Optimizing endothelin receptor antagonist use in the management of pulmonary arterial hypertension

Endothelin receptor antagonism has emerged as an important therapeutic approach in pulmonary arterial hypertension (PAH). Bench to bedside scientific research has shown that endothelin-1 (ET-1) is overexpressed in several forms of pulmonary vascular disease and may play an important pathogenetic role in the development and progression of PAH. Oral endothelin receptor antagonists (ERAs) improved exercise capacity, functional status, pulmonary hemodymanics, and delayed the time to clinical worsening in several randomized placebo-controlled trials. Two ERAs are currently approved by the US Food and Drug Administration: bosentan, a dual ERA for patients with class III and IV PAH, and ambrisentan, a selective ERA for patients with class II and III PAH. Sitaxsentan, another selective ERA, has been approved in Europe, Canada, and Australia. The objective of this review is to evaluate the available evidence describing the pharmacology, efficacy, safety, and tolerability, and patient-focused perspectives regarding the different types of endothelin receptor antagonists. Ongoing and forthcoming randomized trials are also highlighted including the approach of combining this class of drugs with other drugs that target different cellular pathways believed to be etiologically important in PAH

Safety and tolerability of bosentan in the management of pulmonary arterial hypertension

Endothelin receptor antagonism has emerged as an important therapeutic approach in pulmonary arterial hypertension (PAH). Bench to bedside scientific research has clearly shown that endothelin-1 (ET-1) is over-expressed in several forms of pulmonary vascular disease and plays an important pathogenetic role in the development and progression of PAH. Oral endothelin receptor antagonists (ERAs) have been shown to improve exercise capacity, functional status, pulmonary hemodynamics, and delay the time to clinical worsening in several randomized placebo-controlled trials. Bosentan, the first oral ERA, was approved in 2001 and since that time it has established a strong record of safety and efficacy in PAH. More recently, two additional ERAs, ambrisentan and sitaxsentan, have been approved for use. The objective of this review is to evaluate the available evidence supporting the efficacy, pharmacology, safety and tolerability, and patient-focused perspectives for bosentan, the first approved ERA for PAH. Ongoing and forthcoming randomized trials are also highlighted including the application of bosentan in combination with other PAH therapies

Practical management of riociguat in patients with pulmonary arterial hypertension

Riociguat is one of several approved therapies available for patients with pulmonary arterial hypertension (PAH). Treatment should be initiated and monitored at an expert center by a physician experienced in treating PAH, and the dose adjusted in the absence of signs and symptoms of hypotension. In certain populations, including patients with hepatic or renal impairment, the elderly, and smokers, riociguat exposure may differ, and dose adjustments should therefore be made with caution according to the established scheme. Common adverse events are often easily managed, particularly if they are discussed before starting therapy. Combination therapy with riociguat and other PAH-targeted agents is feasible and generally well tolerated, although the coadministration of phosphodiesterase type 5 inhibitors (PDE5i) and riociguat is contraindicated. An open-label, randomized study is currently ongoing to assess whether patients who do not achieve treatment goals while receiving PDE5i may benefit from switching to riociguat. In this review, we provide a clinical view on the practical management of patients with PAH receiving riociguat, with a focus on the opinions and personal experience of the authors. The reviews of this paper are available via the supplemental material section

Lung-specific interleukin 6 mediated transglutaminase 2 activation and cardiopulmonary fibrogenesis

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

Results of an Expert Consensus Survey on the Treatment of Pulmonary Arterial Hypertension With Oral Prostacyclin Pathway Agents

Background Treatment of pulmonary arterial hypertension (PAH) has evolved substantially over the past two decades and varies according to etiology, functional class (FC), hemodynamic parameters, and other clinical factors. Current guidelines do not provide definitive recommendations regarding the use of oral prostacyclin pathway agents (PPAs) in PAH. To provide guidance on the use of these agents, an expert panel was convened to develop consensus statements for the initiation of oral PPAs in adults with PAH. Methods A systematic literature search was conducted using MEDLINE. The established RAND/University of California Los Angeles appropriateness method, which incorporates the Delphi method and the nominal group technique, was used to create consensus statements. Idiopathic, heritable, repaired congenital heart defect, and drug- or toxin-induced PAH (IPAH+) was considered as one etiologic grouping. The process was focused on the use of oral treprostinil or selexipag in patients with IPAH+ or connective tissue disease-associated PAH and FC II or III symptoms receiving background dual endothelin receptor antagonist/phosphodiesterase type 5 inhibitor therapy. Results The panel developed 14 consensus statements regarding the appropriate use of oral PPAs in the target population. The panel identified 13 clinical scenarios in which selexipag may be considered as a treatment option. Conclusions The paucity of clinical evidence overall, and particularly from randomized trials in this setting, creates a gap in knowledge. These consensus statements are intended to aid physicians in navigating treatment options and using oral PPAs in the most appropriate manner in patients with PAH

Survival and Predictors of Mortality in Systemic Sclerosis‐Associated Pulmonary Arterial Hypertension: Outcomes From the Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma Registry

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/106105/1/acr22121.pd

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

New perspectives in long-term outcomes in clinical trials of pulmonary arterial hypertension

The past two decades have seen significant improvements in the management of patients with pulmonary arterial hypertension (PAH). Although outcome has improved, long-term prognosis remains unsatisfactory. The development of new treatment options is clearly important. Equally important is testing new agents in trials designed to provide robust evidence for sustained clinical benefits enabling clinicians to determine the optimal treatment strategy for individual patients. End-points such as the change in 6-min walk distance (6MWD) have been pivotal in the registration trials of currently available PAH-specific therapies. However, as current clinical trials enrol patients with milder disease, many already on background therapy, there is growing evidence that change from baseline in 6MWD is a weak surrogate of outcome in PAH. In addition, while short-term trials allowed for the rapid approval of PAH therapies in the past, there is increasing recognition that clinical trials for new agents must provide evidence of long-term benefits. Clinical trials need to evolve to provide the long-term, clinically relevant data required to appropriately assess new therapies. Event-driven long-term morbidity and mortality trials are currently underway, and will provide robust data on the frequency and timing of events, and are likely to reflect the future of clinical trial design in PAH