Postgraduate Medical Journal (May 1975) 51, 286-290.

Transvenous endomyocardial biopsy-application of a methodfor diagnosing heart disease

PHILIP CAVES* JOHN COLTARTtF.R.C.S. M.D., M.R.C.P.

MARGARET BILLINGHAM ALAN RIDERM.B., B.S. M.D.

EDWARD STINSONM.D.

Divisions of Cardiology and Cardiovascular Surgery, Stanjord University Medical Center,Stanford, California

IntroductionAlthough biopsy of the kidney, liver, and many

other organs is routine in clinical medicine, biopsyof the heart is infrequently performed. In con-sequence, little is known of the serial histologicalchanges which occur in non-fatal myocardial disease.Published techniques for obtaining myocardialbiopsies have included percutaneous needle biopsyof the left ventricle, catheter needle biopsy of theinterventricular septum, and open thoracotomy.The associated morbidity and mortality with thesemethods have precluded their widespread acceptance(Shirey et al., 1972).

Transvenous biopsy of the endomyocardium ofthe right or left ventricle using a catheter forceps wasfirst described 13 years ago by Sakakibara andKonno in Japan (1962). Despite the availability ofthe Konno-Sakakibara bioptome in this country,there have been few reports of its use outside Japan.In 1972, a modified Konno-Sakakibara bioptomewas first used at Stanford to obtain biopsies fromthe dog heart after orthotopic cardiac transplanta-tion. For the first time it was possible to correlatethe day-by-day changes in graft histology withindirect parameters of graft function such as theelectrocardiogram. It was soon demonstrated thathistological examination of the biopsy specimenspermitted an accurate assessment of the recipientdog's immune response to the donor heart. Serialbiopsies of the transplanted heart could thus beused to monitor acute cardiac allograft rejection,and a technique was developed for the performanceof repeated cardiac biopsy in the dog via the external

* Present address: Department of Cardiovascular Surgery,Royal Infirmary Edinburgh, Scotland.

t Present address: Cardiac Department, St Thomas'sHospital, London.

jugular vein (Caves et al., 1973a). Subsequently,development of a technique for percutaneous intro-duction of the biopsy forceps into the internal jugularvein in man provided the means by which serialendomyocardial biopsies could be obtained fromthe human heart (Caves et al., 1973b).

This paper describes the technique and instrumentdeveloped at Stanford which have been used for theperformance of over 500 cardiac biopsy procedures.

The instrument and biopsy techniqueThe cardiac biopsy instrument is illustrated in

Fig. 1. Opening and closing the instrument handleat one end of the flexible catheter controls the posi-tion of the jaws at the other end. The jaws are con-structed from steel and consist of one fixed and onemobile part, each of which ends in a hollow cup15 mm in diameter. The edges of the cup aresufficiently sharp to provide removal of the specimenby cutting action rather than avulsion. The lengthof the catheter is 50 cm.The biopsy forceps are introduced percutaneously

(Fig. 2) under local anaesthetic. A 16 Medicutcannula is inserted directly into the right internaljugular vein. A flexible guidewire is inserted throughthe cannula and a 9F Desilets-Hoffman false catheterand sheath are passed over the guidewire into thevein. After removal of the guidewire and falsecatheter, the biopsy forceps are introduced throughthe sheath and the rubber plug is inserted into theluerlok connection on the sheath to prevent leakageof blood. The forceps are advanced to the apex ofthe right ventricle under fluoroscopic control (Fig. 3).The open jaws of the instrument are easily pressedagainst the endomyocardium from this approach,since the catheter has only a gentle curve in it where

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Transvenous endomyocardial biopsy 287

a

FIG. 1. (a) The Caves-Schulz-Stanford cardiac biopsyforceps; (b) close-up view of the jaws.

it passes through the tricuspid valve. The jaws areclosed and the instrument is withdrawn steadily. Aslight jerk occurs as a biopsy specimen is removedfrom the endomyocardium. After removal of thebiopsy specimen from the jaws of the instrument,the forceps may be reintroduced to obtain furtherspecimens as necessary. Finally, the patient ispositioned upright and the sheath is removed fromthe vein while pressure is applied over the puncturesite. Bleeding is, thus, immediately controlled andthe vein remains patent for subsequent use. Thebiopsy procedure may be completed within 5 min,using only a few seconds of fluoroscopy time.The electrocardiogram is monitored throughout

the procedure and a routine chest X-ray film isobtained afterwards.

Results and discussionDiagnosis of acute rejection in heart transplantrecipientsThe principal use of this new cardiac biopsy

technique has been in the diagnosis and managementof early acute rejection episodes in heart transplantrecipients. The transplanted heart has proved to beuniquely valuable in assessing the clinical use ofcardiac biopsy because impressive and readilyobserved changes in the endomyocardial histologyevolve so rapidly during acute graft rejection episodes(Fig. 4). However, before the histological changesseen on biopsies of the transplanted heart could beaccepted as reliable evidence of the host immuneresponse to the graft, it was important to answerseveral questions.

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Bioptwne

FIG. 2. Technique used for the insertion of the biopsyforceps into the right internal jugular vein.

(a) Would the small specimen obtained be repre-sentative of the entire myocardium?To answer this question two or more biopsies

were taken from different sites in the right ventricleduring each biopsy procedure. It was soon obvious

that there was excellent correlation between thehistological changes seen in these specimens and so,more recently, only one biopsy specimen has beenroutinely obtained during each procedure. Furtherconfirmation that the samples obtained are represen-tative has come from biopsies performed not longbefore the death of three recipients. The histologicalchanges seen in these biopsies have been the sameas those seen throughout the myocardium atautopsy.

(b) Would the histological changes seen in thebiopsies be specific and reliable in the diagnosis andmanagement of acute graft rejection?

It was found that on each occasion the biopsyhistology appeared to be normal, the patients wereclinically well without evidence of rejection. Con-versely, histological evidence of advancing rejectionwas invariably followed by confirmatory clinicalsigns which prompted initiation of increased im-munosuppressive treatment. Importantly, rejectionepisodes were histologically evident in patients 2-4days before rejection could be established clinicallyon the basis of significant changes in the electro-cardiogram or physical examination. Routine serialbiopsy in the early post-transplant period may,thus, give the first indication of an acute rejectionepisode and permit the earlier initiation of increasedimmunosuppressive treatment before serious damageis caused to the graft by the host immune response.

Serial endomyocardial biopsies also permitted anaccurate assessment of the response to immuno-suppressive treatment (Fig. 4.) When regression ofthe histological changes of rejection occurred, itcorrelated well with the normalization of clinicalparameters.

...

FIG. 3. Plain chest X-ray film taken during a biopsyprocedure showing the forceps in the apex of the rightventricle.

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Transvenous endomyocardial biopsy 289

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-~~~....S....>E # . * -FIG. 4. (a) Biopsy obtained from a heart transplant recipient 16 days post-transplantation.Acute rejection is present with oedema and an infiltrate of mononuclear cells. (b) Biopsyfrom the same patient on post-transplant day 33 following a course of increased immuno-suppression. The myocardium now appears normal with complete reversal of the previouslyseen histological changes.

(c) Would multiple cardiac biopsies be simple andsafe-and acceptable to the cardiac transplantrecipient?Our experience to date has confirmed that these

criteria have been satisfied and frequent biopsy ofthe donor heart is now a routine aspect of clinicalmanagement during the first 2 months after trans-plantation. With the described technique, one to fourbiopsy specimens can be obtained in 3-5 min, using20-60 sec fluoroscopy time. The patient feels only

the injection of the local anaesthetic and is left with atiny incision which quickly heals to an imperceptiblescar without suturing. No serious complications haveoccurred. Three patients have been found to have asmall right pneumothorax on postoperative chestfilms, and two patients developed supraventriculararrhythmias during the biopsy which requiredcardioversion to sinus rhythm. The risk of this pro-cedure is similar to that of right heart catheterizationby a central vein, and, thus, would appear to be

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substantially less than that associated with leftventricular needle biopsy by percutaneous puncture(haemorrhage, cardiac tamponade, ventricular fibril-lation, myocardial infarction) (Shirey et al., 1972).The technical difficulties encountered in transvenousbiopsy via peripheral veins are avoided. The rapidityand safety with which transvenous cardiac biopsy canbe performed have led to its ready acceptance by thetransplant recipients.

Histological studies in long-term cardiac transplantsurvivors

Transvenous cardiac biopsy has provided animportant new method for the assessment of long-term cardiac transplant survivors. A total of thirty-four biopsy procedures have now been performed ineleven long-term survivors following cardiac trans-plantation. These biopsies have demonstrated forthe first time that the healthy cardiac transplantrecipient can have normal cardiac histology up to3 years following transplantation. Since some ofthese patients also have normal cardiac function asdemonstrated by cardiac catheterization and leftventricular cineangiography, and normal coronaryarteriograms, their prospects for continued long-term survival would appear to be excellent.

Studies in patienits with primary cardiomyopathiesMore recently, transvenous cardiac biopsy has

been extended to the study of patients with primarycardiomyopathies. Biopsies obtained from patientshave been examined by light and electron microscopyand histochemical techniques. These biopsies havealready provided new information about these poorlyunderstood diseases and serial biopsies in these

patients may be of particular value in the determina-tion of long-term prognosis. Hopefully, biochemicalanalyses will be performed on the biopsy specimensenabling a haemodynamic, morphological and bio-chemical correlation of the cardiomyopathies to beperformed.

ConclusionOur initial experience with serial percutaneous

transvenous endomyocardial biopsy has establishedthis new technique as a valuable aid to the study ofmyocardial disease. It has been of particular valuein the management of patients following hearttransplantation in whom it has greatly improved theearly management of acute rejection episodes. Onthe basis of our favourable experience with cardiactransplant recipients, we have extended this tech-nique to the study of patients with primary myocar-dial disorders. The technique is safe, efficient andhas rapid patient acceptance. Furthermore, it can beperformed with less morbidity than biopsy of othersolid organs.

ReferencesCAVES, P.K., BILLINGHAM, M.E., SCHULZ, W.P., DONG, E.,

JR, & SHUMWAY, N.E. (1973a) Transvenous biopsy fromcanine orthotopic heart allografts. American Heart Journal,85, 525.

CAVES, P.K., STINSON, E.B., GRAHAM, A.F., BILLINGHAM,M.E., GREHL, T.M. & SHUMWAY, N.E. (1973b) Percu-taneous transvenous endomyocardial biopsy. Journal ofthe American Medical Association, 225, 288.

SAKAKIBARA, S. & KONNO, S. (1962) Endomyocardial biopsy.Japanese Heart Journal, 3, 537.

SHIREY, E.K., HAWK, W.A., MUKERJI, D. & EFFLER, D.B.(1972) Percutaneous myocardial biopsy of the left ventricle.Circulation, 46, 112, 120.

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