B Genetic and phenotypic architecture of myocardial trabeculation in the left and right ventricles

Cardiac trabeculae form a network of muscular strands that line the inner surfaces of the heart. Their development depends on multiscale morphogenetic processes and, while highly conserved across vertebrate evolution, their role in the pathophysiology of the mature heart is not fully understood. We report variant associations across the allele frequency spectrum for trabecular morphology in 47,803 participants of the UK Biobank using fractal dimension analysis of cardiac imaging. For example, we identified a burden of rare variants in 56 genes that regulate myocardial contractility and ventricular development and GWAS identified 68 novel loci in pathways that regulate sarcomeric function, differentiation of the conduction system, and cell fate determination, for the left ventricle. We found that trabeculation-associated variants were modifiers of cardiomyopathy phenotypes with opposing effects in hypertrophic and dilated cardiomyopathy. Together, these data provide insights into mechanisms that regulate trabecular development and plasticity as well as identify a potential role in modifying monogenic disease expression. Introduction Excessive or hypertrabeculation occurs as part of normal variation in apparently healthy individuals, as a physiological and reversible adaptation to altered loading conditions, and is observed in patients diagnosed with cardiomyopathies, heart failure, and other circulatory and muscular disorders. In adults, trabeculation is not a prognostic factor independent of the underlying myocardial disease but may play a role in the natural history of ventricular remodelling. The contribution of rare and common genetic variation, the full spectrum of modifiers, and the relationship with the progression of cardiomyopathies and other cardiovascular diseases has not been determined in the left and right ventricles for this complex and incompletely understood phenotype. We sought to (i) understand the genetic and non-genetic determinants of trabeculation, (ii) understand its role in the causality of disease, and (iii) evaluate trabeculation as a biomarker for diagnosis and stratification. Methods We report genes with a burden of rare variants and novel common variant associations across the allele frequency spectrum for trabecular morphology in 47,803 participants of the UK Biobank using fractal dimension analysis of cardiac imaging (figure 1). We assessed environmental modifiers of trabecular morphology, correlation with cardiac traits, phenome-wide association studies, and the relationship with the progression of cardiomyopathies and heart failure. Results We identified a burden of trabeculation-associated rare variants in genes that regulate myocardial contractility and cardiac development. Genome-wide association studies identified novel loci near genes implicated in congenital heart disease, cardiomyopathies, conduction traits, and signalling pathways that define the early development of trabeculation. For example, for the left ventricle, we identified 56 genes with a burden of rare variants and 68 novel loci from GWAS (e.g., ACTN2, CASQ2, CRYAB, CACNA1C, MYBPC3, MYH7, NKX2–5, NOTCH1, HAND2, NRG1, TBX20). We found that the same trabeculation-associated variants had opposing effects in hypertrophic and dilated cardiomyopathy. The strongest imaging relationships with trabeculation were with measures of volume and strain. Modifiers of trabeculation included African ancestry, alcohol intake, and physical activity. Trabeculation was increased in those diagnosed with hypertrophic and dilated cardiomyopathy, atrial fibrillation, and congenital heart disease. Carriers of cardiomyopathy-associated pathogenic variants had increased trabeculation. Of participants with cardiomyopathy reported after imaging, 25% had hypertrabeculation on imaging and hypertrabeculation was a risk factor for a subsequent diagnosis of heart failure (HR=1.3), mitral valve disorders (HR=1.4), bundle branch block (HR=1.2). Comparisons of biventricular trabeculation showed similarities in trabeculation across the ventricles in cardiomyopathy. Reduced right ventricular trabeculation and end-diastolic volume associated with Type-2 diabetes. Discussion These data provide new insights into the mechanisms that regulate structural complexity in the heart in health and disease. Changes in trabeculation may occur early in the pathogenesis of heart disease, can be modified by genes regulating pathways outside the sarcomere, and causality depends on the underlying cardiomyopathic substrate. Trabeculation progresses with cardiovascular disease, is a useful marker of remodelling, and identifies novel genetic modifiers of ventricular complexity. Contributions K.A.M.: Conceptualization, Methodology, Data Curation, Formal Analysis, Visualization, Writing – Original Draft, Funding Acquisition; J.S.W.: Resources, Writing – Review & Editing; D.P.O'R.: Conceptualization, Resources, Visualization, Writing – Review & Editing.