ATS
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Ann Thorac Surg 2007;84:1528-1536. doi:10.1016/j.athoracsur.2007.05.060
© 2007 The Society of Thoracic Surgeons
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Personal Folders
Right arrow Download to citation manager
Right arrow Author home page(s):
Joseph H. Gorman, III
Robert C. Gorman
Right arrow Permission Requests
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Sakamoto, H.
Right arrow Articles by Gorman, R. C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Sakamoto, H.
Right arrow Articles by Gorman, R. C.
Related Collections
Right arrow Myocardial infarction

Original Articles: Cardiovascular

Effect of Reperfusion on Left Ventricular Regional Remodeling Strains After Myocardial Infarction

Hiroaki Sakamoto, MDa, Landi M. Parish, SBa, Hirotsugu Hamamoto, MDa, Liam P. Ryan, MDa, Thomas J. Eperjesi, BSa, Theodore J. Plappert, CVTb, Benjamin M. Jackson, MDa, Martin G. St John-Sutton, MBBSb, Joseph H. Gorman, III, MDa, Robert C. Gorman, MDa,*

a Harrison Department of Surgical Research, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
b Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

Accepted for publication May 22, 2007.

* Address correspondence to Dr Robert C. Gorman, Harrison Department of Surgical Research, University of Pennsylvania School of Medicine, 313 Stemmler Hall, 36th and Hamilton Walk, Philadelphia, PA 19104-4283 (Email: gormanr{at}uphs.upenn.edu).


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
Background: Reperfusion therapy for myocardial infarction is currently the most effective means for limiting early and late mortality. We sought to elucidate how reperfusion influences remodeling strains in the infarct, borderzone, and remote myocardial regions. Understanding the effects of reperfusion on regional remodeling will help to evaluate and optimize emerging treatments for patients who do not achieve effective reperfusion after myocardial infarction.

Methods: An ovine infarct model (n = 13) was used to assess the effect of 1 hour of ischemia followed by reperfusion on regional and global myocardial geometry, function, and perfusion using sonomicrometry, echocardiography, and microspheres. Thirteen additional animals were assessed chronically (8 weeks) with echocardiography and postmortem analysis after either reperfusion (n = 5) or untreated infarction (n = 8).

Results: During ischemia the area at risk thinned, stretched, and became dyskinetic. The normally perfused borderzone also stretched, and contraction decreased by 40% during ischemia. Reperfusion increased area at risk wall thickness and reduced area at risk stretching but did not restore contractile function. Borderzone stretching was reduced and contractile function improved by reperfusion. Contractile function of remote regions was also improved with reperfusion. Ventricular dilatation after ischemia was reversed within 180 minutes of reperfusion. Chronically, reperfusion significantly improved global remodeling when compared with nonreperfused controls. Reperfused animals had thicker infarcts and akinetic rather than dyskinetic apical segments.

Conclusions: Reperfusion acutely increases area at risk wall thickness, reduces area at risk and borderzone stretching, and improves borderzone and remote function. Reperfusion increases mature scar thickness and improves chronic global remodeling. These beneficial effects of reperfusion result primarily from reduced infarct expansion (stretching).


   Introduction
Top
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
The long-term benefit of reperfusion therapy for acute myocardial infarction (MI) using either mechanical or pharmacologic modalities has been convincingly demonstrated [1]. Reperfusion therapy can be effective even when it is performed late and fails to restore contractile function within the area at risk (AR) [2].

After MI, early infarct expansion (stretching) predicts late generalized left ventricular dilation [3], reduced longevity [4], and progressive loss of cardiac function [4]. We and others have demonstrated that infarct expansion increases strain and decreases contractile function in normally perfused borderzone (BZ) myocardium [5, 6]. Although changes in BZ contractile function are initially caused primarily by adverse mechanical loading associated with infarct expansion, with time inherent strain-induced changes in myocyte and myocardial intersitial structure develop [5–8]. The contractile dysfunction associated with this myopathic process can be so profound that Ratcliffe [9] has termed this phenomenon "non-ischemic infarct extension."

Although previous work has demonstrated that reperfusion therapy limits infarct expansion [10, 11], the effects of reperfusion on regional myocardial remodeling strains in the perfused BZ and remote myocardium have not been fully described.

Using sonomicrometry array localization, quantitative echocardiography, and an established ovine infarction model, we studied the effect of reperfusion therapy on regional remodeling within infarcted, BZ and remote myocardial zones early after MI. The effect of these early reperfusion-induced regional changes were correlated with global left ventricular remodeling both early (3 hours) and late (8 weeks) after MI.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 Acknowledgments
 References
 
Experimental Design
A well-characterized ovine model of infarction-induced ventricular remodeling was used to study acute and chronic effects of reperfusion after 1 hour of ischemia [12, 13].

In the acute portion of the study, sonomicrometry array localization and quantitative echocardiography were used in 13 sheep to assess the effect of 1 hour of ischemia followed by 3 hours of reperfusion on regional and global myocardial mechanics and function. The effects of reperfusion on myocardial salvage and microvascular integrity within the AR were also measured.

In the chronic portion of the study, ischemia was induced in an additional 13 animals. In 5 sheep the infarct was reperfused after 1 hour of ischemia. The remaining 8 animals were not reperfused. All chronic animals were studied with quantitative echocardiography at baseline and during ischemia, then at 2, 4, and 8 weeks after infarction. All animals were treated under experimental protocols approved by the University of Pennsylvania’s Institutional Animal Care and Use Committee (IACUC) and in compliance with National Institutes of Health Publication No. 85-23, revised 1996.

Surgical Protocol
Acute Experiment
Thirteen sheep weighing 35 to 40 kg were used in the acute, nonsurvival, portion of the study. Anesthesia was induced, the animal was monitored, and the heart was exposed as previously described. Atraumatic silicone vascular loops were placed around the left anterior descending artery and its second diagonal branch 40% of the distance from the apex to the base of the heart. Occlusion of these arteries at these locations reproducibly results in a moderately sized infarction involving 20% to 25% of the left ventricular mass at the anteroapex [12].

Sonomicrometry transducers were placed before tightening the coronary snares as described below. Sonomicrometry array localization, echocardiographic, hemodynamic, and microsphere data were collected at baseline, 30 minutes into the ischemic period, between 0 and 10 minutes after reperfusion, and 180 minutes after reperfusion. After 3 hours of reperfusion, animals were euthanized, and the heart was excised. The AR for infarction and infarct size as a percentage of the AR (I/AR) were assessed using the staining technique described below.

Chronic Experiment
Thirteen additional animals were subjected to the same infarction: 5 were reperfused after 1 hour of ischemia, and 8 were not reperfused. All recovered and were serially assessed with echocardiography at 2, 4, and 8 weeks after infarction. Hemodynamic measurements were made at each of the follow-up times. Gross and microscopic postmortem analyses as described below were made in all animals.

Risk Area and Infarct Size Measurements
At the completion of the acute protocol, the coronary snares were retightened and vascular clamps were used to occlude the aorta, pulmonary artery, and inferior vena cava, and the right atrium was incised. One milliliter per kilogram of Evans blue dye was injected through the left atrium to delineate the ischemic myocardial AR. All animals were euthanized, and the heart was explanted. The left ventricle was sectioned perpendicular to its long axis into 6 to 8 slices. The thickness of each slice was measured with a digital micrometer, and all slices were photographed. Infarct area was delineated by photographing and measuring the slices after 20 minutes of incubation in 2% triphenyltetrazolium chloride at 37°C. All photographs were imported into an image-analysis program (Image Pro Plus; MediaCybernetics, Silver Spring, MD), and computerized planimetry was performed. The AR was expressed as a percentage of the left ventricle, and the infarct size was expressed as a percentage of the AR (I/AR).

Regional Blood Flow Measurements
In the acute study sheep, 15 million color-coded, 15.5-µm diameter NuFlow Fluorescent microspheres (IMT Laboratories, Irvine, CA) were injected at baseline, 30 minutes after coronary occlusion, immediately after reperfusion, and 180 minutes after reperfusion. Reference blood samples were taken at all times. Transmural myocardial samples were taken from within the AR and from the BZ myocardium adjacent to the infarct. Each of these specimens was then divided equally into endocardial, mid-myocardial, and epicardial specimens. Myocardial samples and reference blood samples were analyzed using flow cytometry for microsphere content by IMT Laboratories. Regional perfusion was calculated using the following formula: Qm = (Cm x Qr)/Cr, where Qm is myocardial blood flow in milliliters per minute per gram of sample, Cm is microsphere count per gram of tissue in sample, Qr is withdrawal rate of the reference blood sample in milliliters per minute, and Cr is microsphere count in the reference blood sample.

Sonomicrometry Data Collection and Analysis
Animals in the acute study had sonomicrometry transducers placed in the anterior wall of the left ventricle from base to apex. Ten 1-mm hemispherical PZT-5A piezoelectric transducers (Sonometrics Corp, London, Ontario) were placed in the midwall region at the time of infarction as diagramed in Figure 1. This array of transducers defined four myocardial regions: AR, BZ, remote (R), and far remote (FR).


Figure 1
View larger version (148K):
[in this window]
[in a new window]

  		Fig 1. Schematic depicting the ovine heart as viewed through a left thoracotomy. The locations of the sonomicrometry transducers are shown. (AR = area at risk; BZ = borderzone; FR = far remote; LA = left atrium; LV = left ventricle; R = remote; RV = right ventricle.)

 
Sonomicrometry array localization was used to determine the three-dimensional coordinates of each transducer every 5 ms throughout the cardiac cycle, which allowed for the precise determination of regional stretch and contractile function during ischemia and subsequent reperfusion [14, 15]. During data collection, animals were disconnected from the ventilator and atrially paced at 120 beats/min to allow averaging of the data throughout the cardiac cycle. Sonomicrometry data were collected simultaneously with left ventricular pressure, aortic root pressure, and electrocardiogram at baseline, 30 minutes after coronary artery occlusion, immediately after reperfusion, and 180 minutes after reperfusion. To facilitate comparison between data sets, end diastole (ED), end-isovolumic contraction, end systole (ES), and end-isovolumic relaxation were identified, as previously described [15].

Percent change in regional area at ES (%{Delta}AES), relative to preinfarction, was determined during ischemia and reperfusion. Likewise, in each animal, for each regional area, at each experimental time point, fractional areal contraction was calculated by subtracting ES area from ED area, then dividing by ED area; a percent change from the preinfarction value was then calculated. Finally, the mean percent change in fractional areal contraction and percent change in regional area at ES for each regional area was calculated for all animals at each time point. At each time these two quantities, representing mean change in regional myocardial expansion or stretching (percent change in regional area at ES) and mean percent change in regional contraction (percent change in fractional areal contraction), were plotted on orthogonal axes to represent how regional changes in stretch and contractile function are influenced by ischemia and subsequent reperfusion [5]. Systolic shortening rate was calculated as the instantaneous time rate of change of area at mid ejection.

Echocardiography
Quantitative two-dimensional epicardial echocardiograms were obtained in all sheep before coronary artery ligation. In the acute study animals, additional epicardial echocardiograms were obtained 30 minutes into the ischemic period and 180 minutes after reperfusion. Sheep in the chronic study were followed serially with transdiaphragmatic echocardiograms at 2, 4, and 8 weeks after infarction or ischemia–reperfusion [16].

All echocardiograms were collected using a Sonos 7500 platform equipped with a 5-MHz probe (Philips Medical Systems, Andover, MA). Images were recorded on a VHS videotape at 30-Hz (Panasonic AG-6300 VHS Recorder, Panasonic Corporation, Secaucus, NJ). Left ventricular short-axis images at three levels (the tips of the papillary muscles, the bases of the papillary muscles, and the apex) and two orthogonal long-axis views were recorded. Left ventricular volumes at ES (LVESV) and ED (LVEDV) were calculated using Simpson’s rule. Ejection fraction was calculated from LVESV and LVEDV. The apical wall motion abnormality or infarct length and the wall thickness of the apical septum within the AR were also measured.

To assess contractility within the AR in the chronic animals, the percent change in cavity area of the apical cross-sectional image between ED and ES was measured and termed the apical ejection fraction.

Temperature and Hemodynamic Measurements
Mean arterial blood pressure, left ventricular pressure, heart rate, central venous pressure, pulmonary artery pressure, surface electrocardiogram, and rectal temperature were continuously monitored and recorded throughout the infarction and reperfusion procedures in all animals and during the serial follow-up studies in the chronic group. Thermodilution cardiac output and pulmonary capillary wedge pressure were measured in triplicate at each time and averaged.

Euthanasia and Postmortem Examination
In the chronic study, after the last serial study, the heart was arrested and then excised. Caliper measurements of wall thickness were made at the center of the apical infarct.

A tissue section encompassing the infarct and BZ region was fixed in 5% buffered formalin, paraffin embedded, sectioned at 3 to 4 µm, and stained with hematoxylin and eosin as well as Masson’s trichrome stain.

Statistical Analysis
Repeat measures analysis of variance (Statistical Package for the Social Sciences; SPSS Inc, Chicago, IL) was used to assess change in percent stretch relative to baseline, fractional areal contraction, and rate of systolic shortening with time during the experiment. Hemodynamic and echocardiographic data were assessed in parallel with sonomicrometry array localization data, using the same statistical methods. Between groups analysis of variance was used to compare the reperfused and nonreperfused chronic groups. Data are presented as mean ± standard error of the mean. Significance is defined as p less than 0.05.


   Results
Top
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 Acknowledgments
 References
 
Acute Study
Area at Risk and Infarct Size Measurements
The size of the ischemic myocardial AR in the acute study animals was 23.2% ± 1.6% of the left ventricular mass. The I/AR was 71.8% ± 3.0%.

Regional Blood Flow Measurements
Regional perfusion data are summarized in Figure 2. Myocardial ischemia and the absence of collateral circulation were confirmed by the reduction in regional blood flow in the AR to 5% or less of baseline. An initial hyperemic response in the AR was observed at the onset of reperfusion, but after 180 minutes of reperfusion, perfusion was significantly decreased transmurally relative to baseline in the AR.


Figure 2
View larger version (26K):
[in this window]
[in a new window]

  		Fig 2. Regional blood flow measurements are shown for epicardial (dark gray bars), endocardial (black bars), and midwall (light gray bars) blood flow in the area at risk (left) and borderzone (right) at baseline, during ischemia, at reperfusion (rep 0), and 180 minutes after reperfusion (rep 180). *p < 0.05 from baseline; {dagger}p < 0.05 from ischemia; {ddagger}p < 0.05 from reperfusion at 0 minutes.

 
Hemodynamic Data
Hemodynamic data and statistically significant time-dependent changes are presented in Table 1.


View this table:
[in this window]
[in a new window]

  		Table 1 Acute Study Hemodynamic Data a
 
Sonomicrometry Data
Figure 3 summarizes the sonomicrometry data by depicting averaged regional areas normalized to ED values from all 13 animals during one cardiac cycle for AR, BZ, R, and FR myocardium at the baseline, ischemia, early reperfusion, and late reperfusion times. Figure 4 presents changes in expansion and contractility for each region during ischemia and reperfusion relative to baseline. Both figures demonstrate that during ischemia the AR stretches greatly during systole and becomes dyskinetic. Reperfusion results in a progressive decrease in AR stretch; although contractile function is not restored, the region becomes less dyskinetic. The BZ also stretches significantly during ischemia and becomes hypocontractile. Reperfusion decreases BZ stretch and improves (but does not normalize) contractile function. The remote regions experience no increases in regional stretch and demonstrate a compensatory increase in function that is further potentiated by reperfusion.


Figure 3
View larger version (35K):
[in this window]
[in a new window]

  		Fig 3. Mean areas (normalized to end-diastolic values) throughout the cardiac cycle for the four myocardial regions as measured by the sonomicrometry array depicted in Figure 1 at baseline (A), ischemia (B), reperfusion 10 minutes (C), and reperfusion 180 minutes (D). Solid lines indicate the mean values; dotted lines indicate the standard error of the mean at each time.

 

Figure 4
View larger version (20K):
[in this window]
[in a new window]

  		Fig 4. Graphs depicting the relationship between regional expansion (stretching) at end systole (ES) relative to preinfarction (%{Delta}AES) and contractile function relative to preinfarction (%{Delta}FAC) for the four myocardial regions during ischemia (A), 10 minutes after reperfusion (B), and 180 minutes after reperfusion (C). No graph is shown for the preinfarction time because changes (from baseline) in regional expansion and contractile function are plotted. The horizontal line y = 0 represents a myocardial region that has exactly the same fractional contraction as it had at the baseline study; segments that fall between that line and y = 100% are hypocontractile relative to baseline; segments falling below y = 100% demonstrate systolic dyskinesis. Note the reduction in stretching in the area at risk and borderzone as well as the improved borderzone contractile function that result from reperfusion.

 
Regional stretch, fractional areal contraction, and systolic shortening rate are presented in Tables 2, 3, and 4, Go Go respectively. Briefly, after coronary occlusion the AR stretches 36.3% ± 4.2% at ES relative to baseline, and the region becomes dyskinetic with fractional areal contraction decreasing from 5.1% ± 2.0% at baseline to –2.1% ± 1.3% during ischemia (p < 0.05). The normally perfused BZ stretches 14.8% ± 2.3% at ES relative to baseline during ischemia, whereas the fractional areal contraction and systolic shortening rate in this region decrease from 11.2% ± 1.0% and 0.68 ± 0.06 mm2/s at baseline to 5.8% ± 1.1% and 0.36 ± 0.04 mm2/s during ischemia, respectively (p < 0.05).


View this table:
[in this window]
[in a new window]

  		Table 2 Percent Stretch Relative to Baseline a
 

View this table:
[in this window]
[in a new window]

  		Table 3 Fractional Areal Contraction a
 

View this table:
[in this window]
[in a new window]

  		Table 4 Systolic Shortening Rate a
 
After reperfusion the AR remains dyskinetic; however, infarct stretching at ES progressively decreases to 20.5% ± 3.7% at 180 minutes after reperfusion. During reperfusion BZ fractional areal contraction and systolic shortening rate improved to 8.6% ± 0.9% and 0.53 ± 0.04 mm2/s, respectively, after 180 minutes of reperfusion (p < 0.05).

Echocardiography
Echocardiographic data from the acute study are presented in Table 5. During ischemia, LVESV and LVEDV increase from baseline values of 41.4 ± 6.1 mL and 72.6 ± 6.2 mL to 53.8 ± 4.1 mL and 89.2 ± 6.6 mL, respectively (p < 0.05). After reperfusion, both LVESV and LVEDV returned to normal. The length of the wall motion abnormality decreased from 6.9 ± 0.3 cm to 5.5 ± 0.6 cm after reperfusion (p < 0.05). Before ischemia, the ED and ES apical septal wall thicknesses were 0.85 ± 0.02 cm and 1.10 ± 0.05 cm, respectively. During ischemia, wall thickening ceased as ED and ES wall thickness decreased to 0.74 ± 0.03 cm and 0.73 ± 0.04 cm, respectively (p < 0.05). After reperfusion, ED and ES septal wall thickness increased to 1.17 ± 0.04 cm and 1.16 ± 0.05 cm, respectively (p < 0.05).


View this table:
[in this window]
[in a new window]

  		Table 5 Acute Study Echocardiographic Data a
 
Chronic Study
Echocardiography
The echocardiographic data from the chronic study are presented in Table 6. The nonreperfused animals experienced progressive and severe ventricular remodeling during the 8-week follow-up period. In these animals, LVESV increased from 33.4 ± 3.8 mL before infarction to 76.8 ± 7.7 mL at 8 weeks after infarction (p < 0.05). The LVEDV also increased significantly from 56.8 ± 5.2 mL to 103.4 ± 9.2 mL (p < 0.05). Global ejection fraction decreased from 0.412 ± 0.019 to 0.260 ± 0.023 (p < 0.05). In the reperfused animals, the baseline LVESV and LVEDV were 36.2 ± 5.8 mL and 62.8 ± 5.7 mL, respectively. These values increased to 52.4 ± 6.1 mL and 83.7 ± 6.7 mL, respectively, at 8 weeks after infarction (p < 0.05), but were significantly less than the control group (p < 0.05). Ejection fraction declined from 0.429 ± 0.038 to 0.292 ± 0.049 (p < 0.05).


View this table:
[in this window]
[in a new window]

  		Table 6 Chronic Study Hemodynamic and Echocardiographic Data a
 
In both groups, the apical segment became dyskinetic immediately after coronary occlusion. In the control group the apex remained dyskinetic throughout the remodeling period. In the reperfused animals, the apical region became less dyskinetic immediately after reperfusion, and by 2 weeks after reperfusion, paradoxical movement ceased as the region became akinetic (Fig 5).


Figure 5
View larger version (15K):
[in this window]
[in a new window]

  		Fig 5. Apical ejection fraction (AEF) as determined by serial short-axis echocardiographic images of the left ventricular apex in reperfused (open circles) and untreated control (solid circles) sheep. After coronary occlusion the apex became dyskinetic. Reperfusion immediately reduces the degree of apical dyskinesia. In the reperfused animals the apex became akinetic by 2 weeks after infarction whereas the control group remained dyskinetic during the entire 8-week follow-up period. *p < 0.05 from control.

 
Pathologic Assessment
Light microscopy showed a sharp demarcation between infarct and adjacent viable BZ myocardium in all sheep (Fig 6). At the eighth postinfarction week the infarct of nonperfused sheep had a mature, thin-walled scar without viable myocardium except for a very thin endocardial layer seen in some sections. In the reperfused animals, there was significant transmural disruption of normal myocardial structure. Viable-appearing myocytes were found in subepicardial and subendocardial layers separated by mature scar (Fig 6), indicating that the mid myocardial wall was most sensitive to ischemia–reperfusion.


Figure 6
View larger version (82K):
[in this window]
[in a new window]

  		Fig 6. Masson’s trichrome staining in specimens 8 weeks after either a nonreperfused infarct (A, B) or a reperfused infarct (C, D) at x10 (A, C) or x40 (B, D) magnification. Reperfusion resulted in the salvage myocytes primarily in the endocardial and epicardial regions. Nonreperfused infarcts were transmural, with no significant myocyte salvage.

 
Caliper wall thickness measurements at the apex in the infarct were 1.5 ± 0.2 mm in the nonreperfused group and 5.1 ± 0.3 mm in the reperfused group (p < 0.05).


   Comment
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
Acknowledgments
 References
 
Early infarct expansion or stretching is associated with progressive adverse ventricular remodeling manifested by generalized chamber dilatation and decreased global function. It has been previously demonstrated that infarct expansion results in immediate stretching and impaired contractile function in normally perfused myocardium adjacent to the infarct [5, 6]. Although this phenomenon is initially caused primarily by a mechanical disadvantage imposed on this region by infarct expansion, with time the prolonged increase in stretch results in the development of an inherent myopathic process that spreads to involve progressively more perfused myocardium and cannot be fully attributed to a reversible mechanical disadvantage [5, 9]. The data presented here confirm the importance of infarct expansion to the remodeling process and support the important benefit that results from its prevention or limitation.

The infarct used in this experiment is a strong stimulus for remodeling and, without treatment, characteristically results in a doubling of LVESV within 8 to 12 weeks after infarction [12, 16]. In the current experiment, immediately after coronary occlusion, LVESV increased 25% as the AR wall thinned, ceased systolic wall thickening, and stretched nearly 40%.The BZ experienced concomitant stretching and became hypocontractile. Reperfusion of this infarct after 1 hour of ischemia salvaged only 21% of the AR myocardium, primarily in the epicardium and endocardium, did not restore contractile function to the AR, and caused a significant microvascular injury. Despite the severity of this insult, reperfusion rapidly (within 3 hours) reduced infarct and BZ stretching, improved BZ contractile function, and reversed global dilatation.

During the chronic follow-up period, reperfusion greatly reduced, but did not entirely eliminate, ventricular dilatation. The wall thickness of the AR thinned in all animals, but remained greater in the reperfused infarcts compared with control animals (5 mm and 1.5 mm). The fact that the reperfused AR became akinetic, even as it thinned, whereas the nonreperfused infarcts remained dyskinetic, suggests that reperfusion resulted in a greater progressive stiffening of the AR than in nonreperfused control animals.

The mechanism that results in this beneficial infarct stiffening after reperfusion remains to be fully elucidated. Dang and colleagues [17] using an elegant finite element analysis have proposed that an increase in passive infarct stiffness alone cannot cause the infarct to become akinetic. These authors provide a convincing theoretical argument that akinetic (as opposed to dyskinetic) infarcts must contain viable contracting myocytes. Our results support but do not confirm this hypothesis.

Although myocardial salvage is the primary goal, reperfusion therapy is beneficial even though the time to effective reperfusion is typically 4 to 6 hours [13, 18], a period during which the loss of the majority of myocytes within the ischemic region would be expected in the absence of preformed collateral circulation [13, 19–21]. Long-term beneficial effects of reperfusion therapy are evident even after delayed reperfusion (>12 hours) in patients whose MI is complicated by cardiogenic shock [22]. Additionally, although the time delay required for transport to facilities capable of delivering mechanical reperfusion therapy for acute MI is associated with increased infarct size by enzymatic assessment, it does not reduce the benefit of reperfusion therapy on long-term remodeling and survival [23]. This clinical experience suggests that modification of infarct passive (noncontractile) material properties can also contribute to the improved remodeling and long-term outcomes associated with reperfusion therapy. Experiments similar to those reported here but using extended ischemic times that are not associated with myocardial salvage will be required to determine the relative contribution to improved ventricular remodeling of reperfusion-mediated changes in active and passive material properties.

Whatever the biologic mechanism, the primary mechanical factors that contribute to the benefits of reperfusion therapy appear to be an early and persistent increase in wall thickness within the AR as well as a relative increase in stiffness of reperfused infarcts. These geometric and material changes in the infarct would act synergistically to reduce stress distribution within the AR as well as the adjacent BZ myocardium, likely interrupting the stimulus that drives the remodeling process.

Reperfusion therapy is the best available therapeutic modality to modify infarct material properties and geometry; however, the availability and implementation of mechanical reperfusion therapy is offered to approximately half of patients having an acute MI [18, 24]. New technologies, such as cell therapy [25], collagen injection [26], pharmacologic inhibition of matrix metalloproteinase [27], and mechanical infarct restraint [15, 28], are emerging and will allow the infarct to be modified even after effective reperfusion is no longer possible. The data presented in this report will act as a valuable benchmark against which the preclinical evaluation of these emerging treatment strategies can be compared using the ovine anteroapical infarct model.

In this study we used sonomicrometry to assess regional remodeling strains and echocardiography to assess global remodeling and wall thickening. Sonomicrometry allows unprecedented temporal resolution but provides limited spatial resolution, and the currently available transducers only provide reasonable signals for up to 16 weeks. In future studies the use of magnetic resonance imaging would allow for the assessment of three-dimensional remodeling strains as well as a more precise measure of global remodeling for more-extended periods.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
References
 
This work was supported by HL63954, HL71137, and HL76560 grants from the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD.


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 

  1. Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomized trials Lancet 2003;361:13-20.[Medline]
  2. Schomig A, Mehilli J, Antoniucci D, et al. Beyond 12 hours Reperfusion Alternative Evaluation (BRAVE-2) Trial InvestigatorsMechanical reperfusion in patients with acute myocardial infarction presenting more than 12 hours from symptom onset: a randomized controlled trial. JAMA 2005;293:2865-2872.[Abstract/Free Full Text]
  3. Erlebacher JA, Weiss JL, Weisfeldt ML, Bulkley BH. Early dilation of the infarcted segment in acute transmural myocardial infarction: role of infarct expansion in acute left ventricular enlargement J Am Coll Cardiol 1989;4:201-208.
  4. St. John-Sutton M, Pfeffer MA, Moye L, et al. Cardiovascular death and left ventricular remodeling two years after myocardial infarction: baseline predictors and impact of long-term use of captopril: information from the Survival and Ventricular Enlargement (SAVE) trial Circulation 1997;96:3294-3299.[Abstract/Free Full Text]
  5. Jackson BM, Gorman 3rd JH, Moainie S, et al. Extension of borderzone myocardium in postinfarction dilated cardiomyopathy J Am Coll Cardiol 2002;40:1160-1167.[Abstract/Free Full Text]
  6. Guccione JM, Moonly SM, Moustakidis P, et al. Mechanism underlying mechanical dysfunction in the borderzone of left ventricular aneurysm: a finite element model study Ann Thorac Surg 2001;71:654-662.[Abstract/Free Full Text]
  7. Narula N, Narula J, Zhang PJ, et al. Is the myofibrillarlytic myocyte a forme fruste apoptotic myocyte? Ann Thorac Surg 2005;79:1333-1337.[Abstract/Free Full Text]
  8. Wilson EM, Moainie SL, Baskin JM, et al. Region and type specific induction of matrix metalloproteinases in post myocardial infarction remodeling Circulation 2003;107:2857-2863.[Abstract/Free Full Text]
  9. Ratcliffe MB. Non ischemic infarct expansion J Am Coll Cardiol 2002;40:1168-1171.[Free Full Text]
  10. Hochman JS, Choo H. Limitation of myocardial infarct expansion by reperfusion independent of myocardial salvage Circulation 1987;75:299-306.[Abstract/Free Full Text]
  11. Force T, Kemper A, Leavitt M, Parisi AF. Acute reduction in functional infarct expansion with late coronary reperfusion: assessment with quantitative two-dimensional echocardiography J Am Coll Cardiol 1988;11:192-200.[Abstract]
  12. Markovitz LJ, Savage EB, Ratcliffe MB, et al. Large animal model of left ventricular aneurysm Ann Thorac Surg 1989;48:838-845.[Abstract]
  13. Bowen FW, Hattori T, Narula N, et al. Reappearance of myocytes in ovine infarcts produced by six hours of complete ischemia followed by reperfusion Ann Thorac Surg 2001;71:1845-1855.[Abstract/Free Full Text]
  14. Ratcliffe MB, Gupta KB, Streicher JT, Savage EB, Bogen DK, Edmunds Jr LH. Use of sonomicrometry and multidimensional scaling to determine the three-dimensional coordinates of multiple cardiac locations IEEE Trans Biomed Eng 1995;42:587-598.[Medline]
  15. Gorman 3rd JH, Gupta KB, Streicher JT, Gorman RC, Jackson BM, Edmunds Jr LH. Dynamic 3-D imaging of the mitral valve using rapid sonomicrometry array localization J Thorac Cardiovasc Surg 1996;112:712-725.[Abstract/Free Full Text]
  16. Kelley ST, Malekan R, Jackson BM, et al. Restraining infarct expansion preserves left ventricular geometry and function after acute anteroapical infarction Circulation 1999;99:135-142.[Abstract/Free Full Text]
  17. Dang AB, Guccione JM, Mishell JM, et al. Akinetic myocardial infarcts must contain contracting myocytes: finite-element model study Am J Physiol Heart Circ Physiol 2005;288:H1844-H1850.[Abstract/Free Full Text]
  18. Rogers WJ, Canto JG, Lambrew CT, et al. Temporal trends in the treatment of over 1.5 million patients with myocardial infarction in the US from 1990 through 1999: the National Registry of Myocardial Infarction 1, 2 and 3 J Am Coll Cardiol 2005;46:714-719.[Abstract/Free Full Text]
  19. Flameng W, Lesaffre E, Vanhaecke J. Determinants of infarct size in non-human primates Basic Res Cardiol 1990;85:392-403.[Medline]
  20. Horneffer PJ, Healy B, Gott VL, Gardner TJ. The rapid evolution of a myocardial infarction in an end-artery coronary preparation Circulation 1987;76:V39-V42.[Medline]
  21. Reimer KA, Vander Heide RS, Richard VJ. Reperfusion in acute myocardial infarction: effect of timing and modulating factors in experimental models Am J Cardiol 1993;72:13G-21G.[Medline]
  22. Hochman JS, Sleeper LA, Webb JG, et al. Early revascularization in acute myocardial infarction complicated by cardiogenic shockSHOCK Investigators. Should we emergently revascularize occluded coronaries for cardiogenic shock?. N Engl J Med 1999;341:625-634.[Abstract/Free Full Text]
  23. Liem AL, van’t Hof AWJ, Hoorntje JCA, de Boer MJ, Suryapranata H, Zijlstra F. Influence of treatment delay on infarct size and clinical outcome in patients with acute myocardial infarction treated with primary angioplasty J Am Coll Cardiol 1998;32:629-633.[Abstract/Free Full Text]
  24. Hasdai D, Behar S, Wallentin L, et al. A prospective survey of the characteristics, treatments and outcomes of patients with acute coronary syndromes in Europe and the Mediterranean basin Eur Heart J 2002;23:1190-1201.[Abstract/Free Full Text]
  25. Lee MS, Makkar RR. Stem-cell transplantation in myocardial infarction: a status report Ann Intern Med 2004;140:729-737.[Abstract/Free Full Text]
  26. Dai W, Wold LE, Dow JS, Kloner RA. Thickening of the infarcted wall by collagen injection improves left ventricular function in rats: a novel approach to preserve cardiac function after myocardial infarction J Am Coll Cardiol 2005;46:714-719.[Abstract/Free Full Text]
  27. Peterson JT, Hallak H, Johnson L, et al. Matrix metalloproteinase inhibition attenuates left ventricular remodeling and dysfunction in a rat model of progressive heart failure Circulation 2001;103:2303-2309.[Abstract/Free Full Text]
  28. Pilla JJ, Blom AS, Gorman 3rd JH, et al. Early postinfarction ventricular restraint improves borderzone wall thickening dynamics during remodeling Ann Thorac Surg 2005;80:2257-2262.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 Ann. Thorac. Surg.Home page
H. Hamamoto, H. Sakamoto, B. G. Leshnower, L. M. Parish, S. Kanemoto, R. Hinmon, T. Plappert, S. Miyamoto, M. G. St. John-Sutton, J. H. Gorman III, et al.
Very Mild Hypothermia During Ischemia and Reperfusion Improves Postinfarction Ventricular Remodeling
Ann. Thorac. Surg., January 1, 2009; 87(1): 172 - 177.
[Abstract] [Full Text] [PDF]

Home page
 Ann. Thorac. Surg.Home page
A. Anselmi
Invited commentary
Ann. Thorac. Surg., November 1, 2007; 84(5): 1536 - 1537.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Personal Folders
Right arrow Download to citation manager
Right arrow Author home page(s):
Joseph H. Gorman, III
Robert C. Gorman
Right arrow Permission Requests
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Sakamoto, H.
Right arrow Articles by Gorman, R. C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Sakamoto, H.
Right arrow Articles by Gorman, R. C.
Related Collections
Right arrow Myocardial infarction

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
ANN THORAC SURG ASIAN CARDIOVASC THORAC ANN EUR J CARDIOTHORAC SURG
J THORAC CARDIOVASC SURG ICVTS ALL CTSNet JOURNALS