Chakir Khalid, Daya Samantapudi K, Aiba Takeshi, Tunin Richard S, Dimaano Veronica L, Abraham Theodore P, Jaques-Robinson Kathryn M, Lai Edwin W, Pacak Karel, Zhu Wei-Zhong, Xiao Rui-ping, Tomaselli Gordon F, Kass David A
Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
Circulation. 2009 Mar 10;119(9):1231-40. doi: 10.1161/CIRCULATIONAHA.108.774752. Epub 2009 Feb 23.
Cardiac resynchronization therapy (CRT) is the first clinical heart failure treatment that improves chamber systolic function in both the short-term and long-term yet also reduces mortality. The mechanical impact of CRT is immediate and well documented, yet its long-term influences on myocyte function and adrenergic modulation that may contribute to its sustained benefits are largely unknown.
We used a canine model of dyssynchronous heart failure (DHF; left bundle ablation, atrial tachypacing for 6 weeks) and CRT (DHF for 3 weeks, biventricular tachypacing for subsequent 3 weeks), contrasting both to nonfailing controls. CRT restored contractile synchrony and improved systolic function compared with DHF. Myocyte sarcomere shortening and calcium transients were markedly depressed at rest and after isoproterenol stimulation in DHF (both anterior and lateral walls), and CRT substantially improved both. In addition, beta(1) and beta(2) stimulation was enhanced, coupled to increased beta(1) receptor abundance but no change in binding affinity. CRT also augmented adenylate cyclase activity over DHF. Inhibitory G-protein (Galpha(i)) suppression of beta-adrenergic stimulation was greater in DHF and reversed by CRT. Galpha(i) expression itself was unaltered; however, expression of negative regulators of Galpha(i) signaling (particularly RGS3) rose uniquely with CRT over DHF and controls. CRT blunted elevated myocardial catecholamines in DHF, restoring levels toward control.
CRT improves rest and beta-adrenergic-stimulated myocyte function and calcium handling, upregulating beta(1) receptors and adenylate cyclase activity and suppressing G(i)-coupled signaling associated with novel RGS upregulation. The result is greater rest and sympathetic reserve despite reduced myocardial neurostimulation as components underlying its net benefit.
心脏再同步治疗（CRT）是首个能在短期和长期内改善心室收缩功能且降低死亡率的临床心力衰竭治疗方法。CRT的机械作用是即时的且有充分记录，但其对心肌细胞功能和肾上腺素能调节的长期影响（可能有助于其持续获益）在很大程度上尚不清楚。
我们使用了犬类不同步心力衰竭模型（DHF；左束支消融，心房快速起搏6周）和CRT模型（DHF 3周，随后双心室快速起搏3周），并与非衰竭对照组进行对比。与DHF相比，CRT恢复了收缩同步性并改善了收缩功能。在DHF（前壁和侧壁）中，静息时以及异丙肾上腺素刺激后，心肌细胞肌节缩短和钙瞬变均明显降低，而CRT显著改善了这两者。此外，β₁和β₂刺激增强，伴有β₁受体丰度增加，但结合亲和力无变化。与DHF相比，CRT还增强了腺苷酸环化酶活性。DHF中抑制性G蛋白（Gαi）对β肾上腺素能刺激的抑制作用更强，而CRT可使其逆转。Gαi表达本身未改变；然而，与DHF和对照组相比，CRT使Gαi信号负调节因子（特别是RGS3）的表达独特性升高。CRT使DHF中升高的心肌儿茶酚胺水平降低，恢复至对照水平。
CRT改善静息和β肾上腺素能刺激下的心肌细胞功能及钙处理过程，上调β₁受体和腺苷酸环化酶活性，并抑制与新型RGS上调相关的G蛋白偶联信号。结果是尽管心肌神经刺激减少，但静息和交感神经储备增加，这是其净获益的潜在组成部分。
