Progress in Human Pathology SOME R E C E N T A D V A N C E S CARDIAC P A T H O L O G Y *

IN

Margaret E. Billingham, M.B., B.S. t

A number of new areas are emerging in the field of human cardiac pathology. It is not possible to include in this article all the recent significant advances made; however, four areas have been selected for review. Allograft rqjection in both the acute and chronic forms remains the single most challenging problem in effecting successful cardiac transplantation in man. The details of the pathological manifestations, complications, and early diagnosis of rejection in human cardiac recipients and recent work in this area are outlined. With the marked increase in the use and abuse of new drugs there has been an increase in toxic manifestations in the heart. Recent work on the early diagnosis and morphological manifestations of drug cardiotoxicity, particnlarly those of the anthracycline drugs, which are widely used in the treatment of cancer, is also described and reviewed. Progress in our understanding of cardiac transplant pathology and drug cardiotoxicity has been made possible by the development of a new technique for studying the pathology of the heart in vivo, namely, endomyocardial biopsy. Tim procedure is now commonplace in larger medical centers and its nse is spreading. It is safe and simple and can be repeated on man)' occasions in an)'

patient so that for the first time the evolution of a disease process in the myocardium can be studied. With the exception o f tissue taken during cardiac surgery, pathologists have had to rely in the past on postmortem material for studies of the morphology and biochemistry of the human heart. There were ahvays two drawbacks: postmortem artefact, particularly in studying ultrastructural morphology, and the inability to follow the course o f cardiac disease in vivo. Both problems have been significantly ameliorated with the advent of transvenous endomyocardial biopsy. This procedure has significant value in the assessment of immune rejection in transplanted hearts. In tumor chemotherapy (anthracyclines) it is allowing the use of more effective treatment regimens through the direct measurement of cardiotoxicity. The technique has helped to make possible a more precise classification of the cardiomyopathies. Above and beyond these clinical benefits it promises to reveal much about the fundamental mechanisms of heart disease in man. The indications, clinical benefits, and limitations of this technique are discussed. Tissue heart valve replacement is now widely used in cardiac surgery. Correspondingly, the pathology of tissue valves is becoming important, particularly with respect to biodegradation. Recent work in

*Stud) supported in part b) grant IlL 13108 from tile National Institutes of Heahh and in part by grant CA 21555-01 from the National Cancer Institute "t'Assistant Professor of Pathology, Department of Pathology, Stanford UniversitySchool of Medicine, Stanford, California

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HUMAN PATHOLOGY--VOLUME 10, NUMBER 4 July 1979 this area using scanning and electron microscopy is also reviewed.

ENDOMYOCARDIAL BIOPSY

Biopsy of the kidney, liver, and bone marrow is routinely performed in clinical medicine. Endomyocardial biopsy, fast joining the ranks, is also becoming a routine diagnostic procedure in many medical centers? Published techniques for effecting myocardial biopsies have included transthoracic needle biopsy of the left ventricle using Menghini and Vim-Silverman needles, catheter needle biopsy of the interventricular septum, and open thoracotomy. 2-G T h e mortality and morbidity associated with these methods have precluded their widespread acceptance. In 1962 Konno and Sakakibara 7-9 described a technique for obtaining endomyocardial biopsy specimens using a transvenous catheter bioptome. Although still used, the original bioptome was plagued by mechanical failure and was difficult to manipulate. Several modifications emerged: the CavesSchultz Stanford bioptome, the modified Olympus bioptome, and the King endomyocardial bioptome? ~ Although several other groups are performing endomyocardial biopsies, ~ the Stanford experience

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is tO be described because it includes methods for biopsy diagnosis o f acute rejection in heart transplants and methods for assessing cardiotoxicity and anthracycline treated patients with cancer. In 1972 Caves I~ la developed a new transvenous catheter biopsy forceps, shorter and more flexible than the Konno bioptome (Fig. 1). More important, Caves~4,~s designed a new technique for serial percutaneous transvenous biopsy of the right ventricle in man via the right internal jugular vein. The clinical experience at Stanford with the new technique and instrument has been the subject of previous reports? G' ~z T!lis method is now performed safely on an outpatient basis, requires no general anesthesia in adults and no venous cutdown, and is readily accepted by patients. For the first time endomyocardial biopsy has made possible the early morphological detection o f cardiac disease in living patients, allowed the evolution of the disease to be followed and documenting its reversal following therapy. Serial biopsies over time present no problem: in our series up to 32 biopsy specimens have been taken in one patient. Both left and right ventricular biopsies can be performed with the bioptome. ~s-2' More than 1900 end0myocardial biopsies have been performed at the Stanford University Medical Center, with no deaths,

Figure1. Tile Caves-SchuhzStanford biotltome. Inset shows close-up viewof tile cutting bioptomejaws.

SOME RECENT

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IN CARDIAC

PATHOLOGY--BILHNG~IA,xt

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Figure 2. Diagram illustrating a method for preserving snap frozen biopsy tissue embedded in freezing mixture in a plastic Beeln capsule. Retrieval is effected by holding capsule to warm it, sliding out the frozen block, mad trimruing as shown for frozen sectioning on a chuck.

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and with a morbidity less than that accompanying liver and renal biopsies. 2~ A frequent criticism of the endomyocardial biopsy is whether a small piece of myocardium is representative of tile heart as a whole. Obviously in a very focal condition a negative biopsy may not be representative. But at Stanford at least three pieces of myocardium from different sites on the interventricular septum are always sampled to reduce the source of this error. Further most of the indications for endomyocardial biopsy are for diffuse myocardial diseases, some of which have an actual predilection for the endomyocardium, for example, acute rejection and anthracycline cardiotoxicity.

Tissue Preservation and Preparation Endomyocardial biopsy specimens obtained by the Stanford bioptome are seldom more than 0.3 cm. in maximal dimen-

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sion. In general three separate pieces are taken from different sites on tile septum to ensure as representative a sample as possible. All biopsy tissues are fixed immediately: one piece in 2.5 per cent glutaraldehyde at room temperature (to reduce contraction artefact), one piece in 10 per cent phosphate buffered formalin for light microscopy, and a third piece "snap frozen" in isopentane and dry ice for histochemical and immunofluorescence studies. We have found it convenient to "snap freeze" these minute biopsy specimens by placing them in a plastic Beem capsule (of the type used for tissue embedding for electron microscopy) filled with an embedding medium for frozen tissue specimens, closing the lid, and plunging the whole capsule into the isopentane and dry ice mixture. Once labeled, the specimen can be stored indefinitely at -70~ The removal of a biopsy specimen for frozen section examination is depicted in Figure 2.

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HUMAN PATHOLOGY--VOLUME 10, NUMBER 4 July 1979 Whenever myocarditis is clinically suspected, another biopsy piece is placed in a vial of Earle's medium for viral culture. Although biopsy tissue can be divided by a single stroke of a sharp blade, tlfis often causes a "squash" artefact and is not recommended. The myocardial biopsy tissue should be picked up with a needle point. Handling with forceps can also cause artefacts.

Tissue Interpretation The extent to which an accurate diagnosis can be made on the basis of endomyocardial biopsy is variable. In many cases light microscopic evaluation is sufficient for diagnosis; in others ultrastructural examination is necessary. Ultrastructural interpretation relies heavily on the pathologist's experience and the availability of control human endomyocardial biopsy tissue for comparison. In most medical centers control biopsy specimens can be obtained during open heart surgery for certain congenital heart lesions, but it is preferable for the control tissue to be obtained from the healthy hearts of young accident victims who have become cardiac donors. In many cases a definite diagnosis cannot be made, but it is often useful to the clinician if a statement can be made to "rule out" a suspected disease, such as myocarditis, or to substantiate a suspected clinical diagnosis by a statement that the diagnosis is "consistent with but not diagnostic of" the disease in question, for example, congestive cardiomyopathy. After treatment for a particular condition, e.g., myocarditis or acute rejection, a repeat biopsy will help by establishing ongoing disease or reversal of the condition. When the biopsy procedure is routine in an institution, clinicians often seek confirmation of a suspected cardiac condition. One value of the endomyocardial biopsy in humans

clearly lies in its usefulness for the clinician who interprets even "negative" diagnoses as useful, in the same way as for liver and bone marrow biopsies. Olsen, 2z in his series of 67 patients who underwent biopsy, found a firm pathological diagnosis, by either confirmation or exclusion of suspected clinical diagnosis, in 65 per cent of the endomyocardial biopsies. In the Stanford series of 450 "nontransplant" biopsies, using the same criteria as Olsen, 22 we found 60 per cent with firm pathological diagnoses, and in 13 per cent a new and previously unsuspected diagnosis was made. z3

Indications for Endomyocardial Biopsy The indications for endomyocardial biopsy have been summarized in Table 1. The biopsy has been shown to play a major part in the management of cardiac transplant recipients becat/se it permits an early diagnosis of acute rejection. T h e details of how this is done are explained in the section on cardiac transplant pathology. We also believe endomyocardial biopsy to be an invaluable diagnostic tool in selected high risk patients taking anthracycline therapy for cancer, to prevent irreversible cardiotoxicity; a more detailed explanation Is given in the following discussion. In our experience endomyocardial biopsy is indicated, and frequently asked for by cardiologists, to rule out suspected myocarditis. If myocarditis is found, a follow-up biopsy is useful to measure the success or failure of treatment, as in corticosteroid therapy. The onset of sudden heart failure in previously heart disease free patients with inconclusive hemodynamic data is often confirmed by a myocardial biopsy study showing evidence o f a primary cardiomyopathy (using Roberts and Ferrans' classification2~). The light microscopic findings of

TABLE 1. INDICATIONSFOR ENDOMYOCARDIALBIOPSY

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Diagnosis and follow-upof rejection in cardiac transplants Diagnosis of anthracycline induced cardiotoxicity Diagnosis and follow-upof myocarditis Diagnosis of primary cardiomyopathies Diagnosis of secondary cardiomyopathies Diagnosis of restrictive versus constrictive heart disease Diagnostic aid in idiopathic chest pain or arrythmias

SOME RECENT ADVANCES IN CARDIAC I'ATHOLOGY--BILLINGIIAM hypertrophy and increased interstitial fibrosis, although only suggestive of cardiom.yopathy, can be confirmed if electron m~croscopy shows diffuse attenuation o f myocytes with partial or total myofibrillar loss, sarcotubular swelling, membrane degeneration (myelin figures), cristolysis and degenerative mitochondrial change, nuclear degeneration, and other changes previously described. 25, 26 Endomyocardial fibrosis and hypertrophic cardiomyopathy can also be diagnosed by biopsy. Endomyocardial biopsies have been useful in confirming the diagnosis in the secondary cardiomyopathies, for example, hemochromatosis, sarcoidosis, radiation heart disease, and collagen diseases. We have found obvious histopathological changes in endomyocardial biopsies in some patients with idiopathic chest pain who might otherwise have been dubbed "hysterical." And lastly, endomyocardial biopsy is indicated, and preferred over thoracotomy, in order to distinguish restrictive disease, such as amyloid heart disease, from constrictive heart disease. 2T,2s The indications for left versus right ventricular biopsy depend on the suspected cardiac abnormality; for example, lesions producing pressure or volume overloading of the left ventricle are best evaluated by left sided biopsy. Radiation changes, however, may be less obvious in the left side because of thicker walls. If suspected clinically, carcinoid changes are more likely to be found on the right side. In diffuse disease processes like hemochromatosis, neither side has an advantage over the other. In our experience there tends to be more fibrosis and a thicker endocardium on the left side; the Caves technique is easier, quicker, and safer as far as embolism is concerned, than use of the left side. 1~. ,5 Others believe that there is less risk from perforation in a left ventricular biopsy. 29 Although not an indication for diagnosis, endomyocardial biopsies have exciting potential for research application. The use of serial biopsies to follow the evolution of certain disease states and their response to therapy can now be studied. Biochemical and elemental analyses are now being performed on diseased myocardiumflO.3.%33 these studies and reliable ultrastructural observation were not possible previously with cadaver hearts.

HUMAN CARDIAC TRANSPLANTATION

Human heart transplantation began at Stanford University Medical Center in January 1968 after 10 years of study in the laboratory. 3a Since that time 158 patients have had cardiac transplants and there were 67 survivors as of December 1, 1978. There are five long term heart recipients who have survived seven to nine years. The one year survival rate has increased from 22 per cent in the first program year to 61 per cent in the tenth program year. As can be seen, there has been a gradual but steady improvement in the overall survival in patients during the I0 years of this program. Allograft rejection in both acute and chronic forms remains the single most challenging problem limiting the success of the transplant program. Details of patient selection criteria, surgical technique, and immunosuppressive thera W are described elsewhere? 5-37 It was known that acute rejection of orthotopic cardiac allografts in dogs tended to be episodic, 3s and these episodes were usually associated with reduction in voltages of the standard leads of the electrocardiogram. 39 Initial clinical experience confirmed that human cardiac allograft rejection was also episodic and that similar electrocardiographic changes occurred in man and in the dog? ~ In 1971 transvenous biopsy of the orthotopically transplanted canine heart was first performed at Stanford. 41 A modified Konno-Sakakibara bioptome was passed via the right external jugular vein into the apex of the right ventricle where two or more biopsy specimens were obtained easily and without complications. Microscopic examination of the specimens of endomyocardium obtained demonstrated for the first time that significant changes in the electrocardiographic voltages only became evident 24 to 48 hours after histological evidence of acute rejection had been clearly identified. 4z Serial biopsies then proved that early diagnosis of an acute rejection episode could be confidently made on the basis of histological changes and that the severity of the episode could be accurately graded. Of equal importance was the observation that appropriate augmentation of immunosuppressive therapy resulted in the restoration

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ttUMAN PATHOLOGY--VOLUME 10, NUMBER 4 July 1979 of a histologically normal myocardium. Successful reversal of the rejection episode could thus be identified independently of the electrocardiographic changes. It was also confirmed that the histological findings on biopsy were representative of the entire myocardium, since at autopsy in dogs the myocardial changes could be compared with those of biopsy specimens taken from the same dog only hours earlier. 4a In 1972 a technique for serial transvenous biopsy o f the human heart was developed using a percutaneous approach through the right internal jugular vein. ta This technique was introduced into the clinical heart transplant program in August 1972. t5 Initial biopsies were performed with a modified Konno-Sakakibara bioptome, but the majority were performed with a new catheter biopsy forceps designed at Stanford (Fig. 1).44 Transvenous endomyocardial biopsy has since contributed significantly to the clinical management in heart recipients. It provides an objective histological index of the host's immune response to the cardiac allograft and allows an "on line" assessment of the response to immunosuppressive therapy during acute rejection episodes. Thus immunosuppressive treatment can be tailored in individual patients to tim results of direct histological examination of the graft. Pulmonary infection is associated with decreases in externally measured QRS voltages in standard electrocardiographic leads, a cardinal electrocardiographic sign of acute graft rejection. Likewise atrial arrhythmias, although often associated with acute graft rejection episodes, do

not inevitably indicate snch a process. In both these instances morphological assessment by the biopsy techniqne provides an independent and clear-cut evaluation of graft status and may prevent unnecessary and sometimes dangerous augmentation ofimmunosuppressive therapy. Endomyocardial biopsy has evolved into a cornerstone of the clinical management in cardiac recipients.

HistopathoIogical Features of Acute Cardiac Allograft Rejection Over 1500 endomyocardial biopsies have been performed in 158 cardiac transplant patients at Stanfordl On the basis of this experience the histopathological features of acute cardiac allograft rejection in humans have been defined and graded as follows (Table 2): ~ EARLY A C U T E REJECTION. Early acute rejection is characterized by interstitial or endocardial e d e m a with a scanty interstitial, endocardial, and predominantly perivascular infiltrate or pyroninophilic cells with prominent nucleoli (immunoblasts). This lymphocytic infiltrate has been shown in animal studies to be predominantly of the T cell type. 46 Early acute rejection is also heralded by a significant increase in pyroninophilia of both endocardial cells and endothelial ceils of small vessels; this is not seen in donor biopsy tissue at the time of transplantation, but it develops with rejection and may linger for a few days following therapy. It is not seen in long term, rejection free survivors. ~IODERATE ACUTE REJECTION. In moderate acute rejection there is a signifi-

TABLE 2. ENDOMYOCARDIALBIOPSYGRADINGOF ACUTE REJECTIONEI'ISODES

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Early rejection (reversible)

Endocardial and interstitial edema Scanty perivascular and endocardial infiltrate of pyroninophilic lymphocytes with prominent nucleoli Pyroninophilia of endocardial and endothelial cells

Moderate rejection (reversible)

Interstitial, perivascular, and endocardial infiltrate of pyroninophilic lymphocytes with prominent nucleoli Earl)' focal myocytolysis

Severe rejection (irreversible or very difficult to reverse)

Interstitial hemorrlmge and infiltrate of pyroninophilic lymphocytes and polymorphonuclear leukocytes,vascular and myocytenecrosis

Resolving rejection

Active fibrosis, residual small lymphocytes(nonpyroninophilic), plasma cells, and hemosiderin deposits

SOME RECENT ADVANCES IN CARDIAC I'ATHOLOGY--BILLtNGHA,Xt

Figure 3. Myocardiumshowing acute rejection with perivascular and subendocardial lymphocyticinfiltrate (arrows). (Masson'strichrome stain, x 250.)

cant increase in the degree of interstitial exudate and cellular infiltration. The cellular infiltrate consists of both small lymphocytes and larger lymphocytes with vesicular nuclei, prominent nucleoli, and pyroninophilic cytoplasm. The infiltrate is often more prominent in perivascular distribution and in the interstitium is often arranged focally in clumps (Fig. 3). The subendocardium may be widened by edema and infiltration of the pyroninophilic mononuclear cells. Some early focal myocyte degenerative change can sometimes be seen adjacent to clumps of inflammatory ceils. These are manifested by shrinkage of the myocytes, which have pyknotic nuclei and a more basophilic color with Masson's trichrome stain compared with the more eosinophilic staining properties of normal myocardial myocytes. SEVERE ACUTE REJECTION. Severe acute rejection is manifested morphologically by a marked diffuse interstitial cellular infiltrate consisting not only of large

pyroninophilic lymphocytes but also of polymorphonuclear leukocytes and extravasated red blood cells in addition to the myocyte changes already described. Frank myocytolysis may be evident in areas of maximal cellular infiltrate. Vascular wall damage also becomes apparent, and microthrombi may be seen (but this phenomenon depends on tile anticoagulant regimen used). Following treatment for acute rejection, reversal of most of the changes described may occur, including those in the endocardium, even as early as 72 hours after initiation of treatment. A biopsy specimen of a resolving rejection episode typicall)' shows many active spindle shaped fibroblasts, new fibrous tissue, and a residual interstitial infiltrate (usually within fibrous tissue scar) of small nonpyroninophilic lymphocytes. Scanty plasma cells may also be seen in the interstitium. Hemosiderin deposits will be present if the previous rejection episode has been severe.

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hnmunofluorescence The role of immunofluorescence in assessing acute rejection by endomyocardial biopsy has been inconclusive in our experience. In end stage acute rejection, positive immunofluorescence for IgG and C3 has been described in myocytes and around blood vessels. 4~ In our biopsy experience, in early acute rejection, IgG immunofluorescence was positive occasionally in the sarcolemma of myocytes, and complement (C3) and fibrinogen were also observed. However, we have not found this method to be reliable in predicting either the onset of acute rejection or its severity. This may be the result of the augmentation of immnnosuppressive treatment in the early postoperative phase and during acute rejection.

Endomyocardial Biopsies in Long Term Survivors of Cardiac Transplantation

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Transvenous cardiac biopsies have provided an important new method for the assessment of long term cardiac transplant survivors. The biopsies have demonstrated for the first time that a normal cardiac histological picture can be found in the heahhy cardiac transplant recipient ovi~r eight years after transplantation (Fig. 4). In these patients routine biopsies occasionally show late acute rejection episodes years after cardiac transplantation. 4s Sometimes small vessels show endothelial proliferation, and these changes are interpreted as early evidence of chronic rejection. Electron microscopic examination of endomyocardial biopsy tissue from cardiac transplant recipients has not been useful for the management of acute rejection because of the time necessary to process tim samples. However, preliminary serial studies using the electron microscope have yielded much new information about the mechanisms of cellular damage during rejection. In 1968, reports described de novo malignant changes in organ transplant recipients, 49"5~ and shortly thereafter a tumor registry for such cases was established in Denver?' Most malignant tumors have occurred in patients with renal homo-

grafts) 2 and unfortunately the human cardiac transplant program has not escaped this complication: 11 instances o f malignant disease have been reported in 141 cardiac transplant recipients at Stanford) 3 Dermatological cancer and lymphoproliferative diseases made up the majority of cases. The frequencies of occurrence of various neoplasms are similar to those in renal allograft recipients)' and the lesions developing in a younger population group compared with those in nontransplant cancer patients. T h e pathologist should therefore be alert to tile possible development of de novo malignant disease in cardiac recipients.

Infection As a consequence of immunosuppressive therapy in cardiac transplantation as in other types of organ transplants, infectious complications constitute a major cause of postoperative morbidity and mortality. In cardiac recipients the infections may be multiple, varied, and frequently fungal. T h e lungs are the most frequent site of infection and are involved in 60 per cent of all diagnosed infections?' It has been possible to identify coccidioidomycosis, toxoplasmosis, and cytomegalic viral inclusions in the myocardium by endomyocardial biopsy. It is important for pathologists to be aware of the possibility of such infections. They have been the subject of several previous reports and therefore are not dealt with in detail here. 54-57

Retransplantation Occasionally retransplantation of the heart is performed, ss,59 The indications for retransplantation are intractable recurrent rejection and accelerated graft atherosclerosis20.6, Nine patients have underg.one graft replacement for tile second ume and one for the third time at Stanford. P A T H O L O G Y OF DRUG INDUCED

CARDIOTOXICITY Many chronic diseases are treated with therapeutic agents that are administered over prolonged periods of time.

SOME RECENT ADVANCES IN CARDIAC PATHOLOGY--BH+HNoHAxl

Figure 4. Endom)'ocardial biopsy specimen from a cardiac recipient of eight )ears showing normal uhrastructure. (• 5867.)

Their effect on the myocardium is subtle but cumulative. It is important for the pathologist to bear in mind the ever increasing list of drugs known to cause cardiotoxicity, sometimes with fatal results. The acute cardiac effects of high doses of the tricyclic antidepressants are well documented as are those of lithium carbonate and the phenothiazines used in the treatment of psychiatric disorders. ~2-87 Prolonged ethanol ingestion, prolonged steroid administration, and orally administered contraceptives have also been shown to produce morphological chauges. 6s-ra Myocardial lesions produced by sympathetic catecholamines, particularly norepinephrine, are well described, ra-r8 Drugs used less often, such as emetine, methergyside, phenylbutazone, and recently Paraquat have also produced adverse morphological changes in the heart, rg-s6 More recently attention has been focused on the cardiotoxic effects of the widely used antineoplastic drugs, cyclophosphamide and the anthracycline antibiotics, Daunomycin and its analogues, particularly Adriamy-

cin. This group is to be discussed in more detail.

Cyclophosphamlde Cardiotoxicity This alkylating agent is used either alone or as adjuvant chemotherapy for the treatment of cancer. Cardiac damage was described when high dose ranges (240 to 270 mg. per kg. over a two to four day period) were first used. Cyclophosphamide induced cardiotoxicity has an acute onset within hours or days after the beginning of treatment. Buja and Ferrans sr and others 8s have described numerous large loci of hemorrhagic necrosis in the heart, extensive capillary microthrombosis, hemorrhage and fibrin in the interstitium, and necrotic myocytes. Subpericardial and subendocardial ecchymoses with an acute inflammatory infiltrate have also been described. 89 In high dose combination chemotherapy, cyclophosphamide may cause acute myopericarditis. 9~ Electron microscopic examination of the lesions showed capillary endothelial damage and distinc-

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IIUMAN PATHOLOGY--VOLUME 10, NUMBER 4July1979 tive nuclear alterations o f chromatin unraveling so as to produce prominent thick, thin, and intermediate filaments in both myocytes and endothelial cell nuclei suggesting unraveling of chromatin into fibers of various diameters. Other studies in animals showed similar changes. Recent reports suggest that cyclophosphamide used in adjuvant therapy may have potentiating effects on anthracycline cardiotoxicity. 9~

AnthracycHne Cardiotoxicity Adriamycin, or doxorubicin hydrochloride, is an anthracycline antibiotic, which has been shown to have a marked antineoplastic effect in adult and childhood solid tumors and in hematologic cancers. 92 Adriamycin frequently produces toxic side effects, as do man), other antitumor drugs. These effects are generally clinically manageable, and indeed reversible, with the notable exception of cardiotoxicity, which can lead to congestive cardiomyopathy, heart failure, and death. 93 It is now well established that the cardiotoxic effects o f Adriamycin are dose related and that a cumulative dose below 500 mg. per sq. m. yields a low incidence of cardiomyo-

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pathy, whereas in patients receiving a greater total dose tile incidence climbs rapidly. Tile cal'diotoxicit)' of Daunonaycin, an anthracycline analogue of Adriamycin, is also well documented, st, 94 Since autopsy material usually reveals only the end stage lesions in anthracycline induced cardiotoxicity, a study was undertaken o f tile histopathology by making use of the percutaneous transvenous endomyocardial biopsy to stud), the cardiotoxic lesions as tile), develop. 9~ The technique for endomyocardial biopsy was the one already described. In this stud)' the biopsies were performed within one month after the last dose of Adriamycin; however, in three cases the time interval was 11, 22, and 36 months. One hundred ten percutaneous endomyocardial biopsies were performed in patients aged 19 to 78 years who had received anthracyclines, mainly Adriamycin (102 biopsies), but also daunomycin (two biopsies), Adriamycin-DNA complex (three biopsies), and Rubidazone (three biopsies). The cumulative doses of anthracycline at the time of biopsy varied from 90 to 810 nag. per sq. m. of Adriamycin, 700 to 1525 rag. per sq. m. of Rubidazone, and

Figure 5. Epon section of nwocardium showing focal adriamycin effect (arrow). (Toluidine blue stain.

• 3 0)

SOME R E C E N T A D V A N C E S IN C A R D I A C PATHOLOGY--BILLINGnA,~I

Figure 6. Electron micrograph of two shrunken adriamycin affected myoc)tes (arrows) with partial myofibrillar loss adjacent to normal myocytes (M). (x 4100.)

400 to 480 mg. per sq. m. of daunomycin.

The histopathological lesions were found to be both focal and disseminated. Tile earliest lesions were frequently found in the subendocardium. In the earliest lesions single isolated myocytes with degenerative changes were often seen against a background of morphologically intact myocardium (Fig. 5). Two main types of myocyte injury are seen in anthracycline cardiotoxicity in humans.gG, 97 The first is myofibrillar loss within the myocyte, initially partial but then total (Fig. 6). Even with total myofibrillar loss and only Z band remnants remaining, the nucleus may appear unaffected, and the mitochondria, although smaller, retain compact cristae. These cells can be recognized with practice by light microscopy as small shrunken cells with a homogeneous pale cytoplasm, but they are more easily recognized in a thick Epon section or by uhrastructural examination. In the second type of injury, well described in animal models, the myocyte un-

dergoes vacuolar degeneration (Fig. 7). 98 The earliest manifestation of change is distention of the sarcoplasmic reticulum and T tubular system, which eventually swells and coalesces to form large membrane bound clear spaces in the cytoplasm (Fig. 8). This change can also occur with apparent preservation of the nucleus and mitochondria. These two types of degeneration may occur concomitantly in the same cell or in separate cells. There does not seem to be a relationship between the two types of injury and the severity or course of ttle cardiotoxicity. These lesions eventually progress to actual death of the myocyte, when ttle mitochondria do show swelling, cristolysis, and myelin figures. Ttle nuclei at this time become pyknotic and disintegrate. Interstitial fibrosis may be increased in anthracycline cardiomyopathy. Because this is a relatively nonspecific finding, which may also be due to other causes, e.g., radiation, in this study it was not included as a factor in grading the cardiotoxicity. The changes described in the human

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HUMAN PATHOLOGY--VOLUME

Figure 7, stain. • 460.)

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10, N U M B F R 4ffuly 1979

Epon section of mvocardium showing adriamycin damaged, ~acuolated cells. (Toiuidine blue

Figure 8. Electron micrograph of" adriamvcin :~ffected myocyte snov, mg swelling of" sarcoplasmic reticulum (arrows). (• 4200.)

SOME RECENT ADVANCES IN CARDIAC PATHOLOGY--Bu.H,~C.HAXt heart in anthracycline cardiotoxocity included some negative observations: Inflammatory infiltrates were not seen in severe lesions; endothelial cells of interstitial small vessels were apparently unaffected by anthracyclines in the therapeutic dose range at the time of biopsy; and small interstitial nerve endings were also unaffected when compared with normal control biopsy specimens? ~ EndomyocardiaI biopsy tissue from patients who had been treated with the anthracycline analogues, Adriamycin-DNA, Daunorubicin, AD32, and Rubidazone, showed morphological changes similar to those seen in patients treated with Adriamycin alone, although the changes occurred at different dose levels. 9~ 100 Predictive clinical tests to identify patients at risk for the development of heart failure have so far yielded conflicting data. Our study approached tile problem in a different way by trying to define and grade tile morphology and pathology of cardiotoxicity in humans. In carrying out the stud), the major objective was to measure individual variations in Adriamycin cardiotoxicity as the treatment progressed, so that the final cumulative dose could be tailored to the tolerance of each patient. This procedure would then provide each patient with a maximal antineoplastic effect without danger of cardiac failure. The following system was developed to grade the cardiotoxicity changes: 9~ 0 = No change from normal 1 = Scanty affected cells with early change (focal, partial myofibrillar loss or distended sarcotubular system) 2 = Groups of cells with definite change (marked or total myofibrillar loss or coalescing cytoplasmic vacuoles) 3 = Diffuse cell damage with severe changes (many cells with total myofibrillar loss, vacuolar degeneration, loss of organelles, mitochondrial and nuclear degeneration) This grading system combined the extent of ceil damage with the proportion o f cells affected. The grading is usually possible after examination of toluidine blue stained, 1 micron thick, plastic embedded sections, but the cellular changes should alwa.ys be confirmed by electron microscoplc examination. Clinicopathological correlations were made for all the patients undergoing biop-

sy. The results of these correlations are described in other publications. '~176 The results of this study indicate that endomyocardial biopsy is helpfill in scoring the degree of myocardial damage due to anthracycline administration. This technique provided evidence that even low cumulative doses of anthracycline can cause early minor degrees of myocardial damage detectable before any clinical, hemodynamic, or electrophysiological signs become apparent.9~.,0,-,04 The study also supports earlier suggestions that there was considerable biological variation among individuals with regard to the degree of anthracycline toxicity. By applying the scoring method it is now possible to monitor cardiotoxicity and tailor the amount of treatment that any patient should have without exposing him to the risk of irreversible heart failure (there is a 50 per cent mortality in adult patients with heart failure due to anthracycline cardiotoxicity). At Stanford, in over 100 patients no cases of overt heart failure have been encountered since we became aware of tlle role of risk factors and have changed our criteria for dose limitation to include endomyocardial biopsy, although some of our patients have had doses of up to 810 mg. per sq. m. of Adriamycin. This direct method of evaluating myocardial damage has also allowed the determination of the relative cardiotoxicity of various analogues of Adriamycin quickly and simply. 99 It should be made clear that although the morphological ultrastructural changes of anthracycline administration are very characteristic and can be easily recognized, these changes are not necessarily specific: similar degenerative changes can be seen in end stage cardiomyopathies due to other conditions. The assumption has been made in these studies that the patients did not have a cardiomyopathy before treatment with anthracyclines was instituted and that tile changes were in fact due to Adriamycin. Furthermore, these changes can be seen long before dilatation of the heart chambers and heart failure occur, as in end stage congestive cardiomyopathy. In addition to tile chronic morphological changes, acute myopericarditis, which is thought to be reversible, has been described in early anthracycline cardiotoxicity. '~ This syndrome has morphological

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HUMAN PATHOLOGY--VOLUME 10, NUMBER 4 July 1979 features that are similar to the acute cyclophosphamide cardiotoxicity already described. 'J~ In conclusion, it appears that endomyocardial biopsy does provide a useful guide to the administration of anthracyclines in adult patients, that it does serve as a useful tool for arriving at a rational process for dose optimization, and that it provides reliable intbrmation about the identification of risk factors. It is anticipated that this method will be useful in monitoring further clinical trials and other studies of anthracycline analogues, pharmacological antagonists, and different dose delivery schedules in the future.

HOMOGRAFT AND H E T E R O G R A F T VALVE PATHOLOGY In the 18 years since the development of the heart-lung machine made open heart surgery possible, more than 500,000 artificial valves have been implanted in patients whose own heart valves were defective. For many of these patients the quality of life has been improved and its length extended. Encouraging as this record is, artificial heart valves are far from being problem free. There have been man), reviews dealing with mechanical heart valve prostheses and some with the clinical aspects of homograft and heterograft valve implantation. ~~176 Since the heterograft method is widely used, it is pertinent for pathologists to be aware of the biodegradation processes occurring in and accounting for valve failure. T h e principle advantage of bioprosthetic cardiac valves as compared to mechanical substitutes is the relative freedom from embolic complications and anticoagulant related morbidity and mortality. However, the long term durability of tissue prostheses is still under investigation. Biodegradability has proved to be a critical limitation in tissue valves fabricated from fascia lata and pericardium, and these are no longer u s e d y l , ~22

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Previously homograft valves processed by chemical sterilization or other

preservation techniques that caused total loss of cell viability showed unacceptably high rates of valve deterioration in the first few years. 123 The initial popularity of homograft valves stemmed not only from lower thrombogenicity but from the belief that valves obtained in a "fresh" viable state from human cadavers and sterilized with antibiotics would retain viable fibroblasts in the leaflets, which would contribute to long term maintenance of valvular structure and functional integrity. Although these valves were functionally adequate, they began also to show degenerative changes after three to five years. One study by Stinson et al. 116 showed that five years postoperatively 60 per cent of the patients undergoing stinted homograft mitral valve replacement and 51 per cent of those undergoing stinted aortic valve replacement exhibited clinical or pathological evidence of allograft dysfunction of some degree. Barratt-Boyes and coworkers n~ reported a 77 per cent survival rate in 122 patients undergoing fi'ee-hand aortic homograft replacement over six )'ears, although valve rupture developed in 8 per cent. In most reported studies the results with homograft aortic valve replacement have been slightly better than those xdth mitral vah'e replacement, and this is attributed to tl]e fact that left ventricular end systolic pressure is substantiall)' higher than the usual diastolic aortic pressure. The main pathological finding in "fresh" homograft valves was demonstrated by Kosek and collaborators in both canine and human subjects as an early loss of endothelium (even at the time of surgical valve replacement), with gradual collagen disruption and fibrous dysplasia with patchy acellularity. The presence of macrophages, histiocytes, and plasma cells suggested chronic immunological rejection m the homografts. Although human homograft valves have shown viable cells after five years' implantation, an elegant study by H a m m o n et al. suggested that the viability of leaflet fibrocytes in fact deteriorated progressively; they showed a rapid growth of explant, which adhered strongly to glass three months after implantation but which showed sluggish growth and poor adherence one year later. Valve endothelialization by host cells or an ingrowth of host fibrous sheath does not

SOME RECENT ADVANCES IN CARDIAC PATHOLOGY--BILUNGHAXl These data indicated satisfactory performance in terms of bioprothesis related morbidity and mortality and showed no apparent propensity for late failure due to leaflet tissue disruption. Despite these apparently good results, a recent detailed morphological study by Ferrans et al. t26 emphasizes that macroscopic examination of porcine valve heterografts is inadequate to evaluate their structural integrity, as these xenografts may continue to function normally for an as yet undetermined period of time after their collagen framework is extensively altered. Ferrans' recent studies using transmission and scanning electron microscopy showed that the endothelial barrier is largely destroyed in the processing of porcine heterograft valves even before implantation, but a pseudoendothelial covering of fibrin, red cells and platelets covers

occur beyond covering the stint and root of the valve. A recent comprehensive comparative study documented the superiority of Hancock glutaraldehyde preserved porcine valves and the improved Starr-Edwards mechanical valves over that of fresh aortic valve homografts. ~24 It is concluded, therefore, that aortic homografts for mitral and aortic replacement are not sufficiently biostable to warrant their continued use.

Heterograft (Porcine) Valve Pathology A recent study by Oyer et al. t25 included 557 aortic valve replacements, 561 mitral valve replacements, and 167 double aortic and mitral valve replacements with Hancock glutaraldehyde porcine valves over a follow-up interval of seven years.

Figure 9. Heterograft (porcine) aortic valves. A, Leaflet fenestrations (arrow) four }'ears after implantation. B, Leaflet calcifications (arrows) three }'ears after implantation. C, Septic vegetations of leaflets (arrow) six months after implantation.

C

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HUMAN I'ATHOLOGY--VOLUME 10, NUMBER 4Jttly 1979 the e x p o s e d collagen surface within two to t h r e e days a f t e r implantation, t'6 Witltin o n e to two m o n t h s this layer is thicker o n the outflow side, a n d a layer o f m o r e num e r o u s m a c r o p h a g e s grows on the inflow side. A diffusion o f p l a s m a proteins into the spaces between collagen fibrils was noted. T h r e e to 76 m o n t h s a f t e r i m p l a n t a tion the m o s t consistent f e a t u r e was collag e n d i s r u p t i o n , which s o m e t i m e s led to leaflet fenestrations (Fig. 9A). V a r y i n g degrees o f calcification o f the valve leaflets were n o t e d in time (Fig. 9B). It has b e e n o u r observation that this complication is worse in children a n d m a y necessitate early valve r e p l a c e m e n t . Infections o f porcine valves m a y also o c c u r with e x o p h y t i c vegetations, o r colonies o f bacterm m a y be seen d e e p in the substance o f the cusps (Fig. 9C). S p o r e f o r m i n g rodlike bacteria h a v e also b e e n o b s e r v e d ultrastructurally, a n d rodlike o r g a n i s m s with flagellae h a v e b e e n seen b e n e a t h the surface fibrin layer. In the s a m e ultrastructural study by F e r r a n s a n d coworkers, d e a d o r g a n i s m s possibly p o r c i n e in origin were also identified. A review o f p u b l i s h e d rep o r t s o f 47 patients with p o r c i n e h e t e r o g r a f t valve infections indicates tlmt it is u n c o m m o n f o r associated valve ring abscesses to develop. It is c o n c l u d e d tlmt m a r k e d collagen d i s r u p t i o n , infection, a n d o t h e r changes m a y o c c u r even if the valves a p p e a r grossly n o r m a l . Since g l u t a r a l d e h y d e treated valves d o not contain viable cells to replace the collagen f r a m e w o r k , the long t e r m durability o f h e t e r o g r a f t valves is still in question.

CONCLUSION

382

T h i s article has reviewed s o m e recent advances in h u m a n cardiac pathology. T h e areas selected were cardiac t r a n s p l a n t pathology, the lesions o f d r u g cardiotoxicity, a n d the m o r p h o l o g y o f tissue h e a r t valve r e p l a c e m e n t s . T h e proliferation o f w o r k in the first two areas is largely the result o f the successful i n t r o d u c t i o n o f a new proced u r e , e n d o m y o c a r d i a l biopsy, which has m a d e it possible to follow the m o r p h o l o g i cal course o f disease o f the h u m a n h e a r t in vivo. T h e a d v a n t a g e s a n d limitations o f the e n d o m y o c a r d i a l biopsy technique have

b e e n discussed. M o r e w i d e s p r e a d use o f the technique p r o m i s e s considerable clinical benefits. F u r t h e r m o r e it p r o m i s e s to reveal m u c h a b o u t the f u n d a m e n t a l m e c h anisms o f h e a r t disease in m a n . REFERENCES

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123. Buch, W. S., Kosek, J. C., and Angell, W. W.: Deterioration of formalin-treated aortic valve heterografts. J. Thorac. Cardiovasc. Surg., 60:763, 1970. 124. Solomon, N. W., Stinson, E. B., Griepp, R. B., and Shumway, N. E.: Mitral valve replacement: long term evaluation of prosthesis related mortality and morbidity. Circulation, 56:11-94, 1977. 125. Oyer, P. E., Stinson, E. B., Reitz, B. A., Miller, C. D., Rossitter, S., and Shumway, N. E.: Long term evaluation of the porcine xenog.raft bioprosthesis. Submitted for publicatmn. 126. Ferrans, V. J., Spray, T. L., Billingham, M. E., and Roberts, W. C.: Structural changes in glutaraldehyde-treated porcine heterografts used as substitute cardiac valves. Am. J. Cardiol., 41 : 1159, 1978. Department of Pathology Stanford University School of Medicine Stanford, California 94305

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Some recent advances in cardiac pathology.

Progress in Human Pathology SOME R E C E N T A D V A N C E S CARDIAC P A T H O L O G Y * IN Margaret E. Billingham, M.B., B.S. t A number of new ar...
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