Treatment Of Pulmonary Arterial Hypertension Patients Research Articles

Abstract 17370: Activation of Endothelial GCN2 Kinase Contributes to Pulmonary Vascular Remodeling and Pulmonary Arterial Hypertension

Rationale: Pulmonary arterial hypertension (PAH) is characterized by progressive increase of pulmonary vascular resistance and pulmonary vascular remodeling that result in right heart failure. Published studies show that recessive mutations in the EIF2AK4 gene (encoding GCN2, General control nonderepressibe 2 kinase) resulting in reduction of GCN2 are linked to heritable pulmonary veno-occlusive disease (PVOD) in patients and EIF2AK4 mutation was also found in PAH patients although very rare. Objective: To determine the role of endothelial GCN2 kinase in the pathogenesis of PAH. Results: Employing Eif2ak4 -/- mice, we found that loss of GCN2 induced neither spontaneous PVOD nor pulmonary hypertension (PH). In response to chronic hypoxia, loss of GCN2 inhibited hypoxia-induced PH and pulmonary vascular remodeling. RNA-sequencing analysis of mouse lung samples indicated Endothelin-1 as the downstream target of GCN2 in regulating pulmonary vascular remodeling and PH. In cultured human lung microvascular endothelial cells, GCN2 was phosphorylated and activated in response to hypoxia, which mediated hypoxia-induced Endothelin-1 expression through the GCN2/ATF4/HIF-2a/Endothelin-1 pathway. Endothelial cell-targeted nanoparticle delivery of plasmid DNA expressing Endothelin-1 selectively in endothelial cells in Eif2ak4 -/- mice markedly reversed the phenotype in response to hypoxia. Furthermore, nanoparticle delivery of the CRIPSR/Cas9 system-mediated knockout of Eif2ak4 in adult C57BL/6 mice also attenuated hypoxia-induced PH. Additionally, monocrotaline-induced vascular remodeling and PH in rats were inhibited by GCN2 inhibitor A-92 treatment. In lung samples of idiopathic PAH patients, we observed endothelial GCN2 hyperphosphorylation of pulmonary vascular lesions, without marked differences in GCN2 mRNA and protein levels compared to normal donor lungs. Conclusion: These studies demonstrate that endothelial GCN2 activation mediates pulmonary vascular remodeling and PAH development through the GCN2/ATF4/HIF-2a/Endothelin-1 pathway. Targeting GCN2 signaling is a promising therapeutic strategy for treatment of PAH in patients without GCN2 loss of function mutations.

Comprehensive analysis and validation of novel immune and vascular remodeling related genes signature associated with drug interactions in pulmonary arterial hypertension.

Background: Previous studies revealed that the gene signatures are associated with the modulation and pathogenesis of pulmonary arterial hypertension (PAH). However, identifying critical transcriptional signatures in the blood of PAH patients remains lacking. Methods: The differentially expressed transcriptional signatures in the blood of PAH patients were identified by a meta-analysis from four microarray datasets. Then we investigated the enrichment of gene ontology and KEGG pathways and identified top hub genes. Besides, we investigated the correlation of crucial hub genes with immune infiltrations, hallmark gene sets, and blood vessel remodeling genes. Furthermore, we investigated the diagnostic efficacy of essential hub genes and their expression validation in an independent cohort of PAH, and we validate the expression level of hub genes in monocrotaline (MCT) induced PAH rats’ model. Finally, we have identified the FDA-approved drugs that target the hub genes and their molecular docking. Results: We found 1,216 differentially expressed genes (DEGs), including 521 up-regulated and 695 down-regulated genes, in the blood of the PAH patients. The up-regulated DEGs are significantly associated with the enrichment of KEGG pathways mainly involved with immune regulation, cellular signaling, and metabolisms. We identified 13 master transcriptional regulators targeting the dysregulated genes in PAH. The STRING-based investigation identified the function of hub genes associated with multiple immune-related pathways in PAH. The expression levels of RPS27A, MAPK1, STAT1, RPS6, FBL, RPS3, RPS2, and GART are positively correlated with ssGSEA scores of various immune cells as positively correlated with the hallmark of oxidative stress. Besides, we found that these hub genes also regulate the vascular remodeling in PAH. Furthermore, the expression levels of identified hub genes showed good diagnostic efficacy in the blood of PAH, and we validated most of the hub genes are consistently dysregulated in an independent PAH cohort. Validation of hub genes expression level in the monocrotaline (MCT)-induced lung tissue of rats with PAH revealed that 5 screened hub genes (MAPK1, STAT1, TLR4, TLR2, GART) are significantly highly expressed in PAH rats, and 4 screened hub genes (RPS6, FBL, RPS3, and RPS2) are substantially lowly expressed in rats with PAH. Finally, we analyzed the interaction of hub proteins and FDA-approved drugs and revealed their molecular docking, and the results showed that MAPK1, TLR4, and GART interact with various drugs with appropriate binding affinity. Conclusion: The identified blood-derived key transcriptional signatures significantly correlate with immune infiltrations, hypoxia, glycolysis, and blood vessel remodeling genes. These findings may provide new insight into the diagnosis and treatment of PAH patients.

PULMONARY ARTERIAL HYPERTENSION AND INTRADUCTAL PAPILLARY MUCINOUS NEOPLASMS: A NOVEL ASSOCIATION?

PULMONARY ARTERIAL HYPERTENSION AND INTRADUCTAL PAPILLARY MUCINOUS NEOPLASMS: A NOVEL ASSOCIATION?

Economic evaluation of sildenafil for the treatment of pulmonary arterial hypertension in Indonesia

BackgroundThis study aims to assess the cost-effectiveness and budget impact of adopting sildenafil to the benefits package for the indication of pulmonary arterial hypertension (PAH), compared to beraprost.MethodsBased on a societal perspective, a model-based economic evaluation was performed using local and international data to quantify the potential costs and health-related outcomes in terms of life years (LYs) and quality-adjusted life years (QALYs).ResultsThe economic model calculated the incremental cost-effectiveness ratio (ICER) per QALY gained for using sildenafil as first-line therapy compared to beraprost for the patient in functional class (FC) II and III, i.e. USD 3098 and USD 2827, respectively. The results indicated that in spite of sildenafil being more expensive than beraprost, generic sildenafil could potentially be a good value for money since ICER per QALY is below one times gross domestic product (GDP) per capita in Indonesia. Furthermore, budget impact analysis estimated that the incremental budget needed within 5 years for including sildenafil compared to beraprost for PAH patients starting in FC II and FC III was USD 436,775 and USD 3.6 million, respectively.ConclusionsCompared to beraprost, sildenafil would be preferable for the treatment of PAH patients in FC II and FC III in Indonesia. The additional budget for adopting sildenafil compared to beraprost as the treatment of PAH in the benefits package was estimated at around USD 4.0 million.

Screening for pulmonary arterial hypertension in systemic sclerosis.

Pulmonary arterial hypertension (PAH) is a dreaded complication of systemic sclerosis (SSc) that occurs in ∼10% of patients. Most individuals present with severe symptoms, significant functional impairment and severe haemodynamics at diagnosis, and survival after PAH diagnosis is poor. Therefore, early diagnosis through systematic screening of asymptomatic patients has the potential to identify PAH at an early stage. Current evidence suggests that early diagnosis and treatment of PAH in patients with SSc may lead to better clinical outcomes. Annual screening may include echocardiography, but this can miss some patients due to suboptimal visualisation or insufficient tricuspid regurgitation. Other options for screening include the DETECT algorithm or the use of a combination of pulmonary function testing (forced vital capacity/diffusing capacity of the lung for carbon monoxide ratio) and N-terminal-pro-brain natriuretic peptide levels. Symptomatic patients, those with an elevated tricuspid regurgitation velocity on echocardiogram with or without secondary echocardiographic features of PAH, and those who screen positive on the DETECT or other pulmonary function test algorithms should undergo right heart catheterisation. Exercise echocardiography or cardiopulmonary exercise testing, nailfold capillaroscopy and molecular biomarkers are promising but, as yet, unproven potential options. Future screening studies should employ systematic catheterisation to define the true predictive values forPAH.

PCV2 - Characterizing Patients Treated With Macitentan For Pulmonary Arterial Hypertension (PAH) In The U.S. Opsumit Users Registry (OPUS)

Health plans look beyond randomized controlled trials (RCTs) in making formulary decisions. There are three approved endothelin receptor antagonists, but no head-to-head trials. Real world evidence (RWE) informs the application of RCT results to healthcare decision making by assessing care and patient outcomes in routine clinical practice. RWE is derived from registries, medical records, pragmatic trials, and claims databases. OPUS registry (NCT02126943) is a US-based, multi-center, longitudinal, observational drug registry of newly treated macitentan patients. The objective of this analysis is to describe clinical characteristics, co-morbidities, and treatment of PAH patients with macitentan. Patients newly treated with macitentan (initiated < 30 days prior to enrollment visit) were included in the registry, regardless of prior or concomitant PAH therapy. Planned observation period was at least one year. Data collected at enrollment or follow-up included: demographics, clinical characteristics, outcomes, adverse events, macitentan treatment and registry discontinuation. As of June 2017, 1136 patients with PAH had follow-up data--74.2% females and 25.8% males. Of this cohort, 44.5% of patients were > 65 years of age; 57.9% patients had idiopathic PAH, and 24.9%, PAH associated with connective tissue disease. Common baseline comorbidities included: hypertension (52.6%), edema (24.5%), signs of right heart failure (15.8%), and diabetes mellitus (22.5%). Median exposure to macitentan was 9.6 months. Macitentan was initiated as monotherapy in 41.7%, and double or triple combination therapy in 58.2% of patients. Most common adverse events were dyspnea (18.0%) and peripheral edema (8.9%). 12.4% of patients experienced ≥1 PAH-related hospitalization. OPUS reports macitentan use and safety in real world clinical settings. Reported comorbidities are consistent with other large registries and claims analyses. Macitentan is initiated most commonly as double or triple combination therapy. PAH related hospitalizations were lower than previously reported in both claims analysis and registries.

Phosphodiesterase-5 inhibitors for the treatment of pulmonary arterial hypertension

In experimental and clinical cardiology, phosphodiesterase type 5 (PDE-5) inhibitors have brought scientific interest as a therapeutic tool in pulmonary arterial hypertension (PAH) management in recent years. Phosphodiesterases are a superfamily of enzymes that inactivate cyclic adenosine monophosphate and cyclic guanosine monophosphate, the second messengers of prostacyclin and nitric oxide. The rationale for the use of PDE-5 inhibitors in PAH is based on their capacity to overexpresss the nitric oxide pathway pursued inhibition of cyclic guanosine monophosphate hydrolysis. By increasing cyclic guanosine monophosphate levels it promotes vasodilation, antiproliferative and pro-apoptotic effects that may reverse pulmonary vascular remodeling. There is also evidence that these drugs may directly enhance right ventricular contractility through an increase in cyclic adenosine monophosphate mediated by the inhibition of the cyclic guanosine monophosphate -sensitive PDE-3. Sildenafil, tadalafil and vardenafil are 3 specific PDE-5 inhibitors in current clinical use, which share similar mechanisms of action but present some significant differences regarding potency, selectivity for PDE-5 and pharmacokinetic properties. Sildenafil received approval in 2005 by the Food and Drug Administration and the European Medicines Agency and tadalafil in 2009 by the Food and Drug Administration and the European Medicines Agency for the treatment of PAH in patients classified as NYHA/WHO functional class II and III. In Mexico, sildenafil and tadalafil were approved by Comisión Federal de Protección contra Riesgos Sanitarios for this indication in 2010 and 2011, respectively.

Pulmonary Hypertension.

Pulmonary hypertension is said to occur when the mean pulmonary arterial pressure exceeds 25 mmHg at rest or 30 mmHg during exercise. There are many causes but the term Pulmonary arterial hypertension (PAH) is used to describe a rare group of illnesses that share histopathological similarities in the small muscularised pulmonary arterioles leading to vascular remodelling (plexogenic pulmonary arteriopathy) and progressive elevation in the pulmonary vascular resistance. Left untreated, patients die as a consequence of right heart failure and the mortality approaches that of commonly encountered malignancies. There is no effective cure. Most treatment for PAH patients has focused on the endothelial cell vascular dysfunction known to occur in these disorders and indeed agents such as endothelin receptor antagonists, phosphodiesterase pathway V inhibitors and prostacyclin analogues have been shown to improve morbidity and delay rate of deterioration. More recently evidence has emerged that they may have a positive impact on survival. These agents have also been applied to treat patients with chronic thromboembolic pulmonary hypertension (CTEPH) and selected patients with CTEPH may also benefit from pulmonary thromboendarterectomy. For a small number of patients with PAH lung transplantation may be considered.

Prognostication in Pulmonary Arterial Hypertension and Use of Current Risk Prediction Models

Significant therapeutic advances in the field of pulmonary arterial hypertension (PAH), increased awareness and diagnosis, and changing patient demographics in the contemporary era have facilitated the development of better prognostic tools for predicting survival. However, overall patient outcomes remain poor, and measurement of most prognostic factors still occurs at the time of initial PAH diagnosis or enrollment into clinical trials. Treatment of PAH patients requires an individualized approach based on disease severity and burden of risk factors to improve patient outcomes. This article will focus on the use of risk prediction models to map and target individual disease trajectories to avoid future morbid and mortal events.

Clinical advances in pulmonary arterial hypertension

The purpose of this review is to summarize the last year of literature developments in the field of pulmonary arterial hypertension (PAH), with a focus on clinical research. Pulmonary vascular research has expanded rapidly over the last decade, resulting in a change in the treatment strategy for PAH. Epidemiologic data from recent registries suggest that patients with PAH are increasing in age and comorbidities. In the modern treatment era, risk stratification for early mortality is increasingly used to guide clinicians in the choice of pulmonary vasodilator therapy. Risk-score calculators have been published and validated for PAH, currently in both the United States and Europe. In addition to increased comorbidities, pulmonary hypertension centers are encountering complicated management situations in these patients, such as pregnancy. Current data suggest that mortality for pregnant pulmonary hypertension patients remains high, although not as high as historical reports. Oral prostacyclin and prostacyclin agonist therapies are currently under investigation to aid in the management of these patients. Despite treatment advances, mortality remains high for PAH patients. Careful evaluation and risk stratification will help guide the appropriate treatment for PAH patients. Additional therapies are on the horizon for the management of this progressive disease.

SP0123 Pulmonary Vascular Remodeling in Systemic Sclerosis - New Targets for Therapy on the Horizon

Pulmonary arterial hypertension (PAH) and pulmonary fibrosis are major causes of morbidity and death in systemic sclerosis. Recent progresses have been achieved in the treatment of PAH with the development...

New hope for Nutlin-3a therapy for pulmonary arterial hypertension

Pulmonary Arterial Hypertension (PH) is a chronic, progressive, and fatal lung disease characterized by narrowing of pulmonary arteries associated with muscular thickening and intimal proliferation, known as remodeling. If untreated, the 5-year survival rate of PH is 34% (McLaughlin et al., 2002). Unfortunately, there is no systematic strategy established to effectively manage this devastating disease. Currently, the best curative option for PH is lung transplantation. It, however, is applicable for only a few patients mainly due to the lack of suitable donors. Moreover, even if lung transplantation is successfully performed, the patients have to take immunosuppressant for the rest of their life. Administration of long-term immunosuppressant has been associated with high incidence of side effects including severe and sometimes fatal infections. The FDA-approved medications for PH fall into three categories: (i) prostacyclin derivative, which is a very potent vasodilator and also a inhibitor of pulmonary artery smooth muscle cell (PASMC) proliferation, (ii) endothelin-1 receptor antagonist, which counteracts vasoconstriction and PASMC proliferation, and (iii) phosphodiesterase-5 inhibitor, which causes pulmonary vasodilatation and inhibition of PASMC proliferation. These vasodilators have certainly achieved significant advances in the management of PH during the last decade. However, because of their short half-lifes and narrow therapeutic ranges, close monitoring and/or follow-up is required to avoid excessive side effects involved in vasodilation. Some PH patients with severe conditions even require continuous intravenous or subcutaneous administration of these drugs, which can be a big clinical challenge for both patients and health care providers. To get a better way in managing PH conditions and in maintaining long-term patient adherence, a new drug that specifically and strongly blocks PASMC proliferation, a key pathological event in PH, is desired. In the last decade, a good line of evidence has revealed that there is a variety of similarities existent between PH and cancer (McMurtry et al., 2005; Dromparis et al., 2010; Aljubran et al., 2012). Two representatives of them are uncontrolled cellular proliferation and resistance to apoptosis. In the recent issue of Circulation, Mouraret et al. present an elegant study on the effects of Nutlin-3a on PH (Mouraret et al., 2013). Nutlin-3a, which is a cis-imidazoline analog, was originally developed as an anti-cancer drug. It stabilizes p53 by inhibiting the binding of MDM2 (murine double minute 2), a p53-specific E3 ubiquitin ligase that promotes p53 degradation (Vassilev et al., 2004). p53, a representative tumor suppressor protein, plays a critical role in tumor suppression through several different mechanisms primarily involving the DNA repair process. Recently, it has been reported that p53 deletion deteriorates hypoxia-induced PH in mice (Mizuno et al., 2011). Consistent with this report, Mouraret et al. revealed that a p53 stabilizer Nutlin-3a reversed PH in three distinct experimental mouse models with only limited side effects noted in control mice without PH. Moreover, they confirmed that Nutlin-3a requires p53 and p21 expression to work as an anti-PH drug showing that Nutlin-3a exerts no effects on hypoxia-exposed p53−/− and p21−/− mice. Intriguingly, the paper also shows that Nutlin-3a treatment of cultured human PASMCs results in cell growth arrest but not apoptosis, which is consistent with other reports using fibroblasts from mice and humans (Efeyan et al., 2007; Kumamoto et al., 2008). Therefore, it appears that Nutlin-3a has a totally different mechanism of action from currently available drugs and that it is not directly associated with relaxation of smooth muscle and vasodilation of the pulmonary arteries, which lessens the concern about the side effects related to vasodilation. If Nutlin-3a works well for treatment of PH patients and it becomes an approved therapeutic application, PH patients would be able to have more therapeutic options including combination therapies, which ultimately would lead to decreased number of PH patients with advanced stages. The benefit of expanded therapeutic options could have an impact in decreasing the number of PH patients waiting for lung transplantation. On the other hand, one minor drawback of using Nutlin-3a as a potential PH treatment is its slow clinical effect on the patients with severe PH due to its lack of direct vasodilatory effect. However, in spite of the above mentioned disadvantage, this new drug still has an enormous therapeutic potential for treatment of PH. The day may come before long when Nutlin-3a will come out as a blessing for PH patients.

Systemische Sklerose - eine systematische Übersicht

Here we give an overview over treatment recommendations propagated by the European League Against Rheumatism (EULAR), EULAR Scleroderma Trials and Research Group, the German Network for Systemic Sclerosis, the European Respiratory Society, and the International Society of Heart and Lung Transplantation. As response to immunosuppressant (IS) therapy is usually weaker in systematic sclerosis (SSc) compared to other connective tissue disorders IS should be considered with caution. To prevent scleroderma renal crisis steroid doses should not exceed 15 mg/d. The definitive role of a number of new immunosuppressant drugs and the effects of autologous stem cell transplantation in systemic clerosis (SSc) have to be elucidated. Prostanoids, especially iloprost, are widely used as intravenous formulas for the treatment of severe Raynaud's phenomenon (RP) and digital ulcers (DU). Calcium antagonists are of limited therapeutic value. Bosentan, an oral endothelin receptor antagonists (ETRA), was shown to prevent new DU, but failed to heal existing DU, while the oral phopshodiesterase inhibitor (PDI) Sildenafil reduces the occurrence of RP and might be effective in ulcer healing. Combination therapies of PDI with ETRA are currently evaluated. Therapy of pulmonary arterial hypertension (PAH) is usually started as oral monotherapy, frequently using an ETRA. When this first-line therapy is not tolerated ETRA is substituted by PDI. If treatment goals are not reached with monotherapy combinationtherapy is started, for example by adding a PDI to an existing ETRA. In general, treatment of PAH in patients with connective tissue disease follows the same algorithms as in idiopathic PAH.

Pulmonary hypertension: Classification and treatment

Pulmonary hypertension (PH) comprises a variety of conditions that lead to elevated pulmonary arterial pressure. Because the treatment for PH depends on the cause, it is critical to accurately classify the cause of the problem. A useful classification system, developed and refined at the World Conference on Pulmonary Hypertension, held every five years, has been developed. In this system, patients can be classified as having PH due to the following: pulmonary arterial hypertension (PAH); left-sided heart disease; lung or respiratory disease; chronic thromboembolic disease; or multifactorial or unclear mechanisms. Although challenges in classifying patients remain, such as the patient with some left-sided heart disease but ‘out of proportion' PH, this system has been critical in helping guide therapy. For patients who are deemed to be in group 1 (PAH), several approved therapies are available, including prostanoids (available in intravenous, subcutaneous and inhaled forms), endothelin receptor antagonists and phosphodiesterase type 5 inhibitors. Each of these agents has been approved based on improvement in exercise capacity demonstrated in randomized controlled trials. A treatment algorithm that provides guidance for choosing the appropriate treatment for PAH patients has been published. Patients who are considered to be ‘high risk', such as those with overt right heart failure, are generally appropriate for parenteral therapy, whereas those who are only moderate or low risk are usually candidates for initial oral therapy. In addition, close follow-up allows for the consideration of additional therapies. Many current trials, in fact, are studying this ‘goal-directed' approach to the treatment of PAH.

Ambrisentan, an endothelin receptor type A-selective endothelin receptor antagonist, for the treatment of pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a disease of the pulmonary vasculature characterized by vasoconstriction and vascular proliferation, which leads to right heart failure and death. Prostacyclin, NO and endothelin are felt to be key mediators in the development of PAH. We present the available published and presented data about ambrisentan, an ETA-selective endothelin receptor antagonist (ERA) and newest ERA agent to be approved by the FDA for the treatment of PAH in patients with WHO functional class II and III symptoms. Randomized, placebo-controlled trials have demonstrated a significant improvement in exercise capacity and decrease in time to clinical worsening, along with evidence to support an improvement in WHO functional class and quality of life for patients receiving ambrisentan. Long-term data have shown a 1-year survival of 95%; of the survivors, 94% remained on ambrisentan monotherapy. Endothelin receptor antagonists as a drug class have previously been associated with peripheral edema, aminotransferases abnormalities and a teratogenic risk to a developing fetus. Peripheral edema was observed in patients receiving ambrisentan; however, a greater percentage was experienced in patients aged > 65 years. In contrast, significant aminotransferase abnormalities were not observed with ambrisentan treatment in the placebo-controlled trials, and in all clinical trials combined the 1-year risk seems to be low (< 3%). Despite these data, the FDA requires monthly liver function tests monitoring. As with other ERAs, monthly pregnancy testing is required in all women of child bearing potential.

Clinical significance of plasma endothelin-1 level after bosentan administration in pulmonary arterial hypertension

Endothelin (ET)-1 has been shown to play a significant pathogenic role in pulmonary arterial hypertension (PAH). However, the pathobiological significance of increased ET-1 concentration after administration of ET receptor antagonist in patients with PAH has not yet been fully examined. In 16 PAH patients, plasma ET-1 concentration was measured at 0, 1, 3, 6, and 24h after a single 62.5mg dose of bosentan, a dual ET receptor antagonist, and the peak and 24-h change in ET-1 concentration from baseline were examined. The severity of PAH was evaluated by hemodynamic parameters, 6-min walk distance, New York Heart Association (NYHA) functional class, and brain natriuretic peptide (BNP). Plasma ET-1 concentration significantly increased from 1.93+/-0.12 to 3.36+/-0.18 pg/ml after bosentan administration in PAH patients (p<0.01). The peak-to-baseline ratio of ET-1 concentration after bosentan administration showed a significant positive correlation with baseline ET-1 concentration (p<0.05). After 4-week bosentan administration, NYHA functional class improved in 7 patients but was not changed in 9 patients. The optimal cut-off point of % change of ET-1 concentration at 24h for discriminating the two groups was 30%. According to this cut-off point, patients were divided into the higher (n=7) and the lower (n=9) groups. NYHA functional class did not change in the lower group, but significantly improved (p<0.01) in the higher group after 4-week bosentan administration. In addition, plasma BNP levels significantly decreased from baseline in the higher group compared with those in the lower group after 12-week bosentan administration (-44+/-11% vs. 7+/-20%, p<0.05). Although the population in this study is small and heterogeneous, measurement of plasma ET-1 concentration after bosentan administration might predict the responsiveness to bosentan treatment, and be useful in the determination of effective therapy in treatment of PAH patients.

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

Medikamentöse Therapie des Lungenhochdrucks bei Patienten mit angeborenen Herzfehlern

The development of drugs for lowering pressures in pulmonary arterial hypertension (PHT) has provided possible therapeutic application in patients with pulmonary hypertension associated with congenital heart disease (CHD). Prostanoids, both nonselective and selective endothelin-receptor antagonists and phosphodiesterase-V inhibitors have been used for this purpose. The efficacy of these drugs - from different classes of bioactivity - in this context have been shown in several studies. However, the long-term effects of drug treatment on prognosis and course of PHT have not yet been adequately investigated. The current status of drug treatment of PHT in patients with CHD is reviewed in this article.

Management of Pulmonary Arterial Hypertension Associated with Congenital Systemic-to-Pulmonary Shunts and Eisenmenger???s Syndrome

A large proportion of patients with congenital heart disease (CHD), in particular those with relevant systemic-to-pulmonary shunts, will develop pulmonary arterial hypertension (PAH) if left untreated. Persistent exposure of the pulmonary vasculature to increased blood flow, as well as increased pressure, may result in pulmonary obstructive arteriopathy, which leads to increased pulmonary vascular resistance that, if it approaches or exceeds systemic resistance, will result in shunt reversal. Eisenmenger's syndrome, the most advanced form of PAH associated with CHD, is defined as CHD with an initial large systemic-to-pulmonary shunt that induces severe pulmonary vascular disease and PAH, with resultant reversal of the shunt and central cyanosis. The histopathological and pathobiological changes seen in patients with PAH associated with congenital systemic-to-pulmonary shunts, such as endothelial dysfunction of the pulmonary vasculature, are considered similar to those observed in idiopathic or other associated forms of PAH. A pathological and pathophysiological classification of CHD with systemic-to-pulmonary shunt leading to PAH has been developed that includes specific characteristics, such as the type, dimensions and direction of the shunt, extracardiac abnormalities and repair status. A clinically oriented classification has also been proposed. The prevalence of PAH associated with congenital systemic-to-pulmonary shunts in Western countries has been estimated to range between 1.6 and 12.5 cases per million adults, with 25-50% of this population affected by Eisenmenger's syndrome. Clinically, Eisenmenger's syndrome presents with multiple organ involvement, with progressive deterioration of function over time. The signs and symptoms of Eisenmenger's syndrome in the advanced stages include central cyanosis, dyspnoea, fatigue, haemoptysis, syncope and right-sided heart failure. Survival of patients with Eisenmenger's syndrome is clearly less than that of the general population, but appears to be better than that of patients with idiopathic PAH in a comparable functional class. The treatment strategy for patients with PAH associated with congenital systemic-to-pulmonary shunts and, in particular, those with Eisenmenger's syndrome is based mainly on clinical experience rather than being evidence based. General measures include recommendations for physical activity, pregnancy, infections, air travel, exposure to high altitudes and elective surgery, and that psychological assistance be provided as necessary. Phlebotomies are required only when hyperviscosity of the blood is evident, usually when the haematocrit is >65%. The use of supplemental oxygen therapy is controversial and it should be used only in patients in whom it produces a consistent increase in arterial oxygen saturation. Oral anticoagulant treatment with warfarin can be initiated in patients with pulmonary artery thrombosis and absent, or only mild, haemoptysis. The following three classes of drugs targeting the correction of abnormalities in endothelial dysfunction have been approved recently for the treatment of PAH: (i) prostanoids; (ii) endothelin receptor antagonists; and (iii) phosphodiesterase-5 inhibitors. The efficacy and safety of these compounds have been confirmed in uncontrolled studies in patients with PAH associated with corrected and uncorrected congenital systemic-to-pulmonary shunts, as well as in patients with Eisenmenger's syndrome. One randomized controlled trial reported favourable short- and long-term outcomes of treatment with the orally active dual endothelin receptor antagonist bosentan in patients with Eisenmenger's syndrome. Lung transplantation with repair of the cardiac defect or combined heart-lung transplantation are options for Eisenmenger's syndrome patients with a poor prognosis. A treatment algorithm based on the one used in the treatment of PAH patients is proposed for patients with PAH associated with corrected and uncorrected congenital systemic-to-pulmonary shunts and Eisenmenger's syndrome.

Abstract 981: Hypoxia Results in Exacerbation of Pulmonary Arterial Hypertension (PAH) in Male Mice with Deletion of PPARγin Smooth Muscle Cells (SMC) but Females are Protected by Adiponectin Mediated Induction of PPARα

Lung tissues of patients with PAH have reduced levels of the peroxisome proliferator activated receptor gamma (PPARγ) and we previously reported that transgenic male mice with deletion of PPARγ in arterial smooth muscle (SM22CrePPARγ flox/flox ) develop spontaneous PAH. Moreover, PPARγ is necessary in mediating bone morphogenetic protein (BMP-2) inhibition of PDGF-BB induced SMC proliferation. We therefore hypothesized that PAH would be exacerbated in SM22CrePPARγ flox/flox mice under conditions like chronic hypoxia (3 weeks, FiO 2 =0.10) that induce PDGF-BB mediated SMC proliferation. Results: Consistent with this hypothesis, we report a more severe PAH phenotype only in the male SM22CrePPARγ flox/flox mice, as measured by greater right ventricular systolic pressure (RVSP: 38.6 vs. 30.9 mmHg), right ventricular hypertrophy (RVH=right ventricle/left ventricle+septum: 0.58 vs 0.35), and arterial muscularization (90.6 vs 60.3 %), when compared to littermate controls (p&lt;0.05, n=6 – 8 per group, for all comparisons). Interestingly, female SM22CrePPARγ flox/flox mice were resistant to spontaneous or chronic hypoxia-induced PAH (RVSP: 18.5mmHg). We investigated the acute hypoxic vasoconstrictive response and found it exaggerated in the male but suppressed in the female (RVSP: 43.12 vs 20.42mmHg) SM22CrePPARγ flox/flox mice. We found no reduction in endothelin-1 (P&lt;0.05) in the female vs. male SM22CrePPARγ flox/flox mice but serum levels of adiponectin were twofold higher (14.5 vs 6.9 μg/ml; p&lt;0. 001) in females under normoxia and hypoxia. We further show through cell counts, that in pulmonary artery (PA) SMC from male SM22CrePPARγ flox/flox mice, BMP2 fails to suppress PA SMC proliferation in response to PDGF-BB (p&lt;0.01; n=3) but exogenous adiponectin can ‘rescue’ this phenotype (p&lt;0.01, n=3). The mechanism appears to be related to adiponectin mediated induction of PPAR alpha (PPARγ mRNA relative level: 0.37 vs 0.42 after adiponectin pretreatment, p&lt;0.01), which we report for the first time in PA SMC. Conclusion : These findings strengthen the potential efficacy of PPAR-α/ γ agonists in the treatment of PAH patients with low endogenous levels of PPAR-γ and/or adiponectin, such as those with BMP-RII dysfunction or insulin resistance.