Abstract 16897: Antiproliferative Treatment of Endogenous Myofibroblasts Prevents Spontaneous Reentrant Tachyarrhythmias in Rat Myocardial Cultures by Limiting Myofibroblast-Induced Depolarization
Background: Although cardiac fibrosis is associated with increased incidence of cardiac arrhythmias, the underlying proarrhythmic mechanisms remain incompletely understood and antiarrhythmic therapies are still suboptimal.
Objective: To test the hypothesis that myofibroblasts (MFB) proliferation leads to tachyarrhythmias by altering the excitability of cardiomyocytes (CMCs), and that therefore inhibition of MFB proliferation would lower the incidence of such arrhythmias.
Methods&Results: Endogenous MFBs present in neonatal rat CMC cultures proliferated freely, or under control of different dosages of antiproliferative agents (mitomycin-C and paclitaxel). At day 4 and 9, arrhythmogeneity of these cultures was studied by optical and multi-electrode mapping. Cultures were also studied for protein expression and electrophysiological properties. MFB proliferation slowed conduction from 15.3±3.5 cm/s (day 4) to 8.8±0.3 cm/s (day 9) (n=75,p<0.01) and increased ectopic activity, while MFB numbers increased to 37.4±1.7% and 62.0±2%. At day 9, a high percentage (81.3%) of these cultures showed sustained spontaneous reentrant arrhythmias. However, only 2.6% of the mitomycin-C treated cultures (n=76,p<0.0001) showed tachyarrhythmias. Arrhythmia incidence was drug-dose dependent and strongly related to MFB proliferation. Comparable results were found for paclitaxel. CMCs were more depolarized in cultures with ongoing MFB proliferation and only L-type Ca2+ channel-blockade terminated 100% of reentrant arrhythmias, in contrast to Na+-blockade (36%,n=12).
Conclusions: Proliferation of MFBs in myocardial cultures gives rise to spontaneous, sustained reentrant tachyarrhythmias. However, antiproliferative treatment of such cultures prevents the occurrence of arrhythmias by limiting MFB-induced depolarization, conduction slowing and ectopic activity. This study could prove a rationale for a new treatment option for cardiac arrhythmias.
- © 2010 by American Heart Association, Inc.