OSTEO18, a novel urinary proteomic signature, associated with osteoporosis in heart transplant recipients.

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.

Apical papillary muscle displacement is a prevalent feature and a phenotypic precursor of apical hypertrophic cardiomyopathy.

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.

Tools to differentiate between Filamin C and Titin truncating variant carriers: value of MRI.

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.

The international experience of in-situ recovery of the DCD heart: a multicentre retrospective observational study.

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.

Outcomes in patients with cardiac amyloidosis undergoing heart transplantation: the eurotransplant experience.

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, investigating 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 primary endpoint as a dependent variable. RESULTS: Median overall survival following HTX was 6.3 years in the overall collective and the subgroup. 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 amyloidosis 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 outcomes following HTX. Optimal timing and careful patient selection may therefore be particularly important to further improve post-HTX survival in amyloidosis patients.

Combination prophylaxis in CMV high risk heart transplant recipients: A single center experience.

INTRODUCTION: Cytomegalovirus (CMV) is the most clinically relevant infectious agent following heart transplantation (HTX). Data on the beneficial effects of prophylactic use of CMV immunoglobulins (CMVIG) are scarce. METHODS: In this single-center, retrospective study, we reported patient outcomes following cardiac transplantation using prophylactic CMV treatment, including CMVIG. Distinct clinically relevant outcomes were compared across different CMV risk groups (CMV D-/R-, CMV D-/R+, CMV D+/R+, and CMV D+/R- or CMV high risk group). RESULTS: We included 272 heart transplant procedures, performed between 1/1/2009 and 1/11/2020. Sixty-one (22%) procedures belonged to the CMV high risk group, while 96 (35%), 50 (18%), and 65 (24%) were CMV D-/R-, CMV D-/R+, and CMV D+/R+, respectively. Baseline donor and recipient characteristics (sex, age, body mass index, cause of death, indication for HTX), ischemia times and baseline immunosuppressive regimens were similar across the different CMV risk groups, yet fewer patients were bridged with a mechanical circulatory support in the CMV D+/R- group. CMV disease following cardiac transplantation was more common in the CMV D+/R- risk group (n = 40 or 66.7%; p < .001), yet mortality and re-transplantation rates, cardiac allograft vasculopathy (CAV) severity, rejection episodes, and development of donor-specific antibodies (DSA), post-transplant lymphoproliferative diseases (PTLD), and EBV infections were similar across all four CMV risk groups. CONCLUSION: High risk CMV D+/R- patients had a similar survival compared to low and intermediate CMV risk groups using a prophylactic strategy combining CMVIG and viral DNA polymerase inhibitors. This may be related to a number of factors unrelated to prophylaxis strategy as two out of three CMV D+/R- recipients developed CMV primary infection after prophylaxis was discontinued.

Successful heart transplantation from donation after euthanasia with distant procurement using normothermic regional perfusion and cold storage.

While euthanasia has been legalized in a growing number of countries, organ donation after euthanasia is only performed in Belgium, the Netherlands, Spain, and Canada. Moreover, the clinical practice of heart donation after euthanasia has never been reported before. We describe the first case of a heart donated after euthanasia, reconditioned with thoraco-abdominal normothermic regional perfusion, preserved using cold storage while being transported to a neighboring transplant center, and then successfully transplanted following a procurement warm ischemic time of 17 min. Heart donation after euthanasia using thoraco-abdominal normothermic regional perfusion is feasible, it could expand the heart donor pool and reduce waiting lists in countries where organ donation after euthanasia can be performed.

The role of transesophageal echocardiography in guiding heart donation after circulatory death.

Heart donation after circulatory death (DCD) can significantly expand the heart donor pool, helping to overcome the problem of organ shortage and the increase in waiting list mortality and morbidity. To improve the outcome of DCD heart transplantation, thoraco-abdominal normothermic regional perfusion (TA-NRP) can be performed by selectively restoring circulation followed by in vivo functional heart assessment. Here, we report on the use of periprocedural transoesophageal echocardiography (TOE) as a minimally invasive cardiac assessment tool during different stages of a DCD heart procurement procedure using TA-NRP. We conclude that TOE is a valuable method to assess the donor heart for transplantation eligibility before and after withdrawal of life-sustaining therapy and during subsequent TA-NRP.

Impaired biventricular contractile reserve in patients with diastolic dysfunction: insights from exercise stress echocardiography.

AIMS: Cardiac output limitation is a fundamental feature of heart failure with preserved ejection fraction (HFpEF) but the relative contribution of its determinants in symptomatic vs. asymptomatic stages are not well characterized. We aimed to gain insight into disease mechanisms by performing comprehensive comparative non-invasive exercise imaging in patients across the disease spectrum. METHODS AND RESULTS: We performed bicycle stress echocardiography in 10 healthy controls, 13 patients with hypertensive left ventricular (LV) concentric remodelling and asymptomatic diastolic dysfunction (HTDD), 15 HFpEF patients, and 15 subjects with isolated right ventricular (RV) dysfunction secondary to chronic thromboembolic pulmonary hypertension (CTEPH). During exercise, ventricular performance differed across the groups (all P ≤ 0.01 for interaction). Notably in controls, LV and RV function significantly increased (all P < 0.05) while both LV systolic and diastolic reserve were significantly reduced in HFpEF patients. Likewise, RV systolic reserve was also impaired in HFpEF but not to the extent of CTEPH patients (P < 0.001 between groups). HTDD patients behaved as an intermediary group with borderline LV systolic and diastolic reserve and reduced RV systolic reserve. The increased pulmonary vascular (PV) load in HFpEF and CTEPH patients in combination with impaired RV reserve resulted in RV-pulmonary artery uncoupling during exercise. CONCLUSION: The multifaceted decline of cardiac and PV function accompanying disease progression in HFpEF is unmasked by exercise and already emerges in preclinical disease. The revelation of these subtle abnormalities during exercise illustrates the benefit of exercise imaging and creates new prospects for early diagnosis and management.

The novel proteomic signature for cardiac allograft vasculopathy.

AIMS: Cardiac allograft vasculopathy (CAV) is the major long-term complication after heart transplantation, leading to mortality and re-transplantation. As available non-invasive biomarkers are scarce for CAV screening, we aimed to identify a proteomic signature for CAV. METHODS AND RESULTS: We measured urinary proteome by capillary electrophoresis coupled with mass spectrometry in 217 heart transplantation recipients (mean age: 55.0 ± 14.4 years; women: 23.5%), including 76 (35.0%) patients with CAV diagnosed by coronary angiography. We randomly and evenly grouped participants into the derivation cohort (n = 108, mean age: 56.4 ± 13.8 years; women: 22.2%; CAV: n = 38) and the validation cohort (n = 109, mean age: 56.4 ± 13.8 years; women: 24.8%, CAV: n = 38), stratified by CAV. Using the decision tree-based machine learning methods (extreme gradient boost), we constructed a proteomic signature for CAV discrimination in the derivation cohort and verified its performance in the validation cohort. The proteomic signature that consisted of 27 peptides yielded areas under the curve of 0.83 [95% confidence interval (CI): 0.75-0.91, P < 0.001] and 0.71 (95% CI: 0.60-0.81, P = 0.001) for CAV discrimination in the derivation and validation cohort, respectively. With the optimized threshold of 0.484, the sensitivity, specificity, and accuracy for CAV differentiation in the validation cohort were 68.4%, 73.2%, and 71.6%, respectively. With adjustment of potential clinical confounders, the signature was significantly associated with CAV [adjusted odds ratio: 1.31 (95% CI: 1.07-1.64) for per 0.1% increment in the predicted probability, P = 0.012]. Diagnostic accuracy significantly improved by adding the signature to the logistic model that already included multiple clinical risk factors, suggested by the integrated discrimination improvement of 9.1% (95% CI: 2.5-15.3, P = 0.005) and net reclassification improvement of 83.3% (95% CI: 46.7-119.5, P < 0.001). Of the 27 peptides, the majority were the fragments of collagen I (44.4%), collagen III (18.5%), collagen II (3.7%), collagen XI (3.7%), mucin-1 (3.7%), xylosyltransferase 1 (3.7%), and protocadherin-12 (3.7%). Pathway analysis performed in Reactome Pathway Database revealed that the multiple pathways involved by the signature were related to the pathogenesis of CAV, such as collagen turnover, platelet aggregation and coagulation, cell adhesion, and motility. CONCLUSIONS: This pilot study identified and validated a urinary proteomic signature that provided a potential approach for the surveillance of CAV. These proteins might provide insights into CAV pathological processes and call for further investigation into personalized treatment targets.

Characteristics and Outcome of Post-Transplant Lymphoproliferative Disorders After Solid Organ Transplantation: A Single Center Experience of 196 Patients Over 30 Years.

Post-transplant lymphoproliferative disorder (PTLD) is a rare but life-threatening complication after transplantation. In this retrospective, monocentric study we aimed to collect real life data regarding PTLD and determine the role of Epstein Barr Virus (EBV) status and year of diagnosis on prognosis. We identified 196 biopsy-proven PTLD after solid organ transplantation (SOT) diagnosed at the University Hospitals Leuven (Belgium) from 1989 to 2019. EBV status was positive in 61% of PTLD. The median overall survival (OS) was 5.7 years (95% CI: 2.99-11.1). Although EBV positivity was not significantly correlated with OS in multivariate analyses (HR: 1.44 (95% CI: 0.93-2.24); p = 0.10), subgroup analysis showed a significantly better median OS for EBV negative post-transplant diffuse large B-cell lymphoma (DLBCL) compared to EBV positive post-transplant DLBCL (8.8 versus 2.5 years respectively; p = 0.0365). There was a significant relation between year of PTLD diagnosis and OS: the more recent the PTLD diagnosis, the lower the risk for death (adjusted HR: 0.962 (95% CI: 0.931-0.933); p = 0.017). In conclusion, the prognosis of PTLD after SOT has improved in the past decades. Our analysis shows a significant relation between EBV status and OS in post-transplant DLBCL.

Is degree of chronic illness management in heart transplant centers associated with better patient survival? Findings from the intercontinental BRIGHT study.

PURPOSE: To explore the association between the degree of Chronic illness management and survival rates at 1-, 3-, 5-years post heart transplantation. METHODS: Exploratory secondary analysis of a cross-sectional, international study (Building Research Initiative Group study). Latent profile analysis was performed to classify 36 heart transplant centers according to the degree of chronic illness management. RESULTS: The analysis resulted in 2 classes with 29 centers classified as "low-degree chronic illness management" and 7 centers as "high-degree chronic illness management". After 1-year posttransplantation, the high-degree chronic illness management class had a significantly greater mean survival rate compared to the low-degree chronic illness management class (88.4% vs 84.2%, p = 0.045) and the difference had a medium effect size (η2 = .06). No difference in survival for the other time points was observed. Patients in high-degree chronic illness management centers had 52% lower odds of moderate to severe drinking (95% confidence interval .30-.78, p = 0.003). No significant associations between degree of chronic illness management and the other recommended health behaviors were observed. CONCLUSIONS: The findings from this exploratory study offer preliminary insight into a system-level pathway (chronic illness management) for improving outcomes for heart transplant recipients. The signals observed in our data support further investigation into the effectiveness of chronic illness management-based interventions in heart transplant follow-up care.

Liver or Kidney Transplantation After SARS-CoV-2 Infection: Prevalence, Short-term Outcome, and Kinetics of Serum IgG Antibodies.

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.

Speckle-tracking-based global longitudinal and circumferential strain detect early signs of antibody-mediated rejection in heart transplant patients.

AIMS: Acute rejection is an important cause of mortality after heart transplant (HTx), but symptoms develop only when myocardial damage is already extensive. We sought to investigate if echocardiographic parameters can detect and predict an acute cellular rejection (ACR) or antibody-mediated rejection (AMR) episode in HTx patients. METHODS AND RESULTS: Data of 403 consecutive HTx recipients between 2003 and 2020 from our centre were reviewed. Patients with severe ACR (n = 10) and AMR (n = 7) were identified. Each HTx patient presenting with rejection was matched to a control HTx patient. Echocardiographic variables from the moment of rejection and 3, 6, and 12 months before were analysed and compared among groups. At acute rejection episode, patients with rejection had lower values of global longitudinal strain (GLS), global circumferential strain (GCS), and left ventricular ejection fraction (LVEF) compared to controls. HTx patients with AMR showed a progressive decline of GLS and GCS in the months preceding acute rejection, while controls and ACR patients had stable strain values except for the moment of rejection. In our cohort, a GLS cut-off lower than 15.5% and a GCS cut-off lower than 15.2% could distinguish with a sensitivity and specificity of 100.0% AMR from controls 3 months before rejection. LVEF and other conventional echo parameters could not differentiate among groups. CONCLUSION: GLS and GCS show a progressive decrease months before AMR becomes clinically apparent. Our data suggest that global strain assessment by echocardiography allows an early detection of a developing AMR, which could improve the clinical management of HTx patients.

Exercise capacity, muscle strength and objectively measured physical activity in patients after heart transplantation.

Maximal exercise capacity of patients after heart transplantation (HTX) remains limited, affecting their quality of life. Evidence on the evolution of muscle strength and physical activity (PA) post-HTX is lacking, but a prerequisite to tailor cardiac rehabilitation programmes. Forty-five consecutive patients were evaluated every 3 months during the first year post-HTX. Functional exercise capacity (Six minutes walking distance test (6MWD)), peripheral (Quadriceps strength (QF)) and respiratory (Maximal inspiratory strength (MIP)) muscle strength were evaluated. PA (number of steps (PAsteps), active time (PAactive) and sedentary time (PAsed)) was objectively measured. 6MWD, QF, MIP, PAsteps and PAactive significantly improved over time (P < 0.001). No change in PAsed was noticed (P = 0.129). Despite improvements in 6MWD and QF, results remained substantially below those of age-and gender-matched healthy subjects. One year post-HTX, 30% of patients presented with peripheral muscle weakness. Baseline levels of 6MWD and QF were significantly higher in patients with pretransplant LVAD-implantation and this difference was maintained during follow-up. cardiac rehabilitation, combining aerobic exercise training and peripheral muscle strength training, is mandatory in patients post-HTX. Inspiratory muscle training should be implemented when respiratory muscle weakness is present. Programmes improving physical activity and reducing sedentary time post-HTX are essential.

Study design and rationale of the pAtients pResenTing with cOngenital heaRt dIseAse Register (ARTORIA-R).

AIM: Due to improved therapy in childhood, many patients with congenital heart disease reach adulthood and are termed adults with congenital heart disease (ACHD). ACHD often develop heart failure (HF) as a consequence of initial palliative surgery or complex anatomy and subsequently require advanced HF therapy. ACHD are usually excluded from trials evaluating heart failure therapies, and in this context, more data about heart failure trajectories in ACHD are needed to guide the management of ACHD suffering from HF. METHODS AND RESULTS: The pAtients pResenTing with cOngenital heaRt dIseAse Register (ARTORIA-R) will collect data from ACHD evaluated or listed for heart or heart-combined organ transplantation from 16 countries in Europe and the Asia/Pacific region. We plan retrospective collection of data from 1989-2020 and will include patients prospectively. Additional organizations and hospitals in charge of transplantation of ACHD will be asked in the future to contribute data to the register. The primary outcome is the combined endpoint of delisting due to clinical worsening or death on the waiting list. The secondary outcome is delisting due to clinical improvement while on the waiting list. All-cause mortality following transplantation will also be assessed. The data will be entered into an electronic database with access to the investigators participating in the register. All variables of the register reflect key components important for listing of the patients or assessing current HF treatment. CONCLUSION: The ARTORIA-R will provide robust information on current management and outcomes of adults with congenital heart disease suffering from advanced heart failure.

Right ventricular and cyclic guanosine monophosphate signalling abnormalities in stages B and C of heart failure with preserved ejection fraction.

AIMS: Identifying early right ventricular (RV) dysfunction and impaired vasodilator reserve is challenging in heart failure with preserved ejection fraction (HFpEF). We hypothesized that cardiac magnetic resonance (CMR)-based exercise imaging and serial cyclic guanosine monophosphate (cGMP) measurements can identify dynamic RV-arterial uncoupling and responsiveness to pulmonary vasodilators at early stages of the HFpEF syndrome. METHODS AND RESULTS: Patients with HFpEF (n = 16), impaired left ventricular relaxation due to concentric remodelling (LVCR, n = 7), and healthy controls (n = 8) underwent CMR at rest and during supine bicycle exercise with simultaneous measurements of central haemodynamics and circulating cGMP levels, before and after oral administration of 50 mg sildenafil. At rest, mean pulmonary artery pressures (mPAP) were higher in HFpEF, compared with LVCR and controls (27 ± 2, 18 ± 1, and 11 ± 1, respectively; P = 0.01), whereas biventricular volumes, heart rate, and stroke volume were similar. During exercise, LVCR and HFpEF had a greater increase in the ratio of mPAP over cardiac output than controls (5.50 ± 0.77 and 6.34 ± 0.86 vs. 2.24 ± 0.55 in controls, P = 0.005). The ratio of peak exercise to rest RV end-systolic pressure-volume, a surrogate of RV contractility, was significantly reduced in LVCR and HFpEF (2.32 ± 0.17 and 1.56 ± 0.08 vs. 3.49 ± 0.35 in controls, P < 0.001) and correlated with peak exercise VO2 (R2  = 0.648, P < 0.001). cGMP levels increased with exercise across the HFpEF spectrum (P < 0.05 vs. baseline), except when postcapillary pulmonary hypertension was present at rest (P = 0.73 vs. baseline). A single sildenafil administration failed to increase circulating cGMP levels and did not improve RV performance. CONCLUSION: Exercise CMR identifies impaired RV-arterial coupling at an early stage of HFpEF. Circulating cGMP levels phenocopy the haemodynamic spectrum in HFpEF but fail to increase after phosphodiesterase type 5 inhibition, endorsing the need for alternative interventions to increase cGMP signalling in HFpEF.

Heart failure related to adult congenital heart disease: prevalence, outcome and risk factors.

AIMS: Information on the prevalence, outcome and factors associated with heart failure in patients with adult congenital heart disease (CHD) (ACHD-HF) is lacking. We aimed at assessing the prevalence and outcome of ACHD-HF, the variables associated with ACHD-HF, and the differences between major anatomical/pathophysiological ACHD subgroups. METHODS AND RESULTS: We included 3905 patients (age 35.4 ± 13.2 years) under active follow-up in our institution (last visit >2010). Outcome of ACHD-HF cases was compared with sex- and age-matched cases. Univariable and multivariable binary logistic regression with ACHD-HF diagnosis as a dependent variable was performed. Overall prevalence of ACHD-HF was 6.4% (mean age 49.5 ± 16.7 years), but was higher in patients with cyanotic CHD (41%), Fontan circulation (30%), and a systemic right ventricle (25%). All-cause mortality was higher in ACHD-HF cases when compared with controls (mortality rate ratio 4.67 (2.36-9.27); P = 0.0001). In multivariable logistic regression analysis, age at latest follow-up [per 10 years; odds ratio (OR) 1.52; 95% confidence interval (CI) 1.31-1.77], infective endocarditis (OR 4.11; 95%CI 1.80-9.38), history of atrial arrhythmia (OR 3.52; 95%CI 2.17-5.74), pacemaker implantation (OR 2.66; 95% CI 1.50-4.72), end-organ dysfunction (OR 2.41; 95% CI 1.03-5.63), New York Heart Association class (OR 9.28; 95% CI 6.04-14.25), heart rate (per 10 bpm; OR 1.27; 95% CI 1.08-1.50), ventricular dysfunction (OR 3.62; 95% CI 2.54-5.17), and pulmonary hypertension severity (OR 1.66; 95% CI 1.21-2.30) were independently related to the presence of ACHD-HF. Some variables (age, atrial arrhythmia, pacemaker, New York Heart Association, and ventricular dysfunction) were related to ACHD-HF in all anatomical/physiological subgroups, whereas others were not. CONCLUSIONS: ACHD-HF is prevalent especially in complex CHD and is associated with poor prognosis. Our data provide insight in the factors related to ACHD-HF including differences between specific anatomical and physiological subgroups.

Depressive symptoms at 1 year after surgery increase the risk of cardiac allograft vasculopathy and mortality in heart transplant recipients: A prospective cohort study.

OBJECTIVE: To investigate the impact of depressive symptoms at 1-year post-heart transplant (HTx) on cardiac allograft vasculopathy (CAV) and mortality. METHODS: We performed a single-center prospective cohort study of patients 1-year post-HTx consecutively enrolled between January 2001 and September 2015, and followed-up until November 2020. Kaplan-Meier and uni- and multivariate cox proportional hazards models were used to investigate the impact of depressive symptoms (Beck Depression Inventory) on all-cause mortality and clustered CAV events, i.e. time to angiographically detected CAV, revascularizations, retransplantation/CAV-mortality. RESULTS: 23.7% (45/190) (median age 53.5 [IQR 19.3], 77% men) had mild to severe depressive symptoms (BDI 10-63). Forty-four patients (23.2%) died during a 10.4 years median follow-up. Depressive symptoms (BDI ≥ 10) increased all-cause mortality risk (HR = 2.52 [1.35-4.71], p = .004), even after adjusting for confounders (HR = 2.95 [1.50-5.80], p = .002). CAV data were available for 156 patients. During a 9.9 years median follow-up, 51 patients (32.7%) developed CAV or revascularization of which 8 received at least a second revascularization, 3 were re-transplanted, and 9 died from CAV-related causes. Analysis showed a significant increased CAV-risk among depressed patients (HR = 2.27 [1.10-4.69], p = .026), even in adjusted models (HR = 2.25 [1.01-4.98, p = .047). CONCLUSION: Depressive symptoms at 1-year post-HTx unfavorably impact mortality and CAV, highlighting the need for interventions.