Idiopathic Pulmonary Arterial Hypertension Patients Research Articles

Changes in the indicators of hemodynamics and oxygen transport in patients with idiopathic pulmonary arterial hypertension depending on their survival

Background. Idiopathic pulmonary arterial hypertension (IPAH) is a severe disease that affects the vessels of the pulmonary circulation and leads to right ventricular failure and death of patients. Indicators of hemodynamics and oxygen transport play central role in the progression and development of the disease. Objective: to evaluate indicators of hemodynamics, oxygen transport. Materials and methods. The study included 124 patients with IPAH. They were divided into two groups: alive patients (group 1) and those who died (group 2). All of them underwent general clinical examinations, a 6-minute walk test, transthoracic and speckle tracking echocardiography, right heart catheterization, blood gas analysis and calculation of hemodynamic parameters. Results. We calculated and compared the right (RVSWI) (19.93 ± 7.84 vs. 16.47 ± 4.67 g·m·m–2, p = 0.009) and left ventricular stroke work index (LVSWI) (39.47 ± 10.53 vs. 35.92 ± 11.19 g·m·m–2, p = 0.036) and their ratio (RVSWI/LVSWI) (0.59 ± 0.16 vs. 0.46 ± ± 0.13, p = 0.008), right (RVPC) (97.00 ± 2.16 vs. 1.82 ± 1.04 g·m, p = 0.001) and left ventricular pump coefficient (LVPC) (5.36 ± 4.84 vs. 4.41 ± 2.15 g·m, p = 0.04) and their ratio (RVPC/LVPC) (0.54 ± 0.19 vs. 0.44 ± 0.11, p = 0.05) in both groups of patients. Also, we found differences in partial pressure of carbon dioxide (PaCO2) of venous blood (34.5 ± 5.1 vs. 40.2 ± 6.9 mm Hg, p = 0.02), partial pressure of oxygen (PaO2) of arterial blood (90.2 ± 15.1 vs. 78.9 ± 11.2 mm Hg; p = 0.01), arteriovenous oxygen difference (A-vO2) (4.5 ± 1.2 vs. 5.0 ± 0.8 ml/dL, p = 0.02) between both groups. Conclusions. RVSWI, LVSWI, RVSWI/LVSWI, RVPC, LVPC, RVPC/LVPC were significantly different between the groups. The use of the above hemodynamic parameters can help in a deeper understanding of the prognosis in IPAH patients. Performance of oxygen transport indicators (PaCO2, PaO2) and A-vO2 in IPAH patients provides a broader understanding of the status and prognosis of this disease.

The diverging roles of insulin-like growth factor binding proteins in pulmonary arterial hypertension

Pulmonary hypertension (PH) is a progressive, severe and to date not curable disease of the pulmonary vasculature. Alterations of the insulin-like growth factor 1 (IGF-1) system are known to play a role in vascular pathologies and IGF-binding proteins (IGFBPs) are important regulators of the bioavailability and function of IGFs. In this study, we show that circulating plasma levels of IGFBP-1, IGFBP-2 and IGFBP-3 are increased in idiopathic pulmonary arterial hypertension (IPAH) patients compared to healthy individuals. These binding proteins inhibit the IGF-1 induced IGF-1 receptor (IGF1R) phosphorylation and exhibit diverging effects on the IGF-1 induced signaling pathways in human pulmonary arterial cells (i.e. healthy as well as IPAH-hPASMCs, and healthy hPAECs). Furthermore, IGFBPs are differentially expressed in an experimental mouse model of PH. In hypoxic mouse lungs, IGFBP-1 mRNA expression is decreased whereas the mRNA for IGFBP-2 is increased. In contrast to IGFBP-1, IGFBP-2 shows vaso-constrictive properties in the murine pulmonary vasculature. Our analyses show that IGFBP-1 and IGFBP-2 exhibit diverging effects on IGF-1 signaling and display a unique IGF1R-independent kinase activation pattern in human pulmonary arterial smooth muscle cells (hPASMCs), which represent a major contributor of PAH pathobiology. Furthermore, we could show that IGFBP-2, in contrast to IGFBP-1, induces epidermal growth factor receptor (EGFR) signaling, Stat-3 activation and expression of Stat-3 target genes. Based on our results, we conclude that the IGFBP family, especially IGFBP-1, IGFBP-2 and IGFBP-3, are deregulated in PAH, that they affect IGF signaling and thereby regulate the cellular phenotype in PH.

Corosolic acid attenuates platelet-derived growth factor signaling in macrophages and smooth muscle cells of pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a progressive and life-threatening disease that is characterized by vascular remodeling of the pulmonary artery. Pulmonary vascular remodeling is primarily caused by the excessive proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs), which are facilitated by perivascular inflammatory cells including macrophages. Corosolic acid (CRA) is a natural pentacyclic triterpenoid that exerts anti-inflammatory effects. In the present study, the effects of CRA on the viability of macrophages were examined using monocrotaline (MCT)-induced PAH rats and human monocyte-derived macrophages. Although we previously reported that CRA inhibited signal transducer and activator of transcription 3 (STAT3) signaling and ameliorated pulmonary vascular remodeling in PAH, the inhibitory mechanism remains unclear. Therefore, the underlying mechanisms were investigated using PASMCs from idiopathic PAH (IPAH) patients. In MCT-PAH rats, CRA inhibited the accumulation of macrophages around remodeled pulmonary arteries. CRA reduced the viability of human monocyte-derived macrophages. In IPAH-PASMCs, CRA attenuated cell proliferation and migration facilitated by platelet-derived growth factor (PDGF)-BB released from macrophages and PASMCs. CRA also downregulated the expression of PDGF receptor β and its signaling pathways, STAT3 and nuclear factor-κB (NF-κB). In addition, CRA attenuated the phosphorylation of PDGF receptor β and STAT3 following the PDGF-BB simulation. The expression and phosphorylation levels of PDGF receptor β after the PDGF-BB stimulation were reduced by the small interfering RNA knockdown of NF-κB, but not STAT3, in IPAH-PASMCs. In conclusion, CRA attenuated the PDGF-PDGF receptor β-STAT3 and PDGF-PDGF receptor β-NF-κB signaling axis in macrophages and PASMCs, and thus, ameliorated pulmonary vascular remodeling in PAH.

Serum PM20D1 levels in patients with idiopathic pulmonary arterial hypertension and its clinical significance

ObjectiveThis study aimed to investigate the serum levels of Peptidase M20 domain containing 1 (PM20D1) in idiopathic pulmonary arterial hypertension (IPAH) patients and examine its association with lipid metabolism, echocardiography, and hemodynamic parameters.MethodsThis prospective observational research enrolled 103 IPAH patients from January 2018 to January 2022. Enzyme-linked immunosorbent assay (ELISA) was used to measure the serum PM20D1 levels in all patients before treatment within 24 h of admission. Demographic data, echocardiography, hemodynamic parameters and serum biomarkers were also collected.ResultsThe IPAH patients in the deceased group had significantly elevated age, right atrial (RA), mean pulmonary arterial pressure (mPAP), mean right atrial pressure (mRAP), pulmonary capillary wedge pressure (PCWP), pulmonary vascular resistance (PVR) and significantly decreased 6 min walking distance (6MWD) and tricuspid annulus peak systolic velocity (TASPV). IPAH patients showed significant decreases in serum PM20D1, low-density lipoprotein cholesterol (LDL-C), and albumin (ALB). Additionally, PM20D1 was negatively correlated with RA, NT-proBNP and positively correlated with PVR, ALB, 6MWD, and TAPSV. Moreover, PM20D1 has the potential as a biomarker for predicting IPAH patients’ prognosis. Finally, logistic regression analysis indicated that PM20D1, ALB, NT-proBNP, PVR, TASPV, RA and 6MWD were identified as risk factors for mortality in IPAH patients.ConclusionOur findings indicated that the serum levels of PM20D1 were significantly decreased in IPAH patients with poor prognosis. Moreover, PM20D1 was identified as a risk factor associated with mortality in IPAH patients.

Clinical Correlates of a Nonplexiform Vasculopathy in Patients With a Diagnosis of Idiopathic Pulmonary Arterial Hypertension

The clinical phenotype of idiopathic pulmonary arterial hypertension (IPAH) patients has changed. . Whether or not subgroups of IPAH patients have different vascular phenotypes is a subject of debate. What are the histological patterns and their clinical correlates in patients diagnosed with IPAH or hereditary PAH? In this this cross-sectional registry study lung histology of 50 IPAH patients was qualitatively assessed by two experienced pathologists. In addition, quantitative analysis by means of histopathological morphometry using immunohistochemistry was performed. Histopathological characteristics were correlated with clinical and hemodynamic parameters. In this cohort of 50 IPAH patients, a plexiform vasculopathy was observed in 26/50 (52%) of patients, while 24/50 (48%) patients had a non-plexiform vasculopathy. The non-plexiform vasculopathy was characterized by prominent pulmonary microvascular (arterioles and venules) remodeling and vascular rarefaction. While hemodynamic parameters were comparable in plexiform versus non-plexiform vasculopathy, patients with non-plexiform vasculopathy were older, more often male, had a stronger history of cigarette smoking and lower diffusing capacity for carbon monoxide (DLCO) at diagnosis No mutations in established PAH genes were found in the non-plexiform group. This study reveals different vascular phenotypes within the current spectrum of patients diagnosed with IPAH, separated by clinical characteristics (age, sex, , history of cigarette smoking, and DLCO at diagnosis). Potential differences in underlying pathobiological mechanisms between patients with plexiform and non-plexiform / microvascular disease should be taken into account in future research strategies unravelling the pathophysiology of pulmonary hypertension and developing biology-targeted treatment approaches.

Up-regulated expression of two-pore domain K+ channels, KCNK1 and KCNK2, is involved in the proliferation and migration of pulmonary arterial smooth muscle cells in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a severe and rare disease in the cardiopulmonary system. Its pathogenesis involves vascular remodeling of the pulmonary artery, which results in progressive increases in pulmonary arterial pressure. Chronically increased pulmonary arterial pressure causes right ventricular hypertrophy and subsequent right heart failure. Pulmonary vascular remodeling is attributed to the excessive proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs), which are induced by enhanced Ca2+ signaling following the up-/down-regulation of ion channel expression. In the present study, the functional expression of two-pore domain potassium KCNK channels was investigated in PASMCs from idiopathic PAH (IPAH) patients and experimental pulmonary hypertensive (PH) animals. In IPAH-PASMCs, the expression of KCNK1/TWIK1 and KCNK2/TREK1 channels was up-regulated, whereas that of KCNK3/TASK1 and KCNK6/TWIK2 channels was down-regulated. The similar up-regulated expression of KCNK1 and KCNK2 channels was observed in the pulmonary arterial smooth muscles of monocrotaline-induced PH rats, Sugen 5416/hypoxia-induced PH rats, and hypoxia-induced PH mice. The facilitated proliferation of IPAH-PASMCs was suppressed by the KCNK channel blockers, quinine and tetrapentylammonium. The migration of IPAH-PASMCs was also suppressed by these channel blockers. Furthermore, increases in the proliferation and migration were inhibited by the siRNA knockdown of KCNK1 or KCNK2 channels. The siRNA knockdown also caused membrane depolarization and subsequent decrease in cytosolic [Ca2+]. The phosphorylated level of c-Jun N-terminal kinase (JNK) was elevated in IPAH-PASMCs compared to normal-PASMCs. The increased phosphorylation was significantly reduced by the siRNA knockdown of KCNK1 or KCNK2 channels. Collectively, these findings indicate that the up-regulated expression of KCNK1 and KCNK2 channels facilitates the proliferation and migration of PASMCs via enhanced Ca2+ signaling and JNK signaling pathway, which is associated with vascular remodeling in PAH.

Application of a modified clinical classification for pulmonary arterial hypertension associated with congenital heart disease in children: emphasis on atrial septal defects and transposition of the great arteries. An analysis from the TOPP registry.

A proportion of patients with pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD) do not fit in the current classification. We aimed to analyse the applicability of an adapted clinical classification of PAH-CHD to pediatric patients using the TOPP-1 registry (Tracking Outcomes and Practice in Pediatric Pulmonary Hypertension) and focus on atrial septal defects (ASD) and transposition of the great arteries (TGA). Hemodynamic and clinical data of all patients with PAH-CHD in the TOPP cohort were reviewed. Patients were classified according to predefined ABCDE categories (A: Eisenmenger syndrome, B: left-to-right shunt, C: coincidental defects, including all ASDs, D: corrected CHD, E: TGA), or as complex CHD (group 5), by 2 independent investigators. In case of disagreement, a third reviewer could either settle a final decision, or the patient was deemed not classifiable. Survival curves were calculated for each group and compared to idiopathic PAH patients of the registry. A total of 223 out of 531 patients in the registry had PAH-CHD, and 193 were categorized to the following groups: A 39(20%), B 27(14%), C 62(32%) including 43 ASDs, D 58(30%), E 7(4%), whereas 6 patients were categorized as group 5, and 10 patients were unable to be classified. No survival difference could be demonstrated between the groups. This modified classification seems to be more applicable to pediatric PAH-CHD patients than the previous classification, but some patients with PAH-CHD who never had a shunt remain unclassifiable. The role of ASD in pediatric PH should be reconsidered.

Peripheral microvascular function is linked to cardiac involvement on cardiovascular magnetic resonance in systemic sclerosis-related pulmonary arterial hypertension.

Systemic sclerosis (SSc) is characterized by vasculopathy, inflammation, and fibrosis, and carries one of the worst prognoses if patients also develop pulmonary arterial hypertension (PAH). Although PAH is a known prognosticator, patients with SSc-PAH demonstrate disproportionately high mortality, presumably due to cardiac involvement. In this cross-sectional study, the relationship between cardiac involvement revealed by cardiovascular magnetic resonance (CMR) and systemic microvascular disease severity measured with nailfold capillaromicroscopy (NCM) in patients with SSc-PAH is evaluated and compared with patients with idiopathic PAH (IPAH). Patients with SSc-PAH and IPAH underwent CMR, echocardiography, and NCM with post-occlusive reactivity hyperaemia (PORH) testing on the same day. CMR imaging included T2 (oedema), native, and post-contrast T1 mapping to measure the extracellular volume fraction (ECV, fibrosis) and adenosine-stress-perfusion imaging measuring the relative myocardial upslope (microvascular coronary perfusion). Measures of peripheral microvascular function were related to CMR indices of oedema, fibrosis, and myocardial perfusion. SSc-PAH patients (n = 20) had higher T2 values and a trend towards a higher ECV, compared with IPAH patients (n = 5), and a lower nailfold capillary density (NCD) and reduced capillary recruitment after PORH. NCD correlated with ECV and T2 (r = -0.443 and -0.464, respectively, P < 0.05 for both) and with markers of diastolic dysfunction on echocardiography. PORH testing, but not NCD, correlated with the relative myocardial upslope (r = 0.421, P < 0.05). SSc-PAH patients showed higher markers of cardiac fibrosis and inflammation, compared with IPAH patients. These markers correlated well with peripheral microvascular dysfunction, suggesting that SSc-driven inflammation and vasculopathy concurrently affect peripheral microcirculation and the heart. This may contribute to the disproportionate high mortality in SSc-PAH.

Impulse oscillometry in patients with pulmonary arterial hypertension: an exploratory study

IntroductionStudies suggest peripheral airway abnormalities in Pulmonary Arterial Hypertension (PAH). Impulse Oscillometry (IOS) is a noninvasive and sensitive technique for assessing the small airways. It evaluates the impedance of the respiratory system ‒ Resistance (R) and reactance (X) ‒ to a pulse of sound waves sent to the lungs, in a range of frequencies (5‒20 Hz). MethodResistance variables: R5, R20, R5-R20 and reactance variables: AX (reactance area) and Fres (resonance frequency). The aim is to evaluate R and X in patients with idiopathic PAH (IPAH) and to investigate whether there is a correlation between IOS and spirometry. ResultsThirteen IPAH patients and 11 healthy subjects matched for sex and age underwent IOS and spirometry. IPAH patients had lower FVC and FEV1 values (p < 0.001), VEF1/CVF (p = 0.049) and FEF 25-75 (p = 0.006) than healthy patients. At IOS, IPAH patients showed lower tidal volumes and higher AX (p < 0.05) compared to healthy individuals, and 53.8 of patients had R5-R20 values ≥ 0.07 kPa/L/s. Correlation analysis: X5, AX, R5-R20 and Fres showed moderate correlation with FVC (p = 0.036 r = 0.585, p = 0.001 r = -0.687, p = 0.005 r = -0.726 and p = 0.027 r = -0.610); Fres (p = 0.012 r = -0.669) and AX (p = 0.006 r = -0.711) correlated with FEV1; [R5 and R20, (R5-R20)] also correlated with FEV1 (p < 0.001 r = -0.573, p = 0.020 r = -0.634 and p = 0.010 r = -0.683, respectively) in the IPAH group. There were also moderate correlations of FEF 25–75 % with Z5 (p = 0.041), R5 (p = 0.018), Fres (p = 0.043) and AX (p = 0.023). DiscussionPatients showed changes suggestive of increased resistance and reactance in the IOS compared to healthy individuals, and the IOS findings showed a good correlation with spirometry variables.

Phenotypes and treatment outcomes in idiopathic pulmonary arterial hypertension patients with comorbidities.

Idiopathic pulmonary arterial hypertension (IPAH) is often diagnosed in elderly patients with many comorbidities. Whereas a clear treatment strategy and risk assessment is recommended for patients with rare classical IPAH, monotherapy with phosphodiesterase type 5 inhibitors or endothelin receptor antagonists followed by regular follow-up and individualised therapy should be used for patients with many cardiopulmonary comorbidities. Here, we focus on these patients with IPAH and comorbidities, present a review of the literature with a focus on recently published work and summarise factors that may help to provide guidance for individualised treatment approaches in such patients.

The impact of pulmonary hypertension on early postoperative period after lung transplantation with particular emphasis on kidney function

Abstract Background A special group of lung transplantation (LTx) recipients are patients diagnosed with pulmonary hypertension (PH) in the form of idiopathic pulmonary arterial hypertension (IPAH) or chronic lung diseases associated PH (CLD-PH). Acute left heart failure is a major complication observed in the early post-transplant period of patients with PH. To avoid post-transplant cardiac failure, the following measures may be implemented: use of intraoperative veno-arterial extracorporeal membrane oxygenation, administration of inotropic agents, a restrictive fluid management or use of continuous renal replacement therapy. Although, it remains unclear whether such a therapy affects long-term kidney function and patient survival. Purpose To analyze the influence of pulmonary hypertension diagnosis on early postoperative outcome including deterioration of renal function defined as the change in eGFR that occurred between baseline eGFR and the first and seventh day of observation post-LTx. Methods Retrospective data analysis of 79 patients undergoing lung transplantation in 2015-2018 in our institution with diagnosis of PH. Exclusion criterium was absence of 7 days observation post LTx or lack of PH diagnosis. The comparison of pre- and postoperative data was performed between IPAH (N=7) and CLD-PH (N=43) patients. Results We found differences in preoperative serum creatinine levels between IPAH and CLD-PH group (109,5 umol/l (70-126) vs 62,3 umol/l (49,3-73,4), respectively), p&amp;lt;0.05. The greatest decline of eGFR in the early postoperative period was demonstrated on day 7 in both groups (ΔeGFR=42,2±6,7 for CLD-PH group and 56,5±9,8 for IPAH group). Patients did not differ according to age, sex and BMI values. In IPAH group operation tend to last longer (657,9±78,2 min vs 539,6±111,6 min, p&amp;lt;0.05), all of them were performed with the use of cardiopulmonary bypass. All patients from IPAH group and 95,6% from CLD-PH group received inotropic support during LT procedure and early postoperative days. Duration of mechanical ventilation was statistically shorter among CLD-PH patients (2,9 days (0,8-1,4) vs 6,1 days (3,3-39), p&amp;lt;0.001). Conclusion It seems to be probable that pulmonary hypertension could be significant risk factor of kidney deterioration after lung transplantation. Identification of factors modifying renal insufficiency development in lung transplant recipients needs further investigations.

Abstract 12811: Incidence and Phenotypic Predictors of Arrhythmias in Idiopathic Pulmonary Arterial Hypertension

Introduction: Arrhythmias are common in patients with idiopathic pulmonary arterial hypertension (IPAH). However prospective analysis of arrhythmias in a large cohort of IPAH patients using implantable cardiac monitors (ICMs) is lacking. Aims: Establish the rate of arrhythmias in a prospective cohort of IPAH patients using ICMs. Determine factors that predict arrhythmia occurrence in IPAH. Elucidate whether arrhythmia incidence is related to adverse outcomes. Methods: ICMs were implanted into 80 IPAH patients across two UK centres. Arrhythmia and clinical worsening events (defined as death, transplant or hospitalisation due to PAH worsening) were prospectively recorded and characteristics associated with arrhythmia incidence identified. The arrhythmia rate in IPAH patients was compared to 72 age and sex-matched patients without IPAH who had ICMs implanted for clinical indications. Comparisons of data were performed using analysis of variance, χ2 or Kruskal-Wallis calculations as appropriate. The Cox proportional hazards model was used to resolve independent risk factors for significant arrhythmia occurrence. A two-tailed probability level of &lt;0.05 was considered significant. Results: Over 186 patient-years follow-up 79 arrhythmia events were noted in 40% IPAH patients vs 78 events in 41% comparators. Arrhythmia incidence was related to right atrial (RA) enlargement at time of implant, baseline conduction disease and symptom reporting. Arrhythmia incidence predicted clinical worsening (figure).20% of patients had targeted arrhythmia intervention as a direct consequence of ILR studies. Only RA size was independently associated with clinically significant arrhythmia on multivariate analysis Conclusion: Arrhythmias are frequent in IPAH patients and predict worse outcomes. RA enlargement is independently associated with clinically significant arrhythmia incidence. IPAH should be considered a high-risk group for continuous monitoring studies.

Abstract 17370: Activation of Endothelial GCN2 Kinase Contributes to Pulmonary Vascular Remodeling and Pulmonary Arterial Hypertension

Rationale: Pulmonary arterial hypertension (PAH) is characterized by progressive increase of pulmonary vascular resistance and pulmonary vascular remodeling that result in right heart failure. Published studies show that recessive mutations in the EIF2AK4 gene (encoding GCN2, General control nonderepressibe 2 kinase) resulting in reduction of GCN2 are linked to heritable pulmonary veno-occlusive disease (PVOD) in patients and EIF2AK4 mutation was also found in PAH patients although very rare. Objective: To determine the role of endothelial GCN2 kinase in the pathogenesis of PAH. Results: Employing Eif2ak4 -/- mice, we found that loss of GCN2 induced neither spontaneous PVOD nor pulmonary hypertension (PH). In response to chronic hypoxia, loss of GCN2 inhibited hypoxia-induced PH and pulmonary vascular remodeling. RNA-sequencing analysis of mouse lung samples indicated Endothelin-1 as the downstream target of GCN2 in regulating pulmonary vascular remodeling and PH. In cultured human lung microvascular endothelial cells, GCN2 was phosphorylated and activated in response to hypoxia, which mediated hypoxia-induced Endothelin-1 expression through the GCN2/ATF4/HIF-2a/Endothelin-1 pathway. Endothelial cell-targeted nanoparticle delivery of plasmid DNA expressing Endothelin-1 selectively in endothelial cells in Eif2ak4 -/- mice markedly reversed the phenotype in response to hypoxia. Furthermore, nanoparticle delivery of the CRIPSR/Cas9 system-mediated knockout of Eif2ak4 in adult C57BL/6 mice also attenuated hypoxia-induced PH. Additionally, monocrotaline-induced vascular remodeling and PH in rats were inhibited by GCN2 inhibitor A-92 treatment. In lung samples of idiopathic PAH patients, we observed endothelial GCN2 hyperphosphorylation of pulmonary vascular lesions, without marked differences in GCN2 mRNA and protein levels compared to normal donor lungs. Conclusion: These studies demonstrate that endothelial GCN2 activation mediates pulmonary vascular remodeling and PAH development through the GCN2/ATF4/HIF-2a/Endothelin-1 pathway. Targeting GCN2 signaling is a promising therapeutic strategy for treatment of PAH in patients without GCN2 loss of function mutations.

Metabolomic Differences in Connective Tissue Disease-Associated Versus Idiopathic Pulmonary Arterial Hypertension in the PVDOMICS Cohort.

Patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) experience worse survival and derive less benefit from pulmonary vasodilator therapies than patients with idiopathic PAH (IPAH). We sought to identify differential metabolism in patients with CTD-PAH versus patients with IPAH that might underlie these observed clinical differences. Adult participants with CTD-PAH (n=141) and IPAH (n=165) from the Pulmonary Vascular Disease Phenomics (PVDOMICS) study were included. Detailed clinical phenotyping was performed at cohort enrollment, including broad-based global metabolomic profiling of plasma samples. Participants were followed prospectively for ascertainment of outcomes. Supervised and unsupervised machine learning algorithms and regression models were used to compare CTD-PAH versus IPAH metabolomic profiles and to measure metabolite-phenotype associations and interactions. Gradients across the pulmonary circulation were assessed using paired mixed venous and wedged samples in a subset of 115 participants. Metabolomic profiles distinguished CTD-PAH from IPAH, with patients with CTD-PAH demonstrating aberrant lipid metabolism with lower circulating levels of sex steroid hormones and higher free fatty acids (FAs) and FA intermediates. Acylcholines were taken up by the right ventricular-pulmonary vascular (RV-PV) circulation, particularly in CTD-PAH, while free FAs and acylcarnitines were released. In both PAH subtypes, dysregulated lipid metabolites, among others, were associated with hemodynamic and RV measurements and with transplant-free survival. CTD-PAH is characterized by aberrant lipid metabolism that may signal shifted metabolic substrate utilization. Abnormalities in RV-PV FA metabolism may imply a reduced capacity for mitochondrial beta oxidation within the diseased pulmonary circulation.

Clinical features and long-term survival in idiopathic pulmonary arterial hypertension with thyroid dysfunction: insights from a national multicentre prospective study.

Our objective was to clarify the characteristics and long-term survival of idiopathic pulmonary arterial hypertension (IPAH) patients with thyroid dysfunction and compare them with IPAH without thyroid dysfunction. A retrospective analysis was conducted using prospectively collected data. IPAH patients with thyroid dysfunction at baseline were included. Patients with other subgroups of PAH and Group 2-5 pulmonary hypertension were excluded. IPAH patients with euthyroid function were matched 1:1 to IPAH patients with thyroid dysfunction by age and sex. In total, 148 IPAH patients with thyroid dysfunction were included. Patients with hyperthyroidism, hypothyroidism, subclinical hyperthyroidism and subclinical hypothyroidism accounted for 16.2%, 18.9%, 8.1% and 56.8%, respectively. IPAH patients with hyperthyroidism showed the highest mixed venous oxygen saturation (SvO2) and the lowest pulmonary vascular resistance (PVR) at baseline among subgroups, while patients with subclinical hypothyroidism had the lowest SvO2 and highest PVR (p<0.05). Compared with IPAH without thyroid dysfunction, patients with hyperthyroidism (9.14 versus 13.86 WU; p<0.05) and hypothyroidism (10.70 versus 13.86 WU; p<0.05) showed significantly lower PVR. The haemodynamic profiles of patients with subclinical hypothyroidism were similar to IPAH with euthyroid function except for lower right atrial pressure (6 versus 8 mmHg; p=0.009). The long-term survival of patients with clinical thyroid dysfunction was better than IPAH without thyroid dysfunction, while that of those with subclinical diseases was comparable to the latter, even after adjusting for baseline haemodynamics and treatment. IPAH patients with clinical hyper- and hypothyroidism had better haemodynamics and survival than those without thyroid dysfunction, while patients with subclinical hypothyroidism had similar haemodynamics and survival profiles to the latter.

Possibility of evaluation of oxygen transport function in PAH patients on effective selexipag-based therapy

In the complex pathogenesis of idiopathic pulmonary arterial hypertension (IPAH), which includes changes in biochemical and biophysical processes in various cell types as the cause of structural and functional impairment, inflammation and thrombosis of the pulmonary vessels, hypoxia also plays an important role due to conformational changes in hemoglobin molecules with changes in their structure and oxygen transport function impairment.Aim: Using the method of Raman (Raman scattering) spectroscopy, to study changes in the conformation and ability of hemoglobin (Hb) to bind oxygen in blood erythrocytes from the cubital vein in IPAH patients and healthy people. Materials and methods: The study included 39 patients with newly diagnosed IPAH with functional class I – 2 patients, II – 13 patients, III – 22 patients, IV – 2 patients. 15 patients were treatment naive. In 24 patients a “washout” period of trial therapy was conducted for 5–7 days. The control group included 10 healthy volunteers.Results: It was established that the Raman spectra of Hb of whole blood erythrocytes and isolated red blood cells (RBC) of IPAH patients have significant differences from the control group. The IPAH group was characterized by an increase in the probability of finding heme in a «dome-shaped form», which is typical for the deoxygenated form of Hb, changes in the conformation of globin and the porphyrin macrocycle were revealed. A significant role in the change in the oxygen-transport function of Hb in IPAH was played by a change in the conformation of membrane-bound hemoglobin, which was characterized by an increase in the contribution of symmetrical vibrations of pyrrole rings in hemoporphyrin relative to the control, which required further study. Probably, the reason for the decrease in the ability of the oxygen transport function of membrane-bound hemoglobin was the decrease in the efficiency of electrostatic interaction with the protein of band 3. In clinical case positive changes in spectroscopy parameters were shown in IPAH patient with the effective use of selexipag.Conclusions: For the first time, the possibility of using a non-invasive method of Raman spectroscopy to study changes in the oxygen transport function of erythrocytes in IPAH patients has been proven, which can serve as an additional method in the diagnostic algorithm of this disease.

Pulmonary artery dilatation in different causes of pulmonary hypertension

AbstractPulmonary artery (PA) dilatation is commonly observed in patients with pulmonary hypertension (PH). However, the clinical aspects of PA dilatation in various etiology of PH remain unknown. In this study, we investigated the clinical and imaging characteristics of 1018 patients with different subtypes of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). The independent determinants for all‐cause death were identified using univariate and multivariate Cox proportional hazard models. PA dilatation was identified in 88.8% of the patients, and 27.2% had a PA diameter/ascending aorta diameter ratio greater than 1.5. PA diameter was shown to be significantly correlated with hemodynamic parameters and symptom duration in idiopathic PAH patients. PA diameter only correlated with pulmonary circulation volume in patients with PAH associated with congenital heart disease. PA diameter correlated with symptom duration and right ventricular end‐diastolic dimension in CTEPH patients. PA diameter correlated with right ventricular end‐diastolic dimension in patients with PAH associated with connective tissue disease. Only 6‐min walk distance, but not PA dilatation, predicts all‐cause death independently. In conclusion, PA dilatation is a common finding in PH patients. The clinical feature of PA dilatation varies greatly between PH types. PA dilatation is not associated with all‐cause death.

Generation of two induced pluripotent stem cell lines from patients suffering from pulmonary hypertension

Idiopathic pulmonary arterial hypertension (IPAH) is a rare disease, with an estimated 500–1000 new cases diagnosed every year. A portion of these cases may be caused by mutations in the BMPR2 gene, suggesting a possible genetic component in the development of the disease. Here, we report two human induced pluripotent stem cell (iPSC) lines generated from IPAH patients. Both cell lines provide valuable insight into the molecular and cellular mechanisms of IPAH and can be used to further understand the disease.

The Impact of Abnormal Lipid Metabolism on the Occurrence Risk of Idiopathic Pulmonary Arterial Hypertension.

The aim was to determine whether lipid molecules can be used as potential biomarkers for idiopathic pulmonary arterial hypertension (IPAH), providing important reference value for early diagnosis and treatment. Liquid chromatography-mass spectrometry-based lipidomic assays allow for the simultaneous detection of a large number of lipids. In this study, lipid profiling was performed on plasma samples from 69 IPAH patients and 30 healthy controls to compare the levels of lipid molecules in the 2 groups of patients, and Cox regression analysis was used to identify meaningful metrics, along with receiver operator characteristic curves to assess the ability of the lipid molecules to predict the risk of disease in patients. Among the 14 lipid subclasses tested, 12 lipid levels were significantly higher in IPAH patients than in healthy controls. Free fatty acids (FFA) and monoacylglycerol (MAG) were significantly different between IPAH patients and healthy controls. Logistic regression analysis showed that FFA (OR: 1.239, 95%CI: 1.101, 1.394, p < 0.0001) and MAG (OR: 3.711, 95%CI: 2.214, 6.221, p < 0.001) were independent predictors of IPAH development. Among the lipid subclasses, FFA and MAG have potential as biomarkers for predicting the pathogenesis of IPAH, which may improve the early diagnosis of IPAH.

Comprehensive analysis of m6A methylomes in idiopathic pulmonary arterial hypertension

ABSTRACT Idiopathic pulmonary arterial hypertension (IPAH) is a serious and fatal disease. Recently, m6A has been reported to play an important role in the lungs of IPAH patients and experimental pulmonary hypertension models. However, the meaning of m6A mRNAs in the peripheral blood of IPAH patients remains largely unexplored. We aimed to construct a transcriptome-wide map of m6A mRNAs in the peripheral blood of IPAH patients. M6A RNA Methylation Quantification Kit was utilized to measure the total m6A levels in the peripheral blood of IPAH patients. A combination of MeRIP-seq, RNA-seq and bioinformatics analysis was utilized to select m6A-modified hub genes of IPAH. MeRIP-qPCR and RT-qPCR were used to measure the m6A levels and mRNA levels of TP53, RPS27A, SMAD3 and FoxO3 in IPAH patients. Western blot was performed to assess the protein levels of m6A related regulators and m6A related genes in experimental PH animal models, hypoxia-treated and PDGF-BB induced PASMCs. We found that the total m6A levels were increased in peripheral blood of IPAH patients and verified that m6A levels of RPS27A and SMAD3 were significantly elevated and m6A levels of TP53 and FoxO3 were significantly reduced. The mRNA or protein levels of RPS27A, SMAD3, TP53 and FoxO3 were changed in human blood samples, experimental PH animal models and PDGF-BB induced PASMCs. Moreover, METTL3 and YTHDF1 were increased in the hypoxia induced pulmonary hypertension rat model, hypoxia-treated and PDGF-BB induced PASMCs. These finding suggested that m6A may play an important role in IPAH.