Long-Term Pulmonary Arterial Hypertension Disease Management Research Articles

Usefulness of risk assessment tools in predicting hemodynamic outcome after balloon pulmonary angioplasty: a comparative analysis

ABSTRACT Objectives Several parameters of widely used risk assessment tools for pulmonary arterial hypertension (PAH) have been linked to hemodynamic outcomes of balloon pulmonary angioplasty (BPA). Therefore, we aimed to determine whether these risk assessment tools could be used to predict hemodynamic outcomes following BPA. Methods In this retrospective study, we included 139 patients with chronic thromboembolic pulmonary hypertension who had undergone BPA at Center for Pulmonary Vascular Diseases, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College (Beijing, China). We compared the accuracies of seven well-validated risk assessment tools for predicting hemodynamic outcomes following BPA. A favorable hemodynamic outcome was defined as a mean pulmonary arterial pressure < 30 mmHg at follow-up. Results The baseline risk profiles varied significantly among the risk assessment tools. The US Registry to Evaluate Early and Long-Term PAH Disease Management risk scales and the French risk assessment tools rated most patients as high-risk, while the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) series and laboratory examination-based risk scales categorized most patients as having intermediate-risk profile. COMPERA 2.0 (4-strata) exhibited the highest predictive power among all risk stratifications. Noninvasive risk stratification (COMPERA 2.0 [3-strata]) showed a comparable predictive ability to that of invasive risk stratification (COMPERA 1.0) (area under the curve 0.649 vs. 0.648). Moreover, incorporating diffusing capacity of the lungs for carbon monoxide and tricuspid regurgitation velocity into COMPERA 2.0 (4-strata) further enhanced its predictive power (net reclassification index 0.153, 95% confidence interval 0.009–0.298, p = 0.038). Additionally, this refined COMPERA version had a high calibration accuracy (slope 0.96). Conclusion Although the risk strata distribution varied among different risk assessment tools, the proportion of patients achieving favorable hemodynamics decreased with the escalation of risk stratification in most models. The well-validated risk assessment tools for PAH could also predict hemodynamic outcomes following BPA, and the refined COMPERA 2.0 model exhibited the highest predictive ability among these. Applying risk assessment tools before BPA can facilitate early identification of patients in need of closer monitoring and more intensive interventions, contributing to a better prognosis after BPA.

Virtual Echocardiography Screening Tool Identifies Pulmonary Arterial Hypertension Significantly Earlier Than High-Risk Clinical Diagnosis

Pulmonary arterial hypertension (PAH) is often a progressive, fatal disease. Because of nonspecificity of symptoms and limited awareness of PAH, patients are often diagnosed and referred late to accredited pulmonary hypertension (PH) centers, contributing to worsening survival and overall prognosis. The objective of the present study was to determine if the virtual echocardiography screening tool (VEST), a simple scoring system using routinely reported echocardiographic metrics, could capture earlier diagnoses of PAH before clinical recognition and referral to expert PH centers. This study is a retrospective analysis of 132 patients with PAH evaluated consecutively at 2 accredited referral PH centers. VEST scores and time to evaluation at PH center were quantified based on the first available echocardiogram before referral. Clinical risk assessment was calculated at initial evaluation by the PH center using the REVEAL (Registry to Evaluate Early and Long-term PAH Disease Management) 2.0 calculator. An overwhelming majority (93%) of the study participants had markedly abnormal VEST scores predictive of PAH before evaluation at a PH referral center. The median delay from VEST to evaluation was >6months at 206days (quartile 1, quartile 3: 55, 757). At initial evaluation, 72% were intermediate or high-risk based on REVEAL 2.0 risk assessment. In conclusion, we propose that VEST is a powerful yet simple scoring tool that can capture high-risk patients with PAH, prompting earlier diagnosis and referrals to accredited PH centers, and allowing for earlier expert implementation of PH medical therapies.

Do Patients With Low-Risk Pulmonary Arterial Hypertension Really Benefit From Upfront Combination Therapy?: Insight From the AMBITION Trial

Based on results of the Ambrisentan and Tadalafil in Patients with Pulmonary Arterial Hypertension (AMBITION) trial, upfront combination therapy is recommended for treatment-naive patients with low-risk pulmonary arterial hypertension (PAH). However, conflicting data exist whether adopting this treatment strategy in this risk group is beneficial or well tolerated. Do patients with low-risk PAH really benefit from upfront combination therapy? Using the data from the original AMBITION trial, patients with PAH were classified as low, intermediate, or high risk using the Registry to Evaluate Early and Long-term PAH Disease Management 2.0 (REVEAL 2.0) score and the Pulmonary Hypertension Outcomes and Risk Assessment (PHORA) tool. The primary end point was time to clinical worsening (including death, hospitalization for PAH worsening, and disease progression) censored at 1- and 3-year post-enrollment. Side effects that led to withdrawal of treatment were also considered. Patients with low-risk PAH categorized by REVEAL 2.0 and PHORA did not see a statistically significant benefit of upfront combination therapy vsmonotherapy for time to clinical worsening at 1 and 3 years' post-enrollment using Cox proportional analysis (3-year hazard ratio of 0.40 [95%CI, 0.15-1.06; P= .07] and 0.55 [95%CI, 0.26-1.18; P= .12] for REVEAL 2.0 and PHORA, respectively) or considering time to clinical worsening or side effects (3-year hazard ratio of 0.75 [95%CI, 0.39-1.47; P= .4] and 0.87 [95%CI, 0.49-1.54; P= .63] for REVEAL 2.0 and PHORA). Patients with low-risk PAH on upfront combination therapy experienced a higher but not significant incidence of side effects using REVEAL 2.0 and PHORA. In contrast, patients at intermediate or high risk saw a statistically significant benefit of upfront combination therapy considering each of the end points regardless of side effects. This analysis suggests that perhaps some patients with low-risk PAH should be further stratified using other modalities prior to committing to upfront combination therapy, especially when the occurrence of side effects is considered. Further prospective data are needed to validate this hypothesis prior to changes in current guideline directed therapy are contemplated.

Heterogeneity of treatment effects by risk in pulmonary arterial hypertension.

It is currently unknown if disease severity modifies response to therapy in pulmonary arterial hypertension (PAH). We aimed to explore if disease severity, as defined by established risk-prediction algorithms, modified response to therapy in randomised clinical trials in PAH. We performed a meta-analysis using individual participant data from 18 randomised clinical trials of therapy for PAH submitted to the United States Food and Drug Administration to determine if predicted risk of 1-year mortality at randomisation modified the treatment effect on three outcomes: change in 6-min walk distance (6MWD), clinical worsening at 12 weeks and time to clinical worsening. Of 6561 patients with a baseline US Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL 2.0) score, we found that individuals with higher baseline risk had higher probabilities of clinical worsening but no difference in change in 6MWD. We detected a significant interaction of REVEAL 2.0 risk and treatment assignment on change in 6MWD. For every 3-point increase in REVEAL 2.0 score, there was a 12.49 m (95% CI 5.86-19.12 m; p=0.001) greater treatment effect in change in 6MWD. We did not detect a significant risk by treatment interaction on clinical worsening with most of the risk-prediction algorithms. We found that predicted risk of 1-year mortality in PAH modified treatment effect as measured by 6MWD, but not clinical worsening. Our findings highlight the importance of identifying sources of treatment heterogeneity by predicted risk to tailor studies to patients most likely to have the greatest treatment response.

Performance of risk stratification scores and role of comorbidities in older vs younger patients with pulmonary arterial hypertension

Risk scores are important tools for the prognostic stratification of pulmonary arterial hypertension (PAH). Their performance and the additional impact of comorbidities across age groups is unknown. Patients with PAH enrolled from 2001 to 2021 were divided in ≥65 years old vs <65 years old patients. Study outcome was 5-year all-cause mortality. French Pulmonary Hypertension Network (FPHN), FPHN noninvasive, Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) and Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL 2.0) risk scores were calculated and patients categorized at low, intermediate and high risk. Number of comorbidities was calculated. Among 383 patients, 152 (40%) were ≥65 years old. They had more comorbidities (number of comorbidities 2, IQR 1-3, vs 1, IQR 0-2 in <65 years patients). Five-year survival was 63% in ≥65 vs 90% in <65 years. Risk scores correctly discriminated the different classes of risk in the overall cohort and in the older and younger groups. REVEAL 2.0 showed the best accuracy in the total cohort (C-index 0.74, standard error-SE- 0.03) and older (C-index 0.69, SE 0.03) patients, whereas COMPERA 2.0 performed better in younger patients (C-index 0.75, SE 0.08). Number of comorbidities was associated with higher 5-year mortality, and consistently increased the accuracy of risk scores, in younger but not in older patients. Risk scores have similar accuracy in the prognostic stratification of older vs younger PAH patients. REVEAL 2.0 had the best performance in older patients and COMPERA 2.0 had it in younger patients. Comorbidities increased the accuracy of risk scores only in younger patients.

Smoking history and pulmonary arterial hypertension: Demographics, onset, and outcomes.

Smoking prevalence and its association with pulmonary arterial hypertension (PAH) outcomes have not been described in patients in the United States. Using the US-based Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL), the prevalence, demographics, and outcomes in ever- versus never-smokers with PAH were determined. Ever-smoking status was more prevalent in males (61.7%) than in females (42.9%) enrolled in REVEAL. Ever-smokers were older than never-smokers at the time of PAH diagnosis and REVEAL enrollment. The time to first hospitalization, transplant-free survival, and survival did not differ between ever- and never-smokers overall; however, in newly diagnosed males, ever-smoking was associated with earlier death (hazard ratio [HR] 1.8, 95% confidence interval [CI] 1.1-3.0; p=0.0199), the composite of transplant or death (HR 2.2, 95% CI 1.4-3.6; p=0.0008), and first hospitalization (HR 1.8, 95% CI 1.2-2.7; p=0.0063), though smoking exposure (pack-years) did not differ between newly and previously diagnosed males. REVEAL PAH data demonstrate that smoking prevalence in male PAH patients is disproportionate. The prevalence of cigarette smoking was significantly higher in males than females enrolled in REVEAL. Ever-smoking status was associated with increased age at PAH diagnosis and, in newly diagnosed male PAH patients, earlier time to hospitalization and shorter survival after PAH diagnosis.

Derivation of a Risk Score (REVEAL-ECHO) Based on Echocardiographic Parameters of Patients With Pulmonary Arterial Hypertension

Multiparametric risk assessment tools determine mortality risk in patients with pulmonary arterial hypertension (PAH) by combining invasive and noninvasive variables so management strategies can be tailored to individuals. Can a risk score based on common echocardiographic parameters risk-stratify patients with PAH? A Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) echocardiographic risk score (REVEAL-ECHO) was derived using retrospective echocardiographic data from 2,400 adult patients with PAH enrolled in the REVEAL registry database. A stepwise Cox regression model identified echocardiographic parameters significantly predictive of survival. Values were assigned to each selected parameter based on survival at 12months' follow-up (Kaplan-Meier estimates). The REVEAL-ECHO risk score was the sum of individual values. Patients were categorized as having low, intermediate, or high risk based on Kaplan-Meier-predicted 12-month survival. The risk score included four echocardiographic parameters-right ventricular (RV) chamber enlargement, reduced RV systolic function, tricuspid regurgitation severity, and pericardial effusion-and accounted for PAH etiology. Higher REVEAL-ECHO risk scores signaled lower probability of 12-month survival. Statistically significant separation of mortality risk was observed among the risk strata: intermediate vslow (hazard ratio [HR], 1.43; 95%CI, 1.17-1.75; P= .0004) and high vslow (HR, 2.60; 95%CI, 2.19-3.10; P< .0001). Augmentation of the REVEAL Lite 2 risk calculator with REVEAL-ECHO risk scores achieved separation of REVEAL Lite 2 into four risk groups and identified a subgroup of patients with a low REVEAL Lite 2 risk score who were at higher risk (intermediate-low risk) and a subgroup of patients with an intermediate REVEAL Lite 2 risk score who also were at higher risk (intermediate-high risk). A REVEAL-ECHO risk score, derived using four echocardiographic parameters, may discriminate risk further when used as an adjunct to current risk assessment scores. Further validation is required.

Plasma Cell-Free DNA Predicts Survival and Maps Specific Sources of Injury in Pulmonary Arterial Hypertension.

Cell-free DNA (cfDNA) is a noninvasive marker of cellular injury. Its significance in pulmonary arterial hypertension (PAH) is unknown. Plasma cfDNA was measured in 2 PAH cohorts (A, n=48; B, n=161) and controls (n=48). Data were collected for REVEAL 2.0 (Registry to Evaluate Early and Long-Term PAH Disease Management) scores and outcome determinations. Patients were divided into the following REVEAL risk groups: low (≤6), medium (7-8), and high (≥9). Total cfDNA concentrations were compared among controls and PAH risk groups by 1-way analysis of variance. Log-rank tests compared survival between cfDNA tertiles and REVEAL risk groups. Areas under the receiver operating characteristic curve were estimated from logistic regression models. A sample subset from cohort B (n=96) and controls (n=16) underwent bisulfite sequencing followed by a deconvolution algorithm to map cell-specific cfDNA methylation patterns, with concentrations compared using t tests. In cohort A, median (interquartile range) age was 62 years (47-71), with 75% female, and median (interquartile range) REVEAL 2.0 was 6 (4-9). In cohort B, median (interquartile range) age was 59 years (49-71), with 69% female, and median (interquartile range) REVEAL 2.0 was 7 (6-9). In both cohorts, cfDNA concentrations differed among patients with PAH of varying REVEAL risk and controls (analysis of variance P≤0.002) and were greater in the high-risk compared with the low-risk category (P≤0.002). In cohort B, death or lung transplant occurred in 14 of 54, 23 of 53, and 35 of 54 patients in the lowest, middle, and highest cfDNA tertiles, respectively. cfDNA levels stratified as tertiles (log-rank: P=0.0001) and REVEAL risk groups (log-rank: P<0.0001) each predicted transplant-free survival. The addition of cfDNA to REVEAL improved discrimination (area under the receiver operating characteristic curve, 0.72-0.78; P=0.02). Compared with controls, methylation analysis in patients with PAH revealed increased cfDNA originating from erythrocyte progenitors, neutrophils, monocytes, adipocytes, natural killer cells, vascular endothelium, and cardiac myocytes (Bonferroni adjusted P<0.05). cfDNA concentrations derived from erythrocyte progenitor cells, cardiac myocytes, and vascular endothelium were greater in patients with PAH with high-risk versus low-risk REVEAL scores (P≤0.02). Circulating cfDNA is elevated in patients with PAH, correlates with disease severity, and predicts worse survival. Results from cfDNA methylation analyses in patients with PAH are consistent with prevailing paradigms of disease pathogenesis.

COMPARISON BETWEEN PULMONARY ARTERIAL HYPERTENSION (PAH) RISK ASSESSMENT METHODS, INCLUDING PULMONARY HYPERTENSION OUTCOME RISKS ASSESSMENT (PHORA)

COMPARISON BETWEEN PULMONARY ARTERIAL HYPERTENSION (PAH) RISK ASSESSMENT METHODS, INCLUDING PULMONARY HYPERTENSION OUTCOME RISKS ASSESSMENT (PHORA)

Imaging of Improved Right Ventricular Coupling, Risk Status and Survival in Pulmonary Arterial Hypertension

<h3>Purpose</h3> Right ventricular function adaptation to afterload as assessed by the ratio of tricuspid annular plane excursion (TAPSE) to systolic pulmonary artery pressure (PASP) has been shown to be of prognostic relevance in pulmonary arterial hypertension (PAH).To test the hypothesis that improvement in TAPSE/PASP under targeted therapies is associated with the likelihood to achieve a better prognostic low-risk status in PAH. <h3>Methods</h3> The study retrospectively enrolled 677 PAH patients (55 % idiopathic) with follow-up clinical, right heart catheterization and echocardiographic evaluations within 12 months (IQR 180-344 days) after initiation of targeted therapies from 2005 to 2017 in 11 Italian centers. European guidelines-derived and United States Registry to Evaluate Early and Long-Term PAH Disease Management registry REVEAL 2.0 risk scores were assessed at baseline and follow-up. <h3>Results</h3> The patients improved their functional class and 6-min walk distance, but a minority of them achieved or mainteined the low risk status as assessed either with the European or the REVEAL score (30% and 27%, respectively). The TAPSE/PASP ratio increased curvilinearly in proportion to decreased pulmonary vascular resistance (PVR) by more than 50 %. Patients at low risk were respectively, 4.93 and 3.37 times more likely to have TAPSE/PASP ≥ 0.35 mm/mmHg than those at intermediate or high risk, according to the ESC/ERS (OR 4.93, C.I. 3.40-7.14; p=0.0001) and the REVEAL 2.0 score (OR 3.37, C.I. 2.32-4.90; p=0.0001). <h3>Conclusion</h3> Improvement of TAPSE/PASP under targeted therapies in PAH is associated with a low risk status and marked reduction in PVR.

Comparison of Risk Stratification Scores in Pulmonary Arterial Hypertension: A Monocentric Retrospective Study at Lausanne University Hospital

Background: Risk assessment is the cornerstone of pulmonary arterial hypertension (PAH) management. Risk stratification scores predict prognosis and help individualize treatment. Objectives: The aims of the study include the following: (1) to compare the prediction for transplant-free survival (TFs) of 3 risk assessment tools at 3 and 5 years after diagnosis and (2) to analyze whether the initial risk stratification was altered after 1 year of treatment. Method: We collected retrospectively data of 50 patients diagnosed with PAH Group 1. We categorized them as low, intermediate, and high mortality risk at baseline and at 1 year with the (1) Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) risk score version 2.0, (2) Swedish/Comparative Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (PH) (COMPERA) score, and (3) French PH Network Registry (FPHR) score. Results: TFs at 3 years is predicted by the 3 scores computed at baseline with an area under the curve (AUC) of 0.73, 0.73, and 0.77, respectively. The predictive value increased when the scores were calculated after 1 year of treatment (AUC = 0.91, 0.89, and 0.78). The prediction of TFs at 5 years was better evaluated by the COMPERA and FPHR (AUC = 0.85) than by REVEAL 2.0 (AUC = 0.69) computed at baseline. A low risk status was associated with excellent TFs whatever the scoring used. Conclusion: In accordance with the original publications, the 3 scores are able to predict survival up to 5 years after diagnosis. The better performance of the scores after 1 year is a further evidence for their clinical use and an indirect proof for treatment efficacy.

E-REVEAL Lite 2.0 scoring for early prediction of disease progression in pulmonary arterial hypertension.

Risk stratification is an essential tool in the management of pulmonary arterial hypertension (PAH). These tools lack detailed echocardiographic assessment which plays a central role in clinical risk assessment in PAH. Thus, we aimed at assessing whether adding echocardiography‐driven data to REVEAL Lite 2.0 (Registry to Evaluate Early and Long‐Term PAH Disease Management) improves the assessment of risk stratification in PAH. A retrospective analysis of 134 consecutive patients between January 2016 and December 2019 was done. We identified patients who experienced a disease progression “event” defined by the initiation of intravenous (IV) or parenteral prostacyclin, transplant referral, or death due to PAH. All other PAH patients who did not experience an “event” during this period were included in the analysis as controls. Echocardiography and REVEAL Lite 2.0 were collected from 4 to 8 months before the event and compared with the control group to predict the risk of a disease progression event. One hundred and ten patients were included in the final analysis with 22 experiencing a disease progression event and 88 remaining stable during the study period. Different echocardiographic parameters were combined with REVEAL Lite 2.0 scores in both groups. The combination of REVEAL Lite 2.0 and the left ventricular end‐diastolic (LVED) eccentricity index (as a continuous variable) had the highest area under the curve (AUC) of 0.87, which approached a significant difference with that of the REVEAL Lite 2.0 alone (p = 0.052). An additional multivariable regression model that included REVEAL Lite 2.0, LVED eccentricity index as a continuous variable, and RAP achieved the best AUC at 0.88 (0.80, 0.96), which was significantly different from that of the REVEAL Lite 2.0 alone (AUC 0.77 [0.66, 0.88]; p = 0.049). These results suggest that combining different echocardiographic parameters to REVEAL Lite 2.0 provides more statistically accurate risk predictions compared to REVEAL Lite 2.0 alone. A combination of LVED eccentricity index with REVEAL Lite 2.0 achieved the best AUC in predicting the event in our cohort.

121 Imaging of improved right ventricular function and risk status in pulmonary arterial hypertension

Abstract Aims Right ventricular function adaptation to afterload as assessed by the ratio of tricuspid annular plane excursion (TAPSE) to systolic pulmonary artery pressure (PASP) has been shown to be of prognostic relevance in pulmonary arterial hypertension (PAH). To test the hypothesis that improvement in TAPSE/PASP under targeted therapies is associated with the likelihood to achieve a better prognostic low-risk status in PAH. Methods and results The study retrospectively enrolled 677 PAH patients (55% idiopathic) with follow-up clinical, right heart catheterization, and echocardiographic evaluations within 12 months [interquartile range (IQR): 180–344 days] after initiation of targeted therapies from 2005 to 2017 in 11 Italian centres. European guidelines-derived and United States Registry to Evaluate Early and Long-Term PAH Disease Management registry REVEAL 2.0 risk scores were assessed at baseline and follow-up. The patients improved their functional class and 6-min walk distance, but a minority of them achieved or maintained the low risk status as assessed either with the European or the REVEAL 2.0 score (30% and 27%, respectively). The TAPSE/PASP ratio increased curvilinearly in proportion to decreased pulmonary vascular resistance (PVR) by more than 50%. Patients at low risk were, respectively, 4.93 and 3.37 times more likely to have TAPSE/PASP ≥0.35 mm/mmHg than those at intermediate or high risk, according to the ESC/ERS [odds ratio: (OR) 4.93, confidence interval (CI): 3.40–7.14; P = 0.0001] and the REVEAL 2.0 score (OR: 3.37, CI: 2.32–4.90; P = 0.0001). Conclusions Improvement of TAPSE/PASP under targeted therapies in PAH is associated with a low risk status, marked reduction in PVR, and improved outcome.

Abstract 10765: Plasma Cell-Free DNA Predicts Survival and Maps Tissue-Specific Sources of Injury in Pulmonary Arterial Hypertension

Background: Cell-free DNA (cfDNA) is a non-invasive marker of tissue injury. Although being incrementally used as a clinical biomarker, its significance in pulmonary arterial hypertension (PAH) is unknown. Methods: Plasma cfDNA was isolated in two independent PAH cohorts (A, n=48; B, n=161) and healthy controls (n=48). Clinical variables and survival status were collected for Registry to Evaluate Early And Long-term PAH Disease Management (REVEAL 2.0) scores and outcome determinations. Total cfDNA levels were compared amongst controls and PAH patients and also used to predict transplant-free survival. A subset of samples from cohort B (n=96) and controls (n=16) were subjected to bisulfite sequencing and methylation analysis to quantify tissue-specific sources of cfDNA. Results: Median (IQR) cfDNA concentrations were higher in cohort A PAH patients (exploratory cohort) compared to controls and increased according to REVEAL 2.0 risk group: controls 13.7 (10.8-18.8) vs low risk 14.4 (10.0-19.9) vs medium risk 14.6 (11.3-28.2) vs high risk 31.5 (17.2-45.6) ng/ml (P&lt;0.01). cfDNA analysis in cohort B (validation cohort) demonstrated a similar cfDNA pattern: controls 13.7 (10.8-18.8) vs low risk 24.3 (16.0-57.9) vs medium risk 50.4 (29.4-70.9) vs high risk 51.5 (34.0-110.5) ng/ml (P&lt;0.0001). cfDNA tertiles (Log-Rank; P=0.0001) and REVEAL 2.0 risk group (Log-Rank; P&lt;0.0001) similarly predicted transplant-free survival, and the addition of cfDNA to REVEAL 2.0 improved model performance (AUC 0.64 to 0.70; P&lt;0.05). Tissue-specific methylation analysis revealed increased cfDNA originating from vascular endothelium, cardiac myocytes, monocytes, erythrocyte progenitors, neutrophils, natural killer cells, and adipocytes (all P&lt;0.005), but not colon, head/neck, liver, bladder, or kidney. With the exception of natural killer cells, cfDNA from enriched tissues also differentiated PAH patients of varying REVEAL 2.0 risk. Conclusions: cfDNA is elevated in PAH patients, correlates with disease severity and predicts worse survival. Methylation analysis of cfDNA in PAH patients is consistent with prevailing paradigms of disease pathogenesis. Thus, cfDNA may add prognostic power to PAH risk assessment and provide insight into disease progression.

Facemasks and Walk Distance in Pulmonary Arterial Hypertension Patients.

Little is known about the effect of wearing a facemask on the physiological and perceptual responses to exercise in patients with pulmonary arterial hypertension (PAH). We performed a single-center retrospective study to evaluate whether facemask wearing impacted distanced covered, rating of perceived exertion (RPE), and arterial oxygen saturation (SpO2) during a 6-minute walk test (6MWT) in PAH patients. Forty-five patients being treated for group 1 PAH and who performed a 6MWT before and after implementation of a facemask mandate were included in the analysis. Each included patient performed a 6MWT without (test 1) and with (test 2) a facemask between October 1, 2019, and October 31, 2020. At both time points, all patients also underwent a submaximal cardiopulmonary exercise test, echocardiogram, and blood laboratory tests, with a Registry to Evaluate Early and Long-Term PAH Disease Management Lite 2.0 score calculated. The two 6MWTs were performed 81±51 days apart, and all patients were clinically stable at both testing timepoints. Six-minute walk test distance was not different between test 1 and test 2 (405±108 m vs 400±103 m, P=.81). Similarly, both end-test RPE and lowest SpO2 during the 6MWT were not different in test 1 and test 2 (RPE: 2.5±1.7 vs 2.5±2.1, P=.91; SpO2 nadir: 92.8±3.4% vs 93.3±3.3%, P=.55). Our findings show that wearing a facemask has no discernable impact on the arterial oxygen saturation and perceptual responses to exercise or exercise capacity in patients with moderate-to-severe PAH. This study reinforces the evidence that wearing a facemask is safe in PAH patients, even during exercise.

Right ventricular expression of NT-proBNP adds predictive value to REVEAL score in patients with pulmonary arterial hypertension.

AimsThe Registry to Evaluate Early and Long‐Term PAH Disease Management (REVEAL) risk scores differentiate survivals in patients with pulmonary arterial hypertension (PAH). However, measurements of N‐terminal pro B‐type natriuretic peptide (NT‐proBNP) in the peripheral blood may not adequately reflect early‐stage decompensated heart failure (HF). Given that right heart catheterization (RHC) can facilitate measurements of intracardiac NT‐proBNP, in this study our aim was to evaluate the predictive role of right ventricular (RV) NT‐proBNP measurements in patients with PAH.Methods and resultsWe prospectively collected intracardiac blood samples for NT‐proBNP measurements from patients diagnosed with World Health Organization Group I PAH during RHC. Clinical information including the aetiology of PAH (idiopathic, connective tissue disease, or congenital heart disease) and REVEAL scores were recorded. The primary endpoint was hospitalization for decompensated HF; median duration of follow‐up was 28 months. Among the 62 patients evaluated, 12 reached the designated endpoint. REVEAL risk scores were higher among patients hospitalized for HF. We detected no significant differences in plasma NT‐proBNP levels in peripheral circulation, in the right atrium, or in pulmonary arterial blood; however, significantly higher levels of NT‐proBNP were detected in the RV in patients diagnosed with PAH. RV NT‐proBNP was a sensitive predictor (cut‐off value 1500 pg/mL) of subsequent hospitalization for HF. Our findings indicate that RV NT‐proBNP levels add predictive value to REVEAL scores with respect to future hospitalization due to HF.ConclusionsRight ventricular NT‐proBNP levels combined with REVEAL 2.0 could predict the development of subsequent HF in patients with PAH and may be a potential biomarker.

Risk Reduction and Hemodynamics with Initial Combination Therapy in Pulmonary Arterial Hypertension.

Rationale: An initial oral combination of drugs is being recommended in pulmonary arterial hypertension (PAH), but the effects of this approach on risk reduction and pulmonary vascular resistance (PVR) are not known.Objectives: To test the hypothesis that a low-risk status would be determined by the reduction of PVR in patients with PAH treated upfront with a combination of oral drugs.Methods: The study enrolled 181 treatment-naive patients with PAH (81% idiopathic) with a follow-up right heart catheterization at 6 months (interquartile range, 144-363 d) after the initial combination of endothelin receptor antagonist + phosphodiesterase-5 inhibitor drugs and clinical evaluation and risk assessments by European guidelines and Registry to Evaluate Early and Long-Term PAH Disease Management scores.Measurements and Main Results: Initial combination therapy improved functional class and 6-minute-walk distance and decreased PVR by an average of 35% (median, 40%). One-third of the patients had a decrease in PVR <25%. This poor hemodynamic response was independently predicted by age, male sex, pulmonary artery pressure and cardiac index, and at echocardiography, a right/left ventricular surface area ratio of greater than 1 associated with low tricuspid annular plane systolic excursion of less than 18 mm. A low-risk status at 6 months was achieved or maintained in only 34.8% (Registry to Evaluate Early and Long-Term PAH Disease Management score) to 43.1% (European score) of the patients. Adding criteria of poor hemodynamic response improved prediction of a low-risk status.Conclusions: A majority of patients with PAH still insufficiently improved after 6 months of initial combinations of oral drugs is identifiable at initial evaluation by hemodynamic response criteria added to risk scores.

Evaluation of the REVEAL 2.0 simplified three-category model in a pulmonary arterial hypertension cohort enriched with congenital heart disease

Abstract Objectives Despite a remarkable progress in the management of pulmonary arterial hypertension (PAH) over the past decade, PAH still has a poor long-term outlook and remains an incurable condition. Risk assessment continues to be refined to identify patients at risk of early morbidity and mortality. We aimed to evaluate a new model, the US Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) 2.0 risk score proposed for the follow-up of patients in our cohort. Methods We enrolled a mixed prevalent and incident cohort of patients with idiopathic PAH (20%), heritable (2.5%), congenital heart disease (CHD) (59.2%), and connective tissue diseases (18.3%) subsets (n=121) from 4 PAH centers from March 2007 to January 2019. Individual patient REVEAL 2.0 risk scores were applied at 12 months after the diagnosis (follow-up). Risk scores were calculated with 7 or more variables. Kaplan-Meier survival was estimated for a simplified three-category (low, intermediate, and high risk) model up to 60 months from 1 year after the diagnosis, with all-cause mortality as the end point. Log-rank test was used to compare estimates. Results The mean age was 46±16 years (78.5% women). 2/3 of the patients were CHD. The median survival was 60 months. 25 patients had died. The majority of the patients were NYHA FC II (48.8%) and III (42.1%) at follow-up. Figure 1 demonstrates KM 12- and 60- month survival in our cohort according to the simplified three-category (low, intermediate, and high risk) REVEAL 2.0 model. Overall, 58.7%, 15.7%, and 25.6% of the patients were classified as low, intermediate, and high risk, respectively, at follow-up. The REVEAL 2.0 model effectively discriminated risk in our cohort. Both 1 year- and 5 year-survival differed significantly between the 3 risk categories: 12-month mortality estimates were 1.41% for low risk, 5.3% for intermediate risk, and 16.1% for high risk (log-rank, P=0.013); and 60- month mortality estimates were 2.8% for low risk, 10.5% for intermediate risk, and 51.6% for high risk (log-rank, P=0.0001). Conclusions The REVEAL 2.0 simplified three-category model can be applied for risk assessment of the PAH subsets, particularly congenital heart disease at follow-up. Figure 1 Funding Acknowledgement Type of funding source: None

Safety and efficacy of transitioning from the combination of bosentan and sildenafil to alternative therapy in patients with pulmonary arterial hypertension.

The combination of bosentan and sildenafil is commonly used to treat patients with pulmonary arterial hypertension (PAH); however, there is evidence of a significant drug interaction between these two medications. We sought to evaluate the safety and efficacy of transitioning patients with PAH from the combination of bosentan and sildenafil to alternative therapy. A retrospective database review was performed on 16 patients with PAH who were treated with the combination of bosentan and sildenafil and transitioned to alternative treatment at our center. Invasive and non-invasive patient parameters were collected at baseline and after transition. 56.3% of patients were in World Health Organization functional class (WHO FC) III and a majority of patients (68.7%) were on background prostacyclin therapy. The most common reason for transition was concern for a drug interaction in seven patients (43.8%). The most common transition was bosentan to macitentan in eight patients (50%). Fifteen patients (93.8%) tolerated the transition after a median follow-up of 6.5 months with minor adverse events occurring in four patients (25%). In 11 patients, 6-min walk distance (6MWD) was unchanged comparing baseline to post transition measurements with a median change of +8 m (range: −50 to + 70; P = 0.39). Nine patients (81.8%) had stable (within 15% margin) or significant improvement (increase by ≥15%) in 6MWD after transition. All patients demonstrated stable or improved WHO FC after transition. There were no significant changes after transition in hemodynamics, N-terminal pro-brain natriuretic peptide (NT-proBNP) values, or Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) risk scores. In our study, transitioning patients from bosentan and sildenafil to alternative therapy was safe and resulted in clinical stability.

Development and Validation of an Abridged Version of the REVEAL 2.0 Risk Score Calculator, REVEAL Lite 2, for Use in Patients With Pulmonary Arterial Hypertension

BackgroundAchievement of low-risk status is a treatment goal in pulmonary arterial hypertension (PAH). Risk assessment often is performed using multiparameter tools, such as the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) risk calculator. Risk calculators that assess fewer variables without compromising validity may expedite risk assessment in the routine clinic setting. We describe the development and validation of REVEAL Lite 2, an abridged version of REVEAL 2.0.Research QuestionCan a simplified version of the REVEAL 2.0 risk assessment calculator for patients with PAH be developed and validated?Study Design and MethodsREVEAL Lite 2 includes six noninvasive variables—functional class (FC), vital signs (systolic BP [SBP] and heart rate), 6-min walk distance (6MWD), brain natriuretic peptide (BNP)/N-terminal prohormone of brain natriuretic peptide (NT-proBNP), and renal insufficiency (by estimated glomerular filtration rate [eGFR])—and was validated in a series of analyses (Kaplan-Meier, concordance index, Cox proportional hazard model, and multivariate analysis).ResultsREVEAL Lite 2 approximates REVEAL 2.0 at discriminating low, intermediate, and high risk for 1-year mortality in patients in the REVEAL registry. The model indicated that the most highly predictive REVEAL Lite 2 parameter was BNP/NT-proBNP, followed by 6MWD and FC. Even if multiple, less predictive variables (heart rate, SBP, eGFR) were missing, REVEAL Lite 2 still discriminated among risk groups.InterpretationREVEAL Lite 2, an abridged version of REVEAL 2.0, provides a simplified method of risk assessment that can be implemented routinely in daily clinical practice. REVEAL Lite 2 is a robust tool that provides discrimination among patients at low, intermediate, and high risk of 1-year mortality.Trial RegistryClinicalTrials.gov; No.: NCT00370214; URL: www.clinicaltrials.gov;