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The heart in anaphylaxis
The heart in anaphylaxis
Several lines of reasoning have led to the concept that there is a direct participation of the heart in anaphylactic reactions. These include clinical experience, as well as in vivo and in vitro models of anaphylaxis, and the analysis of the effects of anaphylactic mediators and inhibitory drugs on cardiac function. It is the purpose of this editorial to attempt to put into perspective the current evidence regarding the relationship of mast cells and mast cell mediators not only to cardiac function but also to examine the relevance of these findings to the clinical evaluation and therapy of anaphylaxis. As long ago as 1910 it was known that anaphylaxis is associated with disturbances in cardiac rate and rhythm.’ A number of studies in guinea pigs, rabbits, and monkeys both in vivo and in vitro have since attempted to define the association between cardiac responses and anaphylaxis. In the guinea pig, in vivo, anaphylaxis is associated with sinus tachycardia, increased ventricular automaticity, atrioventricular conduction delays, and ventricular tachycardia.’ In the rabbit, anaphylaxis is often accompanied by rightward QRS shifts, ST segment depression, and a variety of dysrhythmias,’ whereas in the monkey ST and T wave changes and intraventricular as well as atrioventricular conduction delays occur.4 It is difficult in these in vivo studies to ascertain whether the changes noted are due to a primary effect of anaphylaxis on the heart or are due to concomitant pulmonary vasoconstriction and hypoxia and/or to hypotension secondary to volume loss and decreased peripheral resistance. In this regard, as cazrdiac changes (increased heart rate and decreased left ventricular pressure) can precede pulmonary responses when antigen is injected into the guinea pig l.eft ventricle as opposed to a peripheral vein, it has been suggested that anaphylaxis can indeed affect the heart directly.’ These analyses have been further pursued in vitro with the use of intact perfused hearts as well as cardiac muscle preparations. In such systems the effect of anaphylactic challenge and of isolated mediators on cardiac function can be directly addressed. In addition, the eft;ect of drugs on the expression of anaphylaxis and the action of defined mediators can be determined. The success of these model systems rests
on the fact that mast cells are prominent in the heart. In the human heart as much as 3 p,g of histamine is present per gram of atrium,6 suggesting a concentration of nearly a million mast cells per gram of cardiac tissue.7 Moreover, mast cells are known to be enriched in areas of atheromatous plaque and to be especially prominent in the adventitia of the coronary arteries.’ Human and guinea pig cardiac mast cells are functionally intact and can release histamine on immunologic or pharmacologic challenge as Levi et a1.9and Graver et al.‘” describe in this issue and elsewhere. In addition, sulfidopeptide leukotrienes” and plateletactivating factor” have been demonstrated to be generated on anaphylactic challenge of guinea pig heart tissue. The consequences of anaphylactic mast cell activation on cardiac function have been attributed to these released mediators. In isolated perfused hearts in vitro, antigen challenge causes initial tachycardia and augmentation of ventricular contraction followed rapidly by contractile failure and diminished coronary blood flo~.~ The duration and degree of cardiac dysfunction observed in guinea pig hearts can be directly correlated to the amount of histamine released by challenge.‘j Additionally, many of the effects noted in anaphylaxis can be induced by the direct intracardiac administration of histamine or be prevented by combined use of H, and H, antihistaminic drugs. Specifically, H, antagonists prevent slowing of atriovenricular conduction’4 as well as inhibit ventricular fibrillation,15 whereas H, antagonism affects sinus and other tachyarrhythmias, ectopic beats, reentrant rhythms, and some instances of atrioventricular conduction delay.6-‘9 In addition, histamine is a potent coronary vasoconstrictor in this species and in humans with coronary disease*’ and a direct positive inotropic agent in humans as well as guinea pigs.“. ‘I The sulfidopeptide leukotrienes are also coronary vasoconstrictors and negative inotropic agents in both human and animal cardiac tissue.“. 23Recent studies also indicate that platelet-activating factor is a potent negative inotropic agent, depresses coronary flow, and induces atrioventricular conduction delays.” Platelet-activating factor and sulfidopeptide leukotrienes exert their cardiac effects at nanomolar concentrations. whereas histamine is active at submillimolar 663
664
Wasserman
levels, and it is these concentrations of these key mediators that are generated during in vitro cardiac anaphylaxis. Just how is the clinician to use this information in the evaluation and treatment of anaphylaxis in humans? Are the cardiac findings in human anaphylaxis (arrhythmia, angina, and myocardial infarction) primary or are they secondary to hypoxia, hypotension, or medication? How can transient left bundle branch block, ST segment, and T wave changes of ischemia, QRS and ST changes of infarction, prolonged PR intervals, wandering atria1 pacemaker, atria1 fibrillation, sinus tachycardia, and atrioventricular and intraventricular conduction defects be explained? Although the clinical literature of anaphylaxis is replete with references to such cardiac effects, it is perhaps appropriate to review some of these articles presented during the last two decades to illustrate the difficulties in assigning a role to primary cardiac effects of anaphylaxis. Stein and Wechsell” reported three instances of cardiac disease accompanying allergic drug reactions. The first patient developed a myocardial infarction 2 hours after epinephrine therapy for cutaneous and respiratory manifestations of anaphylaxis. The second patient suffered a posterior myocardial infarction as a consequence of serum sickness, whereas the third patient had a drug rash and suffered a myocardial infarction while the patient was receiving a sitz bath.24 In none of these cases can a convincing primary relationship between mast cell activation and cardiac effects be made. Booth and Patterson” reported EKG findings in 14 of 23 patients experiencing anaphylaxis and noted abnormalities in six patients. In only three of the patients did electrocardiographic abnormalities precede medical therapy, and they consisted of premature ventricular beats in one instance, sinus tachycardia with ST segment depression in another instance, and nonspecific ST-T segment changes in the third instance. All patients were hypotensive, a finding that may be assumed to have some effect on the cardiac responses noted. Criep and Woehlerz6 reported three cases of anaphylaxis with cardiac findings. In the first patient, a myocardial infarction occurred after emergency treatment of severe anaphylaxis (manifested by wheezing, dyspnea, and eventuating in hypotension and cardiac arrest). A second patient developed EKG findings of transient ischemia after therapy for cutaneous and respiratory changes of anaphylaxis associated with severe hypotension and loss of consciousness. A third patient demonstrated evidence of anterolateral ischemia after treatment of severe anaphylactic shock. Petsas and Kotler2’ reported
J. ALLERGY CLIN. IMMUNOL. MAY 1986
two instances of anaphylaxis to penicillin. In the first patient, left bundle branch block and sinus tachycardia were noted 90 minutes after treatment of shock, whereas in the second patient there were peaked P waves and right axis deviation during a hypotensive episode treated with epinephrine. These reported findings are quite consistent with the effects of respiratory obstruction and epinephrine therapy. Brasher and Sanchez28reported a case of a 62-year-old patient who collapsed 20 minutes after a wasp sting with cyanosis, rales, and inaudible heart sounds in the absence of hypotension. After therapy with glucocorticoids, diuretics, and aminophylline for presumptive infarction, the EKG revealed atria1 fibrillation and anterior ST segment depression that could well have been a consequence of respiratory obstruction and hypoxia in a person of this age. Levine29 also reported EKG findings in two cases of wasp sting anaphylaxis. In the first instance severe hypotension and respiratory obstruction occurred, and the EKG, which was initially normal, became abnormal with ST segment elevation and ventricular ectopy after administration of epinephrine. The second patient who developed urticaria, hypotension, and lost consciousness had tachycardia, irregular heart beat, and, after two injections of epinephrine, revived and then complained of chest pain. EKG at that point revealed atria1 fibrillation and diaphragmatic infarction. The role of hypotension, epinephrine, and possible preexisting coronary disease again make direct cardiac anaphylaxis difficult to ascertain. Druck et a1.3oreported a patient who developed wheezing, dyspnea, rhinorrhea, and epigastric pain 10 minutes after completion of coronary angiography. The patient was hypotensive and hypoxic, and EKG revealed ST segment elevations in inferior leads. Oxygen and hydrocortisone were administered without initial benefit, whereas intravenous nitroglycerine administration led to tachycardia and a transient return of ST segments to normal before inferior infarction became fixed. The angiogram completed just before the reaction revealed occluded first diagonal branch of the left anterior descending and 95% occlusion of the distal circumflex coronary arteries, and the right coronary artery had an aneurysm at its origin. The deleterious effects of hypotension and hypoxia in such a setting are obvious, and the transient effect of nitroglycerine can hardly be used to support a diagnosis of coronary spasm. Sullivan3’ reported two instances of anaphylaxis to penicillin in which an initially normal EKG became abnormal (ventricular tachyarrhythmias) only after administration of intravenous epinephrine. Finally, Austin et a1.32reported a 64-year-old man who developed urticaria, wheezing,
VOLUME77 NUMBER5
and profound hypotension after intravenous administration of a cephalosporin antibiotic. This reaction was treated with epinephrine, diphenhydramine, dexamethasone, and dopamine. Preanaphylaxis EKG was normal, whereas one EKG performed during the anaphylactic response (but whose timing vis-a-vis drug therapy is not clear) demonstrated atria1 fibrillation and ST segment elevations in inferior leads. These changes completely reversed in the course of several hours. Coronary angiography performed subsequently was normal except for anomalous origin of the right cor’onary artery from the sinus of Valsalva. The authors interpret these findings to suggest coronary artery spasm occurred as a part of anaphylaxis, although they also allow that hypotension and subsequent decreased aortic-distending pressure could have led to compression of the ostium of the anomalous coronary artery. The concept of mast cell-dependent coronary artery spasm has recently gained some support from the finding of increased mast cells in the adventitia of coronary arteries of patients with Prinzmetal’s angina.“3 How can one reconcile the clear in vitro and in vivo model data of the effect of experimental anaphylaxis and mediators on the heart with the very confusing clinical literature in which cardiac responses can be attributed to so many possible mechanisms (none of which need imply direct cardiac anaphylaxis)? At present one can only conclude that cardiac anaphylaxis may occur and that its contribution must be eventually separated from the effects of hypoxia, hypotension, and medications by careful observation and judicious human experimentation. It is, however, relevant to consider that cardiac anaphylaxis may explain some of the findiqgs in anaphylaxis and may point the way to the need to use specific therapies and take particular precautions directed to this possibility. For example, the early and aggressive use of antihistaminics (both H, and H,) would be logical on this basis. The fact that mast cells are increased in the coronary arteries of patients with coronary disease suggests that anaphylaxis in the older patient or the patient with known coronary disease may be especially unfortunate both from the view of tolerance of hypotension and hypoxia but also because of the potential for severe cardiac anaphylaxis. Although it is possible that local mast cell activation may lead to coronary vasospasm, it is not yet possible to recommend the use of coronary vasodilators (calcium channel-blocking drugs or nitroglycerin) in therapy of anaphylaxis. Thus, at the present time, cardiac anaphylaxis must be viewed as a very real and potentially critical clinical consideration in anaphylaxis but also as a consideration about
Heart
in anaphylaxis
665
which we cannot yet make particular diagnostic and therapeutic recommendations. Stephen I. Wasserman, M.D. Professor of Medicine Chief, Division of Allergy University of California-San Diego Medical Center 225 W. Dickinson St. San Diego, CA 92103 REFERENCES 1. Aver J, Lewis PA: Physiology of immediate reaction of anaphylaxis in guinea pig. J Exp Med 12:151,1910 2. Feigen GA, Prager DJ: Experimental cardiac anaphylaxis: physiologic, pharmacologic, and biochemical aspects of immune reactions in the isolated heart. Am J Cardiol 24:474, 1969 3. Halonen M, Palmer JD, Lehman IC, et al: Respiratory and circulatory alterations induced by acetylglyceryl ether phosphorylcholine (AGEPC): a mediator of IgE anaphylaxis in the rabbit. Am Rev Respir Dis 122:915, 1980 4. Patterson R, Fink JN, Wennemark J, et al: The biologic consequences of the immediate-type hypersensitivity transferred from man to monkey. J ALLERY 37:295, 1966 5. Zavecz JM, Levi R: Separation of primary and secondary cardiovascular events in systemic anaphylaxis. Circ Res 40:15, 1977 6. Levi R, Guo Z-G: Roles of histamine in cardiac dysfunction. In Tanaka K, editor: Advances in histamine research. New York, 1982, Pergamon Press Inc. p 213 7. Paterson NAM, Wasserman SI, Said JW, et al: Release of chemical mediators from partially purified human lung mast cells. J Immunol 117:1356, 1976 8. Pomerance A: Periarterial mast cells in coronary atheroma and thrombosis. J Path Bacterial 76:55, 1958 9. Levi R, Chenonda AA, Trzeciakowski JP, et al: Effects of histamine on the cardiovascular and respiratory system: dysrrhythmias caused by histamine release in guinea pig and human hearts. Klin Wochenschr 60:965, 1982 10. Graver LM, Robertson DA, Levi R, et al: IgE-mediated hypersensitivity in human heart tissue: histamine release and functionalchanges. J ALLERGY CLIN IMMUNOL 77:709, 1986 II. Levi R, Hattori Y, Burke JA, et al: Leukotriene C, is released from the anaphylactic heart: a case for its direct negative inotropic effect. In Bailey JM, editor: Prostaglandins. leukotrienes, and lipoxins. New York, 1985, Plenum Publishing Carp, p 275 12. Levi R, Burke JA, Guo Z-G, et al: Acetylglyceryl ether phosphorylcholine (AGEPC): a putative mediator of cardiac anaphylaxis in the guinea pig. Circ Res 54:117, 1984 13. Capurro N, Levi R: The heart as a target organ in systemic allergic reactions: comparison of cardiac anaphylaxis in vivo and in vitro. Circ Res 36:520, 1975 14. Capurro N, Levi R: Anaphylaxis in the isolated guinea pig heart: selective inhibition by burimamide of the positive inotropic and chronotropic effects of released histamines. Br J Pharmacol 48:620, 1973 15. Trzeciakowski JP, Levi R: Analysis of receptors mediating histamine-induced decrease in ventricular fibrillation threshold in the guinea pig heart. Fed Proc 40:692, 1981 16. Levi R, Allan G: Histamine-mediated cardiac effects. In Bris-
J. ALLERGY CLIN. IMMUNOL. MAY 1986
666 Wasserman
17. 18. 19. 20. 21.
22.
23.
tow M, editor: Drug-induced heart disease. Amsterdam, 1980, Elsevier-North Holland Biomedical Press, p 377 Houki S: Restoration effects of histamine on action potential in potassium-depolarized guinea pig papillary muscle. Arch Int Pharmacodyn Ther 206:113, 1973 Ledda F, Mantelli L, Mugelli A: Blockade by burimamide of the restorative effect of histamine in tetrodoxotoxin-treated heart preparations. Br J Pharmacol 57:247, 1976 Zavecz JM, Levi R: Histamine-digitalis interaction: modification by histamine H,- and Hz-receptor antagonists. Pharmacologist 18:168, 1976 Kalsner S, Richards R: Coronary arteries of cardiac patients are hyperreactive and contain stores of amines: a mechanism for coronary spasm. Science 223:1435, 1984 Guo Z-G, Levi R, Graver LM, et al: Inotropic effects of histamine in human myocardium: differentiation between positive and negative components. J Cardiovasc Pharmacol 6: 1210, 1984 Mullane K, Barst S, M&tiff JC: Leukotrienes in myocardial ischemia. In Lefer AM, Gee MH, editors: Leukotrienes in cardiovascular and pulmonary function. New York, 1985, Arliss Inc, p 127 Burke JA, Levi R, Guo Z-G, et al: Leukotrienes C,, D,, and E4: effects on human and guinea pig cardiac preparations in vitro. J Pharmacol Exp Ther 221:235, 1982
Bound volumes
available
24. Stein I, Wechsell I: Cardiac disease accompanying allergic drug reactions. J ALLERGY4548, 1970 25. Booth BH, Patterson R: Electrocardiographic changes during human anaphylaxis. JAMA 211:627, 1970 26. Criep LM, Woehler TR: The heart in human anaphylaxis. Ann Allergy 29:399, 1971 27. Petsas AA, Kotler MN: Electrocardiographic changes associated with penicillin anaphylaxis. Chest 64:66, 1973 28. Brasher GW, Sanchez SA: Reversible electrocardiographic changes associated with wasp sting anaphylaxis, JAMA 229:1210, 1974 29. Levine MD: Acute myocardial infarction following wasp sting. Am Heart J 91:365, 1976 30. Druck MN, Johnstone DE, Staniloff H, et al: Coronary artery spasm asa manifestation of anaphylactoid reaction to iodinated contrast material. Can Med Assoc J 125:1131, 1981 31. Sullivan TJ: Cardiac disorders in penicillin-induced anaphylaxis: association with intravenous epinephrine therapy. JAMA 248:2161, 1982 32. Austin SM, Barooah B, Kim CS: Reversible acute cardiac injury during cefoxitin-induced anaphylaxis in a patient with normal coronary arteries. Am J Med 77:729, 1984 33. Forman MB, Oates JA, Robertson D, et al: Increased adventitial mast cells in a patient with coronary spasm. N Engl J Med 313:1138, 1985
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Bound volumes of THEJOURNALOFALLERGYANDCLINICALIMMUNOLOGY are available to subscribers (only) for the 1986 issues from the Publisher, at a cost of $39.00 ($50.00 international) for Vol. 77 (January-June) and Vol. 78 (July-December). Shipping charges are included. Each bound volume contains a subject and author index, and all advertising is removed. Copies are shipped within 30 days after publication of the last issue in the volume. The binding is durable buckram with the journal name, volume number, and year stamped in gold on the spine. Payment must accompany all orders. Contact The C. V. Mosby Co., Circulation Department, 11830 Westline Industrial Dr., St. Louis, MO 63146; phone (800) 325-4177, ext. 351. Subscriptions must be in force to qualify. Bound volumes are not available in place of a regular journal subscription.
Several lines of reasoning have led to the concept that there is a direct participation of the heart in anaphylactic reactions. These include clinical experience, as well as in vivo and in vitro models of anaphylaxis, and the analysis of the effects of anaphylactic mediators and inhibitory drugs on cardiac function. It is the purpose of this editorial to attempt to put into perspective the current evidence regarding the relationship of mast cells and mast cell mediators not only to cardiac function but also to examine the relevance of these findings to the clinical evaluation and therapy of anaphylaxis. As long ago as 1910 it was known that anaphylaxis is associated with disturbances in cardiac rate and rhythm.’ A number of studies in guinea pigs, rabbits, and monkeys both in vivo and in vitro have since attempted to define the association between cardiac responses and anaphylaxis. In the guinea pig, in vivo, anaphylaxis is associated with sinus tachycardia, increased ventricular automaticity, atrioventricular conduction delays, and ventricular tachycardia.’ In the rabbit, anaphylaxis is often accompanied by rightward QRS shifts, ST segment depression, and a variety of dysrhythmias,’ whereas in the monkey ST and T wave changes and intraventricular as well as atrioventricular conduction delays occur.4 It is difficult in these in vivo studies to ascertain whether the changes noted are due to a primary effect of anaphylaxis on the heart or are due to concomitant pulmonary vasoconstriction and hypoxia and/or to hypotension secondary to volume loss and decreased peripheral resistance. In this regard, as cazrdiac changes (increased heart rate and decreased left ventricular pressure) can precede pulmonary responses when antigen is injected into the guinea pig l.eft ventricle as opposed to a peripheral vein, it has been suggested that anaphylaxis can indeed affect the heart directly.’ These analyses have been further pursued in vitro with the use of intact perfused hearts as well as cardiac muscle preparations. In such systems the effect of anaphylactic challenge and of isolated mediators on cardiac function can be directly addressed. In addition, the eft;ect of drugs on the expression of anaphylaxis and the action of defined mediators can be determined. The success of these model systems rests
on the fact that mast cells are prominent in the heart. In the human heart as much as 3 p,g of histamine is present per gram of atrium,6 suggesting a concentration of nearly a million mast cells per gram of cardiac tissue.7 Moreover, mast cells are known to be enriched in areas of atheromatous plaque and to be especially prominent in the adventitia of the coronary arteries.’ Human and guinea pig cardiac mast cells are functionally intact and can release histamine on immunologic or pharmacologic challenge as Levi et a1.9and Graver et al.‘” describe in this issue and elsewhere. In addition, sulfidopeptide leukotrienes” and plateletactivating factor” have been demonstrated to be generated on anaphylactic challenge of guinea pig heart tissue. The consequences of anaphylactic mast cell activation on cardiac function have been attributed to these released mediators. In isolated perfused hearts in vitro, antigen challenge causes initial tachycardia and augmentation of ventricular contraction followed rapidly by contractile failure and diminished coronary blood flo~.~ The duration and degree of cardiac dysfunction observed in guinea pig hearts can be directly correlated to the amount of histamine released by challenge.‘j Additionally, many of the effects noted in anaphylaxis can be induced by the direct intracardiac administration of histamine or be prevented by combined use of H, and H, antihistaminic drugs. Specifically, H, antagonists prevent slowing of atriovenricular conduction’4 as well as inhibit ventricular fibrillation,15 whereas H, antagonism affects sinus and other tachyarrhythmias, ectopic beats, reentrant rhythms, and some instances of atrioventricular conduction delay.6-‘9 In addition, histamine is a potent coronary vasoconstrictor in this species and in humans with coronary disease*’ and a direct positive inotropic agent in humans as well as guinea pigs.“. ‘I The sulfidopeptide leukotrienes are also coronary vasoconstrictors and negative inotropic agents in both human and animal cardiac tissue.“. 23Recent studies also indicate that platelet-activating factor is a potent negative inotropic agent, depresses coronary flow, and induces atrioventricular conduction delays.” Platelet-activating factor and sulfidopeptide leukotrienes exert their cardiac effects at nanomolar concentrations. whereas histamine is active at submillimolar 663
664
Wasserman
levels, and it is these concentrations of these key mediators that are generated during in vitro cardiac anaphylaxis. Just how is the clinician to use this information in the evaluation and treatment of anaphylaxis in humans? Are the cardiac findings in human anaphylaxis (arrhythmia, angina, and myocardial infarction) primary or are they secondary to hypoxia, hypotension, or medication? How can transient left bundle branch block, ST segment, and T wave changes of ischemia, QRS and ST changes of infarction, prolonged PR intervals, wandering atria1 pacemaker, atria1 fibrillation, sinus tachycardia, and atrioventricular and intraventricular conduction defects be explained? Although the clinical literature of anaphylaxis is replete with references to such cardiac effects, it is perhaps appropriate to review some of these articles presented during the last two decades to illustrate the difficulties in assigning a role to primary cardiac effects of anaphylaxis. Stein and Wechsell” reported three instances of cardiac disease accompanying allergic drug reactions. The first patient developed a myocardial infarction 2 hours after epinephrine therapy for cutaneous and respiratory manifestations of anaphylaxis. The second patient suffered a posterior myocardial infarction as a consequence of serum sickness, whereas the third patient had a drug rash and suffered a myocardial infarction while the patient was receiving a sitz bath.24 In none of these cases can a convincing primary relationship between mast cell activation and cardiac effects be made. Booth and Patterson” reported EKG findings in 14 of 23 patients experiencing anaphylaxis and noted abnormalities in six patients. In only three of the patients did electrocardiographic abnormalities precede medical therapy, and they consisted of premature ventricular beats in one instance, sinus tachycardia with ST segment depression in another instance, and nonspecific ST-T segment changes in the third instance. All patients were hypotensive, a finding that may be assumed to have some effect on the cardiac responses noted. Criep and Woehlerz6 reported three cases of anaphylaxis with cardiac findings. In the first patient, a myocardial infarction occurred after emergency treatment of severe anaphylaxis (manifested by wheezing, dyspnea, and eventuating in hypotension and cardiac arrest). A second patient developed EKG findings of transient ischemia after therapy for cutaneous and respiratory changes of anaphylaxis associated with severe hypotension and loss of consciousness. A third patient demonstrated evidence of anterolateral ischemia after treatment of severe anaphylactic shock. Petsas and Kotler2’ reported
J. ALLERGY CLIN. IMMUNOL. MAY 1986
two instances of anaphylaxis to penicillin. In the first patient, left bundle branch block and sinus tachycardia were noted 90 minutes after treatment of shock, whereas in the second patient there were peaked P waves and right axis deviation during a hypotensive episode treated with epinephrine. These reported findings are quite consistent with the effects of respiratory obstruction and epinephrine therapy. Brasher and Sanchez28reported a case of a 62-year-old patient who collapsed 20 minutes after a wasp sting with cyanosis, rales, and inaudible heart sounds in the absence of hypotension. After therapy with glucocorticoids, diuretics, and aminophylline for presumptive infarction, the EKG revealed atria1 fibrillation and anterior ST segment depression that could well have been a consequence of respiratory obstruction and hypoxia in a person of this age. Levine29 also reported EKG findings in two cases of wasp sting anaphylaxis. In the first instance severe hypotension and respiratory obstruction occurred, and the EKG, which was initially normal, became abnormal with ST segment elevation and ventricular ectopy after administration of epinephrine. The second patient who developed urticaria, hypotension, and lost consciousness had tachycardia, irregular heart beat, and, after two injections of epinephrine, revived and then complained of chest pain. EKG at that point revealed atria1 fibrillation and diaphragmatic infarction. The role of hypotension, epinephrine, and possible preexisting coronary disease again make direct cardiac anaphylaxis difficult to ascertain. Druck et a1.3oreported a patient who developed wheezing, dyspnea, rhinorrhea, and epigastric pain 10 minutes after completion of coronary angiography. The patient was hypotensive and hypoxic, and EKG revealed ST segment elevations in inferior leads. Oxygen and hydrocortisone were administered without initial benefit, whereas intravenous nitroglycerine administration led to tachycardia and a transient return of ST segments to normal before inferior infarction became fixed. The angiogram completed just before the reaction revealed occluded first diagonal branch of the left anterior descending and 95% occlusion of the distal circumflex coronary arteries, and the right coronary artery had an aneurysm at its origin. The deleterious effects of hypotension and hypoxia in such a setting are obvious, and the transient effect of nitroglycerine can hardly be used to support a diagnosis of coronary spasm. Sullivan3’ reported two instances of anaphylaxis to penicillin in which an initially normal EKG became abnormal (ventricular tachyarrhythmias) only after administration of intravenous epinephrine. Finally, Austin et a1.32reported a 64-year-old man who developed urticaria, wheezing,
VOLUME77 NUMBER5
and profound hypotension after intravenous administration of a cephalosporin antibiotic. This reaction was treated with epinephrine, diphenhydramine, dexamethasone, and dopamine. Preanaphylaxis EKG was normal, whereas one EKG performed during the anaphylactic response (but whose timing vis-a-vis drug therapy is not clear) demonstrated atria1 fibrillation and ST segment elevations in inferior leads. These changes completely reversed in the course of several hours. Coronary angiography performed subsequently was normal except for anomalous origin of the right cor’onary artery from the sinus of Valsalva. The authors interpret these findings to suggest coronary artery spasm occurred as a part of anaphylaxis, although they also allow that hypotension and subsequent decreased aortic-distending pressure could have led to compression of the ostium of the anomalous coronary artery. The concept of mast cell-dependent coronary artery spasm has recently gained some support from the finding of increased mast cells in the adventitia of coronary arteries of patients with Prinzmetal’s angina.“3 How can one reconcile the clear in vitro and in vivo model data of the effect of experimental anaphylaxis and mediators on the heart with the very confusing clinical literature in which cardiac responses can be attributed to so many possible mechanisms (none of which need imply direct cardiac anaphylaxis)? At present one can only conclude that cardiac anaphylaxis may occur and that its contribution must be eventually separated from the effects of hypoxia, hypotension, and medications by careful observation and judicious human experimentation. It is, however, relevant to consider that cardiac anaphylaxis may explain some of the findiqgs in anaphylaxis and may point the way to the need to use specific therapies and take particular precautions directed to this possibility. For example, the early and aggressive use of antihistaminics (both H, and H,) would be logical on this basis. The fact that mast cells are increased in the coronary arteries of patients with coronary disease suggests that anaphylaxis in the older patient or the patient with known coronary disease may be especially unfortunate both from the view of tolerance of hypotension and hypoxia but also because of the potential for severe cardiac anaphylaxis. Although it is possible that local mast cell activation may lead to coronary vasospasm, it is not yet possible to recommend the use of coronary vasodilators (calcium channel-blocking drugs or nitroglycerin) in therapy of anaphylaxis. Thus, at the present time, cardiac anaphylaxis must be viewed as a very real and potentially critical clinical consideration in anaphylaxis but also as a consideration about
Heart
in anaphylaxis
665
which we cannot yet make particular diagnostic and therapeutic recommendations. Stephen I. Wasserman, M.D. Professor of Medicine Chief, Division of Allergy University of California-San Diego Medical Center 225 W. Dickinson St. San Diego, CA 92103 REFERENCES 1. Aver J, Lewis PA: Physiology of immediate reaction of anaphylaxis in guinea pig. J Exp Med 12:151,1910 2. Feigen GA, Prager DJ: Experimental cardiac anaphylaxis: physiologic, pharmacologic, and biochemical aspects of immune reactions in the isolated heart. Am J Cardiol 24:474, 1969 3. Halonen M, Palmer JD, Lehman IC, et al: Respiratory and circulatory alterations induced by acetylglyceryl ether phosphorylcholine (AGEPC): a mediator of IgE anaphylaxis in the rabbit. Am Rev Respir Dis 122:915, 1980 4. Patterson R, Fink JN, Wennemark J, et al: The biologic consequences of the immediate-type hypersensitivity transferred from man to monkey. J ALLERY 37:295, 1966 5. Zavecz JM, Levi R: Separation of primary and secondary cardiovascular events in systemic anaphylaxis. Circ Res 40:15, 1977 6. Levi R, Guo Z-G: Roles of histamine in cardiac dysfunction. In Tanaka K, editor: Advances in histamine research. New York, 1982, Pergamon Press Inc. p 213 7. Paterson NAM, Wasserman SI, Said JW, et al: Release of chemical mediators from partially purified human lung mast cells. J Immunol 117:1356, 1976 8. Pomerance A: Periarterial mast cells in coronary atheroma and thrombosis. J Path Bacterial 76:55, 1958 9. Levi R, Chenonda AA, Trzeciakowski JP, et al: Effects of histamine on the cardiovascular and respiratory system: dysrrhythmias caused by histamine release in guinea pig and human hearts. Klin Wochenschr 60:965, 1982 10. Graver LM, Robertson DA, Levi R, et al: IgE-mediated hypersensitivity in human heart tissue: histamine release and functionalchanges. J ALLERGY CLIN IMMUNOL 77:709, 1986 II. Levi R, Hattori Y, Burke JA, et al: Leukotriene C, is released from the anaphylactic heart: a case for its direct negative inotropic effect. In Bailey JM, editor: Prostaglandins. leukotrienes, and lipoxins. New York, 1985, Plenum Publishing Carp, p 275 12. Levi R, Burke JA, Guo Z-G, et al: Acetylglyceryl ether phosphorylcholine (AGEPC): a putative mediator of cardiac anaphylaxis in the guinea pig. Circ Res 54:117, 1984 13. Capurro N, Levi R: The heart as a target organ in systemic allergic reactions: comparison of cardiac anaphylaxis in vivo and in vitro. Circ Res 36:520, 1975 14. Capurro N, Levi R: Anaphylaxis in the isolated guinea pig heart: selective inhibition by burimamide of the positive inotropic and chronotropic effects of released histamines. Br J Pharmacol 48:620, 1973 15. Trzeciakowski JP, Levi R: Analysis of receptors mediating histamine-induced decrease in ventricular fibrillation threshold in the guinea pig heart. Fed Proc 40:692, 1981 16. Levi R, Allan G: Histamine-mediated cardiac effects. In Bris-
J. ALLERGY CLIN. IMMUNOL. MAY 1986
666 Wasserman
17. 18. 19. 20. 21.
22.
23.
tow M, editor: Drug-induced heart disease. Amsterdam, 1980, Elsevier-North Holland Biomedical Press, p 377 Houki S: Restoration effects of histamine on action potential in potassium-depolarized guinea pig papillary muscle. Arch Int Pharmacodyn Ther 206:113, 1973 Ledda F, Mantelli L, Mugelli A: Blockade by burimamide of the restorative effect of histamine in tetrodoxotoxin-treated heart preparations. Br J Pharmacol 57:247, 1976 Zavecz JM, Levi R: Histamine-digitalis interaction: modification by histamine H,- and Hz-receptor antagonists. Pharmacologist 18:168, 1976 Kalsner S, Richards R: Coronary arteries of cardiac patients are hyperreactive and contain stores of amines: a mechanism for coronary spasm. Science 223:1435, 1984 Guo Z-G, Levi R, Graver LM, et al: Inotropic effects of histamine in human myocardium: differentiation between positive and negative components. J Cardiovasc Pharmacol 6: 1210, 1984 Mullane K, Barst S, M&tiff JC: Leukotrienes in myocardial ischemia. In Lefer AM, Gee MH, editors: Leukotrienes in cardiovascular and pulmonary function. New York, 1985, Arliss Inc, p 127 Burke JA, Levi R, Guo Z-G, et al: Leukotrienes C,, D,, and E4: effects on human and guinea pig cardiac preparations in vitro. J Pharmacol Exp Ther 221:235, 1982
Bound volumes
available
24. Stein I, Wechsell I: Cardiac disease accompanying allergic drug reactions. J ALLERGY4548, 1970 25. Booth BH, Patterson R: Electrocardiographic changes during human anaphylaxis. JAMA 211:627, 1970 26. Criep LM, Woehler TR: The heart in human anaphylaxis. Ann Allergy 29:399, 1971 27. Petsas AA, Kotler MN: Electrocardiographic changes associated with penicillin anaphylaxis. Chest 64:66, 1973 28. Brasher GW, Sanchez SA: Reversible electrocardiographic changes associated with wasp sting anaphylaxis, JAMA 229:1210, 1974 29. Levine MD: Acute myocardial infarction following wasp sting. Am Heart J 91:365, 1976 30. Druck MN, Johnstone DE, Staniloff H, et al: Coronary artery spasm asa manifestation of anaphylactoid reaction to iodinated contrast material. Can Med Assoc J 125:1131, 1981 31. Sullivan TJ: Cardiac disorders in penicillin-induced anaphylaxis: association with intravenous epinephrine therapy. JAMA 248:2161, 1982 32. Austin SM, Barooah B, Kim CS: Reversible acute cardiac injury during cefoxitin-induced anaphylaxis in a patient with normal coronary arteries. Am J Med 77:729, 1984 33. Forman MB, Oates JA, Robertson D, et al: Increased adventitial mast cells in a patient with coronary spasm. N Engl J Med 313:1138, 1985
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Bound volumes of THEJOURNALOFALLERGYANDCLINICALIMMUNOLOGY are available to subscribers (only) for the 1986 issues from the Publisher, at a cost of $39.00 ($50.00 international) for Vol. 77 (January-June) and Vol. 78 (July-December). Shipping charges are included. Each bound volume contains a subject and author index, and all advertising is removed. Copies are shipped within 30 days after publication of the last issue in the volume. The binding is durable buckram with the journal name, volume number, and year stamped in gold on the spine. Payment must accompany all orders. Contact The C. V. Mosby Co., Circulation Department, 11830 Westline Industrial Dr., St. Louis, MO 63146; phone (800) 325-4177, ext. 351. Subscriptions must be in force to qualify. Bound volumes are not available in place of a regular journal subscription.