Yamaguchi Tomoki, Salavatian Siamak, Kuwabara Yuki, Hellman Abigail, Taylor Bradley K, Howard-Quijano Kimberly, Mahajan Aman
Department of Anesthesiology and Perioperative Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA.
Division of Cardiology, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA 15261, USA.
Biomedicines. 2023 Oct 7;11(10):2720. doi: 10.3390/biomedicines11102720.
A myocardial ischemia/reperfusion (IR) injury activates the transient receptor potential vanilloid 1 (TRPV1) dorsal root ganglion (DRG) neurons. The activation of TRPV1 DRG neurons triggers the spinal dorsal horn and the sympathetic preganglionic neurons in the spinal intermediolateral column, which results in sympathoexcitation. In this study, we hypothesize that the selective epidural administration of resiniferatoxin (RTX) to DRGs may provide cardioprotection against ventricular arrhythmias by inhibiting afferent neurotransmission during IR injury.
Yorkshire pigs ( = 21) were assigned to either the sham, IR, or IR + RTX group. A laminectomy and sternotomy were performed on the anesthetized animals to expose the left T2-T4 spinal dorsal root and the heart for IR intervention, respectively. RTX (50 μg) was administered to the DRGs in the IR + RTX group. The activation recovery interval (ARI) was measured as a surrogate for the action potential duration (APD). Arrhythmia risk was investigated by assessing the dispersion of repolarization (DOR), a marker of arrhythmogenicity, and measuring the arrhythmia score and the number of non-sustained ventricular tachycardias (VTs). TRPV1 and calcitonin gene-related peptide (CGRP) expressions in DRGs and CGRP expression in the spinal cord were assessed using immunohistochemistry.
The RTX mitigated IR-induced ARI shortening (-105 ms ± 13 ms in IR vs. -65 ms ± 11 ms in IR + RTX, = 0.028) and DOR augmentation (7093 ms ± 701 ms in IR vs. 3788 ms ± 1161 ms in IR + RTX, = 0.020). The arrhythmia score and VT episodes during an IR were decreased by RTX (arrhythmia score: 8.01 ± 1.44 in IR vs. 3.70 ± 0.81 in IR + RTX, = 0.037. number of VT episodes: 12.00 ± 3.29 in IR vs. 0.57 ± 0.3 in IR + RTX, = 0.002). The CGRP expression in the DRGs and spinal cord was decreased by RTX (DRGs: 6.8% ± 1.3% in IR vs. 0.6% ± 0.2% in IR + RTX, < 0.001. Spinal cord: 12.0% ± 2.6% in IR vs. 4.5% ± 0.8% in IR + RTX, = 0.047).
The administration of RTX locally to thoracic DRGs reduces ventricular arrhythmia in a porcine model of IR, likely by inhibiting spinal afferent hyperactivity in the cardio-spinal sympathetic pathways.
心肌缺血/再灌注（IR）损伤会激活瞬时受体电位香草酸受体1（TRPV1）背根神经节（DRG）神经元。TRPV1 DRG神经元的激活会触发脊髓背角以及脊髓中间外侧柱中的交感神经节前神经元，从而导致交感神经兴奋。在本研究中，我们假设向DRG选择性硬膜外给予树脂毒素（RTX）可能通过抑制IR损伤期间的传入神经传递来提供针对室性心律失常的心脏保护作用。
将21只约克夏猪分为假手术组、IR组或IR + RTX组。对麻醉的动物进行椎板切除术和胸骨切开术，分别暴露左侧T2 - T4脊髓背根和心脏以进行IR干预。在IR + RTX组中，向DRG给予RTX（50μg）。测量激活恢复间期（ARI）作为动作电位持续时间（APD）的替代指标。通过评估复极离散度（DOR，致心律失常性的标志物）、测量心律失常评分和非持续性室性心动过速（VT）的数量来研究心律失常风险。使用免疫组织化学评估DRG中TRPV1和降钙素基因相关肽（CGRP）的表达以及脊髓中CGRP的表达。
RTX减轻了IR诱导的ARI缩短（IR组为 - 105 ms ± 13 ms，IR + RTX组为 - 65 ms ± 11 ms，P = 0.028）和DOR增加（IR组为7093 ms ± 701 ms，IR + RTX组为3788 ms ± 1161 ms，P = 0.020）。RTX降低了IR期间的心律失常评分和VT发作次数（心律失常评分：IR组为8.01 ± 1.44，IR + RTX组为3.70 ± 0.81，P = 0.037。VT发作次数：IR组为12.00 ± 3.29，IR + RTX组为0.57 ± 0.3，P = 0.002）。RTX降低了DRG和脊髓中CGRP的表达（DRG：IR组为6.8% ± 1.3%，IR + RTX组为0.6% ± 0.2%，P < 0.001。脊髓：IR组为12.0% ± 2.6%，IR + RTX组为4.5% ± 0.8%，P = 0.047）。
在猪IR模型中，向胸段DRG局部给予RTX可减少室性心律失常，可能是通过抑制心 - 脊髓交感神经通路中的脊髓传入神经活动亢进。
