Abstract 11969: Post Myocardial Infarction Hearts Exhibit Larger Calcium Sparks which are Not Modified by Flecainide
A proportion of arrhythmias which occur following MI and ischemic cardiomyopathy may result from increased sarcoplasmic reticulum (SR) Ca2+ leak. In the CAST trial flecainide was assessed for its ability to reduce post-MI arrhythmias but in fact increased arrhythmias and mortality. Recent evidence has shown flecainide to be effective in the therapy of some forms of triggered arrhythmia, in part through reduction in Ca2+ spark amplitude. We set out to assess whether flecainide had a specific effect on post MI cardiomyocytes that might help explain the lack of benefit seen in CAST. Confocal microscopy of isolated intact rat ventricular cardiomyocytes treated with 30nM isoprenaline (ISO) was used to assess sparks in the presence (FLEC) or absence (CTRL) of 5µM flecainide loaded for 5 mins (n=733 sparks from 52 cells). Cells were isolated either from rats with MI induced approximately 4-8 weeks earlier (MI) or age matched controls (AMC). This gave four main conditions for spark measurement - AMC-CTRL, AMC-FLEC, MI-CTRL, MI-FLEC. Consistent with our previous findings in a 16 week post MI model, baseline (prior to FLEC/ISO application) spark amplitude and mass were increased post MI (spark amplitude: AMC F/F0 0.86±0.03, MI 1.14±0.05, p<0.001; spark mass: AMC 26±4 µm3, MI 60±11, p<0.001). Spark frequency was unchanged but together these observations suggest higher spark-mediated SR Ca2+ leak in post-MI ventricular cardiomyocytes. Flecainide application had different effects in ISO treated MI vs AMC cells. Whilst there was no difference in mean spark amplitude between CTRL groups and FLEC groups, assessment of the frequency distribution of spark amplitude revealed a new population of macrosparks in both AMC-FLEC and MI-FLEC groups. By fitting Gaussian distributions to the histograms, mean spark amplitude for the main population of sparks in AMC cardiomyocytes was found to be reduced by flecainide (AMC-CTRL F/F0 1.00± 0.02, AMC-FLEC 0.87± 0.01, p<0.001). This reduction was absent in MI cells (MI-CTRL F/F0 1.11± 0.02, MI-FLEC 1.14± 0.02, p=0.34). The absence of a reduction in spark amplitude of the main population of sparks, together with appearance of a new macrospark population, may explain the proarrhythmic effects of flecainide treatment in patients following MI.
- © 2011 by American Heart Association, Inc.