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Pulmonary arterial hypertension (PAH) is a complex fatal condition that requires aggressive treatment with close monitoring. Significant progress has been made over the last three decades in the treatment of PAH, but, despite this progress, survival has remained unacceptably low. In the quest to improve survival, therapeutic interventions play a central role. In the last few years, there have been remarkable attempts to identify novel treatments. Finally, we have had a breakthrough with the discovery of the fourth treatment pathway in PAH. Activin signaling inhibition distinguishes itself as a potential antiproliferative intervention as opposed to the traditional therapies, which mediate their effect primarily by vasodilatation. With this novel treatment pathway, we stand at an important milestone with an exciting future ahead and the natural question of when to use an activin signaling inhibitor for the treatment of PAH. In this state-of-the-art review, we focus on the placement of this novel agent in the PAH treatment paradigm, based on the available evidence, with special focus on the U.S. patient population. This review also provides an expert opinion of the current treatment algorithm in important subgroups of patients with comorbidities from the U.S. perspective. [ABSTRACT FROM AUTHOR]

Pulmonary hypertension (PH) pathogenesis is driven by inflammatory and metabolic derangements as well as glycolytic reprogramming. Induction of both interleukin 6 (IL6) and transglutaminase 2 (TG2) expression participates in human and experimental cardiovascular diseases. However, little is known about the role of TG2 in these pathologic processes. The current study aimed to investigate the molecular interactions between TG2 and IL6 in mediation of tissue remodeling in PH. A lung-specific IL6 over-expressing transgenic mouse strain showed elevated right ventricular (RV) systolic pressure as well as increased wet and dry tissue weights and tissue fibrosis in both lungs and RVs compared to age-matched wild-type littermates. In addition, IL6 over-expression induced the glycolytic and fibrogenic markers, hypoxia-inducible factor 1α, pyruvate kinase M2 (PKM2), and TG2. Consistent with these findings, IL6 induced the expression of both glycolytic and pro-fibrogenic markers in cultured lung fibroblasts. IL6 also induced TG2 activation and the accumulation of TG2 in the extracellular matrix. Pharmacologic inhibition of the glycolytic enzyme, PKM2 significantly attenuated IL6-induced TG2 activity and fibrogenesis. Thus, we conclude that IL6-induced TG2 activity and cardiopulmonary remodeling associated with tissue fibrosis are under regulatory control of the glycolytic enzyme, PKM2. [ABSTRACT FROM AUTHOR]

A blood test identifying patients at increased risk of pulmonary hypertension (PH) could streamline the investigative pathway. The prospective, multicenter CIPHER study aimed to develop a microRNA‐based signature for detecting PH in breathless patients and enrolled adults with a high suspicion of PH who had undergone right heart catheterization (RHC). The CIPHER‐MRI study was added to assess the performance of this CIPHER signature in a population with low probability of having PH who underwent cardiac magnetic resonance imaging (cMRI) instead of RHC. The microRNA signature was developed using a penalized linear regression (LASSO) model. Data were modeled both with and without N‐terminal pro‐brain natriuretic peptide (NT‐proBNP). Signature performance was assessed against predefined thresholds (lower 98.7% CI bound of ≥0.73 for sensitivity and ≥0.53 for specificity, based on a meta‐analysis of echocardiographic data), using RHC as the true diagnosis. Overall, 926 CIPHER participants were screened and 888 were included in the analysis. Of 688 RHC‐confirmed PH cases, approximately 40% were already receiving PH treatment. Fifty microRNA (from 311 investigated) were algorithmically selected to be included in the signature. Sensitivity [97.5% CI] of the signature was 0.85 [0.80–0.89] for microRNA‐alone and 0.90 [0.86–0.93] for microRNA+NT‐proBNP, and the corresponding specificities were 0.33 [0.24–0.44] and 0.28 [0.20–0.39]. Of 80 CIPHER‐MRI participants with evaluable data, 7 were considered PH‐positive by cMRI whereas 52 were considered PH‐positive by the microRNA signature. Due to low specificity, the CIPHER miRNA‐based signature for PH (either with or without NT‐proBNP in model) did not meet the prespecified diagnostic threshold for the primary analysis. [ABSTRACT FROM AUTHOR]

Group 5 pulmonary hypertension (PH) encompasses diverse diseases, with a few cases linking it to T-cell large granular lymphocytic (LGL) leukemia. We report a case of a 76-year-old woman, diagnosed with LGL leukemia and concomitant PH, treated with oral triple pulmonary arterial hypertension (PAH) therapy. She initially presented with dyspnea on exertion; evaluation revealed severe precapillary PH. Implementing cyclophosphamide for leukemia along with tadalafil and macitentan for PH led to sustained symptomatic and hemodynamic improvement for over 3 years. At that time, deterioration in PH prompted the addition of selexipag, resulting in sustained clinical improvement for an additional 5 years. This case exemplifies the potential for sustained benefits of PAH therapy in leukemia-associated PH and highlights the need for continued research on the mechanistic relationship between LGL leukemia and PH, with the hope of identifying new management strategies. [ABSTRACT FROM AUTHOR]

Introduction Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by precapillary pulmonary hypertension secondary to vaso-occlusive pulmonary vasculopathy and is classified as Pulmonary Hypertension Group 4. The aim of this study is to report the clinical experience of CTEPH in Mexico. Methods Consecutive patients diagnosed with CTEPH were identified from the Registro de Pacientes con Hipertension Pulmonar del Instituto de Seguridad y Servicio Social de los Trabajadores del Estado (REPHPISSSTE) registry between January 2009 and February 2014. Right heart catheterization was not routinely performed prior to August 2010 in the work-up of CTEPH. Results We identified 50 patients with CTEPH; their median age was 63 years and 58 % were female. Patients had multiple associated co-morbidities and moderate hemodynamic impairment. All patients were treated with anticoagulation. Despite surgical evaluation for pulmonary endarterectomy (PEA), only one patient underwent PEA given the lack of infrastructure for post-operative care and lack of insurance for this procedure. Most of the patients were treated with sildenafil, bosentan, or both, with increasing use of rivaroxaban and sildenafil in recent years. The overall survival of the cohort was similar to that reported in other international registries, despite the limitations of care imposed by drug availability and surgical feasibility. Conclusion This is the first report on the CTEPH experience in Mexico. It highlights the similarity of patients in the REPHPISSSTE registry to those in international registries as well as the challenges that clinicians face in a resource-limited setting., Author(s): Nadine Al-Naamani[sup.1] [sup.2] , Gaudalupe Espitia H.[sup.3] , Hugo Velazquez-Moreno[sup.3] , Benjamin Macuil-Chazaro[sup.3] , Arturo Serrano-Lopez[sup.3] , Ricardo S. Vega-Barrientos[sup.3] , Nicholas S. Hill[sup.1] , Ioana R. Preston[sup.1] Author [...]