Table1 summarizes important findings in clinical studies as well as in animal models of cardiac disease.5–42 Additional studies reported ECM proteins as potential biomarkers for cardiac pathologies43; these have been intentionally omitted from the table, the focus of which are ECM and ECM-associated proteins (i.e. extracellular proteases and non-structural proteins that bind to or regulate ECM) from a functional perspective. Most proteins included in the table were individually studied using antibodies and loss-of-function models in order to assign their relevance to disease. Proteomics can quantify most of these ECM proteins in a single experiment, leading to the identification of previously unreported links between ECM components in disease.2–4 For example, in a recent study we demonstrated that genetic deletion of biglycan was accompanied by an unexpected rise of aggrecan in murine aortas.44 Table 1Role of ECM and ECM-associated proteins in cardiac diseaseProteinClinical contextMain findingsAdiponectinCardiac remodelling (m)Induces cell migration, MMP activation, and collagen remodelling via APPL1-AMPK signalling6ADAMTS9Developmental defects (m)Haploinsufficiency leads to reduced versican cleavage, associated with cardiac anomalies7BiglycanMI (m)Required for adaptive remodelling8Cathepsin-KAF (h, rb)Increased levels and activity accompanied atrial changes linked to the AngII/ATR1R signalling pathway9Cathepsin-SMI (m)Mediates fibroblast transdifferentiation during remodelling10Collagen IDilated cardiomyopathy (m)Point mutation induces cardiomyopathy11Collagen VIMI (m)Absence improves cardiac function, structure, and remodelling12Collagen XIVDevelopmental defects (m)Important for growth and structural integrity of the myocardium13Collagen XVHypertension (m)Necessary for remodelling. Deficiency predisposes to cardiomyopathy14Connective tissue growth factorPressure overload (m)Inhibition attenuates left ventricular remodelling and dysfunction15DecorinLeft ventricular assist device implantation (h)Ameliorates adverse remodelling by mediating TGF-beta inhibition16MI (m)Absence leads to abnormal scar tissue formation17FibronectinMI (m, h)Essential for progenitor cell response during cardiac repair18MI (m)Lack of EDA domain promotes survival and prevents adverse remodelling19Fibulin-2MI (m)Loss protects against progressive ventricular dysfunction20Laminin alpha-4Dilated cardiomyopathy (h, z)Mutations cause human cardiomyopathy via defects in cardiomyocytes and endothelial cells21LumicanHypertrophy (m)Deficiency results in cardiomyocyte hypertrophy with altered collagen assembly22MimecanMI (m, h)Prevents cardiac dilatation and dysfunction via collagen strengthening23MMP-14Pressure overload (m)Mediates pro-fibrotic signalling, leading to alterations in interstitial fibrosis and diastolic function24MMP-28MI (m)Deletion exacerbates cardiac dysfunction and rupture by inhibiting M2 macrophage activation25TIMP-2Pressure overload (m)Loss leads to exacerbated left ventricular dysfunction and adverse ECM remodeling26MMP-9AF (p, h)Increased gelatinase activity contributes to atrial ECM remodelling27,28MI (h,m)Crucial for generation of bioactive collagen I fragments that promote scar formation after MI5MI (m)Deletion leads to decreased collagen accumulation and left ventricular enlargement29MMP-2MI (m, r)Contributes to ischemia-reperfusion injury, and deletion/inhibition prevents cardiac rupture30,31OsteopontinMI (m)Deletion leads to left ventricular dilatation and reduced collagen deposition after MI32PeriostinMI (r)Blockade of Exon 17 preserves cardiac performance33Pressure overload (m)Deletion results in less fibrosis and hypertrophy34PerlecanDevelopmental defects (m)Perlecan is critical for heart stability35SPARCMI (m)Mediates early ECM remodeling36Tenascin-CPressure overload (m)Accelerates fibrosis by activating macrophages via the integrin αVβ3/nuclear factor-κB/interleukin-6 axis37MI (m)May aggravate left ventricular remodelling and function38Thrombospondin-1Pressure overload (m)Protects myocardium by modulating fibroblast phenotype and ECM metabolism39MI (d, m)Role in preventing expansion of healing myocardial infarcts40Thrombospondin-4Pressure overload (m)Regulates myocardial fibrosis and remodelling41VersicanDevelopmental defects (m)Associated with chamber specification, septation, and valvulogenesis in the developing heart42MMP, matrix metalloproteinase; ADAMTS, a disintegrin and metalloproteinase with thrombospondin domains; TIMP, tissue inhibitor of metalloproteinases; SPARC, secreted protein acidic and rich in cysteine; MI, myocardial infarction; AF, atrial fibrillation; m, mouse; h, human; rb, rabbit; z, zebrafish; r, rat; p, pig; d, dog.