Biventricular cardiac dynamic shape: genetics and cardiometabolic disease associations

BackgroundGenetic studies using cardiac magnetic resonance (CMR) imaging have identified loci related to cardiac shape, but most focus on static morphology. The value of a dynamic cardiac shape atlas capturing both shape and function remains unknown. MethodsA dynamic shape atlas comprising CMR-derived shape models at end-diastole and end-systole was combined with genetic and outcome data in 36,992 UK Biobank participants. Dynamic shape principal components (PCs) describing >1% of variance were characterized, and tested for associations with prevalent and incident cardiometabolic diseases, including ischemic heart disease (IHD), heart failure (HF), significant atrioventricular block (AVB), and atrial fibrillation (AF), and independent predictive power alongside standard CMR measures. Genome-wide association studies (GWAS) were performed to identify candidate genes and biological pathways, and polygenic risk scores (PRS) were assessed for disease associations. Mendelian randomization (MR) was performed to test causality of observed disease associations. ResultsWe identified 14 dynamic cardiac shape PCs capturing 83.3% of total dynamic cardiac shape variance. These PCs captured distinct functional remodeling patterns such as variation in annular plane systolic excursion, while remaining only modestly correlated with standard CMR measures. All 14 PCs were associated with at least one incident cardiometabolic disease, with the strongest associations observed for incident IHD, HF, and AVB. Notably, incorporating dynamic shape PCs improved the prediction of incident IHD beyond standard CMR measures. GWAS identified 75 genetic loci associated with dynamic shape, including 14 variants previously unreported for cardiac traits, and candidate genes demonstrated enrichment in pathways related to cardiac development and contractile function. PRS derived from dynamic shape loci were significantly associated with multiple outcomes, most prominently HF. MR identified significant causal relationships between several PCs and cardiometabolic disease. ConclusionsDynamic cardiac shape features capture aspects of cardiac structure and function not fully represented by standard CMR measures. These features are strongly associated with incident cardiometabolic disease and provide new insights into the genetic architecture of cardiac remodeling. Clinical perspectiveO_ST_ABSWhat is new?C_ST_ABSO_LIGenetic and outcome relationships with a dynamic statistical shape model capturing both left and right ventricles at end-diastole and end-systole. C_LIO_LIDemonstration of incremental value over existing cardiac shape models, through capture of functional remodeling not represented by standard imaging measures. C_LIO_LIIdentification of genetic susceptibility loci for dynamic cardiac shape, including 14 variants not previously reported for cardiac traits. C_LI What are the clinical implications?O_LIThe results enhance our understanding of the genetic architecture of dynamic cardiac shape and function in the general population and clarify their relationships with other cardiovascular endophenotypes and incident cardiometabolic diseases. C_LIO_LINewly identified candidate genes expand the biological pathways implicated in cardiac remodeling and provide targets for future functional and mechanistic studies. C_LIO_LIThe improved prediction of incident cardiometabolic disease, particularly ischemic heart disease, achieved by adding dynamic shape PCs to traditional CMR measures suggests potential value for their inclusion in evaluation of patients. C_LI