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From the Department of Medicine,* Section ofCardiovascular Sciences, the Section ofCardiology, and the Department ofSurgery, Baylor College of Medicine, theMethodist Hospital, and the DeBakey Heart Center, Houston, Texas
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60%). The samples were
stained with markers for mast cells, mature resident
macrophages, and the monoclonal antibody Mac387 that labels
newly recruited myeloid cells. Dysfunctional segments showed more
extensive fibrosis and higher macrophage density than normal segments.
Among the 23 dysfunctional segments, 12 recovered function as
assessed with echocardiograms 3 months after revascularization.
Segments with postoperative functional recovery had comparable
macrophage and mast cell density with those showing persistent
dysfunction. However, biopsied segments that subsequently
recovered function contained significantly higher numbers of newly
recruited Mac387-positive leukocytes (18.7 ± 3.1
cells/mm2, n = 12
versus 8.6 ± 0.9 cells/mm2,
n = 11; P = 0.009). In
addition, monocyte chemotactic protein-1, a potent
mononuclear cell chemoattractant, was predominantly expressed
in segments with recovery of function. Myocardial hibernation is
associated with an inflammatory response leading to active leukocyte
recruitment. Dysfunctional myocardial segments that show an active
inflammatory reaction have a greater potential for recovery of function
after revascularization. We postulate that revascularization may
promote resolution of the ongoing inflammation,
preventing further tissue injury and fibrosis.
In recent years, substantial evidence has indicated an important role for inflammatory mechanisms in the pathophysiology of cardiovascular disease.13-16 Triggering of the inflammatory process represents the response of vascular tissues to various types of injury. The cytokine cascade associated with myocardial infarction has been extensively studied and seems to be crucial for healing and scar formation, however the potential role of inflammation in mediating pathological changes associated with stable ischemic heart disease has not been adequately investigated. In this study we present evidence for a local inflammatory reaction in the myocardium from patients with myocardial dysfunction because of stable ischemic heart disease undergoing coronary revascularization. We hypothesized that myocardial hibernation may be associated with an active inflammatory process leading to leukocyte recruitment in the cardiac interstitium. We identified newly-recruited leukocytes in the human heart using immunohistochemical staining with the monoclonal antibody Mac387, which recognizes calgranulin, a protein rapidly down-regulated during monocyte to macrophage maturation. Our findings suggest that reversible ischemic myocardial dysfunction is a dynamic process associated with increased synthesis of mononuclear cell chemoattractants and continuous leukocyte recruitment.
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Materials and Methods |
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We enrolled patients scheduled for coronary artery bypass surgery
who had chronic ischemic resting left ventricular dysfunction in the
distribution of 1 coronary artery (70% stenosis). A transthoracic
two-dimensional echocardiogram, dobutamine stress echocardiography, and
201Tl single-photon emission tomography were
performed 2 to 5 days before bypass surgery. During surgery, transmural
myocardial biopsies were obtained from selected myocardial segments,
guided by transesophageal echocardiogram. Patients underwent
transthoracic two-dimensional echocardiography 3 months after surgery
to evaluate changes in regional function. The Institutional Review
Board of Baylor College of Medicine approved the study protocol, and
all patients signed informed consent before enrollment.
Echocardiographic Studies
Imaging was performed in the standard parasternal and apical views
with the patient in the left lateral position (Hewlett Packard Sonos
2500, 2.5- or 3.5-MHz transducer). Regional function was assessed
according to the 16-segment model of the American Society of
Echocardiography, and graded from 1 to 5 (1, normal; 2, mild
hypokinesia; 3, severe hypokinesia; 4, akinesia; and 5, dyskinesia).
Ejection fraction was quantified with the multiple diameter method. The
echocardiographic studies were interpreted without knowledge of the
histopathological data. Regional function recovery was defined by
improvement of 1 grades in wall motion. To match myocardial segments
with coronary distribution, the anterior wall, anterior septum, and
apex were assigned to the left anterior descending coronary artery, the
lateral wall to the circumflex, and the inferoposterior wall and
inferior septum to the right coronary artery.
Dobutamine Echocardiography
Dobutamine infusion was started at 2.5 µg/kg/min and increased at 3-minute intervals to 5, 7.5, 10, 20, 30, and 40 µg/kg/min. Images at baseline, 5, and 7.5 µg/kg/min and peak dobutamine were digitized online in a quad-screen format to provide optimal assessment of viability.17 The response of dysfunctional segments to dobutamine was classified as biphasic (improvement at a low dose with worsening at a high dose), worsening, no change, and sustained improvement (increased thickening without worsening later on). Any response during dobutamine echocardiography was considered indicative of viability.
Rest-Redistribution 201Tl
Rest and 4-hour redistribution
201Tl-single-photon emission tomography scans
were performed after intravenous administration of 3 mCi of
201Tl before surgery. A large field-of-view
rotating 
camera with a high-resolution parallel-hole collimator was
used. Thirty-two frames were acquired over a 180° area (45° left
posterior oblique to 45° left anterior oblique). The reconstructed
images were oriented in the standard short axis, horizontal long axis,
and vertical long axis for interpretation and quantification of
201Tl uptake by nuclear cardiologists unaware of
all other data. Computerized polar maps of the three-dimensional
myocardial radioactivity were generated. A 16-segment model comparable
to that for echocardiography was used. Myocardial
201Tl activity was determined with a region of
interest 40 x 40 pixels (matrix, 128 x 128). The activity
in each segment was normalized to the segment with the highest uptake.
A maximal uptake of 60% at rest or redistribution was considered
indicative of viability, as previously demonstrated.18
Transmural Left Ventricular Biopsies and Tissue Processing
Transmural myocardial biopsies were obtained with a 20-mm 14-gauge Tru-cut biopsy needle at the time of surgery, before cardioplegia. Biopsy of selected segments was directed by transesophageal echocardiography as previously described.19,20 For patients who had segments with normal systolic function, biopsies were acquired from one normal and one dysfunctional segment. For all other patients two dysfunctional segments were biopsied. Segments with high likelihood for viability were targeted by avoiding very thin walls (<7 mm thickness) and echodense myocardium, usually indicative of a completed transmural infarction.21
Experimental Ischemia/Reperfusion Protocols
To develop an immunohistological method of assessing leukocyte
recruitment and inflammatory activity in the heart we used samples from
infarcted canine hearts. An established protocol of canine circumflex
coronary occlusion/reperfusion was used.22,23
Healthy dogs
were instrumented with a hydraulic occluder and underwent 1 hour of
coronary occlusion, followed by reperfusion intervals ranging from 24
hours to 7 days. After the reperfusion periods, hearts were stopped by
the rapid intravenous infusion of 30 meq of KCl and removed from the
chest for sectioning from apex to base into four transverse rings 
1
cm in thickness. The posterior papillary muscle and the posterior free
wall were identified. Tissue samples were isolated from infarcted or
normally perfused myocardium based on visual inspection. Myocardial
segments were fixed in B*5 fixative24
for histological
analysis.
Immunohistochemistry, Histology, and Morphometric Analysis
Samples from human and canine myocardium were fixed in B*5 fixative, to improve antigen preservation,24 and embedded in paraffin. Sections were cut at 3 µm and stained with picrosirius red to identify areas of collagen deposition.25 Serial sections were stained immunohistochemically with the following antibodies: monoclonal anti-tryptase antibody, monoclonal anti-chymase antibody (both from Chemicon, Temecula, CA), monoclonal antibody PM-2K (Biogenesis, Brentwood, NH) that labels mature resident macrophages, monoclonal antibody Mac387 (DAKO, Carpinteria, CA), which identifies newly recruited myeloid cells,26 monoclonal antibody to CD31 (DAKO),27 sheep polyclonal antibody to MMP-9 (The Binding Site, Birmingham, UK), and goat polyclonal antibody to MCP-1 (R&D, Minneapolis, MN). The Mac387 antibody recognizes two calcium-binding myeloid-associated proteins, termed calgranulins, that are not expressed by differentiated monocyte-derived macrophages.28 Staining was performed using a peroxidase-based technique with the Vectastain mouse kit (Vector Laboratories, Burlingame, CA) and developed with diaminobenzidine and nickel (Vector Laboratories). Slides were counterstained with eosin and examined in a Zeiss microscope. Dual immunohistochemical staining was performed combining a peroxidase-based technique for the PM-2K antibody developed with diaminobenzidine and nickel (black), and an alkaline phosphatase-based method for the Mac387 antibody developed with the alkaline phosphatase substrate kit I (Vector Laboratories) (red). Each section was scanned at x200 magnification using a Leaf Lumina digital camera and Adobe Photoshop software (Adobe Systems, San Jose, CA).
Quantitative Analysis
Quantitative analysis was performed using Zeiss Image software. The entire stained biopsied sample (mean area, 3.3 + 0.4 mm2, n = 28) was scanned using Adobe Photoshop software (Adobe Systems), and a Leaf Microlumina digital camera. Collagen staining was expressed as the percentage of the picrosirius-red stained area to the total area of the segment. Macrophage and mast cell density were expressed as cells/mm2. The density of extravascular Mac387-positive cells was used as an index of inflammatory activity. MCP-1 expression was semiquantitated as follows: 0, absent staining; 1, focal staining; 2, diffuse staining in less than half of the section; 3, staining present in more than half of the specimen.
Statistics
Data are presented as mean ± SEM. Unpaired t-test was used to compare the pathological variables between dysfunctional and nondysfunctional segments and segments with and without recovery of function after revascularization. In addition, collagen percent staining was correlated with wall motion score and with macrophage density using the Spearman’s correlation coefficient. Significance was set at P < 0.05.
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Results |
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Fifteen patients (13 men) with ischemic heart disease were
enrolled in the study. The mean age was 62 years (range, 50 to 73
years). The mean left ventricular ejection fraction was 29.4 ±
2%. Ten patients (67%) had hypertension, 9 (60%) were
diabetic, 10 (67%) had angina pectoris, and 8 (56%) had congestive
heart failure. Twenty-eight myocardial segments were used for the
study. Two additional segments were excluded because of inadequate
sampling. Five segments showed normal wall motion, 4 were mildly
hypokinetic, 13 severely hypokinetic, and 6 were akinetic. Thirteen
patients underwent rest-redistribution thallium single-photon emission
tomography before bypass surgery. Mean myocardial
201Tl uptake was 70.2 ± 2.5%. The majority
of biopsied segments were viable [18 of 21 (85.7%) dysfunctional
segments had a thallium uptake 60% and all except one had an uptake
of 50%]. Thirteen patients underwent dobutamine echocardiography
before revascularization, demonstrating that the majority of segments
(17 of 20 dysfunctional segments or 85%) were viable. All patients
underwent complete revascularization without complications. Of the 23
dysfunctional segments, 12 segments recovered function after
revascularization. The mean left ventricular ejection fraction
significantly increased after revascularization (29.4 ± 2% to
38.6 ± 3.3%; P < 0.001, n =
15).
Identification of Mast Cells and Macrophages in the Myocardium—Relation of Macrophage and Mast Cell Density with Collagen Staining and Wall Motion
Collagen content ranged between 6.32% and 72.4%, and correlated
directly with wall motion score (r = 0.55,
P = 0.026, n = 28). Immunohistochemical
staining with the antibody PM-2K (Figure 1)
, that specifically labels mature
tissue macrophages, demonstrated a significant number of macrophages,
predominantly located in areas of fibrosis. Mast cells were identified
as granular interstitial cells with intense expression of the mast
cell-specific proteases tryptase (Figure 1A
and Figure 2A
) and chymase (Figure 2B)
. Macrophage
density directly correlated with percent collagen staining
(r = 0.50, P = 0.007,
n = 28) (Figure 3A)
. In
addition, macrophage density was higher in segments with contractile
dysfunction when compared with normal segments (92.7 ± 4.8
cells/mm2, n = 23,
versus 73.8 ± 4.8 cells/mm2,
n = 5; P = 0.015) (Figure 3B)
. Mast
cell density did not correlate with fibrosis,however mast cell numbers
were significantly higher in akinetic segments (12.2 ± 2.7
cells/mm2, n = 6)
compared to nonakinetic segments (6.57 ± 0.69
cells/mm2, n = 22,
P = 0.038).
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Immunohistochemical staining with the monoclonal antibody Mac387
was used as a marker of active inflammation as previously described.
Mac387 detects an epitope of the calcium-binding protein
MRP14,29
labeling newly recruited myeloid cells and not
mature macrophages. To demonstrate the ability of Mac387
immunohistochemistry to identify newly recruited inflammatory
leukocytes in the injured myocardium, we used sections from the
experimental canine myocardial infarcts. After 1 hour of coronary
occlusion and 24 hours of reperfusion a large number of Mac387-positive
cells was identified in the infarcted area, reflecting extensive
infiltration of the injured territory with myeloid cells (neutrophils
and monocytes) (Figure 4A)
. In contrast,
after 7 days of reperfusion, only a few Mac387-positive cells were
found in the healing area, which was filled with mature macrophages,
identified with the monoclonal antibody PM-2K (Figure 4B)
. Mature
macrophages did not stain for Mac387, indicating that this method can
be used as a marker for new recruitment of leukocytes in the
heart.
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. Hematoxylin and
eosin staining demonstrated that the vast majority of these cells had
mononuclear cell morphology. Dual immunohistochemical staining
combining peroxidase-based labeling with PM-2K and alkaline
phosphatase-based staining with Mac387 demonstrated that mature
resident macrophages significantly outnumbered newly recruited
leukocytes in all biopsied samples (Figure 4, E and F)
. Figure 4, C to F
, shows representative sections from dysfunctional human myocardial
samples; quantitative analysis of the findings will be presented in the
next section. Relation of Functional Recovery with Macrophage and Mast Cell Density—Active Recruitment of Mononuclear Cells in Segments with Functional Recovery
Twelve dysfunctional segments demonstrated recovery of function
after revascularization and 11 segments did not recover. Thallium
uptake was not significantly different between segments with recovery
and those without recovery of function (recovery, 73.1 ± 2.7%;
no recovery, 66.8 ± 4.6%; P = 0.25) Compared
with segments showing persistent dysfunction, those with recovery of
function after revascularization had similar macrophage density
(88.7 ± 4.76 cells/mm2, n =
12, versus 96.8 ± 8.86
cells/mm2, n = 11;
P = NS) and mast cell density (9.2 ± 1.6
cells/mm2, n = 12,
versus 6.2 ± 1.03 cell/mm2,
n = 11, versus P = NS)
(Figure 5)
. However, segments with
recovery had higher numbers of newly recruited Mac387-positive cells
(18.7 ± 3.1 cells/mm2, n =
12, versus 8.6 ± 0.9 cells/mm2,
n = 11; P = 0.009) and a higher ratio
of newly recruited Mac387-expressing cells to mature resident
macrophages (recovery, 0.223 ± 0.045
cells/mm2,
n = 12, versus
no recovery, 0.0965 ± 0.014 cells/mm2,
n = 11; P = 0.019) (Figure 6
and Figure 7
). Serial section staining with an
antibody to matrix metalloproteinase (MMP)-9 demonstrated that a
significant number of newly recruited Mac-387-positive cells showed
intense MMP-9 immunoreactivity (Figure 8)
. Expression of proteolytic enzymes may
suggest the migratory potential of these cells.
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Using immunohistochemical staining we examined MCP-1 protein
localization in the biopsied myocardial samples. Segments with recovery
of function had more intense MCP-1 expression (1.08 ± 0.25
versus 0.27 ± 0.19; P = 0.0179), when
compared with segments without recovery. MCP-1 immunoreactivity was
predominantly localized in cardiomyocytes and microvascular endothelial
cells (identified with CD31 staining) (Figure 9)
from hibernating segments.
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60% in
85.7% (18 of 21 cases) of the dysfunctional segments, and by
dobutamine echocardiography demonstrating a sustained or biphasic
response in 85% (17 of 20 cases) of the dysfunctional segments. Our
study suggests that hibernating myocardium is associated with a dynamic
inflammatory process characterized by myocardial expression of the
monocyte chemoattractant MCP-1 and continuous leukocyte infiltration.
Monocyte-derived macrophages serve as sources of fibrogenic factors and
may mediate fibrosis and contractile dysfunction. Macrophages and Mast Cells in Myocardial Fibrosis
Macrophages and mast cells are thought to play an important role
in fibrotic processes through the production of fibrogenic growth
factors and proteases. Macrophages accumulate in healing myocardial
infarcts23
and their secretory products may regulate
extracellular matrix remodeling. In addition, the number of mast cells
is increased after experimental myocardial infarction32
and in cardiomyopathic hearts.33
Activated mast cells may
be involved in tissue repair through the release of a wide variety of
performed and newly synthesized mediators, such as the potent
fibrogenic protease tryptase and a number of growth factors including
basic fibroblast growth factors, vascular endothelial growth factor,
and transforming growth factor-ß.34
Both
macrophages and mast cells are capable of producing matrix
metalloproteinases,35,36
critical factors in extracellular
matrix metabolism. Accumulation of extracellular matrix proteins
adversely affects myocardial viscoelasticity, leading to diastolic and
systolic dysfunction.37,38
Our findings documented a good
correlation between collagen content and wall motion score. Macrophage
density was higher in dysfunctional myocardial segments and correlated
directly with collagen expression (Figure 2)
. Macrophages appeared to
accumulate predominantly in areas of collagen deposition and may have a
crucial role in regulating extracellular matrix metabolism in the
cardiac interstitium through the production of growth factors and
metalloproteinases. In addition, mast cell numbers were higher in
akinetic segments, but did not correlate with collagen expression.
Recovering Myocardial Segments Demonstrate MCP-1 Expression and Active Leukocyte Infiltration
We did not find a significant difference in macrophage and mast
cell density between segments with recovery of function after
revascularization and segments showing persistent dysfunction. We then
examined new recruitment of Mac387-positive leukocytes in the biopsied
samples as an index of an active inflammatory process. This technique
was validated in a model of experimental canine myocardial infarction
(Figure 4)
, showing a large number of Mac387-positive cells during the
early inflammatory phase, that decreased with maturation of the healing
infarct. In the biopsied human myocardial samples, newly recruited
Mac387-positive leukocytes with morphological characteristics of
mononuclear cells were more frequently found in recovering segments,
suggesting an active dynamic process of monocyte infiltration in these
areas (Figures 6 and 7)
. Mac387-positive cells often demonstrated
expression of MMP-9, exhibiting a matrix-degrading phenotype with a
potential importance in leukocyte migration.39
Segments
with recovery also showed high expression of MCP-1 (Figure 9)
, an
additional indicator of an active inflammatory response. MCP-1 is a
potent monocyte chemoattractant with a significant role in numerous
fibrotic processes40,41
and may be responsible for
continuous recruitment of mononuclear cells in the myocardium. MCP-1
synthesis is up-regulated in patients with dilated
cardiomyopathy,42,43
experimental models of heart
failure,44
and after experimental myocardial
infarction.45,46
Targeted expression of the MCP-1 gene in
murine cardiac muscle induced marked macrophage infiltration, leading
to depressed contractile function, hypertrophy, dilation, and
myocardial fibrosis.47
In addition to its potent
mononuclear cell chemotactic activity, MCP-1 may directly mediate
fibrosis through stimulation of fibroblast collagen and transforming
growth factor-ß expression.48
Inflammation as a Dynamic Reversible Process Mediating Myocardial Hibernation
Fibrosis is the endpoint of an inflammatory process characterized by leukocyte recruitment and activation, fibroblast proliferation, and increased extracellular matrix production. We suggest that myocardial hibernation is characterized by a dynamic, continuous inflammatory process associated with MCP-1 expression in the myocardium and active leukocyte recruitment. Recent experiments from our laboratory demonstrated that a single brief (15 minutes) episode of coronary occlusion induces MCP-1 synthesis in the canine myocardium for at least 5 hours after reperfusion.49 It has been recently suggested that the phenotype of hibernating myocardium may arise from repetitive episodic ischemia with or without an underlying reduction in baseline blood flow. We propose that in the hibernating myocardium repetitive nonlethal ischemic insults may lead to prolonged MCP-1 synthesis and continuous recruitment of mononuclear cells. This dynamic inflammatory process may slowly induce tissue injury, extracellular matrix remodeling, and fibrosis through the production of growth factors and metalloproteinases by monocyte-derived macrophages.
It is possible that this dynamic process has several stages and that we are sampling in a continuum. The early stage of high inflammatory activity may be associated with chemokine induction and leukocyte recruitment. Reversibility through revascularization may depend on timely down-regulation of the inflammatory process, decreased MCP-1 expression and diminished monocyte infiltration. This could lead gradually to lower numbers of resident macrophages and diminished synthesis of fibrogenic substances. In contrast, segments with persistent dysfunction may have reached a point of no return, where long-standing hypoxia-mediated inflammatory reaction has led to extensive tissue injury, lower levels of MCP-1 expression, and decreased active infiltration with inflammatory cells. In this stage there is no reversible inflammatory component and revascularization may have little to offer.
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Acknowledgements |
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Footnotes |
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Supported by the National Institutes of Health (grant HL-42550 to M. L. E. and N. G. F.), the DeBakey Heart Center, the John S. Dunn, Sr., Trust Fund (to W. A. Z.), and the Methodist Hospital Foundation (to N. G. F.).
Accepted for publication January 10, 2002.
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