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Background: Optimal timing of aortic valve replacement remains difficult in patients with asymptomatic, severe aortic stenosis (AS). More accurate diagnostic methods are warranted for the detection of subtle ventricular impairment. We aimed to evaluate diastolic function in asymptomatic patients with severe AS. Methods: In this cross-sectional study, patients with asymptomatic, severe AS were evaluated with right heart catheterization at rest and during moderate exercise. The patients also underwent cardiopulmonary exercise testing to objectify functional capacity and confirm the absence of symptoms. Results: Between February 2019 and May 2021, we included 50 patients aged 70±12 years. The patients had severe AS with peak velocity 4.4±0.4 m/s, mean gradient 46±9 mm Hg, and an indexed valve area of 0.47±0.08 cm 2 at rest. All patients were asymptomatic and had normal left ventricular ejection fraction. Five patients had postcapillary pulmonary hypertension at rest. During exercise, 44 patients (88%) had an increase in the mean pulmonary artery pressure per increase in cardiac output of >3 mm Hg/L per minute, of whom 93% had a concomitant increase in the pulmonary artery wedge pressure per increase in cardiac output >2 mm Hg/L per minute, suggesting exercise-induced pulmonary hypertension due to left heart disease. Female gender and increasing age were associated with a higher increase in the pulmonary artery wedge pressure per increase in cardiac output ratio. The catheterization was well tolerated, and there were no adverse events. Conclusions: A large proportion of asymptomatic patients with severe, degenerative AS have exercise-induced postcapillary pulmonary hypertension.

We hereby present a case of thrombus formation in the noncoronary sinus of Valsalva following primary graft dysfunction. The case highlights that stagnant and nonpulsatile flow can form thrombi in the noncoronary sinus since this sinus does not have a natural distal runoff.

Despite numerous therapeutic advances in pulmonary arterial hypertension, patients continue to suffer high morbidity and mortality, particularly considering a median age of 50 years. This article explores whether early, robust reduction of right ventricular afterload would facilitate substantial improvement in right ventricular function and thus whether afterload reduction should be a treatment goal for pulmonary arterial hypertension. The earliest clinical studies of prostanoid treatment in pulmonary arterial hypertension demonstrated an important link between lowering mean pulmonary arterial pressure (or pulmonary vascular resistance) and improved survival. Subsequent studies of oral monotherapy or sequential combination therapy demonstrated smaller reductions in mean pulmonary arterial pressure and pulmonary vascular resistance. More recently, retrospective reports of initial aggressive prostanoid treatment or initial combination oral and parenteral therapy have shown marked afterload reduction along with significant improvements in right ventricular function. Some data suggest that reaching threshold levels for pressure or resistance (components of right ventricular afterload) may be key to interrupting the self-perpetuating injury of pulmonary vascular disease in pulmonary arterial hypertension and could translate into improved long-term clinical outcomes. Based on these clues, the authors postulate that improved clinical outcomes might be achieved by targeting significant afterload reduction with initial oral combination therapy and early parenteral prostanoids.

Objective Primary cardiac involvement is presumed to account for a substantial part of disease‐related mortality in systemic sclerosis (SSc). Still, there are knowledge gaps on the evolution and total burden of systolic dysfunction in SSc. Here we evaluated prospective left ventricular (LV) and right ventricular (RV) systolic function in an unselected SSc cohort and assessed the burden of systolic dysfunction on mortality. Methods From the Oslo University Hospital cohort, 277 SSc patients were included from 2003‐2016 and compared with healthy controls. Serial echocardiographies were reevaluated in order to detect change in systolic function. Right heart catheterization was performed on patients suspected of pulmonary hypertension. Descriptive and regression analyses were conducted. Results At baseline, LV systolic dysfunction by ejection fraction less than 50%, or a global longitudinal strain greater than −17.0%, was found in 12% and 24%, respectively. RV systolic dysfunction measured by tricuspid annular plane systolic excursion (TAPSE) less than 17 mm was evident in 10%. Follow‐up echocardiography was performed after a median of 3.3 years (interquartile range [IQR] 1.5‐5.6). At follow‐up, LV systolic function remained stable, whereas RV function evaluated by TAPSE deteriorated (mean 23.1 to 21.7 mm, P = 0.005) equaling a 15% prevalence of RV systolic dysfunction. RV systolic function predicted mortality in multivariable models (hazard ratio 0.41, 95% confidence interval [CI] 0.19‐0.90, P value 0.027), whereas LV systolic function lost predictive significance when adjusted for TAPSE. Conclusion In this unselected and prospective study, systolic dysfunction of the LV and RV was a frequent complication of SSc. LV systolic function remained stable across the observation period, whereas RV function deteriorated and predicted mortality. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Background Optimal iron management is crucial to marginal patients such as heart transplant recipients. As inflammatory mechanisms are present in transplant recipients, the definition of iron deficiency used in the general population might not be appropriate. Objective To evaluate the prevalence and determinants of iron deficiency in Norwegian heart transplant recipients. Methods We consecutively assessed iron parameters in all Norwegian heart transplant recipients at their annual follow-up. Several definitions of iron deficiency suggested in the literature were assessed: ferritin Results 179 of 378 heart transplant recipients (47%) had iron deficiency defined as IDHF . 152 patients (40%) had IDF100 , and 103 patients (27%) had IDTsat . 17 patients (5%) had IDF30 . 88 patients (23%) had a C-reactive protein (CRP) >5.0 µg/L. Conclusion Iron deficiency defined as IDHF , IDF100, or IDTsat is prevalent in the heart transplant population, while IDF30 is not. Further research is required to identify the mechanisms of iron homeostasis in heart transplant recipients and to establish a definition of iron deficiency suitable for this population.

Aims Heart transplant recipients have reduced exercise capacity despite preserved graft function. The IronIC trial was designed to test the hypothesis that intravenous iron therapy would improve peak oxygen consumption in these patients. Methods and results This randomized, placebo-controlled, double-blind trial was performed at our national center for heart transplantation. One hundred and 2 heart transplant recipients with a serum ferritin 100 g/liter were enrolled ≥1 year after transplantation. A cardiopulmonary exercise test was performed before administration of the study drug and at 6 months follow-up. The primary endpoint was peak oxygen consumption. Key secondary outcomes included iron status, handgrip strength, quality of life, and safety. Fifty-two patients were randomized to receive ferric derisomaltose 20 mg/kg, and 50 to placebo. The between-group difference in baseline-adjusted peak oxygen consumption was 0.3 ml/kg/min (95% confidence interval -0.9 to 1.4, p = 0.66). In patients with a baseline ferritin

Background and objective - Dysregulated Wnt signalling has been implicated in pulmonary hypertension (PH). We hypothesized that plasma levels of secreted Wnt proteins would be increased in patients with precapillary PH, correlate with indices of vascular resistance and cardiac function and give information on long-term prognosis. Methods - We measured the Wnt ligand Wnt5a and secreted Wnt antagonists Dickkopf (DKK) DKK1, DKK3, secreted frizzled-related protein 3 (sFRP3), Wnt inhibitory factor-1 (WIF1) and sclerostin (SOST) in 106 patients with precapillary PH and 40 healthy controls. A second sample was obtained after a median of 4 months (n = 52). During a median of 90 months follow-up, 67 patients died. Results - Our main findings were (i) Precapillary PH is characterized by enhanced systemic Wnt activity as reflected by elevated plasma levels of Wnt5a and secreted antagonists irrespective of diagnostic subgroups. (ii) WIF1 and in particular Wnt5a correlated with pulmonary vascular resistance and cardiac dysfunction. (iii) High levels of Wnt5a, sFRP3, DKK3 and WIF1 were associated with poor prognosis in age- and sex-adjusted analysis (hazard ratios per log/SD change ~1.4) and for DKK3 after further adjustment with right arterial pressure, pulmonary oxygen saturation, cardiac index, N-terminal pro B-type natriuretic peptide and peak oxygen uptake (VO2). Finally, an elevation of Wnt5a and DKK3 during follow-up was independently associated with poor prognosis. Conclusion - Our data indicate that Wnt signalling pathways could be implicated in the pathogenesis of precapillary PH, and that some of the Wnt-related molecules (i.e., Wnt5a and DKK3) should be further investigated in these patients.

Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): South-Eastern Norway Regional Health Authority Background Elevated left ventricular (LV) filling pressure is an important diagnostic feature of heart failure. Objectives To investigate determinants of left atrial (LA) reservoir and pump strain and if these parameters may serve as markers of LV filling pressure. Methods In a multicenter study of 322 patients with cardiovascular disease of different etiologies, LA strain by speckle tracking echocardiography was compared to conventional echocardiographic markers using invasive pressure as reference. Results Left ventricular filling pressure correlated well with LA reservoir and pump strain (r-values ‑0.52 and ‑0.57, respectively) (Figure). However, LV global longitudinal strain (GLS) was the strongest determinant of LA reservoir strain (r = 0.64), and correlated well with LA pump strain (r = 0.51). For both LA strains, association with filling pressure was strongest in patients with reduced LV ejection fraction. In patients with normal GLS (≥18%), atrial strains provided no information regarding filling pressure (Figure). Reservoir strain Conclusions Left atrial reservoir and pump strain may serve as clinical markers of LV filling pressure, but will be useful predominantly in patients with reduced systolic function. Due to limited diagnostic accuracy, LA strain should be used in combination with other indices. Abstract Figure

Objective: The soluble guanylate cyclase stimulator riociguat is approved for the treatment of adult patients with pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH) following Phase 3 randomized trials. The EXPosurE Registry RiociguaT in patients with pulmonary hypertension (EXPERT) study was designed to monitor the long-term safety of riociguat in clinical practice. Methods: EXPERT was an international, multicenter, prospective, uncontrolled, non-interventional cohort study of patients treated with riociguat. Patients were followed for at least 1 year and up to 4 years from enrollment or until 30 days after stopping riociguat treatment. Primary safety outcomes were adverse events (AEs) and serious adverse events (SAEs) coded using Medical Dictionary for Regulatory Activities preferred terms and System Organ Classes version 21.0, collected during routine clinic visits and collated via case report forms. Results: In total, 956 patients with CTEPH were included in the analysis. The most common AEs in these patients were peripheral edema/edema (11.7%), dizziness (7.5%), right ventricular (RV)/cardiac failure (7.7%), and pneumonia (5.0%). The most common SAEs were RV/cardiac failure (7.4%), pneumonia (4.1%), dyspnea (3.6%), and syncope (2.5%). Exposure-adjusted rates of hemoptysis/pulmonary hemorrhage and hypotension were low and comparable to those in the long-term extension study of riociguat (Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase–Stimulator Trial [CHEST-2]). Conclusion: Data from EXPERT show that in patients with CTEPH, the safety of riociguat in routine practice was consistent with the known safety profile of the drug, and no new safety concerns were identified. © 2020 The Authors Eli Lilly and Company; Pfizer; Bayer; GlaxoSmithKline; Merck; Actelion Pharmaceuticals; Meso Scale Diagnostics; United Therapeutics Corporation; Novartis Pharma; Merck Sharp and Dohme; GlaxoSmithKline Australia; Deutsche Forschungsgemeinschaft; Grupo Ferrer Internacional, S.A The EXPERT registry was funded by Bayer AG (Berlin, Germany) and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co. Inc., Kenilworth, NJ, USA. The authors acknowledge the database administration by Torsten Tille, Dresden, and the project administration of Mrs Romy Hoppenz and Mrs Linda Kottke at GWT-TUD GmbH, Dresden. Medical writing services provided by Richard Murphy PhD of Adelphi Communications Ltd, Macclesfield, UK were funded by Bayer AG in accordance with Good Publication Practice (GPP3) guidelines. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Prof Marius M. Hoeper reports personal fees from Bayer AG, during the conduct of the study; personal fees from Actelion, personal fees from Acceleron, personal fees from MSD, personal fees from Jansen, personal fees from Pfizer, outside the submitted work. Dr Hans Klose reports speaker and consultancy fees from Actelion, Bayer AG, GSK, Novartis, Pfizer, and United Therapeutics and research support from Actelion, Bayer AG, GSK, Pfizer, and MSD. Dr Michael Halank reports personal fees and non-financial support from Actelion, AstraZeneca, Bayer AG, Berlin-Chemie, GSK, OMT, MSD, and Novartis. Dr George Giannakoulas reports speaker and consultancy fees from Actelion, Bayer, ELPEN Pharmaceuticals, GSK, Pfizer, Lilly, and United Therapeutics, and research support from GSK, ELPEN Pharmaceuticals, and Galenica. Dr Henning Gall has received honoraria and/or other support from Actelion, AstraZeneca, Bayer, BMS, GSK, Janssen-Cilag, Lilly, MSD, Novartis, OMT, Pfizer, and United Therapeutics. Dr Pavel Jansa reports consultancy and speaker fees from MSD, AOP Orphan, and Actelion. Prof Ekkehard Grünig reports research grants and speaker honoraria/consultancy fees from Actelion and Bayer/MSD, research grants from GSK, United Therapeutics, Bellerophon, OMT GmbH, Pfizer, Reata, and Novartis, and speaker honoraria from Bial, Medscape, and OrPha Swiss GmbH. Prof David Pittrow reports personal fees from Actelion, Bayer AG, Aspen, Boehringer Ingelheim, Sanofi, Biogen, Shire, and MSD outside the submitted work. Silvia Ulrich reports research grants and personal fees from Actelion, Bayer, MSD, and Orpha Swiss. Tobias J. Lange has received personal fees from Actelion, MSD, Pfizer, and OMT orphan. Dr Iraklis Tsangaris reports speaker and consultancy fees from Actelion, Bayer AG, ELPEN, GSK, MSD, Pfizer, and United Therapeutics. Stephan Rosenkranz reports remunerations for lectures and/or consultancy from Abbott, Actelion, Arena, Bayer, Ferrer, GSK, MSD, Novartis, Pfizer, and United Therapeutics; and research support to his institution from Actelion, Bayer, Novartis, Pfizer, and United Therapeutics. Repke J. Snijder reports grants from Pfizer and Actelion Pharmaceuticals. Prof Iveta Šimková reports consultancy and speaker fees from MSD, AOP Orphan, and Actelion. Dr Marc Humbert reports grants and personal fees from Bayer and GSK, and personal fees from Actelion, Merck, and United Therapeutics. Marion Delcroix has received investigator, speaker, consultant, and steering committee member fees from Actelion, Bayer AG, Bellerophon, Eli Lilly, GlaxoSmithKline, MSD, Pfizer, and Reata, and research grants from Actelion. Joan A. Barberà reports receipt of honoraria for consultation or speaker fees from Actelion and Merck; and research support through his institution from Actelion, Merck, GlaxoSmithKline, and Ferrer. Joanna Pepke-Zaba reports research grants and speaker honoraria/consultancy fees from Actelion, Bayer/MSD, and GSK. Jean-Luc Vachiéry reports ongoing consultancies to Actelion, Sonnivie, Arena Pharma, Bial Portela, and Respira Therapeutics, past consultancies to AstraZeneca, BayerShering, CardioMEMS, GlaxoSmithKline, Pfizer, Merck, and United Therapeutics, and current membership of an advisory board or similar group for Actelion and GlaxoSmithKline. Jean-Luc Vachiéry's institution receives funding from Actelion Pharmaceuticals for performing clinical studies. Regina Steringer-Mascherbauer, Jens Klotsche, and Miguel-Angel Gomez Sanchez have no conflicts of interest relevant to the EXPERT study. Hossein-Ardeschir Ghofrani reports personal fees for advisory board work, and payment for lectures including service on speaker bureaus, from Actelion, Bayer, GSK, Novartis, and Pfizer; consultancy fees from Actelion, Bayer, Bellerophon Pulse Technologies, GSK, MSD, Novartis, and Pfizer; and grants from Deutsche Forschungsgemeinschaft (DFG). Pilar Escribano Subias reports personal fees from Actelion, Bayer AG, GlaxoSmithKline, and Merck Sharp & Dohme, and grants from Actelion, Bayer AG, GlaxoSmithKline, and Ferrer, outside the submitted work. Gérald Simonneau reports personal fees and non-financial support from Actelion, personal fees and non-financial support from Bayer, personal fees and non-financial support from MSD, outside the submitted work. Douglas S. Helmersen reports industry-sponsored research with Bayer AG, United Therapeutics, and Gilead Sciences, Inc., and advisory board/speaker fees from Bayer AG and Actelion. David Langleben reports honoraria, consultation fees, research support, and/or travel expenses from Actelion, Arena, Bayer AG, Northern Therapeutics, PhaseBio, Acceleron, Janssen, and United Therapeutics. Anco Boonstra reports consultancy fees from Pfizer BV and hospitality from Teva Nederland. Lisa M. Mielniczuk reports speaker fees and honoraria from Bayer AG, and speaker fees, consultancy fees, and travel fees from Actelion. Evgenia Williams and Christian Meier are employees of Bayer AG.

OBJECTIVE Pulmonary arterial hypertension (PAH) is a major complication in systemic sclerosis (SSc), a disease marked by vascular and lymphatic vessel abnormalities. This study was undertaken to assess the role of the lymphangiogenic factors vascular endothelial growth factor C (VEGF-C) and angiopoietin 2 (Ang-2) and the soluble forms of their respective cognate receptors, soluble VEGF receptor 3 (sVEGFR-3) and soluble TIE-2, in patients with SSc, and to evaluate their predictive ability as markers for PAH development in SSc. METHODS In this cohort study, we used multiplex bead assays to assess serum levels of lymphangiogenic factors in 2 well-characterized SSc cohorts: an unselected identification cohort of SSc patients from Oslo University Hospital (n = 371), and a PAH-enriched validation cohort of SSc patients from Zurich University Hospital and Oslo University Hospital (n = 149). As controls for the identification and validation cohorts, we obtained serum samples from 100 healthy individuals and 68 healthy individuals, respectively. Patients in whom SSc-related PAH was identified by right-sided heart catheterization (RHC) in both cohorts were studied in prediction analyses. PAH was defined according to the European Society of Cardiology/European Respiratory Society 2015 guidelines for the diagnosis and treatment of PAH. Associations of serum levels of lymphangiogenic factors with the risk of PAH development were assessed in logistic regression and Cox regression analyses. Associations in Cox regression analyses were expressed as the hazard ratio (HR) with 95% confidence interval (95% CI). RESULTS In the identification cohort, SSc patients had lower mean serum levels of VEGF-C and higher mean serum levels of Ang-2 compared to healthy controls (for VEGF-C, mean ± SD 2.1 ± 0.5 ng/ml in patients versus 2.5 ± 0.4 ng/ml in controls; for Ang-2, mean ± SD 6.1 ± 7.6 ng/ml in patients versus 2.8 ± 1.8 ng/ml in controls; each P < 0.001); these same trends were observed in SSc patients with PAH compared to those without PAH. The association of serum VEGF-C levels with SSc-PAH was confirmed in the PAH-enriched RHC validation cohort. For prediction analyses, we assembled all 251 cases of SSc-PAH identified by RHC from the identification and validation cohorts. In multivariable Cox regression analyses adjusted for age and sex, the mean serum levels of VEGF-C and sVEGFR-3 were predictive of PAH development in patients with SSc (for VEGF-C, HR 0.53 [95% CI 0.29-0.97], P = 0.04; for sVEGFR-3, HR 1.21 [95% CI 1.01-1.45], P = 0.042). CONCLUSION These findings support the notion that lymphangiogenesis is deregulated during PAH development in SSc, and indicate that VEGF-C could be a promising marker for early PAH detection in patients with SSc.

BACKGROUND: Cardiac allograft vasculopathy (CAV) is characterized by diffuse thickening of the arterial intima. Statins reduce the incidence of CAV, but despite the use of statins, CAV remains one of the leading causes of long-term death after heart transplant. Inhibitors of proprotein convertase subtilisin-kexin type 9 (PCSK9) substantially reduce cholesterol levels but have not been tested in heart transplant recipients.METHODS: The Cholesterol lowering with EVOLocumab to prevent cardiac allograft Vasculopathy in De-novo heart transplant recipients (EVOLVD) trial (ClinicalTrials.gov Identifier: NCT03734211) is a randomized, double-blind trial designed to test the effect of the PCSK9 inhibitor evolocumab on coronary intima thickness in heart transplant recipients. Adults who have received a cardiac transplant within the past 4 - 8 weeks are eligible. Exclusion criteria include an estimated glomerular filtration rate < 20 mL/min/1.73 m2 , renal replacement therapy, or contraindications to coronary angiography with intravascular ultrasound. 130 patients will be randomized (1:1) to 12-months' treatment with evolocumab or matching placebo. The primary endpoint is the coronary artery intima thickness as measured by intravascular ultrasound.CONCLUSION: The EVOLVD trial is a randomized clinical trial designed to show whether treatment with the PCSK9 inhibitor evolocumab can ameliorate CAV over the first year after heart transplant.

The randomized controlled High-Intensity Interval Training in De Novo Heart Transplant Recipients in Scandinavia (HITTS) study compared 9 months of high-intensity interval training (HIT) with moderate intensity continuous training in de novo heart transplant recipients. In our 3-year follow-up study, we aimed to determine whether the effect of early initiation of HIT on peak oxygen consumption (VO2peak ) persisted for 2 years postintervention. The study's primary end point was the change in VO2peak (mL/kg/min). The secondary end points were muscle strength, body composition, heart rate response, health-related quality of life, daily physical activity, biomarkers, and heart function. Of 78 patients who completed the 1-year HITTS trial, 65 entered our study and 62 completed the study tests. VO2peak increased from baseline to 1 year and leveled off thereafter. During the intervention period, the increase in VO2peak was larger in the HIT arm; however, 2 years later, there was no significant between-group difference in VO2peak . However, the mean change in the anaerobic threshold and extensor muscle endurance remained significantly higher in the HIT group. Early initiation of HIT after heart transplantation appears to have some sustainable long-term effects. Clinical trial registration number: NCT01796379.

Background Studies on the effect of high-intensity interval training (HIT) compared with moderate intensity continuous training (MICT) on health-related quality of life (HRQoL) after heart transplantation (HTx) is scarce. No available studies among de novo HTx recipients exists. This study aimed to investigate the effect of HIT vs. MICT on HRQoL in de novo recipients. Methods The HITTS study randomized eighty-one de novo HTx recipients to receive either HIT or MICT (1:1). The HIT intervention were performed with 2–4 interval bouts with an intensity of 85–95% of maximal effort. The MICT group exercised at an intensity of 60–80% of their maximal effort with a duration of 25 min. HRQoL was assessed by the Short Form-36 version 2 (SF-36v2) and the Hospital Anxiety and Depression Scale, mean 11 weeks after surgery and after a nine months’ intervention. The participants recorded their subjective effect of the interventions on their general health and well-being on a numeric visual analogue scale. Clinical examinations and physical tests were performed. Differences between groups were investigated with independent Student t-tests and with Mann-Whitney U tests where appropriate. Within-group differences were analyzed with Paired-Sample t-tests and Wilcoxon Signed Rank tests. Correlations between SF-36 scores and VO2peak were examined with Pearson’s correlations. Results Seventy-eight participants completed the intervention. Both exercise modes were associated with improved exercise capacity on the physical function scores of HRQoL. Mental health scores remained unchanged. No differences in the change in HRQoL between the groups occurred except for Role Emotional subscale with a larger increase in the HIT arm. Better self-reported physical function was associated with higher VO2peak and muscle strength. Conclusion HIT and MICT resulted in similar mean changes in HRQoL the first year after HTx. Both groups experienced significant improvements in the physical SF-36v2. Trial registration ClinicalTrials.gov number: NCT01796379 Registered 18 February 2013.

Aims: Invasive haemodynamic profiles at rest and during exercise after heart transplantation (HTx) have never been described in a randomized trial where de novo everolimus (EVR)-based therapy with early calcineurin inhibitor (CNI) withdrawal has been compared with conventional CNI treatment. We report central invasive haemodynamic parameters at rest and exercise during a 3 year follow-up after HTx in a sub-study of the SCandiavian Heart transplant Everolimus De novo stUdy with earLy calcineurin inhibitor avoidancE trial. We hypothesized that the nephroprotective properties, the less development of cardiac allograft vasculopathy (CAV), and the antifibrotic properties of EVR, in comparison with CNI-based immunosuppression, would demonstrate favourable invasive haemodynamic profiles in patients at rest and during exercise. Methods and results: Ninety of 115 HTx recipients randomized to EVR or CNI treatment performed right heart catheterization at rest and 68 performed right heart catheterization at exercise up to 3 years after HTx. Haemodynamic profiles were compared between EVR and CNI treatment groups. Resting haemodynamics improved in both groups from pre-HTx to the first follow-up at 7–11 weeks post-HTx and thereafter remained unchanged up to 3 years of follow-up. During follow-up, cardiac reserve during exercise increased with higher levels of maximum heart rate (118 to 148 b.p.m., P < 0.001), mean arterial pressure (103 to 128 mmHg, P < 0.001), and cardiac output (10.3 to 12.2 l/min, P < 0.001). No significant differences in haemodynamic parameters were observed between the EVR and CNI groups at rest or exercise. Isolated post-capillary pulmonary hypertension (mean pulmonary arterial pressure > 20 mmHg, pulmonary arterial wedge pressure ≥ 15 mmHg, and pulmonary vascular resistance

Background Primary cardiac affection is common and is a major cause of death in systemic sclerosis (SSc), but there are knowledge gaps regarding the effect of cardiac dysfunction on mortality. Objectives The purpose of this study was to evaluate diastolic function in a large, unselected SSc cohort and assess the effect of diastolic dysfunction (DD) on mortality. Methods SSc patients followed prospectively at the Oslo University Hospital from 2003 to 2016 with available echocardiographies and matched control subjects were included. DD was assessed by echocardiography according to the 2016 American Society of Echocardiography/European Association of Cardiovascular Imaging guidelines. Pulmonary hypertension (PH) was diagnosed by right heart catheterization. Vital status was available for all patients. Cox regression analyses with hazards ratios (HRs) were conducted. Results Diastolic function was assessed in 275 SSc patients at baseline and in 186 patients at follow-up. At baseline, 46 of the 275 SSc patients (17%) were diagnosed with DD and 195 (71%) had normal diastolic function. After a median follow-up of 3.4 years (interquartile range: 1.6 to 6.2 years), the proportion of DD increased from 17% to 29%. During follow-up, 57% of patients with DD at baseline died, compared with 13% of patients with normal diastolic function. At baseline, 86 patients had performed right heart catheterization, and 43 were diagnosed with PH; of these 60% deceased. In multivariable Cox regression analyses, DD was a stronger predictor of death (HR: 3.7; 95% CI: 1.69 to 8.14; c-index 0.89) than PH (HR: 2.0; 95% CI: 1.1 to 3.9; c-index 0.84). Conclusions DD is frequent in SSc, and the presence of DD is associated with high mortality. DD exceeds PH with respect to predicting mortality.

AIM: To study exercise capacity and determinants of early peak oxygen consumption (VO2peak) in a cohort of de novo heart transplant (HTx) recipients.METHODS: To determine possible central (chronotropic responses, cardiopulmonary and hemodynamic function) and peripheral factors (muscular exercise capacity and body composition) predictive of VO2peak, a number of different measurements and tests were performed, as follows: Cardiopulmonary exercise testing (CPET) was performed mean 11 wk after surgery in 81 HTx recipients > 18 years and was measured with breath by breath gas exchange on a treadmill or bicycle ergometer. Metabolic/respiratory measures include VO2peak and VE/VCO2 slope. Additional measures included muscle strength testing, bioelectrical impedance analysis, echocardiography, blood sampling and health-related quality of life. Based on the VO2peak (mL/kg per minute) median value, the study population was divided into two groups defined as a low-capacity group and a high-capacity group. Potential predictors were analyzed using multiple regression analysis with VO2peak (L/min) as the dependent variable.RESULTS: The mean ± standard deviation (SD) age of the total study population was 49 ± 13 years, and 73% were men. This de novo HTx cohort demonstrated a median VO2peak level of 19.4 mL/kg per min at 11 ± 1.8 wk post-HTx. As compared with the high-capacity group, the low-capacity group exercised for a shorter time, had lower maximal ventilation, O2 pulse, peak heart rate and heart rate reserve, while the VE/VCO2 slope was higher. The low-capacity group had less muscle strength and muscular exercise capacity in comparison with the high-capacity group. In order of importance, O2 pulse, heart rate reserve, muscular exercise capacity, body mass index, gender and age accounted for 84% of the variance in VO2peak (L/min). There were no minor or major serious adverse events during the CPET.CONCLUSION: Although there is great individual variance among de novo HTx recipients, early VO2peak measures appear to be influenced by both central and peripheral factors.

Objective: Systemic sclerosis (SSc) is a major cause of pulmonary arterial hypertension (PAH). Murine models indicate key roles for chemokines CCL19 and CCL21 and their receptor CCR7 in lung inflammation leading to PAH. The objective of this study was to assess the chemokine CCL19–CCL21 axis in patients with SSc-related PAH. Methods: Serum samples obtained from 2 independent prospective SSc cohorts (n = 326), patients with idiopathic PAH (n = 12), and healthy control subjects (n = 100) were analyzed for CCL19/CCL21 levels, by enzyme-linked immunosorbent assay. The levels were defined as either high or low, using the mean + 2 SD value in controls as the cutoff value. Risk stratification at the time of PAH diagnosis and PAH-related events were performed. Descriptive and Cox regression analyses were conducted. Results: CCL21 levels were higher in patients with SSc compared with controls and were elevated prior to the diagnosis of PAH. PAH was more frequent in patients with high CCL21 levels (≥0.4 ng/ml) than in those with low CCL21 levels (33.3% versus 5.3% [P < 0.001]). In multivariate analyses, CCL21 was associated with PAH (hazard ratio [HR] 5.1, 95% CI 2.39–10.76 [P < 0.001]) and occurrence of PAH-related events (HR 4.7, 95% CI 2.12–10.46, P < 0.001). Risk stratification at the time of PAH diagnosis alone did not predict PAH-related events. However, when risk at diagnosis was combined with high or low CCL21 level, there was a significant predictive effect (HR 1.3, 95% CI 1.03–1.60 [P = 0.027]). A high CCL21 level was associated with decreased survival (P < 0.001). Conclusion: CCL21 appears to be a promising marker for predicting the risk of SSc-related PAH and PAH progression. CCL21 may be part of a dysregulated immune pathway linked to the development of lung vascular damage in SSc.

Purpose Health related quality of life (HRQoL) is reduced in heart transplant (HTx) recipients compared to that of healthy individuals. Intravenous iron supplement improves quality of life in patients with heart failure and iron deficiency (ID). The IronIC trial was designed to test if a single dose of ferric derisomaltose, formerly known as iron isomaltoside, could improve exercise capacity in HTx recipients. HRQoL was a prespecified secondary endpoint. Methods In the IronIC trial we randomized 102 HTx recipients with ID to ferric derisomaltose or placebo. ID was defined as ferritin Results There was no between-group difference in peak oxygen consumption in the IronIC trial. However, HRQoL was improved in the ferric derisomaltose group compared to controls at follow-up. A significant between group difference was found in the EQ-5D index (Figure 1A), the EQ-5D-VAS (Figure 1B), and the SF-36 MCS (Figure 1C). The SF-36 MCS MCID was also significant. The SF-36 PCS (Figure 1D) and the SF-36 PCS MCID were not significantly different between the groups at follow up. Conclusion The prespecified secondary outcome HRQoL was better in the ferric derisomaltose group. These findings suggest a possible approach to improve HRQoL in HTx recipients, and could provide the basis for a trial designed to assess this issue.

Albuminuria in maintenance heart transplantation (HTx) is associated with poor renal response when switching to a calcineurin inhibitor (CNI)-lowered or CNI-free immunosuppressive regimen using everolimus (EVR), but the significance of albuminuria associated with EVR treatment after early CNI withdrawal in de novo HTx is unknown.We tested if measured glomerular filtration rate (mGFR, by chrome-ethylenediaminetetraacetic acid clearance) was associated with urine albumin/creatinine ratio (UACR) post-HTx in a subgroup of patients included in the Scandinavian Heart Transplant Everolimus De Novo Study With Early Calcineurin Inhibitor Avoidance trial, where de novo HTx patients (n = 115) were randomized to EVR with complete CNI elimination 7 to 11 weeks post-HTx or standard CNI immunosuppression.In 66 patients, UACR measures were available at 1 year. In 7 patients in the EVR group, a CNI was reintroduced within 12 months. Median mGFR was significantly higher in the EVR group both 1 and 3 years post-HTx (P = 0.0004 and P = 0.03, respectively). Median UACR at 1 year was significantly higher in the EVR group (P = 0.002). There was no correlation between log(UACR) at 1 year and mGFR at 1 or 3 years (r = -0.01, P = 0.9 and r = 0.15, P = 0.26, respectively) and in the EVR group between log(UACR) at 1 year and change in mGFR (Δ1-3 years) (r = 0.27, P = 0.14). Excluding patients in the EVR group in whom a CNI was reintroduced did not significantly change the results.The effects of EVR with early CNI withdrawal after HTx on albuminuria and renal function seem dissociated; hence, the clinical significance of albuminuria in this setting is uncertain and should not necessarily rule out EVR-based immunosuppression.

Balanced immunosuppressive therapy is the key to long-term survival after allograft transplantation. With a worldwide median recipient/graft survival of more than 11 years, heart transplantation is a highly successful treatment for selected patients with end-stage heart failure. However, current immunosuppressive regimens are associated with adverse effects. In the balance between acute rejection, cardiac allograft vasculopathy, infections and an increased risk of malignancy, there is room for improvement. The aim of this review article is to present an overview of immunosuppressive mechanisms and new immune therapy strategies in heart transplantation and to highlight emerging approaches in this field that may influence our immunosuppressive strategies in the future. Calcineurin inhibitors have been the central drug class in post-transplant immunosuppressive regimens. New trials have explored alternative drugs, such as inhibitors of mechanistic target of rapamycin and belatacept. There is ongoing research on the development of strategies to induce long-term allograft tolerance. This review briefly introduces allograft rejection immunology, and sums up contemporary immunosuppressive strategies with emphasis on the development of calcineurin inhibitor-sparing regimens and the prospect of achieving long-term tolerance.

De-novo introduction of everolimus (Eve) in heart transplant recipients opens for early reduction of calcineurin inhibitors (CNI) and potential of preserving renal function, attenuate progression of coronary allograft vasculopathy (CAV) and maintain rejection efficacy.The first trials demonstrated adequate rejection prophylaxis and favorable outcomes on CAV, but observed enhanced nephrotoxicity because of insufficient CNI reduction. The SCHEDULE trial compared de-novo Eve with significantly reduced CNI exposure and conversion to CNI-free treatment week 7-11 postheart transplant, with standard CNI immunosuppression. Improved renal function and attenuation of CAV was found among Eve patients, with higher numbers of treated acute rejections observed. With sustained superior renal and CAV related data also after 36 months with the Eve protocol, cardiac function was equally well preserved in both groups. According to the International Society of Heart and Lunge Transplantation registry, mammalian target of rapamycin inhibitor treatment is uncommon during the first postoperative year, with a prevalence of 20% in patients after 5 years.Current evidence suggests a greater benefit from these immunosuppressives if introduced at an earlier timepoint. Immunosuppressive protocols based on Eve treatment in de-novo patients should be further investigated and developed, enabling CNI avoidance before accelerating side-effects lead to irreversible damage.

Background The diagnosis of heart failure may be challenging because symptoms are rather nonspecific. Elevated left ventricular (LV) filling pressure may be used to confirm the diagnosis, but cardiac catheterization is often not practical. Echocardiographic indexes are therefore used as markers of filling pressure. Objectives This study investigated the feasibility and accuracy of comprehensive echocardiography in identifying patients with elevated LV filling pressure. Methods We conducted a multicenter study of 450 patients with a wide spectrum of cardiac diseases referred for cardiac catheterization. Left atrial volume index, in combination with flow velocities and tissue Doppler velocities, was used to estimate LV filling pressure. Invasively measured pressure was used as the gold standard. Results Mean left ventricular ejection fraction (LVEF) was 47%, with 209 patients having an LVEF Conclusions Echocardiographic assessment of LV filling pressure is feasible and accurate. When combined with clinical data, it leads to a more accurate diagnosis, regardless of LVEF.

Summary of Objectives The HITTS study (High -intensity Interval Training in de novo Heart Transplant Recipients in Scandinavia) is a randomized controlled trial designed to assess the effect of high-intensity interval training (HIT) versus moderate intensity continuous training (MICT) on exercise capacity in de novo heart transplant recipients. The primary endpoint was the change in oxygen consumption (VO2peak) at the end of the intervention period, which began 3 months after heart transplantation (HTx). After the 9-month long intervention period, we reported a between-group difference in VO2peak of 1.8 ml/kg/min in favor of HIT (p = 0.04).We found that HIT was safe, well tolerated and efficient. The HITTS study is the first randomized controlled trial to assess the effectiveness of HIT in de novo heart transplant recipients. However, long-term effects of commencing HIT soon after HTx remain unknown. In this extension of the HITTS trial, our aim was to examine whether the benefits of 9 months of supervised HIT training persist two years after the end of the intervention. Methods In the HITTS study, we randomized 81 adult de novo heart transplant recipients to 9 months of HIT (4 × 4 min intervals at 85-95% of peak heart rate (HR) or 9 months of MICT (60-80% of peak HR). The mean ± SD age was 49 ±13 and 73 % were men. Before the start of the intervention and at follow-up shortly after the intervention, we measured VO2peak, isokinetic muscle strength, body composition, left ventricular function by echo, biomarkers, and health-related quality of life (HRQoL). For the extension study, the measurements will be repeated 3 years after enrollment. VO2peak is measured with breath-by-breath gas exchange on a treadmill or bicycle ergometer. The last patient is scheduled to complete his/her 3-year follow-up at Nov 14th, 2019. Data will be available for presentation at ISHLT 2020. Endpoints The primary outcome is the long-term effect of HIT vs MICT on aerobic exercise capacity as assessed by VO2peak. Secondary outcomes are: Isokinetic muscular strength in the lower limbs by a dynamometer, body composition (bio-impedance analysis), left ventricular function by echo, heart rate response during the cardiopulmonary exercise test, relevant circulation biomarkers (renal function, NT-proBNP and cardiac troponins), HRQoL, tolerability, safety and adverse events.

Purpose High-intensity interval training (HIT) is an effective method to increase exercise capacity in de novo heart transplant recipients, as shown in the recently published HITTS study (High-intensity Interval Training in de novo Heart Transplant recipients in Scandinavia). We were interested to scrutinize the potential effect of HIT in different age categories. The main effects of HIT in one young and one older medically stable de novo heart transplant recipients are reported. Methods The HITTS study is a randomized controlled study comparing HIT versus moderate intensity continuous training (MICT) in de novo heart transplant recipients (mean 11 weeks after heart transplantation). Eighty-one participants were randomized (1:1) to 9 months of HIT or MICT. The primary endpoint was the change in VO2peak. Secondary endpoints included: Heart rate response, muscle strength and self-reported physical function measured by the Short-Form-36. One of the youngest and one of the oldest participants with the highest changes in VO2peak in the HIT intervention group were selected for this case report. Results The youngest male ( 55 years old) increased his VO2peak with 12.6 mL/kg/min (from 15.6 to 28.3 mL/kg/min). Muscle strength, heart rate response, O2 pulse and self-reported physical function also increased substantially (Table). The young heart transplant recipient completed 51 exercise sessions whereas the older heart transplant recipient completed 72 sessions. Conclusion Both the young and the older de novo heart transplant recipient increased their VO2peak with at least 4 METS (> 12 mL/kg/min) after a 9-month long HIT intervention. The results show that both young and older individuals can derive substantial benefit from HIT soon after heart transplantation.

PURPOSE: To evaluate the association between mild acute cellular rejection (ACR) and the development of cardiac allograft vasculopathy (CAV) after heart transplantation (HTx).METHODS: Substudy of the SCHEDULE trial (n=115), where de novo HTx recipients were randomized to (i) everolimus with early CNI elimination or (ii) CNI-based immunosuppression. 76 patients (66%) were included based on matched intravascular ultrasound (IVUS) examinations at baseline and year 3 post-HTx. Biopsy proven ACR within year 1 post-HTx was recorded and graded (1R, 2R, 3R). Development of CAV was assessed by IVUS and coronary angiography at year 3 post-HTx.RESULTS: Median age was 53 years (45-61) and 71% were male. ACR was recorded in 67% and patients were grouped by rejection profile: no ACR (33%), only 1R (42%), ≥ 2R (25%). Median ∆MIT(maximal intimal thickness)BL-3Y was not significantly different between groups (p=0.84). The incidence of CAV was 49% by IVUS and 26% by coronary angiography with no significant differences between groups. No correlation was found between number of 1R and ∆MITBL-3Y (r=-0.025, p=0.83). Number of 1R was not a significant predictor of ∆MITBL-3Y (p=0.58) and no significant interaction with treatment was found (p=0.98).CONCLUSION: The burden of mild ACR was not associated with CAV development.

BACKGROUND: A calcineurin inhibitor free immunosuppressive regimen has been demonstrated to improve renal function early after heart transplantation, but long-term outcome of such a strategy has not been well described.METHODS: In the randomized SCHEDULE trial, de novo heart transplant recipients received (1) everolimus with reduced-exposure calcineurin inhibitor (CNI, cyclosporine) followed by CNI withdrawal at weeks 7-11 post-transplant or (2) standard-exposure cyclosporine, both with mycophenolate mofetil and corticosteroids; 95/115 randomized patients were followed up at 5-7 years post-transplant.RESULTS: Mean measured GFR was 74.7mL/min and 62.4mL/min with everolimus and CNI, respectively. The mean difference was in favor of everolimus by 11.8 mL/min in the intent-to-treat population (P = 0.004) and 17.2 mL/min in the per protocol population (n = 75; P < 0.001). From transplantation to last follow-up, the incidence of biopsy-proven acute rejection (BPAR) was 77% (37/48) and 66% (31/47) (P = 0.23) with treated BPAR in 50% and 23% (P < 0.01), in the everolimus and CNI groups, respectively; no episode led to hemodynamic compromise. Coronary allograft vasculopathy (CAV) assessed by coronary intravascular ultrasound was present in 53% (19/36) and 74% (26/35) of everolimus- and CNI-treated patients, respectively (P = 0.037). Graft dimensions and function were similar between groups. Late adverse events were comparable.CONCLUSIONS: These results suggest that de novo heart transplant patients randomized to everolimus and low-dose CNI followed by CNI-free therapy maintain significantly better long-term renal function as well as significantly reduced CAV, than patients randomized to standard CNI treatment. Increased BPAR in the everolimus group during year 1 did not impair long-term graft function.

Systemic hypertension is prevalent in heart transplant recipients and has been partially attributed to treatment with calcineurin inhibitors (CNIs). SCandinavian HEart transplant De-novo stUdy with earLy calcineurin inhibitors avoidancE trial was the first randomized trial to study early withdrawal of CNIs in de novo heart transplant recipients, comparing an everolimus-based immunosuppressive regimen with conventional CNI-based treatment. As a prespecified secondary endpoint, blood pressure was repeatedly compared across treatment arms.The The SCandinavian HEart transplant De-novo stUdy with earLy calcineurin inhibitors avoidancE trial was a prospective, multicenter, randomized, controlled, parallel-group, open-label trial in de novo adult heart transplant recipients, undertaken at transplant centers in Scandinavia. Blood pressure was assessed with 24-hour ambulatory blood pressure monitoring up to 3 years after heart transplantation (HTx) in 83 patients.Overall, systolic blood pressure fell with time, from 138 ± 15 mm Hg 2 weeks after HTx to 134 ± 11 mm Hg after 12 months and 132 ± 14 mm Hg after 36 months (P = 0.003). Diastolic blood pressure did not change over time. After 12 months, there was a numerically larger fall in systolic blood pressure in the everolimus arm (between-group difference 8 mm Hg; P = 0.053), and after 36 months, there was a significant between group difference of 13 mm Hg (P = 0.02) in favor of everolimus.In this first, randomized trial with early CNI avoidance in de novo HTx recipients, we observed a modest fall in systolic blood pressure over the first 1 to 3 years after transplantation. The fall in systolic blood pressure was more pronounced in patients allocated to everolimus.

Source at https://doi.org/10.1016/j.healun.2019.06.003. BACKGROUND - Alterations in the partly microbiota-dependent carnitine–γ-butyrobetaine (γBB)–trimethylamine N-oxide (TMAO) pathway have been linked to the progression of heart failure and atherosclerotic disease. We evaluated if circulating γBB, TMAO, and their common precursors carnitine and trimethyllysine (TML) were dysregulated after heart transplantation and associated with development of cardiac allograft vasculopathy (CAV) and acute rejection. METHODS - We measured these metabolites in plasma from heart transplant recipients with everolimus-based (n = 32) and standard cyclosporine-based immunosuppression (n = 30) at different time-points and accompanied by assessment of CAV by intravascular ultrasound. RESULTS - Baseline levels of carnitine, TMAO, and TML were elevated in heart transplant recipients compared with controls, and TML remained elevated throughout the observation period. The microbiota-dependent metabolite γBB increased steadily during 3 years of follow-up, with a similar decrease in its endogenous precursor TML. The increase in γBB and the change in TML were associated with a change in total atheroma volume from baseline to 3 years. Increases in γBB and carnitine levels from baseline to 1 year were associated with an increased frequency of acute rejection within the first year after heart transplant. CONCLUSIONS - Our study reveals alterations of the carnitine-γBB-TMAO pathway after heart transplant, with increasing levels of γBB being associated with acute rejection and increase in total atheroma volume during 3 years of follow-up. Future studies should clarify whether interactions between dietary factors, immunosuppressive drugs, and the gut microbiota could influence acute rejection and CAV development to delineate mechanisms and potential novel treatment targets.

This is the pre-peer reviewed version of the following article: Norum, H.M., Michelsen, A.E., Lekva, T., Arora, S., Otterdal, K., Olsen, M.B. ... Ueland, T. (2018). Circulating delta‐like Notch ligand 1 is correlated with cardiac allograft vasculopathy and suppressed in heart transplant recipients on everolimus‐based immunosuppression. American journal of transplantation, 19(4), 1050-1060, which has been published in final form at https://doi.org/10.1111/ajt.15141. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. Cardiac allograft vasculopathy (CAV) causes heart failure after heart transplantation (HTx), but its pathogenesis is incompletely understood. Notch signaling, possibly modulated by everolimus (EVR), is essential for processes involved in CAV. We hypothesized that circulating Notch ligands would be dysregulated after HTx. We studied circulating delta‐like Notch ligand 1 (DLL1) and periostin (POSTN) and CAV in de novo HTx recipients (n = 70) randomized to standard or EVR‐based, calcineurin inhibitor‐free immunosuppression and in maintenance HTx recipients (n = 41). Compared to healthy controls, plasma DLL1 and POSTN were elevated in de novo (P < .01; P < .001) and maintenance HTx recipients (P < .001; P < .01). Use of EVR was associated with a treatment effect for DLL1. For de novo HTx recipients, a change in DLL1 correlated with a change in CAV at 1 (P = .021) and 3 years (P = .005). In vitro, activation of T cells increased DLL1 secretion, attenuated by EVR. In vitro data suggest that also endothelial cells and vascular smooth muscle cells (VSMCs) could contribute to circulating DLL1. Immunostaining of myocardial specimens showed colocalization of DLL1 with T cells, endothelial cells, and VSMCs. Our findings suggest a role of DLL1 in CAV progression, and that the beneficial effect of EVR on CAV could reflect a suppressive effect on DLL1.

Background: There is no consensus on how, when, or at what intensity exercise should be performed after heart transplantation (HTx). We have recently shown that high-intensity interval training (HIT) is safe, well tolerated, and efficacious in the maintenance state after HTx, but studies have not investigated HIT effects in the de novo HTx state. We hypothesized that HIT could be introduced early after HTx and that it could lead to clinically meaningful increases in exercise capacity and health-related quality of life. Methods: This multicenter, prospective, randomized, controlled trial included 81 patients a mean of 11 weeks (range, 7–16 weeks) after an HTx. Patients were randomized 1:1 to 9 months of either HIT (4×4-minute intervals at 85%–95% of peak effort) or moderate-intensity continuous training (60%–80% of peak effort). The primary outcome was the effect of HIT versus moderate-intensity continuous training on the change in aerobic exercise capacity, assessed as the peak oxygen consumption (V o 2 peak). Secondary outcomes included tolerability, safety, adverse events, isokinetic muscular strength, body composition, health-related quality of life, left ventricular function, hemodynamics, endothelial function, and biomarkers. Results: From baseline to follow-up, 96% of patients completed the study. There were no serious exercise-related adverse events. The population comprised 73% men, and the mean±SD age was 49±13 years. At the 1-year follow-up, the HIT group demonstrated greater improvements than the moderate-intensity continuous training group; the groups showed significantly different changes in the V o 2 peak (mean difference between groups, 1.8 mL·kg − 1·min − 1), the anaerobic threshold (0.28 L/min), the peak expiratory flow (11%), and the extensor muscle exercise capacity (464 J). The 1.8-mL·kg − 1·min − 1 difference was equal to ≈0.5 metabolic equivalents, which is regarded as clinically meaningful and relevant. Health-related quality of life was similar between the groups, as indicated by results from the Short Form-36 (version 2), Hospital Anxiety and Depression Scale, and a visual analog scale. Conclusions: We demonstrated that HIT was a safe, efficient exercise method in de novo HTx recipients. HIT, compared with moderate-intensity continuous training, resulted in a clinically significantly greater change in exercise capacity based on the V o 2 peak values (25% versus 15%), anaerobic threshold, peak expiratory flow, and muscular exercise capacity. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier NCT01796379.

Purpose While the treatment of choice for chronic thromboembolic pulmonary hypertension (CTEPH) is pulmonary endarterectomy (PEA), balloon pulmonary angioplasty (BPA) is an emerging option for inoperable patients. Data comparing improvements in hemodynamics and functional capacity of these treatment modalities are scarce. Methods In a single center prospective patient cohort, we compared hemodynamics by right heart catheterization and exercise by cardiopulmonary exercise testing (CPET) at admission and 5 months (±14 days) following treatment. Comprehensive evaluation and selection for PEA or BPA was performed by an expert CTEPH team. Results With similar patient characteristics and a mean age of 60 years, the two groups consisted of 96 consecutive patients who were treated with PEA (n=42) or BPA (n=54). A mean number of 4.6 [2-11] BPA procedures per patient were performed in the BPA group. Eight patients who were initially treated with PEA later received BPA due to residual pulmonary hypertension. At baseline, no significant between-group differences were observed regarding hemodynamics or exercise capacity. At follow up, PEA reduced mPAP and PVR to significantly lower levels than BPA. However, there were no significant between-group differences regarding improvements in cardiac output, central venous oxygen saturation, or exercise capacity. Conclusion In our experience, PEA improves pulmonary arterial pressure and pulmonary arterial vascular resistance to significantly lower levels than with BPA. Nevertheless, with similar improvements in cardiac output and mixed venous oxygen saturation, exercise capacity increased to the same extent in both Groups.

Background Chronic thromboembolic pulmonary hypertension (CTEPH) induces right ventricular (RV) adaptive changes but often results in RV failure and death. Balloon pulmonary angioplasty (BPA) is a treatment option in patients in whom pulmonary endarterectomy is contraindicated and in patients with residual pulmonary hypertension after pulmonary endarterectomy. We hypothesized that RV reverse remodeling and improved RV function would occur after BPA in patients with CTEPH. Methods In 26 patients with CTEPH (59 ± 12 years old; 11 men), echocardiography, cardiopulmonary exercise testing, blood samples, and right-sided cardiac catheterization were performed before and after 4 ± 2 BPA procedures. Echocardiography images were analyzed off-line with particular focus on RV function according to current recommendations. Differences from baseline to follow-up were analyzed by paired samples t tests. Results Significant improvements in hemodynamics, peak oxygen consumption, and levels of N-terminal pro-B-type natriuretic peptide were detected after BPA. All measures of RV function improved considerably, including fractional area change (+6%; p = 0.003), tricuspid annular plane systolic excursion (+3 mm; p p = 0.002). RV end-diastolic diameter, area, and free wall thickness decreased significantly, whereas left ventricular diameter and stroke volume increased. Conclusions After BPA, a significant improvement in RV functional parameters could be observed by echocardiography, adding credibility to this form of treatment in patients with CTEPH.

Summary of Objectives Heart transplant recipients have reduced exercise capacity despite preserved graft function. Numerous mechanisms may contribute to this impaired exercise tolerance, one of which may be iron deficiency (ID). Among our heart transplant survivors, 48 % have ID. The IronIC trial (NCT03662789) was designed to test the hypothesis that intravenous (i.v.) iron therapy will improve exercise capacity assessed by peak oxygen consumption. Methods 102 stable, cardiac transplant recipients with ID, defined as serum ferritin Endpoints The primary objective is to assess baseline-adjusted peak oxygen consumption, six months after one single dose of iron isomaltoside. Secondary objectives are to assess the impact of treatment on iron stores, muscle strength, cognitive function, quality of life, safety and tolerability. This study will give insight to whether heart transplant recipients with ID can benefit from intravenous iron supplement. Results will be ready for presentation at the 2020 ISHLT conference.

Background Cardiac allograft vasculopathy (CAV) limits survival after heart transplantation, and the effect of different immunosuppressive regimens on CAV is not fully understood. The randomized SCHEDULE trial (Scandinavian Heart Transplant Everolimus De Novo Study With Early Calcineurin Inhibitors Avoidance) evaluated whether initiation of the proliferation signal inhibitor everolimus and early cyclosporine elimination can reduce CAV development. Methods and Results The SCHEDULE trial was a multicenter Scandinavian trial, where 115 de novo heart transplantation recipients were randomized to everolimus with complete cyclosporine withdrawal 7 to 11 weeks after heart transplantation or standard cyclosporine-based immunosuppression. Seventy-six (66%) patients had matched intravascular ultrasound examinations at baseline and 12 and 36 months. Intravascular ultrasound analysis evaluated maximal intimal thickness, percent atheroma volume, and total atheroma volume. Qualitative plaque analysis using virtual histology assessed fibrous, fibrofatty, and calcified tissue as well as necrotic core. Serum inflammatory markers were measured in parallel. The everolimus group (n=37) demonstrated significantly reduced CAV progression as compared with the cyclosporine group (n=39) at 36 months (Δ maximal intimal thickness, 0.09±0.05 versus 0.15±0.16 mm [ P=0.03]; Δ percent atheroma volume, 5.3±2.8% versus 7.6±5.9% [ P=0.03]; and Δ total atheroma volume, 33.9±71.2 versus 54.2±96.0 mm

Background Cardiac allograft vasculopathy (CAV) limits survival after heart transplantation, and the effect of different immunosuppressive regimens on CAV is not fully understood. The randomized SCHEDULE trial (Scandinavian Heart Transplant Everolimus De Novo Study With Early Calcineurin Inhibitors Avoidance) evaluated whether initiation of the proliferation signal inhibitor everolimus and early cyclosporine elimination can reduce CAV development. Methods and Results The SCHEDULE trial was a multicenter Scandinavian trial, where 115 de novo heart transplantation recipients were randomized to everolimus with complete cyclosporine withdrawal 7 to 11 weeks after heart transplantation or standard cyclosporine-based immunosuppression. Seventy-six (66%) patients had matched intravascular ultrasound examinations at baseline and 12 and 36 months. Intravascular ultrasound analysis evaluated maximal intimal thickness, percent atheroma volume, and total atheroma volume. Qualitative plaque analysis using virtual histology assessed fibrous, fibrofatty, and calcified tissue as well as necrotic core. Serum inflammatory markers were measured in parallel. The everolimus group (n=37) demonstrated significantly reduced CAV progression as compared with the cyclosporine group (n=39) at 36 months (Δ maximal intimal thickness, 0.09±0.05 versus 0.15±0.16 mm [ P =0.03]; Δ percent atheroma volume, 5.3±2.8% versus 7.6±5.9% [ P =0.03]; and Δ total atheroma volume, 33.9±71.2 versus 54.2±96.0 mm 3 [ P =0.34], respectively]. At 36 months the number of everolimus patients with rejection graded ≥2R was 15 (41%) as compared with 5 (13%) in the cyclosporine group ( P =0.01). Everolimus did not affect CAV morphology or immune marker activity during the follow-up period. Conclusions The SCHEDULE trial demonstrates that everolimus initiation and early cyclosporine elimination significantly reduces CAV progression at 12 months, and this beneficial effect is clearly sustained at 36 months. Clinical trial registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT01266148.

Background Pulmonary arterial hypertension (PAH) continues to be a major complication in systemic sclerosis (SSc); indicating an unmet need for rational therapeutic targets. Recently, we found that chemokine CCL21 was upregulated in SSc and associated with PAH. CCL21 appears to be a key regulator of the expression and secretion of vascular endothelial growth factor-C (VEGF-C); a critical growth factor for lymphatic vessels. This is interesting as SSc is marked by lymphatic vessel abnormalities; and high blood levels of Angiopoietin-2, which is a known regulator of VEGF-C. Moreover, it was recently shown that VEGFR3, the cognate receptor for VEGF-C, is down-regulated in pulmonary arterial endothelial cells from human idiopathic PAH subjects with BMPR2 gene defects. Based on these observations, we reasoned that the observed upregulation of CCL21 in SSc-PAH could be linked to VEGF-C and Ang-2 dysregulation. Objectives Assess serum concentrations of CCL21, the VEGF family and Ang-2 in right heart catheterization (RHC) verified SSc-PAH patients and compare these to patients with borderline PAH, no PH and to healthy controls. Methods Sera from the prospective Oslo University Hospital SSc cohort (n=372) and healthy controls (n=100) were analysed for VEGF-A,C,D, CCL21 and Ang2 using Luminex kits from Millipore. Patients with an incident RHC (n=167) were included in the present study. PAH was defined as precapillary PH (mean pulmonary arterial pressure, mPAP ≥25 mmHg) in the absence of significant interstitial lung disease (ILD), based on high resolution computed tomography and lung function tests. Borderline PAH was defined as mPAP of 20–24 mmHg in in the absence of significant ILD. Patients with pulmonary hypertension (PH) due to other causes were excluded. Descriptive statistics and logistic regression analyses were performed and tested by the goodness-of-fit test with area under the curve (AUC). Results Mean age at onset was 54±14.1, at RHC 61±10.9 years. The time from sera to RHC was 0.9±3.1 years. In total, 73.7% (123) patients had limited cutaneous SSc, 46.7%48 were positive for anti-centromere antibody and 80.2% (134) were females. Of these, 123 (73.7%) patients were included in the study, 28 patients with PAH, 45 borderline PAH and 50 patients with no PH. Mean VEGF-A,C,D, CCL21 and Ang2 levels are shown in figure 1A. VEGF-A was significantly higher in SSc patients compared to healthy controls (p=0.001), no significant differences between PAH and no PH patients were found. VEGF-D was decreased in SSc-PAH but not significantly. CCL21 and Ang2 levels were increased in patients with PAH, whereas in VEGF-C was significantly decreased in patients with PAH (figure 1 B-D). In univariable logistic regression analyses, VEGF-C (OR 0.99, 95% CI 0.997–0.998,p=0.001, AUC=0.79), CCL21 (OR 1, 95% CI 1–1.003,p=0.050, AUC=0.69) and Ang2 (OR 1, 95% CI 1–1.0001,p=0.49, AUC=0.67) were associated with PAH compared to no PH patients. Due to few event numbers, no multivariable analyses were performed. Conclusions The present study is the first to demonstrate dysregulation of lymphangiogenetic factor expression of multiple targets in sera of SSc-PAH patients. Disclosure of Interest None declared

OBJECTIVE: There is a paucity of data on heart transplantation (HTx) in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC), and specific recommendations on indications for listing ARVC patients for HTx are lacking. In order to delineate features pertinent to HTx assessment, we explored the pre-HTx characteristics and clinical history in a cohort of ARVC patients who received heart transplants.METHODS: Data from 31 ARVC/HTx patients enrolled in the Nordic ARVC Registry, transplanted between 1988 and 2014 at a median age of 46years (14-65), were compared with data from 152 non-transplanted probands with Definite ARVC according to 2010 Task Force Criteria from the same registry.RESULTS: The HTx patients were younger at presentation, median 31 vs. 38years (p=0.001). There was no difference in arrhythmia-related events. The indication for HTx was heart failure in 28 patients (90%) and ventricular arrhythmias in 3 patients (10%). During median follow-up of 4.9years (0.04-28), there was one early death and two late deaths. Survival was 91% at 5years after HTx. Age at first symptoms under 35years independently predicted HTx in our cohort (OR=7.59, 95% CI 2.69-21.39, pCONCLUSION: HTx in patients with ARVC is performed predominantly due to heart failure. This suggests that current 2016 International Society for Heart and Lung Transplantation heart transplant listing recommendations for other cardiomyopathies could be applicable in many cases when taking into account the haemodynamic consequences of right ventricular failure in conjunction with ventricular arrhythmia.

Purpose The impact of mild (1R) acute cellular rejection (ACR) on the development of cardiac allograft vasculopathy (CAV) after heart transplantation (HTx) remains unclear. We aimed to investigate the association between mild ACR within 1 year of HTx and development of CAV at 3 years post HTx. Methods This is a substudy of the SCHEDULE trial (n=115) in which de novo HTx recipients were randomized to either (i) everolimus or (ii) conventional CNI-based immunosuppression. 76 patients (66%) were eligible for inclusion based on matched intravascular ultrasound (IVUS) examinations at baseline (BL) and 3 years post HTx. Biopsy proven ACR within year 1 was recorded and graded according to ISHLT criteria (1R, 2R, 3R). Development of CAV was assessed by IVUS and coronary angiography at year 3 post HTx. Results Median age was 53 years (45-61) and 71% were male. In 67% of patients ACR was recorded during year 1 (1R in 63%, 2R in 24%, and 3R in 3% of patients, respectively). Patients were grouped by rejection profile: no ACR (33%), only 1R (42%), at least one 2R/3R (25%). At 3 years post HTx 49% of patients had CAV on IVUS (maximal intimal thickness, MIT ≥ 0.5 mm) with no difference in the incidence of IVUS-CAV between groups (p=0.43). Median ∆MITBL-3Y was 0.09 mm (0.05-0.15) with no significant difference among groups (p=0.84) (figure 1). At 3 years post HTx angiographic CAV was present in 26% of patients with no significant between group difference (no ACR: 40%, only 1R: 24%, at least one 2R/3R: 7%; p=0.06). No correlation was found between number of 1R and ∆MITBL-3Y (r=-0.03, p=0.83). Number of 1R did not predict ∆MITBL-3Y in an adjusted linear regression model (p=0.69). No significant interaction with treatment regimen (everolimus/CNI) was found (p=0.84). Conclusion Mild ACR within 1 year of HTx was not associated with development of CAV assessed by IVUS and coronary angiography at year 3 post HTx.

Purpose A main goal after heart transplantation (HTx) is to achieve good health related quality of life (HRQoL). Exercise training after heart transplantation (HTx) is recommended and high-intensity interval training (HIT) seem to be more effective than moderate continuous training (MICT). Studies on the effect of HIT vs. MICT on HRQoL is scarce, and no studies among de novo HTx recipients exist. Methods Eighty-one de novo HTx recipients were included and were randomized 1:1 to either HIT or MICT. HRQoL was assessed by the Short Form-36 (SF-36v2), the Hospital Anxiety and Depression Scale (HADS) at baseline (mean 11 weeks after surgery) and at 1-yr follow- up, additionally, participants reported their overall health on a numeric visual analouge scale after the intervention period. SF-36 scores were calculated using norm based values with a standardized mean of 50±10. All patients underwent a clinical examination and physical tests. Results At 1-yr follow-up 78 patients were retested. Both groups had significant improvements on the physical function components of HRQoL the first year after HTx, while mental health, anxiety and depression scores remain unchanged. There were no serious adverse events related to exercise in either of the groups during the intervention period. Mean ± SD age for the total population was 49±13 years, 73% were men. There was no significant difference between HIT and MICT in seven of the eight SF-36 subscales, in physical component summary score (PCS) or mental component summary score (MCS). However, there was a statistical significant positive change in the role emotional (RE) subscale mean score in the HIT group compared to the MICT group (Table 1). Conclusion From baseline to 1-yr follow-up HIT vs. MICT resulted in similar mean changes in HRQoL, except from on the SF-36 RE subscale. Both groups had significant improvements in PF, RP and PCS,suggesting that exercise training improves some areas of the multidimensional concept of HRQoL.

Background Elevated levels of soluble ST2 (sST2) are associated with adverse outcome in heart failure. A change in sST2 levels has also been shown to presage outcome. In vitro, ST2 expression is induced by myocardial stress and pro-inflammatory stimuli. The determinants of sST2 levels in vivo, and how they vary with clinical status over time, have not been well described. In a cohort of patients with non-ischemic heart failure, we aimed to assess the association between sST2-levels and hemodynamic parameters reflecting right and left ventricular pre- and afterload, and how these vary with time and clinical status. Methods We prospectively recruited 102 patients with a left ventricular ejection fraction of 26±10% and a diagnosis of idiopathic dilated cardiomyopathy based on patient history, clinical examination, echocardiography and coronary angiography. Patients went through extensive baseline work-up and were re-examined after one year. Subsequently, heart transplantations and deaths were recorded. Determinants of sST2 were analyzed at baseline and after one year. Soluble ST2 was measured with a highly sensitive immunoassay. Results Soluble ST2 levels were associated with hemodynamic parameters, but these associations were attenuated with clinical improvement. Soluble ST2 was elevated in patients with severe symptoms, but did not vary with etiology, viral presence or the amount of myocardial fibrosis. Heart rate and right atrial pressure remained independent predictors of sST2 on multiple regression analysis. Conclusions Our results imply that in non-ischemic heart failure, sST2 reflects hemodynamic stress rather than pathogenic processes in the myocardium.

Background Cognitive impairment is documented early after heart transplantation (HTx), but we lack data on cognitive function beyond the fourth year post-transplant. Against the background of good long-term survival, this knowledge is necessary to improve clinical care throughout the entire post-transplant period. Methods We assessed cognitive function with a neuropsychological test battery in a sample of HTx recipients ≥16 years post-transplant. To improve clinical utility, we also applied adapted consensus criteria for Mild Cognitive Impairment (MCI). Furthermore, we explored sociodemographic and clinical characteristics possibly related to cognitive function. Results Thirty-seven subjects were included 20.3 (±3.8) years after HTx. Mean age was 57.5 (±14.2) years, and 18.9% were women. Up to 38.9% exhibited impaired test performance (ie, performance at least 1.5 standard deviations below the normative mean) on several individual cognitive measures, especially on measures of processing speed, executive functions, memory, and language functions. One subject was diagnosed with dementia, and 30.1% qualified for MCI. Those with MCI had lower hemoglobin than those without. Conclusions A substantial proportion of long-term survivors of HTx might be cognitively impaired. The level of impairment appears comparable to what is defined as MCI in the literature. Modifiable factors related to cognitive impairment might exist.

The Scandinavian heart transplant everolimus de novo study with early calcineurin inhibitors avoidance (SCHEDULE) trial was a 12 month, randomized, open-label, parallel-group trial that compared everolimus (EVR; n=56) to conventional CsA (n=59) immunosuppression. Previously, we reported that EVR outperformed CsA in improving renal function and coronary artery vasculopathy, despite a higher rejection rate with EVR. This study aimed to compare the effects of these treatments on quality of life (QoL). Within five post-operative days, patients (mean age 50±13 years, 27% women) were randomized to EVR or a standard CsA dosage (CsA group). This study assessed quality of life (QoL), based on the Short Form-36, EuroQol-5D, and Beck Depression Inventory (BDI). Assessments were performed pre-HTx and 12 and 36 months post-HTx. At 12 and 36 months, the groups showed similar improvements in Short Form-36 measures (at pre-HTx, 12 and 36 months the values were as follows: Physical component summary: EVR: 31.5±110.9, 49.1±9.7, and 47.9±10.6; P

Objective The DETECT algorithm was developed for screening patients with SSc at high risk of pulmonary arterial hypertension (PAH). We evaluated the impact of this algorithm in a SSc population. Methods Patients from the unselected, prospective Oslo University Hospital SSc study were divided into the Early and DETECT cohorts, respectively, depending on whether an incident right heart catheterization (RHC) was performed before (2009-13) or after (2014-17) the DETECT algorithm was instituted. A PAH diagnosis and patient risk stratification (low, intermediate and high risk) were performed according to 2015 European Society of Cardiology guidelines. Results At the time of the incident RHC, PAH frequency was similar between the DETECT (15/84 with PAH; 18%) and Early (16/77; 21%) cohorts, but more patients had borderline pulmonary hypertension (PH) in the DETECT (31%) than in the Early (17%) cohort. PAH risk levels were distributed differently. In the DETECT cohort, 27% and 27% were at low and high risk, respectively, at the time of PAH diagnosis. In the Early cohort, 19 and 44% were at low and high risk, respectively. A follow-up RHC, performed after [mean (SD)] 2.4 (1.8) years, showed that 39% of patients with borderline PH in the Early cohort had developed PAH. Conclusion The DETECT algorithm did not alter PAH incidence in this unselected SSc population. However, it appeared to affect the risk distribution at the time of PAH diagnosis and increased the frequency of borderline PH cases. These findings may translate into novel opportunities for earlier PAH treatment and, possibly, prevention.