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Cardiac cells undergo depolarization and repolarization to form cardiac action potentials ∼60 times/ minute. The shape and duration of each action potential are determined by the activity of ion channel protein complexes in the membranes of individual cells, and the genes encoding most of these proteins now have been identified. Thus, each heartbeat results from the highly integrated electrophysiologic behavior of multiple proteins on multiple cardiac cells. Ion channel function can be perturbed by inherited mutation/polymorphism, acute ischemia, sympathetic stimulation, or myocardial scarring to create abnormalities of cardiac rhythm, or arrhythmias. Available anti-arrhythmic drugs suppress arrhythmias by blocking flow through specific ion channels or by altering autonomic function. An increasingly sophisticated understanding of the molecular basis of normal and abnormal cardiac rhythm may lead to identification of new targets for anti-arrhythmic drugs and perhaps improved therapies.
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Arrhythmias can range from incidental, asymptomatic clinical findings to life-threatening abnormalities. Mechanisms underlying cardiac arrhythmias have been identified in cellular and animal experiments. In some human arrhythmias, precise mechanisms are known, and treatment can be targeted specifically against those mechanisms. In other cases, mechanisms can be only inferred, and the choice of drugs is based largely on the results of prior experience. Anti-arrhythmic drug therapy can have two goals: termination of an ongoing arrhythmia or prevention of an arrhythmia. Unfortunately, anti-arrhythmic drugs not only help to control arrhythmias but also can cause them, especially during long-term therapy. Thus, prescribing anti-arrhythmic drugs requires that precipitating factors be excluded or minimized, that a precise diagnosis of the type of arrhythmia (and its possible mechanisms) be made, that the prescriber has reason to believe that drug therapy will be beneficial, and that the risks of drug therapy can be minimized.
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PRINCIPLES OF CARDIAC ELECTROPHYSIOLOGY
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The flow of ions across cell membranes generates the currents that make up cardiac action potentials. The factors that determine the magnitude of individual currents and their modulation by drugs can be explained at the cellular and molecular levels (Priori et al., 1999; Nerbonne and Kass, 2005). However, the action potential is a highly integrated entity wherein changes in one current almost inevitably produce secondary changes in other currents. Most anti-arrhythmic drugs affect more than one ion current, and many exert ancillary effects such as modification of cardiac contractility or autonomic nervous system function. Thus, anti-arrhythmic drugs usually exert multiple actions and can be beneficial or harmful in individual patients (Roden, 1994; Priori et al., 1999).
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The Cardiac Cell at Rest: a K+-permeable membrane
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Ions move across cell membranes in response to electrical and concentration gradients, not through the lipid bilayer but through specific ion channels or transporters. The normal cardiac cell at rest maintains a transmembrane potential ∼80-90 mV negative to the exterior; this gradient is established by pumps, especially the Na+, K+-ATPase, and fixed anionic charges ...