Mendelian randomization study on causal association of TEF and circadian rhythm with pulmonary arterial hypertension.

BACKGROUND: Previous research has revealed the potential impact of circadian rhythms on pulmonary diseases; however, the connection between circadian rhythm-associated Thyrotroph Embryonic Factor (TEF) and Pulmonary Arterial Hypertension (PAH) remains unclear. We aim to assess the genetic causal relationship between TEF and PAH by utilizing two sets of genetic instrumental variables (IV) and publicly available Pulmonary Arterial Hypertension Genome-Wide Association Studies (GWAS). METHODS: Total of 23 independent TEF genetic IVs from recent MR reports and PAH GWAS including 162,962 European individuals were used to perform this two-sample MR study. Gain- and loss-of-function experiments were used to demonstrate the role of TEF in PAH. RESULTS: Our analysis revealed that as TEF levels increased genetically, there was a corresponding increase in the risk of PAH, as evidenced by IVW (OR = 1.233, 95% CI: 1.054-1.441; P = 0.00871) and weighted median (OR = 1.292, 95% CI for OR: 1.064-1.568; P = 0.00964) methods. Additionally, the up-regulation of TEF expression was associated with a significantly higher likelihood of abnormal circadian rhythm (IVW: P = 0.0024733, ß = 0.05239). However, we did not observe a significant positive correlation between circadian rhythm and PAH (IVW: P = 0.3454942, ß = 1.4980398). In addition, our in vitro experiments demonstrated that TEF is significantly overexpressed in pulmonary artery smooth muscle cells (PASMCs). And overexpression of TEF promotes PASMC viability and migratory capacity, as well as upregulates the levels of inflammatory cytokines. CONCLUSION: Our analysis suggests a causal relationship between genetically increased TEF levels and an elevated risk of both PAH and abnormal circadian rhythm. Consequently, higher TEF levels may represent a risk factor for individuals with PAH.

The relativity analysis of hypoxia inducible factor-1α in pulmonary arterial hypertension (ascites syndrome) in broilers: a review.

Ascites syndrome (AS) in broiler chickens, also known as pulmonary arterial hypertension (PAH), is a significant disease in the poultry industry. It is a nutritional metabolic disease that is closely associated with hypoxia-inducible factors and rapid growth. The rise in pulmonary artery pressure is a crucial characteristic of AS and is instrumental in its development. Hypoxia-inducible factor 1α (HIF-1α) is an active subunit of a key transcription factor in the oxygen-sensing pathway. HIF-1α plays a vital role in oxygen homeostasis and the development of pulmonary hypertension. Studying the effects of HIF-1α on pulmonary hypertension in humans or mammals, as well as ascites in broilers, can help us understand the pathogenesis of AS. Therefore, this review aims to (1) summarize the mechanism of HIF-1α in the development of pulmonary hypertension, (2) provide theoretical significance in explaining the mechanism of HIF-1α in the development of pulmonary arterial hypertension (ascites syndrome) in broilers, and (3) establish the correlation between HIF-1α and pulmonary arterial hypertension (ascites syndrome) in broilers. HIGHLIGHTSExplains the hypoxic mechanism of HIF-1α.Linking HIF-1α to pulmonary hypertension in broilers.Explains the role of microRNAs in pulmonary arterial hypertension in broilers.

Unraveling the Impact of miR-146a in Pulmonary Arterial Hypertension Pathophysiology and Right Ventricular Function.

Pulmonary arterial hypertension (PAH) is a chronic disorder characterized by excessive pulmonary vascular remodeling, leading to elevated pulmonary vascular resistance and right ventricle (RV) overload and failure. MicroRNA-146a (miR-146a) promotes vascular smooth muscle cell proliferation and vascular neointimal hyperplasia, both hallmarks of PAH. This study aimed to investigate the effects of miR-146a through pharmacological or genetic inhibition on experimental PAH and RV pressure overload animal models. Additionally, we examined the overexpression of miR-146a on human pulmonary artery smooth muscle cells (hPASMCs). Here, we showed that miR-146a genic expression was increased in the lungs of patients with PAH and the plasma of monocrotaline (MCT) rats. Interestingly, genetic ablation of miR-146a improved RV hypertrophy and systolic pressures in Sugen 5415/hypoxia (SuHx) and pulmonary arterial banding (PAB) mice. Pharmacological inhibition of miR-146a improved RV remodeling in PAB-wild type mice and MCT rats, and enhanced exercise capacity in MCT rats. However, overexpression of miR-146a did not affect proliferation, migration, and apoptosis in control-hPASMCs. Our findings show that miR-146a may play a significant role in RV function and remodeling, representing a promising therapeutic target for RV hypertrophy and, consequently, PAH.

Management of pulmonary arterial hypertension：before, during and after pregnancy.

Pregnancy complicated with pulmonary arterial hypertension (PAH) is a severe and dangerous condition for both the mother and the fetus. Pregnancy-specific alterations in the maternal cardiovascular system suggest that PAH in pregnancy may manifest more severe symptoms compared with those in non-pregnant patients. Although most societal guidelines recommend early termination in the case of PAH, some recent data suggests that maternal mortality among patients with PAH is lower than previously observed and suggests if a woman decides to proceed with the pregnancy, she should be counseled about the potential risks of continuing with the pregnancy. This review paper starts with a real clinical case of PAH complicating with pregnancy, then summarizes the clinical features, diagnosis, and risk stratification. Effective treatments were also clarified, including pre-conception counseling and monitoring, general and supportive care, medication and immune therapy, delivery and postpartum care, counseling on contraception and breastfeeding, maternal and fetal outcomes, and cardiac surgery. The article summarizes points of uncertainty in both laboratory and clinical practices, as well as current guidelines and clinical recommendations.

Clinical use of macitentan in the treatment of connective tissue disease-associated pulmonary arterial hypertension.

Background: Connective tissue disease (CTD) is the second most common cause of the pulmonary arterial hypertension (PAH). Currently, clinical data concerning CTD-PAH is scarce. Our study aimed to assess the efficacy and safety of macitentan in the treatment of CTD-PAH. Methods: In this retrospective study, patients diagnosed with CTD-PAH at The First Affiliated Hospital of Soochow University from April 2020 to November 2021 were included. Of the patients, 9 were switched to macitentan monotherapy whereas 23 received initial combination therapy. The mean follow-up time was 24 weeks. Six-minute walking distance (6MWD), World Health Organization functional class (WHO-FC), serum N-terminal pro-brain natriuretic peptide (NT-proBNP), and echocardiography parameters before and after medication were assessed. Adverse reactions were also recorded and compared. Results: After 24 weeks of treatment, 6MWD, NT-proBNP, systolic pulmonary artery pressure (sPAP) estimated by ultrasound, tricuspid regurgitation pressure gradient (TRPG) and tricuspid annular plane systolic excursion (TAPSE) in the macitentan monotherapy group revealed significant differences (Z=-2.67, Z=-2.67, t=6.20, t=5.60, t=-3.04, P<0.05). There were no statistically significant differences in right ventricular diameter (RVD), right atrial diameter (RAD), ascending aortic root inner diameter (AAO) and left ventricular end-diastolic diameter (LVEDd) (P>0.05). After 24 weeks of medication, the number of patients with WHO-FC grade III/IV symptoms decreased from 6 to 3, 1 to 0 respectively (P<0.05), and that of patients with WHO-FC grade I/II symptoms increased from 0 to 2, 2 to 4 respectively(P<0.05). After 24 weeks of treatment, 6MWD, NT-proBNP, LVEDd, sPAP and TRPG in the macitentan combined with sildenafil treatment group revealed statistically significant differences (Z=-4.11, Z=-3.74, Z=-3.83, t=6.88, t=6.54, P<0.001). Significant differences in RVD, RAD, and TAPSE were found (t=3.46, t=3.69, t=-3.12, P<0.05). There were no statistically significant variances in AAO between the groups (P>0.05). The number of patients with WHO-FC grade III/IV symptoms decreased from 16 to 8, 5 to 0 respectively (P<0.05), and that of patients with WHO-FC grade I/II symptoms increased from 0 to 1, 2 to 14 respectively (P<0.001). There were no statistically significant differences before and after treatment in 6MWD, NT-proBNP, RVD, RAD, AAO, LVEDd, sPAP, TRPG and TAPSE between the two groups (P>0.05). There were no statistically significant differences in alanine aminotransferase (ALT), aspartate aminotransferase (AST), serum creatinine (Scr) and hemoglobin (Hb) between 0 and 24 weeks (P>0.05). Conclusions: Exercise tolerance and cardiac function in patients with CTD-PAH were significantly improved after treatment with macitentan, which was well tolerated. Therefore, macitentan may be an effective and safe targeted drug for CTD-PAH.

Echocardiographic right ventricular evaluation in cardiac surgery patients undergoing mitral valve reconstruction: a single center prospective observational study.

Background: Mitral valve (MV) regurgitation (MR) is the second most frequent indication for valvular surgery in Europe. Right ventricular (RV) dysfunction is a common finding after cardiac surgery and might persist for years. The RV-function after MV surgery has been controversially discussed. We therefore aimed to evaluate early RV-performance in patients undergoing MV surgery. Methods: Between 09/2020 and 06/2022, ninety-two patients presenting with MR undergoing MV surgery were consented and prospectively included for evaluation. Echocardiographic evaluation was performed one day before surgery, one week after surgery and three months later. Primary endpoints reported RV-function changes including tricuspid annular plane systolic excursion (TAPSE), RV systolic prime (S') and fractional area change (FAC). Secondary endpoints included stability of MV repair, changes in left ventricular functions and early mortality. Results: Mean patients' age was 59.1±11.4 years. Fifty-five (59.7%) patients were male. Most of patients presented with severe (n=88; 95.7%) MR. Mean systolic pulmonary artery pressure was 35.6±15.7 mmHg. Moderate or severe pulmonary arterial hypertension (PAH) was present in 60 (65.2%) patients. Patients underwent either isolated MV surgery (n=67; 72.8%) or combined with tricuspid valve surgery (n=25; 27.2%). Minimal invasive surgery was performed in 26.1% (n=24) of the patients. Postoperative short-term follow-up at 3 months reported RV-dysfunction in 44.5% (n=41) of the patients as indicated by reductions in TAPSE & RV S' from 21.2±4.7 to 14±3.3 mm (P<0.001) and from 14.7±4.3 to 9.7±2.8 cm/s (P<0.001) respectively. The FAC reduction from 42.9%±9.6% to 42.2%±9.9% was non-significant (P=0.593) and no need for redo mitral or tricuspid valve surgery was reported. Finally, the presence and severity of preoperative PAH played significant roles for the incidence of RV dysfunction, P=0.021 and P=0.047, respectively. Minimal invasive surgical procedure significantly reduced the incidence of postoperative RV-dysfunction (P=0.013). Conclusions: Study early results report a significant reduction of RV-function after MV surgery as measured by TAPSE, & RV S', even when the FAC remains unchanged. Even though, this finding has limited prognostic implications during an uneventful surgical course.

The TREK-1 potassium channel is a potential pharmacological target for vasorelaxation in pulmonary hypertension.

BACKGROUND AND PURPOSE: Pulmonary arterial hypertension (PAH) is a progressive disease in which chronic membrane potential (Em) depolarisation of the pulmonary arterial smooth muscle cells (PASMCs) causes calcium overload, a key pathological alteration. Under resting conditions, the negative Em is mainly set by two pore domain potassium (K2P) channels, of which the TASK-1 has been extensively investigated. EXPERIMENTAL APPROACH: Ion channel currents and membrane potential of primary cultured human(h) PASMCs were measured using the voltage- and current clamp methods. Intracellular [Ca2+] was monitored using fluorescent microscopy. Pulmonary BP and vascular tone measurements were also performed ex vivo using a rat PAH model. KEY RESULTS: TREK-1 was the most abundantly expressed K2P in hPASMCs of healthy donors and idiopathic(I) PAH patients. Background K+-current was similar in hPASMCs for both groups and significantly enhanced by the TREK activator ML-335. In donor hPASMCs, siRNA silencing or pharmacological inhibition of TREK-1 caused depolarisation, reminiscent of the electrophysiological phenotype of idiopathic PAH. ML-335 hyperpolarised donor hPASMCs and normalised the Em of IPAH hPASMCs. A close link was found between TREK-1 activity and intracellular Ca2+-signalling using a channel activator, ML-335, and an inhibitor, spadin. In the rat, ML-335 relaxed isolated pre-constricted pulmonary arteries and significantly decreased pulmonary arterial pressure in the isolated perfused lung. CONCLUSIONS AND IMPLICATIONS: These data suggest that TREK-1is a key factor in Em setting and Ca2+ homeostasis of hPASMC, and therefore, essential for maintenance of a low resting pulmonary vascular tone. Thus TREK-1 may represent a new therapeutic target for PAH.

Impact of rapid sequential combination therapy on distinct haemodynamic measures in newly diagnosed pulmonary arterial hypertension.

AIMS: In pulmonary arterial hypertension (PAH), upfront combination therapy with ERA and PDE5i is associated with a reduction in morbidity and mortality events and improves standard haemodynamics, but data remain limited. Aims of this study were (i) to capture detailed haemodynamic effects of rapid sequential dual combination therapy in patients with newly diagnosed PAH; (ii) to monitor the impact of treatment initiation on clinical variables and patients' risk status, and (iii) to compare the treatment effect in patients with 'classical PAH' and 'PAH with co-morbidities'. METHODS: Fifty patients (median age 57 [42-71] years, 66% female) with newly diagnosed PAH (76% idiopathic) were treated with a PD5i/sGC-S or ERA, followed by addition of the respective other drug class within 4 weeks. All patients underwent repeat right heart catheterization (RHC) during early follow-up. RESULTS: At early repeat RHC (7 ± 2 months), there were substantial reductions in mean pulmonary artery pressure (mPAP: 52.2 ± 13.5 to 39.0 ± 10.6 mmHg; -25.3%), and pulmonary vascular resistance (PVR: 12.1 ± 5.7 to 5.8 ± 3.1 WU; -52.1%), and an increase in cardiac index (2.1 ± 0.4 to 2.7 ± 0.7 mL/min/m2; +32.2%) (all P < 0.05). Haemodynamic improvements correlated with improved clinical parameters including 6-min walking distance (336 ± 315 to 389 ± 120 m), NTproBNP levels (1.712 ± 2.024 to 506 ± 550 ng/L, both P < 0.05) and WHO-FC at 12 months, resulting in improved risk status, and were found in patients with few (n = 37) or multiple cardiovascular co-morbidities (BMI > 30 kg/m2, hypertension, diabetes, coronary artery disease [≥3]; n = 13), albeit baseline PVR in PAH patients with multiple co-morbidities was lower (9.3 ± 4.4 vs. 13.1 ± 5.9 WU) and PVR reduction less pronounced compared with those with few co-morbidities (-42.7% vs. -54.7%). However, comprehensive haemodynamic assessment considering further variables of prognostic relevance such as stroke volume index and pulmonary artery compliance showed similar improvements among the two groups (SVI: +50.0% vs. +49.2%; PAC: 91.7% vs. 100.0%). Finally, the 4-strata risk assessment approach was better able to capture treatment response as compared with other approaches, particularly in patients with co-morbidities. CONCLUSIONS: Rapid sequential combination therapy with PDE5i/sGC-S and ERA substantially ameliorates cardiopulmonary haemodynamics at early follow-up in patients without, and to a lesser extent, with cardiovascular co-morbidities. This occurs in line with improvements of clinical parameters and risk status.

Contemporary survival outcomes of congenital systemic-to-pulmonary shunt in children with borderline pulmonary vascular resistant index compared to Eisenmenger syndrome.

Pulmonary arterial hypertension (PAH) associated with congenital heart disease (PAH-CHD) is a complication that occurs after unrepaired significant systemic-to-pulmonary shunt. Treatment options for PAH-CHD-predominantly left-to-right (L-R) shunt in children with borderline-high pulmonary vascular resistant index (PVRi) have been debated. We aimed to assess the treatment and survival of children with PAH-CHD-predominantly L-R shunt with borderline to high PVRi, using Eisenmenger syndrome (ES) for comparison. In 1995-2021, a total of 142 patients with ES and 192 children with PAH-CHD-predominantly L-R shunt were eligible for our analysis. The PVRi in ES patients was 26.7 ± 16.8 WU m2. Most patients (91%) received PAH-targeted therapy. Of the 192 children with PAH-CHD-predominantly L-R shunt, the baseline PVRi was 9.2 ± 5.8 WU m2. A total of 64 patients (33.3%) had borderline PVRi (4-8 WU m2) and 98 patients (51%) had high PVRi (> 8 WU m2). Most patients (88.5%) responded to acute pulmonary vasodilatory testing and underwent repair, with 158 undergoing defect closure and 12 having fenestrated closure. A treat-and-repair strategy was used in 33 children (17.1%). The 10- and 15-year survival rates for patients with ES were 79.3% and 72.4%, respectively, which was significantly inferior to children with borderline PVRi [97.3% and 87.8% (p = 0.02)]; and high PVRi [91.6% and 89.5% (p = 0.06)], respectively. The survival rate of children receiving treat-and-repair was slightly higher than that of ES (p = 0.16). The independent mortality risk in children with PAH-CHD-predominantly L-R shunt was persistent PAH following the defect correction (adjusted hazard ratio 5.8, 95% CI 1.7-19.9, p = 0.005).Trial registration: TCTR20200420004.

Medeical Therapy For Pulmonary Arterial Hypertention / 결핵및호흡기질환

Pulmonary arterial hypertension (PAH) is often difficult to diagnose and challenging to treat. Untreated, it is characterized by a progressive increase in pulmonary vascular resistance leading to right ventricular failure and death. The past decade has seen remarkable improvements in therapy, driven largely by the conduct of randomized controlled trials. Still, the selection of most appropriate therapy is complex, and requires familiarity with the disease process, evidence from treatment trials, complicated drug delivery systems, dosing regimens, side effects, and complications. We tried to provide evidence?based treatment recommendations for physicians involved in the care of these complex patients. Due to the complexity of the diagnostic evaluation required, and the treatment options available, it is strongly recommended that consideration be given to referral of patients with PAH to a specialized center.