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

Area of Science:

• Cardiovascular Medicine
• Genetics
• Medical Imaging

Background:

• Vascular aging involves structural and geometric remodeling, with some individuals showing supernormal aging and others early aging linked to poor outcomes.
• The aorta shows prominent age-related changes, but the underlying biological mechanisms, genetic architecture, and links to cardiovascular health are not fully understood.

Purpose of the Study:

• To develop sex-specific models for quantifying aortic age using 3D imaging data.
• To assess the associations of aortic age with cardiovascular structure and function.
• To investigate the genetic architecture and causal relationships of aortic aging with cardiovascular diseases.

Main Methods:

• Developed sex-specific models using convolutional neural network-assisted 3D segmentation of aortic imaging data from UK Biobank and Penn Medicine BioBank.
• Calculated Aortic Vascular Age Index (AVAI) based on geometric phenotypes.
• Assessed associations with cardiovascular traits using regression, examined genetic architecture via GWAS, and inferred causality using Mendelian randomization.

Main Results:

• AVAI showed significant associations with increased left ventricular mass, wall thickness, and left atrial volume.
• AVAI demonstrated high genetic heritability (40.24%) with 54 identified genetic loci, including associations with FBN1 and ELN1 genes.
• Mendelian randomization supported causal links between AVAI and atrial fibrillation, vascular dementia, aortic aneurysm, and aortic dissection.

Conclusions:

• Early aortic aging is significantly associated with adverse cardiac remodeling and major cardiovascular diseases.
• The Aortic Vascular Age Index (AVAI) has a polygenic and highly heritable genetic architecture.
• Causal associations exist between AVAI and cardiovascular diseases, including atrial fibrillation, vascular dementia, aortic aneurysms, and aortic dissection.