Pulmonary Hypertension Due to Lung Disease or Hypoxia

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Continuing Education Activity

Pulmonary hypertension (PH) is the elevated pressure in the pulmonary vascular system. Chronic obstructive pulmonary disease (COPD) and diffuse pulmonary lung disease (DPLD), including idiopathic pulmonary fibrosis (IPF) and combined pulmonary fibrosis and emphysema (CPFE), are the most common disease-causing chronic hypoxia and are associated with the highest incidence of pulmonary hypertension in this group. PH is classified according to the underlying pathophysiology of the disease. PH that develops due to advanced lung diseases and prolonged events of hypoxia is included in group 3. PH is a progressive condition with grave consequences if not recognized and optimized early in the disease. This activity reviews the evaluation for early recognition and optimization of PH and highlights the role of the interprofessional team in evaluating and managing patients with this condition.


  • Identify different causes of group 3 pulmonary hypertension.
  • Describe the pathophysiology of pulmonary hypertension due to hypoxia.
  • Review the diagnostic workup to identify the presence of pulmonary hypertension.
  • Identify the adverse events associated with uncontrolled pulmonary hypertension.


Pulmonary hypertension (PH) is a progressive disease that, if left untreated, can be life-threatening and lead to failure of the right ventricle. The 6th world symposium on pulmonary hypertension (WSPH), held in 2019, defined PH as mean pulmonary artery pressure (mPAP) > 20 mmHg.[1] European society of cardiology and European respiratory society updated guidelines in 2022 and further classified PH as pre-capillary PH with pulmonary vascular resistance > 2 wood units and pulmonary wedge pressures less than or equal to 15 and post-capillary PH with pulmonary wedge pressures greater than 15 mmHg.[2] Furthermore, the World Health Organization (WHO) divided PH into five groups based on differences in pathophysiology and therapeutic options.[3] PH associated with respiratory system disorders due to chronic lung disease with or without hypoxemia is included in group 3. This article discusses etiology, epidemiology, clinical and physician manifestation, evaluation, and management.

Other groups of pulmonary hypertension include pulmonary arterial hypertension (group 1), PH due to left heart disease (group 2), PH due to chronic thromboembolic pulmonary hypertension (CTEPH) (group 4), and other miscellaneous disorders causing PH (group 5) will be discussed separately.


Chronic obstructive pulmonary disease (COPD) and diffuse pulmonary lung disease (DPLD), including idiopathic pulmonary fibrosis (IPF) and combined pulmonary fibrosis and emphysema (CPFE), are the most common disease-causing chronic hypoxia and are associated with the highest incidence of pulmonary hypertension in this group.[4] Pulmonary hypertension in this group varies with the severity of the disease. Most patients with COPD have mild to moderate PH, but a small group of patients with advanced COPD develops severe PH. The development of PH in this group of lung diseases is associated with a poor functional status, impaired quality of life, need for supplemental oxygen, and worse prognosis.

Other conditions that PH may also develop are cystic fibrosis, chronic hypersensitivity pneumonitis, lung cancer, and other less common chronic lung diseases, including pulmonary Langerhans histiocytosis and lymphangioleiomyomatosis (LAM). The severity of PH is reported to be proportional to the extent of illness and parenchymal involvement.[5] A small percentage of PH is also reported in developmental lung disorders like bronchopulmonary dysplasia and congenital diaphragmatic hernia.[6]

Other causes include pulmonary hypertension associated with hypoxia at high altitudes, which develops in people living over 2500 meters above sea level.[7] PH is reported more frequently in obesity hypoventilation syndrome (OHS) and overlap syndrome than in obstructive sleep apnea.[8] Due to associated nocturnal desaturation and worsening lung function, these patients with OHS usually present with more severe PH and poor prognosis.[9]


Group 3 PH (associated with chronic lung diseases and hypoxia) has a higher incidence of PH than group 2 PH (due to left heart disease).[4] The prevalence of pulmonary hypertension in COPD is not known precisely, but it is estimated that approximately 10-30% of patients with mild to moderate COPD have PH.[10] The global initiative for chronic obstructive lung disease (GOLD) estimates that almost 90% of patients with COPD stage IV develop PH with mPAP > 20 mmHg.[11] PH is common in patients with IPF, and the prevalence of PH in IPF has been reported to be between 37-41%. The prevalence of PH in IPF may be higher as most of the reports come from patients evaluated for lung transplants with advanced IPF.[12]


The pathophysiology of PH group 3 is multifactorial and depends on the underlying disease processes. Pulmonary vasoconstriction in response to hypoxia plays a prominent role in the early phase of the disease process in both obstructive and restrictive lung disease. Prolonged hypoxemia impairs the release of endothelin-derived vasodilators like nitric oxide and prostaglandins. Also, it promotes the release of pulmonary vasoconstrictors like endothelin, increasing pulmonary vascular resistance (PVR).[13] 

In the late phase, remodeling of pulmonary microvessels with smooth muscle hyperplasia and constriction of intima leads to vascular lumen obliteration.[14] Other mechanical factors include vessel distortion due to the destruction of alveolar space in COPD and fibrosis in IPF elevates the pressure in the pulmonary vascular bed.[15]

History and Physical

Symptoms of pulmonary hypertension significantly overlap with the underlying disease. For group 3 PH, it mimics the clinical manifestations of other groups except for clinical history of chronic lung disease and hypoxia during the day or nighttime. Although unexplained dyspnea is a ubiquitous presentation, in a recent survey of experts, it was not found to be very specific. Instead, the expert panel identified syncope, dizziness, and palpitations as highly predictive of PH.[16] 

Physical exam findings are not specific and cannot accurately predict the disease's progression. Poor oxygen saturation, jugular venous distension, peripheral edema, ascites, altered heart sounds (especially loud P2 or S2), right ventricular heave, and right-sided heart failure signs such as hepatomegaly are helpful but present later in the disease process.[17][18]


Due to the lack of sensitivity and specificity of physical examination, prompt screening and testing are required to establish the diagnosis. Pulmonary function tests (PFT) help to distinguish between restrictive and obstructive impairment. An out-of-proportion decrease in diffusing capacity for carbon monoxide (DLCO) may predict the development of pulmonary hypertension and the need for further investigation. In general, a low DLCO (<40% of predicted) or rapid decline in DLCO (≥ 15%), and a DLCO disproportionate to lung volumes (i.e., FVC/DLCO ratio > 1.6), is a trigger for a low threshold for suspicion for PH.[16] It is also associated with high PVR and is a predictor of increased mortality in patients with interstitial lung disease.[19] Therefore, a screening method was proposed for PH in patients with advanced IPF, which shows that using the ratio of FVC /DLCO when combined with SpO2 in linear regression formula has high sensitivity and negative predictive value to screen patients with mPAP > 21 mmHg.[20]

Six-minute walk test (6MWT) and oxygen saturation on exertion also give insight into the underlying presence of PH. A worsening six-minute walk distance (6MWD) despite stable PFT, need for oxygen supplementation on exertion, and slow heart rate recovery in one minute can predict underlying PH.[21][22] However, there is no specific threshold identified to date for 6MWD or desaturation to predict the presence of PH.

When there is high clinical suspicion of pulmonary hypertension, the consensus from experts recommends obtaining echocardiography and Brain natriuretic peptide (BNP) or NT-proBNP. Transthoracic echocardiography (TTE) is considered the most useful non-invasive screening test for PH. Right ventricular systolic pressure (RVSP) can be estimated using the peak tricuspid regurgitation velocity, and systolic pulmonary artery pressures (sPAP) can be predicted using inferior vena cava (IVC) dilatation and collapsibility as a surrogate marker for right atrial pressures. TTE also helps to distinguish between pre-capillary and post-capillary hypertension by measuring left-sided parameters such as left atrial dilation and elevated diastolic filling pressures. Several studies, however, have shown that estimation of pressure through TTE can significantly overestimate the RVSP in chronic lung disease and lead to overdiagnosis of group 3 PH.[23][5] A study looked into adding other factors, including right ventricular outflow tract (RVOT) diameter and tricuspid annular plane systolic excursion (TAPSE) with RVSP, showed improved sensitivity and negative predictive value to predict PH in patients with advanced lung disease.[24]

Serum biomarkers such as BNP or N terminal-pro-BNP concentrations are useful screening tools for assessing patients with ILD-related-PH. Serum BNP levels are an independent prognostic marker used for risk evaluation. BNP, however, loses sensitivity when PH is cofounded by left heart disease.[25][26]

Pulmonary hypertension can be multifactorial and present as a spectrum of diseases due to the right and left heart disease. Right heart catheterization (RHC) is the gold standard for confirming the diagnosis of PH due to chronic lung disease and hypoxia. RHC can be valuable in distinguishing between pre- and post-capillary disease or the presence of combined pre-capillary and post-capillary disease. RHC is recommended for patients with exaggerated symptoms not explained by the extent of the underlying condition, patients undergoing evaluation for treatment with vasodilators, and patients being considered for a lung transplant. However, a low threshold for RHC is appropriate to confirm a PH diagnosis, particularly in those with high clinical suspicion of PH and right ventricular abnormalities on echocardiography (including dilation or enlargement and a low tricuspid annular plane systolic excursion) and in those with autoimmune ILD.

In addition to PFT and 6MWD, other useful testing modalities are chest Computed Tomography (CT) scans which can be very useful to evaluate ILD stability or progression when symptoms are disproportionate to the severity of the underlying ILD.

CT scan of the chest is commonly obtained in patients with COPD and ILD to measure the disease's extent and screen for lung cancer. There is no significant correlation between the extent of parenchymal changes seen on high-resolution CT imaging and the presence and degree of PH.[27]

The ratio of the main pulmonary artery to ascending aorta greater than 0.9 in IPF predicted PH and worse outcomes.[28][29]

Treatment / Management

The goal of the management of PH in group 3 is to optimize the underlying disease and improve the functional status. This includes guideline-directed therapy using appropriate bronchodilators in obstructive lung disease, antifibrotics in patients with fibrotic lung disease, and immunosuppressive agents in connective tissue disease-induced ILD to slow disease progression.

Patients with obesity hypoventilation syndrome (OHS) should be encouraged to use noninvasive mechanical ventilation (NIV).[30] Long-term use of NIV in OHS has been shown to improve pulmonary hemodynamics.[31]

In patients with advanced disease with hypoxemia, long-term oxygen therapy (LTOT) in patients with COPD has shown a decrease in the progression of PH when used for >15 hours and improvement in PAP when used for >18 hours.[32][33] However, there is no direct evidence to support that the use of LTOT in pulmonary fibrosis slows PH progression. Still, supplementary oxygen should be prescribed to avoid prolonged episodes of hypoxia which can potentially further worsen pulmonary hypertension.

Systemic vasodilators have been associated with concerns regarding the theoretical risk of worsening gas exchange due to hypoxic vasoconstriction and subsequent ventilation-perfusion mismatch.[34] Although this has not been observed in the multiple trials conducted to investigate the potential use of vasodilators in patients with ILD.[4] Trials with endothelin receptor antagonists, including Bosentan, Macitentan, and Ambrisentan, have shown no benefit but may be harmful.[35][36][37] A trial with Riociguat, a soluble guanylate cyclase stimulator, was stopped early due to increased adverse events and mortality.[38] Phosphodiesterase-type 5 inhibitors (PDE5i) have been studied in multiple trials in patients with chronic lung disease with no significant improvement in 6MWD or quality of life.[39][40]

The most recent use of inhaled treprostinil in the INCREASE trial showed an improved six-minute walk distance compared to patients who received a placebo. This supports the idea that inhaled vasodilators may cause less ventilation-perfusion mismatch than systemic use of vasodilators.[41]

While most vasodilator therapies are not effective and may be harmful, inhaled treprostinil is approved in group 3 PH. Based on the INCREASE trial, the US FDA approved inhaled treprostinil as the first and only treatment for group 3 PH associated with ILD. When supportive therapy and inhaled vasodilator therapy fail to control the disease progression, systemic vasodilators can be cautiously trialed on a case-by-case basis in tertiary pulmonary hypertension centers. 

Patients with advanced lung disease should be referred to centers with expertise in advanced lung disease and pulmonary hypertension for early evaluation of the lung transplant.[4] The international society for heart and lung transplant Guidelines recommends that patients with IPF should be referred to the transplant center when FVC < 80% and DLCO < 40% predicted or progressive decline in FVC and DLCO of 10% and 15% of predicted, respectively. Similarly, patients with COPD should be referred with FEV1< 25% of predicted and a BODE score >5.[42]

Differential Diagnosis

Suspected patients with group 3 PH should undergo diagnostic workup to exclude other causes of PH, including valvular heart disease and decompensated left heart disease (group 2), chronic thromboembolism, venous thromboembolism (group 4), and infection. It is essential to distinguish and understand the driving etiology of PH as it changes the management options and prognosis.

Group 3 PH in patients with lung disease can co-exist with group 1 PH, particularly in connective tissue – ILD cases. PH in these patients can be a continuum, contributed by hypoxia and other disease factors. These patients should be referred to a center with PH expertise for individualized management. Patients with group 3 lung disease, particularly ILD patients, can have simultaneous pre-capillary and post-capillary PH due to the prevalence of coronary artery disease.[43]


Pulmonary hypertension in COPD is usually mild to moderate in severity, with mPAP between 20 and 35 mmHg with the progression of pulmonary artery pressures at approximately < 0.5 mmHg/year.[44] A small subgroup of patients (5%) with advanced COPD exhibits a severe progression of PH with pulmonary artery pressures (mPAP > 35 mmHg) with poor circulatory reserves more than the ventilatory reserves expected for the respiratory impairment seen in the pulmonary function test. PH in COPD is a strong predictor of survival and is associated with poor outcomes and high mortality.[4][45]

Pulmonary hypertension associated with IPF is recognized to have a worse prognosis and poor quality of life.[21] Patients with IPF were found to have higher 1-year mortality compared to a cohort of lung transplant patients without PH. Similarly, patients with combined pulmonary fibrosis and emphysema develop severe PH and fear a worse prognosis than patients with IPF without emphysema.[46]


Elevated pressures in the pulmonary artery secondary to hypoxia from untreated and progressively worsening chronic lung disease increase right ventricular afterload. Due to the slow progression of pulmonary vascular resistance (PVR)in the setting of group 3 PH, RV adapts and hypertrophy to compensate for the high afterload. This subsequently causes RV diastolic dysfunction and paves the way to right ventricular and pulmonary artery (RV-PA) uncoupling. In one study, RV dysfunction was seen as worse in group 3 PH compared to patients in group 1 PH despite less severe PVR. Worse outcomes were also observed in the male gender. [46] In addition, lung hyperinflation and an increase in intrapleural pressures decrease the preload and venous return to RV. Under the persistently high afterload, RV eventually fails with reduced systolic function, and cor pulmonale ensues.[47]

Deterrence and Patient Education

Patients with group 3 PH should be educated on adherence to therapy for the underlying disease resulting in pulmonary hypertension. Patients with advanced restrictive and obstructive lung disease requiring oxygen supplementation should be counseled on the continued use of oxygen therapy to avoid periods of prolonged hypoxia. Good compliance with inhalers for patients with COPD and consideration for anti-fibrotic treatment in pulmonary fibrosis may prove to be vital to slow PH progression.

Close follow-up with pulmonologists and early referral to PH experts are crucial to detect the early disease progression and initiation of therapy. Patients should be screened and referred for evaluation of lung transplants.

Enhancing Healthcare Team Outcomes

Group 3 PH onset is silent due to signs and symptoms similar to the underlying lung disease and long-standing hypoxia. Progression of pulmonary hypertension can affect the patient’s quality of life and worsen mortality. Thus, it is imperative to recognize the development of PH in the early stage of the disease, which may improve long-term patient outcomes and survival.

Managing pulmonary hypertension requires an interprofessional team of clinicians, including a primary physician, pulmonologist, PH expert, specialty pharmacist, radiologist, and echocardiography expert. Patients with PH require close follow-up with regular lab work, echocardiography, 6MWD, and oxygen saturation on exertion to track the progression of the disease. Shared decision-making between the multiple specialties is required to plan and advance the treatment. Group 3 PH can overlap with group 1 (PAH) and group 2 PH (left heart disease) and requires referral to centers with expertise in treating PH with ongoing clinical trials.[48] [Class IC recommendation] Due to the progressive nature of some lung diseases causing PH, patients may need evaluation and referral to a center for a lung transplant.



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Simonneau G,Montani D,Celermajer DS,Denton CP,Gatzoulis MA,Krowka M,Williams PG,Souza R, Haemodynamic definitions and updated clinical classification of pulmonary hypertension. The European respiratory journal. 2019 Jan;     [PubMed PMID: 30545968]


Humbert M, Kovacs G, Hoeper MM, Badagliacca R, Berger RMF, Brida M, Carlsen J, Coats AJS, Escribano-Subias P, Ferrari P, Ferreira DS, Ghofrani HA, Giannakoulas G, Kiely DG, Mayer E, Meszaros G, Nagavci B, Olsson KM, Pepke-Zaba J, Quint JK, Rådegran G, Simonneau G, Sitbon O, Tonia T, Toshner M, Vachiery JL, Vonk Noordegraaf A, Delcroix M, Rosenkranz S, ESC/ERS Scientific Document Group. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. European heart journal. 2022 Oct 11:43(38):3618-3731. doi: 10.1093/eurheartj/ehac237. Epub     [PubMed PMID: 36017548]


Task Force for Diagnosis and Treatment of Pulmonary Hypertension of European Society of Cardiology (ESC).,European Respiratory Society (ERS).,International Society of Heart and Lung Transplantation (ISHLT).,Galiè N,Hoeper MM,Humbert M,Torbicki A,Vachiery JL,Barbera JA,Beghetti M,Corris P,Gaine S,Gibbs JS,Gomez-Sanchez MA,Jondeau G,Klepetko W,Opitz C,Peacock A,Rubin L,Zellweger M,Simonneau G, Guidelines for the diagnosis and treatment of pulmonary hypertension. The European respiratory journal. 2009 Dec;     [PubMed PMID: 19749199]


Seeger W,Adir Y,Barberà JA,Champion H,Coghlan JG,Cottin V,De Marco T,Galiè N,Ghio S,Gibbs S,Martinez FJ,Semigran MJ,Simonneau G,Wells AU,Vachiéry JL, Pulmonary hypertension in chronic lung diseases. Journal of the American College of Cardiology. 2013 Dec 24;     [PubMed PMID: 24355635]


Nathan SD,Barbera JA,Gaine SP,Harari S,Martinez FJ,Olschewski H,Olsson KM,Peacock AJ,Pepke-Zaba J,Provencher S,Weissmann N,Seeger W, Pulmonary hypertension in chronic lung disease and hypoxia. The European respiratory journal. 2019 Jan;     [PubMed PMID: 30545980]


Varghese NP,Tillman RH,Keller RL, Pulmonary hypertension is an important co-morbidity in developmental lung diseases of infancy: Bronchopulmonary dysplasia and congenital diaphragmatic hernia. Pediatric pulmonology. 2021 Mar;     [PubMed PMID: 33561308]


Mirrakhimov AE,Strohl KP, High-altitude Pulmonary Hypertension: an Update on Disease Pathogenesis and Management. The open cardiovascular medicine journal. 2016;     [PubMed PMID: 27014374]


Castro-Añón O,Golpe R,Pérez-de-Llano LA,López González MJ,Escalona Velasquez EJ,Pérez Fernández R,Testa Fernández A,González Quintela A, Haemodynamic effects of non-invasive ventilation in patients with obesity-hypoventilation syndrome. Respirology (Carlton, Vic.). 2012 Nov;     [PubMed PMID: 22897169]


Nagaoka M,Goda A,Takeuchi K,Kikuchi H,Finger M,Inami T,Soejima K,Satoh T, Nocturnal Hypoxemia, But Not Sleep Apnea, Is Associated With a Poor Prognosis in Patients With Pulmonary Arterial Hypertension. Circulation journal : official journal of the Japanese Circulation Society. 2018 Nov 24;     [PubMed PMID: 30333436]


Elwing J,Panos RJ, Pulmonary hypertension associated with COPD. International journal of chronic obstructive pulmonary disease. 2008;     [PubMed PMID: 18488429]


Zhang L,Liu Y,Zhao S,Wang Z,Zhang M,Zhang S,Wang X,Zhang S,Zhang W,Hao L,Jiao G, The Incidence and Prevalence of Pulmonary Hypertension in the COPD Population: A Systematic Review and Meta-Analysis. International journal of chronic obstructive pulmonary disease. 2022;     [PubMed PMID: 35711174]

Level 1 (high-level) evidence


Nathan SD,Shlobin OA,Ahmad S,Koch J,Barnett SD,Ad N,Burton N,Leslie K, Serial development of pulmonary hypertension in patients with idiopathic pulmonary fibrosis. Respiration; international review of thoracic diseases. 2008;     [PubMed PMID: 18216461]


Lumb AB,Slinger P, Hypoxic pulmonary vasoconstriction: physiology and anesthetic implications. Anesthesiology. 2015 Apr;     [PubMed PMID: 25587641]


Christou H,Khalil RA, Mechanisms of pulmonary vascular dysfunction in pulmonary hypertension and implications for novel therapies. American journal of physiology. Heart and circulatory physiology. 2022 May 1;     [PubMed PMID: 35213243]


Kolb TM,Hassoun PM, Right ventricular dysfunction in chronic lung disease. Cardiology clinics. 2012 May;     [PubMed PMID: 22548815]


Rahaghi FF,Kolaitis NA,Adegunsoye A,de Andrade JA,Flaherty KR,Lancaster LH,Lee JS,Levine DJ,Preston IR,Safdar Z,Saggar R,Sahay S,Scholand MB,Shlobin OA,Zisman DA,Nathan SD, Screening Strategies for Pulmonary Hypertension in Patients With Interstitial Lung Disease: A Multidisciplinary Delphi Study. Chest. 2022 Jul;     [PubMed PMID: 35176276]


Shellenberger RA,Imtiaz K,Chellappa N,Gundapanneni L,Scheidel C,Handa R,Bhat A, Physical Examination for the Detection of Pulmonary Hypertension: A Systematic Review. Cureus. 2021 Sep;     [PubMed PMID: 34692270]

Level 1 (high-level) evidence


Braganza M,Shaw J,Solverson K,Vis D,Janovcik J,Varughese RA,Thakrar MV,Hirani N,Helmersen D,Weatherald J, A Prospective Evaluation of the Diagnostic Accuracy of the Physical Examination for Pulmonary Hypertension. Chest. 2019 May;     [PubMed PMID: 30826305]


Rose L,Prins KW,Archer SL,Pritzker M,Weir EK,Misialek JR,Thenappan T, Survival in pulmonary hypertension due to chronic lung disease: Influence of low diffusion capacity of the lungs for carbon monoxide. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 2019 Feb;     [PubMed PMID: 30391191]


Zisman DA,Karlamangla AS,Kawut SM,Shlobin OA,Saggar R,Ross DJ,Schwarz MI,Belperio JA,Ardehali A,Lynch JP 3rd,Nathan SD, Validation of a method to screen for pulmonary hypertension in advanced idiopathic pulmonary fibrosis. Chest. 2008 Mar;     [PubMed PMID: 18198245]

Level 1 (high-level) evidence


Lettieri CJ,Nathan SD,Barnett SD,Ahmad S,Shorr AF, Prevalence and outcomes of pulmonary arterial hypertension in advanced idiopathic pulmonary fibrosis. Chest. 2006 Mar;     [PubMed PMID: 16537877]


Swigris JJ,Olson AL,Shlobin OA,Ahmad S,Brown KK,Nathan SD, Heart rate recovery after six-minute walk test predicts pulmonary hypertension in patients with idiopathic pulmonary fibrosis. Respirology (Carlton, Vic.). 2011 Apr;     [PubMed PMID: 20946337]


Arcasoy SM,Christie JD,Ferrari VA,Sutton MS,Zisman DA,Blumenthal NP,Pochettino A,Kotloff RM, Echocardiographic assessment of pulmonary hypertension in patients with advanced lung disease. American journal of respiratory and critical care medicine. 2003 Mar 1;     [PubMed PMID: 12480614]


Nowak J,Hudzik B,Jastrzȩbski D,Niedziela JT,Rozentryt P,Wojarski J,Ochman M,Karolak W,Żegleń S,Gierlotka M,Gąsior M, Pulmonary hypertension in advanced lung diseases: Echocardiography as an important part of patient evaluation for lung transplantation. The clinical respiratory journal. 2018 Mar;     [PubMed PMID: 28052583]


Leuchte HH,Neurohr C,Baumgartner R,Holzapfel M,Giehrl W,Vogeser M,Behr J, Brain natriuretic peptide and exercise capacity in lung fibrosis and pulmonary hypertension. American journal of respiratory and critical care medicine. 2004 Aug 15;     [PubMed PMID: 15087298]


Song JW,Song JK,Kim DS, Echocardiography and brain natriuretic peptide as prognostic indicators in idiopathic pulmonary fibrosis. Respiratory medicine. 2009 Feb;     [PubMed PMID: 19097877]


Zisman DA,Karlamangla AS,Ross DJ,Keane MP,Belperio JA,Saggar R,Lynch JP 3rd,Ardehali A,Goldin J, High-resolution chest CT findings do not predict the presence of pulmonary hypertension in advanced idiopathic pulmonary fibrosis. Chest. 2007 Sep;     [PubMed PMID: 17573485]


Iyer AS,Wells JM,Vishin S,Bhatt SP,Wille KM,Dransfield MT, CT scan-measured pulmonary artery to aorta ratio and echocardiography for detecting pulmonary hypertension in severe COPD. Chest. 2014 Apr;     [PubMed PMID: 24114440]


Yagi M,Taniguchi H,Kondoh Y,Ando M,Kimura T,Kataoka K,Furukawa T,Suzuki A,Johkoh T,Hasegawa Y, CT-determined pulmonary artery to aorta ratio as a predictor of elevated pulmonary artery pressure and survival in idiopathic pulmonary fibrosis. Respirology (Carlton, Vic.). 2017 Oct;     [PubMed PMID: 28488784]


Gong Y, Sankari A. Noninvasive Ventilation. StatPearls. 2024 Jan:():     [PubMed PMID: 35201716]


Schönhofer B,Barchfeld T,Wenzel M,Köhler D, Long term effects of non-invasive mechanical ventilation on pulmonary haemodynamics in patients with chronic respiratory failure. Thorax. 2001 Jul;     [PubMed PMID: 11413350]


Shujaat A,Minkin R,Eden E, Pulmonary hypertension and chronic cor pulmonale in COPD. International journal of chronic obstructive pulmonary disease. 2007;     [PubMed PMID: 18229565]


Weitzenblum E,Sautegeau A,Ehrhart M,Mammosser M,Pelletier A, Long-term oxygen therapy can reverse the progression of pulmonary hypertension in patients with chronic obstructive pulmonary disease. The American review of respiratory disease. 1985 Apr;     [PubMed PMID: 3922267]


Barberà JA,Peinado VI,Santos S, Pulmonary hypertension in chronic obstructive pulmonary disease. The European respiratory journal. 2003 May;     [PubMed PMID: 12765440]


Raghu G,Behr J,Brown KK,Egan JJ,Kawut SM,Flaherty KR,Martinez FJ,Nathan SD,Wells AU,Collard HR,Costabel U,Richeldi L,de Andrade J,Khalil N,Morrison LD,Lederer DJ,Shao L,Li X,Pedersen PS,Montgomery AB,Chien JW,O'Riordan TG,ARTEMIS-IPF Investigators*., Treatment of idiopathic pulmonary fibrosis with ambrisentan: a parallel, randomized trial. Annals of internal medicine. 2013 May 7;     [PubMed PMID: 23648946]

Level 1 (high-level) evidence


Raghu G,Million-Rousseau R,Morganti A,Perchenet L,Behr J,MUSIC Study Group., Macitentan for the treatment of idiopathic pulmonary fibrosis: the randomised controlled MUSIC trial. The European respiratory journal. 2013 Dec;     [PubMed PMID: 23682110]

Level 1 (high-level) evidence


Stolz D,Rasch H,Linka A,Di Valentino M,Meyer A,Brutsche M,Tamm M, A randomised, controlled trial of bosentan in severe COPD. The European respiratory journal. 2008 Sep;     [PubMed PMID: 18448495]

Level 1 (high-level) evidence


Nathan SD,Behr J,Collard HR,Cottin V,Hoeper MM,Martinez FJ,Corte TJ,Keogh AM,Leuchte H,Mogulkoc N,Ulrich S,Wuyts WA,Yao Z,Boateng F,Wells AU, Riociguat for idiopathic interstitial pneumonia-associated pulmonary hypertension (RISE-IIP): a randomised, placebo-controlled phase 2b study. The Lancet. Respiratory medicine. 2019 Sep;     [PubMed PMID: 31416769]

Level 1 (high-level) evidence


Kang J,Song JW, Effect of sildenafil added to antifibrotic treatment in idiopathic pulmonary fibrosis. Scientific reports. 2021 Sep 8;     [PubMed PMID: 34497295]


Goudie AR,Lipworth BJ,Hopkinson PJ,Wei L,Struthers AD, Tadalafil in patients with chronic obstructive pulmonary disease: a randomised, double-blind, parallel-group, placebo-controlled trial. The Lancet. Respiratory medicine. 2014 Apr;     [PubMed PMID: 24717626]

Level 1 (high-level) evidence


Waxman A,Restrepo-Jaramillo R,Thenappan T,Ravichandran A,Engel P,Bajwa A,Allen R,Feldman J,Argula R,Smith P,Rollins K,Deng C,Peterson L,Bell H,Tapson V,Nathan SD, Inhaled Treprostinil in Pulmonary Hypertension Due to Interstitial Lung Disease. The New England journal of medicine. 2021 Jan 28;     [PubMed PMID: 33440084]


Leard LE,Holm AM,Valapour M,Glanville AR,Attawar S,Aversa M,Campos SV,Christon LM,Cypel M,Dellgren G,Hartwig MG,Kapnadak SG,Kolaitis NA,Kotloff RM,Patterson CM,Shlobin OA,Smith PJ,Solé A,Solomon M,Weill D,Wijsenbeek MS,Willemse BWM,Arcasoy SM,Ramos KJ, Consensus document for the selection of lung transplant candidates: An update from the International Society for Heart and Lung Transplantation. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 2021 Nov;     [PubMed PMID: 34419372]

Level 3 (low-level) evidence


Reed RM,Eberlein M,Girgis RE,Hashmi S,Iacono A,Jones S,Netzer G,Scharf S, Coronary artery disease is under-diagnosed and under-treated in advanced lung disease. The American journal of medicine. 2012 Dec;     [PubMed PMID: 22959785]


Chaouat A,Naeije R,Weitzenblum E, Pulmonary hypertension in COPD. The European respiratory journal. 2008 Nov;     [PubMed PMID: 18978137]


Blanco I,Tura-Ceide O,Peinado VI,Barberà JA, Updated Perspectives on Pulmonary Hypertension in COPD. International journal of chronic obstructive pulmonary disease. 2020;     [PubMed PMID: 32606641]

Level 3 (low-level) evidence


Mejía M,Carrillo G,Rojas-Serrano J,Estrada A,Suárez T,Alonso D,Barrientos E,Gaxiola M,Navarro C,Selman M, Idiopathic pulmonary fibrosis and emphysema: decreased survival associated with severe pulmonary arterial hypertension. Chest. 2009 Jul;     [PubMed PMID: 19225068]


Singh N,Dorfmüller P,Shlobin OA,Ventetuolo CE, Group 3 Pulmonary Hypertension: From Bench to Bedside. Circulation research. 2022 Apr 29;     [PubMed PMID: 35482836]


Galiè N,Humbert M,Vachiery JL,Gibbs S,Lang I,Torbicki A,Simonneau G,Peacock A,Vonk Noordegraaf A,Beghetti M,Ghofrani A,Gomez Sanchez MA,Hansmann G,Klepetko W,Lancellotti P,Matucci M,McDonagh T,Pierard LA,Trindade PT,Zompatori M,Hoeper M,ESC Scientific Document Group ., 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). European heart journal. 2016 Jan 1;     [PubMed PMID: 26320113]