PAH Patients Research Articles

P1397 Rehabilitation in pulmonary arterial hypertension: REHAB-HTP

Abstract BACKGROUND Pulmonary arterial hypertension (PAH) is a life-threatening condition. Current ESC guidelines recommend exercise training and rehabilitation in clinically stable PAH patients. PURPOSE To assess the beneficial effect of exercise training on exercise capacity, quality of life and cardiac function as assessed by echocardiography and cardio-pulmonary exercise test. METHODS We prospectively included 12 clinically stable PAH patients over a 6 months period. Exercise stress echocardiography (ESE), cardio-pulmonary exercise test (CPET), SF-12 quality of life health survey, 6 minute walking test distance (6MWD), BNP and clinical assessment were performed before and after cardio-pulmonary rehabilitation. Patients underwent 8 weeks of exercise training (3 times a week of aerobic training and at home daily prescribed exercises). RESULTS All patients underwent ESE and CPET without any complication. 6 patients experienced a reduction in WHO functional class whereas 6 remained stable. Patients significantly improved their physical quality of life (p = 0.006). They also improved their exercise capacity according to maximum workload during CPET (p = 0.008) and CPET duration (p = 0.001) whereas a trend toward an improved 6MWD was observed (+58m, p = 0.10). Anaerobic threshold and peak VO2 (+1.7 ± 2.7 mL/kg/min) improved significantly (p = 0.01 and 0.03). Regarding imaging data, at rest peak strain improved after rehabilitation (p = 0.05) whereas the RV became more dilated. RV contractile reserve, defined by the change in peak systolic longitudinal RV strain between rest and maximum exercise, significantly improved (-3.9 ± 4.7%, p = 0.03) CONCLUSION In this preliminary study, cardio-pulmonary rehabilitation led to an improved quality of life and exercise capacity in PAH. The increased in RV contractile reserve post-rehabilitation might explain, in association with the peripheral muscular effects of exercise training, the clinical benefits of rehabilitation in PAH. Abstract P1397 Figure. echography peak/rest in a PAH patient

The Effect of Oxygen Therapy on 6MWD in PAH and CTEPH Patients With Hypoxemia

The Effect of Oxygen Therapy on 6MWD in PAH and CTEPH Patients With Hypoxemia

PRS13 COST-UTILITY ANALYSIS OF MACITENTAN IN COMPARISON WITH BOSENTAN IN PULMONARY ATRIAL HYPERTENSION (PAH)

Endothelin (ET) receptor antagonists (ERAs), have considerable improvements on PAH patients’ symptoms. Macitentan, a novel ERA, has more significant positive effects like reduction of morbidity and mortality in PAH patients by 45% and decrease PAH hospitalization. Besides, Macitentan was able to improve both physical and mental aspects of patients’ lives. The aim of this study was to evaluate an incremental cost utility analysis of Macitentan compared with Bosentan in PAH patients in Iranian health care system. We developed a hybrid model consisted of a decision tree in which PAH patients would take and continue either Macitentan or Bosentan with different probabilities. Subsequently, each patient would enter one of the 4 Markovs, each consisting of 5 states, PAH fraction I, PAH fraction II, PAH fraction III, PAH fraction IV and death. The cycles and time horizon were considered 3-months and life time, respectively. We assessed the impact of each medicine on patients’ quality adjusted life-years (QALYs) and costs, consequently calculated the ICER (Incremental Cost Effectiveness Ratio). The costs were measured in dollar (1 dollar is equal to 42000 rials) with the perspective of payer. The discount rates were assumed 3% for utility and 5% for costs. Also, sensitivity analysis was conducted. The costs are about 14163 dollars for Bosentan and 13876 dollars for Macitentan for each patient life time. The QALY produced per patient by Macitentan was 0.81 more than that of Bosentan. The calculated ICER was -15013959.37 which means that for each incremental QALY, the payer is charged less. Macitentan is preferable to and dominant over Bosentan in both effectiveness and expenditure. Thus, therapeutic regimen containing Macitentan is introduced as a favorable treatment strategy.

P4493Microvesicles from patients with pulmonary arterial hypertension modulate bFGF from endothelial cells

Abstract Background Pulmonary Arterial Hypertension (PAH) is a progressive condition with remodeling of precapillary arteries. Cytokines involved in angiogenesis have been found elevated in PAH but the role of proangiogenic factors and their regulation is far from fully understood. Microvesicles (MVs) can act as intercellular messengers and modify cell production of proteins. Purpose To evaluate whether MVs from patients with PAH modulate proangiogenic factors in plasma and endothelial cells. Methods 62 patients with PAH and 20 healthy controls were enrolled in the study. The number of MVs were determined in whole blood by flow cytometry. For in vitro studies, MVs were isolated from plasma and a primary endothelial cell line of human pulmonary artery endothelial cells between passages 3 to 7 were used. Protein levels in plasma and conditioned media were analyzed by electrochemiluminescence whereas protein levels in cell lysates were analyzed by western blot (WB). Results The majority of the MVs in whole blood were derived from platelets and patients with PAH had higher concentrations compared to healthy controls (p<0.0001). In plasma both basic Fibroblast Growth Factor (bFGF) and vascular endothelial growth factor receptor 1 (Flt-1) were increased in the patients as compared to healthy controls (median in pg/ml (IQR) Pat. vs Ctrl: bFGF 4.2 (2.5–9.2) vs 1.2 (0.9–2.1); Flt-1 143.0 (88.5–234.5) vs 53.9 (47.7–59.67); p<0.001 for both). Endothelial cells were incubated with or without MVs for 18 hours and effects were monitored by analyzing eNOS and ICAM-1 levels by WB. Both markers were significantly altered, i.e. an about 50% decrease of eNOS and a 50% increase of ICAM-1, by patient MVs but not by the control MVs. The endothelial cells were then incubated with MVs for 6h, 12h, 24h, and 48h and bFGF and Flt-1 were measured in the conditioned media. The presence in media of both proteins were increased over time, but only bFGF was significantly regulated by MVs from PAH patient as compared to MVs from the control group at 24h (2.8 fold increase) and at 48h (12.7 fold increase). Conclusions An increase of two important proangiogenic proteins were found in PAH patients. The MVs from these patients modulate the endothelial response and contribute to a release of bFGF, whereas the Flt-1 levels are regulated by other currently unknown mechanisms. Further studies of the MVs from PAH patients are needed to elucidate how they are involved in the angiogenic process. Acknowledgement/Funding Swedish Research Council, Science For Life Laboratory Sweden

THE IMPACT OF TIME FROM DIAGNOSIS AT BASELINE ON LONG-TERM OUTCOME IN THE GRIPHON STUDY: SELEXIPAG IN PULMONARY ARTERIAL HYPERTENSION (PAH)

Newly diagnosed PAH patients have a poor prognosis. In the randomized, event-driven, long-term GRIPHON trial, the oral IP prostacyclin receptor agonist selexipag significantly reduced the risk of morbidity / mortality events compared with placebo in PAH patients. This post-hoc analysis explores whether early initiation of selexipag, with regards to time from diagnosis, improves outcomes for PAH patients.

P1938In vitro characterization of a novel PI 3-kinase inhibitor for growth factor-induced effects in pulmonary artery smooth muscle cells

Abstract Rationale Pulmonary arterial hypertension (PAH) is characterized by vascular remodeling in pulmonary arterioles. Increased activation of receptor tyrosine kinase (RTK)-mediated signaling pathways lead to increased proliferation and chemotaxis of pulmonary arterial smooth muscle cells (PASMCs). In previous studies, we identified phosphatidylinositol-3-kinase (PI3K) as a key enzyme for these processes. Since systemic PI3K inhibition is potentially associated with undesired side effects, we here for the first time tested the efficacy of the novel PI3K inhibitor CL27c to impede growth factor-mediated cellular effects in human PASMCs. CL27c is topically applicable and as a prodrug it is intracellularly activated and thus offers optimal efficacy in target cells while at the same time minimizing undesired effects in non-target cells. Methods Using Western blotting and immunohistochemistry, activation of the central PI3K effector AKT in human and murine lung tissue was investigated. Quantification of cell proliferation was performed by 5-bromo-2-deoxyuridine (BrdU) incorporation assay. PASMCs were incubated with CL27c [0.1; 0.3; 1; 3; 10μM] and stimulated either with PDGF-BB [30ng/ml] or with a growth factor combination (GFC) [PDGF-BB 30ng/ml, FGF 2ng/ml, EGF 0.5ng/ml, insulin 0.5μg/ml, FCS 5%]. Chemotaxis was quantified using modified Boyden chambers. The signal transduction cascade was investigated by Western blotting. Results Analysis of AKT activation revealed hyperphosphorylation in both the vascular wall and complete lung homogenates from PAH patients and hypoxia-treated mice. Examination of the mitogenic signal transduction revealed a markedly reduced phosphorylation of AKT and GSK3β in CL27c pretreated PASMCs. In addition, central cell cycle events, such as expression of cyclin D1, were reduced. This was in line with a CL27c concentration-dependent significant reduction of PDGF- and GFC-induced proliferation (control: 2.53±0.26 vs. CL27c: 0.73±0.14 and control: 5.27±0.61 vs. CL27c: 2.80±0.71 both at 10μM, p<0.001). Furthermore, PDGF- and GFC-induced chemotaxis were as well significantly reduced (100% ± 19 vs. CL27c: 24.43% ± 8.58 and 100% ± 5.76 vs CL27c: 25.23% ± 10.57 at 10μM p<0.001). Conclusion These results indicate that CL27c reduces both proliferation and chemotaxis of PASMCs. As these processes play a key role in the development and progression of PAH, this approach is currently being investigated in preclinical models for its therapeutic potential. This “prodrug” approach could avoid non-specific effects and systemic side effects of Pan-PI3K inhibition, especially since the substance is suitable for topical application (inhalation). Thus, CL27c represents a promising treatment option.

55Identification of celastramycin as a novel therapeutic agent for pulmonary arterial hypertension - high-throughput screening of 5,562 compounds

Abstract Background Pulmonary arterial hypertension (PAH) is characterized by enhanced proliferation of pulmonary artery smooth muscle cells (PASMCs) accompanying increased production of inflammatory factors and adaptation of mitochondrial metabolism to a hyperproliferative state. However, at present, since all the drugs in clinical use target pulmonary vascular dilatation, they may not be so effective for patients with advanced PAH. Purposes We aimed to discover a novel drug for PAH that inhibits PASMC proliferation. Methods In the first screening, we examined 5,562 compounds from our original library using high-throughput screening system to discover a compound that inhibits proliferation of PASMCs from PAH patients (PAH-PASMCs). In the second screening, we performed concentration-dependent assays and counter assays with PAH-PASMCs and PASMCs from healthy donors. We also performed apoptosis assays and mechanistic analysis for inflammation, reactive oxygen species (ROS), and mitochondrial function. Results We found that celastramycin, a benzoyl pyrrole-type compound originally found in a bacteria extract, inhibited the proliferation of PAH-PASMCs in a dose-dependent manner with minimal effects on PASMCs from healthy donors. Moreover, celastramycin inhibited proliferation with minimal increase in apoptosis and low rate of cell death. Then, we synthesized 25 analogues of celastramycin, and finally selected the lead compound that significantly inhibited proliferation of PAH-PASMCs and reduced cytosolic ROS levels. Mechanistic analysis demonstrated that celastramycin reduced the protein levels of hypoxia-inducible factor-1α, which was abnormally activated in PAH-PASMCs and impaired aerobic metabolism, and nuclear factor-κB, which induces pro-inflammatory signals, in PAH-PASMCs compared with vehicle controls, leading to reduced secretion of inflammatory cytokines. Importantly, celastramycin treatment reduced the ROS levels in PAH-PASMCs with increased protein levels of NF-E2-related factor 2 (Nrf2), a master regulator of cellular response against oxidative stress. Furthermore, celastramycin treatment improved mitochondrial energy metabolism with recovered mitochondrial network formation in PAH-PASMCs. We also discovered that celastramycin-mediated effects on these transcriptional modulators could be regulated by zinc finger C3H1 domain-containing protein, which is a binding partner of celastramycin. Finally, celastramycin treatment ameliorated pulmonary hypertension in three experimental animal models of PH in mice and rats, accompanied by reduced inflammatory changes in the lungs. Conclusions These results indicate that celastramycin ameliorates pulmonary hypertension through inhibition of excessive proliferation of PAH-PASMCs, for which its anti-inflammatory and beneficial effects on mitochondrial energy metabolism may be involved. Thus, celastramycin could be a novel drug for PAH as it exerts anti-proliferative effects on PAH-PASMCs.

MACITENTAN IN PULMONARY ARTERIAL HYPERTENSION ASSOCIATED WITH CONNECTIVE TISSUE DISEASE: REAL-WORLD EVIDENCE FROM THE COMBINED OPUS/ORPHEUS DATA SETS

MACITENTAN IN PULMONARY ARTERIAL HYPERTENSION ASSOCIATED WITH CONNECTIVE TISSUE DISEASE: REAL-WORLD EVIDENCE FROM THE COMBINED OPUS/ORPHEUS DATA SETS

ONCE DAILY ORAL DOSING OF RODATRISTAT ETHYL (RVT-1201) ACHIEVES REDUCTIONS IN SEROTONIN BIOSYNTHESIS COMPARABLE TO THOSE ASSOCIATED WITH REVERSAL OF VASCULAR REMODELING IN PAH ANIMAL MODELS

SESSION TITLE: Tuesday Electronic Posters 5 SESSION TYPE: Original Inv Poster Discussion PRESENTED ON: 10/22/2019 01:00 PM - 02:00 PM PURPOSE: RVT-1201, a pro-drug for the tryptophan hydroxylase (TPH) inhibitor KAR5417, is being developed for PAH. TPH1 is the rate-limiting enzyme for peripheral biosynthesis of serotonin (5HT), which has been implicated as a causative factor in PAH. RVT-1201 decreased pulmonary vessel wall thickness in 2 PAH rodent models indicating potential to halt/reverse pulmonary remodeling in humans. The median effective dose (100 mg/kg QD) in PAH rat models yielded a ∼35% reduction in 5-HT biosynthesis (based on reduction in urinary 5-HIAA, a metabolite of 5HT). Divided-dose pharmacodynamic (PD) studies in healthy rats (QD vs BID vs TID) demonstrated KAR5417 AUC, rather than Cmax or Cmin, best correlated with lowering of 5-HT, indicating QD dosing was as effective as more frequent dosing. The purpose of this study was to compare reductions in 5-HIAA levels following QD and BID dosing in healthy subjects. METHODS: 24 healthy subjects received 800 mg total daily oral doses of RVT-1201 or placebo (PBO), either as single (800mg QD) or divided (400mg BID) doses for 14 days across two cohorts (9 active: 3 PBO per cohort). KAR5417 plasma levels and change from Baseline (BSL) PD biomarker data (plasma and urine 5-HIAA) were compared between QD and BID cohorts at Day 14. Safety and tolerability were assessed via adverse event (AE) monitoring and laboratory, vital signs and ECG assessments. RESULTS: At Day 14, KAR5417 mean (±SD) AUC0-24 at 800 mg QD (9180 ng*h/mL, ± 4280) was comparable to the mean pAUC0-24 for 400 mg BID (10400 ng*h/mL, ± 3260). 5-HT lowering was similar across both dose regimens, with 800 mg QD achieving mean (± SD) 40.0 (6.32) % and 45.8 (6.59) % reductions in plasma and urinary 5-HIAA at D14, respectively, compared to 49.9 (9.52) % and 55.5 (10.3) % reductions, respectively, with the 400 mg BID regimen. Plasma and urinary 5-HIAA levels were not reduced from BSL in the PBO arms. 5-HIAA reductions in both regimens exceeded those associated with efficacy in the rodent models. Both dose regimens were generally well-tolerated. The overall incidence of GI-related AEs was greater in the QD group (78%) compared to the divided dose group (33%); however, most AEs were mild in intensity and there were no treatment-related withdrawals in either cohort. CONCLUSIONS: Repeated QD dosing of RVT-1201, an investigational treatment for PAH, reduced 5-HT biosynthesis similarly to divided (BID) daily dosing. Reductions in 5-HIAA levels were comparable to those associated with reversal of vascular remodeling in animal PAH models. RVT-1201 was generally well-tolerated in both dose regimens. CLINICAL IMPLICATIONS: RVT-1201 has the potential to reduce serotonin production and impact vascular remodeling in PAH patients. If ultimately proven effective, the potential to dose RVT-1201 once-daily may help improve overall treatment adherence in a disease like PAH in which patients often take more than one drug in combination chronically. DISCLOSURES: Employee relationship with Altavant Sciences Please note: >$100000 Added 02/05/2019 by David Carpenter, source=Web Response, value=Salary Employee relationship with Altavant Sciences Please note: >$100000 Added 03/15/2019 by Katelyn Crizer, source=Web Response, value=Salary Employee relationship with Altavant Sciences Please note: >$100000 Added 03/20/2019 by Laurence Keller, source=Web Response, value=Salary Employee relationship with Altavant Sciences Please note: $1-$1000 Added 03/20/2019 by Laurence Keller, source=Web Response, value=Ownership interest Removed 03/20/2019 by Laurence Keller, source=Web Response Employee relationship with Altavant Sciences Please note: $20001 - $100000 Added 03/15/2019 by Thomas Pack, source=Web Response, value=Salary Employee relationship with Altavant Sciences Please note: $20001 - $100000 Added 03/15/2019 by Michelle Palacios, source=Web Response, value=Salary No relevant relationships by Julie Rurka, source=Web Response No relevant relationships by Michele Snyder, source=Web Response Employee relationship with Altavant Sciences Inc Please note: >$100000 Added 03/18/2019 by Stephen Wring, source=Web Response, value=Salary

HEMOPTYSIS IN EISENMENGER SYNDROME-ASSOCIATED PULMONARY ARTERIAL HYPERTENSION (PAH): FORGOT ABOUT BRONCHIAL ARTERY EMBOLIZATION

SESSION TITLE: Pulmonary Vascular Disease SESSION TYPE: Med Student/Res Case Report PRESENTED ON: 10/23/2019 8:45 AM - 9:45 AM INTRODUCTION: Anticoagulation in Eisenmenger syndrome (ES) associated PAH (ES-PAH) presents a clinical challenge, as there is both an increased prevalence of pulmonary artery thrombosis and hemoptysis. We present a case of ES-PAH complicated by hemoptysis and treated successfully with multi-vessel bronchial artery embolization (BAE). CASE PRESENTATION: A 52-year-old female with an atrial septal defect complicated by ES-PAH treated with continuous epoprostenol infusion, ambrisentan, supplemental oxygen, and thrombophilia previously managed with warfarin; presented with a one-week history with multiple episodes of hemoptysis and chest tightness. She reported a similar episode of hemoptysis one-year previously with no specific source of bleeding identified. At the time of her hemoptysis had resolved with discontinuation of warfarin.On this presentation, her vital signs were unremarkable on 3 LPM nasal cannula. Physical examination demonstrated a right ventricular heave, a loud and prominent P2, and a third heart sound. Electrocardiography revealed normal sinus rhythm and bifascicular block (RBBB and LPFB). CT angiography (CTA) of the chest demonstrated dilated bronchial arteries and patchy ground glass opacities within the left upper and lower lobes, consistent with alveolar hemorrhage.Otorhinolaryngology and interventional pulmonology found no discrete bleeding in the upper or lower respiratory tract. After discussion, prophylactic embolization of the dilated right and left bronchial arteries was performed successfully. No further episodes of hemoptysis were reported post embolization. On outpatient follow-up the patient has remain hemoptysis free. DISCUSSION: Eisenmenger physiology results from chronic left-to-right shunting of blood, leading to increased right-sided pressures, and reversal of shunt flow. Patients with ES-PAH are at increased risk of pulmonary artery thrombosis with concurrent increased risk of hemoptysis and pulmonary hemorrhage(1). Thrombo-embolic risks include atrial fibrillation and indwelling central catheters. Hemoptysis is often due to bronchial artery dilatation and/or rupture. The use of anticoagulation in ES-PAH patients is controversial due to balancing risk between thrombosis and hemoptysis, and survival benefits are unclear(2). BAE in PAH patients is more complex than in patients without PAH, due to frequent higher numbers of culprit arteries and increased anatomical/morphological variability(3). However, BAE has been demonstrated to be a safe and reliable intervention for hemoptysis in PAH3. There is no definitive treatment and repeated BAE for reoccurrence is common. CONCLUSIONS: Anticoagulation in ES-PAH should be used conservatively in an individualized approach. Hemoptysis is an uncommon in ES-PAH and may result from bronchial artery dilatation and rupture. We demonstrated the safety of multi-vessel BAE in ES-PAH and encourage its consideration within this cohort. Reference #1: Wan D, Tsui C, Kiess M, et al. Anticoagulation for Thromboembolic Risk Reduction in Adults With Congenital Heart Disease. Canadian Journal of Cardiology 2017; 33: 1597–1603. Reference #2: Sandoval J, Santos LE, Córdova J, et al. Does Anticoagulation in Eisenmenger Syndrome Impact Long-term Survival?: Anticoagulation in Eisenmenger Syndrome. Congenital Heart Disease 2012; 7: 268–276. Reference #3: Rasciti E, Sverzellati N, Silva M, et al. Bronchial artery embolization for the treatment of haemoptysis in pulmonary hypertension. La radiologia medica 2017; 122: 257–264. DISCLOSURES: No relevant relationships by Olayiwola Amoran, source=Web Response no disclosure on file for Christine Archer-Chicko; Advisory Committee Member relationship with Actelion/Janssen Please note: $5001 - $20000 Added 02/07/2019 by Harold Palevsky, source=Web Response, value=Honoraria Advisory Committee Member relationship with United Therapeutics Please note: $1001 - $5000 Added 02/07/2019 by Harold Palevsky, source=Web Response, value=Honoraria DSMB relationship with Eiger Please note: $1001 - $5000 Added 02/07/2019 by Harold Palevsky, source=Web Response, value=Honoraria No relevant relationships by cyrus vahdatpour, source=Web Response

A Nationwide multicenter registry and biobank program for deep phenotyping of idiopathic and hereditary pulmonary arterial hypertension in Korea: the PAH platform for deep phenotyping in Korean subjects (PHOENIKS) cohort

BackgroundPulmonary arterial hypertension (PAH) is a progressive, chronic disease without curative treatment. Large registry data of these patient populations have been published, although, phenotypic variants within each subtype of PAH have not been elucidated. As interest towards personalized medicine grows, the need for a PAH cohort with a comprehensive understanding of patient phenotypes through multiomics approaches, called deep phenotyping, is on the rise. The PAH Platform for Deep Phenotyping in Korean Subjects (PHOENIKS) cohort is designed to collect clinical data as well as biological specimens for deep phenotyping in patients with idiopathic PAH (IPAH) and heritable PAH (HPAH) in Korea.MethodsA total of 17 regional hospitals are currently working on enrolling up to 100 consecutive IPAH/HPAH patients for obtaining clinical data and biological specimens across Korea. The diagnosis of PAH is based on right heart catheterization. All clinical data is stored in a government-based online database. Each participating hospitals collect a whole blood sample from each patient, through which DNA, RNA, serum, plasma, and peripheral blood mononuclear cells will be extracted from the buffy coat layer for further multiomics analysis.ResultsNot applicable.ConclusionsThe PHOENIKS cohort is enrolling IPAH and HPAH patients across Korea to determine the prognosis and drug response in different phenotypic variant. The data generated by this cohort are expected to open new doors for personalized medicine in PAH patients of South Korea.Trial registrationClinicalTrials.gov NCT03933579. Registered on May 1st, 2019.

Medium-term health-related quality of life in patients with pulmonary arterial hypertension treated with goal-oriented sequential combination therapy based on exercise capacity

BackgroundPulmonary arterial hypertension (PAH) remains a life-threatening condition, despite modern therapies. We prospectively investigated the therapeutic health-related quality of life (HRQOL) effects of goal-oriented sequential combination therapy based on exercise capacity in patients newly diagnosed with PAH.MethodsTo examine the changes in HRQOL in PAH patients, we treated 30 patients newly diagnosed with PAH with goal-oriented sequential combination therapy based on exercise capacity. We monitored exercise capacity by cardiopulmonary exercise testing and observed the benefit of using a peak VO2 cut-off of 15 mL/kg/min to guide combination therapy. First-line treatment was an endothelin receptor antagonist (ERA); second-line treatment was the addition of a phosphodiesterase-5 inhibitor (PDE-5I). At baseline and at 3, 6, and 12 months, HRQOL was evaluated by using the eight-item Medical Outcomes Survey Short Form Health Survey.ResultsAt 12 months, 100% of PAH patients were receiving an ERA, and 82% an ERA + PDE-5I. The mean physical component summary (PCS) score was 33.5 at baseline, 41.2 at 3 months, 40.8 at 6 months, and 42.0 at 12 months, and the mean mental component summary (MCS) scores were 45.6, 47.0, 50.0, and 50.1, respectively. PCS score was significantly greater at 3 months than at baseline (P = 0.035). MCS score was comparable at 3 months and at baseline, but was significantly greater at 6 and 12 months than at baseline (P = 0.033, P = 0.028, respectively). Thus, PCS score improved soon after initiation of therapy, and MCS score improved later.ConclusionsTogether, these results suggest that goal-oriented sequential combination therapy based on exercise capacity improves HRQOL in patients with PAH.

Unique wreath-like smooth muscle proliferation of the pulmonary vasculature in pulmonary veno-occlusive disease versus pulmonary arterial hypertension

Pulmonary veno-occlusive disease (PVOD) is a rare but fatal cause of pulmonary hypertension reported to be linked to mutations of eukaryotic initiation factor 2 alpha kinase 4 (EIF2AK4), also known as general control nonderepressible 2 kinase (GCN2). PVOD is difficult to diagnose and often initially misdiagnosed as other types of idiopathic pulmonary arterial hypertension (IPAH). To rapidly and correctly identify PVOD patients and explore the possible pathogenesis, we thoroughly investigated histopathological features and GCN2 protein levels in non-PAH, PVOD and PAH patients. Lung specimens were examined for histopathological changes, including those of pulmonary arteries and veins, by Masson's trichrome, modified Verhoeff's and α-SMA staining in the PVOD, IPAH, and non-PAH groups. GCN2 and α-SMA expression in lung tissue was examined by immunohistochemistry and western blotting. PVOD and IPAH patients showed significant intimal and medial thickening of muscular pulmonary arteries compared with non-PAH patients. PVOD patients had more prominent intimal and medial thickening of muscular pulmonary veins than the other two groups. Interestingly, specialized muscle bundles surrounding the tunica adventitia of the pulmonary artery and vein were observed in PVOD patients. A significant decrease in GCN2 expression in the PVOD group was confirmed by immunohistochemistry and western blotting. Our study is the first to show remarkable histological structures, including the wreath-like arrangement of a hyperplastic muscle bundle in the adventitia of pulmonary arteries, in PVOD patients as a diagnostic clue and to disclose the biological difference between PAH and PVOD in a Taiwanese population.

Health Technology Assessment on Sildenafil as Treatment of Pulmonary Arterial Hypertension

Sildenafil is a treatment option for PAH patients that is found to offer an additional 1-3 life years gained for PAH patients compared to beraprost, currently the only treatment available in the benefit package under the National Social Health Insurance (Jaminan Kasehatan Nasional - JKN) of Indonesia. Off-label use of sildenafil for treatment of PAH is recommended to be included in the benefit package. The study results indicate that there is a need for the Ministry of Health in Indonesia to consider the use of off-label medicines in the benefit package given the strong Health Technology Assessment evidence showing the drug’s benefit to the Indonesian population.

Chronic thromboembolic and pulmonary arterial hypertension share right ventricular and pulmonary artery CMR features

BackgroundCardiac magnetic resonance (CMR) imaging has gained importance in pulmonary hypertension (PH) and studies have demonstrated its use as a surrogate marker and in following treatment of these patients. The pathophysiology of PH differs between pulmonary arterial hypertension (PAH, group 1) and chronic thromboembolic PH (CTEPH, group 4). ObjectivesThe present study tested the hypothesis that PAH and CTEPH display different characteristics on CMR imaging. Methods46 patients were evaluated for pulmonary vascular disease in the French National Reference Center for PH (23 PAH and 23 CTEPH matched for age and gender). All patients had the right heart catheterization (RHC) and CMR imaging performed within 48h. CMR imaging was performed on a 1.5 T scanner. ResultsPAH and CTEPH had similar body surface area and similar invasive hemodynamics, including mean pulmonary arterial pressure, cardiac index, pulmonary vascular resistance and right atrial pressure. PAH and CTEPH had similar CMR data. Right ventricular (RV) morphology and function and pulmonary artery (PA) data were also similar. ConclusionAge- and sex-matched PAH and CTEPH patients displayed similar values of the CMR indices of RV and PA morphology and function, suggesting that the RV-PA responses are similar in both groups, mostly related to the overall increase in after load.

Validity of transit time-based blood pressure measurements in patients with and without heart failure or pulmonary arterial hypertension across different breathing maneuvers.

Pulse transit time (PTT) derived by ECG and plethysmographic signal can be a promising alternative to invasive or oscillometry-based blood pressure (BP) monitoring in sleep laboratories because it does not cause arousals from sleep. Therefore, this study assessed the validity of PTT for BP monitoring under sleep laboratory-like conditions. Ten volunteers (55.8 ± 19.6years), 12 patients with heart failure with reduced ejection fraction (HFrEF; 67.3 ± 8.6years), and 14 patients with Nizza class I pulmonary arterial hypertension (PAH; 59.5 ± 13.4years) performed different breathing patterns to simulate nocturnal sleep-disordered breathing (SDB). BP was measured at least every 15min over 1h using oscillometry (Task Force Monitor™) and PTT (SOMNOscreen™) devices in free breathing conditions and during SDB simulation (alternating phases of hyperventilation and apneas). One hundred forty-two points of measurements were collected. No difference was found in both mean systolic BP (SBP) and diastolic BP (DBP) between oscillometric PTT-based BP measurements in the whole population and throughout the whole recording (SBP 111.3 ± 15.1mmHg versus 110.0 ± 14.7mmHg, p = 0.051; DBP 69.9 ± 12.2 versus 69.9 ± 14.2mmHg, p = 0.701). Likewise, no significant difference in SBP and DBP was found between the two methods in the subgroups of healthy subjects, HFrEF patients and PAH patients, both in free breathing conditions (p > 0.05) and during SDB simulation (p > 0.05). When monitoring BP in healthy subjects, and in patients with HFrEF or PAH, PTT provides a BP estimation comparable with oscillometric measurement, though slightly inaccurate, both in the condition of regular and unstable breathing.

PRS29 EVALUATION OF THE REAL-WORLD INCREMENTAL COST BURDEN OF NEWLY TREATED PAH IN THE US

To estimate healthcare resource utilization and direct costs among newly treated PAH patients in comparison to a control group of non-PAH patients. The Optum ClinformaticsTM Data Mart was used to identify adult treatment-naïve PAH patients who initiated an oral PAH-specific medication between 1/1/2013 and 6/30/2016, with the earliest claim defined as the index date. PAH patients were matched at a 1:5 ratio to non-PAH control patients by multidimensional matching. Control patients were assigned a random index date close to the index date of their matched counterpart. Patients were required to have continuous enrollment 12 months prior to (baseline period) and after (follow-up period) the index date, as well as ≥1 PAH diagnosis and no diagnoses of WHO Group 4 Pulmonary hypertension or claims for PAH-specific drugs during the baseline period. All-cause healthcare resource utilization and costs during the baseline and follow-up periods were measured and compared between the matched cohorts. 1,153 newly treated PAH patients and 5,765 matched non-PAH controls were identified with a mean±SD age of 68.5±13.0; 65.6% were female and 72.7% had Medicare coverage. Baseline medical and pharmacy costs were $65,101 vs. $4,056 and $6,367 vs. $992, respectively, yielding total costs of $71,468 vs. $5,048 for the matched PAH and non-PAH patients. Baseline medical costs were primarily due to inpatient ($34,065 vs. $1,429) and outpatient ($29,958 vs. $2,398) care. During the follow-up period, mean inpatient costs were $22,782 vs. $1,174, pharmacy costs were $42,192 vs. $876, outpatient costs were $35,499 vs. $2,452 and total costs were $101,607 vs. $4,702 for PAH and non-PAH patients, respectively. The real-world cost burden for PAH is high. There are modest increases in total healthcare spending during the first 12 months after initiating PAH treatment, where the increased PAH-related pharmacy costs were partially offset by decreased inpatient utilization.

PRS16 A RETROSPECTIVE DATABASE STUDY TO EVALUATE THE ECONOMIC BURDEN OF ILLNESS IN ENGLAND BASED ON A PULMONARY ARTERIAL HYPERTENSION (PAH) PATIENT COHORT

To identify a PAH patient cohort using the Hospital Episode Statistics (HES) administrative database and evaluate hospital healthcare resource utilisation (HRU) and economic burden of illness in England. An algorithm was developed to identify a PAH cohort. HES data were extracted (01.04.2012 to 31.03.2018) and patients were identified as those diagnosed (index date) alive on the 1st of June of each calendar year. The number of events and associated costs were calculated for Accident & Emergency (A&E), inpatient, and outpatient services. Over 5 complete years, 2,527 patients were identified, compared with 2,695 reported in The UK 5th National Pulmonary Hypertension (PH) Audit. The PAH cohort presented a mean follow-up period of 44.8 months (SD=20.5). Gender (68.4% female) and age distribution aligned well with reported literature and the National PH Audit. The mean age at index was 58.0 years (SD=16.8). In 2017 (1,825 patients), PAH patients had a mean of 0.4 A&E attendances (SD=1.0) with a mean cost of £123.18 (SD=£247.37) per patient. PAH patients had a mean of 1.4 inpatient admissions (SD=4.3) for a mean cost of £3,832.91 (SD=£6,032.14) and a mean length of stay of 3.3 days (SD=7.6). The mean length of hospitalisation was 3.8 days (SD=8.1) for PAH-related events and 2.3 days (SD=6.2) for non-PAH-related events. PAH patients had a mean of 5.0 outpatient visits (SD=7.4) with an associated mean cost of £895.86 (SD=£831.93) per patient. In 2017, the total cost for PAH patients was £8.9m where £7.0m was associated with inpatient admissions. Of the total inpatient admission costs, £5.7m was attributed to PAH-related admissions. The epidemiological characteristics of the PAH cohort in England were in line with reported literature. In 2017, 64.3% of the total inpatient admission costs were for a PAH-related event. In summary, these results confirm that there is an HRU burden across all services.

PDG6 HEALTHCARE RESOURCE UTILIZATION, COST, AND TREATMENT PERSISTENCE AMONG TREATMENT-NAIVE PAH PATIENTS INITIATING MONOTHERAPY VS. COMBINATION THERAPY

To evaluate treatment persistence, healthcare resource utilization and costs among treatment-naïve PAH patients who initiate monotherapy or combination therapy. Adult treatment-naïve PAH patients who initiated a phosphodiesterase inhibitor (PDE), prostacyclin analogue (PCA), endothelin receptor antagonist (ERA) or soluble guanylate cyclase stimulator (SGC) between 1/1/2013 and 6/30/2016 (earliest claim defined as index date) were identified from the Optum ClinformaticsTM Data Mart. Patients were required to have continuous enrollment 12 months prior to (baseline period) and after (follow-up period) the index date, and ≥1 baseline PAH diagnosis and no baseline diagnoses of WHO Group 4 pulmonary hypertension or claims for PAH-specific drugs. Patients were stratified into cohorts based on treatment received during the first 90-day post-index period (monotherapy: 1 medication, combination therapy: ≥2 medications). Baseline patient characteristics, follow-up period healthcare resource utilization and costs, and drug persistence as measured by Kaplan-Meier analysis of time to treatment change/discontinuation were determined. In comparison to patients who initiated monotherapy (n=1,052), combination therapy patients (n=101) were younger (64 vs. 69 years, p>0.001) and had lower Charlson Comorbidity Index scores (4.16 vs. 4.77, p=0.035). Monotherapy patients predominantly initiated a PDE (78%) or ERA (20%) while combination therapy patients initiated PDE+ERA (88%) or ERA+SGC (10%). Total healthcare costs were higher among combination therapy patients ($159,635 vs. $96,036), primarily due to pharmacy costs ($116,367 vs. $35,071). While patients treated with ERA, PDE, SGC and PDE+ERA have similar time to treatment change, SGC monotherapy had the numerically lowest risk of treatment change. The percentage of patients treated with combination therapy increased from 2013 to 2016. 9% of PAH patients had first-line combination therapy. Combination therapy patients were younger, had less comorbidity, and had higher healthcare spending largely due to pharmacy costs. While drug persistency with combination therapy and monotherapy were comparable, persistence was better with SGC monotherapy than other regimes.

Increased Pulmonary Vascular Impedance in Patients with Severe Pulmonary Arterial Hypertension

IntroductionPulmonary arterial hypertension (PAH) is characterized by increased pulmonary artery (PA) pressure and resistance due to pulmonary vascular remodeling. The functional effect of this vascular remodeling on the pulsatile pulmonary hemodynamics has not been well studied. Pulmonary vascular impedance (PVZ) represents the relationship between pulsatile pressure and flow in the pulmonary artery (PA) and provides a more comprehensive view of pulmonary arterial function. We hypothesized that decreased pulmonary vascular compliance and increased pulmonary vascular resistance (PVR) would significantly alter the pulsatile pulmonary hemodynamics in severe PAH.MethodsGroup 1 PAH patients (mean pulmonary arterial pressure (mPAP) ≥ 25 mmHg, pulmonary capillary wedge pressure ≤ 15 mmHg) and control patients (without pulmonary hypertension (PH), mPAP < 25 mmHg) with both an echocardiogram including right ventricular outflow tract (RVOT) images and a right heart catheterization (RHC) within three months were identified from the University of Arizona PH registry. The PAH patients were divided into those with mild PH (PVR < 7 mmHg*min/L) and severe PH (PVR ≥ 7 mmHg*min/L). RVOT Doppler flow velocity profiles were first traced using a custom MATLAB program. Flow velocity profiles were multiplied by the average PA diameter (ratio of thermodilution cardiac output and mean RVOT flow velocity) to determine PA flow profiles. PVZ was calculated in the frequency domain using RHC measured PA pressure and PA flow profiles. Characteristic Impedance (ZC) was calculated as the mean of Z2–4. Data is presented as mean ± standard error or median [interquartile range].ResultsFourteen subjects were identified (Control: n = 2, 2 female, 70 ± 3 yrs; Mild PAH: n = 6, 2 female, 63 ± 11 yrs; and Severe PAH: n = 6, 4 female, 45 ± 13 yrs, p = 0.05). The median time between the RHC and echo was 8 [1 − 15] days. Severe PAH patients have increased mPAP (60 ± 19 vs 38 ± 17 mmHg, p = 0.04) and end‐diastolic elastance (1.05 ± 0.43 vs 0.39 ± 0.3 mmHg/mL, p = 0.2), decreased stroke volume (61 ± 7 vs 91 ± 20 mL, p = 0.01) and no change in cardiac output (5.16 ± 0.81 vs 6.23 ± 1.3 L/min) compared to controls. Severe PAH showed increased 0 Hz impedance (Z0, 966 ± 138 dynes/sec/cm−5) compared to controls (288 ± 34 dynes/sec/cm−5, p = 0.02) and mild PAH (538 ± 64 dynes/sec/cm−5, p = 0.03, Figure 1). ZC in severe PAH had a non‐significant increase compared to controls (139 ± 23 vs 69 ± 19 dynes/sec/cm−5, respectively). Z1 was significantly increased in severe PAH compared to controls (52 ± 91 vs 5 ± 43 dynes/sec/cm−5, p = 0.02) but not compared to mild PAH (52 ± 91 vs 64 ± 54 dynes/sec/cm−5, p = 0.09).ConclusionPulmonary vascular impedance analysis in a small PAH cohort demonstrated that vascular resistance (Z0) and global vascular stiffness (Z1) are increased in severe PAH patients and that there is a non‐significant increase in proximal vascular stiffness (ZC).Support or Funding InformationThis work was supported in part by grants from the Arizona Biomedical Research Commission (ABRC NIA ADHS18‐198871 (RRV))This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.