Participation of FcγRIIB was interrogated in mice with global or endothelial cell–specific deletion of the receptor. Obesity was induced by high-fat diet (HFD), and blood pressure (BP) was measured by radiotelemetry or tail cuff. The relative sialylation of the Fc glycan on mouse IgG, which influences IgG activation of Fc receptors, was evaluated by Sambucus nigra lectin blotting. Effects of IgG on endothelial NO synthase were assessed in human aortic endothelial cells. IgG Fc glycan sialylation was interrogated in 3442 human participants by mass spectrometry, and the relationship between sialylation and BP was evaluated. Effects of normalizing IgG sialylation were determined in HFD-fed mice administered the sialic acid precursor N-acetyl-D-mannosamine (ManNAc). Results: Mice deficient in B cells were protected from obesity-induced hypertension. Compared with IgG from control chow–fed mice, IgG from HFD-fed mice was hyposialylated, and it raised BP when transferred to recipients lacking IgG; the hypertensive response was absent if recipients were FcγRIIB-deficient. Neuraminidase-treated IgG lacking the Fc glycan terminal sialic acid also raised BP. In cultured endothelial cells, via FcγRIIB, IgG from HFD-fed mice and neuraminidase-treated IgG inhibited vascular endothelial growth factor activation of endothelial NO synthase by altering endothelial NO synthase phosphorylation. In humans, obesity was associated with lower IgG sialylation, and systolic BP was inversely related to IgG sialylation. Mice deficient in FcγRIIB in endothelium were protected from obesity-induced hypertension. Furthermore, in HFD-fed mice, ManNAc normalized IgG sialylation and prevented obesity-induced hypertension. Conclusions: Hyposialylated IgG and FcγRIIB in endothelium are critically involved in obesity-induced hypertension in mice, and supportive evidence was obtained in humans. Interventions targeting these mechanisms, such as ManNAc supplementation, may provide novel means to break the link between obesity and hypertension.

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 .

IMPORTANCE: Higher coronary artery calcium (CAC) identifies individuals at increased atherosclerotic cardiovascular disease (ASCVD) risk. Whether it can also identify individuals likely to derive net benefit from aspirin therapy is unclear. OBJECTIVE: To examine the association between CAC, bleeding, and ASCVD and explore the net estimated effect of aspirin at different CAC thresholds. DESIGN, SETTING, AND PARTICIPANTS: Prospective population-based cohort study of Dallas Heart Study participants, free from ASCVD and not taking aspirin at baseline. Data were analyzed between February 1, 2020, and July 15, 2020. EXPOSURES: Coronary artery calcium score in the following categories: 0, 1-99, and 100 or higher. MAIN OUTCOMES AND MEASURES: Major bleeding and ASCVD events were identified from International Statistical Classification of Diseases and Related Health Problems, Ninth Revision codes. Meta-analysis–derived aspirin effect estimates were applied to observed ASCVD and bleeding rates to model the net effect of aspirin at different CAC thresholds. RESULTS: A total of 2191 participants (mean [SD], age 44 [9.1] years, 1247 women [57%], and 1039 black individuals [47%]) had 116 major bleeding and 123 ASCVD events over a median follow-up of 12.2 years. Higher CAC categories (CAC 1-99 and ≥100 vs CAC 0) were associated with both ASCVD and bleeding events (hazard ratio [HR], 1.6; 95% CI, 1.1-2.4; HR, 2.6; 95% CI, 1.5-4.3; HR, 4.8; 95% CI, 2.8-8.2; P

Background Cholesterol efflux capacity (CEC), which is a key step in the reverse cholesterol transport pathway, is independently associated with atherosclerotic cardiovascular disease (ASCVD). However, whether it predicts ASCVD beyond validated novel risk markers is unknown. Objectives This study assessed if CEC improved ACSVD risk prediction beyond using coronary artery calcium (CAC), family history (FH), and high-sensitivity C-reactive protein (hs-CRP). Methods CEC, CAC, self-reported FH, and hs-CRP were assessed among participants without baseline ASCVD who were enrolled in the Dallas Heart Study (DHS). ASCVD was defined as a first nonfatal myocardial infarction (MI) or stroke, coronary revascularization, or cardiovascular death, assessed over a median 9.4 years. Risk prediction was assessed using various modeling techniques and improvements in the c -statistic, the integrated discrimination index (IDI), and the net reclassification index (NRI). Results The mean age of the population (N = 1,972) was 45 years, 52% had CAC (>0), 31% had FH, and 58% had elevated hs-CRP (≥2 mg/l). CEC greater than the median was associated with a 50% reduced incidence of ASCVD in those with CAC (5.4% vs. 10.5%; p = 0.003), FH (5.8% vs. 10%; p = 0.05), and elevated hs-CRP (3.8% vs. 7.9%; p = 0.004). CEC improved all metrics of discrimination and reclassification when added to CAC ( c -statistic, p = 0.004; IDI, p = 0.02; NRI: 0.38; 95% confidence interval [CI]: 0.13 to 0.53), FH ( c -statistic, p = 0.006; IDI, p = 0.008; NRI: 0.38; 95% CI: 0.13 to 0.55), or elevated hs-CRP ( c -statistic p = 0.008; IDI p = 0.02; NRI: 0.36; 95% CI 0.12 to 0.52). Conclusions CEC improves ASCVD risk prediction beyond using CAC, FH, and hs-CRP and warrants consideration as a novel ASCVD risk marker.

GlycA, a novel inflammatory marker, reflects glycosylation of five acute phase reactants and is associated with incident cardiovascular disease (CVD). We assessed whether GlycA is superior to high-sensitivity C-reactive protein (hsCRP) for CVD risk prediction. GlycA (derived from NMR) and hsCRP

Soluble Fms-like tyrosine kinase-1 (sFlt-1) plays a role in angiogenesis, atherogenesis, and preeclampsia but associations with subclinical atherosclerosis and clinical events in healthy adults are unknown. Participants from the Dallas Heart Study with sFlt-1 measured were included (n=3932).

Objective- To assess the role of HDL (high-density lipoprotein)-mediated cholesterol mass efflux capacity (CMEC) in incident cardiovascular disease and carotid plaque progression. Approach and Results- We measured CMEC in 2 cohorts aged 45 to 84 years at baseline derived from the MESA (Multi-Ethnic Study of Atherosclerosis). Cohort 1 comprised 465 cases with incident cardiovascular disease events during 10 years of follow-up and 465 age- and sex-matched controls; cohort 2 comprised 407 cases with progression of carotid plaque measured by ultrasonography at 2 exams10 years and 407 similarly matched controls. Covariates and outcome events were ascertained according to the MESA protocol. CMEC level was modestly correlated with HDL cholesterol ( R=0.13; P0.001) but was not associated with age, sex, race/ethnicity, body mass index, diabetes mellitus, alcohol use, smoking status, or statin use. Higher CMEC level was significantly associated with lower odds of cardiovascular disease (odds ratio, 0.82 per SD of CMEC [95% CI, 0.69-0.98; P=0.031] in the fully adjusted model) in cohort 1 but higher odds of carotid plaque progression (odds ratio, 1.24 per SD of CMEC [95% CI, 1.04-1.48; P=0.018] in the fully adjusted model) in cohort 2 but without dose-response effect. In subgroup analysis within cohort 1, higher CMEC was associated with lower risk of incident coronary heart disease events (odds ratio, 0.72 per SD of CMEC (95% CI, 0.5-0.91; P=0.007) while no association was found with stroke events. Conclusions- These findings support a role for HDL-mediated cholesterol efflux in an atheroprotective mechanism for coronary heart disease but not stroke.

Statins are currently the most efficacious and widely prescribed lipid-lowering medications. The 2013 ACC/AHA cholesterol guidelines provide a dramatic shift in treatment approach with a focus on fixed-dose statins matched to individual risk scores. Statin intolerance is not uncommon and can be challenging to diagnose and manage; however, several therapeutic strategies have been successful in achieving statin tolerance. Statin use is also associated with liver enzyme elevations and increased risk of incident diabetes, but studies show these individuals benefit from statins. Several guidelines exist and statin use is expected to increase with the new cholesterol guidelines bringing along new challenges for prescribers. This review article will provide practical considerations for statin use and management of statin intolerance.

Background: Excess visceral adipose tissue (VAT) is associated with an increased risk of prediabetes and type 2 diabetes (T2D) independent of body mass index (BMI). Whether expansion of VAT or other fat depots is associated with diabetes risk independent of weight gain is not fully known. Methods: Among participants without prevalent diabetes or cardiovascular disease enrolled in the Dallas Heart Study, we measured body fat distribution by dual energy x-ray absorptiometry and biomarkers of glycemia at baseline (2000-2002) and repeated 7 years later. The incidence of prediabetes and T2D per ADA definitions were assessed at follow-up. Results: The study included 1661 participants (mean age 44, 58% women, 45% black, 39% obese) with median weight gain of 3.0 (-1.1 to 7.2) kg. Eight percent of participants developed T2D and, among those with normal fasting glucose at baseline (n=1551), 36% developed prediabetes or T2D. Changes in fat depots are shown in the Table. VAT and SAT gain were associated with incident T2D and with prediabetes or T2D independent of traditional risk factors, baseline BMI, change in BMI, and baseline fat depot (Table). Increasing lower body fat was not associated with incident diabetes. Conclusions: Expansion of VAT and SAT are both associated with incident T2D independent of weight gain. Abdominal adiposity may be a modifiable target for diabetes prevention even in the absence of generalized weight loss. Disclosure I.J. Neeland: Speaker's Bureau; Self; Boehringer Ingelheim GmbH. Research Support; Self; Novo Nordisk A/S, National Institute of Diabetes and Digestive and Kidney Diseases. Advisory Panel; Self; Advanced MR Analytics AB. C. Ayers: None. K.V. Patel: None. P.H. Joshi: Consultant; Self; Regeneron Pharmaceuticals, Inc. D.K. McGuire: Consultant; Self; AstraZeneca, Sanofi-Aventis, Eli Lilly and Company, Boehringer Ingelheim Pharmaceuticals, Inc., Merck & Co., Inc., Pfizer Inc., Novo Nordisk A/S. Research Support; Self; AstraZeneca, Sanofi-Aventis, Janssen Pharmaceuticals, Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S, Lexicon Pharmaceuticals, Inc., Eisai Inc., GlaxoSmithKline plc., Esperion Therapeutics. S.M. Grundy: None. A. Rohatgi: Research Support; Self; Merck Sharp & Dohme Corp., American Heart Association. Consultant; Self; CSL Behring. Research Support; Self; National Heart, Lung, and Blood Institute. G.L. Vega: None.

High-density lipoprotein (HDL) is dysfunctional in chronic kidney disease (CKD) [(1)][1], but the clinical relevance of this finding is unknown. Cholesterol efflux capacity (CEC), a key HDL function, and total HDL particle number (HDL-P) each inversely associates with cardiovascular events

Background Metabolic diseases such as obesity and diabetes are associated with changes in high-density lipoprotein (HDL) particles, including changes in particle size and protein composition, often resulting in abnormal function. Recent studies suggested that patients with non-alcoholic fatty liver disease (NAFLD), including individuals with non-alcoholic steatohepatitis (NASH), have smaller HDL particles when compared to individuals without liver pathologies. However, no studies have investigated potential changes in HDL particle protein composition in patients with NAFLD, in addition to changes related to obesity, to explore putative functional changes of HDL which may increase the risk of cardiovascular complications. Methods From a cohort of morbidly obese females who were diagnosed with simple steatosis (SS), NASH, or normal liver histology, we selected five matched individuals from each condition for a preliminary pilot HDL proteome analysis. HDL particles were enriched using size-exclusion chromatography, and the proteome of the resulting fraction was analyzed by liquid chromatography tandem mass spectrometry. Differences in the proteomes between the three conditions (normal, SS, NASH) were assessed using label-free quantitative analysis. Gene ontology term analysis was performed to assess the potential impact of proteomic changes on specific functions of HDL particles. Results Of the 95 proteins identified, 12 proteins showed nominally significant differences between the three conditions. Gene ontology term analysis revealed that severity of the liver pathology may significantly impact the anti-thrombotic functions of HDL particles, as suggested by changes in the abundance of HDL-associated proteins such as antithrombin III and plasminogen. Conclusions The pilot data from this study suggest that changes in the HDL proteome may impact the functionality of HDL particles in NAFLD and NASH patients. These proteome changes may alter cardio-protective properties of HDL, potentially contributing to the increased cardiovascular disease risk in affected individuals. Further validation of these protein changes by orthogonal approaches is key to confirming the role of alterations in the HDL proteome in NAFLD and NASH. This will help elucidate the mechanistic effects of the altered HDL proteome on cardioprotective properties of HDL particles. Electronic supplementary material The online version of this article (10.1186/s12014-018-9186-0) contains supplementary material, which is available to authorized users.

Since the release of the American Heart Association and American College of Cardiology’s 2013 pooled cohort equations and the European Cardiology Society’s 2016 SCORE, numerous studies have better characterized the predictive ability of emerging and novel biomarkers for atherosclerotic cardiovascular disease (ASCVD). Here, we review these emerging ASCVD biomarkers, with a focus on those that have been assessed using risk discrimination and reclassification performance indices in large population studies. These biomarkers include genetic risk scores (GRS) based on a growing number of risk alleles, inflammatory and thrombotic markers, lipid components and functional measures, protein metabolites, microRNAs, and a variety of subclinical atherosclerosis imaging measures. While most of these markers have demonstrated some degree of association with and predictive utility for ASCVD, only coronary artery calcium (CAC) has demonstrated consistent risk prediction improvement across multiple population and risk profiles. Although CAC has garnered evidence to merit inclusion in modern risk prediction algorithms, large population studies and high-throughput genetic and protein technologies have shown promise for the risk prediction utility of several emerging biomarkers that may warrant consideration in future multimodality ASCVD risk prediction algorithms.

ObjectivesThis study sought to assess the effect of coronary artery calcium (CAC) on coronary heart disease (CHD) risk prediction in a younger population.BackgroundCAC measured by computed tomography improves CHD risk classification in older adults, but the effectiveness of CAC in younger populations has not been fully assessed.MethodsIn the DHS (Dallas Heart Study), a multiethnic probability-based population sample, traditional CHD risk factors and CAC were measured in participants without baseline cardiovascular disease or diabetes. Incident CHD—defined as CHD death, myocardial infarction, or coronary revascularization—was assessed over a median follow-up of 9.2 years. Predicted CHD risk was assessed with a Weibull model inclusive of traditional risk factors before and after the addition of CAC as ln(CAC + 1). Participants were divided into 3 10-year risk categories

Therapies targeting high-density lipoprotein cholesterol content (HDL-C) have not improved coronary heart disease (CHD) outcomes. High-density lipoprotein particle concentration (HDL-P) may better predict CHD. However, the impact of race/ethnicity on the relations between HDL-P and subclinical atherosclerosis and incident CHD events has not been described. Participants from the Dallas Heart Study (DHS), a multiethnic, probability-based, population cohort of Dallas County adults, underwent the following baseline measurements: HDL-C, HDL-P by nuclear magnetic resonance imaging, and coronary artery calcium by electron-beam computed tomography. Participants were followed for a median of 9.3 years for incident CHD events (composite of first myocardial infarction, stroke, coronary revascularization, or cardiovascular death). The study comprised 1,977 participants free of CHD (51% women, 46% black). In adjusted models, HDL-C was not associated with prevalent coronary artery calcium (p = 0.13) or incident CHD overall (hazard ratio [HR] per 1 SD 0.89, 95% confidence interval [CI] 0.76 to 1.05). However, HDL-C was inversely associated with incident CHD among nonblack (adjusted HR per 1 SD 0.67, 95% CI 0.46 to 0.97) but not black participants (HR 0.94, 95% CI 0.78 to 1.13, p interaction = 0.05). Conversely, HDL-P, adjusted for risk factors and HDL-C, was inversely associated with prevalent coronary artery calcium (p = 0.009) and with incident CHD overall (adjusted HR per 1 SD 0.73, 95% CI 0.62 to 0.86), with no interaction by black race/ethnicity (p interaction = 0.57). In conclusion, in contrast to HDL-C, the inverse relation between HDL-P and incident CHD events is consistent across ethnicities. These findings suggest that HDL-P is superior to HDL-C in predicting prevalent atherosclerosis as well as incident CHD events across a diverse population and should be considered as a therapeutic target.

Cardiovascular disease (CVD) is the leading cause of death in the United States, with both dyslipidemia and chronic kidney disease (CKD) as major risk factors for CVD. In this chapter, we discuss the variation in the lipid profile across a spectrum of kidney disease, including CKD, nephrotic syndrome, peritoneal dialysis, hemodialysis, and kidney transplantation. We also review the trials 4D, AURORA, SHARP, ALERT, and meta-analyses which form the basis of the current KDIGO recommendations for medical management of dyslipidemia in patients with CKD.

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/m2), 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.

ObjectivesThis 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).BackgroundFH 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.MethodsAmong 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.ResultsThe 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.ConclusionsFH 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.

High-density lipoproteins (HDL) exert anti-atherosclerotic effects via reverse cholesterol transport, yet this salutary property is impaired in the setting of inflammation. GlycA, a novel integrated glycosylation marker of five acute phase reactants, is linked to cardiovascular (CV) events. We assessed the hypothesis that GlycA is associated with measures of impaired HDL function and that dysfunctional HDL may contribute to the association between GlycA and incident CV events. Baseline measurements of HDL cholesterol (HDL-C), HDL particle concentration (HDL-P), apoliprotein A1 (Apo A1), cholesterol efflux capacity, GlycA and high-sensitivity C-reactive protein (hs-CRP) were obtained from the Dallas Heart Study, a multi-ethnic cohort of 2643 adults (median 43 years old; 56% women, 50% black) without cardiovascular disease (CVD). GlycA was derived from nuclear magnetic resonance imaging. Participants were followed for first nonfatal MI, nonfatal stroke, coronary revascularization, or CV death over a median of 12.4 years (n = 197). The correlation between GlycA and hs-CRP was 0.58 (p < 0.0001). In multivariate models with HDL-C, GlycA was directly associated with HDL-P and Apo A1 and inversely associated with cholesterol efflux (standardized beta estimates: 0.08, 0.29, -0.06, respectively; all p ≤ 0.0004) GlycA was directly associated with incident CV events (adjusted hazard ratio (HR) for Q4 vs. Q1: 3.33, 95% confidence interval (CI) 1.99, 5.57). Adjustment for cholesterol efflux mildly attenuated this association (HR for Q4 vs. Q1: 3.00, 95% CI 1.75 to 5.13). In a multi-ethnic cohort, worsening inflammation, as reflected by higher GlycA levels, is associated with higher HDL-P and lower cholesterol efflux. Impaired cholesterol efflux likely explains some of the association between GlycA and incident CV events. Further studies are warranted to investigate the impact of inflammation on HDL function and CV disease.

High-density lipoprotein (HDL) is a protein-lipid nanoparticle that has predominately been characterized by its cholesterol concentration (HDL-C). Recent studies have challenged the presumed inverse association between HDL-C and cardiovascular events, suggesting a more U-shaped association. This has opened new opportunities to evaluate more novel measures of HDL metabolism, such as HDL particle number (HDL-P) and one of HDL's key functions, cholesterol efflux. Both HDL-P and cholesterol efflux are inversely associated with incident cardiovascular events and may perhaps be better targets for intervention. This review includes recent research on the emerging U-shaped association between HDL-C and cardiovascular events, recent observational studies related to HDL-P, and the effects of established and novel interventions on cholesterol efflux.

The majority of efforts to halt atherosclerosis have been focused on limiting cholesterol influx into resident macrophages within the arterial wall by reducing circulating levels of atherogenic lipoproteins, which are collectively reflected by non–high-density lipoprotein cholesterol (non–HDL-C

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. Design and methods Among obese participants in the Dallas Heart Study, we examined the cross-sectional associations of abdominal VAT and SAT mass, assessed by magnetic resonance imaging (MRI) and indexed to body surface area (BSA), with circulating biomarkers of insulin resistance, dyslipidemia, and inflammation (n = 942); and with aortic plaque and liver fat by MRI and coronary calcium by computed tomography (n = 1200). Associations of VAT/BSA and SAT/BSA were examined after adjustment for age, sex, race, menopause, and body mass index. Results In multivariable models, VAT significantly associated with the homeostasis model assessment of insulin resistance (HOMA-IR), lower adiponectin, smaller LDL and HDL particle size, larger VLDL size, and increased LDL and VLDL particle number (p Conclusion VAT associated with an adverse metabolic, dyslipidemic, and atherogenic obesity phenotype. In contrast, SAT demonstrated a more benign phenotype, characterized by modest associations with inflammatory biomarkers and leptin, but no independent association with dyslipidemia, insulin resistance, or atherosclerosis in obese individuals. These findings suggest that abdominal fat distribution defines distinct obesity sub-phenotypes with heterogeneous metabolic and atherosclerosis risk.

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.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.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).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.

Left ventricular hypertrophy (LVH) is an independent, modifiable risk factor for cardiovascular disease. However, current screening strategies are limited. In 2478 participants without clinical disease from the Dallas Heart Study, we evaluated a multimarker screening strategy that complements electrocardiographic (ECG) criteria for LVH with 2 biomarkers, amino-terminal pro-B-type natriuretic peptide and highly sensitive cardiac troponin T. An integer LVH risk score from 0 to 3 was determined as the sum of the following: (1) LVH by Sokolow-Lyon ECG; (2) amino-terminal pro-B-type natriuretic peptide in the highest sex-specific quartile; and (3) detectable cardiac troponin T. Cardiac magnetic resonance imaging–determined LVH served as the primary outcome. The probability of LVH increased from 2% with an LVH risk score of 0 to 50% with a score of 3 ( P P =0.0012), consistent with modest improvement in overall discrimination. Better screening for LVH may be achieved by combining simple tests, which collectively provide additional information compared with ECG alone. Further studies are needed to evaluate the impact and cost-effectiveness of a multimarker screening strategy.

Metabolic syndrome (MetS) increases atherosclerotic cardiovascular disease (ASCVD) risk. Low HDL cholesterol (HDL-C) is a diagnostic criterion of MetS and a major ASCVD risk factor. HDL particle concentration (HDL-P) associates with incident ASCVD independent of HDL-C, but its association with incident MetS has not been studied. We hypothesized that HDL-P would be inversely associated with incident metabolic syndrome independent of HDL-C and markers of adiposity and insulin resistance.HDL-P was measured by NMR and visceral fat by MRI in participants of the Dallas Heart Study, a probability-based population sample of adults age 30-65. Participants with prevalent MetS, DM, CVD, and any systemic illlness were excluded. Incident MetS as defined by NCEP ATPIII criteria was determined in all participants after median follow-up period of 7.0 years.Among 1120 participants without DM or MetS at baseline (57% women, 45% Black, mean age 43), 22.8% had incident MetS at follow-up. HDL-P and HDL-C were modestly correlated (r=0.54, p0.0001). In models adjusted for traditional risk factors and MetS risk factors including visceral fat, HS-CRP, triglyceride to HDL-C ratio, and HOMA-IR, the lowest quartile of HDL-P was associated with a 2-fold increased risk of incident MetS (OR 2.1, 95%CI 1.4-3.1; p=0.0003).Low HDL-P is independently associated with incident MetS after adjustment for traditional risk factors, lipid parameters, adiposity, inflammation, and markers of insulin resistance. Further studies are warranted to validate these findings and elucidate the mechanisms underpinning this association.

Objective: Cholesterol efflux capacity (CEC) is associated with incident and prevalent CVD. The effects of regular exercise on CEC are less well known. Thus, we examined the effects of different doses of exercise on CEC in two randomized clinical exercise trials. Methods: CEC was assessed before and after six months of exercise training in two cohorts: STRRIDE-PD (N=106) and E-MECHANIC (N=90). In STRRIDE-PD, sedentary, overweight/obese adults with pre-diabetes (fasting plasma glucose 95-125 mg/dL) were randomized to one of four exercise groups: 1) Low-amount/Moderate-intensity (10 kcal/kg/week (KKW) at 50% VO 2 peak); 2) Low/Mod/Diet: Exercise same as group 1 + goal of 7% weight loss; 3) High-amount/Moderate-intensity (16 KKW at 50% VO 2 peak), and 4) High-amount/Vigorous-intensity (16 KKW at 75% VO 2 peak). E-MECHANIC randomized sedentary, overweight/obese, non-diabetic (fasting plasma glucose 76-106 mg/dL) adults into one of two exercise groups (8 KKW or 20 KKW, both at 65-85% VO 2 peak) or a control group. CEC was assessed by measuring efflux of 3 H-labeled cholesterol from J774 macrophages to apoB-depleted plasma (STRRIDE-PD) or serum (E-MECHANIC) over 4 hours. In STRRIDE-PD, only global CEC (+cAMP) was measured; global, non-ABCA1 (-cAMP), and ABCA1 CEC were assessed in E-MECHANIC. Results: In STRRIDE-PD, global CEC significantly increased in the High-amount/Vigorous group compared to the other groups, in which CEC actually decreased ( Figure 1A ). In E-MECHANIC, only non-ABCA1-CEC significantly increased in the 20 KKW group compared to controls, with no change in the 8 KKW group ( Figure 1B ). Exercise did not affect global CEC or ABCA1-CEC in E-MECHANIC. Conclusions: Within two randomized trials, regular endurance exercise improved CEC only when a high amount of vigorous exercise was performed. Thus, regular vigorous exercise may represent a therapeutic approach for improving HDL function.

Introduction: Myeloperoxidase (MPO) promotes oxidation of lipoproteins whereas high-density lipoprotein (HDL) exerts anti-oxidative effects in part via paraoxonase-1 (PON1). MPO can induce dysfunctional HDL particles; however, the interaction of circulating levels of these measures in cardiovascular disease (CVD) has not been studied in humans. We hypothesized that increased serum levels of MPO indexed to HDL particle concentration would be associated with an adverse phenotype with increased CVD risk and tested this hypothesis in a large multiethnic population 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 (57% women, 49% black). The associations of the MPO/HDLp ratio with incident ASCVD (first nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or CVD death) and total CVD were assessed in Cox proportional-hazards models adjusted for traditional risk factors (age, sex, race, hypertension, smoking, total cholesterol, and statin use). The median follow-up period was 9.4 years. Results: MPO/HDLp was associated directly with total cholesterol, C-reactive protein, interleukin 18, and body mass index, and inversely with PON1 arylesterase activity, HDL-C, and HDL size. In 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 CVD (aHR, 1.91, 95% CI 1.27-2.85). Conclusion: Increasing MPO indexed to HDL particle concentration at baseline is associated with increased risk of incident CVD events in a population initially free of CVD, reflecting increased inflammation and decreased PON1 arylesterase activity. This is the first report of the MPO/HDLp ratio in a large human cohort. Further studies are warranted investigating MPO/HDLp as a biomarker of HDL metabolism and CVD risk.

Introduction: Obesity is linked to an adverse cardiac structural phenotype in cross-sectional studies. However, the effects of longitudinal changes in generalized and central adiposity on left ventricular (LV) remodeling are unknown. Methods: Participants without baseline cardiovascular disease or LV dysfunction in the Dallas Heart Study underwent assessment of body composition and cardiac structure by MRI at baseline and then 7 years later. Associations between change in weight and waist circumference with alterations in structure and function were assessed using multivariable linear regression. Results: The study cohort (n=1262) had a mean age of 44 years and was 43% (545 of 1262) male, 44% (556 of 1262) African-American, and 36% (460 of 1262) obese at baseline. At 7 years follow-up, 7% (85 of 1262) had >10% weight loss, 8% (108 of 1262) had 5-10% weight loss, 44% (551 of 1262) had 10% weight gain. Those who gained >10% weight were younger, had lower BMI and LV mass at baseline, and had greater increases in blood pressure, glucose, triglycerides, LDL cholesterol, and hs-CRP over follow-up. In multivariable models adjusted for age, sex, race, and baseline and interim development of comorbidities, 1-standard deviation increases in body weight and waist circumference over follow-up were significantly associated with higher LV mass, LV wall thickness, and concentricity; but minimally or not significantly associated with LV end-diastolic volume or ejection fraction (EF) (Table). Conclusion: Increases in generalized and central adiposity are characterized primarily by concentric remodeling, with a more modest impact on LV volume and EF. These results support the notion that the development of specific obesity patterns may impact cardiac remodeling with potential implications for the development of cardiac hypertrophy and heart failure.