Abstract 13962: Fibrosis is the target for Slow Conduction Related Arrhythmias
Introduction: Conduction slowing is an important risk factor for reentry based arrhythmias. During arrhythmogenic remodeling of the diseased heart, the levels of sodium channels (Nav1.5) and gap junction channels (Cx43) are decreased, while the levels of fibrosis are increased. We have used several mouse models to explore individual and combined clinically relevant changes in these conduction parameters to search for the dominant and therapeutically important target of slow conduction related ventricular arrhythmias.
Methods and Results: Mice expressing only half the amount of Cx43 or Nav1.5 or with increased levels of fibrosis, had near normal conduction velocities and were not susceptible to arrhythmias. Mice with a combined 50% reduction of both Cx43 and Nav1.5 had moderate conduction slowing (up to 20%), but were not arrhythmogenic. Mice with 50% Nav1.5 expression, combined with increased fibrosis showed severe conduction slowing up to 50%, but no arrhythmias. When reduced Cx43 expression was combined with increased fibrosis, 60% of the mice were susceptible to reentrant arrhythmias. These data indicate that enhanced fibrosis, combined with other impairments lead to slow conduction and arrhythmias. To establish whether enhanced fibrosis is a therapeutic target we applied a mouse model of extreme aging (22 months), in which all three factors are impaired (Cx43 and Nav1.5 are reduced and fibrosis is increased). These senescent mice received inhibitors of the renin angiotensin aldosterone system (Losartan and Eplerenone), which have a known anti-fibrotic effect. Mice were treated starting at 52 weeks for 36 weeks. Of the untreated control mice, 52% were susceptible to reentrant arrhythmias. Threatment with the anti-fibrotic drugs reduced the amount of fibrosis by half and arrhythmogeneity by 70%.
Conclusion: Enhanced fibrosis is the dominant factor for slow conduction related arrhythmias in the background of other impairments. Pharmacologic inhibition of fibrosis proved a successful anti-arrhythmic strategy.
- © 2010 by American Heart Association, Inc.