Cardiac MRI measures as surrogate outcome for heart failure and atrial fibrillation: a Mendelian randomization analysis

Background drug development and disease prevention of heart failure (HF) and atrial fibrillation (AF) are impeded by a lack of robust early-stage surrogates. We determined to what extent cardiac magnetic resonance (CMR) measurements act as surrogates for the development of HF or AF in healthy individuals. Methods Genetic data was sourced on the association with 22 atrial and ventricular CMR measurements. Mendelian randomization was used to determine CMR associations with atrial fibrillation (AF), heart failure (HF), non-ischemic cardiomyopathy (CMP), and dilated cardiomyopathy (DCM). Additionally, for the CMR surrogates of AF and HF, we explored their association with non-cardiac traits. Results In total we found that 10 CMR measures were associated with the development of HF, 8 with development of non-ischemic CMP, 5 with DCM, and 11 with AF. Left-ventricular (LV) ejection fraction (EF), and LV end diastolic volume (EDV) were associated with all 4 cardiac outcomes. Increased LV-MVR (mass to volume ratio) affected HF (odds ratio (OR) 0.83, 95%CI 0.79; 0.88), DCM (OR 0.26, 95%CI 0.20; 0.34), non-ischemic CMP (OR 0.44 95%CI, 0.35; 0.57). We were able to identify 9 CMR surrogates for HF and AF (including LV-MVR, biventricular EDV, right-ventricular EF, and left-atrial maximum volume) which associated with non-cardiac traits such as blood pressure, cardioembolic stroke, diabetes, and late-onset Alzheimer’s disease. Conclusion CMR measurements may act as surrogate endpoints for the development of HF (including non-ischemic CMP and DCM) or AF. Additionally, we show that changes in cardiac function and structure measured through CMR, may affect diseases of other organs leading to diabetes and late-onset Alzheimer’s disease. ### Competing Interest Statement AFS and FWA have received Servier funding for unrelated work. ### Funding Statement AFS is supported by BHF grants PG/18/5033837, PG/22/10989, and the UCL BHF Research Accelerator AA/18/6/34223. CF and AFS received additional support from the National Institute for Health Research University College London Hospitals Biomedical Research Centre. JvS is supported by Dutch Heart Foundation grant 03-004-2019-T045. ATR is supported by the CardioVascular Research Initiative of the Netherlands Heart Foundation (CVON 2015-12 eDETECT) and ZonMW Off Road. This work was supported by grant [R01 LM010098] from the National Institutes of Health (USA) and by EU/EFPIA Innovative Medicines Initiative 2 Joint Undertaking BigData@Heart grant no. 116074, as well as by the UKRI/NIHR Multimorbidity fund Mechanism and Therapeutics Research Collaborative MR/V033867/1 and the Rosetrees Trust. ### 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: The source data were openly available - see data availability section. 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 and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Genetic data for the phewas of non-cardiac traits was sourced for stroke (subtypes) from MEGASTROKE (), venous thromboembolism and abdominal aortic aneurysm from (), blood pressure from Evangelou et.al. (), glycemic traits, and lung function measurement were sourced from (); type 2 diabetes from DIAGRAM (); BMI from GAINT ([https://portals.broadinstitute.org/collaboration/giant/index.php/GIANT\_consortium\_data_files][1]); CRP from (); the CKDGen consortium provided GWAS associations on estimated glomerular filtration rate (eGFR), and chronic kidney disease (); Alzheimer's disease data was sourced from Jansen et.al. () and Kunkle et.al. (); Lewy body dementia from (); [1]: https://portals.broadinstitute.org/collaboration/giant/index.php/GIANT_consortium_data_files