Integrative Observational and Genetic Evidence From the UK Biobank Supports Carotid Intima‐Media Thickness as a Window Into Cardiac Remodeling

ABSTRACT Objective Carotid intima-media thickness (cIMT) is a non-invasive marker of subclinical atherosclerosis and has been linked to future cardiovascular events. However, its relationship with early cardiac structural and functional remodeling and its shared genetic basis with cardiovascular diseases (CVD) remain poorly defined. We investigated the phenotypic and genetic associations between cIMT, aortic and cardiac imaging traits, and CVD in the UK Biobank. Methods We analyzed 51,818 participants with both carotid ultrasound and cardiac magnetic resonance (CMR) imaging, excluding individuals with prior heart failure (HF), atrial fibrillation (AF), myocardial infarction (MI), or stroke. Multivariable linear and logistic regression models, adjusted for age, sex, and body mass index, assessed associations between cIMT, aortic and cardiac traits, and CVD outcomes. Genetic correlations were estimated using linkage disequilibrium score regression (LDSC) based on GWAS summary statistics. Gene-level and pathway enrichment analyses were performed to identify shared molecular mechanisms linking cIMT with aortic and cardiac phenotypes. Results Higher cIMT was significantly associated with larger ascending and descending aortic diameters, increased left ventricular (LV) mass and wall thickness, and greater atrial and ventricular volumes, alongside reduced left and right atrial ejection fractions (all p < 0.001). Elevated cIMT was associated with increased AF risk (OR = 1.39, 95% CI: 1.02 to 1.91, P = 0.04 for left cIMT, OR = 1.90, 95% CI: 1.35 to 2.67, P < 0.001 for right cIMT), and left cIMT additionally predicted HF (OR = 2.05, 95% CI: 1.23 to 3.41, P = 0.006), independent of conventional risk factors. Genetically, cIMT showed strong positive correlations with descending aorta, LV wall thickness, and cardiac chamber volumes, as well as with right ventricular end-diastolic volume, LV cardiac output and LV mass. In contrast, cIMT was negatively correlated with left atrial ejection fraction. Seven shared genes ( CDH13, HAND2, ITCH, FBXO32, TBX20, FBN1 , and CBFA2AT3) were identified, enriched in pathways related to extracellular matrix organization, vascular development, and cardiac morphogenesis. Conclusion Elevated cIMT is independently associated with systemic aortic and cardiac remodeling and impaired atrial and ventricular function related to AF and HF. Integrative genetic analyses reveal shared heritable mechanisms linking vascular thickening and myocardial remodeling, highlighting cIMT as a marker of early cardiovascular structural change and a potential bridge between vascular and cardiac disease processes. GRAPHICAL ABSTRACT