KCNQ1 mutations in patients with a family history of lethal cardiac arrhythmias and sudden death.

Long QT syndrome (LQTS) is the prototype of the cardiac ion channelopathies which cause syncope and sudden death. LQT1, due to mutations of KCNQ1 (KVLQT1), is the most common form. This study describes the genotype-phenotype characteristics in 10 families with mutations of KCNQ1, including 5 novel mutations. One hundred and two families with a history of lethal cardiac events, 55 LQTS, 9 Brugada syndrome, 18 idiopathic ventricular fibrillation (IVF), and 20 acquired LQTS, were studied by single-strand conformational polymorphism (SSCP) and DNA sequence analyzes. Families found to have KCNQ1 mutations were phenotyped using ECG parameters and cardiac event history, and genotype-phenotype correlation was performed. No mutations were found in Brugada syndrome, IVF, or acquired LQTS families. Ten out of 55 LQTS families had KCNQ1 mutations and 62 carriers were identified. Mutations included G269S in domain S5; W305X, G314C, Y315C, and D317N in the pore region; A341E and Q357R in domain S6; and 1338insC, G568A and T587M mutations in the C-terminus. W305X, G314C, Q357R, 1338insC, and G568A, appeared to be novel mutations. Gene carriers were 26 +/- 19 years (32 females). Baseline QTc was 0.47 +/- 0.03 s (range 0.40-0.57 s) and 40% had normal to borderline QTc (< or = 0.46 s). Typical LQT1 T wave patterns were present in at least one affected member of each family, and in 73% of all affected members. A history of cardiac events was present in 19/62 (31%), 18 with syncope, 2 with aborted cardiac arrest (ACA) and six with sudden death (SD). Two out of 6 SDs (33%) occurred as the first symptom. No difference in phenotype was evident in pore vs. non-pore mutations. KCNQ1 mutations were limited to LQTS families. All five novel mutations produced a typical LQT1 phenotype. Findings emphasize (1) reduced penetrance of QTc and symptoms, resulting in diagnostic challenges, (2) the problem of sudden death as the first symptom (33% of those who died), and (3) genetic testing is important for identification of gene carriers with reduced penetrance, in order to provide treatment and to prevent lethal cardiac arrhythmias and sudden death.

Long-term outcomes excellent for atrial septal defect repair in adults.

Congenital atrial septal defect repair is safe and effective in patients of almost any age. Long-term survival among adults is excellent, although children generally appear to fare even better. Our 25-year study of outcomes among adults who underwent suture or patch closure found that survival exceeded 90%. We discuss our observations on use of transesophageal echocardiography, indications for cardiac catheterization, and continuing questions about atrial septal defect in adults.

Outer membrane monolayer domains from two-dimensional surface scanning resistance measurements.

Cellular plasma membranes have domains that are defined, in most cases, by cytoskeletal elements. The outer half of the bilayer may also contain domains that organize glycosylphosphatidylinositol (GPI)-linked proteins. To define outer membrane barriers, we measured the resistive force on membrane bound beads as they were scanned across the plasma membrane of HEPA-OVA cells with optical laser tweezers. Beads were bound by antibodies to fluorescein-phosphatidylethanolamine (Fl-PE) or to the class I major histocompatibility complex (MHC class I) Qa-2 (a GPI-anchored protein). Two-dimensional scans of resistive force showed both occasional, resistive barriers and a velocity-dependent, continuous resistance. At the lowest antibody concentration, which gave specific binding, the continuous friction coefficient of Qa-2 was consistent with that observed by single-particle tracking (SPT) of small gold particles. At high antibody concentrations, the friction coefficient was significantly higher but decreased with increasing temperature, addition of deoxycholic acid, or treatment with heparinase I. Barriers to lateral movement (>3 times the continuous resistance) were consistently observed. Elastic barriers (with elastic constants from 1 to 20 pN/microm and sensitive to cytochalasin D) and small nonelastic barriers (<100 nm) were specifically observed with beads bound to the GPI-linked Qa-2. We suggest that GPI-linked proteins interact with transmembrane proteins when aggregated by antibody-coated beads and the transmembrane proteins encounter cytoplasmic barriers to lateral movement. The barriers to lateral movement are dynamic, discontinuous, and low in density.

Right ventricular arrhythmia in the absence of arrhythmogenic dysplasia: MR imaging of myocardial abnormalities.

PURPOSE: To evaluate right ventricular abnormalities with magnetic resonance (MR) imaging in patients with arrhythmia but without arrhythmogenic dysplasia. MATERIALS AND METHODS: In 53 patients being evaluated for right ventricular arrhythmia and 15 control subjects, MR imaging was performed to evaluate fixed thinning, fatty replacement, or reduced systolic wall thickening or motion. A diagnosis of idiopathic right ventricular outflow tract tachycardia or indeterminate was assigned for each patient, and the severity of arrhythmia was categorized. RESULTS: Right ventricular abnormalities were revealed in 32 (60%) of the 53 patients: fixed thinning in 27 (84%), fatty replacement in eight (25%), and reduced wall thickening or motion in 31 (97%). Right ventricular abnormalities were found in 35 (76%) of 46 patients with idiopathic right ventricular outflow tract tachycardia and in seven (39%) of 18 patients with indeterminate diagnoses (P = .022). CONCLUSION: Mild right ventricular abnormalities are likely sources for arrhythmias, even in the absence of arrhythmogenic right ventricular dysplasia.

Basic laser tweezers.

The basic information has been provided here for designing and building a laser tweezers system for force measurements. If force measurements are not required, then the considerations about the analysis system, a fine piezo stage, and stability are less important. For the initial alignment and characterization of the system, red blood cells provide an easily trapped sample. For a difficult test sample, the smaller latex beads (0.15-0.3 micron in diameter) are stable and easy to obtain. Anyone setting up laser tweezers is encouraged to see a working tweezers system and to compare samples with that system. Everyone has a different background, and there may be aspects critical for you that have not been discussed here. More sophisticated systems are described later in this book.

Bundle branch reentry ventricular tachycardia with two distinct left bundle branch block morphologies.

INTRODUCTION: Bundle branch reentry ventricular tachycardia (VT) is usually amenable to treatment with radiofrequency ablation. Different QRS morphologies during VT are possible when anterograde ventricular activation is over the left bundle branch. Manifestations of this reentrant tachycardia with more than one QRS morphology with anterograde activation via the right bundle have not been reported and would be unusual due to the more discrete anatomy of the right bundle branch. METHODS AND RESULTS: An electrophysiologic study was conducted in a patient with dilated ventricle and diminished ventricular function with VT. Typical characteristics of bundle branch reentry were noted when VT was induced. The study was notable for the presence of a right bundle recording only during macroreentrant beats or VT and the distal location of the recording. Radiofrequency ablation was performed. Postablation stimulation again induced VT, proven to be of the same bundle branch reentry mechanism but of a different QRS morphology. A second ablation was required for complete ablation of this patient's bundle branch reentry VT. CONCLUSION: In bundle branch reentry utilizing the left bundle as the retrograde limb and the right bundle branch as the anterograde limb of the circuit, VT of more than one distinct morphology can be seen. Careful evaluation to assess for the persistence of VT of the same mechanism is necessary to ensure complete ablation of the reentrant circuit. Preexisting right bundle disease and a dilated heart with more dispersed distal right bundle branches may predispose to such a phenomenon.

Isolated noncompaction of the ventricular myocardium.

Isolated noncompaction of the ventricular myocardium is a recently described anomaly. We report the first case of this anomaly presenting as a restrictive cardiomyopathy, and the first association of this entity with endocardial fibrosis.

Improvement in noninvasive electrophysiologic findings in children after transcatheter atrial septal defect closure.

To evaluate whether transcatheter closure of secundum atrial septal defects (ASD) affected noninvasive electrophysiologic variables in children, we reviewed the pre-procedural and 1-year postprocedural electrocardiograms and Holter recordings of 18 consecutive children referred for ASD closure. Patients included in the study were a mean of 5.0 years old (SD 1.1) and weighed a mean of 17.9 kg (SD 4.1). ASDs had a mean diameter of 14.0 mm (SD 2.4) and average shunt ratio (pulmonary-to-systemic flow) of 2.1:1. One year after occluder device placement, 9 children (50%) had detectable residual shunts by transthoracic echocardiograms, but only 2 (11%) had shunts that were felt to be possibly significant. One or more fractured occluder legs were noted by chest roentgenogram in 15 patients (83%). Electrocardiograms at follow-up demonstrated improvement in right ventricular dilation in 4 of 7 patients, right atrial enlargement in 3 of 4 patients, and 1 degree atrioventricular block in 2 of 3 patients. Holter recordings showed a decreased incidence of accelerated atrial rhythm in 3 of 7 patients, prolonged junctional escape rhythm in 2 of 2 patients, and premature atrial contractions in 2 of 2 patients. No finding correlated with patient age, defect or occluder diameter, occluder leg fracture(s), or residual defects. These improvements in electrophysiologic abnormalities compare favorably with changes seen 1 year after surgical closure. In conclusion, placement of a transcatheter ASD device in children diminishes noninvasive electrophysiologic abnormalities at 1-year follow-up. By relieving hemodynamic stress caused by an ASD in childhood, a transcatheter device may prevent arrhythmia disturbance later in life.

A technique for rapid transfemoral catheterization of the coronary sinus with multielectrode catheters.

To minimize procedural and fluoroscopic times and avoid the risks of vascular injury and pneumothorax, some investigators have advocated elimination of routine placement of a coronary sinus (CS) catheter during electrophysiological procedures. We hypothesized that expedient and reproducible CS catheterization could be performed with minimal patient risk by utilizing a femoral vein approach. Fifty consecutive patients referred for radiofrequency ablative procedures underwent attempted CS catheterization using a 6-French steerable, quadripolar catheter via a femoral vein. Procedures were performed utilizing single-plane fluoroscopy without contrast angiographic aid by operators experienced in the technique. Successful catheterization was defined by the attainment, in < 15 minutes, of a stable catheter position with the distal electrode at or beyond the lateral margin of the heart. Successful catheterization of the CS was achieved in 47 (94%) patients. Selective pacing of the left atrium without patient discomfort was possible in all, eliminating the need for a right atrial pacing catheter. The median time to successful catheterization was 1.4 minutes (range 0.3-14.7). Only six patients required > 5 minutes. The median fluoroscopic time required was 1.2 minutes (range 0.3-12.7). No clinical variable was predictive of catheterization failure or time to successful catheterization. No complications were observed as a result of this technique. This prospective evaluation demonstrates that catheterization of the CS via a femoral vein approach is highly successful, expedient, and safe. The ability to selectively pace the left atrium may eliminate the requirement for a right atrial catheter.

Evolving concepts in radiofrequency catheter ablation of atrioventricular nodal reentry tachycardia.

Our results and those of others (Table I) suggest that both anatomic and electrogram (potential) approaches are highly successful in eliminating AVNRT. The use of slow-pathway potentials appears to minimize lesion delivery and to be associated with a very small likelihood of complete AV block. Approaches aimed directly at the midseptum also appear to reduce lesion delivery. It is important, however, to understand that the fast and slow AV-nodal pathways are not always confined to anterosuperior (fast) and posteroinferior (slow) locations (at least as they are determined fluoroscopically). On occasion, the slow pathway may be ablated anteriorly and the fast pathway posteriorly. Our three inadvertent successful fast-pathway ablations support these findings. We prefer to conceptualize the AV node as having three ablation zones. Ablation in the anterosuperior zone most often affects fast-pathway conduction; ablation in the posteroinferior zone most often affects slow pathway conduction; and ablation in the midseptal region predominantly affects slow-pathway conduction. Lesions applied to the midseptum do, however, appear more likely to affect inadvertently the fast (or both) pathway(s), probably because of the anatomic convergence of the posteroinferior and anterosuperior AV-nodal approaches in this region. A preliminary report by Wu et al. supports this three-zone concept. The subsequent larger series reported by this group has raised concern that midseptal approaches may be associated with too great a risk of complete AV block. On the other hand, approaches guided exclusively by potentials may be associated with much longer procedure times. Controversy exists over the acceptable end point for ablation procedures. We have not found it necessary routinely to eliminate dual-nodal conduction to maintain a low (3.2%) overall recurrence rate. Aggressive attempts to eliminate all evidence of slow-pathway conduction must be balanced against the risk of inadvertent complete AV block. In conclusion, cumulative data and our clinical experience with ablation of AVNRT suggest that it is possible to be both pragmatic and highly successful. The key components of our approach are (1) an anatomically based, systematic, time-limited search for potentials; (2) elimination of unnecessary lesions that are too atrial or too ventricular to involve the reentrant circuit; (3) a caudocephalad approach that avoids excessively anterior initial lesions, which may result in inadvertent complete AV block; and (4) avoidance of unnecessary lesions in the most inferoposterior sector, which results in patient discomfort and low clinical efficacy. This approach is safe (with minimal risk of AV block), reproducible, and efficacious.

Memory T waves after radiofrequency catheter ablation of accessory atrioventricular connections in Wolff-Parkinson-White syndrome.

Generalized, extensive electrical repolarization abnormalities, represented by negative or abnormally peaked T waves, are frequently observed after radiofrequency catheter ablation of overt accessory atrioventricular (AV) connections in Wolff-Parkinson-White (WPW) syndrome. Two mechanisms have been proposed to explain these changes: subendocardial injury, secondary to the application of radiofrequency lesions, and memory T waves. The purpose of this study is to evaluate the electrocardiographic (ECG) changes in patients with overt and concealed accessory AV connections after ablation. Fifty-one patients with accessory AV connections who underwent successful radiofrequency ablation were included in the study. Twenty-four patients with clear, manifest, and permanent preexcitation (group 1) were compared with 27 patients with concealed accessory AV connections (group 2). Electrocardiograms were obtained in all patients before ablation, shortly after ablation (within 4 hours), and late after ablation (6 weeks). The frontal and horizontal QRS-T angles in the ECGs, number of lesions, total Joules applied, total peak creatine kinase, and total peak creatine kinase-MB units were compared in both groups. Of the 24 patients with overt accessory AV connections, 23 (95.8%) demonstrated repolarization abnormalities in the ECG shortly after the procedure that reverted almost completely at 6 weeks. Of the 27 patients with concealed accessory AV connections, only 2 (7.4%) demonstrated repolarization abnormalities after the ablation (P < .0001). The persistence of an abnormal QRS-T angle immediately after ablation in patients with overt accessory AV connections is caused by an abnormality in the T wave axis, opposite to the direction of the normal QRS axis.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term follow-up of children after repair of atrial septal defects.

BACKGROUND: It is critical to repair atrial septal defects during childhood to minimize long-term morbidity and mortality. However, only a few studies have examined factors that predict a favorable outcome. OBJECTIVE: To examine prognostic variables in the repair of atrial septal defects. METHODS: Retrospective analysis of children who underwent repair of atrial septal defects between 1957 and 1981. RESULTS: There were 70 girls and 57 boys with a mean age of 9.3 years at the time of surgery (range 4 months to 20 years). The most common presenting symptoms were fatigue and dyspnea. Before surgery, 74% were in New York Heart Association functional class I, 70% had echocardiographic evidence of right ventricular hypertrophy, and 55% had cardiomegaly on chest radiographs. The average mean pulmonary arterial pressure was 17.1 mm Hg. The only factor significantly related to poor outcome was pulmonary hypertension. Age at surgery did not influence long-term results. Ninety-four percent of patients were in functional class I at follow-up. CONCLUSIONS: Repair of atrial septal defects is safe before age 21, but it should be done as early as possible in order to minimize the long-term complications of chronic left-to-right shunting.

Aortic valve replacement in young patients: long-term follow-up.

Thirty-four young patients (28 male and 6 female) underwent aortic valve replacement between 1972 and 1988. Ages ranged from 11 to 20 years (mean 17.7 years). Including reimplantation in the follow-up period, 40 valves were implanted, among which were 17 (43%) St. Jude, 7 (16%) Bjork-Shiley, and 4 (10%) Carpentier-Edwards. Seven patients (18%) had tissue valve prostheses (4 Carpentier-Edwards, 3 Hancock valves). There was one hospital death (2.9%). Follow-up was obtained in 30 of the 33 hospital survivors, with a mean follow-up of 80 months. In the follow-up period, one patient (3%) had a major thromboembolic event and one patient (3%) had prosthetic valve endocarditis. Six patients (18%) required replacement of the implanted valve; three of these had received Hancock tissue valve prostheses. There were three late deaths, yielding 96% survival at 5 years and 84% at 10 years. Twenty-three of 30 survivors are currently New York Heart Association class I. Aortic valve replacement in young patients can be performed with low mortality and morbidity, and with excellent long-term results.

Single-lung transplantation with atrial septal defect repair for Eisenmenger's syndrome.

Heart-lung transplantation has been used successfully for patients with pulmonary vascular disease but its application has been very limited due to the scarcity of donors. We report a patient with Eisenmenger's syndrome who underwent right single-lung transplantation with closure of atrial septal defect; postoperative convalescence was uneventful. Serial magnetic resonance imaging examinations demonstrate improved right heart function.

The value of the autopsy in congenital heart disease.

We reviewed autopsies in 50 consecutive cases of congenital heart disease between 1980 and 1988. Autopsy results were compared to premortem clinical diagnosis. The patients ranged in age from two days to 66.5 years with a mean age of 6.42 years; 68% were less than one year of age. The most common diagnoses were hypoplastic left heart syndrome in 16 (32%) and ventricular septal defect in five (10%). Other common diagnoses included coarctation of the aorta, hypoplastic right heart syndrome, tetralogy of Fallot, transposition of the great vessels and tricuspid atresia. No patient had a missed diagnosis that would have changed survival (Class 1). Four (8%) of the patients had one missed major diagnosis that did not change their survival because they were already being symptomatically treated or because no clinical treatment was available (Class 2). The majority of autopsy derived data were missed minor diagnoses that were related [14 (28%)-Class 3] or unrelated [12 (24%) - Class 4] to the terminal disease process. However, despite the small percentage of autopsy findings that would have directly affected survival, the autopsy provided important additional clinical information in 30 (60%) patients. This information could be used to correct management errors and to develop protocols for prophylaxis against known complications. The pediatric autopsy can provide useful clinical data that may be a guide to altering clinical therapy and is essential in providing genetic counseling.

Transcatheter electrical AV junction ablation: predictors of success.

The initial and long-term results of transcatheter electrical ablation in 29 patients with drug-refractory supraventricular tachyarrhythmias were analyzed. Ablation was immediately successful (defined as induction of chronic complete heart block) in 25 patients (86.2%). Among the group in whom ablation was unsuccessful, there were more patients with ectopic atrial tachycardia and a higher incidence of narrow QRS escape rhythm following the initial ablation. A His amplitude equal to or greater than 0.3 mV was correlated with success. Complications of ablation included deep venous thrombosis and ventricular arrhythmias. Post-ablation stress testing was superior to ambulatory monitoring in identifying early return of atrioventricular conduction.

Long-term follow-up of children with Down syndrome with cardiac lesions.

Two hundred and eighty four patients with Down Syndrome (DS) were seen between 1951-1989. One-hundred and fourteen (40.1%) had a [corrected] cardiac murmur at presentation. A definitive cardiac diagnosis was established in 47 (41%) patients, of which 38 had long term follow-up. Fifteen (33%) patients had atrioventricular canals. There were 21 males and 17 females, with a mean age of 5.3 years. Fifteen (39%) patients were in functional class (FC) I, 16 (42%) in FC II, six (15%) in FC III, and one patient in FC IV at the time of presentation. There were 18 survivors (13 in the surgical group and five in the nonsurgical group) and 20 nonsurvivors (four in the surgical group and 16 in the nonsurgical group). Causes of death in the nonsurgical group included congestive heart failure, pneumonia, and pulmonary vascular disease, and occurred at a mean age of 8.4 years. Post-operative complications accounted for deaths in three of the four surgical patients. The survivors in the surgical group are presently in FC I/II. In the nonsurgical group, there was increased mortality, especially in those who presented in an earlier era, and a deterioration in functional class on follow-up due to the development of pulmonary vascular disease. Our data suggest that a) patients with Down syndrome and heart disease are helped by cardiac surgery with stabilization and improvement of their functional class; b) deterioration in functional class is seen in patients with Down syndrome with cardiac lesions who are managed nonsurgically [corrected] and c) mortality remains high in such patients treated nonsurgically due to development of pulmonary vascular disease and congestive heart failure.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiomyopathy and the use of implanted cardio-defibrillators in children.

Children and adults with cardiomyopathy and ventricular dysrhythmias have a uniformly poor prognosis, despite medical therapy. The use of automatic implantable cardio-defibrillators in adult patients with medically resistant ventricular dysrhythmias has resulted in a positive impact on survival. Because of its size and former lack of programmability, the device has been used rarely in children. Four patients with cardiomyopathy, in whom refractory ventricular dysrhythmias were managed with automatic implantable cardio-defibrillators, are presented. Two of these children are the youngest and smallest known in whom the device has been used; one of them received the first programmable model. The use of the automatic implantable cardio-defibrillator may enhance survival in selected young patients.