Department of Cardiology, Medical University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.
Department of Molecular Neurology, Max-Planck-Institute for Medical Research, Jahnstrasse 29, 69120, Heidelberg, Germany.
Nat Commun. 2019 Jul 23;10(1):3295. doi: 10.1038/s41467-019-11261-2.
HCN channels underlie the depolarizing funny current (I) that contributes importantly to cardiac pacemaking. I is upregulated in failing and infarcted hearts, but its implication in disease mechanisms remained unresolved. We generated transgenic mice (HCN4) to assess functional consequences of HCN4 overexpression-mediated I increase in cardiomyocytes to levels observed in human heart failure. HCN4 animals exhibit a dilated cardiomyopathy phenotype with increased cellular arrhythmogenicity but unchanged heart rate and conduction parameters. I augmentation induces a diastolic Na influx shifting the Na/Ca exchanger equilibrium towards 'reverse mode' leading to increased [Ca]. Changed Ca homeostasis results in significantly higher systolic [Ca] transients and stimulates apoptosis. Pharmacological inhibition of I prevents the rise of [Ca] and protects from ventricular remodeling. Here we report that augmented myocardial I alters intracellular Ca homeostasis leading to structural cardiac changes and increased arrhythmogenicity. Inhibition of myocardial I per se may constitute a therapeutic mechanism to prevent cardiomyopathy.
HCN 通道是去极化有趣电流（I）的基础，I 对心脏起搏有重要贡献。在衰竭和梗死的心脏中，I 上调，但它在疾病机制中的意义仍未解决。我们生成了转基因小鼠（HCN4），以评估 HCN4 过表达介导的 I 在心肌细胞中增加到在人类心力衰竭中观察到的水平的功能后果。HCN4 动物表现出扩张型心肌病表型，细胞心律失常性增加，但心率和传导参数不变。I 的增强诱导舒张 Na 内流，使 Na/Ca 交换平衡向“反向模式”移动，导致 [Ca]增加。钙稳态的改变导致收缩期 [Ca]瞬变显著增加，并刺激细胞凋亡。I 的药理学抑制可防止 [Ca]的升高并防止心室重构。在这里，我们报告说，增强的心肌 I 改变了细胞内 Ca 稳态，导致结构心脏变化和心律失常性增加。心肌 I 的抑制本身可能构成预防心肌病的治疗机制。
