The genetic determinants of aortic function may influence risk for stroke and coronary artery disease (CAD) and may lead to novel targets for medical interventions, according to a new analysis of UK Biobank data. The study, published online Monday and in the April 11 issue of the Journal of the American College of Cardiology, sought to discover epidemiologic correlates and genetic determinants of aortic distensibility and strain. Led by James P. Pirruccello, MD, from the University of California San Francisco, and the Broad Institute of MIT and Harvard, Cambridge, Massachusetts, the team noted that multiple cardiovascular morbidities have been associated with abnormalities of aortic distensibility, including atherosclerosis, aneurysms, hypertension and aging. “Unlike the static measurement of aortic diameter, distensibility accounts for the dynamic change in aortic cross-sectional area during the cardiac cycle and pulse pressure. Despite the importance of this function in the cardiovascular system, few biological determinants have been identified,” they said. “In this study, using a deep learning model that achieved high accuracy, we quantified the thoracic aortic cross-sectional area throughout the cardiac cycle in 42,342 participants to measure strain and distensibility, analyzing their epidemiologic properties and genetic architecture.” Study details Pirruccello and colleagues quantified aortic distention from UK Biobank data to discover epidemiologic associations with anthropomorphic phenotypes, relationships to other medical disorders, and the underlying human genetic architecture of this fundamental aortic function. “All population-level analyses were conducted in the UK Biobank, which is a richly phenotyped, prospective, population-based cohort that recruited 500,000 participants aged 40 to 69 years in the UK via mailer from 2006 to 2010,” they noted, adding that as part of an ongoing imaging sub-study, cardiac magnetic resonance imaging was performed for 42,342 participants. “We measured ascending and descending thoracic aortic strain and distensibility in up to 42,342 UK Biobank participants, investigated their epidemiology, and identified 41 significantly associated loci, many of which have established connections to TGF-b signaling, elastogenesis, and atherosclerosis,” they said, noting that common variant analyses identified 12 and 26 loci for ascending and 11 and 21 loci for descending aortic distensibility and strain, respectively. Of the newly identified loci, 22 were not significantly associated with thoracic aortic diameter, reported the analysis. Furthermore, descending aortic distensibility was inversely associated with future incidence of cardiovascular diseases, such as stroke (hazard ratio [HR]: 0.59 per standard deviation [SD]; P = 0.00031), while the heritability of aortic distensibility was 22% to 25% and that of strain was30% to 33%. “Similar observations were made for CAD and chronic kidney disease (CKD), underscoring the notion that strain and distensibility add information beyond that which is obtained by assessing only aortic diameter,” the authors noted. Indeed, they revealed that aortic strain and distensibility polygenic scores had modest effect sizes for predicting cardiovascular outcomes (delaying or accelerating disease onset by 2% to 18% per SD change in scores) and remained statistically significant predictors after accounting for aortic diameter polygenic scores. A substantial step forward Writing in an accompanying editorial, John W. Belmont, MD, PhD, from the Baylor College of Medicine, Houston, noted that normal function of the aorta depends on its elasticity to buffer the pulsatile flow generated by ventricular contraction – adding that two “useful” measures of this property are strain and distensibility. The editorialist said the new work gives important insights into how these two measures relate to each other and to the risk of cardiovascular diseases such as aortic dissection, hypertension, coronary artery disease, chronic kidney disease and stroke. “Their work represents a substantial step forward in both methodology and insight,” said Belmont, adding that the genetic results from the study are “exceptionally rewarding and informative” and led to a key finding that there are genetic associations specific to ascending and descending aorta. “Many of these loci had already been identified as associated with aortic diameter, again reinforcing the deep connection between these measures,” he said. Sources: Pirruccello JP, Rämö JT, Choi SH, et al. The Genetic Determinants of Aortic Distention. J Am Coll Cardiol 2023;81:1320-1335. Belmont JW. Genetic Epidemiology Highlights the Role of Aortic Strain and Distensibility in Cardiovascular Disease. J Am Coll Cardiol 2023;81:1336-1338. Image Credit: Suriyo – stock.adobe.com