左心室肥厚和心力衰竭过程中心房肌细胞功能进行性损伤。

Progressive impairment of atrial myocyte function during left ventricular hypertrophy and heart failure.

机构信息

Institute of Pharmacology and Clinical Pharmacy, Biochemical and Pharmacological Center (BPC) Marburg, University of Marburg, Karl-von-Frisch-Str. 1, D-35032 Marburg, Germany; Institute for Pharmacology and Toxicology, University of Münster, Domagkstr. 12, D-48149 Münster, Germany.

Institute of Pharmacology and Clinical Pharmacy, Biochemical and Pharmacological Center (BPC) Marburg, University of Marburg, Karl-von-Frisch-Str. 1, D-35032 Marburg, Germany.

出版信息

J Mol Cell Cardiol. 2018 Jan;114:253-263. doi: 10.1016/j.yjmcc.2017.11.020. Epub 2017 Dec 2.

DOI:10.1016/j.yjmcc.2017.11.020

PMID:29191788

Abstract

Hypertensive heart disease (HHD) can cause left ventricular (LV) hypertrophy and heart failure (HF). It is unclear, though, which factors may contribute to the transition from compensated LV hypertrophy to HF in HHD. We hypothesized that maladaptive atrial remodeling with impaired atrial myocyte function would occur in advanced HHD and may be associated with the emergence of HF. Experiments were performed on atrial myocytes and tissue from old (15-25months) normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) with advanced HHD. Based on the absence or presence of elevated lung weight, a sign of lung congestion and heart failure, SHR were divided into a non-failing (SHR-NF) and failing (SHR-HF) group. Compared with WKY, SHR exhibited elevated blood pressure, LV hypertrophy and left atrial (LA) hypertrophy with increased LA expression of markers of hypertrophy and fibrosis. SHR-HF were distinguished from SHR-NF by aggravated hypertrophy and fibrosis. SHR-HF atrial myocytes exhibited reduced contractility and impaired SR Ca handling. Moreover, in SHR the expression and phosphorylation of SR Ca-regulating proteins (SERCA2a, calsequestrin, RyR2 and phospholamban) showed negative correlation with increasing lung weight. Increasing stimulation frequency (1-2-4Hz) of atrial myocytes caused a progressive increase in arrhythmogenic Ca release (including alternans), which was observed most frequently in SHR-HF. Thus, in old SHR with advanced HHD there is profound structural and functional atrial remodeling. The occurrence of HF in SHR is associated with LA and RA hypertrophy, increased atrial fibrosis, impaired atrial myocyte contractility and SR Ca handling and increased propensity for arrhythmogenic Ca release. Therefore, functional remodeling intrinsic to atrial myocytes may contribute to the transition from compensated LV hypertrophy to HF in advanced HHD and an increased propensity of atrial arrhythmias in HF.

摘要

高血压性心脏病（HHD）可导致左心室（LV）肥厚和心力衰竭（HF）。然而，尚不清楚哪些因素可能导致 HHD 从代偿性 LV 肥厚向 HF 的转变。我们假设，适应性不良的心房重构伴心房肌细胞功能障碍将发生在晚期 HHD 中，并且可能与 HF 的出现有关。在来自老年（15-25 个月）正常血压 Wistar-Kyoto 大鼠（WKY）和自发性高血压大鼠（SHR）的心房肌细胞和组织上进行了实验，这些大鼠具有晚期 HHD。根据是否存在升高的肺重量（充血和心力衰竭的标志），将 SHR 分为无衰竭（SHR-NF）和衰竭（SHR-HF）组。与 WKY 相比，SHR 表现出血压升高、LV 肥厚和左心房（LA）肥厚，LA 中肥厚和纤维化的标志物表达增加。SHR-HF 与 SHR-NF 的区别在于肥大和纤维化的加重。SHR-HF 心房肌细胞的收缩力降低，SR Ca 处理受损。此外，在 SHR 中，SR Ca 调节蛋白（SERCA2a、calsequestrin、RyR2 和 phospholamban）的表达和磷酸化与肺重量的增加呈负相关。心房肌细胞刺激频率（1-2-4Hz）的增加导致心律失常性 Ca 释放（包括交替）的进行性增加，在 SHR-HF 中观察到最频繁。因此，在具有晚期 HHD 的老年 SHR 中，存在明显的结构和功能心房重构。SHR 中 HF 的发生与 LA 和 RA 肥厚、心房纤维化增加、心房肌细胞收缩力和 SR Ca 处理受损以及心律失常性 Ca 释放增加有关。因此，内在的心房肌细胞功能重构可能导致晚期 HHD 中从代偿性 LV 肥厚向 HF 的转变，以及 HF 中心房性心律失常的发生率增加。