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Publications

Journal Article Ahead of print

PubMed: 41406504 DOI: 10.1016/j.ebiom.2025.106063

Male survival disadvantage in pulmonary hypertension: independent of aetiology, age, disease severity, comorbidities and treatment.

EBioMedicine 123:106063

Authors: Athiththan Yogeswaran, Jeffrey S Annis, Meike Fünderich, Jochen Wilhelm, David G Kiely, Luke Howard, Allan Lawrie, Martin R Wilkins, Aparna Balasubramanian, Paul M Hassoun, Ziad Konswa, Christina A Eichstaedt, Ekkehard Grünig, Andrew J Sweatt, Roham T Zamanian, Gabor Kovacs, Horst Olschewski, Mona Lichtblau, Silvia Ulrich, Thenappan Thenappan, Imad Al Ghouleh, Stephen Y Chan, Jean Elwing, Arun Jose, John Cannon, Joanna Pepke-Zaba, Robert Frantz, Yuriy Sirenko, Olena Torbas, Sandeep Sahay, Zhenguo Zhai, Zhu Zhang, Alexandra Arvanitaki, George Giannakoulas, Marlize Frauendorf, Paul G Williams, Keiichiro Kuronuma, Hiromi Matsubara, Stefano Ghio, Laura Scelsi, Hanni Sabbour, Khaled Saleh, Anastasia Anthi, Effrosyni Dima, Raphael W Majeed, Hossein-Ardeschir Ghofrani, Friedrich Grimminger, Khodr Tello, Hector R Cajigas, Evan Brittain … and 1 other author

Affiliations

  • Department of Internal Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany; Institute for Lung Health (ILH), Cardio-Pulmonary Institute (CPI), Giessen, Germany.
  • Vanderbilt University Medical Center, Nashville, USA.
  • Department of Internal Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany; Institute for Lung Health (ILH), Cardio-Pulmonary Institute (CPI), Giessen, Germany.
  • Sheffield Pulmonary Vascular Disease Unit, Royal Hallamshire Hospital, University of Sheffield and National Institute for Health and Care Research Sheffield Biomedical Research Centre, UK.
  • National Heart and Lung Institute, Imperial College London, London, UK.
  • Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, USA.
  • Center for Pulmonary Hypertension, Thoraxklinik Heidelberg gGmbH at Heidelberg University Hospital and Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany; Laboratory for Molecular Genetic Diagnostics, Institute of Human Genetics, Heidelberg University, Heidelberg, Germany.
  • Center for Pulmonary Hypertension, Thoraxklinik Heidelberg gGmbH at Heidelberg University Hospital and Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany.
  • Division of Pulmonary, Allergy, and Critical Care, and Vera Moulton Wall Center for Pulmonary Vascular Disease, Stanford University, USA.
  • Division of Respiratory Medicine, Lung Research Cluster, Medical University of Graz, Graz, Austria.
  • Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Infectious Diseases and Respiratory Medicine, Berlin, Germany.
  • Division of Pulmonology, University Hospital Zurich, Switzerland.
  • University of Minnesota, USA.
  • Cardiovascular Research Center, Brown University Health Cardiovascular Institute, Department of Medicine, The Warren Alpert Medical School of Brown University, USA.
  • University of Pittsburgh, USA.
  • University of Cincinnati, USA.
  • Royal Papworth Hospital Cambrigde, UK.
  • Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, USA.
  • Strazhensku Cardiology Institute Kiev, Ukraine.
  • The Methodist, Houston, USA; Milpark Hospital, Johannesburg, ZA, South Africa.
  • Department of Respiratory and Critical Care Medicine, China-Japan Friendship Hospital, Beijing, China.
  • 1th Department of Cardiology, Aristotle University of Thessaloniki, Greece.
  • Milpark Hospital, Johannesburg, ZA, South Africa.
  • Pulmonary Hypertension Center, Department of Cardiology, NHO Okayama Medical Center, Okayama, Japan.
  • University di Pavia, Italy.
  • Cleveland Clinic Abu Dhabi, United Arab Emirates.
  • Evangelismos Hospital Athens, Greece.
  • Department of Internal Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany; Institute for Lung Health (ILH), Cardio-Pulmonary Institute (CPI), Giessen, Germany; Institute of Medical Informatics, RWTH Aachen University, Aachen, Germany.

Abstract

BACKGROUND

Sex-based differences in morbidity and mortality in pulmonary hypertension (PH) are underexplored, yet understanding these differences is vital for improving clinical management. This study investigates the influence of sex on survival of patients with PH in dependency of various disease conditions.

METHODS

The PVRI GoDeep meta-registry integrates data from international PH registries, of which we analysed 21,123 incident hemodynamically fully characterised patients with PH. Survival analyses employed Kaplan-Meier and Cox proportional hazards models, adjusted for confounders and subjected to sensitivity analyses.

FINDINGS

Male patients consistently showed significantly higher mortality than females across the overall PH population (hazard ratio 1.36 [1.23, 1.50] after adjustment) and within PAH and non-PAH groups. These sex differences in survival persisted regardless of P(A)H severities, age and obesity, cardiovascular diseases, and PAH-specific therapies. The male survival disadvantage was noted across low-, intermediate-, and high-risk groups of the ESC/ERS 2022, REVEAL lite 2, and COMPERA 4-strata scores, but not the REVEAL 2.0 risk score, which incorporates male sex as non-modifiable factor. Stratification by race revealed that male sex was associated with worse survival in White patients, but not in Black or Asian patients with PH.

INTERPRETATION

Male patients with PH exhibit significantly higher mortality risks than females across both PAH and non-PAH PH groups. This disparity persists regardless of PH severity, underlying cause, age, obesity, comorbidities, or treatment status, though race might modify the observed risk difference. These insights provide new avenues for investigating underlying mechanisms and suggest including male sex as an independent factor in clinical risk assessment tools.

FUNDING

This work is funded by the Pulmonary Vascular Research Institute (PVRI) and the Cardiovascular Medical Research and Education Fund (CMREF), NIH.

MeSH

Registries, Hypertension, Comorbidity, Mortality, Hypertension, Pulmonary, Biomedical Research, Obesity, Sex, Therapeutics