Tissue Antigens (1976), 7, 227-231 Published by Munksgaard, Copenhagen, Denmark No part may be reproduced by any process without written permission from the authorfs)

HLA Antigens and Acquired Valvular Heart Disease C. Ward', K. Gelsthorpe', R. W. Doughty2 and C. A. Hardisty Cardiothoracic Unit, Northern General Hospital, Sheffield; and the Regional Blood Transfusion Centre, Longley Lane, Sheffield, England The frequency of HLA antigens was determined in 133 patients with acquired valvular heart disease and compared with the frequency of HLA antigens in 1,000 normal individuals by the relative incidence ratio method of Woolf ( 1955). N o significant increases were observed. However, when the patients were divided into those with no rheumatic history and those who have had rheumatic fever or chorea, a significant increase in AW 30/3 1 and A29 was observed in the group with no rheumatic history. Received for publication 27 October, accepted 1 December 1975

Several antigens of the HLA system have been associated with diseases which are thought to have an immunological basis and in which there is a high familial incidence (British Medical Journal 1975). Associations have also been reported with diseases of proven (Morris & Pietsch 1973), o r suspected (Arnason et al. 1974) viral aetiology. In this study we have determined the patterns of HLA antigens in patients with acquired valvular heart disease. There are three reasons for suspecting that such a study might provide useful information:

1) An abnormal immunological response has been implicated in the pathogenesis of rheumatic heart disease (Kaplan 1965) and genetic factors at least partly explain the occurrence of familial cases of rheumatic fever (Wilson & Schweitzer 1954). Thus, by analogy, it might be anticipated that patients with rheumatic heart disease would possess a recognisable pattern of HLA antigens. 2) In addition (or alternatively), determination of HLA antigens in these patients might provide evidence in support of the

' Currently in receipt of British Heart Foundation research Grant No. 496

* In receipt

of a Medical Research Grant from the Trent Regional Health Authority.

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WARD ET. AL

suggestion (Burch et al. 1970) that all acquired valvular heart disease is not rheumatic. Approximately 50% of patients with acquired valvular heart disease are assumed to have had subclinical rheumatic carditis because they have no history of rheumatic fever or chorea. It is possible that at least some of these cases do not have a rheumatic aetiology. A different pattern of HLA antigens in two groups of patients with acquired valvular disease - those with, and those without a rheumatic history - would support this concept. 3) With regard to the work of Falk et al. (1973), there was a suggestion that the incidence of A3 might be decreased; and a possible excess of individuals homozygote for HLA antigens in patients with rheumatic fever and rheumatic heart disease.

Materials and Methods Patient Sdection a) One hundred and thirty-three patients with acquired valvular heart disease attending the cardiothoracic unit, Northern General Hospital, Sheffield, were studied. Each had rheumatic heart disease, i.e. mitral stenosis, mitral stenosis with regurgitations or mitral and aortic valve disease. The diagnosis of valve lesions was initially based upon clinical examination but in the majority of cases was subsequently confirmed or supported by findings at cardiac catherisation or open heart surgery. Patients were divided into two subgroups: those who could recall having had rheumatic fever fever or chorea and those with no rheumatic history.

c) Techniques of HLA typing: A lymphocytotoxic technique (Gelsthorpe & Doughty 197 1) was carried out on patients' lymphocytes, obtained from heparinised peripheral blood samples, usually within 24 h of collection. T h e antisera used were well characterised and in line with the International Workshop antigens. Twelve first segregant series antigens and 15 second segregant series antigens were defined.

d) The statistical method used was the relative incidence analysis of Woolf (1955) as discussed by Svejgaard et al. (1974). Results Table 1 shows the data obtained in this study with regard to all the patients with acquired valvular heart disease (133), there are no significant differences (at the P = 0.05 level) between these and the controls. In the group of 75 patients who had a history of rheumatic fever, there is an increasing incidence of HLA antigens A2 (X2 = 5.5, P = 0.025 and B12 (X2 = 3.8 P = 0.05). When these values are multiplied by the number of factors being investigated, i.e. 27, they are no longer significant. In the group of 58 patients who, despite having acquired valvular heart disease, had no history of rheumatic fever, there is an increased incidence of antigens AW30131 (X2 = 5.67, P = 0.025 - 0.01) and A29 (X' = 8.3, P = 0.05 - 0,001)" Discussion The results of this study show that when patients with rheumatic heart disease are considered as a single group the pattern of HLA antigens is similar to that of the gen-

b) Control group: This consisted of 1,000

random blood donors. All patients and members of the control group were Caucasian.

* When corrected for the number of antigens tested P = 0.115 - 0.027. AW30/31 and A29 belong to the large A w l 9 cross-reacting group.

30.8 54.1 32.3 19.5 3.7 3.0 14.3 3.7 6.0 1.5 9.8 9.8

36.3 47.1 29.7 17.3 3.1 5.6 12.6 5.9 4.7 1.9 6.9 5.7

9.7 27.0 29.9 28.0 3.9 8.3 15.0 9.7 13.5 13.0 3.7 6.0 8.1 1.1 2.8

AW26 A1 1 A28 AW30l31 AW33 AW32 A29

HLA-B B5 B7 B8 B12 B 13 B27 BW15 BW17 BW35 BW40 BW22 B14 B18 BW21 BW37

8.3 32.3 26.3 36.1 4.5 10.5 9.8 9.0 11.2 11.2 4.5 6.8 7.5 2.2 2.2

Relative incidence

w

w

0.839 1.291 0.837 1.452 1. t64 1.299 0.613 0.923 0.814 0.850 1.229 1.137 0.922 2.07 0.801

0.782 1.325 1.130 1.161 1.221 0.522 1.156 0.623 1.297 0.788 0.863 1.792

n =133

n = 1000

0.2791 1.647 0.7277 3.674 0.1094 0.7398 0.2789 0.0625 0.5062 0.3152 0.21 1 1 0.1257 0.0544 0.1222 0.1309

1.527 2.248 0.3812 0.4022 0.1650 1.5277 0.2767 0.9937 0 4176 0.1001 0.1458 3.2662

X2

Acquired valvular heart disease (a +b)

Normal control

12.0 5.3 13.3 14.7 8.0 8.0 9.3 2.6 2.6

8.0

6.7 32.0 25.3 38.7 4.0

30.7 61.3 33.3 21.3 4.0 1.3 16.0 4.0 1.3 1.3 6.7 5.3

%

~

0.664 1.272 0.795 1.621 1.026 0.960 0.772 0.524 0.985 1.150 1.084 1.362 1.167 2.46 0.95 1

0.776 1.781 1.183 1.296 1.302 0.227 1.321 0.664 0.274 0.697 0.063 0.932

Relative incidence

~

n =75

~

~~

~

0.74 0.86 0.6999 3.81 0.00 1 0.0085 0.51 1.525 0.0018 0.17 0.016 0.475 0.145 1.339 0.004

0.959 5.5181 0.422 0.751 1 0.180 2.22 0.71 18 0.495 1.61 0.1215 0.006 0.017

xp

Acquired valvular heart disease with a history of rheumatic fever or chorea (a)

10.3 32.7 27.6 32.7 5.2 13.8 6.9 13.8 8.6 6.9 5.2 5.2 5.2 1.7 1.7

31.0 44.8 31.0 17.2 3.4 5.2 12.1 3.4 12.1 1.7 5.2 15.5

%

1.074 1.317 0.893 1.252 1.344 1.767 0.419 1.489 0.604 0.495 1.419 0.854 0.6188 1.577 0.609

0.7896 0.912 1.065 0.995 1.116 0.919 0.952 0.569 2.783 0.905 0.735 3.038

Relative incidence

n = 58

0.0233 0.927 0.141 0.557 0.226 2.061 2.743 1.016 1.129 1.796 0.324 0.067 0.631 0.188 0.1 156

0.665 0.1 15 0.0455 0.00019 0.02333 1.928 0.014 0.594 5.67 0.0093 0.258 8.262

X2

Acquired valvular heart disease with no history of rheumatic fever (b)

~~

-~

Table 1 Relative incidence of HLA antigens acquired in valvular heart disease with and without a history of rheumatic fever

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WARD ET. AL.

era1 population. However, when examined in two groups, defined by the presence or absence of a rheumatic history, a significantly higher incidence of AW30131 and A29 antigens is found in those who have no history of rheumatic fever. In this series the frequency of A3 was not disturbed neither was there an excess of homozygotes for HLA in the groups tested. Some inaccuracy is inevitable when dependence is placed on the patients recollection of previous rheumatic fever - some will have forgotten a rheumatic attack and in others, a childhood illness may have been incorrectly diagnosed as rheumatic - but such errors are unlikely to account for the differences shown. Nevertheless, because of the danger of sampling errors in a project of this size, conclusions based on the differences shown must be guarded. With this proviso it is reasonable to suggest that the observed differences could be accounted for in one of two ways, either 1 ) All patients have genuine rheumatic disease. If this is the case, the implication of the results is that possession of some of the A w l 9 antigens predisposes the patient to have subclinical (as opposed to overt) rheumatic carditis; or 2) Some patients with no rheumatic history may have valvular disease of a non-rheumatic aetiology. It has been argued that a different incidence of HLA antigens B13 and BW17 in patients with pustular psoriasis and psoriasis vulgaris bespeaks two different aetiologies (Svejgaard et al. 1974).The same conclusion was proposed for a similar reason with respect to juvenile and maturity onset diabetes (Nerup et al. 1974). This interpretation can also be applied to the findings of the present study; the possession of W19 antigens may be a factor which increases the chances of developing non-rheumatic acquired valvular disease. These antigens perhaps define a subgroup of the cases with no rheumatic history which have a common aetiology.

There is evidence that viruses and similar organisms can cause (non-rheumatic) acquired valvular heart disease in experimental animals (Pearce 1939) and in man (Burch 8c Giles 1972). However, there is no acceptable explanation for the fact that cases of apparent viral valvular disease in man are rare compared with the known frequency of human infections with the incriminated viruses. In experimental animals known conditioning factors enhance the cardiotropism of viruses (Pearce 1939). Certain HLA antigens may play a similar role in man analogous to the proposal that antigens HLA, A3 and HLA, B7 appear to increase the neurotropism of poliovirus (Morris & Pletsch 1973). This possibility could readily be studied by examining the HLA antigens patterns in patients with, for example, Coxsackie virus group B myocarditis. The finding of a high incidence of antigens AW30131 and A29 confined to the group of patients with no history of rheumatic fever is more in keeping with there being t w o or more aetiologies for acquired valvular heart disease than with a single rheumatic aetiology. References Arnason, B. G., Fuller, T. C. & Lehrich, J.R. ( 1 974) Histocompatibility types and measles antibodies in multiple sclerosis and optic neuritis. J . neurol. Sci. 22, 419-428. British Medical Journal (1975) Editorial. 2, 238. Burch, G. E., Giles, T. D. & Colcolough, H. L. (1970) Pathogenesis of “rheumatic” heart disease and theory. Heart J . 80, 556-561. Burch, G. E. & Giles, T. D. (1972) The role of viruses in the production of heart disease. J. Cardiol. 29, 231-240. Falk, J. A,, Fleischman, J. L., Zabriskie, J. B. 8c Falk, R. E. (1973) A study of HLA antigen phenotype in rheumatic fever and rheumatic heart disease patients. Tissue Antigens 3, 1 73- 178. Gelsthorpe, K. & Doughty, R.W.(1971) An easily produced microcytotoxic plate with a further modification of the standard microcytotoxic technique for lymphocyte typing. Med. Lab. Techn. 28, 22-25.

HLA ANTIGENS A N D ACQUIRED VALVULAR HEART DISEASE

Kaplan, M. H. (1965) Induction of autoimmunity to heart in rheumatic fever by antigen(s) crossreactive with heart. Fed. Roc. 24, 109-1 12. Morris, P. J. & Pletsch, M. C. (1973) A possible association between paralytic poliomyelitis and multiple sclerosis. Lancet ii, 847-8. Nerup, J., Platz, P. & Anderson, 0. 0. (1974) HLA antigens and diabetes mellitus. Lancet i, 864-866. Pearce, J. M. (1939) Cardiac lesions in rabbits produced by a filtrable virus (Virus 111). Arch. Path. 28, 827-845. Svejgaard, A., Jersild, I., Staub Nielsen, L. Ek Bodmer, W. F. (1974) HLA antigens and disease. Statistical and genetical considerations. Tissue Anttgens 4, 95-105.

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Wilson, M. G. & Schweitzer, M. (1954) Pattern of hereditary susceptibility in rheumatic fever. Circulation 10, 699-704. Woolf, B. (1955) On estimating the relation between blood group and disease. Ann. hum. Genet. 19, 251-253.

Address: K. Gelsthorpe National Blood Transfusion Service Regional Transfusion Centre Longley Lane Sheffield S5 7JN, U.K.

HLA antigens and acquired valvular heart disease.

Tissue Antigens (1976), 7, 227-231 Published by Munksgaard, Copenhagen, Denmark No part may be reproduced by any process without written permission fr...
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