Intravenous electrical vagal nerve stimulation prior to coronary reperfusion in a canine ischemia-reperfusion model markedly reduces infarct size and prevents subsequent heart failure.
BACKGROUND
Reducing myocardial damage is a prerequisite to prevent chronic heart failure after acute myocardial infarction (AMI). Although vagal nerve stimulation (VNS) has been repeatedly demonstrated to have potent anti-infarct effect, technical difficulties have precluded its clinical application. We developed a novel therapeutic strategy of intravenous VNS (iVNS) and examined whether iVNS administered prior to coronary reperfusion in a canine AMI model reduces infarct size and prevents heart failure.


RESULTS
In 35 mongrel dogs, we induced ischemia by ligating the left anterior descending coronary artery and then reperfused 3h later (I/R). We transvenously placed a catheter electrode in the superior vena cava and adjusted the stimulation intensity to a level that induced bradycardia but maintained stable hemodynamics (continuous, 5.1±2.1V, 10Hz). We administered iVNS from onset (iVNS-0, n=7) or 90min after onset (iVNS-90, n=7) of ischemia until one hour after reperfusion. Four weeks after ischemia-reperfusion, iVNS markedly reduced infarct size (iVNS-0: 2.4±2.1%, p<0.05 and iVNS-90: 4.5±4.5%, p<0.05) compared with I/R control (I/R: 13.3±2.5%), and improved cardiac performance and hemodynamics. Atrial pacing (n=7) to abolish iVNS-induced bradycardia significantly attenuated the beneficial effects of iVNS.


CONCLUSIONS
Short-term iVNS delivered prior to coronary reperfusion markedly reduced infarct size and preserved cardiac function one month after AMI. The bradycardic effect plays an important role in the beneficial effect of iVNS. How other mechanisms contribute to the reduction of infarct size remains to be studied.
Department of Cardiovascular Medicine, Graduate School of Medical Sciences, 1-1-3 Maidashi Higashi-ku, Fukuoka 812-8582, Japan. Electronic address: arimurat@cardiol.med.kyushu-u.ac.jp.
Takahiro
T
Arimura
Department of Therapeutic Regulation of Cardiovascular Homeostasis, Center for Disruptive Cardiovascular Medicine, 1-1-3 Maidashi Higashi-ku, Fukuoka 812-8582, Japan. Electronic address: saku@cardiol.med.kyushu-u.ac.jp.
Keita
K
Saku
Department of Cardiovascular Medicine, Graduate School of Medical Sciences, 1-1-3 Maidashi Higashi-ku, Fukuoka 812-8582, Japan. Electronic address: kakino-t@cardiol.med.kyushu-u.ac.jp.
Takamori
T
Kakino
Department of Cardiovascular Medicine, Graduate School of Medical Sciences, 1-1-3 Maidashi Higashi-ku, Fukuoka 812-8582, Japan. Electronic address: nisikawa@cardiol.med.kyushu-u.ac.jp.
Takuya
T
Nishikawa
Department of Cardiovascular Medicine, Graduate School of Medical Sciences, 1-1-3 Maidashi Higashi-ku, Fukuoka 812-8582, Japan. Electronic address: tohyama@cardiol.med.kyushu-u.ac.jp.
Takeshi
T
Tohyama
Department of Cardiovascular Medicine, Graduate School of Medical Sciences, 1-1-3 Maidashi Higashi-ku, Fukuoka 812-8582, Japan. Electronic address: tsaka@cardiol.med.kyushu-u.ac.jp.
Takafumi
T
Sakamoto
Department of Cardiovascular Medicine, Graduate School of Medical Sciences, 1-1-3 Maidashi Higashi-ku, Fukuoka 812-8582, Japan. Electronic address: kazuos@cardiol.med.kyushu-u.ac.jp.
Kazuo
K
Sakamoto
Collaborative Research Institute of Innovative Therapeutics for Cardiovascular Diseases, Center for Disruptive Cardiovascular Medicine, Kyushu University, 1-1-3 Maidashi Higashi-ku, Fukuoka 812-8582, Japan. Electronic address: tkishi@cardiol.med.kyushu-u.ac.jp.
Takuya
T
Kishi
Department of Cardiovascular Medicine, Graduate School of Medical Sciences, 1-1-3 Maidashi Higashi-ku, Fukuoka 812-8582, Japan. Electronic address: tomomi_i@cardiol.med.kyushu-u.ac.jp.
Tomomi
T
Ide
Department of Therapeutic Regulation of Cardiovascular Homeostasis, Center for Disruptive Cardiovascular Medicine, 1-1-3 Maidashi Higashi-ku, Fukuoka 812-8582, Japan. Electronic address: sunagawa@cardiol.med.kyushu-u.ac.jp.
Kenji
K
Sunagawa
D000818:Animals; D004195:Disease Models, Animal; D004285:Dogs; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000517:prevention & control*; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000628:therapy*; D015425:Myocardial Reperfusion / Q000379:methods*; D015428:Myocardial Reperfusion Injury / Q000000981:diagnostic imaging / Q000628:therapy*; D011897:Random Allocation; D055536:Vagus Nerve Stimulation / Q000379:methods*; D014683:Vena Cava, Superior / Q000000981:diagnostic imaging
Acute myocardial infarction; Autonomic nervous system; Chronic heart failure; Infarct size; Vagal nerve stimulation