David A. Murphy

Gross and microscopic anatomy of the human intrinsic cardiac nervous system

The extent and locations of intrinsic cardiac ganglia on the human heart were investigated to facilitate studying their function.

Anatomy of human extrinsic cardiac nerves and ganglia

The anatomy of the human extrinsic cardiac nerves and ganglia was reinvestigated because descriptions of human cardiac innervation vary, detailed analyses of subhuman mammalian cardiac innervation reveal considerable similarities among species and the anatomic pattern of cardiac innervation observed in subhuman mammals differs significantly from those described for humans. The presence of a consistent pattern of cardiac innervation in subhuman mammals raised the question as to whether a similar pattern exists in humans. To investigate this, the cervical and thoracic autonomic nerves and ganglia were dissected in 13 embalmed and 10 autopsy cadavers. All major sympathetic cardiopulmonary nerves were found to arise from the stellate ganglia and the caudal halves of the cervical sympathetic trunks below the level of the cricoid cartilage. These sympathetic cardiopulmonary nerves usually consisted of 3 nerves on the right side and 4 on the left. In contrast to widely accepted reports, no sympathetic cardiopulmonary nerves were found to arise from the superior cervical ganglia or the thoracic sympathetic trunks inferior to the stellate ganglia. Parasympathetic cardiopulmonary nerves were found to arise from the recurrent laryngeal nerves and the thoracic vagi immediately distal to them. These nerves interconnected with sympathetic cardiopulmonary nerves anterior and posterior to the main pulmonary artery to form the ventral and dorsal cardiopulmonary plexuses. These plexuses contained relatively large discrete nerves as well as smaller interconnections. Emerging from these plexuses to innervate the ventricles were 3 distinct relatively large cardiac nerves, the right and left coronary cardiac nerves and the left lateral cardiac nerve. In addition to these 3 major nerves, small cardiac nerves arose from the plexuses and the thoracic vagi. Histologic examination of representative dissections confirmed the presence of neural tissue and identified the locations of neuronal cell bodies in these structures. Cell bodies were located in the nodose, superior cervical, middle cervical, stellate and thoracic sympathetic ganglia. The middle cervical ganglia varied in size and number. Neuronal cell bodies were found in the cervical and thoracic sympathetic trunks and in small mediastinal ganglia located along the courses of the cardiopulmonary and cardiac nerves. Marked similarities exist between the anatomy of the cardiopulmonary nerves and ganglia of humans and baboons.

Bradycardia induced by intravascular versus direct stimulation of the vagus nerve

BACKGROUND Electrical stimulation of the parasympathetic nervous system results in slowing of the heart. We sought to determine whether cardiac vagal efferent axons can be stimulated adequately to induce bradycardia without disturbing the integrity of the thorax. METHODS Cardiodepressor effects elicited by direct stimulation of a vagus nerve in anesthetized dogs and pigs were compared with those generated when the same nerve was stimulated indirectly through bipolar electrodes placed in the adjacent superior vena cava. RESULTS The heart rate of dogs decreased by about 80% when electrical stimuli were delivered to the right thoracic vagus at the level of the thoracic outlet through bipolar electrodes placed either in the adjacent superior vena cava (intravascular method) or directly on the nerve (direct method). Maximal responses were achieved with 10-V, 5-ms, and 20-Hz stimuli. In anesthetized pigs, similar bradycardia occurred when the right cervical vagus or the right cranial thoracic vagus was stimulated either directly or indirectly through the intravascular method. Atrial dysrhythmias occurred when the stimulating electrodes were placed by either method within 1 cm of the right atrium in both animal models. CONCLUSIONS Controlled bradycardia can be induced during operation without the risk of generating cardiac dysrhythmias using electrical stimuli (10 V, 5 ms, and 10 to 20 Hz) delivered to the right cervical vagus nerve or the right cranial thoracic vagus nerve through adjacent intravascular electrodes.

Factors in the early failure of cryopreserved homograft pulmonary valves in children: Preserved immunogenicity?

METHODS Between 1990 and 1995, 48 homograft valves (15 aortic and 33 pulmonary), cryopreserved on-site, were implanted to reconstruct the right ventricular outflow tracts in 44 children (mean age 6.2 +/- 6.0 years; range 3 days to 20.2 years). Blinded serial echocardiographic follow-up evaluation was performed for all 45 valves in the 41 survivors. RESULTS Four homograft valves were replaced because of pulmonary insufficiency (3) or stenosis and insufficiency (1). Freedom from reoperation was 90% (70% interval, 84% to 97%) at 50 months. During the follow-up period 15 valves developed progressive pulmonary insufficiency of at least two grades. Three valves developed transvalvular gradients of > or = 50 mm Hg, and one of these valves was also insufficient. The freedom from echocardiographic failure (two or more grades of pulmonary regurgitation or > or = 50 mm Hg gradient) was 44% at 50 months (70% confidence interval, 32% to 55%). Young age (p = 0.03), low operative weight (p = 0.04), small graft size (p = 0.04), and homograft retrieval-to-cryopreservation time of less than 24 hours (p = 0.02) were significantly associated with failure. The type of donor valve (pulmonic or aortic), donor age, and blood group mismatch were not associated with failure, although blood group mismatch approached significance (p = 0.05). CONCLUSIONS Homografts function well as conduits between the pulmonary ventricle and pulmonary arteries if long-term valve competency is not crucial. However, many rapidly become insufficient. This has important implications for the choice of a valve if the indication for valve replacement is to protect a ventricle failing due to pulmonary insufficiency. Short periods between homograft retrieval and cryopreservation enhance viability and antigenicity. This may suggest an immunologic basis for the failure.

The heart reinnervates after transplantation

BACKGROUND Whether cardiac reinnervation occurs after transplantation remains controversial. If reinnervation does occur, how sympathetic and parasympathetic efferent neurons do this remains unknown. METHODS Power spectral analysis of heart rate variability was assessed for 1 year after cardiac autotransplantation in 9 dogs. After induction of anesthesia 13 months after transplantation, cardiac and intrinsic cardiac neuronal responses elicited by both electrical stimulation of parasympathetic or sympathetic efferent neurons and systemic or local coronary artery administration of nicotine (5 microg/kg), angiotensin II (0.75 microg/kg), and tyramine (1.2 microg/kg) were studied. The transmembrane electrical properties of intrinsic cardiac neurons were studied in vitro. Ventricular tissue catecholamine content, alpha-tubulin expression, and beta-adrenergic receptor density and affinity were studied. The presence of axons crossing suture lines was sought histologically. RESULTS Nerves were identified crossing suture lines. Electrical or chemical (ie, nicotine or angiotensin II) activation of sympathetic efferent neurons enhanced cardiodynamics, as did tyramine. Stimulating vagal efferent preganglionic axons induced bradycardia in half of the dogs. Functional reinnervation did not correlate with specific power spectra derived from rate variability in the conscious state. Responding to nicotine and angiotensin II in situ, transplanted intrinsic cardiac neurons generated spontaneous activity. These neurons displayed nicotine-dependent synaptic inputs in vitro. Ventricular tissue had normal beta-adrenergic receptor affinity and density but reduced catecholamine and alpha-tubulin contents. CONCLUSIONS The intrinsic cardiac nervous system receives reduced input from extracardiac sympathetic efferent neurons after transplantation and inconsistent input from parasympathetic efferent preganglionic neurons. These heterogeneous neuronal inputs are not reflected in heart rate variability or ventricular beta-adrenergic receptor function. Transplanted angiotensin II-sensitive intrinsic cardiac neurons exert greater cardiac control than do nicotine-sensitive ones. The intrinsic cardiac nervous system remodels itself after cardiac transplantation, and this indicates that direct assessment of extracardiac and intrinsic cardiac neuronal behavior is required to fully understand cardiac control after transplantation.

Does Pulsatile Flow Influence the Incidence of Postoperative Hypertension

Twenty patients undergoing primary elective aorta--coronary artery bypass were divided into two equal groups, both receiving identical premedication, anesthetic, and pump primes. The control patients received hypothermic nonpulsatile flow and the study patients received hypothermic pulsatile flow. Hypertension, defined as a pressure of 160/100 mm Hg or higher, was observed in 80% of the control patients and 20% of the patients receiving pulsatile flow (p less than 0.05). Serial renin measurements demonstrated maximum values in the intensive care unit and coincided with the onset of postoperative hypertension in the control patients. Those patients who had received pulsatile flow did not demonstrate notable renin stimulation. Catecholamines were markedly elevated during bypass and in the intensive care unit, but there was no significant difference between the two groups. Peripheral vascular resistance was not significantly lower with pulsatile flow, except in the first study performed in the intensive care unit. We conclude that catecholamines and the renin-angiotensin system contribute to the production of postoperative hypertension and that pulsatile flow diminishes renin stimulation. Pulsatile flow results in a decreased incidence of postoperative hypertension.

Pathology of intrinsic cardiac neurons from ischemic human hearts

Various populations of intrinsic cardiac neurons influence regional cardiac function tonically. It is not known whether such neurons are affected by disease states and, if so, in what manner. Therefore, the morphology of intrinsic cardiac ganglia obtained from patients with angiographic evidence of compromised regional coronary blood supply was studied. Posterior atrial ganglia and surrounding fat, removed at the time of cardiac surgery, were placed immediately in saline and within 15–120 min (average of about 40 min) in 0.5% paraformaldehyde/2.5% glutaraldehyde. In 32 studied ganglia, 35% of 473 intrinsic cardiac neurons displayed striking pathological changes at the light and ultrastructural level. The other cells displayed normal morphology. The cytoplasm of 74% of the abnormal cells had one or more of three types of inclusions: (1) darkly stained lamellated inclusions (Type I), (2) membrane‐bound whorls and parallel arrays of lightly stained membranes, as well as fine granular material (Type II), or (3) concentric layers of lightly stained membranes with a darker, granular core (Type III). Neurons with inclusions were markedly enlarged (66 × 54 μm vs. 40 × 34 μm for normal neurons) and displayed fewer dendrites. Some neurons contained electron lucent vacuoles indicative of degeneration while others showed frank degeneration, being fragmented, shrunken, and misshapen. Phagocytic cells containing lamellated inclusions and cellular debris were found in ganglia with abnormal neurons. Some axon terminals also displayed degenerative changes. The identification of pathological changes in the human intrinsic cardiac nervous system has implications with respect to the functional integrity of this final common regulator of cardiac function in disease states. Anat Rec 259:424–436, 2000.

Human cardiac nerve stimulation

Cardiovascular responses were elicited in 12 patients undergoing cardiac operations when cardiopulmonary neural elements between the aortic root and pulmonary artery or in the right atrial ganglionated plexus were stimulated. Heart rate and left ventricular intramyocardial systolic pressure were augmented when cardiopulmonary nerves between the aorta and pulmonary artery were stimulated in 11 of the 12 patients. Right ventricular intramyocardial systolic pressure was augmented in 7 of these 11 patients. Cardiodepressor responses were elicited when the right atrial ganglionated plexus (9 patients) or a cardiopulmonary nerve (2 patients) was stimulated. These results demonstrate that electrical stimulation of the human extrinsic and intrinsic cardiac nervous systems can alter cardiodynamics, different responses being elicited when different neural structures are stimulated. These data are in accord with those obtained from canine experiments and suggest that the human extrinsic and intrinsic cardiac nervous system contains functionally similar neural elements to those found in other mammals.

Isolated infundibuloarterial inversion {S,D,I}: A newly recognized form of congenital heart disease

A newly recognized form of congenital heart disease is presented that is characterized by viscero-atrial situs solitus (S), D-loop ventricles (D), and inverted normally related great arteries (I), the segmental combination being (S,D,I). This anomaly may be called isolated infundibuloarterial inversion because only the subsemilunar infundibulum and the great arteries are inverted, whereas the atrial and the ventricles are not. All three patients had atrioventricular concordance, ventriculoatrial concordance, dextrocardia, superoinferior ventricles, crisscross atrioventricular relations, underdevelopment of the right ventricle, a large ventricular septal defect, and an inverted tetralogy of Fallot type of malformation of the infundibulum and great arteries. The condition known as crisscross atrioventricular relations was found in these three patients to be a major ventricular malposition characterized by marked clockwise rotation of the ventricles, as seen from the front. Two of these three cases were diagnosed accurately and repaired successfully.

Modification of Supraventricular Tachyarrhythmias by Stimulating Atrial Neurons

The effects of stimulating the right atrial ventral ganglionated plexus on ventricular performance during atrial tachycardia was studied in 8 lightly sedated (pentobarbital, 2.5 mg/kg intravenously) dogs with sterile pericarditis. Atrial arrhythmias were induced by electrical stimulation (10 V, 4 ms, 100 Hz) of the right atrium through previously inserted temporary bipolar pacemaker wires. Various types of supraventricular tachycardias were produced. Atrial fibrillation was produced in 3 dogs, atrial tachycardia in all 8 dogs, different atrioventricular nodal ectopic rhythms in 6 dogs, and atrial flutter in 1 dog. These arrhythmias were associated with irregular ventricular contractions that resulted in low ventricular pressures during many cardiac cycles such that low or no aortic pressure was generated. Right atrial ventral ganglionated plexus stimulation induced slowing of ventricular rate so that every ventricular contraction resulted in aortic pressure generation, thus increasing mean aortic pressure. Responses elicited by atrial ganglionated plexus stimulation were eliminated after atropine administration. We conclude that electrical stimulation of the right atrial ventral ganglionated plexus results in slowing of ventricular contractile rate during supraventricular tachycardia, presumably by activating efferent vagal neuronal elements, thereby improving ventricular performance. If applicable in humans, this technique may be of use in management of postoperative atrial arrhythmias after cardiac operations.