The Genetic Determinants of Aortic Distention

James P Pirruccello; Joel T Rämö; Seung Hoan Choi; Mark D Chaffin; Shinwan Kany; Mahan Nekoui; Elizabeth L Chou; Sean J Jurgens; Samuel F Friedman; Dejan Juric; James R Stone; Puneet Batra; Kenney Ng; Anthony A Philippakis; Mark E Lindsay; Patrick T Ellinor

doi:10.1016/j.jacc.2023.01.044

The Genetic Determinants of Aortic Distention

J Am Coll Cardiol. 2023 Apr 11;81(14):1320-1335. doi: 10.1016/j.jacc.2023.01.044.

Authors

James P Pirruccello¹, Joel T Rämö², Seung Hoan Choi³, Mark D Chaffin³, Shinwan Kany⁴, Mahan Nekoui⁵, Elizabeth L Chou⁶, Sean J Jurgens⁷, Samuel F Friedman⁸, Dejan Juric⁹, James R Stone¹⁰, Puneet Batra¹¹, Kenney Ng¹², Anthony A Philippakis¹³, Mark E Lindsay¹⁴, Patrick T Ellinor¹⁵

Affiliations

¹ Division of Cardiology, University of California San Francisco, San Francisco, California, USA; Institute for Human Genetics, University of California San Francisco, San Francisco, California, USA; Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. Electronic address: james.pirruccello@ucsf.edu.
² Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA; Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland.
³ Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
⁴ Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA; Department of Cardiology, University Heart and Vascular Center Hamburg-Eppendorf, Hamburg, Germany.
⁵ Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA; Harvard Medical School, Boston, Massachusetts, USA.
⁶ Smidt Heart Institute, Division of Vascular Surgery, Cedars-Sinai Medical Center, Los Angeles, California, USA.
⁷ Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA; Department of Experimental Cardiology, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
⁸ Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA; Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
⁹ Harvard Medical School, Boston, Massachusetts, USA; Cancer Center, Massachusetts General Hospital, Boston, Massachusetts, USA.
¹⁰ Harvard Medical School, Boston, Massachusetts, USA; Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA.
¹¹ Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
¹² IBM Research, Cambridge, Massachusetts, USA.
¹³ Eric and Wendy Schmidt Center, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
¹⁴ Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA; Harvard Medical School, Boston, Massachusetts, USA; Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts, USA; Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA; Thoracic Aortic Center, Massachusetts General Hospital, Boston, Massachusetts, USA.
¹⁵ Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA; Harvard Medical School, Boston, Massachusetts, USA; Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts, USA; Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA.

Abstract

Background: As the largest conduit vessel, the aorta is responsible for the conversion of phasic systolic inflow from ventricular ejection into more continuous peripheral blood delivery. Systolic distention and diastolic recoil conserve energy and are enabled by the specialized composition of the aortic extracellular matrix. Aortic distensibility decreases with age and vascular disease.

Objectives: In this study, we sought to discover epidemiologic correlates and genetic determinants of aortic distensibility and strain.

Methods: We trained a deep learning model to quantify thoracic aortic area throughout the cardiac cycle from cardiac magnetic resonance images and calculated aortic distensibility and strain in 42,342 UK Biobank participants.

Results: Descending aortic distensibility was inversely associated with future incidence of cardiovascular diseases, such as stroke (HR: 0.59 per SD; P = 0.00031). The heritabilities of aortic distensibility and strain were 22% to 25% and 30% to 33%, respectively. 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. Nearby genes were involved in elastogenesis and atherosclerosis. Aortic strain and distensibility polygenic scores had modest effect sizes for predicting cardiovascular outcomes (delaying or accelerating disease onset by 2%-18% per SD change in scores) and remained statistically significant predictors after accounting for aortic diameter polygenic scores.

Conclusions: Genetic determinants of aortic function influence risk for stroke and coronary artery disease and may lead to novel targets for medical intervention.

Keywords: aorta; cardiovascular disease; deep learning; distensibility; genetics; strain.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Aorta
Aorta, Thoracic
Aortic Diseases* / pathology
Humans
Magnetic Resonance Imaging
Stroke*

Abstract

Publication types

MeSH terms

Grants and funding