EDITORIALS
Role of the Nervous System in the Genesis of Cardiac Rhythm Disorders
RARRIE
LEVITT,
MD,
FACC’+
NORMAN CAGIN, MD* JACK KLEID, MD, FACC” JOHN SOMBERG, RICHARD GILLIS,
MD* PhDt
York, New York Washmgton, D C
New
The search for effective prophylaxis of sudden cardiac death has led to a consideration of the basic pathogenic mechanisms underlying disorders of cardiac rhythm. Although the myocardmm is undeniably important m the genesis of these disorders, the nervous system may be equally important. Several independent lines of evidence lead to this conclusion Experimental evidence: Experimental procedures that alter central nervous system function have repeatedly been demonstrated to result in cardiac arrhythmias or electrocardiographic changes, or both. Nearly every arrhythmia observed clinically can be reproduced by stimulation of the dlencephalon and mesencephalon l Evans and Gill& have demonstrated that rhythm disorders produced by hypothalamic stimulation can be blocked by the use of antladrenergic and anticholinergic drugs. Simultaneous stimulation of sympathetic and parasympathetic nerve trunks can also produce disorders of rhythm 3 Randall and coworkers4v5 observed that stimulation of the sympathetic nerves could induce both atria1 and ventricular ectopic rhythms Similarly, Alessl, Moe et a1.6 and Ninomaya7 have demonstrated that parasympathetic stlmulatlon From the D~vrs~ons of Cardiology and Clmlcal Pharmacology. Department of Medlctne, New York MedIcal College, New York, N Y and the Department of Pharmacology, Georgetown Unlverslty Schools of Medictne and Dentistry, WashIngton, D C t Irma Hirsch1 Career Scientist $ Career Development Awardee, Natlonal Heart and Lung Institute Address for reprints Norman A Cagin, MD, Department of Medlclne, New York MedIcal College, 1249 Fifth Ave , New York, N Y 10029 l
can produce atria1 tachyarrhythmlas and fibrlllatlon. From the foregoing, it IS clear that neural sites play a major role m the mductlon of cardiac rhythm disorders. Roberts et al a proposed the following explanation for the role of the autonomic system It IS generally recogmzed that the heart 1s richly mnervated with autonomic fibers and that these fibers can influence automatlclty, conductlvlty and excltablhty A conslderatlon of the anatomy of the heart indicates that autonomic influence must be mediated through a multlphcity of mdlvldual neuroeffector synapses, and that each nerve termmal influences its immediate region of the myocardlum. Under normal clrcumstances, each nerve termmal speeds or slows the progression of the cardiac impulse through its domam m concert with the activity of adJacent termmals Under experimental condltlons of synchronous stlmulatlon of extracardlac nerve trunks, the response of the nerve terminals and the underlying myocardmm 1s perforce uniform, and a gross slowing or speeding of the heart results. Insofar as each axon or nerve terminal has the capacity for mdependent actwlty, the system is potentially capable of becoming dlscoordmated Discordant neural activity would result m fractlonatlon of the myocardlum, 1 e. conductlvlty, automaticlty and excltablhty would vary from region to region, and the flow of electrical actlvlty through such a fractionated myocardmm will become turbu-
lent.
Clinical evidence: Patients suffering from cerebrovascular disorders, head injury, or tumors of the central nervous system and those undergoing neurosurgical procedures have a high incidence rate of electrocardlographlc abnormahtles g These abnormahties include T wave changes as well as evidence of bradyar-
June 1976
The American
Journal
of CARDIOLOGY
Volume
37
1111
EDITORIALS
rhythmias, heart block and atria1 and ventricular ectopic rhythms. These rhythm disorders frequently occur in the absence of demonstrable organic heart disease. Emotional factors can also produce important disorders of cardiac rhythm. Greene et al lo have proposed that “in at least 50% of the patients with sudden death, psychological and social factors are associated with the time of sudden death.” These workers and others11J2 describe patients in whom a severe emotional crisis heralded the lethal episode The importance of psychic factors was well expressed m a quotation referred to by Nixon13 and attributed to M F. Oliver: “Coronary disease patients should be nursed out of sight of each other because ventricular fibrillation can be catchmg.” Experimental myocardial infarction: The autonomic nervous system plays an important role m the control of cardiac rhythm associated with both experimental and clinical myocardial infarction. Malllam et al.l* and Gill~~~ observed that augmented sympathetic nerve traffic is associated with coronary occlusion m the cat Gillis further noted that the development of cardiac rhythm disorders was temporally related to increased traffic m the cardiac sympathetic nerves. Spinal cord transection prevented the augmentation of nerve traffic and reduced the incidence of rhythm disorders associated with experimental coronary occlusion. Moreover, survival time was increased sigmficantly after coronary occlusion m the cats with such transection Other workersi have also observed that surgical reduction m sympathetic influence on the heart is associated with a reduction m cardiac rhythm disorders. Drug-induced depression of sympathetic neural activity has also been associated with a decrease in the morbidity and mortality from myocardial infarction in animals. Ether anesthesia and sodium pentobarbital and morphine were observed to reduce mortality associated with experimental myocardial mfarction.17 Admimstration of chlordiazepoxide is also effective m controlling rhythm disorders associated with experimental myocardial mfarction.i8 Grayson and Lapini observed in the dog under deep anesthesia that admnnstration of bretylium prevented the development of electrocardiographic or microscopic evidence of infarction after ligation of the left anterior descending coronary artery In addition, there IS experimental evidence to mdicate that infarcted myocardium is more sensitive than noninfarcted myocardium to adrenergic neural influence and to circulatmg catecholamines.16 On the other hand, cholinergic neural activity is associated with a protective effect m experimental myocardial infarction. Corr and Gillls20 found that vagal section increased the incidence of arrhythmias associated with coronary occlusion in the experimental ammal. Kent et al 21.22similarly observed that vagal nerve stimulation increases the threshold for ventricular fibrillation m both the nonischemic and ischemic canine model. Reduction in vagal influence by admimstration of atropine in the animal with experimental infarction sigmficantly increased the total incidence of rhythm disorders and ventricular fibrillation tended to occur more often 23
1112
June 1976
The Amencan
Journal
of CARDIOLOGY
Volume
Clinical myocardial infarction: Evidence for mvolvement of the nervous system m the mduction of cardiac rhythm disorders in patients with ischemic heart disease or myocardial infarction, or both, has also been suggested Webb et a1.24 proposed that the electrical imbalance that occurs in the early period after acute myocardial mfarction is the result of disordered autonomic function. These workers suggested that both tachyarrhythmias and bradyarrhythmias after myocardial infarction reflect autonomic neural influence. Increased levels of circulatmg catecholammes have been found during the acute phase of myocardial mfarction. Lown et a1.25 observed that the incidence of ventricular rhythm disorders in patients with ischemic heart disease is substantially reduced during sleep. Nixon et al l3 reported that the mduction of a sleep-like state with pethidme and promethazme decreased both morbidity and mortality from myocardial mfarction during the first week after the acute event. In general, it appears that both the sympathetic and parasympathetic systems are intimately mvolved with the control of cardiac rhythm in experimental and climcal myocardial infarction, parasympathetic activity providing a protective effect and sympathetic activity a deleterious effect. Digitalis toxicity: A neural basis for digitalis intoxication has been proposed.8,26*27 Gillis and McLain2g demonstrated that administration of ouabain results in dose-related increments m sympathetic, parasympathetic and phrenic nerve traffic G&s et a130 demonstrated that the increments m nerve traffic are the forerunners of ventricular rhythm disorders and death They further observed that spinal cord transection prevents neural hyperactivity induced by ouabain and increases the dose of ouabain needed to produce death. Levitt et a13i demonstrated that exclusion of the sympathetic nervous system by spinal cord transection increases the dose, serum level and tissue level of ouabam needed to produce ventricular fibrillation or asystole They also observed that tissue levels of ouabain needed to produce “death” in vitro, m the absence of neural influences, were substantially greater than those needed to produce death in ~1~0.~~On the basis of this work, it appears that digitalis toxicity m the intact animal, and presumably man, is largely a neural phenomenon whereas intoxication m the isolated heart probably results from the direct myocardial effect of the drug Moreover, drugs with the capacity to depress sympathetic nervous activity have been demonstrated to be effective m the blockade of digitalis toxicity. Thus, propranolol, reserpine, n-isopropyl-p-mtro-phenylethanolamine (INPEA), guanethidine and diphenylhydantoin among others 33 have been demonstrated to increase the dose of digitahs needed to produce toxic rhythm disorders and death. On the other hand, as m acute myocardial mfarction, the vagus nerve has been reported to protect against digitahs-induced arrhythmias s4 The capacity of digitalis to produce climcal neurotoxicity is well known Indeed, neurotoxicity has long been established as the harbinger of impending “car-
37
EDITORIALS
diotoxicrty “33 Thus, the nervous system appears to play a critical role in the induction of cardiac rhythm dlsorders by digitalis m both animals and man. Clinical implication: A new approach to the problems of cardiac rhythm and sudden death must be found if srgmficant inroads are to be made m the fight against
them. The evidence suggests that the nervous system 1s an important target m the research effort to prevent cardiac rhythm disorders. Antlarrhythmrc drugs and procedures should be sought among those that inhibit neurally induced arrhythmias and spare the myocardrum the effects of nonspeclfrc depression.
References 1 Hockman CH, Mauk HP Jr, Hoff EC: ExperImental neurogenlc arrhythmtas Bull NY Acad Med 43 1097-l 106, 1967 2 Evans DE, Glllis RA: Effect of dtphenylhydantoln and lldocame on cardrac arrhythmtas Induced by hypothalamic stimulatton J Pharmacol Exp Ther 19 1 506-5 17, 1974 3 Manning JW, Cotton MdeV. Mechanism of cardiac arrhythmias induced by dlencephaltc sttmulatron Am J Phys~ol203 1120-l 124, 1962 4 Armour JA, Hageman GR, Randall WC: Arrhythmtas Induced by local nerve stimulation Am J Physlol 223 1068-1076, 1972 5 Geesbrecht JM, Randall WC: Area localrzatron of shlftrng cardiac pacemakers during sympathetic stimulation Am J Phystol 220 1522-1527, 1971 6 Alessi R, Nusynowdz M, Abildskov JA, et al: Nonuniform drstrrbutton of vagal effects on the atrlal refractory period Am J Physlol 194 406-410, 1958 7 Ninomiya I. Direct evidence of non-uniform distribution of vagal effects on dog atria Clrc Res 19 576-583, 1966 8 Roberts J, Levitt B, Standaerl FG: A possible role of the autonomic nervous system in the control of cardiac rhythm Nature 214 912-913, 1987 9 Abrldskov JA, Millar K, Burgess MJ, et al: The electrocardiogram and the central nervous system Prog Cardiovasc DIS 13 2 1O-2 15, 1970 10 Greene WA, Goldstein S, Moss AJ: Psychosocial aspects of sudden death Arch Intern Med 129 725-731, 1972 11 Wolf S: Neural mechanisms In sudden cardiac death Trans Am Clan Cllmatologtcal Assoc 79 158-176, 1967 12 Wolf S: Central autonomic Influences on cardiac rate and rhythm Mod Concepts Cardiovasc DIS 38 29-34, 1969 13 Nixon PG, Taylor DJ, Morton SD, et al: A sleep regimen for myocardral Infarction Lancet 1 726-728, 1968 14 Malllani A, Schwartz PJ, Zanchetti & A sympathetic reflex elicited by experimental coronary occlusion Am J Physrol217 703-709, 1969 15 Gillis RA- Role of the nervous system In the arrhythmias produced by coronary occlusion In the cat Am Heart J 81 677-684, 197 1 16 Angelakos ET, Torchiana ML. Adrenergic factors In, Cardiac Arrhythmias (Drelfus LS, Ltkoff W, ed) New York, Grune & Stratton, 1973, p 505-516 17 Mannmg GW, McEachern CG, Hall GE* Reflex coronary artery spasm following sudden occlusion of other coronary branches Arch Intern Med 64 661-674, 1939 18 Gillis RA, Thibodeaux H, Barr L: Anti-arrhythmic properties of chlordlazepoxide Circulation 49 272-282, 1974 19 Grayson J, Laprn BA. Observatrons on the mechanisms of in-
farction In the dog after expertmental occlusion of the coronary artery Lancet 1 1284-1288, 1966 20 Corr PB, Gillis RA: Role of the vagus nerve In the cardiovascular changes Induced by coronary occlusion Clrculatlon 49 86-97, 1974 21 Kent KM, Smith ER, Redwood DR, et al. Electrical stability of acutely lschemlc myocardlum Influences of heart rate and vagal stimulation Circulation 47 291-293, 1973 22 Kent KM, Epstein SE, Cooper T, et al: Cholmergic innervation of the canine and human conducting system Circulation 50 948-955, 1974 23 Goldstein RE, Karsh RB, Smith ER, et al: Influence of atroplne and vagally medtated bradycardta on the occurrence of ventncular arrhythmias following acute coronary occlusion In closed-chested dogs Circulation 47 1180-l 190, 1973 24 Webb SW, Adgey AA, Pantrrdge JF: Autonomic disturbance at onset of acute myocardlal tnfarction Br Med J 3 89-92, 1972 25 Lown B, Tykocinski M, Garfein A, et al: Sleep and ventricular premature beats Circulation 48 691-701, 1973 26 Mendez C, Aceves J, Mendez R. The antladrenerglc action of dtgitalis on the refractory period of the AV transmtsslon system J Pharmacol Exp Ther 131 199-204, 1961 27 Wallace AG, Schaal SF, Suglmoto T, et al: The electrophysiologlc effects of beta adrenerglc blockade and cardiac denervation Bull NY AcadMed43 1119-1137, 1967 28 Gillis RA* Cardiac sympathetrc nerve activity changes Induced by ouabaln and propranolol Science 166 508-510. 1969 29 McLain PL: Effects of cardiac glycosides on spontaneous efferent activity in vagus and sympathetic nerves of cats Int J Neuropharmacol 8 379-387, 1969 30 Gillis RA, Raines A, Sohn YJ, et al. Neurolexcltatory effects of digitalis and their role In the development of cardiac arrhythmias J Pharmacol Exp Ther 183 154-168, 1972 31 Levitt B, Cagin N, Somberg J, et al: Alteration of the effects and distribution of ouabaln by spinal cord transection In the cat J Pharmacol Exp Ther 185 24-28, 1973 32 Cagin N, Freeman E, Somberg J, et al: A comparison of the in VIVO and in vitro actions of ouabain to produce cardiac arrhythmia Arch Int Pharmacodyn Ther 207 162-169, 1974 33 Levitt B, Rames A, Sohn YJ, et al* The nervous system as a site of actton for digitalis and antlarrhythmic drugs J Mt Sinai Hosp 37 227-340, 1970 34 Levitt B, Giflis R, Roberts J, et al* Influence of the cardiac vagus nerves on the cardiotoxcctty of acetylstrophanthrdm. ouabaln, and digltoxln (abstr) Pharmacologist 12 304, 1970
June 1976
The American Journal of CARDIOLOGY
Volume 37
1113
Role of the Nervous System in the Genesis of Cardiac Rhythm Disorders
RARRIE
LEVITT,
MD,
FACC’+
NORMAN CAGIN, MD* JACK KLEID, MD, FACC” JOHN SOMBERG, RICHARD GILLIS,
MD* PhDt
York, New York Washmgton, D C
New
The search for effective prophylaxis of sudden cardiac death has led to a consideration of the basic pathogenic mechanisms underlying disorders of cardiac rhythm. Although the myocardmm is undeniably important m the genesis of these disorders, the nervous system may be equally important. Several independent lines of evidence lead to this conclusion Experimental evidence: Experimental procedures that alter central nervous system function have repeatedly been demonstrated to result in cardiac arrhythmias or electrocardiographic changes, or both. Nearly every arrhythmia observed clinically can be reproduced by stimulation of the dlencephalon and mesencephalon l Evans and Gill& have demonstrated that rhythm disorders produced by hypothalamic stimulation can be blocked by the use of antladrenergic and anticholinergic drugs. Simultaneous stimulation of sympathetic and parasympathetic nerve trunks can also produce disorders of rhythm 3 Randall and coworkers4v5 observed that stimulation of the sympathetic nerves could induce both atria1 and ventricular ectopic rhythms Similarly, Alessl, Moe et a1.6 and Ninomaya7 have demonstrated that parasympathetic stlmulatlon From the D~vrs~ons of Cardiology and Clmlcal Pharmacology. Department of Medlctne, New York MedIcal College, New York, N Y and the Department of Pharmacology, Georgetown Unlverslty Schools of Medictne and Dentistry, WashIngton, D C t Irma Hirsch1 Career Scientist $ Career Development Awardee, Natlonal Heart and Lung Institute Address for reprints Norman A Cagin, MD, Department of Medlclne, New York MedIcal College, 1249 Fifth Ave , New York, N Y 10029 l
can produce atria1 tachyarrhythmlas and fibrlllatlon. From the foregoing, it IS clear that neural sites play a major role m the mductlon of cardiac rhythm disorders. Roberts et al a proposed the following explanation for the role of the autonomic system It IS generally recogmzed that the heart 1s richly mnervated with autonomic fibers and that these fibers can influence automatlclty, conductlvlty and excltablhty A conslderatlon of the anatomy of the heart indicates that autonomic influence must be mediated through a multlphcity of mdlvldual neuroeffector synapses, and that each nerve termmal influences its immediate region of the myocardlum. Under normal clrcumstances, each nerve termmal speeds or slows the progression of the cardiac impulse through its domam m concert with the activity of adJacent termmals Under experimental condltlons of synchronous stlmulatlon of extracardlac nerve trunks, the response of the nerve terminals and the underlying myocardmm 1s perforce uniform, and a gross slowing or speeding of the heart results. Insofar as each axon or nerve terminal has the capacity for mdependent actwlty, the system is potentially capable of becoming dlscoordmated Discordant neural activity would result m fractlonatlon of the myocardlum, 1 e. conductlvlty, automaticlty and excltablhty would vary from region to region, and the flow of electrical actlvlty through such a fractionated myocardmm will become turbu-
lent.
Clinical evidence: Patients suffering from cerebrovascular disorders, head injury, or tumors of the central nervous system and those undergoing neurosurgical procedures have a high incidence rate of electrocardlographlc abnormahtles g These abnormahties include T wave changes as well as evidence of bradyar-
June 1976
The American
Journal
of CARDIOLOGY
Volume
37
1111
EDITORIALS
rhythmias, heart block and atria1 and ventricular ectopic rhythms. These rhythm disorders frequently occur in the absence of demonstrable organic heart disease. Emotional factors can also produce important disorders of cardiac rhythm. Greene et al lo have proposed that “in at least 50% of the patients with sudden death, psychological and social factors are associated with the time of sudden death.” These workers and others11J2 describe patients in whom a severe emotional crisis heralded the lethal episode The importance of psychic factors was well expressed m a quotation referred to by Nixon13 and attributed to M F. Oliver: “Coronary disease patients should be nursed out of sight of each other because ventricular fibrillation can be catchmg.” Experimental myocardial infarction: The autonomic nervous system plays an important role m the control of cardiac rhythm associated with both experimental and clinical myocardial infarction. Malllam et al.l* and Gill~~~ observed that augmented sympathetic nerve traffic is associated with coronary occlusion m the cat Gillis further noted that the development of cardiac rhythm disorders was temporally related to increased traffic m the cardiac sympathetic nerves. Spinal cord transection prevented the augmentation of nerve traffic and reduced the incidence of rhythm disorders associated with experimental coronary occlusion. Moreover, survival time was increased sigmficantly after coronary occlusion m the cats with such transection Other workersi have also observed that surgical reduction m sympathetic influence on the heart is associated with a reduction m cardiac rhythm disorders. Drug-induced depression of sympathetic neural activity has also been associated with a decrease in the morbidity and mortality from myocardial infarction in animals. Ether anesthesia and sodium pentobarbital and morphine were observed to reduce mortality associated with experimental myocardial mfarction.17 Admimstration of chlordiazepoxide is also effective m controlling rhythm disorders associated with experimental myocardial mfarction.i8 Grayson and Lapini observed in the dog under deep anesthesia that admnnstration of bretylium prevented the development of electrocardiographic or microscopic evidence of infarction after ligation of the left anterior descending coronary artery In addition, there IS experimental evidence to mdicate that infarcted myocardium is more sensitive than noninfarcted myocardium to adrenergic neural influence and to circulatmg catecholamines.16 On the other hand, cholinergic neural activity is associated with a protective effect m experimental myocardial infarction. Corr and Gillls20 found that vagal section increased the incidence of arrhythmias associated with coronary occlusion in the experimental ammal. Kent et al 21.22similarly observed that vagal nerve stimulation increases the threshold for ventricular fibrillation m both the nonischemic and ischemic canine model. Reduction in vagal influence by admimstration of atropine in the animal with experimental infarction sigmficantly increased the total incidence of rhythm disorders and ventricular fibrillation tended to occur more often 23
1112
June 1976
The Amencan
Journal
of CARDIOLOGY
Volume
Clinical myocardial infarction: Evidence for mvolvement of the nervous system m the mduction of cardiac rhythm disorders in patients with ischemic heart disease or myocardial infarction, or both, has also been suggested Webb et a1.24 proposed that the electrical imbalance that occurs in the early period after acute myocardial mfarction is the result of disordered autonomic function. These workers suggested that both tachyarrhythmias and bradyarrhythmias after myocardial infarction reflect autonomic neural influence. Increased levels of circulatmg catecholammes have been found during the acute phase of myocardial mfarction. Lown et a1.25 observed that the incidence of ventricular rhythm disorders in patients with ischemic heart disease is substantially reduced during sleep. Nixon et al l3 reported that the mduction of a sleep-like state with pethidme and promethazme decreased both morbidity and mortality from myocardial mfarction during the first week after the acute event. In general, it appears that both the sympathetic and parasympathetic systems are intimately mvolved with the control of cardiac rhythm in experimental and climcal myocardial infarction, parasympathetic activity providing a protective effect and sympathetic activity a deleterious effect. Digitalis toxicity: A neural basis for digitalis intoxication has been proposed.8,26*27 Gillis and McLain2g demonstrated that administration of ouabain results in dose-related increments m sympathetic, parasympathetic and phrenic nerve traffic G&s et a130 demonstrated that the increments m nerve traffic are the forerunners of ventricular rhythm disorders and death They further observed that spinal cord transection prevents neural hyperactivity induced by ouabain and increases the dose of ouabain needed to produce death. Levitt et a13i demonstrated that exclusion of the sympathetic nervous system by spinal cord transection increases the dose, serum level and tissue level of ouabam needed to produce ventricular fibrillation or asystole They also observed that tissue levels of ouabain needed to produce “death” in vitro, m the absence of neural influences, were substantially greater than those needed to produce death in ~1~0.~~On the basis of this work, it appears that digitalis toxicity m the intact animal, and presumably man, is largely a neural phenomenon whereas intoxication m the isolated heart probably results from the direct myocardial effect of the drug Moreover, drugs with the capacity to depress sympathetic nervous activity have been demonstrated to be effective m the blockade of digitalis toxicity. Thus, propranolol, reserpine, n-isopropyl-p-mtro-phenylethanolamine (INPEA), guanethidine and diphenylhydantoin among others 33 have been demonstrated to increase the dose of digitahs needed to produce toxic rhythm disorders and death. On the other hand, as m acute myocardial mfarction, the vagus nerve has been reported to protect against digitahs-induced arrhythmias s4 The capacity of digitalis to produce climcal neurotoxicity is well known Indeed, neurotoxicity has long been established as the harbinger of impending “car-
37
EDITORIALS
diotoxicrty “33 Thus, the nervous system appears to play a critical role in the induction of cardiac rhythm dlsorders by digitalis m both animals and man. Clinical implication: A new approach to the problems of cardiac rhythm and sudden death must be found if srgmficant inroads are to be made m the fight against
them. The evidence suggests that the nervous system 1s an important target m the research effort to prevent cardiac rhythm disorders. Antlarrhythmrc drugs and procedures should be sought among those that inhibit neurally induced arrhythmias and spare the myocardrum the effects of nonspeclfrc depression.
References 1 Hockman CH, Mauk HP Jr, Hoff EC: ExperImental neurogenlc arrhythmtas Bull NY Acad Med 43 1097-l 106, 1967 2 Evans DE, Glllis RA: Effect of dtphenylhydantoln and lldocame on cardrac arrhythmtas Induced by hypothalamic stimulatton J Pharmacol Exp Ther 19 1 506-5 17, 1974 3 Manning JW, Cotton MdeV. Mechanism of cardiac arrhythmias induced by dlencephaltc sttmulatron Am J Phys~ol203 1120-l 124, 1962 4 Armour JA, Hageman GR, Randall WC: Arrhythmtas Induced by local nerve stimulation Am J Physlol 223 1068-1076, 1972 5 Geesbrecht JM, Randall WC: Area localrzatron of shlftrng cardiac pacemakers during sympathetic stimulation Am J Phystol 220 1522-1527, 1971 6 Alessi R, Nusynowdz M, Abildskov JA, et al: Nonuniform drstrrbutton of vagal effects on the atrlal refractory period Am J Physlol 194 406-410, 1958 7 Ninomiya I. Direct evidence of non-uniform distribution of vagal effects on dog atria Clrc Res 19 576-583, 1966 8 Roberts J, Levitt B, Standaerl FG: A possible role of the autonomic nervous system in the control of cardiac rhythm Nature 214 912-913, 1987 9 Abrldskov JA, Millar K, Burgess MJ, et al: The electrocardiogram and the central nervous system Prog Cardiovasc DIS 13 2 1O-2 15, 1970 10 Greene WA, Goldstein S, Moss AJ: Psychosocial aspects of sudden death Arch Intern Med 129 725-731, 1972 11 Wolf S: Neural mechanisms In sudden cardiac death Trans Am Clan Cllmatologtcal Assoc 79 158-176, 1967 12 Wolf S: Central autonomic Influences on cardiac rate and rhythm Mod Concepts Cardiovasc DIS 38 29-34, 1969 13 Nixon PG, Taylor DJ, Morton SD, et al: A sleep regimen for myocardral Infarction Lancet 1 726-728, 1968 14 Malllani A, Schwartz PJ, Zanchetti & A sympathetic reflex elicited by experimental coronary occlusion Am J Physrol217 703-709, 1969 15 Gillis RA- Role of the nervous system In the arrhythmias produced by coronary occlusion In the cat Am Heart J 81 677-684, 197 1 16 Angelakos ET, Torchiana ML. Adrenergic factors In, Cardiac Arrhythmias (Drelfus LS, Ltkoff W, ed) New York, Grune & Stratton, 1973, p 505-516 17 Mannmg GW, McEachern CG, Hall GE* Reflex coronary artery spasm following sudden occlusion of other coronary branches Arch Intern Med 64 661-674, 1939 18 Gillis RA, Thibodeaux H, Barr L: Anti-arrhythmic properties of chlordlazepoxide Circulation 49 272-282, 1974 19 Grayson J, Laprn BA. Observatrons on the mechanisms of in-
farction In the dog after expertmental occlusion of the coronary artery Lancet 1 1284-1288, 1966 20 Corr PB, Gillis RA: Role of the vagus nerve In the cardiovascular changes Induced by coronary occlusion Clrculatlon 49 86-97, 1974 21 Kent KM, Smith ER, Redwood DR, et al. Electrical stability of acutely lschemlc myocardlum Influences of heart rate and vagal stimulation Circulation 47 291-293, 1973 22 Kent KM, Epstein SE, Cooper T, et al: Cholmergic innervation of the canine and human conducting system Circulation 50 948-955, 1974 23 Goldstein RE, Karsh RB, Smith ER, et al: Influence of atroplne and vagally medtated bradycardta on the occurrence of ventncular arrhythmias following acute coronary occlusion In closed-chested dogs Circulation 47 1180-l 190, 1973 24 Webb SW, Adgey AA, Pantrrdge JF: Autonomic disturbance at onset of acute myocardlal tnfarction Br Med J 3 89-92, 1972 25 Lown B, Tykocinski M, Garfein A, et al: Sleep and ventricular premature beats Circulation 48 691-701, 1973 26 Mendez C, Aceves J, Mendez R. The antladrenerglc action of dtgitalis on the refractory period of the AV transmtsslon system J Pharmacol Exp Ther 131 199-204, 1961 27 Wallace AG, Schaal SF, Suglmoto T, et al: The electrophysiologlc effects of beta adrenerglc blockade and cardiac denervation Bull NY AcadMed43 1119-1137, 1967 28 Gillis RA* Cardiac sympathetrc nerve activity changes Induced by ouabaln and propranolol Science 166 508-510. 1969 29 McLain PL: Effects of cardiac glycosides on spontaneous efferent activity in vagus and sympathetic nerves of cats Int J Neuropharmacol 8 379-387, 1969 30 Gillis RA, Raines A, Sohn YJ, et al. Neurolexcltatory effects of digitalis and their role In the development of cardiac arrhythmias J Pharmacol Exp Ther 183 154-168, 1972 31 Levitt B, Cagin N, Somberg J, et al: Alteration of the effects and distribution of ouabaln by spinal cord transection In the cat J Pharmacol Exp Ther 185 24-28, 1973 32 Cagin N, Freeman E, Somberg J, et al: A comparison of the in VIVO and in vitro actions of ouabain to produce cardiac arrhythmia Arch Int Pharmacodyn Ther 207 162-169, 1974 33 Levitt B, Rames A, Sohn YJ, et al* The nervous system as a site of actton for digitalis and antlarrhythmic drugs J Mt Sinai Hosp 37 227-340, 1970 34 Levitt B, Giflis R, Roberts J, et al* Influence of the cardiac vagus nerves on the cardiotoxcctty of acetylstrophanthrdm. ouabaln, and digltoxln (abstr) Pharmacologist 12 304, 1970
June 1976
The American Journal of CARDIOLOGY
Volume 37
1113
