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 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., Günter 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). Other shortcomings of the classification are:
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.
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. 6. Autonomic control mechanisms One of the factors that influence arrhythmias is autonomic control. Receptor systems are linked to
their effectors via a complex series of steps.
As a result of agonist (in the figure, norepinephrine) binding to the beta-adrenergic receptor, the alpha subunit of the G protein, Gs, transduces a linkage to the second messenger system adenylyl cyclase, which enzyme converts adenosine triphosphate to cyclic adenosine monophosphate. This turns on the enzyme protein kinase A, which, via breakdown of adenosine triphosphate to adenosine diphosphate (ATP to ADP), frees a phosphorus molecule which can phosphorylate the pacemaker channel, If, the potassium channel, Ik, as well as the calcium channels. Phosphorylation of the If channel permits it to carry more sodium ions into the cell, thereby enhancing pacemaker rate. Phosphorylation of the potassium channel carries more potassium out of the cell, accelerating repolarization and thereby decreasing action potential duration. Phosphorylation of the calcium channel carries calcium into the cell, which would tend to increase pacemaker rate, increase plateau height and enhance contractility.
7. Mechanisms of arrhythmias: automaticity Automaticity results from spontaneous depolarization during phase 4 of the action potential. Automaticity occurring at low membrane potentials depends on a balance between inward current carried by calcium and outward currents carried by potassium. An important characteristic of abnormal automaticity is its relative insensitivity to overdrive pacing. 8. Mechanisms of arrhythmias: early afterdepolarization (EAD) Another mechanism for abnormal impulse initiation is trigger activity based on afterdepolarizations. Afterdepolarizations are oscillations in membrane potential. They may occur during phase 2 or 3 of the action potential. As opposed to automaticity, which can occur de novo, afterdepolarizations, whether early or delayed, depend on the preceding action potential for their initiation. Early afterdepolarizations are bradycardia or pause dependent. Ik is an important determinant of depolarization, and, as the channel is blocked, action potentials can be prolonged and EAD can occur.
9. Mechanisms of arrhythmias: delayed afterdepolarization (DAD) In contrast with EADs, delayed afterdepolarizations are tachycardia dependent. They may occur during phase 4 of the action potential. These oscillations occur following full repolarization and, if they reach threshold, can induce tachycardias.
10. The excitable gap In anatomical reentry, the head of an activating wave front and its relative refractory tail are usually separated by tissue that is completely excitable: the excitable gap. The excitable gap may be short or long. This may have consequences for the type of antiarrhythmic agents chosen to terminate a tachycardia. Reentrant circuit with a long excitable gap. Within the ring, there is a segment of impaired conduction and excitability. Further depression of conduction and excitability will result in conduction block in that segment.
Prolongation of refractoriness will cause block of the reentrant wave front in its own refractory tail, when the conduction enroaches on the relative refractory period.
Atrial fibrillation can be maintained by the presence of many independent wave fronts. Prolongation of the wavelength of refractoriness reduces the number of wave fronts in a given chamber below a critical number; block and collision terminate the arrhythmia.
We know that sometimes, although we try to suppress the arrhythmia, we create a new one. An explanation of this proarrhythmia phenomenon can be the following:
see Fig-11 11. Targets of drug action Targets of drug action are the
sites at which drugs act. It is important to understand
that these sites are not uniquely the recipients of drug
molecules. Moreover, they can interact with one another (for example cytoplasmic regulators may modulate channels). However, it is these targets, acting individually or in concert, that determine the rhythm of the heart (Fig-12).
Fig-12 12. Use-dependent block Molecules that are ionized are present in the cytosol and interact with the Na+ channel. They gain access to the binding site only when both the "m" and "h" gates are open. The faster the heart is beating and more channel openings there are per unit time, the more rapid will be the binding. This is referred to as rate-or use-dependent block. Drugs which bind and unbind rapidly tend to accumulate minimally and have a short duration of action and a low cardiac toxicity. By contrast, drugs which unbind very slowly tend to accumulate to a more marked extend and have been shown to be far more proarrhythmic. The pharmacokinetics and dynamics of drugs, which often are solely conceived of in terms of equilibria for absorption, metabolism and excretion, are important at the level of the binding site as well, and characterize how a drug will act. Characteristics such as these, which determine both drug efficacy and drug toxicity, must be taken into account for each drug and each binding site if we are to understand the action of antiarrhythmic compounds. 13. Pharmacological indices associated with the functional definition of drug action Use dependence as described before is only one example of drug action. In figure 13 there is a list of indices divided in three major groups:
PHARMACOLOGICAL
INDICES ASSOCIATED WITH THE
Fig-13 14. Concept of the vulnerable parameter Now let us go to what probably is the most critical concept of the Sicilian Gambit: vulnerable parameter. There are two assumptions. First, we assume that, for each arrhythmogenic mechanism, a specific alteration in one or more of several electrophysiological properties will be sufficient to terminate the arrhythmia or to prevent its initiation. Second, we assume that, among the several possible effective changes in electrophysiological properties, usually one is most susceptible to alterations while manifesting a minimum of undesirable effects on the heart. That property which, if appropriately altered, is most likely to prevent or terminate an arrhythmia with the least negative effects is called the "vulnerable parameter". Reentry is an arrhythmogenic mechanism for which the vulnerable parameter is defined. With a long excitable gap, depressing conduction and excitability should induce conduction block in the segment of slow conduction. With a short excitable gap, the most likely way to terminate the tachycardia is by prolonging the refractory period, whereby the head of the wave front will encroach upon its refractory tail. 15. Wolff-Parkinson-White syndrome Let us start with a few examples of specific arrhythmias. During orthodromic circus movement tachycardia, antegrade conduction to the ventricles is through the AV node/His-Purkinje system and retrograde conduction to the atria is through the accessory pathway. There are two potentially
vulnerable segments in this anatomically large circuit:
the AV node and the accessory connection. If we choose to
impair slow AV nodal conduction, the vulnerable parameter
is represented by calcium-dependent conduction and
excitability, and they should be depressed. WPW Orthodromic Atrioventricular Tachycardia
Fig-14 If we choose to delay the fast conduction through the accessory pathway, the vulnerable parameter is represented by conduction and excitability, which should be depressed. The target ionic current is INa, which should be blocked, and the most logical drugs are sodium channel blockers (Fig-15).
Fig-15 However, the reentrant circuit may have a short excitable gap. In that case, the vulnerable parameter is the refractory period of the accessory pathway, which should be prolonged. The target current is IK, and the most logical drugs are potassium channel blockers (Fig-16).
Fig-16 16. Ventricular tachycardia Ventricular tachycardia may occur in different substrates and with different mechanism. Here we will present only the most frequent condition, namely circus movement ventricular tachycardia occurring in patients with chronic ischemic heart disease. The two main therapeutic options are based on the assumption that sodium channel-dependent reentry occurs over a circuit with either a long or a short excitable gap. This example shows that, in long excitable gap reentry with a segment of impaired conduction, the vulnerable parameter is excitability and conduction, which should be decreased. The target ionic current is INa, which should be blocked. The drugs should be chosen among the sodium channel blockers. Clinically, it is often difficult or impossible to determine if a ventricular tachycardia depends on a short or long excitable gap. If the tachycardia can be readily entrained during electrophysiological testing, then it is likely that the excitable gap is long. In this setting, sodium channel-blocking drugs are usually effective (Fig-17). Ventricular Tachycardia (with a long excitable gap)
Fig-17 17. "Torsades de pointes" "Torsades de pointes" constitutes a life-threatening arrhythmia usually caused by trigged activity resulting from EADs. Less frequently, "torsades de pointes" may result from reentry. The vulnerable parameter is either the action potential duration, which should be shortened, or the EAD, which should be suppressed. The ideal target ionic current is Ik, which should be activated in order to accelerate repolarization. Since EADs occur predominantly at slow heart rates or following a long sinus pause, interventions that increase heart rate are antiarrhythmic in this context. Accordingly, the beta-adrenergic receptors (to be activated) or the muscarinic receptors (to be activated) may become important targets. Given the fact that EADs are generated by an excess of inward over outward current, the target ionic currents to suppress the EADs are INa and/or ICa, which should be blocked (Fig-18).
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The
Sicilian Gambit approach to clinically occurring
arrhythmias