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. 2023 Jun 7;8(9):1100-1118.
doi: 10.1016/j.jacbts.2023.03.025. eCollection 2023 Sep.

Vagal Nerve Stimulation Reduces Ventricular Arrhythmias and Mitigates Adverse Neural Cardiac Remodeling Post-Myocardial Infarction

Joseph Hadaya  1   2 , Al-Hassan Dajani  1 , Steven Cha  1 , Peter Hanna  1   2 , Ronald Challita  1 , Donald B Hoover  3   4 , Olujimi A Ajijola  1   2 , Kalyanam Shivkumar  1   2 , Jeffrey L Ardell  1   2
Affiliations

Vagal Nerve Stimulation Reduces Ventricular Arrhythmias and Mitigates Adverse Neural Cardiac Remodeling Post-Myocardial Infarction

Joseph Hadaya et al. JACC Basic Transl Sci. .

Abstract

This study sought to evaluate the impact of chronic vagal nerve stimulation (cVNS) on cardiac and extracardiac neural structure/function after myocardial infarction (MI). Groups were control, MI, and MI + cVNS; cVNS was started 2 days post-MI. Terminal experiments were performed 6 weeks post-MI. MI impaired left ventricular mechanical function, evoked anisotropic electrical conduction, increased susceptibility to ventricular tachycardia and fibrillation, and altered neuronal and glial phenotypes in the stellate and dorsal root ganglia, including glial activation. cVNS improved cardiac mechanical function and reduced ventricular tachycardia/ventricular fibrillation post-MI, partly by stabilizing activation/repolarization in the border zone. MI-associated extracardiac neural remodeling, particularly glial activation, was mitigated with cVNS.

Keywords: myocardial infarction; neurocardiology; sympathetic nervous system; vagal nerve stimulation; ventricular tachycardia/ventricular fibrillation.

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Conflict of interest statement

This work was supported by the National Institutes of Health through the Office of the Director Grant OT2 OD023848 (Drs Shivkumar, Ardell, Ajijola, and Hoover), the National Institute of Biomedical Imaging and Bioengineering Grant U01 EB025138 (Drs Shivkumar and Ardell), and the National Heart, Lung, and Blood Institute Grants F32 HL160163 (Dr Hadaya) and R01 HL159001 (Drs Ajijola, Shivkumar, and Ardell). University of California-Los Angeles has patents developed by Drs Ardell and Shivkumar relating to cardiac neural diagnostics and therapeutics. Drs Ardell, Ajijola, and Shivkumar are cofounders of NeuCures, Inc. All other authors have no relationships relevant to the contents of this paper to disclose.

Figures

None
Graphical abstract
Figure 1
Figure 1
Study Design and Methods (A) Control, MI, and MI + cVNS Yucatan minipigs underwent in vivo and ex vivo evaluation of cardiac mechanical and electrophysiological function, as well as myocardial and extracardiac neural remodeling. (B and C) Representative images of implanted VNS generator at the right vagus nerve. (D) Left coronary angiogram after microsphere embolization of the mid-LAD coronary artery. (E) Spontaneous VT in an ambulatory pig observed 2 days after MI, which led to sudden death. Atrial depolarization (near field) annotated as A, and ventricular depolarization (far field) annotated as V; note maintenance of native atrial rhythm during VT. Scale bar: 1 s. Figure partly created using BioRender.com. cVNS = chronic vagal nerve stimulation; LAD = left anterior descending coronary artery; MI = myocardial infarction; VNS = vagal nerve stimulation; VT = ventricular tachycardia.
Figure 2
Figure 2
cVNS Improves Cardiac Mechanical Performance and Contributes to Greater Cardiac Sympathetic Reserve Post-MI (A) Representative long-axis echocardiograms of MI and MI + cVNS animals. Note the degree of chamber dilation and greater end-systolic volume in MI compared with MI + cVNS. (B) MI resulted in a significant reduction in LV systolic function, with lower ejection fraction and higher LV internal dimension in diastole, which was ameliorated using cVNS. (C) MI animals had impaired inotropic (dP/dtmax) and lusitropic (dP/dtmin) sympathetic responses to both 4 Hz and 10 Hz bilateral sympathetic chain stimulation, which was rescued using cVNS. Data presented as mean ± SEM and analyzed using ANOVA and t test. ∗P < 0.05; ∗∗P < 0.01; ∗∗∗P < 0.001. ANOVA = analysis of variance; Ctrl = control; LV = left ventricular; other abbreviations as in Figure 1.
Figure 3
Figure 3
Antiarrhythmic Effects of cVNS (A) Representative LV pressure tracing, and unipolar and bipolar EGMs during programmed electrical stimulation in MI and MI + cVNS animal. (B) cVNS significantly reduced the inducibility of sustained VT or VF regardless of whether PES was performed with or without active VNS. (C) MI animals demonstrated significantly greater ease of VT/VF induction compared with MI + cVNS pigs. Data presented as count (B) or mean ± SEM (C) and analyzed using chi-square test (B) or Kruskal-Wallis and Wilcoxon rank-sum test (C). ∗P < 0.05; ∗∗P < 0.01; ∗∗∗P < 0.001. EGM = electrogram; NSVT = nonsustained ventricular tachycardia; PES = programmed electrical stimulation; VF = ventricular fibrillation; other abbreviations as in Figures 1 and 2.
Figure 4
Figure 4
cVNS Stabilizes Electrical Activation Across the Infarcted Left Ventricle, Mitigates Conduction Block, and Promotes Homogeneous Activation in Sinus Rhythm (A) High-density electrophysiological mapping was performed across the LV scar-border zone (and equivalent region in control), representative activation maps for control, MI, and MI + cVNS displayed. (B) Representative tissue activation curve demonstrating isotropic conduction in control animals compared with anisotropic conduction with block in MI, which was qualitatively improved with cVNS. (C to F) MI animals displayed significantly worse activation properties in sinus rhythm including greater activation time, dispersion, delay, and maximum activation time. These were all normalized in MI + cVNS animals, except activation dispersion (D). Data presented as mean ± SEM and analyzed using ANOVA or Welch’s ANOVA and t test. ∗P < 0.05; ∗∗P < 0.01; ∗∗∗P < 0.001. Abbreviations as in Figures 1 and 2.
Figure 5
Figure 5
cVNS Reduces Repolarization Heterogeneity and Leads to More Shallow Repolarization Gradients (A) Representative repolarization maps for control, MI, and MI + cVNS demonstrating very steep and heterogeneous repolarization across the scar-border zone in MI animals, which was qualitatively improved in MI + cVNS. (B) Representative tissue repolarization curve demonstrating regions of rapid changes in repolarization time in a MI animal. (C) No significant difference in LV ARI was evident in the studied groups, whereas MI resulted in greater ARI heterogeneity, which was partially improved with cVNS (D). Repolarization gradients (E) were significantly greater in MI animals, and normalized with cVNS. Data presented as mean ± SEM and analyzed using Welch’s ANOVA and t test (C) or Kruskal-Wallis and Wilcoxon rank-sum test (D and E). ∗P < 0.05; ∗∗P < 0.01; ∗∗∗P < 0.001. ARI = activation recovery interval; other abbreviations as in Figures 1 and 2.
Figure 6
Figure 6
cVNS Mitigates Structural Remodeling at the Scar-Border Zone Representative Masson’s trichrome stains from MI (A, inset, B) and MI + cVNS (C, inset, D) animals. MI animals more commonly had myocytolysis (arrow), hypertrophy, and decreased muscle band staining. which was less common in MI + cVNS animals (D, E). Data presented as mean ± SEM and analyzed using Wilcoxon rank-sum test. ∗P < 0.05; ∗∗P < 0.01; ∗∗∗P < 0.001. Abbreviations as in Figure 1.
Figure 7
Figure 7
cVNS Reduces Extracardiac Neural Remodeling in the Stellate Ganglia (A) Cholinergic transdifferentiation occurred after MI in both MI and MI + cVNS groups, and was unaffected by cVNS therapy. (B) Expression of NPY in the stellate ganglia was greater in MI animals compared with control, but similar in MI + cVNS pigs relative to control. (C) Glial activation significantly increased in MI animals compared with controls, which was ameliorated in MI + cVNS. Scale bar: 50 μm (except insets scale bar: 20 μm). Data presented as mean ± SEM and analyzed using Kruskal-Wallis and Wilcoxon rank-sum test (A and B) or Welch’s ANOVA and t test (C). ∗P < 0.05; ∗∗P < 0.01; ∗∗∗P < 0.001. GFAP = glial fibrillatory acidic protein; NPY = neuropeptide Y; PGP9.5 = protein gene product 9.5; S100B = S100 calcium-binding protein B; TH = tyrosine hydroxylase; VAChT = vesicular acetylcholine transporter; other abbreviations as in Figures 1 and 2.
Figure 8
Figure 8
cVNS Reduces Glial Activation After MI in the Thoracic Dorsal Root Ganglia (A) nNOS expression significantly increased after MI, which was mitigated using cVNS. (B) No difference was evident in CGRP expression across study groups. (C) MI resulted in significantly greater glial activation in the thoracic dorsal root ganglia, which was significantly reduced in MI + cVNS animals. Scale bar: 50 μm. Data presented as mean ± SEM and analyzed using Kruskal-Wallis and Wilcoxon rank-sum test. ∗P < 0.05; ∗∗P < 0.01; ∗∗∗P < 0.001. CGRP = calcitonin gene-related peptide; nNOS = neuronal nitric oxide synthase; other abbreviations as in Figures 1, 2, and 7.
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