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(Circulation. 2001;103:1920.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Cell Therapy Attenuates Deleterious Ventricular Remodeling and Improves Cardiac Performance After Myocardial Infarction
From the Cardiac Muscle Research Laboratory (M.J., D.A.B., S.N., P.T., C.S.A., R.L.) and the Myocardial Biology Unit (D.B.S., W.S.C.), Boston University School of Medicine, Boston, Mass; and Diacrin, Inc (H.D., A.S.B.E., A.Z., K.W.), Charlestown, Mass.
Correspondence to Dr Ronglih Liao, Boston University School of Medicine, 650 Albany St, X-726, Boston, MA 02118. E-mail rliao{at}bu.edu
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Abstract |
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Background—Myocardial infarction (MI) promotes deleterious remodeling of the myocardium, resulting in ventricular dilation and pump dysfunction. We examined whether supplementing infarcted myocardium with skeletal myoblasts would (1) result in viable myoblast implants, (2) attenuate deleterious remodeling, and (3) enhance in vivo and ex vivo contractile performance.
Methods and
Results—Experimental MI was induced by 1-hour
coronary ligation followed by reperfusion in adult male Lewis
rats. One week after MI, 106 myoblasts were
injected directly into the infarct region. Three groups of animals were
studied at 3 and 6 weeks after cell therapy: noninfarcted control
(control), MI plus sham injection (MI), and MI plus cell injection
(MI+cell). In vivo cardiac function was assessed by maximum exercise
capacity testing and ex vivo function was determined by pressure-volume
curves obtained from isolated, red cell–perfused, balloon–in–left
ventricle (LV) hearts. MI and MI+cell hearts had indistinguishable
infarct sizes of 
30% of the LV. At 3 and 6 weeks after cell
therapy, 92% (13 of 14) of MI+cell hearts showed evidence of myoblast
graft survival. MI+cell hearts exhibited attenuation of global
ventricular dilation and reduced septum–to–free wall
diameter compared with MI hearts not receiving cell therapy.
Furthermore, cell therapy improved both post-MI in vivo exercise
capacity and ex vivo LV systolic
pressures.
Conclusions—Implanted skeletal myoblasts form viable grafts in infarcted myocardium, resulting in enhanced post-MI exercise capacity and contractile function and attenuated ventricular dilation. These data illustrate that syngeneic myoblast implantation after MI improves both in vivo and ex vivo indexes of global ventricular dysfunction and deleterious remodeling and suggests that cellular implantation may be beneficial after MI.
Key Words: myocardial infarction • remodeling • exercise • myocardial contraction
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Despite advances in the treatment of myocardial infarction (MI), congestive heart failure secondary to infarction continues to be a major complication. MI promotes acute and chronic transformation of both the necrotic infarct zone and the nonnecrotic, peri-infarct tissue, leading to global alterations that have collectively been termed "ventricular remodeling."1 2 3 The cardiomyocytes lost during an MI cannot be regenerated, and the extent of the loss is inversely related to cardiac output, pressure-generating capacity, and, ultimately, survival.4 5 Cell therapy, or the supplementation of tissue with exogenous cells, has previously been used in the treatment of disease in which terminally differentiated cells are irreparably damaged.6 Recently, it has been suggested that cell therapy with skeletal myoblasts may be effective in the treatment of MI.7 8
Myoblasts maintain the regenerative potential of skeletal muscle and, during periods of stress, proliferate and differentiate into myotubes, eventually forming new muscle fibers capable of contraction. Previous studies have shown that myoblasts implanted into myocardium undergo myotube formation, withdraw from the cell cycle, and remain viable.9 10 Furthermore, myoblasts implanted into cryoinfarcted myocardium have yielded similar results, with differentiation into slow-twitch skeletal myocytes expressing ß-MHC and capable of contraction on stimulation.11 Functional studies have also shown an improvement in regional contractility and compliance in cryoinfarcted myocardium after myoblast implantation.12 We therefore hypothesized that supplementing infarcted myocardium with syngeneic skeletal myoblasts would result in the formation of viable muscle grafts capable of attenuating deleterious post-MI remodeling and improving global cardiac performance. With the use of a rat coronary ligation model of MI,1 2 13 we demonstrate the physiological efficacy of myoblast implantation on both in vivo and ex vivo indexes of global cardiac remodeling and contractile failure.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Animal Model
Male inbred adult Lewis rats were obtained from Charles River Laboratories at 8 weeks of age, placed on a rat chow diet and water ad libitum, and housed under an alternating 12-hour light-dark cycle. Experimental MI was induced by coronary ligation of the main branch of the left marginal artery, as previously described.14 After 1 hour of coronary occlusion, the suture was removed, the myocardium reperfused, and the chest closed. Noninfarcted control animals received an identical procedure with the exception of tying of the coronary suture. All animal handling and procedures strictly adhered to the regulations of Boston University Animal Care and the National Society for Medical Research.
Myoblast Generation and Cell
Implantation
Myoblasts were isolated from skeletal hind leg muscle
of neonatal Lewis rats. Neonatal tissue allowed for generation of a
greater number of myoblast cells, with less fibroblast contamination,
in a shorter time frame. We have previously isolated competent skeletal
myoblasts from adult animals and humans with similar
results.
Neonatal tissue was minced and digested (incubated at 37°C
for 10 minutes) with a mixture of trypsin (0.5 mg/mL; GibcoBRL) and
collagenase (0.5 mg/mL; GibcoBRL) to release satellite
cells. Cell release was repeated 10 times for a given tissue isolation
to maximize satellite cell recovery relative to contaminating
fibroblasts. Cells from each isolation were seeded on
poly-L-lysine/laminin
(Sigma)–coated plates for expansion in myoblast growth basal medium
(SkBM; Clonetics) containing 20% fetal bovine serum (Hyclone),
recombinant human epidermal growth factor (rhEGF: 10 ng/mL), and
dexamethasone (0.39 µg/mL). Myoblast-enriched plates were
identified after 48 hours of expansion and harvested with 0.05%
trypsin-EDTA (GibcoBRL). For a given experiment,
107 cells were harvested from 6 to 10
plates, seeded by satellite cells isolated from the limb muscle of 2
neonate equivalents. Similar results have been reported with adult
skeletal
muscle.11 12
Cells were washed and suspended in cold HBSS at
107 cells/mL and kept up to 4 hours on ice
before injection. A total of 100 µL (106
cells) was injected into each animal. Under these conditions, cells
were determined to be 50% myoblasts by flow cytometry with the
monoclonal antibody H36 (anti-rat 
-7
integrin).15 The remaining
cells were fibroblast-like, as determined by cell morphology. The
ability for myoblasts to fuse into multinucleated myotubes in vitro was
also confirmed.
Seven days after MI, infarcted animals were randomized to
receive cell or sham implantation. Rats underwent a second thoracotomy,
and the left ventricle was visualized. Each rat received 6 to 10
injections (total of 106 cells/heart) of 10
to 16 µL of myoblast suspension in HBSS directly into the infarct and
peri-infarct regions, 1 to 2 mm apart, with a 30-gauge Hamilton
needle. Infarcted animals not receiving cells underwent an identical
injection procedure with HBSS alone. Noninfarcted control animals were
subjected to the same surgical procedures without
injection.
Animal Groups
Three groups of animals were studied: control animals
receiving neither infarction nor implantation (control), infarcted
animals without cell therapy (MI), and infarcted animals receiving
myoblast cell therapy (MI+cell). In vivo and ex vivo cardiac physiology
and myoblast cell survival were studied at 3 and 6 weeks after cell
therapy. Cell grafts were also examined at 9 days and 12 weeks after
implantation in several animals to determine the time course of
survival of implanted cells.
In Vivo Maximum Exercise Capacity
Maximum exercise capacity is often used as a measure
of in vivo ventricular function and overall cardiac
performance and recently has been demonstrated to be a valuable
tool in the assessment of cardiac performance in smaller animal
models.16 17
Maximum exercise capacity was assessed before implantation (1 week
after MI) as well as at 3 and 6 weeks after implantation. Maximum
exercise capacity was measured as the distance run on a modified rodent
treadmill (Columbus Instruments) until
exhaustion.18 Exhaustion was
defined as the inability to run for 15 consecutive seconds despite
minor electric shock. Initial treadmill speed was set at 15 m/min at a
15 degree grade and increased by 1-m/min increments every
minute.
Ex Vivo Ventricular
Function
To characterize myocardial remodeling and ex vivo
cardiac function at 3 and 6 weeks after implantation, whole-heart
Langendorff perfusion studies were performed in isolated isovolumically
beating (balloon–in–left ventricle [LV]) hearts as previously
described.19 20
Briefly, isolated hearts were retrogradely perfused with a
perfusate consisting of bovine red blood cells suspended in
modified Krebs-Henseleit buffer at a hematocrit of 40%. A fluid-filled
cling-film balloon connected to a Statham P23Db pressure transducer
(Statham Instruments) was placed into the left ventricle to monitor
ventricular pressures. Coronary perfusion pressure
was set to 80 mm Hg, and active pressure-volume relations were
then generated. From a balloon volume of zero, the balloon was filled
in increments of 0.05 mL, and subsequent peak systolic and
end-diastolic pressures were recorded. Systolic
and diastolic pressure-volume relations were derived as
previously
described.19 20
Tissue Histology and
Morphometry
After pressure-volume experiments, hearts were
arrested in diastole and fixed with 4% buffered
paraformaldehyde at a final ventricular
distending pressure of 5 mm Hg. Hearts were then weighed,
paraffin-embedded, and sectioned (5 to 7 µm thick) from each of 4
equally spread levels (atrium through apex).
Six-micron–thick sections were cut, mounted, and stained with trichrome. Myogenin immunohistochemistry was performed for identification of implanted skeletal myoblasts, whereas skeletal-specific myosin heavy chain immunohistochemistry was performed for identification of differentiated myotubes.9 For detection of myogenin, deparaffinized sections were blocked for endogenous peroxidase activity and subjected to antigen retrieval by boiling for 10 minutes in citrate buffer. Sections were blocked for endogenous biotin before adding primary polyclonal rabbit anti-rat myogenin antibody (Santa Cruz Biotechnology) followed by biotinylated goat anti-rabbit secondary antibody. For detection of myosin heavy chain, deparaffinized sections were incubated directly with alkaline phosphatase–conjugated MY-32 mAb (Sigma), specific for skeletal muscle myosin heavy chain, overnight at 4°C. Sections were developed with diaminobenzidine (DAB Substrate Kit; Vector) for myogenin or with BCIP-NBT (Zymed) for MY-32 mAb and counterstained with nuclear red or fast green.
In addition, trichrome sections were used for morphometric analysis. Stained sections were digitally imaged, and infarct size was determined as the mean percentage of epicardial and endocardial circumference occupied by scar tissue.20 LV endocardial chamber diameter, septal wall thickness, and infarct wall thickness were derived from an average of 5 measurements taken throughout the respective regions.
Statistics
Data were analyzed by 1-factor ANOVA or
paired t test where
appropriate. Pressure-volume relations were analyzed by a
2-factor repeated-measures ANOVA and a least-significant-difference
post hoc test. All data are presented as mean±SEM. A value of
P<0.05 was considered
statistically significant.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Animal Characteristics
Table 1
outlines the animal characteristics of
control, MI, and MI+cell animals at both 3 and 6 weeks after therapy.
All groups had a comparable increase in body weight over time. In
addition, at all time points, hearts from MI and MI+cell groups
displayed comparable degrees of LV hypertrophy of 20%
relative to control animals, as indicated by increased heart weights
and heart–to–body weight ratios. Neither MI nor cell therapy altered
lung or liver wet-to-dry ratios, suggesting the absence of
pulmonary or hepatic congestion.
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Animal Survival, Infarct Size, and
Myoblast Implantation
Experimental MI resulted in 15% acute mortality
rate within 24 hours of operation, whereas the cell implantation
procedure caused no additional animal deaths. Comparable infarct sizes
of 31±1% and 32±1% of the LV were observed in MI and MI+cell
hearts, respectively. Hearts receiving infarction displayed areas of
concentrated fibrosis, whereas noninfarcted control hearts appeared as
continuous viable myocardium with homogenous thickness.
Mortality rate was also similar in MI and MI+cell animals over the
observation period, with no deaths at 3 weeks after implantation and 2
deaths in each group before assessment of cardiac function at 6 weeks
after implantation.
Animals undergoing syngeneic cell therapy displayed no
evidence for cell rejection as determined by excessive
macrophage accumulation in tissue sections. Graft survival was
identified at 9 days
(Figure 1), 3 weeks
(Figure 2, A, C, E, and G), 6 weeks
(Figure 2, B, D, F, and H), and 12 weeks
(Figure 3) after implantation, by immunohistochemical
staining for myogenin (skeletal myoblasts) and for skeletal-specific
myosin heavy chain (skeletal myotubes). Myogenin-positive staining was
observed as early as 9 days
(Figure 1, D, E, and F) and as late as 12 weeks after
implantation
(Figure 3B). Skeletal myosin heavy chain expression was not
detected at 9 days after implantation (data not shown) and was first
observed at 3 weeks after implantation
(Figure 2, E and G). Continued skeletal myosin heavy chain
staining was evident at 6 weeks
(Figure 2, F and H) and 12 weeks
(Figure 3C) after implantation.
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Cell survival was confirmed in 6 of 7 animals at 3 weeks
after therapy and in 7 of 7 animals at 6 weeks after therapy. At all
examined time points, implanted cell grafts ranged in size from large
patches of myoblasts and myotubes to uniformly dispersed single cells
within both the infarct and adjacent peri-infarct regions. Examination
of cell grafts at higher magnification indicated that after 3 weeks,
implanted cells developed the elongated morphology characteristic of
fused polynucleated myotubes. Implanted cells occasionally appeared to
orient parallel to the endocardium and epicardium in similar alignment
to cardiomyocytes. Furthermore, vascular structures were
present within or adjacent to the engrafted areas, suggesting that
blood supply was available for implanted cells. In the nonnecrotic,
peri-infarct region, implanted cells formed regions of myoblasts and
myotubes surrounded by fibrosis
(Figure 2
, C and D).
Maximum Exercise Capacity
As seen in
Figure 4, at baseline, before implantation, both MI and
MI+cell animals exhibited comparable reductions in exercise capacity of
10% relative to control animals, again suggesting similar degrees
of myocardial damage before cell therapy. Control animals maintained a
stable exercise capacity over the observation period. In contrast, MI
animals exhibited a gradual decline in exercise performance
with time, with a >30% reduction in exercise capacity relative to
control animals at 6 weeks. Cell therapy, however, prevented the
continued decline of post-MI exercise capacity, suggesting a protection
against the progressive deterioration of in vivo cardiac
function.
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Ex Vivo Contractile Function
Cardiac contractile function was further investigated
in isolated hearts through generation of systolic
pressure-volume curves
(Figure 5). Noninfarcted control hearts exhibited a typical
rise in systolic pressure with increasing
ventricular volume. Three weeks after implantation (4 weeks
after MI), MI hearts displayed a rightward shift in the
systolic pressure-volume curve
(Figure 5A). Cell implantation prevented this shift in
MI+cell hearts, resulting in greater systolic pressure
generation at any given preload (ventricular volume). There
was, however, no significant difference in the peak systolic
pressure generated at maximum ventricular volume (at an
end-diastolic pressure of 40 mm Hg) among groups. The
beneficial effects of cell therapy were also seen at 6 weeks after
therapy
(Figure 5B), suggesting an improvement of ex vivo cardiac
function with myoblast implantation.
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Ventricular Dilation
In addition to pump dysfunction,
ventricular remodeling characteristically results in
progressive global cavity enlargement. Ventricular dilation
was assessed with diastolic pressure-volume relations,
established in isolated hearts through monitoring of distending
pressures over a range of diastolic volumes
(Figure 6). At all time points during the observation period,
MI hearts exhibited substantially enlarged LVs relative to noninfarcted
control hearts at any given distending pressure, demonstrated by a
rightward repositioning of the pressure-volume curve. Cell therapy,
however, caused a significant reduction in ventricular
cavity dilation, placing hearts from the MI+cell group significantly
leftward of the MI group at both 3 weeks
(Figure 6A) and 6 weeks
(Figure 6B) after implantation, thereby suggesting an
attenuation of deleterious post-MI ventricular remodeling
with cell implantation.
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Ventricular Morphometry
Ventricular remodeling was further
investigated through morphometric analysis of tissue sections
(Table 2). At all time points, MI and MI+cell hearts
exhibited enlarged chamber diameters compared with noninfarcted control
hearts. Six weeks after cell therapy, hearts from the MI+cell group had
a reduced endocardial cavity diameter relative to MI hearts, suggesting
an attenuation of ventricular dilation, similar as seen
with diastolic pressure-volume curves in
Figure 6B. In addition, MI hearts exhibited a decrease in
infarct wall thickness at both 3 and 6 weeks after therapy, suggesting
characteristic post-MI scar thinning and infarct expansion. MI hearts
receiving cell therapy, however, had similar infarct wall thickness
relative to both noninfarcted control and infarcted MI hearts. Septal
wall thickness was comparable among all groups at both 3 and 6 weeks
after therapy.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Previous studies have suggested that implanted myoblasts form viable grafts with the potential to improve regional cardiac function in infarcted myocardium.9 10 11 12 21 Our experiments build on these initial studies and demonstrate the in vivo and ex vivo therapeutic benefits of myoblast implantation on global post-MI ventricular remodeling and cardiac function.
In this model of experimental MI, coronary occlusion release resulted in typical histological and physiological changes characteristic of deleterious post-MI ventricular remodeling,2 4 including an infarct region deficient in endogenous myocytes, infarct wall thinning, ventricular dilation, decreased ventricular function, and impaired exercise tolerance similar to previous reports.14 22 23 24 In addition, MI and MI+cell animals exhibited comparable infarct sizes and similar decreases in maximum exercise capacity before cell implantation, suggesting that differences in cardiac remodeling or function resulting from cell therapy were not due to disparities in initial ischemic injury. Cell implantation at 7 days after MI was selected on the basis of preliminary experiments indicating the greatest degree of cell survival relative to both longer and shorter post-MI time periods. Myoblast cell implantation resulted in focal areas of significant cell graft formation in >90% of animals tested.
LV cavity dilation and exercise intolerance are predictors of cardiovascular morbidity and are often used to gauge efficacy of experimental treatments and to guide therapy.25 26 27 28 Infarcted hearts receiving cell therapy had an attenuation of ventricular dilation assessed both in isolated hearts and LV cross sections. Cell implantation also improved ex vivo contractile function at 6 weeks after implantation and augmented in vivo maximum exercise capacity after MI. No apparent correlation, however, was observed between graft size and cardiac function.
Although global contractile function was increased after cellular implantation, it remains uncertain if implanted myoblasts are actively responsible for force generation during the cardiac cycle. Although several mechanisms may be responsible for the improved cardiac function, our data suggest that enhanced in vivo and ex vivo generated pressures are more likely to be a result of overall attenuation of deleterious ventricular remodeling within the infarcted and viable myocardium rather than an active force generation by myoblasts. In both animals and humans, myocardial pressure–generating capacity and corresponding exercise capacity decline gradually after MI as the infarcted and viable myocardium undergo progressive dilation and remodeling.2 28 Prevention of this dilation, even by physical restraint, results in increased cardiac performance.29 30 Therefore, implanted myoblasts may be responsible for augmented ventricular function through a mechanism involving attenuation of dilation of the viable myocardium and prevention of scar thinning, potentially through an increase in myocardial fibrosis. In addition, it is possible that growth factors, released by implanted cells, may exert a protective effect through stimulation of angiogenesis within the infarct and noninfarct regions.7
Cell therapy has been used effectively in the treatment of a variety of human disorders, from Parkinson’s disease to diabetes, and holds promise in the therapy of many diseases in which nonregenerative cell death or abnormal cellular function plays a role. As with organ transplantation, the limitation of cell therapy revolves around both the availability of human cells and the possibility of immune rejection. It is for these reasons that skeletal myoblast implantation remains highly attractive as a potential medical treatment.8 Skeletal myoblasts are readily available and ensure immunological compatibility of myoblast cells cultured from a skeletal muscle biopsy of the recipient. In addition, myoblasts have been shown to have increased tolerance to ischemia7 and can survive in regions of reduced coronary perfusion, as is often present in patients with coronary artery disease. These data illustrate the therapeutic benefits of syngeneic myoblast implantation after MI on both in vivo and ex vivo indexes of global ventricular dysfunction and deleterious remodeling and suggest that cell therapy may be beneficial after MI.
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Acknowledgments |
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This work was funded by a research grant from Diacrin, Inc.
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Footnotes |
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1 These authors contributed equally to this work.
Received September 13, 2000; revision received November 1, 2000; accepted November 2, 2000.
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