Genetic, sociodemographic, lifestyle, and clinical risk factors of recurrent coronary artery disease events: a population-based cohort study.

AIMS: Complications of coronary artery disease (CAD) represent the leading cause of death among adults globally. This study examined the associations and clinical utilities of genetic, sociodemographic, lifestyle, and clinical risk factors on CAD recurrence. METHODS AND RESULTS: Data were from 7024 UK Biobank middle-aged adults with established CAD at enrolment. Cox proportional hazards regressions modelled associations of age at enrolment, age at first CAD diagnosis, sex, cigarette smoking, physical activity, diet, sleep, Townsend Deprivation Index, body mass index, blood pressure, blood lipids, glucose, lipoprotein(a), C reactive protein, estimated glomerular filtration rate (eGFR), statin prescription, and CAD polygenic risk score (PRS) with first post-enrolment CAD recurrence. Over a median [interquartile range] follow-up of 11.6 [7.2-12.7] years, 2003 (28.5%) recurrent CAD events occurred. The hazard ratio (95% confidence interval [CI]) for CAD recurrence was the most pronounced with current smoking (1.35, 1.13-1.61) and per standard deviation increase in age at first CAD (0.74, 0.67-0.82). Additionally, age at enrolment, CAD PRS, C-reactive protein, lipoprotein(a), glucose, low-density lipoprotein cholesterol, deprivation, sleep quality, eGFR, and high-density lipoprotein (HDL) cholesterol also significantly associated with recurrence risk. Based on C indices (95% CI), the strongest predictors were CAD PRS (0.58, 0.57-0.59), HDL cholesterol (0.57, 0.57-0.58), and age at initial CAD event (0.57, 0.56-0.57). In addition to traditional risk factors, a comprehensive model improved the C index from 0.644 (0.632-0.654) to 0.676 (0.667-0.686). CONCLUSION: Sociodemographic, clinical, and laboratory factors are each associated with CAD recurrence with genetic risk, age at first CAD event, and HDL cholesterol concentration explaining the most.

Cumulative Diastolic Blood Pressure Burden in Normal Systolic Blood Pressure and Cardiovascular Disease.

BACKGROUND: The clinical significance of isolated diastolic hypertension defined by the 2017 American College of Cardiology/American Heart Association blood pressure (BP) guidelines remains inconsistent. We examined whether long-term diastolic burden predicts the first major adverse cardiovascular event in participants with sustained and untreated normal systolic BP. METHODS: The Mass General Brigham Biobank is a New England health care-based cohort recruited between 2010 and 2021. A total of 15 979 participants aged 18 to 64 years and without prior cardiovascular disease, antihypertensives, or high systolic BP were studied. The cumulative diastolic burden was determined as the area under the curve for diastolic BP (DBP) ≥80 mm Hg over 5 years before enrollment. Major adverse cardiovascular event was defined as a composite of first incident ischemic heart disease, stroke, heart failure, or all-cause death. RESULTS: Of the 15 979 participants, mean (SD) age at enrollment was 47.6 (14.3) years, 11 950 (74.8%) were women, and the mean (SD) systolic BP and DBP were 118.0 (12.9) and 72.2 (9.3) mm Hg, respectively. Over a median (interquartile range) follow-up of 3.5 (1.8-5.4) years, 2467 (15.4%) major adverse cardiovascular events occurred. Using Cox proportional hazards regression, each SD increase in cumulative DBP was independently associated with a hazard ratio (95% CI) of 1.06 (1.02-1.10) without effect modification by sex (P=0.65), age (P=0.46), or race/ethnicity (P=0.24). In addition to traditional risk factors, cumulative DBP modestly improved the discrimination C index (95% CI) from 0.74 (0.72-0.75) to 0.75 (0.74-0.76; likelihood ratio test, P=0.037). CONCLUSIONS: Among individuals with normal systolic BP, cumulative DBP may augment cardiovascular disease risk stratification beyond a single DBP measure and traditional risk factors.

Improving Cardiovascular Disease Primary Prevention Treatment Thresholds in a New England Health Care System.

Background: Atherosclerotic cardiovascular disease (ASCVD) risk estimation based on the pooled cohort equation (PCE) overestimates in population-based cohorts. Whether it performs equally across disaggregated demographics in health care populations is less known. Objectives: The purpose of the study was to recalibrate PCE and rederive prevention thresholds in a contemporary health care system and evaluate its performance across sociodemographics. Methods: We retrospectively inspected electronic health records between 2010 to 2012 and 2020 to 2022 within Mass General Brigham health care in New England region. We compared performance of the original vs recalibrated PCE measured by calibration, discrimination, reclassification rate, and net benefit among 160,926 patients aged 40 to 79 years and without prior ASCVD or lipid-lowering medication. Results: Of the 160,926 patients (mean age: 54.6 ± 8.6 years; 61.4% female), 20,373 (12.7%) developed ASCVD over 10 years. The original PCE globally underestimated ASCVD risk (observed vs predicted incidence rate: 0.13 vs 0.05). Recalibration upclassified risk primarily among individuals with low-to-borderline risk by the original PCE and additionally identified 40% of patients who had undergone ASCVD events yet deemed statin-ineligible based on the original PCE. Treatment thresholds yielding the greatest net benefit were ≥24.0% for women (+23.3%) vs ≥26.0% for men (+18.7%), whereas ≥26.0% for White or other race (+24.7%) vs ≥14.0% Black or African American (+12.5%), respectively. Specifically, Hispanic or Latino and non-Hispanic Black patients conferred the greatest sensitivity improvement at ≥12.3% threshold compared to higher ≥23.6% among non-Hispanic Asian or Pacific Islanders. Generally, lower thresholds earlier in life were optimal. Conclusions: Recalibration and personalized treatment thresholds derived within a health system may improve prevention treatment allocation efficiency.

Long-term longitudinal analysis of 4,187 participants reveals insights into determinants of clonal hematopoiesis.

Clonal hematopoiesis of indeterminate potential (CHIP) is linked to diverse aging-related diseases, including hematologic malignancy and atherosclerotic cardiovascular disease (ASCVD). While CHIP is common among older adults, the underlying factors driving its development are largely unknown. To address this, we performed whole-exome sequencing on 8,374 blood DNA samples collected from 4,187 Atherosclerosis Risk in Communities Study (ARIC) participants over a median follow-up of 21 years. During this period, 735 participants developed incident CHIP. Splicing factor genes (SF3B1, SRSF2, U2AF1, and ZRSR2) and TET2 CHIP grow significantly faster than DNMT3A non-R882 clones. We find that age at baseline and sex significantly influence the incidence of CHIP, while ASCVD and other traditional ASCVD risk factors do not exhibit such associations. Additionally, baseline synonymous passenger mutations are strongly associated with CHIP status and are predictive of new CHIP clone acquisition and clonal growth over extended follow-up, providing valuable insights into clonal dynamics of aging hematopoietic stem and progenitor cells. This study also reveals associations between germline genetic variants and incident CHIP. Our comprehensive longitudinal assessment yields insights into cell-intrinsic and -extrinsic factors contributing to the development and progression of CHIP clones in older adults.

Long-term longitudinal analysis of 4,187 participants reveals new insights into determinants of incident clonal hematopoiesis.

Clonal hematopoiesis (CH), characterized by blood cells predominantly originating from a single mutated hematopoietic stem cell, is linked to diverse aging-related diseases, including hematologic malignancy and atherosclerotic cardiovascular disease (ASCVD). While CH is common among older adults, the underlying factors driving its development are largely unknown. To address this, we performed whole-exome sequencing on 8,374 blood DNA samples collected from 4,187 Atherosclerosis Risk in Communities Study (ARIC) participants over a median follow-up of 21 years. During this period, 735 participants developed incident CH. We found that age at baseline, sex, and dyslipidemia significantly influence the incidence of CH, while ASCVD and other traditional risk factors for ASCVD did not exhibit such associations. Our study also revealed associations between germline genetic variants and incident CH, prioritizing genes in CH development. Our comprehensive longitudinal assessment yields novel insights into the factors contributing to incident CH in older adults.

Integrative proteomic analyses across common cardiac diseases yield new mechanistic insights and enhanced prediction.

Cardiac diseases represent common highly morbid conditions for which underlying molecular mechanisms remain incompletely understood. Here, we leveraged 1,459 protein measurements in 44,313 UK Biobank participants to characterize the circulating proteome associated with incident coronary artery disease, heart failure, atrial fibrillation, and aortic stenosis. Multivariable-adjusted Cox regression identified 820 protein-disease associations-including 441 proteins-at Bonferroni-adjusted P <8.6×10 -6 . Cis -Mendelian randomization suggested causal roles that aligned with epidemiological findings for 6% of proteins identified in primary analyses, prioritizing novel therapeutic targets for different cardiac diseases (e.g., interleukin-4 receptor for heart failure and spondin-1 for atrial fibrillation). Interaction analyses identified seven protein-disease associations that differed Bonferroni-significantly by sex. Models incorporating proteomic data (vs. clinical risk factors alone) improved prediction for coronary artery disease, heart failure, and atrial fibrillation. These results lay a foundation for future investigations to uncover novel disease mechanisms and assess the clinical utility of protein-based prevention strategies for cardiac diseases.