Structure And Mechanics of Healing Mi

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Annu. Rev. Biomed. Eng. 2005. 7:22353doi: 10.1146/annurev.bioeng.7.060804.100453

Copyright c 2005 by Annual Reviews. All rights reservedFirst published online as a Review in Advance on February 22, 2005

STRUCTURE AND MECHANICS OF HEALINGMYOCARDIAL INFARCTS

Jeffrey W. HolmesDepartment of Biomedical Engineering, Columbia University, New York, NY 10027;

email: [email protected]

Thomas K. BorgDepartment of Cell and Developmental Biology and Anatomy, University of South

Carolina, Columbia, South Carolina 29208; email: [email protected]

James W. CovellDepartments of Medicine and Bioengineering, University of California San Diego,

La Jolla, California 92093; email: [email protected]

Key Words collagen, constitutive properties, cross-linking, deformation, edema,

scar, strain, stress, necrosis, ventricular function Abstract Therapies for myocardial infarction have historically been developedby trial and error, rather than from an understanding of the structure and function of thehealing infarct. With exciting new bioengineering therapies for myocardial infarctionon the horizon, we have reviewed the time course of structural and mechanical changesin the healing infarct in an attempt to identify key structural determinants of mechanicsat several stages of healing. Based on temporal correlation, we hypothesize that normalpassive material properties dominate the mechanics during acute ischemia, edemaduring the subsequent necrotic phase, large collagen fiber structure during the fibroticphase, and cross-linking of collagen during the long-term remodeling phase. We hopethese hypotheses will stimulate further research on infarct mechanics, particularlystudies that integrate material testing, in vivo mechanics, and quantitative structuralanalysis.

CONTENTS

INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224

IMPACT OF INFARCT MECHANICAL PROPERTIES ON

VENTRICULAR FUNCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225

ACUTE ISCHEMIA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227Structural Changes During Acute Ischemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228

Changes in Mechanical Properties During Acute Ischemia . . . . . . . . . . . . . . . . . . . 228

Determinants of Mechanics During Acute Ischemia . . . . . . . . . . . . . . . . . . . . . . . . 230

Ventricular Function During Acute Ischemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234

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224 HOLMES BORG COVELL

THE NECROTIC PHASE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235

Structural Changes During the Necrotic Phase . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236

Changes in Mechanical Properties During the Necrotic Phase . . . . . . . . . . . . . . . . 236

Determinants of Infarct Mechanics During the Necrotic Phase . . . . . . . . . . . . . . . . 237

Ventricular Function During the Necrotic Phase . . . . . . . . . . . . . . . . . . . . . . . . . . . 239

THE FIBROTIC PHASE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239

Structural Changes During the Fibrotic Phase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240

Changes in Mechanical Properties During the Fibrotic Phase . . . . . . . . . . . . . . . . . 240

Determinants of Infarct Mechanics During the Fibrotic Phase . . . . . . . . . . . . . . . . 242

Ventricular Function During the Fibrotic Phase . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242

THE REMODELING PHASE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243

Structural Remodeling of Myocardial Scar Tissue . . . . . . . . . . . . . . . . . . . . . . . . . . 243

Changes in Mechanical Properties During the Remodeling Phase . . . . . . . . . . . . . 243

Determinants of Infarct Mechanics During the Remodeling Phase. . . . . . . . . . . . .

244Ventricular Function During the Remodeling Phase . . . . . . . . . . . . . . . . . . . . . . . . 244

SUMMARY AND CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245

INTRODUCTION

Each year, approximately 565,000 Americans experience a new myocardial in-

farction; 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 currentlydevoted to management of patients with a healing or healed myocardial infarct.

Excellent progress has been made, particularly in the areas of revascularization

during the first 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-errorbasis 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 adminis-

tration 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 first 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 specific 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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INFARCT STRUCTURE AND MECHANICS 225

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 followinga 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, ven-

tricular 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 atthat time point, hypotheses regarding structural determinants of infarct mechanics

based on temporal correlation of the structural and mechanical data, and finally 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 final section.

IMPACT OF INFARCT MECHANICAL PROPERTIES ON

VENTRICULAR FUNCTION

Below we list and briefly 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 de-

gree of impairment of LV function. Therefore, it follows that an understanding of

the mechanical properties of the healing infarct is essential to understanding, pre-

dicting, 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 first 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 prop-

erties most related to rupture have not been identified, 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 ratherthan 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 finding simply to a reduction in

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Figure 1 Effects of large infarcts on systolic and diastolic pressure-volume relation-

ships predicted by a model of Bogen et al. (21). Data are estimated from figure 8 in

Bogen et al. for healing infarcts corresponding to the phases of healing defined in

this review: control (C), acutely ischemic (I), necrotic (N), and fibrotic (F), assuming

an unstressed volume of 30 ml. Very compliant infarcts (acutely ischemic, I) primar-

ily depress systolic function, whereas very stiff infarcts (fibrotic, 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 com-pliant infarcts primarily disrupt systolic mechanics, the presence of a large

noncompliant infarct severely limits ventricular function by impairing di-

astolic filling (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 theinfarct 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 sug-

gest 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 filling. However, all the reasoning to this point has been one-

dimensional (infarcts are either stiff or compliant) and global (consider-

ing 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 de-spite 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 remodel-ing has been described as a volume-overload hypertrophy of the surviving

myocardium and is characterized by lengthening and thinning of the ven-

tricular wall and overall cavity dilation (32). Although the specific 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 in-

farct expansion, increases in wall stress associated with cavity dilation placenoninfarcted myocardium at a mechanical disadvantage and may lead to a

downward spiral into dilated heart failure.

ACUTE ISCHEMIA

During the first minutes to hours after infarction, the balance between oxygen

supply and demand is a dynamic one, and the final size of the infarct can be

influenced by changes in loading conditions and by pharmacologic agents (3437). 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 define 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 duringthis 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 appear-

ance have been published for healing rat (40) and human (41, 42) infarcts. Cardiacmyocytes are attached by integrins at specific sites near the Z band to an inter-

connected 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, in-

cluding 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 atten-tion has been paid to myocyte-ECM coupling, other ECM components, and ECM

organization.

Within hours after infarction, theinfarctedmuscle loses its striations andchanges

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 fibers 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 finding that matrix metalloproteinase

(MMP) activity is significantly increased 1 h after infarction, with measurablerelease of soluble MMPs after 2 h (54).

Changes in Mechanical Properties During Acute Ischemia

The most important change in mechanical properties in acutely ischemic my-

ocardium is that throughout the first 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, display-

ing in-plane stretching and thinning during filling and isovolumic systole, thenrecoiling 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 constitu-

tive 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 definitively answer this question. As outlined below, there is wide

agreement that passive pressure-segment length curves shift rightward within min-

utes 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 geome-

try and stresses versus changes in material properties to the reported mechanical

behavior in the first 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 infarc-

tion (59, 60). Tracking of segment lengths in the ischemic region using strain

gauges and ultrasonic crystals showed that within 30 s after experimental coro-

nary occlusion, systolic shortening of acutely ischemic myocardium is replacedby systolic stretching (55, 56), which gradually increases in magnitude over the

first 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 seg-

ment 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-diastolicpressures (EDP), when the segment starts from a relatively flat 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 pressure-

length curves increased (61, 63) or decreased (38, 56) during acute ischemia. Therewere a number of methodological differences among these studies, including the

transmural location and orientation of the segments, the use of closed- or open-

chest animals, and the definition 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 first 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 rela-

tionship 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 regionalwall motion abnormalities increased during the first 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 im-

planted markers, Villarreal confirmed that 5 min of experimental ischemia in dog

converted the normal pattern of systolic circumferential and longitudinal shorten-

ing and radial thickening to circumferential and longitudinal stretching and radialthinning as expected (57). They also found that while the magnitude of normal sys-

tolic 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


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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 reflects 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 defined in this review: control (C), acutely

ischemic (I), necrotic (N), fibrotic (F), and remodeling (R).

first hour after infarction could be explained by local geometric changes resultingin increased stresses in the infarct at any given cavity pressure, without postulating

a change in material properties; this possibility is discussed first below. Then, we

briefly 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 andthe necrotic phase discussed later in this review.

CONSTITUTIVE PROPERTIES OF PASSIVE MYOCARDIUM It is clear that acutely is-

chemic 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 reflects 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 circumfer-ential 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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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 pub-

lished by Emery closely resemble the pressure-dimension curves published by anumber 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 elec-

trical stimulation) isolated cardiac trabeculae, suggesting that elevated stress and

stretch alone are not sufficient to induce softening in myocardium unless other

damage has occurred (66). Although this finding 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 pressure-

length 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 de-

pressed systolic function had right-shifted pressure-segment length curves similarto 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 mechanicsof 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 col-

lagenase normally degrades collagen, and this experimental preparation becomes

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rapidly edematous, so it is difficult to separate changes owing to disruption of col-

lagen 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 increasedcompliance 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 com-

pared to the unperfused state, raising the possibility that the increased LV com-

pliance 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 theperfused 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-fiber, and radial strains during passive

inflation of isolated arrested hearts and increased local tissue volume, especially at

the endocardium (76). Because circumferential and fiber strains were not signifi-

cantly altered by perfusion, loss of perfusion would not completelyexplain reported

data for ischemic myocardium, where circumferential remodeling is prominent.

However, the large radial changes reported by May-Newman could account forall 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 (mech-

anism 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 inextensi-

ble. Compared to normally activated systolic myocardium (which has contracted

rather than stretched relative to its end-diastolic configuration), the ischemic region

therefore contains roughly the same volume of extra blood at any physiologic sys-

tolic 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 dias-

tolic 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 flow, 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), withoutpostulating reduced contractility.

THE NECROTIC PHASE

During the first few days after infarction, the dominant pathologic processes are

inflammation and necrosis. We define the necrotic phase as beginning within a

few hours, when the infarct begins to stiffen, and ending when the number of

fibroblasts and amount of new collagen begin to increase rapidly in the healinginfarct [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 significant new collagen has not yet been deposited, it is perhaps surprising

Figure 4 Comparative diagram of the temporal course of the phases of healing de-

fined in this review for various animal models. Time course for other large animal

models is similar to that for dog. Please see text for definition 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 fibers,

indicating intercellular edema, and 90% have clear necrosis characterized by al-

tered staining properties and nuclear pyknosis or karyolysis (41). By the fourth or

fifth 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 first 4 days after infarction in rats, there is a progressive decrease in the

number of normally birefringent collagen fibers, and by 4 days there is a significant

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, ap-

proximately the same time that mRNA for type III (first) and I (slightly later)

procollagens is first detected (90).

Changes in Mechanical Properties During the Necrotic Phase

Two changes in mechanics are apparent in the necrotic infarct. First, circumferen-

tial and longitudinal stiffness increase under multiaxial loading, whereas uniaxial

tests show no change in stiffness, suggesting increased mechanical coupling be-

tween 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 exper-

imental infarction in dogs (63). Circumferential segmental shortening remained

approximately zero in the infarct throughout the first 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 filling was increased more than fivefold 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 unstressedlength 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 first 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 consistentlyindicated 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 myofiber 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 iscurrently 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 datasomewhat, 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 correla-

tive, relating pathologic observations to functional ones, or circumstantial, derivedfrom 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 sufficiently well understood to draw conclusions about specific prop-

erties, such as infarct stiffness or tensile strength, from data on expansion. In spite

of these difficulties, 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 Thetwoprimarystructuralproteinsinpas-

sive myocardium, titin and collagen, both undergo degradation during the necrotic

phase. Necrotic myocytes lose their striations within hours (42), reflecting damage

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to the major myofibrillar proteins that compose the sarcomere, including titin.

Progressive damage to collagen is also seen in the first 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 expan-sion (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 asso-

ciated with cardioplegia have shown that experimentally induced global edema

decreases ventricular compliance, but have not consistently found changes in un-stressed chamber volume (95, 96). Second, studies of the role of edema in postis-

chemic 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 fixed vol-

ume, 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 in-

farcts is more circumstantial. A recent MRI study by Gerber et al. found thatreperfused 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 finding was that the high-MO infarcts

appeared to be not only stiffer but also more isotropic than low-MO infarcts. How-

ever, although high-MO infarcts would likely have more intramyocardial hem-

orrhage and edema than low-MO infarcts, the degree of infarct edema was not

directly verified in this study. Other studies have indicated that infarct water con-

tent is significantly increased several days after infarction, even in the absence of

reperfusion (99).The final line of evidence that edema is an important determinant of mechani-

cal properties in the necrotic infarct is that a variety of pharmacologic agents that

reduce edema and inflammation, including high-dose steroids (100, 101), ibupro-

fen (102), and indomethacin (103, 104), also aggravate infarct expansion in the

first days following experimental infarction. One of the best of these studies, by

Mannisi et al., showed that water content was significantly 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 in-farct 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 antiinflammatory agents promote expansion

by reducing edema.

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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 animalmodels (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 initialmesh of type III collagen forms the scaffold for subsequent deposition of large,

highly aligned type I collagen fibers (116). By 3 weeks after infarction in pig, the

scar is dominated by large type I collagen fibers highly aligned with one another

in each transmural layer (117). The mean orientation of the collagen fibers varies

with depth below the epicardium in a pattern similar to that for normal muscle

fibers except that the transmural range of mean angles is smaller (30). The net

result of this pattern is that the majority of large collagen fibers in the scar are

oriented within 30 of the circumferential direction (118). A similar pattern of

collagen fiber 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). Theslope of the passive pressure-segment length relationship confirmed elevated stiff-

ness, 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, significant passive longitudinal shortening and radial thick-

ening 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 inthe longitudinal direction through the first week to stiffer in the circumferential

direction beyond the second week (29). We found similar anisotropy in 3-week-

old porcine infarcts, which displayed little circumferential stretch in the healing

scar during passive inflation 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 inflation of isolated arrested hearts 2 weeks after infarction in

rat (119). They also found that collagen fibers in the scar straightened more rapidlywith pressure but were not straighter in the unloaded state than collagen fibers in

normal myocardium.

Figure 5 Anisotropy in 3-week-old porcine scar with large collagen fibers oriented

predominantly in the circumferential direction. Lines show transmural pattern of strains

as isolated arrested heart is inflated from a cavity pressure of 5 mm Hg (lowest linein 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 define the fibrotic 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 fibers 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 fibrotic 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

first week after infarction (113), as would be expected if hydroxyproline content

correlates with stiffness of the healing infarct (21, 26).

THREE-DIMENSIONAL COLLAGEN STRUCTURE The findingthat myocardial infarcts

are highly anisotropic during the fibrotic phase of healing (29, 30) implicates the

highly aligned large collagen fiber structure as the second primary determinant

of infarct properties during this phase. The predominance of large collagen fibers

oriented in the circumferential direction (116, 117) is consistent with reports thatmyocardialscar is stiffer in thecircumferential 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).

Ventricular Function During the Fibrotic Phase

The two mechanisms by which infarcts in the fibrotic phase of healing may depress

LV function are impaired filling 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 predictedthat the primary adverse effect of a very stiff infarct would be impaired filling

owing to decreased LV compliance. Janz also suggested that diastolic stretch of

adjacent noninfarcted myocardium would be limited during filling 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-week-

old porcine scars oriented longitudinally on the LV appears to minimize this effect:

high circumferential stiffness prevents stretching of the infarct perpendicular toits 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 noninfarctedmyocardium much more than low-MO infarcts (98).

THE REMODELING PHASE

As healing continues, the mechanical properties of the infarct decouple from colla-

gen 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 defined,the healing scar tissue is a dynamic, biologically active tissue that may never reach

a stable, mature configuration (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 first 4 weeks, Jugdutt found that hydroxyproline

increased only an additional 20% from week 4 to week 6 in dogs (114). Vivaldi

founda50%increaseincollagencontentbetween2and4weeksintheratcompared

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 beenreported. 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 theRemodeling Phase

There is some disagreement in the literature regarding changes in scar mechanical

properties during the remodeling phase. Although Parmley found that strips offibrous 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 theRemodeling Phase

During the early part of the remodeling phase, infarct stiffness decreases while

collagen content continues to increase, indicating that collagen content and fiber

structure are no longer the only important determinants of the mechanical prop-

erties 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 influence the mechanics of healing scar tissue. Similar findings

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 par-

tially normalized LV compliance and EDP 46 weeks after infarction (60, 128),

with few additional functional changes over the remainder of the first year (128,

129). All of the mechanisms for depression of function discussed at the beginningof this review except infarct rupture are involved to some extent in this late improve-

ment in LV function. Scar stiffness remains higher than that of passive or acutely

ischemic myocardium, limiting energy loss owing to systolic stretching (mech-

anism 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 abnormali-

ties 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 reflects limitation of diastolic function owing to reduced di-astolic 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 circumfer-

ence 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 asscar 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 defined four phases of infarct healing

and hypothesized the following: (a) Mechanical properties during acute ischemia

(the first few hours) are essentially the normal constitutive properties of passive

myocardium, (b) mechanical properties during the necrotic phase (the first 5

7 days depending on animal model) are dominated by edema, (c) mechanical

properties during the fibrotic phase (up to 24 weeks) arise from the large collagen

fiber structure, and (d) mechanical properties during the remodeling phase (the

remainder of the healing process) are determined primarily by collagen cross-linking. 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 three-

dimensional 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, andcoupling to adjacent myocardium. The individual studies reviewed here typically

provide complementary, incomplete subsets of information about infarct mechan-

ics. 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 can-not 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 thecourseof postinfarction healing is difficult 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 fiber 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, re-

gional 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 sufficiently understood to predict the impact of proposed

interventions or to specify the design requirements for a tissue-engineered re-

placement. Integrative studies combining material testing, quantitative structuralanalysis, 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

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