Annotations Virus
valvular
heart
disease
Virus antigen has been demonstrated in the heart valves of experimentally infected animals’ and of patients with “r&umatic heart disease.“* Much of the evidence which supports the suggestion that ~~~IIES can cause heart disease in man has recently been reviewed.” It is relevant here to concentrate on experimental and clinical studies in which valvular involvement was induced or detected. In 1939, Pearce’ described pancarditis caused by experimental virus III infection in rabbits. Subsequently,’ using a variety of other viruses he demonstrated that the incidence and severity of these changes were increased by pretreatment with one of several “conditioning” processes. These included direct myocardial trauma and the injection of a variety of pharmacologically active reagents which he claimed operated through the common property of inducing myocardial hypoxia. The implications of these findings were overlooked until the impetus of confirmed cases of viral heart disease in man in the 1950’s stimulated fresh interest. Several reports in the 1960’s relating particularly to Group B Coxsackie virus infections described experimentally induced acute and chronic valve lesions in mice5. 6 and monkeys’, “; these occurred frequently and electron microscope studies demonstrated virus particles in valve tissue.” Adenovirus was similarly demonstrated by other workers9 Macroscopically, chronic valve lesions closely resembled “rheumatic heart disease”for example, mitral stenosis with commissural adhesions and chordal contractures. Histologic changes were also similar to those of rheumatic heart disease and included lesions reminiscent of Aschoff bodies? Thus, in experimental animals there is convincing evidence of an association between viruses and valvular heart disease. Early reports of virus heart disease in man usually implicated Coxsackie viruses predominantly of Group B. In neonates, a severe and often fatal myocarditis was noted, older children were less severely affected, and in adults pericarditis usually dominated the clinical picture.‘O Many other viruses have since been described as causes of myocarditis and pericatitis. One of these two features has characterized most reports, but acute valvulitis has been diagnosed or suspected by several observers. Three out of four cases recorded by Babb, Stoneman, and SternlO had systolic murmurs in two of whom it persisted; one had had a transient mitral diastolic murmur. These were infants and there will remain some doubt about attributing the findings to a specific infectious illness. However, the similarity to cases diagnosed clinically as isolated rheumatic carditis is obvious. Sainani, Krompotic, Slodki,” on the other hand, reporting 22 cases of adult heart disease due to Group B Coxsackie viruses noted systolic murmurs in eight cases, in three of whom it was pansystolic and persistent; in one case a mitral diastolic murmur also became established. One of Smith’s’* cases, described as entirely healthy following an insurance medical examination had a febrile illness two weeks later, and subsequently developed atria1 fibrillation, mitral regurgitation, and a mitral diastolic murmur. He had high titers to Coxsackie B, virus. Thus there is evidence that valve lesions may develop during
804
the COU~W of a viral
illness and become established. This evidence is obviously less impressive than in animal studies and it might be concluded from the paucity of such reports that virus-induced valvular disease is, at most, a rarity. This would, however, be premature for other relevant factors have to be taken into account. 1. Little is known of the long-term effects on the heart of mild virus illnesses, although it was recently demonstrated that permanent cardiac damage can certainly result from trivial influenza perhaps in as many as 5 per cent of infected persons.lJ This could have implications for other virus illnesses which might be expected to act similarly, since observed cases form only a small percentage of all infections with most viruses. This is quite different from the situation which pertains to rheumatic fever in which many cases of a clinically severe illness have occurred over the years, thus facilitating detailed study. 2. Animal studies have clearly shown that virus valvulitis is the result of invasion from adjacent myocardium” and that under appropriate circumstances this sequence of events is common. There is no reason to suppose that human heart valves are any different in this respect. Available evidence indicates that a virus which can cause myocarditis can also produce valvulitif3. 3. The concept that valve disease can develop insidiously is generally accepted. Failure to detect valvular involvement during the acute stage of rheumatic fever has been no bar to attributing to it subsequent established valve disease. The infrequency of documented cases of acute virus valvulitis may be, to some extent, a reflection of the general pattern of virus illness rather than an indication that more cases do not occur. It is also likely that the numbers of reported cases will increase as interest in the subject grows. Immunofluorescent t,echniques adapted to detect virus antigen were employed in several of the experimental studies referred to above.“, * Although such methods have to date been used infrequently in man it has, nevertheless, been established that Coxsackie B, virus antigen occurs frequently in the in the absence of clinical human myocardium,‘5. l6 often evidence of cardiac disease. As in clinical reports, the common theme of these investigative studies has been the Coxsackie B group of viruses. This is understandable for available evidence indicates that this organism is the most common cause of overt viral heart disease in man. However, many other viruses are cardiotropic3. 1 and, in our present state of ignorance, warrant similar attention. These broader implications were the subject of a recent preliminary report,Y the first to specifically examine patients with established valvular heart disease for evidence of past viral carditis using immunofluorescent techniques. Left atria1 and/or valve biopsy specimens from 15 cases with acquired valvular heart disease were studied by the indirect immunofluorescent technique for evidence of antigen from a variety of viruses. The salient findings were; (1) virus antigen was detected in specimens from eleven out of the fifteen cases examined; in the left atria1 biopsy in seven cases and in valve tissue in six cases. (2) Antigen from
December,
1975, Vol. 90, No. 6
Annotatio?w
each of the viruses studied was detected in one or more patients. The most common was echovirus in five cases. (3) Antigen from more than one organism was detected in the same patient on four occcasions. (4) Virus antigens was detected with the same frequency in patients with and without a history of rheumatic fever. Few conclusions are justified on the basis of this small series. It does, however, establish that in patients with acquired valvular disease, as in experimental animals in which valve deformities were induced, invasion of valve tissue by one or more of a variety of viruses may occur. It is also clear as a corollary of this that future studies should not concentrate so exclusively on the Coxsackie group of viruses. Further work is needed to elucidate the significance of virus antigens demonstrated by this study in the valves of patients with valvular heart disease. The high incidence of Coxsackie B antigen in nonvalve-disease patients suggests that synergistic interreactions of different organisms may be involved or that conditioning factors such as operate in experimental animals may also be relevant to man. This will require not only an extension of the preliminary study just outlined, but also an investigation of the basic problems of the pathogenicity of viruses, perhaps particularly with respect in induced autoimmune reactions such as may be involved in the production of established valvular disease. Epidemiological studies are equally important to define the incidence and nature of cardiac involvement in different virus infections. Unfortunately, the mild, often insignificant nature of many virus illnesses makes this difficult and highlights the importance of careful documentation and follow-up of those few cases which are observed. Current work which shows the concept of “rheumatism” as the only significant cause of acquired valvular disease is tenuous, and that many viruses may ultimately come to be implicated demands a less dogmatic approach to this subject than exists at present.
C. Ward, M.B., Ch.B., M.R.C.P. Cardio-Thoracic Department Northern General Hospital Sheffield, S5 ?A U, England REFERENCES 1.
Pearce, filtrable
J. M.:Cardiac virus (virus
Ventricular
III),
lesions in rabbits Arch. Pathol.
tachycardia:
Heart
Journal
3.
4.
5.
6.
7.
8.
9.
10. 11. 12. 13.
14. 15.
Ward, C., and Ward, A. M.: Virus antigen demonstrated in valvular heart disease, Lancet 1:755, 1974. Burch, G. E., and Giles T. D.: The role of viruses in the production of heart disease, Am. d. Cardiol. 29:231. 1972. Pearce, J. M.:Susceptibility of the heart oi the rabbit to specific infection in viral diseases, Arch. Pathol. 34:319, 1942. Burch, G. E., DePasquale, N. P., Sun, S. il., Mogabgah, W. J. and Hale, A. R.: Endocarditis in mice infected with Coxsackie virus B,, Science 15 1:447, 1965, Sun. S. C.. Colcoloueh. H. L.. Burch. G. E.. DePasouale. N. P., and Sohal, R-S.: Immunofluorescent study bf Bi Coxsackie virus valvulitis in mice, Proc. Sot. Exp. Biol. Med. 125:157, 1967. Lou, T. Y., Wenner, H. A., and Kamitsuka, 1’. S.: Experimental infections with Coxsackie viruses. II. myocarditis in cynomolgus monkeys infected with H, virus, Arch Ges Virus Forsch. 10:451, 1960. Sun, S. C., Sohal, R. S., Burch, G. E., Chu, K. C.. and Colcolough, H. L.: Coxsackie virus B, Pancarditis in cynomolgus monkeys resembling rheumatic heart lesions, Br. J. Exp. Pathol. 48:655, 1967. Blailock, Z. R., Rabin, E. R., and Melnick, J. L.: Adenovirus endocarditis in mice, Science 157:69. 1967. Babb. J. M.. Stoneman. M. E. R.. and Stern. H.: Mvocarditis and croup caused’hy Coxsackie virus type B-,“Arrh. Dis. Child. 38:551, 1961. Sainani, G. S., Krompotic, E., and Slodki. S. J.:Adult heart disease due to the Coxsackie virus B infect,ion, Medicine 47:133, 1968. Smith, W. G.: Adult heart disease due to (:oxsarkie virus group B, Br. Heart. J. 28:204, 1966. Verel, D., Ward, C., and Rickards, D. F.: Electrocardiographic changes in A2 England/42/72 influenzae infection in patients treated at home, Proceedings of the British Cardiac Society, Br. Heart J. 38:395, 1974. Burch G. E., and Colcolough, H. L.,: Viral valvulitis. AM. HEART J. 78:119, 1969. Burch. G. E.. Sun. S. C.. Colcoloueh. H. L.. Sohal. R. S.. and DePasquale, N. P.: Coxsackie B viral myocarditis and valvulitis identified in routine autopsy specimens by immunofluorescent techniques, An%. HEART J. 74: 13, ,
.I
1967. 16.
Burch, G. E., Sun, S. C., Chu, Coxsackie virus B myocarditis J. A. M. A. 203:1, 1968.
K. C. et al.: Interstitial and in infants and children,
produced by a 28:827, 1939.
a new
iatrogenic
A prolonged Q-U interval enhancing ventricular tachycardia has been reported in acute myocardial infarction,’ hypokalernia,’ ’ Jervell-Lange-Nielsen syndrome,‘, i Roman0 Ward syndrome”. ’ and during treatment with quinidine,“, o procaineamide,‘“‘I and phenothiazines.“-” Recently, a new iatrogenic possibility has been advanced by Picard, Auzephy, and Chauvin’” who have observed Q-U prolongation, ventricular tachycardia, and related syncopal attacks in patients treated with prenylamine. We’“. ” have also observed five similar cases which confirm this new possibility.
American
2.
possibility
The cases have occurred in patients in which any other known cause of Q-U prolongation failed and who were treated with prenylamine in normal doses (120 to 180 mg. daily). Syncopal attacks produced by recurrent ventricular tachycardias disappeared in a few hours, and Q-U prolongation in a few days after suspension of the drug. Curiously, syncopal attacks and ventricular tachycardia have been described”-‘” only in women of advanced age, while a Q-U prolongation has also been observed in men and in other age groups. Although it is useful that knowledge of this possibility is kept in mind by cardiologists, it must be stressed that its
805
valvular
heart
disease
Virus antigen has been demonstrated in the heart valves of experimentally infected animals’ and of patients with “r&umatic heart disease.“* Much of the evidence which supports the suggestion that ~~~IIES can cause heart disease in man has recently been reviewed.” It is relevant here to concentrate on experimental and clinical studies in which valvular involvement was induced or detected. In 1939, Pearce’ described pancarditis caused by experimental virus III infection in rabbits. Subsequently,’ using a variety of other viruses he demonstrated that the incidence and severity of these changes were increased by pretreatment with one of several “conditioning” processes. These included direct myocardial trauma and the injection of a variety of pharmacologically active reagents which he claimed operated through the common property of inducing myocardial hypoxia. The implications of these findings were overlooked until the impetus of confirmed cases of viral heart disease in man in the 1950’s stimulated fresh interest. Several reports in the 1960’s relating particularly to Group B Coxsackie virus infections described experimentally induced acute and chronic valve lesions in mice5. 6 and monkeys’, “; these occurred frequently and electron microscope studies demonstrated virus particles in valve tissue.” Adenovirus was similarly demonstrated by other workers9 Macroscopically, chronic valve lesions closely resembled “rheumatic heart disease”for example, mitral stenosis with commissural adhesions and chordal contractures. Histologic changes were also similar to those of rheumatic heart disease and included lesions reminiscent of Aschoff bodies? Thus, in experimental animals there is convincing evidence of an association between viruses and valvular heart disease. Early reports of virus heart disease in man usually implicated Coxsackie viruses predominantly of Group B. In neonates, a severe and often fatal myocarditis was noted, older children were less severely affected, and in adults pericarditis usually dominated the clinical picture.‘O Many other viruses have since been described as causes of myocarditis and pericatitis. One of these two features has characterized most reports, but acute valvulitis has been diagnosed or suspected by several observers. Three out of four cases recorded by Babb, Stoneman, and SternlO had systolic murmurs in two of whom it persisted; one had had a transient mitral diastolic murmur. These were infants and there will remain some doubt about attributing the findings to a specific infectious illness. However, the similarity to cases diagnosed clinically as isolated rheumatic carditis is obvious. Sainani, Krompotic, Slodki,” on the other hand, reporting 22 cases of adult heart disease due to Group B Coxsackie viruses noted systolic murmurs in eight cases, in three of whom it was pansystolic and persistent; in one case a mitral diastolic murmur also became established. One of Smith’s’* cases, described as entirely healthy following an insurance medical examination had a febrile illness two weeks later, and subsequently developed atria1 fibrillation, mitral regurgitation, and a mitral diastolic murmur. He had high titers to Coxsackie B, virus. Thus there is evidence that valve lesions may develop during
804
the COU~W of a viral
illness and become established. This evidence is obviously less impressive than in animal studies and it might be concluded from the paucity of such reports that virus-induced valvular disease is, at most, a rarity. This would, however, be premature for other relevant factors have to be taken into account. 1. Little is known of the long-term effects on the heart of mild virus illnesses, although it was recently demonstrated that permanent cardiac damage can certainly result from trivial influenza perhaps in as many as 5 per cent of infected persons.lJ This could have implications for other virus illnesses which might be expected to act similarly, since observed cases form only a small percentage of all infections with most viruses. This is quite different from the situation which pertains to rheumatic fever in which many cases of a clinically severe illness have occurred over the years, thus facilitating detailed study. 2. Animal studies have clearly shown that virus valvulitis is the result of invasion from adjacent myocardium” and that under appropriate circumstances this sequence of events is common. There is no reason to suppose that human heart valves are any different in this respect. Available evidence indicates that a virus which can cause myocarditis can also produce valvulitif3. 3. The concept that valve disease can develop insidiously is generally accepted. Failure to detect valvular involvement during the acute stage of rheumatic fever has been no bar to attributing to it subsequent established valve disease. The infrequency of documented cases of acute virus valvulitis may be, to some extent, a reflection of the general pattern of virus illness rather than an indication that more cases do not occur. It is also likely that the numbers of reported cases will increase as interest in the subject grows. Immunofluorescent t,echniques adapted to detect virus antigen were employed in several of the experimental studies referred to above.“, * Although such methods have to date been used infrequently in man it has, nevertheless, been established that Coxsackie B, virus antigen occurs frequently in the in the absence of clinical human myocardium,‘5. l6 often evidence of cardiac disease. As in clinical reports, the common theme of these investigative studies has been the Coxsackie B group of viruses. This is understandable for available evidence indicates that this organism is the most common cause of overt viral heart disease in man. However, many other viruses are cardiotropic3. 1 and, in our present state of ignorance, warrant similar attention. These broader implications were the subject of a recent preliminary report,Y the first to specifically examine patients with established valvular heart disease for evidence of past viral carditis using immunofluorescent techniques. Left atria1 and/or valve biopsy specimens from 15 cases with acquired valvular heart disease were studied by the indirect immunofluorescent technique for evidence of antigen from a variety of viruses. The salient findings were; (1) virus antigen was detected in specimens from eleven out of the fifteen cases examined; in the left atria1 biopsy in seven cases and in valve tissue in six cases. (2) Antigen from
December,
1975, Vol. 90, No. 6
Annotatio?w
each of the viruses studied was detected in one or more patients. The most common was echovirus in five cases. (3) Antigen from more than one organism was detected in the same patient on four occcasions. (4) Virus antigens was detected with the same frequency in patients with and without a history of rheumatic fever. Few conclusions are justified on the basis of this small series. It does, however, establish that in patients with acquired valvular disease, as in experimental animals in which valve deformities were induced, invasion of valve tissue by one or more of a variety of viruses may occur. It is also clear as a corollary of this that future studies should not concentrate so exclusively on the Coxsackie group of viruses. Further work is needed to elucidate the significance of virus antigens demonstrated by this study in the valves of patients with valvular heart disease. The high incidence of Coxsackie B antigen in nonvalve-disease patients suggests that synergistic interreactions of different organisms may be involved or that conditioning factors such as operate in experimental animals may also be relevant to man. This will require not only an extension of the preliminary study just outlined, but also an investigation of the basic problems of the pathogenicity of viruses, perhaps particularly with respect in induced autoimmune reactions such as may be involved in the production of established valvular disease. Epidemiological studies are equally important to define the incidence and nature of cardiac involvement in different virus infections. Unfortunately, the mild, often insignificant nature of many virus illnesses makes this difficult and highlights the importance of careful documentation and follow-up of those few cases which are observed. Current work which shows the concept of “rheumatism” as the only significant cause of acquired valvular disease is tenuous, and that many viruses may ultimately come to be implicated demands a less dogmatic approach to this subject than exists at present.
C. Ward, M.B., Ch.B., M.R.C.P. Cardio-Thoracic Department Northern General Hospital Sheffield, S5 ?A U, England REFERENCES 1.
Pearce, filtrable
J. M.:Cardiac virus (virus
Ventricular
III),
lesions in rabbits Arch. Pathol.
tachycardia:
Heart
Journal
3.
4.
5.
6.
7.
8.
9.
10. 11. 12. 13.
14. 15.
Ward, C., and Ward, A. M.: Virus antigen demonstrated in valvular heart disease, Lancet 1:755, 1974. Burch, G. E., and Giles T. D.: The role of viruses in the production of heart disease, Am. d. Cardiol. 29:231. 1972. Pearce, J. M.:Susceptibility of the heart oi the rabbit to specific infection in viral diseases, Arch. Pathol. 34:319, 1942. Burch, G. E., DePasquale, N. P., Sun, S. il., Mogabgah, W. J. and Hale, A. R.: Endocarditis in mice infected with Coxsackie virus B,, Science 15 1:447, 1965, Sun. S. C.. Colcoloueh. H. L.. Burch. G. E.. DePasouale. N. P., and Sohal, R-S.: Immunofluorescent study bf Bi Coxsackie virus valvulitis in mice, Proc. Sot. Exp. Biol. Med. 125:157, 1967. Lou, T. Y., Wenner, H. A., and Kamitsuka, 1’. S.: Experimental infections with Coxsackie viruses. II. myocarditis in cynomolgus monkeys infected with H, virus, Arch Ges Virus Forsch. 10:451, 1960. Sun, S. C., Sohal, R. S., Burch, G. E., Chu, K. C.. and Colcolough, H. L.: Coxsackie virus B, Pancarditis in cynomolgus monkeys resembling rheumatic heart lesions, Br. J. Exp. Pathol. 48:655, 1967. Blailock, Z. R., Rabin, E. R., and Melnick, J. L.: Adenovirus endocarditis in mice, Science 157:69. 1967. Babb. J. M.. Stoneman. M. E. R.. and Stern. H.: Mvocarditis and croup caused’hy Coxsackie virus type B-,“Arrh. Dis. Child. 38:551, 1961. Sainani, G. S., Krompotic, E., and Slodki. S. J.:Adult heart disease due to the Coxsackie virus B infect,ion, Medicine 47:133, 1968. Smith, W. G.: Adult heart disease due to (:oxsarkie virus group B, Br. Heart. J. 28:204, 1966. Verel, D., Ward, C., and Rickards, D. F.: Electrocardiographic changes in A2 England/42/72 influenzae infection in patients treated at home, Proceedings of the British Cardiac Society, Br. Heart J. 38:395, 1974. Burch G. E., and Colcolough, H. L.,: Viral valvulitis. AM. HEART J. 78:119, 1969. Burch. G. E.. Sun. S. C.. Colcoloueh. H. L.. Sohal. R. S.. and DePasquale, N. P.: Coxsackie B viral myocarditis and valvulitis identified in routine autopsy specimens by immunofluorescent techniques, An%. HEART J. 74: 13, ,
.I
1967. 16.
Burch, G. E., Sun, S. C., Chu, Coxsackie virus B myocarditis J. A. M. A. 203:1, 1968.
K. C. et al.: Interstitial and in infants and children,
produced by a 28:827, 1939.
a new
iatrogenic
A prolonged Q-U interval enhancing ventricular tachycardia has been reported in acute myocardial infarction,’ hypokalernia,’ ’ Jervell-Lange-Nielsen syndrome,‘, i Roman0 Ward syndrome”. ’ and during treatment with quinidine,“, o procaineamide,‘“‘I and phenothiazines.“-” Recently, a new iatrogenic possibility has been advanced by Picard, Auzephy, and Chauvin’” who have observed Q-U prolongation, ventricular tachycardia, and related syncopal attacks in patients treated with prenylamine. We’“. ” have also observed five similar cases which confirm this new possibility.
American
2.
possibility
The cases have occurred in patients in which any other known cause of Q-U prolongation failed and who were treated with prenylamine in normal doses (120 to 180 mg. daily). Syncopal attacks produced by recurrent ventricular tachycardias disappeared in a few hours, and Q-U prolongation in a few days after suspension of the drug. Curiously, syncopal attacks and ventricular tachycardia have been described”-‘” only in women of advanced age, while a Q-U prolongation has also been observed in men and in other age groups. Although it is useful that knowledge of this possibility is kept in mind by cardiologists, it must be stressed that its
805
