Walter C. Randall

Patterns of Sympathetic Nerve Projections onto the Canine Heart

Major branches from right and left sympathetic ganglia were electrically stimulated while force of contraction was recorded from multiple areas of the right and left ventricles. Stimulation of the stellate ganglia generally elicited alterations in force of contraction from all test segments, but excitation of selected nerve trunks induced responses in highly localized regions of the heart. Ablation of narrow strips of epicardium resulted in obliteration of contractile responses in specific, highly localized regions of the heart; thus a major fraction of the sympathetic innervation of the ventricular chambers is by way of the epicardial plexus. The anterior surface of the right ventricle is supplied by projection pathways arising within the immediately subepicardial regions of the right A-V groove and, to a lesser extent, from the tissues immediately adjacent to the left anterior descending artery. The left ventricle receives minor projections from the right A-V groove with major projections from subepicardial tissues along the left anterior descending artery. In some animals there also exists a definite left ventricular supply from the region of the left A-V groove. Whereas the thoracic vagi send dense projections to the atria, and particularly to nodal tissue, they also supply both ventricles with inhibitory and augmentor fibers. Although isolated cardiac nerves may carry predominantly sympathetic or parasympathetic fibers, many show rich intermingling of these fibers in trunks distal to the caudal cervical ganglion.

The Augmentor Action of the Sympathetic Cardiac Nerves

An augmentor action of the cardiac sympathetic nerves is demonstrated to elicit profound elevations in systolic blood pressure. Diastolic pressure does not rise in an equivalent amount and significant increase in pulse pressure occurs. This persists for a considerable time after removal of the stimulation. During stimulation of the left cardiac sympathetic, an augmentor action is often not accompanied by acceleration. Stimulation of the right cardiac sympathetic evokes both effects. The elevation of blood pressure is chiefly produced by augmentation of ventricular beats, not by cardiac acceleration.

Vagal postganglionic innervation of the canine sinoatrial node.

Differential, selective distribution of parasympathetic, postganglionic innervation to the atrioventricular nodal (AVN) region of the canine heart was recently described. Ablation of parasympathetic pathways to the AVN by disruption of the epicardial fat pad at the junction of the inferior vena cava and inferior left atrium did not interfere with normal vagal control of the sinoatrial node (SAN) function. In sharp contrast, surgical dissection of the fat pad overlying the right pulmonary vein-left atrial junction interrupted the major right and left vagal inputs to the SAN region. The pulmonary vein fat pad (PVFP) in the dog heart is triangular in shape with roughly equilateral dimensions of approximately 1 cm, its base extending from superior to inferior veins, and its apex extending nearly to the sinus nodal artery as it courses rostrally in the sulcus terminalis. Careful dissection of smaller fat pads around the circumference of the pulmonary veins and particularly over the rostral-dorsal surfaces of the right superior pulmonary vein and adjacent right atrium, completed SAN parasympathetic denervation. Care in making these dissections left the vagal supply to the AVN region essentially intact, and preserved the sympathetic supplies to both SAN and AVN regions. Autonomic ganglia, varying in size from 1 or 2 cells to 80-100 cells, were found scattered throughout the ventral PVFP (overlying and surrounding the right pulmonary vein-left atrial junction). The ganglia were generally imbedded in fatty connective tissue, although they commonly rested very close to, or were loosely surrounded by epicardial muscle. Ganglia were also found in smaller fat pads on the dorsal surfaces of the atrium between the azygos and the right superior pulmonary vein.

Parasympathetic ganglia innervating the canine atrioventricular nodal region.

Surgical disruption of the small (approximately 0.7 x 1.0 cm) epicardial fat pad situated at the junction of the inferior vena cava (IVC) and inferior surface of the left atrium (ILA) interrupts both right and left vagal input to the atrioventricular nodal (AVN) region of the canine heart. This intervention eliminates AV block during supramaximal stimulation of both cervical vagi, without interfering with sinus bradycardia normally associated with sinoatrial nodal (SAN) suppression. Independent modulation of SAN and AVN activities by the parasympathetic system is thereby revealed. Histology of the excised IVC-ILA fat pad reveals multiple well organized autonomic ganglia. These ganglia range from 2 to 80 cells per cluster and are associated with numerous nerve trunks. Individual ganglia are commonly surrounded by fatty connective tissue closely adjacent to epicardial muscle. They have not been found imbedded within atrial muscle and have been been found in or close to endocardial muscle layers. Other ganglia, imbedded in the fat pad overlying the posterior surface of the left atrium or in the atrioventricular groove, do not directly modulate A-V conduction. Surgical dissection around the extreme left or middle segments of the great cardiac vein and the coronary sinus failed to interrupt either left or right vagal input to the AVN region. Parasympathetic, preganglionic pathways to these AVN synapses do not, therefore, course from left to right along the atrioventricular groove. However, dissection around the extreme right portion of the coronary sinus at its penetration of the inferior interatrial septum, did interrupt vagal influences upon A-V conduction. Thus, numerous autonomic ganglia have been localized in the canine heart which serve as synaptic stations mediating both right and left vagal regulation of A-V conduction.

Cardiac dysrhythmias induced by autonomic nerve stimulation

Cardiac tachydysrhythmias were induced in anesthetized dogs by electrical stimulation of the ventral lateral cardiac nerve at the level of the left pulmonary veins. Electrical activity was recorded from seven myocardial segments including the areas near the sinoatrial node, anterior, middle and posterior internodal pathways, the atrioventricular (A-V) nodal region (His bundle electrogram), the right bundle branch and the left ventricular epicardium. Electrical stimulation of the ventral lateral cardiac nerve induced a variety of supraventricular and ventricular tachydysrhythmias. Various degrees of heart block were induced, second degree block rostral to the His bundle, and total A-V dissociation. A-V junctional rhythms, bundle of His pacemakers, ventricular pacemakers and Wenckebach arrhythmias were also observed. Atrial rates during the tachydysrhythmias frequently exceeded 500/min; ventricular rates sometimes approached 350/min. The tachydysrhythmias are interpreted as arising from ectopic foci located in the lower right atrium-upper ventricular septal areas. Use of standard pharmacologic blocking agents such as intravenously administered atropine, propranolol and phentolamine did not abolish the induced tachydysrhythmias, but administration of lidocaine or procaine was effective in the termination and prevention of the dysrhythmias. The tachydysrhythmias were also induced in partially sympathectomized dogs, but higher voltages were required. Neurally induced tachydysrhythmias resemble spontaneous arrhythmias in man, thus suggesting the possibility that arrhythmias in the human subject may be of autonomic nervous origin.

Local epicardial chemical ablation of vagal input to sino-atrial and atrioventricular regions of the canine heart

In open-chest, pentobarbitalized dogs, right and left cervical vagi were electrically stimulated (20 Hz, 5.0 ms, 4-6 volts) before and after carefully painting phenol (90%) over each of 6-8 narrow strips (2-3 mm width) and over restricted portions of the superior and inferior right atrium. Successive phenol strips were applied until the sino-atrial nodal (SAN) region had been completely surrounded, and also applied over a triangular fat pad at the junction of the inferior vena cava (IVC) and inferior left atrium (ILA). Electrical excitation of the autonomic trunks following each sequential epicardial phenol blockade resulted in successive deletion of cardio-inhibitory responses, a majority of sympathetic excitatory responses remaining intact. We conclude that most vagal fibers reach the SAN region via the superior-posterior right atrium (SVC and superior pulmonary veins) and these can be ablated leaving most vagal fibers to the atrioventricular nodal AVN region unimpaired. Phenol painting at the junction of IVC and ILA abolished vagal inhibition of conduction across the A-V junction. These studies illustrate distinct vagal distributions to the SAN and AVN regions of the canine heart. After all responses to vagal stimulation have been abolished, sympathetic alterations in heart rate and A-V conduction remain, thus revealing important differentiation in sympathetic fiber distribution to these key regions of automaticity and conduction.

Selective vagal postganglionic innervation of the sinoatrial and atrioventricular nodes in the non-human primate

The distribution of parasympathetic postganglionic nerves to the atrioventricular (AVN) and sinoatrial nodal (SAN) regions was investigated in the non-human primate heart. Eight male monkeys (Macaca fascicularis) weighing 5.5-7.0 kg. were anesthetized (alpha-chloralose, 50 mg/kg and urethane, 500 mg/kg) and instrumented to measure arterial pressure, electrocardiogram, atrial and ventricular electrograms. The cervical vagi were electrically stimulated (20 Hz, 4 V, 2 ms) before and after selective denervation (D) of the AVN and/or SAN. Vagal stimulation was repeated during atrial pacing to assess parasympathetic modulation of AVN conduction. Ablation of parasympathetic pathways to the AVN, accomplished by the disruption of the epicardial fat and surface muscle layer at the junction of the inferior vena cava and inferior left atrium eliminated (P less than 0.01) the dromotropic effects of vagal stimulation without affecting the heart rate response (right vagus, before D, paced: atrial rate 218.0 +/- 6.3, ventricular rate 67.1 +/- 23.7; after D: atrial rate 210.3 +/- 6.4, ventricular rate 210.3 +/- 6.4 beats/min, means +/- S.D.). In sharp contrast, surgical dissection of the fat pad overlying the right pulmonary vein-superior vena cava junction significantly (P greater than 0.01) attenuated negative chronotropic effects of vagal stimulation (left vagus, before D the R-R interval increased by 832.7 +/- 146.4 ms, 209.5% increase; after D 37.4 +/- 18.0 ms, 8.8% increase). These data demonstrate discrete vagal efferent pathways innervate both the SAN and AVN regions of the non-human primate heart.

Cardiac dysrhythmias in the conscious dog after surgically induced autonomic imbalance

The ventrolateral cardiac nerve in the dog is a primary branch of the left sympathetics and represents a direct neural link between the central nervous system and the heart. Its electric excitation elicits characteristic shifts in pacemaker and tachydysrhythmias related to its explicit innervation of the inferior atrial, atrioventricular (A-V) junctional and ventricular tissues. Total denervation of the canine heart, sparing the ventrolateral cardiac nerve, produced a long-term model in which only these portions of the heart retained their sympathetic innervation. The trained unanesthetized model dog was subjected to severe exercise in order to determine the effects of elevated levels of sympathetic tone upon these important regions of the conduction system. Reproducible tachydysrhythmias were elicited in all six animals completing the regimen of periodic testing over a period of 136 to 378 days after operation. The abnormal rhythms consisted of shifting cardiac pacemakers and supraventricular A-V junctional and ventricular tachycardias with frequent premature systoles. Comparable abnormalities were not observed in a similarly tested sham-operated animal or in dogs with a totally denervated heart. The exercise-induced dysrhythmias gradually disappeared with time, presumably in relation to autonomic reinnervation of the heart. The characteristic patterns of ventrolateral cardiac nerve and upon its presumed influence upon Purkinje fiber and A-V nodal automaticity and temporal dispersion of refractoriness in myocardial tissues.

Localized Myocardial Responses to Stimulation of Cardiac Sympathetic Nerves

Myocardial contractile force was recorded at three to five positions on the canine heart while progressively more distal portions of the cardiac sympathetic nerves were electrically stimulated. When the electrodes were applied directly to the stellate ganglion or to the ansa subclavia, positive inotropic responses were generally observed on all of the test regions of the heart. However, when more distal branches of the cardiac nerves were stimulated, individual test regions were successively deleted from the general response. By carefully removing narrow strips of epicardium (epicardial denervation) from different portions of the heart, similar deletions in response were observed. These observations indicate that the peripheral autonomic innervation of the heart is distributed to circumscribed regions of cardiac musculature. Contractile segments of a given region of the heart may be organized in series and each component of the chain influences the contraction of neighboring elements, normally innervated segments mechanically interacting with noninnervated regions. Individual units of cardiac muscle may be markedly influenced through local intervention by the sympathetic nerve supply.

Adverse effects of chronic cardiac denervation in conscious dogs with myocardial ischemia.

The extent to which total chronic cardiac denervation protects the ischemic myocardium was investigated in conscious dogs. The major hemodynamic difference after coronary artery occlusion was that left ventricular end-diastolic pressure rose significantly more, P less than 0.01, in the denervated group (12 +/- 1.5 mm Hg) than in the normal group (4.4 +/- 1.4 mm Hg). Blood flow (radioactive microspheres) in the ischemic endo- and epicardium fell to similar levels at 3-5 minutes after coronary occlusion, but was significantly less (P less than 0.01) in denervated dogs at 3 hours after occlusion in the endo- (0.05 +/- 0.01) and epicardium (0.30 +/- 0.02 ml/min per g), than in the endo- (0.13 +/- 0.03) and epicardium (0.42 +/- 0.05 ml/min per g) in the normal group. A subgroup of normal dogs was also studied, with left ventricular end-diastolic pressure increased by volume loading to levels similar to those observed in the denervated group after coronary occlusion; in these dogs, blood flow was similar to that in the other two groups 3-5 minutes after coronary artery occlusion, but, at 3 hours, was significantly more depressed (P less than 0.01) than that observed in normal dogs without volume loading in both endo- (0.03 +/- 0.01) and epicardial (0.25 +/- 0.03 ml/min per g) layers. Infarct size, as a fraction of the area at risk, was significantly greater (P less than 0.05) in the denervated group (60 +/- 4.3%) and in the subgroup of normal dogs with elevated left ventricular end-diastolic pressure (73 +/- 5.8%), compared with the normal group without volume loading (37 +/- 8.1%). Thus, in conscious dogs, total chronic cardiac denervation exerts an adverse effect on infarct size which may be related to the sustained elevation in left ventricular end-diastolic pressure and consequent impairment of collateral perfusion.