Reverse rate dependence is a problematic property of antiarrhythmic drugs that prolong the cardiac action potential (AP). The prolongation caused by reverse rate dependent agents is greater at slow heart rates, resulting in both reduced arrhythmia suppression at fast rates and increased arrhythmia risk at slow rates. The opposite property, forward rate dependence, would theoretically overcome these parallel problems, yet forward rate dependent (FRD) antiarrhythmics remain elusive. Moreover, there is evidence that reverse rate dependence is an intrinsic property of perturbations to the AP. We have addressed the possibility of forward rate dependence by performing a comprehensive analysis of 13 ventricular myocyte models. By simulating populations of myocytes with varying properties and analyzing population results statistically, we simultaneously predicted the rate-dependent effects of changes in multiple model parameters. An average of 40 parameters were tested in each model, and effects on AP duration were assessed at slow (0.2 Hz) and fast (2 Hz) rates. The analysis identified a variety of FRD ionic current perturbations and generated specific predictions regarding their mechanisms. For instance, an increase in L-type calcium current is FRD when this is accompanied by indirect, rate-dependent changes in slow delayed rectifier potassium current. A comparison of predictions across models identified inward rectifier potassium current and the sodium-potassium pump as the two targets most likely to produce FRD AP prolongation. Finally, a statistical analysis of results from the 13 models demonstrated that models displaying minimal rate-dependent changes in AP shape have little capacity for FRD perturbations, whereas models with large shape changes have considerable FRD potential. This can explain differences between species and between ventricular cell types. Overall, this study provides new insights, both specific and general, into the determinants of AP duration rate dependence, and illustrates a strategy for the design of potentially beneficial antiarrhythmic drugs.
We studied the excitatory and inhibitory effects of overdrive on idioventricular pacemakers in anesthetized dogs with recently induced complete atrioventricular block. The following results were obtained: (1) a slow driving rate may induce a temporary rhythm which may be reinstituted with additional stimuli; (2) the induced rhythm may appear as coupled extrasystoles which, on interruption of the drive, are found to be self-sustaining; (3) during continued slow driving, extrasystoles may appear and disappear in a cyclical manner; (4) a short period of fast driving may be followed by a fast new rhythm, the rate and duration of which are a function of the rate and duration of drive; (5) fast driving may induce a new rhythm at a rate below predrive control; (6) after a long period fast driving, only suppression follows; and (7) intermittent periods of fast driving lead to a summation of inhibition with each successive period. These results suggest the following conclusions: (1) under certain conditions, electrical driving instead of inducing suppression may induce a rhythm ("overdrive excitation") at a rate similar to, faster then, or slower ("inhibited excitation") than control; (2) the duration of diastole and the number of driven beats are major factors in the induction of new rhythms; and (3) overdrive excitation is counteracted by overdrive inhibition, with development of the former requiring fewer beats than the latter.
Fast idioventricular rhythm was studied in dogs with and without recently-induced complete atrioventricular block. The following results were obtained. The fast idioventricular rhythm (1) has an average rate of 92 ± 7.7 beats/min, (2) is either intermittent or continuous, (3) originates from either ventricle, (4) is initiated suddenly by a beat that usually has a different electrocardiogram configuration, (5) may undergo a moderate deceleration before ceasing abruptly, (6) inhibits normal pacemaker activity, (7) when no longer present, can be brought back by a short period of fast driving, (8) can be suppressed by fast driving but the suppression is often preceded by a transient acceleration, (9) requires a longer period of driving than a normal idioventricular rhythm to be suppressed, (10) is accelerated by a short period of driving, (11) is "reset" by driving, (12) can be induced at progressively faster rates by repeated periods of driving during recovery from a prolonged overdrive, (13) is accelerated by sympathetic stimulation or norepinephrine administration, and (14) is accelerated by short periods of driving during submaximal sympathetic stimulation. We conclude that the fast idioventricular rhythm is a form of repetitive activity requiring initiating beats and thus is less sensitive to overdrive suppression. The behavior of this rhythm differs from that of normal idioventricular pacemakers and suggests that this rhythm does not result from an enhancement of a normal pacemaker process but rather from a different mechanism. This mechanism is affected by sympathetic stimulation and by norepinephrine administration and this may result in ventricular tachycardias.TWENTY-SIX dogs were studied shortly after induction of a complete atrioventricular (AV) block. The dogs could be divided into two categories on the basis of the idioventricular rate. In one category the idioventricular rate was below and in the other above 65 beats/min. The reason for selecting this rate to separate the dogs in two groups is that normal idioventricular pacemakers rarely show a rate of discharge higher than 65 beats/min even during maximal sympathetic stimulation. 1 Therefore, it seemed unlikely that in the dogs with the higher rate the idioventricular rhythm could have resulted from an increment in normal idioventricular pacemaker activity. In view of the results obtained in the present study, this abnormal rhythm will be referred to as fast idioventricular rhythm.Several aspects of this arrhythmia are not understood. For this reason, dogs with complete block and a fast idioventricular rhythm were studied. The presence of complete AV block offers several advantages because the behavior of the fast idioventricular rhythm can be contrasted to that of normal pacemakers. For example, one can determine whether this abnormal rhythm is suppressed by overdrive. Also, it is possible to determine both the mode of initiation and of cessation of the fast idioventricular rhythm. In addition, the degree of control of the sympathetic system on thes...
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