Arrhythmia Models Research Articles

Arctigenin, a Potential Anti-Arrhythmic Agent, Inhibits Aconitine-Induced Arrhythmia by Regulating Multi-Ion Channels

Background/Aims: Arctigenin possesses biological activities, but its underlying mechanisms at the cellular and ion channel levels are not completely understood. Therefore, the present study was designed to identify the anti-arrhythmia effect of arctigenin in vivo, as well as its cellular targets and mechanisms. Methods: A rat arrhythmia model was established via continuous aconitine infusion, and the onset times of ventricular premature contraction, ventricular tachycardia and death were recorded. The Action Potential Duration (APD), sodium current (I_Na), L-type calcium current (I_{Ca, L}) and transient outward potassium current (I_to) were measured and analysed using a patch-clamp recording technique in normal rat cardiomyocytes and myocytes of arrhythmia aconitine-induced by. Results: Arctigenin significantly delayed the arrhythmia onset in the aconitine-induced rat model. The 50% and 90% repolarisations (APD₅₀ and APD₉₀) were shortened by 100 µM arctigenin; the arctigenin dose also inhibited the prolongation of APD₅₀ and APD₉₀ caused by 1 µM aconitine. Arctigenin inhibited I_Na and I_Ca,L and attenuated the aconitine-increased I_Na and I_Ca,L by accelerating the activation process and delaying the inactivation process. Arctigenin enhanced I_to by facilitating the activation process and delaying the inactivation process, and recoverd the decreased I_to induced by aconitine. Conclusions: Arctigenin has displayed anti-arrhythmia effects, both in vivo and in vitro. In the context of electrophysiology, I_Na, I_{Ca, L}, and I_to may be multiple targets of arctigenin, leading to its antiarrhythmic effect.

Development of a reentrant arrhythmia model in human pluripotent stem cell-derived cardiac cell sheets

Development of a human cell-derived reentrant arrhythmia model is needed for studying the mechanisms of disease and accurate drug response. We differentiated human pluripotent stem cells (hPSCs) into cardiomyocytes, and then re-plated them into cell sheets that proved capable of forming electrically coupled assemblies. We monitored the function of these re-plated sheets optically with the Ca(2+) sensitive dye Fluo-4, and found that they generated characteristic waves of activity whose velocity and patterns of propagation depended upon the concentration of sodium channel blockers; lidocaine and tetrodotoxin, and also the time after re-plating, as well as the applied stimulation frequency. Importantly, reentrant spiral-wave propagation could be generated in these sheets by applying high-frequency stimulation, particularly when cell-density in the sheets was relatively low. This was because cardiac troponin T-positive cells were more non-homogeneously distributed at low cell densities. Especially in such sheets, we could terminate spiral waves by administering the anti-arrhythmic drugs; nifekalant, E-4031, sotalol, and quinidine. We also found that in these sheets, nifekalant showed a clear dose-dependent increase in the size of the unexcitable 'cores' of these induced spiral waves, an important parallel with the treatment for ventricular tachycardia in the clinical situation, which was not shown properly in cardiac-cell sheets derived from dissociated rodent hearts. We have succeeded in creating from hPSCs a valuable type of cardiomyocyte sheet that is capable of generating reentrant arrhythmias, and thus is demonstrably useful for screening and testing all sorts of drugs with anti-arrhythmic potential.

Synthesis and preliminary evaluation of pharmacological properties of some piperazine derivatives of xanthone

A series of 9 piperazine derivatives of xanthone were synthesized and evaluated for cardiovascular activity. The following pharmacological experiments were conducted: the binding affinity for adrenoceptors, the influence on the normal electrocardiogram, the effect on the arterial blood pressure and prophylactic antiarrhythmic activity in adrenaline induced model of arrhythmia (rats, iv). Three compounds revealed nanomolar affinity for α1-adrenoceptor which was correlated with the strongest cardiovascular (antiarrhythmic and hypotensive) activity in animals’ models. The most promising compound was 4-(3-(4-(2-methoxyphenyl)piperazine-1-yl)propoxy)-9H-xanthen-9-one hydrochloride (12) which revealed antiarrhythmic activity with ED50 value of 0.69mg/kg in adrenaline induced arrhythmia (rats, iv). Other synthesized xanthone derivatives, that is, (R,S)-4-(2-hydroxy-3-(4-(2-methoxyphenyl)piperazine-1-yl)propoxy)-9H-xanthen-9-one hydrochloride (10) and (R,S)-4-(2-acetoxy-3-(4-(2-methoxyphenyl)piperazine-1-yl)propoxy)-9H-xanthen-9-one hydrochloride (11) also acted as potential antiarrhythmics in adrenaline induced model of arrhythmia in rats after intravenous injection (ED50=0.88mg/kg and 0.89mg/kg, respectively). These values were lower than values obtained for reference drugs such as propranolol and urapidil, but not carvedilol.Results were quite promising and suggested that in the group of xanthone derivatives new potential antiarrhythmics and hypotensives might be found.

Calmodulin-Dependent Protein Kinase II: Linking Heart Failure and Arrhythmias

Understanding relationships between heart failure and arrhythmias, important causes of suffering and sudden death, remains an unmet goal for biomedical researchers and physicians. Evidence assembled over the past decade supports a view that activation of the multifunctional Ca(2+) and calmodulin-dependent protein kinase II (CaMKII) favors myocardial dysfunction and cell membrane electrical instability. CaMKII activation follows increases in intracellular Ca(2+) or oxidation, upstream signals with the capacity to transition CaMKII into a Ca(2+) and calmodulin-independent constitutively active enzyme. Constitutively active CaMKII appears poised to participate in disease pathways by catalyzing the phosphorylation of classes of protein targets important for excitation-contraction coupling and cell survival, including ion channels and Ca(2+) homeostatic proteins, and transcription factors that drive hypertrophic and inflammatory gene expression. This rich diversity of downstream targets helps to explain the potential for CaMKII to simultaneously affect mechanical and electrical properties of heart muscle cells. Proof-of-concept studies from a growing number of investigators show that CaMKII inhibition is beneficial for improving myocardial performance and for reducing arrhythmias. We review the molecular physiology of CaMKII and discuss CaMKII actions at key cellular targets and results of animal models of myocardial hypertrophy, dysfunction, and arrhythmias that suggest CaMKII inhibition may benefit myocardial function while reducing arrhythmias.

Selective inhibitors of cardiac ADPR cyclase as novel anti-arrhythmic compounds

ADP-ribosyl cyclases (ADPRCs) catalyse the conversion of nicotinamide adenine dinucleotide to cyclic adenosine diphosphoribose (cADPR) which is a second messenger involved in Ca2+ mobilisation from intracellular stores. Via its interaction with the ryanodine receptor Ca2+ channel in the heart, cADPR may exert arrhythmogenic activity. To test this hypothesis, we have studied the effect of novel cardiac ADPRC inhibitors in vitro and in vivo in models of ventricular arrhythmias. Using a high-throughput screening approach on cardiac sarcoplasmic reticulum membranes isolated from pig and rat and nicotinamide hypoxanthine dinuleotide as a surrogate substrate, we have identified potent and selective inhibitors of an intracellular, membrane-bound cardiac ADPRC that are different from the two known mammalian ADPRCs, CD38 and CD157/Bst1. We show that two structurally distinct cardiac ADPRC inhibitors, SAN2589 and SAN4825, prevent the formation of spontaneous action potentials in guinea pig papillary muscle in vitro and that compound SAN4825 is active in vivo in delaying ventricular fibrillation and cardiac arrest in a guinea pig model of Ca2+ overload-induced arrhythmia. Inhibition of cardiac ADPRC prevents Ca2+ overload-induced spontaneous depolarizations and ventricular fibrillation and may thus provide a novel therapeutic principle for the treatment of cardiac arrhythmias.

Verapamil as an antiarrhythmic agent in congestive heart failure: hopping from rabbit to human?

Repolarization-dependent cardiac arrhythmias only arise in hearts facing multiple 'challenges' affecting its so-called repolarization reserve. Congestive heart failure (CHF) is one such challenge frequently observed in humans and is accompanied by altered calcium handling within the contractile heart cell. This raises the question as to whether or not the well-known calcium channel antagonist verapamil acts as an antiarrhythmic drug in this setting, as seen in arrhythmia models without CHF. According to the study of Milberg et al. in this issue of BJP, the answer is yes. The results of this study, using a rabbit CHF model, raise important questions. First, given that the model combines CHF with a number of other interventions that predispose towards arrhythmia, will similar conclusions be reached in a setting where CHF is a more prominent proarrhythmic challenge; second, what is the extent to which other effects of calcium channel block would limit the clinical viability of this pharmacological approach in CHF? In vivo studies in large animal CHF models are now required to further explore this interesting, but complex, approach to the treatment of arrhythmia. LINKED ARTICLE This article is a commentary on Milberg et al., pp. 557-568 of this issue. To view this paper visit http://dx.doi.org/10.1111/j.1476-5381.2011.01721.x.

Percutaneous method for single-catheter multiple monophasic action potential recordings during magnetocardiographic mapping in spontaneously breathing rodents

To test the feasibility of a novel method to combine magnetocardiographic (MCG) estimate of ventricular repolarization (VR) and multiple monophasic action potential (MultiMAP) recording in spontaneously breathing rodents with percutaneous sub-xyphoid epicardial placement of a MCG-compatible amagnetic catheter (AC), ten Wistar rats (WRs) and ten guinea pigs (GPs) were studied. Under fluoroscopic control, the AC was moved until four stable MAPs were recorded (fixed inter-electrode distance of 1.2 mm). 36-channel DC-SQUID (sensitivity 20 fT Hz–½) were used for MCG mapping. MAPs, differentially amplified (BW: DC-500 Hz), were digitized at 1 kHz. AC pacing provided local ventricular effective refractory period (VERP) estimate. MAP duration (MAPd) was measured at 50% and 90% levels of repolarization. Simultaneous MCG mapping and MultiMAP recording were successful in all animals. Average MAPd50% and MAPd90% were shorter in WRs than in GPs (26.4 ± 2.9 ms versus 110.6 ± 14.3 ms and 60.7 ± 5.4 ms versus 127.7 ± 15.3 ms, respectively). VERP was 51 ± 4.8 ms in WRs and 108.4 ± 12.9 ms in GPs, respectively. The MAP amplitude was 16.9 ± 4.5 in WRs and 16.2 ± 4.2 in GPs. MAP and MCG parameters of VR were in good agreement. All animals survived the procedure. Two also survived a second invasive study; one was followed up until natural death at 52 months. Percutaneous MultiMAP recording is minimally invasive, usually avoids animal sacrifice, is compatible with simultaneous surface MCG mapping and might be used for experimental validation of MCG VR abnormality, to study the arrhythmogenic potential of new drugs and/or animal models of ventricular arrhythmias.

Antiarrhythmic properties of phenylpiperazine derivatives of phenytoin with α1-adrenoceptor affinities

An association between α1-adrenoceptor affinities, hERG K+-antagonistic properties and antiarrhythmic activities for a series of phenylpiperazine derivatives of hydantoin (2a–21a) was investigated. New compounds were synthesized and tested for their affinity for α1-adrenoceptors in radioligand binding assay using [3H]-prazosin as a selective radioligand. Antiarrhythmic activities in adrenaline- and barium chloride-induced arrhythmia models, an influence of the phenylpiperazine derivatives on the ECG-components and blood pressure were tested in vivo in normotensive rats. The hERG K+-antagonistic properties of the most potent antiarrhythmic agents were investigated in silico by the use of program QikProp. The highest α1-adrenoceptor affinity (Ki=4.7nM) and the strongest antiarrhythmic activity in adrenaline induced arrhythmia (ED50=0.1mg/kg) was found for 1-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)-3-methyl-5,5-diphenylimidazolidine-2,4-dione hydrochloride (19a). The results indicated a significant correlation between α1-AR affinities (pKi) and antiarrhythmic activity (ED50) in adrenaline model (R2=0.92, p <0.005). Influence of the examined phenylpiperazine hydantoin derivatives on hERG K+ channel, predicted by means of in silico methods, suggested their hERG K+-blocking properties.

A Novel Discovery of IK1 Channel Agonist

Modulation of the inward rectifier K current (IK1) has profound effect on cardiac excitability and underlies new antiarrhythmic strategies. However, IK1-specific pharmacological tools, especially the selective IK1 agonists, are still lacking in the market. Zacopride, a gastrointestinal prokinetic drug, was found to be a selective IK1 channel agonist. By using the whole-cell patch clamp technique, it was found that zacopride (0.1-10 μmole/L) dose dependently enhanced the IK1 current in isolated rat cardiomyocytes, had no effects on other ion channels, transporters, or pumps. At the same dosage range, zacopride hyperpolarized the resting potential and shortened the action potential duration. When applied at the optimal dose of 1.0 μmole/L, zacopride could prevent or eliminate aconitine induced after depolarization and triggered activity in isolated cardiomyocytes. In a rat model of aconitine-induced arrhythmias both ex vivo and in vivo, zacopride (1.0 μmole/L or 25 μg/kg, respectively) treatment apparently protected the heart from ventricular tachyarrhythmias, which compares favorably with 7.5 mg/kg of lidocaine, a classical aconitine antidote. In conclusion, zacopride was found to be a selective IK1 agonist, and agonizing IK1 could prevent or eliminate aconitine-induced arrhythmias in the rat.

Investigation on SCH00013, a novel cardiotonic agent with Ca++ sensitizing action. 4th communication: influence on experimentally induced ventricular arrhythmia in dogs.

Influence of 4,5-dihydro-6-[1-[2-hydroxy-2-(4-cyanophenyl)ethyl]- 1,2,5,6,-tetrahydropyrido-4-yl]pyridazin-3(2H)-one (SCH00013) and vesnarinone (CAS 81840-15-5) on the arrhythmia experimentally induced by three different methods was investigated in dogs. In digitalis-induced arrhythmia, SCH00013 (3 mg/kg i.v.) showed a tendency to improve the arrhythmia with a decrease in the arrhythmic ratio and an increase in the conducted beats (CB), though these changes did not reach a significant level; it decreased significantly the blood pressure (BP) with no change in the total heart rate (THR) and atrial rate (AR). Vesnarinone (3 mg/kg i.v.) did not affect these parameters except for BP that was decreased significantly. In two-stage coronary ligation-induced arrhythmia, SCH00013 (1 and 3 mg/kg i.v.) did not change the arrhythmic ratio, CB, AR and BP, while the THR being slightly decreased; the arrhythmic ratio showed a tendency to decrease with SCH00013 when examined at 24 h after coronary ligation. Vesnarinone (3 mg/kg i.v.) did not affect these parameters at 24 and 48 h after ligation. In epinephrine (adrenaline)-induced arrhythmia, both SCH00013 and vesnarinone showed exacerbation of arrhythmia. SCH00013 at 1 mg/kg i.v. did not elicit ventricular fibrillation (VF) in five dogs examined, but at 3 mg/kg i.v. it elicited VF in two of three dogs. Vesnarinone at 1 mg/kg i.v. induced VF in all of three dogs examined. Incidence of VF induced by optical isomers of SCH00013 was not significantly different from each other: both isomers elicited VF in two of six dogs at 1 mg/kg i.v. and at 3 mg/kg i.v. each of them induced VF in two dogs examined. The present results indicate that SCH00013 is a cardiotonic agent that is equivalent to or less arrhythmogenic than vesnarinone in animal models of arrhythmia, such as adrenaline- and digitalis-induced arrhythmia and the two-stage coronary ligation-induced arrhythmia. Optical isomers of SCH00013 were essentially equieffective in eliciting exacerbation of adrenaline-induced arrhythmia in the dog.

Effects of SEA0400 on Ouabain-induced Arrhythmias in Guinea Pigs

The sodium-calcium exchange (NCX) is one of the major regulators of intracellular Ca2+ concentration in cardiac myocytes. The effects of NCX blockers as antiarrhythmic agents are still controversial. We investigated antiarrhythmic effects of SEA0400 (SEA), a novel NCX inhibitor, on ouabain-induced arrhythmias in guinea pigs. In the whole animal arrhythmia model, we observed effects of SEA on the ouabain-induced arrhythmia using ECG recordings. In the isolated myocyte, we observed action potential configurations and oscillations due to calcium overload using the current clamp method. In the whole animal model, SEA at a dose range of 1-10 mg/kg (intravenous, bolus) suppressed ouabain-induced arrhythmias dose-dependently. In isolated ventricular myocytes, SEA (0.1-3 µM) suppressed ouabain-induced oscillatory activity observed between action potentials. SEA (0.1-3 µM) also suppressed ouabain-induced NCX current (INCX) that is also called transient inward current (ITI). Our results indicate that NCX is involved in arrhythmia and oscillatory activity induced by ouabain. The inhibition of these arrhythmias and oscillatory activity by SEA might result from the inhibition of NCX.Keywords: Na+-Ca2+ exchange (NCX); SEA0400; NCX inhibitors; current clamp; ECG.© 2012 JSR Publications. ISSN: 2070-0237 (Print); 2070-0245 (Online). All rights reserved.doi: http://dx.doi.org/10.3329/jsr.v4i1.7722J. Sci. Res. 4 (1), 213-225 (2012)

Genes targets identification of 5-amino-exo-3-azatricyclo[5.2.1.02,6]decane-4-one in an in vivo model of arrhythmia

The goal of the current work is to study the molecular mechanisms underlay the action of 5- amino-exo-3-azatricyclo[5.2.1.0(2,6)]decan-4-one (P-11) with combined antiarrhythmic, nootropic, anti-inflammatory and anaesthetic activities. The aconitine-induced experimental rat model of cardiac arrhythmia has been used in our study. Aconitine was administered once intravenously in a dose 50 microg/kg whereas experimental animal group received P-11 in a dose 0.3 mg/kg (the compound was injected intravenously 2 min before acute aconitine treatment). Expression macroarray (Atlas Rat cDNA Expression Array, #7738-1; BD Biosciences) was used to identify the target genes for P-11 compound. Comparative analysis of changes in the status of expression of genes in the heart of rats induced by P-11 against the simulated in vivo arrhythmia identified 16 genes that reproducibly alter the level of expression.These genes encode the extracellular matrix proteins (glypican 1, Gpc1; tissue inhibitor of metalloproteinase 2, 3, Timp2, Timp 3); intracellular signaling molecules (rho GTPase activating protein 7, Dlc1; protein tyrosine phosphatase 4a1, Ptp4a1; phosphodiesterase 4D, PDE4D; PI3-kinase regulatory subunit alpha, PIK3R1; guanine nucleotide binding protein alpha 12, Gna12) and protein of intermediate junctions (junction plakoglobin, Jup), proteins involved in glycolysis (phosphofructokinase I, Pfk1) and hemostasis (tissue plasminogen activator, Plat), plasma membrane transporters (Solute carrier family 16, member 1, Slc16a1; ATPase, Na+/K+ transporting, Atp1a), and ets. (c-fos protooncogene, c-fos; telomerase protein component 1, tlp; Annexin 1, anxa 1). Thus, the data about the selective effect of P-11 on genes whose products are involved in the aritmogenesys mechanisms, allow us to consider this compound as a promising means of pathogenetically oriented pharmacotherapy of cardiac arrhythmias.

Experimental study about ranolazine treatment in vivo myocardial ischemia-reperfusion arrhythmia and heart function in guinea pig

ObjectiveTo investigate ranolazine in guinea pig in vivo ischemia-reperfusion model of cardiac function and arrhythmia and its mechanism.MethodsBy ischemia-reperfusion in vivo model, impact of the ranolazine on SOD, MDA, reperfusion...

Predictive model for late atrial arrhythmia after closure of an atrial septal defect

ObjectivesTo develop a quantitative event-free prediction model of late atrial arrhythmia after atrial septal defect (ASD) repair. BackgroundThe clinical management of ASD is driven by risk factors that determine the occurrence of late atrial arrhythmia. MethodsData from ASD type secundum patients, included in the Belgian Congenital Heart Disease Registry, were analyzed. Based on review of the literature, age at repair, gender, pulmonary hypertension, atrial arrhythmia before and within one month after repair were included in the model. Using Cox-regression analysis, a weighted risk score was derived, which was validated using the Brier score. ResultsA total of 155 patients (117 women; median age at follow-up 53.9years, range 18.0–78.8) having 349 follow-up years was included. Thirty-nine patients (25.2%) presented with late atrial arrhythmia. Multivariate analysis showed that a mPAP≥25mmHg (HR 4.39; 95%CI 2.17–9.09; P<0.0001), the presence of atrial arrhythmia before (HR 3.52; 95%CI 1.75–7.14; P=0.002) and≤1month after repair (HR 6.62; 95%CI 2.38–20.00; P<0.0001) and gender (HR 2.18 95%CI 1.11–4.35) were associated with late atrial arrhythmia. A risk score (0 to 28 points) to predict atrial arrhythmia free survival was derived for follow-up times ranging from one to 5years. Mean Brier score for the model was 0.10. ConclusionsWe formulated a well validated risk model to predict arrhythmia-free survival in ASD patients undergoing ASD repair. Further research is needed whether this model can be used for individual clinical risk stratification and whether the model can be adapted for application in other congenital heart defects.

Chronic atrioventricular block model of microminipig: New in vivo model for drug-induced lethal arrhythmias

Chronic atrioventricular block model of microminipig: New in vivo model for drug-induced lethal arrhythmias

Crystal structures of atisine 15-acetoxyazomethine and 15-hydroxyazomethine and their biological activities

The 15-acetoxyazomethine derivative of atisine was prepared from atisine base. Its structure was confirmed by converting it to atisine 15-hydroxyazomethine and proved by an XSA. Atisine 15-acetoxyazomethine exhibited antiarrhythmic activity in rat cardiac arrhythmia models induced by CaCl2 and aconitine. Atisine 15-acetoxyazomethine, in contrast with atisine 15-hydroxyazomethine, exhibited local anesthetic activity.

Identification of a Chemical Supressor of Cardiac Arrhythmia Induced by Aberrant Calcium Homeostasis

Ca2+ homeostasis is essential for rhythmic contractions of the adult myocardium. In the developing embryo, a role of Ca2+ in establishing cardiac rhythmicity has been proposed, but the underlying mechanism has yet to be fully explored. We have previously shown that zebrafish tremblor mutant embryos develop a fibrillating heart and that the tremblor locus encodes a cardiac-specific isoform of the Na+/Ca2+ exchanger, NCX1h. While rhythmic Ca2+ waves were detected with each cardiac contraction in wild type hearts, only local, unsynchronized Ca2+ signals together with sporadic contractions were observed in tremblor hearts. These data suggest that loss of function of NCX1h induces cardiac fibrillation in tremblor and that tremblor mutants can serve as a model for cardiac arrhythmia induced by aberrant calcium homeostasis.From a collection of small molecules, we found a novel compound, OK-F7, that could restore rhythmic cardiac contractions in tremblor embryos at low micromolar concentrations in a reversible and dosage-dependent manner. We tested the effect of OK-F7 on isolated cardiomyocytes under Ca2+ overload conditions and found that treatment with 1 µM OK-F7 reduces the frequency of spontaneously propagating Ca2+ waves by approximately half, while 25 µM OK-F7 almost entirely abolishes Ca2+ waves. A biochemical pull-down assay using an OK-F7 affinity column isolated a mitochondrial membrane protein that selectively bound to OK-F7. These findings suggest that OK-F7 suppresses cardiac fibrillation by reducing the frequency of arrhythmogenic Ca2+ waves in Ca2+-overloaded cardiomyocytes and indicate a novel role of mitochondria in cardiac Ca2+ handling and control of rhythmicity. Further validation of the target protein and biophysical experiments confirming a role of mitochondria in the mechanism of OK-F7 action are underway and will be discussed.Supported by NIH-1R01HL096980-01A1 and FWF-J3065-B11.

Antiarrhythmic effects and ionic mechanisms of oxymatrine from Sophora flavescens

Accumulating evidence indicates that oxymatrine may exert protective effects on the cardiovascular system. This study was designed to evaluate the antiarrhythmic effects as well as the electrophysiological properties of oxymatrine. The antiarrhythmic activity of oxymatrine was observed in a rat model of arrhythmia induced by coronary ligation. Action potential duration (APD), L-type calcium current (I(Ca-L) ), transient outward potassium current (I(to) ) and inward rectifier potassium current (I(K1)) in rat ventricular myocytes were recorded by utilizing the whole cell patch-clamp technique. The results showed that administration of oxymatrine significantly delayed the onset of ventricular arrhythmia, decreased the duration of ventricular arrhythmia and reduced the arrhythmia score of arrhythmic rats. The beneficial effects of oxymatrine may be related to the shortening of APD through reduction of I(Ca-L) , enhancement of I(to) and inhibition of I(K1).

Early Repolarization Associated With Ventricular Arrhythmias in Patients With Chronic Coronary Artery Disease

Early repolarization, indicated on the standard 12-lead ECG, has recently been associated with idiopathic ventricular fibrillation in patients without structural heart disease. It is unknown whether there is an association between early repolarization and ventricular arrhythmias in the coronary artery disease (CAD) population. Patients with CAD with implantable cardioverter-defibrillators in the healed phase of myocardial infarction were analyzed. In a case-control design, 60 patients who had ventricular arrhythmic events were matched for age and sex with 60 control subjects. ECGs were analyzed for early repolarization, defined as notching or slurring morphology of the terminal QRS complex or J-point elevation ≥0.1 mV above baseline in at least 2 lateral or inferior leads. Results were adjusted for left ventricular ejection fraction. Overall, early repolarization in 2 or more leads was more common in cases than control subjects (32% versus 8%, P=0.005). Early repolarization was noted more commonly in inferior leads (23% versus 8%, P=0.03), and a trend was noted in leads V(4) through V(6) (12% versus 3%, P=0.11). Early repolarization was uncommon in leads I and aVL in cases and control subjects (3% versus 0%). Notching was more common in cases than control subjects (28% versus 7%, P=0.008). Slurring and J-point elevation were not associated with ventricular arrhythmias. Early repolarization and, in particular, notching in the inferior leads is associated with increased risk of life-threatening ventricular arrhythmias in patients with CAD, even after adjustment for left ventricular ejection fraction. Our findings suggest early repolarization, and a notching morphology should be considered in a risk prediction model for arrhythmias in patients with CAD.

Differential effects of four xylidine derivatives in the model of ischemia- and re-perfusion-induced arrhythmias in rats in vivo

The aim of our study was to find the most effective xylidine derivative, which reduced mortality, reduced incidence and duration of severe arrhythmias and had a beneficial influence on hemodynamic parameters in an in vivo setting. We compared the action of lidocaine, articaine, ropivacaine and mepivacaine in a dose 2.5 or 5mg/kg/ml/h infused from 10min before left anterior descending coronary artery occlusion until the end of the experiment. In the rat ischemia- and re-perfusion-induced arrhythmia models, the following parameters were measured or calculated: mortality index, ventricular fibrillation and tachycardia incidence and duration, systolic, diastolic and mean arterial blood pressure, heart rate and pressure rate product. Lidocaine produced the most significant reduction in mortality index (P<0.05) after both doses. At the higher dose, lidocaine and articaine shortened ventricular fibrillation and tachycardia duration (P<0.05–P<0.001), while ropivacaine prolonged them. A hypertensive effect was observed after a lower dose of lidocaine during occlusion and early re-perfusion as compared to others (P<0.05). Beneficial effects were mainly observed with lidocaine, which protected against sudden cardiac death. The novelty was lidocaine's dose independent protection against blood pressure drop in early re-perfusion, which could be linked to the effects observed on the other end-points. Articaine showed beneficial effects but they weren't as pronounced as that of lidocaine. Nevertheless, in the light of our results, articaine could supposedly be used as a substitute for lidocaine in patients with hypertension.