Parasympathetic dysfunction and antiarrhythmic effect of vagal nerve stimulation following myocardial infarction
Marmar Vaseghi, Siamak Salavatian, Pradeep S. Rajendran, Daigo Yagishita, William R. Woodward, David Hamon, Kentaro Yamakawa, Tadanobu Irie, Beth A. Habecker, Kalyanam Shivkumar
Marmar Vaseghi, Siamak Salavatian, Pradeep S. Rajendran, Daigo Yagishita, William R. Woodward, David Hamon, Kentaro Yamakawa, Tadanobu Irie, Beth A. Habecker, Kalyanam Shivkumar
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Research Article Cardiology

Parasympathetic dysfunction and antiarrhythmic effect of vagal nerve stimulation following myocardial infarction

Abstract

Myocardial infarction causes sympathetic activation and parasympathetic dysfunction, which increase risk of sudden death due to ventricular arrhythmias. Mechanisms underlying parasympathetic dysfunction are unclear. The aim of this study was to delineate consequences of myocardial infarction on parasympathetic myocardial neurotransmitter levels and the function of parasympathetic cardiac ganglia neurons, and to assess electrophysiological effects of vagal nerve stimulation on ventricular arrhythmias in a chronic porcine infarct model. While norepinephrine levels decreased, cardiac acetylcholine levels remained preserved in border zones and viable myocardium of infarcted hearts. In vivo neuronal recordings demonstrated abnormalities in firing frequency of parasympathetic neurons of infarcted animals. Neurons that were activated by parasympathetic stimulation had low basal firing frequency, while neurons that were suppressed by left vagal nerve stimulation had abnormally high basal activity. Myocardial infarction increased sympathetic inputs to parasympathetic convergent neurons. However, the underlying parasympathetic cardiac neuronal network remained intact. Augmenting parasympathetic drive with vagal nerve stimulation reduced ventricular arrhythmia inducibility by decreasing ventricular excitability and heterogeneity of repolarization of infarct border zones, an area with known proarrhythmic potential. Preserved acetylcholine levels and intact parasympathetic neuronal pathways can explain the electrical stabilization of infarct border zones with vagal nerve stimulation, providing insight into its antiarrhythmic benefit.

Authors

Marmar Vaseghi, Siamak Salavatian, Pradeep S. Rajendran, Daigo Yagishita, William R. Woodward, David Hamon, Kentaro Yamakawa, Tadanobu Irie, Beth A. Habecker, Kalyanam Shivkumar

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Figure 4

Classification and relationships of parasympathetic neurons in normal and infarcted hearts.

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Classification and relationships of parasympathetic neurons in normal an...
(A) Functional classification of parasympathetic neurons that receive inputs from the left or right vagus is shown in normal hearts. Overall, percentage of convergent parasympathetic neurons that responded to left VNS and at least 1 afferent stimulus (therefore classified as convergent) was 81% (109 of 135 left VNS responsive neurons from 15 normal animals), and the percentage of convergent neurons that responded to right VNS was 82% (109 of 133 right VNS responsive neurons from 15 normal animals). Of these convergent neurons, approximately 30% also received sympathetic input in normal hearts. (B) Type of parasympathetic neurons that receive input from the left or right vagus is shown in hearts with myocardial infarction (MI). Percentage of convergent neurons that responded to left VNS was 79% (42 of 53 left VNS responsive neurons from 10 infarcted animals), and percentage of convergent neurons that responded to right VNS was 82% (41 of 50 total neurons from 10 infarcted animals). These values were not different than normal hearts (P = 0.8, χ2 test). However, percentage of convergent neurons also receiving sympathetic input was significantly increased in infarcted (n = 15 animals) compared with normal hearts (n = 10 animals), representing 65% (27 of 47 convergent neurons) and 68% (28 of 50 convergent neurons) for left and right VNS in infarcted animals, respectively, compared with 31% (34 of 109 convergent neurons) and 30% (33 of 109 convergent neurons) for left and right VNS in normal hearts, respectively (P < 0.05, χ2 test). (C) Conditional probability analysis (probability that a VNS neuron that responded to one stimulus [X] also responded to another stimulus [Y]) for neurons that respond to VNS is shown in normal hearts. Significant relationships are noted for parasympathetic neurons that transduce preload and sensory inputs from the RV and LV due to touch, as well as those that transduce preload and receive sympathetic input. (D) Graphical representation of the conditional probability analysis is shown for VNS-responsive neurons of normal hearts, where significant relationships (those with a value ≥ 0.6) are delineated. (E) Conditional probability analysis for neurons that respond to VNS in infarcted hearts is shown. Significant relationships are noted for parasympathetic neurons that transduce preload and sensory inputs from the RV and LV due to touch, as well as those convergent neurons that transduce preload and receive sympathetic input. However, additional interactions of convergent neurons with sympathetic ganglion neurons exist in infarcted hearts. (F) Graphical representation of the conditional probability analysis is shown for parasympathetic neurons of infarcted hearts, where significant relationships (those with a value ≥ 0.6) are delineated. Eff, efferent; Symp, sympathetic; RV, right ventricle; LV, left ventricle; IVCo, IVC occlusion; Ao, aortic occlusion; SGS, sympathetic ganglion stimulation; VNS, vagal nerve stimulation; MI, myocardial infarction.