The term 'mechanosensation' describes the capacity of cells to translate mechanical stimuli into the coordinated regulation of intracellular signals, cellular function, gene expression and epigenetic programming. This capacity is related not only to the sensitivity of the cells to tissue motion, but also to the decryption of tissue geometric arrangement and mechanical properties. The cardiac stroma, composed of fibroblasts, has been historically considered a mechanically passive component of the heart. However, the latest research suggests that the mechanical functions of these cells are an active and necessary component of the developmental biology programme of the heart that is involved in myocardial growth and homeostasis, and a crucial determinant of cardiac repair and disease. In this Review, we discuss the general concept of cell mechanosensation and force generation as potent regulators in heart development and pathology, and describe the integration of mechanical and biohumoral pathways predisposing the heart to fibrosis and failure. Next, we address the use of 3D culture systems to integrate tissue mechanics to mimic cardiac remodelling. Finally, we highlight the potential of mechanotherapeutic strategies, including pharmacological treatment and device-mediated left ventricular unloading, to reverse remodelling in the failing heart.

Berlin Institute of Health at Charité Universitätsmedizin BIH Center for Regenerative Therapies Berlin Germany

Berlin Institute of Health at Charité Universitätsmedizin Julius Wolff Institute Berlin Germany

Biomedical Research Networking Center Bioengineering Biomaterials and Nanomedicine Madrid Spain

Catalan Institution for Research and Advanced Studies Barcelona Spain

Center for Innovative Biomedicine and Biotechnology Coimbra Institute for Clinical and Biomedical Research Faculty of Medicine University of Coimbra Coimbra Portugal

Charité Universitätsmedizin Department of Cardiology Campus Virchow Klinikum Berlin Germany

Clinical Academic Centre of Coimbra Faculty of Medicine University of Coimbra Coimbra Portugal

Division Heart and Lung Cardiology Experimental Cardiology Laboratory Regenerative Medicine Center University Medical Center Utrecht Utrecht University Utrecht Netherlands

German Centre for Cardiovascular Research Berlin Germany

Institute for Bioengineering of Catalonia Barcelona Institute of Science and Technology Barcelona Spain

International Clinical Research Center St Anne's University Hospital Brno Czech Republic

Regenerative Medicine Program Bellvitge Institute for Biomedical Research Program for Clinical Translation of Regenerative Medicine in Catalonia L'Hospitalet de Llobregat Barcelona Spain

Unità di Ingegneria Tissutale Cardiovascolare Centro Cardiologico Monzino IRCCS Milan Italy

Zobrazit více v PubMed

Pinto, A. R. et al. Revisiting cardiac cellular composition. Circ. Res. 118, 400–409 (2016). PubMed DOI

Litvinukova, M. et al. Cells of the adult human heart. Nature 588, 466–472 (2020). PubMed DOI PMC

Herum, K. M., Choppe, J., Kumar, A., Engler, A. J. & McCulloch, A. D. Mechanical regulation of cardiac fibroblast profibrotic phenotypes. Mol. Biol. Cell 28, 1871–1882 (2017). PubMed DOI PMC

Berry, M. F. et al. Mesenchymal stem cell injection after myocardial infarction improves myocardial compliance. Am. J. Physiol. Heart Circ. Physiol. 290, H2196–H2203 (2006). PubMed DOI

Discher, D. E., Janmey, P. & Wang, Y. L. Tissue cells feel and respond to the stiffness of their substrate. Science 310, 1139–1143 (2005). PubMed DOI

Downing, T. L. et al. Biophysical regulation of epigenetic state and cell reprogramming. Nat. Mater. 12, 1154–1162 (2013). PubMed DOI PMC

Van Linthout, S., Miteva, K. & Tschope, C. Crosstalk between fibroblasts and inflammatory cells. Cardiovasc. Res. 102, 258–269 (2014). PubMed DOI

Steffens, S. et al. Stimulating pro-reparative immune responses to prevent adverse cardiac remodelling: consensus document from the joint 2019 meeting of the ESC Working Groups of Cellular Biology of the Heart and Myocardial Function. Cardiovasc. Res. 116, 1850–1862 (2020). PubMed DOI

van Putten, S., Shafieyan, Y. & Hinz, B. Mechanical control of cardiac myofibroblasts. J. Mol. Cell. Cardiol. 93, 133–142 (2016). PubMed DOI

Yu, J. et al. Topological arrangement of cardiac fibroblasts regulates cellular plasticity. Circ. Res. 123, 73–85 (2018). PubMed DOI PMC

Bracco Gartner, T. C. L. et al. Advanced in vitro modeling to study the paradox of mechanically induced cardiac fibrosis. Tissue Eng. Part. C. Methods 27, 100–114 (2021). PubMed DOI

Majkut, S., Dingal, P. C. & Discher, D. E. Stress sensitivity and mechanotransduction during heart development. Curr. Biol. 24, R495–R501 (2014). PubMed DOI PMC

Andres-Delgado, L. & Mercader, N. Interplay between cardiac function and heart development. Biochim. Biophys. Acta 1863, 1707–1716 (2016). PubMed DOI PMC

Happe, C. L. & Engler, A. J. Mechanical forces reshape differentiation cues that guide cardiomyogenesis. Circ. Res. 118, 296–310 (2016). PubMed DOI PMC

Courchaine, K., Rykiel, G. & Rugonyi, S. Influence of blood flow on cardiac development. Prog. Biophys. Mol. Biol. 137, 95–110 (2018). PubMed DOI PMC

Tallquist, M. D. Developmental pathways of cardiac fibroblasts. Cold Spring Harb. Perspect. Biol. 12, a037184 (2020). PubMed DOI PMC

Majkut, S. et al. Heart-specific stiffening in early embryos parallels matrix and myosin expression to optimize beating. Curr. Biol. 23, 2434–2439 (2013). PubMed DOI PMC

Chiou, K. K. et al. Mechanical signaling coordinates the embryonic heartbeat. Proc. Natl Acad. Sci. USA 113, 8939–8944 (2016). PubMed DOI PMC

Matrone, G., Tucker, C. S. & Denvir, M. A. Cardiomyocyte proliferation in zebrafish and mammals: lessons for human disease. Cell. Mol. Life Sci. 74, 1367–1378 (2017). PubMed DOI

Eulalio, A. et al. Functional screening identifies miRNAs inducing cardiac regeneration. Nature 492, 376–381 (2012). PubMed DOI

Gabisonia, K. et al. MicroRNA therapy stimulates uncontrolled cardiac repair after myocardial infarction in pigs. Nature 569, 418–422 (2019). PubMed DOI PMC

Kennedy-Lydon, T. & Rosenthal, N. Cardiac regeneration: all work and no repair? Sci. Transl Med. 9, eaad9019 (2017). PubMed DOI

Garcia-Gonzalez, C. & Morrison, J. I. Cardiac regeneration in non-mammalian vertebrates. Exp. Cell Res. 321, 58–63 (2014). PubMed DOI

Poss, K. D., Wilson, L. G. & Keating, M. T. Heart regeneration in zebrafish. Science 298, 2188–2190 (2002). PubMed DOI

Sanz-Morejon, A. & Mercader, N. Recent insights into zebrafish cardiac regeneration. Curr. Opin. Genet. Dev. 64, 37–43 (2020). PubMed DOI

Yu, J. K. et al. Cardiac regeneration following cryoinjury in the adult zebrafish targets a maturation-specific biomechanical remodeling program. Sci. Rep. 8, 15661 (2018). PubMed DOI PMC

Sanchez-Iranzo, H. et al. Transient fibrosis resolves via fibroblast inactivation in the regenerating zebrafish heart. Proc. Natl Acad. Sci. USA 115, 4188–4193 (2018). PubMed DOI PMC

Ito, K. et al. Differential reparative phenotypes between zebrafish and medaka after cardiac injury. Dev. Dyn. 243, 1106–1115 (2014). PubMed DOI

Porrello, E. R. et al. Transient regenerative potential of the neonatal mouse heart. Science 331, 1078–1080 (2011). PubMed DOI PMC

Chen, W. C. et al. Decellularized zebrafish cardiac extracellular matrix induces mammalian heart regeneration. Sci. Adv. 2, e1600844 (2016). PubMed DOI PMC

Wang, Z. et al. Decellularized neonatal cardiac extracellular matrix prevents widespread ventricular remodeling in adult mammals after myocardial infarction. Acta Biomater. 87, 140–151 (2019). PubMed DOI PMC

Missinato, M. A., Tobita, K., Romano, N., Carroll, J. A. & Tsang, M. Extracellular component hyaluronic acid and its receptor Hmmr are required for epicardial EMT during heart regeneration. Cardiovasc. Res. 107, 487–498 (2015). PubMed DOI PMC

Wang, J., Karra, R., Dickson, A. L. & Poss, K. D. Fibronectin is deposited by injury-activated epicardial cells and is necessary for zebrafish heart regeneration. Dev. Biol. 382, 427–435 (2013). PubMed DOI

Kuhn, B. et al. Periostin induces proliferation of differentiated cardiomyocytes and promotes cardiac repair. Nat. Med. 13, 962–969 (2007). PubMed DOI

Garcia-Puig, A. et al. Proteomics analysis of extracellular matrix remodeling during zebrafish heart regeneration. Mol. Cell Proteom. 18, 1745–1755 (2019). DOI

Notari, M. et al. The local microenvironment limits the regenerative potential of the mouse neonatal heart. Sci. Adv. 4, eaao5553 (2018). PubMed DOI PMC

Yahalom-Ronen, Y., Rajchman, D., Sarig, R., Geiger, B. & Tzahor, E. Reduced matrix rigidity promotes neonatal cardiomyocyte dedifferentiation, proliferation and clonal expansion. eLife 4, e07455 (2015). PubMed DOI PMC

Wang, X. et al. Microenvironment stiffness requires decellularized cardiac extracellular matrix to promote heart regeneration in the neonatal mouse heart. Acta Biomater. 113, 380–392 (2020). PubMed DOI PMC

Bassat, E. et al. The extracellular matrix protein agrin promotes heart regeneration in mice. Nature 547, 179–184 (2017). PubMed DOI PMC

van der Pol, A. & Bouten, C. V. C. A brief history in cardiac regeneration, and how the extra cellular matrix may turn the tide. Front. Cardiovasc. Med. 8, 682342 (2021). PubMed DOI PMC

Gaetani, R. et al. When stiffness matters: mechanosensing in heart development and disease. Front. Cell Dev. Biol. 8, 334 (2020). PubMed DOI PMC

Perestrelo, A. R. et al. Multiscale analysis of extracellular matrix remodeling in the failing heart. Circ. Res. 128, 24–38 (2021). PubMed DOI

Civitarese, R. A. et al. The α11 integrin mediates fibroblast-extracellular matrix-cardiomyocyte interactions in health and disease. Am. J. Physiol. Heart Circ. Physiol. 311, H96–H106 (2016). PubMed DOI

Gullberg, D. et al. Analysis of alpha 1 beta 1, alpha 2 beta 1 and alpha 3 beta 1 integrins in cell–collagen interactions: identification of conformation dependent alpha 1 beta 1 binding sites in collagen type I. EMBO J. 11, 3865–3873 (1992). PubMed DOI PMC

Balasubramanian, S. et al. β3 Integrin in cardiac fibroblast is critical for extracellular matrix accumulation during pressure overload hypertrophy in mouse. PLoS ONE 7, e45076 (2012). PubMed DOI PMC

Schiller, H. B. & Fassler, R. Mechanosensitivity and compositional dynamics of cell-matrix adhesions. EMBO Rep. 14, 509–519 (2013). PubMed DOI PMC

Sit, B., Gutmann, D. & Iskratsch, T. Costameres, dense plaques and podosomes: the cell matrix adhesions in cardiovascular mechanosensing. J. Muscle Res. Cell Motil. 40, 197–209 (2019). PubMed DOI PMC

Chen, Y., Lee, H., Tong, H., Schwartz, M. & Zhu, C. Force regulated conformational change of integrin α PubMed DOI

Shemesh, T., Geiger, B., Bershadsky, A. D. & Kozlov, M. M. Focal adhesions as mechanosensors: a physical mechanism. Proc. Natl Acad. Sci. USA 102, 12383–12388 (2005). PubMed DOI PMC

Kong, F., Garcia, A. J., Mould, A. P., Humphries, M. J. & Zhu, C. Demonstration of catch bonds between an integrin and its ligand. J. Cell Biol. 185, 1275–1284 (2009). PubMed DOI PMC

Kaushik, G. et al. Vinculin network-mediated cytoskeletal remodeling regulates contractile function in the aging heart. Sci. Transl Med. 7, 292ra299 (2015). DOI

Zhang, J. et al. Targeted inhibition of focal adhesion kinase attenuates cardiac fibrosis and preserves heart function in adverse cardiac remodeling. Sci. Rep. 7, 43146 (2017). PubMed DOI PMC

Manso, A. M. et al. Loss of mouse cardiomyocyte talin-1 and talin-2 leads to β-1 integrin reduction, costameric instability, and dilated cardiomyopathy. Proc. Natl Acad. Sci. USA 114, E6250–E6259 (2017). PubMed DOI PMC

Civitarese, R. A., Kapus, A., McCulloch, C. A. & Connelly, K. A. Role of integrins in mediating cardiac fibroblast-cardiomyocyte cross talk: a dynamic relationship in cardiac biology and pathophysiology. Basic. Res. Cardiol. 112, 6 (2017). PubMed DOI

Hinz, B., Pittet, P., Smith-Clerc, J., Chaponnier, C. & Meister, J. J. Myofibroblast development is characterized by specific cell–cell adherens junctions. Mol. Biol. Cell 15, 4310–4320 (2004). PubMed DOI PMC

Schroer, A. K. & Merryman, W. D. Mechanobiology of myofibroblast adhesion in fibrotic cardiac disease. J. Cell Sci. 128, 1865–1875 (2015). PubMed DOI PMC

Rakshit, S., Zhang, Y., Manibog, K., Shafraz, O. & Sivasankar, S. Ideal, catch, and slip bonds in cadherin adhesion. Proc. Natl Acad. Sci. USA 109, 18815–18820 (2012). PubMed DOI PMC

Yao, M. et al. Force-dependent conformational switch of α-catenin controls vinculin binding. Nat. Commun. 5, 4525 (2014). PubMed DOI

Buckley, C. D. et al. Cell adhesion. The minimal cadherin-catenin complex binds to actin filaments under force. Science 346, 1254211 (2014). PubMed DOI PMC

Vermij, S. H., Abriel, H. & van Veen, T. A. Refining the molecular organization of the cardiac intercalated disc. Cardiovasc. Res. 113, 259–275 (2017). PubMed DOI

Baddam, S. R. et al. The desmosomal cadherin desmoglein-2 experiences mechanical tension as demonstrated by a FRET-based tension biosensor expressed in living cells. Cells 7, 66 (2018). PubMed DOI PMC

Samarel, A. M. Costameres, focal adhesions, and cardiomyocyte mechanotransduction. Am. J. Physiol. Heart Circ. Physiol. 289, H2291–H2301 (2005). PubMed DOI

Galie, P. A., Khalid, N., Carnahan, K. E., Westfall, M. V. & Stegemann, J. P. Substrate stiffness affects sarcomere and costamere structure and electrophysiological function of isolated adult cardiomyocytes. Cardiovasc. Pathol. 22, 219–227 (2013). PubMed DOI

Fancher, I. S. in Cellular Mechanotransduction Mechanisms in Cardiovascular and Fibrotic Diseases Ch. 2 (ed. Fang, Y.) 47–95 (Academic, 2021).

Alonso-Carbajo, L. et al. Muscling in on TRP channels in vascular smooth muscle cells and cardiomyocytes. Cell Calcium 66, 48–61 (2017). PubMed DOI

Jakob, D. et al. Piezo1 and BKCa channels in human atrial fibroblasts: interplay and remodelling in atrial fibrillation. J. Mol. Cell. Cardiol. 158, 49–62 (2021). PubMed DOI

Adapala, R. K. et al. TRPV4 channels mediate cardiac fibroblast differentiation by integrating mechanical and soluble signals. J. Mol. Cell. Cardiol. 54, 45–52 (2013). PubMed DOI

Harada, M. et al. Transient receptor potential canonical-3 channel-dependent fibroblast regulation in atrial fibrillation. Circulation 126, 2051–2064 (2012). PubMed DOI PMC

Du, J. et al. TRPM7-mediated Ca PubMed DOI PMC

Davis, J., Burr, A. R., Davis, G. F., Birnbaumer, L. & Molkentin, J. D. A TRPC6-dependent pathway for myofibroblast transdifferentiation and wound healing in vivo. Dev. Cell 23, 705–715 (2012). PubMed DOI PMC

Dupont, S. & Wickstrom, S. A. Mechanical regulation of chromatin and transcription. Nat. Rev. Genet. 23, 624–643 (2022). PubMed DOI

Roper, J. C. et al. The major β-catenin/E-cadherin junctional binding site is a primary molecular mechano-transductor of differentiation in vivo. eLife 7, e33381 (2018). PubMed DOI PMC

Zhao, X. H. et al. Force activates smooth muscle α-actin promoter activity through the Rho signaling pathway. J. Cell Sci. 120, 1801–1809 (2007). PubMed DOI

Ho, C. Y., Jaalouk, D. E., Vartiainen, M. K. & Lammerding, J. Lamin A/C and emerin regulate MKL1-SRF activity by modulating actin dynamics. Nature 497, 507–511 (2013). PubMed DOI PMC

Arsenovic, P. T. et al. Nesprin-2G, a component of the nuclear LINC complex, is subject to myosin-dependent tension. Biophys. J. 110, 34–43 (2016). PubMed DOI PMC

Elosegui-Artola, A. et al. Force triggers YAP nuclear entry by regulating transport across nuclear pores. Cell 171, 1397–1410.e14 (2017). PubMed DOI

Denais, C. M. et al. Nuclear envelope rupture and repair during cancer cell migration. Science 352, 353–358 (2016). PubMed DOI PMC

Nava, M. M. et al. Heterochromatin-driven nuclear softening protects the genome against mechanical stress-induced damage. Cell 181, 800–817 (2020). PubMed DOI PMC

Tajik, A. et al. Transcription upregulation via force-induced direct stretching of chromatin. Nat. Mater. 15, 1287–1296 (2016). PubMed DOI PMC

Sun, J., Chen, J., Mohagheghian, E. & Wang, N. Force-induced gene up-regulation does not follow the weak power law but depends on H3K9 demethylation. Sci. Adv. 6, eaay9095 (2020). PubMed DOI PMC

Swift, J. et al. Nuclear lamin-A scales with tissue stiffness and enhances matrix-directed differentiation. Science 341, 1240104 (2013). PubMed DOI PMC

Lomakin, A. J. et al. The nucleus acts as a ruler tailoring cell responses to spatial constraints. Science 370, eaba2894 (2020). PubMed DOI PMC

Venturini, V. et al. The nucleus measures shape changes for cellular proprioception to control dynamic cell behavior. Science 370, eaba2644 (2020). PubMed DOI

Schuller, A. P. et al. The cellular environment shapes the nuclear pore complex architecture. Nature 598, 667–671 (2021). PubMed DOI PMC

Zimmerli, C. E. et al. Nuclear pores dilate and constrict in cellulo. Science 374, eabd9776 (2021). PubMed DOI

Andreu, I. et al. Mechanical force application to the nucleus regulates nucleocytoplasmic transport. Nat. Cell Biol. 24, 896–905 (2022). PubMed DOI

Piccolo, S., Dupont, S. & Cordenonsi, M. The biology of YAP/TAZ: hippo signaling and beyond. Physiol. Rev. 94, 1287–1312 (2014). PubMed DOI

Wei, S. C. et al. Matrix stiffness drives epithelial-mesenchymal transition and tumour metastasis through a TWIST1-G3BP2 mechanotransduction pathway. Nat. Cell Biol. 17, 678–688 (2015). PubMed DOI PMC

Zhang, K. et al. Mechanical signals regulate and activate SNAIL1 protein to control the fibrogenic response of cancer-associated fibroblasts. J. Cell. Sci. 129, 1989–2002 (2016). PubMed PMC

Infante, E. et al. The mechanical stability of proteins regulates their translocation rate into the cell nucleus. Nat. Phys. 15, 973–981 (2019). DOI

Ugolini, G. S. et al. On-chip assessment of human primary cardiac fibroblasts proliferative responses to uniaxial cyclic mechanical strain. Biotechnol. Bioeng. 113, 859–869 (2016). PubMed DOI

Niu, L. et al. Matrix stiffness controls cardiac fibroblast activation through regulating YAP via AT1 R. J. Cell. Physiol. 235, 8345–8357 (2020). PubMed DOI

Heallen, T. et al. Hippo signaling impedes adult heart regeneration. Development 140, 4683–4690 (2013). PubMed DOI PMC

Xin, M. et al. Hippo pathway effector Yap promotes cardiac regeneration. Proc. Natl Acad. Sci. USA 110, 13839–13844 (2013). PubMed DOI PMC

Flinn, M. A., Link, B. A. & O’Meara, C. C. Upstream regulation of the Hippo-Yap pathway in cardiomyocyte regeneration. Semin. Cell Dev. Biol. 100, 11–19 (2020). PubMed DOI

Weichhart, T., Hengstschlager, M. & Linke, M. Regulation of innate immune cell function by mTOR. Nat. Rev. Immunol. 15, 599–614 (2015). PubMed DOI PMC

Castillo, E. A., Lane, K. V. & Pruitt, B. L. Micromechanobiology: focusing on the cardiac cell-substrate interface. Annu. Rev. Biomed. Eng. 22, 257–284 (2020). PubMed DOI

Ieda, M. et al. Cardiac fibroblasts regulate myocardial proliferation through β1 integrin signaling. Dev. Cell 16, 233–244 (2009). PubMed DOI PMC

Wu, C. C., Jeratsch, S., Graumann, J. & Stainier, D. Y. R. Modulation of mammalian cardiomyocyte cytokinesis by the extracellular matrix. Circ. Res. 127, 896–907 (2020). PubMed DOI

Heallen, T. et al. Hippo pathway inhibits Wnt signaling to restrain cardiomyocyte proliferation and heart size. Science 332, 458–461 (2011). PubMed DOI PMC

Halder, G. & Johnson, R. L. Hippo signaling: growth control and beyond. Development 138, 9–22 (2011). PubMed DOI PMC

Del Re, D. P. et al. Yes-associated protein isoform 1 (Yap1) promotes cardiomyocyte survival and growth to protect against myocardial ischemic injury. J. Biol. Chem. 288, 3977–3988 (2013). PubMed DOI

Hou, N. et al. Activation of Yap1/Taz signaling in ischemic heart disease and dilated cardiomyopathy. Exp. Mol. Pathol. 103, 267–275 (2017). PubMed DOI PMC

Monroe, T. O. et al. YAP partially reprograms chromatin accessibility to directly induce adult cardiogenesis in vivo. Dev. Cell 48, 765–779.e7 (2019). PubMed DOI PMC

Xiao, Y. et al. Hippo pathway deletion in adult resting cardiac fibroblasts initiates a cell state transition with spontaneous and self-sustaining fibrosis. Genes Dev. 33, 1491–1505 (2019). PubMed DOI PMC

Mosqueira, D. et al. Hippo pathway effectors control cardiac progenitor cell fate by acting as dynamic sensors of substrate mechanics and nanostructure. ACS Nano 8, 2033–2047 (2014). PubMed DOI

Morikawa, Y. et al. Actin cytoskeletal remodeling with protrusion formation is essential for heart regeneration in Hippo-deficient mice. Sci. Signal. 8, ra41 (2015). PubMed DOI PMC

Morikawa, Y., Heallen, T., Leach, J., Xiao, Y. & Martin, J. F. Dystrophin-glycoprotein complex sequesters Yap to inhibit cardiomyocyte proliferation. Nature 547, 227–231 (2017). PubMed DOI PMC

Aharonov, A. et al. ERBB2 drives YAP activation and EMT-like processes during cardiac regeneration. Nat. Cell Biol. 22, 1346–1356 (2020). PubMed DOI

Frangogiannis, N. G. Cardiac fibrosis. Cardiovasc. Res. 117, 1450–1488 (2020). DOI PMC

Zile, M. R. et al. Myocardial stiffness in patients with heart failure and a preserved ejection fraction: contributions of collagen and titin. Circulation 131, 1247–1259 (2015). PubMed DOI PMC

Thomas, D. P., Cotter, T. A., Li, X., McCormick, R. J. & Gosselin, L. E. Exercise training attenuates aging-associated increases in collagen and collagen crosslinking of the left but not the right ventricle in the rat. Eur. J. Appl. Physiol. 85, 164–169 (2001). PubMed DOI

Asif, M. et al. An advanced glycation endproduct cross-link breaker can reverse age-related increases in myocardial stiffness. Proc. Natl Acad. Sci. USA 97, 2809–2813 (2000). PubMed DOI PMC

Hutchinson, K. R., Lord, C. K., West, T. A. & Stewart, J. A. Jr Cardiac fibroblast-dependent extracellular matrix accumulation is associated with diastolic stiffness in type 2 diabetes. PLoS ONE 8, e72080 (2013). PubMed DOI PMC

Angelini, A., Trial, J., Ortiz-Urbina, J. & Cieslik, K. A. Mechanosensing dysregulation in the fibroblast: a hallmark of the aging heart. Ageing Res. Rev. 63, 101150 (2020). PubMed DOI PMC

Villemain, O. et al. Myocardial stiffness evaluation using noninvasive shear wave imaging in healthy and hypertrophic cardiomyopathic adults. JACC Cardiovasc. Imaging 12, 1135–1145 (2019). PubMed DOI PMC

Engler, A. J. et al. Embryonic cardiomyocytes beat best on a matrix with heart-like elasticity: scar-like rigidity inhibits beating. J. Cell Sci. 121, 3794–3802 (2008). PubMed DOI

Pandey, P. et al. Cardiomyocytes sense matrix rigidity through a combination of muscle and non-muscle myosin contractions. Dev. Cell 44, 326–336.e3 (2018). PubMed DOI PMC

Nishimura, M. et al. A dual role for integrin-linked kinase and β1-integrin in modulating cardiac aging. Aging Cell 13, 431–440 (2014). PubMed DOI PMC

Nawata, J. et al. Differential expression of α1, α3 and α5 integrin subunits in acute and chronic stages of myocardial infarction in rats. Cardiovasc. Res. 43, 371–381 (1999). PubMed DOI

Hein, S., Kostin, S., Heling, A., Maeno, Y. & Schaper, J. The role of the cytoskeleton in heart failure. Cardiovasc. Res. 45, 273–278 (2000). PubMed DOI

Heling, A. et al. Increased expression of cytoskeletal, linkage, and extracellular proteins in failing human myocardium. Circ. Res. 86, 846–853 (2000). PubMed DOI

Sessions, A. O. & Engler, A. J. Mechanical regulation of cardiac aging in model systems. Circ. Res. 118, 1553–1562 (2016). PubMed DOI PMC

Neff, L. S. & Bradshaw, A. D. Cross your heart? Collagen cross-links in cardiac health and disease. Cell Signal. 79, 109889 (2021). PubMed DOI

Al-U’datt, D., Allen, B. G. & Nattel, S. Role of the lysyl oxidase enzyme family in cardiac function and disease. Cardiovasc. Res. 115, 1820–1837 (2019). PubMed

Gonzalez-Santamaria, J. et al. Matrix cross-linking lysyl oxidases are induced in response to myocardial infarction and promote cardiac dysfunction. Cardiovasc. Res. 109, 67–78 (2016). PubMed DOI

Grilo, G. A. et al. Age- and sex-dependent differences in extracellular matrix metabolism associate with cardiac functional and structural changes. J. Mol. Cell. Cardiol. 139, 62–74 (2020). PubMed DOI

Yang, J. et al. Targeting LOXL2 for cardiac interstitial fibrosis and heart failure treatment. Nat. Commun. 7, 13710 (2016). PubMed DOI PMC

Bhana, B. et al. Influence of substrate stiffness on the phenotype of heart cells. Biotechnol. Bioeng. 105, 1148–1160 (2010). PubMed

Forte, G. et al. Substrate stiffness modulates gene expression and phenotype in neonatal cardiomyocytes in vitro. Tissue Eng. Part A 18, 1837–1848 (2012). PubMed DOI

McCain, M. L., Yuan, H., Pasqualini, F. S., Campbell, P. H. & Parker, K. K. Matrix elasticity regulates the optimal cardiac myocyte shape for contractility. Am. J. Physiol. Heart Circ. Physiol. 306, H1525–H1539 (2014). PubMed DOI PMC

Jacot, J. G., McCulloch, A. D. & Omens, J. H. Substrate stiffness affects the functional maturation of neonatal rat ventricular myocytes. Biophys. J. 95, 3479–3487 (2008). PubMed DOI PMC

Ribeiro, A. J. et al. Contractility of single cardiomyocytes differentiated from pluripotent stem cells depends on physiological shape and substrate stiffness. Proc. Natl Acad. Sci. USA 112, 12705–12710 (2015). PubMed DOI PMC

Katz, A. M. & Rolett, E. L. Heart failure: when form fails to follow function. Eur. Heart J. 37, 449–454 (2016). PubMed DOI

Fomovsky, G. M., Rouillard, A. D. & Holmes, J. W. Regional mechanics determine collagen fiber structure in healing myocardial infarcts. J. Mol. Cell. Cardiol. 52, 1083–1090 (2012). PubMed DOI PMC

Garoffolo, G. et al. Reduction of cardiac fibrosis by interference with YAP-dependent transactivation. Circ. Res. 131, 239–257 (2022). PubMed DOI

Khalil, H. et al. Fibroblast-specific TGF-β–Smad2/3 signaling underlies cardiac fibrosis. J. Clin. Invest. 127, 3770–3783 (2017). PubMed DOI PMC

Dang, S. et al. Blockade of β-adrenergic signaling suppresses inflammasome and alleviates cardiac fibrosis. Ann. Transl Med. 8, 127 (2020). PubMed DOI PMC

Miteva, K. et al. Human endomyocardial biopsy specimen-derived stromal cells modulate angiotensin II-induced cardiac remodeling. Stem Cell Transl Med. 5, 1707–1718 (2016). DOI

Tschope, C. et al. Modulation of the acute defence reaction by eplerenone prevents cardiac disease progression in viral myocarditis. ESC Heart Fail. 7, 2838–2852 (2020). PubMed DOI PMC

Xia, Y. et al. Endogenous thrombospondin 1 protects the pressure-overloaded myocardium by modulating fibroblast phenotype and matrix metabolism. Hypertension 58, 902–911 (2011). PubMed DOI

Lorenzen, J. M. et al. Osteopontin is indispensible for AP1-mediated angiotensin II-related miR-21 transcription during cardiac fibrosis. Eur. Heart J. 36, 2184–2196 (2015). PubMed DOI PMC

Van Linthout, S. & Tschope, C. The quest for antiinflammatory and immunomodulatory strategies in heart failure. Clin. Pharmacol. Ther. 106, 1198–1208 (2019). PubMed DOI

Wu, Y. et al. S100a8/a9 released by CD11b PubMed DOI

Lindner, D. et al. Cardiac fibroblasts support cardiac inflammation in heart failure. Basic. Res. Cardiol. 109, 428 (2014). PubMed DOI

Pappritz, K. et al. Cardiac (myo)fibroblasts modulate the migration of monocyte subsets. Sci. Rep. 8, 5575 (2018). PubMed DOI PMC

Matz, I., Pappritz, K., Springer, J. & Van Linthout, S. Left ventricle- and skeletal muscle-derived fibroblasts exhibit a differential inflammatory and metabolic responsiveness to interleukin-6. Front. Immunol. 13, 947267 (2022). PubMed DOI PMC

Sandanger, O. et al. The NLRP3 inflammasome is up-regulated in cardiac fibroblasts and mediates myocardial ischaemia-reperfusion injury. Cardiovasc. Res. 99, 164–174 (2013). PubMed DOI

Mia, M. et al. Loss of Yap/Taz in cardiac fibroblasts attenuates adverse remodeling and improves cardiac function. Cardiovasc. Res. 118, 1785–1804 (2022). PubMed DOI

Wong, V. W. et al. Mechanical force prolongs acute inflammation via T-cell-dependent pathways during scar formation. FASEB J. 25, 4498–4510 (2011). PubMed DOI

Li, C. et al. Mineralocorticoid receptor deficiency in T cells attenuates pressure overload-induced cardiac hypertrophy and dysfunction through modulating T-cell activation. Hypertension 70, 137–147 (2017). PubMed DOI

Sun, X. J. et al. Deletion of interleukin 1 receptor-associated kinase 1 (Irak1) improves glucose tolerance primarily by increasing insulin sensitivity in skeletal muscle. J. Biol. Chem. 292, 12339–12350 (2017). PubMed DOI PMC

Huang, H. W., Fang, X. X., Wang, X. Q., Peng, Y. P. & Qiu, Y. H. Regulation of differentiation and function of helper T cells by lymphocyte-derived catecholamines via α PubMed DOI

Woodall, M. C., Woodall, B. P., Gao, E., Yuan, A. & Koch, W. J. Cardiac fibroblast GRK2 deletion enhances contractility and remodeling following ischemia/reperfusion injury. Circ. Res. 119, 1116–1127 (2016). PubMed DOI PMC

Travers, J. G. et al. Pharmacological and activated fibroblast targeting of Gβγ-GRK2 after myocardial ischemia attenuates heart failure progression. J. Am. Coll. Cardiol. 70, 958–971 (2017). PubMed DOI PMC

Sorrentino, G. et al. Metabolic control of YAP and TAZ by the mevalonate pathway. Nat. Cell Biol. 16, 357–366 (2014). PubMed DOI

Iaccarino, G. et al. Elevated myocardial and lymphocyte GRK2 expression and activity in human heart failure. Eur. Heart J. 26, 1752–1758 (2005). PubMed DOI

Mia, M. M. et al. YAP/TAZ deficiency reprograms macrophage phenotype and improves infarct healing and cardiac function after myocardial infarction. PLoS Biol. 18, e3000941 (2020). PubMed DOI PMC

Wang, D. et al. YAP promotes the activation of NLRP3 inflammasome via blocking K27-linked polyubiquitination of NLRP3. Nat. Commun. 12, 2674 (2021). PubMed DOI PMC

Wu, Y. et al. Helicobacter pylori-induced YAP1 nuclear translocation promotes gastric carcinogenesis by enhancing IL-1β expression. Cancer Med. 8, 3965–3980 (2019). PubMed DOI PMC

Ramjee, V. et al. Epicardial YAP/TAZ orchestrate an immunosuppressive response following myocardial infarction. J. Clin. Invest. 127, 899–911 (2017). PubMed DOI PMC

Tomasek, J. J., Gabbiani, G., Hinz, B., Chaponnier, C. & Brown, R. A. Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat. Rev. Mol. Cell Biol. 3, 349–363 (2002). PubMed DOI

Negmadjanov, U. et al. TGF-β1-mediated differentiation of fibroblasts is associated with increased mitochondrial content and cellular respiration. PLoS ONE 10, e0123046 (2015). PubMed DOI PMC

Emelyanova, L. et al. Impact of statins on cellular respiration and de-differentiation of myofibroblasts in human failing hearts. ESC Heart Fail. 6, 1027–1040 (2019). PubMed DOI PMC

Van Linthout, S. et al. Anti-inflammatory effects of atorvastatin improve left ventricular function in experimental diabetic cardiomyopathy. Diabetologia 50, 1977–1986 (2007). PubMed DOI

Van Linthout, S. et al. Human apolipoprotein A-I gene transfer reduces the development of experimental diabetic cardiomyopathy. Circulation 117, 1563–1573 (2008). PubMed DOI

Van Linthout, S. et al. Reduced MMP-2 activity contributes to cardiac fibrosis in experimental diabetic cardiomyopathy. Basic. Res. Cardiol. 103, 319–327 (2008). PubMed DOI

Spillmann, F. et al. High-density lipoproteins reduce palmitate-induced cardiomyocyte apoptosis in an AMPK-dependent manner. Biochem. Biophys. Res. Commun. 466, 272–277 (2015). PubMed DOI

Beauloye, C., Bertrand, L., Horman, S. & Hue, L. AMPK activation, a preventive therapeutic target in the transition from cardiac injury to heart failure. Cardiovasc. Res. 90, 224–233 (2011). PubMed DOI

Wang, W. et al. AMPK modulates Hippo pathway activity to regulate energy homeostasis. Nat. Cell Biol. 17, 490–499 (2015). PubMed DOI PMC

Vinci, M. C., Polvani, G. & Pesce, M. Epigenetic programming and risk: the birthplace of cardiovascular disease? Stem Cell Rev. Rep. 9, 241–253 (2013). PubMed DOI

Felisbino, M. B. & McKinsey, T. A. Epigenetics in cardiac fibrosis: emphasis on inflammation and fibroblast activation. JACC Basic. Transl Sci. 3, 704–715 (2018). PubMed DOI PMC

Yang, C., Tibbitt, M. W., Basta, L. & Anseth, K. S. Mechanical memory and dosing influence stem cell fate. Nat. Mater. 13, 645–652 (2014). PubMed DOI PMC

Stewart-Morgan, K. R., Petryk, N. & Groth, A. Chromatin replication and epigenetic cell memory. Nat. Cell Biol. 22, 361–371 (2020). PubMed DOI

Ferrari, S. & Pesce, M. Cell-based mechanosensation, epigenetics, and non-coding RNAs in progression of cardiac fibrosis. Int. J. Mol. Sci. 21, 28 (2019). PubMed DOI PMC

Santinon, G., Pocaterra, A. & Dupont, S. Control of YAP/TAZ activity by metabolic and nutrient-sensing pathways. Trends Cell Biol. 26, 289–299 (2016). PubMed DOI

Lin, Z. et al. Acetylation of VGLL4 regulates Hippo-YAP signaling and postnatal cardiac growth. Dev. Cell 39, 466–479 (2016). PubMed DOI PMC

Levy, L. et al. Acetylation of β-catenin by p300 regulates β-catenin-Tcf4 interaction. Mol. Cell Biol. 24, 3404–3414 (2004). PubMed DOI PMC

Yang, Y., Li, Z., Guo, J. & Xu, Y. Deacetylation of MRTF-A by SIRT1 defies senescence induced down-regulation of collagen type I in fibroblast cells. Biochim. Biophys. Acta Mol. Basis Dis. 1866, 165723 (2020). PubMed DOI

Bradshaw, P. C. Acetyl-CoA metabolism and histone acetylation in the regulation of aging and lifespan. Antioxidants 10, 572 (2021). PubMed DOI PMC

Francois, A., Canella, A., Marcho, L. M. & Stratton, M. S. Protein acetylation in cardiac aging. J. Mol. Cell. Cardiol. 157, 90–97 (2021). PubMed DOI PMC

Kimball, T. H. & Vondriska, T. M. Metabolism, epigenetics, and causal inference in heart failure. Trends Endocrinol. Metab. 31, 181–191 (2020). PubMed DOI

Ferrari, S. & Pesce, M. Stiffness and aging in cardiovascular diseases: the dangerous relationship between force and senescence. Int. J. Mol. Sci. 22, 3404 (2021). PubMed DOI PMC

Osmanagic-Myers, S., Dechat, T. & Foisner, R. Lamins at the crossroads of mechanosignaling. Genes Dev. 29, 225–237 (2015). PubMed DOI PMC

Hampoelz, B. & Lecuit, T. Nuclear mechanics in differentiation and development. Curr. Opin. Cell Biol. 23, 668–675 (2011). PubMed DOI

Maeshima, K., Tamura, S. & Shimamoto, Y. Chromatin as a nuclear spring. Biophys. Physicobiol. 15, 189–195 (2018). PubMed DOI PMC

Kupfer, M. E. et al. In situ expansion, differentiation, and electromechanical coupling of human cardiac muscle in a 3D bioprinted, chambered organoid. Circ. Res. 127, 207–224 (2020). PubMed DOI PMC

Drakhlis, L. et al. Human heart-forming organoids recapitulate early heart and foregut development. Nat. Biotechnol. 39, 737–746 (2021). PubMed DOI PMC

Tiburcy, M. et al. Defined engineered human myocardium with advanced maturation for applications in heart failure modeling and repair. Circulation 135, 1832–1847 (2017). PubMed DOI PMC

Ott, H. C. et al. Perfusion-decellularized matrix: using nature’s platform to engineer a bioartificial heart. Nat. Med. 14, 213–221 (2008). PubMed DOI

Kanoldt, V., Fischer, L. & Grashoff, C. Unforgettable force – crosstalk and memory of mechanosensitive structures. Biol. Chem. 400, 687–698 (2019). PubMed DOI

Norman, M. D. A., Ferreira, S. A., Jowett, G. M., Bozec, L. & Gentleman, E. Measuring the elastic modulus of soft culture surfaces and three-dimensional hydrogels using atomic force microscopy. Nat. Protoc. 16, 2418–2449 (2021). PubMed DOI

Sadeghi, A. H. et al. Engineered 3D cardiac fibrotic tissue to study fibrotic remodeling. Adv. Healthc. Mater. 6, 1601434 (2017). DOI

Bracco Gartner, T. C. L. et al. Anti-fibrotic effects of cardiac progenitor cells in a 3D-model of human cardiac fibrosis. Front. Cardiovasc. Med. 6, 52 (2019). PubMed DOI PMC

Ragazzini, S. et al. Mechanosensor YAP cooperates with TGF-β1 signaling to promote myofibroblast activation and matrix stiffening in a 3D model of human cardiac fibrosis. Acta Biomater. 152, 300–312 (2022). PubMed DOI

Wang, H., Haeger, S. M., Kloxin, A. M., Leinwand, L. A. & Anseth, K. S. Redirecting valvular myofibroblasts into dormant fibroblasts through light-mediated reduction in substrate modulus. PLoS ONE 7, e39969 (2012). PubMed DOI PMC

Milani-Nejad, N. & Janssen, P. M. Small and large animal models in cardiac contraction research: advantages and disadvantages. Pharmacol. Ther. 141, 235–249 (2014). PubMed DOI

Abramochkin, D. V., Lozinsky, I. T. & Kamkin, A. Influence of mechanical stress on fibroblast–myocyte interactions in mammalian heart. J. Mol. Cell. Cardiol. 70, 27–36 (2014). PubMed DOI

Li, X., Garcia-Elias, A., Benito, B. & Nattel, S. The effects of cardiac stretch on atrial fibroblasts: analysis of the evidence and potential role in atrial fibrillation. Cardiovasc. Res. 118, 440–460 (2022). PubMed DOI

Guo, Y. et al. Extracellular matrix of mechanically stretched cardiac fibroblasts improves viability and metabolic activity of ventricular cells. Int. J. Med. Sci. 10, 1837–1845 (2013). PubMed DOI PMC

Papakrivopoulou, J., Lindahl, G. E., Bishop, J. E. & Laurent, G. J. Differential roles of extracellular signal-regulated kinase 1/2 and p38 PubMed DOI

Watson, C. J. et al. Mechanical stretch up-regulates the B-type natriuretic peptide system in human cardiac fibroblasts: a possible defense against transforming growth factor-β mediated fibrosis. Fibrogenes. Tissue Repair 5, 9 (2012). DOI

Watson, C. J. et al. Extracellular matrix sub-types and mechanical stretch impact human cardiac fibroblast responses to transforming growth factor beta. Connect. Tissue Res. 55, 248–256 (2014). PubMed DOI

Li, Y., Asfour, H. & Bursac, N. Age-dependent functional crosstalk between cardiac fibroblasts and cardiomyocytes in a 3D engineered cardiac tissue. Acta Biomater. 55, 120–130 (2017). PubMed DOI PMC

Kreutzer, F. P. et al. Development and characterization of anti-fibrotic natural compound similars with improved effectivity. Basic. Res. Cardiol. 117, 9 (2022). PubMed DOI PMC

Perbellini, F. & Thum, T. Living myocardial slices: a novel multicellular model for cardiac translational research. Eur. Heart J. 41, 2405–2408 (2020). PubMed DOI

Valls-Margarit, M. et al. Engineered macroscale cardiac constructs elicit human myocardial tissue-like functionality. Stem Cell Rep. 13, 207–220 (2019). DOI

Salvi, M. et al. Automated segmentation of fluorescence microscopy images for 3D cell detection in human-derived cardiospheres. Sci. Rep. 9, 6644 (2019). PubMed DOI PMC

Neuber, S., Nazari-Shafti, T. Z., Nugraha, B., Falk, V. & Emmert, M. Y. The link between regeneration and extracellular matrix in the heart – can three-dimensional in vitro models uncover it? Eur. Heart J. 42, 2518–2522 (2021). PubMed DOI

de Boer, R. A. et al. Towards better definition, quantification and treatment of fibrosis in heart failure. A scientific roadmap by the Committee of Translational Research of the Heart Failure Association (HFA) of the European Society of Cardiology. Eur. J. Heart Fail. 21, 272–285 (2019). PubMed DOI

Santos, G. L., Hartmann, S., Zimmermann, W. H., Ridley, A. & Lutz, S. Inhibition of Rho-associated kinases suppresses cardiac myofibroblast function in engineered connective and heart muscle tissues. J. Mol. Cell. Cardiol. 134, 13–28 (2019). PubMed DOI

Francisco, J. et al. Blockade of fibroblast YAP attenuates cardiac fibrosis and dysfunction through MRTF-A inhibition. JACC Basic. Transl Sci. 5, 931–945 (2020). PubMed DOI PMC

Nagaraju, C. K. et al. Myofibroblast phenotype and reversibility of fibrosis in patients with end-stage heart failure. J. Am. Coll. Cardiol. 73, 2267–2282 (2019). PubMed DOI

Tzahor, E. & Poss, K. D. Cardiac regeneration strategies: staying young at heart. Science 356, 1035–1039 (2017). PubMed DOI PMC

Leach, J. P. et al. Hippo pathway deficiency reverses systolic heart failure after infarction. Nature 550, 260–264 (2017). PubMed DOI PMC

Wang, J., Liu, S., Heallen, T. & Martin, J. F. The Hippo pathway in the heart: pivotal roles in development, disease, and regeneration. Nat. Rev. Cardiol. 15, 672–684 (2018). PubMed DOI

Bouvet, M. et al. Anti-integrin α PubMed DOI PMC

Esposito, M. L. et al. Left ventricular unloading before reperfusion promotes functional recovery after acute myocardial infarction. J. Am. Coll. Cardiol. 72, 501–514 (2018). PubMed DOI PMC

Spillmann, F. et al. Mode-of-action of the PROPELLA concept in fulminant myocarditis. Eur. Heart J. 40, 2164–2169 (2019). PubMed DOI PMC

Burkhoff, D., Topkara, V. K., Sayer, G. & Uriel, N. Reverse remodeling with left ventricular assist devices. Circ. Res. 128, 1594–1612 (2021). PubMed DOI PMC

Levin, H. R. et al. Reversal of chronic ventricular dilation in patients with end-stage cardiomyopathy by prolonged mechanical unloading. Circulation 91, 2717–2720 (1995). PubMed DOI

Mann, D. L., Barger, P. M. & Burkhoff, D. Myocardial recovery and the failing heart: myth, magic, or molecular target? J. Am. Coll. Cardiol. 60, 2465–2472 (2012). PubMed DOI PMC

Birks, E. J. et al. Prospective multicenter study of myocardial recovery using left ventricular assist devices (RESTAGE-HF [Remission from Stage D Heart Failure]): medium-term and primary end point results. Circulation 142, 2016–2028 (2020). PubMed DOI

Diakos, N. A. et al. Myocardial atrophy and chronic mechanical unloading of the failing human heart: implications for cardiac assist device-induced myocardial recovery. J. Am. Coll. Cardiol. 64, 1602–1612 (2014). PubMed DOI

Terracciano, C. M. et al. Clinical recovery from end-stage heart failure using left-ventricular assist device and pharmacological therapy correlates with increased sarcoplasmic reticulum calcium content but not with regression of cellular hypertrophy. Circulation 109, 2263–2265 (2004). PubMed DOI

Diakos, N. A. et al. Evidence of glycolysis up-regulation and pyruvate mitochondrial oxidation mismatch during mechanical unloading of the failing human heart: implications for cardiac reloading and conditioning. JACC Basic Transl Sci. 1, 432–444 (2016). PubMed DOI PMC

Vatta, M. et al. Molecular remodelling of dystrophin in patients with end-stage cardiomyopathies and reversal in patients on assistance-device therapy. Lancet 359, 936–941 (2002). PubMed DOI

Canseco, D. C. et al. Human ventricular unloading induces cardiomyocyte proliferation. J. Am. Coll. Cardiol. 65, 892–900 (2015). PubMed DOI PMC

Symons, J. D. et al. Effect of continuous-flow left ventricular assist device support on coronary artery endothelial function in ischemic and nonischemic cardiomyopathy. Circ. Heart Fail. 12, e006085 (2019). PubMed DOI

Castillero, E. et al. Structural and functional cardiac profile after prolonged duration of mechanical unloading: potential implications for myocardial recovery. Am. J. Physiol. Heart Circ. Physiol. 315, H1463–H1476 (2018). PubMed DOI PMC

Klotz, S. et al. Left ventricular assist device support normalizes left and right ventricular beta-adrenergic pathway properties. J. Am. Coll. Cardiol. 45, 668–676 (2005). PubMed DOI

Bruckner, B. A. et al. Degree of cardiac fibrosis and hypertrophy at time of implantation predicts myocardial improvement during left ventricular assist device support. J. Heart Lung Transpl. 23, 36–42 (2004). DOI

Segura, A. M., Frazier, O. H., Demirozu, Z. & Buja, L. M. Histopathologic correlates of myocardial improvement in patients supported by a left ventricular assist device. Cardiovasc. Pathol. 20, 139–145 (2011). PubMed DOI

Pan, S. et al. Incidence and predictors of myocardial recovery on long-term left ventricular assist device support: results from the United Network for Organ Sharing database. J. Heart Lung Transpl. 34, 1624–1629 (2015). DOI

Topkara, V. K. et al. Myocardial recovery in patients receiving contemporary left ventricular assist devices: results from the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS). Circ. Heart Fail. 9, e003157 (2016). PubMed DOI

Wever-Pinzon, O. et al. Cardiac recovery during long-term left ventricular assist device support. J. Am. Coll. Cardiol. 68, 1540–1553 (2016). PubMed DOI

Margulies, K. B. et al. Mixed messages: transcription patterns in failing and recovering human myocardium. Circ. Res. 96, 592–599 (2005). PubMed DOI

Yang, K. C. et al. Deep RNA sequencing reveals dynamic regulation of myocardial noncoding RNAs in failing human heart and remodeling with mechanical circulatory support. Circulation 129, 1009–1021 (2014). PubMed DOI PMC

Tschope, C. et al. Mechanical unloading by fulminant myocarditis: LV-IMPELLA, ECMELLA, BI-PELLA, and PROPELLA concepts. J. Cardiovasc. Transl Res. 12, 116–123 (2019). PubMed DOI

Weinheimer, C. J. et al. Load-dependent changes in left ventricular structure and function in a pathophysiologically relevant murine model of reversible heart failure. Circ. Heart Fail. 11, e004351 (2018). PubMed DOI PMC

Oriyanhan, W. et al. Determination of optimal duration of mechanical unloading for failing hearts to achieve bridge to recovery in a rat heterotopic heart transplantation model. J. Heart Lung Transpl. 26, 16–23 (2007). DOI

Webber, M., Jackson, S. P., Moon, J. C. & Captur, G. Myocardial fibrosis in heart failure: anti-fibrotic therapies and the role of cardiovascular magnetic resonance in drug trials. Cardiol. Ther. 9, 363–376 (2020). PubMed DOI PMC

Pezel, T. et al. Imaging interstitial fibrosis, left ventricular remodeling, and function in stage A and B heart failure. JACC Cardiovasc. Imaging 14, 1038–1052 (2021). PubMed DOI

Khalique, Z. et al. Diffusion tensor cardiovascular magnetic resonance in cardiac amyloidosis. Circ. Cardiovasc. Imaging 13, e009901 (2020). PubMed DOI PMC

Tschope, C. et al. Cardiac contractility modulation: mechanisms of action in heart failure with reduced ejection fraction and beyond. Eur. J. Heart Fail. 21, 14–22 (2019). PubMed DOI

Daneshgar, A. et al. The human liver matrisome – proteomic analysis of native and fibrotic human liver extracellular matrices for organ engineering approaches. Biomaterials 257, 120247 (2020). PubMed DOI

Moriel, N. et al. NovoSpaRc: flexible spatial reconstruction of single-cell gene expression with optimal transport. Nat. Protoc. 16, 4177–4200 (2021). PubMed DOI

Aghajanian, H. et al. Targeting cardiac fibrosis with engineered T cells. Nature 573, 430–433 (2019). PubMed DOI PMC

Rurik, J. G. et al. CAR T cells produced in vivo to treat cardiac injury. Science 375, 91–96 (2022). PubMed DOI PMC

Croft, A. P. et al. Distinct fibroblast subsets drive inflammation and damage in arthritis. Nature 570, 246–251 (2019). PubMed DOI PMC

Nguyen, P. D., de Bakker, D. E. M. & Bakkers, J. Cardiac regenerative capacity: an evolutionary afterthought. Cell. Mol. Life Sci. 78, 5107–5122 (2021). PubMed DOI PMC

Silva, A. C., Pereira, C., Fonseca, A., Pinto-do, O. P. & Nascimento, D. S. Bearing my heart: the role of extracellular matrix on cardiac development, homeostasis, and injury response. Front. Cell Dev. Biol. 8, 621644 (2020). PubMed DOI

Pesce, M., Messina, E., Chimenti, I. & Beltrami, A. P. Cardiac mechanoperception: a life-long story from early beats to aging and failure. Stem Cell Dev. 26, 77–90 (2017). DOI

del Rio, A. et al. Stretching single talin rod molecules activates vinculin binding. Science 323, 638–641 (2009). PubMed DOI PMC

Fibrotic extracellular matrix impacts cardiomyocyte phenotype and function in an iPSC-derived isogenic model of cardiac fibrosis