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BackgroundThere are significant risks of parenteral prostacyclin use in patients with pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD), which may limit their use. Selexipag is an oral, selective prostacyclin analogue that has been shown to reduce disease progression and improve exercise capacity in patients with PAH-CHD. Administering Selexipag in patients with PAH-CHD could potentially overcome some of the risks of parenteral therapy while improving clinical outcomes.Case summaryWe report five cases highlighting the clinical uses of Selexipag in patients with PAH-CHD. In the first two cases, Selexipag was initiated as part of a Treat-to-close strategy. In the third case, initiation of Selexipag improved symptoms and objective exercise capacity in a patient with Eisenmenger syndrome. In the fourth and fifth cases, rapid cross-titration protocols were used to transition from parenteral prostacyclins to Selexipag. In the fourth case, Selexipag was initiated in the context of significant side effects limiting parenteral prostacyclin use. In the fifth case, Selexipag was used to down-titrate from parenteral prostacyclins following closure of a sinus venosus atrial septal defect and redirection of anomalous pulmonary veins.DiscussionSelexipag is a promising oral therapy for patients with at various stages of the spectrum of PAH-CHD to improve symptoms, exercise capacity and, in some cases, haemodynamics. Our cases also highlight practical aspects of Selexipag use including targeting the individualized maximally tolerated dose for each patient, managing side effects and managing dose interruptions.

Prostacyclin (PGI2) analogues (epoprostenol, treprostonil, iloprost) are the cornerstone of pulmonary arterial hypertension (PAH) treatment. PGI2 analogues inhibit platelet reactivity, but their impact on coagulation and fibrinolysis parameters has not been elucidated. We compared platelet reactivity, thrombin generation, clot permeation, and lysis properties in patients with PAH treated with PGI2 analogues (n = 20) and those not receiving PGI2 analogues (n = 20). Platelet reactivity was lower in patients treated with PGI2 analogues, compared to the control group, as evaluated with arachidonic acid (ASPI), adenosine diphosphate (ADP), and thrombin receptor-activating peptide-6 (TRAP) tests (p = .009, p = .02, p = .007, respectively). In the subgroup analysis, both treprostinil and epoprostenol decreased platelet reactivity to the similar extent. There were no differences regarding thrombin generation, clot permeation, and lysis parameters in patients receiving and not receiving PGI2 analogues (p ≥ .60 for all). In the subgroup analysis, there were no differences regarding coagulation and fibrinolysis parameters between treprostinil, epoprostenol, and no PGI2 analogues. To conclude, patients with PAH treated with PGI2 analogues have reduced platelet reactivity, but similar clot formation and lysis parameters, compared to patients not receiving PGI2 analogues. Further randomized clinical trials are required to confirm these findings.

Patient associations are a valuable resource for managing patients, as they provide educational and emotional support, and can have positive effects on coping, confidence, and outlook.[846] It is recommended that PH centres collaborate with patient associations on initiatives to empower patients and improve the patient experience, addressing issues such as health literacy, digital skills, healthy lifestyles, mental health, and self-management. Mechanical circulatory support has become an established bridging tool to transplantation in patients with irreversible right HF, but is occasionally used as a bridge to recovery in patients with treatable causes and potentially reversible RV failure.[468] No general recommendations can be made regarding the indication for mechanical circulatory support, which needs to be individualized, considering patient factors and local resources.[469],[470] Long-term mechanical support analogous to left ventricular assist devices (LVADs) is not yet available for patients with PH and end-stage right HF. While the age-adjusted mortality of patients with the left heart phenotype seems to be similar to that of patients with classical PAH, patients with a cardiopulmonary phenotype and a low DLCO have a particularly high mortality risk.[77],[78],[161],[450],[451] As patients with cardiopulmonary comorbidities were under-represented in or excluded from PAH trials, no evidence-based treatment recommendations can be made for this patient population. [Extracted from the article]

Prostacyclin (PGI2) analogues (epoprostenol, treprostonil, iloprost) are the cornerstone of pulmonary arterial hypertension (PAH) treatment. PGI2 analogues inhibit platelet reactivity, but their impact on coagulation and fibrinolysis parameters has not been elucidated. We compared platelet reactivity, thrombin generation, clot permeation, and lysis properties in patients with PAH treated with PGI2 analogues (n = 20) and those not receiving PGI2 analogues (n = 20). Platelet reactivity was lower in patients treated with PGI2 analogues, compared to the control group, as evaluated with arachidonic acid (ASPI), adenosine diphosphate (ADP), and thrombin receptor-activating peptide-6 (TRAP) tests (p =.009, p =.02, p =.007, respectively). In the subgroup analysis, both treprostinil and epoprostenol decreased platelet reactivity to the similar extent. There were no differences regarding thrombin generation, clot permeation, and lysis parameters in patients receiving and not receiving PGI2 analogues (p ≥.60 for all). In the subgroup analysis, there were no differences regarding coagulation and fibrinolysis parameters between treprostinil, epoprostenol, and no PGI2 analogues. To conclude, patients with PAH treated with PGI2 analogues have reduced platelet reactivity, but similar clot formation and lysis parameters, compared to patients not receiving PGI2 analogues. Further randomized clinical trials are required to confirm these findings. [ABSTRACT FROM AUTHOR]

Background Idiopathic pulmonary arterial hypertension is associated with high morbidity and mortality. In recent years, the use of targeted therapies has led to an improvement in prognosis. Prostacyclin analogues treprostinil and epoprostenol require continuous subcutaneous or intravenous infusion and are generally administered in a stepwise approach. However, there are no clear recommendations for transition in high-risk patients requiring high doses of prostacyclin analogues. Case summary In this report, we describe the case of a 20-year-old woman under combined treatment with sildenafil, macitentan, and treprostinil who required transition from subcutaneous treprostinil therapy to intravenous epoprostenol due to erratic drug absorption and functional class progression. The transition was performed over 48 h in a stepwise approach reducing treprostinil dose 4 ng/kg/min every 3 h while increasing epoprostenol infusion 2 ng/kg/min until achieving a maintenance dose of 32 ng/kg/min. There were no side effects requiring changes in the infusion rate. Discussion Patients with advanced pulmonary arterial hypertension may necessitate switching from subcutaneous treprostinil to epoprostenol. Although many protocols have been used to date, there are no guidelines to direct this process safely. This 48-h scheme based on the pharmacokinetic properties of each drug was successful and well-tolerated. [ABSTRACT FROM AUTHOR]

Background Intravenous (IV) prostacyclin analogues infusion and balloon atrial septostomy (BAS) are two important treatment options for managing advanced right heart failure in patients with idiopathic pulmonary arterial hypertension (IPAH). References and protocols are rare for dose titrations and transitions between subcutaneous and IV prostacyclin in functional Class IV IPAH patients. Balloon atrial septostomy is rarely done in very few expert centres. Case summary A young female with IPAH who had received maximal medication including subcutaneous prostacyclin analogues injection was admitted due to advanced right heart failure. She received ascites drainage twice. Later, we directly switched the administration route of prostacyclin from subcutaneous to IV at a ratio of 1:1 instantly. Such rapid conversion led her into a state of profound hypotension and drowsy consciousness, which was resolved after escalating IV inotropics and reducing prostacyclin dosage. Five days later, she received BAS under the guidance of intracardiac echocardiography. Her urine output increased and dyspnoea improved gradually. Six months later, clinical worsening happened again with increase of ascites and dyspnoea. She underwent 2nd and 3rd session of graded BAS with relief of symptoms again. She received permanent transition to IV prostacyclin analogues infusions via a peripherally inserted central catheter after three sessions of BAS. Discussion Balloon atrial septostomy is effective in stabilizing the critical right heart failure in IPAH patients but should be intended as a bridge to lung transplant procedure. Transition from subcutaneous to IV prostacyclin is helpful but needs to be titrated in proper aliquots and time intervals to avoid abrupt haemodynamic changes. [ABSTRACT FROM AUTHOR]

Background: This study aims to compare the effectiveness of inhaled prostacyclin or its analoguesversus nitric oxide (NO) in treating pulmonary hypertension (PH) after cardiac or pulmonary surgery remains unclear. Methods: PubMed, Cochrane, and Embase databases were searched for literature published prior to December 2019 using the following keywords: inhaled, nitric oxide, prostacyclin, iloprost, treprostinil, epoprostenol, Tyvaso, flolan, and pulmonary hypertension. Randomized controlled trials and multiple-armed prospective studies that evaluated inhaled NO versus prostacyclin (or analogues) in patients for perioperative and/or postoperative PH after either cardiac or pulmonary surgery were included. Retrospective studies, reviews, letters, comments, editorials, and case reports were excluded. Results: Seven studies with a total of 195 patients were included. No difference in the improvement of mean pulmonary arterial pressure (pooled difference in mean change= −0.10, 95% CI: −3.98 to 3.78, p =.959) or pulmonary vascular resistance (pooled standardized difference in mean change= −0.27, 95% CI: −0.60 to 0.05, p =.099) were found between the two treatments. Similarly, no difference was found in other outcomes between the two treatments or subgroup analysis. Conclusions: Inhaled prostacyclin (or analogues) was comparable to inhaled NO in treating PH after cardiac or pulmonary surgery. This study compared the efficacy of inhaled prostacyclin or its analogues versus inhaled NO to treat PH after surgery. The two types of agent exhibited similar efficacy in managing MPAP, PVR, heart rate, and cardiac output was observed. Inhaled prostacyclin may serve as an alternative treatment option for PH after cardiac or pulmonary surgery. [ABSTRACT FROM AUTHOR]

Bosentan is an effective drug for the treatment of pulmonary arterial hypertension (PAH). The aim of the present meta-analysis was to examine the evidence concerning the efficacy and safety of bosentan therapy combined with prostacyclin analogues or phosphodiesterase type 5 (PDE-5) inhibitors for treating PAH. Eligible published studies were collected from Embase, PubMed, The Cochrane Library and the www.clinicaltrials.gov website. Heterogeneity was assessed using the Cochran Q-statistic test. Results were presented as risk ratios or mean differences with 95% confidence intervals (CI). A total of five studies, comprising 310 patients were included for analysis. No significant improvements in six-minute walk distance (6MWD; mean difference, 16.43 m), clinical worsening (risk ratio, 0.54) and the World Health Organization functional classification (class I: risk ratio, 1.17; class II: risk ratio, 1.18) were observed in patients treated with bosentan in combination with prostacyclin analogues or PDE-5 inhibitors. However, a significant reduction in the mean pulmonary artery pressure (mPAP; 95% CI: −17.06, −6.83; P<0.0001) following bosentan combination therapy was observed. Comparisons of adverse event rates in the bosentan combination therapy (55.6%) and monotherapy (51.8%) suggested that there is no reduction in adverse events (risk ratio, 1.10). The results indicated that bosentan combined with prostacyclin analogues or PDE-5 inhibitors may not improve 6MWD, cardiac function, clinical worsening and adverse events. However, bosentan combined with prostacyclin analogues or PDE-5 inhibitor therapy was able to significantly reduce mPAP compared with the effect of bosentan monotherapy. [ABSTRACT FROM AUTHOR]

Abstract In the summer of 2016, delegates from the German Respiratory Society, the German Society of Cardiology and the German Society of Pediatric Cardiology met in Cologne, Germany, to define consensus-based practice recommendations for the management of patients with pulmonary arterial hypertension (PAH). These recommendations were built on the 2015 European Pulmonary Hypertension guidelines and included new evidence, where available. The treatment algorithm for PAH was modified based on the observation that there are now many patients diagnosed with IPAH who are at an advanced age and have significant cardiopulmonary comorbidities. For patients newly diagnosed with classic forms of PAH, i.e. younger patients without significant cardiopulmonary comorbidities, the consensus-based recommendation was to use initial combination therapy as the standard approach. The use of monotherapies was no longer considered appropriate in such patients. The choice of treatment strategies should be based on the risk assessment as proposed in the European guidelines. In patients presenting with a low or intermediate risk, oral combination therapy with endothelin receptor antagonists and phosphodiesterase-5 inhibitors or soluble guanylate cyclase stimulators, respectively, should be used. In high-risk patients, triple combination therapy including a subcutaneous or intravenous prostacyclin analogue should be considered. For patients who suffer from PAH and significant cardiopulmonary comorbidities, initial monotherapy is recommended and the use of combination therapies should be considered on an individual basis. The latter recommendations are based on the scarcity of evidence supporting the use of combination therapy and the higher risk of drug-related adverse events in such patients. [ABSTRACT FROM AUTHOR]

The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS)Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT)

Data about chronic thromboembolic pulmonary hypertension (CTPH) prevalence is presented. The main CTPH clinical manifestations are described. The possible reasons and pathogenetic mechanisms of CTPH development are discussed. Features of unfavorable disease prognosis are also presented. Indications, results, limitations for CTPH surgical treatment are shown. Data of the currently completed clinical studies on bosentan, prostacyclin analogues and phosphodiesterase-5 inhibitors usage in CTPH are presented.

Abstract Pulmonary arterial hypertension (PAH) is a rare, but severe and life-threatening disease characterized by vasoconstriction and remodeling of the pulmonary arterioles, leading to progressive increase in pulmonary vascular resistance and ultimately to right-heart failure. In the last two decades, significant progress in treatment of PAH has been made, with currently 12 drugs approved for targeted therapy. Among these, the stable prostacyclin analogues iloprost and treprostinil have been repurposed for inhalation. The paper highlights the development of the two drugs emphasizing the rationale and advantages of the inhalative approach. Despite substantial advances in the specific, mainly vasodilatory PAH therapy, disease progression is mostly inevitable and mortality remains unacceptably high. Thus, introduction of new drugs targeting the cancer-like remodeling of the diseased pulmonary arteries is urgently needed. Inhalation offers pulmonary selectivity and will hopefully pioneer the repurposing of novel highly potent drugs for effective aerosol therapy of PAH. Graphical abstract Unlabelled Image [ABSTRACT FROM AUTHOR]

Pulmonary arterial hypertension (PAH) is a disease of the small pulmonary arteries that is characterized by vascular proliferation and remodeling. It results in a progressive increase in pulmonary vascular resistance and, ultimately, right ventricular failure and death. Despite recent major improvements in symptomatic treatments, no current treatment cures this devastating condition. However, during the past 25 years, treatment options for patients with the disease have evolved to help prolong their survival and improve their quality of life. [ABSTRACT FROM AUTHOR]

The present review aims to examine the effect of specific drugs on long-term outcome of pulmonary arterial hypertension (PAH), to critically review the available data, and to derive useful information for daily patient care. PAH is an intrinsic disease of the pulmonary circulation with a malignant evolution as a consequence of progressive right heart failure. Without specific therapy, median survival is only 2.8 yrs. The intravenous prostacyclin analogue epoprostenol is the only treatment with a demonstrated effect on survival, observed during a single 12-week randomised placebo-controlled trial. Three long-term observational studies have also shown that median survival is raised above 6 yrs with this therapy. Subcutaneous treprostinil appears to have similar beneficial effects on survival, as reported in two long-term observational studies. This is not the case for inhaled iloprost, as shown in one study in which a high proportion of patients needed the addition of, or the switch to, another therapy. Among the oral agents, long-term data have only been published for bosentan. The three studies including patients from expert centres also showed very good survival data, but again with a broad use of combination therapy. In less expert hands, with limited access to more complex therapies, reported survival seems much worse. In these studies, baseline New York Heart Association class and 6-min walk distance are repeatedly shown to be important predictors of survival. Finally, there is emerging data that prostanoid therapy results in a tendency to normalise C-reactive protein levels, a factor associated with improved long-term outcomes.

The aim of this study was to evaluate systemic sclerosis (SSc) hospitalizations through a retrospective population-based study analyzing administrative data during 2001-2012 in Sardinia, an Italian region with universal Health System coverage. Data on hospital discharge records with ICD-9-CM code for SSc (710.1) were obtained from the Department of Health and Hygiene. Two-tailed Cochran-Armitage test for trend was applied to analyze the annual trend for primary and non-primary discharge diagnoses. SSc prevalence was also estimated. This study included 4981 hospitalizations in 736 patients (84.8 % women). Hospitalizations with SSc as primary diagnosis were 3631 (72.9 %). Their annual number significantly increased during study period, from 143 in 2001 to 390 in 2012. Annual trend analysis revealed statistically significant increase in number and percentage of interstitial lung disease ( p < 0.0001), pulmonary arterial hypertension ( p < 0.0024), osteoporotic fragility fractures ( p < 0.0001), ulcers, and gangrene ( p = 0.0037) as non-primary diagnoses associated with SSc. Although the number of admissions with SSc as non-primary diagnosis showed a slight reduction during the study period, the annual number and percentage of admissions with respiratory failure ( p = 0.0016) and congestive heart failure ( p < 0.0001) as primary diagnosis showed a significant upward trend. Admissions for intravenous infusion, mainly day-hospital, accounted for 19.1 % of all hospitalizations for SSc and showed a significant ( p = 0.0002) upward trend in 2001-2012. The 2012 SSc prevalence in Sardinia was estimated to be 34.8 per 100,000 inhabitants. Hospital care utilization for SSc is changing over time, showing increased hospitalizations aimed at the early recognition and treatment for the major manifestations and complications of SSc. [ABSTRACT FROM AUTHOR]

Pulmonary arterial hypertension (PAH) is a progressive disease of distal pulmonary arteries in which patients suffer from elevated pulmonary arterial pressure, extensive vascular remodelling and right ventricular failure. To date prostacyclin (PGI 2 ) therapy remains the most efficacious treatment for PAH and is the only approved monotherapy to have a positive impact on long-term survival. A key thing to note is that improvement exceeds that predicted from vasodilator testing strongly suggesting that additional mechanisms contribute to the therapeutic benefit of prostacyclins in PAH. Given these agents have potent antiproliferative, anti-inflammatory and endothelial regenerating properties suggests therapeutic benefit might result from a slowing, stabilization or even some reversal of vascular remodelling in vivo. This review discusses evidence that the pharmacology of each prostacyclin (IP) receptor agonist so far developed is distinct, with non-IP receptor targets clearly contributing to the therapeutic and side effect profile of PGI 2 (EP 3 ), iloprost (EP 1 ), treprostinil (EP 2 , DP 1 ) along with a family of nuclear receptors known as peroxisome proliferator-activated receptors (PPARs), to which PGI 2 and some analogues directly bind. These targets are functionally expressed to varying degrees in arteries, veins, platelets, fibroblasts and inflammatory cells and are likely to be involved in the biological actions of prostacylins. Recently, a highly selective IP agonist, selexipag has been developed for PAH. This agent should prove useful in distinguishing IP from other prostanoid receptors or PPAR binding effects in human tissue. It remains to be determined whether selectivity for the IP receptor gives rise to a superior or inferior clinical benefit in PAH. [ABSTRACT FROM AUTHOR]

Highlights: [•] Treprostinil, iloprost and MRE-269 were investigated in rat pulmonary vasculature as prostacyclin (IP) receptor agonists. [•] Treprostinil-induced relaxation of small pulmonary arteries pre-contracted with U46619, was fully antagonised by IP receptor antagonists. [•] Iloprost-induced relaxation of pre-contracted small pulmonary arteries was partially inhibited by IP antagonists. [•] Treprostinil- and iloprost-induced relaxations of small pulmonary veins were partially inhibited by IP antagonists. [•] By contrast, MRE-265 induced relaxation of pulmonary arteries and veins were not inhibited by the selective IP antagonist. [ABSTRACT FROM AUTHOR]

Systemic sclerosis is a connective tissue disease characterised by microvascular injury and excessive fibrosis of the skin and internal organs. Most patients with this condition experience Raynaud phenomenon, usually as the earliest manifestation of disease. In addition to pain and functional impairment, Raynaud phenomenon can produce tissue ischaemia resulting in digital ulceration and gangrene. Current treatments have been only moderately successful in reducing the frequency and severity of Raynaud phenomenon in patients with systemic sclerosis. This review will address treatments available for Raynaud phenomenon in systemic sclerosis. [ABSTRACT FROM AUTHOR]

Abstract: The prostacyclin analogues, iloprost and treprostinil are extensively used in treating pulmonary hypertension. Their binding profile and corresponding biochemical cellular responses on human prostanoid receptors expressed in cell lines, have now been compared. Iloprost had high binding affinity for EP1 and IP receptors (K i 1.1 and 3.9nM, respectively), low affinity for FP, EP3 or EP4 receptors, and very low affinity for EP2, DP1 or TP receptors. By contrast, treprostinil had high affinity for the DP1, EP2 and IP receptors (K i 4.4, 3.6 and 32nM, respectively), low affinity for EP1 and EP4 receptors and even lower affinity for EP3, FP and TP receptors. In functional assays, iloprost had similar high activity in elevating cyclic AMP levels in cells expressing the human IP receptor and stimulating calcium influx in cells expressing EP1 receptors (EC50 0.37 and 0.3nM, respectively) with the rank order of activity on the other receptors comparable to the binding assays. As with binding studies, treprostinil elevated cyclic AMP with a similar high potency in cells expressing DP1, IP and EP2 receptors (EC50 0.6, 1.9 and 6.2nM, respectively), but had low activity at the other receptors. Activation of IP, DP1 and EP2 receptors, as with treprostinil, can all result in vasodilatation of human pulmonary arteries. However, activation of EP1 receptors can provoke vasoconstriction, and hence may offset the IP-receptor mediated vasodilator effects of iloprost. Treprostinil may therefore differ from iloprost in its overall beneficial pulmonary vasorelaxant profile and other pharmacological actions, especially in diseases where the IP receptor is down-regulated. [Copyright &y& Elsevier]

Although pulmonary arterial hypertension (PAH) is an orphan disease with high mortality and for which there is no cure, current treatment have led to considerable gains in the outcomes of these patients. Oral anticoagulation is proposed for most patients; diuretic treatment and supplemental oxygen are indicated in cases of fluid retention and hypoxemia. High doses of calcium-channel blockers are indicated only in the minority of patients who respond to acute vasoreactivity testing. Nonresponders to acute vaoreactivity testing or who remain in World Health Organization (WHO) functional class III, should be considered candidates for treatment with either an oral phophodiesterase-5 inhibitor or an oral endothelin-receptor antagonist. Continuous intravenous administration of epoprostenol remains the treatment of choice in WHO functional class IV patients. Combination therapy is recommended for patients treated with PAH monotherapy who remain in WHO functional class III. The pharmacologic management of PAH is rapidly evolving as newer therapeutic targets that stabilize or reverse pulmonary vascular disease and as clinical practice pattern shift in favor of earlier diagnosis and aggressive treatment. Questions about preferred first-line therapy and when to institute combination therapies remain. Future drug development targeting other molecular pathways of PAH is essential for definitively improving patient survival. The search for novel treatment continues, with promising new concepts arising from a better understanding of the pathobiology of PAH. [ABSTRACT FROM AUTHOR]

Pulmonary arterial hypertension (PAH) is defined as a group of diseases characterized by a progressive increase in pulmonary vascular resistance (PVR) leading to right ventricular failure and premature death. Untreated, it is a potentially devastating disease. However, the past decade has seen remarkable improvements in our understanding of the pathology associated with the condition and the development of multiple PAH-specific therapies with the ability to alter the natural history of the disease. These new advances provide a significant opportunity for practitioners to detect and treat patients with PAH in a timely and effective manner, thereby improving overall mortality, morbidity, and quality of life associated with this disease. The aim of this review is two-fold: firstly to review the evidence for efficacy and safety of non-parenteral PAH therapies and to discuss treatment selection based on clinically meaningful differences among the approved therapies, such as the potential for serious drug-drug interactions, convenience of dosing schedules, and rates of limiting side effects. Secondly, the central role of the PAH clinical nurse in the multidisciplinary care of patients with PAH will be discussed, together with issues relating to adherence and interventions to enhance patient compliance. [ABSTRACT FROM AUTHOR]

Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by a progressive pulmonary vasculopathy with ensuing right heart failure if left untreated. In the 1980’s, prior to the current treatment era, idiopathic pulmonary arterial hypertension (IPAH) carried a poor prognosis with a 10 month median survival for children after diagnosis. However, in 1995 continuous intravenous epoprostenol was approved for the treatment of severe PAH, improving hemodynamics, quality of life, exercise capacity, functional class and survival. In the past decade there have been further advances in the treatment of PAH; however, there is still no cure. While much of the groundbreaking clinical research has been performed in adults, children have also seen the benefits of PAH novel therapies. The target population among pediatric patients is expanding with the recent recognition of pulmonary hypertension as a risk factor for sickle cell disease patients. With rapid advances, navigating the literature becomes challenging. A comprehensive review of the most recent literature over the past year on available and emerging novel therapies as well as an approach to target pediatric populations provides insights into the management of pediatric PAH patients. [ABSTRACT FROM AUTHOR]

Abstract: Stable prostacyclin analogues can signal through cell surface IP receptors or by ligand binding to nuclear peroxisome proliferator-activated receptors (PPARs). So far these agents have been reported to activate PPARα and PPARδ but not PPARγ. Given PPARγ agonists and prostacyclin analogues both inhibit cell proliferation, we postulated that the IP receptor might elicit PPARγ activation. Using a dual luciferase reporter gene assay in HEK-293 cells stably expressing the IP receptor or empty vector, we found that prostacyclin analogues only activated PPARγ in the presence of the IP receptor. Moreover, the novel IP receptor antagonist, RO1138452, but not inhibitors of the cyclic AMP pathway, prevented activation. Likewise, the anti-proliferative effects of treprostinil observed in IP receptor expressing cells, were partially inhibited by the PPARγ antagonist, GW9662. We conclude that PPARγ is activated through the IP receptor via a cyclic AMP-independent mechanism and contributes to the anti-growth effects of prostacyclin analogues. [Copyright &y& Elsevier]

Aims Advanced therapies (prostacyclin analogues, endothelin receptor antagonists) are successfully used in the treatment of idiopathic pulmonary arterial hypertension. In addition, patients with the Eisenmenger syndrome (ES) seem to benefit from these news drugs regarding symptoms, but there is still no evidence for changes in outcome. [ABSTRACT FROM PUBLISHER]

Abstract: Drug-induced delayed cardiac protection (DCP) against the effects of acute myocardial ischemia was first described 22 years ago by the author and his coworkers. It can be initiated by noninjurious pharmacological doses of prostacyclin (PGI2), its stable analogues, and by catecholamines. DCP protects against many consequences of ischemia, attenuating early morphological changes, limiting infarct size and suppressing arrhythmias, and can also protect against ouabain intoxication. DCP operates under a variety of pathological conditions (atherosclerosis, hypercholesterolaemia, and diabetes). DCP can also be evoked by transient myocardial ischemia and by exercise and is known in this context as “ischemic preconditioning”, specifically the “second window of protection”; transient ischemia also evokes an immediate but short-lived protection known as “classical preconditioning”. DCP is fundamentally different in concept to conventional drug therapy because the process appears to depend on the duration of the trigger and be related in a bell-shaped manner to the strength of the trigger. The exact mechanism is uncertain. Prolongation of the effective refractory period (ERP) and of the action potential duration (APD) may contribute to DCP suppression of arrhythmias. The protection is time and dose dependent, with optimal effects 24 to 48 hr after treatment. It can be sustained by intermittent administration of low maintenance doses. Stimulation of the adenylate-cyclase/cyclic adenosine monophosphate (cAMP) system appears to be a common feature of DCP. Responses to β-adrenergic stimuli are also diminished. Cardiac cAMP triggers the induction of phosphodiesterase (PDE) 1 and 4 isoforms and of Na/K-ATPase. Increased amount and activity of PDE isoforms subsequently reduces excess myocardial cAMP production. Changes in Na/K-ATPase moderate ischemic myocardial potassium loss, sodium, and calcium accumulation, as well as the toxicity of ouabain. The future therapeutic challenge is to identify new drugs that can mimic DCP. [Copyright &y& Elsevier]

(1) Background: Prostacyclin analogues (epoprostenol, treprostinil, and iloprost) induce vasodilation in pulmonary arterial hypertension (PAH) but also inhibit platelet function. (2) Objectives: We assessed platelet function in PAH patients treated with prostacyclin analogues and not receiving prostacyclin analogues. (3) Methods: Venous blood was collected from 42 patients treated with prostacyclin analogues (49.5 ± 15.9 years, 81% female) and 38 patients not receiving prostacyclin analogues (55.5 ± 15.6 years, 74% female). Platelet reactivity was analyzed by impedance aggregometry using arachidonic acid (AA; 0.5 mM), adenosine diphosphate (ADP; 6.5 µM), and thrombin receptor-activating peptide (TRAP; 32 µM) as agonists. In a subset of patients, concentrations of extracellular vesicles (EVs) from all platelets (CD61+), activated platelets (CD61+/CD62P+), leukocytes (CD45+), and endothelial cells (CD146+) were analyzed by flow cytometry. Platelet-rich thrombus formation was measured using a whole blood perfusion system. (4) Results: Compared to controls, PAH patients treated with prostacyclin analogues had lower platelet reactivity in response to AA and ADP (p = 0.01 for both), lower concentrations of platelet and leukocyte EVs (p ≤ 0.04), delayed thrombus formation (p ≤ 0.003), and decreased thrombus size (p = 0.008). Epoprostenol did not affect platelet reactivity but decreased the concentrations of platelet and leukocyte EVs (p ≤ 0.04). Treprostinil decreased platelet reactivity in response to AA and ADP (p ≤ 0.02) but had no effect on the concentrations of EVs. All prostacyclin analogues delayed thrombus formation and decreased thrombus size (p ≤ 0.04). (5) Conclusions: PAH patients treated with prostacyclin analogues had impaired platelet reactivity, EV release, and thrombus formation, compared to patients not receiving prostacyclin analogues. [ABSTRACT FROM AUTHOR]

Prostacyclin and analogues are successfully used in the treatment of pulmonary arterial hypertension (PAH) due to their vasodilatory effect on pulmonary arteries. Besides vasodilatory effect, prostacyclin analogues inhibit platelets, but their antiplatelet effect is not thoroughly established. The antiplatelet effect of prostacyclin analogues may be beneficial in case of increased risk of thromboembolic events, or undesirable in case of increased risk of bleeding. Since prostacyclin and analogues differ regarding their potency and form of administration, they might also inhibit platelets to a different extent. This review summarizes the recent evidence on the antiplatelet effects of prostacyclin and analogue in the treatment of PAH, this is important to consider when choosing the optimal treatment regimen in tailoring to an individual patients' needs.

Background: There are significant risks of parenteral prostacyclin use in patients with pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD), which may limit their use. Selexipag is an oral, selective prostacyclin analogue that has been shown to reduce disease progression and improve exercise capacity in patients with PAH-CHD. Administering Selexipag in patients with PAH-CHD could potentially overcome some of the risks of parenteral therapy while improving clinical outcomes., Case Summary: We report five cases highlighting the clinical uses of Selexipag in patients with PAH-CHD. In the first two cases, Selexipag was initiated as part of a Treat-to-close strategy. In the third case, initiation of Selexipag improved symptoms and objective exercise capacity in a patient with Eisenmenger syndrome. In the fourth and fifth cases, rapid cross-titration protocols were used to transition from parenteral prostacyclins to Selexipag. In the fourth case, Selexipag was initiated in the context of significant side effects limiting parenteral prostacyclin use. In the fifth case, Selexipag was used to down-titrate from parenteral prostacyclins following closure of a sinus venosus atrial septal defect and redirection of anomalous pulmonary veins., Discussion: Selexipag is a promising oral therapy for patients with at various stages of the spectrum of PAH-CHD to improve symptoms, exercise capacity and, in some cases, haemodynamics. Our cases also highlight practical aspects of Selexipag use including targeting the individualized maximally tolerated dose for each patient, managing side effects and managing dose interruptions., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Pulmonary arterial hypertension (PAH) results from pulmonary vascular disease and may eventually lead to right heart failure and death. Vasodilator therapy has greatly improved PAH prognosis. Circulating microvesicles are considered as surrogate markers of endothelial and hematopoietic cell activation., Aim: Thus, our purpose was to determine if MVs are upregulated in pediatric PAH such as reported in adult patients, and to analyze the impact of vasodilator therapies on MV count and function., Patients: Population study consisted of 26 patients of median age 6.09 years, with Congenital Heart Disease (CHD) and elevated pulmonary vascular resistance (CHD-PAH) or idiopathic PAH (iPAH)., Results: Compared to healthy controls, all circulating MV subpopulations were found higher in untreated PAH patients. No significant differences of annexin-V+ total MV, endothelial, or leukocyte derived-MV counts were found between untreated patients and those receiving oral vasodilator therapies. Conversely, platelet MVs were significantly lower in the group treated with SC-treprostinil compared with both untreated PAH and oral therapy groups (P = 0.01), and exhibited a significant decrease of phospholipid procoagulant activity. Control samples treated in vitro with treprostinil at therapeutic concentrations showed as expected a significant decrease of platelet aggregation but also a reduced spontaneous MV generation., Conclusion: Our results suggest that treprostinil, besides vasodilation, might exert its beneficial effect through an inhibition of platelet activation, resulting in a decreased number and procoagulant activity of circulating MVs., (© 2018 Wiley Periodicals, Inc.)

Pulmonary arterial hypertension (PAH), the first category of pulmonary hypertension, is a chronic and progressive disorder characterised by angioproliferative vasculopathy in the pulmonary arterioles, leading to endothelial and smooth muscle proliferation and dysfunction, inflammation and thrombosis. These changes increase pulmonary vascular resistance and subsequent pulmonary arterial pressure, causing right ventricular failure which leads to eventual death if untreated. The management of PAH has advanced rapidly in recent years due to improved understanding of the condition’s pathophysiology, specifically the nitric oxide, prostacyclin-thromboxane and endothelin-1 pathways. Five classes of drugs targeting these pathways are now available: phosphodiesterase-5 inhibitors, soluble guanylate cyclase stimulators, prostacyclin analogues, prostacyclin receptor agonists and endothelin receptor antagonists. These developments have led to substantial improvements in mortality rate in recent decades. Recently, long-term studies have demonstrated sustained progression-free survival and have created a new paradigm of initial combination therapy. Despite these targeted therapies, PAH is still associated with significant morbidity and mortality. As such, further research into broadening our understanding of PAH pathophysiology is underway with potential of increasing the repertoire of drugs available. [ABSTRACT FROM AUTHOR]