Idiopathic Pulmonary Arterial Hypertension Group Research Articles

Demographic, hemodynamic characteristics, and therapeutic trends of pulmonary hypertension patients: The Pulmonary Hypertension Mexican registry (REMEHIP).

Data on demographic characteristics and therapeutic approaches in Latin American pulmonary arterial hypertension (PAH) patients are scarce. Pulmonary Hypertension Mexican registry (REMEHIP) is a multicenter Mexican registry of adult and pediatric patients, including prevalent and incident cases. Objective: assess clinical characteristics, treatment trends, and in-hospital outcomes. Inclusion: age >2 years, diagnosis of pulmonary hypertension(PH) (groups 1 and 4),right heart catheterization with mPAP ≥25 mmHg, PWP ≤ 15 mmHg, and PVR > 3 Wood unit(WU). We included 875 PH patients, 619 adults, 133 pediatric idiopathic PAH (IPAH), and 123 chronic thromboembolic pulmonary hypertension (CTEPH) patients. We enrolled 48.4% of the incident and 51.6% of the prevalent adult and pediatric patients. PAH adults: age 43 ± 15, females 81.9%, functional class (FC) (I/II) 66.5%, 6-min walk distance (6MWD)378 ± 112 m, mPAP 57.3 ± 19.0 mmHg, confidence interval (CI) 3.3 ± 1.5 L/min/m2, PVR 12.0 ± 8.1 WU. PAH pediatrics: age 9 ± 5, females 51.1%, FC (I/II) 85.5%, 6MWD 376 ± 103 m, mPAP 49.7 ± 13.4 mmHg, CI 2.6 ± 0.9 L/min/m2, PVR 16.4 ± 13.5 WU. CTEPH: age 44 ± 17, females 56.1%, FC (I/II) 65.5%, 6MWD 369 ± 126 m, mPAP 49.7 ± 13.4 mmHg, CI 2.6 ± 0.9 L/min/m2, PVR 10.5 + 6.5 WU. When we analyzed the IPAH group separately, it sustained a high functional class I/II incidence. REMEHIP shows better functional class in young females with severe PAH than in American and European patients. Also, PAH pediatric patients had a better functional class than other registries. However, our registry also shows that our population's access to specific pharmacologic treatments is still far from optimal.

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.

Results of long-term riociguat therapy, including a switching strategy from sildenafil, in patients with pulmonary hypertension of various genesis

Aim: to study the influence of riociguat on the functional and hemodynamic status, remodeling of the right heart, as well as the safety of therapy in both previously untreated patients with idiopathic pulmonary arterial hypertension (IPAH) and inoperable chronic thromboembolic PH (CTEPH), and those not achieved treatment goals with sildenafil therapy and switching to riociguat.Materials and methods. A total of 161 pts with precapillary PH were included in the study; 137 pts completed the three-year observation period. Of 55 IPAH pts riociguat was started after diagnosis verification in 39 pts (subgroup 1); 16 pts previously taking sildenafil who did not achieve treatment goals comprised subgroup 2 of switching to riociguat. Of 82 inoperable CTEPH pts riociguat was started in 45 naїve pts; a switching strategy riociguat was implemented in 37 pts after 24-hour withdrawal of sildenafil. The dose titration of riociguat was started from 1 mg TID according to the standard algorithm up to 7.5 mg/day. By month 36 92.4% and 94.8% of pts with IPAH and CTEPH, respectively, received 7.5 mg/day. At baseline, at month 12, 24 and 36 all pts underwent a 6-minute walking test (6MWT) with the assessment of the dyspnea index according to the Borg scale and SpO2, echocardiography (Echo), right heart catheterization (RHC), and the safety profile was assessed.Results. At baseline, the proportion of pts with FC III-IV in CTEPH group compared to IPAH group, was significantly higher (70.7% vs 41.8%)); the distance in T6MX (d6MWT) was 291 [232;385] m vs 379 [300;448] m (p&lt;0.001). CTEPH pts had lower values of sPAP, PVR, SaO2 and SvO2 assessed by RHC. In the switching subgroups 2 of pts with IPAH and CTEPH, achieved levels of sPAP (p=0.01), sRAP (p=0.001) and PVR (p=0.01) (RHC) were significantly lower than in subgroups 1. The baseline levels of CI and SV were significantly higher in subgroups 2 (p&lt;0.05). During riociguat treatment in both subgroups of IPAH, a significant increase in d6MWT was achieved by 6 months with FC I-II (WHO) in 75% and 70% of patients. In the subgroup 1 to 36 months the greatest increase by 97m was achieved; in the switching subgroup the increase in d6MWT was noticed by month 6, which was maintained by month 36. In CTEPH patients, there was a significant improvement in FC (p=0.001) with ∆dT6MX 48m (p=0.001). In subgroup 1 with CTEPH, the d6MWT increase was 68.2m (p = 0.001), reaching 82.6m by month 36. In subgroup 2 the significant change of d6MWT were noted by the 1st year of FU, reaching 136.6m by month 36. In IPAH and CTEPH pts by month 36 of riociguat therapy, a significant decrease of mPAP, SPAP were found by echo, which was confirmed by RHC; there was a decrease in the basal size of the right ventricle (RV) (p=0.04) and an increase in RV FAC (p=0.04 and p=0.03, respectively). In subgroups 1, ∆SvO2 in ts with IPAH and CTEPH were significantly higher compared to subgroups 2. During FU period the proportion of low-risk pts increased to 26.7% in IPAH group and 44.8% in CTEPH group at month 36. In subgroups 2 riociguat therapy resulted in maintenance of treatment regimens throughout the year. Only 6.2% of pts by month 24 and 36 required the prescription of a 3d specific drug. No serious adverse events (AEs) were observed during treatment. The most common AEs were nasopharyngitis, nasal congestion, and dyspnea.Conclusions: Riociguat therapy for 36 months demonstrated a persistent positive effect on the functional and hemodynamic status, remodeling of the right heart both in previously untreated patients with IPH and inoperable CTEPH, and in patients from the switching groups who did not achieve treatment goals with sildenafil therapy.

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.

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.

Analysis of relationship between P wave dispersion and diagnosis of pulmonary arterial hypertension and risk stratification

BackgroundThe aim of this study was to measure the P-wave dispersion(PWD) in the ECG of patients with pulmonary arterial hypertension(PAH). MethodsA total of 103 PAH patients were collected, including 55 patients related with congenital heart disease(CHD) and 44 patients with idiopathic pulmonary arterial hypertension(IPAH). In addition, 30 CHD patients without PAH (nPAH-CHD group) and 30 healthy controls (HCG group) were collected as control. Patients in the PAH group were categorized into the low-risk group (30 cases), moderate-risk group (53 cases) and high-risk group (20 cases), followed by comparison of PWD difference between groups. The ROC curve was used to evaluate the diagnostic efficacy of PWD on PAH-CHD and IPAH. ResultsThe levels of PWD and maximum P wave duration(Pmax) in PAH-CHD and IPAH group were significantly higher than those in nPAH-CHD and HCG group (P < 0.05). PWD level was positively correlated with right ventricular end-diastolic diameter(RVD), right atrial end-systolic diameter(RAS), mean pulmonary arterial pressure(mPAP), pulmonary vascular resistance(PVR)(r = 0.407, 0.470, 0.477, 0.423, P < 0.001), and was negatively correlated with systolic displacement of tricuspid valve annulus(TAPSE) level (r = −0.551, P < 0.001). After risk quantification in 103 PAH patients, we found that PWD was significantly different among the low-risk, moderate-risk and high-risk groups (43.89 ± 9.91 vs. 51.29 ± 6.61, 62.15 ± 10.44, P < 0.001). CHD-PAH and IPAH were identified by PWD with a cut off value of 41.5 ms (P < 0.001), and a cut off value of 41.45 ms (P < 0.001), respectively. ConclusionsPWD might be an effective ECG indicator for PAH, which might be used as a relatively economical indicator for PAH patients to assist in early diagnosis, disease severity assessment and prognosis evaluation.

Left ventricular dysfunction and intra-ventricular dyssynchrony in idiopathic pulmonary arterial hypertension

BackgroundLeft ventricular (LV) filling pressures are normal in idiopathic pulmonary arterial hypertension (IPAH). However, direct and indirect interactions between the RV and LV can affect LV performance. We explored LV strain and LV intra-ventricular dyssynchrony in IPAH using feature tracking CMR (CMR-FT). MethodsSeventy IPAH patients and 40 healthy volunteers were included. Patients underwent CMR and right heart catheterisation. The 4-chamber cine was used to calculate LV longitudinal strain (EllLV). LV circumferential (EccLV) and radial strain (ErrLV) were derived from a short axis cine. LV longitudinal, circumferential and radial intra-ventricular dyssynchrony indices were calculated. ResultsThere were no differences between the IPAH and healthy volunteer group in LV ejection fraction (66.1% vs 64.2% p = 0.6672). EccLV (−29.1 vs −32.1 p = 0.0323) and EllLV (−16.6 vs −23.7 p < 0.0001) were lower in IPAH. In patients with more severe disease, there was greater impairment of ErrLV compared to mild disease (50.9 vs 87.5 P < 0.0001). LV synchrony was impaired in all directions in IPAH. ErrLV was associated with RV ejection fraction (r = 0.66), RV end-systolic volume index (r = −0.59), pulmonary vascular resistance (PVR)(r = 0.51) and stroke volume index (SVI)(r = 0.44). In a multivariate model with age, SVI and PVR, ErrLV (HR 0.970 p = 002) and radial dyssynchrony (HR 3.759 p < 0.0001) independently predicted survival. ConclusionIn IPAH, LV is dyssynchronous with impaired function. Measures of LV strain and intraventricular synchrony were associated with known markers of disease severity. These LV variables which are likely to be related to ventricular interaction, may add incremental value to known prognostic variables in IPAH.

Gene expression signature analysis of peripheral blood mononuclear cells from patients with for high altitude pulmonary hypertension and value for potential drug selection

Objective: To investigate the gene expression characteristics of peripheral blood mononuclear cells from patients with high altitude pulmonary hypertension (HAPH) in Naxi residents living in Lijiang, Yunnan, and to explore the underlying pathogenesis and value for potential drug selection. Methods: This is a case-control study. Six patients with HPAH (HPAH group) and 4 normal subjects (control group) were selected from the Naxi residents who originally lived in Lijiang, Yunnan Province. The general clinical data of the two groups were collected, and the related indexes of pulmonary artery pressure were collected. Peripheral blood mononuclear cells of the subjects were collected for RNA sequencing. The differences on gene expression, regulatory network of transcription factors and drug similarity between the two groups were compared. The results were compared with the public data of idiopathic pulmonary arterial hypertension (IPAH). Biological processes and signal pathways were analyzed and compared between HPAH and IPAH patients. Results: The age of 6 patients with HAPH was (68.1±8.3) years old, and there were 2 males (2/6). The age of 4 subjects in the control group was (62.3±10.9) years old, and there were 2 males (2/4). Tricuspid regurgitation velocity, tricuspid pressure gradient and pulmonary systolic pressure in HAPH group were significantly higher than those in control group (all P<0.05). The results of RNA sequencing showed that compared with the control group, 174 genes were significantly upregulated and 169 genes were downregulated in peripheral blood mononuclear cells of HAPH group. These differentially expressed genes were associated with 220 biological processes, 52 molecular functions and 23 cell components. A total of 21 biological processes and 2 signal pathways differed between HPAH and IPAH groups, most of which were related to inflammation and immune response. ZNF384, SP1 and STAT3 were selected as highly correlated transcription factors by transcription factor prediction analysis. Trichostatin A and vorinostat were screened out as potential drugs for the treatment of HAPH by drug similarity analysis. Conclusions: There are significant differences in gene expression in peripheral blood monocytes between HAPH patients and normal population, and inflammation and immune dysfunction are the main pathogenic factors. Trichostatin A and Vorinostat are potential drugs for the treatment of HAPH.

LOW LEVELS OF COAGULATION FACTOR XI AND XII IN CHRONIC THROMBOEMBOLIC PULMONARY HYPERTENSION COMPARED WITH PUMONARY EMBOLISM

TYPE: Late Breaking Abstract TOPIC: Pulmonary Vascular Disease PURPOSE: We aimed to explore the difference of coagulation factor XI and XII in chronic thromboembolic pulmonary hypertension (CTEPH), pulmonary embolism (PE) and idiopathic pulmonary arterial hypertension (IPAH). METHODS: The retrospectively cross-sectional study included 316 patients from June 2013 to June 2017. Plasma activity of factor XI and XII were measured and compared in 111 CTEPH patients, 82 APE survivors, who have not developed chronic pulmonary hypertension after at least 2 years from the acute episode, and123 IPAH patients. All the clinical and laboratory profiles were documented after a full anti-coagulation therapy at least for 3 months in PE and CTEPH patients. RESULTS: In CTEPH patients, factor XI activity was significant lower than in PE patients (P<0.001) and IPAH group (P<0.001), while PE was higher than IPAH patients. Factor XII activity of CTEPH was lower than PE patients’ (P<0.001) while comparable to IPAH. Receiver-operating characteristic curves showed the great performance of factor XI and XII activity in distinguishing PE from CTEPH. Besides, Adjustment for age, gender, BMI, antiphospholipid antibody syndrome, autoimmune diseases, thyroid replacement therapy, splenectomy, and blood group didn’t change the effect size of every 10% increase of factor XI and XII activity for risk of CTEPH (OR = 0.78, 95%Cl 0.70-0.87 and 0.90, 95%Cl 0.83-0.98). CONCLUSIONS: Plasma XI and XII activity seems to represent important factors in CTEPH pathophysiology and may have been continuously consumed during the whole process of its pathophysiology, which may contribute to the clinical diagnosis and therapy. CLINICAL IMPLICATIONS: This results may contribute to the clinical diagnosis and therapy. DISCLOSURE: Nothing to declare. KEYWORD: FACTOR XI; FACTOR XII; CTEPH; PULMONARY EMBOLISM

The Different Effects of Direct Bilirubin on Portopulmonary Hypertension and Idiopathic Pulmonary Arterial Hypertension.

Background To observe different roles of direct bilirubin (Dbil) on portopulmonary hypertension (POPH) and idiopathic pulmonary arterial hypertension (IPAH). Methods Thirty incident patients with POPH and 180 with IPAH (matched by the WHO functional classification in a 1 : 6 ratio) between March 2010 and December 2020 were included. The receiver operating curve and Kaplan–Meier method were applied to estimate the ability to distinguish between the two and survival, respectively. Univariate and forward multiple stepwise regression analyses were performed to access the relationship between pulmonary vascular resistance (PVR) and clinical indices. Results Compared to IPAH, the POPH group had better hemodynamics including PVR (7.08 ± 3.95 vs. 14.89 ± 7.11, P < 0.001) and higher total bilirubin (Tbil) and Dbil. Tbil and Dbil had a negative correlation with PVR in the POPH group (r = −0.394, P=0.031; r = −0.364, P=0.048, respectively) but positive correlation in the IPAH group (r = 0.218, P=0.003; r = 0.178, P=0.018, respectively). Increased neutrophil counts (r = 0.394, P=0.031) and elevated NT-proBNP (r = 0.433, P < 0.001) would help predict the elevation of PVR in POPH and IPAH groups independent of Dbil, respectively. Dbil could distinguish POPH from IPAH (AUC = 0.799, P=0.009), and the ability was elevated when taking aspartate aminotransferase together (AUC = 0.835, P < 0.001). The overall survival was better in POPH than in IPAH (7 dead cases of POPH and 96 of IPAH, P=0.002). Survival was better in POPH than in IPAH in the group of Dbil ≥7 μmol/L (P=0.001) but showed no significant difference between POPH and IPAH in the group of Dbil <7 μmol/L (P=0.192). Conclusions The POPH group had a better hemodynamic profile than IPAH. Dbil was associated oppositely with the elevation of PVR in POPH and IPAH. Patients with POPH had better survival than those with IPAH in the total cohort and in the group of Dbil ≥7 μmol/L, but limited dead cases of POPH should be noted.

Identification of Crucial Hub Genes and Differential T Cell Infiltration in Idiopathic Pulmonary Arterial Hypertension Using Bioinformatics Strategies.

Background: Idiopathic pulmonary arterial hypertension (IPAH) is a life-threatening disease. Growing evidence indicated that IPAH is a chronic immune disease. This study explored the molecular mechanisms and T cell infiltration of IPAH using integrated bioinformatics methods. Methods: Gene expression profiles of dataset GSE113439 were downloaded from the Gene Expression Omnibus and analyzed using R. Protein-protein interaction (PPI) network and gene set enrichment analysis (GSEA) were established by NetworkAnalyst. Gene Ontology enrichment analysis was performed using ClueGO. Transcription factors of differentially expressed genes (DEGs) were estimated using iRegulon. Transcription factors and selected hub genes were verified by real-time polymerase chain reaction (qPCR) in the lung tissues of rats with pulmonary artery hypertension. The least absolute shrinkage and selection operator regression model and the area under the receiver operating characteristic curve (AUC) were applied jointly to identify the crucial hub genes. Moreover, immune infiltration in IPAH was calculated using ImmuCellAI, and the correlation between key hub genes and immune cells was analyzed using R. Results: A total of 512 DEGs were screened, and ten hub genes and three transcription factors were filtered by the DEG PPI network. The DEGs were mainly enriched in mitotic nuclear division, chromosome organization, and nucleocytoplasmic transport. The ten hub genes and three transcription factors were confirmed by qPCR. Moreover, MAPK6 was identified as the most potent biomarker with an AUC of 100%, and ImmuCellAI immune infiltration analysis showed that a higher proportion of CD4-naive T cells and central memory T cells (Tcm) was apparent in the IPAH group, whereas the proportions of cytotoxic T cells (Tc), exhausted T cells (Tex), type 17 T helper cells, effector memory T cells, natural killer T cells (NKT), natural killer cells, gamma-delta T cells, and CD8 T cells were lower. Finally, MAPK6 was positively correlated with Tex and Tcm, and negatively correlated with Tc and NKT. Conclusion: MAPK6 was identified as a crucial hub gene to discriminate IPAH from the normal group. Dysregulated immune reactions were identified in the lung tissue of patients with IPAH.

Prognostic Value of Follicle-Stimulating Hormone Levels in Predicting Survival in Men With Idiopathic Pulmonary Arterial Hypertension.

The objective of the study was to assess the association between changes in plasma follicle-stimulating hormone (FSH) and the potential effect on idiopathic pulmonary arterial hypertension (IPAH) in male patients. A total of 116 male patients with IPAH and 53 healthy controls were included from XX Hospital. Plasma FSH concentration was assessed in all participants. Receiver operating characteristic curves were used to assess the mortality risk. Kaplan–Meier curve and Cox regression analyses were used to predict the value of FSH on the survival rate of male IPAH patients. The plasma FSH concentration in the IPAH group was significantly higher than that in the control group (p = .017). Nonsurvivors had significantly higher levels of FSH than survivors (p < .0001). FSH levels were positively correlated with World Health Organization Functional Class, mean pulmonary artery pressure, and pulmonary vascular resistance (PVR; p = .023, p < .0001, and p < .0001, respectively) and negatively correlated with 6-min walk distance (6MWD) and cardiac output (CO; p = .004 and p = .010). Cox regression model analysis showed that the levels of FSH were also the independent factors of mortality in male IPAH patients (p < .0001). The IPAH patients with higher FSH levels had higher PVR, lower 6MWD, CO, and a lower survival rate (p = .042, p = .003, p = .029, and p < .0001, respectively). Therefore, we identified that increased FSH levels were associated with disease severity in male patients with IPAH and independently predicted risk of disease and poor survival rate.

Impact of cyanosis on ventilatory responses during stair climb exercise in Eisenmenger syndrome and idiopathic pulmonary arterial hypertension

Studies assessing exercise ventilatory responses during real-life exercise in pulmonary arterial hypertension (PAH) which include patients with cyanotic congenital heart disease are scarce. We assessed the ventilatory response to stairclimbing in patients with idiopathic PAH (IPAH) and congenital heart disease-associated PAH with Eisenmenger (EIS) physiology compared to healthy controls. Fifteen adults with IPAH, six EIS and 15 age and body mass index (BMI) matched controls were prospectively recruited. Participants completed spirometry and a self-paced stair-climb (48 steps) with portable cardiopulmonary exercise testing (CPET) equipment in-situ. Borg dyspnoea scores were measured at rest and on stair-climb cessation. Both IPAH and EIS groups had amplified ventilatory responses compared to Controls. The rate of increase in minute ventilation (VE) was exaggerated in EIS driven by an early increase in tidal volume (Tv) and more gradual increase in respiratory rate (RR). Peak Tv, RR, Tv: forced vital capacity (FVC) ratio, VE/VCO2 slope and stairclimb duration were significantly higher in EIS and IPAH compared to controls despite similar baseline spirometry and change in oxygen uptake on exercise. A decline in end-tidal carbon dioxide (CO2) and arterial oxygen saturations in early exercise distinguished EIS and IPAH patients. Significant correlations were observed between peak exercise Borg score and stair-climb time (r = 0.73, p = 0.002), peak end-tidal CO2 (r = −0.73, p = 0.001), peak VE (r = 0.53, p = 0.008), peak RR (r = 0.42, p = 0.011) and VE/VCO2 slope (r = 0.54, p = 0.001). Patients with IPAH and EIS have exaggerated ventilatory responses to stair-climbing compared to the controls with more severe levels of dyspnoea perception in Eisenmenger syndrome for equivalent oxygen uptake and work.

Peripheral Arterial Stiffness in Acute Pulmonary Embolism and Pulmonary Hypertension at Short-Term Follow-Up.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a severe and under-recognized complication of acute pulmonary embolism (PE). Forty consecutive patients with acute PE (Group 1), predominantly female (22, 55%) with a mean age of 69 ± 15 years, were matched for demographic data with 40 healthy subjects (Group 2), 40 systemic hypertension patients (Group 3) and 45 prevalent idiopathic pulmonary arterial hypertension (IPAH) patients (Group 4). The baseline evaluation included physical examination, NYHA/WHO functional class, right heart catheterization (RHC) limited to IPAH patients, echocardiographic assessment and systemic arterial stiffness measurement by cardio-ankle vascular index (CAVI). Patients with PE underwent an echocardiographic evaluation within 1 month from hospital discharge (median 27 days; IQR 21–30) to assess the echo-derived probability of PH. The CAVI values were significantly higher in the PE and IPAH groups compared with the others (Group 1 vs. Group 2, p < 0.001; Group 1 vs. Group 3, p < 0.001; Group 1 vs. Group 4, p = ns; Group 4 vs. Group 2, p < 0.001; Group 4 vs. Group 3, p < 0.001; Group 2 vs. Group 3, p = ns). The predicted probability of echocardiography-derived high-risk criteria of PH increases for any unit increase of CAVI (OR 9.0; C.I.3.9–20.5; p = 0.0001). The PE patients with CAVI ≥ 9.0 at the time of hospital discharge presented an increased probability of PH. This study highlights a possible positive predictive role of CAVI as an early marker for the development of CTEPH.

Inspiratory flow patterns with dry powder inhalers of low and medium flow resistance in patients with pulmonary arterial hypertension.

Inhalation profiles to support use of dry powder inhalers for drug delivery in patients with pulmonary arterial hypertension have not been reported. We aimed to evaluate the inspiratory flow pattern associated with low and medium flow resistance dry powder inhaler devices (RS01-L and RS01-M, respectively) in patients with pulmonary arterial hypertension. This single-center study enrolled patients with pulmonary arterial hypertension associated with connective tissue disease (n = 10) and idiopathic pulmonary arterial hypertension (n = 10) to measure the following inhalation parameters: inspiratory effort (kPa), peak inspiratory flow rate (L/min), inhaled volume (L), and flow increase rate (L/s2) using the two devices. We identified a trend toward higher mean pulmonary artery pressure in the idiopathic pulmonary arterial hypertension group (50 ± 13 mmHg vs. 40 ± 11 mmHg in pulmonary arterial hypertension associated with connective tissue disease; p = 0.077). On average, peak inspiratory flow rate was higher with RS01-L vs. RS01-M (84 ± 19.7 L/min vs. 70.4 ± 13.2 L/min; p = 0.015). In the overall group, no differences between RS01-L and RS01-M were observed for inhaled volume, inspiratory effort, or flow increase rate. Inhaled volume with RS01-L was higher in pulmonary arterial hypertension associated with connective tissue disease vs. idiopathic pulmonary arterial hypertension patients: 1.6 ± 0.4 L vs. 1.3 ± 0.2 L; p = 0.042. For the RS01-L, inhaled volume correlated with forced expiratory volume in one second (r = 0.460, p = 0.030) and forced vital capacity (r = 0.507, p = 0.015). In patients with pulmonary arterial hypertension associated with connective tissue disease using RS01-L, both inspiratory effort and flow increase rate were highly correlated with pulmonary vascular compliance (r = 0.903, p = 0.0001 and r = 0.906, p = 0.0001; respectively); while with RS01-M, inspiratory effort was highly correlated with pulmonary vascular compliance (r = 0.8, p = 0.001). Our data suggest that the use of RS01-L and RS01-M dry powder inhaler devices allowed adequate inspiratory flow in pulmonary arterial hypertension patients. The correlation between flow increase rate and pulmonary vascular compliance in pulmonary arterial hypertension associated with connective tissue disease deserves further investigation.

Endostatin and Vascular Endothelial Growth Factor-A165b May Contribute to Classification of Pulmonary Hypertension.

Background: Pulmonary hypertension (PH) is characterized by dysregulation of small pulmonary arteries. In addition to endostatin (ES), placenta growth factor (PlGF), vascular endothelial growth factor-A (VEGF-A), and the anti-angiogenesis isoform of VEGF-A (VEGF-A165b) are associated with PH. However, the usefulness of these biomarkers in PH in unknown. We investigated whether these 4 biomarkers are related to PH classification.Methods and Results: Between July 2015 and August 2017, 33 control patients and 107 PH patients were enrolled in the study. Among the PH patients, 48 had pulmonary arterial hypertension (PAH), 5 had left heart disease-associated PH (LHD-PH), 4 had lung disease-associated PH (LD-PH), and 50 had chronic thromboembolic PH (CTEPH). Among the PAH patients, 16 had idiopathic PAH (IPAH) and 17 had connective tissue disease-associated PAH (CTD-PAH). PlGF, total VEGF-A, and VEGF-A165b levels were measured in the control and PH groups. ES was only measured in the PH group. VEGF-A165b levels were significantly higher in the LD-PH group than in the PAH, LHD-PH, and CTEPH groups (all P<0.001). PlGF levels were significantly higher in the CTD-PAH group than in the IPAH and control groups. ES levels were significantly correlated with the 6-min walk distance (P<0.001), B-type natriuretic peptide (P<0.001), and pulmonary vascular resistance (P=0.008).Conclusions: ES could detect CTD-PAH in PAH and may be an indicator of PH severity. VEGF-A165b was useful in detecting LD-PH.

Pulmonary Hypertension in Patients With COPD: Results From the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA)

Pulmonary hypertension (PH) in COPD is a poorly investigated clinical condition. Which factors determine the outcome of PH in COPD? We analyzed the characteristics and outcome of patients enrolled in the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) with moderate or severe PH in COPD as defined during the 6th PH World Symposium who received medical therapy for PH and compared them with patients with idiopathic pulmonary arterial hypertension (IPAH). The population included incident patients with moderate PH in COPD (n= 68), with severe PH in COPD (n= 307), and with IPAH (n= 489). Patients with PH in COPD were older, predominantly male, and treated mainly with phosphodiesterase-5 inhibitors. Despite similar hemodynamic impairment, patients with PH in COPD achieved a worse 6-min walking distance (6MWD) and showed a more advanced World Health Organization functional class (WHO FC). Transplant-free survival rates at 1, 3, and 5 years were higher in the IPAH group than in the PH in COPD group (IPAH: 94%, 75%, and 55%vsPH in COPD: 86%, 55%, and 38%; P= .004). Risk factors for poor outcomes in PH in COPD were male sex, low 6MWD, and high pulmonary vascular resistance (PVR). In patients with severe PH in COPD, improvements in 6MWD by≥ 30m or improvements in WHO FC after initiation of medical therapy were associated with better outcomes. Patients with PH in COPD were functionally more impaired and had a poorer outcome than patients with IPAH. Predictors of death in the PH in COPD group were sex, 6MWD, and PVR. Our data raise the hypothesis that some patients with severe PH in COPD may benefit from PH treatment. Randomized controlled studies are necessary to explore this hypothesis further. ClinicalTrials.gov; No.: NCT01347216; URL: www.clinicaltrials.gov.

Identification of Potential Biomarkers and Immune Infiltration Characteristics in Idiopathic Pulmonary Arterial Hypertension Using Bioinformatics Analysis.

Objectives: Idiopathic pulmonary arterial hypertension (IPAH) is a rare but severe lung disorder, which may lead to heart failure and early mortality. However, little is known about the etiology of IPAH. Thus, the present study aimed to establish the differentially expressed genes (DEGs) between IPAH and normal tissues, which may serve as potential prognostic markers in IPAH. Furthermore, we utilized a versatile computational method, CIBERSORT to identify immune cell infiltration characteristics in IPAH.Materials and Methods: The GSE117261 and GSE48149 datasets were obtained from the Gene Expression Omnibus database. The GSE117261 dataset was adopted to screen DEGs between IPAH and the control groups with the criterion of |log2 fold change| ≥ 1, adjusted P < 0.05, and to further explore their potential biological functions via Gene Ontology analysis, Kyoto Encyclopedia of Genes and Genomes Pathway analysis, and Gene Set Enrichment Analysis. Moreover, the support vector machine (SVM)-recursive feature elimination and the least absolute shrinkage and selection operator regression model were performed jointly to identify the best potential biomarkers. Then we built a regression model based on these selected variables. The GSE48149 dataset was used as a validation cohort to appraise the diagnostic efficacy of the SVM classifier by receiver operating characteristic (ROC) analysis. Finally, immune infiltration was explored by CIBERSORT in IPAH. We further analyzed the correlation between potential biomarkers and immune cells.Results: In total, 75 DEGs were identified; 40 were downregulated, and 35 genes were upregulated. Functional enrichment analysis found a significantly enrichment in heme binding, inflammation, chemokines, cytokine activity, and abnormal glycometabolism. HBB, RNASE2, S100A9, and IL1R2 were identified as the best potential biomarkers with an area under the ROC curve (AUC) of 1 (95%CI = 0.937–1.000, specificity = 100%, sensitivity = 100%) in the discovery cohort and 1(95%CI = 0.805–1.000, specificity = 100%, sensitivity = 100%) in the validation cohort. Moreover, immune infiltration analysis by CIBERSORT showed a higher level of CD8+ T cells, resting memory CD4+ T cells, gamma delta T cells, M1 macrophages, resting mast cells, as well as a lower level of naïve CD4+ T cells, monocytes, M0 macrophages, activated mast cells, and neutrophils in IPAH compared with the control group. In addition, HBB, RNASE2, S100A9, and IL1R2 were correlated with immune cells.Conclusion: HBB, RNASE2, S100A9, and IL1R2 were identified as potential biomarkers to discriminate IPAH from the control. There was an obvious difference in immune infiltration between patient with IPAH and normal groups.

Exercise Capacity and Quality of Life in Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a progressive pulmonary vascular disease with a high mortality rate that can be divided into different groups according to etiology and prognosis. Few studies have investigated differences in the exercise capacity and quality of life (QOL) among the different groups of PAH patients. Therefore, we aimed to (1) compare the hemodynamic exercise responses between patients with idiopathic pulmonary arterial hypertension (IPAH) and PAH associated with other diseases (APAH), and (2) determine the factors associated with exercise capacity in patients with PAH. Six patients diagnosed with IPAH and eight with APAH [congenital heart disease (CHD)-dominant PAH] were included in this study. The main outcome measures included body composition, exercise capacity, hemodynamic measurements, physical activity levels, fatigue severity, and QOL. The CHD-dominant PAH group had a significantly lower predicted peak oxygen consumption (VO2pred %), pressure of end-tidal carbon dioxide at the peak and at anaerobic threshold (PETCO2peak and PETCO2@AT), and significantly elevated ventilatory equivalent (VE/VCO2slope and VE/VCO2@AT) compared with the IPAH group. Multiple regression analysis indicated that PETCO2@AT was significantly associated with either VO2peak (β = 0.805, adjusted R2 = 0.619, p = 0.001) or 6-minute walk distance (β = 0.816, adjusted R2 = 0.638, p < 0.001). Patients with CHD-dominant PAH had poor exercise capacity and exercise responses compared to those with IPAH. Evaluating exercise capacity and the patient response to exercise using cardiopulmonary exercise testing is increasingly important in view of the etiology of PAH.

Comparison of pulmonary vascular resistance and pulmonary artery compliance during exercise between IPAH and CTEPH with normal pulmonary artery pressure

Abstract Background Pulmonary vascular resistance (PVR) and pulmonary artery compliance (PAC) are inversely related. However, the little is known about dynamics during exercise by disease difference. The aim of this study was to reveal the relationships of PVR and PAC during exercise between idiopathic pulmonary arterial hypertension (IPAH) and chronic thromboembolic pulmonary hypertension (CTEPH) patients. Methods Sixty-two IPAH patients (45±9 y.o) and 359 CTEPH patients (63±13 y.o) with normal mean PAP and PAWP at rest underwent symptom-limited exercise test using supine cycle ergometer with right heart catheter. Results There were no differences between baseline mean PAP and PAWP in 2 groups, however, cardiac output, SaO2 and SvO2 were lower in CTEPH group. Lower PAC (2.9±1.1 vs. 3.7±1.7 ml/mmHg, p&amp;lt;0.001) and higher PVR (2.3±1.0 vs. 1.9±1.0 wood.unit, p=0.016) were observed in CTEPH group. These trends were also seen at peak exercise. PVR-PAC relationship in CTEPH group was leftward shift compared with IPAH group (Figure 1). Conclusion Resting and exercise PVR and PAC in CTEPH patients were worse than those in IPAH patients who had normal PAP and PAWP at rest. Figure 1 Funding Acknowledgement Type of funding source: None