Determinants of ventricular arrhythmias457Flecainide reduces wave frequency and mean spark amplitude in isolated rat ventricular cardiomyocytes

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Abstract

Flecainide, a class 1c antiarrhythmic drug, has been shown to reduce spark amplitude and mass in a Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) mouse model. It has also been reported to be successful in treatment of two human subjects with the condition, through reduction in arrhythmogenic events such as ventricular tachycardias, as assessed by implantable cardioverter-defibrillator interrogation over a five month period. These and other types of arrhythmic events may be mediated by abnormal sarcoplasmic reticulum (SR) calcium (Ca) release observed as aberrant sparks and waves. We studied the effects of flecainide on spark and wave characteristics in healthy adult rat cardiomyocytes. Confocal microscopy of isolated, intact ventricular cardiomyocytes superfused with normal tyrode (NT) + /- 3x10-8M isoprenaline (ISO) + /- 5μM flecainide (FLEC) was used to record Ca sparks and waves. 113 sparks from 36 cells were assessed in the presence of ISO + /-FLEC. Although there was no significant change in spark frequency in the presence of flecainide, mean spark amplitude was significantly reduced in the NT + ISO + FLEC group (ΔF/F0 1.11 ± 0.05) compared to NT + ISO (1.15 ± 0.02), p=0.0064. The variance for spark amplitude was significantly greater in the NT + ISO + FLEC group than in NT + ISO (p < 0.0001 using F-test to compare variances), due to a subpopulation of larger amplitude sparks ("macrosparks") that appeared with flecainide. The amplitude of these "macrosparks", defined as being the largest 5% of sparks, was significantly greater in the FLEC group (ΔF/F0 2.71 ± 0.21) compared with NT + ISO (2.22 ± 0.07), p=0.034. Spark mass of "macrosparks" was also significantly greater in the NT + ISO + FLEC group (877.1μm3 ± 262.5) compared with NT + ISO (220.2 ± 48.5), p=0.003. To assess the effects of these changes in elemental release on Ca waves, we used a rapid (5Hz) stimulation protocol to induce an increase in SR Ca. Wave frequency was assessed in a subsequent 10s quiescent period in cells superfused with NT and compared to cells superfused with NT + FLEC. Wave frequency was significantly reduced in the NT + FLEC group (6.0 ± 1.0 waves/minute) compared with NT (13.1 ± 2.2 waves/minute). Despite the appearance of a population of larger "macrosparks" induced by flecainide, mean spark amplitude was reduced. The large "macrosparks" may represent aborted waves, especially given the reduction in wave frequency in the presence of flecainide. It follows that mean spark amplitude may be more important in wave formation than the presence of a "macrospark" population.

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