Search Results (13)

Background and Clinical Significance: Idiopathic pulmonary arterial hypertension is a rare disorder, often linked to genetic predisposition. Canonical pulmonary arterial hypertension genes such as BMPR2, KCNK3, and TBX4 are well described, but novel associations continue to emerge. Glomulin (GLMN) encodes a protein essential for vascular smooth-muscle biology, classically implicated in glomuvenous malformations, yet not previously associated with pulmonary arterial hypertension. Case Presentation: We present a 49-year-old woman with progressive dyspnea, edema, and persistent hypercapnic respiratory failure. Right-heart catheterization confirmed precapillary pulmonary hypertension. Comprehensive evaluation, including ventilation/perfusion scanning, autoimmune panel, polysomnography, and high-resolution computed tomography, excluded secondary causes. Respiratory assessment revealed diaphragmatic weakness and reduced respiratory muscle pressures, consistent with primary myopathy and explaining the unusual hypercapnic profile. Whole-genome sequencing identified a heterozygous pathogenic GLMN nonsense variant, while canonical pulmonary arterial hypertension genes were negative. No cutaneous or mucosal glomuvenous malformations were found. The patient was treated with oxygen therapy, diuretics, non-invasive ventilation, and dual oral pulmonary arterial hypertension therapy (ambrisentan and tadalafil), with stabilization but persistent hypercapnia. Conclusions: To our knowledge, this is the first reported co-occurrence of idiopathic pulmonary arterial hypertension and a pathogenic GLMN variant. While causality cannot be inferred, glomulin’s role in vascular smooth-muscle maturation provides a plausible link to pulmonary vascular remodeling. This case underscores the importance of assessing respiratory muscle function in idiopathic pulmonary arterial hypertension patients with hypercapnia and highlights the potential relevance of extended genetic testing in rare pulmonary vascular disease. Full article

Animal preclinical experiments in pulmonary hypertension (PH) need to be conducted with detailed methodological rigor to improve their translational relevance. One of its crucial yet insufficiently studied aspects is animal body weight (BW). Thus, our study aimed to examine the influence of initial BW on the severity of PH development induced by monocrotaline (MCT) and the effectiveness of the reference combined therapy (ambrisentan and tadalafil given for 21 days). Male rats were divided into three weight Sets: Set I (200–219 g); Set II (220–239 g); and Set III (240–259 g), after which, MCT-PH was induced. The measurements taken included in vivo echocardiographic evaluations, ex vivo functional experiments (on isolated right ventricle papillary muscles and pulmonary arteries), and histological and morphometric assessments. In all three Sets of animals, we noticed evidence of PH development. More pronounced changes confirming the severity of PH were observed in Set II compared to Sets I and III. The effectiveness of the reference therapy was also most evident in Set II, where the reversal of PH-related aggravations was best documented. We demonstrated that both the severity of MCT-induced PH in rats and the effectiveness of the reference combined therapy strongly depend on the animals’ initial BW. Full article

Objective: Pulmonary arterial hypertension (PAH) is a progressive and life-threatening disease. Adverse events (AEs) related to its drug treatment seriously damaged the patient’s health. This study aims to clarify the causal relationship between PAH drugs and these AEs by combining pharmacovigilance signal detection with the Bayesian causal network model. Methods: Patient data were obtained from the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS), covering reports from 2013 to 2023. In accordance with standard pharmacovigilance methodologies, disproportionality analysis was performed to detect signals. Target drugs were selected based on the following criteria: number of reports (a) ≥ 3, proportional reporting ratio (PRR) ≥ 2, and chi-square (χ²) ≥ 4. Bayesian causal network models were then constructed to estimate causal relationships. The do-calculus and adjustment formula were applied to calculate the causal effects between drugs and AEs. Results: Signal detection revealed that Ambrisentan, Bosentan, and Iloprost were associated with serious AEs, including death, dyspnea, pneumonia, and edema. For Ambrisentan, the top-ranked adverse drug events (ADEs) based on average causal effect (ACE) were peripheral swelling (ACE = 0.032) and anemia (ACE = 0.021). For Iloprost, the most prominent ADE was hyperthyroidism (ACE = 0.048). Conclusions: This study quantifies causal drug–event relationships in PAH using Bayesian causal networks. The findings offer valuable evidence regarding the clinical safety of PAH medications, thereby improving patient health outcomes. Full article

Pulmonary hypertension (PH) is a severe vascular complication of connective tissue diseases (CTD). Patients with CTD may develop PH belonging to diverse groups: (1) pulmonary arterial hypertension (PAH), (2) PH due to left heart disease, (3) secondary PH due to lung disease and/or hypoxia and (4) chronic thromboembolic pulmonary hypertension (CTEPH). PAH most often develops in systemic scleroderma (SSc), mostly in its limited variant. PAH-CTD is a progressive disease characterized by poor prognosis. Therefore, early diagnosis should be established. A specific treatment for PAH-CTD is currently available and recommended: prostacyclin derivative (treprostinil, epoprostenol, iloprost, selexipag), nitric oxide and natriuretic pathway: stimulators of soluble guanylate cyclase (sGC: riociguat) and phosphodiesterase-five inhibitors (PDE5i: sildenafil, tadalafil), endothelin receptor antagonists (ERA: bosentan, macitentan, ambrisentan). Moreover, novel drugs, e.g., sotatercept, have been intensively investigated in clinical trials. We aim to review the literature on recent advances in the treatment strategy and prognosis of patients with PAH-CTD. In this manuscript, we discuss the mechanism of action of PAH-specific drugs and new agents and the latest research conducted on PAH-CTD patients. Full article

Background and objective: Unilateral agenesis of pulmonary arteries (UAPA) is a rare disease, with approximately 400 cases reported to date. UAPA is often associated with congenital heart disease, and the uncomplicated form is isolated UAPA, which accounts for approximately 30% of all cases of UAPA. The incidence of pulmonary hypertension due to UAPA has been reported to range from 19 to 44%. There is no consensus treatment for pulmonary hypertension associated with UAPA. We present the first reported case in which a three-drug combination, comprising of iloprost inhalation, riociguat, and ambrisentan, was administered to a patient with UAPA, and was followed-up for 3 years post-diagnosis. Case presentation: A 68-year-old Japanese woman presented to our hospital with dyspnea and chest discomfort. She underwent chest radiography, blood tests, and echocardiography; however, the cause of the patient’s symptoms could not be identified. During regular follow-up, an echocardiography 21 months after the initial visit revealed elevated right ventricular pressure (peak tricuspid regurgitation velocity: 5.2 m/s and right ventricular systolic pressure: 120 mmHg) and a diagnosis of pulmonary hypertension was made. Contrast-enhanced computed tomography (CT) of the chest and a pulmonary blood flow scintigram were performed to investigate the cause of pulmonary hypertension, and isolated UAPA was diagnosed. The patient was treated with a three-drug combination of iloprost inhalation, riociguat, and ambrisentan and followed up for 3 years with good therapeutic outcomes. Conclusions: We present a case of pulmonary hypertension caused by isolated UAPA. Although rare, this disease can lead to pulmonary hypertension and should be treated cautiously. While there is no consensus regarding the treatment of this disease, a three-drug combination of iloprost inhalation, riociguat, and oral ambrisentan proved effective. Full article

Background: The aim of this study is to present the first United Arab Emirates pulmonary hypertension registry of patients’ clinical characteristics, hemodynamic parameters and treatment outcomes. Method: This is a retrospective study describing all the adult patients who underwent a right heart catheterization for evaluation of pulmonary hypertension (PH) between January 2015 and December 2021 in a tertiary referral center in Abu Dhabi, United Arab Emirates. Results: A total of 164 consecutive patients were diagnosed with PH during the five years of the study. Eighty-three patients (50.6%) were World Symposium PH Group 1-PH; nineteen patients (11.6%) were Group 2-PH due to left heart disease; twenty-three patients (14.0%) were Group 3-PH due to chronic lung disease; thirty-four patients (20.7%) were Group 4-PH due to chronic thromboembolic lung disease, and five patients (3.0%) were Group 5-PH. Among Group 1-PH, twenty-five (30%) had idiopathic, twenty-seven (33%) had connective tissue disease, twenty-six (31%) had congenital heart disease, and five patients (6%) had porto-pulmonary hypertension. The median follow-up was 55.6 months. Most of the patients were started on dual then sequentially escalated to triple combination therapy. The 1-, 3- and 5-year cumulative probabilities of survival for Group 1-PH were 86% (95% CI, 75–92%), 69% (95% CI, 54–80%) and 69% (95% CI, 54–80%). Conclusions: This is the first registry of Group 1-PH from a single tertiary referral center in the UAE. Our cohort was younger with a higher percentage of patients with congenital heart disease compared to cohorts from Western countries but similar to registries from other Asian countries. Mortality is comparable to other major registries. Adopting the new guideline recommendations and improving the availability and adherence to medications are likely to play a significant role in improving outcomes in the future. Full article

Endothelin-1 (ET-1) has been implicated in the pathogenesis of cardiac fibrosis. Stimulation of endothelin receptors (ETR) with ET-1 leads to fibroblast activation and myofibroblast differentiation, which is mainly characterized by an overexpression of α-smooth muscle actin (α-SMA) and collagens. Although ET-1 is a potent profibrotic mediator, the signal transductions and subtype specificity of ETR contributing to cell proliferation, as well as α-SMA and collagen I synthesis in human cardiac fibroblasts are not well clarified. This study aimed to evaluate the subtype specificity and signal transduction of ETR on fibroblast activation and myofibroblast differentiation. Treatment with ET-1 induced fibroblast proliferation, and synthesis of myofibroblast markers, α-SMA, and collagen I through the ET_AR subtype. Inhibition of G_αq protein, not G_αi or G_βγ, inhibited these effects of ET-1, indicating the essential role of G_αq protein-mediated ET_AR signaling. In addition, ERK1/2 was required for ET_AR/G_αq axis-induced proliferative capacity and overexpression of these myofibroblast markers. Antagonism of ETR with ETR antagonists (ERAs), ambrisentan and bosentan, inhibited ET-1-induced cell proliferation and synthesis of α-SMA and collagen I. Furthermore, ambrisentan and bosentan promoted the reversal of myofibroblasts after day 3 of treatment, with loss of proliferative ability and a reduction in α-SMA synthesis, confirming the restorative effects of ERAs. This novel work reports on the ET_AR/G_αq/ERK signaling pathway for ET-1 actions and blockade of ETR signaling with ERAs, representing a promising therapeutic strategy for prevention and restoration of ET-1-induced cardiac fibrosis. Full article

Pulmonary arterial hypertension (PAH) is a progressive and inevitably fatal disease characterized by the progressive increase of pulmonary vascular resistance and obliterative pulmonary vascular remodeling, which lead to right-sided heart failure and premature death. Many of the genetically modified mouse models do not develop severe PH and occlusive vascular remodeling. Egln1^Tie2Cre mice with Tie2Cre-mediated deletion of Egln1, which encodes hypoxia-inducible factor (HIF) prolyl hydroxylase 2 (PHD2), is the only mouse model with severe PAH, progressive occlusive pulmonary vascular remodeling, and right-sided heart failure leading to 50–80% mortality from the age of 3–6 months, indicating that the Egln1^Tie2Cre mice model is a long-sought-after murine PAH model. However, it is unknown if Egln1^Tie2Cre mice respond to FDA-approved PAH drugs in a way similar to PAH patients. Here, we tested the therapeutic effects of the three vasodilators: sildenafil (targeting nitric oxide signaling), ambrisentan (endothelin receptor antagonist), and treprostinil (prostacyclin analog) on Egln1^Tie2Cre mice. All of them attenuated right ventricular systolic pressure (RVSP) in Egln1^Tie2Cre mice consistent with their role as vasodilators. However, these drugs have no beneficial effects on pulmonary arterial function. Cardiac output was also markedly improved in Egln1^Tie2Cre mice by any of the drug treatments. They only partially improved RV function and reduced RV hypertrophy and pulmonary vascular remodeling as well as improving short-term survival in a drug-dependent manner. These data demonstrate that Egln1^Tie2Cre mice exhibit similar responses to these drugs as PAH patients seen in clinical trials. Thus, our study provides further evidence that the Egln1^Tie2Cre mouse model of severe PAH is an ideal model of PAH and is potentially useful for enabling identification of drug targets and preclinical testing of novel PAH drug candidates. Full article

Patients with type two diabetes mellitus (T2DM) are at increased risk for cardiovascular diseases. Impairments of endothelin-1 (ET-1) signaling and mTOR pathway have been implicated in diabetic cardiomyopathies. However, the molecular interplay between the ET-1 and mTOR pathway under high glucose (HG) conditions in H9c2 cardiomyoblasts has not been investigated. We employed MTT assay, qPCR, western blotting, fluorescence assays, and confocal microscopy to assess the oxidative stress and mitochondrial damage under hyperglycemic conditions in H9c2 cells. Our results showed that HG-induced cellular stress leads to a significant decline in cell survival and an impairment in the activation of ET_A-R/ET_B-R and the mTOR main components, Raptor and Rictor. These changes induced by HG were accompanied by a reactive oxygen species (ROS) level increase and mitochondrial membrane potential (MMP) loss. In addition, the fragmentation of mitochondria and a decrease in mitochondrial size were observed. However, the inhibition of either ET_A-R alone by ambrisentan or ET_A-R/ET_B-R by bosentan or the partial blockage of the mTOR function by silencing Raptor or Rictor counteracted those adverse effects on the cellular function. Altogether, our findings prove that ET-1 signaling under HG conditions leads to a significant mitochondrial dysfunction involving contributions from the mTOR pathway. Full article

Human cytomegalovirus (HCMV) infection is an important cause of morbidity and mortality in immunocompromised patients and a major etiological factor for congenital birth defects in newborns. Ganciclovir and its pro-drug valganciclovir are the preferred drugs in use today for prophylaxis and treatment of viremic patients. Due to long treatment times, patients are at risk for developing viral resistance to ganciclovir and to other drugs with a similar mechanism of action. We earlier found that the endothelin receptor B (ETBR) is upregulated during HCMV infection and that it plays an important role in the life cycle of this virus. Here, we tested the hypothesis that ETBR blockade could be used in the treatment of HCMV infection. As HCMV infection is specific to humans, we tested our hypothesis in human cell types that are relevant for HCMV pathogenesis; i.e., endothelial cells, epithelial cells and fibroblasts. We infected these cells with HCMV and treated them with the ETBR specific antagonist BQ788 or ETR antagonists that are approved by the FDA for treatment of pulmonary hypertension; macitentan, its metabolite ACT-132577, bosentan and ambrisentan, and as an anti-viral control, we used ganciclovir or letermovir. At concentrations expected to be relevant in vivo, macitentan, ACT-132577 and BQ788 effectively inhibited productive infection of HCMV. Of importance, macitentan also inhibited productive infection of a ganciclovir-resistant HCMV isolate. Our results suggest that binding or signaling through ETBR is crucial for viral replication, and that selected ETBR blockers inhibit HCMV infection. Full article

Several cytochrome P450 (CYP) CYP3A polymorphisms were associated with reduced enzyme function. We aimed to evaluate the influence of these alleles on the pharmacokinetic parameters (PK) of several CYP3A substrates. We included 251 healthy volunteers who received a single dose of ambrisentan, atorvastatin, imatinib, aripiprazole, fentanyl, amlodipine, donepezil, olanzapine, fesoterodine, or quetiapine. The volunteers were genotyped for CYP3A4 and CYP3A5 polymorphisms by qPCR. To compare the PK across studies, measurements were corrected by the mean of each parameter for every drug and were logarithmically transformed. Neither CYP3A phenotype nor individual CYP3A4 or CYP3A5 polymorphisms were significantly associated with differences in PK. However, regarding the substrates that are exclusively metabolized by CYP3A, we observed a higher normalized AUC (p = 0.099) and a tendency of lower normalized Cl (p = 0.069) in CYP3A4 mutated allele carriers what was associated with diminished drug metabolism capacity. CYP3A4 polymorphisms did not show a pronounced influence on PK of the analysed drugs. If so, their impact could be detectable in a very small percentage of subjects. Although there are few subjects carrying CYP3A4 double mutations, the effect in those might be relevant, especially due to the majority of subjects lacking the CYP3A5 enzyme. In heterozygous subjects, the consequence might be less noticeable due to the high inducible potential of the CYP3A4 enzyme. Full article

The endothelin axis, recognized for its vasoconstrictive action, plays a central role in the pathology of pulmonary arterial hypertension (PAH). Treatment with approved endothelin receptor antagonists (ERAs), such as bosentan, ambrisentan, or macitentan, slow down PAH progression and relieves symptoms. Several findings have indicated that endothelin is further involved in the pathogenesis of certain other diseases, making ERAs potentially beneficial in the treatment of various conditions. In addition to PAH, this review summarizes the use and perspectives of ERAs in cancer, renal disease, fibrotic disorders, systemic scleroderma, vasospasm, and pain management. Bosentan has proven to be effective in systemic sclerosis PAH and in decreasing the development of vasospasm-related digital ulcers. The selective ERA clazosentan has been shown to be effective in preventing cerebral vasospasm and delaying ischemic neurological deficits and new infarcts. Furthermore, in the SONAR (Study Of Diabetic Nephropathy With Atrasentan) trial, the selective ERA atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease. These data suggest atrasentan as a new therapy in the treatment of diabetic nephropathy and possibly other renal diseases. Preclinical studies regarding heart failure, cancer, and fibrotic diseases have demonstrated promising effects, but clinical trials have not yet produced measurable results. Nevertheless, the potential benefits of ERAs may not be fully realized. Full article

A simple, rapid, and highly selective RP-HPLC method was developed for the simultaneous determination of Ambrisentan (AMB) and Tadalafil (TADA) drug substances in the fixed dosage strength of 10 mg and 40 mg, respectively. Effective chromatographic separation was achieved using a Hypersil GOLD C18 column (150 mm × 4.6 mm internal diameter, 5 μm particle size) with a mobile phase composed of methanol, water, and acetonitrile in the ratio of 40:40:20 (by volume). The mobile phase was pumped using a gradient HPLC system at a flow rate of 0.5 mL/min, and quantification of the analytes was based on measuring their peak areas at 260 nm. The retention times for Ambrisentan and Tadalafil were about 2.80 and 7.10 min, respectively. The reliability and analytical performance of the proposed HPLC procedure were statistically validated with respect to system suitability, linearity, ranges, precision, accuracy, specificity, robustness, detection, and quantification limits. Calibration curves were linear in the ranges of 1–20 μg/mL for Ambrisentan and 4–80 μg/mL for Tadalafil with correlation coefficients >0.990. The proposed method proved to be selective and stability-indicating by the resolution of the two analytes from the forced degradation (hydrolysis, oxidation, and photolysis) products. The validated HPLC method was successfully applied to the analysis of AMB and TADA in pharmaceutical dosage form. Full article