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The Extracellular Matrix in Ischemic and Nonischemic Heart Failure

Originally published Research. 2019;125:117–146


    The ECM (extracellular matrix) network plays a crucial role in cardiac homeostasis, not only by providing structural support, but also by facilitating force transmission, and by transducing key signals to cardiomyocytes, vascular cells, and interstitial cells. Changes in the profile and biochemistry of the ECM may be critically implicated in the pathogenesis of both heart failure with reduced ejection fraction and heart failure with preserved ejection fraction. The patterns of molecular and biochemical ECM alterations in failing hearts are dependent on the type of underlying injury. Pressure overload triggers early activation of a matrix-synthetic program in cardiac fibroblasts, inducing myofibroblast conversion, and stimulating synthesis of both structural and matricellular ECM proteins. Expansion of the cardiac ECM may increase myocardial stiffness promoting diastolic dysfunction. Cardiomyocytes, vascular cells and immune cells, activated through mechanosensitive pathways or neurohumoral mediators may play a critical role in fibroblast activation through secretion of cytokines and growth factors. Sustained pressure overload leads to dilative remodeling and systolic dysfunction that may be mediated by changes in the interstitial protease/antiprotease balance. On the other hand, ischemic injury causes dynamic changes in the cardiac ECM that contribute to regulation of inflammation and repair and may mediate adverse cardiac remodeling. In other pathophysiologic conditions, such as volume overload, diabetes mellitus, and obesity, the cell biological effectors mediating ECM remodeling are poorly understood and the molecular links between the primary insult and the changes in the matrix environment are unknown. This review article discusses the role of ECM macromolecules in heart failure, focusing on both structural ECM proteins (such as fibrillar and nonfibrillar collagens), and specialized injury-associated matrix macromolecules (such as fibronectin and matricellular proteins). Understanding the role of the ECM in heart failure may identify therapeutic targets to reduce geometric remodeling, to attenuate cardiomyocyte dysfunction, and even to promote myocardial regeneration.

    The ECM (extracellular matrix) is a highly dynamic noncellular 3-dimensional network that is present in all tissues and plays a critical role in homeostasis and disease.1 The ECM does not simply function as a mechanical support system that preserves tissue integrity, but also serves as a signaling hub that transduces cascades critical for cell function, and as a reservoir of growth factors that can be released following injury to modulate cell behavior and to activate a reparative program.2 Organ homeostasis is critically dependent on the ECM network, as components of the matrix continuously interact with the cellular elements providing a stable structural support network, and coordinating cellular responses, to ensure functional integration of the cells. On the other hand, under conditions of stress, the ECM network may shield the cells from injurious stimuli, while serving as a key component in tissue repair, by orchestrating cellular responses. In many pathological conditions, expansion of the ECM network or changes in the biochemical composition of matrix proteins contribute to the pathogenesis of disease either by directly perturbing normal organ structure and function, or by transducing maladaptive signals to the cells.

    The adult mammalian heart is a syncytium comprised of cardiomyocytes and interstitial cells, enmeshed within a network of ECM proteins. Most myocardial diseases are associated with expansion of the cardiac interstitium, accompanied by marked alterations in the biochemical composition of the ECM network. The myocardial ECM does not simply serve as structural scaffold that determines the mechanical properties of the myocardium. Under conditions of stress, ECM macromolecules can drive cell biological responses with an important role in ventricular dysfunction and in the pathogenesis of heart failure.

    It should be emphasized that human heart failure is pathophysiologically heterogeneous. Depending on the underlying cause, several distinct pathophysiologic conditions, such as ischemia, volume and pressure overload, genetic factors, aging, and metabolic dysregulation may contribute to the pathogenesis of myocardial dysfunction. Animal model investigations suggest that the various pathophysiologic causes of heart failure trigger distinct ECM perturbation patterns that reflect the characteristics of the primary insult. For example, myocardial infarction (MI) rapidly activates a potent acute inflammatory response driven by necrotic cells, thus stimulating early ECM degradation. As the infarct is cleared from dead cells, suppression of inflammation and induction of growth factors favor activation of a fibrogenic program leading to formation of a scar. On the other hand, in the pressure-overloaded myocardium, mechanical stress stimulates release of neurohumoral mediators and activates mechanosensitive cascades, stimulating matrix-preserving pathways in cardiomyocytes and fibroblasts, in the absence of significant cellular necrosis. This response contrasts with the predominant disruption of the collagen network that has been described in the volume-overloaded myocardium (typically associated with valvular regurgitant lesions). This review article discusses ECM-related mechanisms associated with the most common pathophysiologic conditions that cause heart failure, while attempting to identify unifying features that may link alterations of the ECM network and cardiac dysfunction.

    Normal Cardiac ECM

    The cardiac ECM network is comprised of an interstitial component that surrounds all myocardial cells and forms a structural scaffold, and a pericellular component that is in close contact with certain cell types.3 The basement membrane, a specialized form of ECM comprised of laminins, type IV collagens and proteoglycans is the predominant type of pericellular matrix and separates cardiomyocytes from the surrounding interstitial matrix.4 Because the heart is perfused by a rich microvascular network, significant amounts of basement membrane ECM are also present in the interface between endothelial cells and pericytes. In mammalian hearts, the myocardial ECM network is organized on 3 interconnected levels: the epimysium encases the entire organ, the perimysium defines major bundles of myofibers, and the endomysium surrounds individual cardiomyocytes.5,6 In addition to the intramyocardial (endomysial and perimysial) ECM network, significant amounts of matrix proteins are present in the adventitia of myocardial arteries and arterioles.

    Early studies on the composition of the normal cardiac ECM focused predominantly on the collagens, the major structural components of the interstitial matrix.7 Type I collagen predominantly forms thick rod-like fibers in the epimysium and perimysium and is the major structural component of the cardiac interstitium.8,9 In contrast, type III collagen forms a fine network of fibers that is more prominent in the endomysium.8,10,11 In addition to the fibrillar collagens, the cardiac ECM also contains glycosaminoglycans (such as hyaluronan), Fn (fibronectin), glycoproteins, and proteoglycans, and serves as a reservoir for growth factors and proteases, which are stored in the interstitium, and can be released or activated following injury. Recent proteomic studies have revealed the remarkable complexity of the cardiac ECM network in health and disease.12–15

    The role of the myocardial ECM as a mechanical scaffold that preserves cardiac geometry and facilitates force transmission seems intuitive. However, a growing appreciation of the interactions between matrix macromolecules and myocardial cells suggests that the cardiac ECM does not simply provide structural support, but may also transduce key signals regulating cardiomyocyte function. For example, the dystrophin-glycoprotein complex serves as a molecular link between the contractile machinery of the cardiomyocytes and the surrounding ECM.16 The transmembrane protein dystroglycan connects the cytoskeletal components of the cardiomyocytes to the ECM through interactions with the α2 chain of laminin 2,16,17 playing an important role in cardiac homeostasis. Unfortunately, very little is known about the role of specific ECM-dependent molecular pathways in mediating the coordinated contraction of cardiomyocytes in normal hearts. In addition to their effects in contractile function, ECM proteins may also interact with cardiomyocytes, vascular cells, and interstitial cells to transduce survival signals.18

    Link Between the ECM and Cardiac Dysfunction: The Significance of Cardiac Fibrosis

    Although the ECM remains inconspicuous in health, it takes center stage in myocardial disease, as the cardiac interstitium undergoes dramatic and dynamic changes that have a major impact on cardiac function. The term cardiac fibrosis is used to describe the expansion of the ECM network that accompanies most forms of myocardial disease.19 Using simple histopathologic analysis, 3 forms of cardiac fibrosis can be recognized, reflecting distinct mechanisms of fibrotic remodeling. The term replacement fibrosis describes the formation of a scar in areas of myocardial necrosis, represents the end-result of a reparative process in response to primary cardiomyocyte injury, and reflects the negligible regenerative capacity of adult mammalian cardiomyocytes. Replacement fibrosis is typically the result of MI.20 In contrast, a wide range of injurious stimuli, including a pressure load, metabolic dysfunction, and aging may cause interstitial fibrosis, widening the endomysium and perimysium due to deposition of structural ECM proteins, or perivascular fibrosis, leading to expansion of the periadventitial collagenous area in the cardiac microvasculature. Interstitial and perivascular fibrotic lesions may not be driven by cardiomyocyte death. Whether perivascular and interstitial fibrotic changes have distinct functional consequences remains unknown. In heart failure patients, periadventitial microvascular fibrosis has been associated with reduced coronary blood flow,21 and may perturb coronary vasodilatory responses,22 thus exacerbating the imbalance between supply and demand under conditions of stress.23

    Robust clinical evidence suggests a strong association between expansion of the cardiac ECM and adverse outcome in patients with heart failure. In heart failure with reduced ejection fraction patients, the severity of fibrosis predicts death and adverse cardiac events.24 On the contrary, heart failure with preserved ejection fraction (HFpEF) patients typically exhibit expansion of the interstitial ECM network, associated with coronary microvascular rarefaction and inflammatory activation.25,26 In subjects with HFpEF, interstitial ECM expansion is associated with increased mortality and higher hospitalization rates.27 Although the prognostic significance of cardiac ECM deposition in heart failure is well-documented, whether worse outcome in patients with extensive fibrotic lesions is due to the adverse consequences of fibrosis, or simply reflects a more pronounced reparative response to more severe primary cardiomyocyte injury is unclear. Several mechanisms may contribute to direct adverse effects of ECM expansion and remodeling on both systolic and diastolic function. First, accentuated deposition of cross-linked collagen in the cardiac interstitium may increase myocardial stiffness, resulting in diastolic dysfunction. Second, ECM deposition may promote systolic dysfunction by perturbing the coordination of myocardial excitation-contraction coupling. Third, expansion of the periadventitial ECM may disrupt cardiomyocyte perfusion. Fourth, perturbations in the protease/antiprotease balance in the cardiac interstitium may trigger degradation of fibrillar collagens, thus disrupting ECM-dependent pathways that regulate cardiomyocyte contraction, and leading to systolic dysfunction.28 Moreover, perturbations in the matrix network may also deprive cardiomyocytes from crucial prosurvival signals transduced by intact ECM proteins.18,29 Fifth, generation of ECM fragments may activate proinflammatory pathways, recruiting immune cells to the interstitium and leading to cardiomyocyte dysfunction and death.30

    The relation between perturbations in the cardiac ECM network and adverse outcome may also involve an increased incidence of arrhythmic events and conduction abnormalities. ECM deposition disrupts impulse propagation and often results in generation of reentry circuits.31 The cellular composition of the fibrotic lesions and the ECM profile of the cardiac interstitium may play an important role in determining arrhythmogenicity in failing hearts.32 It should be emphasized that changes in the ECM network may have an impact in geometry and function of all cardiac chambers. Changes in the right ventricular matrix may contribute to the morbidity and mortality in patients with pulmonary hypertension.33 Atrial ECM remodeling and fibrosis are implicated in the pathogenesis and complications of atrial tachyarrhythmias.34

    ECM Network in the Pathogenesis of Heart Failure

    Heart failure is characterized by remarkable pathophysiologic heterogeneity. The patterns of ECM perturbations and the relative role of matrix macromolecules in the pathogenesis of heart failure are dependent on the type and duration of myocardial injury. Pressure overload, volume overload, ischemic injury, diabetes mellitus, obesity, and metabolic dysregulation are associated with distinct patterns of ECM alterations.

    ECM in Heart Failure Associated With Pressure Overload

    Cellular Effectors of ECM Remodeling in the Pressure-Overloaded Heart

    Left ventricular pressure overload is the predominant pathophysiology in systemic hypertension and in conditions associated with left ventricular outflow obstruction (such as aortic stenosis) and leads to progressive development of heart failure.35,36 In both animal models of left ventricular pressure overload, and in human patients with sustained pressure loads, early development of cardiac hypertrophy initially serves as an adaptive response that preserves cardiac output.37 However, prolonged pressure overload triggers fibrosis and perturbs cardiomyocyte relaxation, increasing myocardial stiffness, and causing diastolic dysfunction. Persistent pressure overload eventually results in dilative remodeling and systolic dysfunction. Extensive evidence suggests that the changes in the myocardial ECM network in response to pressure overload not only increase passive stiffness by altering the mechanical properties of the ventricle, but also play a critical role in regulating inflammatory, fibrotic, and hypertrophic cellular responses. Although cardiac fibroblasts are considered essential modulators of the matrix network following pressure overload, several other cell types, including immune cells, vascular cells, and cardiomyocytes have been implicated in ECM remodeling either directly (by secreting proteases or antiproteases with a critical role in matrix metabolism) or indirectly (by modulating fibroblast phenotype) (Figure 1).

    Figure 1.

    Figure 1. The cellular effectors of ECM (extracellular matrix) remodeling in the pressure-overloaded heart. Mechanical stress triggers transduction of mechanosensitive signaling cascades, activates TGF (transforming growth factor)-β, and stimulates neurohumoral mediator release (such as angiotensin, aldosterone, and norepinephrine). Fibroblasts are the main effectors of ECM expansion, producing both structural and matricellular ECM proteins. Activated myofibroblasts in the pressure-overloaded heart predominantly originate from local resident fibroblasts, other interstitial cells, such as cardiac pericytes, may also undergo myofibroblast conversion (blue arrows). Other cell types (such as endothelial cells) appear to have very limited direct contributions to the myofibroblast population in the remodeling myocardium. Cardiomyocytes, immune cells, and vascular cells are important regulators of ECM remodeling. Mechanical stress triggers synthesis of proinflammatory mediators in cardiomyocytes, promoting recruitment of lymphocytes and macrophages. Activated endothelial cells also participate in recruitment of immune cells. Macrophages and lymphocytes may promote fibroblast activation by secreting growth factors (such as TGF-βs). All myocardial cells are capable of producing proteases, involved in ECM remodeling.

    Fibroblasts and Myofibroblasts

    Expansion and activation of fibroblasts are consistently noted in experimental models of cardiac pressure overload.38,39 Activated fibroblasts typically undergo myofibroblast conversion, expressing contractile proteins, such as α-SMA (α-smooth muscle actin)38 and the embryonic isoform of smooth muscle myosin heavy chain,40 and synthesizing large amounts of structural and matricellular ECM proteins.41 Although some investigations have suggested that endothelial cells42 and circulating fibroblast progenitors may undergo fibroblast conversion, recent lineage tracing studies demonstrated that resident fibroblast populations are the main cellular source of activated myofibroblasts in the pressure-overloaded myocardium.43,44 Activation of fibroblasts in response to mechanical stress likely involves several distinct mechanisms.45 First, fibroblasts sense increased mechanical load through activation of surface integrins,46–48 syndecans,49 and mechanosensitive membrane channels.50,51 Subsequent stimulation of mechanosensitive intracellular signaling cascades, such as the RhoA (Ras homolog gene family, member A)/ROCK (Rho-associated protein kinase),52,53 FAK (focal adhesion kinase),54–56 and MAPK (mitogen-activated protein kinase)39 pathways may promote a fibrogenic program through activation of the transcription factor MRTF (myocardin-related transcription factor).57,58 Second, mechanical stress has been linked with integrin-dependent activation of TGF (transforming growth factor)-β,59 a critical mediator in myofibroblast conversion that triggers integrin synthesis in cardiac fibroblasts60 and promotes activation of a matrix-synthetic and matrix-preserving program.30,61 Third, pressure overload may trigger systemic and local activation of the renin-angiotensin-aldosterone system, stimulating fibroblast proliferation and ECM protein synthesis through AT1R (angiotensin II type 1 receptor) signaling. Fourth, pressure overload induces expression of fibroblast-specific microRNAs that activate MAPK signaling in fibroblasts promoting expansion of the interstitial ECM.62 The potential link between mechanical stress and a fibrogenic microRNA profile has not been investigated. Fifth, activation of fibroblasts in the pressure-overloaded heart may require mechanosensitive activation of other cell types, including immune cells, vascular cells, and cardiomyocytes.

    Immune Cells

    Macrophages,63–65 lymphocytes,66–68 and mast cells69,70 have been implicated in the fibrotic response in the pressure-overloaded heart (Figure 2). Although immune cells do not produce significant amounts of structural ECM proteins and do not undergo conversion to fibroblasts,43 they may function as key effectors of ECM expansion in the pressure-overloaded myocardium by releasing fibrogenic mediators70 and matricellular proteins,72 or by transducing adhesion-dependent fibrogenic signals to cardiac fibroblasts.68 Moreover, immune cell subpopulations may directly remodel the cardiac ECM by secreting MMPs (matrix metalloproteinases), or other matrix-degrading proteases.73 What is the central mechanism that activates immune cells in the pressure-overloaded myocardium? First, macrophages and lymphocytes may respond directly to mechanical stress, activating a fibrogenic program. Mechanical stress has been suggested to stimulate T lymphocyte-driven inflammation that may activate fibrogenic signaling.74 Macrophages may also sense mechanical cues to alter their level of activation.75 Expression of mechanosensitive ion channels (such as TRPV [transient receptor potential cation channel subfamily V member]-4) has been observed in macrophages and may modulate their functional properties,76 promoting a fibrogenic phenotype. Second, resident myocardial immune cells may acquire a fibrogenic profile in response to the local or systemic release of neurohumoral mediators or fibrogenic growth factors. In vivo studies have suggested that mineralocorticoid receptor signaling in myeloid cells promotes a fibrogenic macrophage phenotype,65 that is critical for expansion of the interstitial ECM in models of hypertensive heart disease77,78 or left ventricular pressure overload.65 Mineralocorticoid receptor-mediated activation of lymphocytes has also been implicated in the pathogenesis of interstitial fibrosis in the pressure-overloaded heart.79 Third, fibrosis in the pressure-overloaded heart may reflect new recruitment of fibrogenic immune cells, mediated through proinflammatory activation of the microvascular endothelium,80,81 or through paracrine actions of cardiomyocytes.82

    Figure 2.

    Figure 2. The link between immune cell infiltration and ECM (extracellular matrix) expansion in the pressure-overloaded heart. Serial sections from a mouse heart undergoing transverse aortic constriction for 7 d stained with hematoxylin+eosin (H&E), the macrophage marker Mac2, and Sirius red (to label collagen fibers) show periadventitial infiltration with abundant macrophages in areas of perivascular fibrosis (arrows). Original data and images reported in our published work.71

    It should be noted that not all studies support the importance of inflammatory cells in pressure overload–induced heart failure. Macrophage depletion using a genetic model did not affect the progression of myocardial remodeling in mice with established pressure overload–induced heart failure.83

    Vascular Cells

    The impressive perivascular ECM deposition in pressure-overloaded hearts (Figure 2)71 suggests that vascular cells may be important contributors to the cardiac fibrotic response. Some experimental studies have suggested that endothelial cells may contribute to ECM remodeling in the pressure-overloaded heart by undergoing endothelial to mesenchymal transition,42 thus acquiring a fibroblast-like phenotype. However, this notion was refuted by robust lineage tracing studies44 that reported very low numbers of endothelial-derived fibroblasts in the remodeling myocardium.84 Endothelial cells may activate fibroblasts by secreting profibrotic mediators, such as TGF-β1, FGFs (fibroblast growth factors), or ET (endothelin)-1,85 or by facilitating recruitment of fibrogenic immune cell subpopulations through expression of adhesion molecules and chemokines.80

    The role of cardiac pericytes in matrix deposition and metabolism following pressure overload remains poorly documented. This is due, at least in part, to challenges in identification and characterization of cardiac pericyte populations. Pericytes may contribute to ECM remodeling through conversion to activated myofibroblasts,86 or through secretion of fibroblast-activating growth factors.


    Mechanical stress activates a proinflammatory and fibrogenic gene expression program in cardiomyocytes through a pathway that has been suggested to involve angiotensin II–induced stimulation of CaMKII (Ca2+/calmodulin-dependent protein kinase II)-δ.82,87 In a mouse model of deoxycorticosterone/salt-induced cardiac remodeling, cardiomyocyte-specific mineralocorticoid receptor signaling mediated expansion of the ECM network.88 Growth factors released and activated in response to mechanical stress may also activate a fibrogenic profile in cardiomyocytes. In a model of left ventricular pressure overload, TGF-β receptor II signaling in cardiomyocytes was found to contribute to the development of cardiac fibrosis.89

    ECM Proteins in the Pressure-Overloaded Myocardium
    Fibrillar Collagens

    Fibrillar collagens90 constitute a subgroup within the collagen family whose members confer mechanical strength and support tissue organization in many organs. In addition to their structural role, fibrillar collagens may also interact with cell surface receptors, transducing signals. Increased deposition of fibrillar collagens by activated cardiac fibroblasts is consistently noted in pressure-overloaded hearts. Table 1 summarizes our knowledge on the expression and role of fibrillar collagens in failing hearts.

    Table 1. Fibrillar Collagens in the Heart

    Fibrillar CollagenCardiac LocalizationRole in Cardiac HomeostasisChanges in Hypertensive Heart FailureChanges in Ischemic Heart FailureChanges in Other Myocardial Conditions
    Col ICol I is the predominant fibrillar collagen in adult mammalian hearts.Thick Col I fibers may preserve cardiac geometry and structure, and regulate compliance, while contributing to force transmission. Mice with a mutation in the proa2(I) chain have a more compliant ventricle on passive inflation.91Both Col I and Col III are overexpressed in pressure-overloaded hearts.92 Predominance of Col I was associated with increased stiffness in some human and experimental studies.93,94 However, in SHR hearts, myocardial stiffness was not associated with changes in Col I:Col III ratio, but was rather attributed to cross-linking.95 Moreover, in human patients with aortic stenosis, comparable induction of Col I and III was noted.96In the rat model of MI, a greater increase in Col I in noninfarcted myocardium.97 In rats undergoing infarction protocols, Col III levels seemed to increase earlier in the infarcted heart.98,99In patients with DCM, increased Col I:Col III ratio may be associated with reduced myocardial compliance.100 Inflammatory cardiomyopathy was associated with a higher proportion of Col III.101 Conflicting findings on the effects of aging have been reported. Col I was highly expressed in neonatal hearts,102 whereas Col III was increased with aging.103 In other studies, aging was associated with increased number and thickness of Col I fibers.104
    Col IIISignificant amounts of Col III are found in normal hearts. The ratio of Col III:Col I is dependent on species and age.105Col III forms a thin network of fibers more prominent in the endomysium. A higher Col III:Col I ratio has been associated with increased elasticity.
    Col VExpressed in developing valves and in fetal myocardium. In adult rat hearts, Col V immunoreactivity was reported in the vascular matrix.106Col V regulates collagen fibril diameter and assembly in the valves and in the left ventricular myocardium.107Increased levels of Col V have been reported in pressure-overloaded rat myocardium.108,109Col V immunoreactivity was reported in the peri-infarct region in a rat model of infarction.106 Increased ColVα2 was found in proteomic analysis of the cardiac ECM of ischemic and reperfused porcine hearts.15Autoantibodies against Col V have been suggested to play a role in antibody-mediated cardiac allograft rejection, or allograft vasculopathy.110
    Col XICol XI is expressed in developing heart valves, in the supporting apparatus and in left ventricular trabeculae.107Col XI regulates collagen fibril assembly predominantly in the valves.107N/ANot found to be upregulated in porcine model of I/R.15N/A
    Col XXIVCol XXIV is involved in Col I fibrillogenesis in the developing bone and eye.111 Col24a1 mRNA expression not found in mouse myocardium.112N/AN/ANot found to be upregulated in a model of porcine I/R.15N/A
    Col XXVIICol XXVII is transiently expressed in developing coronary vessels.113 It is localized in fine fibrillar structures independent of classical collagen fibrils. In adult mice, its expression is restricted to cartilage.N/AN/AN/AN/A

    DCM indicates dilated cardiomyopathy; ECM, extracellular matrix; I/R, ischemia/reperfusion; MI, myocardial infarction; N/A, no information available; and SHR, spontaneously hypertensive rats.

    Activation of a matrix-synthetic phenotype in cardiac fibroblasts may involve neurohumoral mediators (such as angiotensin II and aldosterone), and growth factors (such as TGF-βs).114 ACE (angiotensin-converting enzyme) inhibition, AT1R blockade, and mineralocorticoid antagonism attenuated collagen deposition in most,115–117 but not all118 experimental studies in models of left ventricular pressure overload. In contrast to the fibrogenic actions of the AT1R, the AT2R (angiotensin II type 2 receptor) may play an inhibitory role,119 attenuating fibroblast proliferation, and reducing ECM deposition in models of hypertension.120 To what extent the beneficial effects of ACE inhibition and AT1R blockade in human patients with heart failure are due to attenuated ECM expansion remains unclear.

    It has been suggested that the relative amount of collagen I versus collagen III fibers may regulate myocardial compliance in remodeling hearts. Collagen I forms thicker and stiffer fibers, whereas the finer reticular collagen III fibers are more compliant and increase elasticity. In models of hypertensive cardiac fibrosis, type I collagen exhibits more intense and prolonged upregulation than collagen III.121 Thus, it is attractive to suggest that the predominance of type I fibers in the pressure-overloaded myocardium may mediate diastolic dysfunction. This notion is supported by some associative evidence. High levels of type I collagen was associated with increased myocardial stiffness in some human and experimental studies.93,94 Moreover, ACE inhibition has been suggested to reduce the myocardial type I to type III collagen ratio in models of hypertension.121 However, other studies did not support an important role of the collagen type profile in the pathogenesis of diastolic dysfunction. In hypertensive rats, myocardial stiffness was not associated with changes in collagen I/III ratio, but was rather attributed to cross-linking.95 Moreover, in human patients with aortic stenosis, comparable induction of collagen type I and type III was noted.96 The technical challenges in assessment of collagen I and III levels in the myocardium may explain, at least in part, the conflicting findings.

    Increased synthesis of procollagens transcripts by activated myofibroblasts is followed by secretion of soluble procollagens into the extracellular space. Once outside the cells, procollagen chains are processed, assembled into fibrils, and cross-linked. Very limited information is available on the molecular steps regulating collagen processing and maturation in pressure-overloaded hearts. Cleavage of the N- and C-terminal propeptides attached to procollagen is a critical part of collagen processing. A study in a model of left ventricular pressure overload demonstrated that the enhancer protein PCOLCE (procollagen C-endopeptidase enhancer)-2 regulates C-terminal propeptide cleavage by enhancing the activity of the C-proteinase BMP (bone morphogenetic protein)-1.122 The matricellular protein SPARC (secreted protein acidic and rich in cysteine) also contributes to postsynthetic processing of collagen in the pressure-overloaded heart and increases diastolic stiffness.123

    Collagen cross-linking plays an important role in regulation of geometric remodeling and dysfunction in the pressure-overloaded heart. Several cross-linking enzymes are upregulated in the remodeling myocardium, including members of the LOX (lysyl oxidase) family124,125 and TG (transglutaminase)-2 (also known as tissue transglutaminase).126,127 In addition to its transamidase-dependent enzymatic actions, TG-2 bind to the ECM and may also act as a signaling molecule modulating fibroblast-mediated MMP and TIMPs (tissue inhibitor of metalloproteinases) synthesis through nonenzymatic mechanisms.128 Studies in human patients support the significance of collagen cross-linking in the pathogenesis of heart failure. In hypertensive patients with heart failure, the degree of cross-linking and not the total amount of collagen was associated with elevated filling pressures.129 Moreover, in patients with hypertensive heart failure, increased collagen cross-linking assessed through endomyocardial biopsy was associated with a higher incidence of hospitalizations.130 However, preservation of geometry and function in the myocardium likely requires some matrix cross-linking activity. In models of cardiac pressure, overload was associated with reduction in myocardial collagen cross-linking.131

    Nonfibrillar Collagens

    Nonfibrillar collagens do not form large fibrillar bundles, but can associate with type I and type III collagen fibrils to regulate anchoring, networking, and organization of the ECM.132 Moreover, nonfibrillar collagens may bind to cell surface receptors, modulating cellular phenotype, or yield bioactive fragments that regulate cellular responses. On the basis of their structural properties and functions, nonfibrillar collagens are classified into 6 groups (Table 2). Unfortunately, the information available on the role of nonfibrillar collagens in remodeling of the pressure-overloaded heart is limited. Table 2 summarizes our current understanding on the expression patterns and role of nonfibrillar collagens in heart failure.

    Table 2. Nonfibrillar Collagens in Heart Failure

    SubfamilyMemberCardiac Localization and Role in Myocardial HomeostasisRole in Nonischemic Heart FailureRole in MI and in Ischemic Heart Failure
    Network-forming collagens (IV, VIII, X)IVCol IV is a major component of the basement membrane that surrounds cardiomyocytes and contributes to the vascular structure in the myocardium. Col IV is produced by both cardiomyocytes and interstitial cells.133 Col IV may mediate homeostatic functions in cardiomyocytes and vascular cells through activation of integrin signaling. Col IV–derived peptides (such as canstatin) have been implicated in regulation of cardiomyocyte L type Ca2+ channel activity.134Col IV induction has been observed in many cardiomyopathic conditions135,136 and in diabetic and aging hearts.137,138 Collagen IV–derived peptide canstatin may regulate angiogenesis, fibroblast migration, and cardiomyocyte survival in failing hearts.139Col IV is upregulated in the infarct border zone in experimental models of MI.140
    VIIICol VIII is expressed transiently during cardiogenesis. Low levels of Col VIII expression are noted in normal adult hearts.141In the pressure-overloaded myocardium, Col VIII expression is reduced in animals with decompensated heart failure.142 Endogenous Col VIII has been implicated in activation of myofibroblasts and may protect the heart from dilation.143N/A
    XCol X is expressed predominantly in cartilage. Expression in valve leaflets from patients with aortic stenosis has been reported.144N/AN/A
    FACITs (IX, XII, XIV, XVI, XIX, XX, XXI, XXII)IXCol IX is codistributed with Col II in cartilage, and eye and inner ear. Transient Cola1IX mRNA expression has been reported in developing hearts.145N/AN/A
    XIICol XII expression has been detected in the epicardium of zebrafish.146 Col XII mRNA expression has been reported in human hearts.147N/AIn zebrafish, epicardial expression of Col XII was increased following cryoinjury.146
    XIVCol XIV is highly expressed in embryonic hearts and regulates collagen fibril organization, cardiomyocyte proliferation, and fibroblast survival.148N/ACol XIV was overexpressed in reperfused porcine MI.15.
    XVIAn immunohistochemical study suggested expression of col XVI in developing and adult mouse hearts.149N/AN/A
    XXICol XXI mRNA expression has been reported in adult human hearts, predominantly localized in the right atrium and ventricle.150N/AN/A
    XXIICol XXII expression was found in the mammalian myocardium localized at insertion points of the chordae tendinae to the myocardium.151N/AN/A
    MACITs (XIII, XVII, XXIII, XXV)XIIICol XIII, a transmembrane collagen, is expressed in the intercalated discs of the adult heart.152 Transgenic overexpression of Col XIII caused fetal lethality, associated with myocardial defects and dysfunction.153,154N/AN/A
    XVIICol XVII expression has been reported in developing and adult mouse hearts and is a component of hemidesmosomes.155N/AN/A
    XXIIICol XXIII mRNA expression was found in developing mouse hearts.156N/AN/A
    XXVAlthough Col XXV is predominantly expressed in the brain, weak expression in the developing heart has been suggested.157N/AN/A
    Anchoring fibrils (VII)VIICol VII is predominantly expressed in the dermal-epidermal junction. Cardiac expression has not been systematically studied.A subset of patients with dystrophic epidermolysis bullosa (a condition caused by Col VII mutations) exhibit dilated cardiomyopathy.158,159N/A
    Beaded filament forming collagens (VI, XXVI, XXVIII)VICol VI is highly expressed in developing and adult hearts.160,161 In adult mammals, Col VI represents ≈5% of total collagen and is broadly distributed in the endomysium and in the media and adventitia of myocardial vessels.8 However, Col VI KO mice had no significant baseline cardiac defects162 and patients with Bethlem myopathy, a condition associated with Col VI mutations163 do not seem to exhibit myocardial disease.164Increased Col VI deposition has been reported in many cardiomyopathic conditions.165 Patients with DCM exhibit increased Col VI deposition, localized in the perivascular and interstitial space,166 and within t-tubules.161 Considering its role in myofibroblast activation,167 Col VI may be involved in fibrosis of the pressure-overloaded heart.Following infarction, Col VI was found to play a protective role, limiting infarct size, and attenuating adverse remodeling.162 The protective actions may involve effects on cardiomyocyte survival and on activation of reparative myofibroblasts.167
    XXVIIICol XXVIII mRNA was detected in neonatal mouse hearts, but not in adult hearts.168N/AN/A
    MULTIPLEXIN (XV, XVIII)XVCol XV is expressed in developing and adult hearts169,170 and plays a crucial role in cardiac homeostasis. Col XV null mice developed a cardiomyopathy, associated with increased vascular permeability, defective interstitial network formation, and perturbed organization of cardiomyocytes.171Col XV loss was associated with exercise-induced myocardial injury,172 presumably due to protective actions of Col XV on stressed cardiomyocytes and vascular cells. Pressure-overloaded mouse hearts exhibited increased Col XV deposition.171N/A
    XVIIICollagen XVIII is highly expressed in embryonic and adult hearts.173,174 However, genetic loss of Col XVIIIa1 did not have any functional consequences in mouse hearts, despite basement membrane alterations in atrioventricular valves.175 Proteolytic cleavage of Col XVIII within its C-terminal domain yields release of endostatin, an endogenous inhibitor of angiogenesis.In patients with chronic heart failure, circulating endostatin levels may predict adverse outcome.176Myocardial ischemia triggers endostatin release due to Col XVIII cleavage.177 Endostatin is a potent inhibitor of angiogenesis,178 and endostatin levels inversely correlate with collateral formation in patients with ischemic heart disease.179 However, in a model of MI, endostatin neutralization had adverse effects suggesting protective actions of Col XVIII, presumed due to antifibrotic actions, and to inhibition of protease activity.180

    DCM indicates dilated cardiomyopathy; FACIT, fibril-associated collagens with interrupted triple helices; KO, knockout; MACIT, membrane-associated collagens with interrupted triple helices; MI, myocardial infarction; MULTIPLEXIN, multiple triple-helix domains and interruptions; and N/A, no information available.

    Fibrogenic growth factors (such as TGF-β) and neurohumoral mediators (such as angiotensin II) implicated in induction and secretion of fibrillar collagens are also capable of inducing synthesis of several members of the nonfibrillar collagen subfamilies (such as collagen IV, VI, and VIII).181,182 Thus, in fibrotic pressure-overloaded hearts, deposition of collagens I and III may be accompanied by concomitant upregulation of nonfibrillar collagens that may play an important role in organization of the ECM and in activation of cardiac interstitial cells.183,184 In vitro, collagen VI has been identified as a potent stimulus for myofibroblast conversion,167 whereas collagen VIII may activate ECM expansion by promoting fibroblast migration and by enhancing TGF-β synthesis.143 In vivo, loss of collagen VIII was associated with reduced infiltration of the pressure-overloaded heart with myofibroblasts and attenuated fibrosis. These antifibrotic effects were associated with increased mortality and left ventricular dilation, supporting the importance of matrix-preserving actions in protecting the heart from adverse remodeling.143 The cellular mechanisms for the effects of nonfibrillar collagens in the remodeling heart may not be limited to fibroblast activation, but may also involve actions on cardiomyocyte survival, inflammatory cell activation, and vascular cell function.162 Several nonfibrillar collagens can be cleaved following injury, generating bioactive fragments with important biological functions. For example, collagen IV–derived peptides (such as canstatin) have been suggested to regulate cardiomyocyte survival, fibroblast migration, and angiogenesis in failing hearts.182 Moreover, endostatin a collagen XVIII-derived peptide is a potent endogenous inhibitor of angiogenesis178 that may play an important role in regulation of cellular responses in failing hearts.

    Specialized Matrix Proteins

    Remodeling of the pressure-overloaded myocardium is associated with secretion and deposition of specialized ECM proteins, which are not part of the normal adult cardiac matrisome and do not play a primary structural role, but are induced under conditions of stress and transduce molecular signals in cardiomyocytes and interstitial cells, modulating important cellular responses. Increased expression of embryonic isoforms of cellular Fn, matricellular proteins, and extracellular proteoglycans has been extensively documented in animal models of cardiac pressure overload and in failing human hearts.185–187 In failing and remodeling hearts, the ECM is enriched with a broad range of macromolecules that modulate growth factor and protease activity, or bind to cell surface receptors, regulating cell survival, proliferation, and gene expression. Mechanotransductive signaling, TGF-βs, and neurohumoral mediators (such as angiotensin II) are potent inducers of specialized ECM proteins in the pressure-overloaded heart.


    Cardiac pressure overload triggers marked upregulation of splice variants of Fn that contain the ED-A (extra domain A; ED-A+Fn), or the extra domain B (ED-B+Fn).188 ED-A Fn has been suggested to cooperate with TGF-β, stimulating myofibroblast conversion in vitro and in vivo.189–191 The molecular mechanism responsible for the interaction between ED-A+Fn and TGF-β remains poorly understood. In vitro experiments suggest that ED-A+Fn may bind to LTBP (latent TGF-β–binding protein)-1, contributing to the spatial localization of activatable TGF-β in tissues.192 On the contrary, the role of ED-B+Fn, in heart failure is unclear. ED-B deficient fibroblasts exhibit slow growth and have attenuated synthesis of ECM proteins.193 Whether induction of ED-B+Fn in the pressure-overloaded myocardium mediates fibroblast activation has not been investigated. Polymerization of Fn following secretion plays a critical role in regulation of fibroblast phenotype and increases the tensile strength of collagen fibers.194,195

    Matricellular Proteins

    Tissue remodeling is associated with induction of a wide range of extracellular macromolecules that bind to the structural ECM, interact with growth factors and proteases, and modulate signaling responses in many cell types by binding to cell surface receptors, such as integrins and syndecans. These proteins, termed matricellular do not play a primary structural role, but serve as a molecular bridge between the ECM and the cells, acting as dynamic integrators of microenvironmental changes and as essential mediators of tissue remodeling.185,196–198 The founding members of the matricellular family were tenascin-C, SPARC, and TSP (thrombospondin)-1; however, recognition of the complexity of matrix responses following injury resulted in rapid expansion of the family with the inclusion of several additional proteins, such as TSP-2 and TSP-4, tenascin-X, osteopontin, periostin, the fibulins, and the members of the CCN (connective tissue growth factor, cystein-rich protein, nephroblastoma overexpressed gene) family. In vivo studies have revealed a remarkable functional complexity of matricellular proteins, reflecting the contextual nature of their effects that depend on the various structural proteins, cytokines, and growth factors they associate with, and the cell types with which they interact in different tissues, and in various pathological conditions.

    Cardiac pressure overload induces marked induction and interstitial deposition of several members of the matricellular family.185 In the remodeling myocardium, cardiomyocytes, fibroblasts, immune cells, and vascular cells, all major cellular effectors of fibrosis, have been identified as important targets of the matricellular proteins. Table 3 summarizes our knowledge on the expression and role of the major members of the matricellular family in heart failure. Although each member has a unique repertoire of functional effects and molecular interactors, several common themes have emerged about their cell biological actions. First, several matricellular proteins have been implicated in regulation of fibroblast proliferation, survival and activation, and in myofibroblast conversion.41,199,213,251,252,273 Thus, in pressure-overloaded hearts, matricellular proteins, such as TSP-1 (Figure 3), TSP-4, periostin, and osteopontin may act by stimulating a fibrogenic program in cardiac fibroblasts. Although most members of the family have been suggested to exert fibrogenic actions in vivo, matricellular actions that inhibit fibroblast responses, or contribute to resolution of fibrosis have also been reported.283 Second, immune cell subpopulations are increasingly recognized as important cellular targets of matricellular proteins. For example, tenascin-C (Figure 4) may act as an important modulator of macrophage phenotype in remodeling pressure-overloaded hearts.218,219,228 Third, some matricellular proteins may have direct actions on cardiomyocyte survival under conditions of stress.209,215 Fourth, although the traditional definition of a matricellular protein implies absence of a structural role, several members of the matricellular family (such as SPARC, TSP-1, and TSP-2) have been implicated in collagen fibril assembly and in regulation of ECM cross-linking.123,203,284

    Table 3. Expression, Role, and Mechanisms of Action of the Major Members of the Matricellular Family in Heart Failure

    Matricellular ProteinExpression and Role in Nonischemic CardiomyopathyExpression and Role in MI and in Ischemic CardiomyopathyProposed Mechanisms of Action
    TSP-1Expression: Transiently upregulated and deposited in the interstitial and perivascular ECM in models of LV pressure overload.199,200 Upregulated in perivascular areas in diabetic hearts.201Expression: Transiently induced in the infarct border zone.202Activation of TGF-β may promote myofibroblast conversion and acquisition of a matrix-synthetic phenotype200,202
    Role: Protects from adverse remodeling, limiting expansion of the inflammatory infiltrate.202Inhibition of MMPs199
    Role: Has been reported to protect the pressure-overloaded myocardium from dysfunction by stabilizing the ECM.199Interaction with collagens and LOX precursors203
    Angiostatic effects201
    The TSP-1/TGF-β axis has been reported to promote fibrosis and dysfunction in the diabetic pressure-overloaded heart.200Anti-inflammatory actions202
    TSP-1/CD47 actions may induce HDAC-3
    The TSP-1/CD47 axis has been suggested to promote heart failure in a model of pressure overload.204TSP-1/CD47 regulates effects of NO on the microvasculature205
    Mediates capillary rarefaction in diabetic hearts.201
    TSP-2Expression: Highly expressed in pressure-overloaded hearts and in human patients with cardiac hypertrophy.206 High circulating TSP-2 are associated with adverse outcome in HFpEF patients.207No published dataInhibition of MMP synthesis and activity208
    Role: Protects the pressure-overloaded heart from rupture206 and the aging heart from dilative cardiomyopathy.209Activation of Akt-mediated prosurvival pathways in cardiomyocytes208
    Protective role in viral myocarditis through T reg-mediated anti-inflammatory actions.210
    Protects cardiomyocytes and preserves the integrity of the cardiac ECM in doxorubicin-induced cardiomyopathy.208
    TSP-3Promotes cardiomyocyte injury in response to stress.211UnknownInduction of integrins in stressed cardiomyocytes through intracellular actions that promote sarcolemmal destabilization211
    TSP-4Expression: Rapidly upregulated in the myocardium in response to angiotensin II-treatment, or TAC.212UnknownSuppression of ECM protein synthesis in fibroblasts and endothelial cells213
    Role: Protects the pressure-overloaded heart from functional decompensation, systolic dysfunction and death, and restrains hypertrophy.214Transduces protective mechanosensitive signals require for augmentation of contractility in response to an acute pressure load215 has also been suggested to inhibit fibrosis in the pressure-overloaded heart.213,216
    Activation of mechanosensitive Erk and Akt signaling in cardiomyocytes in response to stress215Intracellular actions, augmenting ER function and protecting from injury-related ER stress217
    Tenascin-CExpression: Consistently upregulated and deposited in the cardiac interstitium in pressure-overloaded hearts,71,218,219 and in myocarditis.220 Upregulated in cardiomyocytes subjected to mechanical stress.221 In human patients with DCM, increased serum levels of tenascin-C, and myocardial tenascin-C expression have been linked with adverse outcome.222,223Expression: Highly expressed in the infarct border zone, and in remodeling myocardial areas in experimental models224 and in human patients with myocardial scars225 or ischemic cardiomyopathy.226 In patients with ischemic cardiomyopathy, interstitial activity evidenced by tenascin-C deposition predicted segmental recovery following revascularization.226Activation of integrin-mediated secretion of fibrogenic cytokines in macrophages219
    Modulation of TLR responses in macrophages227
    Negative regulation of inflammation228
    Accentuation of fibroblast migration229 and fibroblast activation through TLR-dependent mechanisms230
    Role: Has been suggested to accelerate fibrosis, hypertrophy, and dysfunction of the pressure-overloaded heart.218,219,231 However, in another study tenascin-C derived from bone marrow cells protected the pressure-overloaded heart from dysfunction and fibrosis by attenuating inflammation.228Role: Has been suggested to accelerate adverse postinfarction remodeling by perturbing macrophage functions.227Modulation of adhesive interactions between the cardiomyocytes and the ECM224
    SPARCExpression: Increased levels of myocardial SPARC are noted in experimental models of pressure overload,123 in aging hearts.232,233 SPARC expression was associated with fibrosis in human cardiac allografts.234Expression: Upregulated in experimental models of MI.235,236Contribution to postsynthetic procollagen processing123
    Role: Mediates collagen processing and fibrosis, and promotes diastolic dysfunction in models of pressure overload.123 Has been suggested to protect against inflammation in viral inflammation.238Role: Protects the infarcted heart from cardiac rupture and dysfunction by preserving the ECM network.237Activation of TGF-β signaling responses in cardiac fibroblasts237
    Osteopontin (OPN)Expression: Marked myocardial upregulation of osteopontin is noted in experimental models of heart failure induced through pressure overload,239 in volume overload,240 in diabetic hearts,241 and in hearts from mice with muscular dystrophy.242 Myocardial osteopontin was increased in patients with end-stage dilated cardiomyopathy; levels were reduced on unloading.243 Highly expressed in the myocardium of patients with nonischemic cardiomyopathy and associated with fibrotic lesions and hypertrophy.244 In human patients with hypertension, osteopontin promoter variants that affect transcription were associated with diastolic function.245Expression: Upregulated in myocardial infarcts and predominantly localized in activated macrophages.246–248Stimulation of fibroblast proliferation through integrin activation,249,250 and protection of fibroblasts from apoptosis251
    Activation of prosurvival pathways in fibroblasts through miR-21252
    Role: Protects the infarcted heart from ventricular dilation by promoting collagen deposition.253Stimulation of myofibroblast conversion254
    Activation of reparative and fibrogenic macrophages through galectin-3 upregulation248,255
    Activation of lymphocytes256
    Role: Suggested to mediate fibrosis, while preventing dilation in pressure-overloaded hearts and on neurohumoral activation.249,258–260 Prohypertrophic effects have been less consistently observed.Stimulation of cardiomyocyte apoptosis via CD44257
    In aging hearts, osteopontin derived from adipose tissue (and not from the myocardium) was suggested to promote cardiac fibrosis and dysfunction.261 In a mouse model of Chagas disease, OPN was implicated in cardiac inflammation, fibrosis, and dysfunction.262 OPN mediated fibrosis in a model of viral myocarditis263; however, in a model of autoimmune myocarditis, osteopontin did not affect inflammation.264
    PeriostinExpression: Upregulated in activated myofibroblasts and deposited in the cardiac interstitium in models of cardiac pressure overload.41,265–267 Increased myocardial expression in senescent mice,268 in a model of volume overload,269 and in models of cardiomyopathy induced through renal failure.270 Negligible expression in a model of type II diabetes mellitus-related cardiomyopathy.271 In human patients, increased periostin expression in failing hearts was reduced on unloading.272Expression: Markedly upregulated in infarct myofibroblasts and deposited in the ECM following infarction.41,273,274Activation and differentiation of cardiac fibroblasts, promoting migration and myofibroblast conversion273,275,276
    Regulation of collagen fibrillogenesis277
    Role: Following nonreperfused infarction, periostin is essential for cardiac repair and protects from rupture, but mediates fibrosis and adverse remodeling.41,273Stimulation/activation of TGF-β signaling pathways278
    Modulation of MMP synthesis by many cell types, including interstitial cells and macrophages279
    Role: Promotes hypertrophy and fibrosis in experimental models of pressure overload.41 Promotes dysfunction in a model of hypertensive heart disease.266Has been suggested to promote cardiac regeneration in neonatal,281 and even in adult mice.280Stimulation of adult cardiomyocyte proliferation involving PI3K activation has been reported280
    Regenerative effects in adult animals were not supported by studies using genetic manipulation strategies.282

    DCM indicates dilated cardiomyopathy; ECM, extracellular matrix; ER, endoplasmic reticulum; HDAC, histone deacetylase; HFpEF, heart failure with preserved ejection fraction; LOX, lysyl oxidase; LV, left ventricular; MI, myocardial infarction; MMP, matrix metalloproteinase; OPN, osteopontin; PI3K, phosphoinositide 3-kinase; SPARC, secreted protein acidic and rich in cysteine; TAC, transverse aortic constriction; TGF, transforming growth factor; TLR, toll-like receptor; and TSP, thrombospondin.

    Figure 3.

    Figure 3. Expression and actions of TSP (thrombospondin)-1 in failing hearts. In a mouse model of cardiac pressure overload induced through transverse aortic constriction, TSP-1 immunoreactivity is localized predominantly in perivascular and interstitial areas (data from our published work199). TSP-1 overexpression in the pressure-overloaded heart may modulate inflammation, fibrosis, and matrix metabolism through several distinct molecular pathways. First, TSP-1 plays an important role in TGF (transforming growth factor)-β activation by binding to the LAP (latency-associated peptide), thus triggering release of bioactive TGF-β. Second, TSP-1 may inhibit MMP (matrix metalloproteinase) activation, promoting matrix preservation. Third, TSP-1 may exert angiostatic actions. Fourth, TSP-1 may exert anti-inflammatory actions through effects on lymphocytes and macrophages. Fifth, TSP-1 may inhibit NO production and signaling.

    Figure 4.

    Figure 4. Expression and function of the matricellular protein tenascin-C in the failing heart. A and B, Tenascin-C immunoreactivity is localized in the interstitial and perivascular areas in a mouse model of cardiac pressure overload induced through transverse aortic constriction. Images from our own published work.71 Tenascin-C may be produced by cardiomyocytes, myofibroblasts, and leukocytes in response to mechanical stress or neurohumoral activation. When bound to the interstitial ECM (extracellular matrix), tenascin-C may exert fibrogenic actions by directly stimulating synthesis of ECM proteins by fibroblasts, or by activating macrophages through integrin or Toll-like receptor (TLR)–dependent mechanisms. Effects of tenascin-C on cardiomyocytes remain understudied.

    The molecular targets of the matricellular proteins include a broad range of cytokines and growth factors, proteases, integrins, and nonintegrin cell surface receptors, such as CD44 and CD36. An additional layer of complexity in understanding the effects of the matricellular proteins was added by recently reported experimental findings suggesting important intracellular actions of the TSPs.211,217 Considering the diverse functions of matricellular proteins, their multiple functional domains and their context-dependent effects, the relative contributions of specific actions in vivo remains poorly documented.


    Proteoglycans are glycosylated proteins that consist of a core protein with one or more covalently attached glycosaminoglycan chains. In the mammalian heart, the profile of ECM proteoglycan composition is dependent on topography. The pericellular matrix contains predominantly heparan sulfate proteoglycans, which are typically associated with the cell surface. In areas more distant from the surface of the cells, chondroitin sulfate- and dermatan sulfate-containing proteoglycans (CSPGs [chondroitin sulfate proteoglycans] and DSPGs [dermatan sulfate proteoglycans], respectively) predominate.285 In both human patients with heart failure and in animal models of myocardial disease, CSPGs accumulate in fibrotic regions.286 The ECM in the pressure-overloaded heart is also enriched with a wide range of SLRPs (small leucine-rich proteoglycans), such as biglycan, decorin, fibromodulin, lumican, and osteoglycin. TGF-βs, angiotensin II, proinflammatory cytokines, and mechanotransductive signaling markedly upregulate expression of SLRPs in cardiac fibroblasts.287–289 Once secreted in the cardiac interstitium, SLRPs bind to collagen fibrils and organize the structural ECM, but may also interact with growth factors, and cell surface receptors to transduce or modulate signaling responses. In vivo studies have implicated several SLRPs in regulation of cardiac fibrosis, remodeling, and dysfunction following pressure overload.186 In a model of transverse aortic constriction, biglycan was found to mediate fibrosis and cardiomyocyte hypertrophy in the pressure-overloaded myocardium.290 Other SLRPs have been implicated in negative regulation of fibrotic and hypertrophic myocardial remodeling. In hypertensive rats, decorin gene therapy attenuated fibrosis and hypertrophy and improved function by inhibiting TGF-β signaling.291 Lumican has also been suggested to protect against systolic dysfunction in an isoproterenol infusion model, the cellular mechanism for the protective actions was not studied.292 Osteoglycin protected the pressure-overloaded myocardium from diastolic dysfunction by attenuating inflammatory activation of macrophages and by inhibiting TGF-β–driven fibrogenic responses.293 The combined experience from various mouse models of cardiac remodeling suggests important roles for SLRPs in regulation of fibrosis and hypertrophy; however, their functional role is dependent on the pathophysiologic context, and the cellular targets and molecular interactors remain unknown. Moreover, proteomic studies in human hearts suggested that myocardial SLRP profiles may be dependent on topography, identifying atrial-specific processed forms of decorin that may be involved in atrial fibrillation.294

    Role of ECM Metabolism in Regulation of Geometry and Function in the Pressure-Overloaded Heart

    In both experimental models of left ventricular pressure overload and in human patients with long-standing untreated hypertension or aortic stenosis, early increases in myocardial stiffness occur in the absence of systolic dysfunction, and may be followed by late dilative remodeling and systolic functional depression. Although the basis for the transition likely involves several different cellular processes, changes in the composition of the ECM may be critical in regulation of cardiac geometry and function. Regulation of the balance between proteases and antiproteases plays a crucial role in the biochemical profile of interstitial ECM proteins and has profound functional implications (Figure 5). Although only fibroblasts produce significant amounts of fibrillar collagens, the main structural components of the matrix, virtually all myocardial cell types (including cardiomyocytes, fibroblasts, immune cells, and vascular cells) can produce and activate proteolytic enzymes that process ECM proteins,295 thus altering the geometry and the mechanical properties of the myocardium. Cardiac pressure overload is associated with induction and activation of collagenases (such as MMP-1, MMP-8, and MMP-13), gelatinases (such as MMP-2 and MMP-9), stromelysins/matrilysins, and membrane-type MMPs.296,297 TIMPs are also upregulated in remodeling hearts and may exert matrix-preserving actions.298,299 A large body of evidence suggests that MMP induction and activation may generate a predominantly proteolytic environment in the cardiac interstitium, leading to degradation of ECM proteins.300 The relatively slow synthesis rate of collagen by cardiac fibroblasts is accelerated following pressure overload, but may not be sufficient to compensate for the pronounced matrix-degrading effects of MMPs.10,301,302 Excessive degradation of endomysial collagen may precipitate systolic dysfunction in patients with hypertensive heart failure.303 MMP induction may be mediated through activation of proinflammatory signaling pathways. For example, TNF (tumor necrosis factor)-α induces synthesis of a wide range of MMPs in both cardiomyocytes and fibroblasts and promotes dilation of the pressure-overloaded heart by degrading the supporting ECM.304 The proinflammatory cytokine IL (interleukin)-1β also stimulates MMP expression in cardiac fibroblasts and may exert similar actions in vivo.305,306 Development of systolic dysfunction in the presence of excessive MMP activation in the cardiac interstitium may involve several distinct mechanisms. First, because cardiomyocytes are dependent on interactions with a preserved matrix network, loss of survival signals transduced by intact ECM proteins may promote apoptosis and contractile dysfunction of cardiomyocytes under conditions of stress. Second, ECM fragments (matrikines) generated through protease activation may induce proinflammatory cascades,30 or activate proapoptotic pathways in cardiomyocytes. Third, several members of the MMP family have been suggested to regulate signaling cascades through effects independent of ECM processing. MMPs can process CC and CXC chemokines307,308 and cytokines (such as TNF-α),309 thus exerting context-dependent proinflammatory or anti-inflammatory actions. Moreover, MMPs have been implicated in TGF-β activation,310 and may cleave transmembrane receptors, such as integrins311 or syndecans,312 thus modulating essential proinflammatory or fibrogenic cascades. MMPs may also act as intracellular mediators, promoting degradation of contractile proteins in cardiomyocytes, or modulating signal transduction responses in interstitial cells.313–315 In contrast to the effects of MMP activation, overactive matrix-preserving mediators (such as induction of TIMPs) may promote deposition of structural ECM proteins, increasing myocardial stiffness, and accentuating diastolic dysfunction.316 It should be emphasized that, much like MMPs, TIMPs can also exert actions independent of MMP activity or ECM remodeling. For example, TIMP-1 has been suggested to promote cardiac fibrosis by facilitating a CD63/β1 integrin cascade that activates Smad-dependent signaling in cardiac fibroblasts.299

    Figure 5.

    Figure 5. Sustained pressure overload triggers progressive left ventricular dilation and systolic dysfunction through changes in the protease/antiprotease balance. In the early phase, mechanical stress induces a matrix-preserving fibroblast phenotype inducing collagen synthesis and production of antiproteases (such as TIMPs [tissue inhibitor of metalloproteinase]). Accentuated ECM (extracellular matrix) deposition increases myocardial stiffness causing diastolic dysfunction. Prolonged pressure overload may be associated with transition of infiltrating fibroblasts to a matrix-degrading phenotype that produces MMPs (matrix metalloproteinases), thus causing ECM degradation and generating matrix fragments (matrikines). Matrikines may cause systolic dysfunction by promoting cardiomyocyte apoptosis and by inducing inflammation. Moreover, degradation of the ECM network may deprive cardiomyocytes from matrix-dependent signals required for preservation of function.

    In addition to the established role of MMPs in myocardial ECM turnover, emerging evidence implicates 2 other families of proteases, the ADAM (a disintegrin and metalloproteinase), and the ADAMTS (ADAM with thrombospondin motifs).317,318 ADAM and ADAMTS family members can be activated in response to a wide range of stimuli and have multiple substrates. ADAMs mediate ectodomain shedding, the proteolytic cleavage of the extracellular domain of membrane-bound molecules. ADAMTS members, however, typically act as secreted proteases and have ECM protein substrates. In a model of left ventricular pressure overload, ADAM-17 expression in cardiomyocytes protected the heart from dilation, dysfunction, and fibrosis through cleavage of β1 integrin.319 ADAMTS-2, however, was found to be upregulated in the pressure-overloaded myocardium and attenuated cardiac hypertrophy by inhibiting the PI3K/Akt axis.320

    Effects of Volume Overload on the Cardiac ECM

    Despite its important role in heart failure associated with severe valvular regurgitant lesions, and its involvement in other cardiomyopathic conditions, volume overload remains a pathophysiologic and cell biological enigma. In contrast to the marked deposition of fibrillar collagens in the interstitium of pressure-overloaded hearts, volume overload is associated with loss of interstitial collagen, prominent ECM degradation, and induction of MMPs (Figure 6).321–323 The cellular basis for the loss of collagen and the dominant activation of proteases in volume overload–induced cardiomyopathy remains unknown. Mechanical stretch in response to volume overload may affect gene expression in both interstitial cells and cardiomyocytes. Fibroblasts from volume-overloaded hearts exhibited a hypofibrotic phenotype, characterized by reduced collagen and α-SMA synthesis.324 It has been suggested that increased oxidative stress induced by mechanical stretch may activate an autophagic degradation of procollagen in volume-overloaded hearts.325 Effects of volume overload on macrophages and mast cells have also been implicated.73,326 As important sources of MMPs and proinflammatory cytokines, mast cells and macrophages may promote degradation of the interstitial ECM, leading to dilative remodeling and systolic dysfunction. Although in vitro and in vivo studies have suggested that mechanical stretch in response to volume overload may promote cardiomyocyte apoptosis327 and alters the conformation of caveolae,328 whether cardiomyocytes serve as important cellular effectors of ECM loss in volume-overloaded hearts has not been investigated.

    Figure 6.

    Figure 6. The enigmatic basis of ECM (extracellular matrix) degradation in the volume-overloaded heart. Experimental evidence suggests that cardiac volume overload is associated with a matrix-degrading fibroblast phenotype and with high levels of interstitial MMPs (matrix metalloproteinases). Immune cells (macrophages and mast cells) may contribute to the proteolytic environment by secreting MMPs. Persistent ECM degradation may trigger cardiomyocyte apoptosis and dysfunction and may be responsible for the dilation and systolic dysfunction typically observed in volume-overloaded hearts. The molecular links between mechanical stretch induced by volume overload and the selective activation of proteolytic pathways remain unknown.

    Dynamic Alterations of the Cardiac ECM in the Infarcted Heart and in Chronic Ischemic Cardiomyopathy

    The adult mammalian heart has negligible regenerative capacity. Thus, following MI, the heart heals through activation of an inflammatory response that clears the wound from dead cardiomyocytes and activates reparative myofibroblasts, ultimately leading to formation of a scar, predominantly comprised cross-linked collagen. Repair of the infarcted myocardium can be divided into 3 distinct but overlapping phases: the inflammatory phase, the proliferative phase, and the maturation phase.20 Dynamic changes in the biochemical profile and composition of the ECM play a critical role in regulation of key cellular events in all 3 phases of infarct healing.196,329 During the inflammatory phase, early degradation of the ECM generates matrikines that may serve as danger signals contributing to activation of an inflammatory and reparative program. Moreover, formation of a provisional fibrin-based matrix network derived from extravasated fibrinogen and plasma Fn235 serves as a highly plastic conduit for infiltrating inflammatory cells. As macrophages clear the infarct from dead cells and matrix debris, induction of anti-inflammatory mediators suppresses inflammation and marks the transition to the proliferative phase. At this stage, activated myofibroblasts deposit both structural and matricellular ECM proteins,98 preserving the structural integrity of the ventricle. Finally, during the maturation phase, the collagenous ECM is cross-linked and the fibroblasts become quiescent,330 and may undergo apoptosis. The matrix-dependent molecular steps that regulate the reparative response following MI are critical for protection of the infarcted heart from cardiac rupture and from the pathogenesis of heart failure. Moreover, a large body of evidence suggests that disruption of matricellular genes exclusively or predominantly induced in the infarct zone has a major impact on the extent of adverse postinfarction remodeling.202,237,331 These observations suggest that the characteristics and biochemical composition of the scar are a major determinant of cardiac remodeling following MI and that dysregulation of ECM-dependent responses in the healing infarct may drive postinfarction heart failure. The role of the ECM network in postinfarction cardiac remodeling has been recently reviewed.196

    As the infarct heals, the viable noninfarcted myocardium remodels, exhibiting cardiomyocyte hypertrophy, accompanied by progressive interstitial fibrosis. Thus, although endogenous anti-inflammatory signals suppress inflammation in the infarct zone, in the viable noninfarcted segments, increased wall stress may locally activate cardiomyocytes, macrophages, and fibroblasts, triggering chronic remodeling of the ECM network.332,333 Studies in human patients surviving acute MI suggest that high circulating levels of MMPs may predict adverse dilative remodeling, systolic dysfunction, and progression to heart failure.334,335 Although it is tempting to hypothesize that accentuated and accelerated chamber dilation in a subset of MI patients may be caused by overactive matrix-degrading pathways, the contribution of chronic ECM remodeling in noninfarcted segments to adverse remodeling and development of postinfarction heart failure remains poorly documented. Understanding the functional consequences of specific cellular events in remote viable myocardial segments is particularly challenging, considering that traditional loss- or gain-of-function interventions also target cells in the infarct and in the border zone that may affect cardiac hemodynamics, thus indirectly modulating responses in the noninfarcted myocardium.

    Alterations in the ECM network may also contribute to the pathogenesis of chronic ischemic cardiomyopathy, in the absence of MI. Unfortunately, the effects of low flow ischemia or brief ischemic insults on the myocardial ECM remain underexplored and poorly understood. In a porcine model, reduction of coronary flow to 50% of the baseline for 90 minutes was sufficient to activate MMP-9 without affecting collagenase levels, or have effects on the structure of the cardiac ECM.336 Moreover, in a mouse model of brief repetitive myocardial ischemia and reperfusion, deposition of the matricellular protein tenascin-C accompanied interstitial fibrosis, in the absence of a completed infarction.337 These findings suggest that ischemic events of low duration or intensity may trigger remodeling of the cardiac ECM without causing lethal cardiomyocyte injury. Oxidative stress triggered by ischemia/reperfusion may be responsible for the ECM changes. The clinical relevance of these observations in ischemic cardiomyopathy is supported by studies in human patients. MMP-2 and MMP-9 activation were noted following reperfusion after cardioplegia in myocardial samples from patients undergoing aortocoronary bypass.338 Moreover, patients with ischemic cardiomyopathy exhibited increased myocardial MMP-9 expression and activity, and high MMP-14 levels339,340; increased MMP expression was reversed following unloading through left ventricular assist device implantation.341 Recovery of function following revascularization in ischemic cardiomyopathy may also involve the cardiac ECM. In patients undergoing aortocoronary bypass surgery for chronic ischemic cardiomyopathy, segments with functional recovery had higher levels of tenascin-C, associated with a more cellular interstitium.226 In contrast, myocardial segments exhibiting reduced interstitial activity, evidenced by lower levels of matricellular proteins, reduced numbers of inflammatory leukocytes and more mature collagen, did not recover function following revascularization.226,342 Thus, an active, highly cellular interstitial environment, enriched in matricellular proteins and capable of transducing growth factor responses may be required for structural and functional recovery of chronically ischemic fibrotic myocardial segments.

    ECM in Diabetes Mellitus-Associated Heart Failure

    Diabetes mellitus, obesity, and metabolic dysfunction are associated with progressive expansion of the interstitial or perivascular ECM in experimental animal models271 and in human patients.343 The cellular basis of diabetes mellitus-associated fibrosis remains poorly understood,344 as studies exploring cell-specific actions in vivo are lacking. Oxidative stress, generation of AGEs (advanced glycation end products), neurohumoral activation, ET-1 induction, adipokine secretion, and stimulation of proinflammatory cascades in response to metabolic dysregulation may directly activate cardiac fibroblasts, promoting a matrix-synthetic phenotype. Induction of matricellular proteins, such as TSP-1, is prominent in diabetic hearts201,345 and may contribute to activation of TGF-β signaling, directly activating cardiac fibroblasts. Despite evidence suggesting local TGF-β activation,346 diabetes mellitus-associated cardiac fibrosis may not involve myofibroblast conversion.271 Macrophages, cardiomyocytes, vascular endothelial cells, and pericytes may also acquire a fibrogenic program, secreting growth factors, and stimulating fibroblast-derived ECM synthesis. AGE-induced cross-linking of the collagenous ECM in vessels and myocardium may reduce vascular compliance and increase myocardial stiffness.347

    In human patients, obesity, diabetes mellitus, and metabolic dysfunction markedly increase the risk of HFpEF, independently of the coronary artery disease.348,349 Clinical studies have identified a distinct obesity-related phenotype of human HFpEF,350 associated with increased plasma volume, more severe concentric left ventricular hypertrophy and greater right ventricular dilatation, despite lower plasma levels of natriuretic peptides.350,351 Microvascular inflammation in obese diabetic subjects may stimulate fibrogenic signaling,26,352 promoting ECM expansion and collagen cross-linking, and significantly contributing to diastolic dysfunction.26 Considering the perturbations in cardiomyocyte and vascular cell phenotype and function typically associated with diabetes mellitus,353,354 to what extent fibrogenic actions and ECM remodeling contribute to diastolic dysfunction and adverse outcome in diabetic patients remains unclear.

    ECM in Age-Associated Cardiac Dysfunction

    Studies in both human subjects and animal models have consistently documented perivascular and interstitial accumulation of collagen in senescent hearts.104,355,356 Some studies have suggested that age-associated fibrosis may reflect attenuation of matrix degradation due to a reduction in MMP synthesis, rather than accentuated collagen transcription.357–360 Increased collagen cross-linking may also contribute to fibrosis in aging hearts, by reducing the susceptibility of the interstitial ECM to protease-mediated degradation.361

    Aging-associated fibrosis may have important functional consequences. Aging is typically associated with a decline in diastolic function and reduced exercise capacity in the absence of significant effects on systolic function at rest. Deposition of cross-linked collagen fibers may reduce myocardial compliance, contributing to the pathogenesis of HFpEF in elderly subjects. However, because aging also affects cardiomyocyte relaxation properties, the relative contribution of interstitial ECM changes in the pathogenesis of senescence-associated diastolic dysfunction remains poorly documented. Myocardial deposition of ECM proteins may also account for the increased prevalence of conduction defects and arrhythmic events in older patients.

    The mechanisms responsible for aging-associated cardiac fibrosis remain poorly understood. Activation of neurohumoral pathways, chronic low-level induction of proinflammatory mediators, activation of TGF-βs and other fibrogenic mediators, reactive oxygen species generation, and downmodulation of protective antifibrotic signals have been implicated in activation of a fibrotic response in the aging heart.362 However, the fundamental link between aging and activation of a fibrogenic program remains unclear, and most of the evidence implicating specific mediators is associative.

    ECM in Genetic Cardiomyopathies

    Monogenic cardiomyopathies caused by single pathogenetic mutations account for a relatively small proportion of heart failure patients.363 It is unclear whether certain mutations can cause heart failure through primary activation of a fibrogenic program in cardiac interstitial cells. In postmortem autopsies of young patients dying from sudden cardiac death, primary cardiac fibrosis (defined as myocardial fibrosis in the absence of identifiable causes, or known cardiomyocyte pathology) is commonly found.364 However, in many of these cases, genetic analysis identified cardiomyocyte-specific gene mutations,365 suggesting that fibrosis may not be triggered through primary activation of interstitial cells, but may reflect actions of cardiomyocyte-derived fibrogenic signals. In a recent study, subjects with a frameshift mutation of SEPRINE1, the gene encoding PAI (plasminogen activator inhibitor)-1, exhibited primary cardiac fibrosis, attributed to the release of cardiomyocyte-derived TGF-β.366 In the much more common genetic conditions associated with dilated cardiomyopathy367 or hypertrophic cardiomyopathy,368,369 interstitial fibrotic changes have been extensively documented and are associated with worse prognosis.369 Transgenic mice recapitulating the human disease also exhibit substantial interstitial fibrosis.370,371 In most monogenic cardiomyopathies, heart failure is due to primary alterations in myofilament function. Traditional concepts have suggested that interstitial cell activation and ECM perturbations may simply represent an epiphenomenon, reflecting increased hemodynamic loads, or responses to primary cardiomyocyte injury. However, recent evidence from mouse models of genetic cardiomyopathies has challenged the notion that ECM remodeling is an innocent companion. In transgenic mouse models of hypertrophic cardiomyopathy, myofibroblast-specific disruption or pharmacological inhibition of TGF-β signaling reduced myocardial fibrosis, prolonged survival, and preserved cardiac function.372,373 These observations may suggest that activation of a fibrogenic program may exacerbate dysfunction and worsen outcome in subjects with sarcomeric mutations.

    Patients with arrhythmogenic right ventricular cardiomyopathy develop arrhythmias, associated with expansion and activation of fibroadipocyte populations, ECM deposition, and fatty infiltration.33,374–377 Experimental evidence suggests that in subsets of arrhythmogenic right ventricular cardiomyopathy patients, fibrofatty infiltration may be triggered by primary phenotypic alterations of interstitial cells. Genetic analysis has identified mutations in genes encoding desmosome proteins (including plakophilin-2, desmoplakin, and desmoglein-2) in many arrhythmogenic right ventricular cardiomyopathy patients.378–380 In mice, loss of desmoplakin in a subset of fibroadipocyte-like interstitial cells triggered adipocyte differentiation through modulation of Wnt-dependent signaling.381,382 To what extent these cells act by remodeling the cardiac ECM is unknown. In other cases, fibrosis may reflect activation of a fibrogenic program in cardiomyocytes.383 Thus, the cellular basis of ECM remodeling in arrhythmogenic right ventricular cardiomyopathy remains unclear.

    ECM Modulation in Heart Failure Therapeutics

    Because of its important role in preserving cardiac geometry and function, its ubiquitous presence in the microenvironment of all cell types, and its crucial involvement in regulation of cellular responses in myocardial remodeling, the ECM is an attractive therapeutic target in heart failure. In fact, some of the established therapeutic approaches for heart failure patients may act, at least in part by targeting the ECM. ACE inhibition, AT1R blockade, β-adrenergic receptor antagonism, and mechanical unloading modulate deposition and metabolism of the ECM in human patients with heart failure.341,384 Whether the effects of these interventions on the ECM are causally implicated in mediating their protective actions remains unknown. Emerging concepts suggest that targeting the cardiac ECM may hold promise to prevent adverse remodeling in both ischemic and nonischemic cardiomyopathy, and to attenuate diastolic dysfunction in HFpEF patients. Moreover, some experimental studies have suggested that the cardiac ECM may hold the key to the visionary goal of myocardial regeneration.

    ECM Modulation to Preserve Geometry and Function of the Failing Infarcted Heart

    In the remodeling infarcted heart, tight regulation of ECM deposition and cross-linking may protect from dilative remodeling and from the development of heart failure, while preventing overactive fibrosis and diastolic dysfunction. Experimental evidence suggests that an optimal balance of matrix-synthetic and matrix-degrading pathways is needed. Excessive accumulation of cross-linked collagenous ECM increases myocardial stiffness and promotes diastolic dysfunction. On the contrary, overactivation of MMP-driven proteolysis may promote dilative remodeling, causing systolic dysfunction. The major therapeutic challenge for implementation is to achieve the optimal balance of matrix metabolism for every patient at risk for postinfarction heart failure. Considering the pathophysiological heterogeneity of postinfarction remodeling, use of biomarkers and imaging strategies to measure ECM composition and metabolism is needed to stratify the patients385 and to identify candidates for specific interventions. Individuals with overactive profibrotic responses may benefit from antifibrotic strategies targeting ECM deposition or cross-linking. On the contrary, other patients may exhibit a predominant proteolytic environment in the infarcted heart and may require strategies that restore the ECM network increasing tensile strength of the infarct. Findings suggesting age-associated defects in growth factor responses and in ECM deposition following MI386 may suggest that in the elderly, measures to improve the reparative reserve may be more appropriate.

    Targeting the Cardiac ECM in HFpEF

    The association between collagen deposition and myocardial stiffness in HFpEF patients is well-established.387 Although inhibition of cardiac fibrosis seems an attractive therapeutic approach for HFpEF patients, implementation is hampered by several concerns. First, in contrast to fibrotic conditions in other systems (such as idiopathic pulmonary fibrosis or scleroderma), cardiac fibrosis is not a primary pathological condition and often reflects activation of a reparative program in an organ that lacks effective regenerative capacity. It is difficult to establish a causative relation between ECM deposition and adverse outcome in human patients with HFpEF. Although fibrosis changes in HFpEF have clear and consistent adverse prognostic implications, these associations may represent an epiphenomenon, reflecting worse outcome in subjects with worse primary cardiomyocyte injury. Interstitial cells are heterogeneous and have a wide range of functions. The reparative actions of cardiac myofibroblasts are obvious in MI60; however, even in models of noninfarctive cardiac fibrosis that may recapitulate some features of human HFpEF, protective actions of cardiac myofibroblasts have been demonstrated.30 Second, human HFpEF is pathophysiologically heterogeneous. Extensive biomarker-driven stratification may be required to identify subjects exhibiting overactive fibrotic responses that may be responsible for dysfunction and heart failure.388 Third, the reparative functions of fibroblasts and the need to preserve and repair injury-related perturbations of the ECM network may limit chronic implementation of antifibrotic strategies. Even if patient subsets with inappropriate chronic myocardial ECM deposition are identified, the need for continuous administration of agents that attenuate fibroblast activation may carry significant risks, by abrogating essential reparative responses. Ultimately, success or failure of antifibrotic strategies in the heart will need to be tested in carefully designed clinical investigations.

    Matricellular Targets in Failing Hearts

    The biology of the matricellular proteins may suggest attractive strategies to modulate adverse remodeling in failing hearts. Experimental studies have demonstrated that members of the matricellular family (such as TSP-1 and SPARC) may protect the failing heart from adverse remodeling and dysfunction.185,199,202,237 Matricellular proteins are multidomain molecules that regulate cellular responses through outside-in signaling. Thus, identification of specific domains responsible for the protective effects of matricellular proteins could lead to development of peptide-based approaches that reproduce these effects and localize protective signaling in the area of interest. Unfortunately, therapeutic implementation of such approaches is hampered by the daunting complexity and contextual actions of matricellular proteins that may be dependent on the profile of the interstitial cellular infiltrate, the composition of the ECM, and the cytokine and growth factor milieu.

    Can Manipulation of the ECM Promote Cardiac Regeneration?

    Despite intriguing early findings, regeneration of the adult heart remains an unfulfilled promise. In vitro studies, the role of the ECM in embryonic cardiac development, and in vivo experiments in amphibian or fish models and in neonatal mice suggest that the composition of the ECM may play a critical role in activation of a regenerative program in the myocardium. First, in vitro, ECM composition profoundly affects cell cycle entry in cardiomyocyte progenitors and in neonatal cardiomyocytes.389,390 Second, in zebrafish, genetic ablation of matrix-producing fibroblasts or Fn loss impaired the myocardial regenerative response.391,392 Clearly, gaining translationally relevant insights from fish models is a major challenge. Despite the abundant presence of myofibroblasts and high expression of Fn mammalian infarcts do not remuscularize, suggesting that ECM- and fibroblast-dependent actions may not be sufficient to activate a regenerative program. Third, some experimental studies in mammals have suggested that matricellular macromolecules may trigger proliferation of neonatal and even adult cardiomyocytes. Agrin, a large extracellular heparan sulfate proteoglycan, has been suggested to serve as an essential component of the regenerative neonatal ECM, promoting cardiomyocyte cell cycle reentry in both neonatal and adult mice.393 Moreover, periostin triggered cell cycle reentry in differentiated adult cardiomyocytes in an integrin-dependent manner, and when administered as an epicardial gelfoam patch following infarction, improved cardiac function, and attenuated cardiac remodeling.280 Considering known biology on the challenges and complexities of myocardial regeneration, the notion that a single matrix macromolecule can remuscularize the adult mammalian heart is not plausible. For example, the idea that periostin can regenerate the heart is challenged by the abundance of periostin in the infarcted mouse myocardium in the absence of regeneration, and by the lack of regenerative capacity in infarcted periostin-overexpressing mice.282 Despite some promising early findings, whether modulation of the ECM profile in failing hearts could be used to facilitate activation of a regenerative program remains unknown. Clearly, any attempt to remuscularize the heart would require a matrix environment that supports proliferating cardiomyocytes, or cardiomyocyte progenitors, and promotes syncytial function. Studies demonstrating the role of YAP (Yes-associated protein) signaling in neonatal heart regeneration highlight the requirement for molecular links between the ECM and the cardiac cytoskeleton.394,395 However, a regenerative ECM profile is unlikely to be sufficient to trigger formation of new myocardium, a process that may also require activation of an endogenous regenerative program by cardiomyocytes and vascular cells.

    Matrix-Driven Strategies to Engineer a Bioartificial Heart

    Recent technological advances in perfusion-decellularization strategies have generated decellularized cardiac matrices that may serve as scaffold to engineer cardiac grafts.396–398 Subsequently, the matrices can be repopulated with induced pluripotent stem cell-derived cardiomyocytes to generate structures resembling human myocardium. This technology is at an early stage. Although tissue constructs with definitive sarcomeric structure, contractile function and electrical conduction have been generated,399 several major challenges remain that currently preclude clinical translation. Coagulation dysfunction due to incomplete re-endothelialization and subsequent activation of the coagulation system, the absence of functional valvular structures, the lack of a conduction system for transmission of electrical activity, and the potential for immunogenicity and inflammatory activation are major limiting factors of this intriguing strategy. Despite these challenging problems, this approach may represent the first step towards the generation of functional bioartificial cardiac grafts.


    The myocardial ECM network contributes to cardiac homeostasis, not only by providing structural support, but also by facilitating force transmission and by transducing molecular signals that regulate cell phenotype and function. In failing hearts, expansion of the cardiac interstitium, induction of both structural and matricellular ECM proteins, generation of bioactive matrix fragments, and alterations in matrix biochemistry may play a critical role in regulating inflammatory, reparative, fibrotic, angiogenic, and even regenerative responses. Thus, the cardiac ECM is a key regulator of cardiac remodeling both through effects of its structural constituents on the mechanical properties of the heart and through regulation of cellular responses. Dissecting the mechanistic contributions of ECM macromolecules in cardiac remodeling is critical for understanding the pathogenetic basis of heart failure in both ischemic and nonischemic cardiomyopathy. Moreover, systematic characterization of the biochemical profile of ECM proteins in patients with myocardial disease is needed to identify perturbations associated with human heart failure.

    Nonstandard Abbreviations and Acronyms


    α-smooth muscle actin


    angiotensin-converting enzyme


    a disintegrin and metalloproteinase


    a disintegrin and metalloproteinase with thrombospondin motifs


    advanced glycation end products


    angiotensin II type 1 receptor


    angiotensin II type 2 receptor


    bone morphogenetic protein


    Ca2+/calmodulin-dependent protein kinase II


    chondroitin sulfate proteoglycans


    dermatan sulfate proteoglycans


    extracellular matrix


    extra domain A




    focal adhesion kinase


    fibroblast growth factor




    heart failure with preserved ejection fraction




    lysyl oxidase


    latent TGF-β–binding protein


    mitogen-activated protein kinase


    myocardial infarction


    matrix metalloproteinase


    myocardin-related transcription factor


    plasminogen activator inhibitor-1


    procollagen C-endopeptidase enhancer-2


    Ras homolog gene family, member A


    Rho-associated protein kinase


    small leucine-rich proteoglycans


    secreted protein acidic and rich in cysteine




    transforming growth factor


    tissue inhibitor of metalloproteinases


    tumor necrosis factor


    transient receptor potential cation channel subfamily V member 4




    Yes-associated protein


    Correspondence to Nikolaos G. Frangogiannis, MD, The Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, 1300 Morris Park Ave, Forchheimer G46B, Bronx, NY 10461. Email


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