Cathode Make 10 mA

Anode Make + 10 mA

Cathode Break -2 mA

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Figure 5: The transmembrane potential measured during unipolar stimulation of rabbit epicardium. The number in each frame is the time in milliseconds. The electrode is at the center, and the fibers are oriented from lower right to upper left (Wikswo et al., by permission of the authors and the Biophysical Society)49

anode (Figs. 4b and 5b). Because the depolarization under the electrode during cathodal stimulation is stronger than the depolarization at the virtual cathode during anodal stimulation, the threshold stimulus current is larger for anode make than cathode make stimulation.

Cathode break stimulation occurs following the end, or "break," of the stimulus pulse (Figs. 4c and 5c). The tissue under the cathode is depolarized and the sodium channels become unexcitable. However, the tissue at the virtual anode is hyperpolarized, so there the sodium channels are fully excitable. Following the end of the stimulus pulse, the depolarization under the cathode diffuses into the excitable tissue at the virtual anode, exciting it. The resulting wavefront propagates initially through the excitable path carved out by the virtual anode, which in this case is parallel to the fiber direction. The two crucial features of break excitation are the creation of an excitable path at the virtual anode (deexcitation) followed by electrotonic interaction (diffusion) of adjacent depolarization into the excitable tissue. Because the virtual anode must be strong enough to create an excitable path, the threshold stimulus current is higher for break excitation than for make excitation. In general, cathode make excitation will occur preferentially over cathode break excitation unless the tissue is refractory at the time the stimulus turns on, in which case make excitation is suppressed but break excitation can still occur.

The mechanism for anode break excitation is analogous to that for cathode break excitation, except that the excitable path, under the anode, is now in the direction perpendicular to the fibers, and the virtual cathodes are in the direction parallel to the fibers (Figs. 4d and 5d). The initial direction of propagation is therefore perpendicular to the fibers. At first glance, anode break excitation is puzzling because one might expect that the strong hyperpolarization under the anode would diffuse into the weaker virtual cathode and not result in excitation, rather than the weak depolarization diffusing into the strong hyperpolarization and triggering excitation. Anode break excitation works because the nonlinear behavior of the membrane causes the hyperpolarization to decay more rapidly than the depolarization, so that the remnant depolarization can then diffuse into the excitable tissue. Because nonlinear behavior is essential for this mechanism to work, the threshold for anode break excitation is higher than the threshold for the other three mechanisms.

One aspect of break excitation that is often underappreciated is that it is predicted to occur for pulses as short as 2ms, albeit with very strong stimuli (15mA).54 Were it not for optical imaging of the distributed virtual electrode pattern, it would be difficult from timing alone to determine whether the excitation was make or break; high-speed, high-resolution optical imaging enables the identification of which region served as the site of activation, and hence can help identify break activation for short, 10 ms stimuli.55 Measurements of strength-interval curves for an S2 duration of 2-20 ms showed that for a 2 ms anodal stimulus, the curve still has a dip, which suggests break stimulation.56

Elevated extracellular potassium ion concentration, [K]o, influences the mechanism of stimulation.55'57 For normal [K]o (4mM), diastolic stimulation occurs by the make mechanism. However, for elevated [K]o (10mM), the mechanism switches to break (Fig. 6). Roth and Patel58 found similar results using numerical simulations: high [K]o predisposes cardiac tissue to break excitation. Because ischemia raises [K]o, break excitation may play a more important role in defibrillation than is suggested by simulations and experiments using normal [K]o levels.

Nikolski et al.59 observed break excitation during diastole in tissue with normal [K]o, but this may be caused by the output impedance of the quiescent current source used for stimulation.60 Ranjan et al.61'62 suggest that break excitation may arise because of a hyperpolarized activated membrane current. Although such a mechanism is possible,63 the fact that break excitation typically originates from a hyperpolarized region adjacent to a depolarized region, rather than from the location where hyperpolarization is greatest, makes this explanation unlikely.

Cathodal Anodal

Figure 6: Activation isochrones for cathodal and anodal pacing during diastole with normal (4mM) and elevated (10 mM) extracellular potassium ion concentration. Make excitation occurs with normal [K]o and break with elevated [K]o (Sidorov et al., by permission of the authors, ©2002 IEEE)57

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