Yeh Yung-Hsin, Burstein Brett, Qi Xiao Yan, Sakabe Masao, Chartier Denis, Comtois Philippe, Wang Zhiguo, Kuo Chi-Tai, Nattel Stanley
Department of Medicine, Montreal Heart Institute Research Center and Université de Montréal, Montreal, Quebec, Canada.
Circulation. 2009 Mar 31;119(12):1576-85. doi: 10.1161/CIRCULATIONAHA.108.789677. Epub 2009 Mar 16.
Sinoatrial node (SAN) dysfunction is frequently associated with atrial tachyarrhythmias (ATs). Abnormalities in SAN pacemaker function after termination of ATs can cause syncope and require pacemaker implantation, but underlying mechanisms remain poorly understood. This study examined the hypothesis that ATs impair SAN function by altering ion channel expression.
SAN tissues were obtained from 28 control dogs and 31 dogs with 7-day atrial tachypacing (400 bpm). Ionic currents were measured from single SAN cells with whole-cell patch-clamp techniques. Atrial tachypacing increased SAN recovery time in vivo by approximately 70% (P<0.01), a change which reflects impaired SAN function. In dogs that underwent atrial tachypacing, SAN mRNA expression (real-time reverse-transcription polymerase chain reaction) was reduced for hyperpolarization-activated cyclic nucleotide-gated subunits (HCN2 and HCN4) by >50% (P<0.01) and for the beta-subunit minK by approximately 42% (P<0.05). SAN transcript expression for the rapid delayed-rectifier (I(Kr)) alpha-subunit ERG, the slow delayed-rectifier (I(Ks)) alpha-subunit KvLQT1, the beta-subunit MiRP1, the L-type (I(CaL)) and T-type (I(CaT)) Ca2+-current subunits Cav1.2 and Cav3.1, and the gap-junction subunit connexin 43 (were unaffected by atrial tachypacing. Atrial tachypacing reduced densities of the HCN-related funny current (I(f)) and I(Ks) by approximately 48% (P<0.001) and approximately 34% (P<0.01), respectively, with no change in voltage dependence or kinetics. I(Kr), I(CaL), and I(CaT) were unaffected. SAN cells lacked Ba2+-sensitive inward-rectifier currents, irrespective of AT. SAN action potential simulations that incorporated AT-induced alterations in I(f) accounted for slowing of periodicity, with no additional contribution from changes in I(Ks).
AT downregulates SAN HCN2/4 and minK subunit expression, along with the corresponding currents I(f) and I(Ks). Tachycardia-induced remodeling of SAN ion channel expression, particularly for the "pacemaker" subunit I(f), may contribute to the clinically significant association between SAN dysfunction and supraventricular tachyarrhythmias.
窦房结（SAN）功能障碍常与房性快速心律失常（ATs）相关。ATs终止后SAN起搏功能异常可导致晕厥，需要植入起搏器，但潜在机制仍知之甚少。本研究检验了ATs通过改变离子通道表达损害SAN功能这一假说。
从28只对照犬和31只接受7天房性快速起搏（400次/分钟）的犬获取SAN组织。采用全细胞膜片钳技术测量单个SAN细胞的离子电流。房性快速起搏使体内SAN恢复时间增加约70%（P<0.01），这一变化反映了SAN功能受损。在接受房性快速起搏的犬中，超极化激活环核苷酸门控亚基（HCN2和HCN4）的SAN mRNA表达（实时逆转录聚合酶链反应）降低>50%（P<0.01），而微小K（minK）β亚基的表达降低约42%（P<0.05）。快速延迟整流钾电流（I(Kr)）α亚基ERG、缓慢延迟整流钾电流（I(Ks)）α亚基KvLQT1、β亚基MiRP1、L型钙电流（I(CaL)）和T型钙电流（I(CaT)）的钙电流亚基Cav1.2和Cav3.1以及缝隙连接亚基连接蛋白43的SAN转录表达不受房性快速起搏影响。房性快速起搏使HCN相关的起搏电流（I(f)）和I(Ks)密度分别降低约48%（P<0.001）和约34%（P<0.01），电压依赖性或动力学无变化。I(Kr)、I(CaL)和I(CaT)不受影响。无论是否存在AT，SAN细胞均缺乏Ba2+敏感的内向整流电流。纳入AT诱导的I(f)改变的SAN动作电位模拟解释了周期减慢，I(Ks)变化无额外作用。
AT下调SAN的HCN2/4和minK亚基表达以及相应的电流I(f)和I(Ks)。心动过速诱导的SAN离子通道表达重塑，特别是“起搏”亚基I(f)，可能导致SAN功能障碍与室上性快速心律失常之间临床上的重要关联。
