Basic/Translational Science -> Intact Heart Electrophysiology (includes Pharmacology and Optical Mapping) D-PO01 - Featured Poster Session (ID 11) Poster

D-PO01-204 - Antiarrhythmic Effect Of Ranolazine In Combination With Selective Ncx-inhibition In An Experimental Model Of Atrial Fibrillation (ID 143)

Disclosure
 G. Frommeyer: Nothing relevant to disclose.

Abstract

Background: Previous studies showed an antiarrhythmic effect of ranolazine in clinical and experimental studies.
Objective: The aim of this study was to investigate the effects of a combination of ranolazine with different selective NCX-inhibitors in an experimental model of atrial fibrillation (AF).
Methods: 18 rabbit hearts were retrogradely perfused. Left and right atrial catheters were used to record monophasic action potentials. Hearts were paced at three different cycle lengths to assess atrial action potential duration (aAPD90), atrial effective refractory period (aERP) and atrial post-repolarization refractoriness (aPRR). Vulnerability to AF was tested by a standardized protocol employing burst pacing. After generating baseline data, the hearts were perfused with a combination of acetylcholine (ACh, 1µM) and isoproterenol (Iso, 1µM) to increase occurrence of AF. Afterwards, the hearts were assigned to two groups and additionally perfused with a combination of 10 µM ranolazine and 1 µM of the selective NCX-inhibitor ORM-10103 (group 1: Rano-ORM) or 10 µM ranolazine and 1 µM of another NCX-inhibitor, SEA0400 (group 2: Rano-SEA).
Results: Infusion of ACh/Iso led to a shortening of aAPD90 (group 1/2: -27.2ms/ -24.5ms p<0.05), aERP (-29.2ms/ -35.6ms p<0.05), aPRR (-12.2ms/ -13.7ms p=ns) and the occurrence of AF-Episodes was significantly increased (group 1: baseline 6 episodes to 34 episodes under ACh/Iso p<0.05, group 2: baseline 7 episodes to 26 episodes under ACh/Iso p<0.05). Additional perfusion with ranolazine and ORM-10103 did not alter aAPD90 (-0,47ms) while effective refractory periods (+21.4ms, p<0.05) and aPRR (+43ms, p<0.05) were significantly prolonged and AF episodes were effectively reduced to 15 episodes (p<0.05). In group 2, Rano-SEA led to a slight decrease in aAPD90 (-9.5ms) while aERP (+13.3ms, p<0.05) and aPRR (+19.8ms, p<0.05) were prolonged. The occurrence of AF episodes was reduced to 15 episodes (p=0.1).
Conclusion: Atrial repolarization was not significantly changed with either drug combination. However, both combinations prolonged aERP and aPRR and thereby suppressed induction of AF. Combining novel cellular targets may therefore lead to new potentially interesting options for antiarrythmic AF therapy.
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