Search

BACKGROUND: Schistosomiasis is a parasitic infection that can cause pulmonary hypertension (PH). Th2 CD4 T cells are necessary for experimental Schistosoma-PH. However, if T cells migrate to the lung to initiate, the localized inflammation that drives vascular remodeling and PH is unknown. METHODS: Mice were sensitized to Schistosoma mansoni eggs intraperitoneally and then challenged using tail vein injection. FTY720 was administered, which blocks lymphocyte egress from lymph nodes. T cells were quantified using flow cytometry, PH severity via heart catheterization, and cytokine concentration through ELISA. RESULTS: FTY720 decreased T cells in the peripheral blood, and increased T cells in the mediastinal lymph nodes. However, FTY720 treatment resulted in no change in PH or type 2 inflammation severity in mice sensitized and challenged with S. mansoni eggs, and the number of memory and effector CD4 T cells in the lung parenchyma was also unchanged. Notably, intraperitoneal Schistosoma egg sensitization alone resulted in a significant increase in intravascular lymphocytes and T cells, including memory T cells, although there was no significant change in parenchymal cell density, IL-4 or IL-13 expression, or PH. CONCLUSION: Blocking T cell migration did not suppress PH following Schistosoma egg challenge. Memory CD4 T cells, located in the lung intravascular space following egg sensitization, appear sufficient to cause type 2 inflammation and PH.

BACKGROUND: Aging-associated left ventricular dysfunction promotes cardiopulmonary fibrogenic remodeling, Group 2 pulmonary hypertension (PH), and right ventricular failure. At the time of diagnosis, cardiac function has declined, and cardiopulmonary fibrosis has often developed. Here, we sought to develop a molecular positron emission tomography (PET)-magnetic resonance imaging (MRI) protocol to detect both cardiopulmonary fibrosis and fibrotic disease activity in a left ventricular dysfunction model. METHODS AND RESULTS: Left ventricular dysfunction was induced by transverse aortic constriction (TAC) in 6-month-old senescence-accelerated prone mice, a subset of mice that received sham surgery. Three weeks after surgery, mice underwent simultaneous PET-MRI at 4.7 T. Collagen-targeted PET and fibrogenesis magnetic resonance (MR) probes were intravenously administered. PET signal was computed as myocardium- or lung-to-muscle ratio. Percent signal intensity increase and Δ lung-to-muscle ratio were computed from the pre-/postinjection magnetic resonance images. Elevated allysine in the heart (P=0.02) and lungs (P=0.17) of TAC mice corresponded to an increase in myocardial magnetic resonance imaging percent signal intensity increase (P

Various erythropoietic abnormalities are highly prevalent among patients with pulmonary arterial hypertension (PAH) and associated with worse disease severity. Given the poorly understood yet important roles of dysregulated erythropoiesis and iron metabolism in PAH, we sought to further characterize the hematologic and iron profiles in PAH and their relationship to PAH severity. We recruited 67 patients with PAH and 13 healthy controls. Hemodynamics attained within 1 year of blood sample collection were available for 36 patients. Multiple hematologic, iron, and inflammatory parameters were evaluated for their association with hemodynamics. The subset with hemodynamic data consisted of 29 females (81%). The most common etiologies were idiopathic PAH (47%) and connective tissue disease-related PAH (33%). 19 (53%) had functional class 3 or 4 symptomatology, and 12 (33%) were on triple pulmonary vasodilator therapy. Immature reticulocyte fraction (IRF) had significant positive correlations with mean pulmonary artery (PA) pressure (mPAP) (0.59, p

Current predictors of clinical outcomes after pulmonary thromboendarterectomy (PTE) in patients with chronic thromboembolic pulmonary hypertension (CTEPH) are largely limited to preoperative clinical characteristics. N-terminal-pro-brain natriuretic peptide (NT-pro-BNP), a biomarker of right ventricular dysfunction, has not yet been well described as one such predictor. From 2017 to 2021, 816 patients with CTEPH referred to the University of California, San Diego for PTE were reviewed for differences in NT-pro-BNP to predict preoperative characteristics and postoperative outcomes up to 30 days post-PTE. For analysis, NT-pro-BNP was dichotomized to less than/equal to or greater than 1000 pg/mL based on the mean of the study population. Mean NT-pro-BNP was 1095.9 ±1783.4 pg/mL and median was 402.5 pg/mL (interquartile range: 119.5-1410.8). Of the 816 patients included, 250 had NT-pro-BNP > 1000 pg/mL. Those with NT-pro-BNP > 1000 pg/mL were significantly more likely to have worse preoperative functional class (III-IV) and worse preoperative hemodynamics. Patients with NT-pro-BNP > 1000 pg/mL also tended to have more postoperative complications including reperfusion pulmonary edema (22% vs. 5.1%, p  1000 pg/mL had a 2.48 times higher odds (95% confidence interval: 1.45-4.00) of reaching a combined endpoint that included the above complications. Preoperative NT-pro-BNP > 1000 pg/mL is a strong predictor of more severe preoperative hemodynamics and identifies patients at higher risk for postoperative complications.

AIMS: Pulmonary hypertension (PH) is a pulmonary vascular disease characterized by a high mortality rate. Pulmonary arterial endothelium cells (PAECs) serve as a primary sensor of various environmental cues, such as shear stress and hypoxia, but PAEC dysfunction may trigger vascular remodelling during the onset of PH. This study aimed to illustrate the role of Sirtuin 7 (SIRT7) in endothelial dysfunction during PH and explore the potential therapeutic strategy for PH. METHODS AND RESULTS: SIRT7 levels were measured in human and murine experimental PH samples. Bioinformatic analysis, immunoprecipitation, and deacetylation assay were used to identify the association between SIRT7 and Krüpple-like factor 4 (KLF4), a key transcription factor essential for endothelial cell (EC) homeostasis. Sugen5416 + hypoxia (SuHx)-induced PH mouse models and cell cultures were used for the study of the therapeutic effect of SIRT7 for PH. SIRT7 level was significantly reduced in lung tissues and PAECs from PH patients and the SuHx-induced PH mouse model as compared with healthy controls. Pulmonary endothelium-specific depletion of Sirt7 increased right ventricular systolic pressure and exacerbated right ventricular hypertrophy in the SuHx-induced PH model. At the molecular level, we identified KLF4 as a downstream target of SIRT7, which deacetylated KLF4 at K228 and inhibited the ubiquitination-proteasome degradation. Thus, the SIRT7/KLF4 axis maintained PAEC homeostasis by regulating proliferation, migration, and tube formation. PAEC dysfunction was reversed by adeno-associated virus type 1 vector-mediated endothelial overexpression of Sirt7 or supplementation with nicotinamide adenine dinucleotide (NAD)+ intermediate nicotinamide riboside which activated Sirt7; both approaches successfully reversed PH phenotypes. CONCLUSION: The SIRT7/KLF4 axis ensures PAEC homeostasis, and pulmonary endothelium-specific SIRT7 targeting might constitute a PH therapeutic strategy.

Pulmonary hypertension is a cardiovascular disorder manifested by elevated mean arterial blood pressure (>20 mmHg) together with vessel wall stiffening and thickening due to alterations in collagen, elastin, and smooth muscle cells. Hypoxia-induced (type 3) pulmonary hypertension can be studied in animals exposed to a low oxygen environment for prolonged time periods leading to biomechanical alterations in vessel wall structure. This study introduces a novel approach to formulating a reduced order nonlinear elastic structural wall model for a large pulmonary artery. The model relating blood pressure and area is calibrated using ex vivo measurements of vessel diameter and wall thickness changes, under controlled pressure conditions, in left pulmonary arteries isolated from control and hypertensive mice. A two-layer, hyperelastic, and anisotropic model incorporating residual stresses is formulated using the Holzapfel-Gasser-Ogden model. Complex relations predicting vessel area and wall thickness with increasing blood pressure are derived and calibrated using the data. Sensitivity analysis, parameter estimation, subset selection, and physical plausibility arguments are used to systematically reduce the 16-parameter model to one in which a much smaller subset of identifiable parameters is estimated via solution of an inverse problem. Our final reduced one layer model includes a single set of three elastic moduli. Estimated ranges of these parameters demonstrate that nonlinear stiffening is dominated by elastin in the control animals and by collagen in the hypertensive animals. The pressure-area relation developed in this novel manner has potential impact on one-dimensional fluids network models of vessel wall remodeling in the presence of cardiovascular disease.

INTRODUCTION: Hypoxia is a common pathological driver contributing to various forms of pulmonary vascular diseases leading to pulmonary hypertension (PH). Pulmonary interstitial macrophages (IMs) play pivotal roles in immune and vascular dysfunction, leading to inflammation, abnormal remodeling, and fibrosis in PH. However, IMs response to hypoxia and their role in PH progression remain largely unknown. We utilized a murine model of hypoxia-induced PH to investigate the repertoire and functional profiles of IMs in response to acute and prolonged hypoxia, aiming to elucidate their contributions to PH development. METHODS: We conducted single-cell transcriptomic analyses to characterize the repertoire and functional profiles of murine pulmonary IMs following exposure to hypobaric hypoxia for varying durations (0, 1, 3, 7, and 21 days). Hallmark pathways from the mouse Molecular Signatures Database were utilized to characterize the molecular function of the IM subpopulation in response to hypoxia. RESULTS: Our analysis revealed an early acute inflammatory phase during acute hypoxia exposure (Days 1-3), which was resolved by Day 7, followed by a pro-remodeling phase during prolonged hypoxia (Days 7-21). These phases were marked by distinct subpopulations of IMs: MHCIIhiCCR2+EAR2+ cells characterized the acute inflammatory phase, while TLF+VCAM1hi cells dominated the pro-remodeling phase. The acute inflammatory phase exhibited enrichment in interferon-gamma, IL-2, and IL-6 pathways, while the pro-remodeling phase showed dysregulated chemokine production, hemoglobin clearance, and tissue repair profiles, along with activation of distinct complement pathways. DISCUSSION: Our findings demonstrate the existence of distinct populations of pulmonary interstitial macrophages corresponding to acute and prolonged hypoxia exposure, pivotal in regulating the inflammatory and remodeling phases of PH pathogenesis. This understanding offers potential avenues for targeted interventions, tailored to specific populations and distinct phases of the disease. Moreover, further identification of triggers for pro-remodeling IMs holds promise in unveiling novel therapeutic strategies for pulmonary hypertension.

BACKGROUND: Schistosomiasis is a common cause of pulmonary hypertension (PH) worldwide. Type 2 inflammation contributes to the development of Schistosoma-induced PH. Specifically, interstitial macrophages (IMs) derived from monocytes play a pivotal role by producing thrombospondin-1 (TSP-1), which in turn activates TGF-β, thereby driving the pathology of PH. Resident and recruited IM subpopulations have recently been identified. We hypothesized that in Schistosoma-PH, one IM subpopulation expresses monocyte recruitment factors, whereas recruited monocytes become a separate IM subpopulation that expresses TSP-1. METHODS: Mice were intraperitoneally sensitized and then intravenously challenged with S. mansoni eggs. Flow cytometry on lungs and blood was performed on wildtype and reporter mice to identify IM subpopulations and protein expression. Single-cell RNA sequencing (scRNAseq) was performed on flow-sorted IMs from unexposed and at day 1, 3 and 7 following Schistosoma exposure to complement flow cytometry based IM characterization and identify gene expression. RESULTS: Flow cytometry and scRNAseq both identified 3 IM subpopulations, characterized by CCR2, MHCII, and FOLR2 expression. Following Schistosoma exposure, the CCR2+ IM subpopulation expanded, suggestive of circulating monocyte recruitment. Schistosoma exposure caused increased monocyte-recruitment ligand CCL2 expression in the resident FOLR2+ IM subpopulation. In contrast, the vascular pathology-driving protein TSP-1 was greatest in the CCR2+ IM subpopulation. CONCLUSION: Schistosoma-induced PH involves crosstalk between IM subpopulations, with increased expression of monocyte recruitment ligands by resident FOLR2+ IMs, and the recruitment of CCR2+ IMs which express TSP-1 that activates TGF-β and causes PH.

Statin therapy is a cornerstone in the treatment of systemic vascular diseases. However, statins have failed to translate as therapeutics for pulmonary vascular disease. Early pulmonary vascular disease in the setting of congenital heart disease (CHD) is characterized by endothelial dysfunction, which precedes the more advanced stages of vascular remodeling. These features make CHD an ideal cohort in which to re-evaluate the potential pulmonary vascular benefits of statins, with a focus on endothelial biology. However, it is critical that the full gamut of the pleiotropic effects of statins in the endothelium are uncovered. The purpose of this investigation was to evaluate the therapeutic potential of simvastatin for children with CHD and pulmonary over-circulation, and examine mechanisms of simvastatin action on the endothelium. Our data demonstrate that daily simvastatin treatment preserves endothelial function in our shunt lamb model of pulmonary over-circulation. Further, using pulmonary arterial endothelial cells (PAECs) isolated from Shunt and control lambs, we identified a new mechanism of statin action mediated by increased expression of the endogenous Akt1 inhibitor, C-terminal modifying protein (CTMP). Increases in CTMP were able to decrease the Akt1-mediated mitochondrial redistribution of endothelial nitric oxide synthase (eNOS) which correlated with increased enzymatic coupling, identified by increases in NO generation and decreases in NOS-derived superoxide. Together our data identify a new mechanism by which simvastatin enhances NO signaling in the pulmonary endothelium and identify CTMP as a potential therapeutic target to prevent the endothelial dysfunction that occurs in children born with CHD resulting in pulmonary over-circulation.

Whether all Schistosoma species cause pulmonary hypertension (PH) is unclear. Experimentally exposing mice to Schistosoma haematobium eggs caused PH, which was less severe than that induced by S. mansoni exposure. These findings align with the relatively uncommon reports of pulmonary arterial hypertension associated with S. haematobium.

Patients with group 1 pulmonary hypertension (PH) and risk factors for heart failure with preserved ejection fraction (HFpEF) demonstrate worse response to pulmonary vasodilator therapy. The mechanisms and optimal diagnostic approach to identify such patients remain unclear. The purpose of this study was to compare exercise capacity, cardiac function, and hemodynamic responses to provocative maneuvers among patients with group 1 PH based upon pretest probability of HFpEF. Pretest probability for HFpEF was determined using the validated HFpEF-ABA algorithm based on age, body mass index, and history of atrial fibrillation among group 1 PH patients recruited to the multicenter PVDOMICS (Redefining Pulmonary Hypertension through Pulmonary Vascular Disease Phenomics) study. Functional capacity, quality of life, and dynamic pulmonary capillary wedge pressure (PCWP) responses were compared between those with low (<25%), intermediate (25%-74%), and high (≥75%) ABA score-based HFpEF probability. Among 424 patients with group 1 PH, 54% (n = 228) had intermediate HFpEF probability and 15% (n = 64) had high HFpEF probability. Resting PCWP increased progressively with higher HFpEF probability (P < 0.0001), and patients with group 1 PH and high HFpEF probability had the greatest increases in PCWP with nitric oxide, fluid challenge, and exercise (P < 0.001 for all), changes that were comparable to patients with HFpEF with no pulmonary vascular disease (n = 194), but lower than those with HFpEF and combined precapillary and postcapillary PH. Left ventricular/atrial size, diastolic function, quality of life, 6-minute walk distance, and peak VO 2 were most abnormal in patients with group 1 PH and high HFpEF probability compared with those with low or intermediate HFpEF probability (P < 0.0001 for all). Increasing HFpEF probability in group 1 PH was associated with greater risk of death (HR per decile of HFpEF probability 1.09; 95% CI: 1.05-1.13; P < 0.0001). Quantifying pretest probability for HFpEF in patients with group 1 PH identifies a subset of patients with worse dynamic PCWP response indicative of subclinical left heart disease, with poorer functional status, quality of life, and survival. Further study in this group 1 PH subgroup is indicated to determine whether PH therapies are effective and safe, and also whether HFpEF-specific therapies can improve functional status and outcomes. [Display omitted] [ABSTRACT FROM AUTHOR]

We evaluated whether fluid status could be accurately assessed (and corrected if necessary) prior to right heart catheterisation (RHC), to diagnose accurately post‐capillary pulmonary hypertension (PHT) in patients with left heart disease risk factors. A non‐invasive measure of fluid status prior to RHC identified fluid‐depleted patients. Baseline RHC measurements were performed, and a novel provocation technique (passive leg raise) was compared to a ‘one‐dose‐fits‐all’ fluid challenge and found to be equivalent. [ABSTRACT FROM AUTHOR]

Background: Current clinical guidelines support use of parenteral prostacyclin therapy for patients with pulmonary arterial hypertension (PAH) at intermediate risk. The objective of this study was to assess parenteral prostacyclin therapy use among patients at intermediate risk according to the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) 2.0 four-strata risk assessment model. Methods: This was a retrospective chart review and cross-sectional online survey of healthcare professionals (HCPs). Included patients were classified as intermediate-low or intermediate-high risk per COMPERA 2.0 between 2016 and 2020 (index visit), initiated on a parenteral prostacyclin any time following intermediate risk assessment, and had World Health Organization (WHO) Functional Class (FC), 6-minute walk distance (6MWD), and B-type natriuretic peptide/N-terminal pro B-type natriuretic peptide (BNP/NT-proBNP) assessments at index and first comprehensive follow-up visits (follow-up). Results: A total of 139 HCPs (53% community-based, 47% Pulmonary Hypertension Care Center-based) participated in the survey and provided 350 patient records; among these, mean age (SD) was 54.1 (15.3) years and 52% were female. Median (IQR) time from parenteral prostacyclin initiation to follow-up was 3.0 months (2.0, 7.0). At parenteral prostacyclin initiation for the 280 patient records with available COMPERA 2.0 assessments, 62% of patients were intermediate-high risk, 33% were intermediate-low risk and 3% were low risk, improving to 38%, 53%, and 8%, respectively, at follow-up. Conclusions: Improvements were seen for the individual COMPERA 2.0 risk calculator parameters and for several other clinical parameters. Findings from this study substantiate recent guidelines suggesting earlier use of this treatment in intermediate-risk patients with PAH. Clinical trial number: Not applicable. [ABSTRACT FROM AUTHOR]

Pulmonary hypertension (PH) is a devastating disease characterized by vascular remodeling, resulting in right ventricular failure and death. Dysregulation of energy metabolism is linked to PH pathogenesis. Trimetazidine (TMZ), a selective long-chain 3-ketoacyl coenzyme A thiolase inhibitor, is critical in maintaining energy metabolism. Despite the indicated TMZ's inhibitory effect on pulmonary vascular remodeling in PH development, the integrated evaluation of the changes in biomolecules, such as metabolites and transcripts, that TMZ induces in the lung and heart tissues is largely unknown in vivo. For an improved understanding of the molecular mechanism involving the effects of TMZ on PH development, we performed a comprehensive analysis of the changes in cardiac metabolites and pulmonary transcripts of SU5416-Hypoxia (Su/Hx) rats treated with TMZ. Metabolomic analysis of the Su/Hx-induced PH hearts demonstrated that TMZ reduced the long-chain fatty acid concentration. Additionally, TMZ alleviated PH degree and excessive strain on the right heart functions in rats with Su/Hx-induced PH. We identified the candidate target genes for TMZ treatment during PH development. Interestingly, the mRNA levels of the fatty acid transporters were substantially downregulated by TMZ administration in the lungs with Su/Hx-induced PH. Notably, TMZ suppressed excessive proliferation of human pulmonary artery smooth muscle cells under hypoxic conditions. Our study suggests that TMZ ameliorates PH development by involving energy metabolism in the lungs and heart. [ABSTRACT FROM AUTHOR]

Introduction: While a patent ductus arteriosus (PDA) helps offload the right ventricle in the acute congenital diaphragmatic hernia (CDH)-associated pulmonary hypertension, its role on long-term outcomes in CDH has not been investigated. Our objective was to examine associations of the PDA with long-term clinical outcomes in CDH. Methods: A single-center retrospective descriptive study of 122 CDH patients dichotomized by duration with PDA, as ≤14 versus >14 postnatal days (PND) and ≤30 versus >30 PND. Fisher’s exact test, Wilcoxon rank-sum test, and multiple linear and logistic regression analyses were used for analyses. Results: In unadjusted and adjusted for CDH severity comparisons, patients with PDA >14 PND and >30 PND had a higher risk of death, longer length of stay, mechanical ventilation duration, and need for tracheostomy, diuretics, and PH medications at discharge. Conclusion: A PDA beyond the newborn period is associated with adverse outcomes in infants with CDH. [ABSTRACT FROM AUTHOR]

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, TGFβ/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. [ABSTRACT FROM AUTHOR]

Pulmonary arterial hypertension (PAH) is a disease characterized by pulmonary vascular remodeling. Since dephosphorylated-uncarboxylated Matrix Gla-Protein (dp-ucMGP) is associated with cardiovascular mortality in systemic sclerosis, a disease associated with PAH, and immune-system involvement in PAH is increasingly recognized, we investigated the relationship between dp-ucMGP, vascular remodeling and soluble immune-checkpoint proteins in PAH. This prospective cohort study included patients with idiopathic (I)PAH, connective tissue disease (CTD)-PAH, chronic thrombo-embolic PH (CTEPH) and CTD patients without PAH. Patients with IPAH and CTD-PAH were stratified by clinical signs of immune-mediated inflammatory disease (IMID). We measured dp-ucMGP plasma levels, soluble immune-checkpoint proteins (sICPs), and vascular smooth muscle cell (iVSMC) calcification. We found elevated dp-ucMGP levels in all PAH subtypes and CTD patients compared to healthy controls. PAH patients showed increased iVSMC calcification, but no direct correlation was found with dp-ucMGP. IMID-PAH patients had higher dp-ucMGP levels than non-IMID PAH patients. dp-ucMGP correlated with several sICPs in both IPAH and CTD patients; multiple sICPs were elevated in IMID PAH patients. High dp-ucMGP levels in IPAH patients were associated with worse survival. Our findings suggest dp-ucMGP as a potential biomarker of immune-mediated vascular remodeling in PAH. Hence, dp-ucMGP, could help identify PAH patients who might benefit from immunosuppressive therapies. [ABSTRACT FROM AUTHOR]

Background: Pulmonary hypertension (PH) secondary to chronic obstructive pulmonary disease (COPD) is a common complication that requires early detection for better patient outcomes. Computed tomography pulmonary angiography (CTPA) offers comprehensive assessment of the pulmonary vessels and cardiac chambers in patients with suspected PH. This study aimed to evaluate the diagnostic performance of CTPA in predicting COPD-associated PH and to identify optimal CTPA parameters for its diagnosis. Methods: This cross-sectional study included 30 COPD patients who underwent CTPA. The following measurements were recorded: main pulmonary artery (MPA) diameter, right and left PA diameters, MPA/ascending aorta diameters ratio, segmental PA/accompanying bronchus ratio, right ventricular (RV) lumen diameter, left ventricular (LV) lumen diameter, RV lumen/LV lumen ratio, RV wall thickness, and RV outflow tract thickness. According to transthoracic echocardiography (TTE) findings (reference standard), patients were classified into those with PH and without PH. Diagnostic performance of CTPA was evaluated using a 2x2 contingency table to estimate its accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). Receiver operating characteristic (ROC) curve analysis with calculation of the area under the curve (AUC) was performed for each CTPA parameter. Results: CTPA showed 80% accuracy, 85% sensitivity, 70% specificity, 85% PPV, and 70% NPV (p=0.002) in predicting COPD-associated PH. MPA diameter was the optimal parameter to predict PH, demonstrating the highest AUC = 1 at cut-off value of = 28.7 mm. Conclusions:CTPA showed good diagnostic performance in predicting COPD-associated PH, with MPA diameter being the optimal parameter. [ABSTRACT FROM AUTHOR]

The extracellular isoform of superoxide dismutase (SOD3) is decreased in patients and animals with pulmonary hypertension (PH). The human R213G single-nucleotide polymorphism (SNP) in SOD3 causes its release from tissue extracellular matrix (ECM) into extracellular fluids, without modulating enzyme activity, increasing cardiovascular disease risk in humans and exacerbating chronic hypoxic PH in mice. Given the importance of interstitial macrophages (IMs) to PH pathogenesis, this study aimed to determine whether R213G SOD3 increases IM accumulation and alters IM reprogramming in response to hypoxia. R213G mice and wild-type (WT) controls were exposed to hypobaric hypoxia for 4 or 14 days compared with normoxia. Flow cytometry demonstrated a transient increase in IMs at day 4 in both strains. Contrary to our hypothesis, the R213G SNP did not augment IM accumulation. To determine strain differences in the IM reprogramming response to hypoxia, we performed RNAsequencing on IMs isolated at each timepoint. We found that IMs from R213G mice exposed to hypoxia activated ECM-related pathways and a combination of alternative macrophage and proinflammatory signaling. Furthermore, when compared with WT responses, IMs from R213G mice lacked metabolic remodeling and demonstrated a blunted anti-inflammatory response between the early (day 4) and later (day 14) timepoints. We confirmed metabolic responses using Agilent Seahorse assays, whereby WT, but not R213G, IMs upregulated glycolysis at day 4 that returned to baseline at day 14. Finally, we identify differential regulation of several redox-sensitive upstream regulators that could be investigated in future studies. NEW & NOTEWORTHY: Redistributed expression of SOD3 out of tissue ECM due to the human R213G SNP exacerbates chronic hypoxic PH. Highlighting the importance of macrophage phenotype, our findings reveal that the R213G SNP does not exacerbate pulmonary macrophage accumulation in response to hypoxia but influences their metabolic and phenotypic reprogramming. We demonstrate a deficiency in the metabolic response to hypoxic stress in R213G macrophages, associated with weakened inflammatory resolution and activation of profibrotic pathways implicated in PH. [ABSTRACT FROM AUTHOR]

Among survivors of acute pulmonary embolism (PE), roughly half report persistent dyspnea, impaired functional status, and decreased quality of life. Post-pulmonary embolism syndrome (PPES) is a broad condition which has been increasingly recognized in recent years and may be due to post-pulmonary embolism functional impairment, chronic thromboembolic disease, or the most severe long-term complication of PE, chronic thromboembolic pulmonary hypertension. Despite guideline recommendations for appropriate follow-up for post-pulmonary embolism patients, PPES remains underrecognized and diagnostic testing underutilized. Patients with symptoms suggestive of PPES at follow-up should undergo a transthoracic echocardiogram to screen for the presence of pulmonary hypertension; additional testing, such as a ventilation/perfusion scan, right heart catheterization, and cardiopulmonary exercise testing may be indicated. The pathophysiology of post-pulmonary embolism syndrome is complex and heterogeneous. In chronic thromboembolic pulmonary hypertension, the pathophysiology reflects persistent pulmonary arterial thrombi and a progressive small vessel vasculopathy. In patients with chronic thromboembolic disease or chronic thromboembolic pulmonary hypertension, medical therapy, balloon pulmonary angioplasty, or pulmonary thromboendarterectomy should be considered, and in cases of chronic thromboembolic pulmonary hypertension, pulmonary thromboendarterectomy significantly improves mortality. In all causes of post-pulmonary embolism syndrome, rehabilitation is a safe treatment option that may improve quality of life. [ABSTRACT FROM AUTHOR]

Sotatercept acts as a type IIA-Fc activin receptor, thereby scavenging free activin from its physiological membrane receptor. Through this type of action, sotaterpect leads to a rebalancing of the proliferation and antiproliferation pathways of pulmonary smooth muscle cells in response to bone morphogenic protein (BMP). Although sotatercept has been approved as the fourth pillar of therapy for group 1 pulmonary arterial hypertension (PAH) in the United States and Europe, several studies are ongoing to broaden the application of the drug to non-Group 1 PAH. We provide an overview of the clinical and preclinical evidence of targeting the activation pathway by sotatercept in the treatment of PAH. We also discuss other potential applications of sotatercept in the context of pulmonary hypertension other than PAH group 1. [ABSTRACT FROM AUTHOR]

Background: A reversal of time difference between the onset of early diastolic velocity (e') during tissue Doppler imaging and the onset of mitral inflow (E) has been observed in cases of elevated left atrial pressure. Whether this interval (Te'-E) may be useful to assess right atrial pressure has never been investigated, neither in healthy subjects nor in pulmonary hypertension patients. Methods: Right ventricular Te'-E was assessed in patients with pre-capillary pulmonary hypertension and compared with healthy volunteers who underwent comprehensive echocardiography examination. Te'-E is the difference between the interval from R wave at the superimposed electrocardiogram to the e' wave during right ventricular tissue Doppler imaging and the interval from the R wave to transtricuspid E wave during pulsed wave Doppler imaging. Right atrial pressure was invasively measured in pulmonary hypertension patients. Results: Fifty-six patients were enrolled. Te'-E was prolonged in pulmonary hypertension subjects compared with healthy subjects (p < 0.001). Amongst the pulmonary hypertension patients, strong correlations were found between Te'-E and right atrial pressure (r = −0.885, p < 0.001), systolic pulmonary pressure (r = −0.85, p < 0.001) and the duration of tricuspid regurgitation (r = 0.72, p < 0.001). The area under the receiver operating characteristic curve of Te'-E in identifying right atrial pressure higher than 15 mm of mercury was 0.992 (sensitivity 100%, specificity 83%). Conclusions: In contrast to the left ventricle, there is a delay in the proto-diastolic filling in pulmonary hypertension patients, which correlates with the increase in systolic pulmonary arterial pressure, right atrial pressure, tricuspid regurgitation duration and restrictive diastolic pattern. [ABSTRACT FROM AUTHOR]

Pulmonary hypertension (PH) significantly impairs exercise capacity and the quality of life in patients, which is influenced by dysfunctions in multiple organ systems, including the right ventricle, lungs, and skeletal muscles. Recent research has identified metabolic reprogramming and mitochondrial dysfunction as contributing factors to reduced exercise tolerance in PH patients. In this study, we investigated the therapeutic potential of enhancing mitochondrial function through the activation of the mitochondrial deacetylase SIRT3, using SIRT3 activator Honokiol combined with the SIRT3 co-factor nicotinamide adenine dinucleotide (NAD), in a Sugen/Hypoxia-induced PH rat model. Our results show that Sugen/Hypoxia-induced PH significantly impairs RV, lung, and skeletal muscle function, leading to reduced exercise capacity. Treatment with Honokiol and NAD notably improved exercise endurance, primarily by restoring SIRT3 levels in skeletal muscles, reducing proteolysis and atrophy in the gastrocnemius, and enhancing mitochondrial complex I levels in the soleus. These effects were independent of changes in cardiopulmonary hemodynamics. We concluded that targeting skeletal muscle dysfunction may be a promising approach to improving exercise capacity and overall quality of life in PH patients. [ABSTRACT FROM AUTHOR]

Pulmonary artery endothelial cells (PAECs) are a major contributor to hypoxic pulmonary hypertension (PH) due to the possible roles of reactive oxygen species (ROS). However, the molecular mechanisms and functional roles of ROS in PAECs are not well established. In this study, we first used Amplex UltraRed reagent to assess hydrogen peroxide (H2O2) generation. The result indicated that hypoxic exposure resulted in a significant increase in Amplex UltraRed-derived fluorescence (i.e., H2O2 production) in human PAECs. To complement this result, we employed lucigenin as a probe to detect superoxide (O2−) production. Our assays showed that hypoxia largely increased O2− production. Hypoxia also enhanced H2O2 production in the mitochondria from PAECs. Using the genetically encoded H2O2 sensor HyPer, we further revealed the hypoxic ROS production in PAECs, which was fully blocked by the mitochondrial inhibitor rotenone or myxothiazol. Interestingly, hypoxia caused an increase in the migration of PAECs, determined by scratch wound assay. In contrast, nicotine, a major cigarette or e-cigarette component, had no effect. Moreover, hypoxia and nicotine co-exposure further increased migration. Transfection of lentiviral shRNAs specific for the mitochondrial Rieske iron–sulfur protein (RISP), which knocked down its expression and associated ROS generation, inhibited the hypoxic migration of PAECs. Hypoxia largely increased the proliferation of PAECs, determined using Ki67 staining and direct cell number accounting. Similarly, nicotine caused a large increase in proliferation. Moreover, hypoxia/nicotine co-exposure elicited a further increase in cell proliferation. RISP knockdown inhibited the proliferation of PAECs following hypoxia, nicotine exposure, and hypoxia/nicotine co-exposure. Taken together, our data demonstrate that hypoxia increases RISP-mediated mitochondrial ROS production, migration, and proliferation in human PAECs; nicotine has no effect on migration, increases proliferation, and promotes hypoxic proliferation; the effects of nicotine are largely mediated by RISP-dependent mitochondrial ROS signaling. Conceivably, PAECs may contribute to PH via the RISP-mediated mitochondrial ROS. [ABSTRACT FROM AUTHOR]

Objective: Pulmonary artery hypertension (PAH) is a devastating syndrome. Our previous studies showed that perillyl alcohol (P), berberine (B) and quercetin (Q) improve PAH. In this study, we investigated the effects of sub-effective doses of these derivatives in double and triple combination forms on PAH in rats. Materials and Methods: Forty nine rats were divided into seven groups (n=7): 1) control, 2) monocrotaline (MCT), 3) MCT+vehicle (veh), 4) MCT+BP, 5) MCT+PQ, 6) MCT+BQ, and 7) MCT+BPQ. After three weeks of PAH induction with MCT (60 mg/kg), either vehicle (ethanol 5% in saline) or one of the above combinations (dose of 20 mg/kg for B, and doses of 20 and 10 mg/ kg for P and Q in vehicle) was administered for three weeks. Right ventricular (RV) pressure, contractility indices, lung pathology, miR-204 expression, oxidative stress markers, inflammation and apoptosis were assayed. Results: MCT increased RV systolic pressure and hypertrophy, and lung arteriole wall thickness, fibrosis and leukocyte infiltration in the MCT group compared to the CTL group. All treatments improved these effects significantly. Furthermore, MCT reduced antioxidant factors, Bax, P21 and miR-204 expression and increased Tumor Necrosis Factor alpha (TNF-α), Interleukin 6 (IL-6) and Bcl-2. All of these effects were recovered by combination treatments. Conclusion: The results showed that combination therapy with subeffective/ ineffective doses of these compounds had ameliorative effects against PAH. [ABSTRACT FROM AUTHOR]

Schistosomiasis-induced pulmonary hypertension (PH) presents a significant global health burden, yet the underlying mechanisms remain poorly understood. Here, we investigate the involvement of platelets and the complement system in the initiation events leading to Schistosoma-induced PH. We demonstrate that Schistosoma exposure leads to thrombocytopenia, platelet accumulation in the lung, and platelet activation. In addition, we observed increased plasma complement anaphylatoxins C3a and C5a, indicative of complement system activation, and elevated platelet expression of C1q, C3, decay activating factor (DAF), and complement C3a and C5a receptors. Our findings suggest the active involvement of platelets in responding to complement system signals induced by Schistosoma exposure and form the basis for future mechanistic studies on how complement may regulate platelet activation and promote the development of Schistosoma-induced PH. NEW & NOTEWORTHY: Schistosomiasis-induced pulmonary hypertension (PH) is a significant global health burden, yet the underlying mechanisms remain poorly understood. We demonstrate that Schistosoma exposure leads to platelet accumulation in the lung and platelet activation. We observed increased plasma levels of C3a and C5a, indicative of complement system activation, and elevated expression of platelet complement proteins and receptors. These findings underscore the role of platelets and complement in the inflammatory responses associated with Schistosoma-induced PH. [ABSTRACT FROM AUTHOR]

Unilateral chronic thromboembolism pulmonary disease (CTEPD) is very rare. There is limited information on the safety and efficacy of pulmonary endarterectomy (PEA) in this population. This study investigated the effectiveness of PEA in this unique disease. This multicentre study included patients with unilateral CTEPD from three referral centres in the United States, Turkey, and Iran. The patients' demographic information, 6-minute walk test distance (6MWD), New York Heart Association (NYHA) functional class, and haemodynamics were evaluated. Of the 1,031 patients who had undergone PEA, 39 patients (3.7%) had pure unilateral involvement, of whom 28 were female (71.8%). There was a significant improvement in the mean pulmonary artery pressure (mPAP, 26 mmHg vs 21 mmHg; p=0.011) and pulmonary vascular resistance (PVR, 202 vs 136 dynes∗sec1∗cm-5; p=0.014). There was also a significant improvement in NYHA functional class (p<0.001) and 6MWD (360 vs 409 m; p<0.001). In the nine patients with normal haemodynamic parameters at rest, there was no significant change in median 6MWD (448.5 vs 449 m; p=0.208), mPAP (19 mmHg vs 16.5 mmHg; p=0.397), and PVR (129 vs 84.5 dynes∗sec1∗cm-5; p=0.128). The most common postoperative complication was ipsilateral pleural effusion. One patient needed extracorporeal membrane oxygenation support. No patient died within the 1-year follow up. Pulmonary endarterectomy is a safe and effective procedure for improving the symptoms and haemodynamic parameters of patients with unilateral CTEPH. Symptomatic patients with unilateral chronic thromboembolic disease are suitable for PEA. [ABSTRACT FROM AUTHOR]

This guideline was developed according to the British Society for Rheumatology Guidelines Protocol by a Guideline Development Group comprising healthcare professionals with expertise in SSc and people with lived experience, as well as patient organization representatives. It is an update of the previous 2015 SSc guideline. The recommendations were developed and agreed by the group and are underpinned by published evidence, assessed by systematic literature review and reinforced by collective expert opinion of the group. It considers all aspects of SSc including general management, treatment of organ-based complications, including cardiopulmonary, renal and gastrointestinal tract manifestations, as well as broader impact of disease. Whilst it is focused on adults with SSc we expect that the guideline will be relevant to people of all ages and expert input and review by paediatric rheumatologists and other relevant specialists considered where the guideline was, or may not be, applicable to young people with SSc and juvenile-onset disease. In addition to providing guidance on disease assessment and management the full guideline also considers service organization within the National Health Service and future approaches to audit of the guideline. The lay summary that accompanies this abstract can be found in Supplemental information 1. [ABSTRACT FROM AUTHOR]

Pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension are the main precapillary forms of pulmonary hypertension (PH) summarized as pulmonary vascular diseases (PVD). PVDs are characterized by exertional dyspnoea and oxygen desaturation, and reduced quality of life and survival. Medical therapies improve life expectancy and physical performance of PVD patients, of whom many wish to participate in professional work and recreational activities including traveling to high altitude. The exposure to the hypobaric hypoxic environment of mountain regions incurs the risk of high altitude adverse events (AEHA) due to severe hypoxaemia exacerbating symptoms and further increase in pulmonary artery pressure, which may lead to right heart decompensation. Recent prospective and randomized trials show that altitude‐induced hypoxaemia, pulmonary haemodynamic changes and impairment of exercise performance in PVD patients are in the range found in healthy people. The vast majority of optimally treated stable PVD patients who do not require long‐term oxygen therapy at low altitude can tolerate short‐term exposure to moderate altitudes up to 2500 m. PVD patients that reveal persistent severe resting hypoxaemia (SpO2${{S}_{{\mathrm{p}}{{{\mathrm{O}}}_{\mathrm{2}}}}}$ <80% for >30 min) at 2500 m respond well to supplemental oxygen therapy. Although there are no accurate predictors for AEHA, PVD patients with unfavourable risk profiles at low altitude, such as higher WHO functional class, lower exercise capacity with more pronounced exercise‐induced desaturation and more severely impaired haemodynamics, are at increased risk of AEHA. Therefore, doctors with experience in PVD and high‐altitude medicine should counsel PVD patients before any high‐altitude sojourn. This review aims to summarize recent literature and clinical recommendations about PVD patients travelling to high altitude. [ABSTRACT FROM AUTHOR]

This Symposium Review examines challenges to surviving birth and infancy at high altitudes. Chronic exposure to the environmental hypoxia of high altitudes increases the incidence of maternal vascular disorders of pregnancy characterized by placental insufficiency, restricted fetal growth and preterm delivery, and impairs pulmonary vascular health during infancy. While each condition independently contributes to excess morbidity and mortality in early life, evidence indicates vascular disorders of pregnancy and infantile pulmonary vascular dysfunction are intertwined. By integrating our recent scientific and clinical observations in Bolivia with existing literature, we propose potential avenues to reduce the infant mortality burden at high altitudes and reduce pulmonary vascular disease in highland neonates, and emphasize the need for further research to address unresolved questions. [ABSTRACT FROM AUTHOR]

Exercise hemodynamics are recommended for early detection of pulmonary arterial hypertension (PAH) and have been suggested to be predictive of future development of PAH in high-risk populations such as BMPR2 mutation carriers. However, the optimal exercise hemodynamic screening parameter remains to be determined. Recent data suggest that pulmonary vascular distensibility (α) may serve as a useful parameter for early detection of PAH. What is the value of exercise hemodynamics, including α, for predicting the occurrence of PAH during long-term follow-up in BMPR2 mutation carriers? Fifty-two asymptomatic BMPR2 mutation carriers who underwent symptom-limited exercise hemodynamic assessment were followed up for a median of 10 years. The impact of hemodynamics at rest and exercise, presence of exercise pulmonary hypertension, and α on occurrence of PAH during long-term follow-up were assessed. During long-term follow-up, five patients developed PAH. Patients who developed PAH showed a significantly lower α (0.8 ± 0.4%/mm Hg) than patients without PAH (1.8 ± 0.8%/mm Hg; P =.008). The only hemodynamic parameter that predicted the occurrence of PAH during long-term follow-up at regression analysis was α. Receiver operating characteristic analysis showed that α ≤ 1.5%/mm Hg predicted PAH occurrence with a specificity of 75% and sensitivity of 100%. The results of this study indicate that before development of PAH in BMPR2 mutation carriers, α is reduced markedly and may serve as a useful parameter in the setting of early disease detection. Given the low event rate, caution is warranted in interpreting these results, highlighting the need for validation studies. [ABSTRACT FROM AUTHOR]

According to the most recent pulmonary hypertension (PH) guidelines, a main pulmonary artery (MPA) diameter > 25 mm on transthoracic echocardiography supports the diagnosis of PH. However, the size of the pulmonary artery (PA) may vary according to body size, age, and cardiac phases. (1) What are the reference limits for PA size on transthoracic echocardiography, considering differences in body size, sex, and age? (2) What is the diagnostic value of the PA size for classifying PH? (3) How does the selection of different reference groups (healthy volunteers vs patients referred for right heart catheterization [RHC]) influence the diagnostic OR (DOR)? The study included a reference cohort of 248 healthy individuals as control patients, 693 patients with PH proven by RHC, and 156 patients without PH proven by RHC. In the PH cohort, 300 had group 1 PH, 207 had group 2 PH, and 186 had group 3 PH. MPA and right PA diameters and areas were measured in the upper sternal short-axis and suprasternal notch views. Reference limits (5th-95th percentile) were based on absolute values and height-indexed measures. Quantile regression analysis was used to derive median and 95th quantile reference equations for the PA measures. DORs and probability diagnostic plots for PH were then determined using healthy control and non-PH cohorts. The 95th percentile for indexed MPA diameter was 15 mm/m in diastole and 19 mm/m in systole in both sexes. Quantile regression analysis revealed a weak age effect (pseudo- R 2 of 0.08-0.10 for MPA diameters). Among measures, the MPA size in diastole had the highest DOR (156.2; 95% CI, 68.3-357.5) for detection of group 1 PH. Similarly, the DORs were also high for groups 2 and 3 PH when compared with the control cohort but significantly lower compared with the non-PH cohort. This study presents novel reference limits for MPA based on height indexing and quantile regression. [ABSTRACT FROM AUTHOR]

Little research is available to provide practical guidance to health care providers for exercise preparticipation screening and referral of patients with interstitial lung diseases (ILDs), including lymphangioleiomyomatosis (LAM), to participate in remote, unsupervised exercise programs. What exercise preparticipation screening steps are essential to determine whether a patient with LAM is medically appropriate to participate in a remote, unsupervised exercise program? Sixteen experts in LAM and ILD participated in a two-round modified Delphi study, ranking their level of agreement for 10 statements related to unsupervised exercise training in LAM, with an a priori definition of consensus. Additionally, 60 patients with LAM completed a survey of the perceived risks and benefits of remote exercise training in LAM. Seven of the 10 statements reached consensus among experts. Experts agreed that an in-person clinical exercise test is indicated to screen for exercise-induced hypoxemia and prescribe supplemental oxygen therapy as indicated prior to initiating a remote exercise program. Patients with recent pneumothorax should wait to start an exercise program for at least 4 weeks until after resolution of pneumothorax and clearance by a physician. Patients with high cardiovascular risk for event during exercise, severe resting pulmonary hypertension, or risk for falls may be more appropriate for referral to a rehabilitation center. A LAM-specific remote exercise preparticipation screening tool was developed from the consensus statements and agreed upon by the panelists. A modified Delphi study approach was useful to develop disease-specific recommendations for safety and preparticipation screening prior to unsupervised, remotely administered exercise in LAM. The primary product of this study is a clinical decision aid for providers to use when medically screening patients prior to participation in the newly launched LAM Fit remote exercise program. [ABSTRACT FROM AUTHOR]

• Among all PH, PH-LHD is the least treated with drugs on the pulmonary circulation. • Management of PH-LHD with pulmonary vasodilators requires randomized trials. • Perform an adequate diagnostic work-out to differentiate group 1 PAH from PH-LHD. • Optimize the management of the underlying LHD. • Treat comorbidities and do not treat patients with heart failure as PAH patients. Pulmonary hypertension associated to left heart disease (PH-LHD) refers to a clinical and haemodynamic condition of pulmonary hypertension associated with a heterogeneous group of diseases affecting any of the compartments that form the left ventricle and left atrium. PH-LHD is the most common cause of PH, accounting for 65–80 % of diagnoses. Based on the haemodynamic phase of the disease, PH-LDH is classified into three subgroups: postcapillary PH, isolated postcapillary PH and combined pre-postcapillary PH (CpcPH). Several signaling pathways involved in the regulation of vascular tone are dysfunctional in PH-LHD, including nitric oxide, MAP kinase and endothelin-1 pathways. These pathways are the same as those altered in PH group 1, however PH-LHD can heardly be treated by specific drugs that act on the pulmonary circulation. In this manuscript we provide a state of the art of the available clinical trials investigating the safety and efficacy of PAH-specific drugs, as well as drugs active in patients with heart failure and PH-LHD. We also discuss the different phenotypes of PH-LHD, as well as molecular targets and signaling pathways potentially involved in the pathophysiology of the disease. Finally we will mention some new emerging therapies that can be used to treat this form of PH. [ABSTRACT FROM AUTHOR]

Background: Assessment of the pattern of the RV outflow tract Doppler provides insights into the hemodynamics of chronic thromboembolic pulmonary hypertension (CTEPH). We studied whether pre-operative assessment of timing of the pulmonary flow systolic notch by Doppler echocardiography is associated with long-term survival after pulmonary endarterectomy (PEA) for CTEPH. Methods: Fifty-nine out of 61 consecutive CETPH patients (mean age 53 ± 14 years, 34% male) whom underwent PEA between June 2002 and June 2005 were studied. Clinical, echocardiographic and hemodynamic variables were assessed pre-operatively and repeat echocardiography was performed 3 months after PEA. Notch ratio (NR) was assessed with pulsed Doppler and calculated as the time from onset of pulmonary flow until notch divided by the time from notch until end of pulmonary flow. Long-term follow-up was obtained between May 2021 and February 2022. Results: Pre-operative mean pulmonary artery pressure (mPAP) was 45 ± 15 mmHg and pulmonary vascular resistance (PVR) was 646 ± 454 dynes.s.cm-5. Echocardiography before PEA showed that 7 patients had no notch, 33 had a NR < 1.0 and 19 had a NR > 1.0. Three months after PEA, echocardiography revealed a significant decrease in sPAP in long-term survivors with a NR < 1.0 and a NR > 1.0, while a significant increase in TAPSE/sPAP was only observed in the NR < 1.0 group. Mean long-term clinical follow-up was 14 ± 6 years. NR was significantly different between survivors and non-survivors (0.73 ± 0.25 vs. 1.1 ± 0.44, p < 0.001) but no significant differences were observed in mPAP or PVR. Long-term survival at 14 years was significantly better in patients with a NR < 1.0 compared to patients with a NR > 1.0 (83% vs. 37%, p = < 0.001). Conclusion: Pre-operative assessment of NR is a predictor of long-term survival in CTEPH patients undergoing PEA, with low mortality risk in patients with NR < 1.0. Long-term survivors with a NR < 1.0 and NR > 1.0 had a significant decrease in sPAP after PEA. However, the TAPSE/sPAP only significantly increased in the NR < 1.0 group. In the NR < 1.0 group, the 6-min walk test increased significantly between pre-operative and at 1-year post-operative follow-up. NR is a simple echocardiographic parameter that can be used in clinical decision-making for PEA. [ABSTRACT FROM AUTHOR]

Previously, we have shown that endothelial nitric-oxide synthase (eNOS) dimer levels directly correlate with the interaction of eNOS with hsp90 (heat shock protein 90). Further, the disruption of eNOS dimerization correlates with its redistribution to the mitochondria. However, the causal link between these events has yet to be investigated and was the focus of this study. Our data demonstrates that simvastatin, which decreases the mitochondrial redistribution of eNOS, increased eNOS-hsp90 interactions and enhanced eNOS dimerization in cultured pulmonary arterial endothelial cells (PAEC) from a lamb model of pulmonary hypertension (PH). Our data also show that the dimerization of a monomeric fraction of human recombinant eNOS was stimulated in the presence of hsp90 and ATP. The over-expression of a dominant negative mutant of hsp90 (DNHsp90) decreased eNOS dimer levels and enhanced its mitochondrial redistribution. We also found that the peroxynitrite donor3-morpholinosydnonimine (SIN-1) increased the mitochondrial redistribution of eNOS in PAEC and this was again associated with decreased eNOS dimer levels. Our data also show in COS-7 cells, the SIN-1 mediated mitochondrial redistribution of wildtype eNOS (WT-eNOS) is significantly higher than a dimer stable eNOS mutant protein (C94R/C99R-eNOS). Conversely, the mitochondrial redistribution of a monomeric eNOS mutant protein (C96A-eNOS) was enhanced. Finally, we linked the SIN-1-mediated mitochondrial redistribution of eNOS to the Akt1-mediated phosphorylation of eNOS at Serine(S)617 and showed that the accessibility of this residue to phosphorylation is regulated by dimerization status. Thus, our data reveal a novel mechanism of pulmonary endothelial dysfunction mediated by mitochondrial redistribution of eNOS, regulated by dimerization status and the phosphorylation of S617. [Display omitted] • Stain treatment increases eNOS-hsp90 interactions in PH. • Hsp90 is necessary for eNOS dimerization. • Dimer status is important for eNOS phosphorylation at Ser617. • Ser617 phosphorylation is needed for the mitochondrial redistribution of eNOS. • The mitochondrial redistribution of monomeric eNOS induces mitochondrial dysfunction. [ABSTRACT FROM AUTHOR]

The discovery of soluble GC (sGC) stimulators and sGC activators provided valuable tools to elucidate NO–sGC signalling and opened novel pharmacological opportunities for cardiovascular indications and beyond. The first‐in‐class sGC stimulator riociguat was approved for pulmonary hypertension in 2013 and vericiguat very recently for heart failure. sGC stimulators enhance sGC activity independent of NO and also act synergistically with endogenous NO. The sGC activators specifically bind to, and activate, the oxidised haem‐free form of sGC. Substantial research efforts improved on the first‐generation sGC activators such as cinaciguat, culminating in the discovery of runcaciguat, currently in clinical Phase II trials for chronic kidney disease and diabetic retinopathy. Here, we highlight the discovery and development of sGC stimulators and sGC activators, their unique modes of action, their preclinical characteristics and the clinical studies. In the future, we expect to see more sGC agonists in new indications, reflecting their unique therapeutic potential. [ABSTRACT FROM AUTHOR]

BACKGROUND: Beneficial effects of breathing at FIO2 < 0.21 on disease outcomes have been reported in previous preclinical and clinical studies. However, the safety and intra-hospital feasibility of breathing hypoxic gas for 5 d have not been established. In this study, we examined the physiologic effects of breathing a gas mixture with FIO2 as low as 0.11 in 5 healthy volunteers. METHODS: All 5 subjects completed the study, spending 5 consecutive days in a hypoxic tent, where the ambient oxygen level was lowered in a stepwise manner over 5 d, from FIO2 of 0.16 on the first day to FIO2 of 0.11 on the fifth day of the study. All the subjects returned to an environment at room air on the sixth day. The subjects' SpO2, heart rate, and breathing frequency were continuously recorded, along with daily blood sampling, neurologic evaluations, transthoracic echocardiography, and mental status assessments. RESULTS: Breathing hypoxia concentration dependently caused profound physiologic changes, including decreased SpO2 and increased heart rate. At FIO2 of 0.14, the mean SpO2 was 92%; at FIO2 of 0.13, the mean SpO2 was 93%; at FIO2 of 0.12, the mean SpO2 was 88%; at FIO2 of 0.11, the mean SpO2 was 85%; and, finally, at an FIO2 of 0.21, the mean SpO2 was 98%. These changes were accompanied by increased erythropoietin levels and reticulocyte counts in blood. All 5 subjects concluded the study with no adverse events. No subjects exhibited signs of mental status changes or pulmonary hypertension. CONCLUSIONS: Results of the current physiologic study suggests that, within a hospital setting, delivering FIO2 as low as 0.11 is feasible and safe in healthy subjects, and provides the foundation for future studies in which therapeutic effects of hypoxia breathing are tested. [ABSTRACT FROM AUTHOR]

• Progressive exercise intolerance is a hallmark in pulmonary hypertension (pH.) • Pre-clinical and clinical studies published in the last 10 years strengthens the integrated nature of the pH physiopathology via functional and structural changes in the peripheral reflexes (such as peripheral chemoreflex and baroreflex) and in the respiratory, cardiovascular and musculoskeletal systems. • These findings shed light into future therapeutic targets that can assist in improving exercise tolerance and quality of life in patients with pH. Background: Progressive exercise intolerance is a hallmark of pulmonary hypertension (pH), severely impacting patients' independence and quality of life (QoL). Accumulating evidence over the last decade shows that combined abnormalities in peripheral reflexes and target organs contribute to disease progression and exercise intolerance. Objective: The aim of this study was to review the literature of the last decade on the contribution of the cardiovascular, respiratory, and musculoskeletal systems to pathophysiology and exercise intolerance in pH. Methods: A systematic literature search was conducted using specific terms in PubMed, SciELO, and the Cochrane Library databases for original pre-clinical or clinical studies published between 2013 and 2023. Studies followed randomized controlled/non-randomized controlled and pre-post designs. Results: The systematic review identified 25 articles reporting functional or structural changes in the respiratory, cardiovascular, and musculoskeletal systems in pH. Moreover, altered biomarkers in these systems, lower cardiac baroreflex, and heightened peripheral chemoreflex activity seemed to contribute to functional changes associated with poor prognosis and exercise intolerance in pH. Potential therapeutic strategies acutely explored involved manipulating the baroreflex and peripheral chemoreflex, improving cardiovascular autonomic control via cardiac vagal control, and targeting specific pathways such as GPER1, GDF-15, miR-126, and the JMJD1C gene. Conclusion: Information published in the last 10 years advances the notion that pH pathophysiology involves functional and structural changes in the respiratory, cardiovascular, and musculoskeletal systems and their integration with peripheral reflexes. These findings suggest potential therapeutic targets, yet unexplored in clinical trials, that could assist in improving exercise tolerance and QoL in patients with pH. [Display omitted] [ABSTRACT FROM AUTHOR]

This article reviews and discusses non-myocardial disorders that represent diagnostic challenges when evaluating patients for suspected heart failure with preserved left ventricular ejection fraction. This includes pre-capillary pulmonary hypertension, which is important to differentiate from post-capillary hypertension caused by left-sided heart disease. The impact of electrical disorders on LV diastolic function is also reviewed, and includes a discussion of left bundle branch, which has both a direct effect on LV diastolic function, as well as a long-term effect due to remodelling. Furthermore, evaluation of diastolic function in patients with atrial fibrillation is discussed. Pericardial diseases are reviewed as well as effects of a normal pericardium on diastolic function in failing hearts. Finally, the article reviews how valvular diseases impact LV diastolic function. [ABSTRACT FROM AUTHOR]

Phase‐resolved functional lung (PREFUL) MRI is a proton‐based, contrast agent‐free technique derived from the Fourier decomposition approach to measure regional ventilation and perfusion dynamics during free‐breathing. Besides the necessity of extensive PREFUL postprocessing, the utilized MRI sequence must fulfill specific requirements. This study investigates the impact of sequence selection on PREFUL‐MRI–derived functional parameters by comparing the standard spoiled gradient echo (SPGRE) sequence with a lung‐optimized balanced steady‐state free precession (bSSFP) sequence, thereby facilitating PREFULs clinical application in pulmonary disease assessment. This study comprised a prospective dataset of healthy volunteers and a retrospective dataset of patients with suspected chronic thromboembolic pulmonary hypertension. Both cohorts underwent PREFUL‐MRI with both sequences to assess the correspondence of PREFUL ventilation and perfusion parameters (A). Additionally, healthy subjects were scanned a second time to evaluate repeatability (B), whereas patients received dynamic contrast‐enhanced (DCE)‐MRI, considered the perfusion gold standard for comparison with PREFUL‐MRI (C). Signal‐to‐noise ratio (SNR), calculated from the unprocessed images, was compared alongside median differences of PREFUL‐MRI–derived parameters using a paired Wilcoxon signed rank test. Further evaluations included calculation of the Pearson correlation, intraclass‐correlation coefficient for repeatability assessment, and spatial overlap (SO) for regional comparison of PREFUL‐MRI and DCE‐MRI. bSSFP showed a clear SNR advantage over SPGRE (median: 23 vs. 9, p < 0.001). (A) Despite significant differences, parameter values were strongly correlated (r ≥ 0.75). After thresholding, binary maps showed high healthy overlap across both cohorts (SOHealthy > 86%) and high defect overlap in the patient cohort (SODefect ≥ 48%). (B) bSSFP demonstrated slightly higher repeatability across most parameters. (C) Both sequences demonstrated comparable correspondence to DCE‐MRI, with SPGRE excelling in absolute quantification and bSSFP in spatial agreement. Although bSSFP showed superior SNR results, both sequences displayed spatial defect concordance and highly correlated PREFUL parameters with deviations regarding repeatability and alignment with DCE‐MRI. [ABSTRACT FROM AUTHOR]

This article reviews the clinical signs, different causes, and approach to the clinical diagnosis of, and current therapies for, pulmonary hypertension in dogs. Echocardiography is the most commonly used test to diagnose pulmonary hypertension in dogs, although it may not be accessible for all patients. In its absence, other diagnostics can be performed in general practice to increase the index of suspicion. Successful management of pulmonary hypertension requires identification of the underlying cause and implementation of specific, targeted treatment. [ABSTRACT FROM AUTHOR]

Rationale: Quantitative interstitial abnormalities (QIAs) are a computed tomography (CT) measure of early parenchymal lung disease associated with worse clinical outcomes, including exercise capacity and symptoms. The presence of pulmonary vasculopathy in QIAs and its role in the QIA–outcome relationship is unknown. Objectives: To quantify radiographic pulmonary vasculopathy in QIAs and determine whether this vasculopathy mediates the QIA–outcome relationship. Methods: Ever-smokers with QIAs, outcomes, and pulmonary vascular mediator data were identified from the Genetic Epidemiology of COPD (COPDGene) study cohort. CT-based vascular mediators were right ventricle–to–left ventricle ratio, pulmonary artery–to–aorta ratio, and preacinar intraparenchymal arterial dilation (pulmonary artery volume, 5–20 mm2 in cross-sectional area, normalized to total arterial volume). Outcomes were 6-minute walk distance and a modified Medical Council Research Council Dyspnea Scale score of 2 or higher. Adjusted causal mediation analyses were used to determine whether the pulmonary vasculature mediated the QIA effect on outcomes. Associations of preacinar arterial dilation with select plasma biomarkers of pulmonary vascular dysfunction were examined. Measurements and Main Results: Among 8,200 participants, QIA burden correlated positively with vascular damage measures, including preacinar arterial dilation. Preacinar arterial dilation mediated 79.6% of the detrimental impact of QIA on 6-minute walk distance (56.2–100%; P < 0.001). Pulmonary artery–to–aorta ratio was a weak mediator, and right ventricle–to–left ventricle ratio was a suppressor. Similar results were observed in the relationship between QIA and modified Medical Council Research Council dyspnea score. Preacinar arterial dilation correlated with increased pulmonary vascular dysfunction biomarker levels, including angiopoietin-2 and N-terminal brain natriuretic peptide. Conclusions: Parenchymal QIAs deleteriously impact outcomes primarily through pulmonary vasculopathy. Preacinar arterial dilation may be a novel marker of pulmonary vasculopathy in QIAs. [ABSTRACT FROM AUTHOR]

Rationale: Inhibition of aromatase with anastrozole reduces pulmonary hypertension in experimental models. Objectives: We aimed to determine whether anastrozole improved the 6-minute-walk distance (6MWD) at 6 months in pulmonary arterial hypertension (PAH). Methods: We performed a randomized, double-blind, placebo-controlled phase II clinical trial of anastrozole in subjects with PAH at seven centers. Eighty-four postmenopausal women with PAH and men with PAH were randomized in a 1:1 ratio to receive anastrozole 1 mg or placebo by mouth daily, stratified by sex using permuted blocks of variable sizes. All subjects and study staff were masked. The primary outcome was the change from baseline in 6MWD at 6 months. By intention-to-treat analysis, we estimated the treatment effect of anastrozole using linear regression models adjusted for sex and baseline 6MWD. Assuming 10% loss to follow-up, we anticipated having 80% power to detect a difference in the change in 6MWD of 22 meters. Measurements and Main Results: Forty-one subjects were randomized to placebo and 43 to anastrozole, and all received the allocated treatment. Three subjects in the placebo group and two in the anastrozole group discontinued the study drug. There was no significant difference in the change in 6MWD at 6 months (placebo-corrected treatment effect, −7.9 m; 95% confidence interval, −32.7 to 16.9; P = 0.53). There was no difference in adverse events between the groups. Conclusions: Anastrozole did not show a significant effect on 6MWD compared with placebo in postmenopausal women with PAH and in men with PAH. Anastrozole was safe and did not have adverse effects. Clinical trial registered with (NCT03229499). [ABSTRACT FROM AUTHOR]

Lung involvement in children with congenital cytomegalovirus infection has been scarcely described. We describe three new cases of persistent pulmonary hypertension in children with congenital cytomegalovirus and review the other seven cases reported in the literature since 1988. All children had a symptomatic infection, including severe central nervous system or visceral findings. Morbidity and mortality were high. Persistent pulmonary hypertension may be a rare complication in severely symptomatic congenital cytomegalovirus infants. It is important to screen for congenital cytomegalovirus in cases of idiopathic refractory persistent pulmonary hypertension. Intensive treatment should be undertaken to treat this potentially rare lung involvement in combination with antiviral treatment. [ABSTRACT FROM AUTHOR]

Background: Cardiac tamponade (CT) has an atypical presentation in patients with underlying pulmonary hypertension (PH). Evidence regarding the impact of PH on CT in-hospital outcomes is lacking. Methods: We used the National Inpatient Sample database to identify adult hospitalizations with a diagnosis of CT between 2016 and 2020, using relevant ICD-10 diagnostic codes. Baseline characteristics and in-hospital outcomes were compared in patients with and without a PH. Multivariate logistic regression analyses and case-control matching were performed, adjusting for age, race, gender, and statistically significant co-morbidities between cohorts. Results: A total of 110,285 inpatients with CT were included, of which 8,670 had PH. Patients with PH tended to be older (66 ± 15.7) and female (52.5%), had significantly higher rates of hypertension (74% vs 65%), CAD (36.9% vs. 29.6%), CKD (39% vs 23%), DM (32.1%, vs. 26.9%), chronic heart failure (19.0% vs 9.7%) and COPD (26% vs 18%)(P<0.001 for all). After multivariate logistic regression, PH was associated with higher all-cause mortality (aOR 1.29; 95% CI: 1.11–1.49), higher rates of cardiogenic shock (aOR: 1.19; 95% CI: 1.01–1.41), ventricular arrythmias (aOR: 1.63; 95% CI: 1.33–2.01), longer length of stay (11 days vs 15 days), and higher total hospitalization costs ($228,314 vs $327,429) in patients presenting with CT. Despite pericardiocentesis being associated with lower in-hospital mortality, patients with PH were less likely to undergo pericardiocentesis (aOR: 0.77; 95% CI: 0.69–0.86). Conclusion: PH was associated to increased in-hospital mortality and a higher rate of cardiovascular complications in an inpatient population with CT. Pericardiocentesis was associated with reduced mortality in patients with CT, regardless of whether they had PH. However, patients with PH underwent pericardiocentesis less frequently than those without PH. [ABSTRACT FROM AUTHOR]

Pulmonary hypertension is a progressive disease of the pulmonary arteries that begins with increased pulmonary artery pressure, driven by progressive remodeling of the small pulmonary arteries, and ultimately leads to right heart failure and death. Vascular remodeling is the main pathological feature of pulmonary hypertension, but treatments for pulmonary hypertension are lacking. Determining the process of vascular proliferation and dysfunction may be a way to decipher the pathogenesis of pulmonary hypertension. In this review, we summarize the important pathways of pulmonary hypertension pathogenesis. We show how these processes are integrated and emphasize the benign role of aerobic exercise, which, as an adjunctive therapy, may be able to modify vascular remodeling in pulmonary hypertension. [ABSTRACT FROM AUTHOR]

Background: Chronic obstructive pulmonary disease (COPD) has become one of the major death-related causes. Chronic pulmonary heart disease (CPHD) is an adverse complication of COPD causing poor prognosis of patients. This study evaluated the role of lncRNA XIST in COPD and CPHD aiming to identify a potential biomarker for the screening and prediction of COPD. Methods: The study enrolled 127 COPD patients, including 73 patients occurred CPHD with 76 healthy individuals as the control group. The expression of XIST was evaluated by PCR and compared between COPD patients with different severity, grades, and complications. The diagnostic and prognostic values of XIST in COPD and CPHD were assessed by ROC and Kaplan-Meier analyses. Results: Significant upregulation of XIST was observed in the serum of COPD patients relative to healthy individuals, which distinguished COPD patients and showed a correlation with the respiratory and pulmonary function of COPD patients. COPD patients with acute exacerbations and CPHD showed a higher expression level. Increasing serum XIST discriminated COPD patients combined CPHD and positively correlated with right ventricular hypertrophy and pulmonary hypertension. Higher serum XIST levels could indicate the adverse 3-year prognosis of COPD patients, especially for COPD patients combined with CPHD. Conclusion: Upregulated XIST served as a biomarker for screening COPD and predicting adverse prognosis of COPD and COPD patients with CPHD. [ABSTRACT FROM AUTHOR]