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Biomedical subjects

Charles I Berul

Publications and source records attributed to Charles I Berul.

At least 19 recordsLinked to original sources
PubMed2007

Electrophysiological interventions for treatment of congestive heart failure in pediatrics and congenital heart disease.

Heart failure therapy, while well tested in the adult population, therapeutic interventions are less well defined in the pediatric population. Several treatment strategies are available for the adult patient with heart failure, thought few of these therapies have been proven in children. Morbidity and mortality in the pediatric population with a failing heart is significant, and rhythm management as well as strategies to improve hemodynamics are important in the care of these children. This review will address issues of rhythm management and resynchronization therapy in pediatric and congenital heart disease patients with heart failure.

Adrenergic beta-Antagonists↗
PubMed2006

The Jervell and Lange-Nielsen syndrome: natural history, molecular basis, and clinical outcome.

BACKGROUND: Data on the Jervell and Lange-Nielsen syndrome (J-LN), the long-QT syndrome (LQTS) variant associated with deafness and caused by homozygous or compound heterozygous mutations on the KCNQ1 or on the KCNE1 genes encoding the I(Ks) current, are still based largely on case reports. METHODS AND RESULTS: We analyzed data from 186 J-LN patients obtained from the literature (31%) and from individual physicians (69%). Most patients (86%) had cardiac events, and 50% were already symptomatic by age 3. Their QTc was markedly prolonged (557+/-65 ms). Most of the arrhythmic events (95%) were triggered by emotions or exercise. Females are at lower risk for cardiac arrest and sudden death (CA/SD) (hazard ratio, 0.54; 95% CI, 0.34 to 0.88; P=0.01). A QTc >550 ms and history of syncope during the first year of life are independent predictors of subsequent CA/SD. Most mutations (90.5%) are on the KCNQ1 gene; mutations on the KCNE1 gene are associated with a more benign course. beta-Blockers have only partial efficacy; 51% of the patients had events despite therapy and 27% had CA/SD. CONCLUSIONS: J-LN syndrome is a most severe variant of LQTS, with a very early onset and major QTc prolongation, and in which beta-blockers have limited efficacy. Subgroups at relatively lower risk for CA/SD are identifiable and include females, patients with a QTc < or =550 ms, those without events in the first year of life, and those with mutations on KCNE1. Early therapy with implanted cardioverter/defibrillators must be considered.

Adolescent↗
PubMed2006

Cryoablation for accessory pathways located near normal conduction tissues or within the coronary venous system in children and young adults.

BACKGROUND: Cryoablation may offer advantages over radiofrequency (RF) ablation for certain arrhythmia substrates, such as septal accessory pathways (APs). Data for young patients, especially regarding recurrence risk, require expansion. OBJECTIVES: The purpose of this study was to study institutional outcomes for cryoablation of APs located in potentially difficult septal regions for children and young adults. METHODS: Cryoablation was attempted in 35 young patients (mean age 15.6 years) with 37 APs that were either close to normal conduction tissues or inside the coronary venous system. Outcomes were compared with previously published institutional data for RF ablation at these same locations. RESULTS: Acute cryoablation success was achieved for 29 (78%) of 37 APs. Apart from permanent PR prolongation in one case and right bundle branch block in one other, there were no detrimental effects on normal conduction. At median follow-up of 207 days (range 2-695 days), AP conduction recurred for 13 (45%) of 29 ablated APs. Younger patient age and midseptal AP location correlated with higher likelihood of recurrence. Acute success rates for cryoablation were similar to RF ablation in our laboratory, but recurrence rates were significantly higher (P <.001). CONCLUSION: Cryoablation yields acute success rates comparable with RF ablation for difficult septal APs in young patients. The risk of AP recurrence appears higher after cryoablation, although safety benefits may provide suitable compensation for this deficiency. Methods for creating more effective cryoablation lesions need to be explored.

Adolescent↗
PubMed2006

Transient prolonged corrected QT interval in Lyme disease.

Lyme disease, caused by the spirochete Borrelia burgdorferi, has known cardiovascular effects typically manifesting in varying degrees of atrioventricular block. Three patients presented with QT interval prolongation associated with Lyme disease, a previously unreported manifestation of Lyme carditis. Implications and a proposed clinical management approach are discussed.

Adolescent↗
PubMed2006

Microvolt t-wave alternans with exercise in pediatrics and congenital heart disease: limitations and predictive value.

BACKGROUND: Microvolt t-wave alternans (TWA) in early exercise is a noninvasive marker of life-threatening ventricular arrhythmia in some adult cardiac populations. The incidence and potential significance of sustained TWA in pediatric and congenital heart disease (CHD) populations has not been well defined. METHODS: TWA treadmill exercise studies in pediatric patients with CHD, myopathy, potential myocardial ischemia, syncope, or history of cardiac arrest were analyzed. Tests were categorized as abnormal for sustained TWA with onset heart rate < 130 beats/min with specific analyses for lower onset heart rates. Patient characteristics were analyzed as possible correlates of TWA. RESULTS: Over 2 years, 318 consecutive TWA exercise studies were performed in 304 patients (60% male, median 14 years, 6-41) for indications of syncope, cardiac arrest, possible ventricular arrhythmia, or evaluation of functional myocardial perfusion. Underlying conditions included apparently normal hearts (45%), CHD (16%), cardiomyopathy (11%), coronary anomalies (11%), electrical myopathy (9%), and transplant (8%). Abnormal TWA was seen in 24 (7%, onset HR 106 +/- 18) and included 19 at high clinical risk for serious events including 3 with cardiac arrest. By multivariate analysis sustained TWA was associated with cardiac arrest, ventricular arrhythmias, and a clinical classification of high risk. CONCLUSIONS: TWA is associated with pediatric and CHD diagnoses at high risk of serious events and may contribute, with other diagnostic tools, to management choices. While the absence of TWA has relatively high negative predictive value, it does not completely exclude the potential for serious sustained ventricular arrhythmias. A more robust noninvasive marker for risk stratification in these populations is required.

Adolescent↗
PubMed2006

Ablation of nonautomatic focal atrial tachycardia in children and adults with congenital heart disease.

INTRODUCTION: Nonautomatic focal atrial tachycardia (NAFAT) has been characterized in adults with structurally normal hearts. This article characterizes NAFAT in a population of patients with complex congenital heart disease. METHODS AND RESULTS: Electrophysiologic and electroanatomic mapping data and acute outcomes were reviewed in patients undergoing mapping and ablative procedures for atrial tachycardia at Children's Hospital, Boston, between January 1999 and December 2003. Twenty-two NAFAT foci were identified in 17 patients out of 216 patients studied. Fourteen of these 17 patients had congenital heart disease. The average age of the patients with a NAFAT mechanism was 27 years and there was no gender predilection. The presumptive diagnosis based on clinical grounds and surface ECG assessment in 11 of 17 patients with NAFAT was atrial flutter. None of the 17 patients were suspected of having a NAFAT mechanism by noninvasive assessment. Four of the 10 patients had both NAFAT and macroreentrant atrial tachycardias. NAFAT cycle lengths varied widely (200-680 ms) between patients. Sixteen of the 22 NAFAT foci were mapped to the anatomic right atrium (RA). Acute ablative success was achieved in 17 out of 22 foci (77%). CONCLUSION: NAFAT is relatively uncommon in a pediatric tertiary care setting, and in that setting occurs most often in adults with congenital heart disease. NAFAT is indistinguishable from other forms of atrial tachycardia by noninvasive means and can mimic other forms of atrial tachycardia on electrocardiogram. The foci were predominantly found in the RA and were, in most cases, acutely amenable to catheter ablation therapy.

Adolescent↗
PubMed2006

Inherited conduction system abnormalities--one group of diseases, many genes.

The cardiac conduction system can be anatomically, developmentally, and molecularly distinguished from the working myocardium. Abnormalities in cardiac conduction can occur due to a variety of factors, including developmental and congenital defects, acquired injury or ischemia of portions of the conduction system, or less commonly due to inherited diseases that alter cardiac conduction system function. So called "idiopathic" conduction system degeneration may have familial clustering, and therefore is consistent with a hereditary basis. This "Molecular Perspectives" will highlight several diverse mechanisms of isolated conduction system disease as well as conduction system degeneration associated with other cardiac and non-cardiac disorders. The first part of this review focuses on channelopathies associated with conduction system disease. Human genetic studies have identified mutations in the sodium channel SCN5A gene causing tachyarrhythmia disorders, as well as progressive cardiac conduction system diseases, or overlapping syndromes. Next, the importance of embryonic developmental genes such as homeobox and T-box transcription factors are highlighted in conduction system development and function. Conduction system diseases associated with multisystem disorders, such as muscular and myotonic dystrophies, will be described. Last, a new glycogen storage cardiomyopathy associated with ventricular preexcitation and progressive conduction system degeneration will be reviewed. There are a myriad of mutations identified in genes encoding cardiac transcription factors, ion channels, gap junctions, energy metabolism regulators, lamins and other structural proteins. Understanding of the molecular and ionic mechanisms underlying cardiac conduction is essential for the appreciation of the pathogenesis of conduction abnormalities in structurally normal and altered hearts.

Arrhythmias, Cardiac↗
PubMed2006

Inaccuracy of Wolff-Parkinson-white accessory pathway localization algorithms in children and patients with congenital heart defects.

INTRODUCTION: ECG algorithms used to localize accessory pathways (AP) in patients with Wolff-Parkinson-White (WPW) syndrome have been validated in adults, but less is known of their use in children, especially in patients with congenital heart disease (CHD). We hypothesize that these algorithms have low diagnostic accuracy in children and even lower in those with CHD. METHODS: Pre-excited ECGs in 43 patients with WPW and CHD (median age 5.4 years [0.9-32 years]) were evaluated and compared to 43 consecutive WPW control patients without CHD (median age 14.5 years [1.8-18 years]). Two blinded observers predicted AP location using 2 adult and 1 pediatric WPW algorithms, and a third blinded observer served as a tiebreaker. Predicted locations were compared with ablation-verified AP location to identify (a) exact match for AP location and (b) match for laterality (left-sided vs right-sided AP). RESULTS: In control children, adult algorithms were accurate in only 56% and 60%, while the pediatric algorithm was correct in 77%. In 19 patients with Ebstein's anomaly, diagnostic accuracy was similar to controls with at times an even better ability to predict laterality. In non-Ebstein's CHD, however, the algorithms were markedly worse (29% for the adult algorithms and 42% for the pediatric algorithms). A relatively large degree of interobserver variability was seen (kappa values from 0.30 to 0.58). CONCLUSIONS: Adult localization algorithms have poor diagnostic accuracy in young patients with and without CHD. Both adult and pediatric algorithms are particularly misleading in non-Ebstein's CHD patients and should be interpreted with caution.

Adolescent↗
PubMed2006

Age, size, and lead factors alone do not predict venous obstruction in children and young adults with transvenous lead systems.

BACKGROUND: Venous occlusion is a recognized complication of transvenous pacing, and lead cross-sectional area indexed to body surface area (BSA) has been used to predict venous obstruction in children. OBJECTIVE: The aim of this study was to identify the risk factors and incidence of angiographic venous obstruction after transvenous lead implantation in both children and young adults. METHODS: Contrast venography was obtained in 85 of 90 consecutive patients undergoing repeat pacemaker or ICD procedures from 2002 to 2004 at a single cardiac center. Venograms were graded as complete venous obstruction, significant partial obstruction (>70% with collaterals), or patent. RESULTS: The cohort had a median age of 15.0 years at implant and was divided into two age groups: 3-12 years (n = 35) and 13 years and over (n = 50). After a median interval of 6.5 years, complete obstruction was seen in 11 of 85 patients (13%) and partial obstruction in another 10 patients (12%). No significant differences were seen in the incidence of obstruction between the two age groups although younger patients had a larger lead indexed to BSA ratio (6.82 vs 5.05, P = 0.005). There were no significant differences between obstructed and nonobstructed patients in relation to age, size, growth, or lead factors. CONCLUSION: Transvenous lead systems implanted in young children have a similar incidence of venous occlusion compared to older patients. Furthermore, patient age, body size, and lead characteristics at implant do not clearly predict venous occlusion.

Adolescent↗
PubMed2005

Somatic events modify hypertrophic cardiomyopathy pathology and link hypertrophy to arrhythmia.

Sarcomere protein gene mutations cause hypertrophic cardiomyopathy (HCM), a disease with distinctive histopathology and increased susceptibility to cardiac arrhythmias and risk for sudden death. Myocyte disarray (disorganized cell-cell contact) and cardiac fibrosis, the prototypic but protean features of HCM histopathology, are presumed triggers for ventricular arrhythmias that precipitate sudden death events. To assess relationships between arrhythmias and HCM pathology without confounding human variables, such as genetic heterogeneity of disease-causing mutations, background genotypes, and lifestyles, we studied cardiac electrophysiology, hypertrophy, and histopathology in mice engineered to carry an HCM mutation. Both genetically outbred and inbred HCM mice had variable susceptibility to arrhythmias, differences in ventricular hypertrophy, and variable amounts and distribution of histopathology. Among inbred HCM mice, neither the extent nor location of myocyte disarray or cardiac fibrosis correlated with ex vivo signal conduction properties or in vivo electrophysiologically stimulated arrhythmias. In contrast, the amount of ventricular hypertrophy was significantly associated with increased arrhythmia susceptibility. These data demonstrate that distinct somatic events contribute to variable HCM pathology and that cardiac hypertrophy, more than fibrosis or disarray, correlates with arrhythmic risk. We suggest that a shared pathway triggered by sarcomere gene mutations links cardiac hypertrophy and arrhythmias in HCM.

Animals↗
PubMed2005

Increased alpha2 subunit-associated AMPK activity and PRKAG2 cardiomyopathy.

BACKGROUND: AMP-activated protein kinase (AMPK) regulatory gamma2 subunit (PRKAG2) mutations cause a human cardiomyopathy with cardiac hypertrophy, preexcitation, and glycogen deposition. PRKAG2 cardiomyopathy is recapitulated in transgenic mice overexpressing mutant PRKAG2 N488I in the heart (TGgamma2N488I). AMPK is a heterotrimeric kinase consisting of 1 catalytic (alpha) and 2 regulatory (beta and gamma) subunits. Two alpha-subunit isoforms, alpha1 and alpha2, are expressed in the heart; however, the contribution of AMPK utilization of these subunits to PRKAG2 cardiomyopathy is unknown. Mice overexpressing a dominant-negative alpha2 subunit of AMPK (TGalpha2DN) provide a tool for selectively inhibiting alpha2, but not alpha1, subunit-associated AMPK activity. METHODS AND RESULTS: In compound-heterozygous TGgamma2N488I/TGalpha2DN mice, AMPK activity associated with alpha2 but not alpha1 was decreased compared with TGgamma2N488I. The TGalpha2DN transgene reduced the disease phenotype of TGgamma2N488I, partially or completely normalizing the ECG, cardiac function, cardiac morphology, and exercise capacity in compound-heterozygous mice. TGgamma2N488I hearts had normal resting levels of high-energy phosphates and could improve cardiac performance during exercise. Cardiac glycogen content decreased in TGgamma2N488I mice after exercise stress, indicating availability of the stored glycogen for metabolic utilization. No differences in glycogen-metabolizing enzymes were observed. CONCLUSIONS: The PRKAG2 N488I mutation causes inappropriate AMPK activation, which leads to glycogen accumulation and conduction system disease. The accumulated glycogen can serve as an energy source, and the animals have contractile reserve during exercise. Because the dominant-negative alpha2 subunit attenuates the mutant PRKAG2 phenotype, AMPK complexes containing the alpha2 rather than the alpha1 subunit are the primary mediators of the effects of PRKAG2 mutations.

AMP-Activated Protein Kinase Kinases↗
PubMed2005

Functional role of AMP-activated protein kinase in the heart during exercise.

AMP-activated protein kinase (AMPK) plays a critical role in maintaining energy homeostasis and cardiac function during ischemia in the heart. However, the functional role of AMPK in the heart during exercise is unknown. We examined whether acute exercise increases AMPK activity in mouse hearts and determined the significance of these increases by studying transgenic (TG) mice expressing a cardiac-specific dominant-negative (inactivating) AMPKalpha2 subunit. Exercise increased cardiac AMPKalpha2 activity in the wild type mice but not in TG. We found that inactivation of AMPK did not result in abnormal ATP and glycogen consumption during exercise, cardiac function assessed by heart rhythm telemetry and stress echocardiography, or in maximal exercise capacity.

AMP-Activated Protein Kinases↗
PubMed2005

Comparison of modern steroid-eluting epicardial and thin transvenous pacemaker leads in pediatric and congenital heart disease patients.

OBJECTIVE: Optimal pacemaker lead choice in pediatric patients eligible for either epicardial or transvenous leads remains unclear. We compared performances of modern thin transvenous (TTV) and steroid-eluting epicardial (SEE) leads in patients followed at one pediatric center. METHODS: Retrospective review of patients with qualifying leads implanted from August 1997 to March 2004. Threshold energy (TE) at implant and follow-up, sensing thresholds, lead complications, and repeat pacing-related procedures were analyzed. Lead performances were compared using t-tests, Wilcoxon rank-sum tests and Cox regression. Survival curves were plotted using Kaplan-Meier analysis. RESULTS: A total of 370 implant procedures, 521 leads, and 1549 visits were evaluated. In all, 256 leads were SEE (49%, 184 implants) and 265 were TTV (51%, 186 implants). Median follow-up was 29 months (range 1-80 months). Patients with SEE systems were younger at implant (6 vs. 17 yrs, p < 0.001), and more had congenital heart defects (82% vs. 57%, p < 0.001). At follow-up, ventricular TEs were higher for SEE leads at implant (p < 0.001), 1 month (p < 0.001), and up to 4 years (p = 0.019). When compared across all follow-up durations combined, TTV TEs were significantly lower than SEE TEs for both atrial and ventricular leads (p < 0.001). A total of 70 repeat procedures were performed in 60 patients during the study period, which comprised 18% of SEE and 14% of TTV system patients (p = NS). In all, 18 TTV and 19 SEE leads failed (p = NS). Estimated freedom from lead failure at 1, 3, and 5 years was 97%, 88%, 85% for TTV leads and 96%, 92%, and 58% for SEE leads (log rank P = NS). CONCLUSIONS: Both SEE and TTV leads showed good mid-term performance and survival in our cohort. Higher TEs seen for SEE leads, especially ventricular and unipolar leads, may result in higher current drain and thus more generator replacements than TTV systems. Lead failure rates were comparable across lead types. TTV leads offer a promising alternative to SEE systems in terms of performance for young patients without intracardiac shunting who do not require open-chest surgery for another indication.

Adolescent↗
PubMed2005

Prospective trial of electroanatomically guided, irrigated catheter ablation of atrial tachycardia in patients with congenital heart disease.

BACKGROUND: Ablation success rates reported for atrial tachycardia (AT) patients with congenital heart disease (CHD) is lower than the rates reported for other varieties of supraventricular tachycardia. Retrospective studies suggest these rates might be increased by the use of irrigated radiofrequency (RF) ablation. OBJECTIVES: The purpose of this study was to determine whether irrigated RF ablation increases ablation success rates in patients with CHD and AT. METHODS: Patients were studied in a prospective, randomized, nonblinded manner. The operator was limited to use of randomized therapy (standard or irrigated ablation) for the first 6 minutes of RF application to each targeted arrhythmia. Lesion characteristics were recorded, and acute ablation success was ascertained. Structured clinical follow-up was performed over a 6-month period. RESULTS: Forty-seven ATs were targeted in 26 patients; 72% of these ATs were ablated. Within the 6-minute randomization period, no difference in success rates of standard and irrigated catheters was noted. However, crossover from standard to irrigated ablation more likely was successful than vice versa (irrigated: 8 successes/8 attempts vs standard: 1 success/4 attempts, P = .018), and overall success was greater using irrigated catheters (66% vs 33%, P = .019). Mean delivered power was slightly higher in irrigated lesions (32.5 W vs 30.2 W, P = .025), and mean temperature was much lower (33.5 degrees C vs 59.3 degrees C, P < .001). A composite AT intensity score was significantly reduced compared with preablation values at 6-month follow-up of all patients. CONCLUSIONS: Ablation of ATs in patients with CHD results in symptomatic improvement over short-term follow-up. Irrigated ablation may result in higher acute success rates in these patients.

Adolescent↗
PubMed2005

Cost-effectiveness analysis of genetic testing for familial long QT syndrome in symptomatic index cases.

BACKGROUND: Genetic testing for long QT syndrome (LQTS) has been available in a research setting for the past decade, and a commercial test has recently become available. However, the costs and effectiveness of genetic testing have not been estimated. OBJECTIVES: The purpose of this study was to conduct a cost-effectiveness analysis of genetic testing in the management of patients who have or are suspected to have familial LQTS. METHODS: We examined the incremental cost-effectiveness of genetic testing compared with no genetic testing for symptomatic index cases and how this varied according to changes in assumptions and data inputs. Data were obtained from the published literature and a clinical cohort. RESULTS: We found that genetic testing is more cost-effective than not testing for symptomatic index cases at an estimated cost of 2,500 US dollar per year of life saved. These results were generally robust, although they were sensitive to some data inputs such as the cost of testing and the mortality rate among untreated individuals with LQTS. CONCLUSION: A genetic test for familial LQTS is cost-effective relative to no testing, given our assumptions about the population to be tested and the relevant probabilities and costs. The primary benefit of testing is to more accurately diagnose and treat individuals based on a combination of clinical scores and test results. Future economic analyses of testing for familial LQTS should consider the potential benefits of genetic testing of broader populations, including family members.

Adolescent↗
PubMed2005

Absence of Msx2 does not affect cardiac conduction or rescue conduction defects associated with Nkx2-5 mutation.

INTRODUCTION: The transcription factors governing embryonic development of the AV conduction system are largely unknown. Heterozygous mutations of the cardiac transcription factor Nkx2-5 cause AV conduction defects, which are associated with anatomic hypoplasia of the conduction system. In situ expression patterns of Msx2 in the mouse and chick embryonic heart have suggested a developmental function for this transcription factor. Homozygous Nkx2-5 knockout mouse embryos express Msx2 ectopically throughout the myocardium, suggesting Msx2 affects conduction system development through a transcriptional cascade starting with Nkx2-5. Several observations support a model in which Msx2 negatively regulates formation of the conduction system and inappropriate Msx2 up-regulation causes the conduction defects associated with Nkx2-5 mutation. METHODS AND RESULTS: We obtained surface ECGs and performed intracardiac electrophysiologic studies in Msx2 knockout mice and in Nkx2-5 wild-type and heterozygous null mutant mice in an Msx2 null mutant background. Msx2 null mutant mice had normal cardiac conduction and no increased vulnerability to inducible arrhythmia. Absence of Msx2 did not alter the conduction defects observed in heterozygous Nkx2-5 knockout mice. CONCLUSION: Msx2 likely does not contribute to development of the conduction system. Abnormal Msx2 expression likely does not cause the AV conduction defects present in Nkx2-5 knockout mice.

Animals↗