PAH Patients Research Articles

Role for RUNX2/HDAC6 Axis in Pulmonary Arterial Hypertension

IntroductionPulmonary arterial hypertension (PAH) is a vascular remodeling disease characterized by enhanced pulmonary artery smooth muscle cells (PASMC) proliferation, migration, calcification and suppressed apoptosis. Numerous biological pathways have been implicated in this phenotype, including HIF‐1α. Recent studies have shown that miR‐204 downregulation upregulates the expression of RUNX2. RUNX2 is implicated in many features seen in PAH‐PASMC in part through the activation of HIF‐1α by a HDAC6‐depepdent mechanism. Thus we hypothesis that miR‐204‐dependent upregulation of RUNX2/HDAC6 axis promotes HIF‐1α and development of PAH.ResultsUsing human lungs, distal PAs and isolated PASMC from both control and PAH patients, we demonstrated a significant upregulation of RUNX2 and HDAC6 in PAH. Gain and loss of functions experiments in PASMC showed that downregulation of miR‐204 in controls PASMC increase RUNX2 expression, while increases miR‐204 in PAH‐PASMC decrease it. In controls PASMC, RUNX2 upregulation increases calcification,migration, proliferation, resistance to apoptosis through an HDAC6 and HIF‐1α dependent mechanism, as both tubastatin A (HDAC6 inhibitor) and siHIF‐1α blocks RUNX2 effects. Similarly in PAH‐PASMC siRUNX2 has the opposite effects. Finally, in sugen/hypoxia rat model of PAH, nebulization of siRUNX2 decreased mean PA pressure, pulmonary vascular resistance and increased compliance and cardiac output.ConclusionTaken together, our study uncovers a new miR‐204 dependent up regulation of RUNX2/HDAC6 axis contributing to calcification and to normoxic activation of HIF‐1α leading to proliferation, migration and resistance to apoptosis in PAH‐PASMC.

(369) - A Study to Explore the Feasibility and Safety of Using an Implantable Hemodynamc Monitor in PAH Patients

(369) - A Study to Explore the Feasibility and Safety of Using an Implantable Hemodynamc Monitor in PAH Patients

Emerging role of epigenetic in pulmonary arterial hypertension right ventricular failure

INTRODUCTIONPulmonary arterial hypertension (PAH) is associated with a global impairment of angiogenesis. Although the origin of the angiogenic defect remains unknown. since a few years epigenetic has become an important research area in many diseases including PAH. Role for miRNAs has been widely demonstrated; nonetheless a role for long noncoding RNA (LncRNA) remains unknown. In the present study we focused our role on the expression level of miR‐126 and MALAT‐1 both of which are enriched in endothelial cells and known to be implicated in angiogenesis regulation. We hypothesized that aberrantly express miR‐126 and MALAT‐1 contributes to angiogenesis impairment see in PAH.RESULTSUsing qRT‐PCR we showed that miR126 was decreased in human PAH RV (p<0.05) compare to control while MALAT‐1 expression was upregulated p<0.05). These finding were associated in vitro with a significant reduction in EC proliferation (Ki67;p<0.05) and tube formation (p<0.05) measured in freshly isolated human RV endothelial cells from both PAH compare to EC from control RV. Both miR‐126 and MALAT‐1 are critical regulators of angiogenesis and are likely dependent of each other; in fact we showed that miR‐126 expression inversely correlates with MALAT‐1 expression in PAH RV (p<0.05). CONCLUSIONWe demonstrated, for the first time in PAH that the endothelial‐enriched noncoding RNAs miR‐126 and MALAT‐1 are aberrantly expressed in human RV from PAH patients contributing to the impairment of angiogenesis. The endothelial specific miR‐126 is known to regulate endothelial cells proliferation while MALAT‐1 up regulation has been associated with decreased endothelial cells migration and sprouting, suggesting that these two noncoding RNAs are implicated in angiogenesis defect.

Role for Bromodomain‐Containing Protein 4 in Pulmonary Arterial Hypertension

BackgroundPulmonary arterial hypertension (PAH) is associated with sustained DNA damage accounting for a PARP‐1‐dependent downregulation of miR‐204, promoting the expression of oncogenes (Survivin, Pim‐1). Once activated through the transcription factor NFAT, they contribute to the pro‐proliferative and anti‐apoptotic phenotype of PAH‐pulmonary arterial smooth muscle cells (PAH‐PASMC). In cancer, the epigenetic reader Bromodomain‐containing protein 4 (BRD4) sustains cell proliferation. Interestingly, BRD4 is upregulated by DNA damage and is a predicted target of miR‐204. We hypothesized that the PARP‐1/miR‐204‐dependent upregulation of BRD4 triggers the pro‐proliferative and anti‐apoptotic phenotype seen in PAH‐PASMC.Method/ResultsBRD4 is upregulated (immunoblot; p<0.01) in distal PAs and PASMC of PAH patients (n=9) compared to control (n=5). This increase is miR‐204 dependent, as miR‐204 upregulation using mimic in PAH‐PASMC decreases BRD4 (p<0.05). BRD4 activation in PAH‐PASMC induces Survivin and Pim‐1 expression (immunoblot; p<0.05), leading to mitochondrial hyperpolarization (TMRM; p<0.05), decreasing mitochondrial respiration (Seahorse XFe 24) and increasing NFAT activation (p<0.05), all of which were reversed upon molecular (siRNA) and pharmacological ((+)JQ1) inhibition of BRD4. BRD4 inhibition reverses PAH‐PASMC proliferation (Ki67; p<0.05) and resistance to apoptosis (TUNEL; p<0.05). In vivo, BRD4 inhibition reverses sugen/hypoxia induced PAH in rats.ConclusionThrough a miR‐204‐dependent mechanism, BRD4 upregulation triggers the expression of oncogenes contributing to the proliferative and anti‐apoptotic phenotype seen in PAH‐PASMC, whereas BRD4 inhibition improves PAH.

Oestrogen receptor alpha in pulmonary hypertension.

AimsPulmonary arterial hypertension (PAH) occurs more frequently in women with mutations in bone morphogenetic protein receptor type 2 (BMPR2) and dysfunctional BMPR2 signalling underpinning heritable PAH. We have previously shown that serotonin can uncover a pulmonary hypertensive phenotype in BMPR2+/− mice and that oestrogen can increase serotinergic signalling in human pulmonary arterial smooth muscle cells (hPASMCs). Hence, here we wished to characterize the expression of oestrogen receptors (ERs) in male and female human pulmonary arteries and have examined the influence of oestrogen and serotonin on BMPR2 and ERα expression.Methods and resultsBy immunohistochemistry, we showed that ERα, ERβ, and G-protein-coupled receptors are expressed in human pulmonary arteries localizing mainly to the smooth muscle layer which also expresses the serotonin transporter (SERT). Protein expression of ERα protein was higher in female PAH patient hPASMCs compared with male and serotonin also increased the expression of ERα. 17β-estradiol induced proliferation of hPASMCs via ERα activation and this engaged mitogen-activated protein kinase and Akt signalling. Female mice over-expressing SERT (SERT+ mice) develop PH and the ERα antagonist MPP attenuated the development of PH in normoxic and hypoxic female SERT+ mice. The therapeutic effects of MPP were accompanied by increased expression of BMPR2 in mouse lung.ConclusionERα is highly expressed in female hPASMCs from PAH patients and mediates oestrogen-induced proliferation of hPASMCs via mitogen-activated protein kinase and Akt signalling. Serotonin can increase ERα expression in hPASMCs and antagonism of ERα reverses serotonin-dependent PH in the mouse and increases BMPR2 expression.

Collagen Metabolism Biomarkers and Health Related Quality of Life in Pulmonary Arterial Hypertension.

The goal of this study was to investigate the association between collagen metabolism biomarkers and health related quality of life (HRQoL) in PAH patients. We prospectively enrolled 68 stable idiopathic, anorexigen-associated, and hereditary PAH subjects and 37 healthy controls. Serum samples were analyzed for N-terminal propeptide of type III procollagen (PIIINP), c-terminal telopeptide of collagen type I (CITP), matrix metalloproteinase 9 (MMP-9) and tissue inhibitor of metalloproteinase 1 (TIMP-1). The Minnesota Living with Heart Failure (MLWHF), Euro QoL-5D (EQ-5D), Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) and Short Form (SF-36) general health survey were administered at the time of blood draw. General linear models, as well as logistic regression models were used to assess associations between variables. CITP, PIIINP, MMP9, and TIMP1 levels, and all HRQoL domains were significantly different between controls and PAH patients (p<0.001 for each). Interestingly, PIIINP levels were significantly associated with MLWHF physical (coef=1.63, and p=0.02), SF-36 physical (coef=-2.93, p=0.004), and EQ-5D aggregate (coef=0.34, p=0.001) scores. Several of the CAMPHOR scores strongly linearly associated with PIIINP. The odds of obtaining a walk distance ≥330 meters decrease by 38% per unit increase in PIIINP (OR=0.62; 95% CI=0.43, 0.90) and a PIIINP cutoff of 5.53 μg/L provided 81% sensitivity and 82% specificity. PIIINP is a good predictor of disease severity, and is strongly related to HRQoL scores in PAH patients. These relationships suggest PIIINP as a promising tool for PAH clinicians to determine or confirm the level of disease severity.

PHPN: Meeting the Challenge of Hospitalized PAH Patients Receiving IV Prostacyclins

In this PHPN column, we invited members from around the country to share their experiences and tips on several aspects of dealing with PAH patients in the hospital setting, particularly related to infusion pumps. Former section editor Martha Kingman, DNP, FNP-C, University of Texas Southwestern Medical Center at Dallas, provides valuable insight as an introduction to the topic.

Roundtable: Pulmonary Hypertension and Right Heart Failure in the ICU: Tackling Difficult Issues

A group of thought leaders in management of pulmonary hypertension gathered by phone on January 27, 2015 to discuss their approach to difficult issues encountered when PAH and RV-failure patients are in the ICU. Read on to learn their perspective as guest editor Deborah Levine, MD, medical director of the PH Center at University of Texas Health Science Center in San Antonio moderates a discussion among Jeffrey Sager, MD, director of the Cottage Pulmonary Hypertension Center in Santa Barbara, California; Stephen Mathai, MD, MHS, assistant professor of medicine at Johns Hopkins University and member of the pulmonary hypertension program; and Todd Bull, MD, director of the Pulmonary Vascular Disease Program at the University of Colorado and member of the pulmonary and critical care and cardiology sections.

Modulation of Pulmonary Vascular Remodeling in Hypoxia: Role of 15-LOX-2/15-HETE-MAPKs Pathway

Background: We have previously shown that 15-hydroxyeicosatetraenoic acid (15-HETE) plays a critical role in pulmonary hypertension (PH)-associated vascular remodeling. However, the signaling mechanisms remain unclear. The purpose of this study was to investigate the role of 15-lipoxygenase-2 (15-LO-2)/15-HETE-mitogen-activated protein kinases (MAPKs) pathway in hypoxia-induced pulmonary vascular remodeling and the underlying mechanisms. Methods: The arterial wall thickness was measured by hematoxylin and eosin (HE) staining in distal pulmonary arteries isolated from normal and PAH patient-derived lungs. The protein expression of phosphorylated extracellular signal-regulated kinase (p-ERK) and phosphorylated p38 mitogen-activated protein kinases (p-p38MAPK) were measured by Western blot in the lungs of PAH patients and hypoxia-induced rats. The apoptosis of cultured rat pulmonary arterial smooth muscle cells (PASMCs) was determined by Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and Flow cytometry. The cell proliferation and cell cycle in PASMCs following hypoxia were analyzed by bromodeoxyuridine incorporation and flow cytometry, respectively. Results: Our results showed that the levels of p-ERK and p-p38MAPK were both drastically elevated in lungs from human patients and hypoxic rats. The HE staining revealed that the medial wall thickness was higher in patients with PAH than normal humans. In cultured PASMCs, Hypoxia stimulated the cell proliferation, the cell cycle progression, and subsequently promoted cell differentiation and cell migration leading to the suppressed cell apoptosis. Furthermore, MAPKs- induced cell proliferation and anti-apoptosis in PASMCs is 15-LO-2/15HETE activation-dependent. Conclusion: Our study indicates that hypoxia-induced pulmonary vascular remodeling is associated with increased levels of 15-LO-2 and 15-HETE. 15-LO-2/15-HETE stimulates the cell proliferation and anti-apoptosis in PASMCs through phosphorylation of ERK and p38MAPK, which subsequently contributing to hypoxia-induced pulmonary vascular remodeling.

FEATURES OF PULMONARY ARTERIAL HYPERTENSION IN THE RUSSIAN REGISTER

The aim of the multicenter prospective open study: to assess demographic and clinical characteristics of PAH patients, regions of their accommodation, features of diagnostic and medical strategy, and survival. Materials and methods. In the study we included PAH patients (group 1) aged >18 years observed in 10 expert centers of the Russian Federation from 01.01.2012 to 30.04.2014. Patients' data were brought in the electronic forms on the registry site www.pul-hyp.medibase.ru. Results. 198 patients (160 women/38 men) from 44 regions of the country were included in the study: 55.0% - IPAH, 35.9% - PAH associated with congenital heart disease, 7,6% - PAH associated with connective tissue disease, 1.0% - heritable PAH, 0.5% - PAH associated with portal hypertension. At the time of including in the register the patients' age median was 38.1 (28.753.8) years, the disease duration median was 5.9 (2.3-13.7) years. The 6MW distance was 394.84 ± 111.10 meters, dyspnea Borg index - 3.34 ± 1.41 points. 9.2% had FC I, 43.7% of FC II, 36.2% of FC III, 10.9% of FC IV. According to RHC mean PAP was 55 (43.25-64.0) mm Hg, CV 3.5 (2.9-4.33) l/min, CI 2.0 (1.82.3) l/min/m 2 , PVR 1079 (762-1424.8) dinхс/см 5 . Positive acute vasodilator testing was found in 25% of patients. The spectrum of the most frequent associated diseases included gastrointestinal diseases (27%), arterial hypertension (14%), urolithiasis (9%) were. PAH-specific therapy was prescribed to 68% of patients (sildenafil - 75.4%, bosentan - 40.4%, iloprost - 9.5%). 9.6% of patients were observed in clinical trials. PAH monotherapy was prescribed to 66.7% of pts, the combined two-component therapy was recommended to 31.7% of pts, triple therapy- to 1.6% of pts. 51% of pts were treated with calcium channel blockers, 59% - diuretics, 82% - antitrombotic drugs. In PAH group the 1-y survival was 98%, the 2-y survival - 96%. Conclusion. Harmoniously built system network of expert centers will allow to improve early diagnostic of PAH, providing proper observation and lowering mortality rate.

Skeletal muscle abnormalities in pulmonary arterial hypertension.

BackgroundPulmonary arterial hypertension is a progressive disease that is characterized by dyspnea and exercise intolerance. Impairment in skeletal muscle has recently been described in PAH, although the degree to which this impairment is solely determined by the hemodynamic profile remains uncertain. The aim of this study was to verify the association of structural and functional skeletal muscle characteristics with maximum exercise in PAH.MethodsThe exercise capacity, body composition, CT area of limb muscle, quality of life, quadriceps biopsy and hemodynamics of 16 PAH patients were compared with those of 10 controls.ResultsPAH patients had a significantly poorer quality of life, reduced percentage of lean body mass, reduced respiratory muscle strength, reduced resistance and strength of quadriceps and increased functional limitation at 6MWT and CPET. VO2 max was correlated with muscular variables and cardiac output. Bivariate linear regression models showed that the association between muscular structural and functional variables remained significant even after correcting for cardiac output.ConclusionOur study showed the coexistence of ventilatory and quadriceps weakness in face of exercise intolerance in the same group of PAH patients. More interestingly, it is the first time that the independent association between muscular pattern and maximum exercise capacity is evidenced in PAH, independently of cardiac index highlighting the importance of considering rehabilitation in the treatment strategy for PAH.

The first annual Drug Discovery and Development Symposium for Pulmonary Hypertension.

The first annual Drug Discovery and Development Symposium for Pulmonary Hypertension.

GW25-e5413 Elevated circulating BMP7 reflects dysfunction of pulmonary vasculature in PAH patients

This study aimed to show whether circulating BMPs levels are associated with phenotype and increased risk of mortality in PAH patients. Circulating BMPs were measured by ELISA in plasma samples from 10 patients with HPAH and 16 corresponding unaffected relatives with BMPR2 mutations. We also

O-024 Outcome Research In 77 Patients With Pulmonary Arterial Hypertension Receiving Sildenafil: A Double-blind, Randomised Controlled Study

Purpose PAH resulting from CHD – a major cause of postoperative morbidity and death. Sildenafil: selective inhibitor of phosphodiesterase-5 - an effective and promising pulmonary vasodilator, with minors reverse effects. Methods This monocentric, randomised placebo-controlled study evaluated the efficacy, safety, tolerability of oral Sildenafil in children with severe PAH secondary congenital shunts (simple (14 patients), mixed (35), complex (28)). 77 PAH patients (35 – repaired shunts, 31 – palliative, 11 inoperable) assigned to placebo or Sildenafil – dose of 1–2 mg/kg/day each 8h: 6–12 months. Sildenafil group - 38 (mean age 19, 9 ± 5, 3 months: 16 boys/22 girls); placebo – 39 (mean age 21, 7 ± 7, 8 months: 22 boys/17 girls). Research protocol: FC NYHA; 6-min walk test; O2 saturation; echocardiography PAPm, myocardial performance index (MPI/Tei index), right cardiac catheterisation – PVRI; questionnaire for adverse reactions was available. Results Sildenafil patients improved FC from 3,16 ± 0, 1–2, 15 ± 0,1 (p 2 saturation (+3,1 ± 0,5%) but placebo (+0,6 ± 0,3%), (p 2 (p 2 (p Conclusions Sildenafil – efficient in treating severe PAH secondary to congenital shunts, but even more effective in children after cardiac surgery. Sildenafil improves FC, effort tolerability, O 2 saturation, RV global function, diminishing PAPm and PVRI comparing with placebo. Sildenafil has good safety, tolerability, favourable impact on life quality – insignificant adverse reactions.

ANGIOGENESIS, MICRO-RNA AND RIGHT VENTRICLE FAILURE IN PULMONARY ARTERIAL HYPERTENSION

Right Ventricular Failure (RVF) is the most important predictor for both morbidity and mortality in pulmonary hypertension (PHT). Nonetheless, RVF remains understudied compared to the left ventricle (LV) and the reason for which the RV fails faster than the LV remains unknown. Recent studies have established that impaired RV metabolism and decreased RV vascular density contribute to RVF. Nonetheless the mechanisms for these anomalies remain unknown. MicroRNAs (miRNAs) have emerged as important determinants for both metabolism and angiogenesis especially angio-miR-126, which by inhibiting SPRED-1, triggers VEGF pathway by increasing RAF/MAP signaling, thus promoting angiogenesis and increasing metabolism activity. We hypothesized that specific miR-126 downregulation will promote RV ischemia and the transition from a compensated (CRV) to a decompensated RV (DRV). We studied free RV wall tissue from humans with normal RV functions (n=20), CRV (Fallot and pulmonary valve stenosis) (n=7) and PAH patients with (DRV) (n=6). We used qRT-PCR to study the expression of miR-126 and CD31 immunofluorescence to measure the heart’s microcirculation. As expected, when compared with control and CRV, DRV had decreased miR-126 expression (n=5; p<0.05) and microvessels density (n=5; p<0.05) creating an imbalance between O2 demand and delivery, therefore leading to decreased oxidative metabolism (PDH activity). Interestingly, under the same conditions miR-126 and micro vessels density were not affected in LV. We identified molecular signature in DRV through miR-126 downregulation leading to an increase in SPRED-1, decreasing the activation of RAF (P-RAF/RAF) and MAP kinase (P-MAP/MAP) thus decreasing VEGF pathway (p<0.05). Furthermore, in vitro matrigel assay from primary culture of human endothelial cells showed that miR-126 up-regulation using mimic increased angiogenesis of human DRV cells while downregulation of miR-126 (antagomir) in control or CRV reproduces PAH phenotype by decreasing angiogenesis. In other hand, using pressure volume catheterization in closed chest we showed that In vivo miR-126 up regulation (mimic-126 i.v injection) improved cardiac function of monocrotaline-induced PAH (increase cardiac output, stroke volume and decrease RV end diastolic pressure; p<0.05). We demonstrated for the first time that 1) Specific downregulation of miR-126 in RV leads to decrease in both vascular density and oxidative metabolism which could explain RV decompensation in PAH. 2) miR-126 represents a new and safe therapeutic way to improve RV function in PAH patients.

EVALUATION OF PULMONARY GLUCOSE METABOLISM WITH FDG-PET/CT IN PATIENTS WITH PULMONARY ARTERY HYPERTENSION AND PULMONARY HYPERTENSION DUE TO LEFT HEART DISEASE

Pulmonary arterial hypertension (PAH; WHO group 1) is a progressive disease characterized by profound vascular remodeling of the media with proliferation of smooth muscle cells in pulmonary arteries and arterioles. In contrast, pulmonary hypertension (PH) associated with left heart disease (WHO group 2) is caused largely by passive transmission of elevated pulmonary venous pressures into the lung arterial system. Recent studies showed increased glucose metabolism in the lung parenchyma in animal models or small PAH patient cohorts, and may reflect underlying metabolic abnormalities in the remodeled pulmonary vasculature. However, there is no study to compare lung FDG uptake in patients with PAH with those with PH due to left heart disease (group 2 PH), in which the same metabolic abnormalities may not be evident. The aim of this study was to compare lung FDG uptake among three groups including PAH groups, group 2 PH and control subjects. Twenty-two patients with PAH (13 patients with idiopathic PAH and 9 patients with connective tissue disease), 8 patients with group 2 PH, as well as 14 control subjects (no lung disease, no uncontrolled diabetes or PH) were included. There were no significant differences in the mean age between cohorts (PAH 55.6±14.0 vs control 55.9±17.1 vs group 2 PH 59.4±14.5 yrs, p=0.83). Mean pulmonary arterial pressure (mPAP) was assessed with right heart catheterization and was not significantly different between PAH and group 2 PH (45.0±12.1 vs 42.1 mmHg, p=0.56). All subjects underwent FDG-PET/CT imaging. Regions of interest (ROIs) were drawn manually to include the lateral one-third of the lungs on the sagittal images to avoid including obvious pulmonary vessels or non-specific fibrosis. The mean standard uptake value (SUV g/cc) of FDG in each lung was obtained and average values of both lungs were calculated as mean lung FDG SUV. The correlation between mPAP and mean lung FDG SUV was also analyzed in PAH and group 2 PH. PAH patients demonstrated significantly increased mean lung FDG SUV compared with control subjects and group 2 PH (PAH: 0.79±0.27 vs control: 0.53±0.19 vs group 2 PH: 0.35±0.20, p<0.0001). The mean lung FDG SUV did not correlate with mPAP either in PAH or group 2 PH. PAH is associated with increased pulmonary FDG uptake indicating increased glucose metabolism in the lung. This may represent active inflammation and requires further study.

Alternatives to the six-minute walk test in pulmonary arterial hypertension.

IntroductionThe physiological response during the endurance shuttle walk test (ESWT), the cycle endurance test (CET) and the incremental shuttle walk test (ISWT) remains unknown in PAH. We tested the hypothesis that endurance tests induce a near-maximal physiological demand comparable to incremental tests. We also hypothesized that differences in respiratory response during exercise would be related to the characteristics of the exercise tests.MethodsWithin two weeks, twenty-one PAH patients (mean age: 54(15) years; mean pulmonary arterial pressure: 42(12) mmHg) completed two cycling exercise tests (incremental cardiopulmonary cycling exercise test (CPET) and CET) and three field tests (ISWT, ESWT and six-minute walk test (6MWT)). Physiological parameters were continuously monitored using the same portable telemetric device.ResultsPeak oxygen consumption (VO2peak) was similar amongst the five exercise tests (p = 0.90 by ANOVA). Walking distance correlated markedly with the VO2peak reached during field tests, especially when weight was taken into account. At 100% exercise, most physiological parameters were similar between incremental and endurance tests. However, the trends overtime differed. In the incremental tests, slopes for these parameters rose steadily over the entire duration of the tests, whereas in the endurance tests, slopes rose sharply from baseline to 25% of maximum exercise at which point they appeared far less steep until test end. Moreover, cycling exercise tests induced higher respiratory exchange ratio, ventilatory demand and enhanced leg fatigue measured subjectively and objectively.ConclusionEndurance tests induce a maximal physiological demand in PAH. Differences in peak respiratory response during exercise are related to the modality (cycling vs. walking) rather than the progression (endurance vs. incremental) of the exercise tests.

SAT0014 Registry of Pulmonary Arterial Hypertension in Chinese Patients with Systemic Lupus Erythematosus: 10-Years' Experience from A Single Center in China

BackgroundPulmonary Arterial Hypertension (PAH) is a severe complication of Systemic Lupus Erythematosus (SLE). With more widely access of Right Heart Catheterization (RHC) as the gold standard, detection of PAH in...

Ferric carboxymaltose improves exercise capacity and quality of life in patients with pulmonary arterial hypertension and iron deficiency: A pilot study

BackgroundPulmonary arterial hypertension (PAH) is a progressive condition harboring a poor prognosis. Iron deficiency in PAH correlates with disease severity and mortality. While replacement therapy may be beneficial, dietary iron absorption is impaired in PAH patients by hepcidin, a key regulatory protein of iron homoeostasis. We therefore assessed the therapeutic potential and safety of intravenous iron supplementation in patients with PAH and iron deficiency. Methods20 patients with PAH and iron deficiency, who were on stable targeted PAH therapy, received a single infusion of ≤1000mg ferric carboxymaltose. All patients were assessed at baseline and two months after iron treatment. Exercise capacity was evaluated based on the 6-minute-walking distance (6MWD), and quality of life (QoL) was assessed by the SF-36 questionnaire (100 point scale). The effects were compared to 20 matched patients with stable PAH without iron deficiency who did not receive ferric carboxymaltose. ResultsIn iron deficient patients, iron supplementation led to a marked improvement of iron status (serum iron 5.7±0.4 to 11.1±1.1μmol/L, ferritin 29.3±6.3 to 145.2±25.4μg/L, transferrin saturation 7.5±0.7 to 19.3±2.3%, all p≤0.001). Iron-deficient patients receiving ferric carboxymaltose showed a significant increase of the 6MWD from 346.5±28.3 to 374.0±25.5m (p=0.007), whereas no significant changes were found in the control group not receiving iron supplementation (6MWD 389.9±25.3 to 379.6±26.2m; n.s.), resulting in a net increase in the 6MWD of 37.8m (p=0.003). This was associated with an improvement in QoL (SF-36 score from 44.3±3.7 to 50.6±3.6; p=0.01). Only minimal side-effects were reported. ConclusionsThese data indicate that parenteral iron supplementation with ferric carboxymaltose significantly improves exercise capacity and QoL and is well tolerated in patients with PAH and iron deficiency, and when administered in addition to targeted PAH therapies. Our results provide proof of concept for further studies evaluating the potential of iron as an adjunct in PAH treatment on a larger scale.

The crucial role of calcium sensing receptor for hypoxia‐induced pulmonary arterial hypertension in mice (889.2)

Rationale: An increase in cytosolic free Ca2+ in pulmonary arterial smooth muscle cells (PASMC) is not only a major trigger for pulmonary vasoconstriction but also an important stimulus for PASMC proliferation. Our previous data showed that the extracellular calcium sensing receptor (CaSR) expression and function were both enhanced in PASMC from idiopathic PAH patients. However, the implication of CaSR in the development of PAH remains elusive.Methods: CaSR and parathyroid hormone double knockout (DK) mice were used to test the hypothesis that CaSR modulates pulmonary vascular tone and the response to hypoxia. Wild type (WT) and DK mice were exposed to 10% oxygen for up to three weeks. Pulmonary vascular remodeling was evaluated using tissue morphometrics. Right ventricle systolic pressures (RVSP) and right ventricular hypertrophy by, RV/(LV+S) ratios, were measured to evaluate pulmonary hypertensive development. We also isolated PASMC from WT or DK mice, followed with cell proliferation assay and cytosolic Ca2+ concentration ([Ca2+]cyt) measurement.Results: WT and DK mice displayed normal systemic and pulmonary arterial pressure under normoxic conditions. However, compared to WT mice, DK mice had significantly lower RVSP, RV/LV+S ratios, and displayed less pulmonary vascular remodeling when exposed to hypoxia. Extracellular Ca2+ caused an increase in [Ca2+]cyt in PASMC isolated from hypoxic WT mice. However, restoration of extracellular Ca2+ had little effect on [Ca2+]cyt in DK mice. Additionally, a decrease in store‐operated Ca2+ entry (SOCE) was observed in PASMC from DK mice, as compared to SOCE in PASMC from WT mice.Conclusion: These data indicate that CaSR plays an important role in the development and progression of pulmonary vascular remodeling in mice with PH. CaSR deletions prevent the development of hypoxia‐induced PAH in mice via its modulation of extracellular Ca2+ entry in PASMC, suggesting that CaSR may be a novel therapeutic candidate for the treatment of PAH.Grant Funding Source: Supported by NIH (HL066012; HL115014)