Download Age-related changes in cardiac structure and function in Fischer 344

Am J Physiol Heart Circ Physiol 290: H304 –H311, 2006.
First published September 2, 2005; doi:10.1152/ajpheart.00290.2005.
Age-related changes in cardiac structure and function in
Fischer 344 ⫻ Brown Norway hybrid rats
Timothy A. Hacker,1 Susan H. McKiernan,2 Pamela S. Douglas,3 Jonathan Wanagat,1 and Judd M. Aiken2
1
Department of Medicine and 2Department of Animal Health and Biomedical Sciences, University of Wisconsin,
Madison, Wisconsin; and 3Division of Cardiovascular Medicine, Duke University, Durham, North Carolina
Submitted 24 March 2005; accepted in final form 23 August 2005
hybrid rat; echocardiography
CARDIAC STRUCTURE AND FUNCTION are remarkably similar among
mammalian species, and the use of animal models has been
extremely helpful in developing treatment strategies for alleviating heart disease in humans. Extending animal studies
beyond young adult ages to very old ages may provide similar
benefits to cardiovascular health of the growing aged population. In mammalian tissues, aging manifests as detrimental
alterations in structure and function. Structural changes in the
aging heart extend from cardiomyocyte cell loss, left ventricular (LV) hypertrophy, changes in ventricle chamber diameter,
and collagen deposition (3, 13, 14), leading to overt functional
changes such as lengthening of contraction and relaxation
times and thus a decrease in heart rate (15), decreases in
fractional shortening, decreased LV end-systolic pressure (15,
33), and reduced cardiac output. These normal aging changes
do not necessarily contribute to morbidity but are clearly
associated with the general decline observed with aging.
The Fischer 344 (F344) rat has been a standard model of
aging with an extensive database on this genotype (29). Even
though the F344 rat has been widely used in research, concerns
Address for reprint requests and other correspondence: T. A. Hacker, Rm.
1671 Medical Science Center, 1300 Univ. Ave., Madison, WI 53706 (e-mail:
[email protected]).
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have been raised whether this specific strain is appropriate for
all gerontological studies because of its overuse and some
severe age-related pathologies (53). The National Institute on
Aging and the National Center for Toxicological Research
responded to these concerns and found that, among others, the
Fischer 344 ⫻ Brown Norway F1 hybrid rat (FBN) would
complement the F344 aging studies (53). The FBN rat had
significantly fewer pathological lesions compared with the
F344 and a greater mean age for 50% mortality (29): ⬃33 mo
for FBN compared with ⬃27 mo for F344 (46). Population
analyses of the FBN show a longer maximal life span compared with F344 [⬃43 and ⬃35 mo, respectively (46)], and
they provide an increased period of time in which changes
associated with age can be examined in the relative absence of
disease (29).
Echocardiography is a safe, repeatable, and portable technology that has been underutilized in the assessment of cardiac
function in important mammalian experimental model systems
(51). Studies in humans have provided visualization of structural or functional abnormalities that appear long before the
detection of overt clinical disease (18). Structural and functional features of left ventricles assessed using echocardiography have been validated and have considerable accuracy compared with necropsy samples (17, 18, 42, 54). The efficacy of
echocardiography in the rat model has been confirmed (10, 40,
41), and it has been used to evaluate treatment effects on
cardiac function (34), to assess cardiac structural and functional characteristics of rats with surgically induced myocardial
infarct (30) and hypertension (24, 32), and in genetic models of
hypertrophic heart failure (37). Only recently has there been a
report on baseline echocardiographic values for normal adult
rats (51) and age-associated changes in the female F344 rat
heart (9).
Although several studies have characterized the cardiovascular system in older rats (1, 5, 8, 9, 14, 21, 23, 33, 37), no
study has examined functional and structural alterations over
30 mo of age. In this study we determined standard reference
values for adult (12 mo) and aging (18 to 39 mo in 3-mo
intervals) FBN male rat cardiovascular structure and function
by using echocardiographic, hemodynamic, and histological
measures.
MATERIALS AND METHODS
A total of 54 male ad libitum-fed FBN hybrid rats were purchased
from the National Institute on Aging’s colony at Harlan (Oregon, WI).
Baseline assessments of heart function and structure were conducted
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Hacker, Timothy A., Susan H. McKiernan, Pamela S. Douglas,
Jonathan Wanagat, and Judd M. Aiken. Age-related changes in
cardiac structure and function in Fischer 344 ⫻ Brown Norway hybrid
rats. Am J Physiol Heart Circ Physiol 290: H304 –H311, 2006. First
published September 2, 2005; doi:10.1152/ajpheart.00290.2005.—
The effects of aging on cardiovascular function and cardiac structure
were determined in a rat model recommended for gerontological
studies. A cross-sectional analysis assessed cardiac changes in male
Fischer 344 ⫻ Brown Norway F1 hybrid rats (FBN) from adulthood
to the very aged (n ⫽ 6 per 12-, 18-, 21-, 24-, 27-, 30-, 33-, 36-, and
39-mo-old group). Rats underwent echocardiographic and hemodynamic analyses to determine standard values for left ventricular (LV)
mass, LV wall thickness, LV chamber diameter, heart rate, LV
fractional shortening, mitral inflow velocity, LV relaxation time, and
aortic/LV pressures. Histological analyses were used to assess LV
fibrotic infiltration and cardiomyocyte volume density over time.
Aged rats had an increased LV mass-to-body weight ratio and deteriorated systolic function. LV systolic pressure declined with age.
Histological analysis demonstrated a gradual increase in fibrosis and
a decrease in cardiomyocyte volume density with age. We conclude
that, although significant physiological and morphological changes
occurred in heart function and structure between 12 and 39 mo of age,
these changes did not likely contribute to mortality. We report
reference values for cardiac function and structure in adult FBN male
rats through very old age at 3-mo intervals.
CARDIAC FUNCTION IN AGING RATS
Table 1. Body weight and LV mass
determinations for aging rats
Age, mo
12
18
21
24
27
30
33
36
39
Body Weight, g
a,b,c
517⫾20 (6)
499⫾26 (6)a,c
540⫾40 (6)a,b,c
594⫾21 (3)a,b,c
516⫾55 (6)a,b,c
560⫾27 (5)a,b,c
558⫾50 (5)a,b,c
468⫾30 (7)a
459⫾39 (5)a
Postmortem LV
Weight, g
a
0.84⫾0.079 (6)
0.82⫾0.033 (6)a
0.86⫾0.048 (6)a,b
0.93⫾0.062 (3)a,b,c
0.85⫾0.14 (6)a
0.99⫾0.14 (6)c,d
1.03⫾0.14 (6)c,d
0.99⫾0.11 (7)b,c,d
1.09⫾0.076 (5)d
LV Mass Estimated by
Echocardiography
a
0.92⫾0.16 (6)
0.88⫾0.088 (6)a
0.85⫾0.089 (6)a
0.78⫾0.057 (3)a
0.94⫾0.16 (6)a,b
0.96⫾0.065 (5)a,b
1.12⫾0.14 (5)b
1.35⫾0.227 (7)c
1.35⫾0.170 (5)c
R
0.84
0.86
0.87
0.89
0.92
0.87
0.79
0.78
0.87
on rats at 12 mo and then performed at 3-mo intervals between 18
and 39 mo of age (n ⫽ 6 rats per time point) to provide an aging
continuum from middle to extreme old age. All animals were
healthy and free of clinical signs of short- or long-term illnesses.
In accordance with the “Guiding Principles in the Care and Use of
Animals,” institutional approval was granted for this experimental
protocol by the University of Wisconsin-Madison.
Heart function and structure were measured using echocardiography at all nine time points. Immediately after echocardiography,
hemodynamic analysis was completed on 12- (n ⫽ 6), 18- (n ⫽ 6), 21(n ⫽ 2), 24- (n ⫽ 4), 36- (n ⫽ 7), and 39-mo-old rats (n ⫽ 5).
Transthoracic echocardiography was performed using a Sonos
5500 ultrasonograph with a 12-MHz transducer (Philips). Noninvasive acquisition of two-dimensional guided M-mode images at the tip
of papillary muscles and Doppler studies were recorded on anesthetized rats (50 mg/kg ketamine). The thickness of the posterior and
anterior walls of the LV chamber and the LV chamber diameter
during systole and diastole were measured using the leading edge-toleading edge convention. All parameters were measured over at least
three consecutive cardiac cycles. These parameters were used to
calculate LV mass and fractional shortening as previously described
(22). Pulse-wave Doppler was used to measure the velocity of blood
through the mitral and aortic valves and to qualitatively examine the
valve for evidence of mitral regurgitation. From these images, heart
rate and the time between closure of the mitral valve and the opening
of the aortic valve were calculated.
After echocardiography was completed, rats underwent hemodynamic analysis. Rats were further anesthetized (1 mg/kg
Fig. 1. Structural features of the aging rat left ventricle determined using echocardiography: LV mass (A), LV mass-to-body weight ratio (B), posterior wall
thickness-to-body weight ratio (C), anterior wall thickness-to-body weight ratio (D), relative wall thickness-to-body weight ratio (E), and LV chamber
diameter-to-body weight ratio (F). Regression analysis was performed to determine whether there was a significant effect of age on a specific left ventricular
(LV) structure. ANOVA was used to determine differences among ages.
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Values are means ⫾ SD; nos. in parentheses are the number of animals
analyzed. R is the correlation coefficient between the left ventricular (LV) mass
determined by postmortem weighing and estimation of LV mass by M-mode
echocardiography. a,b,c,d Body weights and echo LV masses with different
superscripts are significantly different (P ⬍ 0.05) using ANOVA.
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CARDIAC FUNCTION IN AGING RATS
Table 2. Echocardiographic analysis of aging rats
Age, mo
n
LV/Body WT, mg/g
PW d, mm
AW d, mm
LVD d, mm
12
18
21
24
27
30
33
36
39
6
6
6
3
6
5
5
7
5
1.77⫾0.27b,c
1.77⫾0.14b,c
1.58⫾0.16c,d
1.32⫾0.14d
1.82⫾0.19b,c
1.72⫾0.16b,c
2.02⫾0.20b
2.91⫾0.61a
2.95⫾0.33a
1.9⫾0.1b,c,d,e
1.9⫾0.2b,c,d
1.8⫾0.2c,d,e
1.9⫾0.1e
2.0⫾0.2b,c,d,e
1.9⫾0.1d,e
2.1⫾0.1b,c,d,e
2.1⫾0.4a
2.0⫾0.3a,b
1.8⫾0.2a
1.9⫾0.1a,b
1.7⫾0.2c
1.8⫾0.2c
2.1⫾0.1a
1.9⫾0.1b,c
1.9⫾0.1b,c
1.9⫾0.1a
1.8⫾0.2a
6.9⫾0.5b
6.6⫾0.2b
6.9⫾0.b
6.3⫾0.1c
6.3⫾0.4b,c
7.0⫾0.2b
7.4⫾0.8b
8.2⫾0.8a
8.7⫾0.6a
LV/body WT, left ventricle mass to body weight ratio; PW d, left ventricle
posterior wall thickness in diastole; AW d, left ventricle anterior wall thickness
in diastole; and LVD d, left ventricle diameter in diastole. a,b,c,d,e Within each
column, values with different superscripts are significantly different (P ⬍ 0.05).
RESULTS
Body weight and echocardiographic structural features.
Body weight of the rats between the ages of 12 and 33 mo
remained relatively constant between 500 and 600 g. A significant decline in weight was observed at 36 mo (468 g) and 39
mo (459 g) (P ⫽ 0.0003; Table 1). LV mass as measured by
wet weights obtained at necropsy gradually increased with age.
At 39 mo, LV wet weights were significantly higher than those
measured at 12–27 mo of age, and at 36 mo, LV weight was
significantly greater than that observed at 12 and 18 mo of age
(Table 1). LV mass as measured by echocardiography signif-
Fig. 2. Measurement of systolic and diastolic parameters of the aging rat left ventricle performed using echocardiography: heart rate (A), percent fractional
shortening (%FS; B), velocity of blood flow across the mitral valve in early diastole, reported as peak E (C), and time between closure of the aortic valve and
opening of the mitral valve, or the isovolumic relaxation time (IVRT, D). Regression analysis was used to determine whether there was a significant effect of
age on a specific LV structure. ANOVA was used to determine differences among ages.
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acepromazine, 3 mg/kg xylazine, 35 mg/kg ketamine), and the left
carotid artery was surgically exposed and cannulated with a 2-French
micromanometer-tipped catheter (Millar Instruments, Houston, TX).
The catheter was advanced into the ascending aorta to measure aortic
pressure and then advanced across the aortic valve to measure LV
pressure.
After hemodynamic analysis was completed, the animals were
deeply anesthetized and euthanized via exsanguination. The thorax
was opened quickly, and the heart was removed. The hearts were
rinsed in saline, weighed, and then dissected to separate the left and
right ventricles and reweighed. The left ventricle was bisected transversely, embedded in OTC (optimal temperature cutting medium;
Saleura), and frozen in liquid nitrogen. Twenty-five 10-␮m-thick
frozen sections were taken at the midpapillary level. Gomori’s
trichrome stain was used to assess the volume densities of cardiomyocytes and interstitial fibrosis of frozen sections. Gomori-stained LV
sections from the 12-, 18-, 24-, 30-, and 36-mo-old animals were
examined. Each LV section was delineated into quarters, and eight
digital images (⫻20) were taken within the epicardium and eight
images within the endocardium using an Olympus BH2 microscope
and a Hitachi three-chip charge-coupled device camera (Hitachi,
Japan). A 100-point grid was masked over the images. At each
intersection of the grid, myocytes, interstitial fibrosis, or other was
recorded, and the volume densities of cardiomyocytes [Vv(cm)] and
fibrosis [Vv(fb)] were determined for each animal as follows: Vv ⫽
PP (structure)/PT, where PP is the number of points hitting the
structure and PT is the total number of test points (7). Mean volume
densities for myocytes and fibrosis were determined for the whole left
ventricle (1,600 test points) as well as the epicardium (800 test points)
and the endocardium (800 test points).
Regression analysis was performed on the cross-sectional echocardiographic data sets to determine the effect of age on each measure.
Echocardiographic, hemodynamic, and histological data also were
analyzed using an ANOVA to determine differences among ages. All
analyses were performed using the GLM procedure of SAS (SAS
Institute, 1989). Significance was set at P ⬍ 0.05.
CARDIAC FUNCTION IN AGING RATS
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Table 3. Echocardiographic analysis of heart
function of aging rats
Age, mo
n
12
18
21
24
27
30
33
36
39
6
6
6
3
6
5
5
7
5
HR, beats/min
413⫾13
412⫾53
371⫾14
424⫾24
417⫾21
373⫾55
389⫾22
404⫾16
397⫾37
%FS
b
58⫾7
57⫾8b
69⫾6a
63⫾2a,b
57⫾3b
46⫾8c
44⫾5c
38⫾8c,d
30⫾6d
Peak E, cm/s
b,c
84⫾10
82⫾16c
82⫾9c
81⫾4c
96⫾7b,c
100⫾20a,b
101⫾8a,b
98⫾13a,b,c
115⫾18a
IVRT, s
0.021⫾0.001b,c
0.020⫾0.001c,d
0.016⫾0.003e
0.016⫾0.003d,e
0.019⫾0.003c,d,e
0.024⫾0.005a,b
0.024⫾0.002a,b
0.025⫾0.002a,b
0.027⫾0.004a
icantly increased with age from 0.92 g at 12 mo to 1.35 g at 36
and 39 mo of age (P ⬍ 0.001; Fig. 1A and Table 1). ANOVA
revealed no change in LV mass between 12 and 30 mo of age;
however, at 33 mo of age, LV mass was significantly greater
than that observed at ages ⬍24 mo. LV mass increased between 33 and 36 mo of age, with no further increase between
36 and 39 mo of age. Correlation coefficients calculated for the
relationship between LV mass determined by postmortem
weighing and LV mass estimated by echocardiography ranged
from 0.78 to 0.92. When LV mass was normalized to body
weight (Fig. 1B and Table 2), the values for 36- and 39-mo-old
rats were significantly greater than for 12- to 33-mo-old rats
(P ⬍ 0.0001).
LV posterior and anterior wall thicknesses were measured;
values were very close, and no age-related trends were observed using regression analysis. However, ANOVA picked up
some significant variations (Table 2). When wall thicknesses
were normalized to body weight, there were significant increases with age with both regression analysis and ANOVA
(Fig. 1, C and D). Aging, in general, had no effect on the
relative wall thickness (Fig. 1E; P ⫽ 0.1034). The diameter of
the LV chamber increased over 25% between 12 and 39 mo of
age (P ⬍ 0.0001). The size of the ventricle at 36 and 39 mo
was significantly greater compared with that at earlier time
points (P ⬍ 0.0001; Fig. 1F and Table 2).
Functional features. Heart rate (beats/min) measured during
echocardiography did not change with age and was ⬃400 ⫾ 20
beats/min (Fig. 2A and Table 3). LV fractional shortening, used
as a measure of systolic function, significantly decreased with
Fig. 3. Effects of aging on end-diastolic diameter (length) and %FS (tension)
produced in rats. This plot demonstrates that aged rats are on the descending
arm of the length-tension relationship (Frank-Starling).
age (Fig. 2B and Table 3). The velocity of blood flow across
the mitral valve in early diastole, reported as peak E (cm/s),
significantly increased as the animals aged (Fig. 2C and Table
3). We saw evidence of mitral regurgitation with the use of
color-wave transmitral Doppler in ⬍10% of all animals tested,
evenly distributed throughout all age groups. The time between
the closure of the aortic valve and the opening of the mitral
valve is the isovolumic relaxation time (IVRT), which is used
as a measure of diastolic function. Relaxation increased from a
baseline (12 mo) IVRT of 0.021 s to an IVRT of 0.027 s at 39
mo, indicating a decline in diastolic function as rats age (Fig.
2D and Table 3).
Hemodynamic analyses. Hemodynamic analyses were performed on animals at 12, 18, 21, 24, 36, and 39 mo of age.
Measures of aortic mean pressure and LV pressure in systole
and diastole were recorded (Table 4). Mean aortic and peak LV
systolic pressures increased significantly from 12 and 18 mo to
21 and 24 mo and then significantly decreased at 36 and 39 mo,
whereas there was an increase in LV end-diastolic pressure at
the oldest ages compared with the younger animals. A plot of
end-diastolic volume vs. percent fractional shortening (%FS),
essentially a graph of the Frank-Starling curve, reveals a
decrease in %FS as the left ventricle dilates, demonstrating that
these aging hearts are on the descending arm of the lengthtension relationship (Fig. 3). A plot of end-systolic volume vs.
end-systolic pressure demonstrates a gradual decrease in elastance as the animals age (Fig. 4).
Table 4. Hemodynamic parameters for aging rats
Age, mo
n
HR, beats/min
AoP Mean, mmHg
LVP Peak, mmHg
LVEDP, mmHg
12
18
21
24
36
39
6
6
2
4
7
4
250⫾14
248⫾15
291⫾24
293⫾17
275⫾126
274⫾25
80⫾6a
79⫾6a
107⫾13b
97⫾11b
72⫾10a
69⫾11a
90⫾6b
90⫾4b
105⫾10a
106⫾7a
76⫾6c
71⫾9c
⫺3⫾2b,c
⫺1⫾2b,c
⫺3⫾2b,c
⫺4⫾3c
0⫾2a,b
3⫾2a
AoP mean, mean aortic pressure; LVP Peak, peak left ventricular pressure;
and LVEDP, left ventricular end-diastolic pressure. a,b,c Within each column,
values with different superscripts are significantly different (P ⬍ 0.05).
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Fig. 4. Effects of aging on LV elastance in rats. The plot of end-systolic
diameter vs. LV pressure is a surrogate measure for LV elastance, which
progressively decreases with age (m, month).
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HR, heart rate, (ANOVA model showed no significant differences in HR);
%FS, percent fractional shortening of the left ventricle; Peak E, peak velocity
of early diastolic blood flow through the mitral valve; and IVRT, isovolumic
relaxation time. a,b,c,d,e Within each column, values with different superscripts
are significantly different (P ⬍ 0.05).
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CARDIAC FUNCTION IN AGING RATS
Fig. 5. Fibrotic infiltration of the left ventricle in
aging rats. A: midpapillary cross sections of an
18-mo-old rat left ventricle. B: a 36-mo-old left
ventricle stained with Gomori trichrome for fibrosis (fibrotic tissue stained blue).
DISCUSSION
The present study provides reference values for cardiac
function in adult (12 mo) FBN male rats through middle to
very old age (18 –39 mo) at 3-mo intervals. Cardiac structural
Fig. 6. A: Fibrotic tissue volume density (A) and cardiomyocyte volume
density (B) of left ventricles in aging rats. Total volume densities were
analyzed using ANOVA. a,b,cColumns with different letters indicate significantly different values (P ⬍ 0.05).
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measures in the adult (12–24 mo) FBN male rat were very
similar to reported values from similar ages and various other
strains with respect to LV mass-to-body weight ratio (5, 8, 9,
20, 21, 28, 36, 37), anterior and posterior wall thicknesses (9,
21, 28, 37), and LV diastolic dimension (1, 5, 9, 21, 23, 28, 37).
LV function in the present study was also similar to that
reported in 12- to 25-mo-old rats of various strains. The %FS
for the FBN rat between 12 and 24 mo of age ranged between
57 and 69%, indicating maintenance of systolic function
through middle age. Other published reports for %FS ranged
from 35 to 84% (1, 5, 9, 21, 23, 28, 37). This large range may
be related to differences in heart rate, side effects of anesthesia,
or measurement variables for different strains. LV pressure for
our 12- to 24-mo-old rats also fell within one standard deviation of the ranges reported in the literature (LV pressure
105–130 mmHg) (1, 5, 8, 21, 23, 28, 33, 36, 37).
Functional cardiac measurements at old ages (27–39 mo)
revealed a decline in %FS and LV pressure with age and
indicated that these hearts were on the descending portion of
the length-tension curve. The length-tension relationship in the
heart, also known as the Frank-Starling mechanism, states that
the greater the stretch or length of the LV fibers, the greater the
force of contraction; however, if the fibers are overstretched,
force declines. In this study a surrogate measure for the
Frank-Starling relationship, a plot of end-diastolic volume vs.
%FS, showed that the increased dilation of these aging hearts
was detrimental as fractional shortening declined (i.e., they are
on the descending arm of the length-tension relationship). A
crude measure of contractility (the plot of end-systolic volume
vs. end-systolic pressure) revealed a decrease in the performance of the heart similar to that recently reported using the
pressure-volume relationship to measure LV function (33). The
fall in %FS and LV pressure are quite striking and may be at
least partially explained by the increase in fibrosis, apoptosis,
and/or alterations in the ␤-adrenergic system. Snyder et al. (44)
identified a decrease in the release of norepinephrine, which
may affect blood pressure and %FS. Indeed, others also have
shown a reduced response to catecholamines in aged aortas and
hearts (5, 19, 25, 38, 44). Arosio et al. (5) also have reported
an increase in adenosine A1 receptor gene expression in the
aging rat heart, which would have a similar antiadrenergic
effect.
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Histological analysis. Frozen cross sections of the left ventricle were taken at the midpapillary level and analyzed for
volume densities of fibrosis and cardiomyocytes. Fibrotic infiltration of the left ventricle significantly increased with age
[Fig. 5, A (18 mo) and B (36 mo), and Fig. 6A]. Fibrosis was
more concentrated in the endocardium compared with the
epicardium (Fig. 6A). The volume density of cardiomyocytes
for the total left ventricle significantly decreased with age in rat
hearts and was significantly less at 24 and 30 mo compared
with that at 12 and 18 mo and decreased further at 36 mo
(Fig. 6B).
CARDIAC FUNCTION IN AGING RATS
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cluding the rate of relaxation, diastolic suction, and passive
stiffness (11).
Cardiomyocyte loss with age was evident as the volume
density of cardiomyocytes decreased with the increase in
fibrosis over time. In the endocardium of the aged rat left
ventricle, there were many atrophied cardiomyocytes surrounded by interstitial fibrosis and significantly enlarged myocytes. Myocyte loss and hypertrophy are characteristic of the
heart’s aging process, and these changes were found to precede
the occurrence of ventricular dysfunction in the Fisher 344 rat
(2). The mechanisms of myocyte loss are via apoptosis and/or
necrosis, the necrotic process leading to an inflammatory
reaction with macrophage infiltration, fibroblast activation, and
scar formation. Mitochondrial dysfunction may initiate cardiomyocyte loss via the mitochondrial pathway of apoptosis.
Mitochondrial DNA (mtDNA) mutations accumulate with age
in nonreplicative tissues such as skeletal muscle, heart, and
brain. mtDNA deletion mutations remove genes encoding
critical subunits of the electron transport system, resulting in
mitochondrial enzymatic dysfunction that appears to cause
muscle fiber atrophy and fiber loss in aging rats (12, 49).
Mitochondrial deletion mutations have been detected in both
ventricles of aging FBN rat hearts, increasing in number with
age (50). In turn, mtDNA mutations have been shown to
activate apoptosis in cardiac tissue of mice (27, 55).
The effects of age on rat cardiovascular function were very
similar to changes observed in clinically normal aging humans.
Humans free of cardiovascular disease show decreasing myocardial systolic performance over time as indicated by decline
in midwall fractional shortening and a decrease in cardiac
index (43). In addition, normal aging in humans is accompanied by a decrease in diastolic function as indicated by an
increase in IVRT (31, 45), which also was seen in our aging
rats.
Reference values for cardiac structure and function in the
aging FBN rat model have been presented in this study.
Understanding the structural and functional changes of these
aged, altered hearts and how they continue to sustain sufficient
function may provide valuable insight into the postponement or
prevention of cardiovascular disease.
ACKNOWLEDGMENTS
We thank Larry Whitesell, Roger Klopp, and Fue Vang for expert technical
assistance and Tom Tabone for advice on the statistical analyses.
GRANTS
This work was supported by National Institute on Aging Grant AG-17543.
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