Paulus Kirchhof

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.

Wolff-Parkinson-White Syndrome Associated with Brugada Syndrome

A 30-year-old male soccer player suddenly collapsed during the break of a football match. He was found to have ventricular fibrillation and was successfully resuscitated. There was no history of prior syncope or palpitations nor a family history of sudden cardiac death. The resting electrocardiograph (ECG) demonstrated normal sinus rhythm with a short PR interval and delta waves that were positive in leads I, II, aVL, and V2 through V6, and isoelectric or negative in III, aVR, aVF, and V1, consistent with a right septal accessory pathway (AP) (Fig. 1). During electrophysiological study, there was antegrade block in the AP at a cycle length of 590 ms (Fig. 2). In addition, intermittent antegrade block in the AP was observed. After administration of orciprenaline, a supraventricular tachycardia with a cycle length of 290 ms was inducible. During this tachycardia, the earliest atrial activation was recorded near the His position; the ventriculoatrial (VA) interval was 90 ms. In the presence of orciprenaline, antegrade conduction block in the AP already occurred at a cycle length of 320 ms, which did not explain the occurrence of ventricular fibrillation. During electrophysiological study, there was intermittent occurrence of a right bundle branch block-like pattern with ST-segment elevation in the right precordial leads (Fig. 3). This ECG pattern could be unmasked by intravenous (IV) ajmaline (1mg/kg). Ventricular fibrillation was reproducibly inducible with three extrastimuli from the right ventricular outflow tract (basic pacing cycle length of 500 ms, coupling intervals: 220/200/200 ms). Discussion Patients with Wolff-Parkinson-White (WPW) syndrome, who have been resuscitated from ventricular fibrillation as a consequence of a WPW related tachyarrhythmia, are invariably found to have atrial fibrillation with rapid ventricular response (minimum preexcited RR interval , 250 ms) at baseline electrophysiological study. Therefore, the finding of a minimum preexcited RR interval of # 250 ms has been proposed as a sensitive marker for identification of patients at risk of sudden cardiac death. In the present patient, intermittent antegrade conduction was observed during sinus rhythm and early antegrade block during atrial stimulation at a cycle length of 590 ms. In addition, after challenge with orciprenaline, antegrade block was noted at 320 ms. Therefore, atrial fibrillation with rapid ventricular response leading to ventricular fibrillation is very unlikely. However, it can not be excluded that an orthodromic atrioventricular reentrant tachycarWolff-Parkinson-White Syndrome Associated with Brugada Syndrome

A patient with "atrial torsades de pointes".

Atrial Torsades de Pointes. A patient with long QT syndrome and a history of palpitations underwent electrophysiologic study. Runs of polymorphic self‐terminating atrial tachyarrhythmias were easily induced and occurred spontaneously several times. Atrial monophasic action potential (MAP) durations were prolonged at short pacing cycle lengths. Premature high right atrial extrastimuli prolonged MAP duration in the low right atrium, resulting in an inverse electrical restitution curve, and increased dispersion of repolarization. MAP morphology showed gradually increasing early afterdepolarizations. When the arrhythmia was initiated, a new action potential reproducibly emerged from these afterdepolarizations. To the knowledge of the authors, this is the first reported case of “atrial torsades de pointes” in a patient.

Can we improve outcomes in AF patients by early therapy

Atrial fibrillation affects at least 1% of the population and causes marked society-wide morbidity and mortality. Current management of atrial fibrillation including antithrombotic therapy and management of concomitant conditions in all patients, rate control therapy in most patients, and rhythm control therapy in patients with severe atrial fibrillation-related symptoms can alleviate atrial fibrillation-related symptoms but can neither effectively prevent recurrent atrial fibrillation nor suppress atrial fibrillation-related complications. Hence, there is a need for better therapy of atrial fibrillation.The etiology of atrial fibrillation is complex. Most of the causes of atrial fibrillation which are known at present perpetuate themselves in vicious circles, and presence of the arrhythmia by itself causes marked damage of atrial myocardium. These pathophysiological insights suggest that early diagnosis and comprehensive therapy of atrial fibrillation, including adequate therapy of all atrial fibrillation-causing conditions, rate control, and rhythm control therapy, could help to prevent progression of atrial fibrillation and reduce atrial fibrillation-related complications. Such a therapy should make use of safe and effective therapeutic modalities, some of which have become available recently or will become available in the near future. The hypothesis that early diagnosis and early, comprehensive therapy of atrial fibrillation can improve outcomes requires formal testing in controlled trials.

Arrhythmogenic right ventricular cardiomyopathy

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy accounting for life-threatening ventricular tachyarrhythmias and sudden death in young individuals and athletes. Over the past years, mutations in desmosomal genes have been identified as disease-causative. However, genetic heterogeneity and variable phenotypic expression alongside with diverse disease progression still render the evaluation of its prognostic implication difficult. ARVC was initially entered into the canon of cardiomyopathies of the World Health Organization in 1995, and international efforts have resulted in the 2010 modified diagnostic criteria for ARVC. Despite all additional insights into pathophysiology, clinical management, and modern risk stratification, under-/misdiagnosing of ARVC remains a problem and hampers reliable statements on the incidence, prevalence, and natural course of the disease.This review provides a comprehensive overview of the current literature on the pathogenesis, diagnosis, treatment, and prognosis of ARVC and sheds some light on potential new developments in these areas.ZusammenfassungDie arrhythmogene rechtsventrikuläre Kardiomyopathie ist eine vererbbare Herzmuskelerkrankung, die für das Auftreten lebensbedrohlicher ventrikulärer Tachyarrhythmien und insbesondere für den plötzlichen Herztod bei jungen Menschen und Athleten verantwortlich zeichnet. In den letzten Jahren wurden Mutationen in überwiegend desmosomalen Genen als ursächlich identifiziert und somit auch diese Kardiomyopathieform als genetisch klassifiziert. Typisch sind eine genetische Heterogenität, variable klinische Expression und insbesondere Erkrankungsprogression, was eine valide prognostische Einstufung erschwert. Seit der Einordnung als Kardiomyopathie durch die Weltgesundheitsorganisation 1995 wurden die Diagnosekriterien mehrfach überarbeitet und zuletzt 2010 unter Einbeziehung genauerer Bildgebungskriterien veröffentlicht. Dennoch bleibt die korrekte Diagnose der insgesamt seltenen Erkrankung komplex, was mitunter Fehl- oder Nichtdiagnostizieren beinhaltet und damit Aussagen zur erkrankungsspezifischen Inzidenz, Prävalenz und zum „natürlichen“ Erkrankungsverlauf einschränkt.Dieser Beitrag gibt eine Übersicht über die aktuelle Literatur zur Pathogenese, Diagnose, Therapie und Prognose der ARVC und einen Ausblick auf zukünftige Entwicklungen in den genannten Bereichen.

Ablation of atrial fibrillation: for whom and how?

Atrial fibrillation (AF) is the most common sustained arrhythmia. Approximately seven million people suffer from AF in Europe, and it is likely that several more millions suffer from ‘silent’, undiagnosed AF.1 w1–w3 Once AF has manifested, it is usually a chronically progressing arrhythmia (figure 1A). The presence of AF, especially of long periods of the arrhythmia, causes pronounced electrical and structural alterations in the atria, thereby perpetuating AF and promoting its recurrence. In addition, chronic underlying comorbidities, a genetic predisposition to AF, and ‘natural’ ageing processes remodel the atria and contribute to the initiation and progression of AF (figure 1B).nnnnFigure 1 n(A) ‘Natural’ time course of atrial fibrillation (AF) in a patient. Before the diagnosis of AF, most patients probably experience asymptomatic episodes of the arrhythmia. With the exception of rare patients with ‘true lone AF’, AF recurrences become longer and more frequent over time, and finally result in chronic forms of AF. The majority of patients progresses from persistent AF—that is, AF that is managed by rhythm control interventions—to long lasting persistent AF and finally permanent or accepted AF that is managed by rate control and antithrombotic therapy. Reproduced with permission from Kirchhof et al .1 (B) Different ‘vicious circles’ that contribute to AF. In addition to electrical triggers, often located in the pulmonary veins and the posterior left atrium (red circle), shortening of the atrial action potential can promote multiple wavelet reentry (blue circle), and structural remodelling of the atria contributes to conduction disturbances and electrical isolation of atrial myocardium (green circle). Furthermore, there is a bidirectional interaction between left ventricular dysfunction and atrial dysfunction (brown circle) in AF patients. Unfortunately, only a part of the atrial damage can be prevented by preventing AF (black pie piece), while other parts are due to other, often extracardiac …

Torsade de pointes induced by ajmaline

Ajmalin, ein Reserpin-Derivat, ist ein potentes Klasse-I-Antiarrhythmikum. Wir berichten über zwei Fälle von abnormer QT-Verlängerung und Torsade de Pointes, die während Behandlung mit der Substanz auftraten. Da Ajmalin zunehmend häufiger zur Akutbehandlung von Tachykardien mit breitem QRS-Komplex und bei der Abklärung von Synkopen sowie idiopathischen ventrikulären Tachyarrhythmien eingesetzt wird, erscheint uns aufgrund der vorliegenden Fälle eine besondere Beachtung der Effekte der Substanz auf das QT-Intervall angebracht; die Möglichkeit der Induktion von Torsade de Pointes sollte berücksichtigt werden. Ajmaline, a reserpine derivative, is an effective class I antiarrhythmic agent. Herein we report two cases of ajmaline-induced abnormal QT prolongation accompanied by polymorphic ventricular tachycardia of the torsade de pointes type. Since ajmaline is increasingly used for the acute termination of wide complex tachycardia and as a diagnostic tool after syncope and in patients with idiopathic ventricular tachyarrhythmias, our observations suggest that caution should be exercised with regard to the effects of the drug on the QT interval and its potency to induce proarrhythmia of the torsade de pointes type.

Genetic aspects in acquired long QT syndrome : a piece in the puzzle

Torsade de pointes (TdP) is a serious complication which is induced by a large variety of cardiovascular and non-cardiovascular drugs. Many clinical conditions and risk factors for the occurrence of TdP during administration of drugs with a proarrhythmic potential have been identified. All such drugs have in common that they reversibly alter myocardial repolarization due to the prolongation of the action potential (acquired QT interval prolongation) which is per se not arrhythmogenic. TdP is initiated (acquired long QT (LQT) syndrome) only when a threshold level is reached leading to early after-depolarizations (EADs) and triggered beats together with a marked dispersion in recovery of excitability. The underlying mechanisms of TdP are not yet satisfactorily elucidated but, in general, alterations in cardiac ion currents which tune the normal action potential play a major role in arrhythmogenesis.nnFollowing recent advances in molecular biology and genetics, it has become clear that in some clinical instances (e.g. congestive heart failure or cardiac hypertrophy) ion channel genes become less expressed (down-regulated) and the consequent reduced ion currents (e.g. IKr) are likely to cause prolonged myocardial repolarization. In this setting, the use of drugs with action potential-prolonging properties could possibly be harmful and could not be compensated by the normal cardiac ‘repolarization reserve’. In congenital LQT syndrome some of the same ion channel components were found to be genetically altered, suggesting that either quantitative or qualitative changes of ion currents may be involved in ventricular arrhythmogenesis through similar mechanisms (‘final common pathway’). A variable clinical expressivity and, especially, an incomplete penetrance has been found in patients carrying the same LQT genotype, even when near-relatives, which raises the question on the frequency and importance of ‘silent’ (i.e. minor functional) ion channel gene mutations that may become functionally significant in presence of action potential prolonging drugs and other coexisting factors. The observation of adverse drug reactions in apparently healthy (‘normal heart’) individuals is suggestive of a genetic susceptibility for ‘acquired’ arrhythmias. This report reviews and summarizes the recent knowledge on unapparent ion channel gene mutations and preliminary concepts about ‘acquired’ arrhythmias.

In vivo recording of monophasic action potentials in awake dogs

Assessment of cardiac repolarization in dogs in vivo is of interest in numerous experimental canine models. Previous studies have used monophasic action potentials (MAPs) to investigate repolarization in vitro and in vivo in anesthetized animal models. Therefore, an approach for recording MAPs in awake dogs without the interference of anesthesia is desirable. We describe an experimental technique to record MAPs in conscious dogs by means of conventional rubber introducers which are implanted into the internal jugular vein. Atrial as well as ventricular MAPs can be simultaneously measured without complications. Pacing thresholds are low and stable over time. Continuous MAP recordings of stable amplitude can be achieved from the same endocardial site for periods up to 1h. Antegrade and retrograde atrioventricular nodal conduction properties can be assessed. Programmed stimulation can be performed to simultaneously determine local refractory periods and MAP duration at cycle lengths from 500 to 200ms. In awake, unsedated dogs measuring MAPs via rubber introducers permits safe, long-term recording of MAPs. Such recordings may be useful for safety pharmacologic studies in evaluating cardiovascular and noncardiovascular drugs with respect to their effects on repolarization. In various canine in vivo models including in vivo models of long QT syndrome, heart failures or sudden cardiac death, the present technique permits electrophysiologic measurements without the interference of anesthesia.

Vorhofflimmern: Molekularbiologische Grundlagen

HintergrundVorhofflimmern ist die häufigste anhaltende Herzrhythmusstörung. Die Arrhythmie ist in den meisten Fällen erworben, in Einzelfällen kann sie familiär gehäuft, mit autosomal dominantem Erbgang, auftreten. Die zelluläre, genetische und molekularbiologische Grundlagenforschung hat in den letzten Jahren erheblich zu einer Erweiterung unseres Verständnisses von dem Mechanismen, die für die Initiierung, die Aufrechterhaltung und für die Chronifizierung der Rhymthmusstörung verantwortlich sind, beigetragen. Bei familiärem Vorhofflimmern konnte mittlerweile der mit der Erkrankung assoziierte Lokus kartiert werden (Chromosom 10q22–y23), die Identifikation des verantwortlichen Gens steht noch aus.n Atriales Remodeling Ganz im Vordergrund steht das Konzept des sog. atrialen Remodelings. Hierunter werden all die Mechanismen und Veränderungen dazu neigt, sich selbst aufrechtzuerhalten (“atrial fibrillation begets atrial fibrillation”). Den entscheidenden Reiz für das Auftreten von atrialem Remodeling bildet die hohe Frequenz des flimmernden Vorhofs.n Perspektive: Durch weitere Fortschritte bei der Aufklärung der zugrunde liegenden Mechanismen und Integration der erhobenen Befunde darf zukünftig eine Optimierung der Behandlung von Vorhofflimmern, die auch heute noch oft unbefriedigend ist, erhofft werden.BackgroundAtrial fibrillation is the most frequent form of sustained arrhythmia. In most cases the arrhythmia is acquired, in rarer cases it may occur as a familial disease with a autosomal dominant pattern of inheritance. Recent advances in molecular biology and genetics have had a major impact on our understanding of the mechanisms responsible for the initiation, maintenance and chronification of the arrhythmia. Recently, the chromosomal locus for familial atrial fibrillation has been mapped to chromosome 10q22–q23, however, so far the causative gene has not been identified.n Atrial Remodeling: Atrial fibrillation itself modifies atrial electrical properties in a way that promotes the occurrence and maintenance of the arrhythmia, in other words “atrial fibrillation begets atrial fibrillation”. The principle stimulus for atrial remodeling is the rapid atrial rate.n Perspectives: It is hoped that the results of future studies will not only further improve our understanding of the mechanisms underlying atrial fibrillation but may also help to develop new therapeutic strategies.