Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, Homburg, Saarland University, Germany.
Klinik und Poliklinik für Kardiologie, Universitätsklinikum Leipzig, Leipzig, Germany.
Eur J Heart Fail. 2019 Apr;21(4):482-491. doi: 10.1002/ejhf.1392. Epub 2019 Jan 24.
Atrial fibrillation is the most prevalent sustained arrhythmia associated with arrhythmic ventricular contractions, incident heart failure, increased morbidity and mortality. The relationship between arrhythmic contractions and ventricular remodelling is incompletely understood. The aim of this study was to characterize the influence of irregular contractions on pro-fibrotic signalling in neonatal rat ventricular cardiomyocytes (NRVM).
Neonatal rat ventricular cardiomyocytes were paced via field stimulation at 3 Hz for 24 h. Irregularity was created by pseudorandomized variation of stimulation intervals and compared to regular pacing. Treatment of neonatal cardiac fibroblasts (NCF) with medium of irregularly paced NRVM increased protein expression of collagen I (206 ± 62%, P = 0.0121) and collagen III (51 ± 37%, P = 0.0119). To identify the underlying mechanism, expression of pro-fibrotic connective tissue growth factor (CTGF) and transforming growth factor beta (TGF-β) was assessed. In irregularly paced NRVM, increased protein expression of CTGF (80 ± 22%, P = 0.0035) and TGF-β (122 ± 31%, P = 0.0022) was associated with enhanced excretion of both proteins into the medium. Electron paramagnetic resonance spectroscopy revealed an increased production of reactive oxygen species (46 ± 21%, P = 0.0352) after irregular pacing accompanied by increased 8-hydroxydeoxyguanosine staining (214 ± 53%, P = 0.0011). Irregular pacing was associated with elevated mRNA levels of anti-oxidative superoxide dismutase 1 (25 ± 7%, P = 0.0175), superoxide dismutase 3 (20 ± 7%, P = 0.0309), and catalase (20 ± 7%, P = 0.046).
These data demonstrate that irregular pacing is an important inductor of pro-fibrotic signalling in NRVM involving paracrine effects of CTGF and TGF-β as well as increased oxidative stress. Thus, irregularity of the heart beat might directly be involved in the progression of maladaptive remodelling processes in atrial fibrillation.
心房颤动是最常见的持续性心律失常，与心律失常性室性收缩、心力衰竭事件、发病率和死亡率增加有关。心律失常性收缩与心室重构之间的关系尚未完全阐明。本研究旨在描述不规则收缩对新生大鼠心室肌细胞（NRVM）成纤维信号的影响。
通过场刺激以 3Hz 的频率对新生大鼠心室肌细胞进行 24 小时起搏。通过随机变化刺激间隔来创建不规则性，并与规则起搏进行比较。用不规则起搏的 NRVM 培养基处理新生心肌成纤维细胞（NCF）可增加胶原 I（206±62%，P=0.0121）和胶原 III（51±37%，P=0.0119）的蛋白表达。为了确定潜在机制，评估了促纤维化结缔组织生长因子（CTGF）和转化生长因子β（TGF-β）的表达。在不规则起搏的 NRVM 中，CTGF（80±22%，P=0.0035）和 TGF-β（122±31%，P=0.0022）的蛋白表达增加与这两种蛋白向培养基中的分泌增加有关。电子顺磁共振波谱显示，不规则起搏后活性氧（ROS）的产生增加（46±21%，P=0.0352），同时 8-羟基脱氧鸟苷染色增加（214±53%，P=0.0011）。不规则起搏与抗氧化超氧化物歧化酶 1（25±7%，P=0.0175）、超氧化物歧化酶 3（20±7%，P=0.0309）和过氧化氢酶（20±7%，P=0.046）的 mRNA 水平升高有关。
这些数据表明，不规则起搏是 NRVM 中成纤维信号的重要诱导因素，涉及 CTGF 和 TGF-β 的旁分泌作用以及氧化应激的增加。因此，心跳的不规则性可能直接参与心房颤动中适应性重构过程的进展。
