05025nas a2200385 4500008004100000022001400041245011300055210006900168260001200237300001100249490000700260520391000267653002204177653001204199653002704211653002504238653002404263653001004287653002804297653004004325653002704365653002904392653001404421653001604435653001404451653001404465653001204479653002404491100001304515700001904528700001704547700001404564700001404578856004704592 1997 eng d a0735-109700aOptical mapping of drug-induced polymorphic arrhythmias and torsade de pointes in the isolated rabbit heart.0 aOptical mapping of druginduced polymorphic arrhythmias and torsa c03/1997 a831-420 v293 a

OBJECTIVES: 

This study sought to 1) test the hypothesis that in the setting of bradycardia and drug-induced action potential prolongation, multiple foci of early afterdepolarizations (EADs) result in beat to beat changes in the origin and direction of the excitation wave front and are responsible for polymorphic arrhythmias; and 2) determine whether EADs may initiate nonstationary reentry, giving rise to the typical torsade de pointes (TDP) pattern.

BACKGROUND: 

In the past, it has been difficult to associate EADs or reentry with the undulating electrocardiographic (ECG) patterns of TDP.

METHODS: 

A voltage-sensitive dye was used for high resolution video imaging of electrical waves on the epicardial and endocardial surface of the Langendorff-perfused rabbit heart. ECG and monophasic action potentials from the right septal region were also recorded. Bradycardia was induced by ablation of the atrioventricular node.

RESULTS: 

Perfusion of low potassium chloride Tyrode solution plus quinidine led to prolongation of the action potential and the QT interval. Eventually, EADs and triggered activity ensued, giving rise to intermittent episodes of polymorphic arrhythmia. In one experiment, triggered activity was followed by a long episode of vortex-like reentry with an ECG pattern characteristic of TDP. However, in most experiments, focal activity of varying origins and propagation patterns was observed. Triggered responses also showed varying degrees of local block. Similar results were obtained with E-4031. Burst pacing both at control conditions and in the presence of quinidine consistently led to vortex-like reentry whose ECG pattern resembled TDP. However, the cycle length of the arrhythmia with quinidine was longer than that for control ([mean +/- SEM] 194 +/- 12 vs. 132 +/- 8 ms, p < 0.03).

CONCLUSIONS: 

Drug-induced polymorphic ventricular arrhythmias may result from beat to beat changes in wave propagation patterns initiated by EADs or EAD-induced nonstationary reentrant activity. In contrast, burst pacing-induced polymorphic tachycardia in the presence or absence of drugs is the result of nonstationary reentrant activity.

10aAction Potentials10aAnimals10aAnti-Arrhythmia Agents10aArrhythmias, Cardiac10aElectrocardiography10aHeart10aHeart Conduction System10aImage Processing, Computer-Assisted10aModels, Cardiovascular10aOrgan Culture Techniques10aPerfusion10aPiperidines10aPyridines10aQuinidine10aRabbits10aTorsades de Pointes1 aAsano, Y1 aDavidenko, J M1 aBaxter, Bill1 aGray, R A1 aJalife, J uhttp://www.ncbi.nlm.nih.gov/pubmed/909153101811nas a2200373 4500008004100000022001400041245008700055210006900142260001200211300001200223490000700235520078300242653001201025653002601037653001501063653001801078653002401096653002501120653002101145653002201166653001001188653002701198653002701225653001501252653001001267653002001277100001201297700001701309700001901326700001701345700001401362700001401376856004701390 1996 eng d a0006-349500aVortex shedding as a precursor of turbulent electrical activity in cardiac muscle.0 aVortex shedding as a precursor of turbulent electrical activity  c03/1996 a1105-110 v703 a

In cardiac tissue, during partial blockade of the membrane sodium channels, or at high frequencies of excitation, inexcitable obstacles with sharp edges may destabilize the propagation of electrical excitation waves, causing the formation of self-sustained vortices and turbulent cardiac electrical activity. The formation of such vortices, which visually resembles vortex shedding in hydrodynamic turbulent flows, was observed in sheep epicardial tissue using voltage-sensitive dyes in combination with video-imaging techniques. Vortex shedding is a potential mechanism leading to the spontaneous initiation of uncontrolled high-frequency excitation of the heart.

10aAnimals10aBiophysical Phenomena10aBiophysics10aCell Membrane10aComputer Simulation10aElectric Stimulation10aElectrochemistry10aElectrophysiology10aHeart10aModels, Cardiovascular10aMyocardial Contraction10aMyocardium10aSheep10aSodium Channels1 aCabo, C1 aPertsov, A V1 aDavidenko, J M1 aBaxter, Bill1 aGray, R A1 aJalife, J uhttp://www.ncbi.nlm.nih.gov/pubmed/878527000781nas a2200289 4500008004100000022001400041245004000055210003900095260001200134300003200146490000800178653001200186653002400198653002400222653002100246653002700267653001200294653002900306100001400335700001400349700001600363700001700379700001200396700001900408700001700427856004700444 1995 eng d a0036-807500aMechanisms of cardiac fibrillation.0 aMechanisms of cardiac fibrillation c11/1995 a1222-3; author reply 1224-50 v27010aAnimals10aComputer Simulation10aElectrocardiography10aHeart Ventricles10aModels, Cardiovascular10aRabbits10aVentricular Fibrillation1 aGray, R A1 aJalife, J1 aPanfilov, A1 aBaxter, Bill1 aCabo, C1 aDavidenko, J M1 aPertsov, A V uhttp://www.ncbi.nlm.nih.gov/pubmed/750205504137nas a2200313 4500008004100000022001400041245013200055210006900187260001300256300001200269490000700281520321100288653001203499653002403511653001003535653004003545653002703585653001403612653001203626653002903638100001403667700001403681700001603695700001703711700001203728700001903740700001703759856004703776 1995 eng d a0009-732200aNonstationary vortexlike reentrant activity as a mechanism of polymorphic ventricular tachycardia in the isolated rabbit heart.0 aNonstationary vortexlike reentrant activity as a mechanism of po c05/1995  a2454-690 v913 a

BACKGROUND: 

Ventricular tachycardia may result from vortexlike reentrant excitation of the myocardium. Our general hypothesis is that in the structurally normal heart, these arrhythmias are the result of one or two nonstationary three-dimensional electrical scroll waves activating the heart muscle at very high frequencies.

METHODS AND RESULTS: 

We used a combination of high-resolution video imaging, electrocardiography, and image processing in the isolated rabbit heart, together with mathematical modeling. We characterized the dynamics of changes in transmembrane potential patterns on the epicardial surface of the ventricles using optical mapping. Image processing techniques were used to identify the surface manifestation of the reentrant organizing centers, and the location of these centers was used to determine the movement of the reentrant pathway. We also used numerical simulations incorporating Fitzhugh-Nagumo kinetics and realistic heart geometry to study how stationary and nonstationary scroll waves are manifest on the epicardial surface and in the simulated ECG. We present epicardial surface manifestations (reentrant spiral waves) and ECG patterns of nonstationary reentrant activity that are consistent with those generated by scroll waves established at the right and left ventricles. We identified the organizing centers of the reentrant circuits on the epicardial surface during polymorphic tachycardia, and these centers moved during the episodes. In addition, the arrhythmias that showed the greatest movement of the reentrant centers displayed the largest changes in QRS morphology. The numerical simulations showed that stationary scroll waves give rise to monomorphic ECG signals, but nonstationary meandering scroll waves give rise to undulating ECGs characteristic of torsade de pointes.

CONCLUSIONS: 

Polymorphic ventricular tachycardia in the healthy, isolated rabbit heart is the result of either a single or paired ("figure-of-eight") nonstationary scroll waves. The extent of the scroll wave movement corresponds to the degree of polymorphism in the ECG. These results are consistent with our numerical simulations that showed monomorphic ECG patterns of activity for stationary scroll waves but polymorphic patterns for scroll waves that were nonstationary.

10aAnimals10aElectrocardiography10aHeart10aImage Processing, Computer-Assisted10aModels, Cardiovascular10aPerfusion10aRabbits10aTachycardia, Ventricular1 aGray, R A1 aJalife, J1 aPanfilov, A1 aBaxter, Bill1 aCabo, C1 aDavidenko, J M1 aPertsov, A V uhttp://www.ncbi.nlm.nih.gov/pubmed/772903303423nas a2200337 4500008004100000022001400041245009300055210006900148260001200217300001200229490000700241520247800248653001202726653002402738653002602762653001002788653001602798653002802814653001102842653002702853653002902880653001002909653002602919100001202945700001702957700001702974700001902991700001403010700001403024856004703038 1994 eng d a0009-733000aWave-front curvature as a cause of slow conduction and block in isolated cardiac muscle.0 aWavefront curvature as a cause of slow conduction and block in i c12/1994 a1014-280 v753 a

We have investigated the role of wave-front curvature on propagation by following the wave front that was diffracted through a narrow isthmus created in a two-dimensional ionic model (Luo-Rudy) of ventricular muscle and in a thin (0.5-mm) sheet of sheep ventricular epicardial muscle. The electrical activity in the experimental preparations was imaged by using a high-resolution video camera that monitored the changes in fluorescence of the potentiometric dye di-4-ANEPPS on the surface of the tissue. Isthmuses were created both parallel and perpendicular to the fiber orientation. In both numerical and biological experiments, when a planar wave front reached the isthmus, it was diffracted to an elliptical wave front whose pronounced curvature was very similar to that of a wave front initiated by point stimulation. In addition, the velocity of propagation was reduced in relation to that of the original planar wave. Furthermore, as shown by the numerical results, wave-front curvature changed as a function of the distance from the isthmus. Such changes in local curvature were accompanied by corresponding changes in velocity of propagation. In the model, the critical isthmus width was 200 microns for longitudinal propagation and 600 microns for transverse propagation of a single planar wave initiated proximal to the isthmus. In the experiments, propagation depended on the width of the isthmus for a fixed stimulation frequency. Propagation through an isthmus of fixed width was rate dependent both along and across fibers. Thus, the critical isthmus width for propagation was estimated in both directions for different frequencies of stimulation. In the longitudinal direction, for cycle lengths between 200 and 500 milliseconds, the critical width was < 1 mm; for 150 milliseconds, it was estimated to be between 1.3 and 2 mm; and for the maximum frequency of stimulation (117 +/- 15 milliseconds), it was > 2.5 mm. In the transverse direction, critical width was between 1.78 and 2.32 mm for a basic cycle length of 200 milliseconds. It increased to values between 2.46 and 3.53 mm for a basic cycle length of 150 milliseconds. The overall results demonstrate that the curvature of the wave front plays an important role in propagation in two-dimensional cardiac muscle and that changes in curvature may cause slow conduction or block.

10aAnimals10aComputer Simulation10aElectric Conductivity10aHeart10aHeart Block10aHeart Conduction System10aHumans10aModels, Cardiovascular10aMotion Pictures as Topic10aSheep10aStaining and Labeling1 aCabo, C1 aPertsov, A V1 aBaxter, Bill1 aDavidenko, J M1 aGray, R A1 aJalife, J uhttp://www.ncbi.nlm.nih.gov/pubmed/7525101