Metabolomic signature of weight loss and association with heart failure

Background Obesity is a major risk factor for heart failure (HF), but the molecular mediators linking adiposity to HF remain unclear. The molecular mechanisms by which weight loss reduces the risk of HF are also unknown. Understanding these mechanisms could highlight potential therapeutic targets for all HF patients, including those who are normal weight. We aimed to identify a common metabolic perturbation profile by comparing different weight-loss interventions and to estimate their associations with HF using Mendelian randomisation (MR).

We first integrated mass spectrometry and nuclear magnetic resonance metabolomic profiling from two weight-loss interventions - a structured diet programme (DiRECT trial) and bariatric surgery (By-Band-Sleeve trial) - with estimates of the effect of life-time body mass index (BMI) exposure on metabolite levels through MR analyses, to identify a consistent BMI-metabolite signature across differing sources of BMI variation. We then assessed the impact of these BMI-metabolites on incident HF within a two sample MR framework.

1706 metabolites were analysed across three different sources of BMI variation: bariatric surgery, dietary intervention and life-time BMI exposure. 153 (9%) showed strong evidence for association with all three exposures with concordant direction of effect, predominantly comprising lipid fractions, lipoproteins, and amino acid metabolites. Among these metabolites, 44 (29%) had evidence of causal association with at least one HF subtype in MR. Notably, circulating levels of the non-lipid metabolites N-acetylglycine and asparagine were each inversely associated with BMI and with the risk of HF and HF with preserved ejection fraction risk, respectively. Both metabolites have previously been implicated in myocardial function and HF.

Our findings suggest that despite differences in the modality of weight loss delivery, there exists a consistent metabolomic profile coincident with weight change. Investigating the association of the identified metabolites with HF provides insights into molecular mediators of the effects of adiposity on HF and potential novel targets for therapeutic intervention. Competing Interest Statement The authors have declared no competing interest. Clinical Trial ISRCTN03267836 and ISRCTN00786323 Funding Statement NS is funded by the GW4-CAT Wellcome PhD programme. LP and NS work in a Medical Research Council (UKRI) funded unit (MC_UU_00032/1 and MC_UU_00032/3). This research was supported by the National Institute for Health and Care Research (NIHR) Bristol Biomedical Research Centre (BRC) (NIHR203315). RTL is supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre (NIHR203328), Health Data Research UK (MR/S003754/1). The project was additionally supported by a Pfizer Innovative Targets Exploration Network Grant with UCL, the BigData@Heart Consortium, funded by the Innovative Medicines Initiative-2 Joint Undertaking (grant agreement 116074), and the UCL British Heart Foundation Accelerator (AA/18/6/34223). LJC is funded by the Medical Research Council Integrative Epidemiology Unit (MRC-IEU) at the University of Bristol, which is supported by the University of Bristol and UK Medical Research Council (MRC; MC_UU_00011/1). NJT is the PI of the Avon Longitudinal Study of Parents and Children (MRC & WT 217065/Z/19/Z), is supported by the University of Bristol NIHR Biomedical Research Centre, the MRC IEU (MC_UU_00011/1) and works within the Cancer Research UK (CRUK) Integrative Cancer Epidemiology Programme (ICEP; C18281/A29019). MLS was supported by the Wellcome Trust through a PhD studentship (218495/Z/19/Z). By-Band-Sleeve was funded by National Institute of Health and Care Research (NIHR) Health Technology Assessment Programme (HTA 09/127/53). We also acknowledge funding from the MRC ConDuCT-II Hub for Trials Methodology Research and the NIHR Biomedical Research Centre (BRC) at the University of Bristol (IS-BRC-1215-20011). This trial was designed and delivered in collaboration with the Bristol Trials Centre, a UKCRC registered clinical trials unit (CTU), which is in receipt of NIHR CTU support funding. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. The DiRECT study was funded as a Strategic Research Initiative by Diabetes UK (award number 13/0004691). The formula diet was donated by Cambridge Weight Plan. Neither organisation had any input into the study design, data analysis or interpretation. Metabolomics data generation in BBS and DiRECT was funded by a Wellcome Trust Investigator Award held by NJT (202802/Z/16/Z). This research was funded in whole, or in part, by the Wellcome Trust [202802/Z/16/Z, 218495/Z/19/Z]. For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. 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: Ethics approval for DiRECT was granted by West 3 Ethics Committee in January 2014, with approvals by the National Health Service (NHS) health board areas in Scotland and clinical commissioning groups in Tyneside. All participants provided written informed consent. Ethical approval for BBS was granted by the Southwest Frenchay Research Ethics Committee (reference 11/SW/0248) and written informed consent was obtained from all participants. All samples were used, stored and disposed of in accordance with the Human Tissue Act 2004. 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 Data Availability All data produced in the present work are contained in the manuscript