M. Borggrefe

Anterior-posterior versus anterior-lateral electrode positions for external cardioversion of atrial fibrillation: a randomised trial

BACKGROUND External cardioversion is a readily available treatment for persistent atrial fibrillation. Although anatomical and electrophysiological considerations suggest that an anterior-posterior electrode position should create a more homogeneous shock-field gradient throughout the atria than an anterior-lateral position, both electrode positions are equally recommended for external cardioversion in current guidelines. We undertook a randomised trial comparing the two positions with the endpoint of successful cardioversion. METHODS 108 consecutive patients (mean age 60 years [SD 16]) with persistent atrial fibrillation (median duration 5 months, range 0.1-120) underwent elective external cardioversion by a standardised step-up protocol with increasing shock strengths (50-360 J). Electrode positions were randomly assigned as anterior-lateral or anterior-posterior. If sinus rhythm was not achieved with 360 J energy, a single cross-over shock (360 J) was applied with the other electrode configuration. A planned interim analysis was done after these patients had been recruited; it was by intention to treat. FINDINGS Cardioversion was successful in a higher proportion of the anterior-posterior than the anterior-lateral group (50 of 52 [96%] vs 44 of 56 [78%], difference 23.7% (95% CI 9.1-37.8, p=0.009). Cross-over from the anterior-lateral to the anterior-posterior electrode position was successful in eight of 12 patients, whereas cross-over in the other direction was not successful (two patients). After cross-over, cardioversion was successful in 102 of 108 randomised patients (94%). INTERPRETATION An anterior-posterior electrode position is more effective than the anterior-lateral position for external cardioversion of persistent atrial fibrillation. These results should be considered in clinical practice, for the design of defibrillation electrode pads, and when guidelines for cardioversion of atrial fibrillation are updated.

Short-term versus long-term antiarrhythmic drug treatment after cardioversion of atrial fibrillation (Flec-SL): a prospective, randomised, open-label, blinded endpoint assessment trial

BACKGROUND Antiarrhythmic drugs prolong the atrial action potential and refractory period, and thereby prevent recurrent atrial fibrillation after cardioversion. The atrial action potential normalises after 2-4 weeks of sinus rhythm, suggesting that antiarrhythmic drugs might not be needed beyond that period. Therefore, we investigated whether short-term antiarrhythmic drug treatment after cardioversion is non-inferior to long-term treatment. METHODS We enrolled patients in a prospective, randomised, open-label, blinded endpoint assessment trial between May 4, 2007, and March 12, 2010, at 44 centres in Germany. Eligible patients were adults with persistent atrial fibrillation undergoing planned cardioversion. After successful cardioversion, patients were randomly assigned in permuted blocks of six per centre to: no antiarrhythmic drug treatment (control); treatment with flecainide (200-300 mg per day) for 4 weeks (short-term treatment); or flecainide for 6 months (long-term treatment). The primary endpoint was time to persistent atrial fibrillation or death. Patients and clinicians were unmasked to group assignment and treatment. The primary outcome was assessed in a core laboratory, members of which were masked to treatment group. Patients were monitored for 6 months by daily telemetric electrocardiograph (ECG) and centrally adjudicated Holter ECG recordings whenever atrial fibrillation was noted in two consecutive ECGs. Analyses were per protocol. This trial is registered, number ISRCTN62728742. FINDINGS After assay sensitivity was established with 4-week follow-up data from 242 patients showing that flecainide was superior to no treatment (Kaplan-Meier survival 70·2%vs 52·5%; p=0·0160), the trial continued to compare short-term versus long-term treatment. The primary outcome occurred in 120 (46%) of 261 patients receiving short-term treatment and in 103 (39%) of 263 patients receiving long-term treatment (event-free survival 48·4% [95% CI 41·9-55·0] vs 56·4% [49·1-63·6]; Kaplan-Meier estimate of difference 7·9% [-1·9 to 17·7]; p=0·2081 for non-inferiority; margin prespecified at 12%). In a post-hoc landmark analysis of patients who had not reached the primary endpoint in the first month, long-term treatment was superior to short-term treatment (Kaplan-Meier estimate of difference 14·3% [5·1-23·6]; hazard ratio 0·31 [0·18-0·56]; p=0·0001). INTERPRETATION Short-term antiarrhythmic drug treatment after cardioversion is less effective than is long-term treatment, but can prevent most recurrences of atrial fibrillation. FUNDING The German Federal Ministry of Education and Research, Deutsche Forschungsgemeinschaft, 3M Medica, and MEDA Pharmaceuticals.

Insights into the location of type I ECG in patients with Brugada syndrome: Correlation of ECG and cardiovascular magnetic resonance imaging

BACKGROUND Brugada syndrome is characterized by ST-segment abnormalities in V1-V3. Electrocardiogram (ECG) leads placed in the 3rd and 2nd intercostal spaces (ICSs) increased the sensitivity for the detection of a type I ECG pattern. The anatomic explanation for this finding is pending. OBJECTIVE The purpose of the study was to correlate the location of the Brugada type I ECG with the anatomic location of the right ventricular outflow tract (RVOT). METHODS Twenty patients with positive ajmaline challenge and 10 patients with spontaneous Brugada type I ECG performed by using 12 right precordial leads underwent cardiovascular magnetic resonance imaging (CMRI). The craniocaudal and lateral extent of the RVOT and maximal RVOT area were determined. Type I ECG pattern and maximal ST-segment elevation were correlated to extent and maximal RVOT area, respectively. RESULTS In all patients, Brugada type I pattern was found in the 3rd ICS in sternal and left-parasternal positions. RVOT extent determined by using CMRI included the 3rd ICS in all patients. Maximal RVOT area was found in 3 patients in the 2nd ICS, in 5 patients in the 4th ICS, and in 22 patients in the 3rd ICS. CMRI predicted type I pattern with a sensitivity of 97.2%, specificity of 91.7%, positive predictive value of 88.6%, and negative predictive value of 98.0%. Maximal RVOT area coincided with maximal ST-segment elevation in 29 of 30 patients. CONCLUSION RVOT localization determined by using CMRI correlates highly with the type I Brugada pattern. Lead positioning according to RVOT location improves the diagnosis of Brugada syndrome.

A novel nonfluoroscopic catheter visualization system (LocaLisa) to reduce radiation exposure during catheter ablation of supraventricular tachycardias

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Clofilium in the isolated perfused rabbit heart: A new model to study proarrhythmia induced by class III antiarrhythmic drugs

AbstractObjective: The clinical usefulness of class III antiarrhythmic drugs for the treatment of tachyarrhythmias is limited by their potential proarrhythmic effects, mainly torsades-depointes (TdP). The goal of this experimental study was to develop an isolated whole-heart model exhibiting typical characteristics of class III drug-induced ventricular arrhythmias. Methods: Isolated rabbit hearts were perfused with a Krebs-Henseleit buffer containing 10 μM clofilium and then exposed to a modified Krebs-Henseleit buffer with 2.0 mM K2 and 0.5 mM Mg2+. Hearts subjected to either clofilium alone or modified buffer alone were used as controls. Results: Under clofilium the QT interval increased from 187±16 to 282±33 ms. Within 8 to 25 s after the change of the perfusate, ventricular arrhythmias developed in all hearts associated with a further QT prolongation to 380±73 ms when the first ventricular extrasystole occurred. Simultaneously, the monophasic action potential durations increased relatively more during late repolarization; from 99±21 to 110±25 ms (+11%) at 50% repolarization, from 143±24 to 178±40 ms (+24%) at 70%, and from 200±30 to 275±53 ms (+38%) at 90%. The predominant rhythm was polymorphic with either two alternating or multiple QRS morphologies exhibiting the characteristic features of torsades-depointes. All control hearts stayed in normal sinus rhythm. Conclusion: Under the conditions selected, the isolated perfused rabbit heart represents a useful experimental approach to study the proarrhythmic effects of class III agents. This model provides a convenient way to manipulate the ionic and pharmacologic millieu in a preparation conserving the functional anatomy of the whole organ without interference by cardiovascular reflexes. It might be useful for analyzing the conditions favoring and preventing drug-induced torsades-depointes.

The LQT syndromes--current status of molecular mechanisms.

Molekulargenetische Erkenntnisse bei angeborenen Herzrhythmusstörungen wurden, im Vergleich beispielsweise zu den familiären Kardiomyopathien, relativ spät bekannt, was zu einem Teil auf eine hohe Sterblichkeit und einen frühzeitigen Krankheitsbeginn dieser Erkrankungen zurückzuführen ist. Die Durchführung von genetischen Kopplungsanalysen, für die große Familien mit vielen Merkmalsträgern notwendig sind, war zunächst erschwert. 1991 wurde erstmals ein Genort auf dem Chromosom 11p15.5 beschrieben, der mit angeborenem QT-Syndrom assoziiert ist. Das ursächliche Gen KCNQ1, das eine Untereinheit eines Kaliumkanals kodiert, wurde erst 1996 identifiziert. Ferner wurden vier weitere Genloci für QT-Syndrom beschrieben und an drei von vier Mutationen in Genen, die Ionenkanaluntereinheiten kodieren, identifiziert. Zusammenfassend ist das QT-Syndrom eine genetisch heterogene Krankheit kardialer Ionenkanäle. Die Kenntnis der verursachenden Gene für QT-Syndrom hat außerdem zur Identifizierung wichtiger Komponenten geführt, die Ionenströme regulieren und an der Repolarisation beteiligt sind. Mittels In-vitro-Expression wurde gezeigt, daß die strukturell veränderten Ionenkanäle entweder eine Reduktion des Kaliumstromes I (K) während der Phase III des Aktionspotentials oder einen veränderten Natriumstrom während der Phase 0 bedingen. Mittlerweile ist die genomische Struktur der vier LQT-Gene fast vollständig bekannt; Mutationsdetektion mittels SSCP-Analysen und anschließender Sequenzierung hat das diagnostische Spektrum für diese Erkrankung erweitert und ist besonders bei der Diagnosestellung von Patienten, die keine eindeutigen EKG-Veränderungen haben, hilfreich. Die Kenntnis der krankheitsursächlichen Mutation ermöglicht eine präsymptomatische Diagnostik innerhalb einer betroffenen Familie. Derzeit werden Genotyp-Phänotyp-Untersuchungen durchgeführt, um die Penetranz und klinische Expressivität der Erkrankung zu bestimmen und weiteren Aufschlußüber inter- und intrafamiliäre Unterschiede in der Krankheitsmanifestation zu bekommen. In diesem Kapitel wird der jetzige Stand der Molekulargenetik, Elektrophysiologie und klinischen, genotypbezogenen Untersuchungen dargestellt. Our knowledge on the molecular genetics of inherited cardiac arrhythmias is very recent in comparison to the advances of genetics achieved in other inherited cardiac disorders. This is related to the high mortality and early disease onset of these arrhythmias resulting in mostly small nucleus families. Thus, traditional genetic linkage studies that are based on the genetic information obtained from large multi-generation families were made difficult. In 1991, the first chromosomal locus for congenital long-QT (LQT) syndrome was identified on chromosome 11p15.5 (LQT1 locus) by linkage analysis. Meanwhile, the disease-causing gene at the LQT1 locus (KCNQ1), a gene encoding a K+ channel subunit of the IKs channel, and three other, major genes, all encoding cardiac ion channel components, have been identified. Taken together, LQT syndrome turned out to be a heterogeneous channelopathy. Moreover, the power of linkage studies to reveal the genetic causes of the LQT syndrome was also important to identify unknown but fundamental channel components that contribute to the ion currents tuning ventricular repolarization. In-vitro-expression of the altered ion channel genes demonstrated in each case that the altered ion channel function produces prolongation of the action potential and thus the increasing propensity to ventricular tachyarrhythmias. Since these ion channels are pharmacological targets of many antiarrhythmic (and other) drugs, individual and potentially deleterious drug responses may be related to genetic variation in ion channel genes. Very recently, also in acquired LQT syndrome, which is a frequent clinical disorder in cardiology a genetic basis has been proposed in part since mutations in LQT genes have been specifically found. The discovery of ion channel defects in LQT syndrome represents the major achievement in our understanding and implies potential therpeutic options. The knowledge of the genomic structure of the LQT genes now offers the possibility to detect the underlying genetic defect in 80–90% of all patients. With this specific information, containing the type of ion channel (Na+ versus K+ channel) and electrophysiological alteratio n by the mutation (loss-of-function versus change-of-function mutation), gene-directed, elective drug therapies have been initiated in genotyped LQT patients. Based on preliminary data, that were supported by in vitro studies, this approach may be useful in recompensating the characteristic phenotypes in some LQT patients. Mutation detection is a new diagnostic tool which may become of more increasing importance in patients with a normal QTc or just a borderline prolongation of the QTc interval at presentation. These patients represent approximately 40% of all familial cases. Moreover, LQT3 syndrome and idiopathic ventricular fibrillation are allelic disorders and genetically overlap. In both mutations in the LQT3 gene SCN5A encoding the Na+ channel alpha-subunit for INa have been reported. Thus, the clinical nosology of inherited arrhythmias may be reconsidered after elucidation of the underlying molecular bases. Meanwhile, genotype-phenotype correlation in large families are on the way to evaluate intergene, interfamilial, and intrafamilial differences in the clinical phenotype reflecting gene specific, gene-site specific, and individual consequences of a given mutation. LQT syndrome is phenotypically heterogeneous due to the reduced penetrance and variable expressivity associated with the mutations. This paper discusses the current data on molecular genetics and genotype-phenotype correlations and the implications for diagnosis and treatment.

A hybrid approach for quantification of aortic valve stenosis using cardiac magnetic resonance imaging and echocardiography

SummaryWe replaced Dopplerderived stroke volume in the continuity equation (method A) by either right heart catheterizationderived stroke volume (method B) or cardiovascular magnetic resonance–derived stroke volume (method C) to calculate aortic valve area in 20 consecutive patients with moderate or severe aortic stenosis. Comparison of both hybrid methods (methods B and C) by Bland–Altman analysis showed a mean difference near zero, a spread within two standard deviations and very similar limits of agreement. More importantly, all patients were classified into the same category of severity by both methods.

Molecular genetics of arrhythmias – a new paradigm

The molecular genetic background of inherited cardiac arrhythmias has only recently been uncovered. This late development in comparison to other inherited cardiac disorders has partly been due to the high mortality and early disease onset of these arrhythmias resulting in mostly small nucleus families. Thus, traditional genetic linkage studies, which are based on the genetic information obtained from large multi-generation families, were made difficult. Inherited arrhythmogenic disorders can be divided into ‘primary electrical disorders’ (e.g., long-QT [LQT] syndrome) in which a detectable, organic heart disease is not evident, and into inherited diseases of the myocardial structure (e.g., hypertrophic cardiomyopathies) in which the arrhythmias occur combined with the structural alterations. To date, all inherited arrhythmogenic disorders in which the causative genes have been identified turned out to be channelopathies, since the genes encode channel subunits that regulate important ion currents that tune the cardiac action potential. The discovery of the genetic bases of the LQT syndrome became a now methodologic paradigm; because with the use of ‘classical’ genetic linkage strategies (named [positional] candidate strategies) not only the causative genes have been found, but moreover, functional components with a previously unknown but fundamental role for a normal repolarization process were discovered. Disease mutations turned out to be not only a family-specific event with a distinct phenotype and the potential of an additional diagnostic tool, but also, when expressed in heterologous expression systems, characterize the defective ion channel in a topological way and lead to a more specific understanding of ion channel function. Most, if not all, primary electrical cardiac disorders show a high genetic diversity. For the LQT syndromes, sixth disease loci and the responsible gene have been recently discovered (socalled locus or genetic heterogeneity). Within all disease genes, the mutations are spread over the entire gene (allelic heterogeneity); in addition, more than one disease mutation may be present. This complexity requires, at least, complete mutation analysis of all LQT genes before medical advice should be given. Meanwhile, genotype-phenotype correlations in large families are being used to evaluate intergene, interfamilial and intrafamilial differences in the clinical phenotype, reflecting gene specific, gene-site specific and individual consequences of a given mutation. A widespread phenotypic heterogenity even within mutation carriers in the same family raises the importance of modifying factors and genes that are mostly unknown to date. The reduced penetrance and variable expressivity associated with the LQT mutations remain still to be explained. First insights into the complex actions of mutations are being extracted, from expression data; these preliminary results may lead to potential implications for a specific (gene-site directed) therapy. This paper discusses the current data on molecular genetics and genotype-phenotype correlations in LQT syndrome and related disorders and the potential implications for diagnosis and treatment.

Prevalence, Clinical Characteristics, and Predictors of Patients with Thromboembolic Events in Takotsubo Cardiomyopathy

Background Several acute complications related to takotsubo cardiomyopathy (TTC) have been documented recently. However, the incidence and clinical significance of acute thromboembolic events in TTC is not well established. Methods A detailed investigation of the clinical characteristics and in-hospital complications of 114 consecutive patients diagnosed with TTC between January 2003 and September 2015 was carried out. This study was initiated to reveal the predictors, clinical significance, and short-term and long-term outcomes of patients with TTC associated with acute thromboembolic events on index presentation. Results The incidence of acute thromboembolic events related to TTC was around 12.2%, and these included ventricular thrombi, cerebrovascular events, retinal and brachial artery pathologies, renal, splenic, and aortic involvement. The most frequent complication on initial presentation was cardiogenic shock (20%) accompanied with pulmonary congestion (20%). Interestingly, patients experiencing thromboembolic events had higher C-reactive protein (CRP) levels as compared to the non-thromboembolic group (P = 0.02). Certain thromboembolic events were characterized by the presence of ST-segment elevation in electrocardiogram (P 0.02). Chest pain was the primary symptom in these patients (P 0.09). Furthermore, there was significant right ventricular involvement (as assessed by transthoracic echocardiography) in patients presenting with an acute thromboembolic event (P 0.08). A Kaplan–Meier analysis indicated a significantly higher mortality rate over a mean follow-up of three years in the thromboembolic group than the non-thromboembolic group (log-rank, P = 0.02). Conclusions Our results confirmed the relative common occurrence of thromboembolic events in the setting of TTC. Inflammation might play an important role in the development of thromboembolic events, and a right ventricular involvement and ST-segment elevation could be positive predictors for this occurrence. In order to circumvent the risk of a negative outcome, it is recommended that an anticoagulation therapy be initiated in all high-risk patients.

Low stroke risk after elective cardioversion of atrial fibrillation: An analysis of the Flec-SL trial

BACKGROUND Current recommendations for anticoagulation management during cardioversion are largely based on historical data and expert consensus. METHODS AND RESULTS To characterize current practice of anticoagulation during and after elective cardioversion for AF and the risk of stroke and bleeding events, all patients enrolled into the Flec-SL trial were analyzed for stroke/transient ischemic attack and major bleeds after cardioversion. Flec-SL (ISRCTN62728743, NCT00215774) enrolled 635 patients (mean age 63.7 ± 10.9, 66% male). 629 (99.1%) patients received periprocedural anticoagulation, 556 (87.6%) were adequately anticoagulated following current recommendations. 202 (31.8%) patients underwent transesophageal echocardiography-guided cardioversion. Electrical cardioversion was used in 508 patients (80.0%), pharmacological cardioversion in 127 (20%). Six patients suffered from stroke (n = 5) or transient ischemic attack (3 TIAs in 1 patient, event rate 0.9%, 95% CI 0.4-2.1), five others from major bleeds (event rate 0.8%, 95% CI 0.3-1.9), consistent with the low reported event rates in prior studies. Three strokes occurred in the first 5 days after cardioversion. Events were independent of type of cardioversion or the use of TEE to exclude thrombi. CONCLUSION Strokes are rare in this large, prospectively followed cohort of patients undergoing cardioversion for AF and receiving antithrombotic therapy following local routine. These results support adherence to current recommendations for anticoagulation during cardioversion of AF.