Mechanisms of enhanced beta-adrenergic reserve from cardiac resynchronization therapy.
Mechanisms of enhanced beta-adrenergic reserve from cardiac resynchronization therapy.
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DOI：
10.1161/circulationaha.108.774752
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发表时间：
2009-03-10
期刊：
影响因子：
37.8
通讯作者：
Kass DA
中科院分区：
文献类型：
--
作者：
Chakir K;Daya SK;Aiba T;Tunin RS;Dimaano VL;Abraham TP;Jaques-Robinson KM;Lai EW;Pacak K;Zhu WZ;Xiao RP;Tomaselli GF;Kass DA
心脏复律治疗（CRT）是第一个临床心力衰竭治疗，急性和慢性改善心室收缩功能，同时降低死亡率。CRT的机械影响是即时的，并有充分的记录，但其对肌细胞功能和肾上腺素能调节的慢性影响，可能有助于其持续的利益在很大程度上是未知的。我们使用了不同步心力衰竭犬模型（DHF;左束消融，心房快速起搏6周）和CRT（DHF 3周，随后3周双心室快速起搏），将两者与非失败对照组进行对比。与DHF相比，CRT恢复了收缩同步性并改善了收缩功能。肌细胞肌节缩短和钙瞬变显着抑制在休息和异丙肾上腺素刺激后DHF（前壁和侧壁）和CRT大幅改善。β1和β2刺激增强，伴随β1受体丰度增加，但结合亲和力无变化。CRT也增强腺苷酸环化酶活性超过DHF。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，CRT可逆转这种抑制作用。Gαi表达本身没有改变;然而，与DHF和对照组相比，CRT组Gαi信号负调节因子（特别是RGS 3）的表达独特地升高。CRT减弱DHF中升高的心肌儿茶酚胺，使水平恢复至对照水平。CRT改善静息和β-肾上腺素能刺激的肌细胞功能和钙处理，上调β1受体、腺苷酸环化酶活性，并抑制与新型RGS上调相关的Gi偶联信号。结果是更大的休息和交感神经储备，尽管减少心肌神经刺激，作为其净效益的组成部分。
Cardiac resynchronization therapy (CRT) is the first clinical heart failure treatment that both acutely and chronically improves chamber systolic function while reducing mortality. The mechanical impact of CRT is immediate and well documented, yet its chronic 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-wks) and CRT (DHF for 3 weeks, bi-ventricular tachypacing for subsequent 3-wks), contrasting both to non-failing controls. CRT restored contractile synchrony and improved systolic function compared to 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. β1 and β2 stimulation was enhanced, coupled to increased β1 receptor abundance but no change in binding affinity. CRT also augmented adenylate cyclase activity over DHF. Inhibitory G-protein (Gαi) suppression of β-adrenergic stimulation was greater in DHF and reversed by CRT. Gαi expression itself was unaltered; however, expression of negative regulators of Gαi signaling (particularly RGS3) rose uniquely with CRT over DHF and controls. CRT blunted elevated myocardial catecholamines in DHF, restoring levels towards control. CRT improves rest and β-adrenergic stimulated myocyte function and calcium handling, up-regulating β1 receptors, adenylate cyclase activity, and suppressing Gi-coupled signaling associated with novel RGS upregulation. The result is greater rest and sympathetic reserve despite reduced myocardial neuro-stimulation, as components underlying its net benefit.