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PURPOSE OF REVIEW: To provide an overview of new concepts in the pharmacotherapy of patients with peripheral artery disease (PAD).RECENT FINDINGS: Modern therapeutic strategies for patients with PAD include specific symptom management and multidisciplinary prevention of cardiovascular events. Low-dose rivaroxaban in combination with aspirin improves outcomes compared with aspirin monotherapy among patients with PAD. Other novel concepts include the use of bosentan, vorapaxar or sildenafil among symptomatic patients with PAD. Likewise, lipid-lowering therapy reduces the risk of major cardiovascular and limb events.SUMMARY: Personalized management, identification of risk factors and shared-decision making are crucial in improving the best medical therapy for patients with PAD. Further studies are needed to assess the long-term safety and efficacy of novel strategies in real-world patients.

Целью данной статьи был обзор данных литературы относительно эффективности и безопасности применения бозентана в лечении легочной гипертензии. Кроме того, освещаются вопросы диагностики, классификации и патогенеза легочной гипертензии. Автор делает вывод, что бозентан является достаточно эффективным препаратом как в монотерапии, так и в составе комбинированной терапии пациентов с легочной артериальной гипертензией. При хронической тромбоэмболической легочной гипертензии применение бозентана возможно, но положительные изменения являются не такими выраженными, как у пациентов с легочной артериальной гипертензией. Рассматриваются данные литературы о возможных побочных явлениях бозентана и способах их избежать.

Mutations in ACTA2 gene can lead to multisystemic smooth muscle dysfunction, including cerebrovascular disease. Treatment strategies for this rare entity remain controversial, and patients are at increasing risk of neurological sequelae. We herein present the case of an 11-year-old boy previously diagnosed with an ACTA2 gene mutation who developed repetitive transient ischemic attacks and treated with bosentan, an oral endothelin receptor antagonist. Magnetic resonance imaging revealed bilateral, periventricular white matter T2 hyperintensities, and magnetic resonance angiography identified several abnormalities including fusiform dilatation in the proximal segments of internal cerebral arteries, together with followed by terminal segmental stenosis. The distal branches showed a markedly straightened course with no increase in lenticulostriate collaterals. Magnetic resonance imaging also revealed an increase in the number and size of large periventricular white matter lesions located in the left frontal lobe with the progression of ischemic symptoms. Instead of revascularization surgery, the administration of bosentan was started due to the high risk of perioperative ischemic sequelae. After bosentan initiation, the patient’s repetitive episodes of cerebral ischemia ceased, and there has been no increase in the number of white matter lesions for 7 years. Bosentan might be beneficial for treating cerebral ischemia associated with ACTA2 cerebral arteriopathy by maintaining the dilatation of stenotic vessels and adequate systemic blood flow and should be considered before performing revascularization surgery.

After reviewing the current definitions and classification of pulmonary hypertension (PH) associated with congenital heart disease (CHD), based on an analysis of 59 clinical trials (of which 14 are randomized controlled trials) drugs registered in the Russian Federation, the evidence base for PH therapy in adults with CHD is provided. The presence of a randomized controlled trial of bosentan BREATHE-5 and uncontrolled trials of other drugs became the basis for a higher class and level of evidence of bosentan (IB) compared to other drugs (IIaC) for Eisenmenger syndrome in the current European (ERS/ESC 2015) and updated Russian (2020) guidelines. According to the updated European (ESC 2020) guidelines for congenital heart disease in adults, in Eisenmenger patients with reduced exercise capacity (6MWT distance 450 m), a treatment strategy with initial endothelin receptor antagonist monotherapy should be considered followed by combination therapy if patients fail to improve (IIaB), in low- and intermediate-risk patients with repaired simple lesions and pre-capillary PH, initial oral combination therapy or sequential combination therapy is recommended and high-risk patients should be treated with initial combination therapy including parenteral prostanoids (IA) and endothelin receptor antagonists and phosphodiesterase 5 inhibitors may be considered in selected patients with elevated pulmonary pressure/resistance in the absence of elevated ventricular end diastolic pressure (IIbC). Only three (bosentan, macitentan and selexipag) out of seven specific pulmonary vasodilators registered in the Russian Federation have indications for pulmonary arterial hypertension associated with congenital heart disease and Eisenmenger syndrome or pulmonary arterial hypertension associated with corrected simple congenital heart disease in the instructions for use.После рассмотрения современных определений и классификации легочной гипертензии (ЛГ), ассоциированной с врожденными пороками сердца (ВПС), на основе анализа 59 клинических исследований (из них 14 рандомизированные контролируемые исследования) зарегистрированных в Российской Федерации препаратов приводится доказательная база терапии ЛГ у взрослых с ВПС. Наличие рандомизированного контролируемого исследования бозентана BREATHE-5 и неконтролируемых исследований других препаратов стало основанием для более высокого класса и уровня доказательности бозентана (IB) по сравнению с другими препаратами (IIaС) при синдроме Эйзенменгера в действующих Европейских (ERS/ESC 2015) и обновленных Российских (2020 г.) рекомендациях по ЛГ. Согласно обновленным Европейским (ESC 2020) рекомендациям по ВПС у взрослых пациентам с синдромом Эйзенменгера и сниженной переносимостью физической нагрузки (дистанция теста 6-минутной ходьбы 450 м) показана монотерапия антагонистами рецепторов эндотелина, а при отсутствии эффективности комбинированная терапия (IIaB), пациентам низкого и промежуточного риска с корригированными простыми ВПС и прекапиллярной ЛГ рекомендуется пероральная начальная или последовательная комбинированная терапия, пациентов же высокого риска следует лечить начальной комбинацией, включающей парентеральные простаноиды (IA), и антагонисты рецепторов эндотелина и ингибиторы фосфодиэстеразы 5 могут быть рассмотрены у отдельных пациентов после операции Фонтена с повышенным давлением в легочной артерии/легочным сосудистым сопротивлением при отсутствии повышения конечного диастолического давления системного желудочка (IIbC). Лишь 3 (бозентан, мацитентан и селексипаг) из 7 зарегистрированных в РФ специфических легочных вазодилататоров имеют показания легочная артериальная гипертензия, ассоциированная с ВПС и синдромом Эйзенменгера, или легочная артериальная гипертензия, ассоциированная с корригированными простыми ВПС, в инструкциях по применению.

Clinical hypertension (HT) is associated with renal inflammation and elevated circulating levels of proinflammatory cytokines. Interleukin (IL)-1 receptor antagonist (IL-1Ra) is one of the most important anti-inflammatory cytokines and plays a crucial role in inflammation. Inhibition of IL-1 may contribute to modulation of the Angiotensin II (Ang II)-induced HT response. The present study aimed to elucidate the effects of IL-1Ra and anti-IL-1β antibody (01BSUR) on Ang II-induced renal injury. To determine the contribution of IL-1Ra to Ang II-induced renal inflammation, male wildtype (WT) and IL-1Ra-deficient (IL-1Ra−/−) mice were infused with Ang II (1000 ng/kg/min) using subcutaneous osmotic pump for 14 days. We checked renal function, histological change, and several mRNA expressions 14 days after infusion. Fourteen days after infusion, systolic blood pressure (197 ± 5 vs 169 ± 9 mmHg, P

WHAT IS KNOWN AND OBJECTIVE Two endothelin receptor antagonists, ambrisentan and bosentan, have been demonstrated to be effective individually compared with placebo in the treatment of patients with pulmonary arterial hypertension (PAH). This network meta-analysis compared the efficacy and safety of ambrisentan and bosentan in patients with PAH. METHODS Clinical trials were identified from the Cochrane Central Register of Controlled Trials (CENTRAL/CCTR), EMBASE and PubMed databases. Weighted mean differences (MD) with 95% confidence intervals (CI) were calculated for continuous outcomes (6-min walk distance [6MWD] and Borg dyspnoea index [BDI]). Hazard ratio (HR) was calculated for binary outcomes, including clinical worsening, discontinuation due to adverse events (AEs) and liver dysfunction. Surface under cumulative ranking curve (SUCRA) was used to rank the treatments in each index. RESULTS Five clinical trials from four published studies (total patients: n = 920) were included. Ambrisentan and bosentan showed no significant difference in 6MWD (MD: -1.32; 95% CI: -27.87, 25.31, SUCRA score: ambrisentan 0.73, bosentan 0.77), BDI (MD: -0.16; 95% CI: -0.98, 0.65, SUCRA score: ambrisentan 0.83, bosentan 0.66), clinical worsening (HR: 0.99; 95% CI: 0.33, 2.94, SUCRA score: ambrisentan 0.75, bosentan 0.74) and discontinuation due to AEs (HR: 0.84; 95% CI: 0.11, 5.86, SUCRA score: ambrisentan 0.47, bosentan 0.57). However, ambrisentan was significantly better than bosentan with respect to abnormal liver function (HR: 23.18; 95% CI: 2.24, 377.20, SUCRA score: ambrisentan 0.99, bosentan 0.02). WHAT IS NEW AND CONCLUSION The results of this network meta-analysis suggest that ambrisentan was similar to bosentan in efficacy, while it exhibited better tolerability with respect to abnormal liver function in comparison with bosentan, in patients with PAH.

The prevalence of persistent pulmonary hypertension of newborn (PPHN) has been estimated 1.9/1000 live births. Although the efficacy of inhaled nitric oxide and extracorporeal membrane oxygenation in PPHN is well established but it is difficult to administer and monitor in resource limited countries. Owing to this, other treatment options need to be evaluated.This is a prospective observational study conducted in the Pediatric Cardiology Department, NICVD, Karachi, from February 2020 to October 2020 after the approval from the Institutional Ethical Review Committee. All the neonates referred to our Unit were screened by echocardiography (echo) and those who fulfilled the inclusion criteria were included. Echo were done before starting sildenafil and after 72 h to assess the pressure gradient across tricuspid valve and right to left or bidirectional shunt across patent ductus arteriosus , patent foramen ovale , or both. Sildenafil was started with a dose of 1 mg/kg/dose thrice a day and increased to 2 mg/kg/dose after 48 h if partial pressure of oxygen (POTotal 82 newborns were enrolled. Fifty-two patients improved after 48 h so were continued on same treatment. Sildenafil dose was increased in 30 (37.9%) patients whose POThe results of our study show effectiveness of oral Sildenafil in treating PPHN. The overall improvement observed in the patients was overwhelming. Combination of Sildenafil with Bosentan is beneficial in patients who did not respond on Sildenafil alone.

Pulmonary artery hypertension (PAH) is a common and serious disease which is characterized by pulmonary vascular remodeling. Bosentan (BST) is the first approved oral targeted drug of endothelin-1 (ET-1) receptor antagonists for the treatment of PAH. MicroRNA-27a (miR-27a) and peroxisome proliferator-activated receptor γ (PPARγ) were found to be related to the pathogenesis of PAH. To further explore the signal transduction mechanism of BST in the treatment of PAH, we examined the effects of BST on endothelin receptors, miR-27a, and PPARγ. Meanwhile, the influence of miR-27a in the formation and development of PAH was discussed. Our results demonstrated that during the pathophysiology of PAH, miR-27a, PPARγ, and ET-1 were cross-inhibited, which indicated that the miR-27a/PPARγ/ET-1 signaling pathway was dysregulated; in addition, BST could competitively bind to ET-1 receptors and inhibit the miR-27a/PPARγ/ET-1 signaling pathway, thereby delaying the proliferation of PASMCs and affecting the development of PAH. Our results give a new understanding of the pathogenesis and treatment of PAH and provide more reliable evidence for the application of BST in the treatment of PAH in the clinic.

Chronic thromboembolic disease (CTEPH) is one of the causes for developing pulmonary hypertension (PH). PH is characterized by an increase in pulmonary vascular pressure and resistance, ultimately leading to chronic overload. This study describes the clinical, functional, and hemodynamic characteristics as well as the established treatment strategy for a cohort of patients diagnosed with CTEPH in Bucaramanga, Colombia. In Colombia, PH is considered as an orphan disease with limited epidemiological data. We aim to provide useful information in order to help guide future clinical decisions for PH treatment and prevention. We conducted a cross-sectional study, obtaining clinical data from patients under follow-up, over 18 years of age, with hemodynamic confirmation of CTEPH in two pulmonary outpatient centers in Bucaramanga, Colombia between 2012 and 2018. 35 patients with diagnosis of CTEPH were included. Mean age was 52.3 ± 17.9 years. The mean time between the onset of symptoms to diagnosis was 14 months. 71% had a previous thrombotic event and 69% had functional class III and IV according to the world health organization (WHO) criteria. Most of the patients were classified as at high risk of mortality according to the European Society of Cardiology (ESC) and the European Respiratory Society (ERS/ESC) criteria and 60% were referred to undergo thromboendarterectomy. Most of the patients were under monotherapy treatment with Bosentan, the most prescribed medication in both monotherapy and dual therapy. This study identified a high number of patients in advanced stages of CETPH due to late diagnosis, related to health care limitations. This resulted in worse prognosis and quality of life. In addition, low adherence to non-pharmacological interventions was evidenced in patients who were not candidates for thromboendarterectomy despite the onset of pharmacological therapy.

Although pulmonary endarterectomy (PEA) is the treatment of choice for chronic thromboembolic pulmonary hypertension (CTEPH), many patients have inoperable disease, and some have persistent or recurrent pulmonary hypertension (PH) after surgery. Alternative options (balloon pulmonary angioplasty (BPA) and PH-targeted medical therapy) are, therefore, required. Studies of medical therapies for CTEPH have evolved since Aerosolized Iloprost Randomized (AIR), the first randomized, controlled study of a PH-targeted therapy (inhaled iloprost) to include patients with CTEPH. Key learnings from these studies include the need to evaluate CTEPH separately from other types of PH, the importance of prospective operability adjudication as part of the protocol, and the need for sufficient duration to allow treatment benefits to become apparent. The 16-week Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase-Stimulator Study 1 (CHEST-1) study was the first to operationalize these learnings, demonstrating a significant mean improvement in 6-minute walk distance (+46 m) and improvements in hemodynamic endpoints with riociguat versus placebo. Findings from previous studies will inform the design of future studies to address key issues related to combination medical therapy. Data on combinations of macitentan with phosphodiesterase type 5 inhibitors or oral prostanoids are available from MERIT, the first study to allow such regimens. No data on combinations including riociguat, the only licensed medical therapy for CTEPH, are available. Studies are also needed for multimodality treatment, including medical therapy plus BPA, and medical therapy as a bridge to PEA in selected operable patients. To address these issues and improve patient outcomes, it is vital that we learn from current studies to improve future trial design.

Introductions A specific mutation in the ACTA2 gene is known to cause multisystemic smooth muscle dysfunction syndrome, which is associated with cerebrovascular diseases and various organ disorders. Cerebral infarctions resulting from severe vasculopathy can be refractory; however, there are no previous reports describing the detailed clinical course of recurrent cerebral infarctions due to an ACTA2 mutation. Herein, we report a patient with an ACTA2 mutation who experienced multiple refractory cerebral infarctions in early childhood. Patient description The patient was aged 1 year and 5 months at her first episode of cerebral infarction. Arteriopathy due to an ACTA2 mutation was diagnosed based on the characteristic cerebrovascular findings and abnormal physical findings, such as bilateral dilated pupils. Bilateral encephaloduroarteriosynangiosis and encephalogaleosynangiosis were performed after the first episode. Because the cerebral infarctions recurred postoperatively, administration of cilostazol followed by bosentan was started. However, despite these treatments she experienced seven cerebral infarctions by age 2 years and 6 months. Interpretation Cerebral infarctions in patients with a specific ACTA2 mutation can occur even in early childhood, recur frequently, and cause severe motor and cognitive impairment. Physicians should be highly aware of this disease and be ready to provide the medical and surgical interventions necessary to minimize the disabling sequelae.

Sex dependent differences in coronary artery vasoregulation may be due to variations in responses to endogenous vasoactive compounds including endothelin (ET-1) and nitric oxide (NO).Septal coronary arteries (200 μm) from healthy, sexually mature male, female and ovariectomized (i.e. surgical menopause) Sprague-Dawley rats were used. Myogenic tone, measured by pressure myography, was initially determined for all vessel segments studied before and after exposure to the nonselective ETMyogenic tone was 26 ± 7% in male, 20 ± 7% in female (p = 0.04 versus male) and 24 ± 3% in ovariectomized (p = NS versus male/female) vessels. Antagonism of ET-1 receptors produced a greater reduction in myogenic tone in male, compared to female rats over a similar range of intraluminal pressure (20-80 mmHg). Robust constrictor responses to cumulative concentrations of ET-1 were observed in all vessels; however, male rats exhibited greater sensitivity to vasoconstrictor effects of ET-1. After exposure to L-NAME vessel responses to ET-1 were normalized in male and female (not studied in ovariectomized) groups.These findings confirm marked sex differences for myogenic tone and vessel constrictor responses to ET-1 in coronary resistance vessels. Results also suggest greater sensitivity to vasoconstrictor effects of ET-1 in male coronary resistance vessels.

Hemolytic anemia is a very important immune-mediated reaction, which its late diagnosis can be fatal. Medications along with other causes can induce hemolytic anemia. Drug induced immune hemolytic anemia (DIIHA) is caused by the development of autoantibodies. Accordingly, DIIHA is rare and there is not enough data for its prevalence. Number of drugs that can cause DIIHA have increased in recent decades. A 17-year-old man who had congenital single ventricle heart (CHB) and pulmonary artery hypertension (PAH) was admitted at Imam Khomeini hospital complex affiliated to Tehran University of Medical Sciences, with chief complaint of jaundice and icter. Bosentan and Tadalafil were in the list of the drugs used by this patient. Although both drugs were recommended to be discontinued in the patient, in the course of hospitalization, the patient accidentally continued to take his Tadalafil. However, the patient’s recovery continued. Given that the patient’s Coombs test was positive, his hemolytic anemia mechanism was drug-induced immune-mediated hemolytic anemia. As a result, according to Naranjo score = 6, Bosentan was considered as the main possible culprit to induce DIIHA in this patient. Following the discontinuation of Bosentan and receiving Prednisolone, the patient’s clinical symptoms and laboratory parameters resolved and the patient was then discharged. [Image: see text]

FormUlation of bosenTan in pUlmonary arterial hypeRtEnsion (FUTURE) 3 was a 24-week open-label, prospective, and randomized phase 3 study that assessed the pharmacokinetics of bosentan 2 mg/kg b.i.d. or t.i.d. in children with pulmonary arterial hypertension (PAH). We report findings from a post-hoc analysis that explored the prognostic value of echocardiographic changes during FUTURE 3 in relation to clinical outcomes observed during the 24-week core study and 48-week extension. Patients aged ≥3 months to n = 64) received oral doses of bosentan 2 mg/kg b.i.d. or t.i.d. (1:1) for 24 weeks, after which they were eligible to enter the extension with continued bosentan administration. Echocardiographic evaluations were performed at baseline, Week 12, and 24 of the core study via central reading, and analyzed post-hoc for correlation with clinical outcomes (time to PAH worsening, time to death, and vital status). Sixty-four patients were randomized in the core study [median (IQR) age 3.8 (1.7–7.8) years]; and 58 patients (90.6%) entered the 48-week extension. Most of the patients (68.8%) were receiving ≥1 PAH medication at baseline. Echocardiographic changes during the core study were small but with high variability. There were statistically significant associations at Week 24 between worsening of the parameters, systolic left ventricular eccentricity index (LVEIS) and E/A ratio mitral valve flow, and the outcomes of time to death and time to PAH worsening. Additional studies that utilize simple and reproducible echocardiographic assessments are needed to confirm these findings and subsequently identify potential treatment goals in pediatric PAH.

Pulmonary arterial hypertension (PAH) is an uncommon but lethal and progressive disease in which prostacyclin, nitric oxide and endothelin-1 pathways are disturbed and contribute to the pathophysiology of this disease. Endothelin receptor antagonists are a class of drugs that have been approved as PAH therapy. Macitentan is a lipophilic, tissue specific, dual receptor antagonist with a higher potency than bosentan and a reduced risk of hepatic injury. Macitentan has shown a reduction in morbidity and mortality due to PAH at long-term follow-up and improvements in hemodynamics, exercise capacity and functional class at the short term. Its main adverse events are nasopharyngitis, bronchitis and an increased risk of anemia. We review the clinical data of macitentan and its use in PAH.

Background Although there are some data on how to manage and treat patients with Eisenmenger syndrome due to simple cardiac defects, little evidence exists to guide best management of pulmonary vascular disease in cases with more complex anatomy such as common arterial supply to both the systemic and pulmonary circulations or univentricular physiology. Beyond the uncertainty on how to best assess and manage such patients, there are added concerns with regards to the potential effects of treatment on the risk of cardiac arrhythmia, valve regurgitation and excessive load to the ventricle with increased pulmonary blood flow. Case presentation We present a case of a patient with double inlet left ventricle and evidence of pulmonary hypertension and describe his outcome on the therapies prescribed. Conclusions We review the literature and describe our approach to the patient’s management in light of the available evidence and published literature.

Pulmonary arterial hypertension (PAH) is severe and often times rapidly progressive disease with fatal outcome. The concept of initial combination of PAH-specific therapies in high risk patients at baseline was first described in the European guidelines on pulmonary hypertension (PH) in 2009, and in low or intermediate risk patients at baseline in 2015. Interestingly, that in Cologne Experts Consensus, and then in the 6th World Symposium on PH medical community started considering initial combination therapy as one of the most important pillars in PAH treatment algorithms in 2018. As of August 2020, as many as 8 formulations of 7 reference PAH-specific drugs are licensed for medical use in the Russian Federation. On top of that, 6 abbreviated drugs (generics) have also become available few years ago. Unfortunately, intravenous and subcutaneous prostacyclin analogs (PCA) and tadalafil are not approved for PH patients treatment in the Russian Federation. In this narrative review paper we attempted to describe studies on initial dual combination therapy with PAH-specific drugs registered in Russia, i.e. ambrisentan and riociguat, macitentan and riociguat, macitentan and sildenafil in low or intermediate risk patients at baseline, as well as iloprost inhaled and sildenafil, iloprost inhaled and bosentan in high risk patients. Some beneficial pharmacological effects due to the synergy between ambrisentan plus riociguat, and inhaled iloprost plus sildenafil appear to be interesting and require further clinical confirmation. Other initial combinations of PAH-specific agents require large-scale clinical trials as well.

After suffering pulmonary embolism (PE), doctors are confronted with various consequences of the disease, from asymptomatic residual pulmonary thrombosis to the formation of chronic thromboembolic pulmonary hypertension (CTEPH). There is also a subgroup of patients who have undergone pulmonary embolism, who experience shortness of breath during physical exertion, absent before pulmonary embolism, or shortened dyspnea preceding PE, combined with residual thrombosis of pulmonary artery (PA) and normal average pressure in PA at rest during catheterization of the right heart (CRH). This condition is defined as chronic thromboembolic pulmonary disease or post thromboembolic syndrome. Pathogenetic aspects of this condition are not fully investigated. It is important to predict the development of postembolic syndrome and to develop algorithms for the diagnosis, treatment and rehabilitation of patients with symptoms and residual pulmonary thrombosis. In case of the development of pulmonary vasculopathy in some patients who have undergone pulmonary embolism, a severe life-threatening condition forms - CTEPH, characterized by an increase in pressure in the pulmonary artery, right heart failure due to the presence of organized blood clots that have entered the pulmonary vascular bed during PE. The volume of thrombotic masses does not always correlate with clinical symptoms, which indicates the importance of microvascular remodeling. If CTEPH is suspected, a diagnostic algorithm is required, including ventilation-perfusion scintigraphy, CT angiopulmonography and catheterization of the right heart. Treating a patient with CTEPH is a difficult task fora doctor. The timely referral of the patient to the center where they are involved in treatment, including surgery and CTEPH is extremely important. Timely performed thrombendarterectomy in some cases allows to completely cure the patient. In the case of inoperable CTEPH or residual pulmonary hypertension after thrombendarterectomy, balloon angioplasty of the PA is used as well as drug treatment with specific drugs that reduce the pressure in the PA (riociguat), endothelin receptor antagonists (bosentan, macitentan), prostanoids (inhalant illoprost) phosphodiesterase-5 inhibitor and combined therapy. In this article we considered some consequences directly related to PE: asymptomatic residual pulmonary thrombosis, chronic thromboembolic pulmonary disease, chronic thromboembolic pulmonary hypertension.

Pulmonary hypertension (PH) is a disease characterized by an increase in the pulmonary vascular resistance that typically progresses to right heart failure and death. It is classified into five groups. Management depends on the group classification. Group four PH, chronic thromboembolic pulmonary hypertension (CTEPH) is thought to be a result of acute pulmonary emboli that cause fibrosis and scarring of the pulmonary arteries with consequent obstruction. The diagnosis of CTEPH is made by identifying perfusion abnormalities on ventilation/perfusion (V/Q) scan. Other studies required for the diagnostic evaluation include transthoracic echocardiogram, right heart catheterization, NT pro-B-type natriuretic peptide and thrombophilia evaluation. Several other tests needed to exclude other causes of pulmonary hypertension include high-resolution computed tomography (HRCT), connective tissue disease evaluation, thyroid function testing, human immunodeficiency virus testing, and liver ultrasonography to exclude portal hypertension. The treatment for CTEPH is surgical pulmonary endarterectomy (PEA). In patients who are not candidates or decline PEA, pulmonary balloon angioplasty may be useful, however, further studies are required. Several pulmonary artery hypertension medications have been studied in the management of inoperable CTEPH or persistent PH following PEA including bosentan (improves hemodynamics but not exercise capacity), macitentan (improves both hemodynamics and clinical parameters), and riociguat (improves both hemodynamics and exercise capacity). However, only riociguat is approved by the Food and Drug Administration for this indication.

We assessed efficacy and effectiveness of pharmacological and nonpharmacological interventions in improving symptom control, functional exercise capacity and quality of life (QoL) in people living with fibrotic interstitial lung disease (ILD). We summarised evidence from three previous reviews (to June 2014) and conducted an updated search of nine databases and grey literature (2011–2019) (registration: CRD42017065933) for prospective studies of interventions aimed to alleviate symptoms, improve QoL or functional exercise capacity in fibrotic ILD. Data were synthesised through narrative synthesis or meta-analysed as appropriate. Forty-seven studies with 2527 participants were included. From 22 pharmacological studies of 11 different interventions (n=1683), the most tested interventions were bosentan and sildenafil. From 25 nonpharmacological studies, the most tested intervention was for pulmonary rehabilitation/exercise training (PR) (22 studies, n=748). There was an improvement in 6-min walk distance immediately following PR (six studies; n=200, mean difference (MD) (95% CI) 39.9 m (18.2 to 61.5)), but not longer term (3 or 6 months, four studies; n=147, MD 5.3 m (−12.9 to 23.4). Multiple, varied outcome measures were used (e.g. 37 studies assessing dyspnoea used 10 different scales with a lack of reporting of rate of deterioration in outcomes). Evidence gap mapping highlighted the most and least researched symptoms, as dyspnoea and cough, respectively. This evidence synthesis highlights overwhelmingly that the most researched symptom is dyspnoea and the strongest evidence base is for short-term PR. The least researched symptom was cough. Research going forward must focus on prioritising and standardising meaningful outcomes and focussing interventions on neglected symptoms., Cough is a neglected symptom in ILD. Future research must prioritise and standardise meaningful outcomes, and focus interventions on neglected symptoms while ensuring dyspnoea is prioritised as a primary end-point for future studies. https://bit.ly/2RNg9KH

This article summarizes the likely attenuation properties of RRx-001 in COVID-19 based on its mechanism of action and the putative pathogenesis of the disease, which appears to activate inflammatory, oxidative, and immune cascades with the potential to culminate in acute respiratory distress syndrome, cytokine storm and death. An ongoing pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), COVID-19 appears to present with 3 major patterns of clinical symptomatology: (1) mild upper respiratory tract infection, (2) non–life-threatening pneumonia, and (3) severe pneumonia and acute respiratory distress syndrome that initially manifest as a mild prodrome lasting for 7–8 days before rapid clinical and radiological deterioration requiring ICU transfer. RRx-001 is a targeted nitric oxide donor. This small molecule, which has been evaluated in multiple Phase 1–2 clinical trials for cancer as well as a Phase 3 clinical trial for the treatment of small cell lung cancer called REPLATINUM (NCT03699956), is minimally toxic and demonstrates clear evidence of antitumor activity. During the course of these clinical trials it was noted that the rate of chronic obstructive pulmonary disease exacerbation and pneumonia in actively smoking small cell lung cancer patients treated with RRx-001 is less than 1%. Due to extensive history of tobacco use, 40%–70% of patients with lung cancer have chronic obstructive pulmonary disease [1] and the expected rate of pulmonary infection in this population is 50%–70% [2], which was not observed in RRx-001 clinical trials. Moreover, in preclinical studies of pulmonary hypertension, RRx-001 was found to be comparable with or more effective than the FDA approved agent, Bosentan. The potential pulmonary protective effects of RRx-001 in patients with recurrent lung infections coupled with preclinical models demonstrating RRx-001-mediated reversal of pulmonary hypertension suggests RRx-001 may have therapeutic activity in patients with acute respiratory symptoms due to COVID 19. Clinical trials have been initiated to confirm the hypothesis that RRx-001 may be repurposed to treat SARS-CoV-2 infection.

Background Prospective registry studies of congenital heart disease (CHD)-associated pulmonary artery hypertension (PAH) are rare. We established a multicenter registry of CHD-PAH: the TACHYON (TAiwan Congenital Heart disease associated with pulmonarY arterial hypertension) registry. Methods The prospective TACHYON registry was initiated in January 2016. Nine pediatric cardiology centers with 99 patients were included. Using this database, we evaluated clinical characteristics and outcomes. Results Twelve patients with incomplete data were excluded. For the remaining 87 patients, mean age of enrollment was 37.4 (SD 18.2) years, and the male to female ratio was 60:27. PAH after defect closure accounted for 46 (52.9%) and Eisenmenger syndrome for 30 (34.5%) cases. Atrial septal defect was the most common (48.3%) disease, followed by ventricular septal defect. Mean pulmonary artery pressure was 56.7 (SD 19.4) mmHg. PAH-targeted therapy was used in 95.4% of patients. Sildenafil and bosentan were the most common drugs. After mean 23.9 months of follow-up, the 2-year Kaplan–Meier survival rate was 93.2%. According to univariate Cox regression analysis, significant risk factors included right heart failure signs, symptom progression, high-risk baseline N-terminal pro–brain natriuretic peptide (BNP)/BNP, high-risk baseline 6-min walking distance (6MWD), and high baseline hemoglobin/hematocrit level. Using the three noninvasive parameters (functional class, 6MWD, NT-pro BNP/BNP) proposed by the European Society of Cardiology, the total number of high-risk criteria predicted survival rate reliably. Conclusions Using the TACHYON registry is feasible, but the physicians' adherences to guidelines are unsatisfactory. Midterm outcomes of PAH-target therapy are favorable and predictable using noninvasive parameters.

This systematic review and meta-analysis was conducted to identify if long-term bosentan is an effective and safe treatment for pulmonary arterial hypertension (PAH) regardless of type, including idiopathic PAH (IPAH), and PAH associated with congenital heart disease (APAH-CHD), connective tissue disease (APAH-CTD), and human immunodeficiency virus (APAH-HIV). All relevant observations were systematically searched by two independent investigators and obtained from three databases, including PubMed, EMBASE and the Cochrane Library, from the inception of each database to February 2020. Currently, long-term administration was defined as no less than 12 months. A random-effects or fixed-effects model was selected according to outcomes of the heterogeneity test for meta-analysis, where standardized mean difference (SMD) with 95% confidence intervals (CIs) was used for continuous outcomes, in addition to the estimated effect (ES; 95% CI) for the synthesized survival rate. Furthermore, subgroup analysis was applied to analyze the differences of efficacy and survivals in each type of PAH cohort. Fifteen studies including a total of 659 subjects undergoing oral bosentan administration for at least 12 months were pooled in this quantitative review. Meta-analysis and subgroup analysis indicated that significant clinical benefits existed, including an improved 6-min walk distance (6MWD) and functional class (FC), in patients with APAH-CHD (6MWD: SMD 0.72, 95% CI 0.52–0.93, p

In children with single ventricle physiology, increased pulmonary vascular resistance may impede surgical progression or result in failing single ventricle physiology. The use of pulmonary vasodilators has been suggested as a potential therapy. However, knowledge on indication, dosage, and effect is limited. A retrospective case notes review of all (n = 36) children with single ventricle physiology, treated with pulmonary vasodilators by the UK Pulmonary Hypertension Service for Children 2004–2017. Therapy was initiated in Stage 1 (n = 12), Glenn (n = 8), or TCPC (n = 16). Treatment indications were high mean pulmonary arterial pressure, cyanosis, reduced exercise tolerance, protein-losing enteropathy, ascites, or plastic bronchitis. Average dose of sildenafil was 2.0 mg/kg/day and bosentan was 3.3 mg/kg/day. 56% had combination therapy. Therapy was associated with a reduction of the mean pulmonary arterial pressure from 19 to 14 mmHg (n = 17, p n = 16, p

Objective: Endothelin (ET) receptor antagonists (ERAs) have considerable improvements in pulmonary arterial hypertension (PAH) patients’ symptoms. Macitentan, a novel ERA, has more significant positive effects like reduction of morbidity and mortality in PAH patients by 45% and decreases PAH hospitalization. Besides, macitentan was able to improve both the physical and mental aspects of patients’ lives. This study aimed to evaluate an incremental cost-utility analysis of macitentan compared with bosentan in PAH patients in the Iranian health care system. Methods: We developed a hybrid model consisting of a decision tree in which PAH patients would take and continue either macitentan or bosentan with different probabilities. Subsequently, each patient would enter one of the 4 Markov's, each consisting of 5 states, PAH fraction I, PAH fraction II, PAH fraction III, PAH fraction IV, and death. The cycles and time horizon were considered 3 months and lifetime, respectively. We assessed the impact of each medicine on patients’ quality-adjusted life-years (QALYs) and costs, consequently calculated the ICER (Incremental Cost-Effectiveness Ratio). The costs were measured in the dollar (1 dollar is equal to 42000 rials) with the perspective of the payer. The discount rates were assumed 3% for utility and 5% for costs. In addition, a sensitivity analysis was conducted. Results: The costs are about 14163 dollars for bosentan and 13876 dollars for macitentan for each patient in a lifetime. The QALY produced per patient by macitentan was 0.81 more than that of bosentan. The calculated ICER was -357.47 which means that for each incremental QALY, the payer is charged less. Conclusion: Macitentan is preferable to and dominant over bosentan in both effectiveness and expenditure. Thus, the therapeutic regimen containing macitentan is introduced as a favorable treatment strategy.

Objective Biventricular repair of double-outlet right ventricle with noncommitted ventricular septal defect is preferred, but previously developed surgical procedures are complicated and associated with high mortality and morbidity. We developed a technique using an intraventricular conduit to connect the ventricular septal defect and the aorta in this anomaly in patients aged more than 2 years. Methods Thirty-one patients (age 2-23 years; median, 5.4) with double-outlet right ventricle with noncommitted ventricular septal defect underwent biventricular repair with intraventricular conduit. A 16-mm or 19-mm polytetrafluoroethylene (Gore-Tex; WL Gore & Associates, Flagstaff, Ariz) vascular prosthesis was used to construct the intraventricular conduit rerouting the ventricular septal defect to the aorta, with enlargement of the ventricular septal defect and resecting the hypertrophic muscular bands in the bilateral conus when necessary. Follow-up was made in all patients with a median duration of 93 months (range, 8-140 months). Results One patient died during hospitalization and 1 patient died at 8 months after operation, making the mortality 6.5%. The peak pressure gradient across the left ventricular outflow tract was less than 30 mm Hg in all patients but 1 (3.3%). In the last patient, it increased from 16 mm Hg early after operation to 50 mm Hg at 7 years follow-up. The peak pressure gradient across the right ventricular outflow tract ranged from 6 to 30 mm Hg in all patients. One patient had moderate mitral regurgitation with New York Heart Association class II. One patient had preoperative severe pulmonary arterial hypertension (mean pressure, 50 mm Hg) and was treated with bosentan. Other patients were in New York Heart Association class I. Conclusions Biventricular repair with intraventricular conduit is a relatively simple and safe procedure for patients aged more than 2 years with double-outlet right ventricle with noncommitted ventricular septal defect, with excellent early and midterm outcomes.

Supplemental Digital Content is available in the text., GPR81 (G-protein-coupled receptor 81) is highly expressed in adipocytes, and activation by the endogenous ligand lactate inhibits lipolysis. GPR81 is also expressed in the heart, liver, and kidney, but roles in nonadipose tissues are poorly defined. GPR81 agonists, developed to improve blood lipid profile, might also provide insights into GPR81 physiology. Here, we assessed the blood pressure and renal hemodynamic responses to the GPR81 agonist, AZ′5538. In male wild-type mice, intravenous AZ′5538 infusion caused a rapid and sustained increase in systolic and diastolic blood pressure. Renal artery blood flow, intrarenal tissue perfusion, and glomerular filtration rate were all significantly reduced. AZ′5538 had no effect on blood pressure or renal hemodynamics in Gpr81−/− mice. Gpr81 mRNA was expressed in renal artery vascular smooth muscle, in the afferent arteriole, in glomerular and medullary perivascular cells, and in pericyte-like cells isolated from kidney. Intravenous AZ′5538 increased plasma ET-1 (endothelin 1), and pretreatment with BQ123 (endothelin-A receptor antagonist) prevented the pressor effects of GPR81 activation, whereas BQ788 (endothelin-B receptor antagonist) did not. Renal ischemia-reperfusion injury, which increases renal extracellular lactate, increased the renal expression of genes encoding ET-1, KIM-1 (Kidney Injury Molecule 1), collagen type 1-α1, TNF-α (tumor necrosis factor-α), and F4/80 in wild-type mice but not in Gpr81−/− mice. In summary, activation of GPR81 in vascular smooth muscle and perivascular cells regulates renal hemodynamics, mediated by release of the potent vasoconstrictor ET-1. This suggests that lactate may be a paracrine regulator of renal blood flow, particularly relevant when extracellular lactate is high as occurs during ischemic renal disease.

The aim of this study was to investigate whether a dual endothelin receptor antagonist bosentan modulates the kinetics of bone marrow-derived stem cells in inhibiting the development of pulmonary hypertension. Bone marrow chimeric mice, transplanted with enhanced green fluorescent protein (eGFP)-positive bone marrow mononuclear cells, were exposed to hypobaric hypoxia or kept in the ambient air, and were daily treated with bosentan sodium salt or saline for 21 days. After the treatment period, right ventricular pressure was measured and pulmonary vascular morphometry was conducted. Incorporation of bone marrow-derived cells was analyzed by immunohistochemistry. Gene expression and protein level in the lung tissue were evaluated by quantitative real-time PCR and western blotting, respectively. The results showed that, in hypoxic mice, right ventricular pressure and the percentage of muscularized vessel were increased and pulmonary vascular density was decreased, each of which was reversed by bosentan. Bone marrow-derived endothelial cells and macrophages in lungs were increased by hypoxia. Bosentan promoted bone marrow-derived endothelial cell incorporation but inhibited macrophage infiltration into lungs. Quantitative real-time PCR analysis revealed that interleukin 6, stromal cell-derived factor-1, and monocyte chemoattractant protein-1 were upregulated by hypoxia, in which interleukin 6 and monocyte chemoattractant protein-1 were downregulated and stromal cell-derived factor-1 was upregulated by bosentan. Protein level of endothelial nitric oxide synthase (eNOS) in the whole lung was significantly upregulated by hypoxia, which was further upregulated by bosentan. Bosentan modulated kinetics of bone marrow-derived ECs and macrophages and related gene expression in lungs in ameliorating pulmonary hypertension in mice. Altered kinetics of bone marrow-derived stem cells may be a novel mechanism of the endothelin receptor blockade in vivo and confer a new understanding of the therapeutic basis for pulmonary hypertension.

Acute respiratory distress syndrome is characterized by dyspnea at presentation, tachypnea on physical examination, findings of bilateral infiltration in chest radiography, refractory hypoxia, and high mortality. Although the main treatment approach is to address the underlying disease, there are also pharmacological and nonpharmacological options for supportive treatment. There is currently no pharmacological agent with proven efficacy in this syndrome, and many drugs are being studied for this purpose. One of these is the endothelin receptor antagonist bosentan.

Resumen En los pacientes con Hipertensión Arterial Pulmonar (HAP) de alto riesgo, en clase funcional (CF)IV, la terapia específica debe ser combinada y debe incluir una prostaciclina (PGI2) de uso sistémico en espera de trasplante bipulmonar (TBP). En el sistema público la única PGI2 disponible para asociar a Sildenafil y algún inhibidor de endotelina (Ambrisentan o Bosentan) es Iloprost nebulizado, que si bien es efectiva, no logra estabilizar los casos graves con severa disfunción del ventrículo derecho (VD). Se presenta el primer caso en el Instituto del Tórax, centro de referencia nacional de HAP, del uso de treprostinil en una paciente de 24 años con HAP grave e indicación de TBP. Treprostinil es un análogo sintético de PGI2 de uso subcutáneo en dosis desde 1 a 40 ng/kg/min. La paciente presentaba una situación de extrema gravedad: CF IV, distancia recorrida en el test de caminata de 6 min (DRTC 6 min) < 300 m,derrame pericárdico y severa disfunción del VD con TAPSE (índice de disfunción del VD) de 13 cm/s asociado a ProBNP >2.500 pg/ml. Luego de 6 meses de hospitalización en intermedio, terapia triple (Sildenafil, Ambrisentan e Iloprost nebulizado) asociado a O2,diuréticos y milrinona, logró ser dada de alta a las 3 semanas del inicio de treprostinil, regresando al trabajo a los 2 meses y estabilizando su condición en CF III, con DRTC 6 min > 440 m, mejoría de la función del VD(TAPSE 19). El ProBNP persistió elevado, 1.491 pg/ml, indicando que su enfermedad es grave y progresiva; sin embargo, ha logrado un nivel de estabilidad clínica que le permite una adecuada vida de relación familiar y laboral.

Pulmonary hypertension is a serious complication of systemic sclerosis and remains one of the leading causes of mortality. Pulmonary veno-occlusive disease (PVOD), recently reclassified as pulmonary arterial hypertension (PAH) with overt features of venous/capillaries involvement, is a subgroup of group 1 pulmonary hypertension, which has been rarely reported in systemic sclerosis patients. It is symptomatically indistinguishable from idiopathic pulmonary arterial hypertension and should be suspected in those with manifestations of pulmonary arterial hypertension who have evidence of pulmonary venous congestion in the absence of left-sided heart disease. Thoracic high-resolution computed tomography can give important hints for the diagnosis, such as ground-glass opacities/nodules, mediastinal lymph node enlargement and interlobular septal thickening. Patients with PVOD usually have a poor prognosis and might experience acute pulmonary oedema after introduction of pulmonary vasodilators. Due to clinical similarities between scleroderma-related PAH and PVOD, some patients are misdiagnosed and this could explain, in part, the worse prognosis associated with this clinical condition, when compared with idiopathic PAH. We report the case of a 72-year-old woman with limited systemic sclerosis, who was initially diagnosed with systemic sclerosis-related pulmonary arterial hypertension. However, after introduction of sildenafil and bosentan, the patient developed acute pulmonary oedema, and findings from complementary exams were suggestive of PVOD.

Pediatric pulmonary arterial hypertension (PAH) is a rare but severe disease with no cure. In this review, we discuss an approach to the evaluation and management of a pediatric patient with suspected or confirmed PAH. Proceedings published from the 2018 World Symposium updated the definition of pulmonary hypertension to include all adults and children with mean pulmonary artery pressure > 20 mmHg. A classification scheme for patients with PAH associated with congenital heart disease is now also well recognized. Recent research and guidelines have described a series of risk stratification criteria as well as specific criteria for operability in children with unrepaired systemic-to-pulmonary shunt lesions. Although multiple medications have been used off-label, in 2017, bosentan became the first targeted PAH therapy approved for use in children. In recent years, advanced imaging and clinical monitoring have allowed improved risk stratification of PH patients. New therapies, approved in adults and used off-label in pediatric patients, have led to improved outcomes for affected children. However, no targeted pulmonary hypertension medications are approved for children

This thesis focuses on clinical outcomes of CTEPH patients treated with PH-specific medical therapy or balloon pulmonary angioplasty (BPA). It provides long-term results of medically treated patients, the first results of BPA treatment in the Netherlands and assesses quality of life (QoL) in CTEPH patients. In chapter 2 the long-term outcome of CTEPH patients using riociguat is assessed. After a follow-up of three years, 94% of all patients using riociguat was still alive and 78% of all patients did not experience clinical worsening (all-cause mortality, hospital admission or lower 6-minute walking distance (6MWD) plus lower functional class). In addition, patients using riociguat experienced significant improved functional class, exercise tolerance (measured with 6MWD) and lower NT-proBNP compared to measurements before the start of PH-specific medical therapy. In chapter 3 long-term results of CTEPH patients using macitentan are described. CTEPH patients using macitentan were divided in two groups: one group with technical inoperable disease and another group with clinical inoperable disease. Patients in the first group had distal lesions unsuitable for PEA, while patients in the latter group were inoperable due to comorbidities or were reluctant to undergo PEA. Survival rates two years after the start of treatment with macitentan were 86% and 100% for the technical and clinical inoperable CTEPH patients respectively. Both groups had significant improved 6MWD, while 30% of all patients experienced non-severe adverse events. In chapter 4 the outcomes between CTEPH patients using macitentan and bosentan are compared. In our cohort, survival and improvements in functional class, NT-proBNP and 6MWD of patients using macitentan were similar compared to patients using bosentan. Significant baseline predictors of survival were right atrial pressure, cardiac output and lowest saturation during 6MWD. In chapter 5 outcomes of CTEPH patients using PH-specific medical monotherapy are compared with CTEPH patients using PH-specific medical combination therapy. In our study, patients starting combination therapy had more severe disease at baseline, but survival up to five years after start of therapy was similar in both groups. In chapter 6 the first results of BPA in the Netherlands are reported. Our study includes data of 38 CTEPH patients who underwent 172 BPA procedures. There was a significant improvement of functional class, 6MWD and pulmonary hemodynamics. Non-severe complications occurred in 12% of all procedures. In chapter 7 results of change in ventilation/perfusion (V/Q) scan after BPA treatment are presented. A V/Q scan was performed in 20 CTEPH patients at baseline and 6 months after completion of BPA treatment. Both visual assessment and a semi-quantitative calculated pulmonary vascular obstruction index showed perfusion improvement. Nevertheless, the improvement of perfusion did not correlate with clinical outcome. In chapter 8 we reported longitudinal follow-up results of the use of the EmPHasis-10 and CAMPHOR questionnaires in CTEPH and PAH patients. We showed a significant reduction in scores of both the EmPHasis-10 and CAMPHOR (quality of life and symptoms) domains after one year of treatment. In addition, the EmPHasis-10 score showed a good correlation with the scores of all CAMPHOR domains.

Background Persistent pulmonary hypertension of the newborn (PPHN) has been known for more than three decades, and lots of advancements have been made regarding its diagnosis and management. However, the exact causes of PPHN and the best treatment strategies remain debatable. This study aimed to compare the effectiveness of sildenafil and bosentan versus sildenafil and beraprost in the management of persistent pulmonary hypertension of the newborn (PPHN). Methodology This open-label, non-randomized, quasi-experimental study was conducted at the Department of Pediatric Cardiology and Neonatology, The Children’s Hospital & The Institute of Child Health, Multan, Pakistan, from January 2021 to June 2021. We enrolled a total of 50 newborns (25 in each group) aged

Background:Potential therapy and confounding factors including typical co‐administered medications, patient’s disease states, disease prevalence, patient demographics, medical histories, and reasons for prescribing a drug often are incomplete, conflicting, missing, or uncharacterized in spontaneous adverse drug event (ADE) reporting systems. These missing or incomplete features can affect and limit the application of quantitative methods in pharmacovigilance for meta-analyses of data during randomized clinical trials.Methods:Data from patients with hypertension were retrieved and integrated from the FDA Adverse Event Reporting System; 134 antihypertensive drugs out of 1131 drugs were filtered and then evaluated using the empirical Bayes geometric mean (EBGM) of the posterior distribution to build ADE-drug profiles with an emphasis on the pulmonary ADEs. Afterward, the graphical least absolute shrinkage and selection operator (GLASSO) captured drug associations based on pulmonary ADEs by correcting hidden factors and confounder misclassification. Selected drugs were then compared using the Friedman test in drug classes and clusters obtained from GLASSO.Results:Following multiple filtering stages to exclude insignificant and noise-driven reports, we found that drugs from antihypertensives agents, urologicals, and antithrombotic agents (macitentan, bosentan, epoprostenol, selexipag, sildenafil, tadalafil, and beraprost) form a similar class with a significantly higher incidence of pulmonary ADEs. Macitentan and bosentan were associated with 64% and 56% of pulmonary ADEs, respectively. Because these two medications are prescribed in diseases affecting pulmonary function and may be likely to emerge among the highest reported pulmonary ADEs, in fact, they serve to validate the methods utilized here. Conversely, doxazosin and rilmenidine were found to have the least pulmonary ADEs in selected drugs from hypertension patients. Nifedipine and candesartan were also found by signal detection methods to form a drug cluster, shown by several studies an effective combination of these drugs on lowering blood pressure and appeared an improved side effect profile in comparison with single-agent monotherapy.Conclusions:We consider pulmonary ADE profiles in multiple long-standing groups of therapeutics including antihypertensive agents, antithrombotic agents, beta-blocking agents, calcium channel blockers, or agents acting on the renin-angiotensin system, in patients with hypertension associated with high risk for coronavirus disease 2019 (COVID-19). We found that several individual drugs have significant differences between their drug classes and compared to other drug classes. For instance, macitentan and bosentan from endothelin receptor antagonists show major concern while doxazosin and rilmenidine exhibited the least pulmonary ADEs compared to the outcomes of other drugs. Using techniques in this study, we assessed and confirmed the hypothesis that drugs from the same drug class could have very different pulmonary ADE profiles affecting outcomes in acute respiratory illness.Funding:GJW and MJD accepted funding from BioNexus KC for funding on this project, but BioNexus KC had no direct role in this article.

Obesity is associated with dysregulation of the endothelin system. In individuals with obesity, an exaggerated pressor response to acute stress is accompanied by increased circulating endothelin-1 (ET-1). The impact of combined endothelin A/B receptor (ET(A/B)) antagonism on the stress-induced pressor response in overweight/obese (OB) individuals is unknown. The objective of this study is to test the hypothesis that treatment with an ET(A/B) antagonist (bosentan) would reduce the stress-induced pressor response and arterial stiffness in overweight/obese compared with normal weight (NW) individuals. Forty participants [normal weight (NW): n = 20, body mass index (BMI): 21.7 ± 2.4 kg/m(2) and overweight/obese (OB): n = 20, BMI: 33.8 ± 8.2 kg/m(2)] were randomized to placebo or 125 mg of bosentan twice a day (250 mg total) for 3 days. Hemodynamics were assessed before, during, and after a cold pressor test (CPT). Endothelin-1 was assessed at baseline and immediately after CPT. Following a washout period, the same protocol was repeated with the opposite treatment. The change from baseline in mean arterial pressure (MAP) during CPT following bosentan was significantly lower (P = 0.039) in the OB group than in the NW group (OB: 28 ± 12 vs. NW: 34 ± 15 mmHg). These results suggest that ET(A/B) antagonism favorably blunts the pressor response to acute stress in overweight/obese individuals. NEW & NOTEWORTHY Findings from our current translational investigation demonstrate that dual endothelin A/B receptor antagonism blunts the pressor response to acute stress in overweight/obese individuals. These results suggest that modulation of the endothelin system may represent a novel therapeutic target to reduce cardiovascular disease (CVD) risk by blunting the stress response in overweight/obese individuals.

Diabetic nephropathy is becoming a more predominant cause of end-stage renal disease, as the prevalence of diabetes mellitus worldwide is on the rise. In this systematic review, we aimed to define the role of endothelin receptor antagonists, in the prevention and treatment of diabetic nephropathy, in addition to determining their safety. For this review, PubMed, Google Scholar, and Cochrane Library databases, in addition to ClinicalTrials.gov, were searched for publications in the last 20 years. We included 14 studies, seven randomized control trials, and seven post hoc analyses in this paper. Atrasentan decreased albuminuria, reduced blood pressure, and improved lipid profiles with more manageable fluid overload-related adverse events than avosentan and bosentan. Overall, endothelin receptor antagonists, in combination with renin-angiotensin-aldosterone system inhibitors, effectively reduce albuminuria and prevent the progression of diabetic kidney disease. However, more extensive clinical trials still need to be conducted to confirm these relationships and to learn more about the specific factors affecting their efficacy in individual patients.

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Background & Aims Intrahepatic vascular resistance is increased in early non-alcoholic fatty liver disease (NAFLD), potentially leading to tissue hypoxia and triggering disease progression. Hepatic vascular hyperreactivity to vasoconstrictors has been identified as an underlying mechanism. This study investigates vasoconstrictive agonism and antagonism in 2 models of early NAFLD and in non-alcoholic steatohepatitis (NASH). Methods The effects of endothelin-1 (ET-1), angiotensin II (ATII) and thromboxane A2 (TxA2) agonism and antagonism were studied by in situ ex vivo liver perfusion and preventive/therapeutic treatment experiments in a methionine-choline-deficient diet model of steatosis. Furthermore, important results were validated in Zucker fatty rats after 4 or 8 weeks of high-fat high-fructose diet feeding. In vivo systemic and portal pressures, ex vivo transhepatic pressure gradients (THPG) and transaminase levels were measured. Liver tissue was harvested for structural and mRNA analysis. Results The THPG and consequent portal pressure were significantly increased in both models of steatosis and in NASH. ET-1, ATII and TxA2 increased the THPG even further. Bosentan (ET-1 receptor antagonist), valsartan (ATII receptor blocker) and celecoxib (COX-2 inhibitor) attenuated or even normalised the increased THPG in steatosis. Simultaneously, bosentan and valsartan treatment improved transaminase levels. Moreover, bosentan was able to mitigate the degree of steatosis and restored the disrupted microvascular structure. Finally, beneficial vascular effects of bosentan endured in NASH. Conclusions Antagonism of vasoconstrictive mediators improves intrahepatic vascular function. Both ET-1 and ATII antagonists showed additional benefit and bosentan even mitigated steatosis and structural liver damage. In conclusion, vasoconstrictive antagonism is a potentially promising therapeutic option for the treatment of early NAFLD. Lay summary In non-alcoholic fatty liver disease (NAFLD), hepatic blood flow is impaired and the blood pressure in the liver blood vessels is increased as a result of an increased response of the liver vasculature to vasoconstrictors. Using drugs to block the constriction of the intrahepatic vasculature, the resistance of the liver blood vessels decreases and the increased portal pressure is reduced. Moreover, blocking the vasoconstrictive endothelin-1 pathway restored parenchymal architecture and reduced disease severity., Graphical abstract, Highlights • The transhepatic pressure gradient and thus portal pressure are increased in severe hepatic steatosis. • Vasoconstrictor antagonists attenuate the transhepatic gradient to near normal in steatosis. • Vasoconstrictor antagonists attenuate the transhepatic gradient in steatosis. • Bosentan and valsartan attenuate increased transaminase levels in severe steatosis. • Bosentan treatment decreases steatosis and restores the microvascular architecture.

Pulmonary arterial hypertension (PAH) is characterized by pulmonary artery remodeling that may subsequently culminate in right heart failure and premature death. Although there are currently both non-pharmacological (lung transplantation, etc.) and pharmacological (Sildenafil, Bosentan and new oral drugs on trial) therapies available, PAH remains a serious and fatal pulmonary disease. Traditional herbal medicine (THM) treatment, as a unique medical treatment, has gradually exerted its advantages in the treatment of PAH worldwide through a multi-level and multi-target approach. Additionally, the potential mechanisms of THM were deciphered, including suppression of proliferation and apoptosis of pulmonary artery smooth muscle cells, controlling the processes of inflammation and oxidative stress, regulations of vasoconstriction, ion channels and so on. In this review, the effects and mechanisms of the frequently studied compound THM, single herbal preparations, and multiple active components from THM are comprehensively summarized, as well as their related mechanisms on the several classical preclinical PAH models. It is worth mentioning that the sodium tanshinone IIA sulfonate sodium and tetramethylpyrazine are under clinical trials and considered as the most promoting medicines for PAH treatment. Last, reverse pharmacology, a strategy to discover THM or THM-derived components has been also proposed here for PAH. This review discusses the current state towards THM, their working mechanisms against PAH and future prospects of reverse pharmacology, which is expected to facilitate the natural anti-PAH medicine discovery and development, as well as its bench to bedside transformation.

Tadalafil, a phosphodiesterase 5 inhibitor, is being investigated as a treatment for pulmonary arterial hypertension (PAH) in children aged 6 months to less than 18 years. Tadalafil pharmacokinetic (PK) data in children less than 2 years old are unavailable, therefore a physiologically based pharmacokinetic (PBPK) model was developed to enable estimation of tadalafil doses in children less than 2 years old. The model was verified in adults and extended for use in children by modifying CYP3A‐mediated intrinsic clearance to include CYP3A7. To account for co‐dosing of the commonly prescribed moderate CYP3A4 inducer bosentan, predicted exposures were increased by a factor of 1.54 based on changes in exposure in adults with PAH. This factor was predictable using a bosentan PBPK model. The tadalafil model was verified in children aged greater than or equal to 2 years by comparing predicted and observed exposures. Tadalafil doses for children less than 2 years old were calculated as target area under the concentration curve from zero to 24 h (AUC0–24)/predicted AUC0–24, with target AUC0–24 of 10,000 ng*h/ml based on adult 40 mg single dose exposures determined in patients without bosentan background treatment. These doses were 2 mg, 3 mg, 4 mg, and 6 mg, respectively, for children aged birth to less than 1 month, 1 month to less than 6 months, 6 months to less than 1 year, and 1 to less than 2 years. Due to uncertainties in CYP maturation, a nonmechanistic steady‐state volume scalar, and lack of PK data in children less than 2 years old, accumulation of tadalafil to steady‐state in children less than 2 years was not verifiable. Safety of proposed doses is supported by postmarketing research and investigator‐led trials.

Drug-induced liver injury, including cholestasis, is an important clinical issue and economic burden for pharmaceutical industry and healthcare systems. However, human-relevant in vitro information on the ability of other types of chemicals to induce cholestatic hepatotoxicity is lacking. This work aimed at investigating the cholestatic potential of non-pharmaceutical chemicals using primary human hepatocytes cultured in 3D spheroids. Spheroid cultures were repeatedly (co-) exposed to drugs (cyclosporine-A, bosentan, macitentan) or non-pharmaceutical chemicals (paraquat, tartrazine, triclosan) and a concentrated mixture of bile acids for 4 weeks. Cell viability (adenosine triphosphate content) was checked every week and used to calculate the cholestatic index, an indicator of cholestatic liability. Microarray analysis was performed at specific time-points to verify the deregulation of genes related to cholestasis, steatosis and fibrosis. Despite the evident inter-donor variability, shorter exposures to cyclosporine-A consistently produced cholestatic index values below 0.80 with transcriptomic data partially supporting its cholestatic burden. Bosentan confirmed to be hepatotoxic, while macitentan was not toxic in the tested concentrations. Prolonged exposure to paraquat suggested fibrotic potential, while triclosan markedly deregulated genes involved in different types of hepatotoxicity. These results support the applicability of primary human hepatocyte spheroids to study hepatotoxicity of non-pharmaceutical chemicals in vitro.

Introduction: Whipple’s disease (WD) is a rare multivisceral disorder with few descriptions of pulmonary hypertension (PH) Aims and objectives: To describe the association between PH and WD (PH-WD). Methods: We report the characteristics and outcomes of two patients with PH-WD hospitalized in the French PH reference center. Results: PH-WD was diagnosed in two men (54 and 59-yo) hospitalized for right heart failure. Both reported a deterioration in general state over the previous year, associated with diarrhea and mood change (patient 1) and a seronegative polyarthritis and purpura (patient 2). Initial right heart catheterization (RHC) confirmed severe precapillary PH in patient 1: mean pulmonary artery pressure 40 mmHg, cardiac index 2 L/min/m2, pulmonary artery wedge pressure13 mmHg, pulmonary vascular resistance 8 WU. The second patient presented with advanced right heart failure, high echocardiographic probability of PH and no evidence of left heart disease. Both patients were treated with intravenous dobutamine and large spectrum antibiotics. The diagnosis of WD was established by duodenal biopsies and positive T. whipplei PCR in the saliva (patient 1) and in the blood and stools (patient 2). The first patient rapidly improved and experienced complete recovery after one year of treatment associating bosentan, tadalafil, doxycycline and hydroxychloroquine. The second patient rapidly deteriorated and died 24h after his admission because of end-stage right heart failure. Conclusions: WD is a rare cause of severe but potentially reversible PH. Due to poor awareness, delayed diagnosis may lead to death due to end-stage right heart failure.

Background Patients with Eisenmenger syndrome are chronically hypoxaemic and should therefore mount a secondary erythrocytosis. This response can be attenuated by iron deficiency. Historically, patients with Eisenmenger-associated erythrocytosis often underwent venesection but recent data have challenged this practice. Case presentation An illustrative case of a 30-year-old female with Eisenmenger syndrome secondary to a ventricular septal defect is discussed. Her resting saturations on room air were 84%. She was receiving pulmonary arterial hypertension targeted therapy with sildenafil 25 mg three times a day and bosentan 125 mg twice daily. Her local haematologist was planning on therapeutic venesection as her haematocrit was elevated at 0.57. Her haemoglobin was 16.7 g/dl, ferritin levels were 15 μg/L and transferrin saturations were 10.5%. What are the indications for venesection? Should she receive iron supplementation instead? Data to help guide decision-making are reviewed and a clinical approach is suggested. Conclusions Iron status should be regularly checked in Eisenmenger syndrome patients and replaced appropriately. There is no role for routine venesection in patients with Eisenmenger syndrome; this should be reserved for the small proportion of patients with symptoms of hyperviscosity in the absence of dehydration.

Raynaud’s phenomenon (RP) is an episodic digital vasospastic condition that is prevalent among 5% of the population. The symptoms range from reversible pallor to ischemia and gangrene. RP can be primary or secondary. We discuss a case of severe RP secondary to granulomatosis with polyangiitis (GPA) that presented with ischemia and gangrene. Studies show that approximately

Background: Systemic sclerosis is an autoimmune disease that could significantly affect internal organs, increasing the mortality associated with the disorder. Pulmonary hypertension is one of the conditions that increase the morbidity and mortality of the disease. The aim of the study was to develop a systematic literature review about the different pharmacological treatments for systemic sclerosis-associated pulmonary hypertension. Materials and methods: A systematic literature review was made on Cochrane, PubMed and EMBASE. Randomized controlled clinical trials, controlled clinical trials, cohort and case-control studies using any of the available treatments such as prostacyclin analogs, endothelin receptor antagonists, phosphodiesterase inhibitors or soluble guanylate cyclase stimulants were included. The methodological quality of the studies was assessed using Cochrane methodology for clinical trials, and the SIGN tool was applied for cohort and case-control studies. Results: Initially, 870 studies were found, and 20 studies were finally included in the systematic review after applying inclusion and exclusion criteria. Most studies included Bosentan in the treatment strategies (N = 13). Also, most studies took data from the most important clinical trials for pharmacological treatment of pulmonary hypertension of several etiologies. Some studies using Bosentan did not give information about data regarding some outcomes. Half of the selected studies were clinical trials, of which two were randomized. The quality of these studies was good. The other half were observational studies, with moderate quality of evidence. In general, it was found that approved medications improve the 6-minute walk distance, WHO functional class, NYHA functional classification, or Borg dyspnea score, depending on the given dose in several studies, and also compound outcomes that include hospitalizations, clinical worsening, death, etc. Regarding mortality, there were significant differences in survival rates when comparing approved medications vs. placebo, being combined therapies superior to monotherapy. Measurements of hemodynamic variables such as cardiac index, pulmonary resistances, and pulmonary pressures were improved. Also, NT-proBNP levels were reduced, with some exceptions. Conclusions: In most studies with good quality of evidence, it was found an improvement in clinical and non-clinical outcomes, favoring the use of approved medications for the treatment of systemic sclerosis-associated pulmonary hypertension. RESUMEN Antecedentes: La esclerosis sistémica es una enfermedad autoinmune que puede afectar significativamente los órganos internos, aumentando la mortalidad asociada con dicho trastorno. La hipertensión pulmonar es una de las afecciones que aumentan la morbimortalidad de la enfermedad. El objetivo del estudio fue desarrollar una revisión sistemática de la literatura sobre los diferentes tratamientos farmacológicos para la hipertensión pulmonar asociada a la esclerosis sistémica. Materiales y métodos: Se hizo una revisión sistemática de la literatura en Cochrane, PubMed y EMBASE. Se incluyeron ensayos clínicos aleatorizados controlados, ensayos clínicos controlados, así como estudios de cohortes y de casos y controles utilizando alguno de los tratamientos disponibles, tales como los análogos de la prostaciclina, los antagonistas de los receptores de endotelina, los inhibidores de la fosfodiesterasa o los estimulantes de la guanilato ciclasa soluble. Se evaluó la calidad metodológica de los estudios utilizando la metodología Cochrane para los ensayos clínicos, y se aplicó la herramienta SIGN para los estudios de cohortes y de casos y controles. Resultados: Inicialmente se encontraron 870 estudios, de los cuales finalmente se incluyeron 20 en la revisión sistemática, después de aplicar los criterios de inclusión y exclusión. La mayoría de los estudios incluyeron el bosentán en las estrategias de tratamiento (n = 13). Además, la mayoría de los estudios tomaron datos de los ensayos clínicos más importantes sobre el tratamiento farmacológico de la hipertensión pulmonar de diversas etiologías. Algunos estudios que utilizaron el bosentán no suministraron información sobre datos relacionados con algunos resultados. La mitad de los estudios seleccionados fueron ensayos clínicos, de los cuales dos fueron aleatorizados. La calidad de estos estudios fue buena. La otra mitad incluyó estudios observacionales, con evidencia de calidad moderada. En general, se encontró que los medicamentos aprobados mejoran la distancia en la caminata de seis minutos, la clase funcional de la OMS, la clasificación funcional de la NYHA, o el puntaje de disnea en la escala de Borg, dependiendo de la dosis administrada en los diferentes estudios, y también los desenlaces compuestos que incluyen hospitalizaciones, empeoramiento clínico, muerte, etc. En cuanto a la mortalidad, se encontraron diferencias significativas en las tasas de supervivencia al comparar los medicamentos aprobados versus placebo, siendo las terapias combinadas superiores a la monoterapia. Las mediciones de variables hemodinámicas tales como el índice cardíaco, las resistencias pulmonares y las presiones pulmonares mejoraron. Además, los niveles de NT-pro BNP se redujeron, con algunas excepciones. Conclusiones: En la mayoría de los estudios con buena calidad de evidencia, se encontró una mejoría en los desenlaces clínicos y no clínicos, que favorece el uso de los medicamentos aprobados para el tratamiento de la hipertensión pulmonar asociada a la esclerosis sistémica.