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1 Department of Oral Biology, Ohio State University, Columbus 43210; 2 Center for Anesthesiology Research, Cleveland Clinic Foundation, Cleveland, Ohio 44195; and 3 Division of Cardiology, Department of Pediatrics, University of Washington, Seattle, Washington 98195
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The goal of this study was to test
the hypothesis that the relative amounts of the cardiac myosin heavy
chain (MHC) isoforms MHC-
and MHC-
change during development and
transition to heart failure in the human myocardium. The relative
amounts of MHC- and MHC- in ventricular and atrial samples from
fetal (gestational days 47-110) and nonfailing and
failing adult hearts were determined. The majority of the fetal right
and left ventricular samples contained small relative amounts of
MHC- (mean < 5% of total MHC). There was a small significant
decrease in the level of MHC- in the ventricles between 7 and 12 wk
of gestation. Fetal atria expressed predominantly MHC- (mean > 95%), with MHC- being detected in most samples. The majority of
adult nonfailing right and left ventricular samples had detectable
levels of MHC- ranging from 1 to 10%. Failing right and left
ventricles expressed a significantly lower level of MHC-. MHC-
comprised ~90% of the total MHC in adult nonfailing left atria,
whereas the relative amount of MHC- in the left atria of individuals
with dilated or ischemic cardiomyopathy was ~50%. The
differences in MHC isoform composition between fetal and nonfailing
adult atria and between fetal and nonfailing adult ventricles were not
statistically significant. We concluded that the MHC isoform
compositions of fetal human atria are the same as those of nonfailing
adult atria and that the ventricular MHC isoform composition is
different between adult nonfailing and failing hearts. Furthermore, the
marked alteration in atrial MHC isoform composition, associated with
cardiomyopathy, does not represent a regression to a pattern that is
uniquely characteristic of the fetal stage.
development; myocardium; dilated cardiomyopathy; ischemic cardiomyopathy
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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MYOSIN FORMS CROSS-BRIDGES with actin in cardiac, smooth, and skeletal muscle, and cyclic cross-bridge activity is the basis for muscular contraction. Myosin is a hexameric enzyme that hydrolyzes ATP, and this reaction provides the energy required for muscle contraction. Each myosin molecule is composed of two heavy chains (~220 kDa each), each of which contains an actin-binding site and an ATP hydrolysis site, and four light chains (~20 kDa each). Isoforms of each myosin subunit are expressed in cardiac, skeletal, and smooth muscle, and many are associated with distinct contractile properties in the muscles or single muscle fibers in which they are expressed (reviewed in Refs. 26 and 30).
The -isoform of mammalian cardiac myosin heavy chain (MHC-) is
associated with higher actomyosin ATPase activity (23) compared with MHC-, which is the other isoform of mammalian cardiac MHC. Hyperthyroidism promotes MHC- expression in the myocardium (20). Ventricular strips from hyperthyroid compared with
euthyroid rats have faster rates of isotonic shortening and isometric
contractions and lower economy of force generation (1, 2),
demonstrating an association between cardiac MHC isoform expression and
functional properties. The specific pattern of cardiac MHC isoform
expression, therefore, could strongly influence the contractile
properties and energetics of human atria and ventricles during
different developmental stages. Additionally, downregulation of MHC-
and upregulation of MHC- occur during experimental induction of
heart failure in mammalian myocardium that normally expresses
predominantly MHC- (e.g., Refs. 4 and 28). This
transition in MHC isoform expression results in a slowing of myocardial
contraction and increased economy. If the normal human ventricle
expresses a significant amount of MHC- before the onset of failure,
then humans might be able to undergo similar adaptation.
Historically, myosin protein expression in the human heart has been
studied electrophoretically with pyrophosphate gels (10, 11, 18,
27). Myosin migrates as the intact hexameric enzyme under the
nondenaturing conditions of pyrophosphate gels either as the V1
isoenzyme (which contains two molecules of MHC-), the V3 isoenzyme
(which contains two molecules of MHC-), or the V2 isoenzyme (which
contains one molecule of MHC- and one of MHC-) (12).
Whether different isoenzymes observed on native gels consisted of
different heavy chains and/or myosin light chains was not always clear
in these previous studies. Conceivably, small but important amounts of
MHC- could not be detected in previous studies in which the large
hexameric myosin was studied electrophoretically. Doubts concerning the
results from these previous electrophoretic studies are supported by
recent findings (15, 22) suggesting that the human
myocardium expresses substantial levels of -myosin mRNA, which
decreases during transition to heart failure. These findings suggested
that similar expression patterns occur at the protein level, which are
subject to developmental and contractile state. Detectable levels of
MHC- protein in nonfailing human ventricles from measurements based
on a denaturing gel electrophoretic protocol have been recently
reported (19). We examined MHC- and MHC- protein
patterns in human left atrial and right and left ventricular samples
from adult nonfailing hearts and those from adults with dilated or
ischemic cardiomyopathy in an attempt to confirm the presence
of significant amounts of MHC- in nonfailing human ventricles. We
also utilized a denaturing gel electrophoretic protocol that yields
sufficient separation of MHC- and MHC- for reliable quantitation
of the relative amounts of these two isoforms in a given sample
(24). Human fetal atria and ventricles were also analyzed
to determine whether developmental transitions occur in the MHC isoform
expression of these chambers. Our results indicate that normal as well
as dilated and ischemic cardiomyopathic adult human ventricles
express predominantly MHC- and very low levels of MHC- but that
the level of MHC- is lower in failing ventricles. Furthermore,
although MHC- predominates in fetal atria, MHC- clearly
predominates in fetal ventricles at all ages examined. We concluded
that adult human ventricular myosin isoform expression changes during
the development of cardiomyopathy. The results of the present study
also indicate that there is a much greater relative amount of the
MHC- isoform in the failing compared with nonfailing left atrium.
Furthermore, this study provides quantitative information on human
cardiac myosin isoform expression over ~25% of the gestational
period and indicates that a small significant change in myosin
expression occurs in fetal ventricles between gestational weeks 7 and 12.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Tissue preparation. Fetal heart tissue was obtained from the Laboratory for the Study of Embryology at the University of Washington. The tissue was obtained under informed consent and under a protocol that was conducted in compliance with state and federal guidelines and approved by the Institutional Review Board of the University of Washington Medical Center. Twelve whole fetal hearts (gestational ages 47-110 days), obtained from electively terminated pregnancies, were immediately immersed and stored in iced saline. Within 2-3 h, cardiac chambers were identified and separated under a dissecting microscope. Right atrial samples from three fetuses and left atrial samples from two fetuses were not obtained. Free wall portions of each chamber were then immersed in liquid nitrogen for storage until analyzed for MHC composition.
Tissue from failing adults was obtained from the transplant program at the Cleveland Clinic Foundation, and nonfailing adult tissue was obtained from the unmatched hearts of organ donors. Consent from the next of kin was obtained before collecting samples from the nonfailing hearts. Adult left atrial and right and left ventricular samples were obtained from the hearts of 14 nonfailing individuals (10 men, 38-64 yr; 4 women, 26-62 yr) without any signs of cardiovascular disease, 12 individuals with ischemic cardiomyopathy (10 men, 48-68 yr; 2 women, 43 and 56 yr), and 12 individuals with dilated cardiomyopathy (9 men, 17-68 yr; 3 women, 37-60 yr). Atrial samples were not available from five of the individuals with nonfailing hearts. Ventricular samples were not available from one individual with a nonfailing heart. Samples from the left atrium and right and left ventricle from all other adult individuals were examined. Failing heart tissue was obtained from the explanted hearts of cardiac transplant recipients at the Cleveland Clinic Foundation. This protocol was approved by the Institutional Review Board of the Cleveland Clinic Foundation. The entire heart was obtained in the operating room after cardioplegic arrest. The heart was transported immediately to the laboratory while immersed in the same cardioplegic solution. The average time between explant and arrival in the laboratory was 30 min. After a brief pathological examination, the heart tissue was separated by chamber and immediately frozen in liquid nitrogen or
80°C until MHC analysis. Nonfailing human heart tissue
was obtained from the unmatched hearts of organ donors through
cooperation of Life Banc of Northeast Ohio (Cleveland, OH). No
hearts used in this study had been rejected for cardiac function. All
nonfailing hearts were transported from the donor institution to the
laboratory at the Cleveland Clinic in cold cardioplegic solution. The
duration from explant until arrival in the laboratory was 60-90
min for the nonfailing hearts due to the time in transit from the donor institution.
Protein analysis.
The composition of gel sample buffer, preparation of gel samples, gel
preparation and composition, and the gel running conditions were
identical to those described by Reiser and Kline (24). Briefly, samples (25-40 mg) that were free of visible fat and connective tissue were prepared with homogenization after adding 30 µl of sample buffer per milligram of tissue. The samples were heated
to 95°C for 2 min and centrifuged for 5 min at 12,000 rpm in an
Eppendorf centrifuge (model 5415). The supernatant was diluted 1:10
with sample buffer, and 3 or 4 µl, corresponding to 10-13 µg
of tissue, were loaded. A set of molecular weight standards (Bio-Rad
Laboratories; Hercules, CA) was loaded in one lane of two gels (Figs. 1
and 4) to verify the identification of the MHC bands. Assuming ~20%
of tissue mass is protein, these loads corresponded to 2-3 µg of
protein. Stacking gels contained 4% total acrylamide and 5% (vol/vol)
glycerol. Separating gels contained 6% or 8% total acrylamide and 5%
(wt/vol) glycerol. Gels were run for 19 h (6% gels) or 30 h
(8% gels). All of the adult samples were run on an initial set of
gels, which were stained with GelCode Blue Stain Reagent (Pierce;
Rockford, IL). The gels were scanned with a GS300 scanning densitometer
(Hoefer Scientific; San Francisco, CA) to determine the relative
amounts of MHC- and MHC- in those samples in which both bands
were visible on the stained gels. The results from these gels suggested
that the relative level of MHC- was below detection in the majority
of the ventricular samples. A subsequent set of gels, on which all of
the adult ventricular and all of the fetal samples were run, were
silver stained. The results from this set of gels revealed that MHC-
was present in the majority of adult ventricular samples. The reported
values of the relative amounts of MHC- in all of the fetal samples
and all of the adult ventricular samples were determined on
silver-stained gels. The percentage of total MHC in a sample that was
expressed as the -isoform (or the -isoform) is referred to as
"the relative amount of MHC- (or MHC-)." The linearity of
densitometric scanning of the stained gels was tested by loading onto
one gel several volumes, ranging from 1 to 12 µl, of a sample that
contained nearly equal amounts of MHC- and MHC-. The linear
correlation coefficients between densitometric peak area and sample
volume were 0.955 for MHC- and 0.943 for MHC-.
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Statistical analysis.
Analysis of variance was conducted separately on the atrial samples
(fetal right and left atria and nonfailing left atria and failing left
atria) and the ventricular samples (fetal and nonfailing and failing
adult right and left ventricles). Both analyses indicated that
significant differences exist among the sets of atrial samples and
among the sets of ventricular samples. Student's two-tailed
t-test was employed to test whether the means of two atrial
sets differed significantly. Fisher's exact test was used for the
ventricles because many of the individual values for the failing right
and left ventricles were 0% MHC-. The level of significance was set
at P < 0.05. The results obtained from the samples
prepared from two fetal hearts (gestational ages 47 and 54 days) were
not included in the calculation of mean values or in the statistical
analyses because right and left chambers could not be distinguished
from each other during sample preparation. The ventricular samples from
the 47- and 54-day-old fetuses were included when testing, with linear
regression, whether there is a significant change in ventricular myosin
expression during fetal development. Results are expressed as an
individual value, range, or means ± SE.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Representative gels on which fetal and adult atrial and
ventricular samples were analyzed are shown in Figs. 1, 3, and 5. The
mean relative amounts of MHC- in all of the fetal and adult samples
are presented in Table 1.
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Fetal atria.
MHC- was the predominant isoform in fetal right and left atria (Fig.
1). The relative levels of MHC- in the
atrial samples from the 47- and 54-day-old fetuses (right and left
atrial samples from these fetuses were not distinguished from each
other, see METHODS) were 96 and 97%, respectively. There
was no change in the pattern of MHC isoform expression within the fetal
atria over the gestational age range included in this study as tested
with linear regression (P > 0.05).
Fetal ventricles.
MHC- predominated in fetal right and left ventricles (Fig. 1). The
relative levels of MHC- in the ventricular samples from the 47- and
54-day-old fetuses were 93 and 90%, respectively. Two papillary
muscles isolated from two fetal left ventricles contained 98 and 100%
MHC-. All of the fetal right ventricular samples contained low
levels of MHC-. Seven of ten fetal left ventricles contained low
levels of MHC-, whereas this isoform was not detected in the
remaining three fetal left ventricular samples. When analyzed
separately, neither the right nor left ventricle underwent a
significant change in the level of MHC- expression between
gestational days 82-110. However, a significant decline
with increasing fetal age in the relative amount of MHC- in the
fetal ventricles was detected when the relative MHC- values from all
(n = 22) of the ventricular samples, including those from the 47- and 54-day-old fetuses, were regressed linearly against gestational age (Fig. 2).
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Nonfailing adult atria.
Relatively large amounts of MHC- were detected in all of the
nonfailing adult left atrial samples. The mean relative amount of
MHC- in the adult nonfailing left atrial samples was not different from those in fetal right or left atria.
Failing adult atria.
The mean relative amounts of MHC- in the ischemic
cardiomyopathic left atria and in the dilated cardiomyopathic left
atria were significantly higher than the nonfailing left atrial value (Fig. 3 and
4). The variation in the amount of
MHC- in the failing adult left atria was not correlated
(P > 0.05) with age when tested with linear
regression. Furthermore, the amount of MHC- in the failing left
atria was not correlated with ejection fraction, heart weight, drug
therapy, or the presence or absence of previous surgery among the
patients included in this study. Four of five female cardiomyopathic
left atria had relatively high levels of MHC- (i.e., low levels of
MHC-; Table 2); however, a gender difference was not statistically evaluated due to the relatively small
number of samples from adult females in this study.
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Nonfailing adult ventricles.
The nonfailing adult right and left ventricular samples also contained
predominantly MHC- (Fig. 5 and Table
3). The majority (20 of 24) of
nonfailing right and left ventricles had detectable levels of MHC-.
The differences between the means in the nonfailing adult right and
left ventricles were not significant from each other, and there were no
significant differences in the MHC isoform expression within the right
or left ventricles between fetal and nonfailing adult samples. It
appears that the level of MHC- in fetal ventricles attains the adult
level of MHC- at approximately gestational week 12 (Fig.
2).
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Failing adult ventricles.
The failing adult right and left ventricular samples contained
predominantly MHC- (Table 2). Only 7 of 24 failing (dilated and
ischemic cardiomyopathic samples combined) right ventricles and
8 of 24 failing left ventricles had detectable levels of MHC-. The
differences between the adult nonfailing and failing right ventricle
and between the adult nonfailing and failing left ventricle were
significant. The cardiomyopathic right ventricles differed significantly from the fetal ventricles by expressing lower levels of
MHC-, but the cardiomyopathic adult left ventricles were not different from fetal left ventricle (P = 0.054).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Cardiac MHC isoform expression was examined at the protein level
utilizing a recently described gel electrophoresis protocol (24). The results indicate that MHC- predominates in
fetal and nonfailing adult atria with coexpression of low levels of MHC-, while the opposite pattern, with MHC- predominating, exists in fetal and nonfailing and failing adult ventricles. The quantitative results obtained in this study are, overall, very consistent with the
qualitative immunohistochemical results of Wessels et al. (31) and the electrophoretic results of Cummins and
Lambert (5), two earlier studies focusing exclusively on
nonfailing hearts. The SDS gel format has several advantages over the
pyrophosphate gels that have been utilized by others to examine the
hexameric myosin isoenzyme composition of human cardiac samples. First, it allows the comparison of multiple samples from several individuals on a single gel, thereby eliminating differences in running conditions and gel staining. Second, it provides a direct examination of, specifically, the heavy chain portion of myosin isoenzymes that is the
myosin subunit with the most critical role in determining the rate of
myosin ATPase activity and, therefore, cross-bridge cycling kinetics.
A direct examination of MHC expression at the protein level, as
in the present study, has an additional advantage over other studies
that must draw inferences from mRNA levels, because mRNA levels do not
necessarily reflect actual protein isoform composition. Quantitative
differences in the relative amount of MHC- were observed between
different heart chambers (atrium vs. ventricle). Furthermore, large
ranges in the relative amount of MHC- in the left atrium of adults
with either dilated or ischemic cardiomyopathy were detected.
This study also provides quantitative information on human cardiac
myosin isoform expression over a period of fetal development that
represents ~25% of the total normal gestational period. Although the
observations of fetal hearts were confined to gestational days
47-110, the results indicate that over this period of
development, there is no change in atrial MHC expression, whereas the
relative level of MHC- in the ventricles decreased with increasing
gestational age. Furthermore, it appears that the adult level of
MHC- is established by approximately week 12 of fetal
development and does not change subsequently.
The results of this study indicate that the level of expression of
MHC- is very low in fetal and adult human left and right ventricles,
both nonfailing as well as ischemic and dilated
cardiomyopathic. Cummins and Lambert (5) reported that
MHC- was the only MHC isoform expressed in the human ventricle at
fetal, neonatal, and adult ages. The small level of MHC- in human
fetal and adult ventricles in the present study was detected with more
sensitive gel stains (see METHODS) compared with the stain
employed by Cummins and Lambert (5). The decrease in adult
human ventricular contractility during failure (7, 8, 21)
cannot, therefore, be attributed to a shift in the expression of MHC
isoforms, consistent with the conclusion of Mercadier et al.
(18). Hirzel et al. (9) also reported that
the ventricular MHC content was not different between normal and
cardiomyopathic patients.
A low level of MHC- was detected in fetal right and left ventricles,
which is in contrast to an earlier immunohistochemical study
(29) in which this isoform was not detected in fetal human ventricles. The discrepancy is likely due to differences in sensitivity between the techniques employed in the present and previous studies.
Miyata et al. (19), with the use of the electrophoretic
technique described by Reiser and Kline (24), reported
that MHC- is minimally expressed in the adult nonfailing ventricular
myocardium. They suggested that the MHC- band on silver-stained gels
can obscure faint MHC- bands. However, gels from our study (Figs. 1
and 2) demonstrated high resolution and clear separation of both the
MHC- and MHC- bands when even minimal MHC- expression is
apparent. Thus the absence of MHC- expression in the adult nonfailing and failing myocardium as well as in the fetal left ventricular myocardium was not due to technical limitations in this
electrophoretic technique. The small differences between our study and
the study by Miyata et al. (19), e.g., 2.5 versus 7%
MHC- in nonfailing left ventricles, might be due to technical differences involved in separation of these bands. Regardless, both
studies show low levels of MHC- expression in failing ventricles and
extremely low expression in nonfailing ventricles.
The low level of MHC-, or V1 myosin isoenzyme (12),
protein in the adult human ventricle is consistent with the results of
the majority of previous studies in which human ventricular MHC isoform
composition has been examined with a variety of experimental approaches
(e.g., Refs. 3, 10, and 29). Therefore,
an option to increase the relative amount of MHC- in adult human
ventricles, which is near 100% normally, does not exist. This could
otherwise result in a presumably slower than normal and a more
economical mode of contraction during the progression to heart failure,
as is observed in experimentally induced failure in smaller mammals (e.g., Refs. 4 and 28).
The results from several laboratories (reviewed in Ref. 25) have shown that increases in cardiac work load in several animal models (especially small mammals; e.g., Ref. 6) are associated with reexpression of a fetal gene program coding for growth factors, sarcomeric proteins, and products of protooncogenes in the hypertrophied heart. The results of the present study clearly indicate that the fetal pattern of MHC isoform expression in human ventricles is very similar to the adult pattern and that marked changes do not occur during the progression to failure, at least in individuals with dilated or ischemic cardiomyopathy. Furthermore, we conclude that there is no distinct "fetal pattern" of MHC isoform expression in the left atrium because no difference was detected between fetal and adult nonfailing left atria. Thus the MHC isoform expression pattern in the left atrium of the failing myocardium is distinctive and does not recapitulate the fetal/nonfailing pattern.
The results also indicate that there is a much higher level of MHC-
protein in the left atrium than the ventricles, consistent with the
long recognized relatively greater level of V1 myosin isoenzyme in
normal atria compared with ventricles (3). The results
indicate that the relative level of MHC- in the atria is not
significantly different between fetal and adult ages. Cummins and
Lambert (5) reported that the mean level of MHC- in
human fetal atria is less than one-half of that in adult atria, but whether the difference was statistically significant was not stated. The present results indicate that level of atrial MHC- is
significantly lower and to a similar extent in individuals with either
dilated or ischemic cardiomyopathy. The relative amount of left
atrial MHC- also decreases during canine rapid pacing-induced heart failure (13). The results do not show whether the level of
MHC- in the left atrium decreases during cardiomyopathy (as an
adaptive response) or is initially lower in those individuals that
develop cardiomyopathy (as a factor that contributes to heart failure). An increase in the relative amount of MHC- of the left atrium during
the development of heart failure could be beneficial by increasing the
economy of contraction (14). This could be especially important if the left atrium has a greater role in facilitating diastolic filling of the left ventricle in an effort to increase stroke
volume and cardiac output. Alternatively, a lower level of MHC- in
the left atrium, as an antecedent to failure, is expected to result in
a slower rate of atrial contraction, which in turn could lead to a
slower rate of ventricular diastolic filling. This, in turn, could
result in a smaller stroke volume and reduced cardiac output. The
increase in the relative amount of left atrial MHC- during
cardiomyopathy is consistent with a reported greater atrial systolic
function (work load) during heart failure in humans (16,
17) and in a canine model (13).
In conclusion, MHC- is expressed at very low levels in fetal and
adult human right and left ventricles, and small but significant changes in ventricular MHC isoform protein expression occur during adult human dilated and ischemic cardiomyopathies. Furthermore, there is a significantly greater relative amount of MHC- in the adult human cardiomyopathic left atrium, which could have marked consequences on myocardial contraction and disease progression. Finally, MHC isoform expression in the atria and ventricles of the
human fetus does not comprise a unique fetal pattern.
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ACKNOWLEDGEMENTS |
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The assistance of the Heart Transplant Team and the Department of Pathology at the Cleveland Clinic Foundation in providing failing human heart tissue and of Life Banc of Northeast Ohio in providing nonfailing human heart tissue is acknowledged. Human tissue was also provided by the Cooperative Human Tissue Network, which is funded by the National Cancer Institute.
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FOOTNOTES |
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This study was supported in part by Grant-in-Aid 96009610 from the American Heart Association (AHA) National Center (to P. J. Reiser) and by National Institutes of Health Grants R01 HL-60666 (to M. A. Portman) and R24 HD-00836. C. S. Moravec was supported by National Heart, Lung, and Blood Institute Grant HL-49929, AHA National Center Grant 95007700, and an Established Investigator Award from the AHA. No funds from the AHA were used to support the fetal portion of this study.
Address for reprint requests and other correspondence: P. Reiser, Dept. of Oral Biology, Ohio State Univ., 305 West 12th Ave., PO Box 182357, Columbus, OH 43218-2357 (E-mail: reiser.17{at}osu.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 21 July 2000; accepted in final form 27 November 2000.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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, Values obtained from 47- and
54-day-old fetal samples in which right and left ventricles were not
distinguished from each other. 
and 
,
Values obtained from the right and left, respectively, ventricles from
other fetuses. The slope of the linear fit between all of the values
and gestational age is significantly different from zero
(P < 0.04). The correlation coefficient between all of
the MHC-
