Günter Breithardt

Genotype-phenotype relationship in Brugada syndrome: electrocardiographic features differentiate SCN5A-related patients from non–SCN5A-related patients☆

OBJECTIVESnWe have tested whether a genotype-phenotype relationship exists in Brugada syndrome (BS) by trying to distinguish BS patients with (carriers) and those without (non-carriers) a mutation in the gene encoding the cardiac sodium channel (SCN5A) using clinical parameters.nnnBACKGROUNDnBrugada syndrome is an inherited cardiac disease characterized by a varying degree of ST-segment elevation in the right precordial leads and (non)specific conduction disorders. In a minority of patients, SCN5A mutations can be found. Genetic heterogeneity has been demonstrated, but other causally related genes await identification. If a genotype-phenotype relationship exists, this might facilitate screening.nnnMETHODSnIn a multi-center study, we have collected data on demographics, clinical history, family history, electrocardiogram (ECG) parameters, His to ventricle interval (HV), and ECG parameters after pharmacologic challenge with I(Na) blocking drugs for BS patients with (n = 23), or those without (n = 54), an identified SCN5A mutation.nnnRESULTSnNo differences were found in demographics, clinical history, or family history. Carriers had a significantly longer PQ interval on the baseline ECG and a significantly longer HV time. A PQ interval of > or =210 ms and an HV interval > or =60 ms seem to be predictive for the presence of an SCN5A mutation. After I(Na) blocking drugs, carriers had significantly longer PQ and QRS intervals and more increase in QRS duration.nnnCONCLUSIONSnWe observed significantly longer conduction intervals on baseline ECG in patients with established SCN5A mutations (PQ and HV interval and, upon class I drugs, more QRS increase). These results concur with the observed loss of function of mutated BS-related sodium channels. Brugada syndrome patients with, and those without, an SCN5A mutation can be differentiated by phenotypical differences.

Dilated cardiomyopathy in mice deficient for the lysosomal cysteine peptidase cathepsin L

Dilated cardiomyopathy is a frequent cause of heart failure and is associated with high mortality. Progressive remodeling of the myocardium leads to increased dimensions of heart chambers. The role of intracellular proteolysis in the progressive remodeling that underlies dilated cardiomyopathy has not received much attention yet. Here, we report that the lysosomal cysteine peptidase cathepsin L (CTSL) is critical for cardiac morphology and function. One-year-old CTSL-deficient mice show significant ventricular and atrial enlargement that is associated with a comparatively small increase in relative heart weight. Interstitial fibrosis and pleomorphic nuclei were found in the myocardium of the knockout mice. By electron microscopy, CTSL-deficient cardiomyocytes contained multiple large and apparently fused lysosomes characterized by storage of electron-dense heterogeneous material. Accordingly, the assessment of left ventricular function by echocardiography revealed severely impaired myocardial contraction in the CTSL-deficient mice. In addition, echocardiographic and electrocardiographic findings to some degree point to left ventricular hypertrophy that most likely represents an adaptive response to cardiac impairment. The histomorphological and functional alterations of CTSL-deficient hearts result in valve insufficiencies. Furthermore, abnormal heart rhythms, like supraventricular tachycardia, ventricular extrasystoles, and first-degree atrioventricular block, were detected in the CTSL-deficient mice.

The ajmaline challenge in Brugada syndrome: Diagnostic impact, safety, and recommended protocol

AIMSnThe diagnostic ECG pattern in Brugada syndrome (BS) can transiently normalize and may be unmasked by sodium channel blockers such as ajmaline. Proarrhythmic effects of the drug have been well documented in the literature. A detailed protocol for the ajmaline challenge in Brugada syndrome has not yet been described. Therefore, we prospectively studied the risks of a standardized ajmaline test.nnnMETHODS AND RESULTSnDuring a period of 60 months, 158 patients underwent the ajmaline test in our institution. Ajmaline was given intravenously in fractions (10mg every two minutes) up to a target dose of 1mg/kg. In 37 patients (23%) the typical coved-type ECG pattern of BS was unmasked. During the test, symptomatic VT appeared in 2 patients (1.3%). In all other patients, the drug challenge did not induce VT if the target dose, QRS prolongation >30%, presence/appearance of the typical ECG, or the occurrence of premature ventricular ectopy were considered as end points of the test. A positive response to ajmaline was induced in 2 of 94 patients (2%) with a normal baseline ECG, who underwent evaluation solely for syncope of unknown origin.nnnCONCLUSIONnThe ajmaline challenge using a protocol with fractionated drug administration is a safe method to diagnose BS. Because of the potential induction of VT, it should be performed under continuous medical surveillance with advanced life-support facilities. Due to the prognostic importance all patients with aborted sudden death or unexplained syncope without demonstrable structural heart disease and family members of affected individuals should presently undergo drug testing for unmasking BS.

Experimental models of torsade de pointes

Torsade de pointes is a potentially life threatening form of polymorphic ventricular tachycardia typically seen in the setting of congenital and acquired abnormal QT-prolongation. Numerous in vitro studies have investigated basic ionic mechanisms underlying delayed repolarization. The role of different ion channels and the induction of early afterdepolarizations have been studied in various cardiac cells including M cells. In addition, isolated heart models with and without electrical stimulation and/or the use of drugs which prolong repolarization have been developed in recent years. Some of these models have simulated conditions likely to exist in the clinical setting of torsade de pointes, such as bradycardia and hypokalemia. In in vivo canine and rabbit models, torsade-like polymorphic ventricular tachyarrhythmias have been induced by the administration of different agents such as cesium, neurotoxins, e.g., anthopleurin or various class III drugs under conditions designed to mimic the clinical situation. In the context of recent advances in the molecular genetics of long QT syndrome, those models which have used sodium or potassium channel blockers have gained particular interest. Based on all experimental studies it seems probable that the first beats of torsade occur due to early afterdepolarizations and triggered activity. The development of subsequent beats is less clear. Reentry based on inhomogeneity of refractoriness has been suggested as the underlying mechanism.

Clusters of ventricular tachycardias signify impaired survival in patients with idiopathic dilated cardiomyopathy and implantable cardioverter defibrillators.

OBJECTIVESnThis retrospective study was undertaken to provide data on occurrence, significance and therapy of ventricular tachyarrhythmia (VT) clusters (VTCs) in patients with dilated cardiomyopathy (DCM) and implantable cardioverter defibrillators (ICDs).nnnBACKGROUNDnData on the clinical significance of VTCs are lacking in patients with DCM and ICDs.nnnMETHODSnBaseline characteristics of 106 consecutive patients with DCM and ICDs were prospectively collected, and chart reviews and episode data retrospectively analyzed. A VTC was defined as > or =3 sustained VTs/24 h.nnnRESULTSnDuring a mean follow-up of 33+/-23 months, 73 patients (68.9%) had recurrent VT or ventricular fibrillation (VF), 43 patients (40.6%) suffered only single VTs and 30 patients (28.3%) experienced 52 clusters of VTs. Actuarial survival free of VT or VF was 44.6%, 33.0% and 26.5%, and survival free of VTC was 77.3%, 72.2% and 67.1% after one, two and three years, respectively. Independent predictors of VT clusters were heart failure before ICD implantation (p = 0.033), presenting monomorphic VT (p = 0.044), EF <0.40 (p = 0.014) and inducible mVT, especially with right bundle branch block and superior axis configuration (p<0.001). Survival free of recurrent VTCs was 50.8%, 38.1% and 19.0% after one, two and three years, respectively. Once a VTC had occurred, only 56.7%, 46.4%, 30.9% and 15.5% of patients survived and were not transplanted after one, two, three and four years, respectively. Survival was even more reduced if a VTC was associated with cardiac decompensation: 65.6% and 21.9% after one and two years, respectively.nnnCONCLUSIONSnDespite antiarrhythmic intervention, clusters of VTs occur and recur frequently in patients with DCM. They signify impaired survival, especially if they are associated with cardiac decompensation, and may be a harbinger of progressive myocardial deterioration rather than a primarily arrhythmic problem. The benefit of ICD therapy may therefore be low in these patients.

Arrhythmogenic Right Ventricular Cardiomyopathy

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a major cause of sudden cardiac death and ventricular tachyarrhythmias in young, apparently healthy individuals and athletes. Myocardial atrophy with subsequent fibrofatty replacement predominantly affects right ventricular myocardium and results in global and regional dysfunction as well as areas of slow conduction and dispersion of refractoriness which are prerequisites for reentrant ventricular tachyarrhythmias.Patients affected with ARVC should be excluded from competitive sports and vigorous training. To provide optimal treatment, a detailed diagnostic evaluation and risk stratification are mandatory. Tailored treatment strategies aim at the suppression or effective termination of recurrent ventricular tachyarrhythmias and prevention of sudden death by antiarrhythmic drug therapy, catheter ablation, or implantation of a cardioverter defibrillator (ICD).Antiarrhythmic drugs may be used as a stand-alone treatment to suppress ventricular tachycardia (VT) recurrences in patients with ARVC and low risk of sudden death. Sotalol (preferred) or amiodarone in combination with β-blockers showed the highest efficacy rates. In patients at higher risk, an ICD should be implanted and antiarrhythmic drugs be used only as an adjunct to prevent or suppress frequent VT recurrences and ICD discharges.Catheter ablation using conventional or electroanatomic mapping techniques yields good acute results for eliminating the targeted arrhythmia substrate. However, during the progressive long-term course of ARVC, VT recurrences from new arrhythmia foci are frequent and therefore limit the curative value of catheter ablation. In patients with frequent VT recurrences and ICD discharges, however, catheter ablation plays an important role as a palliative and adjunctive treatment option for arrhythmia suppression.ICD therapy has been increasingly used for secondary and also primary prevention of sudden death in patients with ARVC. In secondary prevention, the ICD has shown to improve the long-term prognosis of patients at high risk of sudden death by effective termination of life-threatening recurrences of ventricular tachyarrhythmias. However, adequate lead placement may be difficult and lead-related complications during long-term follow-up must be taken into account. The role of ICD therapy for primary prevention of sudden death in ARVC is not yet adequately defined.Ongoing international registries will provide important additional data to improve risk stratification and refine treatment algorithms in order to select the best individual treatment for arrhythmia suppression and prevention of sudden death in patients with ARVC.ZusammenfassungDie arrhythmogene rechtsventrikuläre Kardiomyopathie (ARVC) ist eine wesentliche Ursache ventrikulärer Tachyarrhythmien und plötzlicher Herztodesfälle bei jungen, scheinbar herzgesunden Patienten und Sportlern. Durch regionale Atrophie vorwiegend rechtsventrikulären Myokards und nachfolgenden Ersatz durch Fett- und Bindegewebe kommt es neben globalen oder regionalen Funktionsstörungen zu lokaler Verzögerung der Erregungsleitung und Dispersion der Refraktärzeiten des rechten Ventrikels, die eine Grundlage für Reentrymechanismen sind und damit zu den klinisch im Vordergrund stehenden ventrikulären Tachykardien (VT) führen.Patienten mit ARVC sollten vom Leistungssport ausgeschlossen werden und systematisches Training sowie starke körperliche Belastungen vermeiden. Eine detaillierte Diagnostik und Risikostratifikation sind entscheidend für die Planung einer individuellen Therapiestrategie, welche die Behandlung ventrikulärer Arrhythmien und die Prävention des plötzlichen Herztodes zum Ziel hat. Hierzu stehen die antiarrhythmische Pharmakotherapie, die Katheterablation und die Implantation eines Kardioverter-Defibrillators (ICD) zur Verfügung.Bei Patienten mit ARVC und geringem Risiko für plötzlichen Herztod können primär Antiarrhythmika zur Suppres sion ventrikulärer Arrhythmien eingesetzt werden, wobei Sotalol oder Amiodaron in Kombination mit β-Blockern die höchsten Effektivitätsraten aufweisen. Bei Patienten mit hohem Risiko sollte dagegen ein Schutz durch ICD-Implantation erfolgen und eine antiarrhythmische Therapie nur adjuvant zur Suppression häufiger VT-Rezidive eingesetzt werden.Die Katheterablation von VT mit konventionellen und/oder elektroanatomischen Mapping-Techniken liefert bei Patienten mit ARVC gute Akutergebnisse hinsichtlich der Elimination des behandelten Arrhythmiesubstrats. Im Langzeitverlauf kommt es durch die fortschreitende Grunderkrankung jedoch häufig zu VT-Rezidiven aus neu entstehenden Substraten, so dass der kurative Wert der Katheterablation deutlich eingeschränkt ist. Unter palliativen Gesichtspunkten ist die Katheterablation jedoch insbesondere bei Patienten mit häufigen VT-Rezidiven und ICD-Schocks von großem Wert.Bei Patienten mit ARVC und hohem Risiko für plötzlichen Herztod führt die ICD-Therapie zu einer deutlichen Verbesserung der Langzeitprognose, da häufig auftretende lebensbedrohliche VT-Rezidive sicher erkannt und beendet werden. Die Platzierung der rechtsventrikulären Elektrode kann sich jedoch schwierig gestalten. Zudem muss die vor allem elektrodenbezogene Komplikationsrate der ICD-Therapie im Langzeitverlauf bei dem jungen Kollektiv mit ARVC berücksichtigt werden. Die Rolle der ICD-Therapie in der Primärprävention des plötzlichen Herztodes ist bei Patienten mit ARVC bislang nur unzureichend untersucht.Laufende internationale multizentrische Register werden in den kommenden Jahren weitere wichtige Daten zur Risikostratifikation und Therapieeffektivität liefern, so dass erwartet wird, dass derzeit empfohlene Algorithmen zur Behandlung der Arrhythmien und Prävention des plötzlichen Herztodes weiter verbessert werden können.

Prolonged action potential durations, increased dispersion of repolarization, and polymorphic ventricular tachycardia in a mouse model of proarrhythmia.

Introduction: In the congenital long QT syndrome, inhomogeneously prolonged action potentials, bradycardia, and hypokalemia can cause afterdepolarizations and torsade de pointes. Other genetic factors may contribute to similar forms of ventricular tachycardias in hypertrophied or failing hearts, especially if the outward current IKr is blocked pharmacologically. We sought to develop a mouse heart model for such arrhythmias in order to identify the proarrhythmic potential in transgenic animals. Methods and results: Hearts of adult wild-type (CD1) mice were isolated and the aorta was retrogradely perfused. Three monophasic action potentials and a volume-conducted ECG were simultaneously recorded. Sotalol (10-5M and 2 × 10-5M) prolonged action potential duration (APD) in a concentration-dependent and reverse frequency-dependent fashion (from 34 ± 1 to 48 ± 2 ms at 100 ms basic cycle length (BCL), from 38 ± 2 to 54 ± 3 ms at 180 ms BCL for APD90, p < 0.05). Sotalol did not alter the relation between refractoriness and APD (ERP/APD ratio = 0.76 - 0.93). AV nodal block caused ventricular bradycardia and doubled dispersion of APD (APD70max-min: 11 ± 1 vs. 4 ± 1 ms, APD90max-min: 12 ± 1 vs. 5 ± 1 ms, p < 0.05). If combined with hypokalemia, afterdepolarizations induced polymorphic ventricular tachycardias in 1 of 8 hearts at K+ =3.0 mM and in 10 of 12 hearts at K+ = 2.0 mM. Prior to polymorphic ventricular tachycardia, dispersion of APD further increased (APD70max-min: 17 ± 3 ms; APD90max-min: 25 ± 3 ms; p < 0.05). Conclusions: This isolated beating mouse heart model can be used to study drug-induced action potential prolongation and repolarization-related ventricular arrhythmias provoked by bradycardia and hypokalemia. It may be suitable to identify a genetic predisposition to ventricular arrhythmias that may only become apparent under such proarrhythmic conditions.

Ventricular Tachycardias Above the Initially Programmed Tachycardia Detection Interval in Patients With Implantable Cardioverter-Defibrillators Incidence, Prediction and Significance

OBJECTIVESnThis retrospective study was performed to provide data on ventricular tachycardias (VT) with a cycle length longer than the initially programmed tachycardia detection interval (TDI) in patients with implantable cardioverter defibrillators (ICDs).nnnBACKGROUNDnIt has been clinical practice to program a safety margin of 30 to 60 ms between the slowest spontaneous or inducible VT and the TDI.nnnMETHODSnBaseline characteristics of 659 consecutive patients with ICDs were prospectively; follow-up information was retrospectively collected.nnnRESULTSnDuring a mean follow-up of 31+/-23 months, 377 patients (57.2%) had at least one recurrent VT or ventricular fibrillation; 47 patients (7.1%) suffered 61 VTs above the TDI. The risk of a VT above the TDI ranged between 2.7% and 3.5% per year during the first four years after ICD implantation. The difference between the cycle length of the slowest VT before ICD implantation, spontaneous or induced, and the first VT above TDI was 108+/-58 ms. Fifty-four VTs (88.5%) above the TDI were associated with significant clinical symptoms (angina or palpitation 63.9%, heart failure 6.6% and syncope 8.2%). Six patients (9.8%) had to be resuscitated. Kaplan-Meyer analysis identified New York Heart Association class II or III (p = 0.021), ejection fraction < 0.40 (p = 0.027), spontaneous (p<0.001) or inducible (p<0.001) monomorphic VTs and the use of class III antiarrhythmic drugs (amiodarone, p<0.001; sotalol, p = 0.004) as risk predictors of VTs above the TDI. The risk of recurrent VTs above TDI was 11.8%, 12.5% and 26.6% during the first, second and third year after first VT above TDI, respectively.nnnCONCLUSIONSnThe risk of VTs above the TDI is significantly increased in some patients, and many VTs above TDI cause significant clinical symptoms. A larger safety margin between spontaneous or inducible VTs and the TDI seems to be necessary in selected patients. This is in conflict with an increased risk of inadequate episodes and demands highly specific and sensitive detection algorithms in these patients.

THREE-DIMENSIONAL ELECTROMAGNETIC CATHETER TECHNOLOGY : ELECTROANATOMICAL MAPPING OF THE RIGHT ATRIUM AND ABLATION OF ECTOPIC ATRIAL TACHYCARDIA

Electroanatomical Mapping. Introduction: The difficult catheter orientation and navigation associated with conventional technology and mono‐/multiplane fluoroscopy may complicate ablation procedures of atrial tachycardias. A new three‐dimensional catheter technology for electroanatomical mapping of the right atrium and ablation of ectopic atrial tachycardia is described.

Efficacy and Safety of the Initial Use of Stability and Onset Criteria in Implantable Cardioverter Defibrillators

Primary Programming of Stability and Onset Criteria. Introduction: Inappropriate therapies are the most frequent adverse event in patients with implantable cardioverter defibrillators (ICDs). Most ICDs offer a stability criterion to discriminate ventricular tachycardia (VT) from atrial fibrillation and an onset criterion to discriminate VT from sinus tachycardia. The efficacy and safety of these criteria, if used immediately after implantation, is unknown.