Broad sensitivity of rodent arrhythmia models to class I, II, III, and IV antiarrhythmic agents

To determine specificity of rodent models of arrhythmia for different Vaughan Williams classes of antiarrhythmic drugs, we tested 17 drugs from the four classes in one in vitro and four in vivo models. In the mouse chloroform-induced ventricular fibrillation model and in the guinea pig ouabain-induced arrhythmia model, drugs of classes I (amefalone, aprindine, lidocaine, mexiletine, phenytoin, procainamide, or quinidine), II (metoprolol or propranolol), and IV (bepridil) were active. Class III drugs (bretylium, clofilium, or melperone did not suppress ouabain arrhythmias, but were active in the mouse chloroform model. In the rat coronary artery ligation model, disopyramide (class I), amefalone and melperone significantly (P less than 0.05) reduced the number of extrasystoles. Propranolol, sotalol, and verapamil (class IV) were less effective. In the rat coronary artery ligation/reperfusion model, all four classes of antiarrhythmic agents were active in vitro (isolated heart) and in vivo (anesthetized rat). Thus, one model of automaticity, the guinea pig ouabain model, detected class I, II, and IV drugs, whereas another automaticity model, the mouse chloroform model, also detected class III agents. The model of reentry induced by ischemia plus reperfusion (rat coronary artery ligation reperfusion) can be recommended as a screen for new antiarrhythmic agents based on its sensitivity to all four classes of antiarrhythmic drugs. The Vaughan Williams class of an antiarrhythmic agent must be determined, however, by additional mechanism studies.     

Antiarrhythmic drug therapy: new drugs and changing concepts

The effective treatment of life-threatening ventricular arrhythmias (VA) leading to sudden cardiac death remains a major health problem. Cellular electrophysiological techniques that have provided insight into the underlying mechanisms of these arrhythmias have also provided a convenient classification of antiarrhythmic drugs based on their dominant electrophysiological action. Traditional pharmacological approaches to the management of VA have involved primarily class I agents. Newer drugs in this class are potent conduction depressants (class IC agents), which, however, have been limited in their clinical impact on VA because of unwanted cardiac and extracardiac side effects. Other recent approaches include the introduction of class III agents, which are thought to interrupt primarily reentrant impulses by specific prolongation of action potential duration and refractoriness without compromising normal cardiac conduction. Newer approaches may also include drugs with greater specificity of action, agents with combinations of electrophysiological effects (class I/III, I/II), drugs exemplifying novel mechanisms of action such as anion antagonism (class V), and agents controlling sympathetic neural outflow. The growing awareness of the potential proarrhythmic effects of antiarrhythmic drugs has also become important in drug development and assessment, as emphasized by the search for improved methods of drug selection (e.g., programmed electrical stimulation). Finally, the desired characteristics of a new antiarrhythmic agent are presented as a goal for future drug development.     

Antiarrhythmic effect of magnesium sulfate against occlusion-induced arrhythmias

The antiarrhythmic effect of magnesium sulfate (Mg) as well as the hemodynamics were studied using the coronary ligation and reperfusion models in rats.In the study on coronary ligation arrhythmia, i.v. administration of Mg (0.6, 2, 6, 20 and 60 \sgmaelig;mol) was conducted at 5 min after coronary ligation. Mg had an action to decrease the total number of premature ventricular contraction (PVC), the duration of ventricular tachycardia (VT), the frequency of VT and ventricular fibrillation (Vf) and the mortality ratio for 30 min after coronary ligation. In the 6-60 \sgmaelig;mol groups, significant antiarrhythmic action (p < 0.01 vs. control) was attained.In the study on reperfusion arrhythmia, i.v. administration of Mg (20, 60 and 200 \sgmaelig;mol) was conducted at 4 min after coronary ligation, and at 1 min after ligation, the coronary artery was reperfused. Mg had an action to decrease the frequency of Vf, the mortality ratio and the duration of VT and Vf and to extend the interval between the initiation of reperfusion and the occurrence of VT and Vf for 10 min after reperfusion. In the 200 \sgmaelig;mol group, significant antiarrhythmic action (p < 0.05 vs. control) was attained. Administration of Mg decreased the heart rate and blood pressure.We concluded that Mg can control myocardial ischemia-induced and reperfusion-induced arrhythmia and that sudden cardiac death which occurs as a result of arrhythmia can be prevented.     

Ventricular Tachycardia Storm - An Atypical Presentation of Sarcoidosis Exacerbation

Management of ventricular tachycardia (VT) storm in a patient with an implantable cardioverter-defibrillator (ICD) is a challenging medical emergency. We describe a patient with cardiac sarcoidosis (CS) and an ICD who is admitted with VT storm. Management of VT was difficult due to resistance to multiple antiarrhythmic drugs. He responded to immunosuppressive therapy supporting active CS as the cause of his VT. This case suggests that CS may underlie some cases of refractory VT and that immunosuppressive therapy may be effective in controlling this arrhythmia.     

Cardiomyopathy induced by incessant ventricular tachycardia originating in the vicinity of the His bundle

A 04-year-old boy was referred to our institution with severe, progressive heart failure of 4-months duration associated with a persistent wide QRS tachycardia with left bundle branch block and severe left ventricular dysfunction. Because of incessant wide QRS tachycardia refractory to antiarrhythmic drugs, he was referred for electrophysiological study. The ECG was suggestive of VT arising from the right ventricle near the His area. Electrophysiological study revealed that origin of tachycardia was septum of the right ventricle, near His bundle, however the procedure was not successful and an inadvertent complete atrioventricular conduction block occurred. The same ventricular tachycardia recurred. A second procedure was performed with a retrograd aortic approach to map the left side of the interventricular septum. The earliest endocardial site for ablation was localized in the anterobasal region of left ventricle near His bundle. In this location, one radiofrequency pulse interrupted VT and rendered it not inducible. The echocardiographic evaluation showed partial reversal of left ventricular function in the first 3 months. The diagnosis was idiopathic parahisian left ventricular tachycardia leading to a tachycardia mediated cardiomyopathy, an extremely rare clinical picture in children.     

Preventing sudden death and the use of prophylactic implanted defibrillators

Implanted defibrillators have become mainstream therapy for the prevention of sudden cardiac death from ventricular tachyarrhythmias. A decade of studies has confirmed the superiority of ICDs over antiarrhythmic drug therapy in prolonging the life of patients with a prior history of sustained VT or VF. More recent studies have compared ICD therapy to drugs or no antiarrhythmic therapy as 'primary prophylaxis' in patients considered at high risk for sudden death or with prior MIs. In selected patients, ICDs lead to important relative and absolute reductions in mortality in patients with no prior history of sustained VT or VF. Clinicians need to carefully consider these studies in their management of patients with CAD and severe LV dysfunction.     

Protective Effect of ACE Inhibitors on Ischemia-Reperfusion-induced Arrhythmias in Rats: Is this Effect Related to the Free Radical Scavenging Action of these Drugs?

The antiarrhythmic effects of captopril, a sulphydrylcontaining angiotensin converting enzyme (ACE) inhibitor, were compared with those of the non-sulphydryl-containing ACE inhibitor lisinopril and the sulphydryl-containing agent glutathione in an in vivo rat model of coronary artery ligation. To produce arrhythmia, the left main coronary artery was occluded for 7 min, followed by 7 min of reperfusion. Captopril (3 mg kg^-1) and lisinopril (0.1, 0.3 or 1 mg kg^-1) caused marked decreases in mean arterial blood pressure (BP) and heart rate, whereas glutathione (5 mg kg^-) had no effect on them. The incidence of ventricular tachycardia (VT) on ischemia and reperfusion was significantly reduced by captopril and lisinopril. Captopril and 1 mg kg^-1 lisinopril also significantly decreased the number of VEB during occlusion and the duration of VT on reperfusion, respectively. These drugs also attenuated the incidence of reversible ventricular fibrillation (VF) and the number of ventricular ectopic beats (VEB) during reperfusion. However, glutathione only reduced the incidence of VT on reperfusion, significantly. These results suggest that, in this experimental model, ACE inhibitors limit the arrhythmias following ischemia-reperfusion and free radical scavenging action of these drugs does not have a major contributory role in their protective effect.     

Catheter Ablation of Hemodynamically Unstable Ventricular Tachycardia in a Patient with Dextro - Transposition of the Great Arteries and Mustard's Repair

Introduction

A patient with D-TGA and surgical repair (Mustard''s procedure) presented with appropriate ICD shocks due to monomorphic ventricular tachycardia, refractory to antiarrhythmic medications.

Methods and Results

The patient underwent an electrophysiological study and catheter ablation for the VT. Substrate and pace mapping techniques, with the help of an electroanatomical mapping system, was used to localize and ablate the tachycardia successfully.

Conclusions

In patients with D-TGA and Mustard''s repair, scar tissue resulting from VSD repair can act as a substrate for recurrent VT. Catheter ablation of VT is useful in management of VT that occurs despite antiarrhythmic therapy and/or when it is unstable.     

Significance of ATP-sensitive K(+)-channel in the mechanism of antiarrhythmic and cardioprotective effect of adaptation to intermittent hypobaric hypoxia

Adult male Wistar rats were exposed to intermittent hypobaric hypoxia (5000 m, 6 h/day, 6 weeks). It has been found that such mode of adaptation increased cardiac tolerance to arrhythmogenic action of a 45-min coronary artery occlusion but did not change an infarct size/area at risk (IS/AAR) ratio. In a separate series, rats were exposed to stronger intermittent hypobaric hypoxia (7000 m, 8 h/day, 6 weeks) and subjected to 20-min coronary artery occlusion and 3-h reperfusion on the day after the last hypoxic exposure. It has been established that in this case adaptation decreased the IS/AAR ratio, increased cardiac tolerance to arrhythmogenic action of reperfusion but had no effect on the incidence of ventricular arrhythmias occurred during ischemic period. We found that cardioprotective and antiarrhythmic effect of adaptation to the "altitudes" of 7000 m and antiarrhythmic effect of adaptation to the "altitude" of 5000 m is mediated via K(ATP)-channel activation.     

Antiarrhythmic and electrophysiological properties of etmozin and its diethylamine analog]

Effects of antiarrhythmic drug etmosin and its diethylamine analogue (etmosin DAA) were compared in dogs with the ventricular rhythm disturbances induced by coronary artery ligation according to Harris' method. As demonstrated, both drugs stopped ventricular rhythm disturbances, but etmosin DAA had a more rapid and prolonged effect. Electrophysiological properties of etmosin and etmosin DAA were studied by the method of potential fixation on trabeculae of frog atria. Both drugs proved to reduce rapid sodium inflow, etmosin DAA acting more intensively and longer. Taking into account the high antiarrhythmic activity of etmosin DAA it is believed that this drug had good prospects for further investigation.     

Theoretical Study of Cardiac Transient Conduction Blocks on Reentries Induction. Applications to Antiarrhythmic Drugs

Limitations of antiarrhythmic drugs on cardiac sudden death prevention appeared since the early 80's. The "Cardiac Arrhythmia Suppression Trial"(CAST) showed more recently that mortality was significantly higher inpatients treated with some particular antiarrhythmic drugs than in non-treated patients. In this field, our group recently demonstrated that a bolus of a Class 1B antiarrhythmic drug was able to trigger a ventricular fibrillation due to transient blocks induction. The aim of the present work was to systematically study, by use of the van Capelle and Durrer (VCD) model which allows to simulate ventricular activation wave propagation, the link between arrhythmogenic effects and the ability of transient blocks to possibly degenerate in severe arrhythmias. A fragment of the ventricular wall is represented by an array of 16384elements electrically coupled. Effects of induction of one or several transient blocks, as the effects of their size and duration on possible induction of reentries have been studied. Results obtained show that various combinations between these different parameters may trigger reentries, ventricular tachycardia and/or more complex patterns assimilable to ventricular fibrillation. These results clearly evidence the fact that possible induction of transient blocks may directly be related to risk factor associated to arrhythmogenic effects of antiarrhythmic drugs. This revised version was published online in June 2006 with corrections to the Cover Date.     

In silico optimization of atrial fibrillation-selective sodium channel blocker pharmacodynamics

Atrial fibrillation (AF) is the most common type of clinical arrhythmia. Currently available anti-AF drugs are limited by only moderate efficacy and an unfavorable safety profile. Thus, there is a recognized need for improved antiarrhythmic agents with actions that are selective for the fibrillating atrium. State-dependent Na(+)-channel blockade potentially allows for the development of drugs with maximal actions on fibrillating atrial tissue and minimal actions on ventricular tissue at resting heart rates. In this study, we applied a mathematical model of state-dependent Na(+)-channel blocking (class I antiarrhythmic drug) action, along with mathematical models of canine atrial and ventricular cardiomyocyte action potentials, AF, and ventricular proarrhythmia, to determine the relationship between their pharmacodynamic properties and atrial-selectivity, AF-selectivity (atrial Na(+)-channel block at AF rates versus ventricular block at resting rates), AF-termination effectiveness, and ventricular proarrhythmic properties. We found that drugs that target inactivated channels are AF-selective, whereas drugs that target activated channels are not. The most AF-selective drugs were associated with minimal ventricular proarrhythmic potential and terminated AF in 33% of simulations; slightly fewer AF-selective agents achieved termination rates of 100% with low ventricular proarrhythmic potential. Our results define properties associated with AF-selective actions of class-I antiarrhythmic drugs and support the idea that it may be possible to develop class I antiarrhythmic agents with optimized pharmacodynamic properties for AF treatment.     

Dronedarone in patients with atrial fibrillation

Dronedarone is a recently developed new class III antiarrhythmic drug which possesses electrophysiological properties of all four Vaughan-Williams classes. An important difference with amiodarone is that it does not contain an iodine component and therefore lacks the iodine-related adverse effects. Based on currently available data, dronedarone can not be recommended as first-line therapy for either rhythm or rate control. We recommend to initiate rhythm or rate control with drugs as indicated in the 2006 guidelines of the ESC and other organisations. As amiodarone, dronedarone can be given to patients for whom standard drug therapy is not effective, or limited by (severe) side effects, although it is less effective than amiodarone. Nevertheless, it may be considered to give dronedarone initially to patients who would otherwise have received amiodarone, since the latter has more severe side effects than the former drug. The daily dosage of dronedarone is oral administration, 400 mg twice daily. Dronedarone is contraindicated in patients with impaired left ventricular function (NYHA class III/IV) and haemodynamic instability. (Neth Heart J 2010;18:370-3.)     

The canine virtual ventricular wall: a platform for dissecting pharmacological effects on propagation and arrhythmogenesis

We have constructed computational models of canine ventricular cells and tissues, ultimately combining detailed tissue architecture and heterogeneous transmural electrophysiology. The heterogeneity is introduced by modifying the Hund–Rudy canine cell model in order to reproduce experimentally reported electrophysiological properties of endocardial, midmyocardial (M) and epicardial cells. These models are validated against experimental data for individual ionic current and action potential characteristics, and their rate dependencies. 1D and 3D heterogeneous virtual tissues are constructed, with detailed tissue architecture (anisotropy and orthotropy, due to fibre orientation and sheet structure) of the left ventricular wall wedge extracted from a diffusion tensor imaging data set. The models are used to study the effects of tissue heterogeneity and class III drugs on transmural propagation and tissue vulnerability to re-entry.

We have determined relationships between the transmural dispersion of action potential duration (APD) and the vulnerable window in the 1D virtual ventricular wall, and demonstrated how changes in the transmural heterogeneity, and hence tissue vulnerability, can lead to generation of re-entry in the 3D ventricular wedge. Two class III drugs with opposite qualitative effects on transmural APD heterogeneity are considered: d-sotalol that increases transmural APD dispersion, and amiodarone that decreases it. Simulations with the 1D virtual ventricular wall show that under d-sotalol conditions the vulnerable window is substantially wider compared to amiodarone conditions, primarily in the epicardial region where unidirectional conduction block persists until the adjacent M cells are fully repolarised.

Further simulations with the 3D ventricular wedge have shown that ectopic stimulation of the epicardial region results in generation of sustained re-entry under d-sotalol conditions, but not under amiodarone conditions or in control. Again, APD increase in M cells was identified as the major contributor to tissue vulnerability—re-entry was initiated primarily due to ectopic excitation propagating around the unidirectional conduction block in the M cell region. This suggests an electrophysiological mechanism for the anti- and proarrhythmic effects of the class III drugs: the relative safety of amiodarone in comparison to d-sotalol can be explained by relatively low transmural APD dispersion, and hence, a narrow vulnerable window and low probability of re-entry in the tissue.     

Catheter Ablation in Patients with Electrical Storm in Early Post Infarction Period (6 Weeks): A Single Centre Experience

Background

Electrical storm (ES) due to drug refractory ventricular tachycardia (VT) occurring within first few weeks of acute myocardial infarction (MI) has poor prognosis. Catheter ablation has been proposed for treating VT occurring late after MI, but there is limited data on catheter ablation in VT within first few weeks of MI.

Methods and Results

Five patients (4 males, mean age 54.2±12.11 years) between June 2008 to July 2012, referred for VT presenting as ES refractory to antiarrhythmic drugs in the early post infarction period (six weeks following MI) despite revascularization. Three patients had anterior wall MI and two inferior wall MI with left ventricular ejection fraction ranging from 26 to 35%.All underwent catheter ablation within 48 hours of being in VT except one who presented late. Clinical VT was induced in all five patients. Total number of VTs induced were 11 (2.2±1.09 per patient). Two patients needed epicardial ablation via pericardial puncture. Though acute success was 100%, one patient had recurrence of clinical VT the next day of procedure.One patient succumbed to sepsis with multiple organ failure. The remaining four patients are doing well without further clinical recurrence of VT over a period of 3.7 years of follow-up.

Conclusion

Catheter ablation can be a useful adjunctive therapy for patients with recurrent VT in the early post infarction period. This procedure appears to be safe with acceptable success rate.     

Mechanisms of destabilization and early termination of spiral wave reentry in the ventricle by a class III antiarrhythmic agent, nifekalant

Nifekalant (NF) is a novel class III antiarrhythmic agent that is effective in preventing life-threatening ventricular tachycardia/fibrillation (VT/VF). We investigated mechanisms of destabilization and early termination of spiral-type reentrant VT by NF in a two-dimensional subepicardial myocardial layer of Langendorff-perfused rabbit hearts (n = 21) using a high-resolution optical action potential mapping system. During basic stimulation, NF (0.1 microM) caused uniform prolongation of action potential duration (APD) without affecting conduction velocity and an increase of APD restitution slope. VTs induced by direct current stimulation in the presence of NF were of shorter duration (VTs > 30 s: 2/54 NF vs. 19/93 control). During VTs in control (with visible rotors), the wave front chased its own tail with a certain distance (repolarized zone), and they seldom met each other. The average number of phase singularity (PS) points was 1.31 +/- 0.14 per 665 ms (n = 7). In the presence of NF, the wave front frequently encountered its own tail, causing a transient breakup of the spiral wave or sudden movement of the rotation center (spatial jump of PS). The average number of PS was increased to 1.63 +/- 0.22 per 665 ms (n = 7, P < 0.05) after NF. The mode of spontaneous termination of rotors in control was in most cases (9/10, 90.0%) the result of mutual annihilation of counterrotating wave fronts. With NF, rotors frequently terminated by wave front collision with the atrioventricular groove (12/19, 63.2%) or by trapping the spiral tip in a refractory zone (7/19, 36.8%). Destabilization and early termination of spiral wave reentry induced by NF are the result of a limited proportion of excitable tissue after modulation of repolarization.     

Opposite change with ischaemia in the antifibrillatory effects of class I and class IV antiarrhythmic drugs resulting from the alteration in ion transmembrane exchanges related to depolarization

It is known that class I antiarrhythmic drugs lose their antifibrillatory activity with severe ischaemia, whereas class IV antiarrhythmic drugs acquire such activity. Tachycardia, which is also a depolarizing factor, has recently been shown to give rise to an alteration of ion transmembrane exchanges which is particularly marked in the case of calcium. This leads one to wonder if the change in antifibrillatory activity of antiarrhythmic drugs caused by ischaemia depends on the same process. The change in antifibrillatory activity was studied in normal conditions ranging to those of severe ischaemia with a class I antiarrhythmic drug, flecainide (1.00 mg x kg(-1) plus 0.04 mg x kg(-1)x min(-1), a sodium channel blocker, and a class IV antiarrhythmic drug, verapamil (50 microg x kg(-1) plus 2 microg x kg(-1) x min(-1)), a calcium channel blocker. The experiments were performed in anaesthetized, open-chest pigs. The resulting blockade of each of these channels was assessed at the end of ischaemic periods of increasing duration (30, 60, 120, 180, 300, and 420 s) by determining the ventricular fibrillation threshold (VFT). VFT was determined by means of trains of diastolic stimuli of 100 ms duration delivered by a subepicardial electrode introduced into the myocardium (heart rate 180 beats per min). Ischaemia was induced by completely occluding the left anterior descending coronary artery. The monophasic action potential was recorded concurrently for the measurement of ventricular conduction time (VCT). The monophasic action potential duration (MAPD) varied with membrane polarization of the fibres. The blockade of sodium channels by flecainide, which normally raises VFT (7.0 +/- 0.4 to 13.8 +/- 0.8 mA, p < 0.001) and lengthens VCT (28 +/- 3 to 44 +/- 5 ms, p < 0.001), lost its effects in the course of ischaemia. This resulted in decreased counteraction of the ischaemia-induced fall of VFT and decreased aggravation of the ischaemia-induced lengthening of VCT. The blockade of calcium channels, which normally does not alter VFT (between 7.2 +/- 0.6 and 8.4 +/- 0.7 mA, n.s.) or VCT (between 30 +/- 2 and 34 +/- 3 ms, n.s.), slowed the ischaemia-induced fall of VFT. VFT required more time to reach 0 mA, thus delaying the onset of fibrillation. Membrane depolarization itself was opposed as the shortening of MAPD and the lengthening of VCT were also delayed. Consequently there is a progressive decrease in the role played by sodium channels during ischaemia in the rhythmic systolic depolarization of the ventricular fibres. This reduces or suppresses the ability of sodium channel blockers to act on excitability or conduction, and increases the role of calcium channel blockers in attenuating ischaemia-induced disorders.     

Effects of HNS-32, a novel antiarrhythmic drug,on ventricular arrhythmias induced by coronary artery occlusion and reperfusion in anesthetized rats

HNS-32 (N¹,N¹-dimethyl-N²-(2-pyridylmethyl)-5-isopropyl-3, 8-dimethylazulene-1-carboxamidine: CAS 186086-10-2) is a newly synthesized compound, and possesses antiarrhythmic properties with vasodilator action in dog hearts. The aim of this study was to investigate the dose-dependent effects of HNS-32 on ischemia- and/or reperfusion-induced ventricular arrhythmias in anesthetized rats in vivo and compared with those of mexiletine. Saline or drugs were administered intravenously 5 min prior to coronary artery occlusion. On the ischemia-induced ventricular arrhythmias, HNS-32 showed dose-dependent reduction of total number of premature ventricular complexes (PVC) from 2091 ± 225 to 656 ± 116 and 286 ± 69 beats/30 min (p < 0.05), the ventricular tachycardia (VT) duration from 183 ± 33 to 28 ± 9 and 4 ± 2 sec (p < 0.05), the incidence of VT from 100 to 90 (n.s.) and 40% (p < 0.05), and the incidence of ventricular fibrillation (VF) from 50 to 0 and 0% (p < 0.05) with 3 and 5 mg/kg, respectively. Mexiletine also reduced these parameters to 936 ± 159 beats/30 min (p < 0.05), 39 ± 22 sec (p < 0.05), 90% (n.s.) and 10% (n.s.), respectively. HNS-32 completely suppressed the late reperfusion-induced arrhythmias, however mexiletine did not affect them. On the early reperfusion-induced ventricular arrhythmias, HNS-32 showed dose-dependent reduction of VT duration from 126 ± 34 to 37 ± 12 and 3 ± 2 sec (p < 0.05), incidence of VT from 100 to 90 (n.s.) and 40% (p < 0.05), incidence of VF from 100 to 10 and 0% (p < 0.05), and mortality rate from 90 to 0 and 0% (p < 0.05), with 3 and 5 mg/kg, respectively. Mexiletine also reduced these parameters to 16 ± 9 sec (p < 0.05), 80 (n.s.), 50 (p < 0.05), and 10% (p < 0.05), respectively. HNS-32 significantly reduced the heart rate in a dose-dependent manner, from 399 ± 14 to 350 ± 8 and 299 ± 10 beats/min (p < 0.05) with 3 and 5 mg/kg, respectively. The antiarrhythmic effects of HNS-32 were more potent than that of the similar dose of mexiletine against occlusion-induced and reperfusion-induced arrhythmias in in vivo rats.     

Action potential duration restitution and ventricular fibrillation due to rapid focal excitation

The focal source hypothesis of ventricular fibrillation (VF) posits that rapid activation from a focal source, rather than action potential duration (APD) restitution properties, is responsible for the maintenance of VF. We injected aconitine (100 microg) into normal isolated perfused swine right ventricles (RVs) stained with 4-[beta-[2-(di-n-butylamino)-6-naphthyl]vinyl]pyridinium (di-4-ANEPPS) for optical mapping studies. Within 97 +/- 163 s, aconitine induced ventricular tachycardia (VT) with a mean cycle length 268 +/- 37 ms, which accelerated before converting to VF. Drugs that flatten the APD restitution slope, including diacetyl monoxime (10-20 mM, n = 6), bretylium (10-20 microg/ml, n = 3), and verapamil (2-4 microg/ml, n = 3), reversibly converted VF to VT in all cases. In two RVs, VF persisted despite of the excision of the aconitine site. Simulations in two-dimensional cardiac tissue showed that once VF was initiated, it remained sustained even after the "aconitine" site was eliminated. In this model of focal source VF, the VT-to-VF transition occurred due to a wave break outside the aconitine site, and drugs that flattened the APD restitution slope converted VF to VT despite continuous activation from aconitine site.     

The role of prostaglandins in the antiarrhythmic effect of ischemic preconditioning

The role of prostaglandins in the antiarrhythmic effect of ischemic preconditioning (IP) was investigated in pentobarbital-anesthetized rats. In 5 unpreconditioned control rats, 30 min of occlusion of the left coronary artery elicited ventricular tachycardia (VT) and fibrillation (VF), with an average duration of VT and VF of 51 +/- 6 and 43 +/- 4 s, respectively. Frequent ventricular premature beats (VPBs; average 1,249 +/- 145) were also documented in these animals. Thirty minutes of reperfusion after the prolonged coronary occlusion in these animals caused more severe arrhythmias, including irreversible VF. In animals pretreated with IP (n = 5), which was achieved by 3 cycles of 3 min of occlusion followed by 5 min of reperfusion, 30 min of coronary artery occlusion caused neither VT nor VF, but occasional VPBs (average 2 +/- 1, p < 0.001 vs. control). Only occasional VPBs were observed during 30 min of reperfusion in this group. In animals pretreated with indomethacin (1 mg/kg i.v., n = 5) followed by IP, prolonged ischemia and reperfusion led to frequent VPBs but no VT or VF. The average number of VPBs during ischemia and reperfusion in this indomethacin-treated group was less than that of the controls but greater than the IP-only group (p < 0.01). In conclusion, prostaglandins appear to play a role in the protective effect of IP against VPBs during acute ischemia and reperfusion.