M. Monserrat

Reflection and ectopic activity induced by early after depolarizations. A computer modeling study

A computer model of two partially coupled ventricular fibers was used to study conditions in which EADs developed in an area of ventricular myocardium propagate to other areas, generating ectopic activity or reflection. We simulate the interactions between two areas of myocardium coupled through an area of unexcitable tissue, simulated by a resistance R. EADs are induced in one of the segments by enhancing I/sub Ca/ current and decreasing I/sub K/ current while the other is kept under normal conditions. The results show that the likelihood of ectopic activity and reflection depends on both EAD conditions and R values. For low values of R (in the range from 5 /spl Omega//spl middot/cm/sup 2/ to 10 /spl Omega//spl middot/cm/sup 2/) ectopic activity and reflection only appear for strong EAD conditions (I/sub Ca/ enhanced by 80% and I/sub K/ blocked by 80%). However, when higher R values are used, the ectopic activity and reflection appear at less extreme EAD conditions. For R=50 /spl Omega//spl middot/cm/sup 2/, both phenomena appear for I/sub Ca/ enhanced by 60% and I/sub K/ blocked by 60%. The study shows that ectopic activity and reflection in a zone of myocardium could be induced by EADs generated in neighboring zones.

Modulation of the regional dispersion of repolarization by the action of class III antiarrhythmic drug dofetilide

It is well known that short-long (S-L) sequences frequently precede the onset of malignant ventricular arrhythmias. Experimental studies have shown that a single long coupled extra-beat (L) after a previous basic cycle length resulted in a critical increase of the dispersion of repolarization pattern that promoted reentrant excitation. However, in normal intact heart little differences in repolarization among different myocardial layers have been observed after abrupt slowing of heart rate. We used the Luo and Rudy model (LRd00) of AP and the model of IKr blockade by the action of dofetilide previously developed by our group to study the effect of dofetilide (a class III antiarrhythmic drug) on the modulation of APD dispersion in a strand of ventricular tissue. Our results show that dofetilide increases dramatically the APD of the strand and that the effect of dofetilide on the modulation of dispersion is complex, indicating that the highest dispersion could appear before the highest effect of the drug is reached

Effects of acute ischemia on the restitution curves of myocardial tissue: a simulation study

The Electrical Restiitution Curve (ERC) may play an important role in the generation and maintenance of Ventricular fibrillation (VF). As VF usually appears in ischemic hearts, we have studied the changes exerted by acute ischemia in ERCs using computer simulations. Our results show that the main effects of ischemia on rhe ERC are that (a) it shifts the ERC towards lower action potential durations (APDs) and (b) it significantly reduces the slope of the ERC. These findings are in accordance with experimental observations. When analyzing ionic currenis, it became clear that, as expected, the slow component of the delayed K current (I) was responsible for the slope of the ERC in normal conditions. However, an increased Ca inward current (IcaL) provoked by the altered [Ca2+] dynamics accounted for the flattening of the ERC in ischemia

Effects of the antiarrhythmic drug dofetilide on regional heterogeneity of action potential duration: a computer modelling study

DifSerent experimental studies have shown that ventricular cells present several diflerences between epicardium, endocardium and M-cells. M-cells have longer APDs and higher sensitivity to agents with class III actions and they could contribute to APD heterogeneity in the ventriculum. However, in-vivo studies have observed that the strong cellular coupling reduces the APD dispersion in intact heart. We used the Luo and Rudy model (LRdOO) of AP and the model of IKr blockade by the action of dofetilide developed previously by our group ro study the effect of dofetilide (a class III antiarrhythmic drug) on the APD dispersion in a strand of ventricular tissue. Our results show that dofetilide increases dramatically the APD dispersion and may modify the transmural gradient of APR even in normal coupling condirions such as those in intact heart, Higher dispersion and, a more complex behaviour, such as 2:1 block, could appear when the coupling decreases.

Effects of the antiarrhythmic drug dofetilide on myocardial electrical activity: a computer modelling study

Dofetilide selectively inhibits the rapid component of the delayed potassium current (I/sub Kr/). In this work, a mathematical model of dofetilide effects on I/sub Kr/ has been developed. This model has been incorporated to the Luo and Rudy (II) model of guinea pig ventricular action potential and the effect of different dofetilide concentrations on the action potential characteristics has been studied. Our results show that the steady-state block of I/sub Kr/ is dose-dependent with a block of 10%, 53% and 92% for 1 nM, 10 nM and 100 nM of dofetilide respectively (IC/sub 50/=8.7 nM). This increment of I/sub Kr/ block when the concentration increases induces a prolongation of APD also in a dose-dependent way. We observed prolongations of APD/sub 90/ of 13% and 28% for 10 nM and 100 nM of dofetilide respectively. In agreement with experimental results, the interaction between dofetilide and the receptor in the channel presents slow kinetics and reverse use-dependence in our model.

Effects of antiarrythmic drug lidocaine on ventricular electrical activity. a computer modelling study

Lidocaine is a class Ib antiarrythmic drug that acts blocking the fast sodium current. In this work, a mathematical model of lidocaine effects has been developed. This model has been incorporated to the Luo Rudy model of guinea pig ventricular action potential and the effect of different basic cycle lengths (BCL) and concentrations of drug on the action potential characteristics has been studied. Our results show that at BCL 300 ms lidocaine reduces maximum current sodium to 7% and 39% for 10 muM and 100 muM respectively. If we increase BCL, the blockade is reduced. In addition, lidocaine reduces the maximal upstroke velocity, for BCL 500 ms the inhibition is 0.9%, 7% and 38% for 1muM, 10 muM and 100 muM respectively. This reduction depends on BCL. Conduction velocity is also affected by lidocaine, It is reduced to 4% and 23% for 10 muM and 100 muM respectively (BCL 300 ms); lower concentrations do not affect the conduction velocity

A computer model of reflection induced by early afterdepolarizations in ventricular tissue

A computer model has been developed in which reflection was observed. Reflection is a type of reentry in a one-dimensional structure of cardiac cells. The model consists of two segments of ventricular tissue partially coupled by a coupling resistance (R) and it was used to study conditions that provoke the development of EADs, and the generation of reflection and ectopic activity. In the present study, EADs were induced in one segment by enhancing ICaL current and decreasing IKr and IKS currents. The other segment was maintained under normal physiological conditions. The results suggest that ectopic activity in a zone of myocardium could appear due to the reflection induced by EADs generated in neighboring tissue zones. The coupling between areas and the blocked factor of the two components of the delayed rectifier K+ current (IKr and IKs ), have a great influence. The results suggest that a partial coupling between segments and severe conditions in the abnormal segment increase the likelihood of both the ectopic activity and the triggered activity

Effects of pinacidil on refractoriness in acutely ischemic tissue: insights from experiments and simulations

A controversy exits regarding the arrhythmogenic effect of potassium channel openers, such as pinacidil, during acute myocardial ischemia. In order to throw some insight into this issue, the effect of pinacidil on the refractoriness of normal and acutely ischemic tissue has been experimentally and theoretically studied. Experiments with Lungendom perjused rabbit hearts were conducted, as well as computer simulations based on Luo-Rudy phase II model of the cardiac action potential. Our results show that pinacidil significantly reduces the effective refractory period (ERP) in normal tissue. However, in spite of strongly reducing QT interval, pinacidil does not have a signijkanr efect on ERP in acutely ischemic tissue. In conclusion, during myocardial ischemia, despite action potential durution (APD) reduction provoked by pinacidil, ERP is not significantly modified by the drug due to the counteracting effect of 1K(ATP) on depolarization currents

Development and propagation of early after depolarizations in a Purkinje-ventricular computer model

A computer model that represents the connection of a Purkinje fiber to a two-dimensional ventricular muscle tissue is used to study the ionic mechanism responsible for the development of phase 3 early after depolarizations (EADs) in Purkinje fibers, and their propagation to ventricular muscle cells as ectopic beats. The conditions that favor EAD generation (EAD conditions) are only applied to Purkinje cells. The electrical behavior of these cells is described using the DiFrancesco-Noble equations and EAD conditions are simulated multiplying the fast second inward current of the model, i/sub Ca.s/, by 1.7 (70% i/sub Ca,s/ enhancement) and the delayed K/sup +/ current, i/sub K/, by 0.3 (70% i/sub K/ blockade). For these conditions, a single phase 3 EAD developed in the Purkinje fiber propagates to the ventricular muscle tissue generating an ectopic beat. In our simulations, the ionic mechanism underlying phase 3 EAD development is the reactivation of the fast sodium current in Purkinje cells near the Purkinje-ventricular junction. The reactivation of this current is due to greater h-gate values reached as a result of a decrease in the rate of repolarization induced by EAD conditions. The propagation of these phase 3 EADs to the ventricular muscle tissue may trigger some ventricular arrhythmias.

Simulation study of the ionic mechanisms involved in the all-or-none repolarization observed under ischemic conditions

Several studies in dog have suggested that a mild (simulated) ischemia produces an heterogeneous shortening of the action potentials (APs) in the epicardium, by means of the suppression of the dome only in some areas, giving place to what is known as all-or-none repolarization. This produces a different restitution curve in epicardium and endocardium. The goal of the present work is to study the ionic mechanisms responsible for the characteristic restitution curve of the epicardium under metabolic inhibition conditions. The study has been carried out by means of computer simulations, using a modified version of the model from Priebe and Beuckelmann for human myocytes. Metabolic inhibition was simulated activating the potassium ATP-dependent channels (I/sub KATP/). Our results show that the activation of the I/sub KATP/ may account for the restitution curve observed in other studies. In this study 1% of this channels open produce the abolition of the dome for interstimulus intervals greater than 600 ms (BCL of 2000 ms).