(Press-News.org) How would you summarize your study for a lay audience?
Heart failure remains a substantial burden for patients due to its high prevalence and limited therapeutic options. Heart failure is classified into two major clinical subtypes— heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF). While there have been significant therapeutic advances in HFrEF, the rate of complications and death from HFrEF remains high. Additionally, most drugs that have shown benefits for patients with HFrEF have not demonstrated a comparable benefit in patients with HFpEF, highlighting a critical need for the development of targeted therapies for both subtypes.
In our new study, we analyzed a large genetic dataset and used multi-omics to identify 58 novel drug targets for both HFpEF and HFrEF. Our findings have the potential to guide the development of effective drugs for patients with different types of heart failure.
What methods or approach did you use?
We used a large-scale multi-omics approach to analyze genetic data from 55,378 patients with HFpEF and HFrEF from the Veterans Affairs (VA) Million Veteran Program (MVP). We leveraged transcriptomics and proteomic data to analyze over 15,000 genes to identify targets with causal relevance to both HFpEF and HFrEF.
For each gene identified as a potential therapeutic target through our analyses, we further explored additional biological evidence to strengthen the causal link between protein and heart failure subtype. Then we validated our findings in a multi-ancestry genetics dataset of 175,000 individuals of African American, Hispanic and European-descent and replicated the results using an alternative proteomics platform.
What did you find?
From our evaluation, we identified 70 genes associated with HFrEF and 10 genes associated with HFpEF. Notably, the drug targets for HFpEF and HFrEF did not overlap, highlighting the importance for developing subtype-specific therapeutic strategies.
Among the genes identified, we found several with strong potential for novel drug discovery. Additionally, we identified several genes that, when targeted, may be suitable for drug repurposing for both subtypes of heart failure.
What are the implications?
Our findings reveal promising opportunities for both drug development and drug repurposing. We anticipate that our identification of several genes as putative therapeutic targets for HFpEF and HFrEF will be of value in the development of novel therapeutic strategies for these conditions.
What are the next steps?
We will need to conduct experimental studies using new datasets to further explore the biological mechanisms underlying these targets, particularly those with limited prior biological evidence. These types of studies will be critical to validate the therapeutic potential of the identified targets and advancing them toward clinical application.
Authorship: In addition to Rasooly, Mass General Brigham authors include Hesam Dashti, Daniel Golden, Andrea R. V. R. Horimoto, Kelly Cho, J. Michael Gaziano and Alexandre C. Pereira
Paper cited: Rasooly D et al., “Large-scale multi-omics identifies drug targets for heart failure with reduced and preserved ejection fraction” Nature Cardiovascular Research DOI: 10.1038/s44161-025-00609-1
Funding: This work was supported by the Million Veteran Program (#MVP037 [BLR&D Merit Award BX005831] and #MVP001 [I01-BX004821]), a Veterans Affairs Grant (I01CX001922), a VA Merit Grant (I01-CX001025), the British Heart Foundation (PG/14/89/31194), the National Institute of Health and Care Research Barts Biomedical Research Centre (NIHR203330), the UK Research and Innovation (UKRI) Programme Grant (MC_UU_00002/18), “SmartHeart” EPSRC Programme Grant (EP/P001009/1) and the Medical Research Council (MR/X020924/1).
Disclosures: This publication does not represent the views of the Department of Veterans Affairs or the United States Government. Steffen E. Petersen provides consultancy to Circle Cardiovascular Imaging, Inc., Calgary, Alberta, Canada. John Whittaker holds membership of scientific advisory boards/consultancy for Relation Therapeutics and Silence Therapeutics and ownership of GSK shares. Juan P. Casas is employed full-time by the Novartis Institute of Biomedical Interest (his major contributions to this project were while employed at VA Boston Healthcare System).
END
Research spotlight: Researchers identify potential drug targets for future heart failure therapeutics
2025-02-06
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