Myocardial Extracellular Matrix Structure and Composition

The myocardial ECM contains a fibrillar collagen network, a basement membrane, proteoglycans and glycosaminoglycans, and bioactive signaling molecules. The myocardial fibrillar collagens, such as collagen types I and III, ensure the structural integrity of adjoining myocytes, provide the means by which myocyte shortening is translated into overall LV pump function, and are essential for maintaining the alignment of myofibrils within the myocyte through a collagen-integrin-cytoskeletal-myofibril relation. While the fibrillar collagen matrix was initially considered to form a relatively static complex, it is now recognized that these structural proteins can undergo rapid degradation and fairly rapid turnover. Collagen fibril formation entails posttranslational modification. The carboxyterminal of the procollagen fibril is cleaved by a proteolytic reaction that results in a conformational change necessary for collagen fibril cross-linking and triple helix formation. A critical step in the proper formation and structural orientation of the fibrillar collagen matrix is collagen cross-linking. Interruption of collagen cross-linking has been clearly demonstrated to alter myocardial ECM structure and in turn LV geometry and function. Furthermore, alterations in fibrillar collagen cross-linking have been identified in myocardial samples taken from patients with end-stage HF. While the newly formed, uncross-linked collagen fibrils are vulnerable to degradation, the triple helical collagen fiber is resistant to nonspecific proteolysis, and further degradation requires specific enzymatic cleavage. During collagen cross-link formation, the carboxyterminal peptide is released into the vascular space. Collagen type I fiber formation results in the release of a 100-kDa procollagen type I carboxyterminal propeptide (PIP). Similarly, the formation of mature collagen III fibers results in the release of a 42 kDa procollagen peptide (PIIIP). As will be discussed, a number of associated proteins are necessary for the proper transport, assembly, and stability of the collagen fibril, and monitoring these collagen peptides and associated proteins has been demonstrated to provide diagnostic utility in terms of ECM remodeling and HF progression.

The integrins are a family of transmembrane proteins that serve multiple functions with respect to myocardial structure and function. The integrins form the binding interface with proteins comprising the basement membrane and therefore directly influencing myocyte growth and geometry. Moreover, the integrins coalesce at important structural sites within the myocyte, called costameres, which are composed of cytoskeletal proteins, such as alpha-actinin and vinculin, which form a key intracellular support network for contractile protein assembly and maintaining sarcomeric alignment. The myocyte costamere is also where the integrins appear to cluster and interdigitate with an intracellular signaling cascade system, such as focal adhesion kinase. Thus, disruptions of normal integrin–ECM interactions will likely result in significant changes in myocyte structure and function.

There are a number of extracellular proteins that comprise the basement membrane, such as collagen IV, fibronectin, and laminin. Thus, while fibrillar collagen has been the focus of most past studies, both basic and clinical, collagen is actually a modest component of the ECM. Thus, studies that evaluate both collagen content as well as other constituents of the ECM are beginning to emerge. For example, patients with DCM and mechanical assist devices demonstrate marked shifts in both fibrillar collagen and the basement membrane component, laminin. Representative images from this study are shown in Fig. 4.1 . It is the basement membrane that forms the anchoring points for the fibrillar matrix and contact points for other proteoglycans, such as chondroitin sulfate within the ECM. For example, the abundant binding of negatively charged unbranched glycosaminoglycans within chondroitin sulfate results in a molecule with a high osmotic activity. Accordingly, changes in the content and distribution of these proteoglycan will affect hydration within the extracellular space, and in turn directly influence myocardial compliance characteristics. Moreover, these highly charged molecules within the ECM result in the formation of a hydrated gel that serves as a reservoir for signaling molecules and bioactive peptides. Therefore, the ECM is an important determinant of extracellular receptor–ligand interactions. Another important function of the myocardial ECM is that it serves as a reservoir for critical biological signaling molecules that regulate myocardial structure and function. For example, tumor necrosis factor (TNF) is initially a membrane-bound molecule that requires proteolytic processing and release into the interstitial space in order to form ligand complexes with cognate receptors. Another example is transforming growth factor (TGF)-β, which exists in a latent form bound to the ECM, and requires proteolytic processing within the myocardial interstitium to become a competent signaling molecule. TGF signaling produces multiple cellular responses—most importantly, the stimulation of ECM protein synthesis. Thus, while this chapter will primarily focus upon the collagen fibrillar network, it is becoming recognized that the myocardial interstitium is a complex environment, which contains structural and signaling molecules that directly affect overall myocardial form and function.

Representative left ventricular (LV) sections taken from biopsies of nonfailing referent patients, patients with heart failure with reduced ejection fraction ( HFrEF ) dilated cardiomyopathy (DCM ) , and HFrEF patients receiving LV assist devices (LVAD) with respect to histological changes in fibrillar collagen content (top panels) and laminin (bottom panels) . Histological staining for increased collagen accumulation (“fibrosis”) is evident by the blue staining pattern and is increased with HFrEF and reduced with LVAD support. In terms of the basement membrane laminin, which plays a critical role in myocyte binding and transduction to the extracellular matrix (ECM), shifts in the relative distribution occurred with HFrEF and again with LVAD support. Thus, dynamic changes in both fibrillar collagen and other key constituents of the ECM occur with HFrEF, which are modifiable by mechanical support. Bars indicate 100 μm. From Sakamuri SS, Takawale A, Basu R, et al. Differential impact of mechanical unloading on structural and nonstructural components of the extracellular matrix in advanced human heart failure. Transl Res . 2016;172:30–44.

The Myocardial Fibroblast

The most abundant cell type within the LV myocardium is the fibroblast. This is the predominant cell type that is responsible for maintaining ECM homeostasis in terms of collagen synthesis and degradation. This does not imply that the fibroblast is operative in isolation, as significant biomechanical and bioactive signals between the cardiocyte-fibroblast and endothelial cell–fibroblast interactions likely dictate the rate and type of ECM synthesis and degradation. What appears to occur in disease states, whereby enhanced fibrosis and/or ECM remodeling occurs, is a significant change in the fibroblast phenotype. This process, whereby a significant population of phenotypically differentiated fibroblasts arises with ECM remodeling, can been termed as a transdifferentiation process, and the resultant cell type has been defined as the myofibroblast. However, this does not imply that the normal fibroblast phenotype is extinguished, but rather there is likely increased proliferation of fibroblasts that do not express the myofibroblast phenotype. Thus, in ECM remodeling there is likely expansion and proliferation of both fibroblasts and myofibroblasts, which in turn will significantly affect the balance between collagen synthesis and degradation. In terms of myocardial ECM remodeling in HFrEF, changes in the synthesis-degradation axis occur, resulting in ECM instability ( Fig. 4.2 ). In contrast, with HFpEF, robust expansion of myofibroblasts occurs, resulting in increased ECM synthesis and accumulation ( see Fig. 4.2 ). The specific cell type of origin with respect to the myofibroblast remains unclear and may arise from a stem-cell type, pericyte, or a clonal expansion of endogenous fibroblasts. Whatever the case, the myofibroblast is not found in normal LV myocardium but is readily identifiable in the context of LV remodeling. The myofibroblast is typically identified through cellular constituents and by function. Specifically, the mature myofibroblast expresses alpha smooth muscle actin (SMA), whereas normal fibroblasts do not. In addition, cultured myofibroblasts demonstrate much higher proliferation, margination, invasion, and ECM contractile behavior.

TOP : In patients with heart failure with reduced ejection fraction (HFrEF) , in this case end-stage dilated cardiomyopathy requiring transplantation, left ventricular (LV) myocardial fibroblast growth patterns and phenotype were altered when compared to referent nonfailing LV biopsy specimens. Bars indicate 25 μm. BOTTOM : In patients with LV hypertrophy (LVH) , fibroblast proliferation occurs but is also associated with shifts in myocardial fibroblast phenotype, as defined by patterns of cell surface and contractile protein markers. In heart failure with preserved ejection fraction (HFpEF) secondary to LVH, the emergence of this proliferative and differentiated fibroblast occurs and is associated with shifts in extracellular matrix synthetic and degradative pathways. Courtesy of Dr. Adam Hartstone-Rose, Cell Biology and Anatomy, University of South Carolina School of Medicine.

One of the more active areas of research in the cancer field is that of mesenchymal cell transdifferentiation (MET), whereby mesenchymal cells under control of the local environment will transdifferentiate into a proliferative cancer type. There are significant similarities in the signaling pathways that are evoked during this mesenchymal transdifferentiation process to that of fibroblast–myofibroblast transdifferentiation. Since the myocardial fibroblast is a cell type of mesenchymal origin, it follows that the expression of specific transcription factors and cell markers would be operative similar to that of MET. There is compelling evidence to suggest that this fibroblast transdifferentiation is accompanied by an intermediate step or cell type, the proto-myofibroblast. This proto-myofibroblast will express unique cell markers, such as a splice variant of fibronectin—the extra-domain A (fibronectin ED-A). What is clear is that the canonical thought that the fibroblast is a single phenotypic entity must be revisited, and changes in the type, proliferation, and function of sub populations of fibroblasts likely contribute to specific forms of ECM remodeling, and in turn will influence myocardial form and function with HF.

Myocardial Extracellular Matrix Proteolytic Degradation: The Matrix Metalloproteinases

The matrix metalloproteinase (MMP) are a diverse family of zinc-dependent proteases that play a role in normal ECM turnover as well as in pathological tissue remodeling processes. Currently, over 25 distinct human MMPs have been identified and characterized. While initially thought to only cause ECM proteolysis, a highly diverse set of biological functions have been identified, which include cytokine processing and activation of pro-fibrotic signaling molecules. Moreover, MMP activity is highly dynamic within the human myocardial ECM. Specifically, using microdialysis techniques coupled with MMP fluorescent substrates, it has been identified that continuous MMP activity exists within the human myocardium under ambient conditions, which can increase significantly in a matter of seconds. The MMPs were historically classified into sub groups based upon substrate specificity and/or structure, and an informal nomenclature for some of the individual MMPs arose from these initial substrate studies. However, there is significant overlap in MMP proteolytic substrates, and a more rigid numerical classification is now utilized. Important MMPs in the context of myocardial ECM remodeling include the collagenases, such as MMP-1 and MMP-13; the stromelysins/matrilysins, which include MMP-3/MMP-7; the gelatinases, which include MMP-9 and MMP-2; and the membrane-type MMPs (MT-MMPs). Taken together, once the MMPs are activated, these enzymes can degrade all ECM components; therefore it is important that the activity of these enzymes is kept under tight control and interaction. The regulation of MMPs can take place at the level of transcription, posttranscription, posttranslation, and endogenous inhibition. These levels of control are briefly outlined in the next few paragraphs with examples of how this regulation is operative in the context of myocardial ECM remodeling.

Matrix Metalloproteinase Posttranscriptional Regulation

Posttranscriptional events are directly influenced by small noncoding RNA molecules ( see also Chapter 2 ) termed microRNAs (miRs). miRs can bind to mRNA and interfere with the initiation of translation and/or accelerate mRNA degradation. As depicted in Fig. 4.3 , it is becoming apparent that specific miRs will cause posttranscriptional alterations in functional clusters of proteins that would be relevant to LV remodeling and to the ECM in particular. Largely utilizing mouse models of MI and aortic constriction, preclinical studies have investigated the effects of specific miRs, as well as the associated mechanisms on ECM remodeling and myocardial fibrosis. For example, miR-328 was found to upregulate TGF-beta and increase fibrillary collagen deposition. Other miRs, such as miR-19b, advance myocardial fibrosis by promoting fibroblast proliferation and migration. Furthermore, miR-21 and miR-155 are among a subset of miRs that contribute to fibrosis by both increasing profibrotic growth factors and promoting fibroblast survival. Conversely, a robust group of miRs, such as miR-29, miR-214, or miR-133, have been associated with antifibrotic outcomes. However, there are not always clear categorical distinctions between pro- and antifibrotic miRs. For instance, miR-15 has been observed to influence all of the aforementioned pathways. As the complex relationships between miRs and LV remodeling have become better understood, the clinical potential of miRs in cardiovascular disease has become apparent as well.

A Venn diagram depiction of microRNAs (miRs) and functional domains relevant to extracellular matrix remodeling. A number of these miRs cross over to more than one generalized functional domain and is reflective of the fact that miRs have more than one target sequence. The miRs designated herein have been identified from the published literature (PubMed Search, March 2017) and a number of these references have been cited in the text.

Clinical studies are demonstrating the prognostic potential of these miRs to identify those patients at increased risk for HF and to diagnose HF and monitor disease progression. miRs can be actively transported into the interstitial space, and thus, a pool of miRs exist within the ECM. These miRs can egress to the systemic circulation allowing for detection in patient plasma. For example, miR-34a promotes fibroblast survival, and plasma levels can predict patient development of ischemic HF after an MI. In patients with chronic HFrEF and HFpEF, the temporal trends of miR-22 correlated with the composite primary outcome of HF hospitalization, cardiovascular mortality, cardiac transplant, or LV assist device placement. Additionally, miR concentrations in the plasma of patients with various etiologies of HF have been screened against those in healthy controls to detect miR patterns unique to HF. From these studies, miR-21 was identified as being consistently upregulated in the plasma of HFrEF patients and can make a diagnosis of HFrEF with high sensitivity and specificity. miR-21, along with miR-208 and miR-1, also correlate with measurements of disease severity and may aid in identification of disease progression. These trends are further depicted graphically in Fig. 4.4 .

4 Schematic of the relationship between heart failure (HF) progression and changes in plasma levels for specific microRNAs (miRs) that have been identified to regulate key pathways in extracellular matrix (ECM) remodeling. It is notable that certain miRs that can modulate pro-fibrotic pathways actually fall with HF progression, indicating that increased transcription of ECM proteins and signaling molecules likely occur. Thus, unlike classical biomarker profiles, which most often rise as a function of disease progression, a relative fall in plasma levels for certain miRs may hold relevant prognostic as well as mechanistic insight into adverse ECM remodeling with HF. In addition, the pattern and time course of these changes in plasma miRs may be specific to HF phenotype, and examples of this are shown in Table 4.2 . LV , Left ventricular. Schematic produced from data reported from references 1–10, 86–90, 116–142, 245, 256.

Similar screening studies have compared plasma miRs in patients with HFrEF to those in patients with HFpEF. Beber et al. reported that co-testing of five miRs present in the plasma could distinguish between HFrEF and HFpEF. Included in this group of miRs are three that are known to regulate ECM remodeling: miR-30, miR-146, and miR-328. Patterns in HFrEF and HFpEF of these and additional miRs involved in ECM remodeling are presented in Table 4.2 . The discovery that miRs can influence ECM remodeling in patients with HFrEF and HFpEF has led to efforts to harness the potential of miR expression as a therapeutic. This concept has been investigated in mouse models of aortic constriction and hypertension. Overexpression of the antifibrotic miR-29 decreased LV fibrosis, and reduced expression of profibrotic mediators such as TGF beta. miR-214 has also been implicated as a potential therapeutic as infusion in angiotensin II treated mice attenuated cardiac fibrosis and decreased the expression of TGF beta and fibrillary collagen in mouse models of acute MI. Additionally, transgenic overexpression of miR-133 in mice undergoing transverse aortic constriction improved myocardial fibrosis as well as diastolic dysfunction. Translating these concepts from animal models to clinical research has the potential to introduce a novel strategy for treating both HFrEF and HFpEF.

TABLE 4.2

Plasma miR Patterns in Heart Failure With Reduced Ejection Fraction and Heart Failure With Preserved Ejection Fraction in Extracellular Matrix Remodeling

miR	Effect	Pattern in HFrEF	Pattern in HFpEF	Citations
miR-21	Fibroblast survival and growth, ECM deposition	Increased, correlated with disease severity	Increased	46, 52, 53, 55, 57–60, 152, 153, 177
miR-155	Fibroblast proliferation and inflammation, collagen deposition	Increased	?	61, 72
miR-208	Regulate collagen deposition	Increased in end stage HFrEF	?	29, 30, 56, 75
miR-133	Reduce collagen expression and cardiomyocytes apoptosis	Decreased after cardiac injury, increased in end stage HFrEF	?	56
miR-30	Decrease collagen deposition and regulate apoptosis	Decreased	Decreased	31, 63, 76
miR-328	Regulate profibrotic pathways	Decreased	Decreased	76
miR-146	Regulate collagen deposition	Decreased	Decreased	27, 28, 76
miR-1	Reduce ECM deposition	Decreased, correlated with disease severity	?	70, 71, 153
miR-150	Inhibit activation of cardiac fibroblasts	Decreased in end stage HFrEF	?	73

 

ECM , Extracellular matrix; HFpEF , heart failure with preserved ejection fraction; HFrEF , heart failure with reduced ejection fraction; miR , microRNA.

Heart Failure With Reduced Ejection Fraction and Extracellular Matrix Remodeling—Myocardial Infarction ( see also Chapter 34 , Chapter 19 )

A prolonged ischemic event, with or without reperfusion, causes a cascade of biological events that can be considered a wound-healing process and thus the canonical phases of wound healing are often utilized, which consist of three overlapping phases: inflammation, proliferation, and maturation. The first phase is the acute period in which reactive oxygen species, bioactive signaling molecules, and peptides released from the local environment cause inflammatory cell recruitment and invasion. The initiation of the inflammatory phase is likely due to the release of molecules as a result of myocyte death, and in turn induce the expression of cytokines, such as TNF alpha and the interleukins. A more comprehensive examination of cell viability and inflammation are found elsewhere in this text. Some key aspects of the early post-MI inflammatory process include: (a) activation of the intracellular transduction pathway, nuclear factor kappa B; (b) induction of a diverse family of chemokines; and (c) neutrophil recruitment and margination. While initially considered a rather monochromatic cell type in terms of form and function, the macrophages within the MI region appear to be quite heterogeneous and may ultimately influence the magnitude and direction of the localized inflammatory process. While this inflammatory process is critical to initiate a reparative response following myocardial injury, it appears that unlike other sites of tissue injury, the inflammatory response is prolonged within the MI region. The second phase is heralded by proliferation and transdifferentiation of myocardial fibroblasts into myofibroblasts. Further, released matrix structural proteins, such as fibrillar collagens, and matrix–integrin–cytoskeletal interactions facilitate contraction of the wound. The third phase of the wound-healing process normally results in complete contraction of the wound, apoptosis of the myofibroblasts, and the formation of a relatively acellular scar. However, in the context of post-MI remodeling, this canonical set of events does not necessarily occur. Rather, there is a continued proliferation and transdifferentiation of fibroblasts within the MI and border regions accompanied by a shift in matrix proliferative/degradative pathways within these transformed cells.

Significant changes within the ECM occur during all time points post-MI and likely contribute to the overall adverse LV remodeling process. First, the inflammatory response causes the release of MMPs as well as other proteases to degrade the ECM and allow for margination of inflammatory cells. However, with a persistent inflammatory state, MMP induction will also destabilize the newly formed ECM and the nascent scar. Second, the continued proliferation and altered expression of myofibroblasts within the MI region in terms of the balance between MMP and TIMP levels cause ECM instability and infarct expansion. Specifically, the transformed fibroblast population within the MI region likely results in a shift in the relative balance of MMPs and TIMPs, favoring accelerated ECM turnover and the failure of mature scar formation. Third, a robust expression of “profibrotic” signaling molecules occurs within the myofibroblasts and the residual myocyte populations, such as TGF, but this does not result in a well-formed ECM. Specifically, TGF signaling is enhanced within the MI region and causes significantly higher fibrillar collagen transcription; however, a number of critical posttranslational events involving collagen assembly are likely to be defective. For example, a loss of the matricellular protein, secreted protein acidic and rich in cysteine (SPARC), which is involved in procollagen processing to a mature collagen fibril, resulted in impaired collagen maturation and MI scar formation. Further, the interactions of the glycoproteins fibronectin and tenascin C may directly alter cell–ECM interactions, whereby other bioactive molecules, such as osteopontin, can directly influence ECM biosynthesis through a number of signaling pathways. Transmembrane receptors and co-receptors, such as endoglin and syndecan, which can modify profibrotic signaling through TGF and other growth factors, also likely play an important role not only in ECM synthesis and degradation but also in terms of myofibroblast transformation. Thus, abnormalities in fibroblast phenotype coupled with defects in both ECM synthesis and degradation pathways possibly converge to cause a feed-forward process in terms of MI wall thinning and dyskinesis, increased radial wall stress, and local strain patterns, and ultimately contribute to overall infarct expansion, LV remodeling, and HFrEF. These pathways and processes, as they may relate to the prognosis and diagnosis of HFrEF, are presented in a subsequent section.

Heart Failure With Reduced Ejection Fraction and Extracellular Matrix Remodeling-Dilated Cardiomyopathy ( see also Chapter 20 )

DCM constitutes a broad classification of primary myocardial disease states, which contribute to a significant proportion of patients with HFrEF, and several chapters within this text examine in detail the several animal models of DCM that have identified increased MMPs within the myocardium. In the rapid pacing DCM model, increased abundance of several MMP types occurred, with a loss of ECM structural integrity that coincided with the onset of LV remodeling and dilatation. Moreover, these changes in MMP myocardial levels and LV geometry preceded significant alterations in cardiomyocyte contractile function, which underscored the functional importance of MMP-mediated ECM disruption as an early event in this model of DCM. More definitive cause–effect relationships between LV myocardial remodeling and MMP induction have been established through the use of pharmacological MMP inhibitors. For example, MMP inhibition in the pacing DCM model attenuated the degree of LV dilation and dysfunction. In the canine model of ischemic DCM, pharmacological MMP inhibition attenuated the progression of LV dilation and systolic dysfunction. Thus, a contributory mechanism for the LV remodeling that occurs during the experimental form of DCM is MMP induction and heightened MMP activity within the LV myocardium.

A number of studies have examined relative MMP and TIMP expression in end-stage human DCM. Uniformly, these past studies have demonstrated an increase in certain MMP species in end-stage human HF. One of the first studies was by Gunja-Smith and colleagues in which increased myocardial MMP gelatinolytic activity was reported in DCM. Using immunoblotting procedures, subsequent studies identified that several MMP species were increased in LV myocardial extracts taken from patients with end-stage DCM. For example, increased MMP-3 and MMP-9 levels were observed in the DCM myocardial extracts. While MMP-13 was barely detected in the normal myocardium, a robust immunoreactive signal for MMP-13 was observed in DCM myocardium. Interestingly, MMP-13 has been associated with pathological remodeling states, such as breast carcinomas. The most robust change in MMP types within the DCM myocardium was that of MT1-MMP. A persistent induction and expression of MT1-MMP occurred in DCM fibroblasts when compared to myocardial fibroblasts harvested from nonfailing patients. Li et al. provided evidence to suggest that changes in the MMP/TIMP stoichiometric ratio occurred with end-stage DCM disease. In DCM, an absolute reduction in MMP-1/TIMP-1 complex formation has been observed. In a transgenic model of TIMP-3 deletion, a DCM phenotype was reported as a function of age. In DCM patients, chronic unloading of the LV through the use of ventricular assist devices was associated with a reduction in LV chamber dilation and myocardial MMP levels. Taken together, these results suggest that reduced MMP/TIMP complex formation may occur in cardiomyopathic disease states, which in turn would contribute to increased myocardial MMP activity and ECM remodeling.

Myocardial Extracellular Matrix Remodeling in Heart Failure—Diagnostic Potential

Chapter 33 has been dedicated to biomarker profiling and HF, and thus the focus herein will be to examine specific biomarkers that hold relevance to ECM remodeling, with particular attention to those that hold diagnostic/prognostic potential. In terms of plasma biomarker profiling with HFrEF and a post-MI etiology, plasma troponin levels and other biomarkers are obviously relevant; thus it is likely that a specific portfolio of ECM biomarkers will provide specific prognostic information in the post-MI period. For example, past studies have demonstrated that increased plasma levels of collagen peptide fragments occur following MI and in progressive HFrEF. In keeping with ECM degradation, the induction of ECM proteases, such as the MMPs, occur in patients following MI and likely hold predictive value in terms of identifying those patients at greatest risk for the early development of HFrEF. For example, the magnitude of plasma MMP-9 levels that occur within the early post-MI period is associated with a greater degree of LV dilation at 6 months post-MI. In a study by Wagner and colleagues, the early increase in MMP-9 levels was associated with an increased risk of the later development of HF (odds ratio of 6.5). In a recent report that compiled the results from approximately 60 studies in patients post-MI, those that were most consistently present in prediction models included indices of neurohormonal activation, such as brain natriuretic peptide and indices of ECM degradation, such as MMP-9. Cytokine/chemokine release that would cause the induction of pathways relevant to ECM degradation and fibroblast transformation, as well as the release of matrikines, all occur in patients in the post-MI period. Other matrix-related molecules, such as galectin-3, have been associated with determinants of ECM remodeling but are not necessarily independently predictive of HFrEF. In addition to plasma biomarkers for ECM degradation, increased markers for ECM synthesis have also been identified, which include the TGF co-receptor endoglin and the matrikines tenascin-C, osteopontin, and syndecan-4. In large survey studies that included subjects with MI and DCM, plasma levels of MMPs and TIMPs have provided clear prognostic information with respect to cardiovascular events and mortality. Finally, plasma profiling of these determinants of ECM remodeling may hold value as both a diagnostic and a therapeutic predictor, that is, theragnostic. For example, retrospective plasma samples taken from HFrEF patients with a 12-month follow-up after cardiac resynchronization therapy (CRT) identified that TIMP-1 levels may hold predictive value in terms of CRT response.

Since the ECM likely plays a critical role in the pathophysiology of HFpEF, strategies that can evaluate and quantify changes in this entity hold prognostic relevance. A summary of representative plasma biomarkers that have been evaluated in the context of HFpEF that may hold relevance to ECM remodeling is presented in Table 4.3 . For example, plasma profiles of peptide fragments of fibrillar collagens (types I and III) have been used in patients with developing and established HFpEF. The collagen fibril may undergo posttranslational modification by enzyme mediated cross-link reactions as well as nonenzyme mediated cross-link formation. Of note, nonenzymatic cross-link formation can be mediated by advanced glycation end products (AGEs). AGEs bind to specific cell membrane receptors that include the receptor for AGE (RAGE). Since increased fibrillar collagen stability can occur through increased RAGE interactions, profiling plasma levels of soluble RAGE (sRAGE) as well as indices of AGE formation may hold prognostic/functional relevance in HFpEF. A biologically relevant consequence of increased collagen AGEs is reduced susceptibility to MMP-mediated degradation and turnover. Significant and directional changes in the plasma profiles of MMPs and TIMPs occur in patients with developing HFpEF and have been shown to hold potential prognostic utility. For example, a specific cassette of MMPs and TIMPs, coupled with N-terminal pro b-type natriuretic peptide (NT-BNP), provided significant prediction in terms of patients at risk for the development of HFpEF. Other ECM chemokines/matrikines, such as cardiotrophin, have been associated with the development and progression of HFpEF. It is notable that the recent American Heart Association scientific position statement regarding the use of biomarkers for HFpEF identified a number of ECM-related proteins and pathways, which are those prominently identified in Table 4.3 .

TABLE 4.3

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