Stable Pulmonary Arterial Hypertension Patients Research Articles

Angiopoietin-2 and D-dimer add prognostic information to clinical risk in pulmonary arterial hypertension

Thrombosis and endothelial injury are pathologic hallmarks of pulmonary arterial hypertension (PAH). We aimed to evaluate whether markers of endothelial dysfunction and coagulation in the blood would provide insight into disease activity, treatment response, and outcomes in PAH. MethodsWe prospectively collected baseline and 3-month follow-up blood samples from treatment-naïve PAH patients (n=22) and those who had a clinical indication to intensify therapy (n=19). In addition, we recruited 12 healthy people and clinically stable PAH patients (n=45) as controls who had two blood samples collected twice within 14 days. We generated platelet-free plasma and measured D-dimer, angiopoietin-2, thrombin time, soluble P-selectin, von Willebrand factor, and vascular endothelial growth factor. We assessed treatment response with Reveal Lite 2 scores (all patients had NT-pro-BNP, 6-minute-walk, and functional class assessment at both visits) and followed clinical outcomes for 3 years. ResultsAngiopoietin-2 levels were elevated and fell with response to effective therapy (drop in Reveal Lite 2 score). At follow-up, persistently elevated angiopoietin-2 levels predicted clinical events and even identified low-risk participants who subsequently had events. D-dimer levels were also elevated in PAH patients but didn’t change in response to therapy. Several other abnormalities in endothelial and platelet activation were identified (including elevated soluble P-selectin, elevated von Willebrand factor, and elevated vascular endothelial growth factor) but these did not change with treatment or predict outcome. ConclusionsAngiopoietin-2 and D-dimer are elevated in PAH patients and may add prognostic information to routine clinical assessment.

Assessment of sub clinical right ventricular ischemia using oxygen sensitive cardiac magnetic resonance imaging in patients with systemic sclerosis: mechanistic insights from advanced cardiac imaging

Abstract Background Cardiac involvement in Systemic Sclerosis (SSc) is common, with manifestations ranging from subclinical to life-threatening 1. Cardiopulmonary complications, including, right ventricular (RV) dysfunction is the leading cause of SSc-related mortality2. Pulmonary arterial hypertension (PAH) occurs in 8-12% of SSc patients and remains a leading cause of death, with a 3-year survival rate around 50%2. The progressive decline in RV function in PAH is often attributed to RV ischemia3. Oxygen Sensitive Cardiac Magnetic Resonance imaging (OS-CMR) has been previously used by our group to assess RV myocardial oxygenation in patients with PAH3, including SSc-associated PAH 3. The objective of this study was to use OS-CMR to assess RV myocardial oxygenation in SSc patients prior to the onset of PAH. Methodology In this prospective, multicentre study, three study groups were established. Group 1 comprised SSc patients without PAH or known cardiac disease. Group 2 included stable PAH patients confirmed by right heart catheterization, matched for age and sex, but without SSc. Group 3 comprised healthy normal volunteers (NV), matched for age and sex. All patients underwent a 3T CMR which included: cine images, rest cine OS-CMR, stress cine OS-CMR, native T1 mapping, stress perfusion, and late gadolinium enhancement (LGE). The primary outcome was change in inferior RV myocardial signal intensity (SI) in diastole, measured by the change in OS-CMR between rest and stress within each group. Two experienced independent reviewers performed the CMR analysis with an inter-assessor correlation coefficient of 0.8, 95% Cl [0.3, 0.9]. Results A total of 44 patients were enrolled. Of these, n=26 group 1 (SSc), n=8 group 2 (PAH), n=10 group 3 (NV). Study results are listed in Table 1. Mean age within the SSc, PAH, and NV groups were 59±10, 67±12 and 57 ±7 years respectively (p=0.482). The RV OS-CMR SI was significantly lower in the SSc group when compared to the NV group (p=0.017). In contrast, there was no significant difference between the PAH and SSc groups (p=0.426), indicating a similar degree of RV ischemia in the established PAH patients and the SSc patients. All SSc patients exhibited inferior and anterior RV insertion fibrosis, with no perfusion defects noted. Five (19%) of SSc patients presented with LGE hyperenhancement in the LV. Eighteen (69%) of SSc patients obtained at least 1 abnormal T1 mapping segment in the LV. Conclusion SSc patients without overt PAH had a similar degree of RV ischemia when compared to patients with overt PAH from other causes. Our findings imply that in SSc, RV adverse effects occur prior to the onset of PAH, and that this effect is mediated by RV ischemia secondary to changes in the microvasculature. Our findings may have screening and/or therapeutic implications.

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

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.

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

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.

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.

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.

408 The relationship between right ventricle-arterial coupling and cardiac metabolism in pulmonary arterial hypertension - multimodal study

Abstract Background Right ventricular (RV) function is a major determinant of survival in patients with pulmonary arterial hypertension (PAH). The concept of coupling mainly refers to the relationship between ventricular contractility and afterload. In advanced PAH, to maintain cardiac output, RV dilates and the uncoupling occurs with wall stress and increased metabolic demand. We previously confirmed that impaired RV function is associated with increased glucose uptake of RV myocytes estimated by PET, which marks patients with worse prognosis. Purpose Whether echocardiographic approach of coupling parameters in PAH patients has relationship with RV metabolic alterations. Methods Twenty-six stable PAH patients (mean age 49.92 ± 15.94 years) and sixteen healthy subjects (control group) were enrolled into the study. The TAPSE, reflecting RV contractility, was obtained by mono-dimensional echo in standard technique. The echo estimation of the sPAP was reflecting RV afterload. Ventricular-arterial coupling was evaluated by the ratio between those two parameters. All PAH patients had also right heart catheterization (RHC) and PET performed during baseline visit. Heart glucose metabolism was assessed with fluorodeoxyglucose (FDG) as a tracer in PET. Its uptake was quantified as mean standardized uptake value (SUV) for both left ventricle (LV) and RV. 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. Results Most of enrolled patients were in the WHO functional Class III (61%, 16). There were significant correlations between echo-derived hemodynamic parameters and RHC-derived values e.g. emPAP vs mPAP (RHC), r = 0.86, p &amp;lt; 0.001. Echo-estimated RV ventricular-arterial coupling parameter (TAPSE/sPAP) was 0.35 ± 0.20 in PAH group and 1.51 ± 0.22 in control group, p &amp;lt; 0.001. Mean SUV RV/LV ratio was 1.03 ± 0.68 in PAH group and 0.19 ± 0.08 in controls, p &amp;lt; 0.005. Echo-derived TAPSE/sPAP significantly correlated with hemodynamic parameters from RHC – cardiac output and pulmonary vascular resistance. Interestingly, we also observed significant correlations of TAPSE/sPAP with glucose uptake in PET - SUV RV as well as with SUV RV/LV (r=-0.63, p = 0.0006; r=-0.50, p = 0.0009), confirming higher metabolic demand in uncoupled heart in case of PAH. Furthermore, patients who reached CEP (n = 15, 57%) had a significantly lower TAPSE/esPAP ratio (0.29 ± 0.17 vs 0.43 ± 0.21, p = 0.04) and higher SUV RV/LV (1.39 ± 0.79 vs 0.55 ± 0.45, p = 0.01). ROC analysis revealed significant cut-off value of TAPSE/esPAP in predicting CEP (AUC 0.72 (95% CI 0.52-0.92), p = 0.03). Patients with TAPSE/esPAP lower than 0.25 mm/mmHg had worse prognosis, log-rank test, p = 0.001 (Figure 1). Conclusions Simple echocardiographic parameter reflecting RV coupling (TAPSE/esPAP) related to altered myocardium metabolism in PAH may predict outcome in patients with PAH. Abstract 408 Figure 1

Rehabilitation in Pulmonary Arterial Hypertension: REHAB-HTP

Pulmonary arterial hypertension (PAH) is a life-threatening condition. Current ESC guidelines recommend exercise training and rehabilitation in clinically stable PAH patients. 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. We prospectively included 11 clinically stable PAH patients over a 6-months period. Exercise echocardiography (EE), cardio-pulmonary exercise test (CPET), SF-12quality of life questionnaire, 6-minute walking test (6MWT), 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). All patients underwent EE and CPET without any complication. Five patients experienced a reduction in WHO functional class whereas 5 remained stable. Patients significantly improved their physical quality of life ( P = 0.006). They also improved their exercise capacity according to the maximum workload during CPET ( P = 0.008) and CPET duration ( P = 0.001) whereas a trend toward an improved 6MWT was observed (+58 m, 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). In this preliminary study, cardio-pulmonary rehabilitation led to improved quality of life and exercise capacity in PAH. The increased RV contractile reserve post-rehabilitation might explain, in association with the peripheral muscular effects of exercise training, the clinical benefits of rehabilitation in PAH.

P4686Multimodal assessment of right ventricular-arterial coupling allows better prognostication in pulmonary arterial hypertension patients

Abstract Background The concept of coupling mainly refers to the relationship between ventricular contractility and afterload. Together, strictly related parameters may provide a more accurate estimation of the RV performance status. Indexing RV function, assessed by CMR feature tracking analysis, with a pulmonary artery systolic pressure (PASP) obtained from right heart catheterization (RHC) allows estimation of ventricular-arterial coupling and could help in prognostic stratification of pulmonary arterial hypertension (PAH) patients. Aim To verify the prognostic value of multimodal approach to estimate RV ventricular-arterial coupling in PAH patients. Methods Twenty-six stable PAH patients (mean age 49.92±15.94 years) and twelve healthy subjects (control group, 44.75±13.51 years) were enrolled into the study. CMR feature tracking analysis of the RV was performed for generation of RV global longitudinal strain (RV GLS); RV ejection fraction was also obtained by CMR. Right heart catheterization was carried out only in the PAH group with a standard technique.RV- arterial coupling was evaluated by the ratio of RV GLS/PASP. 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. Results In study group, RV GLS significantly correlated with hemodynamic parameters from RHC – mean pulmonary artery pressure, mPAP (r=0.53, p=0.04) and pulmonary vascular resistance, PVR (r=0.57, p=0.002). Mean RV GLS/PASP ratio in PAH group was (−)0.24±0.15%/mmHg. Patients who reached CEP (n=15) had a significantly higher RV GLS and RV GLS/PASP ratio (−13.3±7.9% vs −20.4±6.2%, p=0.01 and −0.15±0.09%/mmHg vs −0.36±0.19%/mmHg, p=0.005, respectively). However, ROC analysis revealed higher area under curve (AUC) of RV GLS/PASP in predicting CEP than of RV GLS alone (0.82 (95% CI 0.64–1) vs 0.77 (95% CI 0.58–0.96), p&lt;0.0001). Interestingly, at univariate analysis only RV GLS/PASP (HR: 0.89; 95% CI: 0.79–1.08; p=0.03), together with mPAP were all significantly associated with CEP. Patients with RV GLS/PASP cut-off value (ROC analysis) higher than (−)0.29%/mmHg had worse prognosis, log-rank test, p=0.01 (Figure 1). Figure 1 Conclusions Combining CMR and hemodynamic measurements via catheterization offers the potential for more comprehensive assessment of pulmonary vascular load and right heart function, as required for evaluation of the hemodynamic state in patients with PAH. Acknowledgement/Funding This work was supported by National Center for Science in Poland [“Preludium” grant 2017/25/N/NZ5/02689 to R.K.]

EXPRESS: Transition from Parental Prostacyclin to Selexipag: A Case Series of Five Pulmonary Arterial Hypertension Patients.

Parental prostacyclin is the only therapy with a proven survival benefit in pulmonary arterial hypertension (PAH). However, some patients are unable to tolerate continuous prostacyclin infusion because of central line infection, side effects, or sociocultural factors. Selexipag is a recently approved prostacyclin receptor agonist that is able to blunt PAH disease progression. Although in the same molecular pathway, the interchangeability of selexipag with prostacyclin infusions is relatively unexplored. Here, we present a case series of five stable PAH patients who were functional class (FC) I or II that were transitioned from prostacyclin infusion to selexipag using a standardized protocol in the inpatient setting. We show that the transition to selexipag in five highly selected patients was tolerated with no significant changes in FC, minimal changes in pulmonary vascular disease severity, and no significant PAH-related complications. However, there was a trend for a reduction in cardiac index after transition to selexipag. These data suggest that a transition from prostacyclin infusion to selexipag can be achieved in clinically stable PAH patients who are unable to tolerate continuous prostacyclin infusion. However, this approach should only be selectively implemented at specialized centers with close follow-up due to the trend for a reduction in cardiac index after transition to selexipag.

A prescribed walking regimen plus arginine supplementation improves function and quality of life for patients with pulmonary arterial hypertension: a pilot study.

Current evidence suggests that exercise training is beneficial in pulmonary arterial hypertension (PAH). Unfortunately, the standard supervised, hospital-based programs limit patient accessibility to this important intervention. Our proof-of-concept study aimed to provide insight into the usefulness of a prescribed walking regimen along with arginine supplementation to improve outcomes for patients with PAH. Twelve PAH patients (all women) in New York Heart Association (NYHA) functional class (FC) II (n = 7) or III (n = 5) and in stable condition for ≥ 3 months were enrolled. Patients performed home- and fitness-center- based walking at 65–75% heart rate (HR) reserve for 45 min, six sessions/week for 12 weeks. Concomitant L-arginine supplementation (6000 mg/day) was provided to maximize beneficial endothelial training adaptations. Cardiopulmonary exercise testing, 6-min walk testing (6MWT), echocardiography, laboratory studies, and quality of life (QoL) survey (SF-36) were performed at baseline and 12 weeks. Eleven patients completed the study (72 session adherence rate = 96 ± 3%). Objective improvement was demonstrated by the 6MWT distance (increased by 40 ± 13 m, P = 0.01), VO2max (increased by 2 ± 0.7 mL/kg/min, P = 0.02), time-to-VO2max (increased by 2.5 ± 0.6 min, P = 0.001), VO2 at anaerobic threshold (increased by 1.3 ± 0.5 mL/kg/min, P = 0.04), HR recovery (reduced by 68 ± 23% in slope, P = 0.01), and SF-36 subscales of Physical Functioning and Energy/Fatigue (increased by 70 ± 34% and 74 ± 34%, respectively, P < 0.05). No adverse events occurred, and right ventricular function and brain natriuretic peptide levels remained stable, suggesting safety of the intervention. This proof-of-concept study indicates that a simple walking regimen with arginine supplementation is a safe and efficacious intervention for clinically stable PAH patients, with gains in objective function and QoL measures. Further investigation in a randomized controlled trial is warranted.

Inspiratory muscle training in pulmonary arterial hypertension.

The purpose of this study was to investigate the effects of inspiratory muscle training (IMT) on functional capacity, respiratory muscle strength, pulmonary function, quality of life, and fatigue and dyspnea perception in patients with pulmonary arterial hypertension (PAH). Twenty-nine clinically stable PAH patients were included in this study. These patients were randomly assigned to a 6-week IMT program (14 patients) or to a sham IMT protocol (15 patients). Before and after the treatment, pulmonary function, respiratory muscle strength, functional capacity, dyspnea and fatigue perception, and quality of life were evaluated. There were significant increases in maximal inspiratory and expiratory pressure, forced expiratory volume in 1 second (% predicted) and 6-minute walk distance in the IMT group compared with the control group (P < .05). There were significant decreases in the Fatigue Severity Scale score, Modified Medical Research Council dyspnea scores, and Nottingham Health Profile emotional reactions subscale in the IMT group compared with the control group (P < .05). Inspiratory muscle training promotes significant improvements in respiratory muscle strength and functional capacity, thus resulting in a reduction of dyspnea during activities of daily living and less fatigue in PAH patients. Inspiratory muscle training is a clinically practical treatment for PAH without any complications.

Incremental Shuttle Walk Test as a Valuable Assessment of Exercise Performance in Patients With Pulmonary Arterial Hypertension

Nearly all clinical trials investigating patients with pulmonary arterial hypertension (PAH) have used the 6-min walk test (6MWT) to evaluate exercise tolerance. The incremental shuttle walk test (SWT), however, has been proposed as a more valid and reproducible alternative to the 6MWT in the evaluation of exercise tolerance in patients with chronic obstructive pulmonary disease. The efficacy of SWT in clinical practice to evaluate the exercise capacity of patients with PAH was investigated. The peak oxygen consumption (pVO2) and oxygen consumption at anaerobic threshold (VO2 at AT), the gold standard for measurement of exercise tolerance, 6MWT and SWT were measured in 19 clinically stable PAH patients (WHO functional class II-III) and the data compared. There was a higher correlation between SWT walk distance and pVO2 than between 6MWT walk distance and pVO2 (r=0.866 and 0.765, respectively; P<0.05), and a higher correlation between SWT walk distance and VO2 at AT than between 6MWT walk distance and VO2 at AT (r=0.775 and 0.587, respectively; P<0.05). No adverse events occurred during the exercise tests. SWT is a better reflection than 6MWT of exercise tolerance in PAH patients, and thus is a preferable alternative for assessment of exercise tolerance in PAH patients.