Integrating metabolomics and proteomics to identify novel drug targets for heart failure and atrial fibrillation

Background. Altered metabolism plays a role in the pathophysiology of cardiac diseases, such as atrial fibrillation (AF) and heart failure (HF). We aimed to identify novel plasma metabolites and proteins associating with cardiac disease. Methods. Mendelian randomisation (MR) was used to assess the association of 174 metabolites measured in up to 86,507 participants with AF, HF, dilated cardiomyopathy (DCM), and non-ischemic cardiomyopathy. Subsequently, we sourced data on 1,567 plasma proteins and performed cis MR to identify proteins affecting the identified metabolites as well as the cardiac diseases. Proteins were prioritised on cardiac expression and druggability, and mapped to biological pathways. Results. We identified 35 metabolites associating with cardiac disease. AF was affected by seventeen metabolites, HF by nineteen, DCM by four, and NCIM by taurine. HF was particularly enriched for phosphatidylcholines (p=0.029) and DCM for acylcarnitines (p=0.001). Metabolite involvement in AF was more uniform, spanning for example phosphatidylcholines, amino acids, and acylcarnitines. We identified 38 druggable proteins expressed in cardiac tissue, with a directionally concordant effect on metabolites and cardiac disease. We recapitulated known associations, for example between the drug target of digoxin (AT1B2), taurine and NICM risk. Additionally, we identified numerous novel findings, such as higher RET values associating with phosphatidylcholines and decreasing AF and HF, and RET is targeted by drugs such as regorafenib which has known cardiotoxic side-effects. Pathway analysis implicated involvement of GDF15 signalling through RET, and ghrelin regulation of energy homeostasis in cardiac pathogenesis. Conclusion. This study identified 35 plasma metabolites involved with cardiac diseases and linked these to 38 druggable proteins, providing actionable leads for drug development. ### Competing Interest Statement AFS has received funding from New Amsterdam and Servier for unrelated work. ### Funding Statement MvV and JvS are supported by the Dutch Heart Foundation grant 2019T045. AFS is supported by BHF grants PG/18/5033837, PG/22/10989, the UCL BHF Research Accelerator AA/18/6/34223, and received additional support from the National Institute for Health Research University College London Hospitals Biomedical Research Centre. ### 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 study used ONLY openly available human data from from Lotta et al, deCODE, SCALLOP, Ahola-Olli et al, Framingham, AGES-Reykjavik, INTERVAL, Gilly et al, Yang et al, Nielsen et al, Shah et al, Garnier et al, and Aragam et al. 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 All data produced in the present study will be made available upon publication.