Abstract 2667: Effects of Ranolazine in a Goat Model of Lone Atrial Fibrillation
BACKGROUND: In MERLIN TIMI-36, ranolazine (RAN) reduced the indicidence of new onset AF (Scirica et al, Circ 2007;116:1647). At therapeutic concentrations, RAN inhibits the persistent sodium current. At higher concentrations, RAN also inhibits IKs, IKr and late ICaL. We investigated the effects RAN on cardiac electrophysiology in a goat model of AF. In this model, AF itself leads to a progressive shortening of the effective refractory period (ERP) and a gradual increase in AF stability.
METHODS: Arrays of atrial epicardial electrodes were implanted in 7 Dutch milk goats. After recovery, experiments were performed at baseline and after 2 and 14 days of artificially maintained AF. At these time points, RAN was infused intravenously for 1 hour to result in plasma concentrations of 4, 8 and 16 uM. ECG parameters, ERP, conduction velocity (CV), AF cycle length (AFCL) and AF episode duration (AFdur) were determined.
RESULTS: The main parameters are summarized in the table⇓. At baseline and after 2 days of AF, 8 and 16 uM RAN significantly prolonged the PQ and RR intervals. After 2 days of AF, 8 and 16 uM RAN also significantly prolonged the QT interval and shortened the AFdur. After 14 days of AF, all goats were in persistent AF. At this time, 8 and 16 uM RAN significantly prolonged the AFCL, from 103±3 during solvent infusion to 109±3, 119±5* and 139±9* at 4, 8 and 16 uM RAN, respectively. However, only one out of 7 goats cardioverted during infusion of 16 uM RAN.
CONCLUSION: The lowest concentration of ranolazine tested here, which mainly inhibits the late sodium current, did not significantly affect the atrial electrophysiological parameters assessed in this study. Higher doses of ranolazine significantly reduced CV, prolonged ERP and AFCL, and shortened AF episode duration. In the goat model of AF the antiarrhythmic effect appears to be due to action potential prolongation rather than due to late sodium current blockade.