Ventricular volume asymmetry as a novel imaging biomarker for disease discrimination and outcome prediction

Background: The utility of ventricular asymmetry as an imaging biomarker for cardiovascular risk has not been assessed in population cohorts. Objectives: This study presents a comprehensive assessment of the population distribution of ventricular asymmetry and its relationships across a range of prevalent and incident cardiorespiratory diseases. Methods: Cardiovascular magnetic resonance (CMR) imaging metrics derived from automated image analysis were examined, along with clinical outcomes ascertained through linked health records. Ventricular asymmetry was expressed as the ratio of left and right ventricular (LV, RV) end-diastolic volumes. The normal range for ventricular symmetry was defined in a healthy subset without cardiorespiratory disease. Participants with values outside the 5th-95th percentiles of the healthy distribution were classed as either LV dominant (LV/RV > 112%) or RV dominant (LV/RV < 80%) asymmetry. Associations of LV and RV dominant asymmetry with vascular risk factors, CMR features, and prevalent and incident cardiovascular diseases were examined using regression models, adjusting for vascular risk factors, prevalent diseases, and conventional CMR measures. Results: The analysis includes 44,796 participants (average age 64.1, SD 7.7 years; 51.9% women). Ventricular asymmetry, in either direction, was associated with older age and adverse cardiovascular remodeling. LV-dominance was linked to an array of pre-existing vascular risk factors and cardiovascular diseases, and a two-fold increased risk of incident heart failure, non-ischemic cardiomyopathies, and left-sided valvular disorders. RV dominance was associated with an elevated risk of all-cause mortality. Conclusions: Ventricular asymmetry has clinical utility for cardiovascular risk assessment, providing information that is incremental to traditional risk factors and conventional CMR metrics. ### Competing Interest Statement SEP provides consultancy to Cardiovascular Imaging Inc, Calgary, Alberta, Canada. SN is a founder, shareholder and former board member of Perspectum. TEN provides consultancy to Perspectum Ltd, Oxford, UK. All other authors declare no conflicts of interest. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted. ### Funding Statement Barts Charity (G-002346) contributed to fees required to access UK Biobank data [access application 2964]. SN and CM were supported by the Oxford NIHR Biomedical Research Centre and (IS-BRC-1215-20008) and SN by the Oxford British Heart Foundation Centre of Research Excellence. ZRE recognises the National Institute for Health and Care Research (NIHR) Integrated Academic Training program which supports her Academic Clinical Lectureship post. SEP acknowledges support from the SmartHeart EPSRC programme grant (www. nihr.ac.uk; EP/P001009/1). SEP and LS have received funding from the European Union's Horizon 2020 research and innovation program under grant agreement No 825903 (euCanSHare project). SEP and SN acknowledge the British Heart Foundation for funding the manual analysis to create a cardiovascular magnetic resonance imaging reference standard for the UK Biobank imaging-resource in 5000 CMR scans (www.bhf.org.uk; PG/14/89/31194). This work acknowledges the support of the National Institute for Health and Care Research Barts Biomedical Research Centre (NIHR203330); a delivery partnership of Barts Health NHS Trust, Queen Mary University of London, St Georges University Hospitals NHS Foundation Trust and St Georges University of London. NCH acknowledges support from MRC (MC\_UU\_12011/1) and NIHR Southampton Biomedical Research Centre. The funders provided support in the form of salaries for authors as detailed above but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study complies with the Declaration of Helsinki; the work was covered by the ethical approval for UK Biobank studies from the National Health Service (NHS) National Research Ethics Service on 17th June 2011 (Ref 11/NW/0382) and extended on 18 June 2021 (Ref 21/NW/0157) with written informed consent obtained from all participants. This study was conducted under UK Biobank access application 59867. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes This research was conducted using the UK Biobank resource under access application 59867. UK Biobank will make the data available to all bona fide researchers for all types of health-related research that is in the public interest, without preferential or exclusive access for any persons. All researchers will be subject to the same application process and approval criteria as specified by UK Biobank. For more details on the access procedure, see the UK Biobank website: https://www.ukbiobank.ac.uk/enable-your-research/register