Cardiovascular Calcification and Bone Mineralization (Contemporary Cardiology)

Foreword
Preface
Contents
Contributors
Part I: Cardiovascular Calcification
	Chapter 1: The History of Cardiovascular Calcification
		Introduction to the History of Cardiovascular Calcification
		Pathological Mineralization: Marker and Maker of Cardiovascular Morbidity
		The Tangled History of Physiological and Pathological Calcification
		Concluding Remarks
		References
	Chapter 2: Basic Pathology of Arterial and Valvular Calcification in Humans
		Introduction
		Classification of Vascular Calcification
		Pathology of Coronary Artery Calcification
			Natural History of Atherosclerosis Progression
			Atherosclerotic Intimal Calcification and Its Progression
		Pathology of Peripheral Artery Calcification
			Medial Calcification or Mönkeberg’s Sclerosis
			Lower Extremity Calcification
			Carotid Artery Calcification
		Pathology of Aortic Valve Calcification
			Structure of Aortic Valve
			Aortic Valve Calcification (Tricuspid)
			Congenital Aortic Valve Disease and Calcification (Bicuspid and Unicuspid)
		Pathology of Mitral Valve Calcification
			Structure of Mitral Valve
			Pathology of Mitral Annulus Calcification
		Conclusion
		References
	Chapter 3: Developmental Pathways and Aortic Valve Calcification
		Introduction
		Overview of Aortic Valves (AVs)
			Aortic Valve Structure
			Valve Cell Diversity
		Development of the Aortic Valves
			Overview
			Embryonic Origins of Aortic Valves
			Transcription Factors Involved in Aortic Valve Development
			Signaling Pathways Involved in Aortic Valve Development
		Skeletal Development
			Overview of Endochondral Bone Formation
			Characteristics of Cartilage and Bone Tissue
			Transcriptional Regulation of Skeletal Development
			Signaling Pathways Involved in Bone Development
			Similarities Between Valve and Skeletal Development
		Reactivation of Developmental Pathways in CAVD
			Overview
			Cell Origins of Calcifying Aortic VICs During CAVD
			CAVD: A Bone-Like Process of Calcification
			Developmental Transcription Factors in CAVD
			Intersecting Signaling Pathways in CAVD
		Conclusions
		References
	Chapter 4: Differential Mechanisms of Arterial and Valvular Calcification
		Arterial and Valvular Tissue Microenvironments and Cells
			Calcification Morphology and Tissue Microenvironment
			Smooth Muscle Cells and Valvular Interstitial Cells
			Progenitor Cells
			Endothelial Cells
			T Lymphocytes
			Macrophages/Monocytes
			Dendritic Cells, B Cells, and MAST Cells
		Arterial and Valvular Calcification Molecular Mechanisms
			Mineral Metabolism
			Endogenous Calcification Inhibitors
			Inflammation, Lipids, and Oxidative Stress
			Genetic Drivers of Calcification
		Conclusions
		References
	Chapter 5: Calcifying Extracellular Vesicles: Biology, Characterization, and Mineral Formation
		Extracellular Vesicles in Physiological and Pathological Calcification
			Extracellular Vesicles in Vascular Calcification
		Methods to Analyze Extracellular Vesicle Properties
			Physical Analysis of Extracellular Vesicles
				General Characterization of Extracellular Vesicles
				Particle-by-Particle Analysis of Extracellular Vesicles
			Structural Analysis of Extracellular Vesicles
			Biomolecular Analysis of Extracellular Vesicles
			Analysis of Extracellular Vesicle Mineralization
		Future Perspectives
		References
	Chapter 6: Role of Biomechanical Stress and Mechanosensitive miRNAs in Calcific Aortic Valve Disease
		Introduction
		Aortic Valve Structure and Biomechanical Forces
		Mechanosensing in the Aortic Valve
		miRNAs in the Aortic Valve
			miRNAs with Undefined Mechanosensitivity in the Aortic Valve
			Shear-Dependent miRNAs in AV
			Stretch-Dependent miRNAs in AV
		Future Perspectives in Calcific Aortic Valve Disease Research and Treatment
		References
	Chapter 7: The Role of Chronic Kidney Disease in Ectopic Calcification
		What Is Chronic Kidney Disease?
		The Risk Factors of CKD and Their Association with Ectopic Calcification
			Dysregulated Mineral Metabolism: CKD Leads to Hyperphosphataemia, which is Exacerbated by Klotho Deficiency and Ineffective Fibroblast Growth Factor 23 (FGF23)
			Dysregulated Mineral Metabolism: Vitamin D Deficiency in CKD and Reduced Ca Intake
			Dysregulated Mineral Metabolism: CKD Is a State of SHPT Resulting in Hypercalcaemia and Hyperphosphataemia
			Dysregulated Mineral Metabolism: The Risk of Ectopic Calcification and Cardiovascular Disease
			The Alternative CKD Risk Factors for Calcification: The Uraemic Milieu
		What Is Ectopic Calcification?
			Vascular Calcification: CKD Is Associated with Arteriosclerosis
		Mechanisms of Vascular Calcification and the Impact of CKD
			Apoptosis of Vascular Smooth Muscle Cells
			Extracellular Vesicle Release
			Perturbation in the Level of Physiological Calcification Inhibitors
			Osteo/Chondrogenic Differentiation
			Ageing-Related DNA Damage and Senescence
			Inflammation
		Treatment Strategies
			Treatments to Reduce the Risk Factors of Calcification
			Treatments to Directly Target Calcification
		Summary
		References
	Chapter 8: The Role of Calcification in Peripheral Artery Disease
		Population Studies and Risk Factors
		Histology
		Calcification and PAD Severity
		Outcomes of Patients with Peripheral Calcification and PAD
		The Effect of Calcification on Treatment Options for PAD
		Calcification and Arterial Stiffness
		Treatment for Calcification in PAD
		Conclusion
		References
	Chapter 9: Bioprosthetic Heart Valve Calcification: Clinicopathologic Correlations, Mechanisms, and Prevention
		Native Heart Valve Functional Structure
		Valvular Heart Disease
		Heart Valve Replacement
			Surgical Valve Replacement
			Transcatheter Aortic Valve Implantation (TAVI) and Other Bioprosthesis Interventions
		Structural Considerations in Bioprosthetic Heart Valves
		Bioprosthetic Valve Structural Degeneration
		Calcific and Noncalcific Mechanisms of Bioprosthetic Valve Structural Deterioration
			Experimental Models for Investigation of Bioprosthetic Valve Calcification
			Pathophysiology of Bioprosthetic Heart Valve Calcification
				Role of Host Biological Factors
				Role of Substrate Factors
				Role of Biomechanical Factors
				Role of Immunologic Factors
			Noncalcific Mechanisms of Bioprosthetic Valve Structural Deterioration
		Prevention of Bioprosthetic Valve Calcification
			Inhibitors of Hydroxyapatite Formation
				Trivalent Metal Ions
				Calcium Diffusion Inhibitor
			Removal/Modification of Calcifiable Material
				Surfactants
				Alcohol Treatments
			Glutaraldehyde Neutralization
				Decellularization
			Modification of Glutaraldehyde Fixation and Other Tissue Fixatives
		References
Part II: Ectopic Calcification
	Chapter 10: Electron Microscopy for the Characterization of Soft Tissue Mineralization
		Electron Microscopy
		Scanning Electron Microscopy and Pathological Minerals
			Imaging
			Density-Dependent Color Scanning Electron Microscopy (DDC-SEM)
			Chemical Analysis: Energy-Dispersive X-Ray Spectroscopy (EDS)
		SEM Sample Preparation of Biological Material
			Coating and Silver Painting
		Transmission Electron Microscopy and Pathological Minerals
			Imaging
		TEM Sample Preparation of Biological Material
		Summary
		References
	Chapter 11: Cardiovascular Calcification in Hutchinson-Gilford Progeria and Correlation with Age-Related Degenerative Calcification
		Hutchinson-Gilford Progeria Syndrome (HGPS)
		Mechanisms Underlying Non-HGPS Progeroid Syndromes
		Mechanisms Underlying HGPS Syndrome
		Mechanisms for Vascular Pathology in HGPS
		Relation of HGPS to “Normal” Aging
		Conclusion
		References
	Chapter 12: Calcinosis in Scleroderma
		Introduction
		Crystal Composition
		Pathophysiology of Calcinosis
		Clinical Presentation
		Scleroderma Disease Subset Associations with Calcinosis
		Diagnostic Approach
		Treatment Modalities
		Therapies for Inflammation
		Calcium Channel Blockers
		Bisphosphonates
		Warfarin
		Intravenous Immunoglobulin
		Biologic Agents
		Nonmedical Therapies
		Conclusion
		References
	Chapter 13: Placental Calcification: Long-standing Questions and New Biomedical Research Directions
		Introduction to the Placenta
		Placental Calcification and Maternal and Fetal Outcomes
		Observed Mineral Deposition Patterns in Human Placenta
		Calcium and Phosphate Homeostasis in Pregnancy
		Lessons from Animal Model Development Studies
		Molecular Biology of Calcification in the Placenta
		Pro-calcific Transmembrane Proteins
		Secreted Pro-calcific Factors
		Pro-calcific Transcription Factors
		Anti-calcific Transmembrane Proteins
		Secreted Anti-calcific Factors
		Anti-calcific Transcription Factors
		Computer Vision: A New Frontier in Placental Calcification Research
		Conclusions
		References
	Chapter 14: Heterotopic Ossification Following Traumatic Blast Injury
		Blast Injury
		Heterotopic Ossification
			Aetiology and Epidemiology
			Biology
				Environment/Inflammation
				Cells
			Diagnosis, Prevention, and Treatment
				Diagnosis
				Current Preventions
				Current Treatment
				Novel Therapies
		Outlook
		References
Part III: Bone Mineralization
	Chapter 15: The Paradoxical Relationship Between Skeletal and Cardiovascular Mineralization
		Introduction
		Similarities Between Vascular and Skeletal Mineralization
		Location of Cardiovascular Calcification
		Clinical Significance
		Paradoxical Relation to Osteoporosis
		Oxidant Stress, Lipids, and Inflammatory Cytokines
		Statin Class of Drugs
		Teriparatide
		Bisphosphonates
		Vitamin D and Calcium Supplementation
		References
	Chapter 16: Cellular Contributors to Bone Homeostasis
		Introduction
		Osteoblasts
			Osteoblast Differentiation
			Regulatory Pathways
		Osteoclasts
			Osteoclast Differentiation
			Osteoclast Resorptive Capacity
			Fine-Tuning of Osteoclast Formation and Function
		Osteocytes
			Regulatory Pathways Involved in Osteocytogenesis
			Regulatory Pathways Involved in Mineralization
			Regulatory Pathways Involved in Phosphate Homeostasis
			Regulatory Pathways Involved in Osteocytic Osteolysis
			Regulatory Pathways Involved in Mechanosensation and Mechanotransduction
		Immune Cells That Participate in Skeletal Homeostasis
			T Lymphocytes
			B Lymphocytes
			Mast Cells
			Monocytes/Macrophages
		Coupling of Bone Resorption and Formation
		Bone Homeostasis Contributes to the Inter-organ Crosstalk Between Bone and Peripheral Organs
			FGF23
			Osteocalcin
			Other Osteokines
		Conclusion
		References
	Chapter 17: Bone Biology, Modeling, Remodeling, and Mineralization
		Introduction
		Bone Biology
			Components of the Bone
			Types of Bone Matrix
		Bone Formation During Development
		Bone Remodeling
		Bone Modeling
		Measures of Bone Modeling/Remodeling
		Bone Matrix Mineralization
		References
	Chapter 18: Osteoclasts in Cardiovascular Calcification
		Osteoclasts Are Crucial Regulators of Bone Resorption
		Osteoclastogenesis
			Proliferation and Differentiation of Osteoclast Precursors
			Osteoclast Precursor Commitment
			Osteoclast Precursor Motility and Fusion
			Osteoclast Functionality
		Critical Pathways in Bone Resorption
			M-CSF/RANK/RANKL/OPG
			Classical and Alternative NF-κB Pathways in Osteogenesis
			c-Fos and AP-1-Associated Pathways
			Inflammatory Regulators of Osteoclastogenesis
		MicroRNAs in Osteoclast Differentiation and Function
			Positive miRNA Regulators of Osteoclastogenesis
			Negative miRNA Regulators of Osteoclastogenesis
		The Calcification Paradox
		References
Part IV: Imaging, Treatment, and Target Discovery
	Chapter 19: Imaging Cardiovascular Calcification Activity with 18F-Fluoride PET
		Introduction
		How Does 18F-Fluoride PET Work?
			Positron Emission Tomography
		Aortic Stenosis
		Mitral Annular Calcification
		Bioprosthetic Valve Degeneration
		Coronary Atherosclerosis
		Carotid Atherosclerosis
		Abdominal Aortic Aneurysms
		Penile Uptake
		Limitations
		Conclusion
		References
	Chapter 20: The Role of Elastin Degradation in Vascular Calcification: Possibilities to Repair Elastin and Reverse Calcification
		Definitions
		Introduction
			Vascular Calcification in Intima and Media
		Elastin Is an Integral Part of the Arterial Structure to Maintain Homeostasis of Cells
			Elastin Is Essential for Regulating Arterial Mechanical Properties
			Proper Elastic Fiber Assembly During Development Is Required to Resist Vascular Calcification
		Elastin Degradation and Vascular Calcification
			Role of Elastolytic Enzymes in Calcification
			Role of Elastin-Derived Peptides
			Elastin-Associated Components That Activate Osteogenesis Through Degradation of Elastic Fibers
			Role of Elastin Degradation in Atherosclerotic Calcification
		Potential Treatment Strategies to Prevent Vascular Calcification
			Prevention of Vascular Calcification in Chronic Kidney Disease (CKD)
			Prevention of Vascular Calcification in Diabetics
			Prevention of Vascular Calcification in Atherosclerosis
		Regression of Preexisting Vascular Calcification: Calcium Sequestration
			Targeted Drug Delivery to Degraded Elastin to Reverse Vascular Calcification and Repair Elastin Causing a Return of Homeostasis in Arteries
		Summary
		References
	Chapter 21: Clinical Trials and Calcification-Based Treatment Decisions
		Clinical Studies of Methods to Assess Cardiovascular Calcification
		Blood Calcification Propensity and Cardiovascular Events
		Clinical Trials of Pharmacological Therapeutics
			Vitamin K
			Sodium Thiosulfate
			Bisphosphonates
			Magnesium
			SNF472
			Denosumab
		Clinical Studies of the Invasive Diagnosis and Treatment of Cardiovascular Calcification
		Percutaneous Coronary Intervention for Calcified Plaques and Coronary Arteries
		Coronary Artery Bypass Grafting Surgery in Patients with Calcified Coronary Arteries
		Peripheral Arterial Disease and the Role of Calcification in Treatment Decision-Making
		Calcification of the Mitral Valve
		Conclusion
		References
	Chapter 22: Surgical Versus Transcatheter Aortic Valve Replacement
		Epidemiology and Mechanism of Calcific Aortic Stenosis
		Symptoms and Severity of Aortic Stenosis
		Surgical Aortic Valve Replacement
		Mechanical Valves
		Bioprosthetic Valves
		Choice of Valve Type
		Life Expectancy with Prosthetic Valves
		Anticoagulation
		Trends in Choice of Prosthetic Aortic Valves
		Transcatheter Aortic Valve Replacement
		Evolution of TAVR Indications
		Pre-procedural Evaluation
		Procedure and Recovery
		References
	Chapter 23: Target Discovery in Calcification Through Omics and Systems Approaches
		Omics-Informed Pathobiology and Drug Discovery
		Interrogation of Nucleic Acids: Genomics and Transcriptomics
			Genome-Wide Studies on Cardiovascular Calcification
			Transcriptomics Bridges the Gap Between Genetic and Environmental Regulation of Calcification
			Epigenetics and the Genetic Structure of Calcification
		Evaluating Roles for Functional Biomolecules in Calcification Via Proteomics and Metabolomics
			Mass Spectrometry as a Tool to Investigate Protein-Mediated Regulation of Calcification
			Metabolomics: Assessing the Final Link Between Genotype and Phenotype
		Systems-Based Computational Approaches in Cardiovascular Calcification
			Bioinformatics to Extract Biological Insights
			Multi-omics Data Integration
		The Promise of Omics-Driven Target Discovery
		References
Index