Light-induced termination of spiral wave arrhythmias by optogenetic engineering of atrial cardiomyocytes

被引：103

作者：

Bingen, Brian O. ^{[1
]}

Engels, Marc C. ^{[1
]}

Schalij, Martin J. ^{[1
]}

Jangsangthong, Wanchana ^{[1
]}

Neshati, Zeinab ^{[1
]}

Feola, Iolanda ^{[1
]}

Ypey, Dirk L. ^{[1
]}

Askar, Said F. A. ^{[1
]}

Panfilov, Alexander V. ^{[2
]}

Pijnappels, Daniel A. ^{[1
]}

de Vries, Antoine A. F. ^{[1
]}

机构：

[1] Leiden Univ, Med Ctr, Lab Expt Cardiol, Dept Cardiol,Heart Lung Ctr Leiden, NL-2300 RC Leiden, Netherlands

[2] Univ Ghent, Dept Phys & Astron, B-9000 Ghent, Belgium

来源：

CARDIOVASCULAR RESEARCH | 2014年 / 104卷 / 01期

关键词：

Cardiomyocyte; Atrial fibrillation; Optogenetics; Lentiviral vector; Optical mapping; CARDIAC OPTOGENETICS; FUNCTIONAL REENTRY; IN-VITRO; FIBRILLATION; DEFIBRILLATION; MUSCLE; MECHANISMS; EXPRESSION; DYNAMICS; CELLS;

D O I：

10.1093/cvr/cvu179

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Aims Atrial fibrillation (AF) is the most common cardiac arrhythmia and often involves reentrant electrical activation (e. g. spiral waves). Drug therapy for AF can have serious side effects including proarrhythmia, while electrical shock therapy is associated with discomfort and tissue damage. Hypothetically, forced expression and subsequent activation of light-gated cation channels in cardiomyocytes might deliver a depolarizing force sufficient for defibrillation, thereby circumventing the aforementioned drawbacks. We therefore investigated the feasibility of light-induced spiral wave termination through cardiac optogenetics. Methods and results Neonatal rat atrial cardiomyocyte monolayers were transduced with lentiviral vectors encoding light-activated Ca2+-translocating channelrhodopsin (CatCh; LV.CatCh similar to eYFP up arrow) or eYFP (LV.eYFP up arrow) as control, and burst-paced to induce spiral waves rotating around functional cores. Effects of CatCh activation on reentry were investigated by optical and multi-electrode array (MEA) mapping. Western blot analyses and immunocytology confirmed transgene expression. Brief blue light pulses (10 ms/470 nm) triggered action potentials only in LV.CatCh similar to eYFP up arrow-transduced cultures, confirming functional CatCh-mediated current. Prolonged light pulses (500 ms) resulted in reentry termination in 100% of LV.CatCh similar to eYFP up arrow-transduced cultures (n = 31) vs. 0% of LV.eYFP up arrow-transduced cultures (n = 11). Here, CatCh activation caused uniform depolarization, thereby decreasing overall excitability (MEA peak-to-peak amplitude decreased 251.3 +/- 217.1 vs. 9.2 +/- 9.5 mu V in controls). Consequently, functional coresize increased and phase singularities (PSs) drifted, leading to reentry termination by PS-PS or PS-boundary collisions. Conclusion This study shows that spiral waves in atrial cardiomyocyte monolayers can be terminated effectively by a light-induced depolarizing current, produced by the arrhythmogenic substrate itself, upon optogenetic engineering. These results provide proof-of-concept for shockless defibrillation.

引用

页码：194 / 205

页数：12

共 33 条

[1] Repeated Cortico-Striatal Stimulation Generates Persistent OCD-Like Behavior [J].