Early Vascular Aging Determined by 3-Dimensional Aortic Geometry: Genetic Determinants and Clinical Consequences

BACKGROUND: Vascular aging is an important phenotype characterized by structural and geometric remodeling. Some individuals exhibit supernormal vascular aging, associated with improved cardiovascular outcomes; others experience early vascular aging, linked to adverse cardiovascular outcomes. The aorta is the artery that exhibits the most prominent age-related changes; however, the biological mechanisms underlying aortic aging, its genetic architecture, and its relationship with cardiovascular structure, function, and disease states remain poorly understood. METHODS: We developed sex-specific models to quantify aortic age on the basis of aortic geometric phenotypes derived from 3-dimensional tomographic imaging data in 2 large biobanks: the UK Biobank and the Penn Medicine BioBank. Convolutional neural network–assisted 3-dimensional segmentation of the aorta was performed in 56 104 magnetic resonance imaging scans in the UK Biobank and 6757 computed tomography scans in the Penn Medicine BioBank. Aortic vascular age index (AVAI) was calculated as the difference between the vascular age predicted from geometric phenotypes and the chronological age, expressed as a percent of chronological age. We assessed associations with cardiovascular structure and function using multivariate linear regression and examined the genetic architecture of AVAI through genome-wide association studies, followed by Mendelian randomization to assess causal associations. We also constructed a polygenic risk score for AVAI. RESULTS: AVAI displayed numerous associations with cardiac structure and function, including increased left ventricular mass (standardized β=0.144 [95% CI, 0.138, 0.149]; P <0.0001), wall thickness (standardized β=0.061 [95% CI, 0.054, 0.068]; P <0.0001), and left atrial maximum volume (standardized β=0.060 [95% CI, 0.050, 0.069]; P <0.0001). AVAI exhibited high genetic heritability ( h 2 =40.24%). We identified 54 independent genetic loci ( P <5×10 − 8 ) associated with AVAI, which further exhibited gene-level associations with the fibrillin-1 ( FBN1 ) and elastin ( ELN1 ) genes. Mendelian randomization supported causal associations between AVAI and atrial fibrillation, vascular dementia, aortic aneurysm, and aortic dissection. A polygenic risk score for AVAI was associated with an increased prevalence of atrial fibrillation, hypertension, aortic aneurysm, and aortic dissection. CONCLUSIONS: Early aortic aging is significantly associated with adverse cardiac remodeling and important cardiovascular disease states. AVAI exhibits a polygenic, highly heritable genetic architecture. Mendelian randomization analyses support a causal association between AVAI and cardiovascular diseases, including atrial fibrillation, vascular dementia, aortic aneurysms, and aortic dissection.