Survival in patients with pulmonary arterial hypertension treated with first-line bosentan

Background  Pulmonary arterial hypertension (PAH) is a devastating disease of the small pulmonary arteries and arterioles, characterized by intimal fibrosis, medial hypertrophy and plexiform lesions. When untreated both the idiopathic form (IPAH, formerly termed primary pulmonary hypertension, PPH) and PAH related to various other conditions such as scleroderma (SSc) often take a progressive course with high mortality. There is ongoing search for disease-specific treatments that are able to improve survival in these patients. The oral dual endothelin (ET A /ET B ) antagonist bosentan has been shown to improve exercise capacity, time to clinical worsening, haemodynamics and quality of life in short-term studies. Materials and methods  To determine the long-term effects of bosentan on survival, patients from the two double-blind, randomized trials and their open-label extensions, treated with first-line bosentan, were followed for up to 3 years. Data on survival were collected between September 1999 (first patient included in the placebo-controlled trials) and December 2002. Vital status was verified in each patient. The survival cohorts of these patients were compared with either the predicted survival for each patient based on an equation from the National Institutes of Health (NIH) PPH registry or with historical controls. Results  Observed survival up to 36 months was reported as a Kaplan-Meier estimate in three cohorts: (1) In 169 PPH patients treated with first-line bosentan, 1- and 2-year survival was 96% and 89%, respectively, vs. predicted untreated survival at 1 and 2 years of 69% and 57%, respectively; (2) in 50 patients with PAH associated with SSc (PAH-SSc), 1-, 2- and 3-year survival was 82%, 67% and 64%, respectively, vs. ∼45%, ∼35% and ∼28%, respectively, from registry data of untreated PAH-SSc patients; and (3) in 139 PPH patients in WHO functional class III, 1- and 2-year survival was 97% and 91%, respectively, vs. 91% and 84% in a historical cohort of 346 patients treated with epoprostenol in five major referral centres. Conclusions  The present analyses suggest that first-line bosentan therapy, followed by the addition of other disease-specific therapies as required, improves survival in patients with advanced PAH. Eur J Clin Invest 2006; 36 (Suppl. 3): 10 –15Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/71978/1/j.1365-2362.2006.01688.x.pd

Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia

BACKGROUND: Most patients with familial primary pulmonary hypertension have defects in the gene for bone morphogenetic protein receptor II (BMPR2), a member of the transforming growth factor beta (TGF-beta) superfamily of receptors. Because patients with hereditary hemorrhagic telangiectasia may have lung disease that is indistinguishable from primary pulmonary hypertension, we investigated the genetic basis of lung disease in these patients. METHODS: We evaluated members of five kindreds plus one individual patient with hereditary hemorrhagic telangiectasia and identified 10 cases of pulmonary hypertension. In the two largest families, we used microsatellite markers to test for linkage to genes encoding TGF-beta-receptor proteins, including endoglin and activin-receptor-like kinase 1 (ALK1), and BMPR2. In subjects with hereditary hemorrhagic telangiectasia and pulmonary hypertension, we also scanned ALK1 and BMPR2 for mutations. RESULTS: We identified suggestive linkage of pulmonary hypertension with hereditary hemorrhagic telangiectasia on chromosome 12q13, a region that includes ALK1. We identified amino acid changes in activin-receptor-like kinase 1 that were inherited in subjects who had a disorder with clinical and histologic features indistinguishable from those of primary pulmonary hypertension. Immunohistochemical analysis in four subjects and one control showed pulmonary vascular endothelial expression of activin-receptor-like kinase 1 in normal and diseased pulmonary arteries. CONCLUSIONS: Pulmonary hypertension in association with hereditary hemorrhagic telangiectasia can involve mutations in ALK1. These mutations are associated with diverse effects, including the vascular dilatation characteristic of hereditary hemorrhagic telangiectasia and the occlusion of small pulmonary arteries that is typical of primary pulmonary hypertension

Clinical profile, outcomes and improvement in symptoms and productivity in rhinitic patients in Karachi, Pakistan

<p>Abstract</p> <p>Background</p> <p>Rhinitis can cause a heavy toll on patients because of its bothersome effects on productivity. This retrospective study was conducted to explore the clinical profile, outcomes and improvement in the symptoms and productivity resulting from treatment of allergic rhinitis in Pakistan.</p> <p>Methods</p> <p>We carried out a retrospective file review of all allergic rhinitis patients who presented to the Ear, Nose, Throat Consulting Clinic from January, 2006 to June, 2008 using a structured proforma especially designed for this purpose. Data was entered and analyzed using SPSS v. 16.0.</p> <p>Results</p> <p>The charts of 169 patients were reviewed. The mean age of the patients was 35.2 ± 9.1 years. Sixty percent patients were male. Ninety eight patients (58%) reported allergy symptoms to be present at both home and work. One hundred and two patients (60.4%) had symptoms severe enough to cause absence from work or academic activities. Up to seventy one percent patients were spending between 1000 - 3000 Pakistani Rupees (1 US$= 83.3 Pakistani rupees) on the treatment of allergic rhinitis per year. One hundred and fifty one patients (89.3%) reported an improvement in rhinitic symptoms and productivity while 18 patients (10.7%) didn't. This improvement was significantly associated with satisfaction with treatment (p < 0.001).</p> <p>Conclusion</p> <p>Allergic rhinitis, a ubiquitous disease, was seen to cause a strain on patients in the form of recurrent treatment-related expenses as well as absenteeism from work or other daily activities. Symptoms and productivity improved significantly after treatment.</p

A pilot randomised controlled trial investigating a mindfulness-based stress reduction (MBSR) intervention in individuals with pulmonary arterial hypertension (PAH): the PATHWAYS study

Background: Pulmonary arterial hypertension (PAH) is an uncommon condition with progressive heart failure and premature death. Treatment costs up to £120,000 per patient per year, and the psychological burden of PAH is substantial. Mindfulness-based stress reduction (MBSR) is an intervention with the potential to reduce this burden, but to date, it has not been applied to people with pulmonary hypertension. We wished to determine whether a trial of MBSR for people with PAH would be feasible. Methods: A customised gentle MBSR programme of eight sessions was developed for people with physical disability due to PAH, and they were randomised to group-based MBSR or treatment as usual. The completeness of outcome measures including Beck Anxiety Index, Beck Depression Inventory and standard physical assessment at 3 months after randomisation were recorded. Health care utilisation was measured. Attendance at the sessions and the costs involved in delivering the intervention were assessed. Semi-structured interviews were conducted to explore the acceptability of the MBSR intervention and when appropriate the reasons for trial non-participation. Results: Fifty-two patients were recruited, but only 34 were randomised due to patients finding it difficult to travel to sessions. Twenty-two completed all questionnaires and attended all clinics, both routine and additional in order to collect outcomes measures. The MSBR sessions were delivered in Bristol, Cardiff and London, costing, on average, between £2234 (Cardiff) and £4128 (London) per patient to deliver. Attendance at each session averaged between two patients in Bristol and Cardiff and three in London. For those receiving treatment as usual, clinician blinding was achievable. Interviews revealed that people who attended MBSR found it interesting and helpful in managing their symptoms and minimising the psychological component of their disease. Conclusions: We found that attendance at group MBSR was poor in people with chronic PAH within the context of a trial. Achieving better MBSR intervention attendance or use of an Internet-based programme might maximise the benefit of MBSR

Feasibility and efficacy of bypassing the right ventricle and pulmonary circulation to treat right ventricular failure: an experimental study

<p>Abstract</p> <p>Background</p> <p>Right ventricular failure (RVF) and -support is associated with poor results. We aimed for a new approach of right - sided assistance bypassing the right ventricle and pulmonary circulation in order to better decompress the right ventricle and optimize left ventricular filling.</p> <p>Methods</p> <p>From a microaxial pump (Abiomed), a low resistance oxygenator (Maquet and Novalung) and two cannulas (28 and 27 Fr) a system was set up and evaluated in an ovine model (n = 7). Connection with the heart was the right and left atrium. One hour the system was operated without RVF and turned of again. Then a RVF was induced and the course with the system running was evaluated. Complete hemodynamic monitoring was performed as well as echocardiography, flow measurement and blood gas analysis.</p> <p>Results</p> <p>The overall performance of the system was reliable. Without RVF no relevant changes of hemodynamics occurred; blood gases were supra normal. In RVF a cardiogenic shock developed (MAP 35 ± 13 mmHg, CO 1,1 ± 0,7 l/min). Immediately after starting the system the circulation normalized (significant increase of MAP to 85 ± 13 mmHg, of CO to 4,5 ± 1,9). Echocardiography also revealed right ventricular recovery. After stopping the system, RVF returned.</p> <p>Conclusions</p> <p>Bypassing the right ventricle and pulmonary circulation with an oxygenating assist device, which may offer the advantages of enhanced right ventricular decompression and augmented left atrial filling, is feasible and effective in the treatment of acute RVF. Long time experiments are needed.</p

Acute pressure overload of the right ventricle. Comparison of two models of right-left shunt. Pulmonary artery to left atrium and right atrium to left atrium: experimental study

<p>Abtract</p> <p>Background</p> <p>In right ventricular failure (RVF), an interatrial shunt can relieve symptoms of severe pulmonary hypertension by reducing right ventricular preload and increasing systemic flow. Using a pig model to determine if a pulmonary artery - left atrium shunt (PA-LA) is better than a right atrial - left atrial shunt (RA-LA), we compared the hemodynamic effects and blood gases between the two shunts.</p> <p>Methods</p> <p>Thirty, male Large White pigs weighting in average 21.3 kg ± 0.7 (SEM) were divided into two groups (15 pigs per group): In group 1, banding of the pulmonary artery and a pulmonary artery to left atrium shunt with an 8 mm graft (PA-LA) was performed and in group 2 banding of the pulmonary artery and right atrial to left atrial shunt (RA-LA) with a similar graft was performed. Hemodynamic parameters and blood gases were measured from all cardiac chambers in 10 and 20 minutes, half and one hour interval from the baseline (30 min from the banding). Cardiac output and flow of at the left anterior descending artery was also monitored.</p> <p>Results</p> <p>In both groups, a stable RVF was generated. The PA-LA shunt compared to the RA-LA shunt has better hemodynamic performance concerning the decreased right ventricle afterload, the 4 fold higher mean pressure of the shunt, the better flow in left anterior descending artery and the decreased systemic vascular resistance. Favorable to the PA-LA shunt is also the tendency - although not statistically significant - in relation to central venous pressure, left atrial filling and cardiac output.</p> <p>Conclusion</p> <p>The PA-LA shunt can effectively reverse the catastrophic effects of acute RVF offering better hemodynamic characteristics than an interatrial shunt.</p

Novel computed tomographic chest metrics to detect pulmonary hypertension

<p>Abstract</p> <p>Background</p> <p>Early diagnosis of pulmonary hypertension (PH) can potentially improve survival and quality of life. Detecting PH using echocardiography is often insensitive in subjects with lung fibrosis or hyperinflation. Right heart catheterization (RHC) for the diagnosis of PH adds risk and expense due to its invasive nature. Pre-defined measurements utilizing computed tomography (CT) of the chest may be an alternative non-invasive method of detecting PH.</p> <p>Methods</p> <p>This study retrospectively reviewed 101 acutely hospitalized inpatients with heterogeneous diagnoses, who consecutively underwent CT chest and RHC during the same admission. Two separate teams, each consisting of a radiologist and pulmonologist, blinded to clinical and RHC data, individually reviewed the chest CT's.</p> <p>Results</p> <p>Multiple regression analyses controlling for age, sex, ascending aortic diameter, body surface area, thoracic diameter and pulmonary wedge pressure showed that a main pulmonary artery (PA) diameter ≥29 mm (odds ratio (OR) = 4.8), right descending PA diameter ≥19 mm (OR = 7.0), true right descending PA diameter ≥ 16 mm (OR = 4.1), true left descending PA diameter ≥ 21 mm (OR = 15.5), right ventricular (RV) free wall ≥ 6 mm (OR = 30.5), RV wall/left ventricular (LV) wall ratio ≥0.32 (OR = 8.8), RV/LV lumen ratio ≥1.28 (OR = 28.8), main PA/ascending aorta ratio ≥0.84 (OR = 6.0) and main PA/descending aorta ratio ≥ 1.29 (OR = 5.7) were significant predictors of PH in this population of hospitalized patients.</p> <p>Conclusion</p> <p>This combination of easily measured CT-based metrics may, upon confirmatory studies, aid in the non-invasive detection of PH and hence in the determination of RHC candidacy in acutely hospitalized patients.</p

Membrane diffusion- and capillary blood volume measurements are not useful as screening tools for pulmonary arterial hypertension in systemic sclerosis: a case control study

<p>Abstract</p> <p>Background</p> <p>There is no optimal screening tool for the assessment of pulmonary arterial hypertension (PAH) in patients with systemic sclerosis (SSc). A decreasing transfer factor of the lung for CO (TLCO) is associated with the development of PAH in SSc. TLCO can be partitioned into the diffusion of the alveolar capillary membrane (Dm) and the capillary blood volume (Vc). The use of the partitioned diffusion to detect PAH in SSc is not well established yet. This study evaluates whether Dm and Vc could be candidates for further study of the use for screening for PAH in SSc.</p> <p>Methods</p> <p>Eleven SSc patients with PAH (SScPAH+), 13 SSc patients without PAH (SScPAH-) and 10 healthy control subjects were included. Pulmonary function testing took place at diagnosis of PAH. TLCO was partitioned according to Roughton and Forster. As pulmonary fibrosis in SSc influences values of the (partitioned) TLCO, these were adjusted for fibrosis score as assessed on HRCT.</p> <p>Results</p> <p>TLCO as percentage of predicted (%) was lower in SScPAH+ than in SScPAH- (41 ± 7% <it>vs</it>. 63 ± 12%, p < 0.0001, respectively). Dm% in SScPAH+ was decreased as compared with SScPAH- (22 ± 6% <it>vs</it>. 39 ± 12%, p < 0.0001, respectively), also after adjustment for total fibrosis score (before adjustment: B = 17.5, 95% CI 9.0–25.9, p = < 0.0001; after adjustment: B = 14.3, 95% CI 6.0–21.7, p = 0.008). No difference was found in Vc%. There were no correlations between pulmonary hemodynamic parameters and Dm% in the PAH groups.</p> <p>Conclusion</p> <p>SScPAH+ patients have lower Dm% than SScPAH- patients. There are no correlations between Dm% and hemodynamic parameters of PAH in SScPAH+. These findings do not support further study of the role of partitioning TLCO in the diagnostic work- up for PAH in SSc.</p

Elevated plasma CXCL12 alpha is associated with a poorer prognosis in pulmonary arterial hypertension.

Recent work in preclinical models suggests that signalling via the pro-angiogenic and proinflammatory cytokine, CXCL12 (SDF-1), plays an important pathogenic role in pulmonary hypertension (PH). The objective of this study was to establish whether circulating concentrations of CXCL12α were elevated in patients with PAH and related to mortalit

Lung vasodilatory response to inhaled iloprost in experimental pulmonary hypertension: amplification by different type phosphodiesterase inhibitors

Inhaled prostanoids and phosphodiesterase (PDE) inhibitors have been suggested for treatment of severe pulmonary hypertension. In catheterized rabbits with acute pulmonary hypertension induced by continuous infusion of the stable thromboxane analogue U46619, we asked whether sildenafil (PDE1/5/6 inhibitor), motapizone (PDE3 inhibitor) or 8-Methoxymethyl-IBMX (PDE1 inhibitor) synergize with inhaled iloprost. Inhalation of iloprost caused a transient pulmonary artery pressure decline, levelling off within <20 min, without significant changes in blood gases or systemic hemodynamics. Infusion of 8-Methoxymethyl-IBMX, motapizone and sildenafil caused each a dose-dependent decrease in pulmonary artery pressure, with sildenafil possessing the highest efficacy and at the same time selectivity for the pulmonary circulation. When combining a per se ineffective dose of each PDE inhibitor (200 μg/kg × min 8-Methoxymethyl-IBMX, 1 μg/kg × min sildenafil, 5 μg/kg × min motapizone) with subsequent iloprost nebulization, marked amplification of the prostanoid induced pulmonary vasodilatory response was noted and the area under the curve of P(PA )reduction was nearly threefold increased with all approaches, as compared to sole iloprost administration. Further amplification was achieved with the combination of inhaled iloprost with sildenafil plus motapizone, but not with sildenafil plus 8MM-IBMX. Systemic hemodynamics and gas exchange were not altered for all combinations. We conclude that co-administration of minute systemic doses of selective PDE inhibitors with inhaled iloprost markedly enhances and prolongs the pulmonary vasodilatory response to inhaled iloprost, with maintenance of pulmonary selectivity and ventilation perfusion matching. The prominent effect of sildenafil may be operative via both PDE1 and PDE5, and is further enhanced by co-application of a PDE3 inhibitor