BASIC PRINCIPLES OF NEUROCARDIOLOGY IN HEALTH AND DISEASE

R.D.Foreman¹; J.L.Ardell² J.A.Armour³, B.Linderoth⁴, M.J.L.DeJongste^5
1 Department of Physiology, OUHSC, Oklahoma City, OK 73190; ²Department of Pharmacology, East Tennessee State University, Johnson City, TN 37614; ³Department of Physiology and Biophysics, Dalhousie University, Halifax Nova Scotia, B3H 4H7, Canada; ⁴Department of Neurosurgery, Karolinska Institute, S-171 76 Stockholm, Sweden; ⁵Cardiology Department, University and University Hospital of Groningen, Netherlands

Abstract: Spinal cord stimulation applied to the dorsal aspect of the T1-T2 spinal segments is an important adjuvant therapy for treating patients with chronic refractory angina pectoris.  These patients do not get sufficient pain relief or restoration of function even from optimal medical treatment.  This therapy has been used successfully in more than 80% of the treated patients and approximately 60% have demonstrated anti-ischemic effects of the heart and improved quality of life.  Even though this therapy has been used successfully, the underlying mechanisms producing anti-ischemic changes that occur with SCS have not been described.  The purpose of this presentation is to show that SCS modulates activity generated by the intrinsic cardiac nervous system, because this system serves to regulate information processing of the central nervous system and then alter cardiac function.  Results show that activity generated by the intrinsic cardiac neurons of the right atrial ganglionated plexus was suppressed whether SCS occurred immediately before, during or after occlusion of the left anterior descending coronary artery. Thus, this form of therapy may influence the function of the final common neuronal pathway of the heart, the intrinsic cardiac nervous system, in the presence of severe ischemic challenge.

INTRODUCTION

Angina pectoris resulting from ischemic heart disease is pain that is referred to the chest wall, although it can often radiate to the left arm and left jaw [1,2] and generally is described by patients as crushing, burning, and squeezing.  Typically, chronic stable angina can be treated with re-vascularization procedures such as percutaneous transluminal angioplasty or coronary artery bypass surgery and/or with medications, such as ACE inhibitors, beta-blockers, and calcium channel inhibitors [3].  However, a significant number of patients have chronic refractory angina pectoris but do not get sufficient pain relief or restoration of function even from optimal medical treatment [3].    Approximately 100,000 people in Europe and the United States have this problem but are not being treated adequately (MLJ deJongste, personal communication). 

An important adjuvant therapy for relieving chronic refractory angina pectoris is neuromodulation via the use of spinal cord stimulation (SCS).  In Europe, this therapy has been beneficial in more than 80% of the cases [4] and approximately 60% of the patients experienced anti-ischemic effects of the heart and improved quality of life for at least five years [5,6].  Patients who receive SCS still experience the pain of myocardial infarction even when the stimulator is on, thus the warning system is still intact [7,8,9,10].  This therapy appears to be a safe, cost effective and reversible but its mechanism of action is still not understood [11]. 

A critical key for using SCS therapy is to understand the underlying mechanisms that produce the anti-ischemic changes that occur with this treatment.  Previous studies have shown that SCS modulates processing of information within the central nervous system [12,13] and increases peripheral blood flow [14,15,16,17,18,19].  The purpose of this presentation is to show that SCS modulates activity generated by the intrinsic cardiac nervous system, since this system serves as a final common neuronal regulator of cardiac function [20] and is interposed between the information processing of the central nervous system and cardiac function (Fig.1) [21]. 

METHODS

Details of the methods can be found in articles by Foreman et al. [21] and Armour et al., [22].  A brief summary will be presented here.  These experiments followed the guidelines outlined by the International Association for the Study of Pain as well as the NIH Guide for the Care and Use of Laboratory Animals (National Academy Press, Washington, D.C., 1996).  Dogs of mixed breed were anesthetized in a standard manner by first administering a bolus dose of sodium thiopental (20 mg/kg, iv) and then maintained throughout the experiment with alpha chloralose (75 mg/kg, iv).  Thereafter, doses of alpha chloralose (20 mg/kg, iv) were administered repeatedly, as required, during the remainder of the experiment.   

To implant the SCS electrodes, a Toughy needle was used to penetrate the epidural space of the mid-thoracic spinal column using A-P fluoroscopy and the loss-of-resistance technique, as is routinely done in the clinical setting.  A four-pole catheter electrode was passed through the Toughy needle and its tip was advanced to the T1 level of the spinal column, slightly to the left of the midline.  The electrode lead, covered by a Teflon protective sleeve, was fixed to adjacent interspinous ligaments with a suture.  Extension wires attached to the electrode leads were then connected to a Grass stimulator. 

After placing the animal in a supine position, a bilateral thoracotomy was made in the fifth intercostal space.  The ventral pericardium was incised and retracted laterally to expose the heart and the ventral right atrial deposit of fat containing the ventral component of the right atrial ganglionated plexus.  A circular ring of stiff wire was placed gently on the fatty epicardial tissue overlying the ventral surface of the right atrium that contained the right atrial ganglionated plexus­.   A tungsten microelectrode (10 µm shank diameter; exposed tip of 1 µm; impedance of 9-11 Mohms at 1000 Hz) mounted on a micromanipulator and lowered with a microdrive into this ganglionated plexus to record action potentials generated by the somata and/or dendrites of intrinsic atrial neurons.  This activity was amplified differentially, displayed on a 8 channel rectilinear recorder along with the cardiovascular variables, and stored on a digital tape system for later analysis. 

To induce ischemia of the ventricle later in the experiments, the left anterior descending (LAD) coronary artery approximately 1.5 cm from its origin and distal to its first diagonal branch was occluded by pinching the artery with silk (3-0) suture having the ligatures passed through short segments of polyethylene tubing.  Since the arterial blood supply of the right atrial neurons arises from major branches of the right and distal circumflex coronary arteries, their blood supply remained patent during coronary artery occlusions. 

Electrical stimuli were delivered at 50 Hz and 0.2 ms duration to the dorsal aspect of the thoracic spinal cord for various time periods.  An intensity of 90% of motor threshold (MT) was used for all stimulations (Linderoth & Foreman, 1999[18]). 

Figure 1:  Schematic diagram of the hierarchical organization important in neural control of the heart. The hierarchy in the central nervous system is comprised of descending projections from the Spinal Cord, Medulla and, and Higher Centers including the brainstem and cortex. These descending projections continuously influence activity in the Intrathoracic Extracardiac Ganglia and/or the Intrinsic Cardiac Nervous System in ganglionated plexi of the heart. Dashed lines and open boxes represent afferent feedback originating from the heart.  Black arrows illustrate direct and successive synaptic relays from the medulla and spinal cord to sites within this autonomic neuronal hierarchy. The black arrows within the Intrinsic Cardiac Nervous System and IEG represent afferent and efferent connections, and Local Circuit Neurons (LCN). This hierarchy composed of peripheral autonomic nested feedback loops functions in an interdependent manner to regulate regional cardiac function on a beat-to-beat basis. NODOSE, ganglion for vagal afferent fibers; DRG, Dorsal Root Ganglia for sympathetic afferent fibers; Symp, Sympathetic; Parasymp, Parasympathetic; b1, Beta-adrenergic receptors; M₂, Muscarinic receptors.) [Adapted from 20,23,24]

Figure 2: Responses of the averaged activity (impulses per minute, imp/min) generated by the intrinsic cardiac nervous system (right atrial ganglionated plexus) during occlusion of the left coronary artery and spinal cord stimulation. The hatched horizontal bar represents the period of coronary artery occlusion (CAO) and the stippled bar is the period of spinal cord stimulation (SCS). The first bar is control intrinsic activity and the last bar is recovery of activity. These results show that SCS significantly reduces activity generated by intrinsic cardiac neurons even during CAO. * Represents data that were significantly different from control values (P<0.05). [Adapted from 24]

Figure 4: Average intrinsic cardiac neuronal activity recorded in five animals before, during and after SCS (black bar) applied in the presence of coronary artery occlusion (CAO: stippled bar). [Adapted from 22]  

RESULTS

Occlusion of the left anterior descending and circumflex coronary arteries for 2 minutes was used to induce ventricular ischemia in neurally intact preparations.  This intervention increased the activity generated by right atrial neurons increased by 46% despite the fact that their blood supply was unaffected (Fig.2).  Immediately after reperfusion began neuronal activity increased even more (+68% compared to control values).  Monitored cardiac indices did not change significantly during these initial 2 minutes of coronary artery occlusion or during the reperfusion phase.

Activity generated by a majority of the identified right atrial neurons was reduced when SCS was applied for 4 minutes at 90% MT (Fig.2).  Neuronal activity remained depressed for 5-25 seconds after SCS had ceased, returning to control levels after 30-45 seconds.  SCS did not change monitored cardiac indices overall.  The presence of SCS prevented the increases in neuronal activity elicited by coronary artery occlusion (Fig.2) Monitored cardiovascular variables did not change significantly when the combined coronary artery occlusion and SCS protocols were instituted.  The salient point derived from these data is that although intrinsic cardiac neurons were activated during myocardial ischemia, intrinsic cardiac neuronal activity did not increase when ischemia was induced concomitant with spinal cord stimulation.

Within 30 seconds of the onset of SCS in normally perfused hearts, activity generated by right atrial neurons was reduced significantly (Fig.3).  After coronary artery occlusion had been maintained for one-minute (2 minutes after beginning SCS) right atrial neuronal activity was 15.1±3.1 ipm and remained suppressed during the coronary artery occlusion (15 minutes).  After discontinuing SCS (17 minutes), neuronal activity gradually increased toward control levels after 45 minutes.  Monitored cardiovascular indices did not change overall when SCS was applied during coronary artery occlusion.  Ischemia-induced alterations in ECG patterns also remained the same throughout the period when SCS was applied concomitant with the occlusions. 

DISCUSSION

Neuro-suppressor effects occurred whether SCS occurred immediately before, during or after coronary artery occlusion.  These data supported the idea that SCS could exert suppressor effects on the ability of a significant population of intrinsic cardiac neurons that generate activity.  Furthermore, SCS could override reperfusion-induced intrinsic cardiac neuronal excitation occurring both during and immediately after periods of acute ventricular ischemia.  These results also argue against the idea that the anti-ischemic effects of SCS in a clinical setting can be ascribed to alterations in hemodynamics [25, 21] or coronary artery blood flow [26].  More likely SCS exerts its primary effects on the intrinsic cardiac nervous system that, in turn, may influence control over regional cardiac electrical or mechanical events.

These data also indicate that SCS initiates spinal neuronal activity that induces a conformational change in the intrinsic cardiac nervous system that persists long after discontinuing the stimulation.  This remodeling of the intrinsic cardiac nervous system can override excitatory inputs to it arising from the ischemic myocardium.  These results lead to the suggestion that thoracic spinal neurons can function to stabilize the intrinsic cardiac nervous system even in the presence of ventricular ischemia and during reperfusion [22].  Thus, the prolonged salutary effects that SCS produces in some patients long after it is discontinued may, in part, be due to remodeling of the intrinsic cardiac nervous system. 

We have proposed that the intrinsic cardiac nervous system acts as the final common regulator of cardiac function [27,28,29,30].  The effects that SCS induces in a clinical setting may, in part, reside in the capacity of such therapy to stabilize this common regulator in the presence of ventricular ischemia.  Since the intrinsic cardiac nervous system receives inputs arising from cardiac sensory neurites as well as from central neurons (Fig.1)[28], SCS may exert multiple effects on this local neuronal circuitry.  Excessive activation of intrinsic cardiac neuron populations might eventually produce unstable cardiac afferent neuronal regulation, which, in turn, could lead to the genesis of ventricular tachydysrhythmias [31] or perhaps critical coronary artery changes that enhanced the effects of myocardial ischemia.  Data obtained in the present experiments indicated that SCS reduced the excitability of intrinsic cardiac neurons, even those sensitive to ventricular ischemia.

In summary, this form of therapy may influence the function of the final common neuronal pathway of the heart, the intrinsic cardiac nervous system, in the presence of severe ischemic challenge.  Thus, SCS most likely acts to protect the heart from some of the deleterious consequences resulting from myocardial ischemia that produces angina pectoris.

Acknowledgments:  Supported by the Bakken Research Center and Medtronic, Inc., the Medical Research Council of Canada (MT-10122) (JAA), the NIH (grants # HL58140 (JLA), HL52986 (RDF), NS36775 (RDF), and NS35471 (RDF)), the Swedish Medical Research Council (MFR) (BL), the American Heart and Stroke Foundation (JAA) and the American Heart Association (JLA).  Special Thanks to Julie Marley for formatting the figures and the manuscript.

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