Michael Hofbeck

Comprehensive genotype–phenotype analysis in 230 patients with tetralogy of Fallot

Background Tetralogy of Fallot (ToF), the most frequent cyanotic congenital heart disease, is associated with a wide range of intra- and extracardiac phenotypes. In order to get further insight into genotype–phenotype correlation, a large cohort of 230 unselected patients with ToF was comprehensively investigated. Methods and results 230 patients with ToF were studied by karyotyping, comprehensive 22q11.2 deletion testing and sequencing of TBX1, NKX2.5 and JAG1, as well as molecular karyotyping in selected patients. Pathogenic genetic aberrations were found in 42 patients (18%), with 22q11.2 deletion as the most common diagnosis (7.4%), followed by trisomy 21 (5.2%) and other chromosomal aberrations or submicroscopic copy number changes (3%). Mutations in JAG1 were detected in three patients with Alagille syndrome (1.3%), while NKX2.5 mutations were seen in two patients with non-syndromic ToF (0.9%). One patient showed a recurrent polyalanine stretch elongation within TBX1 which represents a true mutation resulting in loss of transcriptional activity due to cytoplasmatic protein aggregation. Conclusion This study shows that 22q11.2 deletion represents the most common known cause of ToF, and that the associated cardiac phenotype is distinct for obstruction of the proximal pulmonary artery, hypoplastic central pulmonary arteries and subclavian artery anomalies. Atrioventricular septal defect associated with ToF is very suggestive of trisomy 21 and almost excludes 22q11.2 deletion. We report a further patient with a recurrent polyalanine stretch elongation within TBX1 and for the first time link TBX1 cytoplasmatic protein aggregation to congenital heart defects.

Contact force–controlled zero-fluoroscopy catheter ablation of right-sided and left atrial arrhythmia substrates

BACKGROUND Conventional catheter ablation of cardiac arrhythmias is associated with radiation risks for patients and laboratory personnel. However, nonfluoroscopic catheter guidance may increase the risk for inadvertent cardiac injury. A novel radiofrequency ablation catheter capable of real-time tissue-tip contact force measurements may compensate for nonfluoroscopic safety issues. OBJECTIVE To investigate the feasibility of contact force-controlled zero-fluoroscopy catheter ablation. METHODS In 30 patients (including 12 pediatric patients), zero-fluoroscopy catheter ablation of right-sided (right atrium, n = 20; right ventricle, n = 2) and left atrial (n = 8) arrhythmias was attempted. Inclusion criteria were symptomatic suspected atrioventricular nodal reentrant tachycardia, atrioventricular reentrant tachycardia, focal right atrial and ventricular arrhythmias, and lone atrial fibrillation. A novel irrigated-tip catheter with an integrated contact force sensor was used for nonfluoroscopic 3-dimensional electroanatomical mapping and radiofrequency ablation. Transseptal access was gained under transesophageal guidance for ablation of left-sided arrhythmias. RESULTS Procedural success without fluoroscopy was achieved in 29 of the 30 patients (97%). In 1 patient, endocardial nonfluoroscopic ablation failed because of an epicardial accessory pathway within a coronary sinus aneurysm. Mean total contact force and amplitude of force undulations were kept below 50 g during mapping and below 40 g during ablation to prevent contact force peaks (>100 g). Apart from a transient second-degree type I atrioventricular block, no complications occurred. The mean procedure time was 2.8 ± 0.9 hours. There were no arrhythmia recurrences during a mean follow-up of 6.2 ± 4.2 months. CONCLUSION Contact force-controlled zero-fluoroscopy catheter ablation is generally feasible in right-sided and left atrial cardiac arrhythmias.

Recommendations for improving the quality of the interdisciplinary medical care of grown-up with congenital heart disease (GUCH).

BACKGROUND/OBJECTIVES The number of adult congenital heart disease (ACHD) patients will be larger in the medium to long term than that of children and adolescents with congenital heart disease. The present structures for the medical care of ACHD patients are not sufficient and need to be improved. Therefore the task forces assignment and objective was to develop recommendations for the structure of the interdisciplinary medical care of adults with congenital heart disease (GUCH). METHODS The members of the interdisciplinary task force were selected on the basis of their special clinical, scientific and organizational expertise. Initially, a sub-group of the interdisciplinary task force compiled a draft version of these recommendations, with reference to international recommendations. It was circulated and then agreed with all task force members in two joint meetings. The recommendations were then submitted to the relevant committees of all participating societies and groups and approved following detailed discussion. RESULTS With the publication of this document the interdisciplinary task force considers its first task as completed. CONCLUSIONS The compiled recommendations for the structure of the interdisciplinary medical care of adults with congenital heart disease (GUCH) should ensure that the structural and medical pre-conditions for comprehensive GUCH medical care are created.

Medizinische Leitlinie zur Behandlung von Erwachsenen mit angeborenen Herzfehlern (EMAH)

Univ.-Prof. Dr. med. Dr. h. c. G. Breithardt (&) Medizinische Klinik und Poliklinik C (Kardiologie und Angiologie) Universitätsklinikum Münster Albert-Schweitzer-Str. 33 48149 Münster, Germany Tel.: +49-251/834-7617 Fax: +49-251/834-7864 A.A. Schmaltz (Vorsitzender der Ad-hoc-Gruppe Leitlinien) U. Bauer H. Baumgartner R. Cesnjevar F. de Haan C. Franke H. Gabriel C. Gohlke-Bärwolf S. Hagl J. Hess M. Hofbeck H. Kaemmerer H.C. Kallfelz P.E. Lange H. Nock E. Oechslin K.R. Schirmer U. Tebbe P. Trigo Trindade M. Weyand G. Breithardt (Vorsitzender der Task Force)

Use of the implantable loop recorder in children and adolescents.

INTRODUCTION Recurrent but infrequent syncopes represent a diagnostic challenge, since they frequently remain unexplained despite extensive investigations. This applies specifically for patients who carry an increased risk of potentially lifethreatening arrhythmias, either due to congenital cardiac disease or primary electrical disorders. Implantable loop recorders permit long-term electrocardiographic monitoring. Experience with these devices is still limited in children. PATIENTS AND METHODS Between January 1999 and August 2005, 12 patients underwent implantation of a loop recorder in our tertiary referral centre. The mean age was 10.9 years, with a range from 2 to 17 years. Of the patients, 6 had structural disease, 3 had primary electrical abnormalities, and 3 had no cardiovascular disease. RESULTS Resyncope occured in 9 of the 12 patients. Arrhythmic origin of the syncope was diagnosed in 4 of these patients. The events recorded were ventricular fibrillation in 2, intermittent asystole in 1, and pacemaker-syndrome in the other patient. Malignant arrhythmia was ruled out in the remaining 5 patients. There were no complications related to implantation of the loop recorder, and the mean duration until explantation was 8.3 months. CONCLUSIONS Based on our experience, we suggest that implantation of a loop recorder represents an additional tool for a selected group of children. Due to its invasive nature, it should be restricted to patients at high risk, or those in which there is substantial clinical suspicion of the likelihood of serious arrhythmias when conventional testing has been inconclusive. In this cohort, implantation of the loop recorder either helps to establish the correct diagnosis, or to exclude an arrhythmic event, thus avoiding unnecessary escalation of therapy and providing reassurance for the family.

Search for somatic 22q11.2 deletions in patients with conotruncal heart defects

A wide range of clinical variability in patients with 22q11.2 deletions has been demonstrated in numerous studies. Nevertheless, it is still an open question if major genetic factors contribute to clinical expression. Therefore one aim of this study was to investigate, if patients with 22q11.2 deletion and conotruncal heart defects show a “second hit” somatic 22q11.2 deletion in tissue from the conotruncus, heart vessels or thymus. The second aim was to analyse patients with conotruncal heart defects without 22q11.2 deletion in blood cells for somatic deletion mosaicism. We were able to study tissue samples from heart surgery from 23 patients, 9 of whom had 22q11 deletions by FISH analysis on metaphase spreads from peripheral lymphocytes. Analysis of 18 polymorphic markers from the 22q11.2 region in DNA prepared from thymus and/or heart vessels and/or conotruncus tissue and peripheral lymphocytes in each patient did not show any allelic loss. Thus somatic 22q11.2 deletions apparently do not play a major role in conotruncal heart defects in patients with or without germ line 22q11.2 deletion.

The diagnostic yield from implantable loop recorders in children and young adults.

BackgroundSyncope and palpitations occur frequently in young patients. Noninvasive diagnostic testing may be inconclusive.AimTo assess the diagnostic yield of implantable loop recorders in young patients.Patients and methodsThirty-three young patients underwent implantation of a loop recorder for long-term monitoring of cardiac rhythm, to establish symptom–rhythm correlation. They belonged to one of three subgroups: those with structurally normal heart, normal electrocardiogram at rest, and negative family history (n = 16); patients with structural heart disease and previous surgical repair (n = 11), and patients with proven or suspected primary electrical disease (n = 6). A combination of automatic and patient-activated recordings was used to monitor cardiac rhythm during symptomatic episodes.ResultsThere were no procedural complications. Diagnostic electrograms could be obtained in all patients. A high degree of symptom–rhythm correlation was established. In 8/33 patients, no recurrence of symptoms was observed either until end of battery life of the device (n = 4) or until last follow-up (n = 2). Specific cardiac therapy was required, based on rhythms recorded by the device in 15 patients (until last follow-up). This consisted of catheter ablation of a tachyarrhythmia (n = 7), pacemaker implantation or upgrade (n = 5) or ICD implantation (n = 5). In the remaining patients (n = 10), recurrence of symptoms was associated with a normal electrocardiogram, and in two of these patients a non-cardiac diagnosis was made.ConclusionsIn selected patients, the implantable loop recorder provides valuable diagnostic information to guide further therapy.

Medizinische Leitlinie zur Behandlung von Erwachsenen mit angeborenen Herzfehlern (EMAH) : der deutsch-österreichisch-schweizerischen kardiologischen Fachgesellschaften

Univ.-Prof. Dr. med. Dr. h. c. G. Breithardt (&) Medizinische Klinik und Poliklinik C (Kardiologie und Angiologie) Universitätsklinikum Münster Albert-Schweitzer-Str. 33 48149 Münster, Germany Tel.: +49-251/834-7617 Fax: +49-251/834-7864 A.A. Schmaltz (Vorsitzender der Ad-hoc-Gruppe Leitlinien) U. Bauer H. Baumgartner R. Cesnjevar F. de Haan C. Franke H. Gabriel C. Gohlke-Bärwolf S. Hagl J. Hess M. Hofbeck H. Kaemmerer H.C. Kallfelz P.E. Lange H. Nock E. Oechslin K.R. Schirmer U. Tebbe P. Trigo Trindade M. Weyand G. Breithardt (Vorsitzender der Task Force)

Open heart surgery immediately after birth following prenatal diagnosis of a large right pulmonary artery to left atrium communication.

A 24-year-old gravida II para I was referred at 37 + 4 weeks of pregnancy for prenatal ultrasound because of fetal cardiomegaly. The second trimester scanning was reported as normal. High resolution ultrasound (HDI 5000, ATL, Zipf, Austria, 5 to 7 MHz curved array) confirmed massive cardiomegaly with ventricular hypertrophy (apical wall thickness 11 mm; Figure 1a) and 100◦ left axis deviation. Mild regurgitation of the mitral and tricuspid valve was present. The left atrium showed an anomalous saccular aneurysm of about 12 mm in diameter. Color Doppler sonography demonstrated continuous turbulent flow in this area, directing toward the left atrium (Figure 1b). At atrial level a secundum atrial septal defect with left to right shunting was found. The main pulmonary artery was markedly dilated (21 mm, >95th percentile) and showed regurgitation with oscillating flow (Figure 1c). A right pulmonary artery (RPA) to left atrium (LA) fistula was diagnosed based on visualization of a large vessel (11 mm) originating from the pulmonary artery communicating with the aneurysmatic bulge of the left atrium (Figure 1d). The pulmonary veins appeared to drain normally into the LA. No other malformations were found. Further Doppler examination revealed absent end-diastolic flow in the umbilical artery and an abnormal flow in the ductus venosus but no other hemodynamic impairment signs. Two days later the situation deteriorated, as evidenced by a reverse flow in the ductus, increasing atrioventricular regurgitation and intermittent premature atrial contractions, so that delivery was planned. In view of the expected poor circulatory condition, an emergency cardiac surgical repair was scheduled in continuity with the cesarean section.

Hypoparathyroidism in conotruncal heart defects

Abstract. This retrospective study was designed to evaluate serum levels of intact parathyroid hormone and calcium in patients with conotruncal heart defects with or without microdeletion 22q11.2 in order to investigate a correlation between various types of conotruncal heart defect and hypoparathyroidism. A total of 67 patients with truncus arteriosus, tetralogy of Fallot, pulmonary atresia and ventricular septal defect, interrupted aortic arch or vascular ring were included of whom 28 had a 22q11.2 deletion (Group I) and 39 did not (Group II). In two patients of Group I and in one patient of Group II, parathyroid hormone level was decreased with normal serum calcium levels. No patient of Group II showed hypocalcaemia. In Group I, complete hypoparathyroidism with low parathyroid hormone and hypocalcaemia occurred in seven patients; 5 patients had bilateral anomalies of the right and the left 4th aortic arch derivates. In addition to an interrupted aortic arch type B or a high aortic arch, the contralateral subclavian artery arose cervically, high thoracically or anomalously from the descending aorta. Two patients had unilateral anomalies of the 4th aortic arch system: The origin of the right subclavian artery was cervical or from the descending aorta. Conclusion: hypoparathyroidism occurred in 7 of our 28 patients with conotruncal heart defect and monosomy 22q11.2 and was associated with an extended regression of the 4th aortic arch development on both sides of the aortic arch system.