PAH Therapy Research Articles

ROLE OF SEROTONIN AND ITS METABOLITE 5-HIAA IN THE DEVELOPMENT OF PULMONARY HYPERTENSION. NEW APPROACHES TO TREATMENT AND NON-INVASIVE DIAGNOSTICS?

Objective: Development of new methods for diagnostics and new approaches to treatment of PAH from the standpoint of serotonergic regulation. The obtained data points out that a potential marker of PAH is an increase in the concentration of 5-HIAA in urine which is shown by a positive correlation with the stage of PAH. Design and method: I.The patients (n = 43, 20 days - 16 y.o.): Patients with congenital heart disease (CHD) and severe PAH; Patients with CHD with mild to moderate PAH; Healthy children (controls). II.PAH was induced in immature rats by subcutaneous injection of monocrotaline (MCT) (60 mg / kg) at the age of 4 weeks. The studies were carried out 1, 2, 4 weeks after the administration of MCT, namely: - study of 5-HIAA in urine in ELISA - invasive study of pressure in the right heart and pulmonary artery - immunohistochemical and morphological examination of the right and left ventricle, pulmonary artery and aorta. Results: A statistically significant increase in pressure in the right ventricle was found in MIPHM, which indicates the adequacy of the selected model of PAH; - Patients with PH have significantly increased plasma 5-HIAA levels compared to other groups; - There were statistically significant intergroup differences in amount of 5-HIAA in urine; - Direct positive dependence of amount of 5-HIAA in urine on the stage of PAH was revealed. Conclusions: Comparing the data of our studies, it can be concluded that 5-HIAA levels characterize the activity of pathogenetic processes in PAH. Thus, the possibility of plasma or urine 5-HIAA levels measurement in order to assess the severity of PAH and the effectiveness of its therapy is assumed. The hypothesis based on our results give us the opportunity to continue working in direction with the aim of introducing drugs of 5-HT receptor antagonists class for the PAH therapy. Simplicity, availability and non-invasiveness of the assessment method of PAH process activity makes it promising to introduce the determining of 5-HIAA levels in urine in the clinical pathology of the PAH stage and the effectiveness of its therapy.

Abstract 10188: Sotatercept Phase 3 Program Design and Rationale: A Novel Treatment for Pulmonary Arterial Hypertension

Introduction: PAH is characterized by pulmonary vascular remodeling and right ventricular dysfunction. Sotatercept acts as a reverse remodeling agent proposed to rebalance anti- and pro-proliferative signaling based on pre-clinical models of PAH. Clinical efficacy and safety of sotatercept are being studied in the Phase 2 PULSAR and SPECTRA studies. Sotatercept will be further investigated in a Phase 3 clinical program comprised of 4 studies to establish efficacy, safety, and its potential value on top of background therapy across the spectrum of PAH. Methods: Sotatercept will be administered at a starting dose of 0.3 mg/kg, with a target dose of 0.7 mg/kg, subcutaneously every 21 days. All participants will be on background PAH therapy. The efficacy/safety of sotatercept in patients with WHO FC II/III will be assessed in STELLAR (NCT04576988), a double-blind, placebo-controlled, randomized study. The primary endpoint is change in 6MWD from baseline to week 24. A secondary endpoint is multicomponent improvement (MCI), defined as meeting all the following at week 24 vs baseline: ≥30m increase in 6MWD, decrease in NT-proBNP ≥30% or maintenance/achievement of <300 ng/L, and WHO FC improvement or maintenance of WHO FC II. The effects of sotatercept on PAH patients diagnosed within 6 months of screening, with WHO FC II/III, and at intermediate- and high-risk will be studied in HYPERION (NCT04811092), a randomized, double-blind, placebo-controlled study with a primary endpoint of time to clinical worsening. Sotatercept will also be assessed in PAH patients with WHO FC III/IV at high-risk in ZENITH (NCT04896008), a double-blind, placebo-controlled, randomized study evaluating time to first confirmed morbidity or mortality event. Participants transitioning from parent PAH sotatercept clinical studies will further be evaluated for long term safety/tolerability in SOTERIA (NCT04796337), a long-term follow up study. Results: HYPERION, ZENITH and SOTERIA are active, and STELLAR is recruiting, with a target enrollment of 284 participants. Conclusion: The robust Phase 3 clinical program has the potential to further characterize the efficacy and safety of sotatercept across a broad spectrum of patients with PAH and provide a novel treatment option.

Twenty-year experience and outcomes in a national paediatric pulmonary hypertension service

Abstract Background/Introduction Paediatric pulmonary hypertension (PH) is an important cause of childhood morbidity and mortality, but there are limited data on the range of associated diseases (including several paediatric-specific aetiologies), contributions of different PH subtypes, therapeutic strategies and clinical outcomes in paediatric patients. Purpose In this study, we report the 20-year experience of a UK National Paediatric Pulmonary Hypertension Service focusing on the aetiology, management and outcomes of children with PH. Methods Consecutive patients presenting to the service between January 2001 and January 2021 were included in this retrospective study. Other inclusion criteria were: age ≤18 years at diagnosis and diagnosis of PH following specialist assessment. Only incident patients (without pre-existing PH) were entered in the survival analysis. Results A total of 1104 (81.5%) PH patients were included during the study period: 51% female, median age 2.6 [0.8–8.2] years. The most common PH diagnosis was group 1 (pulmonary arterial hypertension, PAH) in 532 (48.2%) patients, followed by group 3 PH (due to lung disease) in 358 (32.4%), group 2 (101, 9.1%), group 5 (93, 8.4%), and group 4 disease (20, 1.8%). The most common PAH subgroup was PAH associated with congenital heart disease (CHD, 63.3%), followed by idiopathic PAH (22.4%). One quarter of patients (23.6%) had multiple contributory factors for PH, fitting more than one diagnostic group. Resolution of PH, defined as normalisation of pulmonary artery pressures following cessation of PAH therapy, occurred in 172 (15.6%) patients at a median age of 3.7 [2.1–5.7] years and was more common in group 3 than other PH groups (33.5% vs. 9.1% at 5 years post-diagnosis, p<0.0001). Overall, 909 (82.3%) patients received PAH therapy. Patients with group 3 PH were as likely to receive PAH therapy as an initial treatment strategy as group 1 patients (86.6% vs. 82.3%, p=0.11), but were more likely to receive sildenafil monotherapy (p=0.002) and less likely to be offered triple therapy (p<0.0001). During follow-up, maintenance or escalation to triple therapy was required in 103 (9.3%) patients and was far more common in idiopathic compared to other PAH subgroups (37.7% vs. 7.8%, p<0.0001). Transplant-free survival was 86.7% (95% CI: 84.5–88.9%) at 1 year, 74.2% (95% CI: 71.1–77.5%) at 5 years, and 68.9% (95% CI: 65.1–73%) at 10 years (Figure 1). PAH related to CHD had the highest transplant-free survival (HR 0.62, 95% CI: 0.46–0.84, p=0.002). Group 2 had the lowest transplant-free survival (HR 2.09, 95% CI: 1.42–3.09, p=0.0002) whereas groups 3,4 and 5 did not differ significantly from PAH (Figure 2). Conclusions In this large, national cohort of paediatric PH patients, the most common type of PH was PAH, followed by group 3 PH. Multiple contributory causes for PH are common and PH resolution was not uncommon, especially in group 3 patients. Despite widespread use of PAH therapy, the prognosis remains guarded. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Dr Constantine has received a PhD grant from Janssen-Cilag Ltd. as the CHAMPION PhD Fellow. Figure 1Figure 2

Pulmonary arterial hypertension associated with congenital heart disease in children: clinical characterisation, outcomes and changes in demographics over time

Abstract Background/Introduction Pulmonary arterial hypertension (PAH) is a common complication of congenital heart disease (CHD) in children and is associated with significant morbidity and mortality. The impact of different phenotypes on management and survival remains unclear. Purpose To examine the clinical features, management and outcomes of paediatric PAH-CHD patients based on the 20-year experience of the UK National Paediatric Pulmonary Hypertension (PH) Service. Methods Consecutive PAH-CHD patients entering the service between January 2001 and January 2021 were included and classified into: Eisenmenger syndrome (ES, group A), PAH related to a significant systemic-pulmonary shunt (group B), PAH with small or co-incidental CHD (group C) and PAH following defect repair (group D). Incident patients (without pre-existing PAH) were included in survival analysis. Results Of the overall PH paediatric cohort of 1104 patients, 819 (74.2%) had co-existing CHD and 354 (32.1%) patients received a diagnosis of PAH-CHD: 57.1% female, median [IQR] 4.6 [1.7–10.9] years. Group D PAH-CHD was the commonest subgroup, accounting for 36%, while the least frequent subtype was group C (14%). Group A and group B PAH-CHD represented 26% and 24%, respectively. Down syndrome was present in over one third (122, 34.5%) of PAH-CHD patients and was more commonly associated with ES (p=0.02). PAH therapy was started in 79.9% of PAH-CHD patients. At the end of follow-up, patients with group C PAH-CHD were more likely to be on combination therapy than any other group (64.6% vs. 28.4%, p<0.0001). Prostanoid therapy was used in a minority (11%) of patients. The subgroup distribution of PAH-CHD at diagnosis changed from the early (2000–2005) to late (2015–2020) period (Figure 1). The proportion of ES patients decreased from 43.4% to 14.6% of PAH-CHD (p<0.0001). The proportion of group B PAH-CHD patients increased (9.4% vs. 33.3%, p<0.0001), with the majority (59.3%) deemed “operable” on specialist assessment. There was a trend for an increase in repaired PAH-CHD patients between the early and late era (31.1% vs. 43.8%, p=0.09). Transplant-free survival in PAH-CHD was 90.9% (95% CI: 87.8–94%) at 1 year, 77.9% (95% CI: 73.1–83.1%) at 5 years, and 74.9% (95% CI: 69.6–80.7%) at 10 years (Figure 2). Group C PAH-CHD had a lower transplant-free survival than the other 3 groups (HR 2.54, 95% CI: 1.51–4.28, p=0.0005). There was no difference in outcome between group A and group D PAH-CHD (HR 1.19, 95% CI: 0.62–2.28, p=0.6). Conclusions Repaired PAH-CHD, not ES, was the most common subtype in this large paediatric cohort. Over time, there were fewer ES patients and more “operable” patients with left-right shunts, suggesting an improvement in early diagnosis and management. Despite widespread use of PAH therapy, PAH-CHD remains a life-limiting disease with the poorest outcomes in PAH with co-incidental CHD. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Dr Constantine received a personal PhD fellowship grant (CHAMPION PhD Fellowship) Figure 1Figure 2

The thromboxane receptor antagonist NTP42 improves haemodynamics, inhibits remodelling, and restores function within the cardiopulmonary system in preclinical pulmonary arterial hypertension models

Abstract Background Pulmonary arterial hypertension (PAH) is a rare and fatal disease characterised by a progressive increase of pulmonary artery pressure leading to right heart failure. While current PAH therapies provide symptomatic relief and some improvement in quality of life, they show limited benefit in preventing disease progression and often have severe side effects. Recent studies by us reported that a novel thromboxane A2 receptor (TP) antagonist NTP42 attenuated multiple disease hallmarks of PAH in two preclinical models of the disease. Purpose The aim of this study was to assess the efficacy of a novel oral formulation of NTP42 developed for pharmaceutical use on monocrotaline (MCT)-induced PAH in rats across a range of cardiopulmonary parameters, and when compared with standard of care (SOC) PAH therapies. It also aimed to evaluate the expression of the TP, the target receptor for NTP42, in tissues from the MCT-induced PAH model and related disease models. Methods PAH was induced by subcutaneous injection of 60 mg/kg MCT. Rats were randomly assigned to 7 groups: (1) No MCT; (2) MCT Only; (3) MCT+NTP42 Formulation (1 mg/kg); (4) MCT+Sildenafil (50 mg/kg); (5) MCT+Macitentan (30 mg/kg), (6) MCT+Selexipag (1 mg/kg), and (7) MCT+Riociguat (5 mg/kg), where in all cases twice-daily oral dosing was initiated 7 days post-MCT and continued for 22 days. Results The results show that the formulated NTP42 reduced the severity of MCT-induced PAH as determined from haemodynamic measurements of mean pulmonary artery pressure (mPAP) and right ventricular systolic pressure (RVSP), Fulton's Index of cardiac hypertrophy and histological assessments of pulmonary vascular remodelling, pulmonary oedema, inflammation and fibrosis, and right ventricular fibrosis. In addition, these assessments showed that NTP42 inhibited these effects at least to a similar extent relative to the SOC drugs Sildenafil, Macitentan, Selexipag and Riociguat. Notably, unlike most of the PAH SOCs, NTP42 had no adverse effects on liver weight and or on hepatic histopathology. Importantly, NTP42 had no effects on either the systemic mean arterial pressure (mAP) or heart rate (HR). Furthermore, while abundant expression of the target TP was noted in numerous cell and tissue types of both cardiac and pulmonary tissue, there were highly significant upregulations of TP expression observed following PAH-induction (RV, >2-fold, p=0.0002). Conclusions Taken together, these data demonstrate that NTP42 significantly attenuates MCT-induced PAH and to a similar or greater extent relative to market leader PAH SOC drugs. Notably, we reveal that expression of the TP, the target receptor for NTP42, was shown to be highly significantly upregulated throughout the cardiopulmonary system, validating the potential importance of this largely ignored PAH target ripe for pharmaceutical intervention. Funding Acknowledgement Type of funding sources: Public grant(s) – EU funding. Main funding source(s): EU Horizon 2020 SME Instrument

Novel genetic and molecular pathways in pulmonary arterial hypertension associated with connective tissue disease

Abstract Introduction PAH is a severe complication of CTD, with remarkable morbidity and mortality. SSc is most commonly associated with PAH, but it can be present in other CTD. Despite major advances in PAH therapy, survival in CTD-PAH remains poor. Furthermore, the molecular and genetic basis of PAH in CTD are not well established. Purpose This study aimed to screen for genetic defects in a cohort of patients with CTD-PAH. Methods Since November 2011, genetic testing is offered to all patients with idiopathic, hereditable and associated forms of PAH, and PVOD included in a national registry of PAH. A PAH-specific panel of 35 genes was designed. Results During enrolling, 79 patients were recruited: 59 SSc, 11 SLE and 9 other. 69 female, mean age 55,6±1,9 years, mean PVR 8,6±0,5 WU and mean DLCO 47,5±2%. Disease-associated variants were observed in 9 patients: 4 pathogenic/likely pathogenic in 4 different genes (TBX4, ABCC8, KCNA5 and GDF2/BMP9) and 5 VUS in 4 genes (ABCC8, NOTCH3, TOPBP1 and CTCFL). Clinical characteristics of patients with pathogenic/likely pathogenic variants and variant analyses are shown in Tables 1 and 2. Patient 1 is a Caucasian female with mixed CTD, diagnosed with PAH at 58 years of age. She has a frameshift pathogenic variant in TBX4. Pulmonary function test (PFT) ruled out interstitial lung disease (ILD), but a reduction in DLCO was observed (61% of predicted). Two patients carry variants in ABCC8. Patient 2 is a Caucasian female with SSc, diagnosed with PAH at 27 years of age. She carries a splicing variant in ABCC8, classified as likely pathogenic. Her mother was diagnosed with PAH associated with a repaired ASD at 61 years of age. In the genetic testing, no variants were observed in PAH genes. DLCO was 71% of predicted, without signs of ILD. Patient 3 is a Caucasian male, with clinical suspicion of PVOD associated with SSc and HIV infection. PAH was diagnosed at 57 years of age. He presented a missense variant in ABCC8, located in a gating regulatory region, and classified as VUS. Her sister was also diagnosed with PVOD associated with SSc at 48 years of age. No blood or tissue samples are available. In patient 3, DLCO was 22% of predicted value. CT scan showed the typical triad of PVOD. Patient 4 is a Latin American female with SLE, diagnosed with PAH at 25 years of age. She presented a pathogenic nonsense variant in GDF2/BMP9. Patient 5 is a Caucasian female with SSc, diagnosed with PAH at 70 years of age. She presented a pathogenic variant in KCNA5. Patients 6–9 have SSc-PAH and carry VUS in NOTCH1, CTCFL, CTCFL and TOPBP1, respectively. Conclusions We demonstrate the practical diagnostic utility of genetic testing with a panel in CTD-PAH. The discovery of rare variants in these patients forces us to take a comprehensive approach and accurate genetic counseling. Further research is still necessary to confirm these findings and help to provide a personalized medicine approach to these patients. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): This project was founded by project “Bases Genético Moleculares de la Medicina de Precisiόn en la Hipertensiόn Arterial Pulmonar”. Funder: Instituto Carlos III. Ministerio de Economía y Competitividad.

Impact of left heart disease risk factors on risk stratification and treatment response in pulmonary arterial hypertension

Abstract Background Contemporary registries have documented a change in the epidemiology of PAH patients displaying increasing co-morbidities associated with left heart disease (LHD). These patients are often excluded from randomized clinical trials. It is unclear whether the presence of LHD comorbidities may adversely impact the accuracy of risk stratification and response to PAH therapy. Method Data was extracted from the Pulmonary Hypertension Society of Australia and New Zealand registry for incident patients with a diagnosis with idiopathic/heritable/toxin-induced (I/H/D)-PAH and connective tissue disease (CTD) associated PAH from 2011 - 2020. Patients without available medication and follow up data were excluded. We used the AMBITION trial exclusion criteria to define the subpopulation with LHD risk factors and haemodynamic phenotype (PAH-rLHD). Results 489 patients (I/H/D-PAH=251, CTD-PAH=238) were included in our analysis, with 103 (21.0%) fulfilling the definition of PAH-rLHD (34 had ≥3 risk factors for left heart disease (rLHD-hypertension, diabetes, obesity or ischaemic heart disease) and 76 had borderline haemodynamics (mean capillary wedge pressure 13–15 with pulmonary vascular resistance <500 dynes sec/cm5) including 7 who met both criteria). Compared to classical PAH, patients with PAH-rLHD were older at diagnosis (66±13 vs 58±19, p<0.001), had lower pulmonary vascular resistance (PVR: 393±266 vs 708±391, p=0.031) but worse exercise capacity (6MWD: 286±130m vs 327±136m, p=0.005). PAH-rLHD were more likely to be started on initial monotherapy, compared with “classical” PAH (73% vs 56%, p=0.002). In the monotherapy groups, endothelin receptor antagonists (ERA) were used in 73% PAH-rLHD, compared with 66% in classical PAH group. Both groups exhibited similar response to both mono- and combination therapy with commensurate improvements in WHO functional class (mean change 0.3±0.6 vs 0.3±0.8, p=0.443) and 6-minute walk distance (mean change 44±82 vs 48±101, p=0.723). There was no difference in survival between classical PAH and PAH-rLHD (log rank, p=0.29). The REVEAL 2.0 risk score effectively discriminated risk in both populations at baseline and first follow up (classical PAH: baseline C statistic 0.750, follow up 0.774 and PAH-rLHD: baseline C statistic 0.756, follow up 0.791). Conclusion Despite lower PVR at diagnosis, PAH-rLHD patients and “classical” PAH demonstrate similar response to first-line therapy with similar long term survival. The REVEAL 2.0 risk score can be effectively applied to the subpopulation of PAH-rLHD in real life clinical practice. Funding Acknowledgement Type of funding sources: None.

PH Roundtable: Conundrums and Controversies in PH-ILD: To Treat or Not to Treat—Identifying Optimal Treatment Candidates

PH Roundtable: Conundrums and Controversies in PH-ILD: To Treat or Not to Treat—Identifying Optimal Treatment Candidates

HEALTHCARE RESOURCE UTILIZATION AND TREATMENT PATTERNS BEFORE AND AFTER INITIATION OF INHALED TREPROSTINIL

TOPIC: Pulmonary Vascular Disease TYPE: Original Investigations PURPOSE: Inhaled treprostinil (i-TRE) has been shown in large scale clinical trials to improve exercise capacity and quality of life in patients with pulmonary arterial hypertension. However, real-world evidence is limited for initial i-TRE and particularly in patients on prior dual background PAH therapy with an endothelin receptor antagonist (ERA) and phosphodiesterase-5 inhibitor (PDE5i) or soluble guanylate cyclase (SGC). METHODS: A retrospective cohort study of patients initiating i-TRE was conducted using the Optum® De-identified Clinformatics® Data Mart. Patients were identified having a pharmacy or medical claim for i-TRE between 01-JAN-2011 through 30-SEP-2019 and indexed on date of first claim. Patients were required to be ≥18 years of age at index, have ≥1 inpatient or ≥2 outpatient medical claims separated by at least 30 days with a diagnosis of pulmonary hypertension (International Classification of Diseases, 9th/10th Edition, Clinical Modification: 416.0, 416.8, 416.9, I27.0, I27.2, I27.20, I27.21, I27.81, I27.89, I27.9) in the 12-months pre-index, continuous enrollment from the 12-months pre-index through 12-months post-index, and no claim for i-TRE in the pre-index. Dual background therapy was classified as having an ERA and PDE5i or SGC in the 3-months prior to index. Outcomes were compared in the pre-index period to the post-index period. Continuous variables were compared using Wilcoxon signed rank sum test and dichotomous variables were compared using McNemar’s test. RESULTS: 332 patients initiating i-TRE met full selection criteria and a subgroup of 76 were categorized as having dual background therapy. Baseline characteristics were fairly similar with a mean (standard deviation[SD]) age at index of 65.1(13.0) and 60.9(14.6), percent female 65.7% and 64.5%, and mean(SD) Quan-Charlson Comorbidity Index of 3.44(1.8) and 3.43(1.8) for all initiators and dual background therapy patients, respectively. The percent of all initiators experiencing an all-cause hospitalization significantly decreased from 170 (51.2%) in the pre-index to 130 (39.2%) in the post-index period (p=0.0007). A larger significant decrease in hospitalizations was seen in dual background therapy initiators with 40 (52.6%) experiencing any hospitalization in the pre-index versus 23 (30.3%) in the post-index (p=0.0011). For all initiators and dual background therapy, no changes were observed for utilization of emergency department visits, physician office visits, or other outpatient visits. CONCLUSIONS: In this analysis of real-world data, inhaled treprostinil was effective in reducing hospitalization, a known risk factor for poor outcomes. The benefit remained substantial even in patients on prior dual background therapy with an ERA and PDE5i or SGC. CLINICAL IMPLICATIONS: This claims analysis suggest the use of inhaled treprostinil is an effective treatment modality to reduce hospitalizations for pulmonary hypertension. DISCLOSURES: No relevant relationships by Charles Burger, source=Web Response Employee relationship with United Therapeutics Please note: >$100000 by Peter Classi, source=Web Response, value=Salary Employee relationship with United Therapeutics Please note: >$100000 by Andrew Nelsen, source=Web Response, value=Salary Employee relationship with United Therapeutics Please note: 07/2019 - present Added 04/20/2021 by Christine Park, source=Web Response, value=Salary Employee relationship with United Therapeutics Corporation Please note: Present Added 04/01/2021 by Benjamin Wu, source=Web Response, value=Salary

Children with cerebral palsy exhibit a cautious approach to lateral stability throughout single limb support during a targeted stepping task

Little is known about the effects of current PAH therapies and receptor tyrosine kinase inhibitors on heart remodeling. We sought to investigate the effects of the multikinase inhibitors sunitinib (PDGFR-, VEGFR- and KIT-inhibitor) and sorafenib (raf1/b-, VEGFR-, PDGFR-inhibitor) on pressure overload induced right ventricular (RV) remodeling.We investigated the effects of the kinase inhibitors on hemodynamics and remodeling in rats subjected either to monocrotaline (MCT)-induced PH or to surgical pulmonary artery banding (PAB). MCT rats were treated from days 21 to 35 with either vehicle, sunitinib (1 mg/kg, 5 mg/kg and 10 mg/kg/day) or sorafenib (10 mg/kg/day). PAB rats were treated with vehicle, sunitinib (10 mg/kg/day) or sorafenib (10 mg/kg/day) from days 7 to 21. RV function and remodeling were determined using echocardiography, invasive hemodynamic measurement and histomorphometry.Treatment with both sorafenib and sunitinib decreased right ventricular systolic pressure, pulmonary vascular remodeling, RV hypertrophy and fibrosis in MCT rats. This was associated with an improvement of RV function. Importantly, after PAB, both compounds reversed RV chamber and cellular hypertrophy, reduced RV interstitial and perivascular fibrosis, and improved RV function.We demonstrated that sunitinib and sorafenib reversed RV remodeling and significantly improved RV function measured via a range of invasive and non-invasive cardiopulmonary endpoints in experimental models of RV hypertrophy.

Pulmonary arterial hypertension in adults with congenital heart disease: markers of disease severity, management of advanced heart failure and transplantation

ABSTRACT Introduction Pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD) is a progressive, life-limiting disease. Areas covered In this paper, we review the classification and pathophysiology of PAH-CHD, including the mechanisms of disease progression and multisystem effects of disease. We evaluate current strategies of risk stratification and the use of biological markers of disease severity, and review principles of management of PAH-CHD. The indications, timing, and the content of advanced heart failure assessment and transplant listing are discussed, along with a review of the types of transplant and other forms of available circulatory support in this group of patients. Finally, the integral role of advance care planning and palliative care is discussed. Expert opinion/commentary All patients with PAH-CHD should be followed up in expert centers, where they can receive appropriate risk assessment, PAH therapy, and supportive care. Referral for transplant assessment should be considered if there continue to be clinical high-risk features, persistent symptoms, or acute heart failure decompensation despite appropriate PAH specific therapy. Expert management of PAH-CHD patients, therefore, requires vigilance for these features, along with a close relationship with local advanced heart failure services and a working knowledge of listing criteria, which may disadvantage congenital heart disease patients.

Factors related to the quality of life in patients with pulmonary arterial hypertension

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Pulmonary arterial hypertension (PAH) is a rare disease, with an incidence of 15–50 cases per million annually. The disease is associated with further progress and worsening of symptoms despite pharmacotherapy. The severity of PAH symptoms and their effects reduce the patients" quality of life (QoL). Numerous studies show that the quality of life is related to the therapeutic effect of the treatment. Available studies demonstrate that patients QoL deteriorates as the condition progresses. Consequently, the goals of PAH therapy have expanded from increasing survival to improving health-related quality of life. The aim of the study was to determine the clinical and sociodemographic factors influencing the quality of life in PAH patients. Methods The study involved 55 patients with PAH who were examined using the Polish version of the PAH-SYMPACT quality of life questionnaire. The PAH-SYMPACT questionnaire results were correlated with several variables. Results It was shown that the quality of life correlates significantly (p˂0,05) with WHO Functional Class, NT-pro BNP (N-terminal prohormone of brain natriuretic peptide) value, elderly age (the higher the value, the worse the QoL). On the other hand, the lower the 6MWT (6 minuts walk test) result, the worse the QoL. Moreover, the intensity of the accompanying PAH symptoms, such as chest pain, dyspnoea, arrhythmias, fatigue and weakness were associated with a lower quality of life in patients (p < 0,05). Conclusion Patients" quality of life correlates with many variables, both clinical and sociodemographic. In addition, there is a correlation between the quality of life of patients with PAH and the severity of several symptoms associated with this condition. Determination of factors affecting the quality of life of patients with PAH enables the selection of a more comprehensive therapy.

Circulating Cell Biomarkers in Pulmonary Arterial Hypertension: Relationship with Clinical Heterogeneity and Therapeutic Response.

Background: Endothelial dysfunction is central to PAH. In this study, we simultaneously analysed circulating levels of endothelial microvesicles (EMVs) and progenitor cells (PCs) in PAH and in controls, as biomarkers of pulmonary endothelial integrity and evaluated differences among PAH subtypes and as a response to treatment. Methods: Forty-seven controls and 144 patients with PAH (52 idiopathic, 9 heritable, 31 associated with systemic sclerosis, 15 associated with other connective tissue diseases, 20 associated with HIV and 17 associated with portal hypertension) were evaluated. Forty-four patients with scleroderma and 22 with HIV infection, but without PAH, were also studied. Circulating levels of EMVs, total (CD31+CD42b−) and activated (CD31+CD42b−CD62E+), as well as circulating PCs (CD34+CD133+CD45low) were measured by flow cytometry and the EMVs/PCs ratio was computed. In treatment-naïve patients, measurements were repeated after 3 months of PAH therapy. Results: Patients with PAH showed higher numbers of EMVs and a lower percentage of PCs, compared with healthy controls. The EMV/PC ratio was increased in PAH patients, and in patients with SSc or HIV without PAH. After starting PAH therapy, individual changes in EMVs and PCs were variable, without significant differences being observed as a group. Conclusion: PAH patients present disturbed vascular homeostasis, reflected in changes in circulating EMV and PC levels, which are not restored with PAH targeted therapy. Combined measurement of circulating EMVs and PCs could be foreseen as a potential biomarker of endothelial dysfunction in PAH.

Management of Pulmonary Hypertension Due to Chronic Lung Disease.

Pulmonary hypertension (PH) is a known complication of chronic parenchymal lung diseases, including chronic obstructive lung disease, interstitial lung diseases, and more rare parenchymal lung diseases. Together, these diseases encompass two of the five clinical classifications of PH: group 3 (chronic lung disease [CLD] and/or hypoxia) and group 5 (unclear and/or multifactorial mechanisms). The principal management strategy in PH associated with CLD is optimization of the underlying lung disease. There has been increasing interest in therapies that treat pulmonary arterial hypertension (group 1, PAH), and although some studies have explored the use of these oral PAH-targeted therapies to treat PH associated with CLD, there is currently no evidence to support their routine use; in fact, some studies suggest harm. Inhaled therapies that target the pulmonary vasculature may avoid certain problems observed with oral PAH therapies. Recent studies suggest a promising role for inhaled PAH therapies in group 3 PH, but this requires further study. The objective of this article is to review the current treatment strategies for group 3 and group 5 PH.

The Challenge to Decide between Pulmonary Hypertension Due to Chronic Lung Disease and PAH with Chronic Lung Disease.

Chronic lung diseases are strongly associated with pulmonary hypertension (PH), and even mildly elevated pulmonary arterial pressures are associated with increased mortality. Chronic obstructive pulmonary disease (COPD) is the most common chronic lung disease, but few of these patients develop severe PH. Not all these pulmonary pressure elevations are due to COPD, although patients with severe PH due to COPD may represent the largest subgroup within patients with COPD and severe PH. There are also patients with left heart disease (group 2), chronic thromboembolic disease (group 4, CTEPH) and pulmonary arterial hypertension (group 1, PAH) who suffer from COPD or another chronic lung disease as co-morbidity. Because therapeutic consequences very much depend on the cause of pulmonary hypertension, it is important to complete the diagnostic procedures and to decide on the main cause of PH before any decision on PAH drugs is made. The World Symposia on Pulmonary Hypertension (WSPH) have provided guidance for these important decisions. Group 2 PH or complex developmental diseases with elevated postcapillary pressures are relatively easy to identify by means of elevated pulmonary arterial wedge pressures. Group 4 PH can be identified or excluded by perfusion lung scans in combination with chest CT. Group 1 PAH and Group 3 PH, although having quite different disease profiles, may be difficult to discern sometimes. The sixth WSPH suggests that severe pulmonary hypertension in combination with mild impairment in the pulmonary function test (FEV1 > 60 and FVC > 60%), mild parenchymal abnormalities in the high-resolution CT of the chest, and circulatory limitation in the cardiopulmonary exercise test speak in favor of Group 1 PAH. These patients are candidates for PAH therapy. If the patient suffers from group 3 PH, the only possible indication for PAH therapy is severe pulmonary hypertension (mPAP ≥ 35 mmHg or mPAP between 25 and 35 mmHg together with very low cardiac index (CI) < 2.0 L/min/m2), which can only be derived invasively. Right heart catheter investigation has been established nearly 100 years ago, but there are many important details to consider when reading pulmonary pressures in spontaneously breathing patients with severe lung disease. It is important that such diagnostic procedures and the therapeutic decisions are made in expert centers for both pulmonary hypertension and chronic lung disease.

Hemodynamic Response to Treatment and Outcomes in Pulmonary Hypertension Associated With Interstitial Lung Disease Versus Pulmonary Arterial Hypertension in Systemic Sclerosis: Data From a Study Identifying Prognostic Factors in Pulmonary Hypertension Associated With Interstitial Lung Disease.

Patients with systemic sclerosis and both pulmonary hypertension and interstitial lung disease (SSc-PH-ILD) generally carry a worse prognosis than patients with SSc and pulmonary arterial hypertension (SSc-PAH) without ILD. There is no evidence of the efficacy of PAH therapies in SSc-PH-ILD. We undertook this study to compare survival of and response to treatment in patients with SSc-PH-ILD and those with SSc-PAH. We analyzed 128 patients (66 with SSc-PH-ILD and 62 with SSc-PAH) from 15 centers, in whom PH was diagnosed by right-sided heart catheterization; they were prospectively included in the PH registry. All patients received PAH-specific therapy. Computed tomography of the chest was used to confirm or exclude ILD. At baseline, patients with SSc-PH-ILD had less severe hemodynamic impairment than those with SSc-PAH (pulmonary vascular resistance 5.7 Wood units versus 8.7 Wood units; P = 0.0005) and lower diffusing capacity for carbon monoxide (median 25% [interquartile range (IQR) 18%, 35%] versus 40% [IQR 31%, 51%]; P=0.0005). Additionally, patients with SSc-PH-ILD had increased mortality (8.1% at 1 year, 21.2% at 2 years, and 41.5% at 3 years) compared to those with SSc-PAH (4.1%, 8.7%, and 21.4%, respectively; P = 0.04). Upon treatment with PAH-targeted therapy, no improvement in the 6-minute walk distance was observed in either group. Improvement in the World Health Organization functional class was observed less frequently in patients with SSc-ILD-PH compared to those with SSc-PAH (13.6% versus 33.3%; P = 0.02). Hemodynamics improved similarly in both groups. ILD confers a worse prognosis to SSc-PH. Response to PAH-specific therapy is clinically poor in SSc-PH-ILD but was not found to be hemodynamically different from the response observed in SSc-PAH.

Critical Neonatal Congenital Heart Disease – a Rare Complication after Successful Surgical Correction

Abstract Pulmonary arterial hypertension (PAH) is a rare but severe complication that should be investigated in patients diagnosed with transposition of the great arteries who have undergone neonatal arterial switch operation. Early diagnosis and aggressive combination therapy for PAH could help to improve survival in these patients. We report a favorable clinical response 6 months after the initiation of vasodilator therapy in a pediatric case with transposition of the great arteries, successfully repaired in the neonatal period, who developed pulmonary arterial hypertension at the age of 5 years.

Standardized exercise training is feasible, safe, and effective in pulmonary arterial and chronic thromboembolic pulmonary hypertension: results from a large European multicentre randomized controlled trial.

This prospective, randomized, controlled, multicentre study aimed to evaluate efficacy and safety of exercise training in patients with pulmonary arterial (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). For the first time a specialized PAH/CTEPH rehabilitation programme was implemented in 11 centres across 10 European countries. Out of 129 enrolled patients, 116 patients (58 vs. 58 randomized into a training or usual care control group) on disease-targeted medication completed the study [85 female; mean age 53.6 ± 12.5 years; mean pulmonary arterial pressure 46.6 ± 15.1 mmHg; World Health Organization (WHO) functional class II 53%, III 46%; PAH n = 98; CTEPH n = 18]. Patients of the training group performed a standardized in-hospital rehabilitation with mean duration of 25 days [95% confidence interval (CI) 17-33 days], which was continued at home. The primary endpoint, change of 6-min walking distance, significantly improved by 34.1 ± 8.3 m in the training compared with the control group (95% CI, 18-51 m; P < 0.0001). Exercise training was feasible, safe, and well-tolerated. Secondary endpoints showed improvements in quality of life (short-form health survey 36 mental health 7.3 ± 2.5, P = 0.004), WHO-functional class (training vs. control: improvement 9:1, worsening 4:3; χ2P = 0.027) and peak oxygen consumption (0.9 ± 0.5 mL/min/kg, P = 0.048) compared with the control group. This is the first multicentre and so far the largest randomized, controlled study on feasibility, safety, and efficacy of exercise training as add-on to medical therapy in PAH and CTEPH. Within this study, a standardized specialized training programme with in-hospital start was successfully established in 10 European countries.

Abstract 17272: Frequency of Acute Vasodilator Response in Incident and Prevalent Patients With Pulmonary Arterial Hypertension (Group 1): Results From the Pulmonary Vascular Disease Omics (PVDOMICS) Study

Introduction: The prevalence of acute vasodilator response (AVR) to inhaled NO (defined as a reduction in mPAP ≥ 10 mmHg with an absolute value of mPAP ≤ 40 mmHg with increased/unchanged CO) is reported to be around 12% in incident patients with idiopathic PAH (IPAH). The prevalence of AVR, however, is reportedly lower in other disease-associated PAH in Group 1, such as connective tissue disease (CTD). Furthermore, the prevalence of AVR for combined inhaled NO and oxygen, and in patients on PAH therapy (prevalent cohort), is less known. Hypothesis: We hypothesized there would be differences in the prevalence of AVR in PAH subgroups in the large PVDOMICS cohort of incident and prevalent patients. Methods: Group 1 PAH patients enrolled in PVDOMICS underwent right heart catheterization for baseline measurements. AVR was then measured in response to 100% inhaled oxygen (O 2 ) and 100% O 2 plus NO at 40 ppm (O 2 +NO) for 5 min each before hemodynamic measurements. Details of the PVDOMICS methodology and core adjudication of hemodynamic measurements were reported previously. Rates of AVR to 100% O 2 and 100% O 2 +NO were compared between incident and prevalent patients in each PAH subgroup. Results: 351 patients, mostly female (73%), average age of 52.9 years, with mostly prevalent disease (87%) and an average of 4 years from PAH diagnosis, underwent AVR assessment. A positive AVR was found in 0.6% of patients in response to 100% oxygen and 6% of patients in response to 100%+NO for the overall cohort. AVR was similar in incident and prevalent IPAH patients (6 and 6.9%, respectively). It was, however, 0% and 6.9%, in incident vs. prevalent CTD-PAH patients, respectively. There were no responders to either challenge in any other PAH subgroup. Conclusions: The prevalence of AVR is relatively rare in IPAH and CTD-PAH (~ 6%) and absent in other subgroups. There was no response to 100% O2 alone, suggesting specificity of AVR to NO in PAH. AVR is more common than previously reported in CTD-PAH, but only in prevalent disease. Whether the latter is related to long-term PAH therapy affecting pulmonary vasomotor response and/or vascular remodeling in these patients would warrant further studies.

Treatment of HIV-associated pulmonary arterial hypertension: single-center experience

Abstract Introduction Currently there is no evidence-based strategy for PAH drug application adjusted for patients with HIV-associated PAH. Data regarding the use of sildenafil and endothelin receptors antagonists (ERA) are limited case series. Purpose To present the long-term data on treatment with sildenafil, macitentan and ambrisentan in pts with HIV-PAH. Material and methods In prospective study were consecutively enrolled 18 treatment-naïve pts with HIV-PAH (7 males, 34.5 yrs; 29; 53 yrs), mean follow-up was 1.64yrs; 0,16–59–9.28 yrs. 4 pts were in IV FC, 5-III FC and 9 in II FC PAH (WHO). RHC, ECHO, 6MWT, ergospirometry and NTproBNP level were evaluated at a baseline. Intravenous drug abuse reported in 72% pts, all of them were co-infected with hepatitis. Nine pts (50%) treated with HAART therapy at a baseline. Five pts did not have PAH-specific therapy, 11 pts received sildenafil, 1 IV FC PAH pt with HAART – sildenafil+macitentan and 1 III FC PAH pt with HAART-sildenafil+ambrisentan. Follow-up data (FC, 6MWT, ECHO, ergospirometry, NT-proBNP) were available for 8 PAH-treated pts. Results Pts on PAH therapy had achieved improvement in 6 MWT with mean distance increase 69.3±52 m (p=0.01); NTproBNP level decrease (p=0.018) and FC PAH improvement in 7 pts. In pts with PAH therapy the size of right atrium decreased (56.4±7.8 vs 47.8±6.7 mm, p=0.027). The combinations of sildenafil and macitentan and sildenafil with ambrisentan were well tolerated and resulted 6MWT increase, low NTproBNP and FC improvement. Nevertheless there was no significant changes in peak VO2 consumption. Two pts with sildenafil therapy lost for follow up. Three pts with sildenafil but without HAART therapy dead: in one case due to pneumonia, other 2 cases due to pulmonary embolism. Four pts without HAART and PAH therapy dead. In our population strong association between survival and HAART therapy presence was revealed (p=0.01). Conclusion No adverse reactions of PAH-specific therapy were reported in pts on HAART. PAH therapy had a positive influence on FC, exercise capacity, heart remodeling and NT-proBNP level. There were no deaths in pts who receive HAART and PAH therapy. Nevertheless in our population strong association between survival and HAART therapy presence was revealed. Funding Acknowledgement Type of funding source: None