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Immunometabolic mechanisms of heart failure with preserved ejection fraction

Nature Cardiovascular Research volume 1, pages 211–222 (2022)Cite this article

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Abstract

Heart failure with preserved ejection fraction (HFpEF) is increasing in prevalence worldwide, already accounting for at least half of all cases of heart failure. As most patients with HFpEF are obese with metabolic syndrome, metabolic stress has been implicated in syndrome pathogenesis. Recently, compelling evidence for bidirectional cross-talk between metabolic stress and chronic inflammation has emerged, and alterations in systemic and cardiac immune responses have been shown to participate in HFpEF pathophysiology. Indeed, based on both preclinical and clinical evidence, comorbidity-driven systemic inflammation, coupled with metabolic stress is held to participate in HFpEF pathogenesis. As metabolic alterations impact immune function(s) in HFpEF, major changes in immune cell metabolism are also recognized in HFpEF and in HFpEF-predisposing conditions. Both arms of immunity—innate and adaptive—are implicated in the cardiomyocyte response in HFpEF. Indeed, we submit that cross-talk among adipose tissue, the immune system and the heart represents a critical component of HFpEF pathobiology. Here, we review recent evidence in support of immunometabolic mechanisms as drivers of HFpEF pathogenesis, discuss pivotal biological mechanisms underlying the syndrome, and highlight questions requiring additional inquiry.

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Fig. 1: Overview of common phenotypes of heart failure with preserved ejection fraction.
Fig. 2: Cardiometabolic HFpEF.
Fig. 3: Cardiometabolic stress triggers alterations in adaptive immunity in heart failure with preserved ejection fraction.
Fig. 4: Potential contributions of innate immunity to the pathogenesis of cardiometabolic heart failure with preserved ejection fraction.

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Acknowledgements

This work was supported by grants from the DZHK (German Centre for Cardiovascular Research) to G.G.S.; the Deutsche Forschungsgemeinschaft (German Research Foundation; SFB-1470-A02) to G.G.S.; IMI2-CARDIATEAM (no. 821508) and the Netherlands Cardiovascular Research Initiative, Dutch Cardiovascular Alliance CVON2016-Early HFPEF, 2015-10, CVON She-PREDICTS, no. 2017-21 (to S.H.); US National Institutes of Health (HL144477 to P.A., HL122309 to E.B.T., HL160273, HL107577, HL127028, HL140731, HL149423 to S.J.S. and HL126012, HL128215, HL120732, HL147933 and HL155765 to J.A.H.) and the American Heart Association (19TPA34910006 to J.A.H.). We regret that we were unable to recognize all pertinent research in this field and contributions from all investigators owing to journal space limitations. All figures were created with BioRender.com licensed to G.G.S.

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Authors and Affiliations

  1. Center for Cardiovascular Research (CCR), Department of Cardiology, Charité - Universitätsmedizin Berlin, Berlin, Germany

    Gabriele G. Schiattarella

  2. DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany

    Gabriele G. Schiattarella

  3. Translational Approaches in Heart Failure and Cardiometabolic Disease, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany

    Gabriele G. Schiattarella

  4. Division of Cardiology, Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy

    Gabriele G. Schiattarella

  5. Department of Internal Medicine (Cardiology), University of Texas Southwestern Medical Center, Dallas, TX, USA

    Gabriele G. Schiattarella, Thomas G. Gillette & Joseph A. Hill

  6. Department of Immunology, Tufts University School of Medicine, Boston, MA, USA

    Pilar Alcaide

  7. Humanitas University, Pieve Emanuele, Italy

    Gianluigi Condorelli & Marinos Kallikourdis

  8. Cardio Center, Humanitas Research Hospital IRCCS, Rozzano, Italy

    Gianluigi Condorelli

  9. Department of Cardiology, Maastricht University, CARIM School for Cardiovascular Diseases, Maastricht, the Netherlands

    Stephane Heymans & Elizabeth A. V. Jones

  10. Centre for Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium

    Stephane Heymans & Elizabeth A. V. Jones

  11. Adaptive Immunity Lab, Humanitas Research Hospital IRCCS, Rozzano, Italy

    Marinos Kallikourdis

  12. Department of Pathology, Brigham and Women’s Hospital, Boston, MA, USA

    Andrew Lichtman

  13. William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK

    Federica Marelli-Berg

  14. Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    Sanjiv J. Shah

  15. Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

    Edward B. Thorp

  16. Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Joseph A. Hill

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  1. Gabriele G. Schiattarella
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Contributions

G.G.S., P.A., G.C., T.G.G., S.H., E.A.V.J., M.K., A.L., F.M.-B., S.J.S., E.B.T. and J.A.H. contributed substantially to the conception, design and writing of the article. Each reviewed and interpreted the relevant literature and revised the manuscript critically for important intellectual content. All authors have approved the submitted version.

Corresponding author

Correspondence to Joseph A. Hill.

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Competing interests

S.J.S. has received research grants from Actelion, AstraZeneca, Corvia, Novartis, and Pfizer; and has received consulting fees from Abbott, Actelion, AstraZeneca, Amgen, Aria CV, Axon Therapies, Bayer, Boehringer-Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cardiora, Coridea, CVRx, Cyclerion, Cytokinetics, Edwards Lifesciences, Eidos, Eisai, Imara, Impulse Dynamics, Intellia, Ionis, Ironwood, Lilly, Merck, MyoKardia, Novartis, Novo Nordisk, Pfizer, Prothena, Regeneron, Rivus, Sanofi, Shifamed, Tenax, Tenaya, and United Therapeutics. All the other authors declare no competing interests.

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Nature Cardiovascular Research thanks Christoph Maack, Barry Borlaug and the other, anonymous, reviewers for their contribution to the peer review of this work.

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Schiattarella, G.G., Alcaide, P., Condorelli, G. et al. Immunometabolic mechanisms of heart failure with preserved ejection fraction. Nat Cardiovasc Res 1, 211–222 (2022). https://doi.org/10.1038/s44161-022-00032-w

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