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

BO Bingen, MC Engels, MJ Schalij… - Cardiovascular …, 2014 - academic.oup.com
BO Bingen, MC Engels, MJ Schalij, W Jangsangthong, Z Neshati, I Feola, DL Ypey…
Cardiovascular research, 2014academic.oup.com
Aims Atrial fibrillation (AF) is the most common cardiac arrhythmia and often involves
reentrant electrical activation (eg 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 …
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∼eYFP↑) or eYFP (LV.eYFP↑) 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∼eYFP↑-transduced cultures, confirming functional CatCh-mediated current. Prolonged light pulses (500 ms) resulted in reentry termination in 100% of LV.CatCh∼eYFP↑-transduced cultures (n = 31) vs. 0% of LV.eYFP↑-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 μV 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.
Oxford University Press