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Published in final edited form as: J Mol Cell Cardiol. 2009 Jun 11;48(3):564–569. doi: 10.1016/j.yjmcc.2009.06.001

Extracellular Matrix Remodeling During the Progression of Volume Overload-Induced Heart Failure

Kirk R Hutchinson 1,2, James A Stewart Jr 2, Pamela A Lucchesi 2,*
PMCID: PMC2824070  NIHMSID: NIHMS129201  PMID: 19524591

Abstract

Volume overload-induced heart failure results in progressive left ventricular remodeling characterized by chamber dilation, eccentric cardiac myocyte hypertrophy and changes in extracellular matrix (ECM) remodeling changes. The ECM matrix scaffold is an important determinant of the structural integrity of the myocardium and actively participates in force transmission across the LV wall. In response to this hemodynamic overload, the ECM undergoes a distinct pattern of remodeling that differs from pressure overload. Once thought to be a static entity, the ECM is now regarded to be a highly adaptive structure that is dynamically regulated by mechanical stress, neurohormonal activation, inflammation and oxidative stress, that result in alterations in collagen and other matrix components and a net change in matrix metalloproteinase (MMP) expression and activation. These changes dictate overall ECM turnover during volume overload hear failure progression. This review will discuss the cellular and molecular mechanisms that dictate the temporal patterns of ECM remodeling during heart disease progression.

Heart failure (HF) pathophysiology encompasses physiological, neurohormonal, molecular, and cellular changes that culminate in the activation of compensatory mechanisms aimed at maintaining heart function. When prolonged, these alterations can evolve into maladaptive processes. Hearts subjected to volume overload are challenged by distinct hemodynamic and mechanical stress and neurohormonal activation resulting from increased preload. Mitral and aortic valve regurgitation are the primary causes of volume overload, but septal defects, and areas opposite myocardial infarction can also lead to the pathology [1]. To accommodate the increased preload, the left ventricle (LV) undergoes structural and functional changes such as eccentric cardiac hypertrophy and extracellular matrix (ECM) remodeling. This results in progressive chamber dilatation characterized by a disproportionate increase in the ratio of LV end-diastolic diameter to wall thickness (LVEDD/wt ratio), increased myocardial wall stress, and development of congestive HF. These responses initially foster an adaptive change of the LV chamber as an attempt to accommodate the increase in hemodynamic overload. LV remodeling in response to volume overload includes myocardial and endothelial apoptosis, progressive cardiac myocyte contractile dysfunction, altered cardiac fibroblast function and extensive ECM remodeling.

Experimental Models of Volume Overload

Animal models of pure volume overload include aortocaval fistula (ACF) and mitral regurgitation (MR). ACF is the most widely used method for inducing volume overload, especially in rodents. Briefly, this method involves puncturing the shared midwall between the aorta and inferior vena cava using a surgical needle [2]. The resultant shunt causes a reliable increase in cardiac preload. In larger animals, MR induced by surgically damaging the mitral valve or chordae tendonae is more frequently used to create volume overload [3].

Although these experimental models consistently generate LV volume overload induced heart failure, they have intrinsic caveats that should be considered. The most notable limitation is that induced damage tends to be immediate as opposed to gradual, unlike the pathologic scenarios most often observed in humans. Secondly, volume overload is created in “healthy” animals that do not have other cardiovascular diseases (e.g. hypertension, infarction, coronary artery disease) that would compound the hemodynamic overload and alter both disease severity and progression. For a technical standpoint, the temporal progression of HF in ACF models varies amongst laboratories depending on the initial size of the shunt. Finally, ACF produces a decrease in mean arterial pressure immediately following the procedure that persists throughout the compensatory stage [4].

Volume Overload and LV ECM Remodeling

The ECM is a highly adaptive structure that is dynamically regulated by mechanical stress, neurohormonal activation, inflammation and oxidative stress. Volume overload is characterized by a state of remodeling that promotes wall thinning and chamber dilatation, whereas excess matrix deposition is observed in pressure overload. The net composition and turnover of the ECM is dictated by cardiac fibroblasts, myocytes, mast cells, and infiltrating inflammatory cells. Cardiac fibroblasts produce an extensive network of fibrillar collagens, laminin and fibronectin to maintain the structural integrity of the myocardium. Fibrillar collagens are comprised of five different types of collagen, with types I and III representing approximately 85% and 15%, respectively[5]. All cell types mentioned above secrete proteins that regulate ECM turnover, including matrix metalloproteinases (MMPs), their tissue inhibitors (TIMPs) and other proteolytic enzymes.

Progressive Structural and Functional LV Remodeling in Response to Volume Overload

The majority of studies that have characterized the molecular mechanisms of LV remodeling in volume overload have used the ACF model in rodents. This model confirms studies in humans that volume overload HF is characterized by increased ECM turnover. In ACF, three stages of HF progression in response to volume overload have been characterized: acute stress (12 hours to 7 days), compensatory remodeling (3-10 weeks) and decompensated failure (> 15 weeks) [6] (Figure 1).

Figure 1.

Figure 1

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Putative mechanisms involved in progressive LV and ECM remodeling in response to volume overload.

In the acute stage, ACF causes an increase in preload resulting in increased LVEDP and increased wall stress. This triggers rapid, transitory LV remodeling that results in net overall increases in compliance and mild LV dilation [4, 7]. Remodeling at this time point primarily involves rapid ECM degradation followed by formation of matrix with changes in collagen isoform and organization [4].

During the compensated stage, continued volume overload causes a sustained increase in LVEDP and further chamber dilation (increased LVEDD). The net result appears to be preserved systolic function (fractional shortening, +dp/dt), increased LV compliance [8] and progressive wall thinning. Similar results were reported in patients with valvular heart disease [9]. At this phase, continued ECM turnover with an increase in MMP/TIMP ratio and further isoform shift from collagen I to III leads to a net degradation. Since the characteristics of the ECM are the primary determinants of the passive LV diastolic properties and play a key role in force transmission, the net ECM degradation during the compensatory phase may actually contribute to the transition to decompensated heart failure and compromise diastolic and systolic function.

Decompensated failure occurs between 15-21 weeks post-ACF and is characterized by systolic and diastolic dysfunction, continued wall thinning, further increases in chamber compliance and eventual pump failure [8]. Similar results have been reported for rats [10] and patients [11] with severe aortic regurgitation. Despite the profound chamber dilation at this stage, increased ECM turnover with a net deposition is observed [12], perhaps in an attempt to compensate for the increase in compliance.

Dynamic ECM Regulation During Volume Overload-Induced Heart Failure Progression

Early decreases in collagen concentrations in response to volume overload were noted by Murray et al. [13], who reported a decrease in fibrillar collagen at 1 and 5 days post ACF. These results confirm an earlier observation by Ryan et al. [4], who reported an acute, 50% decrease in total collagen at 2 days that returned towards normal 5 days post-ACF. In addition to changes in net ECM turnover, changes in collagen isoform distribution can affect diastolic properties and therefore compliance within the myocardium [14]. During this compensatory phase, increases in the ratio of collagen type III (more compliant) to collagen type I and elevated fibronectin and elastin expression have been observed [15]. During end-stage heart failure, total collagen content is actually increased and is particularly seen in the endocardium as perivascular fibrosis is manifested [16]. More recently, microarray analysis of canine LV tissue at 4 months post mitral regurgitation has identified new matrix components downregulated in volume overload heart failure, including decorin, fibulin1 and fibrillin1 [17]. Although the functional consequences were not assessed in this model, it is tempting to speculate that these changes contribute to LV dilation and compliance. Decorin facilitates collagen fiber assembly and increases their tensile strength [18]. Fibulin-1 is a key component of elastic fibers and is also down-regulated following cardiac ischemia in young rats [19]. Finally, fibrillin-1 is involved in elastic fibrogenesis and is increased during angiotensin II (Ang II)-dependent myocardial fibrosis [20]. Further studies are warranted to correlate changes in expression of these proteins with ECM remodeling during HF progression.

ECM Turnover: An Imbalance Between ECM Degradation and Accumulation (Figure 2)

Figure 2.

Figure 2

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Mechanisms that control activation of MMP expression in response to LV volume overload.

As mentioned in the preceding section, volume overload heart failure is characterized by continued ECM remodeling, regulated in part by the balance between MMPs that degrade collagen and other matrix components and proteins that either inhibit MMPs (TIMPs) or prevent MMP activation (plasminogen activator inhibitor-1, PAI-1). MMPs are secreted as latent zymogens termed pro-MMPs, which must be activated by proteolytically degrading the amino terminal propeptide domain, thereby exposing the Zn2+-binding site in the catalytic domain, termed the “cysteine switch” [21]. In the myocardium, interstitial collagenase (MMP-1) and collagenase-3 (MMP-13) degrade intact fibrillar collagen, as well as proteoglycans. The resultant denatured collagen fibrils are unable to maintain a stable triple helical formation, rendering them subject to further degradation by other MMPs, including the gelatinases MMP-2/9 [21]. Membrane-type 1 (MT-1) MMP is unique in that it is fully active once it is inserted into the cellular membrane and it can degrade a diverse range of substrates including all fibrillar collagens and all basement membrane components[21]. Expression and activity of MMP-1, MMP-2, MMP-9 and/or MMP-13 are increased in severe congestive HF and in human cardiomyopathic hearts [22, 23].

Increased MMP activity is associated with progressive LV dilatation and ECM degradation, contractile dysfunction, and neurohormonal activation in animal models of chronic pacing-induced tachycardia[24, 25]. During the first 5 days of acute volume overload, there was an early decrease and subsequent increase in the ECM that was predicted by changes in MMP/TIMP expression[4]. Moreover, MMP inhibition significantly attenuated LV dilatation in pacing-induced tachycardia in the pig [26], myocardial infarction in the mouse [27] and rabbit [28], and ACF in the rat [29].

TIMPs counterbalance MMP-activation pathways by binding to the active site of the MMPs, thereby inhibiting binding to the ECM substrate. Four TIMPs (1, 2, 3 and 4) are expressed in the heart and TIMP-4 is of particular interest because of its predominant cardiac expression [30, 31]. TIMPs also undergo dynamic regulation in response to neurohormonal stress. Advanced human dilated and ischemic cardiomyopathies (NYHA Stage III and IV) are associated with increased MMP-9, decreased levels of TIMP-1, and TIMP-3 protein levels with no change in TIMP-2, thus favoring ECM degradation and turnover [30]. Interesting, a decrease in myocardial TIMP-4 proteins levels was specific to patients with ischemic cardiomyopathy, which may imply a specific role for this TIMP in advanced ischemic heart failure.

It is important to note any given timepoint in HF progression represents a composite “snapshot” of the extracellular matrix that reflects both causative vs. compensatory changes in matrix regulatory proteins. As such, determination of the composite MMP/TIMP/ECM profile may be a more accurate representation of the overall quality and quantity of the matrix, rather that individual profiling of any given molecule. Further, a much more comprehensive temporal analysis in animal models of volume overload is required to dissect which molecular changes are causative vs. compensatory.

Mechanisms of Mechanical Stress-Induced ECM Remodeling

Changes in hemodynamic and mechanical load are the earliest perturbations that occur in response to acute volume overload and result in increased myocardial stress and end-diastolic strain. Abnormal wall motion induced by ventricular pacing in dogs is linked to early ECM degradation that is associated with MMP and plasmin activation, inflammatory infiltration and oxidative stress [32]. Cells within the myocardium appear to respond to these mechanical stimuli in a cell-type specific manner, ultimately altering the balance between pro- and anti-fibrotic mechanisms. Mechanical stretch of neonatal cardiac myocytes results in an increase in MMP-14 and MMP-2 expression via activation of the JAK-STAT signaling pathways [33], while Saygili et al. [34] independently demonstrated that calcineurin-NFAT axis are potential mediators in stretch-induced activation of MMP-2/9 in atrial myocytes.

Cardiac fibroblasts also display rapid responses to mechanical stretch. Several groups demonstrated that both cyclic and static uniaxial stretch resulted in an increase in both collagen I and collagen III mRNA expression [35]. More recently, Husse et al. [36] reported that mechanical stretch of adult cardiac fibroblasts caused a net increase in MMP-2, TIMP-2 and collagens I/III in serum-free conditions but a significant decrease in collagen I/III in the presence of serum. Presumably, serum-derived growth factors are responsible for the observed differences. Taken together these results seem to indicate that the cardiac fibroblast response to in vitro mechanical stretch favors net ECM accumulation and expression of pro-fibrotic factors similar to that seen in pressure overload, while the cardiac myocyte response seems to favor MMP expression, similar to what was reported in vivo in acute volume overload. Therefore, it can be speculated that expression of anti-fibrotic factors by cardiac myocytes in vivo in response to acute volume overload may be important contributors to net ECM degradation. A caveat to this assumption is that much of the work involving mechanical stretch of specific cell types has been performed in vitro. It is unlikely that in vitro models can recapitulate the complex hemodynamic forces observed within a volume-overloaded myocardium and do not take into account the effects of cell-cell and cell-ECM interactions.

Mast Cells and VO-Induced ECM Remodeling

Mast cell infiltration and subsequent degranulation has been implicated in the pathogenesis of VO-induced heart failure. Mast cells release vasoactive mediators, proteases, a myriad of cytokines and growth factors and can activate the renin-angiotensin system (RAS) through the release of renin [37]. Su et al. [38] studied the relationship between mast cells and the ECM and found that chymase activity was increased after 16 weeks of VO induced by MR, which was associated with reduced collagen content and consequently increased LVEDD. Thus, a cause-effect relationship was demonstrated in that mast cell degranulation products contribute to ECM turnover and subsequent changes in LV structure. Janicki et al. [12] demonstrated that cardiac mast cell infiltration occurred early in VO progression and was accompanied by an increase in myocardial MMP-2 activity. Stewart et al. [39] found a similar, strong correlation between mast cell infiltration and MMP-2 activation in a dog MR model. A recent study from Levick et al. mast cell deficient rats displayed decreased MMP-2 activity at 5 days, increased collagen volume at 5 days and 8 weeks, and an overall decrease in LVEDD beginning at 2 weeks after ACF-induced volume overload and continuing throughout the 8-week study [40].

The exact mechanisms that trigger mast cell activation are unclear. Murray et al. implicated endothelin-1 as a causative factor in mast cell degranulation and further demonstrated that endothelin-1 receptor antagonism can reduce mast cell density, prevent MMP-2 activation, and restore collagen content early in ACF in the rat [13]. The observation that mechanical stretch of cardiac myocytes in vitro increases endothelin secretion [41], may suggest that acute hemodynamic overload leads to the paracrine release of neurohormones that may lead to mast cell infiltration and degranulation. The use of Ang II receptor blockers and β-adrenergic receptor blockers in vivo is necessary to conclusively link these neurohormones to mast cell activation.

The relationship between mast cell degranulation and ECM remodeling involves increased cytokine secretion (e.g. TNF-α) and protease release (tryptase, chymase) [16]. Work by Janicki's group demonstrated an upregulation in TNF-α and MMP activity and an increase in collagen degradation after initiation of ACF in wild type rats at 5 days post-fistula that was not evident in mast cell deficient rats [40]. In TNF-α overexpressing mice, a TNF-α neutralizing antibody improved LV function and limited cardiac dilation [42]. These data in are supported by evidence for elevated cytokines in humans with heart failure. Circulating serum protein levels of the proinflammatory cytokine TNF-α as well as TNF receptors were elevated in a patient population with mitral regurgitation [43].

In summary, it appears that mast cells may initiate a series of molecular events that culminate in cytokine production, MMP activation and continued ECM turnover in volume overload. However, the contribution of other cell types, especially cardiac myocytes and infiltrating neutrophils, cannot be ruled out.

Cardiac Fibroblasts and VO-induced ECM Remodeling

Cardiac fibroblasts are the most abundant cell type in the heart and control the composition of the ECM through synthesis and deposition of matrix proteins and through the regulation of anti- and profibrotic factors. Despite the wealth of data concerning the role of cardiac fibroblasts in pressure-overload, myocardial infarctions and hypertensive heart diseases, there is a paucity of data concerning the role of these cells in VO-induced HF.

There are very few studies of fibroblasts isolated from volume-overloaded hearts. Most investigators expose cultured cardiac fibroblasts to cytokines or reactive oxygen species that are known to increase in volume overload and then determine their effects on ECM regulatory processes. For example, TNF-α treatment of cultured cardiac fibroblasts induced the expression of MMP-13, activation of MMP-2/9 and decreased collagen synthesis [44]. In general, results from such studies (see below) suggest that these factors stimulate net anti-fibrotic effects in naïve fibroblasts. A caveat to this approach is the assumption that control fibroblasts and fibroblasts subjected to volume overload in vivo are phenotypically identical. However, Borer et al showed increased fibronectin and collagen type III expression and no changes in collagen type I expression in cardiac fibroblasts isolated from rabbits with chronic aortic regurgitation compared to controls [45]. These findings suggest that cardiac fibroblasts exposed to chronic volume overload in vivo undergo phenotypic modulation, which is consistent with our observation that cardiac fibroblasts from decompensated ACF rats show different basal expression patterns of inducible nitric oxide synthase and MMPs (Hutchinson and Lucchesi, unpublished observations).

Oxidative Stress and VO remodeling

Reactive oxygen species (ROS) lead to cardiac dysfunction, including reduced contractility, cardiac hypertrophy, ECM turnover and cellular apoptosis. A link between increased ROS and volume overload heart failure has been well established [46, 47].

ROS have been shown to regulate MMPs through changes in expression and by direct interactions with Zn-thiol groups[48] or through nitration of cysteine residues in the autoinhibitory domain [49]. Conversely, ONOO−-induced nitration of TIMP-4 attenuates its inhibitory activity against MMP-2 activity in endothelial cells [50]. ROS also activate MMP secretion [51] and suppress collagen production in cardiac fibroblasts [52].

Regulation of ECM Remodeling In VO-Induced Heart Failure by Ang II/Bradykinin

Volume overload HF is accompanied by an upregulation in the renin-angiotensin system leading to increased interstitial Ang II levels in the myocardium. Evidence from Balcells et al. suggested that the majority of the Ang II production in human and dog hearts is due to chymase activity, whereas in rat, rabbit and mouse most of the Ang II production is due to angiotensin converting enzyme (ACE) activity [53]. Ang II induces a variety of pro-fibrotic mechanisms including increased secretion of PAI-1, TIMPs and collagen production and Ang II lead to an overall profibrotic state characterized by a net increase in ECM deposition and a net decrease in collagen degradation. However, The progressive increase in interstitial Ang II in VO results in a markedly different pattern of LV remodeling characterized by an increase in ECM turnover [4, 54]. Although the exact mechanisms for this observation are unclear, a concommitant increase in interstitial levels of the anti-fibrotic bradykinin (BK) could account for this discrepancy. BK decreases collagen and fibronectin synthesis in cultured fibroblasts by a NO and cyclic GMP pathway [52]. Another mechanism by which BK can modulate MMP activation is through the plasminogen activator (PA) system. BK is one of the most potent stimuli of tissue PA (tPA) release in the circulation in both rodent [55] and human vasculature [56]. Urokinase (uPA) induces MMP-2 cleavage by directly activating MT1-MMP [57] or by activating plasmin, which can cleave MMPs from their latent to active forms. Taken together, these data suggest that the ratio of Ang II to BK may be a more crucial determinant of ECM remodeling than the absolute concentration of each individual neurohormone.

Ang II and BK have divergent effects on intracellular signaling cascades that regulate ECM turnover. Many of the cardiovascular effects of Ang II are mediated by activation of the plasma membrane-bound NADPH oxidases, while BK2R-dependent NO production is involved in mediating the anti-fibrotic effects of BK. In adult cardiac fibroblasts, BK decreases collagen type I and III production and this effect is sensitive to NOS inhibition with L-NAME [58]. Our previous reports indicate that the interstitial ratio of Ang II/BK levels changes during HF progression, with high levels at all stages and progressive increases in Ang II that peak at 15 and 21 weeks [4, 39, 54]. In summary, dynamic changes in the ratio of Ang II/BK levels cause cardiac fibroblast phenotypic changes during volume overload progression to favor net ECM turnover. In early volume overload this ratio favors BK and ECM degradation; treatment with the BK2R inhibitor reversed these effects, while ACE inhibitor therapy had no effects [4].

Summary and Perspectives

Volume overload heart failure results in a unique pattern of hemodynamic stress and neurohormonal activation that results in continued ECM remodeling. The cellular and molecular mechanism that control ECM turnover in volume overload are distinct from those activated in response to pressure overload and reflect global changes in fibrillar collagens, matrix scaffolding proteins, MMPs, TIMPs and profibrotic matrikines. The relative contributions of each of these proteins are likely to change during different stages of heart failure progression. Despite the progress in our understang of the ECM remodeling a number of questions remain to be addressed (Table 1). Most importantly, the precise spatiotemporal pattern of pro- and anti-fibrotic proteins must be characterized so that causative vs. compensatory mechanisms can be identified at each stage of HF progression. Final studies have to be extended into human tissue and serum to validate new molecular candidates for biomarkers of disease progression and/or therapeutic intervention.

Table 1.

Future Directions

♥ Spatiotemporal analysis of matrix regulatory proteins in volume overload HF.
♥ Serum biomarker analysis for progressive LV ECM remodeling in volume overload.
♥ Assessment of spatiotemporal patterns of neurohormone and cytokine levels.
♥ Studies with cardiac fibroblasts isolated from hearts subjected to volume overload.
♥ Analysis of changes in MMP substrate specificity during HF progression.
♥ Defining a role for non-collagen matrix proteins in volume overload HF.
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Acknowledgements

We thank Dr. Loren Wold and Dr. Aaron Trask for their careful review of this manuscript. This work was supported by NIH HL56046 (PAL).

Footnotes

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