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Introduction: Myotonic dystrophy type 1 (DM1) is a multisystemic genetic disorder caused by the increased number of CTG repeats in 3' UTR of Dystrophia Myotonia Protein Kinase (DMPK) gene. DM1 patients experience conduction abnormalities as well as atrial and ventricular arrhythmias with increased susceptibility to sudden cardiac death. The ionic basis of these electrical abnormalities is poorly understood. Methods: We evaluated the surface electrocardiogram (ECG) and key ion currents underlying the action potential (AP) in a mouse model of DM1, DMSXL, which express over 1000 CTG repeats. Sodium current (INa), L-type calcium current (ICaL), transient outward potassium current (Ito), and APs were recorded using the patchclamp technique. Results: Arrhythmic events on the ECG including sinus bradycardia, conduction defects, and premature ventricular and atrial arrhythmias were observed in DMSXL homozygous mice but not in WT mice. PR interval shortening was observed in homozygous mice while ECG parameters such as QRS duration, and QTc did not change. Further, flecainide prolonged PR, QRS, and QTc visually in DMSXL homozygous mice. At the single ventricular myocyte level, we observed a reduced current density for Ito and ICaL with a positive shift in steady state activation of L-type calcium channels carrying ICaL in DMSXL homozygous mice compared with WT mice. INa densities and action potential duration did not change between DMSXL and WT mice. Conclusion: The reduced current densities of Ito, and ICaL and alterations in gating properties in L-type calcium channels may contribute to the ECG abnormalities in the DMSXL mouse model of DM1. These findings open new avenues for novel targeted therapeutics. [ABSTRACT FROM AUTHOR]

Increased proinflammatory interleukin-6 (IL-6) levels are associated with acquired long QT-syndrome (LQTS) in patients with systemic inflammation, leading to higher risks for life-threatening polymorphic ventricular tachycardia such as Torsades de Pointes. However, the functional and molecular mechanisms of this association are not known. In most cases of acquired LQTS, the target ion channel is the human ether-á-go-go-related gene (hERG) encoding the rapid component of the delayed rectifier K current, IKr, which plays a critical role in cardiac repolarization. Here, we tested the hypothesis that IL-6 may cause QT prolongation by suppressing IKr. Electrophysiological and biochemical assays were used to assess the impact of IL-6 on the functional expression of IKr in HEK293 cells and adult guinea-pig ventricular myocytes (AGPVM). In HEK293 cells, IL-6 alone or in combination with the soluble IL-6 receptor (IL-6R), produced a significant depression of IKr peak and tail current densities. Block of IL-6R or Janus kinase (JAK) reversed the inhibitory effects of IL-6 on IKr. In AGPVM, IL-6 prolonged action potential duration (APD) which was further prolonged in the presence of IL-6R. Similar to heterologous cells, IL-6 reduced endogenous guinea pig ERG channel mRNA and protein expression. The data are first to demonstrate that IL-6 inhibition of IKr and the resulting prolongation of APD is mediated via IL-6R and JAK pathway activation and forms the basis for the observed clinical QT interval prolongation. These novel findings may guide the development of targeted anti-arrhythmic therapeutic interventions in patients with LQTS and inflammatory disorders. [ABSTRACT FROM AUTHOR]

Mancarella S, Yue Y, Karnabi E, Qu Y, El-Sherif N, Boutjdir M. Impaired Ca[sup2+] homeostasis is associated with atrial fibrillation in the α1D L-type Ca[sup2+] channel KU mouse. Am J Physiol Heart Circ Physiol 295: H2017-H2024, 2008. First published September 12, 2008; doi: 10.1152/ajpheart.00537.2008.-The novel α1D Ca[sup2+] channel together with α1D Ca[sup2+] channel contribute to the L-type Ca[sup2+] current (I[subCa-L]) in the mouse supraventricular tissue. However, its functional role in the heart is just emerging. We used the α1D gene knockout (KO) mouse to investigate the electrophysiological features, the relative contribution of the α1D Ca[sup2+] channel to the global I[subCa-L], the intracellular Ca[sup2+] transient, the Ca[sup2+] handling by the sarcoplasmic reticulum (SR), and the inducibility of atrial fibrillation (AF). In vivo and ex vivo ECG recordings from α1D KO mice demonstrated significant sinus bradycardia, atrioventricular block, and vulnerability to AF. The wild-type mice showed no ECG abnormalities and no AF. Patch-clamp recordings from isolated α1D KO atrial myocytes revealed a significant reduction of I[subCa-L] (24.5%; P < 0.05). However, there were no changes in other currents such as I[subNa], I[subCa-T], I[subK], If, and I[subf] and no changes in α[subIC] mRNA levels of α1D KO atria. Fura 2-loaded atrial myocytes showed reduced intracellular Ca[sup2+] transient (-40%; P < 0.05) and rapid caffeine application caused a 17% reduction of the SR Ca[sup2+] content (P < 0.05) and a 28% reduction (P < 0.05) of fractional SR Ca[sup2+] release in α1D KO atria. In conclusion, genetic deletion of α1D Ca[sup2+] channel in mice results in atrial electrocardiographic abnormalities and AF vulnerability. The electrical abnormalities in the α1D KO mice were associated with a decrease in the total I[subCa-L] density, a reduction in intracellular Ca[sup2+] transient, and impaired intracellular Ca[sup2+] handling. These findings provide new insights into the mechanism leading to atrial electrical dysfunction in the α1D KO mice. [ABSTRACT FROM AUTHOR]

Introduction: Atrial standstill is a rare heterogeneous arrhythmia characterized by electrical and mechanical standstill and electrical inexcitability. A long-lasting progressive form is seen with cardiac and neuromuscular diseases, and a familial or idiopathic form may have a genetic basis. A transient form was described secondary to drug intoxication, electrolyte imbalance, cardiac inflammation, and ischemia. Methods: We investigated three patients with long-standing atrial tachyarrhythmia (AT) (atrial flutter in two, and focal atrial tachycardia in one). All patients underwent a complete electrophysiological study with mapping of right and left atrial activity and radiofrequency ablation (RF Abl) of AT. Results: Following RF Abl of AT, all three patients manifested transient atrial electrical silence in the absence of known reversible causes. Atrial electrical silence was observed when, following AT termination, an escape atrioventricular (AV) junctional rhythm (in two patients) and an escape VVI pacemaker rhythm (in one patient) showed transient ventriculo-atrial (VA) conduction block (up to 30 seconds). A dominant sinus rhythm was observed to return 30 minutes, 90 minutes, and 12 hours, respectively, in the three patients. Two patients received a dual chamber pacemaker and a decision was made not to upgrade the patient with VVI pacemaker. Discussion and Conclusions: The present report expands the spectrum of the syndrome of atrial standstill and raises interesting questions regarding possible electrophysiologic mechanism(s) of prolonged post overdrive atrial standstill. The report suggests that chronic overdrive of sinus and subsidiary atrial pacemakers may result in calcium overloading of cardiac cells, which is known to cause suppression of pacemaker activity as well as increased intracellular resistance. These mechanisms can possibly result in either prolonged suppression of sinus and atrial pacemaker activity and/or pacemaker exit block. [ABSTRACT FROM AUTHOR]

The cardiovascular drug carvedilol is characterized by multiple pharmacological actions, which translate into a wide-spectrum therapeutic potential. Its major molecular targets are membrane adrenoceptors, ion channels, and reactive oxygen species. Carvedilol's favorable hemodynamic effects are due to the fact that the drug competitively blocks β1-, β2-, and α1- adrenoceptors. Several additional properties have been documented and may be clinically important, including antioxidant, antiproliferative/antiatherogenic, anti-ischemic, and antihypertrophic effects. The antiarrhythmic action of carvedilol may be related to a combination of its β-blocking effects with its modulating effects on a variety of ion channels and currents. Several studies suggest that the drug may be useful in reducing cardiac death in high-risk patients with prior myocardial infarction and/or heart failure, as well as for primary and secondary prevention of atrial fibrillation. This article will review experimental data available on the electrophysiologic properties of carvedilol, with a focus on their clinical relevance. [ABSTRACT FROM AUTHOR]

Repolarization alternans has been considered a strong marker of electrical instability. The objective of this study was to investigate the hypothesis that ischemia-induced contrasting effects on the kinetics of membrane voltage and intracellular calcium transient (CaiT) can explain the vulnerability of the ischemic heart to repolarization alternans. Ischemia-induced changes in action potential (AP) and CaiT resulting in alternans were investigated in perfused Langendorff guinea pig hearts subjected to 10–15 min of global no-flow ischemia followed by 10–15 min of reperfusion. The heart was stained with 100 μl of rhod-2 AM and 25 μl of RH-237, and AP and CaiT were simultaneously recorded with an optical mapping system of two 16 × 16 photodiode arrays. Ischemia was associated with shortening of AP duration (D) but delayed upstroke, broadening of peak, and slowed decay of CaiT resulting in a significant increase of CaiT-D. The changes in APD were spatially heterogeneous in contrast to a more spatially homogeneous lengthening of CaiT-D. CaiT alternans could be consistently induced with the introduction of a shorter cycle when the upstroke of the AP occurred before complete relaxation of the previous CaiT and generated a reduced CaiT. However, alternans of CaiT was not necessarily associated with alternans of APD, and this was correlated with the degree of spatially heterogeneous shortening of APD. Sites with less shortening of APD developed alternans of both CaiT and APD, whereas sites with greater shortening of APD could develop a similar degree of CaiT alternans but slight or no APD alternans. This resulted in significant spatial dispersion of APD. The study shows that the contrasting effects of ischemia on the duration of AP and CaiT anad, in particular, on their spatial distribution explain the vulnerability of ischemic heart to alternans and the increased dispersion of repolarization during alternans. [ABSTRACT FROM AUTHOR]

Repolarization Distribution in LQT3. Introduction: The occurrence of significant spatial dispersion of repolarization in vivo as it relates to the mechanism of arrhythmia formation in the long QT syndrome (LQTS) continues to be questioned. Methods and Results: We investigated a guinea pig model of LQT3 using anthopleurin-A (AP-A) to study the contribution of rate-dependent spatial dispersion of repolarization in the intact heart to the arrhythmogenicity of LQTS. Optical action potentials were measured using potentiometric fluorescent dye di-4ANEPPS in Langendorff-perfused hearts with induced AV block. AP-A exacerbated the normal uniform epicardial apex-base action potential duration (APD) gradient, resulting in rate-dependent increased APD dispersion and nonuniform APD gradient. Spontaneous focal premature beats induced functional conduction block along boundaries where large nonuniform APD gradient occurred setting the stage for circulating wavefronts and ventricular tachyarrhythmia (VT). Endocardial ablation abolished spontaneous VT, but nonuniform epicardial APD gradient persisted and could be challenged by a stimulated premature stimulus to induce VT. Conclusion: The study shows that in LQT3, spatial variations in steady-state properties result in zones of nonuniform APD gradients. These provide a substrate for functional conduction block and reentrant excitation when challenged by subendocardial “early afterdepolarization-triggered” premature beats. The study emphasizes the key importance of spatial dispersion of repolarization, whether located in epicardial or intramyocardial layers, in arrhythmia formation in LQTS. (J Cardiovasc Electrophysiol, Vol. 15, pp. 323-331, March 2004) [ABSTRACT FROM AUTHOR]

Introduction: Azimilide dihydrochloride blocks both the rapid (IKr) and slow (IKs) components of the delayed rectified K+ current; dofetilide blocks only IKr. Their efficacies were assessed on atrial flutter reentrant circuits in dogs with surgically induced right atrial enlargement. Methods and Results: Multiple biopsies of the tricuspid valve and banding of the pulmonary artery in male mongrel dogs made them susceptible, about 3 weeks postoperatively, to stimulation-induced sustained (5 min or longer) atrial flutter. Azimilide 3 mg/kg administered intravenously (IV) terminated flutter in 8 of 8 dogs, but a slower, nonsustained arrhythmia could be reinduced in 5. In these 5 dogs, azimilide 10 mg/kg terminated flutter and prevented reinduction. This dose increased effective refractory period significantly more in the slow conduction zone (25%) than in the normal zone (17%) and increased flutter cycle length (37%). Termination followed progressive conduction delay in the slow zone of the reentrant circuit. Dofetilide 1 μg/kg IV terminated flutter in 6 of 6 dogs, but the arrhythmia could be reinduced. At 3 μg/kg, flutter terminated in all dogs and could not be reinduced. Dofetilide also increased the effective refractory period significantly more in the slow zone (17%) than in the normal zone (12%) and increased cycle length (33%), leading to interruption of the arrhythmia circuit. Conclusion: In the canine right atrial enlargement model of circus movement atrial flutter, both azimilide 10 mg/kg IV and dofetilide 3 μg/kg IV were 100% effective in terminating flutter and preventing reinduction. Efficacy relied on a similar mechanism of differentially prolonged refractoriness in the slow conduction component of the reentrant circuit where drug-induced termination occurred. [ABSTRACT FROM AUTHOR]

Previous tridimensional activation mapping showed that the development of functional conduction block at the onset of torsades de pointes was regionally heterogeneous; conduction block was frequently observed in the L V and the interventricular septum (IVS) but not in the RV, in the canine anthopleurin-A (AP-A) model of long QT syndrome (LQTS). This may be related to the distribution of mvocytes with M celllike electrophysiological characteristics. To better understand the regional difference of arrhythmogenicity in LQTS, the authors investigated cycle length related modulation of ventricular repolarization among three different layers: the endocardium (End), mid-myocardium (Mid), and epicardium (Epi) of the LV and RV and at two different areas: the Epi and septum (Sep) in the IVS. The LQT3 model was produced by AP-A in dogs. Using constant pacing and single premature stimulation (S1S2), the ventricular repolarization pattern was analyzed from 256 unipolar electrograms. Activation-recovery intervals (ARIs) were used to estimate local repolarization. In seven experiments, AP-A increased regional AW dispersion to 88.1 ± 36.0 ins in the LV, to 72.9 ± 35.7ms in the IVS. and to 23.0 ± 8.7 ms in the RV at the pacing cycle length (CL) of 7,000 ms. Development of the large ARI dispersion was due to greater ARI prolongation at the Mid site in the LV and at Sep site in the IVS. As the S1S2 interval was shortened, regional ARI dispersion decreased gradually, and finally, ARI dispersion showed a reversal gradient of repobarization between the Mid and Epi sites in the LV and between the Sep and Epi sites in the IVS. Two factors contributed to create the reversal gradient of repolarization: (1) a difference in restitution kinetics at the Mid site in the LV and at the Sep site in the IVS, characterized by a larger Δ ARI and slower time constant (τ), and (2) a difference in diastolic intervals at each site resulting in different input to restitution at the same CL. However, the RV showed small alteration in the transmural dispersion of repolarization in the S1S2 protocol. S2 created heterogeneous functional conduction block in the LV and IVS but not in the RV. In the LQT3 model, the arrhvthmogenicity of torsades do pointes is primarily due to dispersion of repolarizatian in the LV and IVS because of prominent distribution of M cells. The RV seems to participate passively in reentrant excitation during torsades de pointes. [ABSTRACT FROM AUTHOR]

Introduction: L-type calcium channels were studied in cell-attached patches from ventricular cell membranes of human fetal heart. Methods and Results: Experiments were performed in the presence of 70 mM Ba2+ as the charge carrier at 22°C to 24°C. Unitary current sweeps were evoked by 300-msec depolarizing pulses to 0 mV from a holding potential of -50 mV at 0.5 Hz. Recorded currents were blocked by nisoldipine (1 μM) and stimulated by (-)Bay K 8644 (1 μM). During control, channel activity was seen in 13.9% ± 4.2% of the total 200 sweeps. Ensemble average current amplitude was 0.03 ± 0.01 pA (n = 6) and average conductance was 20.4 ± 0.2 pS (n = 5). Analysis of single channel kinetics showed open time and closed time histograms were best fit by one and two exponentials, respectively. Mean open time was To = 0.99 ± 0.05 msec (n = 6). Mean closed time fast (Tcf) and slow (Tcs) component values were Tcf = 0.85 ± 0.09 msec and Tcs = 8.0 ± 0.94 msec (n = 6), respectively. With intrapipette (-)Bay K 8644 (1 μM), mean open time was best fit by two exponentials, Tcf = 0.9 ± 0.2 msec (n = 10) and Tos = 134 ± 2.6 msec (n = 10); mean close time values were Tcf = 0.6 ± 0.1 msec (n = 10) and Tcs = 9.8 ± 1.9 msec (n = 10), respectively. With (-)Bay K 8644, channel activity was 66.5% ± 7.4%, the ensemble average current was 0.52 ± 0.04 pA (n = 10) and the conductance 20.7 ± 0.5 pS (n = 5). conclusion: (1) the data establishes the characteristics of L-type Ca channels of human fetal hearts and their modulation by dihydropyridines; (2) the open time kinetics differ from those of avian embryonic and rat fetal hearts; and (3) the findings provide new and relevant information for understanding the physiologic behavior of unitary Ca2+ channels in the developing human heart and the baseline comparison for diseases that implicate Ca2+ channels in their etiology, such as autoimmune-associated congenital heart block. [ABSTRACT FROM AUTHOR]

The effects of a single intravenous infusion of 750 mg of procainamide was studied in 12 patients with symptomatic chronic recurrent venlricular tachycardia in whom arrhythmias could reproducibly be initiated and terminated by programmed electrical stimulation of the heart. Sustained ventricular tachycardia was induced in 6 patients and non-sustained tachycardia was induced in the remaining 6 patients during control studies. Following procainamide (plasma level 10.3 ± 3.7 mcg/ml], ventricular tachycardia could be induced in 10/12 patients, sustained in 4 patients and non-sustained in the remaining 6 patients. In 8/12 patients (66%). induction of ventricular tachycardia was facilitated as demonstrated by: (1) tachycardia zone was widened in 4 patients and was unchanged in another 3 patients; (2) non-sustained ventricular tachycardia was changed to sustained ventricular tachycardia in one patient. The ventricular tachycardia had a faster rate and a different QRS morphology; [3] in 4 patients tachycardia was inducible with a lesser number of extrastimuli and/ or by spontaneously occurring ventricular premature depolarization and; (4) increase of the number of induced ventricular responses of non-sustained ventricular tachycardia. In 4/12 patients )(33%), procainamide abolished or modified the induction of ventricular tachycardia as demonstrated by: (1) inability to induce ventricular tachycardia in 2 patients; (2) narrowing of the tachycardia zone and conversion from sustained into non-sustained ventricular tachycardia (one patient) and; (3) decrease in the number of induced ventricular responses in one patient. The response to procainamide could not be predicted from rates of spontaneous ventricular tachycardia, induced ventricular tachycardia during control studies, degree of slowing of ventricular tachycardia or from prolongation of the coupling interval after procainamide. These results suggest that instead of abolishing the arrhythmia, procainamide in frequently employed doses in patients with chronic recurrent ventricular tachycardia can facilitate its initiation sometimes at even faster rates. Patients not responsive to the usual doses of procainamide should undergo acute drug testing trials to determine the optimal dose/drug levels. [ABSTRACT FROM AUTHOR]

A case is described in which ventricular pacing from the middle cardiac vein produced an electrocardiographic pattern which mimicked the morphology of the normally conducted beats. The possible etiologies of this unusual phenomenon and its implications concerning the functional anatomy of the normal conduction system in the human heart are discussed. [ABSTRACT FROM AUTHOR]

The LQTS is a prime example of bow molecular biology, ion channel, cellular, and organ physiology, coupled with clinical observations, promise to be the future paradigm for advancement of medical knowledge. Both the congenital and acquired LQTS are due to abnormalities (intrinsic and/or acquired) of the ionic currents underlying cardiac repolarization. In this review, the continually unraveling molecular biology of congenital LQTS is discussed. The various pharmacological agents associated with the acquired LQTS are listed. Although it is difficult to predict which patients are at risk for TdP, careful assessment of the risk-benefit ratio is important before prescribing drugs known to be able to cause QT prolongation. The in vivo electrophysiological mechanism of TdP in the LQTS is described using, as a paradigm, the anthopleurin-A canine model, a surrogate for LQT3. In the LQTS, prolonged repolarization is associated with increased spatial dispersion of repolarization. Prolongation of repolarization also acts as a primary step for the generation of EADs. The focal EAD induced triggered beat(s) can infringe on the underlying substrate of inhomogeneous repolarization to initiate polymorphic reentrant VT, sometimes having the characteristic twisting QHS configuration known as TdP. The review concludes by discussion of the clinical manifestations and current management of both the congenital and acquired LQTS. The initial therapy of choice for the large majority of patients with the congenital LQTS is a beta-blocking drug. This therapy seems to be effective in LQT1 and LQT2 patients, but may not be as effective in LQT3 patients. Other therapeutic options include pacemakers, cervicothoracic sympathectomy, and the implantable cardioverter defibrillator. Recent molecular genetic studies have suggested several genotype specific therapies; however, long-term efficacy data are not available. [ABSTRACT FROM AUTHOR]

The signal averaged electrocardiogram (SA-ECG), programmed electrical stimulation (PES), and left ventricular ejection fraction (EF) studies were utilized for risk stratification and management of patients with complex ventricular arrhythmias and nonsustained ventricular tachycardia (VT). The study population included 90 patients (63 with coronary artery disease and 27 with dilated cardiomyopathy). Sustained monomorphic VT was induced in 22 cases (24%), ventricular fibrillation (VF) in 10 (11%), and no sustained VT/VF in 58 (64%). An abnormal SA-ECG was recorded in 23 patients (26%) and was more common in patients with than in those without induced sustained VT (68% vs 12%, P < 0.0001). None of 33 patients with normal SA-ECG and EF ≥ 40% had induced VT. Patients were followed-up for 2.5 ± 0.8 years off antiarrhythmic therapy, unless they had induced sustained VT. The 3-year sudden death rate was 19% in the group with induced sustained VT, 0 in that with induced VF, and 9% in that without induced VT/VF (P = NS). The 3-year total cardiac mortality was higher in patients with than in those without EF < 40% (27% vs 7%, P < 0.05). It is concluded that patients with organic heart disease and spontaneous nonsustained VT may not need PES or antiarrhythmic therapy if SA-ECG is normal and EF is ≥ 40%, since their risk of induced VT and sudden death is low. On the other hand, patients with abnormal SA-ECG and/or EF < 40% may require PES, since their risk for induced VT is high. Antiarrhythmic therapy may also be considered in these patients. [ABSTRACT FROM AUTHOR]

Focuses on the importance of reentrant excitation as a mechanism for cardiac arrhythmia. Difficulty of obtaining information on the electrophysiological requirements for reentry; Role of reflection in clinical arrhythmia; Demonstration of the multiple muscular connections between the atrium and ventricle in the human heart.

Presents summaries of pertinent data on attempted ablation of the atrioventricular juntion and ventricular tachycardia foci. Catheter ablation of the atrioventricular junction; Analysis of catheter ablation of ventricular tachycardia foci.

The mechanisms of resetting, entrainment. acceleration, or termination of reentrant ventricular tachycardia by programmed electrical stimulation were studied in the canine post-infarction model. In this model, reentrant circuits were localized in the epicardial layer overlying the infarction and were accessible to detailed mapping by multiplexer techniques. The reentrant circuit has a characteristic figure-eight configuration in the form of two circulating wavefronts around arcs of functional conduction block that coalesce into a slow common reentrant wavefront. Termination of reentrant tachy-cardia occurred when a stimulated wavefront arrived earlier to a strategically located area in the proximal portion of the zone of slow conduction, before refractoriness expired distally, resulting in conduction block. The three factors that determined if the stimulated wavefront could reach this zone in time for conduction block were: (1) the cycle length of stimulation; (2) the number of stimulated beats, and (3) the site of stimulation. The most optimal situation for stimulated termination of reentry was a critically coupled single stimulus applied to the ischemic zone close to the proximal side of the zone of slow conduction that captured locally and conducted prematurely to the strategic zone for conduction block. When a single stimulated wavefront failed to terminate reentry, one or more subsequent wavefronts succeeded. However, the stimulated train had to be terminated following the beat that interrupted reentry. Otherwise, a subsequent stimulated beat could reinitiate the same reentrant circuit or induce a different circuit. The new circuit could have a shorter revolution time, resulting in tachycardia acceleration , and occasionally degeneration into ventricular fibrillation. Overdrive termination of reentry required both a critical cycle length of stimulation and a critical number of beats in a stimulated train. Otherwise, the stimulated train could establish a new.. [ABSTRACT FROM AUTHOR]

Catheter ablation of ventricular tachycardia is a procedure of last resort in critically III patients. The Percutaneous Cardiac Mapping and Ablation Registry was able to collect data on 88 patients undergoing ablation of ventricular tachycardia foci. The mean following interval for the group was 10 ± 8 months. Results were divided into three categories: Group I patients remained asymptomatic and were on no antiarrhythmic medications (33%); Group 11 remained asymptomatic and took antiarrhythmic agents (38%); Group III patients were considered unsuccessful and consisted of 29 percent of the total. More than one-third of patients received two shocks; the remainder received from one to five shocks. Overall mortality included four procedure-related deaths and total follow- up mortality was 25 percent. Catheter ablation for ventricular tachycardia should be undertaken only in highly specialized centers with an expert and experienced electrophysiologist with immediate surgical back-up available. [ABSTRACT FROM AUTHOR]

There are three current prognostic indicators of ventricular electrical instability: (1) categorization and stratification of spontaneous ventricular arrhythmias from standard EGG recordings; (2) programmed electrical stimulation; (3) direct recording of delayed depolarization potentials, usually referred to as late potentials. Of the three, the latter offers a new and promising approach. Late potentials represent delayed activation potentials of diseased myocardial zones and may prove to be a strong independent marker of the propensity to develop reentrant ventricular arrhythmias and sudden cardiac electrical death. The problem in identifying late potentials on the body surface is that the signal is smaller than the electrical noise produced by various sources. Two different techniques have been utilized to improve the signal-to-noise ratio: first, signal averaging, which is applicable to regular repetitive electrocardiographic signals but cannot detect moment-to-moment dynamic changes in the signal; second, low-noise or high-resolution electrocardiography that utilizes spatial averaging techniques as well as other noise-reducing measures to record the late potentials on a heat-to-beat basis. This technique has the potential of directly identifying malignant "reentrant" versus benign "focal" ventricular rhythms. The present report discusses the electrophysiologic basis of late potentials and the clinical results of both signal-averaged and low-noise recordings for evaluation of ventricular electrical instability, particularly in patients with ischemic heart disease. [ABSTRACT FROM AUTHOR]

Introduction: Cocaine has been shown to have broad cardiovascular effects that could be life threatening. Most of the reported electro-physiologic effects of cocaine have been studied in normal but not infarcted myocardium. Methods and Results: Using microelectrode techniques, we investigated the eletrophysiologic effects of cocaine on endocardial canine Purkinje fibers that survived 1 day of myocardial Infarction. In quiescent infarcted preparations, stimulated trains were followed by subthresh-old delayed afterdepolarizations (DADs), in the presence of propranolol (1 μM). Cocaine (10 μM) decreased the amplitude of DADs from 6.1 ± 1.8 mV to 3.0 ± 1.3 mV (P < 0.05, n = 6). When stimulated preparations (n = 23) showing no triggered activity during control (+propra-nolol) were superfused with a low concentration of caffeine (1 mM) or high extracellular Ca2+ (8.1 mM), triggered activity was Induced. Subsequent cocaine (10 μM) superfusion prevented the induction of caffeine- and high Ca2+-induced triggered activity. Cocaine's effects were reversible upon washout. In preparations that showed triggered activity during control conditions (+propranolol), the mean cycle length of triggered activity was 755 ± 45 msec. Cocaine (10 μM) superfusion lengthened the cycle length to 1030 ± 141 msec and terminated triggered activity with a subthreshold DAD (n = 12). In addition, cocaine and ryanodine (10 μM) suppressed triggered activity in a similar manner when tested in the same preparations (n = 4). During control conditions, cocaine did not cause any significant change on the rate of rise of action potential upstroke (from 55.6 ± 24.3 to 54.5 ± 28.6 V/sec, n = 8) and maximum diastolic potential (from -58.4 ± 4.3 to -56.6 ± 6.5 mV, n = 8). In the absence of propranolol, 50 μM but not 10 μM cocaine induced early afterdepolarizations in 62% of the preparations exhibiting triggered activity during control conditions. Conclusion: The results suggest that cocaine modulates DADs and triggered activity in infarcted endocardial fibers via direct inhibition of cyclic release of Ca2+ from sarcoplasmic reticulum (SR) independently from a local anesthetic or sympathomimetic effect. This SR inhibition could account for the myocardial depressant effect of cocaine. However, while cocaine suppressed DADs, its induction of EADs can precipitate malignant ventricular arrhythmias in the setting of cocaine overdose and infarction. [ABSTRACT FROM AUTHOR]

Introduction: Early afterdepolarizations (EADs) are among the mechanisms proposed to underlie ventricular arrhythmias. Sea anemone toxin, ATXII, known to delay Na inactivation and to induce plateau level voltage oscillations, was used to study the formation of EADs. Methods and Results: Action potential and membrane currents were studied in rat ventricular myocytes using whole cell current and voltage clamp techniques. Phase plane trajectories were generated by plotting membrane potential (V) versus the first time derivative of membrane potential (dV/dt). Under current clamp conditions, ATXII (40 nM) consistently prolonged the action potential and induced EADs. The EADs developed at a plateau voltage between -10 and -40 mV. Calcium channel blockers, verapamil 10 /µM and cobalt 4 mM, and the sarcoplasmic reticulum modulator, ryanodine (1 µM), did not antagonize ATXII effects on the action potential and EADs. However, Na channel blockers, tetrodotoxin 03 µM and lidocaine 40 µM, and rapid stimulation consistently shortened the prolonged action potential and suppressed EADs. Under voltage clamp conditions in the presence of ATXII, a slowly decaying inward current followed the fast inward current during depolarizing pulses. Membrane currents flowing at or later than 100 msec after the test pulse were analyzed. The control isochronal current-voltage (I-V) curves showed no late inward currents. In the presence of ATXII, all the isochronal I-V curves showed an inward current that was more prominent between -40 and 0 mV. The ATXII-induced current at the 100-msec isochrone activated at a potential of approximately -60 mV, peaked at about -20 mV, and reversed at +40 mV consistent with the Na current I-V curve. The isochronal I-V curves obtained after lidocaine superfusion resembled those of the control. The phase plane trajectory of the action potential obtained with ATXII showed an ascillatory behavior corresponding to the EAD range of potential; within this voltage range, the isochronal I-V curves were shown to cross the abscissa three times instead of once. Conclusion: These results suggest that, in this experimental model, neither sarcolemmal L-type Ca current nor sarcoplasmic reticulum Ca release plays a significant role in the genesis of ATXII-induced EADs. EADs are generated by a voltage-dependent balance between a markedly prolonged Na inward current and K outward currents within the voltage plateau range of the action potential but not by Ca current reactivation and inactivation. [ABSTRACT FROM AUTHOR]

Details the evidence that early afterdepolarizations (EAD) and early afterdepolarization-induced triggered activity play a significant role in the clinical syndrome of long QTU heart wave and polymorphic ventricular tachyarrhythmias. Definition of EAD; Steps required for the manifestation of early afterdepolarization-induced triggered activity; Ionic mechanisms of repolarization;

Presents a case report of an elderly female patient who was referred for cardiac resynchronization therapy (CRT) due to refractory heart failure. Medical history; Effect of CRT on ventricular function; Discussion on transmural dispersion and intraventricular conduction disorder; Impact of CRT on the frequency of ventricular tachyarrhythmias.

Comments on a study regarding the electrophysiologic mechanism of polypleomorphic ventricular tachycardia (PVT). Definition of Torsades de pointes (TdP); Significance of the electrophysiologic mechanism for PVT to the proper management of individual patients; Emphasis on the difference of mechanism for transition of the QRS configuration of TdP in long QT syndrome.

We describe a patient with Wolff-Parkinson-White syndrome in whom a steerable catheter became entrapped in the mitral valve apparatus, during radiofrequency ablation. Treatment consisted of surgical removal of the catheter. The occurrence of this previously unreported complication stresses the need for on-going monitoring of risk and benefits of electrophysiological interventions. [ABSTRACT FROM AUTHOR]

Torsade de pointes is a potentially lethal polymorphic ventricular tachyarrhythmia that can occur in the setting of long QT syndrome (LQTS). LQTS is multi-hit in nature and multiple factors combine their effects leading to increased arrhythmic risk. While hypokalemia and multiple medications are accounted for in LQTS, the arrhythmogenic role of systemic inflammation is increasingly recognized but often overlooked. We tested the hypothesis that the inflammatory cytokine interleukin(IL)-6 will significantly increase the incidence of arrhythmia when combined with other pro-arrhythmic conditions (hypokalemia and the psychotropic medication, quetiapine). Guinea pigs were injected intraperitoneally with IL-6/soluble IL-6 receptor and QT changes were measured in vivo. Subsequently, hearts were cannulated via Langendorff perfusion for ex vivo optical mapping measurements of action potential duration (APD 90) and arrhythmia inducibility. Computer simulations (MATLAB) were performed to investigate I Kr inhibition at varying IL-6 and quetiapine concentrations. IL-6 prolonged QTc in vivo guinea pigs from 306.74 ± 7.19 ms to 332.60 ± 8.75 ms (n = 8, p =.0021). Optical mapping on isolated hearts demonstrated APD prolongation in IL-6- vs saline groups (3Hz APD 90 :179.67 ± 2.47 ms vs 153.5 ± 7.86 ms, p =.0357). When hypokalemia was introduced, the APD 90 increased to 195.8 ± 5.02 ms[IL-6] and 174.57 ± 10.7 ms[saline] (p =.2797), and when quetiapine was added to hypokalemia to 207.67 ± 3.03 ms[IL-6] and 191.37 ± 9.49 ms[saline] (p =.2449). After the addition of hypokalemia ± quetiapine, arrhythmia was induced in 75% of IL-6-treated hearts (n = 8), while in none of the control hearts (n = 6). Computer simulations demonstrated spontaneous depolarizations at ∼83% aggregate I Kr inhibition. Our experimental observations strongly suggest that controlling inflammation, specifically IL-6, could be a viable and important route for reducing QT prolongation and arrhythmia incidence in the clinical setting. • Inflammation is often overlooked in treatment of Long QT Syndrome. • Patients taking psychotropic medication are at increased risk for arrhythmia. • Interleukin-6 can increase action potential duration and QT interval. • Our data shows IL-6 could be a novel therapeutic target for reducing arrhythmia risk. [ABSTRACT FROM AUTHOR]

Presents a letter to the editor published in the January 2003 issue of 'Journal of Cardiovascular Electrophysiology,' on an article published in the September 2002 issue. Discussion on cellular mechanism involved in long QT syndrome; Induction of ventricular fibrillation in arrhythmias study.

Myotonic dystrophy type 1 (DM1) is a multiorgan disorder with significant cardiac involvement. ECG abnormalities, including arrhythmias, occur in 80 % of DM1 patients and are the second-most common cause of death after respiratory complications; however, the mechanisms underlying the arrhythmogenesis remain unclear. The objective of this study was to investigate the basis of the electrophysiological abnormalities in DM1 using the DMSXL mouse model. ECG parameters were evaluated at baseline and post flecainide challenge. Calcium transient and action potential parameters were evaluated in Langendorff-perfused hearts using fluorescence optical mapping. Calcium transient/sparks were evaluated in ventricular myocytes via confocal microscopy. Protein and mRNA levels for calcium handling proteins were evaluated using western blot and RT-qPCR, respectively. DMSXL mice showed arrhythmic events on ECG including premature ventricular contractions and sinus block. DMSXL mice showed increased calcium transient time to peak without any change to voltage parameters. Calcium alternans and both sustained and non-sustained ventricular tachyarrhythmias were readily inducible in DMSXL mice. The confocal experiments also showed calcium transient alternans and increased frequency of calcium sparks in DMSXL cardiomyocytes. These calcium abnormalities were correlated with increased RyR2 phosphorylation without changes to the other calcium handling proteins. The DMSXL mouse model of DM1 exhibited enhanced arrhythmogenicity associated with abnormal intracellular calcium handling due to hyperphosphorylation of RyR2, pointing to RyR2 as a potential new therapeutic target in DM1 treatment. [Display omitted] • DM1 patients have reduced life expectancy due to cardiac causes; however, the underlying mechanisms are unclear. • The DMSXL mouse model of DM1 was more prone to VTs and exhibited arrhythmic events including PVCs and sinus block. • These arrhythmic events were associated with abnormal intracellular calcium transients/sparks in DMSXL mice. • Our findings suggest a significant arrhythmogenic role for RyR2/phospho-RyR2, which provide novel therapeutic targets. [ABSTRACT FROM AUTHOR]

There is a growing consensus in the scientific community that suggests a strong association between obstructive sleep apnea (OSA) and cardiovascular (CVD) conditions and events, including coronary artery disease, hypertension, arrhythmia, heart failure, and sudden cardiac death. We reviewed evidence on the relationship between OSA and arrhythmia. Our conclusion, based on our review of the literature, is that the evidence supports a strong link between OSA and cardiovascular mortality, which warrants treating OSA. Continuous positive airway pressure (CPAP) appears to reduce the CVD consequences of OSA. Future research is expected to clarify the benefits and optimal application of these treatment approaches. [ABSTRACT FROM AUTHOR]

Background--Emerging clinical evidence demonstrates high prevalence of QTc prolongation and complex ventricular arrhythmias in patients with anti-Ro antibody (anti-Ro Ab)-positive autoimmune diseases. We tested the hypothesis that anti-Ro Abs target the HERG (human ether-a-go-go-related gene) K+ channel, which conducts the rapidly activating delayed K+ current, IKr, thereby causing delayed repolarization seen as QT interval prolongation on the ECG. Methods and Results--Anti-Ro Ab-positive sera, purified IgG, and affinity-purified anti-52kDa Ro Abs from patients with autoimmune diseases and QTc prolongation were tested on IKr using HEK293 cells expressing HERG channel and native cardiac myocytes. Electrophysiological and biochemical data demonstrate that anti-Ro Abs inhibit IKr to prolong action potential duration by directly binding to the HERG channel protein. The 52-kDa Ro antigen-immunized guinea pigs showed QTc prolongation on ECG after developing high titers of anti-Ro Abs, which inhibited native IKr and crossreacted with guinea pig ERG channel. Conclusions--The data establish that anti-Ro Abs from patients with autoimmune diseases inhibit IKr by cross-reacting with the HERG channel likely at the pore region where homology between anti-52-kDa Ro antigen and HERG channel is present. The animal model of autoimmune-associated QTc prolongation is the first to provide strong evidence for a pathogenic role of anti-Ro Abs in the development of QTc prolongation. It is proposed that adult patients with anti-Ro Abs may benefit from routine ECG screening and that those with QTc prolongation should receive counseling about drugs that may increase the risk for life-threatening arrhythmias. [ABSTRACT FROM AUTHOR]

Abstract: Pervious biochemical and hemodynamic studies have highlighted the important role of εPKC in cardioprotection during ischemic preconditioning. However, little is known about the electrophysiological consequences of εPKC modulation in ischemic hearts. Membrane permeable peptide εPKC selective activator and inhibitor were used to investigate the role of εPKC modulation in reperfusion arrhythmias. Methods: Protein transduction domain from HIV-TAT was used as a carrier for peptide delivery into intact Langendorff perfused guinea pig hearts. Action potentials were imaged and mapped (124 sites) using optical techniques and surface ECG was continuously recorded. Hearts were exposed to 30min stabilization period, 15min of no-flow ischemia, followed by 20min reperfusion. Peptides (0.5μM) were infused as follows: (a) control (vehicle-TAT peptide; TAT-scrambled ψεRACK peptide); (b) εPKC agonist (TAT-ψεRACK); (c) εPKC antagonist (TAT-εV1). Results: Hearts treated with εPKC agonist ψεRACK had reduced incidence of ventricular tachycardia (VT, 64%) and fibrillation (VF, 50%) compared to control (VT, 80%, P <0.05) and (VF, 70%, P <0.05). However, the highest incidence of VT (100%, P <0.05) and VF (80%) occurred in hearts treated with εPKC antagonist peptide εV1 compared to control and to εPKC agonist ψεRACK. Interestingly, at 20min reperfusion, 100% of hearts treated with εPKC agonist ψεRACK exhibited complete recovery of action potentials compared to 40% (P <0.05) of hearts treated with εPKC antagonist peptide, εV1 and 65% (P <0.5) of hearts in control. At 20min reperfusion, maps of action potential duration from εPKC agonist ψεRACK showed minimal dispersion (48.2±9ms) compared to exacerbated dispersion (115.4±42ms, P <0.05) in εPKC antagonist and control (67±20ms, P <0.05). VT/VF and dispersion from hearts treated with scrambled agonist or antagonist peptides were similar to control. Conclusion: The results demonstrate that εPKC activation by ψεRACK peptide protects intact hearts from reperfusion arrhythmias and affords better recovery. On the other hand, inhibition of εPKC increased the incidence of arrhythmias and worsened recovery compared to controls. The results carry significant therapeutic implications for the treatment of acute ischemic heart disease by preconditioning-mimicking agents. [Copyright &y& Elsevier]

This consensus guideline was prepared on behalf of the International Society for Holter and Noninvasive Electrocardiology and is cosponsored by the Japanese Circulation Society, the Computers in Cardiology Working Group on e-Cardiology of the European Society of Cardiology, and the European Cardiac Arrhythmia Society. It discusses the electrocardiographic phenomenon of T-wave alternans (TWA) (i.e., a beat-to-beat alternation in the morphology and amplitude of the ST- segment or T-wave). This statement focuses on its physiological basis and measurement technologies and its clinical utility in stratifying risk for life-threatening ventricular arrhythmias. Signal processing techniques including the frequency-domain Spectral Method and the time-domain Modified Moving Average method have demonstrated the utility of TWA in arrhythmia risk stratification in prospective studies in >12,000 patients. The majority of exercise-based studies using both methods have reported high relative risks for cardiovascular mortality and for sudden cardiac death in patients with preserved as well as depressed left ventricular ejection fraction. Studies with ambulatory electrocardiogram-based TWA analysis with Modified Moving Average method have yielded significant predictive capacity. However, negative studies with the Spectral Method have also appeared, including 2 interventional studies in patients with implantable defibrillators. Meta-analyses have been performed to gain insights into this issue. Frontiers of TWA research include use in arrhythmia risk stratification of individuals with preserved ejection fraction, improvements in predictivity with quantitative analysis, and utility in guiding medical as well as device-based therapy. Overall, although TWA appears to be a useful marker of risk for arrhythmic and cardiovascular death, there is as yet no definitive evidence that it can guide therapy. [Copyright &y& Elsevier]

This investigation was performed to evaluate the feasibility of detecting repolarization alternans with the heart rate elevated with a bicycle exercise protocol. Sensitive spectral signal-processing techniques are able to detect beat-to-beat alternation of the amplitude of the T wave, which is not visible on standard electrocardiogram. Previous animal and human investigations using atrial or ventricular pacing have demonstrated that T-wave alternans is a marker of vulnerability to ventricular arrhythmias. Using a spectral analysis technique incorporating noise reduction signal-processing software, we evaluated electrical alternans at rest and with the heart rate elevated during a bicycle exercise protocol. In this study we defined optimal criteria for electrical alternans to separate patients from those without inducible arrhythmias. Alternans and signal-averaged electrocardiographic results were compared with the results of vulnerability to ventricular arrhythmias as defined by induction of sustained ventricular tachycardia or fibrillation at electrophysiologic evaluation. In 27 patients alternans recorded at rest and with exercise had a sensitivity of 89%, specificity of 75%, and overall clinical accuracy of 80% (p <0.003). In this patient population the signal-averaged electrocardiogram was not a significant predictor of arrhythmia vulnerability. This is the first study to report that repolarization alternans can be detected with heart rate elevated with a bicycle exercise protocol. Alternans measured using this technique is an accurate predictor of arrhythmia inducibility. [ABSTRACT FROM AUTHOR]