PAH Patients Research Articles

Homoarginine predicts mortality in treatment-naive patients with pulmonary arterial hypertension

BackgroundPulmonary arterial hypertension (PAH) is a rare progressive disease with a 3-year mortality rate of approx. 45% in incident patients. The prostacyclin, endothelin-1 (ET-1), and nitric oxide (NO) pathways are validated therapeutic targets, however the underlying pathomechanisms are not yet fully understood. In the present study, we investigated metabolites of the NO pathway (e.g. l-arginine, asymmetric dimethylarginine (ADMA), and homoarginine), which are potentially involved in the pathophysiology of PAH. MethodsNewly diagnosed, treatment-naïve incident PAH patients were recruited from six centers and followed for three years. In longitudinal analyses we investigated the prognostic potential of these markers. Cross-sectional analysis was later used to study associations between prognostic relevant markers and clinical phenotypes of PAH. ResultsAmong 108 enrolled patients (53±17years, mean±SD), 76 had idiopathic (i)PAH. Kaplan–Meier survival analysis and adjusted Cox proportional hazard models identified homoarginine as an independent predictor of mortality (HR:0.51, CI:0.28–0.94 for PAH and HR:0.41 CI:0.19–0.88 for iPAH), but not l-arginine or ADMA. Homoarginine was lower in 27 patients who died during the follow-up, i.e. 1.26±0.48 vs. 1.64±0.69μmol/L, P<0.01. In Pearson's correlation analysis homoarginine correlated with 6-minute walking distance (r=0.31), cardiac output (r=0.23), right atrial pressure (r=−0.21), big ET-1 (r=−0.31), and NT-proBNP (r=−0.21; P<0.05 for all). ConclusionHomoarginine was found an independent predictor for mortality in newly diagnosed PAH and iPAH patients. Further experimental studies are necessary to elucidate the involvement of homoarginine in the pathophysiology of PAH and its potential role as a therapeutic option for these patients.

Severe pulmonary arterial hypertension: stratification of medical therapies, mechanical support, and lung transplantation.

Severe pulmonary hypertension is recognized by focusing on the clinical signs and tests that demonstrate decompensated right ventricular failure or, in the worst-case scenario, shock. An aggressive treatment regimen including a prostacyclin infusion is required for these patients. Once admitted to the hospital, or the ICU for decompensated right ventricular failure, the short- and long-term outcomes for PAH patients are poor. For those who are candidates, urgent lung transplantation, or extracorporeal membrane oxygenation (ECMO) as a bridge to lung transplantation may be rescue therapy.

(1007) - Survival of the PAH and CTEPH Patients in the Swedish Pulmonary Arterial Hypertension Register 2000-2014

Survival of the PAH and CTEPH Patients in the Swedish Pulmonary Arterial Hypertension Register 2000-2014

HDAC6‐Hsp90 interplay in Pulmonary Arterial Hypertension

BackgroundPulmonary arterial hypertension (PAH) is a progressive and fatal disease characterized by the elevation of mean pulmonary arterial pressure. Pulmonary arterial smooth muscle cells (PASMCs) from PAH patients exhibit a cancer‐like metabolic‐dependent pro‐proliferative, pro‐migratory and anti‐apoptotic phenotype leading to development of progressive pulmonary artery remodeling. The histone deacetylase 6 (HDAC6) is mainly cytoplasmic and involved primarily in “non‐histone” functions. HDAC6 interacts and deacetylates various proteins such as α‐tubulin and Hsp90 promoting proto‐oncogene activation such as Survivin (implicated in PAH) to carry out cancerous functions. We hypothesize that HDAC6/Hsp90 axis is up‐regulated in PAH and contributes to the development of the cancer‐like phenotype through in part Survivin stabilization.Method/ResultsUsing a translational molecule‐cell‐organ‐animal and multidisciplinary approach, we demonstrated that both HDAC6 and HSP90 are up‐regulated (immunofluorescence and immunoblot; p&lt;0.01) in the lungs and PASMCs isolated from PAH patients (n=5) compared to age‐matched controls (n=5). HDAC6 inhibition via a pharmacological (Tubastatin A) or molecular (siHDAC6) approach dose dependently increased α‐tubulin acetylation and decreased PAH‐PASMC migration (wound healing assay; p&lt;0.05), resistance to apoptosis (Annexin‐V; p&lt;0.05) and proliferation (Ki67; p&lt;0.01). Increased apoptosis following Tubastatin A treatment was associated with mitochondrial membrane depolarization (TMRM) of PAH‐PASMCs and inhibition of the oxygen consumption rate in a concentration‐dependent manner (Seahorse XFe 24 system). All these effects were associated with a down‐regulation of Survivin. Similarly, inhibition of Hsp90 (AT13387 or siHsp90) reverses the cancer‐like phenotype and this effect was associated with a down‐regulation of HDAC6, suggesting that HDAC6 up‐regulation in PAH is Hsp90‐mediated. In vivo, HDAC6 inhibition in monocrotaline‐induced PAH decreases both mean pulmonary artery pressure (right heart catheterization, p&lt;0.01) and right ventricular hypertrophy (Fulton index).ConclusionWe provide evidence that Hsp90 and HDAC6 are specifically up‐regulated in human PAH and contributes to the proliferative, migratory and anti‐apoptotic phenotype seen in PAH‐PASMCs. As HDAC6 inhibitors have been tested in cancer, this offers a short‐term new therapeutic avenue for PAH patients.Support or Funding InformationCanada Research Chairs and CIHR grants to S. Bonnet and S. Provencher supported this work

(990) - Parenchymal Lung Disease in PAH Patients Managed with Prostacyclin Agonists

(990) - Parenchymal Lung Disease in PAH Patients Managed with Prostacyclin Agonists

Six-minute walk test in systemic sclerosis: A systematic review and meta-analysis

BackgroundPulmonary arterial hypertension (PAH) and interstitial lung disease (ILD) are the leading causes of death in systemic sclerosis (SSc). Although the six-minute walk test (6MWT) is generally used for evaluating PAH and ILD, utility in SSc is undetermined. This study evaluates the role of 6MWT in SSc by systematic review and meta-analysis. MethodsA systematic literature search on PubMed, Web of Science and Cochrane Library Online was performed using the medical subject heading search terms for “systemic sclerosis”, “CREST” and “six minute walk test”, “six minute walk distance (6MWD)”, “(cardiopulmonary) exercise test”, “treadmill test” or “step test”. ResultsMeta-analysis of 43 included studies (3185 SSc-all patients) revealed that the mean 6MWD was comparable between the SSc–PAH and SSc–ILD–PH subgroups (288m [95% CI: 259–317m] vs 286m [95% CI: 259–314m], p=0.93). The pooled mean of 725 SSc-PAH patients was significantly lower than the pooled mean of 413 SSc–noPAH patients (430m [95% CI: 402–458m], p<0.001). 95 SSc–ILD–PH patients walked significantly less than 328 SSc–ILD patients (388m [95% CI: 362–415m], p<0.001) and significantly less than 86 SSc-noILD patients (420m [95% CI: 325–515m], p=0.008). 81–98% of the SSc–PAH/ILD/ILD–PH patients performed a 6MWT. ConclusionsDuring a 6MWT, SSc–PAH patients walk less than SSc–noPAH patients and SSc–ILD–PH patients walk less than SSc–ILD and SSc–noILD patients.

Metoprolol Reverses β-Adrenergic Remodeling in the Failing Right Ventricle of Pulmonary Artery Hypertensive (PAH) Rats

Heart failure (HF) is the leading cause of death in PAH patients, but under current guidelines there is no treatment directed specifically at the failing right ventricle (RV). In a model of RV HF induced by PAH we examined whether a selective β1AR blocker (BB) metoprolol could slow adverse myocardial remodeling.A single injection of monocrotaline (60 mg/kg, MCT) in male Wistar rats was used to induce PAH leading to RV HF. Control (CON) animals were injected with saline. MCT animals were given metoprolol (10 mg/kg/day, BB group) or placebo (MCT group) daily by oral administration from 15 days post injection. Langendorff-perfused hearts were used for RV myocyte isolation (for functional experiments) or preparation of RV myocardial homogenates (for protein expression via Western blotting). Experiments were performed on the day MCT animals showed HF signs or on the median MCT HF day for BB/CON groups.In response to selective β1AR stimulation (isoproterenol 100nM with 100nM ICI118,551) MCT RV myocytes had a blunted increase in fractional shortening and rate of relaxation compared with CON (P<0.05; n=5-20).This difference was absent in the BB myocytes. Similar trends were observed for Ca2+ transient amplitude and decay. Consistent with observations in LV failure, in MCT RV expression of β1AR and adenylyl cyclase V/VI was reduced, whereas that of Gαi3 and GRK2 was increased compared with CON (P<0.01). In all cases, metoprolol treatment normalizes protein expression. Interestingly, the expression of another protein which regulates the βAR pathway (caveolin 3) was reduced in MCT vs. CON (P<0.05) and normalized in BB. These results add support to the growing evidence for use of selective β1-blockers to reverse detrimental remodeling of the failing RV in PAH patients.

Value of intravascular ultrasound in the assessment of pulmonary vascular properties and mortality in patients with pulmonary artery hypertension associated with connective tissue diseases

To investigate the value of intravascular ultrasound (IVUS) on assessing pulmonary vascular properties (PVPs) and its relationship with hemodynamics, and mortality rate in patients with pulmonary arterial hypertension associated with connective tissue disease (PAH-CTD). Patients (n=51) with highly suspected PAH-CTD were prospectively enrolled in our department between July 2011 and March 2014. All patients underwent right heart catheterization (RHC) and IVUS, and were divided into 3 groups: PAH-CTD (n=25), PAH due to other reasons (n=15), and non-PAH control group (n=11). Based on IVUS, PAH patients were divided into distal (n=22) and proximal (n=18) remodeling subtypes.A total of 408 pulmonary segments were detected by IVUS, and all patients were followed up to (19 ± 10) months. IVUS evidenced higher mean wall thickness (MWT) ((0.30 ± 0.02) mm and (0.33 ± 0.02) mm vs. (0.21 ± 0.02) mm) and percentage of MWT (WTP) ((13.62 ± 0.59)% and (14.39 ± 0.77)% vs. (9.57 ± 0.97)%) values in PAH patients compared to control patients (all P<0.01). Pulmonary vascular mechanical properties (PVMPs) including compliance ((8.85 ± 0.82) × 10(-2)mm(2)/mmHg(1 mmHg=0.133 kPa) and (6.28 ± 0.65) × 10(-2)mm(2)/mmHg vs. (41.59 ± 5.02) × 10(-2) mm(2)/mmHg, all P<0.01), distensibility ((0.83 ± 0.09)%/mmHg and (0.55 ± 0.06)%/mmHg vs. (3.16 ± 0.38) %/mmHg, all P<0.01), elastic modulus ((169.25 ± 15.10) mmHg and (253.00 ± 22.11) mmHg vs.(43.78 ± 4.27) mmHg, all P<0.01) and stiffness index β (4.19 ± 0.41 and 5.18 ± 0.34 vs. 2.39 ± 0.27, P<0.05 or 0.01) in PAH groups were all significantly worse than in control group (all P<0.01). An inverse exponential association was found between PVMPs and hemodynamics with R(2) ranging from 0.544 to 0.777 (P<0.001). PVMPs tended to be better in group PAH-CTD than in PAH group due to other reasons.Mortality rate was similar between the two PAH groups, while PAH with distal remodeling subtype was linked with significantly higher mortality rate than PAH with the proximal remodeling subtype (23 % vs. 0, HR=10.14, P<0.05). IVUS plays an important role in the assessment of PAH-CTD patients in terms of evaluating PVPs and predicting mortality rate. PAH patients have deteriorated PVPs, but PVMPs tended to be better in PAH-CTD than in PAH patients due to other reasons. The mortality rate was similar between PAH groups, while PAH patients with the distal remodeling subtype is linked with a higher mortality rate than PAH patients with the proximal remodeling subtype.

Exercise testing can unmask right ventricular dysfunction in systemic sclerosis patients with normal resting pulmonary artery pressure

BackgroundPulmonary arterial hypertension (PAH) is a frequent complication of systemic sclerosis (SSc). Diagnosis usually occurs late and often after the development of irreversible right heart dysfunction. Exercise testing is increasingly used for assessing right ventricular (RV) function when resting hemodynamics do not account for symptoms. We hypothesized that SSc patients without resting pulmonary hypertension could have impaired exercise capacity and RV contractile reserve with exercise thus unmasking early RV dysfunction and pulmonary vascular disease. MethodsTreadmill exercise stress echocardiography with concurrent expired gas analysis was performed in 25 SSc patients with normal resting pulmonary arterial pressure (PAP) and healthy controls (n=50). Additionally, controls and SSc patients were compared to those with established PAH (n=23). Parameters of RV systolic function (RV fractional area change (FAC), Doppler tissue (DTI) s′ velocity, systolic strain and strain rate (S-Sr)) were evaluated at baseline and post-exercise with the difference (Δ) being contractile reserve. ResultsRV contractile reserve was reduced in the SSc group with normal resting PAP, compared with healthy controls (Δs′: 6.1±2.3 vs 8.0±2.2cms−1, p<0.001; and ΔS-Sr: 2.3±0.5 vs 2.6±0.2s−1, p=0.02) in association with a significantly higher mean PAP with exercise (25.5±6.6 vs 19.9±7.2mmHg, p<0.001). PAH patients demonstrated the lowest levels of contractile reserve (Δs′, Δstrain, ΔS-Sr and ΔFAC, all p<0.05). ConclusionExercise stress testing unmasks reduced RV contractile reserve in SSc patients with normal resting PAP. Subclinical RV dysfunction during exercise may be a surrogate for early pulmonary vascular disease in SSc patients.

Arginase inhibitor attenuates pulmonary artery hypertension induced by hypoxia.

Hypoxia-induced pulmonary arterial hypertension (HPAH) is a refractory disease characterized by increased proliferation of pulmonary vascular smooth cells and progressive pulmonary vascular remodeling. The level of nitric oxide (NO), a potential therapeutic vasodilator, is low in PAH patients. L-arginine can be converted to either beneficial NO by nitric oxide synthases or to harmful urea by arginase. In the present study, we aimed to investigate whether an arginase inhibitor, S-(2-boronoethyl)-L-cysteine ameliorates HPAH in vivo and vitro. In a HPAH mouse model, we assessed right ventricle systolic pressure (RVSP) by an invasive method, and found that RSVP was elevated under hypoxia, but was attenuated upon arginase inhibition. Human pulmonary artery smooth muscle cells (HPASMCs) were cultured under hypoxic conditions, and their proliferative capacity was determined by cell counting and flow cytometry. The levels of cyclin D1, p27, p-Akt, and p-ERK were detected by RT-PCR or Western blot analysis. Compared to hypoxia group, arginase inhibitor inhibited HPASMCs proliferation and reduced the levels of cyclin D1, p-Akt, p-ERK, while increasing p27 level. Moreover, in mouse models, compared to control group, hypoxia increased cyclin D1 expression but reduced p27 expression, while arginase inhibitor reversed the effects of hypoxia. Taken together, these results suggest that arginase plays an important role in increased proliferation of HPASMCs induced by hypoxia and it is a potential therapeutic target for the treatment of pulmonary hypertensive disorders.

Abstract 13921: Dysfunctional Bone Morphogenetic Protein Signaling Interlinks With Interleukin-1ß Mediated Inflammation in Pulmonary Arterial Hypertension

Rationale: Bone morphogenetic protein receptor type 2 (BMPR2) mutations are found in heritable and idiopathic pulmonary arterial hypertension but disease penetrance is incomplete implying the necessity for a ‘second hit’. IL-1ß and IL-6 are increased in PAH patients and animal models and are proposed to play a critical role in disease. Objective: To determine pulmonary specific interplay between BMPR2 and IL-1ß signaling by exploring differences between pulmonary artery and aortic smooth muscle cells (PA / Ao SMC) in response to IL-1ß, and determine the effects of reduced BMPR2 expression using in vitro and in vivo disease models. Methods and Results: Microarray analysis of PASMC and AoSMC mRNA show reduced inflammatory pathway activation in response to IL-1ß in PASMC compared with AoSMCs. Pathway analysis identified an exaggerated inflammatory response to IL-1ß in PASMC lacking BMPR2 (siRNA). Significant up-regulation of IL-6, IL-1α and adhesion molecules (&gt;2-fold) shown by array analysis was validated by qPCR. In the absence of BMPR2 a 1.5-fold increase in proliferation was observed in response to IL-1ß that is not present in PASMC with functional BMPR2. To study this further, R899X+/- BMPR2 transgenic mice were fed western diet for six weeks and given daily injections of IL-1ß. Mice were assessed for inflammatory activation and PAH phenotype (catheter/echo). mRNA and protein changes were measured by TaqMan PCR, western blotting and serum ELISA. Mice treated with IL-1ß had significantly higher white blood cell counts (1.7-fold), and showed trends for increased mRNA of VCAM1, IL-1α (whole lung) and significantly raised serum protein levels of IL-6 and OPG matching in vitro data. IL-1ß treated mice had an increase in early pulmonary vascular remodelling and the full assessment of the inflammatory cell infiltrate in R899X+/- mice is currently underway. Conclusion: IL-1ß induces a pulmonary artery specific transcriptome that is altered by suppression of BMPR2 signaling in vitro. In vivo and in vitro IL-1ß drives an exaggerated inflammatory response under conditions of reduced BMPR2 signaling. This research highlights a mechanism by which increased IL-1ß may provide a “second hit” to reduced BMPR2 signaling and stimulate or potentiate the development of PAH.

Abstract 13504: RV Cardiac Output Calculated From an Implantable Hemodynamic Device: A Correlative Approach Using CMR in PAH Patients

Introduction: The CardioMEMS™ HF System (CMHFS)(St. Jude) is used for wireless monitoring of pulmonary artery (PA) pressure. Pulmonary flow is difficult to model due to prominent reflected waves and McDonald et al have shown that the temporal differential of the initial positive pressure pulse effectively provides the flow driving force for cardiac output (CO), with mean pressure indicating resistance. However, the response of this model to stress conditions in vivo is unknown. Hypothesis: We hypothesize that the temporal differentiation of pressure model of CO applied to the CMHRS data at baseline and during stress provides an accurate calculation of noninvasive CO in PAH. Methods: 10 pts with PAH were implanted with the CMHFS to measure PA pressure, HR, and CO longitudinally. Cardiovascular Magnetic Resonance (CMR) was performed at baseline, and after 1) inhalation of nitric oxide (20 ppm), 2) dobutamine (20 μcg/kg/min), and 3) volumetric challenge (500ml NaCl). Flow through the MPA was measured using phase velocity mapping. The mean pressure and area of the temporal differential of the initial positive pressure pulse from the CMHFS device were measured (Fig 1A) to calculate CO. In each case the calibrating constant to relate to CMR CO was calculated at baseline and then applied during stress. Results: The pressure derived CO correlated with CMR CO via a linear relationship for 32 comparison measures according to the following equation: Pressure CO = 1.1 CMR CO + 0.8Bland-Altman analysis has an offset bias of 0.2, a four standard deviation range of ±3.1 l/m and a correlation of 0.9. (Fig 1B). Conclusions: The temporal differential of the initial positive pressure pulse forms the effective driving force for pulmonary blood supply. This formulation overcomes the difficulties in identifying reflected waves and is highly responsive to stress conditions and may advance current prototypes. This approach may provide additional value once validated for implantable PA manometers.

Abstract 10300: The Effects of the Bone Morphogenetic Protein Receptor Type 2 Mutation on the Right Ventricle in Pulmonary Arterial Hypertension

Introduction: The effects of a mutation in the bone morphogenetic protein receptor 2 gene (BMPR2) gene on right ventricular (RV)adaptation are currently unknown. Therefore, we investigated RV function in PAH patients with and without BMPR2 mutation by combining in vivo measurements with molecular and histological analysis of human RV and left ventricular (LV) tissue. Methods: 97 idiopathic or familial PH patients were genetically screened for the presence of a BMPR2 mutation. 28 patients carried a BMPR2 muation, 69 did not. In vivo measurements were assessed using right heart catheterization (RHC)and cardiac magnetic resonance imaging.To investigate the role of TGF-β and BMPRII signaling, human RV and LV tissue were studied in controls (n=6), mutation carriers (n=5) and non-carriers (n=11). Results: Despite a similar mean pulmonary artery pressure (noncarriers 54±15 vs. mutation carriers 55±9 mmHg)and pulmonary vascular resistance (755 (483-1043) vs. 931 (624-1311) dynes*s/cm 5 ), mutation carriers presented with a more severely compromised RV function (RV ejection fraction: 37.6±12.8 vs. 29.0±9 %: p&lt;0.05, cardiac index 2.7±0.9 vs. 2.2±0.4 l/min/m 2 ). Differences continued to exist after treatment. TGF-β and BMPRII signaling, as well as hypertrophy, fibrosis, capillary density and inflammation were similar between mutation carriers and non-carriers. Conclusions: Despite a similar afterload, RV function is severely more affected in BMPR2 mutation carriers compared to non-carriers. However, these differences cannot be explained by a different TGF-B, BMPR2 signaling or cardiac adaptation.

Characterization of blood pressure and daily stress in Mexican children with Diabetes Mellitus Type 2 risk factors

not been elucidated. Aim: To determine if hemodynamic changes during the Valsalva maneuver promote cerebral hypoperfusion as the etiology of syncope and quantify severity with autonomic failure metrics in a case-control trial. Methods: Hemodynamic changes of nine PAH patients were prospectively obtained and compared with 15 age and gender matched healthy controls. Common Valsalva parameters including adrenergic baroreflex sensitivity, pressure recovery time, systolic blood pressure recovery, diastolic blood pressure recovery, mean arterial pressure recovery, and the Valsalva ratio were calculated. Mann-Whitney U-tests were used to compare continuous variables. The primary end point was adrenergic baroreflex sensitivity. Results: PAH patients had lower adrenergic baroreflex sensitivity (9.7 ± 4.6 vs 18.8 ± 9.2 mmHg/second, P = 0.005), longer pressure recovery time (3.6 ± 2.5 vs 1.7 ± 0.8 seconds, P = 0.008), similar SBP recovery (-13 ± 11vs -12 ± 23 mmHg, P = 0.640), less diastolic blood pressure recovery (13 ± 14 vs -1 ± 12 mmHg, P = 0.025), less mean arterial pressure recovery (-5 ± 11 vs 5 ± 17 mmhg, P = 0.048), and a decreased Valsalva ratio (1.25 ± 0.11 vs 1.60 ± 0.22, P b 0.001) compared to healthy controls. Conclusions: All of the significantly different parameters suggest that primary arterial hypertension patients are more susceptible to cerebral hypoperfusion. PAH patients exhibit a susceptibility to syncope similar to a spectrum of patients with intermediate autonomic failure, who typically experience a systolic blood pressure drop of 10-30 mmHg with standing. Grants: NIH P01 HL 108800, NIH K23 HL 098743

DNA DAMAGE AT THE DAWN OF MICRO-RNA PATHWAY IMPAIRMENT IN PULMONARY ARTERIAL HYPERTENSION

Over the last years, small non-coding microRNAs (miRNAs) have emerged as central actors of PAH etiology. Strong miRNA expression disorders occur in lungs as well as in right ventricle (RV) of PAH patients, which respectively lead to vascular remodeling of the distal pulmonary arteries and to RV failure. On the other hand, our understanding of PAH physiopathology has recently increased with the implication of DNA damage and DNA damage response (DDR) in this disease. Interestingly, DDR was described as a regulator of miRNA processing in both healthy and pathological conditions. In this review, we will first summarize miRNA expression impaired in lung and RV of PAH patients, then we will provide evidence that DDR could be at origin of miRNA pathway defects observed in pulmonary hypertension.

RIOCIGUAT FOR CHRONIC THROMBOEMBOLIC PULMONARY HYPERTENSION - INITIAL EXPERIENCE

s S39 apoptosis and proliferation. LncRNAs were preamplified to facilitate detection, and quantified with a commercial PCR array platform (RT2 system, Qiagen). RESULTS: Only 2 lncRNAs (ZFAS1, GAS5) were detectable in all subjects, while 63 lncRNAs were detected sporadically and 19 lncRNAs were not detectable in any subjects (based on a Cq cutoff threshold of 35). No statistically significant differences in lncRNA levels were observed between groups. The technical performance of the RT-qPCR system was confirmed by integrated reverse transcription and positive PCR controls, which revealed no evidence of reaction inhibition. The quality of the total RNA extraction was validated by the robust recovery of an exogenous spike-in control (cel-miR-39), and the detection of endogenous miRNA (miR-16, miR-126, and miR-145, without preamplification), small nuclear RNA (RN7SK), ribosomal RNA (RPLP0) and messenger RNA (ACTB, B2M) species. CONCLUSION: To the best of our knowledge, this study represents the first examination of circulating lncRNAs in PAH patients. These results suggest that low circulating levels of lncRNA may preclude their use as practical biomarkers for certain diseases. 074 CIRCULATING EXTRACELLULAR MICRORNAS IN THE CHRONIC HYPOXIA MOUSE MODEL OF PULMONARY HYPERTENSION K Schlosser, M Taha, Y Deng, DJ Stewart

CIRCULATING EXTRACELLULAR MICRORNAS IN THE CHRONIC HYPOXIA MOUSE MODEL OF PULMONARY HYPERTENSION

s S39 apoptosis and proliferation. LncRNAs were preamplified to facilitate detection, and quantified with a commercial PCR array platform (RT2 system, Qiagen). RESULTS: Only 2 lncRNAs (ZFAS1, GAS5) were detectable in all subjects, while 63 lncRNAs were detected sporadically and 19 lncRNAs were not detectable in any subjects (based on a Cq cutoff threshold of 35). No statistically significant differences in lncRNA levels were observed between groups. The technical performance of the RT-qPCR system was confirmed by integrated reverse transcription and positive PCR controls, which revealed no evidence of reaction inhibition. The quality of the total RNA extraction was validated by the robust recovery of an exogenous spike-in control (cel-miR-39), and the detection of endogenous miRNA (miR-16, miR-126, and miR-145, without preamplification), small nuclear RNA (RN7SK), ribosomal RNA (RPLP0) and messenger RNA (ACTB, B2M) species. CONCLUSION: To the best of our knowledge, this study represents the first examination of circulating lncRNAs in PAH patients. These results suggest that low circulating levels of lncRNA may preclude their use as practical biomarkers for certain diseases. 074 CIRCULATING EXTRACELLULAR MICRORNAS IN THE CHRONIC HYPOXIA MOUSE MODEL OF PULMONARY HYPERTENSION K Schlosser, M Taha, Y Deng, DJ Stewart

Initial Data Report from “LARIAT”: A Phase 2 Study of Bardoxolone Methyl in PAH Patients on Stable Background Therapy

Initial Data Report from “LARIAT”: A Phase 2 Study of Bardoxolone Methyl in PAH Patients on Stable Background Therapy

Oxidative stress and nitric oxide signaling related biomarkers in patients with pulmonary hypertension: a case control study.

BackgroundOxidative stress (OS) and reduced nitric oxide (NO) bioavailability contribute to the pathogenesis of pulmonary hypertension (PH). Whether there are associations between OS and NO signaling biomarkers and whether these biomarkers are associated with the severity of PH remain unclear.MethodsBlood samples were collected from 35 healthy controls and 35 patients with pulmonary arterial hypertension (PAH, n = 12) or chronic thromboembolic pulmonary hypertension (CTEPH, n = 23). The mean pulmonary artery pressure (mPAP) and pulmonary vascular resistance index (PVRI) were measured by right heart catheterization. We measured the derivative of reactive oxygen molecules (d-ROMs), biological antioxidant potential (BAP) and superoxide dismutase (SOD) by automatic biochemical analyzer, malondialdehyde (MDA) and asymmetric dimethylarginine (ADMA) by enzyme-linked immunosorbent assay. The relationship between oxidative-antioxidative biomarkers and ADMA, as well as their association with pulmonary hemodynamics, were analyzed.ResultsCompared with age- and gender-matched controls, there was no significant difference of d-ROMs in PAH and CTEPH patients; MDA was increased in CTEPH patients (P = 0.034); BAP and SOD were decreased in PAH (P = 0.014, P < 0.001) and CTEPH patients (P = 0.015, P < 0.001); ADMA level was significantly higher in PAH (P = 0.007) and CTEPH patients (P < 0.001). No association between oxidative-antioxidative biomarkers and ADMA was found. Serum ADMA concentration was correlated with mPAP (r = 0.762, P = 0.006) and PVRI (r = 0.603, P = 0.038) in PAH patients.ConclusionsThe antioxidative potential and NO signaling are impaired in PAH and CTEPH. Increased serum ADMA level is associated with unfavorable pulmonary hemodynamics in PAH patients. Thus, ADMA may be useful in the severity evaluation and risk stratification of PAH.

Blood pressure variability and cardiovascular risk in 9 eastern european countries: data from the BP-Care study

Methods: Total 327 patients were enrolled from 2008 to 2011 in the Korean registry program. They met the criteria of PAH and we investigated the clinical data, the medication prescribed and survival status et al. Results: Their mean age was 40.8 15.8years with female /male patient ratio of 2.7:1. The patients in WHO I/II were 32.4% and WHO III/IV were 67.6%. The peak/mean pulmonary arterial pressure was 86.3/ 56.6 mmHg. Idiopathic PAH (22%), connective tissue disease (24%) and congenital heart disease (46%) were predominant. Small number of patients with familial PAH, portal hypertension, HIV infection, pulmonary capillary hemangiomatosis (PCH) existed. The patients described bosentan were 107, sildenafil 50, iloprost 31, and veraprost 49. After follow-up for mean ( SD) duration of 37.2 18.1 months of idiopathic PAH, the survival rates at 1, 2, and 3 years were 70.0%, 64%, and 55% respectively. The survival rates of patients with non-idiopathic PAH were better than that of idiopathic PAH patients. Conclusions: The baseline characteristics and survival rates of our cohort study are close to those of the National Institutes of Health Registry of other countries, and the survival rates of patients with idiopathic PAH were worse than that of non-idiopathic PAH patients. Therefore, the target related therapy should be more popular for the improvement of survival rate of idiopathic PAH patients.