·To
my wife
ANNETTE

·NATURE OF
RHEUMATIC HEART
DISEASE
With Special Reference to Myocardial Disease
and Heart Failure
BY
GEORGE E MURPHY, MD
Department of Pathology, The New York Hospital Cornell Medical Center
With 162 Photomicrographic
Illustrations in Color
SANS
TACHE
THE WILLIAMS & WILKINS CO, BALTIMORE

·Reprinted from MEDICINE
Volume 39 Number 3 September 1960
Copyri, ht 1960
TEE WILLIAMS & WILKINS COYPANY
MADE IN THE CYTTED STATES OF AMERICA
Library of Congress
Catalog Card Number
60-53239
Composed and Printed at the
B AVERLI PRESS INC
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·NATURE OF RHEUMATIC HEART DISEASE WITH SPECIAL REFERENCE TO MYOCARDIAL DISEASE AND HEART FAILURE* GEORGE E MURPHY MD CONTENTS INTRODUCTION 293 294 296 I PURPOBE OF THIS COMUNICATION II CARDIAC DILATATION IN ACTIVE RHEUMATIC HEART DISEASE III EARLY OBSERVATIONS ON THE HISTOPATHOLOGY OF THE MYOCARDIUM IN RHEU MATIC HEART DISEASP SPECIAL REFERENCE TO THE SO-CALLED ASCHOFF BODIES FIRST CLEARLY DESCRIBED BY BRET IV CULMINATION IN RECENT YEARS OF THE CONCEPT OF CONNECTIVE TISSUE ORIGIN OF THE SPECIFIC RHEUMATIC LESIONS IN THE MYOCARDION THAT ARE GENER ALLY KNOWN AS ASCHOFF BODIES 297 300 V EXPERIMENTAL INDUCTION OF MYOCARDIAL LESIONS CLOSELY RESEMBLING THOSE OF ACTIVE RHEUMATIC HEART DIBEABE SPECIAL REFERENCE TO As CHOFF BODIES 301 A Historical background for the experiments 301 B Experimental induction of myocardial lesions closely resembling those of active rheunatic heart disease by repeated focal infections with group A Streptococ 306 VI EVIDENCE THAT ASCHOFF BODIES ARE LESIONS OF MUSCLE CELLS 309 A Evidence from experimental induction of myocardial lesions closely resem bling Aschoff bodies 309 B Origin of interstitial myocardial Aschoff bodies from heart muscle cells in bundles between or among other (often larger) bundles of muscle 310 COngin of Aschoff bodies from heart muscle cells close to blood vessels 311 D Connective tissue in Aschoff bodies some of the reasons for the common in19- interpretation that Aschoff bodies are not myogenic lesions derved from connective tissue elements 311 E Occurrence of (strated) heart muscle cells in cardiac valves and among fat cells in sub epicardial tissue 313 F Elucidation of the myogenic origin of theumatic myocardial legions includ ing Aschoff bodies from findings in human and rabbit skeletal muscle 313 G Origin of Aschoff bodies from heart muscle cells in cardiac atral appendage 314 VII DISEABE OF SMOOTH MUSCLE CELLS IN RAEDMATIC HEART DISEASE 315 A Rheumatic disease of smooth musele cells in the sub-endocardial tissue of the atrium special reference to lesions in atrial appendage that resemble in varying degree Aschoff bodies that are derived from heart muscle cells 315 B Rheumatic disease of smooth muscle cells in valves 316 C Rheumatic disease of smooth musele cells in myocardial arteries 316 From the Department of Pathology of the New York Hospital-Cornell Medical Center The findings in ventricular myocardium and in atrial appendage of the heart that are here illustrated were in large part presented on Apnl 4tb 1959 before the 15th General Assembly of the Japan Medical Congress in Tokyo 289 ·290 GEORGE E MURPHY VIII REASONS FOR THE COMMON MISINTERPRETATION OF THE HISTOPATHOGENESIS AND SIGNIFICANCE OF SPECIFIC RHEUMATIC LESIONS OF MUSCLE CELLS IN RHEUMATIC HEART DISEASE SPECIAL REFERENCE TO THOSE IN ATRIAL Ar PENDAGE 317 IX Various RHEUMATIC LESIONS OTHER THAN ASCEOFF Bodies OF HEART MUSCLE CELLS 318 A Alteration of striations and fatty change 318 B Focal or diffuse necrosis of beart muscle cells associated with joflammatory cells and with or without large cellular elements of myogenic origin 319 Y SPECIFIC REEUMATIC LESIONS OF MUSCLE CELLS GENERALLY REFERRED TO AS ASCHOFF BODIES IN ATRIAL APPENDAGES AB UNEQUIVOCAL EYIDENCE OF Active REEURLATIC HEART DISEASE 320 A Frequent lack of correlation between results of clinical laboratory tests and the occurrence in atrial appendages of specific rheumatic lesions of muscle cells 320 B Close correlation between the occurrence in atrial appendages of specific rheu matic lesions of muscle cells some of which resemble closely ventricular Aschoff bodies and the occurrence of ventricular Aschoff bodies 321 C Importance of recognizing the myogenic nature of specific rheumatıc lesions in atrial appendage and ventricular myocardium to the understanding of the pathologic physiology and failure of the beart in rheumatic heart disease 322 XI THE IMPORTANCE OF ACTIVE RUEOMATIC DISEASE OF HEART MOSCLE CELLS TO CARDIAC Failure 392 A The relation of active rheumatic disease of the myocardium to cardiac farlure in children and young adults often without appreciable valvular deformity systolic and diastolic murmurs caused by active rheumatic disease of the myocardium with cardiac dilatation 33 B Cardiac failure in patients with mitral steno819 special reference to the con siderable benefit from mitral commiggurotomy in many cases and lack of correlation in many cases between subjective improvement and objective chnical findings efter operation 324 C Lack of correlation between the degree of mitral stenosis and cardiac d198 bility and between the degree of mitral and pulmonary vascular change special reference to unoperated patients with marked mitral steno 818 with little or no signs of congestive beart failure er en at advanced age 325 D The relation of active sbeumatic disease of the myocardium to cardiac failure in patients of the third fourth and fifth decades of life and older 326 E The relation of specific rheumatic lesions of muscle celle generally called Aschoff bodies in biopsied cardiac atrial appendages to the preoperative clinical course of patients between 20 and 40 years of age with mitral stenosis who underwent cardiac surgery 328 XII LESIONS OF BLOOD VESSELS IN RHEUMATIC HEART DISEASE AND THEIR RELA TION TO MYOCARDIAL DABIACE 331 XIII RHEUMATIC DISEASE OF CARDIAC VALVES AND CHORDAE TENDINEAE AND RE LATION OF DEFORMITY OF THESE STRUCTURES TO MYOCARDIAL FUNCTION AND FAILTRE 333 VIV SOMHART OF THE AUTHOR & CONCEPTION OF THE ORION OF VARIOUS Ruku MATIC LESIONS INCLUDING THE SO-CALLED AscĦOPY BODIES FROM MUSCLE CELLS ON THE FICART AND OF THE RELATIOY OF THESE LESIOy, TO HEART FAILERE 334 336 EPILOGUE 337 REFERENCES ·NATURE OF RHEUMATIC HEART DISEASE 29 COLOR PLATES Plate 1 (Fige 1-9) Close resemblance between Ascboff bodies in man and experi mentally induced myocardial lesions in rabbits Plate II (Fags 10-18) Marked similarity of rabbit and human lesions and their origin from heart muscle cells (fibers) Plate III (Figs 19-27) Ongin of Aachoff bodies from heart muscle fiberg in small bundles between larger ones Plate IV (Figs 28-36) Splitting of heart muscle fibers into fragments some multi nucleated in rheumatic heart disease Plate V (Fig. 37–45) Multinucleated heart muscle fibers or their fragments very close to blood vessels in rheumatic heart disease Plate VI (Figa 46-54) Early stage of small Aschoff bodies their myogenic orgio and close resemblance to lesions of skeletal muscle cello Plate VII (Fags 55-63) Annular proliferation of myogenic nuclei around and in Barcoplasm in rheumatic myocardial lesions and skeletal muscle Plate VIII (Figs 61-72) Multinucleated structures derived from muscle cells in rheumatic myocardial lesions and skeletal muscle Plate IX (Fige 73-81) Normal appearance of connective tregue in Aschoff bodies and origin of the lesions from heart muscle cells Plate X (Fige 89.90) Ongin of Aschoff bodies from heart muscle cells in atrial ap pendages and left ventricle of the heart Plate XI (Fige 91-99) Ongin of rheumatic lesions from smooth muscle cells in car diac left atnum smooth muscle in mitral valve Plate XII (Figs 100-108) Smooth muscle cells in heart valves Plate XIII (Fags 109–117) Striated muscle cells in heart valves Plate XIV (Fig8 118-126) Ongin of rheumatic lesions from Smooth muscle cells in the media of myocardial arteries—I Plate XV (Figs 127-135) Origin of rheumatic lesions from smooth muscle cells in the media of myocardial arteries-II Plate XVI (Figs 136-144) Alteration of striations and fatty change in heart muscle fibers in rheumatic heart disease Plate XVII (Fig8 145-153) Various rheuinatıc lesions of heart muscle cells heart muscle cells among fat cells in sub-epicardial tissue Plate XVIII (Figs 154-162) Origin of the characteristic rheumatic myocardial le Bion from heart muscle cells IN APPRECIATION The author gratefully acknowledges support of this work by research grant H 1803 of the National Heart Institute of the National Instatutes of Health by grants from The Helen Hay Whitney Foundation and The John Polachek Foundation for Medical Research and by a Lederle Medical Faculty Award The author 19 grateful to Mr Joyce C Hall for the privilege of presenting the histologic findings in this monograph in the form of photoLithographic reproductions made by the Hallmark Coloraster Control Process The lithographic work and printing of the illustrations and explanations of them were done at Hallmark Cards Inc of hansas City Missouri To Mr Kenneth West Mr Harold Rice and Mr Jack Peppers whose interest and painstaking work contrbuted importantly to the fidelity of the reproductions the author 19 grateful The author acknowledges with gratitude support from Mr David T Beals Mrs Charles B Clark the Cross Foundation and the Hallmark Foundation for the reproductions The ad rendered by Miss Gioconda Carrozza in the typing of the manuscript and preparation of the bibliography is appreciated

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·INTRODUCTION Over the past 300 years ob ervations have indicating that progre.sion of rheumatic heart hown that many tisues especially vascular dlea.e has occurred We now how however structures throughout the body are often in that active rheumatic heart disease is often jured in attacks of rheumatic fever (122 a 124 pre ent, ometimes in protracted form without 176-a) The most erious damage occurs in the fever and beneath the clinical horizon and in heart to its muscular substance and to its reference to this form of the disele the terra valves Information labonously collected and cor rheumatic fever appears to be inappropriate related in the past 50 years has shown that Indeed a large proportion of adults with severe infections with group A hemolytic treptococci chronic rheumatic heart disea e do not recall play a causative and key role in the pathogenesis their having experienced any attack of rheu of this disease (32 52 101 116 a 124-a 128 matic fever or chorea We alo know that infec 145 a 146 164 175 a) However many of the tions with group A streptococci may sometimes most important a pects of the pathogenesis are be so mld as to go unrecognized by patient or still poorly understood How interaction of the physician Among the principal questions to be streptococci with the host is related to the de answered concerning rheumatic disea.e is the velopment of rheumatic dlease of the heart and following Why in some patients does active other tissues in only & small proportion of the rheumatic heart diea e continue for prolonged very many human beings who are repeatedly in period cauing progressive cardiac damage fected with these microorganisms has not been sometimes without evidence of the activity from establi hed knowledge that has been gained by clinical or laboratory mvestigation and some experiment concerning this question will be re times without serological evidence of recent ported in this monograph streptococcal infection? It appears probable that hereditary factors In view of the complexity of the pathoare important to the development and outcome genesis of rheumatic heart disease the produc of attacks of rheumatic fever (63 a 170-a tion with regulanty of the duease in animals 203 a) It is also probable that the relationship would be of great value Very important in this to one another of a complicated series of patho endeavor and essential to understanding of the genetic events is important to the natural history nature of rheumatic heart diseame is understand of rheumatic diease For example in the case of ing of the origin and development of morphoa given patient events that occur well in ad logic changes in the heart and their relation to vance of an attack of theumatic fever manifested altered cardiac function in this disease As Opie by obvious polyarthritis and/or chorea and by (133 a) has written The functional aspect of Insidious heart disease at 5 years of age are im disease determines its outward manifestation portant to the developinent and outcome of this and is that from which we suffer The e outward attack The outcome of the attack in turn manifestations and their underlying phycologi may be of great importance to reaction of the cal basis are in eparable from structure which is heart and other t..sues to subsequent events not more static than function He further that may lead eventually to the development of wrote Pathogenesis is a noving picture of intractable heart failure 15 or 50 years after the disea e to be considered from every standpoint rheumatic attack at 5 years of age In such cases and with special emphasis on causation Never there may be strong clinical evidence of one or theless ome aspects of disease tend to be neg more attacks of active rheumatic disea e in the lected in ofar as morphologic phenomena are long interval between the attack at 5 years of ignored That deformity of cardiac valves age and the onset of heart failure many years following protracted or repeated attacks of rheu later But in other such cases there may be de matic valvular disease places an important and tected in this interval either little or no evi sometimes disabling burden on the heart is well dence of active rheumatic duea e other than the recocnized and has been emphasized for many important change in some cases from year to years (39) However it appears to the author year or decade to decade of auscultatory igns that there is wide pread neglect and lack of 293 ·291 GEORGE E MURPHY understanding of the morphologic changes in the the muscle of the heart without affecting such myocardium and of their relation to altered func esternal structures as the joints In 1876 Besnier tion and fatlure of the beart in theumatic heart (16) mthout histologic evidence surmi ed con di eae Structural and functional integrity of cerning the then bttle consdered possibility of heart mucle cells is clearly of primary in por rbevmatic pury to cardiac mu cle as follows tance to normal function of the heart The long This injury accurs frequently if not absolutely beld and now very widely accepted concept that regularly and can be ob erved in advanced derheumatic lesions of the wyocardium, weluding gree wthout considerable damage to the endo the so called Aschoff bodies are nonmyogenic cardrun or pericardium lesians of connective tisue fails to explain the Koowledge concerning rheumatic le ions of altered function and falure of the myocardium heart muscle cells and their important relation in this disea e Furtbermore strong evidence to cardiac failure in rbetsmatic beart diese demonstrates that this concept is locorrect This has been acquired slowly Prmanly because of evidence, acquired from etperiment and de the widespread lack of recognition of the myotauled histopathologic study and observable un genic nature of rheumatic le sons of the myocar der & wide variety of conditions, has been as dium and the strong infuence of the concept sembled and is now submitted to demonstrate of collagen duease or duese of connective that rheumatre lesions in the myocardium in tissue the importance of alteration of heart cludsog the o-called A choff bodies originate muscle cells to altered function and failure of and develop from Theumatic wjury to heart mus the heart in rheumatic heart disea e has beca cle cells them elves Moreover these findings widely neglected After discussing the patho when viewed is relation to clinical observations logic P y dology of cardiac valves and pericar provide evidence of the important causative te dium uw rheumatic beart disease Coombs (39) lation of rheumatic diseze aſ the myocardium to wrote in 1924 as follows As we paus to the altered function and failure of the heart in rheu more important spordid physiology of the myomatic heart di ele in children and adults cardium it is well that we should be reminded that lesions of the serous layers are of impor That attacks of rheumatic fever can damage tance only in so far as they tend totFard the the heart was recognized by Patcairn (141) and final defeat of the cardiac muscle In essence the by Jenner (81) en 1788-89 In 1816 Lennec heart is a mu cle its functions and properties muvented the tethoscope Aided greatly by we of are mu cular and depend in the last resort on this instrument Boulaud who first u ed the the condition of the cells of the myocardium terms endocardium and endocarditis (21) I PURPOSE OF Tus CONSIUNICATION detected igns of heart di case in & large pro portion of patients with acute articular sheu In this communication evidence is presented matism and be attnbuted thus heart do ease ta to demonstrate the origin of Aschoft badres and rheumatic involvement of cardiac valies and other le dons from mu dle cells so sheusnatse pericardiura In 1840 be stated the follotring heart disease This endence stems from the In the great majority of cases of alluse acute experimental induction of myocardial le zon articular rheumatisma with fever there eusts in closely re erbiing those of human rheumatic variable degree a rheumatism of the sero-fibrous heart duease in & stall proportion of many tissues of the heart The colacidence is the rule rabbits of random stock that were repeatedly and the non-coincidence the erception (22) infected focally with group A streptcocci (123 Substantial evidence that the myocardium cau 127 128) Results of the e experiments provide be inoked in rheumatic disease was not ac endence that A. cboff bodies and other myan quired unti the end of the 19th century Pre cardial lesions in human rheumatic heart disene vious to that time Itard (79) u 1821 believing result from repeated focal infections with group that skeletal muscle is often savolsed in rbeu A treptococci even though these lesions de maatism speculated that the heart becau e of selop is only a small proportion of the many ats peccntial mu cular structure eurely is one in the random population ea rafected Further of the viscera which should be most likely the evidence of the close re emblance of the ette of theumatic inflammation and he con naturally-oceumng and experimentally in jectured that rbeumatism may involve primanly duced myocardial lesions 29 bere fubmitted ·NATURE OF RHEUMATIC HEART DISEASE 295 From detailed microscopic study it has been from 29 to 55 years when the appendage was found that the experimentally induced lesions surgically removed at the time of mitral com are derived from injury to heart mu cle cells missurotomy at the New York Hospital in 7 of I his experimental investigation has led to er these patients there were found lesions specific tensive direct evidence of the origin of A choff for active rheumatic heart dLease bodies and other myocardial lesions from heart 3) Heart or skeletal muscle of 16 rabbits (15 muscle cells in buman rheumatic heart disease died 1 was sacrificed while very ill after focal These latter findings some of which have been group A streptococcal infections), comprising 5 previously reported (123, 126) have resulted rabbits of random stock and 11 rabbits of stock from intensive and detailed microscopic study specially bred in long term experiments that in the past ten years of the heart of over 100 are continuing In brief explanation of the spe patients who died with active rheumatic heart cially bred stock it should here be emphasized disease and of the left atrial appendage removed that among the very many rabbits of random from over 150 other patients at the time of stock that have in the past several years been mitral commissurotomy The evidence so ob repeatedly infected focally with group A streptamed and here illustrated is in striking con tococci only a few have developed lesions like with the very widely accepted concept that those of rheumatic heart disease and it is note the e myocardial lesions are non myogenic le worthy that rheumatic fever (and rheumatic sions of connective tissue Furthermore study of heart di ea e) develop in only a few among the myocardial artenes atrial appendages and car random human population who experience re diac valves has led to the finding of the hitherto peated infections with group A streptococci unrecognized origin of certain rheumatic lesions The occurrence however of rheumatic fever from smooth mu.cle cells and some of the e (and rheumatic heart disease) in high incidence latter lesions can as here illustrated re emble to in certain human families motivates our striving Varying degrees Aschoff bodies that are denied to develop by special breeding families of rab from heart mu cle cells bits analogous to these human families with Experimental and histopathologic findings respect to development of lesions of rheumatic here presented are viewed and discussed in re type Several years ago an initial group of lation to clinical observations to show the im breeders were selected from 91 rabbits of 17 portant causative relation of rheumatic disease fitters of known parentage from random stock of heart muscle cells to altered function and of the Rockefeller Institute by testing their failure of the heart in acute and chronic rheu reactivity to repeated focal infections produced matic heart diseawe in children and adults in sequence by group A streptococci of the fol The histopathologic evidence allustrated at lowing erological types Type 19 Type 1 Type the end of this communication in the form of London and Type 3 Approximately one month color photolithographs that were made without elapsed between the first and second and be hand retouching or dot etching from the original tween the econd and third infections and ap photographic transparencies The material al proximately two months between the third and lustrated is from the following sources fourth infections In a rabbit of random stock 1) Heart or skeletal muscle examined at the this system of infections had previously resulted time of autopsy of 36 patients comprising 23 in & fatal illness associated with marked ir females and 13 males with rheumatic heart regularity of cardiac rhythm 10 days after the disease who died at ages ranging from 17 months last infection In the heart of this rabbit were to 70 years (24 patients at New York Hospital found microscopically a variety of lesions of o at Rockefeller Institute Hospital 2 at Babies rheumatic type involving myocardium cardiac Hospital 1 at Mount Sinai Hospital 1 at Belle valve and myocardial arteries The capacity vue Hospital and 1 at New York Nursery and of rabbits to develop cardiac lesions after focal Childs Hospital all in New York City and 1 at streptococcal infections is obviously difficult Johns Hopkins Hospital), among these 36 pa to ascertain dunng ufe in the animals and tients lesions specific for active sheumatic heart micro copic study is the most reliable means di ease were found in 31 of verification Nevertheless after two or more 2) Left atrial appendage of 10 patients com of the infections outlined above signs and symppn ing 9 females and 1 male whose ages ranged toms have occurred which have supplied us ·296 GEORGE E MURPHY with the following enteria for Le in selection of in cardiac atna valves and myocardial ar po stise reactors for further breeding 1) tenes, and it can be seen that some le sons of Cutaneous hyper reactivity to reinfection, 2) sanooth muscle cells in these sites can resemble evidence of general ne s le, weight loss to varying degree Aschoff bodies that are de sustained anorexia, elevated erythrocyte edi rived from (strated) heart muscle cells The mentation rate 3) abnormal cardiac rhythm, Occurrence of heart mu cle fibers in cardiac development of heart sounds of poor quality valses is illustrated in the figures of Plate XIN including lurring and muliling and finally of In Plates XVI and YVII can be seen a variety greatest value development of cardiac zburmurs of rheumatic lesions that are derived from Av cultation wth regulanty of rabbt bearts heart muscle cells in the last several years has indicated that the Pertinent clinical information and histopatho development of systolic murmurs both transzent logical descriptions accompany the photoutkoand permanent is very valuable to the detec graphs Figs 9 49, 51 56 58 62 65 92 95 109 tion of heart di case in election of positive 121 122 151 and 154 are from rabbits of stock animals for further breeding and stethograms pecially bred as outlined earlier in this ection frara the anuals made with an electrocardio Our experimental and direct bustologic find graph stethograph unt (Cambridge Instru ings concerning rheumatic le ions of muscle cells ment Co ) give visual proof of these murmurs In the heart are discu sed in detail in sections V When rabbits die after two or more infections through IV of the text of this monograph In the and their hearts show active lesions or cars interest of achieving hustoncal perspective these their blings that hare most positusely reacted ections are preceded by detailed bastoncal sec to streptococcal infections are set aside for fur trons on cardiac dilatation in active rheumatic ther breeding The occurrence of acarring 12 heart disease the earlier observations on the valves mayocardium and myocardial arteries histopathology of the myocardium 12 rheumatic in addition to occurrence of active lessons in heart disea e and the culmination in recent thee sites us of importance to us from several years of the concept that the characteristic points of view including correlation of cardiac rheumatic myocardial le long ate non myogenic lesions with abnormal cardiac igns in Ife and alterations of connective tissue In sections choice of postive siblings for further breed and V evidence is given of the uportant au 2 ing tive relation of theumatic dues e of beart mus The photolthographs in Plates I and II 33 cle cells to altered function and failure of the lustrate the clo e resemblance between the o beart Finally 12 ections XII and XIII there called A chof bodies in man and myocardial are respectively discussions of the relation of lesions experimentally induced by us in rabbits rheumatic lesions of blood ve...els in the heart to by repeated focal infections with group A my acardial damage and the relation of valvular streptococci Further evidence of the close sum deformity to myocardial function and fazlure zanty of human rheumatic and the experi II CARDEAC DILATATION IN Active RHEU meotally induced myocardial le sons 13 foiznd MATIC HEART DISEASE 10 Plates VI VIII and YVII The figures in Plates II tbrough I and in Plate XVIII illus In fatal ca es of active rheumatic heart dis trate the origin of A choff bodies from heart ease the sentricular chambers particularly the mu cle cell. The figures in Plate IX pointedly left are generally dilated sometimes markedly illu trate the occurrence of a choff bodies in the Such dilatation may be ren wben neather sal ab ence of demonstrable change in connective Yular deformity nor pencardial adhesions are tissue and this is also illustrated in many bg present and 13 as ociated with dilatation of the ures of other plates In Plate X the origin of atno-leatricular salve frogs (39 51, 104 105 ubendocardial A choff bodies from heart mus 199) Da this point Coombs (39) in 1924 wrote as follons If the heart of a cbild dying cle cells in atrial appendages and the triling dunng an active phae of cardiac rheumatism resemblance of these lesions to a rentncular be looked at the fact that mit at once sense subendocardial A choff body (Fig 87) is dem the obser er is the enlargement of the ventricles onstrated The figures a Plates I XII XIV Before the heart 19 opened this is chiefly apand XV taken together du trate the ongia parent as 3 midening of the heart due to in of rheumatse le soos from mooth mu cle cells crea e of the tran1ere diameter of the ven ·NATURE OF RHEUMATIC HEART DISEASE 297 tricle which gives the organ an unduly globular during theumatic attacks an increase in the appearance When the ventricles are open it area of cardiac dullness that was followed by is found that their cavities are widened in the diminution in the size of this area as improve same way As a rule this is especially noticeable ment occurred They also demonstrated increase in the left ventricle The normal ventricle when in the area of cardiac dullness during recurrent examined post mortem is found to have carcely attacks Investigation at autopsy by Herring any cavity but in the e cases there is a quite ham (104) of patients from whom tracings of considerable space to be seen cardiac cutline had been made were cited by In 1878 (sixteen years before Brets and Lees to show that their tracings of the cardiac twenty six years before Aschoffs and Tawara s outline obtained by careful percus.ion indicated description of the lesions now known as Aschoff with con derable accuracy the position of the bodies) West (199) reported the ca e of a young limits of the heart both to the left and to the woman who showed rapid cardiac enlargement right As control material they used tracings and died five days after the onset of migratory of the area of cardiac dullness in 80 children who polyarthritis At autopsy normal heart valves were free of rheumatic heart di ease From anal no evidence of pericarditis and no pericardialysis of the post mortem records of the Great effusion were found but the left ventricle was Ormond Street and St Mary s hospitals in considerably dilated The myocardrum showed London of 150 cases of fatal rheumatic heart several pale patches and West further ob di case is children under twelve years of age served Microscopic examination showed that they found that in 92 cases (610) special men in the e white patches the muscular tissue had tion had been made of cardiac dilatation in the undergone acute granular (fatty) degeneration autopsy records and in 58 cases (389) the its fibers being converted into granular cylinders dilatation had been recorded as marked On the There was no interstitial growth After view other hand excess of pericardial fluid was un ing in the light of this case two other patients common in only 12 of the 150 cases was more with acute rheumatic fever who showed for than two ounces noted Coombs (36) in 1907 many days igns of acute cardiac dilatation with stated that in the great majority of children feeble heart ounds and without evidence of with rheumatic fever studied by hit the signs of pericarditis West concluded It is possible cardiac di ea e were referable to ventricular that more extended and careful ob ervation may dilatation and its corollary mitral incompe show that such dilatation is not by any means tence Of the common dilatation of atrio-ven so uncommon as is usually thought It is capable tricular valve rings he later wrote (39) Slung we know of producing murmurs which usually in the midst of cardiac muscle as these rings are disappear with convalescence and if as seems it is not wonderful that they should participate pousible this dilatation has for its cause organic in the general stretching which the mu culature change in the muscular fiber a reasonable ex of the heart undergoes as we have seen in car planation is provided of the true pathogeny of diac rheumatism many of the o called anemic or blood murmurs of rheumatic fever and a caution is given as to III EARLY OBSERVATIONS ON THE HISTOPA the need of the most careful treatment of such THOLOGY OF THE MYOCARDIUM IN RHEU ca es Fisher (51) in 1896 concluded from MATIC HEART DISEASE SPECIAL REFERENCE clinical pathological analy 18 that mitral insuffi TO THE SO CALLED ASCHOFF BODIES FIRST ciency that develops during attacks of rheuinatic CLEARLY DESCRIBED BY BRET fever is due to dilatation of the left ventricle In a fatal case of rheumatic fever Goodbart rather than to valvular inflammation or de (63) in 1879 observed on microscopic study of formity the heart with widely dilated left ventricle a Lees and Poynton (104 105) submitted ex considerable quantity of interstitial cell growth tensive evidence of acute cardiac dilatation in around the ves els and between the muscular attacks of rheumatic fever in children and young fasciculi In 1887 Cadet de Gassicourt (27) adults After outlining by careful percussion wrote that in the myocardium attacked by in the area of cardiac dullness they made serial flammation in Theumatic fever the intative tracings of this area (without reference to pre proces which develops in the depth of the mus vious tracings in each ca e) und dernonstrated cular substance is rendered evident by the de ·298 GEORGE E SURPHY formation of the muscular nuclei and by the nucleus 23 enormouły enlarged and becomes proliferation of cellular interstitial growth He opaque coasdered rheumatic le sons of the myocardium The above description by Bret appears to be to repre ent interstitial myocarditis krebl (91) the first clear description of the lessons that are 20 1889 reported finding in the myocardium in DON known as Aschoff bodies Bret also de terstitral changes that he interpreted to be sunbed erten ive changes in the myofibers of the progres ive and various degenerative changes papillary muscles of the left yedince, and of this 2.sociated with proliferated intimal and medial change he wrote as follows At some distance elements with patrowag of the lumen of me from the connective tissue and vascular regions dium sized and mall myocardial arteries He the alterations of the fibers are considerable They considered the e changes to be more important show for the most part 83 described by Lepine to heart failure than valvular deformity He end Mollard, 3 considerable exaggeration in the further suggested that precordial pain in theu longitudinal strations, the fibrillar elements, matic fever us directly related to vascular lesions con iderably spread a part one from the other in coronary artenes and analogous to the pain present the aspect of bristles spread apart in a of angina pecrons asociated with coronary metallic brush Some fibers in great numbers, arteriosclero's In 1894 Romberg (153) re appear empty, the clear spaces occupying one ported on the occurrence m the heart in two tbird or one half of the transverse area of the fatal ca.es of rheumatic heart di ease of u cardiac cell Finally at a more advanced stage merous small indurations composed of connective of this ame lesion, the neighboring fibers love tissue which were nich mn nucler and an neply their individuality melting sato a grapular wa.. formed blood vessels and be further observed devoid of nucleus and with granules representing in many sites large cells and in one place with certainty the persistent pruutse cylin poorly stained greatly elongated and distended ders aucler Rebaut (147) in 1899, with respect to changes In the same year Bret (24) published a de in the nuclei of heart muscle fibers un rheumatic tailed micro copic description of the myocardium fever syrote 35 follows The Dudler can increase in a seventeen year old girl who died during an m number, and in this manner reinforce the attack of acute sheumatic fever After describ cellular defense by multiplying in the elements ing embryonic proliferation in the form of volved in the struggle In the ime year numerous and ds seminated foci near arterioles Poynton (142) described in the myocardum faci in the subepicardial area of the mayocardium he of cellular erudatson preading from the blood further described the following Independent of ves.els and cellular etudatson between the the e embryonic perivascular proliferations there muscle fibers in addition to numerous foci of etist deep is the cardsac mu cle at a consider fatty change in heart muscle cells in cases of able distance from the named pericardium Theumatic fever In 1902 Janot (62) reported other foci which appear absolutely independent that in three cases of acute rheumatic myo of all connection with blood ses els or con carditro studied by him the cardiac muscle Bectre tissue They are for the most part fibers were affected blot exclusively in one rounded mases or elongated trails parallel to the case, that of s bez en year old girl he reported direction of the muscle bundles, and in the change in the nayocardium as follotrs The con nective tissue appears not at all affected in our interstuces of the latter They appear to be of unforza con titutions which is approumately le son The intense and recent lesion 13 exclu ections except at one point which 22 an old the following the central part of these infam sively parenchymatous In his econd coe he matory foci is formed of opaque ca eous blochs reported that the myocardial le rons zavolved that stain sery strongly they appear to result the muscle cells only, and in hus third case he 10 our opinion from degeneration of cardiac reported vacuolar alteratsons of the mude cells mu dle fibers At their periphery are arranged with a weak connective tissue reaction a multitude of embryonic elements In certain In 1904 A choff (3) reported on Tamaris much smaller foci sbere the coalescence of these study with bum of the hearts of five patients Istler is le obe sees very distractly in the with articuler rheumatism and he stated that fibers that are destined to degenerate that the they had confirmed the findings of the Leipzig ·NATURE OF RHEUMATIC HEART DISEASE 299 school (Krebl and Romberg) regarding the giant cells from mu cle fibers in cases of idio general occurrence of interstitial change in the pathic myocarditis myocardium associated with valvular insuffi A year later Geipel (57) in 1905 reported ciency As a feature of this change they de results of his studies begun in 1903 on the cribed in the hearts of two of these patients myocardial lesions in theumatic fever In four peculiar nodules whuch appear to be speczfic for teen cases he found nodules like those reported the rheumatic myocarditis They observed these by Bret (24) in 1891 and by Anchoff observed nodules in the neighborhood of small or me that these lesions occurred at some distance as dium stzed blood vessels and they further well as close to blood vessels and considered that wrote The aforementioned nodules are un they were specific for rheumatic fever In agree usually small mostly submuliary, and originate ment with A choff he believed that the large by the conglomeration of large elements with cells arose from wandering vascular adventitral one or more abnormally large indented or poly cells but in contrast with the view of Aschoff morphic nucles The arrangement of the cells he believed that these cells were called out in frequently occurs in the form of a fan or a reaction to a primary degenerative change in rosette The periphery is formed by the large connective tissue in particular swelling followed nucle the center by the paler or colorle a ap by necrosis of collagen He also conceived that pearing necrotic mass of confluent cell proto in these lesions the intercellular connective tis plasmn Thus description is strikingly like that sue substance becomes fibrillar He ascribed reported ten years earlier by Bret Aschoff be damage to heart mu cle cells to atrophy caused lieved that the giant cell like large nucleated by the pressure of adjacent rheumatic nodules elements in these nodules are derived from In a fifteen year old boy who died with acute adventitial cells of blood vessels He and Ta rheumatic heart disease Geipel (58) found var wara were unable to explain the symptoms of vous degenerative changes in many skeletal mus heart failure in rheumatic patients on the ba.23 cles and he condered that these lesions of of the interstitial moyocarditis with or without skeletal mu cle were not specific for rheumatic nodule formation and because they could find fever In the following year A choff and Tawara no histologic pattern for the failure of the mus (6) again denied the origin of the large cells cle mass it was nece.sary to consider that not from heart muscle cells and suggested that they the muscle mass as such but only a certain part were possibly lymphocytoid cells They be was injured namely the so-called atrioventric lieved that a rheumatic virus calls out a pro ular bundle which gives automaticity according liferative reaction of these cells and that necrosis to the myogenic theory But in pone of three of the centrally located proliferated cells is a cases of rheumatic fever with specific myocardial secondary occurrence Saigo (158) in 1908 nodules could Tawara find after detailed study briefly mentioned that some of the giant cells alteration of the atraventncular bundle to ex in Aschoff bodies in one rheumatic heart he had plam the heart failure In discussion of Aschoffs studied might be of myogenic origin whereas report Zur Myokarditisfrage Babes stated the other large cells in these lesions he con that in my experience the changes in muscle idered to be epithelioid cells In the same year cells and nuclei in myocarditis are not so in Coombs (37) suggested that the characteristic significant as it appears Herr Aschoff as rheumatic myocardial nodules represent a pe sumes Furthermore he stated that in tuber culiarly definite type of connective tissue reac culous and syphilitic myocardial le ions grant tion at the actual points of infection by micro cells that he had observed were derived from organisms and in 1910 (38) be drew the analogy muscle cells and he referred to a case of chronic of the Aschoff body in the myocardium standing endocarditis in which be bad demonstrated a in relation to the subcutaneous podule as a peculiar form of segmentation of heart muscle miliary tubercie stands in relation to a large fibers Alo in the discu sion Bus.e reported tuberculous mass Thorel (182) in the same year that the giant cells in large numbers that he interpreted A choff bodies as developing from a had found in hearts with syphilitie inflammation peculiar primary focal degeneration of nuscle undoubtedly onginated from muscle fibers and or connective tissue that is associated with Schmorl on the same occasion reported that he abortive regenerative changes in the muscle had confrmed Fiedler s report on the ongin of fibers and proliferation of neighbonng con ·300 GEORGE E MURPHY 7 mective to the cells and he beliezed the e le cellular proliferation in the first case and proti lons are react:05s to diplostreptococci De Veceks next Sbrnous exudation iz the latter two le-1003 (188) in 1912 considered that Acbofit bodies Swift (174) and Coombs (39) in 1924 m agreeare reactions to focal myocardal decrons pro- ment with Jack on the essential similanty of duced by a rheumatic virus Frank (53) in the the ubcutaneous nodules and the myocardia! same seartated that the primary and essential A choff bodies concluded, as Mallory had in the process repre ented by Theumatic subcutaneous case of the Aschoff bodies that the characteristic Dodules is exudation foloned by an unflamma large cells in both le sons develop from vecular tory reaction associated with probleration of endothelium and Coombs suggested that procorrective to sue elements and in turn by organi hferating va cular endocardial cells can imitate sation of erudate A core of homogeneous ma the large cells of the A choff body A sear later terial taming antensely red with eosid he MacCallum (110) wrote concerning the re believed to be fibrin markable large cells in A choff bodies, that Tlp (183) concluded that nodules found in eseryone agrees they are peculiar to rheuma gales aponeurotica rere hustologically like tho e tism and that the large cells are not derstatives in subcutaneous tissue and like the nodules of the mu cle cells of the myocardrum in con de cribed by Aschoff in the myocardium How trast Letulle Bezangon and Weil (106) in 1926 ever Huzella (77) in 1914 reported the occus submitted histologic evidence in a cale of fatal rence of keletal mu cle lesions very smlar to rheumatic fever that tras very suggestite of the Aschoff bodies 20 two cases of rheumatic fever formation of grant cells from cardiac mu cle He thought he could trace the ongia of giant fiber which they considered to be the result of cells in these le sons from mu cle cells and by fragmentation of myofibers and amitotic division analogy he suggested that some giant cells in of these nuclei Symmers (177) za 1998 though A chof bodies may originate from heart mus he ubrantted no evidence stated that in A choff cle cells But ia discu son of Harella s report bodies the heart muscle fibers themselves appear A choff and Frankel strongly insisted that all to suffer damage followed by an attempt to re A chof bodies are lesions of connective to sue generate with formation of multinucleated giant elerrents and do not compri e myogenic ele cells He further stated that he could see no ments In 1919 Jacki (80) concluded from study bestological relation hip between subcutaneous of subcutaneous nodules that the e lesions repre nodules and Aschoff bodies A year later Graff sent e spatially a prouferative reaction which can (61) distinguished between the forms of reaction be accorapanied by exudation of fibrin and she yn rheumatic fever 1) the Aschoff bodies cons considered that these le sons and Aschoff bodies PMsing predominantly proliferated mobile cella are genetically similar with small differences that he concessed could become fused and 2) being accounted for on the hans of different the extracardiac lesions such as those 12 tendon ground sub tances in various ti sues In the fol heath that ke believed compri e changes of loming sear Alallory (112) interpreted the cbar collagen fibers and other consective tu sue ele Acteristsc rheumatic myocardial le son as repre ments ritha proliferation of cells enting collagen attacked and do solved by the Action of endothelial leukocytes which sometimes IV CULMINATION IN RECENT YEARS OF DIE form multinucleated cells However in the same CONCEPT OF CONNECYN E ISSUE ORIGIN year Thutanan Rod Eastlake (202) reported that OF THE SPECIFIC RHEUMATIC LESIONS IN THE ASYOCARDIUS TESAT ARE GENERALLY they could trace 2 an area of myocardium in one LNOWN AS ASCNOFF Boutes rheumatic heart the origin of some cells in A.cboti bodies from myofibers and in the same In 1850 Neumann (131) described in fiam year Huzella (78) in follow up to his report mation of erot3 tynoy331 apd mucous mere tea in 1914 stated that the characten tic branes and of vascular latima and endocardium con tituents of theumatic podules are myogenic what be interpreted to be a certain structural and I have found this structure not here out zde alteration un consectite tissue for which he in the heart and skeletal mu culature Fabr (49) troduced the term fibrinord degeneration and in 1921 differentiated the myocardial podules on be referred to the product of this change as the one baod from subcutaneous and synovia! fibrigord Eub tance becausc at sesrindled and je ions on the other on the ba 13 of predominant täibed like fibra Tie interpreted verrucous ·NATURE OF RHEUMATIC HEART DISEASE 301 endocarditis as probably representing inflamed degenerative that is characterized by myxoma proliferated valvular tis ve which had undergone tous edema and degeneration of the intermediary the de cribed fibrinoid metamorphosis but he substances Proliferation of cells is lacking In found the differentiation from layered throm the extra cardial localizations there is added to botic mas.es of fibrous material to be very the e changes a prominent deposit of fibrinous difficult In 1896 Neumann (132) reported ex exudate In the case of the myocardial localiza tension of his ob ervations on fibroid de tion of the process the exudative-degenerative generation inflammation 10 synovia moment is usually weak and the process appears pleura pericardium endocardium peritoneum to begin with a primary cellular prolferation and in diphtheritic inflammation in the mucous which is in accord with the views of Aschoff membrane of the trachea In addition he de In the came of what he referred to as fibrinoid scribed fibrinoid substance in the wall of substance in Aschoff bodies Talalajew left the tuberculous cavities He concluded that this question open as to whether it represents substance represented a fibrin like transforma fibrinous erudate or fibrinous transformation tion of collagen fibers At this time he alo of the collagenous substance Talalajew furtber stated that he was convinced that verrucous wrote If one takes into consideration princi endocarditis is the product of fibrinoid de- pally the extra cardiac localizations of the theu generation of connective tu cue matic process which are usually considered to be In the same year Marchand (116) concluded pathogenetically the same as the alterations in that fibrinod degeneration of connective tissue the heart one must emphasize that the exuda belongs to the vague ideas of pathology tive degenerative stage is especially clear and which are only suitable for be fogging well in unequivocal vestigated proces es and for this rea on must be From 1930-33 Klipge (91) and associates discarded reported results of extensive studies on the pa The views of Talalajew summarized by him in thology of rheumatic fever They concluded that 1929 (178) amplified the concept that rheu their findings fully confirmed the view of Talala matic lesions develop from primary alteration jew that the basic and characteristic rheumatic of connective tissue He suggested that there are lesion in whatever tissue of the body at occure three phases in the life cycle of theumatic le is essentially a degenerative change in the con sions 1) primary exudative-degenerative change nective tissue They wrote as follows In this in connective tissue 2) a econdary proliferative primary lesion which exhibits & swelling of the process with development of syncytial masses ground substance of the connective tusue with and finally 3) a sclerotic or healing phae He subsequent degeneration we believe that one wrote as follows The views of Frank Thorel sees the esential change found in all rheumatic and Geipel were brought together by Talalajew lesions From this primary lesion there develops in & omewhat different formulation The ex -by proliferation of the mesenchyme cells—the udative-degenerative changes in the intermediary cellular nodules the mot distinctive form of substance of the connective ti cue (stage of dis which is the Anchoff heart nodule Klinge organization) he presumed to be primary and stated that the earliest change is in the collagen the proliferative changes econdary Of his con fibers and he called this change Fruhinfiltrat ception of this primary change Talalajevy wrote ( rheumatische Fruhinfiltrat des Lollagenen In cases of acute rheumatı m with early fatal Bindegewebes ) and this change he conceived termination there are seen to develop first for to be followed by a degeneration of the inter the localization of the rheumatic granuloma typi fibrıllary substance of the collagen fibers that cal foci of a myxomatous edema with typical then acquire the property of staining like fibrin ba ophilic diffuse discoloration and basophilia (fibrinoid degeneration) The acute stage of of the collagenous fibrous tissue develops And Fruhinfiltrat and fibrinoid degeneration of the he further wrote The collagenous burdles swell collagen fibers ( akutes degenerative exsudatives and become homogeneous Al o there is swelling Stadium ) be conceived to be followed by a of the cellular elements an mcrease of their subacute chronic granulomatous stage (granulo circumference and an ob ervable destruction of mato es Stadium des Zellknotchens ) the stage occa.ional cells This stage of the rheumatic of the fully developed A choff body in which proces we have designated as the exudative there is proliferation of me enchymal connec TCAI CT ·302 GEORGE E MURPHY myositis tive tissue cells in reaction to the collagen dam some of the lessons te embled those of pem age, and this 23 followed by sear formation arteritis Rodosa thrombo angutis obliterans and (Narbenstadım') Klinge illustrated in sys especially rheumatic arteritis Klinge Veubel tematic drawings in color his concept concerning and Junghans concluded that their animal ex the sequence of changes in collagen fibers That periments supported the concept that hyper Lcle cells are not directly involved is myo sensitivity is the be ic pathogenetic mechanism cardial nodules Klinge believed could not be in rheumatic fever and Klinge ettended this questioned But he recognized that heart muscle pathogenetie hypothesis for thematic fever to cells are often damaged in rheumatic fever, several human diseases on the basis of the ac and be attributed this damage in some instances currebce of lesions that he considered to repre in agreement with Geipel to pressure exerted by sent fibrinod degeneratson of connective lis A.choff bodies on contiguous muscle cells and sue Hence theumatoid arthritis pariarteritis in other instances to direct theurastic injury to nodosa thrombo apgutis obliterans dermatomuscle cells certaia nephritides, and malignant In 1901 Menzer (121) sugge ted that acute nephro clero is were regarded by his as con rheumatism lops is certain individuals who ditions with an allergic basis By the ane token because of hereditary or acqured conditions Ras le (154) and Jaeger (81) bekeved that react ua a special way to infection with various fibrinoid degeneration of collagen us a charac microorganisme especialy pathogenic strepto ters tic and constant morphological feature of cocci in the mouth Schuck (163) 0 1907 sug disez.es of allergic or patbergic background gested that the Nachkrankheiten of scarlet fever and proposed that such disea es as rheumatic including migratory polyartentis and heart fever rheumatosd arthritis periarteritis noda %, duele are allergic reactions Fredberger sad and thrombo angutus obuterans should be desig Cederberg (55) in 1913 reported that rabbits nated as the rheumatic group of diseases sensitized to foreign serum developed strikibs From 1930-33 Gross add Ehrlich (69 70) re joint swelling 5 to 6 hours after intra articular ported on their studies on the Aschoff body injection of the same foreign seran and Wein found in the unterstices of the myocardsal bun traud (197) in the same year concluded that dles They referred to this lesiog 13 the myorheumatic fever 19 an anaphylactic reaction due cardial A. choł body regarded it as bemg partic to a secondary allergic condition caused by in ularly specific for rheumatic lever and did not {ection In cutaneous Axthus tesetzons in rab consider that heart muscle cells are ever issolved bits made hypersensitive to sheep werum Gerlack in the formatson of this lesion They stated that (59) 22 1923 reported periyascular lessons and So many authors have etaphasized the domi Etselling of collagen fibers (the precent author Dant role played by injury to the collagen frame fibrinoid material in the lestons work in the development of the Aschoff body Gerlach s illu trations) Klussge (91) in 1929 pro that this can be considered to be an accepted duced arthritis by injectiog horse serum to the fact' They further stated that in the cave of knee jolots of rabbits casitired to borse serum the A cboff body it seerns fairly certain that He interpreted the reaction in the rabbit joints the earliest stages conist of swelling EOSINO as repre exting essentially a degenerative proces philie raetamorphosis and a certain amount of in the connective tu sue ground substance 10 fusion of the collagen fibers sth pan passti which bnoord necro 13 was 3 prominent proliferation of tbe me enchymal elements One feature and he kkened these changes to those the bass of their studies they suggested & classi jo human rheumatic polyarthritis He also de fication of Anchosi bosses comprising seven types scnbed in some of the sensitized rabbits pers that appeared to them to repre eat different cular lesions in the heart that he con dered stages in the life cycle They further wrote that to be analogous to Aschoff bodies Vaybel (187) Studies on the Auckoff body very early in its and Junghans (85) saduced artentis is the best deselarment invariably diclo e a Eweling of the and other organs and valvular endocarditis in interstitsał collagen fibers as the most con pie rabbit by repeated parenteral injections of uous phenomenon' To then the mot reliable foreign serum aubel interpreted some of }u tologie guude an attempting to fix the opet ** cutar changes as representing fibrinoid of an attack of rheumatic fever appeared to be stelling of collagen and he considered that the state of the collagen and concerning this sees 20 ·NATURE OF RHEUMATIC IIEART DISEASE 303 point they stated In common with & number fibrinoid change and the other is the cellular of observers we were impressed with the fact response And Robbins (151) concerting the that the collagen was the first to show damage in tissue changes in rheumatic fever has recently the form of swelling and the assumption of written as follows The specific lesion 13 known eosinophilic properties The earliest appearance as the Aschoff body which 9 a microscopic focus of swelling was therefore taken as confirmatory of fibrinold degeneration and granulomatous in evidence that we were dealing with the begin flammation Baggenstoss and Saphir (9) also ning of the cycle (70) With respect to the very closely following the concept of Talalajew variable appearance of A choff bodies they and Klinge have recently stated their interpre concluded The histological tructure of the tation of the early stage of Anchoff body formalesion apparently depends upon whether the tion as being swelling edema, and fibrinoid de A choff body originates from the dense or the generation of collagen and of the second or loose collagen on that phase of the híe cycle granulomatous stage (Aschoff body) as repre of the lesion that is being studied and also to enting proliferation of connective tissue cells ome extent on the individual reaction of the m reaction to the primary connective tissue given ca.e injury The histologic studies cited in the foregoing McEwen (117) in 1932 from study of supra portion of this section of the prevent communica vitally stained scrapings of subcutaneous nodules tion led to the now widely accepted histopatho in patients with rheumatic fever concluded that logical concept that rheumatic fever is essen the predominant cells he observed in the scraptially a duease of the connective tissue and ings represented theumatic granuloma cells they also served as the foundation for the ex that arose from undifferentiated mesenchymal panded concept whereby rheumatic fever is elements of loose connective tissue although he linked and classified with certain other diseases considered it possible that they arose in some 1 e periarteritis nodosa disseminated lupus instances from endothelial cells He further erythematosus rheumatoid arthntis sclero wrote Since there is little doubt that the sub derma dermatomyositis and other pathological cutaneous nodules are pathologically identical conditions on an anatomical basis of presumed with rheumatic granulomata elsewhere in the primary alteration of collagen and/or other body these conclusions are considered applicable intercellular connective tusue elements Terms also to the Aschoff body cells of the myocardızı used to link these dieases on this bus are submiliary nodules In contrast Saphir and collagen disea e diffuse collagen disease and dis Wale (162) at that time reemphauized the mor eases of the connective ti sue In accord with the phological differences between the Aschoff body concepts of Jack Talalajew and Klinge it has and the subcutaneous nodule and stated We been and continues to be widely assumed by have used the term Aschoff body exclusively for many that rheumatic lesions in subcutaneous the specific lesion found in the myocardium tissue tendon heaths synovia and many other and Saphir (160) has recently written Sub ites are very similar lesions with components cutaneous nodules and nodules in the synovialis like tho e in the so called Aschoff bodies in the should never be confused with Aschoff bodies heart Furthermore it is believed by many that With respect to drawing conculsions about As in the myocardium damage to muscle cells is choff bodies from study of subcutaneous nod only incidental to connective tusue alterations ules Gross and Ehrlich (69) stated Certainly and it is very widely believed that muscle cells the subcutaneous nodule pre ents a histological are not involved in the formation of the so appearance that is different from that of the called Aschoff bodies Talalajew and Klinge con Aschoff body and apparently lacks the clear sidered that the characteristic cellular elements cut specificity of the latter They further stated in the o called Aschoff bodies are proliferated that The Aschoff body occurring in the heart connective tissue cells that are only secondary to should be considered apart from the corre a basic connective tissue change in agreement sponding Theumatic lesions found in other tusues with this concept Bennett (14) in 1951 wrote such as skin diaphragm tendinous insertions as follows concerning the so-called Aschoff body and so on inasmuch as the myocardial lesions There are two evential components to it One present specific characteristics that are either 13 change in connective tissue the so called lacking in the other sites or have been insuf ·GEORGE E MURPHY ficiently studied as yet. The pre ent author's to prove a bacienal etiology of rheumatic feser OPIDON 18 in agreement t3th tho e here sted was that of Popova (135) in 1887 This investr of Fahr (49), Symmers (177) Graff (64) Saphir gator znoculated culture medium with bloom (160) and Gro s and Ehrlich (69) that there from a patient with rheumatic fever, and re are clear and uportant morphological differ ported that growth of macrococci resulted and ences between A choff bodies and subcutaneous that the intravenous inoculation of the ecronodules organisms in rabbits was follosed by the de- Gro s and Ehrlich (70) concluded in 1934 that velopment of arthntis, pencarditis and endotheir histopathological interpretation of the carditis from such lessons the micrococci could life cycle of myocardial A cboff bodies of rherz be cultivated In 1899 Westphal et al (200) and matrc fever 22 the last analy 15, must await Poynton and Paine (143) independently reported confirmation by the futberto unsucce sful trans that with diplococct zsolated from blood and 221 zon of this disea e to animals tissues of patients with rheumatic fever they V EXPERIBLEVTAL INDUCTION OF MYOCARDIAZ were able to induce in animals one or more of the following arthritis endocarditis and pets LESIONS CLOSELY RESEMBLING THOSE OF ACTIVE RILEUMATIC HEART DISEASE SPE carditis Cole (34) in 1904 reported that lesions in joints and heart could be produced in ani CIAL REFERENCE TO ABCHOFF BODIES mals following intravenous injection with vari A Hustomcal Background Jor the Experiments Ous streptococci from various humanources Since the last quarter of the past century other than patients with rheumatic fever many efforts have been made to produce in ani Schottmüller (165) described in 1903 a blood mals cardiac le sons like tho e characteristic of agar technique for differentiating hemolytic rheumatic heart disease in the hope of acquir from non hemolytic streptococci and in 1915 ing zaportant Inowledge of the etiology and Smith and Brown (167) distinguished between pathogenesis of the disease A review of tho e beta hemolytic and alpha or viridans strepto efforts up to 1952 has been reported by the COCCI by e of blood agar By this time there author (124 a) At least as long as 150 years had accumulated a large sumber of reports of ago mome play scans commented on an As OCI bacterema due to vindens beta hemolytic and ation between sore throat and acute articular other streptococcs in sheumatic fever patients rheumatı m In 1805 Klaygarth (74) mentioned and vindang streptococci had been reported to cyzanche as a not uncommon antecedent of occur in blood and lesions of rheumatic fever attacks of rheumatic fever With the rise of the patients far more frequently than other streptoscience of bacteriology in the last quarter of the COCCI Yet Swift and Kinsella (176) reported 19th century numerous efforts were made to in 1917 that from acutely involved joints an identify microorganismus as the cau e of tlus patients mth rbeumatic fever the cultures made deea e Webs (88) 2 1878 having attempted by them unformly showed no bacteria They re to diferentiate rheumatic valvular disease from ported the occurrence of vir dans or non hemo mahgnant ulcerative endocarditis stated that he lytic streptococci in blood cultures from le a thin had obseried cacer { tropads) valves in 10% of the many rheumatic patients studied by ca.es of acute rheumatic valvulitis Fowler (52) them Such streptococcz were recovered from in 1880 reported 20 well documented ca es in valvular leerons in 3 out of 6 fatal cues of which not only first attacks of acute rheumatism Theumatsc fever and hemolytse streptococcr but a one second attacks as well were pre were obtained from culture of an affected valve ceded by tonsillitis or pharyngiti9 He stated 1 of these fata) ca es that about 80% of the many cases of rheumatic 10 1901 Menzer (121) suggested that acute ferer which he had observed sere preceded by rheraatin develops in certain individuals who syraptoms of throat infection et en interval becau e of bereditary or acquired coodstion varying from a few days to a month Mantje rezet in a special way to infection with various (115) in 1888 reported recovery of diplococci microorganismos especially pathogenic strepton and short bacills from joint fluid and blood cocel in the mouth Schick (163) u 1903 Eug of patients with rheumatic fever gested that the Nachkrankheten of scarlet Apparently the first attempt to satu.fy the feser secludus migratory polyarthnts and cnteria in the Henle-Koch po tulates ia trying heart di ere are allergic reactions Weintraud ·NATURE OF RHEUMATIC HEART DISEASE 305 (197) in 1913 impres.ed by the clinical re em rheumatic fever in children Schlesinger (164) blance of the polyarthritis of rheumatic fever suggested in 1930 that repeated infection with and that of erum di ease suggested the follow streptococci may be important to sensitize the ing hypothesis for the pathogene is of rheu body adequately enough for the development matic fever The disease exhibits an individual of rheumatic fever In the following year Coburn reaction of the organu.m not to primary bac (32) submitted strong epidemiologic and bac terial invasion or bactenal touns but rather tenologic evidence that hemolytic streptococci a kind of anaphylatıc reaction due to a secondary among all microorganisms are uniquely causa allergic condition caused by infection The work tive of the infections that are followed by rheu of the Dicks (42) and of Dochez and a.sociates matic fever In the succeeding sear Todd (184) (43) reported in 1923–24 convincingly demon reported a method for titrating antibodies in strated the causative role of beta hemolytic the serum against a streptolysın of hemolytic streptococci in carlet fever By this time it streptococci This investigator (185) and Co had been hown (39) that the heart di ease that burn and Pauli (33) found that a consistent in follows in the wake of scarlet fever with tonsil crease in titer of antibodies to streptolysın O litis or pharyngitis is histologically identical occurs in the blood after infection by hemolytic with rheumatic heart di ease which had itself streptococci They found this increased titer to for many years been observed to follos tonsil occur similarly after infections with hemolytic hitis or pharyngitis Hector (75) after clinical streptococci and after such infections that were study of the effects of scarlet fever on numerous followed by rheumatic fever They found that the rheumatic subjects reported m 1926 that the titer in rheumatic subjects with inactive dis almost invariable result of scarlet fever upon ease was usually normal or slightly elevated a heart already damaged by rheumatism 18 a and they further reported a clo e relation be rekindling of the old trouble which in some cases tween occurrence of increase in titer and the had been quiescent for a considerable period clinical manifestations of rheumatic activity (in case 6 for 20 years) In the same year The work of Lancefield (101) and of Griffith a milk borne epidemic of sore throat ( angin3 ) (68) made possible a clear serological differenti caused by hemolytic streptococci involved about ation between strains of hemolytic streptococci 2500 inhabitants of Lolding Denmark Of 840 Lancefield (99) reported in 1933 that strains patients under medical treatment 30 were ob of these microorganisms can be differentiated served to develop rheumatic fer er late in the serologically by means of precipitin reactions course of the epidemic (103) In 1925–26 Swift into sharply defined groups which bear a defi (175) and Bezançon and Weil (17) independ nite relation to the animal source of the cultures ently drew attention to the similarity of change Thus group A was found to compre chiefly with passage of time of the recurring manifes strains of human origin Group A streptococci tations of dwease in tuberculo 13 syphillis and can be further divided into specific types on the Theumatic fever and they believed that al basis of serologically distinct type specific M lergy plays an important role in these changes proteins (Lancefield—98) Lancefield and awso The analogies between Theumatic fever and ciates (100) demonstrated both passive and ac serum disease remained largely on a clinical tive type specific immunity to group A strepto basis until hlinge and associates (85 92 187) coccal infections in mice in 1929-34 directed attention to hi topathologi That the character of the response of children cal resemblances in some of the lesions induced to hemolytic streptococcal infection changes to by them in rabbits by repeated injections of ward localization with age and with successive foreign serum and some of those described by infections was emphasized by Powers and a so them in ca es of rheumatic fever Renewed in ciates (13) and becau e this trend toward terest in attempting to elucidate the patho- localization re embles in some respects compar genesis of rheumatic fever by production of able phenomena in tuberculo is they introduced lesions in rabbits by intravenous injections of the term streptococcosis huttner and Lennert horse serum was subsequently greatly stimu (97) after tudies made over a 6 year period lated by the experiments of Rich and Gregory reported in 1914 that each successive attach (149) in 1943-44 of group A streptococcal pharyngitis in a given From study of first attacks and recurrences of individual had always been observed by them ·306 GEORGE E KURPKY to be due to microorganisms of a serological type slowed grossly visible verrucae, but bemolytic different from that causing preceding fection streptococcs were pot obtained in cultures from suggesting that type specific immunity was oper them The results of this study appear to proatre in streptococcal infections in man In the vde good evidence that the occurrence of rheu following year Hantu Boisvert, and Spink (146) madic valvultis is aot dependent on the pres. reported observations which suggested that te ence of streptococci in the valvular tissue infection with group A streptococci of diferent types may be important to the development of B Expenmental Induction of Myocardia! Theumatic fever Watson Rothbard and Smit Lesions, Closely resembling Those of Active (105) demonstrated active type-specific umu Rheumatic Heart Dwense, by Repeated Focal nity to group A streptococci u mankeys that Infections with Group A Streptococci - Ia an were inoculated intransally effort to experimentally induce cardiac lerons That rheumatic cardiac le.ions in particular like tho e in rheumatic heart disease tke author Yalvulas lesions are attended by, if not the and Dr Homer F Swift began a genes of long direct result of inve ion of the tissues by group terza esperiments i 1946 at the Rockefeller A streptococca was suggested by the reports of Institute These experimeots are continuing Green (66) Cols (85), and Thomson And New Zealand red and bare brota rabbits of Innes (161) on cultures at autopsy of beart the random stock of the Rorkefeller Instute valves of patients who died with rheumatic were intrally employed Subsequently we have fever In the e three studies taken together recov used rabbits of a stock specially bred As out ery of beta hemolytic streptococca was reported lined in the ection on purpose of Thu Com from one or more affected heart valses of 24 munication We selected group A streptococcs of the total of 36 patients who e valves were isolated from patents that had undergone cultured This view is aot supported, however many mouse passages (intraperitoneal) and by results of the following studies Swift and some strains in addition were paced intra Kawella (176) obtaided hemolytic streptococca venously through many rabbits The streptofrom an affected valve in only one out of 6 cacci have growu matt or mucord colonies fatal cases of theumatic lever in which the heart on rabbst blood agar and produced relatively Valves were cultured, Angevine Rothbard and large amounts of NL protein in Todd Hewitt Cecal (2) did not obtain bemolytic streptococcz broth made 19th Deo peptose in the intal in cultures of the valves in 5 iatal cases of theu experiments 15 to 20 hour broth cultures were matic fever and Klein (89) did not obtain hemm erially diluted 12 tenfold steps with Todd lytic treptococcs a cultures of valves of mandy Hewitt broth In subsequent experiments the patients who died with endocarditis of several dilutions have been made mth freskily ftered forms, mcluding Theumatic valvulitis Further Tyrodes solution to which 1% normal rabbit inore Watson Hurst and Lancefield (194) used Berum is added Because it seemed impractical sinct 3 eptic surgical technique during post to attempt to produce sutably sized repeated mortem examination of patients apging in focal infections in the throats of rabbits and age from 3 to 13 years who died with acute impossible to follos carefully the local response rheumatic heart disease in pointed effort to cul to such infections in that sste repeated focal cutaneous infection each with streptococco ture group A streptococc from the heart valves of these patent: A} heart valves in these 4 of different erological types, bave been set ca.es were cultured but no microorganismis sere up in clo ely clipped night and left gluteal or obtained Grossly visible verrucae were present lumbar shans at approximately mothly intes on the mitral valve in all 4 czes, on the aortic vals Inocwa, given intracutaneously in 01 cc volume hate contained between 10 and 10 cc valve 10 2 cases and on the tricuspid valve in of the orginal culture A period of 2 to 4 months 1 cae When they did not ob erve strict Deptic has been allowed to elapse before the last or surgical technique jo cultures of 28 beart valses of 7 other fatal cases of Theumatic fes er ranging 'challenge infection Esrker results of these experiments have been un age from 6 to 18 years they Isolated hemo reported u detail (123 127, 128) Summanzed lytse streptococcs from cultures of only 2 valves both of which showed gro fy viable verrucae brehy they mise as follows After sustaining however among these 7 patients 14 other valves multiple succe e focal cutaneous infection ·NATURE OF RHEUMATIC HEART DISEASE 307 аст. some rabbits sickened Among these some were focal infections with group A streptococci in allowed to recover (category A) and were ub rabbits with special reference to A. choff bodies sequently reinfected focally & portion were as shown in Figs 1-18 49–54 66 69 148 149 acrificed within 10-15 days following the lat 151 and 152 Among rabbits of random stock infection (category B) while exhibiting definite we have not found these lesions in 1) very symptoms of illness leukocytoºls and erythro numerous normal control rabbits 2) many cyte edunentation rates that were higher some that dicd or were sacrificed a few days to everal times markedly than occurred in controls omul weeks after one infection 3) many immunized taneou.ly infected with the same streptococci by intravenous route with killed group A strepa few developed severe and fatal alne s after tococci OT 4) many that died or were repeated infections (category C) whereas con ficed a few days to everal weeks after receiving trol anmals undergoing their first infections by intravenous route a large inoculum of living with the same streptococcı usually survived A group A streptococci of one of everal different very few here de ignated C-1 in category C erological types Furthermore among the very died within 2-5 days after the last infection many rabbits of random stock that have been re (even though a very large majority of normal peatedly infected focally by us with group A controls survived infection with the same strep streptococce only a small to moderate proportion tococc) and in all except one of these rapidly have shown rheumatic type lesions of blood vesfatal cases streptococcal bacteremma was estab sels and only a few have shown myocardial le I hed Among the rabbits in category C a few sions resembling Aschoff bodies and valvular bere designated C-2 that died between 6 and lesions like tho e in acute rheumatic fever How 14 days after the last of repeated infections de ever among a strain of rabbits specially bred as veloped streptococcal bacteremia but in the outlined earlier in this communication the inci remainder bere designated category C-3 of the dence of myocardial and of valvular lesions for animals that died between 6 and 14 days after lowing repeated focal infections with group A the last infection streptococci could not be streptococci 18 considerably greater These find cultured from the blood either before or shortly ings will be the subject of a future communica after death although streptococci were system tion atically sought for in blood cultures in every Our investigations thus indicate that in animal There were found in the hearts of some portant to the pathogenesis of rheumatic heart animals in categories B and C fre h valvular disease is a particular altered host reactivity myocardial and coronary arterial lesions closely to infection with group A streptococci that is Te embling tho e of active rheumatic heart dis induced by previous infection with these microea e and these lesions occurred in various com organisms The results of these experiments are binations Myocardial lesions closely re.embling in harmony with the fact that theumatic heart Achoff bodies and fre h vascular lesions were disease occurs in nature in only a small profound in the animals in categories B C-2 and portion of the very many in the random human C-3 that lived longer than tho e animals in population who experience repeated focal in category C-1 and the e myocardial and vas fections with group A streptococci Furthermore cular lesions and those of human Theumatic heart the results of these experiments appear to satisfy diseae differ in several important respects from the postulates that Opie (133) suggested should those of experimental and human serum dis be fulfilled before one could attribute an im eae (128) Myocardial scarring and healed portant role to hypersensitivity in cauation of arterial lesions like those of rheumatic heart a di ease In 1936 Opre wrote as follows The duease were found in the hearts of some rabbits evidence as embled to show that allergy usesthat sickened and also in the hearts of other sential to the production of certain disea.es for rabbits that were sacrificed after repeated in example rheumatic fever glomerular nephntıs fections but without signs or symptoms of active and lobar pneumonia is inconclusive even though disease at the time of sacrifice it is evident that allergic phenomena modify In the pre ent communication further evi their course It would be unwie to attempt the dence is submitted of the clo e te emblance be elaboration of postulates defining allergic dis tween myocardial lesions in active rheumatic ele after the model of Koch s postulates con heart diease and tho e induced by repeated cerning the causation of infectious dzea es ·308 GEORGE E MURPHY Nevertbeless certain condstsons mu t be fulfilled then of course, the lessons described bere could before thr allergic origin of disea e can be be designated 23 Abchod bodies If such a established It must be shown that sep stiza broadened criterion were accepted the mar tion precedes the production of tbe disease phologie diagnosis of theumatic carditis would by its inciting Agent This inciting agent lose its specificity for the only pathognomonic must be capable of reproducing the disease es feature the morphologist now has for diagnosis perimentally in sensitized apunals The inciting would have been acrificed Agent must be demonstrade in such relation The use of proper toorphologic criteria 25 to the human disea e that its symptomatology es entsal so bustopathological studies From the and lesions are explainable Though much sug endence at hand it appears to the pre ent gestive evidence has been collected the e con author that the morpkologic criteris employed ditions Exte not as yet been fulfilled for any by Sapbir as to what does or does not constitute infectious ds c2e In the case of our experi the true Aschoff body are not only unduly ments ve infected animals with microorganismas arbitrary but they fail to take into account at of the species causative of the nasopharyngeal all the involvement of my cle cells which our ofections that commonly precede attacks of evidence ubmitted previou ly (123 126) and rheumatic fever That sensitization preceded here shotss is es.cntial for the desclopment of development of the rabbit myocardial leszops these and other rheumatic lesions of the myo is indicated by the fact that these lesions DC cardium Saphir (159) has recently witer curred only after repeated focal infections As in brief reyset of attempts to experimentally propatients who develop sheumatic fever so too in duce in animal myocardia) jestops like tho e the rabbits of these experiments the strepto characteri tic of rheumatic beart disease and Concel rofectioa nas focalized distant from the in this review he rejects the evidence that we heart and as an human rheumatic rayocardial had previously submitted (123 128) to shoty lesions too in the experimentally induced not only the clo e resemblance between human my acardial le sons streptococcy could not be Aschoff bodies and myocardial lesions induced dertionstrated by us in addits but alo to demonstrate the Beveral students of rheumatic fever hare essential involvement of tu cle cells in Aschoff not accepted our evidence of the clo e resem bodies In beginning this review Saphis states blance between the rabbit and human lesions The follos ing discoure is not unbiased rather and Saphir (159) has been insistently critical at refects the experience gained from any obof our evidence in regard to 4 choff bodies servations Sunce in the course of reiteration fou 12 patients who died with acute rheu of his rejection of our evidence he (9) kas matic heart disea e that were ustrated by us written that scrutraj af relevent photomiero and submitted to demonstrate the close re graphs for comparison with the typical body semblance of these buman lesions to those in in the granulomatous stage should be reiealog duced by us a rabbits (123) Saphur and LAD to the unbiased obwerver it would appear gendorf (161) stated that in our opinion thr e pertinent to refer to the judgement of patholomu cular lesions are bot Anchoff bodies since Eats wbo are tinbiased 12 thus regard and yet they are at variance with the criteria as to what have had cos iderable experience in the study constitutes a typical Aschoff body while it is of the patholom of sheumatic heart d es e possible as Murplus showed that such lessons Wemperer (10) 2n pointed respect both to in the myocardous involving muscle fibers can the rabbit lesions produced by its and to the be reproduced experimentatis a typical Aschoff criteris of Saplur as to what does or does not body as Jet has not been reduplicated in an constitute the scalled A chofi bodies recently Opperimental animal The importance of clansary stated that I cannot eup ocr the astonistung og structures as A chof bodies only if they imilarity between the expenmental leesons and fulfill the cnteri3 cannot be overstreued If the A choff bodies in the human sumply becau a the e criteria as to what constitutes a specific the latter have been arbitranly defined Com Theumatic nodule or an Aschoff body were ye cerning endevee presiously submitted by 03 I lated to include parenchymatous nodules with wrot (123 127 128) Kemperat centers of pecrotic muscle surrounded by cells bare very carefully studied luus plater that com like those _ually found is an Achoff body pare the lesions experimentally induced by him ·NATURE OF RHEUMATIC HEART DISEASE 309 with those of human myocarditis I have spent to repeated infections by Group A streptococci considerable time reviewing the classic publica of varying serological types One question still tions of Gross and Ehrlich and the most recent remains ungnswered Recurrent Group A strep articles of Saphir and Langendorf and of Rueb tococcal tonsillitas 13 an excessively common ex ner I have studied in these last months many perience at all ages yet the proportion of those ca.es of rheumatic myocarditis from our files susceptible to this recurrent infection who deand I have become amazed by the great similar velop recurrent carditis u inerplicably small ity of the human lesions and those that have The same low incidence of cardiac lesions was been produced by Dr Murphy in the rabbit found by Murphy and Swift 1n experimental Concerning our experimental studies referred animals to here Harrison (72) has written as follows VI EVIDENCE THAT ASCHOFF BODIES ARE LE Recently Murphy and Swift (1949-50) have SIONS OF MUSCLE CELLS attempted to reproduce rheumatism in rabbits by following what they believe to be the usual A Evdence from Experimental Induction of course of events an man They assumed that Myocardial Lesions Closely Resembling Aschoff rheumatism in man followed repeated infec Bodies -- In contrast with the generally accepted tions with Group A beta hemolytic strepto concept that all Aschoff bodies represent primary coccı but they argued that in all probability injury to collagen and/or other connective tissue succeeding infections were caused by different components to which nonmyogenic cellular ele serological types They therefore induced re ments react our comparative studies on the peated infections in rabbits by giving carefully histopathogenesis of lesions of Aschoff body type graded small intradermal doses of Group A induced experimentally by repeated focal group streptococci of different types which would pro A streptococcal infections in rabbits and of duce infections well within the capacity of the Aschoff bodies in a very large number of pa animal to overcome These infections were re tients have revealed the following Aschoff peated at about monthly intervals over six bodies originate and evolve from theumatıc in months or a year They noted that if they gave jury to heart mu. cle cells The mono multi and the injections at different sites the later oneg nonnucleated structures characteristic of these produced a more violent local reaction than the lesions are of two types 1) damaged muscle cells early ones suggesting the development of an fragments thereof (Fags 28-45 61-90 154- increa.ed sensitivity After a vamable number 162) and 2) syncytial mases of myogenic origin of injections some of their rabbits became ill that proliferate from inside the sarcolemma in with dyspnoea leukocytos3 rapid uregular the tracks of diintegrated muscle cells (Figs pulse and raised sedimentation rate and died 7 8 10-18 52 53 57 and 59) and these in 4-14 days In these rabbits they found endo syncytial masses usually ba ophilic appear in cardial and myocardial lesions which bear a the beginning to represent an attempt at re striking histological and cytological resemblance generation of heart muscle cells Mono-or multi ta tho e of acute rheumatism Furthermore nucleated fragments of myofibers are very they did not find evidence of the polyarteritis commonly mistaken for histiocytes or other non which so often accompares the cardiac lesions myogenic mesenchymal cells and nonnucleated in animals made hypereensitive to foreiga serum eo inophilic sarcoplasmic fragments of myofibers On the other hand arterial lesions were pro (Figs 10-27 48-60 147 160 and 162) that bave duced which closely resembled those of natu completely lost their striations are usually er rally occurring theumatic artentis The interest roneously called swollen collagen fibrinoid of this work lies not only in the remarkable collagen or fibrinoid In later stages in the simularity of the lesions to those of human evolution of Aschoff bodies necrotic myofibers rheumatizm but in the fact that the mode of are commonly replaced by thick, new collagen production is similar to that which is believed fibers and the formation of this collagen in the to operate in human cases It 13 obviously scarring process commonly masks the evidence hazardous to apply the results of animal ex in these lesions of the earlier primary damage to periments directly to man but there now seems myofibers In patients who die after repeated at to be good evidence for the belief that acute tacks of theumatic fever myofiber fragments rheumatism 19 an expresion of altered sensitivity near arteries or at a distance from arteries may ·310 GEORGE E MURPHY be ob cured by collagen that has been lad pared mth such a hypothetical reaction in cox down erther during the previous attacks or sn the nective tue elsewbere 12 the heart or in othe! coure of the final ones parts of the body with respect to this point B Ongin of Interstitial Myocardial Aschoff Gross and Ehruch (69) wrote as follows While Bodies From Heart Muscle Cells in Bundles Be a con_iderable concentration of collagen ts found tween or Among Other (Oſten Larger) Bundles around blood yes els and so the subendocardium of Afucle - Aschoff bodies have been repeatedly its distribution in the heart considered as X described as occurring in unterstices between bun whole s not o widespread around the va cular dles of myofibers The word interstitial 19 de bed and subendocardura As it is in the inter scription of rheumatic myocardial lesioss was stitial to sue between the muscle burdles used by Goodhast in 1879 in referring to inter In the reports that I have read of many pa stitial cell growth around the ves els and between thologists since 1879 who have stro.sed the oc the mucular facicuh, by Cadet de Gassicourt currence of Aschof bodies in the interstitiuma in 1887 un reference to "prouferation of cellular between large burdles of myofibers I have been unterstitial growth, by Krebl in 1889 who re aston bed at the consstent failure to take into ferred to interstitial myocarditis , by Aschoff 28 account the occurrence of myobbers fey 13 1904 who referred to the specific lesions 29 in number or in small or larger buddies between ter trtial myocarditis and recently by Baggen or arcong other bundles of szyofibers Qute sto.8 as Saphir who refer to the Aschof body clearly myofibers occur in shall aggregates or 19 representing focal interstitial myocarditis bundles and in larger bundles betueen or among In accord with his concept that all characteris other bundles of myofibers (Figs 19-27 70-74 tic rheumatic lesions essentially repre ent reac 76 77, 79-81) Usually by the time the patholo tion of connective tissue to injury Talalszex gist ob ertes the lessons in rbeumatic heart disea e involved interstitial muscle between or stated that in the case of the myocardial locals zation of the process the exudative-degenerative has been so altered that st 19 no longer recogniz among other muscle bas been destroyed or it moment is usually weak, and the process appears to begin with the przegry cellular proliferation able as muscle in the myocardial lesions Figs 2 which is in accord with the views of Aschoff 6 13, 19-27 55 74 80 and 81 illustrate the Concerning the hustologic characteristics of origin of so-called interstitial Aschoff bodres sheumatsc cardiac injury Baggenstos and from cardiac mu cle libera ol bundles between Saphur have receatly stated that attention has larger bundles of nucle fibers And Figs 48, been conceptrated primarily on the proliferative 50 54 55 73 76 77, 79 and 162 further indicate and etudative phae of the siammatory read how Ascboff bodies, derived from bundles of tion to the neglect of what 19 now widely ac cardiac myofibers among other bundles will cepted as the primary injury to the connective them elves eventually be converted in the scat tissue The lack of study of this phase of the nag process unto interstitial areas of connec mflammatory proces us coderstandable because tive ti.sue between intact contiguou buudles of it 15 relatively poorly developed in the myo myofibers When siøgle myofibers (Figs 28-31 cardial legions and often obscured by the ex 34-36 70 72 156 and 161) or myofibers 16 small udative and proliferative processes Why I or larger aggregates (Figs 2 4,6 8 25 27, 73 would like to k should the hypothetical ex 74 76 77 79-81 157-160 and 162) between or udative-degenerative moment of connective tisamong other) bundles of my ofiters become ɛue change referred to by Talalajes be weaker damaged beyond recogn2tion in the formation of in the myocardium than elsewhere the structures characteristic of theumstic dlce Or why should the hypothetical primary anjury to the of the myocardiunt st 13 understandable how connective tissue be relatively poorly devel advocates of the generally accepted connective oped in the myocardial lessons (Baggensto s ti sue concept of the origin of the e lessons fail to and Saphır) 29 compared with rheumatic lesions take into account the essential in volsemeat of eLerbere? There 13 do lack of collagenous con my ofbers for recognizable fragstents of the pectre tissue in the myocardium to explain & myofibers are only found in the early stage of bypothetical resk or poorly developed pri development of the e rheutda uc lesions In later maty reaction in connective tueue here as com stages the unrecognizable myogenic elements are ·disease and although tine stiert: db NATURE OF RHEUMATIC HEART DISEASE 311 often further obscured by collagen laid down mented clumped or fused collagen fibrinoid in scarring collagen , or fibrinoid Figs 10-12 and 17 from a rabbit and Figs 15 and 18 from humans show C Ongin of Aschoff Bodies From Heart Mus central cores of sarcoplasm in intimate connec cle Ceus Close to Blood Vessels -Aschoff bodies tion with myogenic multinucleated masses The have al o been repeatedly described as occurring lesion in hg 16 from a buman 19 strikingly like very near arteries (Figs 4 75 and 78) I have that in Fig 17 from the rabbit and the changes repeatedly observed that individual as well as small and larger aggregates of myofibers occur in Fig 13 from a human are strikingly like those in Fig 10 from a rabbit Likewise the syncytial in very clo e proximity to blood vessels Indeed multinucleated structure at the top of Fig 14 heart muscle fibers sometimes occur so close to from a human bears very striking re emblance the medis of myocardial vessels that it is diffi to that in Fig 11 from a rabbit Figs 10-18 cult to see vascular adventitia between Figs 16 37-45 75 and 78 illustrate the occurrence of illustrate what in my view is probably a limited attempt at regeneration of cardiac muscle cells muscle cells close to blood vessels and the ongin in both the experimental lesions and the human of the cellular elements so characteristic of rheumatic lesions and Fig 52 from a human and Aschoff bodies from muscle cells so located When my ofibers in these sites become damaged Fig 53 from a rabbit illustrate this same point Taken alone the lesions in Figs 50 52 54 57 beyond recognition (Fags 75 and 78) in the for 59 and 60 from humans might be interpreted by mation of rheumatic leuions it is understandable many as showing a central core of fibrinoid how one may fail to take into account the es sential involvement of myofibers near blood however when studied together with the other pictures of human and rabbit lesions of muscle ves els for recognizable fragments of the para cells in these two plates (Figs 46-63) and with Vascular myofibers may only be evident in the earliest stage of the Aschoff body formation The Figs 10–18 it hould appear obvious that these are lesions with a central core of sarcoplasm end result of rheumatic damage to paravascular muscle cells in the myocardium is replacement of Figs 52 and 59 are sections of the same lesion these muscle cells by often thick collagen fibers In the myocardium of patients with active rheumatic heart disease there may occur focal of scar areas of thick collagen fibers some of which may D Connective Tissue in Aschof Bodies Some with certain techniques stain like fibrin inter of The Reasons for The Common Misinterpreta mingled with small and large cellular element tron That Aschoff Bodies Are Non-myogenic Le In interpreting the significance of such che sions Derived From Connective Tissue Elements the following observations are pertinant 1, In Aschoff bodies previously illustrated and Some collagen fibers in normal tissues pay 12 submitted by us evidence of the myogenic the same stain as fibrin with various origin of these lesions (123 126) there was techniques 2) in the myocardium autres * neither fibrinoid alteration of collagen fibers who have experienced attacks of the nature for you nor fibrinoid material between collagen fibers many years before succumbing to dayken and although some thick collagen was evident rhosis of the liver associated with Lozoy **** in some lesions the collagen in the majonty of of alcohol over many years I Lay fit ? lesions was thin and stained as normal collagen ome of the thick collagen fibere y In the present communication there are sub- cardial scars stated like fbnn es est elmer mitted many more illustrations of Aschoff bodies absence of cellular reaction 1, a to its in which the connective tissue appears normal of death of these patients that for 1021 In the Aschoff bodies in Figs 33 73-81 and 8 or histological evidence of 2nd year 2018 - 00 the connective tissue is normal the collagen ease in any of the many tente ?) delicate As previously mentioned in the first collagen in the scarred and state for these part of this section Figs 10-21 23 24 27 33 patients aLo stained lk. The gove 49 50 52 54 55 57 59 60 77 80 81 147 160 just referred to had in 15 in ore 225.ceeds and 162 illustrate sarcoplasmic fragments of having Laennec s cinkog modele myofibers that have completely lost their stria pointedly concerned tions Such sarcoplastic fragments are very often erroneou ly referred to 29 swollen frag * *rdy of attacks of rbeuro Euro por 107 ·312 GEORGE E MURPHY death there were so clinical or bistological find often mjured 10 Theumatic fever, and such wgs to suggent that the patients had ever been material is bordetimes found in valves and not in cardiac failure, and the cirlboss, therefore Uncommonly in pericardrum, subcutaneous nod was not related to congestive heart failure The ules ou and beneath the lining cells of synovial observations cited just above when taken to membranes, and in other tissues That Aschoff gether wdicate that in evaluation of the signifi bodies and expenmental lesions of Ascboff body cance of thuck colagen fibers, some of which type can occur, as Illustrated previou ly (123, may stain de fibrin, in the bearts of patients 126) 19 the absence of fibrinord and in the with inactive or active rheumatst besrt de ease, absence of strands of tripgy taxifying matena! the following must be considered as a hlely that taun hike fibrin u further clearly demon explanation the thick collagen fibers were prob- strated here in Figs 1-5 33, 73-90 157, and 159 ably laid dawa in scanning during previous sbeu In thus connection it is pertinent that Anchoff matic attacks and/or in the course of the final (5), in 1939 after study of these lesions over A attack period of thurty five years pubushed illustrations In connection with this point it is pertinent in color of several characteristsc fresh Aschoti to refer to the detailed morphologic studies of bodses in the myocardnm of & six year old Gross and Ehruch (69, 70) who attempted to child After commenting on the normal appear trace the life cycle of myocardial Asekoff badies ance of the connective tissue in the Aschoff One of the seven structural configurations of bodies in this case, de further wrote in criticism Aschoff bodies which they described is the small of the hypothesis concerning fibrinod u theu cell coronel type which, according to these matic lesions Despite the celular overgrowth authors compre a central mass of swollen which has caused the formation of the modules collagen surrounded by a mantle of swaall baso there is no trace of a fibrinaid degeneration of philic cells They believed that this lesson repre the ground substance' Azd in reference to tayo sents a very early stage of sheumatic damage cardial Aschoff bodies in general he concluded Jet they failed to find this lesion in any of the It is in no way essential that the formation of patients who died during & first attack of theu the richly cellular nodules should be preceded by matic fever This lesion was found by them only fibroid degeneration of the ground substance an tho e cases in which more than one attack of On the basis of my own studies carried out in rheumatic fever bad occurred If as they main tepsively in the past ten consecutive years, of a tamed this lesion really represents one of the very large number of cames of active rheumatic two earliest stages of Aschoff bodies one would heart disea e I am in complete agreement with certainly expect to find this lesion 20 a first Aschofi on this point and 10 obvious disagree attack rather than only after repeated attacks ment with the conclusons of Talalajew (178) In my view there are two possibilities that best Klinge (91) and the many who have followed explain the occurrence of the so called small cell them (9 23 76, 151 156 159 179, 193) coronal type Aschott bady 1) The "swollen The lesions in the mz ocardum know2 geper collagen may represent tluck collagen Eard down ally as A choff bodies, have in my opinson char during previous attacks or in the course of the acteristic features that clearly distingurh them final attack, and 2) the central core io some of not only from rheumatic leszong outade the heart these lessons is not collagen 1t 13 sarcoplasm of but alo from the great bulk of rheumatic lesions muscle that has disintegrated as show in Figs in cardiac valses and sub-pericardial tisue Thus 50 $4, 57, 59 sed 60 Indeed, the lesson m Fig distinction in my viem, z8 baned on the primary 60 has an almost identical appearance to that 10 and marked damage to heart muscle cells that Fig 1 in & paper by Gross and Ehrlich (69) 11 results in the two types of cell masses that I lustrated as their example of the small cell have previou.ly (123 126) and more extenst vely coronal Aschoff body bere described and Bustrated in this connection In active rheumatic beart disease focs of It is pertinent to mention that Aschoff (5) 17 strands of strogy, ramifyug sometimes inter 1939 placed particular, and to me distingul king lacing material, that stan uxe abra are occa emphasis on the specific rheumatic le long in the sonally found in the myocardsum This matenal myocardium 19 compared with rheumatie en may very well be sbrin Lelf that has pas ed Erons elsewhere Achoff wrote Bayisy but from the blood through smal vesels that are Vesed the world Iterature I am still coannced ·NATURE OF RHEUMATIC HEART DISEASE 313 that rheumatic nodules as seen in the heart mus to the submılary nodule It is noteworthy that cle (pre ent author & italics), are pecific to this MacCallum (110) found such lesions in sub rheumatic disease, and he further stated As epicardial ti sue but never in the parietal layer a result of my experience I can state emphati of the pencardrum In rheumatic pericarditis cally that the rheumatic nodules u hich appear in deposits of fibrin may be misinterpreted as the myocardium (pre ent author 8 italics) are fibrinoid or fibrnold degeneration of con specific to the Boullaud Graff diease (theu nective tissue In Etes of such exudate histio matic fever) cytes may be found and I have in several ca.es The occurrence of beart muscle cells in cardiac been able to identify mesothelial lining cells of valves (Figs 109-116) and among fat cells in the epicardium that are ba. ophilic and have be sub-epicardial tissue (Fig 153) s discussed in come sequestered in this exudate or in the ection VI.E and the occurrence of smooth mus chronic inflammatory reaction that follows And cle cells in atnal appendage and cardiac valves not uncommonly I have observed pseudo-glan (Figs 91-108) 13 discus ed in sections VII.A dular proliferation of these sequestered epicar and B dial cells like that shown by Baggenstos (8) E Occurrence of (Strated) Heart Muscle Certainly focal acute and chronic inflammatory reactions that reernble those in valves synovil Cells in Cardiac Valies and Among Fat Cells in and subcutaneous nodules occur in rheumatic Sub epicardial Tussue –One argument that has pericarditis But the e changes should not be been employed by ome investigators (156 193) against evidence of the myogenic origin of interpreted as A. choff bodies on the other hand cardiac muscle fibers occurring singly in small Aschoff bodies is to use the words of one critic aggregrates or in larger aggregates often appear that Aschoff cells are often found in tuations to be Lolated in sub-epicardial tissue from the where there is no muscle ie in the sub-epi cardial tissue and in the valves (156) Evidence body of myocardium Fig 153 hows such a cluster of heart muscle fibers among fat cells subratted with the present communication dem well out 22 sub-epicardiel tissue and connection onstrates that this criticism is not valid All of this muscle to the body of myocardium beauriculo ventricular valve cusps have inserted neath does not occur in this section Such aggreinto them a wedge of myocardium that extends gates very probably represent finger like or other for greater or le ser distances down the valve forms of projection of myocardium which hap- Fig 110 illustrates this point in a human mitral pen to be sectioned in such a way as to appear valve and Figs 109 and 111 llustrate this in isolated in sub-epicardial tissue Rheumatic in rabbit tricuspid and mitral valves Figs 112-114 volvement of such apparently Lolated heart illustrate the occurrence of considerable strated muscle fibers could result in a myocardial Aschoff heart muscle half way between tbe mitral sulcus and the tip of a mitral valve in a nine year old body that would appear to be in the sub-epicar dium and isolated from the rest of the myocar boy who died with acute glomerulonephntis drum (there was no evidence of active rheumatic heart duese) Fig 115 illustrates clusters of striated F Elucidation of the Myogenic Ongin of heart muscle cells in the first portion of a mitral Rheumatic Myocardial Leszons Including As valve and Fig 116 shows considerable stnated choff Bodies From Findings in Human and Rab heart muscle in an extension of a wedge of bit Skeletal Muscle--In two cases of rheumatic strated myocardium well out into the aortic fever Huzella (77) described lesions in skeletal leaflet of a mitral valve Fig 117 shows striated musele that closely resembled Aschoff bodies in heart muscle fibers in erted well down along and into a chorda tendinea the myocardium He believed that he could trace The occurrence of smooth mu cle cells in car the origin of giant cells closely resembling those diae valves illustrated in Figs 99-108 will be in Aschofi bodies from muscle cells in these dicussed later in this communication lesions of skeletal muscle This has also been my Lesions resembling the myocardial A.choff experience and our findings in both human and bodies have been reported in sub-epicardial tisrabbit skeletal mu.cle shed light on the myogenic sue Coombs (39) illustrated and described in nature of myocardial Achoff bodies Fig 46 from rheumatıc pericarditis pervascular areas of skeletal mu cle of & rheumatic subject and Fig fibrinous depo it and cellular infiltration similar 47 from skeletal muscle of a rabbit repeatedly ·314 GEORGE E MURPRI infected focally with group A streptococcare found in respectively patients who died sith strikingly like the myocardial Aschot body in rheumatic heart disea e and rabbsts that mark Fig 48 In turn the e three lesions are like tho e edly cảened after repeated focal infections with in Frus 49 and 50 Fig 55 shows an A choff group A streptococct and the e le ions are ia body that would be referred to by many as cluded in this monograph because of the ad sater titial This A choff body is derived 25 they give in elucidating the histopathogene s are the le ions in Figs 20 23 24 and 27 from the of rheumatic lessons of heart mu cle cells same patient from a bundle of myofibers betreer larger bundles in this A choll body the G Ongin of Aschoff Bodies from Heart N/ track of a di integrated myofiber can be traced cle Cells in Cardiac Atnal Appendages Since from the upper left portion to the fos er nght 1931 many reports have been publ ked (18 portion and in the upper portion of this track 28-30 41 44 47 48 83, 9a 102 108 111 114 Is granular sarcoplasm and in the lowet portiota 118-120 126 139 140 150 156 170 179 180 of the track a sughtly basophilic elongated mass 186 190) og histologic tudies of left atral ap of sarcopla-m At the top central portion of the persdages removed at the time of operation per A choff body s & multinucleated structure with formed to alleviate mitral stenosis in patients who annular arrangement of Rucles This structure 13 howed gas and symptoms of cardiac identical to tho e in Figs 57 and 61 from the failure of varying seventy and duration Al ame patient Note the striking re emblance though the very large majority sere con idered al the e structures to that in rabbit skeletal to os no clinical evidence of rheumatic ac mu cle (Fig 56) which is ad obviously myogenic tivity at the tsme of the cardiac surgery a large structure with anouar arrangement of myogenic proportion bave shown specific rheumatic le nucles around a core of sarcoplasm Note also sions generally referred to as Aschoft bodie the strong resemblance of the annular lesions 10 in the bropsied left atral appendage Figs 55-57 and 61 to that in Fg 59 from a13 The atrial le rons that resemble closely some other patient Fig 59 and Fig 52 are sections at Aschof bodies in the ventricular myocardium different levels of the same lesion Then aote the are described by many as occurring in the endo striking re emblance of the myogenic lesions in cardum of the atriura Since cardiac myofibers do bot occur in the endocardium ome ob ervers rabbit skeletal muscle in Fig 58 to the human rheumatic lesson in Fig 59 Furthermore the bave interpreted the repeated findings of A chof bodies in the mural endocardium of the structure sith the angular arrangement of nucler in the rheumatic lesion in Fig 63 is very strik auricular appendages (193) as evidence con ingly be the obviously myogenic structure of trary to our evidence of the development of the rabbit Leletal muscle in Fig 62 in wbich Aschoff bodies from injured mu cle cells How the nucles are arranged 10 & ring within the ever my om findings bave hond that such atrial Aschoff bodies (Figs 82-86 89-) that sarcoplasm Fig 64 is from keletal muscle of a closely resemble ome of tho e in the ventricular rheumatic patient who died with A..choit bodies in the myocardrum That thrs 13 & myogenic myocardium (Fig 87) originate from damaged lesion with basophilic sarcopla m and prolul heart muscle fibers just subjacent to the subendocardrei zone of emooth muscle and connec erated myogenic nuclei is evident Fig 67 from tre t..sue (125 126) As it expands an A choff rabbit keletal muscle shots & very similar body developing from heart mu cle cells in this lesion compri ing only and sery obviously multi area often thrusts ats way toward the endonucleated frogments of a mis ofiber The lessons cardium o that part of the A choff body comes of rabbit keletal muscle in Figs 65 and 67 hate to lie in the subcadocardura When 12 tho e multinucleated my ogenic structures that sery areas where the subendacardial zone 29 thin clo ely re,emble the human one 10 Fig 63 that these myocardial A chorf bodies in expanding us from the myocardium of a patient who died come to lie co c to the overlying endocardium Tith actise theumatic heart di ease endo- In my judgment tbe le sons of skeletal muscle they are commonly misinterpreted as cells here illu trated are probably not specific for cardial Aschoff bodies These and other points are 2xlustrated in Figs $9.00 and will not be the equelae of focal infections with group A dheu ed Fix $2 shows several A cboff bodies streptococci 13 esther humans or rabbits The fact remains, however that the e lesions were in the loves portion of the ncture and one at ·NATURE OF RHEUMATIC HEART DISEASE 315 the top center Except wbere the A choff bodies matic heart direale alterations of heart mu cle occur one can see that the myocardium comes fibers in the ainoventricular node (26) and in Very close to the endocardium and the clear the atrozentricular bundle of His and left bun inference here borne out in the other figures of dle branch (107a 173a) like rheumatic lesions this plate is that the Aschoff bodies are recent that occur eLewbere in the myocardium Lumb nodular defects in myocardium just below the and Shacklett (107a) found in the left bundle subendocardium Fig 83 very probably repre branch and allustrated an Achoff body trik sents an early stage of a small Anchoff body ingly like tho e in Figs 2 80 and 81 in the clearly repre.enting focal de integration of heart pre.ent communication The le ions here shown mu cle cells just subjacent to the subendocar in Figs 2 80 and 81 were deep in the posterior dium Collagenization of this little wound would wall of the left ventricle Figs 80 and 81 are be expected to occur and it appears to be under from the patient referred to in Figs 26 38 45 way Fig 81 alo ghoss an Aschoff body derived 69 73 76 and 79 from heart mu cle cells just subjacent to the subendocardium The connective tissue in this VII DISEASE OF SMOOTH MUSCLE CELLS EN RHEUMATIC HEART DISEASE lesion appears normal Note the tendency of the nodule to expand toward the endocardum Fig 4 Rheumatic Disease of Smooth Muscle Cells 87 18 an A choff body that allu trates the same in the Subendocardial Tissue of The Atnum change in the left ventricle Figs 85 and 86 are Special Reference to Lesions in Atrial Append from the same ection stained successively by ages That Resemble in Varying Degree Aschoff two method. The connective tu sue appears por Bodies That Are Derived from Heart Muscle mal in thug lesion which is an Aschoff body and Cells-Fith respect to specific rheumatic le sons clearly derived from a bundle of heart muscle found in the subendocardium of the atrium the cells and it has expanded slightly toward the fact is very often indeed usually not taken into subendocardium Figs 88 and 89 are from the consideration that emooth muscle cells normally same section of another appendage that was occur in varying amount often in large numbers stained succesively by two methods The con and sometimes in strata between atral endo nective tissue appears normal in this lesion which thelium and the body of striated myocardium is also derived from a little bundle of heart mus And in some portions of the atrium including the cle cells Fig 10 very probably represents the atrial appendage Emooth mu.cle occurs very following The atnal myocardium has been close to the endothelium These points are eroded or cut back by rheumatic activity and in clearly illustrated in Figs 91-98 It has long the process A choff bodies from damaged mus been known that smooth mu cle cells in media of cle cells have formed Collagenization of the e myocardial arteries are often damaged in theu myocardial wounds has occurred and is still matic fever (87 129) and I have observed underway multinucleated smooth muscle cells and lesions With re pect to the ongin of rheumatic myo resembling A choff bodies in the media of cardial le long von Albertini (1) was able to myocardial artenes (Figs 118–135) that will be determine that many myocardial nodules are later diecused It appears that reaction to of myogenic origin and Ghosh (60) from rheumatic fever injury of Emooth muscle cells in atrial subendocardial tissue (between endostudy of the heart of patients who died with a clinical diagno is of acute rheumatic beart dis thelium and strated myocardium) results in ease concluded that the pathologic changes were focal lesions homologous with tho e here allu due mainly to degenerative and reactive phe trated in the media of myocardial arteries and nomena on the part of the cardiac muscle cells the e lesions in vatsing degree resemble the so- Rheumatic injury to those cardiac muscle called Aschoff bodies that are derived from fibers that are widely considered to constitute heart muscle cells Fig 91 shows a section of specialized conduction t2 sue should probably be atnal appendage stained with phosphotungstic espected to result in le.ions es entially like or acid hematoxylın to illu trate that an avenue or identical with tho e that result from Theumatic band of smooth mu cle cells normally occurs in injury to other cardiac mu cle fibers Indeed the subendocardium Io Fig 94 just below one there have been reported in ca es of active rheu sees a similar avenue of Emooth muscle in the ·316 GEORGE E MURPHY subendocardium of stnal appendage from an w Valves. The continuation of atra? subendo other patient As the eyes of the viewer move cardial smooth mucie dova into the auricularis dowo thus avenue of smooth muscle, they come Layer of the mitral valve is ilustrated in Fig 99 to a leion that les directly in the lower portion Figs 100-108 illustrate the occurrence of smooth of this avenue and which has the same width as muscle w mitral and aortic valves and the that of the avenue of smooth muscle This le matac involvement of such smooth muscle ng sion is shown in higher magnification in Fig 97 100 shows a central avenue or track of smooth and 13 a specific rheumatic lesion, which re muscle that stains purple Fig 101 skovs sembles an A cbofi body that develops from spindle haped lesion resembling a so-called As heart mu cle cells Indeed, this particular leron chofi body, in the lower portion of the track of resembles tho e myocardial Aschoff bodies desig smooth muscle that 29 a continuation downward pated by Gross and Ehrlich (69) as being of of the smooth muscle track shown in Fig 100, coronal configuration and Fig 102 skows in higher magnification the His 95 18 from a rabbit that died 11 months lesion ja ysg 101 Figs 103 and 101 show smooth after the last of 5 focal infections with group A mu cle in mutral valves and Figs 105-108 shov streptococci Ofconderable interest to the smooth muscle in the ventricular aspect of the writer is the fact that several days after the sortic valve The occurrence in Hg 108 of abnor beginning of the last focal mfection this rabbit mal large cella in rows us uke the occurrence of developed & cardiac syetolic murcaur that per abnormal large cells an atral subendocardrum that sisted until death of the animal Note the stnk MacCallum (109) described as being curiously ing re emblance between the rabbit atre) le forced into rows between elastic fibers That sous in Fig 95 and the human atnal lesions in staooth muscle cells normally occur 10 atria) sub Fig 96 that is from a patient who died with endocardiun un rows or strata between elastic chronic actie rheumatic heart disease fibers has been discussed in the unmediately Io Figs 92 and 93 are seen broad svenues of preceding section of the communication and 11 subendocardial rooth muscle The endence lustrated 10 Figs 92-98 Figs 106 and 107 show bere submitted indicates that the lesions i Fags that smooth muscle (stained purple) occurs 10 94-97 are lesions of smooth muscle cells MRC rows or strata also in the ventricular espect Callum (109) described podwar rheto atic le of the aortic valse and the similar occurrence azons ometunes cunously forced into rows in Fig 108 of abnormal large cells in rows bem between elastic fibers in atnal subendocardura treen elastic fibers in the ventricular aspect of It should be recalled 88 pointed out in the begins the aortic valve strongly sadicates that the e Ang of thus section that smooth mu cle cells large cells are smooth muscle elements and uke occur normally a rows or strata in atrsal sub the abnormal large cells that MacCallum (109) endocardium described as "cunou.ly forced into roses be The legions of smooth muscle cells here dustseen elastic fibers in the atrium trated may well be termed speciae rheumatic C Rheumatic Disease of Smooth Xuscle Ceus Lesions of smooth muce in Nyocardial Artenes -It has long been known Von Glahn (189) described 19 atral sub- As previou ly mentioned, that media in the endocardial tissue rheumatic change comprising arteries of the heart is often damaged in rheu dease infiltration with polymorphonuclear leuko Batic fever (87 199) Vacuolatso edema ne cytes small tound cells a few plasma cells and Croste and abrons of the media which are all Occa.1onal eosinophiles in asociation sth pale sonspecific changes have been deceribed Figs cells with vesicular nucle: It would appear that 118-135 illustrate other theumatic medal this subendocardial change, very probably im changes some of which have to my knowledge nerer been described before in theumatic feres portantly shociated with damaged scooth mus cle elements is analogous to the infiltration of Figs 118-120 and 123 show multinucleated cells darbaged myocardum sitb inflammatory cells very probably smooth mu cle cells, in the medis associated with myogenic cellular elements (as of arteries in the heart of paticate the died mth actre rheumatic heart disease 191 hown in Fig 150) that will be ducussed 20 sec and 12 ilustrate amdar multinucleated cells in tion IX.B of the text the media of rabbit myocardial arteries Fige B Rheumatic Disease of Smooth Bluscle Cells 122-126 hot s focal lesion clearly of the wedia, ·NATURE OF RHEUMATIC HEART DISEASE 317 of a myocardial artery 10 which a multinu those in Figs 130 and 132 in the present com cleated cell occurs and this cell is likewise very munication and did not closely approximate the probably & sirooth muscle cell Fig 127 shows specific character of an Aschoff body in the nght lower portion a defect in the media VIII REASOYS FOR THE COON MISINTER of a large myocardial artery Figs 128 and 129 PRETATION OF THE HISTOPATHOGENESIS AND show with higher magnification that this medial SIGNIFICANCE OF SPECIFIC RHEUMATIC LE lexion comprises basophilic mono and multi SIONS OF MUSCLE CELLS IN RHEUMATIC nucleated ragged-edged elements that are very HEART DISEASE SPECIAL REFERENCE TO probably derived from smooth muscle The larg THOSE IN ATRIAL APPENDAGES est cell in the upper portion of Fig 129 has at least 5 nucler This medial lesion resembles As Figs 118-135 of medial lesions in my ocardial choff bodies that are derived from heart muscle arteries taken together with Figs 91-98 of cells Nodules of medial cellular elements very strial subendocardial smooth muscle and with probably altered smooth muscle cells are seen Figs 99-108 of emooth muscle in rheumatic in the lower left portion of media of an artery in valves are evidence of focal rheumatic involve- Fig 130 and in the right lower portion of the ment of smooth mu cle cells which can some media of another artery in Fg 132 and it is times mimic Aschoff bodies To the knowledge clear that in the case of neither of these nodular of the wnter no one has previously suggested lesions is the specific character of an Aschoff that rheumatic disease of smooth muscle cells body approximated On the other hand Fig 131 can result in such lesions The evidence here shows a segment of arterial media that has been submitted on this point appears to be a satis converted into a lesion that comprises baso factory answer to the criticism of some (156 philic mono and multinucleated ragged-edged 193) that occurrence of lesions resembling elements that are very probably of smooth mus Aschoff bodies in valves and beneath the endo cle origin This lesion resembles an A.cboff body cardium of atria constitute evidence against the Finally Figs 133-135 show at different magnifi myogenic origin of Anchoff bodies cations a nodular lesion that comprises slightly The very great majority of studies to date on ba.ophilic ragged-edged cellular elements that the pathology of rheumatic heart disease have aro e very probably from medial smooth mus not taken into account the occurrence and in cle elements and thus lesion also resembles an volvement of muscle cells in the following sites Aschoff body 1) heart muscle cells (in interstitium) be- In connection with these findings it is note tween other heart muscle cells as shown in Figs worthy that Pappenheimer and Von Glahn 2 6 8 13 19-27 73 74 76 77 79-81 157 (136) reported that in the media of a case of 159 and 162 2) heart mu cle cells very close rheumatic aortitis A few multinucleated cells to blood vessels (Fig9 16 37-45 75 and 78) and in another report (137) they 3) heart muscle cells just beneath atrial and descnbed in rheumatic aortitzs cells resembling ventricular subendocardial tissue (Fig3 82-90 those in Aschoff bodies in the media They did and 160) 4) projection of myocardium into the not attribute the ongin of any of the e celis to loose sub epicardial tissue in such a way that in smooth muscle Karsner and Bayless (87) certain sections aggregates of muscle appear to among a large number of cases of rheumatic be isolated in the sub epicardial tissue (Fig 153) fever in which they examined coronary arteries 5) (strated) heart muscle cells in valves (Figs mentioned 4 cases in which they described ex 109–116) and 6) smooth muscle cells in atrial tension of Aschoff bodies from outside an artery subendocardial tissue and valves (Figs 91–108) into the media of the vessel but they found no Utilizing the concept that Aschoff bodies de evidence that these lesions orginated in the velop from fibrinoid alteration of connective medis nor did they find other lesions resembling tissue respective of muscle cells Tedeschi Aschoff bodies as illustrated in the present Wagner and Pani (179) from study of 400 communication that orginated in the media atrial appendages classified Aschoff bodies ac Perry (139) published an illustration of a small cording to 1) early Aschoff bodies indicative of Dodular le ton in media of a myocardial vein in rheumatic activity and 2) senescent Aschoff a case of rheumatic heart diseae and they con bodies that are not indicative of rheumatic ac idered the cells in the nodule to be of non myo tivity In the genesis of specific theumatic le genic origin This nodule somewhat resembles sions in subendocardial tissue these in estigators vere seen ·318 GEORGE E MURPHY did not take into account primary ani olvement nucleated arcopla, muc fragments of heart of heart mu cle cells just beneath the subendo mu cle cells just beneath the endocardium of cardium as illustrated previously (126) and w deeper or of smooth muscle cells in subendothis communication in Figs S2-90 In thest de cardial tr.sue should not be misinterpreted as velopment from heart muscle cells in this ite fragmented swollen, clumped or fu ed collagen Aschoff bodies may come to lie partially 12 fibrinosd collagen, fibrinold degeneration of subendocardium Furthermore, they did not con ground substance or fibrinoid and m020- sider at all the possibility of involvement of or raultinucleated 27coplasmasc fragments of smooth mu cle cells (Figs 94 and 97) in sub smooth or strated my cle cells and multa endocardial ti ve Yet many of the ene cent nucleated syncytial myogenic elements (Fug lesions that they sllustrate appear to be in sub 160), Ishe tho e in Figs 10-18 should Bot be endocardial 125sue where smooth muscle cells oc misinterpreted as connective ti sue cells re cur often in abundance as kere illustrated in acting to altered connective to sue Furthermore Figs 91-98 Tede cha Waguer and Panz state thuck collagen laid down as scar in previous that the nucler of cells in ene cent Aschoff attacks of rheumatic fever or during the fal bodies differ ia appearance frora tko e o re one should not be su interpreted as fresh rheu cent A choff bodies matic injury to connective t: sue The reaction of emooth rau cle cells to rbeu It has been suggested by Wachstern (191) that matic injury hould not be expected to result in the use of a histochemical techruque for succinc le ons morphologscally identical with tho e dehydrogenie (192) might be helpful in the trated heart muscle cells In my experience dentification of cellular structures derived from the pecific rheumatıc lesions involving smooth myocardium nasmuch as healthy heart mu mu cle in atnal subendocardial tissue as skowa cle cells have been found to give a positive stain in Figs 94 and 97 do not have as large as ing reaction for the presence of this enzyme ba ophilic or as blooming multinucleated ele However as Wachstein and Meisel have shown ments as those (Figs 2 73 82 159 161 and dzintegrating heart muscle cells in mvocardial 262) often seen in A cbof bodies that are de infarction fail to show this eazymatic stang rived from heart muscle cells This does not reaction and reduction of enzymatic activity mean horrever that less rheumatic activity is was noticed by them within a few hours after denoted by lesions of smooth muscle cells or of the beginning of myocardial infarction in mys heart mu cle cells or by other rheumatic lecogs cle fibers sbsch showed no significant changes with les prominent proliferative reaction of with routine staining techniques By the time nucles than that keen in the more forsd choff 40 A choff body is fully developed from damaged bodies It is well nown that an acute and rela heart mu cle cell. the damaged cells have timely rapidly fatal attacks of rheumatic heart disintegrated and one would not expect the distanc fte h or recent lesions of beart mucle leson to show $ po tive staining reaction for cells and of smooth mu cle cells in myocardial SUCCIBJC dehydrogena e In the light of Wach arteries often occur with bttle of 20 nuclear pro stein a investigation at would appear that the liferation in the involved muscle cells And it ve of this technque in the study of theumatic is of cour e mdely known that in many other heart d ea e might be helpful in detectiod of conditions injury to cells can result in acute de the earler changes in beart mu cle cells where geperata e or frank necrotic change in cells with routine staining techniques may fail to reseal httle or no prolsferative reaction of the involved alterations of the cells It should go without mucler In the light of our evidence here presented aying that (uute to demonstrate succinc de e pecially in Figs 82-98 eramination of illus hydrogena e a A choff bodies 19 no evidence trations of le ions submitted by Tedeschi Tag whatever again & the myogenic ongin of the e her and Pani that were soterpreted by them lezyons as being rene cent healed or healing le ions of N VARIOUS RHEOSLATIC LESIONS, OTHER connective tissue that do not indicate rheumatie THAN ABCHOFF BODIES OP HE 487 activity, reveals that the e are instead octie le- MgeCLE CELLS cons of muscle cells Furthermore mth te pect to the many re A Alterotron of Strations and Fatty Change ports of theumatı cardiac legions in Atrial ap. That chabges in heart muscle fibers occur with pendages it should be emphasized that bon out prolleratne or inflammatory resction in ·NATURE OF RHEUSIATIC HEART DISEASE 319 rheumatic heart disease has long been known perienced a stormy clinical course with rapidly (24 199) and previously referred to here Figs fatal outcome My own findings (126) are in 137 and 108 show irregular staining of heart agreement with and extend those of Sktorzofi muscle fibers with focal interruption of their In tudy of a very large number of well docu strations granular change and fragmentation mented cases of active rheumatic fever er in a heart that also showed many A choff bodies ten ne infiltrations with inflammatory cells In Fig 1.6 is een similar change that was made- munly polymorphonuclear leukocyte Were spread in the left atrial appendage of a patient found the atral myocardrum in association with severe cardiac symptoms for everal years with necrosis of myofibers in several children before mitral valvulotomy No Aschoff bodies and in the ab ence of atral Aschoff bodies but were found in this atrial appendage Figs 139 in all these ca es I found Aschoff bodies in the 141 are from two twelve year old boys who died ventricular myocardium In the atral myocar with actre rbeumatic heart disea e associated dium of 2 ten year old boy I have seen diffue with many A choff bodies Marked focal fatty infiltration with lymphocytes and plasma cells change was widely distnbuted throughout the asociated with necro is of myofibers and cells myocardium Note the myogetuc nuclear ele lhe tho e characteristic of Aschoff bodies And ments in the track of a myofiber near the top in the atral myocarenm of a forty-one year old of Fig 139 and in the track of a myofiber in woman I have recently observed diffue infil Fig 142 which 19 from the heart of a ix year tration with eosinophiles lymphocytes and old boy who died with many A choff bodies A plasma cells associated with necrosis of myo stakngly similar picture of myogenic nuclear fibers and in the absence of atral Aschoff elements in the track of a myofiber can be bodies but many Aschoff bodie were found in seen in Fig 143 from rabbit keletal mu cle Fig the ventricular myocardium Furthermore in 144 13 from the heart of a thirty nine year old 3 fifty year old man in whom commisurotomy woman who had rheumatic fever at five years of for mutral stenosis was recently carried out age and progressive dyspnea associated with biopsied atral appendage revealed strikingly low grade fever in the last two years of life extensive diffu.e infiltration of atrial myocar At the time of death she was being evaluated for dium with lymphocytes and especially plasma mitral valvulotomy The erythrocyte sedimen cell associated with marked necrosis of myo tation rate was very rapid several days before fiber and many multinucleated muscle cells death At autopsy the myocardium was found The findings in this latter case are like tho e to be very flabby No Achoff bodies were found reported and illustrated by Butterfield (26) in but many areas of fatty change of cardiac mu cle the case of a sixteen year old girl in whom diffuse fibers such as that seen in Fig 144 were found infiltrations of lymphocytic character' were throughout the myocardium found in the atrial myocardium in association with multinucleated cells like those in Aschoff B Focal or Diffuse Necrosis of Heart Muscle bodies Cells Associated With Inflammatory Cells and In my experience focal and diffuse infiltra II ath or TVithout Large Cellular Elements of tions of the myocardium with small inflamma Myogenic Origin-Focal infiltration of poly tory cells have invariably been associated with morphonuclear leukocytes and/or lymphocytes degeneration of necrosis of muscle cells and it and plasma cells not infrequently occurs in the appears to me that the e infiltrations probably myocardium in rheumatic fever and atnal myo represent reaction to this marked alteration of cardium is a common site (180) Howeser oc muscle cells Figs 145–150 illu trate some of ca ionally diffuse infiltration of the myocardium the e changes Fig 145 shows focal necrosis of with polymorpbonuclear leukocytes and/or lym mu_cle cells a. ociated with very slight reaction phocytes plasma cells and eosinophiles occurs (6 26 57 126 1,0 149 161 166 203) Among appendage A choff bodies were al o found in of inflammatory cells in myocardrum of an atrial the cells of the e infiltrations in some ca es are this appendage Fig 146 hows a focal le-ion in intersper ed cells sometimes in nodular forma tion characteristic of Anchoff bodies Skworzoff the atrial appendage of another patient This le (166) noted that patients who howed estensive sion comprises sarcoplasmic fragments myogenic diffuse infiltration of inflammatory cells in nucles and a rare inflammatory cell Several uch the myocardium were usually children who er le 1003 Fere found in this appendage but no ·320 GEORGE E MURPHY definite Aschofi bodies were found Fig 347 in most senest Edorts to explain this apparent shows & ventncular myocardial lesion rather contradiction base far been disappointing similar to the atrial le ion in Fig 146 The and considerable discus son has arisen con lesion in Fig 147 is in my judgment « small cerning the significance of the e le sons The 50-called Anchofi body As stated in the expla occurrence of these specific rheumatic lesions in nation of plates the figure 13 from a heart that str13 bas not generally correlated fith prolonged contained an extraordinarily large number of electrocardiographic P R intervals elevation of lesions of heart muscle cells including very the antistreptoly 538 Otster, rapid erythrocyte wady typical Aschoft bodies several of which sedimentation rate or the occurrence of Care are seen m other figures here Hustrated (Figs active protein in the blood (18 47, 118 119 2 6 20 21 23 24, 27, 50 54 55 57 60, 61 186) nor has the pre ence of these lesions apand 63) Fig 149 shows a myocardial lesion with peared to be prognostic of the post-operative numerous small cells associated with necrosis of clinical course of these patients (46 138) The e myofibers in a 15 year old patient who died discrepancies have led some students of sheu nine years after a recognized attack of acute matic heart duease to conclude that these spe rheumatic fever and about one week after onset cisc atrial lesions are not indicatuse of rheumatic of cough and sore throat Note the striking activity (48), or that the great majority of the e re emblance of tłus lesion to the one in Fig lesions do not indicate theumatic activity (160) 148 which is from & rabbit that died with although it has been found repeatedly that the markedly irregular cardiac rhythm eight days occurrence of the e lesions in atrai appendage after the last of five focal cutaneous infections correlates closely with the occurrence of Anchoff wth group A streptococci Scarning of these bodies m ventricular myocardium (23 41 96 Lesions would very probably result w a picture 102 109, 118 180) Lke that seen in Figs 151 and 152 that show Employing a concept that characteristic theu myocardial carring 10 respectively, a rabbit matic lesions develop from a basic change in repeatedly infected locally with group A strep. condective tissue Tedeschi Wagner and Pan tococer and a patient who died after repeated (179) have interpreted rheumatic lessons in attacks of rheumatic fever Finally, Fig 150 atrial appendages as being adicatuse of rheu shows a variety of changes in the left ventricle matic activity only if they exhibit certain con of an 8 year old girl There is seen here poor nective tissue changes and erudate inflamma staining vacuolation and necros9 of heart mus tory reaction If the morphological entera cle cells with some cellular reaction and inter and interpretation employed by the latter in spersed Aschoff bodies (12 the center and left vestigators were vald, the incidence of rheu uper portion of the picture) matic activity at the time of mitral commissu rotomy in a large group of patients studied by SPECIFIC RHEUMATIC LESIONS OF MUSCLE them would be only 2% (8 out of 400 patients) CELLS GENERALLY REFERRED TO As As The criteria utilized by these investigators have CROFF BODIES UN ATRIAL APPENDAGES AS been previou ly ducu ed in Section VIII of this UNEQUIVOCAL EVIDENCE OF ACTIVE Rey communication and appear to the present author MATIC HEART DISEASE to be very arbitrary I have submitted endeace A Frequent Lact of Correlation Between Re here to indicate that both 1) the lesions that site of Clinical Laboratory Tests and The Oc they interpret as early or active lesions of con currence 15 Atnal Appendages of Specfic Rheu. Dective tissue which to them indicate theu matic Lesions of Muscle Cells Since patients matic activity, and 2) those that they interpret selected for mitral commi.eurotony to date ene cent begled or beating lessons of have in the very large majonty been considered connective {issue that to them do not indicate free of rheumatic activity at the time of oper rheumatic activity are instead lesions of us Atop often after extensive and careful clinical dle cells that signify theumatic actitty With examination it has appeared somerhat anom te pect to the genesis of subendocardial Aschoff alous that specific rheumatic lessons usually te. bodies in atnal appendages the latter and al ferred to as Anchoff bodies, have been found in most all other investigators to date hase DOC the biopsed leit atral appendage in misby of taken into account rheumatic byolvement of the e patients (from about 40% to about 6576 beart muscle cells just beneath the subendo as ·NATURE OF RHEUMATIC HEART DISEASE 321 cardial tissue as demonstrated in the pre ent These atnal lesions do not meet his cntenia for communication in Figs 82–90 Furthermore making a definite diagnosis of rheumatic activ it appears that no one previou.ly has taken ity However autopsy findings of others (28 41 into account rheumatic involvement of smooth 96 102 103 118 180) bave clearly shown that muscle cells that occur often in abundance when such atnal lesions occurred Aschoff bodies in atrial subendocardial tissue (Figs 91 98) were very commonly, indeed almost always Lake smooth muscle cells in myocardial arteries found in ventricular myocarduum, moreover (Figs 118-135) and in cardiac valves (Figs these latter studies have shown clearly that 100-108) subendocardial smooth muscle cells the absence of such atrial lesions by no means can react to rheumatic injury to form lesions precludes the occurrence of Aschoff bodies in that mimo to varying degrees Aschoff bodies ventricular myocardium or of valvultis In this that are derived from heart muscle cells connection McKeown (118) compared in 22 It appears that there is no laboratory test hearts the occurrence of specific rheumatic le sensitive enough to detect some of the sub sions that she referred to as Aschoff nodules in clinical grades of rheumatic activity It seems the left atral appendage with their occurrence in to the writer most unwise indeed incorrect to the left ventricle She found these lesions in both a.sume as some have done (47) that if such a appendage and ventricle in 17 hearts but laboratory test as the one to detect C-reactive in the remaining 5 hearts she found Aschoff protein in the blood is negative even though spe nodules in the left ventrcle only Thus Mc cific rheumatic lesions such as those in Figs 82 Keown s findings indicate that the absence of 90 and 97 are present in atrial appendages then specific rheumatic lesiong in atrial appendage no ignificant rheumatic activity is present Stol does not preclude the occurrence of Aschoff lerman et al (172) reported that many patients bodies in ventricular myocardium Kuschner with specific rheumatic lesions in their atrial and Levieff (96) found that among 15 hearts appendage at the time of mitral commi.surotomy with histologic evidence of rheumatic activity showed no elevation in serum titer of three kinds subendocardial Aschoff bodies were found in of streptococcal antibodies and as they con the left atrial appendage in 9 ventricular myocluded this is evidence that the atrial lesions cardial Anchoff bodies were found in 10 and in such patients do not represent recent exacer valvulitis in 10 Thomas Averill Castleman bation of the disease due to antecedent strep- and Bland (180) found that among 40 hearts tococcal infection However it does not appear of patients who died with active rheumatic fever to the present author that they are justified in Aschoff bodies were found in atrial appendage also concluding that the lack of significant ele in 29 whereas Aschoff bodies were found in vation in serum titer of streptococcal antibodies routine autopsy sections in 33 These authors 13 evidence that the rheumatic atral lesions further reported that Aschoff bodies occurred are the lingering traces of a very low grade in 22 of 40 atrial appendages removed at the chronic inflammation and bear Little rela time of mitral commissurotomy in comparison tionshup to the functional state of the myocar with their occurrence in 29 of 40 atrial apdium This point is discussed further in the pendages from the patients who died with active next section rheumatic heart disease B Close Correlation Between the Occurrence Sapbar s principal objection concerning the in Atral Appendages of Specific Rheumatıc Le atrial lesions in question appears to be that 82078 of Muscle Cells Some of which Resemble these lesions are not identical with the true Closely Ventricular Aschoff Bodies and The Oc Aschoff bodies and by the true Achoff currence of Ventricular Aschoff Bodies -Sapbur bodies I judge he means the interstitial (160) has recently wntten that the great ma Aschoff bodies found characterstically in the jority of lesions in atrial appendages that have ventricular myocardium and these lesions are been reported by many others as specific rheu derived from aggregates of heart muscle cells matic lesions and usually referred to as Anchoff lying between other aggregates of muscle cells as bodies are in his judgment either not indicative shown in Figs 2 6 13 19-27 73 74 76 77 and of rheumatic activity or of questionable sig 79-81 In a recent article Saphir (159) shows nificance with respect to theumatic activity a lesion in atnal appendage in illustration A of ·322 GEORGE E MURPHY Fig 51 on page 44 which he con ders to be a appendages repre.ent reaction of smooth mu.cle type of lesion that is often erroneously called cells or strated heart muscle cells to rheumatic an A choff body However, it is noteworthy injury (Figs $2-98) and studies at autops by that this lesion appears to be identical with the others (29 41 96 102 108, 118 160) have hamn lessons that are alustrated by him as true Aschoff that when such rheumatic lessons ase found in bodies in Fig 46 on page 36 atral appendage then so-called A choff bodies It would appear that at least many of the are at least very Iskely to be pre ent in sedinic le uns un atral appendages that are so com viar my ocardium Furthermore evidence pre monly referred to 89 A choti bodies are not ented here and previouly (123 126) shorts morpaplogically dentical th certain florid that the o-called Anchoff bodies in vertncular o called unterstitial or true Aschoff bodies myocardiusz) are derived from beurt mu cle cells as Saphir calls thema However I would say The conclusions appear to be sell justified that if one wants to diagnose rheumatic activity therefore that occurrence of these pecific rheu until lesions are found in atnal appendage that matic lesions in stnal appendages 1) is in itself are morphologically identical with the flond evidence of active rheumatic dlease of mu.cle so-called mterstitial A chof bodies that occur cells in atris and 21 sgnifies great likelihood among bundles of myofibers deep u ventricular of active rheumatic disea e of heart muscle cells myocardıım then rheumatic activity in atrial In ventricular my ocardium even though no appendage will rarely 3f ever be diagnosed electrocardiographic endence of theumatic ac On the other hand, Figs 82-86 and 88-90 tity may be found C-reactive protein may not here demonstrate that lessons in atrial ape be pre eat in the blood the erythrocyte edi pendage involving heart rauscle cells just be mentation rate may be normal and there may neath srbeadacardial tissue occur that are like be no erological evidence of a recent mlection and are just as specifically rheumatic as le cons with group A streptococci Furthermore it l. involving ventricular beart muscle cells just clear that the absence of specific atrsal lesions beneath the subendocardial tissue (Fry 87) does not preclude significant theumatic activity And yet the e specific subendocardial lessons of a olving heart mu cle cells in ventricular mayon atrial and ventricular myocardium may not be cardiurna morphologically dentical with larger lesions Those who fail to recognize that the lessons that involve a greater number of muscle cells here di cus.ed sigaily rheumatic disease of mus. among bundles of myofibers deep in ventricular cle cells in the heart will be at a du advantage myocardium ja erorts to explain the natural history of rbeut C Importance of Recognt ing The Alyogenic matic beart diese and to understand the patho- Nature of Specific Rheumatic Lesions in Atnat logic physiology and fallure of the myocardium in this disease Appendage and Ventncular Afyocardium to The Understanding of The Pathologic Physiology The TXIPORTANCE OF ACTIVE REEDMATIC and Falure of The Heart in Rheumatic Heart DISEASE OF HEART Muscle Cells Disease ---Same investigators (179) have insisted TO CARDIAC FAILURE that it is imperative to comprehend that the characteristic and pecific rheumatic cardiac A The Relation of Actite Rheumate Dwease lessons develop from primary and es entral of The Myocardium to Cardiac Fazure in Chi alteration of connectnse tissue qute irrespective dren and young Adults Often Tithout Ap of muscle cells before one cat properly interpret preciable Valvular Deformity The Systolic and whether or not changes so atnal appendages are Drastolc Nurmurs Caused By Actie Rhett indicatne of rheumatic activity I reply that matic Disease of The Myocardium With Cardiac the evidence here submitted desmonstrates that Dilatation Abundast evidence indicates thast in children with rheumatic heart deze cardiac the concept that so-called Aschoff bodies are non my ogemc lessons that are derived from primary failure very often ac ocisted mth considerable and ee entsal alteration of connectise tissue 13 cardiac dilatation is primarily if not essentially pot valid Furthermore the evidence submitted the result of active rheumatic de ease of the bere and previouly (126) demonstrates that myocarduum (20 36 51 104 103 155 199 speciác rheumatic le sons found in subendo 201) and the cardiac future in children often cardial th. ue or subjacest myocardium in atral bat a ochuted with valvular deformity Les and ·NATURE OF RECEUMATIC HEART DISEASE 323 Poynton (103) 1a 1897-93 demonstrated the fre referred to adult cases in which mitral stenosis quency of cardiac dilation in children and young had been diagnosed in life but was not found at adults with acute rheumatic fever and/or autopy chorea They poted that even though dilatation Wilson and Lm (201) bave emphasized the was frequently marked the clinical symptoms of relation of cardiac dilatation to diastolic and the patients at rest were remarkably sught In systolic murmurs that appeared in children dur fatal cases they confirmed at autopsy their elin ang attacks of theumatic fever and regressed with ical finding of cardiac dilatation very often in improsement of the patients with the latter in the absence of valvular deformity and excess vestigators I have observed in the case of a 3 pericardial fluid Poynton and later Coombs year old child who developed a definite apical (39) considered rheumatic disease of the myo diastolic tourmur and howed at autopsy 2 cardium to be of great importance to cardiac mitral valve of normal thickness except for a failure not only in children but in adults as well row of tiny verrucae the following exten. ive even though the morphological change that they disea e of the heart muscle cells including very observed in the myocardium was slight many Aschoff bodies and many foci of NOD West (199) in 1878 and Coombs (36) in 1924 specific necrosis of muscle cells some of which empha ized tbe causathe relation of cardiac were asociated with considerable infiltration of dilatation to su tolic and even diastolie murUTS inflammatory cells and in a 14 months old in attacks of rheumatic fever Bland Jones and child who died after developing an apical di White (20) yn 1936 reported on the disap- astolic murmur and showed at autopsy mitral pearance of apical systolic and diastolc mur leaflets only lightly thickened I have observed murs in 83 rheumatic patients from 8 to 18 years very exterive disease of heart mu cle cells in of age who were mutially considered to bave cluding many Aschoff bodies and focal necrosis active rheumatic valvular disease on the basis of heart muscle cells in many areas associated of the occurrence of the systolic and disastolic with mall inflammatory cells murmurs In 53 of the 83 patients mitral steno In some patients on the other hand as sis and regurgitation were diagnosed at the time Coombs (39) stated when & Murpur pre of the intal examination However nesther a viously heard clearly becomes less audible and systolic nor a diastolic murmur could be heard disappears altogether it is often a sign of in even after exercise of the patients and other ef creasing muscular failure For instance when fort to detect them in any of the 53 patients the mitral cystolic murmur heard in the carditis 3 to 5 years later They stated the following of childhood becomes less distinct during an In those patients who were considered to have acute bout it is a sign of decreasing mu cular mitral valve involvement on the basis of apical power In this connection it is pertinent to systolic and diastoli murmurs the diastolic mur mention that I have several times detected the mur was invariably the first to disappear Oc disappearance a few weeks or several days before casionally this apical diastolic rumble substded death of systolic murmurs that had developed in within a few months after the onset of theumatic rabbits after repeated focal infections with infection during the period while the patient group A streptococci and at autopsy the promi was convalescing and still under observation in nent finding, in the e animals were in the myo the bospital In these cases they attributed the cardium apical systolic and diastolic murmurs that were In 1934 Rothschuld Kugel and Gross (155) re initially heard to cardiac dilatation related to ported results of a chnical pathological study on rheumatic activity Usually they noted more the incidence and significance among 3000 pa gradual Tegression of the murmurs over a period trents who were gutopsied of active rheumatic of years F M Smith in d cussion of this paper disease of the best in cases which presented stated his opinion that subsidence of active anatomically and histologically unmi takable rbeumatic diseame of the myocardium Yas for the evidence of present or past rheumatic heart dis most part responible for the disappearance of ease and in shich complete anatomical investa the murmurs in all 83 cases Bland et al al gation had been made The e rheumatic cases reported that in many other patients they noted numbered 161 and ranged from 17 months to 80 marked regre son of murmurs These inye ti years of age There were 22 cases between 1 and Gators and Bohan in de cussion of their paper 10 years of age All of the e patients succumbed ·324 GEORGE E MURPHY to myocardial failure The authors found that with mitral stenosis there has been an increas In all the e c2.28 the degree of the mechanical ing tendency in recent years to minimize and defect was so slight that it obviously bore no even disregard the role of theumatic lessons of relationshsp to the myocardial failure' A chofi the myocardium, especially those that represent bodies were found in 20 of the e 22 cases There active dease (54) In 1954, Wilson and Green were 44 cases between 10 and 20 years of age wood (203) stated There is considerable doubt and in 41 of these there was active theumatic about the functional importance of lesions in myocardial disea e In 35 of these 41 ca es un the myocardium een un adult rheumatic heart which the patients died of my ocardial faziure disease * and in which the degree of the valvular defect In the light of the widespread lack of under was tudied 9 shoned a tight mitral stenosis and standsng of the involvement of heart muscle 2 moderate valvular stenosis Among the 41 cells in the so-called A chofi bodies and other patients with active rheumatic disea e of the myocardial lesions as here demonstated, it 9 myocardrum A choff bodies were found 10 37 perhaps understandable why there i euch con B Cardiac Failure in Patients with Nitral siderable and widespread doubt about the func Stenose Specral Reference to The Considerable tsonal importance of theumatic lesions in the Benefit from Mitral Commusurotomy in Many adults But I would etaphasize the following myocardum 2 rheumatic heart duene in Cases, and Lach of Correlation in Afany Cases If active rheumatic de ease of heart muele cells Between Subjective Improvement and objective Clinical Findings After Operation Poynton can cau e farlure of children s hearts without the burden of valvular deformity and even Coombs and Rothschild Kugel, and Grong and others condered active rheumatic disea e of the without valvular thickening then it is likely that active rheumatic di ease of heast mu cle myocardium to be of great un portance to cardiac fature not only in chuldren but al o in adults cells can cause facture of adult hearts especsally with or without valvular deformity Kowever those burdened with valvular deformity and wth they and A choff and the great majority of myocardium damaged by previous attacks The results of commissuroramy for mutral pathologists have not recognized the involvement of heart muscle cells in the so-called Aschoff stenosis have hown that this operation 29 of bodies and other myocardial lesions in patients considerable benefit to properly selected patients with rheumatic heart di ease This midespread (10 11 48 62 173) Indeed very striking 22 lack of recognition of the myogenic nature of by many sbservers it appears that the most provement in certain patients has been reported these lesions and the long held and widespread suitable candidates for this operation are thae assumption that they are non myogerie lesions patients with tsgbt mistral stenosis with a mini of connective tisstie gave se to the quandary mal degree of insufficiency who have shown dis recently expres ed by Penninger (140) as fol abling symptoms of cardio pulmonary dysfunc lows Vatıl the relation between the absor tion for a fairly short pessod of time (46 61 malities in the connective tu cue and myocardia] 62 173) The more marked the degree of 29- failure is understood the significance of the e sociated wstral usufbcsency and the more ad histological changes will remain obscure And vanced the state of congestive failure the less Kuschner and Leveff (96) recently stated As Iikeukood there is of benefit from the operation Pinuoger kas porated out, we do not as yet un (46 173) Els Harken and Black (48) have derstand bow the Aschof body a lesion of the recently reported moderate to marked improveinterstitial connective tissue affects myocardial mert following commissurotomy even in 55% function of 206 patients who were mostly cardiac in It appears to be well recognized that active alds Euffering from chronic congestive failure rheumatic dised e of the myocardium is of pri or who were maintained in a precarious state mary 2mportance to heart failure 122 chuldren of compensation only by vigorous medical (even though mavok ement of the heart mu_cle meing cells themselves as here demon., trated 15 6:31 Some ob ervers have found that the subjec very generally not recognized) In empfanatsan tive unprovement so many pauents after mutral of cardiac failure in sbetsmatic heart di esse in comm. surotomy tras not asSociated mth im adults on the other band especially in patients provement in objective clinical findings in par ·XATURE OF RHEUMATIC HEART DISEASE 325 ticular cardiac murmurs heart size and elec logically by them as possible candidates for trocardiographic findings (15 43 169) In 20 mitral commissurotomy Elis et al (46) recently patients followed in eenial roentgenological study stated that Myocardial failure is undoubtedly for penods varying from 6 months to 2 years an important element in the poor results of Soloff and Zatuchni (169) found that the some of the patients or in the deterioration of number of patients with incre2e in heart zze others and Baker and Hancock (12) consider after commisurotomy was greater than the num that a myocardial factor may contnbute to the ber of patients that showed no change or de detenoration and may well be present in those creae in heart size and they attnbuted the in who still maintain good results creze in heart size to intenzification or reactiva C Lack of Correlation Betreen The Degree tion of rheumatic carditis Bergy and Bruce (15) of Mitral Stenosis and Cardiac Dusability and found on post-operative evaluation of 31 pa Between The Degree of Mitral Stenosis and trents at an average of 21 months after mitral commissurotomy that there was considerable Pulmonary Vascular Change Special Reference to Unoperated Patients With Harled Mitral discrepancy between subjective improvement Stenosis with Little or No Signs of Congestive on the one hand and objective findings in re Heart Failure Ezen at Advanced Age-It has sponse to standard exercle tests on the other long been known that in cases of rheumatic In & roentgenological study earned out for from heart dleae with mitral stenosis the degree of 12-30 months (average about 19 months) after mitral commisurotomy in 55 patient. Gary mechanical obstruction due to the stenosis does not necessanly correlate with either the occur (56) found that even though 44 of the 55 pa rence extent or time of on.et of cardiac failure tients were able to resume normal or almost Some patients with considerable even very normal activity the majonty showed no de crease in heart size and in some the heart had marked mitral stenosis can live well past the age of 70 ometimes with little or no evidence of become definitely larger In some patients de layed post-operative mprovement and prolonged cardiac failure Roth.child Kugel and Gross convalescence has occurred and in others post (155) in report of a clinical pathological study of 161 patients who died with evidence of rheuoperative improvement has been followed in several months to a few years by deterioration matic heart diease either active or inactive of cardiac status (12 25 46) Pampuch and commented that it was stnking to note the high Bruce (134) Etudied the clinical course and grade of mechanical defect existing in individ tolerance of standardized exercles of 15 pa uals living to the 5th and 6th decade with little tients with mitral stenosis who did not undergo no evidence of congestive failure They alo surgical treatment of the mutral valve for a reported on two patients with moderate mitral stenosis who curvived to the 8th decade Another variety of rea.ong When the patients were re evaluated one year later it was discovered that patient a woman of 80 years with tight mutral stenosis and marked sortic seno died of the three patients with poorest functional capac thrombosis of a mesenteric artery with no signs ity (class IV N Y Heart Association classifi cation) had died despite the fact that their ages of cardiac failure White and Bland (201) reranged from 35-40 years in the 12 surviving ported on 4 patients with moderate mitral patients with class I II or III functional capac stenosis who lived beyond 80 years of age and on ity reduction had occurred in incidence of one patient who died at 73 years of age of symptoms and signs as well as treatment of bronchopneumonia with but little heart failure pulmonary and cardiac edem.. Harvey et al associated with extreme fih mouth mitral (73) emphasized the importance of recognizing stenosis those rheumatic patients with mitral stenosis in Graham et al (65) reported on correlation of whom myocardial insufficiency was primanly post mortem findings with the clinical course in important They stated that in euch patients 101 cases of mitral stenosis In & considerable in the absence of moderate to severe degree of proportion of the e patients especially of those pulmonary hypertension at rest probably battle over 50 years of age rheumatic heart disease or no important degree of mitral block exists was either not diagnosed during life or only Such patients numbered 8 among 45 patients during the terminal illness Severe mitral stenosis with mitral stenosis who were studied physio was not uncommon in the older age group in ·326 GEORGE E MURPHX ome deed 21 of the 58 patients over 50 years of age chiefy elderly people with valvular deformt; aad 16 of the 38 patients over 10 years of age concluded that progres de changes in the myo had mitral stenous of the most evere grade cardium are more important to heart fasture (Grade III) Although of the 101 patients than the valvular defects Ele emphasized the studied 47 had very marked steno is of fib great variablity with mbsch the hearts of pa mouth everity the chacal records indicated tients with imilas degree of valvular deformity that 15 of these 47 patients had httle or do tolerated burdens such as walling 1arious discardiac di ability up to the time of their death tances star-clubinsteight lifting or or until the terminal part of their allness 16 uperimposed non rheumstic dues e With the of the patients with extremely stenotic mitral Inicro cope he ob ersed various cellular and de valves lived over 60 years and 3 patients ined generatne changes in the myocardium in adds aver 70 years These findings hors that mitra) tion to clerotic chasges in coronary artere and stenosis of a esere grade may be tolerated by arterioles in these patients Rothschild, Kugel come patients for a protracted perod with and Gross (150) carried out a charcal patholog esther httle or no impairment of cardiac re cal study of 161 patients who died sth rheu serve This was aluo appareat in their anals 15 matic heart diez e either actise or actsre of patients in whom rheumatic beart dies e for the purpose of correlating the occurrence was not diagno ed during bfe There were 31 19 of myocardial fasure the degree of a rular this group and 6 of them had maried mitral defects and the presence of myocardial de 80 steno is Al 6 of the e and 21 of the total of 31 together with the various age penods 2x which were able to carry on with either no cardiac death occurred They concluded While the syraptoms or with muld dy prea only prior to causal relation of active myocarditis to circula their terminal aldess They further reported that tory failure is very striking in the first 2 decades of 45 patients with the most severe degree of of life it is not sufficiently appreciated that in mitral teno 19 12 bad no demonstrable organic ca.es of theumatic beart disease in adults of the changes in the pulmonary circulation and in 17 the 3rd 4th and 5th decades of life a recurrent the changes were only mild and 12 only 6 of rheumatic myocarditia rather than healed me the 45 were pulmonary charges reported as chanical defects may in the majority of in marked In a companion tudy Ellis et al (4-1) stances be the precipitating cau e of the circula reported on 10 patients with very sparked tory failure They emphasized that individuals fish mouth mstral stenosis and 2 patients wth quiescent rheumatic heart diese and with stenotic mitral valve admitting one fin considerable valvular deformuty may reach the ger who died after physiologic measujement 7th and 8th decades of Ife and die of a totally (particularly of the cardiac output and pul unrelated disease without having had any evz monary Vacular pressure) had been correlated dence of cardiac failure directly attributable with the chical states of the patients They to their valvular deformity tated It was found that the degree of mitra) Werner (198) {rot tudy of 100 consecutie stenosis and the degree of pulmonary vascular ches of cardiac failure in patients with rheu change could not be clo ely or accurateEy cor matic heart diseae (raaging 182 age from 5 to related either with the degree of diability of 69 years median age 31) concluded that it is the patient or with decrease of cardiac output or not only infection but a specific rheumatic in increase 31 pulmonary pressure although of fection that is the traportant factor in the course there was a general tendency for such production of heart failure Juster (86) carned correlations to enast Active rheumatic myo out a clinical study of 59 ambulator ca.es of chronse rheumatic heart di ese in women be carditis pas ſound at post mortem examination to be pre ent in rei eral patients in whom it syas tween 15 and 14 years of age sbo sere followed for a period of 1-29 months (average of 337 not clinically diagno ed months) in the coure of this study regular D The Relation of Actite Rheumatic Disease edus rhythm 595€ Tay to atrial fibrillation in of The N/yocardium to Cardiac Failure in Pa 9 caes and it appeared to Juster that in esch trents of The Third, Fourth and Fifth Decades instance the cardiac stregulants fupcrsened of Life and Older Krek (94) in 1859 from duning periods of Theumatic actus Os the careful clinical pathological study of 10 patients other hand appeared to him that is certain ·NATURE OF RHEUVIATIC HEART DISEASE 327 cawes rheumatic activity was compatible with correlation reported to date between the occur normal cardiac Teserre He concluded that in rence of specific rheumatic lesions generally many adult ca es prolonged and progressive ac referred to as Aschoff bodies in atrial append tive rheumatic heart disea e per ists sometmes ages and the pre- and postoperative course of so mild as to be scarcely detectable but some patients who have undergone mitral commis times exhibiting high grades of severity surotomy has been pointed to by some as a Even in rheumatic patients in the 6th and 7th reason for believing that these lesions are not decades of life active rheumatic disea.e of the indicative of active rheumatic disease and also myocardium occurs in as ocation with cardiac as evidence that rheumatic activity is not im decompensation Achoff bodies in the myocar portant to cardiac failure in the e patients This dium have been repeatedly found in patients in view has recently been expressed by Fredberg this age group (50 67 113 126 145 152) In (51) as follows The development or progres such patients active rheumatic diseae of the sion of heart failure in the adult with rheumatic myocardium is usually not suspected clinically heart diea e is often attributed to active rheu instead the cardiac decompeni, ation is usually matic fever especially if the patient is febrile attributed entirely to valvular deformity Ferris These diagnostic concepts are based on the and Myers (50) reported on 3 patients between traditional teaching that rheumatic fever is a 61 and 79 years of age who died with numerous per istent chronic di ea e with a tendency to myocardial A choff bodies and only light val recrude cence throughout life This teaching in vular changes in a 59 year old woman who turn was based on po t mortem findings of As died suddenly and without a diagnosis of rheu choff bodies in the myocardium of patients in matıc activity Mallory (113) found on micro the third to ixth decades who died of rheu scopic examination that The heart shows more matic heart di ese and heart failure long after Anchoff bodies per cu tim than any heart I the overt acute attacks of rheumatic fever The have ever seen In this case there was mild Aschoff body was interpreted to signify active mitral stenosis with calcified leaflets but no rheumatic fever This interpretation and the great shortening of chordae In a case of rheu concepts based on it are no longer tenable ince matic heart di ease in a 61 year old woman biopsy pecimens of left atrial appendages have Rakov and Taylor (145) reported that Histo disclosed a high incidence of Aschoff bodies logic studies revealed the large t and greatest without relation to the clinical picture and sub number of Anchoff bodies in the myocardium sequent course leading to the conclusion that that we have ever seen There was moderate the pre ence of Aschoff bodies cannot be re thickening of the mitral valve and some chordae garded as evidence of clinically active rheumatic Rogers and Robbins (152) reported the occur fever If further studies support evidence that rence of Aschoff bodies in several patients over there are fresh and senescent A cboff bodies 60 years of age in whom theumatic activity bad that can be differentiated by special stains the not been diagno ed and they emphasized the fresh A choff body may be found to be accept importance of the active myocardial di ease to able as a pathological criterion of clinically ac cardiac failure in these patients I have recently tive rheumatic fever ob erved a case in which very extenqive active In reply to the views quoted in the above Theumatic disease of beart mu.cle cells including paragraph I will first refer to the evidence suba very large number of Aschoff bodies occurred mitted here in Figs 82-98 and 160 and dis in association with cardiac failure in a 60 year cus.ed in ections VIG VII VIII and of old woman with moderate mitral stenosis and this communication and alo to evidence previ rheumatic activity was not dagoo ed before ou ly ubmitted (126) which shows that pecific death rheumatic le ions generally called Aschoff In the light of the foregoing evidence of evere bodies in atrial appendages represent active active rheumatic myocardial disease a ociated rheumatic le ions of two kinds 1) Achoff with cardiac failure in adults it 13 surpri ing to bodies that originate from rheumatic damage to note a recently expreved view (54) that con (strated) heart muscle cells usually just be gestive heart failure in adults with rheumatic neath tbe subendocardium (Figs 82-86 and 88 beart dreeane should rarely if ever be attributed 90) and 2) lesions that originate from rheumatic to activation of rheumatic feer The lack of damage to smooth mu cle cells in subendo- ·328 GEORGS E MURPHY cardial tu sue (Figs 94-97) and sometimes does not preclude the occurrence of ventricular clo ely re emble A..choff bodies that are derived Anchor bodies (118, 180) from heart mu cle cells This evidence indicates Thus the occurrence of these specific atra! that the classification or division by Tedeschi, lesions is in stself endence of active rheumatic Wagner and Panu (179) of Aschof bodies into disele of mu cle cells in the heart, even though freak and mene cent forms on the bass of changes there may have been no recent progression of in connective tuzue irrespectue of muscle cells symptoms of congestive falure prior to commis is not only arbitrary but it is incorrect Most surotomy, no electrocardiograpluc evidence of unfortunately this classification draws attention rbeltzatıc actinty may be found, C-reactive Away frota the most important changes in the protein may not be present in the blood, the atrial appendages, namely tho e of muscle cells erythrocyte sedimentation rate may be norma that grufy that active rheumatic disease of and there may be no serological evidence of B muscle cells 18 alo very probably present in the recent infection with group A streptococcu ventricies Friedberg states that the high incidence of E The Relation of Specific Rheumatic Lestory Aschoff bodies in atrial appendages 25 witbout re of Muscle Cells Generally called Aschoff Bodies lation to the clinical picture However, a large 112 Biopsied Cardiac Atnal Appendages to The proportion of if not most patients who submit Pre Operative Clinical Course of Patients Be to mitral commissurotoray do so because of teen 20 and 40 ears of Age With Signs of Mitra) Stenasze Tyho Underwent Cardiac Sur progressively worsening symptoms of congestive failure Fredberg further writes The modified gery - Vith respect to the widely beld 1.52 Jones criteria qute properly list congestive tion that the occurrence of specific rheumatic heart failure as a criterion of rheumatic carditis atrial lesions bears no relation to the clinical couree of patients undergoing mitral commis only in patients below the age of twenty five Beyond that age heart failure is most probably surotomy I refer to the work that has due to other causes that cannot be excluded been recently carned out and is being continued by Ds Fredenc G Dalldori and me (40) of the But it would appear to be very arbitrary to Lurssit the u e of coogestive heart failure as & criterion relation of specific rheumatic lesions generally of active rheumatic heart disease to the first called A choff bodies un cardiac atrial append 242 decades of ke The finding of Aschaf bodies ages to the preoperative cknical coure of pa tients with rheumatic heart disease who under m patients with rheumatic beart disease who went mitral commissurotomy die in the 4th and 5th decades because of myo cardial failure has been preysou.Iy here referred Many of not most patients who submit to matral commissurotomy do 60 because tbesr to (155) Endence even in patients in the 6th 7th and 8th decades of congestive heart failure symptoms of cardiac disease are progresszely forsening This raises the question hy does leading to death and due to active rheumatic the cardsac status of these patients deteriorate? myocardial disease that was undiagno ed before It occurred to us that in the e patients active death bas glo been here cited cheurs.atic myocardial disease is a toportant In discussion of theumatic heart disease in factor as it is in younger adults and children adults Coombs (39) stated the following and this 18 indicated by the frequent occurrence Syzaptome are more important than signs and of specific rheumatic lesions of mucle cele when it comes to sig33 tho e that indicate the (Figs 82-$6 88-90 97 Rad 160) generally condition of the muscle are of more value than called Aschot bodies, surgically remoued those ars ing directly from the valvular changes atrial appeadages If this were true then in a It has been shown by many other abservers that there is a close correlation between the group of patients free of other cardiova.cular diseases and conditions which might contnbute occurrence of the specific rbeumatic lesions 2 to fallure of an already damsged beast a definite atral appendages 23 allu_trated in Figs $2-86 correlation might be decorercd betrrcen the &S-90 91 96 and 97 and generally referred to 85 Aschof bodies and occurrence of typical preoperative clinical course and findings in atrial appes dage Aschof bodies in ventricular myocardium (28 Only patients belor the age of 41 years were 41,96, 102, 108 118 180) It has a lo been shown that the absence of these specihic atna) lesions relected for this study to minimize the effect ·NATURE OF RHEUMATIC HEART DISEASE 329 of sonrheumatic arteriosclerotic cardiovascular The onginal vections stained with hematoxylia deea e We obtained the clinical histories of all and eosin of the atrial appendages as well as 3 patients under the age of 41 years who under new sections in each case cut from the paraffin went mitral commissurotomy before 1957 in the blocks and stained respectively with hematoxylın department of surgery of the New York Hospi and eosin phosphotungstic acid hematoxylın tal Histones in these cases had been recorded and Masson tnchrome were examined The in detail by at least three observers on each ad amount of atrial tissue was inadequate in 5 mission Two patients were excluded because cases and they were excluded The histologic their histories were inadequate and 15 ca.es material was classified simply as those cases with were eliminated because of the following condi and tho e without specific rheumatic lesions of tions 11 patients were pregnant at the time muscle cells (generally referred to as Aschoff of operation 1 patient had expenenced repeated bodies) episodes of pulmonary embolization 1 patient The final sample consisted of the clinical was hypertensive 1 patient had diabetes mel histones and atrial tissue from 81 patients, 64 litus and 1 patient was considered to have women and 17 men ranging in age from 20 Lutembacher 8 syndrome In examining the clini to 40 years cal histones particular attention was paid to As seen in Table I the specific rheumatic the time of on.et and to progression of cardiac lesions were found in 38.5% of patients with symptoms prior to operation Emphasis was severe rheumatic heart dieae in whom no evi placed on such symptoms as increasing exertional dent deterioration of cardiac status occurred in dyspnea orthopdea parotyrinal nocturnal the last two years prior to operation (Group dyspnea epi odes of hemoptysis and worsening III) On the other hand these lesions were found fatigue The patients were classified into three in 76.59 of patients showing marked progres major groups Group I consisted of those pa sive worsening of cardiac symptoms for longer tients who showed steadily progressive worsen than 18 months prior to operation (Group IIa) ing of cardiac symptoms with evidence of pro These lesions were found in 86.59 of all patients gressively decreasing cardiac re erve for 18 showing marked progressive worsening of car months or less prior to operation (35 patients) diac symptoms prior to operation (Group la 11 of these had been entirely asymptomatic and IIa combined) And finally it can be seen before their preoperative deterioration Group II that these lesions were found in 95% of those comprued those patients who had shown steadily patients with marked progressive worsening progressive worsening of their cardiac symptoms that began only 18 months or less prior to and evidence of progressively decreasing car operation (Group Ia) The only patient of this diac reserve for a period longer than 18 months last group in whom Aschoff bodies were not prior to operation (33 patients) Group III found showed numerous stall foci of necrosis of comprised those patients who likewze had severe heart muscle cells rheumatic heart disease but had shown no evi It appears evident that a significant relation dent deterioration of their cardiac status during ship has been demonstrated in this study bethe two years prior to operation (13 patients) tween the pre-operative clinical course of pa- The 68 patients showing deterioration prior to tients with rbeumatic heart disease who operation le those in Groups I and II were underwent mitral commi.surotomy and the further subdivided into subgroups & and b occurrence of specific rheumatic lesions in sur depending upon the degree of worsening Those gically removed left atral appendage who had experienced well documented marked It is probable that rheumatic heart dLease deterioration were classified in subgroups a 13 sometimes a chronic smoldering pathologic while those whose deterioration was less marked condition with episodes of remission and ex and sometimes difficult to be sure of were classi acerbation Much evidence indicates that many fied in subgroups b These subdivisions episodes of rheumatic activity do not produce brought the total number of clinical groups to the clinical manifestations classically considered five (Ia Tb II & IIb and III) Examination of to be characteristic of an attack of rheumatic tbe clinical records and decisions as to clinical fever And many of these episodes must be grouping were made without knowledge of find clinically mute in view of the large number of ings in the atrial appendage patients severely handicapped with rheumatic ·330 GEORGE E MURPHY TABLE I Occurrence of Specific Rheumatic Lesions* in Alnal Appendages in Relation to Duranon and Serenity of Preoperatrie Deterioration of Cardiac Status in 81 Patients Betueen 0 and 10 ) ears of Age Armal Clon cal group based DD progres on of symptoms Specific Rheumato Age at patents to gratis S prior t commissurota usy Lestaas Raythm Group Duratou of progress on Sever ty of pr grossen Number #t lest A Number in group (Percest) Averag Medit (Perccet) 30 9 19/20 10/15 95 0 68 7 31 36 900 46 6 13/17 16 5 320 32 70 G la 18 months or less Marked definste Ib 18 months or less Minimal shdet Bite Ila Longer than 18 Marked defiante months Ilb Longer than 18 Minimal indes months Dite No progression of symptoms for at least two years Total 5/16 31 3 344 35 437 5/13 38 5 31 7 31 38 5 51/81 63 0 * The term specsfic sbeumatse lessons in atrial appendages 23 used in reſerence to 1) Aschof bodies that originate from rheumatic damage to (striated) keart muscle cells usually pust beneath the subendo cardrum (Figs 82-86 88-90) and 2) lesions generally desigasted Asckoff bodies by others that orig? nate from rheumatic damage to smooth muscle cells in subendocardial tissue (Figs 94-97) and some times closely resemble Ascboff bodies that are derived from (strated) heart muscle cells Statistical analysys (168) of the incidence of specsfic rheumatas lesions in atrial appendages in the various clumcal groups Groups 1& 4 TIX compared with Groups Ib SIb II X * 12 8 0 001 >>> 01 Groups (a + Ila corapared with Group III a> - 90 001 > p > 0001 Groups 1 + Ib compared with Group IIE Xu) - 6 98 OQI > p > 0001 Group Is compared with Group III A = 0 3 0 01 > P > 0 0ội + This table is essentially like Table I in the paper by Dalldorf F G and Murpky G E eottled Relatonship of Aschof Bodies in Cardiac Atrial Appendages to the Natural History of Rheumatic Heart Disease in press in Am Jour Path Vol 37 Nov 1960 Perm1991 on has been granted by the editor of tbat jourosi to reproduce this data here heart disea e ho give no bustory of experiene * appears to us that the chick cgue of cardiac ing an attack of rheumatic fes er or chorea This decompensation in patients with rheumatic heart is further borne out by our fading of specific duease at least through the age group bere histologic evidence of active sheumatic heart studied is theumatic activity it elf du.ease as manfested by rheumatic lessons of Strong evidence kos 89 discussed 19 sec atral mucle cells in 38.5% of those patients tion & that the presence of the specifia theu (Group III) with evere rheumatic beart disease matic leszone of mu cle cells that are generally who showed do evident deterioration in their called Aschoff bodies in atnal appendage as cardiac status the last to years pnor to diagnostic of active rheumatic beast di ea e commu.surotomy However, other findings shown As prez tou ly mentioned in section XB com 2 Table I indicate that when fub-chnical epi bibed biopsy autopsy findings of others (28 odes of rheumatic actity occur in patients 41 96 102 108 118 180) have clearly shown with bestts aiready everely damaged by pre that when tbe e atra? lesions rere found at the vious rheumatic dhe e they often manifest time of mitral commi-vrotomy typical A choff themseh es by progressive worenog of cardio bodies were nearly alsays found is sentncular Ta.cular symptoms (Groups I and II) Indeed myocardium and moreover, it has been hown ·NATURE OF RHEUMATIC HEART DISEASE 331 that the ab ence of such atrial le ions does not that in examination of the heart of patients preclude the occurrence of ventricular Aschoff with rheumatic heart diseae who die and show bodies (118 180) However the presence of the no histologic evidence in a single routine section atrial le ions in at elf is not prognostic of the of myocardium one should always bear in mind post operatie clinical cour e or of future ei ents as Gross and Ehrlich (70) emphasized that the in the natural history of a patients rheumatic number of blocks of the heart that are studied duesse If a patient has active rheumatic disea e and the sites from which the blocks are taken of given intensity on the day of commissur will have an mportant bearing on whether or otomy it does not necessanly follow that this not so called Aschoff bodies are found Gross particular epi ode of activity will long continue and Ehrlich found these le ions in approximately at the ame intensity and lead to recurrent 59 69 of 161 patients ranging in age from 17 decompen ation associated with progressive months to 80 sears who presented anatomically myocardial changes and/or new valvular altera and histologically unmistakable evidence of pres tions Indeed the surgeon may fracture the pa ent or past rheumatic heart disease Among 46 tients mitral value near the end of a phase patients ranging in age from 20 to 40 years of rheumatic activity and in such instances they found Achoff bodies in 6740 In com one would ob erve marked post operative im parison it is noteworthy that in the recent provement due not only to improved hemo study by Dalldorf and myself specific rheumatic dynamics related to commissurotomy but also lesions (generally called Aschoff bodies) of 1) to improved function of the myocardium result heart muscle cells or 2) subendocardial smooth ing from remission of activity By the same muscle cells were found in the left atral append token absence of rheumatic activity at the time age curgically removed at the time of mitral of operation does not preclude reactivation of commissurotomy in 630 of 81 patients ranging rheumatic activity at a later date associated in age from 20 to 40 years with worsening of myocardial status Although In 1924 Coombs (39) after many years of the question has not been answered satisfac intensive clinical pathological study of rheu toruly it is posible that transient reactivation matic heart disease made the following state of rheumatic activity or intensification of exst ment The more I see of the microscopic and ing sub clinical rheumatic activity results from macroscopic appearance of the rheumatic heart cardiac surgery in some patients On the other the more am I convinced that even in the most hand however it is likely as Black and Harken chronic and apparently extinct lesions it is (19) have stated that in some patients al wrong to forget the possibility of active infec though rheumatic activity is present the patient tion with significant valvular obstruction may handle that myocardial disease better after the obstruct XII LESIONS OF BLO VESSEL IN THE ing factor has been relieved HEART AND THEIR RELATION TO One may inquire Why does the incidence MYOCARDIAL DAMAGE of active rheumatic lesions among biop ied atrial Any thorough explanation of myocardial dam appendages of patients undergoing mitral com age in rheumatic fever must take into consider musurotomy appear to be significantly higher ation the fact that coronary arteries and their than the reported incidence of Aschoff bodies branches are frequently damaged in this dis among hearts in mot eries of autopsied pa ease The occurrence of arterial lesions in rheu tients with rheumatic heart di ewe (31 70 96)? matic fever has been recognized for over 80 This hould not be surprising when one realizes years (94 129 144) and extensive description that in compari on with biopsy erie autopsy and review of rheumatic vascular lesions may be series of ca.es of rheumatic heart diseae usually found elsewhere (71 87 93 137 153) Krebi include older patient many of whom died after (94) Romberg (153) Fahr (49) Swift (174) theumatic disease had become quiescent Fur and harsher and Bayle s (87) considered lesions thermore many of the e people although they of myocardial arteries important to myocardial howed marked stigmata of rheumatic heart damage in theumatic fever All coats of coronary diese died because of an unrelated disease arteries and their branches including arterioles as hown in the study of Rothschild hugel and may be involved and capillaries may be promi Gross (155) My own experience has taught me nently involved Marked by perplastic intimal ·332 GEORGE E BIORPHY rheumatic changes may cause sigaficant patron found in some hearts have not been found, ing of arterial lumina, especially of small and though carefully looked for, in many others medsum sized vessels In ope arteries medial but myocardial Aschof bodies were present is degenerative and/or hyperplastic changes are large numbers Furthermore in fatal cases of prominent Fragmentation of the internat elas thrombotic thrombocytopenic purpura, in which tics of arteries is often found Gross, Kugel, and widespread platelet thrombons of artenoles and Epstein (73) descnbed everal characteristic capillares occurs in tissues including the heart rheumatic lesions of coronary arteries One of 17 122), Ancboff bodies have never been re the most characteristic of these results in intimal ported to occur in the myocardium I (126) bare musculo elastic hyperplastic change that in recently examined many sections of myocardium medium sized and small myocardsal arteries ray in a cae of thrombotic thrombocytopenic pur cau e goificant luminal DarTomog and some pura that are peppered with an extraordinarily times appreciable narroting of large coronary large number of leukocyte-platelet and platelet arterses occurs Although proved thrombosis of thromby both fresh and 12 various stages of large coronary arteries 13 rare ia rheumatic fever organization in capilares vedules, asterple this is not true of cardiac pain, including that of and small arteries These thrombotic lesions are angina pectors Gross and associates (71) de strikingly like those found a rheumatic lever scribed accluding platelet thrombi in the left Thougb carefully looked for several times 20 circumder coronary artery and major branches lesions resem bisog Aschof bodies have been associated with extensive myocardial infarction found in this case, but some minute apfarcta in a fatal came of rheumatic fever in a 17 month were found old chuid Thrombosis of small myocardial arter The earlier studies on the relatsonshup of len ses and arteroles bas been repeatedly found 1 sjons of coromary arteries and their branches rheumatic fever (39, 128 153, 171) In some sa to myocardial damage were carned out without stances it appears that the occluding material the knowledge we have recently gaped that comprues chiefly clumped platelets with some direct rheumatic isjury to mu cle cells us ex fibrin In the small artenes and artenales pro sential to the formation of Anchoff bodies and Iferated and/or damaged endothelial cells are other myocardsal lessons Thus 10 1933 harsner sometimes seen at the base of these thrombi and Bayle... (87) wrote as follows The increas Over all the lesion appears to be verrucous 18g amount of muscle destruction and fibrosis arteritis qute comparable to valvular verrucae mu t be due estber to securring acute cycles of (128) Orgabuzation of these thrombi may Theumatıc fever or to chronse asterial ds eace result in permanent marked Darrowing of these Many cases, if the bustory can be depended upon small vesels are norocyclc Ertensve zayocardial fibrosis In the light of the evidence presented bere in these cases can better be explained by chronic and elsewbere (123 126) to show that Achof arterial disease than otherwise But we now bodies develop from jured myofibers it might know that both protracted and relatively short appear tempting to consider that narrowing or episodes of rheumatic activity may often not be Occlusion of the lumen of small myocardial veg evident clinically, and furthesspore, the en sels by proliferative vascular change or by dence precepted here and elsesphere (123, 126) thrombosis results in the occurrence of Aschaf indicates that sheumatic activity directly dam bodies Indeed Whitmaa and Eastlake (202) con ages muscle cells in the heart Nevertheless as adered this possibilty But the evidence for kas long been recognized (49, 94, 153, 174) apsuch a view is lacking In several cases of fatal preciable nastowing of the lumina of coronary rheumatic fever Stetsot (171) reported a con arteries or these myocardial branches whetber estent correlation between the occurrence of caused by proliferated intimal elements tbrom leukocyte-platelet thrombi in capillanes small bosis, or by the two combined very probably vein. and occasiabally in artersoles at the ode interferes mth myocardial putntion, and such hand and the presence of Aschoff bodies on the vascular lesions of small vessels may well lead other in my ow studies bowever, of many to micro-infarcts as Kredi (91) asd Romberg sections of heart in many cases of active rheu (153) long ago and others (49, 87,174) bave sug matac heart dlease, vascular thrombs, though gested ·NATURE OF PHEONATIC HEART DISEASE 333 VI RHEUMATIC DISEASE OF CARDIAC VALYES posit on inflamed valve surfaces To Ziegler AND CHORDAE TENDINEAE AND RELATIOY OF verrucae represented thrombo-endocarditis DEFORBUTY OF THESE STRUCTURES TO Myo Bulloch (25-a) and Coombs (39) observed CARDIAL FUNCTION AND FAILURE that the earliest rheumatic change in the valves The first known llustration of mitral stenosi3 occurs beneath the endothelium and deep within is found in Vieussens clasic treatise on heart the valvular substance and that the formation of diease published in 1715 (188-a) In this verrucae is of later occurrence There is often treat... Vieussens recorded observationg made intene proliferation of valvular cells including and from clinical study of patients with mitral sten Anil.chkow myocytes and fibroblasts dets and patients with aortic stenosis and in multinucleated cells may be found Infiltration sufficiency and described these valvular changes with lymphocytes and plasina cells occurs at autopsy It is known that in 1788-89 Pitcairn Sometimes in a fulminating attack of rheumatic (141) and Jenner (84) recognized from clinical fever many polymorphonuclear leukocytes may observation that the heart is not infrequently be found Probferation sometimes focal and at injured in attacks of rheumatic fever Bouillaud other times more extensive of valvular endothe- (21 22 and Watson (1953) 1833- 40 em- Lal cells and cells beneath the endothelium omephasized that attacks of rheumatic fever fre times occurs in pallisade like arrangement These quently result in damaged cardiac valves and proliferated cells are often bacophilic and somepericardium Bouillaud described vanous stages times multinucleated We (127 128) have proof the valvular du.ease in the gros from early duced in rabbits valvular lesions very closely inflammatory change« sometimes associated with resembling the.e rheumatic valvular changes verrucae to marked thickening and hardening by repeated local infections with group A with deformity of valves Wat, on descnbed streptococci Acellular DoD bacterial verrucae rheumatic verrucae thickening and puckering appear to be secondary to proliferation and of valves observed that the intral and aortic necroos of the most superficially proliferated valves were most commonly affected and gave valvular cells and the verrucae probably reprea classic description of rheumatic fibrinous sent small thrombt deposited on damaged propericarditis hferated endocardial cells It appears that fibrin With the rue of the cience of bacteriology in sometimes occurs not only in verrucae but in the last quarter of the 19th century numerous subendothelial ates Fibrous and serous efforts were made to identify microorganisms inflammation of valves has been di. cussed by causative of theumatic fever Several ob erva Bohmig (20-8) The importance of serum com tions were reported of bacteria in valvular ponents in the pathogenesis of valvular disease lesions of rheumatic patients and growth of 13 as yet unloowa various bacteria was reported in cultures made Valvular scarning consequent on protracted at autopsy from valves of such patients in the or repeated epi odes of inflammation throughout case of many of these reports it appears that the valve substance rather than the organization rheumatic valvulitis was confu.ed with bacterial of valvular verrucae is now generally believed to valvulitis (bacterial endocarditis) It further ap chiefly account for the thickening of the valve peate that at that time the mportance of leaflets and calcification creates further deaseptic surgical technique in post mortem formity However fibrin and platelets repeatedly cultures of valves was very probably not ap laid down focally on roughened valve surfaces preciated and corporated in the valves over long pen At that time differences in the interpretation ods of time in some subjects may partially ac of the nature of valvular verrucae developed count for valvular thickening In 1880 and again in 1896 Neumann (131 132) A review and detailed systematic study by 29 mentioned previou.ly in section IV of this Gross and Friedberg (71 b) of lesions of cardiac monograph stated that verrucae are formed valves in theumatic fever may be consulted In entirely from valvular connective tusue that another publication these investigators em undergoes fibrinoid metamorphosis Marchand phasized the importance and common occurrence (116) and Ziegler (204-a) on the other hand of inflamingtory changes in valve rings (71 a) considered verrucae to represent thrombotic de Lesions very closely resembling these have been ·334 GEORGE E MURPHY produced by us (127 128) in rabbits by se planation of mitral insufficiency As Coombs peated focal afections wyth Group A strepto farther wrote post rheumatic clerosis of the COCC: Scarring in these ites following protracted salses lsmuts cardiac efficiency when st produces or repeated rheumatıc attach is most marked 1) obstruction with or without constriction at the 10 mitml and aortic valve rings and is par aunculo ventricular openings, in which cues the ticularly damaging to the patient for the follow ramediate burden is borne by the corre ponding ing reson The ring tissue constitutes the hinges atrium 2) Incompetence with or without ob that connect the values to the body of the myon struction at the orifice of the aortic or pulmonary cardium Interference with the normal move artery in which ca.es it is the corresponding verz ment of the valves from their bases follows tricle that bears the burden scarring and deformity of the ring or linge The lack of correlation between the degree tissue Vascularization of scarred valves and of tytral steno is and cardiac di ability has been their rings commonly occurs and in these stes di cussed in Section XI of this communication It numerous capillaries and larger vessels with is al o known as discussed in Section XI that greatly thickened walls may be found some persons wih marked mitral stenosia ean The occurrence of muscle cells at the base of Live to advanced age with little or no signs of and 10 valves has been referred to in Sections VI congestive heart failure Other patrents with and VII and illustrated in Figg 98-116 and similar degree or less mitral stenosis on the rheumatic le ions of smooth mu cle cells 12 other hand develop congestive heart failure in valves are illustrated in Figs IOI 102 and 108 the 3rd decade or earlier These clinical obser As in the case of deformity of the valves and vations taken together appear to point to the their rings thickening shorteuing and fusion great importance of the condition of the most of chordae tendineae result from protracted cardam in Theumatic heart disease The marked or repeated rheumatic inflammation of the e improvement follomog mutral commissurotory structures and importantly contributes to al of many patients with mitral stenosis may be teration of valvular function Scarnng of papil interpreted to show that relies of the obstruction lary muscles also plays a role in this alteration has removed an important burden that the That valvular deformity places an important myocardium cannot well tolerate and sometimes disabling burden on the myon cardrutn clear In the case of the titral valve LIV SOSIAART OF THE AUTHORS CONCEPTIOV maarked ob sructsot to the flot of blood from OP TIE ORIGIN OF VARIOUS REIKIATIC LE left atrum to left ventricle caused by marked BZONS INCLUDING THE SO-CALLED ASCHOFF or tight mitral steno-is b often followed by over Bogres Frox AIUSCLE CELLS OF THE HEART drstention of the left auricle stasis of blood in AXD OF THE RELATION OF THESE LESIov the atrum and pulmonary hyperten.son Sta 3 TO HEABT FAILURE of blood in the left auticle may result in de velopment of thrombus from sich emboli may Our findings in the heart of rabbits that died &rise The burden placed on aina muscle cells or rere zerificed while sick following repeated leads to their ko pertrophy and at least con focal infections with group A streptococci and tributes to eventual fatigue and alteration of in the heart of patients who died with actre their function Marked tricuspid stenosis te Theumatic heart disea a demonstrate that the sults in over-disten on of the night atrum and characteri tre constituents of myocardial Aschoff plusive engorgement of the liver Aortic in bodies are of two types 3) mono- multi or competence due to deformity of the aortic nonnucleated fragments of damaged mu.cle cells valve place an important burden on the left (F1.28-45 30 72 74 77 and 8) and 2) Teatncle and con derable aortic incompetence multinucleated syncytral m2.ses of myogenic for many year may be 1 ociated with great hs angin that probferate from inside the farcopertrophy of the left sentricle The author is lemma into track of dışıntegratiog mus cle cells mainly an agreement mth Coonoba (39) that and appear in the beginwing to represent at injury to the mitral cu not the chief tempt at regeneration of heart muscle celle factor in the production of matral regurgitation (Fig 10-18 52 53 57 and 59) The various in rheumatır beurt deze It is to the so rheumatic lesions of heart muscle cells may be cardal factor that we mu t look for an er 17ened as occurnog la zones of & fpectrum with ·NATURE OF RHEUMATIC HEART DISEASE 335 reference to reaction of the cells to rheumatic sounds that are slurred muffled or of other poor injury as follows 1) In a zone at the left quality and by changes in the electrocardioend of the pectrum is necrosis of muscle cells graphic pattern But in other patients these sometimes with no inflammatory reaction but lower grades of rheumatıc di ease of beart mu often with infiltration of varying numbers of cle may not be detected by the perseverng clin inflammatory cells among which are interspersed ician on careful daily examination even with the mono- and nonnucleated myofiber fragments and of the electrocardiograph and fluoroscope (Figs 145 and 149) Such lesions are probably All or various combinations of the reactions of the result of intense rheumatic injury The heart muscle cells to rheumatic injury occur in wider the extent of injury the more diffue are one case of active theumatic heart disease and the leons Extensive le song in this zone have sometimes many of these reactions may be seen probably been most often found in children in one low power field (Fig 150) who have experienced a stormy clinical course It has al o been here demonstrated that in with rapidly fatal outcome 2) In the next zone cardiac atrial appendage rheumatic subendo- 13 focal necrosis of muscle cells with less some cardial lesions generally referred to as Aschoff times little infiltration of inflammatory cells bodies are of two kinds 1) Aschoff bodies that but with mono and nonnucleated myofiber originate from rheumatic damage to (strated) fragments In addition there 18 proliferative heart muscle cells (Figs 82-86 and 88–90) just nuclear change in the form of an occasional mul subjacent to the subendocardial zone of smooth tinucleated myofiber fragment and/or multi mu cle and connective tue In expanding such nucleated syncytial myogenic mass that repre A choff bodies sometimes come to lie partially sents attempt at regeneration Thus in this zone in the smooth muscle connective tissue zone 2) are lessons like those seen in Figs 50 52 54 57 Lesions generally de gnated A choff bodies that 59 84-89 147 157 and 160 that are generally re lie entirely in the subendocardial smooth mu cle ferred to as Aschoff bodies The e lesions are connective tissue zone and originate from rheu not as flond as those in the next zone 3) Then matic damage to smooth muscle cells (Figs 91 there is a zone of focal necrosis of muscle cells and 97) and some of these lesions can resemble often with very little infiltration of inflammatory to varying degrees Aschoff bodies that are de cells but with mono- and nonnucleated myofiber rived from heart mu cle cells Finally the oc fragments and more prominent than in the currence in rheumatic heart disease of focal previous zone is proliferative nuclear change in lesions of smooth muscle cells in heart valves the form of multinucleated myofiber fragments (Figs 101 102 and 108) and in myocardial and multinucleated syncy taal myogenic masses artenes (Figs 118-120 and 123-135) is also here that have proliferated inside the arcolemma in illustrated and such lesions can occasionally re attempt at regeneration of muscle Thus in this semble Aschoff bodies zone occur florid Aschoff bodies (Fig 2 13 The various rheumatic changes of heart mus 27 73 82 and 159) 4) Then there may be a cle cells mut be considered collectively and zone of focal damage to mu cle cells where together with valvular deformities when pres although less intense injury occurs the cells do ent in explanation of altered function and not survive but regeneration of an occasional failure of the heart In mo t fatal cases of ac cell may occur 5) Finally in a zone at the nght tive rheumatic heart disease with little or no end of the spectrum there occurs impairment valvular deformaty it appears that Achoff of mu cle cells that results from still le 3 severe bodies e pecially the flord one do not occur Injury and the cells curvive in great enough number to account in themselves In the came of the lower grades of rheumatic for myocardial failure In many of the e cases injury to heart muscle cells subtle changes may not be observed on study by light microscopy especially in children the occurrence of le ions However in some patients when euch impair of heart mu cle cells with no or httle prolifera ment is widespread the clinician may detect as tive nuclear change (as found in zones 1 and 2 he can in the case of more severe myocardial dış outlined above) is a more prominent feature ease the over all alteration of myocardial func than the occurrence of lesions of heart mucle tion as manifested by cardiac dilatation with cells with greater proliferatiye nuclear change conequent widening of the mitral valve ring (as found in flond A choff bodies of zone 3) As which can result 16 apical murmurs by heart compared with the intensitv and extent of active ·336 GEORGE E LEURPHY rbeumatic disebe of heart muscle necessary studied by him were in the great majonts of to cau.e failure of hearts without valvular da cases relenable to ventncular dilatation and its formities the inten. ty and ettent of actise theu corollary mittal neompetence » He further matic disele of heart muscle that can pre- stated 'It is I think straining at a gnat and cipitate failure of hearts burdered bith valiular callosing a camel to suppose that tiaz pinkesd deformities and/or damage of heart muce granulations on the valves are respotable for caused by previous injury probably con mitral insufficiency and to igacre the very siderably less In the latter cases where the conliderable stretching of the mutral ning After heart is burdened by evere valvular delormats many years of laten ve clinical and bustopath the less severe myocardial changes found in leologic study of rheumatic heart diese be em ons in zones 4 and 5 of mdespread mas pre-phasized in 1924 that active rheumatic alteration cipitate failure of the beart Although they may of heart mucle is the rery probable cause of not be as important to altered function and cardiac dilstation and failure in children with failure of the myocardium as the order rhet rheumatic heart diese and may be of great matic lesions of heart muscle cells taken toimportance to cardiac (allure in aduits wità thus gether Aschoff bodies in themselves are i dhesse Yet u fatal cases the only changes that portant and unequivocal evidence of octite he observed iz heart mucle cells were cloudy theuroatic heart dieae Furthermore our find swelling in very acute ces that was nerer ings bere illustrated taken together with find very time and Occasions) oca of Sstty ings of others (28 41 98 102 10S 118 180) metamorphosa in ome cases with respect to make it plain that the occurrence of actre spe thus discrepancy he cornmented as follows cific rheatre lesiyas of nucle cells found in Thee are trisag changes but so are those bropaed atnal appendage at the time of surgery found in most forms of myocardial failure This of rheumatic hearts signifies the great kakels discrepancy between functional imparment and hood of active rhetmatic disease of ventricular apparent anatomic integrity is due to the to heart muscle cells adeguscy of histologic methods It 29 to be hoped that someone will find a way of demon EPILOGUE strating clearly finer alterations withun the cells Kaowledge of how the beert reacts to i of the cardiac muscle Coombs regarded the jury in rheumatic heart diease 15 sportant to characteristic beumatic uhmuary zodules understanding of kow the heart is injured in in the myocardium as non myogenic lexons of this disease and essential to understanding of interstitial connectie true the natural history of the disease In ISIS Lees In 1933 Sir Thomas Lems Wrote concertung and Poynton reported their demonstration of the chronic rheumatic beart disease 39 follows common occurrence of cardiac dilatation often Congestion is the usual tersusastrga in cases of mashed and usually traßsient in primary and rbeumatse heart disease Failure 19 due to part repeated attacks of rbeumatic beart diese to the unusual burdens of work that the beart in children and young adults Poyntok com bas to bear such as salve defects of vanous mented on the di crepancy betsreen marked kinds and ometimes strong adhesions for these cardiac dilatation and slight morphologic alters deplete resenes But the chef factor bererthe tons observed microscopically in the myocar lese must be unberent as the mucle itself for dium in fatal ca.es sth or without sppreciable fasure can DCCUT 5531bout the increased burdeo valyutar changes These myocardial alterations And yet muscle that has aled cannot at present compr. 1bg occa.1002) foci of fatty change in be recognized hetologically or biochemically beart mu.cle fibers and foci of cellular eruda There i3 acres e of the inter-t1129) Abrous tissue uo2 betss een the muscle fibers be deemned 12 a little atrophy bere and there a Little fatty adequate to account for the cardiac dilstation change for the mot part the fibers seem sound He tras of the opinion boxeser that not only god the muscle presents to more chuoge thsa ug often found in bearts that have not faved The 12 chudrea but in adults & Tell geture rheuma tem inunng the deart muscle 3 probably of change in the quality of the muscle us more sub tfe and frequently it u brought about by some great importance to cardiac failure In 1907 Coowls reported that the signs of recent infection from thich the patient has mul heart disease in the many rheumatic children fered not only a theumatic infection but infec ·337 NATURE OF RHEUMATIC HEART DISEASE tions of other types endanger or terminate the lives of those who are near to congestion or AC tually display it The above passage was written when the concept that rheumatic myocardial lessons are essentially non myogenic reactions of connective tissue was approaching culmination This pas sage is alo found in the fourth and last edition of Lewis book Duseases of the Heart publ.hed in 1946 when rheumatic fever was becoming widely known as a collagen diseae or diseae of connective tissue Then as now the essential involvernent of mu cle cells in characteristic and other rheumatic lesions of the myocardium was little recognized and then as now the relation of these myocardial lesions very widely thought to be connective tissue lesions to the altered function and failure of the myocardium in rbeu matic heart dueave was generally poorly under stood Evidence bere presented and illustrated dern onstrates the ongin of rheumatic myocardial lesions including the so-called A choff bodies from heart muscle cells themselves and the origin of certain other rheumatic cardiac lesions from smooth muscle cells If active rheumatic disease of heart mu.cle cells can cause failure of children & hearts without the burden of valvular deformity then it is likely that active rheumatic disea.e of heart mu.cle cells can cause failure of adult hearts e pecially tho e burdened with valvular deformity and with myocardium dam aged by previous attacks Derived from expen ment and histopathologie study findings here presented and viewed in relation to clinical observations provide strong evidence of the very important cauzative relation of tbeumatic disease of heart muscle cells to altered function and fail 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Ascboftscbe haoteken a chisur 102 LANNICAN R The Fheumatic process in the gish Stoogenen Hertohrep (austs 251 left suncular appendage J Path and Bact, alle Path 90 903 1983 77 49 1959 121 MENZER A 103 LARSEN S A Vadersdgelser over mselkeepi Die Aetiologe abutes Gelenk rheumatismus Berssa 190 demarer i Danmark Copenhagen Amold Busch 1933 127 MOSCHCOWSZE An acute febrile plero- 104 Lees DB Acute dilatation of the heart in chromic anems with hyalue thrombosis of rheumatic lever Brit Med 32: 19 1898 the terminal arterioles and capillaries Arch Int Med 36: 89 3925 205 Lees DB AND POYNTON FJ Acute dilata tion of the heart in the rheumatism and 227 MURPHY GE The evolution of our chorea of childhood Ray Aled Chur Soc haotledge of rheumatic fever an bastoncal Lond Med Chir Tr., 81: 419 2899 survey with particular empha2% of the matic heart disease Bull List Med, 14: 106 LETULLN M BEZANÇON FAND WELL MP 23 1943 La Légion Dodulaire spécifique de la myocardite rhumatismale Ann Med 19. 137 223 MURPHY GE Evidence that Aschof bodies 1926 of rheumatic myocarditis develop from 10 107 Lewis Taosus Sir Diseases of the Heart jured myofibers y Exper Med 95: 319 1959 Described for Practitioners and Students New York. Alacmillan Co p 204 1933 224 MURPRT GE The butopathology of theu 107. LOMB GAND SEACXLETT RS Murgan m&tre fever A critical reverv In Rheu cardiac conduction trseve lesion Am J matic Fever A Symposium ed Lewis Path 36 411 1960 Thomas Minneapolis URLY of Minesota 108 LOSE SA ROSTED I E AND EDwaros JE Preso p 28 1952 Aschof bodies in Burgically re-ected left 121-4 ALURPHY GE Attempts to induce rheu ma&tae fever in experimental animals In auricular apsendages and elsewhere in the heart in ztral stenosis Lab Invest 3 Rheumatic Fever A Bymposium ed Lens 483 1954 Thomas Mineapolis Voiy of Mideaota Prese > 150 19,7 103 MACCALLUS W GRheumatic lenious of the left auricle of the heart Bull Johns Hop- 125 A[URPNT GE La patologia de la en lins Hosy 35 329 1994 fermedad cardiovascular reviobics Reler 110 MACCALLUM YG Rheumatism J Am ebeis especial la enfermedad miocardica Med Agart. 84. 1515-51 1995 y los cuerpos de Aschof Primer Symposium 111 MAORI CANCELINO PF ACTIS.Daro, A., Interascional sobre Frebre Reumática Metics Instituto Nacional de Cardiologia AND LEVI V Heperti istologici delle auricole p 175 1858 Amputate id corso di talvuotomis mitrahce Mizerya Med 2 1963 1953 198 Murphy G E On Tuscle cells Archoff bodies and cardiac (azlure in the matic 112 MALLORY T 3 The Prisesples of Pathologie heart disease Bud NI Acad Med 35 Histology BB Saunders Philadelpara 10.619 1959 p 433 193 77 Mt PT GE AND SWITT HT The B 113 MALIAKY T B Case report in case records of the Miasg Cen Bosp New Engl J Med duction of cardiac lesions closely resembling 214: 154 1936 those of rheumatic fever, in rabbits follow ng repeated skin infectiong with group A 114 MANCHESTER B SCOTTI, TM RITYOLDS M L AND DAWSOY Y HA.ch oft bodies Streptococsi 3 Lrper Med B9: 687 1919 10 left auricular appendages of patients 128 MTEPIY G E AXO Saint The 10 wtb mitral tex0919 Arch Int Med 95: duction of rheumatiche cardias lesions : 231 1955 rabbits by repeated focal infections with 115 MAYTLE A The setsology of the uza:296 ETOUP A streptococci comparsa with the ·NATURE OF RHEUMATIC HEART DISEASE 341 cardiac lesions of serum disease J Exper Med 91: 485 1950 199 MOSSY G DE Etude clinique sur les indurations des artéres Arch Gen de Med Tome II p 129 1812 130 Nasi AE AND KENNEDT AM Heartblock in acute rheumatic carditis Lancet 2: 1232 1914 131 NEUMANN E Die Picrocarminfarbung und ihre Anwendung auf die Entzundungslehre Arch f nikr Anat 18: 130 1850 139 NEUMANN E Zur Kenntniss der fibrinoiden Degeneration des Bindegewebes bei Entzun dungen Virchows Arch144 201 1896 133 OPIE E L The significance of allergy in disease Medicine 15.489 1936 133-a OPIE E L Pathogenesis cellular pathol ogy and the nomenclature of disease al lustrated by the hepatic necro919 lipidosis and cirrhosis that are caused by protein diet deficiency Bull N Y Acad Med 31 275 1955 134 PAMPUSH J J AND BRUCE, RA Natural history functional capacity and exercise tolerance of unoperated patients with mitral stenosis Am J Med Sci, 228 605 1954 135 Popovs IP Med Prbvlk Morsk Sborn P 401 Nov 1887 136 PAPPENHEIMER AM AND VON GLAHN WC A case of rheumatic aortatis with early lesions in the media. Am J Path 2 15 1926 137 PAPPENHEIMER A M AND Vox GLAHX WC Studies on the pathology of rheumatic fever 2 cases presenting unusual cardiovascular lesions Am J Path 3 583 1997 138 PATEL DJ AND HECHT HH The role of positive auricular biopsy in mitral sten 0919 Dis Chest 32 665 1957 139 Perry C B Thrombophlebitis in acute rheu matism With clinical case notes by 0 CM Davis and Bernard Schlesinger Lancet 225: 966 1933 140 PINNINGER J L The left auricular appendage in mitral stenosis & study of fifteen cases submitted to valvulotomy St Thomas Hosp Rep 7 54 1951 141 PITCAIRN D Cited by Baille M The Mor bid Anatomy of Some of the Most Impor tant parts of the Human Body 3rd ed Lon don 46 1797 142 POYNTON FJ A case of rheumatic peri carditis and extreme dilatation of the heart with an investigation wto the microscopy of rheumatic heart disease Roy Med Chir Soc Lond Med Chir TI 82 355 1899 143 POINTON F J AND PAINE A Researches on Rheumatism London J and A Churchill 141 RADÉ M Contribution Å letude des lesions des artéres dans l infection rheumatismale Presse med 10: 997 1902 145 RAKOV IL AND TATLOK J S Acute theu matic heart disease in aged report of a case with unusual clinical manifestations Am Heart J 21:241 1941 145-8 RASMELKAMP CH DENNY FW., AND WANYAMAKEE LW Studies on the epi demiology of rheumatic fever in the armed services In Rheumatic Fever A sym posium ed Lewis Thomas Minneapolis Uny of Minnesota Press P 72 1952 146 RANTZ LA BOISYEXT PL AND SPINE TY Etiology and pathogenesis of rheumatic fever Arch Int Med 76 131 1915 147 RENAUT M Rapport sur les myocardites aigues Congrès Sciences Médicals de Lille p 23 1899 148 Rich A R Hypersensitivity in disease with special reference to periartentis nodosa rheumatic fever disseminated lupus ery thematosus and rbeumatoid arthritis Har vey Lectures Series 42 p 106 1916-47 149 Rich, A R AND GREGORY JE Further ex perimental cardiac lesions of rheumatic type produced by anaphylactic bypersenstivity Bull Johns Hopkins Hosp, 75 115 1914 150 ROBLES GILJ RODRIQUEZ I AND IBARRA Incidence of asymptomatic active rheumatic cardsac lesions in patients submitted to mitral commissurotomy and the effect of cortisone on these lesions Am Heart J 50 912 1955 151 ROBBINS SL Textbook of Pathology w B Saunders Philadelphia p 441 1957 152 ROGERS J AND ROBBINS, SL Latent rheu matic myocarditis New Engl J Med 237 829, 1947 153 ROMBERG, E Ueber die Bedeutung des Herz muskels fur die Symptome und den Verlauf der acuten Endocarditis und der chroni schen Klappenfehler Deutsche Arch klin Med 53: 141 1894 151 ROSSLE R Zum Formenkreis der theu matischen Gewebsveranderungen mit be sonderer Berucksichtigung der rheumatis. chen Gefassentzundungen Virchows Arch 288 780 1933 155 ROTHSCHILD MA KUGEL M A AND Gross L Incidence and significance of active in fection in cases of rheumatic cardiovascular disease during the various age periods Am Heart J 9 586 1931 156 RUEBNER B The relationship between muscle damage and the Aschoff cell in rheumatic carditis J Path and Bact 68 101 1954 157 SABISTON DC JB AND FOLLIS RH JR Legions in auricular appendages removed at operations for mitral stenosis of presumed rbeumatic origin Bull Johns Hopkins Hosp 91: 178 1952 158 SAIGO Y Die Purkanje schen Muskelfasern ber Erkrankung des Myocards Beitr ? path Anat uz allg Path 44: 296 1908 159 SAPHIRO A text on systemic pathology Vol I Grune-Stratton New York p 33 1958 160 SAPAIS, O The Aschoff nodule editorial Am J Clin Path 31 534 1959 161 SAPHIRO AND LANGENDORF R Nonspecific myocarditis in acute rheumatic fever Am Heart J, 46 440 1953 162 SAPHIE 0 AND WE SA Rheumatic manifestations in subacute bacterial endocarditis in children Am Heart J 9 29 1933 163 SCHICK B Die Nachkrankheiten des Schar lach Jahrb hinderheilk suppl 65 1907 161 SCHLESINGER B The relationship of throat infection to acute rheumatısın in childhood Arch Dis Childhood 5 411 1930 1913 ·340 GEORGE E MURPHY 97 KUTINER A GAND LENNERT TF The Dccurrence of bacteriostatic properties so the considered from a bacterial point of 17 Brit MJ 1: 1381 1887 blood of patients after recovery from strep 116 MARCWAY F Zur heartaise der Abrigos tococcal pharyngitis J Clin Invest 23 151 1914 Exsudation be: Entzundungen Erwideruar 97-8 LAENNEC RTX Traité de l auscultation an Prof L Neturina Virchor & Arch 145 médiate Brosson et Chaude Paris 1819 279 1896 116 & McCARTY M The immune response to 98 LANCEFIELD RC Antigenic com ples of rheumatic fever In Rheumatic Fever A streptococcus bemolyticus demonstration of type specific substance in extracts of symposuim, ed Lewis Thomas Minneapolis Vary of Minnesota Press p 23 295" streptocoecus bemolyticus J Exp Med 47:91 469 3929 117 MCEWEN C Cytologic studies i reumatie 99 LANCEFIELD RC Serological differentiation fever I The characteristic cells of the they of human and other groups of bemolytic matic granulomaa J Exper Med 55: 748 1939 streptococo J Exp Med 578 672 1933 100 LANCEFTELK, RC Type-speciác antigens M 118 McKros T The left aurcular appendage And T of matt and glossy variants of group 10 mitral stenosis Brit Heart J 15 433 1953 A hemolytic streptococe. J Exp Med" 717 119 MICNEELEY W F Euers LB AND BARKEY $21 1940 DE Rheumatic activsty As judged by 101 LANCEFIELD, RC Specific relationship of cell the presence of Aschaf bodies auricular composition to bsological activity of bemolytic streptococci Harvey Lectures series appendages of patients with mstral stez0919 36 P 251, 1940-41 II Clinical aspect Circulation 8: 337, 1953 10% LANVIAAN R The rheumatic process the 120 MEESSEY I Aschoffelbe Koatchen churur BISS woafedett Herzohren (abstr) 201 left auricular appendage J Path and Bact alle Path 90 403 1953 77:49 1949 203 LARSEN SA Undersøgelser over maelkeepi 221 MENZER A Die Aetiologe alutes Gelenk rheumatistaus Berlin 190 demuer i Danmark Copenhagen Arnold 122 MOSCHCOWITZE Busch 1933 An acute febrile pleo- 104 Lees DB Acute dilatation of the heart in chromic anemia with hyaline thrombosis of rheumatic feser Brut Med 3 2 29 1898 the terminal arterioles and capillantes Assb Int Med 36 83 1925 105 LEES D B AND POYNTON PJ Acute dilatitin & MORPHY GE The evolution of our tion of the keart in the rheumatista and chorea of childhood Roy Med Char foc hnowledge Neumatic lever An bistonical Lond Med Cher TT 81: 419 1898 burvey wsth partacular emphasis on the matic heart disease Bull Ilset Med 24 106 LETULLE, M, BEZANÇON F, AND WEIL MP 23 1943 La Leson nodulaire spécifique de la myo 199 MORPHY G E Evidence that Ascbot bodies cardite shumatismale Ann Med. 19 117 1926 of reumatta myocarditis develop from m 107 LEWIS TEOKAS SIR Diseases of the Heart jured myofibers Exper Med 95: 319 1952 Described for Practitioners and Students New York Macmillan Co p 204 1933 124 MIPHY GE The bastopathology of theu 307. LIDONG AND SHACKETT RB Human matc fever A critical review In Rheu cardiac conductson tissue legions Amy matt Fever A Sympostmed Lewis Paib 36 421 1960 Thomas Minneapolis Udy of Minnesota 108 LUSE S A, RUSTED I E AND EDWARDS JE Press p 29 1952 Aschoff bodies in surgically resected left 224 MURPHY G Attempts to induce theu auncular appeodages and elsewhere in the matic fever in experimental animals la Rheumatic Fever A Synpositi ed Lewis beast in mitral stenosis Lab Invest 3 483 1954 Thoma Minteapolis Upy of Minnesota 103 MACCALLUM W G Rheumatic legons of the Press p 150 1951 Jeft aurcle of the heart Bull John Hop 12, MURPITY GE La patologia de la en kias Hosp 35s 329 1924 fermedad cardiovascular reumática Refer 110 MACCALLUM WG Rheumatustu 3 Ama encia especial a la enfermedad miocardica Med Assn 84 1515-51 1995 y los cuerpos de Aschof Primer Sytiponom Internacional sobre Frebre Keumstics 111 MAORI GANCELINO PF ACTIS DATO, A, Merco Instituto Naciobal de Cardiologia AND LEYL V Reperta istologici nelle auricole amputate in corso di salvisotomia mitralica p 175 1959 Minerva Med 2: 1763, 1953 196 Murphy GE On muscle cells Agchoff bodies and cardiac faxure theumato 112 MALLORY TB The Principles of Pathologic Histolog Y B Saunders Philadelp&a heart disease Busi NY Acad Med, 35 435 19:30 10: 619 1959 1 MURAT GE AV SWIT NF The 113 MALLORY, TBCase report in care records of ibe Miss Gen Bogp New Engl J Med duction of cardiac leatony closely resembling 214 156 1936 those of theumstic feser, in rabbits follow 114 MANCHESTER B, SCOTTI TM., RITYOLDS ing repeated ekin infections with group A M L AYD DAWSOY W 1 A cho bodies streptococc 3 Esper Med 89: 697 1919 in left bunicular appendages of patients 12 MOBPNT GE AND Swirt F The in with bitral eteno Arch Int Med, 951 duction of rheumatic uke cardiac lesions : 231 1955 rabbits by repeated focal lections with 115 MAYTLE A The setiology of the natisz group A streptococci comparison with the ·NATURE OF RHEUMATIC HEART DISEASE 3-13 den infectiosen Charakter und den Zum menhang von acutem Gelenkrbeumatismus und Chorea Berl. 1. Wchnschr 36 Bus 1899 201 WHITE PD., AND BLAND EF Matral stenosis after eighty JADA 116 2001 1911 202 HITMAN RC AND EASTLAKE AC Rhen matic myocarditis Arch Int Med., 26 601 1970 3 WILSON JA AND GREENWOOD T F The Datura) bistory of mitral steno99 MAJ., 71 323 1951 203-2 WILSON M G Rheumatic fever en York Commonwealth Fund p 21 1910 204 YILSOY VI G., AND LN YN Short term hormone therapy its effect in actre rheu matic carditis of varying duration New Engl J Med 260 807 1939 2014 Za E Ueber den Bau und die Entstehung der endocarditischen Eflorescenzen Verhandl d kong finn Med 7 339 ISSS 202 ZICHOSKY HUber jolierte VIsokarditis bei Poliarthritze rheumatica Hunchez med Wohnschr., 93 1017 1931 Caz COLOR PLATES FOLLOW

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·I TROBUCTION TO ILLUSTRATIONS The photolithographs that follow provide evidence of the origin of schoff bodies and other lesions from muscle celb in rheumatic heart discase This endence stems from the experimental induction of myocardial lessons closely resembling those of human rheumatic heart disease, in a small pro portion of many rabbits of random stock that were repeatedly infected locally with group A streptococci of different serological types The results of these experiments proside evidence that Aschoff bodies and other myocardial lesions in human rheumatic heart disease de clop in response to repeated local infections with group A streptococci even though these lesions develop in only a small proportion of the many in the random population «o infected Detailed microscopic study of the experimentally induced myocardial lesions resulted in the findng that these lesions are derived from injury to heart muscle cells This experimental investigation led to extensne direct eudence of the origin of ischoff bodies and other myocardial lesions from heart muscle cells in human rheumatic heart disease These latter findings have resulted from detailed mucroscopic study of the heart of over 90 patients who died with atne thrumatic heart discase and from study of the left atrial appendage removed from over 100 other patients at the time of mitral commissurotomy and the evidence so obtained and here illustrated is in contrast with the widely accepted theory that these are primarily and ea entiallı les ons of collagen and/or other components of connectise o suc Furthermore study of myocardial arteries and atrial appendages led to the finding of the origin of certain rheumatic lesions from smooth muscle ce}} 2016 If these latter lesions can as here alustrated resemble Ischef irt derived from (striated) heart muscle cells 150 and the f mooth niuscle and strated muscle in ihes thi hui innt } fuil photo graphic endence of the closest pillu tin hort bdic in man and experimentally induced : 1) it! 17101 The photomicrographs were tih 1 udru lintel Irwd the author on Lodachrome type F 39 m The lithograplu reproductions #t le in EU the Hallmark Colormaster Cute al process without it and ret u hin Ti etching To attain color fid lat and sharpness of itu t/l color rrection has becii achieved phot hanicalls FALCO

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·attain lor fidelity and sharpness of d tai all color corTCCLion has been INTRODUCTION TO ILLUSTRATIONS The photohithographs that follow proside evidence of the origin of Ischoff bodies and other lesions from muscle cells in theumatic heart disease This eudence stems from the experimental induction of myocardial lesions closely resembling those of human rheumatic heart disease in a small pro portion of many rabbits of random stock that were repeatedly infected focally with group A streptococci of different serological types The results of these experiments proside evidence that Aschoff bodies and other myocardial lesions in human rheumatic heart disease develop in response to repeated focal infections with group A streptococci even though these lesions develop in only a small proportion of the many in the random population so infected Detailed microscopic study of the experimentally induced myocardial lesions resulted in the finding that these lesions are derived from injury to heart muscle cells This experimental investigation led to extensive direct evidence of the origin of Aschoff bodies and other myocardial lesions from heart muse cells in human rheumatic heart discase These latter findings have resulted from detailed microscopic study of the heart of over 90 patients who died with active rheumatic heart disease and from study of the left atrial appendage removed from over 100 other patients at the time of mitral commissurotomy and the evidence so obtained and here illustrated is in contrast with the widely accepted theory that these are primarily and essentiallı lesions of collagen and/or other components of connectic tissue Furthermore study of myocardial arteries and atrial appendages led to the finding of the origin of certain rheumatic lesions from smooth muscle cells and some of these latter lesions can as here illustrated resemble Aschoff bodies that are derived from (striated) heart muscle cells Also illustrated is the occurrence of smooth muscle and strated muscle in values of the heart Submitted first is photo graphic evidence of the close resemblance between Aschoff bodies in man and experimentally induced myocardial lesions in rabbits The photomicrographs were taken by Andrew H Littell Jr and the author on hodachrome type F 35 mm film The lithographic reproductions were made in four colors by the Hallmark Colorm ister Control process without hand retouching or dot ctching To achieve I photomechanically ICAL CUI

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·} WellVT ** napp Peyman is V Nuhi Ista that they are ܨܨܙܨ ܕܬܢܥ ܬ ܢ ܢܟ ܕܪ ܪ . ܐ ܐܢ Prinfinit? Cantik men met fint *** te luttet funktion Te duart ME? hit ******* huntil the house 44 **** at the time in the will atteftand to 14014111 21.thefutants the title v kanan atal bak ithat! eden in that the Mt 24417 mai (ther (19178 en 11111 fin viterers and steal af fx en la reunite le att nix fren 41264th it tv kert illatt for it (sented but tak sell mark and trusteet muka inplek mener of the film Montent the wind an 1 - The photonin seine Viele there 11 til 1 mal the anthus an dochuluuk (lje 1 19 am The latter apotaka ecplandectis i tehtud tu konto the lo (llumeet (introl 1948 a boonlistom all in olive fulle lits and are 1944 ** adittuil alle bo letu 11 dhe burnt athurueil photo the chiuk atlı ·GEORGE E MURPHY EXPLANATION OF PLATES From the left ventricle of rabbit 80 65 sacrificed while quite sick 12 days aller onset of the second focal cutaneous intection with group A streptococct Although repeated blood cultures were negatne the animal recesved large amounts of penicillin intramuscularly from the 5t) to Ich day following the last infection in an attempt to enhance chance for recovery Two focal myocardial lesions closely resembling the human Aschoff bodies in Fig? Ilema toxylın and eosint X 322 Fig 2 From the left entre le of a 20 year old man who died during the third recognized attack of rheumatic leser (autopsy 12278 New York Hospital) Tuo Aschoff bodses in myocardium Hematoxylin and cosan x 200 Fig 3 From the left ventricle of the rabbit referred to in fig 1 Focal rayocardial lesions resemblng the human lessons in Fig 2 Hematoxylin and rosin X 200 Frg 4 From the left sentrcle of a 7 year old girl who died during an attack of acute rheu TISANIC fc er (autopsy 37034 Bellevue Hospital) Ascholt body very near a small myocardial artery Nore close resemblance to the rabbst lesion in Fec 5 Gremsa X 200 Frg 5 From the interventricular sepesis of rabbit 70 55 that died 3 days after the last of 8 focal cutaneous infections with group A streptococcI Myocardial lesson closely resembling the human Aschoff bady in fig very near a myocardial Artery Masson trichrome X 100 * From the same block of 15sue of the patient referred to in Fig 2 Aschoff body in myocardium Hematoxyiin and cosin x 200 Fly 7 From the left sesiride of the rabbst referred to in Figs I and 3 Myocardial lesion Vore the marked similarity between this lesion and the human kesan in Fag 8 with respect to the multinucleated mass in thic lower portion of each lesion and the myofiber fragment extending upwards from st Hema toxylın and cosin X 322 From the left ventricte of a 17 year old girl who died during the last of several attacks of theumatic faser (autopsy 179 Ro kefeller Institute Fiospital) Aschoff body in myocardium Nose the marked similarity between this human tesion and the rabbit lesson in Fig 7 with respect to the multinucleated mass in the lower portion of each lesion and the myofiber fragment extending upwards from at Hematoxylin and coun X 322 Fug 9 from the felt sentricle of sabbst 85 38 that died 11 days after the last of 3 fora cutaneous infections with group A streptococci Two myocardial tenons hole the resemblance of the upper lesion to the human Aschoff body in Fig 6 also note the basophilia of ty selts in both of the rabbit lesions (Basophila of indusidual heart muscle cells esident in several fsguses in che last plate of photographı } iematoxylın and on X 327 ·CLOSE RESEMBLANCE BETWEEN ASCHOFF BODIES IN MAN AND EXPERIMENTALLY INDUCED MYOCARDIAL LESIONS IN RABBITS RABBIT HUMAN RABBIT HUMAN RABBIT MUMAN HUMAN RABAT RABBIT ·GEOPGE E MUURPSEY Fig 19 From the left ventricle of a 12 year old girl who died 2 years after the krst recognized attack of rheumatic fever and 1 month after onset of an upper respiratory infection (autops 32833 New York Hospital) Early disintegration of a small bundle of myofiber between larger bundles Hematoxy'n and Cojin X 200 Fug 0 From the I-ft ventricle of the patient referred to sn Figy 2 and 6 Disintegration of a bundle of myofibers between larger bundles llematreylin and most X 00 Fig 1 From the patient referred to in Fre 26 and 20 I'wo small bundles of myofibers between larger bundles Hematoxylon and easin y 200 F18 22 From the I ft ventricle of a 12 year old boy who died about 6 weeks after the begin sing of the fifth recognized attack of theumatic fever (autrpsy 9609 New York Hospitals A bundle of myofibers between larger bundles fematoxylin and eosin 200 Fig 23 From the left ventri le of the patient referred to in Figs 2 S 20 and 21 Alteration of a bundle of myofiber betueen larget bundles This alteration further advanced than that in Figs 19 20 and "I recognizable as an As hoff body and the pink starnıng sarcoplasmic masses might be mynterpreted as altered collagen Ilema toxylin and eosin X 200 Fug 24 From the left ventricle of the patient referred to in Figs 70 71 and 13 Disintegrating bundles of myofibers betwern farger bundles Hemainxylin and cosin * 37 ) Fog 75 From the left ventrcle of a 19 year old female who died during the fourth known attack of shrumatic iner autopsy 9000 New York Hospital) In the lower portion of the pictur is a bundle of myofibers the left portion of which is esolving into an Aschoff body This bundle is between larger bunla in the night upper portion is an Aschoff body very probably derived from a musc bundle situated very much like the bundle in Fig 22 with respect to contiguous muscle Hematoxylin and en X 80 Fre 26 From the teſt ventrcle of a 60 year old woman who died 30 years after the only recognized attack of rheumatic fever and 10 years after the beginning of many episodes of congestise heart failure (autopsy 15310 New York Hospital) A bundle of myofibers between larger bundies Disintegration of a portion of the croiral bur die with a multinucleated structure Many further developed and characteristic Aschoff bodies through out the myocardium were found Ilematoxylin and cosin X 500 Fug 27 From the left sentricle of the patient referred to 15 Figs 2 6 20 21 23 and 24 Di integration of a bundle of myofibers between larger bundles This disintegration that has procreded further than that in Figs 20 21 and 21 is recognizable as an Ashoff body ffematoxylın and eosin X 322 ·ORIGIN OF ASCHOFF BODIES FROM HEART MUSCLE FIBERS IN SMALL BUNDLES BETWEEN LARGER ONES HUMAN 20 HUMAN 27 HUMAN HUMAN 23 HUMAN 24 HUMAN 25 HUMAN 26 HUMAN 27 HUMAN ·GEORGE E MURPHY Fig 28 From the left ventricle of a 25 year old gurl who dred 19 years after a protracted attack of polyarthritss associated with subcutaneous nodules 5 months after development of bilateral ankle edema and 1 week to 10 days after anset of marked dyspnea associated with an upp r respiratory anlection (autopsy 17823 New York Hospital) Heart muscle fiber with three nuclear masses and a small area of interrupted myofibrıls just below the upper nucleus Many Aschoff bodies were found throughout the myocardsum Hema toxylsa and eosin X 500 Fig 29 From the left ventricle of the heart referred to sn Fig 28 The myofiber in the center shows multiple nuclei in the upper portions and multiple nucles in the lower portion Probable fragtsentation of the myofiber just below the upper group of nucle Hematoxylin and eosin x 500 Fig 30 From the left ventricle of a 12 year old girl who died after several attacks of theu matic fever in the previous 5 years and about 3 weeks after the onset of an upper respiratory infection (autopsy 9208 New Yosk Hospital) A heart muscle fiber has split into 4 fragments with multiple nucles in each fragment Thssss a stage of fragmentation later than the one seen in Fig 29 Hematoxylin and cosin X 510 Fig 31 From the left ventricle of a 23 year old girl who died after 4 recognized anacks of rheumatıc fever 294 years after onset of progressise congestive heart failure and 16 months after the insertion of a plastic valve in the aorta for aortic msufficiency (autopsy 16211 New York Hospital) Fragmentation of a myofiber is obvious and the fragments are further apart than those in Fc 30 Many Aschole bodies were found in the heart Hematoxylın and casin X 500 Fig 32 From the left sentricle of the patient referred to in Fig 18 Fragmentation of a myofiber strikingly similar to that an Fug 31 wath the multinucleated fr g ments about the same distance apart as in Fug 31 Connective tissue normal an appearance This lesion is in the center of a large Aschoff body derised from a bundle of myofibers between larger bundles of myofibers Masson trichrome X 500 Fog 33 From the intersentricular septum of a 13 year old girl who died about 6 week after onset of an upper respiratory infection and about 3 weeks after recognition of actise sheumatsc heart disease (autopsy 716 Rockefeller Institute Hospital) Lining up of myofiber fragments some with one nucleus some with multiple nucle and some with no nucles strikingly &ke the lioing up of fragments in a row seen in Fig 30 abone This picture represents most of an Aschall body deri ed from a bussdle of myofibers lying between larger bundles of myofibers The connective tissue appears normal Masson Inchrome X 500 Fug 34 From the left ventrcle of the patient referred to in Fig 31 above Spleng of a myofiber into 3 fragments each with multiple scles and slightly basophilic parcoplasın Kema toxylık and cosin x 200 Fig 35 Highes magnification of the fragment in the lower portion of Fig 34 Note large number of nucles in fragment Hematoxylon and tosin X 500 X 300 Fig 36 From the left ventricle of the patient referred to in Figs 8 and 16 Basophilic myofiber fragment containing over 30 nucle Eosin and methylene blue ·SPLITTING OF HEART MUSCLE FIBERS INTO FRAGMENTS SOME MULTINUCLEATED IN RHEUMATIC HEART DISEASE 20 HUMAN HUMAN 30 HUMAN KO 31 HUMAN HUMAN 3) HUMAN 34 HUMAN 35 HUMAN HUMAN ·GEORGE E YURPHY Fig 37 From the interventricular septum of the patient referred to in Fig 33 Myofiber very close to a small myocardial blood vessel Hematoxylin and cosin X 372 Fig 38 From the left ventricle of the patient referred to sn Fię 26 Myofiber with 2 nuclet very close to a small myocardial blood vessel Masson (tschrome X 640 Fig 39 From the left entricle of the heart referred to in Fig 30 Multinucleated myofiber very close to a small myocardial blood vessel Hematovykst and eosin X 798 Fig 40 From the left ventricle of the pauent referred to in Figs 8 16 and 36 Basophilic multinucleated myofiber very near a myocardial blood vessel Eosin and methylene blue X 500 Fig 41 From the left ventricle of the patient referred to in Figs 8 16 36 and 40 Two basophilic and multinucleared portions of a myofiber slung like a hammock around a small myocardial blood vessel By focusing with the microscope one can just see connocuon between these two fragments Eosin and methylene blue X 1250 Fig 42 From the left sentricle of the patient referred to in Fig 4 Slightly basophilic multinucleared myofiber fragment close to a myocardial islood sessel Hemi toxylin and cosin X 680 Fig 3 From the left ventricle of the heart referred to in Fig 15 Fresh spl tting of a myofiber into 2 multinucleated basophilic fragments between large bundles of myofibers Hematoxylin and eosin X 500 ry near a capillary Fig 44 From the left entrcle of a 10 yeas old boy who died after 3 muths of recognized acine Theumatic heart disease (autopsy 325 Rockefeller Institute Hospital) Myofiber in intimate relationship to a small myocardial blood sessel gert herantoxylın X 500 Fig 45 From the left ventricle of the patient referred to in Figs 26 and 38 Myocardial lesion in animate asprsation with a myocardial blood sessci wyd sery probably representing fragmostaten of a myofiber such as that sery close to a blood sessel in Fig 4+ Masson trichrome X 500 ·HA JETIFULLFATED HEAFI . VEPLIE in BCsV 6 - Priya L ·GEORGE E MURPHY Fig 55 From the left sentricle of the heart referred to in Figs 26 20 21 23 24 27 56 and 54 Aschoff body derived froits a bundle of myofibers between larger bundles Note the ghost like semnants of myofibers that represent myofiber disintegration further advanced than that scen in the same patent in Figs 20 21 and 24 Nore also the slightly basophilsc portion of a myofiber shaft near the night lower portion of this figurt and like that in the rabbit myocardial lesion in Fig 7 and that in the human lesion in Fig & and note the annular arrangement of nucler at the top central portion that closely resembles the rabbit skeletal muscle lesion in Fig 56 and the human myocardsal lessons in Fige 51 and 61 (same patient) and Fig 59 This illustrates as da Figs 19 27 how so-called interstiral Aschoff bodies arise from bundles of myofibers between large bundles Hematoxylın and eosin X 322 Fig 55 From skeletal muscle of rabbit 82 45 that was sacrificed after marked weight loss and while quite sok 9 weeks after the last of 3 local infections with group A streptococc? Interststal valvulitis tiny (microscopic) verrucae on mitral valve acute proliferans change in chordae tendineae and fresh local myocardial lessons were evident Skeletal muscl lesion occurring entit within the sarcolemma of a myofiber and showing annular arrangement of myou genic nucler around disintegrared sarcoplasm Note close resemblance to the other annular lesions sa figures in this plate No connective tissue reaction presens Hematoxylın and cosin 500 Frg 57 From the same patient referred to in Figs 26 20 21 23 24 27 50 54 and 55 A tiny Aschoff body struksngly like the rabbit skeletal muscle lesions in Figs 56 and 58 and the human myocardial lesions in Figs 59 and 61 Note the annulat arrangement of les around disintegrated sarcoplasm Such a sarcoplasmic mass is often incorrectly considered to b swobes collagen Hematoxylin and ensin X500 Ftg 58 Froma skeletal muscle of rabbit 86 38 that died many months after the shord focal snfection with group A streptococca Changes within skeletal muscle cells like that in Fig 56 with myogenic sucles around sarcoplasmic material Hematoxylin and cosi X 322 nang and Fig 59 From the left ventricle of the patient referred to in Figs 4 42 and 52 Foral myocardsal testos with annular arrangement of myogenic nuclet around a sw oplastruc mass like that in Figs 56 57 58 and 61 The sarcoplasmsc core of thu kttle lesion might be mistaken for alteresi collagen The figure here illustrated as a further cut of the teston Hustrated in Fis 52 and Fig 52 llustrates even more clearly the sarcoplasme fragment with the mult nucleated syncytial structure surrounding at Hernatoxylin and toxin Y 798 Frg 60 From the left ventricle of the patient referred to in Figs 2 6 20 21 23 25 97 50 54 55 and 57 Tiny focal myocardial lesion showing disintegration of sarcoplasm like that in Figs su and 34 (same patient) This little lesion derived from muscle would be relexred to by some as cell coronal Ascholl body and the sarcoplasmic core of such a lesion 2 incorrectly frysrted by many as a swollen mass of collagen Ffematorylia and cosin X 500 sma! Fie 61 From the left ventricle of the patient referred to in Figs 26 20 21 23 24 77 50 54 55 57 and 60 Annular arrangement of nucles at the penpluery of a sarcoplasmic mass like that in Fyg: SS 59 Hematoxylin and costs X 500 Fug 62 From skeletal muscle of the rabbit referred to in Fig 58 Annular arrangement of myogenic nucles within a sarcoplasmic mass Note the striking sosem blance to the human myocardial lesson in Fig 53 Metrtstoryka and com X 500 7 SO Fig 63 From the left ventricic of the patient rclerred to in Figs 2 6 20 23 23 24 54 55 57 60 and 6) Annular arrangement of myogenic nucles within a sarcoplasmic mass in the smyocardiun the striking resemblance to the rabbit skeletal muscle lesson in Fig 62 Hematoxylin and Yots 1 sin y ·ANNULAR PROLIFERATION OF MYOGENIC NUCLEI AROUND AND IN SARCOPLASM IN RHEUMATIC MYOCARDIAL LESIONS AND SKELETAL MUSCLE 55 HUMAN 56 RABBIT 57 HUMAN 5& RABBIT 59 HUMAN 60 HUMAN LIEBE ·GEORGE E MURPHY Fig 64 From the skeletal muscle of a 20 year old girl who died after several attacks of thew matic fever 5 year after onset of progressic congestive heart failure and 11 days after mitral commuurptomy (autopsy 15320 New York Hospital) Aschoft bodies were found in the myocardium The skeletal muscle lestan shown here comprises basophilse fragments of sarcoplasm and myogenic nuclei Gremsa X 500 Fag 65 From skeletal muscle of the rabbit referred to in Fig 56 Skeletal muscle lesion showing Cissntegration of sarcoplasm and very numerous myogenic nucles within a sarcoplasmic mass Note normal appcarance of connectsse tissue and the striking rerem blance of this lesion to the human myocardial lesion in Fig 68 Hematoxyds and eosin X 500 Fug 66 From the left ventricic of the rabbit referred to in Figs 1 3 7 10 11 12 17 and 53 Multinucleated basophilic myogenic mass strikingly resembling the human myocardial one in Frg 69 Hematoxylın and eosin X 500 Fig 67 From skeletal muscle of the rabbit referred to in Figs 58 and 62 Mulunucleated sarcoplasmie masses Nore normal appearance of the connecti e tissue Hema toxylon and porn X 500 Fig 68 From the left ventrcle of the patient referred to in Figo 26 and 38 Multınucleated basophilic myocarchal mass strikingly like the rabbit skeletal muscle lesion in Frg 65 Hematoxylın and coun X 799 Fig 69 From the left ventricle of the patient seferred to in Figs 31 34 and 35 Multinucleated basophilic myogenic mass strikingly like the rabbit one in Fig 66 Hematoxyde and tosin X 500 Fug 70 From the left ventricle of the patient referred to in Figs 44 and 48 Myofsber fragment the upper one with many nucles Note resemblance to th multinucleared fragments in Figs 38 39 40 and 43 and note the relationship to conuguous myf bere aer kingly like that of the myofiber in the central lower portion in Fig 71 to conuguous myofbers Weigert heraatoxyån X 530 Fug 71 From the left ventricle of the pauent referred to in Figy 44 48 and o Myofsbers lying between farge bundles of myofibers Note relationship of the ni yoriber in the central lower portion to consiguous myofibers I ke that in Fig 70 Phospholungstic acid hematoxylın X 322 Fug 72 From the left ventricle of the patient referred to in Figs & 16 38 40 and 41 A dwintegrasing myofiber wih multiple nucles in the upper portion lying between large bundlet of myofibers Note the empty portion of the myofiber track like that in the lower central portion in Fig 71 also note alteration of myofibers above the central one Eosin and methylene ble X 500 ·YES MULTINUCLEATED STRUCTURES DE IN RHEUMATIC MYOCARDIAL LES Lau 64 HUMAN 65 RABBIT o ÇANNETTIIN 62 RABBIT HUMAN 70 HUMAN HUMAN ·GEDAGF & MURPHY Fig 73 From the left ventrcle of the patient referred to in Figs 26 38 45 and 68 Aschofs body in myocardium The identical section restained with Weigest van Geeson och nique in Fix 76 below and then restained with Masson trichtomic in Fig 79 below shows the normal appearance of the connecuve tissue in this Aschoff body Hematorylin and cosin X 322 From the left ventrcle of an 8 year old girl who died about 5% weeks after recognition of onset of the fsrst recognized attack of rheumarc fever (autopsy 86?7 New Work Hospital) Aschoff body derived from mynfibers lying between lange bundles of myofibers Note the normal appearance of the connective assue and the imng up of nucleated and non nucleated myofiber fragments in a row like that in Figs 29 34 77 and 80 This }psion and those Figs 77 and 80 Illustrate the point brought out in Figs 19 27 that interstitial Aschoff bodses are denied from heart muscle cells lying among or between large bundles of myofibers Masson trichrome X 400 Fig 75 From the left ventricle of a 11 month old boy who died about 7 days aftes com plaining of pain in the right ankle {autopsy 6852 Mount Sinai Hospital Now York) Many Aschoff bodies were found throughout the myocardium Aschoff body very near a myo cardial artery The identical section stained wied Weigest van Gieson in Fig 78 immediately dclow shows the normal appearance of the connectar fysgue in this son Hematoxvita «nd cosin X 9 Weigert van Gieson stain of the identical section shown in Fog 73 ind illustranng the normal appearance of the connectise tissue within the Archolí body 322 Fug 77 From the left venircle of the patient referred to in Figs 44 48 70 and 71 Aschoff Body derived from heart muscle cells among bund)cs of myofibers "ore normal appear ance of connective tissue in the lesion and the liring up of nucleated and non nucleated myofiber fragments in a row like that in Frgs 19 T4 This illu trates the point brought out in Figy 19 27 and 74 that intensita} Aschoff bodies are derived from heart muscle cells lying among or between bundles of myofibers Masson tnchrome X 500 Fs8 78 Weigert van Cyeson stain of the sdonneal section shown in F28 5 and illustrating the normal appearance of the connective tissue within the Aschoff body that s ery close to a myocardial artery (Closeness of heart muscle fibers to vessels is illustrated in Figs 37-45 ) X32? Fig 79 Masson trichrome stain of the identicel schon shown in Figx 79 and 76 and illus trating the normal appcarance of the connective tissue within the Aschoft body X 392 Fig 80 Aschoft body derived from a bundle of beart suscle cells lying between large bundle Fragmentation of the myofibers and lining up in a row of Rucicated and non nuci trd Iragments like that seert in Figs 74 and 77 and to Frgs 29 34 Nate the delicate and normal appearance of the connectae tipue in the Aschoff body teigert van Greson X 250 Fig B3 Kemacoxyton and conin atain of the identi di prction of the Aschof budy shown in Frg 80 X 322 ·NORMAL APPEARANCE OF CONNECTIVE TISSUE IN ASCHOFF EO3 AND ORIGIN OF THE LESIONS FROM HEART MUSCLE CELLS 24 KUMAN 73 HUMAN 15 JMAN HUMAN HUMAN HUW.AM ·GEORGE E MURPHY Fig 73 From the left ventrcle of the patient referred to in Figy 26 38 45 and 68 Aschoff body in myocardium The identical section restained with Weigert van Gieson tech nique in Fig 76 below and then restained with Masson trichrome in Frg 79 below shows the nomat appearance of the connective tissue in this Aschoff body Hematoxylitz and cosin X 322 From the left ventricle of an 8 year old girl who died about 54. weeks after recognition of onset of the first recognized attack of rheumatic fever (autopsy 8627 New Jork Hospital) Aschoff body derived from toyofibers lying between large bundles of myofibers Note the normal appearance of the connective tissue and the long up of nucleated and non nucleated myofiber fragments in a row like that in Figs 29 34 77 and 80 This lesson and those in Figs 77 and BO allustrate the point brought out in Figs 19 27 that interstitial Aschoff bodses are derived from heart muscle cells tying among or between large bundles of myofibers Masson trichrome X 400 Fug 75 From the left ventricle of a 17 month old boy who died about 27 days after com plamıng of pais on the right ankle (autopsy 6852 Mount Sinai Hospital New York) Many Asckoff bodies were found throughout the myocardium Aschoff body very near a myo cardial artery The Identrcal section stained with Weigert van Greson in Fig 78 immediately below shows the normal appearance of the connective tissue in this lesson Hematoxylın and tosin X 322 Fig 76 Weigert van Gjeson stain of the sdentical section shown in Fig 73 and illustrating the normal appearance of the connective tissue within the Aschoff body X 322 Fug 77 From the lelt ventricle of the parent referred to in Figs 44 48 70 and 71 Aschoff body derived from heart muscle cells among bundles of myofibers Nore normal appear ance of connective tussue in the lesion and the haing up of nucleated and non nucleated myofiber fragments in a row like that in Figs 29 34 This illustrates the point brought out sa Figs 1927 and 74 that suiterstitial Ascholt bodies are derived from heart muscle cells lying among or between bundles of myofibers Masson trschronne X 500 Fug 78 Wergert van Greson stain of the identical section shown in Fig 75 and illustrating the normat appearance of the connective tassue within the Aschoft body that is very close to a myocardial astery (Closeness of heart muscle fibers to vessels ss illustrated in Figu 37 45 ) X 32" Fig 79 Mayson trichrome stain of the identical section shown in Figs 73 and 76 and Ulustrating the normal appearance of the connective tissue within the Aschoff body x 322 Fig 80 Aschoff body derived from a bundle of heart muscle cells yang between large bundles Fragmentation of the myofibers and lining up in a row of nucleated and non nucleared fragments Iike that seen in Figs 74 and 77 and in Figy 29 34 Nore the delicate and norma} appearance of the connective tissue in the Aschoff body Weigert van Geson x 250 Fig 81 Hematoxylın and cosin atain of the identical section of the Aschoff body shown in Fig 80 X 322 ·ORIGIN OF ASCHOFF BODIES FROM HEART MUSCLE CELLS IN ATRIAL APPENDAGES AND LEFT VENTRICLE OF THE HEART *2 HUMAN 33 HUMAN HUMAN $$ HUMAN MUMAN 32 HUMAN ·GEORGE E. MURPHY Fig 82 From the left atral appendage remated at the time of a a 55 year old woman with no history of rheumatic lever or chorea who nocturnal dyspnea and dyspnea on exertion 5 6 weeks prior to operation mitral stenosis with slight regurgitation was found Aschoft bodies shown as the lower and upper central portion of the pict heart muscle cells just subjacent to the sub endocardium This point u brou pictures in this plate (8 56 7754) Hematoxylın and cosin X 80 Fig 83 From the left atrai appendage removed at the time of mutral cc 50 year old man who had polyarthrits 38 years presiously and noted gradual years before operator that progressed gradually an the last 2 years At operatian regurgitation was found Early stage of an Aschoff body clearly representing focal disintegration of just subjacent to the sub-endocardium a httle bite out of the myocardium this httle wound would be expected to occur (S 51 1479) Masson Inchrome Fig 84 From the left atral appendage remosed at the time of mitral co a 50 year old woman with no history of acute rheumatic lever or chorea Rheu diagnosed and dyspnea on exestion developed 12 years prior to operation orthopnea and ankle edema developed and about 1 year prior to operation there of symptoms At operatton marked mitral stenosis with helle segurgitation was fo Aschoff body very probably in a little later stage than that is Fig 83 deri muscle cells just subjacent to the sub endocardium Connective tissue in lesion (8 56 8148) Massos trschrose X 200 Ftg 85 an exertion From te left atrial appendage removed at the time of operation on a 29 year old woman who had rheumato le er 17 years previously followed by pers Four years prior to operation asckes and marked ankle edema deve cardiac symptoms approximately stationary in the past 2 years At operation marked ficiency was found and no commaussurotorny was carried out An Aschoff body derived from a little bundle of heart muscle cells has thrust is toward the subendor ardust Connective tissue in lesion appears normal (S 55 2976) and conn X 200 Fag 66 Phosphorungstic acid hematoxylın stasn of the identical section shown in Ilustrate the ortgin Aschoff body from Ittle bundle of heart muscle cells Conne in lesson appears normal (S 55 2996) x 200 Fig 87 From a 10 year old girl who died 10 years after an attack of chorea 1 rheumatic heart disease 2 years after another attack of active heart disease and 4 mos polyarthrites and steady worsening of cardiac status (autopsy 9531 New York Hospital} Aschoff body derived from heart muscle cells and possibly representing a litle later ! that seen an Fig 84 flematoxylin and eosin X 200 Fig 88 From the left atrial appendage removed at the time of mitral commissurotor 39 year old woman who had chorea 31 years previously 343 years prior to operation ack matic heart disease was diagnosed and increased shortsess of breath de eloped In the yer operation increasing dyspsea on exertion and orthopnea occurred At operation marked stenosis with some regurgtation was found Aschofſ body developing from a little bundle of heart muscle cells (S 56 2678) Hema! and cosin X 200 F1g 49 Masson trchrome sait of the dentical section shown in Fig 88 and illustr normal appearance of connective tissue wathin the le309 ( 56 2678) X 200 Fig 90 From the left atrial appendage of the patient referred to in F1g 89 This p clure would appear to represent the following the myocardium has been troded or bark by mheutatse damage and in the process focal Aschoff bodies have formed collagenization the myocardial wounds has occurred (5 56 7754) Masson trichromt X 80 ·ORIGIN OF RHEUMATIC LESIONS FROM SMOOTH MUSCLE CELLS IN CARDIAC LEFT ATRIUM SMOOTH MUSCLE IN MITRAL VALVE 91 HUMAN 92 RABBIT 93 HUMAN 94 HUMAN 93 RABBIT 96 HUMAN 97 KUMAN 99 HUMAN LIMAN ·GEORGE E MURPHY Fig 91 From the left atrial appendage removed at the time of mitral comma surotomy of a 34 year old woman who had chorea 22 years previously and descloped dyspnea on exertion that had been serere in the past several years Marked mitral stenosis with no evident regurgitation was found No Aschoff bodies were found in the atral appendage This section is shown to illustrate the avenue or band of smooth muscle cells that normally occurs in the sub-endocardium of the atrial wall (S 55 4662) Phosphotungstec acid hematoxyhn X 80 Fug 92 From the left atrism of rabbis 94 96 to allustrate the broad avenue or band of smooth muscle cells that occurs in the sub endocardrum of the rabbit atrium as in the human Masson trichrome X 200 F1g 93 From the left atrial appes dage renoved at the time of mitral Commssurotomy of a 34 year old woman who had rheumatic feser 27 years previously in the y te prior to operation marked progression of dyspnea and orthopnea occurred At operation marked itral stenosis without regurgitation was found This picture shows a broad avenue ar band of smooth muscle cells the sub endocardium (S 55 270) Masson trschrome X 80 Frg 94 From the left atrial appendage removed at the time of mitral ommassurotomy of * 38 year old woman who had acute rheumatic fever 32 years before operatio > Dyspnea de eloped 5 years prior to operation and was stationary until she past several months pror to operation when st became progressively severe and was attended by the de elopment of paraxyser al nocturnal dyspnea At operation marked mitral stenosis without regurgitation was found As the eye of the viewer moes down the avenue of smooth muscle in the sub endocardiums comes to a lesson lying in the lower portion of the a enuc that is a specific rheu dric lesion resembling the Aschoff bodies that develop from heart muscle cells See highes macrification in Fig 97 (S 56 8219) Phasphotungauc acid hematoxylin X BO Fig 95 From she left atrsuin of rabbit 82 42 that died several months after the last of 5 focal cutaneous infections with group A streptococci Two focal lessons in the sub endocardium strikingly like those in stse human ainal sub endocardium in Fig 96 These lessons occur where smooth muscle 19 known to o rur Gremsa X 200 Fig 96 From the left atrium of the patient referred to sa Fsgs 31 34 5 and 69 Two focal rheumatic lesions in the sub-endocardus strikingly like thos in the rabbit atrial sub endocardium in Fig 95 and occurring where smooth muscle is known to wrcur Grensia X 80 Fag 97 Higher magnificatson of Fig 94 Lesion of Aschoff body type of urring in the middle of the avenue of sub endocardial ssssoosh muscle and very probably derived from smooth muscle cells Phosphotungstic acid hematoxylin X 200 Fig 98 From the atrial appendage shown in Fig 93 to illustrate the avenue of smooth muscle in the atrial sub endocardium Massos trichrome X 80 Fig 99 From the base of the mural valve of a 12 year old girl who died 7 years after an atrack of polyarthritis 2 years after another attack of theumatic fever with congestive heart failure and 3 months after an upper respiratory infection followed by congestive heart la lure {autopsy 8072 New York Hospital) This picture illustrates the manner in which smooth muscle continues into the mirral salve from the left atrium Phosphatunk tic acid hematoxylın X 32 ·SMOOTH MUSCLE CELLS IN HEART VALVES 100 HUMAN 101 HUMAN 102 HUMAN 103 HUMAN 104 HUMAN 105 HUMAN 106 HUMAN 107 HUMAN 108 HUMAN ·GEORGE E MURPHY Fig 100 From the aortic leaflet of the mutral valve of a sn year old man who died about 2 weeks after onset of an attack of actis rheumatic fever (autopsy 40 Rockefeller Institute Hospital) Many Aschoff bodies were found throughout the myocardium This section of mitral valve shows bundles of smooth mustls that stain purple Phosphatungstic Acid hematoxylın X 80 Fig 101 From the same valve referred to in Fig 100 Spindle shap d 1 son resembling an Aschoff body seen in the lower portion of the track of smooth us lc I hosphotungstic acid hematoxylın X 80 13 Fig 102 Higher magnification of the lesion in the lower portion of Fig 101 Phosphotungstic acid hematoxylın * 200 Fig 103 From the aortic leaflet of the mitral valve of a 24 vear ol girl who died after several attacks of rheumatic fever and with sub acute bacterial endocarditis became apparent several months after tooth extractions (autopsy 10188 New York Hospital) This picture illustrates the occurrence of bundles of smooth muscle sta na red in the mitral valve Heidenhain connective tissue stain X 80 Fug 10+ From the aortic leaflet of the mitral value of a 17 year old 1 oy who died 9 years after an attack of chorra 4 years after a bous of active rheumatic heart disease with decompen ation and after 2 other attacks in the last 2 years of life as ociated with increas y signs of congestie heart failure (autopsy 9622 New York Hospital) This picture shows that a considerable amount of smooth muscle stair dark purple o curs un bundles in this portion of the valve Phosphotungstic acid hematoxylın 3? Fig 105 From the aortic value of a 28 year old man who died 18 ye alter onset of chorea that secussed in the best 2 years and 2 years and 8 months respectiv ly all recurrent attacks of rheumatic fever (autopsy 9128 New York f[ospital) Note the bundles of smooth muscle sfaining dark purple to black beneath the valvular endocardium Phosphotunost: acid hematoxylın Y 80 Page 106 F10m the adriic abye of an 11 year old girl who died aft r the last of several attacks of rheumatic feser (autopsy 426 Rockefeller Institute Hospital) This picture illustrates the occurrence of smooth muscle staining purple occurring in bun des beneath the endocardium Phosphotungstic acid hematoxylın x 37 Fig 207 Ingher magnication of Fog 106 10 Bustrate th occurrence ( bundles of smooth muscle stasning purple beneath the salvular endocardium Phosphotungstec acid hematorylin X 80 Figing From the aortic salse of the patient referred to in Figs 44 48 70 71 and 7 This elastic tissue stain illustrates the occurrence of smooth musc! clls between Jaming of clastic fibers basophilia and multinucleation of some of the mood smooth muscle cells » d nt Weert van Cieson Y 200 ·SMOOTH MUSCLE CELLS IN MEART VALVES 100 MUMAN 101 HUMAN TOZ HUMAN TOJ HUMAN 104 HUMAN 105 HUMAN 100 HUMAN ) 107 HUMAN 300 MAN ·GEORGE E MURPHY Fig 127 From the left ventricle of the patient referred to in Fig 25 Myocardial artery showing a focal nodular lesion in the media in the low right portion of the picture Phosphotungstic acid hematoxylın X 80 Fig 198 Higher magnification of the nodular lesion shown in Fig 127 Phosphotungstic acid hematoxylın X 200 Fug 129 Higher magnification of the lesion shown in Figs 127 and 128 This medial lesions somewhat resembling an Aschoff body contains several multinucleated elements Phosphotungstic acid hematorylını X 500 Fig 130 From the left ventricle of the patient referred to in Figs 76 79 80 and 81 Myocardial artery A small portion of media in the lower portion of the picture is the site of a nodule of medial cellular elements Hematoxylın and eosin X 200 Fig 131 From the left ventricle of the patient referred to in Figs 28 and 29 The media of the lower portion of this small myocardial artery replaced by a focal lesion chat contains basophilic and multinucleated cellular elements. This lesion resembles an Aschoff body and is very probably derived from smooth muscle cells in the media Gremsa X 500 Fig 132 From the left Patricle of the patrent referred to in Figs 87 and 115 Nodule of medial cellular elements in the night lower central portion of the media of a myocardial artery Hematoxylin and cosin X 200 Fig 133 From the left sentricle of the patient referred to in Figs 30 and 39 Nodule in the night lower portion of the media of a myocardial artery Broad zont of scarred adventitia Hematorylin and eosin X 80 Fig 134 cosin X 200 Higher magnification of the medial lesion shown in Fig 133 Hematoxylin and Fig 135 Higher magnification of the lesion shown in Figs 133 and 134 This lesion resembles an Aschoff body llematorylın and cosin X 500 ·ORIGIN OF RHEUMATIC LESIONS FROM SMOOTH MUSCLE CELLS IN THE MEDIA OF MYOCARDIAL ARTERIES - 11 128 HUMAN 129 HUMAN 127 HUMAN 131 KUMAN 132 HUMAN 130 HUMAN 134 MUMAN 139 MWAN ·GEORGE E MURPHY Fig 154 From the left ventricle of rabbit 81 97 that dred 8 days after the last of 4 focal cutaneous infections with group A streptococci Basophilia of heart muscle cells is here illustrated Giemsa X 500 Fig 155 From the left ventricle of the patient referred to in Figs 44 48 71 and 108 Basophilia in the upper portion of a myofiber To the right of this myofiber is cellular proliferation in tracks of necrotic myofibers like that in Figs 10 13 156 157 158 159 and in many other figures among these illustrations Hematoxylin and eosin X 500 Fig 156 From the left ventricle of the patient referred to in Figs 8 16 36 40 41 and 79 Basophilia and prohferation of nuclei in a myofiber fragment among bundles of myofibers Eosin and methylene blue X 500 Fug 157 From the left ventricle of the patient referred to in Figs 8 115 and 132 Early Aschoff body that is clearly developing from interruption and da age of heart muscle fibers that show some reactive change Note the resemblance of this lesion to the one in the atrial appendage in Fig 160 below Hematoxylın and eosin X 200 Fig 158 From the left ventricle of the patient referred to in Figs 8 16 40 41 72 and 156 Fragmentation and multinucleation of heart muscle cells Joke that in F 156 157 and 160 among many others Eosin and methylene blue X 500 Fig 159 From the patient referred to in Figs 87 115 132 and 15 An Aschoff body that has developed from heart mu fibers shows th same mulunucleared elements as seen in Figy 156 157 158 10 13 and many others Hematoxylın and cosin X 250 Fig 160 From the left atrial appendage of the patient referred to in to 84 An Aschoff body derived from heart muscle cells near the tip of the nocardium Note the striking resemblance to the Aschoff body above in Fig 157 Hematoxylın ani 0510 200 Fug 161 From the left ventricle of the patient referred to in Figs 8 16 36 40 41 7" 156 and 158 Basophilic multinucleated myofiber mass Note the struations extending from the right portion of this mass Eosin and methylene blue x 500 Fig 162 From the left ventrcle of the patient referred to in Figs 4 42 59 and 123 An Aschoff body with a mult.nucleated myogenic mass 1 ke that in Fig 161 nd with other nucleated and non nucleated sarcoplasmic fragments Hematoxylın and costa X 3?)

·ORIGIN OF THE CHARACTERISTIC RHEUMATIC MYOCARDIAL LESION FROM HEART MUSCLE CELLS 154 RABBIT 153 HUMAN 136 HUMAN 157 HUMAN 158 HUMAN 199 HUMAN 1. 165 HUMAN 162 MUMAN

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·ACKNOWLFDGVENTS The author acknowledges with much gratitude the technical aid of Andrew H Littell Jr Mrs Barbara Lamarsh Mrs Phyllis Granberg Helmut liction Mrs Michel Zwirn M155 Gioconda Carrozza Mrs Rita Wursett Fdward Carney John Shuman and Miss Judith Chesner during various periods of these long term investigations

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