Carotid artery stiffness has been associated with cognitive performance; however, the association among men with HIV (MWH) remains unclear. We examined the relationship between carotid artery distensibility and cognitive performance in the Multicenter AIDS Cohort Study (MACS). We analyzed data from 717 men (459 MWH and 258 men without HIV [MWoH]) who underwent carotid artery ultrasound and completed neuropsychological testing at least twice. Carotid artery distensibility was divided into tertiles. Cognitive outcomes included psychomotor speed (Trail Making Test A), executive function (Trail Making Test B), and processing speed (Symbol Digit Modalities Test). Multivariable mixed effects linear regressions were used to estimate longitudinal associations between distensibility tertiles and cognitive scores, with adjustments for socio-demographics, cardiovascular risk factors, and HIV-related characteristics. Regardless of HIV serostatus, lower vascular distensibility was associated with older age, higher systolic and diastolic blood pressure, and greater prevalence of cardiometabolic risk factors. In fully adjusted analyses, lower carotid artery distensibility was significantly associated with slower performance on Trail Making Test A and B in MWH. These associations were weaker and not statistically significant among MWoH perhaps due to low sample size. In the combined sample, the rate of decline in executive function with age was similar across distensibility tertiles, but absolute scores were lowest in the low distensibility group. Lower carotid artery distensibility is linked to worse cognitive performance among MWH, suggesting that vascular aging may compound HIV-related cognitive decline.

Aims:People with HIV (PWH) and undetectable virus experience elevated cardiovascular risk independent of traditional risk factors. Vascular inflammation may contribute to this residual risk. The perivascular fat attenuation index (FAI), derived from coronary computed tomography angiography (CCTA), is a biomarker of coronary inflammation. Lipoprotein(a) [Lp(a)] carries oxidized phospholipids that may promote inflammation. Statins have demonstrated cardiovascular benefit in PWH, including pleiotropic anti-inflammatory effects. This study assessed the associations of Lp(a) and of statin use with coronary inflammation (FAI) in men with HIV (MWH). Methods and results:We analysed FAI of the left anterior descending (LAD) and the right coronary arteries (RCA) in 583 men from the Multicenter AIDS Cohort Study, a prospective, multicentre cohort study, including 280 with undetectable HIV RNA, <50 copies/ml. Associations between log10[Lp(a)] and LAD and RCA FAI were assessed using linear regression, adjusting for demographic and cardiovascular risk factors. Log10[Lp(a)] was associated with LAD FAI in MWH with undetectable HIV in adjusted analysis [+1.99 HU (0.38, 3.59); P = 0.02] but not among men without HIV (MWoH) or MWH with detectable HIV. Associations with RCA FAI were only significant in the unadjusted analysis. Statin use was associated with lower FAI, less inflammation in the LAD in MWH with undetectable virus, but did not modify the association between Lp(a) and coronary inflammation. Conclusion:Lp(a) was associated with increased coronary inflammation, independent of traditional cardiovascular risk factors, in MWH with undetectable virus. Statin therapy did not modify the relationship between coronary inflammation and Lp(a).

BACKGROUND:People with HIV are at elevated risk for atherosclerotic cardiovascular disease despite viral suppression, suggesting contributions from nontraditional mechanisms. Coronary vascular inflammation may play a role, but its relationship to plaque progression remains incompletely defined. The perivascular fat attenuation index (FAI) score, derived from coronary computed tomography angiography, is associated with vascular inflammation. We evaluated whether coronary inflammation is associated with the incidence and progression of coronary plaque and whether these relationships differ by HIV status. METHODS:A total of 504 men (n=292 with HIV; n=212 without HIV) from the Multicenter AIDS Cohort Study underwent coronary computed tomography angiography over a median of 4.5 years (3.8-4.9). FAI measurements were performed on baseline scans. Changes in noncalcified, calcified, and total plaque volumes were categorized into tertiles of progression. Associations were estimated using multinomial logistic regression adjusted for interscan time and cardiovascular risk factors. Modified Poisson regression estimated incident plaque. RESULTS:Higher FAI scores in the left anterior descending (LAD) and left circumflex were associated with greater odds of belonging to the highest tertile of noncalcified (LAD odds ratio [OR], 1.83 [1.27-2.64]; left circumflex OR, 2.55 [1.66-3.91]); calcified (LAD OR, 2.62 [1.64-4.18]; left circumflex OR, 3.92 [2.36-6.51]); and total plaque progression (LAD OR, 1.81 [1.25-2.62]; left circumflex OR, 2.65 [1.71-4.10]) among men with HIV (MWH), per SD increase in FAI score after adjusting for cardiovascular risk factors, and remained significant after adjustment for baseline plaque. Higher LAD FAI score was associated with incident calcified plaque in men with HIV (RR, 1.21 [1.01-1.46]). Associations for noncalcified and calcified plaque progression were stronger in men with HIV than in men without HIV. CONCLUSIONS:Coronary inflammation, assessed by FAI, is independently associated with incident and progressive coronary plaque in men with HIV. These findings support a role for vascular inflammation in accelerated atherosclerosis in people with HIV and highlight FAI as a potential biomarker for risk stratification.

Sex hormones and HIV infection both influence cardiovascular health. However, the association between sex hormones and subclinical atherosclerosis is not fully understood, especially in the context of HIV. Among 321 men (65

Introduction: The role of circulating monocytes in non-ischemic cardiac remodeling and heart failure (HF) is complex and unclear, due in part to monocyte heterogeneity and plasticity. We assessed the hypothesis that monocyte gene expression profiles reflecting activation and tissue inflammation are associated with cardiac structure and function and incident adjudicated HF in the Multi-Ethnic Study of Atherosclerosis. Methods: Monocytes were isolated from peripheral blood, and RNA was quantified using an Illumina BeadChip microarray. Cardiac magnetic resonance was performed concurrently. We used multivariable linear regression to estimate cross-sectional associations between gene expression levels and cardiac structure and function and Cox regression to estimate associations with time to incident HF. Results: We studied 12,369 transcripts mapping to 9,430 genes among 813 participants (mean age 69±9 years; 50% female; 22% Black; 29% Hispanic). Independent of traditional risk factors, expression levels of 55 transcripts were associated with left ventricular (LV) ejection fraction, 1136 with LV strain, 16 with LV geometry, 1020 with myocardial interstitial fibrosis, and 483 with left atrial size (FDR<0.05). Enrichment analysis implicated T and B cell activation, cytokine production, phagocytosis, wound healing, oxidative stress, and cell migration. Expression levels of three genes—PCCB, MTCP1, and VIM—were associated with more than one cardiac metric as well as time to clinical HF ( n =45 events over a median follow-up of 7.7 years). Conclusion: These unique data support an association between monocyte-mediated immune processes and subclinical cardiac remodeling and incident HF in the absence of ischemic injury. Agnostically identified profiles were enriched for processes related to both pro-inflammatory and pro-resolving activated monocyte function and immunometabolism, as well as tissue migration and homeostasis. These insights may help generate hypotheses toward novel therapeutic targets for HF.

Multiple germline and somatic genomic factors are associated with risk of coronary artery disease, but there is no single measure of risk that integrates all information from a DNA sample. To address this gap, we develop an integrated genomic model that includes six germline and somatic genetic drivers for coronary artery disease, including polygenic risk score, genetically-proxied proteomic/metabolomic risk scores, and clonal hematopoiesis of indeterminate potential. We evaluated its predictive power in the UK Biobank (N = 391,536), and validate it using data from the TOPMed program (N = 34,177). The 10-year coronary artery disease risk based on the integrated genomic model profile ranges from 1.1% to 15.5% in the UK Biobank and from 3.8% to 33.0% in TOPMed, with a more pronounced gradient in males than females. The integrated genomic model captures the cumulative effect of multiple genetic drivers, identifying individuals at high risk for coronary artery disease despite lacking any single high-risk genetic factor, as well as individuals at low risk despite carrying known high-risk factors. In middle age, the integrated genomic model augments the performance of the Pooled Cohort Equations, a clinical risk calculator for coronary artery disease. While the integrated genomic model yields only modest incremental predictive value over polygenic risk score at the population level, it identifies approximately 13% of high-risk individuals not detected by polygenic risk score alone.

Evidence on metformin’s skeletal effects remains conflicting. We emulated a target trial to evaluate associations between metformin therapy and deep learning–based CT-derived vertebral bone mineral density (vBMD). We also assessed variation across prespecified subgroups. Within the Multi-Ethnic Study of Atherosclerosis (MESA), incident metformin users (Exams 4 and 5) were compared with propensity score–matched controls. Noncontrast chest CT scans from Exams 5 and 6 were processed using a previously validated deep learning–based vertebral segmentation and calibration pipeline to quantify trabecular vBMD from T1 to T10. Median imaging follow-up was 6.4 years. Linear mixed-effects models estimated annualized Fracture Risk Assessment Tool (FRAX) absolute vBMD change, applying inverse probability of censoring weights. Prespecified subgroup analyses examined demographic, metabolic, and inflammatory modifiers. Among 238 trial entries (86 metformin, 152 controls), metformin was not associated with overall vBMD change (time × treatment interaction β, 0.27 mg/cm3 per year; 95

Over 75 Alzheimer's disease (AD) and dementia-associated variants have been identified through genome-wide association studies, but the utility of polygenic risk scores (PRS) for predicting AD and dementia in diverse and admixed populations remains unclear. We compared how PRS approaches differing in p -value thresholds, variant weights, and source ancestry perform in predicting dementia in 6,338 African American, Chinese, Hispanic, and White individuals from the Multi-Ethnic Study of Atherosclerosis. We tested clumping and thresholding (C+T) methods with varying parameters against Bayesian approaches (PRS-CS, PRS-CSx). We compared the ability of each method to predict incident dementia in all participants and in groups stratified by self-reported race/ethnicity. We additionally analyzed performance across groups stratified by estimated proportion of non-Finnish European (NFE)-like ancestry. Including more variants does not improve performance. The PRS based on C+T method with only 15 SNPs is more strongly associated with dementia (HR 5e-08 = 1.21, 95% CI: 1.11-1.31) than PRS derived from Bayesian models that include >800,000 SNPs (HR CSx = 1.13, 95% CI: 1.04-1.23), even in populations genetically dissimilar from the source data (HR lowNFE _ 5e-08 = 1.26, 95% CI: 1.08-1.47; HR lowNFE _ CSx = 1.13, 95% CI: 0.96-1.32). More selective PRS models using fewer SNPs may offer better AD prediction across diverse populations.

Objective: To identify proteomic signatures underlying 3-year progression from impaired fasting glucose (IFG) to diabetes. Research Design and Methods: We examined IFG progression in the Atherosclerosis Risk in Communities (ARIC) Study from visit 2 (1990-2) to visit 3 (1993-5). We tested associations of 4,955 plasma proteins (SOMAScan™ v4.0) with ~3-year progression from IFG (FG 100-125 mg/dL without diabetes) to diabetes (diagnosis, medication, or FG ≥126 mg/dL) using logistic regression models adjusted for demographics, cardiometabolic risk factors, and baseline glucose with Bonferroni correction (p<10-5). We explored biological pathways enriched among top proteins and calculated improvements in prediction (∆AUC and net reclassification using 3-year risk thresholds of 6% and 15% in 80% training and 20% internal validation subsamples). We validated results in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort. Results: There were 3,786 ARIC participants with IFG (mean age 57y, SD: 6; 52% female, 28% Black adults). The 3-year cumulative incidence of diabetes was 6%. Six proteins were associated with ~3-year progression to diabetes, namely lower receptor-type tyrosine-protein phosphatase S (PTPRS), anthrax toxin receptor-2 (ANTXR2), adiponectin (ADIPOQ), ciliary neurotrophic factor receptor subunit-alpha (CNTFR), Transmembrane protein-132C (TMEM132C), and higher ADAMTS-like protein-2 (ADAMTSL2). Altered carbohydrate metabolism and glycolysis were key pathways. Adding the 6 proteins to covariates improved discrimination (optimism-corrected AUC=0.81; ∆AUC=0.03, p=0.005) and net reclassification (training: 12.2%, internal validation: 12.0%) with predicted diabetes risk quintiles spanning <1% to ~20%. Two of the 6 proteins validated in MESA (p<0.008). Conclusions: We identified proteins associated with 3-year IFG progression with improvements in diabetes risk stratification.

BACKGROUND:Exercise unmasks limitations in multi-organ system reserve capacity characteristic of heart failure with preserved ejection fraction (HFpEF). However, the metabolic and genetic underpinnings of exercise deficits, and their cumulative contribution to HFpEF severity and prognosis, remain incompletely understood. METHODS:We used invasive cardiopulmonary exercise testing (iCPET), metabolite profiling, and genomics to simultaneously characterize seven exercise physiologic deficits in HFpEF patients: reduced exercise stroke volume and heart rate, steep pulmonary capillary wedge pressure/cardiac output (PCWP/CO) slope, elevated pulmonary vascular resistance, pulmonary mechanical limitation to exercise, impaired peripheral oxygen extraction, and obesity-related exaggerated metabolic cost of initiating exercise. We first mapped the distribution, functional, and prognostic significance of these exercise deficits. We then applied LASSO regression to identify metabolite signatures of each exercise deficit, and measured the relation of these signatures with clinical-demographic features, cardiac magnetic resonance imaging, and incident HF in 6345 individuals in the Multi-Ethnic Study of Atherosclerosis (MESA) study with ≈20-year follow-up. Finally, we mapped deficit-implicated metabolites to tissue-specific genetic variation in ≈2M individuals with HF, and in the largest genome-wide association study (GWAS) studies of HFpEF comorbidities (obesity, renal disease, diabetes) to evaluate shared metabolic mechanisms of HFpEF pathophysiology. RESULTS:Our iCPET HFpEF cohort (61.7±14.1 years, 54% female, BMI 30.6±6.7 kg/m2 ) exhibited a broad range of compound cardiac and extra-cardiac exercise deficits. Individuals with ≥5 exercise deficits had a nearly 4-fold higher hazard of incident cardiovascular event or mortality (HR 3.90, 95% CI 1.74-8.75, P<0.0001). The metabolite signature of exercise PCWP/CO slope conferred a HR of 1.43 per SD increment, 95% CI 1.20-1.71, P<0.001 for incident HF in MESA. Addition of all iCPET deficit metabolic signatures in a single model yielded ≈20% continuous net reclassification improvement over traditional HFpEF risk factors. Genes implicated by the exercise deficit metabolome were enriched in the HF GWAS (≈2M) and shared with obesity, renal dysfunction, and diabetes, highlighting a lifelong shared predisposition to HF (including HFpEF) and its comorbidities. CONCLUSIONS:Organ-specific responses to exercise and their circulating metabolite signatures are strongly linked to HFpEF development and prognosis. These results offer a paradigm for parsing HFpEF subphenotypes and prioritizing metabolic mechanisms of HFpEF.

BACKGROUND:Lp(a) (lipoprotein[a]) is a known cardiovascular risk factor; however, its role in cardiac remodeling and functional changes over time across diverse racial and ethnic groups remains underexplored. METHODS:MESA is a prospective multi-ethnic cohort study of individuals without a history of cardiovascular disease on enrollment (2000-2002), conducted across 6 sites in the United States. Participants with baseline Lp(a) measurements and cardiac magnetic resonance imaging at both baseline and 10-year follow-up exam were included. Lp(a) was treated as both a log-transformed continuous variable (per SD log) and a categorical variable based on data-driven Lp(a) terciles. Multivariable regression models adjusted for sociodemographic, and cardiovascular risk factors, including coronary artery calcium and interim myocardial infarction, were used to assess associations between Lp(a) and longitudinal changes in left ventricular and atrial structure and function over a decade across different racial/ethnic groups. RESULTS:A total of 2366 participants were included. The average age at baseline was 60±9 with 53% women, 43% White, 24% Black, 21% Hispanic, and 12% Chinese. Each 1-SD increase in log-transformed Lp(a) was associated with an increase in left ventricular end-systolic volume index (β, 0.60 [95% CI, 0.02-1.18]), and left atrial minimum volume index (β, 0.81 [95% CI, 0.09-1.52]), and a decline in left ventricular ejection fraction (β, -0.75 [95% CI, -1.34 to -0.17]), and total left atrial emptying fraction (β, -1.17 [95% CI, -2.09 to -0.24]) in Hispanic subjects over a decade. No significant associations were seen in White, Black, or Chinese participants. The observed findings persisted after adjusting for coronary artery calcium, interim myocardial infarction, and atrioventricular decoupling, and when Lp(a) was treated as a categorical variable with race-specific terciles. CONCLUSIONS:Elevated Lp(a) levels were independently associated with maladaptive left ventricular and left atrial remodeling in Hispanic adults over a decade, while no statistically significant relationships were observed in White, Black, and Chinese participants. This suggests a unique susceptibility of Hispanic individuals to Lp(a)-mediated cardiovascular remodeling, independent of ischemic pathways.

Introduction:Coronary artery disease (CAD) is a leading cause of death and disability worldwide. Although genome-wide association studies (GWAS) have identified over 300 loci associated with CAD risk, the molecular mechanisms linking these variants to disease and subclinical atherosclerosis are not fully understood. Methods:We performed integration of multi-ancestry CAD GWAS with transcriptomic data from the Multi-Ethnic Study of Atherosclerosis (MESA) obtained through the Trans-Omics for Precision Medicine (TOPMed) program. For integration, we applied Bayesian colocalization analysis with and without statistical fine-mapping to identify genes whose expression levels colocalize with CAD-associated loci. We further applied causal weighted gene co-expression network analysis (cWGCNA) to identify gene co-expression modules and key driver genes associated with subclinical atherosclerosis traits in MESA. Results:We identified 108 genes showing evidence of colocalization with CAD loci, including 24 shared between the two colocalization approaches and 48 novel genes not previously reported in CAD GWAS. Follow-up replication and validation analyses prioritized 5 novel ( CCDC30, ZEB1-AS1, ZPR1, PLEKHJ1 and AC018816.3 ) and 8 previously reported genes ( DHDDS, DDX59, LNPEP, DAGLA, ZKSCAN1, LIPA, OPRL1 and EIF2B2 ) with putative roles in both CAD and subclinical atherosclerosis. cWGCNA identified five gene modules significantly associated with subclinical atherosclerosis in MESA. Additionally, three key driver genes ( ATG9B, PRAM1 and ZBTB46 ) identified by cWGCNA were also identified as CAD-colocalized genes. Discussion:Our integrative analysis highlights key genetic drivers and regulatory networks underlying CAD and subclinical atherosclerosis. These findings underscore the value of incorporating statistical fine-mapping in colocalization studies and demonstrate the utility of combining colocalization with co-expression network analysis to prioritize functional genes and pathways.

BACKGROUND:Genetic risk scores may be useful for analyzing risks for coronary artery disease (CAD). However, comparisons between restricted and genome-wide scores have been underexplored, particularly for individuals at increased risk by one score but not the other. Here, we compared restricted polygenic risk scores with 181 high-confidence genetic variants (PRS181) and genome-wide risk scores that encompass 6.6 million single-nucleotide polymorphisms (GRS6.6M). METHODS:Data were from the RS (Rotterdam Study; n=11 001), MESA (Multi-Ethnic Study of Atherosclerosis; n=2685), and the Sanford Health study (n=25 166). We analyzed score associations with CAD (prevalent and incident), age at onset, and lipid medication use. Combined use of both scores was also examined. RESULTS:There were robust associations with CAD per SD of the scores for men (PRS181: hazard ratio [HR], 1.19 [95% CI, 1.13-1.26]; GRS6.6M: HR, 1.32 [95% CI, 1.26-1.39]) and women (PRS181: HR, 1.24 [95% CI, 1.16-1.32]; GRS6.6M: HR, 1.32 [95% CI, 1.25-1.40]). PRS181 was more strongly associated with early-onset CAD in men (β=-0.93 [95% CI, -1.36 to -0.50]) and women (β=-0.76 [95% CI, -1.31 to -0.21]). Both scores correlated with lipid medication use, but the scores were also associated with CAD among nonusers. Individuals at high risk by both scores had the highest risk and the earliest age at onset. CONCLUSIONS:PRS181 and GRS6.6M appear to identify different subsets of individuals. Use of both scores together may provide better association information on CAD risk and age at onset than each score alone.

BACKGROUND AND AIMS:People with Type 2 diabetes (T2D) are twice as likely to develop cardiovascular disease (CVD), though not all excess risk has been fully elucidated. Plasma metabolomics profiles shared between these conditions may uncover molecular mechanisms linking T2D to CVD. METHODS:We conducted a cross-sectional case-control analysis, comparing T2D individuals who had prevalent CVD to those without CVD at the time of metabolite measurement. Using untargeted liquid chromatography-mass spectrometry (LC-MS), we collected 522 metabolite abundances measured in 1374 participants with T2D (224 CVD cases) from the Trans-Omics for Precision Medicine (TOPMed) program. We used a mixed effects linear model to assess the association of CVD events with each metabolite abundance, adjusting for key covariates. Metabolites meeting a suggestive significance threshold were examined using metabolite set enrichment analysis and evaluated for replication in an independent cohort Atherosclerosis Risk in Communities (ARIC) (n = 1891; 214 CVD cases). We performed meta-analysis to combine both the discovery and replication associations, and assessed overall significance using an experiment-wide Bonferroni-corrected threshold. RESULTS:Metabolites meeting a suggestive threshold were enriched in metabolite sets linked to obesity and kidney disease. Meta-analysis identified eight metabolites reaching experiment-wide significance, confirming previously established associations of asymmetric dimethylarginine, phosphatidylcholines, and gluconic acid, while additionally identifying specific phosphatidylethanolamine species, N-acetyl-L-methionine, and allantoin associated with prevalent CVD among individuals with T2D. CONCLUSIONS:Our results established and replicated metabolite associations with prevalent CVD in people with T2D. These metabolites may help characterize metabolic alterations underlying cardiovascular complications that arise in T2D.

BACKGROUND:How gut microbiota alterations may contribute to host inflammation and metabolomic profiles affecting atherosclerosis is not fully elucidated, especially in the context of HIV. METHODS:We examined associations between gut microbial features (measured by shotgun metagenomics) and subclinical carotid atherosclerosis, as assessed by high-resolution B-mode ultrasound, in 359 men from the MACS/WIHS Combined Cohort Study. We measured 822 plasma metabolites using LC-MS/MS, and up to 2866 circulating proteins by the Olink Explore 3072/384 platform (with a primary focus on 617 proteins related to inflammation and immune function). FINDINGS:Carotid artery plaque was detected in 115/359 men (32%). Adlercreutzia equolifaciens and Eubacterium sp3131 were associated with lower odds of plaque (OR [95% CI] = 0.57 [0.43, 0.77], 0.84 [0.76, 0.93], respectively), while Coprococcus sp13142 was associated with higher odds of plaque (OR [95% CI] = 1.14 [1.06, 1.23]). Results were consistent in men both with and without HIV. A. equolifaciens was positively correlated with HDL cholesterol and inversely correlated with systolic blood pressure. These plaque-associated microbial species were also associated with a range of circulating metabolites and inflammatory proteins. For example, A. equolifaciens positively correlated with the metabolites palmitoyl-EA and mesobilirubinogen, and inversely correlated with the pro-inflammatory chemokine CXCL9, the immune regulator CD160, and IL-24. INTERPRETATION:We identified gut microbial features associated with carotid artery atherosclerosis, consistent across HIV status; these associations were partially explained by specific microbiota-related metabolites and inflammatory markers. If validated, these findings suggest gut microbiota-related targets for CVD prevention. FUNDING:The study was funded by the National Heart, Lung, and Blood Institute (U01HL146204-04S1, K01HL169019).

BACKGROUND AND AIMS:Lipoprotein(a) [Lp(a)] and LDL cholesterol (LDL-C) are causally linked to aortic valve calcium (AVC) and aortic stenosis (AS). Lipoprotein(a) has anti-fibrinolytic properties; therefore, aspirin may reduce cardiovascular disease risk among individuals with high Lp(a). This analysis sought to determine the association of aspirin with incident AVC and AS across Lp(a) and LDL-C levels. METHODS:This observational study included up to 6598 participants in the Multi-Ethnic Study of Atherosclerosis. Aortic valve calcium was measured on non-contrast cardiac computed tomography. Multivariable Cox hazards regression assessed the association of self-reported regular aspirin use (≥3 days/week) with incident AVC and severe AS, stratified by Lp(a) and LDL-C. Aortic valve calcium and Lp(a) values were not reported to participants. RESULTS:Mean age was 62 years, 53% were women, 23% reported regular aspirin use, 8% developed AVC (median 8.9 years), and 1% developed severe AS (median 16.7 years). Among individuals with elevated Lp(a), regular aspirin use was associated with a lower risk of incident AVC (Lp(a) ≥75 mg/dL: hazard ratio (HR) .42, 95% confidence interval (CI) .19-.93; Lp(a) ≥100 mg/dL: HR .17, 95% CI .04-.67) and severe AS (Lp(a) ≥50 mg/dL: HR .13, 95% CI: .04-.47; Lp(a) ≥75 mg/dL: HR .02, 95% CI .001-.29). For participants with elevated LDL-C, there was no association of regular aspirin use with incident AVC (LDL-C ≥130 mg/dL: HR 1.02, 95% CI .66-1.58; LDL-C ≥160 mg/dL: HR 1.51, 95% CI .53-4.28) or severe AS (LDL-C ≥100 mg/dL: HR .70, 95% CI .39-1.26; LDL-C ≥130 mg/dL: HR .46, 95% CI .14-1.47). CONCLUSIONS:In this exploratory analysis of prospective observational cohort data, regular aspirin use was associated with a lower risk of AVC and severe AS in persons with high Lp(a), but not high LDL-C. Confirmatory studies are required to determine the role of aspirin in the prevention of AVC and AS for persons with high Lp(a).