Collagens are the most abundant and well-studied ECM proteins in the heart (Eghbali and Weber, 1990; Ricard-Blum, 2011). They are deposited in the ECM and play structural roles contributing to mechanical properties, organization, and shape of tissues (Eghbali and Weber, 1990; Ricard-Blum, 2011; Villarreal and Dillmann, 1992). They interact with cells via several receptor families and regulate their proliferation, migration, and differentiation (Ricard-Blum, 2011).

Proteoglycans are complex molecules composed of a core protein and long chains of glycosaminoglycans (GAGs) (Hynes and Naba, 2012; Rienks et al., 2014). They play essential roles in the ECM, contributing to tissue structure, cell signaling, and various physiological processes. In the myocardium, proteoglycans are crucial for maintaining the structural integrity of the cardiac ECM and influencing cell behavior (Hynes and Naba, 2012; Wang et al., 2019). The expression of proteoglycans in the myocardium is tightly regulated and can be influenced by various physiological and pathological conditions (Wang et al., 2019; Barallobre-Barreiro et al., 2021). In cardiac diseases such as myocardial infarction or heart failure, alterations in proteoglycan expression and remodeling of the ECM occur, impacting cardiac function. While not specific to HCM, proteoglycans expression has been reported to change in the aging heart, and some of the principles may apply to cardiac diseases (Christensen et al., 2019; Silva et al., 2020).

Hyalectans: Versican: a large chondroitin sulfate proteoglycan (CSPG) involved in tissue morphogenesis and inflammation (Sasi et al., 2023). It has been identified in the heart, where it influences cell adhesion and migration and has been known to be the major CSPG in the heart (Barallobre-Barreiro et al., 2021). It has recently been reported that versican is expressed after induction of pressure overload in mice, preceding collagen accumulation, particularly in collagen expressing CFs in transforming growth factor beta-dependent pathway (Sasi et al., 2023). Further, versican appeared to increase in the heart of HCM patients in conjunction with collagen increase, which suggests an involvement in the cardiac fibrosis (Previs et al., 2022; Sasi et al., 2023). Aggrecan: a large proteoglycan that forms giant hydrated aggregates with hyaluronan in the ECM is present in the heart and present in cardiac jelly, developing heart valves, and blood vessels during cardiovascular development, and contributes to the resilience and mechanical loading of the tissue (Krawetz et al., 2022). Mice with mutant aggrecan have been reported to have HCM (Koch et al., 2020). Further, Wistar rats undergone aortic banding, exhibited an increase in aggrecan mRNA, along with versican and other proteases (Vistnes et al., 2014). Aggrecan has also been reported for its overexpression in the aneurysmal aortic walls, increasing interlamellar swelling pressure, and disorganizing the aortic wall’s microstructure (Barallobre-Barreiro et al., 2020), which is has recently been reported to be associated with HCM (Ibrahim et al., 2022b). BM proteoglycans: Perlecan: A heparan sulfate proteoglycan, found in the BM and participates in cell-matrix interactions and helps regulate growth factor activities (Sasse et al., 2008; Johnson et al., 2024). Altered expression of Perlecan has been observed in cardiac diseases, including HCM, where it may contribute to abnormal cell-matrix interactions and affect growth factor signaling (Johnson et al., 2024). Perlecan null mice, had a severe effect on laminin and collagen IV, components of BM, compared to controls, and further exhibited a more severe dysfunction upon myocardial infarction, due to impaired BM composition and cardiomyocytes crosstalk with surrounding stroma and ECM (Sasse et al., 2008). Of interest, human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) cultured on a Perlecan substrate have exhibited hypertrophy and show heightened nucleation, characteristic of hypertrophic growth (Johnson et al., 2024). Interestingly, Perlecan appears to exert an opposing influence compared to Agrin, fostering cellular maturation instead of hyperplasia and proliferation (Johnson et al., 2024).

Cell membrane proteoglycans: Syndecan: Syndecans are a family of transmembrane heparan sulfate proteoglycans that play important roles in the myocardium, contributing to various cellular processes and tissue functions, such as Cell-ECM interaction, signal transduction, regulating CMs function, angiogenesis and tissue repair and remodeling (Lunde et al., 2016). Syndecans, particularly syndecan-4, are also involved in cardiac development, where they regulate signaling pathways involved in heart development, including Wnt, FGF, and BMP signaling (Mathiesen et al., 2019). A recent investigation into syndecan-4 underscored its significance in triggering the Ca²⁺-dependent calcineurin-NFAT signaling pathway, leading to hypertrophic remodeling and dysfunction in CMs under pressure overload conditions (Mathiesen et al., 2019; Lunde et al., 2022). Additionally, syndecan-4 has been reported to mediate muscle LIM protein nuclear translocation in CMs, a mechanism associated to HCM and dilated cardiomyopathy (DCM) (Mathiesen et al., 2019). Further, mice lacking syndecan-4 exhibited less collagen cross linking and fibrosis (Herum et al., 2015; Finsen et al., 2011), and further exhibited diminished capillary density, reduced cardiomyocyte size, and deteriorated left ventricular cardiac function following transverse aortic constriction (Li et al., 2017). Further, Syndecan‐4 was found to bind to osteopontin in LV and CFs protecting over deposition of collagen fibers (Herum et al., 2020). Interestingly, serum syndecan-4 has been shown potential as a new diagnostic and prognostic biomarker for LV remodeling in failing hearts (Takahashi et al., 2011).

Small Leucine Rich proteoglycans: Decorin is a small leucine-rich proteoglycan is expressed in the heart and is involved in collagen fibrillogenesis and interacts with various growth factors (Merline et al., 2009). Decorin has been suggested to induce cardiac hypertrophy by regulating the CaMKII/MEF-2 signaling pathway (Yang et al., 2021). However, other reports showed that Decorin overexpression can inhibit hypertension-induced cardiac fibrosis and hypertrophy and improved cardiac function (Yan et al., 2009), and can further inhibit TGF-β pathway and its pro-fibrotic effects on the failing human heart (Yan et al., 2009; Jahanyar et al., 2007), which makes it a potential candidate in HCM pathogenesis. Lumican (LUM) is a keratan sulfate small leucine-rich proteoglycan (SLRP) localized to the ECM, and known to regulate collagen fibrillogenesis in connective tissues, e.g., cornea, tendon and skin (Nikitovic et al., 2008). LUM is abundant in fibrotic tissues including the thickened intima of human atherosclerotic coronary arteries and is present in the developing myocardium (Mohammadzadeh et al., 2019; Hultgårdh-Nilsson et al., 2015). It has previously shown that LUM levels are increased in hearts of mice and patients with heart failure, via mediation cardiac remodeling, fibrosis, and inflammation (Mohammadzadeh et al., 2019; Mohammadzadeh et al., 2020), and accumulates with collagen fibers during HCM (Rixon et al., 2023). Proteomic analysis of myocardial specimens of HCM patients has shown that LUM is upregulated, correlating with the left atrial area myocardial fibrosis and the presence of a pathogenic sarcomere mutation (Coats et al., 2018), however this expression is yet debatable whether it could have a cardio-protective function (Guo et al., 2023).

Fibronectin (Fn) is a glycoprotein found in the ECM of tissues and plays a crucial role in various cellular processes, such as cell adhesion, migration, and signaling (Früh et al., 2015). In the myocardium, Fn contributes to the structural integrity of the ECM and participates in the regulation of cardiac development, remodeling, and repair (Talman and Ruskoaho, 2016). During embryonic development, Fn is expressed in the developing heart, where it contributes to the formation of the cardiac ECM (Jallerat and Feinberg, 2020). In adult myocardium, Fn is present in the ECM of the normal adult myocardium, where it forms a network that interacts with other ECM components, including collagen and proteoglycans (Chute et al., 2019). It further serves as a substrate for cell adhesion, allowing cells to attach and interact with the ECM via integrins and BM proteins (Farhadian et al., 1996). In response to cardiac injury, Fn expression can be upregulated in the myocardium in association with collagen deposition and TGF-beta 1 signaling (Villarreal and Dillmann, 1992; Wi et al., 1991). During myocardial fibrosis, there may be an excessive deposition of Fn as part of the fibrotic response (Piek et al., 2016). It has been reported that Fn contributes to pathological cardiomyocyte hypertrophy in vitro and in vivo via Nuclear Factor of Activated T cells activation (Konstandin et al., 2013) or via integrin beta 1-dependent activation (Chen et al., 2005). Further, Fn signaling is thought to stimulate BNP secretion, a gold standard indicator of HCM and cardiac fibrosis (Hasegawa et al., 1993), accompanied by hypertrophic responses in vitro (Ogawa et al., 2002). Of interest, circulating levels of fibronectin have been reported to be reduced in patients with HCM (Fucikova et al., 2016; Moretti et al., 2007), which raises the question of whether Fn in the circulation correlates to the myocardial expression in HCM.

Laminin (LN) is an essential component of the BM providing the integrity and function of CMs and blood vessels within the heart (Oliviéro et al.). It also contributes to the structural framework of the myocardium, specifically in anchoring CMs to the ECM, facilitating cell-to-cell communication, and contributing to the overall mechanical stability for cardiac tissues homeostasis (Oliviéro et al., 2000; Schwach and Passier, 2019). In hypertrophied CMs, LN was thought to contribute to alterations in sarcolemmal properties (Oliviéro et al., 2000), and its deficiency can lead to malformation in the myocardial microvasculature and subsequent ischemia, represented in elevated levels of hypoxia-inducible factor 1α (Hif1α) and vascular endothelial growth factor A (VEGFA) transcripts (Wang et al., 2006). Of note, mutation in the laminin alpha4 chain results in an abnormal myocardial ECM and subsequent muscle hypertrophy (Wang et al., 2006).

Fibulins (FBLNs) are a family of glycoproteins involved in ECM assembly and stabilization in different biological systems (Timpl et al., 2003). The widespread distribution of FBLNs correlates with their broad binding repertoire for fibronectin, collagens, BM proteins, elastin and proteoglycans (Timpl et al., 2003; Argraves et al., 2003). FBLN 1 and 2 are highly expressed in migratory cardiac mesenchymal during cardiac valvular septal formation (Argraves et al., 2003; Cooley et al., 2008), which dragged attention to their role in cardiac development and further in pathological conditions such as HCM. While research on FBLNs in HCM is not extensive, recent reports indicated that FBLN2 plays an essential role in Ang II-induced TGF-β signaling and subsequent myocardial fibrosis (Khan et al., 2016). FBLN4 was reported to be crucial for elastic fiber formation (Halabi et al., 2017), and mutations in the FBLN4 gene have been associated with aortic aneurysms and dissections (Loeys et al., 2005). FBLN5 is also involved in elastic fiber assembly and is expressed in various tissues, including the heart (Chapman et al., 2010; Wang et al., 2005). Knowledge on FBLN5 in the context of HCM specifically is limited, nonetheless, its role in ECM maintenance suggests potential implications for cardiac remodeling (McLaughlin et al., 2007). Of interest, we recently reported that CF-associated transcriptomics signature comprised upregulation of FBLN1 and FBLN5 genes, which was further confirmed in the tissues of HCM patients (Ibrahim et al., 2020a). We further reported that FBLN2, which has common binding partners with FBLN1 and FBLN5, is upregulated in the CMs and the circulation of HCM patients, however, protein expression in CFs did not significantly change; an observation that was further confirmed by our generated transcriptome signature of HCM-CFs (Ibrahim et al., 2020a). Further, it has been suggested that FBLN5 modulate TGF-β signaling, a pathway implicated in tissue fibrosis and remodeling (Nakasaki et al., 2015), hallmarks of HCM. It has also been reported that FBLNs 1, 2 and 5 are reduced in the aorta of HCM patients, in association with an increase in aortic stiffness, which introduce FBLNs as targets for cardiac and extra-cardiac tissues (Ibrahim et al., 2022b).

Periostin is a member of the glycoprotein family (Stansfield et al., 2009). Studies have indicated the significant involvement of periostin in fostering collagen fibrogenesis and promoting a fibroblastic lineage during the maturation of atrioventricular valves in cardiac development (Norris et al., 2008; Norris et al., 2009). While its expression remains low in adult hearts, periostin is crucial for maintaining the biomechanical characteristics of mature myocardium (Kühn et al., 2007). Periostin has been shown to correlate and contribute to cardiac remodeling and fibrosis in overloaded hearts and heart failure (Zhao et al., 2014; Ioakeimidis et al., 2023). Interestingly, periostin has been shown to mediate the AngII via ERK1/2 and TGF-β1/Smad signaling (Li et al., 2011). Nevertheless, some reports showed that periostin might be involved in the transdifferentiation of CMs leading to cardiac repair (Kühn et al., 2007). The distribution and expression patterns of periostin, which correlated with the degree of myocardial fibrosis, could serve as a potential biomarker for cardiac remodeling in patients with HCM heart failure (Zhao et al., 2014).

Tenascin-C (TNC) is a glycoprotein categorized as a matricellular protein and exhibits transient expression patterns at various crucial stages of embryonic heart development (Imanaka-Yoshida et al., 2020; Tucker and Chiquet-Ehrismann, 2009). In the normal adult heart, its presence is minimal, yet under pathological conditions linked to inflammation, such as myocardial infarction, hypertensive cardiac fibrosis, myocarditis, dilated cardiomyopathy, and Kawasaki disease, TNC is re-expressed in a spatially and temporally confined manner (Imanaka-Yoshida et al., 2020; Tucker and Chiquet-Ehrismann, 2009). It has recently been reported that upon myocardial infarction, interstitial cells located in the border zone begin producing TNC serving to weaken the adhesion between surviving CMs and ECM, potentially facilitating the reorganization of the tissue (Imanaka-Yoshida et al., 2001). TNC has also demonstrated the ability to induce inflammatory reactions by hastening the migration of macrophages and the production of proinflammatory and profibrotic cytokines through the integrin αVβ3/FAK-Src/NF-κB pathway, leading to an increased fibrosis (Shimojo et al., 2015). TNC has been reported to prompt cardiac myocytes to enhance the activation of genes linked to hypertrophy and MMPs (Podesser et al., 2018). Conversely, removing TNC could lessen the inflammatory and fibrotic changes, as well as hypertrophy, and diminish contractile dysfunction in hearts undergoing TAC (Podesser et al., 2018). Of interest, serum TNC has shown a prognostic power in HCM patients (Kitaoka et al., 2012).

MMPs are enzymes responsible for collagen degradation, while TIMPs inhibit MMP activity (Nagase et al., 2006). The balance between MMPs and TIMPs influences collagen turnover (Spinale, 2007; Cambronero et al., 2009). Of the known MMPs in the myocardium are: MMP-1 and MMP-8, which are involved in the degradation of type I and type III collagens (which are classical major components of the myocardial fibrillar collagen and interstitial fibrosis) (Takahashi et al., 1999). MMP-2 (Gelatinase A), which is involved in the degradation of type IV collagen (Spinale, 2007), MMP-9 (Gelatinase B), which is involved in the degradation of type IV collagen and is associated with tissue remodeling and inflammatory processes (Yabluchanskiy et al., 2013), MMP-3 (Stromelysin-1), which participates in the breakdown of fibronectin and laminin (Rodríguez et al., 2010), MMP-13 (Collagenase-3), which targets type II collagen (Takahashi et al., 1999; Uesugi and Sakata, 2005), and MMP-14 (MT1-MMP), which plays a crucial role in ECM remodeling and activates other MMPs, contributing to tissue homeostasis (Nagase et al., 2006). In pathological cardiac remodeling, a group of MMPs such as MMP-2 and MMP-9, are upregulated, leading to increased ECM degradation and subsequent fibrosis (Roldán et al., 2008; Takawale et al., 2017). and their levels in plasma were associated to NT-proBNP levels and further related to clinical parameters such as LV ejection fraction, LV end-diastolic dimension, exercise capacity and the maximum LV wall thickness (Roldán et al., 2008; Kitaoka et al., 2011; Bi et al., 2021). Although MMPs have been associated with myocardial fibrosis, MMP1 has been reported to attenuate the development of cardiac fibrosis in mouse models (Foronjy et al., 2008), however other studies reported the increase of circulating MMP1 levels in HCM patients (Fernlund et al., 2017). Therefore, understanding the pathophysiology mechanisms of MMPs, and cell-specific MMPs and (Ibrahim et al., 2022a; Toba et al., 2017), is crucial for identifying personalized targeting approaches.

TIMPs, on the other hand, act as inhibitors and regulators of MMPs (Nagase et al., 2006). TIMP-1, is a broad-spectrum inhibitor of MMPs and primarily inhibits MMP-1, MMP-2, MMP-3, and MMP-9 (Brew and Nagase, 2010), TIMP-2, inhibits a range of MMPs, including MMP-1, MMP-2, MMP-3, and MMP-9 and is also involved in regulating cell growth and apoptosis (Stetler-Stevens and on, 2008), TIMP-3, has a broader inhibitory profile, affecting MMP-1, MMP-2, MMP-3, MMP-9, and ADAMs (a disintegrin and metalloproteinases), and plays a crucial role in maintaining tissue integrity and inhibiting angiogenesis (Brew et al., 2000), and TIMP-4 inhibits MMP-2 and MMP-9 and plays a role in modulating tissue responses to injury and inflammation (Cabral-Pacheco et al., 2020). Circulating TIMP1 and TIMP2 were reported to be increased in HCM, in association with LV end‐systolic dimension, Left atrium dimension, and LV ejection fraction (Kitaoka et al., 2010). Of interest, a recent study has shown that TIMP1 deficiency have significantly reduced myocardial fibrosis via meditating an association between CD63 (cell surface receptor for TIMP1) and integrin β1 on CFs, leading to de novo collagen synthesis, reducing myocardial fibrosis, independent from MMPs (Takawale et al., 2017).

Besides, ADAMs are membrane-anchored proteins that mediate ectodomain shedding of substrate proteins, and play diverse roles in the normal myocardium, including cell adhesion, proteolysis, and signaling, however, their exact role requires further investigation (Weber and Saftig, 2012). ADAM12 for instance, mitigates the excess hypertrophic response by attenuating integrin-mediated downstream signaling (Nakamura et al., 2020).

Further, activation of protease-activated receptors (PARs) by proteases, such as thrombin, has been implicated in cardiac hypertrophy (Antoniak et al., 2011). PARs may contribute to signaling pathways that influence hypertrophic responses (Antoniak et al., 2011).

Cytokines are small signaling proteins that play crucial roles in the regulation of immune responses, inflammation, tissue repair, remodeling, and adaptation to various physiological stimuli (Hanna and Frangogiannis, 2020). While the heart is traditionally viewed as an organ with limited immune activity, it does produce and respond to certain cytokines under healthy conditions (Hanna and Frangogiannis, 2020; Mann, 2015). In physiological conditions, the myocardium maintains a balanced and regulated environment, and the expression of cytokines is generally at low levels (Fang et al., 2017). In HCM however, pro-inflammatory cytokines are elevated, contributing to fibrosis and ECM alterations, which has been suggested to compose a chronic “low grade” inflammatory microenvironment (Hanna and Frangogiannis, 2020; Lillo et al., 2023). Interleukin-10 (IL-10) and IL-1β are pro-inflammatory cytokines that are involved in immune responses and inflammation (Xu et al., 2021). In physiological conditions, their expression in the heart is generally low, only sufficient to help regulate immune responses and reduce inflammation (Xu et al., 2021). In HCM, IL-10 may play a protective role by modulating inflammatory responses and attenuating myocardial remodeling (Sziksz et al., 2015). IL-1β is involved in inflammatory responses and may contribute to the progression of cardiac hypertrophy in HCM (Schwinger et al., 1994).

TGF-β is a multifunctional cytokine involved in maintaining tissue integrity and preventing excessive inflammation in the myocardium (Hanna and Frangogiannis, 2019). In HCM, TGF-β signaling has been long known for its upregulation in experimental models of myocardial infarction and cardiac hypertrophy (Frangogiannis, 2020; Teekakirikul et al., 2010). Endogenous TGF-β plays a crucial role in the development of cardiac fibrotic and hypertrophic remodeling, as well as in regulating ECM metabolism in the pressure-overloaded heart (Frangogiannis, 2020). TGF-β deactivates inflammatory macrophages while facilitating myofibroblast transdifferentiation and ECM synthesis through Smad3-dependent pathways (Saadat et al., 2020). Consequently, TGF-β may function as the pivotal “master switch” orchestrating the transition from the inflammatory phase to scar formation in the infarcted heart (Rienks et al., 2014), and activate Angiotensin II signaling (via FBLN2 mediation) (Zhang et al., 2014) (Figure 3), all of which are hallmarks of HCM. Efforts aimed at translating these concepts into therapeutic approaches to mitigate cardiac hypertrophy and fibrosis face challenges due to the intricate, multifaceted nature of TGF-β signaling (Hanna and Frangogiannis, 2019). Concerns arise regarding the potential harmful effects of inhibiting TGF-β and the possibility of limited benefits for patients already receiving optimal treatment with ACE inhibitors and β-adrenergic blockers (Lim et al., 2001; D et al., 2011).

IL-6 has both pro-inflammatory and anti-inflammatory properties, and may contribute to normal physiological processes, such as the response to exercise and stress (Scheller et al., 2011). IL-6 has been associated with inflammation and cardiac hypertrophy in HCM and increased IL-6 levels may contribute to disease progression (Teekakirikul et al., 2010). IL-6 has been found to be essential in increasing collagen content regulated by isolated CFs and played a role in mediating a phenotypic conversion to myofibroblasts, via Angiotensin II induction (Meléndez et al., 2010). It has also been reported for its mediation to the Angiotensin II signaling during cardiac hypertrophy (Gro et al., 2019; Högye et al., 2004). Higher IL-6 levels in the both the myocardium and the circulation have been associated with larger infarct size and decreased cardiac function in HCM (Gro et al., 2019; Högye et al., 2004).

Tumor Necrosis Factor-Alpha (TNF-α) is a pro-inflammatory cytokine that is typically associated with immune responses and plays a role in adaptation to exercise (Jang et al., 2021). (Xu et al., 2021)TNF-α has been reported to contribute to myocardial dysfunction (Tian et al., 2015), with an association of higher expression along with IL6, with HCM (Sano et al., 2000). CMs-specific expression of TNF-α has shown to lead to LV hypertrophy (Schumacher and Naga Prasad, 2018), however, studies have shown contradiction of TNF-α effect based on its source (Miao et al., 2020; Yokoyama et al., 1997; Feldman et al., 2000). Of interest, inhibition of TNF-α reduces adverse myocardial remodeling in a rat model of volume overload (Jobe et al., 2009). Another recently studied interleukin in HCM is IL11, which is a member of the IL6 family, and its receptors are mainly expressed in CFs (Alter et al., 2023). In IL11-stimulated CFs, collagen, ECM remodeling components such as periostin and MMP2 are strongly upregulated at the protein level (Sweeney et al., 2020). Blocking of IL11 signaling with Lutein has recently been suggested to attenuate angiotensin II- induced cardiac remodeling and fibrosis (Chen et al., 2021) (Figure 3). As a biomarker, elevated plasma IL-11 levels have been associated with a notable rise in cardiac events and indicate a poor prognosis in HCM and heart failure patients (Ye et al., 2019). On the other hand, chemokines, such as monocyte chemoattractant protein-1 (MCP-1), play a role in recruiting immune cells to the heart during inflammation, which can subsequently impact ECM homeostasis (Sun et al., 2021). MCP-1/CCL2 is associated with the recruitment of monocytes and macrophages to the site of inflammation (Shen et al., 2014). Myocardial and circulating MCP1 levels have been reported to increase in HCM patients particularly in patients with systolic dysfunction (Iwasaki et al., 2009). MCP1-driven pro-inflammatory signaling may accentuate cardiomyocyte death and can mediate fibrosis upon recruiting monocytes and macrophages that secrete mediators, such as TGF-β (Hanna and Frangogiannis, 2020), a key driver in myocardial fibrosis in HCM (Ibrahim et al., 2020a). Of interest, in vitro experiments have revealed that a combination of IL-6 with MCP1 sustained STAT3 activation in CMs, promoting the differentiation of CFs into myofibroblasts under hypoxic conditions (Morimoto et al., 2006). In agreement, we have recently reported that CCL2 is overexpressed in HCM CFs and myocardium in association with IL6 and other pro-inflammatory drivers, such as CCL11 and CCL4 (Ibrahim et al., 2022a).

Osteopontin (OPN) is a matricellular protein that mediates diverse biological functions and functions as a proinflammatory cytokine promoting cell-mediated immune responses (Shirakawa and Sano, 2021). OPN has been implicated in the progression of fibrosis induced by Ang II (Mohamed et al., 2019; Matsui et al., 2004), a key driver of interstitial fibrosis in HCM (Zhang et al., 2014). It has exhibited interactions with diverse ECM proteins such as fibronectin and collagen, indicating its potential involvement in organizing and stabilizing the matrix structure (Matsui et al., 2004). Lack of OPN could potentially decrease the rise in blood pressure induced by Ang II and improve the progression of cardiac fibrosis (Matsui et al., 2004). It has therefore been suggested as a therapeutic target for HCM and heart failure for its role in cardiac fibrosis (Mohamed et al., 2019).

Fibroblast growth factors 2 and 16 (FGF2 and FGF16): FGFs are proteins that serve a variety of functions in the tissue development, repair, and metabolism (Itoh and Ornitz, 2008). FGF16 stands out among paracrine FGFs as it is predominantly expressed in cardiac tissue (Itoh and Ohta, 2013; Hotta et al., 2008). While FGF16 expression is relatively low in the embryonic heart, it becomes more abundant during adulthood compared to embryonic stages, which suggest potential roles for FGF16 in cardiac function (Tacer et al., 2010). A recent study on a mouse model, has shown that FGF16 prevents angiotensin II-induced cardiac hypertrophy and fibrosis by antagonizing FGF2 (Matsumoto et al., 2013). Further, deleting FGF2 attenuates muscle hypertrophy in adult mice (Schultz et al., 1999). We have recently reported CF-specific upregulation of FGF16 and downregulation of FGF2 in HCM patients. Nonetheless, the interplay between FGF16 and FGF2 in the cardiac tissue microenvironment is yet debatable and arise from their competition on FGFR to activate MAPK signaling and induce tissue remodeling (Itoh and Ohta, 2013).

Integrins: Integrins play several crucial roles in the myocardium, serving as key mediators of cell-cell and cell-ECM interactions (Ross and Borg, 2001). They can be expressed on either CFs or CMs, mainly for mediating the interaction between them and the ECM, particularly collagen (such as integrins α1β1, α2β1, α11β1) (Ross and Borg, 2001; Mezu-Ndubuisi and Maheshwari, 2020; Harston and Kuppuswamy, 2011). Integrins are also involved in Mechanical Signaling bidirectionally between the ECM and the intracellular cytoskeleton, which is essential for regulating cellular processes such as cell contraction, proliferation, and gene expression in response to changes in mechanical forces (Ross and Borg, 2001; Israeli-Rosenberg et al., 2014). Signal Transduction via activating intracellular signaling pathways in response to ECM ligands, for cell survival, proliferation, differentiation, and gene expression (Harston and Kuppuswamy, 2011; Ross, 2002). Angiogenesis via mediating the adhesion and migration of endothelial cells (ECs), which are essential for the formation of new blood vessels during myocardial development, tissue repair, and ischemic injury (Mezu-Ndubuisi and Maheshwari, 2020). Electrical Coupling between CMs and the ECM, contributing to the transmission of electrical signals between cells and modulating cardiac conduction properties (Valencik et al., 2006; Dabiri et al., 2012).

Several In vitro and in vivo models have studied the association of integrins with cardiac hypertrophy (Harston and Kuppuswamy, 2011). In the pathological myocardium, expression of the integrins isoforms is altered leading to alterations in CFs, the ECM and CMs, and in response to the mechanical stretch resulting from hypertrophy (Brancaccio et al., 2006). Integrin pathological signaling may result in the activation of myofibroblasts or the development of CM hypertrophy (Maitra et al., 200). Deletion of β1 integrin in mice has been reported to reduce myocardial proliferation and impaired ventricular compaction. (Maitra et al., 200).Interestingly, it has been recently reported that Integrin beta-like 1 is an important functional mediator between fibroblast–cardiomyocyte crosstalk and could be an effective target for cardiac remodeling in myocardial hypertrophy and HCM (Chen et al., 2023), particularly with its reported interaction with multiple ECM proteins during myocardial remodeling (Laser et al., 2000).

CFs represent the major non-cardiomyocyte cell lineage that maintain the myocardial homeostasis and ECM turnover (Travers et al., 2017). They are the primary cell type responsible for producing and regulating the majority of the known ECM components (Fan et al., 2012; Travers et al., 2017). CFs are the main source of collagen, particularly collagen types I and III (Verdecchia et al., 2012; Kanisicak et al., 2016). They also contribute to the synthesis of Fn, MMPs and TIMPs (Fan et al., 2012; Travers et al., 2017). During myocardial injury and HCM, CFs become activated, via mechanical and/or molecular signaling, and may differentiate to myofibroblasts, with an expression of smooth muscle actin (SMA), increased secretion of inflammatory mediators, and increased deposition of ECM proteins (Marian and Braunwald, 2017; Fan et al., 2012), which represent stress responses that aggravate heart diseases (Fan et al., 2012). CFs-associated FGF2 and FGF16 contribute to cardiac hypertrophy via stimulating CMs in a paracrine fashion (Fujiu and Nagai, 2014). Further, interleukins such as IL6 and IL11 were reported to be secreted by CFs during cardiac injury and hypertrophy (Hall et al., 2021). CFs alternatively respond to inflammatory mediators and adipokines either via autocrine or paracrine loops, contributing to an inflammatory environment that influences ECM remodeling in HCM (Camelliti et al., 2005; Tallquist and Molkentin, 2017). Activated CFs exhibit dysregulated MMPs and TIMPs expression, influencing ECM turnover (Fan et al., 2012). They are involved in the activation of the TGF-β signaling pathway, which is associated with fibrosis and ECM remodeling in HCM (Fujiu and Nagai, 2014; Lasala et al., 2012).

The crosstalk between CFs and CMs, as well as with the surrounding stroma/ECM, is bidirectional and crucial for tissue homeostasis (Hall et al., 2021; Bursac, 2014). In pathological conditions, all these elements are influenced by altered signaling cascades, leading to a microenvironment that chronically affects CFs phenotype and relevant response (Hall et al., 2021). CM-associated signals such as TGF-β, angiotensin II, and microRNAs promoting CFs activation, myofibroblast transition, and increased collagen, fibronectin, and periostin synthesis. CFs have recently become targets for novel cardiac therapeutics due to their primary contribution to ECM remodeling, their direct interaction with CMs, and their ability to differentiate and regenerate (Hall et al., 2021). While CFs are the primary ECM-producing cells in the myocardium, the intricate crosstalk between CMs and other cell types in the heart contributes to the dynamic and finely tuned process of ECM remodeling (Camelliti et al., 2005; Bursac, 2014). Understanding these interactions is crucial for unraveling the complexities of cardiac physiology and pathology, particularly in conditions like myocardial infarction, hypertrophy, and heart failure.

While CMs are traditionally recognized for their contractile function in the heart, CMs also play a significant role in ECM remodeling (Rienks et al., 2014; Mouw et al., 2014). CMs can secrete fibronectin and MMPs, regulated, in part, by factors like mechanical stretch, cytokines, and neurohormones (Aoyagi and Matsui, 2011). CMs-Integrins mediate the interaction between CMs and the ECM which activates intracellular signaling pathways that can influence cell behavior, including gene expression related to ECM remodeling (Aoyagi and Matsui, 2011). Mechanical forces, such as those generated during contraction, can affect CMs behavior and gene expression, and can activate pathways that influence ECM synthesis and remodeling for maintaining tissue integrity and preventing adverse remodeling (Martino et al., 2018). CMs release extracellular vesicles, including exosomes, which can transport bioactive molecules including microRNAs, that influence neighboring cells, including CFs involved in ECM regulation (Aoyagi and Matsui, 2011). Adaptive Responses to Stress: Under conditions of stress, such as hypertrophy or ischemia, CMs can undergo adaptive changes that influence ECM remodeling. This may involve alterations in gene expression profiles that impact the synthesis and degradation of ECM components. Indeed, the genetic variations encompass HCM etiology, particularly those associated with sarcomere proteins (Marian and Braunwald, 2017; Allouba et al., 2023), accounts for the cellular and molecular alterations in CMs that can cause downstream alterations in the ECM (Dour et al., 2017).

Endothelial Cells are lining the blood vessels within the myocardium secrete various ECM components, including BM proteins such as laminin and collagen IV (Widyantoro et al., 2010). ECs can also secrete various ECM components, including fibronectin and laminins, which are important for maintaining the structural integrity of blood vessels and the surrounding tissue (Yousif et al., 2013). ECs are crucial for angiogenesis, which requires balanced ECM remodeling for vessel sprouting, branching, and stabilization (Gogiraju et al., 2019). ECs release various growth factors and cytokines that influence the behavior of neighboring cells, including CFs (Mai et al., 2013). These factors can modulate ECM turnover and remodeling (Davis and Senger, 2005; Bischoff et al., 2005). Of interest, ECs produce nitric oxide (NO), which has vasodilatory effects and plays a role in maintaining vascular tone (Bischoff et al., 2005). Dysregulation of NO production may influence ECM remodeling and contribute to vascular changes (Heiss et al., 2015). Of note, changes in the microvasculature, influenced by ECs, may impact nutrient and oxygen supply to the myocardium. These changes can have downstream effects on ECM homeostasis.

Various immune cells, including macrophages, play a role in tissue repair (Davies et al., 2013; Wang et al., 2020). While immune cells are primarily associated with the immune response and inflammation, their interactions with other cell types, including CFs and CMs, can influence ECM remodeling (Toba et al., 2017; Lavine et al., 2018). Immune cells can infiltrate the myocardium in response to various stimuli and contribute to ECM remodeling and has recently been suggested to halt myocardial fibrosis and promote angiogenesis (Revelo et al., 2021; O’Rourke et al., 2019). Immune cells release cytokines, which are signaling molecules that can influence the behavior of CFs and other cells involved in ECM maintenance (Frieler and Mortensen, 2015). An Altered cytokine expression, including pro-inflammatory cytokines, has been reported in HCM and may contribute to cardiac remodeling (Piek et al., 2016). As mentioned earlier, immune cells can produce MMPs and TIMPs, in response to pathological stimuli and in coordination with CFs and CMs (Lavine et al., 2018; Frieler and Mortensen, 2015). CFs may respond to signals from immune cells, influencing collagen synthesis and deposition (Hitscherich and Lee, 2021). This stimulation cascade varies based on tissue status. During acute myocardial infarction, pro-inflammatory cytokines are released to initiate inflammation and clear necrotic tissue. Once the necrotic tissue is removed, macrophages transition to an anti-inflammatory phenotype, stimulating CFs to deposit collagen and promote fibrotic tissue formation (Chen et al., 2024), a mechanism similarly observed in cancer models (Ibrahim et al., 2020b; Wang et al., 2020). This interplay is activated in various cardiac pathologies, including ischemia and pressure-overloaded myocardium, and is linked to the regulation of ECM proteins, such as MMPs (Chen et al., 2024; Waleczek et al., 2022), and can be orchestrated via myocardium-resident macrophages (Waleczek et al., 2022), or previously activated monocytes (Chen et al., 2024).

Adipocytes are fat cells found in the myocardial tissue and can contribute to the ECM by secreting various adipokines and other signaling molecules (Chait and den Hartigh, 2020). The specific role of adipocytes in ECM maintenance in the myocardium, particularly in HCM, has not been extensively studied. Increased epicardial fat thickness has been associated with disease severity and adverse clinical outcomes (Hajsadeghi et al., 2014; Talman et al., 2014), such as atrial fibrillation and coronary heart conditions, which are complications of HCM (Macintyre and Lakdawala, 2016). Associations between epicardial adipose tissue volume and arrhythmias may have relevance to HCM patients with arrhythmic complications (Conte et al., 2022). Adipokines secreted by the adipose tissue, such as adiponectin and leptin, have the potential to influence the restructuring of the ECM in the myocardium, via regulating the expression of proteases (TIMPs and MMPs). plasminogen activator inhibitor type 1, primarily synthesized by adipose tissue, controls the function of plasmin, a serine protease crucial for regulating the ECM (Zibadi et al., 2011; Schram and Sweeney, 2008). Adipocytes can engage in paracrine signaling with neighboring cells, including CFs and CMs (Krishnan et al., 2021). The interplay between adipocytes and the cardiac microenvironment is an active area of research, and there are several considerations regarding their potential contributions.