Risk Stratification In Pulmonary Arterial Hypertension Research Articles

Risk assessment according to the presence of left heart disease phenotype in pulmonary arterial hypertension patients: a multicenter cohort study

Abstract Introduction Subclinical left heart disease (LHD) may impact the management of pulmonary arterial hypertension (PAH) [1]. Purpose To evaluate the influence of a LHD phenotype on PAH risk stratification. Methods We retrospectively reviewed the data of consecutive PAH patients followed at 7 tertiary centers from 2001 to 2021, and selected those with all parameters available to determine risk of death by means of the COMPERA and COMPERA 2.0 scores, both at baseline and at the first disease reassessment including right heart catheterization. These subjects were classified as no-LHD or LHD according to the AMBITION trial criteria, i.e. absence or presence, respectively, of ≥ 3 among body mass index ≥ 30 kg/m2, systemic hypertension, diabetes mellitus, and coronary artery disease; and/or pulmonary vascular resistance between 3 and 3.75 WU or between 3.75 and 6.25 WU together with pulmonary artery wedge pressure (PAWP) between 13 and 15 mmHg [2,3]. The characteristics between the 2 groups were compared by chi-square test, T-test, or Mann-Whitney test, and Kaplan-Meier curves for overall survival by log-rank test. Results Of 286 patients included in the analysis, 57 (20%) had a LHD phenotype. The first complete reassessment was performed 7 ± 5 months after baseline. Compared with no-LHD, subjects with LHD were older, had more often cardiovascular comorbidities, and had higher E/e’ ratio, left atrial area and PAWP, but had lower brain natriuretic peptide concentrations and better right ventricular function and pulmonary hemodynamics (Figure 1). They were also less commonly treated with phosphodiesterase inhibitors or riociguat (54% vs 70%, P=0.03) and dual oral therapy (26% vs 43%, P=0.03), while they used more beta-blockers (47% vs 16%, P<0.001) and ACE inhibitors or angiotensin receptor blockers (40% vs 21%, P=0.004). At baseline, the proportion of patients with low vs high risk was greater in LHD than in no-LHD with COMPERA, but not with COMPERA 2.0. Moreover, risk profile significantly improved during follow-up only in no-LHD with COMPERA, but in both groups with COMPERA 2.0 (Figure 1). While all-cause mortality was significantly different across baseline COMPERA and COMPERA 2.0 risk strata in no-LHD, either approach for risk stratification failed to discriminate LHD subgroups with different prognosis (Figure 2). However, both COMPERA and COMPERA 2.0 risk categories differentiated mortality in LHD at the first disease reassessment (log-rank P <0.001, not shown). Conclusions This study suggests that the performance of risk stratification scores COMPERA and COMPERA 2.0 in PAH subjects with a LHD phenotype is limited, although the former may retain value during follow-up. Alternative tools may be needed for prognostication in this patient subset.

Comparing the efficacy and safety of low, medium, and high dosages of selexipag for treating pulmonary hypertension: A systematic review and meta-analysis.

The maintenance dosage of selexipag is categorized as low, medium or high. In order to assess the efficacy and safety of different dosages of selexipag for the risk stratification of pulmonary arterial hypertension (PAH), we performed a systematic review and meta-analysis. Studies assessing PAH risk stratification indices, such as the World Health Organization functional class (WHO-FC), six-minute walk distance (6MWD), N-terminal pro-B-type natriuretic peptide (NT-proBNP) level, right atrial pressure (RAP), cardiac index (CI) and mixed venous oxygen saturation (SvO2), were included. Thirteen studies were included. Selexipag led to improvements in the 6MWD (MD: 24.20 m, 95% CI: 10.74-37.67), NT-proBNP (SMD: -0.41, 95% CI: -0.79-0.04), CI (MD: 0.47 L/min/m2, 95% CI: 0.17-0.77) and WHO-FC (OR: 0.564, 95% CI: 0.457-0.697). Subgroup analysis demonstrated that all three dosages improved the 6MWD. A moderate dosage led to improvements in the CI (MD: 0.30 L/min/m2, 95% CI: 0.15-0.46) and WHO-FC (OR: 0.589, 95% CI: 0.376-0.922). Within 6 months of treatment, only the WHO-FC and CI were significantly improved (OR: 0.614, 95% CI: 0.380-0.993; MD: 0.30 L/min/m2, 95% CI: 0.16-0.45, respectively). More than 6 months of treatment significantly improved the 6MWD, WHO-FC and NT-proBNP (MD: 40.87 m, 95% CI: 10.97-70.77; OR: 0.557, 95% CI: 0.440-0.705; SMD: -0.61, 95% CI: -1.17-0.05, respectively). Low, medium, and high dosages of selexipag all exhibited good effects. When treatment lasted for more than 6 months, selexipag exerted obvious effects, even in the low-dosage group. This finding is important for guiding individualized treatments.

Preliminary findings from a risk stratification, quality of life and burden of illness in pulmonary arterial hypertension pilot study

Abstract Funding Acknowledgements Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Janssen Australia and New Zealand (Janssen-Cilag Pty Ltd) Pulmonary Arterial Hypertension (PAH) management strategies focus on lowering mortality risk, extending the patient’s life span through the control and alleviation of disease symptoms, improving Quality of Life (QoL) and decreasing the burden of illness. This paper describes preliminary results of an Investigator Initiated pilot study exploring the relationship between PRO measures (PAH-SYMPACT, EQ5D5L); Burden of Illness assessment; and the ESC/ERS Risk Stratification. Findings Measures of PAH risk and QoL were assessed in 42 patients presenting to the IPAH clinic for management; mean age 69.2 [range 39, 84]; females 35 (83.3%), males 7 (16.7%). Tools analysed and compared included: PAH-SYMPACT and EQ-5D-5L as PRO and QoL measures; and ESC-ERS PAH risk stratification criteria to assess mortality risk. Health utility scores were derived from existing value sets: there was a 20% median reduction in QALYs for our patient population, with detrimental effects being more marked in those patients with greater impairment of EQ-5D-5L physical and cognitive-emotional domains (respectively: r = -0.92, p<0.001; and r = -0.85, p<0.001), PAH-SYMPACT physical domain reduction (r = -0.59, p<0.01), and PAH-SYMPACT cardiovascular symptoms (r = 0.64), p<0.01) and cardiorespiratory (r = 0.64, p<0.01) involvement. Physical domain scores were highly correlated for the two PROs studied (r = 0.74, p<0.001), but an unexpected poor correlation was seen in the cognitive/emotional domain (non-significant negative correlation) which requires further exploration. Unsurprisingly, EQ-5D-5L Visual Analogue Score for well-being was inversely correlated with physical domain impairment (r = -0.59, p<0.01), although it was noted that this did not apply for the cognitive/emotional domain. The agreement between tools was variable, with highest concordance seen for assessment of the physical domain (r = 0.74, p<0.001), and this raises the need to further define the merits of disease-specific (PAH-SYMPACT) vs generic (EQ-5D-5L) PRO analytic approaches. Tools examined in this study were well-correlated with symptomatic impairment, but neither PRO tool correlated with established risk markers as characterized in compound prognostic guides such as ESC-ERS criteria. Conclusions The fact that PRO indices showed little correlation with established risk stratification markers implies that the information provided by PROs is not redundant, and it is yet be assessed whether the incorporation of PRO’s may add further to the precision of risk assessment, a little-studied area which this group is further exploring. There should be more widespread and uniform use of PRO measures as part of standard PAH management.

The Role of Strain by Cardiac Magnetic Resonance Imaging in Predicting the Prognosis of Patients with Chronic Thromboembolic Pulmonary Hypertension.

Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by thrombotic obstruction of the pulmonary arteries, and right ventricular (RV) dysfunction is a major cause of death. Cardiac magnetic resonance (CMR) is the gold standard for assessing heart wall deformation; therefore, we aimed to determine the prognostic value of CMR strain in patients with CTEPH. Strain derived by CMR was measured at the time of diagnosis in 45 patients with CTEPH, and the relationship between RV strain and prognosis was determined through follow-up. The value of RV strain in the prognostic model was compared with that of pulmonary arterial hypertension (PAH) risk stratification. The RV global peak longitudinal strain (GLS) and global peak circumferential strain (GCS) in CTEPH patients were lower than the normal references of RV strain in the control group. GLS and longitudinal strain in the basal segment were independent risk factors for adverse events (P < .050). Adding CMR parameters to PAH risk stratification improved its predictive power in patients with CTEPH. GLS and GCS scores were impaired in patients with chronic RV overload. RV strain derived by CMR imaging is a promising noninvasive tool for the follow-up of patients with CTEPH.

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)

Risk Stratification of Patients with Pulmonary Arterial Hypertension: The Role of Echocardiography.

Background: Given the morbidity and mortality associated with pulmonary arterial hypertension (PAH), risk stratification approaches that guide therapeutic management have been previously employed. However, most patients remain in the intermediate-risk category despite initial therapy. Herein, we sought to determine whether echocardiographic parameters could improve the risk stratification of intermediate-risk patients. Methods: Prevalent PAH patients previously enrolled in observational studies at 3 pulmonary hypertension centers were included in this study. A validated PAH risk stratification approach was used to stratify patients into low-, intermediate-, and high-risk groups. Right ventricular echocardiographic parameters were used to further stratify intermediate-risk patients into intermediate-low- and intermediate-high-risk groups based on transplant-free survival. Results: From a total of 146 patients included in our study, 38 patients died over a median follow-up of 2.5 years. Patients with intermediate-/high-risk had worse echocardiographic parameters. Tricuspid annular plane systolic excursion (TAPSE) and the degree of tricuspid regurgitation (TR) were highly associated with survival (p < 0.01, p = 0.04, respectively) and were subsequently used to further stratify intermediate-risk patients. Among intermediate-risk patients, survival was worse for patients with TAPSE < 19 mm compared to those with TAPSE ≥ 19 mm (estimated one-year survival 74% vs. 96%, p < 0.01) and for patients with moderate/severe TR compared to those with no/trace/mild TR (estimated one-year survival 70% vs. 93%, p < 0.01). Furthermore, among intermediate-risk patients, those with both TAPSE < 19 mm and moderate/severe TR had an estimated one-year survival (56%) similar to that of high-risk patients (56%), and those with both TAPSE ≥ 19 mm and no/trace/mild TR had an estimated one-year survival (97%) similar to that of low-risk patients (95%). Conclusions: Echocardiography, a routinely performed, non-invasive imaging modality, plays a pivotal role in discriminating distinct survival phenotypes among prevalent intermediate-risk PAH patients using TAPSE and degree of TR. This can potentially help guide subsequent therapy.

The role of serial right heart catheterization in risk stratification and management of pulmonary arterial hypertension

Introduction Pulmonary arterial hypertension (PAH) is characterized by elevated pulmonary arterial blood pressure secondary to increased pulmonary vascular resistance. Despite the advances in medical therapy, PAH continues to be a significant cause of morbidity and mortality. Areas covered Invasive hemodynamic assessment by performing a right heart catheterization (RHC) remains the gold standard to confirm the diagnosis and further management of PAH. The RHC also helps to determine the severity of RV dysfunction and can be used to test for pulmonary vasoreactivity. After diagnosis and initiation of therapy, many PAH centers continue to perform RHC at regular intervals to monitor for disease progression and alter management. In this review, we discuss the importance of risk stratification in PAH, the role of RHC in the evaluation and treatment of these patients and compare non-invasive risk assessment tools to that of RHC. Expert opinion RHC is useful for diagnosis of PAH, assessing the risk of mortality and morbidity, directing the escalation and de-escalation of therapy, and monitoring for disease progression. In the current era of improved non-invasive cardiac hemodynamic assessment, the role for routine follow-up serial RHC in patients with PAH needs to be reassessed in future studies. With the availability of non-invasive risk assessment tools such as REVEAL Lite 2, it may be reasonable to reconsider the role of annual or protocoled RHC, and instead, move to an “as needed” and individual basis.

Inclusion of echocardiographic measure of right ventricular function in the non-invasive French pulmonary arterial hypertension risk stratification method

Although preserved right ventricular (RV) function is consistently associated with better survival in pulmonary arterial hypertension (PAH), the French risk assessment method has not yet considered echocardiographic criteria of RV function. In the present study, we tested the value of tricuspid annular plane systolic excursion (TAPSE) measured by echocardiography for non-invasive PAH risk assessment. We retrospectively studied a cohort of 306 incident PAH patients treated in two French expert centers who underwent follow-up TAPSE measurement from echocardiographic apical 4-chamber view in addition to previously validated invasive and non-invasive risk stratification variables. The primary composite outcome was 3-year lung transplantation free survival after follow-up assessment. At re-evaluation, 66% of patients were in NYHA functional class I-II and mean pulmonary arterial pressure, cardiac index, N-Terminal pro brain natriuretic peptide (NTproBNP), and 6-minute walk distance (6MWD) were 40 ± 16 mmHg, 3.5 ± 1.1 L/min/m 2 , 270 [interquartile range (IQR) 896] ng/L and 401 (IQR 213) meters, respectively. The primary outcome occurred in 58 (19%) patients. In multivariable Cox regression analysis, NYHA functional class I-II ( P = 0.02), NTproBNP < 300 ng/L or BNP < 50 ng/L ( P = 0.02), 6MWD > 440 m ( P = 0.049) and TAPSE≥17 mm ( P = 0.02) were associated with lung transplantation free survival. TAPSE provided similar information over 6MWD when both were used alternatively to stratify PAH patients at low risk (log-rank < 0.001); Harrell's c-index 0.73 ( Fig. 1 ). Three dichotomized low-risk criteria (TAPSE, 6MWD and NTproBNP or BNP plasma levels) allow non-invasive risk assessment in PAH.

Plasma matrix metalloproteinase 2 is associated with severity and mortality in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a life‐threatening disease characterized by vasoconstriction and remodeling of the pulmonary vessels. Risk stratification in PAH could potentially be improved by including novel biomarkers related to PAH pathobiology. We aimed to investigate the relationship between extracellular matrix (ECM)‐related proteins, survival, and European Society of Cardiology and European Respiratory Society (ESC/ERS) risk stratification scores in patients with PAH. Plasma samples and hemodynamics were collected from PAH patients during right heart catheterizations at diagnosis (n = 48) and early follow‐up, after treatment initiation (n = 33). Plasma levels of 14 ECM‐related proteins, with altered levels in PAH compared to healthy controls, were analyzed with proximity extension assays, and related to hemodynamics, transplant‐free survival time, and ESC/ERS risk score. Glypican‐1 levels were higher before versus after treatment initiation (p = 0.048). PAH patients with high plasma levels of matrix metalloproteinase (MMP) ‐2, MMP‐7, MMP‐9, MMP‐12, perlecan, and tissue inhibitor of metalloproteinase 4 (TIMP‐4) at baseline, had worse transplant‐free survival (p < 0.03) than patients with low levels. Hazard ratio (95% confidence interval) was for MMP‐2 1.126 (1.011–1.255), perlecan 1.0099 (1.0004–1.0196), and TIMP‐4 1.037 (1.003–1.071) in age and sex‐adjusted Cox‐regression model. MMP‐2 correlated with ESC/ERS risk scores (r s = 0.34, p = 0.019), mean right atrial pressure (r s = 0.44, p = 0.002), NT‐proBNP (r s = 0.49, p ≤ 0.001), and six‐minute walking distance (r s = −0.34, p = 0.02). The present study indicates that high levels of MMP‐2, perlecan, and TIMP‐4 are associated with poor survival in PAH. High plasma MMP‐2, correlated with poor prognosis in PAH. Further validation in larger studies is needed to better determine this association.

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.

Longitudinal echocardiographic evaluation predicts transplant-free survival better than baseline evaluation among PAH patients

In pulmonary arterial hypertension (PAH), patients are serially investigated to stratify their risk of death and pulmonary transplantation with better discrimination at follow-up than baseline. The question whether right ventricular (RV) function by transthoracic echocardiography (TTE) is of prognostic significance at baseline or during follow-up is unanswered. To investigate the prognosis of PAH patients with several indices of RV size and function determined both at baseline and follow-up. Between 2002 and 2019, 126 PAH patients were included and treated in a single PAH center according to guidelines. In addition to regular risk stratification parameters, the following RV echocardiographic indices were measured at baseline and at 1-y follow-up: Tricuspid Annular Plane Systolic Excursion by M-mode (TAPSE, mm), RV annular peak systolic tissue Doppler S wave (S-TDI, cm/s), RV fractional area change (RV-FAC), RV end-diastolic area (RV-EDA), and the ratio of TAPSE/systolic pulmonary arterial pressure. Primary endpoints were death from all-cause or pulmonary transplantation. A majority (63%) were female, mean age 59 ± 18 yo. Baseline mean PAP was 42 (33, 52) mmHg from mainly due to idiopathic (28%) and connectivite tissue disease (24%). Under PAH treatment, NYHA (P < 0.01), NT-proBNP (P < 0.001) significantly improved. TAPSE (P < 0.01), S-TDI (P < 0.01), RV-FAC (P < 0.01) as well as TAPSE/systolic pulmonary arterial pressure (P = 0.03) were also improved. 24 patients died while 1 patient were transplanted at 3y F/U. At baseline, none of the echocardiographic indices were associated with the primary endpoint whereas TAPSE, S-TDI, RV-EDA as well as TAPSE/systolic pulmonary arterial pressure but not RV-FAC were of prognostic significance from Cox proportional hazard (Table 1). Right ventricular function by transthoracic echocardiography must be investigated at follow-up rather than baseline for PAH risk stratification.

A Feasibility Study on Using Single-Photon Emission Computed Tomography Pulmonary Perfusion/Ventilation Imaging for the Diagnosis of Chronic Thromboembolic Pulmonary Hypertension and Patient Risk Assessment.

ObjectiveThe study is designed to evaluate the diagnostic ability of single-photon emission computed tomography (SPECT) pulmonary ventilation/perfusion (V/Q) imaging in patients with chronic thromboembolic pulmonary hypertension (CTEPH) and investigate its feasibility in assessing patient risk.MethodsA total of 83 patients suspected of having CTEPH who received V/Q tomography were retrospectively analyzed. The consistency between SPECT V/Q imaging and pulmonary angiography was compared to investigate the correlation between the percentage of pulmonary perfusion defect score (PPDs%) and the hemodynamic indices. Patients were grouped according to the pulmonary arterial hypertension risk stratification, and the V/Q imaging results were compared between different groups.ResultsFor the 1494 pulmonary segments of the 83 patients, the sensitivity, specificity, and accuracy of identifying pulmonary segments with defects using V/Q imaging was 87.05%, 82.78% (668/807), and 84.74% (1266/1494), respectively. The average PPDs% (58.8 ± 12.6%) was positively correlated with the mean pulmonary arterial pressure (mPAP), pulmonary vascular resistance (PVR), and right ventricular pressure (RVP; r =0.316, 0.318, and 0.432, respectively; P < 0.05) and negatively correlated with the six-minute walk distance (6MWD; r = −0.309; P < 0.05). There were 37 patients in the low-risk group and 46 in the medium-high-risk group. The number of pulmonary segments with perfusion defects (NPSPDs) and PPDs% were higher in the medium-high risk than in the low-risk group (t = −6.721, −5.032; P < 0.05). In the low- and medium-high-risk groups, the cut-off values for the NPSPDs (7.2 ± 2.1 and 10.2 ± 2.0) and PPDs% (51.9 ± 11.1% and 64.3 ± 11.1%,) were 8.5 and 61.25%, respectively.ConclusionSPECT V/Q imaging achieved an accurate diagnosis of CTEPH. The semi-quantitative analysis index (PPDs%) was correlated with the hemodynamic indices and 6MWD. SPECT V/Q could be used for the preoperative risk assessment of patients with CTEPH.

Inclusion of echocardiographic measure of right ventricular function in the non-invasive French pulmonary arterial hypertension risk stratification method

Abstract Background Although preserved right ventricular (RV) function is consistently associated with better survival in pulmonary arterial hypertension (PAH), the French risk assessment method has not yet considered echocardiographic criteria of RV function. Purpose In the present study, we tested the value of tricuspid annular plane systolic excursion (TAPSE) measured by echocardiography for non-invasive PAH risk assessment. Methods We retrospectively studied a cohort of 306 incident PAH patients treated in two French expert centers who underwent follow-up TAPSE measurement from echocardiographic apical 4-chamber view in addition to previously validated invasive and non-invasive risk stratification variables. The primary composite outcome was 3-year lung transplantation free survival after follow-up assessment. Results At re-evaluation, 66% of patients were in NYHA functional class I-II and mean pulmonary arterial pressure, cardiac index, N-Terminal pro brain natriuretic peptide (NTproBNP), and 6-minute walk distance (6MWD) were 40±16 mmHg, 3.5±1.1 L/min/m2, 270 [interquartile range (IQR) 896] ng/L and 401 (IQR 213) meters, respectively. The primary outcome occurred in 58 (19%) patients. In multivariable Cox regression analysis, NYHA functional class I-II (p=0.02), NTproBNP &amp;lt;300 ng/L or BNP &amp;lt;50 ng/L (p=0.02), 6MWD &amp;gt;440m (p=0.049) and TAPSE≥17 mm (p=0.02) were associated with lung transplantation free survival. TAPSE provided similar information over 6MWD when both were used alternatively to stratify PAH patients at low risk (log-rank&amp;lt;0.001); Harrell's c-index 0.73. Conclusion Three dichotomized low-risk criteria (TAPSE, 6MWD and NTproBNP or BNP plasma levels) allow non-invasive risk assessment in PAH. Funding Acknowledgement Type of funding sources: None. 3-years transplant-free survival

Children with Bronchopulmonary Dysplasia-Associated Pulmonary Hypertension Treated with Pulmonary Vasodilators-The Pediatric Cardiologist Point of View.

Pulmonary hypertension in children with bronchopulmonary dysplasia (BPD-PH) significantly worsens the prognosis. Pulmonary vasodilators are often used in BPD-PH but the short-term outcome of treatment is not well described. The aim of this study was to evaluate BPD-PH children diagnosed beyond 36 weeks postmenstrual age treated with pulmonary vasodilators (sildenafil, bosentan, or both) and to assess the short and long-term effect of oral pulmonary vasodilators treatment. Twenty patients were included in the study. Cardiology evaluation (WHO-FC, NTproBNP, oxygen saturation, pulmonary to systemic pressure ratio PAP/SAP) was performed at diagnosis and after treatment initiation. In the majority of patients improvement in all evaluated factors was observed. No side effects of vasodilators were observed. PH resolved in 10 patients after a mean of 21.4 months of treatment. Six patients died. The number of poor prognostic factors commonly used to assess patients with pulmonary arterial hypertension (PAH) decreased significantly during BPD-PH treatment. The influence of BPD-PH perinatal risk factors on prognosis was considered but was not confirmed. In conclusion, the treatment of BPD-PH with pulmonary vasodilators was well tolerated and led to a clinical improvement with the possibility of discontinuation without recurrence of PH. Prognostic factors used in pediatric PAH risk stratification also seem to be useful in assessing treatment efficacy and prognosis in patients with BPD-PH.

Hemodynamic Parameters in Predicting Survival in Pulmonary Arterial Hypertension

<h3>Purpose</h3> Hemodynamics are considered to be extremely relevant when clinically assessing patients with pulmonary arterial hypertension (PAH), especially for estimating prognosis. Yet, inclusion of hemodynamic data in PAH risk-stratification remains inconsistent and controversial, having been derived from limited data-sets. <h3>Methods</h3> We analyzed hemodynamic variables obtained at baseline in 4 PAH clinical trials: SERAPHIN, BREATHE-1, PATENT-2 and the subcutaneous treprostinil study; and at follow-up from SERAPHIN (week 26), PATENT-2 (week12), and the subcutaneous treprostinil study (week12). Primary outcome analyzed was mortality at <i>time to event</i> noted in each individual trial. Only the significant p-values (p-value<0.05) of each hemodynamic variable were aggregated across the clinical trials using Stouffer's method, weighed by their ‘n' in clinical trials. Then, we converted the aggregated p-value for each hemodynamic into a prioritization matrix (a sig. Stouffer's w) using the logarithmic function, for visualization. A sig. Stouffer's w of 1.3 is equivalent to a p-value = 0.05, with higher values being increasingly significant. <h3>Results</h3> Collective data from 2,211 patients were available at baseline and for 1,487 patients at follow-up. 30 hemodynamic variables (a combination of calculated and derived data) were considered for this analysis. At baseline, the most significant variables predictive of primary outcomes were PA sat, stroke work, stroke volume, stroke volume index and pulmonary arterial elastance (more reflective of output). At follow-up, the most predictive variables were PA sat, total pulmonary resistance, pulmonary vascular resistance, pulmonary arterial elastance, and right atrial pressure (more reflective of RV afterload) <h3>Conclusion</h3> To our knowledge, this is the largest aggregated attempt to analyze hemodynamic parameters in predicting survival. This analysis will be used to select features for derivation of machine-learned PAH patient risk stratification models.

Prognostic Value of Early Risk Stratification in Pediatric Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a life-threatening disease with risk stratification-based treatment strategy in adults. Although the risk factors have been studied individually in children, effective risk stratification is still lacking. We have tested the prognostic accuracy of pediatric PAH risk factors in our patient group. Records of 58 PAH patients treated between 1995 and 2019 were reviewed retrospectively. Median age at diagnosis was 4.2 years (range, 0.1-16.1 years), and follow-up was 5.4 years (range, 0.01-24.1 years). Data collected at diagnosis were demographics, World Health Organization functional class, evidence of right ventricular failure, and parameters of echocardiography and cardiac catheterization. Mortality was 29% and 33% reached the composite endpoint. Patients with idiopathic PAH (n=12) had increased risk of mortality compared with the congenital heart disease-associated PAH group (n=32) (P=.0024). Neither the initial World Health Organization functional class staging nor the echocardiographic parameters significantly predicted the prognosis. The number of risk factors had no significant prognostic value either. In contrast, patients with higher pulmonary vascular resistance index (PVRI) had significantly increased risk (each 10 Wood units ⋅ m2 increase in PVRI being associated with 49.1% higher hazard, P=.0048). Survival analysis showed that PAH etiology might be an important determinant in pediatric PAH risk stratification. We confirmed that PVRI has predictive value in prognostic assessment. We could not establish the prognostic value of nonweighted single risk factors or their combination to predict pediatric PAH outcome due to the low sample size, but these results indicate that such studies are warranted.

The Growing Role of Echocardiography in Pulmonary Arterial Hypertension Risk Stratification: The Missing Piece.

Pulmonary arterial hypertension (PAH) is a rare, progressive disease with a poor prognosis. The pathophysiologic model is mainly characterized by an afterload mismatch in which an increased right ventricle afterload, driven by increased pulmonary vascular resistance (PVR), leads to right heart failure. International guidelines recommend optimization of treatment based on regular risk assessments to achieve or maintain a low-risk status. Current risk scores are based on a multi-modality approach, including demographic, clinical, functional, exercise, laboratory, and hemodynamic parameters, which lack significant echocardiographic parameters. The originality of echocardiography relies on the opportunity to assess in a non-invasive way a physiologically meaningful combination of easy to measure variables tightly related to right ventricle adaptation/maladaptation to increased afterload, the main determinant of a patient’s prognosis. Echo-derived morphological and functional parameters have been investigated in PAH, proving to have prognostic relevance. Different therapeutic strategies proved to have different effects in reducing PVR. An upfront combination of drugs, including a parenteral prostacyclin, has shown to be associated with right heart reverse remodeling in a greater proportion of patients than other treatment strategies as a function of PVR reduction. Adding echocardiographic data to current risk scores would allow better identification of right ventricle (RV) adaptation in PAH patients’ follow-up. This additional information would allow better stratification of the patient, leading to optimized and personalized therapeutic management.

Factors associated with incident severe pulmonary arterial hypertension in systemic autoimmune rheumatic diseases: a nationwide study.

To assess the association of severe pulmonary arterial hypertension (PAH) with particulate matter <2.5 μm (p.m.2.5) and clinical data in patients with systemic autoimmune rheumatic diseases (SARDs). We used the 2003-2017 nationwide data in Taiwan to identify patients with SARDs, including systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, dermatomyositis/polymyositis and primary Sjögren's syndrome. We identified 479 cases with severe PAH and selected controls matched (1:4) for age, sex, and index year. We used conditional logistic regression analysis to determine factors associated with risks for severe PAH shown as odds ratios (ORs) with 95% confidence intervals (CIs). We found that severe PAH was highly associated with interstitial lung disease (OR, 8.57; 95% CI: 5.52, 13.32), congestive heart failure (OR, 7.62; 95% CI: 5.02, 11.55), valvular heart disease (OR, 3.34; 95% CI: 2.03, 5.50) and slightly associated with thyroid diseases (OR, 1.88; 95% CI: 1.18, 3.00), but not the level of exposure to p.m.2.5. Increased risk for PAH was found in patients receiving corticosteroid (prednisolone equivalent dosage, mg/day, OR, 1.03; 95% CI: 1.01, 1.05), biologics (OR, 2.18; 95% CI: 1.15, 4.12) as well as immunosuppressants, including ciclosporin (OR, 2.17; 95% CI: 1.31, 3.59), azathioprine (OR, 1.96; 95% CI: 1.48, 2.61), cyclophosphamide (OR, 2.01; 95% CI: 1.30, 3.11) and mycophenolate mofetil/mycophenolic acid (OR, 2.42; 95% CI: 1.37, 4.27), and those with the highest level of insured amount (reference, lowest level; OR, 0.53; 95% CI: 0.34, 0.83). The population-based study identified risks for severe PAH in patients with SARDs, and these findings provide evidence for PAH risk stratification in patients with SARDs.

Plasma proteoglycan prolargin in diagnosis and differentiation of pulmonary arterial hypertension.

AimsRight ventricular dysfunction may arise because of pulmonary arterial hypertension (PAH). Development of new diagnostic methods able to identify PAH and allow for earlier treatment initiation, before the development of vascular remodelling and manifest right heart failure (HF), could potentially improve prognosis. Proteoglycans and inflammatory proteins are involved in vascular remodelling. We aimed to investigate their potential as biomarkers to differentiate PAH in a dyspnoeic population.Methods and resultsPlasma from 152 patients with PAH (n = 48), chronic thrombo‐embolic pulmonary hypertension (n = 20), pulmonary hypertension due to HF with reduced (n = 36) or preserved (n = 33) ejection fraction, and HF without pulmonary hypertension (n = 15) and 20 healthy controls were analysed with proximity extension assays. Haemodynamics were assessed in the patients with right heart catheterization. Plasma prolargin levels in PAH were lower compared with all the other studied disease groups (P < 0.001) but higher than the controls' levels (P = 0.003). Receiver operating characteristic curve of prolargin as a PAH‐differentiating marker in a pooled population, encompassing all the other studied disease groups, had a sensitivity of 74% and a specificity of 83.3% (area under the curve = 0.84, P < 0.001). Prolargin correlated with the mean right atrial pressure (r s = 0.65, P < 0.001), N‐terminal pro‐brain natriuretic peptide (r s = 0.64, P < 0.001), cardiac index (r s = −0.31, P = 0.029), stroke volume index (r s = −0.41, P = 0.004), right ventricular stroke work index (r s = −0.31, P = 0.032), six‐minute walking distance (r s = −0.41, P = 0.005), and mixed venous blood oxygen saturation (r s = −0.42, P = 0.003).ConclusionsPlasma prolargin levels differentiate PAH patients from controls and the other investigated dyspnoea groups including HF. Its potential in PAH differentiation may be enhanced by inclusion in a multi‐marker panel. Larger studies are needed to evaluate its discriminative ability of PAH in relation to other dyspnoea aetiologies and its potential role in PAH risk stratification and pathobiology.

Goal-oriented treatment strategy in PAH patients: TAPSE does as well as published guidelines to achieve a 1-year mortality below 5%

Using multiparametric approach, pulmonary arterial hypertension (PAH) treatment is goal-oriented to get an estimated 1-year mortality below 5 %. Yet, transthoracic echocardiography (TTE) interest in a goal-oriented treatment strategy remains sparse. We aimed to investigate whether the non-invasive serial assessment of several parameters by TTE may help to achieve this goal. Between 2002 and 2019, all consecutive PAH patients were included and treated in a single PAH centre, using the current guidelines. As recommended, patients were reassessed within a year for PAH risk stratification. In addition to regular parameters, thirteen right ventricular TTE indices and their changes were either measured. Primary composite outcome was 3-years all-cause mortality or pulmonary transplantation. We used supervised machine learning with conditional inference tree, which provides more information than Cox Proportional analysis to link TTE parameters to risk stratification and to determine cut-off values from hierarchy of multiple covariates. Next, survival analysis was performed using Kaplan–Meier curves (log-rank test). In total, 126 patients were included (63% female, mean age 59 ± 18 y). At baseline, 70% were in NYHA functional class 3 or 4. Mean pulmonary arterial pressure, 6-min walking distance and NT-pro-BNP levels averaged 45 ± 17 mmHg, 290 ± 136 m and 2127 ± 3438 ng/L, respectively. From conditional inference tree, TAPSE increase > 0 mm ( P < 0.01), tricuspid S wave increase > 1 cm/s ( P < 0.01) and RV end-diastolic area decrease > 2 cm 2 ( P < 0.01) at 1-year were of prognostic significance, even after adjustment to their baseline value. One, two and 3-year mortality rate with TAPSE improvement is 3.6%, 18.2%, 29.2%, respectively ( Fig. 1 ). One-year TAPSE improvement (> 0 mm) under vasodilatation therapy in PAH should be a new goal-oriented treatment strategy to get an estimated 1-year mortality below 5%, especially when regular parameters are challenging.