Pharmacologic control of bea-to-beat variability of repolarization to suppress and prevent dofetilide-induced Torsades de Pointes in the anesthetized CAVB dog

Abstract

The human hart is a biological pomp, due to its function blood flows continuously through the whole body. The rhythmic contraction of the heart muscle is due electrical impulses that start in the pacemaker cells and spread to the rest of the myocardium. In every heart cell this electric impulse leads to changes in the membrane potential by activating ions currents that pas the cell membrane, depolarization which is followed by repolarization. These potential changes recorded in time form an action potential and all the action potentials of the hart cells form the basis of the electrocardiogram. This action potential produces an increase in the calcium concentration and so contraction takes place. Restoring the low calcium concentration in the cells is the basis of relaxation needed for a refilling of the heart with blood. Changes in the repolarization process (e.g. due to disease or drugs) are the background of certain dangerous rhythm disorders, like Torsades de Pointes (TdP). On the electrocardiogram measuring the QT interval (between Q wave and end T wave) one can gather information about repolarization. It is known that changes in the repolarization (increased repolarization duration like in genetic or acquired long QT syndromes) are the basis of such dangerous ventricular rhythm disorder and sudden cardiac death. Still the prolongation of the repolarization duration is not always predictive for such arrhythmias. Recently has been shown that beat-to-beat variability of repolarization (BVR) is a better predictive parameter for drug-induced TdP than the QT interval. In this book we show that BVR is related to complex adaptation and changes that occur in a specific animal model: the dog with total AV block, a very vulnerable model for TdP and sudden cardiac death. A normal heart has stable repolarization duration, thus a low BVR. In this model BVR is increased and even higher in individuals vulnerable for TdP. When these animals are challenged with a drug (Dofetilide) that can induce TdP a further increase in BVR is seen only when TdP occur. In such individuals we tried with several antiarrhythmic drugs to decrease and to stabilize the BVR in order to suppress and prevent TdP. The antiarrhythmic effects against TdP were the best reflected by BVR, while changes in the QT parameter were variable. These studies bring new insights into ventricular polymorphic tachyarrhythmias, in particular TdP and which parameter can predict their risk. By reducing BVR in proarrhythmic circumstances we can suppress TdP and by reducing and by stabilizing baseline BVR is it possible to prevent TdP. Surprisingly in these studies was that also the antiarrhythmic efficacy was linked to effects on BVR. In this experimental setting by determining the BVR it is possible to study new drugs and to differentiate them in pro and anti-arrhythmic drugs. Quantifying BVR imply a simple algorithm which could be applied in the clinic. With this parameter one can do risk stratification in a patient population in order to detect the vulnerable individuals. Thus by determining BVR is it possible to early detect the risk patients and by a proper treatment to prevent dangerous rhythm disorders and sudden cardiac death. With these studies we bring new insights in the diagnostic of such ventricular tachyarrhythmias and strategies in their treatment and prevention