Significance of Pulmonary Vascular Dysfunction in Chronic Obstructive Pulmonary Disease

Authors: Steven D. Nathan, Lucilla Piccari, Steven H. Abman, Aparna Balasubramanian, Reda E. Girgis, Gabor Kovacs, Horst Olschewski, Oksana A. Shlobin, Norman Stockbridge, S. John Wort, George R. Washko, Sylvia M. Nikkho

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.

Introduction

The Pulmonary Vascular Research Institute's Innovative Drug Development Initiative (PVRI IDDI) has initiated several workstreams to address various aspects of pulmonary hypertension (PH), with one such group devoted to PH associated with lung diseases. This endeavor is a comprehensive collaborative effort constituted by academicians from across the globe, with pharmaceutical and regulatory representation. The aim of our working group is to strengthen the community's understanding of the pulmonary vasculature in chronic parenchymal lung disease, including but not limited to interstitial lung disease (ILD) and chronic obstructive lung disease (COPD). The ultimate goals of our working group are to improve the care and quality of life (QoL) of affected patients by providing guidance in their management and to suggest a framework for future research, including observational and interventional studies for this large unmet need. Our group has previously addressed PH in the context of ILD in a series of papers [1, 2, 3, 4]. The most recent publication in this series provided a “bridge” from ILD to COPD, since it dealt with the diagnosis of PH associated with lung disease, a topic that is agnostic to the type of chronic lung disease (CLD) [5]. In our initial series, our focus was on PH associated with ILD. The narrative has shifted through in‐depth dialog and presentations, from a primary focus on PH to encompassing the wider implications of the pulmonary vasculature in CLDs, with the focus on COPD in this paper.

Inflammation, remodeling, and destruction of the pulmonary vasculature are fundamental aspects of the biology and pathophysiology of COPD. The pulmonary vasculature is at the center of the lungs' susceptibility to injury from noxious exposures and is a potential contributor to emphysematous destruction of the lung parenchyma. From a clinical standpoint, the relevance of PH and of the broader concept of pulmonary vascular (PV) disease, in the context of COPD, is highlighted by multiple observations and the high prevalence of COPD‐PH worldwide [6]. 1. The complex etiology of PV disease in COPD: There is growing recognition that PV disease in COPD patients arises not merely from hypoxia‐induced vascular remodeling, but through multifactorial processes involving diverse and interactive pathophysiological pathways. Underlying mechanisms include reduced vascular surface area due to emphysematous destruction, regression of the distal pulmonary vasculature associated with impaired growth, vascular wall structural remodeling, and altered vascular tone and reactivity. This understanding necessitates the need for a holistic approach to the diagnosis and management of PV disease in the COPD population.2. Impact on functional capacity and QoL: The significant functional limitations imposed by PV disease in COPD patients, specifically when this progresses to PH (COPD‐PH), underscore the critical need for interventions to halt or reverse these downstream morbidity and mortality consequences.3. **Association with acute exacerbations of COPD and ** There is a common recognition that the frequency and severity of acute COPD exacerbations are associated with significant morbidity and mortality, and there are data demonstrating a link between PV disease and the propensity for acute COPD exacerbations [7]. This further underscores the imperative for early identification, strategic management, and continued research for therapies to ameliorate the detrimental effects of PV disease on morbidity and mortality in COPD patients.4. Accessibility of hemodynamic measurements: The worldwide prevalence of COPD, especially in underserved areas, precludes the universal employment of right heart catheterization (RHC) for routine clinical evaluation.5. Issues with hemodynamic measurements in COPD patients: Variability in measurements may arise from the effects of airflow obstruction, dynamic hyperinflation, respiratory effort, and the variable use of supplemental oxygen. Additionally, the interpretation of hemodynamic data in the context of COPD can be complicated by the presence of comorbidities that also affect the pulmonary arterial and left‐sided pressures.6. Lack of awareness: There is a general lack of awareness of the detrimental effects of PV disease in patients with COPD. Specifically, since the airflow obstruction of COPD is not fully reversible, it is therefore easy to attribute any persistent symptoms to the airways and not the vasculature.

The clinical repercussions of PV disease include reduced exercise tolerance, acute exacerbations of COPD, and increased mortality, and notably, these problems may be observed before PH develops. As a result, we have expanded our scope to “pre‐PH” PV disease, which may accompany the development of COPD before the identification of PH, and that these may even be found in people at risk for developing COPD, who are now referred to as having pre‐COPD. In the following section, we propose concepts about the categorization of PV disease that will be used throughout this manuscript. These concepts reflect the potential implications of PV disease within the COPD framework, emphasizing the necessity for a greater understanding of its pathophysiology, the importance of addressing functional impairments, and the possibility of improving outcomes through preemptive and targeted treatment strategies.

This manuscript serves as an introduction to our collective's discourse on the role and impact of PV disease in COPD. Subsequent publications will explore the distinct facets of this complex association in more detail.

PV Categorization: A Conceptual Framework

Similar to pulmonary arterial hypertension (PAH), COPD‐PH is diagnosed hemodynamically by RHC. However, PH represents only the tip of the PV disease iceberg in COPD patients, as abnormalities may exist without hemodynamically defined PH, despite the recently lowered threshold for a PH diagnosis [8]. It is necessary to delineate and distinguish three different entities or concepts involving the pulmonary vasculature in COPD. These likely evolve along a continuum of PV disease, although the association and interplay between these are a subject for future research (Figure 1). We feel it necessary to distinguish these, since these terms have been used without a clear definition in the prior literature.

Pulmonary vasculopathy in COPD: We propose that this should refer to structural changes or remodeling within the pulmonary vasculature, characterized by morphologic alterations in the pulmonary vessels. This can span the spectrum from microscopic changes to imaging demonstrating enlargement of large vessels or narrowing of small vessels, as well as vessel loss or neovascularization. Thickening of vessel walls is another morphologic change that results from hyperplasia of the intimal layer and thickening of the media [9]. Imaging data suggest that vascular pruning is associated with increased progression of emphysema [10, 11, 12]. It is unclear whether all forms of vascular remodeling may have an impact on clinical outcomes, but PV pruning observed on computerized tomography (CT) scans has been associated with reduced exercise intolerance and increased mortality in COPD patients [13]. Etiological factors resulting in morphological changes in the pulmonary vessels will be discussed in depth in a subsequent manuscript, but may be summarized as either related to genetic predisposition, developmental abnormalities, or environmental exposures. PV dysfunction in COPD: This term spans the spectrum of either the functional impairment of the pulmonary vasculature or the functional impairment of the patient. The former includes endothelial dysfunction, arterial stiffness, impaired vasodilation, increased vascular permeability, and heightened vasoconstrictive responses [14, 15]. The patient's dysfunction may include increased symptoms, reduced exercise tolerance, and other patient‐centric outcomes, including increased hospitalizations and mortality. Clinically, PV dysfunction may be associated with mildly increased or above‐average but still normal mean pulmonary arterial pressure (mPAP) values. Indeed, mPAPs lower than 20 mmHg may be associated with abnormal hemodynamic responses to exercise, risk of exacerbations, exercise intolerance, and increased mortality [7, 16, 17, 18, 19, 20, 21]. There is abundant evidence demonstrating that PV dysfunction in COPD patients and even in smokers with normal lung function [22, 23] can be attributed to tobacco and other environmental exposures. The chronic inflammatory state and hypoxic environment seen in COPD may advance to further vascular remodeling and ultimately to the development of PH; on the other hand, PV dysfunction may precede and potentially trigger the development of emphysema [21]. PH in COPD: Precapillary PH in COPD (COPD‐PH, classified in Group 3) is defined by the 7th World Symposium on PH (WSPH) as a mPAP > 20 mmHg, a pulmonary arterial wedge pressure (PAWP) ≤ 15 mmHg, and a PV resistance (PVR) > 2 Wood Units (WU) [8, 24, 25]. Severe PH in the context of CLD has previously been proposed by the 2022 ESC/ERS PH guidelines as a mPAP > 20 mmHg together with a PVR > 5 WU [25]. This definition is based on clinical evidence from a single‐center retrospective study of 142 COPD patients with PH that identified a PVR > 5 WU as the best hemodynamic marker to discriminate mortality [26]. The definition of severe PH in the context of lung disease raises the question of whether and how to categorize PH that is non‐severe. We propose that non‐severe PH be further categorized as moderate (PVR 3 to < 5) or mild ( > 2 to < 3). The rationale for a PVR of 3 marking the threshold is based on the prior definition of precapillary PH, which was also used in the only positive Group 3 PH study that resulted in an approved therapy in certain countries for ILD‐PH. While we propose these categories, it should be recognized that elevation in the PVR is a continuum with a likely more linear relationship to prognosis and potential for response to therapy. These categories are proposed to provide a framework for future mechanistic, prognostic, and therapeutic studies. It should be acknowledged that the 7th WSPH defined early PH as a mPAP 21–24 mmHg and/or PVR 2–3 WU [8]. However, we believe that maintaining the PVR as the only variable to define the three grades of severity will lead to less confusion.

To understand, diagnose, and manage properly the spectrum of PV disease manifestations, there is a growing recognition for exploring other reliable diagnostic markers and criteria that can be employed in COPD patients, especially in settings where advanced hemodynamic assessments are not feasible.

Epidemiology and Prevalence

COPD remains one of the most common causes of PH in both resource‐rich and resource‐poor countries, accounting for 42% and 24% of all PH cases in these respective settings [6, 27]. Conducting epidemiologic studies in COPD‐PH is challenging, as estimates differ depending on the diagnostic modalities employed, the population studied, and the threshold for defining PH. In addition, due to the selective indication for RHC testing, the reported prevalence of COPD‐PH varies widely, ranging in previous studies from as low as 11% to over 80% [28]. In addition, there is very limited data on the prevalence of PV disease before the development of PH [28, 29]. With these limitations, a recent meta‐analysis estimated the worldwide prevalence of echocardiographically suspected or hemodynamically diagnosed PH among individuals with COPD at 39% [30]. As nearly 300 million individuals worldwide are living with COPD [31], many of whom are undiagnosed, it is possible that over 115 million people worldwide are affected by concomitant PH. Additionally, recent research conducted in Canada observed an increasing prevalence of PH, including Group 3 disease, between 2002 and 2012. The study found that the frequency of Group 3 disease within the overall adult PH population was 47.0%, with 83% of that attributed to the COPD subpopulation [32]. Together, these findings, as outlined in Table 1, demonstrate a major unrecognized burden of PH and likely an even higher burden of PV disease in the worldwide COPD population.

Severe PH in COPD, however, is a rare condition that affects approximately 1%–5% of patients with COPD [24, 41, 43, 44, 45]. Its presence is associated with a worse prognosis when compared to patients with COPD and no PH or those with mild to moderate PH [24, 41, 43, 44, 45, 46, 47].

Spectrum of the Continuum Between Group 1 and Group 3 PH

The classification of PH into groups hinges on underlying predisposing factors and diseases. The Group 3 PH category was updated by the 7th WSPH such that subcategories are now based on the underlying lung disease rather than lung function criteria [8, 48]. In many cases, an exact categorization is often challenging, especially the oftentimes difficult distinction between Group 1 and Group 3 PH. Specifically, it remains unclear how much parenchymal lung disease is permissible within Group 1 PAH before it should be regarded as Group 3 [48]. Another issue is COPD preceding the onset of PH chronologically, and when it should be regarded as the cause of COPD‐PH versus regarded as a comorbidity associated with PAH.

The term “pulmonary vascular phenotype” has been suggested previously to designate the rare occurrence of mild‐moderate airflow limitation, profound impairment of gas exchange, and severe precapillary PH [29, 44, 49]. This small group of COPD patients (around 1%) shares hemodynamic and clinical characteristics with Group 1 PH (PAH) patients [29], although they are often more hypoxemic [9]. These patients have a poor prognosis when compared to other COPD subjects with no or mild‐to‐moderate PH [46, 47], and indeed, these patients appear to be a specific phenotype that might benefit from therapy with PH drugs [44, 45, 49]. A COMPERA registry analysis recently identified three clusters of idiopathic PAH (iPAH) patients based on age, sex, comorbidities, smoking status, and diffusion capacity for carbon monoxide (DLCO) [50]. The largest (52%) cluster consisted of elderly males, either former or current smokers, with a high burden of cardiovascular comorbidities, a low DLCO, and a poor survival despite PH therapy [50]. The term “IPAH with lung phenotype” was then introduced in a subsequent analysis of the COMPERA and ASPIRE registries to designate former or current smoking iPAH patients with no apparent lung disease and a low DLCO ( < 45% predicted) [51]. However, the description was limited by the absence of chest CT scans in most of the patients; out of the 546‐patient cohort, only 86 had available imaging, and in 73% (66/86) of these, there was evidence of parenchymal lung disease. Recent registry data also suggest that the presence of any degree of emphysema has a significant prognostic impact in patients classified as iPAH [52, 53]. Moreover, when treated with PH medications, these patients have a worse response to therapy in comparison to those with iPAH and no lung disease [53]. Ultimately, the coexistence of COPD and of PH may be regarded as a continuum, where at one end of the spectrum lies iPAH with no discernible parenchymal or airflow abnormality, and at the opposite end is advanced COPD with a variable degree of PV involvement. Although PV disease is most commonly appreciated in more advanced COPD, it has been noted that structural and functional vascular abnormalities may be present in mild COPD without hypoxemia and even in smokers with normal lung function [54, 55, 56]. These findings suggest that early endothelial damage, potentially caused by cigarette smoke components and inflammatory changes, might predispose patients to further vascular damage [54], highlighting the need to better understand the complex pathophysiology underlying both conditions. The determination of where to draw the line between a chance coexistence and a causal one might only be reached once the complex pathophysiology of COPD and PV disease has been thoroughly disentangled.

The various pathogenetic pathways involved in the development of PV disease in COPD patients and the distinct phenotypes observed will be the subject of a subsequent manuscript from our group.

Symptoms and Signs in COPD‐PH

There is surprisingly little evidence comparing symptoms in COPD patients with and without PH, which is likely due to the underappreciated prevalence of PV disease in this population. There is significant overlap between symptoms associated with COPD and those ascribable to PH. This shared symptomatology contributes to an underappreciation of PH and its delayed diagnosis. A conceptual framework of symptoms and how these relate to the underlying pathophysiology is shown in Figure 2. One of the few studies to consider patients' symptoms in PH associated with lung disease described similar frequencies for the most common symptoms (dyspnea, cough, and fatigue) in COPD and ILD patients, with shortness of breath identified as the single most bothersome symptom for most patients [57]. In a study of COPD patients, those with suspected PH on echocardiography had similar modified Medical Research Council (mMRC) and COPD Assessment Test (CAT) score results compared to those in whom PH was unlikely [58]. In any event, worsening symptoms, gas exchange, or exercise intolerance in the setting of stable COPD should trigger the suspicion for underlying PH [25]. Severe PH may progress to right heart failure, with the development of increased jugular venous distension, peripheral edema, abdominal swelling, and possibly syncope. Peripheral edema may be a late sign of more significant PH in COPD patients, but may also be caused by decreased renal perfusion and activation of the renin‐angiotensin‐aldosterone system, causing increased fluid retention. This can be seen especially during exacerbations when these phenomena may be exacerbated by air trapping, hyperinflation, hypoxemia, and hypercapnia [59].

QoL in COPD‐PH

One area which remains understudied is the impact of PV disease in COPD on patient‐reported outcome measures (PROMs), but, unfortunately, there are no specific COPD‐PH PROMs [60, 61, 62]. More widely used PROMs, such as the 36‐item (SF‐36) or the 12‐item Medical Outcomes Study Short Form survey, and PAH‐specific PROMs, such as the emPHasis‐10, Cambridge Pulmonary Hypertension Outcome Survey (CAMPHOR), and PAH symptoms and impact (PAH‐SYMPACT), have been minimally studied and never validated in COPD‐PH. Recent work conducted using the emPHasis‐10 score, SF‐36, and the Minnesota Living with Heart Failure Questionnaire scores across various groups of PH etiologies noted worse HrQoL among those with lung disease‐related PH as compared to other etiologies [63]. Additionally, in a single‐center study using the PAH‐SYMPACT score, individuals with PH secondary to CLD were similarly observed to have worse HRQoL than patients with PAH [64, 65]. A large cohort study assessing PROMs in all PH groups described lower scores in emPAHsis‐10 and in the physical component score of the SF‐36 in Group 3 patients compared to PAH patients; in addition, HRQoL was correlated with survival [64]. Further validation of various HRQoL measures remains a key step in understanding the impact of PV disease on HRQoL within a COPD population.

Impact on Clinical Outcomes

The presence of PH and even an mPAP at the upper limit of normal in the context of COPD is strongly associated with decreased functional capacity [18], worse HRQoL, increased hospitalizations, more healthcare resource utilization, and an increased risk of mortality (Table 2) [74, 75, 76, 77].

Since the recognition of PH associated with COPD, it has been clear that individuals with elevated pulmonary pressures have worse survival than those with COPD alone [36, 39, 67]. Interestingly, COPD as a comorbidity in PAH patients also appears to confer a higher risk of mortality; specifically, in the REVEAL registry, 25% of PAH patients were found to have comorbid COPD, which together conferred a worse survival than PAH alone [78]. There is a complex interplay between PH and COPD, where each condition can influence the progression and severity of the other.

The presence of PH significantly and independently reduces exercise tolerance in COPD patients [79]. In fact, exercise PH is probably very common in COPD patients, even in those without hemodynamically defined PH [7, 21]. Based on our conceptual construct, we would regard these patients as having PV dysfunction. An abnormally steep rise in pulmonary artery pressure relative to cardiac output with exercise (PAP/CO slope) is present in the majority of patients with COPD [19, 21]. However, the functional and prognostic impact of exercise PH remains unclear. Although this condition may represent pulmonary vasculopathy and PV dysfunction, other factors may also contribute, including left‐heart disease [44] and hyperinflation [80]. Consistent with the concept of PV disease as a continuum is the finding of an increased risk of COPD exacerbations in patients with an mPAP ≥ 18 mmHg compared to COPD patients with pressures below this threshold [7]. Indeed, evidence of pulmonary vasculopathy or PV dysfunction obtained by various noninvasive modalities has also been observed to have an impact on clinical outcomes among individuals with COPD. For example, imaging findings of a pulmonary artery to ascending aorta ratio > 1 have been associated with an increased risk of acute exacerbations [81]. While it is unknown if these patients had PH, they would qualify as having a pulmonary vasculopathy based on this structural abnormality with associated dysfunction in the form of acute exacerbations.

Arterial vascular pruning on CT was shown to be associated with right ventricular (RV) dilation and mortality, as well as progression of emphysema and airflow obstruction over time [12, 13]. A low diffusing capacity (DLCO) independent of airflow obstruction and emphysema is associated with worse patient‐reported symptoms, lower QoL scores, acute exacerbations, and increased mortality, suggesting pulmonary vasculopathy as a potential mechanism for this dysfunction, even in the absence of PH [12, 82, 83, 84]. Echocardiographically measured RV systolic pressure estimates. Do COPD patients with “severe PH” benefit and markers of RV dysfunction, including RV strain, fractional area change, and RV index of myocardial performance, have also been associated with worse clinical outcomes, including mortality, exacerbations, and clinical deterioration [85, 86, 87, 88]. Similarly, cardiac MRI estimates of pulmonary pressures and RV function in COPD patients have also been noted to be predictive of mortality [89]. All of these studies, albeit agnostic to the presence or absence of PH, provide clues to the possible links among pulmonary vasculopathy, PV dysfunction, and clinical outcomes.

Management of COPD‐PH

The management of PV disease in COPD, and whether PH‐specific therapies may benefit individuals, remains unclear, as high‐quality, prospective controlled studies are lacking. There are no studies to date examining therapeutic options in individuals with PV disease before the development of overt PH. Although continuation of guideline‐based COPD management with inhaled therapies is recommended, these medications have not been studied directly for benefit in COPD patients with PV disease or PH. A recent study using administrative data of COPD‐PH suggests that only 69% of patients are prescribed these therapies [90], which is lower than the previously reported use of inhaled therapy in the general COPD populations [91, 92]. This suggests that there is room for improvement in current guideline‐based management in COPD populations with PH. Pulmonary rehabilitation is a general recommendation for both COPD and PH patients [25]. It makes intuitive sense, therefore, that this simple intervention would be of benefit in COPD‐PH patients. Indeed, a cohort of COPD patients, some with RHC‐confirmed PH and some with echocardiography suspected PH, had improvement of endurance time during cardiopulmonary exercise test, distance in the 6‐min walking test, and St George Respiratory Questionnaire score after 12 weeks of pulmonary rehabilitation in a prospective trial [93].

Studies of therapeutic options in COPD‐PH have primarily focused on reducing the PVR by vasodilation with long‐term oxygen therapy and PAH‐specific drugs. The correction of hypoxemia with supplemental oxygen was shown many years ago to have modest beneficial effects on resting pulmonary hemodynamics [94]. This led to the landmark randomized multicenter Nocturnal Oxygen Therapy Trial (NOTT) and the Medical Research Council (MRC) studies demonstrating the lifesaving benefits of supplemental oxygen in COPD patients with severe hypoxemia [95, 96]. NOTT investigators also found that oxygen therapy resulted in > 10% reduction in PVR and that a higher baseline PVR was associated with an increased risk of death [95]. Indeed, supplemental oxygen remains one of the few interventions in COPD to be associated with improved survival in those with more advanced disease [97]. However, it is noteworthy that the LOTT study (oxygen in mild hypoxemia) showed no clinical benefit [98].

The availability of multiple medications for PAH has led to their use in COPD‐PH with mixed results. Although there have been one pilot study and two meta‐analyses that have suggested benefit, the largest randomized controlled trials to date did not demonstrate any benefit [99, 100, 101]. The role of therapy with PAH medications therefore remains controversial, and it is as yet unknown if there are specific phenotypes more likely to respond and possibly others who might be harmed by pulmonary vasoactive therapies. The topic of prior clinical trials, lessons learnt from these, and guidance for future clinical trials will be the subject of a future manuscript from our group.

Summary

The pulmonary vasculature plays a pivotal role in the development and clinical impact of COPD. There is a continuum of PV disease in COPD patients manifesting as pulmonary vasculopathy, PV dysfunction, and eventually PH. There have been attempts to link pulmonary hemodynamics to physiologic disease severity, but the role and impact of lung morphologic changes have been largely ignored until recently. The most widely accepted COPD guidelines (GOLD) have previously acknowledged the role of abnormalities of the pulmonary circulation during the course of COPD and included a chapter on PH in 2024 [102]. Nonetheless, there remains a lack of guidance in how best to address the spectrum of PV disease and PH in COPD from a clinical standpoint. The goal of this paper and our subsequent planned manuscripts is to raise awareness, provide evidence‐based guidance, and encourage future research. Such research should include multiomics, imaging, and other noninvasive assessments of the vasculature to better endotype and phenotype COPD patients based on the presence/absence and spectrum of PV disease. Ultimately, the hope is that such studies will lay the foundation for targeted therapies and clinical trials directed to the vasculature in COPD. This introductory manuscript has provided an overview of COPD‐PH, while future manuscripts are planned to further address pathogenesis and phenotypes, and the role of medical therapy, including future clinical trial considerations. Our group will continue to work collaboratively and methodically to synthesize the existing literature, recognizing that there are numerous unanswered questions, including the

Main open questions and gaps in the evidence What is the relationship between parenchymal changes, PV disease, and PH?Which patients with COPD should undergo RHC, and how should this decision be influenced by the underlying physiology and morphology?How should pharmacological approaches for PH depend on the phenotypes and severity of COPD?What is the role of imaging in phenotyping COPD patients, and can imaging of the vasculature be used as a surrogate for treatment responsiveness? An example of image‐based reconstruction of the pulmonary vasculature is shown in Figure 3.Do COPD patients with “severe PH” benefit from PH drugs and if yes, what is the best pharmacological approach for severe PH in COPD?Are there subgroups of patients with non‐severe PH associated with COPD who may be candidates for PH‐targeted therapy?Are the mechanisms of vascular remodeling and dysfunction different in patients with severe COPD‐PH and PAH patients with concomitant COPD?What is the relationship between pulmonary vasculopathy and PV dysfunction? What are the best noninvasive surrogates to detect them, and do they warrant detection? How and when do they lead to PH, and when is it best to address these therapeutically?What are the clinical features differentiating patients classified as COPD‐PH and those patients with a smoking history and low DLCO (< 45%) without visible changes on high‐resolution chest CT and normal or near‐normal pulmonary function tests?What, if any, is the indication for assessment of exercise hemodynamics in COPD?

Author Contributions

Steven Nathan, Sylvia Nikkho, and Lucilla Piccari were involved in the conception and design of the study, conducted the searches and data extraction, wrote the first draft, and drafted the figures of the manuscript. All authors analyzed and interpreted the data, revised the manuscript critically for important intellectual content, approved the final manuscript, and agreed to be accountable for its overall content.

Ethics Statement

The authors have nothing to report.

Consent

The authors have nothing to report.

Conflicts of Interest

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.