Scleroderma-associated Pulmonary Arterial Hypertension Research Articles

THU0248 Efficacy of imatinib mesylate on scleroderma associated pulmonary arterial hypertension

BackgroundScleroderma is an autoimmune disorder mainly characterized by progressive dermal and vascular fibrosis. It has been reported that abnormal signaling through the platelet derived growth factor (PDGF) and transforming growth...

Leptin and regulatory T-lymphocytes in idiopathic pulmonary arterial hypertension

Immune mechanisms and autoimmunity seem to play a significant role in idiopathic pulmonary arterial hypertension (IPAH) pathogenesis and/or progression, but the pathophysiology is still unclear. Recent evidence has demonstrated a detrimental involvement of leptin in promoting various autoimmune diseases by controlling regulatory T-lymphocytes. Despite this knowledge, the role of leptin in IPAH is currently unknown. We hypothesised that leptin, synthesised by dysfunctional pulmonary endothelium, might play a role in the immunopathogenesis of IPAH by regulating circulating regulatory T-lymphocytes function. First, we collected serum and regulatory T-lymphocytes from controls, and IPAH and scleroderma-associated pulmonary arterial hypertension (SSc-PAH) patients; secondly, we recovered tissue samples and cultured endothelial cells after either surgery or transplantation in controls and IPAH patients, respectively. Our findings indicate that serum leptin was higher in IPAH and SSc-PAH patients than controls. Circulating regulatory T-lymphocyte numbers were comparable in all groups, and the percentage of those expressing leptin receptor was higher in IPAH and SSc-PAH compared with controls, whereas their function was reduced in IPAH and SSc-PAH patients compared with controls, in a leptin-dependent manner. Furthermore, endothelial cells from IPAH patients synthesised more leptin than controls. Our data suggest that endothelial-derived leptin may play a role in the immunopathogenesis of IPAH.

Comparison of Baseline Predictors of Prognosis in Pulmonary Arterial Hypertension in Patients Surviving ≤2 Years and Those Surviving ≥5 Years After Baseline Right-Sided Cardiac Catheterization

Idiopathic pulmonary arterial hypertension (PAH) is usually associated with a poor outcome but the prognosis with other forms of PAH is not well-described. Advances in therapy have furthered clouded the disease course. We sought to determine the baseline indicators of prognosis in patients with PAH. We reviewed the records of patients with PAH followed up at our institution to identify those who died within 2 years (reduced survival group; n = 21) and those who survived >5 years (long survival group; n = 60). The groups were compared for prognostic significance of the baseline clinical parameters. The reduced survival group were older (p = 0.001) and more likely to have scleroderma-associated PAH (p = 0.01), have pericardial effusion (p = 0.01), have a shorter 6-minute walk test (6MWT) distance (p = 0.001), to require oxygen during 6MWT (p = 0.02), have a worse World Health Organization functional class (p <0.001), and have greater serum brain natriuretic peptide levels (p = 0.01). Regression analysis showed age, World Health Organization functional class, 6MWT distance, the need for oxygen during the 6MWT, and renal disease to be independently associated with a poor prognosis. In conclusion, age, PAH etiology, World Health Organization functional class, pericardial effusion, 6MWT distance, the need for oxygen during the 6MWT, and brain natriuretic peptide are predictors of prognosis in patients PAH receiving specific therapy and might help identify a group that could benefit from aggressive upfront therapy.

Right Ventricular Dysfunction Is Less Treatment Responsive in the First Year on PH Specific Therapy in Scleroderma Associated Pulmonary Arterial Hypertension

PURPOSE: Patients with scleroderma associated pulmonary arterial hypertension (SSc-PAH) have a worse prognosis vs. idiopathic PAH (iPAH). We sought to determine the relative changes in clinical characteristics and right ventricular (RV) function in incident SSc-PAH vs. iPAH following 1 year of PH specific therapy.

Right and Left Ventricular Myocardial Perfusion Reserves Correlate with Right Ventricular Function and Pulmonary Hemodynamics in Patients with Pulmonary Arterial Hypertension

To evaluate the relationships of right ventricular (RV) and left ventricular (LV) myocardial perfusion reserves with ventricular function and pulmonary hemodynamics in patients with pulmonary arterial hypertension (PAH) by using adenosine stress perfusion cardiac magnetic resonance (MR) imaging. This HIPAA-compliant study was institutional review board approved. Twenty-five patients known or suspected to have PAH underwent right heart catheterization and adenosine stress MR imaging on the same day. Sixteen matched healthy control subjects underwent cardiac MR imaging only. RV and LV perfusion values at rest and at adenosine-induced stress were calculated by using the Fermi function model. The MR imaging-derived RV and LV functional data were calculated by using dedicated software. Statistical testing included Kruskal-Wallis tests for continuous data, Spearman rank correlation tests, and multiple linear regression analyses. Seventeen of the 25 patients had PAH: 11 with scleroderma-associated PAH, and six with idiopathic PAH. The remaining eight patients had scleroderma without PAH. The myocardial perfusion reserve indexes (MPRIs) in the PAH group (median RV MPRI, 1.7 [25th-75th percentile range, 1.3-2.0]; median LV MPRI, 1.8 [25th-75th percentile range, 1.6-2.1]) were significantly lower than those in the scleroderma non-PAH (median RV MPRI, 2.5 [25th-75th percentile range, 1.8-3.9] [P = .03]; median LV MPRI, 4.1 [25th-75th percentile range, 2.6-4.8] [P = .0003]) and control (median RV MPRI, 2.9 [25th-75th percentile range, 2.6-3.6] [P < .01]; median LV MPRI, 3.6 [25th-75th percentile range, 2.7-4.1] [P < .01]) groups. There were significant correlations between biventricular MPRI and both mean pulmonary arterial pressure (mPAP) (RV MPRI: ρ = -0.59, Bonferroni P = .036; LV MPRI: ρ = -0.79, Bonferroni P < .002) and RV stroke work index (RV MPRI: ρ = -0.63, Bonferroni P = .01; LV MPRI: ρ = -0.75, Bonferroni P < .002). In linear regression analysis, mPAP and RV ejection fraction were independent predictors of RV MPRI. mPAP was an independent predictor of LV MPRI. Biventricular vasoreactivity is significantly reduced with PAH and inversely correlated with RV workload and ejection fraction, suggesting that reduced myocardial perfusion reserve may contribute to RV dysfunction in patients with PAH.

Imatinib Mesylate Has The Potential to Exert Its Efficacy by Down-Regulating The Plasma Concentration of Platelet-Derived Growth Factor in Patients With Pulmonary Arterial Hypertension

Recently, platelet-derived growth factor (PDGF) has been implicated in the abnormal proliferation and migration of pulmonary artery vascular smooth muscle cells. Imatinib meslylate, a PDGF receptor antagonist, has been reported to dramatically improve pulmonary arterial hypertension (PAH) in some human cases as well as animal models. Five patients with PAH (3 scleroderma-associated PAH and 2 idiopathic/familial PAH) taking no less than 2 PAH agents were treated with low-dose imatinib (100 mg/day) for 24 weeks. Imatinib was titrated up to 200 mg/day unless major complications were observed. Before and after the treatment, right heart catheterization, cardiopulmonary exercise test, respiratory function test, and plasma concentration measurements of PDGF-BB and vascular endothelial growth factor (VEGF) were performed. Plasma PDGF-BB levels were significantly decreased after 12 weeks of treatment (P = 0.04), while VEGF did not change. Although 24 week administration of imatinib did not show a significant effect on hemodynamics and exercise capacity, 2 patients with high plasma PDGF-BB levels showed a good initial response of more than a 15% decrease in pulmonary vascular resistance. Diffusion capacity of the lung for carbon monoxide significantly improved after 12 weeks of treatment (P < 0.01) and this improvement tended to be sustained for 24 weeks (P = 0.05). Renal dysfunction was observed in 3 patients during imatinib therapy. The upregulated PDGF-BB in patients with PAH could be suppressed by imatinib treatment, and also seemed to be one of the determinant factors for its efficacy.

Reduced right and left ventricular myocardial perfusion reserve in patients with scleroderma-associated and idiopathic (IPAH) pulmonary arterial hypertension due to impaired microvascular vasoreactivity

Address: 1Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, , USA, 2Mallinckrodt Institute of Radiology, Washington University School of Medicine, Saint Louis, MO, USA, 3Department of Cardiology, Johns Hopkins University School of Medicine, Baltimore, USA, 4Department of Radiology and Imaging Sciences, National Institutes of Health, Bethesda, USA and 5Department of Pulmonology, Johns Hopkins University School of Medicine, Baltimore, USA * Corresponding author

Longterm Survival Among Patients with Scleroderma-associated Pulmonary Arterial Hypertension Treated with Intravenous Epoprostenol

Pulmonary arterial hypertension (PAH) remains challenging to treat, especially in association with scleroderma. We examined survival rates among patients with PAH in association with scleroderma who received epoprostenol (Flolan) through continuous intravenous (i.v.) infusion in an uncontrolled open-label 3-year extension study following an initial randomized, controlled 12-week study. One hundred two patients diagnosed with PAH in association with scleroderma who received epoprostenol were included in the analyses. This included 51 PAH patients from a subject population of 56 who received epoprostenol in the randomized controlled study, and 46 patients from an initial population of 55 subjects on conventional therapy in the randomized controlled study, who received epoprostenol in the extension study. All patients in this extension study received open-label epoprostenol. Adverse events, survival, and dosing information were collected throughout the study. The probabilities of survival during the first and second years for all subjects who received epoprostenol during the initial randomized controlled study or during the extension study were 0.71 and 0.52, respectively. This measure remained constant at 0.48 during the third and fourth years. This study reports longterm survival rates for patients with scleroderma-associated PAH treated with i.v. epoprostenol. Although comparisons to historical data should be made with caution, this study reports a better survival outcome than natural history data on patients with scleroderma-associated PAH.

Pulmonary arterial hypertension in systemic lupus erythematosus: should we bother?

Pulmonary arterial hypertension in systemic lupus erythematosus: should we bother?

Trends in pulmonary arterial hypertension

Past decades have witnessed an increasing interest in the field of pulmonary arterial hypertension (PAH). The large number of publications related to PAH reflects this interest. As a result, in contrast to 15 yrs ago, there are now at least seven different drugs as specific therapy targeting the pulmonary circulation that are approved for use in the USA and European Union, with some of them also approved for use in Canada, Japan, Australia and in some countries in Latin America. These medications have proved to increase exercise capacity [1–5], haemodynamics [2, 3, 6], quality of life [7–9] and even survival [5]. Nevertheless, there is still room for further improvements, since the mortality rate remains significantly high [10, 11]. Haemodynamically, PAH is characterised by progressive increase in pulmonary vascular resistance, as a consequence of vascular remodelling within the pre-capillary territory, leading to right ventricular failure and, eventually, death [12]; numerically, this is translated to the presence of a mean pulmonary artery pressure >25 mmHg, with normal pulmonary artery occlusion pressure (<15 mmHg) [13]. This definition, although extremely important for the proper characterisation of a pre-capillary impairment, might be misleading when focusing on specific patients or, more properly, specific forms of PAH. The most recent published nomenclature for pulmonary hypertension date from 2003 [13], and despite the fact that it has been recently revised (at the International Symposium of Pulmonary Hypertension, held in Dana Point, CA, USA, in the first quarter of 2008) it still includes in group 1 (PAH) several diseases that share the haemodynamic profile of pre-capillary pulmonary hypertension but present a completely distinct clinical course, such as idiopathic PAH, scleroderma-associated PAH and portopulmonary hypertension [10, 14, …

Significant improvement of right ventricular function by imatinib mesylate in scleroderma-associated pulmonary arterial hypertension

Sirs: Pulmonary arterial hypertension (PAH) is a devastating disease that harbours a poor prognosis, particularly in patients with scleroderma-associated PAH. Although modern therapies such as endothelin receptor antagonists (ERA), phosphodiesterase type-5 inhibitors (PDE5i) and prostanoids have improved the clinical situation and outcome of affected patients [5], the current medical treatment of PAH is not satisfactory. Recent experimental data suggest that platelet-derived growth factor (PDGF) plays a pivotal role in the pathobiology of PAH by initiating and maintaining the underlying pulmonary vascular remodelling [9]. Consistently, inhibition of PDGF receptor (PDGFR) signalling by the tyrosine kinase inhibitor imatinib mesylate was recently shown to reverse PAH in animal models and to improve the clinical situation in selected patients [3, 7, 9, 10]. However, imatinib was also shown to exert significant cardiotoxicity in animals and humans through its inhibitory effect on the non-receptor Abelson tyrosine kinase (c-Abl) [4]. Further analyses of clinical studies revealed that congestive heart failure is a rare event in patients receiving imatinib therapy, but occurs more frequently in patients with pre-existing cardiac conditions [1]. The latter fact may be of particular significance in patients with PAH and impaired right ventricular function since the right ventricle responds particularly sensitive to hemodynamic and/or cardiotoxic impairment. In addition, patients with scleroderma-associated PAH harbour a lower right ventricular contractility as compared to those with idiopathic PAH [6].

Six-Minute Walk Test in Scleroderma-Associated Pulmonary Arterial Hypertension: Are We Counting What Counts?

> Everything that can be counted does not necessarily count; > > Everything that counts cannot necessarily be counted > > —Albert Einstein Systemic scleroderma (SSc) is a multisystem disease with protean manifestations, but pulmonary involvement is the leading cause of mortality. Interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH) are 2 serious pulmonary complications of SSc that commonly cause clinical symptoms of dyspnea and exercise intolerance, can be associated with severe functional limitation, and often have a poor prognosis for longterm survival. SSc-associated PAH (SSc-PAH) is a serious disease of progressive pulmonary vascular obliteration characterized by persistent elevation of pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR). Untreated SSc-PAH usually results in right-sided heart failure and high risk of death. The average survival in SSc patients diagnosed with PAH is 1–2 years1–3. Patients with SSc-PAH have a worse prognosis than most other PAH patients, including primary or idiopathic PAH (IPAH)4,5. Many new PAH-specific therapies have been studied and are available for the treatment of patients with SSc-PAH. These include prostacyclin derivatives (intravenous epoprostenol, subcutaneous or intravenous treprostinil), a novel family of oral endothelin receptor antagonists (bosentan, sitaxsentan, and ambrisentan), as well as an oral phosphodiesterase type 5 inhibitor (sildenafil)6. Treatment of PAH patients, including SSc-PAH, with these PAH-specific medications is associated with subjective and objective clinical benefit. Given that PAH is a disease of disturbed pulmonary hemodynamics, reductions in mean PAP and PVR, as well as improved right ventricular (RV) function, as evidenced by increased cardiac output, have been expectations of PAH therapy. However, repeated assessment of pulmonary hemodynamics by invasive rightheart catheterization is not feasible, and not necessarily indicated. Doppler echocardiographic assessment of RV systolic pressure (RVSP) is commonly used as a surrogate for systolic PAP. Moreover, other echo parameters, such … See Limitations to the 6-minute walk test in interstitial lung disease and pulmonary hypertension in scleroderma, page 330 Address reprint requests to Dr. S. Mehta, Division of Respirology, London Health Sciences Center-Victoria Hospital, Room E2.623, Professional Building, 800 Commissioner’s Road East, London, Ontario N6A 5W9, Canada. E-mail: sanjay.mehta{at}lhsc.on.ca

Peripheral endothelial dysfunction in patients with pulmonary arterial hypertension

Pulmonary endothelium plays an important role in the mechanism of pulmonary arterial hypertension (PAH). However, there is only a few data regarding the systemic endothelium in this syndrome. This study focused on the systemic endothelial involvement in PAH. Endothelial function was evaluated in 54 patients with idiopathic (n=28), scleroderma-associated (n=10), chronic thromboembolic (n=7), or Eisenmenger (n=9) PAH and 21 controls (13 healthy; eight scleroderma and normal pulmonary pressure). All underwent clinical evaluation, pulmonary assessment, echocardiography, and pulmonary cardiac stress test. Endothelial function was evaluated by measuring the forearm blood flow dilatation response to brachial arterial occlusion by a non-invasive plethysmograph, yielding a peripheral arterial tone (PAT) ratio. The PAT ratio was significantly lower (p<0.05) than healthy controls in all patients except the Eisenmenger group (control: 2.20+/-0.25; idiopathic 1.84+/-0.51; scleroderma 1.66+/-0.66; thromboembolic 1.89+/-0.32; Eisenmenger 2.17+/-0.62). The impaired hyperemic response significantly correlated with disease severity, as measured by NYHA classification (r=-0.210, p=0.035), pulmonary pressure (r=-0.228, p=0.035), 6 min walking distance (r=0.215, p=0.047), and oxygen desaturation on effort (r=0.207, p=0.038). Mean systolic pulmonary pressure among patients was 54-99 mmHg. A systemic component of endothelial dysfunction might be involved in idiopathic, scleroderma-associated and chronic thromboembolic PAH that is correlated with disease severity.

Screening and therapy of pulmonary hypertension in systemic sclerosis

Systemic sclerosis is a major risk factor for the development of pulmonary arterial hypertension. Often this disease is far advanced by the time it is detected in the individual patient, severely impacting quality of life and survival. Therapeutic options available for patients with scleroderma-associated pulmonary arterial hypertension have increased significantly over the last few years, fueling our desire to improve early detection of disease. During the course of this manuscript I will review the literature examining approaches towards screening for scleroderma-associated pulmonary arterial hypertension. I will then discuss the most recent studies examining therapeutic options for patients with this disease.

Antibodies to fibroblasts in idiopathic and scleroderma-associated pulmonary hypertension

The aim of the present study was to investigate the presence of anti-fibroblast antibodies in patients with idiopathic or scleroderma-associated pulmonary arterial hypertension (PAH) and healthy controls. PAH was documented by right-heart catheterisation (mean pulmonary artery pressure at rest >25 mmHg). Serum immunoglobulin (Ig)G and IgM reactivities of patients with idiopathic PAH (n = 35), scleroderma-associated PAH (n = 10), diffuse (n = 10) or limited cutaneous (n = 10) scleroderma without PAH and age- and sex-matched healthy individuals (n = 65) were analysed by cell-based ELISA and immunoblotting on normal human fibroblasts. As assessed by ELISA, 14 out of 35 (40%) patients with idiopathic PAH and three out of 10 (30%) patients with scleroderma-associated PAH expressed anti-fibroblast IgG antibodies. IgG from all individuals bound to one major 40-kDa protein band. IgG from patients with idiopathic PAH bound to two 25- and 60-kDa bands with a higher intensity than IgG from other individuals. In conclusion, immunoglobulin G anti-fibroblast antibodies are present in the serum of patients with pulmonary arterial hypertension. Immunoglobulin G from patients with idiopathic pulmonary arterial hypertension or scleroderma-associated pulmonary arterial hypertension express distinct reactivity profiles with fibroblasts antigens, suggesting distinct target antigens.

N-terminal brain natriuretic peptide in scleroderma-associated pulmonary arterial hypertension

We read with great interest the report by Williams et al .1 regarding N-TproBNP levels in patients with scleroderma-associated pulmonary arterial hypertension (SSc-PAH). In studying a large cohort of scleroderma patients, the authors found that N-TproBNP levels (i) significantly correlate with cardiopulmonary haemodynamics, (ii) predict development of pulmonary hypertension in patients with scleroderma, and (iii) predict survival. These findings are quite important given the need for reliable non-invasive tools to assess …