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Coronary vasospasm: A neuro-behavioral event?
Medical Hypotheses 0 Longman Group
(1987) 24, 369-374 UK Ltd 1987
COX&lARYVASOSPASM:ANEURO-BEHAVIORALEVENT? Unit (127A),VA Medical Benjamin H. Natelson. Primate Neuro-behavioral Center, East Orange NJ 07019 and Departmentof Neurosciences,New Jersey Medical School,Newark NJ 07103 ABSTRACT
Evidence exists for the presence of a neuro-anatanythat can produce cardiac vasospasm. Recent experimentaland clinical data suggest that this neuro-anatcmicmechanism can be activated by behavioralevents in the psycho-socialsurround of the patient with coronary artery disease. I hypothesize that this mechanism can produce myocardial ischemia and can explain the variabilityin onset of clinicalangina. I~ION Because training in medical schools focuses on pathology and functionof individualorgans and tends not to integrateknowledgefor the organism as a whole, medical specialistsoften have tunnel vision about the organ system in which they are expert. That a problemexists with this "molecular"approach is evident frcm recent evidence linking the brain, the psychosocialsurround and the heart in the genesis of cardiac arrhythmiasand sudden cardiac death (l-4). But, despite this growingawarenessand despite the well known fact that emotionalarousal can produce myocardial ischemic pain, thinking about the mechanisms controllingcoronary vasamotionfocuses on the heart itself or on the post-synapticautonanic nerves innervating it (5,6). This focus in clinical research, parallelingclinical expertise,exists despite new information(a) indicatingthat there are central neural mechanismsfor producingmyocardialischemiaby changingcoronaryartery blood flow and (b) suggesting that events in the psycho-socialsurround can activate these mechanisms. These concurrentdevelopmentsat the lab bench and the bedside indicate that a more integrativeview of the mechanismof vascmotion is necessary. To foster this, I want to hypothesizethat myocardial ischemiaoccurringwithout increasesin cardiac demand is a neuro-behavioralevent and one which can explain the variability in onset of clinicalangina. Coronary artery spasm and symptanaticmyocardial ischemic syndranes. Formerly "ischemiawas thought to be caused in almost all instancesby increased myocardial oxygen demands in the face of limited oxygen delivery caused by fixed, firm and sanetimes calcified atheranatous plaques which reduced the lumina of the major epicardial coronary arteries" (5). Today, the majority (5) of symptomatic myocardial ischemicsyndromesappear to reflecta dynamic interactionbetween fixed coronary artery disease (CAD) and coronaryvasoconstriction.The spec-
369
trum of this dynamic syndromeranges from "variantangina" occurringat rest or during sleep and accorqanied by ST se-nt elevations with completelynormal coronaryarteries,to the same syndrczne but with CAD, to "mixed angina" occurring predictablyat's ceiling of exertion and unpredictably either at rest or at low levels of exertion and accwanied by ST segment depressionwith varying amounts of CAD, to frank myocardial infarctionusually but not invariablyassociatedwith marked CAD. Along the entire breadth of this syndrome, coronary vasospasmeither has been seen directlyat angiography(7,8)or has been inferredeither fran studies of myocardialoxygen consumption(9), fran studies of regional myccardialperfusion,or fran the fact that hernodynamic changes most often do not precede the attack (7). That these forms of myocardial ischemia are really parts of a continuum is supportedby recent evidencewhich blurs the differencebetween "variant" and "exertional" angina: Crea et al reported that exercise produced myocardial ischemia in 70% of patients with "variant"angina and that ergonovine did the same in about 30% of patients with "exertional"angina (10). And Amim et al reportedboth ST elevation and depressionwith considerableoverlap among the characteristicsof both types of ST-segmentchange in a group of patientswith symptanatic CAD (11). CNS mechanisms for decreased coronary blood flow. Both intracerebroventricularor intravenousinjection of picrotoxin,a drug known to block CNS CADAergic mechanisms with resultant increases in central syqathetic outflow, elicits ST segment elevation and increases in coronary vascular resistancereversibleby alpha adrenergicblockade, sympathectanyor central GABAergic stimulation (12,13). A similar alpha-adrenergic mediated increase in coronary vascular resistancewas reportedfollowingelectricalstimulationof area postrema (14). Frank, but transient,decreases in coronary blood flow - also alpha-adrenergically mediated -- occur during electricalstimulationof the lateral hypothalamusbut only when masking by the beta-adrenergicsystem is pharmacologically blocked (15). In the presenceof stenoticcoronaries, such masking is not necessary;this indicatesthat the presence of a structural lesion can sensitize this neural mechanism for decreasing coronary flow (16). The problem with all this work is its clinical relevancein that alpha adrenergicblockersplay almost no role in the therapeutic attack on vasospasm. Nonetheless, suggestive evidence exists that neural connectionsmay be functionallyimportant. Ten patientswith ccanplex partial epilepsyhad symptchns referrableto their hearts. Four of them had ccmqlaintsof chest pain with a pain pattern typical of myocardial ischemia. Of the 10 patients, 6 had dramatic symptomrelief after treatmentwith anti-epileptics(17). Understanding the nature of the angina-likesymptoms that develop in sane epileptic patients requires further work marrying the skills of the neurologist and cardiologist. Arousal and myocardial ischemia. An explosion of informationin the last few years indicatesthat attacks of angina are a far less camyln manifestationof myocardialischemiathan episodesof painless ischemia as manifested by ST changes on Holter recordings and areas of ventricularhype-perfusionon PET scans of the heart; as with angina, the majority of episodes are not preceded by appreciableincreasesin heart rate and thus many of these episodes are inferred to reflect decreases in coronaryblood flow unrelatedto demand (18,19). Spisodes 370
of silent ischemiaalso occur in patients who are asymptanaticbut are known to have coronaryartery disease -- patientswith prior historyof proven coronaryartery disease, myocardial infarction,angirqraphically Correlationof the time of and a silent positive exercise test (20). their episodes of ischemiawith diaries of the patients' daily a&ivitieS revealed that 14% occurredduring times rated as stressfulby the patient. More importantly,only the minority of episodes (38%) were associatedwith physicalexertionwhile in contrast 78% occurredduring the individual'snormal activitiesof daily life. Moreover,of all 37 episodesrecorded,35% were preceded by no change in heart rate and 32% by increasesof less than 10 beats/min- thus indicatingthat at least l/3 of these episodeswzre not precipitatedby hmic demands. A ncnnber of recent studieshave directlyevaluatedthe effect of stressorinducedmental arousalon myocardialischenia(21-24). Dependingon the severity of the patient's underlyingdisease plus the end-point used (i.e., overt angina1 pain, ST-segmentchanges or ventricularperfusion abnormalities), as many as 75% of the patients tested positively. Ischemia in these studies is usually associated with increased hemodynamicdemands but often less than that requiredwith exercise;of 4 patientsundergoingstudy of coronaryresistance,the one with variant angina showed increases,suggestiveof coronaryvasoconstriction, during mental arousal (23). One study of coronary patients found no stressinduced changes in coronary flow, but none of their patients showed evidenceof cardiac ischemiaduring the study (25). Synthesis and hypothesis. Laboratorystudies have revealed a neural mechanism for coronary vasospasm. Preliminary evidence has been reported to indicate that coronary vascular resistancecan increaseor decrease appreciably during behavioral manipulation (26). Clinical studies have revealedthat episodesof painless ischemiaoccur far nwre often than episodes associatedwith angina and reflect an index which can be followed along the breadth of the broad syndrane of coronary artery disease. The majorityof these episodesoccur "spontaneously" -that is, without being precipitatedby hemodynamicchanges.Most of the studies done to date have used as subjects patients with symptcmatic coronary artery disease because of the problem of false positives in non-invasiveassessmentof CAD. A recent effort to cope with this problem by studying asymptcmaticpatients with definite evidence of CAD produced important findings. These patients developed episodes of asynptomatic ST+iegment depression that shared many of the characteristicsof episodes seen in patients with clinical angina and which are knmn to reflectmyocardialischemia;thus it seems reasonable to infer that the episodes showed by them also reflected painless ischemia. These episodesoccurredmuch n-oreoften during "normalmental activity"than during physicalexertion.A preliminarystudy of episodes of ST-segmentdepression in angina patients showed a similar distribution (27), characterizedas being "more frequently associated with differentlevels of mental arousal than with any other activity"(28). coNCUJs1cNS Studying the aymptcanaticpatient with CAD seems particularly important in understanding the role of bio-behavioral factors in coronary spasm. Patientswith symptomaticCAD have a reduced cardiac reserve and thus very small increases in hemodynamicdemands due to behavioralarousal could explainwhy angina begins. Such an explanation cannot be invokedto explain the episodesoccurringduring normalmental 371
activity and preceded by unchangingor even decreasingheart rates in the asymptanatic patients discussed above. These data strongly implicatebio-behavioralfactors as mediated via the CNS as important influencersof coronaryvascular tone: they lead to the hypothesisthat behavioral situations producing mental arousal can influencecoronary nt basis. This hypothesisis strengthened blood flow on a manent-tm by a recentdouble-blindstudy showing that treatmentwith alprazolam,a minor tranquillizer, decreased the duration of episodes of silent myocardialischemia (29). Such an explanation,tying periods of neuro-psychiatric arousal to coronaryvascular tone, would provide a reason for the variabilitywith which angina1 attacks develop in a clinicalpopulationwith mixed restexertionalangina. To test this hypothesiswill require a molar rather than a mlecular approach to the problem of myccardial ischemia. And because moderate mental arousal produces increased cardiac mrk which obfuscates evaluating the role of coronary vasoconstrictionin the genesis of myocardialischemia,the approachwill demand the ability to assess and quantify subtler levels of mental arousal. To do this will requirethat clinicianslay aside preconceivednotionsabout diseaseand collaborate with people with similar interests but very different backgrounds. If such an experiment in integrativemedicine proves successful,it may have ramificationsfor medical education(30). REFERENCES 1.
Trichopoulos D, XatsouyanniK, ZavitsanosX, et al. Psychological stress and fatal heart attack: The Athens (1981) earthquake naturalexperiment.Lancet i:441, 1983.
2. Natelson BH. Neuro-cardiology.an interdisciplinaryarea for the eighties.Arch Neural 42:178, 1985. 3. Blumhardt LD, Smith PEM, Owen L. Electrocardiographic accanpaniments of temporallobe epilepticseizures.Lancet i:lOSl,1986. 4. NatelsonBH. Need for an integrativeapproachin medical diagnosis. Am J Med 80:1017,1986. 5. Braunwald E, A Symposium: Experimentaland Clinical Aspects of Coronary Vasoconstriction- Introduction.Am J Cardiol 56:1E, 1985. 6. ShepherdJT, Vanhoutte FM. Spasm of the coronary arteries: causes and consequences (the scientist's viewpoint). Mayo Clin Proc 60:333, 1985. 7. Maseri A. Pathogeneticmechanisms of angina pectoris: expanding view. Br Heart J 43:648, 1980. 8. Maseri A, L'Abbate A, Baroldi G, et al. Coronary vasospasm as a possible cause of myocardial infarction.N Engl J Med 299:1271, 1978. 9. ChierchiaS, LazzariM, FreedmanB, et al. Impairmentof nyocardial perfusion and functionduring painlessmyocardial'ischemia. J Am Co11 Cardiol 1:924, 1983. 10. Crea F, Davies G, Haneo F, et al. Myocardialischemiaduring ergonovine testing: different susceptibilityto coronary vasocon1273
striction in patientswith exertionaland variant angina. Circul 69:690, 1984. of episodesof 11. von Amim T, HoflingB, SchreiberM. Characteristics ST elevation or ST depression during ambulatory monitoring in patients subsequentlyundergoingcoronaryangicgraphy.Br Heart J 54:484, 1985. 12. Segal SA, Pearle DL, Gillis RA. Coronary spasm produced by picrotoxinin cats. Eur J Phannacol76:447,1981. 13. Segal SA, Jacob T, Gillis RA. Blockade of central nervous system GABAergic tone causes sympathetic-mediated increasesin coronary vascularresistancein cats. Circ Res 55:404, 1984. 14. SanbergJC. Centrallymediatedcoronaryvasoconstriction. Circul 68: 11X-31, 1983. 15. Bonham AC, GuttermanCo, Arthur JA, et al. Electricalstimulationin perifornicallateralhypothalamusdecreasescoronaryblood flow in cat. Am J Physiol in press. The effects of cardiac sympatheticnerve 16. Heusch G, Daussen A. stimulationon perfusionof stenoticcoronaryarteriesin the dog. Circ Res 53:8, 1983. 17. Devinsky 0, Price BH, Cohen SI. Cardiac manifestationsof ccmplex partial seizures.Am J Med 80:195,1986. 18. Deanfield JE, Maseri A, Selwyn AP, et al. Myocardial ischaemia during daily life in patientswith stable angina: its relationto symptomsand heart rate changes.Lancet ii:753, 1983. 19. Deanfield JE, Shea M, Ribiero P, et al. Transient ST-segment depression as a marker of myocardialischemiaduring daily life. Am J Cardiol 54:1195,1984. 20. Campbell S, Barry J, Rebecca GS, et al. Active transientmyocardial ischemiaduring daily life in asymptcmaticpatientswith positive exercisetests and coronaryartery disease. Am J Cardiol 57:1010, 1986. 21. Schiffer F, Hartley U-I, Schulman CL, et al. Evidence for emotionally-inducedcoronary arterial spasm in patients with angina pectoris.Br Heart J 44:62, 1980. 22. DeanfieldJE, Shea M, KensettM, et al. Silent myocardialischaemia due to mental stress.Lancet ii:lOOl,1984. 23. Specchia G., de Servi S. FalconeC, et al. Mental arithmeticstress testing in patients with coronary artery disease. Am Heart J 108:56,1984. 24. L'Abbate A, Carpeggiani,Trivella MG, et al. Myocardial ischemia induced by emotion in patients with angina pectoris. p 81 in Stress and Heart Disease. (RE Beamish ed) Martinus Nijhoff, Boston, 1985. 25. Bassan, MM, Marcus HS, Ganz W. Effect of mild-tenoderate mental stress on coronary hemx@namics in patients with coronary artery disease. Circul 62:933, 1980.
373
26. Verrier RL, Hagestad EL, HohnloserSH, Lawn B. Belayed myocardial ischemiainducedby behavioralstress.Circul 72:111-242,1985. 27. Rebecca GS, Wayne RR, Campbell S, et al. Transient ischemia in coronary disease is associatedwith mental arousal during daily life. J Am Co1 Cardiol 7:239A, 1986. 28. Selwyn AP, Shea .MJ, Deanfield JE, et al. Clinical problems in coronary disease are caused by wide variety of ischemicepisodes that affect patients out of hospital. Am J Mad 79(Suppl 3A):12-17,1985. 29. Shell WE, Swan I-UC. Treatment of silent myocardial ischemiawith transdermalnitroglycerinadded to beta-blockersand alprazolam. Cardiol Clin 4:697, 1986. 30. Natelson BH. Medicine in the eighties: need for an integrative approach.Am J Med, 81:1048,1986.
374
(1987) 24, 369-374 UK Ltd 1987
COX&lARYVASOSPASM:ANEURO-BEHAVIORALEVENT? Unit (127A),VA Medical Benjamin H. Natelson. Primate Neuro-behavioral Center, East Orange NJ 07019 and Departmentof Neurosciences,New Jersey Medical School,Newark NJ 07103 ABSTRACT
Evidence exists for the presence of a neuro-anatanythat can produce cardiac vasospasm. Recent experimentaland clinical data suggest that this neuro-anatcmicmechanism can be activated by behavioralevents in the psycho-socialsurround of the patient with coronary artery disease. I hypothesize that this mechanism can produce myocardial ischemia and can explain the variabilityin onset of clinicalangina. I~ION Because training in medical schools focuses on pathology and functionof individualorgans and tends not to integrateknowledgefor the organism as a whole, medical specialistsoften have tunnel vision about the organ system in which they are expert. That a problemexists with this "molecular"approach is evident frcm recent evidence linking the brain, the psychosocialsurround and the heart in the genesis of cardiac arrhythmiasand sudden cardiac death (l-4). But, despite this growingawarenessand despite the well known fact that emotionalarousal can produce myocardial ischemic pain, thinking about the mechanisms controllingcoronary vasamotionfocuses on the heart itself or on the post-synapticautonanic nerves innervating it (5,6). This focus in clinical research, parallelingclinical expertise,exists despite new information(a) indicatingthat there are central neural mechanismsfor producingmyocardialischemiaby changingcoronaryartery blood flow and (b) suggesting that events in the psycho-socialsurround can activate these mechanisms. These concurrentdevelopmentsat the lab bench and the bedside indicate that a more integrativeview of the mechanismof vascmotion is necessary. To foster this, I want to hypothesizethat myocardial ischemiaoccurringwithout increasesin cardiac demand is a neuro-behavioralevent and one which can explain the variability in onset of clinicalangina. Coronary artery spasm and symptanaticmyocardial ischemic syndranes. Formerly "ischemiawas thought to be caused in almost all instancesby increased myocardial oxygen demands in the face of limited oxygen delivery caused by fixed, firm and sanetimes calcified atheranatous plaques which reduced the lumina of the major epicardial coronary arteries" (5). Today, the majority (5) of symptomatic myocardial ischemicsyndromesappear to reflecta dynamic interactionbetween fixed coronary artery disease (CAD) and coronaryvasoconstriction.The spec-
369
trum of this dynamic syndromeranges from "variantangina" occurringat rest or during sleep and accorqanied by ST se-nt elevations with completelynormal coronaryarteries,to the same syndrczne but with CAD, to "mixed angina" occurring predictablyat's ceiling of exertion and unpredictably either at rest or at low levels of exertion and accwanied by ST segment depressionwith varying amounts of CAD, to frank myocardial infarctionusually but not invariablyassociatedwith marked CAD. Along the entire breadth of this syndrome, coronary vasospasmeither has been seen directlyat angiography(7,8)or has been inferredeither fran studies of myocardialoxygen consumption(9), fran studies of regional myccardialperfusion,or fran the fact that hernodynamic changes most often do not precede the attack (7). That these forms of myocardial ischemia are really parts of a continuum is supportedby recent evidencewhich blurs the differencebetween "variant" and "exertional" angina: Crea et al reported that exercise produced myocardial ischemia in 70% of patients with "variant"angina and that ergonovine did the same in about 30% of patients with "exertional"angina (10). And Amim et al reportedboth ST elevation and depressionwith considerableoverlap among the characteristicsof both types of ST-segmentchange in a group of patientswith symptanatic CAD (11). CNS mechanisms for decreased coronary blood flow. Both intracerebroventricularor intravenousinjection of picrotoxin,a drug known to block CNS CADAergic mechanisms with resultant increases in central syqathetic outflow, elicits ST segment elevation and increases in coronary vascular resistancereversibleby alpha adrenergicblockade, sympathectanyor central GABAergic stimulation (12,13). A similar alpha-adrenergic mediated increase in coronary vascular resistancewas reportedfollowingelectricalstimulationof area postrema (14). Frank, but transient,decreases in coronary blood flow - also alpha-adrenergically mediated -- occur during electricalstimulationof the lateral hypothalamusbut only when masking by the beta-adrenergicsystem is pharmacologically blocked (15). In the presenceof stenoticcoronaries, such masking is not necessary;this indicatesthat the presence of a structural lesion can sensitize this neural mechanism for decreasing coronary flow (16). The problem with all this work is its clinical relevancein that alpha adrenergicblockersplay almost no role in the therapeutic attack on vasospasm. Nonetheless, suggestive evidence exists that neural connectionsmay be functionallyimportant. Ten patientswith ccanplex partial epilepsyhad symptchns referrableto their hearts. Four of them had ccmqlaintsof chest pain with a pain pattern typical of myocardial ischemia. Of the 10 patients, 6 had dramatic symptomrelief after treatmentwith anti-epileptics(17). Understanding the nature of the angina-likesymptoms that develop in sane epileptic patients requires further work marrying the skills of the neurologist and cardiologist. Arousal and myocardial ischemia. An explosion of informationin the last few years indicatesthat attacks of angina are a far less camyln manifestationof myocardialischemiathan episodesof painless ischemia as manifested by ST changes on Holter recordings and areas of ventricularhype-perfusionon PET scans of the heart; as with angina, the majority of episodes are not preceded by appreciableincreasesin heart rate and thus many of these episodes are inferred to reflect decreases in coronaryblood flow unrelatedto demand (18,19). Spisodes 370
of silent ischemiaalso occur in patients who are asymptanaticbut are known to have coronaryartery disease -- patientswith prior historyof proven coronaryartery disease, myocardial infarction,angirqraphically Correlationof the time of and a silent positive exercise test (20). their episodes of ischemiawith diaries of the patients' daily a&ivitieS revealed that 14% occurredduring times rated as stressfulby the patient. More importantly,only the minority of episodes (38%) were associatedwith physicalexertionwhile in contrast 78% occurredduring the individual'snormal activitiesof daily life. Moreover,of all 37 episodesrecorded,35% were preceded by no change in heart rate and 32% by increasesof less than 10 beats/min- thus indicatingthat at least l/3 of these episodeswzre not precipitatedby hmic demands. A ncnnber of recent studieshave directlyevaluatedthe effect of stressorinducedmental arousalon myocardialischenia(21-24). Dependingon the severity of the patient's underlyingdisease plus the end-point used (i.e., overt angina1 pain, ST-segmentchanges or ventricularperfusion abnormalities), as many as 75% of the patients tested positively. Ischemia in these studies is usually associated with increased hemodynamicdemands but often less than that requiredwith exercise;of 4 patientsundergoingstudy of coronaryresistance,the one with variant angina showed increases,suggestiveof coronaryvasoconstriction, during mental arousal (23). One study of coronary patients found no stressinduced changes in coronary flow, but none of their patients showed evidenceof cardiac ischemiaduring the study (25). Synthesis and hypothesis. Laboratorystudies have revealed a neural mechanism for coronary vasospasm. Preliminary evidence has been reported to indicate that coronary vascular resistancecan increaseor decrease appreciably during behavioral manipulation (26). Clinical studies have revealedthat episodesof painless ischemiaoccur far nwre often than episodes associatedwith angina and reflect an index which can be followed along the breadth of the broad syndrane of coronary artery disease. The majorityof these episodesoccur "spontaneously" -that is, without being precipitatedby hemodynamicchanges.Most of the studies done to date have used as subjects patients with symptcmatic coronary artery disease because of the problem of false positives in non-invasiveassessmentof CAD. A recent effort to cope with this problem by studying asymptcmaticpatients with definite evidence of CAD produced important findings. These patients developed episodes of asynptomatic ST+iegment depression that shared many of the characteristicsof episodes seen in patients with clinical angina and which are knmn to reflectmyocardialischemia;thus it seems reasonable to infer that the episodes showed by them also reflected painless ischemia. These episodesoccurredmuch n-oreoften during "normalmental activity"than during physicalexertion.A preliminarystudy of episodes of ST-segmentdepression in angina patients showed a similar distribution (27), characterizedas being "more frequently associated with differentlevels of mental arousal than with any other activity"(28). coNCUJs1cNS Studying the aymptcanaticpatient with CAD seems particularly important in understanding the role of bio-behavioral factors in coronary spasm. Patientswith symptomaticCAD have a reduced cardiac reserve and thus very small increases in hemodynamicdemands due to behavioralarousal could explainwhy angina begins. Such an explanation cannot be invokedto explain the episodesoccurringduring normalmental 371
activity and preceded by unchangingor even decreasingheart rates in the asymptanatic patients discussed above. These data strongly implicatebio-behavioralfactors as mediated via the CNS as important influencersof coronaryvascular tone: they lead to the hypothesisthat behavioral situations producing mental arousal can influencecoronary nt basis. This hypothesisis strengthened blood flow on a manent-tm by a recentdouble-blindstudy showing that treatmentwith alprazolam,a minor tranquillizer, decreased the duration of episodes of silent myocardialischemia (29). Such an explanation,tying periods of neuro-psychiatric arousal to coronaryvascular tone, would provide a reason for the variabilitywith which angina1 attacks develop in a clinicalpopulationwith mixed restexertionalangina. To test this hypothesiswill require a molar rather than a mlecular approach to the problem of myccardial ischemia. And because moderate mental arousal produces increased cardiac mrk which obfuscates evaluating the role of coronary vasoconstrictionin the genesis of myocardialischemia,the approachwill demand the ability to assess and quantify subtler levels of mental arousal. To do this will requirethat clinicianslay aside preconceivednotionsabout diseaseand collaborate with people with similar interests but very different backgrounds. If such an experiment in integrativemedicine proves successful,it may have ramificationsfor medical education(30). REFERENCES 1.
Trichopoulos D, XatsouyanniK, ZavitsanosX, et al. Psychological stress and fatal heart attack: The Athens (1981) earthquake naturalexperiment.Lancet i:441, 1983.
2. Natelson BH. Neuro-cardiology.an interdisciplinaryarea for the eighties.Arch Neural 42:178, 1985. 3. Blumhardt LD, Smith PEM, Owen L. Electrocardiographic accanpaniments of temporallobe epilepticseizures.Lancet i:lOSl,1986. 4. NatelsonBH. Need for an integrativeapproachin medical diagnosis. Am J Med 80:1017,1986. 5. Braunwald E, A Symposium: Experimentaland Clinical Aspects of Coronary Vasoconstriction- Introduction.Am J Cardiol 56:1E, 1985. 6. ShepherdJT, Vanhoutte FM. Spasm of the coronary arteries: causes and consequences (the scientist's viewpoint). Mayo Clin Proc 60:333, 1985. 7. Maseri A. Pathogeneticmechanisms of angina pectoris: expanding view. Br Heart J 43:648, 1980. 8. Maseri A, L'Abbate A, Baroldi G, et al. Coronary vasospasm as a possible cause of myocardial infarction.N Engl J Med 299:1271, 1978. 9. ChierchiaS, LazzariM, FreedmanB, et al. Impairmentof nyocardial perfusion and functionduring painlessmyocardial'ischemia. J Am Co11 Cardiol 1:924, 1983. 10. Crea F, Davies G, Haneo F, et al. Myocardialischemiaduring ergonovine testing: different susceptibilityto coronary vasocon1273
striction in patientswith exertionaland variant angina. Circul 69:690, 1984. of episodesof 11. von Amim T, HoflingB, SchreiberM. Characteristics ST elevation or ST depression during ambulatory monitoring in patients subsequentlyundergoingcoronaryangicgraphy.Br Heart J 54:484, 1985. 12. Segal SA, Pearle DL, Gillis RA. Coronary spasm produced by picrotoxinin cats. Eur J Phannacol76:447,1981. 13. Segal SA, Jacob T, Gillis RA. Blockade of central nervous system GABAergic tone causes sympathetic-mediated increasesin coronary vascularresistancein cats. Circ Res 55:404, 1984. 14. SanbergJC. Centrallymediatedcoronaryvasoconstriction. Circul 68: 11X-31, 1983. 15. Bonham AC, GuttermanCo, Arthur JA, et al. Electricalstimulationin perifornicallateralhypothalamusdecreasescoronaryblood flow in cat. Am J Physiol in press. The effects of cardiac sympatheticnerve 16. Heusch G, Daussen A. stimulationon perfusionof stenoticcoronaryarteriesin the dog. Circ Res 53:8, 1983. 17. Devinsky 0, Price BH, Cohen SI. Cardiac manifestationsof ccmplex partial seizures.Am J Med 80:195,1986. 18. Deanfield JE, Maseri A, Selwyn AP, et al. Myocardial ischaemia during daily life in patientswith stable angina: its relationto symptomsand heart rate changes.Lancet ii:753, 1983. 19. Deanfield JE, Shea M, Ribiero P, et al. Transient ST-segment depression as a marker of myocardialischemiaduring daily life. Am J Cardiol 54:1195,1984. 20. Campbell S, Barry J, Rebecca GS, et al. Active transientmyocardial ischemiaduring daily life in asymptcmaticpatientswith positive exercisetests and coronaryartery disease. Am J Cardiol 57:1010, 1986. 21. Schiffer F, Hartley U-I, Schulman CL, et al. Evidence for emotionally-inducedcoronary arterial spasm in patients with angina pectoris.Br Heart J 44:62, 1980. 22. DeanfieldJE, Shea M, KensettM, et al. Silent myocardialischaemia due to mental stress.Lancet ii:lOOl,1984. 23. Specchia G., de Servi S. FalconeC, et al. Mental arithmeticstress testing in patients with coronary artery disease. Am Heart J 108:56,1984. 24. L'Abbate A, Carpeggiani,Trivella MG, et al. Myocardial ischemia induced by emotion in patients with angina pectoris. p 81 in Stress and Heart Disease. (RE Beamish ed) Martinus Nijhoff, Boston, 1985. 25. Bassan, MM, Marcus HS, Ganz W. Effect of mild-tenoderate mental stress on coronary hemx@namics in patients with coronary artery disease. Circul 62:933, 1980.
373
26. Verrier RL, Hagestad EL, HohnloserSH, Lawn B. Belayed myocardial ischemiainducedby behavioralstress.Circul 72:111-242,1985. 27. Rebecca GS, Wayne RR, Campbell S, et al. Transient ischemia in coronary disease is associatedwith mental arousal during daily life. J Am Co1 Cardiol 7:239A, 1986. 28. Selwyn AP, Shea .MJ, Deanfield JE, et al. Clinical problems in coronary disease are caused by wide variety of ischemicepisodes that affect patients out of hospital. Am J Mad 79(Suppl 3A):12-17,1985. 29. Shell WE, Swan I-UC. Treatment of silent myocardial ischemiawith transdermalnitroglycerinadded to beta-blockersand alprazolam. Cardiol Clin 4:697, 1986. 30. Natelson BH. Medicine in the eighties: need for an integrative approach.Am J Med, 81:1048,1986.
374