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BACKGROUND: In chronic thromboembolic pulmonary hypertension (CTEPH), fibrotic remodeling of tissue and thrombi contributes to disease progression. Removal of the thromboembolic mass by pulmonary endarterectomy (PEA) improves hemodynamics and right ventricular function, but the roles of different collagens before as well as after PEA are not well understood.METHODS: In this study, hemodynamics and 15 different biomarkers of collagen turnover and wound healing were evaluated in 40 CTEPH patients at diagnosis (baseline) and 6 and 18 months after PEA. Baseline biomarker levels were compared with a historical cohort of 40 healthy subjects.RESULTS: Biomarkers of collagen turnover and wound healing were increased in CTEPH patients compared with healthy controls, including a 35-fold increase in the PRO-C4 marker of type IV collagen formation and a 55-fold increase in the C3M marker of type III collagen degradation. PEA reduced pulmonary pressures to almost normal levels 6 months after the procedure, with no further improvement at 18 months. There were no changes in any of the measured biomarkers after PEA.CONCLUSIONS: Biomarkers of collagen formation and degradation are increased in CTEPH suggesting a high collagen turnover. While PEA effectively reduces pulmonary pressures, collagen turnover is not significantly modified by surgical PEA.

Pulmonary embolism is a risk factor for chronic thromboembolic pulmonary hypertension (CTEPH), but the prognostic impact of CTEPH on venous thromboembolism (VTE) mortality remains unclear. We examined the impact of CTEPH and other pulmonary hypertension (PH) subtypes on long-term mortality after VTE. We conducted a nationwide, population-based cohort study of all adult Danish patients alive 2 years after incident VTE without previous PH from 1995 to 2020 (n = 129,040). We used inverse probability of treatment weights in a Cox model to calculate standardized mortality rate ratios (SMRs) of the association between receiving a first-time PH diagnosis ≤2 years after incident VTE and mortality (all-cause, cardiovascular, and cancer). We grouped PH as PH associated with left-sided cardiac disease (group II), PH associated with lung diseases and/or hypoxia (group III), CTEPH (group IV), and unclassified (remaining patients). Total follow-up was 858,954 years. The SMR associated with PH overall was 1.99 (95% confidence interval 1.75 to 2.27) for all-cause, 2.48 (1.90 to 3.23) for cardiovascular, and 0.84 (0.60 to 1.17) for cancer mortality. The SMR for all-cause mortality was 2.62 (1.77 to 3.88) for group II, 3.98 (2.85 to 5.56) for group III, 1.88 (1.11 to 3.20) for group IV, and 1.73 (1.47 to 2.04) for unclassified PH. The cardiovascular mortality rate was increased approximately threefold for groups II and III but was not increased for group IV. Only group III was associated with increased cancer mortality. In conclusion, PH diagnosed ≤2 years after incident VTE was associated with an overall twofold increased long-term mortality driven by cardiovascular causes.

Resting right ventricular (RV) systolic function has in some studies been shown to be impaired after correction of an atrial septal defect (ASD) whereas impairment of left ventricular (LV) systolic function is uncertain. In the present study we examine the LV and RV systolic response to exercise in patients with a previously corrected ASD in order to investigate the myocardial capacity. Thirty-six adult ASD patients with a corrected isolated secundum ASD and eighteen adult age-matched controls underent a semi-supine exercise stress echocardiographic examination. At rest, LV parameters were comparable between groups, and RV global longitudinal strain (RV-GLS) was lower for the ASD group (−18.5%, 9 5% CI −20.0—−17.0%) compared with controls (−24.5%, 95% CI −27.7—−22.4%, p p = 0.01). Peak LV global longitudinal strain (LV-GLS) was borderline significantly lower (ASD: -18.4%, 95% CI −20.2—−16.6%, controls: −21.3%, 95% CI −23.6—−19.0%, p = 0.059). Both RVEF (ASD: 64%, 95% CI 60–68%, controls: 73%, 95% CI 65–80%, p = 0.05) and tricuspid annular plane systolic excursion (TAPSE) (ASD: 2.5 cm, 95% CI 2.3–2.7 cm, controls: 3.2 cm, 95% CI 2.9–3.6 cm, p 2/kg/min, 95% CI 30.3–35.5 mL O2/kg/min, controls: 35.2 mL O2/kg/min, 95% CI 31.6–38.8 mL O2/kg/min, p = 0.3). Corrected ASD patients demonstrate a reduced LV and RV systolic exercise response decades after ASD correction whereas resting parameters of LV and RV systolic function were within normal range. The presence of subclinical systolic myocardial dysfunction during exercise might be associated with the long-term morbidities documented in this patient group.

BACKGROUND: A substantial number of chronic thromboembolic pulmonary hypertension (CTEPH) patients experience dyspnea on exertion and limited exercise capacity despite surgically successful pulmonary endarterectomy (PEA). We sought to prospectively evaluate resting and peak exercise hemodynamics before, 3 and 12 months after PEA in consecutive CTEPH-patients and correlate it to physical functional capacity.METHODS AND RESULTS: Twenty consecutive CTEPH-patients were examined. Twelve months after PEA, 75% of patients with severely increased pre-PEA mean pulmonary arterial pressure (mPAP) at rest had normal or mildly increased mPAP. However, mPAP reduction was less pronounced during exercise where only 45% had normal or mildly increased mPAP at 12 months. Hemodynamic changes during exercise were tested using the pressure-flow relationship (i.e. mPAP/cardiac output (CO) slope). The average mPAP/CO slope was 7.5 ± 4.2 mm Hg/L/min preoperatively and 3.9 ± 3.0 mm Hg/L/min at 12 months (p CONCLUSION: Invasive exercise hemodynamic examination in CTEPH-patients demonstrates that after otherwise successful PEA surgery, >50% of patients have a significant increase in exercise mPAP, and the CO reserve remains compromised 12 months after PEA. Improvement in physical capacity is correlated with ∆CO.

Studies have suggested sex-related survival differences in chronic thromboembolic pulmonary hypertension (CTEPH). Whether long-term prognosis differs between men and women following pulmonary endarterectomy for CTEPH remains unclear. We investigated sex-specific survival after pulmonary endarterectomy for CTEPH. We included all patients who underwent pulmonary endarterectomy for CTEPH at two Scandinavian centers and obtained baseline characteristics and vital statuses from patient charts and national health-data registers. Propensity scores and weighting were used to account for baseline differences. Flexible parametric survival models were employed to estimate the association between sex and all-cause mortality and the absolute survival differences. The expected survival in an age-, sex-, and year of surgery matched general population was obtained from the Human Mortality Database, and the relative survival was used to estimate cause-specific mortality. A total of 444 patients were included, comprising 260 (59%) men and 184 (41%) women. Unadjusted 30-day mortality was 4.2% in men versus 9.8% in women (p = 0.020). In weighted analyses, long-term survival did not differ significantly in women compared with men (hazard ratio: 1.36; 95% confidence interval: 0.89-2.06). Relative survival at 15 years conditional on 30-day survival was 94% (79%-107%) in men versus 75% (59%-88%) in women. In patients who underwent pulmonary endarterectomy for CTEPH, early mortality was higher in women compared with men. After adjustment for differences in baseline characteristics, female sex was not associated with long-term survival. However, relative survival analyses suggested that the observed survival in men was close to the expected survival in the matched general population, whereas survival in women deviated notably from the matched general population.

We explored the use of the augmentation index (AI) based on pulse wave analysis (PWA) in the pulmonary circulation as a measure of wave reflection and arterial stiffness in individuals with and without pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). Right heart catheterization was performed using a pressure and Doppler flow sensor–tipped catheter to obtain simultaneous pressure and flow velocity measurements in the pulmonary artery in 10 controls, 11 PAH patients, and 11 CTEPH patients. PWA was applied to the measured pressure, while wave intensity analysis (WIA) and wave separation analysis (WSA) were performed using both the pressure and velocity to determine the magnitudes and timings of reflected waves. Type C (AI 12%) waveform dominated in PAH patients, while there was a mixture of types A, B, and C among CTEPH patients. AI was greater and the inflection time shorter in CTEPH compared to PAH patients. There was a poor correlation between AI and arterial wave speed as well as measures of wave reflection derived from WIA and WSA. The infection point did not match the timing of the backward compression wave in ~50% of the cases. In patients with type C waveforms, the inflection time correlated well to the timing of the late systolic forward decompression wave caused by ventricular relaxation. In conclusion quantifying pulmonary arterial wave reflection and stiffness using AI based on PWA may be inaccurate and should therefore be discouraged., We characterized the pressure waveforms in the pulmonary arteries in individuals with and without pulmonary hypertension. Pulse wave analysis (PWA) is unreliable in the pulmonary circulation due to the challenges related to reliable identification of an inflection point and indices derived from PWA may not be indicative of wave reflection or arterial stiffness, particularly when type C pressure waveforms are common. Assessing wave reflection in the pulmonary artery based on PWA should therefore be discouraged.

Background To investigate changes in tricuspid annulus (TA) and tricuspid valve (TV) morphology among chronic thromboembolic pulmonary hypertension (CTEPH) patients before and 12 months after pulmonary thromboendarterectomy (PEA) and compare these findings to normal control subjects. Methods 20 CTEPH patients and 20 controls were enrolled in the study. The patients were examined with echocardiography, right heart catherization and cardiac magnetic resonance imaging prior to PEA and 12 months after. Results Right atrium (RA) volume was significantly reduced from baseline to 12 months after PEA (30 ± 9 vs 23 ± 5 ml/m2, p p = 0.11) and was comparable to controls. The leaflet area, tenting volume and tenting height in systole were significantly increased at baseline but decreased significantly with comparable values to controls after 12 months (p p = 0.02), TV tenting volume (r = − 0.73, p p = 0.01) from baseline to 12 months after PEA. Tricuspid regurgitation jet area/RA area was significantly (p Conclusion In CTEPH patients selected for PEA, TV tenting height, volume and valve area are significantly increased whereas annulus size and shape are less affected. The alterations in TV morphology are fully reversed after PEA and correlates to improvements of right ventricular-pulmonary arterial coupling.

Background Despite correction of the atrial septal defect (ASD), patients experience atrial fibrillation frequently and have increased morbidity and mortality. We examined physical capacity, cardiac performance, and invasive hemodynamics in patients with corrected ASD. Methods and Results Thirty‐eight corrected patients with isolated secundum ASD and 19 age‐matched healthy controls underwent right heart catheterization at rest and during exercise with simultaneous expired gas assessment and echocardiography. Maximum oxygen uptake was comparable between groups (ASD 32.7±7.7 mL O 2 /kg per minute, controls 35.2±7.5 mL O 2 /kg per minute, P =0.3), as was cardiac index at both rest and peak exercise. In contrast, pulmonary artery wedge v wave pressures were increased at rest and peak exercise (rest: ASD 14±4 mm Hg, controls 10±5 mm Hg, P =0.01; peak: ASD 25±9 mm Hg, controls 14±9 mm Hg, P =0.0001). The right atrial v wave pressures were increased at rest but not at peak exercise. The transmural filling pressure gradient (TMFP) was higher at peak exercise among patients with ASD (10±6 mm Hg, controls 7±3 mm Hg, P =0.03). One third of patients with ASD demonstrated an abnormal hemodynamic exercise response defined as mean pulmonary artery wedge pressure ≥25 mm Hg and/or mean pulmonary artery pressure ≥35 mm Hg at peak exercise. These patients had significantly elevated peak right and left atrial a wave pressures, right atrial v wave pressures, pulmonary artery wedge v wave pressures, and transmural filling pressure compared with both controls and patients with ASD with a normal exercise response. Conclusions Patients with corrected ASD present with elevated right and in particular left atrial pressures at rest and during exercise despite preserved peak exercise capacity. Abnormal atrial compliance and systolic atrial function could predispose to the increased long‐term risk of atrial fibrillation. Registration Information clinicaltrials.gov. Identifier: NCT03565471.

High wave speed and large wave reflection in the pulmonary artery have previously been reported in patients with chronic thromboembolic pulmonary hypertension (CTEPH). We assessed the impact of pulmonary endarterectomy (PEA) on pulmonary arterial wave propagation and reservoir function in patients with CTEPH. Right heart catheterization was performed using a combined pressure and Doppler flow sensor-tipped guidewire to obtain simultaneous pressure and flow velocity measurements in the pulmonary artery in eight patients with CTEPH before and 3 mo after PEA. Wave intensity and reservoir-excess pressure analyses were then performed. Following PEA, mean pulmonary arterial pressure (PAPm; ∼49 vs. ∼32 mmHg), pulmonary vascular resistance (PVR; ∼11.1 vs. ∼5.1 Wood units), and wave speed (∼16.5 vs. ∼8.1 m/s), i.e., local arterial stiffness, markedly decreased. The changes in the intensity of the reflected arterial wave and wave reflection index (pre: ∼28%; post: ∼22%) were small, and patients post-PEA with and without residual pulmonary hypertension (i.e., PAPm ≥ 25 mmHg) had similar wave reflection index (∼20 vs. ∼23%). The reservoir and excess pressure decreased post-PEA, and the changes were associated with improved right ventricular afterload, function, and size. In conclusion, although PVR and arterial stiffness decreased substantially following PEA, large wave reflection persisted, even in patients without residual pulmonary hypertension, indicating lack of improvement in vascular impedance mismatch. This may continue to affect the optimal ventriculoarterial interaction, and further studies are warranted to determine whether this contributes to persistent symptoms in some patients. NEW & NOTEWORTHY We performed wave intensity analysis in the pulmonary artery in patients with chronic thromboembolic pulmonary hypertension before and 3 mo after pulmonary endarterectomy. Despite substantial reduction in pulmonary arterial pressures, vascular resistance, and arterial stiffness, large pulmonary arterial wave reflection persisted 3 mo postsurgery, even in patients without residual pulmonary hypertension, suggestive of lack of improvement in vascular impedance mismatch.

Supplemental Digital Content is available in the text., Background: Myocardial utilization of 3-hydroxybutyrate (3-OHB) is increased in patients with heart failure and reduced ejection fraction (HFrEF). However, the cardiovascular effects of increased circulating plasma-3-OHB levels in these patients are unknown. Consequently, the authors’ aim was to modulate circulating 3-OHB levels in HFrEF patients and evaluate: (1) changes in cardiac output (CO); (2) a potential dose-response relationship between 3-OHB levels and CO; (3) the impact on myocardial external energy efficiency (MEE) and oxygen consumption (MVO2); and (4) whether the cardiovascular response differed between HFrEF patients and age-matched volunteers. Methods: Study 1: 16 chronic HFrEF patients (left ventricular ejection fraction: 37±3%) were randomized in a crossover design to 3-hour of 3-OHB or placebo infusion. Patients were monitored invasively with a Swan-Ganz catheter and with echocardiography. Study 2: In a dose-response study, 8 HFrEF patients were examined at increasing 3-OHB infusion rates. Study 3 to 4: 10 HFrEF patients and 10 age-matched volunteers were randomized in a crossover design to 3-hour 3-OHB or placebo infusion. MEE and MVO2 were evaluated using 11C-acetate positron emission tomography. Results: 3-OHB infusion increased circulating levels of plasma 3-OHB from 0.4±0.3 to 3.3±0.4 mM (P

BackgroundVeno-arterial extracorporeal membrane oxygenation (V-A ECMO) is commonly used to provide haemodynamic support for patients with severe cardiac failure. However, timing ECMO weaning remains challenging. We aimed to examine if an integrative weaning approach based on pre-defined haemodynamic, respiratory and echocardiographic criteria is associated with successful weaning.MethodsAll patients weaned from ECMO between April 2017 and April 2019 at Aarhus University Hospital, Denmark, were consecutively enrolled. Pre-defined haemodynamic, respiratory and echocardiographic criteria were assessed before and during ECMO flow reduction. A weaning attempt was commenced in haemodynamic stable patients and patients remaining stable at minimal flow were weaned from ECMO. Comparisons were made between patients who met the criteria for weaning at first attempt and patients who did not meet these criteria. Patients completing a full weaning attempt with no further need for mechanical support within 24 hours were defined as successfully weaned. ResultsA total of 38 patients were included in the study, of whom 26 (68 %) patients met the criteria for weaning. Among these patients 25 (96%) could be successfully weaned. Successfully weaned patients were younger, had less need for inotropic support and ECMO duration was shorter. Fulfilling the weaning criteria was associated with successful weaning and both favourable 30-day survival and survival to discharge.ConclusionAn integrative weaning approach based on haemodynamic, respiratory and echocardiographic criteria may strengthen the clinical decision process in predicting successful weaning in patients receiving ECMO for refractory cardiac failure.

Background To investigate if acute pulmonary vasodilation by sildenafil improves right ventricular function in patients with acute intermediate-high risk pulmonary embolism (PE). Methods Single center, explorative trial. Patients with PE were randomized to a single oral dose of sildenafil 50 mg (n = 10) or placebo (n = 10) as add-on to conventional therapy. The time from hospital admission to study inclusion was 2.3 ± 0.7 days. Right ventricular function was evaluated immediately before and shortly after (0.5–1.5 h) randomization by right heart catheterization (RHC), trans-thoracic echocardiography (TTE), and cardiac magnetic resonance (CMR). The primary efficacy endpoint was cardiac index measured by CMR. Results Patients had acute intermediate-high risk PE verified by computed tomography pulmonary angiography, systolic blood pressure of 135 ± 18 (mean ± SD) mmHg, increased right ventricular/left ventricular ratio 1.1 ± 0.09 and increased troponin T 167 ± 144 ng/L. Sildenafil treatment did not improve cardiac index compared to baseline (0.02 ± 0.36 l/min/m2, p = 0.89) and neither did placebo (0.00 ± 0.34 l/min/m2, p = 0.97). Sildenafil lowered mean arterial blood pressure (− 19 ± 10 mmHg, p p = 0.97). Conclusion A single oral dose of sildenafil 50 mg did not improve cardiac index but lowered systemic blood pressure in patients with acute intermediate-high risk PE. The time from PE to intervention, a small patient sample size and low pulmonary vascular resistance are limitations of this study that should be considered when interpreting the results. Trial Registration: The trial was retrospectively registered at www.clinicaltrials.gov (NCT04283240) February 2nd 2020, https://clinicaltrials.gov/ct2/show/NCT04283240?term=NCT04283240&draw=2&rank=1.

Introduction: After atrial septal defect (ASD) correction, pulmonary arterial pressures drop and the right-sided chambers start to remodel. Full normalization may not occur, which can explain the increased morbidity and mortality observed later in life. We described cardiac physiology in adults with a corrected ASD in order to understand the long-term morbidity and mortality. Hypothesis: ASD patients have enlarged right atria and increased pulmonary arterial pressures despite correction. Methods: Participants (percutaneously (n=19) and surgically (n=19) corrected ASD patients and 11 controls of similar age) underwent echocardiography, International Physical Activity Questionnaire, right heart catheterization, cardiopulmonary exercise test, and Holter-monitoring 15-20 years after ASD correction as part of a larger study. Echocardiographic measurements and invasive pressures obtained at rest are reported. Results: Right and left atrial end-systolic volumes, volume index, and filling pressures are higher in corrected ASD patients (particularly the surgically corrected) when compared with controls. Conclusion: ASD patients (particularly surgically corrected) have higher atrial volumes compared with healthy matched controls 15-20 years after correction, while still within the normal range. During systole, the peak atrial pressures are increased in ASD corrected patients, which correlate well with the atrial volumes seen on echocardiography. These findings show that cardiac remodeling has occurred post-correction, but full normalization is not reached. The differences in atrial size and filling pressure in corrected ASD compared to that in controls may be a marker of ASDs leading to myocardial disease and explain why ASD patients experience increased morbidity and mortality later in life.

OBJECTIVES: The DANHEART trial is a multicenter, randomized (1:1), parallel-group, double-blind, placebo-controlled study in chronic heart failure patients with reduced ejection fraction (HFrEF). This investigator driven study will include 1500 HFrEF patients and test in a 2 × 2 factorial design: 1) if hydralazine-isosorbide dinitrate reduces the incidence of death and hospitalization with worsening heart failure vs. placebo (H-HeFT) and 2) if metformin reduces the incidence of death, worsening heart failure, acute myocardial infarction, and stroke vs. placebo in patients with diabetes or prediabetes (Met-HeFT).METHODS: Symptomatic, optimally treated HFrEF patients with LVEF ≤40% are randomized to active vs. placebo treatment. Patients can be randomized in either both H-HeFT and Met-HeFT or to only one of these study arms. In this event-driven study, it is anticipated that 1300 patients should be included in H-HeFT and 1100 in Met-HeFT and followed for an average of 4 years.RESULTS: As of May 2020, 296 patients have been randomized at 20 centers in Denmark.CONCLUSION: The H-HeFT and Met-HeFT studies will yield new knowledge about the potential benefit and safety of 2 commonly prescribed drugs with limited randomized data in patients with HFrEF.

Aims This study aimed to characterize invasive haemodynamics during exercise in subjects with cardiac amyloidosis (CA). Methods and results The study population numbered 44 subjects. Group A (CA-positive, n = 24) comprised wild-type transthyretin patients (n = 10), familial transthyretin amyloidosis mutation carriers (ATTRm) with cardiac involvement (n = 5), and light-chain amyloidosis patients with cardiac involvement (n = 9). Group B (CA-negative, n = 20) comprised four healthy ATTRm subjects without cardiac involvement documented by 11C-PIB positron emission tomography and 16 healthy controls. All subjects underwent a symptom-limited, semi-supine exercise test with expired gas analysis and simultaneous right heart catheterization. CA patients had lower peak oxygen consumption [15 ± 6 mL/min/kg bodyweight (bwt) vs. 33 ± 7 mL/min/kg bwt; P

Background A substantial number of chronic thromboembolic pulmonary hypertension (CTEPH) patients experience dyspnoea on exertion and limited exercise capacity despite surgically successful pulmonary endarterectomy (PEA). Purpose We sought to prospectively evaluate resting and peak exercise haemodynamics before, 3 and 12 months after PEA in consecutive CTEPH patients and correlate it to physical functional capacity. Methods Twenty CTEPH patients who underwent PEA treatment were examined between December 2014 and January 2017. The patients were examined pre-operatively and 3 and 12 months post-operatively with right heart catheterisation at rest and during a maximal symptom-limited, semi-supine cardiopulmonary exercise test. Finally, the data were compared with 15 healthy controls who had previously undergone the same protocol. Results Twelve months after PEA, 75% of patients with severely increased pre-PEA mean pulmonary arterial pressure (mPAP) at rest had normal or mildly increased mPAP. However, mPAP reduction was less pronounced during exercise where only 45% had normal or mildly increased mPAP at 12 months. Cardiac output (CO) reserve (CO increase from rest to peak exercise) was increased (5.7±2.9 L/min) 12 months after PEA compared with pre-PEA (2.5±1.8 L/min), p Figure 1 Conclusion Invasive exercise haemodynamic examination in CTEPH patients demonstrates that after otherwise successful PEA surgery, more than 50% of patients have a significant increase in exercise mPAP, and the CO reserve remains compromised 12 months after PEA. Improvement in physical capacity is correlated with ΔCO. Acknowledgement/Funding Danish Heart Foundation, Aarhus University, Arvid Nilssons Fond, Eva & Henry Frænkels Mindefond, and Snedkermester Sophus Hustru Astrid Jacobsens Fond

Guidelines summarize and evaluate available evidence with the aim of assisting health professionals in proposing the best management strategies for an individual patient with a given condition. Guidelines and their recommendations should facilitate decision making of health professionals in their daily practice. However, the final decisions concerning an individual patient must be made by the responsible health professional(s) in consultation with the patient and caregiver as appropriate.

AIMS: The study evaluated exercise left ventricular global longitudinal strain (LVGLS) and invasive haemodynamics for major adverse cardiac events (MACE) prediction in heart-transplanted (HTx) patients.METHODS AND RESULTS: The study comprised 74 stable consecutive HTx patients who were followed at the Department of Cardiology, Aarhus University Hospital, Denmark, from August 2013 to January 2017. All patients were transplanted a minimum of 12 months before study entry and were included at the time of their routine annual coronary angiography. A symptom-limited haemodynamic exercise test with simultaneous echocardiographic study was performed. The primary endpoint was MACE during follow-up defined as heart failure hospitalization, treated rejection episodes, coronary event, or cardiac death. The median time since transplant was 5 years [1:12] and the median follow-up was 1095 days [391;1506]. Thirty patients (41%) experienced MACE during follow-up. Patients who suffered MACE had an impaired resting and peak exercise systolic function in form of a lower LV ejection fraction (Rest: 56 ± 12% vs. 65 ± 7%, P < 0.001; Peak 64 ± 13% vs. 72 ± 6%, P < 0.01) and LVGLS (Rest: 13 ± 4% vs. 16 ± 2%, P < 0.01; Peak: 15 ± 6% vs. 20 ± 4%, P = 0.0001) than patients without MACE episodes. In contrast, resting diastolic filling patterns were comparable between patients suffering from MACE and patients without MACE. At rest, pulmonary capillary wedge pressure (mPCWP) and cardiac index did not predict MACE, whereas increased right atrial pressure (mRAP) was associated with increased MACE risk. Patients with peak exercise mPCWP >23 mmHg [hazard ratio (HR) 2.5, 95% confidence interval (CI): 1.2-5.4], cardiac index 13 mmHg (HR 2.7, 95% CI: 1.1-6.3) had increased MACE risk. Patients with exercise-induced LVGLS increase 23 mmHg [HR 6.1 (95% CI: 2.1-17.5)] or mRAP >13 mmHg [HR 7.5 (95% CI: 2.3-23.9)] had the highest MACE risk.CONCLUSIONS: Resting haemodynamic parameters were poor MACE predictors in long-term HTx patients. In contrast, peak exercise mPCWP, mRAP, and CI were significant MACE predictors. LVGLS both at rest and during exercise were significant MACE predictors, and the combined model with peak exercise LVGLS and peak exercise mPCWP, mRAP, and CI clearly identified high-risk HTx patients in relation cardiovascular endpoints independently of time since HTx.

Aims: To characterize right ventricular (RV) geometry and function in chronic thromboembolic pulmonary hypertension (CTEPH) patients at rest and during exercise before pulmonary thromboendarterectomy (PEA), and at 3 and 12 months after PEA using two-dimensional and three-dimensional echocardiography with reference to clinical performance and exercise capacity. Methods and results: Forty subjects (20 CTEPH patients and 20 controls) were enrolled between December 2014 and January 2017. Three-dimensional echocardiography demonstrated a significant reduction and normalization of end-diastolic and end-systolic RV volumes in CTEPH patients 12 months after PEA. RV systolic function improved after PEA; however, tricuspid annular plane systolic excursion (TAPSE) (baseline 18 ± 6 mm vs 15 ± 3 mm at 12 months after PEA, P

Background: Pulmonary hypertension (PH) is a serious complication to interstitial lung disease (ILD) and has a poor prognosis. PH is often diagnosed by screening with echocardiography followed by right heart catheterisation. A previous study has shown that a value of NT-pro-brain natriuretic peptide (NT-proBNP) 95 ng/l for signs of PH on echocardiography were calculated. The study was approved by the Danish Health Authority. Results: In 118 patients, data from both echocardiography and measurements of NT-proBNP were available. Eleven of these were screened positive for PH on echocardiography. Sensitivity, specificity, NPV and PPV of NT-proBNP

Background: Recent studies have demonstrated distinctive arterial wave characteristics in patients with chronic thromboembolic pulmonary hypertension (CTEPH)1. Therefore, we aimed to assess the impact of pulmonary endarterectomy (PEA) on pulmonary arterial wave propagation and reservoir function in CTEPH patients. Methods: Right heart catheterization was performed using a pressure and Doppler flow sensor tipped guidewire to obtain simultaneous pressure and flow velocity measurements in the pulmonary artery in eight CTEPH patients before and 3 months after PEA. Wave intensity and reservoir-excess pressure analyses2 were subsequently applied to the acquired data and the diastolic pressure decay time was estimated. Results: Following PEA, mean pulmonary pressure (49 ± 10 mmHg versus 32 ± 13 mmHg), pulmonary vascular resistance (PVR) and wave speed, i.e. local arterial stiffness, significantly improved. However, there were no significant changes in arterial wave energy and wave reflection index (29.3 % [11.4–41.4 %] versus 21.2 % [16.2 – 25.9 %] post-PEA), even in patients with normalized pulmonary pressure. The RC-time (product of PVR and compliance) decreased post-PEA. Furthermore, the reservoir pressure related to arterial compliance, excess pressure caused by arterial waves and asymptotic pressure at which the flow would cease significantly decreased post-PEA and the changes were associated with improved right ventricular afterload, function and size. Conclusion: Large wave reflection persisted post-PEA indicating lack of normalization of vascular impedance mismatch. Decreased RC-time suggests structural damage to the pulmonary vasculature. Wave intensity and reservoir-excess pressure analysis may be used as an additional assessment of the hemodynamic outcomes following PEA.

BackgroundIn contrast to systemic hypertension, the significance of arterial waves in pulmonary hypertension (PH) is not well understood. We hypothesized that arterial wave energy and wave reflection are augmented inPHand that wave behavior differs between patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH).Methods and ResultsRight heart catheterization was performed using a pressure and Doppler flow sensor–tipped catheter to obtain simultaneous pressure and flow velocity measurements in the pulmonary artery. Wave intensity analysis was subsequently applied to the acquired data. Ten control participants, 11 patients withPAH, and 10 patients withCTEPHwere studied. Wave speed and wave power were significantly greater inPHpatients compared with controls, indicating increased arterial stiffness and right ventricular work, respectively. The ratio of wave power to mean right ventricular power was lower inPAHpatients thanCTEPHpatients and controls. Wave reflection index inPHpatients (PAH: ≈25%;CTEPH: ≈30%) was significantly greater compared with controls (≈4%), indicating downstream vascular impedance mismatch. Although wave speed was significantly correlated to disease severity, wave reflection indexes of patients with mildly and severely elevated pulmonary pressures were similar.ConclusionsWave reflection in the pulmonary artery increased in PH and was unrelated to severity, suggesting that vascular impedance mismatch occurs early in the development of pulmonary vascular disease. The lower wave power fraction inPAHcompared withCTEPHindicates differences in the intrinsic and/or extrinsic ventricular load between the 2 diseases.

PURPOSE: This study aimed to assess clinical, functional, and hemodynamic characteristics of heart-transplanted (HTX) patients during exercise.METHODS: We performed comprehensive echocardiographic graft function assessment during invasive hemodynamic semi-supine exercise test in 57 HTX patients. According to hemodynamics findings, patients were divided into: Group A: Normal left ventricular (LV) filling pressure (FP): Pulmonary capillary wedge pressure (PCWP) RESULTS: Thirty-one patients (54%) had normal LV-FP and 26 patients (46%) had elevated LV-FP. The latter had higher cumulative rejection burden (p1) (pCONCLUSION: Elevated LV-FP can be demonstrated in approximately 50% of HTX patients. Patients with elevated LV-FP have impaired myocardial deformation capacity, higher prevalence of CAV, higher rejection burden, and were more symptomatic. Exercise test with assessment of longitudinal myocardial deformation should be considered in routine surveillance of HTx patients as a marker of restrictive filling. This article is protected by copyright. All rights reserved.

We aimed to characterize and estimate survival rates in patients diagnosed with pulmonary arterial hypertension (PAH) in western Denmark in the modern management era. All incident cases of PAH were consecutively enrolled in our single-center prospective cohort study between January 2000 and March 2012. A total of 134 patients fulfilling the inclusion criteria were followed up from first diagnostic right heart catheterization to either death or the end of the study. Kaplan-Meier survival analysis was used to estimate 1-, 3-, and 5-year survival rates with 95% confidence intervals (CIs). Survival in the total cohort was 86.4% (95% CI, 79.3%-91.2%) after 1 year, 72.9% (95% CI, 64.1%-79.9%) after 3 years, and 65.4% (95% CI, 55.8%-73.4%) after 5 years. Significantly better survival was seen in the group of patients with PAH associated with congenital heart disease than in the group of patients with idiopathic PAH, heritable PAH, connective tissue disease, HIV infection, and portal hypertension. In conclusion, survival rates in the Danish PAH population were similar to or slightly better than survival rates estimated in other modern registries. However, PAH remains a fatal disease, despite modern targeted therapies.

OBJECTIVES: Chronic thromboembolic pulmonary hypertension is a fatal disease if left untreated, and pulmonary endarterectomy (PEA) is the potentially curable treatment of choice. We aimed to estimate the current in-hospital mortality rate, complication rate and long-term survival for patients with chronic thromboembolic pulmonary hypertension undergoing PEA in Denmark.METHODS: All chronic thromboembolic pulmonary hypertension patients who underwent PEA in the period 1994 till 2016 were consecutively enrolled in our single-centre study. All patients were followed from PEA until death or end of study. Kaplan-Meier survival analysis was used to estimate the 3-, 5- and 10-year survival rates with 95% confidence interval (CI).RESULTS: In total, 239 patients were operated in the study period. A significant reduction in mean pulmonary arterial pressure from 48 mmHg to 33 mmHg, and pulmonary vascular resistance from 800 dynes s cm -5 to 289 dynes s cm -5 , was observed during the first postoperative day after PEA. Overall, in-hospital mortality rate was 8.4%. A significantly lower mortality rate in the late decade (2005-2016) compared with the early decade (1994-2004) was observed (4.3% vs 22.6%, P CONCLUSIONS: PEA in Denmark is associated with a low in-hospital mortality rate and significant improvements in both haemodynamics and exercise capacity. Long-term survival is excellent and similar to high-volume international centres.

Unusual forms of pulmonary hypertension include pulmonary hypertension related to mediastinal fibrosis and the use of serotonergic drugs. Here, we describe a patient with diffuse mediastinal fibrosis and pulmonary hypertension while she was on dopamine agonist therapy. A young woman, who was treated with cabergoline and bromocriptine for hyperprolactinemia, presented with progressive dyspnea over several months. Based on the clinical investigation results, in particular, elevated pulmonary arterial pressures and significant perfusion defects on computed tomography pulmonary angiography and ventilation/perfusion scintigraphy, chronic thromboembolic pulmonary hypertension (CTEPH) was initially considered the most plausible diagnosis. However, during an attempted pulmonary endarterectomy, loose fibrous tissues were observed in the mediastinum and cryosection of the right pulmonary artery showed fibrosis and chronic inflammation. Subsequent investigations revealed that diffuse mediastinal fibrosis with concurrent pulmonary hypertension, and not CTEPH, was the most likely diagnosis and cabergoline and bromocriptine may have triggered the fibrotic changes. Both drugs are ergot-derived dopamine agonists, which are known to cause cardiac valve fibrosis and less frequently, non-cardiac fibrotic changes. The underlying mechanism is attributed to their interactions with serotonin receptors. There is much evidence that serotonin, a potent vasoconstrictor and mitogen, is involved in the pathogenesis of pulmonary hypertension. In conclusion, as computed tomography and ventilation/perfusion scintigraphy findings can occasionally be deceptive, physicians should be particularly aware of differential diagnoses in patients without obvious history of venous thromboembolism that are suspected of having chronic thromboembolic pulmonary hypertension.

Riociguat is a novel soluble guanylate cyclase stimulator that is approved for the treatment of patients with pulmonary arterial hypertension (PAH) and patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH) or persistent/recurrent CTEPH after pulmonary endarterectomy (PEA). As riociguat is a relatively new drug, experience of its use in clinical practice is limited, especially in patients who would not have met the inclusion criteria for the pivotal Phase III clinical trials, PATENT-1 and CHEST-1. This article shares our initial practical and clinical experience in switching patients with PAH and CTEPH from the phosphodiesterase type-5 inhibitor sildenafil to riociguat, based on three selected case reports of patients who discontinued sildenafil therapy owing to side effects or disease progression (one patient with idiopathic PAH and two patients with persistent/recurrent CTEPH after PEA). Two cases illustrate our experience with direct switch from sildenafil to riociguat (6-8 h between the last sildenafil dose and the first riociguat dose), and one case illustrates switch to riociguat in a patient who underwent treatment with other PAH-specific therapies between stopping sildenafil and starting riociguat. Symptoms improved with riociguat therapy in two cases; in the third case the patient experienced worsening symptoms 1 month after initiating riociguat and was switched back to sildenafil. These case experiences contribute practical information to assist clinicians in the switch from sildenafil to riociguat therapy in patients with PAH or CTEPH.

This study aimed to characterize invasive haemodynamics during exercise in subjects with cardiac amyloidosis (CA).The study population numbered 44 subjects. Group A (CA-positive, n = 24) comprised wild-type transthyretin patients (n = 10), familial transthyretin amyloidosis mutation carriers (ATTRm) with cardiac involvement (n = 5), and light-chain amyloidosis patients with cardiac involvement (n = 9). Group B (CA-negative, n = 20) comprised four healthy ATTRm subjects without cardiac involvement documented byCardiac amyloid deposits are associated with severely reduced inotropic myocardial reserve and increased left and right ventricular filling pressures during exercise. Furthermore, CA subjects have severely reduced PAC, which may contribute to right heart failure and reduced exercise capacity.

Background: The objective of the study was to apply wave intensity analysis (WIA) in the pulmonary artery to characterise the magnitude, origin, type and timing of arterial waves in individuals with and without pulmonary hypertension (PH). Methods: Right heart catheterisation was performed using a pressure and Doppler flow sensor tipped catheter to obtain simultaneous pressure and flow velocity measurements in the pulmonary artery. WIA was applied to the acquired data (1). Results: In controls (n = 10), the wave speed in the pulmonary artery was 3.03 m/s (2.69 – 3.91 m/s) and this increased in pulmonary arterial hypertension (PAH, n = 11, 11.9 m/s [10.5 – 16.4 m/s]) and chronic thromboembolic pulmonary hypertension patients (CTEPH, n = 10, 15.1 m/s [11.5 – 16.8 m/s]). Wave intensity was significantly greater in PH patients compared to controls. Wave reflection index (WRI) was 3.81 % (3.58 – 6.24 %) in controls, 23.4 % (17.5 – 29.7 %) in PAH and 30.4 % (11.9 – 35.6 %) in CTEPH patients. WRI was not related to pulmonary vascular resistance or right ventricular fractional area change and patients with mildly and severely elevated pulmonary pressure had similar WRI. Conclusions: Wave speed, wave intensity and wave reflection in the pulmonary artery was higher in PH patients indicating increased arterial stiffness, right ventricular work and vascular impedance mismatch, respectively. While WRI does not reflect the severity of PH in established disease, the presence of increased wave reflection could be a novel early marker of pulmonary vascular disease.

Background— Chronic thromboembolic pulmonary hypertension, a rare complication of acute pulmonary embolism, is characterized by fibrothrombotic obstructions of large pulmonary arteries combined with small-vessel arteriopathy. It can be cured by pulmonary endarterectomy, and can be clinically improved by medical therapy in inoperable patients. A European registry was set up in 27 centers to evaluate long-term outcome and outcome correlates in 2 distinct populations of operated and not-operated patients who have chronic thromboembolic pulmonary hypertension. Methods and Results— A total of 679 patients newly diagnosed with chronic thromboembolic pulmonary hypertension were prospectively included over a 24-month period. Estimated survival at 1, 2, and 3 years was 93% (95% confidence interval [CI], 90–95), 91% (95% CI, 87–93), and 89% (95% CI, 86–92) in operated patients (n=404), and only 88% (95% CI, 83–91), 79% (95% CI, 74–83), and 70% (95% CI, 64–76) in not-operated patients (n=275). In both operated and not-operated patients, pulmonary arterial hypertension–targeted therapy did not affect survival estimates significantly. Mortality was associated with New York Heart Association functional class IV (hazard ratio [HR], 4.16; 95% CI, 1.49–11.62; P =0.0065 and HR, 4.76; 95% CI, 1.76–12.88; P =0.0021), increased right atrial pressure (HR, 1.34; 95% CI, 0.95–1.90; P =0.0992 and HR, 1.50; 95% CI, 1.20–1.88; P =0.0004), and a history of cancer (HR, 3.02; 95% CI, 1.36–6.69; P =0.0065 and HR, 2.15; 95% CI, 1.18–3.94; P =0.0129) in operated and not-operated patients, respectively. Additional correlates of mortality were bridging therapy with pulmonary arterial hypertension–targeted drugs, postoperative pulmonary hypertension, surgical complications, and additional cardiac procedures in operated patients, and comorbidities such as coronary disease, left heart failure, and chronic obstructive pulmonary disease in not-operated patients. Conclusions— The long-term prognosis of operated patients currently is excellent and better than the outcome of not-operated patients.

SummaryBackgroundPulmonary hypertension (PH) is an important complication to interstitial lung disease (ILD). The aim of the present study was to investigate the prevalence and impact of PH on prognosis and exercise capacity in ILD patients.Methods212 ILD patients were screened for PH by echocardiography. Criteria for PH were either a tricuspid pressure regurgitation gradient >40 mmHg, a tricuspid annular plane systolic excursion

PURPOSE: This study aimed to characterize right heart function in heart transplantation (HTx) patients using advanced echocardiographic assessment and simultaneous right heart catheterization (RHC).METHODS AND RESULTS: Comprehensive two-dimensional (2D) and three-dimensional (3D) echocardiographic assessment of right heart function was performed in 105 subjects (64 stable HTx patients and 41 healthy controls). RHC was performed at rest and during semi-supine maximal exercise test. Compared with controls, HTx patients had impaired right ventricle (RV) systolic function in terms of decreased RV-free wall (FW) global longitudinal strain (GLS) (-20±5% vs -28±5%, pCONCLUSION: RV systolic function is reduced in HTx patients compared with controls. 3D RVEF and 2D longitudinal deformation analysis are associated with clinical performance in stable HTx patients and seem suitable in non-invasive routine right heart function evaluation after HTx. Invasively assessed RV systolic reserve was strongly associated with exercise capacity. This article is protected by copyright. All rights reserved.

In patients with pulmonary arterial hypertension (PAH), chest pain is most likely due to right ventricular demand ischemia. We report a patient with idiopathic PAH who developed severe angina due to extrinsic compression of the left main coronary artery (LMCA) from a dilated pulmonary artery trunk. The diagnosis was verified by electrocardiogram after exercise, coronary angiography including intravascular ultrasound, and cardiac multidetector computed tomography (MDCT). The origin of the LMCA was high in the left coronary sinus, facilitating extrinsic compression. The patient was successfully treated by percutaneous coronary intervention with stent implantation in the LMCA. Extrinsic compression of the LMCA is a severe and potentially fatal complication that should be considered in all patients with PAH and angina. MDCT is the method of choice for first-line diagnosis.

Pulmonary arterial hypertension (PAH) is a devastating disease characterized by pulmonary vasoconstriction, pulmonary arterial remodeling, abnormal angiogenesis and impaired right ventricular function. Despite progress in pharmacological therapy, there is still no cure for PAH. The peptide apelin and the G-protein coupled apelin receptor (APLNR) are expressed in several tissues throughout the organism. Apelin is localized in vascular endothelial cells while the APLNR is localized in both endothelial and smooth muscle cells in vessels and in the heart. Apelin is regulated by hypoxia inducible factor -1α and bone morphogenetic protein receptor-2. Patients with PAH have lower levels of plasma-apelin, and decreased apelin expression in pulmonary endothelial cells. Apelin has therefore been proposed as a potential biomarker for PAH. Furthermore, apelin plays a role in angiogenesis and regulates endothelial and smooth muscle cell apoptosis and proliferation complementary and opposite to vascular endothelial growth factor. In the systemic circulation, apelin modulates endothelial nitric oxide synthase (eNOS) expression, induces eNOS-dependent vasodilatation, counteracts angiotensin-II mediated vasoconstriction, and has positive inotropic and cardioprotective effects. Apelin attenuates vasoconstriction in isolated rat pulmonary arteries, and chronic treatment with apelin attenuates the development of pulmonary hypertension in animal models. The existing literature thus renders APLNR an interesting potential new therapeutic target for PH.

A 46-year-old woman presented with a 6-month history of dyspnea and weight loss on a background of previous pneumonectomy for bronchial adenoid cystic carcinoma 14 years beforehand. Several years prior to this presentation, she had developed left vocal cord palsy and a metastatic lesion to the right buttock confirmed at resection. Investigations included CT pulmonary angiography and right heart catheterisation and demonstrated pulmonary artery stenosis suggestive of vascular encasement, severe pulmonary arterial hypertension and pulmonary nodules. Subsequent pulmonary artery stenting markedly improved both pulmonary artery pressures and the patient's symptoms. The diagnosis of pulmonary artery stenosis due to mediastinal infiltration by metastatic bronchial adenoid cystic carcinoma was based on these findings as well as the presence of the pulmonary nodules and the previous mediastinal (recurrent laryngeal nerve) and metastatic complications. This case is the first report of successful pulmonary artery stenting for this rare complication.

Objectives The purpose of this study was to determine the respiratory, hemodynamic, and clinical effects of switching between β1-selective and nonselective beta-blockers in patients with chronic heart failure (CHF) and chronic obstructive pulmonary disease (COPD). Background Carvedilol, metoprolol succinate, and bisoprolol are established beta-blockers for treating CHF. Whether differences in beta-receptor specificities affect lung or vascular function in CHF patients, particularly those with coexistent COPD, remains incompletely characterized. Methods A randomized, open label, triple-crossover trial involving 51 subjects receiving optimal therapy for CHF was conducted in 2 Australian teaching hospitals. Subjects received each beta-blocker, dose-matched, for 6 weeks before resuming their original beta-blocker. Echocardiography, N-terminal pro-hormone brain natriuretic peptide, central augmented pressure from pulse waveform analysis, respiratory function testing, 6-min walk distance, and New York Heart Association (NYHA) functional class were assessed at each visit. Results Of 51 subjects with a mean age of 66 ± 12 years, NYHA functional class I (n = 6), II (n = 29), or III (n = 16), and left ventricular ejection fraction mean of 37 ± 10%, 35 had coexistent COPD. N-terminal pro-hormone brain natriuretic peptide was significantly lower with carvedilol than with metoprolol or bisoprolol (mean: carvedilol 1,001 [95% confidence interval (CI): 633 to 1,367] ng/l; metoprolol 1,371 [95% CI: 778 to 1,964] ng/l; bisoprolol 1,349 [95% CI: 782 to 1,916] ng/l; p Conclusions Switching between β1-selective beta-blockers and the nonselective beta-blocker carvedilol is well tolerated but results in demonstrable changes in airway function, most marked in patients with COPD. Switching from β1-selective beta-blockers to carvedilol causes short-term reduction of central augmented pressure and N-terminal pro-hormone brain natriuretic peptide. (Comparison of Nonselective and Beta1-Selective Beta-Blockers on Respiratory and Arterial Function and Cardiac Chamber Dynamics in Patients With Chronic Stable Congestive Cardiac Failure; Australian New Zealand Clinical Trials Registry, ACTRN12605000504617)

IMPORTANCE: Worsening chronic heart failure (HF) is a major public health problem.OBJECTIVE: To determine the optimal dose and tolerability of vericiguat, a soluble guanylate cyclase stimulator, in patients with worsening chronic HF and reduced left ventricular ejection fraction (LVEF).DESIGN, SETTING, AND PARTICIPANTS: Dose-finding phase 2 study that randomized 456 patients across Europe, North America, and Asia between November 2013 and January 2015, with follow-up ending June 2015. Patients were clinically stable with LVEF less than 45% within 4 weeks of a worsening chronic HF event, defined as worsening signs and symptoms of congestion and elevated natriuretic peptide level requiring hospitalization or outpatient intravenous diuretic.INTERVENTIONS: Placebo (n = 92) or 1 of 4 daily target doses of oral vericiguat (1.25 mg [n = 91], 2.5 mg [n = 91], 5 mg [n = 91], 10 mg [n = 91]) for 12 weeks.MAIN OUTCOMES AND MEASURES: The primary end point was change from baseline to week 12 in log-transformed level of N-terminal pro-B-type natriuretic peptide (NT-proBNP). The primary analysis specified pooled comparison of the 3 highest-dose vericiguat groups with placebo, and secondary analysis evaluated a dose-response relationship with vericiguat and the primary end point.RESULTS: Overall, 351 patients (77.0%) completed treatment with the study drug with valid 12-week NT-proBNP levels and no major protocol deviation and were eligible for primary end point evaluation. In primary analysis, change in log-transformed NT-proBNP levels from baseline to week 12 was not significantly different between the pooled vericiguat group (log-transformed: baseline, 7.969; 12 weeks, 7.567; difference, -0.402; geometric means: baseline, 2890 pg/mL; 12 weeks, 1932 pg/mL) and placebo (log-transformed: baseline, 8.283; 12 weeks, 8.002; difference, -0.280; geometric means: baseline, 3955 pg/mL; 12 weeks, 2988 pg/mL) (difference of means, -0.122; 90% CI, -0.32 to 0.07; ratio of geometric means, 0.885, 90% CI, 0.73-1.08; P = .15). The exploratory secondary analysis suggested a dose-response relationship whereby higher vericiguat doses were associated with greater reductions in NT-proBNP level (P CONCLUSIONS AND RELEVANCE: Among patients with worsening chronic HF and reduced LVEF, compared with placebo, vericiguat did not have a statistically significant effect on change in NT-proBNP level at 12 weeks but was well-tolerated. Further clinical trials of vericiguat based on the dose-response relationship in this study are needed to determine the potential role of this drug for patients with worsening chronic HF.TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01951625.

To evaluate survival and functional outcome in patients treated by pulmonary endarterectomy (PEA) for chronic thromboembolic pulmonary hypertension in Denmark.Follow-up of the first 50 patients operated at Aarhus University Hospital, Denmark.Fifty patients underwent PEA in the period from 1994 to mid 2004. Prior to surgery all patients were in World Health Organization (WHO) function class III (n=33) or IV (n=17). The mean pulmonary artery pressure was 50 mmHg (range 25-76), cardiac index 1.8 l min(-1)m(-2) (range 0.8-2.8) and pulmonary vascular resistance 819 dyn s cm(-5) (range 241-3,067). In-hospital mortality was 12/50 (24%). Surgical mortality was highest in the early period. Since year 2000 in-hospital deaths occurred in only 2 among 23 patients (9%). Leading causes of death were persistent pulmonary hypertension and bleeding. Three patients died during long-term follow-up with a median observation time of 3 years. The overall 5 year survival rate was 74%. At 3 months follow-up 90% of the patients (34/38) had improved one or more WHO functional classes and the systolic pulmonary artery pressure estimated by Doppler echocardiography had decreased from 80 mmHg (range 49-115) to 43 mmHg (range 14-95).Pulmonary endarterectomy has been successfully implemented in Denmark. The perioperative mortality was reduced over time to 9% during the past 5 years. Functional outcome and long-term survival were excellent stressing the importance of surgical treatment for chronic thromboembolic pulmonary hypertension.