The Heart of Rett Syndrome: A Quantitative Analysis of Cardiac Repolarization.

Background: Rett syndrome (RTT) is a developmental encephalopathy disorder that is associated with a high incidence of sudden death presumably from cardiorespiratory etiologies. Electrocardiogram (ECG) abnormalities, such as prolonged heart-rate corrected QT (QTc) interval, are markers of cardiac repolarization and are associated with potentially lethal ventricular arrhythmias. This study investigates the cardiac repolarization characteristics of RTT patients, including QTc and T-wave morphology characteristics. Methods: A retrospective quantitative analysis on 110 RTT patients and 124 age and sex-matched healthy controls was conducted. Results: RTT patients had longer QTc, more abnormal T-wave morphology, and greater heterogeneity of cardiac repolarization parameters compared to controls. Even RTT patients without prolonged QTc had more abnormal ECG and T-wave characteristics than controls. Among RTT patients, MECP2 patients had prolonged QTc compared to CDKL5 and FOXG1 patients. A subset of five RTT patients who died had normal QTc, but more abnormal T-wave morphology than the remaining RTT patients. Conclusions: Cardiac repolarization abnormalities are present in RTT patients, even without long QTc. T-wave morphology is related to RTT genotype and may be predictive of mortality. These findings could be used to help the management and monitoring of RTT patients.

Ivabradine Overdose in a Newborn: Precautions of Dispensing in Infants.

Ivabradine is currently approved to reduce heart rate in children with chronic heart failure and dilated cardiomyopathy. Ivabradine has also been used off-label in children to treat automatic tachyarrhythmias such as ectopic atrial tachycardia and junctional ectopic tachycardia. Adverse effects of ivabradine at physiological doses as well as its toxicity at supra-physiological doses have rarely been reported in adults. In children, weight-based dosing requires dilution of commercially available ivabradine oral solution for accuracy. We describe a case of ivabradine overdose in a newborn (treated for ectopic atrial tachycardia) secondary to inaccurate dosing leading to the infant receiving 10 times more drug than prescribed. This case highlights potential pitfalls of ivabradine prescription and preparation in children.

ATRX proximal protein associations boast roles beyond histone deposition.

The ATRX ATP-dependent chromatin remodelling/helicase protein associates with the DAXX histone chaperone to deposit histone H3.3 over repetitive DNA regions. Because ATRX-protein interactions impart functions, such as histone deposition, we used proximity-dependent biotinylation (BioID) to identify proximal associations for ATRX. The proteomic screen captured known interactors, such as DAXX, NBS1, and PML, but also identified a range of new associating proteins. To gauge the scope of their roles, we examined three novel ATRX-associating proteins that likely differed in function, and for which little data were available. We found CCDC71 to associate with ATRX, but also HP1 and NAP1, suggesting a role in chromatin maintenance. Contrastingly, FAM207A associated with proteins involved in ribosome biosynthesis and localized to the nucleolus. ATRX proximal associations with the SLF2 DNA damage response factor help inhibit telomere exchanges. We further screened for the proteomic changes at telomeres when ATRX, SLF2, or both proteins were deleted. The loss caused important changes in the abundance of chromatin remodelling, DNA replication, and DNA repair factors at telomeres. Interestingly, several of these have previously been implicated in alternative lengthening of telomeres. Altogether, this study expands the repertoire of ATRX-associating proteins and functions.

Interactions With Histone H3 & Tools to Study Them.

Histones are an integral part of chromatin and thereby influence its structure, dynamics, and functions. The effects of histone variants, posttranslational modifications, and binding proteins is therefore of great interest. From the moment that they are deposited on chromatin, nucleosomal histones undergo dynamic changes in function of the cell cycle, and as DNA is transcribed and replicated. In the process, histones are not only modified and bound by various proteins, but also shuffled, evicted, or replaced. Technologies and tools to study such dynamic events continue to evolve and better our understanding of chromatin and of histone proteins proper. Here, we provide an overview of H3.1 and H3.3 histone dynamics throughout the cell cycle, while highlighting some of the tools used to study their protein-protein interactions. We specifically discuss how histones are chaperoned, modified, and bound by various proteins at different stages of the cell cycle. Established and select emerging technologies that furthered (or have a high potential of furthering) our understanding of the dynamic histone-protein interactions are emphasized. This includes experimental tools to investigate spatiotemporal changes on chromatin, the role of histone chaperones, histone posttranslational modifications, and histone-binding effector proteins.

Temporary atrial pacing for cardiac output after pediatric cardiac surgery.

Pediatric cardiothoracic surgery is often associated with low cardiac output in the postoperative period. This study sought to determine whether increasing heart rate via temporary atrial pacing is beneficial in augmenting cardiac output. Patients younger than 18 years who underwent cardiothoracic surgery and had no perioperative arrhythmias were eligible for the study. Patients not paced postoperatively were atrial paced at a rate of 15 % above the intrinsic sinus rate (not to exceed 170 beats per minute, less for older patients) for 15 min. Patients paced for cardiac output postoperatively had their pacemakers paused for 15 min. Markers of cardiac output were measured before and after the intervention. Of the 60 patients who consented to participate, 30 completed the study. Failure to complete the study was due to tachycardia (n = 13), lack of pacing wires (n = 7), junctional rhythm (n = 4), advanced atrioventricular block (n = 3), and other cause (n = 3). Three patients were paced at baseline. There was no change in arteriovenous oxygen saturation difference, mean arterial blood pressure, central venous pressure, toe temperature, or lactate with atrial pacing. Atrial pacing was associated with a decrease in head and flank near-infrared spectroscopy (p = 0.01 and <0.01 respectively). Secondary analysis found an inverse relationship between mean arterial pressure response to pacing and bypass time. Temporary atrial pacing does not improve cardiac output after pediatric cardiac surgery and may be deleterious. Future research may identify subsets of patients who benefit from this strategy. Practitioners considering this strategy should carefully evaluate each patient's response to atrial pacing before its implementation.

Role of molecular analysis after autopsy negative sudden death in the young.

Sudden death is a rare event, particularly in the young. A traditional comprehensive autopsy often reveals diseases that were not recognized prior to death. For a significant proportion of sudden deaths in the young, there is no clear etiology following autopsy. These unexplained sudden deaths are often secondary to primary arrhythmogenic diseases, where there is a defect in the structure or function of the channels that regulate the ion movement responsible for the electrical activation of the heart. As a group, these diseases are known as channelopathies. Channelopathies are often secondary to genetic mutations which may be inherited and place surviving relatives at risk. While these conditions cannot be detected by the traditional comprehensive autopsy, there is increasing evidence that they may be detected by molecular genetic analysis using blood or tissue from the deceased individual. There is no conclusive evidence to show the benefit of systematic screening for channelopathies in sudden unexplained death; however, there is increasing circumstantial evidence supporting the practice. There is currently insufficient infrastructure for the systematic implementation of such a screening program, including insufficient financial resources. While no clear legal obligation exists, there is a moral obligation to inform surviving family members of their potential risk. Strong consideration should be given to augmenting the traditional autopsy with a molecular analysis in the presence of unexplained sudden death in the young.

Relation of right ventricular pacing site to left ventricular mechanical synchrony.

Transvenous pacing leads are regularly placed in the right ventricular (RV) apex. Pediatric patients can develop myopathic changes after long-term RV apical pacing. Left ventricular (LV) mechanical dyssynchrony, estimated with echocardiography, may explain the acute decrease in LV function and long-term histopathologic changes. Ts-4w is an established echocardiographic measurement of LV synchrony, using tissue Doppler imaging (TDI). The purpose of this study was to determine whether TDI could identify acute changes in LV synchrony during pacing from different RV sites. We prospectively measured Ts-4w and Doppler-derived cardiac output after 5 minutes of pacing in 19 subjects undergoing catheter ablation. Each subject underwent pacing at 4 sites in random order: high right atrium, high RV septum (septal), RV outflow tract, and RV apex. Ts-4w was measured during sinus rhythm and each pacing protocol, with a value >65 ms defining mechanical dyssynchrony. Ts-4w during high right atrial (32.6 +/- 17.6 ms) and septal (28.9 +/- 10.9 ms) pacing were not different from sinus rhythm (39.5 +/- 15.5 ms). RV apex (85.7 +/- 18.4 ms) and RV outflow tract (84.2 +/- 20.4 ms) pacing induced mechanical dyssynchrony (p <0.0001). In conclusion, TDI demonstrated significant differences in LV synchrony related to pacing site. Ts-4w may be useful to determine ideal lead placement because it correlates with acutely improved hemodynamics.

Aspirin resistance in children with heart disease at risk for thromboembolism: prevalence and possible mechanisms.

Aspirin is used to prevent thromboembolism in children with heart disease without evidence supporting its efficacy. Studies in adults report a 5%-51% prevalence of aspirin resistance, yet the mechanisms involved are poorly understood. Our aims were to determine its prevalence in these children and to explore its possible mechanisms. One hundred twenty-three cardiac patients routinely receiving aspirin were prospectively enrolled. Platelet function was measured by Platelet Function Analyzer (PFA)-100 using epinephrine and adenosine diphosphate (ADP) agonists. Aspirin resistance was defined as failure to prolong the epinephrine closure time following aspirin administration. Urine levels of 11-dehydro-thromboxane B(2) (11-dTXB(2)) were measured to determine inhibition of the cyclo-oxygenase pathway. The prevalence of aspirin resistance was 26%. Median ADP closure time was shorter for aspirin-resistant (79.60-115 s) than for aspirin-sensitive (100.60-240 s) patients (p < 0.01). 11-dTXB(2) levels did not correlate with aspirin resistance. Aspirin-resistant patients had higher 11-dTXB(2) levels before (7297 vs. 4160 pg/mg creatinine; p < 0.01) and after (2153 vs. 1412 pg/mg; p = 0.03) aspirin, with a similar percentage decrease in thromboxane (70.5% vs. 66.1%; p = 0.43). Our findings suggest that resistance is not entirely due to lack of inhibition of platelet thromboxane production. Alternative sources of thromboxane and thromboxane-independent mechanisms, such as ADP-induced platelet activation, may contribute to aspirin resistance.

Sensitivity and specificity of an automated external defibrillator algorithm designed for pediatric patients.

OBJECTIVE: Electrocardiographic (ECG) rhythm analysis algorithms for cardiac rhythm analysis in automated external defibrillators (AEDs) have been tested against pediatric patient rhythms (patients < or = 8 years old) using adult ECG algorithm criteria. However these adult algorithms may fail to detect non-shockable pediatric tachycardias because they do not account for the difference in the rates of normal sinus rhythm and typical tachyarrhythmias in childhood. METHODS: This study was designed to define shockable and non-shockable rhythm detection criteria specific to pediatric patients to create a pediatric rhythm database of annotated rhythms, to develop a pediatric-based AED rhythm analysis algorithm, and to test the algorithm's accuracy. Pediatric rhythm detection criteria were defined for coarse ventricular fibrillation, rapid ventricular tachycardia, and non-shockable rhythms, including pediatric supraventricular tachycardia. Pediatric rhythms were collected as sustained, classifiable, rhythms > or = 9 s in length, and were annotated by pediatric electrophysiologists as clinically shockable or non-shockable based on pediatric criteria. Rhythms were placed into a pediatric rhythm database; each rhythm was converted to digitally accessible, public-domain, MIT rhythm data format. The database was used to evaluate a pediatric-based AED rhythm analysis algorithm. RESULTS: Electrocardiographic rhythms from 198 children were recorded. There were 120 shockable rhythms from 49 patients (sensitivity; coarse ventricular fibrillation: 42 rhythms, 100%; rapid ventricular tachycardia: 78 rhythms, 94%), for combined sensitivity of 96.0% (115/120). There were 585 non-shockable rhythms from 155 patients (specificity normal sinus: 208 rhythms, 100%; asystole: 29 rhythms, 100%; supraventricular tachycardia: 161 rhythms, 99%; other arrhythmias: 187 rhythms, 100%), for combined specificity of 99.7% (583/585). Overall accuracy for shockable and non-shockable rhythms was 99.0% (702/709). CONCLUSIONS: New pediatric rhythm detection criteria were defined and analysis based on these criteria demonstrated both high sensitivity (coarse ventricular fibrillation, rapid ventricular tachycardia) and high specificity (non-shockable rhythms, including supraventricular tachycardia). A pediatric-based AED can detect shockable rhythms correctly, making it safe and exceptionally effective for children.

Left ventricular function and response to enalapril in patients with duchenne muscular dystrophy during the second decade of life.

The role of angiotensin-converting enzyme inhibitors in the management of cardiomyopathy related to Duchenne muscular dystrophy has not been completely defined. The purposes of this study were to describe the response to enalapril and its relation to dystrophin mutation type, ventricular size, or age at the onset of left ventricular (LV) systolic dysfunction. Serial clinical and echocardiographic data from 50 patients with Duchenne muscular dystrophy (aged 10 to 20 years) were retrospectively reviewed. Twenty-seven patients (46%) developed LV systolic dysfunction (mean age 13.2 +/- 2.4 years). Ten (43%) responded to enalapril with the normalization of function. Responders and nonresponders developed LV systolic dysfunction at similar ages (p = 0.91). At the onset of LV systolic dysfunction, only 2 patients (1 responder, 1 nonresponder) had dilated left ventricles. The positive response to enalapril was sustained in 7 patients (median follow-up 23 months, range 5 to 58). No specific mutation was associated with the response to enalapril (p = 0.66) or predictive of the development of LV systolic dysfunction (p = 0.8). In conclusion, 10 of 26 patients (43%) with Duchenne muscular dystrophy responded to the use of enalapril with normalization of the shortening fraction. Age at the onset of LV systolic dysfunction and the type of mutation were not predictors of response to enalapril.

The extracardiac lateral tunnel Fontan, constructed with bovine pericardium: comparison with the extracardiac conduit Fontan.

BACKGROUND: The Fontan procedure performed with an extracardiac conduit (ECC) has gained wide acceptance as an alternative to the intracardiac lateral tunnel because it avoids placement of extensive atrial suture lines and use of prosthetic material in the systemic circulation. The extracardiac lateral tunnel (ELT) is a modification of the Fontan procedure which uses pericardium and the external surface of the atrium to create a conduit from the inferior vena cava to the pulmonary artery. This surgery theoretically avoids disruption of intra-atrial conduction by eschewing endocardial suturing while maintaining conduit growth potential and the ability to easily create a fenestration to the systemic circulation. METHODS: We retrospectively analyzed the short-term outcome of 96 consecutive patients who underwent an extracardiac Fontan procedure. An ELT using bovine pericardium was performed in 59 patients, whereas 37 patients received a traditional ECC. RESULTS: The 2 groups were similar with respect to age (P = .96), body surface area (P = .54), number of preoperative Fontan risk factors (P = .43), and ventricular morphology (P = .72). There were no significant differences in the following outcome variables between the ELT and the traditional ECC: length of hospitalization (P = .73), duration of chest tube drainage (P = .48), abnormal rhythm at time of discharge (P = .27), and mortality (P = .63). CONCLUSIONS: The ELT Fontan can be performed with a low risk of mortality and complications. The results are equivalent to the traditional ECC procedure. The theoretical advantages of the procedure suggest that it should be considered a useful modification of Fontan surgery.

Chloral hydrate sedation for pediatric echocardiography: physiologic responses, adverse events, and risk factors.

OBJECTIVE: The physiologic responses to chloral hydrate sedation in the setting of a pediatric echocardiography laboratory have not been well documented; neither has the population at risk been identified adequately. The purpose of this study was to describe the physiologic responses to chloral hydrate sedation, to report the occurrence of adverse events, and to identify any risk factors that predicted these adverse events in children who underwent sedation for echocardiography at our institution. METHODS: We analyzed retrospectively 1095 patients who were sedated for echocardiography. Vital signs and oxygen saturations were recorded every 5 minutes, and adverse events were noted. Potential risk factors for sedation-related adverse events were analyzed. RESULTS: Thirty-eight percent of patients were classified as American Society of Anesthesiologists class 3 or 4, reflecting the significant comorbidity in the study population. Hemodynamic responses to chloral hydrate sedation included > or = 20% decreases in heart rate (24% of the patients) and blood pressure (59% of the patients). There were no deaths or permanent morbidity. Adverse events occurred in 10.8% of patients and included apnea (n = 3 [0.3%]), airway obstruction (n = 15 [1.4%]), hypoxia (n = 65 [5.9%]), hypercarbia (n = 40 of 603 [6.6%]), hypotension with poor perfusion (n = 4 [0.4%]), vomiting (n = 4 [0.4%]), and prolonged sedation (n = 36 [3.3%]). No intervention was required in 92.5%, minor interventions were necessary in 7%, and major interventions were required in 0.5% of all patients. Multivariate analysis identified only age younger than 6 months as a predictor for adverse events, whereas cyanosis, hospitalization, American Society of Anesthesiologists class, fasting time, oxygen requirement, and use of additional sedation were not predictors. CONCLUSIONS: Moderate decreases in heart rate and blood pressure, in the absence of clinical deterioration, are expected responses to chloral hydrate sedation in this pediatric population. The majority of adverse events were minor, and major events were uncommon. Infants who were younger than 6 months were found to be at higher risk for serious adverse events.

Intravenous amiodarone for incessant tachyarrhythmias in children: a randomized, double-blind, antiarrhythmic drug trial.

BACKGROUND: Intravenous (IV) amiodarone has proven efficacy in adults. However, its use in children is based on limited retrospective data. METHODS AND RESULTS: A double-blind, randomized, multicenter, dose-response study of the safety and efficacy of IV amiodarone was conducted in 61 children (30 days to 14.9 years; median, 1.6 years). Children with incessant tachyarrhythmias (supraventricular arrhythmias [n=26], junctional ectopic tachycardia [JET, n=31], or ventricular arrhythmias [n=4]) were randomized to 1 of 3 dosing regimens (low, medium, or high: load plus 47-hour maintenance) with up to 5 open-label rescue doses. The primary efficacy end point was time to success. Of 229 patients screened, 61 were enrolled during 13 months by 27 of 48 centers in 7 countries. Median time to success was significantly related to dose (28.2, 2.6, and 2.1 hours for the low-, medium-, and high-dose groups, respectively; P=0.028). There was no significant association with dose for any arrhythmia subgroup, including JET, but the subgroups were too small for an accurate assessment. Adverse events (AEs) were common (87%), leading to withdrawal of 10 patients. There were 5 deaths in the 30-day follow-up period (2 possibly related to the study drug). Dose-related AEs included hypotension (36%), vomiting (20%), bradycardia (20%), atrioventricular block (15%) and nausea (10%). CONCLUSIONS: In children, the overall efficacy of IV amiodarone, as measured by time to success, was dose related but not significantly for any arrhythmia subgroup. AEs were common and appeared to be dose related. Although efficacious for critically ill patients, the dose-related risks of IV amiodarone should be taken into account when treating children with incessant arrhythmias. Prospective, placebo-controlled trials would be helpful in assessing antiarrhythmic drug efficacy in children, because their results may differ from retrospective series and adult studies.

Echocardiographic characteristics of perimembranous ventricular septal defects associated with aortic regurgitation.

Development of aortic regurgitation (AR) can complicate an isolated perimembranous ventricular septal defect (VSD). The objective of this study was to identify echocardiographic features of perimembranous VSDs associated with AR. Echocardiograms were evaluated for the presence of aortic cusp override, aortic cusp movement abnormality, and presence of color flow mapping across the ventricular septum in a standard, parasternal long-axis view. Echocardiograms of 26 patients with isolated VSDs were included in the study, 13 had AR and 13 had no evidence of AR. Aortic cusp override in the apical 5-chamber and subcostal coronal views were correlated with the presence of AR, with high sensitivity and low specificity. Flow across the septum in the parasternal long-axis view was associated with AR, with moderate sensitivity and specificity. Aortic cusp movement abnormalities had high sensitivity and low specificity. Our data indicate that these findings may identify patients with perimembranous VSD susceptible to AR.

Sedation for pediatric echocardiography: evaluation of preprocedure fasting guidelines.

In an effort to increase the safety of sedated procedures, there is a recent trend to increase preprocedure fasting times. However, optimal fasting times have never been established for a sedated echocardiogram. We retrospectively analyzed 334 patients divided into 2 groups. Group 1 (140 patients) had fasting times less than 2 hours, whereas group 2 (184 patients) had fasting times more than 2 hours. When the entire population was considered, there was no difference in efficacy between the 2 groups (P =.08). However, in patients younger than 6 months, group 2 had decreased efficacy compared with group 1 (P =.03). There were no major complications in either group. There was no difference in the rate of minor complications between the 2 groups. Our study concludes that longer fasting times are less efficacious in children younger than 6 months, and do not improve safety.

Assessment of cardiac function in adolescents with Duchenne muscular dystrophy: importance of neurohormones.

Initial signs of cardiac dysfunction caused by Duchenne muscular dystrophy are usually detected during adolescence. However, decreased physical activity can allow better tolerance of decreased cardiac function. Mild myocardial dysfunction secondary to ischemic or idiopathic cardiomyopathy is accompanied by elevation of plasma levels of norepinephrine and atrial natriuretic factor. This is considered an adaptation to maintain adequate perfusion. We evaluated neurohormone levels in 17 adolescents (median age 14 years) with Duchenne muscular dystrophy and different degrees of ventricular dysfunction determined by echocardiography. All patients were asymptomatic. Electrocardiographic abnormalities were present in 14 of 17 (82%). Shortening fraction was below normal in 9 of 17 (53%). Norepinephrine plasma levels were elevated in 3, and all had normal atrial natriuretic factor levels. There was no association between fractional shortening and norepinephrine plasma level (P = .66). The majority of younger adolescents with Duchenne muscular dystrophy and abnormal ventricular function do not show signs of inadequate perfusion, as evidenced by normal measurements of neurohormones.

Fenestration improves clinical outcome of the fontan procedure: a prospective, randomized study.

BACKGROUND: The Fontan procedure is the definitive operation for palliation of complex congenital heart disease with single-ventricle physiology. Fenestration of the Fontan circuit allows for shunting of deoxygenated blood to the systemic circulation. This procedure improved the clinical outcomes of patients who are at high risk for poor Fontan results. However, it is controversial whether fenestration is beneficial for standard-risk patients. METHODS AND RESULTS: This prospective, randomized trial evaluated the clinical utility of fenestration in patients with standard preoperative risk profiles for Fontan surgery. Forty-nine consecutive patients were assigned to undergo either a fenestrated (25 patients) or nonfenestrated (24 patients) Fontan procedure. The fenestrated and nonfenestrated groups were comparable with respect to age (P=0.944), body surface area (P=0.250), number of preoperative risk factors for poor outcome (P=0.681), cardiopulmonary bypass time (P=0.302), number of patients who required aortic cross-clamping (P=0.240), preoperative oxygen saturation (P=0.101), and number of patients with dominant left ventricular morphology (P=0.534). Patients in the fenestrated group had 55% less total chest tube drainage (P=0.036), 41% shorter total hospitalization (P=0.018), and 67% fewer additional procedures in the postoperative period (P=0.006) than those in the nonfenestrated group. CONCLUSIONS: Baffle fenestration performed at the time of Fontan surgery improves short-term outcome in standard-risk patients by decreasing pleural drainage, hospital length of stay, and need for additional postoperative procedures.