Pulmonary Arterial Hypertension Group Research Articles

Human umbilical cord mesenchymal stem cells attenuate experimental pulmonary arterial hypertension

Abstract Background Pulmonary arterial hypertension (PAH) is characterized by the remodeling of pulmonary arteries, with an increased pulmonary arterial pressure and right ventricle (RV) overload. Until now, there is still a lack of effective treatment applied. Experimental research has reported beneficial effects of mesenchymal stem cells (MSCs) therapy in PAH. However, there are few studies on human umbilical cord mesenchymal stem cells (hUC-MSCs) transplantation in the treatment of PAH. Purpose The purpose of the present study was to observe the protective effect of hUC-MSCs against experimental PAH and the colonization of hUC-MSCs in lung tissue. Methods Sprague Dawley rats were randomly divided into three groups: control group, monocrotaline (MCT)-induced PAH group, and stem cell therapy group (PAH+ hUC-MSCs). Rats with PAH were induced by a one-time intraperitoneal injection of 60mg/kg monocrotaline (PAH and PAH+hUC-MSCs groups) at the beginning of the experiment, while a control group received saline (SAL) instead. Huc-Mscs were treated by tail vein injection twice 1 and 2 weeks later (PAH+huc-MSC group dose: 3x106/each time), Ctr and PAH groups were given the same volume of SAL in tail vein. On day 28, Right ventricular systolic pressures (RVSP) were measured by right cardiac catheterization. WT% and WA% of pulmonary arterioles were evaluated by ipp6.0 Image Analysis Software. Right ventricular hypertrophy index (RVHI) were measured by weighing method. The colonization of hUC-MSCs in lung tissue was detected by immunohistochemistry. Results The RVHI and RVSP in MCT-induced PAH group were significantly higher than those in the control group (P<0.05). Compared with the control group, the WT% and the WA% were significantly increased in MCT-induced PAH group (P<0.05). The RVHI, RVSP, WT%, and the WA% in stem cell therapy group were significantly lower than those in the MCT-induced PAH group (P<0.05). Immunohistochemical examination of lung tissue showed that the nuclear staining of the stem cell therapy group was brown, while no staining was observed in the control group and PAH group. Conclusions In MCT-induced PAH, hUC-MSCs can transplanted into the lung tissues by tail vein injection. hUC-MSCs therapy can reduced lung vascular remodeling, improved hemodynamics. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): National Natural Science Fundation of China (82060018) and Natural Science Fundation of Yunnan (202101AS070043, 202102AA31003-7).

Health care utilization and productivity loss associated with pulmonary arterial hypertension: a Swedish nationwide register study

Abstract Background Pulmonary arterial hypertension (PAH) is a rare and serious disease with a significant impact on the quality of life and life expectancy. Purpose To estimate the health care resource utilization (HCRU) and productivity loss associated with PAH five years before and five years after diagnosis in a nationwide setting, compared to a matched control group. Methods This retrospective observational case-control study included adult patients diagnosed with PAH and registered in the Swedish PAH registry between January 1, 2008, through June 30, 2019. The control group consisted of five individuals per PAH patient matched on sex, birth year and municipality of residence at the time of PAH patients' diagnosis. The study was based on a dataset of individual level data compiled from several interlinked Swedish national registries. Mean (SD) HCRU (inpatient, outpatient, and drug utilization) and productivity loss (sick leave and disability benefits) were summarized for patients versus controls. Patients and controls with up to five years of follow-up data, i.e. alive and uncensored, were analyzed. Results In total 749 PAH patients were included in this study of which, 307 were censored and 234 died during the five-year follow-up period post diagnosis. The mean (SD) age of patients and controls were 61.8 (16.2) years and 64% were female. For the PAH group, the mean number of inpatient admissions and outpatient visits followed a similar trend, with an increase starting three years prior to diagnosis that peaked at the time of diagnosis (Figure 1). After diagnosis, mean inpatient admissions and outpatient visits decreased gradually. For the PAH group, drug utilization began to increase three years before diagnosis (Figure 1) and continued to increase after diagnosis. Controls showed much lower healthcare utilization compared to the PAH group. In a subgroup of the PAH group (work force participants only, n=449, Figure 1), the mean sick leave days per patient per year (PPPY) was three times higher for the PAH group compared to controls five years before diagnosis. On average, over the full ten-year period mean sick leave days was five times higher for PAH patients compared to controls. Mean disability pension days PPPY for the PAH group followed a similar trend as in- and outpatient utilization. This peaked around time of diagnosis and was eight times higher for the PAH group than controls. An estimation of the societal cost burden (Table 1) showed that the top cost drivers for the PAH group were drug use, disability pension and sick leave. Conclusions PAH is associated with a heavy economic burden on both the health care system and society, starting several years before time of diagnosis. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Actelion Pharmaceuticals, a Janssen Pharmaceutical Company of Johnson & Johnson, Allschwil, Switzerland.

Genetic background of pediatric PAH in Spain and its clinical implications: data from the REHIPED Spanish Registry

Abstract Background The genetic background of pulmonary arterial hypertension (PAH) in the Spanish pediatric population could be different from the genetic background described in other countries. Besides, clinical implications of a positive genetic result in the PAH pediatric population are not fully understood yet, and could result in the “reclassification” of patients from one PAH group to another type among the current pediatric classification. Material and methods Patients under 19 years at diagnosis included in the REHIPED registry from January 2011 to December 2021 were included. Clinical variables and genetical results were recorded. Succesive NGS panels involving up to 35 genes were used. After the results of the genetic testing, we analyzed differences in survival, and if patients “moved” to another category in the current Nice classification. Results In the selected cohort of 98 patients (56.1% female), median age at diagnosis was 7.1 years (IQr 1.5–14.7), and ethnicity as follows: Caucasian (81.6%), Romani (8.2%), others (10.2%) (Table 1). Before the genetic testing, patients had been classified as Idiopathic (53.1%), Congenital Heart Disease-PAH (30.6%), Heritable (5.1%), Pulmonary veno-oclusive disease (PVOD) 6.1%, and Multisystemic disorder associated with PAH (5.1%). Pathogenic or likely pathogenic variants were found in 44 of the screened patients (44.9%): BMPR2 (12 cases), EIF2AK4 (9), TBX4 (n=4), MECP2 (n=3), KCNK3 (n=2), FOXF1 (n=2), NFU1 (N=4), ACVRL1 (n=1), BMPR1B (n=1), CLBCI (n=1), GBE1 (n=1), GDF2 (n=1), SOX17 (n=1), VHL (n=1), and digenic pathogenic variant in ABCC8/SMAD1 (n=1). After genetic analysis, 28 patients (28.6%) were “reclassified” (Fig. 1, panel A), with HPAH, PVOD and multisystemic disorders increasing up to 18.4%, 8.2%, and 12.2%, respectively. Worse Survival from death or lung transplantation was observed in heritable PVOD and multisystemic disorders (Fig. 1, panel B). Conclusions The Spanish pediatric PAH population showed higher prevalence of EIF2AK4 than other pediatric registries. Genetic testing resulted in the “reclassification” of a significant number of patients. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Rio Hortega grant from the Spanish Ministry of Science and Innovation (Instituto de Salud Carlos III).

Early echocardiographic evaluation of right ventricular load adaptability after sequential combination treatment in pulmonary arterial hypertension.

Using the tricuspid annular plane systolic excursion (TAPSE)/pulmonary arterial systolic pressure (PASP) ratio as an index of right ventricular load adaptability, we aimed to evaluate early changes in right heart contractile function of patients with group1 pulmonary artery hypertension (PAH) after sequential combination PAH-specific therapy. Atotal of 49patients with group1 PAH and 31control participants were included in the study. The baseline clinical and echocardiographic data of the control and PAH group were compared. Subsequently, clinical and echocardiographic data of PAH patients before treatment and at 6months after PAH-specific treatment were analyzed. Asignificant increase in the TAPSE/PASP ratio was found in patients at 6months of PAH-specific treatment (0.25 ± 0.14; 0.33 ± 0.16, p < 0.001). Right atrial pressure (8 mm Hg [5-10]; 5 mm Hg [3-8], p < 0.001) and PASP (80.8 ± 30.6 mm Hg; 65.9 ± 25.7 mm Hg, p < 0.001) were significantly lower after sequential combination PAH-specific therapy. Negative correlations were found between the TAPSE/PASP ratio and N‑terminal pro-B-type natriuretic peptide (r = -0.524, p < 0.001), tricuspid regurgitation velocity (r = -0.749, p < 0.001), right atrial area (r = -0.298, p = 0.037), and right atrial pressure (r = -0.463, p = 0.001). In patients with group1 PAH, echocardiographic evaluation at the early stage of treatment (6months) shows asignificant improvement in the TAPSE/PASP ratio indicating right ventricular load adaptation. Comprehensive studies are needed on the routine use of the TAPSE/PASP ratio in the risk assessment of PAH patients.

Role of Endothelin-1 in Right Atrial Arrhythmogenesis in Rabbits with Monocrotaline-Induced Pulmonary Arterial Hypertension.

Atrial arrhythmias are considered prominent phenomena in pulmonary arterial hypertension (PAH) resulting from atrial electrical and structural remodeling. Endothelin (ET)-1 levels correlate with PAH severity and are associated with atrial remodeling and arrhythmia. In this study, hemodynamic measurement, western blot analysis, and histopathology were performed in the control and monocrotaline (MCT, 60 mg/kg)-induced PAH rabbits. Conventional microelectrodes were used to simultaneously record the electrical activity in the isolated sinoatrial node (SAN) and right atrium (RA) tissue preparations before and after ET-1 (10 nM) or BQ-485 (an ET-A receptor antagonist, 100 nM) perfusion. MCT-treated rabbits showed an increased relative wall thickness in the pulmonary arterioles, mean cell width, cross-sectional area of RV myocytes, and higher right ventricular systolic pressure, which were deemed to have PAH. Compared to the control, the spontaneous beating rate of SAN–RA preparations was faster in the MCT-induced PAH group, which can be slowed down by ET-1. MCT-induced PAH rabbits had a higher incidence of sinoatrial conduction blocks, and ET-1 can induce atrial premature beats or short runs of intra-atrial reentrant tachycardia. BQ 485 administration can mitigate ET-1-induced RA arrhythmogenesis in MCT-induced PAH. The RA specimens from MCT-induced PAH rabbits had a smaller connexin 43 and larger ROCK1 and phosphorylated Akt than the control, and similar PKG and Akt to the control. In conclusion, ET-1 acts as a trigger factor to interact with the arrhythmogenic substrate to initiate and maintain atrial arrhythmias in PAH. ET-1/ET-A receptor/ROCK signaling may be a target for therapeutic interventions to treat PAH-induced atrial arrhythmias.

Abstract P1133: Association Of Mesenchymal Stem Cells Therapy And An Agonist Of Adenosine Receptor On Monocrotaline-induced Pulmonary Arterial Hypertension In Rats

Introduction: Pulmonary arterial hypertension (PAH) is characterized by an intense inflammatory component leading to vascular remodeling, increasing the pulmonary artery pressure, eventually resulting in right ventricular dysfunction. Hypothesis: Association of human mesenchymal stem cells (hMSC) therapy and LASSBio-1860 (agonist of adenosine receptors) would reduce the inflammatory response and vascular remodeling, decreasing the vascular resistance and pulmonary artery pressure, improving right ventricle function and reducing hypertrophy. Methods: Protocols were approved by Animal Care and Use Committee at Universidade Federal do Rio de Janeiro. PAH was induced in male Wistar rats by injection of monocrotaline (MCT; 60 mg/kg, i.p.) and confirmed within 14 days by transthoracic echocardiography. Groups were orally treated daily during 14 days with vehicle, LASSBio-1860 (180 μmol/kg) after a single intravenous injection of 10 5 hMSC At the end of protocol, tissues were collected and processed to evaluate expression of proteins using immunohistochemical and western-blotting analysis. Results: Mean pulmonary artery acceleration time (PAAT) was reduced in MCT-induced PAH group compared to the control group from 31.0 ± 1.5 to 21.9 ± 1.3 ms. In contrast, the association of LASSBio-1860 and hMSC has recovered the PAAT to 31.0 ± 2.0 ms, which effect was not observed in isolated treatment either with LASSBio-1860 or hMSC (23.5 ± 2.1 and 22.2 ± 2.2 ms). Table 1 shows hemodynamic, molecular and immunohistochemical parameters. In conclusion, the association of LASSBio-1860 and hMSC improved hemodynamic, morphologic and inflammatory parameters in an MCT-induced model of PAH.

Decreased low-density lipoprotein and the presence of pulmonary arterial hypertension among newly diagnosed drug-naïve patients with systemic lupus erythematosus: D-dimer as a mediator.

Pulmonary arterial hypertension (PAH) is commonly associated with systemic lupus erythematosus (SLE). The present study investigated the relationship between coagulation and changes in lipid parameters in newly-diagnosed patients with SLE in the presence of PAH and whether the coagulation parameters were mediators between lipids and PAH presence. A total of 301 subjects scheduled for new-onset drug-naïve SLE were consecutively enrolled. Baseline data for patients without PAH and with PAH were gathered and compared. Coagulation and lipid parameters were compared across patients without lipid regulating and anticoagulation medications. Multivariable logistic regression model was applied to examine potential predictors of PAH in SLE. The relationships between them were examined using Spearman's correlation analysis. The relationship between coagulation index and lipids with SLE-PAH was evaluated using mediation analysis. Female patients accounted for 88.0% of the 301 subjects, and the average age was 32 years (range, 25-45 years). A total of 40 patients (13.3%) had PAH, and the average pulmonary artery systolic pressure (sPAP) was 55.825±26.67 mmHg. Patients with PAH were older and had higher levels of fibrin/fibrinogen degradation products (FDP), D-dimer, C-reactive protein, lower levels of complement 3, complement 4 and 25-hydroxy vitamin D3 compared with the non-PAH group. Multivariable logistic regression analysis showed that age and D-dimer were independent predictor factors for PAH. Among patients without lipid regulating and anticoagulation medications, patients in the PAH group had higher levels of D-dimer and FDP, and lower low-density lipoprotein (LDL) levels compared with patients without PAH. There was also a positive relationship between sPAP and D-dimer and FDP, and a negative relationship between sPAP and total cholesterol and LDL. Mediation analysis indicated that 25.61% of the effect of low LDL on PAH presence in systemic lupus erythematosus was mediated by D-dimer. Overall, the effect of low LDL on SLE-PAH appeared to be mediated by D-dimer, which mediated 25.61% of this effect.

Silencing TUFM Inhibits Development of Monocrotaline-Induced Pulmonary Hypertension by Regulating Mitochondrial Autophagy via AMPK/mTOR Signal Pathway.

Pulmonary arterial hypertension (PAH) is an extremely malignant cardiovascular disease which mainly involves the uncontrollable proliferation of the pulmonary arterial smooth muscular cells (PASMCs). Recent studies have confirmed that mitochondria play an important role in the pathogenesis of pulmonary hypertension through sensing cell hypoxia, energy metabolism conversion, and apoptosis. As a mitochondrial membrane protein, TUFM has been regarded to be related to mitochondrial autophagy (mitophagy), apoptosis, and oxidative stress. Considering these factors are closely associated with the pathogenesis of PAH, we hypothesize that TUFM might play a role in the development of PAH. Our preliminary examination has showed TUFM mainly expressed in the PASMCs, and the subsequent test indicated an increased TUFM expression in the SMCs of pulmonary arteriole in monocrotaline- (MCT-) induced PAH rat model compared with the normal rat. The TUFM knockdown (Sh-TUFM) or overexpressed (OE-TUFM) rats were used to establish PAH by treating with MCT. A notable lower pulmonary arterial systolic pressure together with slightly morphological changes of pulmonary arteriole was observed in the Sh-TUFM group compared with the single MCT-induced PAH group. Increased levels of P62 and Bax and reduced LC3II/I, BECN1, and Bcl2 were detected in the Sh-TUFM group, while the expressions of these proteins in the OE-TUFM group were contrast to the results of the Sh-TUFM group. To elucidate the possible mechanism underlying biological effect of TUFM in PAH, PASMCs were treated with silence or overexpression of TUFM and then exposed to hypoxia condition. An obviously high levels of P62 and Bax along with a decreased LC3 II/I, BECN1, ULK1, Atg12, Atg13, and Bcl2 levels were noticed in cells with silence of TUFM. Moreover, the phosphorylated AMPK and mTOR which was well known in mitophagy modulating vary by the alternation of TUFM. These observations suggested that TUFM silence inhibits the development of MCT-induced PAH via AMPK/mTOR pathway.

The hemodynamic characteristics of severe chronic lung disease referred for lung transplantation.

Severe pulmonary hypertension (PH) is not common even in patients with severe chronic lung disease (CLD) but data on hemodynamic characteristics among patients with severe CLD is scarce. All adult patients who had right heart catheterization for lung transplant assessment for severe CLD in the only lung transplant service and for PAH management in the only tertiary pulmonary hypertension service in Hong Kong from 2010 to 2020 were included and classified into CLD group and PAH group. Patient characteristics and hemodynamic parameters were analyzed. There were 153 patients included with 106 patients in the CLD group and 47 in the PAH group. There were only 19.8% of the patients in the CLD group had severe pulmonary hypertension. Patients in the CLD group had significantly lower systolic pulmonary arterial pressure (PAPs), lower mean pulmonary arterial pressure (PAPm), higher cardiac index, and lower PVR when compared with the PAH group (p < 0.001). The area under curve (AUC) of PAPs, PAPm, and PVR were excellent, 0.973, 0.970, and 0.938, respectively for discrimination between CLD and PAH on receiver operator characteristics curve analysis. Optimal cutoff values were 55.5 mmHg, 35.5 mmHg, and 6.1 Wood Units for PAPs, PAPm, and PVR with Youden Index 0.85, 0.80, and 0.82, respectively. There were distinct hemodynamic characteristics between the CLD group and the PAH group. Systolic pulmonary arterial pressure, mean pulmonary arterial pressure, and pulmonary vascular resistance are useful to discriminate between the phenotype of severe CLD and PAH.

Clinically important changes in right ventricular volume and function in pulmonary arterial hypertension assessed with cardiac magnetic resonance imaging.

Right ventricular (RV) dilatation predicts clinical worsening in pulmonary arterial hypertension (PAH) and RV volumes can be measured with high precision using cardiovascular magnetic resonance imaging. In regular follow‐up of patients and in studies of improvement in RV function, knowledge of clinically significant changes of RV volumes and function are of relevance. Patients with PAH were followed with cardiovascular magnetic resonance imaging and clinical assessment at 6‐month intervals. Changes in RV volumes associated with changes in clinical status were assessed. Twenty‐five patients with PAH (Group 1) were included and examined every 6 months for 2.5 years, with a total of 107 MRI scans. For a step change in WHO functional class, the associated change in RV volume was 11% (confidence interval 7%−14%, p < 0.0001) and in stroke volume 9% (confidence interval 3%−15%, p = 0.003). This study found an 11% change in RV volume to be clinically significant. The combination of clinically significant changes and the known precision in the measurements enables individualized follow‐up of RV‐function in PAH. To our knowledge, this study is the first to use repeated assessments to suggest clinically significant changes of RV volume based on changes in clinical presentation.

Metabolomics and Cytokine Analysis for Identification of Schizophrenia with Auditory Hallucination.

To investigate the metabolic profile and biomarkers of schizophrenia with auditory hallucinations (AHs). A total of 18 schizophrenic patients with the symptom of pure AHs (pAHs), 28 without AH (nAHs) and 43 age-matched healthy persons (Con) were enrolled in this study. Participants in pAHs and nAHs groups had relapsed into exacerbations of psychosis after self-discontinuing antipsychotics for at least one month; blood samples were drawn prior to restarting anti-psychotic treatment. Participants with history of recreational substance use were excluded. Positive and Negative Syndrome Scale (PANSS) and Auditory Hallucinations Rating Scale (AHRS) were used to assess the clinical mental state of all samples. Enzyme-linked immunosorbent assay (ELISA) was used to estimate the level of cytokines, and metabolomics analysis to identify potential biomarkers and pathways in the three groups. Graphpad 8.0 software was used to calculate the area under the receiver operating characteristic (ROC) curve. The relationship between metabolites and cytokines were determined using correlation analysis. Questionnaire scores showed significant differences in the positive symptom scale and PANSS total between nAHs and pAHs groups. Four cytokines (BDNF, IL-2, NGF-β and TNF-α) differed significantly among the three groups. Six molecules in the nAHs group (phenylalanine, hippurate, serine, glutamate, valine and cystine) and four in the pAHs group (phenylalanine, serine, glutamate and cystine) were identified as potential biomarkers. In addition, phenylalanine was shown as a potential independent diagnostic biomarker for pAHs. Correlation analysis revealed that cystine and serine were significantly negatively correlated with IL-2 in the pAHs group. This study revealed the metabolic profile of patients with schizophrenia with AHs and provided new information to support the diagnosis. The identification of unique biomarkers would contribute to objective and reliable diagnoses of patients with schizophrenia with AH.

Relation between endothelial nitric oxide synthase genetic polymorphisms and pulmonary arterial hypertension in newborns with congenital heart disease

ABSTRACT Objective To investigate whether endothelial nitric oxide synthase (eNOS) rs1799983, rs2070744, and rs61722009 gene polymorphisms are associated with pulmonary arterial hypertension (PAH) in South Fujian newborns with congenital heart disease (CHD). Methods Genotyping for the eNOS rs1799983, rs2070744, and rs61722009 polymorphisms was performed using Sanger sequencing in 50 newborns with PAH secondary to CHD [CHD PAH (+)], 52 newborns with CHD without PAH [CHD PAH (-)], and 60 healthy controls. Results The genotype and allele frequency distributions of eNOS rs1799983, rs2070744, and rs61722009 were similar between CHD and healthy controls (P > .05). The frequencies of the eNOS rs1799983 G/T allele were 85% and 15% in the CHD PAH (+) group and 96.15% and 3.85% in the CHD PAH (-) group, the frequency of the T allele was higher in the CHD PAH (+) group than in the CHD PAH (-) group(P< .05), and patients with the GT/TT genotypes of eNOS rs1799983 may present higher PAH (OR = 4.412, 95%CI:1.411–13.797, P= .011). Newborns with the GT/TT genotypes had decreased plasma NO production compared to newborns with the GG genotype (P< .01), and NO levels in the CHD PAH (+) group were significantly lower than those in the CHD PAH (-) group (P < .05). Conclusion The T allele could be a risk factor for PAH in newborns with CHD in South Fujian through decreased levels of nitric oxide production by the endothelium.

Analysis of miRNA profile in circulating extracellular vesicles of patients with pulmonary arterial hypertension

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Swedish Research Council Introduction Pulmonary arterial hypertension (PAH) is characterized by a progressive elevation of pulmonary pressure leading to right ventricular dysfunction and is associated with a poor prognosis. Patients with PAH have increased numbers of circulating extracellular vesicles (EVs), which are small membrane vesicles (&amp;lt;1 µm) released from different cells. EVs contain surface antigens, proteins and genetic material, and serve as vectors of intercellular communication. MicroRNAs (miRs) are small RNAs that act as post-transcriptional regulators inhibiting gene expression. Alteration of miR expression is associated with stage, progression and severity of different diseases making them suitable as potential biomarker. The aim of the study was to evaluate the miRNA profile contained in EVs derived from plasma of both control healthy subjects and patients with PAH. Methods Circulating EVs, purified from platelet free plasma, from 9 healthy controls (HC) and 10 PAH patients were analyzed. After total RNA isolation, fixed volumes of total RNA were biotinylated to generate fragmented cRNA. Samples were then subjected to Microarray analysis using GeneChip miRNA 4.0 Array. Data was further analysed using various bioinformatics tools. Results Total of 762 miRs were identified while comparing PAH vs HC groups, of which 22 were found to be down-regulated and 3 were up-regulated in PAH group (Table 1). Gene ontology enrichment analysis revealed various cell signaling pathways where-in identified miRs are involved. Conclusions PAH patients pack and transport a differentiated expression profile of miRs, suggesting that EVs might serve as signaling vectors. Further analyses of the functionality of EVs' miRs is currently undergoing in our lab to understand its role during PAH progression and/or inhibition.

REDUCTION OF HEART RATE VIA P2X4 RECEPTOR ACTIVATION AS A PROMISING TREATMENT STRATEGY IN PULMONARY ARTERIAL HYPERTENSION

Objective: Mounting evidence suggest that the ATP-sensitive ionotropic P2X4 receptor (P2X4R) improves cardiac performance and optimizes myocardial energy demand by reducing chronotropy. Here, we set to investigate whether the digitalis-like effect of the P2X4R in the sinus node was preserved in rats with right heart failure due to pulmonary arterial hypertension (PAH). Design and method: Male Wistar rats received a single subcutaneous injection of either monocrotaline (MCT; PAH group) or vehicle (CTRL group). Right heart failure associated to PAH normally occurs in Wistar rats 21 to 25 days after MCT administration. Myographic recordings were performed in spontaneously beating atria (chronotropic effect) isolated from both animal groups. Results: Baseline spontaneous atrial rate was 250 ± 5 (n = 26) bpm in CTRL and 237 ± 7 bpm (n = 23) in PAH group (p &gt; 0.05). ATP (0.01–1 mM) concentration-dependently reduced the spontaneous atrial rate of both animal groups. The negative chronotropic effect of ATP (100 M) was smaller in PAH rats (-9 ± 2%; n = 14 vs. -22 ± 4%; n = 25, p &lt; 0.05), but this divergence was attenuated upon increasing the concentration of ATP to 1 mM (CTRL: -54 ± 5%; n = 15 vs. MCT: -50 ± 7%; n = 8; p &gt; 0.05). The P2X4R antagonist, 5-BDBD (10 M), attenuated the negative chronotropic action of ATP (100 M) in CTRL (from -19 ± 5% to -13 ± 3%; n = 5, p &gt; 0.05) and PAH (from -8 ± 3% to 1 ± 8%; n = 4, p &gt; 0.05) rats. The positive allosteric modulator of P2X4R, ivermectin (30 M), potentiated the negative chronotropic effect of ATP (100 M) in CTRL (from -31 ± 5% to -56 ± 14%; n = 5, p &gt; 0.05) and PAH (from -12 ± 6% to -24 ± 9%; n = 4, p &lt; 0.05). The non-selective P2XR agonist, CTP (1 mM), which contrary to ATP does not breakdown into adenosine, also decreased atrial chronotropy in CTRL (-24.31 ± 6.73%; n = 6) and PAH (-11.82 ± 1.98%; n = 6) rats. Conclusions: Data suggest that the negative chronotropic effect of P2X4R activation is preserved in atria of rats with heart failure associated to PAH, thus strengthening the hypothesis that heart rate reductions using this ATP-sensitive receptor may increase cardiac performance in patients with PAH-induced heart failure.

Characteristics and health risks of parent, alkylated, and oxygenated PAHs and their contributions to reactive oxygen species from PM2.5 vehicular emissions in the longest tunnel in downtown Xi'an, China

A vehicular emission study was conducted in the longest inner-city tunnel in Xi'an, northwestern China in four time periods (I: 07:30–10:30, II: 11:00–14:00, III: 16:30–19:30, and IV: 20:00–23:00 LST). A sum of 40 PAHs, including parent (p-PAHs), alkylated (a-PAHs), and oxygenated (o-PAHs) in fine particulate matter (PM2.5) were quantified. The relationships between the PAHs and the formation of reactive oxygen species (ROS) were also studied. The average total quantified PAHs concentration was 236.3 ± 48.3 ng m−3. The p-PAHs were found to be the most dominated group, accounting for an average of 88.1% of the total quantified PAHs, followed by a-PAHs (6.1%) and o-PAHs (5.8%). On the base of the number of aromatic rings, the groups of ≤5 rings (92.5 ± 1.2%) had higher fractions than the high ones (≥6 rings, 7.5 ± 1.2%) for pPAHs. Diurnal variations of PAHs subgroups exhibited the highest levels in Period III, consistent with the largest traffic counts in evening rush hours. However, less reduction of few PAHs in the night period demonstrates that the emissions of compressed natural gas (CNG) and methanol-fueled vehicles cannot be ignored while their contribution increased. High ROS activity levels were observed in the traffic-dominated samples, implying the potential oxidative damages to humans. Additionally, diurnal variation of the ROS activity was consistent with the total quantified PAHs and toxic equivalency of benzo[a]pyrene. Good correlations (R > 0.6, p < 0.05) were seen between individual groups of PAHs (especially for 3–5 rings p-PAHs, 4 rings a-PAHs, and 2–3 rings o-PAHs) and ROS activity, supporting that the vehicular emitted PAHs possibly initiate oxidative stress. The multiple linear regression analysis further illustrated that chrysene contributed the highest (25.0%) to ROS activity. In addition to highlighting the potential hazards to the PAHs from the vehicular emission, their roles to mitigate the health effects by formations of ROS were firstly reported in northwestern China.

Role of Highly Sensitive Cardiac Troponin I in the Prediction of Pediatric Pulmonary Hypertension due to Congenital Heart Disease

Background: CHD is a major health problem in pediatric population. It is associated with abnormal hemodynamic load and neurohormonal activation. Which leads to pulmonary hypertension causing myocardial injury. So, it needs timely intervention. Cardiac troponins are specific for myocardial injury. HscT I enhances accuracy for diagnosis of myocardial injury even in early stage of Pulmonary Hypertension. In recent years role of HscT I suggested to be useful in evaluation of PAH due to CHD in children. Objectives: To analyze the role of HscT I as a diagnostic tool for PAH due to CHD in Children. Methods: This prospective cross-sectional study was conducted in Pediatric cardiology department, BSMMU over a period of 1 year. The study included total 54 patients with moderate to large VSD/PDA. Patients were selected according to inclusion and exclusion criteria. Results: Total 54 cases was divided into two group PAH group (n=27) and non-PAH (n=27) group. Among PAH group 20 patient (74.1%) had VSD and 7 patient (25.9%) had PDA. In non PAH group 15 had VSD (55.6%) and 12 had PDA (44.4%). The mean troponin I level was significantly higher in PAH group than non-PAH group (0.03052±0.0511 vs. 0.0087±0.0075, p=0.03). Conclusion: In this study, there was significant difference between HscT I level of PAH group and non-PAH group and significant positive correlation between HscT I level and mean PAP. As a marker of myocardial injury, HscT I can be a predictor of raised pulmonary arterial pressure in children with post tricuspid left to right shunt.

Biventricular Myocardial Strain Analysis in Patients with Pulmonary Arterial Hypertension Using Cardiac Magnetic Resonance Tissue-Tracking Technology.

: ObjectivesTo evaluate both left and right ventricular (LV and RV) function in patients with pulmonary arterial hypertension (PAH) using cardiac magnetic resonance tissue-tracking (CMR-TT) technology and explore its clinical value. Methods: A total of 79 participants (including 47 patients with PAH and 32 healthy controls) underwent cardiac magnetic resonance imaging (CMRI) with a short-axis balanced steady-state free precession (SSFP) sequence. The biventricular cardiac function parameters and strain parameters were obtained by postprocessing with CVI42 software. A comparative analysis was performed between the LV and RV strain parameters in all PAH patients and in PAH patients with reduced or preserved cardiac function. Results: The results showed preferable repeatability of CMR-TT in analyzing the global radial strain (GRS), circumferential strain (GCS), and longitudinal strain (GLS) of the left and right ventricles in the PAH group. The GRS, GCS, and GLS of the left and right ventricles except for LV GRS (LVGRS) of PAH patients were significantly lower than those of healthy controls (p < 0.05 for all). The GRS and GCS of the left and right ventricles showed a moderate correlation in the PAH group (r = 0.323, p = 0.02; r = 0.301, p = 0.04, respectively). PAH patients with preserved RV function (n = 9) showed significantly decreased global and segmental RS, CS, and LS of the right ventricles than healthy controls (p < 0.05 for all), except for basal RVGCS (RVGCS-b, p = 0.996). Only the LVGLS was significantly different between the PAH patients with preserved LV function (n = 32) and the healthy controls (−14.23 ± 3.01% vs. −16.79 ± 2.86%, p < 0.01). Conclusions: As a nonradioactive and noninvasive technique, CMR-TT has preferable feasibility and repeatability in quantitatively evaluating LV and RV strain parameters in PAH patients and can be used to effectively detect early biventricular myocardial damage in patients with PAH.

Cytokine profiling in pulmonary arterial hypertension: the role of redox homeostasis and sex

Pulmonary arterial hypertension (PAH) is a fatal disease with a well-established sexual dimorphism. Activated inflammatory response and altered redox homeostasis, both known to manifest in a sex-specific manner, are implicated in the pathogenic mechanisms involved in PAH development. This study aimed to evaluate the impact of sex and plasma redox status on circulating cytokine profiles. Plasma oxidation-reduction potential (ORP), as a substitute measure of redox status, was analyzed in male and female Group 1 PAH and healthy subjects. The profiles of 27 circulating cytokines were compared in 2 PAH groups exhibiting the highest and lowest quartile for plasma ORP, correlated with clinical parameters, and used to predict patient survival. The analysis of the PAH groups with the highest and lowest ORP revealed a correlation between elevated cytokine levels and increased oxidative stress in females. In contrast, in males, cytokine expressions were increased in the lower oxidative environment (except for IL-1b). Correlations of the increased cytokine expressions with PAH severity were highly sex-dependent and corresponded to the increase in PAH severity in males and less severe PAH in females. Machine learning algorithms trained on the combined cytokine and redox profiles allowed the prediction of PAH mortality with 80% accuracy. We conclude that the profile of circulating cytokines in PAH patients is redox- and sex-dependent, suggesting the vital need to stratify the patient cohort subjected to anti-inflammatory therapies. Combined cytokine and/or redox profiling showed promising value for predicting the patients' survival.

Meeting abstracts from the 15th international conference on neonatal and childhood pulmonary vascular disease

Meeting abstracts from the 15th international conference on neonatal and childhood pulmonary vascular disease

Dual-energy CT lung perfusion characteristics in pulmonary arterial hypertension (PAH) and pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis (PVOD/PCH): preliminary experience in 63 patients.

In the stratification of potential causes of PH, current guidelines recommend performing V/Q lung scintigraphy to screen for CTEPH. The recognition of CTEPH is based on the identification of lung segments or sub-segments without perfusion but preserved ventilation. The presence of mismatched perfusion defects has also been described in a small proportion of idiopathic pulmonary arterial hypertension (PAH) and pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis (PVOD/PCH). Dual-energy CT lung perfusion changes have not been specifically investigated in these two entities. To compare dual-energy CT (DECT) perfusion characteristics in PAH and PVOD/PCH, with specific interest in PE-type perfusion defects. Sixty-three patients with idiopathic or heritable PAH (group A; n = 51) and PVOD/PCH (group B; n = 12) were investigated with DECT angiography with reconstruction of morphologic and perfusion images. The number of patients with abnormal perfusion did not differ between group A (35/51; 68.6%) and group B (6/12; 50%) (p = 0.31) nor did the mean number of segments with abnormal perfusion per patient (group A: 17.9 ± 4.9; group B: 18.3 ± 4.1; p = 0.91). The most frequent finding was the presence of patchy defects in group A (15/35; 42.9%) and a variable association of perfusion abnormalities in group B (4/6; 66.7%). The median percentage of segments with PE-type defects per patient was significantly higher in group B than in group A (p = 0.041). Two types of PE-type defects were depicted in 8 patients (group A: 5/51; 9.8%; group B: 3/12; 25%), superimposed on PH-related lung abnormalities (7/8) or normal lung (1/8). The iodine concentration was significantly lower in patients with abnormal perfusion (p < 0.001) but did not differ between groups. Perfusion abnormalities did not differ between the two groups at the exception of a higher median percentage of segments with PE-type defects in patients with PVOD/PCH. • Patchy perfusion defect was the most frequent pattern in PAH. • A variable association of perfusion abnormalities was seen in PVOD/PCH. • Lobular and PE-type perfusion defects larger than a sub-segment were depicted in both PAH and PVOD/PCH patients.