Essel Research and Development Inc., Toronto, 337 Sheppard Ave East, Toronto, Ontario M2N 3B3, Canada.
Spanish National Cardiovascular Research Center, Carlos III (CNIC), Myocardial Pathophysiology Area, Melchor Fernández Almagro, 3, Madrid, Spain.
Cardiovasc Res. 2019 Sep 1;115(11):1659-1671. doi: 10.1093/cvr/cvz039.
Cardiac optical mapping is the gold standard for measuring complex electrophysiology in ex vivo heart preparations. However, new methods for optical mapping in vivo have been elusive. We aimed at developing and validating an experimental method for performing in vivo cardiac optical mapping in pig models.
First, we characterized ex vivo the excitation-ratiometric properties during pacing and ventricular fibrillation (VF) of two near-infrared voltage-sensitive dyes (di-4-ANBDQBS/di-4-ANEQ(F)PTEA) optimized for imaging blood-perfused tissue (n = 7). Then, optical-fibre recordings in Langendorff-perfused hearts demonstrated that ratiometry permits the recording of optical action potentials (APs) with minimal motion artefacts during contraction (n = 7). Ratiometric optical mapping ex vivo also showed that optical AP duration (APD) and conduction velocity (CV) measurements can be accurately obtained to test drug effects. Secondly, we developed a percutaneous dye-loading protocol in vivo to perform high-resolution ratiometric optical mapping of VF dynamics (motion minimal) using a high-speed camera system positioned above the epicardial surface of the exposed heart (n = 11). During pacing (motion substantial) we recorded ratiometric optical signals and activation via a 2D fibre array in contact with the epicardial surface (n = 7). Optical APs in vivo under general anaesthesia showed significantly faster CV [120 (63-138) cm/s vs. 51 (41-64) cm/s; P = 0.032] and a statistical trend to longer APD90 [242 (217-254) ms vs. 192 (182-233) ms; P = 0.095] compared with ex vivo measurements in the contracting heart. The average rate of signal-to-noise ratio (SNR) decay of di-4-ANEQ(F)PTEA in vivo was 0.0671 ± 0.0090 min-1. However, reloading with di-4-ANEQ(F)PTEA fully recovered the initial SNR. Finally, toxicity studies (n = 12) showed that coronary dye injection did not generate systemic nor cardiac damage, although di-4-ANBDQBS injection induced transient hypotension, which was not observed with di-4-ANEQ(F)PTEA.
In vivo optical mapping using voltage ratiometry of near-infrared dyes enables high-resolution cardiac electrophysiology in translational pig models.
心脏光学标测是测量离体心脏标本中复杂电生理的金标准。然而，新的体内光学标测方法一直难以捉摸。我们旨在开发和验证一种在猪模型中进行体内心脏光学标测的实验方法。
首先，我们在离体条件下对两种近红外电压敏感染料（di-4-ANBDQBS/di-4-ANEQ（F）PTEA）进行了特征描述，这两种染料是为成像血灌注组织而优化的（n=7）。然后，在 Langendorff 灌注心脏中的光纤记录表明，比率测量允许在收缩期间（n=7）记录最小运动伪影的光学动作电位（AP）。离体比率光学标测还表明，可以准确测量光学动作电位持续时间（APD）和传导速度（CV），以测试药物作用。其次，我们开发了一种经皮染料加载方案，在暴露心脏的心外膜表面上方使用高速摄像系统，对（运动最小化的）VF 动力学进行高分辨率比率光学标测（n=11）。在起搏时（运动显著），我们通过与心外膜表面接触的 2D 光纤阵列记录了比率光学信号和激活（n=7）。在全身麻醉下，体内光学 AP 显示出明显更快的 CV[120（63-138）cm/s 比 51（41-64）cm/s；P=0.032]和较长的 APD90[242（217-254）ms 比 192（182-233）ms；P=0.095]的统计学趋势，与在收缩心脏中进行的离体测量相比。体内 di-4-ANEQ（F）PTEA 的信号与噪声比（SNR）衰减平均速率为 0.0671±0.0090min-1。然而，用 di-4-ANEQ（F）PTEA 重新加载完全恢复了初始 SNR。最后，毒性研究（n=12）表明，冠状染料注射不会引起全身或心脏损伤，尽管 di-4-ANBDQBS 注射会引起短暂的低血压，但在用 di-4-ANEQ（F）PTEA 时没有观察到这种情况。
使用近红外染料的电压比率的体内光学标测能够在转化猪模型中进行高分辨率心脏电生理学研究。
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