EADs, or early afterdepolarizations, are more likely to occur in cardiac cells with prolonged action potentials rather than cells with shorter action potentials. Myocytes from the midmyocardial region of the ventricular walls are more susceptible to EADs due to their longer action potential duration. Certain antiarrhythmic drugs, like quinidine, can increase the likelihood of EAD occurrence by prolonging the action potential. Thus, some antiarrhythmic drugs can have proarrhythmic effects. A mutation in the GJA5 gene, which impairs the assembly of gap junctions in myocytes, can lead to atrial fibrillation. This mutation reduces electrical coupling between cells. The correlation between a cell's action potential duration and its susceptibility to EADs is directly related to the recovery time of calcium channels in the cell membranes. Prolonged action potentials allow calcium channels to recover from inactivation and potentially trigger an EAD before the cell fully repolarizes. EADs are associated with the congenital and drug-induced long QT syndrome, which can manifest as polymorphic ventricular tachycardia or torsades de pointes. Torsades de pointes can progress to ventricular fibrillation and sudden death. Hypokalemia and bradycardia are clinical markers of this condition, and restoring extracellular potassium levels and increasing heart rate are approaches used to prevent torsades de pointes. In contrast to EADs, DADs, or delayed afterdepolarizations, are more likely to occur at high heart rates. DADs are associated with elevated intracellular calcium levels. Interventions that raise intracellular calcium, such as increasing extracellular calcium and administering toxic amounts of digitalis glycosides, can increase the amplitude of DADs. The elevated intracellular calcium levels provoke the release of calcium from the sarcoplasmic reticulum, resulting in small rhythmic changes in the force developed by myocardial cells. The high intracellular calcium levels also activate membrane channels that allow the passage of sodium and potassium ions. This leads to a transient inward current, known as iti, which contributes to the appearance of DADs. The elevated intracellular calcium levels may also activate the 3Na+-Ca++ antiporter, which generates a net inward cation current that contributes to the appearance of DADs.
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.