Thoracic Dorsal Root Ganglion Application of Resiniferatoxin Reduces Myocardial Ischemia-Induced Ventricular Arrhythmias

Background: 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 c...

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Main Authors: Tomoki Yamaguchi, Siamak Salavatian, Yuki Kuwabara, Abigail Hellman, Bradley K. Taylor, Kimberly Howard-Quijano, Aman Mahajan
Format: Article
Language:English
Published: MDPI AG 2023-10-01
Series:Biomedicines
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Online Access:https://www.mdpi.com/2227-9059/11/10/2720
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author Tomoki Yamaguchi
Siamak Salavatian
Yuki Kuwabara
Abigail Hellman
Bradley K. Taylor
Kimberly Howard-Quijano
Aman Mahajan
author_facet Tomoki Yamaguchi
Siamak Salavatian
Yuki Kuwabara
Abigail Hellman
Bradley K. Taylor
Kimberly Howard-Quijano
Aman Mahajan
author_sort Tomoki Yamaguchi
collection DOAJ
description Background: 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. Methods: Yorkshire pigs (<i>n</i> = 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. Results: The RTX mitigated IR-induced ARI shortening (−105 ms ± 13 ms in IR vs. −65 ms ± 11 ms in IR + RTX, <i>p</i> = 0.028) and DOR augmentation (7093 ms<sup>2</sup> ± 701 ms<sup>2</sup> in IR vs. 3788 ms<sup>2</sup> ± 1161 ms<sup>2</sup> in IR + RTX, <i>p</i> = 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, <i>p</i> = 0.037. number of VT episodes: 12.00 ± 3.29 in IR vs. 0.57 ± 0.3 in IR + RTX, <i>p</i> = 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, <i>p</i> < 0.001. Spinal cord: 12.0% ± 2.6% in IR vs. 4.5% ± 0.8% in IR + RTX, <i>p</i> = 0.047). Conclusions: 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.
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spelling doaj.art-736632245f934dbaa138755e94b7c2202023-11-19T15:46:08ZengMDPI AGBiomedicines2227-90592023-10-011110272010.3390/biomedicines11102720Thoracic Dorsal Root Ganglion Application of Resiniferatoxin Reduces Myocardial Ischemia-Induced Ventricular ArrhythmiasTomoki Yamaguchi0Siamak Salavatian1Yuki Kuwabara2Abigail Hellman3Bradley K. Taylor4Kimberly Howard-Quijano5Aman Mahajan6Department of Anesthesiology and Perioperative Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USADepartment of Anesthesiology and Perioperative Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USADepartment of Anesthesiology and Perioperative Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USADepartment of Anesthesiology and Perioperative Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USADepartment of Anesthesiology and Perioperative Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USADepartment of Anesthesiology and Perioperative Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USADepartment of Anesthesiology and Perioperative Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USABackground: 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. Methods: Yorkshire pigs (<i>n</i> = 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. Results: The RTX mitigated IR-induced ARI shortening (−105 ms ± 13 ms in IR vs. −65 ms ± 11 ms in IR + RTX, <i>p</i> = 0.028) and DOR augmentation (7093 ms<sup>2</sup> ± 701 ms<sup>2</sup> in IR vs. 3788 ms<sup>2</sup> ± 1161 ms<sup>2</sup> in IR + RTX, <i>p</i> = 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, <i>p</i> = 0.037. number of VT episodes: 12.00 ± 3.29 in IR vs. 0.57 ± 0.3 in IR + RTX, <i>p</i> = 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, <i>p</i> < 0.001. Spinal cord: 12.0% ± 2.6% in IR vs. 4.5% ± 0.8% in IR + RTX, <i>p</i> = 0.047). Conclusions: 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.https://www.mdpi.com/2227-9059/11/10/2720neuromodulationmyocardial ischemiacardiac arrhythmiasdeafferentationautonomic nervous systemRTX
spellingShingle Tomoki Yamaguchi
Siamak Salavatian
Yuki Kuwabara
Abigail Hellman
Bradley K. Taylor
Kimberly Howard-Quijano
Aman Mahajan
Thoracic Dorsal Root Ganglion Application of Resiniferatoxin Reduces Myocardial Ischemia-Induced Ventricular Arrhythmias
Biomedicines
neuromodulation
myocardial ischemia
cardiac arrhythmias
deafferentation
autonomic nervous system
RTX
title Thoracic Dorsal Root Ganglion Application of Resiniferatoxin Reduces Myocardial Ischemia-Induced Ventricular Arrhythmias
title_full Thoracic Dorsal Root Ganglion Application of Resiniferatoxin Reduces Myocardial Ischemia-Induced Ventricular Arrhythmias
title_fullStr Thoracic Dorsal Root Ganglion Application of Resiniferatoxin Reduces Myocardial Ischemia-Induced Ventricular Arrhythmias
title_full_unstemmed Thoracic Dorsal Root Ganglion Application of Resiniferatoxin Reduces Myocardial Ischemia-Induced Ventricular Arrhythmias
title_short Thoracic Dorsal Root Ganglion Application of Resiniferatoxin Reduces Myocardial Ischemia-Induced Ventricular Arrhythmias
title_sort thoracic dorsal root ganglion application of resiniferatoxin reduces myocardial ischemia induced ventricular arrhythmias
topic neuromodulation
myocardial ischemia
cardiac arrhythmias
deafferentation
autonomic nervous system
RTX
url https://www.mdpi.com/2227-9059/11/10/2720
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