Circ Arrhythm Electrophysiol 2018 03;11(3):e005659
From the Division of Cardiovascular Medicine, Department of Internal Medicine, Columbia University, New York, NY (U.M.R.A.); Division of Cardiovascular Medicine, Department of Internal Medicine, Center for Arrhythmia Research (J.J.H., C.R.V., K.K., R.R.-M., J.A., H.H.V.) and Department of Surgery (A.R.-P.), University of Michigan, Ann Arbor; Medical Device Development and Regulation Research Center, The University of Tokyo, Japan (M.Y.); Department of Cardiology, Brown University, Providence, RI (A.C., J.K.); Department of Medicine and Research Center, Montreal Heart Institute, Université de Montréal, Québec (S.N.); Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada (S.N.); and Institute of Pharmacology, West German Heart and Vascular Centre, University Duisburg-Essen (S.N.).
Background: The mechanisms underlying spontaneous atrial fibrillation (AF) associated with atrial ischemia/infarction are incompletely elucidated. Here, we investigate the mechanisms underlying spontaneous AF in an ovine model of left atrial myocardial infarction (LAMI).
Methods And Results: LAMI was created by ligating the atrial branch of the left anterior descending coronary artery. ECG loop recorders were implanted to monitor AF episodes. In 7 sheep, dantrolene-a ryanodine receptor blocker-was administered in vivo during the 8-day observation period (LAMI-D, 2.5 mg/kg, IV, BID). LAMI animals experienced numerous spontaneous AF episodes during the 8-day monitoring period that were suppressed by dantrolene (LAMI, 26.1±5.1; sham, 4.3±1.1; LAMI-D, 2.8±0.8; mean±SEM episodes per sheep, <0.01). Optical mapping showed spontaneous focal discharges (SFDs) originating from the ischemic/normal-zone border. SFDs were calcium driven, rate dependent, and enhanced by isoproterenol (0.03 µmol/L, from 210±87 to 3816±1450, SFDs per sheep) but suppressed by dantrolene (to 55.8±32.8, SFDs per sheep, mean±SEM). SFDs initiated AF-maintaining reentrant rotors anchored by marked conduction delays at the ischemic/normal-zone border. NOS1 (NO synthase-1) protein expression decreased in ischemic zone myocytes, whereas NADPH (nicotinamide adenine dinucleotide phosphate, reduced form) oxidase and xanthine oxidase enzyme activities and reactive oxygen species (DCF [6-carboxy-2',7'-dichlorodihydrofluorescein diacetate]-fluorescence) increased. CaM (calmodulin) aberrantly increased [H]ryanodine binding to cardiac RyR2 (ryanodine receptors) in the ischemic zone. Dantrolene restored the physiological binding of CaM to RyR2.
Conclusions: Atrial ischemia causes spontaneous AF episodes in sheep, caused by SFDs that initiate reentry. Nitroso-redox imbalance in the ischemic zone is associated with intense reactive oxygen species production and altered RyR2 responses to CaM. Dantrolene administration normalizes the CaM response, prevents LAMI-related SFDs, and AF initiation. These findings provide novel insights into the mechanisms underlying ischemia-related atrial arrhythmias.