(849.4) Chronic Vagal Nerve Stimulation Rescues Sympathetic Control of the Heart following Myocardial Infarction

Poster Board Number: E4

Joseph Hadaya (University of California), Christopher Chan (University of California), Shumpei Mori (University of California), Donald Hoover (Quillen College of Medicine, East Tennessee State University), Kalyanam Shivkumar (University of California), Jeffrey Ardell (University of California)

Cardiac injury, such as myocardial infarction (MI), leads to neurohormonal activation and autonomic remodeling, resulting in reflexive sympathoexcitation and parasympathetic dysfunction, which further contribute to progression of disease. The purpose of this study was to determine whether chronic cervical vagal nerve stimulation (VNS) influences MI-associated changes in cardiac sympathetic function. Yucatan minipigs were divided into control (n=6), chronic MI (n=7), and chronic MI + chronic VNS (n=8) groups. VNS therapy was delivered to the right cervical vagus nerve and systematically titrated to an optimal intensity based on heart rate dynamics (5Hz, 2.1±0.3mA, 250μs, 17.5% duty cycle) using telemetry in the conscious state. Chronic MI was created using percutaneous embolization of the left anterior descending coronary artery with polystyrene beads under fluoroscopy (Figure 1A). VNS therapy was started 2 days following MI, and the animals maintained for 6-8 weeks. At terminal study, we evaluated hemodynamic responses to graded bilateral sympathetic chain stimulation (BSS). Left ventricular (LV) strips encompassing regions of scar, border zone, and normal myocardium were fixed in 10% formalin, embedded in paraffin, sectioned, and studied using Massons trichrome stain (Figure 1B-C). Structural changes at the peri-infarct area were scored (0-3) for myocyte morphology and presence of hypertrophy or myocytolysis. Animals with MI alone exhibited spontaneous ventricular arrhythmias, including two that experienced sudden cardiac death (Figure 1D). At terminal study, there were no significant differences in baseline systolic function among groups. Moderate (4Hz) and high (10Hz) intensity BSS increased LV contractility (dp/dtmax) in all groups (Figure 2A-B); however, evoked changes were significantly reduced in the chronic MI compared to control or MI + VNS groups. While control animals displayed evidence of contractile reserve at 10Hz vs 4Hz (1297±266 mmHg/s, p=0.03), chronic MI animals did not (631.9±264 mmHg/s, p=0.11), which was improved with chronic VNS therapy (1027±160.6 mmHg/s, plt;0.01, Figure 2C). Chronic VNS therapy also significantly reduced MI-associated structural remodeling in the peri-infarct area, including the degree of myocytolysis and dysmorphic myocytes (structural abnormality index 0.6±0.2 vs 1.8±0.2, plt;0.01). Our findings suggest that chronic VNS ameliorates sympathetic functional remodeling following myocardial infarction and improves cardiac mechanical performance in response to simulated stress. Furthermore, chronic VNS reduces pathologic myocardial remodeling at the peri-infarct zone, potentially stabilizing the resultant ventricular scar.

This work was supported by the National Institutes of Health (NIH) Office of The Director through the Stimulating Peripheral Activity to Relieve Conditions (SPARC) Program (OT2 OD023848, PI: KS), the NIH National Institute of Biomedical Imaging and Bioengineering (U01 EB025138, PI: JLA), the NIH National Heart, Lung, and Blood Institute (F32 HL160163, PI: JH), and the American Heart Association (Fellowship 836169, PI: JH).





Figure 1. Validation of porcine MI model. (A) Coronary angiogram with acute occlusion of left anterior descending coronary artery (arrow). (B) and (C) Pressure perfusion-fixed heart and representative Masson’s trichrome stain demonstrating region of MI. (D) Normal ambulatory electrogram and ambulatory electrogram of animal with spontaneous sudden cardiac death (arrow indicates initiation of ventricular tachycardia).; Figure 2. Chronic VNS improves cardiac mechanical performance following MI. Responses to bilateral sympathetic chain stimulation at 4Hz (A) and 10Hz (B) were significantly greater in MI + VNS vs MI animals. Control and MI + VNS animals displayed significant increases in dP/dtmax at 10Hz vs 4Hz, while MI animals did not (C). *p < 0.05, **p < 0.01.