Acute effects of amiodarone upon the canine sinus node and atrioventricular junctional region.

Amiodarone was selectively perfused into the sinus node artery and atrioventricular node artery of 51 dogs. Amiodarone had an immediate negative chronotropic and dromotropic effect. Threshold concentration was 2.5 micrograms/ml. 25 and 50 micrograms/ml of amiodarone injected into the sinus node artery slowed the heart by 25.6 +/- 3.1 and 33.7 +/- 2.6 beats/min (mean +/- 1 SEM), respectively. Amiodarone 25 and 50 micrograms/ml injected into the AV node artery during AV junctional rhythm slowed the AV junctional pacemaker by 12.2 +/- 1.8 and 17.4 +/- 1.7 beats/min, respectively. Injections of amiodarone into the AV node artery during sinus rhythm regularly increased AV conduction time sometimes causing 2 degrees AV block at the highest concentration used. Impaired conduction was exclusively measured at the level of the A-H interval in the His electrogram. Neither atropine nor propranolol prevented the negative chronotropic effects of amiodarone. Amiodarone had no significant effect on sinus node response to either stellate stimulation or intranodal administration of norepinephrine. The negative chronotropic action of amiodarone was significantly enhanced when amiodarone was administered in a perfusate containing low (0.6 mM) instead of normal calcium. Taken collectively these observations indicate that amiodarone has immediate depressant electrophysiologic effects on both the sinus node and the AV junction and that these early effects might involve the blockade of the slow channel.

Mechanism of postarrhythmic renal vasoconstriction in the anesthetized dog.

The mechanism of postarrhythmic renal vasoconstriction was studied in 28 dogs anesthetized with pentobarbital sodium (30 mg/kg i.v.). Rapid atrial or ventricular pacing or induction of atrial fibrilation were used to produce at least 20% prompt decrease in cardiac output and mean arterial blood pressure. Return to control cardiac output and blood pressure occurred within 3 minutes after cessation of the arrhythmia, but renal blood flow remained significantly decreased (26%) with gradual recovery by 17.7 +/- 6.6 min. Infusion of phentolamine (0.25 mg/min) into the renal artery, intravenous hexamethonium (l mg/kg), adrenal demedullation, or cooling the cervical vagi prevented postarrhythmic renal vasoconstriction. In contrast, renal denervation, intravenous bretylium (10 mg/kg), intravenous atropine (0.5 mg/kg) or intrarenal SQ 20881 (0.20 mg/min) has no effect on postarrhythmic renal vasoconstriction. Intravenous propranolol (0.5 mg/kg) intensified postarrhythmic renal vasoconstriction. These data suggested that the postarrhythmic renal vasoconstrictive response required intact vagi and was due to alpha adrenergic stimulation by adrenal catecholamines. However, femoral arterial catecholamine levels were not elevated above control during postarrhythmic renal vasoconstriction. We therefore sought local vascular pathways by which catecholamines might reach the kidneys. An adrenorenal vascular network was found in each dog. Collection of catecholamines from these vessels during postarrhythmic renal vasoconstriction in six dogs revealed catecholamine concentrations threefold higher than simultaneously collected femoral arterial catecholamines levels. Because ligation of these vessels abolished postarrhythmic renal vasoconstriction in each dog, we conclude that postarrhythmic renal vasconstriction is due to adrenal catecholamines reaching the kidneys through an adreno-renal vascular network and that the response requires intact vagi.

Degenerative lesions of a coronary chemoreceptor and nearby neural elements in the hearts of victims of sudden death.

A coronary chemoreceptor and its neighboring nerves and ganglia were studied by serial section from the hearts of 11 victims of sudden unexpected death. Either focal or extensive inflammatory destruction was present in the chemoreceptors of 10 of the 11 hearts, and similar abnormalities of local nerves and ganglia were present in all 11 hearts. Because an identical coronary chemoreceptor in the dog has previously been shown to be the site of origin of a powerful reflex with major influence on the electrical activity of the heart, the functional significance of the neural abnormalities found in these 11 human hearts may include important distortion of cardiac rhythm, conduction or repolarization. Future studies are needed to determine the prevalence of such lesions in the hearts of other victims of sudden death and among control subjects, as well as to determine the etiology of this special neuropathology of the heart.

Primary and secondary cardioneuropathies and their functional significance.

For most functions of the heart its nerves are as important as its coronary arteries, but this is particularly true concerning cardiac rhythm, conduction and repolarization. It is thus paradoxical that postmortem correlative studies of sudden death virtually always include careful scrutiny of the coronary arteries but only rarely of the cardiac nerves or ganglia. In this review, abnormalities of the cardiac nerves and ganglia, collectively termed cardioneuropathies, are examined from the dual standpoint of their structural appearance and functional significance. Some cardioneuropathies are found in the absence of any other significant structural abnormality detectable in the heart and these are designated as primary cardioneuropathies. A viral etiology or some heritable disorder must rank high among possible causes. Secondary cardioneuropathies are those observed in association with almost every disease that can affect the heart; examples include myocardial infarction, infections, amyloidosis and cancer, but there are many others. Because abnormalities of the heart's nerves and ganglia not only have their own unstabilizing influence on cardiac electrical activity but can also profoundly alter a patient's responses to pharmacologic treatment, it is hoped that future clinicopathologic examinations will more often include their careful study and thereby add to our meager knowledge about these important structures.

Chance and sudden death.

An aura of mystery has always surrounded the subject of sudden unexpected death. Part of the explanation is an absence of a single or unusual explanation, although electrical instability of the heart does serve as a unifying concept for the final common pathway. In this review, emphasis is placed on the random aggregation of a wide variety of contributing factors in the pathogenesis of sudden death. Such factors include coronary disease, platelet aggregation, neural control of the heart, apoplexy of the heart, normal and abnormal variations in the structure of the atrioventricular junction, lessons from certain rare cardiac tumors and the nature of ventricular fibrillation. Useful thinking about these and related causes should employ both a horizontal (concurrence of events) and vertical (sequence of events) matrix, in all of which chance plays a major role. One impediment to understanding sudden death associated with coronary disease is the prevalent assumption that one is due to the other without proper examination of the other factors involved, some of which may be more susceptible to intervention or modification. The multifactorial nature of the pathogenesis of sudden death and the recognition that chance is a major determinant of which factors convene and when they will aggregate in the victim are essential elements to consider if more effective means of treatment and prevention are to be obtained.

Anatomy of the crista supraventricularis: its importance for understanding right ventricular function, right ventricular infarction and related conditions.

During careful studies of the human cardiac conduction system the anatomy of the crista supraventricularis is an inescapable concomitant demonstration. For the purpose of this report the observations from about 1,000 human hearts were combined with special additional studies of 75 human hearts (50 adults, 25 infants), 30 dogs and 5 chickens. The crista supraventricularis is similar in human and canine hearts. Avian hearts differ from mammal hearts in that they contain only a muscular right atrioventricular valve which replaces the crista supraventricularis. In addition to dividing the inflow and outflow pathways of the right ventricle, the crista supraventricularis is crucially located to join the interventricular septum and left ventricle to much of the right ventricular free wall, thereby playing an important role in emptying the right ventricle and closing the tricuspid valve. On the basis of these observations, the function of the crista supraventricularis is examined relative to right ventricular systole, right ventricular infarction, various electrophysiologic problems, the performance of cardiac surgery and new questions in cardiac imaging.

The spectrum of diseases of small coronary arteries and their physiologic consequences.

There is a wide spectrum of abnormalities in the structure of small coronary arteries, with regard both to the portion of the arterial wall involved and to the histologic nature of the disease. A fuller understanding of this spectrum permits more useful interpretation of the pathophysiologic basis for the functional consequences of small coronary artery disease. In this review based on personal observations during examination of more than 1,000 human hearts postmortem there is initially a description of the wide variety of structural abnormalities, then a discussion of the functional consequences of these abnormalities and finally a section of general comments to weave together the structural and functional discussion in the context of clinical evaluation of patients who have small coronary artery disease. Future studies should apply fractal analysis and quantitative topology, methods that lend themselves particularly well to an investigation of the progressively smaller branching of the human coronary tree.

Normal variations and pathologic changes in structure of the cardiac conduction system and their functional significance.

The rarity with which the cardiac conduction system is carefully examined in cases of sudden unexpected cardiac death is deplorable. Whatever the reasons for this failure, it is clearly one of the major lost opportunities for improving our understanding of a major national heart problem. To illustrate some of the morphologic changes found in such cases, two categories are discussed: normal variations (which may themselves promote electrical instability) and changes due to disease. During normal postnatal morphogenesis of the atrioventricular (AV) node and His bundle, there are a variety of derangements that may cause malfunction of those critical structures. In addition to large vessel coronary disease and platelet disorders, narrowing of small coronary arteries may also lead to ischemic damage in the conduction system. Certain intracardiac tumors and systemic diseases of an infiltrative or inflammatory nature may also involve elements of the conduction system, leading to arrhythmias or conduction disturbances with their clinical counterparts of syncope and sudden death. How any of these and many related anatomic changes may participate in the pathogenesis of electrical instability of the heart deserves much more careful study, but an essential requirement will be the wider practice of making careful clinicopathologic correlations.

Sudden death due to isolated acute infarction of the His bundle.

A 29 year old black man considered to be in good health died suddenly and unexpectedly. At postmortem examination there were no significant gross abnormalities, all drug screens were normal and sicklemia was not present. Special studies of the cardiac conduction system demonstrated isolated acute infarction of the His bundle, with no similar evidence of myocardial infarction anywhere else in the heart. The atrioventricular (AV) node artery was moderately narrowed, but its branch supplying the His bundle was occluded greater than 95% by focal fibromuscular dysplasia. There were no other significant coronary lesions or other abnormalities in the heart.

Function of the atrioventricular node considered on the basis of observed histology and fine structure.

From the hearts of 20 young dogs, the region of the atrioventricular (AV) node was studied in vitro utilizing direct perfusion of the AV node artery. Intracellular impalement with microelectrodes provided records of local transmembrane action potentials in all 20 dogs. These were correlated with serial section histologic studies in 7 of the 20 dogs to characterize a smaller region that served as an anatomic guide for electron microscopic examination in 4 other dog hearts. This report describes the variety of specific cells found, including their intracellular content and organization, as well as the nature of their intercellular junctions. On the basis of these findings, AV nodal cells were arbitrarily divided into two types, transitional cells and P cells, although three somewhat different groups of transitional cells were identified. The first group, found principally at the outer margin of the AV node, has long and slender cells that exhibit large profiles of gap junctions or nexuses. The second and third groups of transitional cells, which constitute most of the body of the AV node, are oblong or oval and contain fewer and smaller gap junctions. P cells of the AV node resemble those more abundantly present in the sinus node; they are found principally at the junction of the AV node and His bundle. On the basis of these fine structural features and the histologic organization and transmembrane action potentials observed, clinical and experimental aspects of the local electrophysiologic events are discussed.

Differential modulation of autonomic activity by ethmozin and ethacizin (analog of ethmozin) on the canine sinus node and atrioventricular junction.

The chronotropic and dromotropic actions of ethmozin and its diethylamine analog ethacizin were studied in the presence and absence of combined muscarinic, beta- and alpha-adrenoreceptor blockade in the intact canine heart in situ (n = 38). Injections of ethacizin, 5, 10 and 25 micrograms/ml, into the sinus node artery caused an immediate and significant (p less than 0.001) sinus bradycardia of 2, 6 and 11%, respectively. Injection of 25 and 50 micrograms/ml of ethacizin into the atrioventricular (AV) node artery significantly (p less than 0.001) prolonged AV conduction time with occasional second degree heart block. Conduction delay was located exclusively during the AH interval of the His bundle electrogram. Autonomic blockade did not alter the negative chronotropic or negative dromotropic effects of ethacizin. Ethacizin, 25 micrograms/ml, injected into the sinus node artery immediately reduced the sinus node response to vagal stimulations by 30% and the effect of acetylcholine, 0.1 micrograms/ml, injected into the sinus node artery by 50%. Ethacizin, 25 micrograms/ml, injected into the AV node artery immediately reduced the duration of complete AV block elicited by vagal stimulation or intranodal acetylcholine, 0.5 micrograms/ml, by 90%. Ethacizin caused a minor reduction in sinus node response to right stellate stimulations without, however, altering the sinus node response to intranodal norepinephrine. Ethmozin injections of up to 50 micrograms/ml into the sinus and AV node arteries had no chronotropic or dromotropic effects. Ethmozin had a minor and variable vagolytic action but significantly (p less than 0.05) reduced the sinus node response to sympathetic nerve stimulation. Hence, ethacizin, in contrast to ethmozin, has a direct depressing action on both the sinus node and the AV junction.(ABSTRACT TRUNCATED AT 250 WORDS)

Serial production of controlled periods of temporary heart block used to unmask and assess latent ventricular automaticity during experimental acute myocardial ischemia.

This study examined the onset, time course of development and response to overdrive stimulation of ventricular tachycardia in 10 dogs that underwent a Harris two-stage ligation of the left anterior descending coronary artery. Transient (12 +/- 3 minutes) complete atrioventricular (AV) block was produced 2, 3, 4, 5, 8, 12, 16, 20 and 24 hours after onset of infarction through selective injection of physostigmine salicylate into the AV node artery. Seven of the 10 dogs had early transient arrhythmic episodes that occurred within 20 to 40 minutes after coronary occlusion but none of the dogs had any spontaneous ventricular tachycardia in the ensuing 2 hours. Two hours after left anterior descending coronary artery ligation, complete AV block unmasked in every dog a slow (37 +/- 9 beats/min) AV junctional rhythm readily suppressed by overdrive. Three hours after coronary ligation, AV block revealed a monomorphic ventricular tachycardia (106 +/- 10 beats/min) in 3 of the 10 dogs. Four and five hours after coronary ligation, five and eight dogs, respectively, had ventricular tachycardia during AV block and in three the tachycardia was polymorphic. The two remaining dogs did not develop ventricular tachycardia during the 24 hours of observation. Ventricular tachycardia always began abruptly, first with brief and then longer bursts. Soon after onset the rate of tachycardia began to increase to reach a plateau 2 to 3 hours later at frequencies 21 +/- 9% greater than the initial tachycardia rate. Concomitant with this increase in rate there was a steady decline of overdrive suppressibility and during the plateau phase there was little or no overdrive suppression.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical and pathologic manifestations of pulmonary vascular disease in the toxic oil syndrome.

The toxic oil syndrome in Spain affected greater than 20,000 people. In the initial stages, it was characterized by a respiratory distress syndrome with myalgias and eosinophilia. Pulmonary hypertension developed in 20% of the patients and in many, it has spontaneously regressed. Nevertheless, in a small subgroup, it has progressed to a malignant course of cor pulmonale, leading rapidly to death. Clinical and pathologic features of 40 patients with severe pulmonary hypertension due to the toxic oil syndrome are presented (32 female and 8 male patients; mean age 26 +/- 13 years). The study began in June 1981, which was near the onset of the toxic oil epidemic, and ended in December 1987, greater than 6 years later. The pulmonary hypertension is clinically and pathologically indistinguishable from primary pulmonary hypertension. Direct endothelial injury by the toxic agent is proposed as the initial trigger of this type of pulmonary hypertension, but an interaction between the toxic agent and specific individual susceptibility is probably required in its pathogenesis.

Cardiac abnormalities in the toxic oil syndrome, with comparative observations on the eosinophilia-myalgia syndrome.

Early in the course of studies of the Spanish toxic oil syndrome it was recognized that vascular lesions were a major problem, most logically attributable to endothelial damage by the toxic oil. However, most clinical attention has been directed to the pulmonary complications and the evolution into a scleroderma-like illness later. In this study of 11 victims of the toxic oil syndrome careful postmortem studies of the coronary arteries and conduction system and neural structures of the heart demonstrated major injury to all those components of the heart. Obliterative fibrosis of the sinus node in four cases resembled findings in fatal scleroderma heart disease, and in eight the cardiac lesions resembled those of lupus erythematosus. The more impressive pathologic features involved the coronary arteries and neural structures, which were abnormal in every heart. The arterial disease included widespread focal fibromuscular dysplasia, but there was also an unusual myointimal proliferative degeneration of both small and large coronary arteries in five patients, four of whom were young women. In two hearts, portions of the inner wall of the sinus node artery had actually detached and embolized downstream. Coronary arteritis was rarely found. Inflammatory and noninflammatory degeneration of cardiac nerves was widespread. Fatty infiltration, fibrosis and degeneration were present in the coronary chemoreceptor. In most respects these cardiac abnormalities resemble those described in the eosinophilia-myalgia syndrome caused by an altered form of L-tryptophan. In both diseases there is good reason to anticipate more clinical cardiac difficulties than have so far been reported, and even more basis for future concern, especially relative to coronary disease and cardiac electrical instability.

Persistent fetal dispersion of the atrioventricular node. Association with the Wolff-Parkinson-White syndrome.

Symptomatic supraventricular tachycardias developed in a 58-year-old man not long before he also was found to have metastatic cancer. During electrophysiological studies, type A Wolff-Parkinson-White syndrome was defined and at least four different forms of supraventricular tachycardias were documented. When he died of his cancer, autopsy studies included special examination of his heart and its conduction system. There was a slender connection between the left atrium and left ventricle posterior to the margo obtusus, composed of ordinary working myocardial cells. There was also persistent fetal dispersion of the atrioventricular (AV) node within the central fibrous body, forming a suitable anatomical substrate for reentrant tachycardias originating entirely there. The anatomical and electrophysiological findings are discussed relative to the question of surgery in such patients, since cutting the lateral AV connections might eliminate the delta wave but not the supraventricular tachycardias.

Parasympathetic and sympathetic efferent traffic during a cardiogenic hypertensive chemoreflex.

Activation of a cardiac chemoreceptor with serotonin elicits a reflex which includes changes in heart rate, contractile force, regional blood flow and hypertension. In six anaesthetised dogs we simultaneously recorded parasympathetic and sympathetic efferent traffic elicited during this cardiogenic reflex. The parasympathetic fibres were confirmed by reciprocal frequency changes with changes in blood pressure. The sympathetic fibre activity (anterior ansa subclavia) was attenuated or eliminated by ganglionic blockade or by clonidine. Whereas the phasic sympathetic multifibre discharge was only followed by a quiet period, the parasympathetic multifibre discharge was both preceded and followed by a quiet period. The sympathetic discharge preceded the parasympathetic discharge by 683 +/- 170 ms. These autonomic efferent discharges were not elicited by administration of serotonin into the carotid artery, but were abolished by pretreatment with the serotonin antagonist, cyproheptadine. Cyproheptadine blockade could be overcome by increasing the serotonin concentration tenfold. This remarkable neural asynchrony has important implications concerning the electrical stability of the heart.

Clonidine attenuation of a cardiogenic hypertensive chemoreflex.

Clonidine is an antihypertensive agent with a primary action mediated by alpha adrenergic stimulation in the central nervous system, thus inhibiting sympathetic efferent activity. Serotonin activates a cardiogenic hypertensive chemoreflex which induces discharges of sympathetic efferent neurons. The purpose of this study was to determine the effects of intravenous clonidine upon the thoracic sympathetic efferent discharges in chloralose-anesthetized dogs, their peripheral autonomic receptors being blocked with atropine, propranolol, and phentolamine. Efferent nerve traffic was quantified using a Schmitt trigger and Digital PDP8/e computer. Control spontaneous activity (tone) following autonomic blockade was normalized at 100%. Serotonin (100 microgram/ml, 2 ml, left atrium) caused an increase in the reflex efferent sympathetic activity to 192% +/- 16% of control (p less than 0.001). Following clonidine, the tone was decreased to 63% +/- 6% of control, and the reflex sympathetic discharge elicited by serotonin was significantly (p less than 0.001) reduced from 192% to 116% +/- 9% of control tone (before clonidine). The attenuation of the reflexly elicited discharge was significantly (p less than 0.05) greater than the attenuation of the tone. In four dogs that did not receive atropine, the vago-vagal reflex sinus bradycardia induced by serotonin was not affected by clonidine.

Dysautonomia in mitral valve prolapse.

Many of the clinical features of patients with mitral valve prolapse can logically be attributed to abnormal autonomic neural function. Accordingly, we have studied heart rate and blood pressure response to a standardized Valsalva maneuver and postural test in 44 untreated patients with demonstrated mitral valve prolapse. Fifteen healthy subjects of similar age served as controls. The directional changes of blood pressure and heart rate were similar in control subjects and patients in both tests, but patients differed from control subjects by their widely oscillating heart rate during the upright posture, and their exaggerated and prolonged bradycardia during the recovery phase of the Valsalva maneuver and following their return to recumbency in the postural test. This bradycardia persisted for 30 to 90 seconds after blood pressure returned to control values. Patients also showed a greater respiratory variation of R-R interval, which became especially marked during the adjustment to changes of posture. We postulate an abnormal central modulation of baroreflexes as the best explanation for the dysautonomic responses of symptomatic patients with prolapsed mitral valves.

Morphologic characteristics and functional significance of focal fibromuscular dysplasia of small coronary arteries.

Focal fibromuscular dysplasia of small coronary arteries is not so rare as it is unrecognized. Although sometimes occurring as an isolated abnormality, it more often accompanies a variety of other lesions including inflammation or infiltration. In this review based on personal study of over 1,000 human hearts, the 3 topics include a description of the morphologic characteristics of the lesion, a discussion of its functional consequences affecting coronary flow, and an iteration of theoretical explanations for its development. The typical lesion is focal in distribution, is comprised of both fibrous and smooth muscle elements, and the histologic organization is one of dysplastic array. Included among the subjects discussed in functional consequences are coronary spasm, coronary reserve, chest pain, electrical instability of the heart, and comments on the role of focal fibromuscular dysplasia of small coronary arteries in hypertension, myocardial hypertrophy and heart failure. Theories as to its development include primary faults of smooth muscle or collagen, and focal abnormalities of clotting or neurovascular relation, but it is likely that the cause is multifactorial.

The sinus node.

This discussion of the sinus node begins with a description of its normal anatomy, particularly in the human heart, and then proceeds to a review of the several pathologic changes known to affect the sinus node. The latter include diseases of the sinus node artery, changes in the normal collagen framework of the node, pericarditis and certain infiltrative processes. The concluding section combines an examination of function and structure of the sinus node on the basis of experimental observations. Some new laws of the heart dealing with governance of normal cardiac rhythm are presented.