Dynamic restitution of action potential duration during electrical alternans and ventricular fibrillation

Abstract

.-The restitution kinetics of action potential duration (APD) were investigated in paced canine Purkinje fibers (P; n ϭ 9) and endocardial muscle (M; n ϭ 9), in isolated, perfused canine left ventricles during ventricular fibrillation (VF; n ϭ 4), and in endocardial muscle paced at VF cycle lengths (simulated VF; n ϭ 4). Restitution was assessed with the use of two protocols: delivery of a single extrastimulus after a train of stimuli at cycle length ϭ 300 ms (standard protocol), and fixed pacing at short cycle lengths (100-300 ms) that induced APD alternans (dynamic protocol). The dynamic protocol yielded a monotone increasing restitution function with a maximal slope of 1.13 Ϯ 0.13 in M and 1.14 Ϯ 0.17 in P. Iteration of this function reproduced the APD dynamics found experimentally, including persistent APD alternans. In contrast, the standard protocol yielded a restitution relation with a maximal slope of 0.57 Ϯ 0.18 in M and 0.84 Ϯ 0.20 in P, and iteration of this function did not reproduce the APD dynamics. During VF, the restitution kinetics at short diastolic interval were similar to those determined with the dynamic protocol (maximal slope: 1.72 Ϯ 0.47 in VF and 1.44 Ϯ 0.49 in simulated VF). Thus APD dynamics at short coupling intervals during fixed pacing and during VF were accounted for by the dynamic, but not the standard, restitution relation. These results provide further evidence for a strong relationship among the kinetics of electrical restitution, the occurrence of APD alternans, and complex APD dynamics during VF. restitution kinetics; complex dynamics; ventricular arrhythmias RATE-DEPENDENT ALTERATIONS of action potential duration (APD) and refractoriness are believed to be important determinants of ventricular arrhythmias (6,7,9,13,16,17,19,23,28,30). The changes in APD that accompany changes in rate reflect the dependence of APD on the preceding diastolic interval (DI), a relationship characterized by electrical restitution (2-4, 10-12). Several experimental and computer modeling studies (9, 15-17, 19, 20, 26) have suggested that the kinetics of electrical restitution have important implications for the development of ventricular arrhythmias. In particular, it has been proposed that a steep slope (Ն1) of the restitution relation may determine whether single spiral waves of electrical activity splinter into multiple smaller spirals, thereby creating a transition from ventricular tachycardia to ventricular fibrillation (5, 17, 31).The breakup of spiral waves is thought to be precipitated by oscillations of APD that are of sufficiently large amplitude to cause conduction block along the spiral wave front (17). This type of oscillation, also known as APD alternans, is a well-recognized phenomenon that occurs in ventricular tissue at rapid rates of stimulation and after abrupt shortening of the cycle length (21,25,26). During alternans, a short (long) DI sequence generates a short (long) APD sequence. This dynamic property is linked to the slope of the restitution relation in that, for persiste...

Mechanisms for Discordant Alternans

“…20,25,26,32 Results from the present study suggest that discordant alternans that arises by the second scenario could be prevented by drugs that increase conduction velocity or reduce range of DI over which conduction velocity varies, even if concordant alternans is not preventable.…”

“…3,14,15 Theoretical work suggests that concordant APD alternans is sustained when the maximum slope of APD restitution is . 1 and BCL is short, [16][17][18] although there are experiments showing some discrepancy from theory, 19 and some experimental 20,21 and theoretical 22 studies ascribe a more important role to the slope of dynamic rather than standard restitution curve in alternans production. The APD restitution curve of the BR model as measured with an S1S2 protocol has a maximum slope that is .…”

An Ionically Based Mapping Model with Memory for Cardiac Restitution

“…For the map (26), which is derived from the ODE's (21,22), it is shown in Mitchell and Schaeffer (2003) that this threshold behavior follows from asymptotic analysis of the 14 Incidentally, the APD's in Figure 7 are on the order of 5% longer than the values graphed in Figure 3. This discrepancy provides an estimate for the degree of accuracy of the aymptotic approximation.…”

“…Many other protocols have been used: see for example 3 , Fenton et al 2002,Fox et al 2003d,Kobayashi et al 1992,Koller et al 1998.…”

“…We augment the two-current model (21,22) by adding a third variable, a generalized concentration c, and modifying the equations as follows:…”