Non-invasive myocardial tissue deformation and discoordination indices predict cardiac allograft vasculopathy in pediatric heart transplantation patients.

There is an urgent need for non-invasive imaging-based biomarkers suitable for diagnostic surveillance of cardiac allograft vasculopathy (CAV) in pediatric heart transplant (PHT) patients. The purpose of this study was to comprehensively investigate left ventricular (LV) myocardial deformation in conjunction with electromechanical discoordination in PHT. PHT patients with and without CAV were evaluated for echocardiography derived global longitudinal strain (GLS) and electromechanical discoordination indices including systolic stretch fraction (SSF) and diastolic relaxation fraction (DRF). SSF was increased in CAV(+) patients at the time of CAV diagnosis (median CAV(+) 5.0 vs. median CAV(-) 0.0, P = 0.008) and in the echocardiogram preceding the CAV diagnosis (median CAV(+) 29.0 vs. median CAV(-) 0.0, P < 0.001). DRF was also increased in the echocardiogram that preceded CAV diagnosis in CAV(+) patients (0.31 ± 0.08 vs. 0.25 ± 0.05, P = 0.008). The final model using indices 6-12 months prior to CAV diagnosis included GLS, SSF, and DRF providing AUC of 0.94 with sensitivity 98.5%, specificity 80.0%, positive predictive value 85.0%, and negative predictive value 94.1%. Systolic and diastolic electro-mechanical discoordination indices are significantly worse in PHT patients experiencing CAV. Non-invasive imaging guided surveillance using echocardiographic myocardial deformation indices can be improved by adding SSF and DRF to standard GLS measurements.

A Preliminary Study of One Year Safety and Tolerability of Attention-Deficit/Hyperactivity Disorder Medications in Youth with Fontan Palliation or Heart Transplant.

There are no published studies that examine the safety and tolerability of medication to treat attention-deficit/hyperactivity disorder (ADHD) in children with histories of Fontan palliation (Fontan) or heart transplant (HT), despite the high prevalence of ADHD in these populations. To address this gap, we examined the cardiac course, somatic growth, and incidence of side effects for one year after medication initiation amongst children with Fontan or HT and comorbid ADHD. The final sample comprised 24 children with Fontan (12 medication-treated, 12 control) and 20 children with HT (10 medication-treated, 10 control). Demographic, somatic growth (height and weight percentile-for age), and cardiac data (blood pressure, heart rate, results of 24 h Holter monitoring, electrocardiograms) were extracted from electronic medical records. Medication-treated and control subjects were matched by cardiac diagnosis (Fontan or HT), age, and sex. Nonparametric statistical tests were utilized to compare between- and within-group differences prior to, and one year post, medication initiation. There were no differences in somatic growth or cardiac data when comparing medication-treated participants to matched controls, regardless of cardiac diagnosis. Within the medication group, a statistically significant increase in blood pressure was observed, though the group average remained within clinically acceptable limits. While results are preliminary in nature due to our very limited sample size, our findings suggest that ADHD medications can be tolerated with minimal cardiac or somatic growth effects amongst complex cardiac patients. Our preliminary results favor treating ADHD with medication, which has considerable implications for long-term academic/employment outcomes and quality of life for this population. Close collaboration between pediatricians, psychologists, and cardiologists is essential to individualizing and optimizing interventions and outcomes for children with Fontan or HT.

Rationale and Design of the Multicenter Catheter Ablation of Ventricular Tachycardia Before Transcatheter Pulmonary Valve Replacement in Repaired Tetralogy of Fallot Study.

Patients with repaired tetralogy of Fallot are at elevated risk for ventricular arrhythmia and sudden cardiac death. Over the past decade, the pathogenesis and natural history of ventricular tachycardia has become increasingly understood, and catheter ablation has emerged as an effective treatment modality. Concurrently, there has been great progress in the development of a versatile array of transcatheter valves that can be placed in the native right ventricular outflow tract for the treatment of long-standing pulmonary regurgitation. Although such valve platforms may eliminate the need for repeat cardiac operations, they may also impede catheter access to the myocardial substrates responsible for sustained macro-reentrant ventricular tachycardia. This manuscript provides the rationale and design of a recently devised multicenter study that will examine the clinical outcomes of a uniform, preemptive strategy to eliminate ventricular tachycardia substrates before transcatheter pulmonary valve implantation in patients with tetralogy of Fallot.

Extraction and Digitization of ECG Signals from Standard Clinical Portable Document Format Files for the Principal Component Analysis of T-wave Morphology.

INTRODUCTION: T-wave analysis from standard electrocardiogram (ECG) remains one of the most available clinical and research methods for evaluating myocardial repolarization. T-wave morphology was recently evaluated to aid with diagnosis and characterization of diastolic dysfunction. Unfortunately, PDF stored ECG datasets limit additional numerical post-processing of ECG waveforms. In this study, we apply a simple custom process pipeline to extract and re-digitize T-wave signals and subject them to principal component analysis (PCA) to define primary T-wave shape variations. METHODS: We propose simple pre-processing and digitization algorithms programmable as a MATLAB tool using standard thresholding functions without the need for advanced signal analysis. To validate digitized datasets, we compared clinically standard measurements in 20 different ECGs with the original ECG machine interpreted values as a gold standard. Afterwards, we analyzed 212 individual ECGs for T-wave shape analysis using PCA. RESULTS: The re-digitized signal was shown to preserve the original information as evidenced by excellent agreement between original - machine interpreted and re-digitized clinical variables including heart rate: bias ~ 1 bpm (95% CI: -1.0 to 3.5), QT interval: bias ~ 0.000 ms (95% CI: -0.012 to 0.012), PR interval: bias = -0.015 ms (95% CI: -0.015 to 0.003), and QRS duration: bias = -0.001 ms (95% CI: -0.007 to 0.006). PCA revealed that the first principal component universally modulates the T-wave height or amount of repolarization voltage regardless of the investigated ECG lead. The second and third principal components described variation in the T-wave peak onset and the T-wave peak morphology, respectively. CONCLUSION: This study presents a straightforward method for re-digitizing ECGs stored in the PDF format utilized in many academic electronic medical record systems. This process can yield re-digitized lead specific signals which can be retrospectively analyzed using advanced custom post-processing numerical analysis independent of commercially available platforms.

Myocardial strain-curve deformation patterns after Fontan operation.

Myocardial deformation analysis by cardiac MRI (CMR) yielding global circumferential and longitudinal strain (GCS and GLS) is an increasingly utilized method to accurately quantify systolic function and predict clinical events in patients with Fontan circulation. The purpose of this study was to use principal component analysis (PCA) to investigate myocardial temporal deformation patterns derived from strain-time curves to learn about latent strain features beyond peak values. We conducted the study with specific attention to dominant single left or right ventricle (SLV and SRV) morphologies. Methods and Results: Patients remote from Fontan operation who underwent follow-up CMR were analyzed for standard volumetric and function hemodynamics including myocardial deformation parameters including GCS and GLS. We applied PCA to investigate in an unbiased fashion the strain-time curve morphology and to calculate patient specific shape scores. All variables were subjected to single variable Cox regression analysis to detect composite clinical outcome including death, heart transplant, protein losing enteropathy and plastic bronchitis. A total of 122 patients, (SLV = 67, SRV = 55) with a mean age of 12.7 years underwent comprehensive CMR analysis. The PCA revealed 3 primary modes of strain-curve variation regardless of single ventricle morphology and type of strain investigated. Principle components (PCs) described changes in (1) strain-time curve amplitude, (2) time-to-peak strain, and (3) post-systolic slope of the strain-time curve. Considering only SLV patients, GCS was only CMR variable predictive of clinical events (HR 1.46, p = 0.020). In the SRV group, significant CMR predictors of clinical events were derived indexed end-diastolic (HR 1.02, p = 0.023) and end-systolic (HR 1.03, p = 0.022) volumes, GCS (HR 1.91, p = 0.003) and its related first component score (HR 1.20, p = 0.005), GLS (HR 1.32, p = 0.029) and its third component score (HR 1.58, p = 0.017). CMR derived global strain measures are sensitive markers of clinical outcomes in patients with Fontan circulation, particularly in patients with the SRV morphology. Myocardial strain-time curve morphology specific to SLV and SRV patients inspired by unbiased PCA technique can further aid with predicting clinical outcomes.

High-density electroanatomic mapping with grid catheter in pediatrics and congenital heart disease.

BACKGROUND: The Advisor™ HD Grid mapping catheter (Abbott Laboratories; Chicago, IL) allows for bipolar electrogram collection in both orthogonal and perpendicular planes, unique when compared to traditional and branch catheters. Experience in pediatric patients and congenital heart disease (CHD) is limited. The purpose of this work was to evaluate the utility and safety of the Advisor™ HD Grid mapping catheter in pediatric and CHD populations. METHODS: Retrospective review of all pediatric patients and those with CHD (regardless of age) at Children's Hospital Colorado and University of Colorado undergoing electrophysiologic study in which the Advisor™ HD Grid mapping catheter was utilized. RESULTS: Sixty-five procedures in 60 patients (N = 31 female (47.6%), median age 17 years (15-24.1)) were included. Patients had CHD in 30 procedures (46.1%). Eight-eight arrhythmia substrates were mapped including atrial flutter/intra-atrial reentrant tachycardia (N = 33), focal atrial tachycardia (N = 20), isolated PVCs (N = 10), accessory pathways (N = 9), atrioventricular nodal reentrant tachycardia (N = 7), right ventricular substrate mapping (N = 7), and ventricular tachycardia (N = 2). Median time per map was 11.8 (7.5-20.1) min with 3.2 (± 1.7) maps per procedure and a median of 2634 (1767-7654) points used per map. Patients with CHD required more maps (p < 0.001) and points per map (p < 0.001). Ablation was successful in 92.4% of procedures. CONCLUSIONS: The Advisor™ HD Grid mapping catheter is safe and effective in the pediatric and congenital heart disease population. A wide variety of arrhythmia substrates can be mapped with high point density and low mapping time.

Left Ventricular Dysfunction Following the Ross-Konno Reconstruction is Independent of the Operation.

The Ross-Konno (RK) operation is a well-established surgical treatment for combined left ventricular outflow tract obstruction and aortic valve pathology in children. Prior study has demonstrated that mechanical and electrical dyssynchrony exist post-RK compared to normal controls. The purpose of this study was to evaluate myocardial function pre- and post-RK as defined by echocardiography. Patients undergoing the RK operation (n = 13; median age: 1.3 years; range: 0.5-13.3 years) were evaluated by echocardiography at defined timepoints: pre-RK, post-RK, 1-year post-RK, and 2 years post-RK. Defined parameters of left ventricular performance were analyzed: systolic mechanical dyssynchrony (M-Dys), global left ventricular circumferential strain (GCS), and diastolic relaxation fraction (DRF). Patients with post-operative atrioventricular block (n = 6) were analyzed separately. No pre- versus post-RK differences existed in M-Dys, GCS, or DRF in patients both with and without post-RK atrioventricular block. Further, 1- and 2-year follow-up post-RK demonstrated significant heterogeneity in evaluated parameters of function with no pre- and post-RK differences in M-Dys, GCS, or DRF. Mechanical dyssynchrony exists post-RK reconstruction in both short- and long-term follow-up yet these echocardiographic parameters of ventricular performance are independent of the RK operation. Further study is, therefore, warranted to define causal relationships for observed short- and long-term ventricular dysfunction post-RK as the findings of the present study suggest a deleterious mechanism apart from the technical RK reconstruction.

Repolarization Dispersion Is Associated With Diastolic Electromechanical Discoordination in Children With Pulmonary Arterial Hypertension.

Background Electromechanical dyssynchrony is a well described comorbidity in pulmonary arterial hypertension (PAH). ECG-derived measurements reflective of diastolic dysfunction and electromechanical imaging markers are yet to be investigated. In this study we investigated the ECG- derived marker of repolarization dispersion, interval between the peak and end of T wave (TpTe), in pediatric patients with PAH and left ventricular (LV) diastolic dysfunction. Methods and Results We measured TpTe from a standard 12-lead ECG and in 30 children with PAH and matched control subjects. All participants underwent same-day echocardiography and myocardial strain analysis to calculate the diastolic electromechanical discoordination marker diastolic relaxation fraction. When compared with control subjects, patients with PAH had increased TpTe (93±15 versus 81±12 ms, P=0.001) and elevated diastolic relaxation fraction (0.33±0.10 versus 0.27±0.03, P=0.001). Patients with PAH with LV diastolic dysfunction had significantly increased TpTe when compared with patients with PAH without diastolic dysfunction (P=0.012) and when compared with control group (P<0.001). Similarly, patients with PAH with LV diastolic dysfunction had increased diastolic relaxation fraction when compared with PAH patients without diastolic dysfunction (P=0.007) and when compared with control group (P<0.001). A 10-ms increase in TpTe was significantly associated with 0.023 increase in diastolic relaxation fraction (P=0.008) adjusting for body surface area, heart rate, right ventricular volumes, and function. Conclusions Prolonged myocardial repolarization and abnormal LV diastolic electromechanical discoordination exist in parallel in children with PAH and are associated with worse LV diastolic function and functional class.

Diastolic inflow is associated with inefficient ventricular flow dynamics in Fontan patients.

OBJECTIVE: This study used cardiac magnetic resonance imaging to evaluate flow characteristics and ventricular hemodynamics for children with single right (hypoplastic left heart syndrome) and single left (hypoplastic right heart syndrome) systemic ventricle anatomy after Fontan palliation compared with normal biventricular controls. METHODS: Twenty children with single ventricle anatomy (hypoplastic left heart syndrome, n = 10; hypoplastic right heart syndrome, n = 10) underwent standardized 4-dimensional flow cardiac magnetic resonance and were compared with age-matched controls (n = 10). End-diastolic volume was partitioned into 4 defined components of variable kinetic energy (direct flow, retained inflow, delayed ejection, and residual volume) and compared between groups. Further, volumetric and functional parameters as defined by cardiac magnetic resonance were evaluated. RESULTS: Children with hypoplastic left heart syndrome had significantly increased indexed end-diastolic and end-systolic volumes compared with both hypoplastic right heart syndrome and control groups. Flow component analysis demonstrated diastolic inefficiency in both hypoplastic left heart syndrome and hypoplastic right heart syndrome groups compared with controls as defined by decreased direct flow and increased residual volumes. Decreased direct flow correlated with decreased ejection fraction and increased end-diastolic and end-systolic volume indices. Increased residual volume correlated with decreased ejection fraction and increased end-systolic volume index. CONCLUSIONS: Fontan-palliated patients with single ventricle physiology (hypoplastic left heart syndrome and hypoplastic right heart syndrome) demonstrate altered and inefficient flow patterns in the systemic ventricle as defined by 4-dimensional flow cardiac magnetic resonance compared with normal biventricular controls. Decreased direct flow and increased residual volume indicate that diastolic ventricular dysfunction is prevalent after Fontan palliation. This study provides a foundation for future predictive modeling and cardiac magnetic resonance flow diagnostic studies in this high-risk patient population.

Fasciculoventricular and atrioventricular accessory pathways in patients with Danon disease and preexcitation: A multicenter experience.

BACKGROUND: Studies have suggested that a fasciculoventricular pathway (FVP) may be the cause of preexcitation in patients with Danon disease, a rare X-linked dominant genetic disorder of hypertrophic cardiomyopathy. OBJECTIVE: The purpose of this study was to describe the prevalence of ventricular preexcitation on resting 12-lead electrocardiogram (ECG) in patients with Danon disease and the electrophysiological study (EPS) results of those with preexcitation. METHODS: Patients with confirmed Danon disease diagnosed with preexcitation (PR ≤120 ms, delta wave, QRS >110 ms) on ECG were included from a multicenter registry. The incidence of arrhythmias, implantable cardioverter-defibrillator (ICD) procedures, ICD shocks, and EPS results were collected. RESULTS: Thirteen of 40 patients (32.5%) with Danon disease were found to have preexcitation (mean age 17.3 years; 38% women). EPS performed in 9 of 13 patients (69%) demonstrated FVP only in 2 (22.2%), extranodal pathway without exclusion of FVP in 2 (22.2%), and both FVP and extranodal pathway in 5 (55.6%). Two patients had malignant accessory pathway (AP) properties. Over median follow-up of 842 days (interquartile range 138-1678), 11 patients (85%) had ICD placement, and 6 (46.1%) underwent heart transplantation. No patients required therapy for ventricular tachycardia, and 2 patients (15%) had paroxysmal atrial fibrillation. CONCLUSION: In a large multicenter cohort of patients with Danon disease, there was a high prevalence of FVP and extranodal pathways diagnosed on EPS in those with preexcitation. These findings suggest patients with preexcitation and Danon disease should undergo EPS to assess for FVP and potentially malignant extranodal AP.

Cardiac ryanodine receptor calcium release deficiency syndrome.

Cardiac ryanodine receptor (RyR2) gain-of-function mutations cause catecholaminergic polymorphic ventricular tachycardia, a condition characterized by prominent ventricular ectopy in response to catecholamine stress, which can be reproduced on exercise stress testing (EST). However, reports of sudden cardiac death (SCD) have emerged in EST-negative individuals who have loss-of-function (LOF) RyR2 mutations. The clinical relevance of RyR2 LOF mutations including their pathogenic mechanism, diagnosis, and treatment are all unknowns. Here, we performed clinical and genetic evaluations of individuals who suffered from SCD and harbored an LOF RyR2 mutation. We carried out electrophysiological studies using a programed electrical stimulation protocol consisting of a long-burst, long-pause, and short-coupled (LBLPS) ventricular extra-stimulus. Linkage analysis of RyR2 LOF mutations in six families revealed a combined logarithm of the odds ratio for linkage score of 11.479 for a condition associated with SCD with negative EST. A RyR2 LOF mouse model exhibited no catecholamine-provoked ventricular arrhythmias as in humans but did have substantial cardiac electrophysiological remodeling and an increased propensity for early afterdepolarizations. The LBLPS pacing protocol reliably induced ventricular arrhythmias in mice and humans having RyR2 LOF mutations, whose phenotype is otherwise concealed before SCD. Furthermore, treatment with quinidine and flecainide abolished LBLPS-induced ventricular arrhythmias in model mice. Thus, RyR2 LOF mutations underlie a previously unknown disease entity characterized by SCD with normal EST that we have termed RyR2 Ca2+ release deficiency syndrome (CRDS). Our study provides insights into the mechanism of CRDS, reports a specific CRDS diagnostic test, and identifies potentially efficacious anti-CRDS therapies.

Increased Aortic Stiffness and Left Ventricular Dysfunction Exist After Truncus Arteriosus Repair.

BACKGROUND: The purpose of this study was to determine whether aortic biomechanical properties are abnormal in children with repaired truncus arteriosus (TA) and to concurrently evaluate left ventricular (LV) function post-repair utilizing a novel platform for regional ventricular function. METHODS: Cardiac magnetic resonance (CMR) studies from 26 children (mean age: 15.6 ± 7.2 years) post-TA repair were compared with 20 normal controls (mean age: 14.7 ± 2.6 years). Parameters of aortic stiffness (pulse wave velocity and relative area change) were measured. Flow hemodynamic metrics (aortic regurgitant fraction, peak systolic flow, and peak systolic velocity) and LV function (volumetric data, ejection fraction, regional wall strain) were also compared. RESULTS: Ascending aortic pulse wave velocity was elevated and relative area change was decreased in TA patients compared with controls. Patients post-TA repair demonstrated elevated end diastolic and end systolic volumes in addition to decreased regional wall strain and increased mechanical dyssynchrony. LV functional changes were independent of aortic biomechanical properties. CONCLUSIONS: Children with repaired TA have increased ascending aortic stiffness and altered LV function as measured by CMR imaging. Longitudinal studies and advanced CMR assessments are warranted to better determine the long-term potential for late aortic complications and to optimize both the medical and surgical management of these patients after TA repair.

Subcutaneous Implantable Cardioverter-Defibrillators in Pediatrics and Congenital Heart Disease: A Pediatric and Congenital Electrophysiology Society Multicenter Review.

OBJECTIVES: The primary goal of this study was to evaluate the implant experience and midterm results of subcutaneous implantable cardioverter-defibrillators (S-ICDs) in pediatric patients and those with congenital heart disease. BACKGROUND: The S-ICD was developed to avoid the lead-related complications associated with transvenous systems. The absence of intravascular or intracardiac components offers potential advantages to pediatric patients and those with congenital heart disease. METHODS: This international, multicenter, retrospective, standard-of-care study was conducted through the Pediatric & Congenital Electrophysiology Society. Complications at 30 and 360 days, inappropriate shocks, and delivery of appropriate therapy were assessed. RESULTS: The study included 115 patients with a median follow-up of 32 (19 to 52) months. Median age was 16.7 years (14.8 to 19.3 years), 29% were female, and 55% had a primary prevention indication. Underlying disease substrate was cardiomyopathy (40%), structural heart disease (32%), idiopathic ventricular fibrillation (16%), and channelopathy (13%). The complication rate was 7.8% at 30 days and 14.7% at 360 days. Overall, inappropriate shocks occurred in 15.6% of patients, with no single clinical characteristic reaching statistical significance. At implant, 97.9% of patients had successful first shock conversion with 96% requiring ≤65 J. Appropriate therapy was delivered to 11.2% of patients with an annual incidence of 3.9% and an acute first shock conversion success rate of 92.5%. CONCLUSIONS: This study found that in a heterogeneous population of pediatric patients and those with congenital heart disease, the S-ICD had comparable rates of complications, inappropriate shocks, and conversion efficacy compared with previously published studies on transvenous systems in similar populations.