Original Investigation
The Genetic Determinants of Aortic Distention

https://doi.org/10.1016/j.jacc.2023.01.044Get rights and content

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.

Section snippets

Study design

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 2010.11 As part of an ongoing imaging substudy, cardiac magnetic resonance imaging (MRI) was performed for 42,342 participants with 1.5-T scanners (Magnetom Aera, Siemens Healthcare).12 Access was provided under UK Biobank application no. 7089 and approved by the Mass General

Semantic segmentation of aorta with deep learning

The deep learning model had high accuracy: In a held-out test set of 20 images not used for training, the average Dice scores (maximum 1.0) (Supplemental Methods) were 0.97 for the ascending aorta and 0.96 for the descending aorta (Supplemental Table 2). The model was applied to all available aortic distensibility images in 42,342 UK Biobank participants. This allowed measurement of aortic diameter and circumferential aortic strain (Central Illustration). Strain was divided by a previously

Discussion

Multiple cardiovascular morbidities have been associated with abnormalities of aortic distensibility, most prominently 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. In this study, using a deep

Conclusions

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-β signaling, elastogenesis, and atherosclerosis.

COMPETENCY IN MEDICAL KNOWLEDGE: Aortic distensibility is predictive of incident cardiovascular diseases and may be an intermediate phenotype for changes in aortic diameter.

TRANSLATIONAL OUTLOOK:

Funding Support and Author Disclosures

This work was funded by a collaboration between the Broad Institute and IBM Research. Support for title page creation and format was provided by AuthorArranger, a tool developed at the National Cancer Institute. Dr Pirruccello was supported by a Sarnoff Scholar Award and National Institutes of Health (NIH) grant K08HL159346. Dr Rämö was funded by a Fellowship from the Sigrid Jusélius Foundation. Dr Chou was funded by NIH grant T32HL007208. Dr Lindsay was supported by the Fredman Fellowship for

References (36)

  • H. Weidmann et al.

    SASH1, a new potential link between smoking and atherosclerosis

    Atherosclerosis

    (2015)
  • B. Chen et al.

    Wnt1 inhibits vascular smooth muscle cell calcification by promoting ANKH expression

    J Mol Cell Cardiol

    (2019)
  • B.M. Koeppen et al.

    Berne & Levy Physiology

    (2017)
  • L.M. Resnick et al.

    Direct magnetic resonance determination of aortic distensibility in essential hypertension: relation to age, abdominal visceral fat, and in situ intracellular free magnesium

    Hypertension

    (1997)
  • M.P. Pase et al.

    Aortic stiffness and the risk of incident mild cognitive impairment and dementia

    Stroke

    (2016)
  • C. Sudlow et al.

    UK Biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age

    PLoS Med

    (2015)
  • J. Howard et al.

    a layered API for deep learning

    Information

    (2020)
  • T.M. Therneau et al.

    Modeling Survival Data: Extending the Cox Model

    (2000)
  • Cited by (7)

    • Editor-in-Chief's Top Picks From 2023

      2024, Journal of the American College of Cardiology
    • Using Genomics to Identify Novel Therapeutic Targets for Aortic Disease

      2024, Arteriosclerosis, Thrombosis, and Vascular Biology
    • Bicuspid aortic valve and its ascending aortopathy

      2023, Current Opinion in Pediatrics
    View all citing articles on Scopus

    Listen to this manuscript's audio summary by Editor-in-Chief Dr Valentin Fuster on www.jacc.org/journal/jacc.

    The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.

    Drs Lindsay and Ellinor contributed equally to this work.

    View full text