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on CCB monotherapy, 14.7% on initial CCB plus another initial PAH therapy, and the remaining patients had the CCB withdrawn and/or PAH therapy added.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.

Impact of rapid sequential combination therapy on distinct haemodynamic measures in newly diagnosed pulmonary arterial hypertension.

AIMS: In pulmonary arterial hypertension (PAH), upfront combination therapy with ERA and PDE5i is associated with a reduction in morbidity and mortality events and improves standard haemodynamics, but data remain limited. Aims of this study were (i) to capture detailed haemodynamic effects of rapid sequential dual combination therapy in patients with newly diagnosed PAH; (ii) to monitor the impact of treatment initiation on clinical variables and patients' risk status, and (iii) to compare the treatment effect in patients with 'classical PAH' and 'PAH with co-morbidities'. METHODS: Fifty patients (median age 57 [42-71] years, 66% female) with newly diagnosed PAH (76% idiopathic) were treated with a PD5i/sGC-S or ERA, followed by addition of the respective other drug class within 4 weeks. All patients underwent repeat right heart catheterization (RHC) during early follow-up. RESULTS: At early repeat RHC (7 ± 2 months), there were substantial reductions in mean pulmonary artery pressure (mPAP: 52.2 ± 13.5 to 39.0 ± 10.6 mmHg; -25.3%), and pulmonary vascular resistance (PVR: 12.1 ± 5.7 to 5.8 ± 3.1 WU; -52.1%), and an increase in cardiac index (2.1 ± 0.4 to 2.7 ± 0.7 mL/min/m2; +32.2%) (all P < 0.05). Haemodynamic improvements correlated with improved clinical parameters including 6-min walking distance (336 ± 315 to 389 ± 120 m), NTproBNP levels (1.712 ± 2.024 to 506 ± 550 ng/L, both P < 0.05) and WHO-FC at 12 months, resulting in improved risk status, and were found in patients with few (n = 37) or multiple cardiovascular co-morbidities (BMI > 30 kg/m2, hypertension, diabetes, coronary artery disease [≥3]; n = 13), albeit baseline PVR in PAH patients with multiple co-morbidities was lower (9.3 ± 4.4 vs. 13.1 ± 5.9 WU) and PVR reduction less pronounced compared with those with few co-morbidities (-42.7% vs. -54.7%). However, comprehensive haemodynamic assessment considering further variables of prognostic relevance such as stroke volume index and pulmonary artery compliance showed similar improvements among the two groups (SVI: +50.0% vs. +49.2%; PAC: 91.7% vs. 100.0%). Finally, the 4-strata risk assessment approach was better able to capture treatment response as compared with other approaches, particularly in patients with co-morbidities. CONCLUSIONS: Rapid sequential combination therapy with PDE5i/sGC-S and ERA substantially ameliorates cardiopulmonary haemodynamics at early follow-up in patients without, and to a lesser extent, with cardiovascular co-morbidities. This occurs in line with improvements of clinical parameters and risk status.

CT-derived lung vessel morphology correlates with prognostic markers in precapillary pulmonary hypertension.

BACKGROUND: While computed tomography pulmonary angiography (CTPA) is an integral part of the work-up in patients with suspected pulmonary hypertension (PH), there is no established CTPA-derived prognostic marker. We aimed to assess whether quantitative readouts of lung vessel morphology correlate with established prognostic indicators in PH. METHODS: We applied a fully-automatic in-house developed algorithm for segmentation of arteries and veins to determine lung vessel morphology in patients with precapillary PH who underwent right heart catheterization and CTPA between May 2016 and May 2019. Primary endpoint of this retrospective study was the calculation of receiver operating characteristics for identifying low and high mortality risk according to the 3-strata risk assessment model presented in the current guidelines. RESULTS: We analyzed 73 patients, median age 65 years (interquartile range (IQR): 54-76), female/male ratio 35/38, median mean pulmonary arterial pressure 37 mm Hg (IQR: 30-46), and found significant correlations with important prognostic factors in pulmonary arterial hypertension. N-terminal pro-brain natriuretic peptide, cardiac index, mixed venous oxygen saturation, and 6-minute walking distance were correlated with the ratio of the number of arteries over veins with vessel diameters of 6-10 mm (Spearman correlation coefficients ρ = 0.64, p < 0.001; ρ = -0.60, p < 0.001; ρ = -0.47, p = 0.005; ρ = -0.45, p = 0.001, respectively). This ratio predicted a low- and high-risk score with an area under the curve of 0.73 (95% confidence interval (CI): 0.56-0.90) and 0.86 (95% CI: 0.74-0.97), respectively. CONCLUSIONS: The ratio of the number of arteries over veins with diameters between 6 and 10 mm is significantly correlated with prognostic markers in pulmonary hypertension and predicts low and high mortality risk.

Dual-layer dual-energy CT-derived pulmonary perfusion for the differentiation of acute pulmonary embolism and chronic thromboembolic pulmonary hypertension.

OBJECTIVES: To evaluate dual-layer dual-energy computed tomography (dlDECT)-derived pulmonary perfusion maps for differentiation between acute pulmonary embolism (PE) and chronic thromboembolic pulmonary hypertension (CTEPH). METHODS: This retrospective study included 131 patients (57 patients with acute PE, 52 CTEPH, 22 controls), who underwent CT pulmonary angiography on a dlDECT. Normal and malperfused areas of lung parenchyma were semiautomatically contoured using iodine density overlay (IDO) maps. First-order histogram features of normal and malperfused lung tissue were extracted. Iodine density (ID) was normalized to the mean pulmonary artery (MPA) and the left atrium (LA). Furthermore, morphological imaging features for both acute and chronic PE, as well as the combination of histogram and morphological imaging features, were evaluated. RESULTS: In acute PE, normal perfused lung areas showed a higher mean and peak iodine uptake normalized to the MPA than in CTEPH (both p < 0.001). After normalizing mean ID in perfusion defects to the LA, patients with acute PE had a reduced average perfusion (IDmean,LA) compared to both CTEPH patients and controls (p < 0.001 for both). IDmean,LA allowed for a differentiation between acute PE and CTEPH with moderate accuracy (AUC: 0.72, sensitivity 74%, specificity 64%), resulting in a PPV and NPV for CTEPH of 64% and 70%. Combining IDmean,LA in the malperfused areas with the diameter of the MPA (MPAdia) significantly increased its ability to differentiate between acute PE and CTEPH (sole MPAdia: AUC: 0.76, 95%-CI: 0.68-0.85 vs. MPAdia + 256.3 * IDmean,LA - 40.0: AUC: 0.82, 95%-CI: 0.74-0.90, p = 0.04). CONCLUSION: dlDECT enables quantification and characterization of pulmonary perfusion patterns in acute PE and CTEPH. Although these lack precision when used as a standalone criterion, when combined with morphological CT parameters, they hold potential to enhance differentiation between the two diseases. CLINICAL RELEVANCE STATEMENT: Differentiating between acute PE and CTEPH based on morphological CT parameters is challenging, often leading to a delay in CTEPH diagnosis. By revealing distinct pulmonary perfusion patterns in both entities, dlDECT may facilitate timely diagnosis of CTEPH, ultimately improving clinical management. KEY POINTS: • Morphological imaging parameters derived from CT pulmonary angiography to distinguish between acute pulmonary embolism and chronic thromboembolic pulmonary hypertension lack diagnostic accuracy. • Dual-layer dual-energy CT reveals different pulmonary perfusion patterns between acute pulmonary embolism and chronic thromboembolic pulmonary hypertension. • The identified parameters yield potential to enable more timely identification of patients with chronic thromboembolic pulmonary hypertension.

Preexisting Chronic Thromboembolic Pulmonary Hypertension in Acute Pulmonary Embolism.

BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) is considered a complication of pulmonary embolism (PE). However, signs of CTEPH may exist in patients with a first symptomatic PE. RESEARCH QUESTION: Which radiologic findings on CT pulmonary angiography (CTPA) at the time of acute PE could indicate the presence of preexisting CTEPH? STUDY DESIGN AND METHODS: This study included unselected patients with acute PE who were prospectively followed up for 2 years with a structured visit schedule. Two expert radiologists independently assessed patients' baseline CTPAs for preexisting CTEPH; in case of disagreement, a decision was reached by a 2:1 majority with a third expert radiologist. In addition, the radiologists checked for predefined individual parameters suggesting chronic PE and pulmonary hypertension. RESULTS: Signs of chronic PE or CTEPH at baseline were identified in 46 of 303 included patients (15%). Intravascular webs, arterial narrowing or retraction, dilated bronchial arteries, and right ventricular hypertrophy were the main drivers of the assessment. Five (1.7%) patients were diagnosed with CTEPH during follow-up. All four patients diagnosed with CTEPH early (83-108 days following acute PE) were found in enriched subgroups based on the experts' overall assessment or fulfilling a minimum number of the predefined radiologic criteria at baseline. The specificity of preexisting CTEPH diagnosis and the level of radiologists' agreement improved as the number of required criteria increased. INTERPRETATION: Searching for predefined radiologic parameters suggesting preexisting CTEPH at the time of acute PE diagnosis may allow for targeted follow-up strategies and risk-adapted CTEPH screening, thus facilitating earlier CTEPH diagnosis.

Profiles and treatment patterns of patients with pulmonary arterial hypertension on monotherapy at experienced centres.

AIMS: Guideline recommendations highlight the critical role of combination therapy for the treatment of pulmonary arterial hypertension (PAH). Conversely, registry data demonstrate that a considerable number of PAH patients remain on monotherapy. The reasons for this discrepancy remain elusive. The aim of this study was to assess the patient profiles, treatment patterns, and disease characteristics of patients diagnosed with PAH who were kept on monotherapy at experienced pulmonary hypertension (PH) centres and to capture potential reasons for monotherapy. METHODS AND RESULTS: We analysed the patient profiles of 182 patients on monotherapy with PAH-targeted drugs, managed at experienced PH expert centres (Cologne, Giessen, Heidelberg, and Dresden). Patients were identified based on their latest follow-up visit and analysed retrospectively from the time of PAH diagnosis to last follow-up. Patients were dichotomized by age, and patient characteristics, treatment patterns, response to therapy, change in risk status, and drug tolerability were recorded during the course of their disease. Patients' mean age was 69.1 ± 13.1 years at the most recent follow-up (Key Time Point 1) and 64.5 ± 14.9 years at the time of diagnosis (Key Time Point 2). The mean time on monotherapy was 60.7 ± 53.8 months; 35.7/64.3% of patients were male/female. The majority (66.5%) had idiopathic PAH, followed by PAH associated with connective tissue disease (17.0%) and portopulmonary PH (8.2%). Among patients on monotherapy, there were five main clusters: (i) patients with failed escalation attempts mostly because of intolerability (26.9%); (ii) low risk on monotherapy, favourable response, and no reason for escalation (24.2%); (iii) patients with mild PAH (36.3%); (iv) elderly patients with PAH and multiple co-morbidities (38.5%); and (v) patients with associated forms of PAH where the level of evidence for combination therapies is considered low (16.5%). There were substantial differences between patients above or below the median age (68 years). The most frequently used monotherapy for PAH was phosphodiesterase type 5 inhibitors (75.3%). CONCLUSIONS: A considerable number of PAH patients are on monotherapy at large PH expert centres, characterized by specific reasons that justify this kind of treatment. Nevertheless, as comprehensive treatment strategies have shown improved long-term outcomes even in mildly symptomatic patients, each case of monotherapy should be justified.

Spectral Detector CT-Derived Pulmonary Perfusion Maps and Pulmonary Parenchyma Characteristics for the Semiautomated Classification of Pulmonary Hypertension.

Objectives: To evaluate the usefulness of spectral detector CT (SDCT)-derived pulmonary perfusion maps and pulmonary parenchyma characteristics for the semiautomated classification of pulmonary hypertension (PH). Methods: A total of 162 consecutive patients with right heart catheter (RHC)-proven PH of different aetiologies as defined by the current ESC/ERS guidelines who underwent CT pulmonary angiography (CTPA) on SDCT and 20 patients with an invasive rule-out of PH were included in this retrospective study. Semiautomatic lung segmentation into normal and malperfused areas based on iodine density (ID) as well as automatic, virtual non-contrast-based emphysema quantification were performed. Corresponding volumes, histogram features and the ID SkewnessPerfDef-Emphysema-Index (δ-index) accounting for the ratio of ID distribution in malperfused lung areas and the proportion of emphysematous lung parenchyma were computed and compared between groups. Results: Patients with PH showed a significantly greater extent of malperfused lung areas as well as stronger and more homogenous perfusion defects. In group 3 and 4 patients, ID skewness revealed a significantly more homogenous ID distribution in perfusion defects than in all other subgroups. The δ-index allowed for further subclassification of subgroups 3 and 4 (p < 0.001), identifying patients with chronic thromboembolic PH (CTEPH, subgroup 4) with high accuracy (AUC: 0.92, 95%-CI, 0.85-0.99). Conclusion: Abnormal pulmonary perfusion in PH can be detected and quantified by semiautomated SDCT-based pulmonary perfusion maps. ID skewness in malperfused lung areas, and the δ-index allow for a classification of PH subgroups, identifying groups 3 and 4 patients with high accuracy, independent of reader expertise.

Chronic thromboembolic pulmonary hypertension and impairment after pulmonary embolism: the FOCUS study.

AIMS: To systematically assess late outcomes of acute pulmonary embolism (PE) and to investigate the clinical implications of post-PE impairment (PPEI) fulfilling prospectively defined criteria. METHODS AND RESULTS: A prospective multicentre observational cohort study was conducted in 17 large-volume centres across Germany. Adult consecutive patients with confirmed acute symptomatic PE were followed with a standardized assessment plan and pre-defined visits at 3, 12, and 24 months. The co-primary outcomes were (i) diagnosis of chronic thromboembolic pulmonary hypertension (CTEPH), and (ii) PPEI, a combination of persistent or worsening clinical, functional, biochemical, and imaging parameters during follow-up. A total of 1017 patients (45% women, median age 64 years) were included in the primary analysis. They were followed for a median duration of 732 days after PE diagnosis. The CTEPH was diagnosed in 16 (1.6%) patients, after a median of 129 days; the estimated 2-year cumulative incidence was 2.3% (1.2-4.4%). Overall, 880 patients were evaluable for PPEI; the 2-year cumulative incidence was 16.0% (95% confidence interval 12.8-20.8%). The PPEI helped to identify 15 of the 16 patients diagnosed with CTEPH during follow-up (hazard ratio for CTEPH vs. no CTEPH 393; 95% confidence interval 73-2119). Patients with PPEI had a higher risk of re-hospitalization and death as well as worse quality of life compared with those without PPEI. CONCLUSION: In this prospective study, the cumulative 2-year incidence of CTEPH was 2.3%, but PPEI diagnosed by standardized criteria was frequent. Our findings support systematic follow-up of patients after acute PE and may help to optimize guideline recommendations and algorithms for post-PE care.

Detection of patients with chronic thromboembolic pulmonary hypertension by volumetric iodine quantification in the lung-a case control study.

BACKGROUND: To evaluate whether volumetric iodine quantification of the lung allows for the automatic identification of patients with chronic thromboembolic pulmonary hypertension (CTEPH) and whether the extent of pulmonary malperfusion correlates with invasive hemodynamic parameters. METHODS: Retrospective data base search identified 30 consecutive patients with CTEPH who underwent CT pulmonary angiography (CTPA) on a spectral-detector CT scanner. Thirty consecutive patients who underwent an identical CT examination for evaluation of suspected acute pulmonary embolism and had no signs of pulmonary embolism or PH, served as control cohort. Lungs were automatically segmented for all patients and normal and malperfused volumes were segmented based on iodine density thresholds. Results were compared between groups. For correlation analysis between the extent of malperfused volume and mean pulmonary artery pressure (mPAP) and pulmonary vascular resistance (PVR) 3 patients were excluded because of a time span of more than 30 days between CTPA and right heart catheterization. RESULTS: Patients with CTEPH had a higher percentage of malperfused lung compared to controls (43.25%±24.72% vs. 21.82%±20.72%; P=0.001) and showed reduced mean iodine density in malperfused and normal-perfused lung areas, as well as in the vessel volume. Controls showed a left-tailed distribution of iodine density in malperfused lung areas while patients with CTEPH had a more symmetrical distribution (Skew: -0.382±0.435 vs. -0.010±0.396; P=0.004). Patients with CTEPH showed a significant correlation between the percentage of malperfused lung volume and the PVR (r=0.57, P=0.001). CONCLUSIONS: Volumetric iodine quantification helps to identify patients with CTEPH by showing increased areas of malperfusion. The extent of malperfusion might provide a measurement for disease severity in patients with CTEPH.

Selonsertib in adults with pulmonary arterial hypertension (ARROW): a randomised, double-blind, placebo-controlled, phase 2 trial.

BACKGROUND: Data obtained in human lung tissue and preclinical models suggest that oxidative stress and increased apoptosis signal-regulating kinase 1 (ASK1) activity might have a prominent role in the pathobiology of pulmonary arterial hypertension (PAH). The purpose of this study was to determine the efficacy, safety, and tolerability of the ASK1 inhibitor selonsertib compared with placebo in patients with PAH. METHODS: We did a randomised, double-blind, placebo-controlled, phase 2 trial at 46 centres located in Canada, France, Germany, Italy, the Netherlands, Spain, the UK, and the USA. Participants were aged 18-75 years and had an established diagnosis of idiopathic or hereditary PAH, or PAH associated with connective tissue disease, drugs or toxins, human immunodeficiency virus, or repaired congenital heart defects. Patients were stratified by PAH aetiology and background therapy, and randomly assigned (1:1:1:1) using an interactive voice-response or web-response system to placebo or selonsertib 2 mg, 6 mg, or 18 mg administered orally once daily. Both placebo and selonsertib were in tablet form. The primary efficacy endpoint was change in pulmonary vascular resistance, measured by right heart catheterisation, from baseline to week 24 in the full analysis set. Pair-wise comparisons between each of the selonsertib groups and the placebo group were made with a stratified Wilcoxon (van Elteren) rank sum test for participants without major protocol deviations who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT02234141. FINDINGS: Between Dec 3, 2014, and Nov 13, 2015, 151 patients were enrolled and randomly assigned. Of 150 participants who received selonsertib or placebo, 134 (89%) completed 24 weeks of the randomly assigned treatment; all were on background PAH therapy (138 [92%] on combination therapy). 90 (60%) patients were in functional class II and 60 (40%) in functional class III. Mean baseline pulmonary vascular resistance was 772 (SD 334) dyn·s/cm5. Change in pulmonary vascular resistance was 6·0 dyn·s/cm5 (SD 28·0; n=31) for placebo, and 35·0 (35·4) dyn·s/cm5 (n=35; p=0·21 vs placebo) for 2 mg selonsertib, -28·0 (30·2) dyn·s/cm5 (n=34; p=0·27 vs placebo) for 6 mg selonsertib, and -21·0 (37·9) dyn·s/cm5 (n=36; p=0·60 vs placebo) for 18 mg selonsertib. The most frequent adverse events were headache (17 [15%]), abnormal dreams (eight [7%]), nausea (seven [6%]), and diarrhoea (seven [6%]) in the selonsertib groups, and headache (six [16%]), nausea (five [14%]), and diarrhoea (two [5%]) in the placebo group. Serious adverse events occurred in 23 (20%) of 113 selonsertib-treated patients and seven (19%) of 37 patients who received placebo. INTERPRETATION: Selonsertib once daily for 24 weeks did not lead to a significant reduction in pulmonary vascular resistance or to clinical improvement in patients with PAH, but appeared to be safe and well tolerated. Although these data do not support the clinical use of selonsertib in PAH, further study of the potential of targeting the ASK1-p38 pathway in PAH is warranted. FUNDING: Gilead Sciences.

k-t accelerated multi-VENC 4D flow MRI improves vortex assessment in pulmonary hypertension.

BACKGROUND: 4D flow imaging can be used to evaluate vortex formation in the pulmonary artery seen in patients with pulmonary hypertension. We evaluated if a k-t accelerated multi-VENC (velocity encoding) 4D flow acquisition improves image quality, inter-reader agreement and correlation with hemodynamic parameters. METHODS: A total of 14 patients with pulmonary hypertension (5 females, 9 males; mean age 61 ± 16 years) underwent 4D flow MRI (magnetic resonance imaging) and right heart catheterization. In addition to that, 13 healthy volunteers (2 females, 11 males, mean age 33 ± 12 years) also underwent 4D flow MRI. Multi- and single-VENC datasets were reconstructed and evaluated for vortex formation and vortex duration by two blinded readers and image quality was rated on a 5-point scale. RESULTS: Both readers rated image quality as significantly higher on multi-VENC datasets (3.96 ± 0.71 vs. 2.56 ± 0.93, p < 0.001; 4.70 ± 0.61 vs. 4.07 ± 0.92, p = 0.003). Inter-reader correlation for vortex duration quantification was higher on multi-VENC datasets compared to single-VENC datasets (r = 0.63 vs. r = 0.44). No significant correlation was found between vortex duration and mean pulmonary artery pressure in patients with PH. CONCLUSION: Multi-VENC 4D flow MRI significantly improves image quality and inter-reader agreement for the evaluation of vortex formation in the pulmonary artery.

Ferric carboxymaltose in patients with pulmonary arterial hypertension and iron deficiency: a long-term study.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a progressive disease with limited survival. Iron deficiency (ID) correlates with disease severity and mortality. While oral iron supplementation was shown to be insufficient in such patients, the potential impact of parenteral iron on clinical measures warrants further investigation. METHODS: We retrospectively analysed the long-term effects of intravenous ferric carboxymaltose (FCM) on iron status and clinical measures in patients with PAH and ID [ferritin < 100 µg/L or ferritin 100-300 µg/L and transferrin saturation (TSAT) < 20%] who were on stable targeted PAH therapy, compared with matched controls without ID. Patients with ID received a single infusion of FCM (500 to 1000 mg). Clinical measures monitored included exercise capacity, World Health Organization (WHO) functional class, ESC/ERS risk status, and hospitalizations. The observation period was up to 18 months. RESULTS: One hundred and seventeen patients (mean age 60.9 ± 16.1 years; 64.1% females) with confirmed PAH and on stable targeted therapy for ≥3 months were included (58 with and 59 patients without ID who did not receive FCM). In patients with ID, iron supplementation with FCM resulted in an immediate and sustained improvement of iron status for up to 18 months (serum iron, ferritin, TSAT, all P < 0.01). Fourteen patients in the FCM group received a second FCM infusion after 9.6 ± 4.8 months due to recurrent ID. At 6 and 18 months after FCM infusion, 6 min walk distance improved from 377.5 ± 15.9 at baseline to 412.5 ± 15.1 and 400.8 ± 14.5 m, respectively (both P < 0.05). WHO functional class (P < 0.05) and ESC/ERS risk status also improved, and there was a reduction of hospitalizations for worsening PAH in the 12 months post vs. prior to iron repletion (P = 0.029). No significant changes were observed in the control group. FCM was well tolerated in all patients, with no severe adverse events. CONCLUSIONS: In addition to targeted therapy, correction of ID by parenteral iron supplementation with FCM appears feasible and safe, has sustained effects on iron status, and may improve the clinical status and hospitalization rates in patients with PAH. Larger controlled studies are required to confirm this finding.

Quality of Life 3 and 12 Months Following Acute Pulmonary Embolism: Analysis From a Prospective Multicenter Cohort Study.

BACKGROUND: Few data are available on the long-term course and predictors of quality of life (QoL) following acute pulmonary embolism (PE). RESEARCH QUESTION: What are the kinetics and determinants of disease-specific and generic health-related QoL 3 and 12 months following an acute PE? STUDY DESIGN AND METHODS: The Follow-up after Acute Pulmonary Embolism (FOCUS) study prospectively followed up consecutive adult patients with objectively diagnosed PE. Patients were considered for study who completed the Pulmonary Embolism Quality of Life (PEmb-QoL) questionnaire at predefined visits 3 and 12 months following PE. The course of disease-specific QoL as assessed using the PEmb-QoL and the impact of baseline characteristics using multivariable mixed effects linear regression were studied; also assessed was the course of generic QoL as evaluated by using the EuroQoL Group 5-Dimension 5-Level utility index and the EuroQoL Visual Analog Scale. RESULTS: In 620 patients (44% women; median age, 62 years), overall disease-specific QoL improved from 3 to 12 months, with a decrease in the median PEmb-QoL score from 19.4% to 13.0% and a mean individual change of -4.3% (95% CI, -3.2 to -5.5). Female sex, cardiopulmonary disease, and higher BMI were associated with worse QoL at both 3 and 12 months. Over time, the association with BMI became weaker, whereas older age and previous VTE were associated with worsening QoL. Generic QoL also improved: the mean ± SD EuroQoL Group 5-Dimension 5-Level utility index increased from 0.85 ± 0.22 to 0.87 ± 0.20 and the visual analog scale from 72.9 ± 18.8 to 74.4 ± 19.1. INTERPRETATION: In a large cohort of survivors of acute PE, the change of QoL was quantified between months 3 and 12 following diagnosis, and factors independently associated with lower QoL and slower recovery of QoL were identified. This information may facilitate the planning and interpretation of clinical trials assessing QoL and help guide patient management. CLINICAL TRIAL REGISTRATION: German Clinical Trials Registry (Deutsches Register Klinischer Studien: www.drks.de); No.: DRKS00005939.

Pulmonary hypertension associated with left-sided heart failure.

PURPOSE OF REVIEW: Pulmonary hypertension is a common phenomenon in heart failure patients that is highly relevant for morbidity and outcome. Although postcapillary in nature, the pathophysiology of pulmonary hypertension in patients with heart failure with reduced or preserved ejection fraction is complex, and decisions about management strategies remain challenging. RECENT FINDINGS: Recently, the hemodynamic definitions and subclassification of postcapillary pulmonary hypertension have been revisited. The distinction between isolated postcapillary pulmonary hypertension (IpcPH) and combined post and precapillary pulmonary hypertension (CpcPH) and their definition are essential. Novel data on the prognostic impact of hemodynamic variables and right ventricular function highlight the importance of cardiopulmonary interaction in patients with left-sided heart failure (LHF). Furthermore, the impact of management strategies including medical therapy, remote hemodynamic monitoring, and interventional approaches on hemodynamics and outcome has recently been investigated. Here, we critically review recent developments and future considerations in this field, and highlight distinct treatment strategies targeting the underlying left heart condition, the pulmonary circulation, and/or impaired right ventricular function. SUMMARY: Detailed hemodynamic characterization and proper phenotyping are essential for prognostication and the management of patients with pulmonary hypertension associated with LHF, both in clinical practice and when addressing research questions.

Flow rate variance of a fully implantable pump for the delivery of intravenous treprostinil in pulmonary arterial hypertension.

Implantable infusion pumps might improve the convenience and safety of intravenous treprostinil for pulmonary arterial hypertension. The LENUS Pro® pump (approved in Europe) has a fixed flow rate. Based on 126 pumps and 2853 refills, we retrospectively analyzed the actual flow rate from 09/2010 to 09/2018. A relevant flow rate variance is evident after three years; therefore, flow rate monitoring and dose adjustment are mandatory.

Diagnosis of pulmonary hypertension using spectral-detector CT.

OBJECTIVES: To evaluate the value of spectral-detector CT (SDCT) in the diagnosis of chronic thromboembolic pulmonary hypertension (CTEPH), its differentiation against other etiologies of pulmonary hypertension (PH) and in the prediction of disease severity. MATERIALS AND METHODS: 60 patients with suspected PH underwent SDCT. Additional diagnostic tests in accordance with the ESC guidelines including right heart catherization and VQ-SPECT were performed. After full diagnostic work-up patients were classified as: 21 precapillary PH, 5 postcapillary PH, 6 combined pre- and postcapillary PH, 19 CTEPH, 9 no PH. SDCT examinations were analyzed by two blinded readers deciding on the diagnosis of CTEPH and scoring the extent of perfusion abnormalities on iodine density images. An additional reading was performed using conventional CTPA images only. RESULTS: With access to SDCT data, both readers reached a sensitivity of 100% for the diagnosis of CTEPH with a specificity of 95.1% and 87.8%. On analysis of conventional CTPA images alone, specificity and diagnostic confidence decreased for both readers (Specificity 90.2 and 85.3%) while sensitivity dropped for the less experienced reader only (Sensitivity 78.9%). Patients with PH showed significantly more perfusion abnormalities than patients without PH (16.6 ±â€¯8.4 vs. 9.5 ±â€¯8.9 p < 0.001) and the extent of perfusion abnormalities correlated with the mean pulmonary artery pressure (r = 0.37 p = 0.008). CONCLUSIONS: SDCT offers confident identification of patients with CTEPH and enables a comprehensive analysis of pulmonary vasculature, pulmonary perfusion and the lung parenchyma in a single examination for patients with suspected PH.

High-risk pregnancy in a patient with pulmonary arterial hypertension due to congenital heart disease (PAH-CHD) with temporary shunt inversion and deoxygenation.

Atrial septal defect (ASD) is one of the most frequent congenital heart diseases (CHD). Up to 10% of adults with an ASD develop pulmonary arterial hypertension (PAH, PAH-CHD) in their lifetime. Despite improved therapy options, gravidity remains a substantial risk for both maternal and neonatal mortality in PAH-CHD patients. In our patient, gravidity remained uncomplicated until week 32, under specific monotherapy with tadalafil, before onset of dyspnea and markedly increase of systolic pulmonary arterial pressure (PAP) was observed in echocardiography. Urgent Caesarian delivery was performed without any complications and a healthy baby was born. However, immediately afterwards, the patient desaturated (SpO2 65%, PaO2 37 mmHg) due to a shunt inversion with now right-to-left shunt through the residual ASD. She was admitted to our intensive care unit and specific PH therapy was escalated to a triple combination of tadalafil, ambrisentan, and iloprost. Hereafter, in a slow process of approximately three weeks, the patient's condition improved to baseline. This rare case of a young woman with high-risk pregnancy in PAH-CHD highlights the hemodynamic changes and treatment options during pregnancy in these patients and emphasizes the urgency of a close monitoring at specialized GUCH/PAH centers with experience in managing PAH under these circumstances.

Therapeutic potential of phosphodiesterase type 5 inhibitors in heart failure with preserved ejection fraction and combined post- and pre-capillary pulmonary hypertension.

OBJECTIVE: Heart failure with preserved ejection fraction (HFpEF) is frequently associated with pulmonary hypertension (PH), which substantially impacts survival. Based on pulmonary vascular resistance (PVR) and the diastolic pressure gradient (DPG), current guidelines distinguish between isolated post-capillary PH (IpcPH) and combined post- and pre-capillary PH (CpcPH). However, the therapeutic consequences of this sub-classification remain entirely unclear. We specifically investigated the efficacy and safety of PDE5i in patients with HFpEF and CpcPH. METHODS: In 40 hemodynamically precisely characterized patients with HFpEF and Cpc-PH who were treated with a PDE5i for at least 12 months, the therapeutic effect on 6-minute walk distance (6MWD), WHO functional class (FC), NTproBNP levels, right ventricular function, and hospitalization rates was evaluated. RESULTS: Patients' mean age was 73 ±â€¯9 years, and comorbidities were frequent (78% hypertension, 58% atrial fibrillation, 35% diabetes). Initially, 38 patients (95%) were in WHO-FC III and 2 patients (5%) in WHO-FC II. Prior to PDE5i initiation, mean PAPm was 46.2 ±â€¯10.3 mmHg, PAWP 21.2 ±â€¯4.7 mmHg, DPG 5.5 ±â€¯7.2 mmHg, and PVR 6.2 ±â€¯3.0 WU. After 12 months of PDE5i therapy, the 6MWD increased from initially 277 ±â€¯17 to 340 ±â€¯18 m (p < 0.001), and the proportion of patients in WHO-FC I/II increased from 5% to 37.5%. NTproBNP levels decreased by 33% (p = 0.004), and TAPSE improved from 16.8 ±â€¯0.7 mm at baseline to 18.2 ±â€¯0.6 mm (p = 0.01). The rate of HF-associated hospitalizations was substantially lower in the 12 months post PDE5i initiation compared to the prior 12 months. The DPG had no impact on the response to therapy. No deaths occurred, and typical side effects of PDE5i were observed. CONCLUSION: These data indicate that at least a subset of precisely characterized patients with HFpEF and CpcPH who tolerate PDE5i may benefit from targeted therapy. A randomized study in this particular sub-population is warranted.