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  • Review Article
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Mechanisms and treatment of pulmonary arterial hypertension

Nature Reviews Cardiology (2024)Cite this article

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Abstract

Substantial progress has been made in the management of pulmonary arterial hypertension (PAH) in the past 25 years, but the disease remains life-limiting. Established therapies for PAH are mostly limited to symptomatic relief by correcting the imbalance of vasoactive factors. The tyrosine kinase inhibitor imatinib, the first predominantly non-vasodilatory drug to be tested in patients with PAH, improved exercise capacity and pulmonary haemodynamics compared with placebo but at the expense of adverse events such as subdural haematoma. Given that administration by inhalation might reduce the risk of systemic adverse effects, inhaled formulations of tyrosine kinase inhibitors are currently in clinical development. Other novel therapeutic approaches for PAH include suppression of activin receptor type IIA signalling with sotatercept, which has shown substantial efficacy in clinical trials and was approved for use in the USA in 2024, but the long-term safety of the drug remains unclear. Future advances in the management of PAH will focus on right ventricular function and involve deep phenotyping and the development of a personalized medicine approach. In this Review, we summarize the mechanisms underlying PAH, provide an overview of available PAH therapies and their limitations, describe the development of newer, predominantly non-vasodilatory drugs that are currently being tested in phase II or III clinical trials, and discuss future directions for PAH research.

Key points

  • Established therapies for pulmonary arterial hypertension (PAH), which has a complex vascular pathobiology characterized by cell proliferation, extracellular matrix deposition and inflammation, have predominantly vasodilatory effects.

  • The tyrosine kinase inhibitors imatinib and seralutinib have predominantly anti-proliferative properties and have been reported to be efficacious in the treatment of PAH in clinical trials; administration by inhalation might address the safety concerns associated with orally administered imatinib.

  • Therapy with the activin receptor type IIA ligand trap sotatercept was effective in patients with PAH in clinical trials; an ongoing extension study might address questions regarding long-term cardiac and systemic vascular safety.

  • The effect of PAH therapy on load-independent right ventricular function, an important determinant of outcomes in these patients, requires further investigation.

  • Individual responses to different PAH treatments might vary; deep phenotyping might help to identify biomarkers associated with drug-specific responses and support the development of a personalized medicine approach.

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Fig. 1: Pathomechanisms of pulmonary arterial hypertension.
Fig. 2: Overview of key adverse effects of approved and advanced investigative therapies for pulmonary arterial hypertension.
Fig. 3: Key investigative treatment options with novel targets in pulmonary vascular disease.

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Acknowledgements

H.-A.G. has received research funds from the German Research Foundation (DFG; CRC 1213 projects B08 and A09), the Cardiopulmonary Institute (CPI), the Institute for Lung Health (ILH) and the German Center for Lung Research (DZL). L.Z. has received research funds from the British Heart Foundation (PG/19/17/34275, RE/18/4/34215), DFG (CRC 1213 project B08), the CPI, the ILH and the DZL. F.G. has received research funds from public sources from the DFG (CRC 1213 project A08), the CPI, the ILH and the DZL.

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Authors and Affiliations

  1. Department of Internal Medicine, Justus-Liebig-University Giessen, Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Giessen, Germany

    Hossein-Ardeschir Ghofrani

  2. George Washington University School of Medicine and Health Sciences, Department of Medicine, Washington, DC, USA

    Mardi Gomberg-Maitland

  3. National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, UK

    Lan Zhao

  4. Department of Internal Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), Institute for Lung Health (ILH), Cardio-Pulmonary Institute (CPI), German Center for Lung Research (DZL), Giessen, Germany

    Friedrich Grimminger

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  1. Hossein-Ardeschir Ghofrani
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  2. Mardi Gomberg-Maitland
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  3. Lan Zhao
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  4. Friedrich Grimminger
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All authors contributed to all aspects of this manuscript.

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Correspondence to Hossein-Ardeschir Ghofrani.

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Competing interests

H.-A.G. has received fees for lectures and/or consultations from Aerovate, Altavant/Enzyvant, Bayer AG, Gossamer Bio, Janssen/Actelion, MorphogenIX, MSD/Acceleron, Pfizer, and United Therapeutics and fees for participation in a data safety monitoring board from Insmed. His spouse was an employee of Altavant/Enzyvant from January 2023 until August 2023; her work for the company was intentionally separated from H.-A.G.’s active interactions in conjunction with the clinical development programme. M.G.-M. has received research grants paid to her institution from Aerovate, Altavant, Acceleron (a subsidiary of Merck), and Bayer and consultation fees from Aerami, Acceleron (a subsidiary of Merck), Bayer, Janssen Biotech, Keros Therapeutics, and United Therapeutics Corporation. She holds leadership roles on the Board of Directors for the International Society of Heart and Lung Transplantation and the Scientific Advisory Board of United Therapeutics. Her spouse is a Senior Director in Clinical Development at Intellia Therapeutics. The other authors declare no competing interests.

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Ghofrani, HA., Gomberg-Maitland, M., Zhao, L. et al. Mechanisms and treatment of pulmonary arterial hypertension. Nat Rev Cardiol (2024). https://doi.org/10.1038/s41569-024-01064-4

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