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We report on our experience with transhepatic access for catheter interventions in six children (age range 2.5 months-9 years). Three had systemic venous anomalies, and one infant a femoral venous occlusion. In two further patients with bradyarrhythmia after a Fontan operation with an intraatrial Gore-Tex tunnel, transhepatic access was chosen to achieve a perpendicular orientation of the transseptal needle to the atrial baffle, allowing puncture of the Gore-Tex membrane. Two of the patients underwent ablation of an accessory pathway; in one an atrial septal defect was closed. A 2.5 month old baby after Norwood I operation, underwent balloon dilation of the pulmonary arteries. Two patients after prior Fontan surgery underwent DDDR pacemaker implantation. The size of the introducer sheath ranged from 4 F up to two 9 F introducers in the same vein for pacemaker insertion. At the end of the procedure, hemostasis was achieved by external compression.Transhepatic access could be established in all six patients (using a mirror image approach in children with left atrial isomerism) and the interventional procedures could be performed as planned. In one patient with implantation of a permanent pacemaker, a subcutaneous hematoma occurred, requiring blood transfusion.In selected pediatric patients, transhepatic access for catheter intervention can easily be achieved.

Microelectrode arrays enable to map extracellular field potentials of excitable organs (eg, cardiac tissue) in an electrocardiogram-like manner: They allow to detect (a) rhythmicity, (b) the origin and route of excitation, (c) repolarization, and (d) conduction in heart tissue in short- and long-term experimental approaches. Using it as a screening tool for potential side effects of drugs, we here provide evidence for d-sotalol-induced delayed repolarization in human embryonic stem (hES) cell-derived cardiomyocytes. Thus, the combination of the microelectrode array system with cardiac clusters derived from hES cells heralds a paradigm shift toward improved pharmaceutical drug safety. However, the mixture of various cell types in hES cell cardiac clusters (eg, atrial, immature and mature ventricular cardiomyocytes) indicates the strong need for improved selectivity of cardiac differentiation protocols using hES cells.

Background: In contrast to isolated cells, the anatomic and functional integrity of tissue slices remains preserved. Aim of the study was to establish the slice technique in embryonic mouse hearts in order to perform physiological and pharmacological investigations of wild-type mice and genetically engineered mouse models of heart disease. Methods: Ventricular slices (thickness: 300 µm) were cut from agar-embedded embryonic mouse hearts (ED 16.5-18.5) with a vibratome. Histology, immunostaining with markers for apoptosis induction, intracellular recordings with sharp electrodes and field potential recordings using microelectrode arrays were performed to assess viability. Results: Slices exhibited normal histology without prominent signs of apoptosis for at least 24 hours. Intracellular recordings revealed the typical electrophysiological fingerprint of ventricular cardiomyocytes. Field potential recordings proved that adrenergic and muscarinic signaling was preserved. Conclusion: Functionally intact heart slices can be generated from murine embryos.

Background The 12-lead electrocardiogram demonstrates noninvasively many details concerning cardiac arrhythmias and their mechanism, but only for a limited period. A Holter system can record heart rhythm for a longer period, but shows 2 or 3 leads only. An ambulatory 12-lead Holter recording system combines the advantages of both. We report on our experience with the 12-lead Holter system in children. Study Population Twenty-four patients (age range, 3-22 years) underwent one or more 12-lead Holter recordings. Twelve patients had suspected or documented tachyarrhythmia, and 12 patients had suspected or proven long QT syndrome (LQTS). Results In the tachyarrhythmia group, 4 patients had supraventricular tachycardia and 7 ventricular tachycardia (VT). In the supraventricular tachycardia, group 1 patient had intra-atrial reentrant tachycardia with a single reentrant circuit, whereas another had multiple P-wave morphologies, suggesting multiple circuits. Two others had evidence for concealed atrioventricular accessory pathways. One patient had isolated supraventricular ectopy. In the VT group, 4 patients had uniform VT, and 3 patients had polymorphic VT. One patient with LQTS had macroscopic T-wave alternans. Two others showed intermittent extreme QT prolongation and T-wave notching during 12-lead Holter recording. Therapeutic Implications Patients with uniform VT underwent catheter ablation, guided in 2 instances by intracardiac pace mapping and comparison with the 12-lead Holter QRS morphology. All reentrant supraventricular arrhythmias with single P-wave morphology were ablated. One patient with intra-atrial reentrant tachycardia and multiple circuits received an antitachycardia pacemaker. In the LQTS group, the neonate with T-wave alternans received mexiletine in addition to β-blocker therapy. Conclusion In individual patients, the 12-lead Holter system provides important additional information about the arrhythmia and helps to plan appropriate therapy. Intermittent T-wave morphology changes can be diagnosed using 12-lead Holter recordings in patients with LQTS, allowing dynamic T-wave changes to be monitored. In specific cases, this may help identify patients with LQTS and also influence pharmacological therapy.

We occluded a large arterial duct in a patient with atrial fibrillation, using an Amplatzer duct occluder, with no residual shunt at the end of the procedure. Follow-up revealed recanalization, which was successfully treated with a 4 mm Amplatzer ASD occluder. It is speculated the reopening of the initially occluded duct was the consequence of anticoagulation needed because of the atrial fibrillation.

The analysis of the sequential excitation of cardiac tissue is of high relevance, both for clinical pathophysiological purposes, eg, detection of sustained ventricular arrhythmias, as well as for experimental electrophysiology. Clinically, different technical approaches such as single electrode measurements and bipolar mapping electrode catheters have been used. In experimental setups several techniques to record cardiac activity have been proposed. Beside the well-established intracellular current-clamp recordings of action potentials, recent studies have performed extracellularly activation sequence mapping or simultaneous multichannel action potential electrode array measurements. Measurement of extracellularly recorded field potentials (FPs) hereby especially provides detailed information about the origin and spread of excitation in the heart. A similar analytical approach for cardiac FPs advanced the analysis of excitation spread and arrhythmic activity in multicellular preparations like developmental differentiation tissue of mouse embryonic stem cells, multicellular preparations of isolated native embryonic cardiomyocytes or the embryonic heart in toto. The use of substrate-integrated Microelectrode Arrays (MEAs, Multi Channel Systems, Reutlingen, Germany) with 60 electrodes of 10–30 μm diameters on a 100–200 μm grid, coated with porous titanium nitride to minimize the impedance allows recording of FPs at a high signal to noise ratio. The possibility to electrically stimulate the tissue further expands the range of applications and bioassays. It may thus facilitate the evaluation of drug research providing detailed information about the interplay of the complex cardiac network, and might improve the predictability of physiological and pathophysiological conditions or drug effects in embryonic heart tissue.

Both secundum atrial septal defect (ASD) and patent foramen ovale (PFO) have been closed interventionally using several different occluding devices. At a single institution we strived for interventional occlusion of interatrial communications using the Amplatzer device exclusively. During a study period of 22 months, we studied 48 patients ranging in age from 1 to 48 years with an ASD (n = 45) or a PFO (n = 3). Successful implantation of an Amplatzer device was possible in 92% of the patients, and 95% of these patients had a complete early closure of their defect. There were no complications related to the procedure. We conclude that interventional closure of interatrial communications with the Amplatzer device is feasible and safe for selected patients.

Ventricular repolarization continues to be an enigma to clinical cardiologists and cardiac electrophysiologists. On the one hand, a century of experience has documented an association between abnormal T-wave morphology, QT prolongation and dispersion, T-wave alternans, and nonspecific ST-T waves with arrhythmia risk or negative prognostic outcome. On the other hand, recent advances in molecular electrophysiology have definitively implicated abnormal function and structure of cardiac ion channels associated with repolarization as primary arrhythmogenic mechanisms in long QT syndrome, Brugada's Syndrome, and idiopathic ventricular fibrillation and ventricular tachycardia. In spite of this extensive clinical experience and newly established mechanistic knowledge, robust measurements of repolarization and sensitive algorithms for reliable assessment of risk and prediction of arrhythmia occurrence have remained elusive. New insights into electrocardiographic waveform that reflect and capture the underlying spatial and dynamic characteristics of repolarization offer opportunity to devise clinical indices of repolarization that might be more predictive of risk or outcome than those currently used. Experimental and model data show evidence that the location and size of repolarization lesions may be deduced from T waveform. The changes of repolarization induced by altered activation sequence, and cycle length mediated alterations to repolarization offer additional means to assess the magnitude and significance of such lesions that are linked to increased arrhythmogenic risk. This article explores indices of repolarization that are sensitive to repolarization and its change and that provide opportunity to better characterize and assess repolarization for risk stratification.

T-wave alternans (TWA) is a harbinger of ventricular vulnerability and an important prognostic indicator for torsade de pointes and likely sudden death in patients with LQTS. We analyzed the occurrence of TWA in 18 patients with LQTS (7 males, 11 females, ages ranging from 6 months to 32 years--median 8.4 years). Analysis was performed with software to investigate dynamics of cycle length mediated repolarization changes. Digital Holter ECG analysis revealed macroscopic, true TWA in 3 of 18 patients. TWA showed a variable morphological expression. One patient had continuous changes of T wave polarity, but not on a periodic beat-to-beat basis. Onsets of macroscopic TWA were preceded by long/short cycle length sequences and tachycardic rates above 130 to 140 bpm. Impact of ventricular premature beats on TWA onset was insignificant. Two of the identified patients with TWA had sudden cardiac death during follow-up (one refused PM therapy). At present, TWA cannot be detected automatically from Holter ECGs and therefore may be missed, despite the potential danger for the individuals. The observation that predominantly high beat rates and not beat rate changes, per se, triggered episodes of TWA renders difficult general therapeutic recommendations for the identified patients at risk.

Sudden cardiac death (SCD) is one of the major remaining challenges in clinical cardiology. Every year, approximately 300000 people die of sudden cardiac—in most cases, arrhythmic death. Unlike most other diseases, the first clinical manifestation of SCD is often fatal. Therefore, it is of utmost importance to detect patients at risk before their first event. Identification of these patients is most relevant as the implantable defibrillator provides a therapeutic option. The mechanisms that cause ventricular arrhythmias, the main cause of SCD, in hearts with advanced structural heart disease, for example, in patients with advanced cardiomyopathies or survivors of myocardial infarction, are well known, and clinical parameters such as QRS duration or left ventricular ejection fraction can reliably identify such patients. The past decade has identified another potentially large population of patients at risk for SCD due to primary electrical diseases. These patients, who often suffer from monogenic genetic abnormalities, can often be identified by a careful analysis of the surface electrocardiogram (ECG). Abnormal duration and/or shape of the ventricular action potential is one of the main changes associated with such primary electrical diseases: the first, and one of the most prevalent, is the long QTsyndrome. A prolongation of the QT interval (corrected QT interval N0.46) is an established sign of such a risk for proarrhythmia. The genetic causes of the long QT syndrome are mutations in potassium and sodium channels. Recently, the opposite sign, a relevant shortening of the QT interval, has been identified as another marker for SCD (so-called short QT syndrome). This condition is much less frequent than the long QT syndrome and may also be associated with mutations in potassium channels. A corrected QT interval b0.32 is suggestive of the diagnosis. Ventricular preexcitation, identified by a delta wave in the

Prolonged and/or fractionated depolarization due to tissue degeneration of the ventricular myocardium is a feature of cardiomyopathy. Signal averaged electrocardiography uses high-pass filters of the Butterworth type to quantify, noninvasively, fractionated high-frequency components at the end of the QRS complex. In this study a finite impulse response high-pass filter of the 90th order (cutoff at 37 Hz) was applied to magnetocardiograms (MCGs) and high-resolution electrocardiograms (ECGs) order to quantify high-frequency components throughout the myocardial depolarization. Additionally, late-potential analysis on the signal-averaged ECG was performed. A prospective investigation was made of 23 cardiologically asymptomatic patients, 11 females and 12 males, with type I diabetes mellitus. Their mean age was 21.7 years (range, 13-34 years). The mean duration of diabetes was 14 years (range, 1-27 years). Data were compared with those of 22 control subjects (12 females, 10 males) of mean age, 23.2 years (range, 11-35 years). The ECGs and MCGs were simultaneously recorded and signal-averaged, digitally filtered, and quantified by a score obtained by multiplying the amplitude variation of the signal by the number of maximal/minimal in the QRS complex. Echocardiograms were used to calculate the left ventricular mass and to document the presence of cardiomyopathy. Scores were higher in the MCGs of with type I diabetes mellitus than in the control subjects (P < .001). High scores correlated with an increased left ventricular muscular mass index (P < .05) and duration of the diabetes (P < .05). The high-resolution ECG, processed analogously, showed similar results in relation to left ventricular mass (P = .06) and duration of diabetes (P = .07), respectively (nonsignificant). No late potentials were found. These findings suggest that using a linear-phase high-pass finite impulse response filter may be useful for the noninvasive identification of patients with cardiomyopathy who exhibit possible disturbances of intraventricular depolarization. Our findings also suggest that analysis using the total QRS complex, rather than the final part of the QRS complex only, may improve identification of patients at risk.

Signals from 37 magnetocardiographic sensors and simultaneously recorded 32 ECG leads were obtained in three healthy male subjects (including two reinvestigations). After recordings at rest, the heart rate was increased by pharmacologic stress (117 to 142 beats/min). Comparison of the repolarization of rest and stress showed substantial changes in the magnetocardiogram (MCG) up to T wave inversions during stress. In the ECG only junctional ST-T segment shifts were present. For quantification, correlation coefficients between pairs of rest and stress MCG and rest and stress ECG distributions were calculated for the same time instant at the beginning of T wave under rest and stress conditions. In addition, equivalent electrical current dipole moment and magnetic dipole moment vectors were calculated from the MCG, and their change from rest to stress evaluated. Correlation coefficients for MCG comparison ranged from 0.3 to 0.5; ECG comparison suggested much less change from stress, ranging from 0.7 to 1.0. Current dipole moment changes at T wave onset were marginal; in contrast, the magnetic dipole moment changed substantially. Since the magnetic dipole reflects vortex currents, changes in its intensity and/or orientation during repolarization suggest this as the biophysical basis of the striking difference in the response of the MCG and ECG to pharmacologic stress. Normal ECG findings at rest and under stress in healthy subjects support the conclusion that the repolarization changes in the MCG were of nonpathologic origin.

Endothelin-1 (ET-1) has been implicated in the pathogenesis of pulmonary vascular disease in patients with congenital heart disease. We studied the effect of pulmonary blood flow on plasma ET-1 concentrations. Systemic venous, pulmonary arterial, and pulmonary venous blood samples were obtained from 40 patients with atrial septal defect II (n = 21), ventricular septal defect (n = 10), persistent ductus arteriosus (n = 6), and complete (n = 2) and partial (n = 1) atrioventricular canal at cardiac catheterization and analyzed by radioimmunoassay. Median age (range) was 5.2 years (8 months to 66 years), and the resistance ratio ( Rp Rs ) was 0.08 (0.03 to 0.67). Pulmonary vein to pulmonary artery ET-1 ratio in patients with “high flow” ( n = 26, Qp Qs ≥ 1.5 ; ET-1 ratio = 0.8) did not differ from those with “low flow” ( n = 14, Qp Qs ; ET-1 ratio = 1.0). We conclude that an increase in pulmonary blood flow alone does not result in an increase in plasma ET-1.

A 15 year-old girl who had c-ALL diagnosed in 1982 was presented in our clinic suffering from an ascended flaccid paresis and dysaesthesia of both legs. These are typical symptoms of polyradiculitis of the nerve roots L2-S2. A lumbal puncture revealed a pleocytosis with lymphoblasts which were up to 40% CD10 (cluster of differentiation) up to 70% CD19 and TdT (terminal transferase) positive. The diagnosis of late isolated CNS relapse was made. It is assumed that local residual infiltrations of leukemic cells into the nerve roots L2-S2 got into cell cycle and caused these rare CNS leukemia symptoms. Therefore the value of a craniospinal irradiation to prevent a CNS and systemic relapse is discussed.

Objectives. The aim of this study was to set up reference values for Doppler flow-derived left ventricular filling parameters and to evaluate physiologic determinants of changes in signal expression related to maturation.Background. In left ventricular diastolic function studies, age-related modulations in signal expression are observed. Assuming degenerative myocardial changes to be absent during childhood and adolescence, the determinants of these modulations must be different from those suspected in adults.Methods. Pulsed wave Doppler signals from the mitral valve tip region were recorded in 329 healthy subjects aged 2 months to 39 years. Multiple linear regression was used to evaluate statistical relations between Doppler flow signals and stroke volume in the mitral valve area.Results. Increasing early filling time velocity integral throughout maturation caused a decrease in atrial filling fraction from 0.34 ± 0.06 to 0.24 ± 0.04 (p < 0.005). Peak flow velocities during atrial systole decreased from infancy to adolescence (66 ± 15 to 41 ± 10 cm/s). Main effects on signal modulation were caused by heart rate, stroke volume and mitral ring area with a linear model fit (R2) of 0.79 for early filling phase (E)-time velocity integral, 0.6 for atrial filling phase peak velocity 0.84 for total E duration and 0.73 for E deceleration time. Atrial filling phase-time velocity integral, albeit significantly dependent on heart rate, was stable throughout growth.Conclusions. During infancy and childhood, the stroke volume crossing the mitral valve is a main modulator for early filling phase (E)-time velocity integral and diastolic time intervals during early filling, whereas atrial filling phase parameters are mainly dependent on heart rate. This results in a more pronounced atrial filling during infancy and childhood.

Patients with dilated and hypertrophic cardiomyopathies represent a high risk group for sudden cardiac death (Griffin et al.,1988 and McKenna et al.,1988). Usually they die from ventricular fibrillation as a result of micro-reentry mechanisms in the severely compromised myocardium (Swerdlow et al.,1983). Most often the left ventricular myocardium is involved. These cardiomyopathies are either acquired as the result of viral infections or they are the result of an inborn error of metabolism. A comparable anatomical and functional state of the heart can be seen after surgical correction of Tetrade of Fallot (TOF). These hearts offer a suitable model of abnormal pressure and/or volume load of the right ventricular myocardium. The significant mortality and morbidity in this patient group is also related to severe ventricular arrhythmias. Because mortality in both groups of patients depends on pathological electrophysiological phenomena, which usually can only be studied by invasive catheter procedures, the possibility of a non-invasive assessment of these changes by magnetocardiography is an intriguing idea.

Patients with Romano-Ward Syndrome show abnormal long QT-intervals in ECG and have a high risk of sudden cardiac death. The QT-syndrome is a pure electrophysiological disease in otherwise normal hearts. The underlying electrophysiological mechanism triggering ventricular flutter/fibrillation in these patients is an uneven depolarization and repolarization of the myocardium and the specialized conducting tissue (Schwartz et al., 1975). Like in other autosomal dominant inherited diseases expression of symptoms is variable among family members. Up to now a specific method for the discrimination of these high-risk patients does not exist.