Note: Preface -- Contents -- Contributors -- About the Editors -- Cardiac Fibrosis and Heart Failure-Causeor Effect? -- Primary Contribution of Cardiac Fibrosis to HeartFailure -- References -- Fibroblast Activation in the Infarcted Myocardium -- 1 Introduction -- 2 Cardiac Fibroblasts in Normal Mammalian Hearts -- 3 The Phases of Cardiac Repair -- 4 Cardiac Fibroblasts During the Inflammatory Phase -- 4.1 Cardiac Fibroblasts as Inflammatory Cells Following an Ischemic Insult -- 4.2 Do activated Fibroblasts Participate in Resolution of Post-Infarction Inflammation? -- 5 Cardiac Fibroblasts During the Proliferative Phase -- 5.1 Activated Fibroblasts as the Dominant Reparative Cells in the Infarcted Myocardium -- 5.2 Characteristics and Origin of Activated Fibroblasts Following Infarction -- 5.3 Myofibroblast Transdifferentiation -- 5.4 Role of TGF-β Signaling and its Importance in Fibrosis -- 5.5 Signals Regulating Fibroblast Migration in the Infarcted Myocardium -- 5.6 The Renin Angiotensin Aldosterone System (RAAS) and Growth Factors Regulate Fibroblast Function in the Infarcted Myocardium -- 5.7 The Extracellular Matrix as a Modulator of Fibroblast Phenotype: The Matricellular Proteins -- 6 Cardiac Fibroblasts During the Maturation Phase of Infarct Healing -- 7 Cardiac Fibroblasts in the Remodeling Non-Infarcted Heart -- 8 Therapeutic Opportunities: Targeting the Cardiac Fibroblast Following Myocardial Infarction -- 9 Conclusions -- References -- Mechanical and Matrix Regulation of Valvular Fibrosis -- 1 Introduction -- 1.1 Aortic Valve Biology, Physiology, and Function -- 1.2 Aortic Valve Fibrosis -- 2 Fibrosis, Biomechanics and the Myofibroblast -- 3 TGF-β-Mediated Mechanotransduction of Valvular Myofibrogenesis -- 4 Mechanical Control of Valvular Myofibroblast Differentiation Independent of TGF-β. , 5 Impact of Aortic Valve Disease and Biomechanics on Cardiac Fibrosis -- 6 Conclusions -- References -- Bone Marrow-Derived Progenitor Cells, micro-RNA, and Fibrosis -- 1 Introduction -- 2 Cell Sources of Fibrosis -- 2.1 Mesenchymal Progenitor Cells (MPCs) -- 2.2 Fibrocytes -- 2.3 Other Differentiating Cell Sources -- 3 Influence of miRNA on Cell Differentiation and Fibrosis -- 4 Conclusions -- References -- The Stressful Life of Cardiac Myofibroblasts -- 1 Introduction -- 2 A Myofibroblast is a Myofibroblast, Of Course, Of Course? -- 2.1 Myofibroblast Features -- 2.2 Cardiac Myofibroblast Precursors -- 3 More than Just Material for Myofibroblasts: The ECM of the Heart -- 3.1 Composition and Function of the ECM in the Heart -- 3.2 ECM Mechanics Matters for Myofibroblast Activation -- 4 TGF-β1 at the Cross-Roads of ECM and Growth Factor Signalling -- 5 ECM Receptors in Cardiac Myofibroblast Differentiation -- 6 Conclusions -- References -- Pathogenic Origins of Fibrosis in the Hypertensive Heart Disease that Accompanies Aldosteronism -- 1 Introduction -- 2 Hypertensive Heart Disease -- 2.1 Human HHD -- 2.2 An Animal Model of HHD -- 2.3 Remodeling Independent of Hypertension -- 3 Cardiac Myocyte Necrosis as Pathogenic Origin to Microscopic Scarring -- 3.1 Prooxidant Pathway -- 3.2 Antioxidant Pathways in Cardioprotection -- 4 An Immunostimulatory State as Pathogenic Origin to Perivascular Fibrosis -- 4.1 The Proinflammatory Vascular Phenotype -- 4.2 Induction of Oxidative Stress -- 4.3 Cardioprotection -- 5 Myofibroblasts and Cardiac Fibrosis -- 6 Summary and Conclusions -- References -- Embryological Origin of Valve Progenitor Cells -- 1 Introduction -- 2 Early Cardiogenesis and Valve Progenitor Specification -- 2.1 Overview of Cardiac Development and Key Concepts -- 2.2 Endocardium Formation -- 2.3 Epicardium -- 2.4 Neural Crest. , 3 Valve Maturation -- 4 Valvulopathies, Cardiac Fibrosis and Aortic Stenosis -- 5 Conclusions -- References -- Diverse Cellular Origins of Cardiac Fibroblasts -- 1 Introduction -- 2 Phenotypes -- 2.1 Fibroblasts -- 2.2 Protomyofibroblasts -- 2.3 Myofibroblasts -- 3 Origin of Cardiac Fibroblasts During Development -- 4 Sources of Fibroblast Generation in Cardiac Pathology -- 5 Resident Fibroblasts -- 6 Epithelial to Mesenchymal Transition (EMT) -- 7 EMT Derived Fibroblasts in Cardiac Diseases -- 8 Endothelial to Mesenchymal Transition (EndMT) -- 9 Bone Marrow-Derived (BMD) Progenitor Cells -- 10 Monocytes -- 11 Fibrocytes -- 12 Perivascular Cells -- 13 Benefits of Understanding the Origin of Fibroblasts -- References -- Non-Canonical Regulation of TGF-β1 Signaling: A Role for Ski/Sno and YAP/TAZ -- 1 TGF-β Signaling -- 2 TGF-β1 and Mechanical Stress -- 3 The Ski/Sno Superfamily -- 4 TGF-β Regulation of Ski/Sno -- 5 Ski/Sno Regulation of TGF-β1 Signaling -- 6 Implications of Ski/Sno Function in the Pathology of Cardiac Fibrosis -- 7 The Hippo Pathway -- 8 YAP/TAZ and Mechanical Stress -- 9 Cross-Talk Between the Hippo and TGF-β Pathways -- 10 The Effects of YAP in the Heart -- 11 Synopsis -- References -- Molecular Mechanisms of Smooth Muscle and Fibroblast Phenotype Conversions in the Failing Heart -- 1 Atherosclerosis and Restenosis -- 2 Role of VSMCs in Atherosclerosis -- 3 Transcriptional Regulation of Smooth Muscle Phenotype Conversions -- 4 Fibrosis -- 5 Fibroblast to Myofibroblast Transition -- 6 Molecular Regulation of the Smooth Muscle Actin Gene in Phenotype Conversion -- 7 Concluding Remarks -- References -- Current and Future Strategies for the Diagnosis and Treatment of Cardiac Fibrosis -- 1 Clinical Presentation of Cardiac Fibrosis -- 2 Diagnosing Cardiac Fibrosis -- 3 Biomarkers of Cardiac Fibrosis -- 4 Current Treatments. , 4.1 Targeting the Renin-Angiotensin-Aldosterone System -- 4.1.1 Angiotensin-Converting Enzyme Inhibitors -- 4.1.2 Angiotensin II Receptor Antagonists -- 4.1.3 Aldosterone Antagonists or Anti-mineralocorticoids -- 4.1.4 Direct Renin Inhibitors -- 4.2 Diuretics -- 4.3 The Sympathetic Nervous System -- 4.3.1 Beta-Adrenergic Blockade -- 4.3.2 Alpha-Adrenergic Blockade -- 4.4 Calcium Channel Blockers -- 4.5 Statins -- 4.6 Inhibition of Transforming Growth Factor-β -- 4.7 Anti-inflammatory Agents -- 5 Future Directions -- 5.1 Endothelin-1 -- 5.2 MicroRNAs -- 5.3 Targeting the Extracellular Matrix -- 6 Summary -- References -- Remodelling of the Cardiac Extracellular Matrix: Role of Collagen Degradation and Accumulation in Pathogenesis of Heart Failure -- 1 Introduction -- 2 Myocardial Extracellular Matrix (ECM) -- 3 Different Types of Myocardial Fibrosis and Impact on Cardiac Function -- 4 Collagen Synthesis, Assembly and Deposition and Related Biomarkers in the Heart -- 5 Collagen Degradation and Related Biomarkers in Heart Disease -- 6 Clinical Markers of Collagen Synthesis and Degradation, and Their Prognostic Significance -- 7 Management of Cardiac Fibrosis -- 8 Conclusions -- References -- Matrix Metalloproteinase 9 (MMP-9) -- 1 Introduction -- 2 Regulation of Transcription and mRNA -- 3 MMP-9 Structure -- 3.1 Pro-, Active, and Inactive MMP-9 -- 4 Post-translational Modifications -- 5 MMP-9 and Adverse Cardiac Remodeling Post-MI -- 5.1 In Cardiac Inflammation -- 5.2 In Cardiac Fibrosis -- 5.3 In Post Myocardial Infarction -- 6 MMP-9 Bioactive ECM Substrates -- 7 A Pathophysiological Biomarker -- 8 MMP-9 Inhibitors -- 8.1 Endogenous MMP-9 Inhibitors -- 8.2 Pharmacological MMP-9 Inhibitors -- 8.3 MMP-9 Inhibition in Translational Medicine -- 9 Conclusion and Future Directions -- References -- Collagen Processing and its Role in Fibrosis. , 1 Introduction and Clinical Considerations -- 2 Functional Importance of Cardiac Extracellular Matrix -- 3 Responses of the Cardiac Extracellular Matrix in Disease -- 4 Cardiac Fibroblasts and Myofibroblasts in Response to Hypertension and Diabetes -- 5 Conversion of Fibroblasts to Pro-Fibrotic Myofibroblasts -- 6 Remodeling of Collagen -- 7 Collagen Degradation by Phagocytosis -- 8 Matrix Metalloproteinases and Processing in Collagen Phagocytosis -- 9 Future Prospects -- References -- Mechanisms of Cardiac Fibrosis and Heart Failure -- 1 Structure and Function of the Extracellular Matrix -- 2 Cardiac Fibroblasts and Myofibroblasts -- 3 Collagen Synthesis and Regulation -- 4 Matrix Metalloproteinases and Tissue Inhibitors of MMPs -- 5 Cardiac Remodelling Following Myocardial Infarction -- 6 Cardiac Remodelling, Pressure, and Volume Overload -- 7 Cardiac Fibrosis in Reverse Remodelling -- 8 Regulation of the ECM in Diabetes and the Metabolic Syndrome -- 9 Conclusions -- References -- Mathematical Simulations of Sphingosine-1-Phosphate Actions on Mammalian Ventricular Myofibroblasts and Myocytes -- 1 Introduction -- 2 Model Development -- 2.1 Mathematical Model Abbreviations -- 2.2 Myocyte Equations -- 2.3 Myofibroblast Equations -- 2.4 Electrotonic Coupling -- 2.5 Myofibroblast Membrane Potential -- 2.6 In silico Syncytium -- 3 Results -- 3.1 Baseline Simulations of the Effects of S-1-P -- 3.2 Simulations of Heart Failure in Ventricular Myocytes -- 4 Discussion -- References -- Extracellular Matrix and Cardiac Disease: Surgical and Scientific Perspectives -- 1 Introduction -- 2 The ECM of the Heart -- 2.1 The Fibrous Skeleton -- 2.2 ECM Architecture and Cardiac Function -- 2.3 ECM as a Dynamic Microenvironment -- 3 Role of the ECM in Cardiac Disease and Dysfunction -- 3.1 ECM Dysregulation and Cardiac Dysfunction -- 3.2 ECM and Aortic Disease. , 3.3 ECM and Valvular Heart Disease.