Published Online
on January 15, 2007

A more recent version of this article appeared on January 23, 2007

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Submitted on September 19, 2006
Accepted on November 10, 2006

Model-Dependent Effects of the Gap Junction Conduction-Enhancing Antiarrhythmic Peptide Rotigaptide (ZP123) on Experimental Atrial Fibrillation in Dogs

Akiko Shiroshita-Takeshita MD, Masao Sakabe MD, Ketil Haugan MD, James K. Hennan PhD, and Stanley Nattel MD^*

From the Department of Medicine and Research Center (A.S.-T., M.S., S.N.), Montreal Heart Institute and University of Montreal, Montreal, Quebec, Canada; Zealand Pharma A/S (K.H.), Glostrup, Denmark; and Wyeth Research (J.K.H.), Philadelphia, Pa.

^* To whom correspondence should be addressed. E-mail: stanley.nattel{at}icm-mhi.umontreal.ca.

Background--Abnormal intercellular communication caused by connexin dysfunction may be involved in atrial fibrillation (AF). The present study assessed the effect of the gap junctional conduction-enhancing peptide rotigaptide on AF maintenance in substrates that result from congestive heart failure induced by 2-week ventricular tachypacing (240 bpm), atrial tachypacing (ATP; 400 bpm for 3 to 6 weeks), and isolated atrial myocardial ischemia.

Methods and Results--Electrophysiological study and epicardial mapping were performed before and after rotigaptide administration in dogs with ATP and congestive heart failure, as well as in similarly instrumented sham dogs that were not tachypaced. For atrial myocardial ischemia, dogs administered rotigaptide before myocardial ischemia were compared with no-drug myocardial ischemia controls. ATP significantly shortened the atrial effective refractory period (P=0.003) and increased AF duration (P=0.008), with AF lasting >3 hours in all 6-week ATP animals. Rotigaptide increased conduction velocity in ATP dogs slightly but significantly (P=0.04) and did not affect the effective refractory period, AF duration, or atrial vulnerability. In dogs with congestive heart failure, rotigaptide also slightly increased conduction velocity (P=0.046) but failed to prevent AF promotion. Rotigaptide had no statistically significant effects in sham dogs. Myocardial ischemia alone increased AF duration and impaired conduction (based on conduction velocity across the ischemic border and indices of conduction heterogeneity). Rotigaptide prevented myocardial ischemia-induced conduction slowing and AF duration increases.

Conclusions--Rotigaptide improves conduction in various AF models but suppresses AF only for the acute ischemia substrate. These results define the atrial antiarrhythmic profile of a mechanistically novel antiarrhythmic drug and suggest that gap junction dysfunction may be more important in ischemic AF than in ATP remodeling or congestive heart failure substrates.

Key words: antiarrhythmia agents • electrophysiology • ion channels • conduction • electrocardiography • ischemia

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