Bacterial sodium channels as gene therapy for cardiac arrhythmia: slow (activation and inactivation kinetics) and steady wins the race.
Bacterial sodium channels as gene therapy for cardiac arrhythmia: slow (activation and inactivation kinetics) and steady wins the race.
复制标题
细菌钠通道作为心律失常的基因疗法：缓慢（激活和失活动力学）和稳定赢得比赛。
DOI：
10.1152/ajpheart.00676.2023
复制
发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Weinberg,SethH
中科院分区：
文献类型：
--
作者：
Moreno,JonathanD;Weinberg,SethH
心源性猝死（SCD）是一种组织性心律的快速丧失，如果不迅速纠正，结果可能在几分钟内致命。仅在美国，SCD每年造成350，000例死亡，占所有心血管死亡的50%（1）。换句话说，SCD每天夺走1,000人的生命，这是COVID-19疫情最严重时的死亡人数。即使对于那些接受干预的患者，存活率仍然很低。对于那些在医院外患有SCD的患者，只有十分之一的人能够存活。使问题复杂化的是，导致恶性室性心律失常和SCD的机制仍然明显不同，包括由于缺血环境中瘢痕组织形成引起的获得性心律失常、通过纤维化区域的传导不良、药物诱导的传导减慢、电解质紊乱（例如，高钾血症）、过早兴奋和由于通道病引起的遗传性心律失常综合征，包括心脏Na+通道（SCN 5A）基因的突变。然而，最后的共同途径是由于非传导性心肌形成传导阻滞和形成传播心律失常的折返途径。心脏的电传导系统是一个非常强大和非凡的工程壮举。尽管平均每人每天有100，000次心跳，但绝大多数心跳都按预期传播。然而，基质、离子稳态环境或甚至单个离子通道类型的功能中的小扰动都可能导致致命的节律紊乱。许多疾病表型（例如，长QT 3和Brugada综合征）与心脏Na+通道有关，该通道负责动作电位和冲动传播的快速上升。特别是Brugada综合征，是一种功能丧失性Na+通道病，是心脏Na+通道（NaV 1. 5)细胞膜，并警告门控特性，导致增加的失活（2）。这些变化，加上增加早期复极的Ito电流导致受损的动作电位（AP）脉冲的产生，减慢传导，和跨壁复极heterogeneitys.Medicine取得了显着的进展，在抗心律失常治疗，包括药物，设备，并通过消融在EP套房基板调制。然而，每种疗法都有潜在的副作用，并且没有一种疗法专门针对心律失常的潜在细胞机制。例如，大多数抗心律失常药物的治疗窗口较窄，在较高剂量下可导致心律失常。此外，最常用的抗心律失常药物（胺碘酮）在长时间使用时可引起肝、肺、眼和甲状腺毒性（3）。植入式心脏除颤器设备可以挽救生命，但只有在患者遭受心律失常后才能提供痛苦的电击，价格昂贵（10，000 - 25，000美元），需要进行小型手术植入，并且可能导致严重的恐惧和焦虑，除颤器随时都会放电。最后，消融治疗试图通过识别折返回路并通过产生额外的瘢痕和纤维化区域来中断电通路来修改基底。该手术成本高昂，需要住院治疗，并且在技术上很难将消融导管充分引导到感兴趣区域。
Sudden cardiac death (SCD) is the rapid loss of an organized heart rhythm, and if not rapidly corrected, the results can be deadly within minutes. In the United States alone, SCD accounts for 350,000 deaths annually, comprising 50% of all cardiovascular deaths (1). Stated differently, SCD takes the lives of 1,000 people a day, the approximate number of deaths from COVID-19 at the height of the epidemic. Even for those patients with intervention, survival rates remain abysmal. For those patients who suffer from SCD outside of the hospital, only 1 in 10 will survive. Complicating matters, the mechanisms that lead to malignant ventricular arrhythmia and SCD remain markedly varied including acquired arrhythmias due to scar tissue formation in the setting of ischemia, poor conduction through areas of fibrosis, drug-induced conduction slowing, electrolyte disturbances (eg, hyperkalemia), premature excitation, and inherited arrhythmia syndromes due to channelopathies, including mutations in the cardiac Na þ channel (SCN5A) gene. The final common pathway for most, however, is the formation of a conduction block due to nonconducting myocardium and the formation of a reentrant pathway that propagates the arrhythmia. The electrical conduction system of the heart is a highly robust and a remarkable feat of engineering. Despite the average person having 100,000 heartbeats per day, the vast majority of heartbeats propagate as intended. However, small perturbations in either the substrate, the ionic homeostatic milieu, or the function of even a single ion channel type can lead to deadly rhythm disturbances. Numerous disease phenotypes (eg, the long QT3 and Brugada syndrome) have been linked to the cardiac Na þ channel, which is responsible for the rapid upstroke of the action potential and impulse propagation. The Brugada syndrome, in particular, is a loss-of-function Na þ channelopathy, as a result of impaired trafficking of cardiac Na þ channel (NaV1. 5) to the cellular membrane, and alerted gating properties leading to increased inactivation (2). These changes, coupled with an increase in early repolarization of the Ito current lead to impaired action potential (AP) impulse generation, slowed conduction, and transmural repolarization heterogeneities.Medicine has made remarkable progress in antiarrhythmic therapies, including drugs, devices, and substrate modulation via ablation in the EP suite. However, each therapy carries potential side effects, and no therapy specifically targets the underlying cellular mechanism of arrhythmia. For example, most antiarrhythmic drugs have a narrow therapeutic window and, in higher doses, can lead to proarrhythmia. In addition, the most commonly prescribed antiarrhythmic drug (amiodarone) can cause liver, pulmonary, ocular, and thyroid toxicity when used for an extended duration (3). Implanted cardiac defibrillator devices are lifesaving but deliver painful shocks only after patients suffer the arrhythmia, are costly ($10,000–25,000), require a minisurgery to implant, and can lead to significant fear and anxiety that at any given moment the defibrillator will discharge. Finally, ablation therapy attempts to modify the substrate by identifying the reentrant circuit and interrupting the electrical pathway by creation of additional areas of scar and fibrosis. The procedure is costly, requires inpatient hospitalization, and can be technically challenging to adequately direct the ablation catheters to the area of interest.