Enhanced transmural fiber rotation and connexin 43 heterogeneity are associated with an increased upper limit of vulnerability in a Transgenic rabbit model of human hypertrophic cardiomyopathy
Enhanced transmural fiber rotation and connexin 43 heterogeneity are associated with an increased upper limit of vulnerability in a Transgenic rabbit model of human hypertrophic cardiomyopathy
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DOI：
10.1161/circresaha.107.161240
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发表时间：
2007-11-09
影响因子：
20.1
通讯作者：
Efimov, Igor R.
中科院分区：
文献类型：
--
作者：
Ripplinger, Crystal M.;Li, Wenwen;Efimov, Igor R.
人类肥厚型心肌病，以心肌肥大和心肌细胞紊乱为特征，是年轻人心脏性猝死的最常见原因。肥厚型心肌病常由肌节基因突变引起。我们试图确定心律失常的倾向和潜在的机制，导致心律失常的转基因（TG）兔模型（β-肌球蛋白重链-Q403）的人肥厚型心肌病。光学映射来自TG（n = 6）和野生型（WT）兔（n = 6）的Langendorff灌注心脏。脆弱性的上限和下限，动作电位时程（APD）恢复，和传导速度进行了测量。使用扩散张量MRI测定透壁纤维角位移。免疫组化法检测连接蛋白43的跨壁分布。TG心脏的易损性上限显著高于WT心脏（13.3 +/- 2.1 vs 7.4 +/- 2.3 V/cm; P = 3.2e（-5）），而易损性下限相似。APD恢复、传导速度和各向异性也相似。TG心脏的左心室透壁纤维旋转显著高于WT心脏（95.6 +/- 10.9 vs 79.2 +/- 7.8;度P = 0.039）。与WT相比，TG心脏中层心肌中连接蛋白43密度显著增加（5.46 +/- 2.44%对2.68 +/- 0.77%; P = 0.024），心内膜和心外膜中观察到相似的密度。由于在TG心脏中观察到易损性上限增加了近2倍，而APD恢复、传导速度或各向异性比没有显著变化，因此我们得出结论，结构重构可能是人类肥厚型心肌病易损性上限升高的基础。
Human hypertrophic cardiomyopathy, characterized by cardiac hypertrophy and myocyte disarray, is the most common cause of sudden cardiac death in the young. Hypertrophic cardiomyopathy is often caused by mutations in sarcomeric genes. We sought to determine arrhythmia propensity and underlying mechanisms contributing to arrhythmia in a transgenic (TG) rabbit model (beta-myosin heavy chain-Q403) of human hypertrophic cardiomyopathy. Langendorff-perfused hearts from TG (n = 6) and wild-type (WT) rabbits (n = 6) were optically mapped. The upper and lower limits of vulnerability, action potential duration (APD) restitution, and conduction velocity were measured. The transmural fiber angle shift was determined using diffusion tensor MRI. The transmural distribution of connexin 43 was quantified with immunohistochemistry. The upper limit of vulnerability was significantly increased in TG versus WT hearts (13.3 +/- 2.1 versus 7.4 +/- 2.3 V/cm; P = 3.2e(-5)), whereas the lower limits of vulnerability were similar. APD restitution, conduction velocities, and anisotropy were also similar. Left ventricular transmural fiber rotation was significantly higher in TG versus WT hearts (95.6 +/- 10.9 versus 79.2 +/- 7.8;degrees P = 0.039). The connexin 43 density was significantly increased in the mid-myocardium of TG hearts compared with WT (5.46 +/- 2.44% versus 2.68 +/- 0.77%; P = 0.024), and similar densities were observed in the endo- and epicardium. Because a nearly 2-fold increase in upper limit of vulnerability was observed in the TG hearts without significant changes in APD restitution, conduction velocity, or the anisotropy ratio, we conclude that structural remodeling may underlie the elevated upper limit of vulnerability in human hypertrophic cardiomyopathy.