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Nature Sep 2019Fibrosis is observed in nearly every form of myocardial disease. Upon injury, cardiac fibroblasts in the heart begin to remodel the myocardium by depositing excess...
Fibrosis is observed in nearly every form of myocardial disease. Upon injury, cardiac fibroblasts in the heart begin to remodel the myocardium by depositing excess extracellular matrix, resulting in increased stiffness and reduced compliance of the tissue. Excessive cardiac fibrosis is an important factor in the progression of various forms of cardiac disease and heart failure. However, clinical interventions and therapies that target fibrosis remain limited. Here we demonstrate the efficacy of redirected T cell immunotherapy to specifically target pathological cardiac fibrosis in mice. We find that cardiac fibroblasts that express a xenogeneic antigen can be effectively targeted and ablated by adoptive transfer of antigen-specific CD8 T cells. Through expression analysis of the gene signatures of cardiac fibroblasts obtained from healthy and diseased human hearts, we identify an endogenous target of cardiac fibroblasts-fibroblast activation protein. Adoptive transfer of T cells that express a chimeric antigen receptor against fibroblast activation protein results in a significant reduction in cardiac fibrosis and restoration of function after injury in mice. These results provide proof-of-principle for the development of immunotherapeutic drugs for the treatment of cardiac disease.
Topics: Animals; Antigens, Surface; CD8-Positive T-Lymphocytes; Endomyocardial Fibrosis; Fibroblasts; Humans; Immunotherapy, Adoptive; Male; Mice; Ovalbumin; Wound Healing
PubMed: 31511695
DOI: 10.1038/s41586-019-1546-z -
Cells Jul 2021Cardiac fibrosis is the excess deposition of extracellular matrix (ECM), such as collagen. Myofibroblasts are major players in the production of collagen, and are... (Review)
Review
Cardiac fibrosis is the excess deposition of extracellular matrix (ECM), such as collagen. Myofibroblasts are major players in the production of collagen, and are differentiated primarily from resident fibroblasts. Collagen can compensate for the dead cells produced by injury. The appropriate production of collagen is beneficial for preserving the structural integrity of the heart, and protects the heart from cardiac rupture. However, excessive deposition of collagen causes cardiac dysfunction. Recent studies have demonstrated that myofibroblasts can change their phenotypes. In addition, myofibroblasts are found to have functions other than ECM production. Myofibroblasts have macrophage-like functions, in which they engulf dead cells and secrete anti-inflammatory cytokines. Research into fibroblasts has been delayed due to the lack of selective markers for the identification of fibroblasts. In recent years, it has become possible to genetically label fibroblasts and perform sequencing at single-cell levels. Based on new technologies, the origins of fibroblasts and myofibroblasts, time-dependent changes in fibroblast states after injury, and fibroblast heterogeneity have been demonstrated. In this paper, recent advances in fibroblast and myofibroblast research are reviewed.
Topics: Animals; Cardiotonic Agents; Cell Differentiation; Cell Lineage; Collagen; Cytokines; Discoidin Domain Receptor 2; Endomyocardial Fibrosis; Extracellular Matrix; Fibroblasts; Gene Expression Regulation; Humans; Macrophages; Myocardium; Myocytes, Cardiac; Myofibroblasts; Signal Transduction
PubMed: 34359886
DOI: 10.3390/cells10071716 -
Autopsy & Case Reports 2017
PubMed: 29043203
DOI: 10.4322/acr.2017.024 -
JACC. Case Reports May 2020Tropical endomyocardial fibrosis is a common cause of restrictive cardiomyopathy worldwide, but is relatively rare in developed countries. We present a case of tropical...
Tropical endomyocardial fibrosis is a common cause of restrictive cardiomyopathy worldwide, but is relatively rare in developed countries. We present a case of tropical endomyocardial fibrosis with right ventricular involvement initially mistaken as Ebstein's anomaly. We highlight the need for timely and accurate diagnosis to ensure appropriate management. ().
PubMed: 34317354
DOI: 10.1016/j.jaccas.2020.02.020 -
Journal of the American College of... May 2010
Topics: Adult; Electrocardiography; Endomyocardial Fibrosis; Humans; Male; Tricuspid Valve Insufficiency; Ultrasonography
PubMed: 20466198
DOI: 10.1016/j.jacc.2009.06.072 -
Journal of the American College of... May 2016About one-half of the patients with congestive heart failure have preserved left ventricular ejection fraction (HFpEF). Although the etiology of HFpEF is most commonly... (Review)
Review
About one-half of the patients with congestive heart failure have preserved left ventricular ejection fraction (HFpEF). Although the etiology of HFpEF is most commonly related to long-standing hypertension and atherosclerosis, a significant number of suspected HFpEF patients have a restrictive cardiomyopathy or chronic pericardial disease. Recognizing these syndromes is important because early diagnosis may lead to instituting specific therapy that may prolong survival, improve quality of life, and/or recognize and treat an underlying systemic disorder. Advances in diagnostic imaging, biomarkers, and genetic testing today allow identification of the specific etiology in most cases. Novel pharmacological, immunologic, and surgical therapies are leading to improved quality of life and survival.
Topics: Algorithms; Amyloidosis; Antimalarials; Cardiomyopathy, Restrictive; Diagnostic Imaging; Electrocardiography; Endomyocardial Fibrosis; Friedreich Ataxia; Glycogen Storage Disease; Heart Failure; Hemochromatosis; Humans; Pericarditis, Constrictive; Radiotherapy
PubMed: 27126534
DOI: 10.1016/j.jacc.2016.01.076 -
Matrix Biology : Journal of the... Sep 2020Inflammation contributes to the development of heart failure (HF) through multiple mechanisms including regulating extracellular matrix (ECM) degradation and deposition.... (Review)
Review
Inflammation contributes to the development of heart failure (HF) through multiple mechanisms including regulating extracellular matrix (ECM) degradation and deposition. Interactions between cells in the myocardium orchestrates the magnitude and duration of inflammatory cell recruitment and ECM remodeling events associated with HF. More recently, studies have shown T-cells have signficant roles in post-MI wound healing. T-cell biology in HF illustrates the complexity of cross-talk between inflammatory cell types and resident fibroblasts. This review will focus on T-cell recruitment to the myocardium and T-cell specific factors that might influence cardiac wound healing and fibrosis in the heart with consideration of age and sex as important factors in T-cell activity.
Topics: Age Factors; Antigens, CD; Cell Communication; Cytokines; Endomyocardial Fibrosis; Extracellular Matrix; Female; Fibroblasts; Gene Expression Regulation; Heart Failure; Humans; Inflammation; Macrophages; Male; Myocardial Infarction; Myocardium; Myocytes, Cardiac; Signal Transduction; T-Lymphocytes
PubMed: 32438054
DOI: 10.1016/j.matbio.2020.04.001 -
Matrix Biology : Journal of the... Sep 2020Fibroblasts are the primary regulator of cardiac extracellular matrix (ECM). In response to disease stimuli cardiac fibroblasts undergo cell state transitions to a... (Review)
Review
Fibroblasts are the primary regulator of cardiac extracellular matrix (ECM). In response to disease stimuli cardiac fibroblasts undergo cell state transitions to a myofibroblast phenotype, which underlies the fibrotic response in the heart and other organs. Identifying regulators of fibroblast state transitions would inform which pathways could be therapeutically modulated to tactically control maladaptive extracellular matrix remodeling. Indeed, a deeper understanding of fibroblast cell state and plasticity is necessary for controlling its fate for therapeutic benefit. p38 mitogen activated protein kinase (MAPK), which is part of the noncanonical transforming growth factor β (TGFβ) pathway, is a central regulator of fibroblast to myofibroblast cell state transitions that is activated by chemical and mechanical stress signals. Fibroblast intrinsic signaling, local and global cardiac mechanics, and multicellular interactions individually and synergistically impact these state transitions and hence the ECM, which will be reviewed here in the context of cardiac fibrosis.
Topics: Animals; Cell Differentiation; Cell Lineage; Endomyocardial Fibrosis; Extracellular Matrix; Extracellular Matrix Proteins; Gene Expression Regulation; Humans; Mice; Myocardial Infarction; Myocardium; Myofibroblasts; Signal Transduction; Transcription, Genetic; Transforming Growth Factor beta; p38 Mitogen-Activated Protein Kinases
PubMed: 32416242
DOI: 10.1016/j.matbio.2020.04.002 -
Cardiovascular Journal of Africa 2017Endomyocardial fibrosis (EMF) is a rare disease and is often an underdiagnosed and forgotten cardiomyopathy. The objective of this study was to document the current...
OBJECTIVE
Endomyocardial fibrosis (EMF) is a rare disease and is often an underdiagnosed and forgotten cardiomyopathy. The objective of this study was to document the current frequency of EMF in Sudan by defining and selecting cases from patients attending the echocardiography laboratory. Additionally we aimed to create an EMF registry for Sudan.
METHODS
The study started in January 2007 and is on-going. All the patients attending our echocardiography clinics in four different hospitals in Khartoum, Sudan, were included. Transthoracic echocardiography was used as the main diagnostic and selection tool. The diagnosis of EMF was based on predefined criteria and definitions, and was further supported by additional clinical, ECG, laboratory and chest X-ray findings.
RESULTS
Out of 4 332 cases studied, 23 (0.5%) were found to have features of EMF. Females constituted 52% and the age range was 24 to 67 years. All patients presented with dyspnoea grades III-IV. Advanced heart failure with gross fluid overload was seen in 54% of cases and ascites was seen in 30%. EMF was biventricular in 53%, left ventricular in 29% and right ventricular in 18% of cases. Apical and ventricular wall fibrosis was found in all cases, followed by atrial enlargement, atrioventricular valve incompetence, ventricular cavity obliteration, restrictive flow pattern and pericardial effusion. Additional echocardiographic features are defined and discussed.
CONCLUSION
Although a rare disease, cases of EMF can be identified in Sudan if a high index of suspicion is observed. New echocardiographic features of ventricular wall layering, endocardial fibrous shelf and endomyocardiopericarial fibrosis were identified and are discussed.
Topics: Adult; Aged; Disease Management; Echocardiography; Endomyocardial Fibrosis; Female; Follow-Up Studies; Heart Ventricles; Humans; Incidence; Male; Middle Aged; Prospective Studies; Sudan; Young Adult
PubMed: 28906536
DOI: 10.5830/CVJA-2016-079 -
La Radiologia Medica Nov 2020The restrictive cardiomyopathies constitute a heterogeneous group of myocardial diseases with a different pathogenesis and overlapping clinical presentations. Diagnosing... (Review)
Review
The restrictive cardiomyopathies constitute a heterogeneous group of myocardial diseases with a different pathogenesis and overlapping clinical presentations. Diagnosing them frequently poses a challenge. Echocardiography, electrocardiograms and laboratory tests may show non-specific changes. In this context, cardiac magnetic resonance (CMR) may play a crucial role in defining the diagnosis and guiding treatments, by offering a robust myocardial characterization based on the inherent magnetic properties of abnormal tissues, thus limiting the use of endomyocardial biopsy. In this review article, we explore the role of CMR in the assessment of a wide range of myocardial diseases causing restrictive patterns, from iron overload to cardiac amyloidosis, endomyocardial fibrosis or radiation-induced heart disease. Here, we emphasize the incremental value of novel relaxometric techniques such as T1 and T2 mapping, which may recognize different storage diseases based on the intrinsic magnetic properties of the accumulating metabolites, with or without the use of gadolinium-based contrast agents. We illustrate the importance of these CMR techniques and their great support when contrast media administration is contraindicated. Finally, we describe the useful role of cardiac computed tomography for diagnosis and management of restrictive cardiomyopathies when CMR is contraindicated.
Topics: Adult; Aged, 80 and over; Amyloidosis; Cardiac Imaging Techniques; Cardiomyopathies; Cardiomyopathy, Restrictive; Endomyocardial Fibrosis; Female; Humans; Iron Overload; Lysosomal Storage Diseases; Magnetic Resonance Imaging; Male; Middle Aged; Radiation Injuries; Sarcoidosis
PubMed: 32970272
DOI: 10.1007/s11547-020-01287-8