Department of Biophysics, Universidade Federal de São Paulo, São Paulo, Brazil.
Department of Pharmacology and Physiology, Biological Sciences Institute, Universidade Federal de Minas Gerais, Minas Gerais, Brazil.
PLoS Negl Trop Dis. 2021 Jun 2;15(6):e0009421. doi: 10.1371/journal.pntd.0009421. eCollection 2021 Jun.
Chagas disease (CD) is a neglected disease that induces heart failure and arrhythmias in approximately 30% of patients during the chronic phase of the disease. Despite major efforts to understand the cellular pathophysiology of CD there are still relevant open questions to be addressed. In the present investigation we aimed to evaluate the contribution of the Na+/Ca2+ exchanger (NCX) in the electrical remodeling of isolated cardiomyocytes from an experimental murine model of chronic CD.
METHODOLOGY/PRINCIPAL FINDINGS: Male C57BL/6 mice were infected with Colombian strain of Trypanosoma cruzi. Experiments were conducted in isolated left ventricular cardiomyocytes from mice 180-200 days post-infection and with age-matched controls. Whole-cell patch-clamp technique was used to measure cellular excitability and Real-time PCR for parasite detection. In current-clamp experiments, we found that action potential (AP) repolarization was prolonged in cardiomyocytes from chagasic mice paced at 0.2 and 1 Hz. After-depolarizations, both subthreshold and with spontaneous APs events, were more evident in the chronic phase of experimental CD. In voltage-clamp experiments, pause-induced spontaneous activity with the presence of diastolic transient inward current was enhanced in chagasic cardiomyocytes. AP waveform disturbances and diastolic transient inward current were largely attenuated in chagasic cardiomyocytes exposed to Ni2+ or SEA0400.
CONCLUSIONS/SIGNIFICANCE: The present study is the first to describe NCX as a cellular arrhythmogenic substrate in chagasic cardiomyocytes. Our data suggest that NCX could be relevant to further understanding of arrhythmogenesis in the chronic phase of experimental CD and blocking NCX may be a new therapeutic strategy to treat arrhythmias in this condition.
恰加斯病（CD）是一种被忽视的疾病，在疾病的慢性期，约 30%的患者会导致心力衰竭和心律失常。尽管人们做出了巨大努力来理解 CD 的细胞病理生理学，但仍有一些相关的开放性问题需要解决。在本研究中，我们旨在评估钠/钙交换器（NCX）在慢性 CD 实验性小鼠模型分离的心肌细胞电重构中的作用。
方法/主要发现：雄性 C57BL/6 小鼠感染哥伦比亚株克氏锥虫。实验在感染后 180-200 天的小鼠和年龄匹配的对照组的左心室心肌细胞中进行。使用全细胞膜片钳技术测量细胞兴奋性，实时 PCR 检测寄生虫。在电流钳实验中，我们发现起搏频率为 0.2 和 1 Hz 时，来自 Chagas 病小鼠的心肌细胞的动作电位（AP）复极化延长。在慢性期实验 CD 中，亚阈和自发性 AP 事件的后去极化更明显。在电压钳实验中，停搏诱导的自发性活动伴随着舒张期内向瞬变电流的存在在 Chagas 病心肌细胞中增强。AP 波形紊乱和舒张期内向瞬变电流在 Chagas 病心肌细胞暴露于 Ni2+或 SEA0400 时大大减弱。
结论/意义：本研究首次描述了 NCX 作为 Chagas 病心肌细胞的细胞性心律失常基质。我们的数据表明，NCX 可能与进一步理解实验性 CD 慢性期的心律失常发生有关，并且阻断 NCX 可能是治疗该病症心律失常的新治疗策略。
