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Sex-related similarities and differences in responses to heart failure therapies

Nature Reviews Cardiology (2024)Cite this article

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Abstract

Although sex-related differences in the epidemiology, risk factors, clinical characteristics and outcomes of heart failure are well known, investigations in the past decade have shed light on an often overlooked aspect of heart failure: the influence of sex on treatment response. Sex-related differences in anatomy, physiology, pharmacokinetics, pharmacodynamics and psychosocial factors might influence the response to pharmacological agents, device therapy and cardiac rehabilitation in patients with heart failure. In this Review, we discuss the similarities between men and women in their response to heart failure therapies, as well as the sex-related differences in treatment benefits, dose–response relationships, and tolerability and safety of guideline-directed medical therapy, device therapy and cardiac rehabilitation. We provide insights into the unique challenges faced by men and women with heart failure, highlight potential avenues for tailored therapeutic approaches and call for sex-specific evaluation of treatment efficacy and safety in future research.

Key points

  • Men and women with heart failure with reduced ejection fraction derive similar benefits from pharmacotherapy with renin–angiotensin system inhibitors, angiotensin receptor–neprilysin inhibitors, β-blockers, mineralocorticoid receptor antagonists and sodium–glucose cotransporter 2 inhibitors.

  • In patients with heart failure with preserved ejection fraction, treatment heterogeneity by sex has been observed with angiotensin receptor–neprilysin inhibitors and spironolactone, whereby women seem to derive greater benefit than men.

  • Optimal doses of renin–angiotensin–aldosterone system inhibitors and β-blockers might be lower in women than in men, whereas adverse effects, such as dry cough and angio-oedema with angiotensin-converting enzyme inhibitors, might be more common in women than in men.

  • Among patients with left bundle branch block, women derive greater benefit from cardiac resynchronization therapy at a shorter QRS duration for reducing mortality than men.

  • In relation to the patient-oriented outcomes of quality of life and functional status, women derive similar benefits from baroreceptor activation therapy but less benefit from mitral valve intervention compared with men.

  • Women with heart failure might derive greater benefit from cardiac rehabilitation than men but have lower rates of enrolment and adherence.

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Fig. 1: Sex-specific considerations in heart failure therapy.
Fig. 2: Sex-related differences in pharmacokinetics.
Fig. 3: Sex-based considerations in the response to pharmacological and non-pharmacological therapies for heart failure.
Fig. 4: Factors influencing sex-related differences in device therapies for heart failure.

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Author notes

  1. These authors contributed equally: Janice Y. Chyou and Hailun Qin.

Authors and Affiliations

  1. Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Janice Y. Chyou

  2. Department of Cardiology, University of Groningen, University Medical Centre Groningen, Groningen, Netherlands

    Hailun Qin & Adriaan A. Voors

  3. Department of Medicine, University of Mississippi School of Medicine, Jackson, MS, USA

    Javed Butler

  4. Baylor Scott and White Research Institute, Dallas, TX, USA

    Javed Butler

  5. National Heart Centre Singapore and Duke-NUS Medical School, Singapore, Singapore

    Carolyn S. P. Lam

Authors
  1. Janice Y. Chyou
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  2. Hailun Qin
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  3. Javed Butler
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  4. Adriaan A. Voors
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  5. Carolyn S. P. Lam
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The authors contributed substantially to all aspects of the article.

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Correspondence to Carolyn S. P. Lam.

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Competing interests

J.B. has received consultancy and/or research fees from Abbott, American Regent, Amgen, Applied Therapeutics, AskBio, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardiac Dimension, Cardiocell, Cardior, CSL Behring, CVRx, Cytokinetics, Daxor, Edwards, Element Science, Faraday, Foundry, G3P, Innolife, Impulse Dynamics, Imbria, Inventiva, Ionis, Lexicon, Eli Lilly, LivaNova, Janssen, Medtronics, Merck, Occlutech, Owkin, Novartis, Novo Nordisk, Pharmacosmos, Pharmain, Pfizer, Prolaio, Regeneron, Renibus, Roche Diagnostics, Salamandra, Sanofi, SC Pharma, Secretome, Sequana, SQ Innovation, Tenex, Tricog, Ultromics, Vifor, and Zoll. A.A.V. has received consultancy and/or research fees from Anacardio, AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Cytokinetics, Corteria, Eli Lilly, Moderna, Novartis, Novo Nordisk, Pfizer and Roche Diagnostics. C.S.P.L. is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has received research support from Novo Nordisk and Roche Diagnostics; has served as consultant or on the Advisory Board/Steering Committee/Executive Committee for Alleviant Medical, Allysta Pharma, Amgen, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, CardioRenal, Cytokinetics, Darma Inc., EchoNous Inc, Eli Lilly, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceutical, Janssen Research & Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Prosciento, Quidel Corporation, Radcliffe Group, Recardio, ReCor Medical, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics and Us2.ai; and serves as co-founder and non-executive director of Us2.ai. J.Y.C. has received consultancy fees from Medtronic. H.Q. has no competing interests.

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Chyou, J.Y., Qin, H., Butler, J. et al. Sex-related similarities and differences in responses to heart failure therapies. Nat Rev Cardiol (2024). https://doi.org/10.1038/s41569-024-00996-1

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