Abstract 11948: Flecainide Induces a New Population of Calcium Sparks in Rat Cardiomyocytes
Flecainide has previously been reported to reduce spark amplitude and mass, but increase frequency, in ventricular cardiomyocytes from a Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) mouse model. We studied the therapeutic potential of flecainide to suppress catecholamine-induced Ca2+ sparks in healthy cardiomyocytes. Confocal microscopy of isolated intact adult rat ventricular cardiomyocytes treated with 30nM isoprenaline was used to record Ca2+ sparks, transients and SR Ca2+ load in the presence (FLEC) or absence (CTRL) of 5µM flecainide loaded for 5 mins. In concordance with previous results flecainide reduced Ca2+ transient amplitude consistent with its known negatively inotropic effects (CTRL F/F0 8.7±0.4, FLEC 7.8 ± 0.4, p=0.0003, n=24 cells) despite SR load being similar between the two groups. With respect to mean spark parameters (n=380 sparks from 31 cells), there were no significant differences in frequency, amplitude, spark mass or spark-mediated SR leak (mass x frequency). However the variances for spark amplitude and mass were significantly greater in the FLEC group than CTRL (P<0.0001 using F-test to compare variances) due to the appearance of a population of larger amplitude sparks (macrosparks) which broaden the distribution of the overall spark population. By fitting Gaussian distributions to the frequency histograms of spark amplitudes in CTRL and FLEC we found that mean spark amplitude was reduced for the main population of sparks in the FLEC group (CTRL F/F0 1.00± 0.02, FLEC 0.87± 0.01, p=0.0007). The macrosparks (defined as the largest 5% of sparks) had a greater amplitude in the FLEC group (F/F0 2.86 ± 0.21) than in the CTRL group (2.28 ± 0.07), p=0.005. Similarly, the spark mass of the largest 5% of sparks was significantly greater in FLEC group than CTRL (728±93 µm3 vs 281±70, p=0.001). In conclusion, although the majority of Ca2+ sparks had a smaller amplitude and mass in the presence of flecainide, the appearance of a population of potentially arrhythmogenic larger sparks occurred. This may limit use of flecainide as part of the treatment of triggered arrhythmia in conditions other than CPVT.
- © 2011 by American Heart Association, Inc.