Images in cardiovascular medicine. Life-threatening neonatal arrhythmia: successful treatment and confirmation of clinically suspected extreme long QT-syndrome-3.
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Bradycardia↗
Biomedical subjects
Wilhelm Haverkamp
Publications and source records attributed to Wilhelm Haverkamp.
Genetic variations of KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 in drug-induced long QT syndrome patients.
Administration of specific drugs may occasionally induce acquired long QT syndrome (aLQTS), a disorder that predisposes to ventricular arrhythmias, typically of the torsade de pointes (TdP) type, and sudden cardiac death. "Forme fruste" mutations in congenital LQTS (cLQTS) genes have been reported repeatedly as the underlying cause of aLQTS, and are therefore considered as an important risk factor. We evaluated the impact of genetic susceptibility for aLQTS through mutations in cLQTS genes. Five cLQTS genes ( KCNH2, KCNQ1, SCN5A, KCNE1, KCNE2) were thoroughly screened for genetic variations in 32 drug-induced aLQTS patients with confirmed TdP and 32 healthy individuals. Missense forme frust mutations were identified in four aLQTS patients: D85N in KCNE1 (two cases), T8A in KCNE2, and P347S in KCNH2. Three other missense variations were found both in patients and controls, and are thus unlikely to significantly influence aLQTS susceptibility. In addition, 13 silent and six intronic variations were detected, four of which were found in a single aLQTS patient but not in the controls. We conclude that missense mutations in the examined cLQTS genes explain only a minority of aLQTS cases.
Adolescent↗
Phytanic acid accumulation is associated with conduction delay and sudden cardiac death in sterol carrier protein-2/sterol carrier protein-x deficient mice.
INTRODUCTION: The sterol carrier protein-2 gene encodes two functionally distinct proteins: sterol carrier protein-2 (SCP2, a peroxisomal lipid carrier) and sterol carrier protein-x (SCPx, a peroxisomal thiolase known as peroxisomal thiolase-2), which is involved in peroxisomal metabolism of bile acids and branched-chain fatty acids. We show in this study that mice deficient in SCP2 and SCPx (SCP2null) develop a cardiac phenotype leading to a high sudden cardiac death rate if mice are maintained on diets enriched for phytol (a metabolic precursor of branched-chain fatty acids). METHODS AND RESULTS: In 210 surface and 305 telemetric ECGs recorded in wild-type (C57BL/6; wt; n = 40) and SCP2 null mice (n = 40), no difference was observed at baseline. However, on diet, cycle lengths were prolonged in SCP2 null mice (262.9 +/- 190 vs 146.3 +/- 43 msec), AV conduction was prolonged (58.3 +/- 17 vs 42.6 +/- 4 ms), and QRS complexes were wider (19.1 +/- 5 vs 14.0 +/- 4 ms). In 11 gene-targeted Langendorff-perfused hearts isolated from SCP2 null mice after dietary challenge, complete AV blocks (n = 5/11) or impaired AV conduction (Wenckebach point 132 +/- 27 vs 92 +/- 10 msec; P < 0.05) could be confirmed. Monophasic action potentials were not different between the two genotypes. Left ventricular function studied by echocardiography was similar in both strains. Phytanic acid but not pristanic acid accumulated in the phospholipid fraction of myocardial membranes isolated from SCP2 null mice. CONCLUSION: Accumulation of phytanic acid in myocardial phospholipid membranes is associated with bradycardia and impaired AV nodal and intraventricular impulse conduction, which could provide an explanation for sudden cardiac death in this model.
Animals↗
Comparison of the in vitro electrophysiologic and proarrhythmic effects of amiodarone and sotalol in a rabbit model of acute atrioventricular block.
The mechanisms for the different proarrhythmic potential of antiarrhythmic drugs in the presence of comparable QT prolongation are not completely understood. The reasons for the lower proarrhythmic potential of amiodarone as compared with other class-III antiarrhythmic drugs such as sotalol, a fact that has been well established for years, is insufficiently known. Therefore, the aim of our study was to assess the different electrophysiologic effects of amiodarone and sotalol in a previously developed experimental model of proarrhythmia. In eight male rabbits, amiodarone (280-340 mg/d) was fed over a period of six weeks. Hearts were excised and retrogradely perfused. Up to eight simultaneous epi- and endocardial monophasic action potentials (MAP) were recorded. Results were compared with sotalol-treated (10-50-100 microM) hearts (n = 13). Amiodarone and sotalol (50 microM and 100 microM) led to a significant increase in QT interval (mean increase: amiodarone: 31 +/- 6 ms; sotalol: 41 +/- 4 ms and 61 +/- 9 ms) and MAP-duration (mean increase-MAP90: amiodarone: 20 +/- 5 ms; sotalol: 17 +/- 5 ms and 25 +/- 8 ms) (P < 0.01). In bradycardic (AV-blocked) hearts, MAP-recordings demonstrated reverse-use dependence and a significant increase in dispersion of repolarization (MAP90) in the presence of sotalol (P < 0.01), but not in amiodarone-treated hearts (10%; p = ns). Sotalol led to early afterdepolarizations (EAD) and torsade de pointes (TdP) after lowering of potassium concentration (6 of 13 hearts). In amiodarone-treated, hypokalemic hearts, no EAD or TdP occurred. Sotalol changed the MAP configuration to a triangular pattern (ratio-MAP90/50: 1.52 as compared with 1.36 at baseline) whereas amiodarone caused a rectangular pattern of MAP prolongation (ratio-MAP90/50: 1.36). In conclusion, these results show no direct correlation between the occurrence of TdP and the degree of QT prolongation. Several factors including reverse-use dependence, dispersion of repolarization, and the propensity to induce early afterdepolarizations but also differences in the action potential configuration may help to understand proarrhythmic side effects of drugs.
Action Potentials↗
Cardiac and ocular pathologies in a mouse model of mucopolysaccharidosis type VI.
Mucopolysaccharidosis type VI (MPS VI) is a lysosomal storage disease caused by a deficiency of arylsulfatase B (ASB) which has its function in the sequential degradation of glycosaminoglycans (GAG). Targeted disruption of the ASB gene resulted in a mouse model of MPS VI that has been closely investigated for skeletal and chondral dysplasia. As ocular and cardiac impairment are also clinically important manifestations of the MPS VI syndrome, the present study was initiated for detailed biochemical, histologic and functional analysis of cornea, optic nerve and heart in ASB-deficient mice. Biochemical evidence for GAG-storage could be obtained for liver, kidney, spleen and myocardium as well as for heart valves, cornea and optic nerve from ASB-deficient mice. In MPS VI mice, histology revealed structural impairment of corneal stroma and epithelium as well as a thickening of the heart valves. According to histologic investigations, the optic nerve appeared not to be altered. However, GAG-storage in the dura mater could be demonstrated in MPS VI mice. Heart function was assessed by echocardiography. While the dimensions of MPS VI hearts were not altered, these hearts clearly showed decreased myocardial contraction and a 50% reduction of cardiac output. In addition, insufficiencies in the mitral and aortic valves were detected. Thus, ASB-deficient mice resemble the phenotype of human MPS VI not only in the skeletal but also in the ocular and cardiac symptoms. To our knowledge, these in vivo evaluations of heart function represent the first respective investigation of a MPS VI animal model and should provide a valuable measure for therapy studies in the MPS VI mouse.
Animals↗
Effect of pacing and mexiletine on dispersion of repolarisation and arrhythmias in DeltaKPQ SCN5A (long QT3) mice.
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 DeltaKPQ SCN5A(Delta/+) 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 microg/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.
Action Potentials↗
Advances for treating in-hospital cardiac arrest: safety and effectiveness of a new automatic external cardioverter-defibrillator.
OBJECTIVES: The purpose of this study was to prospectively analyze the performance and safety of a new programmable, fully automatic external cardioverter-defibrillator (AECD) in a European multicenter trial. BACKGROUND Although, the response time to cardiac arrest (CA) is a major determinant of mortality and morbidity, in-hospital strategies have not significantly changed during the last 30 years. METHODS: Patients (n = 117) at risk of CA in monitored wards (n = 51) and patients undergoing electrophysiologic testing or implantable cardioverter-defibrillator (ICD) implantation (n = 66) were enrolled. The accuracy of the automatic response of the device to any change of rhythm (lasting >1 s and >4 beats) was confirmed by reviewing the simultaneously recorded Holter data and the programmed parameters. RESULTS: During 1,240 h, 1,988 episodes of rhythm changes were documented. A total of 115 episodes lasted > or =10 s or needed treatment (pacing, n = 32; ICD, n = 51; AECD, n = 35) for termination. The device detected ventricular tachyarrhythmias with a sensitivity of 100% and specificity of 97.6% (true negatives, n = 1,454; true positives, n = 499; false positives, n = 35; false negatives, n = 0). The false positives were all caused by T-wave oversensing during ventricular pacing. There were no complications or adverse events. The mean response time was 14.4 s for those episodes needing a full charge of the capacitor. CONCLUSIONS: This new AECD is safe and effective in detecting, monitoring, and treating spontaneous arrhythmias. This fully automatic device shortens the response time to treatment, and it is likely that it will significantly improve the outcome of patients with in-hospital CA.
Aged↗
Sodium channel gene (SCN5A) mutations in 44 index patients with Brugada syndrome: different incidences in familial and sporadic disease.
The Brugada syndrome (BS) is a distinct form of idiopathic ventricular fibrillation and may cause sudden cardiac death in healthy young individuals. In the surface ECG, BS can be recognized by an atypical right bundle branch block and ST-segment elevation in the right precordial leads. Mutations in the cardiac sodium channel gene SCN5A are only known to cause BS. In a multi-center effort, we have collected clinical data on 44 unrelated index patients and family members and performed a complete genetic analysis of SCN5A. In 37% the disease was familial, whereas in the majority it was sporadic (63%). Five novel SCN5A mutations (2602delC, resulting in: E867X; 2581_2582del TT: F861fs951X; 2673G>A: E1225K; 4435_4437delAAG: K1479del; and 5425C>A: S1812X) were found and were randomly located in SCN5A. Mutation frequencies (SCN5A+) differed significantly between familial (38%) and sporadic disease (0%) (p=0.001). Disease penetrance was complete in the SCN5A+ adult patients, but incomplete in SCN5A+ children (17%). Genetic testing of SCN5A is especially useful in familial disease to identify individuals at cardiac risk. In sporadic cases, however, a genetic basis and the value of mutation screening has to be further determined. These results are in line with a possibly genetic and clinical heterogeneity of BS.
Adolescent↗
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 I(Kr) 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(-5)M and 2 x 10(-5)M) 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.
Action Potentials↗
The ajmaline challenge in Brugada syndrome: diagnostic impact, safety, and recommended protocol.
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 (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. 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.
Adolescent↗
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.
Action Potentials↗
Electrical alternans in long QT syndrome resembling a Brugada syndrome pattern.
Isolated T wave alternans (repolarization alternans) is frequently associated with long QT syndrome. However, electrical alternans involving the P wave, QRS complex, ST segment (depolarization alternans), and the T wave is a rare finding. This report describes a 62-year-old woman with long QT syndrome and an electrical alternans occurring after previous syncope. Alternating QRS complexes showed a prolonged PR interval, a Brugada syndrome resembling pattern of the QRS complexes (elevation and downslope of the ST segments), and a T wave alternans. A genetic basis for the long QT syndrome has been ruled out by sequencing of all coding areas of the LQT genes. Potential mechanisms for the electrical alternans are discussed.
Bundle-Branch Block↗
Endocardial mapping of right ventricular outflow tract tachycardia using noncontact activation mapping.
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 measured 33 +/- 13 msec before onset of QRS. Virtual unipolar electrograms at this site demonstrated QS morphology. Guided by a locator signal, ablation was performed with a mean of 6.9 +/- 2.2 radiofrequency 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.
Adult↗
Prolonged atrial action potential durations and polymorphic atrial tachyarrhythmias in patients with long QT syndrome.
UNLABELLED: Atrial APD and Polymorphic AT in LQTS. INTRODUCTION: Prolongation of the QT interval and torsades de pointes tachycardias due to altered expression or function of repolarizing ion channels are the hallmark of congenital long QT syndrome (LQTS). The same ion channels also contribute to atrial repolarization, and familial atrial fibrillation may be associated with a mutated KVLQT1 gene. We therefore assessed atrial action potential characteristics and atrial arrhythmias in LQTS patients. METHODS AND RESULTS: Monophasic action potentials (MAPs) were simultaneously recorded from the right atrial appendage and the inferolateral right atrium in 10 patients with LQTS (8 with identifiable genotype) and compared to 7 control patients. Atrial arrhythmias also were compared to MAPs recorded in patients with persistent (n = 10) and induced (n = 4) atrial fibrillation. Atrial action potential durations (APD) and effective refractory periods (ERP) were prolonged in LQTS patients at cycle lengths of 300 to 500 msec (APD prolongation 30-41 msec; ERP prolongation 26-52 msec; all P < 0.05). Short episodes of polymorphic atrial tachyarrhythmias (polyAT, duration 4-175 sec) occurred spontaneously or during pauses after pacing in 5 of 10 LQTS patients, but not in controls (P < 0.05). P waves showed undulating axis during polyAT. Cycle lengths of polyAT were longer than during persistent and induced atrial fibrillation. Afterdepolarizations preceded polyAT in 2 patients. The electrical restitution curve was shifted to longer APD in LQTS patients and to even longer APD in LQTS patients with polyAT. CONCLUSION: This group of LQTS patients has altered atrial electrophysiology: action potentials are prolonged, and polyAT occurs. PolyAT appears to be a specific arrhythmia of LQTS reminiscent of an atrial form of "torsades de pointes".
Action Potentials↗
Recurrent syncope in a young patient with long QT syndrome: possible relationship of atrioventricular nodal re-entrant tachycardia with neurally mediated spells?
This is a case of a 15-year-old woman with long QT syndrome (LQTS) and a history of 14 events of syncope, demonstrating that the underlying mechanism for any symptomatic episode is not necessarily based on torsades de pointes. The need for careful distinction between true ventricular tachyarrhythmia and other forms of supraventricular tachycardia in the LQTS is the subject of the article. To the knowledge of the authors, this is the first reported case of an association of LQTS with AV nodal re-entrant tachycardia.
Adolescent↗
Effect of sotalol and acute ventricular dilatation on action potential duration and dispersion of repolarization after defibrillation shocks.
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.
Action Potentials↗
Amiodarone-induced postrepolarization refractoriness suppresses induction of ventricular fibrillation.
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.
Action Potentials↗
Molecular site of action of the antiarrhythmic drug propafenone at the voltage-operated potassium channel Kv2.1.
The effects of the antiarrhythmic drug propafenone at Kv2.1 channels were studied with wild-type and mutated channels expressed in Xenopus laevis oocytes. Propafenone decreased the Kv2.1 currents in a time- and voltage-dependent manner (decrease of the time constants of current rise, increase of block with the duration of voltage steps starting from a block of less than 19%, increase of block with the amplitude of depolarization yielding a fractional electrical distance delta of 0.11 to 0.16). Block of Kv2.1 appeared with application to the intracellular, but not the extracellular, side of membrane patches. In mutagenesis experiments, all parts of the Kv2.1 channel were successively exchanged with those of the Kv1.2 channel, which is much more sensitive to propafenone. The intracellular amino and carboxyl terminus and the intracellular linker S4-S5 reduced the blocking effect of propafenone, whereas the linker S5-S6, as well as the segment S6 of the Kv1.2 channel, abolished it to the value of the Kv1.2 channel. In the linker S5-S6, this effect could be narrowed down to two groups of amino acids (groups 372 to 374 and 383 to 384), which also affected the sensitivity to tetraethylammonium. In segment S6, several amino acids in the intracellularly directed part of the helix significantly reduced propafenone sensitivity. The results suggest that propafenone blocks the Kv2.1 channel in the open state from the intracellular side by entering the inner vestibule of the channel. These results are consistent with a direct interaction of propafenone with the lower part of the pore helix and/or residues of segment S6.
Amino Acid Sequence↗