Vagus nerve stimulation exerts cardioprotection against myocardial ischemia/reperfusion injury predominantly through its efferent vagal fibers

  • Watthana Nuntaphum
  • Wanpitak Pongkan
  • Suwakon Wongjaikam
  • Savitree Thummasorn
  • Pongpan Tanajak
  • Juthamas Khamseekaew
  • Kannaporn Intachai
  • Siriporn C. Chattipakorn
  • Nipon Chattipakorn
  • Krekwit ShinlapawittayatornEmail author
Original Contribution


Vagus nerve stimulation (VNS) has been shown to exert cardioprotection against myocardial ischemia/reperfusion (I/R) injury. However, whether the cardioprotection of VNS is mainly due to direct activation through its ipsilateral efferent fibers (motor) rather than indirect effects mediated by the afferent fibers (sensory) have not been clearly understood. We hypothesized that VNS exerts cardioprotection predominantly through its efferent vagal fibers. Thirty swine (30–35 kg) were randomized into five groups: I/R no VNS (I/R), and left mid-cervical VNS with both vagal trunks intact (LC-VNS), with left vagus nerve transection (LtVNX), with right vagus nerve transection (RtVNX) and with atropine pretreatment (Atropine), respectively. VNS was applied at the onset of ischemia (60 min) and continued until the end of reperfusion (120 min). Cardiac function, infarct size, arrhythmia score, myocardial connexin43 expression, apoptotic markers, oxidative stress markers, inflammatory markers (TNF-α and IL-10) and cardiac mitochondrial function, dynamics and fatty acid oxidation (MFN2, OPA1, DRP1, PGC1α and CPT1) were determined. LC-VNS exerted cardioprotection against myocardial I/R injury via improvement of mitochondrial function and dynamics and shifted cardiac fatty acid metabolism toward beta oxidation. However, LC-VNS and LtVNX, both efferent vagal fibers are intact, produced more profound cardioprotection, particularly infarct size reduction, decreased arrhythmia score, oxidative stress and apoptosis and attenuated mitochondrial dysfunction compared to RtVNX. These beneficial effects of VNS were abolished by atropine. Our findings suggest that selective efferent VNS may potentially be effective in attenuating myocardial I/R injury. Moreover, VNS required the contralateral efferent vagal activities to fully provide its cardioprotection.


Vagus nerve stimulation Efferent fiber Ischemic/reperfusion injury Cardioprotection 



This study was funded by the Thailand Research Fund Royal Golden Jubilee program (STC and NC); a NSTDA Research Chair Grant from the National Science and Technology Development Agency Thailand (NC); the Thailand Research Fund RSA5880015 (KS), RTA6080003 (SCC), and a Chiang Mai University Center of Excellence Award (NC).

Compliance with ethical standards

Conflict of interest

The authors declare that there are no conflicts of interest associated with this study.

Ethical approval

All animal procedures were approved by the Faculty of Medicine, Chiang Mai University Institutional Animal Care and Use Committee (Permit No. 33/2554) and investigative procedures were carried out according to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health.

Supplementary material

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Supplementary material 1 (TIFF 15803 kb)
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Supplementary material 2 (TIFF 22740 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Watthana Nuntaphum
    • 1
    • 2
    • 3
  • Wanpitak Pongkan
    • 1
    • 2
    • 3
  • Suwakon Wongjaikam
    • 1
    • 2
    • 3
  • Savitree Thummasorn
    • 1
    • 2
    • 3
  • Pongpan Tanajak
    • 1
    • 2
    • 3
  • Juthamas Khamseekaew
    • 1
    • 2
    • 3
  • Kannaporn Intachai
    • 1
    • 2
    • 3
  • Siriporn C. Chattipakorn
    • 1
    • 2
    • 3
    • 4
  • Nipon Chattipakorn
    • 1
    • 2
    • 3
  • Krekwit Shinlapawittayatorn
    • 1
    • 2
    • 3
    Email author
  1. 1.Faculty of Medicine, Cardiac Electrophysiology Research and Training CenterChiang Mai UniversityChiang MaiThailand
  2. 2.Cardiac Electrophysiology Unit, Department of Physiology, Faculty of MedicineChiang Mai UniversityChiang MaiThailand
  3. 3.Center of Excellence in Cardiac Electrophysiology ResearchChiang Mai UniversityChiang MaiThailand
  4. 4.Department of Oral Biology and Diagnostic Sciences, Faculty of DentistryChiang Mai UniversityChiang MaiThailand

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