Incident Atherosclerotic Cardiovascular Disease Research Articles

Lipoprotein(a) as a Risk Factor for Recurrent Acute Myocardial Infarction and Mortality: Insights from Routine Clinical Practice.

Lipoprotein(a) [Lp(a)] is a well-established risk factor for incident atherosclerotic cardiovascular (CV) disease. However, evidence regarding its association with recurrent events is limited. To address this gap, we conducted a retrospective analysis of routine clinical data, focusing on patients hospitalized for acute myocardial infarction (AMI) between 2000 and 2022 with available admission Lp(a) results. Patients were stratified into three groups based on their Lp(a) level (≤50 mg/dL, 51-90 mg/dL, and >90 mg/dL). A multivariable-adjusted Cox regression analysis was performed to assess the associations of Lp(a) with recurrent AMI, CV mortality, and all-cause mortality. A total of 2248 patients (31.5% women), with a mean age of 64.7 ± 12.2 years, were retrospectively followed until 31 December 2022, or death. The multivariable-adjusted hazard ratios (HRs) for recurrent AMI were 1.01 (p = 0.921) for levels 51-90 mg/dL and 1.51 (p = 0.013) for levels > 90 mg/dL, compared with levels ≤ 50 mg/dL. The corresponding HRs for CV mortality were 1.13 (p = 0.300) and 1.14 (p = 0.348), and those for all-cause mortality were 1.09 (p = 0.310) and 1.20 (p = 0.090), respectively. Stratification by sex and age revealed a significant association of Lp(a) with recurrent AMI only in women aged > 65 years, with adjusted HRs of 2.34 (p = 0.013) for levels 51-90 mg/dL and 3.94 (p < 0.001) for levels > 90 mg/dL, compared with levels ≤ 50 mg/dL. In the presented study, Lp(a) was associated with a significantly higher risk of recurrent AMI only in women aged > 65 years with Lp(a) levels > 50 mg/dL. We found no significant associations between Lp(a) and CV or all-cause mortality.

Cardiovascular Health Score and Atherosclerotic Cardiovascular Disease in the Million Veteran Program

The American Heart Association proposed Life's Essential 8 (LE8) as an enhanced measurement tool for cardiovascular health. To examine the association of LE8 with risk of atherosclerotic cardiovascular disease (ASCVD) incidence and prognosis in veterans. This was a prospective cohort study of US veterans enrolled in the Department of Veterans Affairs (VA) Million Veteran Program (MVP) between 2011 and 2022. Data were analyzed from 2023 to 2024. LE8 score ranged from 0 to 100, with higher score indicating better cardiovascular health. The primary outcome was total ASCVD incidence in veterans without baseline ASCVD, and the secondary outcome was incidence of a major adverse cardiovascular event (MACE) among veterans with and without ASCVD at baseline. A total of 413 052 veterans (mean [SD] age, 65.8 [12.1] years; 378 162 [91.6%] male) were included. Based on 1.7 million person-years of follow-up of 279 868 veterans without any ASCVD at baseline, 45 067 veterans had an ASCVD event during follow-up. Total LE8 score and each component LE8 factor score was associated with incident ASCVD in an inverse, linear, dose-response manner. For veterans without prior ASCVD, those with an LE8 score between 80 and 100 had lower risk of ASCVD compared with those with an LE8 score of 0 to 49 (adjusted hazard ratio [aHR], 0.36 [95% CI, 0.35-0.38]). Similarly, risk of MACE was significantly lower among veterans with an LE8 score of 80 to 100 regardless of baseline ASCVD status (with ASCVD: aHR, 0.52 [95% CI, 0.48-0.56]; without ASCVD: aHR, 0.14 [95% CI, 0.13-0.15]) compared with those with ASCVD and an LE8 score of 0 to 49. In this cohort study of US veterans, higher LE8 scores were associated with significantly lower ASCVD incidence risk and lower likelihood of developing adverse cardiovascular events regardless of ASCVD status at baseline. These results support the utility of LE8 for health promotion and ASCVD prevention.

Incidence and Prevalence of Atherosclerotic Cardiovascular Disease in Cutaneous Lupus Erythematosus

Autoimmune diseases such as systemic lupus erythematosus (SLE) and psoriasis have been previously associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD). Whether similar increased ASCVD risk is seen with cutaneous lupus erythematosus (CLE) remains unclear. To evaluate the incidence and prevalence of ASCVD among those with CLE, SLE, and psoriasis compared with a disease-free control group. This retrospective, matched longitudinal cohort study used data from January 2018 to December 2020 in the IBM MarketScan Commercial Claims and Encounters Database. The control population included individuals free of CLE, SLE, and psoriasis, matched 10:1 with the CLE population on age, sex, insurance type, and enrollment duration. Data were analyzed from September 2022 to April 2024. Prevalent ASCVD was defined as coronary artery disease, prior myocardial infarction, or cerebrovascular accident. Incident ASCVD was assessed through the number of hospitalization events through the end of follow-up (up to 3 years) in each group. Multivariable logistic regression and Cox proportional hazards models were performed to compare the prevalence and incidence of ASCVD between exposure groups, adjusting for age, sex, and cardiovascular risk factors. A total of 8138 persons with CLE (median [IQR] age, 49 [40-47] years; 6618 [81%] female), 24 675 with SLE (median [IQR] age, 46 [36-54] years; 22 432 [91%] female), 192 577 persons with psoriasis (median [IQR] age, 48 [36-56] years; 106 631 [55%] female), and 81 380 control individuals (49 [40-57] years; 66 180 [81%] female) were identified. In multivariable analysis, the odds of ASCVD were higher than control for CLE (odds ratio [OR], 1.72 [95% CI, 1.45-2.02]; P < .001) and SLE (OR, 2.41 [95% CI, 2.14-2.70]; P < .001), but not psoriasis (OR, 1.03 [95% CI, 0.95-1.11]; P = .48). At median 3 years follow-up, incidence rates of ASCVD were highest for SLE (24.8 [95% CI, 23.3-26.4] per 1000 person-years), followed by CLE (15.2 [95% CI, 13.1-17.7] per 1000 person-years), psoriasis (14.0 [95% CI, 13.5-14.4] per 1000 person-years), and then controls (10.3 [95% CI, 9.77-10.94] per 1000 person-years). In multivariable Cox proportional regression modeling with the control group as a reference group, the highest risk of incident ASCVD was in those with SLE (hazard ratio [HR], 2.23 [95% CI, 2.05-2.43]; P < .001), followed by CLE (HR, 1.32 [95% CI, 1.13-1.55]; P < .001), and psoriasis (HR, 1.06 [95% CI, 0.99-1.13]; P = .09). In this retrospective matched longitudinal cohort study, CLE was associated with an increased risk for ASCVD, similar to the risk in SLE but higher than the risk in psoriasis. The role of comorbidities that augment ASCVD risk like smoking status should be further investigated. Clinicians treating patients with CLE can consider them at increased ASCVD risk and institute appropriate screening tests.

Traditional Risk Factors, Optimal Cardiovascular Health, and Elevated Lipoprotein(a).

To assess the association of traditional risk factor burden and Life's Simple 7 (LS7) score with incident atherosclerotic cardiovascular disease (ASCVD) across Lp(a) levels. There were 6,676 participants without clinical ASCVD from the Multi-Ethnic Study of Atherosclerosis who underwent Lp(a) testing and were followed for incident ASCVD events (coronary heart disease and stroke). Low, intermediate, and elevated Lp(a) were defined as <30, 30-49, and >50 mg/dL, respectively. Cox proportional hazards regression assessed the association of traditional risk factors and LS7 score (poor: 0-8, average: 9-10, optimal: 11-14) with incident ASCVD across Lp(a) groups during a median follow-up of 17.7 years, adjusting for demographics and time-varying statin and aspirin therapy. The mean age was 62.1 years, 53% were women, and 61% were non-white. The median Lp(a) was 17 (IQR 8-41) mg/dL, 13% had Lp(a) 30-49 mg/dL, and 20% had Lp(a) >50 mg/dL. Individuals with Lp(a) >50 mg/dL had higher absolute event rates across all LS7 categories. There was no significant interaction between Lp(a) and LS7 score on incident ASCVD (p-interaction=0.60). Compared to a poor LS7 score, optimal LS7 conferred a lower risk for incident ASCVD among individuals with Lp(a) <30 (HR=0.45, 95% CI: 0.28-0.71), Lp(a) 30-49 (HR=0.12, 95% CI: 0.02-0.89), and Lp(a) >50 mg/dL (HR=0.35, 95% CI: 0.13-0.99). Participants without clinical ASCVD who achieved an optimal LS7 score had ASCVD risk reduction regardless of Lp(a) level. These results emphasize the importance of a healthy lifestyle and ASCVD risk factor control among individuals with elevated Lp(a).

Abstract 4124446: Traditional Risk Factors, Cardiovascular Health, and Elevated Lipoprotein(a): The Multi-Ethnic Study of Atherosclerosis

Introduction: One in five individuals have elevated lipoprotein(a) [Lp(a)], an inheritable risk factor that is causally associated with atherosclerotic cardiovascular disease (ASCVD). Whether individuals with elevated Lp(a) derive similar benefit from control of ASCVD risk factors has not been well-studied. Hypothesis: The magnitude of benefit associated with optimal cardiovascular health will be similar across the spectrum of Lp(a). Aim: To assess the association of traditional risk factor burden and Life’s Simple 7 (LS7) score with incident ASCVD across Lp(a) values. Methods: We studied 6,676 participants from the Multi-Ethnic Study of Atherosclerosis who underwent Lp(a) testing and were followed for incident ASCVD events (coronary heart disease and stroke). Elevated Lp(a) was defined as &gt; 50 mg/dL. As defined by the American Heart Association, LS7 metrics included smoking, physical activity, body mass index, diet, total cholesterol, blood pressure, and glucose. Multivariable Cox proportional hazards regression assessed the association of traditional risk factor burden and LS7 score (poor: 0-8, average: 9-10, optimal: 11-14) with incident ASCVD for individuals with and without elevated Lp(a) during a median follow-up of 17.7 years. Results: The mean age was 62.1 years, 53% were women, and 61% were non-white. The median Lp(a) was 17 mg/dL and 20% had Lp(a) &gt; 50 mg/dL. Individuals with Lp(a) &gt; 50 mg/dL had the highest burden of traditional risk factors except cigarette smoking. Compared to those with a poor LS7 score, those with an optimal LS7 score had a lower ASCVD risk that was significant for participants with Lp(a) &lt;50 mg/dL (HR=0.37, 95% CI: 0.25-0.55), but borderline significant for participants with Lp(a) &gt; 50 mg/dL (HR=0.41, 95% CI: 0.16-1.02). Individuals with Lp(a) &gt; 50 mg/dL had the highest absolute event rates across all LS7 categories, and there was no significant interaction between Lp(a) and LS7 score on incident ASCVD (p-interaction=0.64, Figure ). Conclusions: Participants with an optimal LS7 score had similar reduction in ASCVD risk regardless of their Lp(a) burden. These results emphasize the importance of a healthy lifestyle and ASCVD risk factor control among patients with elevated Lp(a).

Abstract 4138332: Lipoprotein (a), Triglyceride-Glucose Index and Incident Atherosclerotic Cardiovascular Disease (ASCVD): Analysis of the UK Biobank

Background: The triglyceride-glucose index (TyG), an inexpensive novel surrogate marker for insulin resistance, and lipoprotein (a) [Lp(a)] are both risk factors for atherosclerotic cardiovascular disease (ASCVD). However, it is uncertain whether TyG modifies the relationship of Lp(a) with incident ASCVD. Objective: To investigate the relationship of Lp(a) and TyG with the risk of incident ASCVD. Methods: We included UK Biobank participants without ASCVD at enrollment. Baseline TyG was calculated as ln[fasting triglycerides (mg/dL) × fasting plasma glucose (mg/dL)/2]. We classified TyG values as high (≥75th percentile) or low (&lt;75th percentile), and Lp(a) levels, in nmol/L, as &lt;125 or ≥125. Participants were then stratified into four groups: Group-1: Low TyG with Lp(a), &lt;125, Group-2: Low TyG with Lp(a) ≥125, Group-3: High TyG with Lp(a) &lt;125, and Group-4: High TyG with Lp(a) ≥125. We used multivariable Cox regression to estimate the risk of ASCVD (a composite of peripheral arterial disease, coronary artery disease, myocardial infarction, ischemic stroke, and cardiovascular mortality) of TyG and Lp(a) adjusted for the other, and in the four combination groups. Results: Eligible participants (N=254,377) had a mean (SD) age of 56.0 (8.1) years, and 53.2% were female. The median follow-up was 14.6 years. In separate models additionally adjusted for cardiovascular risk factors (see Figure legend), the hazard ratio (HR [95% CI]) for ASCVD was 1.18(1.13–1.23) for Lp(a) ≥125 nmol/L (vs. &lt;125 nmol/L), adjusted for TyG, and 1.09(1.05–1.13) for high TyG (vs. low), adjusted for Lp(a). A statistically significant interaction between TyG and Lp(a) was observed in the fully adjusted model (p &lt;0.001). Compared to Group-1 (low TyG with Lp(a) &lt;125nmol/L), the adjusted HR (95% CI) of incident ASCVD in Group-2, -3 and -4 were: 1.07(1.04–1.13), 1.15 (1.09–1.21) and 1.34(1.25–1.44), respectively (Figure). Conclusions: These findings demonstrate that TyG and Lp(a) are associated with incident ASCVD risk independently of each other. Moreover, TyG modified the effect of Lp(a) on ASCVD, suggesting that insulin resistance may amplify the atherogenic, inflammatory, and/or thrombotic effects of Lp(a), thereby further increasing ASCVD risk.

Abstract 4137058: Clinical Characteristics and Outcomes of South Asians Presenting with Acute Coronary Syndrome

Background: Patients of South Asian descent have a higher incidence of atherosclerotic cardiovascular disease and are affected by clinically significant coronary artery disease at an earlier age when compared to the general population. As a result, they have been shown to have a higher rate of cardiovascular events. This at-risk population has not been well studied as it pertains to acute coronary syndrome. Methods: Out of 1610 patients who presented to one of two tertiary care centers between 2021-2022 with a diagnosis of acute coronary syndrome and underwent coronary angiography, 240 patients were identified as being South Asian and were included in the study. 480 non-South Asian patients were randomly selected as controls. A retrospective analysis was conducted to study the demographics, risk factors, clinical presentation, diagnostic features, and outcomes of the two groups. Results: South Asian patients who were diagnosed with acute coronary syndrome and underwent coronary angiography were significantly younger than non-South Asian patients (61 vs 65 years, p &lt; 0.001). Though they were less likely to be smokers, they were significantly more likely to have other known risk factors including hypertension, dyslipidemia, and a history of prior myocardial infarction (p &lt; 0.001). South Asians had mean lower HDL (p = 0.02), higher triglycerides (0.006), and higher Hgb A1C (p &lt; 0.001). Surprisingly, rates of multivessel disease (defined as stenosis of 50% or greater in two or three vessels) were similar between the two groups. South Asians were more likely to be referred for CABG after initial coronary angiography most likely due to diffuse disease (p = 0.014). Clinical outcomes including pre-discharge LVEF, and 2-year mortality were similar between the groups. Conclusions: South Asians are a notoriously high-risk group when it comes to early-onset and more severe coronary artery disease. The pathophysiology behind this disproportionate manifestation of cardiovascular disease is not entirely understood, but several efforts to delineate this are ongoing. Our data demonstrate that this is at least in part, due to a higher prevalence of conventional modifiable and nonmodifiable risk factors in South Asian patients.

Abstract 4121568: The Influence of Cardiovascular Health on Atherosclerotic Cardiovascular Disease Progression and Life Expectancy Among Individuals with Type 2 Diabetes

Objective: This study aims to evaluate whether cardiovascular health (CVH) plays a similar role in the transition from a healthy state to atherosclerotic cardiovascular disease (ASCVD) and subsequent mortality rates in diabetic patients compared to those without diabetes. It also evaluates the effectiveness of CVH in reducing diabetes-related ASCVD risks and enhancing ASCVD-free life expectancy. Research design and methods: This cohort study included 176,669 adults from the UK Biobank, among whom 10,109 (22.3%) were diagnosed with type 2 diabetes mellitus (T2DM). CVH was assessed using the Life's Essential 8 score, encompassing diet, physical activity, smoking, sleep, BMI, blood lipids, blood glucose, and blood pressure. CVH scores were categorized into low, moderate, and high levels based on their distribution among diabetic patients. The main outcomes were the transitions from no ASCVD to the onset of ASCVD and then to mortality, as well as the ASCVD-free life expectancy. Results: In patients with T2DM, high CVH levels were associated with lower ASCVD risk (HR: 0.55, 95% CI: 0.45-0.68 for women; HR: 0.57, 95% CI: 0.50-0.65 for men) and reduced mortality in those with ASCVD (HR: 0.62, 95% CI: 0.39-0.98 for women; HR: 0.62, 95% CI: 0.48-0.79 for men), compared to the low CVH group. No significant difference in CVH's effect on ASCVD and mortality was observed between diabetic and non-diabetic groups. When compared with non-diabetic individuals, no excess risk was observed in incident ASCVD and post-ASCVD mortality among diabetic patients with high CVH. At the age of 40, women with low CVH were expected to live 38.5 years (38.0-39.1) free from ASCVD, which increased to 42.9 years (42.4-43.5) for those with high CVH, while non-diabetic women were predicted to have an ASCVD-free life expectancy of 44.1 years (43.5-44.6). For men at the age of 40, those with low CVH had an ASCVD-free life expectancy of 32.0 years (31.3-32.6), which rose to 37.9 years (37.4-38.6) with high CVH. Non-diabetic men were expected to live 38.3 years (37.7-39.0) free from ASCVD. Notably, life expectancy with ASCVD did not increase with higher CVH levels in both genders. Conclusions: Our findings suggest that the American Heart Association’s recommendations for promoting CVH, initially designed for the general population, are also beneficial for individuals with T2DM. Adopting these guidelines can help mitigate ASCVD progression and enhance life expectancy in diabetic patients.

Abstract 4136554: Comparison of short- and long-term atherosclerotic cardiovascular disease risk assessment tools in US young adults

Background: In 2023, the AHA published the PREVENT equations for estimating atherosclerotic cardiovascular disease (ASCVD) risk in adults aged 30-79 years. Research Questions: In young adults aged 20-39 years, does PREVENT improve risk prediction for 10- and 30-year ASCVD compared with existing risk assessment tools recommended in the current US guidelines (i.e., Pooled Cohort Equations [PCEs] and Pencina et al. equations)? Aims: To compare the performance of PREVENT vs. PCEs in predicting 10-year ASCVD, and PREVENT vs. Pencina equations in predicting 30-year ASCVD in young adults. Methods: We analyzed data from two complementary sources: (1) pooled data from two large cohorts: Coronary Artery Risk Development in Young Adults (CARDIA) and Framingham Heart Study (FHS; including the Offspring, Third Generation, Omni 1, and Omni 2 cohorts), and (2) electronic health records from Kaiser Permanente Southern California (KPSC). We included adults aged 20-39 years without a history of ASCVD at baseline. The outcome was incident ASCVD (defined as myocardial infarction, fatal coronary heart disease, fatal and nonfatal stroke) at 10 or 30 years. Model discrimination (Harrell’s C) and mean calibration (estimated as the ratio of predicted to observed event rates) were calculated for the overall population and stratified by sex and race/ethnicity. Results: We included 7,606 young adults (mean age 29 years, 53% female, 30% Black) from the pooled cohorts, and 284,667 (mean age 32 years, 61% female, 8% Black, 46% Hispanic) from KPSC. When predicting 10-year risk, PREVENT improved discrimination in both the pooled cohort (ΔHarrell’s C=0.052; 95% CI: 0.014, 0.095) and KPSC (ΔHarrell’s C=0.039; 95% CI: 0.028, 0.049) compared with the PCEs. PREVENT had good calibration (mean calibration ranged from 0.77 to 1.54), whereas the PCEs overestimated 10-year risk (mean calibration ranged from 1.99 to 4.82). When predicting 30-year risk, discrimination was similar for PREVENT and Pencina equations, but both algorithms underestimated 30-year risk with PREVENT showing worse calibration (mean calibration 0.61). Conclusion: PREVENT improved 10-year ASCVD risk prediction in young adults compared to the PCEs but underestimated 30-year risk.

Abstract 4134911: Coronary Artery Calcium Predicts Cardiovascular Events in Individuals with Controlled Atherosclerotic Risk Factors: A Multi-Cohort Study

Background: There is residual risk of atherosclerotic cardiovascular disease (ASCVD) that remains despite adequate risk factor (RF) control. Coronary artery calcium (CAC) has demonstrated value in ASCVD risk stratification. We evaluated the value of CAC in identifying residual risk of ASCVD events among those with traditional RF control. Methods: Participants without clinical ASCVD were pooled from the Multi-Ethnic Study of Atherosclerosis, Heinz Nixdorf Recall Study, Framingham Heart Study, and Jackson Heart Study. RF control was classified as “guideline-concordant” and “optimal” (Figure 1). Participants were stratified by the number of controlled RFs at baseline and CAC score (CAC = 0, 1-99, ≥100). Cox proportional hazards models examined the association between CAC and incident ASCVD events. Results: The study included 14,780 individuals (mean age 58 years (SD: 11), 54% female, 59% White, 27% Black, 50% CAC = 0). Over a median follow-up of 14.6 years, there were 1,441 incident ASCVD events. The distribution of CAC and ASCVD event incidence is shown in Panel A; 10% of those with 3 optimal RFs and 19% of those with 3 guideline-concordant RFs controlled had CAC &gt; 100. The rate of ASCVD events decreased with more RFs controlled and increased with higher CAC. Overall, optimal RF control was associated with lower ASCVD event rates compared to guideline-concordant control. At every level of RF control, CAC &gt; 100 was associated with increased HRs for incident ASCVD (Panel B). Those with CAC ≥ 100 and controlled RFs experienced ASCVD rates numerically comparable to or exceeding those with uncontrolled RFs but CAC = 0 (Panel A). Adjusted HR (95% CI) for ASCVD events with CAC &gt; 100 compared to CAC = 0 was 5.0 (2.0, 12.9) in optimal RF control and 3.7 (2.6, 5.4) in guideline-concordant RF control. Conclusion: There is significant heterogeneity in residual ASCVD risk among those with optimal or guideline-concordant traditional RF control and CAC can help identify this risk. Irrespective of RF control, a higher CAC burden was associated with increased ASCVD risk. Future studies could use CAC testing to identify those with higher residual ASCVD risk despite effective traditional RF control to target for novel therapies.

Abstract 4134572: Assessing Sex Differences in the Relationship Between Social Isolation and Incident Atherosclerotic Cardiovascular Disease and Death Using Data from the U.S. Health and Retirement Study

Background: Inadequate social connection has been associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD) and mortality. There are insufficient and conflicting data on whether sex differences play a role in this relationship. Therefore, we sought to further examine the relationship between sex, social isolation, and these subsequent events. Methods: We analyzed Health and Retirement Study (HRS) and RAND data collected biennially from 8,987 individuals enrolled from 2004-2020 who completed at least 1 Leave Behind Questionnaire (LBQ). Social isolation was determined from LBQ data using a previously validated 6-item scale where scores of 3 or greater indicated social isolation. Development of ASCVD was classified as new self-reported myocardial infarction or stroke at any follow-up assessment. Mortality was determined with RAND longitudinal data, which was available for all individuals. We examined the incidence of ASCVD in socially isolated and not socially isolated individuals using a cumulative incidence function accounting for the competing risk of death. Results: Mean age at baseline LBQ survey was 55.7 years and 43% of the sample were male. In the sample, 23% identified as Black, 63% identified as White, and 13% identified as Other. Social isolation was present in 1,653 (18%) individuals at their baseline survey. ASCVD developed in 484 (5%) participants, and 593 (7%) participants died over the study’s follow-up period. Cumulative incidence analysis showed no significant difference in ASCVD incidence between socially isolated and non-socially isolated groups for either sex (male p-value: 0.15; female: 0.09) (Figure). However, the incidence of death was significantly increased for both socially isolated sexes (male p-value: &lt;0.001; female: &lt;0.001). Conclusion: While socially isolated participants were not at significantly increased risk of incident ASCVD, they were at significantly increased risk of mortality, irrespective of sex. This highlights the need for continued public health initiatives that foster social connection to enhance the well-being of the general population. The study is limited by reliance on self-report for ASCVD, which may underestimate disease incidence.

Abstract 4136592: Comparative performance of PREVENT and Pooled Cohort Equations to predict cardiovascular disease in multisite healthcare populations

Introduction: The American Heart Association’s race-agnostic Predicting Risk of cardiovascular EVENTs (PREVENT) framework has emerged to better capture multilevel determinants of health in contemporary population. Whether PREVENT better predicts incident atherosclerotic cardiovascular disease (ASCVD) than the preceding Pooled Cohort Equations (PCE) is unknown in healthcare populations. We evaluated calibration and discrimination of the two equations across three major U.S. healthcare networks. Methods: We retrospectively evaluated electronic health records of 209,879 individuals (Mass General Brigham [MGB]: 118,801; Mount Sinai Healthcare System: 38,834; Penn Medicine: 52,424) aged 40-79 years and without prior ASCVD between 2010-2012. Calibration was assessed using discordance ratio between 10-year observed and predicted risk. Discrimination was evaluated by Harrell’s C-index. Results: Based on PREVENT, the mean [SD] estimated 10-year ASCVD risk ranged from 5.5 [4.7] % in MGB (mean age 56y, 42% female), 6.6 [5.6]% in Mount Sinai (59y, 54% female), and 6.4 [5.2]% in Penn (60y, 55% female). PREVENT substantially underestimated empirical 10-year ASCVD incidence in MGB (16.9%) and Mount Sinai (10.9%), whereas it closely mirrored the observed rate in Penn (5.5%). Both PCE and PREVENT had comparable discrimination C-index [95% CI] across MGB (0.69 [0.69-0.70] vs. 0.69 [0.68-0.69]), Mount Sinai (0.72 [0.71-0.73] vs. 0.70 [0.70-0.71]), and Penn (0.68 [0.67-0.69] vs. 0.67 [0.66-0.68]). Nevertheless, compared to PREVENT, PCE demonstrated better overall calibration in MGB (-70% vs. -42%) and Mount Sinai (-36% vs. +5%), whereas largely overestimated risk in Penn (+3% vs +94%). Calibration varied across demographics with PREVENT consistently underestimating risk in Hispanics, Asians, Black and African Americans across all sites, whereas PCE largely overestimated risk for White or multiracial Penn healthcare patients. Conclusions: The race-agnostic PREVENT model discriminated ASCVD incidence comparably or better than the race-informed PCE across three geographically distinct academic health systems in the Northeast. However, calibration metrics between the two models varied widely across health systems and demographics.

Abstract 4137527: Evaluation of 10-Year Atherosclerotic Cardiovascular Risk Prediction Performance using the PREVENT versus Pooled Cohort Equations in a US Integrated Healthcare System

Background: The American Heart Association published the new PREVENT equations for estimating atherosclerotic cardiovascular disease (ASCVD) risk. Question: Do the PREVENT equations improve risk prediction for 10-year ASCVD compared with the pooled cohort equations (PCEs) in a large diverse population? Aim: To assess ASCVD risk prediction performance of the two PREVENT equations [PREVENT Base, PREVENT Base plus optional predictors including urine albumin-to-creatinine ratio, glycated hemoglobin, and social deprivation index (PREVENT Full)] compared with the PCEs. Methods: We included adults aged 40-75 years without a history of ASCVD or diabetes from Kaiser Permanente Southern California in 2009 and followed them through 2019. Outcome was incident ASCVD defined as myocardial infarction, fatal coronary heart disease, fatal and nonfatal stroke. We compared model discrimination (Harrell’s C), mean calibration (estimated as the ratio of predicted to observed event rates), and calibration curve among the overall population and stratified by sex and race/ethnicity. Results: Of the 559,111 adults (mean age 54, 11% Black, 32% Hispanic), 10,695 developed an ASCVD event during a median follow-up of 10 years. Harrell’s C among the overall population was 0.741 (95% CI 0.736-0.745) for PREVENT Base, 0.743 (0.738-0.748) for PREVENT Full, and 0.741 (0.736-0.746) for the PCEs ( Table ). Compared with the PCEs, both PREVENT equations improved Harrell’s C in men but not in women, and in Black adults but not in other racial/ethnic groups. Both PREVENT equations were well-calibrated (mean calibration ranged 0.83-1.37; calibration slope ranged 0.71-1.28), while the PCEs overestimated 10-year ASCVD risk (mean calibration ranged 1.80-2.20; calibration slope ranged 0.34-0.45) ( Table &amp; Figure ). Conclusion: Compared with the PCEs, both PREVENT Base and Full equations improved calibration in predicting 10-year ASCVD risk, with minimal improvement in discrimination in men and Black adults only.

Abstract 4133257: Circulating Ketone Bodies, Lipoprotein(a) and Incident Cardiovascular Outcomes and Mortality: Insights from The UK Biobank

Background: Lipoprotein(a) [Lp(a)] is an independent risk factor for atherosclerotic cardiovascular disease (ASCVD). Recent epidemiological studies have revealed an association between ketone bodies (KB) and adverse cardiovascular outcomes, offering a unique insight into metabolic health and its impact on mortality risk. Elevated levels of both Lp(a) and KB may synergistically amplify pathological processes, including endothelial dysfunction, inflammation, and oxidative stress, through their involvement in shared pathophysiological pathways, thereby exacerbating disease progression beyond the impact of each biomarker individually. Methods: Utilizing data from the UK Biobank, KB were measured by nuclear magnetic resonance spectroscopy and serum Lp(a) concentrations were measured using an immunoturbidimetric assay. Four groups were created as follows: Group 1: Lp(a)&lt;125 nmol/L and Total KB&lt;75 th percentile (&lt;94 μmol/L); Group 2: Lp(a)≥125 nmol/L and Total KB&lt;75 th percentile; Group 3: Lp(a)&lt;125 nmol/L and Total KB≥75 th percentile; and Group 4: Lp(a)≥125 nmol/L and Total KB≥75th percentile. Multivariable-adjusted Cox proportional hazard models were used to examine the association of Lp(a) and total KB with incident cardiovascular outcomes and mortality. Results: A total of 72,704 UK Biobank participants (mean age 56 y, SD=8, 55% women) without prevalent CVD or HF with a median follow up of 13.4 years were included. In the fully adjusted model, compared with those in the reference group (Group 1), participants in Group 2, Group 3, and Group 4 demonstrated a 14%, 17%, and 38%, increased risk of incident ASCVD events, respectively (p&lt;0.01 for all). However, those with Lp(a) ≥ 125 nmol/L and total KB &lt; 75th percentile demonstrated no increased risk of HF, all-cause mortality, stroke, or CVD mortality. Participants with elevated levels of both Lp(a) and KB had significantly increased risk of all outcomes (Table). There was no evidence for a statistically significant interaction between Lp(a) and KB on any outcome. Conclusion: Consistent with prior literature, Lp(a) was associated with atherosclerotic outcomes. However, elevated KB was associated with all outcomes, irrespective of Lp(a) levels.

Polygenic Risk Scores and Extreme Coronary Artery Calcium Phenotypes (CAC=0 and CAC≥1000) in Adults ≥75 Years Old: The ARIC Study.

Coronary artery calcium (CAC) is heterogeneous in older age and is incompletely explained by traditional atherosclerotic cardiovascular disease risk factors. The extremes of subclinical atherosclerosis burden are strongly associated with either a low or high 10-year risk of incident atherosclerotic cardiovascular disease, respectively. However, the genetic underpinnings of differences in arterial aging remain unclear. We sought to determine the independent association of 2 polygenic scores for coronary heart disease (CHD) with CAC in adults ≥75 years of age. There were 1865 ARIC (Atherosclerosis Risk in Communities) participants who underwent genetic testing at visit 1 (1987-1989) and CAC scans at visit 7 (2018-2019). In the primary analysis, an externally derived multi-ancestry polygenic CHD risk score was calculated for both White and Black participants. Results were confirmed using a separate ARIC-derived polygenic CHD risk score, including ≥6 million variants computed for White participants. We used multivariable logistic regression models to assess the association of polygenic CHD risk with CAC, after adjusting for baseline, time-averaged lifestyle, traditional risk factors, and local ancestry principal components. In the primary analysis, the average age was 80.6 years old, 61.6% were women, and the median CAC score was 246 (189 participants with CAC=0, 364 participants with CAC≥1000). Compared with persons below the 20th percentile of polygenic CHD risk, persons with polygenic-CHD risk above the 80th percentile had 82% lower odds of having CAC=0 (odds ratio, 0.18 [95% CI, 0.09-0.37]) and had >4-fold higher odds of CAC≥1000 (odds ratio, 4.77 [95% CI, 2.88-7.88]). On a continuous scale, each SD increment increase in the polygenic risk score was associated with a 78% higher CAC score. Results were nearly identical using a second confirmatory polygenic CHD risk score in White participants. Polygenic CHD risk is robustly associated with a lower prevalence of CAC=0 and a higher prevalence of CAC≥1000 in adults ≥75 years of age, beyond lifestyle and traditional risk factors. These results suggest a heritable contribution to distinct healthy and unhealthy arterial aging phenotypes that persist throughout the life course.

Combination of moderate-intensity statins and ezetimibe versus high-intensity statins alone for primary prevention of cardiovascular events

Abstract Background Combination of a moderate-intensity statin with ezetimibe can lead to similar reductions in cardiovascular events as monotherapy with a high-intensity statin in patients with established atherosclerotic cardiovascular disease (ASCVD). The comparative effectiveness of these two cholesterol-lowering strategies in the primary prevention setting is unknown. Purpose To compare incident ASCVD events associated with a combination of moderate-intensity statin and ezetimibe versus monotherapy with a high-intensity statin in adults without prior history of cardiovascular disease. Methods We conducted a new-user active comparator retrospective population-based cohort study in Canada. We included all adults aged ≥ 67 years (eligible for drug coverage) with a first prescription of either a combination of moderate-intensity statin with ezetimibe ("combination therapy") or high-intensity statin alone between January 2010 and December 2022. Patients were excluded if they had not received any prior lipid lowering therapies or had a history of myocardial infarction (MI), stroke, heart failure, peripheral vascular disease or prior coronary revascularisation at any time before or within 3 months of treatment initiation. The primary outcome was a composite of all-cause death, hospitalization for MI or stroke, or coronary revascularization. An inverse probability of treatment weighting propensity score was used to account for confounding (demographics, comorbidities, laboratory tests, other medications). Results Among 67,884 patients (mean age: 74.0±5.5y; 53% females), 8,798 (13%) initiated combination therapy and 59,086 (87%) initiated a high-intensity statin. At 1 year, after weighting, the mean achieved LDL-C was ~1.9 mmol/L in both groups. The median follow-up was 6.5 years. The cumulative incidence of the primary outcome at 10 years in the weighted cohort was 32.7% in the combination therapy group and 36.1% in the high-intensity statin group (HR: 0.87; 95% CI: 0.82 to 0.92; p&amp;lt;0.001; absolute risk reduction: 3.5%; 95% CI: 0.8 to 6.1; Figure 1). This result was primarily driven by a lower risk of all-cause death (HR: 0.85; 95% CI: 0.80 to 0.91; p&amp;lt;0.001; Figure 2) and stroke (cause-specific [cs] HR: 0.86; 95% CI 0.74 to 0.99; p=0.04), whereas no differences were observed in the risk of MI (csHR: 0.97; 95% CI: 0.82 to 1.15) or coronary revascularization (csHR: 0.97; 95% CI 0.85 to 1.11). Conclusion The combination of moderate-intensity statins with ezetimibe was associated with a lower risk of incident ASCVD compared with high-intensity statins alone among primary prevention patients in a real-world setting. These results were driven by a lower risk of all-cause death and stroke, but not coronary events. The influence of statin intolerance on the allocated strategy and adherence to therapy cannot be addressed in this analysis, which, along with verifying these estimates, may be best determined in a prospective randomized trial.

Risk-enhancing factors and social determinants of health in risk assessment for atherosclerotic cardiovascular disease.

The Pooled Cohort Equations (PCEs) do not accurately estimate atherosclerotic cardiovascular disease (ASCVD) risk in certain populations. The 2018 AHA/ACC cholesterol guideline identified risk-enhancing factors as a supplement to PCEs-based risk assessment. However, the role of each risk-enhancing factor in ASCVD risk assessment has not been well quantified. Further, social determinants of health (SDOH) are not included in the PCEs nor considered as risk-enhancing factors in the US cholesterol guideline. We sought to evaluate ASCVD risk associated with each risk-enhancing factor and commonly collected SDOH including education, income, and employment status, and to assess if adding risk-enhancing factors and SDOH to the PCEs improve ASCVD risk prediction. We included individuals aged 40 to 75 years, without ASCVD or diabetes at baseline, and with low-density lipoprotein cholesterol 70-189 mg/dL from two contemporary prospective cohort studies (MESA and REGARDS) and from Kaiser Permanente Southern California (KPSC). The primary endpoint was incident ASCVD defined as nonfatal myocardial infarction, fatal coronary heart disease, or fatal or nonfatal stroke over a 10-year period (median follow-up 10 years). We used Cox proportional hazards models to estimate associations between risk-enhancing factors and SDOH with ASCVD. We also assessed changes in model performance after adding risk-enhancing factors and SDOH to the PCEs. We included 13,863 adults (mean age 60.7 years) from the prospective cohorts and 307,931 adults (mean age 54.8 years) from KPSC. Risk-enhancing factors including hypercholesterolemia, hypertriglyceridemia, metabolic syndrome, and chronic kidney disease were associated with a higher ASCVD risk, independent of 10-year risk estimated by the PCEs. Low education, low income, and unemployment were also associated with higher ASCVD risk. While adding individual risk-enhancing factors or SDOH to the PCEs had limited impact on model performance, adding multiple risk-enhancing factors and SDOH simultaneously led to modest improvements in discrimination (C-index increased by up to 0.07), calibration (integrated Brier score reduced by up to 2.3%), and net reclassification improvement up to 41.4%. These findings suggest including SDOH and risk-enhancing factors may improve ASCVD risk assessment.

Recent trends in GLP-1 RA and SGLT2i use among people with type 2 diabetes and atherosclerotic cardiovascular disease in the USA

IntroductionThis study aimed to assess recent trends in the US use of glucagon-like peptide-1 receptor agonist (GLP-1 RA) and sodium-glucose cotransporter 2 inhibitor (SGLT2i) in people with type 2 diabetes...

Atherosclerotic Cardiovascular Diseases Are Associated With Incident Metastatic and Nonmetastatic Cancer.

Cardiovascular diseases are associated with higher cancer risk. However, their relationship with metastatic cancer, the primary determinant of cancer prognosis, has not been studied. This study aimed to determine the association between atherosclerotic cardiovascular disease and the presence of metastasis at the time of cancer diagnosis. We analyzed data from 21,654 self-referred adults who were free of cancer and atherosclerotic cardiovascular disease at enrollment in a preventive health care program. To exclude silent cancers, a 1-year blanking period was implemented at the start of the follow-up. The relationship between atherosclerotic cardiovascular disease and metastatic cancer was assessed using cause-specific Cox regression, treating incident atherosclerotic cardiovascular disease as a time-dependent covariate. Interaction analysis further elucidated differences in metastasis risks between middle-aged adults (Q1-Q3 age≤54 years) and older adults (Q4 age >54 years). Over a median follow-up of 6 years (Q1-Q3: 3-12 years), we recorded 1,333 cases of atherosclerotic cardiovascular disease (6.2%) and 1,793 cases of cancer (8.3%), of which 1,036 (4.8 %) were nonmetastatic and 757 (3.5%) were metastatic at diagnosis. After adjusting for shared risk factors, atherosclerotic cardiovascular disease was independently associated with an increased risk of cancer metastasis at the time of cancer diagnosis (HR: 1.75; 95% CI: 1.33-2.29). This association was more pronounced among middle-aged adults (HR: 1.64; 95% CI: 1.03-2.61; P=0.036) than in older adults (HR: 1.11; 95% CI: 0.78-1.60; P=0.56), with a significant interaction (P interaction=0.039). Atherosclerotic cardiovascular disease is associated with a significantly increased risk of cancer,specifically metastasis at the time of cancer diagnosis, particularly in middle-aged adults. Recognizing thisassociation could enhance the prevention and treatment of metastatic cancer in patients with atherosclerotic cardiovascular disease.

MicroRNA-615-3p decreases apo B expression in human liver cells

Plasma lipids are mainly carried in apolipoprotein B (apoB) containing lipoproteins. High levels of these lipoproteins are associated with several metabolic diseases and lowering their plasma levels is associated with reduced incidence of atherosclerotic cardiovascular disease. MicroRNAs (miRs) are small non-coding RNAs that reduce the protein expression of their target mRNAs and are potential therapeutic agents. Here, we identified a novel miR-615-3p that interacts with human 3′-UTR of apoB mRNA, induces post-transcriptional mRNA degradation, and reduces cellular and secreted apoB100 in human hepatoma Huh-7 cells. Reducing cellular miR-615-3p levels by CRISPR-sgRNA increased cellular and secreted apoB100 indicating endogenous miR regulates apoB expression. Overexpression of miR-615-3p along with or without palmitic acid treatment decreased cellular and media apoB and increased cellular triglyceride levels without inducing endoplasmic reticulum stress. These studies have identified miR-615-3p as a negative regulator of apoB expression in human liver-derived cells. It is likely that there are more miRs that regulate apoB-containing lipoprotein assembly and secretion. Discovery of additional miRs may uncover novel mechanisms that control lipoprotein assembly and secretion.