© 1998 American Heart Association, Inc.
Original Contributions |
Time-Dependent Changes in Matrix Metalloproteinase Activity and Expression During the Progression of Congestive Heart Failure
Relation to Ventricular and Myocyte Function
From the Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston, SC.
Correspondence to Francis G. Spinale, MD, PhD, Division of Cardiothoracic Surgery, Room 418 CSB, 171 Ashley Ave, Medical University of South Carolina, Charleston, SC 29425.
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Abstract |
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Abstract—The development of congestive heart failure (CHF) is associated with left ventricular (LV) dilation and myocardial remodeling. However, fundamental mechanisms that contribute to this remodeling process with the progression of CHF remain unclear. The matrix metalloproteinases (MMPs) have been demonstrated to play a significant role in tissue remodeling in a number of pathological processes. The present project tested the hypothesis that the LV dilation and remodeling during the progression of CHF is associated with early changes in MMP expression and zymographic activity. LV and myocyte function, collagen content, and MMP expression and zymographic activity were serially measured during the progression of CHF caused by pacing-induced supraventricular tachycardia (SVT) in pigs. After 7 days of SVT, LV end-diastolic dimension and myocyte length both increased by 15% from control values, and LV fractional shortening fell by 20%. At the level of the myocyte, percent shortening fell by 16% after 7 days of SVT, with no change in the steady-state velocity of shortening. Longer durations of SVT caused progressive LV dilation, LV pump failure, and myocyte contractile dysfunction. Specifically, 21 days of SVT resulted in a >50% increase in LV dimension, a 56% fall in LV fractional shortening, and a 33% decline in myocyte velocity of shortening. The decline in LV and myocyte function with 21 days of SVT was accompanied by signs and symptoms of CHF. Thus, SVT causes time-dependent changes in LV geometry and function and the subsequent development of CHF. LV myocardial collagen content and confluence fell by >25% after 7 days of SVT and were accompanied by an 80% increase in LV myocardial MMP zymographic activity against the substrate gelatin. After 14 days of SVT, total LV myocardial collagen content was reduced by 24%, and LV myocardial MMP zymographic activity increased by >100% from control values. Interstitial collagenase (MMP-1), stromelysin (MMP-3), and 72-kD gelatinase (MMP-2) were increased by
2-fold after 7 days of SVT. LV MMP zymographic activity and
abundance remained elevated with longer durations of SVT. The results
of the present study demonstrated that in this model of CHF, early
changes in LV myocardial MMP zymographic activity and protein levels
occurred with the initiation and progression of LV dilation and
dysfunction. These findings suggest that an early contributory
mechanism for the initiation of LV remodeling that occurred in this
model of developing CHF is enhanced expression and potentially
increased activity of LV myocardial MMPs.
Key Words: heart failure • metalloproteinase • myocardial remodeling
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Introduction |
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An important event in the progression to CHF is LV dilation and subsequent pump dysfunction.1 2 3 These past clinical observations suggest that LV remodeling is an important initiating event in the transition to severe CHF. However, the cellular and molecular mechanisms that play a direct contributory role in the initiation and progression of changes in LV geometry and function during the development of the CHF process are unknown. Chronic pacing-induced tachycardia in animals causes well-defined, predictable, and progressive LV dilation, contractile dysfunction, and neurohormonal system activation.4 5 6 7 8 9 10 11 12 13 14 15 These functional and neurohormonal changes are similar to the clinical spectrum of CHF.1 2 3 16 17 Therefore, this chronic pacing model may provide an opportunity to identify the early and contributory events responsible for the progression of LV dilation and dysfunction that occurs with CHF. It has been demonstrated that the structure and composition of the fibrillar collagen matrix, which provides structural integrity of adjoining myocytes,18 19 20 21 are significantly altered in pacing-induced CHF.7 9 12 13 14 15 22 Furthermore, we have recently reported that concomitant ACE inhibition with chronic tachycardia preserved myocardial collagen content and reduced the LV dilation associated with this disease process.9 These past studies provide indirect evidence that changes in the myocardial collagen matrix contribute to the LV dilation and subsequent dysfunction that occur in this rapid-pacing model of CHF. Accordingly, the overall goal of this project was to define the time-dependent structural and molecular events that occur within the extracellular matrix during the progression of pacing-induced CHF.
The MMPs constitute an important enzyme system that has been demonstrated to contribute to the tissue remodeling process.23 24 25 26 27 28 29 30 The MMPs are a class of zinc-dependent enzymes that have a high specificity for components of the extracellular matrix.23 24 25 26 27 28 29 30 Increased expression and activity of MMPs have been identified in pathological processes such as tumor metastases and rheumatoid arthritis.24 28 29 Increased MMP expression and activity have been identified in atherosclerotic lesions31 and have been implicated in atheroma formation and plaque rupture.30 Increased myocardial MMP activity has also been reported with the development of severe CHF, such as in cardiomyopathic disease.32 33 34 However, whether increased MMP zymographic activity and abundance are early events in the evolution of the CHF process remains unexplored. Accordingly, the present study was designed to determine the relationship of time-dependent changes in MMP expression and zymographic activity to LV and myocyte function and geometry during the progression of CHF.
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Materials and Methods |
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The present project used a model of chronic SVT in pigs that has been shown clearly in previous studies to produce signs and symptoms of CHF after 3 weeks of SVT.5 6 7 8 LV geometry and function, neurohormonal system activity, myocyte contractility, myocardial collagen content and structure, and MMP expression and activity were measured with each week of SVT.
Model of Pacing CHF and Experimental Design
Thirty Yorkshire pigs (20 to 25 kg, male) were chronically
instrumented in order to measure LV function and arterial
blood pressure while they were conscious. The pigs were
anesthetized with isoflurane (3%, 1.5 L/min) and nitrous oxide
(0.5 L/min), intubated with a cuffed endotracheal tube, and ventilated
at a flow rate of 22 mL · kg-1 ·
min-1 and a respiratory rate of 15/min. The left
internal carotid artery was exposed, and a catheter was connected to a
vascular access port (model GPV, 9F, Access Technologies), advanced to
the aortic arch, and sutured in place. The access port was buried in a
subcutaneous pocket over the thoracolumbar fascia. Through a left
thoracotomy, a shielded stimulating electrode was sutured onto the left
atrium, connected to a modified programmable pacemaker (model 8329,
Medtronic, Inc), and buried in a subcutaneous pocket. The pericardium
was left open, the thoracotomy was closed, and the pleural space was
evacuated of air. The animals were allowed a recovery period of 7 to 10
days. Six pigs each were then randomly assigned to undergo 7, 14, or 21
days of SVT or to serve as sham-operated controls. In six pigs,
measurements were obtained throughout the 21-day pacing protocol in
order to determine temporal changes with respect to in vivo indices of
LV contractile performance. Thus, for indices of LV size and
function and neurohormonal activity, observations were performed on 12
pigs at baseline and with each week of SVT. With respect to LV myocyte
function, collagen biochemistry, morphometry, and MMP zymographic
activity, complete studies were performed on six pigs in the control
state and with each week of SVT. All animals used in the present
study were treated and cared for in accordance with the National
Institutes of Health's Guide for the Care and Use of Laboratory
Animals (National Research Council, 1985, NIH publication
86–23).
LV Function and Plasma Collection
Indices of LV pump function were obtained from
simultaneously recorded pressure and
echocardiographic measurements previously described by
this laboratory.5 6 7 8 9 Briefly, the animals were
sedated with diazepam (20 mg PO, Valium, Hoffmann-La Roche) and placed
in a custom-designed sling that allowed the animal to rest comfortably.
The pacemaker was deactivated (SVT groups only). All studies
were performed after a 30-minute acclimation period with the animals in
the conscious state and without additional use of sedation. The
vascular access port was entered using a 12-gauge Huber needle (Access
Technologies), and basal resting arterial pressure and
heart rate were recorded. Pressures from the fluid-filled aortic
catheter were obtained using an externally calibrated transducer
(Statham P23ID, Gould). Two-dimensional and M-mode
echocardiographic studies (ATL Ultramark 7, 3.5-MHz
transducer) were used to image the LV from a right parasternal
approach. Echocardiographic data were measured with the
use of American Society of Echocardiography
criteria, including the leading-edge convention. The two-dimensional
parasternal long-axis view of the LV was first recorded in order to
precisely define the LV long axis and papillary muscles. A
perpendicular view with respect to the LV long axis was then obtained
in order to obtain the two-dimensional parasternal short-axis view. LV
short-axis two-dimensional and M-mode echocardiographic
recordings were then obtained. The LV dimensions were performed
from the septum to the posterior LV free wall with the cursor directed
between the papillary muscles. LV end-diastolic and
end-systolic dimension, LV end-systolic and
end-diastolic wall thickness, and fractional shortening
were computed from the two-dimensional targeted M-mode
recordings.8 10 35 Peak circumferential
global average wall stress was computed using a spherical model of
reference8 12 :
(g/cm2)=[PD/4 hours(1+h/D)]x1.36, where
P is aortic systolic pressure, D is minor-axis
dimension at end diastole, and h is wall thickness. After
steady-state LV function measurements, 35 mL of blood was drawn from
the arterial access port into chilled tubes containing EDTA
(1.5 mg/mL). The blood samples were immediately centrifuged
(2000g, 10 minutes, 4°C), and the plasma was decanted into
separate tubes, frozen in a dry ice/methanol bath, and stored at
-80°C until the time of assay.
LV fractional shortening was measured after incremental increases in LV
myocardial wall stress8 36 37 38 in five pigs in
the normal state and with each week of SVT. Simultaneous
recordings of two-dimensional targeted M-mode echocardiograms
and aortic pressure were obtained by a phenylephrine
infusion started at a rate of 1.3 µg ·
kg-1 · min-1 and
increased in such a manner as to obtain three to six isochronal LV
peak circumferential wall stress versus shortening points for each pig
with each week of SVT. This approach for measuring the LV
shortening-stress relation has been described previously by this
laboratory and others.8 36 37 38 Determination of
the LV shortening-afterload relation was chosen, since it provides a
relative index of LV contractile performance and does not
require theoretical muscle models and development of LV pressure-volume
loops.39 40 However, this approach may not
completely describe in vivo LV myocardial contractile
performance; accordingly, the LV systolic stiffness
constant was determined using methods described
previously.41 42 Briefly, isochronal LV wall
stress-strain values were obtained under ambient conditions and after
phenylephrine infusion. The LV myocardial stiffness
constant k, was determined from the following exponential
relationship: =Cekln(1/h), where is
wall stress and ln(1/h) is the natural logarithm of the reciprocal of
LV wall thickness. This in vivo index of LV myocardial
performance has been shown previously to be unaffected by
changes in LV loading conditions and
volumes.41 42
Terminal Study: Myocardial Sampling and Myocyte Isolation
After the final set of LV function measurements and plasma
collection, the animals were anesthetized as described in the
preceding section, a sternotomy was performed, and the heart was
quickly extirpated and placed in a phosphate-buffered ice slush. The
great vessels, atria, and right ventricle were carefully trimmed away,
and the LV was weighed. The region of the LV free wall incorporating
the circumflex artery (5x5 cm) was excised and prepared for myocyte
isolation. The region of the LV free wall composing the left anterior
descending artery (3x5 cm) was cannulated and prepared for perfusion
fixation. The posterior region of the LV free wall (3x3 cm) was
snap-frozen in liquid nitrogen for subsequent biochemical
analysis of collagen content and MMP zymographic activity and
expression.
Myocytes were isolated from the LV free wall using methods described by this laboratory previously.5 6 7 9 Briefly, the left circumflex coronary artery was perfused with a collagenase solution (0.5 mg/mL, Worthington, type II; 146 U/mg) for 35 minutes. The tissue was then minced into 2-mm sections and gently agitated. After 15 minutes, the supernatant was removed and filtered, and the cells were allowed to settle. The myocyte pellet was then resuspended in DMEM/F-12 (GIBCO Laboratories). The number of viable myocytes was counted at x100 magnification using a hemocytometer (Reichert-Jung, Cambridge Instruments Inc) and resuspended to a final concentration of (5x104 cells/mL). Viable myocytes were defined as those cells that maintained a rod shape and were quiescent in culture. By use of this myocyte isolation method, a high yield (85±5%) of viable myocytes was obtained in all LV preparations used in the present study. Viable myocytes were defined as those cells that retained a rod shape, were calcium tolerant, responded to electrical stimulation, and excluded trypan blue.
Neurohormonal Measurements
The plasma samples were assayed for renin activity, endothelin
concentration, and catecholamine levels. Plasma renin
activity was determined by computing angiotensin I
production using a radioimmunoassay (NEA-026, New England
Nuclear). The interassay variation for the measurement of plasma renin
activity was 15%. For the endothelin assays, the plasma was first
eluted over a cation exchange column (C-18 Sep-Pak, Waters Associates)
and then dried by vacuum centrifugation. The samples
were reconstituted in 0.02 mol/L borate buffer, and a high-sensitivity
radioimmunoassay was performed (RPA545, Amersham). The recovery from
the extraction procedure was 75±5%, which was based on plasma-spiked
standards (4 to 20 fmol/mL). The interassay variation was 10%, and the
intra-assay variation was 9% for the endothelin radioimmunoassay
procedure. Plasma norepinephrine and epinephrine
were measured using HPLC and were normalized to picograms per
milliliter of plasma. All assays were performed in duplicate.
LV Myocyte Contractile Function
Isolated myocyte function was examined as previously reported by
this laboratory.5 6 7 9 Briefly, a
thermostatically controlled chamber (37°C) containing a volume of 2.5
mL and two stimulating platinum electrodes was used to image the
isolated myocytes on an inverted microscope (Axiovert IM35, Zeiss Inc).
A x20 long-working-distance Hoffmann modulation contrast objective
(Modulation Optics Inc) was used to image the myocytes. Myocyte
contractions were elicited by field-stimulating the tissue chamber at 1
Hz (S11 stimulator, Grass Instruments) using current pulses of
5-millisecond duration and voltages 10% above contraction threshold.
Myocyte motion signals were captured and input through an edge-detector
system (Crescent Electronics). The distance between the left and right
myocyte edges was converted into a voltage signal, digitized, and input
to a computer (No. 80386, model ZBV2526, Zenith Data Systems) for
analysis. Parameters computed from the digitized
contraction profiles include percent shortening, velocity of
shortening, velocity of relengthening, time to peak contraction, and
duration of contraction. In addition to basal measurements of
contractility, myocyte function was determined after
ß-adrenergic receptor stimulation with 25 nmol/L isoproterenol.
LV Myocardial Structure
The LV section for microscopic analysis was perfused
with a buffered sodium cacodylate solution containing 2%
paraformaldehyde and 2% glutaraldehyde
solution (pH 7.4, 325 mOsm) for 20 minutes using a perfusion pressure
of 100 mm Hg.9 12 LV myocardial samples
were then prepared for scanning electron microscopy and light
microscopic examination. For scanning electron microscopy,
perfusion-fixed LV myocardial samples were flash-frozen in liquid
nitrogen and freeze-fractured.9 12 13 15 The
freeze-fractured samples (0.25x0.25 cm) were then dehydrated and
critical point–dried (Ladd Research Industries). The samples were
mounted on 10x10-mm stubs using conductive adhesive tape (Scotch
commercial tape, 3M Inc) and sputter-coated with gold (Hummer II,
Technics). The sections were examined in a JOEL JSM-25S scanning
electron microscope at an accelerating voltage of 15 kV. LV samples
were prepared in triplicate, and 10 photomicrographs of the
extracellular space were obtained from each sample at a final
magnification of x4000. These photomicrographs were coded and
evaluated using the following semiquantitative scale developed by
Bishop et al22 : 1, an absent collagen weave; 2,
reduced collagen distribution; 3, normal collagen density and
distribution; 4, increased collagen density; and 5, significantly
increased collagen density and distribution. The categorical grading
system was performed in a blinded fashion in which the photomicrograph
codes were not broken until the completion of the study.
Light-microscopic examination was performed on the perfusion-fixed LV myocardium in order to determine myocyte cross-sectional area, the percent area occupied by extracellular space, and the connectivity of the extracellular network.12 15 For examination of the extracellular matrix, LV sections were stained using the picrosirius histochemical technique.14 21 43 The stained LV sections were then digitized at a final magnification of x320 and analyzed using an image analysis system (Zeiss/Kontron, IBAS). The percent area of extracellular staining was computed from 15 random fields within the midmyocardium in order to exclude large epicardial arteries and veins and any cutting or compression artifact. The integrity or continuity of the collagen network was examined in these same fields by using a grid pattern of 100-µm horizontal and vertical lines.44 The percentage of collagen profiles intersecting this grid was computed and was used as an index of the integrity of the collagen latticework.12 15
For determination of myocyte cross-sectional area, full-thickness perfusion-fixed LV myocardial sections were stained with hematoxylin and eosin. These sections were imaged using an epifluorescence illuminator with a rhodamine filter at a magnification of x1000. Myocytes in a cross-sectional orientation were digitized and analyzed using the previously described image analysis system. Only those myocytes in which the nucleus was centrally located within the cell were digitized and analyzed in order to ensure uniformity for the measurement of cross-sectional area.
LV myocardial collagen content was also determined by a biochemical assay for hydroxyproline using methods well described previously.12 Briefly, the LV midmyocardial sections were weighed and lyophilized. The sections were then hydrolyzed and measured spectrophotometrically (550 nm) after reaction with Ehrlich's reagent.12 A conversion factor of 7.46 was used to convert the final hydroxyproline values to total collagen values. All measurements were performed in duplicate and expressed as collagen content in milligrams per gram wet weight of LV myocardium.
LV Zymographic MMP Activity
After a stringent washing in ice-cold saline, the LV myocardial
samples were homogenized (three 30-second bursts) in 5 mL
of an ice-cold extraction buffer (1:3 wt/vol) containing cacodylic acid
(10 mmol/L), NaCl (0.15 mol/L), ZnCl (20 mmol/L),
NaN3 (1.5 mmol/L), and 0.01% Triton X-100
(pH 5.0). The maintenance of a low pH and temperature prevented
proteolytic activation during the extraction process. The
homogenate was then centrifuged (4°C, 10 minutes,
1200g), and the supernatant was decanted and saved on ice.
The pellet was resuspended in extraction buffer, and the procedure was
repeated in triplicate. The samples were then raised to a pH of 7.6
using Tris buffer and concentrated using an Amicon B-15 concentrator
(Amicon Inc) at 4°C. Final protein concentration of the myocardial
extracts was determined using a standardized
colorimetric assay (Bio-Rad protein assay). These
extracts were aliquoted, immediately flash-frozen using liquid
nitrogen, and stored at -80°C until the time of assay.
The myocardial extracts were directly loaded onto electrophoretic gels (SDS-PAGE) containing gelatin (0.5 mg/mL, Sigma Chemical Co).28 32 33 34 45 46 A homogeneous impregnation of this MMP substrate into the gels was facilitated by constant stirring and heating to 45°C before casting. The myocardial extracts at a final protein content of 4 µg were loaded onto the gels using a 3:1 sample buffer (10% SDS, 4% sucrose, 0.25 mol/L Tris-Cl, and 0.1% bromophenol blue, pH 6.8). The gels were run at 15 mA/gel through the stacking phase (4%) and at 20 mA/gel for the separating phase (10%), maintaining a running buffer temperature of 4°C. After SDS-PAGE, the gels were washed twice in 2.5% Triton X-100 for 30 minutes each, rinsed twice in PBS, and incubated for 3 hours in a substrate buffer at 37°C (50 mmol/L Tris-Cl, 5 mmol/L CaCl2, 0.5% Brij-35, and 0.02% NaN3, pH 8). After incubation, the gels were stained using 0.1% amido black, destained in water, digitized, and analyzed as described in the following paragraph. In order to provide a means of comparison with respect to the zymographic activity obtained from the present study, samples were collected from the cell culture medium of the human fibrosarcoma HT 1080 cell line (American Type Culture Collection) as described previously.28 45 Briefly, HT 1080 cells were grown to confluence in DMEM with 10% fetal calf serum and then incubated for 24 hours in serum-free medium containing 1 mmol/L insulin and 5 mg/L transferrin. After which, the cell cultures were incubated for 24 hours in the presence and absence of 100 ng/mL of PMA (Sigma).45 Treatment of this cell culture system with a phorbol ester has been demonstrated previously to increase MMP zymographic activity.28 45 After this incubation period, the cell culture medium was drawn off, concentrated, and subjected to zymography.
The zymograms were digitized using a Kodak DCS 420 digital camera
(Kodak Inc), which provides high resolution (1500x1000 pixels) and
consistent exposure control between scans. The proteolytic
regions for each sample were determined by quantitative image
analysis (Gel-Pro Analyzer, Media Cybernetics). A
3-pixel-wide profile was constructed along the long axis of each lane
and plotted as a two-dimensional array with line intensity on the
y-axis and molecular weight on the x-axis. The peaks that correspond to
proteolytic zones were summated by two-dimensional integrated optical
density (OD) as follows: 
OD(x,y)=1/{-log
[intensity(x,y)-black reference/incident light-black reference]}.
These two-dimensional integrated OD values were converted to pixel
values on the basis of internal standardization with bacterial
collagenase (0.1 to 1 µg/mL, Worthington, type II; 146
U/mg). Zymographic analysis was performed in control and weekly
SVT samples on the same gel using identical protein concentrations.
LV Myocardial MMP Abundance
Relative abundance of MMPs was examined in LV myocardial
extracts using standard immunoblotting
procedures.26 27 28 Before
immunoblotting, the LV myocardial extracts were eluted
over an anion exchange column as previously
described.47 Briefly, myocardial extracts were
chromatographed on a DEAE column (Bio-Rad Laboratories) in
20 mmol/L Tris-HCl and 10 mmol/L CaCl2,
containing 0.02% NaN3, in which stepwise pH
changes were performed in order to elute the MMPs of interest.
Fractions (1 mL) were collected at pH 9.0 for MMP-1 and at pH 7.5 for
MMP-2 and -3. This chromatographic procedure was optimized
for these MMP species in preliminary immunoblotting
studies. The LV myocardial extracts were lyophilized and reconstituted
in electrophoresis buffer (0.1 mol/L Tris-HCl and 0.2 mol/L
dithiothreitol, pH 6.8, containing 4% SDS and 0.01% bromophenol
blue). LV extracts (3.0 µg) were then loaded on an 8%
SDS-polyacrylamide gel and separated at 40 mA in 0.02 mol/L
Tris-base and 0.2 mol/L glycine, pH 6.8, containing 0.1% SDS. The
separated proteins were transferred at 100 V to a nitrocellulose
membrane (Trans-blot transfer medium, 0.45 µm, Bio-Rad
Laboratories) in 0.025 mol/L Tris-base and 0.2 mol/L glycine, pH 8.2,
containing 20% methanol (vol/vol).48 49
Membranes were blocked with 0.2 mol/L Tris-base and 1.4 mol/L NaCl, pH
7.6, containing 5% powdered goat milk, 0.1% Tween 20, and 0.02%
NaN3. After they were washed with 0.2 mol/L
Tris-base and 1.4 mol/L NaCl, pH 7.6, containing 0.1% Tween 20,
membranes were incubated overnight at 4°C in monoclonal antibodies
corresponding to MMP-1, -2, or -3 (1.0 µg/mL, Oncogene Research
Products). The antibody for MMP-1 (clone 41–1E5) was a mouse
monoclonal generated by immunizing mice with the oligopeptide
corresponding to residues 332 to 350 of human MMP-1. The antibody for
MMP-2 was a mouse monoclonal antibody generated by immunizing mice with
the oligopeptide corresponding to residues 524 to 539 of human MMP-2
(clone 42–5D11). The antibody for MMP-3 was a mouse monoclonal
antibody generated by immunizing mice with human pro-MMP-3 purified
from the conditioned media of rheumatoid synovial fibroblasts. The
primary antisera were diluted in 0.2 mol/L Tris-base and 1.4 mol/L
NaCl, pH 7.6, containing 1% powdered goat milk, 0.1% Tween 20, 0.08%
BSA, 13% DMEM/F-12 cell culture medium (GIBCO Life Technologies), and
0.02% NaN3. After a stringent washing, the
membranes were incubated for 1 hour in horseradish
peroxidase–conjugated goat anti-mouse antibody (1:5000 dilution,
Bio-Rad Laboratories). The membranes were washed again, and the
horseradish peroxidase–conjugated secondary antibody was
activated with peracid and luminol (ECL Western blotting
detection reagents, Amersham Life Science). The luminescent signal was
detected by exposure to x-ray film (Eastman Kodak Co) for exactly 5
minutes. Positive controls for MMP-2 and -3 were included in all
immunoblots and were obtained from human epithelial and
fibroblast cell lines (AG771 and AG770, respectively, Chemicon
International Inc). Cell culture medium from a PMA-stimulated HT 1080
fibrosarcoma cell line45 50 was also used as a
positive control for immunoblotting. Prestained
molecular weight markers (Bio-Rad Laboratories) were used to ensure
adequate protein separation and transfer. The intensity of the signal
was analyzed as described in the previous paragraph and
normalized to control values.
Data Analysis
Indices of LV and myocyte function, collagen structure and
composition, and MMP zymographic activity and expression were compared
with each week of SVT using multivariate ANOVA. If the
ANOVA revealed significant differences, pairwise tests of individual
group means were compared using Bonferroni probabilities. The LV
shortening-stress data obtained at each week of pacing were fit to a
polynomial regression model. Comparisons of the coefficients obtained
from the LV shortening-stress relation were compared using the
t distribution. For comparisons of neurohormonal profiles,
the Student-Newman-Keuls test was used. With respect to the myocyte
function data, each pig was considered a complete block. Thus, the
numbers of myocytes studied from each pig were considered repeated
observations within each block. The summary statistics include the
number of myocytes studied from each group; however, all statistical
comparisons were performed on a per pig (block) basis. The categorical
scores obtained from the scanning electron micrographs were compared
between groups using 
2 analysis. All
statistical procedures were performed using the BMDP statistical
software package (BMDP Statistical Software Inc). Results are
presented as mean±SEM. Values of P<.05 were
considered to be statistically significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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All of the pigs that were assigned to undergo chronic SVT successfully completed the protocol. The animals that underwent 3 weeks of chronic SVT exhibited signs and symptoms of CHF, which included ascites, tachypnea, and hepatomegaly.
LV Function and Neurohormonal Profiles With the Progression of
SVT-Induced CHF
Weekly changes in LV function with SVT are summarized in Table 1
. All measurements were performed with
the pacemaker deactivated and with the animals in the
conscious state. After 7 days of chronic SVT, LV
end-diastolic dimension increased, wall thickness was
reduced, and LV peak systolic wall stress was increased. These
changes in LV geometry after 7 days of SVT were associated with a
decline in LV fractional shortening. After 14 days of SVT, the basal
resting heart rate was increased from control levels. After 14 days of
SVT, LV end-diastolic dimension and peak wall stress were
significantly increased, and wall thickness was significantly reduced
from both control and 7-day SVT values. The changes in LV geometry and
wall stress that occurred after 14 days of SVT were associated with a
significant decline in LV fractional shortening compared with control
and 7-day SVT values. After 21 days of SVT, a further increase in LV
end-diastolic dimension and wall stress was observed, along
with a continued decline in LV fractional shortening. After 21 days of
SVT, mean aortic pressure was significantly reduced. LV mass did not
significantly change at any time point with chronic SVT. Thus,
time-dependent changes in LV pump function and geometry occurred during
the development of SVT-induced CHF.
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In order to more carefully examine LV myocardial performance,
the LV ejection-afterload relation was serially measured under normal
conditions and with each week of SVT, and the results from these
studies are shown in Fig 1. In normal
conscious pigs, the LV fractional shortening fell in a proportional
manner with increased LV wall stress, and this curvilinear relation is
consistent with the force-velocity relation obtained in human
and animal subjects.36 37 38 39 40 Since this relation
was curvilinear, the isochronal LV fractional shortening–wall
stress points were subjected to polynomial regression. The results from
the regression analysis with each week of SVT are shown in
Table 2. After 7 days of SVT, the
isochronal LV fractional shortening–wall stress points fell below
the control curvilinear relation, but the regression coefficients were
not different from control values. However, with longer durations of
SVT, this relation shifted down and to the right, with a significant
change in the regression coefficients computed from this relationship.
In addition to the LV shortening-stress relation, LV myocardial
performance was also examined through computing the LV
systolic stiffness constant with each week of SVT (Fig 2). After 7 days of SVT, the LV
systolic stiffness constant was similar to control values.
However, after 2 and 3 weeks of SVT, the LV systolic stiffness
constant was significantly lower than control values. Thus, using
either the stress-shortening relation or the systolic stiffness
constant as indices of LV myocardial performance, a significant
and time-dependent fall in LV myocardial function was observed during
the progression of SVT-induced CHF.
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In light of the fact that activation of several neurohormonal systems
commonly occurs during the development of CHF, weekly changes in
neurohormonal profiles with each week of SVT were determined and are
summarized in Table 1
. Plasma norepinephrine increased by
3-fold from control values after 7 days of SVT and increased another
2-fold from these elevated values after 21 days of SVT. Plasma
endothelin levels significantly increased after 14 days of SVT and
increased further after 21 days of SVT. Similarly, plasma renin
activity significantly increased by over 120% after 14 days of SVT and
by over 250% after 21 days of SVT compared with control values. Thus,
consistent with clinical forms of severe
CHF,16 17 the development and progression of
SVT-induced CHF was associated with increased neurohormonal system
activity.
LV Myocyte Geometry and Contractile Performance With
Progression of SVT-Induced CHF
Since LV dilation occurred in the absence of
hypertrophy with the development of SVT-induced CHF,
significant myocardial remodeling must have occurred. Accordingly,
isolated LV myocyte geometry was examined with each week of SVT.
Myocyte cross-sectional area was determined from >700 myocyte profiles
from each group, and this analysis resulted in an approximate
gaussian distribution for this parameter. After 7 days of
chronic SVT, myocyte cross-sectional area was unchanged from control
values (356±4 versus 363±5 µm2,
P>.70). However, after 14 and 21 days of SVT, myocyte
cross-sectional area significantly decreased (305±4 and 282±4
µm2, respectively) from control values
(P<.05).
Steady-state myocyte contractile function for controls and after each
week of SVT are shown in Table 3. Resting
myocyte length was increased after 7 days of SVT and significantly
increased from this value after 21 days of SVT. After 7 days of SVT,
myocyte steady-state percent shortening was reduced from control
values, but shortening velocity was unchanged. After 14 and 21 days of
SVT, steady-state myocyte contractile performance was
significantly reduced from both control and 7-day SVT values.
Specifically, after 14 days of SVT, steady-state percentage and
velocity of shortening fell by 25% from control values. After 21 days
of chronic SVT, myocyte percentage and velocity of shortening was
reduced by over 30% from control values. Myocyte contractile function
was also examined after ß-adrenergic receptor stimulation with the
nonselective ß-receptor agonist isoproterenol. The results from this
portion of the study are summarized in Table 3. Myocyte ß-adrenergic
responsiveness was reduced after 7 days of SVT. The reduced myocyte
ß-adrenergic response continued to deteriorate with longer durations
of SVT. For example, compared with control values, myocyte velocity of
shortening was 15% lower after 7 days of SVT and 28% lower after 14
days of SVT and was reduced by >50% after 21 days of SVT. Thus, the
progression of SVT-induced CHF was accompanied by significant changes
in isolated LV myocyte geometry, contractility, and
inotropic responsiveness.
|
LV Myocardial Collagen With Progression of SVT-Induced CHF
Fibrillar collagen structure and composition were examined during
the development of SVT-induced CHF, and the results from this
analysis are summarized in Fig 3.
Morphometric analysis of picrosirius-stained LV myocardial
sections revealed a significant reduction in the confluence, or
connectivity, of the collagen matrix after 7 days of SVT. The confluent
nature of the collagen weave continued to decline with longer durations
of SVT. Representative scanning electron micrographs
taken of control myocardium and of myocardial samples taken
after 7, 14, and 21 days of SVT are shown in Fig 4. In control myocardium, a
fine weave of collagen was observed within the interstitial
space. After 7 days of SVT, this collagen weave surrounding individual
myocytes appeared significantly disrupted. After 14 days of SVT, the
fine fibrillar nature of the collagen weave could not be readily
appreciated, and the interstitial spaces between adjacent
myocytes appeared devoid of collagen fibrils. After 21 days of SVT,
significant disruption and dissolution of the collagen matrix could be
readily observed in the majority of LV myocardial samples.
Semiquantitative grading of these scanning electron micrographs
revealed a pattern similar to that observed at the light-microscopic
level using computer-assisted morphometry. Specifically, after 7 days
of SVT, the grade of the fibrillar collagen weave was reduced from
control values (2.4±0.3 versus 3.3±0.1, respectively;
P<.05) and significantly fell from this value after 21 days
of SVT (1.8±0.2, P<.05). In order to more carefully
quantify biochemical changes in LV myocardial collagen,
analysis of hydroxyproline was performed on LV midmyocardial
samples and converted to collagen values (Fig 3). LV myocardial
collagen content fell in a time-dependent fashion with SVT, and a
significant fall from control values was observed after 7 days of SVT.
Therefore, the significant LV dilation that occurred during the
progression of SVT-induced CHF was paralleled by changes in LV
myocardial collagen structure and content.
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|
LV Myocardial Zymographic Activity and MMP Abundance With
Progression of SVT-Induced CHF
In order to examine whether changes in LV myocardial collagen
degradative processes occurred during the progression of SVT-induced
CHF, MMP zymographic activity and relative abundance were examined from
LV myocardial extracts with each week of SVT. A
representative zymogram from control LV
myocardium and after each week of SVT using gelatin as a
proteolytic substrate is shown in Fig 5.
In control LV myocardium, zymographic activity could be
identified between the 70- and 50-kD region on the basis of calibrated
molecular weight markers, which were included in each zymogram. After 7
days of SVT, zymographic activity appeared increased from time 0
control values and remained elevated with longer durations of SVT. The
LV myocardial gelatin zymograms were subjected to densitometric
analysis in order to determine total proteolytic activity. LV
myocardial MMP gelatinolytic activity increased
after 7 days of SVT compared with control values (67±5 versus 36±12
pixels, P<.05) and remained increased from control values
at 14 days (74±6 pixels, P<.05) and 21 days (63±5 pixels,
P<.05) of SVT. In order to provide an internal reference,
cell culture medium (2 µg total protein) from HT 1080 cells incubated
for 24 hours in the and absence and presence of 100 ng/mL of PMA were
included in all zymograms (Fig 5). Incubation with PMA significantly
increased zymographic activity in the HT 1080 cell culture medium and
is consistent with past
reports.28 45 50 51 From the PMA-treated HT 1080
cell culture experiments, a more rapidly migrating band that likely
represents the activated form of MMP-2 was
observed.51 In an additional series of studies,
MMP zymographic activity was examined in the presence of 10 mmol/L
EDTA or 2 mmol/L of PMSF. Incubation with EDTA inhibited all
zymographic activity, consistent with past reports (data not
shown)28 ; however, in the presence of 2
mmol/L PMSF, a serine proteinase inhibitor, zymographic
activity was unchanged, consistent with MMP
activity.52 53
|
In order to determine whether the increased MMP zymographic activity
observed during the progression of SVT-induced CHF was accompanied by
an absolute increase in MMP abundance, immunoblotting
was performed for interstitial collagenase
(MMP-1), the 72-kD gelatinase (MMP-2), and stromelysin (MMP-3). A
representative immunoblot for these
specific MMP species with each week of SVT is shown in Fig 6. In all LV myocardial samples, a
distinct immunoreactive band could be localized to the appropriate
molecular weight that corresponded to the specific MMP of interest. The
internal controls included in each immunoblotting
procedure resulted in a strong immunoreactive signal consistent
with the molecular weight for these specific MMP
species.23 24 25 26 27 28 30 52 53 After 7 days of SVT, the
immunoreactive signals for MMP-1, MMP-2, and MMP-3 were increased from
control levels. With longer durations of SVT, the relative abundance of
MMP-1 appeared to increase in a time-dependent manner. Densitometry of
the immunoblots was performed, and the results were
normalized to control values (Fig 7).
After 7 days of SVT, the abundance of MMP-1 increased by 150±15% from
control values and by 360±30% after 21 days of SVT. The relative
abundance of MMP-2 and MMP-3 increased by 2-fold after 7 days of SVT
and appeared to plateau with longer durations of SVT. Thus, increased
MMP zymographic activity was demonstrable in LV myocardial extracts
during the progression of SVT-induced CHF and was accompanied by a
relative increase in the abundance of several MMP species.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Structural remodeling of the LV and subsequent changes in LV geometry are common events in the progression to CHF.1 2 3 18 19 20 34 However, fundamental mechanisms that contribute to the LV remodeling and the temporal relationship that contributes to changes in myocyte contractile performance with developing CHF remain unclear. The LV fibrillar collagen matrix ensures structural integrity of adjoining myocytes, provides the means by which myocyte shortening is translated into overall LV pump function, and has been postulated to be essential for maintaining alignment of myofibrils within the myocyte through a collagen-integrin-cytoskeletal-myofibril relation.18 19 20 21 A number of past reports have demonstrated that abnormalities in LV fibrillar collagen structure and composition occur with changes in LV geometry and function.7 9 12 13 14 15 18 21 22 32 The MMPs selectively degrade extracellular proteins such as the fibrillar collagens and have been implicated in directly contributing to tissue remodeling in a number of pathological processes.23 24 25 26 27 28 29 30 31 32 33 34 The present study was designed in order to test the hypothesis that an early event in the progression to CHF is LV remodeling and increased MMP zymographic activity. Accordingly, the present study measured time-dependent changes in LV geometry, myocyte contractility, myocardial collagen content, and MMP zymographic activity and expression during the progression of SVT-induced CHF. The significant and unique finding of the present study was that a time course of events in the progression of SVT-induced CHF is LV dilation and myocyte lengthening, alterations in LV myocardial collagen structure, and significantly increased MMP zymographic activity and abundance. These observations suggest that early and dynamic changes in collagen degradative pathways occur within the LV myocardial interstitium during the progression of CHF.
LV and Myocyte Function During Progression of SVT-Induced
CHF
This study examined time-dependent changes in LV geometry and
myocyte contractile processes during the development of SVT-induced
CHF. After 1 week of SVT, significant LV dilation and increased LV peak
wall stress accompanied by a fall in LV fractional shortening occurred.
The diminished LV pump function that occurred early with SVT may be due
to differences in loading conditions, chamber geometry, contractile
performance, or a combination of these determinants.
Accordingly, indices of LV myocardial performance and isolated
myocyte contractile function were serially examined during the
progression of SVT-induced CHF. After 1 week of SVT, the LV
ejection-afterload relation and the LV systolic stiffness
constant were not significantly reduced from control values. Using
these relatively load-independent indices of LV myocardial function,
the results from the present study suggest that the reduction in LV
pump function that occurred after 1 week of chronic SVT may have not
been solely due to changes in myocardial contractile
performance. However, after 1 week of SVT, plasma
catecholamines were increased by 4-fold from control values
and would suggest that significantly increased LV myocardial
sympathetic activation had occurred. Thus, the in vivo measurements of
LV myocardial function that were obtained in control conditions and
after 1 week of SVT were likely performed under different inotropic
states. As a result, inherent defects in LV myocardial contractile
function that may have occurred early in the progression of SVT-induced
CHF would have been difficult to detect. Accordingly, the present
study examined LV isolated myocyte contractile function after each week
of SVT. Through this approach, differences in external loading
conditions and neurohormonal influences that occurred during the
progression of SVT-induced CHF were removed. After 1 week of SVT,
isolated LV myocyte length was increased and paralleled the LV
dilation that had occurred. The increased LV myocyte length after 1
week of SVT was accompanied by a significant reduction in myocyte
percent shortening. This reduction in myocyte percent shortening was
similar to the relative reduction in LV fractional shortening that
occurred after 1 week of SVT. Although myocyte percent shortening was
reduced after 1 week of SVT, myocyte velocity of shortening, which
reflects the rate of actin-myosin crossbridge formation, was not
changed from control values. Taken together, these findings would
suggest that contributory mechanisms for the reduction in LV pump
function that occurred early in the progression of SVT-induced CHF
include changes in both LV and myocyte geometry and shortening
characteristics. However, after 2 weeks of SVT, the continued LV
dilation and reduction in LV pump function were paralleled by
diminished capacity of the LV myocardium to generate
contractile force. Furthermore, these changes in LV geometry and
function after 2 weeks of SVT were associated with diminished
steady-state myocyte contractile function. Consistent with past
reports,5 6 7 3 weeks of SVT caused signs and
symptoms consistent with severe CHF and was accompanied by
significant LV and myocyte contractile dysfunction. Past clinical and
experimental reports have documented that changes in LV geometry occur
with the development of LV dysfunction.1 2 3 4 5 19
However, the time course of changes in LV geometry and the relationship
to inherent contractile performance are not well understood.
The findings of the present study would suggest that early events
in the progression to LV failure in this model of chronic SVT are LV
and myocyte remodeling and intrinsic defects in contractile
performance.
The present study demonstrated that indices of LV myocardial performance were relatively preserved after 1 week of SVT. These findings are consistent with a report by Morgan et al38 in which indices of LV contractility were serially assessed with chronic pacing in dogs. In their study, rapid atrial pacing in dogs (with confirmed atrioventricular capture rates of 220 to 260 bpm) was not associated with reduced indices of LV contractile performance until after 1 week of pacing.38 However, past studies have reported an early reduction in several indices of LV contractile function after rapid ventricular pacing.4 54 55 The divergence between these past reports and the present study is likely due to methodological differences, which include the mode and site of pacing, as well as the conditions under which LV measurements were performed. Nevertheless, the findings from the present study as well as these past reports have clearly demonstrated a reduction in LV contractile function with more prolonged durations of chronic rapid pacing, irrespective of these methodological differences.4 6 8 9 13 54 55 The present study builds on these past reports by demonstrating that a potential contributory mechanism for the diminished LV pump performance that occurs early in the progression of SVT-induced CHF is LV and myocyte remodeling, which is accompanied by significant defects in LV and myocyte contractile performance.
Although the present study provides evidence that an early event in the progression of SVT-induced CHF is LV and myocyte remodeling, it must be recognized that other factors contribute to the progressive decline in LV pump function and myocyte contractile performance. After 1 week of SVT, myocyte length was increased, with no change in steady-state velocity of shortening. However, these measurements were performed under ambient conditions in the absence of neurohormonal stimulation or external loading conditions. Accordingly, in an additional series of studies, myocyte function was examined after ß-adrenergic receptor stimulation. Myocyte ß-adrenergic responsiveness was significantly reduced after 1 week of SVT. In the present study and consistent with past reports, chronic rapid pacing causes an early and sustained increase in plasma catecholamines.9 10 56 The early increase in plasma catecholamines with chronic rapid pacing has been reported to cause defects in ß-adrenergic–mediated phosphorylation and transduction.56 57 Thus, an early defect in the progression of pacing-induced CHF appears to be diminished ß-receptor transduction and myocyte inotropic responsiveness. After 2 weeks of SVT, steady-state myocyte function was significantly reduced. Abnormalities in a number of processes responsible for myocyte excitation-contraction have been identified with the development of pacing-induced CHF. For example, defects in Ca2+ homeostatic mechanisms have been identified to occur with the development of tachycardia-induced CHF.58 59 Taken together, these past reports suggest that a number of cellular and intracellular processes likely contribute to the progression of SVT-induced CHF. Thus, the present study demonstrated that early events in the progression of this CHF process include LV and myocyte remodeling and inherent defects in the capacity of the myocyte to respond to an inotropic stimulus.
LV Collagen Matrix Remodeling During Progression of
SVT-Induced CHF
In the present study, early changes in fibrillar collagen
structure were observed to occur with chronic SVT and paralleled
changes in LV geometry. The early fall in LV pump performance
with SVT was accompanied by LV dilation and wall thinning and by
myocyte lengthening. A contributory factor in these changes in LV and
myocyte geometry may have been a loss of myocardial fibrillar collagen
support. Furthermore, the changes in the myocardial fibrillar collagen
matrix that were observed early in the development of SVT-induced CHF
may have contributed to a loss in the coordination between myocyte
contractile performance and an effective LV ejection. The
collagen matrix has been proposed to provide the support essential for
maintaining alignment of myofibrils within the myocyte as well as for
maintaining myocyte alignment within the LV free
wall.18 19 20 21 This laboratory and others have
demonstrated previously that significant alterations in extracellular
myocyte support and basement membrane adhesion capacity occur with
pacing-induced CHF.7 12 13 14 15 22 The loss of
fibrillar collagen tethering of the myocyte that occurred during the
development of SVT-induced CHF could potentially result in myocyte
lengthening, LV wall thinning, and dilation. In the present study,
the first time point chosen for LV myocardial collagen and MMP studies
was after 1 week of SVT. This time point was selected since global
changes in LV geometry and pump function had been clearly documented to
occur after this period of chronic rapid
pacing.4 9 10 However, Weber et
al14 have reported changes in LV myocardial
collagen structure after 24 hours of pacing tachycardia in
dogs. In light of the findings from the present study in which
changes in LV collagen content and structure were temporally related to
the onset of LV dilation and pump dysfunction, future studies examining
LV myocardial collagen structure and MMP activity at earlier time
points in the progression of this CHF process would be appropriate.
This laboratory has demonstrated previously that concomitant ACE inhibition with chronic rapid pacing reduced the degree of LV dilation and improved LV myocardial collagen structure compared with that of untreated animals undergoing chronic rapid pacing.9 Thus, the reduced LV dilation that was observed with concomitant ACE inhibition during rapid pacing may have been due, at least in part, to a preservation of myocardial collagen–mediated extracellular support. Cleavage of fibrillar collagen molecules by MMPs occurs at specific peptide lengths and sequences.23 29 The remaining collagen fragments would not be reflected in the total LV myocardial hydroxyproline pool but would be evident on structural analysis. Thus, the present study coupled LV myocardial hydroxyproline measurements with quantitative histomorphometry in order to determine LV fibrillar collagen structure as well as total abundance. In the present study, early LV dilation was paralleled by changes in both LV myocardial structure and hydroxyproline content. These findings suggest that changes in fibrillar collagen support is an early contributory mechanism responsible for the LV dilation and diminished pump function with chronic SVT. However, the present study did not address whether possible changes in collagen phenotypes or stability occurred during the development of SVT-induced CHF. It has been clearly demonstrated that alterations in myocardial collagen phenotype and cross-linking can occur in different cardiac pathologies,34 60 which would influence steady-state myocardial collagen content. Thus, appropriate future studies would include examination of potential changes in collagen synthetic pathways, both transcriptional and posttranslational, which occur during the development of SVT-induced CHF.
LV MMPs During Progression of SVT-Induced CHF
An important determinant of collagen degradation is through the
activation of the MMPs, which have high selectivity and affinity for
components of the extracellular matrix.23 24 25 26 27 28 29 30
MMPs are secreted in a proenzyme form and require proteolytic cleavage
for activation.23 26 27 29 52 53 Studies have
provided evidence that an important MMP activation process occurs
through a proteolytic cascade that can be initiated by serine
proteases.23 24 25 26 27 28 29 30 52 53 One approach for measuring
relative MMP activity in tissue extracts is through the use of
zymographic assays.26 27 28 31 33 34 45 46 47 50 51 52 53
A significant and sustained increase in MMP zymographic activity
against the proteolytic substrate gelatin was observed early in the
progression of SVT-induced CHF. Through the use of in vitro assay
systems, several past reports have provided evidence to support the
concept that increased MMP activity may contribute to the development
of LV remodeling.18 32 33 34 61 After 3 hours of
coronary occlusion in the rat, a 2-fold increase in LV collagen
protease activity occurred and was associated with a loss in the
fibrillar collagen weave and transmural LV wall
thinning.61 Increased MMP zymographic activity
has been reported to occur as a function of age in the Syrian
cardiomyopathic hamster model.32
More recently, MMP zymographic activity has been demonstrated to be
significantly increased in human end-stage
cardiomyopathic disease.34 The
present study builds on these past reports by demonstrating that a
potential contributory mechanism for the LV myocardial remodeling that
occurs during the progression of a CHF process may be due to increased
MMP activity.
There are a number of species of MMPs that have different specificities to the fibrillar collagens.23 24 25 26 27 28 29 30 In the present study, proteolytic banding patterns were observed on the zymograms, suggesting that several species of MMPs likely contributed to the LV myocardial collagen remodeling during the progression of SVT-induced CHF. However, the proteolytic patterns observed with gelatin zymography may not necessarily reflect different species of MMPs, and quantification of MMP species based on zymographic activity can be problematic.29 30 53 For example, Atkinson et al51 demonstrated that in type IV collagen film assays, MMP-9 and MMP-2 migrated to molecular weights that differed from the predicted molecular weight on the basis of primary sequence data. Accordingly, the present study used immunoblotting techniques in order to examine whether the increase in LV myocardial zymographic activity during the progression of SVT-induced CHF was associated with changes in the relative abundance of specific MMPs. The results from this portion of the study demonstrated that after 1 week of SVT, the relative abundance of several species of MMPs was increased. Specifically, a significant increase in LV myocardial content of interstitial collagenase (MMP-1), the 72-kD gelatinase (MMP-2), and stromelysin (MMP-3) occurred after 1 week of chronic SVT and was temporally related to the development of LV dilation and reduced myocardial collagen content.
Although increased MMP-2 abundance was observed in LV myocardial extracts during the progression of SVT-induced CHF, LV myocardial zymographic activity, which would correspond to the activated form of this species of MMP, did not appear increased. There are several problematic issues surrounding the in vitro zymographic assays performed in the present study that prevent direct extrapolation to in vivo LV myocardial MMP activity. First, it is likely that only a relatively small proportion of total myocardial MMPs is active at any one point in time. Second, the zymographic assays were performed under optimal enzymatic conditions and substrate availability. Third, an important control point of MMP activity is the TIMPs.23 24 29 30 45 62 63 These TIMPs form tight complexes with MMPs and therefore play an important role in overall MMP enzymatic activity. The MMP assays performed in the present study could not address whether potential changes in TIMP abundance and/or the stoichiometric relation to specific MMPs may have occurred during the development of SVT-induced CHF. Moreover, in the absence of activation, the overall increase in MMP abundance that was observed to occur in this model of LV dilation and dysfunction may not necessarily result in increased LV myocardial MMP activity. In light of the findings of the present study in which increased MMP zymographic activity was observed to occur early in the progression of this CHF process, future studies focusing on the determinants that regulate MMP activity in vivo would be appropriate.
Using immunoblotting techniques, the present study demonstrated that a significant increase in MMP-3 abundance occurred early in the progression of SVT-induced CHF. The early increase in MMP-3 abundance has particular relevance with respect to collagen degradation and MMP activation states. MMP-3 has the widest range of substrates and includes all of the fibrillar collagens as well as components of the basement membrane.23 24 27 29 53 MMP-3 can activate other MMPs as well as proenzyme and intermediate forms of MMP-3 (autoactivation).23 27 29 30 Thus, the increased abundance of MMP-3 that was observed to occur early during the progression of SVT-induced CHF may have had two important consequences. First, early LV myocardial MMP-3 activity with chronic SVT would result in the cleavage of fibrillar collagens with subsequent disruption of the collagen weave surrounding myocytes. Second, the early increase in MMP-3 abundance within the LV myocardium that was observed to occur during the progression of SVT-induced CHF may have induced the proteolytic activation of other MMPs within the LV myocardium.
Chronic pacing-induced tachycardia in animals causes well-defined, predictable, and progressive LV dilation, contractile dysfunction, and neurohormonal activation.4 5 6 7 8 9 10 11 12 13 38 54 55 56 57 Although the etiology of clinical CHF is diverse, a common end point is LV remodeling and pump dysfunction.1 2 3 The SVT model was chosen for the present study since it provides a reliable and practical means for identifying early and contributory events responsible for the LV remodeling and progression of LV dilation and dysfunction that occur with severe CHF. However, there are inherent differences in this specific model of SVT with respect to past studies, which have employed rapid ventricular pacing to induce the CHF phenotype.4 10 11 13 56 57 For example, ventricular pacing in dogs has been reported previously to result in reduced indices of LV contractile function, such as peak rate of LV pressure development, after 1 week of chronic rapid pacing.4 However, a heterogeneous pattern of LV contractile performance has been reported after 1 week of ventricular pacing in dogs.54 In a study by Scott et al,64 differences in the time-dependent changes in LV geometry were reported in which rapid pacing was induced from the atrium versus the ventricle. The present study used SVT, which preserved normal ventricular activation patterns and provided for a homogeneous LV myocardial contraction. Thus, the temporal differences in the onset of LV contractile dysfunction during the progression of pacing-induced CHF that were observed in past reports and the present study were likely due to changes in myocardial activation sequences, ejection patterns, and filling characteristics that occur with rapid ventricular pacing.64 65 66 Although this rapid pacing model may serve as a useful tool for the elucidation of the mechanisms of CHF, it must be recognized that any animal model will not fully represent the complex clinical spectrum of CHF. Specifically, the changes in LV myocardial structure that occur with pacing-induced CHF are not similar to the clinical forms of CHF that are due to chronic ischemia or hypertensive disease. Thus, extrapolation of the findings from this project to clinical forms of CHF should be done with caution. Gunja-Smith et al34 recently reported that in human idiopathic cardiomyopathic disease, collagen cross-linking was reduced by 50% and MMP zymographic activity was increased by 30-fold. This laboratory has demonstrated previously that SVT-induced CHF was associated with a similar reduction in collagen cross-linking.15 Therefore, this model of SVT could provide fundamental temporal and mechanistic information on MMP activity and expression in the remodeling myocardium. The findings of the present study provide direct evidence that robust and early changes in LV myocardial MMPs occur in the progression of CHF and provide a potential novel pharmacological target for modulating LV structure and geometry in this pathological process.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by National Institutes of Health grants HL-45024 and HL-56603 (Dr Spinale), an American Heart Association Grant-in Aid (Dr Spinale), the Thoracic Surgery Foundation for Research and Education (Dr Walker), a Medical University of South Carolina postdoctoral research award (Dr Walker), and a basic research grant from Pfizer (Dr Spinale). Dr Walker participated in this study as a Nina S. Braunwald Research Fellow. C.V. Thomas performed this work as a Medical Student Fellow of the American Heart Association. Dr Spinale is an Established Investigator of the American Heart Association. The authors wish to extend their appreciation to Drs Thomas Borg and Louis Terracio, University of South Carolina, for their advice and support during the execution of this project. The technical assistance of Patrick Thomas, Steve Krombach, Julie Ianninni, Catherine R. Aversa, Maria Webb, and Charles Basler is gratefully acknowledged.
Received September 3, 1996; accepted December 15, 1997.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Y. Huang, S. N. Hunyor, L. Jiang, O. Kawaguchi, K. Shirota, Y. Ikeda, T. Yuasa, G. Gallagher, B. Zeng, and X. Zheng Remodeling of the chronic severely failing ischemic sheep heart after coronary microembolization: functional, energetic, structural, and cellular responses Am J Physiol Heart Circ Physiol, June 1, 2004; 286(6): H2141 - H2150. [Abstract] [Full Text] [PDF]
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Y. Sakata, K. Yamamoto, T. Mano, N. Nishikawa, J. Yoshida, M. Hori, T. Miwa, and T. Masuyama Activation of Matrix Metalloproteinases Precedes Left Ventricular Remodeling in Hypertensive Heart Failure Rats: Its Inhibition as a Primary Effect of Angiotensin-Converting Enzyme Inhibitor Circulation, May 4, 2004; 109(17): 2143 - 2149. [Abstract] [Full Text] [PDF]
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R. M. Delgado III, M. A. Nawar, A. M. Zewail, B. Kar, W. K. Vaughn, K. K. Wu, N. Aleksic, N. Sivasubramanian, K. McKay, D. L. Mann, et al. Cyclooxygenase-2 Inhibitor Treatment Improves Left Ventricular Function and Mortality in a Murine Model of Doxorubicin-Induced Heart Failure Circulation, March 23, 2004; 109(11): 1428 - 1433. [Abstract] [Full Text] [PDF]
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A. Khan, G. W. Moe, N. Nili, E. Rezaei, M. Eskandarian, J. Butany, and B. H. Strauss The cardiac atria are chambers of active remodeling and dynamic collagen turnover during evolving heart failure J. Am. Coll. Cardiol., January 7, 2004; 43(1): 68 - 76. [Abstract] [Full Text] [PDF]
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T. Yamazaki, J.-D. Lee, H. Shimizu, H. Uzui, and T. Ueda Circulating matrix metalloproteinase-2 is elevated in patients with congestive heart failure Eur J Heart Fail, January 1, 2004; 6(1): 41 - 45. [Abstract] [Full Text] [PDF]
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R. E. Chapman and F. G. Spinale Extracellular protease activation and unraveling of the myocardial interstitium: critical steps toward clinical applications Am J Physiol Heart Circ Physiol, January 1, 2004; 286(1): H1 - H10. [Full Text] [PDF]
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J. M. Guccione, A. Salahieh, S. M. Moonly, J. Kortsmit, A. W. Wallace, and M. B. Ratcliffe Myosplint decreases wall stress without depressing function in the failing heart: a finite element model study Ann. Thorac. Surg., October 1, 2003; 76(4): 1171 - 1180. [Abstract] [Full Text] [PDF]
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S. Hayashidani, H. Tsutsui, M. Ikeuchi, T. Shiomi, H. Matsusaka, T. Kubota, K. Imanaka-Yoshida, T. Itoh, and A. Takeshita Targeted deletion of MMP-2 attenuates early LV rupture and late remodeling after experimental myocardial infarction Am J Physiol Heart Circ Physiol, August 7, 2003; 285(3): H1229 - H1235. [Abstract] [Full Text] [PDF]
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C. Boixel, V. Fontaine, C. Rucker-Martin, P. Milliez, L. Louedec, J.-B. Michel, M.-P. Jacob, and S. N. Hatem Fibrosis of the left atria during progression of heart failure is associated with increased matrix metalloproteinases in the rat J. Am. Coll. Cardiol., July 16, 2003; 42(2): 336 - 344. [Abstract] [Full Text] [PDF]
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B. D. Hoit Matrix metalloproteinases and atrial structural remodeling J. Am. Coll. Cardiol., July 16, 2003; 42(2): 345 - 347. [Full Text] [PDF]
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N. Nishikawa, K. Yamamoto, Y. Sakata, T. Mano, J. Yoshida, T. Miwa, H. Takeda, M. Hori, and T. Masuyama Differential activation of matrix metalloproteinases in heart failure with and without ventricular dilatation Cardiovasc Res, March 1, 2003; 57(3): 766 - 774. [Abstract] [Full Text] [PDF]
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M. K. King, M. L. Coker, A. Goldberg, J. H. McElmurray III, H. R. Gunasinghe, R. Mukherjee, M. R. Zile, T. P. O'Neill, and F. G. Spinale Selective Matrix Metalloproteinase Inhibition With Developing Heart Failure: Effects on Left Ventricular Function and Structure Circ. Res., February 7, 2003; 92(2): 177 - 185. [Abstract] [Full Text] [PDF]
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C. Qun Gao, G. Sawicki, W. L Suarez-Pinzon, T. Csont, M. Wozniak, P. Ferdinandy, and R. Schulz Matrix metalloproteinase-2 mediates cytokine-induced myocardial contractile dysfunction Cardiovasc Res, February 1, 2003; 57(2): 426 - 433. [Abstract] [Full Text] [PDF]
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E. E. J. M. Creemers, J. N. Davis, A. M. Parkhurst, P. Leenders, K. B. Dowdy, E. Hapke, A. M. Hauet, P. G. Escobar, J. P. M. Cleutjens, J. F. M. Smits, et al. Deficiency of TIMP-1 exacerbates LV remodeling after myocardial infarction in mice Am J Physiol Heart Circ Physiol, January 1, 2003; 284(1): H364 - H371. [Abstract] [Full Text] [PDF]
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J. Peng, D. Gurantz, V. Tran, R. T. Cowling, and B. H. Greenberg Tumor Necrosis Factor-{alpha}-Induced AT1 Receptor Upregulation Enhances Angiotensin II-Mediated Cardiac Fibroblast Responses That Favor Fibrosis Circ. Res., December 13, 2002; 91(12): 1119 - 1126. [Abstract] [Full Text] [PDF]
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T. Tsuruda, G. Boerrigter, B. K. Huntley, J. A. Noser, A. Cataliotti, L. C. Costello-Boerrigter, H. H. Chen, and J. C. Burnett Jr Brain Natriuretic Peptide Is Produced in Cardiac Fibroblasts and Induces Matrix Metalloproteinases Circ. Res., December 13, 2002; 91(12): 1127 - 1134. [Abstract] [Full Text] [PDF]
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S. Hein, W. H. Gaasch, and J. Schaper Giant Molecule Titin and Myocardial Stiffness Circulation, September 10, 2002; 106(11): 1302 - 1304. [Full Text] [PDF]
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B. Schwartzkopff, M. Fassbach, B. Pelzer, M. Brehm, and B. E. Strauer Elevated serum markers of collagen degradation in patients with mild to moderate dilated cardiomyopathy Eur J Heart Fail, August 1, 2002; 4(4): 439 - 444. [Abstract] [Full Text] [PDF]
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G. L. Brower, A. L. Chancey, S. Thanigaraj, B. B. Matsubara, and J. S. Janicki Cause and effect relationship between myocardial mast cell number and matrix metalloproteinase activity Am J Physiol Heart Circ Physiol, August 1, 2002; 283(2): H518 - H525. [Abstract] [Full Text] [PDF]
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R. Nakamura, K. Egashira, Y. Machida, S. Hayashidani, M. Takeya, H. Utsumi, H. Tsutsui, and A. Takeshita Probucol Attenuates Left Ventricular Dysfunction and Remodeling in Tachycardia-Induced Heart Failure: Roles of Oxidative Stress and Inflammation Circulation, July 16, 2002; 106(3): 362 - 367. [Abstract] [Full Text] [PDF]
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F. A. Tibayan, D. T. M. Lai, T. A. Timek, P. Dagum, D. Liang, G. T. Daughters, N. B. Ingels, and D. C. Miller Alterations in left ventricular torsion in tachycardia-induced dilated cardiomyopathy J. Thorac. Cardiovasc. Surg., July 1, 2002; 124(1): 43 - 49. [Abstract] [Full Text] [PDF]
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A. L. Chancey, G. L. Brower, and J. S. Janicki Cardiac mast cell-mediated activation of gelatinase and alteration of ventricular diastolic function Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H2152 - H2158. [Abstract] [Full Text] [PDF]
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A. M. Romanic, S. M. Harrison, W. Bao, C. L. Burns-Kurtis, S. Pickering, J. Gu, E. Grau, J. Mao, G. M. Sathe, E. H. Ohlstein, et al. Myocardial protection from ischemia/reperfusion injury by targeted deletion of matrix metalloproteinase-9 Cardiovasc Res, June 1, 2002; 54(3): 549 - 558. [Abstract] [Full Text] [PDF]
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W. S. Bradham, G. Moe, K. A. Wendt, A. A. Scott, A. Konig, M. Romanova, G. Naik, and F. G. Spinale TNF-alpha and myocardial matrix metalloproteinases in heart failure: relationship to LV remodeling Am J Physiol Heart Circ Physiol, April 1, 2002; 282(4): H1288 - H1295. [Abstract] [Full Text] [PDF]
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F. G. Spinale Matrix Metalloproteinases: Regulation and Dysregulation in the Failing Heart Circ. Res., March 22, 2002; 90(5): 520 - 530. [Abstract] [Full Text] [PDF]
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Y. Y. Li, T. Kadokami, P. Wang, C. F. McTiernan, and A. M. Feldman MMP inhibition modulates TNF-alpha transgenic mouse phenotype early in the development of heart failure Am J Physiol Heart Circ Physiol, March 1, 2002; 282(3): H983 - H989. [Abstract] [Full Text] [PDF]
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W. S. Bradham, B. Bozkurt, H. Gunasinghe, D. Mann, and F. G. Spinale Tumor necrosis factor-alpha and myocardial remodeling in progression of heart failure: a current perspective Cardiovasc Res, March 1, 2002; 53(4): 822 - 830. [Abstract] [Full Text] [PDF]
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T. Walther, A. Schubert, V. Falk, C. Binner, A. Kanev, S. Bleiziffer, C. Walther, N. Doll, R. Autschbach, and F. W. Mohr Regression of Left Ventricular Hypertrophy After Surgical Therapy for Aortic Stenosis Is Associated With Changes in Extracellular Matrix Gene Expression Circulation, September 18, 2001; 104 (2009): I-54 - I-58. [Abstract] [Full Text] [PDF]
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Y. Y. Li, Y. Feng, C. F. McTiernan, W. Pei, C. S. Moravec, P. Wang, W. Rosenblum, R. L. Kormos, and A. M. Feldman Downregulation of Matrix Metalloproteinases and Reduction in Collagen Damage in the Failing Human Heart After Support With Left Ventricular Assist Devices Circulation, September 4, 2001; 104(10): 1147 - 1152. [Abstract] [Full Text] [PDF]
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E. E.J.M. Creemers, J. P.M. Cleutjens, J. F.M. Smits, and M. J.A.P. Daemen Matrix Metalloproteinase Inhibition After Myocardial Infarction: A New Approach to Prevent Heart Failure? Circ. Res., August 3, 2001; 89(3): 201 - 210. [Abstract] [Full Text] [PDF]
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M. L. Coker, J. R. Jolly, C. Joffs, T. Etoh, J. R. Holder, B. R. Bond, and F. G. Spinale Matrix metalloproteinase expression and activity in isolated myocytes after neurohormonal stimulation Am J Physiol Heart Circ Physiol, August 1, 2001; 281(2): H543 - H551. [Abstract] [Full Text] [PDF]
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S. M. Dolgilevich, F. M. Siri, S. A. Atlas, and C. Eng Changes in collagenase and collagen gene expression after induction of aortocaval fistula in rats Am J Physiol Heart Circ Physiol, July 1, 2001; 281(1): H207 - H214. [Abstract] [Full Text] [PDF]
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J. T. Peterson, H. Hallak, L. Johnson, H. Li, P. M. O'Brien, D. R. Sliskovic, T. M. A. Bocan, M. L. Coker, T. Etoh, and F. G. Spinale Matrix Metalloproteinase Inhibition Attenuates Left Ventricular Remodeling and Dysfunction in a Rat Model of Progressive Heart Failure Circulation, May 8, 2001; 103(18): 2303 - 2309. [Abstract] [Full Text] [PDF]
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M.H. Yacoub A novel strategy to maximize the efficacy of left ventricular assist devices as a bridge to recovery Eur. Heart J., April 1, 2001; 22(7): 534 - 540. [PDF]
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G. L. Brower and J. S. Janicki Contribution of ventricular remodeling to pathogenesis of heart failure in rats Am J Physiol Heart Circ Physiol, February 1, 2001; 280(2): H674 - H683. [Abstract] [Full Text] [PDF]
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A. J. Woodiwiss, O. J. Tsotetsi, S. Sprott, E. J. Lancaster, T. Mela, E. S. Chung, T. E. Meyer, and G. R. Norton Reduction in Myocardial Collagen Cross-Linking Parallels Left Ventricular Dilatation in Rat Models of Systolic Chamber Dysfunction Circulation, January 2, 2001; 103(1): 155 - 160. [Abstract] [Full Text] [PDF]
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F. G. Spinale, M. L. Coker, L. J. Heung, B. R. Bond, H. R. Gunasinghe, T. Etoh, A. T. Goldberg, J. L. Zellner, and A. J. Crumbley A Matrix Metalloproteinase Induction/Activation System Exists in the Human Left Ventricular Myocardium and Is Upregulated in Heart Failure Circulation, October 17, 2000; 102(16): 1944 - 1949. [Abstract] [Full Text] [PDF]
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R. B. New, A. C. Sampson, M. K. King, J. W. Hendrick, M. J. Clair, J. H. McElmurray III, J. Mandel, R. Mukherjee, Marc de Gasparo, and F. G. Spinale Effects of Combined Angiotensin II and Endothelin Receptor Blockade With Developing Heart Failure : Effects on Left Ventricular Performance Circulation, September 19, 2000; 102(12): 1447 - 1453. [Abstract] [Full Text] [PDF]
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S. Kinugawa, H. Tsutsui, S. Hayashidani, T. Ide, N. Suematsu, S. Satoh, H. Utsumi, and A. Takeshita Treatment With Dimethylthiourea Prevents Left Ventricular Remodeling and Failure After Experimental Myocardial Infarction in Mice : Role of Oxidative Stress Circ. Res., September 1, 2000; 87(5): 392 - 398. [Abstract] [Full Text] [PDF]
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B. H. Lorell and B. A. Carabello Left Ventricular Hypertrophy : Pathogenesis, Detection, and Prognosis Circulation, July 25, 2000; 102(4): 470 - 479. [Full Text] [PDF]
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F. G Spinale, M. L Coker, B. R Bond, and J. L Zellner Myocardial matrix degradation and metalloproteinase activation in the failing heart: a potential therapeutic target Cardiovasc Res, May 1, 2000; 46(2): 225 - 238. [Abstract] [Full Text] [PDF]
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I. M.C. Dixon, J. Hao, N. L. Reid, and J. C. Roth Effect of chronic AT1 receptor blockade on cardiac Smad overexpression in hereditary cardiomyopathic hamsters Cardiovasc Res, May 1, 2000; 46(2): 286 - 297. [Abstract] [Full Text] [PDF]
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J.T. Peterson, H. Li, L. Dillon, and J. W. Bryant Evolution of matrix metalloprotease and tissue inhibitor expression during heart failure progression in the infarcted rat Cardiovasc Res, May 1, 2000; 46(2): 307 - 315. [Abstract] [Full Text] [PDF]
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H. Senzaki, N. Paolocci, Y. A. Gluzband, M. L. Lindsey, J. S. Janicki, M. T. Crow, and D. A. Kass {beta}-Blockade Prevents Sustained Metalloproteinase Activation and Diastolic Stiffening Induced by Angiotensin II Combined With Evolving Cardiac Dysfunction Circ. Res., April 14, 2000; 86(7): 807 - 815. [Abstract] [Full Text] [PDF]
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Y. Nagatomo, B. A. Carabello, M. L. Coker, P. J. McDermott, S. Nemoto, M. Hamawaki, and F. G. Spinale Differential effects of pressure or volume overload on myocardial MMP levels and inhibitory control Am J Physiol Heart Circ Physiol, January 1, 2000; 278(1): H151 - H161. [Abstract] [Full Text] [PDF]
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