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Journal ArticleDOI

Structure and Mechanics of Healing Myocardial Infarcts

08 Jul 2005-Annual Review of Biomedical Engineering (Annu Rev Biomed Eng)-Vol. 7, Iss: 1, pp 223-253
TL;DR: It is hypothesized that normal passive material properties dominate the mechanics during acute ischemia, edema during the subsequent necrotic phase, large collagen fiber structure during the fibroticphase, and cross-linking of collagen during the long-term remodeling phase.
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 fiber structure during the fibrotic 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.
Citations
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Journal ArticleDOI
TL;DR: Both experimental and clinical evidence suggests that cardiac fibrotic alterations may be reversible, and understanding the mechanisms responsible for initiation, progression, and resolution of cardiac fibrosis is crucial to design anti-fibrotic treatment strategies for patients with heart disease.
Abstract: Cardiac fibrosis is characterized by net accumulation of extracellular matrix proteins in the cardiac interstitium, and contributes to both systolic and diastolic dysfunction in many cardiac pathophysiologic conditions. This review discusses the cellular effectors and molecular pathways implicated in the pathogenesis of cardiac fibrosis. Although activated myofibroblasts are the main effector cells in the fibrotic heart, monocytes/macrophages, lymphocytes, mast cells, vascular cells and cardiomyocytes may also contribute to the fibrotic response by secreting key fibrogenic mediators. Inflammatory cytokines and chemokines, reactive oxygen species, mast cell-derived proteases, endothelin-1, the renin/angiotensin/aldosterone system, matricellular proteins, and growth factors (such as TGF-β and PDGF) are some of the best-studied mediators implicated in cardiac fibrosis. Both experimental and clinical evidence suggests that cardiac fibrotic alterations may be reversible. Understanding the mechanisms responsible for initiation, progression, and resolution of cardiac fibrosis is crucial to design anti-fibrotic treatment strategies for patients with heart disease.

1,092 citations

Journal ArticleDOI
TL;DR: Insight is provided into the properties of cardiac fibroblasts that underscores their importance in the remodeling heart, including their origin, electrophysiological properties, role in matrix metabolism, functional responses to environmental stimuli and ability to secrete bioactive molecules.

927 citations


Cites background from "Structure and Mechanics of Healing ..."

  • ...scar tissue following MI (Holmes et al., 2005) and in mature infarct scars a persistence of myoFb has been documented (Sun & Weber,...

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  • ...teins and proteases (Eghbali & Weber, 1990; Corda et al., 2000; Holmes et al., 2005)....

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Journal ArticleDOI
TL;DR: Insight is provided into the various properties of cardiac fibroblasts that helps illustrate their importance in maintaining proper cardiac function, as well as their critical role in the remodeling heart.
Abstract: The permanent cellular constituents of the heart include cardiac fibroblasts, myocytes, endothelial cells, and vascular smooth muscle cells. Previous studies have demonstrated that there are undulating changes in cardiac cell populations during embryonic development, through neonatal development and into the adult. Transient cell populations include lymphocytes, mast cells, and macrophages, which can interact with these permanent cell types to affect cardiac function. It has also been observed that there are marked differences in the makeup of the cardiac cell populations depending on the species, which may be important when examining myocardial remodeling. Current dogma states that the fibroblast makes up the largest cell population of the heart; however, this appears to vary for different species, especially mice. Cardiac fibroblasts play a critical role in maintaining normal cardiac function, as well as in cardiac remodeling during pathological conditions such as myocardial infarct and hypertension. These cells have numerous functions, including synthesis and deposition of extracellular matrix, cell-cell communication with myocytes, cell-cell signaling with other fibroblasts, as well as with endothelial cells. These contacts affect the electrophysiological properties, secretion of growth factors and cytokines, as well as potentiating blood vessel formation. Although a plethora of information is known about several of these processes, relatively little is understood about fibroblasts and their role in angiogenesis during development or cardiac remodeling. In this review, we provide insight into the various properties of cardiac fibroblasts that helps illustrate their importance in maintaining proper cardiac function, as well as their critical role in the remodeling heart.

894 citations

Journal ArticleDOI
TL;DR: This review summarizes the current knowledge on the role of TGF-β in infarct healing and cardiac remodeling and suggests that T GF-β signaling may be crucial for repression of inflammatory gene synthesis in healing infarCTs mediating resolution of the inflammatory infiltrate.
Abstract: Transforming Growth Factor (TGF)-beta is markedly induced and rapidly activated in the infarcted myocardium. However, understanding of the exact role of TGF-beta signaling in the infarcted and remodeling heart has been hampered by the complex and unusual biology of TGF-beta activation and by the diversity of its effects eliciting multiple, and often opposing cellular responses. Experimental studies suggest that TGF-beta signaling may be crucial for repression of inflammatory gene synthesis in healing infarcts mediating resolution of the inflammatory infiltrate. In addition, TGF-beta may play an important role in modulating fibroblast phenotype and gene expression, promoting extracellular matrix deposition in the infarct by upregulating collagen and fibronectin synthesis and by decreasing matrix degradation through induction of protease inhibitors. TGF-beta is also a key mediator in the pathogenesis of hypertrophic and dilative ventricular remodeling by stimulating cardiomyocyte growth and by inducing interstitial fibrosis. In this review we summarize the current knowledge on the role of TGF-beta in infarct healing and cardiac remodeling.

818 citations


Cites background from "Structure and Mechanics of Healing ..."

  • ...Activation of TGF-β signaling pathways in the infarct may be crucial for the formation and maintenance of a collagenous scar, increasing tensile strength and preventing left ventricular dilation [ 91 ]....

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Journal ArticleDOI
TL;DR: Accordion-like honeycombs can overcome principal structural-mechanical limitations of previous scaffolds, promoting the formation of grafts with aligned heart cells and mechanical properties more closely resembling native myocardium.
Abstract: Tissue-engineered grafts may be useful in myocardial repair; however, previous scaffolds have been structurally incompatible with recapitulating cardiac anisotropy. Here, we use microfabrication techniques to create an accordion-like honeycomb microstructure in poly(glycerol sebacate), which yields porous, elastomeric three-dimensional (3D) scaffolds with controllable stiffness and anisotropy. Accordion-like honeycomb scaffolds with cultured neonatal rat heart cells demonstrated utility through: (1) closely matched mechanical properties compared to native adult rat right ventricular myocardium, with stiffnesses controlled by polymer curing time; (2) heart cell contractility inducible by electric field stimulation with directionally dependent electrical excitation thresholds (p<0.05); and (3) greater heart cell alignment (p<0.0001) than isotropic control scaffolds. Prototype bilaminar scaffolds with 3D interconnected pore networks yielded electrically excitable grafts with multi-layered neonatal rat heart cells. Accordion-like honeycombs can thus overcome principal structural–mechanical limitations of previous scaffolds, promoting the formation of grafts with aligned heart cells and mechanical properties more closely resembling native myocardium. Construction of tissue-engineering scaffolds that mimic cardiac anisotropy is a challenge. Now, accordion-like honeycomb scaffolds have been created that can form tissue grafts with preferentially aligned heart cells, and with mechanical properties that closely resemble the anisotropy of native myocardium.

798 citations


Cites background from "Structure and Mechanics of Healing ..."

  • ...In particular, we reasoned accordion-like honeycomb scaffolds exhibiting distinct preferred and orthogonal, cross-preferred material directions could potentially: (1) match the anisotropic in-plane mechanical response of native myocardium within the physiologic regime, (2) provide low in-plane resistance to contraction and (3) provide an inherent structural capacity to guide cardiomyocyte orientation in the absence of external stimuli....

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  • ...05); and (3) greater heart cell alignment (p < 0....

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References
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Journal ArticleDOI
TL;DR: The extent of ventricular enlargement after infarction is related to the magnitude of the initial damage to the myocardium and, although an increase in cavity size tends to restore stroke volume despite a persistently depressed ejection fraction, ventricular dilation has been associated with a reduction in survival.
Abstract: An acute myocardial infarction, particularly one that is large and transmural, can produce alterations in the topography of both the infarcted and noninfarcted regions of the ventricle. This remodeling can importantly affect the function of the ventricle and the prognosis for survival. In the early period, infarct expansion has been recognized by echocardiography as a lengthening of the noncontractile region. The noninfarcted region also undergoes an important lengthening that is consistent with a secondary volume-overload hypertrophy and that can be progressive. The extent of ventricular enlargement after infarction is related to the magnitude of the initial damage to the myocardium and, although an increase in cavity size tends to restore stroke volume despite a persistently depressed ejection fraction, ventricular dilation has been associated with a reduction in survival. The process of ventricular enlargement can be influenced by three interdependent factors, that is, infarct size, infarct healing, and ventricular wall stresses. A most effective way to prevent or minimize the increase in ventricular size after infarction and the consequent adverse effect on prognosis is to limit the initial insult. Acute reperfusion therapy has been consistently shown to result in a reduction in ventricular volume. The reestablishment of blood flow to the infarcted region, even beyond the time frame for myocyte salvage, has beneficial effects in attenuating ventricular enlargement. The process of scarification can be interfered with during the acute infarct period by the administration of glucocorticosteroids and nonsteroidal antiinflammatory agents, which result in thinner infarcts and greater degrees of infarct expansion. Modification of distending or deforming forces can importantly influence ventricular enlargement. Even short-term augmentations in afterload have deleterious long-term effects on ventricular topography. Conversely, judicious use of nitroglycerin seems to be associated with an attenuation of infarct expansion and long-term improvement in clinical outcome. Long-term therapy with an angiotensin converting enzyme inhibitor can favorably alter the loading conditions on the left ventricle and reduce progressive ventricular enlargement as demonstrated in both experimental and clinical studies. With the former therapy, this attenuation of ventricular enlargement was associated with a prolongation in survival. The long-term clinical consequences of long-term angiotensin converting enzyme inhibitor therapy after myocardial infarction is currently being evaluated. Although studies directed at attenuating left ventricular remodeling after infarction are in the early stages, it does seem that this will be an important area in which future research might improve long-term outcome after infarction.

2,815 citations

Journal ArticleDOI
TL;DR: This article will review postinfarction remodeling, pathophysiological mechanisms, and therapeutic intervention in left ventricular remodeling and provide important insights into the remodeling process and a rationale for future therapeutic strategies.
Abstract: Left ventricular remodeling is the process by which ventricular size, shape, and function are regulated by mechanical, neurohormonal, and genetic factors.1 2 Remodeling may be physiological and adaptive during normal growth or pathological due to myocardial infarction, cardiomyopathy, hypertension, or valvular heart disease (Figure 1⇓). This article will review postinfarction remodeling, pathophysiological mechanisms, and therapeutic intervention. Figure 1. Diagrammatic representation of the many factors involved in the pathophysiology of ventricular remodeling. ECM indicates extracellular matrix; RAAS, renin-angiotensin-aldosterone system; CO, cardiac output; SVR, systemic vascular resistance; LV, left ventricular; and AII, angiotensin II. ### Postinfarction Left Ventricular Remodeling The acute loss of myocardium results in an abrupt increase in loading conditions that induces a unique pattern of remodeling involving the infarcted border zone and remote noninfarcted myocardium. Myocyte necrosis and the resultant increase in load trigger a cascade of biochemical intracellular signaling processes that initiates and subsequently modulates reparative changes, which include dilatation, hypertrophy, and the formation of a discrete collagen scar. Ventricular remodeling may continue for weeks or months until the distending forces are counterbalanced by the tensile strength of the collagen scar. This balance is determined by the size, location, and transmurality of the infarct, the extent of myocardial stunning, the patency of the infarct-related artery, and local tropic factors.1 3 The myocardium consists of 3 integrated components: myocytes, extracellular matrix, and the capillary microcirculation that services the contractile unit assembly. Consideration of all 3 components provides important insights into the remodeling process and a rationale for future therapeutic strategies. The cardiomyocyte is terminally differentiated and develops tension by shortening. The extracellular matrix provides a stress-tolerant, viscoelastic scaffold consisting of type I and type III collagen that couples myocytes and maintains the spatial relations between the myofilaments and their capillary microcirculation.4 5 The collagen framework couples adjacent myocytes by intercellular struts that …

1,737 citations

Journal ArticleDOI
TL;DR: It is concluded that the hemodynamic status and neurohumoral background at the time of occlusion and for up to 3 hr thereafter can alter the extent and severity of myocardial ischemic injury andMyocardial necrosis.
Abstract: The purpose of this study was the determination of whether hemodynamic and pharmacologic factors influence the extent and severity of myocardial necrosis produced by coronary occlusion. In 48 dogs, 10 to 14 epicardial leads were recorded on the anterior surface of the left ventricle in the distribution and vicinity of the site of occlusion of a branch of the left anterior descending coronary artery. The average S-T segment elevation for each animal was determined at 5-min intervals after occlusion. This elevation was used as an index of the presence and severity of myocardial ischemic injury. The number of sites showing this elevation provided an additional measure of the size of the injured area. Occlusion alone raised the average S-T segment elevation from 0.22 ± 0.04 to 3.32 ± 0.37 mv (SEM). Isoproterenol, ouabain, glucagon, bretylium, and tachycardia given prior to a repeated occlusion increased the severity and extent of ischemic injury, while propranolol decreased it. Elevation of arterial pressure ...

1,506 citations

Journal ArticleDOI
TL;DR: In this model of histologically healed myocardial infarction, the impairment of left ventricular function was directly related to the loss of myocardium, and the entire spectrum of postinfarction ventricularfunction was observed, from no detectable impairment to congestive failure.
Abstract: To define the relationship between infarct size and ventricular performance, we performed hemodynamic studies in rats 21 days after left coronary artery occlusion. Ventricular performance was assessed under ether anesthesia by measurements of baseline hemodynamics and stressed performance as determined by the peak cardiac output and stroke volume obtained during intravenous volume loading and by the peak left ventricular developed pressure obtained during occlusion of the ascending aorta. Infarct size was determined by planimetry of the endocardial circumference of each of four histological slices of the left ventricle. Rats with small (4-30%) myocardial infarctions had no discernible impairment in either baseline hemodynamics or peak indices of pumping and pressure-generating ability when compared to the sham-operated, noninfarcted rats. Rats with moderate (31-46%) infarctions had normal baseline hemodynamics but reduced peak flow indices and developed pressure. Rats with infarctions greater than 46% had congestive heart failure, with elevated filling pressures, reduced cardiac output, and a minimal capacity to respond to pre- and after load stresses. The entire spectrum of postinfarction ventricular function was observed, from no detectable impairment to congestive failure. In this model of histologically healed myocardial infarction, the impairment of left ventricular function was directly related to the loss of myocardium.

1,324 citations

Journal ArticleDOI
TL;DR: Desc descriptions of a technique and of a type of optical myograph suitable for such studies and an analysis of the changes in optical myograms which follow clamping of a large coronary vessel are concerned.
Abstract: Many students of the coronary circulation must have noted that the ventricular zone affected by ligating a large coronary branch not only appears cyanotic and dilated, but that it seems to alter in its mode of contraction. The detailed and sequential changes in contraction are not easily followed by the unaided eye and so far have not been recorded myographically. The reasons for this were the lack of an adequate and suitable myograph and a technic for the application of one to a limited ventricular surface so that records obtained represent, at least reasonably well, changes in muscle length and not predominantly artefacts due to position changes, thrusts and vibrations of the vigorously beating ventricle. This communication concerns itself with descriptions of a technique and of a type of optical myograph suitable for such studies and an analysis of the changes in optical myograms which follow clamping of a large coronary vessel. APPARATUS. After preliminary efforts to obtain satisfactory ventricular myograms with the segment myograph used by one of us (Wiggers, 1916) to study auricular contraction, it became obvious that in order to overcome the distortions produced by twists and thrusts of the beating ventricle an instrument was needed in which the movable lever arm operates in fixed bearings. A suitable myograph which retains the compactness, lightness and efficiency of the earlier form is illustrated in figure 1. The body of the instrument consists of a small receiving tambour, E, (2.5 cm. in diameter) from which a tube leads off at right angles for connection with an optical segment capsule. The lever arms which are of aluminum are spaced 1.5 cm. apart. The rigid arm, A, is attached solidly to the back of the tambour and the movable one, B, is pivoted in jewel bearings, C, as indicated in the insert sketch. The total weight of the myograph is only

1,139 citations