Schotten Ulrich, Neuberger Hans Ruprecht, Allessie Maurits A
Department of Physiology, University of Maastricht, P.O. Box 616, 6200, Maastricht, The Netherlands.
Prog Biophys Mol Biol. 2003 May-Jul;82(1-3):151-62. doi: 10.1016/s0079-6107(03)00012-9.
Numerous clinical investigations as well as recent experimental studies have demonstrated that atrial fibrillation (AF) is a progressive arrhythmia. With time paroxysmal AF becomes persistent and the success rate of cardioversion of persistent AF declines. Electrical remodeling (shortening of atrial refractoriness) develops within the first days of AF and contributes to the increase in stability of the arrhythmia. However, 'domestication of AF' must also depend on other mechanisms since the persistence of AF continues to increase after electrical remodeling has been completed. During the first days of AF in the goat, electrical and contractile remodeling (loss of atrial contractility) followed exactly the same time course suggesting that they are due to the same underlying mechanism. Contractile remodeling not only enhances the risk of atrial thrombus formation, it also enhances atrial dilatation by increasing the compliance of the fibrillating atrium. In goats with chronic AV-block atrial dilatation increased the duration of artificially induced AF-episodes but did not change atrial refractoriness or the AF cycle length. When AF was maintained a couple of days in these animals, a shortening of the atrial refractory period did occur. However, the AF cycle length did not decrease. Long lasting episodes of AF with a long AF cycle length and a wide excitable gap suggest that in this model AF is mainly promoted by conduction disturbances. Chronic atrial stretch induces activation of numerous signaling pathways leading to cellular hypertrophy, fibroblast proliferation and tissue fibrosis. The resulting electroanatomical substrate in dilated atria is characterized by increased non-uniform anisotropy and macroscopic slowing of conduction, promoting reentrant circuits in the atria. Prevention of electroanatomical remodeling by blockade of pathways activated by chronic atrial stretch therefore provides a promising strategy for future treatment of AF.
大量临床研究以及近期的实验研究均表明，心房颤动（AF）是一种进行性心律失常。随着时间推移，阵发性房颤会转变为持续性房颤，且持续性房颤转复的成功率会下降。电重构（心房不应期缩短）在房颤发生后的最初几天内就会出现，并促使心律失常的稳定性增加。然而，“房颤的驯化”肯定还依赖于其他机制，因为在电重构完成后房颤的持续性仍在增加。在山羊房颤发生的最初几天，电重构和收缩性重构（心房收缩力丧失）遵循完全相同的时间进程，这表明它们是由相同的潜在机制所致。收缩性重构不仅增加了心房血栓形成的风险，还通过增加颤动心房的顺应性促进心房扩张。在患有慢性房室传导阻滞的山羊中，心房扩张增加了人工诱发房颤发作的持续时间，但并未改变心房不应期或房颤周期长度。当在这些动物中维持房颤数天时，心房不应期确实出现了缩短。然而，房颤周期长度并未缩短。房颤周期长度长且可兴奋间隙宽的持续性房颤发作表明，在该模型中房颤主要由传导障碍所促发。慢性心房牵张会诱导众多信号通路激活，导致细胞肥大、成纤维细胞增殖和组织纤维化。扩张心房中由此产生的电解剖学基质的特征是各向异性增加且不均匀，以及宏观传导减慢，从而促进心房内的折返环形成。因此，通过阻断慢性心房牵张激活的信号通路来预防电解剖学重构，为未来房颤治疗提供了一种有前景的策略。
