European Society Of Cardiology/European Respiratory Society Research Articles

The spectrum of systemic sclerosis-associated pulmonary hypertension: Insights from the ASPIRE registry

There are limited data assessing the spectrum of systemic sclerosis-associated pulmonary hypertension (PH). Data for 912 systemic sclerosis patients assessed between 2000and 2020 were retrieved from the Assessing the Spectrum of Pulmonary hypertension Identified at a REferral centre (ASPIRE) registry and classified based on 2022 European Society of Cardiology/European Respiratory Society(ESC/ERS) guidelines and multimodality investigations. Reduction in pulmonary vascular resistance (PVR) diagnostic threshold to >2WU resulted in a 19% increase in precapillary PH diagnoses. Patients with PVR ≤2WU had superior survival to PVR >2-3WU which was similar to PVR >3-4WU. Survival in pulmonary arterial hypertension (PAH) was superior to PH associated with lung disease. However, patients with mild parenchymal disease on CT had similar characteristics and outcomes to patients without lung disease. Combined pre- and postcapillary PH had significantly poorer survival than isolated postcapillary PH. Patients with mean pulmonary arterial wedge pressure (PAWP) 13-15mmHg had similar haemodynamics and left atrial volumes to those with PAWP>15mmHg. Unclassified-PH had more frequently dilated left atria and higher PAWP than PAH. Although Unclassified-PH had a similar survival to No-PH, 36% were subsequently diagnosed with PAH or PH associated with left heart disease. The presence of 2-3 radiological signs of pulmonary veno-occlusive disease was noted in 7% of PAH patients and was associated with worse survival. Improvement in incremental shuttle walking distance of ≥30m following initiation of PAH therapy was associated with superior survival. PAH patients diagnosed after 2011 had greater use of combination therapy and superior survival. A number of systemic sclerosis PH phenotypes can be recognized and characterized using haemodynamics, lung function and multimodality imaging.

The prognosis and management of reclassified systemic lupus erythematosus associated pulmonary arterial hypertension according to 2022 ESC/ERS guidelines.

The 2022 European Society of Cardiology/European Respiratory Society (ESC/ERS) guideline has recently revised the hemodynamic definition of pulmonary arterial hypertension. However, there is currently limited research on the prognosis and treatment of system lupus erythematosus-associated pulmonary arterial hypertension (SLE-PAH) patients that have been reclassified by the new hemodynamic definition. This study aims to analyze the prognosis of newly reclassified SLE-PAH patients and provide recommendations for the management strategy. This retrospective study analyzed records of 236 SLE-PAH patients who visited Peking Union Medical College Hospital (PUMCH) from 2011 to 2023, among whom 22 patients were reclassified into mild SLE-PAH (mean pulmonary arterial pressure (mPAP) of 21-24mmHg, pulmonary vascular resistance (PVR) of 2-3 WU, and PAWP ≤ 15mmHg) according to the guidelines and 14 were defined as unclassified SLE-PAH patients (mPAP 21-24mmHg and PVR ≤ 2 WU). The prognosis was compared among mild SLE-PAH, unclassified SLE-PH, and conventional SLE-PAH patients (mPAP ≥ 25mmHg and PVR > 3WU). Besides, the effectiveness of pulmonary arterial hypertension (PAH)-specific therapy was evaluated in mild SLE-PAH patients. Those mild SLE-PAH patients had significantly longer progression-free time than the conventional SLE-PAH patients. Among the mild SLE-PAH patients, 4 did not receive PAH-specific therapy and had a similar prognosis as patients not receiving specific therapy. This study supports the revised hemodynamic definition of SLE-PAH in the 2022 ESC/ERS guideline. Those mild and unclassified SLE-PH patients had a better prognosis, demonstrating the possibility and significance of early diagnosis and intervention for SLE-PAH. This study also proposed a hypothesis that IIT against SLE might be sufficient for those reclassified SLE-PAH patients.

Outcomes and risk assessment in pulmonary veno-occlusive disease.

Pulmonary veno-occlusive disease (PVOD) is a rare and severe subtype of pulmonary arterial hypertension (PAH). Although European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines advise assessing PAH severity at baseline and during follow-up, no existing risk assessment methods have been validated for PVOD. This study aimed to identify prognostic factors, examine the impact of treatment strategies and evaluate risk assessment methods for PVOD patients. The study analysed all incident PVOD patients included in the French Pulmonary Hypertension Registry between 2006 and 2021. Survival was assessed based on initial treatment strategy and risk status and compared to a matched (age, sex, pulmonary vascular resistance) PAH group. Six risk assessment methods (number of four low-risk and three noninvasive low-risk variables, ESC/ERS guidelines three-strata and four-strata models, REVEAL 2.0 and Lite 2) were applied at baseline and early follow-up, and their accuracy was compared using Harrell's c-statistic. Among the 327 included PVOD patients, survival rates at 1, 3 and 5 years were 86%, 50% and 27%, respectively. Multivariate analysis showed that only 6-min walk distance was associated with survival, with no significant difference based on initial treatment strategy. All six risk assessment methods could discriminate mortality risk, and the ESC/ERS four-strata model was the most accurate at both baseline and follow-up (C-index 0.64 and 0.74). PVOD survival rates were consistently lower than PAH when comparing baseline risk status using the ESC/ERS four-strata model. PVOD is associated with poor outcomes, and initial treatment strategies do not significantly affect survival. Risk assessment methods can be useful in predicting survival for PVOD patients.

Applicability of the 3-Strata ESC/ERS risk model at baseline in pulmonary veno-occlusive disease

Abstract Introduction The risk of death or lung transplantation in Pulmonary Arterial Hypertension (PAH) is influenced by many factors. The recently published European Society of Cardiology/ European Respiratory Society (ESC/ERC) Guidelines for the study and management of PAH recommend the use of a multiparametric 3-strata model for risk stratification at diagnosis [1]. Heritable pulmonary veno-occlusive disease (PVOD) is an especially infrequent form of PAH caused by homozygous variants in the gene encoding the Eukaryotic Translation Initiation Factor 2 Alpha Kinase 4 (EIF2AK4). PVOD has a dramatically low long-term survival. There is no evidence confirming the applicability of the risk scores in PVOD. Our aim was to evaluate the usefulness of the 3-strata ESC/ERC score at diagnosis in patients with heritable PVOD. Methods We considered patients with the diagnosis of heritable PVOD included in the Spanish registry of PAH (REHAP) between 2011 and 2022. The diagnosis required a homozygous variant in EIF2AK4, and a diagnostic right heart catheterization (RHC). The other group was composed of patients with PAH and pathogenic or likely pathogenic variants in the gene BMPR2. The prognostic evaluation was done when these patients were included in the registry. All participants signed informed consent. Results In the 2011-2022 period up to 32 cases of PVOD in 23 unrelated families and 28 cases in 23 families were collected. 10 patients were excluded due to incomplete RHC at diagnosis. The baseline characteristics of the population can be seen in the Table. After a median follow-up of 16.9 months, up to 15 patients with PVOD needed lung transplantation (46.9%), and 6 patients died (18.7%). On the contrary, only 4 patients needed lung transplantation and one died in the BMPR2 group after a median follow-up of 97.1 months. Most of the included PVOD patients had an intermediate risk of mortality after the application of the 3-strata European model (62.5%), and only one case (3.1%) was categorized as high-risk. There was a non-significant tendency for patients with BMPR2 variants to have lower risk levels. The application of the 3-strata model at diagnosis in patients with PVOD demonstrated a good global prognostic capacity (C Index of 0.707). In our PVOD population, those patients at intermediate risk had a hazard ratio of 9.53 (2.15-42.17, p=0.003) when compared with patients at low risk. Similarly, those patients at high risk at diagnosis had a hazard ratio of 9.49 (0.86-104.69, p=0.066) when compared with patients at intermediate risk (Figure). Conclusions The application of the ESC/ERC three-strata risk tool in patients with PVOD demonstrates a good global prognostic capacity. Nevertheless, the risk of death or lung transplantation can be higher than predicted in this population, enhancing the need for an early evaluation for lung transplantation.Figure

Predictors of the response to phosphodiesterase-5 inhibitors in pulmonary arterial hypertension: an analysis of the Spanish registry

BackgroundAchieving and maintaining a low-risk profile is associated with favorable outcome in pulmonary arterial hypertension (PAH). The effects of treatment on risk profile are variable among patients.ObjectiveTo Identify variables that might predict the response to treatment with phosphodiesterase-5 inhibitors (PDE-5i) in PAH.MethodsWe carried out a cohort analysis of the Spanish PAH registry in 830 patients diagnosed with PAH that started PDE5i treatment and had > 1 year follow-up. 644 patients started PDE-5i either in mono- or add-on therapy and 186 started combined treatment with PDE-5i and endothelin receptor antagonist (ERA). Responders were considered when at 1 year they: (1) were alive; (2) did not present clinical worsening; and (3) improved European Society of Cardiology/European Respiratory Society (ESC/ERS) risk score or remained in low-risk. Univariate and multivariate logistic regression models were used to analyze variables associated with a favorable response.ResultsTwo hundred and ten patients (33%) starting PDE-5i alone were classified as responders, irrespective of whether it was mono- or add-on therapy. In addition to known predictors of PAH outcome (low-risk at baseline, younger age), male sex and diagnosis of portopulmonary hypertension (PoPH) or HIV-PAH were independent predictors of favorable response to PDE-5i. Diffusing capacity for carbon monoxide (DLco) ≤ 40% of predicted was associated with an unfavorable response. When PDE-5i were used in upfront combination, 58% of patients were responders. In this group, diagnosis of idiopathic PAH (IPAH) was an independent predictor of favorable response, whereas connective tissue disease-PAH was associated with an unfavorable response.ConclusionMale sex and diagnosis of PoPH or HIV-PAH are predictors of favorable effect of PDE-5i on risk profile when used as mono- or add-on therapy. Patients with IPAH respond more favorably to PDE-5i when used in upfront combination. These results identify patient profiles that may respond favorably to PDE-5i in monotherapy and those who might benefit from alternative treatment strategies.

Diagnosing post-capillary hypertension in patients with left heart disease: impact of new guidelines.

In 2022, the definition of pulmonary hypertension (PH) in the presence of left heart disease was updated according to the new joint guidelines of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS). The impact of the new ESC/ERS definition on the prevalence of post-capillary PH (pc-PH) and its subgroups of isolated post-capillary (Ipc-PH) and combined pre- and post-capillary PH (Cpc-PH) in patients with left heart disease is unclear. We retrospectively identified N = 242 patients with left heart disease with available data on right heart catheterisation (RHC) and cardiac magnetic resonance imaging (CMR). The proportion of pc-PH and its subgroups was calculated according to the old and new ESC/ERS PH definition. As the old definition did not allow the exact allocation of all patients with pc-PH into a respective subgroup, unclassifiable patients (Upc-PH) were regarded separately. Seventy-six out of 242 patients had pc-PH according to the new ESC/ERS definitions, with 72 of these patients also meeting the criteria of the old definition. Using the old definition, 50 patients were diagnosed with Ipc-PH, 4 with Cpc-PH, and 18 with Upc-PH. Applying the new definition, Ipc-PH was diagnosed in 35 patients (4 newly), and Cpc-PH in 41 patients. No CMR parameter allowed differentiating between Ipc-PH and Cpc-PH, regardless of which guideline version was used. Applying the new ESC/ERS 2022 guideline definitions mildly increased the proportion of patients diagnosed with pc-PH (+ 5.5%) but markedly increased Cpc-PH diagnoses. This effect was driven by the allocation of patients with formerly unclassifiable forms of post-capillary PH to the Cpc-PH subgroup and a significant shift of patients from the Ipc-PH to the Cpc-PH subgroup. Distribution of post-capillary pulmonary hypertension (pc-PH) subgroups according to the European Society of Cardiology/European Respiratory Society (ESC/ERS) PH guidelines from 2015 and 2022 in N = 242 patients with left heart disease.

Screening for pulmonary arterial hypertension in patients with systemic sclerosis in the era of new pulmonary arterial hypertension definitions.

This study compares the performance of three composite pulmonary arterial hypertension (PAH) screening tools in a real-life SSc cohort, according to both the previous 2015 ESC/ERS guideline and the recent 2022 ESC/ERS guideline haemodynamic criteria. Consecutive SSc patients without a previous diagnosis of pulmonary hypertension (PH) were screened for PAH using the European Society of Cardiology/European Respiratory Society (ESC/ERS), DETECT, and Australian Scleroderma Interest Group (ASIG) algorithms. Right heart catheterisation (RHC) referral performances for PAH were compared according to the 2022 ESC/ERS PAH criteria. Thirty-five of the 81 patients required RHC; 15 (18.5%) according to ESC/ERS, 27 (33.3%) according to DETECT, and 25 (31%) according to ASIG. The final diagnoses were no-PH in 17 patients, WHO group 1 PH (PAH) in 8 patients, WHO group 2 PH in 8 patients, and WHO group 3 PH in 2 patients. When the hemodynamic criteria of the previous ESC/ERS guideline were applied, only one patient was diagnosed with PAH. The sensitivities of the algorithms for the diagnosis of PAH were 62.5% for ESC/ERS, 75% for DETECT, 87.5% for ASIG according to the 2022 ESC/ERS guideline definition, and 100% for all according to the previous ESC/ERS guideline. With the recent criteria, PAH diagnosis in patients with SSc increased by 1.8-fold. Current algorithms for screening PAH are less sensitive with these revised criteria. Although the ASIG algorithm seems more sensitive, it can still miss the diagnosis. The multimodal/algorithmic approach seems to be the best option for predicting PAH.

Plasma TRAIL and ANXA1 in diagnosis and prognostication of pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a rare vasculopathy, with high morbidity and mortality. The sensitivity of the current european society of cardiology/european respiratory society (ESC/ERS) risk assessment strategy may be improved by the addition of biomarkers related to PAH pathophysiology. Such plasma-borne biomarkers may also reduce time to diagnosis, if used as diagnostic tools in patients with unclear dyspnea, and in guiding treatment decisions. Plasma levels of proteins related to tumor necrosis factor (TNF), inflammation, and immunomodulation were analyzed with proximity extension assays in patients with PAH (n = 48), chronic thromboembolic pulmonary hypertension (PH; CTEPH, n = 20), PH due to left heart failure (HF) with preserved (HFpEF-PH, n = 33), or reduced (HFrEF-PH, n = 36) ejection fraction, HF without PH (n = 15), and healthy controls (n = 20). TNF-related apoptosis-inducing ligand (TRAIL) were lower in PAH versus the other disease groups and controls (p < 0.0082). In receiver operating characteristics analysis, TRAIL levels identified PAH from the other disease groups with a sensitivity of 0.81 and a specificity of 0.53 [area under the curve: 0.70; (95% confidence interval, CI: 0.61-0.79; p < 0.0001)]. In both single (p < 0.05) and multivariable Cox regression models Annexin A1 (ANXA1) [hazard ratio, HR: 1.0367; (95% CI: 1.0059-1.0684; p = 0.044)] and carcinoembryonic antigen-related cell adhesion molecule 8 [HR: 1.0603; (95% CI: 1.0004-1.1237; p = 0.0483)] were significant predictors of survival, adjusted for age, female sex and ESC/ERS-initial risk score. Low plasma TRAIL predicted PAH among patients with dyspnea and differentiated PAH from those with CTEPH, HF with and without PH; and healthy controls. Higher plasma ANXA1 was associated with worse survival in PAH. Larger multicenter studies are encouraged to validate our findings.

Continuous long-term heart rate variability and risk assessment in pulmonary hypertension

ObjectiveCurrent multimodal risk assessment for pulmonary hypertension (PH) has been redefined with a simplified assessment for follow-up in the new European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines. Follow-up risk...

Refined risk stratification, current treatment, and new therapeutic approaches in pulmonary arterial hypertension.

The 2022 European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines for pulmonary hypertension have introduced arefined risk stratification to guide both initial and subsequent treatment of pulmonary arterial hypertension (PAH). The risk stratification at PAH diagnosis still comprises three risk categories (low, intermediate, high) and lists some new parameters. As the estimated 1‑year mortality is more than 20% in high-risk patients after diagnosis, an initial triple-combination therapy including parenteral prostacyclin analogues is recommended for this group. All other patients should receive adual-combination therapy with an endothelin receptor antagonist and aphosphodiesterase‑5 inhibitor. However, this approach of initial combination therapy is only recommended for classic PAH, while monotherapy followed by regular follow-up and individualized therapy should be used for patients with cardiopulmonary comorbidities. For PAH patients without cardiopulmonary comorbidities, it is recommended to assess their risk at follow-up with anew 4‑strata classification, where the intermediate-risk group is split on the basis of three noninvasive parameters. Importantly, changes from intermediate-high to intermediate-low risk have been shown to be associated with abetter prognosis. In addition, the recommendations on treatment escalation became more precise with the addition of aprostacyclin receptor agonist or switching aphosphodiesterase‑5 inhibitor to asoluble guanylate cyclase stimulator for intermediate-low risk and proceeding to triple-combination therapy with parenteral prostacyclin analogues already for intermediate-high risk. With sotatercept, the first non-vasodilator PAH treatment will become available in the near future to further enrich our treatment options for this chronic and still severe disease.

Outcomes and prognostic factors of decompensated pulmonary hypertension in the intensive care unit

BackgroundPatients with acute decompensation of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) admitted to intensive care unit (ICU) have high in-hospital mortality. We hypothesized that pulmonary hypertension (PH) severity, measured by a simplified version of European Society of Cardiology/European Respiratory Society (ESC/ERS) risk assessment, and the severity of organ dysfunction upon ICU admission, measured by sequential organ failure assessment score (SOFA) were associated with in-hospital mortality in decompensated patients with PAH and CTEPH. We also described clinical and laboratory variables during ICU stay. MethodsObservational study including adults with decompensated PAH or CTEPH with unplanned ICU admission between 2014 and 2019. Multivariate logistic regression models were used to evaluate the association of ESC/ERS risk assessment and SOFA score with in-hospital mortality. ESC/ERS risk assessment and SOFA score were included in a decision tree to predict in-hospital mortality. Results73 patients were included. In-hospital mortality was 41.1%. ESC/ERS high-risk group (adjusted odds ratio = 95.52) and SOFA score (adjusted odds ratio = 1.80) were associated with in-hospital mortality. The decision tree identified four groups with in-hospital mortality between 8.1% and 100%. Nonsurvivors had a lower central venous oxygen saturation, higher arterial lactate and higher brain natriuretic peptide in the end of first week in the ICU. ConclusionsHigh-risk on a simplified version of ERS/ESC risk assessment and SOFA score upon ICU admission are associate with in-hospital mortality. A decision tree based on ESC/ERS risk assessment and SOFA score identifies four groups with in-hospital mortality between 8.1% and 100%.

Risk assessment in pulmonary hypertension based on routinely measured laboratory parameters

γ-glutamyl transferase (GGT), the aspartate aminotransferase/alanine aminotransferase (AST/ALT) ratio, and the neutrophil-to-lymphocyte ratio (NLR) are prognostic biomarkers in several cardiovascular diseases, but their relevance in pulmonary hypertension (PH) is not fully understood. We aimed to assess their prognostic value in patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic PH (CTEPH). We retrospectively analyzed 731 incident patients with idiopathic PAH or CTEPH who entered the Giessen PH registry during 1993-2019. A risk stratification score based on GGT, AST/ALT ratio, and NLR tertiles was compared with a truncated version of the European Society of Cardiology/European Respiratory Society (ESC/ERS) risk stratification scheme. Associations with survival were evaluated using Kaplan-Meier and Cox regression analyses. External validation was performed in 311 patients with various types of PAH or CTEPH from a second German center. GGT levels, AST/ALT, and NLR independently predicted mortality at baseline and during follow-up. The scoring system based on these biomarkers predicted mortality at baseline and during follow-up (both log-rank p < 0.001; hazard ratio [95% confidence interval], high vs low risk: baseline, 7.6 [3.9, 15.0]; follow-up, 13.3 [4.8, 37.1]). Five-year survival of low, intermediate, and high risk groups was 92%, 76%, and 51%, respectively, at baseline and 95%, 78%, and 50%, respectively, during follow-up. Our scoring system showed characteristics comparable to the ESC/ERS scheme, and predicted mortality in the validation cohort. GGT, AST/ALT, and NLR were reliable prognostic biomarkers at baseline and during follow-up, with predictive power comparable to the gold standard for risk stratification.

Mortality trends in pulmonary arterial hypertension in Canada: a temporal analysis of survival per ESC/ERS guideline era.

BackgroundThe evolution in pulmonary arterial hypertension (PAH) management has been summarised in three iterations of the European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines. No study has assessed whether changes in management, as reflected in the changing guidelines, has translated to improved long-term survival in PAH.MethodsWe performed a mixed retrospective/prospective analysis of treatment-naïve, incident PAH patients (n=392) diagnosed at three major centres in Canada from 2009 to 2021. Patients were divided into two groups based on their diagnosis date and in accordance with the 2009 and 2015 ESC/ERS guideline iterations. Overall survival was assessed based on date of diagnosis and initial treatment strategy (i.e. monotherapy versus combination therapy).ResultsThere was a shift towards more aggressive upfront management with combination therapy in Canada after the publication of the 2015 ESC/ERS guidelines (10.4% and 30.8% in patients from 2009 to 2015 and 36.0% and 57.4% in patients diagnosed after 2015 for baseline and 2-year follow-up, respectively). A key factor associated with combination therapy after 2015 was higher pulmonary vascular resistance (p=0.009). The 1-, 3- and 5-year survival rates in Canada were 89.2%, 75.6% and 56.0%, respectively. Despite changes in management, there was no improvement in long-term survival before and after publication of the 2015 ESC/ERS guidelines (p=0.53).ConclusionsThere was an increase in the use of initial and sequential combination therapy in Canada after publication of the 2015 ESC/ERS guidelines, which was not associated with improved long-term survival. These data highlight the continued difficulties of managing this aggressive pulmonary disease in an era without a cure.

The angiostatic peptide endostatin enhances mortality risk prediction in pulmonary arterial hypertension.

Currently available noninvasive markers for assessing disease severity and mortality risk in pulmonary arterial hypertension (PAH) are unrelated to fundamental disease biology. Endostatin, an angiostatic peptide known to inhibit pulmonary artery endothelial cell migration, proliferation and survival in vitro, has been linked to adverse haemodynamics and shortened survival in small PAH cohorts. This observational cohort study sought to assess: 1) the prognostic performance of circulating endostatin levels in a large, multicentre PAH cohort; and 2) the added value gained by incorporating endostatin into existing PAH risk prediction models.Endostatin ELISAs were performed on enrolment samples collected from 2017 PAH subjects with detailed clinical data, including survival times. Endostatin associations with clinical variables, including survival, were examined using multivariable regression and Cox proportional hazards models. Extended survival models including endostatin were compared to null models based on the REVEAL risk prediction tool and European Society of Cardiology/European Respiratory Society (ESC/ERS) low-risk criteria using likelihood ratio tests, Akaike and Bayesian information criteria and C-statistics.Higher endostatin was associated with higher right atrial pressure, mean pulmonary arterial pressure and pulmonary vascular resistance, and with shorter 6-min walk distance (p<0.01). Mortality risk doubled for each log higher endostatin (hazard ratio 2.3, 95% CI 1.6–3.4, p<0.001). Endostatin remained an independent predictor of survival when incorporated into existing risk prediction models. Adding endostatin to REVEAL-based and ESC/ERS criteria-based risk assessment strategies improved mortality risk prediction.Endostatin is a robust, independent predictor of mortality in PAH. Adding endostatin to existing PAH risk prediction strategies improves PAH risk assessment.

Pulmonary hypertension in patients with chronic myeloid leukemia.

Dasatinib, a tyrosine kinase inhibitor (TKI), induces pulmonary hypertension (PH) in patients with chronic myeloid leukemia (CML). However, information on other TKIs is limited.We retrospectively analyzed PH prevalence by reviewing transthoracic echocardiography (TTE) findings in a population of Korean CML patients treated with TKI at a single hospital between 2003 and 2020. PH was defined as a high PH probability according to the European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines.Of the 189 patients treated with TKI(s) during the study period, 112 (59.3%) underwent TTE. Among the 112 patients treated with a TKI for a median of 40.4 months (range: 1.1–167.2 months), PH was found in 12 (10.7%), most frequently in those treated with dasatinib (ie, in 3 [7.5%] of 40 of those treated with imatinib, 1 [3.1%] of 32 of those treated with nilotinib, and 8 [21.6%] of 37 of those treated with dasatinib). PH resolved in 4 (50.0%) of the 8 dasatinib-treated patients after discontinuation of the agent. One nilotinib-treated and all three imatinib-treated patients recovered from PH. In multivariate analyses, age >60 years, dasatinib treatment, and positive cardiopulmonary symptoms/signs at the time of transthoracic echocardiography were statistically significant risk factors for developing PH.These results show that PH is induced not only by dasatinib, but also by imatinib and nilotinib. Careful screening for PH during any TKI treatment may thus be warranted in patients with CML.

Performance of the DETECT Algorithm for Pulmonary Hypertension Screening in a Systemic Sclerosis Cohort.

Pulmonary arterial hypertension (PAH) is one of the leading causes of mortality in systemic sclerosis (SSc). This study was undertaken to assess predictive accuracies of the DETECT algorithm and the 2015 European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines in SSc patients who underwent right-sided heart catheterization (RHC) for pulmonary hypertension (PH) evaluation. Patients with SSc who had diagnostic RHC, had no PH or had PAH, and had available data on variables to allow application of the DETECT and 2015 ESC/ERS guidelines were included for analysis. PH classification was based on hemodynamics using the 2018 revised criteria and extent of lung fibrosis shown on high-resolution computed tomography. Sensitivity and predictive accuracies of the DETECT algorithm and 2015 ESC/ERS guidelines were calculated, including analysis of subjects with a diffusing capacity for carbon monoxide (DLco) of ≥60% predicted. Sixty-eight patients with SSc had RHC, of whom 58 had no PH and 10 had PAH. The mean age was 60.0 years, and 58.8% had limited cutaneous SSc. The DETECT algorithm had a sensitivity of 1.00 (95% confidence interval [95% CI] 0.69-1.00) and a negative predictive value (NPV) of 1.00 (95% CI 0.80-1.00), whereas the 2015 ESC/ERS guidelines had a sensitivity of 0.80 (95% CI 0.44-0.97) and an NPV of 0.94 (95% CI 0.81-0.99). In patients with a DLco of ≥60% (n = 27), the DETECT algorithm had a sensitivity of 1.00 (95% CI 0.29-1.00) and an NPV of 1.00 (95% CI 0.59-1.00), whereas the 2015 ESC/ERS guidelines had a sensitivity of 0.67 (95% CI 0.09-0.99) and an NPV of 0.94 (95% CI 0.71-1.00). The DETECT algorithm has high sensitivity and NPV for diagnosis of PAH, including among individuals with a DLco of ≥60%.

Outcomes of patients with decreased arterial oxyhaemoglobin saturation on pulmonary arterial hypertension drugs.

Drugs approved for the treatment of pulmonary arterial hypertension (PAH) improve long-term outcomes. These drugs have pulmonary vasodilator properties which may potentially cause a decrease in arterial oxyhaemoglobin saturation (S aO2 ) in some patients. The present retrospective study of the French Pulmonary Hypertension Registry aimed to describe the clinical characteristics and outcomes of patients showing a ≥3% decrease in S aO2 while treated with PAH drugs. We reviewed 719 PAH patients. The exclusion criteria were PAH associated with congenital heart disease and PAH with overt features of venous/capillaries involvement. 173 (24%) patients had a ≥3% decrease in S aO2 . At diagnosis, they were older with a lower diffusing capacity of the lung for carbon monoxide and a shorter 6-min walk distance compared with those who did not display a ≥3% decrease in S aO2 . The percentage of patients meeting the European Society of Cardiology/European Respiratory Society (ESC/ERS) low-risk criteria at re-evaluation was significantly lower in those with a ≥3% decrease in S aO2 and more patients started long-term oxygen therapy in this group (16% versus 5%; p<0.001). A ≥3% decrease in S aO2 was associated with a poorer survival (hazard ratio 1.81, 95% CI 1.43-2.34; p<0.0001). In a multivariate Cox analysis, a ≥3% decrease in S aO2 was a prognostic factor independent of age at diagnosis and ESC/ERS risk stratification at follow-up. When treated with PAH drugs, a large subset of patients experience a ≥3% decrease in S aO2 , which is associated with worse long-term outcomes and reduced survival.

Pulmonary arterial hypertension: guidelines and unmet clinical needs.

The term pulmonary arterial hypertension (PAH) identifies a heterogeneous group of diseases characterized by a progressive increase in pulmonary arterial resistance (PVR), which causes a significant burden in terms of quality of life, right heart failure and premature death. The pathogenesis of PAH is not completely clear: the remodeling of the small pulmonary vessels is crucial, causing an increase in the resistance of the pulmonary circle. Its diagnosis is based on cardiac catheterization of the right heart. According to the present hemodynamic definition of pulmonary hypertension (PH) proposed by the Guidelines of the European Society of Cardiology/European Respiratory Society (ESC-ERS), the mean pulmonary arterial pressure (mPAP) values are ≥25 mmHg. In case of PAH, apart from an mPAP value ≥25 mmHg, patients must have a >3 Wood units increase in PVR and normal pressure values of the left heart. PH is a pathophysiological condition observed in more than 40 different diseases, while PAH is a primary disease of the pulmonary bloodstream potentially treatable with specific drugs. PAH is a severe complication of systemic sclerosis (SSc) affecting about 10% of the patients. Due to the devastating nature of SSc-PAH, there is a clear need to systematically adopt appropriate screening programs. In fact, despite awareness of the negative impact of SSc-PAH on quality of life and survival, as well as on the severity of lung function, at the moment standardized and shared guidelines and/or screening programs for the diagnosis and the subsequent early treatment of PAH in SSc are not available. The aim of the present paper is to highlight the lights and shadows of SSc-PAH, unraveling the unmet clinical needs on this topic with a proposal of clinical-diagnostic and therapeutic guidelines.

Plasma insulin-like growth factor binding protein 1 in pulmonary arterial hypertension

Background Beside the pulmonary vasoconstriction observed in pulmonary arterial hypertension (PAH), severe proliferative and antiapoptotic cellular phenotypes result in vascular remodelling. Many recent findings indicate similarities between PAH and tumour pathology. For instance, insulin-like growth factor (IGF)-1 signalling, which is known to promote tumour development, is implicated in PAH. Higher circulating IGF binding protein (IGFBP)-1 levels are associated with worse survival in PAH. The present study aimed to investigate the relationship between plasma levels of various tumour-related biomarkers and PAH. Methods: IGFBP-1, -2 and -7, along with other tumour-related biomarkers, were measured in plasma from 48 treatment-naïve PAH patients and 16 healthy controls, using proximity extension assays. Among the PAH patients, 33 were also studied at an early treatment follow-up. Results: Plasma IGFBP-1 (p < .003), IGFBP-2 (p < .001), IGFBP-7 (p < .008), vimentin (p < .001), carbonic anhydrase 9 (p < .001), S100A11 (p < .001), human epididymis protein 4 (p < .001) and folate receptor-α (p < .004) were elevated in PAH, compared to controls. IGFBP-1 exhibited the most interesting correlations to clinical parameters and was selected for further analyses. IGFBP-1 correlated specifically to N-terminal prohormone of brain natriuretic peptide (NT-proBNP) (r = 0.44, p < .002), mean right atrial pressure (r = 0.41, p < .004), venous oxygen saturation (r = –0.43, p < .003), cardiac index (r = –0.32, p < .03) and 6-minute walking distance (r = –0.29, p < .05). Plasma IGFBP-1 also correlated to risk scores based on the European Society of Cardiology/European Respiratory Society (ESC/ERS) PAH guidelines (r = 0.43, p < .003) and the REVEAL model (r = 0.46, p < .001). PAH patients with supra-median baseline IGFBP-1 levels showed a trend for worse overall survival than those with infra-median levels (p = .087). IGFBP-1 was unaltered between baseline and an early treatment follow-up. However, IGFBP-1 changes, between baseline and follow-up, correlated to changes in NT-proBNP (r = 0.48, p < .006). Conclusion: Plasma IGFBP-1 levels at PAH diagnosis show moderate association to NT-proBNP and hemodynamics as well as with ESC/ERS and REVEAL risk scores.

Risk assessment in severe pulmonary hypertension due to interstitial lung disease

The updated hemodynamic definition of pulmonary hypertension (PH) due to interstitial lung disease (ILD) differentiates severe and non-severe phenotypes, but no further risk stratification strategy has been established or validated for severe PH due to ILD. We aimed to assess the prognostic value of a truncated version of the European Society of Cardiology/European Respiratory Society (ESC/ERS) PH risk stratification scheme in severe PH due to ILD. We retrospectively analyzed 185 patients with severe PH (mean pulmonary artery pressure of ≥35 mmHg or ≥25 mmHg with cardiac index <2.0liter/min/m2) due to ILD who were enrolled in the Giessen PH Registry after being referred for invasive diagnostic work-up of suspected PH during 1995‒2018. A truncated ESC/ERS risk stratification scheme (based on 8 parameters from the full scheme) was applied. Kaplan-Meier and univariate Cox regression analyses were used to evaluate transplant-free survival and hazard ratios, respectively. During follow-up (median [interquartile range]: 19 [7-40] months), 146 events occurred. Using baseline data for risk stratification, 5-year transplant-free survival of low-, intermediate-, and high-risk groups was 43%, 15%, and 4%, respectively (log-rank p = 0.010; hazard ratio of high- vs low-risk group: 3.116 [95% CI: 1.428-6.800]). Using follow-up data (at 11 [6.0-32.5] months) for risk stratification, 5-year survival of low-, intermediate-, and high-risk groups was 22%, 3%, and 0%, respectively (log-rank p = 0.005). The truncated ESC/ERS scheme was clinically useful and demonstrated prognostic relevance in severe PH due to ILD.