Pathogenesis and Phenotypes of Pulmonary Vascular Disease in COPD: A Consensus Statement From the Pulmonary Vascular Research Institute's Innovative Drug Development Initiative – PH Group 3 Workstream

ABSTRACT

Chronic obstructive pulmonary disease (COPD) is frequently associated with pulmonary vascular disease (PVD) yet pulmonary vascular involvement remains underrecognized and incompletely phenotyped. Emerging evidence demonstrates that pulmonary vasculopathy may precede overt emphysema and airflow obstruction, suggesting that vascular remodeling is an early and integral component of COPD pathobiology rather than solely a late consequence of advanced lung disease. Multiple mechanisms contribute to COPD‐associated PVD, including genetic susceptibility, abnormal lung development, cigarette smoke and environmental exposures, endothelial dysfunction, hypoxia, inflammation, hyperinflation, and comorbid cardiovascular and infectious diseases, which are discussed in this paper. These processes lead to heterogeneous clinical phenotypes that span a continuum from early pulmonary vascular abnormalities without resting PH to severe hemodynamically defined PH. Conventional spirometry and resting hemodynamics incompletely capture this complexity, whereas advanced imaging, gas‐exchange assessment, and exercise testing improve identification of pulmonary vascular involvement. Distinct pulmonary vascular phenotypes may carry important implications for exercise limitation, exacerbation risk, progression, and survival. Recognizing COPD‐associated PVD as a continuum rather than a late‐stage complication has major implications for screening, phenotyping, and clinical trial design. This article reflects deliberations of the Pulmonary Vascular Research Institute's Innovative Drug Development Initiative (PVRI IDDI) Group 3 Pulmonary Hypertension Workstream on the pathophysiology and phenotypes of PVD in COPD.

1. Introduction

Chronic obstructive pulmonary disease (COPD) is a highly prevalent disease that is commonly associated with pulmonary hypertension (PH) [1]. COPD‐associated PH (COPD‐PH) has heterogenous pathophysiology and phenotypic variability, including evidence of pulmonary vascular injury driving the development of emphysema. Yet, pulmonary vascular disease (PVD) is still widely considered a complication of advanced COPD [2], entirely consequent to the development of airflow obstruction and emphysema. Advances in our understanding of the genetic and molecular underpinnings of PVD in COPD have enabled glimpses into the complex interplay between pulmonary vasculopathy, airway abnormalities, and alveolar alterations. Further, there is a growing interest in phenotyping clinical populations with COPD and COPD‐PH [3, 4, 5], but defining distinct phenotypes are limited in part due to differing PH detection methods, changing definitions of PH, and a focus on advanced COPD in pre‐transplant cohorts.

The Pulmonary Vascular Research Institute (PVRI) Innovative Drug Development Initiative (IDDI) group dedicated to PH associated with lung diseases has broadened its focus beyond hemodynamically‐defined COPD‐PH, to include PVD that co‐occurs with COPD, well before a hemodynamic diagnosis of PH can be made. This conceptual frameshift for the field has been previously delineated [6], but in short was motivated by three main considerations. First, the hemodynamic threshold for PH diagnosis has been lowered several times [7, 8, 9], with accumulating evidence that pressure elevations, that were considered normal previously, have impactful consequences [10, 11]. Second, the diagnosis of PH requires right heart catheterization (RHC), an invasive procedure and scarce resource, especially in underserved areas. Further, obtaining accurate hemodynamic pressure tracings during RHC at rest are often complicated by COPD pathophysiology, for example, large respiratory swings [12]. In addition, in some cases RHC assessment during exercise offers valuable insights into pathophysiology, which requires experience and specific equipment. Consequently, referral to PH expert centers is commonly necessary, which are however similarly scarce and often limited to urban settings [9, 13]. Finally, with acknowledgment that tobacco‐ and air pollution‐related exposures are growing worldwide and affect both the lung parenchyma and the vessels, further aggravates the need to properly phenotype COPD‐PVD [14]. The cumulative result of these considerations is that clinically meaningful PVD in COPD (COPD‐PVD) and COPD‐PH are likely vastly underdiagnosed.

The present manuscript will focus on the spectrum of pathophysiological alterations in the pulmonary vasculature from early PVD to overt PH in COPD, describing current knowledge and outlining gaps in our understanding of COPD‐PH phenotypes. Finally, we will highlight research priorities to further our understanding and hopefully provide a foundation for clinical trials in COPD‐PVD.

The screening and diagnosis of COPD‐PH have been previously addressed by our task force [13] and will not be covered within this current manuscript.

1.1. Pathogenesis of COPD With PVD

The notion that COPD is associated with pulmonary vasculopathy has been recognized by the scientific community for over 150 years [14]. While traditionally chronic hypoxia and parenchymal destruction have been considered the main causes of pulmonary vasculopathy in COPD [15], many other pathogenic mechanisms have since been identified.

The development of COPD can be attributable to a combination of host susceptibility features and external exposures as genetic and developmental factors predispose individuals to maladaptive inflammatory and aberrant remodeling responses of the airways to noxious stimuli. Additionally, susceptible hosts predisposed to maladaptive vascular remodeling in response to noxious exposures can develop inadequate attainment of maximal vascular structure and progressive destruction or remodeling over time. Importantly, small pulmonary arteries and the microvasculature of both COPD and COPD‐PH demonstrate increased pulmonary arterial remodeling [16], highlighting how microvascular PVD occurs before the establishment of hemodynamically‐defined PH [17].

As in the previous introductory article from our group [6], we will use a set of specific terms to define gradations of vascular disease. Pulmonary vasculopathy will designate the microscopic and macroscopic structural changes observed in the pulmonary circulation of COPD patients, such as pruning and obliteration, vascular intimal thickening, or enlargement of the main pulmonary artery. PVD will refer to dysfunction of the pulmonary vasculature that results in clinical burden, including symptoms, quality of life, reduced exercise capacity, COPD exacerbations, cardiopulmonary hospitalizations and death. Finally, COPD‐PH will refer to the hemodynamically defined condition classified as Group 3 PH according to the most recent classification of PH [1]: PH is present with a mean pulmonary arterial pressure (mPAP) > 20 mmHg measured by right heart catheterization. COPD‐PH is further subclassified into non‐severe PH, defined as mPAP > 20 mmHg, pulmonary vascular resistance (PVR) ≤ 5 Wood Units (WU) and severe PH, defined as PVR > 5 WU [9]. In our introductory paper, we suggested also defining mild (PVR > 2 to < 3) and moderate (PVR 3 to < 5) PH in the context of COPD and other Group 3 conditions [6]. Although these thresholds have not been validated, it is likely that the impact of PVR is on a continuum, and that these thresholds might prove useful in future clinical trial designs. The terminology used in this manuscript are summarized in Table 1.

Table 1.

Terminology and definitions used in this manuscript.

Term	Definition
Pulmonary vasculopathy	Microscopic and macroscopic structural changes observed in the pulmonary circulation, such as pruning, such as pruning and obliteration, vascular intimal thickening, or enlargement of the main pulmonary artery
Pulmonary vascular disease (PVD)	Dysfunction of the pulmonary vasculature that results in clinical burden, including symptoms, quality of life, reduced exercise capacity, COPD exacerbations, cardiopulmonary hospitalizations and death
COPD‐PVD	COPD patients with signs of PVD, but without overt resting PH
COPD‐PH	COPD and mPAP > 20 mmHg
COPD with mild PH	COPD and mPAP > 20 mmHg + PVR 2‐3 WU
COPD with moderate PH	COPD and mPAP > 20 mmHg + PVR 3‐5 WU
COPD with severe PH	COPD and mPAP > 20 mmHg + PVR > 5 WU

Abbreviation: PH, pulmonary hypertension.

Key pathophysiological domains underlying the development and progression of PVD in COPD which are discussed in the following sections are summarized in Table 3.

Table 3.

Key pathophysiological domains underlying development and progression of pulmonary vascular disease in COPD.

Domain	Contributors to pulmonary vascular disease in COPD	Pathophysiologic mechanisms
Genetic susceptibility	Genetic polymorphisms	Increase susceptibility to pulmonary vascular remodeling, endothelial dysfunction, and PH development
	Epigenetic modifications/miRNA dysregulation	Promote smooth muscle proliferation, oxidative stress, and maladaptive vascular remodeling
Developmental and early life factors	Prematurity/Bronchopulmonary dysplasia	Impaired distal lung and vascular development; reduced vascular surface area
	Antenatal/perinatal insults (chorioamnionitis, placental dysfunction, maternal smoking, preeclampsia, IUGR)	Disrupted angiogenesis and abnormal pulmonary vascular growth trajectories
Environmental and exposure related injury	Cigarette smoking	Direct endothelial injury, oxidative stress, apoptosis, vascular remodeling, emphysema
	Biomass exposure	Pulmonary vascular remodeling, endothelial dysfunction, intimal thickening
	Ambient air pollution	Associated with RV remodeling and pulmonary vascular structural abnormalities
	Other environmental toxins (heavy metals, microplastics, etc.)	Potential endothelial injury (evidence emerging)
Hypoxia and gas exchange abnormalities	Chronic alveolar hypoxia	Hypoxic pulmonary vasoconstriction and vascular remodeling
	Nocturnal intermittent hypoxemia	Promotes chronic vasoconstrictive and remodeling responses
Parenchymal lung disease	Emphysema, alveolar destruction	Loss of alveolar‐capillary bed and vascular surface area
	Microvascular rarefaction	Reduces pulmonary vascular cross‐sectional area and increases PVR
Primary pulmonary vascular injury	Endothelial dysfunction	Reduced NO signaling, increased endothelin/VEGF/TGF‐β, apoptosis
	Impaired endothelial repair	Reduced endothelial progenitor cells and vascular regeneration
	Endothelial‐to‐mesenchymal transition	Pro‐proliferative phenotype promoting remodeling
Mechanical factors	Dynamic hyperinflation	Increased intrathoracic pressure, increased PVR, impaired RV filling
Inflammatory and immune factors	Systemic inflammation	Elevated CRP, TNF‐α, IL‐6 associated with PH/PVD
	Pulmonary vascular inflammation	Inflammatory infiltrates in PA promote remodeling
	Eosinophilic COPD phenotype	Associated with increased risk of precapillary PH
Infectious disease	Pulmonary tuberculosis, HIV, others	Depending on underlying lung disease, for example, HIV, accelerated emphysema development
Comorbid and overlapping conditions	Left heart disease, cardiovascular disease	Can contribute to post‐capillary or combined PH
	Sleep‐disordered breathing, OSA	Worsens nocturnal hypoxemia and pulmonary pressures
	Chronic thromboembolic disease	Alternative contributor to pulmonary vascular obstruction
Disease behavior, progression	Acute COPD exacerbations	Increase inflammation, hypoxia, and cardiopulmonary stress

1.2. Genetic Mechanisms for Pulmonary Vascular Disease Associated With COPD

Recent data suggest that genetic factors may confer susceptibility to developing PVD in COPD and may offer novel therapeutic targets. The LL genotype of the serotonin transporter gene has been associated with a greater expression in pulmonary arterial smooth muscle cells, as well as hemodynamic severity as opposed to the SS genotype [18, 19]. Similarly, the GG genotype on the interleukin‐6 (IL‐6) encoding gene has been found to correlate with an increase in mPAP in COPD patients [20]. Single nucleotide polymorphism (SNP) analysis has also been used to show how the frequency of specific alleles of the gene for brain natriuretic peptide (BNP) is associated with PH in COPD patients, and with the expression of BNP, apelin and fibrinogen [21]. Furthermore, a genome‐wide association study (GWAS) [22] of advanced COPD patients found an association between pulmonary vasculopathy (in the form of pulmonary artery to aorta diameter ratio, PA/Ao, ratio > 1) and SNP loci in the iron‐responsive element‐binding protein 2 gene (IREB2, related to iron cell levels in response to hypoxia), and the galactosylceramidase gene (GALC, responsible for a rare disease of sphingolipids metabolism). Some of these genetic variations are also implicated in pulmonary arterial hypertension (PAH), suggesting that a subset of COPD‐PH may mirror the pathogenesis of PAH.

Gene expression is also modulated by microRNAs (miRNAs) and epigenetic modifications of DNA, such as histone methylation and acetylation, reflecting gene by environment interactions modifying disease development and trajectory in COPD [23, 24, 25]. For example, downregulation of miR‐197 has been linked to pulmonary vascular remodeling and airflow obstruction in COPD, likely through the induction of smooth muscle cell proliferation [26]. Qi et al. [27] demonstrated that methylation of histone H4 lysine 20, mediated by the enzyme Suv4‐20h1, was reduced in COPD lungs compared with normal controls and those with idiopathic pulmonary arterial hypertension (iPAH). Further, deficiency of Suv4‐20h1 led to COPD‐PH changes in a mouse model via the repression of superoxide dismutase‐3 and consequent increased oxidative stress, offering a unique mechanism for development of COPD‐PH distinct from iPAH [27].

It is unclear how the genetic footprint may predispose patients to the development of PVD with or without subsequent PH. Similarly, it is unclear if there are genetic mechanisms that are protective of PVD or progression to PH. As continued advancements in genetic research sheds more light on the pathogenesis of PH in COPD, genomics are likely to play an integral role in the clinical phenotyping of PVD in COPD.

1.3. Impaired Lung Development: The Early Origins of COPD and Vasculopathy

There has been a growing awareness that perinatal factors, especially related to premature birth and antenatal factors like chorioamnionitis, placental dysfunction with intrauterine growth restriction, preeclampsia, and maternal smoking, are critical determinants of COPD and PVD [5, 28, 29, 30, 31, 32, 33, 34]. These features contribute to an increased risk for bronchopulmonary dysplasia (BPD), a chronic lung disease defined as the need for neonatal respiratory support beyond 36 weeks gestational age [28], respiratory disease during [5] infancy and early childhood, even in the absence of BPD, and dysanapsis, which is characterized by reduced airway caliber relative to total lung volume, airway instability due to loss of alveolar tethering elements, variable bronchial hyperreactivity and poor growth of the distal lung airspace and vasculature [35, 36]. These abnormalities in distal lung development such as dysanapsis persist into adulthood [36], setting the stage for failure to achieve full growth potential of the lung in young adults, and abnormal trajectories of lung function that can worsen over time [33, 37]. Attainment of peak lung health has been shown to be an important risk factor for developing COPD. How this impacts the vasculature and the risk of subsequent PVD is an area for future research.

In addition to altered airway structure and distal airspace growth, the developing lung circulation is markedly affected by adverse antenatal exposures and perinatal injury, leading to reduced lung vascular surface area due to impaired angiogenesis (the so‐called “vascular hypothesis” of BPD) [34, 38, 39, 40, 41, 42]. Early disruption of angiogenesis is strongly associated with a high risk for PH and reduced alveolar growth due to the loss of angiocrine signaling [34, 41]. Early signs of PVD in preterm infants at 7 days of postnatal life are strongly associated with the subsequent development of BPD, late PH and respiratory disease during the first 2 years of life [42, 43]. Importantly, reduced lung vascular surface area as based on a low diffusing capacity (DLCO) in young adults born preterm may contribute to the late development of overt PH during adulthood [44, 45]. Thus, although still an area of active research, there is strong suggestion that abnormal trajectories of airway size and distal lung growth from preterm birth and prenatal/early life exposures may lead to COPD and related PVD in later life.

1.4. Exposures and Their Effects on Pulmonary Vasculature and Parenchyma

Ever since the mid‐20th century, it has been established that smoking was associated with the development of COPD in a dose‐dependent manner [46]. The association between COPD and exposure to other agents such as biomass and environmental pollution have been increasingly recognized [5], but only recently the focus of research in this domain has shifted to the vascular component of the lungs.

1.5. Smoking and Environmental Exposure to Smoke Products

Smoking is the largest researched exposure contributing to COPD, inflammation, PA remodeling and the development of emphysema. Each of these aspects, clinically as well as pre‐clinically is described in detail in the following sections of ‘Pulmonary Vascular Pathophysiology in COPD’. Environmental exposures may contribute to PVD in COPD through direct vascular toxicity, alveolar–vascular crosstalk, and possible stage‐dependent reversibility. Although most literature resides with cigarette exposure it is likely that other exposures, such as wood‐smoke exposure and indoor pollutants [47, 48], could have a same or similar effects on the pulmonary vasculature [49]. The correlation between parenchymal damage and vascular remodeling resulting from smoking is uncertain. Data from the smoking mouse and guinea pig model indicate that smoking induced pulmonary vascular remodeling may precede the development of overt emphysema. These findings support the concept that cigarette smoke exerts direct pathogenic effects on the pulmonary vasculature independent of hypoxia or emphysema development [50, 51, 52]. Crosstalk within the alveolar–vascular unit may further contribute to disease development. Cigarette smoke can simultaneously affect alveolar and vascular compartments through shared inflammatory and oxidative pathways [53].

Finally, the potential for reversibility may depend on disease stage. Early functional vascular abnormalities may be more amenable to reversal following removal of the exposure than established structural remodeling and vascular loss. Experimental studies demonstrate reversibility of smoke‐induced PH and vascular remodeling [53]; however, whether PVD is reversable following exposure cessation in humans remains unknown.

1.6. Indoor and Outdoor Air Pollution, Extreme Temperatures and Weather Events

Biomass air pollution is an important risk factor for COPD, especially in low‐income areas where the use of indoor biomass stoves is widespread [54]. Epidemiologic data on COPD‐PH in these settings remain limited and are predominantly derived from small, hospital‐based studies using echocardiography; however, available studies suggest a potentially high burden. A meta‐analysis reported substantial geographic heterogeneity in COPD‐PH prevalence, with the highest estimated prevalence in Africa (64%) [55]. These findings underscore both the potential importance of environmental exposures in COPD‐associated PVD and the need for more rigorous epidemiologic studies in LMIC populations. A study of biomass (wood smoke)‐associated COPD from Mexico noted a 70% prevalence of RHC‐defined PH, the majority of patients having severe PH and pulmonary intimal thickening was present in a subgroup with lung biopsies [47]. Additionally, echocardiographic features of PH, as well as systemic endothelial dysfunction, have been observed in subjects with biomass‐associated and tobacco‐induced COPD [56]. There are no studies directly investigating the effect of environmental pollution on the pulmonary vessels in patients with COPD [57], but evidence accumulated in the large Multi‐Ethnic Study of Atherosclerosis (MESA) study shows that exposure to common pollutants [58, 59, 60, 61] are associated with higher right ventricular (RV) mass and end‐diastolic volume as well as an increase in total vascular structures on chest CT, suggesting increased pulmonary vascular remodeling. Moreover, a large UK biobank population study [62] demonstrated that PH incidence and mortality were increased with exposure to air pollutants, demonstrating a synergistic effect with that of tobacco exposure. Heavy metal exposure, noise pollution and circulating microplastics [63] also affect the systemic endothelium, and extreme temperatures and weather events have been associated with mortality and exacerbations in COPD [64, 65, 66, 67, 68], but their effects on the pulmonary circulation are unclear.

1.7. Pulmonary Vascular Pathophysiology in COPD Patients

Molecular pathways and environmental exposures trigger the development of PVD in COPD through numerous pathophysiologic pathways. Traditionally, PVD has been considered to be the result of chronic hypoxia and emphysematous destruction of pulmonary vessels, although other mechanisms such as endothelial dysfunction, inflammation and hyperinflation have since also been shown to play a role.

1.8. The Role of Chronic Hypoxia and Emphysema in COPD‐PVD

Chronic hypoxia has long been considered the primary pathophysiologic factor in COPD‐PH, since vascular hypoxic vasoconstriction acutely increases pulmonary vascular resistance (PVR), and chronic hypoxia can lead to pulmonary vascular remodeling [69]. In hypoxaemic COPD, long‑term oxygen therapy mitigates hypoxia‑induced pulmonary vasoconstriction and stabilizes PVR, thereby slowing or partially reversing the haemodynamic progression of PH, although established pulmonary vascular remodeling is rarely reversed. [70, 71]. However, hypoxia is not sufficient to explain PVD in COPD; specifically, not all COPD patients with PH are hypoxic and even in advanced COPD, hypoxia accounts for only a fraction of the elevation in mPAP [72].

Similarly, a more complex picture of interconnected mechanisms between PVD and emphysema in COPD is now also postulated. It is increasingly appreciated that emphysema, characterized by alveolar destruction and loss of the alveolar capillary bed, can occur before clinical or spirometric manifestations of COPD [73, 74]. Robust histopathologic studies demonstrate that pulmonary vascular remodeling is present in smokers and patients with mild COPD, often before clinically overt airflow limitation or emphysema, indicating that vascular alterations occur early in the pathogenesis of COPD rather than representing a purely late consequence. [52, 75]. Smokers with normal lung function can manifest endothelial dysfunction and intimal remodeling, characterized by proliferation of endothelial and smooth muscle cells, leading to medial hypertrophy and intimal sclerosis. Furthermore, smokers with normal lung function, patients with small airways disease and those with mild to moderate COPD alike have fewer peripheral pulmonary arterial vessels and increased wall thickness [76]. This may occur, in part, due to aberrant endothelial cell transformation into a pro‐proliferative mesenchymal phenotype [76], also seen in PAH [77, 78]. These early changes may then drive the development of airway and parenchymal abnormalities. In a pre‐clinical model of emphysema, mice exposed to cigarette smoke developed endothelial apoptosis mediated by inducible nitric oxide synthase prior to development of emphysema [53]. An in‐vitro study also demonstrated that microvascular endothelial cells, which provide support for the proliferation of alveolar type 2 epithelial cells, are reduced in emphysematous areas and this support is further impaired by cigarette smoke [79]. A pre‐clinical treatment model also demonstrated that delivery of healthy lung endothelial cells to elastase‐induced murine models of emphysema elicits tissue repair and regeneration [80]. Furthermore in aging mice, endothelial cell telomerase, which maintains telomere length and prevents the accumulation of senescent cells, also attenuates loss of capillary density and pulmonary emphysema [81]. These findings highlight a potential mechanism by which vasculopathy is causally linked to the development of emphysema.

1.9. Hyperinflation and PVD

Another pathophysiologic pathway for PVD in COPD involves hyperinflation of the lung. Resting or dynamic lung hyperinflation is associated with worse cardiovascular (CV) response to exercise [82], increased exacerbations and a higher risk of mortality in COPD patients [83]. More specific to PVD, increases in intra‐thoracic and intra‐abdominal pressure due to flattening of the diaphragm from hyperinflation and gas trapping cause a reduction in venous return and right heart filling [84]. Increased pleural pressure increases PVR and impairs RV afterload, LV preload, and LV compliance [85]. The overall effect is a reduction in cardiac output (CO) and impairment of oxygen delivery, including to respiratory muscles and the myocardium [84].

Although hyperinflation has direct pathophysiologic mechanisms for COPD‐PVD, its treatment has demonstrated mixed results in improving PH. The National Emphysema Treatment Trial [86] of lung volume reduction surgery (LVRS) versus optimal medical therapy in severe emphysema demonstrated that LVRS was associated with a reduction in pulmonary artery wedge pressure, likely reflecting lung deflation, without consistent improvement in pulmonary arterial pressure or resistance. Some studies reported improvement in pulmonary haemodynamics with LVRS [87, 88] or endoscopic valve placement [89, 90], while others found no differences [86, 91, 92, 93] or even worsening [94]. It is noteworthy that some of these studies only included small cohorts of patients [95], and others relied on echocardiography for the determination of PH [88].

1.10. Endothelial Dysfunction and Pulmonary Vasculopathy in COPD

Endothelial dysfunction is characterized by increased expression of endothelin [96], vascular endothelial growth factor [97], transforming growth factor beta [98], and reduced activity of endothelial nitric oxide synthetase [99], all of which have been observed in COPD. In COPD, endothelial cells also undergo increased apoptosis and insufficient repair due to reduced circulating endothelial progenitor cells [99], ultimately producing structural damage, or pulmonary vasculopathy, thus leading to PVD.

Pulmonary vasculopathy in established COPD‐PH has been explored using histopathologic studies in explanted lungs from COPD patients. In one study, the pulmonary arterioles of COPD lungs were analysed and the authors observed a gradual increase in remodeling severity from no PH to severe PH, with increasing muscularization, medial hypertrophy and intimal concentric laminar fibrosis [100]. Interestingly, the arterioles from some patients with very severe hemodynamics demonstrated plexiform and angiomatoid lesions, indistinguishable from iPAH. Another study [4] of 30 explanted COPD lungs found that COPD patients with moderate PH had a significantly thinner intimal area compared to those without PH. In contrast, in severe PH, capillary density was also significantly lower and muscularisation of arterioles significantly higher, while no patients demonstrated plexiform lesions. An analysis [16] comparing 39 explanted COPD lungs to iPAH and healthy lung donor specimens also found that intimal and medial thickening increased with increasing mPAP. Interestingly, emphysema was worse in patients without PH or with moderate PH, compared to those with severe PH, and airway thickening was worse in patients without PH, despite all patients having advanced COPD. Finally, Andersen and colleagues [101] compared pulmonary venous remodeling in COPD with and without pre‐capillary PH to iPAH specimens in 101 lung explants. A certain degree of venous remodeling was present even in the group without PH, but was progressively worse across the haemodynamic spectrum, and was worst in iPAH patients. Venous remodeling was correlated with arterial remodeling and mPAP, and inversely correlated with DLCO, while plexiform lesions were found in only 2% of COPD explants. It is important to bear in mind that the aforementioned studies were in patients who had undergone lung transplantation and therefore might not reflect changes in earlier disease or in patients who are not transplant candidates. Therefore, it appears that in COPD the severity of PA remodeling seems to correlate with PH severity and predominantly affects the intima and media. Furthermore, histological remodeling patterns in COPD differ substantially from those observed in patients with iPAH.

1.11. Additional Pathophysiologic Pathways

Systemic inflammation is a feature of COPD and has been postulated as a specific phenotype of COPD [102]. Not every COPD patient has systemic inflammation, but inflammatory markers have been shown to be associated with hospital admission and death [103]. Systemic inflammation in COPD may increase the risk of PH; variably, c‐reactive protein, tumor necrosis factor alpha [104] and IL‐6 [20] have been associated with PH. In the lung, muscular arteries in mild COPD do manifest increased inflammatory infiltrates and endothelial dysfunction compared to smoking and non‐smoking controls [105].

Systemic inflammation may also provide a link between COPD and CV disease, and thus post‐capillary PH, although this is incompletely understood. The shared risk factors of age, physical inactivity and tobacco exposure are important determinants and recently, mendelian randomization, a genetic epidemiological method, helped establish a causal link between genetically determined COPD and systemic arterial hypertension, acute cerebrovascular disease and heart failure, with body mass index, smoking and FEV1 also playing a role [106]. Systemic inflammation in COPD is also associated with coronary artery calcification and increased mortality [107], while patients with COPD and CV disease have higher levels of fibrinogen, IL‐6 and IL‐8 [108]. Exacerbations of COPD, which further worsen inflammation, portend an increased risk of CV events, with associated increases in IL‐6 and fibrinogen [109]. Whether these factors may contribute to the development of post‐capillary or combined pre‐ and post‐capillary PH in COPD patients remains unknown.

Finally, eosinophilia in COPD, especially a blood eosinophil count 300cell/L, has been identified as a treatable trait in COPD patients, which is also associated with a specific sputum microbiome [110] and a type 2 inflammation profile [111]. In a recent single‐center study [112], eosinophilia was more frequent in COPD patients with PH than in those without PH, its presence conferring a threefold increased risk of pre‐capillary PH.

2. COPD‐PH Phenotypes

Phenotypes in COPD have been defined as “a single or combination of disease attributes that describe differences between individuals with COPD as they relate to clinically meaningful outcomes (symptoms, exacerbations, response to therapy, rate of disease progression, or death)” [113]. Therefore to determine distinct phenotypes, consideration should be given to multiple domains and how they intersect. These domains include pulmonary functions tests, functional tests, hemodynamic profile, and lung (including vascular) morphology. The existence of a distinct phenotype finds support in evidence of clustering of cases and not an arbitrary carving out of a cohort within the spectrum of the disease. There should also be a difference in their clinical course and outcomes and possibly a differential response to therapy. Not all these elements need to necessarily be fulfilled to discern a distinct phenotype. The most commonly used outcome to phenotype COPD‐PH is survival, while other additional outcomes include propensity for acute exacerbations and theratyping by response to PH‐specific therapies. While exercise capacity and health‐related quality of life (HR‐QoL) might be useful, they are likely influenced more by disease severity rather than being elements to define phenotypes.

There is growing interest in the general phenotyping of COPD patients. As these are considered it is important to “layer on” how these might intercept with PVD. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) has introduced the GETomics framework, or gene(G)‐environment(E) over a lifetime(T) [5] to classify COPD into aetiotypes, such as genetic, abnormal lung development, cigarette smoking, and pollution/biomass. The cigarette smoking aetiotype has sub‐phenotypes amenable to specific management [114] and treatable traits [115] have been identified. Additionally, new “early‐COPD” entities, such as pre‐COPD (respiratory symptoms and/or structural abnormalities without spirometric impairment) [116] and preserved ratio impaired spirometry (PRISm) [117] have been proposed. Analogous phenotyping within COPD‐PVD is currently lacking, with a notable paucity of evidence demonstrating unique populations by aetiotypes. Domains to consider in defining COPD phenotypes are shown in Figure 1. Phenotypes identified by the author group are presented in Table 2 and shown in Figure 3.

Figure 1.

Domains to consider in defining COPD phenotypes. A phenotype is characterized by a distinct combination of features within these domains: distinct etiology, distinct morphologic‐physiologic features, disease impact and therapeutic approach (theratype). Endotypes with management implications are shown. A1AT, alpha‐1‐antitrypsin; LVR, lung volume reduction; UL, upper lobe.

Table 2.

Phenotypes in COPD‐PVD and COPD‐PH.

Phenotype	Characteristics/comments
COPD with evidence of PVD at rest or PH during exercise	Any GOLD stage
	No PH at rest
	Abnormal increase of PAP during exercise
	Increase hospitalizations for exacerbation of COPD
GOLD 2‐4 with mild‐moderate PH	Probably the most common phenotype
	Non‐severe PH, with relatively slow progression
	Moderately reduced exercise tolerance
	Increased exacerbations of COPD
	Ventilatory impairment to exercise
	DLCO not dramatically decreased
	Mild to moderate emphysema
	May progress to severe PH, which then is associated with very poor prognosis and severe alteration of gas exchange (PaO2) and severely reduced exercise tolerance
Severe Emphysema and mild‐moderate PH	Severe Emphysema on imaging
	Mild to moderate or even severe PH
	Increased exacerbations of COPD
	Ventilatory impairment to exercise
	Very low DLCO
	Elevated pCO2
	Poor survival
Pulmonary vascular phenotype	Rare phenotype (1%–5%)
	GOLD stages 1 or 2, but severe reduction of DLCO and PaO2
	Severe PH (PVR > 5 WU)
	Severely reduced exercise tolerance
	Cardiovascular impairment to exercise
	Vascular pruning on imaging
	No severe emphysema on imaging
	Increased mortality and hospitalization
COPD with isolated post‐capillary PH phenotype	Any GOLD stage
	Mild‐Moderate PH
	Increased cardiovascular comorbidity burden
	Moderately reduced exercise tolerance

Figure 3.

Distinct phenotypes in COPD‐PVD/PH. Not all COPD patients may fit into one of these designated phenotypes. Longitudinal phenotype switching may occur. Created with GPT.

2.1. Pulmonary Function and Gas Exchange Profiles

Lung function and gas exchange impairment have also been considered in phenotyping COPD‐PVD. FEV1 and DLCO are both strong, independent predictors of mortality in COPD patients [118, 119, 120, 121], but in COPD‐PH, only DLCO is associated with haemodynamic severity [122, 123]. and mortality [122, 123, 124]. In some previous studies, FEV1 has been described to be significantly higher in severe compared to non‐severe PH [125, 126, 127], while in other studies there was no difference [16, 128].

COPD with severe PH and hypoxemia but only mild to moderate airflow obstruction has been described in 1%–7% of patients. Patients with COPD GOLD stages 1–2 and non‐severe PH have significantly better outcomes compared to GOLD stages 3–4 with severe PH, while a group comprising the PVP as well as severe COPD with non‐severe PH manifest an intermediate survival between these two [129].

2.2. Hemodynamic Severity

PH associated with COPD is usually not severe [55] and with relatively slow progression (0.4–0.7 mmHg/year) [130, 131]. The presence of PH, even with a mPAP as low as 19 mmHg, is associated with an increased risk of COPD exacerbations [131]. The relationship between the presence of PH and the severity of airflow obstruction is unclear [132], and a systematic assessment of the prevalence and severity of PH across the COPD spectrum is unfeasible due to the highly selective indications and scarce availability of RHC for COPD patients. Hemodynamic evaluation is usually restricted to lung transplant and LVRS candidates, or upon suspicion of severe PH, introducing an obvious selection bias. Worse survival is uniformly observed when COPD‐PH is compared to COPD without PH [133, 134, 135], and patients with severe hemodynamic impairment, defined by higher mPAP or PVR and/or lower cardiac index (CI), have worse survival than those with milder haemodynamic impairment [122, 124, 125, 128, 130, 131, 136, 137]. Indeed, some data suggests an increase in mortality risk for each 1 mmHg increment in mPAP in COPD patients as with PH of any group [122, 125].

Reliance on a single hemodynamic parameter (such as mPAP or PVR) [138] or outcome (such as mortality) may also not be sufficient to discriminate phenotypes. Recent data suggests that both the 6th World Symposium on Pulmonary Hypertension (WSPH) definition of severe PH (mPAP ≥ 35 mmHg or mPAP 25–34 mmHg with CI < 2 L/min/m2) and PVR > 5 Wood Units (WU) could be good predictors of mortality [122, 125, 137]. In an international cohort of 147 COPD patients 125 of whom had Group 3 PH, those with severe PH either by the 6th WSPH definition or stratified as PVR > 5 WU had markedly worse survival compared to patients without PH or with non‐severe PH [125]. Another single center study of 139 COPD patients with PH found both an mPAP ≥ 33 mmHg and PVR > 5 WU to be associated with worse outcomes [137]. Other reports stratifying by a cutoff of mPAP > 30 mmHg (or ≥ 40 mmHg) similarly found worse survival in severe COPD‐PH patients [93, 124]. On the other end of the spectrum, no difference in survival was found between COPD patients with no PH compared to those with an mPAP > 20 mmHg and a PVR < 3 WU [122, 139] or those with mPAP ≤ 20 mmHg and PVR > 3 WU [139]; the latter representing a group (or perhaps a phenotype) with PVD without overt PH. These studies highlight that PVD is a hemodynamic continuum [11], where distinct categories are somewhat arbitrary, at least as relevant to mortality.

Mild COPD with severe PH represents a diagnostic challenge, as it may be difficult to distinguish “true” Group 3 PH from iPAH with coexisting COPD. In the Pulmonary Vascular Disease Phenomics Program (PVDOMICS) cohort, a significant proportion of patients exhibited overlapping WSPH phenotypes; specifically, approximately 17% of patients classified as Group 1 PAH were adjudicated as having concomitant lung disease consistent with Group 3 PH [140]. In patients with iPAH from the COMPERA registry, a majority (52%) of mostly older males with a history of smoking and DLCO < 45%, termed the “lung phenotype”, demonstrated a poorer response to treatment and worse survival than the classical iPAH phenotype. However, the analysis of COMPERA database is limited by the lack of chest CT imaging, so the extent of emphysema was not assessed [141]. A comparison between the iPAH with ‘lung phenotype” and Group 3 PH patients from two European registries (COMPERA and ASPIRE) demonstrated that the former group clinically behaved similar to Group 3 PH in response to treatment and survival [142]. A study [143] reporting the lung histology of 50 patients with a clinical diagnosis of iPAH provides further insight into the nexus between COPD and PVD. Specifically, 52% exhibited a classic “plexiform” vasculopathy, while 48% demonstrated a “non‐plexiform” vasculopathy. The latter group had similar PH severity and were an older, male population with lower DLCO who on histology demonstrated alveolar basement membrane thickening, microvascular rarefaction with remodeling, and microscopic emphysema. Among ex‑smokers with normal spirometry and chest CT emphysema metrics, a lower DLCO was associated with worse symptoms, reduced exercise capacity, and abnormal hyperpolarised [3]. The MRI findings of early emphysema [144]. These data suggest that patients with iPAH with lung phenotype are likely to represent a separate group that should likely be classified under the Group 3 umbrella.

These findings the concept that PVD and COPD exist on a spectrum, where at one extreme there is PVD without any significant alveolar, airway (or interstitial) disease, and at the other end there is overt lung disease with no evidence of vascular involvement. There is likely a continuum of patient phenotypes from iPAH and microemphysema representing a very early stage of lung disease, to “IPAH with lung phenotype” characterized by varying degrees of mild emphysema on CT scans without airflow obstruction, to PVP which is characterized by very mild airflow obstruction. However, we know that the degree of emphysema or airflow obstruction is not always correlated to hemodynamics, as the severe PH‐severe COPD profile suggests. Figure 2A shows the theoretical framework of these phenotypes. Figure 2B shows a phenotype template for the pulmonary vascular phenotype in COPD.

Figure 2.

(A) Phenotype template in COPD. Phenotypic framework may change with evolving data on lung morphology and physiology. (B) Phenotype template for the pulmonary vascular phenotype in COPD. DLCO, diffusing capacity of the lungs for carbon monoxide; FEV1, Forced expiratory volume in 1 s; mPAP; mean pulmonary arterial pressure; PA, pulmonarty artery; PVR, pulmonary vascular resistance; RV, residual volume; TLC, total lung capacity.

2.3. Exercise Tolerance and Exercise PH

In COPD‐PH, mPAP and PVR at rest are inversely correlated with 6MWD even when adjusted for age, sex, height, weight, FEV1 and pulmonary artery wedge pressure [132]. These patients also have reduced exercise capacity on CPET compared to those without PH [145], with reports of both ventilatory and circulatory limitations across a wide range of airflow obstruction [146]. Although no large clinical trials have examined exercise limitation profiles across COPD‐PH phenotypes, one study did report a circulatory limitation in COPD patients with severe PH and a ventilatory limitation in non‐severe PH [147]. Interestingly, COPD patients without PH have reduced exercise tolerance on CPET that is associated with pruning of small pulmonary vessels [148]. Furthermore, COPD patients in whom PVD is suspected through echocardiography [149] or a PA/Ao > 1 indicating pulmonary arterial enlargement on CT scan [150], and even smokers with RV enlargement [151] have significantly reduced 6MWD. In a prospective study [131] of 133 COPD patients with no PH at rest, 57% had exercise PH (defined as mPAP > 30 mmHg during steady state exercise at 40 W). This group had higher rest and exercise PAP, worse hypoxemia and hypercapnia, and at follow‐up 25% of them developed PH at rest (mPAP increase of 0.4 mmHg/year). In this study, 31% of patients demonstrated an accelerated increase of mPAP (≥ 0.5 mmHg/year) but no accelerated worsening of airflow obstruction or gas exchange. In another prospective study [132] 58% of COPD patients without PH at rest met the current definition of exercise PH. These patients were older and had lower 6MWD and PaO2 both at rest and on exercise, compared to those without exercise PH. Furthermore, the increase in pulmonary pressures was not due to an occult post‐capillary component, thus demonstrating true PVD in these subjects. In addition, COPD without significant resting PH have been shown to have an increase in mPAP/CO slope during exercise, characteristic of exercise PH, which in turn is associated with a decreased peak Vo2 and 6MWD [152]. These collective data highlight the role of early PVD in COPD that contribute to impaired exercise capacity.

2.4. Lung Morphology and the Role of Imaging

Imaging is commonly used to discern COPD phenotypes such as airway versus emphysema‐centric disease. In particular, emphysema patterns are known to associate with differential mortality risk [153]. Data from the central hilar structures, including the PA/Ao and right ventricular size, is informative regarding COPD exacerbation and mortality risk. For example, an increased PA/Ao ratio on chest imaging is associated with increased COPD exacerbation risk [150, 154], and worse outcomes [155]. More recent data suggests that this risk is not mediated by loss of the distal pulmonary arterial vasculature or pruning [154]. However, PA/Ao does demonstrate sensitivity for predicting PH [156, 157]. Quantification of the distal pulmonary arterial vasculature does provide critically relevant information. For example, in COPD, vascular pruning, defined by a lower ratio of small artery volume (< 5 mm2; BV5) to total lung artery volume (BV5a/TBVa) predicts accelerated progression of emphysema and increased emphysema related mortality [158]. In fact, decreases in arterial BV5 predict increases in CT‐measured right ventricular volume suggesting that arterial changes mediate cor pulmonale (right heart failure) and death in COPD‐PH [151].

Recent work in COPDGene highlights the strength of CT vascular features to differentially associate with adverse outcomes. For example, vascular pruning, or loss of the distal arterial vasculature, was significantly associated with all‐cause mortality in smokers with and without COPD. Additionally, pre‐acinar dilation or an increase in pulmonary artery volume, 5–20 mm2 in cross‐sectional area, normalized to total arterial volume, was specifically associated with mortality risk in smokers with COPD. Conversely, PA/Ao did not predict mortality risk but did uniquely predict risk of acute respiratory exacerbations [154]. More recent research expands beyond COPD to advance our understanding of PH associated with COPD.

A recent quantitative CT study evaluating pulmonary vascular volume as the summation of arterial and venous compartments demonstrated that patients with hemodynamically severe COPD‑PH (defined by mPAP ≥ 35 mmHg) had significantly lower total pulmonary vascular volume compared with those with mild‑to‑moderate disease. Notably, pulmonary vascular resistance did not significantly correlate with small vessel volume when arterial and venous vasculature were analysed together [159]. Chest CT based emphysema quantification and arterial vascular volume measurements may be useful to advance COPD‐PH phenotyping [160]. For example, in a study of nearly 300 subjects with spirometrically confirmed COPD and presumed PH based on a PA/Ao > 1, application of cluster analysis to four variables pertinent to disease phenotyping including FEV1% and DLCO%, total percent emphysema and vascular pruning identified 3 distinct COPD‐PH subgroups [161]. Cluster 2 (C2) and 3 (C3) in particular, were defined by similar degrees of pruning but significantly different quantitation of emphysema; 4% in C2 [10] and 45 in C3 [15]. Subjects in C3 experienced a significantly higher mortality risk than those in C2. These results raised the possibility of an imaging correlate for the clinically described “pulmonary vascular phenotype” whereby pruning in Cluster 2, represents a reflection of the primary pulmonary vascular disease that can occur in COPD in the absence of emphysematous destruction. Conversely, Cluster 3 may represent patients with emphysema‐mediated vascular destruction or compression due to air trapping. Future research should work to deconstruct the heterogeneity of the umbrella term of “COPD‐PH” and use similar imaging features to sub‐phenotype disease within populations with hemodynamically confirmed PH.

Given the available evidence, we propose probable phenotypes of COPD with PVD, illustrated in Table 2.

3. Other Considerations

3.1. Disease Behavior: Acute Exacerbations

There is evidence that patients with COPD‐PH have a higher incidence of acute exacerbations. An increased PA/Ao ratio on chest imaging has been associated acute exacerbations [150].

3.2. Eosinophil Phenotype

There is at least one paper that has described a greater propensity for PH among patients with an eosinophilic phenotype [112]. Whether eosinophils will help to further discern distinct COPD‐PH phenotypes is another area for future research. This association does underscore that investigators and stakeholders within the COPD community should work hand in hand in defining phenotypes and a path forward. Specifically, those with an interest in the pulmonary vasculature should be cognizant and work hand in hand with COPD investigators who have more of an interest in the COPD “inflammasome” and visa versa.

3.3. Infectious Causes

Pulmonary tuberculosis (TB) and human immunodeficiency virus (HIV) are major infectious contributors to COPD worldwide. Post‐tuberculosis lung disease affects up to 50% of patients after pulmonary tuberculosis and results from chronic inflammation, fibrosis, airway distortion, and parenchymal destruction causing persistent airflow obstruction and emphysema [162]. A recent systematic review and meta‐analysis reported an overall pooled PH prevalence of 48% among post‐TB populations, with prevalence ranging from 6% in community‐based outpatients to 67% in patients with chronic respiratory failure [163]. HIV is associated with accelerated emphysema development, often at younger ages, through chronic immune activation, oxidative stress, recurrent pulmonary infections, and enhanced susceptibility to smoking‐related lung injury [164, 165]. Other infectious diseases leading to COPD/emphysema, such as non‐tuberculosis mycobacteria or severe childhood infections also contribute to COPD and associated PVD burden.

4. Contributory Comorbidities

4.1. Cardiac Comorbidities

Patients with COPD often have CV conditions, such as ischemic heart disease, heart failure and atrial fibrillation [166, 167]. Importantly, patients with both COPD and CV comorbidities have more dyspnea, worse exercise tolerance, impaired HR‐QoL, more frequent hospitalizations and higher mortality [108, 168]. Indeed, CV diseases are a major cause of death in COPD, particularly in patients with mild‐to‐moderate airflow obstruction [169, 170]. Several socio‐economic factors may favour the development of concomitant CV and respiratory diseases that warrant further investigation in COPD‐PH [171]. Isolated post‐capillary (Ipc) and combined pre‐post capillary (Cpc) PH have been reported in 34% and 22% of general COPD populations respectively [122], and in 18% and 5% of COPD transplant candidates [139]. Furthermore, in patients with Ipc COPD‐PH, severe PH patients have more CV comorbidities compared to those with moderate or no PH [125, 126]. Since heart failure with preserved ejection fraction is a frequent comorbidity in COPD, untangling the mechanism of the vasculopathy might require provocative hemodynamic maneuvers [172, 173]. The characterization of Ipc and Cpc PH is still vague in COPD patients, especially given the difficulties of obtaining an accurate pulmonary artery wedge pressure. More studies are encouraged to better understand the intersection between Group 2 and Group 3 PH in COPD.

4.2. Sleep‐Disordered Breathing

Concomitant COPD and sleep‐disordered breathing is common [174]. In studies analysing COPD patients, obstructive sleep apnea (OSA) was detected in 3%–66%, depending on OSA severity and other baseline factors, such as body mass index [175, 176, 177]. On the other hand, COPD is often encountered in OSA cohorts, with prevalence rates ranging between 7% and 55% [175]. Patients with both COPD and OSA tend to be older, have an increased BMI, as well as other cardiovascular comorbidities. They tend to be heavier smokers, and also manifest an increased pCO2, and worse nocturnal hypoxemia [175, 177]. Patients with these co‐existing conditions also have worse outcome [178, 179] as compared to patients with either condition alone. COPD patients with PH require thorough screening for potential concomitant underlying causes of PH [9], such as OSA and if present, appropriate treatment. This might include weight loss (if applicable), continuous positive airway pressure, non‐invasive ventilation in selected hypercapnic patients, long‐term oxygen therapy and pulmonary rehabilitation.

4.3. Thromboembolic Disease

Chronic thromboembolic pulmonary hypertension (CTEPH) is categorized under Group 4 pulmonary hypertension and is characterized by persistent, organized thromboembolic obstruction of the pulmonary arteries [180]. The prevalence of COPD in CTEPH cohorts ranges from 9% to 37% depending on the severity of airflow limitation [181, 182]. The presence of COPD as a comorbidity in CTEPH is clinically relevant, as it has been associated with a higher risk of residual pulmonary hypertension after pulmonary endarterectomy, as well as prolonged hospitalization, and increased mortality [181]. Conversely, pulmonary embolism is relatively common in COPD, with reported prevalences of 12%–20% [183, 184], and COPD itself confers an approximately 2–3‐fold increased risk of venous thromboembolism [185, 186]. Although the prevalence of CTEPH among patients with COPD remains uncertain and is likely low, it requires special attention in all COPD patients under evaluation for PH, as confirmed CTEPH requires distinct diagnostic evaluation and management.

4.4. Recommendations for Future Research in Pathogenesis and Phenotypes of COPD and PVD

As has been described thus far, there remain many significant gaps in knowledge on the intersection of COPD, PVD and PH which should be addressed in future observational and interventional studies.

Epidemiology

• Developing validated screening tools for PVD is strongly encouraged given the ubiquity of COPD to better capture the true worldwide prevalence of PVD and to explore potential early intervention in mitigating poor outcomes. Molecular and imaging biomarkers are of particular interest.

• The effects of biomass, pollution, extreme temperatures and weather event, and other environmental exposures on COPD‐PVD should be prioritized for investigation. The existing evidence on the impacts of climate change and pollution on chronic heart failure and COPD would suggest that the effects on the pulmonary vasculature are underrecognized and could be substantial.

Pathogenesis

• Whole genome sequencing, and the integration of genetics, epigenetics, transcriptomics, proteomics and metabolomics to elucidate the mechanisms of PVD and PH in COPD are needed.

• The early development of emphysema, airway disease and PVD, with a focus on causative links are of interest. Airway and vascular dysanapsis require further investigation, as does the association between perinatal exposures and early life disease with COPD‐PVD.

Phenotypes

• Non‐invasive tests to predict COPD‐PVD phenotypes/theratypes in clinical settings are needed. Specifically, novel imaging techniques defining lung morphologies, molecular testing, and linking to existing lung function testing, gas exchange abnormalities, and serologic biomarkers are of interest.

• The development and validation of patient reported outcomes (PRO) specific to COPD‐PH, and to investigate the specificities of HR‐QoL in the distinct COPD‐PVD phenotypes are strongly encouraged, particularly as potential clinical trial outcomes.

• The longitudinal development trajectories of PVD in COPD should be further investigated, as few studies have addressed this to date. Further, the prevalence, clinical features and trajectories of exercise PH in COPD require further study.

• The intersection of COPD aetiotypes and COPD‐PH phenotypes should be explored, as the majority of studies have focused on the cigarette smoking aetiotype. Furthermore, the prevalence, characteristics and outcomes of patients with emphysema without lung function impairment or PRISm who develop PH should be elucidated.

• Studies focusing on Ipc and Pcp COPD‐PH, addressing their relationship with CV comorbidities outcomes and investigating treatment options are encouraged.

• The role of PVD within established COPD phenotypes should be further explored; for example, the frequent exacerbators and those with an eosinophilic phenotype.

5. Conclusion

PVD is an integral component of COPD that often develops early and spans a wider spectrum than just hemodynamically defined PH. Evidence across experimental, imaging, and clinical studies demonstrates that pulmonary vasculopathy can precede overt PH and contribute independently to exercise limitation, disease progression, exacerbations, and mortality.

COPD‑associated PVD exhibits substantial heterogeneity, reflecting complex interactions between vascular remodeling, airway disease, emphysema, developmental factors, environmental exposures, and comorbidities. Conventional spirometry and resting hemodynamics incompletely capture this complexity, whereas advanced imaging and gas‑exchange measurements improve detection and phenotyping of pulmonary vascular involvement.

Recognizing COPD‑PVD as a continuum rather than a late complication has important implications for diagnosis, phenotyping, and clinical trial design. Earlier identification of vascular involvement and refined phenotypic classification are essential steps toward precision medicine approaches and improved outcomes in COPD.

Author Contributions

Drs. Piccari, Zeder, Balasubramanian, Nathan, Wort, Abman, Johnson, Shlobin, Washko, Allwood, Girgis, Balasubramanian were involved in the conception and design of the review, conducting literature searches as well as writing the first draft of the manuscript. All co‐authors analysed 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.

Funding

The authors have nothing to report.

Ethics Statement

The authors have nothing to report.

Conflicts of Interest

Lucilla Piccari*, reports no conflicts. Katarina Zeder*, received grants from CMREF and United Therapeutics and honoraria from AstraZeneca. Aparna Balasubramanian, reports no conflicts. Brian W. Allwood, reports no conflicts. Stephen John Wort, Dr Wort has received honoraria from MSD, Ferrer Bayer and Janssen. He has received research grants from Ferrer. Shelsey W. Johnson, reports no conflicts. Reda E. Girgis, reports no conflicts. Oksana Shlobin, reports no conflicts. Steven H. Abman, serves as consultant to Chiesi Pharmaceuticals and serves as chairperson of a data safety monitoring board for Bayer Pharmaceutical. Gabor Kovacs, reports no conflicts. George Washko, reports no conflicts. Sylvia M. Nikkho is an employee of Bayer AG. Steven D. Nathan, reports no conflicts.

Piccari L., Zeder K., Balasubramanian A., et al., “Pathogenesis and Phenotypes of Pulmonary Vascular Disease in COPD: A Consensus Statement From the Pulmonary Vascular Research Institute's Innovative Drug Development Initiative – PH Group 3 Workstream,” Pulmonary Circulation 16 (2026): e70409. 10.1002/pul2.70409.

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.