- Email: [email protected]
Cardiac pathology in asthma
VOLUME NUMBER
80 3. PART 2
Airway
increase in resistance produced by normal smooth muscle contraction by an order of magnitude. Thus the problem in most cases of severe and fatal asthma may be the excessive inflammatory process in the submucosa and lumen of the airways that results in severe airways narrowing when coupled with either normal or excessive smooth muscle contraction. REFERENCES
12.
13.
I. Moreno RH, Hogg JC, Pare PD. Mechanisms of airway narrowing. Am Rev Respir Dis 1986;133:1171-80. 2. Barnes PJ. Neurocontrol of human airways in health and disease. Am Rev Respir Dis 1986;134:1289-1314. 3. Dunnill MS, Massarella GR. Anderson IA. A comparison of the quantitative anatomy of the bronchi in normal subjects. in status asthmaticus, in chronic bronchitis and in emphysema. Thorax 1969;24: 176-9. 4. Huber HL, Koessler KK. The pathology of bronchial asthma. Arch Intern Med 1922;30:689. 5. Sobonya RE. Concise clinical study. Quantitative structural alterations in .Inng-standing allergic asthma. Am Rev Respir Dis 1984;130:289. 6. Heard BE, Hossdin S. Hyperplasia of bronchial muscle in asthma. J Path01 1973;110:319. 7. Armour CL, Lazar NM, Schellenberg RR, et al. A comparison of in vivo and in vitro human airway reactivity to histamine. Am Rev Respir Dis 1984;129:907-10. 8. Vincent JS, Black JL, Yan K, Armour CL, Donnelly PD, Woolcock AJ. A comparison of in vivo and in vitro responses to histamine in human airways. Am Rev Respir Dis 1983; 12X:X75-9. 9. Taylor SM. Pare PD. Armour CL, Hogg JC, Schellenberg RR. Airway reactivity in chronic obstructive pulmonary disease. Am Rev Respir Dis 1985;132:32-5. 10. Adams OK, Lichtenstein LM. In vitro studies of antigen-
Cardiac pathology Frederick
11.
J. Schoen,
14.
15.
16. 17.
18.
19. 20. 21. 22. 23.
narrowing
in severe
and fatal
asthma
induced bronchospasm: effect of antihistamine and SRS-A antagonist on response of sensitized guinea pig and human airways to antigen. J Immunol 1979;122:555-62. Patterson JW, Lulich KL, Goldie RG. The role of beta adrenergic receptors in bronchial hyperreactivity. In: Morley I, ed. Bronchial hyperreactivity. London: Academic Press. 1982: 19-39. Schellenberg RR. Foster A. In vitro response of human asthmatic airway and pulmonary vascular smooth muscle. Int Arch Allergy Appl lmmunol 1984:75:237-41. James AL. Pare PD. Moreno R, Hogg JC. Smooth muscle shortening and airway narrowing in porcine tracheal ring. Am Rev Respir Dis 1986; 133: I I3A. Moreno RH, Dahlby R, Hogg JC, Pare PD. Increased airway responsiveness caused by airway cartilage softening in rabbits. Am Rev Respir Dis 1985;13lA:288. Martin JG, Dong-Jie D, Macklem PT. Effective lung volume on methacholine-induced bronchoconstriction in normal subjects. Am Rev Respir Dis 1986;133:15A. Macklem PT. Proctor DF, Hogg JC. The stability of peripheral airways. Respir Physiol 1970;8:191-203. Dunnill MS. The pathology of asthma, with special reference to the changes in the bronchial mucosa. J Clin Path01 1960;13:27-33. Dunnill MS. The pathology of asthma. In: Porter R, Birch J, eds. Identification of asthma. Ciba Foundation Symposium Study Group No. 38. Edinburgh, London: Churchill Livingstone Inc. 1971:35-46. Riglcr L. Bronchial asthma. Am J Roentgen01 1938;39:353. Sanerkin NG, Evans DMD. The sputum in bronchial asthma: pathopneumonic patterns. J Pathol Bacterial 1965;89:535-41. Naylor B. The shedding of the mucosa of rhe bronchial tree in man. Thorax 1962:17:69. McCarter JH: Vazquez JJ. The bronchial basement membrane in asthma. Arch Path01 1966;82:328. Freedman BJ. Functional geometry of the bronchi. Bull Physiol Pathol Respir 1972;85:45-5 I.
in asthma
M.D., Ph.D. Boston, Mass.
Asthma-related death is relatively uncommon, but cardiac changes could be contributory in some cases. Severe alterations of cardiopulmonary physiology occur during acute asthmatic attacks.’ However, unexpected death is not always related to an acute prolonged episode’ and may occur despite and during From the Department of Pathology, Harvard Medical School and Brigham and Women’s Hospital, Boston, Mass. Reprint requests: Frederick J. Schoen, M.D., Ph.D., Department of Pathology, Brigham and Women’s Hospital, 75 Francis St., Boston, MA 02115.
apparent recovery from an acute attack.3,4 Unexpected death is often sudden, suggesting arrhythmia as a mechanism. However, whether and to what degree cardiac morphologic changes are associated (and potentially contributory) have not been adequately studied. Injury could be either acute or the cumulative effect of multiple recent or old episodes. Furthermore, the bronchodilators used in asthma treatment may cause adverse reactions. P-Adrenergic agonists both alone’ and in concert with methylxanthines6 have been implicated. Nevertheless, despite tie potential importance of cardiac effects of asthma and its treatment, 419
J. ALLERGY
FIG. 1. Myocardial contraction band necrosis (MCBN) a 13-year-old boy dying of asthma. Contraction bands necrotic myocytes are indicated by arrows. (Hematoxylin and eosin stain; magnification x 350.)
in in
neither the importance nor the potential mechanisms involved are known. During severe attacks of asthma, there is marked impairment of cardiopulmonary function, manifested by reduced airhow rates, air trapping, a ventilationperfusion imbalance that leads to hypoxemia and hypercapnia, large changes in intrathoracic pressure, increased pulmonary vascular resistance, right ventricular systolic overload, and increased effort in breathing. ‘. * However, although development of right ventricular failure due to pulmonary hypertension is a common complication of severe chronic bronchitis and emphysema,’ car pulmonale is rare in bronchial asthma.* A 20-year-old patient with extrinsic asthma, persistent hypoxemia, carbon dioxide retention, secondary polycythemia, and car puhnonale was recently described.” The recognition of acute cardiac morphologic abnormalities with increasing frequency in the past several years in patients dying with asthma suggests that such deaths could be related to cardiac damilge. Most
CLIN. IMMUNOL. SEPTEMBER 1987
cardiac lesions encountered have been labeled only as focal necrosis” or subendocardial myolysis and necrosis , ’’ and are usually explained as the result of catecholamines and other bronchodilators used in the treatment of the disease. For example, multiple areas of myocardial necrosis were found at postmortem examination of an l&year-old woman with asthma who had a sudden cardiorespiratory arrest during treatment of status asthmaticus with intravenous isoproterenol and aminophylline. lo A recent study” demonstrated myocardial contraction band necrosis (MCBN) in four of 13 (3 1%) children who died with acute asthmatic attacks, suggesting that this cardiac lesion may play a role in the deaths of some patients with asthma. The myocardial lesion from one patient is illustrated in Fig. 1. Because this study identified MCBN in two patients who died with asthma who had not received exogenous sympathomimetics, mechanisms other than exogenous catecholamines (such as emotional stress) are probably involved in the production of cardiac lesions in individuals with asthma. Characteristic MCBN occurs in a variety of situations, including catecholamine infusion, central nervous system stimulation, emotional stress, and transient myocardial ischemia with reperfusion.‘3-‘b Epinephrine or isoproterenol infusions produce ECG changes similar to those observed in widespread ischemia, but the morphology noted after catecholamine administration (largely MCBN) is distinct from the coagulation necrosis of typical myocardial infarction without reperfusion. ‘I. Is. ” Whereas typical ischemic coagulation necrosis is characterized by cellular relaxation, in MCBN cells die in tetanic contraction with intracellular calcium overload. Gross myocardial hemorrhage may be conspicuous on the endocardial surfaces of the left ventricle. On microscopic examination there is loss of definition of the linear arrangement of myofibrils, with areas of dense eosinophilic transverse banding alternating with lighter-staining granular zones of cytoplasm (contraction bands). Polymorphonuclear leukocytes are sparse, and necrotic debris is removed by macrophages. Deposits of calcium phosphate in the mitochondria may generalize to widespread calcification of entire cells. Elucidation of the relationship of cardiac damage (especially MCBN) to fatal asthma requires further work. In this regard, continued efforts to obtain postmortem examination of patients with asthma who die are important. Autopsies should include careful study of the heart through transmural histologic sections of the right ventricle, ventricular septum, and the left ventricular apex and anterior, lateral, and posterior free walls. Therapeutic agents commonly used in the treatment
VOLUME NUMBER
80 3, PART 2
of asthma may have undesirable effects on cardiac or pulmonary function. Adverse effects and complications of treatment with B-adrenergic agonist drugs have been reviewed.’ Epinephrine causes an increase in the rate and force of cardiac contraction with increases in cardiac output and oxygen consumption, a decrease in cardiac efficiency (work relative to oxygen consumption), and increases in both systolic and diastolic blood pressures. In humans, large doses of epinephrine can cause premature ventricular systoles, and inadvertent intravenous administration has elicited ventricular premature systoles followed by multifocal ventricular tachycardia. Treatment of asthma with intravenous infusions of isoproterenol can cause chest pain and ECG evidence of myocardial ischemia in both adults and children.“. ‘* The cardiac morphologic changes produced by high doses of catecholamines have been reviewed recently. ” Epinephrine and norepinephrine may produce myocardial hypertrophy and myocardial necrosis, including MCBN. The synthetic catecholamine isoproterenol is associated with a particular type of “infarctlike” necrosis related to MCBN. The mechanisms responsible for isoproterenol-induced myocardial necrosis include relative regional hypoxia, coronary microcirculatory effect, and cellular effects, including altered membrane permeability, myofilament overstimulation, high-energy phosphate deficiency, and calcium ion overload.” Catecholamine-induced myocardial alterations are morphologically similar to those that occur in association with pheochromocytoma, coronary vasospasm and subsequent myocardial ischemit damage, some sudden deaths related to stress (stress cardiomyopathy), as well as myocardial lesions in relationship to open-heart surgery.13, Is. I9 The recent evidence suggesting that calcium channel blocker drugs reduce myocardial necrosis in association with open heart surgery is consistent with a major contribution of calcium overload in the mediation of cell death.‘” Elevation of the cardiac-specific serum creatine phosphokinase MB (CPK-MB) isoenzyme was noted in 15 of 19 admissions of children with asthma treated with intravenous isoproterenol.2’ The demonstration that isoproterenol can induce significant cardiotoxicity stimulated the development of less cardiotoxic B2 agents. Their long-term safety, however, when used singly or in combination with theophylline products has not been established; it has been suggested that their use in combination with theophylline contributes to an increase in the number of sudden deaths among individuals with asthma.** Although B-receptors in the heart are different from those in the respiratory tract, there are significant numbers of B,-receptors in the heart and P,-agonists are
Cardiac
pathology
in asthma
421
not free from cardiovascular effects.6 Cardiac arrhythmias may occur with B,-adrenergic agonists. It has been shown that 8 mg of slow-release albuterol can induce arrhythmias in patients with asthma who are clinically free of heart disease, and a single dose of oral terbutaline (5 mg) can cause premature ventricular contractions in susceptible adults with chronic obstructive pulmonary disease.‘3 However, in a study of 20 adults with asthma who were clinically free of heart disease, ventricular extrasystoles occurred equally frequently in groups that received albuterol and placebo, suggesting that therapeutic doses of albuterol aerosol (two puffs four times a day on 2 successive days) in individuals with asthma without heart disease or severe hypoxemia should not be considered a cause of cardiac arrhythmias.‘4 The added effectiveness of xanthine derivatives and P-adrenergic agonists is well established, and these drugs are commonly used together in the treatment of bronchial obstruction. However, their combined use may yield a variety of extrapulmonary effects, including the potential to cause arrhythmias and myocardial necrosis.’ Indeed, combination bronchodilator therapy has been suggested as a possible cause of unexpected death in asthma by induction of arrhythmias.2’ Although theophylline is ionotropic and chronotropic and at toxic levels can produce arrhythmias, methylxanthines probably produce little direct cardiotoxicity.6 Methylxanthines likely augment the effects of P-agonists.6 Recent studies have suggested that, although combined oral bronchodilator treatment in patients with mild to moderate obstructive lung disease in a stable phase but without ischemic or other heart disease has an arrhythmogenic potential, it is in general of minor clinical importance.” One study of untreated severe acute asthma in children demonstrated that, although cardiac output was slightly increased above resting levels, aminophylline and albuterol were safe and effective treatments.26 Inhalation of albuterol via a nebulizer was recommended in preference to intravenous injection, because similar improvement in airway function was achieved with little or no cardiovascular disturbance. A recent study of 14 adults with asthma who were taking continuous sustained-release theophylline and. B,-adrenergic agents showed no increase in ventricular ectopic activity with combination therapy. 27 Hypokalemia resulting in part from BZ stimulant drugs has been proposed as a cause of potentially fatal arrhythmia in patients with asthma.2” Theophylline toxicity, noted on occasion to precede death, also induces hypokalemia. 29 The possibility that hypokalemia caused by BZ stimulant drugs or theophylline
422
Schoen
could give rise to potentially fatal arrhythmias requires further evaluation.’ Fluorocarbons used in aerosol inhalers for treating asthma are capable, at least theoretically, of inducing cardiac arrhythmias. It has been suggested that fluorocarbons (fluoalkane gases present as propellants) might be directly cardiotoxic3” or sensitize the heart to the action of catecholamines during hypoxemia.“’ However. this view has recently been challenged? The potentiation of cardiotoxicity of sympathomimetic agents by steroids has also been proposed.3’ The well-recognized increased frequency of death from asthma at night or in the early morning has been linked to a pronounced diurnal variation in airflow limitation.“, M A similar variation has been noted in the temporal onset of acute transmural myocardial infarction.35 It has been suggested that this is related to a diurnal variation in endogenous circulating sympathetic amines and the secondary effects on sympathetic vascular tone and platelet reactivity. Their possible role in asthma deaths with similar mechanisms of increased vascular tone and platelet reactivity remains obscure. COruCl.UslONS The role of cardiac pathology in death from asthma remains uncertain. Although some patients who die suddenly of asthma have focal myocardial necrosis, the mechanisms and significance of such damage are unknown. The clinical importance of the arrhythmogenic potential of bronchodilator drugs (and combinations thereof) used in the acute and chronic treatment of asthma remains unresolved. REFERENCES I. Scharf SM. Mechanical cardiopulmonary interactions with asthma. Clin Rev Allergy 1985;3:487-500. 2. Benatar SR. Fatal asthma. N Engl J Med 1986;314:423-9. 3. Hetzel MR. Clark TJH, Branthwaite MA. Asthma: analysis of sudden deaths and ventilatory arrests in hospital. Br Med J 1977;1:808-Il. 4. MacDonald JB, Seaton A, Williams LX Asthma deaths in Cardiff, 1963-74. 53 deaths in hospital. Br Med J 1976;l: 1493-s. 5. American Academy of Allergy and Inununology-Committee on Drugs: Position statement: adverse effects and complications of treatment with beta-adrenergic agonist drugs. J ALLERGY CLIN hMUNOL 1985;75:443-9. 6. Nicklas RA. Balazs T. Adverse effects of theophylline-beta agonist interactions. J ALLERGY Ct.t~ IMMUNOL 1986;78: 806-11. 7. Renzetti AD, McClement JH, Litt BD. Moxtality in relation to respiratory function in chronic obstructive pulmonary disease. Am J Med 1966,41:115-29. 8. Clark TJH. Adult asthma. In: Clark TJH, Godfrey S, eds. Asthma. London: Chapman and Hall, 1977.
J. ALLERGV
CLIN. IMMUNOL. SEPTEMBER 1987
9. Calverley PMA. Catterall JR, Shapiro t ‘. Douglas Yl. Cor pulmonale in asthma. Br J Dis Chest 19X3:77:303-?. IO. Kurland G, Williams 1, Lewiston NJ. latal nl~c~r-:irdritl tknrui! during continuous infusion intravenous isoprotct-cnol rhcrap~ of asthma. J ALLERGY CLIN l~hlt;Not. 1979:h.:..J(J7-! I. II. Luchtrath H. Zur Pathologie des akutcn Herrtodcs bcim asthma bronchialc. Virchow Arch A Path Anat IHi%!c~l 1079:?FI. 343-52. H. Schocn Il. Strunk 12. Drislane FW, Samuels MA. Kozakewich RC. Myocardial contraction band Icsions in patients with fatal asthma: possible neurocardiologic mechanisms. Am RLY Kcspir Dis 1987;135:498-501. 13. Reichenbach DD, Benditt EP. Catecholamincs and cardiomyopathy. The pathogenesis and potential importance of myofibrillar degeneration. Hum Pathol 1970; I : I ?.S-SO. manifestations of' ncuro14. Samuels MA. Electrocardiographic logic disease. Sem Neural 1984;4:453-61. ME. Myocardial contraction bands rc15. Karch SB. Billingham visited. Hum Pathol 1986:17:9-13. ischemid 16. Jennings RB, Reimer KA, Steenberger C. Myocardial revisited. The osmolar load. membrane damage. and repcrfusion. J Mol Cell Cardiol 1986:18:769-80. 17. Winsor T, Mills B, Winbury MM, Howe BB. Berger HJ. lntramyocardial diversion of coronary blood flow: effects of isoproterenol-induced subendocardial ischemia. Microvasc Res 1975;9:261-78. ischcmia 18. Matson JR, Loughlin GM, Strunk RC. Myocardial complicating the use of isoproterenol in asthmatic children. J Pediatr 1978;92:776-8. cardiotoxicity. J Mol Cell Cardiol 19. Rona G. Catecholamine 1985:17:291-306. and calcium antagonists: a review. 20. de Jong JW. Cardioplegia .4nn Thorac Surg 1986;42:593-8. specific crea21. Maguire JF, Geha RS. Umetsu DT. Myocardial tine phosphokinase isoenzyme elevation in children with asthma treated with intravenous isoporterenol. J ALLERGY CLIN IMMUNOL 1987:78:631-6. 22. Wilson ID, Sutherland DC, Thomas AC. Has the change to beta-agonist combined with oral theophylline increased cases of fatal asthma? Lancet 1981;1:1235-7. 23. Al-Hillawi AH, Hayward R, Johnson NM. Incidence of cardiac arrhythmias in patients taking slow release salbutamol and slow release terhutaline for asthma. Br Med J 1984;288:367. 24. Martelli NA, Raimondi AC, Lazzari JO. Asthma, cardiac arrhythmias, and albuterol aerosol. Chest 1986;89:192-4. 25. Conrddson TB , Ekhmdh G, Olofsson B. Pahlm 0, Persron G Cardiac arrhythmias in patients with mild-to-moderate obstructive lung disease. Comparison to beta-agonist therapy alone and in combination with a xanthine derivative, enpmfylline or theophylline. Chest 1985;88:537-42. 26. Edmunds AAT, Godfrey S. Cardiovascular response during severe acute asthma and its treatment in chiidren. Thorax 1981;36:534-40. 27. Kelly HW, Menendez R, Voyles W. Lack of significant arrythmogenicity from chronic theophylline and beta-2 adrenergic combination therapy in asthmatic subjects. Ann Allergy 1985;54:405-IO. 28. Haalboom JRE, Deenstra M, Struyvenberg A. Hypokalemia induced by inhalation of fenoteml. Lancet 1985;1:1125-7. 29. Hall KW, Dobson KE, Dalton JG, Ghignone MC, Penner SB. Metabolic abnormalities associated with intentional theophylline overdose. Ann Intern Med 1984;101:457-62. 30. Taylor GJ. Cardiac toxicity of aemsol propehants. JAMA 1970;214:81-5.
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80 3, PART 2
Cardiac pathology
31. Jack D. Sniffing syndrome. Br Med J 1971;2:708-9. 32. Newhouse MT, Dolovich MB. Control of asthma by aerosols. N Engl J Med 1986;315:870-4. 33. Lehr D. Isoproterenol and sudden death of asthmatic patients in ventricular fibrillation. N Engl J Med 1972;287:987-8. 34. Cochrane GM, Clark TJH. A survey of asthma mortality in
Fatal asthma-Is Desmond Poynter,
in asthma
patients between ages 35 and 64 in the Greater London hospitals in 1971. Thorax 1975;30:300-5. 35. Muller JE, Stone PH, Turi Z, et al. Circadian variation in the frequency of onset of acute myocardial infarction. N Engl J Med 1985;313:1315-22.
treatment
incriminated?
Ph.D. Ware, Hertfordshire, United Kingdom
In fatal asthma the exacerbation of the disease will doubtless have demanded treatment, which in some cases may well have been repeated with more than one drug. This inevitably leads to the suggestion that such treatment or its excess may play a part in any ensuing tragedy. The purpose of this article is to discuss those drugs used in asthma treatment and to refer to some of the studies, experimental and otherwise, performed with them to see if there are any facets of their toxicologic profiles that might indicate a potential hazard. It is relevant to inquire at the outset whether any specific pulmonary diseases are associated with those substances used for the therapy of asthma. In his review of iatrogenic lung disease Cuthbert’ mentions the paradoxic effect that sympathomimetic amines may have in also relaxing smooth muscle in the pulmonary vasculature, thus producing pulmonary vasodilation with resultant hypoxia. However, in their review of drug-induced lung disease Whimster and de Poitiers’ refer to only one compound that is used to treat asthma. They note that steroids may induce thoracic changes by way of mediastinal fat deposition, which may be recognizable radiologically. Fifteen caseswere summarized as part of the generalized known effects of high-level steroid therapy, with the changes taking 5 years to become noticed when a dose of 7.5 mg/day was used and only 7 months when a dose of 30 mglday was used. The current therapeutic agents used in asthma are generally not incriminated in producing pulmonary
From the Pathology Division, Glaxo Group Research, Ware, Hertfordshim, United Kingdom. Reprint requests: Desmond Poynter, Ph.D., Glaxo Group Research Limited, Ware, Hertfordshire, SGl2 ODJ, United Kingdom.
disease as such. However, they are potent compounds and if used inappropriately some of them may produce significant toxic effects that will not improve the course of the disease. SYMPATHOMlMETlC
AMIMES
Sympathomimetic amines may produce myofibrillar lesions in animal hearts, and the epidemiologic association between an increased death rate in young people with asthma and the abuse of pressurized aerosols containing isoproterenol 3-5has provoked much interest. Much experimental work has been undertaken in animals but its extrapolation to humans is not easy. Thus, although it is well documented that isoproterenol can cause myocardial necrosis in rats,6 hamsters,’ and rabbits,* no such effect has been described in humans. However, isoproterenol has cardiotoxic effects in the dog9 that are exacerbated by hypoxia, and in the cat heart-lung preparation” there is evidence that a fatigued heart working at a high level is ten times as sensitive as a normal heart. The introduction of more selective P-agonists that are markedly more active on bronchial smooth muscle than on cardiac muscle provided safer medication. In a direct comparison of nonselective isoproterenol and selective albuterol, isoproterenol was lethal to the hypoxic dog but albuterol was not.’ Thus there is experimental evidence that nonselective P-agonists may under certain circumstances be lethal to animals. That the selective P-agonist albuterol has a very different effect upon the heart was well illustrated by the work of Nayler” who, using papillary muscle from dogs and from humans, concluded that the action of albuterol on P-adrenergic receptors in heart muscle was minimal compared with that of equipotent bronchodilator doses of isoproterenol . 423
80 3. PART 2
Airway
increase in resistance produced by normal smooth muscle contraction by an order of magnitude. Thus the problem in most cases of severe and fatal asthma may be the excessive inflammatory process in the submucosa and lumen of the airways that results in severe airways narrowing when coupled with either normal or excessive smooth muscle contraction. REFERENCES
12.
13.
I. Moreno RH, Hogg JC, Pare PD. Mechanisms of airway narrowing. Am Rev Respir Dis 1986;133:1171-80. 2. Barnes PJ. Neurocontrol of human airways in health and disease. Am Rev Respir Dis 1986;134:1289-1314. 3. Dunnill MS, Massarella GR. Anderson IA. A comparison of the quantitative anatomy of the bronchi in normal subjects. in status asthmaticus, in chronic bronchitis and in emphysema. Thorax 1969;24: 176-9. 4. Huber HL, Koessler KK. The pathology of bronchial asthma. Arch Intern Med 1922;30:689. 5. Sobonya RE. Concise clinical study. Quantitative structural alterations in .Inng-standing allergic asthma. Am Rev Respir Dis 1984;130:289. 6. Heard BE, Hossdin S. Hyperplasia of bronchial muscle in asthma. J Path01 1973;110:319. 7. Armour CL, Lazar NM, Schellenberg RR, et al. A comparison of in vivo and in vitro human airway reactivity to histamine. Am Rev Respir Dis 1984;129:907-10. 8. Vincent JS, Black JL, Yan K, Armour CL, Donnelly PD, Woolcock AJ. A comparison of in vivo and in vitro responses to histamine in human airways. Am Rev Respir Dis 1983; 12X:X75-9. 9. Taylor SM. Pare PD. Armour CL, Hogg JC, Schellenberg RR. Airway reactivity in chronic obstructive pulmonary disease. Am Rev Respir Dis 1985;132:32-5. 10. Adams OK, Lichtenstein LM. In vitro studies of antigen-
Cardiac pathology Frederick
11.
J. Schoen,
14.
15.
16. 17.
18.
19. 20. 21. 22. 23.
narrowing
in severe
and fatal
asthma
induced bronchospasm: effect of antihistamine and SRS-A antagonist on response of sensitized guinea pig and human airways to antigen. J Immunol 1979;122:555-62. Patterson JW, Lulich KL, Goldie RG. The role of beta adrenergic receptors in bronchial hyperreactivity. In: Morley I, ed. Bronchial hyperreactivity. London: Academic Press. 1982: 19-39. Schellenberg RR. Foster A. In vitro response of human asthmatic airway and pulmonary vascular smooth muscle. Int Arch Allergy Appl lmmunol 1984:75:237-41. James AL. Pare PD. Moreno R, Hogg JC. Smooth muscle shortening and airway narrowing in porcine tracheal ring. Am Rev Respir Dis 1986; 133: I I3A. Moreno RH, Dahlby R, Hogg JC, Pare PD. Increased airway responsiveness caused by airway cartilage softening in rabbits. Am Rev Respir Dis 1985;13lA:288. Martin JG, Dong-Jie D, Macklem PT. Effective lung volume on methacholine-induced bronchoconstriction in normal subjects. Am Rev Respir Dis 1986;133:15A. Macklem PT. Proctor DF, Hogg JC. The stability of peripheral airways. Respir Physiol 1970;8:191-203. Dunnill MS. The pathology of asthma, with special reference to the changes in the bronchial mucosa. J Clin Path01 1960;13:27-33. Dunnill MS. The pathology of asthma. In: Porter R, Birch J, eds. Identification of asthma. Ciba Foundation Symposium Study Group No. 38. Edinburgh, London: Churchill Livingstone Inc. 1971:35-46. Riglcr L. Bronchial asthma. Am J Roentgen01 1938;39:353. Sanerkin NG, Evans DMD. The sputum in bronchial asthma: pathopneumonic patterns. J Pathol Bacterial 1965;89:535-41. Naylor B. The shedding of the mucosa of rhe bronchial tree in man. Thorax 1962:17:69. McCarter JH: Vazquez JJ. The bronchial basement membrane in asthma. Arch Path01 1966;82:328. Freedman BJ. Functional geometry of the bronchi. Bull Physiol Pathol Respir 1972;85:45-5 I.
in asthma
M.D., Ph.D. Boston, Mass.
Asthma-related death is relatively uncommon, but cardiac changes could be contributory in some cases. Severe alterations of cardiopulmonary physiology occur during acute asthmatic attacks.’ However, unexpected death is not always related to an acute prolonged episode’ and may occur despite and during From the Department of Pathology, Harvard Medical School and Brigham and Women’s Hospital, Boston, Mass. Reprint requests: Frederick J. Schoen, M.D., Ph.D., Department of Pathology, Brigham and Women’s Hospital, 75 Francis St., Boston, MA 02115.
apparent recovery from an acute attack.3,4 Unexpected death is often sudden, suggesting arrhythmia as a mechanism. However, whether and to what degree cardiac morphologic changes are associated (and potentially contributory) have not been adequately studied. Injury could be either acute or the cumulative effect of multiple recent or old episodes. Furthermore, the bronchodilators used in asthma treatment may cause adverse reactions. P-Adrenergic agonists both alone’ and in concert with methylxanthines6 have been implicated. Nevertheless, despite tie potential importance of cardiac effects of asthma and its treatment, 419
J. ALLERGY
FIG. 1. Myocardial contraction band necrosis (MCBN) a 13-year-old boy dying of asthma. Contraction bands necrotic myocytes are indicated by arrows. (Hematoxylin and eosin stain; magnification x 350.)
in in
neither the importance nor the potential mechanisms involved are known. During severe attacks of asthma, there is marked impairment of cardiopulmonary function, manifested by reduced airhow rates, air trapping, a ventilationperfusion imbalance that leads to hypoxemia and hypercapnia, large changes in intrathoracic pressure, increased pulmonary vascular resistance, right ventricular systolic overload, and increased effort in breathing. ‘. * However, although development of right ventricular failure due to pulmonary hypertension is a common complication of severe chronic bronchitis and emphysema,’ car pulmonale is rare in bronchial asthma.* A 20-year-old patient with extrinsic asthma, persistent hypoxemia, carbon dioxide retention, secondary polycythemia, and car puhnonale was recently described.” The recognition of acute cardiac morphologic abnormalities with increasing frequency in the past several years in patients dying with asthma suggests that such deaths could be related to cardiac damilge. Most
CLIN. IMMUNOL. SEPTEMBER 1987
cardiac lesions encountered have been labeled only as focal necrosis” or subendocardial myolysis and necrosis , ’’ and are usually explained as the result of catecholamines and other bronchodilators used in the treatment of the disease. For example, multiple areas of myocardial necrosis were found at postmortem examination of an l&year-old woman with asthma who had a sudden cardiorespiratory arrest during treatment of status asthmaticus with intravenous isoproterenol and aminophylline. lo A recent study” demonstrated myocardial contraction band necrosis (MCBN) in four of 13 (3 1%) children who died with acute asthmatic attacks, suggesting that this cardiac lesion may play a role in the deaths of some patients with asthma. The myocardial lesion from one patient is illustrated in Fig. 1. Because this study identified MCBN in two patients who died with asthma who had not received exogenous sympathomimetics, mechanisms other than exogenous catecholamines (such as emotional stress) are probably involved in the production of cardiac lesions in individuals with asthma. Characteristic MCBN occurs in a variety of situations, including catecholamine infusion, central nervous system stimulation, emotional stress, and transient myocardial ischemia with reperfusion.‘3-‘b Epinephrine or isoproterenol infusions produce ECG changes similar to those observed in widespread ischemia, but the morphology noted after catecholamine administration (largely MCBN) is distinct from the coagulation necrosis of typical myocardial infarction without reperfusion. ‘I. Is. ” Whereas typical ischemic coagulation necrosis is characterized by cellular relaxation, in MCBN cells die in tetanic contraction with intracellular calcium overload. Gross myocardial hemorrhage may be conspicuous on the endocardial surfaces of the left ventricle. On microscopic examination there is loss of definition of the linear arrangement of myofibrils, with areas of dense eosinophilic transverse banding alternating with lighter-staining granular zones of cytoplasm (contraction bands). Polymorphonuclear leukocytes are sparse, and necrotic debris is removed by macrophages. Deposits of calcium phosphate in the mitochondria may generalize to widespread calcification of entire cells. Elucidation of the relationship of cardiac damage (especially MCBN) to fatal asthma requires further work. In this regard, continued efforts to obtain postmortem examination of patients with asthma who die are important. Autopsies should include careful study of the heart through transmural histologic sections of the right ventricle, ventricular septum, and the left ventricular apex and anterior, lateral, and posterior free walls. Therapeutic agents commonly used in the treatment
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of asthma may have undesirable effects on cardiac or pulmonary function. Adverse effects and complications of treatment with B-adrenergic agonist drugs have been reviewed.’ Epinephrine causes an increase in the rate and force of cardiac contraction with increases in cardiac output and oxygen consumption, a decrease in cardiac efficiency (work relative to oxygen consumption), and increases in both systolic and diastolic blood pressures. In humans, large doses of epinephrine can cause premature ventricular systoles, and inadvertent intravenous administration has elicited ventricular premature systoles followed by multifocal ventricular tachycardia. Treatment of asthma with intravenous infusions of isoproterenol can cause chest pain and ECG evidence of myocardial ischemia in both adults and children.“. ‘* The cardiac morphologic changes produced by high doses of catecholamines have been reviewed recently. ” Epinephrine and norepinephrine may produce myocardial hypertrophy and myocardial necrosis, including MCBN. The synthetic catecholamine isoproterenol is associated with a particular type of “infarctlike” necrosis related to MCBN. The mechanisms responsible for isoproterenol-induced myocardial necrosis include relative regional hypoxia, coronary microcirculatory effect, and cellular effects, including altered membrane permeability, myofilament overstimulation, high-energy phosphate deficiency, and calcium ion overload.” Catecholamine-induced myocardial alterations are morphologically similar to those that occur in association with pheochromocytoma, coronary vasospasm and subsequent myocardial ischemit damage, some sudden deaths related to stress (stress cardiomyopathy), as well as myocardial lesions in relationship to open-heart surgery.13, Is. I9 The recent evidence suggesting that calcium channel blocker drugs reduce myocardial necrosis in association with open heart surgery is consistent with a major contribution of calcium overload in the mediation of cell death.‘” Elevation of the cardiac-specific serum creatine phosphokinase MB (CPK-MB) isoenzyme was noted in 15 of 19 admissions of children with asthma treated with intravenous isoproterenol.2’ The demonstration that isoproterenol can induce significant cardiotoxicity stimulated the development of less cardiotoxic B2 agents. Their long-term safety, however, when used singly or in combination with theophylline products has not been established; it has been suggested that their use in combination with theophylline contributes to an increase in the number of sudden deaths among individuals with asthma.** Although B-receptors in the heart are different from those in the respiratory tract, there are significant numbers of B,-receptors in the heart and P,-agonists are
Cardiac
pathology
in asthma
421
not free from cardiovascular effects.6 Cardiac arrhythmias may occur with B,-adrenergic agonists. It has been shown that 8 mg of slow-release albuterol can induce arrhythmias in patients with asthma who are clinically free of heart disease, and a single dose of oral terbutaline (5 mg) can cause premature ventricular contractions in susceptible adults with chronic obstructive pulmonary disease.‘3 However, in a study of 20 adults with asthma who were clinically free of heart disease, ventricular extrasystoles occurred equally frequently in groups that received albuterol and placebo, suggesting that therapeutic doses of albuterol aerosol (two puffs four times a day on 2 successive days) in individuals with asthma without heart disease or severe hypoxemia should not be considered a cause of cardiac arrhythmias.‘4 The added effectiveness of xanthine derivatives and P-adrenergic agonists is well established, and these drugs are commonly used together in the treatment of bronchial obstruction. However, their combined use may yield a variety of extrapulmonary effects, including the potential to cause arrhythmias and myocardial necrosis.’ Indeed, combination bronchodilator therapy has been suggested as a possible cause of unexpected death in asthma by induction of arrhythmias.2’ Although theophylline is ionotropic and chronotropic and at toxic levels can produce arrhythmias, methylxanthines probably produce little direct cardiotoxicity.6 Methylxanthines likely augment the effects of P-agonists.6 Recent studies have suggested that, although combined oral bronchodilator treatment in patients with mild to moderate obstructive lung disease in a stable phase but without ischemic or other heart disease has an arrhythmogenic potential, it is in general of minor clinical importance.” One study of untreated severe acute asthma in children demonstrated that, although cardiac output was slightly increased above resting levels, aminophylline and albuterol were safe and effective treatments.26 Inhalation of albuterol via a nebulizer was recommended in preference to intravenous injection, because similar improvement in airway function was achieved with little or no cardiovascular disturbance. A recent study of 14 adults with asthma who were taking continuous sustained-release theophylline and. B,-adrenergic agents showed no increase in ventricular ectopic activity with combination therapy. 27 Hypokalemia resulting in part from BZ stimulant drugs has been proposed as a cause of potentially fatal arrhythmia in patients with asthma.2” Theophylline toxicity, noted on occasion to precede death, also induces hypokalemia. 29 The possibility that hypokalemia caused by BZ stimulant drugs or theophylline
422
Schoen
could give rise to potentially fatal arrhythmias requires further evaluation.’ Fluorocarbons used in aerosol inhalers for treating asthma are capable, at least theoretically, of inducing cardiac arrhythmias. It has been suggested that fluorocarbons (fluoalkane gases present as propellants) might be directly cardiotoxic3” or sensitize the heart to the action of catecholamines during hypoxemia.“’ However. this view has recently been challenged? The potentiation of cardiotoxicity of sympathomimetic agents by steroids has also been proposed.3’ The well-recognized increased frequency of death from asthma at night or in the early morning has been linked to a pronounced diurnal variation in airflow limitation.“, M A similar variation has been noted in the temporal onset of acute transmural myocardial infarction.35 It has been suggested that this is related to a diurnal variation in endogenous circulating sympathetic amines and the secondary effects on sympathetic vascular tone and platelet reactivity. Their possible role in asthma deaths with similar mechanisms of increased vascular tone and platelet reactivity remains obscure. COruCl.UslONS The role of cardiac pathology in death from asthma remains uncertain. Although some patients who die suddenly of asthma have focal myocardial necrosis, the mechanisms and significance of such damage are unknown. The clinical importance of the arrhythmogenic potential of bronchodilator drugs (and combinations thereof) used in the acute and chronic treatment of asthma remains unresolved. REFERENCES I. Scharf SM. Mechanical cardiopulmonary interactions with asthma. Clin Rev Allergy 1985;3:487-500. 2. Benatar SR. Fatal asthma. N Engl J Med 1986;314:423-9. 3. Hetzel MR. Clark TJH, Branthwaite MA. Asthma: analysis of sudden deaths and ventilatory arrests in hospital. Br Med J 1977;1:808-Il. 4. MacDonald JB, Seaton A, Williams LX Asthma deaths in Cardiff, 1963-74. 53 deaths in hospital. Br Med J 1976;l: 1493-s. 5. American Academy of Allergy and Inununology-Committee on Drugs: Position statement: adverse effects and complications of treatment with beta-adrenergic agonist drugs. J ALLERGY CLIN hMUNOL 1985;75:443-9. 6. Nicklas RA. Balazs T. Adverse effects of theophylline-beta agonist interactions. J ALLERGY Ct.t~ IMMUNOL 1986;78: 806-11. 7. Renzetti AD, McClement JH, Litt BD. Moxtality in relation to respiratory function in chronic obstructive pulmonary disease. Am J Med 1966,41:115-29. 8. Clark TJH. Adult asthma. In: Clark TJH, Godfrey S, eds. Asthma. London: Chapman and Hall, 1977.
J. ALLERGV
CLIN. IMMUNOL. SEPTEMBER 1987
9. Calverley PMA. Catterall JR, Shapiro t ‘. Douglas Yl. Cor pulmonale in asthma. Br J Dis Chest 19X3:77:303-?. IO. Kurland G, Williams 1, Lewiston NJ. latal nl~c~r-:irdritl tknrui! during continuous infusion intravenous isoprotct-cnol rhcrap~ of asthma. J ALLERGY CLIN l~hlt;Not. 1979:h.:..J(J7-! I. II. Luchtrath H. Zur Pathologie des akutcn Herrtodcs bcim asthma bronchialc. Virchow Arch A Path Anat IHi%!c~l 1079:?FI. 343-52. H. Schocn Il. Strunk 12. Drislane FW, Samuels MA. Kozakewich RC. Myocardial contraction band Icsions in patients with fatal asthma: possible neurocardiologic mechanisms. Am RLY Kcspir Dis 1987;135:498-501. 13. Reichenbach DD, Benditt EP. Catecholamincs and cardiomyopathy. The pathogenesis and potential importance of myofibrillar degeneration. Hum Pathol 1970; I : I ?.S-SO. manifestations of' ncuro14. Samuels MA. Electrocardiographic logic disease. Sem Neural 1984;4:453-61. ME. Myocardial contraction bands rc15. Karch SB. Billingham visited. Hum Pathol 1986:17:9-13. ischemid 16. Jennings RB, Reimer KA, Steenberger C. Myocardial revisited. The osmolar load. membrane damage. and repcrfusion. J Mol Cell Cardiol 1986:18:769-80. 17. Winsor T, Mills B, Winbury MM, Howe BB. Berger HJ. lntramyocardial diversion of coronary blood flow: effects of isoproterenol-induced subendocardial ischemia. Microvasc Res 1975;9:261-78. ischcmia 18. Matson JR, Loughlin GM, Strunk RC. Myocardial complicating the use of isoproterenol in asthmatic children. J Pediatr 1978;92:776-8. cardiotoxicity. J Mol Cell Cardiol 19. Rona G. Catecholamine 1985:17:291-306. and calcium antagonists: a review. 20. de Jong JW. Cardioplegia .4nn Thorac Surg 1986;42:593-8. specific crea21. Maguire JF, Geha RS. Umetsu DT. Myocardial tine phosphokinase isoenzyme elevation in children with asthma treated with intravenous isoporterenol. J ALLERGY CLIN IMMUNOL 1987:78:631-6. 22. Wilson ID, Sutherland DC, Thomas AC. Has the change to beta-agonist combined with oral theophylline increased cases of fatal asthma? Lancet 1981;1:1235-7. 23. Al-Hillawi AH, Hayward R, Johnson NM. Incidence of cardiac arrhythmias in patients taking slow release salbutamol and slow release terhutaline for asthma. Br Med J 1984;288:367. 24. Martelli NA, Raimondi AC, Lazzari JO. Asthma, cardiac arrhythmias, and albuterol aerosol. Chest 1986;89:192-4. 25. Conrddson TB , Ekhmdh G, Olofsson B. Pahlm 0, Persron G Cardiac arrhythmias in patients with mild-to-moderate obstructive lung disease. Comparison to beta-agonist therapy alone and in combination with a xanthine derivative, enpmfylline or theophylline. Chest 1985;88:537-42. 26. Edmunds AAT, Godfrey S. Cardiovascular response during severe acute asthma and its treatment in chiidren. Thorax 1981;36:534-40. 27. Kelly HW, Menendez R, Voyles W. Lack of significant arrythmogenicity from chronic theophylline and beta-2 adrenergic combination therapy in asthmatic subjects. Ann Allergy 1985;54:405-IO. 28. Haalboom JRE, Deenstra M, Struyvenberg A. Hypokalemia induced by inhalation of fenoteml. Lancet 1985;1:1125-7. 29. Hall KW, Dobson KE, Dalton JG, Ghignone MC, Penner SB. Metabolic abnormalities associated with intentional theophylline overdose. Ann Intern Med 1984;101:457-62. 30. Taylor GJ. Cardiac toxicity of aemsol propehants. JAMA 1970;214:81-5.
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31. Jack D. Sniffing syndrome. Br Med J 1971;2:708-9. 32. Newhouse MT, Dolovich MB. Control of asthma by aerosols. N Engl J Med 1986;315:870-4. 33. Lehr D. Isoproterenol and sudden death of asthmatic patients in ventricular fibrillation. N Engl J Med 1972;287:987-8. 34. Cochrane GM, Clark TJH. A survey of asthma mortality in
Fatal asthma-Is Desmond Poynter,
in asthma
patients between ages 35 and 64 in the Greater London hospitals in 1971. Thorax 1975;30:300-5. 35. Muller JE, Stone PH, Turi Z, et al. Circadian variation in the frequency of onset of acute myocardial infarction. N Engl J Med 1985;313:1315-22.
treatment
incriminated?
Ph.D. Ware, Hertfordshire, United Kingdom
In fatal asthma the exacerbation of the disease will doubtless have demanded treatment, which in some cases may well have been repeated with more than one drug. This inevitably leads to the suggestion that such treatment or its excess may play a part in any ensuing tragedy. The purpose of this article is to discuss those drugs used in asthma treatment and to refer to some of the studies, experimental and otherwise, performed with them to see if there are any facets of their toxicologic profiles that might indicate a potential hazard. It is relevant to inquire at the outset whether any specific pulmonary diseases are associated with those substances used for the therapy of asthma. In his review of iatrogenic lung disease Cuthbert’ mentions the paradoxic effect that sympathomimetic amines may have in also relaxing smooth muscle in the pulmonary vasculature, thus producing pulmonary vasodilation with resultant hypoxia. However, in their review of drug-induced lung disease Whimster and de Poitiers’ refer to only one compound that is used to treat asthma. They note that steroids may induce thoracic changes by way of mediastinal fat deposition, which may be recognizable radiologically. Fifteen caseswere summarized as part of the generalized known effects of high-level steroid therapy, with the changes taking 5 years to become noticed when a dose of 7.5 mg/day was used and only 7 months when a dose of 30 mglday was used. The current therapeutic agents used in asthma are generally not incriminated in producing pulmonary
From the Pathology Division, Glaxo Group Research, Ware, Hertfordshim, United Kingdom. Reprint requests: Desmond Poynter, Ph.D., Glaxo Group Research Limited, Ware, Hertfordshire, SGl2 ODJ, United Kingdom.
disease as such. However, they are potent compounds and if used inappropriately some of them may produce significant toxic effects that will not improve the course of the disease. SYMPATHOMlMETlC
AMIMES
Sympathomimetic amines may produce myofibrillar lesions in animal hearts, and the epidemiologic association between an increased death rate in young people with asthma and the abuse of pressurized aerosols containing isoproterenol 3-5has provoked much interest. Much experimental work has been undertaken in animals but its extrapolation to humans is not easy. Thus, although it is well documented that isoproterenol can cause myocardial necrosis in rats,6 hamsters,’ and rabbits,* no such effect has been described in humans. However, isoproterenol has cardiotoxic effects in the dog9 that are exacerbated by hypoxia, and in the cat heart-lung preparation” there is evidence that a fatigued heart working at a high level is ten times as sensitive as a normal heart. The introduction of more selective P-agonists that are markedly more active on bronchial smooth muscle than on cardiac muscle provided safer medication. In a direct comparison of nonselective isoproterenol and selective albuterol, isoproterenol was lethal to the hypoxic dog but albuterol was not.’ Thus there is experimental evidence that nonselective P-agonists may under certain circumstances be lethal to animals. That the selective P-agonist albuterol has a very different effect upon the heart was well illustrated by the work of Nayler” who, using papillary muscle from dogs and from humans, concluded that the action of albuterol on P-adrenergic receptors in heart muscle was minimal compared with that of equipotent bronchodilator doses of isoproterenol . 423