Aschoff Nodule As a Characteristic and Pathognomonic Lesion of the Rheumatic Process Has Received Wide Acceptance

Mini Review

Aschoff Nodule-Revisited

P. CHOPRA, M.D.,* J. NARULA, M.D., and R. TANDON,M.D.

Additional Indexing Words: Rheumatic heart disease Myocarditis Left atrial appendage

HE true nature of Aschoff nodules is frustratingly elusive. What ex- T actly are Aschoff nodules? Where are they located? Do they represent activity? Where do Aschoff cells come from? There are many other controversies that continue to intrigue pathologists and clinicians more than 80 years after the recognition of Aschoff nodules.

What is an AschoffNodule? Aschoff nodule as a characteristic and pathognomonic lesion of the rheumatic process has received wide acceptance. The nodule is of variable size and may be round, oval or elongated. It consists of a collection of large cells with an ill-defined, irregular cell margin, abundant pink-blue cytoplasm and prominent vesicular nuclei which may be one, two or multiple in number. A few inflammatory cells, mainly lymphocytes and plasma cells, are also present. The Aschoff nodule may or may not have a central core of eosino- philic, fragmented collagen that is fibrinoid degeneration.1) The Aschoff cell under the electron microscope shows numerous profiles of rough endoplasmic reticulum. Many of these are distended and contain a light electron-dense material. Free ribosomes are increased. Only occasional lipid droplets, dense bodies and Golgi apparatus are identifiable. The cell membrane is ruffled and thrown into folds. The nuclei are large, round to ovoid with an irregular nuclear membrane showing occasional in- vaginations.1),2) Aschoff nodules can be identified easily under the scanning electron microscope. They are seen as fairly well defined nodular aggregates, sand- wiched between the endocardium and the myocardium or lying well within the endocardium/myocardium. These cells are closely packed together and

From the Departments of Pathology* and Cardiology, All India Institute of Medical Sciences, New Delhi, India. Address for reprints: P. Chopra, M.D., Department of Pathology, All India Institute of Medi- cal Sciences, New Delhi-110029, India. Received for publication July 25, 1988. Accepted November 30, 1988. 479 Jpn. Heart J. J 480 CHOPRA, NARULA, AND TANDON uly 1989

Table I. Endomyocardial Infiltrates (percentages) of Lymphomononuclear Cells in Excised Left Atrial Appendages

All values are expressed in percentages as mean•}standard deviation. Abbreviations: Macro= macrophages; TH=T helper-inducer lymphocytes; TS=T suppressor- cytotoxic; n=number of specimens included.

are elongated, oblong and often angulated. The surface of the cells is either finely reticulated or relatively smooth and a few blunt projections may be evident on the surface.3)

Where do Aschoffcells comefrom? The origin of Aschoff cells has received more than its fair share of at- tention. They have been considered to have arisen from cardiac myocytes, smooth muscle cells, fibroblasts, histiocytes, lymphocytes and endothelial cells. The myogenic origin was proposed because of light microscopic re- semblance and similarity of staining characteristics (with Masson's trichrome and phosphotungstic acid--hematoxylin) between cardiac muscle cells and Aschoff cells.4) Such staining characteristics, we believe, may be nonspecific. Ultra- structural findings refute such a correlation and suggest a similarity with macrophages and fibroblasts.1) Fibroblasts however, do not have multiple nuclei, rarely reach the size of Aschoff cells and have fewer branching processes. Moreover, there is no evidence of fibrillogenesis in the vicinity of As- choff cells.2) The presence of complex branching processes favors (altered) macrophages. Histochemically, Aschoff cells show a strong reaction to nonspecific esterases and acid phosphatase which identify macrophages.1) Our recent immunohistochemical observations confirm that these cells are of macrophage-monocytic origin.5) Aschoff cells showed a consistently positive staining with mouse monoclonal antibodies against macrophages and did not stain with antimyosin antibodies by immunoperoxidase using the avdin- biotin method. Moreover, these cells showed positive staining for HLA-DR (Ia) antigens. A recent case report has also revealed positive staining of Aschoff cells with macrophage antibodies.8) The observations from 50 left atrial appendages excised during closed mitral valvotomies showed (Table I) that one fourth of the cell population in the endomyocardium was comprised of cells of macro-monocytic lineage5) (Table I). Vol.30 No.4 ASCHOFF NODULE-REVISITED 481

What are the characteristicsof Aschoffnodules? The description and consequent controversies regarding the appearance and location of so called Aschoff bodies is rather perplexing. Consider the following: "they are not true Aschoff bodies if not accompanied by myofiber necrosis in myocardium"; "the reports of Aschoff bodies in the surgically excised left auricular appendages are based on an erroneous concept because they are present when clinically the rheumatic process is quiescent"; "rheumatic subcutaneous nodule and nodules in synovialis should never be con- fused with Aschoff bodies as they are not characteristic"; "experimentally produced cellular accumulations are not true Aschoff bodies".7) What should one look for in the Aschoff bodies then? Aschoff himself could not have been so possessive. Moreover, the interpretations have varied in different hands, e.g. rewriting from descriptive to tabular form changes the ideal location from the subendocardial7) to the endocardial region.8) The Aschoff body thus appears to be a sacrosanct entity which, if it does not agree com- pletely with a 'book picture', should not be named an Aschoff body as it is suggested that it is better to err by not diagnosing rather than by mis- diagnosing or overdiagnosing. We would then probably end up with not diagnosing the rheumatic process most of the times. The cell wall and membrane of beta-hemolytic group A streptococci share cross reactivity with human heart antigens9) and the cytotoxic mechan- isms initiated thereof may result in carditis.10)-12) Cytotoxicity is probably effected by the preferential migration of the cytotoxic T lymphocytes.12) The T helper cells may possibly assist transformation of cardiac macrophages into Aschoff cells. It is conjectural whether these cells can mediate cytotoxicity. The evolution of the Aschoff cells however is peculiar and is limited to rheumatic heart disease. If we extrapolate, it could be a reaction unique to the streptococcal challenge, as some nonspecific perivascular nodules have been demonstrated in scarlet fever7) and some Aschoff body-like lesions have been produced in experimental situations.4) Con- version of the cardiac macrophages to Aschoff cells may not be ubiquitous and the histiocytic-macrophage aggregates in acute rheumatic fever appear as characteristic as Aschoff nodules, since they are not encountered in any other type of myocarditis.12) Such a change has been described in acute rheumatic myocarditis13) but has never been considered important as a pos- sible predecessor of the Aschoff nodule or even as a characteristic/pathognomonic lesion. We have observed them almost universally in endomyocardial biopsies as well as in autopsies of patients with acute rheumatic fever.12) We for all practical purposes, would be satisfied with the connective tissue changes (with or without fibrinoid degeneration) and the macrophage- Jpn. Heart J. J 482 CHOPRA, NARULA, AND TANDON uly 1989

Table II. Frequency of Aschoff Nodules in Chronic Rheumatic Heart Disease

Parenthetical figures represent percentages. n=number of specimens included. histiocytic aggregates (closely resembling Aschoff nodules topographically) for the diagnosis of acute rheumatic myocarditis. The additional presence of characteristic Aschoff/Anitschkow cells would of course be reassuring. Thereafter whether the reaction is perivascular or not, be it in the endocardium, myocardium or pericardium, either round or otherwise is incon- sequential. However, for the sake of calling it an Aschoff nodule, we would agree that we should not compromise on the appearance of Aschoff cells.

Do Aschoffnodules suggest rheumatic activity? Or, are they just the pathognomonic feature of rheumatic heart disease? The answer may be a little circuitous. Aschoff nodules do form during rheumatic fever but they continue to be seen after the disappearance of clinical features of activity. The confusion has occurred because of the large number of Aschoff nodules having been demonstrated in chronic rheumatic heart disease in the auricular appendages removed during mitral valvotomy and sent for histologic examination. Aschoff nodules have been reported in 16 to 74% of cases.7) We can recall our eminent pathologist running up the stairs to the operating room after doing frozen sections of a left atrial appendage from our first closed mitral valvotomy to inform the surgeon that he had opened up an active rheumatic patient. Rows of Aschoff nodules in chronic quiescent cases must have baffled pathologists and only thence the Aschoff nodules must have been thought to be an indicator of rheumatic pathology rather than rheumatic activity. Table II demonstrates the frequency of Aschoff nodules in chronic rheumatic heart disease. Myocardial specimens obtained from 208 autopsies of chronic RHD were compared with 326 left auricular appendages excised during closed mitral commissurotomies. There was no clinical or laboratory evidence of rheumatic activity in any of these cases. The Aschoff nodules were arbitrarily quantified as absent, few, and abundant. In atrial appendages the presence of Aschoff nodules in the endomyocardium was signi- Vol.30 No.4 ASCHOFF NODULE-REVISITED 483

Table III. Frequency of Aschoff Nodules in Necropsy Myocardial Specimens from Active and Inactive Rheumatic Heart Disease

Parenthetical figures represent percentages. Abbreviations: RF=rheumatic fever; RHD=rheumatic heart disease; n=number of specimens included. * Two cases with few Aschoff nodules revealed numerous histiocytic aggregates in the interstitium.

ficantly higher than in the ventricular myocardium. Random sampling of the histology of the left atrial appendage, however, has confirmed our belief that the Aschoff bodies are far more common in left atrial appendicular endocardium as compared to the ventricular myocardium. This possibly implies that the Aschoff nodules not only commonly occur but continue to develop in the auricular endocardium.

The thickness of the normal endocardium varies in different cardiac chambers, being thickest in the left atrium. It may be 30 times thicker in the left atrial appendage as compared to the ventricles. Okada14) demonstrated a left atrial endocardial thickness of 300ƒÊ (c.f. ventricular endocardium=10ƒÊ), while in our study it measured up to 857ƒÊ.15) Appendicular endocardium moreover is loose and has an abundant elastic content which probably makes the appendix an ideal soil for Aschoff bodies.8) It is worth- while to mention that the Aschoff nodule measures on average 40•~80ƒÊ.

With healing of the rheumatic process they diminish in the left atrial endocardium and ventricular myocardium but continue to be frequent in the left

atrial appendage and this is not readily explainable. Probably the sluggish circulation within the appendicular cavity is responsible. The cavity that can become conducive to thrombus formation may also not interfere with ongoing surrounding activity. The comparative avascularity of the atrial

appendage may also be a contributory factor. Left atrial appendicular endocardium thus appears to be a privileged location for Aschoff nodules

and the significance of them being found in the appendages becomes question- able.

Table III presents our observations in myocardial specimens from necropsy cases of acute rheumatic fever and chronic rheumatic heart disease.

The frequency and the magnitude of occurrence of Aschoff nodules is strik- ingly higher during the acute rheumatic process. If we believe that the 484 CHOPRA, NARULA, AND TANDON Jpn. Heart J. July 1989

Aschoff nodules are the sine-qua-non of rheumatic activity , then why should they be seen in chronic rheumatic heart disease at all? Their presence in quiescent disease (at least in values), has been considered as evidence of clinically covert, recurrent, active inflammation that results in chronic fibrosing valvular disease.8) Demonstration of heavy inflammatory infiltrates in surgically excised rheumatic mitral valves16),17) and left atrial appendages5) in chronic rheumatic heart disease also supports this contention . It has been suggested that the disappearance of clinical features of activity may not truly suggest the remission of carditis, and subsidence of arthritis or decline in antistreptolysin 'O' titers may not go hand in hand with carditis .5) In fact, Read et al have demonstrated a heightened cellular immune response against cardiogenic streptococcal antigens persisting for 5 years after the initial attack of acute rheumatic fever.18) Additional evidence of the possibility of subclinical carditis is the lack of history of acute rheumatic fever in one-half of the patients with chronic rheumatic heart disease, and since rheumatic heart disease has to follow rheumatic carditis, obviously carditis has gone undetected in those cases. More objective evidence has recently been provided by Veasy et al.19) Near- ly 20% of their cases of rheumatic fever were found to have carditis only after Doppler echocardiography. We have to accept the fact that we miss carditis. Precise identification and follow up of the carditis is imperative if the sequence of rheumatic heart disease following rheumatic carditis is to be interrupted.

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