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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: Predictive performance of polygenic risk scores (PRS) varies across populations. To facilitate equitable clinical use, we developed PRS for coronary heart disease (CHD; PRS CHD ) for 5 genetic ancestry groups. METHODS: We derived ancestry-specific and multi-ancestry PRS CHD based on pruning and thresholding (PRS PT ) and ancestry-based continuous shrinkage priors (PRS CSx ) applied to summary statistics from the largest multi-ancestry genome-wide association study meta-analysis for CHD to date, including 1.1 million participants from 5 major genetic ancestry groups. Following training and optimization in the Million Veteran Program, we evaluated the best-performing PRS CHD in 176,988 individuals across 9 diverse cohorts. RESULTS: Multi-ancestry PRS PT and PRS CSx outperformed ancestry-specific PRS PT and PRS CSx across a range of tuning values. Two best-performing multi-ancestry PRS CHD (ie, PRS PTmult and PRS CSxmult ) and 1 ancestry-specific (PRS CSxEUR ) were taken forward for validation. PRS PTmult demonstrated the strongest association with CHD in individuals of South Asian ancestry and European ancestry (odds ratio per 1 SD [95% CI, 2.75 [2.41–3.14], 1.65 [1.59–1.72]), followed by East Asian ancestry (1.56 [1.50–1.61]), Hispanic/Latino ancestry (1.38 [1.24–1.54]), and African ancestry (1.16 [1.11–1.21]). PRS CSxmult showed the strongest associations in South Asian ancestry (2.67 [2.38–3.00]) and European ancestry (1.65 [1.59–1.71]), lower in East Asian ancestry (1.59 [1.54–1.64]), Hispanic/Latino ancestry (1.51 [1.35–1.69]), and the lowest in African ancestry (1.20 [1.15–1.26]). CONCLUSIONS: The use of summary statistics from a large multi-ancestry genome-wide meta-analysis improved the performance of PRS CHD in most ancestry groups compared with single-ancestry methods. Despite the use of one of the largest and most diverse sets of training and validation cohorts to date, improvement of predictive performance was limited in African ancestry. This highlights the need for larger genome-wide association study datasets of underrepresented populations to enhance the performance of PRS CHD .

SummaryAmong 301 newly diagnosed patients with acute myeloid leukaemia receiving venetoclax and a hypomethylating agent, 23 (7.6%) experienced major cardiac complications: 15 cardiomyopathy, 5 non‐ST elevation myocardial infarction and/or 7 pericarditis/effusions. Four patients had more than one cardiac complication. Baseline characteristics included median age ± interquartile range; 73 ± 5 years; 87% males; 96% with cardiovascular risk factors; and 90% with preserved baseline ejection fraction. In multivariate analysis, males were more likely (p = 0.02) and DNMT3A‐mutated cases less likely (p < 0.01) to be affected. Treatment‐emergent cardiac events were associated with a trend towards lower composite remission rates (43% vs. 62%; p = 0.09) and shorter survival (median 7.7 vs. 13.2 months; p < 0.01). These observations were retrospectively retrieved and warrant further prospective examination.

BACKGROUND: Greater left atrial size is associated with a higher incidence of cardiovascular disease and mortality, but the full spectrum of diagnoses associated with left atrial enlargement in sex-stratified clinical populations is not well known. Our study sought to identify genetic risk mechanisms affecting left atrial diameter (LAD) in a clinical cohort. METHODS: Using Vanderbilt deidentified electronic health record, we studied 6163 females and 5993 males of European ancestry who had at least 1 LAD measure and available genotyping. A sex-stratified polygenic score was constructed for LAD variation and tested for association against 1680 International Classification of Diseases code–based phenotypes. Two-sample univariable and multivariable Mendelian randomization approaches were used to assess etiologic relationships between candidate associations and LAD. RESULTS: A phenome-wide association study identified 25 International Classification of Diseases code–based diagnoses in females and 11 in males associated with a polygenic score of LAD (false discovery rate q<0.01), 5 of which were further evaluated by Mendelian randomization (waist circumference [WC], atrial fibrillation, heart failure, systolic blood pressure, and coronary artery disease). Sex-stratified differences in the genetic associations between risk factors and a polygenic score for LAD were observed (WC for females; heart failure, systolic blood pressure, atrial fibrillation, and WC for males). By multivariable Mendelian randomization, higher WC remained significantly associated with larger LAD in females, whereas coronary artery disease, WC, and atrial fibrillation remained significantly associated with larger LAD in males. CONCLUSIONS: In a clinical population, we identified, by genomic approaches, potential etiologic risk factors for larger LAD. Further studies are needed to confirm the extent to which these risk factors may be modified to prevent or reverse adverse left atrial remodeling and the extent to which sex modifies these risk factors.

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: Hospitalization for COVID-19 is often associated with myocardial injury (elevated cardiac troponin [cTn]). In the initial pandemic waves, patients with myocardial injury had increased likelihood of cardiovascular complications and inpatient mortality; however, the differences in impact of distinct subtypes of myocardial injury on mortality is unclear. In addition, little is known about how these outcomes compare with the subsequent, milder, Omicron wave. Methods: Utilizing Mayo Clinic enterprise patients we developed algorithms based on diagnostic/procedural codes, cTn levels, and temporal relationships to positive COVID-19 PCR tests, to determine 5 common subtypes of myocardial injury: stress cardiomyopathy, myocarditis, pericarditis, pulmonary embolism, and myocardial infarction. We examined hospitalized adults with COVID-19; those with elevated cTn designated as cases and others as controls. We fitted Cox models using the following covariates: spline transformed age, sex, race, ethnicity, index date and clinical comorbidities. Patients were analyzed based on admission dates coinciding with either the Alpha-Delta or Omicron waves. Results: Across both wave cohorts, hospitalized patients with acute COVID-19 complicated by myocardial injury had an increased risk of mortality compared to those without ( Figure ). Patients with one of the 5 subtypes examined tended to have higher risk than those in the “other myocardial injury” category. Admission during the Omicron wave, compared to the Alpha-Delta waves, tended to have higher mortality risk in all subtypes except myocarditis. Conclusions: Our algorithms successfully identified subgroups of myocardial injury in patients hospitalized with acute COVID-19 leading to stratification of mortality risk. Surprisingly, among hospitalized patients during the Omicron wave, myocardial injury of most subtypes was tended to have increased risk of mortality compared to the Alpha-Delta waves.

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.

Background Cardio-ankle vascular index (CAVI) is a measure of arterial stiffness associated with cardiovascular (CV) events and mortality. African American (AA) adults have a higher prevalence of CV risk factors (RFs) and adverse social determinants of health (SDOH) leading to a higher CV mortality risk than White adults. These disparities may be associated with arterial stiffness, however limited research exists on the association of CV RFs, SDOH, and CAVI among AAs. Hypotheses We hypothesized that CV RFs (eg, diabetes) and SDOH (eg, income) would be associated with CAVI among AA adults. Our secondary hypothesis was that AA adults would have a higher prevalence of abnormal CAVI scores (≥8.0) than White adults. Methods In the FAITH! HH+ study, CAVI measurements, CV RFs, and SDOH surveys were obtained. We collected CAVI readings and CV RFs from a secondary cohort of White adults (n=600), referred for echocardiography and without structural cardiac disease. The association of CV RFs, SDOH and CAVI scores among AAs was assessed via ANOVA and univariable linear regression. We compared CV RFs among both cohorts using Chi-squared tests and ANOVA, followed by comparing CAVI scores between cohorts using a multivariable linear regression model. Results In total, 48 AAs were included from the FAITH! HH+ cohort (mean age [SD]: 54.2 [11.5] years, 67.4% women). There was no significant association between CV RFs or SDOH with CAVI scores. In the 600 White adults assessed, mean age was 59.5 [14.7] years and 45.7% were women. Compared to White adults, AA participants had a lower burden of hyperlipidemia (43.5% vs 61.4%; p=0.017), but a higher burden of hypertension (73.9% vs 57.7%; p=0.031), diabetes (28.3% vs 9.3%; p<0.001), and obesity (71.7% obese vs 36.0%; p<0.001). There was no significant difference in CAVI scores between groups when adjusted for age, sex, and CV RFs (AA cohort: mean: 8.0 [1.4] vs White cohort: 8.4 [1.5]; p=0.790). Conclusions In this pilot study, SDOH and CV RFs were not associated with CAVI scores among AAs. There was no significant difference in CAVI scores between AA and White adults, despite a significantly higher burden of CV RFs in the AA cohort. Further studies are warranted to identify factors linked with onset and progression of arterial stiffness among AAs.

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.