Stable Pulmonary Arterial Hypertension Research Articles

Effect of experimental pulmonary arterial hypertension on renal and bone parameters of rats submitted to resistance exercise training.

Pulmonary arterial hypertension (PAH) is characterized by right ventricular failure and diminished cardiac output, potentially leading to renal and bone impairments. In contrast, resistance exercise training (RT) offers cardiovascular and bone health benefits. This study aimed to assess the impacts of stable PAH induced by monocrotaline (MCT) and RT on renal morphometry, as well as bone morphometry and biomechanical properties in male Wistar rats. Four experimental groups, untrained control (UC, n=7), trained control (TC, n=7), untrained hypertensive (UH, n=7), trained hypertensive (TH, n=7), were defined. After the first MCT or saline injection (20 mg/kg), trained rats were submitted to a RT program (i.e., Ladder climbing), 5 times/week. Seven days later the rats received the second MCT or saline dose. After euthanasia, renal and femoral histomorphometry and femoral biomechanical properties were assessed. PAH reduced renal glomerular area and volume, which was prevented by the RT. While PAH did not harm the femoral morphometry, structural and mechanical properties, RT improved the femoral parameters (e.g., length, percentage of trabeculae and bone marrow, ultimte and yield loads). Experimental stable PAH promotes renal but not bone damages, whereas RT prevents renal deteriorations and improves the femoral morphological and biomechanical properties.

Effects of inhaled seralutinib on right ventricular-pulmonary arterial (RV-PA) coupling and right heart function in pulmonary arterial hypertension (PAH)

Abstract Background Impaired RV-PA coupling portends a poor prognosis in PAH, and right ventricular free wall strain/systolic pulmonary artery pressure (RVFWS/sPAP) has been reported as a measure of RV-PA coupling. Furthermore, increased RVFWS and right atrial area (RAA), as well as decreased pulmonary artery compliance (PAC) are associated with increased mortality risk in PAH. Seralutinib is a novel, small molecule kinase inhibitor that targets PDGFR, CSF1R, and c-KIT administered via dry powder inhaler. TORREY, a phase 2, double-blind, randomised, placebo-controlled study of inhaled seralutinib in patients with PAH (NCT04456998) met its primary endpoint, demonstrating a significant reduction in pulmonary vascular resistance (PVR) from baseline (BL) to Week 24 compared to placebo. In addition, seralutinib significantly decreased NT-proBNP. Purpose To test the hypothesis that seralutinib would improve RVFWS/sPAP and other measures of right heart function after 24 weeks of treatment compared to placebo in the TORREY study. Methods Eighty-six patients with WHO Group 1 PH (Functional Class II, III), ages ≥18 years, pulmonary vascular resistance ≥400 dyne*s/cm5, and on stable PAH standard of care therapy (the majority of whom were on double and triple therapy with approved PAH medications) were enrolled. Right heart catheterisation (RHC) and full echocardiography were performed at BL and Week 24 and at BL, Week 12, and Week 24, respectively; both were analysed in a blinded central laboratory. To calculate RVFWS/sPAP, the pulmonary artery systolic pressure from RHC was used. PAC was calculated from RHC data with the formula (SV/(PAS-PAD)). Statistical analysis was performed using ANCOVA. Results At Week 24, the change in RVFWS/sPAP was lower in the seralutinib group compared to placebo (Table). The changes in RVFWS and RAA were lower in the seralutinib group vs placebo at Week 12 and Week 24 (Table). Change in NT-proBNP correlated with change in RAA (r = 0.43). At Week 24, change in PAC was greater in the seralutinib group (-0.02 ± 0.085 placebo, 0.19 ± 0.089 seralutinib; LSMD 0.22 (0.104) p = 0.04). There was no effect of seralutinib on left ventricular ejection fraction. Conclusion Treatment with seralutinib was associated with a significant reduction of RVFWS/sPAP. In addition, significant differences in RVFWS itself, RAA, and PAC were observed. These treatment effects support improved RV-PA coupling and right heart function. In conjunction with concordant reductions in PVR and NT-proBNP, these data suggest potential favourable effects of seralutinib in PAH. Seralutinib is in clinical development as a potential new treatment option for patients with PAH.

Effects of Exercise Training on Circulating Biomarkers of Endothelial Function in Pulmonary Arterial Hypertension.

In stable patients with pulmonary arterial hypertension (PAH), pulmonary rehabilitation (PR) is an effective, safe and cost-effective non-pharmacological treatment. However, the effects of PR on vascular function have been poorly explored. This study aimed to compare the amounts of circulating progenitor cells (PCs) and endothelial microvesicles (EMVs) in patients with PAH before and after 8 weeks of endurance exercise training as markers of vascular competence. A prospective study of 10 consecutive patients with PAH that successfully finished a PR program (8 weeks) was carried out before and after this intervention. Levels of circulating PCs defined as CD34+CD45low progenitor cells and levels of EMVs (CD31+ CD42b-) were measured by flow cytometry. The ratio of PCs to EMVs was taken as a measure of the balance between endothelial damage and repair capacity. All patients showed training-induced increases in endurance time (mean change 287 s). After PR, the number of PCs (CD34+CD45low/total lymphocytes) was increased (p < 0.05). In contrast, after training, the level of EMVs (CD31+ CD42b-/total EMVs) was reduced. The ratio of PCs to EMVs was significantly higher after training (p < 0.05). Our study shows, for the first time, that endurance exercise training in patients with stable PAH has a positive effect, promoting potential mechanisms of damage/repair in favor of repair. This effect could contribute to a positive hemodynamic and clinical response.

Physiological and Psychological Response to Acute Mental Stress in Female Patients Affected by Chronic Pulmonary Arterial Hypertension: An Explorative Controlled Pilot Trial.

Little is known about physiological and psychological responses to mental stress in stable patients affected by pulmonary arterial hypertension (PAH). The current explorative controlled pilot study was conducted to investigate whether heart rate (HR) and perceived stress would differ during standardized mental stress testing in PAH patients compared to healthy subjects. Correlation analysis between HR, perceived stress, participants' psychological status and performance on the mental stress task was also performed. The study included 13 female PAH patients (average age: 44.38 ± 10.88 years; average education: 14 ± 3.07 years; mean duration of illness: 9.15 ± 5.37 years) and 13 female controls similar in age (mean age: 47.85 ± 6.36 years) and education (15.92 ± 1.55 years). Participants performed a standardized 9 min mental stress test (computer based, adaptive math task). HR and perceived stress during the task were compared to resting baseline and correlated with psychological state and task performance. Both HR and perceived stress significantly increased during mental stress in a similar way in both groups. A significant correlation was found between HR and perceived stress. Our data show that moderate mental stress has a comparable effect on HR and perceived stress increase in stable PAH patients and control subjects.

The impact of specific pulmonary arterial hypertension therapy on cardiac fluorodeoxyglucose distribution in PET/MRI hybrid imaging–follow-up study

BackgroundPET/MRI hybrid imaging in pulmonary arterial hypertension (PAH) provides important prognostic information identifying patients who might benefit from early therapy escalation, as right ventricle (RV) metabolic alterations are linked with hemodynamics and might precede clinical deterioration. Now, we hypothesize that adequate PAH therapy escalation may result in reversal of unfavourable increased glucose uptake of RV, which is associated with improved prognosis.MethodsOut of twenty-six initially clinically stable PAH patients who had baseline PET/MRI scans, twenty (49.9 ± 14.9 years) had second PET/MRI after 24 months. SUVRV/SUVLV ratio was used to estimate and compare cardiac glucose uptake. Occurrences of clinical endpoints (CEP), defined as death or clinical deterioration, were assessed during 48-month follow-up from baseline.ResultsIn first 24 months of observation, sixteen patients had CEP and needed PAH therapy escalation. At follow-up visits, we observed significant improvement of RV ejection fraction (45.1 ± 9.6% to 52.4 ± 12.9%, p = 0.01), mean pulmonary artery pressure (50.5 ± 18.3 to 42.8 ± 18.6 mmHg, p = 0.03), and SUVRV/SUVLV, which tended to decrease (mean change -0.20 ± 0.74). Patients with baseline SUVRV/SUVLV value higher than 0.54 had worse prognosis in 48 months observation (log-rank test, p = 0.0007); follow up SUVRV/SUVLV > 1 predicted CEP in the following 24 months, regardless of previously escalated treatment.ConclusionsPAH therapy escalation may influence RV glucose metabolism, what seems to be related with patients’ prognosis. PET/MRI assessment may predict clinical deterioration regardless of previous clinical course, however its clinical significance in PAH requires further studies. Importantly, even mild alterations of RV glucose metabolism predict clinical deterioration in long follow-up.Clinical Trial Registration ClinicalTrials.gov, NCT03688698, 05/01/2016, https://clinicaltrials.gov/ct2/show/study/NCT03688698?term=NCT03688698&draw=2&rank=1

The discrepancy between FDG uptake and myocardial fibrosis in patients with pulmonary arterial hypertension – PET/MRI study

Abstract Background Inflammatory processes play an important role in pulmonary arterial hypertension (PAH) pathophysiology. We previously confirmed that in case of right ventricle (RV) failure, changes of cytokines' levels are correlated with myocardial metabolic and hemodynamic alterations observed in PET/MRI hybrid imaging. Presence of late gadolinium enhancement (LGE) in RV insertion points (RVIPs) has been found in majority of PAH patients and is often recognized as evidence of myocardial fibrosis due to RV pressure overload. As qualitative and/or quantitative assessments of LGE may vary due to natural PAH progression or specific therapy, we hypothesized that simple presence of LGE at RVIPs is not unequivocal to fibrotic tissue (without metabolic activity). Purpose To check the relationship between LGE mass and 18F-fluorodexyglucose uptake in RV insertion points in PAH patients using PET/MRI hybrid imaging. Methods Twenty-eight clinically stable PAH patients (49.9±15.9 years) had simultaneous PET/MRI scans during baseline and follow up (FU) visits, Figure. 18F-fluorodexyglucose (FDG) was used as a tracer and its cardiac uptake was presented as a maximum standardized uptake value (SUV) for RV insertion points (SUV in RVIPS). Septal delayed enhancement mass was quantified in RVIPs and presented as LGE mass. Occurrences of clinical end-points (CEP, defined as death or clinical deterioration) were assessed during 24 months observation. Results LGE was found in RVIPs of all PAH patients. Mean LGE mass was 6.32±4.41 g and mean SUV in RVIPS was 7.28±5.36. Follow up values were 8.01±7.75g (p=0.4) and 5.80±3.16 (p=0.16), respectively. We observed significant correlation between baseline SUV in RVIPS and mean pulmonary pressure, mPAP (r=0.49, p=0.04) but no correlation was found between LGE mass and SUV in RVIPS (in both baseline and FU scans). Between baseline and follow up visits, 16 patients had CEP and needed PAH therapy escalation. CEP+ group of PAH patients presented higher baseline LGE mass (7.53±4.75 vs 3.92±2.21, p=0.04) and SUV in RVIPS (7.27±5.42 vs 6.01±4.52, p=0.4). In all CEP patients who initiated prostacycline therapy and survived (n=8, 50%), SUV in RVIPS decreased in FU PET scans together with an increase in LGE mass in MRI. At FU visits we also observed significant improvement of MRI-derived RV ejection fraction (45.1±9.6% to 52.4±12.9%, p=0.01), and mPAP (50.5±18.3 to 42.8±18.6 mmHg, p=0.03). Conclusions Effective PAH therapy have an impact on both LGE mass and FDG uptake in cardiac local tissue changes. Since there was no correlation between LGE mass and FDG uptake RV insertion points, the question arises what the cause of these LGE changes is. Increased fibrosis should cause diminished local glucose metabolism. This phenomenon opens new questions concerning pathophysiology processes in RVIPs and requires confirmation on bigger PAH population. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Center for Science in Poland

Assessing Daily Life Physical Activity by Actigraphy in Pulmonary Arterial Hypertension: Insights From the Randomized Controlled Study With Selexipag (TRACE)

Reduced daily life physical activity (DLPA) in pulmonary arterial hypertension (PAH) contributes to a poor quality of life. Can actigraphy be used to assess changes in DLPA in patients with PAH receiving selexipag or placebo? Effect of Selexipag on Daily Life Physical Activity of Patients With Pulmonary Arterial Hypertension (TRACE) was a prospective, multicenter, randomized, placebo-controlled, double-blind, exploratory phase 4 study enrolling patients with PAH in World Health Organization functional class II/III, receiving stable endothelin receptor antagonist with/without phosphodiesterase type 5 inhibitor background therapy. Primary end points were change from baseline to Week 24 in actigraphy-assessed DLPA (recorded by using an accelerometer), including daily time spent in nonsedentary physical activity (NSPA), daily time spent in moderate to vigorous physical activity (MVPA), daily volume of activity, and daily number of steps. At baseline, patients (N= 108) were prevalent, on stable background PAH therapy, and at low risk of disease progression. Patients showed high compliance with wear of the accelerometer throughout the study. From baseline to Week 24, mean daily time spent in NSPA increased by 1.1min and decreased by 16.7min in the selexipag and placebo groups (treatment difference [95%CI], 17.8 [-6.0, 41.6] min); mean time spent in MVPA increased by 0.3min and was reduced by 2.0min in the selexipag and placebo groups (treatment difference [95%CI], 2.3 [-10.8, 15.4] min); and mean number of daily steps decreased by 0.3 and 201.9 in the selexipag and placebo groups (treatment difference [95%CI], 201.6 [-243.0, 646.2]). TRACE enrolled a prevalent population on background therapy and at low risk of disease progression. Changes in DLPA were small and highly variable, with no statistically significant differences between treatment groups. This patient-centric study was the first randomized trial in PAH to capture high-quality actigraphy data and to describe DLPA in terms of mean/median and variability, which may inform the design of future studies. ClinicalTrials.gov; No.: NCT03078907; URL: www. gov.

Physical Activity in Pulmonary Arterial Hypertension during Pandemic COVID-19 and the Potential Impact of Mental Factors.

One of the non-pharmacological recommendations for stable patients with pulmonary arterial hypertension (PAH) is to increase physical activity. The study aimed to analyze the degree of physical activity of PAH patients and check if mental factors may have a potential negative impact during the COVID-19 pandemic. Forty patients with stable PAH were included in the study. Physical activity was assessed by pedometer (Omron HJ-321-E) for four weeks. At baseline, in addition to the 6 min walk test (6MWT) and functional assessment, patients completed the quality-of-life questionnaire SF-36, fear of COVID-19 scale, and hospital anxiety and depression scale (HADS). The mean age of the study group was 45.5 years, 80% were women, and 62.5% had idiopathic/heritable PAH. Low physical activity defined as <5000 steps/day had 19 (47.5%), and moderate/high physical activity (≥5000 steps/day) had 21 (52.5%) patients. Patients with low physical activity less frequently worked compared with the moderate–high-activity sub-group, 42% vs. 81%, p = 0.03, and had the shorter distance in 6-6MWT, p = 0.03. There was no significant correlation between steps/day and different mental factors. Almost half of the study group had low activity during the pandemic. Mental factors did not impact physical activity in PAH patients during the pandemic.

Impact of COVID‐19 lockdown on exercise capacity in PAH patients

The outbreak of novel coronavirus‐19 disease (COVID‐19) was classified as a global pandemic thanks to the rapid viral spread, and restrictive policy measures of infection containment, including “lockdown” periods and self‐isolation, were first instituted in Belgium from March to June 2020. The consequent reduction in physical activity could have a negative impact on exercise capacity, especially in frail patients with pre‐existing chronic diseases, such as pulmonary arterial hypertension (PAH). With the aim to define the impact of COVID‐19 lockdown on functional status, we included in our observational analysis clinically stable PAH patients, who had performed at least four consecutive 6‐min walking tests (6MWT) during 2019–2020, to compare their exercise performance before and after the lockdown. In the 63 patients included, a comparison between the distance covered at 6MWT after the lockdown period and the pooled mean of the previous three 6MWTs showed a mean reduction of 14 m after the lockdown (p = 0.004). Moreover, the mean distance covered at 6MWT went from 447 m in March 2020 to 434 m in June 2020, with a significant average loss of 13 m (p = 0.024). Our results showed that PAH patients were less performing at 6MWT after 3 months of reduced physical activity, despite constant clinical stability and the absence of signs of disease progression, suggesting that this confounding factor should be kept in mind when evaluating changes in 6MWT during or after COVID‐19 pandemic.

Platelet sTWEAK and plasma IL-6 are associated with 18F-fluorodeoxyglucose uptake in right ventricles of patients with pulmonary arterial hypertension: A pilot study.

Cytokines soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) and interleukin 6 (IL-6) are involved in immune response, proliferation, apoptosis, and cardiovascular pathologies. We have previously confirmed that changes of their platelet or plasma contents are associated with pulmonary arterial hypertension (PAH). The positron emission tomography/magnetic resonance imaging (PET/MRI) hybrid imaging provides detailed insight into right ventricle (RV) hemodynamic and metabolic function. To evaluate the relationship between RV parameters obtained using PET/MRI and concentrations of plasma and platelet sTWEAK and IL-6 in stable PAH patients. Eighteen stable PAH patients (48.44 ±16.7 years) had simultaneous PET/MRI scans with 18F-fluorodeoxyglucose (18F-FDG) performed. Its uptake was presented as a standardized uptake value (SUV) for RV and left ventricle (LV). Cytokines concentrations were measured in platelet-poor plasma and platelet lysate. Follow-up time of this study was 58 months; the combined endpoint (CEP) was defined as death or clinical deterioration. We observed significant correlations between platelet sTWEAK levels, plasma IL-6 and PET parameter SUVRV/LV (r = -0.57, p = 0.011; r = 0.50, p = 0.032, respectively). In logistic regression, platelet sTWEAK and IL-6 were both prognostic factors for unfavorable ratio of SUVRV/LV higher than 1 (hazard ratio (HR) = 0.44, 95% confidence interval (95% CI): [0.23; 0.84], p = 0.017; and HR = 3.62, 95% CI: [1.21; 10.17], p = 0.011, respectively). Furthermore, their concentrations were related with prognostically important higher late gadolinium enhancement mass index (LGEMI) and RV global longitudinal strain/systolic pulmonary artery pressure (RV GLS/sPAP) values. Patients who had CEP in follow-up (n = 13) had significantly lower platelet sTWEAK content and higher plasma IL-6 at baseline than stable patients. Lower platelet sTWEAK was related to a worse prognosis in log-rank test (p = 0.006). Platelet sTWEAK and plasma IL-6 together with RV GLS/sPAP, RV ejection fraction (RVEF), mean pulmonary arterial pressure (mPAP), and SUVRV/LV were significantly associated with time to CEP in univariate Cox analysis. The sTWEAK and IL-6 concentrations in PAH patients are linked with metabolic and functional changes of RV visualized in PET/MRI, and both sTWEAK and IL-6 predict clinical deterioration.

Effectiveness and safety of a simple home-based rehabilitation program in pulmonary arterial hypertension: an interventional pilot study

BackgroundRehabilitation plays an important role in the management of patients with pulmonary arterial hypertension (PAH) and current guidelines recommend implementation of a monitored individualized exercise training program as adjuvant therapy for stable PAH patients on optimal medical treatment. An optimal rehabilitation model for this group of patients has not yet been established. This randomized prospective study assessed the effectiveness and safety of a 6-month home-based caregiver-supervised rehabilitation program among patients with pulmonary arterial hypertension.MethodsA total of 39 patients with PAH were divided into two groups: intervention group (16 patients), subjected to a 6-month home-based physical training and respiratory rehabilitation program adapted to the clinical status of participants, and control group (23 patients) who did not perform physical training. The 6-min walk test (6MWT), measurement of respiratory muscle strength, quality of life assessment (SF-36, Fatigue Severity Scale – FSS) were performed before study commencement, and after 6 and 12 months. Adherence to exercise protocol and occurrence of adverse events were also assessed.ResultsPhysical training significantly improved 6MWT distance (by 71.38 ± 83.4 m after 6 months (p = 0.004), which remained increased after 12 months (p = 0.043), and respiratory muscle strength after 6 and 12 months (p < 0.01). Significant improvement in quality of life was observed after the training period with the use of the SF-36 questionnaire (Physical Functioning, p < 0.001; Role Physical, p = 0.015; Vitality, p = 0.022; Role Emotional, p = 0.029; Physical Component Summary, p = 0.005), but it did not persist after study completion. Adherence to exercise protocol was on average 91.88 ± 14.1%. No serious adverse events were noted.ConclusionAccording to study results, the home-based rehabilitation program dedicated to PAH patients is safe and effective. It improves functional parameters and quality of life. Strength of respiratory muscles and 6MWD remain increased 6 months after training cessation.Trial registrationClinicalTrials.gov, NCT03780803. Registered 12 December 2018

Echocardiographic Assessment of Right Ventricular-Arterial Coupling in Predicting Prognosis of Pulmonary Arterial Hypertension Patients.

In response to an increased afterload in pulmonary arterial hypertension (PAH), the right ventricle (RV) adapts by remodeling and increasing contractility. The idea of coupling refers to maintaining a relatively constant relationship between ventricular contractility and afterload. Twenty-eight stable PAH patients (mean age 49.5 ± 15.5 years) were enrolled into the study. The follow-up time of this study was 58 months, and the combined endpoint (CEP) was defined as death or clinical deterioration. We used echo TAPSE as a surrogate of RV contractility and estimated systolic pulmonary artery pressure (sPAP) reflecting RV afterload. Ventricular–arterial coupling was evaluated by the ratio between these two parameters (TAPSE/sPAP). In the PAH group, the mean pulmonary artery pressure (mPAP) was 47.29 ± 15.3 mmHg. The mean echo-estimated TAPSE/sPAP was 0.34 ± 0.19 mm/mmHg and was comparable in value and prognostic usefulness to the parameter derived from magnetic resonance and catheterization (ROC analysis). Patients who had CEP (n = 21) had a significantly higher mPAP (53.11 ± 17.11 mmHg vs. 34.86 ± 8.49 mmHg, p = 0.03) and lower TAPSE/sPAP (0.30 ± 0.21 vs. 0.43 ± 0.23, p = 0.04). Patients with a TAPSE/sPAP lower than 0.25 mm/mmHg had worse prognosis, with log-rank test p = 0.001. the echocardiographic estimation of TAPSE/sPAP offers an easy, reliable, non-invasive prognostic parameter for the comprehensive assessment of hemodynamic adaptation in PAH patients.

Health-related quality of life and disease progression in pulmonary arterial hypertension patients: a 3-year study.

ObjectivesThe role of health-related quality of life (HRQoL) and psychological variables in pulmonary arterial hypertension (PAH) progression remains poorly quantified. We aimed to investigate the relationship between disease progression in PAH patients and HRQoL and psychological characteristics.MethodsA 3-year longitudinal cohort was initiated. Patients with stable PAH (groups I–IV ineligible for angioplasty/endarterectomy) were included (n=55). Standard clinical variables, including invasive haemodynamic parameters, were prospectively recorded. A battery of questionnaires was used to characterise the psychological status of patients upon study initiation, and HRQoL was quantified using the SF-36 Questionnaire every 3 months for 24 months, and then again at 36 months. Guideline-defined disease progression and progression-free survival were recorded for 36 months.Measurements and main resultsPsychological distress was highly prevalent at baseline. The Physical Component Summary (PCS) and the Mental Component Summary (MCS) of the HRQoL were poor (PCS=37.13±8.18; MCS=42.42±10.88) but stable over 3 years of follow-up. Among PCS subscales, Physical Functioning (PF) (p=0.012) was identified as being independently associated with disease progression (Cox survival model), along with mean pulmonary arterial pressure (p=0.003) and cardiac output (p=0.005). Depression was the unique independent psychological characteristic associated with PF (p=0.0001).ConclusionsPAH patients have poor HRQoL. In addition to already known criteria related to disease severity, the HRQoL PF subscale is independently associated with disease progression in PAH. This may be explained by depression.

Multimodal assessment of right ventricle overload-metabolic and clinical consequences in pulmonary arterial hypertension

BackgroundIn pulmonary arterial hypertension (PAH) increased afterload leads to adaptive processes of the right ventricle (RV) that help to maintain arterio-ventricular coupling of RV and preserve cardiac output, but with time the adaptive mechanisms fail. In this study, we propose a multimodal approach which allows to estimate prognostic value of RV coupling parameters in PAH patients.MethodsTwenty-seven stable PAH patients (49.5 ± 15.5 years) and 12 controls underwent cardiovascular magnetic resonance (CMR). CMR feature tracking analysis was performed for RV global longitudinal strain assessment (RV GLS). RV-arterial coupling was evaluated by combination of RV GLS and three proposed surrogates of RV afterload—pulmonary artery systolic pressure (PASP), pulmonary vascular resistance (PVR) and pulmonary artery compliance (PAC). 18-FDG positron emission tomography (PET) analysis was used to assess RV glucose uptake presented as SUVRV/LV. Follow-up time of this study was 25 months and the clinical end-point was defined as death or clinical deterioration.ResultsCoupling parameters (RV GLS/PASP, RV GLS/PVR and RV GLS*PAC) significantly correlated with RV function and standardized uptake value (SUVRV/LV). Patients who experienced a clinical end-point (n = 18) had a significantly worse coupling parameters at the baseline visit. RV GLS/PASP had the highest area under curve in predicting a clinical end-point and patients with a value higher than (−)0.29%/mmHg had significantly worse prognosis. It was also a statistically significant predictor of clinical end-point in multivariate analysis (adjusted R2 = 0.68; p < 0.001).ConclusionsCoupling parameters are linked with RV hemodynamics and glucose metabolism in PAH. Combining CMR and hemodynamic measurements offers more comprehensive assessment of RV function required for prognostication of PAH patients.Trial Registration: NCT03688698, 09/26/2018, retrospectively registered; Protocol ID: 2017/25/N/NZ5/02689

Association of daily physical activity with psychosocial aspects and functional capacity in patients with pulmonary arterial hypertension: a cross-sectional study.

Pulmonary arterial hypertension impairs exercise tolerance and daily physical activity. Aside from the hemodynamic limitations, physical, cognitive, and emotional factors may play a relevant and as yet unexplored role. We investigated whether there is an association between the physical activity level and psychological disorders, health-related quality of life, and daily activities. We also searched for an association of the physical activity level with clinical factors and functional capacity. This was an analytical, cross-sectional, observational study conducted in a Brazilian University Hospital. Twenty stable pulmonary arterial hypertension subjects wore an accelerometer for a week and completed an activity diary. They answered the quality of life questionnaire (SF-36), as well as the Hospital Anxiety and Depression scale, and the Manchester Respiratory Activities of Daily Living questionnaire. Transthoracic echocardiography, the six-minute walk test, the one-minute sit-to-stand test, and spirometry were performed. For statistical analysis, we used Chi-square tests or Fisher’s test as appropriate and the Mann–Whitney test to compare numerical values between two groups. The relationship between the parameters was assessed using the Spearman correlation test. The mean age was 44.3 years, 80% were women, 80% had idiopathic pulmonary arterial hypertension, and 20% had connective tissue disease. The mean daily step count was 4280 ± 2351, and the mean activity time was 41.6 ± 19.3 min. The distance covered (six-minute walk test) was 451.5 m, and the number of movements (one-minute sit-to-stand test) was 23.8. Thirty percent scored positive for anxiety, and 15% for depression (Hospital Anxiety and Depression scale). There was a significant correlation between accelerometer data and walking distance (six-minute walk test), number of movements (one-minute sit-to-stand test), level of daily physical activity (Manchester Respiratory Activities of Daily Living questionnaire), and depression symptoms. Our findings support the hypothesis that other aspects beyond physical and hemodynamic ones might impact the daily physical activity of patients with pulmonary arterial hypertension.

Prognostic value of late gadolinium enhancement mass index in patients with pulmonary arterial hypertension

PurposeDysfunction of the right ventricle (RV) is an important determinant of survival in patients with pulmonary arterial hypertension (PAH). The presence of late gadolinium enhancement (LGE) in cardiac magnetic resonance (CMR) at RV insertion points (RVIPs) has been found in majority of PAH patients and was associated with parameters of RV dysfunction. We hypothesize, that more detailed quantification of LGE may provide additional prognostic information. Material and methodsTwenty-eight stable PAH patients (mean age 49.9 ​± ​15.9 years) and 12 healthy subjects (control group, 44.8 ​± ​13.5 years) were enrolled into the study. Septal LGE mass was quantified at the RVIPs and subsequently indexed by subject’s body surface area. Mean follow-up time of this study was 16.6 ​± ​7.5 months and the clinical end-point (CEP) was defined as death or clinical deterioration. ResultsMedian LGE mass index (LGEMI) at the RVIPs was 2.75 ​g/m2 [1.41–4.85]. We observed statistically significant correlations between LGEMI and hemodynamic parameters obtained from right heart catheterization – mPAP (r ​= ​0.61, p ​= ​0.001); PVR (r ​= ​0.52, p ​= ​0.007) and from CMR – RVEF (r ​= ​−0.54, p ​= ​0.005); RV global longitudinal strain (r ​= ​0.42, p ​= ​0.03). Patients who had CEP (n ​= ​16) had a significantly higher LGEMI (4.49 [2.75–6.17] vs 1.67 [0.74–2.7], p ​= ​0.01); univariate Cox analysis confirmed prognostic value of LGEMI. Furthermore, PAH patients with LGEMI higher than median had worse prognosis in Kaplan-Meier analysis (log-rank test, p ​= ​0.0006). ConclusionsThe body surface indexed mass of LGE at RV septal insertion points are suggestive of RV hemodynamic dysfunction and could be a useful non-invasive marker of PAH prognosis.

Abstract 14345: Cardiopulmonary Best Abstract Award: Improves Right Ventricular - Pulmonary Arterial Coupling and Right Ventricular Function in the Pulsar Study: A Phase 2, Double-blind, Placebo-controlled, Randomized Study to Compare the Efficacy and Safety of Sotatercept versus Placebo When Added to Standard of Care for the Treatment of Pulmonary Arterial Hypertension (PAH)

Background: The right ventricle (RV) and pulmonary arteries become uncoupled as RV function deteriorates in PAH, a consequence of pulmonary vascular remodeling which is ultimately fatal. Restoration of RV-PA coupling and RV function is a crucial aim of PAH treatment. Preclinically, sotatercept, a first-in-class fusion protein, has been shown to reverse right heart remodeling and improve right heart structure and function and acts by suppressing TGF-β signaling and rebalancing BMPR2 signaling. The PULSAR study (NCT03496207, EudraCT 2017-004738-27) released positive topline results earlier this year. Methods: The PULSAR study enrolled 106 patients with WHO Group 1 PAH and WHO functional classes (FC) II-III; age ≥18; pulmonary vascular resistance of ≥5 Wood units by right heart catheterization; stable PAH standard of care (SOC) therapy (all combinations allowed). Sotatercept was administered by SC injection every 21 days for a 24-week double-blind, placebo-controlled treatment period in 3 arms: placebo + SOC, 0.3 mg/kg sotatercept + SOC, 0.7 mg/kg sotatercept + SOC. 2D Doppler echocardiography was performed at baseline and 24 weeks and read in a central laboratory. RV-PA coupling was assessed by TAPSE/PASP. Results: Significant improvement was seen in LS mean (SE) change from baseline to week 24 in RV-PA coupling, RVFAC, RVEDA, RVESA, PASP, and RAP in both sotatercept dose level groups vs placebo. No changes were seen in TAPSE or, notably, in CO. For RV-PA coupling, all patients started below the 0.31 mm/mmHg prognostic threshold; both treatment arms improved above that threshold by 24 weeks while the placebo arm remained below. Conclusions: In the PULSAR study, treatment with sotatercept compared to placebo was associated with statistically significant improvements in RV-PA coupling and RV function. Sotatercept has the potential to be a new treatment option for PAH patients with consistent and encouraging effects on RV-PA coupling and RV function.

Heart rate monitoring improves clinical assessment during 6-min walk.

Right ventricular (RV) function is a predictor of outcomes in pulmonary arterial hypertension (PAH). The 6-min walk test (6MWT) is likely an indirect measure of RV function during exercise, but changes in absolute walk distance can also be influenced by factors like effort and musculoskeletal disease. Paired 6MWT with continuous electrocardiogram monitoring was performed in stable PAH patients, patients adding PAH therapies, and healthy controls. Heart rate expenditure (HRE) was calculated (integrating pulse during 6MWT) and then divided by walk distance (HRE/d). We also evaluated changes in peak heart rate, time above age-adjusted maximum predicted heart rate, and heart rate at 6 min. HRE/d was compared to invasive hemodynamic measures in patients who had right heart catheterization performed within seven days, WHO functional class assessment, and Emphasis 10 questionnaire. We measured two 6MWT in 15 stable PAH patients, 13 treatment intensification patients, and 8 healthy controls. HRE/d was reproducible in the stable PAH group (median difference, −0.79%), while it decreased (median difference, 23%, p = 0.0001) after adding vasodilator therapy. In 11 patients with right heart catheterization, HRE/d correlated strongly with stroke volume, r = −0.72, p = 0.01. Peak heart rate decreased after adding vasodilator therapy. HRE/d also correlated with WHO functional class and Emphasis 10 score. Continuous heart rate monitoring during 6MWT provides valuable physiologic data accounting for effort. HRE/d appears to enhance test reproducibility in stable patients while detecting change after adding therapy as compared to walk distance alone.

Experience in Transitioning From Parenteral Prostacyclins to Selexipag in Pulmonary Arterial Hypertension.

Parenteral prostacyclin therapies remain first-line therapy for patients with pulmonary arterial hypertension (PAH) with class IV symptoms. In selected patients who have been clinically stabilized, switching to selexipag, a chemically distinct prostacyclin receptor agonist, may alleviate risks associated with long-term parenteral therapy. We report our experience with transition of patients from parenteral prostacyclin therapy to selexipag. From January 2016 to July 2017, patients with PAH at the Duke University Pulmonary Vascular Disease Center with functional class II symptoms on stable parenteral prostacyclin therapy were offered the opportunity to transition to selexipag. A standardized protocol was developed to guide titration of therapies. Patients underwent pre- and post-transition assessments of hemodynamics, echocardiography, laboratory biomarkers, and functional status. We studied 14 patients with PAH (11 women; median age 53 years) in total. Overall, 13 patients tolerated the switch to selexipag and remained on the drug at study completion, and 1 patient passed away due to progressive liver failure. Surrogate markers including NT-proBNP, 6MWD, RV function, and TAPSE, and right heart catheterization hemodynamics were similar before and after transition. The transition from parenteral prostanoid therapy to oral selexipag was overall well-tolerated in patients with stable PAH and functional class II symptoms. Finally, doses of selexipag up to 3200 μg twice daily were well-tolerated in patients who had been treated with prior parenteral prostacyclins.

Reliability and responsiveness of incremental shuttle walk test to estimate exercise capacity in patients with pulmonary arterial hypertension

The purpose of the present study was to evaluate the reliability and responsiveness of the incremental shuttle walk test (ISWT) to estimate exercise capacity in patients with pulmonary arterial hypertension (PAH). This was a cross-sectional longitudinal study performed on stable PAH patients (n=30, mean age ± standard deviation, 60±13.6 years) with World Health Organization functional class II &amp; III. Reliability was assessed by comparing the distance covered between ISWT-1 (initial) and ISWT-2 (retest). Responsiveness was determined by comparing the distance covered in the ISWT-3 post pulmonary rehabilitation (PR) to the ISWT-1. The distance covered between ISWT-1 (177±87.85 m) and ISWT-2 (191.67±96.39 m) was not statistically significant. The result of the relative reliability has shown to be excellent with an intraclass correlation coefficient (ICC2,1 = 0.98, 95%CI = 0.95-0.99). Absolute reliability was evaluated through the standard error of the measurement and minimal detectable change at a 95% confidence interval (MDC95) were 12.29 and 33.9 m, respectively. Bland Altman plot showed good agreement between the two ISWTs. Following PR, the effect size (ES=0.78) and standardised response mean (SRM=1.50) were moderate and large respectively. ISWT is considered to be a reliable and responsive measure to estimate exercise capacity in patients with PAH. The ISWT may be considered a suitable alternative tool over a 6-min walk test and in the absence of equipment availability or expertise for conducting cardiopulmonary exercise test for the assessment of exercise capacity in these patients.