There exist a lot of variation in the intensity of cellular electrophysiologic currents between the different animal species. Ito, for instance, is very intense in the human being, dog, rabbit, cat, and rat, but very weak in other species. Within the same animal, there exist also a large variation in the intensity of electrophysiologic currents from endocardium to epicardium. Ito is much more expressed at epicardial than at endocardial level. Because of this heterogeneity, it is easy to understand that the effects of antiarrhythmic drugs also vary from species to species and from endocardium to epicardium. Several physiologic, and not necessarily pathologic electrophysiologic changes may result in an electrophysiologic and electrocardiographic pattern as observed in the syndrome under discussion.

At birth, rats show an isoelectric repolarization between QRS and T wave, but they develop a progressive ST elevation after the second week of life. The ST elevation coincides with an increase in the intensity of the Ito. In man, this happens around 6 months of life. However, like in other large mammalians, no elevation of the ST segment is observed under normal circumstances. Hypothermia results in ST segment elevation. Experimental application of cold at the epicardium, or application of pressure also results in ST segment elevation. Pharmacologic interventions blocking the sodium channel or the calcium channel, or the activation of ATP-dependent potassium currents also result in elevation of the ST segment because of shortening of the duration of the action potential of cells with an intense Ito.

When inward Ca currents (ICa) are overwhelmed by Ito, a reduction of up to 70% in the duration of the action potential is possible. This causes loss of the dome of the action potential at some areas at epicardial level, while other areas maintain the normal duration of the action potential. This results in severe heterogeneity of duration of action potentials and consequently in refractory periods. Cells with a short duration of action potential can be re-excited by adjacent cells with a normal duration of the action potential (phase 2 re-entry, picture 11). These mechanisms have been elegantly shown by Antzelevitch and co-workers in the dog's heart with the administration of flecainide, potassium channel openers, increase in extracellular calcium, metabolic inhibition and simulated ischemia. When Ito is blocked under these circumstances, homogeneity is recovered and phase 2 re-entry disappears.

The cellular mechanisms underlying this syndrome of right bundle branch block, ST segment elevation from V1 to V3 and sudden death have been recently extensively reviewed. The loss of the dome of the action potential occurs because of a disequilibrium between Ito and ICa during phase 1 of the action potential. Any influences which come to alter this disequilibrium in one or another sense, will result in changes in the degree of ST segment elevation. For instance, interventions increasing the potassium current will increase ST segment elevation, while interventions increasing calcium current will decrease the amount of ST elevation. On the contrary, a decrease in potassium current will decrease ST segment elevation, and block of calcium currents will increase the amount of ST segment elevation. The observations by Miyazaki and co-workers and by others in patients with this syndrome are in agreement with these predictions (picture 9).