Structure and Mechanics of Healing Mi

Annu. Rev. Biomed. Eng. 2005. 7:22353 doi: 10.1146/annurev.bioeng.7.060804.100453 Copyright c 2005 by Annual Reviews.
All rights reserved First published online as a Review in Advance on February 22, 2005
STRUCTURE AND MECHANICS OF HEALING MYOCARDIAL INFARCTS

Jeffrey W. Holmes
Annu. Rev. Biomed. Eng. 2005.7:223-253. Downloaded from arjournals.annualreviews.org by University of California - San Diego on 07/25/05. For personal use only.
Department of Biomedical Engineering, Columbia University, New York, NY 10027; email: jh553@columbia.edu
Thomas K. Borg
Department of Cell and Developmental Biology and Anatomy, University of South Carolina, Columbia, South Carolina 29208; email: BORG@gw.med.sc.edu
James W. Covell
Departments of Medicine and Bioengineering, University of California San Diego, La Jolla, California 92093; email: jcovell@ucsd.edu
Key Words collagen, constitutive properties, cross-linking, deformation, edema, scar, strain, stress, necrosis, ventricular function Abstract Therapies for myocardial infarction have historically been developed by trial and error, rather than from an understanding of the structure and function of the healing infarct. With exciting new bioengineering therapies for myocardial infarction on the horizon, we have reviewed the time course of structural and mechanical changes in the healing infarct in an attempt to identify key structural determinants of mechanics at several stages of healing. Based on temporal correlation, we hypothesize that normal passive material properties dominate the mechanics during acute ischemia, edema during the subsequent necrotic phase, large collagen ber structure during the brotic phase, and cross-linking of collagen during the long-term remodeling phase. We hope these hypotheses will stimulate further research on infarct mechanics, particularly studies that integrate material testing, in vivo mechanics, and quantitative structural analysis. CONTENTS
INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IMPACT OF INFARCT MECHANICAL PROPERTIES ON VENTRICULAR FUNCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ACUTE ISCHEMIA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Structural Changes During Acute Ischemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Changes in Mechanical Properties During Acute Ischemia . . . . . . . . . . . . . . . . . . . Determinants of Mechanics During Acute Ischemia . . . . . . . . . . . . . . . . . . . . . . . . Ventricular Function During Acute Ischemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1523-9829/05/0815-0223$20.00 224 225 227 228 228 230 234
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THE NECROTIC PHASE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Structural Changes During the Necrotic Phase . . . . . . . . . . . . . . . . . . . . . . . . . . . . Changes in Mechanical Properties During the Necrotic Phase . . . . . . . . . . . . . . . . Determinants of Infarct Mechanics During the Necrotic Phase . . . . . . . . . . . . . . . . Ventricular Function During the Necrotic Phase . . . . . . . . . . . . . . . . . . . . . . . . . . . THE FIBROTIC PHASE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Structural Changes During the Fibrotic Phase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Changes in Mechanical Properties During the Fibrotic Phase . . . . . . . . . . . . . . . . . Determinants of Infarct Mechanics During the Fibrotic Phase . . . . . . . . . . . . . . . . Ventricular Function During the Fibrotic Phase . . . . . . . . . . . . . . . . . . . . . . . . . . . . THE REMODELING PHASE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Structural Remodeling of Myocardial Scar Tissue . . . . . . . . . . . . . . . . . . . . . . . . . . Changes in Mechanical Properties During the Remodeling Phase . . . . . . . . . . . . . Determinants of Infarct Mechanics During the Remodeling Phase . . . . . . . . . . . . . Ventricular Function During the Remodeling Phase . . . . . . . . . . . . . . . . . . . . . . . . SUMMARY AND CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
INTRODUCTION
Each year, approximately 565,000 Americans experience a new myocardial infarction; of these, 75% of men and 62% of women survive for at least one year (1). In addition, each year nearly 300,000 Americans experience a recurrent infarction (1). As a result, a large portion of the practice of clinical cardiology is currently devoted to management of patients with a healing or healed myocardial infarct. Excellent progress has been made, particularly in the areas of revascularization during the rst hours following infarction (2, 3) and pharmacologic therapy to limit adverse geometric remodeling of the left ventricle (LV) and progression to dilated heart failure (46). Even more dramatic therapies are on the horizon. Direct stem cell transplantation into the healing infarct is already in use as an experimental therapy (710), and tissue-engineered replacement patches of myocardium may not be far behind (11, 12). However, these therapies continue to be developed primarily on a trial-and-error basis rather than from an understanding of the mechanical properties of the healing infarct and its coupling to the LV. This trial-and-error approach has led not only to some dramatic successes but also to some catastrophic failures. For example, preliminary evidence that steroid administration limits postinfarction necrosis led to a trial of postinfarction steroid therapy in which high-dose steroid administration caused dramatic increases in infarct size and the incidence of ventricular arrhythmias, and in which 5 of 12 patients in the high-dose group died (13). This review, therefore, has two primary goals. The rst goal is to review what is known about the evolving structure and mechanics of healing myocardial infarcts. The second goal is to temporally correlate structural and mechanical information from a range of studies to formulate hypotheses about which specic structural features are the primary determinants of infarct mechanics during each temporal phase of infarct healing. It is our hope that this new analysis of the temporal
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course of infarct healing in terms of key structural determinants will stimulate new research on the mechanics of healing infarcts and provide a conceptual platform for improved rational design of postinfarction therapies. This review focuses on the structure and mechanics of healing infarcts following a single, nonreperfused myocardial infarction, and is organized as follows. First, we outline the different mechanisms by which the presence of a myocardial infarct may impair ventricular function. This list includes many of the potential adverse consequences of myocardial infarction, including rupture, infarct expansion, ventricular remodeling, hypertrophy, and heart failure, the occurrence and severity of which all depend on the mechanical properties of the healing infarct. The next four sections address different temporal phases of healing and each has the same general format: a review of the composition and structure of healing infarcts at that time point, a review of available data on the mechanics of healing infarcts at that time point, hypotheses regarding structural determinants of infarct mechanics based on temporal correlation of the structural and mechanical data, and nally a brief discussion of which of the mechanisms of functional impairment are most relevant at each temporal stage of healing. General conclusions and challenges for future work are addressed in the nal section.
IMPACT OF INFARCT MECHANICAL PROPERTIES ON VENTRICULAR FUNCTION

Below we list and briey explain six different ways in which the presence of a healing myocardial infarct can impair overall pump function of the LV. In each case, the size and mechanical properties of the healing infarct determine the degree of impairment of LV function. Therefore, it follows that an understanding of the mechanical properties of the healing infarct is essential to understanding, predicting, and ultimately modifying the short- and long-term changes in ventricular function that occur following myocardial infarction. 1. An infarct may fail catastrophically (rupture). Infarct rupture accounts for 15%30% of deaths in the rst week after infarction (14, 15). Rupture obviously represents the most catastrophic way in which the presence of an infarct can impair ventricular function. Although the exact mechanical properties most related to rupture have not been identied, the balance between the mechanical properties of the infarct and the stresses placed on it clearly determines whether rupture occurs (1618). 2. Infarct bulging or stretching wastes energy generated by healthy myocardium. Because lost myocardium is replaced by scar tissue rather than by regenerated muscle, clinical studies have shown that once 40% of the LV myocardium has been lost, either through a single large infarction or a combination of smaller ones, the LV is at risk of pump failure (19, 20). Although it is tempting to attribute this nding simply to a reduction in
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Figure 1 Effects of large infarcts on systolic and diastolic pressure-volume relationships predicted by a model of Bogen et al. (21). Data are estimated from gure 8 in Bogen et al. for healing infarcts corresponding to the phases of healing dened in this review: control (C), acutely ischemic (I), necrotic (N), and brotic (F), assuming an unstressed volume of 30 ml. Very compliant infarcts (acutely ischemic, I) primarily depress systolic function, whereas very stiff infarcts (brotic, F) primarily restrict diastolic function.
the amount of healthy myocardium contributing to ejection, model studies have found that the degree of systolic impairment is directly related to the compliance of the infarct (Figure 1). For very stiff infarcts, little systolic dysfunction is predicted (21). For compliant infarcts, much of the work of the remaining myocardium is wasted stretching the infarct, reducing systolic pump function dramatically (2124). 3. Infarct stiffness may limit diastolic function of the remaining healthy myocardium. Model studies have also shown an important disadvantage to an overly noncompliant infarct. Bogen et al. predicted that whereas compliant infarcts primarily disrupt systolic mechanics, the presence of a large noncompliant infarct severely limits ventricular function by impairing diastolic lling (Figure 1) (21). The presence of the very stiff infarct impairs diastolic function by increasing overall chamber stiffness (25) and limiting the ability of remaining healthy myocardium to utilize the Frank-Starling mechanism to adjust ventricular output (26). 4. Infarct expansion and cavity dilation increase wall stress throughout the LV. One common postinfarction complication is infarct expansion, a remodeling process characterized by rearrangement of material within the infarct to yield a thinner infarct with increased endocardial surface area (27). This dilatation and thinning clearly increases the wall stress within the infarct at any cavity pressure, potentially worsening problems already mentioned, such as systolic stretching and the risk of rupture. The resulting increase
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in cavity size also increases wall stress in the remainder of the ventricle, forcing noninfarcted myocardium to generate higher stresses to achieve the same systolic cavity pressure (27, 28). 5. Coupling to the infarct may limit deformation of adjacent myocardium. The arguments outlined above regarding infarct compliance appear to suggest that in terms of ventricular function, the stiffer the healing infarct the better, except in the limit of a healing infarct large and stiff enough to impair diastolic lling. However, all the reasoning to this point has been onedimensional (infarcts are either stiff or compliant) and global (considering two-compartment models with infarcted and normal segments). In fact, healing infarcts are anisotropic (29, 30) and coupled locally to adjacent noninfarcted myocardium. During acute ischemia, coupling to the compliant infarct creates a functional border zone where deformation is reduced despite normal perfusion (31). Later in healing, we have argued that stiff infarcts may also restrict the deformation of adjacent noninfarcted myocardium (30). For example, high circumferential stiffness may limit systolic stretching of the infarct, but high radial stiffness would limit radial thickening of adjacent myocardium tethered to the infarct (30). 6. The infarct sets boundary conditions for ventricular hypertrophy and remodeling. Over the long term, the presence of an infarct may also impair ventricular function indirectly by triggering adverse ventricular remodeling that increases wall stress throughout the remodeled ventricle. This remodeling has been described as a volume-overload hypertrophy of the surviving myocardium and is characterized by lengthening and thinning of the ventricular wall and overall cavity dilation (32). Although the specic stimuli that drive volume-overload hypertrophy are still incompletely understood (33), in the postinfarction setting the values of most of the likely mechanical candidates (stress, strain, work) in the noninfarcted myocardium, and hence the resulting pattern of hypertrophy and remodeling, are determined largely by the material properties and remodeling of the healing infarct. As with infarct expansion, increases in wall stress associated with cavity dilation place noninfarcted myocardium at a mechanical disadvantage and may lead to a downward spiral into dilated heart failure.
ACUTE ISCHEMIA
During the rst minutes to hours after infarction, the balance between oxygen supply and demand is a dynamic one, and the nal size of the infarct can be inuenced by changes in loading conditions and by pharmacologic agents (34 37). During this period, the mechanics of the infarct region are dominated by the conversion of the infarcted myocardium from an active, force-generating material to a passive, viscoelastic material. Initially, the material properties of the infarct appear to change little; by 6 h after permanent coronary occlusion the infarct
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clearly begins to stiffen (38, 39). We therefore dene acute ischemia from the point of view of infarct mechanics as beginning with the experimental or natural occlusion of the coronary artery supplying the infarct and ending when stiffening becomes evident, 46 h after infarction in large animal models. Reperfusion during this period may dramatically alter many or all aspects of the subsequent healing process. Owing to space limitations, we have limited the discussion throughout this review to nonreperfused infarcts, taking this as the simplest starting point for understanding the subsequent effects of a variety of interventions, including reperfusion.
Structural Changes During Acute Ischemia

Excellent descriptive studies of the time course of changes in pathologic appearance have been published for healing rat (40) and human (41, 42) infarcts. Cardiac myocytes are attached by integrins at specic sites near the Z band to an interconnected collagen network containing other mechanically and biologically active extracellular matrix (ECM) components, including glycoproteins, proteoglycans, growth factors, cytokines, and proteases (4346). During cardiac remodeling and wound healing, any change to this network may alter mechanical properties, including changes within the myocytes, remodeling of myocyte attachments to the ECM (47, 48), changes in ECM content (49), and remodeling of ECM organization and structure (50). In general, postinfarction changes in active myocyte properties and in ECM content have received the most attention, whereas much less attention has been paid to myocyte-ECM coupling, other ECM components, and ECM organization. Within hours after infarction, the infarcted muscle loses its striations and changes its staining properties (42). Breakdown of matrix-associated glycoproteins has been reported as early as 40 min after infarction and damage to collagen and elastin bers has been demonstrated 2 h after coronary ligation (51, 52); one study reported a 50% drop in infarct collagen content after 3 h (53). This time course of matrix damage is consistent with the recent nding that matrix metalloproteinase (MMP) activity is signicantly increased 1 h after infarction, with measurable release of soluble MMPs after 2 h (54).
Changes in Mechanical Properties During Acute Ischemia

The most important change in mechanical properties in acutely ischemic myocardium is that throughout the rst few minutes of ischemia, the myocardium gradually loses its ability to generate systolic force. The ischemic myocardium then behaves as a passive elastic material throughout the cardiac cycle, displaying in-plane stretching and thinning during lling and isovolumic systole, then recoiling passively during ejection and isovolumic relaxation (5557). The central question with regard to the mechanical properties of acutely ischemic myocardium is whether it simply behaves as passive myocardium or whether its constitutive properties are altered by ischemia. Surprisingly, although acute ischemia has
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received far more attention in the literature than later phases of healing, it is still not possible to denitively answer this question. As outlined below, there is wide agreement that passive pressure-segment length curves shift rightward within minutes after infarction, so that in-plane lengths at any pressure are greater than control. There is also solid evidence that by several hours after infarction, the infarct region begins to stiffen. However, the relative contributions of changes in local geometry and stresses versus changes in material properties to the reported mechanical behavior in the rst hours after infarction are still largely unresolved. The LV is more compliant than normal 1 h after experimental coronary ligation (58), but becomes less compliant than normal within a few hours after infarction (59, 60). Tracking of segment lengths in the ischemic region using strain gauges and ultrasonic crystals showed that within 30 s after experimental coronary occlusion, systolic shortening of acutely ischemic myocardium is replaced by systolic stretching (55, 56), which gradually increases in magnitude over the rst 5 min (56, 61). The passive nature of the ischemic segment deformation was demonstrated convincingly by Tyberg et al., who constructed pressure-length loops throughout the cardiac cycle and showed that the ischemic segments convert from a counterclockwise loop, indicating work being performed by the segment prior to occlusion, to a clockwise loop, indicating work being performed on the segment by adjacent myocardium, 5 min after experimental occlusion (56). Akaishi showed that the ischemic region operates on a highly nonlinear tension-length curve, with the amount of systolic stretching much higher at low end-diastolic pressures (EDP), when the segment starts from a relatively at part of the curve, than at high EDP, when the segment operates on a very steep portion of the same curve (62). Many of these early studies also compared diastolic pressure-segment length curves before and after coronary occlusion to assess possible changes in ischemic region compliance. Although all studies agreed that the diastolic pressure-length curves shift rightward (greater segment lengths at a given diastolic pressure) (38, 39, 56, 61, 63), there was disagreement over whether the slope of the pressurelength curves increased (61, 63) or decreased (38, 56) during acute ischemia. There were a number of methodological differences among these studies, including the transmural location and orientation of the segments, the use of closed- or openchest animals, and the denition of slope directly from the curves versus from log-transformed plots, but on close review none of these factors can completely resolve the discrepancy. In any case, it seems clear that stiffness of the ischemic region begins to increase during the next few hours after infarction. Vokonas et al. reported a gradual decrease in systolic stretching of an ischemic segment beginning 15 min after and continuing throughout the rst 6 h following infarction, without concurrent changes in the EDP or end-diastolic segment length (39). Pirzada et al. reported a similar time course for diminishing systolic stretching of the ischemic segment and found that the slope of the diastolic pressure-segment length relationship increased in parallel over the same time period (38). Theroux, working in closed-chest animals at much higher diastolic pressures, saw very little systolic
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stretching at 5 min or 2 h, but found that the slope of the diastolic pressure-length relationship doubled between these time points (63). Analysis of regional wall motion using echocardiography revealed a slightly different time course in the same animal model. Both the circumferential extent and the severity of regional wall motion abnormalities increased during the rst 30 min, then remained stable up to 6 h after coronary ligation (64). Subsequent two- and three-dimensional analyses of the mechanics of acutely ischemic myocardium have added detail but still have not clearly resolved the question of whether the constitutive properties of ischemic myocardium differ from those of normal passive myocardium. Using a three-dimensional array of implanted markers, Villarreal conrmed that 5 min of experimental ischemia in dog converted the normal pattern of systolic circumferential and longitudinal shortening and radial thickening to circumferential and longitudinal stretching and radial thinning as expected (57). They also found that while the magnitude of normal systolic strains typically increases from epicardium to endocardium, during ischemia the systolic strains were transmurally uniform. An increase in EDP from 2.3 1.5 mm Hg at control to 4.6 1.0 mm Hg after 10 min of ischemia produced a small transmurally uniform stretch (remodeling strain <0.10) in the longitudinal direction but large and transmurally nonuniform circumferential stretch (remodeling strain approximately 0.10 in the epicardial third, 0.30 in the endocardial third of the wall) as well as transmurally nonuniform radial thinning (57). Consistent with the segment length data reviewed above, these ndings imply a rightward shift of pressure-strain curves, but indicate a differential response in the circumferential and longitudinal directions. Without knowledge of changes in local geometry in the infarct region, it is difcult to judge whether the differential responses observed by Villarreal in the circumferential and longitudinal directions reected differential responses to ischemia, differences in loading, material anisotropy, or a combination of these effects. The best direct data on material anisotropy are those reported by Gupta et al. in specimens tested 4 h after experimental infarction in sheep (Figure 2) (29). They reported stresses at 15% equibiaxial stretch of full-thickness specimens in the control state and 4 h after infarction. Although none of the differences were statistically signicant owing to large variability among samples, there were strong trends consistent with the in vivo strains reported by Villarreal. Stresses at 15% equibiaxial stretch were roughly threefold higher in the circumferential direction and fourfold higher in the longitudinal direction in the 4-h infarct samples compared to control; in both control and 4-h specimens, longitudinal stresses were three- to fourfold greater than circumferential stresses (29).
Determinants of Mechanics During Acute Ischemia

As outlined above, acutely ischemic myocardium behaves as a passive nonlinearly viscoelastic material, but it is unknown whether its material properties differ substantially from normal passive myocardium. Most of the reported behavior in the
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Figure 2 Data from Gupta et al. on the evolution of anisotropy in healing ovine infarcts (29). Graph is based on data in table 3 of Gupta et al. and reects stresses in the circumferential and longitudinal directions during 15% equibiaxial extension of excised full-thickness infarcts. Stresses peak at 12 weeks, and the direction of greatest stress switches from longitudinal to circumferential between 1 and 6 weeks. Each time point corresponds to one phase of healing as dened in this review: control (C), acutely ischemic (I), necrotic (N), brotic (F), and remodeling (R).
rst hour after infarction could be explained by local geometric changes resulting in increased stresses in the infarct at any given cavity pressure, without postulating a change in material properties; this possibility is discussed rst below. Then, we briey consider mechanisms that would act to decrease infarct stiffness: strain softening, disruption of key structural proteins, and loss of coronary perfusion pressure. We omit ischemic contracture because it would shift pressure-segment length curves leftward in contrast to experimental observations and therefore does not appear to dominate the mechanics of acute ischemia. We consider it likely that the stiffening of the infarct reported to begin hours after infarction is due to edema, and therefore take this time as the break point between acute ischemia and the necrotic phase discussed later in this review.
CONSTITUTIVE PROPERTIES OF PASSIVE MYOCARDIUM
It is clear that acutely ischemic myocardium is stretched in the circumferential and longitudinal directions and thinned in the radial direction at end-diastole compared to preinfarction control (57). Although some of this diastolic remodeling reects increased EDP during ischemia, diastolic remodeling is more pronounced in the ischemic region than in remote regions of the same heart (39, 61, 65). This disproportionate local stretching and thinning in the ischemic region would be expected to result in higher circumferential and longitudinal stresses in the ischemic region than in remote nonischemic myocardium at any given pressure. Therefore, even if the constitutive properties of the ischemic and nonischemic regions were identical, pressure-segment length curves in the ischemic region would shift rightward, with a given cavity pressure
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Figure 3 Simple thin-walled spherical model to illustrate the possibility that shifts along the same stress-strain curve, rather than changes in material properties, could explain observed rightward shifts in pressure-segment length behavior during acute ischemia. Left panel: Open circles show mean control pressure-segment length data, closed circles show acute ischemia data from Tyberg et al. (56). Solid line shows t to control data; dotted line shows predicted behavior assuming a 10% increase in infarct radius of curvature and 10% decrease in infarct wall thickness, but no change in stressstrain behavior. Right panel: Changes in regional geometry shifted the infarct (closed circles) higher on the stress-strain curve calculated from control data (open circle, solid line).
producing an elevated stress and thereby a larger diastolic strain and segment length. This is illustrated for a simple thin-walled sphere in Figure 3, but the basic reasoning should hold for any computational or experimental model. As shown in Figure 3, a 10% increase in radius of curvature and 10% decrease in wall thickness could account for the parallel shift in pressure-length curves reported by Tyberg (56), even if material properties remained constant. Although there is disagreement among various studies regarding whether pressure-segment length slopes increase or decrease during acute ischemia, a review of the actual curves shows that the dominant effect is the rightward shift, with relatively modest changes in slope in either direction. Therefore, the simplest explanation of reported mechanical behavior of acutely ischemic myocardium is that active force generation ceases, the mechanical behavior of the ischemic myocardium is governed throughout the cardiac cycle by the normal passive constitutive properties of myocardium, and local stresses increase modestly at any given pressure owing to local geometric remodeling.
STRAIN SOFTENING
Strain softening describes a dependence of current stiffness on the maximum strain previously experienced by a material and is distinguished from viscoelasticity by a lack of recovery, even following an extended rest period (66). Emery and coworkers have demonstrated strain softening in isolated arrested rat hearts, where pressure-volume and pressure-strain curves show an increase in compliance when the arrested heart is exposed to a new maximum cavity pressure
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of 30 mm Hg or 120 mm Hg (67, 68). This effect certainly seems relevant to acutely ischemic myocardium, which is exposed to new maximum stresses and stretches during systole once active force generation ceases. The pressure-strain curves published by Emery closely resemble the pressure-dimension curves published by a number of investigators during acute ischemia, with a near-parallel rightward shift at pressures above 10 mm Hg, a decreased slope at lower pressures, and no change in zero-pressure lengths (67). Kirton et al. recently reported that strain softening occurs only in nonviable (i.e., incapable of generating a twitch in response to electrical stimulation) isolated cardiac trabeculae, suggesting that elevated stress and stretch alone are not sufcient to induce softening in myocardium unless other damage has occurred (66). Although this nding does not rule out a role for strain softening in acutely ischemic myocardium, at least two studies suggest that strain softening alone cannot explain observed changes in mechanics during ischemia. First, Summerour et al. could not reproduce the changes in opening angle that occur following 30 min of left coronary occlusion in the rat by inducing global strain-softening in nonischemic rat hearts (69). Second, Paulus et al. demonstrated that strain softening is not required to obtain the right-shifted passive pressurelength curves typical of ischemic myocardium. They induced relative ischemia by pacing tachycardia in dogs with coronary stenoses and found that segments with well-preserved systolic function during ischemia had left-shifted diastolic pressure-segment length curves compared to control, whereas segments with depressed systolic function had right-shifted pressure-segment length curves similar to those observed following coronary occlusion (70). Because systolic stretch was not required to produce a rightward shift of the diastolic pressure-segment length curves, strain softening was not responsible for the shift in this study.
DISRUPTION OF STRUCTURAL PROTEINS
Most of the passive stiffness of normal myocardium appears to reside in two structural proteins: titin determines stiffness at lower sarcomere lengths, whereas collagen is the primary determinant at the higher end of the working sarcomere length range (71). Therefore, disruption of either of these proteins during acute ischemia could result in changes in mechanics of the ischemic region. Titin is a particularly appealing candidate because increased compliance at low stresses (owing to titin disruption) with preserved properties at higher stresses (owing to intact collagen) would appear as a rightward shift in pressure-segment length curves at the relatively high end-diastolic pressures typical of acute ischemia. However, structural studies identifying damage to the myocardial collagen network early in ischemia suggest that collagen disruption may also play a role. Support for this idea comes from a study by MacKenna et al., in which bacterial collagenase treatment of perfused isolated arrested rat LVs caused a rightward shift in passive pressure-volume and pressure-strain curves (72). MacKennas pressure-strain data resembled data from acute ischemia in that the rightward shifts occurred with little change in slope and the largest shifts were in circumferential strain. However, the changes in this study were faster than collagenase normally degrades collagen, and this experimental preparation becomes
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rapidly edematous, so it is difcult to separate changes owing to disruption of collagen or collagen-myocyte attachments from changes owing to edema. Although a discussion of myocardial stunning is beyond the scope of this review, experiments on stunning have also provided evidence linking collagen damage and increased compliance of passive myocardium (73, 74).
LOSS OF PERFUSION PRESSURE
Perfusion of isolated arrested hearts is associated with decreased LV compliance and left-shifted passive pressure-strain curves compared to the unperfused state, raising the possibility that the increased LV compliance and rightward shift in pressure-dimension curves reported during acute ischemia could be explained, in part, by a loss of coronary perfusion pressure in the occluded vessel. Allaart et al. found that perfusion increased axial stiffness and unstressed length in papillary muscles owing to an increase in axial stiffness of the perfused blood vessels (75). From their data, loss of perfusion might be expected to decrease both stiffness and unstressed length, but changes in unstressed length have not been reported during acute ischemia. May-Newman and coworkers found that perfusion decreased longitudinal, cross-ber, and radial strains during passive ination of isolated arrested hearts and increased local tissue volume, especially at the endocardium (76). Because circumferential and ber strains were not signicantly altered by perfusion, loss of perfusion would not completely explain reported data for ischemic myocardium, where circumferential remodeling is prominent. However, the large radial changes reported by May-Newman could account for all of the thinning reported by Villarreal in acutely ischemic myocardium (57), and thereby for rightward shifting of pressure-dimension curves through locally increased stresses.
Ventricular Function During Acute Ischemia

Three of the mechanisms by which the presence of an infarct depresses LV function are relevant to acute ischemia: energy loss through stretching of the infarct (mechanism 2), elevated wall stresses owing to infarct and LV dilation (mechanism 4) and impaired function of adjacent myocardium owing to physical coupling with the infarct (mechanism 5). Systolic stretching of the ischemic region is apparent experimentally as a parallel rightward shift of the end-systolic pressure-volume relationship (ESPVR) (77), which can be explained using simple compartmental (22, 77) or spherical membrane (21) models (Figure 1). The key to the response is the exponential passive stress-strain behavior of ischemic myocardium. Although the ischemic region may be relatively extensible at low pressures, at the much higher pressures and wall stresses typical of end-systole, the ischemic region is stretched onto a portion of its stress-strain curve so steep it is essentially inextensible. Compared to normally activated systolic myocardium (which has contracted rather than stretched relative to its end-diastolic conguration), the ischemic region therefore contains roughly the same volume of extra blood at any physiologic systolic pressure, accounting for the rightward shift of the ESPVR. Systolic stretching
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of the ischemic region also depresses global ventricular function through a second mechanism not explicitly incorporated in simple compartmental models. Reduced systolic ejection eventually leads to a new steady state in which systolic and diastolic volumes are increased relative to control and ejection fraction is depressed, in other words, to global ventricular dilation (78). Dilation places the noninfarcted myocardium at a mechanical disadvantage, with higher systolic stresses required to eject against a given pressure. In addition to the impact of systolic stretching of the infarct region, studies of regional function during acute ischemia have indicated that the extent of regional dysfunction extends beyond the region of reduced blood ow, creating a functional border zone (31). Recently, a combination of modeling and experimental studies have shown that border zone dysfunction can be explained by physical coupling to the ischemic region (79) and elevated border zone stresses (8083), without postulating reduced contractility.
THE NECROTIC PHASE

During the rst few days after infarction, the dominant pathologic processes are inammation and necrosis. We dene the necrotic phase as beginning within a few hours, when the infarct begins to stiffen, and ending when the number of broblasts and amount of new collagen begin to increase rapidly in the healing infarct [approximately 7 days after infarction in the human (41) and 5 days after infarction in the rat (40) (Figure 4)]. Infarct rupture is most common during this period (14, 15). Given that the infarcted muscle is dead and undergoing necrosis, and signicant new collagen has not yet been deposited, it is perhaps surprising
Figure 4 Comparative diagram of the temporal course of the phases of healing dened in this review for various animal models. Time course for other large animal models is similar to that for dog. Please see text for denition of phases and primary references for various models.
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that every infarct does not rupture during this phase. Infarct mechanics during this critical period are still poorly understood. In this section, we attempt to identify structural features responsible for infarct mechanical properties and maintenance of infarct integrity during the necrotic phase.
Structural Changes During the Necrotic Phase

Within hours after infarction, the infarcted muscle loses its striations and changes its staining properties (42). Within 24 h, 94% of human infarcts have wavy bers, indicating intercellular edema, and 90% have clear necrosis characterized by altered staining properties and nuclear pyknosis or karyolysis (41). By the fourth or fth day, removal of dead muscle is clearly observed (41, 42). Collagenase and gelatinase activity of MMP-1, MMP-2, and MMP-9 is elevated during the necrotic phase of infarct healing (84, 85), and disruption of the collagen network continues. During the rst 4 days after infarction in rats, there is a progressive decrease in the number of normally birefringent collagen bers, and by 4 days there is a signicant reduction in the number of collagen struts that laterally connect myocytes (86). As the necrotic phase concludes, deposition of new ECM components begins, forming a scaffold for the deposition of new collagen. Fibronectin (87, 88), laminin (89), and collagen type IV (89) all appear at 34 days in the healing rat infarct, approximately the same time that mRNA for type III (rst) and I (slightly later) procollagens is rst detected (90).
Changes in Mechanical Properties During the Necrotic Phase

Two changes in mechanics are apparent in the necrotic infarct. First, circumferential and longitudinal stiffness increase under multiaxial loading, whereas uniaxial tests show no change in stiffness, suggesting increased mechanical coupling between the two directions. Second, unstressed segment length increases, at least in the circumferential direction, whereas end-diastolic length does not. The net effect is an increase of segment lengths below end-diastolic pressure but a decrease in segment lengths at higher pressures. Theroux et al. tracked the distance between pairs of circumferentially oriented sonomicrometers implanted in the subendocardium over 4 weeks following experimental infarction in dogs (63). Circumferential segmental shortening remained approximately zero in the infarct throughout the rst week (0% at 1 day, 1.9 0.1% at 1 week). EDP and segment length were unchanged from preinfarction control at 1 day and 1 week. However, the slope of the diastolic pressure-length relationship during lling was increased more than vefold at 1 day, 2 days, and 1 week. Hood reported a similarly dramatic increase in the slope of the diastolic pressure-circumferential segment length relation and an increase in unstressed length in 5-day-old canine infarcts both in vivo and in isolated arrested hearts (91), whereas Lima et al. found reduced systolic principal strains in 1-week-old ovine infarcts using MRI tagging (92). Because mild thinning of the infarcted region typically occurs over the rst week, stresses in the infarcts were likely similar to
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or slightly greater than in control regions at a given diastolic pressure. Therefore, these studies imply increased stiffness and unstressed length in healing myocardial infarcts throughout the necrotic phase. By contrast, uniaxial tests of strips of healing infarct tissue have consistently indicated that infarct material properties do not change during the necrotic phase of healing. Laird et al. studied uniaxial strips cut from the midwall of infarcted rabbit hearts along the original myober direction (nearly circumferential) and found no change in stiffness during the 10 days following infarction (24). In a more detailed study at a single time point, Przyklenk et al. tested longitudinally oriented strips cut from several transmural layers of normal canine myocardium and 24-h-old infarcts. They found no differences between normal and necrotic myocardium in stiffness, tensile strength, or strain at rupture (93). Only a single report of biaxial mechanical testing of healing infarct tissue is currently available, and the results agree better with in vivo studies. Gupta and coworkers measured circumferential and longitudinal stresses at 15% equibiaxial stretch in healing anterior ovine infarcts during each of the phases of infarct healing outlined in this review (29). At 1 week, although collagen content had increased by less than twofold, longitudinal stress at 15% equibiaxial stretch reached its peak value for the entire time course studied, roughly six times control values (Figure 2). Circumferential stress at 15% equibiaxial stretch was also increased at 1 week to more than eight times its control value, although it did not peak until 2 weeks. Although the use of only a single test protocol limits the interpretation of their data somewhat, their equibiaxial stretch data, like the in situ pressure-length curves, suggest a several-fold increase in infarct stiffness at 1 week, before the bulk of new collagen deposition occurs.
Determinants of Infarct Mechanics During the Necrotic Phase

Unfortunately, very little direct information is available regarding the determinants of mechanical properties during the necrotic phase. Most evidence is either correlative, relating pathologic observations to functional ones, or circumstantial, derived from the outcome of various experimental interventions. In addition, most of the evidence relates to the prevention or aggravation of infarct expansion. Although the degree of infarct expansion likely depends on infarct material properties, the process is not sufciently well understood to draw conclusions about specic properties, such as infarct stiffness or tensile strength, from data on expansion. In spite of these difculties, the evidence reviewed below strongly suggests that interstitial edema is responsible for reported increases in infarct stiffness during the necrotic phase, whereas infarct expansion is the most likely basis for the reported increase in unstressed dimensions of the necrotic infarct.
MATRIX AND MYOFIBRILLAR NECROSIS
The two primary structural proteins in passive myocardium, titin and collagen, both undergo degradation during the necrotic phase. Necrotic myocytes lose their striations within hours (42), reecting damage
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to the major myobrillar proteins that compose the sarcomere, including titin. Progressive damage to collagen is also seen in the rst days following infarction. Although the impact of this damage on infarct material properties has not been studied directly, the degree of damage correlates with the degree of infarct expansion (86), and selective MMP inhibition limits infarct expansion (94). If titin or collagen normally bear some tension in the stress-free state, their degradation could produce the increase in unstressed segment length reported in necrotic infarcts, but would not explain the reported increase in infarct stiffness.
INTERSTITIAL EDEMA
Several lines of evidence support the idea that interstitial edema increases myocardial stiffness. First, studies of iatrogenic edema associated with cardioplegia have shown that experimentally induced global edema decreases ventricular compliance, but have not consistently found changes in unstressed chamber volume (95, 96). Second, studies of the role of edema in postischemic reperfusion injury have shown that interstitial edema increases stiffness in the ischemic region. For example, reperfusion following experimental global ischemia increased ventricular water content and diastolic pressure at a xed volume, whereas reperfusion with a hypertonic solution returned water content to normal and diastolic pressure toward normal (97). Although these studies demonstrate that edema could increase stiffness in necrotic myocardium, the evidence that edema actually does this in necrotic infarcts is more circumstantial. A recent MRI study by Gerber et al. found that reperfused experimental infarcts with high levels of microvascular obstruction (MO) showed less systolic stretching at 48 h postinfarction than infarcts with low levels of MO (98). Another interesting nding was that the high-MO infarcts appeared to be not only stiffer but also more isotropic than low-MO infarcts. However, although high-MO infarcts would likely have more intramyocardial hemorrhage and edema than low-MO infarcts, the degree of infarct edema was not directly veried in this study. Other studies have indicated that infarct water content is signicantly increased several days after infarction, even in the absence of reperfusion (99). The nal line of evidence that edema is an important determinant of mechanical properties in the necrotic infarct is that a variety of pharmacologic agents that reduce edema and inammation, including high-dose steroids (100, 101), ibuprofen (102), and indomethacin (103, 104), also aggravate infarct expansion in the rst days following experimental infarction. One of the best of these studies, by Mannisi et al., showed that water content was signicantly increased in the infarct region at 24 h in rats, steroids prevented this water increase, and steroids did not change infarct size or the prevalence of expansion but did increase the extent of infarct expansion when it occurred (101). Although the relationship between infarct material properties and infarct expansion is not well understood, these studies suggest that edema reinforces the necrotic infarct against expansion by increasing stiffness and/or tensile strength, and antiinammatory agents promote expansion by reducing edema.
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INFARCT EXPANSION
Infarct expansion does not occur in all infarcts, but when it occurs it should change two aspects of infarct mechanics. First, a dilated, thinned infarct will have higher wall stresses at any cavity pressure. This should not change the true stiffness of the infarct, but it could act to decrease the apparent stiffness of the infarct as assessed by pressure-dimension data. This is likely at most a minor effect because pressure-dimension studies consistently show apparent stiffening of the infarct. Although infarct expansion cannot explain reported increases in necrotic infarct stiffness, it is an excellent candidate for explaining the increase in unstressed segment length. Expansion proceeds by rearrangement of existing material, with slippage of bundles of cells relative to one another in planes parallel to the epicardium the primary mechanism (105). Grossly, the endocardial and epicardial area of the infarct increase and the wall thickness decreases (27, 65, 106108). Thus, the unloaded length of a circumferential or longitudinal segment under long-term monitoring would increase as expansion proceeds. In an in vitro model of this process, Connelly and coworkers showed that during cyclic stretching of strips of 1-day rabbit infarcts, elevated peak stress induced a 4%5% per hour permanent increase in unstressed length (109).
Ventricular Function During the Necrotic Phase

Of the mechanisms for depression of ventricular function discussed at the outset, the most concerning during the necrotic phase is infarct rupture (mechanism 1). Nearly all infarct ruptures occur during this phase (within the rst week in humans) (14, 15). Otherwise, the determinants of function are similar to those discussed for acute ischemia. Moderate stiffening of the infarct through the necrotic phase increasingly limits detrimental infarct stretching (mechanism 2) (110). However, continued infarct expansion and ventricular dilation, if present, will exacerbate both local and global increases in wall stress (mechanism 5). Whether ventricular function improves or worsens will be determined by a balance between these effects. For example, Kumar showed that ventricular function curves were consistently depressed during acute ischemia in dogs but recovered substantially at 1 week, allowing the dogs to maintain control levels of cardiac output at enddiastolic pressures that were greater than control but less than those observed during acute ischemia (111).
THE FIBROTIC PHASE

Although pathologic signs of necrosis persist for weeks to months in humans (41, 42) and large animals (112), the healing infarct soon enters a phase where new collagen deposition is the primary determinant of structural and mechanical changes. Collagen content increases rapidly (29, 113, 114) and infarct stiffness roughly correlates with collagen content (29). We dene the brotic phase as beginning when the number of broblasts and amount of new collagen begin
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to increase rapidly in the healing infarct [approximately 7 days after infarction in the human (41) and 5 days after infarction in the rat (40) (Figure 4)], and ending when collagen accumulation slows and mechanical properties decouple from collagen content. This occurs at approximately 3 weeks in large animal models (29), presumably earlier in the rat and later in humans (Figure 4).
Structural Changes During the Fibrotic Phase

Collagen content increases steadily from 1 to 6 weeks after experimental infarction in dogs (112, 114) and sheep (29). Qualitative observations at autopsy indicate a similar time course for human myocardial infarction (41, 42). In rats, the collagen content begins rising on day 4 or 5 (40) and continues to increase for at least 3 weeks (40, 115). The healing infarct contains a mixture of collagen types I, III, and other minor subtypes (115), and Whittaker et al. have suggested that an initial mesh of type III collagen forms the scaffold for subsequent deposition of large, highly aligned type I collagen bers (116). By 3 weeks after infarction in pig, the scar is dominated by large type I collagen bers highly aligned with one another in each transmural layer (117). The mean orientation of the collagen bers varies with depth below the epicardium in a pattern similar to that for normal muscle bers except that the transmural range of mean angles is smaller (30). The net result of this pattern is that the majority of large collagen bers in the scar are oriented within 30 of the circumferential direction (118). A similar pattern of collagen ber alignment has been reported 2 weeks after infarction in rat (119) and at 6 weeks in dog (116).
Changes in Mechanical Properties During the Fibrotic Phase

Only a few studies have evaluated mechanics during this phase of healing. The available evidence suggests that during this phase infarct stiffness peaks and the healing infarct acquires a distinctive anisotropy. Theroux reported that segment lengths changed only approximately 2% over the cardiac cycle at 1, 2, and 3 weeks after infarction in dogs, suggesting high stiffness in the healing infarcts (63). The slope of the passive pressure-segment length relationship conrmed elevated stiffness, varying from six to nine times control values depending on EDP (63). Gibbons et al. found that the circumferential extent of abnormal wall motion peaked 48 h after infarction in the dog and then decreased over the next 6 weeks (120). When we studied the three-dimensional mechanics of healing porcine infarcts, we also found that systolic strains were not different from zero at 1 week, consistent with elevated stiffness (121). However, although circumferential stretching remained minimal at 3 weeks, signicant passive longitudinal shortening and radial thickening returned, suggesting developing mechanical anisotropy in the healing scar. Connelly and Lerman both reported that uniaxial tensile strength of excised strips of 1-week-old rabbit myocardial scar tissue was roughly double that for control myocardium, but did not report stiffness values at this time point (113, 122). Gupta et al. performed equibiaxial mechanical tests of excised ovine scar tissue and found that stress at 15% equibiaxial stretch peaked at 1 week in the longitudinal
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direction at a value 6 times control and at 2 weeks in the circumferential direction at a value 16 times control (Figure 2) (29). Although longitudinal stresses at 15% equibiaxial stretch remained roughly twice circumferential stresses at all time points for noninfarcted myocardium, the healing scar switched from stiffer in the longitudinal direction through the rst week to stiffer in the circumferential direction beyond the second week (29). We found similar anisotropy in 3-weekold porcine infarcts, which displayed little circumferential stretch in the healing scar during passive ination of isolated arrested hearts over a physiologic range of cavity pressures, but roughly 50% greater longitudinal stretch at any pressure as remote noninfarcted myocardium (Figure 5) (123). By contrast, Omens et al. found a greater reduction in longitudinal than in circumferential epicardial strains in the scar during passive ination of isolated arrested hearts 2 weeks after infarction in rat (119). They also found that collagen bers in the scar straightened more rapidly with pressure but were not straighter in the unloaded state than collagen bers in normal myocardium.
Figure 5 Anisotropy in 3-week-old porcine scar with large collagen bers oriented predominantly in the circumferential direction. Lines show transmural pattern of strains as isolated arrested heart is inated from a cavity pressure of 5 mm Hg (lowest line in each panel, with symbols) in 5-mm Hg increments to 25 mm Hg (highest line, with symbols). Circumferential strains are much smaller at all depths and pressures in the scar (upper right panel ) compared to remote noninfarcted myocardium (upper left), whereas longitudinal strains are similar in the scar (lower right) and muscle (lower left) (123).
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Determinants of Infarct Mechanics During the Fibrotic Phase

In this review, we dene the brotic phase as the phase of healing dominated by new collagen deposition. During this phase, both the amount of collagen and the three-dimensional structure of the collagen bers are important determinants of infarct mechanics. Other matrix components may also be important, but there is not yet enough information to assess their role relative to collagen.
COLLAGEN CONTENT
Because infarct stiffness and collagen content increase in parallel during the brotic phase, it seems obvious that collagen content is one primary determinant of the mechanical properties of the healing infarct during this phase. However, the effects of alterations in collagen content and subtype ratios on scar mechanics have not been systematically studied. Lerman found that passive stiffness of the rabbit LV correlated with hydroxyproline content over the rst week after infarction (113), as would be expected if hydroxyproline content correlates with stiffness of the healing infarct (21, 26). The nding that myocardial infarcts are highly anisotropic during the brotic phase of healing (29, 30) implicates the highly aligned large collagen ber structure as the second primary determinant of infarct properties during this phase. The predominance of large collagen bers oriented in the circumferential direction (116, 117) is consistent with reports that myocardial scar is stiffer in the circumferential direction in most animal models (29, 30). However, more work is needed, particularly in the development of structural constitutive models for myocardial scar tissue (118).
THREE-DIMENSIONAL COLLAGEN STRUCTURE
Ventricular Function During the Fibrotic Phase

The two mechanisms by which infarcts in the brotic phase of healing may depress LV function are impaired lling owing to elevated chamber stiffness (mechanism 3) and impaired systolic function of adjacent noninfarcted myocardium owing to coupling with the infarct (mechanism 5). Janz (26) and Bogen (21) both predicted that the primary adverse effect of a very stiff infarct would be impaired lling owing to decreased LV compliance. Janz also suggested that diastolic stretch of adjacent noninfarcted myocardium would be limited during lling by tethering to the very stiff infarct, reducing systolic function via the Frank-Starling mechanism (26). We have proposed that tethering of adjacent noninfarcted myocardium to a stiff isotropic infarct would directly retard both systolic shortening parallel to the infarct border and radial thickening (30). The anisotropy we observed in 3-weekold porcine scars oriented longitudinally on the LV appears to minimize this effect: high circumferential stiffness prevents stretching of the infarct perpendicular to its border, whereas low longitudinal and radial stiffness allow the scar to deform compatibly with adjacent myocardium in these directions (30). Evidence in support of this hypothesis includes the fact that longitudinal shortening and wall thickening in the healing infarct disappear at 1 week in this animal model (when the infarct is
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stiff and isotropic) then reappear at 3 weeks (once infarct anisotropy is established), despite the absence of viable myocardium. Another consistent observation is that, in the study by Gerber et al. discussed above, high-MO infarcts, which appeared to be stiffer and more isotropic, reduced wall thickening in adjacent noninfarcted myocardium much more than low-MO infarcts (98).
THE REMODELING PHASE

As healing continues, the mechanical properties of the infarct decouple from collagen content. Collagen content may continue to rise for several weeks while infarct stiffness drops (29), suggesting that other factors now dominate the mechanics. We term this phase the remodeling phase, and although its onset can be dened, the healing scar tissue is a dynamic, biologically active tissue that may never reach a stable, mature conguration (healed as opposed to healing) that could be taken to mark the end of remodeling (124).
Structural Remodeling of Myocardial Scar Tissue

Remodeling of the myocardial scar occurs during this phase at both the gross and microscopic levels. On the gross level, the dominant effect is shrinkage of the scar to occupy a reduced percentage of the LV wall. In canine models, direct topographic measurements indicated a 40% shrinkage of the infarct over 6 weeks (114), whereas condensation of microspheres indicated 30% to more than 70% shrinkage (99, 125), depending on infarct size and location. At the microscopic level, the rise in collagen content slows but cross-linking continues to increase. After a tenfold increase in the rst 4 weeks, Jugdutt found that hydroxyproline increased only an additional 20% from week 4 to week 6 in dogs (114). Vivaldi found a 50% increase in collagen content between 2 and 4 weeks in the rat compared to a doubling of cross-link concentration over the same period (115). Data from McCormick et al. at 13 weeks in the rat showed the same collagen content and another 50% increase in cross-linking compared to Vivaldis 4-week data (126). Qualitative changes in collagen have also been reported. Whittaker found continued increases in molecular organization as assessed by optical retardation for at least 6 weeks in a canine model (116).
Changes in Mechanical Properties During the Remodeling Phase

There is some disagreement in the literature regarding changes in scar mechanical properties during the remodeling phase. Although Parmley found that strips of brous human aneurysms tested uniaxially months to years after infarction were many times stiffer than muscular aneurysms from patients who died days after infarction (23), Connelly reported only moderately (twofold) increased stiffness in samples from 3-week-old rabbit scar tissue compared to noninfarcted myocardium
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(122). Scar anisotropy may largely explain these differences; in 6-week-old ovine scar stretched equibiaxially by 15%, Gupta et al. reported longitudinal stresses identical to those in control myocardium, whereas circumferential stresses were tenfold greater in the scar (Figure 2) (29).
Determinants of Infarct Mechanics During the Remodeling Phase

During the early part of the remodeling phase, infarct stiffness decreases while collagen content continues to increase, indicating that collagen content and ber structure are no longer the only important determinants of the mechanical properties of the healing infarct. Structural changes during this phase of healing have received much less attention, but one factor that does appear to correlate with infarct mechanics late in healing is the degree of cross-linking.
COLLAGEN CROSS-LINKING
Connelly et al. compared uniaxial mechanics of strips of rabbit scar tissue 3 weeks after infarction in rabbits, with or without reperfusion. Late reperfusion (3 h after infarction) did not change scar collagen content or stiffness, but it did reduce cross-link density and tensile strength, suggesting that cross-linking can inuence the mechanics of healing scar tissue. Similar ndings have been reported in healing rabbit ligament, where reduced crosslink density is associated with reduced failure strength despite normal collagen concentrations (127). More work is needed to determine the effect of cross-linking on multiaxial mechanics of healing myocardial scar.
Ventricular Function During the Remodeling Phase

In many patients and experimental models, LV function improves as healing reaches the later stages. Clinical studies show improved hemodynamics and partially normalized LV compliance and EDP 46 weeks after infarction (60, 128), with few additional functional changes over the remainder of the rst year (128, 129). All of the mechanisms for depression of function discussed at the beginning of this review except infarct rupture are involved to some extent in this late improvement in LV function. Scar stiffness remains higher than that of passive or acutely ischemic myocardium, limiting energy loss owing to systolic stretching (mechanism 2), and anisotropy appears to limit local tethering effects (mechanism 5). Scar shrinkage acts like infarct expansion in reverse, reducing the volume of the scar and infarct-associated cavity dilation (mechanism 4): wall motion abnormalities partially resolve (120, 125, 130), and the reduction in wall motion abnormality correlates closely with scar contraction (125). To the extent that LV dysfunction remains, it primarily reects limitation of diastolic function owing to reduced diastolic compliance (mechanism 3, Figure 1). For example, Weisse found normal hemodynamics with mildly depressed ventricular function curves at 34 and 6 8 weeks following infarction in dogs. The depressed ventricular function curves were due entirely to a stiffer end-diastolic pressure-volume relationship (EDPVR),
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resolving when stroke work was plotted as a function of end-diastolic circumference rather than pressure (131). However, there are some exceptions to this generally improving course. When very large infarcts are present, cavity dilation dominates other effects, such as scar shrinkage, leading to increased wall stresses and progressively depressed function (mechanism 6) (132, 133). If an aneurysm forms, the severely altered local geometry increases stresses (134) and depresses function (134136) in the adjacent myocardium, creating a functional border zone analogous to that discussed for acute ischemia.
SUMMARY AND CONCLUSIONS

Based on temporal correlation of reported changes in structure and mechanics of healing myocardial infarcts, we have dened four phases of infarct healing and hypothesized the following: (a) Mechanical properties during acute ischemia (the rst few hours) are essentially the normal constitutive properties of passive myocardium, (b) mechanical properties during the necrotic phase (the rst 5 7 days depending on animal model) are dominated by edema, (c) mechanical properties during the brotic phase (up to 24 weeks) arise from the large collagen ber structure, and (d ) mechanical properties during the remodeling phase (the remainder of the healing process) are determined primarily by collagen crosslinking. We intend these hypotheses to stimulate further, mechanistic research on the mechanics of healing myocardial infarcts. Certainly, this review suggests many areas where more data are needed: Quantitative structural studies of the threedimensional organization of important matrix components and determination of constitutive relations for scar tissue at multiple time points during healing would head our list. However, the mechanics of healing infarct tissue, like those of heart tissue in general, depend both on constitutive properties and on loading conditions, which in turn are determined by hemodynamics, ventricular and local geometry, and coupling to adjacent myocardium. The individual studies reviewed here typically provide complementary, incomplete subsets of information about infarct mechanics. Studies using ventriculography and echocardiography provide information on global ventricular function and shape, plus more limited information on regional deformation in the infarct. Studies using implanted sonomicrometers or radiopaque markers provide more regional detail, with the advantages that infarct mechanics can still be related to overall ventricular function and that the deformation of an infarcted segment can be tracked not only throughout the cardiac cycle but also throughout longer-term remodeling; the primary disadvantage is that stresses cannot be measured directly but must be estimated from hemodynamic and geometric data by modeling (118). Finally, excision and mechanical testing of tissue provides the most direct characterization of tissue material properties, with the caveat that excision itself may alter those properties.
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Remarkably few studies have tried to integrate these different experimental methods to obtain a complete picture of infarct mechanics even at a single time in a single animal model. The primary consequence of this lack of integration is that the wealth of information on changes in infarct deformation patterns over the course of postinfarction healing is difcult to interpret. In future studies, much more attention needs to be paid to differentiating changes in material properties (shifts of the stress-strain curve) from changes in loading (shifts along the stress-strain curve) because completely different therapeutic approaches may be appropriate to address these two different bases for altered mechanics. Multiaxial testing of infarcts at the various stages of healing is needed, but should include careful registration of these data to the in vivo working range. The other type of integration that is largely missing from the literature is direct integration of structural and mechanical data. No study we reviewed reported collagen content, cross-linking, and ber structure along with mechanics of a healing infarct, and none of the studies directly altered tissue composition to test hypotheses about the structural basis for observed mechanical properties. In summary, although much is known about changes in ventricular function, regional deformation, and tissue composition during the course of infarct healing, the underlying mechanics of the simplest case, permanent coronary occlusion without reperfusion, are still not sufciently understood to predict the impact of proposed interventions or to specify the design requirements for a tissue-engineered replacement. Integrative studies combining material testing, quantitative structural analysis, and in vivo functional studies are needed, as are structural constitutive models. By allowing prediction of the changes in mechanics and function that will follow from proposed changes to healing infarct structure, these new studies would allow rational design of bioengineering therapies to improve long-term survival and quality of life for patients who suffer myocardial infarction. ACKNOWLEDGMENTS This work was supported by National Institutes of Health grant HL-075639 (J.W.H.). The authors wish to acknowledge Dr. Kevin Costa and the students of the Cardiac Biomechanics Group at Columbia University for comments on the developing manuscript. The Annual Review of Biomedical Engineering is online at http://biomed.annualreviews.org LITERATURE CITED
1. American Heart Association. 2003. Heart Disease and Stroke Statistics2004 Update. Dallas, TX: Am. Heart Assoc. 2. Topol EJ. 2003. Current status and future prospects for acute myocardial infarction therapy. Circulation 108:III613 3. Armstrong PW, Collen D, Antman E. 2003. Fibrinolysis for acute myocardial
INFARCT STRUCTURE AND MECHANICS infarction: the future is here and now. Circulation 107:253337 Udelson JE. 2004. Ventricular remodeling in heart failure and the effect of betablockade. Am. J. Cardiol. 93:43B48B Sharpe N. 2004. Cardiac remodeling in coronary artery disease. Am. J. Cardiol. 93:17B20B Sutton MG, Sharpe N. 2000. Left ventricular remodeling after myocardial infarction: pathophysiology and therapy. Circulation 101:298188 Forrester JS, Price MJ, Makkar RR. 2003. Stem cell repair of infarcted myocardium: an overview for clinicians. Circulation 108:113945 Thompson RB, Emani SM, Davis BH, van den Bos EJ, Morimoto Y, et al. 2003. Comparison of intracardiac cell transplantation: autologous skeletal myoblasts versus bone marrow cells. Circulation 108(Suppl. 1):II26471 Ghostine S, Carrion C, Souza LC, Richard P, Bruneval P, et al. 2002. Long-term efcacy of myoblast transplantation on regional structure and function after myocardial infarction. Circulation 106:I131 36 Jain M, DerSimonian H, Brenner DA, Ngoy S, Teller P, et al. 2001. Cell therapy attenuates deleterious ventricular remodeling and improves cardiac performance after myocardial infarction. Circulation 103:192027 Zimmermann WH, Melnychenko I, Eschenhagen T. 2004. Engineered heart tissue for regeneration of diseased hearts. Biomaterials 25:163947 Matsubayashi K, Fedak PW, Mickle DA, Weisel RD, Ozawa T, Li RK. 2003. Improved left ventricular aneurysm repair with bioengineered vascular smooth muscle grafts. Circulation 108(Suppl. 1): II21925 Roberts R, DeMello V, Sobel BE. 1976. Deleterious effects of methylprednisolone in patients with myocardial infarction. Circulation 53:I-2045
247
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14. Birnbaum Y, Chamoun AJ, Anzuini A, Lick SD, Ahmad M, Uretsky BF. 2003. Ventricular free wall rupture following acute myocardial infarction. Coron Artery Dis. 14:46370 15. Wehrens XH, Doevendans PA. 2004. Cardiac rupture complicating myocardial infarction. Int. J. Cardiol. 95:285 92 16. Bogen DK, McMahon TA. 1979. Do cardiac aneurysms blow out? Biophys. J. 27: 30116 17. Radhakrishnan S, Ghista DN, Jayaraman G. 1980. Mechanical analysis of the development of left ventricular aneurysms. J. Biomech. 13:103139 18. Radhakrishnan S, Ghista DN, Jayaraman G. 1986. Mechanics of left ventricular aneurysm. J. Biomed. Eng. 8:923 19. Page DL, Cauleld JB, Kastor JA, DeSanctis RW, Sanders CA. 1971. Myocardial changes associated with cardiogenic shock. N. Engl. J. Med. 285:13337 20. Alonso DR, Scheidt S, Post M, Killip T. 1973. Pathophysiology of cardiogenic shock. Quantication of myocardial necrosis, clinical, pathologic and electrocardiographic correlations. Circulation 48:58896 21. Bogen DK, Rabinowitz SA, Needleman A, McMahon TA, Abelmann WH. 1980. An analysis of the mechanical disadvantage of myocardial infarction in the canine left ventricle. Circ. Res. 47:72841 22. Swan HJ, Forrester JS, Diamond G, Chatterjee K, Parmley WW. 1972. Hemodynamic spectrum of myocardial infarction and cardiogenic shock. A conceptual model. Circulation 45:1097110 23. Parmley WW, Chuck L, Kivowitz C, Matloff JM, Swan HJ. 1973. In vitro lengthtension relations of human ventricular aneurysms. Relation of stiffness to mechanical disadvantage Am. J. Cardiol. 32: 88994 24. Laird JD, Vellekoop HP. 1977. Time course of passive elasticity of myocardial tissue following experimental infarction
248
HOLMES
BORG
COVELL Factors inuencing infarct size following experimental coronary artery occlusions. Circulation 43:6782 Harken AH, Simson MB, Haselgrove J, Wetstein L, Harden WR, Barlow CH. 1981. Early ischemia after complete coronary ligation in the rabbit, dog, pig, and monkey. Am. J. Physiol. Heart Circ. Physiol. 241:H20210 Connelly C, Vogel WM, Hernandez YM, Apstein CS. 1982. Movement of necrotic wavefront after coronary artery occlusion in the rabbit. Am. J. Physiol. Heart Circ. Physiol. 243:H68290 Miura T, Yellon DM, Hearse DJ, Downey JM. 1987. Determinants of infarct size during permanent occlusion of a coronary artery in the closed chest dog. J. Am. Coll. Cardiol. 9:64754 Pirzada FA, Ekong EA, Vokonas PS, Apstein CS, Hood WB. 1976. Experimental myocardial infarction. XIII. Sequential changes in left ventricular pressure-length relationships in the acute phase. Circulation 53:97075 Vokonas PS, Pirzada FA, Hood WB. 1976. Experimental myocardial infarction. XII. Dynamic changes in segmental mechanical behavior of infarcted and non-infarcted myocardium. Am. J. Cardiol. 37:85359 Fishbein MC, Maclean D, Maroko PR. 1978. Experimental myocardial infarction in the rat: qualitative and quantitative changes during pathologic evolution. Am. J. Pathol. 90:5770 Fishbein MC, Maclean D, Maroko PR. 1978. The histopathologic evolution of myocardial infarction. Chest 73:843 49 Mallory KG, White PD, Salcedo-Salgar J. 1939. The speed of healing of myocardial infarction: a study of the pathologic anatomy in seventy-two cases. Am. Heart J. 18:64771 Cauleld JB, Borg TK. 1979. The collagen network of the heart. Lab Invest. 40:36472
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
in rabbits and its relation to mechanical dysfunction. Circ. Res. 41:71521 Smith M, Russell RO, Feild BJ, Rackley CE. 1974. Left ventricular compliance and abnormally contracting segments in postmyocardial infarction patients. Chest 65:36878 Janz RF, Waldron RJ. 1978. Predicted effect of chronic apical aneurysms on the passive stiffness of the human left ventricle. Circ. Res. 42:25563 Weisman HF, Healy B. Myocardial infarct expansion, infarct extension, and reinfarction: pathophysiologic concepts. Prog. Cardiovasc. Dis. 1987:73110 Bogaert J, Bosmans H, Maes A, Suetens P, Marchal G, Rademakers FE. 2000. Remote myocardial dysfunction after acute anterior myocardial infarction: impact of left ventricular shape on regional function: a magnetic resonance myocardial tagging study. J. Am. Coll. Cardiol. 35: 152534 Gupta KB, Ratcliffe MB, Fallert MA, Edmunds LH Jr, Bogen DK. 1994. Changes in passive mechanical stiffness of myocardial tissue with aneurysm formation. Circulation 89:231526 Holmes JW, Nunez JA, Covell JW. 1997. Functional implications of myocardial scar structure. Am. J. Physiol. Heart Circ. Physiol. 272:H212330 Gallagher KP, Gerren RA, Stirling MC, Choy M, Dysko RC, et al. 1986. The distribution of functional impairment across the lateral border of acutely ischemic myocardium. Circ. Res. 58:57083 Pfeffer MA, Braunwald E. 1990. Ventricular remodeling after myocardial infarction. Experimental observations and clinical implications. Circulation 81:1161 72 Holmes JW. 2004. Candidate mechanical stimuli for hypertrophy during volume overload. J. Appl. Physiol. 97:1453 60 Maroko PR, Kjekshus JK, Sobel BE, Watanabe T, Covell JW, et al. 1971.
35.
36.
37.
38.
39.
40.
41.
42.
43.
INFARCT STRUCTURE AND MECHANICS 44. Borg TK, Cauleld JB. 1981. The collagen matrix of the heart. Fed. Proc. 40: 203741 45. Weber KT. 1989. Cardiac interstitium in health and disease: the brillar collagen network. J. Am. Coll. Cardiol. 13:1637 53 46. Legrice IJ, Hunter PJ, Smaill BH. 1997. Laminar structure of the heart: a mathematical model. Am. J. Physiol. Heart Circ. Physiol. 272:H246676 47. Goldsmith EC, Borg TK. 2002. The dynamic interaction of the extracellular matrix in cardiac remodeling. J. Card. Fail. 8:S31418 48. Goldsmith EC, Carver W, McFadden A, Goldsmith JG, Price RL, et al. 2003. Integrin shedding as a mechanism of cellular adaptation during cardiac growth. Am. J. Physiol. Heart Circ. Physiol. 284:H2227 34 49. Jugdutt BI. 2003. Ventricular remodeling after infarction and the extracellular collagen matrix: when is enough enough? Circulation 108:1395403 50. Whittaker P. 1998. Collagen organization in wound healing after myocardial injury. Basic Res. Cardiol. 93(Suppl. 3):2325 51. Sato S, Ashraf M, Millard RW, Fujiwara H, Schwartz A. 1983. Connective tissue changes in early ischemia of porcine myocardium: an ultrastructural study. J. Mol. Cell. Cardiol. 15:26175 52. Cauleld JB, Tao SB, Nachtigal M. 1985. Ventricular collagen matrix and alterations. Adv. Myocardiol. 5:25769 53. Takahashi S, Barry AC, Factor SM. 1990. Collagen degradation in ischaemic rat hearts. Biochem. J. 265:23341 54. Etoh T, Joffs C, Deschamps AM, Davis J, Dowdy K, et al. 2001. Myocardial and interstitial matrix metalloproteinase activity after acute myocardial infarction in pigs. Am. J. Physiol. Heart Circ. Physiol. 281:H98794 55. Tennant R, Wiggers CJ. 1935. The effect of coronary occlusion on myocardial contraction. Am. J. Physiol. 112:35136
249
56. Tyberg JV, Forrester JS, Wyatt HL, Goldner SJ, Parmley WW, Swan HJC. 1974. An analysis of segmental ischemic dysfunction using the pressure-length loop. Circulation 49:74854 57. Villarreal FJ, Lew WYW, Waldman LK, Covell JW. 1991. Transmural myocardial deformation in the ischemic canine left ventricle. Circ. Res. 68:36881 58. Forrester JS, Diamond G, Parmley WW, Swan HJC. 1972. Early increase in left ventricular compliance after myocardial infarction. J. Clin. Invest. 51:598603 59. Diamond G, Forrester JS. 1972. Effect of coronary artery disease and acute myocardial infarction on left ventricular compliance in man. Circulation 45:1119 60. Bleifeld W, Mathey D, Hanrath P. 1974. Acute myocardial infarction. VI. Left ventricular wall stiffness in the acute phase and in the convalescent phase. Eur. J. Cardiol. 2:19198 61. Theroux P, Franklin D, Ross J Jr, Kemper WS. 1974. Regional myocardial function during acute coronary artery occlusion and its modication by pharmacologic agents in the dog. Circ. Res. 35:896908 62. Akaishi M, Weintraub WS, Schneider RM, Klein LW, Agarwal JB, Helfant RH. 1986. Analysis of systolic bulging. Mechanical characteristics of acutely ischemic myocardium in the conscious dog. Circ. Res. 58:20917 63. Theroux P, Ross J Jr, Franklin D, Covell JW, Bloor CM, Sasayama S. 1977. Regional myocardial function and dimensions early and late after myocardial infarction in the unanesthetized dog. Circ. Res. 40:15865 64. Gillam LD, Franklin TD, Foale RA, Wiske PS, Guyer DE, et al. 1986. The natural history of regional wall motion in the acutely infarcted canine ventricle. J. Am. Coll. Cardiol. 7:132534 65. Kass DA, Maughan WL, Ciuffo A, Graves W, Healy B, Weisfeldt ML. 1988. Disproportionate epicardial dilation after
250
HOLMES
BORG
COVELL and myocardial collagen damage: differential effects of single and repeated occlusions. Am. Heart J. 121:43441 Allaart CP, Sipkema P, Westerhof N. 1995. Effect of perfusion pressure on diastolic stress-strain relations of isolated rat papillary muscle. Am. J. Physiol. Heart Circ. Physiol. 268:H94554 May-Newman K, Omens JH, Pavelec RS, McCulloch AD. 1994. Three-dimensional transmural mechanical interaction between the coronary vasculature and passive myocardium in the dog. Circ. Res. 74:116678 Sunagawa K, Maughan WL, Sagawa K. 1983. Effect of regional ischemia on the left ventricular end-systolic pressurevolume relationship of isolated canine hearts. Circ. Res. 52:17078 Seals AA, Pratt CM, Mahmarian JJ, Tadros S, Kleiman N, et al. 1988. Relation of left ventricular dilation during acute myocardial infarction to systolic performance, diastolic dysfunction, infarct size and location. Am. J. Cardiol. 61:224 29 Bovendeerd PH, Arts T, Delhaas T, Huyghe JM, van Campen DH, Reneman RS. 1996. Regional wall mechanics in the ischemic left ventricle: numerical modeling and dog experiments. Am. J. Physiol. Heart Circ. Physiol. 270:H398410 Schuster EH, Bulkley BH. 1979. Expansion of transmural myocardial infarction: a pathophysiologic factor in cardiac rupture. Circulation 60:153238 Mazhari R, Omens JH, Covell JW, McCulloch AD. 2000. Structural basis of regional dysfunction in acutely ischemic myocardium. Cardiovasc. Res. 47:284 93 Mazhari R, McCulloch AD. 2000. Integrative models for understanding the structural basis of regional mechanical dysfunction in ischemic myocardium. Ann. Biomed. Eng. 28:97990 Jackson BM, Gorman JH 3rd, Salgo IS, Moainie SL, Plappert T, et al. 2003.
66.
67.
68.
69.
70.
71.
72.
73.
74.
transmural infarction of the canine left ventricle: acute and chronic differences. J. Am. Coll. Cardiol. 11:17785 Kirton RS, Taberner AJ, Young AA, Nielsen PMF, Loiselle DS. 2004. Strain softening is not present during axial extensions of rat intact right ventricular trabeculae in the presence or absence of 2,3butanedione monoxime. Am. J. Physiol. Heart Circ. Physiol. 286:H70815 Emery JL, Omens JH, McCulloch AD. 1997. Biaxial mechanics of the passively overstretched left ventricle. Am. J. Physiol. Heart Circ. Physiol. 272:H2299305 Emery JL, Omens JH, McCulloch AD. 1997. Strain softening in the rat left ventricular myocardium. J. Biomech. Eng. 119:612 Summerour SR, Emery JL, Fazeli B, Omens JH, McCulloch AD. 1998. Residual strain in ischemic ventricular myocardium. J. Biomech. Eng. 120:71014 Paulus WJ, Grossman W, Serizawa T, Bourdillon PD, Pasipoularides A, Mirsky I. 1985. Different effects of two types of ischemia on myocardial systolic and diastolic function. Am. J. Physiol. Heart Circ. Physiol. 248:H71928 Granzier HL, Irving TC. 1995. Passive tension in cardiac muscle: contribution of collagen, titin, microtubules, and intermediate laments. Biophys. J. 68:1027 44 MacKenna DA, Omens JH, McCulloch AD, Covell JW. 1994. Contribution of collagen matrix to passive left ventricular mechanics in isolated rat hearts. Am. J. Physiol. Heart Circ. Physiol. 266:H1007 18 Zhao MJ, Zhang H, Robinson TF, Factor SM, Sonnenblick EH, Eng C. 1987. Profound structural alterations of the extracellular collagen matrix in postischemic dysfunctional (stunned) but viable myocardium. J. Am. Coll. Cardiol. 10:1322 34 Whittaker P, Boughner DR, Kloner RA, Przyklenk K. 1991. Stunned myocardium
75.
76.
77.
78.
79.
80.
81.
82.
83.
INFARCT STRUCTURE AND MECHANICS Border zone geometry increases wall stress after myocardial infarction: contrast echocardiographic assessment. Am. J. Physiol. Heart Circ. Physiol. 284:H475 79 Cleutjens JP, Kandala JC, Guarda E, Guntaka RV, Weber KT. 1995. Regulation of collagen degradation in the rat myocardium after infarction. J. Mol. Cell. Cardiol. 27:128192 Carlyle WC, Jacobson AW, Judd DL, Tian B, Chu C, et al. 1997. Delayed reperfusion alters matrix metalloproteinase activity and bronectin mRNA expression in the infarct zone of the ligated rat heart. J. Mol. Cell. Cardiol. 29:245163 Whittaker P, Boughner DR, Kloner RA. 1991. Role of collagen in acute myocardial infarct expansion. Circulation 84: 212334 Knowlton AA, Connelly CM, Romo GM, Mamuya W, Apstein CS, Brecher P. 1992. Rapid expression of bronectin in the rabbit heart after myocardial infarction with and without reperfusion. J. Clin. Invest. 89:106068 Ulrich MM, Janssen AM, Daemen MJ, Rappaport L, Samuel JL, et al. 1997. Increased expression of bronectin isoforms after myocardial infarction in rats. J. Mol. Cell. Cardiol. 29:253343 Morishita N, Kusachi S, Yamasaki S, Kondo J, Tsuji T. 1996. Sequential changes in laminin and type IV collagen in the infarct zoneimmunohistochemical study in rat myocardial infarction. Jpn. Circ. J. 60:10814 Cleutjens JP, Verluyten MJ, Smiths JF, Daemen MJ. 1995. Collagen remodeling after myocardial infarction in the rat heart. Am. J. Pathol. 147:32538 Hood WB, Bianco JA, Kumar R, Whiting RB. 1970. Experimental myocardial infarction. IV. Reduction of left ventricular compliance in the healing phase. J. Clin. Invest. 49:131623 Lima J, Ferrari V, Reichek N, Kramer C, Palmon L, et al. 1995. Segmental mo-
251
93.
84.
94.
85.
86.
95.
87.
96.
88.
97.
89.
98.
90.
99.
91.
92.
tion and deformation of transmurally infarcted myocardium in acute postinfarct period. Am. J. Physiol. Heart Circ. Physiol. 268:H130412 Przyklenk K, Connelly CM, McLaughlin RJ, Kloner RA, Apstein CS. 1987. Effect of myocyte necrosis on strength, strain, and stiffness of isolated myocardial strips. Am. Heart J. 114:134959 Lindsey ML, Gannon J, Aikawa M, Schoen FJ, Rabkin E, et al. 2002. Selective matrix metalloproteinase inhibition reduces left ventricular remodeling but does not inhibit angiogenesis after myocardial infarction. Circulation 105:753 58 Weng ZC, Nicolosi AC, Detwiler PW, Hsu DT, Schierman SW, et al. 1992. Effects of crystalloid, blood, and University of Wisconsin perfusates on weight, water content, and left ventricular compliance in an edema-prone, isolated porcine heart model. J. Thorac. Cardiovasc. Surg. 103:50413 Amirhamzeh MM, Hsu DT, Cabreriza SE, Jia CX, Spotnitz HM. 1997. Myocardial edema: comparison of effects on lling volume and stiffness of the left ventricle in rats and pigs. Ann. Thorac. Surg. 63:129397 Vogel WM, Cerel AW, Apstein CS. 1986. Post-ischemic cardiac chamber stiffness and coronary vasomotion: the role of edema and effects of dextran. J. Mol. Cell. Cardiol. 18:120718 Gerber B, Rochitte C, Melin J, McVeigh E, Bluemke D, et al. 2000. Microvascular obstruction and left ventricular remodeling early after acute myocardial infarction. Circulation 101:273441 Reimer KA, Jennings RB. 1979. The changing anatomic reference base of evolving myocardial infarction. Underestimation of myocardial collateral blood ow and overestimation of experimental anatomic infarct size due to tissue edema, hemorrhage and acute inammation. Circulation 60:86676
252
HOLMES
BORG
COVELL sponse to increases in preload and afterload. Circulation 84:38799 Hood WB. 1970. Experimental myocardial infarction. III. Recovery of left ventricular function in the healing phase. Contribution of increased ber shortening in noninfarcted myocardium. Am. Heart J. 79:53138 Kumar R, Hood WB, Joison J, Norman JC, Abelmann WH. 1970. Experimental myocardial infarction. II. Acute depression and subsequent recovery of left ventricular function: serial measurements in intact conscious dogs. J. Clin. Invest. 49:5562 Karsner HT, Dwyer JE. 1916. Studies in infarction IV: experimental bland infarction of the myocardium, myocardial regeneration and cicatrization. J. Med. Res. 34:2139 Lerman RH, Apstein CS, Kagan HM, Osmers EL, Chichester CO, et al. 1983. Myocardial healing and repair after experimental infarction in the rabbit. Circ. Res. 53:37888 Jugdutt BI, Amy RWM. 1986. Healing after myocardial infarction in the dog: changes in infarct hydroxyproline and topography. J. Am. Coll. Cardiol. 7:91102 Vivaldi MT, Eyre DR, Kloner RA, Schoen FJ. 1987. Effects of methylprednisolone on collagen biosynthesis in healing acute myocardial infarction. Am. J. Cardiol. 60: 42425 Whittaker P, Boughner DR, Kloner RA. 1989. Analysis of healing after myocardial infarction using polarized light microscopy. Am. J. Pathol. 134:87993 Holmes JW, Covell JW. 1996. Collagen ber orientation in myocardial scar tissue. Cardiovasc. Pathobiol. 1:1522 Costa KD, Holmes JW, McCulloch AD. 2001. Modelling cardiac mechanical properties in three dimensions. Phil. Trans. R. Soc. London A 359:123350 Omens JH, Miller TR, Covell JW. 1997. Relationship between passive tissue strain and collagen uncoiling during healing of
100. Hammerman H, Kloner RA, Hale S, Schoen FJ, Braunwald E. 1983. Dosedependent effects of short-term methylprednisolone on myocardial infarct extent scar formation and ventricular function. Circulation 68:44652 101. Mannisi JA, Weisman HF, Bush DE, Dudeck P, Healy B. 1987. Steroid administration after myocardial infarction promotes early infarct expansion. J. Clin. Invest. 79:143139 102. Brown EJ, Kloner RA, Schoen FJ, Hammerman H, Hale S, Braunwald E. 1983. Scar thinning due to ibuprofen administration after experimental myocardial infarction. Am. J. Cardiol. 51:87783 103. Hammerman H, Kloner RA, Schoen FJ, Brown EJ, Hale S, Braunwald E. 1983. Indomethacin-induced scar thinning after experimental myocardial infarction. Circulation 67:129095 104. Hammerman H, Schoen FJ, Braunwald E, Kloner RA. 1984. Drug-induced expansion of infarct: morphologic and functional correlations. Circulation 69:611 17 105. Weisman HF, Bush DE, Mannisi JA, Weisfeldt ML, Healy B. 1988. Cellular mechanisms of myocardial infarct expansion. Circulation 78:186201 106. Eaton LW, Weiss JL, Bulkley BH, Garrison JB, Weisfeldt ML. 1979. Regional cardiac dilatation after acute myocardial infarction: recognition by two-dimensional echocardiography. N. Engl. J. Med. 300: 5762 107. Eaton LW, Bulkley BH. 1981. Expansion of acute myocardial infarction: its relationship to infarct morphology in a canine model. Circ. Res. 49:8088 108. Hochman JS, Bulkley BH. 1982. Expansion of acute myocardial infarction: an experimental study. Circulation 65:1446 50 109. Connelly CM, McLaughlin RJ, Vogel MW, Apstein CS. 1991. Reversible and irreversible elongation of ischemic, infarcted, and healed myocardium in re-
110.
111.
112.
113.
114.
115.
116.
117.
118.
119.
INFARCT STRUCTURE AND MECHANICS infarcted myocardium. Cardiovasc. Res. 33:35158 Gibbons EF, Hogan RD, Franklin TD, Nolting M, Weyman AE. 1985. The natural history of regional dysfunction in a canine preparation of chronic infarction. Circulation 71:394402 Holmes JW, Yamashita H, Waldman LK, Covell JW. 1994. Scar remodeling and transmural deformation after infarction in the pig. Circulation 90:41120 Connelly CM, Vogel WM, Wiegner AW, Osmers EL, Bing OHL, et al. 1985. Effects of reperfusion after coronary artery occlusion on post-infarction scar tissue. Circ. Res. 57:56277 Holmes JW. 1995. Remodeling, deformation, and tissue structure in healing myocardial infarcts. PhD thesis. Univ. Calif., San Diego. 249 pp. Sun Y, Kiani MF, Postlethwaite AE, Weber KT. 2002. Infarct scar as living tissue. Basic Res. Cardiol. 97:34347 Choong CY, Gibbons EF, Hogan RD, Franklin TD, Nolting M, et al. 1989. Relationship of functional recovery to scar contraction after myocardial infarction in the canine left ventricle. Am. Heart J. 117:81929 McCormick RJ, Musch TI, Bergman BC, Thomas DP. 1994. Regional differences in left ventricular collagen accumulation and mature crosslinking following myocardial infarction in the rat. Am. J. Physiol. Heart Circ. Physiol. 266:H354 59 Frank C, McDonald D, Wilson J, Eyre D, Shrive N. 1995. Rabbit medial collateral ligament scar weakness is associated with decreased collagen pyridinoline crosslink density. J. Orthop. Res. 13:15765 Kupper W, Bleifeld W, Hanrath P, Mathey D, Effert S. 1977. Left ventricular hemodynamics and function in acute myocardial infarction: studies during the
253
120.
129.
121.
130.
122.
131.
123.
124.
132.
125.
133.
126.
134.
127.
135.
136.
128.
acute phase, convalescence and late recovery. Am. J. Cardiol. 40:9005 Sehgal M, Hirose K, Reed JE, Rumberger JA. 1996. Regional left ventricular wall thickness and systolic function during the rst year after index anterior wall myocardial infarction: serial effects of ventricular remodeling. Int. J. Cardiol. 53:4554 Kittleson MD, Knowlen GG, Johnson LE. 1987. Early and late global and regional left ventricular function after experimental transmural myocardial infarction: relationships of regional wall motion, wall thickening, and global performance. Am. Heart J. 114:7078 Weisse AB, Saffa RS, Levinson GE, Jacobson WW, Regan TJ. 1970. Left ventricular function during the early and late stages of scar formation following myocardial infarction. Am. Heart J. 79:370 83 Pfeffer MA, Pfeffer JM, Fishbein MC, Fletcher PJ, Spadaro J, et al. 1979. Myocardial infarct size and ventricular function in rats. Circ. Res. 44:50312 Pfeffer JM, Pfeffer MA, Fletcher PJ, Braunwald E. 1991. Progressive ventricular remodeling in rat with myocardial infarction. Am. J. Physiol. Heart Circ. Physiol. 260:H140614 Lessick J, Sideman S, Azhari H, Marcus M, Grenadier E, Beyar R. 1991. Regional three-dimensional geometry and function of left ventricles with brous aneurysms: a cine-computed tomography study. Circulation 84:107286 Nicolosi AC, Spotnitz HM. 1988. Quantitative analysis of regional systolic function with left ventricular aneurysm. Circulation 78:85662 Kramer CA, Lima JAC, Reichek N, Ferrari VA, Llaneras MR, et al. 1993. Regional differences in function within noninfarcted myocardium during left ventricular remodeling. Circulation 88:127988
Annual Review of Biomedical Engineering Volume 7, 2005
CONTENTS
FRONTISPIECE, Werner Goldsmith WERNER GOLDSMITH: LIFE AND WORK (19242003), Stanley A. Berger,
Albert I. King, and Jack L. Lewis
xii 1 21 55 77 105
DNA MECHANICS, Craig J. Benham and Steven P. Mielke QUANTUM DOTS AS CELLULAR PROBES, A. Paul Alivisatos, Weiwei Gu,
and Carolyn Larabell
BLOOD-ON-A-CHIP, Mehmet Toner and Daniel Irimia BIOCHEMISTRY AND BIOMECHANICS OF CELL MOTILITY, Song Li,
Jun-Lin Guan, and Shu Chien
MOLECULAR MECHANICS AND DYNAMICS OF LEUKOCYTE RECRUITMENT DURING INFLAMMATION, Scott I. Simon
and Chad E. Green 151 187 223 255 287 327 361
DETERMINISTIC AND STOCHASTIC ELEMENTS OF AXONAL GUIDANCE,

Susan Maskery and Troy Shinbrot
STRUCTURE AND MECHANICS OF HEALING MYOCARDIAL INFARCTS,

Jeffrey W. Holmes, Thomas K. Borg, and James W. Covell
INSTRUMENTATION ASPECTS OF ANIMAL PET, Yuan-Chuan Tai

and Richard Laforest
IN VIVO MAGNETIC RESONANCE SPECTROSCOPY IN CANCER,

Robert J. Gillies and David L. Morse
FUNCTIONAL ELECTRICAL STIMULATION FOR NEUROMUSCULAR APPLICATIONS, P. Hunter Peckham and Jayme S. Knutson RETINAL PROSTHESIS, James D. Weiland, Wentai Liu, and Mark S. Humayun INDEXES
Subject Index Cumulative Index of Contributing Authors, Volumes 17 Cumulative Index of Chapter Titles, Volumes 17
403 413 416
ERRATA
An online log of corrections to Annual Review of Biomedical Engineering chapters may be found at http://bioeng.annualreviews.org/ v

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Annu. Rev. Biomed. Eng. 2005. 7:22353 doi: 10.1146/annurev.bioeng.7.060804.100453 Copyright c 2005 by Annual Reviews.

STRUCTURE AND MECHANICS OF HEALING MYOCARDIAL INFARCTS

INFARCT STRUCTURE AND MECHANICS

IMPACT OF INFARCT MECHANICAL PROPERTIES ON VENTRICULAR FUNCTION

INFARCT STRUCTURE AND MECHANICS

Structural Changes During Acute Ischemia

Changes in Mechanical Properties During Acute Ischemia

INFARCT STRUCTURE AND MECHANICS

Determinants of Mechanics During Acute Ischemia

INFARCT STRUCTURE AND MECHANICS

INFARCT STRUCTURE AND MECHANICS

Ventricular Function During Acute Ischemia

INFARCT STRUCTURE AND MECHANICS

THE NECROTIC PHASE

Structural Changes During the Necrotic Phase

Changes in Mechanical Properties During the Necrotic Phase

INFARCT STRUCTURE AND MECHANICS

Determinants of Infarct Mechanics During the Necrotic Phase

INFARCT STRUCTURE AND MECHANICS

Ventricular Function During the Necrotic Phase

THE FIBROTIC PHASE

Structural Changes During the Fibrotic Phase

Changes in Mechanical Properties During the Fibrotic Phase

INFARCT STRUCTURE AND MECHANICS

Determinants of Infarct Mechanics During the Fibrotic Phase

THREE-DIMENSIONAL COLLAGEN STRUCTURE

Ventricular Function During the Fibrotic Phase

INFARCT STRUCTURE AND MECHANICS

THE REMODELING PHASE

Structural Remodeling of Myocardial Scar Tissue

Changes in Mechanical Properties During the Remodeling Phase

Determinants of Infarct Mechanics During the Remodeling Phase

Ventricular Function During the Remodeling Phase

INFARCT STRUCTURE AND MECHANICS

SUMMARY AND CONCLUSIONS

Annual Review of Biomedical Engineering Volume 7, 2005

DETERMINISTIC AND STOCHASTIC ELEMENTS OF AXONAL GUIDANCE,

STRUCTURE AND MECHANICS OF HEALING MYOCARDIAL INFARCTS,

INSTRUMENTATION ASPECTS OF ANIMAL PET, Yuan-Chuan Tai

IN VIVO MAGNETIC RESONANCE SPECTROSCOPY IN CANCER,

403 413 416

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