Early afterdepolarizations (EADs)
EADs occur as a result of abnormal
prolongation of action potential
duration (APD) in some cardiac
myocytes, which results in a
secondary depolarization phase prior
to full repolarization. Certain cardiac
myocyte cell types are more prone to
the generation of EADs, such as
Purkinje fibers of the conduction
system and M cells of the midmyocardium.
When repolarization is
delayed long enough at plateau
voltages to allow recovery of a
fraction of inactivated L-type
calcium channels, these channels
can reopen to provide added inward
current, thereby initiating the EAD
An EAD can, in some circumstances, excite nearby myocardium to reach threshold to
stimulate or trigger an action potential and, if this triggered action potential is propagated
through the heart, it causes a premature ventricular beat. In the setting of the long QT
syndrome, there is exaggerated heterogeneity of total APD throughout the heart, and
therefore, premature triggered ventricular beats can lead to complex reentrant (see below)
circuits of excitation resulting in a specific form of polymorphic ventricular tachycardia. On
the surface electrocardiogram, a changing QRS axis pattern is observed, hence the name
torsades de pointes or twisting of the points (Figure 17). This arrhythmia produces
symptoms of palpitations and syncope, is often self-limited, but it can also degenerate into
ventricular fibrillation and result in sudden cardiac death.
APD prolongation typically occurs in the setting of acquired long QT syndrome or congenital
long QT syndrome.
Acquired long QT syndrome can be due to drug effects, electrolyte abnormalities
(especially hypokalemia), or ischemia. The acquired long-QT syndrome can be a
potentially lethal side effect of some medications. In fact, drug-induced QT
prolongation is the most common cause of drugs being withdrawn from the U.S.
market or from development in the last 20 years. A combination of a QT-prolonging
drug with hypokalemia can be a particularly potent stimulus for arrhythmia.
Congenital long QT syndrome is due to an inherited mutation in an ion channel
protein or associated protein that results in delayed repolarization. In the case of
channels important in repolarization, loss of function mutations are implicated in
channels such as KCNQ1 (responsible for IKs) and KCNH2 (responsible for IKr).
Alternatively, gain of function mutations in channels that depolarize myocytes have
been identified in channels such as SCN5A (responsible for INa) or CACNAC1
(responsible for ICa,L).
