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EXPERT was an international, multicenter, prospective, uncontrolled, non-interventional cohort study in patients with pulmonary hypertension treated with riociguat. Patients were followed for 1-4 years, and the primary outcomes were adverse events (AEs) and serious AEs (SAEs), including embolic/thrombotic and hemorrhagic events. Here we report data on patients with chronic thromboembolic pulmonary hypertension (CTEPH) receiving a vitamin K antagonist (VKA; n = 683) or a non-vitamin K antagonist oral anticoagulant (NOAC; n = 198) at baseline. AEs and SAEs were reported in 438 patients (64.1%) and 257 patients (37.6%), respectively, in the VKA group, and in 135 patients (68.2%) and 74 patients (37.4%) in the NOAC group. Exposure-adjusted hemorrhagic event rates were similar in the two groups, while exposure-adjusted embolic and/or thrombotic event rates were higher in the NOAC group, although the numbers of events were small. Further studies are required to determine the long-term effects of anticoagulation strategies in CTEPH., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Pulmonary hypertension (PH) due to left heart disease (LHD) is a frequent complication of heart failure (HF) and is associated with exercise intolerance, poor quality of life, increased risk of hospitalisations, and reduced overall survival. Since the recent Sixth World Symposium on Pulmonary Hypertension in 2018, there have been significant changes in the hemodynamic definitions and clinical classification of PH-LHD. PH-LHD can be subdivided into (1) isolated postcapillary PH (IpcPH) and (2) combined precapillary and postcapillary PH (CpcPH). This categorisation of PH-LHD is important because CpcPH shares certain pathophysiologic, clinical, and hemodynamic characteristics with pulmonary arterial hypertension and is associated with worse outcomes compared with IpcPH. A systematic approach using clinical history and noninvasive investigations is required in the diagnosis of PH-LHD. Right heart catheterisation with and without provocative testing is performed in expert centres and is indicated in selected individuals. Although the definition of IpcPH and CpcPH is based on measurements made with right heart catheterisation, distinguishing between these two entities is not always necessary. Despite strong evidence for medical therapy in patients with pulmonary arterial hypertension, those options have limited benefit in PH-LHD. Expert PH centres in Canada have been established to provide ongoing care for the more complex patient subgroups., (Copyright © 2020 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Objective: The soluble guanylate cyclase stimulator riociguat is approved for the treatment of adult patients with pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH) following Phase 3 randomized trials. The EXPosurE Registry RiociguaT in patients with pulmonary hypertension (EXPERT) study was designed to monitor the long-term safety of riociguat in clinical practice., Methods: EXPERT was an international, multicenter, prospective, uncontrolled, non-interventional cohort study of patients treated with riociguat. Patients were followed for at least 1 year and up to 4 years from enrollment or until 30 days after stopping riociguat treatment. Primary safety outcomes were adverse events (AEs) and serious adverse events (SAEs) coded using Medical Dictionary for Regulatory Activities preferred terms and System Organ Classes version 21.0, collected during routine clinic visits and collated via case report forms., Results: In total, 956 patients with CTEPH were included in the analysis. The most common AEs in these patients were peripheral edema/edema (11.7%), dizziness (7.5%), right ventricular (RV)/cardiac failure (7.7%), and pneumonia (5.0%). The most common SAEs were RV/cardiac failure (7.4%), pneumonia (4.1%), dyspnea (3.6%), and syncope (2.5%). Exposure-adjusted rates of hemoptysis/pulmonary hemorrhage and hypotension were low and comparable to those in the long-term extension study of riociguat (Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase-Stimulator Trial [CHEST-2])., Conclusion: Data from EXPERT show that in patients with CTEPH, the safety of riociguat in routine practice was consistent with the known safety profile of the drug, and no new safety concerns were identified., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The landscape of pulmonary hypertension (PH) has changed significantly since the last Canadian Cardiovascular Society/Canadian Thoracic Society position statement in 2005. Since then, advances in our understanding of the pathophysiology of PH and improvements in diagnostic and therapeutic options have transformed the care of patients with PH. Globally, PH has an estimated prevalence of 1%, increasing to 10% in those aged 65 years and older, most commonly due to left heart or lung disease. Although pulmonary arterial hypertension (PAH) is less common, the morbidity and mortality is significant and early diagnosis and treatment are essential. This document is targeted at clinicians and describes a framework for screening and diagnosis of PH, with recommendations for performance and interpretation of echocardiography, cardiac magnetic resonance imaging, and right heart catheterization. In addition, the current approach to PAH management in Canada including risk stratification and pharmacologic therapy aimed at achieving a low-risk profile is discussed. The rationale to avoid specific PAH therapy in patients with left heart disease and lung disease-related PH is emphasized, along with special considerations for the diagnosis and management of chronic thromboembolic PH. Future advancements in the identification of novel pathways and therapies, personalized approaches to direct therapy, as well as interventional approaches such as balloon pulmonary angioplasty for chronic thromboembolic PH promise to continue the rapid evolution of this field., (Copyright © 2020 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Background: The extent to which saline loading (SL) during cardiac catheterization influences clinical practice in pulmonary hypertension (PH) is unknown. We surveyed a national cohort of PH specialists to determine how SL affected diagnosis and management., Methods: Relevant clinical and hemodynamic data pre-SL for patients with a baseline pulmonary arterial wedge pressure (PAWP) ≤15 mm Hg were presented as surveys to 7 PH specialists. The specialists were asked to classify patients according to the WHO classification scheme, rate their confidence, and state their treatment plans. Hemodynamic data following 500 mL of SL was then presented, and specialists answered the same questions. A positive fluid challenge (PFC) was defined as PAWP >18 mm Hg after SL., Results: Seven specialists evaluated 48 cases, for a total of 336 surveys. SL influenced PH classification with 19.6% of cases reclassified as having a component of Group 2 PH. SL increased confidence in PH classification (mean difference 0.25; 95% CI 0.15-0.35). With a PFC, physicians were more likely to classify patients as PH due to left heart disease (OR 6.1; 95% CI 2.8-13.1), extend time to follow-up (OR 3.2; 95% CI 1.6-6.7), and discharge patients from PH clinic (OR 5.0; 95% CI 1.9-13.1). SL changed the treatment plan in 6.5% of cases, mostly with a PFC causing reconsideration in treatment initiation., Conclusion: The addition of SL to hemodynamic assessment of PH can impact physicians' classification and management decisions. However, decisions are not solely based on the SL results, but rather the entirety of the clinical data available., Competing Interests: Declaration of competing interest Dr. Weatherald reports grants, personal fees and non-financial support from Actelion Pharmaceuticals, personal fees and non-financial support from Bayer, personal fees from Novartis, grants from Canadian Vascular Network, grants from European Respiratory Society, outside the submitted work; Dr. Hambly reports grants and personal fees from Boehringer Ingelheim, grants and personal fees from Actelion Pharmaceuticals, personal fees from Bayer, personal fees from Novartis, grants and personal fees from Roche, outside the submitted work., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The past 2 decades have witnessed a >40% improvement in mortality for patients with heart failure and left ventricular systolic dysfunction. 1 This success has coincided with the stepwise availability of drugs that target neurohormonal activation: β-adrenergic receptor blockers (β-blockers), ACE (angiotensin-converting enzyme) inhibitors and ANG (angiotensin) II blockers, neprilysin inhibitors, and aldosterone antagonists. Our understanding of right heart failure (RHF) has lagged behind and many proven targeted therapies for left heart failure do not appear to provide similar benefits for RHF. Until recently, the right ventricle (RV) has often been viewed as less important than the left ventricle and in contemporary literature received the moniker "The Forgotten Ventricle". Recent advances in echocardiography and magnetic resonance imaging have enabled detailed assessments of RV anatomy and physiology in both health and disease allowing us to more accurately describe the clinical sequelae and end-organ manifestations of RHF. RV function is now recognized as one of the most important predictors of prognosis in many cardiovascular disease states. 2 Despite the significance of RV function to survival, there are no clinically approved therapies that directly nor selectively improve RV function. As well, relative to our understanding of left heart failure, the basis for RHF remains poorly understood. This article aims to condense the current knowledge on RV adaptation and failure, review current management strategies for RHF, and explore evolving therapeutic approaches.

Background: The effects of riociguat treatment on right ventricular (RV) metabolism, perfusion, and output in patients with chronic thromboembolic pulmonary hypertension (CTEPH) are unknown. In this study, RV changes associated with riociguat therapy were investigated., Methods: Six patients with CTEPH received riociguat for 6 months. Right heart catheterization (only baseline), cardiac magnetic resonance imaging, and positron emission tomography using tracers for myocardial glucose uptake ( 18 F-fluorodeoxyglucose [ 18 F-FDG]) and perfusion ( 13 N-ammonia) were performed at baseline and follow-up time points., Results: At baseline, median RV ejection fraction (RVEF) was 47% (22%-53%) with a mean pulmonary artery pressure (PAP) of 42 mm Hg (27-57 mmHg). Two patients were New York Heart Association functional class III and the rest were class II. Baseline RV 18 F-FDG uptake was inversely correlated with RVEF (r s  = -0.82; P = 0.04) and positively correlated with mean PAP (r s  = 0.94; P = 0.004). Riociguat treatment was associated with a significant increase in RV stroke volume index by 13.5 mL/m 2 (6.8-17.5 mL/m 2 ; P = 0.03) and a trend of improved RVEF by 5% (1%-9%; P = 0.09). Myocardial fibrosis indicated by the volume of myocardium exhibiting late gadolinium enhancement was reduced by 4.4 mL (0.2-5.2 mL; P = 0.09). 18 F-FDG (metabolism) and 13 N-ammonia (perfusion) positron emission tomography did not show a significant difference over the follow-up period. The studied patients (except for 1) had a reduction in the ratio of RV 18 F-FDG uptake to RV perfusion, suggesting improved RV metabolism-flow relationships., Conclusions: Riociguat treatment was associated with increased RV stroke volume index and trends for improvement in myocardial remodelling in patients with CTEPH. A larger clinical study is warranted to observe the therapeutic benefits of riociguat on RV remodelling., (Copyright © 2018 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Purpose: A proportion of patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) do not achieve treatment goals or experience side effects on their current therapy. In such cases, switching patients to a new drug while discontinuing the first may be a viable and appropriate treatment option. CAPTURE was designed to investigate how physicians manage the switching of patients to riociguat in real-world clinical practice. Observations from the study were used to assess whether recommendations in the riociguat prescribing information are reflected in clinical practice., Methods: CAPTURE was an international, multicenter, uncontrolled, retrospective chart review that collected data from patients with PAH or inoperable or persistent/recurrent CTEPH who switched to riociguat from another pulmonary hypertension (PH)-targeted medical therapy. The primary objective of the study was to understand the procedure undertaken in real-world clinical practice for patients switching to riociguat., Results: Of 127 patients screened, 125 were enrolled in CAPTURE. The majority of patients switched from a phosphodiesterase type 5 inhibitor (PDE5i) to riociguat and the most common reason for switching was lack of efficacy. Physicians were already using the recommended treatment-free period when switching patients to riociguat from sildenafil, but a slightly longer period than recommended for tadalafil. In line with the contraindication, the majority of patients did not receive riociguat and PDE5i therapy concomitantly. Physicians also followed the recommended dose-adjustment procedure for riociguat., Conclusion: Switching to riociguat from another PH-targeted therapy may be feasible in real-world clinical practice in the context of the current recommendations.

Background: Altered myocardial energy metabolism has been linked to worsening of RV function in pulmonary arterial hypertension (PAH). The aim of this study was to evaluate RV glucose and fatty acid metabolism in vivo in a rat model of PAH using positron emission tomography (PET) and investigate the effects of Macitentan on RV substrate utilization., Methods: PAH was induced in male Sprague-Dawley rats by a single subcutaneous injection of Sugen 5416 (20 mg/kg) followed by 3 weeks of hypoxia (10% oxygen). At week 5 post-injection, the PAH rats were randomized to Macitentan (30 mg/kg daily) treatment or no treatment. Substrate utilization was serially assessed 5 and 8 weeks post-injection with 2-[ 18 F]fluoro-2-deoxyglucose (FDG) and 14(R,S)-[18F]fluoro-6-thia-heptadecanoic acid (FTHA) PET for glucose and fatty acid metabolism respectively and correlated with in vivo functional measurements., Results: PAH induction resulted in a 2.5-fold increase in RV FDG uptake (standardized uptake value (SUV) of normal control: 1.6 ± 0.4, week 5: 4.1 ± 1.9, week 8: 4.0 ± 1.6, P < 0.05 for all groups vs. control). RV FTHA showed twofold increased uptake at week 5 (SUV control: 1.50 ± 0.39, week 5: 3.06 ± 1.10, P = 0.03). Macitentan significantly decreased RV FDG uptake at 8 weeks (SUV: 2.5 ± 0.9, P = 0.04), associated with improved RV ejection fraction and reduced RV systolic pressure, while FTHA uptake was maintained., Conclusion: PAH is associated with metabolic changes in the RV, characterized by a marked increase in FDG and FTHA uptake. Macitentan treatment reduced PAH severity and was associated with a decrease in RV FDG uptake and improved RV function.

Aims: We investigated the role of metabolic alterations in the development of a maladaptive right ventricular (RV) response in pulmonary arterial hypertension (PAH), which has not previously been undertaken. This study evaluated relationships between glucose and fatty acid metabolism obtained using PET with invasive pulmonary haemodynamics, RV measurements, and RV function to gain insight into the mechanism of RV maladaptation., Methods and Results: Seventeen consecutive PAH patients (mean age 56 ± 15) who underwent right heart catheterization [mean pulmonary arterial pressure (mPAP) 43 ± 12 mmHg] had cardiac 18F-fluoro-2-deoxyglucose (FDG) and (18)F-fluoro-6-thioheptadecanoic acid (FTHA) PET imaging. RV and left ventricular (LV) FDG and FTHA uptake standard uptake values (SUVs) were measured. The SUV was corrected for the partial volume effect (SUV PVE ) based on cardiac magnetic resonance imaging (CMR). Right ventricular ejection fraction (RVEF) was determined by CMR. There was a significant positive correlation between mPAP and RV/LV FDG SUV PVE (r = 0.68, P = 0.003), and the ratio of RV/LV FDG SUV : RV/LV FTHA SUV (r = 0.60, P = 0.02). RVEF was negatively correlated with RV/LV FDG SUV PVE uptake (r = -0.56, P = 0.02) and RV/LV FTHA SUV PVE (r = -0.62, P = 0.019)., Conclusion: Increased pulmonary arterial pressures are associated with increases in the ratio of FDG/FTHA uptake in the RV. Inverse correlation between the uptake of the metabolic tracers and RV function may reflect a shift towards increased fatty acid oxidation and glycolysis associated with RV failure in maladaptive remodelling., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Pulmonary arterial hypertension is an uncommon and devastating chronic illness with no known cure. Little is known about the disease, and even less about the psychosocial burdens. While it is important to create awareness about the physical aspects of the disease, it is equally important to create awareness about the psychosocial burdens patients and their families face. We reviewed the literature to better understand these psychosocial burdens, which include impact from physical limitations, emotional strains, financial burdens, social isolation, lack of intimacy in relationships, and an overall lack of information. The findings can be used to assist health care providers to understand the psychosocial challenges that are being experienced by patients and families in order to better provide supportive care. The creation of a standardized tool to assess the psychosocial burdens at each clinic visit can benefit health care providers by addressing challenges faced and facilitate subsequent referral to appropriate specialists.

Background: In recent years, a significant number of costly oral therapies have become available for the treatment of pulmonary arterial hypertension (PAH). Funding decisions for these therapies requires weighing up their effectiveness and costs., Objective: The aim of this study was to assess the cost effectiveness of monotherapy with oral PAH-specific therapies versus supportive care as initial therapy for patients with functional class (FC) II and III PAH in Canada., Methods: A cost-utility analysis, from the perspective of a healthcare system and based on a Markov model, was designed to estimate the costs and quality-adjusted life-years (QALYs) associated with bosentan, ambrisentan, riociguat, tadalafil, sildenafil and supportive care for PAH in treatment-naïve patients. Separate analyses were conducted for cohorts of patients commencing therapy at FC II and III PAH. Transition probabilities, based on the relative risk of improving and worsening in FC with treatment versus placebo, were derived from a recent network meta-analysis. Utility values and costs were obtained from published data and clinical expert opinion. Extensive sensitivity analyses were conducted., Results: Analysis suggests that sildenafil is the most cost-effective therapy for PAH in patients with FC II or III. Sildenafil was both the least costly and most effective therapy, thereby dominating all other treatments. Tadalafil was also less costly and more effective than supportive care in FC II and III; however, sildenafil was dominant over tadalafil. Even given the uncertainty within the clinical inputs, the probabilistic sensitivity analysis showed that apart from sildenafil and tadalafil, the other PAH therapies had negligible probability of being the most cost effective., Conclusion: The results show that initiation of therapy with sildenafil is likely the most cost-effective strategy in PAH patients with either FC II or III disease.

Interferon (IFN) therapy has an important role in the treatment of multiple sclerosis and chronic hepatitis C infection. A few case reports have described an association between IFN therapy and the development of irreversible pulmonary arterial hypertension (PAH), and it is currently listed as a possible drug-induced cause of PAH in the most recent classification of pulmonary hypertension. A causal link between IFN use and PAH remains to be elucidated; many reports of PAH resulting from IFN occur in individuals with some other risk factor for PAH. The authors present a case involving a patient with multiple sclerosis with no known risk factors for PAH, who developed severe PAH after exposure to IFN therapy. The patient experienced significant clinical and hemodynamic improvement, with normalization of her pulmonary pressures after the initiation of combination therapy for PAH. At 28 months after diagnosis, she remains asymptomatic with no hemodynamic evidence of PAH and has been off all PAH therapy for 10 months.

Pulmonary hypertension (PH) continues to be a devastating disease, with a poor prognosis and high mortality rate if not treated early. Unfortunately, most patients are still diagnosed late in the course of the disease. Therefore, it is crucial to have a low threshold for suspecting PH and to refer patients early to specialized centres for diagnostic workup and management. In this article we focus on updated evidence-based screening and diagnosis in adults, based on the fifth World Symposium on Pulmonary Hypertension in 2013. The updated hemodynamic definition of PH includes a pulmonary vascular resistance > 3 Wood units. A new component to the hemodynamic definition of PH has been proposed in left heart disease, based on a diastolic pulmonary gradient (diastolic pulmonary arterial pressure - mean pulmonary artery wedge pressure), > 7 mm Hg. The term "borderline PH" for mean pulmonary artery pressures 21-24 mm Hg is discouraged, with emphasis on its significance for careful follow-up in high-risk patients, especially in systemic sclerosis. Annual pulmonary arterial hypertension (PAH) screening with a 2-step algorithm is recommended in asymptomatic systemic sclerosis patients. An updated simplified PH diagnostic algorithm approach is proposed. Genetic testing reveals mutations in bone morphogenic protein receptor type II in 70% of familial PAH, and is useful for screening asymptomatic family members. Important associated conditions that should be considered include thyroid disease, left heart disease, toxic causes, lung diseases (including pulmonary thromboembolism), hemolytic anemia, and human immunodeficiency virus infection. Biomarkers have been identified that correlate with PAH severity and mortality and are useful in follow-up., (Copyright © 2015 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

We describe a patient with fibrosing mediastinitis after childhood histoplasmosis who presented with severe pulmonary hypertension secondary to pulmonary vein stenoses. Stenting of 2 stenosed pulmonary veins via a transseptal approach resulted in an immediate decrease in systolic pulmonary artery pressure from 90 to 68 mm Hg and improvement in dyspnea and cardiac index, which was sustained at 6 months. This case highlights the importance of routinely assessing the pulmonary veins during workup for pulmonary hypertension., (Copyright © 2015 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Pulmonary arterial hypertension (PAH) is a syndrome characterized by lung vascular intimal lesions, smooth muscle layer hypertrophy, perivascular inflammation, and concomitant right ventricular (RV) remodeling which can ultimately lead to the RV function decline known as RV failure (RVF). A key determining factor for RVF development is the RV metabolic state defined by the level of ischemia and glycolysis which constitute a vicious cycle of hypoxia, metabolic shift from glucose oxidation (GO) to glycolysis, increased RV systolic pressure (RVSP), decreased RV output, and further myocardial ischemia. In this context, 2-deoxy-2-[(18)F]fluoro-D-glucose (FDG) positron emission tomography (PET) has been used for the measurement of glucose uptake (GU) as an indicator of glucose metabolism in the right heart and pulmonary vasculature. The focus of this review is the application of FDG PET modality for assessing PAH severity and clinical outcome.

Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are serious and often fatal diseases. The pathophysiology of both diseases is complex and in part is attributed to alterations in the nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate pathway. Riociguat, a novel sGC stimulator, acts on this pathway through a dual mechanism of action by directly stimulating sGC in a NO-independent manner and also increasing the sensitivity of sGC to NO. Based on benefits from clinical trials for both PAH and CTEPH, riociguat was approved by Health Canada and the US Food and Drug Administration as the first medical therapy for patients with CTEPH who are deemed inoperable or have residual/recurrent PH after pulmonary endarterectomy (PEA), and as a novel treatment option for patients with PAH. This article reviews the key findings from the phase III trials for riociguat that led to these approvals and the implications this has for the treatment of patients with PAH and CTEPH., (Copyright © 2014 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Purpose: The right ventricle (RV) has a high capacity to adapt to pressure or volume overload before failing. However, the mechanisms of RV adaptation, in particular RV energetics, in patients with pulmonary hypertension (PH) are still not well understood. We aimed to evaluate RV energetics including RV oxidative metabolism, power and efficiency to adapt to increasing pressure overload in patients with PH using (11)C-acetate PET., Methods: In this prospective study, 27 patients with WHO functional class II/III PH (mean pulmonary arterial pressure 39.8 ± 13.5 mmHg) and 9 healthy individuals underwent (11)C-acetate PET. (11)C-acetate PET was used to simultaneously measure oxidative metabolism (k mono) for the left ventricle (LV) and RV. LV and RV efficiency were also calculated., Results: The RV ejection fraction in PH patients was lower than in controls (p = 0.0054). There was no statistically significant difference in LV k mono (p = 0.09). In contrast, PH patients showed higher RV k mono than did controls (0.050 ± 0.009 min(-1) vs. 0.030 ± 0.006 min(-1), p < 0.0001). PH patients exhibited significantly increased RV power (p < 0.001) and hence increased RV efficiency compared to controls (0.40 ± 0.14 vs. 0.017 ± 0.12 mmHg·mL·min/g, p = 0.001)., Conclusion: The RV oxidative metabolic rate was increased in patients with PH. Patients with WHO functional class II/III PH also had increased RV power and efficiency. These findings may indicate a myocardial energetics adaptation response to increasing pulmonary arterial pressure.

Pulmonary arterial hypertension (PAH) is a disorder in which pulmonary arterial remodeling and vasoconstriction progressively lead to right heart failure (HF), exercise intolerance, and high mortality. Beta-blockers have been shown to decrease mortality in left-sided HF, but their efficacy in isolated right HF associated with PAH is uncertain. Patients with PAH may have cardiac co-morbidities for which β-blocker therapy is indicated, and the relative risk benefit of this therapy remains to be proved. This is a prospective cohort study of 94 consecutive patients with PAH divided into 2 groups with and without β-blocker use at baseline. Rate of all-cause mortality, PAH-related hospitalization, change in 6-minute walk test, right ventricular structure and function measured by echocardiography, and hemodynamics measured by right heart catheterization were determined between subjects with and without β-blocker use. Beta-blocker use was common (28%) in this cohort. After a median follow-up of 20 months, changes in pulmonary hemodynamics and right ventricular size and function were similar between groups. There were no statistically significant differences in adverse events including PAH-related hospitalization or all-cause mortality (p = 0.19), presence of right HF by last visit (p = 0.75), or change in last 6-minute walk distance (p = 0.92). In conclusion, β-blocker use is not uncommon in a select group of patients with PAH and cardiac co-morbidities and did not appear to exert detrimental effects in clinical, functional, and hemodynamic outcomes. Further randomized data are needed to evaluate the potential benefits and risks of β-blocker use in patients with PAH., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Increased central venous pressures have been associated with the development of worsening renal function (WRF), an important marker of prognosis. We sought to determine the incidence and prognostic significance of WRF in pulmonary hypertension patients (PH) with isolated right HF. A prospective study of PH clinic patients admitted to hospital for right HF. WRF was defined as a rise in creatinine of 26 μmol/L (0.3 mg/dL) within the first 48 hours of admission. A total of 32 patients were enrolled in this study, 67% of patients had moderate-severe chronic kidney disease with an eGFR ≤ 60 mL/min and 34% (n=11) developed WRF during their admission. The mean right atrial pressure was higher in patients with WRF (19 ± 7 mm Hg vs 12 ± 6 mm Hg, P=.05). A total of 36% of patients with WRF died in hospital compared to 5% in the group that did not develop WRF (OR for hospital death 13.3 ± 16, P=.03). The combined endpoint of death or readmission at 6 months was 45% in the WRF group and 43% in the group without WRF (P=.89). Significant renal dysfunction is common in patients with PH and an acute decline in renal function is an important marker of in hospital death and short term mortality in right heart failure., (© 2012 Wiley Periodicals, Inc.)

Background: Use of endothelin receptor antagonists (ERA), phosphodiesterase type-5 (PDE-5) inhibitors and prostaglandin analogues has resulted in improved outcomes in idiopathic pulmonary arterial hypertension (IPAH) and systemic sclerosis-associated PAH (SSc-PAH) patients. However, patients often deteriorate on monotherapy. The objective of this study is to evaluate the effect of dual therapy on outcomes in IPAH and SSc-PAH., Methods: A systematic review of MEDLINE (1950-2011), EMBASE (1980-2011) and CINAHL (inception-2011) was conducted to identify studies that evaluated the effect of any dual combination of ERA, PDE-5 inhibitors or prostaglandin analogues on 6-min walk distance (6MWD), functional class (FC), haemodynamics, quality-of-life (QoL) or time-to-clinical-worsening in IPAH or SSc-PAH. A standardized form was used to abstract design, sample size, aetiology, outcome and treatment effect., Results: Twenty-six observational studies and 6 randomized trials were identified. Using combination PDE-5 inhibitor and prostaglandin analogues, 6/7 studies reported improvement in 6MWD, 6/8 studies reported improvement in FC, 6/6 studies reported improvement in haemodynamics and 1 trial demonstrated improvement in QoL and time-to-clinical-worsening. Using combination ERA and prostaglandin analogues, 4/6 studies and 1 trial reported improvement in 6MWD, 3/3 studies and 1 trial reported improvement in FC, 4/5 studies and 1 trial reported improvement in PAP. Using combination ERA and PDE-5 inhibitor, 4/7 studies reported an improvement in 6MWD, and 2/6 report improvement in FC., Conclusion: The evidence suggests a beneficial effect of dual therapy in IPAH and SSc-PAH, particularly those who are deteriorating on monotherapy. Research should focus on subsets of patients to identify the optimal timing and combination of dual therapy., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: We explored the mechanism of maladaptive right ventricular (RV) remodeling in Fischer compared with Sprague-Dawley (SD) rats exposed to pressure overload.Methods: Pulmonary hypertension was induced by injection of the VEGFR antagonist, SU5416, followed by a 3-week exposure to hypoxia (Sugen chronic hypoxia). In vivo oxidative metabolism was assessed by RV/left ventricle ratio of [11C]acetate positron emission tomography clearance (kmono). Unbiased, global transcriptional and proteomic profiling was performed in Fischer and SD rats at baseline and after Sugen chronic hypoxia.Results: All Fischer rats succumbed to RV failure by 5 weeks, whereas SD rats showed preserved RV function and 88% survival beyond 9 weeks (P<0.0001). Fischer rats exhibited increased oxidative metabolism at 4 weeks (P<0.05) and impaired RV efficiency compared with SD (work metabolic index: 52±10 versus 91±27 mmHg·mL/cm2, respectively; P<0.05), but no differences in mitochondrial complex activity. AK1 (adenylate kinase 1) was among the top 10 differentially expressed genes between Fischer and SD rats, with markedly lower RV expression in Fischer rats (FC: 3.36, P<0.05), confirmed by proteomic analysis and validated by Western blotting (>10-fold reduction, P<0.001). While whole-genome sequencing failed to reveal any coding region mutations in Fischer rats, there was a unique variant in a highly conserved upstream flanking region likely involved in the regulation of AK1 expression.Conclusions: Therefore, Fischer rats exhibit profound AK1 deficiency and inefficient cardiac energetics likely related to reduced adenosine triphosphate shuttling from the mitochondria to the contractile fibers. This represents a novel mechanism for RV failure in response to chronic increases in afterload. [ABSTRACT FROM AUTHOR]