Action Potentials of Cardiac Cells

The electrical activity of individual heart muscle cells can be recorded with a microelectrode capable of entering the intracellular space of a single cell, as shown schematically in Figure 22.1. Some of the common terms used to describe the configuration and ionic determinants of cardiac action potential components are defined here (Adams, 1986):

1. 
   

   Membrane potential is the voltage difference across the cell membrane, that is the difference in electrical voltage between the intracellular and extracellular spaces. By convention, the resting membrane potential is defined as the charge inside the cell relative to the extracellular side, in which case the resting potential is a negative charge. An increase in resting membrane potential would therefore designate a more negative intracellular charge (e.g., an increase from −70 to −90 mV), while a decrease in resting membrane potential would designate a less negative intracellular charge (e.g., a decrease from −70 to −50 mV).

   
   
2. Depolarization is the loss or decrease in electronegativity of the intracellular space, for example a decrease in membrane potential from −90 to −50 mV (partial depolarization) or from −90 to 0 mV (complete depolarization).
   
3. Hyperpolarization is an increase in electronegativity of the intracellular space.
   
4. Inward current is the change in electrical charge across the cell membrane that results from influx of positively charged ions or, alternatively, from efflux of negatively charged ions.
   
5. Spontaneous depolarization of automatic cells is a physiological and progressive decrease in resting potential during diastole, leading spontaneously to threshold and automatic firing.
   
6. Threshold potential is the membrane potential required for excitation of the cell, initiating the action potential and affiliated cellular responses.
   
7. Phase 0 is the rapid depolarization phase of the action potential of the excited cell, mediated by a rapid inward current carried by Na⁺ through fast sodium channels of the cell membrane.
   
8. Phase 1 is the initial early repolarization phase of the action potential.
   
9. Phase 2 is the plateau phase of the action potential, mediated in part by a slow inward current carried by Ca⁺⁺ through slow calcium channels of the cell membrane.
   
10. Phase 3 is the rapid repolarization phase of the action potential, returning membrane potential to the diastolic level.
    
11. Phase 4 is the membrane potential during diastole; it is constant in working muscle cells but undergoes spontaneous depolarization in cells with auto-maticity.
    
12. Refractory period is that early and late interval of the action potential during which excitability of the cell is essentially absent (functional refractory period) or depressed (relative refractory period), respectively.
    
13. Depressed fast sodium ion (Na⁺) responses are slowly rising phase 0 depolarizations due either to premature excitation during the relative refractory period of normal cells or excitation of sick cells with low diastolic potentials; depressed fast Na⁺ response action potentials develop cardiac impulses that propagate poorly with reduced conduction velocity.
    
14. Slow Ca⁺⁺ responses are analogous to the slow inward Ca⁺⁺ current during phase 2; this term is used to describe the very slowly rising phase 0 depolarizations mediated by Ca⁺⁺ when the fast Na⁺ channels are inoperative. Slow Ca⁺⁺ action potentials develop cardiac impulses that propagate poorly with extremely slow conduction.

When a cardiac cell is stimulated, the electrical potential measured across the cell membrane undergoes a depolarization and repolarization cycle that can be differentiated into five sequential components. These components are referred to as phases 0, 1, 2, 3, and 4 (Figure 22.1). The precise morphology of the 5 phases of the cardiac action potential varies with the anatomic region of the heart. A schematic diagram illustrating the configuration of action potentials derived from sinoatrial (SA) tissue, atrial muscle (AM), Purkinje fibers (PF), and ventricular muscle (VM) is depicted in Figure 22.2 along with corresponding waveforms of the electrocardiogram (ECG). Action potentials of a sinoatrial pacemaker cell (Figure 22.1B) and a typical working heart muscle cell (Figure 22.1A) will be addressed as examples of cardiac tissue with and without normal automaticity, respectively.

Disturbances in Automaticity

The action potential from the SA node, AM, PF, and VM are shown in Figure 22.2. The five phases of the action potential (0, 1, 2, 3, 4) are numbered in the first complex of VM. Notice spontaneous depolarization (SD), maximal diastolic potential (MDP), and threshold potential (TP) in the automatic cells of SA and PF. The resting membrane potential (RMP) is shown in the nonautomatic cells of the AM and VM. The P wave of the ECG corresponds to depolarization of SA and AM, while the QRS complex and T wave correspond to depolarization and repolarization, respectively, of ventricular cells (Figure 22.2).

Automatic cells of the SA node normally are the dominant pacemaker, reaching threshold first with the resultant propagating impulse exciting all other potential pacemaker cells before they spontaneously attain threshold values (Figure 22.2). If automaticity of the SA node is depressed or the spontaneous firing rate in some other tissue (latent pacemaker) is accelerated, regions of the heart other than the SA node may serve as the pacemaker and initiate ectopic impulses. Examples are shown in Figure 22.3.

Automaticity is enhanced when the slope of phase 4 SD is increased (e.g., from a to b in I of Figure 22.3); this decreases the time required to reach TP, thereby increasing the frequency of spontaneous discharge. The result is an increase in heart rate when the SA pacemaker is involved or emergence of ectopic beats if a normally latent pacemaker is involved. By decreasing the slope of spontaneous depolarization (e.g., from b to a or from a to c in I of Figure 22.3), drugs can depress ectopic foci and restore normal sinus rhythm without affecting MDP or TP. If a drug raises TP to less negative values (e.g., from TP-a to TP-b in II of Figure 22.3), additional time will be required to reach TP, thereby depressing automaticity. By increasing the MDP (e.g., from MDP-a to MDP-b in III of Figure 22.3), a drug can suppress automaticity because additional time would be required before TP is attained.

Disturbances in Impulse Conduction

A schematic demonstration of impulse reentry at a junctional region between PF and ventricular muscle is shown in Figure 22.4 (Adams, 1986). Conduction can be significantly slowed by pathological lesions in the heart tissue. Because of slowed conduction, a reentry stimulus can excite tissue that would have otherwise been refractory. Reentry theoretically could be controlled by a drug that either creates bidirectional block or bidirectional conduction through the region of cells causing the unidirectional block; accelerates speed of impulse conduction, thus returning the impulse to the site of reentry when cells are still refractory; prolongs action potential duration of normal cells, thereby extending their refractory period; or exhibits a combination of the above actions.

Other forms of cardiac electrophysiological disturbances, in addition to primary abnormalities of impulse conduction and automaticity, may be important. Examples include abnormal excitability, early/late afterdepolarizations, and triggered electrical activities. These types of abnormalities overlap mechanistically with disturbances of automaticity and impulse conduction. Arrhythmias arising from primary automaticity and conduction abnormalities are adequate for modeling the classes of antiarrhythmic drugs relative to their effects on cardiac action potential characteristics and arrhythmogenesis.