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Cardiovascular Research 2003 57(3):594-598; doi:10.1016/S0008-6363(02)00877-5
© 2003 by European Society of Cardiology
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Copyright © 2003, European Society of Cardiology

Collagen cross-linking: new dimension to cardiac remodeling

Santhosh K.G Koshy*, Hanumanth K Reddy and Himanshu H Shukla

University of Missouri—Columbia, Columbia, MO, USA

koshys{at}health.missouri.edu

* Corresponding author. DC 034.00, Division of Cardiology, University of Missouri—Columbia, 1 Hospital Drive, Columbia, MO 65212, USA. Tel.: +1-573-882-2296; fax: +1-573-884-7743.

See article by Badenhorst et al. [1] (pages 632–641) in this issue.

Left ventricular (LV) dysfunction has become a leading area of research as the prevalence of heart failure is reaching epidemic proportions. LV chamber remodeling and stiffness are consequent to significant structural and functional alteration of both the myocyte and extracellular matrix (ECM). Both these factors are important determinants of chamber size and geometry as well as its contractile and relaxation properties. Numerous papers have been published about the seminal role of collagen concentration and collagenolysis in hypertrophic and dilated cardiomyopathies; however, the qualitative aspects of these changes were not correlated well with the functional characteristics of cardiac chambers. In this issue of Cardiovascular Research, Baldenhorst et al. [1] show the influence of collagen cross-linking on chamber stiffness and remodeling.

Cellular mechanisms responsible for transformation of compensatory myocardial hypertrophy to a dysfunctional dilated ventricle remain enigmatic. Earlier studies focused on structural changes in the cardiac myocyte to explain chamber dysfunction in hypertensive heart disease [2–5]. This included studies related to changes in its size and spatial orientation [2–4]. The depression of systolic function and an increase in passive stiffness were noted even in isolated muscle preparations [5]. This suggested that physiological changes in the myocardial chamber were related to structural changes at the cardiac myocyte level.

More recent studies have focused on the contribution of the ECM to cardiac contraction and relaxation functions [6–11]. The collagen matrix provides support for the maintenance of both myocyte and myofibrillar alignment, thereby ensuring structural integrity for individual myocyte shortening and relaxation, which then translates into overall myocardial systolic and diastolic properties. Therefore, the patterns of collagen synthesis and degradation play a seminal role in determining the altered systolic and diastolic properties of a remodeled ventricle in response to a host of volume and pressure overload states. However, prior to the systolic dysfunction and overt heart failure, diastolic dysfunction predominates and may be the initial clue to more aggressive interventions in the hope of preventing overt systolic dysfunction.

Normal aging, hypertension and diabetes mellitus have been associated with functional alterations of ECM, especially fibrillar collagen. There are three major changes described: (1) change in the collagen content [6–8,12], (2) conformational change in the type of fibrillar collagen (amount of type III collagen decreases and type I increases) [12], and (3) increase in collagen cross-linking [13–18]. In myocardial tissue, these changes cause varying degrees of diastolic stiffness.

Pathologic myocardial hypertrophy is a resultant of the changes in the myocyte structure, including hypertrophy, apoptosis, and necrosis of myocytes. This is accompanied by changes in the ECM. The extent of this phenomenon is the result of a dynamic equilibrium between cell growth and death, and involves various signals that regulate these processes [6]. Abnormal and disproportionate synthesis of collagen within the heart, termed cardiac collagenosis, is further classified as reparative and reactive fibrosis depending on the presence or absence of myocardial necrosis as the stimulus for collagen formation [6,7]. Hyperplasia and migration of cardiac fibroblast to the interstitium in long standing systemic hypertension is facilitated by various growth factors (mainly fibroblast growth factor and transforming growth factor-β) and fibrogenic cytokines interleukin-1 and tumor necrosis factor-{alpha}. This results in an increase in collagen content and also in structural changes in collagen network causing abnormal diastolic stiffness.

Collagen deposition in the extracellular compartment comprises of primarily two subtypes of collagen, type I and III. A shift in the ratio of these collagen subtypes from type III to type I was thought to be responsible for the increased chamber stiffness. This was later challenged and several reports were published suggesting that changes in total myocardial collagen concentration or shifting of the collagen phenotype do not necessarily translate into increased myocardial stiffness [7,12].

The third, probably the most important change in the myocardial fibrillar collagen, is the morphological change in the collagen cross-linking. Changes in the degree of collagen cross-linking are important in cardiac hypertrophy as well as in late remodeling. However, its role in late cardiac remodeling was unclear till the present study by Baldenhorst et al. [1]


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Myocardial stiffness does not always correlate with the amount of collagen deposition. This has lead to the proposal that it is not the amount of collagen that matters; it is the cross-linking [13,14] or the relative proportion of stiffer collagen phenotype (type I) to that of more elastic type (type III) [15], which determines the stiffness. The importance of cross-linking has been eloquently described in the article by Baldenhorst et al. [1]. They have described a key missing component to our current understanding of impaired relaxation process associated with diastolic dysfunction. This study in conjunction with previous work produced out of their laboratory has shown that while there is an increased deposition of collagen, this does not always translate into increased stiffness [16]. Presence of collagen cross-linking leads to increased stiffness, while non-linking collagen leads to adverse remodeling. Cross-linking of proteins, such as collagen, increases with aging and is accelerated with certain pathophysiological conditions like diabetes. One of the underlying mechanisms of this accelerated cross-linking is the formation of advanced glycation end products (AGE) [17]. AGE formation alters the functional properties of several important matrix molecules. Intermolecular cross-linking by AGEs in type I collagen induces an expansion of the molecular packing and alters the function of myocardial tissue. Aminoguanidine, a nucleophilic hydrazine compound has been shown to prevent the formation of AGE and glucose derived collagen cross-links [18].


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With time, the LV chamber remodels and becomes dilated in hypertensive heart disease. As stated earlier, fundamental mechanisms underlying this change in chamber morphology remain unclear. Disorganization of the collagen fibrillar network may be responsible for these changes.

The structural support provided by the fibrillar collagen matrix is an important determinant of myocyte shape and alignment and the transduction force of myocyte shortening. The increase of the collective degradation enzymes, called matrix metalloproteinases (MMPs) has been implicated as an etiology for the development of adverse remodeling [9–11]. The enhanced collagen degradation by MMPs reduces the amount of collagen available for fibril formation and this results in chamber dilatation. However, LV dilatation is more frequently associated with normal or increased myocardial collagen. Therefore increased MMP activity is not sufficient to explain adverse remodeling. The importance of collagen pyridinoline cross-links in LV remodeling was addressed subsequently [19–21]. A loss of collagen support due to increased degradation of mature collagen with replacement by newly synthesized collagen with decreased cross-linking may contribute directly to LV dilatation and systolic dysfunction [1].


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Other factors also play an important role in remodeling seen in chronic pressure overload hypertrophy. Interestingly, the chronic release of reactive oxygen species (ROS) has been linked to the development of left ventricular hypertrophy and heart failure progression [22]. The chronic release of ROS appears to derive from the nonphagocytic NAD(P)H oxidase and mitochondria. The fibrosis, collagenosis and activation of MMPs involved in the remodeling of the failing myocardium are dependent on ROS released during the phenotypic transformation of fibroblasts to myofibroblasts associated with progression of end-stage heart failure.

Studies showed that collagen promoting gene expression increased to a greater extent in spontaneously hypertensive rats with clinical heart failure than in those without heart failure. The appearance of clinical heart failure was marked by an increase in transforming growth factor β1 mRNA and up regulation of fibronectin and collagen genes [23].

The signal transducer and activator of transcription (STAT) protein 3 is important for glycoprotein130 (gp 130) mediated cardiac myocyte hypertrophy. The binding of ligands to gp130 activates the JAK (Janus kinase)/STAT signal transduction pathway, where STAT3 plays a central role in transmitting signals from the membrane to the nucleus [24]. Disruption of gp130 results in heart failure in response to mechanical stress accompanied by an increase in apoptosis. Hence, inactivation of STAT3 consequent to loss of gp130 plays an important role in the transition of stable cardiac hypertrophy to heart failure [25]. Vascular endothelial growth factor and bcl-xL have been identified as target genes of STAT [26,27] and these can promote cardiac myocyte survival by prevention of apoptosis. Activation of STAT mediated signaling in the cardiac myocyte has been proposed as a novel therapeutic strategy for the prevention of heart failure [24,25,27].


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Our current understanding of matrix collagen changes seen in myocardial hypertrophy and remodeling is summarized in Fig. 1. The collagen changes explaining diastolic dysfunction and chamber remodeling have been shown in animals. We have to extrapolate these findings to late ventricular remodeling that occurs in hypertensive heart disease in humans. The primary inciting stimulus for these changes in collagen type and structure is not clearly known. Limited data is available to understand and explain the transformation of cross-linked to non-cross-linked collagen leading to cardiac remodeling. Does the altered non cross-linked collagen synthesis have a cause or effect relationship with increased cleavage of cross-linked collagen or are these processes independent?


Figure 1
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  		Fig. 1 Schematic diagram depicting the influence of changes in matrix collagen in the genesis of myocardial hypertrophy and chamber remodeling. ACE—Angiotensin converting enzyme.

 
Changes in the constitutive properties of myocyte also contribute to the abnormalities in myocardial stiffness that develops in pressure overload hypertrophy [28]. The changes in the matrix seem to be independent of these changes in the myocyte. Whether these changes in myocyte and matrix occur simultaneously or one precedes the other is unknown.

The importance of these data needs to be translated to clinical field. The key clinical issue is prevention of heart failure in hypertensive heart disease. The change in phenotype and cross-linking of collagen appears to have a significant impact on the ventricular remodeling seen in pressure overload hypertrophy. Therapeutic strategies targeted at preventing remodeling in these patients are of paramount importance. Table 1 shows the list of antihypertensive medications with their action on collagen cross-linking and other actions leading to inhibition of chamber hypertrophy and remodeling. Certain antihypertensives like hydralazine and calcium channel blockers can prevent heart failure and LV dilatation without affecting the degree of hypertrophy [29] where as angiotensin converting enzyme inhibitors and angiotensin receptor blockers would cause regression of LV hypertrophy and dilatation [29–32]. Endothelin receptor inhibitors show a similar effect on the cardiac hypertrophy and remodeling [33] Unlike drugs targeting the renin–angiotensin system, hydralazine [15,31] and amlodipine [34] do not affect the increased collagen content. It is possible that these agents do not inactivate mechanical signaling mediated through ECM-integrin pathway. The potential role of the antioxidant actions of carvedilol [35] resulting in prevention of apoptosis, can be an important reason for its future use in treatment of hypertension prior to onset of clinical heart failure. Drugs targeted to cause activation of STAT mediated signaling in the cardiac myocytes are yet to be studied [24,25].


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  		Table 1 Antihypertensive medications and their effect on collagen cross-linking and left ventricular remodeling

 


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