Management of pulmonary hypertension in special conditions.

Care of pulmonary hypertension (PH) patients in special situations requires insightful knowledge of the pathophysiology of the cardiopulmonary system and close interaction with different specialists, depending on the situation. The role of this task force was to gather knowledge about five conditions that PH patients may be faced with. These conditions are 1) perioperative care; 2) management of pregnancy; 3) medication adherence; 4) palliative care; and 5) the influence of climate on PH. Many of these aspects have not been covered by previous World Symposia on Pulmonary Hypertension. All of the above conditions are highly affected by psychological, geographical and socioeconomic factors, and share the need for adequate healthcare provision. The task force identified significant gaps in information and research in these areas. The current recommendations are based on detailed literature search and expert opinion. The task force calls for further studies and research to better understand and address the special circumstances that PH patients may encounter.

Effects of Modulating BMP9, BMPR2, and AQP1 on BMP Signaling in Human Pulmonary Microvascular Endothelial Cells.

Pulmonary arterial hypertension (PAH) is a chronic disease characterized by a progressive increase in mean pulmonary arterial pressure. Mutations in the BMPR2 and AQP1 genes have been described in familial PAH. The bone morphogenetic proteins BMP9 and BMP10 bind with high affinity to BMPR2. Administration of BMP9 has been proposed as a potential therapeutic strategy against PAH, although recent conflicting evidence dispute the effect of such a practice. Considering the involvement of the above molecules in PAH onset, progression, and therapeutic value, we examined the effects of modulation of BMP9, BMPR2, and AQP1 on BMP9, BMP10, BMPR2, AQP1, and TGFB1 expression in human pulmonary microvascular endothelial cells in vitro. Our results demonstrated that silencing the BMPR2 gene resulted in increased expression of its two main ligands, namely BMP9 and BMP10. Exogenous administration of BMP9 caused the return of BMP10 to basal levels, while it restored the decreased AQP1 protein levels and the decreased TGFB1 mRNA and protein expression levels caused by BMPR2 silencing. Moreover, AQP1 gene silencing also resulted in increased expression of BMP9 and BMP10. Our results might possibly imply that the effect of exogenously administered BMP9 on molecules participating in the BMP signaling pathway could depend on the expression levels of BMPR2. Taken together, these results may provide insight into the highly complex interactions of the BMP signaling pathway.

Transpulmonary Plasma Endothelin-1 Arterial:Venous Ratio Differentiates Survivors from Non-Survivors in Critically Ill Patients with COVID-19-Induced Acute Respiratory Distress Syndrome.

Endothelin-1 (ET-1) is a potent vasoconstrictor produced by endothelial cells and cleared from circulating blood mainly in the pulmonary vasculature. In a healthy pulmonary circulation, the rate of local production of ET-1 is less than its rate of clearance. In the present study, we aimed to investigate whether the abnormal pulmonary circulatory handling of ET-1 relates to poor clinical outcomes in patients with coronavirus disease 2019 (COVID-19)-induced acute respiratory distress syndrome (ARDS). To this end, central venous and systemic arterial ET-1 plasma levels were simultaneously measured on Days 1 and 3 following ICU admission in mechanically ventilated COVID-19 patients with ARDS (COVID-19 ARDS, N = 18). Central venous and systemic arterial ET-1 plasma levels were also measured in two distinct SARS-CoV-2-negative mechanically ventilated critically ill patient groups, matched for age, sex, and critical illness severity, with ARDS (non-COVID-19 ARDS, N = 14) or without ARDS (non-COVID-19 non-ARDS, N = 20). Upon ICU admission, COVID-19-induced ARDS patients had higher systemic arterial and central venous ET-1 levels compared to the non-COVID-19 ARDS and non-COVID-19 non-ARDS patients (p < 0.05), yet a normal systemic arterial:central venous (A:V) ET-1 ratio [0.63 (0.49-1.02)], suggesting that pulmonary ET-1 clearance is intact in these patients. On the other hand, the non-COVID-19 ARDS patients demonstrated abnormal ET-1 handling [A:V ET-1 ratio 1.06 (0.93-1.20)], while the non-COVID-19 non-ARDS group showed normal ET-1 handling [0.79 (0.52-1.11)]. On Day 3, the A:V ratio in all three groups was <1. When the COVID-19 ARDS patients were divided based on 28-day ICU mortality, while their systemic arterial and central venous levels did not differ, the A:V ET-1 ratio was statistically significantly higher upon ICU admission in the non-survivors [0.95 (0.78-1.34)] compared to the survivors [0.57 (0.48-0.92), p = 0.027]. Our results highlight the potential importance of ET-1 as both a biomarker and a therapeutic target in critically ill COVID-19 patients. The elevated A:V ET-1 ratio in non-survivors suggests that the early disruption of pulmonary ET-1 handling may be a key marker of poor prognosis.

Riociguat: Clinical research and evolving role in therapy.

Riociguat is a first-in-class soluble guanylate cyclase stimulator, approved for the treatment of adults with pulmonary arterial hypertension (PAH), inoperable chronic thromboembolic pulmonary hypertension (CTEPH), or persistent or recurrent CTEPH after pulmonary endarterectomy. Approval was based on the results of the phase III PATENT-1 (PAH) and CHEST-1 (CTEPH) studies, with significant improvements in the primary endpoint of 6-minute walk distance vs placebo of +36 m and +46 m, respectively, as well as improvements in secondary endpoints such as pulmonary vascular resistance and World Health Organization functional class. Riociguat acts as a stimulator of cyclic guanosine monophosphate synthesis rather than as an inhibitor of cGMP metabolism. As with other approved therapies for PAH, riociguat has antifibrotic, antiproliferative and anti-inflammatory effects, in addition to vasodilatory properties. This has led to further clinical studies in patients who do not achieve a satisfactory clinical response with phosphodiesterase type-5 inhibitors. Riociguat has also been evaluated in patients with World Health Organization group 2 and 3 pulmonary hypertension, and other conditions including diffuse cutaneous systemic sclerosis, Raynaud's phenomenon and cystic fibrosis. This review evaluates the results of the original clinical trials of riociguat for the treatment of PAH and CTEPH, and summarises the body of work that has examined the safety and efficacy of riociguat for the treatment of other types of pulmonary hypertension.

Knockdown of bone morphogenetic protein type II receptor leads to decreased aquaporin 1 expression and function in human pulmonary microvascular endothelial cells.

Bone morphogenetic proteins (BMPs) were once considered only to have a role in bone formation. It is now known that they have pivotal roles in other organ diseases, including heritable pulmonary arterial hypertension (PAH), where genetic mutations in the type II BMP receptor (BMPR2) are the commonest cause of receptor dysfunction. However, it has also recently been demonstrated that aquaporin 1 (Aqp1) dysfunction may contribute to PAH, highlighting that PAH development may involve more than one pathogenic pathway. Whether reduction in BMPR2 affects Aqp1 is unknown. We therefore studied Aqp1 in BMPR2-silenced human pulmonary microvascular endothelial cells (HPMECs). We demonstrated reduced Aqp1 mRNA, protein, and function in the BMPR2-silenced cells. Additionally, BMPR2-silenced cells exhibited lower expression of BMP-signaling molecules. In conclusion, decreased BMPR2 appears to affect Aqp1 at the mRNA, protein, and functional levels. This observation may identify a contributory mechanism for PAH.

Pulmonary capillary surface area in supine exercising humans: demonstration of vascular recruitment.

In exercising humans, cardiac output (CO) increases, with minor increases in pulmonary artery pressure (PAP). It is unknown if the CO is accommodated via distention of already perfused capillaries or via recruitment of nonconcomitantly perfused pulmonary capillaries. Ten subjects (9 female) performed symptom-limited exercise. Six had resting mean PAP (PAPm) <20 mmHg, and four had PAPm between 21 and 24 mmHg. The first-pass pulmonary circulatory metabolism of [3H]benzoyl-Phe-Ala-Pro (BPAP) was measured at rest and at peak exercise, and functional capillary surface area (FCSA) was calculated. Data are means ± SD. Mean pulmonary arterial pressure rose from 18.8 ± 3.3 SD mmHg to 28.5 ± 4.6 SD mmHg, CO from 6.4 ± 1.6 to 13.4 ± 2.9 L/min, and pulmonary artery wedge pressure from 14 ± 3.3 to 19.5 ± 5 mmHg (all P ≤ 0.001). Percent BPAP metabolism fell from 74.7 ± 0.1% to 67.1 ± 0.1%, and FCSA/body surface area (BSA) rose from 2,939 ± 640 to 5,018 ± 1,032 mL·min-1·m-2 (all P < 0.001). In nine subjects, the FCSA/BSA-to-CO relationship suggested principally capillary recruitment and not distention. In subject 10, a marathon runner, resting CO and FCSA/BSA were high, and increases with exercise suggested distention. Exercising humans demonstrate pulmonary capillary recruitment and distention. At moderate resting CO, increasing blood flow causes principally recruitment while, based on one subject, when exercise begins at high CO, further increases appear to cause distention. Our findings clarify an important physiologic question. The technique may provide a means for further understanding exercise physiology, its limitation in pulmonary hypertension, and responses to therapy.

Pathophysiology of the right ventricle and of the pulmonary circulation in pulmonary hypertension: an update.

The function of the right ventricle determines the fate of patients with pulmonary hypertension. Since right heart failure is the consequence of increased afterload, a full physiological description of the cardiopulmonary unit consisting of both the right ventricle and pulmonary vascular system is required to interpret clinical data correctly. Here, we provide such a description of the unit and its components, including the functional interactions between the right ventricle and its load. This physiological description is used to provide a framework for the interpretation of right heart catheterisation data as well as imaging data of the right ventricle obtained by echocardiography or magnetic resonance imaging. Finally, an update is provided on the latest insights in the pathobiology of right ventricular failure, including key pathways of molecular adaptation of the pressure overloaded right ventricle. Based on these outcomes, future directions for research are proposed.

RESPITE: switching to riociguat in pulmonary arterial hypertension patients with inadequate response to phosphodiesterase-5 inhibitors.

A proportion of pulmonary arterial hypertension (PAH) patients do not reach treatment goals with phosphodiesterase-5 inhibitors (PDE5i). RESPITE investigated the safety, feasibility and benefit of switching from PDE5i to riociguat in these patients.RESPITE was a 24-week, open-label, multicentre, uncontrolled study. Patients in World Health Organization (WHO) functional class (FC) III, with 6-min walking distance (6MWD) 165-440 m, cardiac index <3.0 L·min-1·m-2 and pulmonary vascular resistance >400 dyn·s·cm-5 underwent a 1-3 day PDE5i treatment-free period before receiving riociguat adjusted up to 2.5 mg maximum t.i.d Exploratory end-points included change in 6MWD, WHO FC, N-terminal prohormone of brain natriuretic peptide (NT-proBNP) and safety.Of 61 patients enrolled, 51 (84%) completed RESPITE. 50 (82%) were receiving concomitant endothelin receptor antagonists. At week 24, mean±sd 6MWD had increased by 31±63 m, NT-proBNP decreased by 347±1235 pg·mL-1 and WHO FC improved in 28 patients (54%). 32 patients (52%) experienced study drug-related adverse events and 10 (16%) experienced serious adverse events (2 (3%) study drug-related, none during the PDE5i treatment-free period). Six patients (10%) experienced clinical worsening, including death in two (not study drug-related).In conclusion, selected patients with PAH may benefit from switching from PDE5i to riociguat, but this strategy needs to be further studied.

Molecular imaging of the human pulmonary vascular endothelium in pulmonary hypertension: a phase II safety and proof of principle trial.

PURPOSE: The adrenomedullin receptor is densely expressed in the pulmonary vascular endothelium. PulmoBind, an adrenomedullin receptor ligand, was developed for molecular diagnosis of pulmonary vascular disease. We evaluated the safety of PulmoBind SPECT imaging and its capacity to detect pulmonary vascular disease associated with pulmonary hypertension (PH) in a human phase II study. METHODS: Thirty patients with pulmonary arterial hypertension (PAH, n = 23) or chronic thromboembolic PH (CTEPH, n = 7) in WHO functional class II (n = 26) or III (n = 4) were compared to 15 healthy controls. Lung SPECT was performed after injection of 15 mCi 99mTc-PulmoBind in supine position. Qualitative and semi-quantitative analyses of lung uptake were performed. Reproducibility of repeated testing was evaluated in controls after 1 month. RESULTS: PulmoBind injection was well tolerated without any serious adverse event. Imaging was markedly abnormal in PH with ∼50% of subjects showing moderate to severe heterogeneity of moderate to severe extent. The abnormalities were unevenly distributed between the right and left lungs as well as within each lung. Segmental defects compatible with pulmonary embolism were present in 7/7 subjects with CTEPH and in 2/23 subjects with PAH. There were no segmental defects in controls. The PulmoBind activity distribution index, a parameter indicative of heterogeneity, was elevated in PH (65% ± 28%) vs. controls (41% ± 13%, p = 0.0003). In the only subject with vasodilator-responsive idiopathic PAH, PulmoBind lung SPECT was completely normal. Repeated testing 1 month later in healthy controls was well tolerated and showed no significant variability of PulmoBind distribution. CONCLUSIONS: In this phase II study, molecular SPECT imaging of the pulmonary vascular endothelium using 99mTc-PulmoBind was safe. PulmoBind showed potential to detect both pulmonary embolism and abnormalities indicative of pulmonary vascular disease in PAH. Phase III studies with this novel tracer and direct comparisons to lung perfusion agents such as labeled macro-aggregates of albumin are needed. CLINICAL TRIAL: ClinicalTrials.gov, NCT02216279.

Endothelial NO-Synthase Gene-Enhanced Progenitor Cell Therapy for Pulmonary Arterial Hypertension: The PHACeT Trial.

RATIONALE: Pulmonary arterial hypertension (PAH) remains a progressive and eventually lethal disease characterized by increased pulmonary vascular resistance because of loss of functional lung microvasculature, primarily at the distal (intracinar) arteriolar level. Cell-based therapies offer the potential to repair and regenerate the lung microcirculation and have shown promise in preclinical evaluation in experimental models of PAH. OBJECTIVE: The Pulmonary Hypertension and Angiogenic Cell Therapy (PHACeT) trial was a phase 1, dose-escalating clinical study of the tolerability of culture-derived endothelial progenitor cells, transiently transfected with endothelial nitric oxide synthase, in patients with PAH refractory to PAH-specific therapies. METHODS AND RESULTS: Seven to 50 million endothelial nitric oxide synthase-transfected endothelial progenitor cells, divided into 3 doses on consecutive days, were delivered into the right atrium via a multiport pulmonary artery catheter during continuous hemodynamic monitoring in an intensive care unit setting. Seven patients (5 women) received treatment from December 2006 to March 2010. Cell infusion was well tolerated, with no evidence of short-term hemodynamic deterioration; rather, there was a trend toward improvement in total pulmonary resistance during the 3-day delivery period. However, there was 1 serious adverse event (death) which occurred immediately after discharge in a patient with severe, end stage disease. Although there were no sustained hemodynamic improvements at 3 months, 6-minute walk distance was significantly increased at 1, 3, and 6 months. CONCLUSION: Delivery of endothelial progenitor cells overexpressing endothelial nitric oxide synthase was tolerated hemodynamically in patients with PAH. Furthermore, there was evidence of short-term hemodynamic improvement, associated with long-term benefits in functional and quality of life assessments. However, future studies are needed to further establish the efficacy of this therapy. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00469027.

Riociguat for the treatment of pulmonary arterial hypertension.

BACKGROUND: Riociguat, a soluble guanylate cyclase stimulator, has been shown in a phase 2 trial to be beneficial in the treatment of pulmonary arterial hypertension. METHODS: In this phase 3, double-blind study, we randomly assigned 443 patients with symptomatic pulmonary arterial hypertension to receive placebo, riociguat in individually adjusted doses of up to 2.5 mg three times daily (2.5 mg-maximum group), or riociguat in individually adjusted doses that were capped at 1.5 mg three times daily (1.5 mg-maximum group). The 1.5 mg-maximum group was included for exploratory purposes, and the data from that group were analyzed descriptively. Patients who were receiving no other treatment for pulmonary arterial hypertension and patients who were receiving endothelin-receptor antagonists or (nonintravenous) prostanoids were eligible. The primary end point was the change from baseline to the end of week 12 in the distance walked in 6 minutes. Secondary end points included the change in pulmonary vascular resistance, N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, World Health Organization (WHO) functional class, time to clinical worsening, score on the Borg dyspnea scale, quality-of-life variables, and safety. RESULTS: By week 12, the 6-minute walk distance had increased by a mean of 30 m in the 2.5 mg-maximum group and had decreased by a mean of 6 m in the placebo group (least-squares mean difference, 36 m; 95% confidence interval, 20 to 52; P<0.001). Prespecified subgroup analyses showed that riociguat improved the 6-minute walk distance both in patients who were receiving no other treatment for the disease and in those who were receiving endothelin-receptor antagonists or prostanoids. There were significant improvements in pulmonary vascular resistance (P<0.001), NT-proBNP levels (P<0.001), WHO functional class (P=0.003), time to clinical worsening (P=0.005), and Borg dyspnea score (P=0.002). The most common serious adverse event in the placebo group and the 2.5 mg-maximum group was syncope (4% and 1%, respectively). CONCLUSIONS: Riociguat significantly improved exercise capacity and secondary efficacy end points in patients with pulmonary arterial hypertension. (Funded by Bayer HealthCare; PATENT-1 and PATENT-2 ClinicalTrials.gov numbers, NCT00810693 and NCT00863681, respectively.).

Endothelin-1 Pathway Polymorphisms and Outcomes in Pulmonary Arterial Hypertension.

RATIONALE: Pulmonary arterial hypertension (PAH) is a progressive fatal disease. Variable response and tolerability to PAH therapeutics suggests that genetic differences may influence outcomes. The endothelin pathway is central to pulmonary vascular function, and several polymorphisms and/or mutations in the genes coding for endothelin (ET)-1 and its receptors correlate with the clinical manifestations of other diseases. OBJECTIVES: To examine the interaction of ET-1 pathway polymorphisms and treatment responses of patients with PAH treated with ET receptor antagonists (ERAs). METHODS: A total of 1,198 patients with PAH were prospectively enrolled from 45 U.S. and Canadian pulmonary hypertension centers or retrospectively from global sites participating in the STRIDE (Sitaxsentan To Relieve Impaired Exercise) trials. Comprehensive objective measures including a 6-minute-walk test, Borg dyspnea score, functional class, and laboratory studies were completed at baseline, before the initiation of ERAs, and repeated serially. Single-nucleotide polymorphisms from ET-1 pathway candidate genes were selected from a completed genome-wide association study performed on the study cohort. MEASUREMENTS AND MAIN RESULTS: Patient efficacy outcomes were analyzed for a relationship between ET-1 pathway polymorphisms and clinical efficacy using predefined, composite positive and negative outcome measures in 715 European descent samples. A single-nucleotide polymorphism (rs11157866) in the G-protein alpha and gamma subunits gene was significantly associated, accounting for multiple testing, with a combined improvement in functional class and 6-minute-walk distance at 12 and 18 months and marginally significant at 24 months. CONCLUSIONS: ET-1 pathway associated polymorphisms may influence the clinical efficacy of ERA therapy for PAH. Further prospective studies are needed.

Evaluation of the Microstat™ sublingual PCO2 monitor in ambulatory patients.

Physicians often need to measure arterial PCO2 in clinical practice. Arterial blood gas sampling is typically available only in hospitals and may be unpleasant for patients. Minimally invasive techniques for measuring PCO2 offer the potential for overcoming these limitations. The MicroStat monitor non-invasively measures PCO2 in the sublingual tissues, which should track arterial PCO2 in hemodynamically stable patients. This was a prospective observational study. Patients undergoing routine cardiac catheterization were recruited. Following arterial cannulation, two sequential sublingual PCO2 measurements were taken and a contemporaneous arterial sample was sent for blood gas analysis. For each subject we calculated the mean sublingual-arterial CO2 gradient and the test-retest sublingual PCO2 difference. Twenty-five patients were studied. Mean sublingual-arterial PCO2 gradient was +6.8 mmHg (95 % limits of agreement -3.0 to 16.6 mmHg). Test-retest difference was 3.4 mmHg (95 % limits of agreement -1.1 to 7.9 mmHg), p = 0.11 (Wilcoxon test), repeatability was 11 mmHg. The MicroStat sublingual PCO2 monitor over-estimates arterial PCO2 with wide limits of agreement. Test-retest repeatability was poor. Use of sublingual PCO2 monitoring with the MicroStat monitor cannot currently replace blood gas sampling.

Riociguat for the treatment of pulmonary arterial hypertension: a long-term extension study (PATENT-2).

Riociguat is a soluble, guanylate cyclase stimulator, approved for pulmonary arterial hypertension. In the 12-week PATENT-1 study, riociguat was well tolerated and improved several clinically relevant end-points in patients with pulmonary arterial hypertension who were treatment naïve or had been pretreated with endothelin-receptor antagonists or prostanoids. The PATENT-2 open-label extension evaluated the long-term safety and efficacy of riociguat. Eligible patients from the PATENT-1 study received riociguat individually adjusted up to a maximum dose of 2.5 mg three times daily. The primary objective was to assess the safety and tolerability of riociguat; exploratory efficacy assessments included 6-min walking distance and World Health Organization (WHO) functional class. Overall, 396 patients entered the PATENT-2 study and 324 (82%) were ongoing at this interim analysis (March 2013). The safety profile of riociguat in PATENT-2 was similar to that observed in PATENT-1, with cases of haemoptysis and pulmonary haemorrhage also being observed in PATENT-2. Improvements in the patients', 6-min walking distance and WHO functional class observed in PATENT-1 persisted for up to 1 year in PATENT-2. In the observed population at the 1-year time point, mean±sd 6-min walking distance had changed by 51±74 m and WHO functional class had improved in 33%, stabilised in 61% and worsened in 6% of the patients versus the PATENT-1 baseline. Long-term riociguat was well tolerated in patients with pulmonary arterial hypertension, and led to sustained improvements in exercise capacity and functional capacity for up to 1 year.

EPITOME-2: An open-label study assessing the transition to a new formulation of intravenous epoprostenol in patients with pulmonary arterial hypertension.

BACKGROUND: Continuous infusion of epoprostenol is the treatment of choice in patients with pulmonary arterial hypertension in functional classes III to IV. However, this treatment's limitations include instability at room temperature. A new epoprostenol formulation offers improved storage conditions and patient convenience. METHODS: The EPITOME-2 trial was an open-label, prospective, multicenter, single-arm, phase IIIb study. Patients with pulmonary arterial hypertension on long-term, stable epoprostenol therapy were transitioned from epoprostenol with glycine and mannitol excipients (Flolan; GlaxoSmithKline, Durham, NC) to epoprostenol with arginine and sucrose excipients (Veletri; Actelion Pharmaceuticals Ltd, Allschwil, Switzerland). Patients were followed up for 3 months, and dose adjustments were recorded. Efficacy measures included the 6-minute walk distance, hemodynamics assessed by right heart catheterization, and New York Heart Association functional class. Safety and tolerability of the transition were also evaluated. Quality of life was assessed using the Treatment Satisfaction Questionnaire for Medication. RESULTS: Forty-two patients enrolled in the study, and 1 patient withdrew consent before treatment; thus, 41 patients received treatment and completed the study. Six patients required dose adjustments. There were no clinically relevant changes from baseline to month 3 in any of the efficacy end points. Adverse events were those previously described with intravenous prostacyclin therapy. Treatment Satisfaction Questionnaire for Medication scores showed an improvement from baseline to month 3 in the domain of treatment convenience. CONCLUSIONS: Transition from epoprostenol with glycine and mannitol excipients to epoprostenol with arginine and sucrose excipients did not affect treatment efficacy, raised no new safety or tolerability concerns, and provided patients with an increased sense of treatment convenience.

Recommendations for screening and detection of connective tissue disease-associated pulmonary arterial hypertension.

OBJECTIVE: Pulmonary arterial hypertension (PAH) affects up to 15% of patients with connective tissue diseases (CTDs). Previous recommendations developed as part of larger efforts in PAH did not include detailed recommendations for patients with CTD-associated PAH. Therefore, we sought to develop recommendations for screening and early detection of CTD-associated PAH. METHODS: We performed a systematic review of the literature on the screening and diagnosis of PAH in CTD. Using the RAND/University of California, Los Angeles consensus methodology, we developed case scenarios followed by 2 stages of voting. First, international experts from a variety of specialties voted anonymously on the appropriateness of each case scenario. The experts then met face-to-face to discuss and resolve discrepant votes to arrive at consensus recommendations. RESULTS: The key recommendation stated that all patients with systemic sclerosis (SSc) should be screened for PAH. In addition, patients with mixed connective tissue disease or other CTDs with scleroderma features (scleroderma spectrum disorders) should be screened for PAH. It was recommended that screening pulmonary function tests (PFTs) with single-breath diffusing capacity for carbon monoxide, transthoracic echocardiogram, and measurement of N-terminal pro-brain natriuretic peptide (NT-proBNP) be performed in all patients with SSc and scleroderma spectrum disorders. In patients with SSc and scleroderma spectrum disorders, transthoracic echocardiogram and PFTs should be performed annually. The full screening panel (transthoracic echocardiogram, PFTs, and measurement of NT-proBNP) should be performed as soon as any new signs or symptoms are present. CONCLUSION: We provide consensus-based, evidence-driven recommendations for screening and early detection of CTD-associated PAH. It is our hope that these recommendations will lead to earlier detection of CTD-associated PAH and ultimately improve patient outcomes.

[Definitions and diagnosis of pulmonary hypertension]. / Pulmoner hipertansiyon tani ve tanimlar.

Pulmonary hypertension (PH) is defined by a mean pulmonary artery pressure 25 mm Hg at rest, measured during right heart catheterization. There is still insufficient .evidence to add an exercise criterion to this definition. The term pulmonary arterial hypertension (PAH) describes a subpopulation of patients with PH characterized hemodynamically by the presence of pre-capillary PH including an end-expiratory pulmonary artery wedge pressure (PAWP) 15 mm Hg and a pulmonary vascular resistance >3 Wood units. Right heart catheterization remains essential for a diagnosis of PH or PAH. This procedure requires further standardization, including uniformity of the pressure transducer zero level at the midthoracic line, which is at the level of the left atrium. One of the most common problems in the diagnostic workup of patients with PH is the distinction between PAH and PH due to left heart failure with preserved ejection fraction (HFpEF). A normal PAWP does not rule out the presence of HFpEF. Volume or exercise challenge during right heart catheterization may be useful to unmask the presence of left heart disease, but both tools require further evaluation before their use in general practice can be recommended. Early diagnosis of PAH remains difficult, and screening programs in asymptomatic patients are feasible only in high-risk populations, particularly in patients with systemic sclerosis, for whom recent data suggest that a combination of clinical assessment and pulmonary function testing including diffusion capacity for carbon monoxide, biomarkers, and echocardiography has a higher predictive value than echocardiography alone. (J Am Coll Cardiol 2013;62: D42-50) ©2013 by the American College of Cardiology Foundation.

Safety and efficacy of riociguat in patients with pulmonary arterial hypertension and cardiometabolic comorbidities: Data from interventional clinical trials.

BACKGROUND: There is limited evidence to support treatment recommendations in patients with pulmonary arterial hypertension (PAH) and comorbidities. To investigate the impact of riociguat treatment in this patient population, we analyzed pooled data from randomized controlled trials of riociguat. METHODS: This post hoc analysis included data from the PATENT-1, PATENT-2, PATENT PLUS, and REPLACE studies. Safety, efficacy (6-minute walk distance [6MWD], World Health Organization functional class [WHO-FC], and N-terminal probrain natriuretic peptide [NT-proBNP]), and COMPERA 2.0 risk status were assessed in patients with 0, 1 to 2, or 3 to 4 cardiometabolic comorbidities (obesity, systemic hypertension, diabetes mellitus, coronary artery disease) in the main phase of the studies. Safety was also assessed in the long-term extensions. RESULTS: The analysis included 686 patients (riociguat, n = 440; placebo, n = 132; phosphodiesterase type 5 inhibitors [PDE5i], n = 114), of whom 55%, 39%, and 6% had 0, 1 to 2, and 3 to 4 comorbidities, respectively. In the main phase, rates and severity of adverse events (AEs) were similar in riociguat-treated patients across comorbidity subgroups. After 2 years, discontinuations of riociguat due to AEs were also similar across subgroups. Compared with placebo and PDE5i, riociguat improved 6MWD and NT-proBNP across comorbidity groups and improved WHO-FC and COMPERA 2.0 risk status in patients with 0 or 1 to 2 comorbidities. CONCLUSIONS: Riociguat had an acceptable safety profile in PAH patients with cardiometabolic comorbidities. Efficacy and risk assessment results suggest that riociguat can be beneficial for patients with PAH, irrespective of the presence of comorbidities.

Application of REVEAL Lite 2 and COMPERA 2.0 risk scores to patients with pulmonary arterial hypertension switching to riociguat in the REPLACE study.

In Riociguat rEplacing PDE5i therapy evaLuated Against Continued PDE5i thErapy (REPLACE) (NCT02891850), improvements in risk status were observed in patients with pulmonary arterial hypertension (PAH) at intermediate risk switching to riociguat versus continuing phosphodiesterase-5 inhibitors (PDE5i). This post hoc study applied the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) Lite 2 and Comparative Prospective Registry of Newly Initiated Therapies for Pulmonary (COMPERA) 2.0 risk-assessment tools to REPLACE to investigate the impact of baseline risk status on clinical improvement. The proportions of riociguat- and PDE5i-treated patients achieving the primary end-point at REVEAL Lite 2 low, intermediate, and high baseline risk reflected the overall population. Proportions of riociguat-treated patients achieving the primary end-point were comparable between the COMPERA 2.0 intermediate-low risk (39%) and intermediate-high risk (43%) groups. Our findings show that patients in REPLACE achieved clinical improvement by switching from PDE5i to riociguat across all COMPERA 2.0 and most REVEAL Lite 2 baseline risk strata.

Safety and efficacy of rodatristat ethyl for the treatment of pulmonary arterial hypertension (ELEVATE-2): a dose-ranging, randomised, multicentre, phase 2b trial.

BACKGROUND: The role of serotonin in pulmonary arterial hypertension has been extensively studied in recent decades, with preclinical data strongly indicating involvement in disease pathogenesis; however, clinical studies have yielded mixed results. METHODS: ELEVATE-2 was a phase 2b dose-ranging, randomised, double-blind, placebo-controlled, multicentre trial investigating rodatristat ethyl as a treatment for patients with pulmonary arterial hypertension. The study was conducted at 64 sites across 16 countries in Europe and North America. Eligible participants were aged 18 years or older, had pulmonary arterial hypertension with WHO functional class II or III symptom severity, and had received a stable dose and regimen of one or more pulmonary arterial hypertension treatments for at least 12 weeks. Participants were randomly assigned 1:1:1 to receive two placebo tablets, one placebo and one rodatristat ethyl 300 mg tablet, or two rodatristat ethyl 300 mg tablets twice daily using an interactive response system. Participants, investigators, site personnel, and sponsors were masked to treatment allocation. Participants who completed the 24 week treatment period were invited to continue in an open-label extension. The primary endpoint was percent change in pulmonary vascular resistance (PVR) from baseline to week 24. Primary efficacy analyses were conducted on the intention-to-treat population and analyses of harms were conducted in the safety population, which included all patients who received any amount of the study drug. This trial is registered with ClinicalTrials.gov, NCT04712669, and is now complete. FINDINGS: Between March 18, 2021 and Dec 13, 2022, 108 participants were enrolled and randomly assigned. 36 participants received placebo, 36 received rodatristat ethyl 300 mg, and 36 received rodatristat ethyl 600 mg twice daily. Overall, 85 (79%) of participants were female and 23 (21%) were male. The mean age was 52·8 years (SD 14·7) in the full analysis set. In the open-label extension phase, 62 (82%) of participants were female and 14 (18%) were male, and the mean age was 52·8 years (SD 14·7); this phase was terminated following sponsor review of unmasked main study results. Least-squares mean percent change in PVR from baseline to week 24 favoured placebo and was 5·8% (SE 18·1) for the placebo group, 63·1% (18·5) for the rodatristat ethyl 300 mg group, and 64·2% (18·0) for the rodatristat ethyl 600 mg group. Treatment-emergent adverse events (TEAE) were reported for 29 (81%) patients in the placebo group, 33 (92%) patients in the rodatristat ethyl 300 mg group, and all 36 (100%) patients in the rodatristat ethyl 600 mg group. TEAE leading to study discontinuation were reported for three (8%) patients in the placebo group, four (11%) patients in the rodatristat ethyl 300 mg group, and four (11%) in the rodatristat ethyl 600 mg group. There was one (3%) TEAE leading to death in the rodatristat ethyl 300 mg group. INTERPRETATION: Our results indicate that reducing peripheral serotonin concentrations via rodatristat ethyl has a negative effect on pulmonary haemodynamics and cardiac function in patients with pulmonary arterial hypertension. This finding suggests that manipulating this pathway might not be a suitable option for pulmonary arterial hypertension therapy. FUNDING: Enzyvant Therapeutics (now Sumitomo Pharma America).