Delayed Repolarization Underlies Ventricular Arrhythmias in Rats With Heart Failure and Preserved Ejection Fraction.
Delayed Repolarization Underlies Ventricular Arrhythmias in Rats With Heart Failure and Preserved Ejection Fraction.
复制标题
DOI：
10.1161/circulationaha.117.028202
复制
发表时间：
2017-11-21
期刊：
影响因子：
37.8
通讯作者：
Cingolani E
中科院分区：
文献类型：
--
作者：
Cho JH;Zhang R;Kilfoil PJ;Gallet R;de Couto G;Bresee C;Goldhaber JI;Marbán E;Cingolani E
射血分数保留性心力衰竭（HFpEF）约占心力衰竭的一半，其发病率持续增加。HFpEF死亡的主要原因是猝死，但对潜在机制知之甚少。Dahl盐敏感大鼠从7周龄开始喂食高盐饮食（8%NaCl）以诱导HFpEF（n=38）。以正常盐饮食（0.3%NaCl）喂养的大鼠作为对照（n=13）。从14周龄开始进行超声心动图评估收缩和舒张功能。HFpEF验证和对照大鼠进行程序电刺激（PES）。用体表心电图（ECG）测定QTc间期。室性心律失常（VA）的机制进行了探讨，通过光学映射，全细胞膜片钳测量动作电位时程和离子电流，定量聚合酶链反应和蛋白质印迹法研究离子通道表达的变化。高盐饮食7周后，38只大鼠中有31只表现出舒张功能障碍和射血分数沿着心力衰竭的体征，因此诊断为HFpEF。PES显示HFpEF大鼠对VA的易感性增加（p < 0.001，与对照组相比）。HFpEF大鼠致心律失常指数增加（p < 0.001），心电图QTc间期延长（p < 0.001）。HFpEF心脏的光学标测显示诱导VA期间动作电位延长（p < 0.05）和多个折返回路。从HFpEF大鼠分离的心肌细胞的单细胞记录证实了复极延迟（p=0.001），并显示瞬时外向钾电流（Ito）下调（p < 0.05）。延迟整流钾电流（IKr）的快速成分和内向整流钾电流（IK1）也下调（p < 0.05），但电流密度远低于Ito。与Ito的降低一致，HFpEF大鼠心脏中Kcnd3转录和Kv4.3蛋白水平均降低。HFpEF大鼠对VA的敏感性明显增加。潜在的异常包括QTc延长、钾电流下调导致的复极延迟以及VA期间的多个折返回路。我们的研究结果是一致的假设，钾电流下调导致异常复极HFpEF，这反过来又容易VA和心脏性猝死。
Heart failure with preserved ejection fraction (HFpEF) represents approximately half of heart failure, and its incidence continues to increase. The leading cause of mortality in HFpEF is sudden death, but little is known about the underlying mechanisms. Dahl salt-sensitive rats were fed a high-salt diet (8% NaCl) from 7 weeks of age to induce HFpEF (n=38). Rats fed a normal-salt diet (0.3% NaCl) served as controls (n=13). Echocardiograms were performed to assess systolic and diastolic function from 14 weeks of age. HFpEF-verified and control rats underwent programmed electrical stimulation (PES). QTc interval was measured by surface electrocardiography (ECG). The mechanisms of ventricular arrhythmias (VA) were probed by optical mapping, whole-cell patch clamp to measure action potential duration and ionic currents, and quantitative polymerase chain reaction and western blotting to investigate changes in ion channel expression. After 7 weeks of high-salt diet, 31 of 38 rats showed diastolic dysfunction and preserved ejection fraction along with signs of heart failure, hence diagnosed with HFpEF. PES demonstrated increased susceptibility to VA in HFpEF rats (p < 0.001 vs. controls). The arrhythmogenicity index was increased (p < 0.001), and the QTc interval on ECG was prolonged (p < 0.001) in HFpEF rats. Optical mapping of HFpEF hearts demonstrated prolonged action potentials (p < 0.05) and multiple re-entry circuits during induced VA. Single-cell recordings of cardiomyocytes isolated from HFpEF rats confirmed a delay of repolarization (p=0.001) and revealed down-regulation of transient outward potassium current (Ito) (p < 0.05). The rapid component of the delayed rectifier potassium current (IKr), and the inward rectifier potassium current (IK1), were also down-regulated (p < 0.05), but the current densities were much lower than for Ito. In accordance with the reduction of Ito, both Kcnd3 transcript and Kv4.3 protein levels were decreased in HFpEF rat hearts. Susceptibility to VA was markedly increased in rats with HFpEF. Underlying abnormalities include QTc prolongation, delayed repolarization from down-regulation of potassium currents, and multiple re-entry circuits during VA. Our findings are consistent with the hypothesis that potassium current down-regulation leads to abnormal repolarization in HFpEF, which in turn predisposes to VA and sudden cardiac death.