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Aims Arrhythmogenic right ventricular cardiomyopathy (ARVC) patients have an increased risk of ventricular arrhythmias (VA). Four implantable cardioverter-defibrillator (ICD) recommendation algorithms are available The International Task Force Consensus (‘ITFC’), an ITFC modification by Orgeron et al. (‘mITFC’), the AHA/HRS/ACC guideline for VA management (‘AHA’), and the HRS expert consensus statement (‘HRS’). This study aims to validate and compare the performance of these algorithms in ARVC. Methods and results We classified 617 definite ARVC patients (38.5 ± 15.1 years, 52.4% male, 39.2% prior sustained VA) according to four algorithms. Clinical performance was evaluated by sensitivity, specificity, ROC-analysis, and decision curve analysis for any sustained VA and for fast VA (>250 b.p.m.). During 6.4 [2.8–11.5] years follow-up, 282 (45.7%) patients experienced any sustained VA, and 63 (10.2%) fast VA. For any sustained VA, ITFC and mITFC provide higher sensitivity than AHA and HRS (94.0–97.8% vs. 76.7–83.5%), but lower specificity (15.9–32.0% vs. 42.7%-60.1%). Similarly, for fast VA, ITFC and mITFC provide higher sensitivity than AHA and HRS (95.2–97.1% vs. 76.7–78.4%) but lower specificity (42.7–43.1 vs. 76.7–78.4%). Decision curve analysis showed ITFC and mITFC to be superior for a 5-year sustained VA risk ICD indication threshold between 5–25% or 2–9% for fast VA. Conclusion The ITFC and mITFC provide the highest protection rates, whereas AHA and HRS decrease unnecessary ICD placements. ITFC or mITFC should be used if we consider the 5-year threshold for ICD indication to lie within 5–25% for sustained VA or 2–9% for fast VA. These data will inform decision-making for ICD placement in ARVC.

Placental severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with a specific histiocytic intervillositis. Placental fibrin depositions can decrease the maternal-fetal interface causing fetal distress. Coronavirus disease 2019-related placental inflammation can lead to SARS-CoV-2-associated pediatric inflammatory multisystem syndrome., Background In general, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during pregnancy is not considered to be an increased risk for severe maternal outcomes but has been associated with an increased risk for fetal distress. Maternal-fetal transmission of SARS-CoV-2 was initially deemed uncertain; however, recently a few cases of vertical transmission have been reported. The intrauterine mechanisms, besides direct vertical transmission, leading to the perinatal adverse outcomes are not well understood. Methods Multiple maternal, placental, and neonatal swabs were collected for the detection of SARS-CoV-2 using real-time quantitative polymerase chain reaction (RT-qPCR). Serology of immunoglobulins against SARS-CoV-2 was tested in maternal, umbilical cord, and neonatal blood. Placental examination included immunohistochemical investigation against SARS-CoV-2 antigen expression, with SARS-CoV-2 ribonucleic acid (RNA) in situ hybridization and transmission electron microscopy. Results RT-qPCRs of the oropharynx, maternal blood, vagina, placenta, and urine were all positive over a period of 6 days, while breast milk, feces, and all neonatal samples tested negative. Placental findings showed the presence of SARS-CoV-2 particles with generalized inflammation characterized by histiocytic intervillositis with diffuse perivillous fibrin depositions with damage to the syncytiotrophoblasts. Conclusions Placental infection by SARS-CoV-2 leads to fibrin depositions hampering fetal-maternal gas exchange with resulting fetal distress necessitating a premature emergency cesarean section. Postpartum, the neonate showed a fetal or pediatric inflammatory multisystem-like syndrome with coronary artery ectasia temporarily associated with SARS-CoV-2 for which admittance and care on the neonatal intensive care unit (NICU) were required, despite being negative for SARS-CoV-2. This highlights the need for awareness of adverse fetal and neonatal outcomes during the current coronavirus disease 2019 pandemic, especially considering that the majority of pregnant women appear asymptomatic.

Aims Arrhythmogenic right ventricular cardiomyopathy (ARVC) is diagnosed by a complex set of clinical tests as per 2010 Task Force Criteria (TFC). Avoiding misdiagnosis is crucial to prevent sudden cardiac death as well as unnecessary implantable cardioverter-defibrillator implantations. This study aims to validate the overall performance of the TFC in a real-world cohort of patients referred for ARVC evaluation. Methods and results We included patients consecutively referred to our centres for ARVC evaluation. Patients were diagnosed by consensus of three independent clinical experts. Using this as a reference standard, diagnostic performance was measured for each individual criterion as well as the overall TFC classification. Of 407 evaluated patients (age 38 ± 17 years, 51% male), the expert panel diagnosed 66 (16%) with ARVC. The clinically observed TFC was false negative in 7/66 (11%) patients and false positive in 10/69 (14%) patients. Idiopathic outflow tract ventricular tachycardia was the most common alternative diagnosis. While the TFC performed well overall (sensitivity and specificity 92%), signal-averaged electrocardiogram (SAECG, P = 0.43), and several family history criteria (P ≥ 0.17) failed to discriminate. Eliminating these criteria reduced false positives without increasing false negatives (net reclassification improvement 4.3%, P = 0.019). Furthermore, all ARVC patients met at least one electrocardiogram (ECG) or arrhythmia criterion (sensitivity 100%). Conclusion The TFC perform well but are complex and can lead to misdiagnosis. Simplification by eliminating SAECG and several family history criteria improves diagnostic accuracy. Arrhythmogenic right ventricular cardiomyopathy can be ruled out using ECG and arrhythmia criteria alone, hence these tests may serve as a first-line screening strategy among at-risk individuals.

Background Different disease stages of arrhythmogenic right ventricular cardiomyopathy (ARVC) can be identified by right ventricle (RV) longitudinal deformation (strain) patterns. This requires assessment of the onset of shortening, (systolic) peak strain, and postsystolic index, which is time‐consuming and prone to inter‐ and intra‐observer variability. The aim of this study was to design and validate an algorithm to automatically classify RV deformation patterns. Methods We developed an algorithm based on specific local characteristics from the strain curves to detect the parameters required for classification. Determination of the onset of shortening by the algorithm was compared to manual determination by an experienced operator in a dataset containing 186 RV strain curves from 26 subjects carrying a pathogenic plakophilin‐2 (PKP2) mutation and 36 healthy subjects. Classification agreement between operator and algorithm was solely based on differences in onset shortening, as the remaining parameters required for classification of RV deformation patterns could be directly obtained from the strain curves. Results The median difference between the onset of shortening determined by the experienced operator and by the automatic detector was 5.3 ms [inter‐quartile range (IQR) 2.7–8.6 ms]. 96% of the differences were within 1 time frame. Both methods correlated significantly with ρ = 0.97 (P

Aims Patients with non‐ischaemic dilated cardiomyopathy (DCM) are at increased risk of sudden cardiac death. Identification of patients that may benefit from implantable cardioverter‐defibrillator implantation remains challenging. In this study, we aimed to determine predictors of sustained ventricular arrhythmias in patients with DCM. Methods and results We searched MEDLINE/Embase for studies describing predictors of sustained ventricular arrhythmias in patients with DCM. Quality and bias were assessed using the Quality in Prognostic Studies tool, articles with high risk of bias in ≥2 areas were excluded. Unadjusted hazard ratios (HRs) of uniformly defined predictors were pooled, while all other predictors were evaluated in a systematic review. We included 55 studies (11 451 patients and 3.7 ± 2.3 years follow‐up). Crude annual event rate was 4.5%. Younger age [HR 0.82; 95% CI (0.74–1.00)], hypertension [HR 1.95; 95% CI (1.26–3.00)], prior sustained ventricular arrhythmia [HR 4.15; 95% CI (1.32–13.02)], left ventricular ejection fraction on ultrasound [HR 1.45; 95% CI (1.19–1.78)], left ventricular dilatation (HR 1.10), and presence of late gadolinium enhancement [HR 5.55; 95% CI (4.02–7.67)] were associated with arrhythmic outcome in pooled analyses. Prior non‐sustained ventricular arrhythmia and several genotypes [mutations in Phospholamban (PLN), Lamin A/C (LMNA), and Filamin‐C (FLNC)] were associated with arrhythmic outcome in non‐pooled analyses. Quality of evidence was moderate, and heterogeneity among studies was moderate to high. Conclusions In patients with DCM, the annual event rate of sustained ventricular arrhythmias is approximately 4.5%. This risk is considerably higher in younger patients with hypertension, prior (non‐)sustained ventricular arrhythmia, decreased left ventricular ejection fraction, left ventricular dilatation, late gadolinium enhancement, and genetic mutations (PLN, LMNA, and FLNC). These results may help determine appropriate candidates for implantable cardioverter‐defibrillator implantation.

Background: Patients treated for non-Hodgkin lymphoma are at risk of cardiovascular adverse events, with the risk of heart failure being particularly high. A regimen of cyclophosphamide, doxorubicin, vincristine, and prednisone, with (R-CHOP) or without (CHOP) rituximab is the standard first-line treatment for aggressive non-Hodgkin lymphoma, and doxorubicin and cyclophosphamide are both associated with left ventricular dysfunction. The aim of this systematic review and meta-analysis was to evaluate the cardiovascular toxicity of this regimen. Methods: We systematically searched PubMed, EMBASE, and the Cochrane Library from database inception to June 3, 2019, for clinical trials and observational studies in adult patients with non-Hodgkin lymphoma (diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, peripheral T-cell lymphoma, and non-Hodgkin lymphoma not otherwise specified) that received first-line treatment with R-CHOP or CHOP. Studies reporting on cardiovascular adverse events and treatment-related cardiovascular mortality were included. Abstracts and articles not written in English were excluded. The main outcomes were the proportion of patients with grade 3–4 cardiovascular adverse events and heart failure. Meta-analyses of one-sample proportions were done in all patients receiving CHOP or R-CHOP. Subgroup analyses on summary estimates were done to determine the effect of number of CHOP or R-CHOP cycles, cycle interval, age, and sex. Findings: Of 2314 identified entries, 137 studies (21 211 patients) published between April, 1984, and June, 2019 were eligible (9541 patients treated with CHOP, 11 293 patients treated with R-CHOP, 377 both regimens used in the study; median follow-up 39·0 months [IQR 25·5–52·8]). From the included studies, 85 subgroups were treated with CHOP, 76 with R-CHOP, and in four studies both CHOP and R-CHOP were used without a subdivision in separate groups. The pooled proportion for grade 3–4 cardiovascular adverse events, based on 77 studies (n=14 351 patients), was 2·35% (95% CI 1·81–2·93; heterogeneity test Q=326·21; τ 2=0·0042; I 2=71·40%; p

Aims In arrhythmogenic cardiomyopathy (ACM), sustained ventricular tachycardia (VT) typically displays a left bundle branch block (LBBB) morphology while a right bundle branch block (RBBB) morphology is rare. The present study assesses the VT morphology in ACM patients with sustained VT and their clinical and genetic characteristics. Methods and results Twenty-six centres from 11 European countries provided information on 954 ACM patients who had ≥1 episode of sustained VT spontaneously documented during patients’ clinical course. Arrhythmogenic cardiomyopathy was defined according to the 2010 Task Force Criteria, and VT morphology according to the QRS pattern in V1. Overall, 882 (92.5%) patients displayed LBBB-VT alone and 72 (7.5%) RBBB-VT [alone in 42 (4.4%) or in combination with LBBB-VT in 30 (3.1%)]. Male sex prevalence was 79.3%, 88.1%, and 56.7% in the LBBB-VT, RBBB-VT, and LBBB + RBBB-VT groups, respectively (P = 0.007). First RBBB-VT occurred 5 years after the first LBBB-VT (46.5 ± 14.4 vs 41.1 ± 15.8 years, P = 0.011). An implanted cardioverter-defibrillator was more frequently implanted in the RBBB-VT (92.9%) and the LBBB + RBBB-VT groups (90%) than in the LBBB-VT group (68.1%) (P Conclusion RBBB-VT accounts for a significant proportion of sustained VTs in ACM. Sex and type of pathogenic mutations were associated with VT type, female sex with LBBB + RBBB-VT, and DSP mutation with RBBB-VT.

BackgroundTruncating variants in desmoplakin (DSPtv) are an important cause of arrhythmogenic cardiomyopathy (ACM), however the genetic architecture and genotype-specific risk factors are incompletely understood. We evaluated phenotype, risk factors for ventricular arrhythmias, and underlying genetics ofDSPtv cardiomyopathy.MethodsIndividuals withDSPtv and any cardiac phenotype, and their gene-positive family members were included from multiple international centers. Clinical data and family history information were collected. Event-free survival from ventricular arrhythmia was assessed. Variant location was compared between cases and controls, and literature review of reportedDSPtv performed.ResultsThere were 98 probands and 72 family members (mean age at diagnosis 43 ± 18 years, 59% female) with aDSPtv, of which 146 were considered clinically affected. Ventricular arrhythmia (sudden cardiac arrest, sustained ventricular tachycardia, appropriate implantable cardioverter defibrillator therapy) occurred in 56 (33%) individuals.DSPtv location and proband status were independent risk factors for ventricular arrhythmia, while prior risk factors showed no association. Further, gene region was important with variants in cases (cohort n=98, Clinvar n=168) more likely to occur in the regions resulting in nonsense mediated decay of both majorDSPisoforms, compared to n=124 gnomAD control variants (148 [83.6%] versus 29 [16.4%], pConclusionsIn the largest series of individuals withDSPtv, we demonstrate variant location is a novel risk factor for ventricular arrhythmia, can inform variant interpretation, and provide critical insights to allow precision-based clinical management.

AIMS: Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC) is characterized by ventricular arrhythmias (VAs) and sudden cardiac death (SCD). We aimed to develop a model for individualized prediction of incident VA/SCD in ARVC patients. METHODS AND RESULTS: Five hundred and twenty-eight patients with a definite diagnosis and no history of sustained VAs/SCD at baseline, aged 38.2 ± 15.5 years, 44.7% male, were enrolled from five registries in North America and Europe. Over 4.83 (interquartile range 2.44-9.33) years of follow-up, 146 (27.7%) experienced sustained VA, defined as SCD, aborted SCD, sustained ventricular tachycardia, or appropriate implantable cardioverter-defibrillator (ICD) therapy. A prediction model estimating annual VA risk was developed using Cox regression with internal validation. Eight potential predictors were pre-specified: age, sex, cardiac syncope in the prior 6 months, non-sustained ventricular tachycardia, number of premature ventricular complexes in 24 h, number of leads with T-wave inversion, and right and left ventricular ejection fractions (LVEFs). All except LVEF were retained in the final model. The model accurately distinguished patients with and without events, with an optimism-corrected C-index of 0.77 [95% confidence interval (CI) 0.73-0.81] and minimal over-optimism [calibration slope of 0.93 (95% CI 0.92-0.95)]. By decision curve analysis, the clinical benefit of the model was superior to a current consensus-based ICD placement algorithm with a 20.6% reduction of ICD placements with the same proportion of protected patients (P

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy characterised by fibrofatty replacement of predominantly the right ventricle and high risk of ventricular arrhythmias and sudden cardiac death (SCD). Early diagnosis and accurate risk assessment are challenging yet essential for SCD prevention. This manuscript summarises the current state of the art on ARVC diagnosis and risk stratification. Improving the 2010 diagnostic criteria is an ongoing discussion. Several studies suggest that early diagnosis may be facilitated by including deformation imaging (‘strain’) for objective assessment of wall motion abnormalities, which was shown to have high sensitivity for preclinical disease. Adding fibrofatty replacement detected by late gadolinium enhancement or T1 mapping in cardiac MRI as criterion for diagnosis is increasingly suggested but requires more supporting evidence from consecutive patient cohorts. In addition to the traditional right-dominant ARVC, standard criteria for arrhythmogenic cardiomyopathy (ACM) and arrhythmogenic left ventricular cardiomyopathy (ALVC) are on the horizon. After diagnosis confirmation, the primary management goal is SCD prevention, for which an implantable cardioverter-defibrillator is the only proven therapy. Prior studies determined that younger age, male sex, previous (non-) sustained ventricular tachycardia, syncope, extent of T-wave inversion, frequent premature ectopic beats and lower biventricular ejection fraction are risk factors for subsequent events. Previous implantable cardioverter-defibrillator indication guidelines were however limited to three expert-opinion flow charts stratifying patients in risk groups. Now, two multivariable risk prediction models (arvcrisk.com) combine the abovementioned risk factors to estimate individual risks. Of note, both the flow charts and prediction models require clinical validation studies to determine which should be recommended.

In relatives of index patients with dilated cardiomyopathy and arrhythmogenic cardiomyopathy, early detection of disease onset is essential to prevent sudden cardiac death and facilitate early treatment of heart failure. However, the optimal screening interval and combination of diagnostic techniques are unknown. The clinical course of disease in index patients and their relatives is variable due to incomplete and age-dependent penetrance. Several biomarkers, electrocardiographic and imaging (echocardiographic deformation imaging and cardiac magnetic resonance imaging) techniques are promising non-invasive methods for detection of subclinical cardiomyopathy. However, these techniques need optimisation and integration into clinical practice. Furthermore, determining the optimal interval and intensity of cascade screening may require a personalised approach. To address this, the CVON-eDETECT (early detection of disease in cardiomyopathy mutation carriers) consortium aims to integrate electronic health record data from long-term follow-up, diagnostic data sets, tissue and plasma samples in a multidisciplinary biobank environment to provide personalised risk stratification for heart failure and sudden cardiac death. Adequate risk stratification may lead to personalised screening, treatment and optimal timing of implantable cardioverter defibrillator implantation. In this article, we describe non-invasive diagnostic techniques used for detection of subclinical disease in relatives of index patients with dilated cardiomyopathy and arrhythmogenic cardiomyopathy.

Supplemental Digital Content is available in the text., Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is associated with ventricular arrhythmias (VA) and sudden cardiac death (SCD). A model was recently developed to predict incident sustained VA in patients with ARVC. However, since this outcome may overestimate the risk for SCD, we aimed to specifically predict life-threatening VA (LTVA) as a closer surrogate for SCD. Methods: We assembled a retrospective cohort of definite ARVC cases from 15 centers in North America and Europe. Association of 8 prespecified clinical predictors with LTVA (SCD, aborted SCD, sustained, or implantable cardioverter-defibrillator treated ventricular tachycardia >250 beats per minute) in follow-up was assessed by Cox regression with backward selection. Candidate variables included age, sex, prior sustained VA (≥30s, hemodynamically unstable, or implantable cardioverter-defibrillator treated ventricular tachycardia; or aborted SCD), syncope, 24-hour premature ventricular complexes count, the number of anterior and inferior leads with T-wave inversion, left and right ventricular ejection fraction. The resulting model was internally validated using bootstrapping. Results: A total of 864 patients with definite ARVC (40±16 years; 53% male) were included. Over 5.75 years (interquartile range, 2.77–10.58) of follow-up, 93 (10.8%) patients experienced LTVA including 15 with SCD/aborted SCD (1.7%). Of the 8 prespecified clinical predictors, only 4 (younger age, male sex, premature ventricular complex count, and number of leads with T-wave inversion) were associated with LTVA. Notably, prior sustained VA did not predict subsequent LTVA (P=0.850). A model including only these 4 predictors had an optimism-corrected C-index of 0.74 (95% CI, 0.69–0.80) and calibration slope of 0.95 (95% CI, 0.94–0.98) indicating minimal over-optimism. Conclusions: LTVA events in patients with ARVC can be predicted by a novel simple prediction model using only 4 clinical predictors. Prior sustained VA and the extent of functional heart disease are not associated with subsequent LTVA events.

Background Patients who have undergone the Fontan procedure are at high risk of circulatory failure. In an exploratory analysis we aimed to determine the prognostic value of blood biomarkers in a young cohort who have undergone the Fontan procedure. Methods and Results In multicenter prospective studies patients who have undergone the Fontan procedure underwent blood sampling, cardiopulmonary exercise testing, and stress cardiac magnetic resonance imaging. Several biomarkers including NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide), GDF‐15 (growth differentiation factor 15), Gal‐3 (galectin‐3), ST2 (suppression of tumorigenicity 2), DLK‐1 (protein delta homolog 1), FABP‐4 (fatty acid‐binding protein 4), IGFBP‐1 (insulin‐like growth factor‐binding protein 1), IGFBP‐7, MMP‐2 (matrix metalloproteinase 2), and vWF (von Willebrand factor) were assessed in blood at 9.6 (7.1–12.1) years after Fontan completion. After this baseline study measurement, follow‐up information was collected on the incidence of adverse cardiac events, including cardiac death, out of hospital cardiac arrest, heart transplantation (listing), cardiac reintervention (severe events), hospitalization, and cardioversion/ablation for arrhythmias was collected and the relation with blood biomarkers was assessed by Cox proportional hazard analyses. The correlation between biomarkers and other clinical parameters was evaluated. We included 133 patients who have undergone the Fontan procedure, median age 13.2 (25th, 75th percentile 10.4–15.9) years, median age at Fontan 3.2 (2.5–3.9) years. After a median follow‐up of 6.2 (4.9–6.9) years, 36 (27.1%) patients experienced an event of whom 13 (9.8%) had a severe event. NT‐proBNP was associated with (all) events during follow‐up and remained predictive after correction for age, sex, and dominant ventricle (hazard ratio, 1.89; CI, 1.32–2.68). The severe event‐free survival was better in patients with low levels of GDF‐15 ( P =0.005) and vWF ( P =0.008) and high levels of DLK‐1 ( P =0.041). There was a positive correlation (β=0.33, P =0.003) between DLK‐1 and stress cardiac magnetic resonance imaging functional reserve. Conclusions NT‐proBNP, GDF‐15, vWF, DLK‐1, ST‐2 FABP‐4, and IGFBP‐7 levels relate to long‐term outcome in young patients who have undergone the Fontan procedure.

IntroductionIn general SARS-CoV-2-infection during pregnancy is not considered to be an increased risk for severe maternal outcomes, but has been associated with an increased risk for fetal distress. So far, there is no direct evidence of intrauterine vertical transmission and the mechanisms leading to the adverse outcomes are not well understoodResultsAn asymptomatic pregnant woman with preterm fetal distress during the COVID19 pandemic was included. We obtained multiple maternal, placental and neonatal swabs, which showed a median viral load in maternal blood, urine, oropharynx, fornix posterior over a period of 6 days was 5.0 log copies /mL. The maternal side of the placenta had a viral load of 4.42 log copies /mL, while the fetal side had 7.15 log copies /mL. Maternal breast milk, feces and all neonatal samples tested negative. Serology of immunoglobulins against SARS-CoV-2 was tested positive in maternal blood, but negative in umbilical cord and neonatal blood. Pathological examination of the placenta included immunohistochemical investigation against SARS-CoV-2 antigen expression in combination with SARS-CoV-2 RNA in situ hybridization and transmission electron microscopy. It showed the presence of SARS-CoV-2 particles with generalized inflammation characterized by histiocytic intervillositis with diffuse perivillous fibrin depositions with damage to the syncytiotrophoblasts.DiscussionPlacental infection by SARS-CoV-2 lead to fibrin depositions hampering fetal-maternal gas exchange most likely resulted in fetal distress necessitating a premature emergency caesarean section. Postpartum, the neonate showed a clinical presentation resembling a pediatric inflammatory multisystem syndrome including coronary artery ectasia, most likely associated with SARS-CoV-2 (PIMS-TS) for which admittance and care on the Neonatal Intensive Care unit (NICU) was required, despite being negative for SARS-CoV-2. This highlights the need for awareness of adverse fetal and neonatal outcomes during the current COVID-19 pandemic, especially considering that the majority of pregnant women appear asymptomatic.

BackgroundMyocardial deformation by speckle tracking echocardiography provides additional information on left ventricular function. Values of myocardial deformation (strain and strain rate) depend on the type of ultrasound machine and software that is used. Normative values for QLAB (Philips) are scarce, especially for children. It is important to evaluate the influence of age and body size on myocardial deformation parameters, since anthropometrics strongly influence many standard echocardiographic parameters. The aim of this study was to provide comprehensive normal values for myocardial deformation of the left ventricle using a Philips platform and to evaluate the association with anthropometric and standard echocardiographic parameters.MethodsHealthy children between 1 and 18 years of age were prospectively examined using a standard echocardiographic protocol. Short-axis and apical four-chamber, two-chamber, and three-chamber views were used to measure peak systolic circumferential and longitudinal strain and systolic and early diastolic strain rate of the left ventricle using dedicated software.ResultsA total of 103 children were included with a mean age of 10.8 and inter-quartile range 7.3–14.3 years. Global circumferential strain values (±SD) were −24.2±3.5% at basal, −25.8±3.5% at papillary muscle, and −31.9±6.2% at apex levels. Global left ventricular longitudinal strain values were −20.6±2.6% in apical four-chamber view, −20.9±2.7% in apical two-chamber, and −21.0 ±2.7% in apical three-chamber. Age was associated with longitudinal strain, longitudinal systolic and early diastolic strain rate, but not with circumferential strain.ConclusionsNormal values for left ventricular deformation parameters in children are obtained using a Philips platform. Age partly explains normal variation of strain and strain rate.

Coarctation of aorta(CoA), complicated by endarteritis in a children is very rare. Here we present a case of endarteritis in an unoperated CoA in a four year old boy. CoA had been diagnosed in the referring hospital, yet the diagnosis of endocarditis distal to CoA, was made in the tertiary center using modified transthoracic echo windows or focused views. After six weeks of intravenous antibiotic treatment, a coarctectomy and end‐to‐end anastomosis was performed and he recovered clinically well. This case report concludes that echocardiography remains as the standard diagnostic method for identifying intracardiac manifestations of infective endocarditis/endarteritis. Last but foremost, it delineates the importance of modified transthoracic echo windows or focused views in identifying the unusual position of endocarditis.

Survival of children with single ventricle heart defects after the total cavopulmonary connection (TCPC) has improved, but impaired cardiac function remains a major cause of morbidity and mortality. Cardiac magnetic resonance imaging (cMRI) is the gold standard in assessing single ventricle volume and function, but high costs and limited availability hamper its routine use. A cheaper and more available alternative is echocardiography. Myocardial function can be studied in more detail using speckle tracking echocardiography (STE). The purpose of the study was to describe the association between myocardial deformation assessed by speckle tracking echocardiography (STE) and single ventricle function assessed by cMRI and to evaluate differences in myocardial deformation in children with single left and single right ventricular morphology. Cross-sectional, multicenter study in 77 children after TCPC was conducted. STE segmental and global longitudinal peak strain and systolic strain rate (SR) of the dominant ventricle were measured. Impaired SV function by cMRI was defined as ejection fraction (EF)

HexaBody®-CD38 (GEN3014) is a next-generation CD38-specific IgG1 molecule with a hexamerization-enhancing mutation that leads to highly efficient induction of complement-dependent cytotoxicity (CDC) upon binding to CD38 positive tumor cells. HexaBody-CD38 is designed to induce strong anti-tumor activity in patients with CD38-expressing hematological malignancies through CDC and other Fc-mediated effector functions. Previously we have shown that HexaBody-CD38 induces highly potent CDC-mediated cell death in multiple myeloma (MM), acute myeloid leukemia (AML), and B-cell non-hodgkin lymphoma (B-NHL) cells, including tumor cells in bone marrow samples from MM patients. In addition, HexaBody-CD38 demonstrated efficient ADCC and ADCP and induction of direct cell kill after Fc-crosslinking. Moreover HexaBody-CD38 induced strong inhibition of CD38 cyclase activity, which may contribute to reduction of immune suppression in the tumor microenvironment. In this study, we show that in a panel of 23 MM, AML and B-NHL cell lines HexaBody-CD38 induced CDC, with EC50 values on average 7-fold lower than those of the CD38-targeting mAb daratumumab, which is part of the standard of care for MM. Cytotoxic activity of HexaBody-CD38 showed a positive correlation with CD38 expression levels. HexaBody-CD38 was especially more potent than daratumumab in cell lines with lower CD38 expression. Sensitivity to HexaBody-CD38-induced CDC was correlated with lower expression levels of complement regulatory proteins, including CD46, CD55 and CD59. To exclude that the enhanced potency of HexaBody-CD38 resulted in lysis of healthy cell subsets known to express low levels of CD38, CDC in healthy donor leukocytes was assessed in vitro. HexaBody-CD38 (20 μg/mL) did not induce lysis of monocytes, B cells, T cells, granulocytes or erythrocytes, and only minor cytotoxicity of NK cells (median 13% lysis, range 9.5-55.1%). NK-cell lysis by daratumumab, assessed in parallel, was in the same range (median 8%, range 4.5-21.2%). Thus, HexaBody-CD38 shows superior potency in CD38-positive tumor cells while sparing healthy donor leukocytes and erythrocytes in vitro. The anti-tumor activity of HexaBody-CD38 in vivo was evaluated in patient-derived AML and B-NHL xenograft (PDX) models in nude mice. In a screen using 9 B-NHL PDX models in a 1-3 mice-per-treatment-group design, administration of two weekly doses of 5 mg/kg HexaBody-CD38 induced a strong anti-tumor response (relative tumor growth ≤10%, i.e. tumor stasis or tumor regression) in 2 models. Two models were classified as non-responder (relative tumor growth >70%) and 5 models could not be classified as either responder or non-responder (intermediates, relative tumor growth between 10 and 70%). A dose-response experiment in one of the responding models (Ly12638, 9 mice per group), confirmed potent anti-tumor activity of HexaBody-CD38, inducing complete tumor regression at a dose of 10 mg/kg (Figure 1A). In a screen using 5 AML PDX models in a 1-3 mouse-per-treatment-group design, HexaBody-CD38 (5 mg/kg) induced a strong anti-tumor response in one model. One model was classified as non-responder and the remaining 3 models could not be classified as either responder or non-responder (intermediates). A dose-response experiment in one of the intermediate models (AML11810), demonstrated statistically significant and dose-dependent anti-tumor activity of HexaBody-CD38 in an in vivo study using a classical 9 mice per treatment group design (Figure 1B). In summary, HexaBody-CD38 induced potent CDC in MM, B-NHL and AML cell lines, with superior potency compared to benchmark antibody daratumumab. HexaBody-CD38 was able to induce CDC in tumor cell lines with lower levels of CD38 expression, while sparing healthy leukocyte subsets. HexaBody-CD38 showed potent anti-tumor activity in vivo both in B-NHL and AML PDX models in nude mice. In these models, the contribution of mouse complement to the anti-tumor activity is limited and therapeutic activity is thought to be driven mainly through FcγR-mediated effector functions. This indicates that besides highly potent CDC, FcɣR-mediated effector mechanisms contribute to the preclinical activity of HexaBody-CD38 in hematological tumor models. These preclinical data support clinical investigation of HexaBody-CD38 in CD38 positive hematologic malignancies, including MM, AML, and B cell lymphomas. Figure Disclosures Hiemstra: Genmab: Current Employment, Current equity holder in publicly-traded company. Janmaat:Genmab: Current Employment, Current equity holder in publicly-traded company. Boross:Genmab: Current Employment, Current equity holder in publicly-traded company. van den Brakel:Genmab: Current Employment, Current equity holder in publicly-traded company. ten Hagen:Genmab: Current Employment, Current equity holder in publicly-traded company. van Dooremalen:Genmab: Current Employment, Current equity holder in publicly-traded company. Bosgra:Genmab: Current Employment, Current equity holder in publicly-traded company. De Goeij:Genmab: Current Employment, Current equity holder in publicly-traded company. Andringa:Genmab: Current Employment, Current equity holder in publicly-traded company. Kil:Genmab: Current Employment, Current equity holder in publicly-traded company. Sasser:Genmab: Current Employment, Current equity holder in publicly-traded company. Ahmadi:Genmab: Current Employment, Current equity holder in publicly-traded company. Satijn:Genmab: Current Employment, Current equity holder in publicly-traded company. Breij:Genmab: Current Employment, Current equity holder in publicly-traded company.

Fragmented QRS complexes (fQRS) are common in patients with arrhythmogenic cardiomyopathy (ACM). A new method of fQRS quantification may aid early disease detection in pathogenic variant carriers and assessment of prognosis in patients with early stage ACM. Patients with definite ACM (n = 221, 66%), carriers of a pathogenic ACM-associated variant without a definite ACM diagnosis (n = 57, 17%) and control subjects (n = 58, 17%) were included. Quantitative fQRS (Q-fQRS) was defined as the total amount of deflections in the QRS complex in all 12 electrocardiography (ECG) leads. Q-fQRS was scored by a single observer and reproducibility was determined by three independent observers. Q-fQRS count was feasible with acceptable intra- and inter-observer agreement. Q-fQRS count is significantly higher in patients with definite ACM (54 &plusmn, 15) and pathogenic variant carriers (55 &plusmn, 10) compared to controls (35 &plusmn, 5) (p &lt, 0.001). In patients with ACM, Q-fQRS was not associated with sustained ventricular arrhythmia (p = 0.701) at baseline or during follow-up (p = 0.335). Both definite ACM patients and pathogenic variant carriers not fulfilling ACM diagnosis have a higher Q-fQRS than controls. This may indicate that increased Q-fQRS is an early sign of disease penetrance. In concealed and early stages of ACM the role of Q-fQRS for risk stratification is limited.

OBJECTIVES Our goal was to report the long-term serial follow-up after transatrial–transpulmonary repair of tetralogy of Fallot (TOF) and to describe the influence of the timing of the repair on outcome. METHODS We included all patients with TOF who had undergone transatrial–transpulmonary repair between 1970 and 2012. Records were reviewed for patient demographics, operative details and events during the follow-up period (death, pulmonary valve replacement, cardiac reinterventions and hospitalization/intervention for arrhythmias). In patients with elective early primary repair of TOF after 1990, a subanalysis of the optimal timing of TOF repair was performed. RESULTS A total of 453 patients were included (63% male patients; 65% had transannular patch); 261 patients underwent primary elective repair after 1990. The median age at TOF repair was 0.7 years (25th–75th percentile 0.3–1.3) and decreased from 1.7 to 0.4 years from before 1990 to after 2000, respectively (P CONCLUSIONS Transatrial–transpulmonary repair of TOF before the age of 6 months may be associated with more events during the long-term follow-up period.

HexaBody-CD38 (GEN3014) is a novel, hexamerization-enhanced human IgG1 targeting CD38 with superior complement dependent cytotoxicity (CDC) activity, in addition to other effector mechanisms. HexaBody-CD38 carries the E430G mutation and binds a different epitope than the clinically validated CD38 monoclonal antibody daratumumab, which is currently being established as backbone therapy for the treatment of multiple myeloma. Introduction of the E430G mutationfacilitates the natural process of antibody hexamer formation through increased intermolecular Fc-Fc interactions after antigen binding at the cell surface (Diebolder et al., Science 2014; de Jong et al., PLoS Biol 2016). Improved IgG hexamer formation can increase binding of the hexavalent complement component C1q, thereby potentiating or unlocking antibody-mediated complement-dependent cytotoxicity (CDC). Preclinical data demonstrate highly potent CDC-mediated tumor cell kill in vitro in a panel of cell lines derived from hematological malignancies, including multiple myeloma (MM), B cell lymphoma and acute myeloid leukemia (AML). In these cell lines, at the highest dose tested (10 µg/mL), HexaBody-CD38 induced approximately 2-fold more CDC-mediated lysis compared to daratumumab. Of note, in those cell lines that were responsive to daratumumab in CDC assays (>50% tumor cell lysis), CDC activity of HexaBody-CD38 was superior to daratumumab, with IC50 values for HexaBody-CD38 2.4- to 13-fold lower than for daratumumab. Moreover, HexaBody-CD38 unlocked CDC activity in 17 out of 28 tumor cell lines that were not sensitive to daratumumab in CDC assays ( In addition to superior CDC, HexaBody-CD38 was shown to induce comparable antibody-dependent cell mediated cytotoxicity (ADCC) and antibody-dependent cell mediated phagocytosis (ADCP) as daratumumab. HexaBody-CD38 demonstrated more efficient inhibition of CD38 cyclase activity, which has been postulated to contribute to immune suppression in the tumor microenvironment. Importantly, in the presence of monocytes, HexaBody-CD38 treatment resulted in the removal of CD38 from the cell membrane of CD38 expressing cells, including T regulatory cells. This suggests downmodulation of CD38 as another potential mechanism to reduce CD38-generated metabolites and associated immune suppression. Finally, HexaBody-CD38 induced promising anti-tumor activity in vivo in PDX models of diffuse large B cell lymphoma in nude mice. Anti-tumor activity was associated with CD38 expression levels. In conclusion, HexaBody-CD38 is a novel CD38 antibody that shows superior capacity to induce CDC-mediated tumor cell kill compared to daratumumab, including in tumor samples from MM patients. Furthermore, HexaBody-CD38 induces FcγR-mediated effector functions and effectively inhibits CD38 enzymatic activity, either directly or indirectly by removal of CD38 from the cell membrane, thereby potentially contributing to immune activation. Targeting CD38 with HexaBody-CD38 could have therapeutic potential in daratumumab-naïve and -refractory MM patients, as well as in CD38-positive tumors in which daratumumab does not have single agent efficacy, such as DLBCL and AML. The promise of HexaBody-CD38 warrants further clinical investigation in CD38-positive hematological malignancies, including MM, B cell lymphoma and AML. Disclosures De Goeij: Genmab BV: Employment, Other: stock and/or warrants. Janmaat:Genmab BV: Employment, Other: stock and/or warrants. Andringa:Genmab BV: Employment, Other: stock and/or warrants. Kil:Genmab: Employment, Other: stock and/or warrants. Van Kessel:Genmab: Other: stock and/or warrants. Lingnau:Genmab: Employment, Other: stock and/or warrants. Freidig:Genmab BV: Employment, Other: stock and/or warrants. Mutis:Onkimmune: Research Funding; BMS: Research Funding; Janssen Pharmaceuticals: Research Funding; Celgene: Research Funding; Novartis: Research Funding; Amgen: Research Funding; Aduro: Research Funding. Sasser:Genmab: Employment, Other: stock and/or warrants. Breij:Genmab: Employment, Other: stock and/or warrants. Van De Donk:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; AMGEN: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Ahmadi:Genmab Inc: Employment, Other: stock and/or warrants. Satijn:Genmab BV: Employment, Other: stock and/or warrants.

Background Patients with non-ischemic dilated cardiomyopathy (NIDCM) are at increased risk of ventricular arrhythmias and sudden cardiac death (SCD). However, identifying patients at high risk for life-threatening ventricular arrhythmia (LTVA) who may benefit from an implantable cardioverter defibrillator (ICD) remains challenging. Methods We searched MEDLINE and EMBASE for prognostic studies describing predictors of LTVA (defined as sustained ventricular tachycardia (VT), haemodynamically unstable VT, ventricular fibrillation, (aborted) SCD or appropriate ICD intervention) in patients with NIDCM. We excluded articles with composite heart failure and arrhythmic endpoints but lacking (subgroup) analysis for LTVA. Study quality and risk of bias was assessed using the QUIPS-tool, and articles with high risk of bias in ≥2 areas were excluded from analysis. Univariable hazard ratios of reported predictors were pooled from the remaining studies in a meta-analysis using a random-effects model and presented with 95% confidence interval (CI). Results Out of 1996 unique citations, 51 studies were included comprising 9798 patients with 1493 arrhythmic events. 28 studies were pooled for meta-analysis (mean age 55±4.1 years, 72% male) with a mean follow-up of 3.7±1.9 years. Crude event rate was 4.3% (95% CI 4.02–4.57) per year. From our meta-analysis, hypertension (HR 1.95; CI [1.26–3.00]), history of out of hospital cardiac arrest or sustained VT (HR 4.15; CI [1.32–13.02]), T-wave alternans (HR 6.50; CI [2.46–17.14]), LVEDV per 10ml/m2 increase (HR 1.10; CI [1.10–1.10]), LVESV per 10ml/m2 increase (HR 1.10; CI [1.00–1.22]) and delayed gadolinium enhancement (HR 5.55; CI [4.02–7.67]) were significantly associated with LTVA (figure). The quality of evidence was moderate and there was significant heterogeneity (median i2 57%; IQR 76%) among studies. Additionally from data that could not be pooled, decreased LVEF, history of nsVT and decreased heart rate variability were significantly associated with LTVA. Summary of meta-analysis results Conclusion The risk of LTVA in NIDCM is 4.3% per year and is considerably higher in patients with hypertension, history of LTVA, decreased LVEF, high LVEDV, high LVESV, T-wave alternans, history of nsVT, decreased heart rate variability and delayed gadolinium enhancement. These results may help determine appropriate candidates for ICD implantation. The high heterogeneity in reported results indicate the need for future multicentre studies to further improve risk stratification in NIDCM. Acknowledgement/Funding ERA-CVD JTC2016: DETECTIN-HF, 680969 & Dutch Heart Foundation (2016T096)

Background/Introduction The founder mutation p.Arg14del in the gene encoding phospholamban (PLN) is a known cause of arrhythmogenic cardiomyopathy (ACM) with distinct clinical features, such as microvoltages on the ECG and right or left ventricular dysfunction or both. At present, risk stratification for ICD implantation in carriers of this mutation is based on left ventricular ejection fraction and previous ventricular arrhythmia's, which are not specific risk factors for the PLN p.Arg14del cardiomyopathy. Purpose Our goal is to develop a mutation specific prediction model for incident malignant ventricular arrhythmia to guide ICD implantation. Methods Data were collected from p.Arg14del carriers with no history of malignant VA at baseline, identified between September 2009 and June 2018 in three Dutch university hospitals. Genetic analysis of PLN was performed in a clinical setting in index patients with clinical signs of DCM/ACM, or in family members of p.Arg14del carriers. We collected clinical data from the first cardiac evaluation and follow-ups. Malignant VAs were defined as sustained VA, appropriate ICD intervention or (aborted) sudden cardiac death. A prediction model was developed using Cox Proportional Hazard regression. Candidate baseline predictors were pre specified based on literature and clinical expertise. Age, sex, proband status, sudden cardiac death (SCD) in 1st degree relative, repolarization abnormalities, microvoltages, premature ventricular complexes (PVC) burden on 24hrs Holter monitoring, LVEF and non-sustained ventricular arrhythmias (NSVT) were considered. The multivariable model was fitted using stepwise backward selection based on Akaike's Information Criterion. Results We included 440 p.Arg14del carriers with a mean age of 41±18 years and 41% males. During a median follow-up of 4.7 years (IQR 1.7–7.3), 44 incident malignant VA occurred, 20 sustained VAs and 24 appropriate ICD therapies. The multivariable HR's of selected predictors were: 2.2 for minor and 4.5 for major repolarization abnormalities vs no abnormalities (p value respectively 0.06 and 0.01), 2.2 for LVEF 500PVC/24hrs (p value 0.003). Carriers with and without events could be accurately distinguished with this model, with an optimism corrected C-statistic of 0.81. The model calibrated well, with agreement of observed and predicted 5 year malignant VA risk. Risk groups were split into quintiles of predicted risk, figure 1 shows the Kaplan Meier curve of incident malignant VA per risk group. The 5 year risk of incident malignant VA in the lowest 3 quintiles was 0%, 9% in the 4th quintile and 25.2% in the highest quintile. Conclusion We created a PLN p.Arg14del mutation specific prediction model to estimate risk of incident malignant VA. With this model a clear distinction between high risk and low risk patients can be made and can be used to guide ICD implantation for primary prevention.

Introduction: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetically determined disease associated with a significant risk of ventricular arrhythmias and sudden cardiac death (SCD)...

To mitigate climate change a renewable energy transition is needed. Existing power systems will need to be redesigned to balance variable renewable energy production with variable energy demand. We investigate the meteorological sensitivity of a highly-renewable European energy system using large ensemble simulations from two global climate models. Based on 3 × 2000 years of simulated weather conditions, daily wind and solar energy yields, and energy demand are calculated. From this data, 1-, 7- and 14-days events of extreme low renewable energy production and extreme high energy shortfall are selected. Energy shortfall is defined as the residual load, i.e. demand minus renewable production. 1-day low energy production days are characterised by large-scale high pressure systems over central Europe, with lower than normal wind speeds. These events typically occur in winter when solar energy is limited due to short day lengths. Situations of atmospheric blocking lead to long lasting periods of low energy production, such 7- and 14-days low production events peak late summer. High energy shortfall events occur due to comparable high pressure systems though now combined with below normal temperatures, driving up energy demand. In contrast to the low energy production events, 1-, 7- and 14-days high shortfall events all occur mid-winter, locked to the coldest months of the year. A spatial redistribution of wind turbines and solar panels cannot prevent these high-impact events, options to import renewable energy from remote locations during these events are limited. Projected changes due to climate change are substantially smaller than interannual variability. Future power systems with large penetration of variable renewable energy must be designed with these events in mind.

Aims Evaluation of left ventricular (LV) myocardial deformation by speckle tracking echocardiography (STE) is useful for clinical and research purposes. However, strain measurements depend on the used software. Normative data for QLAB 10 (Philips) are scarce. Additionally, little is known about the influence of anthropometric factors. We aimed to establish normal adult STE-derived strain and strain rate values and to evaluate associations with anthropometrics. Methods One hundred fifty-five healthy subjects aged 20 to 72 years (≥28 subjects per decile) were prospectively gathered and examined with electrocardiography and two-dimensional echocardiography. With STE, we assessed peak systolic LV global longitudinal strain (GLS), segmental longitudinal strain, and strain rate from the three standard apical views. Results We included 147 healthy subjects (age 44.6±13.7 years, 50% female, GLS −20.8±2.0%). Men had significantly lower GLS than women (−20.1±1.8% vs −21.5±2.0%, P

The demand-supply balance of electricity systems is fundamentally linked to climate conditions. In light of this, the present study aims to model the effect of climate change on the European electricity system, specifically on its long-term reliability. A resource adequate power system – a system where electricity supply covers demand – is sensitive to generation capacity, demand patterns, and the network structure and capacity. Climate change is foreseen to affect each of these components. In this analysis, we focused on two drivers of power system adequacy: the impact of temperature variations on electricity demand, and of water inflows changes on hydro generation. Using a post-processing approach, based on results found in the literature, the inputs of a large-scale electricity market model covering the European region were modified. The results show that climate change may decrease total LOLE (Loss of Load Expectation) hours in Europe by more than 50%, as demand will largely decrease because of a higher temperatures during winter. We found that the climate change impact on demand tends to decrease LOLE values, while the climate change effects on hydrological conditions tend to increase LOLE values. The study is built on a limited amount of open-source data and can flexibly incorporate various sets of assumptions. Outcomes also show the current difficulties to reliably model the effects of climate change on power system adequacy. Overall, our presented method displays the relevance of climate change effects in electricity network studies.

OBJECTIVES: This study sought to compare electrocardiogram (ECG) variants in athletic and arrhythmogenic right ventricular cardiomyopathy (ARVC) cohorts matched for the confounders of age, sex, and ethnicity.BACKGROUND: Anterior T-wave inversion (TWIV1-V4) is a common electrocardiographic finding in both athletes and patients with ARVC, and is a frequent conundrum in the setting of pre-participation screening. J-point elevation (JPE) has been proposed as an accurate means of identifying athletes, whereas disease markers, including premature ventricular contractions (PVCs) and low-voltage signals, have been associated with ARVC.METHODS: This study examined 200 subjects with TWI V1-V4, including 100 healthy athletes and 100 ARVC patients matched 1:1 for age, sex, and ethnicity (age: 21 ± 5 years for athletes vs. 22 ± 5 years for ARVC patients; 47% male; 97% Caucasian). The presence of TWI, JPE, PVCs, and left ventricular hypertrophy (LVH) were assessed.RESULTS: JPE was observed in 27% of athletes versus 16% of ARVC patients (p = 0.09). Thus, JPE had poor specificity (27%) and accuracy (60%) in identifying healthy athletes. In contrast, ARVC patients demonstrated a greater prevalence of precordial TWI beyond lead V3 (34% vs. 8%; p < 0.001), inferior TWI (31% vs. 3%; p < 0.001), PVCs (18% vs. 0%; p < 0.001), and lower LVH scores (SV1 + RV5; 19 ± 1 mm vs. 30 ± 1 mm; p < 0.001). These combined factors provided more reliable differentiation between health and disease (specificity 82%, accuracy 81%).CONCLUSIONS: PVCs and low QRS voltages are more prevalent among ARVC patients than athletes, whereas JPE is a relatively poor discriminator of health and disease when the confounders of age, sex, and ethnicity are considered.

Premature birth and bronchopulmonary dysplasia (BPD) are risk factors for the development of echocardiographic signs of pulmonary hypertension (PH) and are associated with changes in cardiac structure and function. It is unclear whether this association persists beyond early infancy. The aims of this study are to prospectively investigate the prevalence of PH in children with severe BPD and to investigate the effect of BPD and PH on myocardial structure and function at six months corrected age. Preterm infants (gestational age ≤ 32 weeks) with severe BPD were included. Echocardiography was used to define PH and to measure speckle tracking derived longitudinal and circumferential strain of the left ventricle (LV) and right ventricle (RV). Sixty-nine infants with a median (interquartile range [IQR]) gestational age of 25.6 (24.9–26.4) weeks and a median birthweight of 770 (645–945) gram were included. Eight (12%) infants had signs of PH at six months corrected age. RV fractional area change was lower in infants with severe BPD and PH at six months compared to infants without PH (35% ± 9% vs. 43% ± 9%, P = 0.03). RV mean longitudinal systolic strain was lower in infants with severe BPD and PH compared to infants without PH (17.6% [−19.5%/−16.1%] vs. −20.9% [−25.9%/−17.9%], P = 0.04). RV size and LV longitudinal and circumferential strain in children with BPD with or without PH were similar. Signs of PH were found in 12% of infants with severe BPD at six months corrected age and the presence of PH is associated with reduced RV systolic function.

Item does not contain fulltext BACKGROUND: Exercise can improve physical fitness in children and adults with congenital heart disease. We hypothesized that exercise training would not lead to adverse cardiac remodelling in this population. METHODS AND RESULTS: This multi-centre randomized controlled trial included children and young adults (10 to 25 years) with either corrected tetralogy of Fallot or Fontan circulation. The exercise-group was enrolled in a 12 week standardized aerobic dynamic exercise training program. The control-group continued their life-style and received care as usual. Both groups underwent cardiopulmonary exercise testing, cardiac magnetic resonance imaging (MRI), echocardiography and neurohormonal assessment, within 2 weeks before and 2 weeks after the intervention period. Fifty-six patients were randomized to the exercise-group and 37 to the control-group. We assessed changes between the pre- and the post-intervention period for the exercise group compared to the changes in the control-group. Peak load increased significantly in the exercise-group compared to the control-group (exercise-group 6.9 +/- 11.8 W; control-group 0.8 +/- 13.9 W; p=0.047). There were no adverse events linked to the study. Ventricular systolic parameters, cardiac dimensions and neurohormonal markers during follow-up did not change in patients allocated to the exercise-group and control-group. Although there were some isolated minor changes in inflow parameters, there was no consistent pattern of changes, indicating a lack of true change in the diastolic function. CONCLUSION: We demonstrated that no clinically relevant adverse cardiac remodelling occurred after 12 weeks of exercise training in patients with either corrected tetralogy of Fallot or Fontan circulation. CLINICAL TRIAL REGISTRATION: www.trialregister.nl, identification NTR2731.

While many studies evaluate predictors of ventricular arrhythmias in arrhythmogenic right ventricular cardiomyopathy (ARVC), a systematic review consolidating this evidence is currently lacking. Therefore, we searched MEDLINE and Embase for studies analyzing predictors of ventricular arrhythmias (sustained ventricular tachycardia/fibrillation (VT/VF), appropriate implantable cardioverter-defibrillator therapy, or sudden cardiac death) in patients with definite ARVC, patients with borderline ARVC, and ARVC-associated mutation carriers. In the case of multiple publications on the same cohort, the study with the largest population was included. This yielded 45 studies with a median cohort size of 70 patients (interquartile range 60 patients) and a median follow-up of 5.0 years (interquartile range 3.3 - 6.7 years). The average proportion of arrhythmic events observed was 10.6%/y in patients with definite ARVC, 10.0%/y in patients with borderline ARVC, and 3.7%/y with mutation carriers. Predictors of ventricular arrhythmias were population dependent: consistently predictive risk factors in patients with definite ARVC were male sex, syncope, T-wave inversion in lead >V3, right ventricular dysfunction, and prior (non)sustained VT/VF; in patients with borderline ARVC, 2 additional predictors—inducibility during electrophysiology study and strenuous exercise—were identified; and with mutation carriers, all aforementioned predictors as well as ventricular ectopy, multiple ARVC-related pathogenic mutations, left ventricular dysfunction, and palpitations/presyncope determined arrhythmic risk. Most evidence originated from small observational cohort studies, with a moderate quality of evidence. In conclusion, the average risk of ventricular arrhythmia ranged from 3.7 to 10.6%/y depending on the population with ARVC. Male sex, syncope, T-wave inversion in lead >V3, right ventricular dysfunction, and prior (non)sustained VT/VF consistently predict ventricular arrhythmias in all populations with ARVC.

Changes in vascular and myocardial structure and function have been demonstrated in obese children, but limited data are available on how these changes are related. The aims of this study were to investigate vascular and myocardial changes in obese children with lipid abnormalities and to study the interactions between vascular and myocardial parameters.A cross-sectional, prospective observational study was conducted. Twenty-one obese and 27 normal-weight controls aged 14 ± 2 years participated. Cardiac assessment included geometric parameters and myocardial deformation (strain and strain rate) analysis by color tissue Doppler and speckle-tracking echocardiography. Vascular assessment included carotid intima-media thickness, flow-mediated dilatation, pulse-wave velocity, and other stiffness measures of the aorta and carotid artery, as well as noninvasive estimation of arterial elastance and left ventricular (LV) end-systolic elastance.Obese children compared with controls had lower color tissue Doppler-derived LV systolic radial strain values (45 ± 11% vs 56 ± 12%, P = .002), lower speckle-tracking echocardiography-derived LV systolic longitudinal strain values (-18 ± 2% vs -21 ± 2%, P.001), and lower speckle-tracking echocardiography-derived LV early diastolic strain rate values (1.7 ± 0.3 vs 2.5 ± 0.4, P.001). Carotid intima-media thickness was increased, pulse-wave velocity was faster, and arterial distension coefficients were lower in obese children. The ratio of arterial elastance to LV end-systolic elastance (a marker of ventricular-arterial coupling) was lower in obese children than controls (0.73 ± 0.32 vs 0.47 ± 0.15, P = .003). Changes in vascular parameters were correlated with changes in longitudinal myocardial deformation parameters.Obese children with lipid abnormalities have reduced systolic and diastolic LV deformation characteristics, early vessel wall changes, and increased arterial stiffness. Abnormal ventricular-vascular interaction is suggested by these data and warrants further investigation.

Purpose To assess the frequency and characteristics of discrepant findings between fluorescein angiography (FA) and optical coherence tomography (OCT) in uveitic macular edema (ME). Design Retrospective cross-sectional study of 112 eyes of 78 patients with uveitic ME on FA, OCT, or both. Methods ME was graded on OCT and FA of uveitis patients attending the University Medical Center Utrecht. The frequency and severity of discrepant findings were analyzed, and the clinical findings at the time of imaging were assessed. The imaging studies were compared with the clinical characteristics. Results Positive results of both imaging methods (FA+/OCT+) were observed in 61 (54%) of 112 eyes, whereas discrepant results occurred in 51 (46%) of 112 eyes. The FA+/OCT− discrepancy occurred in 34 (30%) of 112 eyes, and the FA−/OCT+ discrepancy occurred in 17 (15%) of 112 eyes. No correlations between the discrepant imaging results and age, gender, duration of uveitis or ME, visual acuity, or cause of uveitis were identified. FA+/OCT− and FA−/OCT+ discrepancies comprised typically mild degrees of ME. The FA+/OCT− discrepancy occurred in 50% of eyes with birdshot chorioretinopathy (7/14), and the FA−/OCT+ discrepancy occurred more often in intermediate uveitis than in other anatomic locations. Although the FA+/OCT+ consistency was noted frequently in active uveitis, the FA−/OCT+ discrepancy was common in eyes with inactive uveitis (8/18; 44% of inactive eyes). Conclusions Our results emphasize that FA and OCT are complementary investigations, each revealing different aspects of the pathophysiology of uveitic ME.

BACKGROUND: Standard treatment of newly diagnosed HFE hemochromatosis patients is phlebotomy. Erythrocytapheresis provides a new therapeutic modality that can remove up to three times more red blood cells per single procedure and could thus have a clinical and economic benefit. STUDY DESIGN AND METHODS: To compare the number of treatment procedures between erythrocytapheresis and phlebotomy needed to reach the serum ferritin (SF) target level of 50 microg/L, a two-treatment-arms, randomized trial was conducted in which 38 newly diagnosed patients homozygous for C282Y were randomly assigned in a 1:1 ratio to undergo either erythrocytapheresis or phlebotomy. A 50% decrease in the number of treatment procedures for erythrocytapheresis compared to phlebotomy was chosen as the relevant difference to detect. RESULTS: Univariate analysis showed a significantly lower mean number of treatment procedures in the erythrocytapheresis group (9 vs. 27; ratio, 0.33; 95% confidence interval [CI], 0.25-0.45; Mann-Whitney p < 0.001). After adjustments for the two important influential factors initial SF level and body weight, the reduction ratio was still significant (0.43; 95% CI, 0.35-0.52; p < 0.001). Cost analysis showed no significant difference in treatment costs between both procedures. The costs resulting from productivity loss were significantly lower for the erythrocytapheresis group. CONCLUSION: Erythrocytapheresis is highly effective treatment to reduce iron overload and from a societal perspective might potentially also be a cost-saving therapy.

Myocardial deformation parameters obtained by speckle-tracking echocardiography (STE) and color Doppler tissue imaging (CDTI) using two different ultrasound systems and three different software packages were compared.Apical four-chamber, short-axis grayscale, and color Doppler tissue images were prospectively acquired using Vivid 7 and iE33 ultrasound systems in 34 children and then analyzed using EchoPAC and QLAB (STE) and SPEQLE (CDTI).Measurement of myocardial deformation was feasible for all three modalities. Longitudinal strain (epsilon) measurements showed the lowest intraobserver and interobserver variability (intraobserver and interobserver coefficients of variation, 9% and 8% for EchoPAC, 5% and 6% for QLAB, and 14% and 16% for SPEQLE). In addition, longitudinal epsilon had a small bias and narrow limits of agreement when comparing different techniques. The coefficients of variation of circumferential epsilon by EchoPAC and QLAB were 12% and 11% (intraobserver) and 9% and 13% (interobserver), respectively. Circumferential epsilon by STE had a small systematic bias but relatively narrow limits of agreement. The reproducibility of radial epsilon measurements using STE was low, while CDTI epsilon provided better performance (intraobserver and interobserver coefficients of variation for radial posterior epsilon, 12% and 24% for EchoPAC, 39% and 56% for QLAB, and 12% and 14% for SPEQLE). Radial epsilon was on average 50% lower using QLAB compared with EchoPAC and SPEQLE. Systolic strain rate values obtained by STE were lower compared with CDTI-derived values. The limits of agreement for strain rate values among the three modalities were wide, and intraobserver and interobserver variability was poor for all three modalities.Some deformation measurements (e.g., longitudinal and circumferential epsilon) are comparable among different ultrasound machines and software packages, whereas others are significantly different (e.g., radial epsilon and strain rate). This study stresses the need for an industry standard for these techniques.

Background The investigators compared pulsed-wave tissue Doppler (PWTD) and color tissue Doppler (CTD) ventricular tissue velocities obtained using Vivid 7 (GE) and iE33 (Philips) ultrasound systems within a 30-minute time frame and examined interobserver and intraobserver variability. Methods Longitudinal PWTD and CTD images were prospectively acquired in 49 children from the base of the right and left ventricular free wall and septum and stored for offline analysis. Results Intraobserver and interobserver coefficients of variation for PWTD velocities ranged from 4% to 6% and 5% to 10% for GE and from 1% to 10% and 2% to 14% for Philips, respectively. Intraobserver and interobserver coefficients of variation for CTD velocities ranged from 4% to 15% and 6% to 24% for GE and from 6% to 19% and 7% to 25% for Philips, respectively. Mean biases between the two systems for PWTD velocities, expressed as percentage differences, were around 0%, with the narrowest limits of agreement for systolic velocities at the septal annulus and the widest limits of agreement for early diastolic velocities at the lateral tricuspid valve annulus, respectively. Peak CTD-derived velocities were significantly and consistently lower for Philips compared with GE. Conclusions Agreement between GE-derived and Philips-derived PWTD velocities was reasonable, whereas CTD-derived velocities differed substantially.

Background: Loss of tolerance to auto-antigens after vascular injury could trigger vascular remodeling in idiopathic pulmonary arterial hypertension (IPAH) patients. Endothelial cell-specific auto-antibodies produced by B cells could influence the early development of IPAH. Similarities with IPAH pathology have been observed in mice in which B-cell-receptor (BCR) signaling is continuously increased by Bruton9s tyrosine kinase (Btk) overexpression. Therefore, the aim of our study is to investigate if patients with IPAH have activated B cells and if Btk-Tg mice develop signs of PH after pulmonary injury. Methods: Using flow cytometry we determined Btk expression in peripheral B cells from healthy controls (HC) after stimulation with F(ab)2 anti-IgM and in different B-cell subsets in PB mononuclear cells inpatients with IPAH and HC. Finally, we assessed right ventricular weight (RVW) in Btk-Tg and wild type (WT) mice 56 days after bleomycine-induced lung injury. Results: IgM stimulation induced robust Btk protein upregulation in B-cells. IPAH patients (n=13) showed an increased Btk expression in B-cells compared with HC (P Conclusion: Our data suggest that IPAH pathogenesis in humans is driven by B-cell-dependent auto-immune responses. Interestingly, the combination of Btk overexpression in B cells and lung injury in mice could be a novel model to study IPAH and this may be a new tool to study future experimental therapies.

Airway inflammation is an early feature of asthma. Early detection and antiinflammatory treatment may have important therapeutic impact. Exhaled nitric oxide is a noninvasive marker of airway inflammation. The current study investigated the association between exhaled nitric oxide and asthma, wheezing phenotypes, atopy and blood eosinophilia in a large group of 4-yr-old children from the general population.All children participated in the Prevention and Incidence of Asthma and Mite Allergy study, a birth cohort study of high-risk (atopic mother) and low-risk children in the Netherlands. Nitric oxide levels were successfully determined in 429 children.Although there was overlap in the distribution of values of children with and without asthma or atopy, mean values were higher in children with atopy or doctor's diagnosed asthma (geometric mean (ppb) 9.4 and 10.0, respectively) as compared to those without (7.7 and 7.9). Values were highest in atopic symptomatic children. Values were not associated with wheezing phenotype or blood eosinophilia.This study is one of the few large-scale epidemiological studies among 4-yr-old children from the general population showing that children with symptoms of asthma and atopy have higher levels of exhaled nitric oxide than those without.

It is difficult to distinguish young children with respiratory symptoms who will develop asthma from those with transient symptoms only. Measurement of interrupter resistance may help to identify children at high risk of asthma. The aim of this study is to compare interrupter resistance in 4-year-old children with different wheezing phenotypes. All children participated in the Prevention and incidence of Asthma and Mite Allergy cohort, a prospective birth cohort of more than 4,000 children. At 4 years of age, data on interrupter resistance plus wheezing phenotype were available for 838 children. Mean interrupter resistance values (95% confidence interval) were 0.95 (0.93, 0.97), 0.95 (0.92, 0.98), 0.96 (0.87, 1.05), and 1.08 (1.02, 1.14) kPa . L-1 . second for never (n = 482), early transient (n = 236), late-onset (n = 22), and persistent (n = 98) wheezing phenotypes, respectively. Additional analyses were performed for children with atopic and nonatopic mothers separately. Both in children with atopic and nonatopic mothers, children with persistent wheeze had significantly higher interrupter resistance values than children with never and early wheeze. In conclusion, mean interrupter resistance values were higher in children with persistent wheeze as compared with children with never and early transient wheezing phenotypes.

Background It has been suggested that the period immediately after birth is a sensitive period for the development of atopic disease. Objective We investigated whether birth characteristics and environmental factors are associated with the development of atopic dermatitis in the first year of life. Methods Seventy-six children with and 228 without atopic dermatitis, all children of mothers with respiratory allergy or asthma (PIAMA birth cohort study) were included in the study. Atopic dermatitis was defined as a positive history of an itchy skin condition with at least two of the following characteristics: visible dermatitis, history of outer arms/leg involvement, or general dry skin. Multiple logistic regression analysis was performed to study the independent effects of various risk factors. Results A birth weight greater than or equal to4000 g compared to 3000 - 4000 g was a significant risk factor for atopic dermatitis ( odds ratio (OR) = 2.4; 95% CI: 1.1 - 5.1) as was day care attendance (OR = 2.9; 95% CI: 1.5 - 5.9). Exclusive breastfeeding in the first 3 months was negatively associated with atopic dermatitis (OR = 0.6; 95% CI: 0.3 - 1.2), especially with visible dermatitis (OR = 0.4; 95% CI: 0.2-1.0). Gender, gestational age, the presence of siblings or pets, and parental smoking were not significantly associated with atopic dermatitis. Conclusion This study shows that a high birth weight and day care attendance increase the risk of atopic dermatitis in the first year of life, while exclusive breastfeeding is a protective factor when dermatitis is found on inspection.

Respiratory infections in infancy may protect against developing Th2-mediated allergic disease (hygiene hypothesis). To estimate the relative contribution of particular viruses to the development of the immune system and allergic disease, we investigated longitudinally the prevalence of respiratory viral infections in infants. One hundred and twenty-six healthy infants were included in this prospective birth cohort study in their first year of life. Physical examination was performed and nasal brush samples were taken during routine visits every 6 months and during an upper respiratory tract infection (URTI) (sick visits). The prevalence of respiratory viral infections in infants with URTI, infants with rhinitis without general malaise and infants without nasal symptoms was studied. Rhinovirus was the most prevalent pathogen during URTI and rhinitis in 0- to 2-year-old infants (∼40%). During URTI, also respiratory syncytial virus (∼20%) and coronavirus (∼10%) infections were found, which were rarely detected in infants with rhinitis. Surprisingly, in 20% of infants who did not present with nasal symptoms, rhinovirus infections were also detected. During routine visits at 12 months, a higher prevalence of rhinovirus infections was found in infants who attended day-care compared with those who did not. We did not observe a relation between breast-feeding or smoking by one or both parents and the prevalence of rhinovirus infections. The parental history of atopy was not related to the prevalence of rhinovirus infection, indicating that the genetic risk of allergic disease does not seem to increase the chance of rhinovirus infections. In conclusion, rhinovirus infection is the most prevalent respiratory viral infection in infants. It may therefore affect the maturation of the immune system and the development of allergic disease considerably.

Background: The short and long term variability of the interrupter technique was assessed to determine whether interrupter resistance is a stable individual characteristic over time. The effect of field and standardised measurement conditions on the within-subject variability of the interrupter technique was also examined. Methods: The interrupter technique was studied under field and standardised conditions in children aged 3-6 years. Under field conditions, five investigators performed the measurements using two different measurement devices in random sequence. Both short term (20-30 minutes) and long term variability (median 38 days) were assessed in 32 children. Under standardised conditions, a single investigator conducted all measurements using a single device; the repeated measurements were conducted at the same time of day in a familiar quiet classroom. Long term variability (median 11 days) was estimated in 15 children. Within-subject standard deviations were estimated by analysis of variance with adjustment for the effects of different investigators and measurement devices on within-subject variability under field conditions. Results: Under field conditions within-subject standard deviations for short and long term variability were 0.10 kPa/l/s (adjusted 0.10 kPa/l/s) and 0.13 kPa/l/s (adjusted 0.14 kPa/l/s), respectively. Under standardised conditions the within-subject standard deviation for long term variability was 0.10 kPa/l/s. Conclusions: Measurement of interrupter resistance under field conditions only slightly increased the within-subject variability compared with standardised conditions. The results indicate that interrupter resistance is a stable individual characteristic over a period of some weeks.

To investigate the association between various serum markers and atopic symptoms in the first year of life, and to evaluate the prognostic value of these markers for the development of wheezing and skin rash in the second year of life. Data of 86 children on the development of wheezing and skin rash in the first 2 years of life were collected prospectively, making use of parental completed questionnaires, weekly symptom cards, structured interview and physical examination. Serum markers (IL-10, IL-12, IL-13, eotaxin, sE-selectin, sICAM-1, sIL-2R) and total and specific IgE were determined at age 1. Children who developed wheezing in the first year of life had lower serum levels of IL-12 than children without symptoms (median 40.3 pg/ml vs. 49.0 pg/ml, p = 0.01) and a higher serum IL-10/IL-12 ratio (0.41 vs. 0.31, p = 0.001) at age 1. The IL-10/IL-12 ratio increased with an increasing number of wheezing episodes. Levels of sE-selectin in children with wheezing and in children with itchy skin rash in the first year of life were higher than in symptom free children (6.1 ng/ml and 5.9 ng/ml vs. 4.9 ng/ml, p = 0.01 and p = 0.03, respectively). Children who developed wheezing in the second year of life already had increased sICAM-1 levels at age 1. Children who developed wheezing in the first year of life showed a serum cytokine response that is skewed towards a T-helper 2 profile, with lower IL-12 levels and an increased IL-10/IL-12 ratio. Children who developed wheezing in the second year of life had elevated sICAM-1 levels at age 1. Follow-up of the children is needed to evaluate the prognostic value of various serum markers for the development of allergic disease in later childhood.

Background Reduction of allergen exposure from birth may reduce sensitization and subsequent allergic disease. Objective To measure the influence of mite allergen-impermeable mattress encasings and cotton placebo encasings on the amount of dust and mite allergen in beds. Methods A total of 810 children with allergic mothers took part in the Prevention and Incidence of Asthma and Mite Allergy (PIAMA) study. Allergen-impermeable and placebo mattress encasings were applied to the childrens' and the parents' beds before birth. Dust samples were taken from the beds of children and their parents before birth and 3 and 12 months after birth. Extracts of dust samples were analysed for mite allergens (Der p 1 and Der f 1). Results Active mattress encasings were significantly more effective in reducing dust and mite allergen levels than placebo encasings. Mite allergen levels were low in general and the treatment effect was modest. Twelve months after birth, mattresses with active mattress encasings had about half the amount of Der 1 (Der p 1 + Der f 1)/m(2) , compared to mattresses with placebo encasings, for the child's and the parental mattress. Conclusion This study shows that mite-impermeable mattress encasings have a significant but modest effect on dust and mite allergen levels of mattresses with low initial mite allergen levels, compared to placebo.

Background— Public-health guidelines recommend patients with congenital heart disease to exercise. Studies have shown that patients with congenital heart disease can improve physical exercise capacity. The effect of training on regional ventricular performance has hardly been studied. We performed a pilot study to assess whether an exercise training program would result in adverse changes of regional ventricular performance in patients with corrected tetralogy of Fallot. Methods and Results— Multicenter prospective randomized controlled pilot study in patients with tetralogy of Fallot aged 10 to 25 years. A 12-week standardized aerobic dynamic exercise training program (3 one-hour sessions per week) was used. Pre- and post-training cardiopulmonary exercise tests, MRI, and echocardiography, including tissue-Doppler imaging, were performed. Patients were randomized to the exercise group (n=28) or control group (n=20). One patient in the exercise group dropped out. Change in tissue-Doppler imaging parameters was similar in the exercise group and control group (change in right ventricle free wall peak velocity E′ exercise group, 0.8±2.6 cm/s; control group, 0.9±4.1; peak velocity A′ exercise group, 0.4±2.4 m/s; control group 4.6±18.1 cm/s). Conclusions— This randomized controlled pilot study provides preliminary data suggesting that regional ventricular performance is well maintained during 3-month aerobic dynamic exercise training in children and young adults with repaired tetralogy of Fallot. This information might help patients adhere to current public-health guidelines. Clinical Trial Registration— URL: http//:www.trialregister.nl . Unique identifier: NTR2731.