Anti-arrhythmic Effects of I Na, I Kr, and Combined I Kr–I CaL Blockade in an Experimental Model of Acute Stretch-Related Atrial Fibrillation

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Abstract
Atrial dilatation is commonly associated with atrial fibrillation (AF), but the electrophysiological mechanisms and the implications for anti-arrhythmic therapy are poorly understood. In a model of acute stretch-related AF in isolated rabbit hearts, we evaluated the electrophysiological effects of three different anti-arrhythmic drugs: dofetilide, flecainide and BRL-32872 (associating I Kr and I CaL blocking properties). After 30 min of sustained stretch-related AF, we perfused BRL 10–7 M, BRL 3.10–7 M, BRL 10–6 M, flecainide 2.4 10–6 M and dofetilide 10–7 M and iteratively measured atrial effective refractory periods (ERPs), AF inducibility and AF cycle length (AFCL) 15, 30 and 60 min after drug perfusion, respectively. After a significant shortening of the ERPs by acute atrial stretch in the five groups individually (p < 0.001, stretch vs baseline for each group individually), drug perfusion led to a strong lengthening of AFCL, a very significant prolongation of ERPs (p < 0.001 vs stretch) and a reduction of AF inducibility (p < 0.01 vs control group) for each of the five experimental groups. The relative ERP increase was comparable in all groups, whereas a significantly lower AF inducibility was observed in the BRL 10–6 M group (p < 0.05 vs other BRL concentrations). In a model of acute stretch-related AF, dofetilide, flecainide and BRL-32872 terminated AF and prevented its immediate reinduction after having comparatively prolonged AFCL and ERPs. These comparative results suggest that those drugs are equally efficacious, albeit with different mechanisms, in the setting of acute atrial stretch.