Survival Of Pulmonary Arterial Hypertension Patients Research Articles

Long-term efficacies of selective vasodilators in pulmonary arterial hypertension: a comprehensive comparison using a spontaneous reporting database.

There is no clinical evidence of differences in drugs associated with long-term survival in patients with pulmonary arterial hypertension (PAH) due to the small population and lack of information on death in Japanese medical database systems. This study evaluated whether patient data from a spontaneous reporting database could be used for comparing the effects of pulmonary vasodilators on long-term survival in PAH patients. PAH patient data reported in the Japanese Adverse Drug Event Report (JADER) database from April 2004 to July 2022 were extracted. Kaplan-Meier curves were used to compare survival times. Adjusted hazard ratios (aHRs) for all-cause mortality were determined using Cox proportional hazards models. Of 1969 PAH patients reported in the JADER database, 1208 were included in the survival analyses. The patient demographics were similar to those of the PAH population reported in the Japan Pulmonary Hypertension Registry. Among drugs targeting the prostacyclin pathway, epoprostenol was most associated with long-term survival (aHR, 0.38; 95% confidence interval (CI), 0.23-0.64). The PAH patients treated with endothelin receptor antagonists had improved survival, especially among the macitentan users (aHR, 0.30; 95% CI, 0.22-0.42). Sildenafil was associated with a poor prognosis in the PAH patients (aHR, 1.56; 95% CI, 1.19-2.04). Although our results must be interpreted with caution due to several limitations inherent to spontaneous reporting databases, our approach using the JADER database for survival analysis may provide useful information in limited situations such as the treatment of rare diseases including PAH.

Impact of Epicardial Adipose Tissue on Right Cardiac Function and Prognosis in Pulmonary Arterial Hypertension

Although epicardial adipose tissue (EAT) is linked to effects on survival in left-sided heart failure, the association between EAT and right-sided heart failure caused by pulmonary arterial hypertension (PAH) remains unknown. What are the potential impacts of EAT volume (EATV) on right ventricular function, biomarkers of myocardial injury, and long-term prognosis in patients with PAH? A total of 135 age- and BMI-matched patients with PAH and 49 control participants were included in this study. EATV was quantified by using cardiac magnetic resonance and was related to clinical correlates, N-terminal pro-brain natriuretic peptide, and cardiac function. Levels of EATV associated with the risk of clinical worsening were evaluated on a continuous scale (restricted cubic splines) and by previously defined centile categories with Cox proportional hazards regression models and Kaplan-Meier survival estimates. Compared with the control participants, patients with PAH had a lower EATV (ln [EATV], 3.2 ± 0.8mL vs3.5 ± 0.7mL; P= .034). The association of EATV with right ventricular end-diastolic volume (Pnonlinear= .001), right ventricular end-diastolic volume index (P< .001), right ventricular cardiac output (P= .003), N-terminal pro-brain natriuretic peptide (P= .030), and the risk of clinical worsening (P= .014) was U shaped. Compared with individuals with middle-level EATV, multivariable-adjusted hazard ratio for clinical worsening was 6.0 (95%CI, 1.3-27.8) for the individuals with low-level EATV and 6.8 (95%CI, 1.5-30.2) for high-level EATV in patients with PAH. Patients with PAH had a decreased EATV compared with control participants. EATV exhibited a U-shaped association with right ventricular function and biomarkers of myocardial injury in patients with PAH. Low and high levels of EATV might reduce long-term event-free survival in patients with PAH. Chinese Clinical Trial Registry; No. ChiCTR2100049804; www.chictr.org.cn.

Kynurenine metabolites predict survival in pulmonary arterial hypertension: A role for IL-6/IL-6Rα

Activation of the kynurenine pathway (KP) has been reported in patients with pulmonary arterial hypertension (PAH) undergoing PAH therapy. We aimed to determine KP-metabolism in treatment-naïve PAH patients, investigate its prognostic values, evaluate the effect of PAH therapy on KP-metabolites and identify cytokines responsible for altered KP-metabolism. KP-metabolite levels were determined in plasma from PAH patients (median follow-up 42 months) and in rats with monocrotaline- and Sugen/hypoxia-induced PH. Blood sampling of PAH patients was performed at the time of diagnosis, six months and one year after PAH therapy. KP activation with lower tryptophan, higher kynurenine (Kyn), 3-hydroxykynurenine (3-HK), quinolinic acid (QA), kynurenic acid (KA), and anthranilic acid was observed in treatment-naïve PAH patients compared with controls. A similar KP-metabolite profile was observed in monocrotaline, but not Sugen/hypoxia-induced PAH. Human lung primary cells (microvascular endothelial cells, pulmonary artery smooth muscle cells, and fibroblasts) were exposed to different cytokines in vitro. Following exposure to interleukin-6 (IL-6)/IL-6 receptor α (IL-6Rα) complex, all cell types exhibit a similar KP-metabolite profile as observed in PAH patients. PAH therapy partially normalized this profile in survivors after one year. Increased KP-metabolites correlated with higher pulmonary vascular resistance, shorter six-minute walking distance, and worse functional class. High levels of Kyn, 3-HK, QA, and KA measured at the latest time-point were associated with worse long-term survival. KP-metabolism was activated in treatment-naïve PAH patients, likely mediated through IL-6/IL-6Rα signaling. KP-metabolites predict response to PAH therapy and survival of PAH patients.

Outcomes of cardiopulmonary resuscitation in patients with pulmonary arterial hypertension.

Over the past 20 years, despite significant advancements in pulmonary arterial hypertension (PAH) medical therapy, many patients require admission to the hospital and are at risk for in‐hospital cardiac arrest (IHCA). Prior data found poor survival in PAH patients after cardiac arrest. The purpose of this study was to explore post‐IHCA outcomes in PAH patients receiving advanced medical therapies. This is a single‐center retrospective study of PAH patients who underwent cardiopulmonary resuscitation for IHCA between July 2005 and May 2021. Patients were identified through an internal cardiac arrest database. Twenty six patients were included. Half of the cohort had idiopathic PAH, with 54% of patients on combination therapy, 27% on monotherapy, and 19% of patients on no therapy. Mean right atrial pressure, mean pulmonary artery pressure, cardiac index, and pulmonary vascular resistance were 13 ± 6 mmHg, 57 ± 13 mmHg, 2.0 ± 0.7 L/min/m2, and 14.5 ± 7.6 Wood units, respectively. Most common etiology of cardiac arrest was circulatory collapse. Initial arrest rhythm in all but one patient was pulseless electrical activity. Six patients (23%) achieved return of spontaneous circulation (ROSC) and one patient (4%) survived to hospital discharge. Rates of ROSC and survival to discharge after IHCA are poor in patients with PAH. Even patients with mild hemodynamics had low likelihood of survival. In patients who are lung transplant candidates, there should be early consideration of extracorporeal support before cardiac arrest.

Prognostic impact of hypochromic erythrocytes in patients with pulmonary arterial hypertension

BackgroundIron deficiency affects up to 50% of patients with pulmonary arterial hypertension (PAH) but iron markers such as ferritin and serum iron are confounded by several non-disease related factors like acute inflammation and diet. The aim of this study was to identify a new marker for iron deficiency and clinical outcome in PAH patients.MethodsIn this single-center, retrospective study we assessed indicators of iron status and clinical parameters specifying the time to clinical worsening (TTCW) and survival in PAH patients at time of initial diagnosis and at 1-year follow-up using univariable and multivariable analysis.ResultsIn total, 150 patients were included with an invasively confirmed PAH and complete data on iron metabolism. The proportion of hypochromic erythrocytes > 2% at initial diagnosis was identified as an independent predictor for a shorter TTCW (p = 0.0001) and worse survival (p = 0.002) at initial diagnosis as well as worse survival (p = 0.016) at 1-year follow-up. Only a subset of these patients (64%) suffered from iron deficiency. Low ferritin or low serum iron neither correlated with TTCW nor survival. Severe hemoglobin deficiency at baseline was significantly associated with a shorter TTCW (p = 0.001).ConclusionsThe presence of hypochromic erythrocytes > 2% was a strong and independent predictor of mortality and shorter TTCW in this cohort of PAH patients. Thus, it can serve as a valuable indicator of iron homeostasis and prognosis even in patients without iron deficiency or anemia. Further studies are needed to confirm the results and to investigate therapeutic implications.

Single-center prognostic validation of the risk assessment of the 2015 ESC/ERS guidelines in patients with pulmonary arterial hypertension in Japan.

The 2015 European Society of Cardiology/European Respiratory Society guidelines for the diagnosis and treatment of pulmonary hypertension include a multidimensional risk assessment for patients with pulmonary arterial hypertension (PAH). However, prognostic validations of this risk assessment are limited, especially outside Europe. Here, we validated the risk assessment strategy in PAH patients in our institution in Japan. Eighty consecutive PAH patients who underwent right heart catheterization between November 2006 and December 2018 were analyzed. Patients were classified as low, intermediate, or high risk by using a simplified version of the risk assessment that included seven variables: World Health Organization functional class, 6-min walking distance, peak oxygen consumption, brain natriuretic peptide, right atrial pressure, mixed venous oxygen saturation, and cardiac index. The high-risk group showed significantly higher mortality than the low- or intermediate-risk group at baseline (P < 0.001 for both comparisons), and the mortalities in the intermediate- and low-risk groups were both low (P = 0.989). At follow-up, patients who improved to or maintained a low-risk status showed better survival than those who did not (P = 0.041). Our data suggest that this risk assessment can predict higher mortality risk and long-term survival in PAH patients in Japan.

Risk stratification in pulmonary arterial hypertension using Bayesian analysis.

Current risk stratification tools in pulmonary arterial hypertension (PAH) are limited in their discriminatory abilities, partly due to the assumption that prognostic clinical variables have an independent and linear relationship to clinical outcomes. We sought to demonstrate the utility of Bayesian network-based machine learning in enhancing the predictive ability of an existing state-of-the-art risk stratification tool, REVEAL 2.0. We derived a tree-augmented naïve Bayes model (titled PHORA) to predict 1-year survival in PAH patients included in the REVEAL registry, using the same variables and cut-points found in REVEAL 2.0. PHORA models were validated internally (within the REVEAL registry) and externally (in the COMPERA and PHSANZ registries). Patients were classified as low-, intermediate- and high-risk (<5%, 5-20% and >10% 12-month mortality, respectively) based on the 2015 European Society of Cardiology/European Respiratory Society guidelines. PHORA had an area under the curve (AUC) of 0.80 for predicting 1-year survival, which was an improvement over REVEAL 2.0 (AUC 0.76). When validated in the COMPERA and PHSANZ registries, PHORA demonstrated an AUC of 0.74 and 0.80, respectively. 1-year survival rates predicted by PHORA were greater for patients with lower risk scores and poorer for those with higher risk scores (p<0.001), with excellent separation between low-, intermediate- and high-risk groups in all three registries. Our Bayesian network-derived risk prediction model, PHORA, demonstrated an improvement in discrimination over existing models. This is reflective of the ability of Bayesian network-based models to account for the interrelationships between clinical variables on outcome, and tolerance to missing data elements when calculating predictions.

Focus on Early Events: Pathogenesis of Pulmonary Arterial Hypertension Development.

Significance: Pulmonary arterial hypertension (PAH) is a progressive disease of the lung vasculature characterized by the proliferation of all vascular wall cell types, including endothelial, smooth muscle, and fibroblasts. The disease rapidly advances into a form with extensive pulmonary vascular remodeling, leading to a rapid increase in pulmonary vascular resistance, which results in right heart failure.Recent Advances: Most current research in the PAH field has been focused on the late stage of the disease, largely due to an urgent need for patient treatment options in clinics. Further, the pathobiology of PAH is multifaceted in the advanced disease, and there has been promising recent progress in identifying various pathological pathways related to the late clinical picture.Critical Issues: Early stage PAH still requires additional attention from the scientific community, and although the survival of patients with early diagnosis is comparatively higher, the disease develops in patients asymptomatically, making it difficult to identify and treat early.Future Directions: There are several reasons to focus on the early stage of PAH. First, the complexity of late stage disease, owing to multiple pathways being activated in a complex system with intra- and intercellular signaling, leads to an unclear picture of the key contributors to the pathobiology. Second, an understanding of early pathophysiological events can increase the ability to identify PAH patients earlier than what is currently possible. Third, the prompt diagnosis of PAH would allow for the therapy to start earlier, which has proved to be a more successful strategy, and it ensures better survival in PAH patients.

Presence of Kidney Disease as an Outcome Predictor in Patients with Pulmonary Arterial Hypertension

Background: Pulmonary arterial hypertension (PAH) may lead to right heart failure and subsequently alter glomerular filtration rates (GFR). Chronic kidney disease (CKD, GFR <60 mL/min/1.73 m²) may also adversely affect PAH prognosis. This study aimed to assess how right heart hemodynamics was associated with reduced estimated GFR (eGFR) and the association of CKD with survival in PAH patients. Methods: In a prospective PAH cohort (2003–2012), invasive hemodynamics and eGFR were collected at diagnosis (179 patients) and during follow-up (159 patients). The prevalence of CKD was assessed at PAH diagnosis. Variables, including hemodynamics, associated with reduced eGFR at diagnosis and during follow-up were tested in multivariate analysis. The association of CKD with survival was evaluated using a multivariate Cox regression model. Results: At diagnosis, mean age was 60.4 ± 16.5 years, mean pulmonary arterial pressure was 43 ± 12 mm Hg, and eGFR was 74.4 ± 26.4 mL/min/1.73 m². CKD was observed in 52 incident patients (29%). Independent determinants of reduced eGFR at diagnosis were age, systemic hypertension, and decreased cardiac index. Independent determinants of reduced eGFR during follow-up were age, female gender, PAH etiology, systemic hypertension, decreased cardiac index, and increased right atrial pressure. Age ≥60 years, female gender, NYHA 4, and CKD at diagnosis were independently associated with decreased survival. The adjusted hazards ratio for death associated with CKD was 1.81 (95% confidence interval [1.01–3.25]). Conclusion: CKD is frequent at PAH diagnosis and is independently associated with increased mortality. Right heart failure may induce renal hypoperfusion and congestion, and is associated with eGFR decrease.

Intrinsic BMP Antagonist Gremlin-1 as a Novel Circulating Marker in Pulmonary Arterial Hypertension.

Gremlin-1, an intrinsic antagonist of bone morphogenetic protein (BMP) signaling, has been implicated in the pathophysiology of pulmonary arterial hypertension (PAH). However, it is unknown whether gremlin-1 can be detected in the circulation of PAH patients and whether it is associated with patients' functional status and outcome. With a mean level of 242 ± 24 ng/ml, gremlin-1 levels of 31 PAH patients were significantly elevated compared to 151 ± 18 ng/ml in 15 age- and gender-matched healthy subject (p = 0.016). In PAH patients, increasing gremlin-1 levels correlated with N-terminal prohormone of brain natriuretic peptide levels (r = 0.608, p < 0.001) and inversely with the 6-minute walking distance (r = -0.412, p = 0.029). Furthermore, gremlin-1 significantly stratified survival in PAH patients (p = 0.015). Gremlin-1 may represent a new biomarker for PAH which can be linked directly to the underlying pathomechanism. Elevated levels of gremlin-1 are associated with patients' functional status and survival, thus gremlin-1 neutralization could represent a potential therapeutic strategy to increase BMPR2 signaling.

Abstract 12455: Evaluation of N-Terminal Pro-B-type Natriuretic Peptide as a Therapeutic Response Biomarker in Group I Pulmonary Arterial Hypertension

Purpose: Goal directed management of left heart failure with an NT-proBNP target-based approach has some evidence of providing a survival benefit. To evaluate the potential utility of serial NT-proBNP measurements for goal-directed therapy in right heart failure we retrospectively assessed NT-proBNP as a predictor for survival in Group I pulmonary arterial hypertension (PAH) patients. Methods: We identified 103 Group I PAH patients from a pulmonary hypertension registry who had baseline elevated NT-proBNP prior to either the initiation or escalation of therapy and at least two serial NT-proBNP measurements. In a two-step process, we (1) estimated baseline NT-proBNP and slope (rate of change of NT-proBNP) with a linear mixed-effects model using all patient data and then (2) compared the power of serial versus single measurements in predicting survival with measured and model-derived values of baseline NT-proBNP with a Receiver Operative Characteristic (ROC) curve analysis . Survival was determined using the Kaplan-Meier methodology. Results: ROC curve analysis revealed significantly higher AUC for model-derived NT-proBNP values compared to the measured values (AUC: for baseline 0.74 vs 0.66, p= 0.009; for slope 0.78 vs 0.66, p= 0.02). Optimal cutpoints for prediction of survival on baseline NT-proBNP were 2012 (measured) vs. 1810 (model-derived) pg/mL. The optimal cutpoint for model-derived change in NT-proBNP was -0.004 log10pg/mL/month. Sensitivity, specificity, and negative predictive values for the three predictor variables were: 64%, 67%, 80% (measured baseline NT-proBNP), 61%, 80%, 81% (model-derived baseline NT-proBNP) and 73%, 57%, 85% (model-derived slope). Conclusions: In PAH patients, serial NT-proBNP measurements better predict survival than single measurements. This retrospective finding reveals that changes in NT-proBNP are associated with overall survival in PAH patients, and set initial target values for a pilot prospective study of NT-proBNP goal-directed therapy.

Impact of diabetes on survival and right ventricular compensation in pulmonary arterial hypertension.

Insulin resistance is highly prevalent in pulmonary arterial hypertension (PAH) patients. However, the long-term impact of diabetes mellitus (DM) on survival in PAH is unclear. Insulin resistance and DM are associated with left ventricular steatosis and dysfunction, but whether the right ventricle (RV) might be affected by DM in PAH is unknown. We hypothesized that PAH patients with DM would have worse survival than PAH patients without DM and that this would be due to impaired RV compensation. From a large registry of PAH patients at our institution, we analyzed the effect of DM on survival in patients with idiopathic or heritable PAH. Clinical and hemodynamic differences were compared between PAH patients with DM and those without DM. Twenty-nine patients with DM and 84 without DM were included. Gender, body mass index, PAH type and duration, and 6-minute walk distance were similar between groups. PAH patients with DM had significantly lower survival at 10 years than PAH patients without DM. Right atrial pressure, pulmonary arterial pressure, and cardiac output did not differ significantly between the two groups. However, right ventricular stroke work index (RVSWI) was lower in the PAH DM group than in the no-DM patients. Among PAH patients with DM, patients who died had a lower RVSWI than survivors. In conclusion, survival in PAH patients with DM was reduced compared to that of patients without DM; impaired RV compensation may underlie this finding. Further study is needed to understand this effect.

Impact of Parenteral Treprostinil Dosing in Pulmonary Arterial Hypertension

Purpose Data from a recent retrospective analysis (Benza et al, 2011) suggested that higher doses of treprostinil may be associated with better survival in pulmonary arterial hypertension (PAH). Here, we determined whether the dose of treprostinil influences time on therapy and survival of PAH patients in clinical practice. Methods and Materials Retrospective review of all patients in the United States started on intravenous (IV) and subcutaneous (SQ) treprostinil, using data from three specialty pharmacies between September 2009 and October 2011. Deaths from any cause were recorded. Impact of treprostinil dose on the patient’s survival in each month of therapy was analyzed using a Cox proportional hazard model and the ratio was calculated using dose increments of 10 ng/kg/min. Physicians were stratified by experience with parenteral treprostinil (≥5 vs Results 1877 patients (mean age, 51 years) were initiated on parenteral treprostinil. Experienced physicians tended to initiate patients at higher doses and uptitrate more rapidly than less experienced physicians, (P Conclusions Treprostinil dose may influence survival in PAH. More rapid uptitration to a higher dose may be beneficial in these patients. Table 1 Treprostinil Number of patients HR P Value Implications IV+SQ 1877 * 0.992 10 ng/kg/min increase in dose leads to a 7.7% decrease in hazard of death SQ 1032 0.990 0.002 10 ng/kg/min increase in dose leads to a 9.6% decrease in hazard of death IV 837 0.993 0.021 10 ng/kg/min increase in dose leads to a 6.8% decrease in hazard of death * Data pertaining to route of delivery were not available for 8 patients.

Survival in pulmonary hypertension in Spain: insights from the Spanish registry

A pulmonary hypertension (PH) registry (Spanish Registry of Pulmonary Arterial Hypertension) was undertaken to analyse prevalence, incidence and survival of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) in Spain, and to assess the applicability of recent survival prediction equations. Voluntary reporting of previously diagnosed and incident PAH or CTEPH cases (July 2007-June 2008) was performed. Demographic, functional and haemodynamic variables were evaluated. 866 patients with PAH and 162 with CTEPH were included. PAH associated with toxic oil syndrome and pulmonary veno-occlusive disease were reported for the first time in a PAH registry. Estimated prevalences were as follows: PAH, 16 and CTEPH, 3.2 cases per million adult inhabitants (MAI). Estimated incidences were as follows: PAH, 3.7 and CTEPH, 0.9 cases per MAI per yr. 1-, 3- and 5-yr survival was 87%, 75% and 65%, respectively, with no differences between PAH and CTEPH. Male sex, right atrial pressure and cardiac index were independent predictors of death. Matching between observed survival and that predicted by different equations was closer when the characteristics of the cohorts were similar. Epidemiology and survival of PAH patients in the Spanish registry are similar to recent registries. Characteristics of the population from which survival prediction equations are derived influence their applicability to a different cohort. CTEPH is much less prevalent than PAH, although has a similar survival rate.

Pulmonary Hypertension: Clinical Presentation, Diagnosis, Treatment,and Dana Point World Symposium Highlights

Pulmonary arterial hypertension (PAH) is a progressive, debilitating, and potentially fatal disease. Symptoms of PAH are non-specific and may include dyspnea, fatigue, chest discomfort, pre-syncope/syncope, palpitations, lower extremity swelling, non-specific gastro-intestinal symptoms, weight loss, and cyanosis. Pulmonologists are increasingly involved in the care of these patients, whether at the initial presentation and diagnosis, medication titration, or for symptom relief and management of complications. The pulmonologist and intensivist also frequently care for patients that are at an increased risk of developing PAH, such as patients with cirrhosis, hypoxic lung disease, scleroderma, sickle cell disease, and HIV to name a few. An echocardiogram, although often inaccurate in estimating the right-sided heart pressures, is the best screening tool for PAH. A right heart catheterization is the gold standard for diagnosing PAH. Supplemental therapies may include oxygen, diuretics, and anticoagulation. In addition to the limited role of calciumchannel blockers, PAH-specific therapies fall into one of 3 families for now: Phospho-diesterase-5 inhibitors, endothelin receptor antagonists, and prostacyclins. The current estimated 2 year survival of PAH patients now exceeds 90%, compared to a historical median survival of 2-3 years.

Vasoreactivity to Inhaled Nitric Oxide with Oxygen Predicts Long‐Term Survival in Pulmonary Arterial Hypertension

Pulmonary vasodilator testing is currently used to guide management of patients with pulmonary arterial hypertension (PAH). However, the utility of the pulmonary vascular response to inhaled nitric oxide (NO) and oxygen in predicting survival has not been established. Eighty patients with WHO Group I PAH underwent vasodilator testing with inhaled NO (80 ppm with 90% O2 for 10 minutes) at the time of diagnosis. Changes in right atrial (RA) pressure, mean pulmonary artery pressure (mPAP), pulmonary capillary wedge pressure, Fick cardiac output, and pulmonary vascular resistance (PVR) were tested for associations to long-term survival (median follow-up 2.4 years). Five-year survival was 56%. Baseline PVR (mean±SD 850±580 dyne-sec/cm5) and mPAP (49±14 mmHg) did not predict survival, whereas the change in either PVR or mPAP while breathing NO and O2 was predictive. Patients with a ≥30% reduction in PVR with inhaled NO and O2 had a 53% relative reduction in mortality (Cox hazard ratio 0.47, 95% confidence interval (CI) 0.23-0.99, P=0.047), and those with a ≥12% reduction in mPAP with inhaled NO and O2 had a 55% relative reduction in mortality (hazard ratio 0.45, 95% CI 0.22-0.96, P=0.038). The same vasoreactive thresholds predicted survival in the subset of patients who never were treated with calcium channel antagonists (n=66). Multivariate analysis showed that decreases in PVR and mPAP with inhaled NO and O2 were independent predictors of survival. Reduction in PVR or mPAP during short-term administration of inhaled NO and O2 predicts survival in PAH patients.

Impact of RV Remodelling on Survival in PAH Patients: Role of RV Mass/Volume Ratio

PURPOSE: Pulmonary arterial hypertension (PAH) is a group of diseases characterized by an impressive increase in pulmonary vascular resistances (PVR) that causes severe right ventricular (RV) dysfunction. The prognosis is related to the severity of hemodynamic impairment. Because the pathophysiologic model is an afterload mismatch we hypotisize that the best RV adaption should be a “concentric” hypertrophy (i.e. high RV mass/volume ratio).

Current Drug Targets and Future Therapy of Pulmonary Arterial Hypertension

During the last few decades, we have witnessed major improvements in the therapy of pulmonary arterial hypertension (PAH). PAH is characterized by abnormal remodeling of the pulmonary artery (PA) and increased PA pressures, resulting in a high premature mortality. Intravenous epoprostenol was the first effective approach toward improving the symptoms and survival of PAH patients. New prostanoids have also exhibited substantial clinical benefits; however, their long-term effects are under investigation. Endothelin-receptor antagonists and sildenafil have increased the lineup of therapeutic options against PAH. Combination therapy using these drugs is promising and is currently undergoing scrutiny in large clinical trials. An extensive analysis of the molecular mechanisms of PAH will produce novel targeted therapies. Most of the promising molecules target the inflammatory and proliferative processes underlying pathological PA remodeling. Interestingly, drugs used for other diseases, such as statins, Rho-kinase inhibitors, imatinib mesylate, may control the pathological vascular remodeling of PAH. Gene and cell therapy using vectors expressing prostacyclin synthase, endothelial nitric oxide synthase, or vascular endothelial growth factor are also promising strategies. However, the efficacy and safety of these approaches should be further tested in clinical trials. Genetic studies revealed some crucial genetic dispositions of familial PAH, although their pathobiological roles have not yet been fully clarified. Collaboration for integrated research will address these issues and generate greater clinical benefits for PAH patients.

Drug Treatment of Pulmonary Arterial Hypertension

During the last decade we have witnessed substantial improvements in the therapeutic options for pulmonary arterial hypertension (PAH), including true innovations targeting some of the mechanisms involved in the pathogenesis of this devastating disease. Intravenous epoprostenol was the first drug to improve symptoms and survival of patients with PAH. Novel prostanoids, including subcutaneous treprostinil and inhaled iloprost, also have beneficial effects in many patients, although their long-term efficacy is less well known. Among the newer treatments for PAH, endothelin receptor antagonists and phosphodiesterase type 5 (PDE5) inhibitors have reshaped clinical practice. The endothelin receptor antagonist bosentan has been approved in many parts of the world and most current guidelines recommend this drug as first-line treatment for patients with PAH in functional class III. Novel endothelin receptor antagonists such as sitaxsentan sodium and ambrisentan are currently being investigated. The PDE5 sildenafil is also being intensively studied in patients with pulmonary hypertension, and most of the available data look promising, although approval for PAH is still pending. Other PDE5 inhibitors have not yet undergone extensive study in PAH. The increasing insight into the pathogenesis of PAH opens several new therapeutic opportunities, which include vasoactive intestinal peptide, selective serotonin reuptake inhibitors, adrenomedullin and HMG-CoA reductase inhibitors (statins). However, PAH is a complex disorder and targeting a single pathway can not be expected to be uniformly successful. Thus, combining substances with different modes of action is expected to improve symptoms, haemodynamics and survival in PAH patients, although combination therapy has yet to undergo the scrutiny of large randomised clinical trials.