Utility of serum uric acid levels in excluding pulmonary hypertension in severe chronic lung disease: insights from a tertiary care center.

Hyperuricemia is a known predictor of World Health Organization (WHO) Group 1 pulmonary hypertension (PH) (pulmonary arterial hypertension), but its role in excluding PH secondary to chronic lung diseases (WHO Group 3) remains unclear. We retrospectively analyzed data from 323 patients with severe chronic pulmonary diseases who underwent evaluation for lung transplantation at a tertiary medical center between June 2017 and February 2023. We examined the association between hyperuricemia (serum uric acid > 6 mg/dL or > 0.357 mmol/L) and PH [mean pulmonary arterial pressure (MPAP) > 20 mmHg]. Compared to the normouricemia group (n = 211), hyperuricemic patients (n = 112) were more likely to be younger (P = 0.02), male (P < 0.001), and present with PH (P = 0.001) and severe PH (MPAP > 35 mmHg; P < 0.001). These patients also had a higher body mass index (P = 0.004), plasma N-terminal pro-B-type natriuretic peptide (P < 0.001), serum creatinine (P < 0.001), and C-reactive protein levels (P = 0.03). Significant associations with PH included higher body mass index (P = 0.005), uric acid levels (P < 0.001), total lung capacity (P = 0.02), and residual volume (P = 0.01); shorter 6-min walk test distance (P = 0.005); and lower forced expiratory volume in one second (P = 0.006) and diffusing capacity for carbon monoxide (P < 0.001). Multivariate analysis showed elevated uric acid levels remained significantly associated with PH (OR 1.29, 95% CI 1.05-1.58, P = 0.01). In conclusion, normal serum uric acid levels serve as a significant predictor for excluding pulmonary hypertension in patients with severe chronic lung diseases.

Predictive accuracy of the ASIG algorithm in a prospective systemic sclerosis cohort undergoing annual screening for pulmonary arterial hypertension.

The Australian Scleroderma Interest Group (ASIG) algorithm for screening pulmonary arterial hypertension (PAH) in systemic sclerosis (SSc) requires only respiratory function tests and serum N-terminal pro-brain natriuretic peptide as first-tier tests, and is recommended in international guidelines. In this communication, we present the findings of the application of the ASIG screening algorithm to a Singaporean cohort undergoing prospective annual screening for PAH, which shows a high negative predictive value. The ASIG algorithm may offer an alternative to more complex and costly SSc-PAH screening algorithms.

Circulating High Mobility Group Box-1 Does Not Predict Pulmonary Arterial Hypertension in Children with Congenital Heart Disease: A Prospective Cohort Study.

OBJECTIVES: Pulmonary arterial hypertension (PAH) is a devastating complication of pediatric congenital heart disease (CHD). A recent study has identified the protein high mobility group box-1 (HMGB1) as a diagnostic tool in adults with CHD-associated PAH. HMGB1 levels in adults with CHD-associated PAH correlated with mean pulmonary artery pressure and pulmonary vascular resistance, and HGMB1 levels fell in response to sildenafil therapy. We wanted to assess if HGMB1 was a biomarker of pediatric CHD-PAH. DESIGN: Prospective cohort study. SETTING: Quaternary pediatric academic hospital PARTICIPANTS: Children ≤18 years with CHD with and without known pulmonary hypertension. Controls were children undergoing dental or urologic surgery with no known heart disease. INTERVENTIONS: Pulmonary hemodynamics, echocardiographic assessment, and biomarker measurement. Controls had biomarker measurement only. MEASUREMENTS AND MAIN RESULTS: Patients with CHD-PAH had mean pulmonary vascular resistance index of 10 Wood units/m2. Neither HGMB1 nor N-terminal pro-brain-type natriuretic peptide levels were significantly different between the groups. Neither marker correlated with pulmonary hypertension. CONCLUSIONS: Unlike in adults, HGMB1 is not a biomarker of PAH in pediatric CHD. Further work will continue to explore for biomarkers for this high-risk population.

Decreased plasma docosahexaenoic acid concentration in chronic obstructive pulmonary disease patients with pulmonary Hypertension: Findings from human lipidomics and transcriptomics analysis.

Oxylipins derived from polyunsaturated fatty acids (PUFAs) are important endogenous signaling molecules, but are little characterized in pulmonary hypertension (PH) due to chronic obstructive pulmonary disease (COPD). In this study, we identified novel plasma oxylipins associated with PH risk in COPD patients. The plasma oxylipin profiles of COPD patients without PH (COPD-noPH) or with PH (COPD-PH) were obtained from discovery and validation cohort, using the process of LC-MS/MS analysis. There was a significant decrease in the plasma levels of both free docosahexaenoic acid (DHA) and DHA-derived oxylipins in the COPD-PH group. The multivariable logistic regression model identified DHA and four DHA-derived oxylipins (13-HDHA, 10-HDHA, 8-HDHA and 16-HDHA) exhibited significant differences between the two groups after adjusting for sex, BMI, FEV1% predicted, and smoking status. The diagnostic value of these metabolites was further evaluated through ROC curve analysis. The transcriptome profiles in peripheral blood mononuclear cells (PBMCs) of COPD-PH patients and COPD-PH patients were detected through high-throughput sequencing. The enrichment analysis revealed that the upregulated differentially expressed genes (DEGs) were highly enriched in the interferon signaling pathway. In addition, DHA supplementation proved that DHA may inhibit the development of pH by reducing the secretion of interferons derived from PBMCs. This conjecture was further confirmed by the higher level of serum interferon-γ and interferon-α2 of COPD-PH patients than that of COPD-noPH patients. The present study highlights that decreased DHA and DHA-derived oxylipins levels are suggestive of a higher risk of pH development in COPD cases.

New Incremental Model for Predicting Mortality in Pre-Capillary Pulmonary Hypertension. / Novo Modelo Incremental para Predição de Mortalidade na Hipertensão Pulmonar Pré-Capilar.

BACKGROUND: In pulmonary hypertension (PH), the identification of easily obtainable prognostic markers associated with right ventricular (RV) dysfunction and survival is needed. OBJECTIVE: To evaluate the association of red cell distribution width (RDW) with clinical, echocardiographic parameters and survival in patients with pre-capillary PH, with the development of a mortality prediction model. METHODS: Observational, longitudinal, and prospective study conducted from May 2019 to December 2022. Thirty-four patients with pre-capillary PH underwent two-dimensional echocardiography and complete blood count. A cutoff point of 14.5% was considered to define RDW as altered (≥14.5%) or normal (<14.5%). P values <0.05 were considered significant. RESULTS: The median RDW was 14.4%. There was a significant difference in peripheral arterial oxygen saturation (SpO2) (p=0.028), RV strain (p=0.047), and pericardial effusion (p=0.002) between the normal and elevated RDW groups. During a median follow-up of 15 months, 20.6% died. Patients with increased RDW had a shorter overall survival (44.7%, log-rank p=0.019), which was a predictor of mortality in univariate Cox regression (HR 8.55, p=0.048). The addition of RV strain <16% and SpO2 ≤93% to the model including RDW alone showed incremental value in predicting mortality (χ2=8.2, p=0.049; χ2=12.4, p=0.041), with increased area under the receiver operating characteristic curve (0.729 vs. 0.837 vs. 0.909) and decreased probability of survival (44.7% vs. 35.6% vs. 25%, log-rank p=0.019). CONCLUSIONS: RDW provides information on the severity of pre-capillary PH by correlating with echocardiographic parameters of RV dysfunction and mortality, which is best predicted by a model including RDW, RV strain and SpO2.

FUNDAMENTO: Na hipertensão pulmonar (HP), é necessária a identificação de marcadores prognósticos de fácil obtenção associados com disfunção do ventrículo direito (VD) e sobrevida. OBJETIVO: Avaliar a associação do índice de anisocitose eritrocitária (RDW, do inglês red cell distribution width) com parâmetros ecocardiográficos e sobrevida em pacientes com HP pré-capilar, com o desenvolvimento de um modelo de predição de mortalidade. MÉTODOS: Estudo observacional, longitudinal, prospectivo, conduzido entre maio de 2019 e dezembro de 2022. Trinta e quatro pacientes com HP pré-capilar submeteram-se à realização de ecocardiograma bidimensional e hemograma. Um ponto de corte de 14,5% foi adotado para definir o RDW como alterado (≥14,5%) ou normal (<14,5%). Valores de p<0,05 foram considerados significativos. RESULTADOS: O RDW médio foi 14,4%. Houve uma diferença significativa na saturação periférica de oxigênio (SpO2) (p=0,028), strain do VD (p=0,047) e derrame pericárdico (p=0,002) entre os grupos com RDW normal e elevado. Durante um período mediano de 15 meses, 20,6% dos pacientes foram a óbito. Os pacientes com RDW aumentado tiveram uma sobrevida global mais curta (44,7%, log-rank p=0,019), sendo um preditor de mortalidade na regressão univariada de Cox. A adição do strain do VD < 16% e da SpO2 ≤93% ao modelo incluindo somente RDW mostrou valor incremental na predição de mortalidade (χ2=8,2, p=0,049; χ2=12,4, p=0,041), com área sob a curva ROC (do inglês, Receiver Operating Characteristic) aumentada (0,729 vs. 0,837 vs. 0,909) e probabilidade de sobrevida diminuída (44.7% vs. 35.6% vs. 25%, log-rank p=0,019). CONCLUSÕES: O RDW fornece informações sobre a gravidade da HP pré-capilar pela sua correlação com parâmetros ecocardiográficos de disfunção do VD e mortalidade, a qual é melhor predita por um modelo incluindo RDW, strain do VD e SpO2.

Insulin-like Growth Factor-Binding Protein 2 in Severe Aortic Valve Stenosis and Pulmonary Hypertension: A Gender-Based Perspective.

Severe aortic valve stenosis (AS) and pulmonary hypertension (PH) are life-threatening cardiovascular conditions, necessitating early detection and intervention. Recent studies have explored the role of Insulin-like Growth Factor-Binding Protein 2 (IGF-BP2) in cardiovascular pathophysiology. Understanding its involvement may offer novel insights into disease mechanisms and therapeutic targets for these conditions. A total of 102 patients (46 female, 56 male) with severe AS undergoing a transcatheter aortic valve replacement (TAVR) in a single-center study were classified using echocardiography tests to determine systolic pulmonary artery pressure (sPAP) and the presence (sPAP ≥ 40 mmHg) or absence (sPAP < 40 mmHg) of PH. Additionally, serial laboratory determinations of IGF-BP2 before, and at 24 h, 96 h, and 3 months after intervention were conducted in all study participants. Considering the entire cohort, patients with PH had significant and continuously higher serum IGF-BP2 concentrations over time than patients without PH. After subdivision by sex, it could be demonstrated that the above-mentioned results were only verifiable in males, but not in females. In the male patients, baseline IGF-BP2 levels before the TAVR was an isolated risk factor for premature death after intervention and at 1, 3, and 5 years post-intervention. The same was valid for the combination of male and echocardiographically established PH patients. The predictive role of IGF-BP2 in severe AS and concurrent PH remains unknown. A more profound comprehension of IGF-BP2 mechanisms, particularly in males, could facilitate the earlier consideration of the TAVR as a more effective and successful treatment strategy.

Association between preoperative albumin and length of hospital stay in non-cardiac surgery patients with pulmonary hypertension: A secondary retrospective analysis.

To explore the risk factors affecting the length of hospital stay (LOS) as well as to examine the relationship between preoperative serum albumin levels and LOS following non-cardiac, non-obstetric surgery in patients with pulmonary hypertension (PHTN). This study represents a secondary retrospective analysis based on 287 non-cardiac, non-obstetric procedures performed on 195 PTHN patients at a single institution in the USA between 2007 and 2013. The primary outcome was the LOS. We conducted a multiple logistic regression analysis to compare the LOS between the 2 groups, divided at a serum albumin level of 3.5 g/dL. After adjusting for multiple covariates, the ORs for the long length of stay (LOS > 7 days) for the high group(albumin > 3.5 g/dL) compared with the low group (albumin ≤ 3.5 g/dL) were 0.35 (95%CI: 0.21~0.6), 0.41 (95%CI: 0.22 ~0.76), 0.41 (95%CI: 0.18~0.94) from model 2 to model 4. The stratified analysis results indicate that these findings are stable (p for trend > 0.05). In this study, it was observed that low levels of preoperative albumin were associated with an increased risk of prolonged hospital stay after non-cardiac, non-obstetric surgery in patients with PHTN. This implies that optimizing preoperative nutrition could potentially reduce the LOS for non-cardiac, non-obstetric surgery in patients with PHTN.

Clinical Analysis of Myocardial Injury in Highlanders with Pulmonary Hypertension.

Background: Pulmonary hypertension (PH) is a prevalent adverse cardiovascular event at high-altitude environments. Prolonged exposure to high altitudes may result in myocardial injury, which is associated with poor clinical outcomes. This study aims to investigate the clinical characteristics of myocardial injury in patients with PH at high altitude. Methods: Consecutive patients admitted to a general tertiary hospital at the altitude of 3,650 m were selected into this retrospective study. Clinical and biochemical data were collected, as well as based on cardiac troponin I (cTnI) and echocardiography, patients were divided into myocardial injury group and non-myocardial injury group. Results: A total of 231 patients were enrolled, among whom 29 (12.6%) had myocardial injury. We found that body mass index, left ventricular end-diastolic dimension, and serum level of creatine kinase-MB (CK-MB) in myocardial injury group were significantly higher than non-myocardial injury group. Spearman correlation analysis revealed that cTnI has a significant positive correlation with CK-MB and lactic dehydrogenase instead of aspartate aminotransferase. A receiver operating characteristic curve was drawn to demonstrate that CK-MB could significantly predict the occurrence of myocardial injury with an area under the curve of 0.749, and a level of 3.035 (sensitivity = 59.3%, specificity = 90.5%) was optimal cutoff value. Conclusion: The incidence of myocardial injury in highlanders with PH is significant. CK-MB, as a convenient and efficient marker, has been found to be closely associated with cTnI and plays a predictive role in the occurrence of myocardial injury with PH in individuals exposed to high altitude.

Serum ASGR2 level: an efficacy biomarker for balloon pulmonary angioplasty in patients with chronic thromboembolic pulmonary hypertension.

Background: This study aimed to employ plasma proteomics to investigate the molecular changes, pathway alterations, and potential novel biochemical markers associated with balloon pulmonary angioplasty (BPA) in patients with chronic thromboembolic pulmonary hypertension (CTEPH). Methods: Pre- and post-BPA plasma samples from five CTEPH patients in the PRACTICE study were analyzed to identify differentially expressed proteins. Proteomic and bioinformatics analyses were conducted, and the identified proteins were further validated using ELISA assays in a separate cohort of the same study. Correlation and multivariate regression analyses were performed to investigate the associations between these differentially expressed proteins and clinical parameters. Results: Significantly higher serum levels of asialoglycoprotein receptor 2 (ASGR2) were detected in 5 CTEPH patients compared to those in healthy individuals but decreased significantly after successful BPA procedures. The decrease in serum levels of ASGR2 after the completion of BPA procedures was further validated in a separate cohort of 48 patients with CTEPH [0.70 (0.51, 1.11) ng/mL vs. 0.38 (0.27, 0.59) ng/mL, P < 0.001]. Significant associations were found between the pre-BPA ASGR2 level and clinical parameters, including neutrophil percentage (R = 0.285, P < 0.05), platelet (PLT) count (R = 0.386, P < 0.05), and high-density lipoprotein cholesterol (HDL-C) before BPA (R = -0.285, P < 0.05). Significant associations were detected between post-BPA serum ASGR2 levels and lymphocyte percentage (LYM%) (R = 0.306, P < 0.05), neutrophil-to-lymphocyte ratio (R = -0.294, P < 0.05), and pulmonary vascular resistance after BPA (R = -0.35, P < 0.05). Multivariate stepwise regression analysis revealed that pre-BPA ASGR2 levels were associated with HDL-C and PLT count (both P < 0.001), while post-BPA ASGR2 levels were associated with LYM% (P < 0.05). Conclusion: Serum levels of ASGR2 may be a biomarker for the effectiveness of BPA treatment in CTEPH patients. The pre-BPA serum level of ASGR2 in CTEPH patients was associated with HDL-C and the PLT count. The post-BPA serum level of ASGR2 was correlated with the LYM%, which may reflect aspects of immune and inflammatory status.

Predictive Value of Smoking Index Combined with NT-proBNP for Patients with Pulmonary Hypertension Due to Chronic Lung Disease: A Retrospective Study.

Purpose: Smoking is a major risk factor for the group 3 PH. NT-proBNP is a biomarker for risk stratification in PH. This study aims to investigate the effects of smoking status and smoking index (SI) on group 3 PH and to evaluate the value of SI and SI combined with NT-proBNP in early diagnosis and prediction of disease severity. Patients and Methods: Four hundred patients with group 3 PH at the First Hospital of Shanxi Medical University between January 2020 and December 2021 were enrolled and divided into two groups: mild (30 mmHg ≤ pulmonary artery systolic pressure (PASP)≤50 mmHg) and non-mild (PASP >50 mmHg). The effect of smoking on group 3 PH was analyzed using univariate analysis, and logistic analysis was conducted to evaluate the risk of group 3 PH according to smoking status and SI. Spearman correlation coefficient was used to test the correlation between SI and the index of group 3 PH severity. The predictive value of SI was evaluated using a receiver operating characteristic (ROC) curve. Results: Correlation and logistic analyses showed that SI was associated with PH severity. Smoking status (P=0.009) and SI (P=0.039) were independent risk factors for non-mild group 3 PH, and ROC showed that the predictive value of SI (AUC:0.596) for non-mild PH was better than that of the recognized pro-brain natriuretic peptide (NT-proBNP) (AUC:0.586). SI can be used as a single predictive marker. SI and NT-proBNP can be formulated as prediction models for screening non-mild clinical cases (AUC:0.628). Conclusion: SI is a potentially ideal non-invasive predictive marker for group 3 PH. SI and NT-proBNP could be used to develop a prediction model for screening non-mild PH cases. This can greatly improve the predictive specificity of the established PH marker, NT-proBNP.

Resistin predicts disease severity and survival in patients with pulmonary arterial hypertension.

BACKGROUND: Abnormal remodeling of distal pulmonary arteries in patients with pulmonary arterial hypertension (PAH) leads to progressively increased pulmonary vascular resistance, followed by right ventricular hypertrophy and failure. Despite considerable advancements in PAH treatment prognosis remains poor. We aim to evaluate the potential for using the cytokine resistin as a genetic and biological marker for disease severity and survival in a large cohort of patients with PAH. METHODS: Biospecimens, clinical, and genetic data for 1121 adults with PAH, including 808 with idiopathic PAH (IPAH) and 313 with scleroderma-associated PAH (SSc-PAH), were obtained from a national repository. Serum resistin levels were measured by ELISA, and associations between resistin levels, clinical variables, and single nucleotide polymorphism genotypes were examined with multivariable regression models. Machine-learning (ML) algorithms were applied to develop and compare risk models for mortality prediction. RESULTS: Resistin levels were significantly higher in all PAH samples and PAH subtype (IPAH and SSc-PAH) samples than in controls (P < .0001) and had significant discriminative abilities (AUCs of 0.84, 0.82, and 0.91, respectively; P < .001). High resistin levels (above 4.54 ng/mL) in PAH patients were associated with older age (P = .001), shorter 6-min walk distance (P = .001), and reduced cardiac performance (cardiac index, P = .016). Interestingly, mutant carriers of either rs3219175 or rs3745367 had higher resistin levels (adjusted P = .0001). High resistin levels in PAH patients were also associated with increased risk of death (hazard ratio: 2.6; 95% CI: 1.27-5.33; P < .0087). Comparisons of ML-derived survival models confirmed satisfactory prognostic value of the random forest model (AUC = 0.70, 95% CI: 0.62-0.79) for PAH. CONCLUSIONS: This work establishes the importance of resistin in the pathobiology of human PAH. In line with its function in rodent models, serum resistin represents a novel biomarker for PAH prognostication and may indicate a new therapeutic avenue. ML-derived survival models highlighted the importance of including resistin levels to improve performance. Future studies are needed to develop multi-marker assays that improve noninvasive risk stratification.

Plasma Proteomics Identifies B2M as a Regulator of Pulmonary Hypertension in Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Pulmonary hypertension (PH) represents an important phenotype in heart failure with preserved ejection fraction (HFpEF). However, management of PH-HFpEF is challenging because mechanisms involved in the regulation of PH-HFpEF remain unclear. METHODS: We used a mass spectrometry-based comparative plasma proteomics approach as a sensitive and comprehensive hypothesis-generating discovery technique to profile proteins in patients with PH-HFpEF and control subjects. We then validated and investigated the role of one of the identified proteins using in vitro cell cultures, in vivo animal models, and independent cohort of human samples. RESULTS: Plasma proteomics identified high protein abundance levels of B2M (ß2-microglobulin) in patients with PH-HFpEF. Interestingly, both circulating and skeletal muscle levels of B2M were increased in mice with skeletal muscle SIRT3 (sirtuin-3) deficiency or high-fat diet-induced PH-HFpEF. Plasma and muscle biopsies from a validation cohort of PH-HFpEF patients were found to have increased B2M levels, which positively correlated with disease severity, especially pulmonary capillary wedge pressure and right atrial pressure at rest. Not only did the administration of exogenous B2M promote migration/proliferation in pulmonary arterial vascular endothelial cells but it also increased PCNA (proliferating cell nuclear antigen) expression and cell proliferation in pulmonary arterial vascular smooth muscle cells. Finally, B2m deletion improved glucose intolerance, reduced pulmonary vascular remodeling, lowered PH, and attenuated RV hypertrophy in mice with high-fat diet-induced PH-HFpEF. CONCLUSIONS: Patients with PH-HFpEF display higher circulating and skeletal muscle expression levels of B2M, the magnitude of which correlates with disease severity. Our findings also reveal a previously unknown pathogenic role of B2M in the regulation of pulmonary vascular proliferative remodeling and PH-HFpEF. These data suggest that circulating and skeletal muscle B2M can be promising targets for the management of PH-HFpEF.

Circulating Biomarkers in Pulmonary Arterial Hypertension: An Update.

Pulmonary arterial hypertension (PAH) is a rare subtype of group 1 pulmonary hypertension (PH) diseases, characterized by high pulmonary artery pressure leading to right ventricular dysfunction and potential life-threatening consequences. PAH involves complex mechanisms: vasoconstriction, vascular remodeling, endothelial dysfunction, inflammation, oxidative stress, fibrosis, RV remodeling, cellular hypoxia, metabolic imbalance, and thrombosis. These mechanisms are mediated by several pathways, involving molecules like nitric oxide and prostacyclin. PAH diagnosis requires clinical evaluation and right heart catheterization, confirming a value of mPAP ≥ 20 mmHg at rest and often elevated pulmonary vascular resistance (PVR). Even if an early and accurate diagnosis is crucial, PAH still lacks effective biomarkers to assist in its diagnosis and prognosis. Biomarkers could contribute to arousing clinical suspicion and serve for prognosis prediction, risk stratification, and dynamic monitoring in patients with PAH. The aim of the present review is to report the main novelties on new possible biomarkers for the diagnosis, prognosis, and treatment monitoring of PAH.

Platelet hyperresponsiveness and increased platelet-neutrophil aggregates in dogs with myxomatous mitral valve disease and pulmonary hypertension.

BACKGROUND: Pulmonary hypertension (PH) in dogs with myxomatous mitral valve disease (MMVD) is caused by increased pulmonary venous pressure. Thrombosis, vascular remodeling, and vasoconstriction mediated by platelets could exacerbate PH. HYPOTHESIS: Dogs with PH will exhibit a hypercoagulable state, characterized by increased platelet activation, platelet-leukocyte, and platelet-neutrophil aggregate formation. ANIMALS: Eleven dogs (≥3.5 kg) diagnosed with MMVD and PH and 10 dogs with MMVD lacking PH. METHODS: Prospective cohort ex vivo study. All dogs underwent echocardiographic examination, CBC, 3-view thoracic radiographs, and heartworm antigen testing. Severity of PH and MMVD were assessed by echocardiography. Viscoelastic monitoring of coagulation was assessed using thromboelastography (TEG). Platelet activation and platelet-leukocyte/platelet-neutrophil interactions were assessed using flow cytometry. Plasma serotonin concentrations were measured by ELISA. RESULTS: Unstimulated platelets from dogs with MMVD and PH expressed more surface P-selectin than MMVD controls (P = .03). Platelets from dogs with MMVD and PH had persistent activation in response to agonists. The number of platelet-leukocyte aggregates was higher in dogs with MMVD and PH compared with MMVD controls (P = .01). Ex vivo stimulation of whole blood resulted in higher numbers of platelet-neutrophil aggregates in dogs with MMVD and PH (P = .01). Assessment of hypercoagulability based on TEG or plasma serotonin concentrations did not differ between groups. CONCLUSION AND CLINICAL IMPORTANCE: Platelet hyperresponsiveness and increased platelet-neutrophil interaction occur in dogs with MMVD and PH, suggesting that platelets play a role of in the pathogenesis of PH. Clinical benefits of antiplatelet drugs in dogs with MMVD and PH require further investigation.

Phosphoproteomics analysis of serum from dogs affected with pulmonary hypertension secondary to degenerative mitral valve disease.

Pulmonary hypertension (PH), a common complication in dogs affected by degenerative mitral valve disease (DMVD), is a progressive disorder characterized by increased pulmonary arterial pressure (PAP) and pulmonary vascular remodeling. Phosphorylation of proteins, impacting vascular function and cell proliferation, might play a role in the development and progression of PH. Unlike gene or protein studies, phosphoproteomic focuses on active proteins that function as end-target proteins within signaling cascades. Studying phosphorylated proteins can reveal active contributors to PH development. Early diagnosis of PH is crucial for effective management and improved clinical outcomes. This study aimed to identify potential serum biomarkers for diagnosing PH in dogs affected with DMVD using a phosphoproteomic approach. Serum samples were collected from healthy control dogs (n = 28), dogs with DMVD (n = 24), and dogs with DMVD and PH (n = 29). Phosphoproteins were enriched from the serum samples and analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Data analysis was performed to identify uniquely expressed phosphoproteins in each group and differentially expressed phosphoproteins among groups. Phosphoproteomic analysis revealed nine uniquely expressed phosphoproteins in the serum of dogs in the DMVD+PH group and 15 differentially upregulated phosphoproteins in the DMVD+PH group compared to the DMVD group. The phosphoproteins previously implicated in PH and associated with pulmonary arterial remodeling, including small nuclear ribonucleoprotein G (SNRPG), alpha-2-macroglobulin (A2M), zinc finger and BTB domain containing 42 (ZBTB42), hemopexin (HPX), serotransferrin (TRF) and complement C3 (C3), were focused on. Their unique expression and differential upregulation in the serum of DMVD dogs with PH suggest their potential as biomarkers for PH diagnosis. In conclusion, this phosphoproteomic study identified uniquely expressed and differentially upregulated phosphoproteins in the serum of DMVD dogs with PH. Further studies are warranted to validate the diagnostic utility of these phosphoproteins.

Accuracy of brain natriuretic peptide and N-terminal brain natriuretic peptide for detecting paediatric pulmonary hypertension: a systematic review and meta-analysis.

OBJECTIVE: Pulmonary hypertension (PH) is a life-threatening disease, especially in paediatric population. Symptoms of paediatric PH are non-specific. Accurate detection of paediatric PH is helpful for early treatment and mortality reduction. Therefore, we assessed the overall performance of brain natriuretic peptide (BNP) and N-terminal brain natriuretic peptide (NT-proBNP) for diagnosing PH in paediatric population. METHODS: PubMed, Web of Science, Cochrane Library and Embase databases were screened since their respective inceptions until August 2023. A bivariate random model and a hierarchical summary receiver operating characteristic model were used together to evaluate and summarize the overall performance of BNP and NT-proBNP for diagnosing paediatric PH. RESULTS: Eighteen studies using BNP/NT-proBNP were assessed, comprising 1127 samples. The pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR) and area under the curve (AUROC) of BNP/NT-proBNP were separately as 0.81, 0.87, 6.33, 0.21, 29.50 and 0.91, suggesting a good diagnostic performance of BNP/NT-proBNP for detecting PH in paediatric population. For BNP, the pooled sensitivity, specificity, PLR, NLR, DOR and AUROC were 0.83, 0.89, 7.76, 0.19, 40.90 and 0.93, indicating the diagnostic accuracy of BNP for paediatric PH patients was good. For NT-proBNP, the pooled sensitivity, specificity, PLR, NLR, DOR and AUROC were 0.81, 0.86, 5.59, 0.22, 24.96 and 0.90, showing that NT-proBNP could provide a good value for detecting paediatric PH. CONCLUSIONS: Both BNP and NT-proBNP are good markers for differentiating paediatric PH patients from non-PH individuals.

Accurate detection of paediatric PH is helpful for early treatment and mortality reduction. This study shows that both BNP and NT-proBNP are good markers for detecting paediatric PH. In clinical practice, we recommend that BNP and NT-proBNP are auxiliary biomarkers in diagnosing paediatric PH.

Asymmetric Dimethylarginine and NT-proBNP Levels Provide Synergistic Information in Pulmonary Arterial Hypertension.

BACKGROUND: Plasma asymmetric dimethylarginine (ADMA) is elevated in pulmonary arterial hypertension (PAH) and is associated with unfavorable outcomes. OBJECTIVES: The aim of this study was to assess changes in ADMA plasma levels for monitoring disease progression and outcomes during PAH-specific therapy. METHODS: ADMA was measured at baseline and after at least 6 months of follow-up using enzyme-linked immunosorbent assay and high-performance liquid chromatography. Changes in ADMA were analyzed in relation to changes in established PAH markers, including hemodynamic status, N-terminal pro-brain natriuretic peptide (NT-proBNP) and risk assessment scores. Impact on survival was assessed using Kaplan-Meier curves and Cox proportional hazards models. RESULTS: Between 2008 and 2019, ADMA samples were collected prospectively from 215 patients with PAH. Change in ADMA plasma level was a predictor of disease progression and survival. ΔADMA (median -0.03 µmol/L; 95% CI: -0.145 to 0.0135) was correlated with change in mean pulmonary arterial pressure (P < 0.005; rS = 0.287) but was not significantly correlated with ΔNT-proBNP (P = 0.056; rS = 0.135). Patients with decreased ADMA plasma levels at follow-up had better 3-year and 5-year survival rates (88% and 80%, respectively, vs 72% and 53% in those without decreases in ADMA) (P < 0.005; pulmonary hypertension-related mortality or lung transplantation). Patients with decreases in both ADMA and NT-proBNP had better survival rates compared with patients in whom only 1 parameter improved (P < 0.005). ΔADMA was a significant predictor of survival in Cox regression analysis and also when corrected for ΔNT-proBNP (HRs: 1.27 and 1.35, respectively; P < 0.005). CONCLUSIONS: ADMA and NT-proBNP provide synergistic prognostic information for patients with PAH. ADMA could be used as an objective and distinct biomarker for monitoring treatment response in PAH.

Myxomatous mitral valve disease and associated pulmonary hypertension might increase serum angiopoietin-2 in dogs.

OBJECTIVE: To evaluate the relationships between the severity of myxomatous mitral valve disease (MMVD) and pulmonary hypertension (PH) and serum angiopoietin (Ang)-1 and Ang-2 concentrations in dogs with MMVD. ANIMALS: 74 dogs (control, n = 12; MMVD, n = 62) were included. METHODS: Serum Ang-1 and Ang-2 concentrations were estimated using the canine-specific ELISA kit. The concentrations were compared between dogs with MMVD and healthy dogs, and they were analyzed according to the severity of MMVD and PH. RESULTS: The median serum Ang-1 concentration did not differ among the study groups. The median serum Ang-2 concentration was higher in dogs with stage B2 MMVD (P = .041) and acute congestive heart failure (P = .002) than in control dogs. In addition, the median serum Ang-2 concentration was higher in MMVD dogs with PH than in those without PH (P = .031). Serum Ang-2 concentration was correlated with vertebral heart score (rs = 0.36, P = .004) and vertebral left atrial score (r = 0.50, P < .001) in dogs with MMVD, and correlated with vertebral heart score (r = 0.63, P = .01), maximum E wave amplitude of the diastolic transmitral flow (rs = 0.61, P = .018), ejection fraction (rs = -0.77, P < .001) and fractional shortening (rs = -0.56, P = .032) in dogs with acute congestive heart failure. CLINICAL RELEVANCE: Circulating Ang-2 levels increase in dogs with the severity of MMVD and the presence of PH.

Higher sclerostin is associated with pulmonary hypertension in pre-dialysis end-stage kidney disease patients: a cross-sectional prospective observational cohort study.

BACKGROUND: Pulmonary hypertension (PH) is a complication of chronic kidney disease (CKD) that contributes to mortality. Sclerostin, a SOST gene product that reduces osteoblastic bone formation by inhibiting Wnt/ß-catenin signaling, is involved in arterial stiffness and CKD-bone mineral disease, but scanty evidence to PH. This study explored the relationship between sclerostin and PH in CKD 5, pre-dialysis end-stage kidney disease (ESKD) patients. METHODS: This cross-sectional prospective observational cohort study included 44 pre-dialysis ESKD patients between May 2011 and May 2015. Circulating sclerostin levels were measured using an enzyme-linked immunosorbent assay. PH was defined as an estimated pulmonary artery systolic pressure > 35 mmHg on echocardiography. RESULTS: Patients with higher sclerostin levels ≥ 218.18pmol/L had echocardiographic structural cardiac abnormalities, especially PH (P < 0.01). On multivariate logistic analysis, sclerostin over 218.19pmol/L was significantly associated with PH (odds ratio [OR], 41.14; 95% confidence interval [CI], 4.53-373.89, P < 0.01), but multivariate Cox regression analysis showed the systemic vascular calcification score over 1 point (Hazard ratio [HR] 11.49 95% CI 2.48-53.14, P = 0.002) and PH ([HR] 5.47, 95% CI 1.30-23.06, P = 0.02) were risk factors for all-cause mortality in pre-dialysis ESKD patients. CONCLUSIONS: Serum sclerostin and PH have a positive correlation in predialysis ESKD patients. The higher systemic vascular calcification score and PH have an association to increase all-cause mortality in pre-dialysis ESKD patients.

The role of neutrophil to lymphocyte ratio in patients with COPD-OSA overlap syndrome.

PURPOSE: The aim of this study is to investigate the role of the neutrophil to lymphocyte ratio (NLR) in patients diagnosed with the chronic obstructive pulmonary disease-obstructive sleep apnea (COPD-OSA) overlap syndrome and comorbid pulmonary hypertension (PH). PATIENTS AND METHODS: We enrolled a consecutive of stable COPD patients and conducted spirometry measurements, nocturnal polysomnography (PSG), and echocardiography for all participants. Clinical laboratory data were collected. RESULTS: A total of 178 patients with stable COPD were enrolled among whom 33.14% (59/178) were diagnosed with OSA. Of the patients with overlap syndrome, 35.59% (21/59) showed comorbid PH, compared to 34.45% (41/119) in COPD patients without OSA. There was no significant difference in the occurrence of PH between COPD with and without OSA. NLR was significantly higher in patients with overlap syndrome compared to those with either disease alone. The difference in NLR between COPD-OSA patients with and without PH was not significant. Correlation analysis revealed that NLR was associated with age, total sleep time spent with oxygen saturation below 90% (T90), CRP, pulmonary artery systolic pressure (PASP), and minimum peripheral capillary oxygen saturation (SpO2min) in all COPD patients. NLR was identified as an independent factor contributing to OSA in COPD. The median cut-off value for detecting OSA in stable COPD was 2.49. However, NLR was not found to be a predictor for PH in COPD-OSA overlap syndrome. CONCLUSIONS: NLR can serve as a predictive marker for comorbid OSA in patients with COPD. NLR is expected to increase its clinical application as a convenient and cost-effective biomarker for COPD-OSA overlap syndrome.