Laboratory of Experimental Cardiology, Department of Cardiology, Leiden University Medical Center, P.O. Box 9600, Leiden 2300 RC, The Netherlands.
Cardiovasc Res. 2013 Jan 1;97(1):161-70. doi: 10.1093/cvr/cvs288. Epub 2012 Sep 12.
Sustained ventricular fibrillation (VF) is maintained by multiple stable rotors. Destabilization of sustained VF could be beneficial by affecting VF complexity (defined by the number of rotors). However, underlying mechanisms affecting VF stability are poorly understood. Therefore, the aim of this study was to correlate changes in arrhythmia complexity with changes in specific electrophysiological parameters, allowing a search for novel factors and underlying mechanisms affecting stability of sustained VF.
Neonatal rat ventricular cardiomyocyte monolayers and Langendorff-perfused adult rat hearts were exposed to increasing dosages of the gap junctional uncoupler 2-aminoethoxydiphenyl borate (2-APB) to induce arrhythmias. Ion channel blockers/openers were added to study effects on VF stability. Electrophysiological parameters were assessed by optical mapping and patch-clamp techniques. Arrhythmia complexity in cardiomyocyte cultures increased with increasing dosages of 2-APB (n > 38), leading to sustained VF: 0.0 ± 0.1 phase singularities/cm(2) in controls vs. 0.0 ± 0.1, 1.0 ± 0.9, 3.3 ± 3.2, 11.0 ± 10.1, and 54.3 ± 21.7 in 5, 10, 15, 20, and 25 µmol/L 2-APB, respectively. Arrhythmia complexity inversely correlated with wavelength. Lengthening of wavelength during fibrillation could only be induced by agents (BaCl(2)/BayK8644) increasing the action potential duration (APD) at maximal activation frequencies (minimal APD); 123 ± 32%/117 ± 24% of control. Minimal APD prolongation led to transient VF destabilization, shown by critical wavefront collision leading to rotor termination, followed by significant decreases in VF complexity and activation frequency (52%/37%). These key findings were reproduced ex vivo in rat hearts (n = 6 per group).
These results show that stability of sustained fibrillation is regulated by minimal APD. Minimal APD prolongation leads to transient destabilization of fibrillation, ultimately decreasing VF complexity, thereby providing novel insights into anti-fibrillatory mechanisms.
持续性室颤（VF）是由多个稳定的转子维持的。通过影响VF 复杂性（由转子数量定义）来破坏持续性 VF 的稳定性可能是有益的。然而，影响 VF 稳定性的潜在机制仍知之甚少。因此，本研究的目的是将心律失常复杂性的变化与特定电生理参数的变化相关联，从而寻找影响持续性 VF 稳定性的新因素和潜在机制。
将新生大鼠心室肌细胞单层和 Langendorff 灌注的成年大鼠心脏暴露于递增剂量的缝隙连接解偶联剂 2-氨基乙氧基二苯硼酸盐（2-APB）以诱导心律失常。加入离子通道阻滞剂/激动剂以研究其对 VF 稳定性的影响。通过光学映射和膜片钳技术评估电生理参数。在心肌细胞培养物中，随着 2-APB 剂量的增加，心律失常复杂性增加（n > 38），导致持续性 VF：在对照组中为 0.0 ± 0.1 相位奇点/cm2，而在 5、10、15、20 和 25 μmol/L 2-APB 中分别为 0.0 ± 0.1、1.0 ± 0.9、3.3 ± 3.2、11.0 ± 10.1 和 54.3 ± 21.7。心律失常复杂性与波长呈负相关。只有在药物（BaCl2/BayK8644）延长最大激活频率（最小 APD）下的动作电位时程（APD）时，才能诱导纤颤时波长的延长；分别为对照组的 123 ± 32%/117 ± 24%。最小 APD 延长导致 VF 短暂失稳，表现为临界波阵面碰撞导致转子终止，随后 VF 复杂性和激活频率显著降低（52%/37%）。这些关键发现均在大鼠心脏（每组 n = 6）中进行了体外重现。
这些结果表明，持续性纤颤的稳定性受最小 APD 调节。最小 APD 延长会导致纤颤的短暂失稳，最终降低 VF 复杂性，从而为抗纤颤机制提供新的见解。
