Circulation: Genomic and Precision Medicine

BackgroundCardiovascular health (CVH) and genetic susceptibility to adverse left ventricular (LV) remodeling are each linked to cardiovascular diseases (CVD); however, their combined role remains unclear. MethodsFramingham Heart Study participants [n=1,255 Offspring-Exam 8 (2005-2008), n=2,835 Generation 3-Exam 1 (2002-2005)] had assessment of modifiable risk factors comprising the American Heart Associations Lifes Essential 8 (LE8) score with higher scores indicating better CVH health. A Polyg...

BackgroundGenetic testing is now recommended for select patients with early-onset atrial fibrillation (AF). Hemochromatosis is an autosomal recessive syndrome that occurs in patients who carry two pathogenic or likely-pathogenic (P/LP) variants in HFE. HFE is included on some genetic testing panels used for patients with AF. Hemochromatosis causes cardiomyopathy due to iron overload in the ventricle; however, it is unknown whether AF can be an early manifestation that is identified by genetic te...

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...

BackgroundCurrent circulating biomarkers for idiopathic pulmonary arterial hypertension (IPAH) lack specificity for preclinical detection and fail to capture the biological heterogeneity driving disease progression. Furthermore, molecular mechanisms underlying the "sex paradox" of IPAH, where females exhibit higher susceptibility but lower mortality, remain poorly understood, hindering the development of precision therapeutics. MethodsWe performed an integrated proteogenomic analysis characteri...

Neurological complications frequently impact morbidity, mortality, and quality of life in patients with cardiovascular disease, yet the biological mediators connecting cardiovascular and neurological disease are poorly understood. Leveraging data from 53,014 individuals with plasma proteomic profiles and 50,228 with cardiac and brain MRI from the UK Biobank, we systematically identified circulating proteins correlated with MRI imaging-derived phenotypes (IDPs) (404 proteins with cardiac IDPs; 76...

IntroductionPositron emission tomography (PET) myocardial flow reserve (MFR) is a robust indicator of coronary vascular health and a strong predictor of cardiovascular risk. Clinical guidelines typically use fixed MFR thresholds (e.g., <2.0) to stratify risk, yet this approach overlooks individual variation, particularly by age and sex. We aimed to establish age- and sex-adjusted MFR percentiles and to evaluate their prognostic and predictive performance for cardiovascular risk assessment, in co...

BackgroundHypertrophic cardiomyopathy (HCM) is a common inherited cardiovascular disease associated with increased risks of heart failure, sudden cardiac death (SCD), and stroke. Over 1,400 pathogenic variants, primarily in MYH7 and MYBPC3, have been identified, yet the prognostic significance of genetics remains unclear. Recent studies suggest genotype-positive (G+) HCM is linked to earlier diagnosis, greater disease severity, and poorer outcomes, necessitating further research to clarify the r...

BackgroundAortic stenosis (AS) and left ventricular diastolic dysfunction (LVDD) often coexist in heart failure (HF), but the mechanisms linking them remain unclear. While AS increases afterload and promotes myocardial stiffening, emerging AI-based evidence suggests LVDD can precede the development of AS or progress simultaneously, indicating shared upstream mechanobiological and inflammatory drivers. This study explores the genetic contributors connecting AS and LVDD to identify early molecular...

BackgroundThe DES gene encodes the intermediate filament protein desmin, which connects different multi-protein complexes like the cardiac desmosomes and is highly important for the structural integrity of cardiomyocytes. Pathogenic DES-mutations cause filament assembly defects leading to cardiomyopathies. However, most DES-variants listed in genetic disease databases are currently classified as variants of unknown significance. Here, we functionally characterized 21 different DES-variants of un...

BackgroundNaV1.5 channels, encoded by SCN5A, are essential for the genesis and shaping of the cardiac action potential (AP). Gain-of-function (GoF) variants in SCN5A are associated with long QT syndrome (LQTS), whereas loss-of-function (LoF) mutations are linked with Brugada syndrome. MOG1 is an integral part of the NaV1.5 channelosome, increasing both current and membrane expression of NaV1.5. Two LoF variants in MOG1 (E61X and E83D) cause Brugada Syndrome in patients, but no association with L...

BackgroundAortic aneurysm and dissection (AAD) are highly lethal conditions for which hypertension serves as a primary risk factor. The limited efficacy of conventional antihypertensive treatments suggests an inadequate understanding of the molecular mechanisms that connect these conditions. Despite their pivotal role in regulating biological functions, the specific proteomic signatures associated with both hypertension and AAD have not been extensively investigated. This study sought to conduct...

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....

BackgroundPhenotype Risk Scores (PheRS) leverage electronic health record (EHR) data to identify individuals at risk for Mendelian disorders, but their performance remains untested for diseases with common and/or non-specific features such as variant transthyretin amyloidosis (ATTRv), often presenting with heart failure (HF), atrial fibrillation, polyneuropathy, and other prevalent diagnoses. We optimized a PheRS for the most common form of ATTRv by integrating genomic and clinical data in Mount...

IntroductionAcute myocardial infarction (AMI) remains a leading cause of mortality, with the coexistence of other conditions (i.e., multimorbidity) complicating management and outcomes. Currently, healthcare providers see major challenges in consideration of the patient with a multimorbid profile, especially as this is a progressive issue where the temporal evolution of diseases is complex in nature, with a profound impact on clinical outcomes. MethodsData on 12,701 AMI patients from the UK Bio...

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...

BackgroundImproved survival in children with congenital heart disease (CHD) has unveiled associated long-term neurocognitive impairments. However, the long-term effects on academic performance and the influence of sex, family, socioeconomic factors, and surgical era remain understudied, limited by small and incomplete cohorts. MethodsThis total-population cohort study, with nested sibling analysis, included 1 800 477 singletons born in Sweden between January 1, 1987, and December 31, 2005. Acad...

BackgroundConventional cardiometabolic risk markers (blood pressure, glucose, lipids) incompletely capture biological vulnerability in hypertension. We aimed to identify distinct risk phenotypes and define their clinical, prognostic, and proteomic features. MethodsREMODEL is a prospective observational cohort of asymptomatic adults with essential hypertension who underwent 24-hour ambulatory blood pressure monitoring and standardized cardiovascular magnetic resonance (CMR). Among 83 candidate p...

BackgroundThe pathways linking lipoprotein(a) (Lp[a]) to atherosclerotic cardiovascular disease (ASCVD) are unclear. This study aimed to discover Lp(a)-associated plasma proteins and estimate their associations with incident ASCVD. MethodsWe analyzed 48,859 UK Biobank participants with measured Lp(a) and proteomic profiles, with replication in 9,416 individuals in the Atherosclerosis Risk in Communities (ARIC) study cohort utilizing a separate proteomic platform. Linear models assessed associat...