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Factors concerned in cardiac hypertrophy
FACTORS
CONCERNED
IN CARDIAC
HYPERTROPHY
A STUDY MADE AT NEXROPSYOF SEVENTY-NINE HEART DISEASE” FREDRKX
A. WILLI~J~, Xl)., AND HAKKY ROC’HEHTER. MIKK.
CASES OF RHEUIVIATK IJ. SMITH,
M.D.
T
HE problems of cardiac hypertrophy have been t,he basis of numerous investigations as recorded in the older as well as in the more recent medical literature. As early as 1877, Cohnheim experimentally produced aortic i.nsufficienc>- in clogs. in order to st,ucly the effect of this lesion on the heart. His method, unfortunately, permitted only very short periods of observation, HOthat his experimental conditions were in no way comparable to the condit,ion usually observed in man. A year later Rosenbach. a student of C’ohnheim. carried out experiments on rabbits, prodwin, (11aortic insufficienq- in some and mitral insufficiency in others, clemonst,rating the occurrence of cardiac dilatat’ion and hypert~rophy. His experiments covered a longer period, and the conditions protlucecl were more comparable to the chronic lesions seen in man.
Miillert in 1883, clrmonstrated similar experimental resu1t.s by comparing the weight, of the heart to that of the body. IIe also st,udiecl the auricular and ventricular weights differentially by separation, but his technic has been shown to be inaccurate in t,he light of more recent work.17 Tangl, in 1889, procluced chronic aortic insuiX?ficiencyexperimentally which resulted in cardiac hxpertrophy, and concluded that the degree of hypertrophy depended on the time that the lesion which caused regurgitation had existed, ancl on its degree, and also that an increase in size of the individual muscle fibers occurred. Numerous references, other t,han those mentioned, may be found in the literature. It is interesting and appropriate to review some of the hypotheses that have been advanced regardin g the causes of cardiac hypertrophy : (1) Since the early part of the nineteenth century,“, 6, 2Zincreased work of the heart has been considered predominantly as the most important influence in the production of cardiac hypertrophy. (2) Possible increase in coronary blood flow as demanded by t,he increase in muscle mass has been suggested as a contributary influence.l”, ?‘$ (3) The existence of inflammatory lesions of the myocarclium was considered capable of producing cardiac hypertrophy.‘, 21 (4) An increase in in*From
the
Sertion
on
Camliology
and
YiXvision 190
of
Rrwlicinc.
the
Mayo
Clinic.
WILLIUS
AND
SMITH
:
CARDIAC
191
HYPERTROPHY
terstitial myocardial tissue was believed to be a faetor.7* I0 (5) Prolongation of the midsystolic period and its consequent prolonged hyperemia and increased local nutrition mere advanced as a cause.l’ (6) When the heart is subjected to overstrain, as occurs if a valvular lesion is present, the heart dilates, and in order to reestablish normal The stimulus for this seems to lie function, it must increase its force. in the residual blood in the ventricle, which acts as an increased load and tends to increase both the irritability and the force of contraction and to bring about an increase in tonicity.g, l2 (7) More recently, Herrmann has stressed the importance of considering not one influence but a combination of influences in the production of cardiac hypertrophy. The present study was undertaken to determine, if possible, the major factors and their relative importance in the development of cardiac hypertrophy in man. MATERIAL
The material which formed the basis for this study comprised seventy-nine cases The of rheumatic heart disease in which careful necropsy had been conducted. cases were carefully selected, so that all the required data were available in every instance. The requirement for inclusion demanded an accurate record of the time of the initial illness with rheumatic fever, the patient’s age, sex, body weight, and height, with special data regarding the departure of each from his average normal weight during health; also were required the weight of the heart, accurate description of the cardiac lesions, ineluding associated pathological changes, the cause of death, and records of blood pressure. Patients who had hypertension or who presented evidence suggesting previous hypertension, were not included. METHOD
The heart was before weighing.
removed
from
the
OF
body
STUDY
in the
usual
manner,
opened
and
washed
In order to permit comparative analysis the cases were grouped according to The valvular defect, whether it was stenotic or allowed type of valvular lesion. regurgitation, or both, was graded numerically on the basis of 0 (no defect) to 4 (extreme defect) for clearness and brevity. The predominant defect was always considered first, presuming its greater influence on cardiac hypertrophy. When the defect was limited to one valve and was of one type only, it was so considered; and when defects involved more than one valve, they were grouped as such. In the case of mitral endocarditis, the defects were uniformly of the stenotic type and of the type that allowed of regurgitation, the stenotic element universally predominating. NORMAL
CARDIAC
WEIGHTS
In a study predominantly dealing with cardiac weights it is necessary clearly to expound the normal values utilized. The figures for normal cardiac weights are those established by one of us (Smith) in 1928, in a carefully conducted study of 1,000 normal hearts. These figures showed that the average weight of the heart of the adult males was 294 gm. (165 to 320 gm.), and that the average weight of the heart of adult females was 250 gm. (135 to 325 gm.). The data obtained in the
192
THE
AMERICAN
HEART
JOURNAL
study made in 192s demonstrated a definite correlation between the weight of the heart and the weight of the body, the ratios in adults of average weight were 0.43 per cent for males and 11.40 per cent for females. Among thin persons the ratio is slightly higher, whereas among obese persons it is slightly lower. These variations in individual habitus are important, and must always be considered in the computation of cardiac weights. The same former study20 also showed that the weight lated from the weight of the body, with an error varying The weight of the body in pounds is multiplied by the average weight, by 1.8 for females of average weight, by for obese females and by 2.1 for thin persons. These ployed in this study. It was also shownso that the weight of the irrespective of the weight of the body. Previous are fallacious, probably because of the inc!usion !rad had hypertension.
of the heart can be ealeufrom 8 to 10 per cent. coefficient 1.9 for males of 1.6 for obese males, by 1.5 coefficients have been em-
heart does not increase with age, data emphasizing this relationship of hearts of elderly subjects who
RESULTS
In this material there were forty-two males and thirty-seven females. The average age of the paGents was forty and eight-tenths years, the youngest patient was aged eleven years, and the oldest patient was aged sixty-nine years. Nine children are included in this material, and it must be emphasized here that the standards of cardiac weight of children are uncertain, and that the computations in this study with reference to children are probably associated with a greater error than those pertaining to adults. TABLE CARDIAC
HYPERTROPHY
GROUPED (SEVENTY-NINE
I
ACCORDING CASES)
TO VALVULAR
DEFECTS T
I
VALVULAR
/-
AVERA(
LESIONS
Aortic stenosis 9 8 1 48.6 Aortic insul?Eciency 10 7 3 40.9 Multiple valvular 20 12 8 38.7 lesions Mitral stenosis and 35 13 22 39.8 insufficiency Mitral insufficiency 5 2 3 42.4 *Children excluded in computations.
3 B $ E
5 5 2 1
17.4 31.2 17.6 23.3 18.5 20.2
686 574 524
387 290 281
72.6 76.3* 65.2*
173 172” 169*
17.9
21.9
469
222
62.4*
165”
1.76”
-/ 21.2
21.2
314
77
62.9*
164”
0.52*
-
WILLIUS
AND
SMITII
:
CARDIAC
HYPERTROPHY
193
In order to permit comparative study the cases were grouped as is shown in Table I. Our first analysis concerns the average values derived in the subdivision of the cases into the foregoing groups. The greatest cardiac weight occurred in the cases in the first group (aortic stenosis) in which the average weight was 686 gm. In order of cardiac weight, the other groups presented the following average lesions, 524 values: aortic insufficiency, 574 gm.; multiple valvular gm. ; mitral stenosis and insufficiency, 469 gm.; and pure mitral insufficiency, 314 gm. The heart-weight body-weight ratios were inGreased 25 to 131 per cent over normal (male and female average normal 0.415 per cent) (Table I). No definite correlation was evident between cardiac weight on the one hand and, on the other, the interval from the first attack of rheumatic fever to death. However, the longest interval appeared in the cases of aortic stenosis in which occurred the greatest average age at death. The intervals in the other groups mere so closely approximated as to be insignificant. This order of cardiac weights conforms with clinical impressions, and is in agreement with Cabot’s figures, which included 1,230 postmortem examinations. Aortic Xtelzosis.-There were nine cases of aortic stenosis in which all Eight of the t.he requirements for inclusion in this study were present. patients were males and one was a female. The average age was forty-eight and six-tenths years; the youngest patient was thirty-one years of age, and the oldest sixty-six years. Death occurred from heart failure in six cases; in all but one case, that of sudden death, the syndrome of congestive heart failure was present. Death occurred as the result of acute bacterial endocarditis (B. influenzae) in one case, from pyelonephritis in one, and from pneumonia in another. It is necessary to emphasize the fact that studies of weight in the presence of congestive heart failure include a variable error, differing considerably with the individual patient and depending on the amount of edema fluid retained. This variable, which obviously cannot be determined, may materially influence the weight of the body. Congestive heart failure occurred in 58 per cent of+ the entire series of seventynine cases. The data in Table II are arranged according to the degree of aortic stenosis (Grade 0 to 4) ; Grade 4 indicates almost complete closure of the aortic orifice, whereas Grade 1 denotes slight but actual narrowing in the diameter of the orifice. A definite correlation between the degree of stenosis and the average cardiac weights is evident. The correlation between the average cardiac weights, on the one hand, and, on the other, the average intervals from the first attack of rheumatic Only one attack of rheufever to death is suggestive but not definite.
194
TIIE
AMERI(‘AN
HEART
JOURNAL
matic fever occurred among the patients of this group. The other data pertaining to body habitus, individual cardiac weight,s and so forth, are expressed in Table IT.
CIKDIAC
ITYPEKTKOPIIY
IK
PIUWEN~E
OF AOR’L’IC
s g d
48 hI 31
72.7
1x4
___ __79.5
-__ 186 _..~
77.2
171
.iX.6
, 154
7
59.0
162
45
69.2
40
70.4
_.~__ 165 ____ 172
M 8
78.1
172
53
74.2
50 M
65.0
__- 172
66
M Averages 9
(NINE
CASES)
failfail-
-i Teart failure* 1hute bxcterial endocarditis failI 3eart ure” 1&art fail1 0.97 ure ____
173~o.87
81.X
F Average! .___
? Ieart ure” I leart ure* -___
STFXOSIS
183
0.99
failure* 1Pyelo0.48 nephritis -. 0.97
1Heart
0.73 0.49
1Pneumonia
1
i
cart
____ f ail InrP.
Ho1ma.n and Beck produced experimental aortic stenosis in dogs by constricting the aorta with t,ape. Three such experiments are reported, but unfortunately the terminal cardiac weight of only one animal is mentioned. The dog weighed 20 kg.; and after the lapse of six months the heart weighed 165 gm. and the heart-weight body-weight ratio was 1.21 per cent. The normal ratio for dogs is recorded as 0.72 per cent by Joseph and 0.798 per cent by Herrmann, an average of 0.76 per cent. This represents an increase in 37 per cent over the normal average heart-weight body-weight ratio. The aorta was const,rict.ed to half its normal diameter.
Eyster, Meek and Hodges producetl esperimental aortic stenosis in nineteen (logs, and studied the size of the heart, by serial roextgenographic silhouettes, but failed to record terminal cardiac weights. The average increase in silhouet,te for the entire series was 10.5 per cent, of the original area. The initial increase in shaclom is interpretctl by these workers to indicate dilatation from which the heart may entirely or partially recover, whereas subsequent enlargement. cleveloping slowly, probably indicates hypertrophy. AorYir Ill,slb~~ien~!/.-This group comprised ten cases in which seven were males and three females. The average a.ge was forty and ninetent.hs years, seven ant1 seven-tenths years less than that of patients TABLE CAKDIAC
I~PPERTRI)FIIY
Is
PRESENCE
It1
OF AoKTIC
~XSUFFICIENCT
we’
80.9
171
1.11
13.6
172
0.72
173 l(i.5
1.00 1,“1
166
0.M
18G
failwe* il-Ieart fail1 urc*t / ‘E’neumoni;l~ ‘
~IIenrt
itrangulatcd hernia t I).A!’ Intestinal I hemorrhage 0.79 0.92
i1enrtfail-we”
l.(‘O
Heart
~
3 3
~-7 I i
2
~ 2
~
fail-
UIX”
(I.57
Subacute 1 bacterial mdocarditis O.FO Inanition$
* Congestive ; Obesity. % Emaciation.
heart
failure.
1
I 300
(TEN
CASES)
196
THE
AMERIC!AN
HEART
JOURNAI.
with aortic stenosis. The youngest patient was twelve years of agr and the oldest, was sixty-seven years of age. Five patients died of congestive heart failure, one patient, diecl of subacute bacterial endocarditis (~\Yt,~spto~uc,c,,rs ,rriGdn,rl.s) : whereas the remainder of the patients died from diseases unrelated to t,he heart (Table TIZ). Two patients were obese and one was emaciated, which facts were consideretl in the calculation of the increased wright of the heart over the normal for the given person. The data in Table TTI are arranged according to the degree of aortic between insufficiency (,Gratle 0 10 -l). Again, a clear-cut correlation the degree of lesion and the average weight of the hearts occurred. No correlation appeared bet,ween weight,s of the hearts, on the one hand, and, on the other. t,lie individual and avera,ge intervals from the first episode of rheumatic fever t,o deat,h. Only one attack of rheumatic fever occurred among these paCents. Detailetl data dealing with carcliac wright and body habit,us may bc .noted in Table III. We wish to call atleiition to C’ase 8 (Table 1II) of this group. The patient Teas a boy. aged thirteen years, who died of congestive heart failure one year following his tirst attack of rheumatic fever. The heart Tveighed 5’i 1)~ cent more than t.he calculatetl normal cardiac weight for this boy’s Irabitus. This case and three similar cases of patients who survivetl for a short time following rheumatic fever with marked cardiac Irypt~rtrophy are reported in the succeecling groups and will be considered more fully later in this paper. It is of interest to compare these dat,a to similar data dealing with Bazett and Sands, in their experimental aortic insufficiency of clogs. experiments on
WILLJLX
iisn
ShII’I’II
:
(‘ARl)IA(’
IIYPER’IXOPIII
l!)i
As in the previous groups, a definite correlation between the degree of lesion and the average cardiac weight occnrreti. Recanse the lesions defect is coliwere multiple and variecl in this group, the predominant sidered primarily. A correlation betlreen the average weights of the hearts, on the one hand, and, on the other, the interval from the first attack of rheumatic fever to death in these cases was evident. However, in view of t,he findings in the other groups, this relationship may be casual. Two paGents were emaciat.ed and one was obese, am1 t.he proper coefficients were utilized in the computat,ions of cardiac weight. It is interesting that multiple lesions apparently do not exert as great, n mechanical effect as certain isolated lesions. &‘7litraZ Stello.vis a+t(J I?zs~f~ic,~e,~~~y.--This group included thirty-five patients. There were thirteen males and twenty-two females. The average age for the group was thirty-nine and eight-tenths years; the yonngest patient was aged eleven years, ant1 the oldest, sixty-five years. Twenty-three paGents had died of congestive heart failure, five of subacute bacterial endocarditis (Streptororrzt,s r*ir~it7n~sJ, and the remsinder from causes unrelated to t,he heart. A correlation between the severit-y of the lesion and the average cardiac weights is again evident if the case iu which the lesion was graded 4 is ruclnclecl. As this grade is represented by only one case. it is reasonable to presume that a greater number of cases would bring the average cardiac: weight above t,hat in Gratlc S. The stenotic element predominated over that of insufficiency in all chases. and thcrefore formed the basis for grading. Five patients in this group were the only persons in the entire series Four patients hacl to suffer more than one attack of rheumatic fever. two attacks; one patient had six attacks. Our patient was obese, and proper recognition of this fact was made iu nur computations (Table V) . ~~itud I,)/,nc,~c~~nt~~.-There were only fire eases (6 per cent) of pure It is a recognized fact that pure mitral insnffimitral insufficiency. ciency without stenosis is rare, and we believe that our cases thus tabulated are bona fide examples of this lesion. In these cases there were two males and three females. The average age was fort.y-two and four-tenths years; the youngest patient was aged thirteen years, and the oldest sixty-one years. Tt is interesting and significant to note that only one pat.ient died of heart disease (Table VI). A correlation between the degree of lesion ant1 the average weight of the heart likewise appears to prevail in this small group of cases. No correlation between the cardiac weight, on the one hand, and, on the other, the interval from t,he first attack of rheumatic fever to death is evident in the individual cases, although the averages appear to show a trend.
TO
(I.36
12
1
0.9G
11
Averages
Heart
Hwrt
1.42
0.91
O.S.?
10
177
365
Peritonitis
’!
IIcnrt
‘7 “4 -.-
0.70
59.0
! G.0
43 31 GS
i I.74
TTt~:irt
I.Otj
fnilorc:
fnilurc”
failure”
failwe”
jubncutc bacterial wdocarditis Heart failure”
-1:
PKESETCE
DEATH
IN
9
s
7
i 31.1
~
i
172
3
13
i
170
4
F
~, 1.13
I79
3
G
1.37
I
] 7”
3
1.01
I).!lti
BODy , TvEIGHT 1
'1
174
BODP 1iEIGHT' WEIGII! P. C\I. XG.
I I
AGE, I'EARS, t AND SEX
IlATIOOF IIEART x,-EIGHT
~IYPERTROPHY
1
C'ASE
I
I
-
CARDIAC
1
I j
, I
IV
.I.I
LESIONS
AND GRADES oF v.IT,vI~J,AR LESIONS
TYPES
VALVULAR
/
I
I /
~
1
!
(TWENTY
.\litral stenosis 4, nortic insuf-1 ficiency 2, and stenosis Aortic stenosis.L 3 , mitral &en-l osis 2 Aortic insufieiencg 3, mitral, stenosis 2 Sortie stenosis 3, mitral stenosis 2, mitral insufficienr~ 2 Nitral stenosis 3, aartic stell-’ osis L’, tricuspid stenosis 2 Aortic insnfficiencp 3, mitral~ stenosis 1 .\ortic st.enosis 3, mitral stcn-’ osis S Aortic stenosis 2, mitral st.en-/ osis 3, mitral insufficiency 1 Mitral stenosis 3, aortic insuf-, ficiencv :3 Xlitral s'tenosis ::, nortic insuf-1 ficiency 1 Mitral stenosis 3, aortic stcn-i osis 2 Uitral strnodis 3, !riituspid stcn.1 osis L’
IMULTIPLE
TABLE
LESIOK;. GRADE
OF
61"
~
363
(IWREARE
CASES)
1
57
OG
59
‘i 4
40
54
.i
79
61
n9
63
G8
I
19
I~TERVAI~ FROM AGE RHEcTiI NCREASE JIATIC 0IVEK CALFEVERTO 'ULATED , DEATH, SOR.\l.\T, / .- ~YEARS 37 3G
:I I ,ERCRP;T.
~~
17
11
13
20
19
IS
17
16
F (is N
27
F 60 F 31 F 12 Y 11 F
44
M
57
13
CASE
AGE, YEARS bND SEX
F3.G-(
R:>DY ,‘EIGIIT, KG.
1/
x0-
HEIGIIT CM.
‘,
0.71t
0.80
n.(io
0.G” c)
O.G4
0.49
0.87
0.50
K.\TIO OF IIEART WEIGHT T O BODY \VEI(‘HTT
failure
OF
(
u1oren:
Suhacote bacterial endocarditis .Hcart failwe*
Poisoning
Subacute hacterinll endoearditis$ Heart failurc$
Heart
C.iUSE DE.\TlI
j
DOl1I6AN1 VAT,VU LAR LESION i GRADE AND OF LESIOKS
GKADES
sufficiency
2
020
3lKl
:3X()
-1-117
4 :: 3
43.1
471
547
- .39!J
I/-
\Iltlnl stenosis t’ , :lortic insnt ficiency 2 Lortic stenosis 2, mitral strnosis 1, mitral insufficiency 2 \Iitral stenosis 0, mitral iasuffi. eiency 1, aortic insufficiency 2 Jitral stenosis 0, aortic insnf. ficiency 3 YIitral stcnosia 2, nortic insuf. ficiency 1 Jitral stenosis 0, aortic iiisuf. ficienry 1 Llitral insufficicncv ’ L 2 , nortic ‘1 stenosis 1 iortic insufficiencv 2, mitral in.
V.ZLVULbR
TYPES
PERCEKTAGE ‘SCREASE OVER CALCU-
13
INTERVAT. FIiOl\l RHET.\LATIC FEVER T O DEATH, YEARS
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Average;
_-
CASE
9 L
--
41
___~ 43 52 33 48 21 65 44 38 53 45 21 45 3GF 43 34 48 40 37
F M F F F
M F M F M M M M F F M F
AGE, J FEARS, AND SEX
! ~ /
/
61.5
63.6 60.9 65.9 45.9 75.0 84.0 58.6 58.1 54.5 59.0 56.8 90.9 75.0 51.8 54.5 46.8 54.5 54.0
BODY 1 (VEIGHT, KG.
('AKDIAC
166
171 158 181 165 175 171 177 179 156 165 179 172 165 163 165 159 166 162
EIGHT CM.
~
0.90
0.62 1.20 1.07 1.45 0.86 0.75 1..04 0.99 1.02 0.93 0.90 0.53 0.62 0.89 0.78 0.90 0.75 0.62
Ix
-
~~
AT10 OF HEART WEIGHT PO BODY WEIGHT
IIYPERTRoPII~
V
STENOSIS
mdocarditis
OF DRATH
OF MITRAL
Heart failure” Heart failure” IIeart failure+ Heart failure’ IIeart failure* Heart failure’ Heart failure” Heart failure* Heart failure* Subacute bacterial Heart failure* t Heart failure* Heart failure* Heart failure* Cerebral embolism Heart failure* Heart failure*
Heartfailure”-
CAUSE
PRESENCE
TABLE
/
I
4 3 3 3 :: 3 3 3 3 2 3 3 3 3 3 .3 3 3
-___-~
542
413 730 707 G65 644 630 610 585 557 548 514 489 465 465 429 425 410 340
-~
NCREASE IN HEART IT-EIGHT OVER 'ALCULATED NORMAL, Ghl. ~__ 147 489 431 483 330 278 365 342 341 314 276 169 168 360 201 240 194 126 294
~
(THIRTY-FIVE
ACTCAL HEART r-EIGHT, GM.
INSUFFICIENCY
STEPiOSIS, GRADE
AND
53
36 67 61 73 51 44 60 58 61 57 54 35 36 5G 47 56 47 37
'ERCENTAGE INCREASE OVER ‘ALCULATED xorord~~
CASES)
-28
23
43 1G 2G 8 50 4 26 41 21 7 16 15 33 9 3G 14 27
INTERVAL FROM RHEUMATIC FEVER T(~! DEATH, YEARS
19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 --- 34 Averaget ___ 35
CASE
50 1F 40 37 37 55 23 61 OR 40 53 23 42 48 29 11 37 62
F
M F M M F F F F F M F F F F F M
AGE, YEARS, AND SEX
--
95.4 47.7 84.0 79.5 48.1 81.8 44.5 79.5 45.4 56.8 68.1 61.3 45.4 60.4 45.2 32.7 63.6: 54.5
BODY WEIGI-IT, KG.
174 165 169 173 164 171 157 173 160 178 165 163 162 155 155 140 170f 15s
IEIGH'I CM.
--
--
0.77 1.05 0.57 0.59 0.93 0.54 0.91 0.50 0.90 0.61 0.51 0.55 0.70 0.52 0.66 0.90 0.70: ____0.53
OF HEART WEIGHT PO BODY WEIGHT
I LATIO
~.. -~-
CAUSE
OB DEATH
V-CONT'D
11Jremia ~ Subacute bacterial endoearditie Subacute bacterial endocarditic Heart failure" Heart failure* Brain tumor Subacute bacterial endorarditir Diabetic gangrene Subacute bacterial cludocarditir Heart failure* Heart failure* Heart failure* Pneumonia Exophthahnic goiter Heart failure* Heart failure" , I /Carcil1olna of common bile duct!
I
TABLE
2 2 2 2 2 2 2 2 .> Y 2 2 2 2 2 0 .I
STENOSIS, GRADE
I
I
712 505 485 470 450 444 405 397 390 350 349 337 320 31,s 300 294
ACTUAL HEART WEIGHT, GM. ZALCULATED NOR>.[AL, GM. 313 316 133 137 259 120 229 82 210 112 79 Y-4 140 76 105 157 160 67
OVER
LNCREASEIN IIEART WEIGIIT
44 62 27 29 58 27 57 21 54 32 23 28 44 24 35 53 40 ___~~ 24
---
'ERCENTAGE INCREASE OVER :ALCULAT'ED NORAlAL
29 11 22 4 29 37 13 31 10 19 42 12 24 32 17 6 21 9
INTERVAL FROM tHEU&lATIC FEVERTO DEATH, YEARS
202
CO;1IMENT
In a. recent investigation, Levine and C’arr tlirided and n-eighetl a series of hearts of human beings according to lhe experimental methotl of IIerrmann.1n Fractional n-eights were determined in fifteen cases of rheumatic heart disease, inclndin g five cases of mitral stenosis ant1 insufficiency, three cases of aortic stenosis and insufficiency, five cases of mitral and aortic stenosis and insufficirnry, one case of niitrd, aor& and tricuspid stenosis and insufficiency. and one case of tlirombo-endocarditis of the mitral valve. The conclusions pertinent to this study are that, in rheumatic defects of the mitral valve alone the iucrease in cardiac weight is the result of an increase iii the weight of the right ventricle and the auricles. In large hearts associated with aortic insufficiency, rheumatic 01’ syphilitic. liypertrophp of the wliolr heart occurs, but, the greatest increase is in the left ventricle. Levine and Ctarr expressed the belief t,hat mechanical factors are not entirrl> responsible for the production of cardiac hypertrophy. We shall attempt to apI$~ the analysis of our data to the various hypotheses advanced regarding the prntluction of cardiac hypertrophy. The hypothesis that increased cardiac work causes hypertrophy finds unmistakable confirmation in this stnd>r, as almost without cxception the average weight of the hearts I~rallrlrtl tile degree of va.lvular deformity. The work demanded of the heart appears to be primarily concerned with the magnitude of the mechanical barrier. In consiclering increased Trorlr, however. the interval of time during which the heart is subjected to increased work cannot be disregarded; and although it undoubtedly plays an important part in many cases, the mechanical factor may exert its influence ovrr\rliclminffl-, so that the time element apparently becomes submerged. Our study does not deal with the coronary circulation, so that we do not have data regar(linp cnrotlary blootl flow aud cardiac hppertrophy. We know of no proof to the effect that an illcrease in muscle mass provokes an increase in coronary blootl flow. thus furthering cardiac hypertrophy. Tn fact, the oppnsitr conclusion is not, improbable, t,hat in greatly hypert~rophied lIearts the normal coronary circulation becomes relatively insufficient, since its work may be doubled or even treblecl, as t,he case may be. The question of the relationship of inflammatory lesions of the myocardilun to cardiac hypertrophy is one of considerable interest. In this connection it is important t,o consider the cases of the foul children briefly mentioned earlier in this paper who survived for short periods following their first rheumat,ic infcd ioai. REPORT
OF
CASES
C:&F, l.-(Case X, Table 111.) A boy, aged thirteen years, died of congestire heart failure one rear following his first attack uf rheumatic firer. Only 3 slight drgree of aortic insuffieienc(Grade 1) VYIS found at ncclopsy, IJut the heart weighed
xl g111 , an increase uf 19.i gm. (57 per cent) over the degree td the mechanical lesion nor the duration of producing cardiac hglxrtrol)hy of th& magnitude. attack of rheumatic fcwr.
the calculated normal. of the lesion scemcd This
boy
CAR& 2.----( Chse 6, T:ll~lt~ IV.) A girl, aged thirteen years, heart failure one and a half gears following the first episode Multiple lesions were present; namely, aortic insufficirncy Grade (Grade 1. Marked hypertrophy was found, the heart weighing of 472 gm. (79 per cent) over the calculated normal.
had
had
Neither capable only
one
died of congestive of rheumatic fever. 3, and mitral stenosis 595 gm., an increase
C”ASF: 3.-(Vase 4, Table VI.) A girl, aged thirteen years, survived only four months after the initial rind only attack of rhcmnatie fever and died of congestive heart failure. The only \-alvular defect demonstrable was mitral insufficiency Grade 2; yet the heart Tveighrd L’!).? gm., an incw:~w of I.-j1 pm. (.?I per c*ent) over the calculated normal. (2.4~~
uwing
4.-((Case
20,
to the extremely
Table lwicf
IV.) A girl, aged eleven years, was of unusual interest survival lwriod. 811~ died one month after the onset of
8.
Fig.
1.-A,
Section
of
normal 4, Tnblc
B. heart VT),
muscle; mwked
B, section vmxlolar
of heart muscle degeneration.
The valvular lesions demonstrated after death consisted chorea. mitral insufficiency Grade 2. The heart weighed 230 gnr., an increase per
cent)
over
the
calrulatcd
in Case 3 (Case of aortic of 94 gm.
and (43
normal.
One of us repeatedly observed these children, and me are certain that no preexisting cardiac lesion was responsible for the cardiac hypertrophy. The cardiac injury without question occurred with t.he infections as stated. Careful microscopic study of numerous sections of heart muscle of these four subjects revealed unusually marked rvidences of myocarditis (Figs. 1, 2 and 3). There were extensive areas of cellular infiltration, the cells consisting c~hiefl~- of ~~olymorphonuclear leucocytes and small lymphocytes, and certain areas revealed numerous erythrocytes. Considerable fibrin was deposited in these regions. Considerable swelling of the muscle fibers was apparent, and their striations were indistinct. There were numerous collections of cells scattered throughout the
The changes described were myocardium resembling As&off cells. most prominent in Cases 1 a,nd 2, although they were well marked in the other two cases. It appears that the marlird myocarditis of these c!hiltlren was the chief factor contributing to the production of the cardiac hypertrophv, in view of the fact that the degree of entlocarditis present. and its resulting valvular tleformity were considerably less than that occurring in the majority of cases. Stewart’s experimental work indicated a relationship between myocardit,is and cardiac hypertrophy. He produced extensive myocarditis in rabbits by intravenous injection of epinephrine, and found ensuin g hypertrophof considerable degree. The exact manner in which myocarditis produces hypertrophy is not clearly understood, but it is not improbable that it may represent a
compensatory effort on the part of regions of normal or relatively normal muscle. These findings strongly suggest that, in some cases of severe infection the myocardium responds to the injury of hypertrophy. Our investigation resulted in no data concerning the influence of increase in the midsystolic period on cardiac hypertrophy, nor on the influence of residual blood in the ventricle. We concur with Herrmann in his belief that a combination of influences participates in the production of cardiac hypertrophy. CONCLUSIONS
1. The greatest average cardiac weight occurred in cases of aort,ic stenosis. In order of cardiac weight other lesions occurred in the
“Of3
‘I’IIE
AMERI(‘AS
IIEART
.JOIIRKAI,
insufficiency, multiple valvnlar lesions, following sequence : awtic mitral stenosis and insufficiency-, a.ntl pure mitral insufficiency. 2. There was an outst,anclin g correlat,ion between the degree of t,he lesion and the average weight of tire heart. evidenced only in some 3. There was a suggestive correlation, groups, between the average weight of the heart, on t,hr one hand, and, on the ot.her, the interval elapsing from the initial at,tack of rheumatic fever to tleath. 4. The c~ontlition of four children, who lived only for a very short time following their first illness with rheumatic fever, and chorea in one case, and three of whom had rat,her slight valvular defects, strongly suggests that myocardial injury by infection or its toxins in wme ilistances permits the heart to respond by hypertrophy. 5. Although increased cardiac work imposed by t,he ~alvular defect or defects appears to be the outstanclin g influence in the procluetion of cardiac hypertrophy in rheumatic heart. tlisease. ot,her factors appear to exert a definite but less important influence. Among them is the lengt,h of time t,hat thr heart is subjected to tile lesion ant1 actual myocardial injury in a certain group of Cases. REFEKFN( I
‘ES.
Ehrenfricd : Dcr Ilerzmuskvl und wine Bedeutung fiir Physiologit> 1. Alhrecht, Pathologie und Klinik des Herzens, Berlin, Julius Springer. An Experimental Study of Chronic Aortic 2. Bazett, H. C., nnd Sands, Jane: Regurgitation in Dogs, ,J. C’lin. Inrestigution 3: 65, 1926. 3. Cabot, R. c.: Fwts on the Heart, Philadelphia, 1926, W. B. Saunders. J. F.: Vorlrsnnge~~ iilwr a!lgenlctino I’athologie, Berlin, 1877, A. -k. Cohnheim, HirschwaN ;Y Idem : Vorlcsung~w iilwr allg(~n~einc Pathologic. Ed. 2, Berlin, 18x2, A. Hirsch. \dCl.
6. Corrisart, J. &I. : Essui our les nlaladics r+ les 16sions organiqucs du ~wtwr c,t dw gros vaisseaux, Paris, 1806, Miynfwt. 7. Dchio, K. : Uebcr die 1~indegewelJigr Induration des Herstieivhes (M~ofil~rosit Cordis), Dcutxh. nwd. Wchnsrlw. 26: 750, 1900. Cardiac Changes ~ul~scquent sc. Qster, J. PI. E., Meek. W. J., and Hodges, F. J.: to Experimental Aortio Lesions, Arch. Int. Med. 39: 536, 1!)27. 9. Frank, Otto: Die DSnamik dcs TIerzmuskels, Ztschr. f. Biol. 32: 370, 1895. 10. Herrmann, CT. R.: Experimental Heart Disease. I. Methods of Dividing Hearts; With Sectional and Proportional Weights and lintios for %(I Normal Dogs? Hearts. Anr. HE,II:T J. 1: 21:‘:. 192.5. 11. Idem: &perimental Heart D&w. II. The Effect of J&q~erimental Aortic Renureitation on the Heart Weights: With a Consideration of Some Factors Co&e&d in Cardiac Hypcrtropiiy a& a ~un~mary of the Manifestations of Experimental Heart Disease, ,411. IIENX J. 1: 485, 1926. 12. Hirschfelder. A. D.: Discnscs of the Tlenrt and Aorta. I’l~iladelahia.I / IDIS. IL n. 291, J. B: Lippincott. Emile. and Beck, C‘. S.: ‘l’hc I’hysiological Response of the Circulatory 13. Holman. Syst& to E’xpwimcntnl Alterations. Ib. Thk Effect-of Aortic and Pulmon
18. Miillcr, \Vilhehn: dcs n~rnschlichen Hwzms, Berlin, I& ?vIassc~nlvel~h~iltl~is3e lSi8. 19. Rosenbach, Ottomar: Ueber artificiellr IIcrzkl~~l~pcnfel~ler, Arch. f. espcr. I’ath. u. I’hnrmnkol. 9: 1, lSi8. 20. Smith, H. L.: The Relation of the Weight of the Heart to the Weight of the Body and of the Weight of the Heart to Age, AM. HL.$R~ 1. 4: 79, 19%. 21. Stxdler, b2duard: Esperimentelle und histologis~hc Beitriige zur Ilrrzhypertrophic, Deutschcs Arch. f. klin. Med. 91: 98, 1!1Oi. The Node of Action of Adrenalin in the Production of (!ardinr ‘P) Stewart, --. II. A.: Hypertrophy, J. Path. & Bncteriol. 17: G-l-, 1912. 23. Tan@ Franz: Drljer die Hypertrophie und das phpiologische W:~chstl~um des TIerzeus, Virchow ‘s Arch. f. path. Annt. II. Physiol. 116: 132, 1859. der Kwisl:~uforgane des Xcnschw, Ergebn. (1. alla, Fatll. Z-1. Thorel, (‘. : I’athologir IL path. Anat. 17: 90, l!)lc;. 5. Traube, L.: Quoted by Hirschfelder.
CONCERNED
IN CARDIAC
HYPERTROPHY
A STUDY MADE AT NEXROPSYOF SEVENTY-NINE HEART DISEASE” FREDRKX
A. WILLI~J~, Xl)., AND HAKKY ROC’HEHTER. MIKK.
CASES OF RHEUIVIATK IJ. SMITH,
M.D.
T
HE problems of cardiac hypertrophy have been t,he basis of numerous investigations as recorded in the older as well as in the more recent medical literature. As early as 1877, Cohnheim experimentally produced aortic i.nsufficienc>- in clogs. in order to st,ucly the effect of this lesion on the heart. His method, unfortunately, permitted only very short periods of observation, HOthat his experimental conditions were in no way comparable to the condit,ion usually observed in man. A year later Rosenbach. a student of C’ohnheim. carried out experiments on rabbits, prodwin, (11aortic insufficienq- in some and mitral insufficiency in others, clemonst,rating the occurrence of cardiac dilatat’ion and hypert~rophy. His experiments covered a longer period, and the conditions protlucecl were more comparable to the chronic lesions seen in man.
Miillert in 1883, clrmonstrated similar experimental resu1t.s by comparing the weight, of the heart to that of the body. IIe also st,udiecl the auricular and ventricular weights differentially by separation, but his technic has been shown to be inaccurate in t,he light of more recent work.17 Tangl, in 1889, procluced chronic aortic insuiX?ficiencyexperimentally which resulted in cardiac hxpertrophy, and concluded that the degree of hypertrophy depended on the time that the lesion which caused regurgitation had existed, ancl on its degree, and also that an increase in size of the individual muscle fibers occurred. Numerous references, other t,han those mentioned, may be found in the literature. It is interesting and appropriate to review some of the hypotheses that have been advanced regardin g the causes of cardiac hypertrophy : (1) Since the early part of the nineteenth century,“, 6, 2Zincreased work of the heart has been considered predominantly as the most important influence in the production of cardiac hypertrophy. (2) Possible increase in coronary blood flow as demanded by t,he increase in muscle mass has been suggested as a contributary influence.l”, ?‘$ (3) The existence of inflammatory lesions of the myocarclium was considered capable of producing cardiac hypertrophy.‘, 21 (4) An increase in in*From
the
Sertion
on
Camliology
and
YiXvision 190
of
Rrwlicinc.
the
Mayo
Clinic.
WILLIUS
AND
SMITH
:
CARDIAC
191
HYPERTROPHY
terstitial myocardial tissue was believed to be a faetor.7* I0 (5) Prolongation of the midsystolic period and its consequent prolonged hyperemia and increased local nutrition mere advanced as a cause.l’ (6) When the heart is subjected to overstrain, as occurs if a valvular lesion is present, the heart dilates, and in order to reestablish normal The stimulus for this seems to lie function, it must increase its force. in the residual blood in the ventricle, which acts as an increased load and tends to increase both the irritability and the force of contraction and to bring about an increase in tonicity.g, l2 (7) More recently, Herrmann has stressed the importance of considering not one influence but a combination of influences in the production of cardiac hypertrophy. The present study was undertaken to determine, if possible, the major factors and their relative importance in the development of cardiac hypertrophy in man. MATERIAL
The material which formed the basis for this study comprised seventy-nine cases The of rheumatic heart disease in which careful necropsy had been conducted. cases were carefully selected, so that all the required data were available in every instance. The requirement for inclusion demanded an accurate record of the time of the initial illness with rheumatic fever, the patient’s age, sex, body weight, and height, with special data regarding the departure of each from his average normal weight during health; also were required the weight of the heart, accurate description of the cardiac lesions, ineluding associated pathological changes, the cause of death, and records of blood pressure. Patients who had hypertension or who presented evidence suggesting previous hypertension, were not included. METHOD
The heart was before weighing.
removed
from
the
OF
body
STUDY
in the
usual
manner,
opened
and
washed
In order to permit comparative analysis the cases were grouped according to The valvular defect, whether it was stenotic or allowed type of valvular lesion. regurgitation, or both, was graded numerically on the basis of 0 (no defect) to 4 (extreme defect) for clearness and brevity. The predominant defect was always considered first, presuming its greater influence on cardiac hypertrophy. When the defect was limited to one valve and was of one type only, it was so considered; and when defects involved more than one valve, they were grouped as such. In the case of mitral endocarditis, the defects were uniformly of the stenotic type and of the type that allowed of regurgitation, the stenotic element universally predominating. NORMAL
CARDIAC
WEIGHTS
In a study predominantly dealing with cardiac weights it is necessary clearly to expound the normal values utilized. The figures for normal cardiac weights are those established by one of us (Smith) in 1928, in a carefully conducted study of 1,000 normal hearts. These figures showed that the average weight of the heart of the adult males was 294 gm. (165 to 320 gm.), and that the average weight of the heart of adult females was 250 gm. (135 to 325 gm.). The data obtained in the
192
THE
AMERICAN
HEART
JOURNAL
study made in 192s demonstrated a definite correlation between the weight of the heart and the weight of the body, the ratios in adults of average weight were 0.43 per cent for males and 11.40 per cent for females. Among thin persons the ratio is slightly higher, whereas among obese persons it is slightly lower. These variations in individual habitus are important, and must always be considered in the computation of cardiac weights. The same former study20 also showed that the weight lated from the weight of the body, with an error varying The weight of the body in pounds is multiplied by the average weight, by 1.8 for females of average weight, by for obese females and by 2.1 for thin persons. These ployed in this study. It was also shownso that the weight of the irrespective of the weight of the body. Previous are fallacious, probably because of the inc!usion !rad had hypertension.
of the heart can be ealeufrom 8 to 10 per cent. coefficient 1.9 for males of 1.6 for obese males, by 1.5 coefficients have been em-
heart does not increase with age, data emphasizing this relationship of hearts of elderly subjects who
RESULTS
In this material there were forty-two males and thirty-seven females. The average age of the paGents was forty and eight-tenths years, the youngest patient was aged eleven years, and the oldest patient was aged sixty-nine years. Nine children are included in this material, and it must be emphasized here that the standards of cardiac weight of children are uncertain, and that the computations in this study with reference to children are probably associated with a greater error than those pertaining to adults. TABLE CARDIAC
HYPERTROPHY
GROUPED (SEVENTY-NINE
I
ACCORDING CASES)
TO VALVULAR
DEFECTS T
I
VALVULAR
/-
AVERA(
LESIONS
Aortic stenosis 9 8 1 48.6 Aortic insul?Eciency 10 7 3 40.9 Multiple valvular 20 12 8 38.7 lesions Mitral stenosis and 35 13 22 39.8 insufficiency Mitral insufficiency 5 2 3 42.4 *Children excluded in computations.
3 B $ E
5 5 2 1
17.4 31.2 17.6 23.3 18.5 20.2
686 574 524
387 290 281
72.6 76.3* 65.2*
173 172” 169*
17.9
21.9
469
222
62.4*
165”
1.76”
-/ 21.2
21.2
314
77
62.9*
164”
0.52*
-
WILLIUS
AND
SMITII
:
CARDIAC
HYPERTROPHY
193
In order to permit comparative study the cases were grouped as is shown in Table I. Our first analysis concerns the average values derived in the subdivision of the cases into the foregoing groups. The greatest cardiac weight occurred in the cases in the first group (aortic stenosis) in which the average weight was 686 gm. In order of cardiac weight, the other groups presented the following average lesions, 524 values: aortic insufficiency, 574 gm.; multiple valvular gm. ; mitral stenosis and insufficiency, 469 gm.; and pure mitral insufficiency, 314 gm. The heart-weight body-weight ratios were inGreased 25 to 131 per cent over normal (male and female average normal 0.415 per cent) (Table I). No definite correlation was evident between cardiac weight on the one hand and, on the other, the interval from the first attack of rheumatic fever to death. However, the longest interval appeared in the cases of aortic stenosis in which occurred the greatest average age at death. The intervals in the other groups mere so closely approximated as to be insignificant. This order of cardiac weights conforms with clinical impressions, and is in agreement with Cabot’s figures, which included 1,230 postmortem examinations. Aortic Xtelzosis.-There were nine cases of aortic stenosis in which all Eight of the t.he requirements for inclusion in this study were present. patients were males and one was a female. The average age was forty-eight and six-tenths years; the youngest patient was thirty-one years of age, and the oldest sixty-six years. Death occurred from heart failure in six cases; in all but one case, that of sudden death, the syndrome of congestive heart failure was present. Death occurred as the result of acute bacterial endocarditis (B. influenzae) in one case, from pyelonephritis in one, and from pneumonia in another. It is necessary to emphasize the fact that studies of weight in the presence of congestive heart failure include a variable error, differing considerably with the individual patient and depending on the amount of edema fluid retained. This variable, which obviously cannot be determined, may materially influence the weight of the body. Congestive heart failure occurred in 58 per cent of+ the entire series of seventynine cases. The data in Table II are arranged according to the degree of aortic stenosis (Grade 0 to 4) ; Grade 4 indicates almost complete closure of the aortic orifice, whereas Grade 1 denotes slight but actual narrowing in the diameter of the orifice. A definite correlation between the degree of stenosis and the average cardiac weights is evident. The correlation between the average cardiac weights, on the one hand, and, on the other, the average intervals from the first attack of rheumatic Only one attack of rheufever to death is suggestive but not definite.
194
TIIE
AMERI(‘AN
HEART
JOURNAL
matic fever occurred among the patients of this group. The other data pertaining to body habitus, individual cardiac weight,s and so forth, are expressed in Table IT.
CIKDIAC
ITYPEKTKOPIIY
IK
PIUWEN~E
OF AOR’L’IC
s g d
48 hI 31
72.7
1x4
___ __79.5
-__ 186 _..~
77.2
171
.iX.6
, 154
7
59.0
162
45
69.2
40
70.4
_.~__ 165 ____ 172
M 8
78.1
172
53
74.2
50 M
65.0
__- 172
66
M Averages 9
(NINE
CASES)
failfail-
-i Teart failure* 1hute bxcterial endocarditis failI 3eart ure” 1&art fail1 0.97 ure ____
173~o.87
81.X
F Average! .___
? Ieart ure” I leart ure* -___
STFXOSIS
183
0.99
failure* 1Pyelo0.48 nephritis -. 0.97
1Heart
0.73 0.49
1Pneumonia
1
i
cart
____ f ail InrP.
Ho1ma.n and Beck produced experimental aortic stenosis in dogs by constricting the aorta with t,ape. Three such experiments are reported, but unfortunately the terminal cardiac weight of only one animal is mentioned. The dog weighed 20 kg.; and after the lapse of six months the heart weighed 165 gm. and the heart-weight body-weight ratio was 1.21 per cent. The normal ratio for dogs is recorded as 0.72 per cent by Joseph and 0.798 per cent by Herrmann, an average of 0.76 per cent. This represents an increase in 37 per cent over the normal average heart-weight body-weight ratio. The aorta was const,rict.ed to half its normal diameter.
Eyster, Meek and Hodges producetl esperimental aortic stenosis in nineteen (logs, and studied the size of the heart, by serial roextgenographic silhouettes, but failed to record terminal cardiac weights. The average increase in silhouet,te for the entire series was 10.5 per cent, of the original area. The initial increase in shaclom is interpretctl by these workers to indicate dilatation from which the heart may entirely or partially recover, whereas subsequent enlargement. cleveloping slowly, probably indicates hypertrophy. AorYir Ill,slb~~ien~!/.-This group comprised ten cases in which seven were males and three females. The average a.ge was forty and ninetent.hs years, seven ant1 seven-tenths years less than that of patients TABLE CAKDIAC
I~PPERTRI)FIIY
Is
PRESENCE
It1
OF AoKTIC
~XSUFFICIENCT
we’
80.9
171
1.11
13.6
172
0.72
173 l(i.5
1.00 1,“1
166
0.M
18G
failwe* il-Ieart fail1 urc*t / ‘E’neumoni;l~ ‘
~IIenrt
itrangulatcd hernia t I).A!’ Intestinal I hemorrhage 0.79 0.92
i1enrtfail-we”
l.(‘O
Heart
~
3 3
~-7 I i
2
~ 2
~
fail-
UIX”
(I.57
Subacute 1 bacterial mdocarditis O.FO Inanition$
* Congestive ; Obesity. % Emaciation.
heart
failure.
1
I 300
(TEN
CASES)
196
THE
AMERIC!AN
HEART
JOURNAI.
with aortic stenosis. The youngest patient was twelve years of agr and the oldest, was sixty-seven years of age. Five patients died of congestive heart failure, one patient, diecl of subacute bacterial endocarditis (~\Yt,~spto~uc,c,,rs ,rriGdn,rl.s) : whereas the remainder of the patients died from diseases unrelated to t,he heart (Table TIZ). Two patients were obese and one was emaciated, which facts were consideretl in the calculation of the increased wright of the heart over the normal for the given person. The data in Table TTI are arranged according to the degree of aortic between insufficiency (,Gratle 0 10 -l). Again, a clear-cut correlation the degree of lesion and the average weight of the hearts occurred. No correlation appeared bet,ween weight,s of the hearts, on the one hand, and, on the other. t,lie individual and avera,ge intervals from the first episode of rheumatic fever t,o deat,h. Only one attack of rheumatic fever occurred among these paCents. Detailetl data dealing with carcliac wright and body habit,us may bc .noted in Table III. We wish to call atleiition to C’ase 8 (Table 1II) of this group. The patient Teas a boy. aged thirteen years, who died of congestive heart failure one year following his tirst attack of rheumatic fever. The heart Tveighed 5’i 1)~ cent more than t.he calculatetl normal cardiac weight for this boy’s Irabitus. This case and three similar cases of patients who survivetl for a short time following rheumatic fever with marked cardiac Irypt~rtrophy are reported in the succeecling groups and will be considered more fully later in this paper. It is of interest to compare these dat,a to similar data dealing with Bazett and Sands, in their experimental aortic insufficiency of clogs. experiments on
WILLJLX
iisn
ShII’I’II
:
(‘ARl)IA(’
IIYPER’IXOPIII
l!)i
As in the previous groups, a definite correlation between the degree of lesion and the average cardiac weight occnrreti. Recanse the lesions defect is coliwere multiple and variecl in this group, the predominant sidered primarily. A correlation betlreen the average weights of the hearts, on the one hand, and, on the other, the interval from the first attack of rheumatic fever to death in these cases was evident. However, in view of t,he findings in the other groups, this relationship may be casual. Two paGents were emaciat.ed and one was obese, am1 t.he proper coefficients were utilized in the computat,ions of cardiac weight. It is interesting that multiple lesions apparently do not exert as great, n mechanical effect as certain isolated lesions. &‘7litraZ Stello.vis a+t(J I?zs~f~ic,~e,~~~y.--This group included thirty-five patients. There were thirteen males and twenty-two females. The average age for the group was thirty-nine and eight-tenths years; the yonngest patient was aged eleven years, ant1 the oldest, sixty-five years. Twenty-three paGents had died of congestive heart failure, five of subacute bacterial endocarditis (Streptororrzt,s r*ir~it7n~sJ, and the remsinder from causes unrelated to t,he heart. A correlation between the severit-y of the lesion and the average cardiac weights is again evident if the case iu which the lesion was graded 4 is ruclnclecl. As this grade is represented by only one case. it is reasonable to presume that a greater number of cases would bring the average cardiac: weight above t,hat in Gratlc S. The stenotic element predominated over that of insufficiency in all chases. and thcrefore formed the basis for grading. Five patients in this group were the only persons in the entire series Four patients hacl to suffer more than one attack of rheumatic fever. two attacks; one patient had six attacks. Our patient was obese, and proper recognition of this fact was made iu nur computations (Table V) . ~~itud I,)/,nc,~c~~nt~~.-There were only fire eases (6 per cent) of pure It is a recognized fact that pure mitral insnffimitral insufficiency. ciency without stenosis is rare, and we believe that our cases thus tabulated are bona fide examples of this lesion. In these cases there were two males and three females. The average age was fort.y-two and four-tenths years; the youngest patient was aged thirteen years, and the oldest sixty-one years. Tt is interesting and significant to note that only one pat.ient died of heart disease (Table VI). A correlation between the degree of lesion ant1 the average weight of the heart likewise appears to prevail in this small group of cases. No correlation between the cardiac weight, on the one hand, and, on the other, the interval from t,he first attack of rheumatic fever to death is evident in the individual cases, although the averages appear to show a trend.
TO
(I.36
12
1
0.9G
11
Averages
Heart
Hwrt
1.42
0.91
O.S.?
10
177
365
Peritonitis
’!
IIcnrt
‘7 “4 -.-
0.70
59.0
! G.0
43 31 GS
i I.74
TTt~:irt
I.Otj
fnilorc:
fnilurc”
failure”
failwe”
jubncutc bacterial wdocarditis Heart failure”
-1:
PKESETCE
DEATH
IN
9
s
7
i 31.1
~
i
172
3
13
i
170
4
F
~, 1.13
I79
3
G
1.37
I
] 7”
3
1.01
I).!lti
BODy , TvEIGHT 1
'1
174
BODP 1iEIGHT' WEIGII! P. C\I. XG.
I I
AGE, I'EARS, t AND SEX
IlATIOOF IIEART x,-EIGHT
~IYPERTROPHY
1
C'ASE
I
I
-
CARDIAC
1
I j
, I
IV
.I.I
LESIONS
AND GRADES oF v.IT,vI~J,AR LESIONS
TYPES
VALVULAR
/
I
I /
~
1
!
(TWENTY
.\litral stenosis 4, nortic insuf-1 ficiency 2, and stenosis Aortic stenosis.L 3 , mitral &en-l osis 2 Aortic insufieiencg 3, mitral, stenosis 2 Sortie stenosis 3, mitral stenosis 2, mitral insufficienr~ 2 Nitral stenosis 3, aartic stell-’ osis L’, tricuspid stenosis 2 Aortic insnfficiencp 3, mitral~ stenosis 1 .\ortic st.enosis 3, mitral stcn-’ osis S Aortic stenosis 2, mitral st.en-/ osis 3, mitral insufficiency 1 Mitral stenosis 3, aortic insuf-, ficiencv :3 Xlitral s'tenosis ::, nortic insuf-1 ficiency 1 Mitral stenosis 3, aortic stcn-i osis 2 Uitral strnodis 3, !riituspid stcn.1 osis L’
IMULTIPLE
TABLE
LESIOK;. GRADE
OF
61"
~
363
(IWREARE
CASES)
1
57
OG
59
‘i 4
40
54
.i
79
61
n9
63
G8
I
19
I~TERVAI~ FROM AGE RHEcTiI NCREASE JIATIC 0IVEK CALFEVERTO 'ULATED , DEATH, SOR.\l.\T, / .- ~YEARS 37 3G
:I I ,ERCRP;T.
~~
17
11
13
20
19
IS
17
16
F (is N
27
F 60 F 31 F 12 Y 11 F
44
M
57
13
CASE
AGE, YEARS bND SEX
F3.G-(
R:>DY ,‘EIGIIT, KG.
1/
x0-
HEIGIIT CM.
‘,
0.71t
0.80
n.(io
0.G” c)
O.G4
0.49
0.87
0.50
K.\TIO OF IIEART WEIGHT T O BODY \VEI(‘HTT
failure
OF
(
u1oren:
Suhacote bacterial endocarditis .Hcart failwe*
Poisoning
Subacute hacterinll endoearditis$ Heart failurc$
Heart
C.iUSE DE.\TlI
j
DOl1I6AN1 VAT,VU LAR LESION i GRADE AND OF LESIOKS
GKADES
sufficiency
2
020
3lKl
:3X()
-1-117
4 :: 3
43.1
471
547
- .39!J
I/-
\Iltlnl stenosis t’ , :lortic insnt ficiency 2 Lortic stenosis 2, mitral strnosis 1, mitral insufficiency 2 \Iitral stenosis 0, mitral iasuffi. eiency 1, aortic insufficiency 2 Jitral stenosis 0, aortic insnf. ficiency 3 YIitral stcnosia 2, nortic insuf. ficiency 1 Jitral stenosis 0, aortic iiisuf. ficienry 1 Llitral insufficicncv ’ L 2 , nortic ‘1 stenosis 1 iortic insufficiencv 2, mitral in.
V.ZLVULbR
TYPES
PERCEKTAGE ‘SCREASE OVER CALCU-
13
INTERVAT. FIiOl\l RHET.\LATIC FEVER T O DEATH, YEARS
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Average;
_-
CASE
9 L
--
41
___~ 43 52 33 48 21 65 44 38 53 45 21 45 3GF 43 34 48 40 37
F M F F F
M F M F M M M M F F M F
AGE, J FEARS, AND SEX
! ~ /
/
61.5
63.6 60.9 65.9 45.9 75.0 84.0 58.6 58.1 54.5 59.0 56.8 90.9 75.0 51.8 54.5 46.8 54.5 54.0
BODY 1 (VEIGHT, KG.
('AKDIAC
166
171 158 181 165 175 171 177 179 156 165 179 172 165 163 165 159 166 162
EIGHT CM.
~
0.90
0.62 1.20 1.07 1.45 0.86 0.75 1..04 0.99 1.02 0.93 0.90 0.53 0.62 0.89 0.78 0.90 0.75 0.62
Ix
-
~~
AT10 OF HEART WEIGHT PO BODY WEIGHT
IIYPERTRoPII~
V
STENOSIS
mdocarditis
OF DRATH
OF MITRAL
Heart failure” Heart failure” IIeart failure+ Heart failure’ IIeart failure* Heart failure’ Heart failure” Heart failure* Heart failure* Subacute bacterial Heart failure* t Heart failure* Heart failure* Heart failure* Cerebral embolism Heart failure* Heart failure*
Heartfailure”-
CAUSE
PRESENCE
TABLE
/
I
4 3 3 3 :: 3 3 3 3 2 3 3 3 3 3 .3 3 3
-___-~
542
413 730 707 G65 644 630 610 585 557 548 514 489 465 465 429 425 410 340
-~
NCREASE IN HEART IT-EIGHT OVER 'ALCULATED NORMAL, Ghl. ~__ 147 489 431 483 330 278 365 342 341 314 276 169 168 360 201 240 194 126 294
~
(THIRTY-FIVE
ACTCAL HEART r-EIGHT, GM.
INSUFFICIENCY
STEPiOSIS, GRADE
AND
53
36 67 61 73 51 44 60 58 61 57 54 35 36 5G 47 56 47 37
'ERCENTAGE INCREASE OVER ‘ALCULATED xorord~~
CASES)
-28
23
43 1G 2G 8 50 4 26 41 21 7 16 15 33 9 3G 14 27
INTERVAL FROM RHEUMATIC FEVER T(~! DEATH, YEARS
19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 --- 34 Averaget ___ 35
CASE
50 1F 40 37 37 55 23 61 OR 40 53 23 42 48 29 11 37 62
F
M F M M F F F F F M F F F F F M
AGE, YEARS, AND SEX
--
95.4 47.7 84.0 79.5 48.1 81.8 44.5 79.5 45.4 56.8 68.1 61.3 45.4 60.4 45.2 32.7 63.6: 54.5
BODY WEIGI-IT, KG.
174 165 169 173 164 171 157 173 160 178 165 163 162 155 155 140 170f 15s
IEIGH'I CM.
--
--
0.77 1.05 0.57 0.59 0.93 0.54 0.91 0.50 0.90 0.61 0.51 0.55 0.70 0.52 0.66 0.90 0.70: ____0.53
OF HEART WEIGHT PO BODY WEIGHT
I LATIO
~.. -~-
CAUSE
OB DEATH
V-CONT'D
11Jremia ~ Subacute bacterial endoearditie Subacute bacterial endocarditic Heart failure" Heart failure* Brain tumor Subacute bacterial endorarditir Diabetic gangrene Subacute bacterial cludocarditir Heart failure* Heart failure* Heart failure* Pneumonia Exophthahnic goiter Heart failure* Heart failure" , I /Carcil1olna of common bile duct!
I
TABLE
2 2 2 2 2 2 2 2 .> Y 2 2 2 2 2 0 .I
STENOSIS, GRADE
I
I
712 505 485 470 450 444 405 397 390 350 349 337 320 31,s 300 294
ACTUAL HEART WEIGHT, GM. ZALCULATED NOR>.[AL, GM. 313 316 133 137 259 120 229 82 210 112 79 Y-4 140 76 105 157 160 67
OVER
LNCREASEIN IIEART WEIGIIT
44 62 27 29 58 27 57 21 54 32 23 28 44 24 35 53 40 ___~~ 24
---
'ERCENTAGE INCREASE OVER :ALCULAT'ED NORAlAL
29 11 22 4 29 37 13 31 10 19 42 12 24 32 17 6 21 9
INTERVAL FROM tHEU&lATIC FEVERTO DEATH, YEARS
202
CO;1IMENT
In a. recent investigation, Levine and C’arr tlirided and n-eighetl a series of hearts of human beings according to lhe experimental methotl of IIerrmann.1n Fractional n-eights were determined in fifteen cases of rheumatic heart disease, inclndin g five cases of mitral stenosis ant1 insufficiency, three cases of aortic stenosis and insufficiency, five cases of mitral and aortic stenosis and insufficirnry, one case of niitrd, aor& and tricuspid stenosis and insufficiency. and one case of tlirombo-endocarditis of the mitral valve. The conclusions pertinent to this study are that, in rheumatic defects of the mitral valve alone the iucrease in cardiac weight is the result of an increase iii the weight of the right ventricle and the auricles. In large hearts associated with aortic insufficiency, rheumatic 01’ syphilitic. liypertrophp of the wliolr heart occurs, but, the greatest increase is in the left ventricle. Levine and Ctarr expressed the belief t,hat mechanical factors are not entirrl> responsible for the production of cardiac hypertrophy. We shall attempt to apI$~ the analysis of our data to the various hypotheses advanced regarding the prntluction of cardiac hypertrophy. The hypothesis that increased cardiac work causes hypertrophy finds unmistakable confirmation in this stnd>r, as almost without cxception the average weight of the hearts I~rallrlrtl tile degree of va.lvular deformity. The work demanded of the heart appears to be primarily concerned with the magnitude of the mechanical barrier. In consiclering increased Trorlr, however. the interval of time during which the heart is subjected to increased work cannot be disregarded; and although it undoubtedly plays an important part in many cases, the mechanical factor may exert its influence ovrr\rliclminffl-, so that the time element apparently becomes submerged. Our study does not deal with the coronary circulation, so that we do not have data regar(linp cnrotlary blootl flow aud cardiac hppertrophy. We know of no proof to the effect that an illcrease in muscle mass provokes an increase in coronary blootl flow. thus furthering cardiac hypertrophy. Tn fact, the oppnsitr conclusion is not, improbable, t,hat in greatly hypert~rophied lIearts the normal coronary circulation becomes relatively insufficient, since its work may be doubled or even treblecl, as t,he case may be. The question of the relationship of inflammatory lesions of the myocardilun to cardiac hypertrophy is one of considerable interest. In this connection it is important t,o consider the cases of the foul children briefly mentioned earlier in this paper who survived for short periods following their first rheumat,ic infcd ioai. REPORT
OF
CASES
C:&F, l.-(Case X, Table 111.) A boy, aged thirteen years, died of congestire heart failure one rear following his first attack uf rheumatic firer. Only 3 slight drgree of aortic insuffieienc(Grade 1) VYIS found at ncclopsy, IJut the heart weighed
xl g111 , an increase uf 19.i gm. (57 per cent) over the degree td the mechanical lesion nor the duration of producing cardiac hglxrtrol)hy of th& magnitude. attack of rheumatic fcwr.
the calculated normal. of the lesion scemcd This
boy
CAR& 2.----( Chse 6, T:ll~lt~ IV.) A girl, aged thirteen years, heart failure one and a half gears following the first episode Multiple lesions were present; namely, aortic insufficirncy Grade (Grade 1. Marked hypertrophy was found, the heart weighing of 472 gm. (79 per cent) over the calculated normal.
had
had
Neither capable only
one
died of congestive of rheumatic fever. 3, and mitral stenosis 595 gm., an increase
C”ASF: 3.-(Vase 4, Table VI.) A girl, aged thirteen years, survived only four months after the initial rind only attack of rhcmnatie fever and died of congestive heart failure. The only \-alvular defect demonstrable was mitral insufficiency Grade 2; yet the heart Tveighrd L’!).? gm., an incw:~w of I.-j1 pm. (.?I per c*ent) over the calculated normal. (2.4~~
uwing
4.-((Case
20,
to the extremely
Table lwicf
IV.) A girl, aged eleven years, was of unusual interest survival lwriod. 811~ died one month after the onset of
8.
Fig.
1.-A,
Section
of
normal 4, Tnblc
B. heart VT),
muscle; mwked
B, section vmxlolar
of heart muscle degeneration.
The valvular lesions demonstrated after death consisted chorea. mitral insufficiency Grade 2. The heart weighed 230 gnr., an increase per
cent)
over
the
calrulatcd
in Case 3 (Case of aortic of 94 gm.
and (43
normal.
One of us repeatedly observed these children, and me are certain that no preexisting cardiac lesion was responsible for the cardiac hypertrophy. The cardiac injury without question occurred with t.he infections as stated. Careful microscopic study of numerous sections of heart muscle of these four subjects revealed unusually marked rvidences of myocarditis (Figs. 1, 2 and 3). There were extensive areas of cellular infiltration, the cells consisting c~hiefl~- of ~~olymorphonuclear leucocytes and small lymphocytes, and certain areas revealed numerous erythrocytes. Considerable fibrin was deposited in these regions. Considerable swelling of the muscle fibers was apparent, and their striations were indistinct. There were numerous collections of cells scattered throughout the
The changes described were myocardium resembling As&off cells. most prominent in Cases 1 a,nd 2, although they were well marked in the other two cases. It appears that the marlird myocarditis of these c!hiltlren was the chief factor contributing to the production of the cardiac hypertrophv, in view of the fact that the degree of entlocarditis present. and its resulting valvular tleformity were considerably less than that occurring in the majority of cases. Stewart’s experimental work indicated a relationship between myocardit,is and cardiac hypertrophy. He produced extensive myocarditis in rabbits by intravenous injection of epinephrine, and found ensuin g hypertrophof considerable degree. The exact manner in which myocarditis produces hypertrophy is not clearly understood, but it is not improbable that it may represent a
compensatory effort on the part of regions of normal or relatively normal muscle. These findings strongly suggest that, in some cases of severe infection the myocardium responds to the injury of hypertrophy. Our investigation resulted in no data concerning the influence of increase in the midsystolic period on cardiac hypertrophy, nor on the influence of residual blood in the ventricle. We concur with Herrmann in his belief that a combination of influences participates in the production of cardiac hypertrophy. CONCLUSIONS
1. The greatest average cardiac weight occurred in cases of aort,ic stenosis. In order of cardiac weight other lesions occurred in the
“Of3
‘I’IIE
AMERI(‘AS
IIEART
.JOIIRKAI,
insufficiency, multiple valvnlar lesions, following sequence : awtic mitral stenosis and insufficiency-, a.ntl pure mitral insufficiency. 2. There was an outst,anclin g correlat,ion between the degree of t,he lesion and the average weight of tire heart. evidenced only in some 3. There was a suggestive correlation, groups, between the average weight of the heart, on t,hr one hand, and, on the ot.her, the interval elapsing from the initial at,tack of rheumatic fever to tleath. 4. The c~ontlition of four children, who lived only for a very short time following their first illness with rheumatic fever, and chorea in one case, and three of whom had rat,her slight valvular defects, strongly suggests that myocardial injury by infection or its toxins in wme ilistances permits the heart to respond by hypertrophy. 5. Although increased cardiac work imposed by t,he ~alvular defect or defects appears to be the outstanclin g influence in the procluetion of cardiac hypertrophy in rheumatic heart. tlisease. ot,her factors appear to exert a definite but less important influence. Among them is the lengt,h of time t,hat thr heart is subjected to tile lesion ant1 actual myocardial injury in a certain group of Cases. REFEKFN( I
‘ES.
Ehrenfricd : Dcr Ilerzmuskvl und wine Bedeutung fiir Physiologit> 1. Alhrecht, Pathologie und Klinik des Herzens, Berlin, Julius Springer. An Experimental Study of Chronic Aortic 2. Bazett, H. C., nnd Sands, Jane: Regurgitation in Dogs, ,J. C’lin. Inrestigution 3: 65, 1926. 3. Cabot, R. c.: Fwts on the Heart, Philadelphia, 1926, W. B. Saunders. J. F.: Vorlrsnnge~~ iilwr a!lgenlctino I’athologie, Berlin, 1877, A. -k. Cohnheim, HirschwaN ;Y Idem : Vorlcsung~w iilwr allg(~n~einc Pathologic. Ed. 2, Berlin, 18x2, A. Hirsch. \dCl.
6. Corrisart, J. &I. : Essui our les nlaladics r+ les 16sions organiqucs du ~wtwr c,t dw gros vaisseaux, Paris, 1806, Miynfwt. 7. Dchio, K. : Uebcr die 1~indegewelJigr Induration des Herstieivhes (M~ofil~rosit Cordis), Dcutxh. nwd. Wchnsrlw. 26: 750, 1900. Cardiac Changes ~ul~scquent sc. Qster, J. PI. E., Meek. W. J., and Hodges, F. J.: to Experimental Aortio Lesions, Arch. Int. Med. 39: 536, 1!)27. 9. Frank, Otto: Die DSnamik dcs TIerzmuskels, Ztschr. f. Biol. 32: 370, 1895. 10. Herrmann, CT. R.: Experimental Heart Disease. I. Methods of Dividing Hearts; With Sectional and Proportional Weights and lintios for %(I Normal Dogs? Hearts. Anr. HE,II:T J. 1: 21:‘:. 192.5. 11. Idem: &perimental Heart D&w. II. The Effect of J&q~erimental Aortic Renureitation on the Heart Weights: With a Consideration of Some Factors Co&e&d in Cardiac Hypcrtropiiy a& a ~un~mary of the Manifestations of Experimental Heart Disease, ,411. IIENX J. 1: 485, 1926. 12. Hirschfelder. A. D.: Discnscs of the Tlenrt and Aorta. I’l~iladelahia.I / IDIS. IL n. 291, J. B: Lippincott. Emile. and Beck, C‘. S.: ‘l’hc I’hysiological Response of the Circulatory 13. Holman. Syst& to E’xpwimcntnl Alterations. Ib. Thk Effect-of Aortic and Pulmon
18. Miillcr, \Vilhehn: dcs n~rnschlichen Hwzms, Berlin, I& ?vIassc~nlvel~h~iltl~is3e lSi8. 19. Rosenbach, Ottomar: Ueber artificiellr IIcrzkl~~l~pcnfel~ler, Arch. f. espcr. I’ath. u. I’hnrmnkol. 9: 1, lSi8. 20. Smith, H. L.: The Relation of the Weight of the Heart to the Weight of the Body and of the Weight of the Heart to Age, AM. HL.$R~ 1. 4: 79, 19%. 21. Stxdler, b2duard: Esperimentelle und histologis~hc Beitriige zur Ilrrzhypertrophic, Deutschcs Arch. f. klin. Med. 91: 98, 1!1Oi. The Node of Action of Adrenalin in the Production of (!ardinr ‘P) Stewart, --. II. A.: Hypertrophy, J. Path. & Bncteriol. 17: G-l-, 1912. 23. Tan@ Franz: Drljer die Hypertrophie und das phpiologische W:~chstl~um des TIerzeus, Virchow ‘s Arch. f. path. Annt. II. Physiol. 116: 132, 1859. der Kwisl:~uforgane des Xcnschw, Ergebn. (1. alla, Fatll. Z-1. Thorel, (‘. : I’athologir IL path. Anat. 17: 90, l!)lc;. 5. Traube, L.: Quoted by Hirschfelder.