Fig. 16.24 ). EADs are also more likely to occur in cardiac cells with prolonged action potentials than in cells with shorter action potentials. For example, EADs can be induced more readily in myocytes from the midmyocardial region of the ventricular walls than in myocytes from the endocardial or epicardial regions because of the longer action potential of midmyocardial myocytes (see
Fig. 16.5 ). Certain antiarrhythmic drugs, such as quinidine, prolong the action potential. As a consequence, such drugs increase the likelihood that EADs may occur. Hence, some antiarrhythmic drugs are also proarrhythmic.
Insomecases,mutationsintheconnexin40gene(GJA5) underliethedevelopmentofatrialfibrillation.Thismutationimpairstheassemblyofgapjunctionsinmyocytesandthereforereduceselectricalcouplingofthecells,asdescribedbyGollobMHandcolleagues(2006).
The direct correlation between a cell’s action potential duration and its susceptibility to EADs is related to the time required for calcium channels in the cell membranes to recover from inactivation. When action potentials are sufficiently prolonged, the calcium channels that were activated at the beginning of the plateau have sufficient time to recover from inactivation and thus may be reactivated before the cell fully repolarizes. This secondary activation could then trigger an EAD.
ThepathologicalsignificanceofEADswasrecognizedinconnectionwiththecongenitalanddrug-inducedlongQTsyndrome.Astheactionpotentiallengthens,EADsoccurandcausetriggeredautomaticity.Intheelectrocardiogram,thisproblemismanifestedaspolymorphicventriculartachycardia,alsocalledtorsades de pointes. Episodesoftorsadesdepointescanbeself-limitedbutmayprogresstoventricularfibrillationandsuddendeath.Hypokalemiaandbradycardia(see
Fig.16.24) areclinicalhallmarksofthiscondition.RestoringextracellularK+ tonormallevelsandincreasingheartratearetwoapproachesusedtoovercomethepropensityfordevelopmentoftorsadesdepointes.
In contrast to EADs, DADs are more likely to occur when the heart rate is high (Fig. 16.25 ). DADs are associated with elevated intracellular [Ca++]. The amplitudes of DADs are increased by interventions that raise intracellular [Ca++], such as increasing extracellular [Ca++] and administering toxic amounts of digitalis glycosides. The elevated levels of intracellular Ca++ provoke the oscillatory release of Ca++ from the sarcoplasmic reticulum. Hence, in myocardial cells, DADs are accompanied by small rhythmic changes in the force developed. The high intracellular [Ca++] also activates certain membrane channels that allow the passage of Na+ and K+ . The net flux of these cations constitutes a transient inward current (iti), that contributes to the appearance of DADs. The elevated intracellular [Ca++] may also activate the 3Na+-Ca++ antiporter. This electrogenic antiporter, which moves three Na+ ions into the cell for each Ca++ ion that it releases, also creates a net inward cation current that contributes to the appearance of DADs.