Figure - available from: Pulmonary Circulation
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Pulmonary vascular disease histology in interstitial lung disease. On the left panel, a histologic section of explanted lung tissue from a patient with idiopathic pulmonary fibrosis (IPF) who underwent lung transplant, showing marked concentric arterial medial hypertrophy (arrows) (Haematoxylin & Eosin, x100). On the right panel, explanted lung tissue of a patient with IPF without pulmonary hypertension (mean pulmonary artery pressure of 20 mmHg and pulmonary vascular resistance 1.5 wood units, pulmonary arterial wedge pressure 10 mmHg; data obtained 4 months before transplant) but showing signs of venous occlusion. With permission and many thanks to Dr. H. Mani (Inova Fairfax Hospital).
Source publication
Pulmonary hypertension (PH) is a frequent complication of interstitial lung disease (ILD). Although PH has mostly been described in idiopathic pulmonary fibrosis, it can manifest in association with many other forms of ILD. Associated pathogenetic mechanisms are complex and incompletely understood but there is evidence of disruption of molecular an...
Citations
... The processes of parenchymal and vascular destruction through fibrosis and chronic hypoxic pulmonary vasoconstriction are now known to be accompanied by concurrent endothelial changes and chronic remodeling analogous to that seen in PAH. 5 Genetic and molecular factors appear to have considerable influence over these vascular changes, which may occur semi-independently from the underlying lung disease process, which may allow for further research to phenotype which patients with lung disease are likely to benefit from pulmonary vasodilator therapy. As we will discuss further, unlike PAH, only one therapy has been rigorously shown to be effective in treating PH-ILD. ...
... First, this study focused on the antiproliferative properties of GPS2 in CS-PVR. In addition to pulmonary vascular cell dysfunction, lung inflammation and hypoxia associated with interstitial lung lesions can also trigger PH [66,67]. In our study, we observed that CS-exposed rats with overexpressed GPS2 exhibited attenuated interstitial lung lesions, suggesting that GPS2 might play a role in pulmonary hypertension by modulating interstitial lung lesions. ...
Background
Mitogen-activated protein kinase (MAPK)signaling-mediated smoking-associated pulmonary vascular remodeling (PVR) plays an important role in the pathogenesis of group 3 pulmonary hypertension (PH). And G protein pathway suppressor 2 (GPS2) could suppress G-protein signaling such as Ras and MAPK, but its role in cigarette smoking -induced PVR (CS-PVR) is unclear.
Methods
An in vivo model of smoke-exposed rats was constructed to assess the role of GPS2 in smoking-induced PH and PVR. In vitro, the effects of GPS2 overexpression and silencing on the function of human pulmonary arterial smooth cells (HPASMCs) and the underlying mechanisms were explored.
Results
GPS2 expression was downregulated in rat pulmonary arteries (PAs) and HPASMCs after CS exposure. More importantly, CS-exposed rats with GPS2 overexpression had lower right ventricular systolic pressure (RVSP), right ventricular hypertrophy index (RVHI), and wall thickness (WT%) than those without. And enhanced proliferation and migration of HPASMCs induced by cigarette smoking extract (CSE) can be evidently inhibited by overexpressed GPS2. Besides, GPS2siRNA significantly enhanced the proliferation, and migration of HPASMCs as well as activated Ras and Raf/ERK signaling, while these effects were inhibited by zoledronic acid (ZOL). In addition, GPS2 promoter methylation level in rat PAs and HPASMCs was increased after CS exposure, and 5-aza-2-deoxycytidine (5-aza) inhibited CSE-induced GPS2 hypermethylation and downregulation in vitro.
Conclusions
GPS2 overexpression could improve the CS-PVR, suggesting that GPS2 might serve as a novel therapeutic target for PH-COPD in the future.
Graphical Abstract
... PH-ILD risks factors are numerous including genetics, epigenetics and environmental factors. [17] Moreover, underlying ILD disease can be associated with an increased risk of PH-ILD as it is recognized in CPFE and lymphangioleiomyomatosis. Screening tools have been developed to identify PH-ILD but require further validation [18,19]. ...
Shareable abstract (@ERSpublications) Key highlights in pulmonary vascular diseases from #ERSCongress 2023 include insights into disease modification in PAH and novel therapies, PH associated with lung disease, lung embolism and CTEPH https://bit.ly/476G6cT Abstract Pulmonary vascular diseases such as pulmonary embolism and pulmonary hypertension are important and frequently under-recognised conditions. This article provides an overview of key highlights in pulmonary vascular diseases from the European Respiratory Society International Congress 2023. This includes insights into disease modification in pulmonary arterial hypertension and novel therapies such as sotatercept and seralutinib. Exciting developments in our understanding of the mechanisms underpinning pulmonary hypertension associated with interstitial lung disease are also explored. A comprehensive overview of the complex relationship between acute pulmonary embolism and chronic thromboembolic pulmonary hypertension (CTEPH) is provided along with our current understanding of the molecular determinants of CTEPH. The importance of multidisciplinary and holistic care cannot be understated, and this article also addresses advances beyond medication, with a special focus on exercise training and rehabilitation.
... Unfortunately, in some patients, PH-ILD can present at an advanced stage with concomitant RV dysfunction, similar to WHO Group 1 pulmonary arterial hypertension (PAH). In such patients, parental prostacyclin therapy may be considered [11][12]. However, while parenteral prostacyclins have wellestablished bene ts in WHO Group 1 PAH, similar outcomes have not been demonstrated in PH-ILD; in addition, these therapies have the potential to worsen hypoxemia by causing ventilation/perfusion (V/Q) mismatch in the setting of parenchymal lung disease [13][14][15]. ...
... In these patients, early recognition of concomitant PH remains a challenge and the diagnosis may not be established until the disease has progressed to RV dysfunction [5,[21][22]. Despite the ndings from the INCREASE trial, PH-ILD management is much more complex than a single medication treatment algorithm, especially in the patient who has already progressed to signi cant RV dysfunction [11][12]16]. Understanding the nuance of the disease and its overall severity and progression, including an evaluation of concomitant RV dysfunction, is paramount to the PH-ILD management approach including evaluation for lung transplant. ...
Pulmonary hypertension (PH) is a frequent complication in patients with interstitial lung disease (ILD); its occurrence results in significant morbidity and mortality. Currently approved treatment options for PH-ILD include inhaled prostacyclin therapy, although this approach may be insufficient in patients who have developed concomitant right ventricular failure. Moreover, there is no available treatment algorithm regarding the optimal therapy and timing of lung transplant referral for PH-ILD patients based on disease severity. In this study, we created such a tool to guide PH-specific therapy in PH-ILD patients, especially as further treatment strategies are developed. We developed a 4-point PH‐ILD Severity score that integrated both subjective and objective information from retrospective analysis of 57 PH-ILD patients. A score of 3 or greater in the PH-ILD Severity score yielded an AUC of 0.831 (p < 0.001) for the composite endpoint of clinical worsening (hospitalization due to a cardiopulmonary indication; decrease in 6-minute walk distance by > 15% at 2 consecutive visits; all-cause mortality; lung transplantation). Further confirmation and evolution of this PH-ILD Severity score will assist in development of optimal treatment plans in ILD patients diagnosed with concomitant PH.
... Recently, the Pulmonary Vascular Research Institute's Innovative Drug Development Initiative has outlined the importance of distinguishing distinct PH-ILD phenotypes characterizing differences in disease presentation, clinical course, and, possibly, treatment response [28]. Authors suggest that combined pulmonary fibrosis and emphysema (CPFE), PH associated with connective tissue and autoimmune diseases, PH associated with LAM, and post-tuberculosis PH represent different PH-ILD phenotypes with significant differences in their presentation and clinical course. ...
This article provides a comprehensive overview of the latest literature on the diagnostics and treatment of pulmonary hypertension (PH) associated with interstitial lung disease (ILD). Heightened suspicion for PH arises when the advancement of dyspnoea in ILD patients diverges from the expected pattern of decline in pulmonary function parameters. The complexity of PH associated with ILD (PH-ILD) diagnostics is emphasized by the limitations of transthoracic echocardiography in the ILD population, necessitating the exploration of alternative diagnostic approaches. Cardiac magnetic resonance imaging (MRI) emerges as a promising tool, offering insights into hemodynamic parameters and providing valuable prognostic information. The potential of biomarkers, alongside pulmonary function and cardiopulmonary exercise tests, is explored for enhanced diagnostic and prognostic precision. While specific treatments for PH-ILD remain limited, recent studies on inhaled treprostinil provide new hope for improved patient outcomes.
Background
Pulmonary hypertension (PH) is defined by elevated mean pulmonary arterial pressure (MPAP), and elevated pulmonary vascular resistance (PVR) reflects pulmonary vascular abnormalities. The clinical significance of non-severe PH in patients with various interstitial lung diseases (ILDs) has not been fully elucidated. We aimed to investigate the clinical significance of MPAP and PVR for mortality in patients with newly diagnosed ILD.
Methods
We retrospectively analysed consecutive patients with ILD at initial evaluations that included right heart catheterisation from 2007 to 2018. These patients were classified by MPAP and PVR using the 2022 the European Society of Cardiology (ESC)/the European Respiratory Society (ERS) guidelines for PH. The clinical significance of MPAP and PVR for mortality was analysed.
Results
Among 854 patients, 167 (19.6%) had MPAP>20 mm Hg. The proportion of patients with PVR>2 Wood units (WU) among those with MPAP≤20 mm Hg, 20<MPAP<25 mm Hg, and ≥25 mm Hg were 26.2%, 60.4% and 86.4%, respectively. In Cox proportional hazards analyses with adjustment for ILD–Gender, Age and Physiology Index, PVR but not MPAP was associated with a higher mortality rate (HR 1.37, 95% CI 1.23 to 1.52, p<0.0001; HR 0.98, 95% CI 0.96 to 1.01, p=0.1671, respectively). PVR>2 WU was associated with a higher mortality rate (HR 1.61, 95% CI 1.28 to 2.02, p<0.0001) even in a group with MPAP≤20 mm Hg.
Conclusions
Mild elevation of PVR was associated with a higher mortality rate in patients with newly diagnosed ILD, even in those with MPAP≤20 mm Hg.
Interstitial lung diseases (ILD) are a spectrum of disorders often complicated by pulmonary hypertension (PH) in its course. The pathophysiologic mechanism of WHO group 3 PH is different to other forms of PH. The advent of PH is a harbinger for adverse events like mortality and morbidity, implying that the PH component of disease expedites deteriorated clinical outcomes. In fact, WHO group 3 PH due to ILD has the worse prognosis among all groups of PH. Hence, early detection of PH by a comprehensive screening method is paramount. Given considerable overlap in clinical manifestations between ILD and PH, early detection of PH is often elusive. Despite, the treatment of PH due to ILD has been frustrating until recently. Clinical trials utilizing PAH-specific pulmonary vasodilators have been ongoing for years without desired results. Eventually, the INCREASE study (2018) demonstrated beneficial effect of inhaled Treprostinil to treat PH in ILD. In view of this pioneering development, a paradigm shift in clinical approach to this disease phenotype is happening. There is a renewed vigor to develop a well validated screening tool for early detection and management. Currently inhaled Treprostinil is the only FDA approved therapy to treat this phenotype, but emergence of a therapy has opened a plethora of research toward new drug developments. Regardless of all these recent developments, the overall outlook still remains grim in this condition. This review article dwells on the current state of knowledge of pre-capillary PH due to ILD, especially its diagnosis and management, the recent progresses, and future evolutions in this field.
Background
Pulmonary hypertension (PH) worsens the morbidity and mortality in interstitial lung disease (ILD). While the INCREASE trial highlighted the use of inhaled prostacyclin in PH-ILD patients, such therapy may be inadequate when right ventricular failure (RVF) is also present. In this study, we report use of intravenous prostacyclin in three PH-ILD patients to stabilise RV function followed by transition to maintenance inhaled prostacyclin therapy.
Methods
We evaluated three consecutive PH-ILD patients with RVF. RV afterload and pulmonary vascular resistance (PVR) were treated with intravenous prostacyclin during the induction phase of therapy. Patients transitioned from intravenous prostacyclin to maintenance phase of treatment with inhaled prostacyclin once three transition criteria were met: cardiac index (CI) >2 L·min ⁻¹ ·m ⁻² , PVR <7 Wood-units (WU), and tricuspid annular planer systolic excursion (TAPSE) change >1 mm or TAPSE >1.6 cm.
Results
Pre-treatment parameters for the three patients were mean PVR of 14.3 WU, mean Fick CI of 1.8 L·min ⁻¹ ·m ⁻² , and mean TAPSE of 1.4 cm. The average intravenous prostacyclin dose at time of transition to maintenance therapy was 20.7 ng·kg ⁻¹ ·m ⁻² of treprostinil. At 3-month follow-up, the mean PVR was 6.3 WU, Fick CI 2.2 L·min ⁻¹ ·m ⁻² , and TAPSE 1.7 cm.
Conclusion
This case series of three PH-ILD patients with RVF introduces the concept of induction phase of intravenous prostacyclin initiation followed by transition to maintenance inhaled prostacyclin therapy. Further development of this treatment algorithm with refinement of the transition criteria, potential testing in a clinical trial, and longer-term follow-up is warranted to improve the outcomes of advanced PH-ILD patients with concomitant RVF.
Pulmonary hypertension (PH) due to interstitial lung disease (ILD), a commonly encountered complication of fibrotic ILDs, is associated with significant morbidity and mortality. Until recently, the studies of pulmonary vasodilator therapy in PH‐ILD have been largely disappointing, with some even demonstrating the potential for harm. This paper is part of a series of Consensus Statements from the Pulmonary Vascular Research Institute's Innovative Drug Development Initiative for Group 3 Pulmonary Hypertension, with prior publications covering pathogenesis, prevalence, clinical features, phenotyping, clinical trials, and impact of PH‐ILD. It offers a comprehensive review of and a holistic approach to treatment of PH‐ILD, including the management of underlying interstitial lung diseases, importance of treating the comorbidities, emphasis on importance of exercise and palliation of dyspnea, and review of the most up‐to‐date guidelines for referral for potential lung transplant work up. It also summarizes the prior, ongoing, and possibly future studies in treatment of the vascular derangement of this morbid condition.
Purpose of review:
Pulmonary hypertension (PH) is a common complication of both chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD), classified as Group 3 PH. To which extent PH presents and behaves similarly in COPD and ILD is unclear. This review examines the similarities and differences in pathogenesis, clinical presentation, natural history and treatment response of PH in COPD and ILD.
Recent findings:
The latest studies on PH in chronic lung disease have re-evaluated the role of traditionally held etiopathogenetic factors such as tobacco exposure and hypoxia, although new ones such as airborne pollutant and genetic mutations are increasingly recognized. We examine common and diverging factors involved in PH development in COPD and ILD, as well as common and diverging clinical features of presentation, natural history and response to treatment and highlight areas for future research.
Summary:
The development of PH in lung disease significantly worsens the morbidity and mortality of patients with COPD and ILD. However, recent findings show importance of recognizing distinct patterns and behaviors of pulmonary vascular disease, taking into account the specific underlying lung disease and severity of the hemodynamic involvement. Further studies are needed to build evidence on these aspects, especially in early disease.
