Download Prior exercise improves survival, infarct healing, and left ventricular

J Appl Physiol 107: 928–936, 2009;
doi:10.1152/japplphysiol.91281.2008.
Prior exercise improves survival, infarct healing, and left ventricular function
after myocardial infarction
Monique C. de Waard and Dirk J. Duncker
Experimental Cardiology, Dept. of Cardiology, Thoraxcenter, Erasmus MC, University Medical Center Rotterdam, Rotterdam,
The Netherlands
Submitted 24 September 2008; accepted in final form 25 June 2009
cardiac function; infarct healing; remodeling
has been proposed to be an independent
risk factor for cardiovascular disease (4, 48). Indeed, prospective epidemiological data have indicated that moderate (e.g.,
walking) and vigorous exercise in healthy subjects are associated with substantial reductions in the incidence of cardiovascular events (23, 31). The beneficial effects of exercise extend
to patients with established coronary heart disease, in which
regular physical activity also reduces the incidence of cardiac
events and all-cause mortality (44). Furthermore, there is
evidence that exercise initiated after a cardiac event, such as
myocardial infarction (MI), ameliorates left ventricular (LV)
remodeling and dysfunction (8, 14, 22, 27, 36, 37, 49, 52) and
improves clinical outcome (35, 43).
In contrast, there is substantially less information available
as to whether prior exercise affords any protection in situations
where, despite regular exercise, a major cardiovascular event
like MI does occur. Animal studies have suggested that prior
exercise can precondition the myocardium, thereby protecting
the heart against irreversible damage produced by ischemiareperfusion in rats (5, 39, 50, 51) and dogs (10). In addition,
prior exercise may modulate postinfarct remodeling independent of any myocardial preconditioning effect. Thus, two
studies in rats using permanent coronary artery ligation [in
which preconditioning cannot limit acute myocardial necrosis
(33, 46)] showed that infarct size and, likely as a consequence,
LV remodeling were reduced by prior swim training (17, 32).
In contrast, studies into the effects of prior exercise by treadmill running on LV remodeling after MI have not been performed to date. Consequently, the present study was undertaken to test the hypothesis that daily exercise started 2 wk
before an acute MI is associated with improved survival and
attenuated LV remodeling and dysfunction after MI. For this
purpose, we used voluntary free wheel running as a mode of
exercise, which has negligible effects on LV geometry and
function per se but attenuates LV and cardiomyocyte dysfunction when initiated after MI produced by a permanent coronary
artery ligation (8).
METHODS
Experiments in the present study complied with the National
Institutes of Health Guide for Care and Use of Laboratory Animals
(NIH Pub. No. 86-23, Revised 1996) and were approved by the
Erasmus MC Animal Care Committee.
Animals
PHYSICAL INACTIVITY
Address for reprint requests and other correspondence: D. J. Duncker, Div.
of Experimental Cardiology, Dept. of Cardiology, Thoraxcenter, Erasmus MC,
Univ. Medical Center Rotterdam, PO Box 2040, Rotterdam 3000 CA, The
Netherlands (e-mail: [email protected]).
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A total of 186 wild-type C57Bl/6 mice of either sex (⬃12 wk old)
were entered into the study and were randomly assigned to one of six
experimental groups. After 2 wk of voluntary wheel running or
sedentary housing, MI was induced, after which exercise was stopped
(EX-MI-SED and SED-MI-SED groups, where EX is exercise and
SED is sedentary) or continued (EX-MI-EX and SED-MI-EX groups)
for 8 wk. Sham-operated mice (SED-SH-SED and SED-SH-EX
groups, where SH is sham operation) were used as controls.
Exercise
Mice were exposed to voluntary wheel running while daily running
distances were recorded (8). The followup period of 8 wk was chosen
as we have previously shown that this regimen resulted in an ⬃30%
increase in skeletal muscle citrate synthase activity and blunted LV
dysfunction after MI (8). The pre-MI exercise period of 2 wk was
arbitrarily chosen. However, based on the positive results in pilot
experiments of the EX-MI-SED group, the 2-wk time period was used
for the remainder of the study. EX-MI mice were allowed to run until
the morning of surgery. After surgery, all mice were placed back into
their cage after 1–2 h of monitored recovery to allow the SH-EX and
MI-EX groups to exercise the first night after surgery.
8750-7587/09 $8.00 Copyright © 2009 the American Physiological Society
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de Waard MC, Duncker DJ. Prior exercise improves survival, infarct
healing, and left ventricular function after myocardial infarction. J Appl
Physiol 107: 928–936, 2009; doi:10.1152/japplphysiol.91281.2008.—We
investigated the effects of voluntary wheel running before an acute
myocardial infarction (MI) on survival, left ventricular (LV) remodeling and dysfunction and whether exercise before and after MI
provides superior protection compared with either exercise intervention alone. After 2 wk of voluntary wheel running or sedentary
housing, MI was induced in C57Bl/6 mice, after which exercise was
stopped (EX-MI-SED and SED-MI-SED groups, where EX is exercise and SED is sedentary) or continued (EX-MI-EX and SED-MI-EX
groups) for a period of 8 wk. Exercise after MI in SED-MI-EX mice
had no effect on survival, the area of infarction, and global LV
remodeling, but attenuated fibrosis and apoptosis in the remote myocardium and blunted LV dysfunction and pulmonary congestion
compared with SED-MI-SED mice. Exercise before MI in both
EX-MI-SED and EX-MI-EX mice decreased post-MI mortality compared with both SED-MI-SED and SED-MI-EX mice. Furthermore, in
both pre-MI exercise groups, the infarct area was thicker, whereas
interstitial fibrosis and apoptosis in the remote LV myocardium were
blunted. In contrast, the ameliorating effects of either pre-MI or
post-MI exercise alone on LV dysfunction were lost in EX-MI-EX
mice, which may in part be related to the increased daily exercise
distance in the first week post-MI in EX-MI-EX versus SED-MI-EX
mice. In conclusion, exercise before or after MI blunted LV dysfunction, whereas only exercise before MI improved survival. These
findings suggest that even when regular physical activity fails to
prevent an acute MI, it can still act to improve cardiac function and
survival after MI.
CARDIOPROTECTIVE EFFECTS OF EXERCISE
Experimental Procedures
Morphometric Analysis of the Infarct Region
The LV was cut along the long axis into 4-␮m sections, and
Masson’s trichrome staining was used for the analysis of the infarct
region (8). The infarct region was demarcated as the blue-greenstained area of the LV. Endocardial infarct circumference was demarcated, and its length was determined. The minimal infarct thickness
was measured at the shortest distance between the endocardium and
epicardium. The infarct area was demarcated, and the total surface
area was measured. Within the infarct area, the thickness of the
subendocardial rim of the myocardium and the infarct thickness were
each measured at four sites evenly spaced along the infarct area and
then averaged. The operator was blinded to the experimental group
during the analysis.
⫻400. Within each field, segments representing connective and
muscle tissue were identified and manually traced with a digitizing
pad and computer image-analysis software (Clemex Vision PE 3.5)
to calculate the traced area. Collagen content was calculated in
each field as the sum of all connective tissue areas divided by the
sum of all connective tissue and muscle areas and averaged for
each animal. Cardiomyocyte CSA was measured by tracing the
outline of cardiomyocytes showing the nucleus in each field and
averaged for each animal.
Apoptosis. To localize DNA degradation in the remote noninfarcted LV, we used the In Situ Cell Death Detection Kit (Roche
Diagnostics), which is a modification of the 3⬘-terminal deoxynucleotide transferase (TdT)-mediated dUTP nick-end labeling
(TUNEL) assay. In brief, paraffin-embedded sections were deparaffinized, cleared, and hydrated to PBS ( pH 7.4) using a descending series of ethanol. Sections were treated with proteinase-K for
30 min at 37°C, washed in PBS, treated with the TUNEL reaction
mixture, and incubated in the dark for 1 h at 37°C, followed by
washing in PBS. Both positive (DNaseI-treated sections) and
negative controls (no TDT included in the reaction mixture) were
included. Sections were covered with Vectashield including 4⬘,6diamidino-2-phenylindole and immediately photographed using
fluorescence microscopy. TUNEL-positive cells emitted red fluorescence, and all nuclei were blue. Apoptosis was determined as
the number of TUNEL-positive nuclei per 105 nuclei.
Statistics
Data were analyzed using two-way ANOVA followed by post hoc
testing with the Student-Newman-Keuls test. Survival was analyzed
by the Kaplan-Meier method and log-rank (Mantel-Cox) test. Significance was accepted when P ⬍ 0.05. Data are means ⫾ SE.
We tested for sex differences and consistently found across all
groups that females were characterized by ⬃30% lower body weight,
⬃5% smaller tibia length, and ⬃50% lower post-MI mortality (all
P ⬍ 0.05 by ANOVA). However, we did not observe statistically
significant sex differences with respect to the effects of pre-MI and/or
post-MI exercise on post-MI survival, LV dysfunction (fractional
shortening and pulmonary congestion), or LV remodeling (LV enddiastolic diameter and LV weight/tibia length). Consequently, we
pooled male and female mice for the final analysis.
RESULTS
Morphometric Analysis of the Remote NonInfarct Region
Survival and Exercise
Capillary density. Capillaries were detected using lectin staining. Briefly, short-axis LV paraffin sections were deparaffinized,
cleared, and hydrated to Tris-buffered saline (pH 7.4) using a
descending series of ethanol. Sections were treated with trypsin
(pH 7.0) for 20 min at 37°C, washed, and treated with hydrogen
peroxide (3%) for 10 min at room temperature to inhibit the
endogenous peroxide. Sections were incubated overnight at 4°C
with peroxidase-conjugated lectin from Bandeira simplicifolia
(Sigma). Horseradish peroxidase was activated by incubation for
1–2 min with a diaminobenzidine commercial kit (Dako). Sections
were washed, counterstained with hematoxylin, dehydrated with
graded ethanol solutions, cleared in xylene, and mounted. Capillaries were detected as brown endothelial cells, and capillary
density was determined as the number of vessels per millimeter
squared.
Cardiomyocyte cross-sectional area and collagen content. Paraffin-embedded LV sections (4 ␮m thick) were stained with Masson’s trichrome for the analysis of collagen content and cardiomyocyte cross-sectional area (CSA) measurements within the remote
noninfarcted myocardium (8). Four fields were randomly selected
in two sections of eight mice per group and photographed using an
Olympus BH 20 microscope (Olympus) at a magnification of
SED-MI-SED mice demonstrated 60% survival compared
with SED-SH-SED mice (Fig. 1A), which significantly improved to 83% in EX-MI-SED mice, where exercise was
started 2 wk before MI. In contrast, exercise started after MI
had no significant effect on survival. After the induction of MI,
SED-MI-EX mice initially ran significantly shorter distances
per day compared with either SED-SH-EX or EX-MI-EX
mice, in which exercise had already been started 2 wk before
MI and continued after the induction of MI (Fig. 1B). Thus,
over the 8-wk post-MI phase, SED-MI-EX mice ran a total
distance of only 313 ⫾ 23 km compared with 402 ⫾ 28 km in
SED-SH-EX and 456 ⫾ 35 km in EX-MI-EX mice (both P ⬍
0.05 vs. SED-MI-EX mice).
J Appl Physiol • VOL
Global LV Remodeling and Function
MI resulted in marked LV remodeling and dysfunction.
Thus, SED-MI-SED mice exhibited significant LV hypertrophy and dilation and lower levels of LV systolic pressure, rate
of rise of LV pressure at a LV pressure of 30 mmHg (LVdP/
dtP30), fractional shortening, and LVdP/dtmin and higher levels
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All experimental procedures have previously been published in
detail (8, 45). In brief, mice were weighed, sedated with 4% isoflurane, intubated, and pressure-controlled ventilated with O2:N2 [1:2
(vol/vol)] containing ⬃2.5% isoflurane for anesthesia. MI was produced by permanent ligation of the left anterior descending coronary
artery with a 7-0 silk suture (BBraun). This location of the ligation
creates an area at risk that comprises almost half of the LV, of which
⬃90% has become infarcted 24 h later, representing 40 – 45% of the
LV (8). SH animals underwent the operation without infarct induction.
Eight weeks after the induction of MI or SH, hemodynamic
measurements were performed under anesthesia. M-mode LV
echocardiography (Prosound SSD-4000, ALOKA) was performed,
LV diameters at end diastole and end systole were measured, and
LV fractional shortening was calculated (8, 45). A 1.4-Fr microtipped pressure transducer catheter (SPR-671, Millar Instruments) was inserted into the right carotid artery and advanced into
the LV for measurements of LV pressure and its first derivative
(dP/dt) (8, 45).
Immediately after these measurements, mice were killed, and right
ventricular (RV) and LV weights, tibial length, and lung fluid weights
were determined (8). The LV of a subset of mice that were randomly
selected from each group was fixed overnight in freshly prepared 4%
paraformaldehyde in PBS, embedded in paraffin, and used for histological analysis (see below). The operator was blinded to the experimental group during the analysis.
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CARDIOPROTECTIVE EFFECTS OF EXERCISE
remodeling but that this exercise regimen improved LVdP/
dtP30 and fractional shortening and alleviated pulmonary congestion after MI. Similarly, 2 wk of voluntary wheel running
before MI (EX-MI-SED group) had no effect on MI-induced
LV remodeling, whereas it improved fractional shortening and
ameliorated pulmonary congestion. In contrast, the beneficial
effects of each exercise regimen on MI-induced LV dysfunction appeared to be partly lost when post-MI exercise was
added to pre-MI exercise. Thus, in EX-MI-EX mice, LV
dilation was slightly aggravated, whereas fractional shortening
and LVdP/dtP30 were lower (all P ⬍ 0.05) and pulmonary
congestion tended to be increased (P ⫽ not significant) compared with SED-MI-EX mice. As a result, LV fractional
shortening, LVdP/dtP30, and RV and lung fluid weights were
not significantly different between EX-MI-EX and SED-MISED mice (Fig. 2).
Infarct Remodeling
of the relaxation time constant (␶) and LV end-diastolic pressure compared with SED-SH-SED mice (Table 1 and Fig. 2).
The LV dysfunction resulted in pulmonary congestion, as
reflected by an increase in lung fluid weight and RV hypertrophy in SED-MI-SED compared with SED-SH-SED mice. A
comparison of SED-SH-EX with SED-SH-SED mice showed
that 8 wk of voluntary wheel running had negligible effects on
LV function and geometry in SH mice. A comparison of
SED-MI-EX with SED-MI-SED mice showed that 8 wk of
voluntary wheel running had no effect on MI-induced LV
Remodeling of the Remote Myocardium
Cardiomyocyte CSA. The CSA of myocytes in the remote
surviving myocardium was increased after MI by 35%
(Figs. 5B and 6A). Exercise after MI had no effect on
cardiomyocyte size in either SH or MI hearts. In contrast, in
EX-MI-SED mice, cardiomyocyte CSA had increased further compared with SED-MI-SED mice, irrespective of
whether exercise was continued or stopped after MI.
Capillary density. After MI, capillary density (Figs. 5A and
6B) in the remote noninfarcted myocardium decreased by
⬃20%, which was the result of cardiomyocyte hypertrophy as
the capillary-to-myocyte ratio was similar in SED-MI-SED
(1.45 ⫾ 0.20) and SED-SH-SED (1.42 ⫾ 0.22) mice. Exercise
after MI had no effect on either capillary density (Fig. 6B) or
the capillary-to-myocyte ratio (1.55 ⫾ 0.13 in SED-MI-EX
mice). Exercise before MI had also no effect on capillary
Table 1. Anatomic and functional data
Number of mice
Body weight, g
LV weight, mg
Right ventricular weight, mg
Heart rate, beats/min
Mean arterial pressure, mmHg
LV systolic pressure, mmHg
dP/dtmin, mmHg/s
Relaxation time constant, ms
LV end-diastolic pressure, mmHg
SED-SH-SED
SED-SH-EX
SED-MI-SED
SED-MI-EX
EX-MI-SED
EX-MI-EX
30
26⫾1
97⫾3
26⫾1
530⫾10
75⫾2
97⫾2
⫺7,560⫾360
8.6⫾0.6
6.9⫾0.6
15
24⫾1
91⫾2
25⫾1
490⫾10f
82⫾4
99⫾3
⫺6,740⫾470
10.0⫾1.0
5.0⫾0.8
30
25⫾1
113⫾2a
33⫾1a
510⫾10
71⫾2
84⫾2a
⫺4,650⫾240a
12.4⫾1.0a
9.8⫾0.9a
25
24⫾1
112⫾3b
28⫾1b,c
520⫾10b
71⫾2b
85⫾2b
⫺4,840⫾300b
13.5⫾1.1b
8.0⫾0.9b
19
24⫾1
114⫾3a
29⫾1a,c
540⫾5c
66⫾2a,d
82⫾2a
⫺5,490⫾430a
10.8⫾1.0
4.9⫾0.7a,c,d
19
24⫾1
118⫾4b
33⫾3b
540⫾10b
68⫾2b
82⫾3b
⫺4,730⫾400b
11.6⫾1.2
9.6⫾1.6b,e
Values are means ⫾ SE. SED, sedentary; EX, exercise; SH, sham operation; MI, myocardial infarction; LV, left ventricular. a P ⬍ 0.05, MI-SED groups
(SED-MI-SED or EX-MI-SED) vs. the SED-SH-SED group; b P ⬍ 0.05, MI-EX groups (SED-MI-EX or EX-MI-EX) vs. the SED-SH-EX group; c P ⬍ 0.05 vs.
the SED-MI-SED group; d P ⬍ 0.05 vs. the SED-MI-EX group; e P ⬍ 0.05 vs. the EX-MI-SED group; f P ⬍ 0.05, SED-SH-EX group vs. the SED-SH-SED group.
J Appl Physiol • VOL
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Fig. 1. A: Kaplan-Meier survival curves for all six groups. EX, exercise; SED,
sedentary; SH, sham operation; MI, myocardial infarction. Numbers of mice
that entered the study were as follows: 30 SED-SH-SED, 15 SED-SH-EX, 50
SED-MI-SED, 44 SED-MI-EX, 23 EX-MI-SED, and 24 EX-MI-EX mice.
B: daily running distance in SED-SH-EX (n ⫽ 15), SED-MI-EX (n ⫽ 25),
EX-MI-SED (n ⫽ 19), and EX-MI-EX (n ⫽ 19) mice that survived the entire
8-wk followup period. *P ⬍ 0.05, MI-SED groups (SED-MI-SED or EX-MISED) vs. the SED-SH-SED group; ⫹P ⬍ 0.05, MI-EX groups (SED-MI-EX
or EX-MI-EX) vs. the SED-SH-EX group; †P ⬍ 0.05 vs. the SED-MI-SED
group; ‡P ⬍ 0.05 vs. the SED-MI-EX group.
Exercise after MI had no effect on infarct remodeling, as reflected
by an unchanged total infarct area and infarct length and unchanged minimal and average infarct thickness (Figs. 3 and 4,
A–C). In contrast, exercise before MI resulted in increased infarct
thickness, and hence total infarct area, irrespective of whether
mice continued to exercise after MI. Furthermore, the subendocardial rim of the myocardium within the infarct area was thicker,
particularly in the EX-MI-SED group but also in the EX-MI-EX
group (Fig. 4D).
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CARDIOPROTECTIVE EFFECTS OF EXERCISE
density, despite an increase in cardiomyocyte size, which was
due to a commensurate increase in the capillary-to-myocyte
ratio (1.74 ⫾ 0.12 in EX-MI-SED mice and 1.78 ⫾ 0.09 in
EX-MI-EX mice).
Collagen content. MI increased interstitial collagen content
in the remote myocardium (Figs. 5B and 6C). Exercise (which
slightly reduced collagen content in SH hearts) normalized
collagen content in MI hearts to levels observed in SED-SHSED mice. A similar decrease in collagen content was noted in
EX-MI-SED mice. However, combining exercise before and
after MI did not result in a further reduction in interstitial
collagen content in EX-MI-EX mice compared with either
EX-MI-SED or SED-MI-EX mice.
Apoptosis. MI resulted in an increased number of TUNELpositive nuclei in the remote myocardium (Fig. 6D). Exercise
(which tended to decrease apoptosis in SH hearts) normalized
the number of TUNEL-positive nuclei in MI hearts to levels
observed in SED-SH-SED hearts. A similar decrease in
TUNEL-positive nuclei was noted in EX-MI-SED and EXMI-EX mice, although in the latter group this failed to reach
statistical significance (P ⫽ 0.066).
J Appl Physiol • VOL
DISCUSSION
MI results in LV remodeling that serves to restore LV pump
function. However, despite the apparent appropriateness of LV
remodeling to maintain cardiac pump function early after MI,
remodeling is an independent risk factor for the development of
congestive heart failure (28). Recently, we (8) reported that
exercise after MI attenuates LV pump dysfunction in mice. The
present study investigated the impact of 2 wk of voluntary wheel
running before an acute MI on post-MI survival, LV remodeling,
and dysfunction in mice. The main findings were as follows:
1) exercise after MI had no effect on survival and global LV or
infarct remodeling but ameliorated LV dysfunction, interstitial
fibrosis, and apoptosis in the remote myocardium; 2) exercise
before MI, with no exercise after MI, partially attenuated LV
dysfunction, interstitial fibrosis, and apoptosis but also improved
post-MI survival and infarct remodeling; and 3) the combination
of exercise starting 2 wk before MI together with exercise continued after MI also improved survival and infarct remodeling but
did not improve global LV remodeling or dysfunction. The
implications of these findings will be discussed.
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Fig. 2. Effects of exercise on the left ventricular
(LV) weight-to-tibia length (TL) ratio (A), LV enddiastolic diameter (LVEDD; B), LV fractional
shortening (C), rate of rise of LV pressure at a LV
pressure of 30 mmHg (LVdP/dtP30; D), right ventricular (RV) weight-to-TL ratio (E), and lung fluid
weight (F). *P ⬍ 0.05, MI-SED groups (SED-MISED or EX-MI-SED) vs. the SED-SH-SED group;
⫹P ⬍ 0.05, MI-EX groups (SED-MI-EX or EXMI-EX) vs. the SED-SH-EX group; †P ⬍ 0.05 vs.
the SED-MI-SED group; ‡P ⬍ 0.05 vs. the SEDMI-EX group; §P ⬍ 0.05 vs. the EX-MI-SED
group.
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CARDIOPROTECTIVE EFFECTS OF EXERCISE
Effects of Voluntary Wheel Running after MI on LV
Remodeling and Dysfunction
In agreement with previous findings in our laboratory (8,
45), we observed in the present study that a large MI (comprising ⬃40% of LV mass) caused 40% mortality in mice,
which occurred principally during the first 2 wk post-MI. Eight
weeks after the induction of MI, LV remodeling had occurred,
as characterized by LV dilation and myocardial hypertrophy,
as well as increased interstitial collagen deposition, apoptosis and decreased capillary density in the remote surviving
myocardium. MI also produced marked LV dysfunction, as
characterized by decrements in LV pump function (fractional
shortening) and indexes of systolic (LVdP/dtP30) and diastolic
(dP/dtmin and ␶) function, resulting in pulmonary congestion, as
reflected by pulmonary edema and RV hypertrophy (8, 45). LV
end-diastolic pressure increased only modestly despite the
large MI, which is in agreement with previous observations in
mice in our laboratory (8, 9) but contrasts with the marked
increases in LV filling pressure that we typically have observed
in pentobarbital-anesthetized pigs, which have even smaller
(20 –25% of the LV) infarct size (47). It could be speculated
that the MI-induced increase in LV end-diastolic pressure is
blunted due to the fact that we studied the mice under isoflurane anesthesia, which has pulmonary venodilating properties
(18) and could have reduced LV filling pressures. Indeed, the
increases in lung wet weight and RV hypertrophy, which are
less susceptible to the acute hemodynamic effects of anesthetics, strongly suggest that pulmonary congestion was present
and that in the awake state LV filling pressures were likely
elevated.
The effects of exercise after MI on LV remodeling and
dysfunction remain incompletely understood. Several studies
J Appl Physiol • VOL
in humans have reported contradictory effects of exercise on
LV remodeling after MI (12, 14, 20 –22, 25, 27, 29, 38, 42).
Careful inspection of these studies suggests that after a small
MI (ejection fraction ⬎ 40%), exercise has no detrimental
effect (20, 38) or even improves (14, 22, 27) LV geometry and
function, independent of whether exercise was started late, i.e.,
⬃1 yr (14, 22), or early, i.e., ⬍2 mo (20, 27, 38), after MI. In
contrast, in patients with a large MI (ejection fraction ⬍ 40%),
exercise had a beneficial effect on ejection fraction and LV
volumes, but only when started late after MI (14, 22). However, when exercise after a large MI is started at a time when
LV remodeling is still ongoing (⬍3– 4 mo after MI), the
majority of studies have reported that exercise has either no
(12, 20, 38, 42) or even a detrimental (25, 29) effect on LV
dimensions and/or ejection fraction. Similar to these clinical
studies, studies in rats have indicated that exercise started late
(⬎3 wk) after a moderate to large MI (encompassing 35–50%
of the LV mass), at a time when infarct healing is complete,
does not aggravate (30, 34) or even blunts (37, 49, 52) LV
dilation (37) and hypertrophy (30, 34, 37, 49, 52). In contrast,
when started ⬍1 wk after a moderate to large MI (1, 18, 19, 24,
26), exercise resulted in variable outcomes with beneficial (18),
no (1, 24), or detrimental (19, 26) effects on LV remodeling.
These rodent studies lend further support to the concern that
early exercise may have detrimental effects on LV remodeling
after a large MI, although interpretation is hampered by the fact
that late exercise studies in rats have principally used forced
treadmill running (16, 22, 34, 37), whereas early exercise
studies have predominantly used swimming (1, 19, 24, 49).
This is important because the exercise responses to swimming
are markedly different from those to treadmill running (2, 3,
16). For example, treadmill running results in marked increases
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Fig. 3. Macroscopic and microscopic representative examples of the LV infarcted myocardium. Masson’s trichrome staining of longitudinal sections of the LV
is shown. Red staining represents viable cardiomyocytes, whereas blue-green staining represents collagen.
CARDIOPROTECTIVE EFFECTS OF EXERCISE
933
In contrast to these studies using early swim exercise in rats,
we observed that exercise through voluntary wheel running
(which had negligible effects on LV geometry and function in
SH mice) starting gradually early after a large MI [encompassing 40 – 45% of LV (8)] did not aggravate post-MI mortality,
LV remodeling, capillary rarefaction, and cardiomyocyte hypertrophy of the remote myocardium and even reduced myocardial interstitial fibrosis and apoptosis and blunted LV dysfunction and pulmonary congestion (present study and Ref. 8).
These observations could be interpreted to suggest that the
beneficial effects of exercise initiated early after a large MI
depend critically on the exercise mode, i.e., swimming versus
running. However, it is clear that future studies are required to
investigate in detail the influence of not only the mode but also
the intensity and frequency of exercise on LV remodeling and
dysfunction initiated either early or late in animals with a large MI.
Fig. 4. Infarct remodeling as reflected by the infarct area (A), endocardial
infarct length (B), minimal (hatched bars) and average (total bars) infarct
thickness (C), and thickness of the myocardial layer within the infarct area (D).
Numbers of mice per group was as follows: 11 SED-MI-SED, 16 SED-MI-EX,
10 EX-MI-SED, and 12 EX-MI-EX. †P ⬍ 0.05 vs. the SED-MI-SED group;
‡P ⬍ 0.05 vs. the SED-MI-EX group.
in heart rate and cardiac output together with a redistribution of
cardiac output toward active skeletal muscle groups (16). In
contrast, swimming appears to result in minimal changes in
heart rate and cardiac output, so that the increase in skeletal
muscle blood flow is principally the result of a redistribution of
cardiac output (16). Furthermore, swimming is often accompanied by episodes of submersion, resulting in intermittent
hypoxia and diving reflexes (2, 3).
There is a lack of clinical data regarding the effects of prior
exercise on outcome after MI. Animal studies have suggested
that exercise can precondition the myocardium, thereby protecting the heart against irreversible damage produced by
ischemia-reperfusion in rats (5, 39, 50, 51) and dogs (10). In
addition, exercise may modulate postinfarct remodeling independent of any preconditioning effect. Thus, two studies in rats
using permanent coronary artery ligation reported that 5–7 wk
of prior swimming had no effect on post-MI mortality but
reduced infarct size and attenuated LV remodeling, as determined at 2 days (32) or 4 wk (17) after the induction of MI.
Swimming-induced increases in capillary (32) and arteriolar
(17) densities were observed in the remote region, which led
the authors to speculate (collateral blood flow was not actually
measured) that prior exercise may have resulted in increased
collateral blood flow to the area at risk, thereby limiting the
infarct size. Although the myocardial vasculature is known to
be enhanced by swimming in young male rats (13), there is no
evidence to suggest that collateral vessel growth is stimulated
Fig. 5. Microscopic representative examples of the LV remote myocardium. A: in the remote area of the LV, lectin-stained capillaries are visible as brown spots.
B: Masson’s trichrome staining shows collagen as blue-green tissue between the red-stained viable cardiomyocytes.
J Appl Physiol • VOL
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Effects of Prior Exercise on LV Remodeling and Dysfunction
After MI
934
CARDIOPROTECTIVE EFFECTS OF EXERCISE
Fig. 6. Effects of exercise on cardiomyocyte crosssectional-area (CSA; A), capillary density (B), collagen
volume fraction (C), and apoptosis (D) in the remote
noninfarcted myocardium. *P ⬍ 0.05, MI-SED groups
(SED-MI-SED or EX-MI-SED) vs. the SED-SH-SED
group; ⫹P ⬍ 0.05, MI-EX groups (SED-MI-EX or
EX-MI-EX) vs. the SED-SH-EX group; †P ⬍ 0.05 vs.
the SED-MI-SED group; ‡P ⬍ 0.05 vs. the SEDMI-EX group; ¶P ⬍ 0.05, SED-SH-EX group vs. the
SED-SH-SED group.
J Appl Physiol • VOL
Future studies are needed to establish the molecular mechanisms underlying the mitigation of LV dysfunction by pre-MI
exercise, which should include an interrogation of possible
exercise-induced improvements of intact cardiomyocyte and
myofilament function (8).
Combining Exercise Before and After MI
Allowing mice in which voluntary wheel running was
started 2 wk before MI to continue running after the induction
of MI resulted in similar infarct remodeling, improvements in
post-MI survival, and reductions in collagen content of the
remote myocardium compared with mice that were exercised
before MI but were sedentary housed after MI. In contrast, the
mitigating effects of either pre-MI or post-MI exercise on LV
dysfunction were principally lost when mice were subjected to
voluntary exercise both before and after the induction of MI.
Although these observations are difficult to explain, it should
be noted that mice that had been adapted to the running wheel
for 2 wk before the induction of MI (EX-MI-EX group) ran
significantly longer daily distances immediately post-MI (⬃7
km/day during the first week) compared with the initially
shorter daily distances in SED-MI-EX mice during the first 4
wk (⬃2 km/day during the first week). Consequently, it could
be speculated that this higher daily exercise load in the immediate post-MI phase offset some of the beneficial effects of
post-MI exercise and might also explain why studies in rats and
humans have shown variable responses to (forced) exercise
early after MI. A limitation of the present study is that our
wheel rotation recording system did not allow us to determine
whether the mice ran each day at greater speed (intensity) or
for longer duration during the early postinfarct period. This is
relevant information, as there is evidence that the exercise
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by exercise in healthy hearts. Thus, studies pertaining to
exercise of healthy dogs, swine, or rats have consistently
shown that exercise does not increase the innate collateral
blood flow capacity in healthy hearts (13). An alternative
explanation may be that prior exercise affected healing and
remodeling of the infarct area (contracture), thereby leading to
a reduction of infarct length (17, 32).
In contrast to the findings in rats, we observed that exercise
of mice via voluntary wheel running reduced post-MI mortality
from ⬃40% to ⬃20% and blunted LV dysfunction but did not
enhance the vascularity of the remote myocardium or limit
infarct size as measured 8 wk later. The mechanism underlying
the improved survival remains speculative. First, although we
did not determine the occurrence of arrhythmias, we cannot
exclude that pre-MI exercise resulted in a reduction in fatal
arrhythmias in the early phase after the induction of MI (40).
However, mortality in C57Bl/6 mice after permanent coronary
artery ligation appears to be principally caused by cardiac
rupture of the infarct area within the first 2 wk after MI (7).
Interestingly, we observed that infarct thickness was increased,
consistent with an exercise-induced modulation of infarct healing and remodeling. Consequently, it could be speculated that
the increased infarct thickness acted to reduce systolic wall
stress and thereby prevented cardiac rupture, thus enhancing
post-MI survival in mice that had been subjected to prior
exercise.
The precise mechanism for the blunted LV dysfunction in
EX-MI-SED mice cannot be determined from the present
study. There is evidence that the hearts of exercised animals
respond more effectively to stress. For example, rats subjected
to 8 wk of forced treadmill exercise were able to maintain or
increase myocardial contractility more effectively in the face of
a sustained pressure overload than sedentary animals (11).
CARDIOPROTECTIVE EFFECTS OF EXERCISE
10.
11.
12.
13.
14.
15.
16.
17.
Clinical Implications and Conclusions
The beneficial effects of regular physical activity on preventing major cardiac events in healthy individuals and patients with coronary heart disease are now well established (23,
31, 44). The results of the present study show that even when
regular exercise fails to prevent an acute MI, it can still act to
improve cardiac function and survival after MI. These observations warrant an even greater emphasis on lifestyle changes
in individuals that have an increased risk of MI.
18.
19.
20.
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