Circulation Research Thematic Synopsis

Abstract

HomeCirculation ResearchVol. 111, No. 3Circulation Research Thematic Synopsis Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBCirculation Research Thematic SynopsisHeart Failure, Cardiac Hypertrophy, and Ventricular Remodeling The Editors The Editors Search for more papers by this author Originally published20 Jul 2012https://doi.org/10.1161/CIRCRESAHA.112.275891Circulation Research. 2012;111:e67–e88“All the king's horses and all the king's men…”IntroductionSome may argue that maintenance of pump function represents the ultimate goal of cardiovascular medicine. Yet, pump dysfunction is a veritable epidemic in the developed world. Our charge is to answer the question: “How do you fix a broken heart?” Indeed, cardiac scientists continually strive to disassemble and subsequently recapitulate individual aspects of cardiac function to understand how the heart contracts and relaxes and how such essential functions falter during pathophysiology. From genetics to contractile filament structure, proteomics to cell therapy, and micro-RNA to ion channels, all such endeavors can share the common goal of understanding cardiac muscle function and myocardial preservation during disease. Studies in Circulation Research deftly epitomize this interconnectedness. Although many investigators often use genetically modified mice (or chronically instrumented large animals), the Circulation Research portfolio is not simply restricted to publication of articles in animal models of heart failure but also encompasses human studies. It is noteworthy that the Journal has become proactive in publishing human studies. Furthermore, readers will discover important investigations in nonmammalian model organisms, including Danio rerio and Drosophila melanogaster, among the pages of the Journal, thereby complementing studies in Homo sapiens, Mus musculus, and other species.During recent years, the field has witnessed remarkable discoveries. Although many of these discoveries were chronicled in Circulation Research, they are too diverse to summarize in a single review article. To this end, the Editors have crafted this Synopsis to direct the readers' attention to a number of elegant and original studies, as well as selected, thought-leading reviews that have graced the pages of Circulation Research. Despite our collective successes, there has been a measure of futility in our collective efforts because no matter how hard we try, we have yet to succeed to “…put [the heart] back together again.” Until we do, expect this Journal to remain the messenger for cutting-edge advances in heart failure, hypertrophy, and remodeling.The following works represent a selection of recently published Circulation Research articles on heart failure, hypertrophy, and ventricular remodeling, presented in their reverse order of publication. Articles highlighted in yellow represent the top-10 most-read Original Research Articles, selected on the basis of the number of Full Text/PDF downloads, adjusted to compensate for differences in the length of time since online publication.Thrombospondin-4 Is Required for Stretch-Mediated Contractility Augmentation in Cardiac Muscle; Cingolani et al1What Is Known?Cardiac muscle and whole hearts subjected to an acute systolic (afterload) stress respond by gradually increasing contractility within minutes coupled to a rise in myocyte calcium. This behavior is known as the Anrep effect.Thrombospondin 4 is a member of a small family of matricellular proteins, expressed at low levels in cardiac muscle, and is thought to serve as a matrix protein linker.Thrombospondin 4 expression rises markedly in hearts exposed to pressure overload, with chronic hypertrophy, and with heart failure.What New Information Does This Article Contribute?Mice globally lacking thrombospondin 4 do not display the Anrep effect in either the intact heart or isolated cardiac muscle but do so in isolated cardiac myocytes.The absence of thrombospondin 4 worsens chronic pressure overload–induced hypertrophy and cardiac dysfunction.Thrombospondin 4 works as a matrix-myocyte signaling molecule, which couples muscle contractility to an increase in load.ConclusionsThese results identify TSP4 as myocyte-interstitial mechano-signaling molecule central to adaptive cardiac contractile responses to acute stress, which appears to play a crucial role in the transition to chronic cardiac dilatation and failure.Inhibition of PKCα/β With Ruboxistaurin Antagonizes Heart Failure in Pigs After Myocardial Infarction Injury; Ladage et al2What Is Known?Genetic or pharmacological inhibition of protein kinase C (PKC)α in mouse protects from heart failure.Pharmacological inhibition of PKCα in rats protects from heart failure.PKCα activity is increased in heart failureWhat New Information Does This Article Contribute?We provide the first proof that pharmacological inhibition of PKCα/β reduces heart failure in a large-animal model.Ruboxistaurin promotes recovery of myocardial function in a pig model of myocardial infarction–induced heart failure.ConclusionsThese results provide additional evidence in a large animal model of disease that PKCα/β inhibition (with ruboxistaurin) represents a tenable and novel therapeutic approach for treating human heart failure.Analysis of Transcriptome Complexity Through RNA Sequencing in Normal and Failing Murine Hearts; Lee et al3What Is Known?Accurate and de novo transcriptome profiling is a central issue in studying the mechanisms of cardiovascular development and diseases.Understanding of the global cardiac transcriptome landscape is currently limited concerning expression and variation at single exon resolution.Whole-transcriptome sequencing (RNA-Seq) offers a new way to study transcriptomes.What New Information Does This Article Contribute?We present bioinformatic methods to identify transcript structures and to analyze transcriptome complexities with a particular emphasis on quantification of RNA splicing variants at single exon resolution using RNA-Seq data of normal and failing murine hearts.We validate the effectiveness and accuracy of our bioinformatic approaches, based on experimental confirmation and cross-database analyses.We show that the bioinformatic analyses of RNA-Seq allow in-depth profiling and quantification of alternative mRNA structures, novel exons, novel transcript clusters, and long, noncoding RNA genes in mouse heart.ConclusionsOur work provided a comprehensive set of methods to analyze mouse cardiac transcriptome complexity at individual exon and transcript levels. Applications of the methods may infer important new insights to gene regulation in normal and diseased hearts in terms of exon utilization and potential involvement of novel components of cardiac transcriptome.Treatment of Chronic Heart Failure With β-Adrenergic Receptor Antagonists [Review]; Bristow4AbstractDespite the absence of a systematic development plan, β-blockers have reached the top tier of medical therapies for chronic heart failure. The successful outcome was due to the many dedicated investigators who produced, over a 30-year period, increasing evidence that β-blocking agents should or actually did improve the natural history of dilated cardiomyopathies and heart failure. It took 20 years for supportive evidence to become undeniable, at which time in 1993 the formidable drug development resources of large pharmaceutical companies were deployed into phase 3 trials. Success then came relatively quickly, and within 8 years, multiple agents were on the market in the United States and Europe. Importantly, there is ample room to improve antiadrenergic therapy through novel approaches exploiting the nuances of receptor biology and/or intracellular signaling, as well as through pharmacogenetic targeting.Hyperphosphorylation of Mouse Cardiac Titin Contributes to Transverse Aortic Constriction-Induced Diastolic Dysfunction; Hudson et al5What Is Known?Diastolic dysfunction is a prominent aspect of heart failure (HF).Mechanisms that underlie diastolic dysfunction are not well understood.What New Information Does This Article Contribute?We focused on passive stiffness of the left ventricle (LV), using a mouse model of HF, and studied the extracellular matrix (ECM) and titin.HF results in increased ECM-based and titin-based passive stiffness. Changes in titin include isoform switching and hyperphosphorylation of the molecular spring region of titin.Complex changes in titin take place that in combination are a major factor in the increased passive myocardial stiffness in HF.ConclusionsTransverse aortic constriction–induced HF results in increased extracellular matrix–based and titin-based passive stiffness. Changes in titin splicing occur, which lower passive stiffness, but this effect is offset by hyperphosphorylation of residues in titin spring elements, particularly of PEVK S26. Thus, complex changes in titin occur, which, combined, are a major factor in the increased passive myocardial stiffness in HF.PGC-1β Deficiency Accelerates the Transition to Heart Failure in Pressure-Overload Hypertrophy; Riehle et al6What Is Known?PGC-1α and PGC-1β are transcriptional coactivators that regulate mitochondrial biogenesis and oxidative capacity.Pressure-overload cardiac hypertrophy and heart failure are associated with impaired mitochondrial function that correlates with the repression of PGC-1α expression.PGC-1α–deficient hearts have reduced oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO) capacity and develop heart failure more rapidly in response to pressure overload.What New Information Does This Article Contribute?PGC-1β regulates OXPHOS capacity but not the FAO capacity of cardiac mitochondria.PGC-1β deficient hearts rapidly decompensate after pressure overload.PGC-1β deficiency promotes oxidative stress and reduces glucose metabolism in response to pressure-overload hypertrophy.ConclusionsPGC-1β plays an important role in maintaining baseline mitochondrial function and cardiac contractile function after pressure-overload hypertrophy by preserving glucose metabolism and preventing oxidative stress.Telethonin Deficiency Is Associated With Maladaptation to Biomechanical Stress in the Mammalian Heart; Knoll et al7What Is Known?Telethonin is a small (19-kDa) muscle-specific protein.Telethonin is localized to the sarcomeric Z-disk, where it interacts with the giant protein titin.Telethonin mutations are associated with various diseases such as limb girdle muscular dystrophy 2 G (LGMD 2G), cardiomyopathy, and intestinal pseudo-obstruction.What New Information Does This Article Contribute?Telethonin deficiency is not associated with a spontaneous phenotype, at least not in the mammalian heart.Telethonin is not essential for the mechanical stability of the Z-disk.Telethonin promotes cardiac myocyte survival by suppressing p53-mediated apoptosis.ConclusionsTelethonin knockout mice do not reveal defective heart development or heart function under basal conditions but develop heart failure after biomechanical stress, owing at least in part to apoptosis of cardiomyocytes, an effect that may also play a role in human heart failure.Haploinsufficiency of Target of Rapamycin Attenuates Cardiomyopathies in Adult Zebrafish; Ding et al8What Is Known?Rapamycin is a specific inhibitor of the target of rapamycin (TOR) signaling. It exerts cardioprotective effects on cardiomyopathy; however, genetic studies of functions of TOR signaling in cardiomyopathy have yielded conflicting results.The first adult zebrafish model of cardiomyopathy induced by chronic anemia has been generated; however, the value of this new vertebrate model in dissecting underlying signaling pathways remains untested.What New Information Does This Article Contribute?Similar to that in rodents and humans, doxorubicin induces cardiomyopathy in adult zebrafish.Partial reduction of TOR signaling in the zebrafish TOR heterozygous mutant exerts cardioprotective effects on 2 cardiomyopathies of distinct etiology, providing the first genetic evidence indicating that TOR signaling may be a common therapeutic pathway for cardiomyopathies.Both dose- and stage-dependent functions of TOR must be controlled properly when developing TOR-based therapeutics for cardiomyopathies.ConclusionsOur results prove adult zebrafish as a conserved novel vertebrate model for human cardiomyopathies. Moreover, we provide the first genetic evidence to demonstrate a long-term cardioprotective effect of TOR signaling inhibition on at least 2 cardiomyopathies of distinct etiology despite dynamic TOR activities during their pathogenesis.β-Myosin Heavy Chain Is Induced by Pressure Overload in a Minor Subpopulation of Smaller Mouse Cardiac Myocytes; Lopez et al9What Is Known?Reexpression of the cardiac “fetal gene,” β-myosin heavy chain (β-MyHC), is a signature feature of pressure-overload hypertrophy in rodents and is thought to be pathological.Endogenous β-MyHC mRNA and a fusion protein of yellow fluorescent protein-βMyHC have a heterogeneous myocardial expression pattern after stress.What New Information Does This Article Contribute?Endogenous β-MyHC protein is induced by pressure overload in only a small subpopulation of mouse cardiac myocytes.Pressure-overloaded myocytes with β-MyHC are not hypertrophied and are smaller than myocytes that have only α-MyHC, the normal adult MyHC isoform.Myocytes with β-MyHC arise without proliferation or hypertrophy by adding β-MyHC to α-MyHC, and they have more total MyHC per cell than the hypertrophied myocytes with only α-MyHC.Conclusionsβ-MyHC protein is induced by pressure overload in a minor subpopulation of smaller cardiac myocytes. The hypertrophied myocytes after TAC have α-MyHC only. These data challenge the current paradigm of the fetal hypertrophic gene program and identify a new subpopulation of smaller working ventricular myocytes with more myosin.Translational Success Stories: Angiotensin Receptor 1 Antagonists in Heart Failure [Review]; Dell'Italia10AbstractThe title of the proposed series of reviews is “Translational Success Stories.” The definition of “translation” according to Webster is, “an act, process, or instance of translating as a rendering of one language into another.” In the context of this inaugural review, it is the translation of Tigerstedt's and Bergman's discovery in 1898 of the vasoconstrictive effects of an extract of rabbit kidney to the treatment of heart failure. As recounted by Marks and Maxwell, their discovery was heavily influenced by the original experiments of the French physiologist Brown-Séquard, who was the author of the doctrine that “many organs dispense substances into the blood which are not ordinary waste products, but have specific functions.” They were also influenced by Bright's original observation that linked kidney disease with hypertension with the observation that patients dying with contracted kidneys often exhibited a hard, full pulse and cardiac hypertrophy. However, from Tigerstedt's initial discovery, there was a long and arduous transformation of ideas and paradigms that eventually translated to clinical applications. Although the role of the renin-angiotensin system in the pathophysiology of hypertension and heart failure was suspected through the years, beneficial effects from its blockade were not realized until the early 1970s. Thus, this story starts with a short historical perspective that provides the reader some insight and appreciation into the long delay in translation.Reversibility of Adverse, Calcineurin-Dependent Cardiac Remodeling; Berry et al68What Is Known?Left ventricular hypertrophy is associated with adverse cardiovascular events, including heart failure and death.Calcineurin is a cytoplasmic protein phosphatase implicated in the pathogenesis of cardiac hypertrophy.What New Information Does This Article Contribute?Calcineurin signaling in the adult heart triggers ventricular hypertrophy with markers of pathological remodeling.Calcineurin-induced ventricular hypertrophy precedes the development of systolic dysfunction and heart failure.Calcineurin-induced cardiac hypertrophy reverses when calcineurin signaling is turned off.Fetal gene expression and ventricular fibrosis, each a late manifestation of pathological remodeling, manifest significant reversibility.ConclusionsTogether, these data establish and define the deleterious effects of calcineurin signaling in the adult heart and reveal that calcineurin-dependent hypertrophy with concentric geometry precedes systolic dysfunction and heart failure. Furthermore, these findings demonstrate that during much of the disease process, calcineurin-dependent remodeling remains reversible.Placental Growth Factor Regulates Cardiac Adaptation and Hypertrophy Through a Paracrine Mechanism; Accornero et al11What Is Known?Placental growth factor (PGF) can amplify vascular endothelial cell growth factor–driven angiogenesis in cultured endothelial cells.PGF is required for neovascularization during pathological conditions.PGF stimulates angiogenesis and collateral growth in ischemic heart.What New Information Does This Article Contribute?We provide the first proof that PGF supports hypertrophy and cardiac function during pressure overload.We provide the first description of cardiac-specific overexpression of PGF, showing its role as a paracrine mediator of cardioprotection.We provide the first proof that PGF is required for compensatory cardiac remodeling after pressure overload.ConclusionsPGF is a secreted factor that supports hypertrophy and cardiac function during pressure overload by affecting endothelial cells and fibroblasts that in turn stimulate and support the myocytes through additional paracrine factors.Endogenous Muscle Atrophy F-Box Mediates Pressure Overload–Induced Cardiac Hypertrophy Through Regulation of Nuclear Factor-κB; Usui et al12What Is Known?Muscle atrophy F-box (MAFbx/atrogin-1) is a muscle-specific E3 ubiquitin ligase that plays an important role in skeletal muscle atrophy.Overexpressed MAFbx inhibits cardiac hypertrophy in response to pressure overload, whereas endogenous MAFbx negatively regulates cardiac hypertrophy in response to exercise.What New Information Does This Article Contribute?Endogenous MAFbx plays an important role in mediating cardiac hypertrophy and dysfunction in response to pressure overload.MAFbx is upregulated by hypertrophic stimuli, thereby inducing ubiquitin proteasomal degradation of IκB and consequent stabilization of nuclear factor-κB.MAFbx promotes pathological hypertrophy through specific modulation of hypertrophy signaling mechanisms.ConclusionsMAFbx plays an essential role in mediating cardiac hypertrophy in response to pressure overload. Downregulation of MAFbx inhibits cardiac hypertrophy in part through stabilization of IκB-α and inactivation of nuclear factor-κB. Taken together, inhibition of MAFbx attenuates pathological hypertrophy, thereby protecting the heart from progression into heart failure.Phosphatase-Resistant Gap Junctions Inhibit Pathological Remodeling and Prevent Arrhythmias; Remo et al13What Is Known?Gap junctions comprise intercellular channels that electrotonically couple cardiomyocytes with one another and facilitate impulse propagation and normal rhythmicity in the heart.Diverse disease-causing stimuli promote abnormal expression of gap junctions, for example, pathological gap junction remodeling (GJR), and various lines of experimental evidence indicate that GJR contributes to increased arrhythmic propensity.Connexin43 (Cx43), the major cardiac gap junction protein, is posttranslationally phosphorylated by numerous kinases, and these posttranslational events are thought to regulate channel assembly, membrane trafficking, gating, and turnover.In vitro studies indicate that phosphorylation of Cx43 by casein kinase 1δ (CK1δ) at serines 325, 328, and 330 may promote gap junction assembly, which suggests this event may be an important regulator of intercellular coupling and cardiac rhythmicity.What New Information Does This Article Contribute?Using genetically engineered knock-in mice with site-specific mutations introduced into the Cx43 gene, we demonstrate that phosphomimetic mutants of Cx43 at CK1δ-dependent target sites enhance gap junction formation and confer resistance both to pathological GJR and to the induction of ventricular arrhythmias.Conversely, inhibition of phosphorylation at these same target sites diminishes gap junction formation and confers enhanced arrhythmic susceptibility.ConclusionsThese data demonstrate a mechanistic link between posttranslational phosphorylation of Cx43 and gap junction formation, remodeling, and arrhythmic susceptibility.Syndecan-4 Prevents Cardiac Rupture and Dysfunction After Myocardial Infarction; Matsui et al14What Is Known?Syndecan-4 (Syn4), a cell-surface heparan sulfate proteoglycan, functions as a coreceptor and reservoir for extracellular matrix proteins, growth factors, and chemokines, thereby regulating inflammation, wound healing, and tissue remodeling.Syn4 has been detected in the infarct region after myocardial infarction (MI).What New Information Does This Article Contribute?Syn4 plays an important role in the formation of granulation tissue, thereby protecting against cardiac rupture and dysfunction after MI.Syn4-deficient cardiac fibroblasts are defective with respect to cell migration and fibronectin-induced cell signaling and differentiation to myofibroblasts.Syn4 is involved in endothelial cell signaling, proliferation, and tube formation that is dependent on basic fibroblast growth factor.ConclusionsThese results suggest that Syn4 plays an important role in the inflammatory response and granulation tissue formation, thereby preventing cardiac rupture and dysfunction after MI.The Genomic Architecture of Sporadic Heart Failure [Review]; Dorn et al15AbstractCommon or sporadic systolic heart failure (heart failure) is the clinical syndrome of insufficient forward cardiac output resulting from myocardial disease. Most heart failure is the consequence of ischemic or idiopathic cardiomyopathy. There is a clear familial predisposition to heart failure, with a genetic component estimated to confer between 20% and 30% of overall risk. The multifactorial etiology of this syndrome has complicated identification of its genetic underpinnings. Until recently, almost all genetic studies of heart failure were designed and deployed according to the common disease–common variant hypothesis, in which individual risk alleles impart a small positive or negative effect and overall genetic risk is the cumulative impact of all functional genetic variations. Early studies used a candidate gene approach focused mainly on factors within adrenergic and renin-angiotensin pathways that affect heart failure progression and are targeted by standard pharmacotherapeutics. Many of these reported allelic associations with heart failure have not been replicated. However, the preponderance of data supports risk-modifier effects for the Arg389Gly polymorphism of β1-adrenergic receptors and the intron 16 in/del polymorphism of angiotensin-converting enzyme. Recent unbiased studies using genome-wide single nucleotide polymorphism microarrays have shown fewer positive results than when these platforms were applied to hypertension, myocardial infarction, or diabetes, possibly reflecting the complex etiology of heart failure. A new cardiovascular gene—centric subgenome single nucleotide polymorphism array—identified a common heat failure risk allele at 1p36 in multiple independent cohorts, but the biological mechanism for this association is still uncertain. It is likely that common gene polymorphisms account for only a fraction of individual genetic heart failure risk, and future studies using deep resequencing are likely to identify rare gene variants with larger biological effects.Intravenous Gene Therapy With PIM-1 Via a Cardiotropic Viral Vector Halts the Progression of Diabetic Cardiomyopathy Through Promotion of Prosurvival Signaling; Katare et al16What Is Known?Diabetic cardiomyopathy typically progresses from diastolic dysfunction to heart failure in the absence of coronary artery disease or hypertension.The proviral integration site for Moloney murine leukemia virus-1 (Pim-1) is decreased in the myocardium of diabetic mice beginning at the stage of diastolic dysfunction.Pim-1 plays an essential role in cardiomyocyte survival.What New Information Does This Article Contribute?Activation of protein phosphatase-2A (PP2A) and microRNA-1 (miR-1) contributes to Pim-1 downregulation, beginning at the stage of diastolic dysfunction in diabetic hearts.Pim-1 gene therapy with cardiotropic adeno-associated virus serotype-9 (AAV9) at the stage of diastolic dysfunction prevents heart failure in a mouse model of diabetic cardiomyopathy by preserving cardiomyocyte and microvascular cell integrity.Pim-1 gene therapy counteracts the depletive effect of diabetes on c-kit+ cardiac progenitor cells.ConclusionsPim-1 downregulation contributes in the pathogenesis of diabetic cardiomyopathy. Systemic delivery of human PIM-1 via cardiotropic adeno-associated virus serotype-9 represents a novel and effective approach to treat diabetic cardiomyopathy.Mitochondrial Oxidative Stress Mediates Angiotensin II–Induced Cardiac Hypertrophy and Gαq Overexpression–Induced Heart Failure; Dai et al17What Is Known?Oxidative stress and mitochondrial dysfunction have been implicated in several cardiovascular diseases.However, the roles of mitochondrial oxidative stress and DNA damage in hypertensive cardiomyopathy are not well understood.What New Information Does This Article Contribute?Transgenic mice that express catalase in the mitochondria, but not mice that overexpress catalase in peroxisomes, are protected from angiotensin II (Ang II) treatment or Gαq overexpression–induced cardiac hypertrophy and failure.This observation directly demonstrates that mitochondrial reactive oxygen species (ROS) play a critical role in the development of cardiac hypertrophy and failure.This study supports the potential use of mitochondrial-targeted antioxidants for prevention and treatment of hypertensive cardiomyopathy and heart failure.ConclusionsThese data indicate the critical role of mitochondrial ROS in cardiac hypertrophy and failure and support the potential use of mitochondrial-targeted antioxidants for prevention and treatment of hypertensive cardiomyopathy.Interrelationship Between Cardiac Hypertrophy, Heart Failure, and Chronic Kidney Disease [Review]; Dickhout et al18AbstractSynthesis of transmembrane and secretory proteins occurs within the endoplasmic reticulum (ER) and is extremely important in the normal functioning of both the heart and kidney. The dysregulation of protein synthesis/processing within the ER causes the accumulation of unfolded proteins, thereby leading to ER stress and the activation of the unfolded protein response. Sarcoplasmic reticulum/ER Ca2+ disequilibrium can lead to cardiac hypertrophy via cytosolic Ca2+ elevation and stimulation of the Ca2+/calmodulin, calcineurin, NF-AT3 pathway. Although cardiac hypertrophy may be initially adaptive, prolonged or severe ER stress resulting from the increased protein synthesis associated with cardiac hypertrophy can lead to apoptosis of cardiac myocytes and result in reduced cardiac output and chronic heart failure. The failing heart has a dramatic effect on renal function because of inadequate perfusion and stimulates the release of many neurohumoral factors that may lead to further ER stress within the heart, including angiotensin II and arginine-vasopressin. Renal failure attributable to proteinuria and uremia also induces ER stress within the kidney, which contributes to the transformation of tubular epithelial cells to a fibroblast-like phenotype, fibrosis, and tubular cell apoptosis, further diminishing renal function. As a consequence, cardiorenal syndrome may develop into a vicious circle with poor prognosis. New therapeutic modalities to alleviate ER stress through stimulation of the cytoprotective components of the unfolded protein response, including GRP78 upregulation and eukaryotic initiation factor 2α phosphorylation, may hold promise to reduce the high morbidity and mortality associated with cardiorenal syndrome.Lack of Fibronectin-EDA Promotes Survival and Prevents Adverse Remodeling and Heart Function Deterioration After Myocardial Infarction; Arslan et al19What Is Known?Myocardial infarction (MI) initiates a repair response characterized by inflammation and tissue remodeling.Toll-like receptor (TLR) activation enhances inflammation and deteriorates cardiac function and geometry after MI.Extracellular matrix (ECM) components are known to activate circulating blood cells that migrate into injured tissue via TLRs and integrins.Fibronectin-EDA is an ECM protein upregulated after tissue injury that can activate monocytes and fibroblasts.What New Information Does This Article Contribute?Fibronectin-EDA is a critical mediator of cardiac remodeling and subsequent survival after MI in mice.Fibronectin-EDA–deficient mice with wild-type bone marrow exhibited reduced left ventricular dilatation and fibrosis, without affecting proper scar formation after MI.In the absence of fibronectin-EDA, leukocyte influx and cytokine production was reduced, as well as myofibroblast transdifferentiation and activation after MI.Fibronectin-EDA deficiency reduced peripheral monocyte mobilization and reduced monocytic TLR2 and CD49d expression in the blood after MI.ConclusionsOur study demonstrated that parenchymal fn-EDA plays a critical role in adverse cardiac remodeling after infarction. 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