Does Repeated Measurement of a 6-Min Walk Test Contribute to Risk Prediction in Children with Dilated Cardiomyopathy?

A single 6-min walk test (6MWT) can be used to identify children with dilated cardiomyopathy (DCM) with a high risk of death or heart transplantation. To determine if repeated 6MWT has added value in addition to a single 6MWT in predicting death or heart transplantation in children with DCM. Prospective multicenter cohort study including ambulatory DCM patients ≥ 6 years. A 6MWT was performed 1 to 4 times per year. The distance walked was expressed as percentage of predicted (6MWD%). We compared the temporal evolution of 6MWD% in patients with and without the study endpoint (SE: all-cause death or heart transplantation), using a linear mixed effects model. In 57 patients, we obtained a median of 4 (IQR 2-6) 6MWTs per patient during a median of 3.0 years of observation (IQR 1.5-5.1). Fourteen patients reached a SE (3 deaths, 11 heart transplantations). At any time during follow-up, the average estimate of 6MWD% was significantly lower in patients with a SE compared to patients without a SE. In both patients groups, 6MWD% remained constant over time. An absolute 1% lower 6MWD% was associated with an 11% higher risk (hazard) of the SE (HR 0.90, 95% CI 0.86-0.95 p < 0.001). Children with DCM who died or underwent heart transplantation had systematically reduced 6MWD%. The performance of all patients was stable over time, so repeated measurement of 6MWT within this time frame had little added value over a single test.

Left ventricular function and exercise capacity after arterial switch operation for transposition of the great arteries: a systematic review and meta-analysis.

BACKGROUND: The arterial switch operation for transposition of the great arteries was initially believed to be an anatomical correction. Recent evidence shows reduced exercise capacity and left ventricular function in varying degrees in the long term after an arterial switch operation. OBJECTIVE: To perform a meta-analysis on long-term exercise capacity and left ventricular ejection fraction after an arterial switch operation. METHODS: A literature search was performed to cover all studies on patients who had undergone a minimum of 6 years of follow-up that reported either left ventricular ejection fraction, peak oxygen uptake, peak workload, and/or peak heart rate. A meta-analysis was performed if more than three studies reported the outcome of interest. RESULTS: A total of 21 studies reported on the outcomes of interest. Oxygen uptake was consistently lower in patients who had undergone an arterial switch operation compared with healthy controls, with a pooled average peak oxygen uptake of 87.5±2.9% of predicted. The peak heart rate was also lower compared with that of controls, at 92±2% of predicted. Peak workload was significantly reduced in two studies. Pooled left ventricular ejection fraction was normal at 60.7±7.2%. CONCLUSION: Exercise capacity is reduced and left ventricular ejection fraction is preserved in the long term after an arterial switch operation for transposition of the great arteries.

Perioperative Management of an Adolescent Fontan Patient with Narrowing of the Aortopulmonary Space for Posterior Scoliosis Surgery.

Congenital cardiac patients who received neonatal reconstructive aortic arch surgery are at risk of aortopulmonary space narrowing with compression of the left pulmonary artery and left main bronchus (LMB) later in life. We discuss a challenging adolescent single ventricle patient who presented for surgical treatment of a non-idiopathic thoracic scoliosis (posterior spinal fusion) with severe stenosis of the LMB and left pulmonary artery due to a narrow aortopulmonary space. Careful preoperative imaging, evaluation, and decision making resulted in successful surgical treatment and uneventful perioperative course.

Genetic Evaluation of A Nation-Wide Dutch Pediatric DCM Cohort: The Use of Genetic Testing in Risk Stratification.

BACKGROUND: This study aimed to describe the current practice and results of genetic evaluation in Dutch children with dilated cardiomyopathy and to evaluate genotype-phenotype correlations that may guide prognosis. METHODS: We performed a multicenter observational study in children diagnosed with dilated cardiomyopathy, from 2010 to 2017. RESULTS: One hundred forty-four children were included. Initial diagnostic categories were idiopathic dilated cardiomyopathy in 67 children (47%), myocarditis in 23 (16%), neuromuscular in 7 (5%), familial in 18 (13%), inborn error of metabolism in 4 (3%), malformation syndrome in 2 (1%), and "other" in 23 (16%). Median follow-up time was 2.1 years [IQR 1.0-4.3]. Hundred-seven patients (74%) underwent genetic testing. We found a likely pathogenic or pathogenic variant in 38 children (36%), most often in MYH7 (n = 8). In 1 patient initially diagnosed with myocarditis, a pathogenic LMNA variant was found. During the study, 39 patients (27%) reached study endpoint (SE: all-cause death or heart transplantation). Patients with a likely pathogenic or pathogenic variant were more likely to reach SE compared with those without (hazard ratio 2.8; 95% CI 1.3-5.8, P = 0.007), while transplant-free survival was significantly lower (P = 0.006). Clinical characteristics at diagnosis did not differ between the 2 groups. CONCLUSIONS: Genetic testing is a valuable tool for predicting prognosis in children with dilated cardiomyopathy, with carriers of a likely pathogenic or pathogenic variant having a worse prognosis overall. Genetic testing should be incorporated in clinical work-up of all children with dilated cardiomyopathy regardless of presumed disease pathogenesis.

Predicting outcome in children with dilated cardiomyopathy: the use of repeated measurements of risk factors for outcome.

AIMS: We aimed to determine whether in children with dilated cardiomyopathy repeated measurement of known risk factors for death or heart transplantation (HTx) during disease progression can identify children at the highest risk for adverse outcome. METHODS AND RESULTS: Of 137 children we included in a prospective cohort, 36 (26%) reached the study endpoint (SE: all-cause death or HTx), 15 (11%) died at a median of 0.09 years [inter-quartile range (IQR) 0.03-0.7] after diagnosis, and 21 (15%) underwent HTx at a median of 2.9 years [IQR 0.8-6.1] after diagnosis. Median follow-up was 2.1 years [IQR 0.8-4.3]. Twenty-three children recovered at a median of 0.6 years [IQR 0.5-1.4] after diagnosis, and 78 children had ongoing disease at the end of the study. Children who reached the SE could be distinguished from those who did not, based on the temporal evolution of four risk factors: stunting of length growth (-0.42 vs. -0.02 length Z-score per year, P < 0.001), less decrease in N-terminal pro-B-type natriuretic peptide (NT-proBNP) (-0.26 vs. -1.06 2log pg/mL/year, P < 0.01), no decrease in left ventricular internal diastolic dimension (LVIDd; 0.24 vs. -0.60 Boston Z-score per year, P < 0.01), and increase in New York University Pediatric Heart Failure Index (NYU PHFI; 0.49 vs. -1.16 per year, P < 0.001). When we compared children who reached the SE with those with ongoing disease (leaving out the children who recovered), we found similar results, although the effects were smaller. In univariate analysis, NT-proBNP, length Z-score, LVIDd Z-score, global longitudinal strain (%), NYU PHFI, and age >6 years at presentation (all P < 0.001) were predictive of adverse outcome. In multivariate analysis, NT-proBNP appeared the only independent predictor for adverse outcome, a two-fold higher NT-proBNP was associated with a 2.8 times higher risk of the SE (hazard ratio 2.78, 95% confidence interval 1.81-3.94, P < 0.001). CONCLUSIONS: The evolution over time of NT-proBNP, LVIDd, length growth, and NYU PHFI identified a subgroup of children with dilated cardiomyopathy at high risk for adverse outcome. In this sample, with a limited number of endpoints, NT-proBNP was the strongest independent predictor for adverse outcome.

Echocardiography and MRI parameters associated with exercise capacity in patients after the arterial switch operation.

BACKGROUND: The arterial switch operation (ASO) for transposition of the great arteries has excellent survival, but a substantial number of patients suffer from a reduced exercise capacity. The goal of this study was to identify imaging parameters associated with a reduced exercise capacity in patients after ASO. METHODS: A retrospective analysis was performed of ASO patients who underwent cardiopulmonary exercise testing (CPET) between 2007 and 2017. Reduced exercise performance was defined as a reduced workload peak (Wpeak) with Z-score <-2 or a peak oxygen uptake indexed for weight (VO2peak/kg) with Z-score <-2. Data on echocardiography and cardiac magnetic resonance performed within 1 year of the CPET were collected for comparison. RESULTS: A total of 81 ASO patients (age 17±7 years) were included. Reduced exercise performance was found in 22 patients (27%) as expressed by either a reduced Wpeak and/or a reduced VO2peak/kg. Main pulmonary artery gradient and tricuspid regurgitation gradient by echocardiography were found to be associated with reduced Wpeak (p=0.031; p=0.020, respectively). The main pulmonary artery gradient and tricuspid regurgitation gradient by echocardiography were found to be associated with reduced VO2peak/kg (p=0.009; p=0.019, respectively). No left ventricular parameters were found to be associated with abnormal exercise performance. CONCLUSION: This study demonstrates that ASO patients frequently experience reduced exercise capacity. Echocardiographic evidence of main pulmonary artery stenosis and increased right ventricular pressure were associated with reduced exercise capacity, and are therefore key to monitor during serial follow-up of ASO patients.

Ventricular response to dobutamine stress cardiac magnetic resonance imaging is associated with adverse outcome during 8-year follow-up in patients with repaired Tetralogy of Fallot.

AIMS: The aim of this study was to evaluate the possible value of dobutamine stress cardiac magnetic resonance imaging (CMR) to predict adverse outcome in Tetralogy of Fallot (TOF) patients. METHODS AND RESULTS: In previous prospective multicentre studies, TOF patients underwent low-dose dobutamine stress CMR (7.5 µg/kg/min). Subsequently, during regular-care patient follow-up, patients were assessed for reaching the composite endpoint (cardiac death, arrhythmia-related hospitalization, or cardioversion/ablation, VO2 max ≤65% of predicted). A normal stress response was defined as a decrease in end-systolic volume (ESV) and increase in ejection fraction. The relative parameter change during stress was calculated as relative parameter change = [(parameterstress - parameterrest)/parameterrest] * 100. The predictive value of dobutamine stress CMR for the composite endpoint was determined using time-to-event analyses (Kaplan-Meier) and Cox proportional hazard analysis. We studied 100 patients [67 (67%) male, median age at baseline CMR 17.8 years (interquartile range 13.5-34.0), age at TOF repair 0.9 years (0.6-2.1)]. After a median follow-up of 8.6 years (6.7-14.1), 10 patients reached the composite endpoint. An abnormal stress response (30% vs. 4.4%, P = 0.021) was more frequently observed in composite endpoint patients. Also in endpoint patients, the relative decrease in right ventricular ESV decreased less during stress compared with the patients without an endpoint (-17 ± 15 vs. -26 ± 13 %, P = 0.045). Multivariable analyses identified an abnormal stress response (hazard ratio 10.4; 95% confidence interval 2.5-43.7; P = 0.001) as predictor for the composite endpoint. CONCLUSION: An abnormal ventricular response to dobutamine stress is associated with adverse outcome in patients with repaired TOF.

Staged total cavopulmonary connection: serial comparison of intra-atrial lateral tunnel and extracardiac conduit taking account of current surgical adaptations.

OBJECTIVES: Our goals were to compare the outcome of the intra-atrial lateral tunnel (ILT) and the extracardiac conduit (ECC) techniques for staged total cavopulmonary connection (TCPC) and to compare the current modifications of the TCPC technique, i.e. the prosthetic ILT technique with the current ECC technique with a ≥18-mm conduit. METHODS: We included patients who had undergone a staged TCPC between 1988 and 2008. Records were reviewed for patient demographics, operative details and events during follow-up (death, surgical and catheter-based reinterventions and arrhythmias). RESULTS: Of the 208 patients included, 103 had the ILT (51 baffle, 52 prosthetic) technique and 105 had the ECC technique. Median follow-up duration was 13.2 years (interquartile range 9.5-16.3). At 15 years after the TCPC, the overall survival rate was comparable (81% ILT vs 89% ECC; P = 0.12). Freedom from late surgical and catheter-based reintervention was higher for patients who had ILT than for those who had ECC (63% vs 44%; P = 0.016). However, freedom from late arrhythmia was lower for patients who had ILT than for those who had ECC (71% vs 85%, P = 0.034). In a subgroup of patients who had the current TCPC technique, when we compared the use of a prosthetic ILT with ≥18-mm ECC, we found no differences in freedom from late arrhythmias (82% vs 86%, P = 0.64) or in freedom from late reinterventions (70% vs 52%, P = 0.14). CONCLUSIONS: A comparison between the updated prosthetic ILT and current ≥18-mm ECC techniques revealed no differences in late arrhythmia-free survival or late reintervention-free survival. Overall, outcomes after the staged TCPC were relatively good and reinterventions occurred more frequently in the ECC group, whereas late arrhythmias were more common in the ILT group.

Dominant missense mutations in ABCC9 cause Cantú syndrome.

Cantú syndrome is characterized by congenital hypertrichosis, distinctive facial features, osteochondrodysplasia and cardiac defects. By using family-based exome sequencing, we identified a de novo mutation in ABCC9. Subsequently, we discovered novel dominant missense mutations in ABCC9 in 14 of the 16 individuals with Cantú syndrome examined. The ABCC9 protein is part of an ATP-dependent potassium (K(ATP)) channel that couples the metabolic state of a cell with its electrical activity. All mutations altered amino acids in or close to the transmembrane domains of ABCC9. Using electrophysiological measurements, we show that mutations in ABCC9 reduce the ATP-mediated potassium channel inhibition, resulting in channel opening. Moreover, similarities between the phenotype of individuals with Cantú syndrome and side effects from the K(ATP) channel agonist minoxidil indicate that the mutations in ABCC9 result in channel opening. Given the availability of ABCC9 antagonists, our findings may have direct implications for the treatment of individuals with Cantú syndrome.