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oai:repisalud.isciii.es:20.500.12105/99252024-09-27T08:02:11Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605

00925njm 22002777a 4500 dc Ramirez, Rafael J author Takemoto, Yoshio author Martins, Raphaël P author Filgueiras-Rama, David author Ennis, Steven R author Mironov, Sergey author Bhushal, Sandesh author Deo, Makarand author Rajamani, Sridharan author Berenfeld, Omer author Belardinelli, Luiz author Jalife, Jose author Pandit, Sandeep V author 2019-10 BACKGROUND: Ranolazine inhibits Na+ current (INa), but whether it can convert atrial fibrillation (AF) to sinus rhythm remains unclear. We investigated antiarrhythmic mechanisms of ranolazine in sheep models of paroxysmal (PxAF) and persistent AF (PsAF). METHODS: PxAF was maintained during acute stretch (N=8), and PsAF was induced by long-term atrial tachypacing (N=9). Isolated, Langendorff-perfused sheep hearts were optically mapped. RESULTS: In PxAF ranolazine (10 μmol/L) reduced dominant frequency from 8.3±0.4 to 6.2±0.5 Hz (P<0.01) before converting to sinus rhythm, decreased singularity point density from 0.070±0.007 to 0.039±0.005 cm-2 s-1 (P<0.001) in left atrial epicardium (LAepi), and prolonged AF cycle length (AFCL); rotor duration, tip trajectory, and variance of AFCL were unaltered. In PsAF, ranolazine reduced dominant frequency (8.3±0.5 to 6.5±0.4 Hz; P<0.01), prolonged AFCL, increased the variance of AFCL, had no effect on singularity point density (0.048±0.011 to 0.042±0.016 cm-2 s-1; P=ns) and failed to convert AF to sinus rhythm. Doubling the ranolazine concentration (20 μmol/L) or supplementing with dofetilide (1 μmol/L) failed to convert PsAF to sinus rhythm. In computer simulations of rotors, reducing INa decreased dominant frequency, increased tip meandering and produced vortex shedding on wave interaction with unexcitable regions. CONCLUSIONS: PxAF and PsAF respond differently to ranolazine. Cardioversion in the former can be attributed partly to decreased dominant frequency and singularity point density, and prolongation of AFCL. In the latter, increased dispersion of AFCL and likely vortex shedding contributes to rotor formation, compensating for any rotor loss, and may underlie the inefficacy of ranolazine to terminate PsAF. Circ Arrhythm Electrophysiol. 2019; 12(10):e005557 10.1161/CIRCEP.117.005557 1941-3084 1941-3149 Circulation. Arrhythmia and electrophysiology 31594392 http://hdl.handle.net/20.500.12105/9925 Antiarrhythmic drugs Atrial fibrillation Catheter ablation Dofetilide Dominant frequency Ranolazine Rotors Mechanisms by Which Ranolazine Terminates Paroxysmal but Not Persistent Atrial Fibrillation