COXSACKIE INFECTION AND MYOCARDIAL INFARCTION

1200 will hnd sucn a difference easier to demonstrate if they different method for analysing their data. The information on matching allows them to do a paired t test, which ought to give a higher level of significance than the unpaired test which they used. Secondly, which components of the diet, if any, have long-term effects on the H.D.L. concentration? It is this criterion, rather than the food’s effect on L.D.L. level, which should be used to search for the dietary contributor to

COXSACKIE INFECTION AND MYOCARDIAL INFARCTION

leagues use a

C.H.D.

,

M.R.C. Dunn Nutrition Unit, University of Cambridge and Medical Research Council, Cambridge CB4 1XJ

T.

J. COLE

SIR,-The report from the Troms0 Heart Study has impor-

implications for our understanding of the role of diet in the causation of coronary heart-disease (C.H.D.). Epidemiological studies have shown that dietary constituents other than cholesterol and saturated fats are associated with an increased incidence of C.H.D.l and there has been persistent but minority support for the theories of Yudkinzand Cleave3 that sucrose or sucrose and other refined carbohydrates are the major dietary factors influencing the development of C.H.D. As long as raised plasma-total-cholesterol was thought to be the major risk factor in C.H.D. it was natural to concentrate upon those dietary constituents (cholesterol and saturated fat) which most strongly influence plasma-cholesterol. Sucrose and other carbohydrates have a smaller and variable effect on plasmacholesterol. However, if the evidence of the Troms0 Heart Study is correct-namely, that lowered plasma high-densitylipoprotein (H.D.L.) cholesterol concentrations are three times more predictive of C.H.D. than are raised lower-density-lipoprotein cholesterol levels or raised total cholesterol levels.-then those dietary factors which affect plasma-H.D.L.-cholesterol are likely to be the most important dietary factors in the pathogenesis of C.H.D. Three small studies4-6 have shown that diets high in carbohydrates (refined carbohydrates were used) and low in fat cause a lowering of plasma-H.D.L.-cholesterol in normal subjects with only smaller and variable changes in total cholesterol. This evidence, if confirmed, suggests that the role of sucrose and refined carbohydrate in C.H.D. is more important than most workers have assumed. Furthermore I would like to suggest a way in which dietary carbohydrate, fat, and cholesterol may interact in the pathogenesis of C.H.D. A diet high in sucrose or refined carbohydrates, by lowering plasma-H.D.L.-cholesterol, would impair the body’s ability to mobilise cholesterol from the arterial wall.’ In the presence of such a diet, small changes in dietary cholesterol and saturated fat may well have a greater influence on the development of C.H.D. than small changes in dietary carbohydrate. On the other hand, a diet low in sucrose and refined carbohydrate would permit a high cholesterol and fat intake without risk of C.H.D. This may be the factor operating in Eskimos,8 for example, rather than the polyunsaturated-fat content of their diet. These points need to be resolved urgently: before the population is urged to change its diet we must know which advice is correct. tant

Engineering Division, Department of Mechanical Engineering, University of Guildford, Guildford GU2 5XH, Surrey Biomedical

1. 2. 3. 4. 5. 6. 7. 8.

Shaper, A. G., Marr, J. W. Br. med. J. 1977, i, 867. Yudkin, J. Proc. Nutr. Soc. 1972, 31, 331. Cleave, T. L. The Saccharine Disease. Bristol, 1974. Schonfeld, G., and others. Metabolism, 1976, 25, 261. Wilson, D. E., Lees, R. S. J. clin. Invest. 1972, 51, 1051. Levy, R. I., and others. ibid. 1966, 45, 63. Miller, G. J., Miller, N. E. Lancet, 1975, i, 16. Bang, H. O., and others. ibid. 1971, i, 1143.

E.

J. EVANS

SIR,-Dr Nicholls and Dr Thomas (April 23, p. 883) suga relation between Coxsackie-B-virus infection and myocardial infarction. I and my colleagues have also found Coxsackie-B-virus infection in patients with myocardial infarction,!’! but not as frequently as Dr Nicholls and Dr Thomas. Considering as positive only those patients with a fourfold or greater rise in titre, we found that 41 (7-1%) of 573 patients with myocardial infarction had evidence of an active virus infection but only 6 gave a history of a preceding "fiu" like illness.3 It is doubtful whether recent or concomitant Coxsackie infection should be diagnosed on the basis of two fixed titres, no matter how high. Once raised, titres do not generally fall significantly, even over long periods, and they can give little indication of the date of the original infection. We have observed considerable variation in the number of cases with active infection from month to month, presumably due to alterations in the level of the infection in the community at large. The high rate reported in Sussex could be due to an epidemic, but this would not explain the complete absence of infection in the patients without myocardial infarction; it will be interesting to see whether this rate is maintained over a

gest

longer period. 15 Parry Street, Fremantle 6160,

J. D. WOODS

Western Australia.

SIR,-Dr Nicholls and Dr Thomas report an association between recent Coxsackie-B-virus infection and clinical myocardial infarction. In the only death, a limited necropsy was reported as infarction. This study is similar to that of Woods et awl. Also, infarction has been reported in the young after upper-respiratory-tract illnesses,and a case of intarction without coronary obstruction was attributed to giant-cell myocarditis.6 These cases may provide a clue to the pathogenesis of myocardial infarction by focusing attention on the injured myocardium. The myocardium has been indicted as primary in infarction, damage being related to metabolic disturbances secondary to stenotic coronary arteries,7 and I have suggested8.9 that infarction is due to myocardial injury secondary to chronic ischaemia causing coronary-artery spasm (injury vasospasm). While stenotic coronary disease probably is the most common cause of myocardial injury which precipitates spasm, other agents damage the heart. The Coxsackie virus causes significant myocardial damage,10 and Selyell,12 has listed several agents which injure the myocardium. Infarction without coronary obstruction has followed chest injury" and toxic cardiomyopathy.14 Also, infarcts are age dependent, and ageing itself results in myocardial changes.15 1.

Woods, J. D., Nimmo, M. J., Mackay-Scollay, E. M. Med. J. Aust. 1973, ii,

2.

Woods, J. D., Nimmo, M. J., Mackay-Scollay, E. M. Am. Heart J. 1975, 89,

573.

283. 3. Woods, J. D., Nimmo, M. J.,

press). 4. Woods, J. D., Nimmo,

M.

Mackay-Scollay,

E. M. Am.

Heart J. (in the

J., Mackay-Scollay, E. M. Am. Heart J. 1975, 89,

283. 5. Burch, G. E., Shewey, L. L. ibid. 1976, 92, 11. 6. Soyannwo, M. A. O., Abioye, A. A., Abiose, P. A., Akinkugbe, O. O. Nigerian med. J. 1975, 5, 280. 7. Anderson, T. W. Lancet, 1970, ii, 753. 8. Hellstrom, H. R. Perspect. Biol. Med. 1973, 16, 427. 9. Hellstrom, H. R. Am. Heart J. (in the press). 10. Burch, G. E., Harb, J. M., Hiramoto, Y. Hum. Path. 1975, 6, 120. 11. Selye, H. The Chemical Prevention of Cardiac Necroses. New York, 1958 12. Selye, H. Am J. Cardiol. 1970, 26, 289. 13. Harthorne, J. W., Kantrowitz, P. A., Dinsmore, R. E., Saunders, C. A. Ann. intern. Med. 1967, 66, 341. 14. Regan, T. J., Wu, C. F., Weisse, A. B., Moschos, C. B., Ahmed, S. S., Lyons, M. M. Circulation, 1975, 51, 453. 15. Frolkis, V. V., Bogatskaya, L. N., Stupina, A. S., Shevchuk, V. G. Am.

Heart J. 1977, 93, 334.

1201 evidence of the association between corand infarction," and the therapeutic imonary-artery spasm a vasospastic cause of infarction suggests that a of plications high priority should be given to the elucidation of the role of spasm in this disorder. If infarction is due to spasm, vasodilator therapy might relieve ischsemia during the acute attack, and with prompt therapy, might prevent muscle necrosis. Most importantly, about a half of all heart-attacks are fatal before the patient reaches hospital, and recognition of a vasospastic origin might permit therapy for high-risk individuals, especially those with prodromal symptoms, thus preventing sudden death or infarction. There is

growing

Laboratory Service, Veterans Administration Hospital, Pittsburgh, Pennsylvania 15240, U.S.A.,

and School of Medicine, University of Pittsburgh

H. RICHARD HELLSTROM

ANTIBODY RESPONSE TO MEASLES VIRUS IN SUBACUTE SCLEROSING PANENCEPRALITIS

SIR,-Dr Kiessling and his colleagues (Feb. 12. p.324) found high levels of measles-virus-specific IgM antibodies in the serum and cerebrospinal fluid (C.S.F.) of all of twenty patients with subacute sclerosing panencephalitis (S.S.P.E.). We began a similar study a year ago and summarise here the results obtained so far. We used a solid-phase radioimmunoassay (R.I.A.) in which purified measles virions were adsorbed on polystyrene balls.’ In acute measles-virus infection measlesspecific IgM concentrations rose rapidly then tell so that less than 10% of patients still had measles-specific IgM antibodies 3 months after infection.z Of twelve s.s.P.E. patients, only two were positive for measles-specific IgM antibodies: one had this IgM in serum only while the other was positive in both serum and c.s.F. A series of serum/c.s.F. paired specimens was available from the second positive patient, and the initially high measles IgM titre tell to below detectable levels during a 1-year follow-up. The IgM class rheumatoid-factor status of the two measles-IgM positive patients has not yet been ascertained. All twelve S.S.P.E. patients were highly positive in all serum and c.s.F. specimens for measles-specific IgG antibodies (measured

by R.i.A.). Although

details of the R.I.A. technique used by Kiessling et given, we believe that the difference between our findings may be methodological. The specificity of the 1251-labelled anti-human- indicator antibodies used is especially important. A single immunoprecipitation line in an ordinary Ouchterlony test does not guarantee a similar specificity in the much more sensitive R.I.A. We have found that commercially available "monospecific" anti-human-V antisera still contain antibodies which react with human IgG in our R.I.A. system, even though these antisera seem specific for IgM on immunodiffusion and immunoelectrophoresis. Consequently, we repeatedly adsorb commercially obtained antihuman-µ antiserum with human IgG coupled to ’Sepharose’ until, under R.LA. conditions, the iodinated anti-humanshows no reactivity with measles IgG positive, but IgM negative sera. Only then will false-positive IgM R.I.A. results be avoided. The type of antigen used in the measles IgM antibody R.I.A. is also important. We find that the best results are obtained with purified virus. When we used antigens prepared for the measles complement-fixation test, as Kiessling et al. did, measles-IgM-positive sera dropped in titre by 2 or 4 fold. Such infected cell-lysate antigen preparations, however, work equally well in our measles IgG antibody R.I.A.’ Our R.I.A. method is 20-1000 times more sensitive than conal.

13.

were not

Wiener, L., Kasparian, H., Duca, P. R., Walinsky, P., Gottlieb, R. S., Hankel, F., Brest, A. N. Am. J. Cardiol. 1976, 38, 945. 1. Arstila, P., Vuonmaa, T., Kalimo, K., Halonen, P., Viljanen, M., Granfors. K., Toivanen, P. J. gen. Virol. 1977, 34, 167. 2. Vuorimaa, T. Unpublished.

ventional serological techniques. With this test system, we have found that approximately 80% of people having measles IgG antibodies in their serum also have such antibodies in their C.S.F.’ This finding was not surprising since the normal serum/c.s.F. antibody ratio is 200 to 400.4 Provided the blood/brain barrier is intact, only patients having low serum antibody titres would be expected to be negative for similar antibodies in their C.S.F. In contrast Kiessling et al. tbund no measles IgG antibodies in the c.s.F. of the 26 control patients tested even though all were serum positive for measles IgG antibodies. This finding is unexpected since Kiessling et al. report that their R.I.A. is 60-10 000 times more sensitive than the measles haemagglutination-inhibition test. We believe that a measles-specific IgM response occurs at some stages of S.S.P.E., at least in some patients, as indicated by Thomson et al. It does not seem to happen in all patients at all stages of the disease, as reported by Kiessling et al. Wellcontrolled test systems are necessary and longitudinal series of serum and c.s.F. specimens trom the same patients are needed betbre the questions of incidence and persistence of IgM class antibodies to measles virus in S.S.P.E. can be answered. PEKKA HALONEN MARJA-TERTTU MATIKAINEN AIMO SALMI TERJO VUORIMAA BARRY R. ZIOLA

Neurovirology Study Group, Department of Virology, University of Turku 20520 Turku 52, Finland

***This letter has been shown

to

Dr

ter

Meulen and his col-

leagues, whose reply follows.-ED. L. StR,—Dr Halonen and his colleagues agree that a measlesspecific IgM response can occur in S.S.P.E. However, in contrast to our findings, they found measles-specific IgM in only a few of their S.S.P.E. specimens. Dr Halonen and his colleagues believe that the methods used to detect measles-specific IgM antibodies could account for these differences, and they make three points: Specificity of 1251-p.-chain specific antihuman IgM antibodies.-As we said in our paper the specificity of this antiserum is crucial. Our antiserum was specially prepared by the research laboratory of Behringwerke, Marburg, Germany, and had been thoroughly tested for specificity; it is not commercially available. The antiserum had been treated by column chromatography until no cross-reaction with IgG could be detected, even by sensitive radioimmunoassay (R.I.A.). In our test system this antiserum did not cross-react with measles-specific IgG fraction of either serum without specific IgM obtained from late measles convalescent patients or acute measles serum which had been fractionated by protein A treatment.

Type of measles antigen used in R.IA.-We have included measles-infected cell lysates as well as purified measles virus (Woodfolk, a wild virus strain) as antigens to coat microtitre wells for our studies. In our assay system purified measles-virus antigen was not a better antigen than infected cells because a control antigen is needed for a reliable assay and it is difficult to obtain such a control antigen for highly purified measles virus. In our assay’ each serum dilution is tested on wells coated with virus antigen (infected cell extracts) as well as control antigen (uninfected cell extracts) to obtain a correct antibody-binding ratio (A.B.R.). Major differences in the amount of protein between the specific and control antigen preparation will non-specifically affect the A.B.R. and influence the results. The sensitivity of an R.I.A. depends on the antigen/antibody 3. Kalimo, K.O.K., Marttila, R., Ziola, B. R., Matikainen, M.-T. J. med. Microbiol. (In the press). 4. Norrby, E., Link, H., Olsson, J.-E. Archs Neurol. 1974, 30, 285. 5. Thomson, D., Connolly, J. H., Underwood, B. O., Brown, F. J. clin. Path. 1.

1975, 28, 543. L. L., Loh, W.,

Yung, L. press).

ter

Meulen,

V. Med. Microbiol. Immun.

(in

the