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234 SECTION III Cardiovascular-Renal Drugs

Molecular & Genetic Basis of Cardiac Arrhythmias

It is now possible to define the molecular basis of several con- reports suggest that the sodium channel blocker mexiletine can
genital and acquired cardiac arrhythmias. The best example is correct the clinical manifestations of congenital LQT subtype 3,
the polymorphic ventricular tachycardia known as torsades de while β-blockers have been used to prevent arrhythmias trig-
pointes (Figure 14–8), which is associated with prolongation gered by sympathetic stimulation in patients with LQT subtype 1.
of the QT interval (especially at the onset of the tachycardia), The molecular basis of several other congenital cardiac
syncope, and sudden death. This represents prolongation of the arrhythmias associated with sudden death has also recently
action potential of at least some ventricular cells (Figure 14–1). been identified. At least three forms of short QT syndrome have
The effect can, in theory, be attributed to either increased inward been identified that are linked to gain-of-function mutations in
current (gain of function) or decreased outward current (loss different potassium channel genes (KCNH2, KCNQ1, and KCNJ2).
of function) during the plateau of the action potential. Action Catecholaminergic polymorphic ventricular tachycardia, a disease
potential prolongation is thought to generate early afterdepo- that is characterized by stress- or emotion-induced syncope, can
larizations (Figure 14–5) that then trigger torsades de pointes. be caused by mutations in at least two different genes (hRyR2
Recent molecular genetic studies have identified up to 300 and CASQ2) of proteins expressed in the sarcoplasmic reticulum
different mutations in at least eight ion channel genes that that control intracellular calcium homeostasis. Mutations in two
produce congenital long QT (LQT) syndrome (Table 14–1). different ion channel genes (HCN4 and SCN5A) have been linked
Loss-of-function mutations in potassium channel genes (HERG, to congenital forms of sick sinus syndrome. Several forms of
KCNE2, KCNQ1, KCNE1, and KCNJ2) result in decreased outward Brugada syndrome, which is characterized by ventricular fibrillation
plateau current, while gain-of-function mutations in the sodium associated with persistent ST-segment elevation, and progressive
channel gene (SCN5A) or calcium channel gene (CACNA1c) cause cardiac conduction disorder (PCCD), which is characterized by
increases in inward plateau current. impaired conduction in the His-Purkinje system and right or left
The identification of the precise molecular mechanisms bundle block leading to complete AV block, have been linked to
underlying various forms of the LQT syndromes now raises the loss-of-function mutations in the sodium channel gene (SCN5A).
possibility that specific therapies may be developed for individu- At least one form of familial atrial fibrillation is caused by a gain-
als with defined molecular abnormalities. Indeed, preliminary of-function mutation in a potassium channel gene (KCNQ1).

effect can be caused by genetic mutations associated with congenital A serious form of conduction abnormality involves reentry
long QT (LQT) syndrome (see Box: Molecular & Genetic Basis of (also known as “circus movement”). In this situation, one impulse
Cardiac Arrhythmias). A number of drugs (antiarrhythmic as well as reenters and excites areas of the heart more than once. The path
non-antiarrhythmic agents) can produce “acquired” or drug-induced of the reentering impulse may be confined to very small areas,
LQT syndrome, which is typically due to block of rapidly activating such as within or near the AV node or where a Purkinje fiber
delayed rectifier potassium channels. Many forms of LQT syndrome makes contact with the ventricular wall (Figure 14–6), or it may
are exacerbated by other factors that prolong action potential dura- involve large portions of the atria or ventricles. Some forms of
tion, including hypokalemia and slow heart rates. DADs, on the other reentry are strictly anatomically determined. For example, in
hand, often occur when there is an excess accumulation of intracel- Wolff-Parkinson-White syndrome, the reentry circuit consists of
lular calcium (see Chapter 13), especially at fast heart rates. They are atrial tissue, the AV node, ventricular tissue, and an accessory AV
thought to be responsible for arrhythmias associated with digitalis connection (bundle of Kent, a bypass tract). Depending on how
toxicity, excess catecholamine stimulation, and myocardial ischemia. many round trips through the pathway a reentrant impulse makes
before dying out, the arrhythmia may be manifest as one or a few
Disturbances of Impulse Conduction extra beats or as a sustained tachycardia. Circulating impulses can
also give off “daughter impulses” that can spread to the rest of the
The most common form of conduction disturbance affects the heart. In cases such as atrial or ventricular fibrillation, multiple
AV node, causing various degrees of heart block. The result can reentry circuits may meander through the heart in apparently
be a simple slowing of impulse propagation through the AV node, random paths, resulting in the loss of synchronized contraction.
which is reflected by an increase in the PR interval of the ECG. An example of how reentry can occur is illustrated in
At the extreme, the result can be complete heart block, where no Figure 14–6. In this scenario, there are three key elements: (1) First
impulses are conducted from the atria to the ventricles. In this is an obstacle (anatomic or physiologic) to homogeneous impulse
situation, ventricular activity is generated by a latent pacemaker, conduction, thus establishing a circuit around which the reentrant
such as a Purkinje cell. Because the AV node is typically under wave front can propagate. (2) The second element is unidirectional
the tonic influence of the parasympathetic nervous system, which block at some point in the circuit. That is, something has occurred
slows conduction, AV block can sometimes be relieved by anti- such that an impulse reaching the site initially encounters refrac-
muscarinic agents like atropine. tory tissue. This can occur under conditions such as ischemia,