The role of immune cells in the pathogenesis of connective tissue diseases-associated pulmonary arterial hypertension.

Connective tissue diseases-related pulmonary arterial hypertension (CTD-PAH) is a disease characterized by an elevated pulmonary artery pressure that arises as a complication of connective tissue diseases. The number of patients with CTD-PAH accounts for 25.3% of all PAH patients. The main pathological features of CTD-PAH are thickening of intima, media and adventitia of pulmonary arterioles, increased pulmonary vascular resistance, autoimmune activation and inflammatory reaction. It is worth noting that abnormal immune activation will produce autoantibodies and release cytokines, and abnormal immune cell recruitment will promote inflammatory environment and vascular remodeling. Therefore, almost all forms of connective tissue diseases are related to PAH. In addition to general therapy and targeted drug therapy for PAH, high-dose glucocorticoid combined with immunosuppressant can quickly alleviate and stabilize the basic CTD-PAH disease. Given this, the development of therapeutic approaches targeting immune dysregulation and heightened inflammation is recognized as a promising strategy to prevent or reverse the progression of CTD-PAH. This review explores the potential mechanisms by which immune cells contribute to the development of CTD-PAH and examines the clinical application of immunosuppressive therapies in managing CTD-PAH.

Neutrophil extracellular traps and cardiovascular disease: Associations and potential therapeutic approaches.

Cardiovascular disease (CVD) is a significant global health concern, ranking among the top five causes of disability-adjusted life-years (DALY) in 190 countries and territories. Neutrophils, key players in the innate immune system, combat infections by releasing neutrophil extracellular traps (NETs) composed of DNA, histones, elastase, myeloperoxidase, and antimicrobial peptides. This paper explores the relationship between NETs and cardiovascular diseases, focusing on conditions such as heart failure, pulmonary hypertension, atrial fibrillation, and ischemia-reperfusion injury. Particularly, it delves into the impact of NETs on atrial fibrillation and pulmonary hypertension, as well as the role of myeloperoxidase (MPO) and neutrophil elastase (NE) in these diseases. Furthermore, the potential of targeting NETs for the treatment of cardiovascular diseases is discussed.

The effects of standardized intravenous treprostinil in pulmonary arterial hypertension patients after total cavo-pulmonary connection procedure.

OBJECTIVE: Total cavo-pulmonary connection (TCPC) is a palliative treatment for single ventricular malformations. For high-risk patients (preoperative mean pulmonary arterial pressure, mPAP > 15 mmHg), between the inhaled and oral targeted medications, the application of intravenous treprostinil as a bridge therapy to achieve "seamless" management is core postoperative treatment. This study intends to explore the effect of different administration regimens on early postoperative recovery. METHODS: This was a retrospective cohort study. High-risk pediatric patients (age ≤ 14 years) who underwent TCPC procedure in Fu Wai Hospital from 2015 to 2022 were included. Since the regimen of treprostinil was standardized in our center in 2021, the patients in 2020 and before were included in group 1, patients in 2021 and 2022 were included in group 2. The hemodynamic parameters were compared before and after the maintenance dose of treprostinil. The differences of demographic characteristics, surgical data and postoperative recovery were compared between the two groups. RESULTS: A total of 51 pediatric patients were included. Group 1 included 35 patients who received treprostinil at 1-3 postoperative days and an average dose of 12 ± 4 ng/(kg·min). Group 2 included 16 patients who received treprostinil within postoperative 1 day and an average dose of 22 ± 7 ng/(kg·min). There were no significant differences between the two groups in terms of age, weight, preoperative percutaneous oxygen saturation and mPAP,  heterotaxy syndrome, TCPC procedure type, other concurrent procedure, cardiopulmonary bypass time and aortic cross-clamp proportion (p > 0.05). After 24 h of treprostinil treatment, the mPAP in group 1 reduced from 17 ± 3 mmHg to 15 ± 2 mmHg (p < 0.001), and in group 2 from 17 ± 2 mmHg to 14 ± 2 mmHg (p < 0.001), with no difference between groups. In the postoperative recovery, patients in Group 2 exhibited a reduced duration of mechanical ventilation, 19 (11, 25) hours vs 69 (23, 189) hours, p = 0.001; a shorter stay in the ICU, 8 (6, 12) days vs 16 (9,26) days, p = 0.006; and a shorter postoperative length of stay, 27 (17,55) days vs 39 (29,58) days, p = 0.032. Patients in Group 2 also exhibited a lower incidence of thromboembolic events, 0 (0/26) vs 26% (9/35), p = 0.043; and the need for renal replacement therapy, 0 (0/26) vs 31% (11/35), p = 0.011. CONCLUSION: Treprostinil reduces pulmonary artery pressure after TCPC procedure. The standardized application of treprostinil may improve the postoperative recovery which should be proven by randomized controlled trials or matched cohort studies in the future.

CircSSR1 regulates pyroptosis of pulmonary artery smooth muscle cells through parental protein SSR1 mediating endoplasmic reticulum stress.

INTRODUCTION: Pyroptosis, inflammatory necrosis of cells, is a programmed cell death involved in the pathological process of diseases. Endoplasmic reticulum stress (ERS), as a protective stress response of cell, decreases the unfold protein concentration to inhibit the unfold protein agglutination. Whereas the relationship between endoplasmic reticulum stress and pyroptosis in pulmonary hypertension (PH) remain unknown. Previous evident indicated that circular RNA (circRNA) can participate in several biological process, including cell pyroptosis. However, the mechanism of circRNA regulate pyroptosis of pulmonary artery smooth muscle cells through endoplasmic reticulum stress still unclear. Here, we proved that circSSR1 was down-regulate expression during hypoxia in pulmonary artery smooth muscle cells, and over-expression of circSSR1 inhibit pyroptosis both in vitro and in vivo under hypoxic. Our experiments have indicated that circSSR1 could promote host gene SSR1 translation via m6A to activate ERS leading to pulmonary artery smooth muscle cell pyroptosis. In addition, our results showed that G3BP1 as upstream regulator mediate the expression of circSSR1 under hypoxia. These results highlight a new regulatory mechanism for pyroptosis and provide a potential therapy target for pulmonary hypertension. METHODS: RNA-FISH and qRT-PCR were showed the location of circSSR1 and expression change. RNA pull-down and RIP verify the circSSR1 combine with YTHDF1. Western blotting, PI staining and LDH release were used to explore the role of circSSR1 in PASMCs pyroptosis. RESULTS: CircSSR1 was markedly downregulated in hypoxic PASMCs. Knockdown CircSSR1 inhibited hypoxia induced PASMCs pyroptosis in vivo and in vitro. Mechanistically, circSSR1 combine with YTHDF1 to promote SSR1 protein translation rely on m6A, activating pyroptosis via endoplasmic reticulum stress. Furthermore, G3BP1 induce circSSR1 degradation under hypoxic. CONCLUSION: Our findings clarify the role of circSSR1 up-regulated parental protein SSR1 expression mediate endoplasmic reticulum stress leading to pyroptosis in PASMCs, ultimately promoting the development of pulmonary hypertension.

Dyspnea After an Acute Intermediate-Risk Pulmonary Embolism: A Case-Based Approach to Evaluation and Treatment.

Exercise intolerance after acute pulmonary embolism may be caused by residual pulmonary vascular obstruction, which presents as chronic thromboembolic pulmonary disease with or without pulmonary hypertension. We present a case highlighting a systematic approach to evaluating functional limitations due to residual pulmonary vascular obstruction, emphasizing the utility of cardiopulmonary exercise testing.

Inhibition of heterogeneous nuclear ribonucleoproteins A1 and oxidative stress reduces glycolysis via pyruvate kinase M2 in chronic thromboembolic pulmonary hypertension.

Background and Objective: Chronic thromboembolic pulmonary hypertension (CTEPH) is a lethal complication of pulmonary embolism involving pulmonary artery occlusion and microvascular disease. The glucose metabolism and reactive oxygen species (ROS) production may be perturbed in CTEPH, but the precise mechanisms are unclear. This study investigated glucose metabolism in CTEPH employing pulmonary endarterectomy (PEA)-derived pulmonary artery smooth muscle cells (PASMCs) and characterized the roles of pyruvate kinase M2 (PKM2) and its regulation by heterogeneous nuclear ribonucleoproteins A1 (hnRNPA1) and ROS in CTEPH. Methods: PEA tissues and blood samples of CTEPH patients were collected to study the levels of PKM2. Primary PASMCs were isolated from PEA tissues. We used small interfering RNAs to knock down PKM2 and hnRNPAI, and applied antioxidant N-acetylcysteine (NAC) and mito-TEMPO to reduce ROS production. The expression of glucometabolic genes, ROS production, glycolysis rate and proliferative and migratory activities were analyzed in PEA-derived PASMCs. Results: PKM2 levels in serum and PEA tissues of CTEPH patients were higher than that of the healthy controls. Compared to the control PASMCs, PEA-derived PASMCs showed increased PKM2 expression and ROS production. The rates of glycolysis, proliferation and migration were increased in PEA-PASMCs and could be mitigated by PKM2 downregulation through hnRNPA1 or ROS inhibition. Conclusions: Increased glycolysis and PKM2 expression were found in PEA-PASMCs. Inhibition of hnRNPA1 or ROS corrected the aberrant glycolysis, cell proliferation and migration by downregulating PKM2. Regulation of the hnRNPA1/PKM2 axis represents a potential therapeutic target for the treatment of CTEPH.

Prognostic Value of Echocardiographic Coupling Metrics in Systemic Sclerosis-Associated Pulmonary Vascular Disease.

BACKGROUND: Ineffective right ventricular (RV) adaptation to increasing pulmonary arterial (PA) afterload in pulmonary vascular disease (PVD) significantly contributes to morbidity and mortality. PVD in systemic sclerosis (SSc) arises through various mechanisms, yet detecting abnormal contractile response remains challenging. Here, we examine whether echocardiographic RV-PA coupling metrics correlate with invasive pressure-volume (PV) loops, enhancing the prediction of adverse clinical outcomes in SSc-PVD patients. METHODS: Prospectively enrolled patients with SSc-PVD with paired echocardiogram and PV loops were included. Linear regression and receiver-operating curve (ROC) analysis were used to assess the relationship between tricuspid annular plane systolic excursion (TAPSE)/PA systolic pressure (PASP), fractional area change (FAC)/PASP, tissue Doppler velocity (TDI S')/PASP, RV free wall strain (RVFWS)/PASP and coupling thresholds defined by end-systolic to end-arterial elastance (Ees/Ea), obtained by the multi-beat method. The contribution of right atrial strain (RAS) to RV-PA coupling parameters was also investigated. Kaplan-Meier analysis was used to identify the relationship between coupling ratios and composite outcomes including clinical worsening, lung transplant, and death. RESULTS: 42 patients with SSc were studied with mean age 59 ± 12 years, 91% female and varying degrees of PVD: mPAP 29.5 ± 12.8 mmHg, PVR 4.7 ± 4.2 WU, PCWP 10.3 ± 4.1 mmHg. Echocardiographic coupling metrics including TAPSE/PASP, FAC/PASP, TDI S'/PASP, RVFWSglobal and RVFWSbasal/PASP, and RASreservoir/PASP were linearly associated with Ees/Ea. At cut-points obtained through ROC analysis, all ratios were predictive of RV-PA uncoupling, defined by Ees/Ea, and composite outcomes. Additionally, RASreservoir/RVFWS correlated with Ees/Ea even after adjustment for PASP, suggesting that diminished RAS further impacts RV performance and coupling. CONCLUSION: Echocardiographic RV-PA coupling ratios strongly correlate with invasive Ees/Ea and predict adverse clinical outcomes in SSc patients across the spectrum of PVD. Further, we demonstrate how RAS impacts RV performance. These findings may refine risk stratification and prognostication in this at-risk cohort.

Formulation Optimization and Evaluation of Patented Solid Lipid Nanoparticles of Ambrisentan for Pulmonary Arterial Hypertension.

BACKGROUND: Ambrisentan is a new endothelin receptor antagonist extensively used to manage pulmonary or pulmonary arterial hypertension. OBJECTIVE: The therapeutic efficacy of Ambrisentan is limited due to its reduced solubility, higher log P (3.4), and thus less bioavailability. The recent investigation was concentrated on the improvement of solubility, and bioavailability of Ambrisentan for the therapy of hypertension via solid lipid nanoparticles (SLN) administered orally. METHODS: XRD evaluated the compatibility of Ambrisentan with lipids with FTIR, DSC, and crystalline nature. The SLN was developed by High-pressure homogenization method. The Glyceryl monostearate and Tween 80 indicated the highest solubility, hence selected. The optimization was performed with Box-Behnken Design considering the concentration of GMS (X1), Tween 80 (X2), stirring speed (X3) as independent factors and particle size (Y1), entrapment efficiency (Y2) as dependent factors. The Patents on the SLN are Indian 202321053691, U.S. Patent, 10,973,798B2, U.S. Patent 10,251,960B2, U.S. Patent 2021/0069121A1 and U.S. Patent 2022/0151945A1. RESULTS: The optimized batch F1 showed particle size (130 nm), ZP (-18.9 mV), and entrapment efficiency (85.73 %). The dual release pattern (prompt and sustained) was achieved with the SLNloaded Ambrisentan for about 24 hours. The lyophilized sample was subjected to SEM, which also revealed a spherical shape of a colloidal dispersion with a particle size of 126 nm. Hence, the F1 batch is highly recommended for solid oral delivery and also for the pilot-plant scale-up. CONCLUSION: A marked improvement in the solubility and dissolution of Ambrisentan was attained with the SLN. Moreover, the sustained delivery via the oral route enabled the patient's comfort, compliance, and therapeutic efficacy.

N-terminal pro-brain natriuretic peptide is associated with pulmonary hypertension or diastolic dysfunction in patients with systemic sclerosis: An Australian prospective cross-sectional study.

Introduction: Pulmonary arterial hypertension and left ventricular diastolic dysfunction are associated with significant morbidity and mortality in systemic sclerosis. N-terminal pro-brain natriuretic peptide has been proposed as part of composite screening algorithms for pulmonary arterial hypertension. Our aim was to assess the prevalence of pulmonary hypertension and diastolic dysfunction, and evaluate their association with serum N-terminal pro-brain natriuretic peptide in systemic sclerosis patients. Methods: Patients with systemic sclerosis were prospectively enrolled to undergo N-terminal pro-brain natriuretic peptide testing and transthoracic echocardiography at a tertiary Australian centre from January to October 2022. We collected demographic and transthoracic echocardiography variables including pulmonary hypertension estimated by tricuspid regurgitant velocity and diastolic dysfunction assessed by the ASE/EACVI 2016 guidelines. Pearson's correlation coefficient was used to evaluate association between N-terminal pro-brain natriuretic peptide and echocardiographic parameters. Results: Sixty-one patients were enrolled (median age = 62 years (interquartile range = 55-69 years); 84% female). Two-thirds of patients had limited systemic sclerosis (40/61). Five patients (8%) had high likelihood of pulmonary hypertension by transthoracic echocardiography. Seven patients (11%) had diastolic dysfunction; however, seven patients (11%) had indeterminate diastology. Six patients underwent right heart catheterisation, with five patients diagnosed with pulmonary hypertension. N-terminal pro-brain natriuretic peptide in patients with pulmonary hypertension or diastolic dysfunction was significantly higher (median = 207 and 226 pg/mL, respectively) compared to patients without either condition (median = 69 pg/mL, p = 0.01). N-terminal pro-brain natriuretic peptide showed a statistically significant although limited correlation with estimated pulmonary pressures measured by tricuspid regurgitant velocity (r = 0.44, p = 0.002) and left ventricular filling pressures (r = 0.27, p = 0.04). Conclusion: Pulmonary hypertension and diastolic dysfunction are both observed in systemic sclerosis. N-terminal pro-brain natriuretic peptide is associated with both conditions; however, it cannot distinguish between the two disease processes. Right heart catheterisation may be required to make this distinction.

Echinacoside inhibits PASMCs calcium overload to prevent hypoxic pulmonary artery remodeling by regulating TRPC1/4/6 and calmodulin.

Abstract: Research indicates that hypoxic pulmonary hypertension (HPH) potentially stimulates the sympathetic nervous system, which may increase norepinephrine (NE) release and cause excessive Ca2+ influx into pulmonary artery smooth muscle cells (PASMCs), leading to calcium overload and abnormal PASMC proliferation, factors closely associated with pulmonary vascular remodeling (PVR). This study investigates the potential mechanisms underlying echinacoside (ECH) treatment in HPH. Method: In the in vitro experiment, NE-induced PASMCs were used to simulate HPH-induced PASMCs' calcium overload and abnormal proliferation. Postincubation with ECH, [Ca2+]cyt changes were detected using Fluo-4 AM. Flow cytometry was employed to ascertain ECH's inhibitory effect on PASMCs proliferation. For in vivo experiments, rats were exposed to a hypoxic and low-pressure oxygen environment to establish the HPH model. Post-ECH treatment, hematoxylin and eosin (HE) staining was conducted to assess PVR, and western blot analysis was used to examine protein expression in the lung tissues of the different groups. Results: ECH was observed to inhibit [Ca2+]cyt increase in NE-induced PASMCs in a concentration-dependent manner, effectively reducing abnormal cell proliferation. It also reduced the expression of Transient receptor potential channel (TRPC) 1 (TRPC1), TRPC4, TRPC6, and calmodulin in PASMCs. In vivo studies demonstrated that ECH lowered the expression of these proteins in lung tissues of HPH rats, significantly decreased mean pulmonary artery pressure, and mitigated PVR.

Bullous Lung Disease in Turner Syndrome: An Underrecognized Comorbidity?

Congenital pulmonary anomalies in Turner syndrome (TS) are rarely reported. Herein, we describe a female with TS who presented with emphysema in infancy and developed pulmonary hypertension in adulthood. A 4-month-old patient presented with recurrent emesis and failure to thrive. Diagnostic testing indicated cardiomegaly and echocardiogram revealed abnormalities including left aortic arch with aberrant right subclavian artery, aortic coarctation, and left ventricular (LV) dysfunction. At 19-months, she underwent surgical intervention through a lateral thoracotomy which exposed numerous small air-filled blebs over the left lung. She had persistent LV dysfunction postoperatively. At 12-years-old, genetic testing revealed 45,X/46,Xidic(Y)(q11.22) and she subsequently received routine treatment for Turner syndrome. At 23-years-old, this patient presented to the emergency department with dyspnea, worsening cough, and edema. Echocardiogram demonstrated a reduced LVEF, aortic valve insufficiency, and pulmonary artery (PA) hypertension. CT chest showed multiple apical blebs and cardiac catheterization demonstrated pulmonary hypertension. She was treated with intravenous diuresis and cessation of Humira, which normalized LVEF and reduced PA pressure. Repeat cardiac catheterization 6 months later indicated elevated LVEDP, pulmonary vascular resistance, and mean PA pressures. Altered lymphatic drainage in utero of patients with TS may lead to emphysematous changes in the lungs. These changes may not raise concern in infancy but can possibly contribute to cardiopulmonary pathology in the future. We recommend ongoing routine care to monitor for acquired cardiopulmonary co-morbidities. Bullous lung disease may occur due to altered lymphatic drainage in patients with TS and may be a risk factor for developing or contributing to pulmonary hypertension.

SOX17 Prevents Endothelial-Mesenchymal Transition of Pulmonary Arterial Endothelial Cells in Pulmonary Hypertension through Mediating TGF-ß/Smad2/3 Signaling.

Endothelial to mesenchymal transition (EndMT) has been reported to cause pulmonary vascular remodeling of pulmonary hypertension (PH). We have demonstrated that SOX17, a member of the SRY-Box (SOX) transcription factor family, affects pulmonary artery vascular homeostasis through exosomes in an autocrine and paracrine manner. However, the role of SOX17 in mediating EndMT of pulmonary arterial endothelial cells (PAECs) in PH and its underlying intracellular mechanisms are not yet clarified. Here, we show that in the remodeling pulmonary vascular of idiopathic PH patients and Sugen 5416/hypoxia (Sugen/hypoxia)-induced PH rats, the downregulation of SOX17 expression was accompanied by a significant pulmonary arterial EndMT and TGF-ß/Smad2/3 signaling activation. In primary HPAECs, the expression of SOX17 was inhibited by canonical TGF-ß signaling. SOX17 overexpression reversed TGF-ß- and hypoxia-induced EndMT. It is suggested that SOX17 is required for HPAECs to acquire TGF-ß-mediated EndMT. Mechanistically, SOX17 prevented TGF-ß-induced EndMT of PAECs through trans-suppressing ROCK1 expression by binding to the specific promoter region of ROCK1, thereby inhibiting the phosphorylation of MYPT1 and MLC. Further, we found that Tie2-Cre rats with endothelial cell-specific SOX17 overexpression were prevented from Sugen/hypoxia-induced EndMT and pulmonary vascular remodeling. In keeping with the in vitro data, compared with the Tie2-Cre rats treated by Sugen/hypoxia, the rats with SOX17 overexpression showed decreased expression of ROCK1 as well as the MYPT1 and MLC phosphorylation. Overall, our studies demonstrate a novel TGF-ß/SOX17/ROCK1 pathway regulating EndMT of PAECs and propose SOX17 as a potential target for exploring therapeutics to alleviate pulmonary vascular remodeling in PH.

Ortner's syndrome: Hoarseness of voice revealing severe secondary pulmonary hypertension.

Ortner's syndrome or cardiovocal syndrome is a rare condition referring to laryngeal recurrent nerve paralysis due to cardiovascular conditions. We report the case of a 66-year-old man, with a medical history of active smoking, who complained of hoarseness of voice secondary to vocal cord palsy. A neck and thoracic CT scan revealed severe enlargement of pulmonary main artery, which caused compression of the left recurrent laryngeal nerve in the aortopulmonary window. The prolonged course of the left laryngeal nerve makes it susceptible to injury from cardiovascular structures in the mediastinum. Consequently, cardiovascular conditions such as dilated pulmonary artery or an aneurysm of the aortic arch can compress the nerve, resulting in Ortner's syndrome.

The critical roles of caveolin-1 in lung diseases.

Caveolin-1 (Cav-1), a structural and functional component in the caveolae, plays a critical role in transcytosis, endocytosis, and signal transduction. Cav-1 has been implicated in the mediation of cellular processes by interacting with a variety of signaling molecules. Cav-1 is widely expressed in the endothelial cells, smooth muscle cells, and fibroblasts in the various organs, including the lungs. The Cav-1-mediated internalization and regulation of signaling molecules participate in the physiological and pathological processes. Particularly, the MAPK, NF-κB, TGFß/Smad, and eNOS/NO signaling pathways have been involved in the regulatory effects of Cav-1 in lung diseases. The important effects of Cav-1 on the lungs indicate that Cav-1 can be a potential target for the treatment of lung diseases. A Cav-1 scaffolding domain peptide CSP7 targeting Cav-1 has been developed. In this article, we mainly discuss the structure of Cav-1 and its critical roles in lung diseases, such as pneumonia, acute lung injury (ALI), asthma, chronic obstructive pulmonary disease (COPD), pulmonary hypertension, pulmonary fibrosis, and lung cancer.

The role of anticoagulation on the long-term survival of patients with pulmonary arterial hypertension: A meta-analysis of 15 cohort studies.

INTRODUCTION: Anticoagulation was once recommended for patients with pulmonary arterial hypertension (PAH). However, its survival benefit still remained controversial. We performed a meta-analysis to evaluate the effect of anticoagulation on the long-term survival of PAH patients. METHODS: The PubMed, EMBASE, Web of Science, and WanFang electronic database were searched for eligible studies. Pooled hazard ratios (HRs) with 95 % confidence intervals (CIs) were calculated for effect estimate regarding anticoagulation on the survival of PAH patients. RESULTS: Fifteen cohort studies involving 4266 PAH patients were included. Approximately 45.8 % patients received anticoagulation. The mean follow-up period ranged from 2.1 to 14 years. Anticoagulation had a tendency to, however, did not significantly reduce mortality of PAH patients (HR: 0.86, 95 % CI: 0.73-1.02). In subgroup analysis, anticoagulation decreased the mortality risk as analyzed from retrospective studies (HR: 0.80, 95 % CI: 0.65-0.98), but not prospective studies (HR: 0.95, 95 % CI: 0.70-1.29). For both idiopathic PAH (IPAH) and connective tissue disease associated PAH (CTD-PAH), anticoagulation therapy did not significantly improve the long-term survival rate (HR: 0.83, 95 % CI: 0.65-1.07, and HR: 1.05, 95 % CI: 0.77-1.42, respectively), and this result remained unchanged when pooling data from either retrospective or prospective studies. Further analysis showed that anticoagulation had no advantage in reducing mortality in patients with systemic sclerosis associated PAH, systemic erythematosus lupus related PAH (free of antiphospholipid syndrome), or CTD-PAH of non-specified etiology. CONCLUSION: Anticoagulation may not reduce the long-term mortality of PAH patients, including those with IPAH and CTD-PAH. In the management of PAH, anticoagulants should be prescribed with caution before comprehensive risk to benefit evaluation. Larger and more vigorously designed controlled trials are warranted.

Utility of the oxygenation index in management of congenital diaphragmatic hernia: a report from a Thai University Surgical Centre.

BACKGROUND: Oxygenation index (OI) is associated with severity of newborn pulmonary hypertension (PH) in congenital diaphragmatic hernia (CDH). Higher OI may indicate worst degree(s) of PH. OBJECTIVES: This study reports OI dynamic(s) over the first 72 h of life and its correlation with (1) perioperative morbidity and (2) CDH mortality. METHODS: Medical records of inborn CDH babies during 2002-2022 were examined. OI on Days (s) 1-3 and perioperative OI trends were recorded. Operation (primary vs patch repair) and survival rates (%) were studied. RESULTS: Fifty-five CDH newborns (54.5% male: 45.5% female)-mean birth GA 37.5 ± 2.7 wks. had a mean birth weight 2813 ± 684 g with prenatal diagnosis in 32.7% cases. 52/55 (94.5%) were intubated at birth and HFOV deployed in 29 (55.8%). Those requiring HFOV had higher OI on DOL1 (24.8 ± 17 vs 10.3 ± 11.5; p < 0.05), DOL 2 (26.3 ± 22.9 vs 6.7 ± 12.1; p < 0.05) and DOL 3 (21.9 ± 33.8 vs 5.5 ± 9.3; p = 0.04). Operation was undertaken in 36/55 (65.5%). Preoperative mortality group had significant higher OI on DOL 2 (42.1 ± 21.0 vs 14.9 ± 9.3; p = 0.04). CDH defects were-Type A N = 27 (75%), Type B N = 7 (19.4%) and Type C N = 2 (5.6%). Overall mortality was 40% (22/55). Statistically significant OI trends were recorded in non-survival vs. survival groups on DOL 1 (31.6 ± 16.8. vs 10.5 ± 9.0; p < 0.05, DOL 2 (38.1 ± 21.9 vs 6.3 ± 7.1; p < 0.05), and DOL 3 (38.8 ± 39.4; p = 0.012). CONCLUSIONS: OI dynamics are highly predictive for accurate monitoring of CDH cardiorespiratory physiology and crucially may guide ventilatory management as well as timing of surgery.

Platelet aggregates in lung capillaries in severely decompensated pulmonary hypertension.

The mechanism of thrombocytopenia during acute pulmonary hypertension (PH) decompensation may be partly due to platelet aggregation in the lung. Platelet aggregates in explanted lung from 16 lung transplant patients during acute PH decompensation with and without thrombocytopenia were identified by immunohistochemistry. Scanning electron microscopy (SEM) was performed. 7 explant lung controls without PH and thrombocytopenia were also examined. Compared with controls, the median number of platelet aggregates was higher in patients with acute PH decompensation with thrombocytopenia (19.4 [IQR 3.4-38.3] vs 147.5 [IQR 26.5-203.2]). SEM showed capillaries filled with platelet aggregates. Our study suggests that platelets may aggregate in the lungs during acute PH decompensation.

Anesthesia Strategies for the Perioperative Management of Severe Pulmonary Hypertension in Emergency Orthopedic Surgery: A Case Report.

This case report details the perioperative challenges and anesthesia strategies in managing severe pulmonary hypertension (PH) during emergency orthopedic surgery. An 86-year-old male with multiple comorbidities, including severe PH, presented with a hip fracture. Multidisciplinary collaboration was crucial for preoperative optimization, including transfusions, antithrombotic discontinuation, and thromboprophylaxis initiation. Anesthesia management included the use of spinal anesthesia combined with a precautionary epidural catheter insertion, low-dose hyperbaric bupivacaine, and continuous monitoring to prevent hemodynamic instability. Postoperatively, the patient was closely monitored in the surgical intensive care unit. This case highlights the necessity of meticulous planning and proactive monitoring in optimizing outcomes for severe PH in emergency orthopedic surgery.

Metabolic gene therapy in a canine with pulmonary hypertension secondary to degenerative mitral valve disease.

Myxomatous mitral valve disease (MMVD) stands out as the most prevalent acquired canine heart disease. Its occurrence can reach up to 40% in small breed dogs and escalates in geriatric canine populations. MMVD leads to thickening and incomplete coaptation of valve leaflets during systole, resulting in secondary mitral valve regurgitation. Serious complications may arise concurrently with the worsening of mitral valve regurgitation, including left-and right-sided congestive heart failure, and pulmonary hypertension (PH). Ultimately, the PH progression might contribute to the patient's demise or to the owner's decision of euthanasia. Most currently available FDA-approved therapies for PH are costly and aim to address the imbalance between vasoconstriction and vasodilation to restore endothelial cell function. However, none of these medications impact the molecular dysfunction of cells or impede the advancement of pulmonary vascular and right ventricular remodeling. Recent evidence has showcased successful gene therapy approaches in laboratory animal models of PH. In this manuscript, we summarize the latest advancements in gene therapy for the treatment of PH in animals. The manuscript incorporates original data showcasing sample presentations, along with non-invasive hemodynamic assessments. Our findings demonstrate that the use of metabolic gene therapy, combining synthetic adeno-associated virus with acid ceramidase, has the potential to significantly reduce the need for drug treatment and improve spontaneously occurring PH in dogs.

A Belgian consensus on sotatercept for the treatment of pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a rare disease affecting the small pulmonary vessels, ultimately leading to right ventricular failure and death. Current treatment options target three different pathways (endothelin, nitric oxide/cGMP and prostacyclin pathways). Despite their demonstrated efficacy, these therapies (commonly used in combination) do not cure the disease which is why novel pathways beyond the traditional 'big three' are being developed. Sotatercept is a ligand trap for multiple proteins within the TGF-ß superfamily that was recently approved in the US for the treatment of PAH. Unlike currently available therapies, sotatercept has the potential to act as an anti-remodelling agent rather than a vasodilator. The safety and efficacy of subcutaneous (SC) sotatercept have been established in two multicentre, placebo-controlled randomised-controlled trials. The compound has been shown to consistently improve a variety of measurable endpoints, including exercise capacity, haemodynamics, quality of life and delay of clinical worsening. The drug appears to have an acceptable safety profile, although it is associated with an increased risk in developing telangiectasia and biological changes affecting platelet counts and haemoglobin. This study reviews the current evidence on SC sotatercept and provides a Belgian perspective on its place in the future treatment strategy for PAH.