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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.

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.

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.

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.

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.

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.

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 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.

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

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.

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.

Background Studies have shown conflicting results concerning the occurrence of cognitive impairment after successful heart transplantation (HTx). Another unresolved issue is the possible differential impact of immunosuppressants on cognitive function. In this study, we describe cognitive function in a cohort of HTx recipients and subsequently compare cognitive function between subjects on either everolimus- or calcineurin inhibitor (CNI)-based immunosuppression. Methods Cognitive function, covering attention, processing speed, executive functions, memory, and language functions, was assessed with a neuropsychological test battery. Thirty-seven subjects were included (everolimus group: n=20; CNI group: n=17). The extent of cerebrovascular pathology was assessed with magnetic resonance imaging. Results About 40% of subjects had cognitive impairment, defined as performance at least 1.5 standard deviations below normative mean in one or several cognitive domains. Cerebrovascular pathology was present in 33.3%. There were no statistically significant differences between treatment groups across cognitive domains. Conclusions Given the high prevalence of cognitive impairment in the sample, plus the known negative impact of cognitive impairment on clinical outcome, our results indicate that cognitive assessment should be an integrated part of routine clinical follow-up after HTx. However, everolimus- and CNI-based immunosuppressive regimens did not show differential impacts on cognitive function.

In dilated cardiomyopathy (DCM), adverse myocardial remodeling is essential, potentially involving Notch signaling. We hypothesized that secreted Notch ligands would be dysregulated in DCM. We measured plasma levels of the canonical Delta-like Notch ligand 1 (DLL1) and non-canonical Notch ligands Delta-like 1 homologue (DLK1) and periostin (POSN) in 102 DCM patients and 32 matched controls. Myocardial mRNA and protein levels of DLL1, DLK1, and POSN were measured in 25 explanted hearts. Our main findings were: (i) Circulating levels of DLL1 and POSN were higher in patients with severe DCM and correlated with the degree of diastolic dysfunction and (ii) right ventricular tissue expressions of DLL1, DLK1, and POSN were oppositely associated with cardiac function indices, as high DLL1 and DLK1 expression corresponded to more preserved and high POSN expression to more deteriorated cardiac function. DLL1, DLK1, and POSN are dysregulated in end-stage DCM, possibly mediating different effects on cardiac function.

The Wingless (Wnt) pathway has been implicated in the pathogenesis of dilated cardiomyopathy (DCM). To explore the role of Wnt modulators Wnt5a and sFRP3 in DCM patients we analyzed the expression of Wnt5a and sFRP3 in plasma and myocardium of DCM patients and evaluated their effects on NFAT luciferase activity in neonatal mouse cardiomyocytes. Elevated circulating Wnt5a (n = 102) was associated with increased pulmonary artery pressures, decreased right ventricular function and adverse outcome, with a stronger association in more severely affected patients. A higher Wnt5a/sFRP3 ratio (n = 25) was found in the right ventricle vs. the left ventricle and was correlated with NFAT activation as well as pulmonary artery pressures. Wnt5a induced NFAT activation and sFRP3 release in cardiomyocytes in vitro, while sFRP3 antagonized Wnt5a. Wnt5a is associated with right ventricular dysfunction and adverse outcome in DCM patients and may promote the progression of DCM through NFAT signaling. © The Author(s) 2017. Open Access. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

OBJECTIVES: Due to the need for suitable donors for heart transplantation (HTx), older grafts and grafts with prolonged graft ischaemic time (GIT) are accepted. The impact of GIT and donor age on post-transplant cardiac function has not been examined with either newer echocardiographic techniques (tissue Doppler imaging, TDI) or cardiopulmonary exercise testing (CPET). Thus, we studied the influence of GIT and donor age on post-transplant cardiac function and exercise capacity. METHODS: Fifty-two stable recipients underwent echocardiography with colour TDI and CPET at a median of 4 years after HTx. Left ventricular (LV) systolic (s 0 ) and early diastolic (e 0 ) mitral annular velocities, right ventricular (RV) s 0 ,R Ve 0 as well as LV ejection fraction (EF) and VO2peak were analysed. RESULTS: HTx recipients with GIT ≥median value (200 min) had significantly lower septal LVs 0 (15%, P= 0.005), LVEF (9%, P= 0.015), RVs 0 (21%, P= 0.007), septal LVe 0 (22%, P= 0.001) and RVe 0 velocities (23%, P= 0.011), and slightly lower VO2peak (P= 0.098). Recipients with grafts from donor ≥median age (37 years) had significantly lower LVe 0 velocities (septal LVe 0 P= 0.047 and lateral LVe 0 P= 0.010), but not LV systolic or RV parameters. CONCLUSIONS: Prolonged GIT impairs both systolic and diastolic function at the interventricular septum and RV free wall, while increasing donor age impairs LV diastolic function. The duration of graft ischaemia and donor age should be taken into account when evaluating for cardiac dysfunction in HTx recipients.

OBJECTIVES The aim of this study was to assess the overall prevalence of pulmonary hypertension (PH) in an unselected MCTD cohort and review the current knowledge with a systematic database search. METHODS A nationwide multicentre cohort of 147 adult MCTD patients were initially screened for PH by echocardiography, high-resolution computed tomography (HRCT), pulmonary function tests and N-terminal pro-brain natriuretic peptide (NT-proBNP) and then followed up for a mean of 5.6 years. Right-sided heart catheterization was performed when estimated pulmonary artery systolic pressure was >40 mmHg on echocardiography. PH was diagnosed according to the 2009 European Society of Cardiology and European Respiratory Society guidelines. RESULTS At inclusion, 2.0% (3/147) had established PH. Two additional PH patients were identified during follow-up, giving a total PH frequency in the cohort of 3.4% (5/147). All five had elevated serum NT-proBNP. Two had isolated pulmonary arterial hypertension (PAH) and three PH associated with interstitial lung disease (PH-ILD). Three PH patients died during follow-up. Nine other patients in the cohort also died, but none of them had echocardiographic signs of PH prior to death. CONCLUSION The data from the current unselected MCTD cohort suggest that the prevalence of PH is much lower than expected from previous studies but confirm the seriousness of the disease complication.

Objective.Extensive skin disease and renal crisis are hallmarks of anti-RNA polymerase III (RNAP)-positive systemic sclerosis (SSc), while lung and heart involvement data are conflicting. Here, the aims were to perform time-course analyses of interstitial lung disease (ILD) and pulmonary hypertension (PH) in the RNAP subset of a prospective unselected SSc cohort and to use the other autoantibody subsets as comparators.Methods.The study cohort included 279 patients with SSc from the observational Oslo University Hospital cohort with complete data on (1) SSc-related autoantibodies, (2) paired, serial analyses of lung function and fibrosis by computed tomography, and (3) PH verified by right heart catheterization.Results.RNAP was positive in 33 patients (12%), 79% of which had diffuse cutaneous SSc. Pulmonary findings were heterogeneous; 49% had no signs of fibrosis while 18% had > 20% fibrosis at followup. Forced vital capacity at followup was < 80% in 39% of the RNAP subset, comparable to the antitopoisomerase subset (ATA; 47%), but higher than anticentromere (ACA; 13%). Accumulated frequency of PH in the RNAP subset (12%) was lower than in ACA (18%). At 93% and 78%, the 5- and 10-year survival rates in RNAP were comparable to the ATA and ACA subsets.Conclusion.In this cohort, the RNAP subset was marked by cardiopulmonary heterogeneity, ranging from mild ILD to development of severe ILD in 18%, and PH development in 12%. These data indicate that cardiopulmonary risk stratification early in the disease course is particularly important in RNAP-positive SSc.

The chemokine receptor CCR7 regulates lymphocyte trafficking, and CCR7 deficiency induces infiltration of T and B cells adjacent to vessels in mouse lungs. Perivascular infiltration of T and B cells has also been found in human pulmonary arterial hypertension, and downregulation of the CCR7 receptor in circulating leukocytes of such patients has been observed. To investigate whether changes in the CCR7 system contribute to the pathogenesis of pulmonary hypertension, we utilized mice deficient of the CCR7 receptor. The cardiopulmonary and inflammatory responses of CCR7 depletion were evaluated in CCR7-deficient and wild-type mice. Measurements of cytokines upregulated in the animal model were also performed in patients with pulmonary hypertension and controls and in vascular smooth muscle cells. We found that mice lacking CCR7 had increased right ventricular systolic pressure, reduced pulmonary artery acceleration time, increased right ventricular/tibial length ratio, Rho kinase-mediated pulmonary vasoconstriction, and increased muscularization of distal arteries, indicating pulmonary hypertension. These mice also showed increased perivascular infiltration of leukocytes, consisting mainly of T and B cells, and increased mRNA levels of the inflammatory cytokines interleukin-12 and CX3CL1 within pulmonary tissue. Increased serum levels of interleukin-12 and CX3CL1 were also observed in patients with pulmonary hypertension, particularly in those with pulmonary hypertension associated with connective tissue disorder. In smooth muscle cells, interleukin-12 induced secretion of the angiogenic cytokine interleukin-8. We conclude that these results suggest a role for CCR7 in the development of pulmonary arterial hypertension, at least in some subgroups, possibly via pulmonary infiltration of lymphocytes and secretion of interleukin-12 and CX3CL1.

Background The prognostic impact of pulmonary hypertension (PH) before and after heart transplantation (HTx) is debated. We investigated: (i) the significance of pre-operative reversible PH on post-operative survival; (ii) the value of recatheterization while on the waiting list; (iii) the evolution of right heart hemodynamics (RHH) after HTx; and (iv) the prognostic impact of PH at 1 year after HTx. Methods We reviewed the records of 500 HTx recipients transplanted between 1983 and 2007. Pre-operatively, a non-PH group (Group 1, n = 365) fulfilled directly our RHH criteria for HTx, while a PH group (Group 2, n = 135) was accepted after reversibility of PH by acute vasodilatory testing. Recatheterization was performed every third month while on the waiting list and repeatedly after transplantation. Results With a follow-up of 6.8 ± 5.1 years and a 50% survival rate of 12.1 ± 5.4 years, our main findings were as follows: (i) Patients with reversible PH on vasodilatory testing had a survival rate similar to that of patients without PH (11.7 ± 0.8 vs 12.1 ± 0.5 years, p = 0.80). (ii) Pre-operative recatheterization was of limited value as RHH remained stable. Five percent of patients died while on the waiting list and 2 improved clinically and were removed. (iii) Mean pulmonary artery pressure (MAP) was reduced from 28 ± 9 and 40 ± 8 mm Hg pre-operatively to 21 ± 7 and 24 ± 6 mm Hg after 2 weeks and 16 ± 7 and 18 ± 8 mm Hg at 3 years in Groups 1 and 2, respectively. (iv) Recipients with MAP >20 mm Hg at 1 year post-HTx had significantly lower survival than those with MAP ≤20 mm Hg (11.5 ± 0.7 vs 15.6 ± 0.6 years, p Conclusions Elevated pulmonary pressure 1 year after HTx provides significant prognostic information regarding long-term outcome, whereas pre-operative reversible PH in this group does not influence survival.

Aims There are few studies of the use of intra-aortic balloon pump (IABP) treatment as a bridge to heart transplantation (HTx). This is the first study to compare long-term clinical and haemodynamic outcomes in IABP-treated HTx patients and electively transplanted patients. Methods and results This was a retrospective study of all adult HTx recipients between 2001 and 2007. Thirty-two patients (aged 50 ± 13 years) treated with IABP, as a bridge to HTx due to severe hypo-perfusion, were compared with 135 electively transplanted patients (aged 54 ± 11 years). The mean time from onset of IABP to HTx was 21 ± 16 days. Clinical condition improved during IABP treatment. Serum creatinine decreased from 128 ± 56 to 102 ± 29 µmol/L (P < 0.01), aspartate transaminase from 682 ± 1299 to 63 ± 89 U/L (P = 0.01), and ALAT from 483 ± 867 to 126 ± 284 U/L (P = 0.02). Intra-aortic balloon pump treatment related complications were few. Mortality was similar in the IABP and control groups at 30 days post-HTx (6.2 vs.3.7%, P = 0.54), at 1 year (9.4 vs.11.1%, P = 0.80), and beyond. Long-term clinical and haemodynamic indices were similar in the two groups. Conclusion Intra-aortic balloon pump treatment stabilizes patients in end-stage heart failure, is safe, well tolerated, and is successful in bridging acutely decompensated patients to transplantation. Complications are few and manageable. Following IABP and HTx, short- and long-term survival, biochemical and invasive and non-invasive haemodynamic outcomes were similar to those in electively transplanted patients.

The sequential changes of Lp(a) lipoprotein concentrations in patients (n = 59) suffering acute myocardial infarction (AMI) were examined and compared with other plasma proteins. The temporal and quantitative characteristics of the responses in concentration of acute phase reactants (CRP, haptoglobin, alpha 1-antitrypsin, alpha-acid glycoprotein), lipids (total cholesterol, triglycerides, HDL cholesterol, LDL cholesterol) and apolipoproteins AI and B were similar to previous reports. Lp(a) lipoprotein showed transient changes with an initial decrease of 10-25% compared to the 3-month control value, followed by rebound on day 7-11 above admission level, before again declining. We were able to demonstrate a quantitative relationship between infarct size and alterations in plasma levels of acute phase reactants. However, in addition to rather unusual significant fluctuations during AMI, Lp(a) lipoprotein changes seemed unrelated to infarct size. These findings do not support the view that Lp(a) lipoprotein acts as an acute phase reactant.

Impaired renal function is associated with increased mortality among heart failure patients. Although a significant proportion of heart transplant (HTx) recipients have reduced renal function at 1 year post-HTx, no previous study has evaluated the associated risk for both all-cause and cardiac mortality. Hence, we assessed the relationship between glomerular filtration rate (GFR) at 1 year post-HTx and all-cause and cardiac mortality and development of cardiac allograft vasculopathy (CAV).We evaluated 381 patients with a minimum survival of 1 year post-HTx and the Modification of Diet in Renal Disease Study formula was used to calculate estimated GFR. Mortality and angiographic CAV were defined as separate endpoints, and median follow-up was 7.4 and 4.0 years, respectively.During the follow-up period, 122 patients died and 154 patients developed CAV. Reduced GFR pre-HTx was not a risk factor for either endpoint. Overall, 193 (51%) patients had GFR60 ml/min/1.73 m at one year post-HTx and this was an independent predictor of all-cause mortality with an adjusted hazard ratio of 1.7 (P=0.01) for a GFR between 30-60 and 3.2 (P=0.006) for GFR30 ml/min/1.73 m. GFR60 ml/min/1.73 m at 1 year post-HTx was also associated with a higher risk of cardiac mortality (HR=1.9; P=0.04) but did not predict the development of CAV.Renal impairment is evident in a majority of HTx recipients at 1 year post-HTx. It is an important risk factor for both all-cause and cardiac mortality but does not predict the development of angiographic CAV.

Background. Several studies indicate that heart transplantation (HTx) is associated with depression and reduced quality of life. However, the impact of depression on the prognosis for HTx-patients has not yet been sufficiently established. The aim of the present study was to prospectively investigate the influence of depression on mortality in patients with HTx, adjusting for other known risk factors. Methods. In a prospective, cross-sectional study with minimum 5-year follow-up, symptoms of depression were assessed in 147 HTx-patients using the Beck Depression Inventory (BDI). Results. Mild to severe depressive symptoms (BDI 10) were observed in 36 patients (24.5%). Depressive symptoms on inclusion increased the risk of mortality during the follow-up period. The risk remained significant after adjusting for several somatic and lifestyle risk factors, and the adjusted relative risk associated with depression (risk ratio: 2.32; 95% CI: 1.13–4.79; P0.02) was comparable to the adjusted relative risk associated with time since HTx. Conclusions. Symptoms of depression predict mortality independently of somatic and lifestyle risk factors in HTx patients, and this group of patients should be screened for depressive symptoms.

Background Microvascular function in transplanted hearts can be evaluated by methods used in routine left heart catheterization follow-up after heart transplantation (HTx). This sub-study of a randomized study compared the effects of everolimus (EVR) and calcineurin inhibitor (CNI) treatment on microvascular function as expressed by the index of microvascular resistance (IMR) at 1 year after HTx. A secondary objective was to compare the change in IMR from 7–11 weeks to 1 year after HTx between randomized groups. Methods There were 70 HTx recipients included and randomly assigned to combination therapy (EVR and CNI with early CNI withdrawal) vs conventional CNI treatment. Coronary physiologic assessment was performed 7–11 weeks and 1 year after HTx. A linear mixed model was used to assess the group difference at 1 year and the difference in IMR change between 7–11 weeks and 1 year after HTx. Results At 1 year, there was no significant difference in IMR between the EVR group (17.5 mm Hg∙sec ± 8.9) (mean ± SD) and the CNI group (14.9 mm Hg∙sec ± 6.6, p = 0.17). The difference in IMR change between the 2 treatment arms was 1.6 mm Hg∙sec (95% confidence interval, −2.8 to 5.9; p = 0.49). Spearman's rank correlation coefficient at 1 year after HTx between IMR and maximal intimal thickness as assessed with intravascular ultrasound in the left anterior descending artery was −0.13 ( p = 0.28). Conclusions In this prospective, open, randomized study comparing early CNI withdrawal with mammalian target of rapamycin inhibitors immunosuppression during the first year after HTx, early transition from CNI-based immunosuppression to EVR-based treatment did not result in differences in microvascular function as assessed by the IMR.

Outcome is better in patients with idiopathic dilated cardiomyopathy (IDC) than in ischemic heart failure (HF), but morbidity and mortality are nevertheless presumed to be substantial. Most data on the prognosis in IDC stem from research performed before the widespread use of current evidence-based treatment, including implantable devices. We report outcome data from a cohort of patients with IDC treated according to current HF guidelines and compare our results with previous figures: 102 consecutive patients referred to our tertiary care hospital with idiopathic IDC and a left ventricular ejection fraction

Aims Heart failure patients with reduced and preserved left ventricular (LV) ejection fraction (EF) show reduced exercise capacity. We explored the relationship between exercise capacity and systolic and diastolic myocardial function in heart failure patients. Methods and results Exercise capacity, by peak oxygen uptake (VO2), was assessed in 100 patients (56 ± 12 years, NYHA functional class: 2.5 ± 0.9, EF: 42 ± 19%). LV systolic function, as EF and global longitudinal strain (GLS), and right ventricular function were assessed by echocardiography. Left atrial volume index and the ratio of peak early diastolic filling velocity ( E ) to early diastolic mitral annular velocity ( e ′) were measures of diastolic function. Thirty-seven patients had heart failure with preserved EF (HFpEF), defined as EF ≥50% and echocardiographic diastolic dysfunction. LV GLS and peak pulmonary arterial systolic pressure were independently correlated to peak VO2 in the total study population and in HFpEF separately. LV GLS was superior to EF in identifying patients with impaired peak VO2

N-terminal-pro-B-type natriuretic peptide (NT-pro-BNP) is well established as a predictor of prognosis in patients with left ventricular dysfunction. Although a similar prognostic significance has been suggested in 1 study of right ventricular failure and idiopathic pulmonary arterial hypertension, NT-pro-BNP has not been assessed as a marker of disease severity in a more heterogenous group of patients with chronic precapillary pulmonary hypertension (PH). Hence, this study assessed plasma NT-pro-BNP and other clinical variables in 61 consecutively recruited patients with various forms of chronic precapillary PH. Right-sided cardiac catheterization and cardiopulmonary exercise testing were performed at baseline, and the prognostic significance of NT-pro-BNP was investigated with a mean follow-up of 25 months. Compared with age-matched controls (n = 10), plasma NT-pro-BNP was significantly greater in those with idiopathic pulmonary arterial hypertension (n = 16), chronic precapillary PH associated with other diseases (n = 26), and chronic thromboembolic disease (n = 19) and was correlated with hemodynamic variables and functional capacity. In 17 medically treated patients, the significant decrease in NT-pro-BNP levels correlated with improved hemodynamics. During follow-up, 15 patients died from cardiopulmonary causes. Baseline NT-pro-BNP was an independent predictor of mortality. Kaplan-Meier survival analysis according to the median value of NT-pro-BNP (168 pmol/L) demonstrated a significantly higher mortality rate in those with supramedian values than in those with low plasma levels (p = 0.010). In conclusion, these findings suggest that in a heterogenous group of patients with chronic precapillary PH, plasma NT-pro-BNP can be used to determine the clinical severity of disease and is independently associated with long-term mortality.

Objective—Based on its role in inflammation and matrix degradation, we hypothesized a role for osteoprotegerin (OPG), RANK, and RANK ligand (RANKL) in coronary artery disease.Methods and Results—We examined the expression of various members of the OPG/RANKL/RANK axis in patients with stable and unstable angina and in the atherosclerotic lesions of apolipoprotein E–deficient (apoE−/−) mice. Our findings were: (1) Serum levels of OPG were raised in patients with unstable angina (n=40), but not in those with stable angina (n=40), comparing controls (n=20); (2) mRNA levels of RANKL were increased in T-cells in unstable angina patients accompanied by increased expression of RANK in monocytes; (3) strong immunostaining of OPG/RANKL/RANK was seen within thrombus material obtained at the site of plaque rupture during acute myocardial infarction; (4) OPG/RANKL/RANK was expressed in the atherosclerotic plaques of apoE−/−mice, with RANKL located specifically to the plaques; and (5) RANKL enhanced the release of monocyte chemoattractant peptide-1 in mononuclear cells from unstable angina patients, and promoted matrix metalloproteinase (MMP) activity in vascular smooth muscle cells.Conclusions—We show enhanced expression of the OPG/RANKL/RANK system both in clinical and experimental atherosclerosis, with enhanced T-cell expression of RANKL as an important feature of unstable disease.

Background The clinical benefit of percutaneous coronary intervention (PCI) in heart transplant recipients (HTRs) with coronary allograft vasculopathy (CAV) has been questioned. We investigated the degree of inflammatory reaction during PCI in CAV compared to patients with native atherosclerosis, and the possible relationship between PCI-induced inflammation and the degree of re-stenosis in these 2 patient groups. Methods In 11 CAV patients and 10 patients with native atherosclerosis, blood samples were drawn before and 24 hours and 6 months after PCI, and analyzed with regard to hsCRP, MCP-1, components of complement activation, von Willebrand factor (vWf), soluble L-selectin and ICAM-1. Quantitative angiography was performed before and after PCI, and at 6-month follow-up. Results Baseline levels of hsCRP, vWf and MCP-1 were significantly elevated and levels of L-selectin and ICAM-1 and activation products of the alternative pathway of the complement system were decreased in CAV patients compared to those with native atherosclerosis. PCI induced significant increases of hsCRP in both groups as well as an increase in vWf in native atherosclerosis, whereas a decrease in L-selectin was observed in native atherosclerosis. Plasma levels of MCP-1 correlated with percent stenosis at follow-up in both groups, whereas a correlation between hsCRP and percent stenosis was evident only in patients with native atherosclerosis. There were no differences in rates of re-stenosis between the 2 groups. Conclusions HTRs with CAV and patients with native atherosclerosis are characterized by different profiles of immune activation and respond differently to PCI. Nevertheless, an inappropriate inflammatory reactivity may predispose to re-stenosis after PCI in both groups of patients, with pre-procedural inflammation being of particular importance in CAV.

Aims Transplant-associated coronary artery disease (TxCAD) is a major cause of post-transplant graft failure. The aim of this study was to investigate a possible role of mannose-binding lectin (MBL) deficiency and complement activation in TxCAD. Methods and results In a prospective study of heart transplant recipients ( n =38) with a follow-up of 5.3±1.3 years (range: 0.9–6.6), angiographically verified TxCAD ( n =6) was correlated to plasma MBL, complement activation, and endothelial activation (soluble E-selectin). MBL deficiency (

Early initiation of everolimus with calcineurin inhibitor therapy has been shown to reduce the progression of cardiac allograft vasculopathy (CAV) in de novo heart transplant recipients. The effect of de novo everolimus therapy and early total elimination of calcineurin inhibitor therapy has, however, not been investigated and is relevant given the morbidity and lack of efficacy of current protocols in preventing CAV. This 12-month multicenter Scandinavian trial randomized 115 de novo heart transplant recipients to everolimus with complete calcineurin inhibitor elimination 7-11 weeks after HTx or standard cyclosporine immunosuppression. Ninety-five (83%) patients had matched intravascular ultrasound examinations at baseline and 12 months. Mean (± SD) recipient age was 49.9 ± 13.1 years. The everolimus group (n = 47) demonstrated significantly reduced CAV progression as compared to the calcineurin inhibitor group (n = 48) (ΔMaximal Intimal Thickness 0.03 ± 0.06 and 0.08 ± 0.12 mm, ΔPercent Atheroma Volume 1.3 ± 2.3 and 4.2 ± 5.0%, ΔTotal Atheroma Volume 1.1 ± 19.2 mm(3) and 13.8 ± 28.0 mm(3) [all p-values ≤ 0.01]). Everolimus patients also had a significantly greater decline in levels of soluble tumor necrosis factor receptor-1 as compared to the calcineurin inhibitor group (p = 0.02). These preliminary results suggest that an everolimus-based CNI-free can potentially be considered in suitable de novo HTx recipients.

BACKGROUND Proinflammatory cytokines may contribute to clinical complications in heart transplant (HTx) recipients. Previous studies have shown immunomodulating effects of omega-3 fatty acids, but the results are somewhat conflicting. In this study, we examined plasma levels of tumor necrosis factor alpha (TNF-alpha), interleukin (IL) 10, and their relations to antioxidant vitamins in 45 HTx recipients before and after treatment with omega-3 fatty acids or placebo. METHODS The patients were long-time survivors of heart transplantation, randomized in a double-blind fashion to receive omega-3 fatty acids (3.4 g/day) or placebo for 1 year. Plasma levels of cytokines were measured by enzyme immunoassays and vitamin A, vitamin E, and beta-carotene by high-performance liquid chromatography. RESULTS In the omega-3, but not in the placebo group, there was a rise in the proinflammatory cytokine TNF-alpha (P

An elevated plasma homocysteine concentration is an independent risk factor for cardiovascular diseases. In this study, we tested the hypothesis that hyperhomocysteinemia induces endothelial dysfunction mediated, at least in part, through nitric oxide-dependent mechanisms and that folic acid supplementation improves endothelial function in hyperhomocysteinemic subjects.Endothelial function was evaluated in healthy controls and hyperhomocysteinemic subjects by measuring plasma levels of the nitric oxide-derived end products nitrite and nitrate and by assessing vasodilatory responses in the skin microcirculation and forearm vasculature. In the subjects with hyperhomocysteinemia, these measurements were repeated after 6 weeks and 12 months of folic acid supplementation.Compared with healthy controls, hyperhomocysteinemic subjects had significantly lower median plasma levels of nitric oxide-derived end products (12.1 microM [range 4.4 to 41.8] versus 24.6 microM [13.6 to 53.2]; P0.001), a significantly lower endothelium-dependent vasodilatory response to acetylcholine (P0.01), hyperemic response in the microcirculation (P0.01), and total forearm blood flow during reactive hyperemia (P = 0.01). There was no significant difference in the endothelium-independent response. Folic acid treatment for 12 months increased the plasma level of nitric oxide-derived end products by 121% (95% confidence interval [CI], 72% to 170%), the vasodilatory response to acetylcholine by 124% (95% CI, 36% to 212%), and the ischemia-mediated hyperemic responses in the microcirculation by 60% (95% CI, 25% to 96%) and in the forearm vasculature by 47% (95% CI, 21% to 73%).Homocysteine appears to induce its atherogenic effect, at least in part, by depressing endothelial function, possibly through nitric oxide-dependent mechanisms. This effect can be reversed by folic acid supplementation.

Background Hypertension and cyclosporine-induced nephrotoxicity are common complications in heart transplant recipients. Omega-3 fatty acids may prevent blood pressure rise early, but have not been studied long-term after heart transplantation. Methods and Results Forty-five clinically stable hypertensive heart transplant recipients were studied 1–12 years after transplantation and randomized in a double-blind fashion to receive either 3·4g of omega-3 fatty acids daily or placebo for 1 year. Ambulatory 24h blood pressure monitoring and haemodynamic studies were performed before randomization and at the end of the study. Systolic blood pressure increased by 8±3mmHg ( P

Statins appear to have several biologic effects beyond those of lipid metabolism, and we hypothesized that immunomodulating effects of statins are important for the beneficial effects of these medications after heart transplantation. Our findings suggest that pravastatin treatment reduces plasma markers of inflammation and improves peripheral endothelial function in heart transplant recipients, possibly contributing to the observed clinical benefits of statin treatment in these patients.