Ionic mechanisms and repolarization alterations in cardiopathies

At the cellular level, each myocardial electrical event consists in a depol arization wave, the action potential, with a fast rising phase followed by a plateau of more or less complex shape depending on the species, the tissu e and the recording area. The development of this depolarization wave resul ts from inward ionic currents becoming larger than outward currents, wherea s its decay, i.e. its repolarization, results from outward currents becomin g larger than inward currents. In several pathological conditions (hypertro phy, dilatation, heart failure, diabetes, etc.) the action potential is usu ally markedly lengthened, whereas the transient outward current, I-to, know n to induce a fast initial repolarization is reduced or suppressed. This is for example the case in moderate (partial reduction of I-to) and severe hy pertrophy (almost complete suppression of I-to). Because I-to is a transien t current it can control duration of brief action potentials as in human at rial myocytes but not that of long lasting action potentials as in human ve ntricular myocytes. In the latter it can induce mainly a very transient ini tial repolarization often forming a deep notch at the beginning of the plat eau. In dogs and apparently also in humans I-to is almost absent in ventric ular endocardial layers. In contrast, it is prominent in both epicardial an d mid-layers. When inward currents are depressed by liscl-lernia, the notch can become locally so deep that a sudden lass of the major part of the pla teau can occur, thus inducing a dramatic increase in repolarization heterog eneity, a situation known to be the source of severe ventricular arrhythmia s. Because such an event requires a large I,, to occur, the I,, depression, or suppression, observed ill several cardiopathies may be considered as a protective mechanism against certain ischemia-induced ventricular arrhythmi as, Cardiac dilatation and failure are also frequently associated with acti on potential lengthening and I,, depression. Such alterations have been sho wn to occur in different animal models in which hypertrophy does not develo p as shown by the absence of any increase in cell size and capacitance. The action potential lengthening observed in severe hypertrophy and dilatation does not entirely result from I,,, suppression. Other changes have been de scribed in different models but not all, such as a decrease in the sustaine d outward current, I,, or the background It current, I,,, and, more consist ently, in increase in the sodium calcium exchange current, INa-Cal, whereas reported changes in calcium current I-CaL, appear largely variable. I-CaL remains frequently unchanged. during hypertrophy whereas I,,, depression ha s been reported in some conditions of marked dilatation. Cardiomyopathies a re frequently associated with ventricular arrhythmias. They can result from re-entry, as in the case of an increased repolarization heterogeneity and/ or fragmented conduction pathways. In the cardiomyopathic myocyte several s ources of automatism can also result from currents which are poorly develop ed in the normal myocardium such as the low threshold calcium current, I,,, or the pacemaker current, I, which can be more strongly activated in the d iseased than in the normal heart. Recent developments in molecular biology have shown that repolarizing currents such as I-to and I-sus result from ac tivation of channels (alpha-subunits) of the Kv type which can belong to di fferent subfamilies and can be composed of homo or heterotetramers from a g iven subfamily. The fact that I-to is a transient current whereas I-sus is not, results fro m the presence in the I-to molecule of one or more (up to four) amino termi ni forming an inactivation gale: of the <<ball and chain>> type which can o cclude the activated channels. In addition beta subunits that are, or can b e, closely associated with I-to or I-sus channels also possess an inactivat ion gate that can inactivate non-inactivating channels or accelerate inacti vation of inactivating channels, thus complicating the analysis of I-to. No twithstanding this complexity, a successful correction of action potential lengthening in cells front failing heart by adenoviral gene transfer has be en reported.