Fehrentz Timm, Amin Ehsan, Görldt Nicole, Strasdeit Tobias, Moussavi-Torshizi Seyed-Erfan, Leippe Philipp, Trauner Dirk, Meyer Christian, Frey Norbert, Sasse Philipp, Klöcker Nikolaj
Institute of Neural and Sensory Physiology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
Department of Cardiology, Angiology and Pneumology, University Hospital Heidelberg, Heidelberg, Germany.
Br J Pharmacol. 2025 Mar;182(5):1125-1142. doi: 10.1111/bph.17394. Epub 2024 Nov 14.
Patients suffering from ischaemic heart disease and heart failure are at high risk of recurrent ventricular arrhythmias (VAs), eventually leading to sudden cardiac death. While high-voltage shocks delivered by an implantable defibrillator may prevent sudden cardiac death, these interventions themselves impair quality of life and raise both morbidity and mortality, which accentuates the need for developing novel defibrillation techniques.
Photopharmacology allows for reversible control of biological processes by light. When relying on synthetic and externally applied chromophores, it renders genetic modification of target cells dispensable and may hence be advantageous over optogenetic approaches. Here, the photochromic ligand azobupivacaine 2 (AB2) was probed as a modulator of cardiac electrophysiology in an ex vivo intact mouse heart model.
By reversibly blocking voltage-gated Na and K channels, photoswitching of AB2 modulated both the ventricular effective refractory period and the conduction velocity in native heart tissue. Moreover, photoswitching of AB2 was able to convert VA into sinus rhythm.
The present study provides the first proof of concept that AB2 enables gradual control of cardiac electrophysiology by light. AB2 may hence open the door to the development of an optical defibrillator based on photopharmacology.
患有缺血性心脏病和心力衰竭的患者发生室性心律失常（VA）复发的风险很高，最终会导致心源性猝死。虽然植入式除颤器传递的高压电击可能预防心源性猝死，但这些干预措施本身会损害生活质量，并增加发病率和死亡率，这凸显了开发新型除颤技术的必要性。
光药理学可通过光对生物过程进行可逆控制。当依赖合成的和外部应用的发色团时，它无需对靶细胞进行基因改造，因此可能比光遗传学方法更具优势。在此，在离体完整小鼠心脏模型中，对光致变色配体偶氮布比卡因2（AB2）作为心脏电生理调节剂进行了研究。
通过可逆地阻断电压门控钠通道和钾通道，AB2的光开关调节了天然心脏组织中的心室有效不应期和传导速度。此外，AB2的光开关能够将室性心律失常转换为窦性心律。
本研究首次提供了概念证明，即AB2能够通过光逐步控制心脏电生理。因此，AB2可能为基于光药理学的光学除颤器的开发打开大门。
