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.).
Circ Arrhythm Electrophysiol. 2018 Mar;11(3):e005659. doi: 10.1161/CIRCEP.117.005659.
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).
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.
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.
与心房缺血/梗死相关的自发性心房颤动（AF）的机制尚不完全清楚。在这里，我们研究了左心房心肌梗死（LAMI）羊模型中自发性 AF 的机制。
通过结扎左前降支的心房分支来创建 LAMI。植入 ECG 环记录器以监测 AF 发作。在 7 只绵羊中，在 8 天观察期内体内给予丹曲林（一种兰尼碱受体阻滞剂）（LAMI-D，2.5mg/kg，IV，BID）。LAMI 动物在 8 天监测期间经历了许多自发性 AF 发作，丹曲林可抑制这些发作（LAMI，26.1±5.1；假手术，4.3±1.1；LAMI-D，2.8±0.8；每只羊的平均发作次数，<0.01）。光学映射显示源自缺血/正常区边界的自发性局灶放电（SFD）。SFD 是钙驱动的，频率依赖性的，并被异丙肾上腺素（0.03µmol/L，从 210±87 增加到 3816±1450，每只羊的 SFD 数）增强，但被丹曲林抑制（至 55.8±32.8，每只羊的 SFD 数，均值±SEM）。SFD 引发 AF 维持的折返转子，由缺血/正常区边界的明显传导延迟固定。缺血区心肌细胞中一氧化氮合酶-1（NOS1）蛋白表达减少，而 NADPH（烟酰胺腺嘌呤二核苷酸磷酸，还原型）氧化酶和黄嘌呤氧化酶活性以及活性氧（DCF [6-羧基-2'，7'-二氯二氢荧光素二乙酸酯]-荧光）增加。CaM（钙调蛋白）在缺血区异常增加 [H]ryanodine 与心脏 RyR2（兰尼碱受体）的结合。丹曲林恢复了 CaM 对 RyR2 的生理结合。
在绵羊中，心房缺血引起自发性 AF 发作，由引发折返的 SFD 引起。缺血区的硝基-氧化还原失衡与活性氧产生增加和 RyR2 对 CaM 的反应改变有关。丹曲林给药可使 CaM 反应正常化，防止 LAMI 相关 SFD 和 AF 发作。这些发现为缺血相关心房心律失常的机制提供了新的见解。
