Mechanisms of Vascular Disease A Textbook for Vascular Specialists

Contents
Abbreviations
Chapter 1: Vascular Endothelium in Health and Disease
	1.1 Introduction
	1.2 Endothelium-Dependent Regulation of Vascular Tone
		1.2.1 Gaseous Mediators
		1.2.2 Endothelium-Dependent Hyperpolarisation
		1.2.3 Metabolites of Arachidonic Acid
		1.2.4 Endothelins
	1.3 Angiogenesis
	1.4 Haemostasis
	1.5 Inflammation
	1.6 Conclusions
	References
		Further Reading
Chapter 2: Pathophysiology of Atherosclerosis
	2.1 Introduction
	2.2 Normal Vessel Wall
	2.3 Stages of Atherosclerosis
		2.3.1 Intimal Xanthomas or Fatty Streaks
		2.3.2 Fibroatheroma
		2.3.3 Thin-Cap Fibroatheroma
		2.3.4 Plaque Rupture
		2.3.5 Fibrous Calcified Plaque
		2.3.6 Plaque Erosion
	2.4 Pathophysiology of Atherosclerosis and Atherothrombosis
		2.4.1 Endothelial Dysfunction
		2.4.2 Lipoprotein Entry and Modification
		2.4.3 Leukocyte Recruitment
		2.4.4 Foam Cell Formation
		2.4.5 Lymphocyte Responses
		2.4.6 Smooth Muscle Cell Migration and Fibrous Cap Formation
		2.4.7 Macrophage Apoptosis and Necrotic Core Formation
		2.4.8 Calcification
		2.4.9 Neovascularisation and Intraplaque Haemorrhage
		2.4.10 Fibrous Cap Degradation and Plaque Rupture
		2.4.11 Plaque Erosion
	2.5 The Role of Inflammation in Atherosclerosis
	2.6 Risk Factors
		2.6.1 Genetic Risk Factors
		2.6.2 Traditional Risk Factors
	2.7 Conclusion
	References
		Further Reading
Chapter 3: Mechanisms of the Vulnerable Atherosclerotic Plaque and Imaging
	3.1 Introduction
	3.2 Plaque Rupture
		3.2.1 Thin Cap Fibroatheromas
		3.2.2 Plaque Size and Positive Luminal Remodeling
		3.2.3 Lipid-Rich Necrotic Core
		3.2.4 Neovascularisation and Plaque Haemorrhage
		3.2.5 Calcification
	3.3 Plaque Erosion
	3.4 Calcified Nodules
	3.5 Effect of Diabetes on Plaque Morphology
	3.6 Carotid Imaging
		3.6.1 Carotid Ultrasound
		3.6.2 Carotid Computed Tomography
		3.6.3 Carotid Magnetic Resonance Imaging
	3.7 Molecular Imaging
		3.7.1 Imaging Inflammation: Fluorodeoxyglucose (18F-FDG)
		3.7.2 Imaging Microcalcification: Sodium Fluoride (18F-NaF)
	3.8 Intravascular Imaging
		3.8.1 Intravascular Ultrasound (IVUS)
		3.8.2 Optical Coherence Tomography (OCT)
		3.8.3 Intravascular Molecular Imaging
	3.9 Conclusion: Vulnerable Plaques and Vulnerable Patients
	References
		Further Reading
Chapter 4: Current and Emerging Therapies for Atherosclerosis
	4.1 Introduction
	4.2 Risk Stratification
	4.3 Lifestyle Measures
	4.4 Anti-platelet and Anti-thrombotic Therapies
	4.5 Blood Pressure Therapies
	4.6 LDL Cholesterol Lowering Therapies
	4.7 Additional Lipid Modifying Therapies
	4.8 Glucose Lowering Therapies
	4.9 Anti-Inflammatory Therapies
	4.10 Obesity Targeted Therapies
	4.11 Cardiac Rehabilitation
	4.12 Conclusion
	References
		Further Reading
Chapter 5: Pathophysiology of Angiogenesis and Its Role in Vascular Disease
	5.1 Introduction
	5.2 Basic Mechanisms of Angiogenesis
		5.2.1 Sprouting Angiogenesis
		5.2.2 Intussusceptive Angiogenesis
	5.3 Angiogenesis in Health and Disease
		5.3.1 Physiological Angiogenesis
		5.3.2 Pathological Angiogenesis
			5.3.2.1 Angiogenesis and Atherosclerosis
			5.3.2.2 Angiogenesis in Aneurysmal Disease
			5.3.2.3 Diabetes- and Age-Impaired Angiogenesis
	5.4 Targeting Angiogenesis in a Clinical Setting
		5.4.1 Pharmacological Inhibition of Angiogenesis
		5.4.2 Limitations of Current Anti-angiogenic Therapies
		5.4.3 Therapeutic Stimulation of Angiogenesis
		5.4.4 Emerging Angiogenesis-Modulating Therapies
	5.5 Conclusion
	References
		Further Reading
Chapter 6: Vascular Biology of Smooth Muscle Cells and Restenosis
	6.1 Introduction
	6.2 Vascular Smooth Muscle Cells
		6.2.1 Role in Vascular Function
		6.2.2 Regulation of Vascular Function by VSMCs
		6.2.3 Atherosclerosis
		6.2.4 VSMC Apoptosis
		6.2.5 VSMCs Origins; Role in Atherosclerosis
		6.2.6 Restenosis
		6.2.7 Smooth Muscle Cell Phenotype
			6.2.7.1 Contractile Versus Synthetic Phenotype
			6.2.7.2 Trans-differentiation of VSMCs to Macrophages
		6.2.8 Smooth Muscle Progenitor Cells
	6.3 Restenosis
		6.3.1 Causes and Mechanisms of Restenosis
			6.3.1.1 Mechanisms of Inflammation-Driven Neointimal Hyperplasia
			6.3.1.2 Growth Factors
			6.3.1.3 Extracellular Matrix (ECM)
			6.3.1.4 Percutaneous Arterial Interventions That Cause Restenosis and Their Evolution
			6.3.1.5 Bare Metal Stents (BMS)
		6.3.2 Strategies to Reduce Neointimal Hyperplasia
			6.3.2.1 Drug Eluting Stents
			6.3.2.2 Drug-Coated Balloons
			6.3.2.3 Emerging Role of miRNAs in Restenosis
	6.4 Neoatherosclerosis
	6.5 Conclusions
	References
		Further Reading
Chapter 7: Vascular Haemodynamics
	7.1 Introduction
	7.2 Pump Mechanisms in the Circulation
	7.3 Darcy’s Law
	7.4 Poiseuille Flow
	7.5 Laplace’s Law of Wall Tension
	7.6 Viscosity Behaviour
	7.7 Reynolds Number
	7.8 Womersley Number
	7.9 Bernoulli’s Equation
	7.10 Young’s Modulus and Pulsatile Flow
	7.11 Mass Conservation
	7.12 Arterial Dissection, Collateral Circulation and Competing Flows
	7.13 Shear Stress and Pressure
	7.14 Forces on Graft Systems
		7.14.1 Case 1: The Cylindrical Graft
		7.14.2 Case 2: The Windsock Graft
		7.14.3 Case 3: The Curved Graft (Fig. 7.21)
		7.14.4 Case 4: The Symmetrical Bifurcated Graft
	7.15 Conclusion
	References
		Further Reading
Chapter 8: Computational Fluid Dynamics in the Arterial System: Implications for Vascular Disease and Treatment
	8.1 Introduction
	8.2 Terminology
	8.3 Finite Element Analysis (FEA)
	8.4 Computational Fluid Dynamics (CFD)
		8.4.1 Segmentation and Reconstruction
		8.4.2 Numerical Simulation
		8.4.3 Meshing
		8.4.4 Element-Based vs. Volume-Based Meshing
		8.4.5 Fluid: Solid Interaction
	8.5 Material Properties
		8.5.1 Blood Flow Properties
		8.5.2 Blood Vessel Properties
		8.5.3 Initial and Boundary Conditions
	8.6 Pulsatile Flow in Arteries
	8.7 What Is Convergence?
		8.7.1 Result Analysis (Post-processing)
		8.7.2 Validation and Verification
	8.8 Clinical Applications
		8.8.1 Atherosclerosis
		8.8.2 Stenosis
		8.8.3 Aneurysm
		8.8.4 Aortic Dissection
		8.8.5 Stents
	8.9 CFD Benefits and Challenges
	8.10 Conclusion
	References
		Further Reading
Chapter 9: Physiological Haemostasis
	9.1 Introduction
	9.2 Primary Haemostasis
		9.2.1 Platelets
			9.2.1.1 Platelet Adhesion and von Willebrand Factor
			9.2.1.2 Platelet Activation and Shape Change
			9.2.1.3 Platelet Aggregation
	9.3 Interactions Between Primary and Secondary Haemostasis
	9.4 Secondary Haemostasis
	9.5 The Coagulation Cascade
		9.5.1 Initiation
		9.5.2 Amplification
		9.5.3 Propagation
		9.5.4 Other Roles of the Contact Activation System
		9.5.5 Natural Inhibitors of Coagulation
	9.6 Fibrinolysis
	9.7 Conclusions
	References
		Further Reading
Chapter 10: Hypercoagulable States
	10.1 Introduction
	10.2 Classification of Thrombophilia
		10.2.1 Inherited Thrombophilia
			10.2.1.1 Type 1 Conditions
				Antithrombin Deficiency
				Protein C and Protein S Deficiency
			10.2.1.2 Type 2 Conditions
				Factor V Leiden
				The Prothrombin (G20210A) Gene Mutation
				FVL/PGM Compound Heterozygotes
				Other Inherited Conditions
		10.2.2 Acquired Thrombophilia
			10.2.2.1 Antiphospholipid Antibodies
			10.2.2.2 Heparin Induced Thrombocytopenia
			10.2.2.3 Myeloproliferative Disorders
			10.2.2.4 Paroxysmal Nocturnal Haemoglobinuria
	10.3 Potential Reasons for Performing Thrombophilia Testing
		10.3.1 Patients with Venous Thrombosis and Their Relatives
			10.3.1.1 Providing an Understanding of the Aetiology of a Thrombotic Event
			10.3.1.2 Determining the Choice of Antithrombotic Agent for Initial Treatment of Thrombosis
			10.3.1.3 Determining the Risk of Recurrence and Therefore Optimal Duration of Anticoagulation
			10.3.1.4 Determining the Need for Primary Prophylaxis in Asymptomatic Family Members
			10.3.1.5 Making Decisions Regarding the Use of the Oral Contraceptive Pill
			10.3.1.6 Determining the Need for Thromboprophylaxis During Pregnancy
	10.4 Patients with Arterial Thrombosis
	10.5 Potential Detrimental Effects of Thrombophilia Testing
	10.6 Conclusion
	References
		Further Reading
Chapter 11: Platelets in the Pathogenesis of Vascular Disease and Their Role as a Therapeutic Target
	11.1 Introduction
	11.2 Platelet Structure and Function
		11.2.1 Platelet Adhesion Receptors
		11.2.2 Glycoprotein IIb/IIIa (GPIIb/IIIa) Structure
		11.2.3 Glycoprotein GPIIb/IIIIa Activation
		11.2.4 GPIIb/IIIa Inside-Out Signaling
		11.2.5 Glycoprotein IIb/IIIa Outside-In Signalling
		11.2.6 Glycoprotein Ib-IX-V Complex
		11.2.7 Glycoprotein VI
		11.2.8 Other Platelet Receptors
		11.2.9 Platelet Granules
		11.2.10 Platelet Membrane
	11.3 Mediators of Platelet Activation
		11.3.1 Soluble Agonists and Their G Protein-Coupled Receptors (GPCRs)
			11.3.1.1 Adenosine Diphosphate (ADP) and the P2Y Receptors
			11.3.1.2 Thromboxane A2 (TxA2) and the Thromboxane Receptor (TP)
			11.3.1.3 Thrombin and the Protease Activated Receptors (PAR)
	11.4 Platelet Thrombus Formation
		11.4.1 Platelet Adhesion
		11.4.2 Platelet Activation and Aggregation
		11.4.3 Platelet Adhesion to Inflamed Endothelium
	11.5 The Proinflammatory Role of Platelets
		11.5.1 Platelets as Immune and Inflammatory Mediators
		11.5.2 Platelets Induce Endothelial Activation
		11.5.3 The Role of Platelets in Leukocyte Recruitment and Activation
	11.6 The Contribution of Platelets to Atherosclerosis
	11.7 Current Anti-platelet Therapies
		11.7.1 Aspirin
		11.7.2 P2Y12 Receptor Antagonists
			11.7.2.1 Clopidogrel
			11.7.2.2 Prasugrel
			11.7.2.3 Ticagrelor
			11.7.2.4 Cangrelor
		11.7.3 Dual Anti-platelet Therapy
		11.7.4 PAR-1 (Protease Activated Receptor-1) Antagonists
		11.7.5 GPIIb/IIIa Inhibitors
		11.7.6 Phosphodiesterase Inhibitors
		11.7.7 Current Therapeutic Landscape
	11.8 Perioperative Management of Anti-platelet Therapy
	11.9 Novel Anti-platelet Drugs in Development
	11.10 Platelet Function Testing
	11.11 Conclusion
	References
		Further Reading
Chapter 12: Abdominal Aortic Aneurysm Pathology and Progress Towards a Medical Therapy
	12.1 Introduction
	12.2 AAA Epidemiology
		12.2.1 Risk Factors Identified from Epidemiological Studies
	12.3 AAA Pathogenesis
		12.3.1 Tissue Samples
		12.3.2 Blood Samples
		12.3.3 Insight Provided by Genetic Studies
	12.4 Factors Contributing to AAA Rupture
	12.5 Discovering Effective Medications for AAA; Current Progress in Clinical Trials
		12.5.1 Trials Assessing Anti-hypertensive Medications
		12.5.2 Trials Assessing Anti-inflammatory Agents
		12.5.3 Trials Assessing Dyslipidaemic Drugs
		12.5.4 Current Trials
		12.5.5 Interpreting Findings from Clinical Trials
	12.6 Conclusion
	References
Chapter 13: Pathophysiology and Principles of Management of Hereditary Aneurysmal Aortopathies
	13.1 Introduction
	13.2 Epidemiology
	13.3 Pathophysiology
	13.4 Syndromic Thoracic Aortic Aneurysm Presentations
		13.4.1 Marfan Syndrome
		13.4.2 Loeys-Dietz Syndrome
		13.4.3 Shprintzen-Goldberg Syndrome
		13.4.4 Meester-Loeys Syndrome
		13.4.5 Vascular Ehlers-Danlos Syndrome
		13.4.6 Periventricular Nodular Heterotopia Type 1
		13.4.7 Arterial Tortuosity Syndrome
		13.4.8 Autosomal Recessive Cutis Laxa Type 1
	13.5 Non-syndromic Disorders
	13.6 Pathogenesis of Thoracic Aortic Aneurysm/Dissection
		13.6.1 Structural Integrity of the ECM
		13.6.2 Regulation of the VSMC Contractile Unit
		13.6.3 TGF-β Signalling Pathway
	13.7 TAA Management
		13.7.1 Clinical Diagnosis
		13.7.2 Molecular Diagnosis
		13.7.3 Medical Treatment
	13.8 Conclusion
	References
		Further Reading
Chapter 14: Pathophysiology, Classification and Principles of Management of Acute Aortic Syndromes
	14.1 Introduction
	14.2 Anatomical and Molecular Considerations in the Thoracic Aorta
	14.3 Haemodynamics of Thoracic Compared to Abdominal Aorta
	14.4 Risk Factors for the Development of AAS
	14.5 Epidemiology
	14.6 Pathophysiology of Acute Aortic Syndrome
	14.7 Classification Systems for AAS
		14.7.1 Temporal Classification (Acute/Chronic)
		14.7.2 Complicated Versus Uncomplicated Dissection
		14.7.3 Penn Classification
		14.7.4 DeBakey Anatomical Classification
		14.7.5 Stanford Classification
		14.7.6 European Society of Cardiology Task Force on Diagnosis and Treatment of Aortic Diseases
		14.7.7 “DISSECT” Classification
			14.7.7.1 Anatomical Descriptors of the Thoracic Aorta
	14.8 Individual Types of Pathology
		14.8.1 Classical TAAD (Class 1 Dissection)
		14.8.2 Intra-mural Haematoma (IMH) (Class 2 Dissection)
		14.8.3 Penetrating Aortic Ulcer (Class 4 Aortic Dissection)
	14.9 Prognosis of AAS
	14.10 Diagnostic Imaging
		14.10.1 Computed Tomography
		14.10.2 Trans Oesophageal Echocardiography (TOE)/Trans Thoracic Echocardiography (TTE)
		14.10.3 Magnetic Resonance Imaging (MRI)
		14.10.4 Intravascular Ultrasound (IVUS)
		14.10.5 Biochemical Markers
	14.11 Principles of Treatment of AAS
	14.12 Summary
	References
		Further Reading
Chapter 15: Biomarkers in Vascular Disease
	15.1 Introduction
	15.2 What Is a Biomarker?
	15.3 Types of Biomarker
		15.3.1 A Classical Clinical Example
	15.4 Potential Value of Biomarkers in Vascular Disease
	15.5 Biomarker Discovery Steps
	15.6 AAA Biomarkers
		15.6.1 Possible Circulating Biomarkers of AAA (Table 15.3)
			15.6.1.1 Circulating Extracellular Matrix Markers
			15.6.1.2 Matrix-Degrading Enzymes
			15.6.1.3 Proteins Associated with Thrombosis
			15.6.1.4 MicroRNAs
			15.6.1.5 Markers of Inflammation
		15.6.2 Biomarkers of AAA Rupture
		15.6.3 Biomarkers Following Endovascular Repair
	15.7 Unstable Carotid Plaque Biomarkers (Table 15.4)
		15.7.1 Inflammation
		15.7.2 Lipid Accumulation
		15.7.3 Apoptosis
		15.7.4 Thrombosis
		15.7.5 Proteolysis
		15.7.6 Immunity
	15.8 Challenges in Biomarker Discovery
	15.9 Future Work
	15.10 Conclusion
	References
		Further Reading
Chapter 16: Pathophysiology and Principles of Management of Vasculitis and Fibromuscular Dysplasia
	16.1 Introduction
	16.2 Primary Versus Secondary Vasculitis
	16.3 Large Vessel Vasculitis
		16.3.1 Giant Cell Arteritis (Temporal Arteritis)
			16.3.1.1 Biphasic Inflammatory Response in GCA
		16.3.2 Takayasu Arteritis
	16.4 Medium Vessel Vasculitis
		16.4.1 Polyarteritis Nodosa
		16.4.2 Kawasaki Disease
	16.5 Small Vessel Vasculitis
		16.5.1 Anti-neutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis (AAV)
			16.5.1.1 Granulomatosis with Polyangiitis (GPA)
			16.5.1.2 Eosinophilic Granulomatosis with Polyangiitis (EGPA)
			16.5.1.3 Microscopic Polyangiitis (MPA)
		16.5.2 Immune Complex Small Vessel Vasculitis
			16.5.2.1 Immunoglobulin-A Vasculitis (IgAV)
			16.5.2.2 Cryoglobulinemic Vasculitis (CV)
			16.5.2.3 Hypocomplementaemic Urticarial Vasculitis (HUV, Anti-C1q Vasculitis)
			16.5.2.4 Anti-Glomerular Basement Membrane (Anti-GBM) Disease
	16.6 Variable Vessel Vasculitis
		16.6.1 Behcet’s Disease
		16.6.2 Cogan’s Syndrome
	16.7 Vasculitis Associated with Systemic Disease
		16.7.1 Autoimmune Rheumatic Diseases
		16.7.2 IgG4-Related Disease (IgG4-RD)
	16.8 Vasculitis Associated with Probable Aetiology
		16.8.1 Drug-Induced Vasculitis
		16.8.2 Vasculitis Associated with Cancer Immunotherapy
	16.9 Vasculitis Mimics
		16.9.1 Raynaud’s Phenomenon
		16.9.2 Thromboangitis Obliterans (TAO, Buerger’s Disease)
	16.10 Fibromuscular Dysplasia (FMD)
	16.11 Summary
	References
		Further Reading
Chapter 17: Sepsis and Septic Shock
	17.1 Introduction and Definitions
	17.2 Epidemiology
	17.3 Aetiology
	17.4 Pathogenesis
		17.4.1 Innate Immunity in Sepsis
		17.4.2 Immunosuppression in Sepsis
		17.4.3 Microvascular Alterations in Sepsis
		17.4.4 Mitochondrial Dysfunction in Sepsis
		17.4.5 Pathological Vasodilation in Septic Shock
		17.4.6 Sepsis Induced Cardiac Dysfunction
		17.4.7 Other Sepsis Induced Organ Dysfunction
	17.5 Clinical Manifestations
	17.6 Investigation
	17.7 Treatment
		17.7.1 Initial Resuscitation
		17.7.2 Antimicrobial Therapy
		17.7.3 Source Control
		17.7.4 Corticosteroids
		17.7.5 Adjunctive Therapies
	17.8 Conclusion
	References
		Further Reading
Chapter 18: Pathophysiology of Reperfusion Injury
	18.1 Introduction
	18.2 Ischaemia
		18.2.1 ATP and Mitochondrial Function
		18.2.2 Gene Expression During Ischaemia
	18.3 Reperfusion
		18.3.1 Reactive Oxygen Species
		18.3.2 Eicosanoids
		18.3.3 Nitric Oxide
		18.3.4 Endothelin
		18.3.5 Cytokines
		18.3.6 Neutrophils and Endothelial Interactions
		18.3.7 Complement Activation
		18.3.8 Toll-Like Receptors and the Innate Immune System
	18.4 Tissue Destruction
		18.4.1 Proteases and Metalloproteinases
		18.4.2 Apoptotic Cell Death During Ischaemia-Reperfusion Injury
		18.4.3 No Reflow Phenomenon
	18.5 Therapeutic Approaches to IRI
		18.5.1 Ischaemic Preconditioning
		18.5.2 Ischaemic Post-conditioning
		18.5.3 Conditioning Effects of Volatile Anaesthetics
		18.5.4 Pharmacological Treatments
	18.6 Summary
	References
		Further Reading
Chapter 19: Abdominal Compartment Syndrome and Open Abdomen Treatment
	19.1 Introduction
	19.2 Definition of Intra-abdominal Hypertension (IAH)/ Abdominal Compartment Syndrome (ACS)
	19.3 How Common Is IAH/ACS After AAA Repair?
	19.4 Pathophysiology and Risk Factors for ACS After AAA Repair
	19.5 Prevention of ACS and Medical Management
	19.6 Decompression Laparotomy (DL)
	19.7 Prophylactic Open Abdomen Treatment
	19.8 Management of the Patient with Open Abdomen (OA)
	19.9 Prognosis
	19.10 Conclusion
	References
		Further Reading
Chapter 20: Pathophysiology and Management of Limb Compartment Syndromes
	20.1 Introduction
	20.2 Epidemiology
	20.3 Pathophysiology
	20.4 Clinical Presentation
	20.5 Diagnostic Testing
	20.6 Management
		20.6.1 Lower Extremity Operative Techniques
		20.6.2 Upper Extremity Operative Technique
	20.7 Postoperative Care
	20.8 Outcome
	20.9 Conclusion
	References
		Further Reading
Chapter 21: Pathophysiology of Pain
	21.1 Introduction
	21.2 Peripheral Mechanisms
		21.2.1 Nociception/Transduction
		21.2.2 Conduction
	21.3 Spinal Cord Mechanisms
		21.3.1 Ascending Systems
		21.3.2 Descending Control
	21.4 Pain Modulation
		21.4.1 Peripheral Sensitisation
		21.4.2 Central Sensitisation in the Dorsal Horn
	21.5 Neuropathic Pain
		21.5.1 Mechanisms of Neuropathic Pain
			21.5.1.1 Peripheral Mechanisms
				Spontaneous Ectopic Discharge
				Altered Gene Expression
				Spared Sensory Neurones
				Involvement of the Sympathetic Nervous System
				Effects of Bradykinin
			21.5.1.2 Central Mechanisms
				Wind-Up
				Central Sensitisation
				Central Disinhibition
				Expansion in Receptive Field Size (Recruitment)
				Immediate Early Gene Expression
				Anatomical Re-Organisation of the Spinal Cord
				Contribution of Glial Cells to Pain Conditions
		21.5.2 Symptoms of Neuropathic Pain
			21.5.2.1 Stimulus-Dependent Pain
			21.5.2.2 Stimulus-Independent Pain
			21.5.2.3 Sympathetically Maintained Pain (SMP)
	21.6 Neuropathic Pain Syndromes
		21.6.1 Peripheral Neuropathies
			21.6.1.1 Metabolic/Endocrine
			21.6.1.2 Toxic
			21.6.1.3 Post-infectious
			21.6.1.4 Hereditary
			21.6.1.5 Malignant
			21.6.1.6 Vascular
			21.6.1.7 Posttraumatic
		21.6.2 Central Neuropathies
			21.6.2.1 Vascular Lesions in the Brain and Spinal Cord
			21.6.2.2 Multiple Sclerosis
			21.6.2.3 Trauma, Tumours and Infections
	21.7 Nociplastic Pain
	21.8 Conclusion
	References
		Further Reading
Chapter 22: Post Amputation Pain Syndromes
	22.1 Introduction
	22.2 Classification and Incidence
		22.2.1 Stump Pain
		22.2.2 Phantom Sensation
		22.2.3 Phantom Limb Pain
	22.3 Pathophysiology
		22.3.1 Peripheral Factors
		22.3.2 Spinal Factors
		22.3.3 Supraspinal Factors
		22.3.4 Current Pathophysiological Model
	22.4 Prevention
		22.4.1 Risk Factors and Predictors
		22.4.2 Provision of Good Perioperative Analgesia
		22.4.3 Perioperative Lumbar Epidural Blockade
		22.4.4 Peripheral Nerve Blockade
		22.4.5 NMDA Antagonists
	22.5 Evaluation of the Patient with Post Amputation Pain Syndromes
		22.5.1 Examination
	22.6 Therapy
		22.6.1 Calcitonin
		22.6.2 NMDA Receptor Antagonists
		22.6.3 Opioids
		22.6.4 Gabapentin
		22.6.5 Lidocaine
		22.6.6 Tricyclic Antidepressants (TCA)
		22.6.7 Capsaicin
		22.6.8 Symptomatic Treatment of Pain Components
	22.7 Nonpharmacological Therapies
		22.7.1 Invasive Therapies
			22.7.1.1 ECT
			22.7.1.2 Transcutaneous Electrical Nerve Stimulation (TENS)
			22.7.1.3 Peripheral Nerve Stimulation
			22.7.1.4 Spinal Cord and Brain Stimulation
			22.7.1.5 Dorsal Root Entry Zone Lesions
		22.7.2 Psychological Therapy
	22.8 Conclusion
	References
		Further Reading
Chapter 23: Treatment of Neuropathic Pain
	23.1 Introduction
	23.2 Principles of Treatment
	23.3 Pharmacological Treatment
		23.3.1 Conventional Opioids
			23.3.1.1 Recommendations for Clinical Use of Conventional Opioids in Neuropathic Pain
		23.3.2 Atypical Opioids
			23.3.2.1 Tramadol
			23.3.2.2 Tapentadol
		23.3.3 Antidepressants
			23.3.3.1 Tricyclic Antidepressants (TCAs)
			23.3.3.2 Selective Serotonin Re-uptake Inhibitors (SSRIs)
			23.3.3.3 Serotonin/Noradrenaline Reuptake Inhibitors (SNRIs)
			23.3.3.4 Recommendations for Clinical Use of Antidepressants as Analgesics
		23.3.4 Anticonvulsants
			23.3.4.1 Mechanism of Action
			23.3.4.2 Individual Medications
			23.3.4.3 Recommendations for Clinical Use of Anticonvulsants as Analgesics
		23.3.5 Local Anaesthetics and Antiarrhythmics
			23.3.5.1 Recommendations for Clinical Use of Lignocaine in Neuropathic Pain
		23.3.6 N-methyl-d-Aspartate-Receptor (NMDA) Antagonists
		23.3.7 Miscellaneous Agents for Systemic Use
		23.3.8 Topical Treatments
		23.3.9 Non Pharmacological Therapy
			23.3.9.1 Transcutaneous Electrical Nerve Stimulation [47]
			23.3.9.2 Spinal Cord Stimulation (SCS)
			23.3.9.3 Sympathetic Nerve Blocks
			23.3.9.4 Neurosurgical Destructive Techniques
			23.3.9.5 Cognitive-Behavioural Therapy
	23.4 Conclusion
	References
		Further Reading
Chapter 24: Pathophysiology of Varicose Veins, Chronic Venous Insufficiency and Venous Ulceration
	24.1 Introduction
	24.2 Clinical Spectrum of Venous Disease
	24.3 Venous Anatomy
		24.3.1 Superficial Veins
		24.3.2 Deep Veins
		24.3.3 Perforating Veins
		24.3.4 Valvular Anatomy
	24.4 Normal Venous Function
	24.5 Pathophysiology of Chronic Venous Hypertension
		24.5.1 Microcirculatory Changes in Venous Hypertension
	24.6 Causes of Chronic Venous Hypertension
		24.6.1 Venous Reflux
			24.6.1.1 Secondary Valvular (Post-thrombotic) Damage
	24.7 Post Thrombotic Syndrome
		24.7.1 Deep Vein Thrombosis (DVT) and Thrombus Resolution
		24.7.2 Impact of Venous Outflow Obstruction
	24.8 Genetic and Metabolic Profiling in Venous Disease
	24.9 Principles of Management of Venous Disease
		24.9.1 Clinical Evaluation
		24.9.2 Investigations
		24.9.3 Treatment
			24.9.3.1 General Principles
			24.9.3.2 Superficial Venous Interventions
			24.9.3.3 Deep Venous Interventions
	24.10 Conclusions
	References
		Further Reading
Chapter 25: Pathophysiology of Wound Healing
	25.1 Introduction
	25.2 The Wound Healing Process
		25.2.1 Haemostasis
		25.2.2 Inflammation
		25.2.3 The Inflammation Conundrum
		25.2.4 Proliferation
			25.2.4.1 Re-epithelialisation
			25.2.4.2 Matrix Deposition
			25.2.4.3 Angiogenesis
			25.2.4.4 Wound Contraction
		25.2.5 Remodelling
	25.3 The Effects of Ageing on Wound Repair
		25.3.1 Effects of Ageing on Inflammation
		25.3.2 Effects of Ageing on Re-epithelialization
		25.3.3 Effects of Ageing on Matrix Deposition and Remodelling
		25.3.4 Effects of Ageing on Angiogenesis
	25.4 Chronic Wound Healing
		25.4.1 Chronic Wounds
		25.4.2 Diabetic Ulcers
		25.4.3 Pressure Ulcers
		25.4.4 Arterial and Venous Ulcers
	25.5 Wound Infection
		25.5.1 Biofilms
		25.5.2 The Infection Challenge
	25.6 Conclusion
	References
		Further Reading
Chapter 26: Pathophysiology and Principles of Management of the Diabetic Foot
	26.1 Introduction
	26.2 Pathophysiology of the Diabetic Foot
		26.2.1 Neuropathy and Biomechanical Abnormalities
		26.2.2 Peripheral Artery Disease (PAD)
	26.3 Clinical Assessment of the Diabetic Foot
		26.3.1 History and Physical Examination
		26.3.2 Assessment of Foot Perfusion
			26.3.2.1 Ankle-Brachial Index (ABI)
			26.3.2.2 Toe Pressure and Toe:Brachial Index
			26.3.2.3 Doppler Waveform Assessment
			26.3.2.4 Transcutaneous Oxygen Pressure and Skin Perfusion Pressure
		26.3.3 Diagnosis of Osteomyelitis
	26.4 Risk Classification/Staging of the Diabetic Foot
		26.4.1 WIfI Classification
	26.5 Principles of Management of the Diabetic Foot
		26.5.1 Offloading
		26.5.2 Wound Management
		26.5.3 Management of Infection
		26.5.4 Lower Limb Arterial Revascularisation
	26.6 Charcot Neuroarthropathy
	26.7 Prevention
	26.8 Conclusion
	References
		Further Reading
Chapter 27: Lymphoedema
	27.1 Introduction
	27.2 Lymphangiogenesis
		27.2.1 Origin and Differentiation of Lymphatic Endothelial Cells
		27.2.2 Sprouting of Lymphatic Endothelial Cells
		27.2.3 Remodelling of a Lymphatic Vascular System
	27.3 Structure and Function of the Lymphatic System
		27.3.1 Maintenance of Fluid Balance
		27.3.2 Immunity and Infection
		27.3.3 Lymphatics, Fat and Inflammation
	27.4 Lymphoedema
		27.4.1 Introduction
		27.4.2 Epidemiology
		27.4.3 Clinical Features
		27.4.4 Complications of Lymphoedema
	27.5 Secondary Lymphoedema
	27.6 Primary Lymphoedema
		27.6.1 Genetic Syndromes Associated with Lymphoedema (Blue Section of the Pathway)
		27.6.2 Lymphoedema with Systemic (Internal) Lymphatic Abnormalities (Pink Section of the Pathway)
		27.6.3 Lymphoedema in Association with Overgrowth of Tissues (Yellow Section)
		27.6.4 Congenital Lymphoedema (Green Section)
		27.6.5 Late-Onset Primary Lymphoedema (Purple Section)
	27.7 Investigating Lymphoedema
		27.7.1 Lymphography and Lymphoscintigraphy
		27.7.2 Near Infra-Red Lymphangiography
		27.7.3 Magnetic Resonance Lymphangiography (MRL)
	27.8 Management of Lymphoedema
		27.8.1 Physical Therapies
			27.8.1.1 Reduction Phase Treatment
			27.8.1.2 Maintenance Phase Treatment
			27.8.1.3 Manual Lymphatic Drainage (MLD)
			27.8.1.4 Intermittent Pneumatic Compression
		27.8.2 Pharmacological Therapies
		27.8.3 Surgical Options
			27.8.3.1 Excisional Methods
			27.8.3.2 Lymphatico-Venous Anastomosis (LVA) Surgery
			27.8.3.3 Lymph Node Transfer Surgery
			27.8.3.4 Liposuction
	27.9 Summary
	References
Chapter 28: Graft Materials: Present and Future
	28.1 Introduction
	28.2 Pathophysiology of Graft Healing
		28.2.1 The Peri-Anastomotic Area
		28.2.2 Healing of Prosthetic Grafts
		28.2.3 Graft Porosity and Permeability
	28.3 Vascular Graft Failure
		28.3.1 Early Failure
		28.3.2 Late Failure
		28.3.3 Tubular Compliance Mismatch
		28.3.4 Anastomotic Compliance Mismatch
	28.4 Prosthetic Grafts
		28.4.1 Modifications of PET Grafts
			28.4.1.1 Heparin Bonding
			28.4.1.2 Electrospinning
			28.4.1.3 Gelatin Coatings
		28.4.2 Modifications of ePTFE Grafts
			28.4.2.1 Heparin-Bonded ePTFE Grafts
			28.4.2.2 Sulfonated Silk Fibroin Modified ePTFE Grafts
			28.4.2.3 Polymer Coated ePTFE Grafts
	28.5 Polyurethane Grafts
		28.5.1 Modifications of Polyurethane Grafts
			28.5.1.1 Polycarbonate Polyurethane
			28.5.1.2 Composite Polyurethane Grafts
			28.5.1.3 Endothelial Progenitor Cell (EPC) Homing
	28.6 Other Graft Modifications
		28.6.1 Modifications to Reduce Thrombogenicity
		28.6.2 Modifications to Reduce Intimal Hyperplasia
		28.6.3 Mechanical Prevention
		28.6.4 Pharmacological Prevention
		28.6.5 Other Potential Therapies
		28.6.6 Modifications to Improve Haemocompatibility
	28.7 Biological Vascular Grafts
		28.7.1 Bacterial Cellulose
		28.7.2 Allogeneic Grafts
		28.7.3 Biotubes
	28.8 Vascular Tissue Engineering
		28.8.1 Self-Assembled TEVG
		28.8.2 Scaffold-Based TEVG
		28.8.3 Biodregadable Prosthetic Polymer-Based Constructs
		28.8.4 Decellularised Tissue Grafts
		28.8.5 Hybrid TEVG
	28.9 Arteriovenous Grafts
	28.10 Graft Materials for Aortic Stent-Grafts
	28.11 Conclusions and Future Directions
	References
		Further Reading
Chapter 29: Vascular Graft Infections
	29.1 Introduction
	29.2 Natural History of Prosthetic Vascular Graft Infections
	29.3 Mechanisms of Graft Contamination at Operation
	29.4 Pathogenesis of Graft Infections
	29.5 Bacteriology of Vascular Graft Infections
	29.6 Investigations for Detection of Prosthetic Graft Infections
		29.6.1 History and Physical Examination
		29.6.2 Laboratory Investigations
		29.6.3 Diagnostic Imaging
	29.7 Management of Prosthetic Graft Infections
	29.8 Established Infection
		29.8.1 Antibiotic Therapy
		29.8.2 Operative Approaches to Vascular Graft Infection
		29.8.3 Stent Graft Infection
	29.9 Conclusion
	References
		Further Reading
Chapter 30: Radiation Physics and Biological Effects of Radiation in Vascular Surgery
	30.1 A Brief History of Radiation Use in Vascular Surgery
		30.1.1 The Discovery of Radiation
		30.1.2 Endovascular Pioneers
		30.1.3 Exposure to Medical Radiation
			30.1.3.1 General Population
			30.1.3.2 Vascular Patients
	30.2 Radiation Physics, Measurements, Dosimetry and Units
		30.2.1 X-rays
		30.2.2 Interaction with the Body
		30.2.3 Scatter Radiation and The Inverse Square Law
		30.2.4 Measuring Radiation Dose
			30.2.4.1 Conceptual Measurements
				Absorbed Dose: Unit = Gray (Gy)
				Equivalent Dose: Unit = Sievert (Sv)
				Effective Dose: Unit = Sievert (Sv)
			30.2.4.2 Direct Versus Indirect Measurements
			30.2.4.3 Direct Measurements
				Peak Skin Dose: Unit = Gray (Gy)
			30.2.4.4 Indirect Measurements
				Cumulative Air Kerma at the Interventional Reference Point (CAK): Unit = Gray (Gy)
				Dose Area Product (DAP): Unit = Gray.cm2 (Gy.cm2)
				Fluoroscopy Time: Units = minutes (min)
			30.2.4.5 Documenting Dose, Reporting Threshold Limits and Diagnostic Reference Levels
	30.3 The Biological Effects of Radiation
		30.3.1 Interaction of X-rays with Tissue
		30.3.2 Deterministic Effects
			30.3.2.1 Skin Injury
			30.3.2.2 Bone Injury
			30.3.2.3 Eye Injury
			30.3.2.4 Impaired Fertility
		30.3.3 Stochastic Effects
			30.3.3.1 DNA Damage
			30.3.3.2 The Linear No-Threshold Theory
			30.3.3.3 Predicting Stochastic Risk
		30.3.4 What Is the Risk for Interventionalists?
			30.3.4.1 Statistical Risk of Cancer in Interventionalists
			30.3.4.2 Recommended Occupational Exposure Limits
			30.3.4.3 Occupations Limits in the Context of a Career in Vascular Surgery
			30.3.4.4 Brain Cancer and Dementia
			30.3.4.5 Cataracts
			30.3.4.6 Genetic Susceptibility to Radiation Injury
	30.4 Conclusion
	References
		Further Reading
Chapter 31: Radiation Stewardship: Radiation Exposure, Protection and Safety in Contemporary Endovascular Practice
	31.1 Radiation Stewardship
	31.2 Radiation Exposure during Endovascular Interventions
		31.2.1 Radiation Exposure During EVAR
		31.2.2 Procedural Complexity
		31.2.3 Other High Dose Procedures
		31.2.4 Diagnostic Reference Levels
	31.3 Radiation Protection and Safety
		31.3.1 Introduction
		31.3.2 Behaviour
			31.3.2.1 ALARA
			31.3.2.2 Team
			31.3.2.3 Culture
			31.3.2.4 Leadership
			31.3.2.5 Education and Training
			31.3.2.6 Distance from Source
			31.3.2.7 Position Around the Table
			31.3.2.8 Pregnancy
			31.3.2.9 Dosimeters
		31.3.3 Machine Controls
			31.3.3.1 Fluoroscopy Time and Last Image Hold
			31.3.3.2 Automatic Dose Settings
			31.3.3.3 Fluoroscopy and Pulse Rate
			31.3.3.4 Digital Subtraction Angiography and Frame Rate
			31.3.3.5 Collimation
			31.3.3.6 Magnification
			31.3.3.7 Imaging Chain Geometry
			31.3.3.8 C-Arm Angulation
		31.3.4 Imaging Equipment and Workflow
			31.3.4.1 Flat Panel Detectors
			31.3.4.2 Fixed Systems vs. Mobile C-Arms
			31.3.4.3 Operator-Controlled Imaging
			31.3.4.4 Advanced Dose-Reduction Software
			31.3.4.5 Pre-operative Planning Software
			31.3.4.6 3D-Image Fusion Software
		31.3.5 Shielding
			31.3.5.1 Personal Lead Garments
			31.3.5.2 Leaded Eye Glasses
			31.3.5.3 Thyroid Shield
			31.3.5.4 Hats
			31.3.5.5 Hands and Gloves
			31.3.5.6 Ceiling Mounted Shielding
			31.3.5.7 Leg and Foot Shielding
			31.3.5.8 Drapes
		31.3.6 Innovations
			31.3.6.1 Zero Gravity Suspended System
			31.3.6.2 Trinity System
			31.3.6.3 Cathpax Cabin
			31.3.6.4 EggNest Table
			31.3.6.5 Endovascular Robotics
			31.3.6.6 Non-Radiation Imaging
	31.4 Conclusion
	References
		Further Reading
Glossary