- Email: [email protected]
Endothelins come of age
Moreover, inhalation of excreta from infected animals is needed for human infection. B Le Guenno Centre National de Référence des Fièvres Paris, France
Hémorragiques Virales, Institut Pasteur,
Lloyd G. Hantavirus. In: Morgan-Capner P, ed. Current topics in clinical virology. London: PHLS, 1990. 2 Gajdusek D. Virus hemorrhagic fevers. J Pediatr 1962; 60: 845-57. 3 Lee HW, Lee PW. Korean hemorrhagic fever, I: demonstration of causative antigen and antibodies. Korean J Int Med 1976; 19: 371-83. 4 Lee HW, Lee PW, Johnson K. Isolation of the etiologic agent of Korean hemorrhagic fever. J Infect Dis 1978; 137: 289-308. 5 French G, Foulke R, Brand O, Eddy G, Lee HW, Lee PW. Korean hemorrhagic fever: propagation of the etiologic agent in a cell line of human origin. Science 1981; 211: 1046-48. 1
Centers for Disease Control. Outbreak of acute illness—Southwestern United States, 1993. MMWR 1993; 42: 421-23. 7 Nichol S, Spiropoulou C, Morzunov S, et al. Genetic identification of a Hantavirus associated with an outbreak of acute respiratory illness. Science 1993; 262: 914-17. 8 Choo Q-L, Kuo G, Weiner A, Overby L, Bradley D, Houghton M. Isolation of a cDNA clone derived from a blood borne non-A, non-B viral hepatitis genome. Science 1989; 244: 359-61. 9 Nerurkar V, Song K-J, Gajdusek D, Yanagihara R. Genetically distinct hantavirus in deer mice. Lancet 1993; 342: 1059. 10 Kulzer P, Schaefer RM, Heidbreder E, Heidland A. Haemorrhagic fever with renal syndrome, 1993: endemic or unrecognised pandemic? Lancet 1993; 342: 313. 11 Gerding MN, Jordans JGM, Groen J, Osterhaus ADME. Haemorrhagic fever with renal syndrome. Lancet 1993; 342: 495. 6
Endothelins come of age The
by Clozel and colleagues1-3 of a pathophysiological role for endothelin, based on the first studies with orally active endothelin antagonists, emphasise the rapidity of progress in this area since the isolation of endothelin-1in 1988.’ Moreover, this work, in conjunction reports
with the results of other studies on the role of endothelin in health and disease, indicates the exciting clinical potential of endothelin antagonists. The endothelins are a family of three peptides with extremely potent and characteristically sustained vasoconstrictor and vasopressor actions. They also have mitogenic and neuroendocrine properties. Endothelin-1 predominates in the vascular endothelium, where it is generated from proendothelin-1 through the action of a unique neutral metalloprotease, "endothelin converting enzyme". Two distinct endothelin receptors were cloned in 1990.6,7 The ETA receptor is preferentially activated by endothelin-1 and is highly expressed in vascular smooth muscle cells. It is the main receptor subtype causing vasoconstriction. The ET receptor is activated equally by all three endothelin isoforms and is present on the luminal surface of endothelial cells, where it mediates release of endothelium-dependent vasodilator substances, and on the smooth muscle of some tissues, where it causes constriction. The presence of an ET receptor subtype, preferentially activated by endothelin-3, remains controversial. Many studies have shown raised plasma concentrations of immunoreactive endothelin in conditions associated with systemic vasoconstriction, including chronic heart failure, pulmonary hypertension, and vasospastic disorders such as Raynaud’s disease and Prinzmetal’s angina.5 However, endothelin-1 acts in a paracrine fashion rather than as a circulating hormone, because vascular endothelin-1release is mainly abluminal. Consequently, plasma concentrations are a poor reflection of local production. Increased tissue
concentrations of, or binding sites for, endothelin may be more useful; both are found in renal disease and myocardial infarction, providing stronger evidence of a local role for endothelin. Persuasive evidence likewise exists for the sustained vasospasm following subarachnoid haemorrhage. Here, plasma immunoreactive endothelin concentrations are highest in patients with cerebral vasospasm, and cerebrospinal fluid endothelin concentrations are raised only in this subgroup. However, to confirm that production of endothelin-1 fulfils a function in health and contributes to pathophysiology studies with specific inhibitors of its generation or action were needed. The first such studies, in rats, showed that the endothelin converting enzyme inhibitor, phosphoramidon, lowered blood pressure,8indicating that endothelin may contribute to cardiovascular homoeostasis. However, these results had to be confirmed with specific receptor blockers, because phosphoramidon is also a weak inhibitor of the neutral endopeptidase that degrades atrial natriuretic peptide. Endothelin antibodies have been used in several experimental preparations in the rat, where they ameliorate the acute renal failure after arterial occlusion and prevent the renal dysfunction associated with cyclosporin. In addition, they limit the extent of myocardial infarction, even when they are given before coronary artery occlusion. More recent studies with the ETA-specific antagonist, BQ123, and the combined ETA and ET antagonists, Ro 46-2005 and Ro 47-0203, broadly confirm these findings. In a rat model of chronic renal failure with reduced renal mass, dependent more on abnormal growth and fibrosis than on vasoconstriction, BQ123 prevents renal dysfunction and structural changes.9 In a rat model of subarachnoid haemorrhage, in which autologous blood is given into the cisterna magna, pretreatment with Ro 46-2005 profoundly reduces cerebral vasospasm.1 In a similar model in the rabbit, Ro 47-0203 reverses established vasospasm2 without affecting blood pressure. Studies with antagonists also support a role for endothelin-1 in the of maintenance hypertension in spontaneously hypertensive and deoxycorticosterone-salt treated rats,3,10 and for regulation of blood pressure in conditions of sodium
depletion.1 Thus, there is
considerable experimental and some clinical evidence for involvement of endothelin in cardiovascular and renal disease,s where it represents a novel target for therapeutic intervention. There are no effective drug treatments for acute or chronic renal failure, and there is still a substantial need for better treatment in subarachnoid haemorrhage, myocardial infarction, and congestive heart failure. Endothelin antagonists should be explored in these conditions, and may also prove useful in hypertension. Orally active inhibitors have now been developed and these questions will shortly be put to the test in clinical trials. now
David J Webb, William G
Haynes
University Department of Medicine, Western General Hospital, Edinburgh, UK 1
2
3
Clozel M, Breu V, Burri K, et al. Pathophysiological role of endothelin revealed by the first orally active endothelin receptor antagonist. Nature 1993; 365: 759-61. Roux SP, Clozel M, Sprecher U, Gray G, Clozel J-P. Ro 47-0203, a new endothelin receptor antagonist, reverses chronic vasospasm in experimental subarachnoid hemorrhage. Circulation 1993; 88: 1170
(abstr). Clozel M, Clozel J-P, Hesse P. Endothelin receptor antagonism: a new therapeutic approach in experimental hypertension. Circulation 1993; 88: 1316 (abstr).
1439
4
Yanagisawa M, Kurihara H, Kimura S, et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 1988; 332: 411-15.
The endothelin family of peptides: local hormones with diverse roles in health and disease? Clin Sci 1993; 84: 485-500. 6 Arai H, Hori S, Aramori I, Ohkubo H, Nakanishi S. Cloning and expression of a cDNA encoding an endothelin receptor. Nature 1990; 348: 730-32. 7 Sakurai T, Yanagisawa M, Takuwa Y, et al. Cloning of a cDNA encoding a non-isopeptide-selective subtype of the endothelin receptor. Nature 1990; 348: 732-35. 8 McMahon EG, Palomo MA, Moore WM. Phosphoramidon blocks the pressor activity of big endothelin (1-39) and lowers blood pressure in spontaneously hypertensive rats. J Cardiovasc Pharmacol 1991; 17 (suppl 7): S29-33. 9 Benigni A, Zoja C, Corna D, et al. A specific endothelin subtype A receptor antagonist protects against injury in renal disease progression. Kidney Int 1993; 44: 440-45. 10 Nishikibe M, Tsuchida S, Okada M, et al. Antihypertensive effect of a newly synthesised endothelin antagonist, BQ123, in a genetic hypertensive model. Life Sci 1993; 52: 717-24. 5
Haynes WG, Webb DJ.
Adverse reaction
reporting and new
antipsychotics Remoxipride, clozapine, and risperidone number among a new generation of antipsychotics. The most cautious conclusions from the clinical trial data are that these compounds are as effective as the older antipsychotic agents but with far fewer extrapyramidal side-effects.1 Clozapine is probably better than the classic drugs but, because of the risk of neutropenia and agranulocytosis, is restricted to treatment-resistant or intolerant patients, with strict haematological monitoring.2 These new agents also have interesting modes of action that may point the way to a better understanding of schizophrenia and more efficient drug development in the future. Thus clozapine, for a highly effective antipsychotic, has peculiarly low occupancy at D2 receptors in vivo,3 whereas remoxipride has high selectivity for the mesolimbic-specific D2b
receptor.4 The Committee on Safety of Medicines (CSM) in the UK lately issued a warning of 8 reports of aplastic anaemia among 50 000 patients world wide associated with remoxipride and 4 cases of myocarditis in 5000 UK patients exposed to clozapine.5 The CSM rightly urges cautio-but what do we know about the still widely used classic antipsychotics, especially in view of their less favourable side-effect profile? Notwithstanding the basic difficulties that classic drugs are only partly effective and liable to cause several neurological, endocrine, and autonomic side-effects, phenothiazines and similar drugs are additionally associated with arrhythmias, hepatic abnormalities,
convulsions, agranulocytosis, thrombocytopenia, neuroleptic malignant syndrome, myocarditis, severe tardive dyskinesia, and sudden death.6 The frequency of agranulocytosis with phenothiazines is 1/1300/ which is probably an underestimate since adverse events with
1440
standard agents are likely to be under-reported. Thus both myocarditis and life-threatening blood dyscrasias are associated with the older compounds. So, is the burden of risk with remoxipride and clozapine any greater than for phenothiazines? With respect to myocarditis, clozapine use is restricted to treatment-resistant schizophrenia; such patients will almost certainly have had long exposure to phenothiazines which are themselves a potential cause of the cardiac lesions. Moreover, myocarditis is a very difficult condition to define, and is an incidental finding in 10% of routine necropsies.8 Although inflammatory changes were reported in the clozapine cases (CSM, personal communication) it is not clear if these abnormalities were associated with the myocyte degeneration or necrosis required in the Dallas classification of myocarditis.99 Second, much is made of the risk-benefit analysis of the new drugs. At worst they are equieffective and better tolerated then classic neuroleptics. Without proper quantifiable comparisons with other drugs it is difficult to compare the risk profile, but careful elimination of highrisk patients and regular monitoring, to which schizophrenic patients are entitled, will lessen the risk. Resorting to central monitoring, as some suggest, takes the important burden of clinical responsibility away from psychiatrists and runs the risk of pricing the new drugs off the market altogether. Schizophrenia is a common and devastating illness. I believe the new generation of antipsychotics represents an improvement, and pharmacological research into their mechanisms of action is likely to yield even better agents. The call for closer medical monitoring of these drugs is a welcome step in bringing about overall better care for schizophrenics, but just because the new drugs are being made to walk the plank by the drug regulatory agencies we cannot presume that older and potentially dangerous agents are "safe".
Robert Kerwin Institute of
1
2
3
4
5 6 7
8 9
Psychiatry, London, UK
Gerlach J. New antipsychotics: classification, efficacy and adverse effects. Schizophrenia Bull 1991; 17: 289-309. Kane J, Honigfield G, Singer J, et al. Clozapine for the treatment resistant schizophrenic: a double blind comparison versus clozapine. Arch Gen Psychiatry 1988; 45: 789-96. Pilowsky L, Costa DC, Ell PJ, et al. Clozapine single photon emission tomography and the D2 dopamine receptor hypothesis. Lancet 1992; 340: 199-202. Malmberg AH, Jackson DM, Eriksson A, Monell N. Unique binding characteristics of antipsychotic agents interacting with human dopamine D2A D2B and D3 receptors. Mol Pharmacol 1993; 43: 749-54. Committee on Safety of Medicines. Curr Prob Pharmacovig Bull 1993; 19: 9-10. Largactil. In: ABPI data sheet compendium, 1993-1994. London: Datapharm Publications, 1993: 1266-68. Vincent PC. Drug induced aplastic anaemia and agranulocytosis: incidence and mechanisms. Drugs 1986; 31: 52-63. Peters NS, Poole-Wilson PA. Myocarditis: a controversial disease. J R Soc Med 1991; 84: 1-2. Aretz H, Billingham ME, Edwards WD, et al. Myocarditis: a histological definition and classification. Am J Cardiovasc Pathol 1987; 1: 3-14.
Hémorragiques Virales, Institut Pasteur,
Lloyd G. Hantavirus. In: Morgan-Capner P, ed. Current topics in clinical virology. London: PHLS, 1990. 2 Gajdusek D. Virus hemorrhagic fevers. J Pediatr 1962; 60: 845-57. 3 Lee HW, Lee PW. Korean hemorrhagic fever, I: demonstration of causative antigen and antibodies. Korean J Int Med 1976; 19: 371-83. 4 Lee HW, Lee PW, Johnson K. Isolation of the etiologic agent of Korean hemorrhagic fever. J Infect Dis 1978; 137: 289-308. 5 French G, Foulke R, Brand O, Eddy G, Lee HW, Lee PW. Korean hemorrhagic fever: propagation of the etiologic agent in a cell line of human origin. Science 1981; 211: 1046-48. 1
Centers for Disease Control. Outbreak of acute illness—Southwestern United States, 1993. MMWR 1993; 42: 421-23. 7 Nichol S, Spiropoulou C, Morzunov S, et al. Genetic identification of a Hantavirus associated with an outbreak of acute respiratory illness. Science 1993; 262: 914-17. 8 Choo Q-L, Kuo G, Weiner A, Overby L, Bradley D, Houghton M. Isolation of a cDNA clone derived from a blood borne non-A, non-B viral hepatitis genome. Science 1989; 244: 359-61. 9 Nerurkar V, Song K-J, Gajdusek D, Yanagihara R. Genetically distinct hantavirus in deer mice. Lancet 1993; 342: 1059. 10 Kulzer P, Schaefer RM, Heidbreder E, Heidland A. Haemorrhagic fever with renal syndrome, 1993: endemic or unrecognised pandemic? Lancet 1993; 342: 313. 11 Gerding MN, Jordans JGM, Groen J, Osterhaus ADME. Haemorrhagic fever with renal syndrome. Lancet 1993; 342: 495. 6
Endothelins come of age The
by Clozel and colleagues1-3 of a pathophysiological role for endothelin, based on the first studies with orally active endothelin antagonists, emphasise the rapidity of progress in this area since the isolation of endothelin-1in 1988.’ Moreover, this work, in conjunction reports
with the results of other studies on the role of endothelin in health and disease, indicates the exciting clinical potential of endothelin antagonists. The endothelins are a family of three peptides with extremely potent and characteristically sustained vasoconstrictor and vasopressor actions. They also have mitogenic and neuroendocrine properties. Endothelin-1 predominates in the vascular endothelium, where it is generated from proendothelin-1 through the action of a unique neutral metalloprotease, "endothelin converting enzyme". Two distinct endothelin receptors were cloned in 1990.6,7 The ETA receptor is preferentially activated by endothelin-1 and is highly expressed in vascular smooth muscle cells. It is the main receptor subtype causing vasoconstriction. The ET receptor is activated equally by all three endothelin isoforms and is present on the luminal surface of endothelial cells, where it mediates release of endothelium-dependent vasodilator substances, and on the smooth muscle of some tissues, where it causes constriction. The presence of an ET receptor subtype, preferentially activated by endothelin-3, remains controversial. Many studies have shown raised plasma concentrations of immunoreactive endothelin in conditions associated with systemic vasoconstriction, including chronic heart failure, pulmonary hypertension, and vasospastic disorders such as Raynaud’s disease and Prinzmetal’s angina.5 However, endothelin-1 acts in a paracrine fashion rather than as a circulating hormone, because vascular endothelin-1release is mainly abluminal. Consequently, plasma concentrations are a poor reflection of local production. Increased tissue
concentrations of, or binding sites for, endothelin may be more useful; both are found in renal disease and myocardial infarction, providing stronger evidence of a local role for endothelin. Persuasive evidence likewise exists for the sustained vasospasm following subarachnoid haemorrhage. Here, plasma immunoreactive endothelin concentrations are highest in patients with cerebral vasospasm, and cerebrospinal fluid endothelin concentrations are raised only in this subgroup. However, to confirm that production of endothelin-1 fulfils a function in health and contributes to pathophysiology studies with specific inhibitors of its generation or action were needed. The first such studies, in rats, showed that the endothelin converting enzyme inhibitor, phosphoramidon, lowered blood pressure,8indicating that endothelin may contribute to cardiovascular homoeostasis. However, these results had to be confirmed with specific receptor blockers, because phosphoramidon is also a weak inhibitor of the neutral endopeptidase that degrades atrial natriuretic peptide. Endothelin antibodies have been used in several experimental preparations in the rat, where they ameliorate the acute renal failure after arterial occlusion and prevent the renal dysfunction associated with cyclosporin. In addition, they limit the extent of myocardial infarction, even when they are given before coronary artery occlusion. More recent studies with the ETA-specific antagonist, BQ123, and the combined ETA and ET antagonists, Ro 46-2005 and Ro 47-0203, broadly confirm these findings. In a rat model of chronic renal failure with reduced renal mass, dependent more on abnormal growth and fibrosis than on vasoconstriction, BQ123 prevents renal dysfunction and structural changes.9 In a rat model of subarachnoid haemorrhage, in which autologous blood is given into the cisterna magna, pretreatment with Ro 46-2005 profoundly reduces cerebral vasospasm.1 In a similar model in the rabbit, Ro 47-0203 reverses established vasospasm2 without affecting blood pressure. Studies with antagonists also support a role for endothelin-1 in the of maintenance hypertension in spontaneously hypertensive and deoxycorticosterone-salt treated rats,3,10 and for regulation of blood pressure in conditions of sodium
depletion.1 Thus, there is
considerable experimental and some clinical evidence for involvement of endothelin in cardiovascular and renal disease,s where it represents a novel target for therapeutic intervention. There are no effective drug treatments for acute or chronic renal failure, and there is still a substantial need for better treatment in subarachnoid haemorrhage, myocardial infarction, and congestive heart failure. Endothelin antagonists should be explored in these conditions, and may also prove useful in hypertension. Orally active inhibitors have now been developed and these questions will shortly be put to the test in clinical trials. now
David J Webb, William G
Haynes
University Department of Medicine, Western General Hospital, Edinburgh, UK 1
2
3
Clozel M, Breu V, Burri K, et al. Pathophysiological role of endothelin revealed by the first orally active endothelin receptor antagonist. Nature 1993; 365: 759-61. Roux SP, Clozel M, Sprecher U, Gray G, Clozel J-P. Ro 47-0203, a new endothelin receptor antagonist, reverses chronic vasospasm in experimental subarachnoid hemorrhage. Circulation 1993; 88: 1170
(abstr). Clozel M, Clozel J-P, Hesse P. Endothelin receptor antagonism: a new therapeutic approach in experimental hypertension. Circulation 1993; 88: 1316 (abstr).
1439
4
Yanagisawa M, Kurihara H, Kimura S, et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 1988; 332: 411-15.
The endothelin family of peptides: local hormones with diverse roles in health and disease? Clin Sci 1993; 84: 485-500. 6 Arai H, Hori S, Aramori I, Ohkubo H, Nakanishi S. Cloning and expression of a cDNA encoding an endothelin receptor. Nature 1990; 348: 730-32. 7 Sakurai T, Yanagisawa M, Takuwa Y, et al. Cloning of a cDNA encoding a non-isopeptide-selective subtype of the endothelin receptor. Nature 1990; 348: 732-35. 8 McMahon EG, Palomo MA, Moore WM. Phosphoramidon blocks the pressor activity of big endothelin (1-39) and lowers blood pressure in spontaneously hypertensive rats. J Cardiovasc Pharmacol 1991; 17 (suppl 7): S29-33. 9 Benigni A, Zoja C, Corna D, et al. A specific endothelin subtype A receptor antagonist protects against injury in renal disease progression. Kidney Int 1993; 44: 440-45. 10 Nishikibe M, Tsuchida S, Okada M, et al. Antihypertensive effect of a newly synthesised endothelin antagonist, BQ123, in a genetic hypertensive model. Life Sci 1993; 52: 717-24. 5
Haynes WG, Webb DJ.
Adverse reaction
reporting and new
antipsychotics Remoxipride, clozapine, and risperidone number among a new generation of antipsychotics. The most cautious conclusions from the clinical trial data are that these compounds are as effective as the older antipsychotic agents but with far fewer extrapyramidal side-effects.1 Clozapine is probably better than the classic drugs but, because of the risk of neutropenia and agranulocytosis, is restricted to treatment-resistant or intolerant patients, with strict haematological monitoring.2 These new agents also have interesting modes of action that may point the way to a better understanding of schizophrenia and more efficient drug development in the future. Thus clozapine, for a highly effective antipsychotic, has peculiarly low occupancy at D2 receptors in vivo,3 whereas remoxipride has high selectivity for the mesolimbic-specific D2b
receptor.4 The Committee on Safety of Medicines (CSM) in the UK lately issued a warning of 8 reports of aplastic anaemia among 50 000 patients world wide associated with remoxipride and 4 cases of myocarditis in 5000 UK patients exposed to clozapine.5 The CSM rightly urges cautio-but what do we know about the still widely used classic antipsychotics, especially in view of their less favourable side-effect profile? Notwithstanding the basic difficulties that classic drugs are only partly effective and liable to cause several neurological, endocrine, and autonomic side-effects, phenothiazines and similar drugs are additionally associated with arrhythmias, hepatic abnormalities,
convulsions, agranulocytosis, thrombocytopenia, neuroleptic malignant syndrome, myocarditis, severe tardive dyskinesia, and sudden death.6 The frequency of agranulocytosis with phenothiazines is 1/1300/ which is probably an underestimate since adverse events with
1440
standard agents are likely to be under-reported. Thus both myocarditis and life-threatening blood dyscrasias are associated with the older compounds. So, is the burden of risk with remoxipride and clozapine any greater than for phenothiazines? With respect to myocarditis, clozapine use is restricted to treatment-resistant schizophrenia; such patients will almost certainly have had long exposure to phenothiazines which are themselves a potential cause of the cardiac lesions. Moreover, myocarditis is a very difficult condition to define, and is an incidental finding in 10% of routine necropsies.8 Although inflammatory changes were reported in the clozapine cases (CSM, personal communication) it is not clear if these abnormalities were associated with the myocyte degeneration or necrosis required in the Dallas classification of myocarditis.99 Second, much is made of the risk-benefit analysis of the new drugs. At worst they are equieffective and better tolerated then classic neuroleptics. Without proper quantifiable comparisons with other drugs it is difficult to compare the risk profile, but careful elimination of highrisk patients and regular monitoring, to which schizophrenic patients are entitled, will lessen the risk. Resorting to central monitoring, as some suggest, takes the important burden of clinical responsibility away from psychiatrists and runs the risk of pricing the new drugs off the market altogether. Schizophrenia is a common and devastating illness. I believe the new generation of antipsychotics represents an improvement, and pharmacological research into their mechanisms of action is likely to yield even better agents. The call for closer medical monitoring of these drugs is a welcome step in bringing about overall better care for schizophrenics, but just because the new drugs are being made to walk the plank by the drug regulatory agencies we cannot presume that older and potentially dangerous agents are "safe".
Robert Kerwin Institute of
1
2
3
4
5 6 7
8 9
Psychiatry, London, UK
Gerlach J. New antipsychotics: classification, efficacy and adverse effects. Schizophrenia Bull 1991; 17: 289-309. Kane J, Honigfield G, Singer J, et al. Clozapine for the treatment resistant schizophrenic: a double blind comparison versus clozapine. Arch Gen Psychiatry 1988; 45: 789-96. Pilowsky L, Costa DC, Ell PJ, et al. Clozapine single photon emission tomography and the D2 dopamine receptor hypothesis. Lancet 1992; 340: 199-202. Malmberg AH, Jackson DM, Eriksson A, Monell N. Unique binding characteristics of antipsychotic agents interacting with human dopamine D2A D2B and D3 receptors. Mol Pharmacol 1993; 43: 749-54. Committee on Safety of Medicines. Curr Prob Pharmacovig Bull 1993; 19: 9-10. Largactil. In: ABPI data sheet compendium, 1993-1994. London: Datapharm Publications, 1993: 1266-68. Vincent PC. Drug induced aplastic anaemia and agranulocytosis: incidence and mechanisms. Drugs 1986; 31: 52-63. Peters NS, Poole-Wilson PA. Myocarditis: a controversial disease. J R Soc Med 1991; 84: 1-2. Aretz H, Billingham ME, Edwards WD, et al. Myocarditis: a histological definition and classification. Am J Cardiovasc Pathol 1987; 1: 3-14.