SICILIAN
GAMBIT

The Sicilian Gambit is a project started as an iniziative of the Task Force of the Working Group on Arrhythmias of the European Society of Cardiology, co-sponsored by the Basic Science Council of the American Heart Association and the American College of Cardiology in 1990.
This Task Force, which consisted of American and European scientists, wrote a publication entitled

"The Sicilian Gambit. A new approach to the classification of antiarrhythmic Drugs Based on their Action and on Arrhythmogenic Mechanisms."

The Sicilian Gambit is an opening move, able to provide a scientific basis for the consideration of the antiarrhythmic drugs.
Three investigators, Michiel J. Janse (Amsterdam), Michael R. Rosen (New York) and Peter J. Schwartz (Pavia) played a major role in the organization and leading this project.
Participating in the workshop held in Taormina, Sicily, December 1-4, 1990 and coauthoring the paper were: Thomas Bigger Jr., GŁnter Breithardt, Arthur M. Brown, A. John Camm, Edward Carmeliet, Harry A. Fozzard, Brian F. Hoffman, Michiel J. Janse, Ralph Lazzara, Alessandro Mugelli, Robert J. Myerburg, Dan M. Roden, Michael R. Rosen, Peter J. Schwartz, Harold C. Strauss, Raymond L. Woosley and Antonio Zaza.
Not attending but acting as advisors were Ronald W.F. Campbell and Albert L. Waldo.


 

1. Sicily

The Sicilian Gambit is the result of a meeting organized by the Working Group on arrhythmias of the European Society of Cardiology, and was co-sponsored by the Basic Science Council of the American Heart Association and the American College of Cardiology.

The immediate stimulus for the meeting was the continued use of empirical approaches to the antiarrhythmic field at a time when scientific and technological advances had fostered new and exciting approaches to disease therapy in other areas. Also of concern was the result of the Cardiac Arrhythmia Suppression Trial, in which a small group of drugs were found to be more toxic than anticipated in a very specific therapeutic milieu.

Similarly to the Queen’s Gambit in chess, which is an opening with a long-term strategy, the name "Sicilian Gambit" was chosen because it represents a new opening for consideration of arrhythmias and their therapy.

 


2. Vaughan Williams classification

For two decades, the approach to antiarrhythmic drug development and administration has focused on the Vaughan Williams classification. This classification introduces four classes of drug effect.

Class I includes drugs that block the sodium channel and has three separate subgroups: Ia, Ib and Ic.
Class II includes sympatholytic drugs, class III drugs that prolong repolarization and class IV calcium channel-blocking drugs.

The classification is a hybrid in that two classes block ion channels (I and IV), one class prolongs the action potential (III) and one class blocks a receptor (II). The classification is incomplete. It does not include a place for drugs such as digitalis and adenosine. Both these drugs have important antiarrhythmic effects and yet do not fit here.

Other shortcomings of the classification are:

Ÿ it deals with drugs that are antiarrhythmic based on block of channels but leaves no possibility for channel activation;
Ÿ it is primarily based on drugs actions on normal tissues rather than the diseased tissues that generate arrhythmias;
Ÿ it provides no guidance to the fact that drugs may act in several ways, including the slowing of tachycardias (resulting in their being better tolerated), the termination of arrhythmias or the prevention of initiation of arrhythmias;
Ÿ in oversimplifying, the classification implies that we know more than we do.


3. Channels and gates

Three types of channel have been studied intensively to date: the sodium, potassium and calcium channels. We shall describe the properties one might expert of an ion channel. If this pore were simply a "hole" in the membrane, then it would be likely that a variety of ions could pass through it, i.e. the channel would lack specificity with respect to a particular ionic species is a so-called "selectivity filter" that resides in the outer portion of the channel. Not only does this site have a limiting diameter and charge, but its configuration, too, is such that it will favor the passage of one species of ion to the exclusion of others. This property of ionic selectivity alone is not sufficient to confer functional integrity upon a channel. If all the channel possessed were a selectivity filter, then that family of ions for which it was specific could traverse the channel ad libitum until the charge and concentration gradients across the cell membrane were balanced and no transmembrane potential was maintained.

The structures that control the passage of ions are the channel "gates". These reside on the inner portion of the channel and, depending on whether they are in the open or closed position, permit or prevent the passage of ions.

Let us use the Na+ channel as an example. This functions as if it had two gates, functionally designated as "m" and "h" in the classic studies of Hodgkin and Huxly on squid axon. When the cell is in the resting state, the "m" gates are closed and the "h" are open. In this setting, the Na+ ion cannot enter. However, the "m" gate is voltage sensitive. As a result, if an electrical stimulus raises the membrane potential of a cell from its resting to its threshold potential, such that the inward depolarizing current is larger than the repolarizing current from adjacent cells, then the "m" gates open and sodium enters along both concentration (low Na inside) and charge (negative inside) gradients. This results in the occurrence of phase-0 depolarization (i.e. the upstroke of the transmembrane action potential). The "h" gate, too, is voltage depended. As sodium enters and the cell depolarizes, it begins to close. Closure of the "h" gate prevents further entry of the Na+ ion, at which time the channel is said to be inactivated. Both gates also have a time-dependent function. During repolarization, the "m" gate returns to the closed and the "h" gates to the open position. It is to be stressed that the multiple Na channels in the membrane of any one cell do not act entirely in unison.

Indeed, at any time in the electrophysiological cycling of a cell, from the resting to the

active to the repolarizing setting, the largest proportion of Na channels will be in the resting, open and inactivated states, respectively. However, within any one setting, some channels can be found in states other than the dominant one. In other words, there is randomness to channel opening and closing which serves as a further conditioner of channel (and cell) physiology. Moreover, recent studies have suggested the existence of two or more subtypes of Na+ channels, whose gating characteristics differ from one another.

Potassium and calcium channels differ from the sodium channel in their selectivity and their gating characteristics.

Whereas the major function of the sodium channel is in controlling the fast-inward current responsible for phase-0 depolarization of the cell, that of the potassium channels (of which there may be as many as six subtypes) includes modulation of the resting potential, repolarization of the cell and, at times, hyperpolarization. As is the case for potassium and sodium, there is more than one subtype of calcium channel. These are characterized by different amplitudes, different open times and different rates of inactivation. The sum of their contribution to the transmembrane potential is such that, on activation (usually following the fast inward current responsible for phase-0 depolarization), they generate a slow inward current that is responsible for the plateau (phase 2) of the action potential.


4. Action potential

If we integrate the process of sodium, potassium and calcium traveling inward and outward across the cell membrane, we effectively reproduce the ventricular myocardial action potential.

The rapid upstroke is called phase 0, the initial repolarization is phase 1, the plateau is phase 2, the final repolarization is phase 3 and the resting membrane potential is called phase 4.

A variety of currents and channels are involved in generating the action potential.

 


5. Action potentials of the heart

The action potential of the sinus node is responsible for normal impulse initiation. It occurs prior to the P wave on the ECG and generates a signal too small to be seen from the body surface. The action potential for the atrial muscle has a rapid upstroke, propagates rapidly and is responsible for the P wave on the ECG.

The action potential for the AV node is a slow calcium-dependent action potential similar to that in the SA node . AV nodal activation starts during the P wave and is completed during the late portion of the PR interval. The activation of the His bundle, bundle branches and Purkinje fibers follows, all of which occurs during the PR interval. Activation of ventricular muscle coincides with the QRS complex, and its repolarization is concurrent with the T wave on the ECG.


 

Continued frossa.gif (871 bytes)

 

  Home page EINTHOVEN.net