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REVIEW ARTICLESMechanisms of Cardiac Fibrosis inInflammatory Heart DiseaseGabriela Kania,Przemyslaw Blyszczuk,and Urs ErikssonHeart injury from many causes can endup in a commonfinal pathway ofpathologic remodeling and fibrosis,promoting heart failure development.Dilated cardiomyopathy is an important cause of heart failure and oftenresults from virus-triggered myocarditis.Monocytes and monocyte-likecells represent a major subset of heart-infiltrating cells at the injury site.Thesebonemarrow-derivedcellspromotenotonlytissueinjuryintheshortterm but alsoangiogenesisandcollagendepositioninthelongterm.Thus,theyarecriticallyinvolvedinthetypicaltissuefibrosis,whichevolvesinthedilating ventricle during the process of pathologic remodeling.Recentfindingssuggestthatheart-infiltratingmonocyte-likecellsindeedcontainapool of progenitors,which represent the cellular source both foraccumulation of differentiated monocytes during the acute inflammatoryphase and for transforming growth factor-mediated myocardial fibrosisduring the later chronic stages of disease.Obviously,a delicate balance ofproinflammatory and profibrotic cytokines dictates the fate of bonemarrow-derived heart-infiltrating progenitors and directly influences themorphologicphenotypeoftheaffectedheart.Inthisminireview,weprovidean update on these mechanisms and discuss their significance inpathologic remodeling and heart failure progression after myocarditis.(Trends Cardiovasc Med 2009;19:247252)n 2009,Elsevier Inc.?IntroductionInflammatory dilated cardiomyopathy(iDCM)refers to a subtype of dilatedcardiomyopathy characterized by cardi-ac inflammation,progressively impairedcontractility,tissue fibrosis,and ventric-ular dilation.Epidemiologic data suggestthat iDCM is an important cause of heartfailure and sudden death in children andyoung patients.Cardiac inflammation,ormyocarditis,usually results from infec-tions with viruses,such as coxsackievirusB3(CVB3),adenoviruses or parvovirusB19,or protozoan Trypanosoma cruzi(Chagas disease),and it is often associat-ed with autoimmune responses againstheart tissue antigens.Myocarditis ofdifferent etiology can progress to acommon final pathway of ventriculardilation,fibrosis,and heart failure insome of theaffected individuals(Kallwel-lis-Opara et al.2007).In this minireview,we specifically address the mechanismsof postinflammatory cardiac fibrosis.Progression of active myocarditis toiDCM is associated with changes in thehistopathology ofthe myocardium andinthe clinical signature.Myocarditis isclassically defined as the presence ofinflammatory infiltrates with necrosisand/or degeneration of adjacent cardio-myocytes(Aretz et al.,1987).However,detection of N14 CD3-and/or CD68-expressing cells per millimeter squaredby immunohistochemistry provides amore sensitive diagnostic criterion.From a clinical perspective,many myo-carditis patients show minimal symp-toms only or are entirely asymptomatic(McCarthy et al.2000).Heart-infiltratingcells include granulocytes,monocytes,macrophages,dendritic cells,mast cells,and T and B lymphocytes.Inflammatoryinfiltrates produce and secrete variouscytokines,such as interleukin(IL)-1,IL-6,IL-10,IL-12,IL-17,interferon-,transforming growth factor(TGF)-,andtumor necrosis factor(TNF)-modulat-ing the inflammatory response and af-fecting the function of other cells(Afanasyeva et al.2004,Blyszczuk et al.2008).Importantly,cardiac infiltratesalso include precursor cells playing apivotal role in tissues remodeling follow-ing organ damage(Kania et al.2009,Valaperti et al.2008).Inhumans,dilationoftheleftventricleand cardiac fibrosis are hallmarks ofiDCM.Enhancedfibrosisischaracterizedby a disproportionate accumulation offibrillar(mainly type I)collagen,leadingtostiffeningoftheventriclesandimpaireddiastolicfilling.Thelatterisindicativeofapoor prognosis.Myocardial extracellularmatrix(ECM)represents a highly orga-nized dynamic network of fibrillar colla-gen,proteoglycans,glycoproteins,andother bioactive molecules.In the homeo-stasis,ECM turnover is tightly controlledGabriela Kania and Przemyslaw Blyszczuk areat the Cardioimmunology,Cardiovascular Re-search Department,Institute of Physiology,University of Zurich,Winterthurerstrasse 190,CH-8057 Zurich,Switzerland.Urs Eriksson isat the Cardioimmunology,Cardiovascular Re-search Department,Institute of Physiology,University of Zurich,Winterthurerstrasse 190,CH-8057Zurich,Switzerland;andDepartmentof Cardiology,University Hospital,Rmis-trasse 100,CH-8091 Zurich,SwitzerlandAddress correspondence to:Urs Eriksson,Department of Cardiology,UniversityHospital,Rmistrasse 100,CH-8091 Zurich,Switzerland.Tel.:[phone];fax:[phone];e-mail:urs.erikssonusz.ch.2009,Elsevier Inc.All rights reserved.1050-1738/$-see front matter247TCM Vol.19,No.8,2009bycoordinateddegradationandsynthesisof the various ECM components.Proteo-lytic enzymes that mostly belong toa family of zinc-dependent matrixmetalloproteinases(MMPs)process deg-radation of ECM.Thus,MMPs togetherwith their tissue inhibitors(TIMPs)arethe key regulators of ECM homeostasis.A misbalance between MMPs andTIMPs initiates pathologic remodelingby alerting ECM turnover.This leadsto disruption of the normal myocardialstructures and excessive accumulationof collagen and collagen-producingfibroblasts,which finally results incardiac fibrosis(DArmiento 2002,Manabeetal.2002).In the heart,fibroblasts had beenrecognized as key regulators of theECM structure.Heart-resident fibro-blasts are not only the main producersof ECM components but also the majorsource of MMPs and TIMPs.In theinflammatory state,cytokines,growthfactors,and other environmental stimulimodulate fibroblast function by chang-ing the production patterns of ECMcomponents,MMPs,and TIMPs,bystimulating their migration and prolifer-ation,and by mediating the interactionbetween cardiac fibroblasts and othercell types(DArmiento 2002).However,even if the initial myocar-dial dysfunction is confined within thenonfibroblast compartment(e.g.,in car-diomyocytes),functional disturbancescan promote fibroblast activation.Dur-ing iDCM,fibrosis and pathologic remo-deling typically follow resolution ofacute inflammation.In the ischemicheart,inflammatory processes play animportant role as well but are ratherlimited to the ischemic and their im-mediately adjacent areas.?Myocardial FibrosisAdaptationor Maladaptation?Myocardial fibrosis plays a dual role incardiac remodeling after injury.On theone hand,it contributes to ventricularstiffening and heart failure progression;on the other hand,it is a prerequisite forwound healing.In an injured organdebris is either replaced by cells of thesame type(regeneration)or by paren-chymal tissue.In adult mammals,cardi-omyocyte regeneration is insufficient,damaged myocardium is not functionallyrepaired,andas a consequencescarformation takes place.Thus,an initiallyadaptive healing processes turns into apotentially maladaptive response in thelong term.In iDCM,fibrosis results as a conse-quence of massive cell infiltrationswithin the myocardium.In most cases,and in contrast to myocardial infarc-tion,myocarditis is rarely associatedwith a substantial loss of cardiomyo-cytes.Nevertheless,the chronic inflam-matory promotes ongoing myocardialfibrosis,which is a hallmark of endstage heart failure.?Origin of Myocardial FibrosisCardiac fibroblasts belong to the inter-stitial tissue within the healthy myocar-dium.Thus,they may represent anobvious source of fibrosis after cardiacinjury.Indeed,some reports demonstrat-ed that proliferating heart-resident car-diac fibroblasts are the major cellularsource of tissue fibrosis associated withhypertrophy and ischemic heart failure(Cucoranu et al.2005,Yano et al.2005).Furthermore,it has been shown thatheart-resident fibroblast progenitors mi-grated to the inflamed region in responseto ischemia(El-Helou et al.2005).How-ever,several lines of evidences suggestthat fibroblasts of other origins alsosignificantly contribute to remodelingof the injured heart.Studies in a mousemodel of myocardial infarction demon-strated that bone marrow-derived cellsrepresented up to 24%(van Amerongenet al.2008)or 57%(Mollmann et al.2006)of fibroblasts in the infarct zone.Fibroblasts of hematopoietic origin werealso found in a mouse model of fibroticischemia/reperfusion cardiomyopathy(Haudek et al.2006).At the postinflam-matory stage of experimental autoim-mune myocarditis(EAM),a mousemodel of iDCM,N60%of fibroblastscontributing to myocardial fibrosis wereof bone marrow origin(Blyszczuk et al.2009,Kania et al.2009).In a mousemodel of pressure overload,a subset ofcardiac fibroblasts originated from en-dothelial cells in the endothelial-to-mes-enchymal transition process(Zeisberget al.2007).Apparently,resident fibro-blasts and nonresident cells have theability to actively contribute to fibroticprocesses within the heart.As mentioned above,fibroblasts ofbonemarroworiginsignificantlycontrib-ute to myocardial fibrosis in animalmodels of ischemic and inflammatoryheart diseases.In iDCM,fibrosis is adirect consequence of massive infiltra-tionsofhematopoieticcellsintotheheart.Several studies have identified cell popu-lations linking the hematopoietic systemto fibroblasts in diseased hearts.In theinflammatory heart disease,CD133+in-flammatory cells were identified as acellular source for fibroblasts of extra-cardiac origin(Kania et al.2009).Inmodels of ischemic heart failure,inflam-mation of cardiac tissue is limited.How-ever,monocytes accumulating in theperivascular space have been suggestedto transform into myofibroblasts inmouse models of pressure overload(Endo et al.2007)and myocardial infarc-tion(Fujita et al.2007).Fibrocytes repre-sent a unique fibroblast progenitorpopulation circulating in peripheralblood that expresses markers of hemato-poietic progenitor cells and fibroblasts(collagen+/vimentin+/CD34+/CD45+).Inthe mouse model of fibrotic ischemia/reperfusion cardiomyopathy,fibrocytessignificantly accumulated into the cardi-ac tissue after repeated coronary occlu-sion(Haudek et al.2006).?The Role of Progenitor Cellsin iDCMMyocardial inflammation is initiated byrelease of chemoattractants in responseto viral or microbial infections,tissuedamage,or autoimmune responses.Chemokines play a critical role in basaland inflammation-triggered traffickingof bone marrow-derived cells.An elevat-ed level of chemokine ligands is aprominent feature in myocarditis(Goseret al.2006).Some of cells either residual orrecruited to the myocardium are charac-terized as well-defined phenotypes,whereas others represent noncommittedprogenitors.In mouse model of autoim-mune myocarditis,heart-infiltratingCD133+progenitors represent a commonprogenitor for macrophages and fibro-blasts(Kania et al.2009).Recent datafrom ischemic and inflammatory modelsof heart disorders confirmed that bonemarrow-derived precursor cells differen-tiate into diverse subpopulations of in-flammatory cells,such as dendritic cellsand macrophages,depending on thecytokine/chemokine signaling(BujakTCM Vol.19,No.8,2009248et al.2008,Nahrendorf et al.2007).Identification of bone marrow-derivedfibroblasts in fibrotic hearts(Mollmannet al.2006)and in ischemic heartmodels(Endo et al.2007,van Ameron-gen et al.2008)further suggests therecruitment of progenitor cells withfibrogenic potential.Other studies pointed to cardioregen-erative potential of bone marrow-derivedcells(Anversa etal.2006).However,mostresults evaluating bone marrow-derivedstem cells in mouse models of ischemicand inflammatory myocardial disordersshowed either minimal in vivo cardio-myocyte differentiation only(Endo et al.2007)or questioned the cardioregenera-tive potential of stem cell-based therapiesat all(Balsam et al.2004,Murry et al.2004,Nygren et al.2008).Thus,currentevidence supports the view that inflam-matory progenitor cells differentiate intomonocytes/macrophages and fibroblasts,but not cardiomyocytes in affectedhearts.Nevertheless,many clinical stud-ies report some benefits of stem celltherapy in cardiac disorders(Segers andLee 2008).This might be a consequenceof the fact that stem/progenitor cellsmodulate inflammatory processes byparacrine delivery of growth factors andpromote angiogenesis(Gnecchi et al.2008).We have provided in vivo evi-dences that CD11b+monocytes and,inparticular,CD133+progenitor cells re-veal strong immunosuppressive proper-ties and efficiently attenuate EAM(Kaniaet al.2008,2009,Valaperti et al.2008).These findings are in line with otherstudies demonstrating that mesenchymalstem cell transplantation prevented heartfailure development and improved cardi-ac function by inducing neovasculariza-tion and inhibiting inflammatorycytokine production in a rat model ofacute myocarditis(Okada et al.2007).?The Myocardial MicroenvironmentDictates the Fate of Progenitor CellsHealthy,injured,inflamed,and fibroticheart tissue is characterized by distinctpatternofchemokines,cytokines,growth factors,and ECM structure ex-pression pattern,creating a unique andspecific myocardial signaling milieu.Recently,we demonstrated that multi-lineage progenitor cells administratedinto the myocardium at different stagesof myocarditis acquired different cellu-lar phenotypes(Kania et al.2008,2009).These findings suggest that the localcytokine milieu determines the fate ofprogenitor cells recruited to the injuredheart.Transition from acute myocarditisto iDCM is apparently associated withchanges in inflammatory cytokine pat-tern reflecting microenvironments pro-moting macrophage and fibroblastdifferentiation,respectively(Figure 1).Noteworthily,inflammation of the myo-cardium is not necessarily followed byfibrosisandiDCM(Blyszczuketal.2009).Taken together,the fibroblast fate ofinflammatory progenitors requires spe-cific epigenetic inducers affecting thecytokine balanceIn our opinion,micro-environment of the inflamed myo-cardium,determining the fate ofnoncommitted progenitor cells,is a turn-ing point in the development of iDCM.Importantly,the environment of dis-eased myocardium inhibits differentia-tion of multilineage progenitor cells intocardiomyocytes(Kania et al.2009).Sim-ilarly,insightfromischemicheartdiseasemodels suggests that the microenviron-ment promoted the differentiation ofbone marrow-derived,recruited,or ad-ministered progenitor cells into hemato-poietic cell phenotypes,butnotcardiomyocytes(Balsam et al.2004,Endo et al.2007,Murry et al.2004).Thedevelopment of clinically relevant cell-based therapies aiming at cardiac tissueregeneration requires either ex vivomanipulation of progenitor cells render-ing them resistant to the pathogenicenvironment or the combined in vivotargeting of specific cytokines/chemo-kines promoting the cardioregenerativecapacity of progenitor cells.In fact,exvivo pretreatment of autologous bonemarrow-derived progenitor cells withcardiomyogenic growth factors poten-tates their cardiac differentiation andtheir functional regenerative capacity invivo(Bartunek et al.2007).?Inflammatory CytokinesControlling iDCMiDC