Tadalafil for Treatment of Combined Postcapillary and Precapillary Pulmonary Hypertension in Patients With Heart Failure and Preserved Ejection Fraction: A Randomized Controlled Phase 3 Study.

BACKGROUND: We assessed the efficacy and safety of tadalafil, a phosphodiesterase type 5 inhibitor, in patients with heart failure with preserved ejection fraction and combined postcapillary and precapillary pulmonary hypertension. METHODS: In the double-blind PASSION study (Phosphodiesterase-5 Inhibition in Patients With Heart Failure With Preserved Ejection Fraction and Combined Post- and Pre-Capillary Pulmonary Hypertension), patients with heart failure with preserved ejection fraction and combined postcapillary and precapillary pulmonary hypertension were randomized 1:1 to receive tadalafil at a target dose of 40 mg or placebo. The primary end point was the time to the first composite event of adjudicated heart failure hospitalization or all-cause death. Secondary end points included all-cause mortality and improvements in New York Heart Association functional class or ≥10% improvement in 6-minute walking distance from baseline. RESULTS: Initially targeting 372 patients, the study was terminated early because of disruption in study medication supply. At that point, 125 patients had been randomized (placebo: 63; tadalafil: 62,). Combined primary end-point events occurred in 20 patients (32%) assigned to placebo and 17 patients (27%) assigned to tadalafil (hazard ratio, 1.02 [95% CI, 0.52-2.01]; P=0.95). There was a possible signal of higher all-cause mortality in the tadalafil group (hazard ratio, 5.10 [95% CI, 1.10-23.69]; P=0.04). No significant between-group differences were observed in other secondary end points. Serious adverse events occurred in 29 participants (48%) in the tadalafil group and 35 (56%) in the placebo group. CONCLUSIONS: The PASSION trial, terminated prematurely due to study medication supply disruption, does not support tadalafil use in patients with heart failure with preserved ejection fraction and combined postcapillary and precapillary pulmonary hypertension, with potential safety concerns and no observed benefits in primary and secondary end points. REGISTRATION: URL: https://www.clinicaltrialsregister.eu/; Unique identifier: 2017-003688-37. URL: https://drks.de; Unique identifier: DRKS -DRKS00014595.

High Prevalence and Clinical Relevance of Intrapulmonary Vascular Dilatations in Patients Undergoing TIPS Implantation.

BACKGROUND & AIMS: Considerate patient selection is vital to ensure the best possible outcomes after transjugular intrahepatic portosystemic shunt (TIPS) insertion. However, data regarding the impact of intrapulmonary vascular dilatations (IPVDs) or hepatopulmonary syndrome (HPS) on the clinical course after TIPS implantation is lacking. Hence, this study aimed to investigate the relevance of IPVD and HPS in patients undergoing TIPS implantation. METHODS: Contrast enhanced echocardiography and blood gas analysis were utilized to determine presence of IPVD and HPS. Multivariable competing risk analyses were performed to evaluate cardiac decompensation (CD), hepatic decompensation (HD), and liver transplant (LTx)-free survival within 1 year of follow-up. RESULTS: Overall, 265 patients were included, of whom 136 had IPVD and 71 fulfilled the HPS criteria. Patients with IPVD had lower Freiburg index of post-TIPS survival (FIPS) scores, lower creatinine, and more often received TIPS because of variceal bleeding. Presence of IPVD was associated with a significantly higher incidence of CD (hazard ratio [HR], 1.756; 95% confidence interval [CI], 1.011-3.048; P = .046) and HD (HR, 1.841; 95% CI, 1.255-2.701; P = .002). However, LTx-free survival was comparable between patients with and without IPVD (HR, 1.081; 95% CI, 0.630-1.855; P = .780). Patients with HPS displayed a trend towards more CD (HR, 1.708; 95% CI, 0.935-3.122; P = .082) and HD (HR, 1.458; 95% CI, 0.934-2.275; P = .097) that failed to reach statistical significance. LTx-free survival did not differ in those with HPS compared with patients without HPS, respectively (HR, 1.052; 95% CI, 0.577-1.921; P = .870). CONCLUSION: Screening for IPVD before TIPS implantation could help to further identify patients at higher risk of CD and HD.

Doppler-derived pulmonary pulse transit time measurements in chronic obstructive pulmonary disease: Reproducibility and cardiopulmonary function.

INTRODUCTION: Doppler-derived pulmonary pulse transit time (pPTT) is an auspicious hemodynamic marker in chronic pulmonary diseases. The aim is to compare four distinct pPTT measurements and its relation to right cardiac and pulmonary function. METHODS: Prospectively, 25 chronic obstructive pulmonary disease (COPD) patients (four patients excluded) and 32 healthy subjects underwent repeated distinct pPTT measurements, standard echocardiography, and pulmonary function testing on the same day. pPTT was defined as the interval from the R or Q-wave in the electrocardiogram to the corresponding pulse wave Doppler peak late systolic (S) 2 or diastolic (D) pulmonary vein flow velocity (pPTT R-S, Q-S, R-D, Q-D). Reproducibility was assessed using Bland-Altman analysis, coefficient of variation (COV), intraclass correlation coefficient (ICC), and power calculations. Associations with right ventricular RV tissue and pulse wave Doppler velocities (RV E', RV S', RV A', RV E, RV A, RV E/E', RV E/A), TAPSE, right ventricular fractional area change, left ventricular systolic and diastolic function (LV ejection fraction, E, A, E/A, E/E', septal E', lateral E'), LA diameters, as well as forced expiratory volume in 1 s, forced vital capacity (FVC) predicted (%), and in liters were analyzed. RESULTS: There was no significant difference and no bias between pPTT measures (p range: .1-.9). COV was in COPD 1.2%-2.3%, in healthy subjects 1.0%-3.1%. ICC ranged from .92 (COPD) to .96 (healthy subjects). In COPD significant correlations were found for pPTT R-S, Q-S and R-D with RV E`, (all > ρ: .49, < p = .0364), pPTT R-S, Q-S with RV E/E` (both > ρ: .49, < p = .0291), pPTT Q-S with RV S´ (ρ: .58, p = .0134), RV A (ρ: .59, p = .0339) and heart rate > ρ: -.39, < p = .0297). pPTT R-S, R-D showed significant correlations with FVC predicted (%) (ρ: .48 p = .0224) and FVC (l) (ρ:.47 p = .0347). CONCLUSIONS: All pPTT measures exhibited high reproducibility. In COPD patients pPTT measures correlate with diastolic right ventricular function. Defining Q as starting point seems clinically advantageous considering electromechanical desynchrony in patients with conduction disorders.

Positive Vasoreactivity Testing in Pulmonary Arterial Hypertension: Therapeutic Consequences, Treatment Patterns, and Outcomes in the Modern Management Era.

BACKGROUND: Among patients with pulmonary arterial hypertension (PAH), acute vasoreactivity testing during right heart catheterization may identify acute vasoresponders, for whom treatment with high-dose calcium channel blockers (CCBs) is recommended. However, long-term outcomes in the current era remain largely unknown. We sought to evaluate the implications of acute vasoreactivity response for long-term response to CCBs and other outcomes. METHODS: Patients diagnosed with PAH between January 1999 and December 2018 at 15 pulmonary hypertension centers were included and analyzed retrospectively. In accordance with current guidelines, acute vasoreactivity response was defined by a decrease of mean pulmonary artery pressure by ≥10 mm Hg to reach <40 mm Hg, without a decrease in cardiac output. Long-term response to CCBs was defined as alive with unchanged initial CCB therapy with or without other initial PAH therapy and World Health Organization functional class I/II and/or low European Society of Cardiology/European Respiratory Society risk status at 12 months after initiation of CCBs. Patients were followed for up to 5 years; clinical measures, outcome, and subsequent treatment patterns were captured. RESULTS: Of 3702 patients undergoing right heart catheterization for PAH diagnosis, 2051 had idiopathic, heritable, or drug-induced PAH, of whom 1904 (92.8%) underwent acute vasoreactivity testing. A total of 162 patients fulfilled acute vasoreactivity response criteria and received an initial CCB alone (n=123) or in combination with another PAH therapy (n=39). The median follow-up time was 60.0 months (interquartile range, 30.8-60.0), during which overall survival was 86.7%. At 12 months, 53.2% remained on CCB monotherapy, 14.7% on initial CCB plus another initial PAH therapy, and the remaining patients had the CCB withdrawn and/or PAH therapy added. CCB long-term response was found in 54.3% of patients. Five-year survival was 98.5% in long-term responders versus 73.0% in nonresponders. In addition to established vasodilator responder criteria, pulmonary artery compliance at acute vasoreactivity testing, low risk status and NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels at early follow-up correlated with long-term response and predicted survival. CONCLUSIONS: Our data display heterogeneity within the group of vasoresponders, with a large subset failing to show a sustained satisfactory clinical response to CCBs. This highlights the necessity for comprehensive reassessment during early follow-up. The use of pulmonary artery compliance in addition to current measures may better identify those likely to have a good long-term response.

Feasibility, Repeatability, and Correlation to Lung Function of Phase-Resolved Functional Lung (PREFUL) MRI-derived Pulmonary Artery Pulse Wave Velocity Measurements.

BACKGROUND: Pulse wave velocity (PWV) in the pulmonary arteries (PA) is a marker of vascular stiffening. Currently, only phase-contrast (PC) MRI-based options exist to measure PA-PWV. PURPOSE: To test feasibility, repeatability, and correlation to clinical data of Phase-Resolved Functional Lung (PREFUL) MRI-based calculation of PA-PWV. STUDY TYPE: Retrospective. SUBJECTS: 79 (26 female) healthy subjects (age range 19-78), 58 (24 female) patients with chronic obstructive pulmonary disease (COPD, age range 40-77), 60 (33 female) patients with suspected pulmonary hypertension (PH, age range 28-85). SEQUENCE: 2D spoiled gradient echo, 1.5T. ASSESSMENT: PA-PWV was measured from PREFUL-derived cardiac cycles based on the determination of temporal and spatial distance between lung vasculature voxels using a simplified (sPWV) method and a more comprehensive (cPWV) method including more elaborate distance calculation. For 135 individuals, PC MRI-based PWV (PWV-QA) was measured. STATISTICAL TESTS: Intraclass-correlation-coefficient (ICC) and coefficient of variation (CoV) were used to test repeatability. Nonparametric tests were used to compare cohorts. Correlation of sPWV/cPWV, PWV-QA, forced expiratory volume in 1 sec (FEV1 ) %predicted, residual volume (RV) %predicted, age, and right heart catheterization (RHC) data were tested. Significance level α = 0.05 was used. RESULTS: sPWV and cPWV showed no significant differences between repeated measurements (P-range 0.10-0.92). CoV was generally lower than 15%. COPD and PH patients had significantly higher sPWV and cPWV than healthy subjects. Significant correlation was found between sPWV or cPWV and FEV1 %pred. (R = -0.36 and R = -0.44), but not with RHC (P-range -0.11 - 0.91) or age (P-range 0.23-0.89). Correlation to RV%pred. was significant for cPWV (R = 0.42) but not for sPWV (R = 0.34, P = 0.055). For all cohorts, sPWV and cPWV were significantly correlated with PWV-QA (R = -0.41 and R = 0.48). DATA CONCLUSION: PREFUL-derived PWV is feasible and repeatable. PWV is increased in COPD and PH patients and correlates to airway obstruction and hyperinflation. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 2.

Treatment strategies and survival of patients with connective tissue disease and pulmonary arterial hypertension: a COMPERA analysis.

OBJECTIVES: Pulmonary arterial hypertension (PAH) occurs in various connective tissue diseases (CTDs). We sought to assess contemporary treatment patterns and survival of patients with various forms of CTD-PAH. METHODS: We analysed data from COMPERA, a European pulmonary hypertension registry, to describe treatment strategies and survival in patients with newly diagnosed PAH associated with SSc, SLE, MCTD, UCTD and other types of CTD. All-cause mortality was analysed according to the underlying CTD. For patients with SSc-PAH, we also assessed survival according to initial therapy with endothelin receptor antagonists (ERAs), phosphodiesterase type 5 inhibitors (PDE5is) or a combination of these two drug classes. RESULTS: This analysis included 607 patients with CTD-PAH. Survival estimates at 1, 3 and 5 years for SSc-PAH (n = 390) were 85%, 59% and 42%; for SLE-PAH (n = 34) they were 97%, 77% and 61%; for MCTD-PAH (n = 33) they were 97%, 70% and 59%; for UCTD-PAH (n = 60) they were 88%, 67% and 52%; and for other CTD-PAH (n = 90) they were 92%, 69% and 55%, respectively. After multivariable adjustment, the survival of patients with SSc-PAH was significantly worse compared with the other conditions (P = 0.001). In these patients, the survival estimates were significantly better with initial ERA-PDE5i combination therapy than with initial ERA or PDE5i monotherapy (P = 0.016 and P = 0.012, respectively). CONCLUSIONS: Mortality remains high in patients with CTD-PAH, especially for patients with SSc-PAH. However, for patients with SSc-PAH, our results suggest that long-term survival may be improved with initial ERA-PDE5i combination therapy compared with initial monotherapy.

Multilamellated Basement Membranes in the Capillary Network of Alveolar Capillary Dysplasia.

A minimal diffusion barrier is key to the pulmonary gas exchange. In alveolar capillary dysplasia (ACD), a rare genetically driven disease of early infancy, this crucial fibrovascular interface is compromised while the underlying pathophysiology is insufficiently understood. Recent in-depth analyses of vascular alterations in adult lung disease encouraged researchers to extend these studies to ACD and compare the changes of the microvasculature. Lung tissue samples of children with ACD (n = 12), adults with non-specific interstitial pneumonia (n = 12), and controls (n = 20) were studied using transmission electron microscopy, single-gene sequencing, immunostaining, exome sequencing, and broad transcriptome profiling. In ACD, pulmonary capillary basement membranes were hypertrophied, thickened, and multilamellated. Transcriptome profiling revealed increased CDH5, COL4A1, COL15A1, PTK2B, and FN1 and decreased VIT expression, confirmed by immunohistochemistry. In contrast, non-specific interstitial pneumonia samples showed a regular basement membrane architecture with preserved VIT expression but also increased COL15A1+ vessels. This study provides insight into the ultrastructure and pathophysiology of ACD. The lack of normally developed lung capillaries appeared to cause a replacement by COL15A1+ vessels, a mechanism recently described in interstitial lung disease. The VIT loss and FN1 overexpression might contribute to the unique appearance of basement membranes in ACD. Future studies are needed to explore the therapeutic potential of down-regulating the expression of FN1 and balancing VIT deficiency.

Effects of sotatercept on haemodynamics and right heart function: analysis of the STELLAR trial.

BACKGROUND: In the phase 3 STELLAR trial, sotatercept, an investigational first-in-class activin signalling inhibitor, demonstrated beneficial effects on 6-min walk distance and additional efficacy endpoints in pre-treated participants with pulmonary arterial hypertension (PAH). METHODS: This post hoc analysis evaluated data from right heart catheterisation (RHC) and echocardiography (ECHO) obtained from the STELLAR trial. Changes from baseline in RHC and ECHO parameters were assessed at 24 weeks. An analysis of covariance (ANCOVA) model was used to estimate differences in least squares means with treatment and randomisation stratification (mono/double versus triple therapy; World Health Organization functional class II versus III) as fixed factors, and baseline value as covariate. RESULTS: Relative to placebo, treatment with sotatercept led to significant (all p<0.0001 except where noted) improvements from baseline in mean pulmonary artery (PA) pressure (-13.9 mmHg), pulmonary vascular resistance (-254.8 dyn·s·cm-5), mean right atrial pressure (-2.7 mmHg), mixed venous oxygen saturation (3.84%), PA elastance (-0.42 mmHg·mL-1·beat-1), PA compliance (0.58 mL·mmHg-1), cardiac efficiency (0.48 mL·beat-1·mmHg-1), right ventricular (RV) work (-0.85 g·m) and RV power (-32.70 mmHg·L·min-1). ECHO showed improvements in tricuspid annular plane systolic excursion (TAPSE) to systolic pulmonary artery pressure ratio (0.12 mm·mmHg-1), end-systolic and end-diastolic RV areas (-4.39 cm2 and -5.31 cm2, respectively), tricuspid regurgitation and RV fractional area change (2.04% p<0.050). No significant between-group changes from baseline were seen for TAPSE, heart rate, cardiac output, stroke volume or their indices. CONCLUSION: In pre-treated patients with PAH, sotatercept demonstrated substantial improvements in PA pressures, PA compliance, PA-RV coupling and right heart function.

Multicenter Standardization of Phase-Resolved Functional Lung MRI in Patients With Suspected Chronic Thromboembolic Pulmonary Hypertension.

BACKGROUND: Detection of pulmonary perfusion defects is the recommended approach for diagnosing chronic thromboembolic pulmonary hypertension (CTEPH). This is currently achieved in a clinical setting using scintigraphy. Phase-resolved functional lung (PREFUL) magnetic resonance imaging (MRI) is an alternative technique for evaluating regional ventilation and perfusion without the use of ionizing radiation or contrast media. PURPOSE: To assess the feasibility and image quality of PREFUL-MRI in a multicenter setting in suspected CTEPH. STUDY TYPE: This is a prospective cohort sub-study. POPULATION: Forty-five patients (64 ± 16 years old) with suspected CTEPH from nine study centers. FIELD STRENGTH/SEQUENCE: 1.5 T and 3 T/2D spoiled gradient echo/bSSFP/T2 HASTE/3D MR angiography (TWIST). ASSESSMENT: Lung signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were compared between study centers with different MRI machines. The contrast between normally and poorly perfused lung areas was examined on PREFUL images. The perfusion defect percentage calculated using PREFUL-MRI (QDPPREFUL ) was compared to QDP from the established dynamic contrast-enhanced MRI technique (QDPDCE ). Furthermore, QDPPREFUL was compared between a patient subgroup with confirmed CTEPH or chronic thromboembolic disease (CTED) to other clinical subgroups. STATISTICAL TESTS: t-Test, one-way analysis of variance (ANOVA), Pearson's correlation. Significance level was 5%. RESULTS: Significant differences in lung SNR and CNR were present between study centers. However, PREFUL perfusion images showed a significant contrast between normally and poorly perfused lung areas (mean delta of normalized perfusion -4.2% SD 3.3) with no differences between study sites (ANOVA: P = 0.065). QDPPREFUL was significantly correlated with QDPDCE (r = 0.66), and was significantly higher in 18 patients with confirmed CTEPH or CTED (57.9 ± 12.2%) compared to subgroups with other causes of PH or with excluded PH (in total 27 patients with mean ± SD QDPPREFUL = 33.9 ± 17.2%). DATA CONCLUSION: PREFUL-MRI could be considered as a non-invasive method for imaging regional lung perfusion in multicenter studies. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 1.

Pulmonary hypertension associated with lung disease: new insights into pathomechanisms, diagnosis, and management.

Patients with chronic lung diseases, particularly interstitial lung disease and chronic obstructive pulmonary disease, frequently develop pulmonary hypertension, which results in clinical deterioration, worsening of oxygen uptake, and an increased mortality risk. Pulmonary hypertension can develop and progress independently from the underlying lung disease. The pulmonary vasculopathy is distinct from that of other forms of pulmonary hypertension, with vascular ablation due to loss of small pulmonary vessels being a key feature. Long-term tobacco exposure might contribute to this type of pulmonary vascular remodelling. The distinct pathomechanisms together with the underlying lung disease might explain why treatment options for this condition remain scarce. Most drugs approved for pulmonary arterial hypertension have shown no or sometimes harmful effects in pulmonary hypertension associated with lung disease. An exception is inhaled treprostinil, which improves exercise capacity in patients with interstitial lung disease and pulmonary hypertension. There is a pressing need for safe, effective treatment options and for reliable, non-invasive diagnostic tools to detect and characterise pulmonary hypertension in patients with chronic lung disease.

Phase 3 Trial of Sotatercept for Treatment of Pulmonary Arterial Hypertension.

BACKGROUND: Pulmonary arterial hypertension is a progressive disease involving proliferative remodeling of the pulmonary vessels. Despite therapeutic advances, the disease-associated morbidity and mortality remain high. Sotatercept is a fusion protein that traps activins and growth differentiation factors involved in pulmonary arterial hypertension. METHODS: We conducted a multicenter, double-blind, phase 3 trial in which adults with pulmonary arterial hypertension (World Health Organization [WHO] functional class II or III) who were receiving stable background therapy were randomly assigned in a 1:1 ratio to receive subcutaneous sotatercept (starting dose, 0.3 mg per kilogram of body weight; target dose, 0.7 mg per kilogram) or placebo every 3 weeks. The primary end point was the change from baseline at week 24 in the 6-minute walk distance. Nine secondary end points, tested hierarchically in the following order, were multicomponent improvement, change in pulmonary vascular resistance, change in N-terminal pro-B-type natriuretic peptide level, improvement in WHO functional class, time to death or clinical worsening, French risk score, and changes in the Pulmonary Arterial Hypertension-Symptoms and Impact (PAH-SYMPACT) Physical Impacts, Cardiopulmonary Symptoms, and Cognitive/Emotional Impacts domain scores; all were assessed at week 24 except time to death or clinical worsening, which was assessed when the last patient completed the week 24 visit. RESULTS: A total of 163 patients were assigned to receive sotatercept and 160 to receive placebo. The median change from baseline at week 24 in the 6-minute walk distance was 34.4 m (95% confidence interval [CI], 33.0 to 35.5) in the sotatercept group and 1.0 m (95% CI, -0.3 to 3.5) in the placebo group. The Hodges-Lehmann estimate of the difference between the sotatercept and placebo groups in the change from baseline at week 24 in the 6-minute walk distance was 40.8 m (95% CI, 27.5 to 54.1; P<0.001). The first eight secondary end points were significantly improved with sotatercept as compared with placebo, whereas the PAH-SYMPACT Cognitive/Emotional Impacts domain score was not. Adverse events that occurred more frequently with sotatercept than with placebo included epistaxis, dizziness, telangiectasia, increased hemoglobin levels, thrombocytopenia, and increased blood pressure. CONCLUSIONS: In patients with pulmonary arterial hypertension who were receiving stable background therapy, sotatercept resulted in a greater improvement in exercise capacity (as assessed by the 6-minute walk test) than placebo. (Funded by Acceleron Pharma, a subsidiary of MSD; STELLAR ClinicalTrials.gov number, NCT04576988.).

Sotatercept for the treatment of pulmonary arterial hypertension: PULSAR open-label extension.

BACKGROUND: In participants with pulmonary arterial hypertension, 24 weeks of sotatercept resulted in a significantly greater reduction from baseline in pulmonary vascular resistance than placebo. This report characterises the longer-term safety and efficacy of sotatercept in the PULSAR open-label extension. We report cumulative safety, and efficacy at months 18-24, for all participants treated with sotatercept. METHODS: PULSAR was a phase 2, randomised, double-blind, placebo-controlled study followed by an open-label extension, which evaluated sotatercept on top of background pulmonary arterial hypertension therapy in adults. Participants originally randomised to placebo were re-randomised 1:1 to sotatercept 0.3 or 0.7 mg·kg-1 (placebo-crossed group); those initially randomised to sotatercept continued the same sotatercept dose (continued-sotatercept group). Safety was evaluated in all participants who received ≥1 dose of sotatercept. The primary efficacy endpoint was change from baseline to months 18-24 in pulmonary vascular resistance. Secondary endpoints included 6-min walk distance and functional class. Two prespecified analyses, placebo-crossed and delayed-start, evaluated efficacy irrespective of dose. RESULTS: Of 106 participants enrolled in the PULSAR study, 97 continued into the extension period. Serious treatment-emergent adverse events were reported in 32 (30.8%) participants; 10 (9.6%) reported treatment-emergent adverse events leading to study discontinuation. Three (2.9%) participants died, none considered related to study drug. The placebo-crossed group demonstrated significant improvement across primary and secondary endpoints and clinical efficacy was maintained in the continued-sotatercept group. CONCLUSION: These results support the longer-term safety and durability of clinical benefit of sotatercept for pulmonary arterial hypertension.

Risk stratification and response to therapy in patients with pulmonary arterial hypertension and comorbidities: A COMPERA analysis.

BACKGROUND: A diagnosis of idiopathic pulmonary arterial hypertension (IPAH) is frequently made in elderly patients who present with comorbidities, especially hypertension, coronary heart disease, diabetes mellitus, and obesity. It is unknown to what extent the presence of these comorbidities affects the response to PAH therapies and whether risk stratification predicts outcome in patients with comorbidities. METHODS: We assessed the database of COMPERA, a European pulmonary hypertension registry, to determine changes after initiation of PAH therapy in WHO functional class (FC), 6-minute walking distance (6MWD), brain natriuretic peptide (BNP) or N-terminal fragment of probrain natriuretic peptide (NT-pro-BNP), and mortality risk assessed by a 4-strata model in patients with IPAH and no comorbidities, 1-2 comorbidities and 3-4 comorbidities. RESULTS: The analysis was based on 1,120 IPAH patients (n = 208 [19%] without comorbidities, n = 641 [57%] with 1-2 comorbidities, and n = 271 [24%] with 3-4 comorbidities). Improvements in FC, 6MWD, BNP/NT-pro-BNP, and mortality risk from baseline to first follow-up were significantly larger in patients with no comorbidities than in patients with comorbidities, while they were not significantly different in patients with 1-2 and 3-4 comorbidities. The 4-strata risk tool predicted survival in patients without comorbidities as well as in patients with 1-2 or 3-4 comorbidities. CONCLUSIONS: Our data suggest that patients with IPAH and comorbidities benefit from PAH medication with improvements in FC, 6MWD, BNP/NT-pro-BNP, and mortality risk, albeit to a lesser extent than patients without comorbidities. The 4-strata risk tool predicted outcome in patients with IPAH irrespective of the presence of comorbidities.

Phenotyping of idiopathic pulmonary arterial hypertension: a registry analysis.

BACKGROUND: Among patients meeting diagnostic criteria for idiopathic pulmonary arterial hypertension (IPAH), there is an emerging lung phenotype characterised by a low diffusion capacity for carbon monoxide (DLCO) and a smoking history. The present study aimed at a detailed characterisation of these patients. METHODS: We analysed data from two European pulmonary hypertension registries, COMPERA (launched in 2007) and ASPIRE (from 2001 onwards), to identify patients diagnosed with IPAH and a lung phenotype defined by a DLCO of less than 45% predicted and a smoking history. We compared patient characteristics, response to therapy, and survival of these patients to patients with classical IPAH (defined by the absence of cardiopulmonary comorbidities and a DLCO of 45% or more predicted) and patients with pulmonary hypertension due to lung disease (group 3 pulmonary hypertension). FINDINGS: The analysis included 128 (COMPERA) and 185 (ASPIRE) patients with classical IPAH, 268 (COMPERA) and 139 (ASPIRE) patients with IPAH and a lung phenotype, and 910 (COMPERA) and 375 (ASPIRE) patients with pulmonary hypertension due to lung disease. Most patients with IPAH and a lung phenotype had normal or near normal spirometry, a severe reduction in DLCO, with the majority having no or a mild degree of parenchymal lung involvement on chest computed tomography. Patients with IPAH and a lung phenotype (median age, 72 years [IQR 65-78] in COMPERA and 71 years [65-76] in ASPIRE) and patients with group 3 pulmonary hypertension (median age 71 years [65-77] in COMPERA and 69 years [63-74] in ASPIRE) were older than those with classical IPAH (median age, 45 years [32-60] in COMPERA and 52 years [38-64] in ASPIRE; p<0·0001 for IPAH with a lung phenotype vs classical IPAH in both registries). While 99 (77%) patients in COMPERA and 133 (72%) patients in ASPIRE with classical IPAH were female, there was a lower proportion of female patients in the IPAH and a lung phenotype cohort (95 [35%] COMPERA; 75 [54%] ASPIRE), which was similar to group 3 pulmonary hypertension (336 [37%] COMPERA; 148 [39%] ASPIRE]). Response to pulmonary arterial hypertension therapies at first follow-up was available from COMPERA. Improvements in WHO functional class were observed in 54% of patients with classical IPAH, 26% of patients with IPAH with a lung phenotype, and 22% of patients with group 3 pulmonary hypertension (p<0·0001 for classical IPAH vs IPAH and a lung phenotype, and p=0·194 for IPAH and a lung phenotype vs group 3 pulmonary hypertension); median improvements in 6 min walking distance were 63 m, 25 m, and 23 m for these cohorts respectively (p=0·0015 for classical IPAH vs IPAH and a lung phenotype, and p=0·64 for IPAH and a lung phenotype vs group 3 pulmonary hypertension), and median reductions in N-terminal-pro-brain-natriuretic-peptide were 58%, 27%, and 16% respectively (p=0·0043 for classical IPAH vs IPAH and a lung phenotype, and p=0·14 for IPAH and a lung phenotype vs group 3 pulmonary hypertension). In both registries, survival of patients with IPAH and a lung phenotype (1 year, 89% in COMPERA and 79% in ASPIRE; 5 years, 31% in COMPERA and 21% in ASPIRE) and group 3 pulmonary hypertension (1 year, 78% in COMPERA and 64% in ASPIRE; 5 years, 26% in COMPERA and 18% in ASPIRE) was worse than survival of patients with classical IPAH (1 year, 95% in COMPERA and 98% in ASPIRE; 5 years, 84% in COMPERA and 80% in ASPIRE; p<0·0001 for IPAH with a lung phenotype vs classical IPAH in both registries). INTERPRETATION: A cohort of patients meeting diagnostic criteria for IPAH with a distinct, presumably smoking-related form of pulmonary hypertension accompanied by a low DLCO, resemble patients with pulmonary hypertension due to lung disease rather than classical IPAH. These observations have pathogenetic, diagnostic, and therapeutic implications, which require further exploration. FUNDING: COMPERA is funded by unrestricted grants from Acceleron, Bayer, GlaxoSmithKline, Janssen, and OMT. The ASPIRE Registry is supported by Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.