EJCTS Click here to go to Edwards website
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Personal Folders
Right arrow Download to citation manager
Right arrow Permission Requests
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Brower, G. L.
Right arrow Articles by Janicki, J. S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Brower, G. L.
Right arrow Articles by Janicki, J. S.
Related Collections
Right arrow Cardiac - physiology
Right arrow Cardiac - other
Right arrow Congestive Heart Failure

Eur J Cardiothorac Surg 2006;30:604-610
© 2006 Elsevier Science NL

Reviews

The relationship between myocardial extracellular matrix remodeling and ventricular function

Gregory L. Brower, Jason D. Gardner, Mary F. Forman, David B. Murray, Tetyana Voloshenyuk, Scott P. Levick, Joseph S. Janicki*

Department of Cell and Developmental Biology and Anatomy, School of Medicine, University of South Carolina, Columbia, SC 29208, United States

Received 28 April 2006; received in revised form 10 July 2006; accepted 13 July 2006.

* Corresponding author. Tel.: +1 803 733 1536; fax: +1 803 733 1533. (Email: jjanicki{at}gw.med.sc.edu).


   Abstract
Top
 Abstract
1. Introduction
 2. Myocardial fibrillar collagen...
 3. Alterations in ECM...
 4. Alterations in ECM...
 References
 
Elevations in myocardial stress initiate structural remodeling of the heart in an attempt to normalize the imposed stress. This remodeling consists of cardiomyocyte hypertrophy and changes in the amount of collagen, collagen phenotype and collagen cross-linking. Since fibrillar collagen is a relatively stiff material, a decrease in collagen can result in a more compliant ventricle while an increase in collagen or collagen cross-linking results in a stiffer ventricle. If continued elevations in wall stress exceed the ability of the heart to compensate, then the ventricular wall thickness is disproportionately reduced compared to chamber volume and diastolic and systolic dysfunction ensues. This review describes the structural organization of collagen within the myocardium, discusses its effect on ventricular function and considers whether therapy aimed at reducing fibrosis is efficacious in heart failure. The evidence indicates that chamber stiffness can clearly be affected by alterations in both collagen quantity and quality, with the effect of changes in collagen concentration being modified by the extent of collagen cross-linking. The limited evidence available regarding the effects of collagen on systolic function indicates that pharmacological attempts to reduce interstitial collagen have a negative impact. Accordingly, a shift in treatment strategies directed more specifically at affecting collagen cross-linking, rather than reducing the concentration of collagen, may be warranted in the prevention of the adverse impact of collagen alterations on myocardial remodeling.

Key Words: Fibrosis • Collagen • Cross-linking • Collagen types • Myocardial remodeling • Hypertrophy


   1. Introduction
Top
 Abstract
 1. Introduction
2. Myocardial fibrillar collagen...
 3. Alterations in ECM...
 4. Alterations in ECM...
 References
 
The elevation in myocardial stress that results from cardiac injury and/or persistent elevations in ventricular developed pressure or volume initiates a structural remodeling of the myocardium in an attempt to return the tissue stress to its normal value. This process consists of progressive remodeling of the muscular, vascular and extracellular matrix (ECM) components of the heart that manifests as changes in ventricular wall and chamber dimensions. Depending on the cause, duration and magnitude of the increase in myocardial stress, the surviving myocytes undergo hypertrophy through in-series and/or parallel addition of sarcomeres and the ECM undergoes alterations in its interstitial collagen properties (e.g., fibrillar collagen concentration, types and cross-linking). In general, the stressed ventricle is considered to be compensated if the remodeling process results in near normal diastolic and systolic function reflected by attainment of an above normal ventricular mass-to-volume ratio sufficient to normalize myocardial wall stress. However, the heart will eventually fail if the sustained increase in wall stress exceeds the compensatory ability of the heart, exhausting the hypertrophic reserve without normalizing myocardial stress. At this stage of dysfunction, ventricular wall thickness is disproportionately reduced relative to an increase in chamber volume, ventricular geometry is becoming spherical, and there is significant myocardial fibrosis.

As fibrillar collagen is a relatively stiff material that is in intimate contact with all other components of the myocardium, it plays a crucial role in the maintenance of ventricular shape, size and function [1,2]. Degradation of myocardial collagen typically results in ventricular dilatation and a decrease in ventricular stiffness, while an increase in interstitial collagen concentration and/or cross-linking results in a stiffer myocardium and ventricular diastolic dysfunction. While the effects of changes in myocardial collagen on stiffness have been investigated extensively over the past 25 years, the influence of specific alterations in collagen properties on diastolic, systolic and lusitropic function have not been clearly delineated. This review will begin with a brief description of the organization and mechanical properties of myocardial collagen, continue with a synopsis of what is known regarding ECM remodeling and myocardial function, and conclude with a consideration of whether targeted therapy directed at reducing fibrosis in the failing heart would be efficacious.


   2. Myocardial fibrillar collagen structural organization and mechanical properties
Top
 Abstract
 1. Introduction
 2. Myocardial fibrillar collagen...
3. Alterations in ECM...
 4. Alterations in ECM...
 References
 
Interspersed between cardiomyocytes, nerves and blood vessels, the cardiac interstitium is comprised of ground substance and connective tissue which is predominantly collagen with relatively small amounts of fibronectin, laminin and elastin. The fibrillar collagens found in the myocardium include types I, III and V. These fibrillar collagens are comprised of three peptide chains intertwined to form a right-handed super-helix. Once interstitial collagen is deposited in mature form and subsequently cross-linked, it is extremely stable and resistant to degradation. However, interstitial collagen in the myocardium is not a static protein, and changes in the balance between synthesis and degradation may lead to alterations in the composition of the collagen network in the heart [3]. While the relative proportions of these collagens in the myocardium are dependent on both species and the type of digestion utilized to characterize solubility (i.e., pepsin or cyanogen bromide), type I collagen is the predominant type (normally >50%), followed by type III (between 10 and 45%) and type V (<5%) [4–9]. The organization of the fibrillar collagen matrix has been described in terms of three major subdivisions, consisting of (1) the endomysial component which forms intricate networks of fibers that surround and interconnect individual myocytes, including the collagen struts that connect myocytes to neighboring myocytes and capillaries; (2) perimysial fibers that arborize to form weaves of collagen surrounding groups of myocytes and collagen fibers referred to as strands which join adjacent groups of myocytes to one another, as well as tendinous extensions spanning interconnections with the epimysium; and (3) the epimysium which is a sheath of collagenous connective tissue that encompasses muscle bundles [9–12].

In the normal adult heart, morphometric assessments indicate that approximately 2–4% of the myocardium is collagen. However, because collagen is a relatively stiff material with a high tensile strength, small changes in its concentration have been shown to exert marked effects on the passive mechanical properties of the heart [13]. In addition to the concentration of collagen, the passive behavior of the myocardium may also be dependent on the relative proportions of the types of collagen, the diameter of the collagen fibers and their spatial alignment, and the degree of cross-linking. Accordingly, tissue containing predominantly type I collagen, large diameter collagen fibers, and/or a high degree of cross-linking will be stiffer than tissue composed of greater concentrations of type III fibers, relatively small diameter collagen fibers and essentially no cross-linked collagen [14]. Examples of both extremes would be tendinous tissue which is highly resistant to elongation versus relatively compliant skin tissue. Another characteristic of fibrillar collagen which influences passive tissue properties is related to the coiled, spring-like nature or crimp of the collagen fibers [13,15]. Initially as the tissue is stretched, collagen fibers uncoil with minimal resistance, but once uncoiled, the stress required to produce further elongation increases exponentially, effectively restricting further stretch of the tissue.


   3. Alterations in ECM fibrillar collagen properties and left ventricular diastolic function
Top
 Abstract
 1. Introduction
 2. Myocardial fibrillar collagen...
 3. Alterations in ECM...
4. Alterations in ECM...
 References
 
3.1 Increased collagen concentration
An interest in the effects of increased collagen on left ventricular (LV) diastolic function was sparked in the late 1970s and early 1980s by the following seminal studies: Bing et al. [16] reported an increase in myocardial hydroxyproline in hypertrophied LV; Caulfield and Borg [17] reported the first description of the cardiac ECM ultrastructure; and Pearlman et al. [14] documented an increase in myocardial collagen concentration in hypertrophied human hearts from postmortem patients with and without heart failure. Since then there have been numerous studies with experimental (i.e., Goldblatt and abdominal aortic coarctation induced renovascular hypertension, aortic arch constriction, and perinephritic hypertension) or genetic (i.e., spontaneously hypertensive and Dahl salt-sensitive rats) hypertension to indicate a strong relationship between increased LV collagen concentration and chamber stiffness [2,18]. While these models of chronic pressure overload also result in significant myocyte hypertrophy, it has been shown that myocyte enlargement is not the cause of the increased myocardial stiffness. For example, Narayan et al. [19] were able to prevent myocyte hypertrophy with hydralazine but not the abnormal accumulation of collagen in spontaneously hypertensive rats (SHR). A comparison between hydralazine treated and untreated, hypertrophied SHR indicated that the passive myocardial stiffness was similar in both and significantly greater than the corresponding stiffness obtained in the genetic control. Others found no change in myocardial collagen concentration and LV diastolic chamber compliance in dogs with experimental hypertension despite significant hypertrophy [20,21]. Finally, in the athlete with a significant increase in LV mass and presumably physiologic hypertrophy, diastolic function is normal at rest and enhanced during exercise [22,23]. This physiologic hypertrophy is in contrast to hypertensive patients who typically have significant diastolic dysfunction despite an increase in LV mass that is less than that occurring in athletes [24]. In view of the fact that collagen concentration is increased in humans with systemic hypertension [14] and that diastolic abnormalities in hypertensive patients are not related to increases in LV mass [25], it is reasonable to assume that hypertension-related diastolic dysfunction is the result of excessive myocardial collagen.

3.2 Decreased collagen concentration
As stated earlier, collagen is extremely stable and highly resistant to degradation by all proteinases except specific collagenases [26]. While copious amounts of collagenase were first demonstrated in the heart by Monfort and Pérez-Tamayo [27], fortunately only 1–2% of this total myocardial collagenase is normally present in its active form [28,29]. However, most of the latent collagenase is closely associated with the collagen matrix, such that a sudden activation of this ECM-bound enzyme would result in rapid and extensive collagen degradation. Indeed studies have demonstrated significant collagen breakdown occurring within 24 h following an experimentally induced myocardial infarction. Specifically, Takahashi et al. [30] reported degradation of approximately 50% of myocardial collagen in the infarcted area within 3 h of infarction coinciding with a two- to three-fold increase in tissue collagenase activity. A similar increase in collagenase activity and rapid collagen degradation was observed in ischemic reperfused, stunned myocardium [31,32].

Matrix metalloproteinase (MMP) activation and consequent collagen degradation have also been reported in the cardiomyopathic and failing heart. Gunja-Smith et al. [33] reported a 30-fold increase in collagenase activity in explanted hearts from patients with documented dilated cardiomyopathy. Subsequently, others have reported similar increases in MMP activity in patients with heart failure secondary to dilated cardiomyopathy [34–36]. While these findings suggest an association between increased MMP activity and ventricular remodeling (i.e., ventricular dilatation, sphericalization and increased compliance), they are ‘after-the-fact’ findings in that dilatation had already occurred, and did not necessarily reflect a cause and effect relationship. However, a direct cause and effect relationship between increased MMP activity and ventricular remodeling was evident from the findings in a temporal study comparing cardiomyopathic and golden Syrian hamsters between the ages of 150 and 300 days [37]. In contrast to control hearts, in which the collagen volume fraction (CVF) and MMP activity were age-invariant, there was a continual increase in MMP activity in the cardiomyopathic Syrian hamster, such that collagen degradation eventually exceeded synthesis, producing a decrease in CVF which coincided with the occurrence of significant ventricular dilatation and wall thinning.

Further insight into the relation between MMP activity, collagen degradation and adverse ventricular remodeling was demonstrated in a rat aorto-caval (AV) fistula model of chronic biventricular volume overload [38]. Within 12 h of creating the fistula, a significant increase in MMP activity occurred which was sustained for approximately the first week. As a consequence of this mast cell-mediated MMP activation, CVF was significantly decreased by the third day [39]. The onset of progressive ventricular dilatation and hypertrophy was apparent at one week post-fistula [38], and this myocardial remodeling in the initial phase of volume overload was considered to be deleterious in that it resulted in a significant depression in chamber contractility and the ventricle was clearly more compliant. As further evidence of a cause and effect relation between collagen degradation and ventricular dilatation, there are several reports indicating the ability of MMP inhibitors to attenuate ventricular dilatation using this and other experimental models of heart failure [40–43]. From these findings, one could conclude that elevations in MMP activity during the early stages of injury or elevated wall stress and the consequent degradation of fibrillar collagen are responsible for the initiation of a progressive remodeling process that eventually leads to heart failure.

3.3 Altered ratio of collagen types
The ratio of collagen types I/III has been reported to increase in the following disease states: experimentally induced or genetic hypertension [6,8,44]; in patients with dilated cardiomyopathy [45]; and in experimental myocardial infarction [46]. Whereas, in experimental animals and patients with diabetes the type I/III ratio was reported to be below that of a non-diabetic control group [47,48]. However, the functional consequences of altered amounts of type I and/or type III collagens, if any, have not been rigorously determined. Burgess et al. [44] reported a correlation (i.e., r = 0.91) between an index of LV relaxation (i.e., maximal rate of fall of LV pressure divided by mean arterial pressure) and the type I/III ratio indicating a slower relaxation rate as the amount of collagen type I increased relative to type III. Weber et al. [9] reported an early but transient increase in type III collagen relative to type I in hypertensive primates, which corresponded to an increase in myocardial stiffness. An increase in type III collagen, but not type I, was also documented in the myocardium of diabetic patients [47]. However, in addition to alterations in the ratio of collagen types in these studies there were also significant increases in total collagen concentration, which could have influenced the LV relaxation rate, myocardial stiffness or both. This was supported by a study myocardial biopsy specimens and LV function in patients with hypertension, where a significant increase in the collagen type I/III ratio was not associated with an increase in diastolic stiffness when overall collagen content was unchanged [49]. Given the variable relationship between the ratio of collagen types and myocardial stiffness, no definitive conclusions can be drawn regarding the functional consequences of such alterations.

3.4 Altered collagen cross-linking
Cross-linking is a process whereby collagen fibers are covalently linked to one another resulting in increased material stiffness and greater resistance to degradation. The formation of these cross-links occurs naturally with aging [50] and is also exacerbated in chronic diseases such as hypertension [51,52], chronic ventricular volume overload [53,54] and diabetes [48,55]. While there are several types of cross-linking, the most extensively characterized and predominant type is thought to be associated with advanced glycation end (AGE) products [56]. In most studies, the degree of cross-linking has been determined by the amount of insoluble collagen relative to soluble collagen content in the heart. Pertinent to this review, several studies have investigated the influence of collagen cross-linking on diastolic function. Norton et al. [51] concluded that increased myocardial stiffness secondary to hypertension in SHR is the result of enhanced myocardial collagen cross-linking rather than increased collagen concentration. Similarly, Woodiwiss et al. [52] demonstrated that a reduction in collagen cross-linking results in reduced myocardial stiffness and ventricular dilatation, irrespective of collagen concentration or type, in two rat models of pressure-overload induced heart failure (i.e., suprarenal abdominal aortic banding and chronic isoproterenol administration). Finally, Avendano et al. [55] reported aminoguanidine was able to prevent collagen cross-linking and the increase in LV chamber stiffness in diabetic dogs, without preventing diabetes-induced fibrosis. From these studies, it is obvious that the degree of collagen cross-linking has a strong impact on diastolic function, which is independent of myocardial collagen concentration. However, this should not be interpreted as suggesting myocardial stiffness is not influenced by alterations in myocardial collagen concentration. Rather, as Badenhorst et al. [57] elegantly demonstrated using experimental models of pressure overload, myocardial and LV chamber stiffness is affected by changes in both collagen quantity and quality (i.e., cross-linking), with the effect of changes in collagen concentration being modified by collagen quality.


   4. Alterations in ECM fibrillar collagen and left ventricular systolic function
Top
 Abstract
 1. Introduction
 2. Myocardial fibrillar collagen...
 3. Alterations in ECM...
 4. Alterations in ECM...
References
 
In contrast to the preponderance of myocardial ECM studies focused on diastolic function, there have been relatively few which have attempted to assess the effects of ECM alterations on myocardial systolic function. Baicu et al. [1] studied isolated papillary muscle from normal rat and feline hearts, as well as from felines with pressure overload induced hypertrophy and fibrosis, that were treated with plasmin to produce an acute activation of MMPs and disruption of the ECM. This decrease in collagen in the papillary muscles was accompanied by a marked decrease in systolic function (i.e., reduced amount and rate of shortening, reflected by developed tension (T) and +dT/dt) without affecting isolated cardiomyocyte contractility, leading the authors to conclude that myocardial fibrillar collagen is a major contributor to normal myocardial systolic performance. In contrast to these findings, Lamberts et al. [58] reported myocardial function was improved following specific degradation of collagen type I (i.e., an increase in developed tension and the rate of relaxation). Unfortunately, relaxation rates were not reported in the Baicu study, precluding comparison of this parameter. When considering this disparity, however, it should be noted that the preparation used by the Lamberts group was perfused, and consequently significant edema, evident by a significant increase in the diastolic tension-length curve, accompanied the disruption of collagen. In their discussion the authors concluded that an edema-induced Starling response may have masked the functional effects of collagen removal. Recent studies in our laboratory using an isolated, beating rat heart preparation, resulted in significant decreases in the peak isovolumetric pressure (25%) and in the maximal rates of LV pressure development (80%) and relaxation (90%) following an acute decrease of approximately 50% in collagen concentration (unpublished results). While edema also occurred in these studies, collagen degradation resulted in significant dilatation without a change in the overall compliance of the myocardium [59,60]. Thus, our findings are in agreement with the conclusion of Biacu et al. [1] that normal amounts of interstitial collagen contribute to the maintenance of systolic function.

Significant fibrosis is known to occur in human hypertensive, hypertrophied hearts and in the dilated failing heart regardless of etiology [14,61–63]. This has led to the notion that this fibrosis is at least partially responsible for the diminished ventricular function. Accordingly, one could hypothesize that reducing the amount of fibrosis would be beneficial to the failing heart. Thus far, the impact of ECM alterations on functional deterioration in heart failure has been primarily derived from studies of left ventricular assist device (LVAD) performance as a bridge to recovery/transplantation. There is currently intensive interest in identifying those patients who can be successfully weaned from LVAD support [64–66]. The supposition has been that reversal of the deleterious remodeling in heart failure is responsible for the observed clinical improvement in LVAD patients. Some findings appear to corroborate this expectation, with several studies reporting reverse remodeling characterized by significant reductions in the extent of myocardial fibrosis and cardiomyocyte size [67–71]. However, an equivalent number of studies have found improvement in functional parameters despite significant increases in myocardial collagen [72–75]. The improvement in systolic function observed in both cases suggests that the benefit of LVAD support was independent of effects on myocardial fibrosis. This was a possibility raised by Li et al. [76], who found minimal differences in total collagen, but significant increases in collagen cross-linking in LVAD supported hearts. Thus, a definitive cause and effect relationship between fibrosis and depressed systolic function has not been established.

Furthermore, there is evidence to indicate that a reduction in the myocardial collagen matrix could further exacerbate the severity of heart failure. As mentioned above, Baicu et al. [1] reported a decrease in systolic function in papillary muscles from pressure overloaded right ventricles following ECM disruption. Another study indicating that inducing collagen degradation may be contraindicated utilized the spontaneously hypertensive heart failure (SHHF) rat [41]. In the SHHF model, significant elevations in myocardial MMP activity occur between 9 and 13 months of age. During this interval, clinical signs of congestive heart failure become evident and the heart becomes functionally depressed, markedly enlarged and abnormally compliant, such that it can no longer maintain the elevated pressures. However, treatment with a broad-spectrum MMP inhibitor starting at 9 months of age, which presumably prevented collagen degradation, was cardioprotective in that the transition to a decompensated state did not occur [41]. The disconnect between fibrosis and impaired systolic function is also reflected by our findings in the AV fistula model, where LV contractility progressively declined despite myocardial collagen concentration remaining at normal levels prior to the development of heart failure [39]. Finally, if myocardial fibrosis is primarily due to cardiomyocyte necrosis (i.e., reparative or replacement fibrosis), then it is doubtful that collagen degradation would be beneficial. In this case, the heavily cross-linked scar tissue is less vulnerable to degradation than the normal endomysial collagen responsible for maintaining integrity of the myocardial tissue. Significant degradation of this ultrastructural collagen coinciding with the development of ventricular dilatation was noted in the cardiomyopathic hamster even though total collagen remained above normal due to the extensive scarring resulting from myocyte necrosis [77].

While therapy to reduce fibrosis may be contraindicated, the use of pharmacological agents to reduce the degree of cross-linking warrants further clinical investigation. Studies in older animals with and without experimental diabetes using such agents have reported marked improvement in both diastolic and systolic function [48,50,55,56]. The cross-link breaker, alagebrium chloride (ALT-711) has been tested in a clinical study using 21 aged patients with diastolic dysfunction. In this 16-week, open-label study, LV diastolic filling, peak oxygen consumption, aortic distensibility and LV ejection fraction and mass before and after treatment was non-invasively assessed. The results indicated a small but significant reduction in mass and a slight improvement in some of the early filling parameters with no change in the remaining variables. Despite the limited improvement during this relatively short study, these clinical results together with the encouraging animal findings justify additional larger clinical trials of longer duration.

In summary, the properties of the interstitial collagen matrix influence the stiffness of the myocardium, thereby contributing to the development of diastolic dysfunction. While changes in the relative distribution of collagen types occur during the course of myocardial remodeling secondary to sustained elevations in pressure or volume, the functional consequences remain to be determined. In contrast, chamber stiffness can clearly be affected by alterations in both collagen quantity and quality, with the effect of changes in collagen concentration being modified by the extent of collagen cross-linking. The limited evidence available regarding the effects of collagen on systolic function indicates that pharmacological attempts to reduce interstitial collagen have a negative impact. Therefore, a shift in treatment strategies for heart failure directed more specifically at affecting collagen cross-linking, rather than reducing the concentration of collagen, may be warranted in the attenuation of the adverse impact of collagen alterations on myocardial remodeling.


   Acknowledgments
 
This work was supported in part by grants from: NHLBI (RO1-HL-59981, HL-62228, HL-73990 and F32 HL072566) and from the American Heart Association (0435298N).


   Footnotes
 
{star} Presented at Cardiodynamics: Ventricular Wall Structure and Cardiac Function, Institute of Biomedical Engineering, University and ETH Zurich, Switzerland, November 4–5 2005.


   References
Top
 Abstract
 1. Introduction
 2. Myocardial fibrillar collagen...
 3. Alterations in ECM...
 4. Alterations in ECM...
 References
 

  1. Baicu CF, Stroud JD, Livesay VA, Hapke E, Holder J, Spinale FG, Zile MR. Changes in extracellular collagen matrix alter myocardial systolic performance. Am J Physiol Heart Circ Physiol 2003;284:H122-H132.[Abstract/Free Full Text]
  2. Janicki JS, Matsubara BB. Myocardial collagen and left ventricular diastolic dysfunction. In: Gaasch WH, LeWinter MM, editors. Left ventricular diastolic dysfunction. Philadelphia: Lea Febiger; 1993. pp. 125-140.
  3. Bishop JE, Laurent GJ. Collagen turnover and its regulation in the normal and hypertrophying heart. Eur Heart J 1995;16(Suppl. C):38-44.[Abstract]
  4. Mays PK, Bishop JE, Laurent GJ. Age-related changes in the proportion of types I and III collagen. Mech Ageing Dev 1988;45:203-212.[CrossRef][Medline]
  5. Medugorac I. Characterization of intramuscular collagen in the mammalian left ventricle. Basic Res Cardiol 1982;77:589-598.[CrossRef][Medline]
  6. Mukherjee D, Sen S. Collagen phenotypes during development and regression of myocardial hypertrophy in spontaneously hypertensive rats. Circ Res 1990;67:1474-1480.[Abstract/Free Full Text]
  7. Mukherjee D, Sen S. Alteration of collagen phenotypes in ischemic cardiomyopathy. J Clin Invest 1991;88:1141-1146.[Medline]
  8. Mukherjee D, Sen S. Alteration of cardiac collagen phenotypes in hypertensive hypertrophy: role of blood pressure. J Mol Cell Cardiol 1993;25:185-196.[CrossRef][Medline]
  9. Weber KT, Janicki JS, Shroff SG, Pick R, Chen RM, Bashey RI. Collagen remodeling of the pressure-overloaded, hypertrophied nonhuman primate myocardium. Circ Res 1988;62:757-765.[Abstract/Free Full Text]
  10. Borg TK, Caulfield JB. The collagen matrix of the heart. Fed Proc 1981;40:2037-2041.[Medline]
  11. Robinson TF, Cohen-Gould L, Factor SM. Skeletal framework of mammalian heart muscle. Arrangement of inter- and pericellular connective tissue structures. Lab Invest 1983;49:482-498.[Medline]
  12. Robinson TF, Factor SM, Sonnenblick EH. The heart as a suction pump. Sci Am 1986;254:84-91.[Medline]
  13. Robinson TF, Geraci MA, Sonnenblick EH, Factor SM. Coiled perimysial fibers of papillary muscle in rat heart: morphology, distribution, and changes in configuration. Circ Res 1988;63:577-592.[Abstract/Free Full Text]
  14. Pearlman ES, Weber K, Janicki JS, Pietra GG, Fishman AP. Muscle fiber orientation and connective tissue content in the hypertrophied human heart. Lab Invest 1982;46:158-164.[Medline]
  15. MacKenna DA, Omens JH, Covell JW. Left ventricular perimysial collagen fibers uncoil rather than stretch during diastolic filling. Basic Res Cardiol 1996;91:111-122.[CrossRef][Medline]
  16. Bing OHL, Matsushita S, Fanburg BL, Levine HJ. Mechanical properties of rat cardiac muscle during experimental hypertrophy. Circ Res 1971;28:234-245.[Abstract/Free Full Text]
  17. Caulfield JB, Borg TK. The collagen network of the heart. Lab Invest 1979;40:364-372.[Medline]
  18. Jugdutt BI. Extracellular matrix and cardiac remodeling. In: Villarreal FJ, editor. Interstitial fibrosis in heart failure. New York: Springer; 2005. pp. 23-55.
  19. Narayan S, Janicki JS, Shroff SG, Pick R, Weber KT. Myocardial collagen and mechanics after preventing hypertrophy in hypertensive rats. Am J Hypertens 1989;2:675-682.[Medline]
  20. Gelpi RJ, Pasipoularides A, Lader AS, Patrick TA, Chase N, Hittinger L, Shannon RP, Bishop SP, Vatner SF. Changes in diastolic cardiac function in developing and stable perinephritic hypertension in conscious dogs. Circ Res 1991;68:555-567.[Abstract/Free Full Text]
  21. Douglas PS, Tallant B. Hypertrophy, fibrosis and diastolic dysfunction in early canine experimental hypertension. J Am Coll Cardiol 1991;17:530-536.[Abstract]
  22. MacFarlane N, Northridge DB, Wright AR, Grant S, Dargie HJ. A comparative study of left ventricular structure and function in elite athletes. Br J Sports Med 1991;25:45-48.[Abstract/Free Full Text]
  23. Nixon JV, Wright AR, Porter TR, Roy V, Arrowood JA. Effects of exercise on left ventricular diastolic performance in trained athletes. Am J Cardiol 1991;68:945-949.[CrossRef][Medline]
  24. Shapiro LM, McKenna WJ. Left ventricular hypertrophy. Relation of structure to diastolic function in hypertension. Br Heart J 1984;51:637-642.[Abstract/Free Full Text]
  25. Szlachcic J, Tubau JF, O’Kelly B, Massie BM. Correlates of diastolic filling abnormalities in hypertension: a doppler echocardiographic study. Am Heart J 1991;120:386-391.
  26. Woolley DE. Mammalian collagenases. In: Piez K, Reddi AH, editors. Extracellular matrix biochemistry. New York: Elsevier; 1984. pp. 119-158.
  27. Montfort I, Pérez-Tamayo R. The distribution of collagenase in normal rat tissues. J Histochem Cytochem 1975;23:910-920.[Abstract]
  28. Tyagi SC, Matsubara L, Weber KT. Direct extraction and estimation of collagenase(s) activity by zymography in microquantities of rat myocardium and uterus. Clin Biochem 1993;26:191-198.[CrossRef][Medline]
  29. Woolley DE, Tetlow LC, Evanson JM. Collagenase immunolocalization studies of rheumatoid and malignant tissues. In: Woolley DE, Evanson JM, editors. Collagenase in normal and pathological tissues. New York: John Wiley & Sons; 1978. pp. 105-125.
  30. Takahashi S, Barry AC, Factor SM. Collagen degradation in ischaemic rat hearts. Biochem J 1990;265:233-241.[Medline]
  31. Charney RH, Takahashi S, Zhao M, Sonnenblick EH, Eng C. Collagen loss in the stunned myocardium. Circulation 1992;85:1483-1490.[Abstract/Free Full Text]
  32. Takahashi S, Geenen D, Nieves E, Iwazumi T. Collagenase degrades collagen in vivo in the ischemic heart. Biochim Biophys Acta 1999;1428:251-259.[Medline]
  33. Gunja-Smith Z, Morales AR, Romanelli R, Woessner Jr. JF. Remodeling of human myocardial collagen in idiopathic dilated cardiomyopathy—role of metalloproteinases and pyridinoline cross-links. Am J Pathol 1996;148:1639-1648.[Abstract]
  34. Li YY, Feldman AM, Sun Y, McTiernan CF. Differential expression of tissue inhibitors of metalloproteinases in the failing human heart. Circulation 1998;98:1728-1734.[Abstract/Free Full Text]
  35. Reddy HK, Tjahja IE, Campbell SE, Janicki JS, Hayden MR, Tyagi SC. Expression of matrix metalloproteinase activity in idiopathic dilated cardiomyopathy: a marker of cardiac dilatation. Mol Cell Biochem 2004;264:183-191.[CrossRef][Medline]
  36. Thomas CV, Coker ML, Zellner JL, Handy JR, Crumbley AJ, Spinale FG. Increased matrix metalloproteinase activity and selective upregulation in LV myocardium from patients with end-stage dilated cardiomyopathy. Circulation 1998;97:1708-1715.[Abstract/Free Full Text]
  37. Janicki JS. Collagen degradation in the heart. In: Eghbali-Webb M, editor. Molecular biology of collagen matrix in the heart. Austin: R.G. Landes Company; 1995. pp. 61-75.
  38. Brower GL, Henegar JR, Janicki JS. Temporal evaluation of left ventricular remodeling and function in rats with chronic volume overload. Am J Physiol Heart Circ Physiol 1996;271:H2071-H2078.[Abstract/Free Full Text]
  39. Brower GL, Chancey AL, Thanigaraj S, Matsubara BB, Janicki JS. Cause and effect relationship between myocardial mast cell number and matrix metalloproteinase activity. Am J Physiol Heart Circ Physiol 2002;283:H518-H525.[Abstract/Free Full Text]
  40. Chancey AL, Brower GL, Peterson JT, Janicki JS. Effects of matrix metalloproteinase inhibition on ventricular remodeling due to volume overload. Circulation 2002;105:1983-1988.[Abstract/Free Full Text]
  41. Peterson JT, Hallak H, Johnson L, Li H, O’Brien PM, Sliskovic DR, Bocan TM, Coker ML, Etoh T, Spinale FG. Matrix metalloproteinase inhibition attenuates left ventricular remodeling and dysfunction in a rat model of progressive heart failure. Circulation 2001;103:2303-2309.[Abstract/Free Full Text]
  42. Rohde LE, Ducharme A, Arroyo LH, AIkawa M, Sukhova GH, Lopez-Anaya A, McClure KF, Mitchell PG, Libby P, Lee RT. Matrix metalloproteinase inhibition attenuates early left ventricular enlargement after experimental myocardial infarction in mice. Circulation 1999;99:3063-3070.[Abstract/Free Full Text]
  43. Spinale FG, Coker ML, Krombach SR, Mukherjee R, Hallak H, Houck WV, Clair MJ, Kribbs SB, Johnson LL, Peterson JT, Zile MR. Matrix metalloproteinase inhibition during the development of congestive heart failure: effects on left ventricular dimensions and function. Circ Res 1999;85:364-376.[Abstract/Free Full Text]
  44. Burgess ML, Buggy J, Price RL, Abel FL, Terracio L, Samarel AM, Borg TK. Exercise- and hypertension-induced collagen changes are related to left ventricular function in rat hearts. Am J Physiol Heart Circ Physiol 1996;270:H151-H159.[Abstract/Free Full Text]
  45. Marijianowski MMH, Teeling P, Mann J, Becker AE. Dilated cardiomyopathy is associated with an increase in the type I/type III collagen ratio: a quantitative assessment. J Am Coll Cardiol 1995;25:1263-1272.[Abstract]
  46. Wei S, Chow LT, Shum IO, Qin L, Sanderson JE. Left and right ventricular collagen type I/III ratios and remodeling post-myocardial infarction. J Card Fail 1999;5:117-126.[CrossRef][Medline]
  47. Shimizu M, Umeda K, Sugihara N, Yoshio H, Ino H, Takeda R, Okada Y, Nakanishi I. Collagen remodelling in myocardia of patients with diabetes. J Clin Pathol 1993;46:32-36.[Abstract/Free Full Text]
  48. Liu J, Masurekar MR, Vatner DE, Jyothirmayi GN, Regan TJ, Vatner SF, Meggs LG, Malhotra A. Glycation end-product cross-link breaker reduces collagen and improves cardiac function in aging diabetic heart. Am J Physiol Heart Circ Physiol 2003;285:H2587-H2591.[Abstract/Free Full Text]
  49. Linehan KA, Seymour AM, Williams PE. Semiquantitative analysis of collagen types in the hypertrophied left ventricle. J Anat 1998;198:83-92.
  50. Asif M, Egan J, Vasan S, Jyothirmayi GN, Masurekar MR, Lopez S, Williams C, Torres RL, Wagle D, Ulrich P, Cerami A, Brines M, Regan TJ. An advanced glycation endproduct cross-link breaker can reverse age-related increases in myocardial stiffness. Proc Natl Acad Sci 2000;97:2809-2813.[Abstract/Free Full Text]
  51. Norton GR, Tsotetsi J, Trifunovic B, Hartford C, Candy GP, Woodiwiss AJ. Myocardial stiffness is attributed to alterations in cross-linked collagen rather than total collagen or phenotypes in spontaneously hypertensive rats. Circulation 1997;96:1991-1998.[Abstract/Free Full Text]
  52. Woodiwiss AJ, Tsotetsi OJ, Sprott S, Lancaster EJ, Mela T, Chung ES, Meyer TE, Norton GR. Reduction in myocardial collagen cross-linking parallels left ventricular dilatation in rat models of systolic chamber dysfunction. Circulation 2001;103:155-160.[Abstract/Free Full Text]
  53. Iimoto DS, Covell JW, Harper E. Increase in cross-linking of type I and type III collagens associated with volume-overload hypertrophy. Circ Res 1988;63:399-408.[Abstract/Free Full Text]
  54. Herrmann KL, McCulloch AD, Omens JH. Glycated collagen cross-linking alters cardiac mechanics in volume-overload hypertrophy. Am J Physiol Heart Circ Physiol 2003;284:H1277-H1284.[Abstract/Free Full Text]
  55. Avendano GF, Agarwal RK, Bashey RI, Lyons MM, Soni BJ, Jyothirmayi GN, Regan TJ. Effects of glucose intolerance on myocardial function and collagen-linked glycation. Diabetes 1999;48:1443-1447.[Abstract]
  56. Susic D, Vargic J, Ahn JFED. Crosslink breakers: a new approach to cardiovascular therapy. Curr Opin Cardiol 2004;19:336-340.[CrossRef][Medline]
  57. Badenhorst D, Maseko M, Tsotetsi OJ, Naidoo A, Brooksbank R, Norton GR, Woodiwiss AJ. Cross-linking influences the impact of quantitative changes in myocardial collagen on cardiac stiffness and remodelling in hypertension in rats. Cardiovasc Res 2003;57:632-641.[Abstract/Free Full Text]
  58. Lamberts RR, Willemsen MJJMF, Perez NG, Sipkema P, Westerhof N. Acute and specific collagen type I degradation increases diastolic and developed tension in perfused rat papillary muscle. Am J Physiol Heart Circ Physiol 2004;286:H889-H894.[Abstract/Free Full Text]
  59. Murray DB, Gardner JD, Brower GL, Janicki JS. Endothelin-1 mediates cardiac mast cell degranulation, matrix metalloproteinase activation and myocardial remodeling in rats. Am J Physiol Heart Circ Physiol 2004;287:H2295-H2299.[Abstract/Free Full Text]
  60. Chancey AL, Brower GL, Janicki JS. Cardiac mast cell-mediated activation of gelatinase and alteration of ventricular diastolic function. Am J Physiol Heart Circ Physiol 2002;282:H2152-H2158.[Abstract/Free Full Text]
  61. Heneghan MA, Malone D, Dervan PA. Myocardial collagen network in dilated cardiomyopathy. Morphometry and scanning electron microscopy study. Ir J Med Sci 1991;160:399-401.[Medline]
  62. Rossi MA. Patterns of myocardial fibrosis in idiopathic cardiomyopathies and chronic chagasic cardiopathy. Can J Cardiol 1991;7:287-294.[Medline]
  63. Schaper J, Froede R, Hein S, Buck A, Hashizume H, Speiser B, Friedl A, Bleese N. Impairment of the myocardial ultrastructural and changes of the cytoskeleton in dialted cardiomyopathy. Circulation 1991;83:504-514.[Abstract/Free Full Text]
  64. Burkhoff D, Klotz S, Mancini DM. LVAD-induced reverse remodeling: basic and clinical implications for myocardial recovery. J Card Fail 2006;12:227-239.[CrossRef][Medline]
  65. Wohlschlaeger J, Schmitz KJ, Schmid C, Schmid KW, Keul P, Takeda A, Weis S, Levkau B, Baba HA. Reverse remodeling following insertion of left ventricular assist devices (LVAD): a review of the morphological and molecular changes. Cardiovasc Res 2005;68:376-386.[Abstract/Free Full Text]
  66. Mann DL, Willerson JT. Left ventricular assist devices and the failing heart: a bridge to recovery, a permanent assist device, or a bridge too far?. Circulation 1998;98:2367-2369.[Free Full Text]
  67. Thompson LO, Skrabal CA, Loebe M, Lafuente JA, Roberts RR, Akgul A, Jones V, Bruckner BA, Thohan V, Noon GP, Youker KA. Plasma neurohormone levels correlate with left ventricular functional and morphological improvement in LVAD patients. J Surg Res 2005;123:25-32.[CrossRef][Medline]
  68. Kucuker SA, Stetson SJ, Becker KA, Akgul A, Loebe M, Lafuente JA, Noon GP, Koerner MM, Entman ML, Torre-Amione G. Evidence of improved right ventricular structure after LVAD support in patients with end-stage cardiomyopathy. J Heart Lung Transplant 2004;23:28-35.[CrossRef][Medline]
  69. Bruckner BA, Stetson SJ, Perez-Verdia A, Youker KA, Radovancevic B, Connelly JH, Koerner MM, Entman ME, Frazier OH, Noon GP, Torre-Amione G. Regression of fibrosis and hypertrophy in failing myocardium following mechanical circulatory support. J Heart Lung Transplant 2001;20:457-464.[CrossRef][Medline]
  70. Bruckner BA, Stetson SJ, Farmer JA, Radovancevic B, Frazier OH, Noon GP, Entman ML, Torre-Amione G, Youker KA. The implications for cardiac recovery of left ventricular assist device support on myocardial collagen content. Am J Surg 2000;180:498-501.[CrossRef][Medline]
  71. Thohan V, Stetson SJ, Nagueh SF, Rivas-Gotz C, Koerner MM, Lafuente JA, Loebe M, Noon GP, Torre-Amione G. Cellular and hemodynamics responses of failing myocardium to continuous flow mechanical circulatory support using the DeBakey-Noon left ventricular assist device: a comparative analysis with pulsatile-type devices. J Heart Lung Transplant 2005;24:566-575.[CrossRef][Medline]
  72. Klotz S, Foronjy RF, Dickstein ML, Gu A, Garrelds IM, Danser J, Oz M, D’Armiento J, Burkhoff D. Mechanical unloading during left ventricular assist device support increases left ventricular collagen cross-linking and myocardial stiffness. Circulation 2005;112:364-374.[Abstract/Free Full Text]
  73. Barbone A, Holmes JW, Heerdt PM, The’ AH, Naka Y, Joshi N, Daines M, Marks AR, Oz MC, Burkhoff D. Comparison of right and left ventricular responses to left ventricular assist device support in patients with severe heart failure: a primary role of mechanical unloading underlying reverse remodeling. Circulation 2001;104:670-675.[Abstract/Free Full Text]
  74. Madigan JD, Barbone A, Choudhri AF, Morales DL, Cai B, Oz MC, Burkhoff D. Time course of reverse remodeling of the left ventricle during support with a left ventricular assist device. J Thorac Cardiovasc Surg 2001;121:902-908.[Abstract/Free Full Text]
  75. McCarthy PM, Nakatani S, Vargo R, Kottke-Marchant K, Harasaki H, James KB, Savage RM, Thomas JD. Structural and left ventricular histologic changes after implantable LVAD insertion. Ann Thorac Surg 1995;59:609-613.[Abstract/Free Full Text]
  76. Li YY, Feng Y, McTiernan CF, Pei W, Moravec CS, Wang P, Rosenblum W, Kormos RL, Feldman AM. Downregulation of matrix metalloproteinases and reduction in collagen damage in the failing human heart after support with left ventricular assist devices. Circulation 2001;104:1147-1152.[Abstract/Free Full Text]
  77. Janicki JS, Brower GL, Henegar JR. Interstitial collagen remodeling in chronic heart failure. Basic Appl. Myology 1995;5:339-348.



This article has been cited by other articles:


Home page
 Am. J. Pathol.Home page
J. A. Jones, C. Beck, J. R. Barbour, J. A. Zavadzkas, R. Mukherjee, F. G. Spinale, and J. S. Ikonomidis
Alterations in Aortic Cellular Constituents during Thoracic Aortic Aneurysm Development: Myofibroblast-Mediated Vascular Remodeling
Am. J. Pathol., October 1, 2009; 175(4): 1746 - 1756.
[Abstract] [Full Text] [PDF]

Home page
 Circ Heart FailHome page
F. G. Spinale, G. P. Escobar, R. Mukherjee, J. A. Zavadzkas, S. M. Saunders, L. B. Jeffords, A. M. Leone, C. Beck, S. Bouges, and R. E. Stroud
Cardiac-Restricted Overexpression of Membrane Type-1 Matrix Metalloproteinase in Mice: Effects on Myocardial Remodeling With Aging
Circ Heart Fail, July 1, 2009; 2(4): 351 - 360.
[Abstract] [Full Text] [PDF]

Home page
 Cardiovasc ResHome page
N. Hermida, B. Lopez, A. Gonzalez, J. Dotor, J. J. Lasarte, P. Sarobe, F. Borras-Cuesta, and J. Diez
A synthetic peptide from transforming growth factor-{beta}1 type III receptor prevents myocardial fibrosis in spontaneously hypertensive rats
Cardiovasc Res, February 15, 2009; 81(3): 601 - 609.
[Abstract] [Full Text] [PDF]

Home page
 Cardiovasc ResHome page
J. Meyer-Kirchrath, M. Martin, C. Schooss, C. Jacoby, U. Flogel, A. Marzoll, J. W. Fischer, J. Schrader, K. Schror, and T. Hohlfeld
Overexpression of prostaglandin EP3 receptors activates calcineurin and promotes hypertrophy in the murine heart
Cardiovasc Res, February 1, 2009; 81(2): 310 - 318.
[Abstract] [Full Text] [PDF]

Home page
 HypertensionHome page
B. Lopez, R. Querejeta, A. Gonzalez, J. Beaumont, M. Larman, and J. Diez
Impact of Treatment on Myocardial Lysyl Oxidase Expression and Collagen Cross-Linking in Patients With Heart Failure
Hypertension, February 1, 2009; 53(2): 236 - 242.
[Abstract] [Full Text] [PDF]

Home page
 Circ Heart FailHome page
A. Biolo, S. Ramamurthy, L. H. Connors, C. J. O'Hara, H. K. Meier-Ewert, P. T. Soo Hoo, D. B. Sawyer, D. S. Seldin, and F. Sam
Matrix Metalloproteinases and Their Tissue Inhibitors in Cardiac Amyloidosis: Relationship to Structural, Functional Myocardial Changes and to Light Chain Amyloid Deposition
Circ Heart Fail, November 1, 2008; 1(4): 249 - 257.
[Abstract] [Full Text] [PDF]

Home page
 Physiol. GenomicsHome page
S. M. Swift, B. R. Gaume, K. M. Small, B. J. Aronow, and S. B. Liggett
Differential coupling of Arg- and Gly389 polymorphic forms of the {beta}1-adrenergic receptor leads to pathogenic cardiac gene regulatory programs
Physiol Genomics, September 17, 2008; 35(1): 123 - 131.
[Abstract] [Full Text] [PDF]

Home page
 Cardiovasc ResHome page
C. Leipner, K. Grun, A. Muller, E. Buchdunger, L. Borsi, H. Kosmehl, A. Berndt, T. Janik, A. Uecker, M. Kiehntopf, et al.
Imatinib mesylate attenuates fibrosis in coxsackievirus b3-induced chronic myocarditis
Cardiovasc Res, July 1, 2008; 79(1): 118 - 126.
[Abstract] [Full Text] [PDF]

Home page
 Eur Respir JHome page
M. J. Overbeek, J-W. Lankhaar, N. Westerhof, A. E. Voskuyl, A. Boonstra, J. G. F. Bronzwaer, K. M. J. Marques, E. F. Smit, B. A. C. Dijkmans, and A. Vonk-Noordegraaf
Right ventricular contractility in systemic sclerosis-associated and idiopathic pulmonary arterial hypertension
Eur. Respir. J., June 1, 2008; 31(6): 1160 - 1166.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
K. V. Desai, G. A. Laine, R. H. Stewart, C. S. Cox Jr., C. M. Quick, S. J. Allen, and U. M. Fischer
Mechanics of the left ventricular myocardial interstitium: effects of acute and chronic myocardial edema
Am J Physiol Heart Circ Physiol, June 1, 2008; 294(6): H2428 - H2434.
[Abstract] [Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
B. Lopez, A. Gonzalez, J. Beaumont, R. Querejeta, M. Larman, and J. Diez
Identification of a Potential Cardiac Antifibrotic Mechanism of Torasemide in Patients With Chronic Heart Failure
J. Am. Coll. Cardiol., August 28, 2007; 50(9): 859 - 867.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Personal Folders
Right arrow Download to citation manager
Right arrow Permission Requests
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Brower, G. L.
Right arrow Articles by Janicki, J. S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Brower, G. L.
Right arrow Articles by Janicki, J. S.
Related Collections
Right arrow Cardiac - physiology
Right arrow Cardiac - other
Right arrow Congestive Heart Failure

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