Advanced Pulmonary Arterial Hypertension Research Articles

One-year experience with intravenous treprostinil for pulmonary arterial hypertension

Intravenous (IV) epoprostenol has been the mainstay of therapy in advanced pulmonary arterial hypertension (PAH). Continuous IV treprostinil has several potential advantages over IV epoprostenol; however, there has been a lack of published long-term efficacy and safety data on IV treprostinil in PAH. We conducted a 48-week, multicenter, prospective, open-label, uncontrolled, study of continuous IV treprostinil in 16 patients on no prior PAH specific therapy at baseline (de novo), or 31 patients transitioned at baseline from IV epoprostenol (transition). The primary end point was change in exercise capacity assessed by the 6-minute walk distance (6MWD) test. In de novo patients, IV treprostinil increased the mean ± standard error 6MWD by 125 m from 332 ± 21 m at baseline to 457 ± 26 m at Week 48. There were also improvements in the secondary end points of Naughton-Balke treadmill time, Borg Dyspnea Score, and hemodynamics at Week 48 compared with baseline. In 23 patients transitioned from IV epoprostenol with 48-week follow-up data, 6MWD, hemodynamic measures, and World Health Organization functional class at Week 48 were all stable compared with baseline. Side effects were generally mild and consistent with those reported with prostacyclin treatment. During the study, 5 patients died of causes not considered related to the therapy, and 7 discontinued due to adverse events. In this open-label trial, continuous IV treprostinil for 1 year appears to be safe and effective in de novo PAH patients and those transitioned from IV epoprostenol.

Potential Application of the CircuLite® Synergy® Circulatory Support System in the Treatment of Pulmonary Arterial Hypertension

Purpose The high mortality rate of pulmonary arterial hypertension (PAH) mainly relates to progressive right ventricular (RV) failure. With limited efficacy of medical therapies, mechanical circulatory support for the RV has been considered. However, there is lack of understanding of the hemodynamic effects of mechanical support in this setting. Methods and Materials We modeled the cardiovascular system, simulated cases of PAH and RV dysfunction and assessed the theoretical effects of the CircuLite ® Synergy ® continuous flow micro-pump as an Right Heart assist device with flow rates between 2-4.25L/minute. Inflow was sourced either from the RV or RA and outflow was to the pulmonary artery. Synergy support was set at various flow rates and additional simulations were carried out in the presence of atrial septostomy (ASD) and tricuspid regurgitation (TR). Results In the simulation, Synergy support increased LV filling, thus improving cardiac output and arterial pressure, unloading the RA and RV, while raising pulmonary arterial and capillary pressures in an flow-dependent manner. These effects diminished with increasing disease severity. The presence of TR did not significantly impact the hemodynamic effects of Synergy support. ASD reduced the efficacy of Synergy support, since right-to-left shunting decreased and ultimately reversed with increasing Synergy support due to the progressive drop in RA pressure. Conclusions The results of this theoretical analysis suggest that Synergy support can effectively increase cardiac output and decreases RA pressure with the consequence of increasing pulmonary artery and capillary pressures. Especially in advanced PAH, low Synergy flow rates may mitigate these potentially detrimental effects while effectively increasing systemic hemodynamics. Six chronic (60-day) animals studies are scheduled to evaluate the performance of the Synergy device with the inflow cannula implanted in the RA and outflow to the pulmonary artery.

Imatinib Mesylate as Add-on Therapy for Pulmonary Arterial Hypertension

Background— By its inhibitory effect on platelet-derived growth factor signaling, imatinib could be efficacious in treating patients with pulmonary arterial hypertension (PAH). Methods and Results— Imatinib in Pulmonary Arterial Hypertension, a Randomized, Efficacy Study (IMPRES), a randomized, double-blind, placebo-controlled 24-week trial, evaluated imatinib in patients with pulmonary vascular resistance ≥800 dyne·s·cm −5 symptomatic on ≥2 PAH therapies. The primary outcome was change in 6-minute walk distance. Secondary outcomes included changes in hemodynamics, functional class, serum levels of N-terminal brain natriuretic peptide, and time to clinical worsening. After completion of the core study, patients could enter an open-label long-term extension study. Of 202 patients enrolled, 41% patients received 3 PAH therapies, with the remainder on 2 therapies. After 24 weeks, the mean placebo-corrected treatment effect on 6-minute walk distance was 32 m (95% confidence interval, 12–52; P =0.002), an effect maintained in the extension study in patients remaining on imatinib. Pulmonary vascular resistance decreased by 379 dyne·s·cm −5 (95% confidence interval, −502 to − 255; P <0.001, between-group difference). Functional class, time to clinical worsening, and mortality did not differ between treatments. Serious adverse events and discontinuations were more frequent with imatinib than placebo (44% versus 30% and 33% versus 18%, respectively). Subdural hematoma occurred in 8 patients (2 in the core study, 6 in the extension) receiving imatinib and anticoagulation. Conclusions— Imatinib improved exercise capacity and hemodynamics in patients with advanced PAH, but serious adverse events and study drug discontinuations were common. Further studies are needed to investigate the long-term safety and efficacy of imatinib in patients with PAH. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00902174 (core study); NCT01392495 (extension).

Transfection of Human Hepatocyte Growth Factor Gene Inhibits Advancing Pulmonary Arterial Hypertension Induced by Shunt Flow in a Rabbit Model

We investigated gene transfer with human hepatocyte growth factor (HGF) to suppress pulmonary arterial hypertension (PAH) produced by an arteriovenous shunt in a rabbit model. The rabbit model of advanced PAH was used to show that HGF targets pulmonary arteriolar endothelial cells and inhibits disease progression. In the PAH rabbit model transfected with the HGF gene, hemodynamic abnormalities and right ventricular hypertrophy were prevented, as confirmed by invasive measurements and electrocardiographic examinations. In addition to augmented expression of HGF, an increased number of pulmonary arterioles were detected by immunohistochemical analysis. Western Blot and real-time reverse transcriptase-polymerase chain reaction indicated increased protein and mRNA levels of HGF and endothelial nitricoxide synthase (eNOS) in lungs after HGF transfection. Notably, exogenous HGF reduced lung expression of endothelin-1 (ET-1), which was critically involved in PAH-related pathologic changes. Our results suggested that HGF transfection suppresses PAH induced by shunt flow through enhanced expression of HGF with subsequent regulation of the concentrations of eNOS and ET-1 secreted by endothelial cells thereby promoting angiogenesis in injured lung tissue.

Oral Prostacyclin Therapy for Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is characterized by vascular remodeling and cellular proliferation that leads to narrowing and obstruction of small pulmonary arteries. The arteriopathy is clinically manifest as increased pulmonary vascular resistance and elevation of pulmonary arterial pressures. PAH is considered a progressive vasculopathy that ultimately leads to right heart failure and death. Although there is no cure for PAH, current pharmacological therapies have improved morbidity, and in some cases, mortality. The current 3-year survival for patients with PAH managed with state-of-the-art multiple drug therapy remains troubling at ≈58%.1 This is slightly better than in the 1980s, when there were no approved treatments. Article see p 624 In PAH endothelial dysfunction and platelet activation causes an imbalance of arachidonic acid metabolites with reduced prostacyclin levels and increased thromboxane A2 production. Prostacyclin has both vasodilatory and antiproliferative affects on vascular smooth muscle and inhibits platelet aggregation. Prostacyclin synthase levels are decreased in pulmonary arteries of patients with PAH.2 An imbalance between these two arachidonic acid metabolites favoring thromboxane A2 plays an important role in the pathogenesis of PAH.3 This imbalance is addressed by the exogenous administration of prostanoids as therapy in advanced PAH. Epoprostenol was the first prostacyclin used in the treatment of PAH. Intravenous epoprostenol improves hemodynamics, functional capacity, and survival.4–7 The second-generation prostanoid, Treprostinil, which has a considerably longer half-life (4.5 hours versus 4–6 minutes for epoprostenol),8 can be administered subcutaneously, intravenously, or by inhalation, and also improves pulmonary hemodynamics, symptoms, exercise capacity, and survival in PAH.9–11 Prostacyclin remains a mainstay of PAH therapy and is the only therapy with a proven survival …

Intravenous epoprostenol treatment of patients with connective tissue disease and pulmonary arterial hypertension at a single center

To assess the efficacy of epoprostenol treatment in Japanese patients with pulmonary arterial hypertension (PAH) associated with connective tissue disease (CTD). Sixteen patients with PAH-CTD treated with continuous intravenous epoprostenol at a single center between 2000 and 2009 were enrolled. Baseline characteristics, short-term and long-term outcomes, predictors of mortality, and safety profiles were evaluated. For survival analysis, 16 controls were selected who matched the underlying CTD, World Health Organization functional class, and use of PAH drugs, except for epoprostenol. Six patients had systemic lupus erythematosus, five had mixed CTD, four had systemic sclerosis, and one had primary Sjögren's syndrome. The mean pulmonary arterial pressure (mPAP), cardiac index (CI), pulmonary vascular resistance, and functional class were significantly improved during the first 6 months of epoprostenol treatment. Cumulative survival rates at 1, 2, and 3 years in epoprostenol-treated patients were 69, 69, and 55%, respectively, and were significantly better than those of the controls. Functional class, CI at baseline, and reduction of mPAP at 6 months were identified as predictors of survival. Adverse events, including flushing and catheter-related infection, were frequent, but all patients tolerated the treatment. Based on the improvements in both short-term and long-term outcomes among our patient cohort, epoprostenol is an effective treatment for CTD patients with advanced PAH.

Influence of sildenafil and tadalafil on the enzyme- and transporter-inducing effects of bosentan and ambrisentan in LS180 cells

The combinations of the endothelin-1 receptor antagonists bosentan or ambrisentan with the phosphodiesterase 5 inhibitors sildenafil or tadalafil are current standard therapies of advanced pulmonary arterial hypertension. However, these drugs have a number of drug interactions. Changes of bosentan pharmacokinetics by sildenafil are attributed to reduced hepatic uptake as a consequence of inhibition of organic anion transporting polypeptides. We therefore tested in vitro the hypothesis that sildenafil and tadalafil reduce the enzyme- and transporter-inducing effects of bosentan or ambrisentan by preventing cellular access. Although intracellular concentrations of bosentan and ambrisentan (measured by high pressure liquid chromatography coupled with tandem mass-spectrometry) after four days of incubation of LS180 cells were lower when sildenafil or tadalafil were present, quantification of mRNA expression in these cells by real-time reverse transcription polymerase chain reaction revealed that bosentan and ambrisentan-mediated induction was stable or even increased in combination with sildenafil or tadalafil. For the drug transporter P-glycoprotein this was confirmed at the protein and functional level with highly significant correlations between P-gp mRNA, protein, and function. Moreover, using a reporter gene assay in LS180 cells, our study demonstrates for the first time that tadalafil is a potent, ambrisentan a weak, and sildenafil no activator of pregnane X receptor. In conclusion, our study demonstrates that although sildenafil and tadalafil indeed reduce intracellular concentrations of bosentan and ambrisentan in LS180 cells, they do not mitigate the inducing effects of these endothelin-1 receptor antagonists.

Right ventricular assist device in end-stage pulmonary arterial hypertension: insights from a computational model of the cardiovascular system

BackgroundThe high mortality rate of pulmonary arterial hypertension (PAH) mainly relates to progressive right ventricular (RV) failure. With limited efficacy of medical therapies, mechanical circulatory support for the RV has been considered. However, there is lack of understanding of the hemodynamic effects of mechanical support in this setting. MethodsWe modeled the cardiovascular system, simulated cases of PAH and RV dysfunction and assessed the theoretical effects of a continuous flow micro-pump as an RV assist device (RVAD). RVAD inflow was sourced either from the RV or RA and outflow was to the pulmonary artery. RVAD support was set at various flow rates and additional simulations were carried out in the presence of atrial septostomy (ASD) and tricuspid regurgitation (TR). ResultsRVAD support increased LV filling, thus improving cardiac output and arterial pressure, unloading the RA and RV, while raising pulmonary arterial and capillary pressures in an RVAD flow-dependent manner. These effects diminished with increasing disease severity. The presence of TR did not significantly impact the hemodynamic effects of RVAD support. ASD reduced the efficacy of RVAD support, since right-to-left shunting decreased and ultimately reversed with increasing RVAD support due to the progressive drop in RA pressure. ConclusionsThe results of this theoretical analysis suggest that RVAD support can effectively increase cardiac output and decreases RA pressure with the consequence of increasing pulmonary artery and capillary pressures. Especially in advanced PAH, low RVAD flow rates may mitigate these potentially detrimental effects while effectively increasing systemic hemodynamics.

Eisenmenger Syndrome: Not Always Inoperable

Recently, advanced therapies for pulmonary arterial hypertension have become available, and have been effective in reducing pulmonary vascular resistance and symptoms in patients with Eisenmenger syndrome, previously thought to be inoperable. This review summarizes the current knowledge on the pathophysiology and treatment of Eisenmenger syndrome. The recent introduction of targeted therapies in pulmonary arterial hypertension has led to a renewed insight in the pathophysiology and treatment of Eisenmenger syndrome. Patients with Eisenmenger syndrome using a diagnostic-treatment-and-repair strategy are amenable to surgery after successful treatment with advanced therapy. With continued improvements in the diagnosis, preoperative management, refinement of surgical techniques and intra- and postoperative management strategies, the patients with Eisenmenger syndrome selected using a diagnostic-treatment-and-repair strategy are operable with safety and efficacy in the current era with advanced pulmonary arterial hypertension therapy. Future directions of Eisenmenger syndrome may be the combination of reversal of pulmonary vascular remodeling and correction.

Persistence of complex vascular lesions despite prolonged prostacyclin therapy of pulmonary arterial hypertension

Continuous infusion of prostacyclin analogues improves survival in advanced pulmonary arterial hypertension. In addition to its vasodilatory effects, prostacyclin has the potential to decrease inflammation, thrombosis, and smooth muscle proliferation. The aim of this retrospective study was to determine whether pathological data support the ability of prostanoids to prevent progression of vascular disease. Twenty-two autopsied patients with World Health Organization category 1 pulmonary arterial hypertension (primarily idiopathic and connective tissue disease-associated) were divided into those who received long-term prostacyclin (n = 12, PG-long, mean treatment 3.9 years) and those who received 0-1 month of prostacyclin (n = 10, PG-short). Surprisingly, PG-long patients had larger plexiform lesions (P < 0.05), with no decrease in medial and intimal thicknesses as compared with PG-short patients. Plexiform lesion size and density increased with increasing treatment time. Also, PG-long patients had fewer platelet thrombi and more frequent acute diffuse alveolar haemorrhage. Quantification of macrophages and T cells revealed no differences in inflammatory infiltrates. Although long-term prostacyclin therapy may have an antithrombotic effect in addition to its vasodilatory actions, it was not associated with the prevention of advanced vascular lesions. The mechanism by which prostacyclin analogues improve survival in pulmonary arterial hypertension remains uncertain.

Prevalence and Significance of Decreased Bone Density in Pulmonary Arterial Hypertension

Decreased bone mineral density has been found in the advanced stages of various lung diseases. Limited data are available about prevalence and risk factors for osteoporosis/osteopenia (OP) in pulmonary arterial hypertension (PAH). Patients with PAH (either idiopathic or secondary to scleroderma [SSC-PAH]) who underwent bone density testing for lung transplant evaluation were included. Results of bone density testing, demographic data, pulmonary function testing, hemodynamic measures, and 6-minute walk distance test (6MWD) were collected. Thirty-two patients were identified (27 women/5 men, 24 idiopathic PAH/8 SSC-PAH) and OP was found in 22 (69%) patients. Patients with SSC-PAH had more significant indications of OP at all of the measured sites. The OP group had lower FEV1 (P = 0.01) and a significantly lower 6MWD (P = 0.04) as compared with patients with PAH with normal bone density. Hemodynamics indicated no statistically significant differences between the groups other than a lower mean pulmonary artery pressure (P = 0.01) in the OP group. Patients with a history of corticosteroid use and smoking, postmenopausal status, decreased functional capacity (as measured by poor New York Heart Association functional class and 6MWD), SSC-PAH, and need for oxygen during a 6MWD test had an increased risk of OP by univariate logistic regression. Reduced bone density can be seen in a majority of patients with advanced PAH. Risk factors for reduced bone density include SSC-PAH, reduced 6MWD, need for oxygen during 6MWD testing, reduced FEV1, a history of smoking or corticosteroid use, and postmenopausal status.

Signal‐morphology impedance cardiography during incremental cardiopulmonary exercise testing in pulmonary arterial hypertension

Haemodynamic responses to exercise are related to physical impairment and worse prognosis in patients with pulmonary arterial hypertension (PAH). It is clinically relevant, therefore, to investigate the practical usefulness of non-invasive methods of monitoring exercise haemodynamics in this patient population. Using a novel impedance cardiography (ICG) approach that does not require basal impedance estimations and relies on a morphological analysis of the impedance signal (Signal-Morphology-ICG(™)), stroke volume (SV) and cardiac index (CI) were evaluated in 50 patients and 21 age-matched controls during a ramp-incremental cardiopulmonary exercise testing. Technically unacceptable readings were found in 12 of 50 (24%) patients. In the remaining subjects, early decrease (N = 9) or a 'plateau' in SV (N = 8) and Δ (peak-unloaded exercise) SV <10 ml were markers of more advanced PAH (P<0.05). ΔCI ≤ 1.5-fold and early estimated lactate threshold were the only independent predictors of a severely reduced peak oxygen uptake (VO(2)) in patients (R(2) = 0.71, P<0.001). The finding of ΔCI ≤ 1.5-fold plus peak VO(2) < 50% predicted was associated with a number of clinical and functional markers of disease severity (P<0.001). In addition, abnormal SV responses and ΔCI ≤ 1.5-fold were significantly related to 1-year frequency of PAH-related adverse events (death and balloon atrial septostomy, N = 8; P<0.05). 'Qualitative' and 'semi-quantitative' signal-morphology impedance cardiography(™) (PhysioFlow(™)) during incremental exercise provided clinically useful information to estimate disease severity and short-term prognosis in patients with PAH in whom acceptable impedance signals could be obtained.

Predictors of mortality in connective tissue disease-associated pulmonary arterial hypertension: a cohort study

IntroductionPulmonary arterial hypertension (PAH) is a major cause of mortality in connective tissue disease (CTD). We sought to quantify survival and determine factors predictive of mortality in a cohort of patients with CTD-associated PAH (CTD-PAH) in the current era of advanced PAH therapy.MethodsPatients with right heart catheter proven CTD-PAH were recruited from six specialised PAH treatment centres across Australia and followed prospectively. Using survival methods including Cox proportional hazards regression, we modelled for all-cause mortality. Independent variables included demographic, clinical and hemodynamic data.ResultsAmong 117 patients (104 (94.9%) with systemic sclerosis), during 2.6 ± 1.8 (mean ± SD) years of follow-up from PAH diagnosis, there were 32 (27.4%) deaths. One-, two- and three-year survivals were 94%, 89% and 73%, respectively. In multiple regression analysis, higher mean right atrial pressure (mRAP) at diagnosis (hazard ratio (HR) = 1.13, 95% CI: 1.04 to 1.24, P = 0.007), lower baseline six-minute walk distance (HR = 0.64, 95% CI: 0.43 to 0.97, P = 0.04), higher baseline World Health Organization functional class (HR = 3.42, 95% CI: 1.25 to 9.36, P = 0.04) and presence of a pericardial effusion (HR = 3.39, 95% CI: 1.07 to 10.68, P = 0.04) were predictive of mortality. Warfarin (HR = 0.20, 95% CI: 0.05 to 0.78, P = 0.02) and combination PAH therapy (HR = 0.20, 95% CI: 0.05 to 0.83, P = 0.03) were protective.ConclusionsIn this cohort of CTD-PAH patients, three-year survival was 73%. Independent therapeutic predictors of survival included warfarin and combination PAH therapy. Our findings suggest that anticoagulation and combination PAH therapy may improve survival in CTD-PAH. This observation merits further evaluation in randomised controlled trials.

Pulmonary arterial hypertension and lung transplantation

Transplantation remains the only therapeutic option for selected patients with advanced pulmonary arterial hypertension (PAH) who continue to deteriorate despite optimal pulmonary vasodilator therapy – including intravenous prostanoids and combination therapy. Identification of poor prognostic markers in PAH, including persistence in the New York Heart Association functional class III and IV, and adverse pulmonary hemodynamics at right heart catheterization should prompt early referral for transplantation. There is a need for inclusion of more discriminatory markers of PAH prognosis in donor-lung allocation scores to identify patients at risk and optimize survival to transplantation, given the current shortage of donor organ availability worldwide. Double-lung transplantation is the recommended operation for idiopathic PAH. Heart–lung transplantation is reserved for selected patients with idiopathic PAH with severe right ventricular dysfunction, or congenital heart disease with complex or ventricular septal defect-associated PAH. Novel surgical strategies, including atrial septostomy or the pumpless Novalung® lung assist device with conduits, from the pulmonary artery to the left atrium, can be considered as a bridge to transplant for patients with rapid clinical decline, despite maximal medical therapy. Recent transplant outcomes for PAH are encouraging, albeit with early postoperative risks, a requirement for long-term surveillance, immunosuppression and transplant immunosuppression-specific morbidity.

Cell-based therapies in pulmonary hypertension: who, what, and when?

pulmonary hypertension (PH), diagnosed when mean pulmonary arterial pressure exceeds the upper limits of normal (i.e., >25 mmHg) at rest (2), occurs in a variety of clinical situations and is associated with a broad spectrum of histological patterns and abnormalities. PH is currently classified into five distinct World Health Organization (WHO) groups, based on common clinical parameters, potential etiological mechanisms, and responses to treatment (22). Although any form of PH can contribute to increased patient morbidity and mortality, pulmonary arterial hypertension (PAH) (WHO group 1) is a particularly severe and progressive form associated with right heart failure and premature death (1). At present, therapeutic approaches to stabilize or reverse this debilitating condition involve treatment with one or a combination of up to three specific classes of agents, including prostacyclin analogs, endothelin-1 receptor antagonists, and/or phosphodiesterase-5 inhibitors. Retrospective (meta)analyses of these therapeutic strategies have demonstrated a reduction in mortality with their use (7, 12); however, many experts believe that current PAH treatment is inadequate given the persistently high mortality rate and functional hemodynamic impairment in many patients. These observations have led to continued intensive investigation into pathogenetic mechanisms and many proposals for additional alternative new therapies (20, 24). Among the potential new therapies, increasing interest in the role of endothelial progenitor cells (EPCs) as a cell-based therapy has emerged. However, issues remain regarding what group of PH patients are most likely to benefit from treatment, at what point in the disease is treatment most likely to be successful, and what types of cells should be utilized for therapy.

Rationale and design of a trial on the role of bosentan in Fontan patients: Improvement of exercise capacity?

Background The Fontan circulation is a palliative procedure performed in patients with complex congenital heart disease (CHD), making transpulmonary blood flow dependent on the systemic venous pressure. In a Fontan circulation a low pulmonary vascular resistance (PVR) is crucial, as is epitomized by the observation that a high PVR is a strong predictor of mortality. Long-term follow-up has shown that PVR may rise many years after the Fontan procedure has been performed, possibly due to micro-emboli from a dilated right atrium or from the venous system. Other mechanisms of increased PVR might be aging, obstructed airways caused by lymphatic dysfunction, lack of pulsatile pulmonary flow causing a release of endothelium-derived vasoactive molecules, and prolonged overexpression of vasoconstrictors such as endothelin-1. Mean plasma level of endothelin-1 has been shown to be significantly higher in Fontan patients compared to healthy controls. In patients with pulmonary arterial hypertension (PAH), therapy with bosentan, an endothelin-1 receptor antagonist, has demonstrated to improve exercise capacity and to reduce the elevated PVR. In addition, reduction of PVR is shown early and late after the Fontan procedure on treatment with exogenous NO, another advanced PAH therapy. However, the long term effect of reducing the PVR by bosentan treatment on exercise capacity in Fontan patients is still unknown. Methods We designed a prospective, multicenter, randomized open label trial to study the effect of bosentan in Fontan patients. The primary endpoint will be the change in maximum exercise capacity (peak V'O2). Conclusion We hypothesize that treatment with bosentan, an endothelin-1 receptor antagonist, improves maximum exercise capacity and functional capacity in adult Fontan patients.

Unrecognized glucose intolerance is common in pulmonary arterial hypertension

Animal and human data suggest insulin resistance is common in pulmonary arterial hypertension (PAH). Although routine assessment of insulin resistance is difficult, hemoglobin A(1c) (HbA(1c)) is a sensitive test to detect diabetes mellitus (DM) and those at high risk for DM. We aimed to define the prevalence of elevated HbA(1c) in PAH patients and to correlate HbA(1c) levels with functional assessment. HbA(1c) was measured in 41 PAH patients without a diagnosis of DM, along with demographic, functional, and hemodynamic data. Using published criteria, HbA(1c) ≤ 5.9% defined normal, 6.0% to 6.4% was glucose intolerance, and ≥ 6.5% was DM. Twenty-three patients (56%) had HbA(1c) ≥ 6.0%, and 6 (15%) had unrecognized DM (HbA(1c) ≥ 6.5%). Age and body mass index were similar in patients with HbA(1c) ≥ 6.0% vs < 6.0%. There was a trend towards lower mean 6-minute walk distance in patients with elevated HbA(1c) (331.0 ± 126.6 vs 413.6 ± 74.9 meters, p = 0.07). The 6-month event-free survival was not significantly different in patients with elevated HbA(1c). Unrecognized glucose intolerance as assessed by HbA(1c) is common in PAH. Further studies are needed to discern if glucose or insulin dysregulation mediates PAH pathogenesis or is secondary to advanced PAH.

Transition from Intravenous Epoprostenol to Oral or Subcutaneous Therapy in Pulmonary Arterial Hypertension: A Retrospective Case Series and Systematic Literature Review

Intravenous epoprostenol, a prostaglandin analogue, has been a mainstay of therapy for patients with advanced pulmonary arterial hypertension (PAH) since the early 1990s. This medication has multiple side effects, and sudden discontinuation is potentially associated with severe sequelae. Several recent case series have described the transition from intravenous to newer oral or subcutaneous therapies. A case series detailing the authors' experience with such transitions, and a systematic lierature review is presented. All consecutive PAH patients seen at the Vancouver Pulmonary Hypertension Clinic (Vancouver, British Columbia) between June 1995 and July 2009 were reviewed for cases in which weaning or transition from intravenous epoprostenol was attempted. The Cochrane Collaboration, Cochrane Register of Controlled Trials, Journals@Ovid, MEDLINE, EMBASE and Papers First were searched using predefined key words for publications describing transition of PAH patients from parenteral prostanoids to oral or subcutaneous agents. Of the six patients who attempted, all transitioned successfully to oral or subcutaneous agents, having been on intravenous epoprostenol for a mean of 3.8 years (range 1.8 to 9.75 years). Five are living, surviving a mean of 5.5 years after transition. The literature search yielded nine studies and, of 127 patients described, 82 transitioned successfully. The length of pretransition prostanoid treatment (range 1.7 to 7.6 years) and the posttransition follow-up period (range two months to 70 months) were shorter than for patients described in the present study. Given the rarity of PAH, the absolute numbers of patients transitioned from intravenous epoprostenol are still low. With the advent of new therapies, these numbers will hopefully increase; continued study is necessary to identify factors that are predictive of success.

Bosentan and improved pulmonary endothelial function in pulmonary arterial hypertension: Figure 1–

To the Editors: Pulmonary arterial hypertension (PAH) is characterised by pulmonary endothelial dysfunction and smooth muscle cell proliferation 1. Miniaturised catheter-based technology has recently enabled in vivo assessment of both endothelial dysfunction and pulmonary artery thickening in vivo 2, 3. Bosentan, an oral dual endothelin-1 receptor antagonist, has been shown to improve clinical outcomes in PAH 4. In vitro , bosentan has been shown to improve human endothelial cell function 5 and reduce neointimal and smooth muscle proliferation. In pigs in vivo , bosentan has been shown to partially restore hypoxia-induced reductions in nitric oxide 6. The effect of bosentan on human pulmonary artery structure and function in vivo , however, has not been studied. We hypothesised that bosentan therapy might improve pulmonary microvascular endothelial function and pulmonary artery remodelling in patients with established PAH. Therefore, we assessed the effect of 6 months of clinically indicated bosentan therapy in patients with advanced PAH on: 1) pulmonary microvascular function, assessed by Doppler-derived pulmonary blood flow responses to vasoactive agents; and 2) segmental pulmonary artery structure, measured by pulmonary intravascular ultrasound (IVUS). Eight bosentan-naive subjects (three males and five females; five subjects with idiopathic and three with scleroderma-related PAH; mean±sem age 66±4 yrs; weight 79±5 kg) were studied. The institutional review board (Royal Prince Alfred Hospital, Sydney, NSW, Australia) approved the study protocol and informed consent was obtained from all subjects. All patients were in New York Heart Association (NYHA) functional class III, had mean pulmonary arterial pressure ( P pa) >25 mmHg at rest (without demonstrable reversibility) and had pulmonary capillary wedge pressure ≤15 mmHg. Clinically indicated right heart catheterisation, assessing suitability for bosentan prescription, was performed. Thereafter, pulmonary artery IVUS assessment was performed in a distal segmental pulmonary artery of both upper and lower lobes …

S151 TRAIL deficiency is protective in experimental pulmonary arterial hypertension

Introduction and objectivesDespite advances in the overall management of Pulmonary Arterial Hypertension (PAH) significant morbidity and poor prognosis remain a major clinical problem. Identifying key pathways in the pathogenesis of...