We sought to investigate the inter- and intra-country variation in paediatric heart transplantation (HTx) and mechanical circulatory support (MCS) availability and practice in Europe. Data was obtained through a survey circulated to paediatric transplant cardiologists identified through the Association of European Paediatric and Congenital Cardiology between November 2022 and March 2023. Twenty-eight respondents from twenty-eight European countries completed the survey. Twenty-four (86

BACKGROUND:Direct oral anticoagulants (DOACs) are metabolized by CYP3A4 and/or transported by P-glycoprotein. Cyclosporine and tacrolimus can inhibit these pathways, potentially increasing DOAC exposure and bleeding risk. However, data on the relevance of these interactions in transplant recipients are limited. OBJECTIVES:We aimed to study DOAC doses, plasma level monitoring, and interactions with calcineurin inhibitors in transplant recipients. METHODS:We retrospectively (2013-2024) included all adults treated at the University Hospitals Leuven, Belgium, who received both a DOAC and tacrolimus or cyclosporine and had at least 1 DOAC plasma level measurement. DOAC concentrations were compared with on-therapy ranges from phase 3 trials. Levels exceeding the 95th percentile of peak ranges (for peak and intermediate samples) or trough ranges (for trough samples) were classified as above range. RESULTS:Among 495 patients with coprescription, 216 patients had 360 DOAC measurements. The median age was 66 years (IQR, 59-72). Lung (31%) and kidney (29%) transplants were the most common. DOAC dosing was consistent with product labeling in 73% of measurements. Samples were obtained at peak (12%), trough (58%), or intermediate intervals (30%). Overall, 11% of measurements were above range: 4% for edoxaban, 18% for apixaban, and 20% for rivaroxaban. Above-range levels were associated with concomitant strong CYP3A4 or P-glycoprotein inhibitors, lower body weight, lower estimated glomerular filtration rate, cyclosporine use, and DOAC type. CONCLUSION:In transplant recipients selected for DOAC plasma level monitoring, above-range DOAC concentrations were observed in a minority of patients but were more frequent among those with strong CYP3A4 or P-glycoprotein inhibitors, lower body weight, impaired kidney function, or cyclosporine use.

BACKGROUND:Increased myocardial stiffness can lead to diastolic dysfunction, resulting eventually in increased left ventricular filling pressures (LVFPs). The clinical assessment of left ventricular (LV) diastolic function is challenging. Shear wave elastography is a novel method based on tracking shear waves, such as those induced by mitral valve closure (MVC), using high frame rate (HFR) echocardiography. The propagation velocity of shear waves is directly related to myocardial stiffness. OBJECTIVES:This study investigated whether shear wave velocity at MVC is related to invasively measured LVFP. METHODS:Eighty-five patients were prospectively enrolled. Left ventricular mid-diastolic pressure (LVMDP) and left ventricular end-diastolic pressure (LVEDP) were invasively measured. HFR (average frame rate: 1,050 ± 220 Hz) and conventional echocardiography were performed immediately after catheterization. Shear wave velocity at MVC was measured in the anteroseptal wall. The findings were compared with conventional echocardiographic parameters and the multiparametric 2021 guideline-recommended algorithm for the estimation of LVFP. The direct response of shear wave velocity at MVC on changing LV filling pressures was tested in a group of 16 patients with acutely decompensated heart failure (DHF) on admission and after diuretic therapy. RESULTS:Single conventional echocardiographic parameters correlated moderately with LVFP (Pearson r between 0.39 and 0.58) and had a moderate ability to detect elevated LVFP (AUC between 0.66 and 0.79). This was similar for the multiparametric guideline algorithm (LVMDP AUC: 0.78; LVEDP AUC: 0.60). In comparison, shear wave velocities at MVC as a single measure correlated strongly with LVEDP (r = 0.71; P < 0.001) and had an similar ability to predict elevated LVMDP (AUC: 0.79; sensitivity: 87%; specificity: 65%) and an excellent ability to predict elevated LVEDP (AUC: 0.95; sensitivity: 92%; specificity: 94%) when a cutoff value of 4.8 m/s was used. In DHF patients, we observed a significant decrease in shear wave velocity after diuretic therapy (7.1 ± 1.7 m/s vs 5.3 ± 1.3 m/s; P < 0.002). CONCLUSIONS:In comparison with the multivariable guideline approach, end-diastolic shear wave velocity as a single measure had similar accuracy in detecting elevated LVMDP and a higher accuracy for LVEDP. Shear wave elastography might therefore be a promising new tool for the noninvasive assessment of diastolic function.

Background:Transthyretin (ATTR) amyloidosis is more prevalent than initially thought. As much as 13% of patients hospitalized with heart failure with preserved ejection fraction may have ATTR-cardiomyopathy (CM). Conversely, heart transplant patients may manifest left ventricular hypertrophy or diastolic dysfunction, especially late after transplantation. Case summary:We present a case of a 82-year-old male heart transplant patient, 31 years following orthotopic heart transplantation. While he was satisfied with his exercise capacity as an octogenarian, several years before, he required pacemaker implantation due to third-degree atrioventricular block, had bilateral carpal tunnel syndrome treated with carpal tunnel release surgery, and experienced idiopathic sudden deafness. Based on increasing left ventricular wall thickness during routine follow-up, a diagnosis of ATTR amyloidosis was suspected. Ultimately, the diagnosis was confirmed non-invasively with a specific scintigraphic exam, while an additional physicochemical stain on an endomyocardial biopsy taken several years before provided pathological proof. We initiated tafamidis, yet stopped this treatment after 1 month because of gastrointestinal intolerance. Ultimately, our patient died 2 years later due to heart failure. Discussion:Our case shows the long delay between the onset of ATTR deposition, the presence of clinical signs, and the final diagnosis. Echocardiographic findings suggestive for ATTR-CM include left ventricular hypertrophy and diastolic dysfunction, which are both common in heart transplant patients. Yet, ATTR-CM should be considered in the differential diagnosis, especially late after transplantation, in this closely monitored population.

Tacrolimus is an immunosuppressant commonly administered after solid organ transplantation. It is characterized by a narrow therapeutic window and high variability in exposure, demanding personalized dosing. In recent years, population pharmacokinetic models have been suggested to guide model-informed precision dosing of tacrolimus. We aimed to provide a comprehensive overview of population pharmacokinetic models and model-informed precision dosing software modules of tacrolimus in all solid organ transplant settings, including a simulation-based investigation of the impact of covariates on exposure and target attainment. We performed a systematic literature search to identify population pharmacokinetic models of tacrolimus in solid organ transplant recipients. We integrated selected population pharmacokinetic models into an interactive software tool that allows dosing simulations, Bayesian forecasting, and investigation of the impact of covariates on exposure and target attainment. We conducted a web survey amongst model-informed precision dosing software tool providers and benchmarked publicly available tools in terms of models, target populations, and clinical integration. We identified 80 population pharmacokinetic models, including 44 one-compartment and 36 two-compartment models. The most frequently retained covariates on clearance and distribution parameters were cytochrome P450 3A5 polymorphisms and body weight, respectively. Our simulation tool, hosted at https://lpmx.shinyapps.io/tacrolimus/ , allows thorough investigation of the impact of covariates on exposure and target attainment. We identified 15 model-informed precision dosing software tool providers, of which ten offer a tacrolimus solution and nine completed the survey. Our work provides a comprehensive overview of the landscape of available tacrolimus population pharmacokinetic models and model-informed precision dosing software modules. Our simulation tool allows an interactive thorough exploration of covariates on exposure and target attainment.

The role of immunosuppressive therapy on SARS-CoV-2 infection risk and COVID-19 severity remains unclear in unvaccinated solid organ transplant recipients. We included 1957 organ transplant recipients between July 2020 and April 2021 to analyze whether baseline immunosuppressive therapy and other risk factors are associated with SARS-CoV-2 infection and severe COVID-19. In total, 247 (12.6%) had SARS-CoV-2 (defined as positive nasopharyngeal swab and/or positive antibody titer). Of these, 57 (23.1%) had severe COVID-19, defined as oxygen supplementation, intensive care unit admission or death. Multivariable analysis identified diabetes (hazard ratio (HR) 1.39 (95% confidence interval (CI) 1.05-1.83)), chronic lung disease (HR 1.71 (95% CI 1.13-2.60)) and contact with a COVID-19 positive individual (HR 3.61 (95% CI 2.61-4.99) as independent risk factors for SARS-CoV-2 infection. There was no association between immunosuppressive therapy and infection risk. Severe COVID-19 was multivariably associated with hypertension (OR 5.45 (95% CI 1.66-17.84)), chronic kidney disease (OR 3.55 (95% CI 1.75-7.19)), corticosteroid use (OR 2.93 (95% CI 1.03-2.55)) and having a COVID-19 positive housemate (OR 6.77 (95% CI 2.65-17.28)). In conclusion, baseline corticosteroid use, but no other immunosuppressive agent, is independently associated with severe COVID-19 in unvaccinated SOT recipients after correction for hypertension, chronic kidney disease, housemates affected by COVID-19 and transplant type.

Background:Immunosuppressive treatment in heart transplant (HTx) recipient causes osteoporosis. The urinary proteomic profile (UPP) includes peptide fragments derived from the bone extracellular matrix. Study aims were to develop and validate a multidimensional UPP biomarker for osteoporosis in HTx patients from single sequenced urinary peptides identifying the parent proteins. Methods:A single-center HTx cohort was analyzed. Urine samples were measured by capillary electrophoresis coupled with mass spectrometry. Cases with osteoporosis and matching controls were randomly selected from all available 389 patients. In derivation case-control dataset, 1576 sequenced peptides detectable in ≥30 % of patients. Applying statistical analysis on these, an 18-peptide multidimensional osteoporosis UPP biomarker (OSTEO18) was generated by support vector modeling. The 2 replication datasets included 118 and 94 patients. For further validation, the whole cohort was analyzed. Statistical methods included logistic regression and receiver operating characteristic curve (ROC) analysis. Results:In derivation dataset, the AUC, sensitivity and specificity of OSTEO18 were 0.83 (95 % CI: 0.76-0.90), 74.3 % and 87.1 %, respectively. In replication datasets, results were confirmatory. In the whole cohort (154 osteoporotic patients [39.6 %]), the ORs for osteoporosis increased (p < 0.0001) across OSTEO18 quartiles from 0.39 (95 % CI: 0.25-0.61) to 3.14 (2.08-4.75). With full adjustment for known osteoporosis risk factors, OSTEO18 improved AUC from 0.708 to 0.786 (p = 0.0003) for OSTEO18 categorized (optimized threshold: 0.095) and to 0.784 (p = 0.0004) for OSTEO18 as continuously distributed classifier. Conclusion:OSTEO18 is a clinically meaningful novel biomarker indicative of osteoporosis in HTx recipients and is being certified as in-vitro diagnostic.

Transplantation of hearts donated after circulatory death (DCD) is emerging. Currently applied techniques (thoraco-abdominal normothermic regional perfusion and direct procurement followed by normothermic machine perfusion) face financial, ethical, and logistical challenges. We report the first three clinical cases of successful direct procurement followed by hypothermic oxygenated perfusion (DP-HOPE) with good 30-day outcome. DP-HOPE is a promising strategy to improve and simplify DCD heart procurement and preservation.

Summary Background Heart transplantation is an effective treatment offering the best recovery in both quality and quantity of life in those affected by refractory, severe heart failure. However, transplantation is limited by donor organ availability. The reintroduction of heart donation after the circulatory determination of death (DCD) in 2014 offered an uplift in transplant activity by 30%. Thoraco-abdominal normothermic regional perfusion (taNRP) enables in-situ reperfusion of the DCD heart. The objective of this paper is to assess the clinical outcomes of DCD donor hearts recovered and transplanted from donors undergoing taNRP. Method This was a multicentre retrospective observational study. Outcomes included functional warm ischaemic time, use of mechanical support immediately following transplantation, perioperative and long-term actuarial survival and incidence of acute rejection requiring treatment. 157 taNRP DCD heart transplants, performed between February 2, 2015, and July 29, 2022, have been included from 15 major transplant centres worldwide including the UK, Spain, the USA and Belgium. 673 donations after the neurological determination of death (DBD) heart transplantations from the same centres were used as a comparison group for survival. Findings taNRP resulted in a 23% increase in heart transplantation activity. Survival was similar in the taNRP group when compared to DBD. 30-day survival was 96.8% ([92.5%–98.6%] 95% CI, n = 156), 1-year survival was 93.2% ([87.7%–96.3%] 95% CI, n = 72) and 5-year survival was 84.3% ([69.6%–92.2%] 95% CI, n = 13). Interpretation Our study suggests that taNRP provides a significant boost to heart transplantation activity. The survival rates of taNRP are comparable to those obtained for DBD transplantation in this study. The similar survival may in part be related to a short warm ischaemic time or through a possible selection bias of younger donors, this being an uncontrolled observational study. Therefore, our study suggests that taNRP offers an effective method of organ preservation and procurement. This early success of the technique warrants further investigation and use. Funding None of the authors have a financial relationship with a commercial entity that has an interest in the subject.

Whereas truncating variants of the giant protein Titin (TTNtv) are the main cause of familial dilated cardiomyopathy (DCM), recently Filamin C truncating variants (FLNCtv) were identified as a cause of arrhythmogenic cardiomyopathy (ACM). Our aim was to characterize and compare clinical and MRI features of TTNtv and FLNCtv in the Belgian population. In index patients referred for genetic testing of ACM/DCM, FLNCtv and TTNtv were found in 17 (3.6%) and 33 (12.3%) subjects, respectively. Further family cascade screening yielded 24 and 19 additional truncating variant carriers in FLNC and TTN, respectively. The main phenotype was ACM in FLNCtv carriers whereas TTNtv carriers showed either an ACM or DCM phenotype. Non-sustained Ventricular Tachycardia was frequent in both populations. MRI data, available in 28/40 FLNCtv and 32/52 TTNtv patients, showed lower Left Ventricular (LV) ejection fraction and lower LV strain in TTNtv patients (p < 0.01). Conversely, both the frequency (68% vs 22%) and extent of non-ischemic myocardial late gadolinium enhancement (LGE) was significantly higher in FLNCtv patients (p < 0.01). Hereby, ring-like LGE was found in 16/19 (84%) FLNCtv versus 1/7 (14%) of TTNtv patients (p < 0.01). In conclusion, a large number of FLNCtv and TTNtv patients present with an ACM phenotype but can be separated by cardiac MRI. Whereas FLNCtv patients often have extensive myocardial fibrosis, typically following a ring-like pattern, LV dysfunction without or limited replacement fibrosis is the common TTNtv phenotype.

BACKGROUND: When advanced heart failure occurs in cardiac amyloidosis, prognosis is poor. In this setting heart transplantation (HTX) is a treatment option for selected patients. We here present the results of post-transplantation outcomes in cardiac amyloidosis within the Eurotransplant area, investi-gating possible predictors of survival.METHODS: Of 115 patients undergoing HTX due to cardiac amyloidosis in the Eurotransplant region between November 1987 and May 2020, detailed assessment prior to transplantation was available in 85 patients. The present study was conducted in a retrospective approach. Primary endpoint was mortality after HTX. Baseline variables were entered in a Cox proportional hazards model with the pri-mary endpoint as a dependent variable.RESULTS: Median overall survival following HTX was 6.3 years in the overall collective and the sub-group. Univariate Cox proportional hazards model revealed a significant relationship between overall survival and the transplantation period (2008 to 2020 vs 1987 to 2007; median survival 9.7 years vs 1.8 years, hazard ratio 0.45, p = 0.01). Further predictors were albumin concentration (hazard ratio 0.92, p < 0.001), and systolic blood pressure (hazard ratio 0.96, p < 0.001). The transplant period as well as albumin concentration remained significant independent predictors in the AL sub cohort in a multivariate Cox proportional hazards model.CONCLUSIONS: HTX is a viable treatment option for patients at an advanced stage of cardiac amyloid-osis as overall survival after transplantation has improved in the modern age. Patients at a very advanced stage of the disease, indicated by low serum albumin and blood pressure, show worse out-comes following HTX. Optimal timing and careful patient selection may therefore be particularly important to further improve post-HTX survival in amyloidosis patients.J Heart Lung Transplant 2023;42:778-785 (c) 2023 International Society for Heart and Lung Transplantation. All rights reserved.

AIMS:Papillary muscle (PM) abnormalities are considered part of the phenotypic spectrum of hypertrophic cardiomyopathy (HCM). The aim of this study was to evaluate the presence and frequency of PM displacement in different HCM phenotypes.METHODS AND RESULTS:We retrospectively analysed cardiovascular magnetic resonance (CMR) findings in 156 patients (25% females, median age 57 years). Patients were divided into three groups: septal hypertrophy (Sep-HCM, n = 70, 45%), mixed hypertrophy (Mixed-HCM, n = 48, 31%), and apical hypertrophy (Ap-HCM, n = 38, 24%). Fifty-five healthy subjects were enrolled as controls. Apical PM displacement was observed in 13% of controls and 55% of patients, which was most common in the Ap-HCM group, followed by the Mixed-HCM and Sep-HCM groups (respectively: inferomedial PM 92 vs. 65 vs. 13%, P < 0.001; anterolateral PM 61 vs. 40 vs. 9%, P < 0.001). Significant differences in PM displacement were found when comparing healthy controls with patients with Ap- and Mixed-HCM subtypes but not when comparing them with patients with the Sep-HCM subtype. T-wave inversion in the inferior and lateral leads was more frequent in patients with Ap-HCM (100 and 65%, respectively) when compared with Mixed-HCM (89 and 29%, respectively) and Sep-HCM (57 and 17%, respectively; P < 0.001 for both). Eight patients with Ap-HCM had prior CMR examinations because of T-wave inversion [median interval 7 (3-8) years], and in the first CMR study, none showed apical hypertrophy [median apical wall thickness 8 (7-9) mm], while all of them presented with apical PM displacement.CONCLUSION:Apical PM displacement is part of the phenotypic Ap-HCM spectrum and may precede the development of hypertrophy. These observations suggest a potential pathogenetic, mechanical link between apical PM displacement and Ap-HCM.

Rates and modulators of SARS-CoV-2 vaccine nonresponse and breakthrough infections remain unclear in serially vaccinated transplant recipients. In a prospective, mono-centric, observational study, 1878 adult solid organ and hematopoietic cell transplant recipients, with prior SARS-CoV-2 vaccination, were included between March 2021 and February 2022. SARS-CoV-2 anti-spike IgG antibodies were measured at inclusion and details on SARS-CoV-2 vaccine doses and infection were collected. No life-threatening adverse events were reported after a total of 4039 vaccine doses. In transplant recipients without prior SARS-CoV-2 infection (n = 1636), antibody response rates ranged widely, from 47% in lung transplant to 90% in liver transplant and 91% in hematopoietic cell transplant recipients after third vaccine dose. Antibody positivity rate and levels increased after each vaccine dose in all types of transplant recipients. In multivariable analysis, older age, chronic kidney disease and daily dose of mycophenolate and corticosteroids were negatively associated with antibody response rate. Overall rate of breakthrough infections was 25.2% and mainly (90.2%) occurred after third and fourth vaccine dose. Lung transplant recipients had the highest rates of severe breakthrough infection (10.5%) and death (2.5%). In multivariable analysis, older age, daily dose of mycophenolate and corticosteroids were associated with severe breakthrough infection. Transplant recipients with infection before first vaccine dose (n = 160) had higher antibody response rates and levels after each vaccine dose, and a significantly lower overall rate of breakthrough infections compared to those without prior infection. Antibody response after SARS-CoV-2 vaccination and rate of severe breakthrough infections vary largely between different transplant types and are modulated by specific risk factors. The observed heterogeneity supports a tailored approach against COVID-19 in transplant recipients.

Background. There is a paucity of data on the prevalence, adequate timing, and outcome of solid organ transplantation after severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection and the kinetics of immunoglobulin G (IgG) antibodies in these patients. Methods. SARS-CoV-2 antinucleocapsid (N) IgG and polymerase chain reaction via a nasopharyngeal swab were analyzed in all patients within 24 h before liver or kidney transplantation. Kinetics of IgG antibodies were analyzed and compared with an immunocompetent cohort. Results. Between May 1, 2020, and March 18, 2021, 168 patients underwent liver or kidney transplantation in our center, of which 11 (6.54%) patients with a previous SARS-CoV-2 infection were identified. The median interval between SARS-CoV-2 infection and transplantation was 4.5 mo (range, 0.9–11). After a median posttransplant follow-up of 4.9 mo, 10 out of 11 patients were alive without clinical signs of viral shedding or recurrent or active infection. One patient without symptom resolution at time of transplantation died after combined liver-kidney transplantation. In 9 out of 11 patients with previously polymerase chain reaction-confirmed infection, SARS-CoV-2 anti-N and antispike (S) IgG were detectable at day of transplantation. Absolute levels of anti-N and anti-S IgG were positively correlated, declined over time in all patients, and were significantly lower compared with immunocompetent individuals. All patients remained anti-S IgG positive until the last posttransplant follow-up, whereas 3 patients became anti-N negative. Conclusions. We observed an uncomplicated course of liver or kidney transplantation after SARS-CoV-2 infection in selected patients. Although having lower absolute IgG antibody levels than immunocompetent individuals, all seroconverted patients remained anti-S IgG positive. These encouraging data need validation in larger studies.

Dear Editor, Although anal squamous cancer (ASC) remains a relatively rare disease, the rate is increasing by about 2% per year. In the metaanalysis by Clifford et al the incidence rate (IR) for ASC in solid organ transplant recipients (SOTR) was 13 per 100.000 person-years and increasing up to 49.6 in patients that were transplanted more than 10 years ago. The analysis was based on large population studies starting in the 70s and 80s of the previous century. As both the frequency of solid organ transplantation and graft survival have significantly increased since, the incidence of ASC after solid organ transplantation is likely to be rising in the upcoming decades. Recently, we noticed a cluster of patients with ASC after heart transplantation, and performed a retrospective observational study of solid organ transplant recipients diagnosed with anal squamous carcinoma. The database of patients with anal malignancies at our tertiary hospital with extensive transplantation activity (8430 solid organ were transplanted until the end of 2021) was searched for ASC. Between 1 January 2010 and 31 December, 2019 a total of 79 patients was identified with new diagnosis of ASC. Eight of them were solid organ transplant recipients and five had received a heart transplantation (Table 1). The incidence rate of ASC after heart transplantation was calculated to be 136 per 100.000 person-years, much higher than the previously published IR for SOTR and even higher than the IR in HIV-positive men who have sex with men (MSM). The fact that the incidence rate of ASC in SOTR seemed to increase over time after transplantation is strengthened by our observation that the diagnosis of ASC occurred on average 13.4 ± 5.2 years after heart transplantation. The mean age at the time of diagnosis was 60.7 ± 5.9 years, similar to the age of nontransplant patients with ACS (62.5 ± 11.8 years). The exact reason for this extremely high incidence rate remains unclear. Maybe the high median patient survival (currently more than 18 years in our center) and the concomitant long-lasting exposure to immunosuppressive medication, partially explains the high incidence rate of ASC after heart transplantation. The number of patients is unfortunately too small to examine the effect of underlying cardiac disease, type and levels of immunosuppressive therapy. Therefore, we would like to encourage other transplantation centers and/or