24 Mechanisms of Vascular Disease

Mechanisms of Vascular Disease: A Reference Book for Vascular Specialists

Robert Fitridge The University of Adelaide, The Queen Elizabeth Hospital, Woodville, Australia Matthew Thompson St George’s Hospital Medical School, London, UK

Published in Adelaide by

The University of Adelaide, Barr Smith Press Barr Smith Library The University of Adelaide South Australia 5005 [email protected] www.adelaide.edu.au/press

The University of Adelaide Press publishes peer-reviewed scholarly works by staff via Open Access online editions and print editions.

The Barr Smith Press is an imprint of the University of Adelaide Press, reserved for scholarly works which are not available in Open Access, as well as titles of interest to the University and its associates. The Barr Smith Press logo features a woodcut of the original Barr Smith Library entrance.

© The Contributors 2011

This book is copyright. Apart from any fair dealing for the purposes of private study, research, criticism or review as permitted under the Copyright Act, no part may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise without the prior written permission. Address all inquiries to the Director at the above address.

This CIP cataloguing for this work is as follows;

Mechanisms of vascular disease : a reference book for vascular surgeons / Robert Fitridge, Matthew Thompson, [editors].

1. Blood vessels, Diseases. 2. Blood vessels‚ Surgery.

I. Fitridge, Robert II. Thompson, M. M.

For the full Cataloguing-in-Publication data please contact National Library of Australia: [email protected]

ISBN (paperback) 978-0-9871718-2-5

Book design: Midland Typesetters Cover design: Emma Spoehr, based on a diagram by Dave Heinrich of the Medical Illustration and Media Unit, Flinders Medical Centre Paperback edition printed by Griffin Press, South Australia Table of Contents

Contributors vii target 201 Detailed Contents xi Sandeep Prabhu, Rahul Sharma, Karlheinz Peter (Melbourne, Australia) 1. Endothelium 1 12. Pathogenesis of aortic aneurysms 227 Paul Kerr, Raymond Tam, Jonathan Golledge, Guo-Ping Shi, Frances Plane (Calgary, Canada) Paul Norman (Townsville & Perth, 2. Vascular smooth muscle structure and Australia; Boston, USA) function 13 13. Pharmacological treatment of David Wilson (Adelaide, Australia) aneurysms 247 3. Atherosclerosis 25 Matthew Thompson, Janet Powell Gillian Cockerill, Qingbo Xu (London, UK) (London, UK) 14. Aortic dissection and connective tissue 4. Mechanisms of plaque rupture 43 disorders 255 Ian Loftus (London, UK) Mark Hamilton (Adelaide, Australia) 5. Current and emerging therapies in 15. Biomarkers in vascular disease 277 atheroprotection 79 Ian Nordon, Robert Hinchliffe Stephen Nicholls, Rishi Puri (London, UK) (Cleveland, USA) 16. Pathophysiology and principles 6. Molecular approaches to of management of vasculitis and revascularisation in peripheral vascular Raynaud’s phenomenon 295 disease 103 Martin Veller (Johannesburg, Greg McMahon, Mark McCarthy South Africa) (Leicester, UK) 17. SIRS, sepsis and multiorgan 7. Biology of restenosis and targets for failure 315 intervention 115 Vishwanath Biradar, John Moran Richard Kenagy (Seattle, USA) (Adelaide, Australia) 8. Vascular arterial haemodynamics 153 18. Pathophysiology of reperfusion Michael Lawrence-Brown, Kurt injury 331 Liffman, James Semmens, Ilija Prue Cowled, Robert Fitridge Sutalo (Melbourne & Perth, Australia) (Adelaide, Australia) 9. Physiological haemostasis 177 19. Compartment syndrome 351 Simon McRae (Adelaide, Australia) Edward Choke, Robert Sayers, 10. Hypercoagulable states 189 Matthew Bown (Leicester, UK) Simon McRae (Adelaide, Australia) 20. Pathophysiology of pain 375 11. Platelets in the pathogenesis of vascular Stephan Schug, Helen Daly, disease and their role as a therapeutic Kathryn Stannard (Perth, Australia) v vi Mechanisms of Vascular Disease

21. Postamputation pain 389 26. Pathophysiology and principles of Stephan Schug, Gail Gillespie management of the diabetic foot 475 (Perth, Australia) David Armstrong, Timothy Fisher, 22. Treatment of neuropathic pain 401 Brian Lepow, Matthew White, Stephan Schug, Kathryn Stannard Joseph Mills (Tucson, USA) (Perth, Australia) 27. Lymphoedema – Principles, genetics 23. Principles of wound healing 423 and pathophysiology 497 Gregory Schultz, Gloria Chin, Matt Waltham (London, UK) Lyle Moldawer, Robert Diegelmann 28. Graft materials past and future 511 (Florida, USA) Mital Desai, George Hamilton 24. Pathophysiology and principles of (London, UK) varicose veins 451 29. Pathophysiology of vascular graft Andrew Bradbury (Birmingham, UK) infections 537 25. Chronic venous insufficiency and leg Mauro Vicaretti (Sydney, Australia) ulceration: Principles and vascular biology 459 Index 549 Michael Stacey (Perth, Australia) List of Contributors

David G Armstrong Prue Cowled The University of Arizona Department of Surgery Southern Arizona Limb Salvage Alliance University of Adelaide Tucson, AZ The Queen Elizabeth Hospital USA Woodville, SA Australia Vishwanath Biradar Intensive Care Unit Helen Daly The Queen Elizabeth Hospital Royal Perth Hospital Woodville, SA Perth, WA Australia Australia

Matthew Bown Mital Desai Department of Vascular Surgery University Department of Vascular Surgery Royal Free Hospital University of Leicester University College Leicester London UK UK

Andrew W Bradbury Robert F Diegelmann University Department of Vascular Surgery Department of Biochemistry Birmingham Heartlands Hospital Medical College of Virginia Birmingham Richmond, VA UK USA

Edward Choke Timothy K Fisher Department of Vascular Surgery Rashid Centre for Diabetes and Research University of Leicester Sheikh Khalifa Hospital Leicester Ajmon UK UAE

Gillian Cockerill Robert A Fitridge Department of Clinical Sciences Department of Surgery St George’s Hospital Medical School University of Adelaide London The Queen Elizabeth Hospital UK Woodville, SA Australia

vii viii Mechanisms of Vascular Disease

Gail Gillespie Michael MD Lawrence-Brown Royal Perth Hospital Curtin Health Innovation Research Perth, WA Institute Australia Curtin University Perth, WA Jonathan Golledge Australia Vascular Biology Unit School of Medicine & Dentistry Brian Lepow James Cook University The University of Arizona Townsville, QLD Department of Surgery Australia Southern Arizona Limb Salvage Alliance Tucson, AZ USA George Hamilton University Department of Vascular Surgery Kurt Liffman Royal Free Hospital CSIRO Material Science & Engineering University College and School of Mathematical Sciences London Monash University UK Melbourne, Vic Australia Mark Hamilton Department of Surgery Ian Loftus University of Adelaide Department of Vascular Surgery The Queen Elizabeth Hospital St George’s Hospital Woodville, SA London Australia UK

Robert J Hinchliffe Mark J McCarthy St George’s Vascular Institiute Department of Surgery and Cardiovascular St George’s Hospital Sciences London University of Leicester UK Leicester UK Richard D Kenagy Department of Surgery Greg S McMahon University of Washington Department of Surgery and Cardiovascular Seattle, WA Sciences USA University of Leicester Leicester Paul Kerr UK Department of Pharmacology University of Alberta Simon McRae Alberta Adult Haemophilia Treatment Centre Canada SA Pathology Adelaide, SA Australia List of Contributors ix

Joseph L Mills Janet T Powell The University of Arizona Imperial College Southern Arizona Limb Salvage Alliance London Tucson, AZ UK USA Sandeep Prabhu Lyle Moldawer Baker IDI Heart & Diabetes Institute Department of Surgery Alfred Hospital University of Florida Melbourne, Vic Gainesville, FL Australia USA Rishi Puri John L Moran The Heart and Vascular Institute Faculty of Health Sciences Cleveland Clinic University of Adelaide Cleveland, OH The Queen Elizabeth Hospital USA Woodville, SA Australia Stephan A Schug Stephen Nicholls Royal Perth Hospital The Heart and Vascular Institute Perth, WA Cleveland Clinic Australia Cleveland, OH USA Gregory S Schultz Department of Obstetrics and Gynaecology Ian M Nordon University of Florida St George’s Vascular Institiute Gainesville, FL St George’s Hospital USA London UK Rahul Sharma Baker IDI Heart & Diabetes Institute Paul E Norman Alfred Hospital School of Surgery Melbourne, Vic University of WA Australia Fremantle, WA Australia Guo-Ping Shi Department of Cardiovascular Medicine Karlheinz Peter Brigham & Women’s Hospital Baker IDI Heart & Diabetes Institute Harvard Medical School Melbourne, Vic Boston, MA Australia USA

Frances Plane Michael Stacey Department of Pharmacology University Department of Surgery University of Alberta Fremantle Hospital Alberta Fremantle, WA Canada Australia x Mechanisms of Vascular Disease

Ilija D Sutalo Matt Waltham CSIRO Material Science & Engineering Academic Department of Surgery and Curtin Health Innovation St Thomas’ Hospital Research Instutute London Curtin University UK Highett, Vic Matthew L White Raymond Tam Vascular and Endovascular Surgery Department of Pharmacology University of Arizona University of Alberta Tucson, AZ Alberta USA Canada David P Wilson Matthew Thompson School of Medical Sciences St Georges Hospital Medical School Discipline of Physiology London University of Adelaide UK Adelaide SA Australia Martin Veller Department of Surgery Qingbo Xu University of Witwatersrand Department of Cardiology Johannesburg Kings College South Africa University of London UK Mauro Vicaretti Department of Vascular Surgery Westmead Hospital Westmead, NSW Australia Detailed Contents

Chapter 1 – Endothelium Smooth muscle proliferation and vascular remodeling 20 Paul Kerr, Raymond Tam, Frances Plane Summary 22 Introduction 1 References Endothelium-dependent regulation of vascular tone 2 Angiogenesis 7 Chapter 3 – Atherosclerosis Haemostasis 8 Gillian Cockerill, Qingbo Xu Inflammation 9 Introduction 25 Conclusions 10 Atherosclerotic lesions 26 References Fatty streaks Plaque or atheroma Chapter 2 – Vascular Hypercholesterolemia and oxidised-LDL Smooth Muscle Structure 27 and Function High-density lipoproteins role in atheroprotection 28 David Wilson Hypertension and biomechanical stress Introduction 13 29 Smooth muscle (vascular) structure Biomechanical stress-induced cell death Cytoskeleton 14 30 Contractile myofilament Biomechanical stress and inflammation Functional regulation of vascular smooth 31 muscle: Neuronal, hormonal, receptor Biomechanical stress-induced smooth mediated 15 muscle cell proliferation 32 Smooth muscle function 17 Infections and heat shock proteins Myofilament basis of smooth muscle Infections contraction and relaxation Heat shock proteins 33 Smooth muscle contraction and Infections and HSP expression relaxation 18 Infections, sHSP and innate immuntiy Ion channels important in the regulation 34 of smooth muscle function Immune responses 36 Regulation of cellular Ca2+ MHC class II antigens and T cells Sources of cytosolic Ca2+ entry 19 Oxidised LDL as a candidate antigen Potassium channels HSP60 as a candidate antigen 37 Endothelial regulation of smooth muscle B2-gylcoprotein Ib as a candidate antigen vasodilatation 20 Inflammation xi xii Mechanisms of Vascular Disease

C-reactive protein 38 Stephen Nicholls, Rishi Puri CD40/CD40L Background 79 Summary and perspectives 39 Pathology References Risk factor modification 80 Statins, LDL lowering and C-reactive Chapter 4 – Mechansims of protein Plaque Rupture The complexity of HDL 84 The controversy of trigylcerides 87 Ian Loftus Hypertension Introduction 43 Risk factor modification in the diabetic Evidence for the ‘plaque rupture theory’ patient 89 44 Glycaemic control Coronary circulation Global risk factor reduction in diabetics Cerebral circulation 91 The role of individual components of the The metabolic syndrome 92 arterial wall Future targets 93 The endothelium 45 Conclusion The lipid core 47 References 94 The cap of the plaque 49 Smooth muscle cells and collagen production 50 Chapter 6 – Molecular Macrophages and collagen degradation approaches to 51 revascularisation in The vessel lumen 56 peripheral vascular disease The role of angiogenesis in plaque rupture Greg S McMahon, Mark J McCarthy The role of infectious agents in plaque rupture 57 Introduction 103 Risk prediction of plaque instability 58 Mechanisms of vascular growth Imaging Vasculogenesis Blood markers 59 Angiogenesis 104 Therapy aimed at plaque stabilisation Neovessel maturation 105 HMG Co-A reductase inhibitors 60 Microvascular network maturation 106 MMP inhibition Arteriogenesis Tissue inhibitors of metalloproteinases Therapeutic induction of vascular growth (TIMPs) 61 107 Synthetic MMP inhibitors Delivery of molecular activators of Doxycycline vascular growth ACE inhibitors Angiogenic activators 108 Summary 62 Arteriogenic activators 109 References 63 Clinical trials for angiogenic therapy of peripheral vascular disease Chapter 5 – Current and Conclusions 110 emerging therapies in References atheroprotection Detailed Contents xiii

Chapter 7 – Biology of Laplace’s law of wall of tension 154 restenosis and targets for Newtonian fluid 155 intervention Non-Newtonian fluid Poiseuille flow 158 Richard Kenagy Bernoulli’s equation Introduction 115 Young’s modulus and pulsatile flow 159 Mechanisms of restenosis Mass conversion 161 Thrombosis 116 Reynold’s number Remodelling Arterial dissection, collateral circulation Intimal hyperplasia 123 and competing flows 163 Sequence of events after injury Shear stress and pressure 164 Origin of intimal cells 125 Forces on graft systems 165 Inflammation 126 Case 1 – The cylindrical graft 168 Role of ECM production 127 Case 2 – The windsock graft The contribution of specific factors to Case 3 – The curved graft 169 restenosis Case 4 – The symmetric bifurcated graft Growth factors/cytokines Computational modelling 170 Inhibitors 128 Recent development and future directions Coagulation and fibrinolytic factors 129 171 Matrix metalloproteinases Conclusions 172 Extracellular matrix/receptors References 173 Targets for intervention 130 Intracellular signalling molecules mTOR and microtubules Chapter 9 – Physiological Transcription factors haemostasis miRNA 131 Simon McRae Inflammation targets Brachytherapy Introduction 177 Extracellular targets and cell-based Primary haemostasis therapies Platelets Angiotensin pathway Platelet adhesion Cell-based therapies 132 Platelet activation and shape change Differential effects on endothelium and 179 SMCs Platelet aggregation 180 Delivery devices Interactions between primary and Prevention versus reversal of restenosis secondary haemostasis 181 Conclusions 133 Secondary haemostasis References 134 The coagulation cascade 182 Initiation 183 Amplification Chapter 8 – Vascular Propagation 184 arterial haemodynamics Normal inhibitors of coagulation Michael Lawrence Brown, Kurt Liffman, Fibrinolysis 185 James Semmens, Ilija Sutalo Conclusions 186 References Introduction 153 xiv Mechanisms of Vascular Disease

Chapter 10 – vascular disease and their Hypercoagulable states role as a therapeutic target Simon McRae Sandeep Prabhu, Rahul Sharma, Introduction 189 Karlheinz Peter Classification of thrombophilia Inherited thrombophilia 190 Introduction 201 Type 1 conditions Platelet function – Adhesion and Antithrombin deficiency activation Protein C and Protein S deficiency Platelet adhesion 202 Type 2 conditions 191 Platelet activation 203 Factor V Leiden Mediators of platelet activation and The prothrombin (G20210A) gene ‘outside in’ signalling mutation Thrombin and collagen 204 FVL/PGM compound heterozygotes Adenosine diphosphate (ADP) Other inherited conditions Thromboxane A2 (TXA2) Acquired thrombophilia 192 Adrenaline 206 Antiphospholipid antibodies Second messenger systems 207 Heparin induced thrombocytopenia Physiological consequences of platelet Myeloproliferative disorders 193 activation Potential reasons for performing The GP IIb/IIIa receptor and ‘inside- thrombophilia testing out’ signalling Patients with venous thrombosis and Granule exocytosis 208 their relatives Activation-induced conformational Providing an understanding of the change of platelets aetiology of a thrombotic event Platelets and atherosclerosis 209 Determining risk of recurrence and Role of platelets in the initiation of the therefore optimal duration of atherosclerosis anticoagulation 194 Role of the platelets in the progression of Determining the need for primary the atherosclerosis prophylaxis in asymptomatic Role of platelets in vulnerable plaques and family members 195 plaque rupture Making decisions regarding the use of Current and future anti-platelet agents the oral contraceptive pill 196 Determining the need for 210 thromboprophylaxis during Aspirin (salicylic acid) pregnancy Thienopyridines 211 Patients with arterial thrombosis Clopidogrel Potential detrimental effects of Prasugrel 213 thrombophilia testing 197 Ticlopidine Conclusion Ticagrelor References GPIIb/IIIa Antagonists Other anti-platelet agents and promising new deleopments 214 Chapter 11 – Platelets Platelet function testing 215 in the pathogenesis of Light-transmission aggregometry Detailed Contents xv

Whole blood aggregometry 217 response 249 VerifyNow® Assay Non-steroidal anti-inflammatories Flow cytometry 218 Matrix metalloproteinase (MMP) References inhibition Anti-chlamydial therapy 250 Drugs acting on the renin/angiotensin axis Chapter 12 – Pathogenesis HMG Co-A reductase inhibitors 251 of aortic aneurysms The future – Data from recent Jonathan Golledge, Guo-Ping Shi, experimental studies Paul E Norman References Introduction 227 Differences between thoracic and Chapter 14 – abdominal aortic aneurysms 228 Pathophysiology of Aortic Summary of current theories and stages of Dissection and Connective AAA evolution Tissue Disorders Atherosclerosis and AAA Mark Hamilton Immune mechanisms in AAA 229 Extracellular matrix dysfunction 232 Introduction 255 Infection 233 Embryology of thoracic aorta and arch Biomechanical forces vessels Angiogenesis Haemodynamics of thoracic compared to Intra-luminal thrombus abdominal aorta 257 Extracellular matrix proteolysis 234 Sizes of normal aorta Genetics 236 Classification of aortic syndromes Acute/Chronic AAA rupture 237 DeBakey classification of class 1 Biomechanical factors in aneurysms dissection – Type 1, 2, and 3 rupture Stanford classification 258 The role of enzymes in AAA rupture European task force Role of intraluminal thrombus in Pathogenesis of thoracic aortic dissection aneurysm rupture 238 Classical thoracic aortic dissection (class 1 Future research dissection) 260 References Intramural haematoma (class 2 aortic dissection) 261 Chapter 13 – Penetrating aortic ulcer (class 4 aortic Pharmacological dissection) 262 treatment of aneurysms Complications of acute aortic syndromes 263 Matthew Thompson, Janet T Powell Visceral ischaemia /malperfusion Background 247 syndromes Screening programmes Fate of the false lumen Pathophysiology 248 Aneurysmal degeneration and rupture Therapeutic strategies 264 Beta blockade Connective tissue disorders and acute Modification of the inflammatory aortic syndromes xvi Mechanisms of Vascular Disease

Marfan syndrome Chapter 16 – Fibrillin and Marfan syndrome 265 Pathophysiology and The role of transforming growth factor principles of management beta in development of the vascular of vasculitis and Raynaud’s system in health and disease 266 phenomenon Ehlers-Danlos syndrome 267 Diagnosis of Ehlers-Danlos syndrome Martin Veller 268 Vasculitides 295 Loeys-Deitz syndrome 270 Introduction Familial thoracic aortic aneurysm disease Classification of vasculitides 296 271 Clinical presentation of vasculitides Bicuspid aortic valve 273 Investigations of vasculitides Turners Syndrome Principles of treatment of vasculitides Summary 274 297 Reference list The vasculitides of specific interest to vascular surgeons 298 Giant cell arteritis Chapter 15 – Biomarkers in Takayasu’s arteritis 299 vascular disease Thromboangitis obliterans (Buerger’s Ian M Nordon, Robert J Hinchliffe disease) 300 Introduction 277 Behcet’s disease 301 What is a biomarker? Polyarteritis nodosa 302 Types of biomarkers Vasculitides secondary to connective A classical clinical example 278 tissue diseases 303 Potential value of biomarkers in vascular Systemic lupus erythematosus (SLE) disease 279 Antiphospholipid antibody syndrome Biomarker discovery steps 280 (APS) 304 AAA biomarkers Rheumatoid arthritis 305 Circulating extracellular matrix markers Scleroderma 281 Infective vasculitides 306 Matrix-degrading enzymes 283 Human immunodeficiency virus (HIV) Proteins associated with thrombosis Pathophysiology and principles of Markers of inflammation 284 Raynaud’s phenomenon 307 Biomarkers of AAA rupture 285 Prevalence of Raynaud’s phenomenon Biomarkers following endovascular repair 308 Inflammation 287 Clinical findings in Raynaud’s Lipid accumulation phenomenon 309 Apoptosis Diagnosis of Raynaud’s phenomenon Thrombosis Prognosis 310 Proteolysis 288 Treatment Challenges in biomarkers discovery Recommendations 311 Future work References 312 Conclusion 289 References Chapter 17 – SIRS, sepsis and Detailed Contents xvii mug ltior an failure Eicosanoids 334 Nitric Oxide 335 Vishwanath Biradar, John Moran Endothelin 336 Epidemiology 315 Cytokines Historical perspectives and definition 316 Neutrophil and endothelial interactions Risk factors for sepsis 317 338 Causative agents Complement activation 340 Pathophysiology of sepsis Tissue destruction 341 innate immunity and toll-like receptors Proteases and metalloproteinases (TLRs) 319 Apoptotic cell death during ischaemia- Proinflammatory response reperfusion injury Coagulation cascade No-reflow phenomenon 342 Multiorgan dysfunction syndrome Therapeutic approaches to IRI (MODS) 320 Ischaemic preconditioning Epithelial and endothelial dysfunction Ischaemic post-conditioning 343 Immune suppression and apoptosis Conditioning effects of volatile Sepsis, circulatory failure and organ anaesthetics dysfunction Pharmacological treatments 344 Management 322 Summary 345 Steroids 323 References Recombinant human activated protein C (rhAPC) 324 Chapter 19 – Compartment Glucose control 325 Syndrome Renal replacement therapy 3-hydroxy-3-methylglutaryl-coenzyme Edward Choke, Robert Sayers, Matthew reductase inhibitors (HMG-CoA) Bown 326 Definition 351 Other adjuvant therapies in sepsis Acute limb compartment syndrome Cytokines and anticytokine therapies Incidence Pooled immunoglobulin (IVIG) Anatomy/physiology 352 Acute respiratory distress syndrome Aetiology/pathophysiology (ARDS) 327 Clinical presentation 354 References Investigation 355 Treatment 357 Chapter 18 – Complication of LCS 359 Pathophysiology of Outcome 360 reperfusion injury Acute abdominal compartment syndrome Incidence 361 Prue Cowled, Rob Fitridge Aetiology Introduction 331 Pathological effects of raised intra- Ischaemia abdominal pressure 362 ATP and mitochondrial function Clinical presentation 363 Gene expression during ischaemia 332 Investigation Reperfusion 333 Treatment 364 Reactive oxygen species Complications of surgical decompression xviii Mechanisms of Vascular Disease

Outcome 367 Peripheral neuropathies References 368 Central neuropathies 385 References Chapter 20 – Pathophysiology of Pain Chapter 21 – Post-amputation pain Stephan Schug, Helen Daly, Kathryn Stannard Stephan Schug, Gail Gillespie Introduction 375 Introduction 389 Peripheral mechanisms Classification and incidence of post- Nociception/transduction amputation pain syndromes Conduction 376 Stump pain Spinal cord mechanisms Phantom sensation 390 Ascending systems 377 Phantom limb pain Descending control Pathophysiology of post-amputation pain Pain modulation 378 syndromes Peripheral sensation Peripheral factors Central sensitisation in the dorsal horn Spinal factors 391 Neuropathic pain 379 Supraspinal factors Mechanisms of neuropathic pain Current pathophysiological model of post- Peripheral mechanisms amputation pain syndromes 392 Prevention of post-amputation pain Spontaneous ectopic discharge Perioperative lumbar epidural blockade Altered gene expression Peripheral nerve blockade 393 Spared sensory neurons NMDA antagonists Involvement of the sympathetic nervous Evaluation of the patient with post- system 380 amputation pain syndromes Collateral sprouting Examination Effects of bradykinin Therapy of post-amputation pain Central mechanisms syndromes 394 Wind up Calcitonin Central sensitization 381 Ketamine Central disinhibition Analgesic and Co-analgesic compounds Expansion in receptive field size Opioids 395 (recuruitment) Gabapentin Immediate early gene expression Clonazepam Anatomical re-organisation of the spinal Lidocaine cord Carbamazepine Contribution of glial cells to pain Tricyclic antidepressants (TCA) conditions 382 Selective serotonin reuptake inhibitors Symptoms of neuropathic pain Baclofen Stimulus-dependent pain Capsaicin Stimulus-independent pain 383 Symptomatic treatment of pain Sympathetically maintained pain (SMP) components 396 Neuropathic pain syndromes Neuropharmacological therapies Detailed Contents xix

Invasive therapies Phenytoin Electroconvulsive therapy (ECT) Lamotrigene Nerve blockade Recommendations for clinical use of Spinal cord stimulation anticonvulsants as analgesics Implantable intrathecal delivery systems Local anaesthetics and antiarrhythmics Dorsal root entry zone (DREZ) lesions 409 Psychological therapy 397 Mechanism of action Future aims Lignocaine References Mexiletine Recommendations for clinical use of lignocaine and mexiletine in Chapter 22 – Treatment of neuropathic pain neuropathic pain N-methyl-D-aspartate-receptor Stephan Schug, Kathryn Stannard antagonists (NMDA) Ketamine 410 Introduction 401 Other NMDA antagonists Principles of treatment Miscellaneous compounds for systemic Pharmacological treatment 402 use Opioids Clonidine Recommendations for clinical use of Efficacy opioids Baclofen Tramadol Levodopa 411 Mechanism of action Cannabinoids Efficacy 403 Topical treatments Adverse effects Lignocaine 5% medicated plaster Recommendations for clinical use of Capsaicin 412 tramadol in neuropathic pain Mechanism of action Antidepressants Efficacy Tricyclic antidepressants (TCAs) Non-pharmacological therapy Mechanism of action 404 Transcutaneous electrical nerve Adverse effects stimulation (TENS) Selective serotonin re-uptake inhibitors Spinal cord stimulation (SCS) 413 (SSRIs) Sympathetic nerve blocks Serotonin/Noradrenaline reuptake Neurosurgical destructive techniques inhibitors (SNRIs) 405 Cognitive behavious therapy Recommendations for clinical use of References 414 antidepressants as analgesics Anticonvulsants Mechanism of action 406 Chapter 23 – Principles of Individual medications wound healing Clonazepam Gregory Schultz, Gloria Chin, Gabapentin Lyle Moldawer, Robert Diegelmann Pregabalin 407 Carbamazepine Introduction 423 Sodium valproate 408 Phases of acute wound healing Haemostasis xx Mechanisms of Vascular Disease

Inflammation 426 Varicose veins 453 Neutrophils 427 Valvular abnormalities Macrophages 428 Muscle pump failure 455 Proliferative phase 429 Venous recirculation Fibroblast migration 430 Recurrent varicose veins Collagen and extracellular matrix New varicose veins production Persistent varicose veins Angiogenesis 431 True recurrent varicose veins 456 Granulation 432 Cellular and molecular biology of varicose Epithelialization veins Remodelling 433 Conclusion 457 Summary of acute wound healing 435 References Comparison of acute and chronic wounds Normal and pathological responses to injury Chapter 25 – Chronic Biochemical differences in the molecular venous insufficiency and environments of healing and chronic leg ulceration: Principles wounds 436 and vascular biology Biological differences in the response of Michael Stacey chronic wound cells to growth factors Definitions 459 439 Chronic venous insuffiency From bench to bedside Leg ulceration Role of endocrine hormones in the Assessment of cause of leg ulceration regulation of wound healing 460 Molecular basis of chronic non-healing Epidemiology 461 wounds Pathophysiology Chronic venous stasis ulcers 441 Venous abnormality Pressure ulcers Effect of ambulatory venous hypertension Future concepts for the treatment of on the tissues in the leg 463 chronic wounds 442 Influence of venous disease on the wound Bacterial biofilms in chronic wounds healing process 465 443 Genetic associations with venous Conclusion 445 ulceration 466 References Assessment of venous function 467 Treatment of venous ulceration Chapter 24 – Compression therapy Pathophysiology and Dressings 468 principles of management Surgery of varicose veins Prevention of venous ulcer recurrence 470 Andrew Bradbury Sclerotherapy and other techniques to Introduction 451 obliterate surface and perforating veins Anatomy Other therapies 471 Histology 452 References Physiology Detailed Contents xxi

Chapter 26 – Chapter 27 – Lymphoedema Pathophysiology and – Principles, genetics and principles of management pathophysiology of the diabetic foot Matt Waltham David Armstrong, Timothy Fisher, Brian Introduction 497 Lepow, Matthew White, Joseph Mills Classification of lymphoedema Introduction 475 Classification of primary lymphoedema Pathophysiology of the diabetic foot 476 498 Neuropathy The genetics of lymphangiogensis in Structural abnormalities/gait primary lymphoedema 500 abnormalities Milroy’s disease Angiopathy 478 Lymphoedema – distichiasis syndrome Diagnosis 501 History and rapid visual screening Hypotrichosis – lymphoedema – Neurological examination 479 telangiectasia syndrome 502 Monofilament testing Meige disease (primary non-syndromic Vibration testing lymphoedema) Dermatologic examination 480 Other primary lymphoedema disorders Anatomy of occlusive disease – vascular 503 examination Structure and development of the Prediction of wound healing: assessment lymphatic circulation of perfusion 481 Clinical aspects of lymphoedema 505 Arterial imaging Summary Soft tissue imaging 482 References Classification systems 483 Diabetes mellitus foot risk classification University of Texas wound classification Chapter 28 – Graft system materials past and future Clinical problems and principles of Mital Desai, George Hamilton management 484 Ulceration The pathophysiology of graft healing 511 Epidemiology and risk factors The peri-anastomotic area Offloading Healing of prosthetic grafts 512 Non-vascular surgical treatment 485 The healing process of the anastomosis Class I – Elective 486 Graft porosity and permeability Class II – Prophylactic Physical properties of prosthetic materials Class III – Curative 514 Class IV – Emergency (urgent) Tubular compliance Post-operative management Anastomotic compliance mismatch Infections 487 The compliance hypothesis of graft failure Charcot arthopathy Synthetic grafts 515 Prevention 490 Newer developments of Dacron grafts Conclusion 492 Modifications and newer developments of References PTFE grafts 517 Polyurethane grafts xxii Mechanisms of Vascular Disease

Newer developments of polyurethane Chapter 29 – vascular grafts 518 Pathophysiology of Biological vascular grafts 519 vascular graft infections Newer developments of biological Mauro Vicaretti vascular grafts 520 Prosthetic graft modifications Introduction 537 Modifications to reduce graft infection Natural history of prosthetic vascular graft Modifications to improve patency 521 infections Nanocomposite grafts Mechanism of graft contamination at Endothelial cell seeding 522 operation 538 Single stage seeding Pathogenesis of graft infections Two stage seeding Bacteriology of vascular graft infections Vascular tissue engineering Investigations for detection of prosthetic Non-degradable polymer and cell seeding graft infections 539 523 History and physical examination Bioresorbable and biodegradable polymers Laboratory investigations Combined bioresorbable and tissue Diagnostic imaging 540 engineered grafts 524 Management of prosthetic graft infections Mechanical conditioning of seeded Prevention vascular cells Reduction of prosthetic vascular graft Alternative scaffolds infection with rifampicin bonded Tissue-engineered grafts 525 gelatin sealed Dacron 541 Graft materials for aortic endografts 526 Established infection The future Antibiotic therapy References 527 Operative management Conclusion 542 References Acknowledgements

The Editors gratefully acknowledge the outstanding contributions of each Author involved in this reference book. We would also like to acknowledge the invaluable efforts of Ms Sheona Page who has worked tirelessly on this project. We would also like to thank Prue Cowled PhD and Ms Cayley Wright for their assistance.

xxiii Abbreviation List

a1-PI a1-protease inhibitor

5-HT 5-Hydroxytryptamine/Serotonin

AAA Abdominal aortic aneurysm

AAS Acute aortic syndrome

AAV Adeno-associated viruses

ACE Angiotensin converting enzyme

ACS Acute coronary syndrome

ACS Abdominal compartment syndrome

ACTH Adrenocorticotropic hormone

ADAMTS A disintegrin and metalloproteinase with thrombospondin motifs

ADP Adenosine diphosphate

AIDS Acquired immune deficiency syndrome

ALI Acute lung injury

AMP Adenosine monophosphate

AMPA α-amino-3 hydroxy-5-methylisoxazole

ANA Anti-nuclear antibody

ANCA Anti-neutrophil cytoplasmic antibody

AOD Aortic occlusive disease

AP1 Activated protein 1

APC Activated protein C

APC Antigen presenting cell

APLAS Antiphospholipid antibody syndrome

ApoAI Apolipoprotein AI

ApoE Apolipoprotein E

APS Antiphospholipid antibody syndrome

APTT Activated partial thromboplastin time

xxiv Abbreviation List xxv

ARDS Acute respiratory distress syndrome

AT Antithrombin

ATP Adenosine triphosphate

AVP Ambulatory venous thrombosis b2-GPI b2-glycoprotein Ib bFGF Basic fibroblast growth factor

BKCa Large conductance calcium activated potassium channel

BMPs Bone morphogenetic proteins

BMS Bare metal stent

CAD Coronary artery disease

CaM Calmodulin

CAM Cell adhesion molecule cAMP Cyclic adenosine monophosphate

CCK Cholecystokinin cGMP Cyclic guanine monophosphate

CD Cluster of differentiation

CD40L Cluster of differentiation 40 ligand

CEA Carotid endarterectomy

CETP Cholesteryl ester transfer protein

CFD Computational fluid dynamics

CG Cationized gelatin

CGRP Calcitonic gene regulated peptide

CHD Coronary heart disease

CI Confidence interval

CIMT Carotid intimal-media thickness c-JNK c-Jun N-terminal kinase

CK-MB Creatinine kinase (Myocardial specific)

CNCP Chronic noncancer pain cNOS Constitutive nitric oxygen synthase enzyme

COX-1 Cyclooxygenase-1

COX-2 Cyclooxygenase-2

CROW Charcot restraint orthotic walker

CRRT Continuous renal replacement therapy xxvi Mechanisms of Vascular Disease

CRP C-reactive protein

CRPS Complex regional pain syndromes

CT Computational tomography

CTA Computed tomographic angiography

CTD Connective tissue disorders

CTGF Connective tissue growth factor

CYP Cytochrome P450

CVD Cardiovascular disease

CVI Chronic venous insufficiency

DAG Diacylglycerol

DES Drug-eluting stent

DRG Dorsal root ganglion

DNA Deoxyribonucleic acid

DSA Digital subtraction arteriography

DTS Dense tubular system

DVT Deep vein thrombosis

EC Endothelial cell

ECM Extracellular matrix

EDCF Endothelium-derived contracting factor

EDH Endothelium-dependent hyperpolarisation

EDS Ehlers-Danlos syndrome

EET Epoxyeicosatrienoic acids

ELAM-1 Endothelial-leukocyte adhesion molecule-1

ELG Endoluminal grafts

ELISA Enzyme linked immunosorbent assay

EK Equilibrium potential

EM Membrane potential

eNOS Endothelial nitric oxide synthase enzyme

EPC Endothelial progenitor cells

EPCR Endothelial protein C receptor

ePTFE Expanded polytetrafluoroethylene

ERK Extracellular signal-regulated kinase

ESR Erythrocyte sedimentation rate Abbreviation List xxvii

ET Essential thrombocytosis

ET-1 Endothelin 1

EVAR Endovascular aortic aneurysm repair

EVLA Endovenous LASER ablation

FDA Food and drug administration

FDPs Fibrin degradation products (soluble)

FGF Fibroblast growth factor

FGF-2 Fibroblast growth factor 2

FMN Flavin mononucleotide

FVL Factor V Leiden

GABA Gamma-aminobutyric acid

GABA B Gamma-aminobutyric acid subtype B

G-CSF Granulocyte colony stimulating factor

GMCSF Granulocyte-macrophage colony stimulating factor

GP Glycoprotein

GPCR G-protein coupled receptor

GSV Great saphenous vein

HDL High density lipoprotein

HDL-C High density lipoprotein cholesterol

HIF Hypoxia inducible factor

HIT Heparin induced thrombocytopenia

HIV Human immunodeficiency virus

HLA Human leukocyte antigen

HMG Co-A Hydroxymethylglutaryl coenzyme-A

HMW High molecular weight

HPETE Hydroperoxyeicosatetraenoic acid

HETE Hydroxyeicosatetraenoic acids

HR Hazard ratio hsCRP High-sensitive C-reactive protein

HSP Heat shock protein

HUV Human umbilical vein

IAH Intra-abdominal hypertension xxviii Mechanisms of Vascular Disease

IAP Intra-abdominal pressure

IAPP Intra-abdominal perfusion pressure

ICAM-1 Inter-cellular adhesion molecule-1

ICAM-2 Inter-cellular adhesion molecule-2

ICP Intra-compartmental pressure

ICU Intensive care unit

IFN Interferon

IGF-1 Insulin-like growth factor-1

IHD Ischemic heart disease

IL Interleukin

IL-1 Interleukin-1

IL-1α Interleukin-1 alpha

IL1-β Interleukin-1 beta

IL-6 Interleukin-6

IL-8 Interleukin-8

ILT Intraluminal thrombus

IKCa Intermediate conductance calcium-activated potassium channels

IMH Intramural haematoma

IMP Inosine monophosphate

iNOS Inducible nitric oxide synthase enzyme

IP(3) 1,4,5-inositol triphosphate

IRI Ischemia reperfusion injury

IVIG Intravenous pooled immunoglobulin

IVUS Intravascular ultrasound

KGF Keratinocyte growth factor

KGF-2 Keratinocyte growth factor-2

LAP Latency associated peptide

LCS Limb compartment syndrome

LDL Low density lipoprotein

LDS Loeys-Dietz syndrome

LLC Large latent complex

LEC Lymphatic endothelial cells Abbreviation List xxix

LFA-1 Lymphocyte function-associated antigen-1

LO Lipoxygenase

LOX Lysyl oxidase

LOPS Loss of protective sensation

LPA Lysophosphatidic acid

LPS Lipopolysaccharide

LTA Lipoteichoic acid

LTGFBP Latent TGF binding protein

MAC-1 Macrophage-1 antigen

MAPK Mitogen activated protein kinase

MCP-1 Monocyte chemoattractant protein-1

M-CSF Macrophage-colony stimulating factor

MFS Marfan syndrome

MHC Major histocompatibility

MI Myocardial infarction

MIP-1 Macrophage inflammatory protein-1

MLC20 Myosin light chain20

MLCK Myosin light chain kinase

MLCP Myosin light chain phosphatase

MMP Matrix metalloproteinase

MODS Multiple organ dysfunction syndrome

MRA Magnetic resonance angiography

MRI Magnetic resonance imaging mRNA Messenger RNA

MRSA Methicillin resistant Staphylococcus aureus

MRSE Methicillin resistant Staphylococcus epidermidis

MRTA Magnetic resonance tomographic angiography

MTHFR Methylenetetrahydrofolate reductase

MT-MMP Membrane-type MMP

MVPS Mitral valve prolapse syndrome

NADPH Nicotinamide adenine dinucleotide phosphate

NGF Nerve growth factor xxx Mechanisms of Vascular Disease

NFκB Nuclear factor kappa B

NiTi Nitinol

NJP Non-junctional perforators

NMDA N-methyl-D-aspartate

NNH Number needed to harm

NNT Number needed to treat

NO Nitric oxide

NOS Nitric oxide synthase enzyme

NSAID Non-steroidal anti-inflammatory drug

NV Neovascularisation

OCP Oestrogen/progesterone contraceptive pill

OPN Osteopontin

OPG Osteoprotegerin

OR Odds ratio

OxLDL Oxidised low density lipoprotein

PAD Peripheral arterial disease

PAF Platelet activating factor

PAI Plasminogen activator inhibitor

PAI-1 Plasminogen activator inhibitor-1

PAR Protease activated receptor

PAR-1 Protease activated receptor-1

PAR-4 Protease activated receptor-4

PAU Penetrating aortic ulcer

PC Protein C

PCA Poly (carbonate-urea) urethane

PCI Percutaneous coronary intervention (angioplasty)

PCWP Pulmonary capillary wedge pressure

PDGF Platelet-derived growth factor

PDGFb Platelet-derived growth factor-b

PDS Polydioxanone

PECAM-1 Platelet-endothelial cell adhesion molecule-1

PEDF Pigment epithelium-derived factor

PES Paclitaxel-eluting stent Abbreviation List xxxi

PET Positron emission tomography

PF4 Platelet factor 4

PGI2 Prostacyclin

PGG2 Prostaglandin G2

PGH2 Prostaglandin H2

PGEI2/PGI2 Prostaglandin I2

PGN Peptidoglycan

PHN Postherpetic neuropathy

PHZ Para-anastomotic hyper-compliant zone

PI3K Phosphatidylinositol 3-kinase

PIP2 Phosphatidylinositol 4,5-bisphosphate

PLC Phospholipase C

PLOD Procollagen lysyl hydroxylase

PMCA Plasma membrane Ca2+ APTases

PMN Polymorphonuclear leukocyte

POSS Polyhedral oligomeric silsesquioxanes

PPAR Peroxisomal proliferation activating receptor

PPI Proton pump inhibitor

PRV Polycythaemia rubra vera

PS Protein S

PSGL-1 P-selectin glycoprotein ligand-1

PT Prothombin time

PTCA Percutaneous coronary angioplasty

PTFE Polytetrafluoroethylene

PTS Post-thrombotic syndrome

PUFA Polyunsaturated fatty acid

PVI Primary valvular incompetence rAAA Ruptured AAA

Rac Ras activated cell adhesion molecule

RANTES Regulated upon activation, normal T cell expressed and secreted

RAS Renin angiotensin system

RCT Randomised controlled trial xxxii Mechanisms of Vascular Disease

RF Rheumatoid factor

RFA Radiofrequency ablation

rhAPC Recombinant human activated protein C

RNA Ribonucleic acid

ROS Reactive oxygen species

RR Relative risk

RSD Reflex sympathetic dystrophy

S1P Sphingosine-1-phosphate

SAPK Stress-activated protein kinase

SCF Stem cell factor

SCS Spinal cord stimulation

ScvO2 Superior vena cava venous oxygen saturation

SDF-1 Stromal-cell-derived factor-1

SERCA Sarco/endoplasmic reticulum CaATPases

SEP Serum elastin peptides

SES Sirolimus-eluting stent

SEPS Subfascial endoscopic perforator surgery

SFA Superficial femoral artery

SFJ Sapheno-femoral junction

SIRS Systemic inflammatory response syndrome

SKCa Small conductance calcium-activated potassium channels

SLE Systemic lupus erythematosus

SMA Smooth muscle alpha actin

SMC Smooth muscle cell

SMP Sympathetically maintained pain

SNARE Soluble N-ethylmaleimide-sensitive factor activating protein receptors

SNP Single nucleotide polymorphisms

SNRI Serotonin/Noradrenaline reuptake inhibitors

SPJ Sapheno-popliteal junction

SPP Skin perfusion pressure

SR Sarcoplasmic reticulum

SSRIs Selective serotonin re-uptake inhibitors

SSV Small saphenous vein Abbreviation List xxxiii

SVT Superficial thrombophlebitis

STIM1 Stromal interacting molecule 1

TaCE TNFa converting enzyme

TAAD Thoracic aortic aneurysm disease

TAD Thoracic aortic dissection

TAFI Thrombin-activatable fibrinolysis inhibitor

Tc-99 MDP Technetium-99 methylene diphosphonate

TCA Tricyclic antidepressant

TCC Total contact cast

TCR T-cell receptor

TENS Transcutaneous electrical nerve stimulation

TF Tissue factor

TFPI Tissue factor pathway inhibitor

TGF Transforming growth factor

TGF-α Transforming growth factor-alpha

TGF-β Transforming growth factor-beta

TGL Triglycerides

Th T helper

TIA Transient ischemic attack

TIMP Tissue inhibitors of metalloproteinase

TLR Toll-like receptors

TNF Tumour necrosis factor

TNF-α Tumour necrosis factor-alpha tPA Tissue-type plasminogen activator

TRP Transient receptor potential

TRPC Transmembrane receptor potential canonical

TRPV1 Transmembrane receptor potential Vanilloid-type

TXA2 Thromboxane A2 uPA Urokinase

UT University of Texas

VCAM Vascular cell adhesion molecule

VCAM-1 Vascular cell adhesion molecule-1

VEGF Vascular endothelial growth factor xxxiv Mechanisms of Vascular Disease

VEGF-R Vascular endothelial growth factor receptor

VIP Vasoactive intestinal peptide

VLA-1 Very late activating antigen-1

VOCC Voltage operated calcium channels

VPT Vibratory perception threshold

VSMC Vascular smooth muscle cells

VTE Venous thromboembolism

VV Varicose veins

vWF von Willebrand factor

XO Xanthine oxidase 24 • Pathophysiology and Principles of Management of Varicose Veins Andrew W Bradbury

College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK

Introduction to enter the common femoral vein in the groin at the saphenofemoral junction (SFJ). The management of superficial and deep The SSV originates from the lateral end of venous reflux and obstruction that leads to the dorsal venous arch, passes posterior to the development of varicose veins (VV)1 the lateral malleolus and then continues up and the post-thrombotic syndrome (PTS)2 the back of the calf between the heads of forms a large part of the workload for most gastrocnemius to enter the popliteal fossa. vascular and endovascular specialists and is It is joined variably by gastrocnemius veins likely to increase as the population ages.3 and then usually enters the popliteal vein at However, the epidemiology,4,5 genetics6 and the sapheno-popliteal junction (SPJ). The pathophysiology of these conditions remains SPJ may be absent in which case the SSV incompletely defined7,8,9,10,11 and many continues up the postero-medial aspect of clinicians lack a clear understanding of the the thigh (Giacomini vein) and often joins underlying anatomy and vascular biology.12 the GSV. These two systems interconnect As a result, treatment outcomes are not at many other (highly variable) points infrequently sub-optimal. through an extensive network of tributaries. In the deep system, veins, which are often Anatomy paired, accompany each named artery. The Venous blood from the lower limbs returns superficial and deep systems connect at to the right heart against gravity through numerous points at various non-junctional the superficial and deep venous systems. perforators in addition to the SFJ and SPJ. The superficial venous system comprises These systems and interconnections are the great saphenous veins (GSV) and small interdependent, both anatomically and saphenous veins (SSV) and their tributaries.13 functionally in health and disease. The GSV originates from the medial end of In health, the deep venous system the dorsal venous arch, passes anterior to transmits 90% of the venous return from the medial malleolus, and continues up the the leg. The superficial system drains only medial aspect of the calf and then the thigh the skin and subcutaneous tissues, with

451 452 Mechanisms of Vascular Disease most of that blood draining immediately veins down a pressure gradient, filling the into the deep system via perforators in the sinuses. Reverse flow (reflux) during muscle foot, calf and thigh. It also plays a role in relaxation is prevented by the closure of thermoregulation. valves. These are delicate but strong bicuspid leaflets at the base of a localized dilated sinus in the vein. In both superficial and deep Histology systems the density of valves is greatest in The vein wall comprises three layers but the calf and reduces gradually up the lower these are less well defined than in the arterial limb, with the iliac and inferior vena cava system. The intima is thin and surrounded (IVC) frequently lacking valves altogether. by a fine elastic lamina. The media is made Valves are present in venules down to about up of elastin and layers of muscular bundles 0.15mm diameter. that are arranged in different orientations. During systole, blood is prevented from The relative amounts of muscle and elastin re-entering the superficial system through varies with the calibre and working pressure the closure of junctional (SFJ, SPJ) and of the vein. Beyond this, the adventitia non-junctional perforators (NJP). This was merges with the perivenous connective originally thought to occur solely through tissue, which contains nerve fibres and vasa the closure of valves but several studies have vasorum and provides for vessel distension failed to demonstrate such valves in NJP. which is an important part of normal Instead, external pressure from the fascia venous function. With increasing age, and and muscle through which the perforators particularly with the development of disease, pass is thought to be responsible for limit- abnormalities have been described in all three ing outward blood flow; somewhat akin to layers14 and the structure of the vein wall the ‘pinch-cock’ mechanism that prevents becomes progressively more disorganised.15 reflux at the gastro-oesophageal junction. Typically, there is thickening of the intima Importantly, this also protects the superficial with disorientation of the elastic fibres. The veins, subcutaneous tissues and skin from the outer muscle layer of the media becomes extremely high deep venous pressures (up to hypertrophied with dystrophic elastic 250mmHg) generated by the calf muscle fibres and the adventitia is increasingly pump in systole. fibrous. When standing motionless, with venous valves in the neutral position, the pressure in the foot veins gradually increases as blood Physiology continues to enter the veins from the arterial Venous return against gravity is primarily side. As soon as the pressure in one venous dependent on muscle pumps located in the segment exceeds that in the segment just foot and the calf. Pressure on the sole of above, the valve opens. Eventually the hydro- the foot, and muscular contraction (systole) static pressure in the veins of the foot is that in the fascial compartments of the calf developed by an unbroken column from the compresses the sinusoidal intramuscular foot to the right atrium – perhaps 90mmHg veins directing blood into the deep system in a person of average height. With active and thence up the leg. Superficial veins collect movement, deep veins and sinuses are com- blood from the superficial tissues, and during pressed raising venous pressure and mov- muscle relaxation (diastole) this blood enters ing blood cranially and, initially, caudally the deep system through the perforating (Figure 24.1A). However, valve closure Management of Varicose Veins 453 normally prevents retrograde flow within limb and may be primary, or secondary to 0.5-1.0 seconds. At this point, these closed deep venous pathology. The GSV system is valves divide the high-pressure, single col- most frequently affected with the SSV being umn of venous blood described above into involved in about 20% of cases. The aetiology a large number of low-pressure, shorter col- of VV at a microscopic level is still disputed umns (Figure 24.1B). As a result, the pressure but the essential defect macroscopically is in the foot veins falls in health to less than generally agreed to be the failure of venous 25mmHg on walking; the normal ambula- valve closure resulting in the superficial tory venous pressure (AVP) (Figure 24.2). veins becoming dilated, elongated and This reduces venous pooling and lowers tortuous.17,18 The main factor contributing capillary hydrostatic pressure, reducing to the development and progression the tendency for accumulation of intersti- of varicose veins is sustained venous 16 tial fluid (oedema) in the feet. Patients hypertension that increases the diameter of with muscle pump and/or venous valve the superficial veins resulting in further valve failure and/or venous outflow obstruc- incompetence. tion, demon­strate raised AVP. It is this raised AVP that underlies all the symptoms and signs of chronic venous insufficiency Valvular abnormalities (CVI). Failure of valve closure leading to valve incompetence and reflux may affect the deep Varicose veins and/or superficial venous systems and may Varicose veins (VV) are dilated, tortuous be primary or secondary. Primary valvular subcutaneous veins that permit reverse flow. incompetence (PVI) is believed to be due They are most commonly found in the lower to loss of mural elastin and collagen, which

Figure 24.1: Influence of calf muscle pump and valves in venous return. 454 Mechanisms of Vascular Disease

Figure 24.2: Resting and ambulatory venous pressure at the ankle in health. leads to dilatation and separation of the valve by DVT recanalise over the subsequent leaflets.T he commonest clinical consequence 6–12 months the vein is often scarred and of this process is the development of VV. As narrowed and, because the valves have been an investing fascia often supports the main destroyed, incompetent. If recanalisation does GSV trunk, it is often the tributaries that not occur, blood is forced to find an alterna- become varicose. PVI may also affect the tive drainage route. For example, blood may deep venous system although because other be forced out of the deep venous system tissues support the deep veins, the clinical via the SFJ, SPJ and NJP leading to dilata- consequences of PVI are less obvious and tion of the superficial veins (secondary VV). certain. Obstruction of the iliac veins may lead to the Secondary valvular incompetence may development of groin and pelvic collaterals. be due to a developmental weakness in the Venous reflux and obstruction secondary vein wall leading to secondary widening of to DVT leads to PTS which represents the the valve commissures, resulting in valvular most severe form of chronic venous insuffi- incompetence and clinically, primary VV. ciency (CVI). The superficial venous system It also follows thrombosis, most commonly may also be affected by thrombosis, either in in the deep venous system; deep venous isolation or in combination with DVT, lead- thrombosis (DVT). Blood flowing within ing to superficial thrombophlebitis (SVT). the lumen of the vein provides the vascu- Rarely, VV and CVI may be due to lar endothelium with its oxygen and nutri- congenital valve hypoplasia or agenesis, or tion. DVT prevents this, therefore leading due to arterio-venous malformations. In to endothelial destruction and inflamma- Klippel-Trenaunay syndrome, for exam- tion within and around the affected veins. ple, there is deep venous hypoplasia and a Although most venous segments occluded laterally placed venous complex that acts as Management of Varicose Veins 455 the main venous outflow of the limb. All hypertension and skin changes of CVI. the symptoms and signs of chronic venous This accounts for two important clinical insufficiency are due to ambulatory venous observations: hypertension resulting from these various pathological processes acting upon the micro- • CVI & ulceration can develop without vasculature of the skin and subcutaneous primary deep venous pathology tissues. • In a proportion of patients with VV and deep venous reflux the latter dis­ appears following eradication of super­ Muscle pump Failure ficial disease. Any cause of chronic debility or immobility is associated with calf muscle pump Recurrent varicose veins dysfunction; for example, old age, stroke, neuromuscular conditions, arthritis and Recurrent VV after conventional surgical or trauma. Injuries that limit or prevent ankle endovenous intervention may be classified movement have a particularly adverse effect into three groups: new, persistent and true upon the calf muscle pump. recurrent.

Venous recirculation New varicose veins In patients with VV there is often a This is the development of new VV, often in recirculation of venous blood within the a second saphenous system, since the original leg. During calf relaxation abnormally operation.19 This may be due to: large volumes of blood enter the muscle pump from the superficial varices (increased 1) Inadequate assessment at the time of the preload). During exercise the muscle pump initial treatment; however, now that most expels blood from the leg only for it to patients undergo full duplex ultrasound re-enter the lower leg by refluxing down mapping prior to intervention for their GSV and/or SSV VV (akin to an increase VV this should be less common in afterload due to aortic regurgitation). 2) reflux developing at a site that was This blood then re-enters the muscle pump previously demonstrated to be competent; through the perforating veins in the lower in other words, true disease progression calf and so on. The effect is that the same blood can re-circulate up and down the leg Persistent varicose veins several times before eventually finding its way up the iliac veins to the heart. This is due to inadequate treatment of VV Patients with mild superficial reflux and/or at the time of the original intervention. an efficient calf pump are able to compen- Again, with proper use of duplex ultrasound sate for this by increasing their calf muscle and modern techniques this should be a pump ‘stroke volume’ and output. This relatively uncommon scenario in current allows them to still reduce their AVP to phlebological practice. The risk is perhaps (near) normal levels on walking. However greater with catheter based techniques such severe reflux and/or a weak muscle pump as radiofrequency ablation (RFA) and Laser may overwhelm the deep system and lead ablation (EVLA) which, while being highly to the development of sustained venous successful in eradicating truncal reflux, 456 Mechanisms of Vascular Disease do not deal with the varices themselves. treated as an out-patient and so poses no A proportion of patients undergoing RFA real clinical difficulty.19 and EVLA will, therefore, need further treatment, either with foam sclerotherapy Cellular and molecular or local anaesthetic phlebectomies. biology of varicose veins The molecular biology of varicose veins True recurrent varicose veins has recently been reviewed. The aetiology This is where further VV develop in the of varicose veins is undoubtedly multi- same, previously treated saphenous system. factorial. There are some genetic disorders When surgery was the main treatment and mutations that predispose to venous modality most were the result of failure to incompetence and development of vari­ properly perform a ‘flush’ SFJ (SPJ) ligation cosities (FOXC2, NOTCH3). However and/or to ‘strip’ the GSV or SSV. these diseases are rare whilst varicose veins Neovascularisation (NV), defined as the are common. ‘development of new vessels connecting pre- In recent years there has been much viously ligated superficial veins to the deep research to define the structural and molecu- venous system’, and the role it might play in lar events that accompany the formation the development of recurrent VV after sur- of varicose veins, with an overall underly- gery has received a lot of attention over the ing hypothesis that varicose vein formation is most likely due to a structural, cellular years. There is no doubt that in a proportion or molecular abnormality within the vein of patients with recurrent GSV (SSV) VV, wall. On a gross level, varicose veins exhibit duplex ultrasound clearly shows the pres- intimal hyperplastic areas and underly- ence of small venous channels within scar ing plaques with infiltration of leukocytes tissue apparently connecting the ‘stump’ of and mast cells. There is fragmentation of the GSV in the groin (SSV in the popliteal elastin fibres and the total content of elas- fossa) to recurrent VV in the thigh (calf). tin and Type III collagen is reduced. These However, it seems unlikely that such small, extracellular­ matrix abnormalities may be therefore high resistance, veins will be capa- regulated by disordered MMP and TIMP ble of transmitting significant reflux and production. thus of constituting a significant cause of Cell types within the varicose vein may recurrence on their own. In an era where show disordered function with endothelial the vast majority of patients can have non- activation leading to vasodilatation and a surgical treatment for their VV, the whole possible loss of venous tone. Many of the issue of NV becomes much less important. smooth muscle cells in the varicose vessel wall Going forward, most true recurrent VV exhibit a synthetic rather than a contractile are likely to be due to recanalisation of the phenotype, and appear to have reduced rates trunk veins and/or their major tributar- of apoptosis. These cells may have a reduced ies that have previously been occluded by capacity for contraction, which may exacer- means of foam sclerotherapy, RFA or bate the vasodilatory tendency. The stimuli EVLA.20,21 However, unlike redo surgery for the disordered function demonstrated by which is technically demanding and often these intrinsic cells remains ill defined, but associated with disappointing outcomes, hypoxic stress and low shear stress may play such recanalisation can be successfully a role. Management of Varicose Veins 457

There is certain to be further research affect patterns of great saphenous vein in the next few years to further define the reflux in women with varicose veins? vascular biology of varicose veins. There has Phlebology 2010; 25: 190–5. been some suggestion that this may lead to a 6. Fiebig A., Krusche P., Wolf A., medical therapy for varicose veins, although Krawczak M., Timm B., Nikolaus S., the practicality of this is not immediately Frings N., Schreiber S. Heritability apparent. Nevertheless research into the of chronic venous disease. Human molecular aetiology of varicose veins will Genetics 2010; 127: 669–74. continue to define vascular pathways.22 7. Bradbury AW. Varicose veins. In: Vascular and Endovascular Surgery. 4th Edition. Eds: Beard and Gaines. Conclusion Elsevier 2009, pp 303–322. Despite the very large numbers of patients 8. Kendler M, Makrantonaki E, affected by CVI and VV, research into Kratzsch J, Anderegg U, Wetzig T, venous disease is generally given low priority Zouboulis C, Simon JC. Elevated sex and so there are still significant gaps in our steroid hormones in great saphenous knowledge. Further work is needed if we veins in men. Journal of Vascular are to improve our understanding of the Surgery 2010; 51: 639–46. aetiology of the disease and improve 9. Kowalewski R, Malkowski A, the results of treatment. Sobolewski K, Gacko M. Evaluation of transforming growth factor-beta signaling pathway in the wall of References normal and varicose veins. Pathobiology 1. eklof B, Rutherford RB, Bergan JJ 2010; 77(1): 1–6. et al. Revision of the CEAP 10. lee JD, Yang WK, Lai CH. Involved classification for chronic venous intrinsic apoptotic pathway in the disorders: Consensus statement. varicocele and varicose veins. Annals of Journal of Vascular Surgery 2004; 40: Vascular Surgery 2010; 24: 768–74. 1248–52. 11. Ahti TM, Makivaara LA, Luukkaala T, 2. Pesavento R, Villalta S, Prandoni P. Hakama M, Laurikka JO. Lifestyle The post-thrombotic syndrome. factors and varicose veins: does cross- Internal & Emergency Medicine 2010; sectional design result in underestimate 5: 185–92. of the risk? Phlebology 2010; 25: 3. Bradbury AW, Ruckley CV. Clinical 201–6. presentation and initial assessment of 12. Bradbury AW. Venous Physiology. patients with chronic venous disorders. In: Innovative Treatment of Venous In: Handbook of Venous Disorders Disorders. Ed: Wittens C. Edizioni, 3E. Ed: Gloviczki P. Hodder Arnold Minerva Medica 2009. Health Sciences 2009. 13. Caggiati A, Bergan JJ, Gloviczki P, 4. robertson L, Evans C, Fowkes FG. Eklof B, Allegra C, Partsch H. Epidemiology of chronic venous An International Interdisciplinary disease. Phlebology 2008; 23: 103–11. Consensus Committee on 5. engelhorn CA, Cassou MF, Venous Anatomical Terminology. Engelhorn AL, Salles-Cunha SX. Nomenclature of the veins of the lower Does the number of pregnancies limb: Extensions, refinements, and 458 Mechanisms of Vascular Disease

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