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Review
. 2025 Aug 18;15(3):e70144.
doi: 10.1002/pul2.70144. eCollection 2025 Jul.

Significance of Pulmonary Vascular Dysfunction in Chronic Obstructive Pulmonary Disease

Steven D Nathan  1 , Lucilla Piccari  2 , Steven H Abman  3 , Aparna Balasubramanian  4 , Reda E Girgis  5 , Gabor Kovacs  6 , Horst Olschewski  7   8 , Oksana A Shlobin  9 , Norman Stockbridge  10 , S John Wort  11 , George R Washko  12 , Sylvia M Nikkho  13
Affiliations
Review

Significance of Pulmonary Vascular Dysfunction in Chronic Obstructive Pulmonary Disease

Steven D Nathan et al. Pulm Circ. .

Abstract

Chronic obstructive pulmonary disease (COPD) is frequently accompanied by abnormalities of the pulmonary vasculature. This vasculopathy spans the spectrum from mild vascular dysfunction to pulmonary hypertension, which on rare occasions can be severe. Given the worldwide prevalence of COPD, it is conceivable that the morbidity and mortality associated with pulmonary vascular dysfunction have been vastly underappreciated, especially in countries and regions where the infrastructure and resources to define the magnitude of the problem are often limited. This article reflects deliberations of the Pulmonary Vascular Research Institute's Innovative Drug Development Initiative (PVRI IDDI) Group 3 Pulmonary Hypertension Workstream on the role of the pulmonary vasculature in COPD. In this introductory paper, we lay the foundation for forthcoming papers by our group, with our ultimate goals being to increase awareness and encourage more research, including clinical trials, to address this unmet need.

Keywords: chronic obstructive pulmonary disease; clinical trial design and endpoints; epidemiology; prognosis; pulmonary hypertension; pulmonary vascular dysfunction; symptom assessment and management.

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Conflict of interest statement

Dr. Nathan is a consultant for United Therapeutics, PureTech, Boehringer‐Ingelheim, and Daewoong. He is on the Board of Directors for Gossamer Bio. Dr. Piccari has been a consultant for Ferrer, United Therapeutics, and Liquidia; served as speaker for educational activities for Janssen, MSD, Ferrer, and Medscape; received research grants from Ferrer; and received support for attending congresses from Janssen, MSD, and Ferrer, not related to this manuscript. Dr. Abman serves as a scientific advisor to Oak Hill Bio and Chiesi and is a recipient of NHLBI grants HL68702, HL145679, and UHL151458, which are not related to this manuscript. Dr. Balasubramanian received funding from an NHLBI K23HL153778. Dr. Girgis received honoraria from Boehringer Ingelheim and research funding from UT. Dr. Kovacs reports personal fees and nonfinancial support from Actelion, Janssen, Bayer, GSK, MSD, Boehringer Ingelheim, Novartis, Chiesi, Vitalaire, Ferrer, and AOP outside the submitted work. Dr. Olschewski received funding from Actelion, AOP, Astra Zeneca, Bayer, Boehringer, Chiesi, GSK, Iqvia, Janssen, Menarini, MSD, Novartis, Ludwig Boltzmann Society, Ferrer, MedUpdate, and Mondial not related to this study. Dr. Shlobin has consulted for Gossamer, UT, Bayer, Altavant, Aerovate, Aerami, Jenssen, and Merck and is on the speaker bureau for UT. Dr. Stockbridge has consulted for United Therapeutics and Roivant. Dr. S. John Wort received honoraria from Janssen, MSD, Bayer, Ferrer, and Acceleron for advisory boards; honoraria from Janssen for educational activity; unrestricted research grants from Janssen, Ferrer, and Bayer; and travel grants, conference registration, and accommodation from Janssen and Ferrer. Dr. Washko received consultancy fees from AstraZeneca, Intellia Therapeutics, Regeneron, and Sanofi. Dr. Nikkho is an employee of Bayer AG.

Figures

Figure 1
Figure 1
Conceptual diagram of pulmonary vascular disease. Pulmonary vasculopathy refers to structural or anatomic changes (remodeling) within the pulmonary circulation, while pulmonary dysfunction is a physiologic manifestation that may encompass either functional impairment of the pulmonary vasculature or functional impairment of the patient. It is uncertain if vasculopathy is always accompanied by or precedes dysfunction and how these two concepts interrelate on a patient‐by‐patient basis.
Figure 2
Figure 2
Conceptual depiction of patient symptoms and signs as they relate to the underlying pathophysiology of COPD, including the ubiquitous presence of pulmonary vascular disease.
Figure 3
Figure 3
(A) Image‐based reconstruction of the pulmonary vasculature segmented by vessel size in a normal patient. (B) An emphysema patient with associated pulmonary hypertension demonstrating vessel dropout. Similar imaging might find a role in the future phenotyping of patients for clinical trial inclusion.
See this image and copyright information in PMC

References

    1. Nathan S. D., Fernandes P., Psotka M., et al., “Pulmonary Hypertension in Interstitial Lung Disease: Clinical Trial Design and Endpoints: A Consensus Statement From the Pulmonary Vascular Research Institute's Innovative Drug Development Initiative—Group 3 Pulmonary Hypertension,” Pulmonary Circulation 12 (December, 2022): e12178, 10.1002/pul2.12178. - DOI - PMC - PubMed
    1. Nikkho S. M., Richter M. J., Shen E., et al., “Clinical Significance of Pulmonary Hypertension in Interstitial Lung Disease: A Consensus Statement From the Pulmonary Vascular Research Institute's Innovative Drug Development Initiative—Group 3 Pulmonary Hypertension,” Pulmonary Circulation 12 (2022): e12127, 10.1002/pul2.12127. - DOI - PMC - PubMed
    1. Piccari L., Allwood B., Antoniou K., et al., “Pathogenesis, Clinical Features, and Phenotypes of Pulmonary Hypertension Associated With Interstitial Lung Disease: A Consensus Statement From the Pulmonary Vascular Research Institute's Innovative Drug Development Initiative—Group 3 Pulmonary Hypertension,” Pulmonary Circulation 13 (2023): e12213, 10.1002/pul2.12213. - DOI - PMC - PubMed
    1. Shlobin O. A., Shen E., Wort S. J., et al., “Pulmonary Hypertension in the Setting of Interstitial Lung Disease: Approach to Management and Treatment. A Consensus Statement From the Pulmonary Vascular Research Institute's Innovative Drug Development Initiative—Group 3 Pulmonary Hypertension,” Pulmonary Circulation 14 (2024): e12310, 10.1002/pul2.12310. - DOI - PMC - PubMed
    1. Vitulo P., Piccari L., Wort S. J., et al., “Screening and Diagnosis of Pulmonary Hypertension Associated With Chronic Lung Disease (PH‐CLD): A Consensus Statement From the Pulmonary Vascular Research Institute's Innovative Drug Development Initiative—Group 3 Pulmonary Hypertension,” Pulmonary Circulation 14 (2024): e70005, 10.1002/pul2.70005. - DOI - PMC - PubMed

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