Showing papers by "Paulus Kirchhof published in 2003"

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

Abstract: Aims The 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. Methods and results During a period of 60 months, 158 patients underwent the ajmaline test in our institution. Ajmaline was given intravenously in fractions (10 mg every two minutes) up to a target dose of 1 mg/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. Conclusion The 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.

Familial Hypertrophic Cardiomyopathy-Linked Mutant Troponin T Causes Stress-Induced Ventricular Tachycardia and Ca2+-Dependent Action Potential Remodeling

Abstract: The cardiac troponin T (TnT) I79N mutation has been linked to familial hypertrophic cardiomyopathy and high incidence of sudden death, despite causing little or no cardiac hypertrophy in patients. Transgenic mice expressing mutant human TnT (I79N-Tg) have increased cardiac contractility, but no ventricular hypertrophy or fibrosis. Enhanced cardiac function has been associated with myofilament Ca2+ sensitization, suggesting altered cellular Ca2+ handling. In the present study, we compare cellular Ca2+ transients and electrophysiological parameters of 64 I79N-Tg and 106 control mice in isolated myocytes, isolated perfused hearts, and whole animals. Ventricular action potentials (APs) measured in isolated I79N-Tg hearts and myocytes were significantly shortened only at 70% repolarization. No significant differences were found either in L-type Ca2+ or transient outward K+ currents, but inward rectifier K+ current (IK1) was significantly decreased. More critically, Ca2+ transients of field-stimulated ventricular I79N-Tg myocytes were reduced and had slow decay kinetics, consistent with increased Ca2+ sensitivity of I79N mutant fibers. AP differences were abolished when myocytes were dialyzed with Ca2+ buffers or after the Na+-Ca2+ exchanger was blocked by Li+. At higher pacing rates or in presence of isoproterenol, diastolic Ca2+ became significantly elevated in I79N-Tg compared with control myocytes. Ventricular ectopy could be induced by isoproterenol-challenge in isolated I79N-Tg hearts and anesthetized I79N-Tg mice. Freely moving I79N-Tg mice had a higher incidence of nonsustained ventricular tachycardia (VT) during mental stress (warm air jets). We conclude that the TnT-I79N mutation causes stress-induced VT even in absence of hypertrophy and/or fibrosis, arising possibly from the combination of AP remodeling related to altered Ca2+ transients and suppression of IK1.

Dynamic regulation of MEK/Erks and Akt/GSK-3β in human end-stage heart failure after left ventricular mechanical support: myocardial mechanotransduction-sensitivity as a possible molecular mechanism

Abstract: Objective: Left ventricular assist devices (LVAD) are used to ‘bridge’ patients with end-stage heart failure to transplantation. After long-term LVAD support, ventricular function may partially recover, a process called ‘reverse remodeling’. As several kinase-mediated signal transduction pathways have been implicated in the development of cardiac hypertrophy and failure, we examined the activities of the Erks, MEKs, Akt, GSK-3β, p70S6K, JNKs and p38 under LVAD support as well as during single myocyte strain and whole heart stretch. Methods: Western blotting and immunohistochemistry were performed using phospho-specific antibodies in matched samples from ten patients with end-stage heart failure before and after LVAD. Cyclic strain was performed in rat neonatal cardiac myocytes, and tensile stretch applied to Langendorff-perfused mouse hearts via a left ventricular balloon. Results: The activity of Erks and Akt in failing hearts dramatically decreased after LVAD support, while that of GSK-3β increased. There was an endo/epicardial gradient for Erk activity which persisted after LVAD despite the reduction of total Erk activity. TUNEL-positivity and myocyte size decreased after LVAD, but independently of changes in kinase activity. In cardiomyocytes and Langendorff-perfused mouse hearts both strain/stretch and its relief regulated the activities of Erks, Akt, and GSK-3β. Conclusion: Erks and Akt/GSK-3β are highly responsive to myocyte stretch in vitro and in vivo, and may be sensitive molecular parameters of ‘reverse remodeling’ under LVAD support.

Effect of pacing and mexiletine on dispersion of repolarisation and arrhythmias in DeltaKPQ SCN5A (long QT3) mice.

Abstract: Objective: It has been suggested that both pacing and treatment with mexiletine may reduce torsade de pointes (TdP) arrhythmias in patients with long QT syndrome 3 (LQT3), but it is not fully understood how these interventions could prevent TdP. We therefore studied the effects of pacing and mexiletine in mice with a heterozygous knock-in ΔKPQ SCN5AΔ/+ deletion (SCN5A-Tg), a murine LQT3 model. Methods: Three right and left ventricular monophasic action potentials (MAPs) were simultaneously recorded in Langendorff-perfused hearts of SCN5A-Tg and wild type (WT) littermates. AV block was induced, and pacing was performed at baseline and during mexiletine infusion (4 μg/ml). MAP recordings were analysed for action potential duration (APD), APD dispersion, and early afterdepolarisations (EADs) and related to spontaneous arrhythmias. Results: After inducing AV block, SCN5A-Tg hearts were bradycardic [SCN5A-Tg 532±60 vs. WT 284±48 ms cycle length (CL, mean±S.E.M., P <0.05(*))]. EADs occurred in 16/18, and polymorphic ventricular tachycardia (pVT) in 11/18 SCN5A-Tg but not in 19 WT. SCN5A-Tg had longer APD than WT hearts*. At CL of 200 ms and longer, APD dispersion was higher in SCN5A-Tg [dispersion (APD70): 12±3 ms vs. 5±2 ms at CL=200 ms*], and increased to 35±4 ms* directly prior to pVT episodes. Sudden rate accelerations initially increased APD dispersion due to EADs and APD alternans in SCN5A-Tg, but pacing then reduced APD dispersion. Pacing suppressed ( n =9/9) and prevented ( n =49/50) pVT. Mexiletine shortened APD at long CL*, and suppressed pVT ( n =4/5*), but did not prevent pVT during normal rhythm. Conclusions: Bradycardia, increased dispersion of APD and EADs provoke ventricular ectopy and pVT in SCN5A-Tg hearts. Ventricular pacing reduces APD dispersion, suppresses EADs and prevents pVT in SCN5A-Tg hearts. These effects provide a pathophysiological rationale for pacing in LQT3.

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

Abstract: 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.

Endocardial mapping of right ventricular outflow tract tachycardia using noncontact activation mapping.

Abstract: Introduction: Activation mapping and pace mapping identify successful ablation sites for catheter ablation of right ventricular outflow tract (RVOT) tachycardia. These methods are limited in patients with nonsustained tachycardia or isolated ventricular ectopic beats. We investigated the feasibility of using noncontact mapping to guide the ablation of RVOT arrhythmias. Methods and Results: Nine patients with RVOT tachycardia and three patients with ectopic beats were studied using noncontact mapping. A multielectrode array catheter was introduced into the RVOT and tachycardia was analyzed using a virtual geometry. The earliest endocardial activation estimated by virtual electrograms was displayed on an isopotential color map and measured33 ± 13 msecbefore onset of QRS. Virtual unipolar electrograms at this site demonstrated QS morphology. Guided by a locator signal, ablation was performed with a mean of6.9 ± 2.2radiofrequency deliveries. Acute success was achieved in all patients. During follow-up, one patient had a recurrence of RVOT tachycardia. Compared with patients(n = 21)who underwent catheter ablation using a conventional approach, a higher success rate was achieved by noncontact mapping. Procedure time was significantly longer in the noncontact mapping group. Fluoroscopy time was not significantly different in the two groups. Conclusion: Noncontact mapping can be used as a reliable tool to identify the site of earliest endocardial activation and to guide the ablation procedure in patients with RVOT tachycardia and in patients with ectopic beats originating from the RVOT. (J Cardiovasc Electrophysiol, Vol. 14, pp. 602-608, June 2003)

Amiodarone-induced postrepolarization refractoriness suppresses induction of ventricular fibrillation.

Abstract: It is still incompletely understood why amiodarone is such a potent antiarrhythmic drug. We hypothesized that chronic amiodarone treatment produces postrepolarization refractoriness (PRR) without conduction slowing and that PRR modifies the induction of ventricular arrhythmias. In this study, the hearts of 15 amiodarone-pretreated (50 mg/kg p.o. for 6 weeks) rabbits and 13 controls were isolated and eight monophasic action potentials were simultaneously recorded from the epicardium and endocardium of both ventricles. Steady-state action potential duration (APD), conduction times, refractory periods, and dispersion of action potential durations were determined during programmed stimulation and during 50-Hz burst stimuli, and related to arrhythmia inducibility. Amiodarone prolonged APD by 12 to 15 ms at pacing cycle lengths of 300 to 600 ms ( p < 0.05) but did not significantly increase conduction times or dispersion of APD. Amiodarone prolonged refractoriness more than action potential duration, resulting in PRR (refractory period − APD at 90% repolarization, 14 ± 10 ms, p < 0.05 versus controls). PRR curtailed the initial sloped part of the APD restitution curve by 20%. During burst stimulation, pronounced amiodarone-induced PRR (40 ± 15 ms, p < 0.05 versus controls) reduced the inducibility of ventricular arrhythmias ( p < 0.05 versus controls). Furthermore, in 35% of bursts only monomorphic ventricular tachycardias and no longer ventricular fibrillation were inducible in amiodarone-treated hearts ( p < 0.05 versus controls). Chronic amiodarone treatment prevents ventricular tachycardias by inducing PRR without much conduction slowing, thereby curtailing the initial part of APD restitution. PRR without conduction slowing is a desirable feature of drugs designed to prevent ventricular arrhythmias.

Altered sinus nodal and atrioventricular nodal function in freely moving mice overexpressing the A1 adenosine receptor

Abstract: To investigate whether altered function of adenosine receptors could contribute to sinus node or atrioventricular (AV) nodal dysfunction in conscious mammals, we studied transgenic (TG) mice with c...

Effect of electrode position on the outcome of cardioversion.

Abstract: Acute termination of atrial fibrillation is the starting point of any therapy aimed at preventing atrial fibrillation and improves cardiac output in patients with hemodynamic compromise due to the arrhythmia. External electrical cardioversion is a simple procedure to terminate persistent atrial fibrillation in the majority of cases. Initially, Lown et al. used an anterior-lateral position of electrodes to apply a cardioversion shock. Recent pathophysiological studies have shown that atrial fibrillation is maintained by functional re-entry circuits anchored in the left atrium. As the left atrium is located posteriorly in the thorax, an anterior-posterior electrode position may be more efficient for external cardioversion of atrial fibrillation than the commonly used anterior-lateral electrode position. Several recent studies have confirmed that an anterior-posterior electrode position is superior to an anterior-lateral electrode position for external cardioversion of atrial fibrillation. There are no indications that an anterior-posterior electrode position is less safe than an anterior-lateral electrode position. We therefore suggest that an anterior-posterior electrode position should initially be used for external cardioversion of atrial fibrillation.

Incessant supraventricular tachycardia with constant 1:2 atrioventricular ratio: a longitudinally dissociated atrioventricular node?

Abstract: We report a patient with incessant, exercise-limiting supraventricular tachycardia on the ventricular level and a constant 1:2 atrioventricular relation. Careful mapping of the AV nodal region revealed His alternans in the inferior AV nodal area and nonalternating His morphologies in the superior His region. Radiofrequency catheter ablation in the inferior AV node cured the patient (11-month follow-up). Constant dual ventricular activation, His alternans, distinct His morphologies in the superior and inferior His, and long-term suppression of the tachycardia by ablation in the so-called slow pathway region of the AV node are suggestive of permanent dual anterograde AV nodal conduction in this patient.(J Cardiovasc Electrophysiol, Vol. 14, pp. 316-319, March 2003)

Effect of sotalol and acute ventricular dilatation on action potential duration and dispersion of repolarization after defibrillation shocks.

Abstract: Ventricular dilatation shortens action potential duration and increases the defibrillation threshold, whereas sotalol prolongs action potential duration and may decrease the defibrillation threshold. Whether these action potential changes remain after defibrillation shocks, and how they relate to defibrillation success, is not known. In this study, eight monophasic action potentials were recorded simultaneously during electrical defibrillation (shock strength: 20%-200% of the defibrillation threshold) in 16 normal and acutely dilated isolated rabbit hearts at baseline and after addition of sotalol (2 x 10-5 M). Post-shock action potential duration (PS-APD) and dispersion of PS-APD [Disp(PS-APD)] of monophasic action potentials were analyzed after 322 defibrillation shocks at different repolarization levels and related to defibrillation success. Acute ventricular dilatation shortened PS-APD, whereas sotalol prolonged PS-APD. Successful defibrillation was associated with lower Disp(PS-APD) at all repolarization levels in the normal and dilated heart at baseline and with sotalol (mean difference: 33%-46%, all P < 0.005). Minimal PS-APD was longer (mean difference: 5%-11%), while maximal PS-APD was shorter (mean difference: 2%-16%) after successful defibrillation shocks than after failing defibrillation shocks. Therefore, sotalol prolongs action potential duration after defibrillation shocks. Synchronization of repolarization, caused by both prolongation of short PS-APD and shortening of long PS-APD, is associated with successful defibrillation in the normal, acutely dilated, and sotalol-treated heart.

Atrial fibrillation, thromboembolism, and haemostasis: causal or casual associations?

Abstract: Atrial fibrillation is the most common cardiac arrhythmia (1, 2) and is associated with an increased risk of death (3). In addition to the hemodynamic consequences such as loss of atrial contraction and loss of the chronotropic response to increased circulatory demands, atrial fibrillation causes important morbidity and mortality due to thromboembolic events, mainly stroke and myocardial infarction (4). Although atrial fibrillation can be terminated in the vast majority of patients (5), its recurrence can often not effectively be prevented (6-8). In these patients, heart rate control and anticoagulation are primary therapeutic goals. Oral anticoagulation with warfarin or phenprocoumon prevents approximately two thirds of thromboembolic events in patients with atrial fibrillation (9, 4, 10). Apart from typical risk factors for atherosclerosis (10), it is so far difficult to identify patients at high risk for thromboembolic events. In this issue, Vene et al. report that high baseline D-dimer levels are associated with future cardiovascular events in a series of 113 patients with chronic atrial fibrillation (11). Oral anticoagulation with warfarin reduced D-dimer levels, but D-dimer levels remained elevated in patients with cardiovascular events when compared to patients without events. The study is based on the previous concept of a “pro-coagulatory state” in patients with atrial fibrillation (12, 13) that may be initiated by reduced blood flow in the paralyzed, fibrillating atrium. Elevated D-dimer levels indicate increased fibrin formation and/or degradation and, hence, provide a biological marker for such a “pro-coagulatory state”. In addition, D-dimers may also be increased as part of an acute inflammatory response, and potentially also in extensive atherosclerotic disease. In view of this consideration, it is unfortunate that other markers of inflammation (CRP, white blood cell count) were not reported in the publication by Vene et al.(11). High D-dimer levels have been found in survivors of a stroke (14, 15), patients with atherosclerosis (16), and in patients with dementia (17). The present results confirm the suspicion that high fibrin turnover may be a contributing (risk) factor rather than a consequence of cardiovascular events in patients with atrial fibrillation. Whether this is due to the suspected pro-coagulatory effect of atrial fibrillation, due to accompanying inflammation, or due to extensive atherosclerosis, may be determined in future studies. The study by Vene et al. (11) also illustrates the advantages and disadvantages of a single centre study: Patient allocation and treatment was relatively uniform, but the small patient number required a combined end point without any effect on mortality reported. These limitations notwithstanding the data by Vene et al. (11) are a valid starting point for larger, prospective studies to determine the value of D-dimer levels for the prediction of cardiovascular events in patients with atrial fibrillation. Such studies will answer the open question whether D-dimer levels are a modifiable risk factor for thromboembolic events, as has been suggested by others (18), or an epiphenomenon of atherosclerosis and inflammation in patients with atrial fibrillation. In another article of the current issue, Poli and co-authors (19) published a study on the contribution of a specific genetic alteration to thromboembolic events in patients with atrial fibrillation. Due to the clinical observation that, despite a high risk for cerebral stroke, the majority of patients with atrial fibril© 2003 Schattauer GmbH, Stuttgart