Management Of Pulmonary Arterial Hypertension Research Articles

Pulmo-protection of long-term swimming exercise via improving insulin sensitivity in monocrotaline-induced pulmonary hypertensive rats

Exercise has been recognized as an effective intervention in the treatment of pulmonary arterial hypertension (PAH), supported by numerous studies. However, the precise effects of exercise on pulmonary function remain to be fully elucidated. In this study, using a rat model of swimming exercise training and monocrotaline-induced PAH, we aimed to explore its impact on pulmonary morphology and function. Our investigations revealed that MCT-treated rats exhibited augmented mean pulmonary arterial pressure (MPAP) and pulmonary vascular remodeling, which can be attenuated by 4 weeks of swimming exercise training (60 min/day, 5 days/week). Notably, MCT-treated rats showed impaired pulmonary function, as manifested by decreased tidal volume and dynamic compliance, which were reversed by exercise training. Assessment of pulmonary substrate in PAH rats indicated a prominent pro-inflammatory substrate, evidenced by macrophage accumulation through quantitative immunohistological analysis of macrophage-like cell expression (CD68), and extracellular matrix remodeling, evaluated by Masson staining. Importantly, both the pro-inflammatory substrate and extracellular matrix remodeling were ameliorated by swimming exercise training. Additionally, serum biochemical analysis demonstrated elevated levels of low-density lipoprotein cholesterol and Apolipoprotein B following MCT treatment, which were reduced with exercise intervention. Moreover, exercise enhanced systemic insulin sensitivity in both MCT-treated and untreated rats. Notably, MCT and exercise treatment both decreased fasting blood glucose (FBG) levels in rats, whereas exercise training reinstated FBG levels to normal in MCT-treated rats. In summary, our study suggests that swimming exercise confers a pulmonary protective effect in MCT-induced PAH rats, highlighting the potential importance of exercise-based rehabilitation in the management of PAH.

Management of Pulmonary Vascular Disease Associated with Congenital Left to Right Shunts: A Single Center Experience.

To describe the course and outcomes of children under 18 with left-to-right (LR) shunts and pulmonary arterial hypertension (PAH) undergoing one of two management approaches: PAH treatment prior to LR shunt repair (Treat First) and LR shunt repair first, with or without subsequent PAH treatment (Repair First). Retrospective single center study, conducted from September 2015 to September 2021, of children LR shunts and PAH (defined as indexed pulmonary vascular resistance (PVRi) ≥ 4WU*m2) but without Eisenmenger physiology. Patient characteristics, longitudinal hemodynamics data, PAH management, LR shunt repair, and outcomes were reviewed. Of 768 patients evaluated for LR shunt closure, 51 (6.8%) had LR shunt associated PAH [median age 1.1 (0.37,5) years, median PVRi 6 (5.2,8.7) WU*m2]. Of the "Treat First" group (n=33, 65%), 27 (82%) underwent LR shunt closure and 6 (18%) did not respond to PAH therapy and did not undergo LR shunt closure. In the "Repair First" group (n=18, 35%), 12 (67%) received PAH therapy and 6 (33%) did not. Mortality rates were 6% in "Treat First" and 11% in "Repair First", follow-up of 3.4 and 2.5 years, respectively. After LR shunt closure, there was no significant change in PVRi over a median follow-up of 2 years after surgery (p=0.77). In children with LR shunts and associated PAH, treatment with PAH-targeted therapy before defect repair does not appear to endanger the subjects and may have some benefit. The response to PAH-targeted therapy before shunt closure persists 2-3 years post-closure, providing valuable insights into the long-term management of these patients.

Proteasome inhibitor bortezomib prevents proliferation and migration of pulmonary arterial smooth muscle cells.

Pulmonary vascular remodeling is a key pathological process of pulmonary arterial hypertension (PAH), characterized by uncontrolled proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs). Bortezomib (BTZ) is the first Food and Drug Administration (FDA)-approved proteasome inhibitor for multiple myeloma treatment. Recently, there is emerging evidence showing its effect on reversing PAH, although its mechanisms are not well understood. In this study, anti-proliferative and anti-migratory effects of BTZ on PASMCs were first examined by different inducers such as fetal bovine serum (FBS), angiotensin II (Ang II) and platelet-derived growth factor (PDGF)-BB, while potential mechanisms including cellular reactive oxygen species (ROS) and mitochondrial ROS were then investigated; finally, signal transduction of ERK and Akt was examined. Our results showed that BTZ attenuated FBS-, Ang II- and PDGF-BB-induced proliferation and migration, with associated decreased cellular ROS production and mitochondrial ROS production. In addition, the phosphorylation of ERK and Akt induced by Ang II and PDGF-BB was also inhibited by BTZ treatment. This study indicates that BTZ can prevent proliferation and migration of PASMCs, which are possibly mediated by decreased ROS production and down-regulation of ERK and Akt. Thus, proteasome inhibition can be a novel pharmacological target in the management of PAH.

PULMONARY ARTERIAL HYPERTENSION ASSOCIATED WITH CONGENITAL HEART DISEASE: RATIONALE FOR MANAGEMENT ALGORITHM BASED ON A LITERATURE REVIEW

The substantial progress achieved in cardiology and paediatric cardiac surgery has led to a considerable increase of life expectancy of patients with congenital heart disease (CHD), and at the same time to growing number of adult patients developing pulmonary arterial hypertension (PAH) associated with congenital heart defects. Nowadays guidelines were developed and updated for PAH, but no expert recommendations exist for effective management of PAH associated with CHD. Thus, it is important to develop an algorithm for managing these patients, based on international standards and a comprehensive understanding of prognostic markers of worsening the course of pulmonary arterial hypertension (PAH), considering local cardiac tertiary hospitals' capabilities.
 The aim. To highlight the pathophysiology and clinical characteristics of PAH-CHD patients, identify prognostic markers for its onset and progression, and develop a management algorithm for patients.
 Results. The article presents the pathophysiology of PAH-CHD, the mechanisms of right ventricle adaptation to pressure overload, which determine the functional abilities of patients and prognosis, PAH formation, and progression after defects correction. The accurate identification of stages in PAH-CHD (volume overload, mixed, stage of pulmonary vascular disease) is essential for the timely determination of surgical intervention, selecting conservative treatment strategies, and predicting the outcomes of surgical defect correction. The type of defect, its size, and the volume of blood flow through the defect influence the onset and progression of PH-CHD. We review the pathophysiology and clinical features of PAH-CHD, as well as the reasons for the late diagnosis of heart failure at the stage of severe decompensation and irreversible remodelling of the lung vessels when diuretic therapy is not effective enough and inotropic support, circulatory mechanical support and heart / lung complex transplantation are required. The necessity of developing new scales for stratifying the risk of PAH-CHD is justified considering the particularities of the disease course and cardiac hemodynamic in different anatomical types of the defects. Based on this literature review, at the Municipal Enterprise «Dnipropetrovsk Regional Clinical Center for Diagnostics and Treatment» of the Dnipropetrovsk Regional Council» the algorithm for managing patients with PAH-CHD was devised and implemented into clinical practice.
 Conclusions. PAH is a common complication of CHD. The prevalence of PAH-CHD is substantial and it can manifest and progress even in patients with previously corrected heart defects. To effectively manage patients with PAH-CHD, an algorithm has been devised and implemented in clinical practice. It includes factors that have demonstrated associations with poor prognosis which are more than two hospitalizations for HF in the last year, pulmonary vascular resistance (PVR) (or index of PVR), mean pressure in the pulmonary artery, pulmonary capillary wedge pressure, left ventricular ejection fraction, heart failure with a reduced ejection fraction, right ventricle heart failure, NYHA FC, high risk of atrial fibrillation or flutter, 6-minute walking test distance, NTproBNP, highly sensitive C-reactive protein, B-lines on lung ultrasound, glomerular filtration rate, haemoglobin, platelet count, sodium, Model for End-Stage Liver Disease scale.

Activation of CaMKII/HDAC4 by SDF1 contributes to pulmonary arterial hypertension via stabilization Runx2

Stromal derived factor 1 (SDF1) has been shown to be involved in the pathogenesis of pulmonary artery hypertension (PAH). However, the detailed molecular mechanisms remain unclear. To address this, we utilized primary cultured rat pulmonary artery smooth muscle cells (PASMCs) and monocrotaline (MCT)-induced PAH rat models to investigate the mechanisms of SDF1 driving PASMCs proliferation and pulmonary arterial remodeling. SDF1 increased runt-related transcription factor 2 (Runx2) acetylation by Calmodulin (CaM)-dependent protein kinase II (CaMKII)-dependent HDAC4 cytoplasmic translocation, elevation of Runx2 acetylation conferred its resistance to proteasome-mediated degradation. The accumulation of Runx2 further upregulated osteopontin (OPN) expression, finally leading to PASMCs proliferation. Blocking SDF1, suppression of CaMKII, inhibition the nuclear export of HDAC4 or silencing Runx2 attenuated pulmonary arterial remodeling and prevented PAH development in MCT-induced PAH rat models. Our study provides novel sights for SDF1 induction of PASMCs proliferation and suggests that targeting SDF1/CaMKII/HDAC4/Runx2 axis has potential value in the management of PAH.

Comparison Between REVEAL Lite 2 and COMPERA 2.0 for Risk Stratification in Pulmonary Arterial Hypertension

BackgroundRisk stratification is the cornerstone of the management of pulmonary arterial hypertension (PAH). Current ESC/ERS guidelines recommend using the COMPERA 3-strata risk model at baseline, and the COMPERA 2.0 4-strata model at follow-up. However, the guidelines did not take into consideration other available risk scores such as REVEAL Lite 2. Research QuestionIs REVEAL Lite 2 better at discriminating risk than the COMPERA risk assessment models at baseline or follow up evaluations? Study Design and MethodsWe analyzed data from the consecutively enrolled PAH patients between the period of June 2011 to February 2022 in the PAH registry at our expert Pulmonary Hypertension Center. Patients were stratified according to REVEAL Lite 2, COMPERA 3-, and 4-strata risk scores at baseline and follow up to predict the composite outcome for lung transplantation or death. ROC curves in predicting the binary outcome at 3, 5 and 7 years were plotted. Areas under the curve (AUC) of the scores were compared by the chi-square test. The performance of the scores was determined by Harrel’s C-statistic. Results296 patients were included for baseline and 196 for follow up evaluation. The overall transplant-free survival in our patient population at 1, 3, 5, and 7 years was 93.6%, 81.3%, 75.1%, and 68.8% respectively. At baseline, the C-statistic of REVEAL Lite 2 was 0.74 (0.69, 0.80), compared to 0.68 (0.63, 0.74) for the COMPERA 4-strata model, and 0.63 (0.58, 0.69) for the COMPERA 3-strata model. All C-statistic differences between REVEAL Lite 2 and the other models were statistically significant at baseline. InterpretationOur analysis showed that REVEAL Lite 2 was better at baseline at discriminating risk in our patient population. Future guidelines should consider including REVEAL Lite 2 in the management algorithm to help clinicians to make informed decisions. Further analysis in larger cohorts could help validate these findings.

Gut Fungal Microbiota Alterations in Pulmonary Arterial Hypertensive Rats.

The gut microbiome's imbalance has been implicated in the pathogenesis of pulmonary arterial hypertension (PAH), yet the contribution of the gut mycobiome remains largely unclear. This study delineates the gut mycobiome profile in PAH and examines its interplay with the bacterial microbiome alterations. Fecal samples from monocrotaline-induced PAH rats and matched controls were subjected to internal transcribed spacer 1 (ITS1) sequencing for fungal community assessment and 16S ribosomal RNA (rRNA) gene sequencing for bacterial community characterization. Comparative analysis revealed no significant disparities in the overall mycobiome diversity between the PAH and control groups. However, taxonomic profiling identified differential mycobiome compositions, with the PAH group exhibiting a significant enrichment of genera such as Wallemia, unidentified_Branch02, Postia, Malassezia, Epicoccum, Cercospora, and Alternaria. Conversely, genera Xeromyces, unidentified_Plectosphaerellaceae, and Monilia were more abundant in the controls. Correlations of Malassezia and Wallemia abundance with hemodynamic parameters were observed. Indications of bidirectional fungal-bacterial community interactions were also noted. This investigation reveals distinct gut mycobiome alterations in PAH, which are intricately associated with concurrent bacterial microbiome changes, suggesting a possible contributory role of gut fungi in PAH pathophysiology. These findings underscore the potential for novel gut mycobiome-targeted therapeutic interventions in PAH management.

Possible Hereditary Pulmonary Arterial Hypertension: from Clinical to Genetic Investigation in Precision Medicine Era

Background: Pulmonary Hypertension is a life-threatening disease characterized by a progressive increase of pulmonary vascular resistance that often leads to right ventricular (RV) failure and death. Major discoveries have been obtained within the last decade in the field of hereditary predisposition to pulmonary arterial hypertension (PAH). At least 6% of all PAH cases are familial in origin known as Familial Pulmonary Arterial Hypertension (FPAH) and display autosomal dominant inheritance with incomplete penetrance. While early diagnosis is associated with improved long-term survival, however at present, most patients are diagnosed at a very advanced stage of HPAH indicating that the early screening for HPAH is crucial. In this regard, genetic testing is an effective strategy for the early diagnosis and management of PAH, specifically Hereditary Pulmonary Arterial Hypertension (HPAH). We present two cases of Familial Pulmonary Arterial Hypertension and in-depth analysis of diagnostic cascade to allow an earlier and more reliable diagnosis of possible Hereditary Pulmonary Arterial Hypertension (HPAH). Case Illustration: Familial cases, a 44-years old man and his son a 17-years old boy, came with chief complaint of dyspnea. His daughter or his sister passed away when 4 years old due to PH. Both patients had been subsequently diagnosed with PAH with possible HPAH after the exclusion of primary and secondary heart anomalies using electrocardiography, echocardiography, and cardiac marker test. Both patients subsequently were performed right heart catheterization (RHC). Conclusions: We describe familial cases of pulmonary hypertension with clinically presenting right-sided heart failure. Diagnostic investigation was performed according to recent guideline to rule out and rule in all the possible cause of pulmonary hypertension. However, the final assessment showed unknown cause of pre-capillary pulmonary hypertension. Therefore, genetic investigation should be performed in precision medicine era due to high possibility of hereditary pulmonary arterial hypertension.

Risk assessment according to the presence of left heart disease phenotype in pulmonary arterial hypertension patients: a multicenter cohort study

Abstract Introduction Subclinical left heart disease (LHD) may impact the management of pulmonary arterial hypertension (PAH) [1]. Purpose To evaluate the influence of a LHD phenotype on PAH risk stratification. Methods We retrospectively reviewed the data of consecutive PAH patients followed at 7 tertiary centers from 2001 to 2021, and selected those with all parameters available to determine risk of death by means of the COMPERA and COMPERA 2.0 scores, both at baseline and at the first disease reassessment including right heart catheterization. These subjects were classified as no-LHD or LHD according to the AMBITION trial criteria, i.e. absence or presence, respectively, of ≥ 3 among body mass index ≥ 30 kg/m2, systemic hypertension, diabetes mellitus, and coronary artery disease; and/or pulmonary vascular resistance between 3 and 3.75 WU or between 3.75 and 6.25 WU together with pulmonary artery wedge pressure (PAWP) between 13 and 15 mmHg [2,3]. The characteristics between the 2 groups were compared by chi-square test, T-test, or Mann-Whitney test, and Kaplan-Meier curves for overall survival by log-rank test. Results Of 286 patients included in the analysis, 57 (20%) had a LHD phenotype. The first complete reassessment was performed 7 ± 5 months after baseline. Compared with no-LHD, subjects with LHD were older, had more often cardiovascular comorbidities, and had higher E/e’ ratio, left atrial area and PAWP, but had lower brain natriuretic peptide concentrations and better right ventricular function and pulmonary hemodynamics (Figure 1). They were also less commonly treated with phosphodiesterase inhibitors or riociguat (54% vs 70%, P=0.03) and dual oral therapy (26% vs 43%, P=0.03), while they used more beta-blockers (47% vs 16%, P<0.001) and ACE inhibitors or angiotensin receptor blockers (40% vs 21%, P=0.004). At baseline, the proportion of patients with low vs high risk was greater in LHD than in no-LHD with COMPERA, but not with COMPERA 2.0. Moreover, risk profile significantly improved during follow-up only in no-LHD with COMPERA, but in both groups with COMPERA 2.0 (Figure 1). While all-cause mortality was significantly different across baseline COMPERA and COMPERA 2.0 risk strata in no-LHD, either approach for risk stratification failed to discriminate LHD subgroups with different prognosis (Figure 2). However, both COMPERA and COMPERA 2.0 risk categories differentiated mortality in LHD at the first disease reassessment (log-rank P <0.001, not shown). Conclusions This study suggests that the performance of risk stratification scores COMPERA and COMPERA 2.0 in PAH subjects with a LHD phenotype is limited, although the former may retain value during follow-up. Alternative tools may be needed for prognostication in this patient subset.

Macitentan tadalafil Fixed Dose Combination (FDC) in treatment-naive and prior monotherapy patients with Pulmonary Arterial Hypertension (PAH): insights from A DUE

Abstract Background Combination therapy is recommended for the management of pulmonary arterial hypertension (PAH). The A DUE study showed that M/T FDC, a fixed dose combination (FDC) of the endothelin receptor antagonist (ERA) macitentan 10mg (M) and the phosphodiesterase type 5 inhibitor (PDE5i) tadalafil 40mg (T), led to a clinically relevant improvement in pulmonary vascular resistance (PVR) vs macitentan and tadalafil monotherapies in PAH patients. A clinically meaningful trend for improvement in 6-minute walk distance (6MWD) in favor of M/T FDC vs macitentan and tadalafil was observed. Purpose Here we analysed the effect of M/T FDC in the subgroups of treatment-naïve and prior monotherapy patients. Methods In A DUE 187 adult PAH patients in WHO functional class II / III were randomised 2:1:1 to M/T FDC, macitentan or tadalafil if treatment-naïve, 2:1 to M/T FDC or macitentan if on prior ERA, and 2:1 to M/T FDC or tadalafil if on prior PDE5i. The treatment effect of M/T FDC vs macitentan and M/T FDC vs tadalafil was calculated using ANCOVA models for PVR (geometric mean ratios [95% CL]) and for 6MWD (mean change [95% CL]) in treatment-naïve patients and in patients on prior monotherapy (ERA or PDE5i) at randomisation. Results Treatment effects for M/T FDC versus macitentan and versus tadalafil on the change in PVR and 6MWD are reported in the table for each subgroup, along with those for the overall population. The safety profile of M/T FDC was in line with the safety profiles of macitentan and tadalafil. Conclusions In A DUE, the effect of M/T FDC vs both monotherapies on PVR and 6MWD in treatment-naïve and prior ERA/PDE5i patients was consistent with that observed in the overall population.

Evaluation of patients engagement with a digital intervention for daily disease management in pulmonary arterial hypertension

Abstract Introduction Pulmonary arterial hypertension (PAH) is a chronic rare disease with a complex treatment that affects the daily life of patients and requires ongoing monitoring and assessment. In comparison with other chronic diseases, the application of digital health approaches to address patients’ needs in disease self-management has not been comprehensively studied [1], [2]. Within the framework of a clinical study, PAH patients’ engagement level and adherence to using a digital health platform have been studied. The platform allows patients to log health and lifestyle information while also providing structured content for patient education, medication reminders, and lifestyle coaching from a remote HC. Purpose The study aimed to measure the impact of the use of the platform on the Health-Related Quality of Life of the patients (HRQoL) and other clinical endpoints (patient’s functional status, signs and symptoms of PAH, patient costs and healthcare resource utilization) and also to assess patients’ engagement and satisfaction with the use of the platform. Method 53 PAH patients enrolled in a prospective, single cohort, multicentre study [3] from 5 specialized PAH units of reference public Spanish hospitals. The duration of the study was 6 months and to avoid interferences with routine clinical practice, clinical investigation visits matched the clinical guidelines for PAH patients in Spain, which recommend scheduling monitoring visits every 3-6 months. Questionnaires were administered to assess the QoL and satisfaction and for assessing the engagement levels, the app usage data has been analysed. Results Regarding the impact of platform usage for 6 months on the HRQoL and clinical endpoints of PAH patients, no statistically significant changes have been observed. However, as per the engagement, patients showed a great interest in using the app and connecting to the Health Coach (HC). More than 45% of patients finished 2 out of 4 levels of the structured educational content, 96.1% of patients used the activity logging feature. Over 79% of patients visited the app monthly and on average, the app was launched 1500 times per month. The communication between the patients and HC was steady during the study, another indication of adherence to the program. As per user experience, the overall outcomes of the questionnaire showed that 84.2% of patients considered that their needs have been met suggesting that the purpose of the program is well addressed. Additionally, 92.1% of patients were satisfied with the program and would use it again. Moreover, 94.7% of patients expressed that they would recommend the program to a PAH patient. Conclusion Elevated satisfaction and engagement levels of patients demonstrate that the digital intervention is useful for the patients and supports companionship and knowledge. In this context, the development of digital solutions provides opportunities to ensure continuous PAH patient care and patient empowerment.

Applicability of the 3-Strata ESC/ERS risk model at baseline in pulmonary veno-occlusive disease

Abstract Introduction The risk of death or lung transplantation in Pulmonary Arterial Hypertension (PAH) is influenced by many factors. The recently published European Society of Cardiology/ European Respiratory Society (ESC/ERC) Guidelines for the study and management of PAH recommend the use of a multiparametric 3-strata model for risk stratification at diagnosis [1]. Heritable pulmonary veno-occlusive disease (PVOD) is an especially infrequent form of PAH caused by homozygous variants in the gene encoding the Eukaryotic Translation Initiation Factor 2 Alpha Kinase 4 (EIF2AK4). PVOD has a dramatically low long-term survival. There is no evidence confirming the applicability of the risk scores in PVOD. Our aim was to evaluate the usefulness of the 3-strata ESC/ERC score at diagnosis in patients with heritable PVOD. Methods We considered patients with the diagnosis of heritable PVOD included in the Spanish registry of PAH (REHAP) between 2011 and 2022. The diagnosis required a homozygous variant in EIF2AK4, and a diagnostic right heart catheterization (RHC). The other group was composed of patients with PAH and pathogenic or likely pathogenic variants in the gene BMPR2. The prognostic evaluation was done when these patients were included in the registry. All participants signed informed consent. Results In the 2011-2022 period up to 32 cases of PVOD in 23 unrelated families and 28 cases in 23 families were collected. 10 patients were excluded due to incomplete RHC at diagnosis. The baseline characteristics of the population can be seen in the Table. After a median follow-up of 16.9 months, up to 15 patients with PVOD needed lung transplantation (46.9%), and 6 patients died (18.7%). On the contrary, only 4 patients needed lung transplantation and one died in the BMPR2 group after a median follow-up of 97.1 months. Most of the included PVOD patients had an intermediate risk of mortality after the application of the 3-strata European model (62.5%), and only one case (3.1%) was categorized as high-risk. There was a non-significant tendency for patients with BMPR2 variants to have lower risk levels. The application of the 3-strata model at diagnosis in patients with PVOD demonstrated a good global prognostic capacity (C Index of 0.707). In our PVOD population, those patients at intermediate risk had a hazard ratio of 9.53 (2.15-42.17, p=0.003) when compared with patients at low risk. Similarly, those patients at high risk at diagnosis had a hazard ratio of 9.49 (0.86-104.69, p=0.066) when compared with patients at intermediate risk (Figure). Conclusions The application of the ESC/ERC three-strata risk tool in patients with PVOD demonstrates a good global prognostic capacity. Nevertheless, the risk of death or lung transplantation can be higher than predicted in this population, enhancing the need for an early evaluation for lung transplantation.Figure

Lunch Symposium

Pulmonary arterial hypertension (PAH), defined as the presence of artery pulmonary artery pressure > 20 mmHg, pulmonary artery wedge pressure [Formula: see text]15 mmHg, and pulmonary vascular resistance (PVR) > 2Wood units based on expert consensus, is characterized by a progressive and sustained increase in PVR, which may lead to right heart failure and death. PAH is a well-known complication of connective tissue diseases (CTDs), such as systemic sclerosis, systemic lupus erythematosus, Sjögren’s syndrome, and other autoimmune conditions. In the past few years, tremendous progress in the understanding of PAH pathogenesis has been made, with various novel diagnostic and screening methods for the early detection of CTD-PAH proposed worldwide. This symposium would highlight the most updated 2022 ESC/ERS guideline in the disease management of PAH, including latest haemodynmaic definitions of PAH, new risk stratification approach at reassessment and updated PAH treatment recommendations. In addition to the guideline update, important discussion would cover the important diagnostic, and screening algorithm for early detection of CTD-PAH and clinical experiences in managing difficult CTD-PAH cases.

Postpartum diagnosis and management of pulmonary arterial hypertension

A 38-year-old female who was found to have severe pulmonary arterial hypertension (PAH) secondary to HIV in the postpartum period. This case illustrates the treatment and challenges of postpartum PAH. It also demonstrates the need for expert guidance and additional research on the optimal management of PAH in pregnancy and postpartum.

Assessment of Knowledge, Attitude, and Practice Patterns in Pulmonary Arterial Hypertension among Cardiologists and Pulmonologists: Evidence from Turkey.

Background and Objectives: Pulmonary arterial hypertension (PAH) is a rare chronic disease of the small pulmonary arteries that causes right heart failure and death. Accurate management of PAH is necessary to decrease morbidity and mortality. Understanding current practices and perspectives on PAH is important. For this purpose, we intended to determine physicians' knowledge, attitudes, and practice patterns in adult pulmonary arterial hypertension (PAH) in Turkey. Materials and Methods: Between January and February 2022, an online questionnaire was sent via e-mail to all cardiologists and pulmonologists who were members of the Turkish Society of Cardiology (TSC) and the Turkish Thoracic Society (TTS). Results: A total of 200 physicians (122 pulmonologists and 78 cardiologists) responded to the questionnaire. Cardiologists were more frequently involved in the primary diagnosis and treatment of PAH than pulmonologists (37.2% vs. 23.8%, p = 0.042). More than half of the physicians had access to right heart catheterization. In mild/moderate PAH patients with a negative vasoreactivity test, the monotherapy option was most preferred (82.8%) and endothelin receptor antagonists (ERAs) were the most preferred group in these patients (73%). ERAs plus phosphodiesterase-5 inhibitors (PDE-5 INH) were the most preferred (69%) combination therapy, and prostacyclin analogues plus PDE-5 INH was preferred by only pulmonologists. Conclusions: Overall, clinical management of patients with PAH complied with guideline recommendations. Effective clinical management of PAH in specialized centers that having right heart catheterization achieve better outcomes.

Rapidly Progressive Idiopathic Pulmonary Arterial Hypertension in a Paediatric Patient Treated with Lung Transplantation.

Pulmonary arterial hypertension (PAH) is a rare heterogeneous disorder in the paediatric population which is mostly associated with congenital heart disease. The management of paediatric idiopathic PAH (IPAH) is difficult due to insufficient comparative data and depends on the results of evidence-based adult studies with several pulmonary vasodilators, as well as the clinical experiences of paediatric experts. Our aim was to present the case of a 9-year-old girl who underwent several methods of treatment, including pharmacotherapy with a significant reaction to treprostinil, as well as bilateral lung transplantation. The patient's treatment was distinguished by the fact that the dose escalation was as rapid as that observed in the adult population. Due to the limited current evidence and knowledge, the initiation of treatment for these patients remains an individual choice. On the grounds of the number of non-specific symptoms, the diagnosis of this patient was a long process and based mainly on the differential diagnosis. The purpose of this paper is to study this example in order to highlight the importance of early symptoms and the quick implementation of intensive treatment. The applied methods may be useful in doubtful diagnosis processes and treatment procedures in the paediatric population.

RGS5 as a Biomarker of Pericytes, Involvement in Vascular Remodeling and Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by a sustained rise in mean pulmonary artery pressure. Pulmonary vascular remodeling serves an important role in PAH. Identifying a key driver gene to regulate vascular remodeling of the pulmonary microvasculature is critical for PAH management. Differentially expressed genes were identified using the Gene Expression Omnibus (GEO) GSE117261, GSE48149, GSE113439, GSE53408 and GSE16947 datasets. A co-expression network was constructed using weighted gene co-expression network analysis. Novel and key signatures of PAH were screened using four algorithms, including weighted gene co-expression network analysis, GEO2R analysis, support vector machines recursive feature elimination and robust rank aggregation rank analysis. Regulator of G-protein signaling 5 (RGS5), a pro-apoptotic/anti-proliferative protein, which regulate arterial tone and blood pressure in vascular smooth muscle cells. The expression of RGS5 was determined using reverse transcription-quantitative PCR (RT-qPCR) in PAH and normal mice. The location of RGS5 and pericytes was detected using immunofluorescence. Compared with that in the normal group, RGS5 expression was upregulated in the PAH group based on GEO and RT-qPCR analyses. RGS5 expression in single cells was enriched in pericytes in single-cell RNA sequencing analysis. RGS5 co-localization with pericytes was detected in the pulmonary microvasculature of PAH. RGS5 regulates vascular remodeling of the pulmonary microvasculature and the occurrence of PAH through pericytes, which has provided novel ideas and strategies regarding the occurrence and innovative treatment of PAH.

Development of novel bosentan analogues as endothelin receptor antagonists for pulmonary arterial hypertension

Since decades, bosentan has been in use for the treatment of pulmonary arterial hypertension (PAH). However, chronic exposure to bosentan leads to the development of resistance, tolerance, and serious adverse effects that have restricted its usage in clinical practices. To surmount these limitations, some new bosentan derivatives have been synthesized and evaluated for their therapeutic efficacy in PAH. Molecular docking analyses of all the synthesized derivatives were carried out using the endothelin (ET) receptor. In addition, the inhibitory ability of synthesized derivatives was determined in in vitro assay employing an ET-1 human ELISA kit. Among the synthesized derivatives, three derivatives namely 17d, 16j, and 16h with higher docking scores and lower IC50 values were selected for determination of the magnitude of the binding force between the derivative and ET receptor using molecular dynamics (MD) simulations study. Further, these derivatives were subjected to in vivo studies using monocrotaline (MCT) induced PAH in rat model. Results of in vivo studies inferred that the derivatives exhibit impressive ability to reduce PAH. Besides, its protective role was also evidenced in hemodynamic and right ventricular hypertrophy analyses, histological analysis, cardiac biomarkers, hypoxia-inducible factor 1 alpha (HIF1α) levels, and biochemical studies. Furthermore, gene quantification by quantitative RT-PCR and Western blot analysis was also performed to examine its effect on the expression of key proteins in PAH.Notably, amongst three, derivative 16h exhibited the most encouraging results in molecular docking analysis, in vitro, in vivo, histopathological, biochemical, protein expression, and MD studies. Besides, derivative 16h also showed impressive pharmacokinetic features in ADMET analysis.In conclusion, derivative 16 h could act as a reliable ET receptor antagonist and requires further exploration to attain its therapeutic utility in PAH management.

Pharmacogenomics in the Management of Pulmonary Arterial Hypertension: Current Perspectives.

Pulmonary arterial hypertension (PAH) is a rare disease with heterogeneous causes that can lead to right ventricular (RV) failure and death if left untreated. There are currently 10 medications representative of five unique pharmacologic classes that are approved for treatment. These have led to significant improvements in overall clinical outcome. However, substantial variability in dosing requirements and treatment response is evident, leading to suboptimal outcome for many patients. Furthermore, dosing is empiric and iterative and can lead to delays in meeting treatment goals and burdensome adverse effects. Pharmacogenomic (PGx) associations have been reported with certain PAH medications, such as treprostinil and bosentan, and can explain some of the variability in response. Relevant genes associated with treprostinil include CYP2C8, CYP2C9, CAMK2D, and PFAS. CYP2C8 and CYP2C9 are the genes encoding the major metabolizing liver enzymes for treprostinil, and reduced function variants (*2, *3) with CYP2C9 were associated with lower treatment persistence. Additionally, a higher CYP2C9 activity score was associated with a significantly less risk of treatment discontinuation. Other genes of interest that have been explored with treprostinil include CAMK2D, which is associated with right ventricular dysfunction and significantly higher dose requirements. Similarly, PFAS is associated with lower concentrations of cyclic adenosine monophosphate and significantly higher dose requirements. Genes of interest with the endothelin receptor antagonist (ERA) class include GNG2 and CYP2C9. A genetic variant in GNG2 (rs11157866) was linked to a significantly increased rate of clinical improvement with ERAs. The *2 variant with CYP2C9 (encoding for the major metabolizing enzyme for bosentan) was significantly associated with a higher risk for elevations in hepatic aminotransferases and liver injury. In summary, this article reviews the relevant pharmacogenes that have been associated to date with dosing and outcome among patients who received PAH medications.

Neonatal outcomes in pregnant women with pulmonary arterial hypertension associated with heart disease.

As an increasing number of women with pulmonary arterial hypertension (PAH) choose to become pregnant, outcomes in newborns have become a priority. The main purpose of this study was to compare the neonatal outcomes in pregnant women with PAH associated with heart disease. A single-center retrospective study was performed. Pregnancy with heart disease is divided into three groups: no PAH, mild PAH and severe PAH. Neonatal outcomes of pregnant women were compared among groups. Meanwhile, multivariable analyses were used to investigate the association between maternal PAH and adverse neonatal events. A total of 127 pregnant women with heart disease were enrolled. Of these, 82 (64.6%) had no PAH, 19 (15%) had mild PAH and 26 (20.4%) had severe PAH. The offspring of women with severe PAH had a higher risk of preterm delivery, low birth weight, neonatal respiratory distress syndrome (NRDS), neonatal intensive care unit (NICU) admission and recurrence of congenital heart disease (CHD). Compared to the women without PAH, only the risk of preterm delivery (32-36 weeks) and NICU admission were slightly higher in mothers with mild PAH; other neonatal events were similar. Multivariate regression analyses showed that the risk of preterm delivery (<37 weeks) increased with the increasing severity of maternal PAH, with an OR of 3.1 (95% CI, 1.1-8.8) for mild and 21.9 (95%CI, 4.8-99.4) for severe PAH. The same pattern was observed for NICU admission. Mothers with severe PAH were independently associated with low birth weight (OR 13, 95%CI 4.3-39, P<0.001), NRDS (OR 17.9, 95%CI 5.5-58.9, P<0.001) and recurrence of CHD (OR 4.47, 95%CI 1.7-11.6, P=0.002). Pregnancy in women with severe PAH can significantly increase the risks of neonatal events. While neonatal outcomes in pregnant women with mild PAH were considered optimistic in the present study, a multidisciplinary management of PAH in pregnancy would be necessary to have consistently good outcomes.