The Experts below are selected from a list of 17274 Experts worldwide ranked by ideXlab platform

Charles Antzelevitch - One of the best experts on this subject based on the ideXlab platform.

  • differences in the electrophysiological response of canine ventricular Epicardium and endocardium to ischemia role of the transient outward current
    Circulation, 1993
    Co-Authors: Anton Lukas, Charles Antzelevitch
    Abstract:

    BACKGROUND Acute ischemia is known to produce more severe electrophysiological disturbances in canine ventricular Epicardium than endocardium, although the mechanism for the differential sensitivity is still unresolved. Recent studies have demonstrated the presence of a prominent transient outward current (Ito) in ventricular Epicardium but not endocardium. The present study was designed to test the hypothesis that the differential sensitivity of these two tissues to ischemia results, at least in part, from a more prominent Ito in Epicardium than in endocardium. METHODS AND RESULTS Isolated canine ventricular epicardial and endocardial tissues and myocytes were studied by standard microelectrode techniques. Simulated ischemia (hyperkalemia, hypoxia, and acidosis) abolished the action potential plateau and caused a 50% to 60% shortening of action potential duration in Epicardium but only a 10% to 20% shortening in endocardium. 4-Aminopyridine, an Ito inhibitor, restored the plateau in Epicardium and reduced the dispersion of action potential duration between Epicardium and endocardium. Stimulation protocols that minimized the contribution of Ito, such as acceleration of the stimulation rate or introduction of early premature beats, produced a paradoxical prolongation of the epicardial response caused by restoration of the action potential dome. Thus, ischemia-induced dispersion of repolarization was greatly diminished at rapid rates and after premature beats. Similar results were obtained in tissues and myocytes obtained from the same myocardial layers, suggesting that the differential sensitivities of Epicardium and endocardium to ischemia are largely a result of inherent differences in cellular properties. CONCLUSIONS Our data suggest that the presence of a prominent Ito in Epicardium but not endocardium contributes importantly to the selective electrical depression of Epicardium by simulated ischemia. The repolarizing influence of Ito serves to amplify the ischemia-induced changes in inward (ICa and INa) and outward (calcium-activated) currents. By facilitating loss of the dome in Epicardium, Ito contributes to the development of a marked dispersion of repolarization between normal and ischemic Epicardium and between Epicardium and endocardium, thereby providing the electrophysiological substrate for the genesis of reentrant arrhythmias.

  • pinacidil induced electrical heterogeneity and extrasystolic activity in canine ventricular tissues does activation of atp regulated potassium current promote phase 2 reentry
    Circulation, 1993
    Co-Authors: J M Di Diego, Charles Antzelevitch
    Abstract:

    BACKGROUNDPinacidil is known to augment a time-independent outward current in cardiac tissues by activating the ATP-regulated potassium channels. Activation of this current, IK-ATP, is thought to be responsible for increased potassium permeability in ischemia. The contribution of IK-ATP activation to arrhythmogenesis and the role of activation of this current in suppression of arrhythmias are areas of great interest and debate. Because electrical depression attending myocardial ischemia is more accentuated in ventricular Epicardium than in endocardium, we endeavored to contrast the effects of pinacidil-induced IK-ATP activation on the electrophysiology of canine ventricular Epicardium and endocardium.METHODS AND RESULTSStandard microelectrode techniques were used. Pinacidil (1 to 5 mumol/L) produced a marked dispersion of repolarization and refractoriness in isolated canine ventricular Epicardium as well as between Epicardium and endocardium. In endocardium, pinacidil abbreviated action potential duration...

  • flecainide induced arrhythmia in canine ventricular Epicardium phase 2 reentry
    Circulation, 1993
    Co-Authors: S C Krishnan, Charles Antzelevitch
    Abstract:

    BACKGROUNDWe recently reported that sodium channel block can produce opposite effects on action potential duration (APD) and refractoriness in epicardial versus endocardial tissues of the canine ventricle. In addition, strong sodium channel current inhibition was found to cause loss of the action potential dome in Epicardium but not endocardium, thus inducing a marked dispersion of repolarization and refractoriness between Epicardium and endocardium as well as among neighboring epicardial sites. The marked heterogeneity that evolves under these conditions provides a substrate for the development of arrhythmias. Flecainide was found to induce extrasystolic activity more readily than other sodium blockers. The present study contrasts the electrophysiological actions of flecainide in canine ventricular Epicardium and endocardium and examines the characteristics of flecainide-induced arrhythmias in epicardial sheets of canine ventricle.METHODS AND RESULTSStandard microelectrode techniques were used. Flecainid...

  • a subpopulation of cells with unique electrophysiological properties in the deep subEpicardium of the canine ventricle the m cell
    Circulation Research, 1991
    Co-Authors: Serge Sicouri, Charles Antzelevitch
    Abstract:

    Recent studies have shown that canine ventricular Epicardium and endocardium differ with respect to electrophysiological characteristics and pharmacological responsiveness and that these differences are in large part due to the presence of a prominent transient outward current Ito and a spike-and-dome morphology of the action potential in Epicardium but not endocardium. In attempting to quantitate these differences and assess their gradation across the ventricular wall, we encountered a subpopulation of cells in the deep subepicardial layers with electrophysiological characteristics different from those of either Epicardium or endocardium. These cells, which we have termed M cells, display a spike-and-dome morphology typical of Epicardium but a maximal rate of rise of the action potential upstroke that is considerably greater than that of either Epicardium or endocardium. Using the restitution of the amplitude of phase 1 of the action potential as a marker for the reactivation of Ito, we showed M cells to...

Paul R. Riley - One of the best experts on this subject based on the ideXlab platform.

  • The ontogeny, activation and function of the Epicardium during heart development and regeneration.
    Development (Cambridge England), 2018
    Co-Authors: Filipa C. Simões, Paul R. Riley
    Abstract:

    The Epicardium plays a key role during cardiac development, homeostasis and repair, and has thus emerged as a potential target in the treatment of cardiovascular disease. However, therapeutically manipulating the Epicardium and Epicardium-derived cells (EPDCs) requires insights into their developmental origin and the mechanisms driving their activation, recruitment and contribution to both the embryonic and adult injured heart. In recent years, studies of various model systems have provided us with a deeper understanding of the microenvironment in which EPDCs reside and emerge into, of the crosstalk between the multitude of cardiovascular cell types that influence the Epicardium, and of the genetic programmes that orchestrate epicardial cell behaviour. Here, we review these discoveries and discuss how technological advances could further enhance our knowledge of Epicardium-based repair mechanisms and ultimately influence potential therapeutic outcomes in cardiovascular regenerative medicine.

  • Current Protocols in Stem Cell Biology - The Derivation of Primary Human Epicardium-Derived Cells.
    Current protocols in stem cell biology, 2015
    Co-Authors: Caitlin Clunie‐o'connor, Anke M. Smits, Marie-josé Goumans, Charalambos Antoniades, Angela J. Russell, Derek M. Yellon, Paul R. Riley
    Abstract:

    To develop therapeutic strategies for the regeneration of lost heart muscle after myocardial infarction (MI), a source of functional new muscle cells and associated coronary vessels must be identified. The Epicardium is a source of several cardiovascular cell types during heart development and is widely regarded as a resident progenitor population, which becomes dormant during adulthood. In adult mice, MI induces epicardial reactivation characterized by an upregulation of fetal genes and subsequent Epicardium derived cell (EPDC) proliferation, migration, and differentiation. Determining whether the Epicardium can be therapeutically targeted following cardiovascular disease requires an in vitro system for the study of adult human EPDCs (hEPDCs). This protocol describes techniques to establish and maintain human Epicardium explant cultures from patient-derived right atrial appendage biopsies and documents methods to probe the resultant outgrowth of hEPDCs. The model facilitates a high-throughput approach to either genetic or chemical phenotypic screening for drug-like modifiers of hEPDC activation and potential cell fate.

  • the derivation of primary human Epicardium derived cells
    Current protocols in stem cell biology, 2015
    Co-Authors: Caitlin Clunieoconnor, Anke M. Smits, Marie-josé Goumans, Charalambos Antoniades, Angela J. Russell, Derek M. Yellon, Paul R. Riley
    Abstract:

    To develop therapeutic strategies for the regeneration of lost heart muscle after myocardial infarction (MI), a source of functional new muscle cells and associated coronary vessels must be identified. The Epicardium is a source of several cardiovascular cell types during heart development and is widely regarded as a resident progenitor population, which becomes dormant during adulthood. In adult mice, MI induces epicardial reactivation characterized by an upregulation of fetal genes and subsequent Epicardium derived cell (EPDC) proliferation, migration, and differentiation. Determining whether the Epicardium can be therapeutically targeted following cardiovascular disease requires an in vitro system for the study of adult human EPDCs (hEPDCs). This protocol describes techniques to establish and maintain human Epicardium explant cultures from patient-derived right atrial appendage biopsies and documents methods to probe the resultant outgrowth of hEPDCs. The model facilitates a high-throughput approach to either genetic or chemical phenotypic screening for drug-like modifiers of hEPDC activation and potential cell fate.

  • Characterisation of the human embryonic and foetal Epicardium during heart development.
    Development (Cambridge England), 2015
    Co-Authors: Catherine A. Risebro, Joaquim M. Vieira, Linda Klotz, Paul R. Riley
    Abstract:

    The Epicardium is essential for mammalian heart development. At present, our understanding of the timing and morphogenetic events leading to the formation of the human Epicardium has essentially been extrapolated from model organisms. Here, we studied primary tissue samples to characterise human Epicardium development. We reveal that the Epicardium begins to envelop the myocardial surface at Carnegie stage (CS) 11 and this process is completed by CS15, earlier than previously inferred from avian studies. Contrary to prevailing dogma, the formed human Epicardium is not a simple squamous epithelium and we reveal evidence of more complex structure, including novel spatial differences aligned to the developing chambers. Specifically, the ventricular, but not atrial, Epicardium exhibited areas of expanded epithelium, preferential cell alignment and spindle-like morphology. Likewise, we reveal distinct properties ex vivo, such that ventricular cells spontaneously differentiate and lose epicardial identity, whereas atrial-derived cells remained ‘epithelial-like’. These data provide insight into the developing human Epicardium that may contribute to our understanding of congenital heart disease and have implications for the development of strategies for endogenous cell-based cardiac repair.

  • The Epicardium signals the way towards heart regeneration.
    Stem cell research, 2014
    Co-Authors: Megan Masters, Paul R. Riley
    Abstract:

    From historical studies of developing chick hearts to recent advances in regenerative injury models, the Epicardium has arisen as a key player in heart genesis and repair. The Epicardium provides paracrine signals to nurture growth of the developing heart from mid-gestation, and Epicardium-derived cells act as progenitors of numerous cardiac cell types. Interference with either process is terminal for heart development and embryogenesis. In adulthood, the dormant Epicardium reinstates an embryonic gene programme in response to injury. Furthermore, injury-induced epicardial signalling is essential for heart regeneration in zebrafish. Given these critical roles in development, injury response and heart regeneration, the application of epicardial signals following adult heart injury could offer therapeutic strategies for the treatment of ischaemic heart disease and heart failure.

Bin Zhou - One of the best experts on this subject based on the ideXlab platform.

  • thymosin β4 released from functionalized self assembling peptide activates Epicardium and enhances repair of infarcted myocardium
    Theranostics, 2021
    Co-Authors: Yongli Wang, Bin Zhou, Haoran Shen, Haijie Wang, Qiangli Wang, Yuzhen Tan
    Abstract:

    The Epicardium plays an important role in cardiomyogenesis during development, while it becomes quiescent in adult heart during homeostasis. This study investigates the efficiency of thymosin β4 (Tβ4) release with RPRHQGVM conjugated to the C-terminus of RADA16-I (RADA-RPR), the functionalized self-assembling peptide (SAP), to activate the Epicardium and repairing the infarcted myocardium. Methods: The functionalized SAP was constituted with self-assembling motif, Tβ4-binding site, and cell adhesive ligand. Myocardial infarction (MI) models of the transgenic mice were established by ligation of the left anterior descending coronary artery. At one week after intramyocardial injection of Tβ4-conjugated SAP, the activation of the Epicardium was assessed. At four weeks after implantation, the migration and differentiation of Epicardium-derived cells (EPDCs) as well as angiogenesis, lymphangiogenesis and myocardial regeneration were examined. Results: We found that the designer RADA-RPR bound Tβ4 and adhered to EPDCs and that Tβ4 released from the functionalized SAP could effectively activate the Epicardium and induce EPDCs to differentiate towards cardiovascular cells as well as lymphatic endothelial cells. Moreover, SAP-released Tβ4 (SAP-Tβ4) promoted proliferation of cardiomyocytes. Furthermore, angiogenesis, lymphangiogenesis and myocardial regeneration were enhanced in the MI models at 4 weeks after delivery of SAP-Tβ4 along with attenuation of adverse myocardial remodeling and significantly improved cardiac function. Conclusions: These results demonstrate that sustained release of Tβ4 from the functionalized SAP can activate the Epicardium and effectively enhance the repair of infarcted myocardium. We believe the delivery of SAP-Tβ4 may be a promising strategy for MI therapy.

  • Epicardium is required for cardiac seeding by yolk sac macrophages precursors of resident macrophages of the adult heart
    Developmental Biology, 2016
    Co-Authors: Sean M Stevens, Alexander Von Gise, Nathan J Vandusen, Bin Zhou
    Abstract:

    A subset of macrophages that reside in adult tissues originate from the fetal yolk sac, while others derive from circulating monocytes. These ontologically different macrophage subsets have distinct roles in tissue injury responses, with the embryonic population overall having beneficial activity in cardiac repair. Here we show that fetal yolk macrophages are recruited to a niche within and just below the Epicardium, the mesothelial covering of the heart. The Epicardium was required for establishment of yolk sac macrophages in this region of the fetal heart, and this function of Epicardium depended on its expression of the transcription factor WT1. Thus, tissue-specific cues and transcriptional programs recruit or retain embryonic macrophages in their final abodes, where they help to shape organ homeostasis and injury responses.

  • thymosin beta 4 treatment after myocardial infarction does not reprogram epicardial cells into cardiomyocytes
    Journal of Molecular and Cellular Cardiology, 2012
    Co-Authors: Alexander Von Gise, Bin Zhou, Leah B Honor, Ruei-zeng Lin, Juan M Meleromartin, Pingzhu Zhou, Hui Zhang, Yuebo Zhang
    Abstract:

    Myocardial infarction (MI) is one of the leading causes of morbidity and mortality world-wide. Whether endogenous repair and regenerative ability could be augmented by drug administration is an important issue for generation of novel therapeutic approach. Recently it was reported that in mice pretreated with thymosin beta 4 (TB4) and subsequently subjected to experimental MI, a subset of epicardial cells differentiated into cardiomyocytes. In clinical settings, epicardial priming with TB4 prior to MI is impractical. Here we tested if TB4 treatment after MI could reprogram Epicardium into cardiomyocytes and augment the Epicardium's injury response. Using Epicardium genetic lineage trace line Wt1(CreERT2/+) and double reporter line Rosa26(mTmG/+), we found post-MI TB4 treatment significantly increased the thickness of Epicardium and coronary capillary density. However, Epicardium-derived cells did not adopt cardiomyocyte fate, nor did they migrate into myocardium to become coronary endothelial cells. Our result thus indicates that TB4 treatment after MI does not alter epicardial cell fate to include the cardiomyocyte lineage, providing both cautions and insights for the full exploration of the potential benefits of TB4 in the clinical settings. This article is part of a Special Issue entitled 'Possible Editorial'.

  • Isolation and characterization of embryonic and adult Epicardium and Epicardium-derived cells.
    Methods in molecular biology (Clifton N.J.), 2011
    Co-Authors: Bin Zhou
    Abstract:

    Epicardium is the outer cell layer of the heart. Its integrity and function are essential for normal heart development. To study the role of Epicardium in both fetal and adult hearts, it is desirable to isolate and culture pure populations of these cells. Here we describe methods with Cre-loxP technology to lineage tag epicardial cells (EpiCs) and Epicardium-derived cells (EPDCs), dissociate and isolate them by flow-activated cytometry sorting (FACS), and characterize them by quantitative PCR and immunostaining. This platform allows further characterization and manipulation of EpiCs and EPDCs for expression studies and functional assays.

  • wt1 regulates epicardial epithelial to mesenchymal transition through β catenin and retinoic acid signaling pathways
    Developmental Biology, 2011
    Co-Authors: Alexander Von Gise, Bin Zhou, Leah B Honor, Anna Petryk
    Abstract:

    An epithelial sheet, the Epicardium, lines the surface of the heart. In the developing embryo, the Epicardium expresses the transcriptional regulator Wilm's Tumor Gene 1 (Wt1). Through incompletely understood mechanisms, Wt1 inactivation derails normal heart development. We investigated mechanisms by which Wt1 regulates heart development and epicardial epithelial to mesenchymal transition (EMT). We used genetic lineage tracing approaches to track and isolate Epicardium and Epicardium derivatives in hearts lacking Wt1 (Wt1(KO)). Wt1(KO) hearts had diminished proliferation of compact myocardium and impaired coronary plexus formation. Wt1(KO) Epicardium failed to undergo EMT. Wt1(KO) Epicardium expressed reduced Lef1 and Ctnnb1 (β-catenin), key components of the canonical Wnt/β-catenin signaling pathway. Wt1(KO) Epicardium expressed decreased levels of canonical Wnt downstream targets Axin2, Cyclin D1, and Cyclin D2 and exhibited decreased activity of the Batgal Wnt/β-catenin reporter transgene, suggestive of diminished canonical Wnt signaling. Hearts with Epicardium-restricted Ctnnb1 loss of function resembled Wt1(KO) hearts and also failed to undergo epicardial EMT. However, Ctnnb1 inactivation did not alter WT1 expression, positioning Wt1 upstream of canonical Wnt/β-catenin signaling. Wnt5a, a prototypic non-canonical Wnt with enriched epicardial expression, and Raldh2, a key regulator of retinoic acid signaling confined to the Epicardium, were also markedly downregulated in Wt1(KO) Epicardium. Hearts lacking Wnt5a or Raldh2 shared phenotypic features with Wt1(KO). Although Wt1 has been proposed to regulate EMT by repressing E-cadherin, we detected no change in E-cadherin in Wt1(KO) Epicardium. Collectively, our study shows that Wt1 regulates epicardial EMT and heart development through canonical Wnt, non-canonical Wnt, and retinoic acid signaling pathways.

Stanley Nattel - One of the best experts on this subject based on the ideXlab platform.

  • transmural expression of transient outward potassium current subunits in normal and failing canine and human hearts
    The Journal of Physiology, 2004
    Co-Authors: Stephen Zicha, Ling Xiao, Sara Stafford, Tae Joon Cha, Wei Han, Andras Varro, Stanley Nattel
    Abstract:

    The transient outward current (Ito), an important contributor to transmural electrophysiological heterogeneity, is significantly remodelled in congestive heart failure (CHF). The molecular bases of transmural Ito gradients and CHF-dependent ionic remodelling are incompletely understood. To elucidate these issues, we studied mRNA and protein expression of Kv4.3 and KChIP2, the principal alpha and beta subunits believed to form Ito, in epicardial and endocardial tissues and in isolated cardiomyocytes from control dogs and dogs with CHF induced by 240 beats min−1 ventricular tachypacing. CHF decreased Ito density in both Epicardium and endocardium (by 73 and 55% at +60 mV, respectively), without a significant change in relative current density (endocardium/Epicardium 0.11 control, 0.17 CHF). There were transmural gradients in mRNA expression of both Kv4.3 (endocardium/Epicardium ratio 0.3 under control conditions) and KChIP2 (endocardium/Epicardium ratio 0.2 control), which remained in the presence of CHF (Kv4.3 endocardium/Epicardium ratio 0.4; KChIP2 0.4). There were qualitatively similar protein expression gradients in human and canine cardiac tissues and isolated canine cardiomyocytes; however, the KChIP2 gradient was only detectable with a highly selective monoclonal antibody and closely approximated the Ito density gradient. Kv4.3 mRNA expression was reduced by CHF, but KChIP2 mRNA was not significantly changed. CHF decreased Kv4.3 protein expression in canine cardiac tissues and cardiomyocytes, as well as in terminally failing human heart tissue samples, but KChIP2 protein was not down-regulated in any of the corresponding sample sets. We conclude that both Kv4.3 and KChIP2 may contribute to epicardial–endocardial gradients in Ito, and that Ito down-regulation in human and canine CHF appears due primarily to changes in Kv4.3.

Jonathan A. Epstein - One of the best experts on this subject based on the ideXlab platform.

  • Epicardium-Derived Cardiac Mesenchymal Stem Cells: Expanding the Outer Limit of Heart Repair
    Circulation research, 2012
    Co-Authors: Manvendra K. Singh, Jonathan A. Epstein
    Abstract:

    ### Adult Cardiac-Resident MSC-Like Stem Cells With a Proepicardial Origin Chong et al Cell Stem Cell . 2011;9:527–540. The Epicardium is derived from the proepicardial organ, a source of multipotent progenitor cells. Epicardium contribution to the developing coronary vasculature and to cardiac interstitial cells has been established. Studies over the past several years have suggested that Epicardium-derived cells can adopt cardiomyocyte and vascular smooth muscle fates and can contribute to cardiac repair when activated by injury.1,2 Recently, Chong et al3 have provided a detailed characterization of a population of Epicardium-derived multipotent cardiac progenitor cells (cCFU-Fs). These cells, which do not arise from the bone marrow, neural crest, or myocardium, resemble mesenchymal stem cells (MSCs) and may participate in cardiac development, homeostasis, and repair.3 During early cardiac development, cells derived from the proepicardial organ (a cluster of cells located dorsal and adjacent to the looped heart tube) migrate over the myocardium to form the Epicardium. Subsequently, Epicardium-derived progenitor cells undergo epithelial-to-mesenchymal transition, invade the underlying myocardium, and differentiate into various cardiac lineages.4,5 Signals and cellular contributions from the Epicardium have been shown to be indispensable for the establishment of normal coronary vasculature and myocardial architecture.6 Cardiac interstitial cells arise from Epicardium, and recent studies have suggested that reactivation of the Epicardium after injury could contribute to scarring or myocardial repair after injury.1,2,6,7 In this context, the recent report from Chong et al3 is particularly relevant, because they used rigorous gene expression, culture, and fate lineage analysis to characterize a population of multipotent MSC-like cells resident in the heart that they called cardiac colony-forming units–fibroblast (cCFU-Fs). These cells derive from the proEpicardium, not from cardiac myocytes, neural crest, or bone marrow, and they are able to differentiate into endoderm (eg, colonic epithelium), mesoderm (eg, smooth muscle, cardiac muscle, and adipose tissue), and neurectoderm …

  • MicroRNA-processing Enzyme Dicer Is Required in Epicardium for Coronary Vasculature Development
    The Journal of biological chemistry, 2011
    Co-Authors: Manvendra K. Singh, Daniele Massera, Jonathan A. Epstein
    Abstract:

    The Epicardium is a sheet of epithelial cells covering the heart during early cardiac development. In recent years, the Epicardium has been identified as an important contributor to cardiovascular development, and Epicardium-derived cells have the potential to differentiate into multiple cardiac cell lineages. Some Epicardium-derived cells that undergo epithelial-to-mesenchymal transition and delaminate from the surface of the developing heart subsequently invade the myocardium and differentiate into vascular smooth muscle of the developing coronary vasculature. MicroRNAs (miRNAs) have been implicated broadly in tissue patterning and development, including in the heart, but a role in Epicardium is unknown. To examine the role of miRNAs during epicardial development, we conditionally deleted the miRNA-processing enzyme Dicer in the proEpicardium using Gata5-Cre mice. Epicardial Dicer mutant mice are born in expected Mendelian ratios but die immediately after birth with profound cardiac defects, including impaired coronary vessel development. We found that loss of Dicer leads to impaired epicardial epithelial-to-mesenchymal transition and a reduction in epicardial cell proliferation and differentiation into coronary smooth muscle cells. These results demonstrate a critical role for Dicer, and by implication miRNAs, in murine epicardial development.

  • Kicking the Epicardium up a Notch
    Circulation research, 2011
    Co-Authors: Stacey Rentschler, Jonathan A. Epstein
    Abstract:

    see related article, pages 51–59 The Epicardium is a layer of fibrous mesothelium that covers the external surface of the heart. Until recently, the main function of this tissue was thought to be protective and to contribute to production of pericardial fluid. Recently, however, renewed interest in the function of the Epicardium has identified important contributions to cardiac development, disease, and regeneration. In the developing embryo, the Epicardium derives from the proepicardial organ, a cluster of multipotent progenitor cells located dorsal to the looped heart tube during early stages of embryogenesis.1,2 Some proepicardial cells undergo an epithelial-to-mesenchymal transition (EMT) to generate migratory cells that encase the heart, invade the myocardium, and ultimately give rise to fibroblasts, coronary smooth muscle, and possibly endothelial cells and cardiomyocytes.3,–,9 The embryonic Epicardium provides factors necessary for the normal development and expansion of the myocardium; disruption of critical epicardial signaling pathways leads to thin and poorly functioning myocardium.10,–,12 These discoveries have raised the question of whether the Epicardium might play a role in adult cardiac homeostasis or response to injury by providing cells or growth factors that impact cardiac function. Several recent studies, including a study by Russell et al in this issue of Circulation Research ,13 have begun to establish a novel paradigm for the adult Epicardium as a tissue able to undergo dynamic activation in response to stress reminiscent of embryonic epicardial EMT. Prior studies in zebrafish have demonstrated generalized activation of the Epicardium following amputation of the apex of the heart, which subsequently provides a conducive environment …