Experimental animal models to induce cardiac arrhythmias

L. Bhatt

Byline: L. Bhatt, K. Nandakumar, S. Bodhankar

Cardiac arrhythmias are of different types based on their mechanism and origin. The information gathered from animal studies has been instrumental in devising diagnostic and therapeutic strategies; so different animal models are needed for different types of arrhythmias. The origin and mechanism underlying clinical arrhythmias are of considerable significance, since knowledge of these processes may provide a basis for successful therapy. Various animal models that encompass different types of arrhythmias are reviewed. This review classifies various experimental models according to their origin, which are mainly supraventricular and ventricular. Also included are various transgenic animal models for arrhythmias.


Arrhythmias are disorders of heart rhythm. They are due to abnormalities in impulse generation, impulse conduction, or a combination of both. Abnormalities of impulse generation include abnormalities of automaticity and early or delayed after depolarization with triggered activity. Abnormalities of impulse propagation include conduction block and re-entry of the cardiac impulse. Combination of abnormalities of impulse formation and propagation can produce complex arrhythmias.[1] In any arrhythmia, it is useful to know which cardiac tissue participates, the ionic mechanisms and structural abnormalities that promote it. Supraventricular and ventricular arrhythmias differ in origin, ECG changes and clinical manifestations, based on which one must be able to distinguish between supraventricular from ventricular arrhythmias. The mechanism underlying clinical cardiac arrhythmias are of considerable significance and it is unfortunate that these arrhythmias are not easily studied in clinical situations. Now a days, sophisticated electro-physiological techniques are available to study cardiac pathophysiology, both in vivo and in vitro. These techniques have enabled to study the underlying mechanisms of arrhythmias and conduction disturbances in both experimental models and in patients. Although our knowledge of the mechanisms of arrhythmias and conduction disturbances has greatly increased, much remains to be explored. Various animal models [Table 1] have been developed for supraventricular as well as ventricular tachycardia to understand the basic cause, origin, possible mechanisms, manifestations and for development of new therapeutic strategies. Supraventricular tachycardia in an animal model closely resembles the clinical features observed in the patients. But ventricular models are fraught with problems since they cannot be studied in human patients because of the unpredictable occurrence in situations, where electrophysiological changes may develop within minutes. Besides this, many other factors determine whether, and if so how often-ventricular arrhythmias occur in the setting of acute ischaemia and/or a chronic myocardial infarction. In experimental models, usually only a single factor is taken into account. Though, an animal is not the same as a human patient, arrhythmogenic mechanisms derived from animal experiments have tremendously helped us to diagnose and adapt therapeutic strategies.

The therapeutic strategies to treat cardiac arrhythmias include pharmacologic approaches, ablation of specific foci involved in arrhythmogenesis, antiarrhythmic surgical approaches and implantable devices designed to respond to tachyarrhythmic events or to prevent symptomatic bradyarrhythmias. The antiarrhythmic drugs may be classified according to the modified Vaughan Williams[2] system, which categorizes them on the basis of electropharmacologic and electrophysiological properties. Drugs having class-I action possess local anesthetic or membrane stabilizing activity. Their predominant action is to block the fast inward sodium channel. This produces a decrease in the maximum depolarization rate of the action potential (Phase 0) and slows intracardiac conduction. These agents can be further subclassified as class Ia, Ib or Ic on the basis of their effects on specific aspects of intracardiac conduction and refractoriness. Class-II drugs block ?-receptor and thus reduce heart rate, decrease intracellular Ca+ 2sub overload and inhibit after depolarization-mediated automaticity. Class-III antiarrhythmic agents prolong action potential duration, presumably through blockade of K+ channels. Class IV antiarrhythmic agents inhibit the slow calcium influx during the plateau of the action potential through Ca2sub + channel blockade.

Animal models to induce cardiac arrhythmia

Supraventricular tachycardia

Wolf-Parkinson-White syndrome (WPW syndrome)

The WPW syndrome, an electrocardiographic pre-excitation pattern, is associated in a fairly large percentage of cases[3] with attacks of supraventricular tachycardia. At present, all the electrophysiological characteristics of accessory atrioventric”ular connections and their role in causing re-entrant tachycardia have been obtained from studies on human patients.[4] Boineau and Moore described pre-excitation in dogs and studied propagation of activation across an accessory atrioventricular connection in types A and B pre-excitation. In type A, the effective refractory period of the accessory pathway exceeds that of the normal AV nodal His-Purkinje pathway. Therefore, a premature atrial impulse may get blocked at the accessory pathway and conducted anterogradely down the normal pathway. Ultimately, entering the accessory pathway in the retrograde direction and re-entering the atrium to establish a circus movement tachycardia referred to as orthodromic. In type B, a shorter refractory period in the anomalous pathway and then retrograde invasion of the normal pathway, with antegrade conduction down the anomalous pathway and then retrograde invasion of the normal AV nodal pathway to establish an antidromic tachycardia. In type A, the delta wave and QRS complex are predominantly upright in the precordial leads. The dominant R wave in lead V1 may be misinterpreted as right bundle branch block. In type B, the delta wave and QRS complex are predominantly negative in leads V1 and V2 and positive in the other precordial leads, resembling left bundle branch block. In this study, they observed that atrial fibrillation induced in the dog caused ventricular fibrillation as well because the accessory pathway had a short refractory period and conducted many impulses, which otherwise would have been blocked in the AV node.[5]

Human mutations in PRKAG2, the gene encoding the g2 subunit of AMP-activated protein kinase (AMPK), cause cardiomyopathy, characterized by ventricular hypertrophy, WPW syndrome and progressive conduction system disease.[6],[7] Michael et al . developed transgenic mice over-expressing the PRKAG2 cDNA with or without a missense N4881 human mutation. Transgenic mutant mice showed elevated AMP-activated protein kinase activity, accumulated large amount of cardiac glycogen, developed dramatic left ventricular hypertrophy and exhibited ventricular preexcitation and sinus node dysfunction.[8]

Drugs, which can be screened through these models, are adenosine type drugs and class Ia drugs for acute therapy. For chronic therapy class I as well as class III drugs can be screened. Classes II and IV (phenylalkylamine and benzothiazepine like) drugs, which can cause AV nodal block, can also be screened for acute therapy.

Re-entrant arrhythmia of AV node

Paroxysmal supraventricular tachycardia (PSVT) due to AV nodal re-entry is the most common form of supraventricular arrhythmia. The underlying pathophysiology in AV nodal reentry is the presence of dual AV nodal pathways.[9] The AV node in patients with dual-pathway physiology behaves as though there are two types of conduction pathways in the AV node, one capable of faster conduction, which usually has a longer refractory period, and the other more slowly conducting and having a shorter refractory period.[10]

The pioneering clinical studies of the 1980s allowing successful surgical treatment or catheter ablation[11],[12] of the arrhythmia, all quoted the microelectrode studies on the isolated rabbit heart preparations that provided insight into arrhythmia mechanisms on a cellular basis. Janse et al. , demonstrated circus movement within the AV node as a basis for supraventricular tachycardia. They employed multiple microelectrodes recording in the isolated rabbit heart for their study.[13]

The animal model widely used for AV nodal re-entrant tachycardia is the isolated rabbit heart preparation. However, this model does not mimic the heart of patients suffering from AV nodal re-entrant tachycardia.[14] Wit et al., demonstrated an in vitro model of paroxysmal supraventricular tachycardia. They used in vitro preparation of rabbit heart atrium, including the AV node and Bundle of His to evaluate the mechanism of paroxysmal supraventricular tachycardia. Microelectrode recordings from the atrium and AV node were observed. During sinus rhythm the atrial cycle was explored with atrial premature depolarization.[15]

More et al., induced experimentally paroxysmal AV nodal tachycardia in the dog.[16] Lin et al., experimentally created atrioventricular node re-entrant tachycardia in the dog by surgery. They blocked atrial impulses from the anterior input site to the AV node.[17]

Wu et al., used optical mapping in isolated canine atrioventricular nodal re-entrant tachycardia.[18] This study was performed to optically map Koch’s triangle and surrounding atrial tissue in an isolated canine AV nodal preparation. Multiple preferential AV nodal input pathways were observed in all preparation with continuous and discontinuous AV nodal function curves. AV nodal echo beats were induced in 54% (12/22) of preparations. The re-entrant circuit of the slow/fast echo beats (EB) (36%) started as a block in fast pathway and a delay in slow pathway (SP) conduction to the compact AV node, then excited from the AV node to the fast pathway and rapidly returned to the second pathway through the atrial tissue located at the base of Koch’s triangle. The re-entrant circuit of the fast/slow EB (9%, n=2) was in an opposite direction. In the slow/slow EB (9%, n=2), anterograde conduction was over the intermediate pathway (IP) and retrograde conduction was over the SP. Unidirectional conduction block occurred at the junction between the AV node and its input pathways. Conduction over the IP smoothed the transition from the FP to the SP, resulting in a continuous AV nodal function curves. Complete or incomplete echoes were induced in isolated preparations by this method.[19] Patterson et al., have demonstrated that longitudinal dissociation within the posterior AV nodal input can give rise to localized re-entry and AV nodal re-entrant tachycardia.[20]

Adenosine is a potent source to terminate AV nodal re-entrant tachycardia. Hence, drugs such as adenosine can be screened by using these models. Class Ic drugs can be screened for chronic use. AV nodal blockers [classes II and IV (such as verapamil and diltiazem)] may be screened for acute study.

Atrial flutter

Atrial flutter is a rapid regular atrial tachyarrhythmia that is less common than the PSVTs or atrial fibrillation. It is observed only very rarely in normal subjects but may occur at any age in the presence of underlying abnormalities such as those secondary to mitral valve disease, congenital heart disease, cardiomyopathies and less frequently coronary artery disease.[21] Subgroups at particularly high risk for developing atrial flutter are children, adolescents and young adults, who have undergone corrective surgery for complex congenital heart disease, most commonly transposition of the great vessels, tetralogy of Fallot, or atrial septal defects.[22] Lewis et al., concluded that atrial flutter was the result of circus movement in the atria.[23] Successful animal preparations of atrial flutter have been developed over the years. Some important animal models to induce atrial flutter are as follows.

Canine right atrial crush injury model

Gregory et al., used this method for induction of atrial flutter. The atrial crush injury was made with a surgical clamp by lifting the anterior portion of the right atrial plaque after recording baseline sinus rhythm. The crush injury was placed on the right atrial free wall parallel to and approximately 1.5 cm above the atrioventricular groove, extending from the base of the right atrial appendage 1.5-2.5 cm posterior towards the intercaval zone. The crush injury was typically 3-4 mm wide. After right atrial crush injury, attempts were made to induce sustained atrial flutter by programmed atrial stimulation introducing single (S1S2), double (S1S2S3), or triple (S1S2S3S4) premature beats to atrial refractoriness. Sustained atrial flutter was defined as that lasting> 10 min.[24]

Atrial flutter induced by acetylcholine (ACh) and rapid pacing in the dog

Wu et al., induce atrial flutter in the isolated blood perfused canine heart. They produced episodes of rapid atrial flutter by continuous infusion of ACh and rapid atrial pacing. They isolated canine right atria and perfused it with 1-5 [micro]M/l of ACh. Mapping of the endocardium was done by using 477 bipolar electrodes with simultaneously recording transmembrane potentials from the epicardium. The APD was measured during regular pacing with cycle lengths of 300 ms. Atrial arrhythmia was induced by a premature stimulus.[25]

Atrial flutter by aconitine

Scherf et al., [26] provoked atrial flutter in anesthetized dogs by application of a few crystals of aconitine or delphinine to the surface of the right atrium in the appendix area near the head of the sinus node. Nwangw et al., [27] used aconitine (as an arrhythmogenic agent) to screen antiarrhythmic drugs in mice. Dadkar and Bhattacharya recommended aconitine antagonism in conscious mice as screening procedure.[28] Winslow recommended it in anesthetized mice.[29] Also, Winslow established the arrhythmogenic effects of aconitine in cats.[30]

Right atrial enlargement model of atrial flutter

Restivo et al., developed the canine model in which right atrial enlargement was produced by banding of the pulmonary artery thereby producing tricuspid regurgitation which may have a clinical counterpart in patients with chronic obstructive pulmonary disease and tricuspid regurgitation. It is now established that atrial flutter is due to a re-entrant wave in the right atrium, and that a zone of slow conduction located inferiorly and posterior in the right atrium is the target for catheter ablation.[31]

AV nodal blockade is a reliable mechanism to treat atrial flutter. Thus adenosine like drugs, Ca2sub + blockers and beta-adrenergic blockers can be screened on chronic basis through the models, which produce atrial flutter. Class Ia, Ib and class III drugs can be screened for acute therapy.

Atrial fibrillation

The prevalence, presentation, clinical significance and long-term implications of atrial fibrillation depend heavily upon the clinical circumstance in which it occurs. Among the cross-sectional studies of prevalence, there is a large gradient across age categories, ranging from less then 0.5% through the decades from 40 to 70 years and reaching rates in excess of 10% is some beyond age 70.[32] The haemodynamic consequences of atrial fibrillation are due to two factors: (i) the loss of atrial systole may impair ventricular function in the noncompliant ventricle (e.g. aortic stenosis, left ventricle hypertrophy or the dilated ventricle with systolic dysfunction) and (ii) a rapid ventricular rate encroaches upon diastolic filling of the left ventricle and the coronary arteries.[33] The risk of embolism and stroke is a long-term concern of special importance. The left superior vena cava can be the arrhythmogenic source of AF. The left superior vena cava (LSVC) is the embryological precursor of the ligament of Marshall, which has been implicated in the initiation and maintenance of atrial fibrillation. Rarely the LSVC may persist and has been associated with some organized arrhythmias. Li. Fern reported five patients in whom the LSVC was a source of ectopy, initiating atrial fibrillation.[34]

Atrial fibrillation by atrial ischaemia in dogs

Hani et al., induced AF by atrial ischaemia after occluding the right intermediate atrial artery (a branch of the right coronary artery) that perfuses the right atrial free wall. Atrial-arterial occlusion increased the duration of AF induced by burst pacing from 57-32 to 803-214 sec after 0.5 h of occlusion and to 887-209 sec after 3 h of occlusion. Prolonged AF was induced in none of the 16 dogs under control nonischemic conditions, 7 of 16 dogs (44%, P< 0.01) at 0.5-3 h after occlusion, and 5 of 13 dogs (38%, P< 0.01) 3-5 h after occlusion.[35]

Pituitary adenylate cyclase activating polypeptide-27 (PACAP-27) induced biphasic chronotropic effect and atrial fibrillation

PACAP-27 causes negative chronotropic effect through postganglionic nerve activation and it produces the positive chronotropic effect mediated by PACAP receptors with an activation of nonadrenergic nonvasoactive intestinal peptidergic nerves at least in part in the dog heart. Neurally released acetylcholine induced by PACAP-27 participates in the induction of atrial fibrillation.[36]

Atrial fibrillation in dogs by atrial burst pacing

Danshi et al., induced atrial fibrillation by atrial burst pacing (10 Hz, 1 to 5 sec). Atrial fibrillation> 20 min requiring electrical cardioversion for termination was considered persistent. To estimate mean atrial fibrillation duration, atrial fibrillation was induced 10 times if the duration was less than 10 minutes and 5 times if it was 10-20 min. If persistent atrial fibrillation was induced twice, no further atrial fibrillation inductions were performed.[37]

Canine model of chronic atrial fibrillation

Thomas et al., has induced chronic atrial fibrillation in dogs by creating moderate mitral regurgitation and rapidly pacing the right atrium at 640 bpm for > 8 weeks. Chronic atrial fibrillation was established with the combination of rapid atrial pacing and creation of moderate regurgitation. Catheters were introduced into the left and right heart of female mongrel dogs via femoral venous and arterial sheath. Baseline hemodynamic measurements were recorded. A 7F steerable catheter with a stiff 2 mm wire hook at its terminus was placed in the left ventricle and manipulated until mitral chordae tendineae were ensnared and then avulsed. An active fixation atrial J permanent pacemaker lead was placed in the right atrial appendage by a jugular venous approach. The pacemakers were programmed at the rate of 640 bpm or 400 bpm and an output of 2-3 times atrial diastolic threshold. After 6 weeks and weekly thereafter, the pacemakers were reprogrammed to low rates and to subthreshold outputs. After 24 h without pacing, a six lead surface ECG was obtained to verify the presence of atrial fibrillation.[38]

Vagal atrial fibrillation

Parasympathetic stimulation has been used for decades for the induction and maintenance of atrial fibrillation in experimental protocols.[39] Parasympathetic stimulation dramatically shortens the atrial effective refractory period thereby decreasing the wavelength of atrial excitation wave fronts. The shorter the wavelength, the higher is the probability that multiple re-entrant circuits can exist simultaneously in the atrial myocardium; the presence of these multiple circuits, in turn, increases the stability of atrial fibrillation.[40]

For cervical vagal nerve stimulation, the cervical vagosympathetic trunks were cut, and stainless steel wires were introduced in the cranial end of the vagosympathetic trunk. Stimulation of both the vagi was performed with separate isolated constant current sources (SS-202J, Nihon Kohden) driven by a programmable stimulator (SEN-7203, Nihon Kohden). During bilateral vagal stimulation, AF was induced by atrial extrastimulation using a digital programmable stimulator (SEC-2102, Nihon Kohden). AF lasting more than 10 min was repeatedly induced in dog.[41]

Atrial fibrillation in the isolated Langendorff-perfused rabbit heart

Atrial arrhythmias frequently occur under conditions associated with atrial dilation.[42],[43] In patients with acute myocardial infarction, the onset of atrial arrhythmias is thought to be related to the elevated left ventricular end diastolic pressure, resulting in stretch of the atrial wall.[42] In the Langendorff perfused rabbit heart, the interatrial septum was perforated, and after occlusion of the caval and pulmonary veins, bilateral pressure was increased by raising the level of an outflow cannula in the pulmonary artery. Right and left arterial effective refractory periods, monophasic action potentials and inducibility of atrial flutter by single premature stimuli were measured as a function of atrial pressure. Increasing the atrial pressure from 0.5[+ or -]0.7 to 16.2[+ or -]2.2 cm H2O resulted in a progressive shortening of the right atrial effective refractory period (AERP) from 82.2[+ or -]9.8 to 48.0[+ or -]5.1 ms. In the left atrium, an increase in pressure up to 7.4[+ or -]0.3 cm H2O had no effect on the AERP. At higher pressures, however, the left AERP also shortened, from 67.5[+ or -]7.5 to 49.3[+ or -]2.0 ms. The duration of monophasic action potentials (MAP) also decreased by an increase in atrial pressure, showing a high correlation with the shortening in AERP (r=0.94, P< 0.01). All these changes were completely reversible within 3 min after release of the atrial stretch. Dilatation of the atria was a major determinant for the vulnerability to AF.[43]

Atrial fibrillation by fibrillation pacemaker

Goats were chronically instrumented with multiple electrodes sutured to the epicardium of both atria. Two to three weeks after implantation, the animals were connected to a fibrillation pacemaker which artificially maintained atrial fibrillation. Control episodes of AF were short lasting (6[+ or -]3 sec) but artificial maintenance of AF resulted in a progressive increase in the duration of AF to become sustained (>24 h) after 7.1[+ or -]4.8 days.[44]

Atrial fibrillation by rapid atrial pacing and acetylcholine

Burashnikov et al., induced atrial fibrillation in isolated sheep hearts by burst rapid pacing from the epicardial surface of either the right atria after the addition of acetylcholine (1 [micro]M/L) to the perfusate. Transmembrane action potentials, pseudo-ECG (pseudo-ECGs are constructed from optical recordings by integrating the transmembrane fluorescence signal over the left and right halves of the mapped region and taking the difference) and tension development were recorded.[45] Allan et al., recorded the optical recordings of atrial movements to demonstrate wave propagation and lines of block, which changed on a beat to beat basis.[46]

Atrial fibrillation by aconitine

The plant alkaloid aconitine persistently activates sodium channels. Nakayama et al., compared the effects of various beta adrenergic blocking agents with known antiarrhythmics on aconitine arrhythmia.[47] They produced supraventricular arrhythmias by topical application of aconitine in a small cup placed on the right atrium of dogs. Yamamoto et al., used urethane-anesthetized rats under artificial respiration with tubocurarine pretreatment. After thoracotomy and incision of the pericardium, a piece of filter paper soaked with aconitine solution was applied to the right atrium. Test drugs were applied by continuous i.v. infusion. ECG lead II and intra atrial ECG were monitored.[48]

Therapy of atrial fibrillation is almost same as atrial flutter. Thus choice of drugs, which can be screened through these models of atrial fibrillation, is same as atrial flutter.

Ventricular fibrillation

Porcine model of VF

Iyad et al., used this model to show ventricular anti-fibrillation activity of cariporide (sodium-hydrogen exchanger isoform-1 inhibitor). A 5F pacing electrode was advanced through the right cephalic vein into the right ventricle for induction of VF. VF was induced by an alternating current (1-5 mA) delivered to the right ventricular endocardium, and mechanical ventilation was discontinued. The effects on ischemic contracture were investigated by the use of transesophageal echocardiography (TEE). The effects on APD and ventricular ectopic activity were investigated by the use of a monophasic action potential (MAP) recording/pacing catheter.[49]

Ventricular fibrillation induction by 60-Hz alternating current in isolated swine right ventricle.[50]

Voroshilovsky et al., studied seven isolated perfused swine right ventricle in vitro . The action potential duration restitution curve was determined. Alternating current captured the right ventricles at 100[+ or -] 65 [micro]A, which is significantly lower than the direct current pacing threshold (0.77 [+ or -] 0.45 mA P< 0.05). Alternating current induced ventricular tachycardia or ventricular fibrillation at 477 [+ or -] 266 [micro]A, when the stimulated response to alternating current had (1) short activation cycle lengths (128[+ or -]14 ms), (2) short diastolic intervals (16[+ or -]9 ms) and (3) short diastolic intervals associated with a steep action potential duration restitution curve. Optical mapping studies showed that during rapid ventricular stimulation by alternating current, a wave front might encounter the refractory tail of an earlier wave front, resulting in the formation of a wave break and ventricular fibrillation.

Ventricular arrhythmia by various chemicals

Vogel and Vogel described a method in which they administered continuous aconitine infusion into the saphenous vein to produce ventricular arrhythmias.[51] Vaille et al., used CaCl2 continuous i.v. infusion screening method in rats for evaluation of antiarrhythmic calcium antagonists.[52] Lawson induced ventricular fibrillation in mice by using chloroform as an antiarrhythmic agent.[53] Tripathi and Thomas produced ventricular tachycardia in rats and guinea pigs by exposing the animals to benzene vapours for 2 min followed by an intravenous adrenaline injection.[54] Digoxin a cardiac glycoside, if given in overdose produces ventricular extrasystoles, ventricular fibrillation, and finally death. Nagasawa et al., used digitalis induced arrhythmia model in dogs for screening of a new antiarrhythmic drug which was Na+/Ca+[2] exchange inhibitor.[55] Sono et al. induced ventricular fibrillation by isoprenaline in isolated rat hearts.[56] Tomokazu et al., used ouabain or strophanthin K, which is a cardiac glycoside as an arrhythmogenic substance.[57] Ouabain induced ventricular tachycardia and multifocal ventricular arrhythmias in dogs.[58] Ra et al., demonstrated a modified method for the production of cardiac arrhythmias by ouabain in anesthetized cats.[59] Takei described experimental arrhythmia in guinea pigs induced by grayanotoxin-I, a biologically active diterpenoid from the plant family of Ericaceae.[60]

Ischaemia-induced ventricular arrhythmia

Cardiac ischaemia leading to myocardial infarction is a most common cause of morbidity and mortality. Chemical or surgical interventions allow the recovery of the ischaemic myocardium by restoration of blood flow or reperfusion. This reperfusion, however, is known to be associated with ventricular arrhythmias and myocardial dysfunction that can lead to severe cardiac impairment and cell death.[61], [62] Reactive oxygen species (ROS) such as superoxide anion, hydrogen peroxide, hydroxyl radical, and singlet oxygen have been implicated as important factors in the pathogenesis of cellular injury in the postischemic heart. [63],[64],[65]

Coronary artery occlusion and reperfusion in the isolated perfused rat heart, was widely used as a model for assessment of antifibrillatory action of antiarrhythmic agents.[66] Later, coronary occlusion/reperfusion arrhythmias have been shown in anesthetized animals. Clark et al., demonstrated coronary artery ligation in anesthetized rats as a method for the production of experimental dysrhythmias and for the determination of infract size.[67] Harris et al., studied influences of hypothermia, cold and isolation stress on the severity of coronary artery ligation-induced arrhythmias in rats.[68] Bernier et al., used reperfusion-induced arrhythmias and studied oxygen derived free radicals, which causes myocardial infarction and ventricular arrhythmia, in isolated perfused rat heart.[69] Lepran et al., used the coronary artery ligation technique in rats after 7-10 days of surgery. They placed a loose silk loop around the left coronary artery and passed the threshold through a cylinder-shaped polyethylene tube outside the thorax. The loose ligature was tightened and arrhythmia record by ECG.[70] Lubbe et al., used coronary artery occlusion and reperfusion in isolated perfused rat heart for assessment of antifibrillatory action of antiarrhythmic agents.[71] Macleod et al., induced arrhythmia by ischaemia and reperfusion in conscious and anesthetized rats, and they studied the effect on epicardial intracellular action potentials.[72]

In the ischaemia-reperfusion model different parameters can be evaluated, such as mortality, haemodynamic parameter, ventricular extrasystoles, ventricular tachycardia, ventricular fibrillation and infract size. [73],[74],[75] The number of ventricular premature beats, ventricular tachycardia and ventricular fibrillation are counted in the occlusion and reperfusion periods and evaluated according to the guidelines of Lambeth convention.[76] Capasso et al., reported heterogeneity of ventricular remodelling after acute myocardial infarction in rats which was produced by the ischaemia-reperfusion technique.[77] Ruben et al., studied the distribution of extracellular potassium and its relation to electrophysiological changes during acute myocardial ischaemia in the isolated perfused porcine heart.[78] Bradykinin perfusion reduced the incidence of ventricular fibrillation and reduced the release of cytosolic enzyme and preserved glycogen stores.[79] Ventricular arrhythmias occurring secondary to impeded myocardial perfusion is the cause of death in more then one-half of the subjects associated with myocardial infarction and is also an important cause of sudden cardiac death.[80] Two distinct phases of ventricular arrhythmias occur during the first 30 minutes after induction of regional ischaemia by acute occlusion of a coronary artery in canine and porcine heart.[81],[82] In the first phase, Ia (up to approximately 8-10 min of coronary occlusion), there is a rapid change in electrical membrane properties associated with metabolic acidification (anaerobic glycolysis), and cellular loss and extracellular accumulation of [K+].[83] The impacts of these changes are a rapid depolarization of the ischemic myocytes, and a loss of amplitude and duration of the transmembrane potential. In second phase, Ib, which occurs after 10-15 min of occlusion is related to the electrical uncoupling of the myocytes resulting in smaller size of circus movement.[84] William et al., reported that the Ib phase of ventricular arrhythmias in ischemic in situ porcine heart is related to changes in cell-to-cell electrical coupling.[85] Borrett et al., described a myocardial ischaemia model for arrhythmia in rabbits.[86] Vara et al., induced ventricular fibrillation by coronary occlusion during hypothermia in dogs.[87] Baboon open chest model of myocardial ischaemia was described by Premaratne et al., in which a 2 h ischaemia period is followed by 22 h of reperfusion.[88] Naslund et al., presented a closed chest model in pigs. In this model, occlusion was induced in closed chest, pentobarbitone anaesthetized, and mechanically ventilated pigs by injection of a 2 mm ball into a preselected coronary artery. Reperfusion was achieved by retraction of the ball via an attached filament.

Ventricular arrhythmia during exercise by ischaemia

Ventricular fibrillation due to myocardial ischaemia during exercise is the model which resemble most closely the situation in coronary patients.[90],[91] In this model a major surgery is done in dogs, in which transducers are fixed in body followed by two-stage LAD ligation. After 28 days, animals were prepared for test, in which animals are allowed to walk on a motor driven treadmill. The animals run on the treadmill simultaneously the workload was increased in every 3 min for 18 min.[92]

Stretch-induced arrhythmias in isolated canine ventricle

It is commonly accepted that serious ventricular arrhythmias are caused by abnormalities in impulse formation and conduction.[1] These electrophysiological mechanism fail to explain why lethal arrhythmia most commonly arise in patients with severe heart failure and dilated ventricles.[93],[94] David et al., presented a hypothesis that alternation in loading conditions and muscle length influenced the electrophysiology of ventricular myocardium and these alterations might play a role in arrhythmogenesis in globally dilated or dyskinetic ventricles. To test the hypothesis that stretch can initiate arrhythmias in normal myocardium, the response to graded mechanical stretch was studied in seven isolated blood perfused canine ventricles. After eight conditioning contraction produced by His bundle pacing (2 Hz), global stretch of the ventricle was produced by a servo-controlled pump that abruptly increased ventricle volume by a precise amount during early diastole and then returned ventricular volume to the initial holding volume. The probability of a stretch-induced arrhythmia was determined from multiple alternating sequences in which a stretch of known amplitude or no stretch was delivered.[95],[96]

Model for sudden cardiac death

Male mongrel dogs weighing 14-22 kg are used for this model. Programmed electrical stimulation is performed between days 3 and 5 after the induction of anterior myocardial infarction by occlusion/perfusion on the left anterior descending coronary artery. A direct anodal 15 [micro]A current from a 9V nickel-cadmium battery was passed through a 250 Ohm resister and applied to the electrode in the lumen of the left circumflex coronary artery. After 24 h of constant anodal current or development of ventricular fibrillation, the animals were killed, the hearts were excised and the thrombus mass removed and weighed.[97],[98]

Canine model of two-stage ligation

Harris showed that mortality in dogs after coronary occlusion with a two-stage ligation procedure was lower than with one-stage ligation. Left descending coronary artery is partially occluded for 30 min, after which total ligation is performed. This model resembles late arrhythmias occurring in post-infarction patients.[99] Akira et al., used this model to check antiarrhythmic activity of a new compound.[100] Dubray et al . presented methods for producing experimental complete atrioventricular block in dogs.[101]

Drugs, which can be screened for ventricular tachycardia, are class Ia, Ib and class III drugs for both acute and chronic therapy. Ventricular fibrillation is a result of disorganized re-entry and classes Ia and Ib drugs are useful for acute therapy and can be screened for acute uses. For chronic use classes I-III can be screened.

Transgenic mice for arrhythmia

Genetically engineered animal models hold promise for understanding the pathophysiology of mutations that cause human disease.[102],[103] In the last decade various artificial mutation in mice genotype yielded a number of transgenic mice, which are useful in screening for anti-arrhythmics. Berul et al., used cardiac electrophysiology method to study mice harbouring an a-myosin heavy chain Arg 43 Gln missense mutation (a-MHC 403sub /+), which resulted in histological and haemodynamic abnormalities characteristic of familial hypertrophy and sudden death of uncertain etiology during exercise.[104] Wu. et al., studied a mouse model of cardiac hypertrophy attributable to transgenic over-expression of a constitutively active form of CaMK IV that also has increased endogenous CaMK II activity. ECG telemetered transgenic mice had significantly more arrhythmias then wild type littermate controls at baseline.[105] The KCNE 1 gene encodes a channel regulator IsK which, in association with the KvLQT1K+ channel protein, determines the slow component of the delayed rectifier current. Charpentier et al., investigated the cellular electrophysiological characteristics of adult KCNE1 knockout mouse hearts by means of the standard microelectrode technique. They concluded that invalidation of the mouse KCNE1 gene by homologous recombination leads to a mild cardiac phenotype at the cellular level. Berul et al., presented a mouse model of dilated cardiomyopathy resulting from a homozygous mutation in the myosin-binding protein C (MyBY- Ct/t). They also presented a model of familial hypertrophic cardiomyopathy due to heterozygous mutation in the same gene (MyBP-C) that were used to characterize the electrophysiological phenotype and correlate ‘vulnerability to arrhythmia’ with quantitative histopathological changes.[107] As described earlier mutations in the g2 subunit (PRKAG2) of AMP activated protein kinase produce an unusual human cardiomyopathy characterized by ventricular hypertrophy and electrophysiological abnormalities such as: Wolf-Parkinson White syndrome and programmed degenerative conduction system disease. Mutations of the K+ channel genes HERG and KVLQT 1 cause the autosomal dominant long QT syndrome, presumably by interfering with the cardiac currents Ikr and Iks. [108],[109],[110] The precise mechanism by which the mutations lead to QT prolongation and arrhythmias is uncertain. An N-terminal fragment including the first trans-membrane segment of the rat delayed rectifier K+ channel Kv 1.1 (Kv1.1 N 206 Tag), co-assembles with other K+ channels of the Kv1 subfamily in vitro , inhibits the currents encoded by Kv 1.5 in a dominant negative manner when co-expressed in Xenopus oocytes, and traps Kv 1.5 polypeptide in the endoplasmic reticulum of GH3 cells.[111] Barry et al., reported that transgenic mice over-expressing Kv 1.1 n 26 Tag in the heart have a prolonged QT interval and ventricular tachycardia.[112] Nkx 2.5 is a conserved homeodomain containing transcription factor essential for early cardiac development. Both prenatal and postnatal over-expression of DNA of nonbinding mutant Nkx 2.5 are associated with AV conduction malfunction and heart failure; however, more profound progressive electrophysiologic defects are seen when this mutation expresses during fetal and neonatal periods. These conduction abnormalities may contribute to the lethal heart failure and early mortality evident in DNA nonbinding mutant Nkx 2.5 mice.[113] Lande et al., evaluated a transgenic mouse over-expressing a dominant negative KvLQT 1 isoform, as an in vivo screening model for IKr blocking drugs. They concluded that KvLQT invalidated transgenic mice discriminates in vivo drugs that blocks IKr from drugs that block the transient outward current, the sodium current or the calcium current.[114] Transgenic mice over-expressing the inflammatory cytokine tumour necrosis factor TNF-a (TNF-a mice) in the heart develop a progressive heart failure syndrome characterized by biventricular dilation, decreased ejection fraction, atrial and ventricular arrhythmias on ambulatory telemetry monitoring, and decreased survival compared with nontransgenic litter mates. These transgenic animals are more prone to re-entrant arrhythmia.[115]

Antiarrhythmic drugs and screening models Antiarrhythmic drugs generally affect arrhythmia by modulating conduction velocity, or effective refractory period or both. Conduction velocity, depends on the passive electrical properties of cardiac tissue, also is a characteristic of the Na+ channels and Ca+ 2sub channels. Antiarrhythmic drugs that prolongs the action potential duration, and thereby the refractory period are effective against re-entry arrhythmias in two ways: by prolonging the wavelength [the product of (a) refractory period and (b) conduction velocity.[116] The initiation of a re-entrant arrhythmia by a premature impulse may be prevented[117] or an existing arrhythmia may terminate because the wavelength becomes too large with respect to the re-entrant circuit, so that by closing the excitable gap, the head of the re-entrant wavelength will hit the wall of refractoriness and propagation steps.[118] It is well known that there is significant difference in effective refractory period of different species. [119],[120],[121],[122] Depending on action potential duration and effective refractory period selection of animal could be one important aspect. Porcine ventricle myocardium appears to have a diastolic interval similar to that in human ventricle.[119] In contrast to all other species, it may be appreciated that in the rat there is no shortening of refractory periods at the shorter cycle length and rat ventricle is not the first choice if one aims at filling up the diastolic interval by means of a class I or class III antiarrhythmic agent.[120],[121] The rabbit is often used for electrophysiological research, probably because it constitutes a reasonable compromise in terms of cardiac dimensions, basic electrophysiological characteristics and cost.[122],[123] There are clear species differences that determine arrhythmogenesis. These differences should also be considered while choosing an animal model for arrhythmia corresponding to antiarrhythmic agent.


Although no animal model can accurately resemble with human disease condition and species differences also exist, close similarities with humans suffering from or threatened by arrhythmias can be developed by selecting appropriate model and species. Rather than a single model or experimental technique, combinations of investigations, like isolated heart (Langendorff arrangement or working heart), whole hearts in anesthetized or conscious animals, excised cardiac preparations, testing the function of molecules involved in electrical excitation, single cardiac cell preparation, can be performed.


1. Keating MT, Sanguinetti MC. Molecular and cellular mechanisms of cardiac arrhythmias. Cell 2001;104:569-80.

2. Vaughan- Williams EM. Classification of antiarrhythmic drugs. In: SandOe E, Flensted-Jensen E, Olesen KH, editors. Symposium on cardiac arrthmias. Elsinore , Denmark: AB Astra, S ?dert?lje, Sweden. 1970.

3. Keating L, Morris FP, Brady WJ. Electrocardiographic features of Wolff-Parkinson-White syndrome. Emerg Med J 2003;20:491-3.

4. Wellus HJJ. The electrophysiological properties of the accessory pathways in the Wolf-Parkinson-White syndrome. In: Welleus H, Lie KI, Jause MJ, editors. The conduction system of the heart. Leiden: Stenfert Kroese;1988.

5. Boineau JP, Moore EN. Evidence for propagation of activation across an accessory atrioventricular connection in type A and type B preexcitetion. Circulation 1970;41:375-97.

6. Kemp BE, Mitchelhill Kl, Staplenton D. Dealing with energy demand: the AMP activated protein kinase. Trends Biochem Sci 1999:24:22-25

7. Gollob MH, Green Ms, Tang AS. Identification of a gene responsible for familial Wolf-Parkinson-White syndrome. N Eng J Med 2001;344:1823-31.

8. Arad M, Moskowitz IP, Patel VV, Ahmad F. Transgenic mice overexpressing mutant PRKAG2 define the cause of Wolf-Parkinson-White syndrome in glycogen storage cardiomyopathy. Circulation 2003;107:2850-2856.

9. Efimov IR, Nikolski VP, Rothenberg F, Greener ID, Li J, Dobrzynski H, et al . Structure-function relationship in the AV junction. The Anatomical Record 2004;280:952-65.

10. Bharati S. Anatomic-morphologic relations between AV nodal structure and function in the normal and diseased heart. In: Mazgalev TN, Tchou PJ, editors. Atrial-AV nodal electrophysiology: A view from the millenium. Armonk: Futura; 2000. 25-48.

11. Cox JL, Holman HL, Cain ME. Cryosurgical treatmrnt of atrioventricular node reentrant tachycardia. Circulation 1987;76:1329-76.

12. Sung RJ, Waxman HL, Saksen S, Juma Z. Sequence of retrograde atrial activation in patients with dual atrioventricular nodal pathways. Circulation 1981;64:1059-67.

13. Janse MJ, Van Capelle FJL, Freud GE, Durrer D. Circus movement within the A-V node as a basis for supraventricular tachycardia as shown by multiple microelectrode recording in the isolated rabbit heart. Circ Res 1971;28:403-13.

14. Mazgalev TN, Ho SY, Anderson RH. Anatomic-electrophysiological correlations concerning the pathways for atrioventricular conduction. Circulation 2001;103:2660-7.

15. Wit AL, Goldreyer BN, Damato AN. AN in vitro model of paroxysmal supraventricular tachycardia. Circulation 1971;43:862-75.

16. More GK,Cohen W. Vick RL. Experimentally induced paroxysmal A-V nodal tachycardia in the dog. A ‘case report’. Am Heart J 1963;65:87-92.

17. Lin FY, Lo HM, Cheng JJ. Experimentally created atrioventricular node reentrant tachycardia in the dog: Evidence of a brake system for nodal reentry in the anterior interatrial septum. J Am Coll Cardiol 1993;22:1541-7.

18. Wu J, Wu J, Olgin J, Miller JM, Douglas P. Zips; Mechanism underlying the reentrant circuit of atrioventricular nodal reentrant tachycardia in isolated canine atrioventricular nodal preparation using optical mapping. Circ Res 2001;88:1189.

19. Loh P, Siew Yen ho, Kawara T, Hauer RNW, Janse MJ. Reentrant circuits in the canine atrioventricular node during atrial and ventricular echoes. Circulation 2003;108:231.

20. Patterson E, Scherlog BJ. Longitudinal dissociation within the posterior AV nodal input of the rabbit. A substrate for AV nodal reentry. Circulation 1999;99:143-55.

21. Lee K, Yang Y, Scheinman M. Atrial flutter: A review of its history, mechanisms, clinical features, and current therapy. Current Problems in Cardiology 2003;30:121-67.

22. Daoud EG, Fred Morady MD. Pathophysiology of atrial flutter. Ann Rev Med 1998;49:77-83.

23. Ewis T, Drury AN, I Iiescu CC. A demonstration of circus movement in clinical flutter of the auricles. Heart 1921;8:341-57.

24. Feld GK, Rad FS. Mechanism of double potentials recorded during sustained atrial flutter in the canine right atrial crush injury model. Circulation 1992;86:628-41.

25. Wu TJ, Kim YH, Yashima M, Athill CA, Ting CT, Karagueuzian HS, et al . Progressive action potential duration shortening and the conversion from atrial flutter to atrial fibrillation in the isolated canine right atrium. J Am Coll Cardiol 2001;38:1757-65.

26. Scherf D, Blumenteld S, Taner D, Yildiz M. The effect of diphenyldantoin on atrial flutter and fibrillation provoked by focal application of aconitine or delphine. Am Heart J 1960;60:936-47.

27. Nwangwa PV, Holcslaw TL, Stohs JS. A rapid in vivo technique for preliminary screning of antiarrhythmic agents in mice. Arch Int Pharmacodyn 1977;229: 219-26.

28. Dadkar NK, Bhattacharya BK. A rapid screening procedure for antiarrhythmic activity in the mouse. Arch Int Pharmacodyn Ther 1974;212:297-301.

29. Winslow E. Evaluation of antagonism of aconitine induced dysrhythmia in mice as a method of decting and assassing antidysrhythmic activity. Br J Pharmac 1980;71:615-22.

30. Winslow E. Hemodynamic and arrhythmogenic effects of aconitine applied to the left atria of anesthetized cats. Effects of amiodarone and atropine. J Cardiovas Pharmac 1981;3:87-100.

31. Restivo M, Hegazy M, El-Hamami M, Yin H, Caref EB, Assadi MA, et al . Efficacy of azimilide and dofetilide in the dog right atrial enlargement model of atrial flutter. J Cardiovasc Electrophysiol 2001;12:1018-24.

32. Cairns JA, Connolly ST. Nonrheumatic atrial fibrillation: Risk of stroke and role of antithrombotic therapy. Circulation 1991;84:469-81.

33. Myerburg RJ, Kessler KM, Castellanes A. Recognition, clinical assessment and management of arrhythmias and conduction disturbences. Hurst’s the Heart. 8th ed. McGraw Hill, Inc. Health Profession Division 1994.

34. Hsu LF, Jais P, Keane D, Wharton JM, Deisenhofer I. Atrial fibrillation originating from persistent left supeior vena cava. Circulation 2004;109:828-32.

35. Sinno H, Derakhchan K, Libersan D, Merhi Y, Leung TK, Nattle S. Atrial ischaemia promotes atrial fibrillation in dogs. Circulation 2003;107:1930-6.

36. Hirose M, Furukawa Y, Nagashima Y, Lakhe M, Chiba S. Pitutary adenylate cyclase activating polypeptide-27 causes a biphasic chronotropic effect and atrial fibrillation in autonomically decentralized anesthetized dogs. J Pharmacol Exp Ther 1997;282:278-87.

37. Li D, Shinagawa K, Pang L, Leung TK, Cardin S, Wang Z, Nattel S. Effects of angiotensin-converting enzyme inhibition on the development of the atrial fibrillation substrate in dogs with ventricular tachypacing-induced congestive heart failure. Circulation 2001,104:2608-14.

38. Everett TH 4th, Li H, Mangrum JM, McRury ID, Mitchell MA, Redick JA, et al. Electrical, morphological, and ultrastructural remodeling and reverse remodeling in a canine model of chronic atrial fibrillation. Circulation 2000;102:1454-60.

39. Allessie MA, Lammers WJEP, Smeets JRLM. Experimental evaluation of Moc’s multiple wavelet hypothesis of atrial fibrillation. In: Zipes DP, Jalife J, editors. Cardiac Arrhythmias. New York: Grune and Stratton;1985.

40. Schauerte P, Scherlag BJ, Jan P, Scherlag MA. Catheter ablation of cardiac anatomic nerves for prevention of vagal atrial fibrillation. Circulation 2000;102:2774-80.

41. Nagasawa H, Fujiki A, Fujikura N, Matsuda T, Yamashita T, Inoue H. Effects of a novel class III antiarrhythmic agent, NIP-142, on canine atrial fibrillation and flutter. Circ J 2002;66 : 185-91.

42. Manyari DE, Patterson C, Johnson D, Melendez L, Cape RDT. Atrial and ventricular arrhythmias in asymptometic active elderly subjects: correlaion with left atrial size and left ventricular mass. AM Heart J 1990;119:1069-76.

43. Ravelli F, Allessie M. Effect of atrial dilation on refractory period and vulnerability to atrial fibrillstion in the isolated langendroff perfused rabbit heart. Circulation 1997;96:1686-95.

44. Wijffels MC, Kirchhot CJ, Dorland R, Allessie MA. Arial fibrillation begets atrial fibrillation. A study in awake chronically instrumented goats. Circulation 1995;92:1954-68.

45. Burashnikov A, Antzelevitch C. Reinduction of atrial fibrillation immediately after termination of the arrhythmia is mediated by late phase early afterdepolarization-induced triggered activity. Circulation 2003;107:2355-60.

46. Sknes AC, Mandapati R, Berenfeld O, Davidenko JM, Jalife J. Spatiotemporal periodicity during atrial fibrillation in the isolated sheep heart. Circulation 1998;98:1236-48.

47. Nakayama K, Oshima T, Kumakura S, Hashimoto K. Comparison of the effects of various ?-adrenergic blocking agents with known antiarrhythmic drugs on aconitine-arrhythmia produced by the cup method. Eur J Pharmacol 1971;14:9-18.

48. Yamamoto T, Hosoki K, Karasawa T. Anti-arrhythmic effects of a new calcium antagonist, Monopetil, AJ-2615, in experimental arrhythmic models. Clin Exper Pharmacol Physiol 1993;20:497-500.

49. Ayoub IM, Kolsrova J, Yi Z, Trevedi A, Desmukh H, Lubell DL, et al . Sodium hydrogen exchange inhibition during ventricular fibrillation: Beneficial effects on ischemic contracture, action potential duration, reperfusion arrhythmias, myocardial function and resuscitability. Circulation 2003;107:1804-9.

50. Voroshilovskey O, Qu Z, Lee MH, Ohara T, Fishbein GA, Lun HA, et al . Mechanisms of ventricular fibrillation induction by 60 hz alternating current in isolated swine right ventricle. Circulation 2000;102:1569-74.

51. Vogel GH, Vogel WH, Scholkens BA, Sandow J, Muller G, Vogel WF, editors. Drug discovery and evaluation. Pharmacological assays. Berlin: Springer-Verlag; 2nd ed. 2002.

52. Vaille A, Scotto Di Tella AM, Maldonado J, Vanelle P, Selectivity of a CaCl2 continuous infusion screening method in rats. Methods Find Exp Clin Pharmacol 1992;14:183-7.

53. Lawson JW. Antiarrhythmic activity of some isoquiniline derivetives determined by a rapid screening procedure in the mouse. J Pharmacol Exp Ther 1968;160:22-31.

54. Tripathi RM, Thomas GP. A simple method for production of ventricular tachycardia in the rat and guinea pig. J Pharmacol Methods 1986;15:279-82.

55. Nagasawa Y, Zhu BM, Chen J, Kamiya K, Miyamoto S, Hashimoto K . Effects of SEA0400, a Na+/Ca2+ exchange inhibitor, on ventricular arrhythmias in the in vivo dogs. Eur J Pharmacol 2005;506:249-55.

56. Sono K, Akimoto Y, Magaribuchi T, Kurahashi K, Hujiwara A. A new model of ventricular fibrillation induced by isoprenaline and catechol-o-methyl transferase inhibitor at high perfusion temperature in the isolated rat heart. J Pharmacol Methods 1985;14:249-54.

57. Watano T, Harada Y, Harada K, Noriyasu N. Effect of Na+/Ca2+ exchange inhibitor, KB-R7943 on ouabain-induced arrhythmias in guinea-pigs. Br J Pharmacol 1999;127:1846-50.

58. Duce BR, Garerg L, Johansson B. The effect of propranolol and the dextro and leavo isomers of H 56/28 upon ouabain induced ventricular tachycardia in anesthetized dogs. Acta Pharmacol Toxicol 1967;25:41-9.

59. Rao TS, Seth SD, Nayar U, Manchanda SC. Modified method for the production of cardiac arrhythmias by ouabain in anesthetized cats. J Pharmacol Methods 1988;20:255-63.

60. Takei. Grayanotoxin-I induced experimental arrhythmia in guinea pig. J Aichi Med Univ Assoc 1994;22:495-512.

61. Moens AL, Claeys MJ, Timmermans JP, Vrints CJ. Myocardial ischaemia/reperfusion injury, a clinical view on a complex pathophysiological process. Int J Cardiol 2005;100:179-90.

62. Gross GJ, Kersten JR, Warltie DC. Mechanisms of postischemic contractile dysfunction. Ann Thorac Sur 1999;68:1898-904.

63. Webb A, Bond R, McLean P, Uppal R, Benjamin N, Ahluwalia A. Reduction of nitrite to nitric oxide during ischaemia protects against myocardial ischaemia-reperfusion damage. PNAS 2004;101:13683-8.

64. Bolli R, Marban E. Molecular and cellular mechanisms of myocardial stunning. Physiol Rev 1999;79:609-34.

65. Homans DC, Asinger R, Pavek T, Crampton M, Lindstrom P, Peterson D, et al . Effect of superoxide dismutase and catalase on regional dysfunction after exercise-induced ischaemia. Am J Physiol 1992;263:392-8.

66. Lubbe WF, Daries PS, Opie LH. Ventricular arrhythmias associated with coronary artery occlusion and reperfusion in the isolated perfused rat heart: A model for assessment of antifibrillatory action of antiarrhythmic agents. Cardiovasc Res 1978;12:212-20.

67. Clark C, Forman MI, Kane KA, Mc Donald FM, Parratt JR. Coronary artery ligation in anesthetized rats as a method for the production of experimental dysrhythmias and for the determination of infract size. J Pharmacol Methods 1980;3:357-68.

68. Harris N, Kane KA, Muir AW, Winslow E. Influences of hypothermia, cold and isolation stress on the severity of coronary artery ligation induced arrhythmias in rats. J Pharmacol Methods 1982;7:161-71.

69. Bernier M, Hearse DJ, Manning AS. Reperfusion induced arrhythmias and oxygen derived free redicals studies with “anti free redical” interventions and a free redical generating system in the isolated perfused rat heart. Cir Res 1986;58:331-40.

70. Leparn I, Koltai M, Siegmund W, Szekeres L. Coronary artery ligation, early arrhythmias and determination of the ischemic area in conscious rats. J Pharmacol Methods 1983;9:219-30.

71. Inagaki K, Hahn HS, Dorn II GW, Rosen DM. Additive protection of the ischemic heart ex vivo by combined treatment with d-protein kinase C inhibitor and e-protein kinase C activator. Circulation 2003;108:869-75.

72. Macleod BA, Moult M, Saint KM, Walker MJ. The antiarrhythmic efficacy of anipamil against occlusion and reperfusion arrhythmias. Br J Pharmacol 1989;98:1165-72.

73. Black SC, Rodger IW. Methods for studying expermental myocardial ischaemia and reperfusion injury. J Pharmacol Toxicol Methods 1996;35:179-90.

74. Black SC. In vivo models of myocardial ischaemia and reperfusion injury. Application to drug discovery and evaluation. J Pharmacol Toxicol Methods 2000;43:153-67.

75. Chen J, Nagasawa Y, Zhu BM, Ohmori M, Harada K, Fujimura A, et al . Pravastatin prevents arrhythmias induced by coronary artery ischemia/reperfusion in anesthetized normocholesterolemic rats. J Pharmacol Sci 2003;93:87-94.

76. Walker MJ, Curtis MJ, Hearse DJ, Campbell RW, Jause MJ, Yellon DM, et al . The Lambeth convention; guicelines for the study of arrhythmias in ischaemia, infarction and reperfusion. Cardiovass Res 1988;22:447-55.

77. Capasso JM, Li P, Zhang X, Anversa P. Heterogenity of ventricular remodeling after acute myocardial infarction in rats. Am J Physiol 1992;262:486-95.

78. Coronel R, Fiolet JW, Wilms-Schopman FJ, Schaapherder AF, Johnson TA, Gettes LS, et al . Distribution of extracellular potassium and its relation to electrophysiologic changes during acute myocardial ischemia in the isolated perfused porcine heart. Circulation 1988;77:1125-38.

79. Linz W, Wiemer G, Scholkens BA. Beneficial effects of bradykinin on myocardial energy metabolism and infract size. Am J Cardiol 1997;80:118-23.

80. Aaj A. Sudden death, ventricular fibrillation, ventricular defibrillation; historical review and recent advances. In: Aaj A, editor. Acute phase of ischemic heart disease and myocardial infarction. Boston, Mass: Matinus-Nijhoff; 1982.

81. Parker KK, Lavelle JA, Taylor LK, Wang Z, Hansen DE. Stretch-induced ventricular arrhythmias during acute ischaemia and reperfusion. J Appl Physiol 2004;97:377-83.

82. Kaplinskg E, Ogawa S, Balke CW, Derifus LS. Two periods of early ventricular arrhythmia in the canine acute myocardial infarction model. Circulation 1979;60:397-403.

83. Wilde AA, Asknes G. Myocardial potassium loss and cell depolarisation in ischaemia and hypoxia. Cardiovasc Res 1995;29:1-15.

84. Lukas A, Antzelevitch C. Phase 2 reentry as a mechanism of initiation of circus movement reentry in canine epicardium exposed to simulated ischemia. Cardiovasc Res 1996;32:593-603.

85. Smith WT, Fleet WF, Johnson TA, Engle CL, Cascio WE. The Ib phase of ventricular arrhythmias in ischemic in situ procaine heart is related to changes in call-to-call electrical coupling. Circulation 1995;92:3051-60.

86. Barrett TC, MacLeod BA, Walker MJ. A model of myocardial ischaemia for the simultaneous assassment electrophysiological changes and arrhythmias in intact rabbits. J Pharmacol Toxicol Methods 1977;37:27-36.

87. Oka J, Imamura M, Hatta E, Maruyama R, Isaka M, Murashita T, et al . Carrier-mediated norepinephrine release and reperfusion arrhythmias induced by protracted ischemia in isolated perfused guinea pig hearts: effect of presynaptic modulation by alpha(2)-adrenoceptor in mild hypothermic ischemia. J Pharmacol Exp Ther 2002;303:681-7.

88. Premaratne S, Watanable BI, LaPenna WF, McNamara JJ. Effects of hyaluronidase on reducing myocardial infrac size in a baboon model of ischaemia reperfusion. J Surg Res 1995;58:205-10.

89. Naslund U, Haggmark S, Johanson G, Pennert K, Peiz S, Marklund SL. Effects of reperfusion and superoxide dismutase on myocardial infract size in a closed chest pig model.Cardiovasc Res 1992;26:170-8.

90. Billman GF. Role of ATP sensitive potassium channel in extracellular potassium accumulation and cardiac arrhythmias during myocardial ischaemia. Cardiovasc Res 1994;28:762-9.

91. Aversane T, Ouryang P, Silverman H. Blockade of the ATP sensitive potassium channel modulates reactive hyperthermia in the canine coronary circulation. Circ Res 1991;69:618-22.

92. Smith LL, Kukielka M, Billman GE. Heart rate recovery after exercise: A predictor of ventricular fibrillation susceptibility after myocardial infarction. Am J Physiol Heart Circ Physiol 2005;288:1763-9.

93. Meizlish JL, Berger HJ, Plankey M, Errico D, Levy W, Zeret BL. Functional left ventricular aneurysm formation after acute anterior transmural myocardial infarction. N Engl J Med 1984;311:1001-6.

94. Huang SK, Messer JV, Denes P. Significance of ventricular tachycardia in idiopathic dilated cardiomyopathy: observations in 35 patients. Am J Cardiol 1983;51:507-12.

95. Hansen DE, Craig CS, Hondeghem LM. Stretch induced arrythmias in the isolated canine ventricle. Circulation 1990;81:1094-105.

96. Hansen DE, Stacy Jr GP, Taylor LK, Jobe RL, Wang Z, Denton PK, et al . Calcium- and sodium-dependent modulation of stretch-induced arrhythmias in isolated canine ventricles. Am J Physiol Heart Circ Physiol 1995;68:1803-13.

97. Cahn PS, Corvoni P. Current concepts and animal models of sudden cardiac death for the drug development. Drug Dev Res 1990;19:199-207.

98. Chi L, Mu DX, Lucchesi BR. Electrophysiology and antiarrythmic actions of E-4031 in the experimental animal model of sudden coronary death. J Cardiovasc Pharmacol 1991;17:285-95.

99. Krumpl G, Todt H, Schunder-Tatzver S, Raberger G. Holter monitoring in conscious dogs. Assesment of arrythmias occuring during ischaemia and in the early reperfusion phase. J Pharmacol Methods 1989;22:93-102.

100. Takahara A, Hirasawa A, Dohmoto H, Shoji M, Yoshimoto R, Sugiyama A, et al . In vivo antiarrhythmic profile of AP-792 assessed in different canine arrhythmia models. Jpn J Pharmacol 2001;87:21-6.

101. Dubray C, Boucher M, Paire M, Duchene-Marullaz P. A method for determining the atrial effective refractory period in the unanaesthetized dog. J Pharmacol Methods 1983;9:157-64.

102. Paigen K. A miracle enough: The power of mice. Nat Med 1995;1:215-20.

103. Lin MC, Rockman RA, Chin KR. Heart and lung disease in engineered mice. Nat Med 1995;1:749-51.

104. 104.Charles IB, Christe ME, Aronovitz MJ, Seidman CE, Seidman JG, Mendelsohn ME. Electrophysiological abnormalities and arrhythmias in alpha MHC mutant familial hypertrophie cardiomyopathi mice. J Clin Invest 1997;99:570-6.

105. Wu Y, Temple J, Zhang R, Dzhura I, Zhang W, Trimble R, et al . Calmodulin kinase II and arrhythmias in a mouse model of cardiac hypertrophy. Circulation 2002;106:1288-93.

106. Charpentier F, Merot J, Riochet D, Le Marec H, Escande D. Adult KCNE 1- knockout mice exhibit a mild cardio cellular phenotype. Biochem Biophys Res Commun 1998;251:806-10.

107. Berul CI, McConnell BK, Wakimoto H, Moskowitz IP, Maguire CT. Ventricular arrhythmia vulnerability in cardiomyopathic mice with homozygous mutant myosin binding protein C gene. Circulation 2001;104:2734-9.

108. Curran ME, Splawski I, Timothy KW, Vincent GM, Green ED, Keating MT. A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome. Cell 1995;80:795-803.

109. Wang Q, Curran ME, Splawski I, Burn TC, Millhalland JM, Van Raag TJ, et al . Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias. Net Genet 1996;12:17-23.

110. Sanguinetti MC, Jiang C, Curran ME, Keating MT. A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the Ikr, Potassium channel. Cell 1995;81:299-307.

111. Folco E, Mathur R, Mori Y, Buckett P, Koren G. A cellular model for long QT syndrome. J Biol Chem 1997;272:26505-10.

112. London B, Jeron A, Zhou J, Buckket P, Han X, Mitchell GF, et al . Long QT and ventricular arrhythmias in transgenic mice expressing the N terminus and first transmembrane segment of a voltage-gates potassium channel. Proc Natt Acad Sci USA 1998;95:2926-31.

113. Wakimoto H, Kasahara H, Tmaguire C, Izumo S, Berul CI. Coduction failure in mutant NKx 2.5 overexpression mice. Jan Card Elect 2002;13:682-8.

114. Lande G, Demalombe S, Bammert A, Moormal A, Charpentier F, EsCande D. Transgenic mice overexpression human KvLQT1 dominant negative isoform. Part II: Pharmacological profile. Cardvasc Res 2001;50:328-24.

115. London B, Baker LC, Lee JS, Shusterman V, Choi BR, Kubota T, et al . Calcium dependent arrhythmias in transgenic mice with heart failure. Am J Physiol Heart Circ Physiol 2003;284:431-41.

116. Shinagawa K, Takeshita AS, Schram G, Nattel S. Effects of antiarrhythmic drugs on fibrillation in the remodeled atrium. Circulation 2003;107:1440-6.

117. Zuanetti G, Corr PB. Antiarrhythmic efficacy of a new class III agent, UK-68, 798, during chronic myocardial infarction: evaluation using three dimensional mapping. J Pharmacol Exp Ther 1991;256:325-34.

118. Task force of the working group on arrhythmias of the europian society of cardiology. The sicilian gambit. A new approach to the classification of antiarrhythmic drugs based on their actions on arrhythmogenic mechanism. Circulation 1991;84:1831-51.

119. B?nardeau A, Weissenburger J, Hondeghem L, Ertel EA. Effects of the t-type Ca2+ channel blocker mibefradil on repolarization of guinea pig, rabbit, dog, monkey, and human cardiac tissue. J Pharmacol Exp Ther 2000;292:561-75.

120. Janse MJ, Wilms-Schopman F, Opthof T. Mechanisms of antifibrillatory action of Org 7797 in regionally ischemic pig heart. J Cardiovasc Pharmacol 1990;15: 633-43.

121. Vermeulen JT, McGuire MA, Opthof T. Triggered activity and automaticity in ventricle trabeculae of failing human and rabbit heart. Cardiovasc Res 1994; 28:1547-54.

122. Ypma JF. Adaption of refractory period of rat ventricle to changes in heart rate. Am J Physiol 1972;223:894-7.

123. Krusche CA, Moller G, Beier HM, Adamski J. Expression and regulation of 17beta-hydroxysteroid dehydrogenase 7 in the rabbit. Mol Cell Endocrinol 2001;171:169-77.

COPYRIGHT 2005 Medknow Publications

COPYRIGHT 2005 Gale Group

You May Also Like

Effect of folate treatment on homocysteinemia in cardiac patients: A prospective study

Effect of folate treatment on homocysteinemia in cardiac patients: A prospective study K. Mehta Byline: K. Mehta, M. Chag, K. Parik…

Hypolipidemic and antioxidant activities of Asparagus racemosus in hypercholesteremic rats

Hypolipidemic and antioxidant activities of Asparagus racemosus in hypercholesteremic rats N. Visavadiya Byline: N. Visavadiya, A. …

A new strategy to raise HDL cholesterol levels

Torcetrapib: A new strategy to raise HDL cholesterol levels Reena Bhardwaj Byline: Reena. Bhardwaj, P. Bhardwaj Statins are …

Evaluation of antidepressant-like activity of glycyrrhizin in mice

Evaluation of antidepressant-like activity of glycyrrhizin in mice Dinesh Dhingra Byline: Dinesh. Dhingra, Amandeep. Sharma …