Circulation: Genomic and Precision Medicine

BackgroundA coronary artery calcium (CAC) score of 0 is widely considered to indicate low short- to intermediate-term risk for coronary artery disease (CAD) and is frequently used to defer lipid-lowering therapy. However, a subset of individuals with CAC=0 still experience events, highlighting residual risk not captured by imaging alone. Polygenic risk scores (PRS) quantify lifelong inherited susceptibility, but conventional approaches rely on predefined ancestry labels despite human genetic div...

BackgroundCirculating lipoprotein(a) [Lp(a)] levels are highly heritable and linked to atherosclerotic cardiovascular disease, yet clinical measurement rates remain low (<1%) in the United States. The high heritability of Lp(a) across populations makes genetic prediction an attractive approach for closing this testing gap, but existing polygenic scores transfer poorly across populations. Haplotype-based prediction models, which use standard genome-wide genotype data to capture common-, rare-, an...

BackgroundHDL particles can carry microRNAs (miRNAs), capable of regulating gene expression connected to HDL functions. Despite links to some cardiovascular risk factors, miRNA association with incident acute myocardial infarction (AMI) remains unclear. ObjectivesOur aim was to elucidate the association between HDL-bound miRNAs (HDL-miRNAs) and incident AMI using a non-targeted approach in a population-based study. MethodsWe conducted a case-cohort study including 247 participants from the REG...

Congenital heart disease (CHD) occurs in over half of individuals with 22q11.2 deletion syndrome (22q11.2DS) and the types of lesions range from mild to severe. To determine the basis of variation in cardiac phenotypes we analyzed demographic data from 3,016 unrelated individuals with 22q11.2DS from centers in the Northeast US, Canada, Europe, South America, Israel and Australia. Most individuals in this cohort had a 3 million base pair hemizygous deletion between low copy repeat, LCR22 A-D (87....

ObjectivesTo identify unique echocardiographic signatures associated with TTR+ carrier status preceding onset of cardiac amyloidosis. BackgroundCarrier status for the most common pathogenic TTR variant in the United States, Val142Ile (V142I), found in 4% of African Americans (AA) and 1% of Hispanic/Latino (H/L) individuals, confers a 40-60% lifetime risk of developing variant transthyretin amyloidosis (ATTRv), including cardiac amyloidosis (CA) and heart failure (HF). Myocardial amyloid deposit...

BackgroundThe molecular drivers distinguishing valvular heart disease-associated atrial fibrillation (VHD-AF) from other AF etiologies remain poorly defined, with prior transcriptomic studies largely focused on non-valvular AF. MethodsWe performed RNA sequencing on peripheral blood mononuclear cells (PBMCs) from 15 patients with VHD-AF and 15 age- and sex-matched healthy controls. Bioinformatic analyses identified differentially expressed genes (DEGs), enriched pathways, and protein-protein int...

Heart failure with preserved ejection fraction (HFpEF) affects over 30 million people and lacks disease-modifying therapies. Although genomic-led drug discovery increases success by more than 2.6-fold, HFpEF genomic discovery remains constrained by imprecise phenotyping in biobanks, with only two loci identified to date. Biobanks lack HFpEF diagnostic codes and echocardiograms, yet HFpEF diagnosis exists along a continuum and is inherently probabilistic, presenting an opportunity for multimodal ...

AimsLow-dose aspirin is no longer routinely recommended for primary prevention in older adults because bleeding risks outweigh cardiovascular benefits. We aimed to investigate whether polygenic scores (PGSs) could modify the effects of aspirin on major bleeding and major adverse cardiovascular events (MACE) in a trial of older individuals. MethodsWe conducted post-hoc genetic analysis of the Aspirin in Reducing Events in the Elderly (ASPREE) randomized, placebo-controlled trial in Australia and...

Background and AimsDespite advances in reperfusion and medical therapy, survivors of acute myocardial infarction (AMI) remain at risk for adverse left ventricular remodeling (LVR), a precursor to heart failure. Building on prior work outlining 12-month biomarker trajectories linked to early ventricular dysfunction, we aimed to assess whether these circulating biomarkers predict long-term adverse LVR. MethodsWe prospectively enrolled 155 patients experiencing their first AMI. Clinical, biochemic...

Background: Acute heart failure (AHF) exhibits marked heterogeneity in diastolic hemodynamics, yet comprehensive echocardiographic assessment of diastolic function (DF) and filling pressure (FP) is often infeasible. We evaluated whether artificial intelligence-enabled electrocardiography (AI-ECG) could provide scalable DF grading and FP estimation in hospitalized AHF patients. Methods: We retrospectively studied adults hospitalized for AHF across Mayo Clinic sites (2013-2023) who received 1 dose...

BACKGROUNDPeak oxygen uptake (pVO2) is a strong, independent predictor of adverse cardiovascular outcomes, supporting cardiopulmonary exercise testing as a primary end point assessing efficacy of novel drug therapies in obstructive hypertrophic cardiomyopathy (oHCM) clinical trials. However, characterizing changes in pVO2 that patients perceive as beneficial or meaningful (ie, minimal important difference [MID]) has not been determined. METHODSData from patients with symptomatic oHCM enrolled i...

Heart failure with preserved ejection fraction (HFpEF) is an increasingly common cause of morbidity and mortality in older adults that is driven by cardiac and non-cardiac mechanisms. Physical rehabilitation improves frailty and functional capacity in HFpEF, though underlying mechanisms remain less clear. We quantified >5,000 circulating proteins across two randomized clinical trials of rehabilitation in HFpEF (REHAB-HF, SECRET-II), identifying proteins associated with prognostic measures of phy...

AimsCardiac myosin inhibitors (CMIs) have emerged as an alternative to septal reduction therapy (SRT) for obstructive hypertrophic cardiomyopathy (oHCM). However, comparative data on the time-trajectory of myocardial functional adaptation after septal myectomy (SM), alcohol septal ablation (ASA), and CMI are lacking. We compared temporal changes in echocardiographic parameters including LV global longitudinal strain (LVGLS) and LA reservoir strain (LASr) across these treatment strategies. Metho...

BACKGROUNDDilated cardiomyopathy (DCM) presents a highly heterogeneous spectrum, including a familial subset with elevated arrhythmic risk. Traditional demographic and imaging markers, such as late gadolinium enhancement, have been inadequate for identifying high-risk patients before arrhythmic events. Remodelling of the interventricular septum--central to ventricular mechanics and conduction--may offer improved risk stratification. OBJECTIVESTo identify differences in left ventricular (LV) mor...

BackgroundAdvances in wearable devices and machine-learning-based ECG analysis enable highly accurate detection of atrial fibrillation (AF) outside traditional clinical settings, leading to increasing identification of asymptomatic AF. However, the prognostic significance of AI-detected asymptomatic AF and its implications for downstream cardiovascular risk remain unclear. In contrast to clinically diagnosed AF, evidence guiding risk stratification and further evaluation in this population is li...

Background and aims Iron deficiency (ID) and myocardial iron depletion (MID) are causally linked to heart failure (HF) in the general population and in preclinical models. ID is common amongst pregnant women, but its impact on cardiac adaptations to pregnancy is unknown. This study examines that impact, and its potential relevance to peripartum cardiomyopathy (PPCM). Methods. We provided female mice with iron-replete or iron-deficient diets, and monitored cardiac function and morphology longitud...

ObjectiveDiabetes mellitus (DM) approximately doubles the risk of atherosclerotic cardiovascular disease (ASCVD) events, but the molecular basis is poorly understood. We aimed to define arterial differentially expressed genes (DEGs) associated with DM, validate hits as plasma proteins, and ascertain whether these complement ASCVD risk prediction tools. Research design and methodsRNA-sequencing data from the Genotype-Tissue Expression (GTEx) cohort was used to define DEGs associated with DM in t...

Polygenic scores (PGS) show promise for disease risk stratification but suffer from limited portability across populations. American Indians face a disproportionate burden of cardiovascular disease yet remain significantly underrepresented in genomic research, limiting equitable access to precision medicine. Here, we evaluate whether integrating specific lifestyle and clinical context variables with PGS enhances risk prediction for cardiometabolic traits in 424,622 European from UK Biobank (UKB)...

BackgroundElevated resting heart rate is associated with increased mortality, but the underlying mechanisms remain incompletely understood. Subclinical myocardial injury (SCMI), defined by a Cardiac Infarction/Injury Score (CIIS) [&ge;]10, represents silent cardiac damage that predicts poor cardiovascular (CV) outcomes and may partially explain this association. MethodsWe analyzed 7,152 participants from NHANES III who underwent ECG recording and were free of cardiovascular disease. Heart rate ...

BackgroundEmbolic stroke of undetermined source (ESUS) is associated with a high risk of recurrence. However, randomized trials have not shown superiority of anticoagulation over aspirin in unselected patients. Atrial cardiomyopathy (AtCM) may identify a high-risk ESUS phenotype. We investigated whether multimodal AtCM markers distinguish ESUS from controls and predict adverse clinical outcomes. MethodsIn this prospective single-center study, consecutive ESUS patients and age- and sex-matched c...