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Introduction: The cardio-kidney-metabolic pathway has a crucial role in ASCVD, motivating development of the PREVENT equation. There is a need for external validation of the PREVENT equation and assessment of its performance in independent cohorts to assess generalizability across diverse populations. Aim: To compare predictive performance of the PREVENT equation with previously developed risk calculators; pooled cohort equations (PCE), and QRISK3. Methods: We used data from 500k participants of the United Kingdom Biobank (UKB). ASCVD was defined as the composite outcome of fatal and non-fatal myocardial infarction, coronary revascularization, and stroke. We ascertained demographic and clinical covariates required to calculate ASCVD risk, using the base model of PREVENT, PCE, and QRISK3, at the time of recruitment. Those with a diagnosis of ASCVD at the time of recruitment or missing data on age, sex, or ethnicity were excluded. We used the area under the ROC curve (AUC) and calibration plots for analysis. Results: Of 459,681 participants (mean age 56.3±8.1 years, 44.4% male, and 94.7% White), 24,514 (5.4%) participants had a new diagnosis of ASCVD during a 10-year follow-up. The median [interquartile range] of estimated 10-y ASCVD risk was 3.7% [1.9% - 6.1%] for PREVENT, 5.6% [2.4% - 11.3%] for PCE, and 8.0% [3.9% - 13.8%] for QRISK3 (Figure 1A). The calibration slope (95% CI) was 1.71 (1.66 – 1.76) for PREVENT, 0.64 (0.63 – 0.66) for PCE, and 0.66 (0.64 – 0.67) for QRISK3 (Figure 1B). The AUC for ASCVD prediction was 0.741 (0.738 - 0.744) for PREVENT, 0.744 (0.741 – 0.747) for PCE, and 0.751 (0.749 – 0.755) for QRISK3 (Figure 1C). Conclusion: In the UKB cohort, the PREVENT equation underpredicted while the PCE and QRISK3 overpredicted ASCVD risk, with a similar discrimination. Consequently, fewer individuals would be eligible for primary prevention with statins, based on the actionable thresholds of 7.5% or 10% when considering ASCVD risk based on PREVENT. Therefore, the external application of the PREVENT equation requires recalibration and context-specific interpretation.

BACKGROUND: Coronary atherosclerotic burden and adverse coronary heart disease events are related phenotypes with likely shared genetic cause. METHODS: We analyzed 6021 patients with available coronary angiography, genotyping, and exome sequencing data. We tested for associations of polygenic risk scores for coronary heart disease (PRS CHD ) with multiple measures of coronary artery disease (CAD) severity. We assessed the joint associations of PRS CHD and pathogenic/likely pathogenic variants in 3 familial hypercholesterolemia genes, with CAD severity. We performed mediation analyses to explore whether CAD severity mediated the association of PRS CHD with prevalent coronary heart disease and incident myocardial infarction. RESULTS: A 1-SD increase in PRS CHD was associated with multiple measures of CAD severity, including the log Gensini score (β, 0.31 [95% CI, 0.28–0.33]). Carrying a pathogenic/likely pathogenic familial hypercholesterolemia variant was associated with a higher log Gensini score after adjustment for PRS CHD (β, 0.21 [95% CI, 0.03–0.38]). A 1-SD increase in PRS CHD was associated with incident myocardial infarction over a mean follow-up of 9.2 years (hazard ratio, 1.20 [95% CI, 1.13–1.27]; P =5×10 − 10 ), and the Gensini score mediated 90% of this association. CONCLUSIONS: PRS CHD was associated with multiple measures of CAD severity. The association of PRS CHD with incident myocardial infarction was almost fully mediated by CAD severity, indicating a considerable genetic overlap between the 2 phenotypes.

ImportanceClonal hematopoiesis of indeterminate potential (CHIP) may contribute to the risk of atrial fibrillation (AF) through its association with inflammation and cardiac remodeling.ObjectiveTo determine whether CHIP was associated with AF, inflammatory and cardiac biomarkers, and cardiac structural changes.Design, Setting, and ParticipantsThis was a population-based, prospective cohort study in participants of the Atherosclerosis Risk in Communities (ARIC) study and UK Biobank (UKB) cohort. Samples were collected and echocardiography was performed from 2011 to 2013 in the ARIC cohort, and samples were collected from 2006 to 2010 in the UKB cohort. Included in this study were adults without hematologic malignancies, mitral valve stenosis, or previous mitral valve procedure from both the ARIC and UKB cohorts; additionally, participants without hypertrophic cardiomyopathy and congenital heart disease from the UKB cohort were also included. Data analysis was completed in 2023.ExposuresCHIP (variant allele frequency [VAF] ≥2%), common gene-specific CHIP subtypes (DNMT3A, TET2, ASXL1), large CHIP (VAF ≥10%), inflammatory and cardiac biomarkers (high-sensitivity C-reactive protein, interleukin 6 [IL-6], IL-18, high-sensitivity troponin T [hs-TnT] and hs-TnI, N-terminal pro–B-type natriuretic peptide), and echocardiographic indices.Main Outcome MeasureIncident AF.ResultsA total of 199 982 adults were included in this study. In ARIC participants (4131 [2.1%]; mean [SD] age, 76 [5] years; 2449 female [59%]; 1682 male [41%]; 935 Black [23%] and 3196 White [77%]), 1019 had any CHIP (24.7%), and 478 had large CHIP (11.6%). In UKB participants (195 851 [97.9%]; mean [SD] age, 56 [8] years; 108 370 female [55%]; 87 481 male [45%]; 3154 Black [2%], 183 747 White [94%], and 7971 other race [4%]), 11 328 had any CHIP (5.8%), and 5189 had large CHIP (2.6%). ARIC participants were followed up for a median (IQR) period of 7.0 (5.3-7.7) years, and UKB participants were followed up for a median (IQR) period of 12.2 (11.3-13.0) years. Meta-analyzed hazard ratios for AF were 1.12 (95% CI, 1.01-1.25; P = .04) for participants with vs without large CHIP, 1.29 (95% CI, 1.05-1.59; P = .02) for those with vs without large TET2 CHIP (seen in 1340 of 197 209 [0.67%]), and 1.45 (95% CI, 1.02-2.07; P = .04) for those with vs without large ASXL1 CHIP (seen in 314 of 197 209 [0.16%]). Large TET2 CHIP was associated with higher IL-6 levels. Additionally, large ASXL1 was associated with higher hs-TnT level and increased left ventricular mass index.Conclusions and RelevanceLarge TET2 and ASXL1, but not DNMT3A, CHIP was associated with higher IL-6 level, indices of cardiac remodeling, and increased risk for AF. Future research is needed to elaborate on the mechanisms driving the associations and to investigate potential interventions to reduce the risk.

BACKGROUND: Despite the substantial burden of IHD in North Africa and Middle East (NAME) region, temporal trends of the burden of IHD were not systematically evaluated in this region and its countries previously. Methods: We reported deaths, premature mortality, YLLs, YLDs, and DALYs of IHD in NAME region and its 21 countries during 1990-2019 using the results of the Global Burden of Disease Study 2019. Premature IHD mortality was defined as IHD death in males <55 and females <65 years of age. Results: IHD accounted for 0.8 million deaths and 18 million DALYs in NAME in 2019. From 1990-2019, the age-standardized death rate of IHD significantly decreased by 29% (-37 to -22) and reached 219 (194 to 247) per 100,000 in NAME in 2019 (Fig A) compared with the global estimates of -31% (-35 to -27) and 118 (108 to 126), respectively. From 1990-2019, the age-standardized DALY rate of IHD significantly decreased by 33% (95% CI: -41 to -25) and reached 4159 (3651 to 4752) per 100,000 population in NAME in 2019 (Fig B) compared with the global estimates of -29% (-33 to -24) and 2243 (2099 to 2385), respectively. The reduction in age-standardized DALY was mostly derived from the reduction in YLL (-34%) rather than YLD (-4%) compared with worldwide estimates of -29% and -6%. While the decreasing pattern in the age-standardized DALY and death rate of IHD was consistently observed across all 21 NAME countries, it was not statistically significant for Egypt, Libya, Saudi Arabia, Syria, Tunisia, and Yemen (Fig C, D). In 2019, 27% of IHD deaths in females and 18% of IHD deaths in males were premature in NAME, which was higher than the worldwide estimates of 17% and 15%, respectively. Turkey, Iran, and Lebanon showed the greatest reduction in IHD premature mortality during 1990-2019. CONCLUSIONS: Despite the improvements, IHD still remains the leading cause of lost death and DALYs in NAME. People are more likely to die prematurely due to IHD with more pronounced sex disparities in NAME compared with the global average.

Introduction: Lp(a) is a causal risk factor for ASCVD that is often elevated in patients with personal or family history (FHx) of ASCVD. The 2019 ESC guidelines recommend universal Lp(a) testing, while the 2019 AHA/ACC guidelines include Lp(a) as a ‘risk enhancer’. We used electronic health records (EHR) to assess utilization of Lp(a) testing in patients with ASCVD, premature ASCVD, and FHx of ASCVD at Mayo Clinic sites in Rochester MN, Phoenix AZ and Jacksonville FL and the Mayo Clinic Health System (MCHS) from 1999-2021. Methods: We ascertained Lp(a) testing using LOINC codes and ASCVD status using validated ICD/CPT-based algorithms. ASCVD included coronary heart disease (CHD), cerebrovascular disease (CVD) (ischemic stroke and/or carotid artery stenosis), peripheral artery disease, and abdominal aortic aneurysm. Premature ASCVD was defined as occurring in males < 55 years and females < 65 years. We ascertained FHx using EHR survey data from 2017-2021. We estimated the proportion of patients with ASCVD, premature ASCVD, or FHx of ASCVD who underwent Lp(a) testing. Results: Between 1999-2021, we identified 310,760 patients with at least 1 ASCVD subtype of whom 66,710 had premature disease. FHx data was available starting 2017. For the timeframe 2017-2021, we identified 267,177 patients with FHx of ASCVD and 90,269 ASCVD patients. As summarized in Table 1, Lp(a) was tested only in a small proportion of patients; 7% of ASCVD patients, 11% of premature ASCVD patients, and 6% of patients with FHx of ASCVD. Premature CHD patients had the highest testing proportion (17%). Conclusions: Our results demonstrate underutilization of Lp(a) testing in patients with personal or FHx of ASCVD. Lp(a) is one of the mediators of “ASCVD residual risk” in patients on statins, and with new Lp(a)-lowering medications in phase III clinical trials, patient and provider education will be needed to increase awareness of Lp(a) as a modulator of ASCVD risk.

Introduction: Long-term outcomes of young patients with chest pain and normal epicardial coronary arteries (NECA) in angiography remain understudied. Methods: We conducted a prospective study in a tertiary heart hospital between 2004-2020, enrolling men<45 and women<55 years presenting with symptoms or objective findings of coronary artery disease (CAD) and confirmed NECA in angiography. Patients with cardiomyopathy, coronary anomaly, and significant valvular, renal, pulmonary, or liver diseases were excluded. The primary outcome was MACCE, defined as the composite of death, CCU admission (for MI or unstable angina), stroke, and revascularization. Follow-ups were done every 5 years using a standardized questionnaire and a committee of experts reviewed all the events. Expected age and sex-adjusted mortality rates were estimated using national data. The association between exposures and MACCE was studied using multivariable Cox-proportional hazard models. Results: 1257 patients, 340 (27.05%) men (38.34±5.46 years), and 917 (72.95%) women (48.41±4.94 years) were included. 698 (55.53%) had acute and 559 (44.47%) had chronic symptoms. Over the median 9.4 (8.5-11.0) years of follow-up, 134 (10.66%) events happened. CCU admission (6.33%) was the most common event (Figure). The 10-year mortality rate (per 100,000-person-years) was 265 for men and 174 for women, which were 1.6 and 2.5 times higher than the age-sex-matched rate of the normal population, respectively. Diabetes, hypertension, and presenting with acute symptoms were associated with higher MACCE with the hazard ratios (95% CI) of 1.87 (1.05-3.31, P:0.03), 1.72 (1.13-2.61, P:0.01), and 1.56 (1.03-2.36, P:0.04), respectively. During follow-up, 192 (15.27%) repeated angiographies were done and 19.8% developed obstructive CAD. Conclusions: In young patients with chest pain and NECA, approximately 10% experienced MACCE during a 10-year follow-up, and the mortality is higher than expected.

Introduction: Clonal hematopoiesis of indeterminate potential (CHIP) is associated with an increased risk of heart failure (HF) and stroke, particularly HF with preserved ejection fraction and hemorrhagic stroke (HS). Hypothesis: We hypothesized that CHIP is associated with incident hypertension and this association mediates the effect of CHIP on HF and HS. Methods: In 200K UK-Biobank participants with exome sequencing, we ascertained CHIP as variant allele fraction (VAF) ≥2% and large CHIP as VAF ≥10%. Hypertension, HF, and HS diagnosis were determined based on the ICD-9 and ICD-10 codes. Cox proportional hazards models were used to test the association of both CHIP and the CHIP subtypes based on the most implicated driver genes (i.e., DNMT3A , TET2 , and ASXL1 ) with incident hypertension. Logistic regression models were used for mediation analyses, quantifying the extent to which hypertension mediates the effects of CHIP. Results: After excluding those with hematological malignancy (n=1,025) and pre-existing hypertension (n=14,754), 184,760 participants (56.14±8.12 years, 44.25% male, and 95.33% white ethnicity) were included. During a median follow-up of 12.2 years, 42,049 (22.76%) participants developed hypertension. CHIP mutations were significantly associated with incident hypertension (Table). Mutations in DNMT3A and TET2 but not ASXL1 drove this association. Mediation analysis revealed 17.9% (9.4% - 38.2%, P<0.001) of the effect of CHIP on HF and 5.7% (2.4% - 22.4%, P<0.001) of the effect on HS were mediated through the increased risk of hypertension. Conclusion: CHIP is associated with an increased risk of hypertension. The association of CHIP with HF and HS is partially mediated by hypertension. These findings suggest a new mechanistic pathway for the association of CHIP with cardiovascular diseases.

Introduction: Aging and inflammation are associated with risk of atrial fibrillation (AF), to which clonal hematopoiesis of indeterminate potential (CHIP) may contribute. We investigated whether CHIP was associated with AF, inflammatory and cardiac biomarkers and cardiac structural changes. Methods: We ascertained CHIP (variant allele frequency, VAF ≥2%) in the Atherosclerosis Risk in Community Study (ARIC visit-5, n = 4,131) and the UK Biobank (UKBB, n = 195,851) participants. Using multivariable Cox regression models, we studied the association of CHIP and the top three implicated genes (i.e., DNMT3A , TET2 , ASXL1 ) with incident AF and conducted a meta-analysis on both cohorts. We also ascertained high-sensitivity C-reactive protein (hs-CRP), interleukin 6 (IL6), IL18, high-sensitivity troponin T and I (hs-TnT and hs-TnI), NT-proBNP, and echocardiography indices in ARIC. We first standardized the natural log of all markers (st-ln) and used the adjusted quantile regression to compare the median in those with and without CHIP. Results: In ARIC, the mean ± SD age was 75.8 ± 5.2 years, 41% were men, 23% were Black, 25% had CHIP, and 11.6% had large CHIP (VAF ≥10%). These measures in UKBB were 56.4 ± 8.1 years, 45%, 2%, 5.8%, and 2.6%, respectively. In the meta-analysis, compared to those without CHIP, the hazard ratios (95% confidence interval) for AF were 1.12 (1.01 - 1.25, P =0.035), 1.31 (1.07 - 1.60, P =0.009), and 1.48 (1.05 - 2.08, P =0.026) for Large-CHIP, Large- TET2, and Large- ASXL1 , respectively. hs-CRP and IL18 levels were similar in those with and without CHIP as well as gene-specific subgroups. Large- TET2 and ASXL1 were associated with higher IL6, which was separately associated with AF. Additionally, Large- ASXL1 was associated with increased left ventricle mass index and NT-proBNP (coefficients in Figure 1 ). Conclusion: Large TET2 and ASXL1 but not DNMT3A CHIP is associated with higher IL6 levels, indices of cardiac remodeling, and an increased risk of AF.

Background The North Africa and Middle East (NAME) region has one of the highest burdens of ischemic heart disease (IHD) worldwide. This study reports the contemporary epidemiology of IHD in NAME. Methods and Results We estimated the incidence, prevalence, deaths, years of life lost, years lived with disability, disability‐adjusted life years (DALYs), and premature mortality of IHD, and its attributable risk factors in NAME from 1990 to 2019 using the results of the GBD (Global Burden of Disease study 2019). In 2019, 0.8 million lives and 18.0 million DALYs were lost due to IHD in NAME. From 1990 to 2019, the age‐standardized DALY rate of IHD significantly decreased by 33.3%, mostly due to the reduction of years of life lost rather than years lived with disability. In 2019, the proportion of premature death attributable to IHD was higher in NAME compared with global measures: 26.8% versus 16.9% for women and 18.4% versus 14.8% for men, respectively. The age‐standardized DALY rate of IHD attributed to metabolic risks, behavioral risks, and environmental/occupational risks significantly decreased by 28.7%, 37.8%, and 36.4%, respectively. Dietary risk factors, high systolic blood pressure, and high low‐density lipoprotein cholesterol were the top 3 risks contributing to the IHD burden in most countries of NAME in 2019. Conclusions In 2019, IHD was the leading cause of death and lost DALYs in NAME, where premature death due to IHD was greater than the global average. Despite the great reduction in the age‐standardized DALYs of IHD in NAME from 1990 to 2019, this region still had the second‐highest burden of IHD in 2019 globally.

AbstractBackgroundThe prevalence of acute coronary syndrome (ACS) among young adults (premature ACS) has dramatically increased in recent years, especially in developing countries. Yet, the data on these patients' attributed risk factors and outcomes are inconsistent. In this study, we aimed to investigate these data in a cohort of premature ACS cases who underwent percutaneous coronary intervention (PCI) compared to older patients.HypothesisWe hypothesize that premature ACS patients undergoing PCI will exhibit different risk factor profiles and outcomes compared to non‐premature patients. specifically, we anticipate that premature patients do not necessarily have better outcomes than non‐premature.MethodsOverall, 3142 and 10 399 patients were included in premature and non‐premature groups, respectively. Patients' pre‐operative, post‐operative, and follow‐up data were retrieved retrospectively from the Tehran Heart Center PCI databank.ResultsThe mean age of premature and non‐premature cohorts was 48.39 and 67 years, respectively. Patients were predominantly male in both groups. Family history of coronary artery disease (CAD), dyslipidemia, smoking, and opium addiction were more prevalent among the younger cohort. After adjustment, in‐hospital mortality in younger patients was considerably higher, with all‐cause mortality and major cardiovascular and cerebrovascular events (MACCE) exhibiting no noticeable difference among the two groups.ConclusionsRisk factor profile is different in young patients, and traditional cardiovascular risk factors, such as hypertension and diabetes mellitus, are more prevalent among older adults. Younger age is not equivalent to a better prognosis; hence, similar or even more caution should be taken into consideration regarding secondary prevention for these patients.