Stengl Milan, Ramakers Christian, Donker Dirk W, Nabar Ashish, Rybin Andrew V, Spätjens Roel L H M G, van der Nagel Theo, Wodzig Will K W H, Sipido Karin R, Antoons Gudrun, Moorman Antoon F M, Vos Marc A, Volders Paul G A
Department of Cardiology, Cardiovascular Research Institute Maastricht, Maastricht University and Academic Hospital Maastricht, PO Box 5800, 6202 AZ, Maastricht, The Netherlands.
Cardiovasc Res. 2006 Oct 1;72(1):90-100. doi: 10.1016/j.cardiores.2006.07.015. Epub 2006 Jul 25.
Electrical remodeling in cardiac hypertrophy often involves the downregulation of K+ currents, including beta-adrenergic (beta-A)-sensitive IKs. Temporal patterns of ion-channel downregulation are poorly resolved. In dogs with complete atrioventricular block (AVB), we examined (1) the time course of molecular alterations underlying IKs downregulation from acute to chronic hypertrophy; and (2) concomitant changing responses of repolarization to beta-adrenergic receptor (beta-AR) stimulation.
Serial left-ventricular (LV) biopsies were collected from anesthetized dogs during sinus rhythm (SR; control) and at 3, 7 and 30 days of AVB. KCNQ1 mRNA and protein decreased within 3 days (protein expression 58 +/- 10% of control), remaining low thereafter. beta1-AR mRNA and protein decreased more gradually to 53 +/- 8% at 7 days. In chronic-AVB LV myocytes, IKs -tail density was reduced: 1.4 +/- 0.3 pA/pF versus 2.6 +/- 0.4 pA/pF in controls. beta-A enhancement of IKs was reduced. Isoproterenol shortened action-potential duration in control cells, while causing heterogeneous repolarization responses in chronic AVB. beta-A early afterdepolarizations were induced in 4 of 13 chronic-AVB cells, but not in controls. In intact conscious dogs, isoproterenol shortened QTc at SR (by -8 +/- 3% from 295 ms), left it unaltered at 3 days AVB (+1 +/- 3% from 325 ms) and prolonged QTc at 30 days (+6 +/- 3% from 365 ms).
Profound decrease of KCNQ1 occurs within days after AVB induction and is followed by a more gradual decrease of beta1-AR expression. Downregulation and blunted beta-A activation of IKs contribute to the loss of beta-A-induced shortening of ventricular repolarization, favoring proarrhythmia. Provocation testing with isoproterenol identifies repolarization instability based on acquired channelopathy.
心脏肥大中的电重构常涉及钾离子电流的下调，包括对β-肾上腺素能（β-A）敏感的IKs。离子通道下调的时间模式尚未完全明确。在完全性房室传导阻滞（AVB）的犬中，我们研究了：（1）从急性到慢性肥大过程中IKs下调所涉及分子改变的时间进程；（2）复极化对β-肾上腺素能受体（β-AR）刺激的伴随变化反应。
在窦性心律（SR；对照）以及AVB后3天、7天和30天时，从麻醉犬身上采集系列左心室（LV）活检组织。KCNQ1 mRNA和蛋白在3天内下降（蛋白表达为对照的58±10%），此后一直维持在低水平。β1-AR mRNA和蛋白下降更为缓慢，在7天时降至53±8%。在慢性AVB的LV心肌细胞中，IKs尾电流密度降低：对照细胞为2.6±0.4 pA/pF，慢性AVB细胞为1.4±0.3 pA/pF。β-A对IKs的增强作用减弱。异丙肾上腺素可缩短对照细胞的动作电位时程，而在慢性AVB中则引起复极化反应不均一。13个慢性AVB细胞中有4个诱导出β-A早期后去极化，而对照细胞未出现。在清醒的完整犬中，异丙肾上腺素在SR时缩短QTc（从295 ms缩短-8±3%），在AVB 3天时QTc无变化（从325 ms增加1±3%），在30天时延长QTc（从365 ms增加6±3%）。
AVB诱导后数天内KCNQ1显著下降，随后β1-AR表达逐渐下降。IKs的下调和β-A激活减弱导致β-A诱导的心室复极化缩短丧失，有利于心律失常的发生。用异丙肾上腺素进行激发试验可根据获得性通道病识别复极化不稳定性。
