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In pulmonary hypertension (PH), right ventricular (RV) performance determines survival. Pulmonary artery (PA) stiffening is an important biomechanical event in PH and also predicts survival based on the PA relative area change (RAC) measured at rest using magnetic resonance imaging (MRI). In this exploratory study, we sought to generate novel hypotheses regarding the influence of stress RAC on PH prognosis and the interaction between PA stiffening, RV performance and survival. Fifteen PH patients underwent dobutamine stress-MRI (ds-MRI) and right heart catheterization. RACREST, RACSTRESS, and ΔRAC (RAC STRESS - RAC REST) were correlated against resting invasive hemodynamics and ds-MRI data regarding RV performance and RV-PA coupling efficiency (n'vv [RV stroke volume/RV end-systolic volume]). The impact of RAC, RV data, and n'vv on ten-year survival were determined using Kaplan-Meier analysis. PH patients with a low ΔRAC (

BackgroundRight ventricular (RV) function is a major determinant of outcome in pulmonary arterial hypertension (PAH). However, uncertainty persists about the optimal method of evaluation.MethodsWe measured RV end-systolic and end-diastolic volumes (ESV and EDV) using cardiac magnetic resonance imaging and RV pressures during right heart catheterization in 140 incident PAH patients and 22 controls. A maximum RV pressure (Pmax) was calculated from the nonlinear extrapolations of early and late systolic portions of the RV pressure curve. The gold standard measure of RV function adaptation to afterload, or RV-arterial coupling (Ees/Ea) was estimated by the stroke volume (SV)/ESV ratio (volume method) or as Pmax/mean pulmonary artery pressure (mPAP) minus 1 (pressure method) (n=84). RV function was also assessed by ejection fraction (EF), right atrial pressure (RAP) and SV.ResultsHigher Ea and RAP, and lower compliance, SV and EF predicted outcome at univariate analysis. Ees/Ea estimated by the pressure method did not predict outcome but Ees/Ea estimated by the volume method (SV/ESV) did. At multivariate analysis, only SV/ESV and EF were independent predictors of outcome. Survival was poorer in patients with a fall in EF or SV/ESV during follow-up (n=44, p=0.008).ConclusionRV function to predict outcome in PAH is best evaluated by imaging derived SV/ESV or EF. In this study, there was no added value of invasive measurements or simplified pressure-derived estimates of RV-arterial coupling.

Data obtained in human lung tissue and preclinical models suggest that oxidative stress and increased apoptosis signal-regulating kinase 1 (ASK1) activity might have a prominent role in the pathobiology of pulmonary arterial hypertension (PAH). The purpose of this study was to determine the efficacy, safety, and tolerability of the ASK1 inhibitor selonsertib compared with placebo in patients with PAH. We did a randomised, double-blind, placebo-controlled, phase 2 trial at 46 centres located in Canada, France, Germany, Italy, the Netherlands, Spain, the UK, and the USA. Participants were aged 18–75 years and had an established diagnosis of idiopathic or hereditary PAH, or PAH associated with connective tissue disease, drugs or toxins, human immunodeficiency virus, or repaired congenital heart defects. Patients were stratified by PAH aetiology and background therapy, and randomly assigned (1:1:1:1) using an interactive voice-response or web-response system to placebo or selonsertib 2 mg, 6 mg, or 18 mg administered orally once daily. Both placebo and selonsertib were in tablet form. The primary efficacy endpoint was change in pulmonary vascular resistance, measured by right heart catheterisation, from baseline to week 24 in the full analysis set. Pair-wise comparisons between each of the selonsertib groups and the placebo group were made with a stratified Wilcoxon (van Elteren) rank sum test for participants without major protocol deviations who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov , NCT02234141. Between Dec 3, 2014, and Nov 13, 2015, 151 patients were enrolled and randomly assigned. Of 150 participants who received selonsertib or placebo, 134 (89%) completed 24 weeks of the randomly assigned treatment; all were on background PAH therapy (138 [92%] on combination therapy). 90 (60%) patients were in functional class II and 60 (40%) in functional class III. Mean baseline pulmonary vascular resistance was 772 (SD 334) dyn·s/cm5. Change in pulmonary vascular resistance was 6·0 dyn·s/cm5 (SD 28·0; n=31) for placebo, and 35·0 (35·4) dyn·s/cm5 (n=35; p=0·21 vs placebo) for 2 mg selonsertib, −28·0 (30·2) dyn·s/cm5 (n=34; p=0·27 vs placebo) for 6 mg selonsertib, and −21·0 (37·9) dyn·s/cm5 (n=36; p=0·60 vs placebo) for 18 mg selonsertib. The most frequent adverse events were headache (17 [15%]), abnormal dreams (eight [7%]), nausea (seven [6%]), and diarrhoea (seven [6%]) in the selonsertib groups, and headache (six [16%]), nausea (five [14%]), and diarrhoea (two [5%]) in the placebo group. Serious adverse events occurred in 23 (20%) of 113 selonsertib-treated patients and seven (19%) of 37 patients who received placebo. Selonsertib once daily for 24 weeks did not lead to a significant reduction in pulmonary vascular resistance or to clinical improvement in patients with PAH, but appeared to be safe and well tolerated. Although these data do not support the clinical use of selonsertib in PAH, further study of the potential of targeting the ASK1–p38 pathway in PAH is warranted. Gilead Sciences. [ABSTRACT FROM AUTHOR]

Aims This prospective, randomized, controlled, multicentre study aimed to evaluate efficacy and safety of exercise training in patients with pulmonary arterial (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). Methods and results For the first time a specialized PAH/CTEPH rehabilitation programme was implemented in 11 centres across 10 European countries. Out of 129 enrolled patients, 116 patients (58 vs. 58 randomized into a training or usual care control group) on disease-targeted medication completed the study [85 female; mean age 53.6 ± 12.5 years; mean pulmonary arterial pressure 46.6 ± 15.1 mmHg; World Health Organization (WHO) functional class II 53%, III 46%; PAH n  = 98; CTEPH n  = 18]. Patients of the training group performed a standardized in-hospital rehabilitation with mean duration of 25 days [95% confidence interval (CI) 17–33 days], which was continued at home. The primary endpoint, change of 6-min walking distance, significantly improved by 34.1 ± 8.3 m in the training compared with the control group (95% CI, 18–51 m; P  < 0.0001). Exercise training was feasible, safe, and well-tolerated. Secondary endpoints showed improvements in quality of life (short-form health survey 36 mental health 7.3 ± 2.5, P  = 0.004), WHO-functional class (training vs. control: improvement 9:1, worsening 4:3; χ2 P  = 0.027) and peak oxygen consumption (0.9 ± 0.5 mL/min/kg, P  = 0.048) compared with the control group. Conclusion This is the first multicentre and so far the largest randomized, controlled study on feasibility, safety, and efficacy of exercise training as add-on to medical therapy in PAH and CTEPH. Within this study, a standardized specialized training programme with in-hospital start was successfully established in 10 European countries. [ABSTRACT FROM AUTHOR]

Riociguat and phosphodiesterase-5 inhibitors (PDE5i), approved for the treatment of pulmonary arterial hypertension (PAH), act on the same pathway via different mechanisms. Riociguat might be an alternative option for patients with PAH who do not respond sufficiently to treatment with PDE5i, but comparisons of the potential benefits of riociguat and PDE5i in these patients are needed. The aim of this trial was to assess the effects of switching to riociguat from PDE5i therapy versus continued PDE5i therapy in patients with PAH at intermediate risk of 1-year mortality. Riociguat rEplacing PDE5i therapy evaLuated Against Continued PDE5i thErapy (REPLACE) was an open-label, randomised controlled trial in 81 hospital-based pulmonary hypertension centres in 22 countries. The study enrolled patients aged 18–75 years with symptomatic PAH at intermediate risk of 1-year mortality (based on the European Society for Cardiology–European Respiratory Society guideline thresholds for WHO functional class and 6-min walk distance [6MWD]) who were receiving treatment with a PDE5i with or without an endothelin receptor antagonist for at least 6 weeks before randomisation. Patients were excluded if they had been previously treated with riociguat, had used prostacyclin analogues or prostacyclin receptor agonists within 30 days before randomisation, had clinically significant restrictive or obstructive parenchymal lung disease, or had left heart disease. Patients were randomly assigned (1:1) to remain on PDE5i treatment (oral sildenafil [≥60 mg per day] or oral tadalafil [20–40 mg per day]; the PDE5i group) or to switch to oral riociguat (up to 2·5 mg three times per day; the riociguat group), using an interactive voice and web response system, stratified by cause of PAH. The primary endpoint was clinical improvement by week 24, defined as an absence of clinical worsening and prespecified improvements in at least two of three variables (6MWD, WHO functional class, and N -terminal prohormone of brain natriuretic peptide), analysed using last observation carried forward in all randomly assigned patients with observed values at baseline and week 24 who received at least one dose of study medication (the full analysis set). Secondary endpoints included clinical worsening events. The trial has been completed and is registered with ClinicalTrials.gov , NCT02891850. Between Jan 11, 2017, and July 31, 2019, 293 patients were screened, of which 226 patients were randomly assigned to the riociguat group (n=111) or to the PDE5i group (n=115). 211 patients completed the study and 14 patients discontinued (seven in each group). One patient assigned to the PDE5i group did not receive treatment, so 225 patients were included in the safety analysis, and one further patient in the PDE5i group had missing components of the composite primary endpoint at baseline, so 224 patients were included in the full analysis set. The primary endpoint was met by 45 (41%) of 111 patients in the riociguat group and 23 (20%) of 113 patients in the PDE5i group; odds ratio [OR] 2·78 (95% CI 1·53–5·06; p=0·0007). Clinical worsening events occurred in one (1%) of 111 patients in the riociguat group (hospitalisation due to worsening PAH) and 10 (9%) of 114 patients in the PDE5i group (hospitalisation due to worsening PAH [n=9]; disease progression [n=1]; OR 0·10 [0·01–0·73]; p=0·0047). The most frequently occurring adverse events were hypotension (15 [14%]), headache (14 [13%]), and dyspepsia (10 [9%]) in the riociguat group, and headache (eight [7%]), cough (seven [6%]), and upper respiratory tract infection (seven [6%]) in the PDE5i group. Serious adverse events were reported in eight (7%) of 111 patients in the riociguat group and 19 (17%) of 114 patients in the PDE5i group. During the study, four patients died in the PDE5i group, one of them during the safety follow-up period. Switching to riociguat from PDE5i treatment, both of which act via the nitric oxide–soluble guanylate cyclase–cyclic guanosine monophosphate pathway, could be a strategic option for treatment escalation in patients with PAH at intermediate risk of 1-year mortality. Bayer AG, Merck Sharp & Dohme. [ABSTRACT FROM AUTHOR]

Exercise training as treatment has become well established in many cardiorespiratory conditions. This is also increasingly the case in pulmonary arterial hypertension, where several studies have demonstrated improvements in symptoms, exercise capacity and quality of life. There remains, however, much potential for development. Current research is focused on clarifying the mechanism of benefit in pulmonary hypertension and exploring strategies for both optimizing the treatment effect and widening access to this intervention. [ABSTRACT FROM AUTHOR]

Clinical assessment of right ventricular (RV) contractility in diseases such as pulmonary arterial hypertension (PAH) has been hindered by the lack of a robust methodology. Here, a novel, clinically viable, single-beat method was developed to assess end-systolic elastance (Ees), a measure of right ventricular (RV) contractility. We hypothesized that this novel approach reduces uncertainty and interobserver variability in the estimation of the maximum isovolumic pressure (Piso), the key step in single-beat methods. The new method was designed to include a larger portion of the RV pressure data and minimize subjective adjustments by the operator. Data were obtained from right heart catheterization of PAH patients in a multicenter prospective study (data set 1) and a single-center retrospective study (data set 2). To obtain Piso, three independent observers used an established singlebeat method (based on the first derivative of the pressure waveform) and the novel method (based on the second derivative). Interobserver variability analysis included paired t-test, one-way ANOVA, interclass correlation (ICC) analysis, and a modified Bland-Altman analysis. The Piso values obtained from the two methods were linearly correlated for both data set 1 (R² = 0.74) and data set 2 (R² = 0.91). Compared with the established method, the novel method resulted in smaller interobserver variability (P < 0.001), nonsignificant differences between observers, and a narrower confidence interval. By reducing uncertainty and interobserved variability, this novel approach may pave the way for more effective clinical management of PAH. [ABSTRACT FROM AUTHOR]

Daily physical activity is reduced in precapillary pulmonary hypertension (PH), but the underlying mechanisms are inadequately explored. We sought to investigate clinical and physiological relations of daily physical activity and profile differences between less and more active patients with precapillary PH. A prospective, cross-sectional study of 20 patients with precapillary PH who undertook 1) a comprehensive clinical assessment, 2) a preliminary treadmill test, 3) 7-day monitoring of daily walking intensity with triaxial accelerometry, and 4) a personalized treadmill test corresponding to the individual patient mean daily walking intensity with real-time physiological measurements. Significant clinical correlations with individual patient mean walking intensity [1.71 ± 0.27 (SD) m/s²] were observed for log-transformed N-terminal probrain natriuretic peptide (log NT-proBNP; r = −0.75, P = <.001), age (r = −0.70, P = 0.001), transfer factor for carbon monoxide %predicted (r = 0.51, P = 0.022), and 6-min walk distance (r = 0.50, P = 0.026). Significant physiological correlations were obtained for heart rate reserve (r = 0.68, P = 0.001), quadriceps tissue oxygenation index (Q-StO2; r = 0.58, P = 0.008), change in Q-StO2 from rest (r = 0.60, P = 0.006), and ventilatory equivalent for oxygen uptake (r = −0.56, P = 0.013). Stepwise multiple regression analyses retained log NT-proBNP (R² = 0.55), heart rate reserve (R² = 0.44), and Q-StO2 (R² = 0.13) accounting for a significant variance in individual walking intensity. Less active patients had greater physical activity-induced cardiopulmonary impairment, worse quadriceps oxygenation profile, and compromised health-related quality of life compared with more active patients. These preliminary findings suggest a significant relation between right ventricular and peripheral muscle oxygenation status and reduced daily physical activity in precapillary PH. Further research is warranted to unravel the physiological determinants, establish clinical predictors, and identify beneficial interventions. NEW & NOTEWORTHY Daily physical activity holds promise to be a meaningful, patient-related outcome measure in pulmonary hypertension. In this study, novel findings in a representative sample of patients with precapillary pulmonary hypertension link reduced daily walking activity, as measured by triaxial accelerometry, with compromised right ventricular and pulmonary vascular status, peripheral muscle oxygenation, and health-related quality of life, providing a preliminary insight into the physiological mechanisms and clinical predictors of daily physical activity in precapillary pulmonary hypertension. [ABSTRACT FROM AUTHOR]

Background: Patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH), in particular systemic sclerosis (SSc), had an attenuated response compared with idiopathic PAH in most trials. Thus, there is uncertainty regarding the benefit of PAH-targeted therapy in some forms of CTD-PAH.Objective: To explore the safety and efficacy of initial combination therapy with ambrisentan and tadalafil versus ambrisentan or tadalafil monotherapy in patients with CTD-PAH and SSc-PAH enrolled in the AMBITION trial.Methods: This was a post hoc analysis of patients with CTD-PAH and SSc-PAH from AMBITION, an event-driven, double-blind trial in patients with WHO functional class II/III PAH. Treatment-naive patients were randomised 2:1:1 to once-daily initial combination therapy with ambrisentan plus tadalafil or monotherapy with ambrisentan or tadalafil, respectively. The primary endpoint was time to the first clinical failure event (first occurrence of death, hospitalisation for worsening PAH, disease progression or unsatisfactory long-term clinical response).Results: In the primary analysis set (N=500), 187 patients had CTD-PAH, of whom 118 had SSc-PAH. Initial combination therapy reduced the risk of clinical failure versus pooled monotherapy in each subgroup: CTD-PAH (HR 0.43 (95% CI 0.24 to 0.77)) and SSc-PAH (0.44 (0.22 to 0.89)). The most common AE was peripheral oedema, which was reported more frequently with initial combination therapy than monotherapy in the two PAH subgroups. The relative frequency of adverse events between those on combination therapy versus monotherapy was similar across subgroups.Conclusions: This post hoc subgroup analysis provides evidence that CTD-PAH and SSc-PAH patients benefit from initial ambrisentan and tadalafil combination therapy.Trial Registration Number: NCT01178073, post results. [ABSTRACT FROM AUTHOR]

Background: Regulators and clinical experts increasingly recognize the importance of incorporating patient-reported outcomes (PROs) in clinical studies of therapies for pulmonary arterial hypertension (PAH). No PAH-specific instruments have been developed to date in accordance with the 2009 FDA guidance for the development of PROs as endpoints in clinical trials. A qualitative research study was conducted to develop a new instrument assessing PAH symptoms and their impacts following the FDA PRO guidance.Methods: A cross-sectional study was conducted at 5 centers in the US in symptomatic PAH patients aged 18-80 years. Concept elicitation was based on 5 focus group discussions, after which saturation of emergent concepts was reached. A PRO instrument for PAH symptoms and their impacts was drafted. To assess the appropriateness of items, instructions, response options, and recall periods, 2 rounds of one-on-one cognitive interviews were conducted, with instrument revisions following each round. Additional interviews tested the usability of an electronic version (ePRO). PRO development considered input from an international Steering Committee, and translatability and lexibility assessments.Results: Focus groups comprised 25 patients (5 per group); 20 additional patients participated in cognitive interviews (10 per round); and 10 participated in usability interviews. Participants had a mean ± SD age of 53.1 ± 15.8 years, were predominantly female (93 %), and were diverse in race/ethnicity, WHO functional class (FC I/II: 56 %, III/IV: 44 %), and PAH etiology (idiopathic: 56 %, familial: 2 %, associated: 42 %). The draft PRO instrument (PAH-SYMPACT®) was found to be clear, comprehensive, and relevant to PAH patients in cognitive interviews. Items were organized in a draft conceptual framework with 16 symptom items in 4 domains (respiratory symptoms, tiredness, cardiovascular symptoms, other symptoms) and 25 impact items in 5 domains (physical activities, daily activities, social impact, cognition, emotional impact). The recall period is the past 24 h for symptoms, and the past 7 days for impacts.Conclusions: The PAH-SYMPACT® was shown to capture symptoms and their impacts relevant to PAH patients, demonstrating content saturation, concept validity, and ePRO usability. Final content and psychometric validation of the instrument will be based on the results of an ongoing Phase IIIb clinical trial in PAH patients. [ABSTRACT FROM AUTHOR]

Objective: To provide an overview of the drug profile of the orally active, selective endothelin A receptor antagonist ambrisentan, and its efficacy and safety in the treatment of patients with pulmonary arterial hypertension (PAH).Research Design and Methods: Medical literature on the use of ambrisentan in PAH was identified using MEDLINE and EMBASE. Additional references were identified from the reference lists of published articles and from the authors' own bibliographies.Results: Significant improvements in exercise capacity were observed with approved dosages of ambrisentan (5 or 10 mg once daily) in the AMB-220 dose-ranging study and the pivotal ARIES-1 and ARIES-2 trials, with sustained effects up to 2 years observed in ARIES-E. Improvements in cardiopulmonary hemodynamic variables were reported in AMB-220 and ARIES-E (subset analysis). Ambrisentan had little or no effect on hepatic transporters in in vitro studies and displayed a low risk of potential drug-drug interactions, including those with other PAH therapies. Results from the VOLT post-marketing program confirmed the safety profile of ambrisentan observed in the ARIES studies, including the low incidence of liver function test abnormalities. Peripheral edema and anemia were common side effects of endothelin receptor antagonist therapies, including ambrisentan. In the recently completed AMBITION study (ClinicalTrials.gov Identifier: NCT01178073), upfront initial combination therapy with ambrisentan and tadalafil significantly reduced the risk of clinical failure (primary endpoint) by 50% compared with the pooled monotherapy groups.Conclusions: The long-term efficacy and safety profile of ambrisentan in patients with PAH is supported by data from a comprehensive clinical trial program and real-life, post-marketing observations. [ABSTRACT FROM AUTHOR]

The p38 mitogen-activated protein kinase (MAPK) system is increasingly recognized as an important inflammatory pathway in systemic vascular disease but its role in pulmonary vascular disease is unclear. Previous in vitro studies suggest p38 MAPKα is critical in the proliferation of pulmonary artery fibroblasts, an important step in the pathogenesis of pulmonary vascular remodeling (PVremod). In this study the role of the p38 MAPK pathway was investigated in both in vitro and in vivo models of pulmonary hypertension and human disease. Pharmacological inhibition of p38 MAPKα in both chronic hypoxic and monocrotaline rodent models of pulmonary hypertension prevented and reversed the pulmonary hypertensive phenotype. Furthermore, with the use of a novel and clinically available p38 MAPKα antagonist, reversal of pulmonary hypertension was obtained in both experimental models. Increased expression of phosphorylated p38 MAPK and p38 MAPKα was observed in the pulmonary vasculature from patients with idiopathic pulmonary arterial hypertension, suggesting a role for activation of this pathway in the PVremod A reduction of IL-6 levels in serum and lung tissue was found in the drug-treated animals, suggesting a potential mechanism for this reversal in PVremod. This study suggests that the p38 MAPK and the α-isoform plays a pathogenic role in both human disease and rodent models of pulmonary hypertension potentially mediated through IL-6. Selective inhibition of this pathway may provide a novel therapeutic approach that targets both remodeling and inflammatory pathways in pulmonary vascular disease. [ABSTRACT FROM AUTHOR]

Aims Imatinib mesylate, as add-on therapy in patients with pulmonary arterial hypertension (PAH) who remain inadequately treated despite receiving at least two PAH-specific drugs, improves exercise capacity and haemodynamics. We evaluated whether 24 weeks of add-on therapy with imatinib compared with placebo also improves right ventricular (RV) function assessed by echocardiography. Methods and results Echocardiograms were obtained at baseline, 12 weeks, and 24 weeks in 74 patients randomized to imatinib or placebo in the Imatinib in Pulmonary arterial hypertension, a Randomized Efficacy Study (IMPRES) trial. Right ventricular function was assessed by tissue Doppler tricuspid annular peak systolic velocity (TA S′), tricuspid annular plane systolic excursion (TAPSE), RV Tei index, and RV fractional area change. Between-treatment-group differences in the changes from baseline to week-24 were assessed using an ANCOVA with the last observation carried forward. At week-24 patients randomized to imatinib demonstrated greater improvements in TA S′ (1.6 ± 2.3 imatinib vs. 0.5 ± 2.4 cm/s placebo, P = 0.007) and RV Tei index (−0.11 ± 0.18 imatinib vs. 0.05 ± 0.18 placebo, P = 0.005) compared with placebo, but not in TAPSE (0.07 ± 0.44 imatinib vs. 0.03 ± 0.32 cm placebo, P = 0.08). Imatinib therapy was also associated with significant reduction in peak tricuspid regurgitation velocity, increase in LV size, and improvement in LV early diastolic relaxation velocity. Conclusions Among patients with advanced PAH who remain symptomatic on at least two PAH-specific drugs, treatment with imatinib compared with placebo is associated with significant improvements in echocardiographic measures of RV function, in addition to LV size and LV early diastolic relaxation. Clinical trial registration NCT00902174 (Clinicaltrials.gov). [ABSTRACT FROM PUBLISHER]

The right ventricle ( RV) can be described in terms of 3 components: the inlet, the apex, and the infundibulum. In the normal adult, the RV shows an arrangement suited for pumping blood against low resistance, with a mass about one sixth that of left ventricle ( LV) mass, and a larger volume than the LV. The RV is able to manage a progressive increase in the afterload by increasing contractility and remodeling. The gold standard measurement of contractility is maximal elastance (Emax), or the ratio between end-systolic pressure ( ESP) and end-systolic volume ( ESV), and the best measurement of afterload is arterial elastance (Ea), or the ratio between ESP and stroke volume ( SV). The ratio Emax/Ea defines RV-arterial coupling. The optimal energy transfer from the RV to the pulmonary circulation is measured at Emax/Ea ratios of 1.5-2. In the presence of pulmonary hypertension, the SV/ ESV ratio may be an acceptable surrogate of Emax/Ea. The right atrium ( RA) has 3 anatomical components: the appendage, the venous part, and the vestibule. It is a dynamic structure having different functions: reservoir, conduit, and booster pump function. In case of increased afterload, the RA is enlarged, denoting high RA pressure, as a consequence of elevated RV diastolic pressure. RA area is a strong predictor of adverse clinical outcome in pulmonary arterial hypertension. In patients with severe pulmonary hypertension, in several congenital heart diseases, and in Eisenmenger syndrome, symptoms and prognosis are greatly dependent on RV function and its ability to adapt to a chronic increase in afterload. [ABSTRACT FROM AUTHOR]

Copyright of Archives of the Turkish Society of Cardiology / Türk Kardiyoloji Derneği Arşivi is the property of KARE Publishing and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

AbstractWelsh, David J., and Andrew J. Peacock. Cellular responses to hypoxia in the pulmonary circulation. High Alt Med Biol14:111–116, 2013.—Hypoxia can be defined as a reduction in available oxygen, whether in a whole organism or in a tissue or cell. It is a real life cause of pulmonary hypertension in humans both in terms of patients with chronic hypoxic lung disease and people living at high altitude. The effect of hypoxia on the pulmonary vasculature can be described in two ways; Hypoxic pulmonary vasoconstriction (HPV) (resulting from smooth muscle cell contraction) and pulmonary vascular remodelling (PVR) (resulting from pulmonary vascular cell proliferation). The pulmonary artery is made up of three resident cell types, the endothelial (intima), smooth muscle (media) and fibroblast (adventitia) cells. This review will examine the effects of hypoxia on the cells of the pulmonary vasculature and give an insight into the possible underlying mechanisms. [ABSTRACT FROM AUTHOR]

Right ventricular function determines the prognosis of pulmonary hypertension (PAH). Measurement of stroke volume (SV) non-invasively could be a promising method to monitor disease progression. Cardiac magnetic resonance (CMR) imaging is recognized as an accurate and reproducible method to measure SV. Inert gas rebreathing (IGR) using acetylene is a validated but cumbersome method for pulmonary blood flow (PBF) measurement in PAH. A more convenient rebreathing technique using rapid photoacoustic analysis of nitrous oxide has been introduced and validated in left heart failure. We investigated the accuracy of CMR imaging and IGR using photoacoustic analysis to measure SV in patients under investigation for PAH. Thirty-three patients (16♀:17♂) with suspected PAH following echocardiography had SV measured by CMR imaging (using pulmonary arterial{CMR PA} and aortic {CMR Ao} flow methods) and IGR. The results were compared with our reference standard: thermodilution (TD) measured during right heart catheterization (RHC). All methods showed similar correlation for SV. Bland-Altman analysis con-firmed acceptable levels of agreement between the four techniques. TD versus CMR Ao flow had bias (limits of agreement) of −5·41 ml (−22·37 to 11·56 ml), TD versus CMR PA flow 0·12 ml (−20·13 to 20·37 ml) and TD versus IGR 6·25ml (−16·01 to 28·51 ml). Cardiac magnetic resonance imaging and IGR using photoacoustic analysis in patients with suspected PAH provided non-invasive measurements of SV that agreed closely with those obtained from TD measured during RHC. [ABSTRACT FROM AUTHOR]

Pulmonary hypertension is a life-threatening chronic disorder of the pulmonary circulation. Elevated pressure and resistance in the pulmonary vessels lead to progressive right heart failure which results in functional limitations and ultimately the death of most patients. Thus, the monitoring of right ventricular (RV) function is of great importance. Cardiac magnetic resonance imaging (cardiac MRI) has several advantages over other imaging methods. The use of cine acquisition techniques allows precise description of characteristic volumetric and functional variables, such as right ventricular volumes, muscle mass, stroke volume, ejection fraction, or cardiac output. Impaired right ventricular contractility and function have also been assessed using measures like ventricular septal bowing and pressure-volume loops. MRI investigations have been performed to monitor medical treatment, and the improvement in well-established prognostic factors, such as the 6-min walk, were correlated with measures of right ventricular function. Flow-derived parameters of the pulmonary arteries (such as peak velocity, acceleration time and volume, or pulmonary flow profile) are available using velocity-encoded imaging, and may detect early signs of remodelling. Additionally, magnetic resonance angiography is a promising new tool to visualise pulmonary perfusion and to diagnose chronic thromboembolic pulmonary hypertension. The purpose of this review is to summarise recent advances of cardiovascular magnetic resonance imaging, which will play an increasing role in the comprehensive diagnostic work-up of patients with pulmonary hypertension as a tool to monitor the course of the disease and to evaluate new therapeutic approaches. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The article reports on a study that evaluated the significance of the robust correlations among diastolic pulmonary artery pressure (DPAP), systolic PAP (SPAP), and mean PAP (MPAP) in patients at rest with those exercising and those who just received vasodilation therapy. The results revealed a strong correlation between MPAP, SPAP and DPAP and this was preserved under different conditions.

Abstract: Pulmonary arterial hypertension (PAH) is a disease that results in thickening of the vascular wall. Some of the most prominent changes are seen in the adventitia as a result of fibroblast proliferation and increased extracellular matrix deposition. Previous work from this laboratory using animal models has shown that pulmonary but not systemic artery fibroblasts proliferate to hypoxic exposure and that this response is dependent on activation of p38 mitogen-activated protein kinase (p38MAPK). In this study, we wished to determine whether human pulmonary artery fibroblasts (HPAFs) behaved similarly under conditions of acute hypoxic exposure (35mmHg for 24h). Fibroblast proliferation was assessed by [3H]thymidine uptake and protein assays performed using Western blotting techniques. HPAFs proliferated in response to acute hypoxic exposure, human systemic artery fibroblasts did not. This hypoxia-mediated proliferation was p38 MAPK dependent and could be blocked using a specific p38 MAPK inhibitor. Hypoxia-inducible factor-1 (HIF-1) expression was increased in hypoxic pulmonary but not systemic cells and could be partially abrogated with the p38 inhibitor. This work in man confirmed our previous findings in animals that significant differences exist between the pulmonary and systemic circulations in response to hypoxic exposure. This study highlights the importance of p38 MAPK and HIF-1 in hypoxia-mediated proliferation of pulmonary artery adventitial fibroblasts. [Copyright &y& Elsevier]

Aims To determine the presence and extent of delayed contrast enhancement (DCE) in patients with pulmonary hypertension (PHT) using contrast enhanced-cardiovascular magnetic resonance imaging (ce-CMR). [ABSTRACT FROM PUBLISHER]

A letter to the editor is presented in response to the article "Characterization of Connective Tissue Disease-associated Pulmonary Arterial Hypertension From REVEAL: Identifying Systemic Sclerosis as a Unique Phenotype," by Lorinda Chung, Juliana Liu and Lori S. Parsons in the December 2010 issue.

Background The VOLibris Tracking (VOLT) Study was an open-label, prospective, observational, multicenter, post-marketing registry program designed to more fully characterize the safety profile of ambrisentan for the treatment of pulmonary arterial hypertension (PAH). The key outcome was the incidence of aminotransferase elevations >3× the upper limit of normal (ULN). Methods In total, 999 patients from 115 centers in 15 countries, who were prescribed ambrisentan for the treatment of PAH (Functional Class II and III) between 30 June 2008 and 13 May 2011, were enrolled. Of these, 238 had PAH associated with connective tissue disease (PAH-CTD) and 220 had no prior PAH-specific therapy. Routine clinical monitoring data were collected by physicians. Results The incidence of both alanine and aspartate aminotransferase events (>3× ULN) was 0.02 per patient-year (95% confidence interval 0.015 to 0.027). Similar results were reported for the PAH-CTD and PAH-specific-therapy-naive subgroups. Overall, 514 (52%) patients reported treatment-emergent adverse events of special interest, most commonly edema/fluid retention (249, or 25%) and anemia (143, or 14%). Conclusions Data from the VOLT study indicate no new ambrisentan-related safety signals. Ambrisentan was not associated with increases in liver function test abnormalities above the assumed background incidence of 1.5% per year, and the observed safety profile of ambrisentan was consistent with previously published data. [ABSTRACT FROM AUTHOR]

The article discusses the role of cardiac magnetic resonance imaging (MRI) in the prognosis and evaluation of pulmonary hypertension (PH) patients in Great Britain. It mentions that the cardiac MRI can evaluate the condition of the right ventricle in terms of its mass, volume, and interaction with the left ventricle (LV) in patients with suspected PH. It also mentions that the cause of death of PH patients, is due to right -sided heart failure.

Abstract: Many cardiopulmonary diseases are associated with pulmonary hypertension which adds significant co-morbidity. Pulmonary hypertension is due partly to vasoconstriction but sustained by pulmonary vascular remodelling. If pathological endpoints are to be reversed in patients with pulmonary hypertension, the processes by which vascular remodelling occur need to be determined. Hypoxia provides a good model of pulmonary hypertension. We have previously shown that chronic hypoxia results in increased proliferation of pulmonary artery fibroblasts and stimulation of the mitogen-activated protein kinase (MAPK) family of signalling enzymes. Under the same conditions systemic artery fibroblasts were unaffected. This differential response of pulmonary fibroblasts to hypoxia represents a model to investigate the processes of pulmonary artery remodelling. The current study showed that acute hypoxia was capable of causing enhanced proliferation in pulmonary but not systemic artery fibroblasts and was linked to increased activation of p38 MAP kinase. Second, we have now shown that it is alpha and gamma isoforms of p38 MAP kinase, which are responsible. Third we have shown a link between stimulation of p38 MAP kinase and HIF-1∝ induction. An increased understanding of the effects of hypoxia on remodelling and proliferation represents a critical step in identifying targets for the treatment of pulmonary hypertension. [Copyright &y& Elsevier]