Br Heart jf 1986;56:285-91 Peripartum heart disease: an endomyocardial biopsy study J E SANDERSON,* E G J OLSEN,t D GATEI: From the Departments of Medicine, *St Mary's Hospital Medical School, London; and the tUniversity of Nairobi Medical School, Kenya; and the tDepartment of Histopathology, the National Heart Hospital, London SUMMARY Endomyocardial biopsies were performed in 11 African women in Nairobi who presented with the clinical features of peripartum cardiomyopathy. The samples were studied by light and electron microscopy. In five patients there was evidence of a "healing myocarditis", that is the presence of a mild inflammatory cell infiltration within the myocardium with foci of necrosis and variable amounts of hypertrophy and fibrosis. Of the nine patients who were followed up, three out of four with myocarditis had persistent heart failure and four out of five without myocarditis improved. Peripheral blood T lymphocyte cell subsets were measured in nine patients by means of monoclonal antibodies. A high helper:suppressor T cell ratio was found in three patients. Almost half of this group of patients with peripartum cardiomyopathy had myocarditis in their biopsy specimens. The myocarditis may have been due to an inappropriate immunological reaction in some patients. Postpartum or peripartum heart disease, defined as unexplained cardiac failure occurring during late pregnancy or after childbirth, is a well recognised but rare condition in Europe and North America. It appears to be more common in African women than in white women.1 2 Both the cases in the origi- nal descriptions by Hull and Hafkesbring and Hull and Hidden occurred in black patients,34 and most of the patients in Meadows's major review in 1957 of 50 patients were black Americans.' The condition in East Africa is similar to that described in black Americans and it presents as a typical dilated cardio- myopathy. This resembles cases reported by Brockington6 and others7 in southern parts of Nigeria but is quite different from the condition in northern Nigeria in which the predominant feature is fluid retention and which probably is caused by local postpartum rituals.8 9 Postpartum hyper- tension6 '° and malnutrition" may be contributory factors. Recently three patients with peripartum Requests for reprints to Dr J E Sanderson, Taunton and Somerset Hospital (Musgrove Park), Taunton, Somerset TAI 5DA. Accepted for publication 28 April 1986 cardiomyopathy were found by histological exam- ination of endomyocardial biopsy specimens to have myocarditis. Immunosuppressive treatment resulted in a pronounced clinical improvement. 2 Because of these findings we performed endomyocardial biop- sies on 11 patients in East Africa who presented with features typical of peripartum heart disease. Patients and methods Thirteen patients were identified with peripartum heart disease but in two of these further studies were not possible. The remaining 11 patients who pre- sented with unexplained congestive cardiac failure within six months of delivery were studied further. Full history, examination, echocardiography, and cardiac catheterisation were done on all patients. PATIENTS (TABLE 1) Eleven women of mean (SD) age 27 (6) years were studied further. The mean time of onset of symp- toms after delivery was 7(6) weeks. Parity varied from one to eight with median of three. All patients had symptoms and signs of biventricular cardiac fail- ure and on admission the mean blood pressure was 115 (25)/75 (13) mm Hg. The patients came from all 285 on April 11, 2021 by guest. Protected by copyright. http://heart.bmj.com/ Br Heart J: first published as 10.1136/hrt.56.3.285 on 1 September 1986. Downloaded from
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Br Heart jf 1986;56:285-91
Peripartum heart disease: an endomyocardial biopsystudyJ E SANDERSON,* E G J OLSEN,t D GATEI:
From the Departments of Medicine, *St Mary's Hospital Medical School, London; and the tUniversity ofNairobi Medical School, Kenya; and the tDepartment of Histopathology, the National Heart Hospital,London
SUMMARY Endomyocardial biopsies were performed in 11 African women in Nairobi whopresented with the clinical features of peripartum cardiomyopathy. The samples were studiedby light and electron microscopy. In five patients there was evidence of a "healing myocarditis",that is the presence of a mild inflammatory cell infiltration within the myocardium with foci ofnecrosis and variable amounts ofhypertrophy and fibrosis. Ofthe nine patients who were followedup, three out of four with myocarditis had persistent heart failure and four out of five withoutmyocarditis improved. Peripheral blood T lymphocyte cell subsets were measured in nine patientsby means of monoclonal antibodies. A high helper:suppressor T cell ratio was found in threepatients.Almost half of this group of patients with peripartum cardiomyopathy had myocarditis in their
biopsy specimens. The myocarditis may have been due to an inappropriate immunologicalreaction in some patients.
Postpartum or peripartum heart disease, defined asunexplained cardiac failure occurring during latepregnancy or after childbirth, is a well recognisedbut rare condition in Europe and North America.It appears to be more common in African womenthan in white women.1 2 Both the cases in the origi-nal descriptions by Hull and Hafkesbring and Hulland Hidden occurred in black patients,34 and mostof the patients in Meadows's major review in 1957 of50 patients were black Americans.'The condition inEast Africa is similar to that described in blackAmericans and it presents as a typical dilated cardio-myopathy. This resembles cases reported byBrockington6 and others7 in southern parts ofNigeria but is quite different from the condition innorthern Nigeria in which the predominant featureis fluid retention and which probably is caused bylocal postpartum rituals.8 9 Postpartum hyper-tension6 '° and malnutrition" may be contributoryfactors. Recently three patients with peripartum
Requests for reprints to Dr J E Sanderson, Taunton and SomersetHospital (Musgrove Park), Taunton, Somerset TAI 5DA.
Accepted for publication 28 April 1986
cardiomyopathy were found by histological exam-ination of endomyocardial biopsy specimens to havemyocarditis. Immunosuppressive treatment resultedin a pronounced clinical improvement. 2 Because ofthese findings we performed endomyocardial biop-sies on 11 patients in East Africa who presented withfeatures typical of peripartum heart disease.
Patients and methods
Thirteen patients were identified with peripartumheart disease but in two of these further studies werenot possible. The remaining 11 patients who pre-sented with unexplained congestive cardiac failurewithin six months of delivery were studied further.Full history, examination, echocardiography, andcardiac catheterisation were done on all patients.
PATIENTS (TABLE 1)Eleven women of mean (SD) age 27 (6) years werestudied further. The mean time of onset of symp-toms after delivery was 7(6) weeks. Parity variedfrom one to eight with median of three. All patientshad symptoms and signs of biventricular cardiac fail-ure and on admission the mean blood pressure was115 (25)/75 (13)mm Hg. The patients came from all
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the major tribal groups. Table 2 shows the results ofM mode echocardiography which was carried out onall patients. The mean left ventricular end diastolicdimension was 6-3 (0 6) cm and was greater than thenormal range in all but one patient. The meanfractional shortening was 18(3) % (normal >32).Patient 9 had a left ventricular end diastolic dimen-sion of 5-5 cm, which is just within normal limits, butleft ventricular function was considerably reducedwith a fractional shortening (per cent change indimension) of 19% and she was therefore included inthe study. The left atrium was enlarged in six of 11patients. All the patients had normal mitral andaortic valves, both clinically and on echo-cardiography. The normal values for echo-cardiographic measurements were derived fromnormal subjects studied at Kenyatta NationalHospital; these resembled those in Europeans.
Table 2 Echocardiographic data
LVEDD % A dimensionCase No (cm) (fractional shortening) LA (cm)
LA, left atrial dimension; LVEDD, left ventricular end diastolicdimension; LVESD, left ventricular end systolic dimension.
% a dimension = LVEDD-LVESD.0A ~LVEDD
CARDIAC CATHETERISATIONCardiac catheterisation was carried out on all 11patients. In patient 7 a right heart study only wasundertaken and a right ventricular biopsy specimenwas taken. In all the other subjects left ventricularcatheterisation was carried out by the femoral routeand left ventricular biopsy specimens were taken.The King's bioptome and long sheath techniquewere used, as previously described.1314 At leastthree to four specimens were taken from differentsites in the left ventricle. Two specimens for lightmicroscopy were placed in formol saline andembedded in paraffin. Ribbons of 5jm thick sectionswere stained with haematoxylin and eosin, Miller'selastic, and van Gieson stains. Another whole speci-men was examined by electron microscopy. This wasfixed in cacodylate buffered glutaraldehyde. Afterfixing the specimen for one hour at 4°C, we washedoff the fixative and the specimens were transportedin buffered sucrose solution. They were then postfixed in 1% osmium tetroxide, processed by thestandard technique, and finally embedded in Epon.Sections were cut on an ultra microtome and stainedwith toluidine blue. Ultra thin sections were stainedwith uranyl acetate and lead citrate. In some patientsfrozen sections were also taken for furtherimmunological studies.
T LYMPHOCYTE SUBSETSPeripheral blood T lymphocyte subsets were mea-sured in nine of the 11 patients by means of Orthomonoclonal antibodies to identify the total numberof T cells (OKT3), percentage of helper T cells(OKT4), and suppressor-inducer T cells (OKT8)and hence the helper:suppressor ratios. This hasbeen described in detail elsewhere.'5 The helper:suppressor ratio (OKT4:OKT8) is a measure ofactivity of the immunological system. Routine viralserology, including measurement of Coxsackie Bantibodies, was carried out by standard techniques.
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Fig 1 Photomicrograph of an endomyocardial biopsy specimen from a patient that shows evidenceof healing myocarditis. Myocardial fibres are regularly aligned and show evidence of hypertrophy(pyknosis) of the nuclei. In the interstitium, chronic inflammatory cells are clearly seen in closecontact with adjacent myocardial fibres but there is no damage to the contour of these fibres.Haematoxylin and eosin.
Results
BIOPSY SPECIMENS (FIGS 1, 2, AND 3)Table 3 summarises the biopsy reports. Biopsyspecimens from five patients showed evidence ofhealing myocarditis. This was a mild cellularinflammatory infiltrate, predominantly of lympho-cytes, located in the widened interstitium of themyocardium. Adjacent myocardial fibres showedevidence ofnecrosis (fraying) in some foci.There wasalso a variable but usually mild increase of interstitialcollagen tissue. Perivascular infiltration and a vari-able extent of focal myocytolysis was seen. The myo-cardial fibres were normally aligned and showed evi-dence of hypertrophy and attenuation. Theendocardium was increased in thickness in somecases due to a focal increase of the smooth muscle
component, indicating that left ventricular dilatationhad been present for some time. The remaining sixpatients showed non-specific changes of a hyper-trophied, frequently dilated myocardium, with orwithout mild fibrosis in the interstitium. There wereno changes that could positively be attributed to pastmyocarditis.Nine patients were available for follow up (mini-
mum six months), and three of the four with myo-carditis in their biopsy specimens had persistentheart failure. In contrast four out of the five patientswithout myocarditis made a good recovery.
T CELL SUBSETSTable 4 shows the results in the patients studied.There was a considerable increase in the percentageof helper cells (OKT4). Three of the patients had
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Fig 2 Photomicrograph of a patient with hypertrophy and dilatation of the myocardium but noevidence of myocarditis. These changes are non-specific and are similar to those seen in patientswith dilated cardiomyopathy. Haematoxylin and eosin.
high helper:suppressor ratios. In the patient with thehighest helper:suppressor ratio in the study, how-ever, the biopsy specimen did not show evidence ofmyocarditis.
VIRAL SEROLOGYRoutine testing for the common viruses was negativeand Coxsackie B antibodies were not detected.
Discussion
This is the first study of endomyocardial biopsyspecimens from patients with peripartum heartdisease studied in East Africa. Nearly half thepatients had some evidence of a previous myo-carditis. This diagnosis of myocarditis is based onthe presence of an inflammatory cell infiltrationwithin the myocardium associated with varying
amounts of myocardial fibre hypertrophy, oedema,degeneration, and fibrosis. These changes are oftenmild. Myocarditis is one of the most difficult diag-noses to make on morphological examination,especially in the small tissue samples recovered bybioptome. A group of pathologists met in Dallas in1984 to discuss specifically the problems of myo-carditis (ME Billingham, EG J Olsen, J J FenoglioJr, et al, personal communication). The followingdefinition was formulated: "Myocarditis is charac-terised by an inflammatory infiltrate and by injury toadjacent myocardial cells that is not typical ofinfarction".The commonest finding, however, is a healing
(resolved) form ofmyocarditis which implies that theinflammnatory infiltrate has abated. The interstitiummay be normal or fibrotic. An increase of fibroustissue by itself is insufficient evidence of myocarditis
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Peripartum heart disease: an endomyocardial biopsy studyX
.. - AN
Fig 3 Electronmicrograph showing regular alignment of myocardial fibrils. In the interstitial space, lymphocytes andbundles of collagen can be identified. These changes indicate that the healing phase of myocarditis has been reached.Lead citrate and uranyl acetate.
but the presence of conspicuous chronicinflammatory cells, even on a first biopsy specimen,suggests the possibility of a previous myocarditis.Sampling errors may be a problem because of thesmall size of the samples obtained by bioptome. Ithas, however, been shown that if five or more biopsyspecimens are taken from a ventricle, then thesespecimens probably accurately reflect the rest of themyocardium,16 although the Dallas panel recom-mends a minimum of three specimens, as wereobtained in this study; therefore the presence of focalmyocarditis in the "non-myocarditic" groupremains a possibility.
Before making the diagnosis of peripartum heartdisease we excluded other causes of heart failuresuch as excessive alcohol intake, previous hyper-tension, and other systemic diseases. Coronaryangiography was not done on these young women;their age, sex, and African origin make it highlyunlikely that important coronary artery disease was
present.
The cause of the myocarditis is unknown. It isunlikely to be a direct or persisting viral infection perse. Tests for Coxsackie antibodies and viral serologywere negative in all these patients and there was nosign of viral particles on the electron microscopyspecimens. There are some reports, however, thatcardiomyopathy may on rare occasions follow a viralinfection. 17 18 In most patients with cardiomyopathyand in the patients studied here the disease is clearlynot a straightforward virus myocarditis. The myo-cardial damage may be secondary to an abnormalimmunological reaction. Experimentally, and in theoccasional patient, circulatory antimyocardial anti-bodies, interstitial deposits of immunoglobulins andcomplement, and cytotoxic lymphocytes directedagainst autologous myocytes have been demon-strated.'9 20 It has been suggested that there may bea disturbance of immunoregulation in patients withdilated cardiomyopathy that may be either a primarydefect or may merely reflect a persistent immunereaction to an antigen within the heart muscle, possi-
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bly derived from the previous infection. T sup-pressor cell function is defective in some patientswith dilated cardiomyopathy.3 Our work onpatients with dilated cardiomyopathy in East Africahas shown that the percentage ofhelper inducer cellsin the peripheral blood was significantly higher inthe cardiomyopathy group than in normal individu-als, and eight out of 20 of the patients had ahelper:suppressor cell ratio higher than normalrange.15 These results support the concept that themyocardial damage in dilated cardiomyopathy maybe secondary to an immune reaction against the myo-cardial fibres. In this group of postpartum patients,three had high helper:suppressor ratios. Never-theless, the biopsy specimen from the patient withthe highest helper:suppressor ratio did not show evi-
dence of myocarditis. These T cell data may, how-ever, suggest the involvement of an abnormalimmune reaction in causing the myocardial damagein this type of cardiomyopathy.The question of treatment at the stage of healing
myocarditis remains. In the three patients describedby Melvin etal the myocarditis was much moreflorid and all three patients were treated with immu-nosuppressive drugs and there was a pronouncedimprovement in their symptoms.'2 Demakis andRahimtoola found that about 50%O of patients withpostpartum cardiomyopathy improve spontane-ously, however,22 and four of our patients recoveredalmost completely; one had some slight shortness ofbreath (despite a normal heart size and left ventricu-lar function on the echocardiogram), and anotherdeveloped mild hypertension. It seems best toreserve the more vigorous treatment for those withflorid myocarditis. The presence of healing myo-carditis in the biopsy specimens in our patients wasgenerally associated with persisting heart failure;however, the numbers are too small for any definiteconclusions. It is of some concern that in the veryearly stages, when the virus will still be present,treatment with steroids might encourage persistenceof the virus and impede the immunological reactiondirected at the virus particles themselves.There are several possible explanations ofwhy this
type of cardiomyopathy should develop in the peri-partum period. Firstly, it has been shown that if aviral myocarditis is present increase in the cardiacworkload will increase the degree of myocardial
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Peripartum heart disease: an endomyocardial biopsy study 291damage.23 It may be, therefore, that these womenhad a mild viral myocarditis due to a common viruswhich would have been cleared under normal cir-cumstances, but that the increased workload of preg-nancy and labour led to more myocardial damagethan would otherwise have occurred. Secondly, ifthe disease is due to an abnormal immune reaction toa new virus induced antigen on the myocardialfibres, the immunological changes of pregnancy mayfavour such a reaction. Certain other immunologicaldiseases occur more commonly after delivery, forexample postpartum Graves's disease and thy-roiditis,24 and it appears that the fetus may passsuppressor cells or suppressor factor to the motherduring the third trimester, and a rebound of helperT cells may occur two to six months after delivery25;this is also the most common time for thepresentation of peripartum heart disease. "Block-ing" antibodies may also be involved.26
In conclusion, this study has shown that about halfthe patients in East Africa that we studied by endo-myocardial biopsy had evidence of a healing myo-carditis and that in some this was associated withother indicators of an excessive immune reaction(high T cell helper:suppressor ratios). Thesefindings support the notion that in some cases peri-partum heart disease may be due to myocarditis. Inthe remainder, an explanation other than myo-carditis must be sought.
This study was part of a collaborative programme ofthe Department of Medicine, St Mary's Hospital,London, the University of Nairobi Medical School,and the Clinical Research Centre, Nairobi that wasfunded by the Wellcome Trust and a British HeartFoundation grant.
References
1 Cardiomyopathies; report of a WHO Expert Commit-tee. WHO Tech Rep Ser 697. Geneva: World HealthOrganisation, 1984.
2 Homans DC. Peripartum cardiomyopathy. N Engl JMed 1985;312:1432-7
3 Hull E, Hafkesbring E. "Toxic" postpartal heartdisease. New Orleans Med Surg J 1937;89:550-7.
4 Hull E, Hidden E. Postpartal heart failure. South MedJ 1938;31:265-75.
5 Meadows WR. Idiopathic myocardial failure in the lasttrimester of pregnancy and the puerperium. Circu-lation 1957;15:903-14.
14 Brooksby IAB, Swanton RH, Jenkins BS, Webb-Peploe MM. Long sheath technique for introductionof catheter tip manometer or endomyocardialbioptome into left or right heart. Br Heart J1974;36:908-12.
15 Sanderson JE, Koech D, Iha D, Ojiambo HP. T-lymphocyte subsets in idiopathic dilated cardio-myopathy. Am J Cardiol 1985;55:755-8.
16 Baandrup U, Florio RA, Olsen EGJ. Do endomyo-cardial biopsies represent the morphology of the restof the myocardium? A quantitative light microscopicstudy of single versus multiple biopsies with theKing's bioptome. Eur Heart J 1982;3:171-8.
17 Obeyesekere I, Hermon Y. Arborvirus heart disease:myocarditis and cardiomyopathy following dengueand chikungunya fever-a follow-up study. AmHeart J 1973;85:186-94.
18 Cambridge G, MacArthur CGC, Waterson AP, Good-win JF, Oakley CM. Antibodies to Coxsackie Bviruses in congestive cardiomyopathy. Br Heart J1979;41:692-6.
19 Kawai C, Takatsu T. Clinical and experimental studieson cardiomyopathy. N Engl J Med 1975;293:592-7.
20 Anonymous. Virus, immunology and the heart. Lancet1979;ii:1 111-3.
21 Fowles RE, Beiber CP, Stinson EB. Defective in vitrosuppressor cell function in idiopathic congestive car-diomyopathy. Circulation 1979;59:483-91.
23 Woodruff JF. Viral myocarditis. A review. Am J Pathol1980;101:425-84.
24 Amino N, Mori H, Iwatani Y, et al. High prevalence oftransient postpartum thyrotoxicosis and hypo-thyroidism. N Engl Y Med 1982;306:849-52.
25 Froelich CJ, Goodwin JS, Bankhurst AD, WilliamsRC. Pregnancy, a temporary fetal graft of suppressorcells in autoimmune disease? Am J Med 1980;69:329-31.
26 Faulk WP, Johnson PM. Immunological studies ofhuman placentae: basic and practical implications.In: Thompson RA, ed. Recent advances in clinicalimmunology. Vol. II. Edinburgh: Churchill Liv-ingstone, 1980;1-31.
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