Publications by authors named "Anand Rohatgi"

72 Publications

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

J Am Heart Assoc 2020 12 2;9(24):e018136. Epub 2020 Dec 2.

Division of Cardiology Department of Internal Medicine UT Southwestern Medical Center Dallas TX.

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 ( 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 ( 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.
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http://dx.doi.org/10.1161/JAHA.120.018136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955402PMC
December 2020

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

J Clin Psychiatry 2020 Nov 17;82(1). Epub 2020 Nov 17.

Department of Psychiatry, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, MC 8849, Dallas, TX 75390-8849.

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.
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http://dx.doi.org/10.4088/JCP.20m13245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7932005PMC
November 2020

Value of Coronary Artery Calcium Scanning in Association With the Net Benefit of Aspirin in Primary Prevention of Atherosclerotic Cardiovascular Disease.

JAMA Cardiol 2021 Feb;6(2):179-187

Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas.

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 < .001; HR, 5.3; 95% CI, 3.6-7.9; P < .001), but the association between CAC and bleeding was attenuated after multivariable adjustment. Applying meta-analysis estimates, irrespective of CAC, aspirin use was estimated to result in net harm in individuals at low (<5%) and intermediate (5%-20%) 10-year ASCVD risk and net benefit in those at high (≥20%) ASCVD risk. Among individuals at lower bleeding risk, a CAC score of at least 100 identified individuals who would experience net benefit, but only in those at borderline or higher (≥5%) 10-year ASCVD risk. In individuals at higher bleeding risk, there would be net harm from aspirin irrespective of CAC and ASCVD risk.

Conclusions And Relevance: Higher CAC is associated with both ASCVD and bleeding events, with a stronger association with ASCVD. A high CAC score identifies individuals estimated to derive net benefit from primary prevention aspirin therapy from those who would not, but only in the setting of lower bleeding risk and estimated ASCVD risk that is not low.
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http://dx.doi.org/10.1001/jamacardio.2020.4939DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7593878PMC
February 2021

Associations Between High-Density Lipoprotein Particles and Ischemic Events by Vascular Domain, Sex, and Ethnicity: A Pooled Cohort Analysis.

Circulation 2020 Aug 18;142(7):657-669. Epub 2020 Jun 18.

University of Texas Southwestern Medical Center, Dallas (K.S., A.C., T.S., P.H.J., A.K., C.R.A., A.R.).

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]; =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]; <0.0001).

Conclusions: Compared with HDL-C, HDL-P was consistently associated with MI and ischemic stroke in the overall population. Differential associations of both HDL-C and HDL-P for MI by Black ethnicity suggest that atherosclerotic cardiovascular disease risk may differ by vascular domain and ethnicity. Future studies should examine individual outcomes separately.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.045713DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425196PMC
August 2020

Lipoprotein(a) and Family History Predict Cardiovascular Disease Risk.

J Am Coll Cardiol 2020 08;76(7):781-793

Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas. Electronic address:

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.
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http://dx.doi.org/10.1016/j.jacc.2020.06.040DOI Listing
August 2020

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

J Am Heart Assoc 2020 07 10;9(14):e016203. Epub 2020 Jul 10.

Division of Cardiology Department of Internal Medicine University of Texas Southwestern Medical Center Dallas TX.

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%]; <0.001), device-related infection (64% [95% CI 57%-71%] versus 76% [95% CI, 74%-78%]; <0.001), and pump thrombosis or malfunction (64% [95% CI, 57%-70%] versus 76% [95% CI, 74%-78%]; <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.
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http://dx.doi.org/10.1161/JAHA.119.016203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7660737PMC
July 2020

Impaired HDL Metabolism Links GlycA, A Novel Inflammatory Marker, with Incident Cardiovascular Events.

J Clin Med 2019 Dec 3;8(12). Epub 2019 Dec 3.

Department of Internal Medicine, Division of Cardiology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

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 ( = 197). The correlation between GlycA and hs-CRP was 0.58 ( < 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 ≤ 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.
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http://dx.doi.org/10.3390/jcm8122137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6947609PMC
December 2019

Supplementation With the Sialic Acid Precursor N-Acetyl-D-Mannosamine Breaks the Link Between Obesity and Hypertension.

Circulation 2019 12 10;140(24):2005-2018. Epub 2019 Oct 10.

University of Texas Southwestern Medical Center, Dallas (J.P., W.V., S.B., I.S.Y., K.T., A.S., H.C., N.C.S., A.R., K.L.C., C.M., P.W.S.).

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 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.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.043490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7027951PMC
December 2019

Racial Differences in Cardiovascular Biomarkers in the General Population.

J Am Heart Assoc 2019 09 13;8(18):e012729. Epub 2019 Sep 13.

Department of Medicine UT Southwestern Medical Center Dallas TX.

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.
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http://dx.doi.org/10.1161/JAHA.119.012729DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6817997PMC
September 2019

HDL and Reverse Cholesterol Transport Biomarkers.

Methodist Debakey Cardiovasc J 2019 Jan-Mar;15(1):39-46

THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, DALLAS, TEXAS.

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.
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http://dx.doi.org/10.14797/mdcj-15-1-39DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6489608PMC
June 2019

Reverse Cholesterol Transport and Atherosclerosis.

Authors:
Anand Rohatgi

Arterioscler Thromb Vasc Biol 2019 01;39(1):2-4

From the Division of Cardiology, University of Texas Southwestern Medical Center, Dallas.

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http://dx.doi.org/10.1161/ATVBAHA.118.311978DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6550473PMC
January 2019

Is RCT (Reverse Cholesterol Transport) Ready for an RCT (Randomized Controlled Trial)?

J Am Coll Cardiol 2018 12;72(25):3270-3273

Brigham and Women's Hospital Heart & Vascular Center, Harvard Medical School, Boston, Massachusetts. Electronic address: https://twitter.com/DLBHATTMD.

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http://dx.doi.org/10.1016/j.jacc.2018.10.034DOI Listing
December 2018

Long-Term Association of Low-Density Lipoprotein Cholesterol With Cardiovascular Mortality in Individuals at Low 10-Year Risk of Atherosclerotic Cardiovascular Disease.

Circulation 2018 11;138(21):2315-2325

Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas (S.M.A., A.R., D.K.M., J.A.D., S.M.G., J.D.B., A.K.).

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 (<7.5%) for 10-year atherosclerotic CVD events at baseline based on Pooled Cohort Risk Assessment Equations. The associations of fasting LDL-C and non-HDL-C with CVD mortality were tested with Cox proportional hazards models.

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 <100 mg/dL, LDL-C categories 100 to 129 mg/dL, 130 to 159 mg/dL, 160 to 189.9 mg/dL, and ≥190 mg/dL were associated with a significantly higher risk of CVD death, with hazard ratios of 1.4 (95% CI, 1.1-1.7), 1.3 (95% CI, 1.1-1.6), 1.9 (95% CI, 1.5-2.4), and 1.7 (95% CI, 1.3-2.3), and mean reductions in years free of CVD death of 1.8, 1.1, 4.3, and 3.9, respectively. After adjustment for atherosclerotic CVD risk factors, LDL-C categories 160 to 189 mg/dL and ≥190 mg/dL remained independently associated with CVD mortality, with hazard ratios of 1.7 (95% CI, 1.4-2.2) and 1.5 (95% CI, 1.2-2.1), respectively. In multivariable-adjusted models using non-HDL-C <130 mg/dL as the reference, non-HDL-C 160 to 189 mg/dL, 190 to 219 mg/dL, and ≥220 mg/dL were significantly associated with CVD death, with hazard ratios of 1.3 (95% CI, 1.1-1.6), 1.8 (95% CI, 1.4-2.2), and 1.5 (95% CI, 1.2-2.0), respectively. Restricting the cohort to those with 10-year risk <5% did not diminish the associations of LDL-C and non-HDL-C with CVD mortality.

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.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.118.034273DOI Listing
November 2018

JCL roundtable: High-density lipoprotein function and reverse cholesterol transport.

J Clin Lipidol 2018 Sep - Oct;12(5):1086-1094. Epub 2018 Oct 9.

Division of Endocrinology, Metabolism, and Nutrition, Department of Medicine, Duke University Medical Center, Durham, NC, USA. Electronic address:

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.
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http://dx.doi.org/10.1016/j.jacl.2018.09.005DOI Listing
October 2019

Examining the paradox of high high-density lipoprotein and elevated cardiovascular risk.

J Thorac Dis 2018 Jan;10(1):109-112

Division of Cardiology, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA.

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http://dx.doi.org/10.21037/jtd.2017.12.97DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5863140PMC
January 2018

Proteomic characterization of high-density lipoprotein particles in patients with non-alcoholic fatty liver disease.

Clin Proteomics 2018 6;15:10. Epub 2018 Mar 6.

1Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX USA.

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.
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http://dx.doi.org/10.1186/s12014-018-9186-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5839024PMC
March 2018

Effects of Increasing Exercise Intensity and Dose on Multiple Measures of HDL (High-Density Lipoprotein) Function.

Arterioscler Thromb Vasc Biol 2018 04 8;38(4):943-952. Epub 2018 Feb 8.

From the Department of Exercise Science, University of South Carolina, Columbia (M.A.S., J.J.R.-R., J.L.B.); Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC (C.A.S., R.W.M., W.E.K.); Ingestive Behavior and Preventive Medicine Laboratories, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA (J.W.A., M.N.H., T.S.C., C.K.M.); Center for Prevention of Obesity, Cardiovascular Disease & Diabetes, Children's Hospital Oakland Research Institute, Oakland, CA (M.S.B., Y.H., M.N.O.); and Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas (A.R.).

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; =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.
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http://dx.doi.org/10.1161/ATVBAHA.117.310307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5864525PMC
April 2018

Soluble endothelial cell-selective adhesion molecule and incident cardiovascular events in a multiethnic population.

Am Heart J 2017 Sep 23;191:55-61. Epub 2017 Jun 23.

Division of Cardiology, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX. Electronic address:

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.
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http://dx.doi.org/10.1016/j.ahj.2017.06.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5657571PMC
September 2017

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.

Atherosclerosis 2017 08 3;263:156-162. Epub 2017 Jun 3.

University of Texas Southwestern Medical Center, Dallas, TX, USA. Electronic address:

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.
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http://dx.doi.org/10.1016/j.atherosclerosis.2017.06.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5557659PMC
August 2017

Sex-Based Differences in Cardiometabolic Biomarkers.

Circulation 2017 02;135(6):544-555

From Departments of Medicine (J.L., M.S., D.K.M., M.O.G., I.N., J.D.B., A.K., A.R., J.A.d.L.) and Clinical Sciences (C.R.A., D.K.M., J.D.B.), UT Southwestern Medical Center, Dallas, TX; Division of Medicine, Akershus University Hospital, Lørenskog, and University of Oslo, Norway (T.O.); Department of Clinical Pharmacology and Toxicology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany (D.A.); and Department of Cardiovascular Medicine, University of Oxford, United Kingdom (D.A.).

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.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.116.023005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5302552PMC
February 2017

The association between HDL particle concentration and incident metabolic syndrome in the multi-ethnic Dallas Heart Study.

Diabetes Metab Syndr 2017 Nov 12;11 Suppl 1:S175-S179. Epub 2016 Dec 12.

Department of Cardiology, UT Southwestern Medical Center, United States. Electronic address:

Aims: 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.

Materials And Methods: 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.

Results: 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, p<0.0001). 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).

Conclusions: 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.
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http://dx.doi.org/10.1016/j.dsx.2016.12.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6190917PMC
November 2017

Beyond Coronary Calcification, Family History, and C-Reactive Protein: Cholesterol Efflux Capacity and Cardiovascular Risk Prediction.

J Am Coll Cardiol 2016 05;67(21):2480-7

Division of Cardiology, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas. Electronic address:

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.
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http://dx.doi.org/10.1016/j.jacc.2016.03.538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4884307PMC
May 2016

Modulating cholesterol efflux capacity to improve cardiovascular disease.

Curr Opin Lipidol 2016 08;27(4):398-407

Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

Purpose Of Review: Low HDL-cholesterol (HDL-C) levels are predictive of incident atherosclerotic cardiovascular disease events. However, the use of medication to raise HDL-C levels has not consistently shown clinical benefit. As a result, studies have shifted toward HDL function, specifically cholesterol efflux, which has been inversely associated with prevalent subclinical atherosclerosis as well as subsequent atherosclerotic cardiovascular disease events. The purpose of this review is to summarize the effects of current medications and interventions on cholesterol efflux capacity.

Recent Findings: Medications for cardiovascular health, including statins, fibrates, niacin, and novel therapeutics, are reviewed for their effect on cholesterol efflux. Differences in population studied and assay used are addressed appropriately. Lifestyle interventions, including diet and exercise, are also included in the review.

Summary: The modification of cholesterol efflux capacity (CEC) by current medications and interventions has been investigated in both large randomized control trials and smaller observational cohorts. This review serves to compile the results of these studies and evaluate CEC modulation by commonly used medications. Altering CEC could be a novel therapeutic approach to improving cardiovascular risk profiles.
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http://dx.doi.org/10.1097/MOL.0000000000000317DOI Listing
August 2016

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

Curr Atheroscler Rep 2016 Jan;18(1)

Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75390-8830, USA.

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.
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http://dx.doi.org/10.1007/s11883-015-0554-1DOI Listing
January 2016

Cholesterol Efflux Capacity as a Therapeutic Target: Rationale and Clinical Implications.

J Am Coll Cardiol 2015 Nov;66(20):2211-2213

Department of Internal Medicine, University of Texas Southwestern and Veteran Affairs Medical Center, Dallas, Texas. Electronic address:

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http://dx.doi.org/10.1016/j.jacc.2015.09.012DOI Listing
November 2015

Applying a Big Data Approach to Biomarker Discovery: Running Before We Walk?

Circulation 2015 Dec 30;132(24):2289-92. Epub 2015 Oct 30.

From Division of Cardiology, Department of Medicine (J.A.d.L., A.R.) and Department of Clinical Sciences (C.R.A.), University of Texas Southwestern Medical Center, Dallas.

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http://dx.doi.org/10.1161/CIRCULATIONAHA.115.019648DOI Listing
December 2015

Coronary Artery Calcium Improves Risk Classification in Younger Populations.

JACC Cardiovasc Imaging 2015 Nov 14;8(11):1285-93. Epub 2015 Oct 14.

Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas; Division of Cardiology, University of Texas Southwestern Medical Center, Dallas, Texas. Electronic address:

Objectives: This study sought to assess the effect of coronary artery calcium (CAC) on coronary heart disease (CHD) risk prediction in a younger population.

Background: CAC measured by computed tomography improves CHD risk classification in older adults, but the effectiveness of CAC in younger populations has not been fully assessed.

Methods: In 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, <6%, 6% to <20%, and ≥20%, and the net reclassification improvement (NRI) was calculated. We also performed a random-effects meta-analysis of NRI from previous studies inclusive of older individuals.

Results: The analysis comprised 2,084 participants; mean age was 44.4 ± 9.0 years. CAC was independently associated with incident CHD (hazard ratio per SD: 1.90, 95% confidence interval [CI] 1.51 to 2.38; p < 0.001). The addition of CAC to the traditional risk factor model resulted in significant improvement in the C-statistic (delta = 0.03; p = 0.003). Among participants with CHD events, the addition of CAC resulted in net correct upward reclassification of 21%, and among those without CHD, a net correct downward reclassification of 0.5% (NRI: 0.216, p = 0.012). Results remained significant when the outcome was restricted to CHD death and myocardial infarction and when individuals with diabetes were included. The NRI observed in this study was similar to the pooled estimate from previous studies (0.200, 95% CI: 0.140 to 0.258) and the addition of our study to the meta-analysis did not result in significant heterogeneity (I(2) = 0%).

Conclusions: CAC scoring also improves CHD risk classification in younger adults.
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http://dx.doi.org/10.1016/j.jcmg.2015.06.015DOI Listing
November 2015

Niacin Therapy, HDL Cholesterol, and Cardiovascular Disease: Is the HDL Hypothesis Defunct?

Curr Atheroscler Rep 2015 Aug;17(8):43

Department of Internal Medicine, University of Texas Southwestern, Dallas, TX, USA.

High-density lipoprotein cholesterol (HDL-C) has been shown in epidemiologic studies to be associated with cardiovascular (CV) risk and thus significant efforts have been focused on HDL-C modulation. Multiple pharmaceutical agents have been developed with the goal of increasing HDL-C. Niacin, the most widely used medication to raise HDL-C, increases HDL-C by up to 25 % and was shown in multiple surrogate end point studies to reduce CV risk. However, two large randomized controlled trials of niacin, AIM-HIGH and HPS2-THRIVE, have shown that despite its effects on HDL-C, niacin does not decrease the incidence of CV events and may have significant adverse effects. Studies of other classes of agents such as cholesteryl ester transfer protein (CETP) inhibitors have also shown that even dramatic increases in HDL-C do not necessarily translate to reduction in clinical events. While these findings have cast doubt upon the importance of HDL-C modulation on CV risk, it is becoming increasingly clear that HDL function-related measures may be better targets for CV risk reduction. Increasing ApoA-I, the primary apolipoprotein associated with HDL, correlates with reduced risk of events, and HDL particle concentration (HDL-P) inversely associates with incident CV events adjusted for HDL-C and LDL particle measures. Cholesterol efflux, the mechanism by which macrophages in vessel walls secrete cholesterol outside cells, correlates with both surrogate end points and clinical events. The effects of niacin on these alternate measures of HDL have been conflicting. Further studies should determine if modulation of these HDL function markers translates to clinical benefits. Although the HDL cholesterol hypothesis may be defunct, the HDL function hypothesis is now poised to be rigorously tested.
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http://dx.doi.org/10.1007/s11883-015-0521-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4829575PMC
August 2015