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

Abstract

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 (Pϭ0.003) and increased AF duration (Pϭ0.008), with AF lasting Ͼ3 hours in all 6-week ATP animals. Rotigaptide increased conduction velocity in ATP dogs slightly but significantly (Pϭ0.04) 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 (Pϭ0.046) 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 ischemiainduced 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. (Circulation. 2007;115:310-318.)

Connexin40 nonsense mutation in familial atrial fibrillation

“…In a canine sterile pericarditis model, the gap junction conduction-enhancing anti-arrhythmic peptide, Gap-134, improved conduction and reduced AF (44). Similarly, in a canine model of AF due to myocardial ischemia, the administration of ZP123, a gap junction conductanceimproving modifier, prevented ischemia-induced slow conduction, thus lessening AF occurrence and reducing AF duration (45).…”

Omega-3 Polyunsaturated Fatty Acids Prevent Atrial Fibrillation Associated With Heart Failure but Not Atrial Tachycardia Remodeling

“…45,46 Differing effects of PUFAs in AF of different mechanisms may contribute to the variable results reported in previous epidemiological studies of the effects of PUFA. 8 -10 This notion underscores the need for careful planning and evaluation of clinical trials in AF with respect to the homogeneity of the target population.…”

Prevalence and spectrum of GJA5 mutations associated with lone atrial fibrillation

“…In a canine sterile pericarditis model, the gap junction conduction-enhancing antiarrhythmic peptide, Gap-134, improved conduction and reduced AF (59). Similarly, in a dog model of AF due to myocardial ischemia, administration of ZP123, a gap junction conductance-improving modifier, prevented ischemia-induced conduction slowing and reduced AF duration (60). Notably, in experimental swine, gene therapy with adenovirus expressing GJA5 improved cardiac conduction and reduced AF, demonstrating the viability of gene therapy for the prevention of atrial arrhythmias (61).…”