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PATHOPHYSIOLOGY AND NATURAL HISTORY
CONGESTIVE HEART FAILURE
Human myocardial histologic characteristics^ in
congestive heart failure
DONALD V. UNVERFERTH, M.D., JULIE K. FETTERS, B.S., BARBARA J.^ UNVERFERTH, M.S.,
CARL V. LEIER, M.D., RAYMOND D.^ MAGORIEN, M.D., ANTHONY R.^ ARN, B.S., AND PETER B. BAKER, M.D.
ABSTRACT The purpose of this study was to identify the histologic characteristics of^ human myocardium in congestive heart failure (CHF) by cellular hypertrophy, nuclear area, endocardial thickness, and percentage of fibrosis and to correlate histologic findings to^ cause, severity, and duration of disease. Right ventricular endomyocardial biopsies from^109 patients were^ quantitatively analyzed. Ten patients with normal cardiac history, physical examination results, and cardiac^ function served^ as the control group. The remaining patients were^ divided into^ the^ following groups: those treated^ with doxorubicin (n =^ 18), and those with^ chest pain with normal^ coronary arteries^ (n =^ 8), familial CHF^ (n = (^) 3), CHF associated with myotonic dystrophy (n = (^) 3), peripartal CHF (n = (^) 2), valvular CHF (n = 9), alcohol-induced CHF (n =^ 13), postviral CHF (n = 6), or^ idiopathic CHF (n =^ 36). Linear regression analyses showed a^ strong correlation^ between cell diameter and nuclear^ area (r =^ .70, p < .001) and weaker correlations between amount of fibrosis and cell diameter (r =^ .30, p <^ .005) and fibrosis and nuclear area (r =^ .29, p <^ .005). Results of function studies and histologic measurements (e.g., echocardiographically measured change in the minor-axis dimension of the left ventricle with systole and cell diameter) correlated poorly (r =^ -^ .33, p <^ .005). Duration of dyspnea did not correlate with any histologic factor. Within the normal^ group there^ was a^ direct correlation of^ cell diameter with age (r =^ .67, p <^ .05). Analysis of^ covariance^ revealed^ that^ the doxorubicin-treated patients had significantly less cellular hypertrophy but more fibrosis than the other patients. In those with alcohol-induced CHF the^ opposite pattern of^ more hypertrophy and less^ fibrosis was observed. The idiopathic and valvular CHF^ groups did^ not^ differ from each other^ or^ from^ the other groups. The results of this study demonstrate that fibrosis and^ hypertrophy tend^ to^ be^ worse in patients with severe CHF and that some myocardial insults^ (especially that of^ doxorubicin) induce a characteristic response to the injury. Circulation 68, No. 6, 1194-1200, 1983.
THE MYOCARDIUM has a simple structure and a
limited range of responses to a wide variety of insults.
These responses include fibrosis and cellular hypertro-
phy. The pattern and severity of fibrosis and hypertro-
phy have been used with varying success to differenti-
ate hypertrophic from congestive cardiomyopathy,' 2
but have not been used to characterize the various types of nonischemic congestive heart failure (CHF). The endocardial biopsy procedure has facilitated the study of cardiomyopathy. Before the advent of heart biopsy procedures, study was confined to that of au-
topsy specimens. The results of these studies reflected
From the Departments of Medicine and (^) Pathology, Ohio State Uni- versity College of Medicine, Columbus. This study was supported in part by the Samuel J. Roessler Research Foundation, the James^ D.^ Casto Research Foundation, and the Central Ohio Heart Chapter of the American Heart Association. Address for correspondence: Donald V. Unverferth, M.D., 657 Means Hall, 1655 Upham Dr., Columbus, OH 43210. Received Feb. 15, 1983; revision accepted Aug. 11, 1983. 1194
agonal and postmortem autolytic changes and all
specimens were obtained from patients with severe end-stage disease. Endomyocardial biopsy has enabled
pathologists to study cardiomyopathies of different se-
verity and duration.3-7 The purpose of this study was to
use the endomyocardial biopsy to characterize CHF by
cause, severity, and duration of myocardial injury.
The hypothesis was that, although the heart has a limit-
ed range of^ responses to injury, the response will vary
according to^ the^ nature as^ well as the^ duration and
severity of injury. Our results demonstrated that the
light-microscopic characteristics of cellular hyper-
trophy, nuclear size, endocardial thickness, and per-
cent fibrosis correlate weakly with myocardial func-
tion. Doxorubicin-induced CHF had a distinctive
pattern of marked fibrosis with little hypertrophy,
while alcohol-induced and valvular CHF did not have a
distinctive pattern. In addition, age correlated with cell
size in normal subjects. Equally important was the
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PATHOPHYSIOLOGY AND NATURAL HISTORY-CONGESTIVE HEART FAILURE
absence of correlation of histologic changes with dura- tion of dyspnea. It is hoped that this information can help in the understanding of the pathogenesis of CHF and possibly the cause of idiopathic cardiomyopathy. Methods Patient selection. Endomyocardial (^) biopsy samples from 109 patients were evaluated. These patients comprised (^) the 10 fol- lowing groups. (1) Normal subjects (n = 10). These subjects had normal cardiovascular histories and (^) physical examination results. In addition, results of (^) noninvasive tests to determine systolic time intervals and of (^) echocardiographic examinations were normal. Each of these subjects had (^) had a tumor necessitat- ing doxorubicin chemotherapy and had participated in a study in which serial endomyocardial biopsy procedures (including at baseline) were performed.8 Data obtained from the baseline biopsies are the control data in this study. The Human Research Committee of our institution approved the previous study8 and also approved of our use of the tissue for the present study. (2) Doxorubicin-treated patients (n =^ 18). These patients had re- ceived over 200 mg/mi2 of doxorubicin (mean =^400 mg/mi2). Cardiac function test results at the time of biopsy ranged from normal to severely depressed (table 1). The biopsies were taken from I to 6 months after the last dose of doxorubicin. All patients had had normal cardiac function before undergoing doxorubicin chemotherapy. (3) Patients with chest pain and normal coronary arteries (n = 8). These patients had normal systolic function and normal coronary arteries as determined by cardiac (^) catheterization, but each had chest pain that mimicked angina. (4) Patients with familial CHF (n =^ 3). These patients had dilated congestive cardiomyopathy of undetermined cause. Each had two or more first-degree relatives with dilated conges- tive cardiomyopathy. (5) Patients with CHF associated with myotonic dystrophy (n =^ 3). The clinical findings in these patients were consistent with myotonic dystrophy and there was no other apparent cause of their CHF. (6) (^) Patients with peripar- tum CHF (n = 2). These two patients developed heart failure within I month after the delivery of a child and there was no other apparent cause of their CHF. (7) (^) Patients with valvular CHF (n = 9). All patients in (^) this group had severe valvular disease necessitating mitral (in three) or (^) aortic (in four) valve replacement or both (in two). Each of (^) these patients was still in heart failure 3 months or longer after valve (^) replacement surgery. Catheterization revealed normal coronary arteries and normal prosthetic function. (8) Patients with alcohol-induced CHF (n
- 13). Each of these patients had a (^) dilated heart with poor systolic and diastolic function (table 1) and a (^) history of heavy alcohol abuse that included the consumption of (^) greater than I pint of whiskey (or equivalent) per day for over 2 years. None of these patients had consumed alcohol in the 2 months before they underwent the biopsy (^) procedure. (9) Patients with postviral CHF (n = 6). Each of these patients had had biopsy-document- ed inflammatory myocarditis (^) (more than five inflammatory cells per high-power field, n = (^) 4) and/or a rise of viral titers during an (^) acute viral-like illness that included arrhythmias and electrocardiographic changes followed by the development of heart failure (n = 3). The biopsied tissue used for this study was obtained at least 3 months after the acute episode. No inflamma- tory cells were present in the biopsy samples at the time of this study. (10) Patients with idiopathic CHF (n =^ 36). These pa- tients had dilated cardiomyopathies not attributable to alcohol abuse, family history of heart failure, myocarditis, primary valvular disease, cancer chemotherapy, or exposure to other cardiac toxins and onset was not within 3 months of the delivery of a child. They fulfilled the criteria of the World Health Organ- ization for (^) the classification of idiopathic dilated cardiomyopa-
thy.9 Ten of these patients had a history of hypertension (> 140/ 90). None of these 10 had had uncontrolled or malignant hyper- tension. (^) All subjects gave written informed consent before un- dergoing biopsy. Noninvasive testing. Noninvasive cardiac function evalua- tion was performed in all 109 (^) patients. Each patient rested for 30 min before testing. Echocardiograms were performed (^) with a Unirad Series C ultrasonoscope and an Electronics for (^) Medicine VR6 recorder or an SK Echoline 20A echocardiograph with an Irex Recorder. The change in the minor-axis (^) dimension of the left ventricle with systole (^) (%AD) was the (^) echocardiographic determinant of ventricular function. Echocardiographic inter- pretation was performed in (^) accordance with the recommenda- tions of the American Society of Echocardiography.'0 Systolic time intervals were determined with an Electronics for Medicine VR6 or an (^) Irex Continutrace Unit with the specifications pre- viously (^) outlined.1' The ratio of the preejection period to left ventricular (^) ejection time^ was used as the measure of left ventric- ular function. The reproducibility and reliability of these tests have been demonstrated in our laboratory.' Hemodynamic evaluation. Diagnostic cardiac catheteriza- tion was performed in all subjects in groups 3 through 10. No coronary artery had an obstruction measuring > 50% of the diameter of the vessel. Left and right heart pressures were mea- sured with an Electronics for Medicine VR16 Multichannel Recorder, which has an M2101 Pressure Amplification Unit, or a Hewlett-Packard Model 8800 Recording System, which has a 4568C pressure unit. The frequency cutoff for both systems was from 0 to 250 Hz. Left ventriculography was performed with 42 ml of sodium meglumine diatrizoate (Renografin 76) injected over 3.5 sec (12 ml/sec). Left ventricular ejection fraction was calculated by the method of Sandler and Dodge.'3 Cardiac out- put was determined by a dye dilution technique in which indo- cyanin green dye is used.' Endomyocardial biopsy. A right ventricular endomyocar- dial biopsy procedure was performed via the right internal jugu- lar vein'5 within 1 week from the time of the noninvasive tests and cardiac catheterization. Each sample used for this (^) study measured 1 to 2 mm' and weighed I to 4 mg. The tissue was placed in 2% buffered glutaraldehyde solution (pH (^) 7.35) within 20 sec (mean 11 sec) of the closure of the (^) jaws of the bioptome on the right ventricular (^) septal myocardium. This sam- ple was sent for histologic evaluation. (^) Biopsy procedures were repeated until adequate amounts of tissue (^) (> 1 (^) mm3) were ob- tained. Histologic evaluation. The (^) glutaraldehyde-fixed tissue was processed in a routine manner. Light-microscopic slides, 3 to 5 ,um thick, were prepared from paraffin-embedded sections. The slides were stained by hematoxylin and eosin and Masson's trichrome stain by the methods of Sheehan and (^) Hrapchak.' Hematoxylin and eosin-stained myocardial slices were exam- ined with a 43 x objective lens and 1O x (^) eyepiece with an ocular micrometer disc. The diameter of a (^) myocardial cell was determined by measuring the distance across the cell at its most narrow plane across the nucleus. At least 50 cells from each biopsy were measured and the diameters of the 50 cells were averaged to determine the value for each patient. (^) Ninety-five percent of measured cell diameters for a single biopsy were
within 4 gm of the mean. A lesser range was^ noted for normal
biopsy tissue or^ for^ biopsies with^ a^ smaller^ mean^ cell diameter. In addition, the average nuclear area was determined in the 50 cells used for cell size measurements. The (^) height (h) and width (w) of each nucleus was measured and nuclear area was calcu- lated from the formula: nuclear area =^ (h +^ w/4)2 X^ 7r. Ninety-five percent of the measured^ nuclear^ areas^ were^ within 9 ,um2 of the mean.^ Trichrome-stained^ sections^ were^ examined at a magnification of 400 x on a viewing screen. The viewing
Vol. 68, No. 6, December (^1983 )
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PATHOPHYSIOLOGY AND NATURAL HISTORY-CONGESTIVE HEART FAILURE
TABLE 2 Correlations between histologic, hemodynamic, and historical features Cell Nuclear Endocardial Ejection Cardiac Duration dianmeter area thickness % fraction index PCW 4yspnea (pm) (^) (gm2) (,um) Fibrosis %AD PEP/LVET (%) (1/minIm2) (mm Hg) (mO) Nuclear area (^) (gim2) .70(109) p <. Endocardial thickness -.04(109) -.03(109) (,um) % Fibrosis .30(109) .29(109) .14(109) p <^ .005 p <^. %AD - .33(81) -.35(81) - .02(80) -.20(80) p <^ .005 p^ <^. PEP/LVET .23(92) .30(92) .16(91) .15(91) -.73(78) p < .05 p < .005 p <^. Ejection fraction (%) -.13(70) -.22(70) -.24(69) -.16(69) .80(54) .52(59) p <^ .05 p <^ .00?1 p <^. Cardiac index (1/min/m) -.13(68) -.16(68) -.30(67) -.30(67) .42(53) -.33(58) .61(66) p < .05 p <^ .05 p <^ .005 p <^ .01 p <. PCW (mm Hg) .32(67) .17(67) .25(67) .12(67) -.56(53) .39(57) -.65(61) .55(61) p < .01 p < .05 p < .0001 p < .005 p < .001 p <. Duration dyspnea (mo)^ .17(98)^ .12(98)^ -.03(97)^ -.07(97)^ -.07(73)^ .03(83)^ .08(69)^ -.04(67)^ -.18(66) Age (yr) .08(109)^ .02(109)^ .14(109)^ .01(109)^ .06(81)^ -.20(92)^ .20(70)^ .10(68)^ -.09(67)^ .07(98) This table (^) presents the r (^) value, the number of observations (in parentheses), and the p statistic for each significant correlation. Abbreviations are as in table 1.
correlations between cell diameter and percentage of fibrosis and cell diameter and echocardiographic %AD
are shown in figures I and 2. In addition, there was a
correlation between cell diameter and age (r =^ .67, p
< .05; figure 3) in group 1 (10 normal subjects).
Patients with idiopathic CHF were divided into two
groups: those with hypertension and those who were normotensive. Cell diameter was significantly greater
in the hypertensive patients (22.2 +^ 3.8 vs 19.6 ± 3.
,um, p <^ .05). Percentages of^ fibrosis^ were not^ differ-
ent in these two subpopulations. In the idiopathic CHF
group as a whole there were good correlations between
cell diameter and nuclear area (r .67, p <^ .0001)
and cell diameter and fibrosis (r -^ .54, p < .001).
Because cardiac function in the various groups was
not equal, the comparison of the histologic characteris-
tics among the four major groups was accomplished by
cr
-J^ -J w
28 -
26
24-
22-
20-
18
16-
29.3 29. O *.- 0 _ L_
30.4 0
Norma r=.
28
24
20 U, 0 a) m 16 z W (^12) u cc a. 8-
4 8 12 16 20 24 28 32 38 ECHOCARDIOGRAPHIC % AD FIGURE 1. There was a correlation in each group between cell diame- ter and cardiac function as demonstrated by echocardiographic %AD. There was a^ significantly different response of^ cell^ diameter^ change to decreasing cardiac^ function^ between the^ doxorubicin-^ and^ alcohol- induced CHF groups.
4 * J Normal 4 8 12 16 20 24 28 32 36 ECHOCARDIOGRAPHIC %^ aD FIGURE 2.^ With a^ progressive loss^ of^ ventricular function^ (as demon- strated by the^ echocardiographic %AD) fibrosis increased^ to^ varying degrees in the four groups. The doxorubicin-induced CHF group had^ a significantly greater amount of fibrosis than did^ the^ idiopathic or^ alco- hol-induced CHF groups. Vol. 68, No. 6, December 1983 1197
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UNVERFERTH et al.
24 -
22
CELL 20 * DIAMETER ,u 18-
16-
14- rr-. *t p<0. 12 26 34 42 50 58 66 AGE IN YEARS FIGURE 3. In group 1 (10 normal (^) subjects) cell diame directly with the (^) age of the (^) patients.
comparing the slopes for the individual gro
slopes were inscribed by plotting the cel
(figure 2) or percentage of fibrosis (figure
the echocardiographic %AD. The linear
analyses were forced through a "normal'
rived from the data of the 10 normal subjc study. This was done because we assumec
patient was normal before myocardial insult
line for each group should reflect the path
myocardial response to injury.
The comparison of slopes for the change
with progressive heart failure (as determii
echocardiographic %AD) is shown in figur
four largest groups. The slope inscribed b
from the alcohol-induced CHF group was si
different from that inscribed by data from dc
treated patients (p < .05). The idiopathic ar
CHF group slopes were intermediate and I
cantly different from those for either the
duced CHF or doxorubicin-treated groups
illustrates the slopes derived for fibrosis plot
%zcD. The doxorubicin-treated group was s
ly different from the alcohol-induced and
CHF groups (both p < .05), but not from tI
CHF group. The valvular (^) CHF group did from any of the others.
Discussion
Methodologic considerations. The use of q histologic procedures in endomyocardial plagued by the problems of sampling error a
artifact. The biopsied tissue used in this stu
taken from the (^) right side of the interventri
tum. However, Baandrup and Olsen2 have
right ventricular endomyocardial biopsy st
equivalent to those removed from the left. (^) II
our laboratory demonstrated a consistent pattern of
fibrosis, vacuolization, and^ hypertrophy^ in^ samples
/0 from the right and left.'8 Although there are varying
degrees of^ degeneration at different levels of the myo-
cardium, the^ patterns are consistent in CHF. 18 Also, in
a (^) study of myocardial biopsy samples taken close to the time of death, it was demonstrated that these sam- ples were (^) representative of overall cardiac pathol- ogy.3 19 Thus, right-sided endomyocardial biopsies can be used to (^) determine cardiac morphologic alter- ations and can be compared with biopsies of the same -,------,---. area (^) of the hearts of normal subjects and other CHF 74 82 patients. Fixation artifact is primarily a problem in electron
microscopy but can cause some vacuolization in light-
microscopic specimens.20 This problem has been obvi- ups. These ated by the use of tissue samples of similar size (I to 2
11 diameter mm'), eliminating cells with contraction-band arti-
- against facts, and the use of the same techniques for the pro- regression cessing of all tissues. point de- Histologic and clinical correlations. For the total patient ects in this population (n =^ 109), in which there was a spectrum
I that each of normal-to-severe CHF and disparate causes of dis-
Thus, the ease, several interesting correlations were noted. As
way of the expected, cell diameter correlated closely with nuclear
area (r = .70, p < (^) .0001). Increased (^) nuclear activity
in cell size (and therefore size) is a primary requisite for cellular
ned by the hypertrophy.21 22 There were also weak correlations
^e 2 for the between (^) percentage of fibrosis (^) and cell diameter (r =
)y the data .30, p < .005) and percentage of fibrosis and nuclear
Ignificantly area (r = .29, p < .005). This was also expected
)xorubicin- because hypertrophy is a stimulus for fibrosis.23 24 The
ad valvular low r value (.30) probably reflects the many factors
not signifi- besides hypertrophy that promote fibrosis. (^) Endocar-
alcohol-in- dial thickness was independent of the other histologic
Figure 3 markers.
"ted against Cell diameter correlated weakly with cardiac func-
significant- tion measures such as echocardiographic %AD (r -
idiopathic -.33, p < .005), the ratio of preejection period/left
he valvular ventricular ejection time (r = .23, p < .05), and mean
not differ pulmonary capillary wedge pressure (r - .32, p <
.01). The correlation between cell diameter with echo-
cardiographic %AD improved, however, when indi-
vidual groups were considered independently and [uantitative when^ the^ regression^ lines^ were^ forced through^ a^ nor-
biopsies is mal point (figure 1). This suggests an association of
nd fixation worsening heart function with increasing cellular
dy was^ all hypertrophy.
icular sep- Amount of (^) fibrosis also correlated poorly with mea- shown that sures of myocardial function for the total population, imples are but improved for individual groups (figure 2). Percent- n addition, age of fibrosis did not correlate with mean pulmonary (^1198) CIRCULATION
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UNVERFERTH et al.
sies from patients suspected of^ having cardiomyopathy. I: Morpho- logical and^ morphometric aspects. Br Heart^ J 45:^ 475, 1981
- Mackay EH, Littler WA, Sleight P:^ Critical^ assessment^ of^ diagnos- tic value of endomyocardial biopsy. Assessment of cardiac (^) biopsy. Br Heart J 40: (^) 69, 1978
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