Measurement and Application of Incidentally Detected Coronary Calcium: JACC Review Topic of the Week.

Coronary artery calcium (CAC) scoring is a powerful tool for atherosclerotic cardiovascular disease risk stratification. The nongated, noncontrast chest computed tomography scan (NCCT) has emerged as a source of CAC characterization with tremendous potential due to the high volume of NCCT scans. Application of incidental CAC characterization from NCCT has raised questions around score accuracy, standardization of methodology including the possibility of deep learning to automate the process, and the risk stratification potential of an NCCT-derived score. In this review, the authors aim to summarize the role of NCCT-derived CAC in preventive cardiovascular health today as well as explore future avenues for eventual clinical applicability in specific patient populations and broader health systems.

Effect of liraglutide on thigh muscle fat and muscle composition in adults with overweight or obesity: Results from a randomized clinical trial.

BACKGROUND: Excess muscle fat is observed in obesity and associated with greater burden of cardiovascular risk factors and higher risk of mortality. Liraglutide reduces total body weight and visceral fat but its effect on muscle fat and adverse muscle composition is unknown. METHODS: This is a pre-specified secondary analysis of a randomized, double-blind, placebo-controlled trial that examined the effects of liraglutide plus a lifestyle intervention on visceral adipose tissue and ectopic fat among adults without diabetes with body mass index ≥30 kg/m2 or ≥27 kg/m2 and metabolic syndrome. Participants were randomly assigned to a once-daily subcutaneous injection of liraglutide (target dose 3.0 mg) or matching placebo for 40 weeks. Body fat distribution and muscle composition was assessed by magnetic resonance imaging at baseline and 40-week follow-up. Muscle composition was described by the combination of thigh muscle fat and muscle volume. Treatment difference (95% confidence intervals [CI]) was calculated by least-square means adjusted for baseline thigh muscle fat. The association between changes in thigh muscle fat and changes in body weight were assessed using Spearman correlation coefficients. The effect of liraglutide versus placebo on adverse muscle composition, denoted by high thigh muscle fat and low thigh muscle volume, was explored. RESULTS: Among the 128 participants with follow-up imaging (92.2% women, 36.7% Black), median muscle fat at baseline was 7.8%. The mean percent change in thigh muscle fat over median follow-up of 36 weeks was -2.87% among participants randomized to liraglutide (n = 73) and 0.05% in the placebo group (absolute change: -0.23% vs. 0.01%). The estimated treatment difference adjusted for baseline thigh muscle fat was -0.24% (95% CI, -0.41 to -0.06, P-value 0.009). Longitudinal change in thigh muscle fat was significantly associated with change in body weight in the placebo group but not the liraglutide group. The proportion of participants with adverse muscle composition decreased from 11.0% to 8.2% over follow-up with liraglutide, but there was no change with placebo. CONCLUSIONS: In a cohort of predominantly women with overweight or obesity in the absence of diabetes, once-daily subcutaneous liraglutide was associated with a reduction in thigh muscle fat and adverse muscle composition compared with placebo. The contribution of muscle fat improvement to the cardiometabolic benefits of liraglutide requires further study.

Long-Term Mortality in Patients With Severe Hypercholesterolemia Phenotype From a Racial and Ethnically Diverse US Cohort.

BACKGROUND: Tools for mortality prediction in patients with the severe hypercholesterolemia phenotype (low-density lipoprotein cholesterol ≥190 mg/dL) are limited and restricted to specific racial and ethnic cohorts. We sought to evaluate the predictors of long-term mortality in a large racially and ethnically diverse US patient cohort with low-density lipoprotein cholesterol ≥190 mg/dL. METHODS: We conducted a retrospective analysis of all patients with a low-density lipoprotein cholesterol ≥190 mg/dL seeking care at Montefiore from 2010 through 2020. Patients <18 years of age or with previous malignancy were excluded. The primary end point was all-cause mortality. Analyses were stratified by age, sex, and race and ethnicity. Patients were stratified by primary and secondary prevention. Cox regression analyses were used to adjust for demographic, clinical, and treatment variables. RESULTS: A total of 18 740 patients were included (37% non-Hispanic Black, 30% Hispanic, 12% non-Hispanic White, and 2% non-Hispanic Asian patients). The mean age was 53.9 years, and median follow-up was 5.2 years. Both high-density lipoprotein cholesterol and body mass index extremes were associated with higher mortality in univariate analyses. In adjusted models, higher low-density lipoprotein cholesterol and triglyceride levels were associated with an increased 9-year mortality risk (adjusted hazard ratio [HR], 1.08 [95% CI, 1.05-1.11] and 1.04 [95% CI, 1.02-1.06] per 20-mg/dL increase, respectively). Clinical factors associated with higher mortality included male sex (adjusted HR, 1.31 [95% CI, 1.08-1.58]), older age (adjusted HR, 1.19 per 5-year increase [95% CI, 1.15-1.23]), hypertension (adjusted HR, 2.01 [95% CI, 1.57-2.57]), chronic kidney disease (adjusted HR, 1.68 [95% CI, 1.36-2.09]), diabetes (adjusted HR, 1.79 [95% CI, 1.50-2.15]), heart failure (adjusted HR, 1.51 [95% CI, 1.16-1.95]), myocardial infarction (adjusted HR, 1.41 [95% CI, 1.05-1.90]), and body mass index <20 kg/m2 (adjusted HR, 3.36 [95% CI, 2.29-4.93]). A significant survival benefit was conferred by lipid-lowering therapy (adjusted HR, 0.57 [95% CI, 0.42-0.77]). In the primary prevention group, high-density lipoprotein cholesterol <40 mg/dL was independently associated with higher mortality (adjusted HR, 1.49 [95% CI, 1.06-2.09]). Temporal trend analyses showed a reduction in statin use over time (P<0.001). In the most recent time period (2019-2020), 56% of patients on primary prevention and 85% of those on secondary prevention were on statin therapy. CONCLUSIONS: In a large, diverse cohort of US patients with the severe hypercholesterolemia phenotype, we identified several patient characteristics associated with increased 9-year all-cause mortality and observed a decrease in statin use over time, in particular for primary prevention. Our results support efforts geared toward early recognition and consistent treatment for patients with severe hypercholesterolemia.

Novel Size-Based High-Density Lipoprotein Subspecies and Incident Vascular Events.

Background High-density lipoprotein (HDL) particle concentration likely outperforms HDL cholesterol in predicting atherosclerotic cardiovascular events. Whether size-based HDL subspecies explain the atheroprotective associations of HDL particle concentration remains unknown. Our objective was to assess whether levels of specific size-based HDL subspecies associate with atherosclerotic cardiovascular disease in a multiethnic pooled cohort and improve risk prediction beyond traditional atherosclerotic cardiovascular disease risk factors. Methods and Results Seven HDL size-based subspecies were quantified by nuclear magnetic resonance (LP4 algorithm; H1=smallest; H7=largest) among participants without prior atherosclerotic cardiovascular disease in ARIC (Atherosclerosis Risk in Communities), MESA (Multi-Ethnic Study of Atherosclerosis), PREVEND (Prevention of Renal and Vascular Endstage Disease), and DHS (Dallas Heart Study) cohorts (n=15 371 people). Multivariable Cox proportional hazards models were used to evaluate the association between HDL subspecies and incident myocardial infarction (MI) or ischemic stroke at follow-up (average 8-10 years) adjusting for HDL cholesterol and risk factors. Improvement in risk prediction was assessed via discrimination and reclassification analysis. Within the pooled cohort (median age 57 years; female 54%; Black 22%) higher H1 (small) and H4 (medium) concentrations were inversely associated with incident MI (hazard ratio [HR]/SD, H1 0.88 [95% CI, 0.81-0.94]; H4 0.89 [95% CI, 0.82-0.97]). H4 but not H1 improved risk prediction indices for incident MI. Increasing H2 and H4 were inversely associated with improved risk prediction indices for composite end point of stroke, MI, and cardiovascular death (HR/SD, H2 0.94 [95% CI, 0.88-0.99]; H4 0.91 [95% CI, 0.85-0.98]). Levels of the large subspecies (H6 and H7) were not associated with any vascular end point. Conclusions Two of 7 HDL size-based subspecies modestly improved risk prediction for MI and composite vascular end points in a large multiethnic pooled cohort. These findings support assessment of precise HDL subspecies for future studies regarding clinical utility.

Heterogeneity of Lipoprotein(a) Levels Among Hispanic or Latino Individuals Residing in the US.

Importance: Lipoprotein(a) (Lp[a]) is a genetically determined risk-enhancing factor for atherosclerotic cardiovascular disease (ASCVD). The Lp(a) distribution among the diverse Hispanic or Latino community residing in the US has not been previously described, to the authors' knowledge. Objective: To determine the distribution of Lp(a) levels across a large cohort of diverse Hispanic or Latino adults living in the US and by key demographic groups. Design, Setting, and Participants: The Hispanic Community Health Study/Study of Latinos (HCHS/SOL) is a prospective, population-based, cohort study of diverse Hispanic or Latino adults living in the US. At screening, participants aged 18 to 74 years were recruited between 2008 and 2011 from 4 US metropolitan areas (Bronx, New York; Chicago, Illinois; Miami, Florida; San Diego, California). HCHS/SOL included 16 415 noninstitutionalized adults recruited through probability sampling of randomly selected households. The study population represents Hispanic or Latino participants from diverse self-identified geographic and cultural backgrounds: Central American, Cuban, Dominican, Mexican, Puerto Rican, and South American. This study evaluated a subset of HCHS/SOL participants who underwent Lp(a) measurement. Sampling weights and surveys methods were used to account for HCHS/SOL sampling design. Data for this study were analyzed from April 2021 to April 2023. Exposure: Lp(a) molar concentration was measured by a particle-enhanced turbidimetric assay with minimized sensitivity to apolipoprotein(a) size variation. Main Outcome and Measure: Lp(a) quintiles were compared using analysis of variance among key demographic groups, including self-identified Hispanic or Latino background. Median percentage genetic ancestry (Amerindian, European, West African) were compared across Lp(a) quintiles. Results: Lp(a) molar concentration was measured in 16 117 participants (mean [SD] age, 41 [14.8] years; 9680 female [52%]; 1704 Central American [7.7%], 2313 Cuban [21.1%], 1436 Dominican [10.3%], 6395 Mexican [39.1%], 2652 Puerto Rican [16.6%], 1051 South American [5.1%]). Median (IQR) Lp(a) level was 19.7 (7.4-59.7) nmol/L. Across Hispanic or Latino background groups, there was significant heterogeneity in median Lp(a) levels ranging from 12 to 41 nmol/L in those reporting a Mexican vs Dominican background. Median (IQR) West African genetic ancestry was lowest in the first quintile of Lp(a) level and highest in the fifth quintile (5.5% [3.4%-12.9%] and 12.1% [5.0%-32.5%]; respectively; P < .001), whereas the converse was seen for Amerindian ancestry (32.8% [9.9%-53.2%] and 10.7% [4.9%-30.7%], respectively; P < .001). Conclusions and Relevance: Results of this cohort study suggest that differences in Lp(a) level distribution across the diverse US Hispanic or Latino population may carry important implications for the use of Lp(a) level in ASCVD risk assessment for this group. Cardiovascular outcomes data are needed to better understand the clinical impact of differences in Lp(a) levels by Hispanic or Latino background.

Contemporary patterns of lipoprotein(a) testing and associated clinical care and outcomes.

Objective: Elevated lipoprotein(a) [Lp(a)] is associated with atherosclerotic cardiovascular disease, yet little is known about Lp(a) testing patterns in real-world practice. The objective of this analysis was to determine how Lp(a) testing is used in clinical practice in comparison with low density lipoprotein cholesterol (LDL-C) testing alone, and to determine whether elevated Lp(a) level is associated with subsequent initiation of lipid-lowering therapy (LLT) and incident cardiovascular (CV) events. Methods: This is an observational cohort study, based on lab tests administered between Jan 1, 2015 and Dec 31, 2019. We used electronic health record (EHR) data from 11 United States health systems participating in the National Patient-Centered Clinical Research Network (PCORnet). We created two cohorts for comparison: 1) the Lp(a) cohort, of adults with an Lp(a) test and 2) the LDL-C cohort, of 4:1 date- and site-matched adults with an LDL-C test, but no Lp(a) test. The primary exposure was the presence of an Lp(a) or LDL-C test result. In the Lp(a) cohort, we used logistic regression to assess the relationship between Lp(a) results in mass units (< 50, 50-100, and > 100mg/dL) and molar units (<125, 125-250, > 250nmol/L) and initiation of LLT within 3 months. We used multivariable adjusted Cox proportional hazards regression to evaluate these Lp(a) levels and time to composite CV hospitalization, including hospitalization for myocardial infarction, revascularization and ischemic stroke. Results: Overall, 20,551 patients had Lp(a) test results and 2,584,773 patients had LDL-C test results (82,204 included in the matched LDL-C cohort). Compared with the LDL-C cohort, the Lp(a) cohort more frequently had prevalent ASCVD (24.3% vs. 8.5%) and multiple prior CV events (8.6% vs. 2.6%). Elevated Lp(a) was associated with greater odds of subsequent LLT initiation. Elevated Lp(a) reported in mass units was also associated with subsequent composite CV hospitalization [aHR (95% CI): Lp(a) 50-100mg/dL 1.25 (1.02-1.53), p<0.03, Lp(a) > 100mg/dL 1.23 (1.08-1.40), p<0.01]. Conclusion: Lp(a) testing is relatively infrequent in health systems across the U.S. As new therapies for Lp(a) emerge, improved patient and provider education is needed to increase awareness of the utility of this risk marker.

Ivabradine toxicity: a case report.

BACKGROUND: We describe a case of symptomatic bradycardia resulting from ivabradine toxicity by measurement of ivabradine levels, of which there are limited reports in the literature. CASE PRESENTATION: A 43-year-old White female presented with several days of near syncope and dizziness accompanied by a drop in her heart rate to 50 beats per minute. She was taking ivabradine for inappropriate sinus tachycardia. After excluding several other causes of bradycardia, we made the diagnosis of ivabradine toxicity by measurement of serum ivabradine levels, an approach that is currently not clinically available. CONCLUSIONS: Measurement of serum ivabradine levels and knowledge of the pharmacokinetic properties of the drug can be utilized to confirm the diagnosis of ivabradine toxicity.

GlycA, hsCRP differentially associated with MI, ischemic stroke: In the Dallas Heart Study and Multi-Ethnic Study of Atherosclerosis: GlycA, hsCRP Differentially Associated MI, Stroke.

Objective: Inflammatory markers are associated with cardiovascular disease (CVD); however, the ability to specifically predict myocardial infarction (MI) as well as ischemic stroke remains unknown. There has not been a direct comparison of the associations between GlycA and hsCRP and MI and ischemic stroke in a multi-ethnic pooled cohort. Methods: Multi-center, multi-ethnic, population-based community prospective pooled cohort of the Dallas Heart Study (DHS) and Multi-Ethnic Study of Atherosclerosis (MESA). 9,785 participants without baseline CVD enrolled with median follow-up of 13.4 years. Fatal/nonfatal MI and fatal/nonfatal ischemic stroke were assessed separately and then combined. Results: GlycA was moderately associated with hsCRP (R=0.58 in DHS and R=0.55 in MESA). In adjusted Cox proportional hazards models with competing risk adjusted for both inflammatory markers, GlycA was directly associated with MI (HR Q4 vs. Q1 1.90, 95% CI 1.39 to 2.58), whereas hsCRP was not (HR Q4 vs. Q1 0.92, 95% CI 0.70 to 1.21). Conversely, hsCRP was directly associated with ischemic stroke (HR Q4 vs. Q1 1.73, 95% CI 1.15 to 2.59), but GlycA was not (HR Q4 vs. Q1 1.21, 95% CI 0.77 to 1.90). GlycA improved net reclassification for MI and hsCRP did so for ischemic stroke. Conclusions: Although both GlycA and hsCRP were associated with incident CVD, GlycA more strongly predicted incident MI, and hsCRP more strongly predicted ischemic stroke.

Coronary Artery Calcium Score to Refine the Use of PCSK9i in Asymptomatic Individuals: A Multicohort Study.

Background The value of coronary artery calcium (CAC) in the allocation of PCSK9i (proprotein convertase subtilisin/kexin type 9 inhibitors) among individuals without clinically evident atherosclerotic cardiovascular disease (ASCVD) is unknown for indications that do not require confirmed familial hypercholesterolemia. We aimed to assess the ability of CAC to stratify ASCVD risk under 3 non-familial hypercholesterolemia PCSK9i allocation paradigms. Methods and Results We included participants without clinically evident ASCVD from MESA (Multi-Ethnic Study of Atherosclerosis), CARDIA (Coronary Artery Risk Development in Young Adults) study, DHS (Dallas Heart Study), and HNR (Heinz Nixdorf Recall) study. Three PCSK9i eligibility scenarios were defined: a broad scenario informed only by high low-density lipoprotein cholesterol levels (N=567), a restrictive one combining higher low-density lipoprotein cholesterol levels and presence of ≥2 additional risk factors (N=127), and a high-risk scenario where individuals with subclinical organ damage or high estimated risk would be treated to achieve low-density lipoprotein cholesterol <55 mg/dL (N=471). The high-risk scenario had the highest ASCVD event rates (27.8% at 10 years). CAC=0 was observed in 35% participants in the broad scenario, 25% in the restrictive scenario, and 16% in the high-risk scenario. In all, CAC=0 was associated with the lowest incident ASCVD rates at 5 and 10 years, and CAC burden was independently associated with ASCVD events adjusting for traditional risk factors. Conclusions CAC may be used to refine the allocation of PCSK9i, potentially leading to a more conservative use if CAC=0. The value of CAC testing is greater in scenarios that use low-density lipoprotein cholesterol levels and/or traditional risk factors to define PCSK9i eligibility (CAC=0 present in 1 of 3-4 patients), whereas its prevalence is lower when allocation is informed by presence of noncoronary subclinical organ damage.

Association of U.S. birth, duration of residence in the U.S., and atherosclerotic cardiovascular disease risk factors among Asian adults.

Introduction: Prior studies have shown a direct association between U.S. birth and duration of residence with atherosclerotic cardiovascular disease (ASCVD) though, few have specifically focused on Asian Americans. Methods: We utilized cross-sectional data from the 2006 to 2015 National Health Interview Survey. We compared prevalent cardiovascular risk factors and ASCVD among Asian American individuals by U.S. birth and duration of time spent in the U.S. Results: The study sample consisted of 18,150 Asian individuals of whom 20.5 % were Asian Indian, 20.5 % were Chinese, 23.4 % were Filipino, and 35.6 % were of other Asian ethnic groups. The mean (standard error) age was 43.8 (0.21) years and 53 % were women. In multivariable-adjusted logistic regression models, U.S. birth was associated with a higher prevalence odds ratio (95 % confidence interval) of current smoking 1.31 (1.07,1.60), physical inactivity 0.62 (0.54,0.72), obesity 2.26 (1.91,2.69), hypertension 1.33 (1.12,1.58), and CAD 1.96 (1.24,3.11), but lower prevalence of stroke 0.28 (0.11,0.71). Spending greater than 15 years in the U.S. was associated with a higher prevalence of current smoking 1.65 (1.24,2.21), obesity 2.33 (1.57,3.47), diabetes 2.68 (1.17,6.15), and hyperlipidemia 1.72 (1.09,2.71). Conclusion: Heterogeneity exists in cardiovascular risk factor burden among Asian Americans according to Asian ethnicity, U.S. birth, and duration of time living in the U.S.

Independent Association of Lipoprotein(a) and Coronary Artery Calcification With Atherosclerotic Cardiovascular Risk.

BACKGROUND: Elevated lipoprotein(a) [Lp(a)] and coronary artery calcium (CAC) score are individually associated with increased atherosclerotic cardiovascular disease (ASCVD) risk but have not been studied in combination. OBJECTIVES: This study sought to investigate the independent and joint association of Lp(a) and CAC with ASCVD risk. METHODS: Plasma Lp(a) and CAC were measured at enrollment among asymptomatic participants of the MESA (Multi-Ethnic Study of Atherosclerosis) (n = 4,512) and DHS (Dallas Heart Study) (n = 2,078) cohorts. Elevated Lp(a) was defined as the highest race-specific quintile, and 3 CAC score categories were studied (0, 1-99, and ≥100). Associations of Lp(a) and CAC with ASCVD risk were evaluated using risk factor-adjusted Cox regression models. RESULTS: Among MESA participants (61.9 years of age, 52.5% women, 36.8% White, 29.3% Black, 22.2% Hispanic, and 11.7% Chinese), 476 incident ASCVD events were observed during 13.2 years of follow-up. Elevated Lp(a) and CAC score (1-99 and ≥100) were independently associated with ASCVD risk (HR: 1.29; 95% CI: 1.04-1.61; HR: 1.68; 95% CI: 1.30-2.16; and HR: 2.66; 95% CI: 2.07-3.43, respectively), and Lp(a)-by-CAC interaction was not noted. Compared with participants with nonelevated Lp(a) and CAC = 0, those with elevated Lp(a) and CAC ≥100 were at the highest risk (HR: 4.71; 95% CI: 3.01-7.40), and those with elevated Lp(a) and CAC = 0 were at a similar risk (HR: 1.31; 95% CI: 0.73-2.35). Similar findings were observed when guideline-recommended Lp(a) and CAC thresholds were considered, and findings were replicated in the DHS. CONCLUSIONS: Lp(a) and CAC are independently associated with ASCVD risk and may be useful concurrently for guiding primary prevention therapy decisions.

CAC for Risk Stratification Among Individuals With Hypertriglyceridemia Free of Clinical Atherosclerotic Cardiovascular Disease.

OBJECTIVES: In this study, we sought to evaluate whether the coronary artery calcium (CAC) score can enhance current paradigms for risk stratification among individuals with hypertriglyceridemia in primary prevention. The eligibility criteria for icosapent ethyl (IPE) were used as case example. BACKGROUND: Recent trials of atherosclerotic cardiovascular disease (ASCVD) risk-reduction therapies for individuals with hypertriglyceridemia without clinical ASCVD restricted enrollment to participants with diabetes or various other risk factors. These criteria were mirrored in the Food and Drug Administration product label for IPE. METHODS: We pooled 2,345 participants with triglycerides 150 to <500 mg/dL (or >178-<500 mg/dL if not on a statin) and without clinical ASCVD from MESA, CARDIA, the Dallas Heart Study, and the Heinz Nixdorf Recall study. We evaluated the incidence of ASCVD events overall, by IPE eligibility (as defined in the product label), and further stratified by CAC scores (0, >0-100, >100). The number needed to treat for 5 years (NNT5) to prevent 1 event was estimated among IPE-eligible participants, assuming a 21.8% relative risk reduction with IPE. In exploratory analyses, the NNT5 was also estimated among noneligible participants. RESULTS: There was marked heterogeneity in CAC burden overall (45% CAC 0; 24% CAC >100) and across IPE eligibility strata. Overall, 17% of participants were eligible for IPE and 11.9% had ASCVD events within 5 years. Among participants eligible for IPE, 38% had CAC >100, and their event rates were markedly higher (15.9% vs 7.2%) and the NNT5 2.2-fold lower (29 vs 64) than those of the 25% eligible participants with CAC 0. Among the 83% participants not eligible for IPE, 20% had CAC >100, and their 5-year incidence of ASCVD (13.9%) was higher than the overall incidence among IPE-eligible participants. CONCLUSIONS: CAC can improve current risk stratification and therapy allocation paradigms among individuals with hypertriglyceridemia without clinical ASCVD. Future trials of risk-reduction therapies in hypertriglyceridemia could use CAC >100 to enroll a high-risk study sample, with implications for a larger target population.

Comparison of Methods to Estimate Low-Density Lipoprotein Cholesterol in Patients With High Triglyceride Levels.

Importance: Low-density lipoprotein cholesterol (LDL-C) is typically estimated with the Friedewald or Martin/Hopkins equation; however, if triglyceride levels are 400 mg/dL or greater, laboratories reflexively perform direct LDL-C (dLDL-C) measurement. The use of direct chemical LDL-C assays and estimation of LDL-C via the National Institutes of Health Sampson equation are not well validated, and data on the accuracy of LDL-C estimation at higher triglyceride levels are limited. Objective: To compare an extended Martin/Hopkins equation for triglyceride values of 400 to 799 mg/dL with the Friedewald and Sampson equations. Design, Setting, and Participants: This cross-sectional study evaluated consecutive patients at clinical sites across the US with patient lipid distributions representative of the US population in the Very Large Database of Lipids from January 1, 2006, to December 31, 2015, with triglyceride levels of 400 to 799 mg/dL. Data analysis was performed from November 9, 2020, to March 23, 2021. Main Outcomes and Measures: Accuracy in LDL-C classification according to guideline-based categories and absolute errors between estimated LDL-C and dLDL-C levels. Patients were randomly assigned 2:1 to derivation and validation data sets. Levels of dLDL-C were measured by vertical spin-density gradient ultracentrifugation. The LDL-C levels were estimated using the Friedewald method, with a fixed ratio of triglycerides to very low-density lipoprotein cholesterol (VLDL-C ratio of 5:1), extended Martin/Hopkins equation with a flexible ratio, and Sampson equation with VLDL-C estimation by multiple least-squares regression. Results: A total of 111 939 patients (mean [SD] age, 52 [13] years; 65.0% male) with triglyceride levels of 400 to 799 mg/dL were included, representing 2.2% of 5 081 680 patients in the database. Across all individual guideline LDL-C classes (<40, 40-69, 70-99, 100-129, 130-159, 160-189, and ≥190), estimation of LDL-C by the extended Martin/Hopkins equation was most accurate (62.1%) compared with the Friedewald (19.3%) and Sampson (40.4%) equations. In classifying LDL-C levels less than 70 mg/dL across all triglyceride strata, the extended Martin/Hopkins equation was most accurate (67.3%) compared with Friedewald (5.1%) and Sampson (26.4%) equations. In addition, for classifying LDL-C levels less than 40 mg/dL across all triglyceride strata, the extended Martin/Hopkins equation was most accurate (57.2%) compared with the Friedewald (4.3%) and Sampson (14.4%) equations. However, considerable underclassification of LDL-C occurred. The magnitude of error between the Martin/Hopkins equation estimation and dLDL-C was also smaller: at LDL-C levels less than 40 mg/dL, 2.7% of patients had 30 mg/dL or greater differences between dLDL-C and estimated LDL-C using the Martin/Hopkins equation compared with the Friedewald (92.5%) and Sampson (38.7%) equations. Conclusions and Relevance: In this cross-sectional study, the extended Martin/Hopkins equation offered greater LDL-C accuracy compared with the Friedewald and Sampson equations in patients with triglyceride levels of 400 to 799 mg/dL. However, regardless of method used, caution is advised with LDL-C estimation in this triglyceride range.

Cholesterol efflux capacity and its association with prevalent metabolic syndrome in a multi-ethnic population (Dallas Heart Study).

Metabolic syndrome (MetS) is characterized by adiposity and atherogenic dyslipidemia consisting of elevated triglyceride and decreased high density lipoprotein cholesterol (HDL-C) levels however, cholesterol concentration alone does not reflect HDL functionality. Cholesterol efflux capacity (CEC) captures a key anti-atherosclerotic function of HDL; studies linking CEC to MetS have yielded inconsistent findings and lacked racial/ethnic diversity. The aim of this study was to evaluate the association between CEC and MetS in a large multi-ethnic population utilizing two different CEC assays interrogating overlapping but distinct reverse cholesterol transport pathways. A cross-sectional study was performed using the Dallas Heart Study cohort and cholesterol efflux was measured with radiolabeled and fluorescent cholesterol assays. The relationship between CEC and MetS was assessed using multivariable regression analyses. A total of 2241 participants were included (mean age was 50 years; 38% men and 53% Blacks). CEC was independently and inversely associated with MetS irrespective of efflux assay (CEC-radiolabeled, adjusted OR 0·71 [95% CI 0·65-0·80]. CEC-fluorescent, adjusted OR 0·85 [95% CI 0·77-0·94]). Both CEC measures were inversely associated with waist circumference and directly associated with HDL-C but not with other MetS components. There was an interaction by sex but not by race such that the inverse associations between CEC and MetS were somewhat attenuated in men (OR 0·86, 95%CI 0·74-1·01). In this large multi-ethnic cohort, impaired CEC is linked to MetS irrespective of efflux assay and race/ethnicity but less so among men. Future studies are needed to assess whether CEC mediates the atherosclerotic cardiovascular disease risk of MetS.

Associations of High-Sensitivity Troponin and Natriuretic Peptide Levels With Outcomes After Intensive Blood Pressure Lowering: Findings From the SPRINT Randomized Clinical Trial.

Importance: Elevated high-sensitivity cardiac troponin T (hscTnT) and N-terminal pro-B-type natriuretic peptide (NTproBNP) levels are associated with risk of heart failure (HF) and mortality among individuals in the general population. However, it is unknown if this risk is modifiable. Objective: To test the hypothesis that elevated hscTnT and NTproBNP levels would identify individuals with the greatest risk for mortality and HF and the largest benefit associated with intensive systolic blood pressure (SBP) lowering. Design, Setting, and Participants: This is a nonprespecified post hoc analysis of the multicenter, prospective, randomized clinical Systolic Blood Pressure Intervention Trial (SPRINT), conducted from October 20, 2010, to August 20, 2015. A total of 9361 patients without diabetes with increased risk for cardiovascular disease were randomized to receive intensive vs standard SBP lowering. Statistical analysis was performed on an intention-to-treat basis from September 30, 2019, to July 29, 2021. Interventions: Participants were randomized to undergo intensive (<120 mm Hg) or standard (<140 mm Hg) SBP lowering. High-sensitivity cardiac troponin T and NTproBNP levels were measured from stored specimens collected at enrollment, with elevated levels defined as 14 ng/L or more for hscTnT (to convert to micrograms per liter, multiply by 0.001) and 125 pg/mL or more for NTproBNP (to convert to nanograms per liter, multiply by 1.0). Main Outcomes and Measures: The primary outcome of this ancillary study was HF and mortality. Results: Of the 9361 participants enrolled in SPRINT, 8828 (5578 men [63.2%]; mean [SD] age, 68.0 [9.5] years) had measured hscTnT levels and 8836 (5585 men [63.2%]; mean [SD] age, 68.0 [9.5] years) had measured NTproBNP levels; 2262 of 8828 patients (25.6%) had elevated hscTnT levels, 3371 of 8836 patients (38.2%) had elevated NTproBNP, and 1411 of 8828 patients (16.0%) had both levels elevated. Randomization to the intensive SBP group led to a 4.9% (95% CI, 1.7%-7.5%) absolute risk reduction (ARR) over 4 years in death and HF (421 events) for those with elevated hscTnT and a 1.7% (95% CI, 0.7%-2.5%) ARR for those without elevated levels. Similarly, for those with elevated NTproBNP, the ARR for death and HF over 4 years was 4.6% (95% CI, 2.3%-6.5%) vs 1.8% (95% CI, 0.9%-2.5%) in those without elevated levels. For those with elevated levels of both biomarkers, the ARR for death and HF over 4 years was 7.8% (95% CI, 3.3%-11.3%) vs 1.7% (95% CI, 0.8%-2.3%) in those with neither biomarker elevated. No significant treatment group by biomarker category interactions were detected. Conclusions and Relevance: Intensive SBP control led to large absolute differences in death and HF among patients with abnormal hscTnT and NTproBNP levels. These findings demonstrate that risk associated with elevation of these biomarkers is modifiable with intensive BP control. A prospective, randomized clinical trial is needed to evaluate whether these biomarkers may help guide selection of patients for intensive SBP lowering. Trial Registration: ClinicalTrials.gov Identifier: NCT01206062.

Effects of liraglutide on visceral and ectopic fat in adults with overweight and obesity at high cardiovascular risk: a randomised, double-blind, placebo-controlled, clinical trial.

BACKGROUND: Visceral and ectopic fat are key drivers of adverse cardiometabolic outcomes in obesity. We aimed to evaluate the effects of injectable liraglutide 3·0 mg daily on body fat distribution in adults with overweight or obesity without type 2 diabetes at high cardiovascular disease risk. METHODS: In this randomised, double-blind, placebo-controlled, phase 4, single centre trial, we enrolled community-dwelling adults, recruited from the University of Texas Southwestern Medical Center, with BMI of at least 30 kg/m2 or BMI of at least 27 kg/m2 with metabolic syndrome but without diabetes and randomly assigned them, in a 1:1 ratio, to 40 weeks of treatment with once-daily subcutaneous liraglutide 3·0 mg or placebo, in addition to a 500 kcal deficient diet and guideline-recommended physical activity counselling. The primary endpoint was percentage reduction in visceral adipose tissue (VAT) measured with MRI. All randomly assigned participants with a follow-up imaging assessment were included in efficacy analyses and all participants who received at least one dose of study drug were included in the safety analyses. The trial is registered on ClinicalTrials.gov: NCT03038620. FINDINGS: Between July 20, 2017 and Feb 21, 2020 from 235 participants assessed for eligibility, 185 participants were randomly assigned (n=92 liraglutide, n=93 placebo) and 128 (n=73 liraglutide, n=55 placebo) were included in the final analysis (92% female participants, 37% Black participants, 24% Hispanic participants, mean age 50·2 years (SD 9·4), mean BMI 37·7 kg/m2). Mean change in VAT over median 36·2 weeks was -12·49% (SD 9·3%) with liraglutide compared with -1·63% (SD 12·3%) with placebo, estimated treatment difference -10·86% (95% CI -6·97 to -14·75, p<0·0001). Effects seemed consistent across subgroups of age, sex, race-ethnicity, BMI, and baseline prediabetes. The most frequently reported adverse events were gastrointestinal-related (43 [47%] of 92 with liraglutide and 12 [13%] of 93 with placebo) and upper respiratory tract infections (10 [11%] of 92 with liraglutide and 14 [15%] of 93 with placebo). INTERPRETATION: In adults with overweight or obesity at high cardiovascular disease risk, once-daily liraglutide 3·0 mg plus lifestyle intervention significantly lowered visceral adipose tissue over 40 weeks of treatment. Visceral fat reduction may be one mechanism to explain the benefits seen on cardiovascular outcomes in previous trials with liraglutide among patients with type 2 diabetes. FUNDING: NovoNordisk.

Hypertension guidelines and coronary artery calcification among South Asians: Results from MASALA and MESA.

Untreated hypertension may contribute to increased atherosclerotic cardiovascular disease (ASCVD) risk in South Asians (SA). We assessed HTN prevalence among untreated adults free of baseline ASCVD from the MASALA & MESA studies. The proportion of participants who received discordant recommendations regarding antihypertensive pharmacotherapy use by the 2017-ACC/AHA and JNC7 Guidelines across CAC score categories in each race/ethnic group was calculated. Compared with untreated MESA participants (n = 3896), untreated SA (n = 445) were younger (55±8 versus 59±10 years), had higher DBP (73±10 versus 70±10 mmHg), total cholesterol (199±34 versus 196±34 mg/dL), statin use (16% versus 9%) and CAC=0 prevalence (69% versus 58%), with fewer current smokers (3% versus 15%) and lower 10-year-ASCVD-risk (6.4% versus 9.9%) (all p<0.001). A higher proportion of untreated MASALA and MESA participants were diagnosed with hypertension and recommended anti-hypertensive pharmacotherapy according to the ACC/AHA guideline compared to JNC7 (all p<0.001). Overall, discordant BP treatment recommendations were observed in 9% SA, 11% Whites, 15% Blacks, 10% Hispanics, and 9% Chinese-American. In each race/ethnic group, the proportion of participants receiving discordant recommendation increased across CAC groups (all p<0.05), however was highest among SA (40% of participants). Similar to other race/ethnicities, a higher proportion of SA are recommended anti-hypertensive pharmacotherapy by ACC/AHA as compared with JNC7 guidelines. The increase was higher among those with CAC>100 and thus may be better at informing hypertension management in American South Asians.