Balloon pulmonary angioplasty for chronic thromboembolic pulmonary hypertension: a clinical consensus statement of the ESC working group on pulmonary circulation and right ventricular function.

The current treatment algorithm for chronic thromboembolic pulmonary hypertension (CTEPH) as depicted in the 2022 European Society of Cardiology (ESC)/European Respiratory Society (ERS) guidelines on the diagnosis and treatment of pulmonary hypertension (PH) includes a multimodal approach of combinations of pulmonary endarterectomy (PEA), balloon pulmonary angioplasty (BPA) and medical therapies to target major vessel pulmonary vascular lesions, and microvasculopathy. Today, BPA of >1700 patients has been reported in the literature from centers in Asia, the US, and also Europe; many more patients have been treated outside literature reports. As BPA becomes part of routine care of patients with CTEPH, benchmarks for safe and effective care delivery become increasingly important. In light of this development, the ESC Working Group on Pulmonary Circulation and Right Ventricular Function has decided to publish a document that helps standardize BPA to meet the need of uniformity in patient selection, procedural planning, technical approach, materials and devices, treatment goals, complications including their management, and patient follow-up, thus complementing the guidelines. Delphi methodology was utilized for statements that were not evidence based. First, an anatomical nomenclature and a description of vascular lesions are provided. Second, treatment goals and definitions of complete BPA are outlined. Third, definitions of complications are presented which may be the basis for a standardized reporting in studies involving BPA. The document is intended to serve as a companion to the official ESC/ERS guidelines.

Aggressive Afterload Lowering to Improve the Right Ventricle: A New Target for Medical Therapy in Pulmonary Arterial 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.

Iron homeostasis in heart transplant recipients randomized to ferric derisomaltose or placebo.

INTRODUCTION: The randomized IronIC trial evaluated the effect of intravenous ferric derisomaltose on physical capacity in iron-deficient, maintenance heart transplant (HTx) recipients. Iron deficiency was defined as in heart failure with high cut-points for ferritin to compensate for inflammation. However, intravenous iron did not improve physical capacity except in patients with ferritin <30 µg/L. We aimed to explore determinants of iron status in the 102 IronIC participants to better define iron deficiency in the HTx population. METHODS: We assessed key governors of iron homeostasis, such as hepcidin, soluble transferrin receptor (sTfR), and interleukin-6 (IL-6). We also measured growth factors and inflammatory markers with relevance for iron metabolism. The results were compared to those of 21 healthy controls. RESULTS: Hepcidin did not differ between HTx recipients and controls, even though markers of inflammation were modestly elevated. However, HTx recipients with ferritin <30 µg/L or sTfR above the reference range had significantly reduced hepcidin levels suggestive of true iron deficiency. In these patients, intravenous iron improved peak oxygen uptake. Hepcidin correlated positively with ferritin and negatively with sTfR. CONCLUSION: HTx recipients with iron deficiency as defined in heart failure do not have elevated hepcidin levels, although inflammatory markers are modestly increased. The high ferritin cut-offs used in heart failure may not be suitable to define iron deficiency in the HTx population. We suggest that hepcidin and sTfR should be measured to identify patients with true iron deficiency, who might benefit from treatment with intravenous iron.

Thrombus formation in the noncoronary sinus of Valsalva following primary graft dysfunction.

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.

Prevalence of iron deficiency in heart transplant recipients.

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 <100 µg/L, or ferritin 100-300 µg/L combined with transferrin saturation of <20% (IDHF ); ferritin <100 µg/L (IDF100 ); transferrin saturation of <20% (IDTsat ), and ferritin <30 µg/L (IDF30 ). 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.

Circulating regulators of the wingless pathway in precapillary pulmonary hypertension.

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.

Long-term effects of high-intensity training vs moderate intensity training in heart transplant recipients: A 3-year follow-up study of the randomized-controlled HITTS study.

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.

Cholesterol lowering with EVOLocumab to prevent cardiac allograft Vasculopathy in De-novo heart transplant recipients: Design of the randomized controlled EVOLVD trial.

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-month 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.

High-intensity interval training and health-related quality of life in de novo heart transplant recipients - results from a randomized controlled trial.

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.

Circulating delta-like Notch ligand 1 is correlated with cardiac allograft vasculopathy and suppressed in heart transplant recipients on everolimus-based immunosuppression.

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. Trial registration numbers-SCHEDULE trial: ClinicalTrials.gov NCT01266148; NOCTET trial: ClinicalTrials.gov NCT00377962.

The Predictive Value of Depression in the Years After Heart Transplantation for Mortality During Long-Term Follow-Up.

OBJECTIVE: Current understanding of the prognostic impact of depression on mortality after heart transplantation (HTx) is limited. We examined whether depression after HTx is a predictor of mortality during extended follow-up. Subsequently, we explored whether different symptom dimensions of depression could be identified and whether they were differentially associated with mortality. METHODS: Survival analyses were performed in a sample of 141 HTx recipients assessed for depression, measured by self-report of depressive symptoms (Beck Depression Inventory - version 1A [BDI-1A]), at median 5.0 years after HTx, and followed thereafter for survival status for up to 18.6 years. We used uni- and multivariate Cox proportional hazard models to examine the association of clinically significant depression (BDI-1A total score ≥10), as well as the cognitive-affective and the somatic subscales of the BDI-1A (resulting from principal component analysis) with mortality. In the multivariate analyses, we adjusted for relevant sociodemographic and clinical variables. RESULTS: Clinically significant depression was a significant predictor of mortality (hazard ratio = 2.088; 95% confidence interval = 1.366-3.192; p = .001). Clinically significant depression also was an independent predictor of mortality in the multivariate analysis (hazard ratio = 1.982; 95% confidence interval = 1.220-3.217; p = .006). The somatic subscale, but not the cognitive-affective subscale, was significantly associated with increased mortality in univariate analyses, whereas neither of the two subscales was an independent predictor of mortality in the multivariate analysis. CONCLUSIONS: Depression measured by self-report after HTx is associated with increased mortality during extended follow-up. Clinical utility and predictive validity of specific depression components require further study.

Frequencies of borderline pulmonary hypertension before and after the DETECT algorithm: results from a prospective systemic sclerosis cohort.

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.

Effect of everolimus vs calcineurin inhibitors on quality of life in heart transplant recipients during a 3-year follow-up: Results of a randomized controlled trial (SCHEDULE).

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<.01; CsA: 32.5±8.2, 48.4±8.5, and 46.5±11.5; P<.01; mental component summary: EVR: 46.0±12.0, 51.7±11.9, and 52.1±13.0; P<.01; CsA: 38.2±12.5, 53.4±7.1, and 54.3±13.0; P<.01); similar decrease in mean BDI (EVR: 10.9±10.2, 5.4±4.7, and 8.1±9.0; P<.01; CsA: 11.8±7.1, 6.3±5.4, and 6.2±6.5; P<.01); and similar Euro Qol-improvements. Thus, in this small-sized study, EVR-based and conventional CsA immunosuppressive strategies produced similar QoL improvements.

Cognitive function among long-term survivors of heart transplantation.

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.

Cognitive function after heart transplantation: Comparing everolimus-based and calcineurin inhibitor-based regimens.

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.

Everolimus immunosuppression for renal protection, reduction of allograft vasculopathy and prevention of allograft rejection in de-novo heart transplant recipients: could we have it all?

PURPOSE OF REVIEW: 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. RECENT FINDINGS: 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. SUMMARY: 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.

Invasive haemodynamics at rest and exercise in cardiac amyloidosis.

AIMS: Our aim was to investigate haemodynamics at rest and during exercise in patients with transthyretin cardiomyopathy (ATTR-CM) in light of the 2022 European Society of Cardiology (ESC) and European Respiratory Society (ERS) guidelines on pulmonary hypertension (PH). METHODS AND RESULTS: We performed right heart catheterization (RHC) in 57 subjects with ATTR-CM. The proportion of patients with PH was 77% according to the 2022 guidelines versus 47% when applying the 2015 guidelines. Isolated post-capillary PH and combined pre- and post-capillary PH were most prevalent. Thirty-six patients underwent a supine bicycle cardiopulmonary exercise test during RHC. Exercise-induced PH was defined as an increase in mean pulmonary arterial pressure from rest to exercise per increase in cardiac output (ΔmPAP/ΔCO) of > 3 mmHg/L/min. An increase in pulmonary arterial wedge pressure per change in cardiac output (ΔPAWP/ΔCO) from rest to exercise >2 mmHg/L/min was considered suggestive of post-capillary exercise-induced PH. All but two patients who exercised during RHC developed exercise-induced PH. The median ΔmPAP/ΔCO was 7.2 mmHg/L/min and ΔPAWP/ΔCO was 5.1 mmHg/L/min. The median ΔRAP/ΔCO was 3.6 mmHg/L/min and ΔRAP/ΔPAWP was 0.6 mmHg/L/min. CONCLUSIONS: Most patients with ATTR-CM have isolated post-capillary or combined pre- and post-capillary PH at rest, and almost all patients develop exercise-induced PH with a large post-capillary component. There was a pronounced, but balanced increase in atrial pressures on exercise.

The association between body mass index, exercise capacity, and health-related quality of life in heart transplant recipients.

Introduction: Pre-transplant obesity and weight gain after heart transplantation are both associated with increased risk of poor clinical outcomes. We aimed to assess the association between overweight or obesity, exercise capacity, and health-related quality of life in heart transplant recipients. Methods: This study is based on baseline data from the IronIC trial, in which we randomized 102 heart transplant recipients with iron deficiency to ferric derisomaltose or placebo. We performed cardio pulmonary exercise testing in all participants. To assess quality of life, we used the SF-36v2 questionnaire, using two sum scores: the physical component summary and the mental component summary. A minimal clinically important difference was defined as ≥2 and ≥3 for the physical and the mental component summary, respectively. Results: 24/102 heart transplant recipients (24%) had a body mass index (BMI) ≥30 kg/m2. Peak oxygen consumption was 17.3 ± 4.6 ml/kg/min in the obese group vs. 24.7 ± 6.4 ml/kg/min in the group with a BMI <30 for a between-group difference of 7.4 (95% confidence interval 4.7-10.2) ml/kg/min: p < 0.001. The physical component summary score was on average 5.2 points lower in the patients with a body mass index ≥30 than in the lower weight group (p = 0.04). Conclusion: Almost a quarter of our heart transplant recipients in long-term follow-up had a BMI ≥30 kg/m2. These patients had substantially lower exercise capacity and lower quality of life in the physical domain.

Diagnostics, treatment and outcomes of cardiac sarcoidosis in a Norwegian cohort.

BACKGROUND: Evidence-based guidelines for cardiac sarcoidosis (CS) regarding use of second- and third-line agents, treatment duration, surveillance and prognostic factors are lacking. OBJECTIVE: To analyze the clinical presentation, diagnostics, treatment, monitoring and clinical outcomes in a Norwegian cohort. METHODS: Using discharge diagnoses between 2017 through 2020 from a large tertiary center, we identified 52 patients with CS. We performed a systematic chart review following a pre-specified checklist. The primary outcome of major cardiovascular events (MACE) was defined as a composite of cardiovascular hospitalization, defibrillator therapy, cardiac transplantation, or death. RESULTS: 18-fluorodeoxyglucose positron emission tomography (FDG-PET) showed pathological tracer uptake in 35/36 (97%) of immunosuppression-naïve patients. Immunosuppressive treatment was administered to 49/52 patients (94%) for a median of 43 (IQR 34) months; 69% were treated with second-line (methotrexate, azathioprine, mycophenolate mofetil) and 25% with third-line (rituximab, infliximab) agents, respectively. Rituximab reduced inflammation as assessed by interval FDG-PET imaging and was overall well tolerated. Median duration to first MACE was 6 (IQR 10) months and 17/23 patients (74%) experienced a MACE within 12 months from CS diagnosis. No mortality was recorded and 20% achieved full remission. Age below the median of 53 years at time of diagnosis was associated with an increased risk of a MACE. CONCLUSION: Long-term immunosuppression including a liberal use of non-steroidal agents, appeared essential in treating CS. Although the burden of cardiovascular events was substantial, the survival was excellent in this contemporary cohort. Prospective randomized studies are urgently needed to define the best therapy for these patients.

Long-term follow-up of the randomized, prospective Scandinavian heart transplant everolimus de novo study with early calcineurin inhibitors avoidance (SCHEDULE) trial.

BACKGROUND: Early substitution of calcineurin inhibitor (CNI) with mammalian target of rapamycin inhibitors has been shown to improve kidney function and reduce intimal hyperplasia in heart transplant (HTx) recipients but data on long-term outcome of such a regime are still sparse. METHODS: In the SCHEDULE trial, 115 de novo HTx recipients were randomized to (1) everolimus with reduced exposure of CNI followed by CNI withdrawal at week 7-11 post-transplant or (2) standard-exposure with CNI. Both groups received mycophenolate mofetil and corticosteroids. Herein we report on the 10-12-year long-term follow-up of the study. RESULTS: A total of 78 patients attended the follow-up visit at a median time of 11 years post-transplant. In the everolimus intention to treat (ITT) group 87.5% (35/40 patients) still received everolimus and in the CNI ITT group 86.8% (33/38) still received CNI. Estimated glomerular filtration rate (eGFR) (least square mean (95% CI)) at the 10-12 years visit was 82.7 (74.2-91.1) ml/min/1.73 m2 and 61.0 (52.3-69.7) ml/min/1.73 m2 in the everolimus and CNI group, respectively (p < 0.001). Graft function measured by ejection fraction, ECG, NT-proBNP and drug safety were comparable between groups. During the study period there was a total of 28 deaths, but there was no difference in survival between the everolimus and the CNI group (aHR 0.61 (95% CI 0.29-1.30) p = 0.20). For the composite endpoint of death, re-transplantation, myocardial infarction, PCI, dialysis, kidney transplantation or cancer no between group differences were found (aHR 1.0 (95% CI 0.57-1.77) p = 0.99). CONCLUSIONS: De novo HTx patients randomized to everolimus and low dose CNI followed by CNI free therapy sustained significantly better long-term kidney function than patients randomized to standard therapy. The graft function at 10-12 years was similar in both groups and there was no difference in survival.