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BACKGROUND: Numerous studies have linked fine particulate matter (PM2.5) to increased cardiovascular mortality. Less is known how the PM2.5-cardiovascular mortality association varies by use of cardiovascular medications. This study sought to quantify effect modification by statin use status on the associations between long-term exposure to PM2.5 and mortality from any cardiovascular cause, coronary heart disease (CHD), and stroke. METHODS: In this nested case-control study, we followed 1.2 million community-dwelling adults aged ≥66 years who lived in Ontario, Canada from 2000 through 2018. Cases were patients who died from the three causes. Each case was individually matched to up to 30 randomly selected controls using incidence density sampling. Conditional logistic regression models were used to estimate odds ratios (ORs) for the associations between PM2.5 and mortality. We evaluated the presence of effect modification considering both multiplicative (ratio of ORs) and additive scales (the relative excess risk due to interaction, RERI). RESULTS: Exposure to PM2.5 increased the risks for cardiovascular, CHD, and stroke mortality. For all three causes of death, compared with statin users, stronger PM2.5-mortality associations were observed among non-users [e.g. for cardiovascular mortality corresponding to each interquartile range increase in PM2.5, OR = 1.042 (95% CI, 1.032-1.053) vs OR = 1.009 (95% CI, 0.996-1.022) in users, ratio of ORs = 1.033 (95% CI, 1.019-1.047), RERI = 0.039 (95% CI, 0.025-0.050)]. Among users, partially adherent users exhibited a higher risk of PM2.5-associated mortality than fully adherent users. CONCLUSIONS: The associations of chronic exposure to PM2.5 with cardiovascular and CHD mortality were stronger among statin non-users compared to users.

BackgroundWe examined the association between cannabis use and cardiovascular outcomes among the general population, among never-tobacco smokers, and among younger individuals.Methods and resultsThis is a population-based, cross-sectional study of 2016 to 2020 data from the Behavioral Risk Factor Surveillance Survey from 27 American states and 2 territories. We assessed the association of cannabis use (number of days of cannabis use in the past 30 days) with self-reported cardiovascular outcomes (coronary heart disease, myocardial infarction, stroke, and a composite measure of all 3) in multivariable regression models, adjusting for tobacco use and other characteristics in adults 18 to 74 years old. We repeated this analysis among nontobacco smokers, and among men

BACKGROUND: Muscle density is inversely associated with all-cause mortality, but associations with cardiovascular disease (CVD) risk are not well understood. This study evaluated the association between muscle density and muscle area and incident total CVD, coronary heart disease (CHD), and stroke in diverse men and women. METHODS AND RESULTS: Adult participants (N=1869) in the Multi-Ethnic Study of Atherosclerosis Ancillary Body Composition Study underwent computer tomography scans of the L2-L4 region of the abdomen. Muscle was quantified by density (Hounsfield units) and area in cm2. Sex-stratified Cox proportional hazard models assessed associations between incident total CVD, incident CHD, and incident stroke across sex-specific percentiles of muscle area and density, which were entered simultaneously into the model. Mean age for men and women at baseline were 64.1 and 65.1 years, respectively, and median follow-up time was 10.3 years. For men, associations between muscle density and incident CVD were inverse but not significant in fully adjusted models (P trend=0.15). However, there was an inverse association between density and CHD (P trend=0.02; HR, 0.26 for 95th versus 10th percentile), and no association with stroke (P trend=0.78). Conversely, for men, there was a strong positive association between muscle area and incident CVD (HR, 4.19 for 95th versus 10th percentile; P trend

BackgroundMetabolite signatures of long-term alcohol consumption are lacking. To better understand the molecular basis linking alcohol drinking and cardiovascular disease (CVD), we investigated circulating metabolites associated with long-term alcohol consumption and examined whether these metabolites were associated with incident CVD.MethodsCumulative average alcohol consumption (g/day) was derived from the total consumption of beer, wine, and liquor on average of 19 years in 2428 Framingham Heart Study Offspring participants (mean age 56 years, 52% women). We used linear mixed models to investigate the associations of alcohol consumption with 211 log-transformed plasma metabolites, adjusting for age, sex, batch, smoking, diet, physical activity, BMI, and familial relationship. Cox models were used to test the association of alcohol-related metabolite scores with fatal and nonfatal incident CVD (myocardial infarction, coronary heart disease, stroke, and heart failure).ResultsWe identified 60 metabolites associated with cumulative average alcohol consumption (p

AimsTo evaluate the burden of cardiovascular risk factors and disease (CVD) among five Asian groups living in Catalonia (Spain): Indian, Pakistani, Bangladeshi, Filipino, and Chinese.Methods and resultsRetrospective cohort study using the Catalan Health Surveillance System database including 42 488 Pakistanis, 40 745 Chinese, 21 705 Indians, 9544 Filipinos, and 6907 Bangladeshis; and 5.3 million native individuals ('locals'). We estimated the age-adjusted prevalence (as of 31 December 2019) and incidence (during 2019) of diabetes, hypertension, hyperlipidaemia, obesity, tobacco use, coronary heart disease (CHD), cerebrovascular disease, atrial fibrillation, and heart failure (HF). Bangladeshis had the highest prevalence of diabetes (17.4% men, 22.6% women) followed by Pakistanis. Bangladeshis also had the highest prevalence of hyperlipidaemia (23.6% men, 18.3% women), hypertension among women (24%), and incident tobacco use among men. Pakistani women had the highest prevalence of obesity (28%). For CHD, Bangladeshi men had the highest prevalence (7.3%), followed by Pakistanis (6.3%); and Pakistanis had the highest prevalence among women (3.2%). For HF, the prevalence in Pakistani and Bangladeshi women was more than twice that of locals. Indians had the lowest prevalence of diabetes across South Asians, and of CHD across South Asian men, while the prevalence of CHD among Indian women was twice that of local women (2.6% vs. 1.3%). Filipinos had the highest prevalence of hypertension among men (21.8%). Chinese men and women had the lowest prevalence of risk factors and CVD.ConclusionsIn Catalonia, preventive interventions adapted to the risk profile of different Asian immigrant groups are needed, particularly for Bangladeshis and Pakistanis.

ObjectivesThis study sought to assess the relationship between mean vs peak calcified plaque density and their impact on calculating coronary artery calcium (CAC) scores and to compare the corresponding differential prediction of atherosclerotic cardiovascular disease (ASCVD) and coronary heart disease (CHD) mortality.BackgroundThe Agatston CAC score is quantified per lesion as the product of plaque area and a 4-level categorical peak calcium density factor. However, mean calcium density may more accurately measure the heterogenous mixture of lipid-rich, fibrous, and calcified plaque reflective of ASCVD risk.MethodsWe included 10,373 individuals from the CAC Consortium who had CAC >0 and per-vessel measurements of peak calcium density factor and mean calcium density. Area under the curve and continuous net reclassification improvement analyses were performed for CHD and ASCVD mortality to compare the predictive abilities of mean calcium density vs peak calcium density factor when calculating the Agatston CAC score.ResultsParticipants were on average 53.4 years of age, 24.4% were women, and the median CAC score was 68 Agatston units. The average values for mean calcium density and peak calcium density factor were 210 ± 50 HU and 3.1 ± 0.5, respectively. Individuals younger than 50 years of age and/or those with a total plaque area 100.ConclusionMean and peak calcium density may differentially describe plaque composition early in the atherosclerotic process. Mean calcium density performs better than peak calcium density factor when combined with plaque area for ASCVD mortality prediction among persons with Agatston CAC 1-99.

BackgroundAlthough physical activity is generally protective of cardiovascular disease (CVD), less is known about how young adult physical activity relates to premature CVD events. The objective of this study was to determine the association between level and change in physical activity from young adulthood to middle age and incidence of premature CVD events before age 60.MethodsWe analyzed data collected across four urban sites from nine visits over 30 years of follow-up (1985-2016) from the Coronary Artery Risk Development in Young Adults (CARDIA) study, a prospective community-based cohort study of 5115 Black and White women and men aged 18-30 years at baseline (1985-1986). Linear mixed models were used to develop individualized moderate-to-vigorous intensity self-reported physical activity trajectories per participant. Fatal and nonfatal coronary heart disease (CHD), heart failure, and stroke outcomes were analyzed separately and as a combined CVD event outcome.ResultsOverall, physical activity declined in young adults as they progressed through middle age. Lower physical activity scores (per 100 exercise units) in 18 year-olds were associated with higher odds of premature CHD (AOR 1.14, 95% CI 1.02-1.28), heart failure (AOR 1.21, 95% CI 1.05-1.38), stroke (AOR 1.20, 95% CI 1.04-1.39), and any CVD (AOR 1.15, 95% CI 1.06-1.24) events. Each additional annual 1-unit reduction in the physical activity score was associated with a higher annual odds of incident heart failure (1.07, 95% CI 1.02-1.13), stroke (1.06, 95% CI 1.00-1.13), and CVD (1.04, 95% CI 1.01-1.07) events. Meeting the minimum (AOR 0.74, 95% CI 0.0.57-0.96) and twice the minimum (AOR 0.55, 95% CI 0.34-0.91) Department of Health and Human Services physical activity guidelines through follow up was protective of premature CVD events.ConclusionsGiven recent trends in declining physical activity with age and associated premature CVD events, the transition from young adult to midlife is an important time period to promote physical activity.

Background and aimsThe ankle-brachial index (ABI) is a diagnostic test for screening and detecting peripheral artery disease (PAD), as well as a risk enhancer in the AHA/ACC guidelines on the primary prevention of atherosclerotic cardiovascular disease (ASCVD). However, our understanding of the association between ABI and cardiovascular risk in contemporary older populations is limited. Additionally, the prognostic value of ABI among individuals with prior ASCVD is not well understood.MethodsAmong 5,003 older adults at ARIC visit 5 (2011-2013) (4,160 without prior ASCVD [median age 74 years, 38% male], and 843 with ASCVD [median age 76 years, 65% male]), we quantified the association between ABI and the risk of heart failure (HF), and composite coronary heart disease and stroke (CHD/stroke) using multivariable Cox regression models.ResultsOver a median follow-up of 5.5 years, we observed 400 CHD/stroke events and 338 HF cases (242 and 199 cases in those without prior ASCVD, respectively). In participants without a history of ASCVD, a low ABI ≤0.9 (relative to ABI 1.11-1.20) was associated with both CHD/stroke and HF (adjusted hazard ratios 2.40 [95% CI: 1.55-3.71] and 2.23 [1.40-3.56], respectively). In those with prior ASCVD, low ABI was not significantly associated with CHD/stroke, but was with HF (7.12 [2.47-20.50]). The ABI categories of 0.9-1.2 and > 1.3 were also independently associated with increased HF risk. Beyond traditional risk factors, ABI significantly improved the risk discrimination of CHD/stroke in those without ASCVD and HF, regardless of baseline ASCVD.ConclusionsLow ABI was associated with CHD/stroke in those without prior ASCVD and higher risk of HF regardless of baseline ASCVD status. These results support ABI as a risk enhancer for guiding primary cardiovascular prevention and suggest its potential value in HF risk assessment for older adults.

Retinopathy is a microvascular complication of diabetes mellitus (DM); however, it is also increasingly recognized in persons without DM. The microvascular diseases may play a prominent role in coronary heart disease (CHD) development in individuals with DM. We performed the study to evaluate the relation between non-DM retinopathy and CHD and also the association between baseline retinopathy and incidence and progression of CHD in individuals with and without DM. We included 5709 subjects with and without DM from the Multi-Ethnic Study of Atherosclerosis, who had retinal photos and coronary artery calcium score (CACS) available. We studied the association between baseline retinopathy and incidence and progression of coronary artery calcification (CAC) in subjects with and without DM. In DM group, the presence of retinopathy was significantly associated with an increased rate of CAC (RR 1.3 (95% CI [1.02, 1.66]) after adjusting for age, sex, race, follow-up time, and CHD risk factors. In non-DM group, the presence of retinopathy was not significantly associated with increased risk of CAC, however, the interaction between presence of retinopathy and DM status was not statistically significant. Within the DM group with CAC present at baseline, the presence of retinopathy was significantly associated with greater CAC progression (113 Agatson units (AU) greater, (95% CI [51-174]). In the non-DM group with present CAC at baseline; the presence of retinopathy was associated with 24 (95% CI [-0.69, 48.76]) AU higher CAC progression. All findings were adjusted for CHD risk factors. In conclusion, after adjustment for major CHD risk factors, retinopathy was associated with progression of CAC in both DM and non-DM individuals. However, the association was stronger in those with DM.

The relation between elevated lipoprotein(a) and total atherosclerotic cardiovascular disease (ASCVD) residual risk in persons with known cardiovascular disease on statin therapy is not well-established. We examined first and total recurrent ASCVD event risk in statin-treated adults with prior ASCVD. We studied 3,359 adults (mean age 63.6 years, 85.1% male) with prior ASCVD on statin therapy from the AIM-HIGH clinical trial cohort. The first and total ASCVD event rates were calculated by lipoprotein(a) [Lp(a)] categories. Cox regression and Prentice, Williams and Peterson (PWP) models provided hazard ratios (HRs) for ASCVD events over a mean follow-up of 3.3 years, adjusted for age, gender, trial treatment, LDL-C, and other risk factors. A total of 747 events occurred during follow-up, among which 544 were first events. First and total ASCVD event rates were greater with higher Lp(a) levels. Compared with Lp(a)

Background Significant associations have been reported between serum total nonesterified fatty acid (NEFA) concentrations and coronary heart disease (CHD) mortality and incident nonfatal myocardial infarction (MI) in some prospective cohort studies. Little is known about whether individual or subclasses (saturated, polyunsaturated [n-6 and n-3], and trans fatty acids) of serum NEFAs relate to CHD mortality and nonfatal MI. Methods and Results CHS (Cardiovascular Health Study) participants (N=1681) who had no history of MI, angina, or revascularization or were free of MI at baseline (1996-1997) were included. NEFAs were quantified using gas chromatography. Cox regression analysis was used to evaluate associations of 5 subclasses and individual NEFAs with CHD composite (CHD mortality and nonfatal MI), CHD mortality, and incident nonfatal MI. During a median follow-up of 11.7 years, 266 cases of CHD death and 271 cases of nonfatal MI occurred. In the fully adjusted model, no significant associations were identified between individual NEFA and CHD composite. Exploratory analyses indicated that lauric acid (12:0) was negatively associated (hazard ratio [HR], 0.76; 95% CI, 0.59-0.98; P=0.0328) and dihomo-γ-linolenic acid (20:3n-6) was positively associated with CHD mortality (HR, 1.34; 95% CI, 1.02-1.76; P=0.0351). Elaidic acid (18:1n-7t) was positively associated with incident nonfatal MI (HR, 1.46; 95% CI, 1.01-2.12; P=0.0445). No significant associations were observed for NEFA subclass and any outcomes. Conclusions In CHS participants, 2 NEFAs, dihomo-γ-linolenic and elaidic acids, were positively associated with CHD mortality and nonfatal MI, respectively, suggesting potential susceptibility biomarkers for risks of CHD mortality and nonfatal MI.

RATIONALE: Susceptibility to VT/VF (ventricular tachycardia/fibrillation) is difficult to predict in patients with ischemic cardiomyopathy either by clinical tools or by attempting to translate cellular mechanisms to the bedside. OBJECTIVE: To develop computational phenotypes of patients with ischemic cardiomyopathy, by training then interpreting machine learning of ventricular monophasic action potentials (MAPs) to reveal phenotypes that predict long-term outcomes. METHODS AND RESULTS: We recorded 5706 ventricular MAPs in 42 patients with coronary artery disease and left ventricular ejection fraction ≤40% during steady-state pacing. Patients were randomly allocated to independent training and testing cohorts in a 70:30 ratio, repeated K=10-fold. Support vector machines and convolutional neural networks were trained to 2 end points: (1) sustained VT/VF or (2) mortality at 3 years. Support vector machines provided superior classification. For patient-level predictions, we computed personalized MAP scores as the proportion of MAP beats predicting each end point. Patient-level predictions in independent test cohorts yielded c-statistics of 0.90 for sustained VT/VF (95% CI, 0.76-1.00) and 0.91 for mortality (95% CI, 0.83-1.00) and were the most significant multivariate predictors. Interpreting trained support vector machine revealed MAP morphologies that, using in silico modeling, revealed higher L-type calcium current or sodium-calcium exchanger as predominant phenotypes for VT/VF. CONCLUSIONS: Machine learning of action potential recordings in patients revealed novel phenotypes for long-term outcomes in ischemic cardiomyopathy. Such computational phenotypes provide an approach which may reveal cellular mechanisms for clinical outcomes and could be applied to other conditions.

BackgroundCoronary artery calcium (CAC) predicts atherosclerotic cardiovascular disease (ASCVD) events, inclusive of coronary heart disease (CHD) and stroke, and is a decision-making aid for primary prevention. The predictive value of CAC categories for CHD and stroke separately and across sex and race groups of an asymptomatic population is unclear.MethodsWhite, Black, and Hispanic participants of MESA (Multi-Ethnic Study of Atherosclerosis) and DHS (Dallas Heart Study) underwent CAC measurement at enrollment and were followed for incident ASCVD events. Ten-year CHD-to-stroke incidence ratios across CAC score categories 0, 1 to 99, and ≥100 were assessed. Associations of CAC with incident CHD and stroke events were evaluated using multivariable-adjusted Cox models and multiplicative interactions of CAC with sex/race were tested.ResultsAmong 7042 participants (mean age, 57 years, 54% women, 36% Black, 23% Hispanic, 49% CAC=0, 19% CAC ≥100), 574 incident ASCVD events (333 CHD and 241 stroke) were observed over 12.3-year follow-up. Ten-year CHD-to-stroke incidence ratio increased significantly across CAC categories in men, women, Whites, Blacks, and Hispanics (all P

BackgroundCommon chromosome 9p21 single nucleotide polymorphisms (SNPs) increase coronary heart disease risk, independent of traditional lipid risk factors. However, lipids comprise large numbers of structurally related molecules not measured in traditional risk measurements, and many have inflammatory bioactivities. Here, we applied lipidomic and genomic approaches to 3 model systems to characterize lipid metabolic changes in common Chr9p21 SNPs, which confer ≈30% elevated coronary heart disease risk associated with altered expression of ANRIL, a long ncRNA.MethodsUntargeted and targeted lipidomics was applied to plasma from NPHSII (Northwick Park Heart Study II) homozygotes for AA or GG in rs10757274, followed by correlation and network analysis. To identify candidate genes, transcriptomic data from shRNA downregulation of ANRIL in HEK-293 cells was mined. Transcriptional data from vascular smooth muscle cells differentiated from induced pluripotent stem cells of individuals with/without Chr9p21 risk, nonrisk alleles, and corresponding knockout isogenic lines were next examined. Last, an in-silico analysis of miRNAs was conducted to identify how ANRIL might control lysoPL (lysophosphospholipid)/lysoPA (lysophosphatidic acid) genes.ResultsElevated risk GG correlated with reduced lysoPLs, lysoPA, and ATX (autotaxin). Five other risk SNPs did not show this phenotype. LysoPL-lysoPA interconversion was uncoupled from ATX in GG plasma, suggesting metabolic dysregulation. Significantly altered expression of several lysoPL/lysoPA metabolizing enzymes was found in HEK cells lacking ANRIL. In the vascular smooth muscle cells data set, the presence of risk alleles associated with altered expression of several lysoPL/lysoPA enzymes. Deletion of the risk locus reversed the expression of several lysoPL/lysoPA genes to nonrisk haplotype levels. Genes that were altered across both cell data sets were DGKA, MBOAT2, PLPP1, and LPL. The in-silico analysis identified 4 ANRIL-regulated miRNAs that control lysoPL genes as miR-186-3p, miR-34a-3p, miR-122-5p, and miR-34a-5p.ConclusionsA Chr9p21 risk SNP associates with complex alterations in immune-bioactive phospholipids and their metabolism. Lipid metabolites and genomic pathways associated with coronary heart disease pathogenesis in Chr9p21 and ANRIL-associated disease are demonstrated.

BackgroundThe purpose of this study is to determine if a new score calculated with coronary artery calcium (CAC) density and volume is associated with total coronary artery plaque burden and composition on coronary CT angiography (CCTA) compared to the Agatston score (AS).MethodsWe identified 347 men enrolled in the Multicenter AIDS cohort study who underwent contrast and non-contrast CCTs, and had CAC>0. CAC densities (mean Hounsfield Units [HU]) per plaque) and volumes on non-contrast CCT were measured. A Density-Volume Calcium score was calculated by multiplying the plaque volume by a factor based on the mean HU of the plaque (4, 3, 2 and 1 for 130-199, 200-299, 300-399, and ≥400HU). Total Density-Volume Calcium score was determined by the sum of these individual scores. The semi-quantitative partially calcified and total plaque scores (PCPS and TPS) on CCTA were calculated. The associations between Density-Volume Calcium score, PCPS and TPS were examined.ResultsOverall, 2879 CAC plaques were assessed. Multivariable linear regression models demonstrated a stronger association between the log Density-Volume Calcium score and both the PCPS (β 0.99, 95%CI 0.80-1.19) and TPS (β 2.15, 95%CI 1.88-2.42) compared to the log of AS (PCPS: β 0.77, 95%CI 0.61-0.94; TPS: β 1.70, 95%CI 1.48-1.94). Similar results were observed for numbers of PC or TP segments.ConclusionThe new CAC score weighted towards lower density demonstrated improved correlation with semi-quantitative PC and TP burden on CCTA compared to the traditional AS, which suggests it has utility as an alternative measure of atherosclerotic burden.

BackgroundThe majority of people with chronic kidney disease (CKD) are unaware of their kidney disease. Assessing the clinical significance of increasing CKD awareness has critical public health and healthcare delivery implications. Whether CKD awareness among persons with CKD is associated with longitudinal health behaviors, disease management, and health outcomes is unknown.MethodsWe analyzed data from participants with CKD in the REasons for Geographic And Racial Differences in Stroke study, a national, longitudinal, population-based cohort. Our predictor was participant CKD awareness. Outcomes were (1) health behaviors (smoking avoidance, exercise, and nonsteroidal anti-inflammatory drug use); (2) CKD management indicators (angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use, statin use, systolic blood pressure, fasting blood glucose, and body mass index); (3) change in estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR); and (4) health outcomes (incident end-stage kidney disease [ESKD], coronary heart disease [CHD], stroke, and death). Logistic and linear regressions were used to examine the association of baseline CKD awareness with outcomes of interest, adjusted for CKD stage and participant demographic and clinical factors.ResultsOf 6,529 participants with baseline CKD, 285 (4.4%) were aware of their CKD. Among the 3,586 participants who survived until follow-up (median 9.5 years), baseline awareness was not associated with subsequent odds of health behaviors, CKD management indicators, or changes in eGFR and UACR in adjusted analyses. Baseline CKD awareness was associated with increased risk of ESKD (adjusted hazard ratio [aHR] 1.44; 95% CI 1.08-1.92) and death (aHR 1.18; 95% CI 1.00-1.39), but not with subsequent CHD or stroke, in adjusted models.ConclusionsIndividuals aware of their CKD were more likely to experience ESKD and death, suggesting that CKD awareness reflects disease severity. Most persons with CKD, including those that are high-risk, remain unaware of their CKD. There was no evidence of associations between baseline CKD awareness and longitudinal health behaviors, CKD management indicators, or eGFR decline and albuminuria.

BackgroundEpidemiological evidence has demonstrated a positive association between artificially sweetened beverage (ASB) and sugar-sweetened beverage (SSB) consumption and type 2 diabetes (T2D) risk. However, research informing this topic in young adults is limited.ObjectiveThis study examined the association between ASB, SSB, and total sweetened beverage (TSB; combined ASB and SSB) consumption and T2D risk in young adults.MethodsA prospective analysis of 4719 Black and White men and women aged 18-30 y at baseline was conducted from the Coronary Artery Risk Development in Young Adults (CARDIA) study. Each participant's beverage intake was assessed using the CARDIA Diet History at baseline and at study Years 7 and 20. Multivariable Cox proportional hazards regression models were used to examine cumulative average ASB, SSB, and TSB intakes and risk of T2D.ResultsDuring the 30-y follow-up period, 680 participants developed T2D. ASB consumption was associated with a 12% greater risk of T2D per serving/day (HR 1.12, 95% CI 1.04-1.20) in a model adjusted for lifestyle factors, diet quality, and dieting behavior. Further adjustments for baseline BMI (HR 1.07, 95% CI 0.99-1.14) and weight change during follow-up (HR 1.04, 95% CI 0.97-1.12) attenuated the association. SSB and TSB consumption as continuous variables per 1 serving/day of intake were associated with 6% and 5% increased risks of T2D, respectively (HRSSB 1.06, 95% CI 1.01-1.10; HRTSB 1.05, 95% CI 1.01-1.09), in the model accounting for lifestyle factors, dieting behavior, baseline BMI, and weight change. Results were consistent when the exposures were modeled in categories of consumption and quintiles.ConclusionsIn young adults, long-term ASB, SSB, and TSB consumption were associated with increased risks of T2D. However, the estimates for ASB were attenuated when accounting for weight changes.

BackgroundDNA methylation is implicated in coronary heart disease (CHD), but current evidence is based on small, cross-sectional studies. We examined blood DNA methylation in relation to incident CHD across multiple prospective cohorts.MethodsNine population-based cohorts from the United States and Europe profiled epigenome-wide blood leukocyte DNA methylation using the Illumina Infinium 450k microarray, and prospectively ascertained CHD events including coronary insufficiency/unstable angina, recognized myocardial infarction, coronary revascularization, and coronary death. Cohorts conducted race-specific analyses adjusted for age, sex, smoking, education, body mass index, blood cell type proportions, and technical variables. We conducted fixed-effect meta-analyses across cohorts.ResultsAmong 11 461 individuals (mean age 64 years, 67% women, 35% African American) free of CHD at baseline, 1895 developed CHD during a mean follow-up of 11.2 years. Methylation levels at 52 CpG (cytosine-phosphate-guanine) sites were associated with incident CHD or myocardial infarction (false discovery rate

OBJECTIVES:This study evaluated whether lipoprotein apheresis produces immediate changes in resting perfusion in subjects with severe hypercholesterolemia, and whether there is a difference in the response between peripheral and coronary microcirculations. BACKGROUND:Lipoprotein apheresis is used in patients with severe hypercholesterolemia to reduce plasma levels of low-density lipoprotein cholesterol. METHODS:Quantitative contrast-enhanced ultrasound perfusion imaging of the myocardium at rest and skeletal muscle at rest and during calibrated contractile exercise was performed before and immediately after lipoprotein apheresis in 8 subjects with severe hypercholesterolemia, 7 of whom had a diagnosis of familial hypercholesterolemia. Myocardial perfusion imaging was also performed in 14 normal control subjects. Changes in myocardial work and left ventricular function were assessed by echocardiography. Ex vivo ovine coronary and femoral artery ring tension assays were assessed in the presence of pre- and post-apheresis plasma. RESULTS:Apheresis acutely decreased low-density lipoprotein cholesterol (234.9 ± 103.2 mg/dl vs. 67.1 ± 49.5 mg/dl; p < 0.01) and oxidized phospholipid on apolipoprotein B-100 (60.2 ± 55.2 nmol/l vs. 47.0 ± 24.5 nmol/l; p = 0.01), and acutely increased resting myocardial perfusion (55.1 [95% confidence interval: 77.2 to 73.1] IU/s vs. 135 [95% confidence interval: 81.2 to 189.6] IU/s; p = 0.01), without changes in myocardial work. Myocardial longitudinal strain improved in those subjects with reduced pre-apheresis function. Skeletal muscle perfusion at rest and during contractile exercise was unchanged by apheresis. Acetylcholine-mediated dilation of ex vivo ovine coronary but not femoral arteries was impaired in pre-apheresis plasma and was completely reversed in post-apheresis plasma. CONCLUSIONS:Lipoprotein apheresis produces an immediate improvement in coronary microvascular function, which increases myocardial perfusion and normalizes endothelial-dependent vasodilation. These changes are not observed in the periphery. (Acute Microvascular Changes With LDL Apheresis; NCT02388633).

BackgroundPublic statements about the effect of smoking on cardiovascular disease are predominantly based on investigations of coronary heart disease (CHD) and stroke, although smoking is recognized as a strong risk factor for peripheral artery disease (PAD). No study has comprehensively compared the long-term association of cigarette smoking and its cessation with the incidence of 3 major atherosclerotic diseases (PAD, CHD, and stroke).ObjectivesThe aim of this study was to quantify the long-term association of cigarette smoking and its cessation with the incidence of the 3 outcomes.MethodsA total of 13,355 participants aged 45 to 64 years in the ARIC (Atherosclerosis Risk In Communities) study without PAD, CHD, or stroke at baseline (1987 to 1989) were included. The associations of smoking parameters (pack-years, duration, intensity, and cessation) with incident PAD were quantified and contrasted with CHD and stroke using Cox models.ResultsOver a median follow-up of 26 years, there were 492 PAD cases, 1,798 CHD cases, and 1,106 stroke cases. A dose-response relationship was identified between pack-years of smoking and 3 outcomes, with the strongest results for PAD. The pattern was consistent when investigating duration and intensity separately. A longer period of smoking cessation was consistently related to lower risk of PAD, CHD, and stroke, but a significantly elevated risk persisted up to 30 years following smoking cessation for PAD and up to 20 years for CHD.ConclusionsAll smoking measures showed significant associations with 3 major atherosclerotic diseases, with the strongest effect size for incident PAD. The risk due to smoking lasted up to 30 years for PAD and 20 years for CHD. Our results further highlight the importance of smoking prevention and early smoking cessation, and indicate the need for public statements to take PAD into account when acknowledging the impact of smoking on overall cardiovascular health.

ObjectiveGlycA, a novel NMR biomarker of inflammation, has been associated with incident cardiovascular disease (CVD) in the general population, but its association with CVD among HIV-infected individuals is unknown. We examined the associations between GlycA and subclinical coronary plaque among HIV-infected and HIV-uninfected men participating in Multicenter AIDS Cohort Study (MACS).DesignCross-sectional analysis of 935 men with plasma measurement of GlycA and noncontrast cardiac computed tomography (CT) and/or coronary CT angiography.MethodsWe used multivariable Poisson and linear regression to assess associations of GlycA with prevalent coronary atherosclerosis and plaque extent, respectively.ResultsMean ± SD age was 54 ± 7 years; 31% were black; 63% HIV-infected. GlycA levels were higher in HIV-infected compared with HIV-uninfected men (397 ± 68 vs. 380 ± 60 μmol/l, P = 0.0001) and higher for men with detectable viral load vs. undetectable (413 ± 79 vs. 393 ± 65 μmol/l, P = 0.004). After adjusting for HIV serostatus, demographic and CVD risk factors, every 1SD increment in GlycA level was associated with a higher prevalence of coronary artery calcium (CAC >0) [prevalence ratio 1.09 (95% CI 1.03-1.15)] and coronary stenosis at least 50% [1.20 (1.02-1.41)]. These associations were not significantly altered after adjusting for traditional inflammatory biomarkers or differ by HIV serostatus. Among men with plaque, GlycA was positively associated with the extent of CAC and total plaque.ConclusionHIV infection was associated with higher GlycA levels. In both HIV-infected and HIV-uninfected individuals, GlycA was significantly associated with several measures of subclinical coronary atherosclerosis, independent of other CVD risk factors and inflammatory biomarkers. These findings suggest the potential role of GlycA in CVD risk stratification among HIV patients.

BACKGROUND AND AIMS: Constipation is one of the most frequent symptoms encountered in daily clinical practice and is implicated in the development of atherosclerosis, potentially through altered gut microbiota. However, little is known about its association with incident cardiovascular events. METHODS: In a nationally representative cohort of 3,359,653 US veterans with an estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 between October 1, 2004 and September 30, 2006 (baseline period), with follow-up through 2013, we examined the association of constipation status (absence or presence; defined using diagnostic codes and laxative use) and laxative use (none, one, or ≥2 types of laxatives) with all-cause mortality, incident coronary heart disease (CHD), and incident ischemic stroke. RESULTS: Among 3,359,653 patients, 237,855 (7.1%) were identified as having constipation. After multivariable adjustments for demographics, prevalent comorbidities, medications, and socioeconomic status, patients with (versus without) constipation had 12% higher all-cause mortality (hazard ratio [HR], 1.12; 95% CI, 1.11-1.13), 11% higher incidence of CHD (HR, 1.11; 95% CI, 1.08-1.14), and 19% higher incidence of ischemic stroke (HR, 1.19; 95% CI, 1.15-1.22). Patients with one and ≥2 (versus none) types of laxatives experienced a similarly higher risk of all-cause mortality (HRs [95% CI], 1.15 [1.13-1.16] and 1.14 [1.12-1.15], respectively), incident CHD (HRs [95% CI], 1.11 [1.07-1.15] and 1.10 [1.05-1.15], respectively) and incident ischemic stroke (HRs [95% CI], 1.19 [1.14-1.23] and 1.21 [1.16-1.26], respectively). CONCLUSIONS: Constipation status and laxative use are independently associated with higher risk of all-cause mortality and incident CHD and ischemic stroke.

BackgroundEndothelin-1 (ET-1) has been implicated in the development of post-heart transplantation (HT) cardiac allograft vasculopathy (CAV), but has not been well studied in humans.Methods and resultsIn 90 HT patients, plasma ET-1 was measured within 8 weeks after HT (baseline) via a competitive enzyme-linked immunosorbent assay. Three-dimensional volumetric intravascular ultrasound of the left anterior descending artery was performed at baseline and at 1 year. Accelerated CAV (lumen volume loss) was defined with the 75th percentile as a cutoff. Patients were followed beyond the first year after HT for late death or retransplantation. A receiver operating characteristic (ROC) curve demonstrated that a baseline ET-1 concentration of 1.75 pg/mL provided the best accuracy for diagnosis of accelerated CAV at 1 year (area under the ROC curve 0.69, 95% confidence interval [CI] 0.57-0.82; P = .007). In multivariate logistic regression, a higher baseline ET-1 concentration was independently associated with accelerated CAV (odds ratio [OR] 2.13, 95% CI 1.15-3.94; P = .01); this relationship persisted when ET-1 was dichotomized at 1.75 pg/mL (OR 4.88, 95% CI 1.69-14.10; P = .003). Eighteen deaths occurred during a median follow-up period of 3.99 (interquartile range 2.51-9.95) years. Treated as a continuous variable, baseline ET-1 was not associated with late mortality in multivariate Cox regression (hazard ratio [HR] 1.22, 95% CI 0.72-2.05; P = .44). However, ET-1 >1.75 pg/mL conferred a significantly lower cumulative event-free survival on Kaplan-Meier analysis (P = .047) and was independently associated with late mortality (HR 2.94, 95% CI 1.12-7.72; P = .02).ConclusionsElevated ET-1 early after HT is an independent predictor of accelerated CAV and late mortality, suggesting that ET-1 has durable prognostic value in the HT arena.

Background The risk of coronary heart disease remains low in Japan, although distributions of several coronary risk factors have become comparable with those in the United States. We prospectively compared coronary atherosclerosis burden, measured with coronary artery calcium (CAC) progression, between men in the 2 countries. Methods In 2 population-based samples of 1712 US White, Black, Hispanic, Chinese men (baseline, 2000-2002) and 697 Japanese men in Japan (2006-2008) aged 45-74 years without clinical cardiovascular disease, we quantified CAC progression by serial computed tomography with medians of 3.4 and 5.2 years between scans, respectively. Results Among White, Black, Hispanic, Chinese, and Japanese men free of baseline CAC, CAC incidence was observed in 35.2%, 26.9%, 29.2%, 18.9%, and 29.2%, respectively. After adjustment for times between scans, demographics, behaviors, coronary risk factors, and their changes between scans, White men had significantly higher CAC incidence than Japanese men (relative risk, 1.68; 95% CI, 1.13-2.50). Among those with detectable baseline CAC, after similar adjustments, all the US race/ethnic groups had significantly greater annual changes in CAC score (mean [95% CI]: 39.4 [35.2-43.6] for White, 26.9 [21.4-32.4] for Black, 30.6 [24.7-36.5] for Hispanic, and 30.2 [22.6-37.8] for Chinese men) than Japanese men (15.9 [10.1-21.8]). Conclusions We found a higher CAC incidence among US White men and greater increases in existing CAC among all the US race/ethnic groups than among Japanese men in Japan. These differences persisted despite adjustment for differences in coronary risk factors.

BACKGROUND:Mendelian randomization data suggest that the genetic determinants of lifetime higher triglyceride-rich lipoprotein-cholesterol (TRL-C) are causally related to cardiovascular disease and therefore a potential therapeutic target. The relevance of TRL-C among patients receiving statins is unknown. We assessed the relationship between TRL-C and cardiovascular risk, and whether this risk was modifiable among patients receiving statins in the TNT trial (Treating to New Targets). METHODS:Patients with coronary heart disease and low-density lipoprotein cholesterol (LDL-C) 130 to 250 mg/dL entered an 8-week run-in phase with atorvastatin 10 mg/d (ATV10). After this period, participants with LDL-C

OBJECTIVE:Results of the use of the transluminal attenuation gradient (TAG) at coronary CT angiography (CCTA) to predict hemodynamically significant disease vary widely. This study tested whether diagnostic performance of TAG to predict fractional flow reserve (FFR) ≤ 0.8 is improved when applied separately to subsets of coronary arteries that carry similar physiological flow. METHODS:28 patients with 64 × 0.5 mm CCTA and invasive FFR in ≥1 major coronary artery were retrospectively evaluated. Two readers assessed TAG in each artery. The receiver operating characteristic (ROC) area under the curve (AUC) was used to assess the diagnostic performance of TAG to detect hemodynamically significant disease following a clinical use rule [negative: FFR > 0.8 or ≤ 25% diameter stenosis (DS) at invasive catheter angiography; positive: FFR ≤ 0.8 or ≥ 90% DS at invasive catheter angiography]. ROC AUC was compared for all arteries pooled together, vs separately for arteries carrying similar physiological flow (Group 1: all left anterior descending plus right-dominant left circumflex; Group 2: right-dominant RCA plus left/co-dominant left circumflex). RESULTS:Of the 84 arteries, 30 had FFR measurements, 30 had ≤25% DS and 13 had ≥90% DS. 11 arteries with 26-89% DS and no FFR measurement were excluded. TAG interobserver reproducibility was excellent (Pearson r = 0.954, Bland-Altman bias: 0.224 Hounsfield unit cm-1). ROC AUC to detect hemodynamically significant disease was higher when considering arteries separately (Group 1 AUC = 0.841, p = 0.039; Group 2 AUC = 0.840, p = 0.188), than when pooling all arteries together (AUC = 0.661). CONCLUSION:Incorporating information on the physiology of coronary flow via the particular vessel interrogated and coronary dominance may improve the accuracy of TAG, a simple measurement that can be quickly performed at the time of CCTA interpretation to detect hemodynamically significant stenosis in individual coronary arteries. Advances in knowledge: The interpretation of TAG may benefit by incorporating information regarding which coronary artery is being interrogated.

BackgroundMeta-analyses of general population studies report mean low-density lipoprotein cholesterol (LDL-C) reductions of 30% to

ObjectivesTo determine whether severity of non-alcoholic fatty liver disease (NAFLD) and liver fibrosis quantitatively assessed in individuals with diabetes mellitus (DM)-2 correlate with increased coronary heart disease (CHD) risk using non-invasive markers.MethodsWe conducted a single-centre, prospective, cross-sectional study in 100 consecutive diabetic individuals without known CHD recruited between March 2013 and September 2014. History, physical examination, serum markers, cardiac computed tomography (CT), magnetic resonance (MR) imaging-estimated proton density fat fraction (PDFF) and MR elastography (MRE) were obtained for 95 participants. Written informed consent was provided. Institutional review board approved this study. Spearman rank correlation was performed to assess for correlations. Multiple linear regression model determined independent predictors of epicardial adipose tissue (EAT) volume.ResultsA p value < 0.05 determined statistical significance. The EAT volume was higher in the NAFLD group, defined as MR-imaging PDFF ≥ 5 %, compared to the non-NAFLD group (126.5 ml (IQR 80.9) versus 85.4 ml (IQR 44.7), p=0.002). MR imaging-PDFF correlated with EAT (r=0.42, p < 0.0001). MR imaging-PDFF and liver fibrosis were independently associated with EAT.ConclusionsHigher liver fat content and liver fibrosis may portend worse cardiovascular risk in diabetics.Key points• EAT volume is higher in diabetic individuals with NAFLD. • Liver fat content is positively correlated with EAT. • Liver fat content and liver fibrosis were independently associated with EAT. • Higher liver fat content and fibrosis may adversely affect cardiovascular risk.

It is not known whether the concentration of high-density lipoprotein (HDL) cholesterol is related to renal function in statin-treated patients. We therefore investigated whether HDL cholesterol levels predicted renal function in atorvastatin-treated patients in the TNT (Treating to New Targets) trial. A total of 9542 participants were included in this analysis. Renal function was assessed by estimated glomerular filtration rate (eGFR). HDL cholesterol levels at month 3 were used as this is the time point at which on-treatment HDL cholesterol levels became stable. Among 6319 participants with a normal eGFR (≥60 mL/min per 1.73 m2) at baseline, higher HDL cholesterol levels at month 3 were significantly associated with lower risk of decline in eGFR (ie, having eGFR

BACKGROUND:Mortality in end-stage renal disease (ESRD) occurs predominantly from cardiovascular disease (CVD) and sudden cardiac death (SCD). Obstructive sleep apnea (OSA) is characterized by periodic airflow limitation associated with sleep arousal and oxygen desaturation and is prevalent in patients with ESRD. Whether OSA increases the risk for SCD, cardiovascular and all-cause mortality among hemodialysis patients remains unknown. METHODS:In a prospective cohort of 558 incident hemodialysis patients, we examined the association of OSA with all-cause mortality, cardiovascular mortality, and SCD using Cox proportional hazards models controlling for traditional CVD risk factors. RESULTS:Sixty-six incident hemodialysis patients (12%) had OSA. Mean age (56 years) and percentage of males (56%) were identical in OSA and no-OSA groups. Fewer African Americans had OSA than non-African Americans (9 vs. 18%, respectively). Participants with OSA had higher body-mass index, Charlson comorbidity score, and left ventricular mass index and greater prevalence of diabetes and coronary artery disease. During 1,080 person-years of follow-up, 104 deaths occurred, 29% of which were cardiovascular. OSA was associated with a higher risk of all-cause mortality (HR 1.90 [95% CI 1.04-3.46]) and cardiovascular mortality (HR 3.62 [95% CI 1.36-9.66]) after adjusting for demographics and body-mass index. OSA was associated with a higher risk of SCD after adjusting for demographics (HR 3.28 [95% CI 1.12-9.57]) and multiple cardiovascular risk factors. CONCLUSIONS:Incident hemodialysis patients with OSA are at increased risk of all-cause and cardiovascular mortality and SCD. Future studies should assess the impact of screening for OSA and OSA-targeted interventions on mortality in ESRD.

IMPORTANCE: Although the risk of type 2 diabetes is considered to be equivalent to coronary heart disease (CHD) risk, there is considerable heterogeneity among individuals for CHD and atherosclerotic cardiovascular disease (ASCVD) risk. It is not known whether coronary artery calcium (CAC) assessment at baseline in individuals with established metabolic syndrome (MetS) or diabetes identifies CHD and ASCVD prognostic indicators during a long follow-up period. OBJECTIVE: To compare improvement in long-term prognostication of incident CHD and ASCVD using CAC scores among those with diabetes, MetS, or neither condition. DESIGN, SETTING, AND PARTICIPANTS: This study included participants from the Multi-Ethnic Study of Atherosclerosis (MESA), a prospective cohort study of 6814 males and females aged 45 to 84 years without known CVD from 4 race/ethnicity groups (white [38.5%], African American [27.5%], Hispanic [22.1%], and Chinese [11.9%]) recruited from 6 US communities from July 2000 through August 2002. Follow-up for each participant extended to the first occurrence of an incident event, other death, loss to follow-up, or the last follow-up call through December 31, 2013. Data analysis was performed from June 1, 2016, to September 12, 2017. Cox proportional hazards regression models were used to estimate hazard ratios (HRs). Area under the receiver operator characteristic curve and net reclassification improvement were used to compare incremental contributions of CAC score when added to the Framingham risk score, ethnicity/race, and socioeconomic status. MAIN OUTCOMES AND MEASURES: CHD events, including myocardial infarction, resuscitated cardiac arrest, or CHD death. RESULTS: Of 6814 MESA participants, 6751 had complete risk factor and follow-up data and were included in this study (mean [SD] age, 62.2 [10.2] years; 3186 [47.2%] male). A total of 881 (13.0%) had diabetes, 1738 (25.7%) had MetS, and 4132 (61.2%) had neither condition. After 11.1 mean years of follow-up, CHD events occurred in 84 participants with diabetes (135 ASCVD events), 115 with MetS (175 ASCVD events), and 157 with neither (250 ASCVD events). The CAC score was independently associated with incident CHD in multivariable analyses in those with diabetes (HR, 1.30; 95% CI, 1.19-1.43), MetS (HR, 1.30; 95% CI, 1.20-1.41), and neither condition (HR, 1.37; 95% CI, 1.27-1.47). For incident CHD, net reclassification improvement with addition of CAC score was 0.23 (95% CI, 0.10-0.37) in those with diabetes, 0.22 (95% CI, 0.09-0.35) in those with MetS, and 0.25 (95% CI, 0.15-0.35) in those with neither condition. The CAC score was also a prognostic indicator of CHD and ASCVD after controlling for diabetes duration of 10 years or longer at baseline, insulin use, and glycemic control. CONCLUSIONS AND RELEVANCE: In a large multiethnic cohort, the addition of CAC score to global risk assessment was associated with significantly improved risk classification in those with MetS and diabetes, even if diabetes duration was longer than a decade, suggesting a role for the CAC score in risk assessment in such patients.

ImportanceAlthough the risk of type 2 diabetes is considered to be equivalent to coronary heart disease (CHD) risk, there is considerable heterogeneity among individuals for CHD and atherosclerotic cardiovascular disease (ASCVD) risk. It is not known whether coronary artery calcium (CAC) assessment at baseline in individuals with established metabolic syndrome (MetS) or diabetes identifies CHD and ASCVD prognostic indicators during a long follow-up period.ObjectiveTo compare improvement in long-term prognostication of incident CHD and ASCVD using CAC scores among those with diabetes, MetS, or neither condition.Design, setting, and participantsThis study included participants from the Multi-Ethnic Study of Atherosclerosis (MESA), a prospective cohort study of 6814 males and females aged 45 to 84 years without known CVD from 4 race/ethnicity groups (white [38.5%], African American [27.5%], Hispanic [22.1%], and Chinese [11.9%]) recruited from 6 US communities from July 2000 through August 2002. Follow-up for each participant extended to the first occurrence of an incident event, other death, loss to follow-up, or the last follow-up call through December 31, 2013. Data analysis was performed from June 1, 2016, to September 12, 2017. Cox proportional hazards regression models were used to estimate hazard ratios (HRs). Area under the receiver operator characteristic curve and net reclassification improvement were used to compare incremental contributions of CAC score when added to the Framingham risk score, ethnicity/race, and socioeconomic status.Main outcomes and measuresCHD events, including myocardial infarction, resuscitated cardiac arrest, or CHD death.ResultsOf 6814 MESA participants, 6751 had complete risk factor and follow-up data and were included in this study (mean [SD] age, 62.2 [10.2] years; 3186 [47.2%] male). A total of 881 (13.0%) had diabetes, 1738 (25.7%) had MetS, and 4132 (61.2%) had neither condition. After 11.1 mean years of follow-up, CHD events occurred in 84 participants with diabetes (135 ASCVD events), 115 with MetS (175 ASCVD events), and 157 with neither (250 ASCVD events). The CAC score was independently associated with incident CHD in multivariable analyses in those with diabetes (HR, 1.30; 95% CI, 1.19-1.43), MetS (HR, 1.30; 95% CI, 1.20-1.41), and neither condition (HR, 1.37; 95% CI, 1.27-1.47). For incident CHD, net reclassification improvement with addition of CAC score was 0.23 (95% CI, 0.10-0.37) in those with diabetes, 0.22 (95% CI, 0.09-0.35) in those with MetS, and 0.25 (95% CI, 0.15-0.35) in those with neither condition. The CAC score was also a prognostic indicator of CHD and ASCVD after controlling for diabetes duration of 10 years or longer at baseline, insulin use, and glycemic control.Conclusions and relevanceIn a large multiethnic cohort, the addition of CAC score to global risk assessment was associated with significantly improved risk classification in those with MetS and diabetes, even if diabetes duration was longer than a decade, suggesting a role for the CAC score in risk assessment in such patients.

BackgroundDespite recommendations, many middle-age adults neglect to check their blood cholesterol levels. Short message service (SMS, also known as texting) has been seldom studied for preventive education. We estimated how SMS can be a cost-effective method in encouraging people to check their blood cholesterol levels.MethodsIn a field trial, 3600 cell phone users (age > 30) were randomly assigned to the intervention (N: 1200) and the control groups (N: 2400). An SMS was sent to the intervention group for five rounds every two weeks, which targeted the cognitive and affective learning and finally advised the blood cholesterol level to be checked, if not checked during the past twelve months. Two weeks after the last round, both groups were asked for the time/level of their latest blood cholesterol, family history of early cardiac death and having a family member with coronary heart disease (CHD), and to report their attitude about whether annual blood sampling is worth the cost and time to prevent CHD. Moreover, the intervention group was asked if they remembered the SMS content. The cost-effectiveness was evaluated by estimating the "number needed to treat" (NNT) and calculating the cost of sending SMS to that number of people.ResultsIn the intervention group, 629 individuals (72.0%) recalled the SMS content. The factors associated with cholesterol screening during the past two years were older age, diabetes, family history of coronary disease, higher education, female gender and being non-smoker. In both groups, women were significantly more aware of their blood cholesterol level (68.7% vs. 53.6%). The relative frequency of respondents who believed it was not worth checking their cholesterol annually was significantly lower in the intervention group (P

ImportanceMitochondrial dysfunction is a core component of the aging process and may play a key role in atherosclerotic cardiovascular disease. Mitochondrial DNA copy number (mtDNA-CN), which represents the number of mitochondria per cell and number of mitochondrial genomes per mitochondrion, is an indirect biomarker of mitochondrial function.ObjectiveTo determine whether mtDNA-CN, measured in an easily accessible tissue (buffy coat/circulating leukocytes), can improve risk classification for cardiovascular disease (CVD) and help guide initiation of statin therapy for primary prevention of CVD.Design, setting, and participantsProspective, population-based cohort analysis including 21 870 participants (20 163 free from CVD at baseline) from 3 studies: Cardiovascular Health Study (CHS), Atherosclerosis Risk in Communities Study (ARIC), and Multiethnic Study of Atherosclerosis (MESA). The mean follow-up was 13.5 years. The study included 11 153 participants from ARIC, 4830 from CHS, and 5887 from MESA. Analysis of the data was conducted from March 10, 2014, to January 29, 2017.ExposuresMitochondrial DNA-CN measured from buffy coat/circulating leukocytes.Main outcomes and measuresIncident CVD, which combines coronary heart disease, defined as the first incident myocardial infarction or death owing to coronary heart disease, and stroke, defined as the first nonfatal stroke or death owing to stroke.ResultsOf the 21 870 participants, the mean age was 62.4 years (ARIC, 57.9 years; MESA, 62.4 years; and CHS, 72.5 years), and 54.7% of participants were women. The hazard ratios for incident coronary heart disease, stroke, and CVD associated with a 1-SD decrease in mtDNA-CN were 1.29 (95% CI, 1.24-1.33), 1.11 (95% CI, 1.06-1.16), and 1.23 (95% CI, 1.19-1.26). The associations persisted after adjustment for traditional CVD risk factors. Addition of mtDNA-CN to the 2013 American College of Cardiology/American Heart Association Pooled Cohorts Equations for estimating 10-year hard atherosclerosis CVD risk was associated with improved risk classification (continuous net reclassification index, 0.194; 95% CI, 0.130-0.258; P

BackgroundStatins are effective in the primary prevention of atherosclerotic cardiovascular disease. The 2013 American College of Cardiology/American Heart Association (ACC/AHA) guideline expands recommended statin use, but its cost-effectiveness has not been compared with other guidelines.MethodsWe used the Cardiovascular Disease Policy Model to estimate the cost-effectiveness of the ACC/AHA guideline relative to current use, Adult Treatment Panel III guidelines, and universal statin use in all men 45 to 74 years of age and women 55 to 74 years of age over a 10-year horizon from 2016 to 2025. Sensitivity analyses varied costs, risks, and benefits. Main outcomes were incremental cost-effectiveness ratios and numbers needed to treat for 10 years per quality-adjusted life-year gained.ResultsEach approach produces substantial benefits and net cost savings relative to the status quo. Full adherence to the Adult Treatment Panel III guideline would result in 8.8 million more statin users than the status quo, at a number needed to treat for 10 years per quality-adjusted life-year gained of 35. The ACC/AHA guideline would potentially result in up to 12.3 million more statin users than the Adult Treatment Panel III guideline, with a marginal number needed to treat for 10 years per quality-adjusted life-year gained of 68. Moderate-intensity statin use in all men 45 to 74 years of age and women 55 to 74 years of age would result in 28.9 million more statin users than the ACC/AHA guideline, with a marginal number needed to treat for 10 years per quality-adjusted life-year gained of 108. In all cases, benefits would be greater in men than women. Results vary moderately with different risk thresholds for instituting statins and statin toxicity estimates but depend greatly on the disutility caused by daily medication use (pill burden).ConclusionsAt a population level, the ACC/AHA guideline for expanded statin use for primary prevention is projected to treat more people, to save more lives, and to cost less compared with Adult Treatment Panel III in both men and women. Whether individuals benefit from long-term statin use for primary prevention depends more on the disutility associated with pill burden than their degree of cardiovascular risk.

ObjectiveTo determine if hepatocyte growth factor (HGF), a promising biomarker of coronary heart disease (CHD) given its release into circulation in response to endothelial damage, is associated with subclinical and clinical CHD in a racial/ethnic diverse population.MethodsHGF was measured in 6738 participants of the Multi-Ethnic Study of Atherosclerosis (MESA). Highest mean HGF values (pg/mL) were observed in Hispanic, followed by African, non-Hispanic white, then Chinese Americans.ResultsIn all races/ethnicities, HGF levels were associated with older age, higher systolic blood pressure (SBP) and body mass index, lower high-density lipoprotein, diabetes and current smoking. In fully adjusted models, each SD higher HGF was associated with an average increase in coronary artery calcium (CAC) of 55 Agatston units for non-Hispanic whites (p

RationaleTherapies that inhibit CETP (cholesteryl ester transfer protein) have failed to demonstrate a reduction in risk for coronary heart disease (CHD). Human DNA sequence variants that truncate the CETP gene may provide insight into the efficacy of CETP inhibition.ObjectiveTo test whether protein-truncating variants (PTVs) at the CETP gene were associated with plasma lipid levels and CHD.Methods and resultsWe sequenced the exons of the CETP gene in 58 469 participants from 12 case-control studies (18 817 CHD cases, 39 652 CHD-free controls). We defined PTV as those that lead to a premature stop, disrupt canonical splice sites, or lead to insertions/deletions that shift frame. We also genotyped 1 Japanese-specific PTV in 27561 participants from 3 case-control studies (14 286 CHD cases, 13 275 CHD-free controls). We tested association of CETP PTV carrier status with both plasma lipids and CHD. Among 58 469 participants with CETP gene-sequencing data available, average age was 51.5 years and 43% were women; 1 in 975 participants carried a PTV at the CETP gene. Compared with noncarriers, carriers of PTV at CETP had higher high-density lipoprotein cholesterol (effect size, 22.6 mg/dL; 95% confidence interval, 18-27; P

A major goal of biomedicine is to understand the function of every gene in the human genome. Loss-of-function mutations can disrupt both copies of a given gene in humans and phenotypic analysis of such 'human knockouts' can provide insight into gene function. Consanguineous unions are more likely to result in offspring carrying homozygous loss-of-function mutations. In Pakistan, consanguinity rates are notably high. Here we sequence the protein-coding regions of 10,503 adult participants in the Pakistan Risk of Myocardial Infarction Study (PROMIS), designed to understand the determinants of cardiometabolic diseases in individuals from South Asia. We identified individuals carrying homozygous predicted loss-of-function (pLoF) mutations, and performed phenotypic analysis involving more than 200 biochemical and disease traits. We enumerated 49,138 rare (

How African American men and women respond to and manage living with coronary heart disease (CHD) is not well understood despite the well-documented disproportionate burden of CHD and its complications among African Americans in the United States. Through a critical interactionist perspective, we explore illness experiences of African Americans living with CHD and describe a broad range of micro-, meso-, and macro-contextual factors that influence their illness experiences. For participants in this study, CHD has become a "Black disease" wherein certain bodies have become historically and racially marked; a conceptualization maintained and passed on by African Americans themselves. Such findings highlight that CHD is more than a "lifestyle disease" where high-risk behaviors and lack of healthy choices are ultimate culprits. Rather, CHD is perceived by African Americans who have it as yet another product of ongoing racial and socio-structural dynamics through which their health burdens are created, sustained, and reproduced.

ImportanceCardiovascular disease is the leading cause of morbidity and mortality in patients with chronic kidney disease (CKD). Understanding the relative contributions of cardiovascular disease event types to the excess burden of cardiovascular disease is important for developing effective strategies to improve outcomes.ObjectiveTo determine absolute rates and risk differences of incident heart failure (HF), coronary heart disease (CHD), and stroke in participants with vs without CKD.Design, setting and participantsWe pooled participants without prevalent cardiovascular disease from 3 community-based cohort studies: the Jackson Heart Study, Cardiovascular Health Study, and Multi-Ethnic Study of Atherosclerosis. The Jackson Heart Study was conducted between 2000 and 2010, the Cardiovascular Health Study was conducted between 1989 and 2003, and the Multi-Ethnic Study of Atherosclerosis was conducted between 2000 and 2012.ExposuresChronic kidney disease was defined as estimated glomerular filtration rate less than 60 mL/min/1.73 m2, calculated using the combined creatinine-cystatin C CKD-Epidemiology Collaboration Equation.Main outcomes and measuresPoisson regression was used to calculate incidence rates (IRs) and risk differences of adjudicated incident HF, CHD, and stroke, comparing participants with vs without CKD.ResultsAmong 14 462 participants, the mean (SD) age was 63 (12) years, 59% (n = 8533) were women, and 44% (n = 6363) were African American. Overall, 1461 (10%) had CKD (mean [SD] estimated glomerular filtration rate, 49 [10] mL/min/1.73 m2). Unadjusted IRs for participants with and without CKD, respectively, were 22.0 (95% CI, 19.3-24.8) and 6.2 (95% CI, 5.8-6.7) per 1000 person-years for HF; 24.5 (95% CI, 21.6-27.5) and 8.4 (95% CI, 7.9-9.0) per 1000 person-years for CHD; and 13.4 (95% CI, 11.3-15.5) and 4.8 (95% CI, 4.4-5.3) for stroke. Adjusting for demographics, cohort, hypertension, diabetes, hyperlipidemia, and tobacco use, risk differences comparing participants with vs without CKD (per 1000 person-years) were 2.3 (95% CI, 1.2-3.3) for HF, 2.3 (95% CI, 1.2-3.4) for CHD, and 0.8 (95% CI, 0.09-1.5) for stroke. Among African American and Hispanic participants, adjusted risk differences comparing participants with vs without CKD for HF were 3.5 (95% CI, 1.5-5.5) and 7.8 (95% CI, 2.2-13.3) per 1000 person-years, respectively.Conclusions and relevanceAmong 3 diverse community-based cohorts, CKD was associated with an increased risk of HF that was similar in magnitude to CHD and greater than stroke. The excess risk of HF associated with CKD was particularly large among African American and Hispanic individuals. Efforts to improve health outcomes for patients with CKD should prioritize HF in addition to CHD prevention.

Background and aimsTAC is associated with incident CVD and all-cause mortality. Nevertheless, the independent 10-year prognostic value of TAC in individuals with CAC = 0 beyond traditional risk factors is not well established.Methods3415 MESA participants with baseline CAC = 0 were followed for CHD, CVD events and all-cause mortality. TAC was measured in the ascending and descending aorta in all participants and quantified using Agatston's score. Multivariable Cox proportional hazards regression models were used to study the associations between TAC and incident CHD, CVD events and all-cause mortality. Likelihood ratio tests were used to compare prediction models including traditional risk factors plus TAC versus risk factors alone.Results406 participants (11.9%) had TAC>0 at baseline. Over a median follow-up of 11.3 years, unadjusted event rates per 1000 person-years were higher in TAC>0 than in TAC = 0 participants: CHD 2.18 vs. 2.03; CVD 6.85 vs. 3.42; all-cause mortality 12.84 vs. 4.96. However, in multivariable Cox regression analyses adjusting for CVD risk factors, neither TAC>0, TAC>100 nor log(TAC+1) were independently associated with any of the study outcomes, nor improved their prediction compared to traditional risk factors alone (p value of likelihood ratio tests >0.05).ConclusionsIn a multi-ethnic, modern US population of asymptomatic individuals with CAC = 0 at baseline, the prevalence of TAC>0 was low, and TAC did not improve 10-year estimation of prognosis beyond traditional risk factors. In the presence of CAC = 0, measurement of TAC is unlikely to provide sufficient additional prognostic information to further improve risk assessment.

BackgroundGenome-wide association studies have identified loci influencing circulating lipid concentrations in humans; further information on novel contributing genes, pathways, and biology may be gained through studies of epigenetic modifications.Methods and resultsTo identify epigenetic changes associated with lipid concentrations, we assayed genome-wide DNA methylation at cytosine-guanine dinucleotides (CpGs) in whole blood from 2306 individuals from 2 population-based cohorts, with replication of findings in 2025 additional individuals. We identified 193 CpGs associated with lipid levels in the discovery stage (P

ObjectivesDetection of atrial fibrillation (AF) in post-cryptogenic stroke (CS) or transient ischemic attack (TIA) patients carries important therapeutic implications.MethodsTo risk stratify CS/TIA patients for later development of AF, we conducted a retrospective cohort study using data from 1995 to 2015 in the Stanford Translational Research Integrated Database Environment (STRIDE).ResultsOf the 9,589 adult patients (age ≥40 years) with CS/TIA included, 482 (5%) patients developed AF post CS/TIA. Of those patients, 28.4, 26.3, and 45.3% were diagnosed with AF 1-12 months, 1-3 years, and >3 years after the index CS/TIA, respectively. Age (≥75 years), obesity, congestive heart failure, hypertension, coronary artery disease, peripheral vascular disease, and valve disease are significant risk factors, with the following respective odds ratios (95% CI): 1.73 (1.39-2.16), 1.53 (1.05-2.18), 3.34 (2.61-4.28), 2.01 (1.53-2.68), 1.72 (1.35-2.19), 1.37 (1.02-1.84), and 2.05 (1.55-2.69). A risk-scoring system, i.e., the HAVOC score, was constructed using these 7 clinical variables that successfully stratify patients into 3 risk groups, with good model discrimination (area under the curve = 0.77).ConclusionsFindings from this study support the strategy of looking longer and harder for AF in post-CS/TIA patients. The HAVOC score identifies different levels of AF risk and may be used to select patients for extended rhythm monitoring.

Computed tomographic (CT) angiography is an important tool for the evaluation of coronary artery disease but often correlates poorly with myocardial ischemia. Current dynamic CT perfusion techniques can assess ischemia but have limited accuracy and deliver high radiation dose. Therefore, an accurate, low-dose, dynamic CT perfusion technique is needed. A total of 20 contrast-enhanced CT volume scans were acquired in 5 swine (40±10 kg) to generate CT angiography and perfusion images. Varying degrees of stenosis were induced using a balloon catheter in the proximal left anterior descending coronary artery, and a pressure wire was used for reference fractional flow reserve (FFR) measurement. Perfusion measurements were made with only 2 volume scans using a new first-pass analysis (FPA) technique and with 20 volume scans using an existing maximum slope model (MSM) technique. Perfusion (P) and FFR measurements were related by PFPA=1.01 FFR-0.03 (R2=0.85) and PMSM=1.03 FFR-0.03 (R2=0.80) for FPA and MSM techniques, respectively. Additionally, the effective radiation doses were calculated to be 2.64 and 26.4 mSv for FPA and MSM techniques, respectively. A new FPA-based dynamic CT perfusion technique was validated in a swine animal model. The results indicate that the FPA technique can potentially be used for improved anatomical and functional assessment of coronary artery disease at a relatively low radiation dose.

ContextAbnormalities in calcium metabolism may potentially contribute to the development of vascular disease. Calcium metabolism may be different in African American (AA) vs white individuals, but the effect of race on the association of serum calcium with clinical outcomes remains unclear.ObjectiveThis study sought to examine race-specific associations of serum calcium levels with mortality and with major incident cardiovascular events.Design and settingThis was a historical cohort study in the U.S. Department of Veterans Affairs health care facilities.ParticipantsParticipants included veterans (n = 1 967 622) with estimated glomerular filtration rate ≥ 60 mL/min/1.73 m2.Main outcome measuresThe association between serum calcium levels with all-cause mortality, incident coronary heart disease (CHD), and ischemic stroke incidence was examined in multivariable adjusted Cox proportional hazards models, including an interaction term for calcium and race.ResultsThe association of calcium with all-cause mortality was U-shaped in both AA and white patients, but race modified the association of calcium with all-cause mortality. Compared with white patients, AA patients experienced lower risk of mortality when calcium was ≥ 8.8 mg/dL, with a statistically significant interaction (P < .001). Conversely, AA vs white race was associated with higher mortality when calcium was < 8.8 mg/dL. Calcium showed no significant association with ischemic stroke or CHD in both races; and race did not modify these associations (P = .37 and 0.11, respectively for interaction term).ConclusionsRace modified the U-shaped association between calcium and all-cause mortality. Serum calcium is not associated with incident stroke or CHD in either AA or white patients. The race-specific difference in the association of calcium levels with mortality warrants further examination.

BackgroundEpigenetic biomarkers of aging (the "epigenetic clock") have the potential to address puzzling findings surrounding mortality rates and incidence of cardio-metabolic disease such as: (1) women consistently exhibiting lower mortality than men despite having higher levels of morbidity; (2) racial/ethnic groups having different mortality rates even after adjusting for socioeconomic differences; (3) the black/white mortality cross-over effect in late adulthood; and (4) Hispanics in the United States having a longer life expectancy than Caucasians despite having a higher burden of traditional cardio-metabolic risk factors.ResultsWe analyzed blood, saliva, and brain samples from seven different racial/ethnic groups. We assessed the intrinsic epigenetic age acceleration of blood (independent of blood cell counts) and the extrinsic epigenetic aging rates of blood (dependent on blood cell counts and tracks the age of the immune system). In blood, Hispanics and Tsimane Amerindians have lower intrinsic but higher extrinsic epigenetic aging rates than Caucasians. African-Americans have lower extrinsic epigenetic aging rates than Caucasians and Hispanics but no differences were found for the intrinsic measure. Men have higher epigenetic aging rates than women in blood, saliva, and brain tissue.ConclusionsEpigenetic aging rates are significantly associated with sex, race/ethnicity, and to a lesser extent with CHD risk factors, but not with incident CHD outcomes. These results may help elucidate lower than expected mortality rates observed in Hispanics, older African-Americans, and women.

AimsAlthough coronary artery calcium (CAC) has been established as a robust tool for predicting total mortality during intermediate follow-up, less is known about the long-term predictive value of CAC.Methods and resultsThis study included 13 092 asymptomatic patients without known cardiovascular disease who underwent a clinically indicated CAC scan. CAC was categorized as an Agatson score of 0, 1-99, 100-399, and ≥400. We used multivariable Cox proportional hazards to calculate adjusted hazard ratios (HRs) for mortality stratified by age (younger, intermediate, or older) and gender. The mean age of participants was 58 ± 11 years and 67% were men. During a median follow-up of 11.0 ± 3.2 years, there were 522 deaths (4.0%). Compared with CAC = 0, increasing CAC was associated with higher mortality rate: 1-99 [HR: 1.5, 95% confidence interval (95% CI): 1.1-2.1]; 100-399 (HR: 1.8, 95% CI: 1.3-2.5); ≥400 (HR: 2.6, 95% CI: 1.9-3.6). Relative risk according to CAC category did not differ between genders. The strongest associations between CAC and mortality were observed for young and intermediate age participants. Nonetheless, the mortality rate of the older patients with CAC = 0 was far lower than that of the general US population. CAC was more predictive of long-term (15 years) than intermediate-term (5 years) mortality for men [receiver operator characteristics (ROC): 0.723 vs. 0.702] and women (ROC: 0.69 vs. 0.65).ConclusionCAC is strongly associated with the long-term risk of mortality in young- and middle-aged men and women. In older patients, the long-term risk stratification of CAC is lower, due principally to increased mortality rate in patients with low calcium scores; however, even in the older patients, those with absent or low CAC are at a significantly lower risk of mortality compared with the general population.

BackgroundDiagnostic testing in the care of patients newly presenting with symptoms suggestive of coronary artery disease may influence risk factor management, independent of test type or test results. However, little is known about changes in medications and lifestyle after anatomical or functional testing.Methods and resultsWe examined what factors influenced preventive medical therapy and lifestyle practices at 60 days among 10 003 symptomatic patients (53% women; mean age 61 years) randomly assigned to anatomical testing with coronary computed tomographic angiography or functional testing (NCT01174550). We also assessed the association of preventive changes with major cardiovascular events. There were no differences in medications/lifestyle at baseline. At 60 days, relative to baseline, the computed tomographic angiography strategy was associated with a higher proportion of patients newly initiating aspirin (11.8% versus 7.8%), statins (12.7% versus 6.2%), and β-blockers (8.1% versus 5.3%), compared to functional testing (P

Coronary artery calcification (CAC) is an established marker of subclinical atherosclerosis and an independent predictor of future coronary heart disease in the asymptomatic primary prevention population, particularly in the intermediate risk cohort. CAC also helps in reclassifying those patients and their risk of cardiovascular events into higher or lower risk categories. MESA (Multi-Ethnic Study of Atherosclerosis) is a National Heart, Lung, and Blood Institute-sponsored population-based medical research study involving 6,814 men and women from 6 U.S. communities without a medical history of clinical cardiovascular disease. The evidence from this population cohort revealed that CAC scoring was independently predictive and highly effective at risk stratification of major adverse cardiac events. This review provides available data based on MESA. We focus on the utility of CAC for cardiovascular disease risk stratification of individuals, and we describe its diagnostic value in identifying patients at risk.

BackgroundLong-term exposure to fine particulate matter less than 2.5 μm in diameter (PM2.5) and traffic-related air pollutant concentrations are associated with cardiovascular risk. The disease process underlying these associations remains uncertain. We aim to assess association between long-term exposure to ambient air pollution and progression of coronary artery calcium and common carotid artery intima-media thickness.MethodsIn this prospective 10-year cohort study, we repeatedly measured coronary artery calcium by CT in 6795 participants aged 45-84 years enrolled in the Multi-Ethnic Study of Atherosclerosis and Air Pollution (MESA Air) in six metropolitan areas in the USA. Repeated scans were done for nearly all participants between 2002 and 2005, for a subset of participants between 2005 and 2007, and for half of all participants between 2010 and 2012. Common carotid artery intima-media thickness was measured by ultrasound in all participants at baseline and in 2010-12 for 3459 participants. Residence-specific spatio-temporal pollution concentration models, incorporating community-specific measurements, agency monitoring data, and geographical predictors, estimated concentrations of PM2.5 and nitrogen oxides (NOX) between 1999 and 2012. The primary aim was to examine the association between both progression of coronary artery calcium and mean carotid artery intima-media thickness and long-term exposure to ambient air pollutant concentrations (PM2.5, NOX, and black carbon) between examinations and within the six metropolitan areas, adjusting for baseline age, sex, ethnicity, socioeconomic characteristics, cardiovascular risk factors, site, and CT scanner technology.FindingsIn this population, coronary calcium increased on average by 24 Agatston units per year (SD 58), and intima-media thickness by 12 μm per year (10), before adjusting for risk factors or air pollutant exposures. Participant-specific pollutant concentrations averaged over the years 2000-10 ranged from 9.2-22.6 μg PM2.5/m(3) and 7.2-139.2 parts per billion (ppb) NOX. For each 5 μg PM2.5/m(3) increase, coronary calcium progressed by 4.1 Agatston units per year (95% CI 1.4-6.8) and for each 40 ppb NOX coronary calcium progressed by 4.8 Agatston units per year (0.9-8.7). Pollutant exposures were not associated with intima-media thickness change. The estimate for the effect of a 5 μg/m(3) higher long-term exposure to PM2.5 in intima-media thickness was -0.9 μm per year (95% CI -3.0 to 1.3). For 40 ppb higher NOX, the estimate was 0.2 μm per year (-1.9 to 2.4).InterpretationIncreased concentrations of PM2.5 and traffic-related air pollution within metropolitan areas, in ranges commonly encountered worldwide, are associated with progression in coronary calcification, consistent with acceleration of atherosclerosis. This study supports the case for global efforts of pollution reduction in prevention of cardiovascular diseases.FundingUS Environmental Protection Agency and US National Institutes of Health.