Pulmonary Hypertension In Idiopathic Pulmonary Fibrosis Research Articles

DERIVATION AND VALIDATION OF A SIMPLE MULTIDIMENSIONAL MODEL FOR IDENTIFICATION OF COEXISTING PULMONARY HYPERTENSION IN IDIOPATHIC PULMONARY FIBROSIS

DERIVATION AND VALIDATION OF A SIMPLE MULTIDIMENSIONAL MODEL FOR IDENTIFICATION OF COEXISTING PULMONARY HYPERTENSION IN IDIOPATHIC PULMONARY FIBROSIS

Exacerbation of idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is usually characterized by a chronic and slowly progressive course. According to several studies, a small number of patients with IPF (about 515%) develops an acute deterioration of deasese exacerbation of IPF. Exacerbations of IPF can occur at any time of the disease and sometimes becomes the first manifestation of IPF. Pulmonary hypertension in IPF is a fairly frequent complication, which leads to severe violations of gas exchange and reduced tolerance to physical stress. Currently, proven effective treatments for exacerbations of IPF do not exist, the management of this condition is based on supportive therapy (oxygen, respiratory support) and interventions with inadequate evidences (corticosteroids, immunosuppressant). During exacerbation of IPF a careful search of all the possible triggers is justified. In the presented clinical case of exacerbation of IPF there was demonstrated the efficacy of complex therapy including antifibrotic therapy, PAH-specific medicines and enhanced oxygen therapy.

Idiopathic Pulmonary Fibrosis for Cardiologists: Differential Diagnosis, Cardiovascular Comorbidities, and Patient Management.

The presence of rare comorbidities in patients with cardiovascular disease (CVD) presents a diagnostic challenge to cardiologists. In evaluating these patients, cardiologists are faced with a unique opportunity to shorten diagnosis times and direct patients towards correct treatment pathways. Idiopathic pulmonary fibrosis (IPF), a type of interstitial lung disease (ILD), is an example of a rare disease where patients frequently demonstrate comorbid CVD. Both CVD and IPF most commonly affect a similar patient demographic: men over the age of 60 years with a history of smoking. Moreover, IPF and heart failure (HF) share a number of symptoms. As a result, patients with IPF can be misdiagnosed with HF and vice versa. This article aims to increase awareness of IPF among cardiologists, providing an overview for cardiologists on the differential diagnosis of IPF from HF, and describing the signs and symptoms that would warrant referral to a pulmonologist with expertise in ILD. Once patients with IPF have received a diagnosis, cardiologists can have an important role in managing patients who are candidates for a lung transplant or those who develop pulmonary hypertension (PH). Group 3 PH is one of the most common cardiovascular complications diagnosed in patients with IPF, its prevalence varying between reports but most often cited as between 30% and 50%. This review summarizes the current knowledge on Group 3 PH in IPF, discusses data from clinical trials assessing treatments for Group 1 PH in patients with IPF, and highlights that treatment guidelines recommend against these therapies in IPF. Finally, this article provides the cardiologist with an overview on the use of the two approved treatments for IPF, the antifibrotics pirfenidone and nintedanib, in patients with IPF and CVD comorbidities. Conversely, the impact of treatments for CVD comorbidities on patients with IPF is also discussed.Funding: F. Hoffmann-La Roche, Ltd.Plain Language Summary: Plain language summary available for this article.

Pulmonary Hypertension Associated with Idiopathic Pulmonary Fibrosis: Current and Future Perspectives.

Pulmonary hypertension (PH) is commonly present in patients with chronic lung diseases such as Chronic Obstructive Pulmonary Disease (COPD) or Idiopathic Pulmonary Fibrosis (IPF) where it is classified as Group III PH by the World Health Organization (WHO). PH has been identified to be present in as much as 40% of patients with COPD or IPF and it is considered as one of the principal predictors of mortality in patients with COPD or IPF. However, despite the prevalence and fatal consequences of PH in the setting of chronic lung diseases, there are limited therapies available for patients with Group III PH, with lung transplantation remaining as the most viable option. This highlights our need to enhance our understanding of the molecular mechanisms that lead to the development of Group III PH. In this review we have chosen to focus on the current understating of PH in IPF, we will revisit the main mediators that have been shown to play a role in the development of the disease. We will also discuss the experimental models available to study PH associated with lung fibrosis and address the role of the right ventricle in IPF. Finally we will summarize the current available treatment options for Group III PH outside of lung transplantation.

Hypertension pulmonaire au cours des pneumopathies interstitielles diffuses

Pulmonary hypertension (PH) is defined by a mean pulmonary artery pressure (mPAP) highter or equal to 25mmHg. The diagnosis during a diffuse interstitial lung disease (PID) is made during a cardiac ultrasound, which, besides measuring the systolic pulmonary artery pressure, eliminate left heart failure and rank the probability of PH. Conventionally, this is a pre-capillary mechanism in this context. The frequency of PH in idiopathic pulmonary fibrosis (IPF) is from 8 to 50%, depending on the severity of the IPF. There is also a PH over the evolution of combined pulmonary fibrosis emphysema, sarcoidosis, histiocytosis, and more rarely lymphangioleiomyomatosis. Diagnostic confirmation requires the completion of a right heart catheterization performed in a competence or reference PH center. Treatment is based mainly on the management of respiratory disease and the introduction of long term oxygen therapy. Specific treatments for PAH are usually not indicated and can worsen gas exchange. Further studies are needed to determine the potential value of these treatments in patients with particularly severe PH.

Fibrinolytic system related to pulmonary arterial pressure and lung function of patients with idiopathic pulmonary fibrosis.

To investigate urokinase-(uPA) and tissue-type (tPA) plasminogen activator and plasminogen activator inhibitor type-1 (PAI-1) levels in patients with idiopathic pulmonary fibrosis (IPF) and to determine the relationship between fibrinolytic system and pulmonary arterial pressure and pulmonary function. Seventy-nine patients with IPF were included. Bronchoalveolar lavage fluid (BALF) and blood samples were collected. The concentrations of tPA, uPA and PAI-1 were measured using enzyme-linked immunosorbent assay. Doppler echocardiography was used to detect tricuspid regurgitation pressure gradient (TRPG) to estimate pulmonary arterial pressure. BALF tPA elevated (P < 0.005), circulatory PAI-1 decreased (P = 0.05) and the ratio of uPA and PAI-1 decreased (P = 0.01) in BALF in IPF patients with pulmonary hypertension (PH) compared to those without PH. Positive linear correlations were found: BALF tPA and TRPG (r = 0.558, P = 0.013); the predicted percentage of diffusion capacity of lung for carbon monoxide adjustments for alveolar volume and BALF uPA (r = 0.319, P = 0.035). Negative linear correlations were as follows: BALF PAI-1 and the predicted percentage of VCmax (r = -0.325, P = 0.020), or total lung capacity (r = -0.312, P = 0.033); circulatory PAI-1 and TRPG (r = -0.697, P = 0.003). The change of alveolar fibrolytic system in IPF, especially the uPA reduction and the PAI-1elevation, contributes to the deterioration of lung function. During the lung injury initiating fibrosis, tPA and PAI-1 might be leaked out of the pulmonary capillaries into alveoli, resulting in their elevation in alveoli and reduction in circulation, and finally contributing to the development of PH in IPF.

Treatment of pulmonary hypertension in idiopathic pulmonary fibrosis: shortfall in efficacy or trial design?

Idiopathic pulmonary fibrosis (IPF) is a disease that carries a high mortality. Pulmonary hypertension (PH) frequently complicates the course of patients with IPF and is associated with significantly worse outcomes. Whether PH is a surrogate or driver of these worse outcomes remains unanswered, but the presence of PH represents an attractive target for therapy. This review delves into the various pulmonary vasoactive agents that have been subjected to study in IPF, the pitfalls of some of these prior studies, and attempts to lay a foundation for future study designs targeting PH in IPF.

Role of tetrahydrobiopterin in pulmonary vascular remodelling associated with pulmonary fibrosis

BackgroundPulmonary hypertension in idiopathic pulmonary fibrosis (IPF) is indicative of a poor prognosis. Recent evidence suggests that tetrahydrobiopterin (BH4), the cofactor of nitric oxide synthase (NOS), is involved in pulmonary...

Is Resistance Futile?

Is Resistance Futile?

Increased ADORA2B Expression Correlates with Mean Pulmonary Arterial Pressure in Idiopathic Pulmonary Fibrosis

Purpose Idiopathic pulmonary fibrosis (IPF) is often accompanied by pulmonary hypertension (PH), a mortality predictor leading to increased vascular remodeling, right-heart failure and death. Studies have shown that adenosine A2B receptor (ADORA2B) is elevated after tissue injury and it participates in wound healing and tissue remodeling responses. We aimed to show whether mean pulmonary arterial pressure (mPAP) correlated with pulmonary function tests (PFTs) and increased expression of mediators involved in the disease progression. Methods and Materials A retrospective review on 30 patients on post-lung transplantation with IPF where native lung was collected from 02/2011 to 09/2012. Results of PFTs and mPAP were collected. RNA and protein were isolated for qRT-PCR and western blot from frozen lung explant samples. Controls were 18srRNA and β-actin. Linear regression and Pearson’s correlation between transcript levels and mPAP were analyzed. p Results 12/30 presented with PH (IPF+PH group); 63% male; 60% Caucasian. Linear regression analysis demonstrates no association between PFTs or Collagen I (Col1A1 transcript) levels and mPAP values. mPAP compared to FVC%, TLC%, DLCO% and FEV1% showed no statistical significance. When mPAP was compared to ADORA2B expression levels, we found a significant correlation (p=0.0373, r2 0.1685) suggesting a link between heightened ADORA2B expression levels and elevated mPAP. [ figure 1 ] Western blot corroborated by showing heightened ADORA2B protein levels in IPF+PH. Conclusions Results demonstrate a direct positive correlation between ADORA2B and mPAP in patients with IPF; pointing to a role for ADORA2B in the pathophysiology of PH in IPF that could lead to new therapies.

Pulmonary Hypertension in Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with a variable natural history. Pulmonary hypertension (PH) is frequently found in patients with IPF and is associated with an almost 3-fold increase in the risk of death. Pulmonary hypoxic vasoconstriction plays an important role in the pathogenesis of PH in IPF (PH-IPF), although it has become clear that it is not the only mechanism involved. While invasive right heart catheterization is the gold standard modality of hemodynamic assessment, there has been increasing interest in noninvasive testing, such as Doppler echocardiogram, as complementary methods of assessing right ventricular function in these patients. While the expanding array of pharmacologic options for the treatment of pulmonary arterial hypertension has engendered increased interest in the application of these therapies for PH-IPF, supportive evidence for benefit is lacking.

Prevalence of Pulmonary Hypertension in Patients with Idiopathic Pulmonary Fibrosis: Correlation with Physiological Parameters

The aim of this study was to prospectively evaluate the prevalence of pulmonary hypertension (PH) in patients with idiopathic pulmonary fibrosis (IPF). One hundred thirty-nine patients (101 male, mean age=68.6±9years), with confirmed IPF and who were admitted to eight Pulmonary Departments in Greece between November 2005 and December 2006 were included in the study. Pulmonary artery systolic pressure (PASP) was estimated by echocardiography, and PH was defined as PASP>36mmHg. We compared demographics, pulmonary function tests, NYHA functional status, 6-min walk distance (6MWD), B-type natriuretic peptide (BNP), PaO(2), and P(A-a)O(2) at rest data between patients with PH and without PH (PASP≤36mmHg). Increased estimated right ventricular systolic pressure was present in 55% of patients (mean PASP=47.1±11.2mmHg vs. 30.3±3.8mmHg, respectively). Patients with PH had a lower but not statistically significant DL(CO) (47.1±18.8 vs. 52.5±20.1), lower PaO(2) at rest (64.6±12.2 vs. 71.1±11.3, P=0.004), and lower mean 6MWD (282±118 vs. 338±91, P=0.007). Significant differences were also observed in the NYHA functional status between the two groups (P=0.02). Statistically significant correlations were observed between PASP and PaO(2) at rest (r=-0.331, P=0.00), P(A-a)O(2) at rest (r=0.494, P=0.00)(,) 6MWD (r=-0.264, P=0.01), SpO(2) at rest (r=-0.293, P=0.00), SpO(2) at the end of exercise (r=-0.364, P=0.00), and also BNP values (r=0.319, P=0.01). Moreover, PaO(2) (P=0.02), P(A-a)O(2) (P=0.005), and SpO(2) at the end of exercise (P=0.023) were independent predictors of the presence of estimated PH. Using Doppler echocardiography as a screening tool for the estimation of PH, we found that PH is common in patients with IPF. Gas exchange parameters at rest and exercise desaturation might indicate underlying PH in IPF.

Pulmonary Hypertension and Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a disabling disease of the lung parenchyma, characterized by progressive accumulation of scar tissue and myofibroblast activation after repetitive epithelial microinjury. The therapeutic options are limited, and patients usually die within a few years after diagnosis. Pulmonary hypertension (PH) in IPF has been increasingly recognized as a condition with relevance for the overall prognosis. Treatment trials are being designed, but to be effective, it is crucial to better understand the pathobiology of PH in IPF: the traditional concept, that hypoxic vasoconstriction and accumulation of scar tissue are mainly responsible for the development of PH in IPF, has been challenged. Recent studies, including our own in vivo research, suggest that the underlying pathobiology is much more complex, and includes a complicated interaction of epithelial cells, fibroblasts, and vascular cells. This interaction seems to be regulated by a large variety of angiogenesis promoters and inhibitors, as well as growth factors. Central components seem to be endothelial apoptosis and growth factor-induced remodeling of the pulmonary artery wall. The present review gives a conceptual overview about known and putative mechanisms that are involved in the development of PH in IPF. This report summarizes currently available therapeutic options, and also translates experimental research to discuss potential novel biomarkers and therapeutic strategies derived from new concepts in pathogenesis.

Iron deposition and increased alveolar septal capillary density in nonfibrotic lung tissue are associated with pulmonary hypertension in idiopathic pulmonary fibrosis

BackgroundEarly diagnosis of pulmonary hypertension (PH) in idiopathic pulmonary fibrosis (IPF) has potential prognostic and therapeutic implications but can be difficult due to the lack of specific clinical manifestations or accurate non-invasive tests. Histopathologic parameters correlating with PH in IPF are also not known. Remodeling of postcapillary pulmonary vessels has been reported in the nonfibrotic areas of explanted lungs from IPF patients. We hypothesized that iron deposition and increased alveolar capillaries, the findings often seen in postcapillary PH, might predict the presence of clinical PH, independent of the severity of fibrosis or ventilatory dysfunction in IPF patients. To test this hypothesis, we examined the association between these histologic parameters and the degree of PH, with consideration of the severity of disease in IPF.MethodsIron deposition and alveolar septal capillary density (ASCD) were evaluated on histologic sections with hematoxylin-eosin, iron, elastin and CD34 stainings. Percentage of predicted forced vital capacity (FVC%) was used for grading pulmonary function status. Fibrosis score assessed on high resolution computed tomography (HRCT) was used for evaluating overall degree of fibrosis in whole lungs. Right ventricular systolic pressure (RVSP) by transthoracic echocardiography was used for the estimation of PH. Univariate and multivariate regression analyses were performed.ResultsA cohort of 154 patients was studied who had the clinicopathological diagnosis of IPF with surgical lung biopsies or explants during the period of 1997 to 2006 at Mayo Clinic Rochester. In univariate analysis, RVSP in our IPF cases was associated with both iron deposition and ASCD (p < 0.001). In multivariate analysis with FVC% and HRCT fibrosis score included, iron deposition (p = 0.02), but not ASCD (p = 0.076), maintained statistically significant association with RVSP. FVC% was associated with RVSP on univariate analysis but not on multivariate analysis, while fibrosis score lacked any association with RVSP by either univariate or multivariate analyses.ConclusionsIron deposition and ASCD in non fibrotic lung tissue showed an association with RVSP, suggesting that these features are possible morphologic predictors of PH in IPF.

Right ventricular systolic pressure by echocardiography as a predictor of pulmonary hypertension in idiopathic pulmonary fibrosis

Pulmonary hypertension (PH) commonly complicates the course of patients with idiopathic pulmonary fibrosis (IPF). It has a significant impact on outcomes and is, therefore, important to detect. We sought to characterize the accuracy and performance characteristics of the right ventricular systolic pressure (RVSP) as estimated by echocardiography (ECHO) alone and in conjunction with physiologic indices in predicting the presence of PH in IPF patients. Cross-sectional study of IPF patients from two large tertiary centers in whom both ECHO and right-heart catheterization (RHC) were available. There were 110 patients with available ECHOs and RHCs. Estimates of RVSP were reported in 60 of these patients (54.5%) of whom 22 (36.6%) had PH, while 16 of the 50 patients without RVSP estimate (32%) had PH. Twenty-four of 60 (40%) ECHOs accurately reflected the pulmonary arterial systolic pressure as measured by RHC. An optimal RVSP threshold for the screening of PH could not be detected. When assessed in combination with various thresholds of PFT and 6-minute walk test (6MWT) parameters, the performance characteristics of the RVSP were slightly improved. The RVSP is not an accurate test for the assessment of PH in IPF patients. Awareness of the various combinations of threshold values for RVSP with and without PFT and 6MWT might nonetheless assist clinicians in risk stratifying IPF patients for the presence of PH.

Pulmonary hypertension associated with idiopathic pulmonary fibrosis: morphofunctional characteristics of pulmonary artery branches and their relationship with functional cardiorespiratory status

The aim of the study was to investigate functional status of cardiorespiratory system and post-mortem morphometric characteristics of the heart and the lung arteries in secondary pulmonary hypertension (PH) associated with idiopathic pulmonary fibrosis (IPF). A retrospective analysis of functional status of cardiorespiratory system in 10 died patients with IPF (5 males and 5 females, the average age, 63.1 ± 9.2 yrs) was performed. During the last 6 months of their life, all the patients were investigated using body plethysmography, lung diffusing capacity test, arterial blood gas analysis and Doppler echocardiography measuring maximal systolic pulmonary artery (PA) pressure (sysPAP). We also performed histological examination of autopsy samples and morphometric examination of the PA and the heart. Severe restrictive disorders, significant decrease in the lung diffusing capacity with alveolo-capillary block and arterial hypoxemia have been found. The sysPAP was 44.9 ± 17.4 mm Hg in average. Microscopic lung tissue disorders were characteristic for usual interstitial pneumonia. Diameter of the pulmonary vessel lumen in IPF patients was 1.5-fold less and the vessel area was 1.7-fold less than those in controls. In IPF patients, the PA branch wall was 2.9-fold thicker, the proportion of the muscle area was 2.2-fold more and that of the intima area was 4.1-fold more than those in controls. Correlations were found between sysPAP and the cross-sectional area f the PA small branches (r = 0.71; p &lt; 0.05), sysPAP and the proportion of intima area (r = 0.68, p &lt; 0.05). Lumen diameter of the PA small branches correlated with the right atrium length (r = –0.81; p &lt; 0.05) and the right ventricle mass correlated with diameter (r = –0.71; p &lt; 0.05) and the cross-sectional area of the PA small branches (r = –0.75; p &lt; 0.05). Significant correlations were also found between lung function, lung diffusing capacity and function signs of PH. Therefore, secondary PH in IPF is characterized by wall remodeling in the PA branches, mainly due to changes of intima. The 1.5-fold reduction of the vessel lumen is thought to be a cause of moderate growth of sysPAP followed by occurrence of cor pulmonale.

Pulmonary Hypertension in Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is an untreatable diffuse parenchymal lung disease with a median survival of < 3 years. Pulmonary hypertension (PH) is frequently seen in patients with IPF and is commonly attributed to hypoxic vasoconstriction and capillary destruction. Pathology findings include endothelial proliferation and medial hypertrophy that exceed those expected in the setting of hypoxia. Noninvasive evaluation has limited sensitivity and specificity for the diagnosis of PH in IPF; therefore, right-heart catheterization remains the "gold standard" diagnostic test. PH in patients with IPF is associated with decreased exercise capacity and worse survival. Given the grave consequences of this condition, treatment of PH could improve functional outcomes and survival. However, possible treatments such as long-term supplemental oxygen and targeted vascular therapy are either unstudied or remain unproven.

Pulmonary hypertension in patients with pulmonary fibrosis awaiting lung transplant

Pulmonary hypertension (PH) may complicate idiopathic pulmonary fibrosis (IPF) but the prevalence of PH in IPF remains undefined. The present authors sought to describe the prevalence of PH in IPF. The lung transplant registry for the USA (January 1995 to June 2004) was analysed and IPF patients who had undergone right heart catheterisation (RHC) were identified. PH was defined as a mean pulmonary arterial pressure ((Ppa)) > or =25 mmHg and severe PH as a (Ppa) >40 mmHg. Independent factors associated with PH were determined. Of the 3,457 persons listed, 2,525 (73.0%) had undergone RHC. PH affected 46.1% of subjects; approximately 9% had severe PH. Variables independently associated with mild-to-moderate PH were as follows: need for oxygen, pulmonary capillary wedge pressure (P(pcw)) and forced expiratory volume in one second (FEV(1)). Independent factors related to severe PH included the following: carbon dioxide tension, age, FEV(1), P(pcw), need for oxygen and ethnicity. A sensitivity analysis in subjects with P(pcw) <15 mmHg did not appreciably alter the present findings. Pulmonary hypertension is common in idiopathic pulmonary fibrosis patients awaiting lung transplant, but the elevations in mean pulmonary arterial pressure are moderate. Lung volumes alone do not explain the pulmonary hypertension. Given the prevalence of pulmonary hypertension and its relationship with surrogate markers for quality of life (e.g. activities of daily living), future trials of therapies for this may be warranted.

Idiopathic Pulmonary Fibrosis and Pulmonary Hypertension

Idiopathic pulmonary fibrosis (IPF) has a poor prognosis and a course that is unpredictable. Pulmonary hypertension may complicate the course of IPF and potentially impact prognosis. There are multiple factors that might influence the onset and severity of pulmonary hypertension in IPF. The relationship between the physiologic and pathobiologic manifestations of the progressive fibrotic process and interceding pulmonary hypertension has not been well defined. This article serves to explore these relationships and to hypothesize about the possible linkage between these entities. From a prognostic standpoint, recent evidence suggests this to be important to assess for pulmonary hypertension in patients with IPF. The appropriate triggers for evaluating for pulmonary hypertension and the best method of detection require further study. Despite the relative ease of noninvasive methods, such as echocardiography, right-heart catheterization remains the best diagnostic test. The appeal of pulmonary hypertension in IPF is that it may be an enticing therapeutic target in a disease that otherwise does not have any proven effective therapies. Which agent(s) might be useful and when they should be implemented mandate the appropriate studies being performed. Some of the data presented in this article have previously been reported in abstract form only.