Risk stratification in asymptomatic and symptomatic patients with carotid artery stenosis

Anne G. den Hartog

phd_anne.indb 1

16-5-2013 7:59:40

Risk stratification in asymptomatic and symptomatic patients with carotid artery stenosis Thesis, University of Utrecht, Faculty of Medicine, with summary in Dutch Proefschrift, Universiteit Utrecht, met een samenvatting in het Nederlands Copyright © by A.G. den Hartog 2013 All rights reserved. No part of this publication may be reproduced, stored in a retrieval system of any nature or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without prior permission of the author, or when appropriate, the publishers of the papers. ISBN/EAN: 978-94-6108-469-9 Layout: Myra Nijman | www.myranijman.nl Cover design: Jeroen Fontein | image tree: http://deanreddick.blogspot.nl/ Printed by: Gildeprint Drukkerijen Enschede The printing of this thesis was financially supported by: Chipsoft B.V., WL Gore & Associates, Krijnen Medical Associations BV, Vascutek, Chirurgisch Fonds UMC Utrecht Financial support by the Dutch Heart Foundation for the publication of this thesis is gratefully acknowledged

phd_anne.indb 2

16-5-2013 7:59:40

Risk stratification in asymptomatic and symptomatic patients with carotid artery stenosis

Risico inschatting bij asymptomatische en symptomatische patiënten met een carotis stenose (met een samenvatting in het Nederlands)

Proefschrift

ter verkrijging van de graad van doctor aan de Universiteit Utrecht op gezag van de rector magnificus, prof. dr. G.J. van der Zwaan, ingevolge het besluit van het college voor promoties in het openbaar te verdedigen op

dinsdag 2 juli 2013 des ochtends te 10.30 uur

door

Anne Geerte den Hartog geboren op 29 augustus 1982 te Leiderdorp

phd_anne.indb 3

16-5-2013 7:59:40

Promotor :

Prof. Dr. F.L. Moll

Co-promotor :

phd_anne.indb 4

Dr. G.J. de Borst

16-5-2013 7:59:40

Voor mijn ouders

phd_anne.indb 5

16-5-2013 7:59:40

CONTENTS CHAPTER 1

Introduction and outline of thesis

9

PART I

RISK IN PATIENTS WITH ASYMPTOMATIC CAROTID ARTERY STENOSIS

17

CHAPTER 2

Asymptomatic carotid artery stenosis: identification of subgroups 19 with different underlying plaque characteristics

European Journal of Vascular and Endovascular Surgery. 2012 Jun;43(6):632-6

CHAPTER 3

Asymptomatic carotid artery stenosis and the risk of ischemic stroke in patients with clinical manifest arterial disease

33

Stroke. 2013 Apr;44(4):1002-7

CHAPTER 4

The risk of stroke from new carotid artery occlusion during follow-up in the Asymptomatic Carotid Surgery Trial (ACST-1)

47

Stroke. 2013 Apr 30 - Epub ahead of print

CHAPTER 5 The influence of revascularization on cerebral perfusion in patients with asymptomatic carotid artery stenosis.

65

Manuscript submitted

PART II RISK IN PATIENTS WITH SYMPTOMATIC CAROTID ARTERY 81 STENOSIS Delay to carotid endarterectomy in patients with symptomatic carotid CHAPTER 6 artery stenosis

83

Manuscript in preparation

CHAPTER 7 Stenting versus surgery in patients with carotid stenosis after previous cervical radiation therapy: systematic review and meta-analysis.

99

Stroke. 2012 Mar;43(3):793-801

CHAPTER 8

Radiation-induced carotid stenotic lesions have a more stable phenotype than de novo atherosclerotic plaques.



European Journal of Vascular and Endovascular Surgery. 2012

117

Jun;43(6):643-8

phd_anne.indb 6

16-5-2013 7:59:40

CONTENTS PART III

IMAGING OF CAROTID ARTERY STENOSIS

CHAPTER 9 Current status of clinical magnetic resonance imaging for plaque characterization in patients with carotid artery stenosis

131 133

European Journal of Vascular and Endovascular Surgery. 2013 Jan;45(1):7-21

CHAPTER 10 PLACD-7T Study: Atherosclerotic Carotid Plaque Components Correlated with Cerebral Damage at 7 Tesla Magnetic Resonance Imaging

Current Cardiology Reviews. 2011 Feb;7(1):28-34

PART IV

SUMMARY AND FUTURE PERSPECTIVES

179

CHAPTER 11

Summary and future perspectives

180

CHAPTER 12

Summary in Dutch - Samenvatting in het Nederlands

189

PART V

APPENDICES

201

CHAPTER 13 Review committee Acknowledgements - Dankwoord List of publications Curriculum Vitae

phd_anne.indb 7

161



205 207 213 217

16-5-2013 7:59:40

phd_anne.indb 8

16-5-2013 7:59:42

CHAPTER 1 General Introduction and Outline of Thesis

phd_anne.indb 9

16-5-2013 7:59:42

Introduction The overall aim of this thesis is to explore and assess the risks that patients with carotid artery disease, whether asymptomatic or symptomatic, are exposed to, and to explore whether patients that may be subject to these risks can be identified by imaging. This thesis consists of three parts, where each part has been divided into several chapters. By way of introduction and prior to setting out the content of each part and what it aims to discuss, some terms and explanatory remarks pertinent to the topic researched are briefly set out.

Atherosclerosis The definition of atherosclerosis is derived from the Greek word arteria, which means artery, and sclerosis, meaning hardening. The exact etiology of atherosclerosis is unknown, but it is initiated by inflammatory processes in the vessel wall and mostly affects large and mediumsized arteries. First, the aorta is affected, followed by the carotid arteries, coronary arteries, and

10

iliofemoral arteries. Atherosclerosis is a chronic disease which may remain asymptomatic for decades.1 However, symptomatology of atherosclerosis can also result in atherothrombosis and lead to coronary heart disease (CAD), cerebrovascular disease (CVD) or peripheral arterial disease (PAOD).2 This means that atherosclerosis is a leading cause of death and loss of productive life years worldwide. Cerebrovascular disease is a general term which refers to a group of conditions that affects the circulation of blood to the brain. This may lead to a stroke. Stroke is a serious and frequent disease that has major socio-economic consequences worldwide.3 The proportion of deaths caused by stroke is 10–12% in western countries, and approximately 10% of these deaths are in people less than 65 years of age.4,5 In the Netherlands, the amount of hospitalizations due to stroke still increases. Ischemic stroke represents approximately 80% of all strokes and most are caused by atherosclerosis.6,7 An ischemic stroke is caused by an artery inside or leading to the brain that becomes totally blocked, either through arteries affected by atherosclerosis or if an atherosclerotic plaque ruptures and this blocks an artery. This results in a part of the brain that is deprived form blood and oxygen and therefore leads to neurological deficits. Carotid artery stenosis is an important cause of stroke, as it accounts for 10-20% of all ischemic strokes.8 Carotid artery stenosis is defined by narrowing of the carotid arteries due to atherosclerosis. This plaque is mostly situated at the carotid bifurcation. It may be asymptomatic, not causing any neurological symptoms or symptomatic, causing a stroke or

phd_anne.indb 10

16-5-2013 7:59:42

GENERAL INTRODUCTION | CHAPTER 1

transient ischemic attack (TIA). The diagnosis of carotid artery disease can be confirmed, and its severity established, by a noninvasive Duplex ultrasound examination.

Asymptomatic Carotid artery stenosis Asymptomatic carotid artery stenosis (ACAS) is a narrowing of the carotid artery. The disease as such lacks symptoms. The prevalence of severe (≥70%) asymptomatic carotid artery stenosis among the general population ranges from 0% to 3%.9 The annual stroke rate of patients with ACAS varies from 1% up to 3%.10-12 Although large randomized trials have proven carotid endarterectomy (CEA) to be beneficial compared to best medical treatment (BMT) alone, revascularization of ACAS remains a matter of debate.13 The majority of the criticism is founded on the fact that BMT is still improving, and that not all patients in the medical arm of the conducted large randomised trials received this medical treatment uniformly.14-16 In addition, the ability of absolute risk reduction of CEA is relatively small.15,16 It is therefore important to accurately map whether and in what way revascularization effectively reduces risks for patients suffering from ACAS. Risks that patients with ACAS are exposed to may for example include the risk of having a vulnerable plaque, the risk of suffering from a stroke and the risk from progression to occlusion. Furthermore, it is valuable to identify if revascularization

11

actually changes cerebral perfusion in asymptomatic patients.

Symptomatic carotid artery stenosis Symptomatic carotid artery stenosis is defined as stenosis that causes symptoms such as transient ischemic attacks (TIA), amaurosis fugax (AFx) or strokes. For the group of patients suffering from symptomatic carotid artery stenosis several large randomized trials have shown CEA is the treatment of choice in patients with a severe (≥70%) stenosis.17 According to the most recent meta-analysis, surgery remains the best option despite several studies investigating the benefit of carotid artery stenting (CAS) in symptomatic patients.18,19 In literature several factors are described which may influence the selection for or outcome after CEA. This includes the degree of stenosis, plaque composition, timing of surgery and assumed anatomic risk factors. Each of these may be increasingly important for clinical decision making.8,20-23 Vulnerable or unstable plaque characteristics are fibrous cap rupture, large lipid core, dense macrophage infiltrate, intraplaque hemorrhage or microvessels. The presence of smooth muscle cells and collagen are stabilizing plaque components.20,24 The highest risk for a recurrent neurological event is within the first days following the initial symptom and therefore the urge to operate as soon as possible after the first symptom needs special attention.8 Previous cervical radiation therapy (XRT) is one assumed anatomic risk

phd_anne.indb 11

16-5-2013 7:59:43

factor, resulting in a “hostile” neck which presumably leads to technically more challenging surgery.25

Imaging of carotid artery stenosis For all patients -whether symptomatic or asymptomatic-, with severe or less severe stenosis plaque composition can be determinative in assessing the risk for individuals of suffering from a stroke. Within this process, imaging of these specific plaque characteristics is essential for clinical decision-making. As referred to above, the evidence for clinical decision-making is clear for patients with severe stenosis. However, patients with mild to moderate carotid stenosis or patients with a supposed increased risk currently remain an unclassified group. For these patients, non-invasive imaging such as magnetic resonance imaging is an important goal for the near future, as it may give insight into the risks that patients with a less severely stenosis or with assumed risk factors are exposed to.

Outline of this thesis 12 This thesis consists of three parts, each of which has been divided into separate chapters. The first part describes patients with asymptomatic carotid artery stenosis and the associated and presumed risks that follow from this type of stenosis. In studies on patients with asymptomatic carotid artery stenosis often a time line of six months is used to define its asymptomatic status. Chapter 2 compares two sub-groups of asymptomatic patients, based on past ipsilateral symptoms that surfaced six months prior to surgery. It investigates whether carotid plaque characteristics differ between these two sub-groups and whether this impacts potential risks of suffering from stroke. Chapter 3 presents a study that evaluates the risk of stroke in patients with clinically manifest arterial disease and asymptomatic carotid artery stenosis. Carotid artery occlusion is assumed to alter stroke risk.26-31 However, no prospective studies exist that investigate stroke risk when tight carotid artery stenosis progresses to occlusion. Therefore, Chapter 4 describes the risk of stroke from a new carotid artery occlusion. Several earlier studies have investigated hemodynamic changes in patients with symptomatic carotid artery stenosis before and after revascularisation.32-39 An earlier study showed patients with asymptomatic carotid artery stenosis might have compromised brain perfusion due to severe ICA stenosis.40 This compromised brain perfusion is reflected as a reduced cerebral blood flow compared to patients without carotid artery stenosis. We hypothesize that

phd_anne.indb 12

16-5-2013 7:59:43

GENERAL INTRODUCTION | CHAPTER 1

revascularization of the stenosed carotid artery will improve the cerebral blood flow in the territories of the large brain feeding arteries in patients with ACAS. Therefore the influence of revascularization on cerebral perfusion in asymptomatic patients is investigated in Chapter 5. The second part of this thesis highlights the presumed risk for patients with symptomatic carotid artery stenosis. Performing surgery within two weeks from the first neurological symptom is increasingly becoming to be more effective in recurrent stroke prevention. Chapter 6 evaluates the delay between the index event and CEA over time in a large, tertiary referral center in the Netherlands. Moreover, it assesses the difference in delay between the first versus the most recent event as the definition of the so-called “index symptom” influences this specific timeslot. Cervical radiation therapy is a risk factor for the development of carotid artery stenosis and subsequent cerebrovascular events.41 Chapter 7 summarizes literary resources for treating patients with symptomatic carotid artery disease and a history of cervical radiation, often mentioned as a so called risk group for surgery. Studies attempting to identify characteristics of the carotid plaque after radiation are sparse. Chapter 8 aims to identify plaque phenotype of patients with prior cervical radiation therapy and thereby potential future stroke risk. Following the two parts on risk stratification in asymptomatic and symptomatic carotid

13

artery stenosis, the final part of this thesis outlines imaging of carotid artery stenosis. Imaging of specific carotid plaque characteristics enables the identification of patients with a more vulnerable plaque or a higher risk for (recurrent) stroke. Chapter 9 reviews literature discussing the current status of clinical magnetic resonance imaging for the identification of carotid plaque characteristics. By way of conclusion, Chapter 10 demonstrates the protocol of an ongoing study that investigates the value of 7Tesla imaging in patients with carotid artery stenosis.

phd_anne.indb 13

16-5-2013 7:59:43

REFERENCES

14

phd_anne.indb 14

1. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 1993; 362:801-809. 2. Rauch U, Osende JI, Fuster V et al. Thrombus formation on atherosclerotic plaques: pathogenesis and clinical consequences. Ann Intern Med 2001; 134:224-238. 3. Roger VL, Go AS, Lloyd-Jones DM et al. Heart disease and stroke statistics--2012 update: a report from the American Heart Association. Circulation 2012; 125:e2-e220. 4. Bonita R. Epidemiology of stroke. Lancet 1992; 339:342-344. 5. Go AS, Mozaffarian D, Roger VL et al. Executive summary: heart disease and stroke statistics--2013 update: a report from the american heart association. Circulation 2013; 127:143-152. 6. Donnan GA, Fisher M, Macleod M et al. Stroke. Lancet 2008; 371:1612-1623. 7. Thrift AG, Dewey HM, Macdonell RA et al. Incidence of the major stroke subtypes: initial findings from the North East Melbourne stroke incidence study (NEMESIS). Stroke 2001; 32:1732-1738. 8. Naylor AR. Time is brain! Surgeon 2007; 5:23-30. 9. de Weerd M, Greving JP, Hedblad B et al. Prevalence of asymptomatic carotid artery stenosis in the general population: an individual participant data meta-analysis. Stroke 2010; 41:1294-1297. 10. Abbott AL, Chambers BR, Stork JL et al. Embolic signals and prediction of ipsilateral stroke or transient ischemic attack in asymptomatic carotid stenosis. Stroke 2005; 36:1128-1133. 11. Inzitari D, Eliasziw M, Gates P et al. The causes and risk of stroke in patients with asymptomatic internal-carotid-artery stenosis. N Engl J Med 2000; 342:1693-1700. 12. Norris JW, Zhu CZ, Bornstein NM et al. Vascular risks of asymptomatic carotid stenosis. Stroke 1991; 22:1485-1490. 13. Chambers BR, Donnan GA. Carotid endarterectomy for asymptomatic carotid stenosis. Cochrane Database Syst Rev 2005;CD001923. 14. Abbott AL, Bladin CF, Levi CR et al. What should we do with asymptomatic carotid stenosis? Int J Stroke 2007; 2:27-39. 15. Naylor AR, Gaines PA, Rothwell PM. Who benefits most from intervention for asymptomatic carotid stenosis: patients or professionals? Eur J Vasc Endovasc Surg 2009; 37:625-632. 16. Rockman C, Riles T. Carotid artery disease: selecting the appropriate asymptomatic patient for intervention. Perspect Vasc Surg Endovasc Ther 2010; 22:30-37. 17. Rerkasem K, Rothwell PM. Carotid endarterectomy for symptomatic carotid stenosis. Cochrane Database Syst Rev 2011;CD001081. 18. Bonati LH, Lyrer P, Ederle J et al. Percutaneous transluminal balloon angioplasty and stenting for carotid artery stenosis. Cochrane Database Syst Rev 2012; 9:CD000515. 19. Kakisis JD, Avgerinos ED, Antonopoulos CN et al. The European Society for Vascular Surgery guidelines for carotid intervention: an updated independent assessment and literature review. Eur J Vasc Endovasc Surg 2012; 44:238-243. 20. Golledge J, Greenhalgh RM, Davies AH. The symptomatic carotid plaque. Stroke 2000; 31:774-781. 21. Rerkasem K, Rothwell PM. Systematic review of the operative risks of carotid endarterectomy for recently symptomatic stenosis in relation to the timing of surgery. Stroke 2009; 40:e564-e57 22. Rothwell PM, Gibson R, Warlow CP. Interrelation between plaque surface morphology and degree of stenosis on carotid angiograms and the risk of ischemic stroke in patients with symptomatic carotid stenosis. On behalf of the European Carotid Surgery Trialists’ Collaborative Group. Stroke 2000; 31:615-621. 23. Rothwell PM, Eliasziw M, Gutnikov SA et al. Analysis of pooled data from the randomised controlled trials of endarterectomy for symptomatic carotid stenosis. Lancet 2003; 361:107-116. 24. Naghavi M, Libby P, Falk E et al. From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part I. Circulation 2003; 108:1664-1672. 25. Friedell ML, Joseph BP, Cohen MJ et al. Surgery for carotid artery stenosis following neck irradiation. Ann Vasc Surg 2001; 15:13-18. 26. Ballotta E, Da GG, Meneghetti G et al. Progression of atherosclerosis in asymptomatic carotid arteries after contralateral endarterectomy: a 10-year prospective study. J Vasc Surg 2007; 45:516-522. 27. Cote R, Barnett HJ, Taylor DW. Internal carotid occlusion: a prospective study. Stroke 1983; 14:898-902. 28. Grubb RL, Jr., Derdeyn CP, Fritsch SM et al. Importance of hemodynamic factors in the prognosis of symptomatic carotid occlusion. JAMA 1998; 280:1055-1060. 29. Hankey GJ WC. Prognosis of Symptomatic Carotid Artery Occlusion. Cerebrovasc dis 1991; 1:245-256. 30. Klijn CJ, Kappelle LJ, Tulleken CA et al. Symptomatic carotid artery occlusion. A reappraisal of hemodynamic factors. Stroke 1997; 28:2084-2093. 31. Klijn CJ, van Buren PA, Kappelle LJ et al. Outcome in patients with symptomatic occlusion of the internal carotid artery. Eur J Vasc Endovasc Surg 2000; 19:579-586. 32. Blankensteijn JD, van der GJ, Mali WP et al. Flow volume changes in the major cerebral arteries before and after carotid endarterectomy: an MR angiography study. Eur J Vasc Endovasc Surg 1997; 14:446-450.

16-5-2013 7:59:43

GENERAL INTRODUCTION | CHAPTER 1

33. Duan Y, Li G, Yang Y et al. Changes in cerebral hemodynamics after carotid stenting of symptomatic carotid artery. Eur J Radiol 2012; 81:744-748. 34. Jones CE, Wolf RL, Detre JA et al. Structural MRI of carotid artery atherosclerotic lesion burden and characterization of hemispheric cerebral blood flow before and after carotid endarterectomy. NMR Biomed 2006; 19:198-208. 35. van Laar PJ, van der GJ, Moll FL et al. Hemodynamic effect of carotid stenting and carotid endarterectomy. J Vasc Surg 2006; 44:73-78. 36. van Laar PJ, Hendrikse J, Mali WP et al. Altered flow territories after carotid stenting and carotid endarterectomy. J Vasc Surg 2007; 45:1155-1161. 37. Vanninen E, Kuikka JT, Aikia M et al. Heterogeneity of cerebral blood flow in symptomatic patients undergoing carotid endarterectomy. Nucl Med Commun 2003; 24:893-900. 38. Vanninen R, Koivisto K, Tulla H et al. Hemodynamic effects of carotid endarterectomy by magnetic resonance flow quantification. Stroke 1995; 26:84 89. 39. Yun TJ, Sohn CH, Han MH et al. Effect of carotid artery stenting on cerebral blood flow: evaluation of hemodynamic changes using arterial spin labeling. Neuroradiology 2013; 55:271-281. 40. Chaves C, Hreib K, Allam G et al. Patterns of cerebral perfusion in patients with asymptomatic internal carotid artery disease. Cerebrovasc Dis 2006; 22:396-401. 41. Scott AS, Parr LA, Johnstone PA. Risk of cerebrovascular events after neck and supraclavicular radiotherapy: a systematic review. Radiother Oncol 2009; 9 0:163-165.

15

phd_anne.indb 15

16-5-2013 7:59:43

phd_anne.indb 16

16-5-2013 7:59:44

Part I Risk in patients with asymptomatic carotid artery stenosis

phd_anne.indb 17

16-5-2013 7:59:45

phd_anne.indb 18

16-5-2013 7:59:46

RISK IN PATIENTS WITH ASYMPTOMATIC CAROTID ARTERY STENOSIS | PART l

CHAPTER 2 Asymptomatic carotid artery stenosis: identification of subgroups with different underlying plaque characteristics European Journal of Vascular and Endovascular Surgery 2012 Jun;43(6):632-6.

A.G. den Hartog1* G.W. van Lammeren1,2* G. Pasterkamp2 A. Vink3 J-P.P.M. de Vries4 F.L. Moll1 G.J. de Borst1

Department of Vascular Surgery, University Medical Center Utrecht, Utrecht, The Netherlands Experimental Cardiology Laboratory, University Medical Center Utrecht, Utrecht, The Netherlands 3 Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands 4 Department of Vascular Surgery, St Antonius Hospital, Nieuwegein, The Netherlands 1 2

*These authors equally contributed to this study.

phd_anne.indb 19

16-5-2013 7:59:46

ABSTRACT Objectives Optimal surgical treatment of patients with asymptomatic carotid artery stenosis (ACAS) remains a matter of debate. Established definitions of ACAS include: (1) patients who never suffered from ipsilateral cerebrovascular events (group 1) or (2) patients who suffered from ipsilateral cerebrovascular events more than 6 months prior to revascularisation (group 2). Cerebrovascular symptoms are closely related to underlying carotid plaque composition and therefore we investigated potential plaque differences between these definition-based subgroups.

Design Cross-sectional analysis of a longitudinal prospective biobank study.

Methods 20

Carotid atherosclerotic plaques from 264 asymptomatic patients were harvested during endarterectomy, and subjected to histopathological examination. Patients were divided into two groups: group 1: truly asymptomatic (n=182), and group 2: patients with ipsilateral events more than 6 months before carotid endarterectomy (CEA) (n=82).

Results Patients in group 1 had relatively more stable plaque characteristics as compared with patients in group 2, with a higher median plaque smooth muscle cell content (2.1 (0.0-18.7) vs. 1.6 (0.0-14.4); P=0.036), a higher proportion of heavily calcified plaques (67.7% (123/182) vs. 48.8% (40/82); P=0.005) and less frequently intraplaque haemorrhages (11.5% (21/182) vs. 30.5% (25/82); P=0.001).

Conclusion Different plaque characteristics within subgroups of ACAS patients can be identified based on reported past ipsilateral events, which might result in adjusted future treatment strategies.

phd_anne.indb 20

16-5-2013 7:59:47

ASYMPTOMATIC CAROTID PLAQUES AND SUBGROUPS | CHAPTER 2

INTRODUCTION The prevalence of severe asymptomatic carotid artery stenosis (ACAS) in the general population ranges from 0% to 3%.1 The annual stroke rate in patients with ACAS varies from 1% up to 3%.2-4 Several large clinical trials investigated the optimal treatment in patients with ACAS, and focused on best medical treatment (BMT) versus carotid endarterectomy (CEA), and more recently carotid artery stenting (CAS), but results of these trials are conflicting.5-8 There is level one evidence that CEA is beneficial compared to medical therapy.5,6 Recently ACST1 concluded that compared to BMT successful CEA for asymptomatic patients younger than 75 years significantly reduces 10-year stroke risks.9 However, despite this evidence, revascularization of ACAS remains a matter of debate. The majority of the criticism is founded on the fact that BMT is still improving, and not all patients in the medical arm of the conducted large randomized trials did receive this treatment uniformly.10-12 In addition the absolute risk reduction of CEA is relatively small.11,12 The number needed to treat (NNT) of 32 to prevent one disabling stroke over a 5-year follow-up period, and a NNT of 20 over a 10 year follow-up period in patients under the age 75 years,6,9 have to be taken into account and must outweigh

21

the procedural related risks. This relatively high NNT can in part be explained by the underlying carotid plaque composition and morphology. In symptomatic patients plaque composition is strongly associated with presenting symptoms and have relatively unstable, ruptured or rupture prone plaques.13,14 For symptomatic patients with severe carotid stenosis (70-99%), NASCET has reported a cumulative risk of any ipsilateral stroke of 26% for those treated medically.15 In ECST the 3-year risk of stroke was 16.8% for those patients randomized to medical therapy.16 In comparison, asymptomatic patients have relatively stable carotid plaque features with low risk for plaque rupture and subsequent cerebrovascular events. Nevertheless, a proportion of 1-3% within the domain of asymptomatic patients on BMT annually suffers from ipsilateral stroke.2-4 Therefore stratification of patients at risk for future stroke, and who might have a higher benefit of revascularization is warranted. Assumptions about identification of subgroups with a higher stroke risk within asymptomatic patients have been made.12 In several trials and guidelines patients were considered asymptomatic if 1) patients did not have any ipsilateral symptoms in history, or 2) patients with ACAS, but with any ipsilateral symptoms of the carotid territory longer than 6 months ago.8,17,18 Due to the strong association between the index event, and underlying plaque composition in symptomatic patients we hypothesized that carotid plaque features could also differ between these ACAS subgroups.

phd_anne.indb 21

16-5-2013 7:59:47

METHODS Patient population Athero-Express is an ongoing biobank study, collecting carotid plaques harvested during CEA. Medical ethics boards of the two participating tertiary referral hospitals (University Medical Center Utrecht and St. Antonius Hospital Nieuwegein, The Netherlands) approved the study. Between 2002 and 2010, 264 asymptomatic patients could be identified for the current study. All included patients provided written informed consent. First, these patients were screened by a neurologist and a vascular surgeon. Second, computed tomography of their brain did not show fresh ischemic lesions. Indications for CEA were reviewed by a multidisciplinary team and based on recommendations by the Asymptomatic Carotid Atherosclerosis Study and Asymptomatic Carotid Surgery Trial studies.5,6 Asymptomatic restenotic lesions were excluded from the current study. Preoperative carotid artery flow velocity and degree of stenosis were assessed with duplex ultrasound, and interpreted according to the modified Strandness criteria.19 Participating patients filled out an extensive questionnaire including general medical

22

history, cardiovascular morbidity, medication use and cardiovascular risk factors. Missing data from the questionnaires were completed with information from admission charts or the general practitioner was contacted. Patients were considered smokers if they reported to be smoking or did not quit smoking until the year of surgery. Diabetic status was restricted to those patients receiving medical treatment including insulin or oral glucose-lowering drugs. Hypertension was defined as the use of antihypertensive drugs. Coronary artery disease (CAD) was defined as a history of myocardial infarction, percutaneous transluminal coronary angioplasty, coronary artery bypass grafting, or coronary artery stenosis reported from angiograms. Peripheral arterial disease (PAD) was defined as (intermittent) claudication with an ankle-brachial index < 0.7, or a history of peripheral artery surgery including femoral thrombo-endarterectomy, or bypass surgery.

Definitions of study groups All asymptomatic patients were divided into two groups based on the definitions reported in previous studies. The first group was defined as patients who did not have any ipsilateral symptoms in history, and will also be referred to as truly asymptomatic patients (group 1). The second group was defined as patients with ipsilateral symptoms of the carotid artery territory, but longer than 6 months prior to CEA (group 2).8,17,18

phd_anne.indb 22

16-5-2013 7:59:47

ASYMPTOMATIC CAROTID PLAQUES AND SUBGROUPS | CHAPTER 2

Atherosclerotic plaque assessment Atherosclerotic plaques of patients were harvested during carotid endarterectomy (CEA) according to a standardized and previously reported protocol.20,21 In short, the carotid plaque was divided into segments of 5 mm thickness. The section with the largest plaque burden was classified as culprit lesion and subjected to immunohistochemical staining. Plaques were stained for macrophages (CD 68), smooth muscle cells ((SMC), alpha-actin), collagen (Picro-sirius Red (PSR)), calcifications (haematoxylin eosin (H&E)), lipid cores (H&E and PSR), microvessels (CD34) and luminal thrombi or intraplaque haemorrhages (H&E and fibrin [Mallory's phosphotungstic acid-hematoxylin]).20-22 Macrophage content and SMC content were analyzed digitally with Analysis software (AnalySIS 3.2, Soft Imaging Systems GmbH, Münster, Germany). Based on colour thresholds, the software computed the percentage of the plaque that was positive for: CD68 for macrophages, and α-actin for SMC content respectively. Microvessels in the plaque were scored in three hotspots and reported as an average number of vessels per hot spot.22 In addition, collagen and calcifications were scored semiquantatively as no/minor or moderate/heavy staining, according to the following criteria: (1) no or minor staining along part of the luminal border of the plaque, or a few scattered spots within the lesion; (2) moderate or heavy staining along the entire luminal border or

23

evident parts within the lesion. Size of the lipid core was visually assessed and cut off at 40%, based on the association with rupture prone plaques.23 Luminal thrombus was defined as a solid mass formed from fibrin and platelets superimposed on the plaque, within the vascular lumen.24 Loose erythrocytes in the lumen were scored negative for luminal thrombi. Intraplaque haemorrhage was defined as a haemorrhage within the atherosclerotic plaque without signs of cap rupture.24 Intraobserver and interobserver variability of the histological assessment were examined previously and reproducibility was found to be good (κ 0.6-0.9).20

Clinical outcome We investigated the clinical outcome after carotid endarterectomy for both study groups. Endpoints were defined as described previously.21,22 Primary endpoint was a composite of all cardiovascular endpoints, including cardiovascular morbidity (stroke, myocardial infarction, coronary interventions, and peripheral vascular interventions) and cardiovascular mortality (fatal stroke, fatal MI, fatal AAA-rupture). Secondary endpoints were major cardiovascular events (stroke, myocardial infarction or cardiovascular related death). We additionally studied stroke and myocardial infarction as separate endpoints. The endpoint stroke contains all strokes (ipsilateral and contralateral) during follow-up.

phd_anne.indb 23

16-5-2013 7:59:47

Statistical analyses SPSS version 17.0 (SPSS Inc, Chicago, Illinois, United States of America) was used for all statistical analyses. Baseline differences between the two groups of asymptomatic patients and differences in histological plaque parameters were examined with Pearson Chi-square test for binominal variables, and students t-test for continuous variables. If continuous variables showed a non-linear distribution, logarithmic transformation was applied where appropriate. The continuous data of macrophages, SMC and plaque microvessel density were nonparametric and were therefore logarithmically transformed and reported as ‘log macrophages’, ‘log smooth muscle cells’ and ‘log microvessels’ in the tables, and additionally as original data in the manuscript as a reference. To assess the independent association between plaque characteristics and the two groups and thereby correct for baseline differences and potential confounders that showed an association with the two groups with a P-value 70% in combination with a progressive ipsilateral stenosis, bilateral stenosis with an incomplete circle of Willis, or a symptomatic contralateral occlusion. The events that occurred in the 82 patients that were symptomatic, but had their index event more than 6 months before CEA, encompassed transient ischemic attack (n=40), amaurosis fugax (n=15), minor stroke (n=12), stroke (n=9), retinal infarction (n=3), and aspecific hemodynamic complaints (n=3). The median time (interquartile range (IQR)) between the index event and surgery in this group was 237 [207-335] days. Baseline differences between the two groups encompassed a higher prevalence of systemic atherosclerotic disease, including CAD and PAD among the truly asymptomatic patients, who never suffered from an ipsilateral event. (Table 1) In addition, truly asymptomatic patients were on statins before surgery more frequently. (Table 1)

phd_anne.indb 24

16-5-2013 7:59:47

ASYMPTOMATIC CAROTID PLAQUES AND SUBGROUPS | CHAPTER 2

Table 1. Baseline characteristics among the two groups with asymptomatic carotid stenosis Clinical baseline parameter

Truly asymptomatic

Symptomatic >6 months prior to CEA

N=182

N=82

P-value

Gender, male

139 (76.4)

63 (76.8)

0.936

Age, years

65.9 ±9.1

66.8 ±9.5

0.473

Diabetes mellitus

37 (20.8)

17 (20.7)

0.992

Current smoker

49 (28.5)

25 (31.3)

0.654

Hypertension

155 (89.6)

68 (84.0)

0.200

Body mass index (kg/m2)

26.7 ±3.5

26.6 ±3.2

0.877

eGFR (ml/min/1.73m )

68.9 ±19.6

70.9 19.4

0.471

Coronary artery disease

59 (33.9)

15 (18.5)

0.012

2

Peripheral artery disease

47 (26.6)

12 (14.8)

0.037

Statin use

140 (79.5)

56 (68.3)

0.049

Aspirin use

153 (86.9)

72 (87.8)

0.845

Oral anticoagulants use

21 (11.9)

10 (12.2)

0.952

Oral anticoagulants use

21 (11.9)

10 (12.2)

0.952

25

Baseline characteristics presented absolute numbers (percentage) or as means ± standard deviation. Abbreviations: CEA, carotid endarterectomy; eGFR, estimated glomerular filtration rate.

Carotid plaque characteristics SMC content in group 1 was higher with a median of 2.1 (0.0-18.7), compared with a median of 1.6 (0.0-14.4)] in group 2 (adjusted P=0.036). (Table 2) In group 1, 123 carotid plaques (67.7%) showed signs of moderate to heavy carotid plaque calcifications, compared with 40 plaques (48.8%) from group 2 (adjusted P=0.005). The adjusted odds ratio (OR) for moderate or heavy plaque calcifications in this group was 0.453 (0.260-0.788). (Table 2) In addition, intraplaque haemorrhage was present in 21 plaques (11.5%) plaques from patients in group 1, versus 25 plaques (30.5%) plaques from group 2 (adjusted P=0.001). The adjusted OR for the presence of intraplaque haemorrhage for patients in group 2 was 3.351 (1.6866.661) (adjusted P=0.001). (Table 2) Univariate analyses also showed a possible association with plaque collagen content, but after multivariable correction with logistic regression, no significant difference remained. No differences between the patient groups were observed for macrophages, microvessels, lipid core size, or luminal thrombi.

phd_anne.indb 25

16-5-2013 7:59:47

Table 2. Histological parameters and associations with two groups with asymptomatic carotid stenosis. Continuous histological parameters

26

Truly asymptomatic

Symptomatic >6 months prior to CEA

Univariate P-value

Adjusted coefficient (SE)*

Adjusted P-value*

N=182

N=82

Log macrophages

-0.55 ±0.79

Log smooth muscle cells

0.19 ±0.57

-0.51 ±0.79

0.714

0.016 (0.109)

0.886

-0.01 ±0.80

0.023

-0.195 (0.093)

0.036

Log microvessels

0.86 ±0.38

0.90 ±0.22

0.356

0.025 (0.052)

0.630

Binominal histological parameters

Truly symptomatic

Symptomatic >6 months prior to CEA

Univariate P-value

Adjusted OR [95% CI]*

Adjusted P-value*

N=182

N=82

Lipid core > 40% of plaque surface

37 (20.3)

25 (30.5)

0.072

1.542 [0.837-2.841]

0.165

Moderate/ heavy calcifications

123 (67.6)

40 (48.8)

0.004

0.453 [0.260-0.788]

0.005

Moderate/ heavy collagen

157 (86.3)

61 (74.4)

0.019

0.547 [0.280-1.069]

0.078

Intraplaque hemorrhage

21 (11.5)

25 (30.5)

6 months prior to CEA

N=182

N=82

26.4% (48/182)

20.7% (17/82)

P-value*

Odds ratio [95%CI]**

0.203

0.689 [0.401-1.214]

Major cardiovascular endpoint

8.2% (15/182)

7.3% (6/82)

0.684

0.882 [0.389-2.119]

Stroke

4.4% (8/182)

3.7% (3/82)

0.719

0.784 [0.208-2.957]

Myocardial infarction

2.2% (4/182)

3.7% (3/82)

0.585

1.519 [0.339-0.698]

*Calculated with Cox regression analyses. ** Represents the risk of an event for patients who were symptomatic > 6 months prior to CEA (group 2), as compared with truly asymptomatic patients (group 1). Events include endpoints within and after 30 days

phd_anne.indb 26

16-5-2013 7:59:47

ASYMPTOMATIC CAROTID PLAQUES AND SUBGROUPS | CHAPTER 2

Clinical outcome During a mean follow up of 2.35 (±1.0) years, no statistical differences in event rates were observed. (Table 3) Cardiovascular outcome after CEA was therefore comparable between groups.

DISCUSSION With the current analysis we have shown that patients who suffered from ipsilateral cerebrovascular symptoms, but underwent CEA longer than 6 months after the index event, have different plaque characteristics than patients who never experienced ipsilateral symptoms. Patients who were truly asymptomatic had a higher overall plaque SMC content, a higher prevalence of heavily calcified plaques and a lower prevalence of intraplaque haemorrhages. To the best of our knowledge, this is the first study that describes the association between plaque characteristics and two subgroups based on applied definitions for ACAS. We also observed a tendency towards decreased plaque collagen content in group 2, and thus a more vulnerable plaque composition. This tendency is in line with previous findings,

27

describing that a decline in SMC content is accompanied by a decrease in synthesis of collagen type I and III, resulting in weakening of the fibrous cap overlying the plaque which eventually leads to an increased risk of plaque rupture.25 However, after correction for potential confounders through multivariable logistic regression, the difference in plaque collagen content between the two groups was not statistically significant. The finding that plaque calcifications were more frequently present in plaques from truly asymptomatic patients (group 1), might indicate a more stable underlying plaque composition. Plaque calcifications are considered to be potentially stabilizing and are associated with a more fibrous, and stable plaque composition.26 This in line with previous findings from Nandalur and colleagues who have shown that the proportion of carotid plaque calcification, rather than absolute plaque volume is associated with stability and asymptomatic status.27 Unfortunately, no study on stroke risk and histological plaque features has been performed until date. Rothwell et al. described a stroke risk model, including morphological plaque surface features detected with angiography, rather than cellular plaque components such as SMCs plaque hemorrhage and calcifications.28 Future imaging studies with asymptomatic patients on best medical treatment will have to investigate potential associations between plaque composition and stroke risk. Furthermore, patients in group 2 had a higher prevalence of intraplaque haemorrhages compared with truly asymptomatic patients. The presence of intraplaque haemorrhage inside

phd_anne.indb 27

16-5-2013 7:59:47

carotid plaques is considered to be an important vulnerable plaque characteristic, since plaque haemorrhages contribute to atherosclerotic plaque progression and increased risk of plaque upture, and consequently ipsilateral events.25,26,29,30 In addition, carotid plaque haemorrhages are also associated with systemic cardiovascular events after CEA.22 In the current cohort however, we did not observe statistical differences in systemic cardiovascular outcome after CEA between groups. Overall, it might be conceivable that patients on best medical treatment who have never experienced any ipsilateral symptoms are less likely to develop a future ipsilateral event due to their more stable underlying plaque composition including more SMC’s, more calcifications and less intraplaque haemorrhages, compared with patients who did have ipsilateral symptoms but more than 6 months prior to CEA. The fact that no differences in plaque inflammation could be observed, can be ascribed to plaque stabilization after cerebrovascular events.31,32 Shortly after plaque rupture, macrophages enter the plaque. However, over time the plaque macrophage and inflammatory protein content gradually decreases. This might explain why we did not observe a difference between the two groups of ACAS patients. Analyses of carotid plaque rupture were not conducted in our study, due to disruption of

28

plaque morphology caused by surgical trauma.20 This makes interpretation of cap rupture rather difficult, which is in line with findings from Lovett et al., who stated that reproducibility of histological assessment of plaque rupture is limited.33 Possible confounding factors in the current study might be sought in baseline differences between the groups and include CAD, PAD and statin use. Nevertheless, we corrected for these factors in multiple regression analyses and therefore expect that the observed differences are accurate.

Future perspectives The current study might contribute to improved understanding of asymptomatic carotid artery stenosis and underlying plaque composition in subgroups. Patients who suffered from an ipsilateral event longer than six months before CEA are currently classified as asymptomatic, but have a relatively unstable plaque composition compared with patients who never experienced ipsilateral events. This suggests that patients with past events might have different long term ipsilateral stroke risks. This hypothesis will have to be confirmed with data from randomized trials focusing on ACAS. Furthermore, it would be of interest to investigate whether our findings on plaque composition can be confirmed with plaque imaging studies in asymptomatic patients. The current study might thus provide new insights for stratification of subgroups, and adjusted future treatment strategies for patients with ACAS.

phd_anne.indb 28

16-5-2013 7:59:47

ASYMPTOMATIC CAROTID PLAQUES AND SUBGROUPS | CHAPTER 2

CONCLUSION Within the domain of patients with ACAS, individuals that never suffered from ipsilateral symptoms have a higher plaque SMC content, higher prevalence of heavy plaque calcifications, and lower prevalence of intraplaque haemorrhage, compared with individuals who suffered from an event more than 6 months prior to surgery. This implies that subgroups within ACAS patients can be identified based on reported past ipsilateral events, which might result in adjusted future treatment strategies for these specific subgroups.

29

phd_anne.indb 29

16-5-2013 7:59:47

REFERENCES

30

phd_anne.indb 30

1. de WM, Greving JP, Hedblad B et al. Prevalence of asymptomatic carotid artery stenosis in the general population: an individual participant data meta-analysis. Stroke 2010; 41:1294-1297. 2. Abbott AL, Chambers BR, Stork JL et al. Embolic signals and prediction of ipsilateral stroke or transient ischemic attack in asymptomatic carotid stenosis: a multicenter prospective cohort study. Stroke 2005; 36:1128-1133. 3. Inzitari D, Eliasziw M, Gates P et al. The causes and risk of stroke in patients with asymptomatic internal-carotid-artery stenosis. N Engl J Med 2000; 342:1693-1700. 4. Norris JW, Zhu CZ, Bornstein NM et al. Vascular risks of asymptomatic carotid stenosis. Stroke 1991; 22:1485-1490. 5. Executive Committee for the Asymptomatic Carotid Atherosclerosis Study. Endarterectomy for Asymptomatic Carotid Artery Stenosis. JAMA 1995; 273:1421-1428. 6. Halliday A, Mansfield A, Marro J et al. Prevention of disabling and fatal strokes by successful carotid endarterectomy in patients without recent neurological symptoms: randomised controlled trial. Lancet 2004; 363:1491-1502. 7. Hobson RW, Weiss DG, Fields WS et al. Efficacy of carotid endarterectomy for asymptomatic carotid stenosis. The Veterans Affairs Cooperative Study Group. N Engl J Med 1993; 328:221-227. 8. Rudarakanchana N, Dialynas M, Halliday A. Asymptomatic Carotid Surgery Trial-2 (ACST-2): rationale for a randomised clinical trial comparing carotid endarterectomy with carotid artery stenting in patients with asymptomatic carotid artery stenosis. Eur J Vasc Endovasc Surg 2009; 38:239-242. 9. Halliday A, Harrison M, Hayter E et al. 10-year stroke prevention after successful carotid endarterectomy for asymptomatic stenosis (ACST-1): a multicentre randomised trial. Lancet 2010; 376:1074-1084. 10. Abbott AL, Bladin CF, Levi CR et al. What should we do with asymptomatic carotid stenosis? Int J Stroke 2007; 2:27-39. 11. Naylor AR, Gaines PA, Rothwell PM. Who benefits most from intervention for asymptomatic carotid stenosis: patients or professionals? Eur J Vasc Endovasc Surg 2009; 37:625-632. 12. Rockman C, Riles T. Carotid artery disease: selecting the appropriate asymptomatic patient for intervention. Perspect Vasc Surg Endovasc Ther 2010; 22:30-37. 13. Park AE, McCarthy WJ, Pearce WH et al. Carotid plaque morphology correlates with presenting symptomatology. J Vasc Surg 1998; 27:872- 878. 14. Verhoeven B, Hellings WE, Moll FL et al. Carotid atherosclerotic plaques in patients with transient ischemic attacks and stroke have unstable characteristics compared with plaques in asymptomatic and amaurosis fugax patients. J Vasc Surg 2005; 42:1075-1081. 15. North American Symptomatic Carotid Endarterectomy Trial Collaborators. Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. N Engl J Med 1991; 325:445-453. 16. European Carotid Surgery Trialists' Collaborative Group. MRC European Carotid Surgery Trial: interim results for symptomatic patients with severe (70- 99%) or with mild (0-29%) carotid stenosis. European Carotid Surgery Trialists' Collaborative Group. Lancet 1991; 337:1235-1243. 17. Chambers BR, Donnan GA. Carotid endarterectomy for asymptomatic carotid stenosis. Cochrane Database Syst Rev 2005;CD001923. 18. Halliday AW, Thomas D, Mansfield A. The Asymptomatic Carotid Surgery Trial (ACST). Rationale and design. Steering Committee. Eur J Vasc Surg 1994; 8 :703-710. 19. Grant EG, Benson CB, Moneta GL et al. Carotid artery stenosis: grayscale and Doppler ultrasound diagnosis--Society of Radiologists in Ultrasound consensus conference. Ultrasound Q 2003; 19:190-198. 20. Hellings WE, Pasterkamp G, Vollebregt A et al. Intraobserver and interobserver variability and spatial differences in histologic examination of carotid endarterectomy specimens. J Vasc Surg 2007; 46:1147-1154. 21. Verhoeven BA, Velema E, Schoneveld AH et al. Athero-express: differential atherosclerotic plaque expression of mRNA and protein in relation to cardiovascular events and patient characteristics. Rationale and design. Eur J Epidemiol 2004; 19:1127-1133. 22. Hellings WE, Peeters W, Moll FL et al. Composition of carotid atherosclerotic plaque is associated with cardiovascular outcome: a prognostic study. Circulation 2010; 121:1941-1950. 23. Davies MJ, Richardson PD, Woolf N et al. Risk of thrombosis in human atherosclerotic plaques: role of extracellular lipid, macrophage, and smooth muscle cell content. Br Heart J 1993; 69:377-381. 24. Schwartz SM, Galis ZS, Rosenfeld ME et al. Plaque rupture in humans and mice. Arterioscler Thromb Vasc Biol 2007; 27:705-713. 25. Kockx MM, Herman AG. Apoptosis in atherogenesis: implications for plaque destabilization. Eur Heart J 1998; 19 Suppl G:G23-G28. 26. Finn AV, Nakano M, Narula J et al. Concept of vulnerable/unstable plaque. Arterioscler Thromb Vasc Biol 2010; 30:1282-1292. 27. Nandalur KR, Hardie AD, Raghavan P et al. Composition of the stable carotid plaque: insights from a multidetector computed tomography study of plaque volume. Stroke 2007; 38:935-940. 28. Rothwell PM, Mehta Z, Howard SC et al. Treating individuals 3: from subgroups to individuals: general principles and the example of carotid endarterectomy. Lancet 2005; 365:256-265. 29. Kolodgie FD, Gold HK, Burke AP et al. Intraplaque hemorrhage and progression of coronary atheroma. N Engl J Med 2003; 349:2316-2325. 30. Virmani R, Kolodgie FD, Burke AP et al. Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic

16-5-2013 7:59:47

ASYMPTOMATIC CAROTID PLAQUES AND SUBGROUPS | CHAPTER 2

lesions. Arterioscler Thromb Vasc Biol 2000; 20:1262-1275. 31. Peeters W, Hellings WE, de Kleijn DP et al. Carotid atherosclerotic plaques stabilize after stroke: insights into the natural process of atherosclerotic plaque stabilization. Arterioscler Thromb Vasc Biol 2009; 29:128-133. 32. Redgrave JN, Lovett JK, Gallagher PJ et al. Histological assessment of 526 symptomatic carotid plaques in relation to the nature and timing of ischemic symptoms: the Oxford plaque study. Circulation 2006; 113:2320-2328. 33. Lovett JK, Gallagher PJ, Rothwell PM. Reproducibility of histological assessment of carotid plaque: implications for studies of carotid imaging. Cerebrovasc Dis 2004; 18:117-123.

31

phd_anne.indb 31

16-5-2013 7:59:47

phd_anne.indb 32

16-5-2013 7:59:48

RISK IN PATIENTS WITH ASYMPTOMATIC CAROTID ARTERY STENOSIS | PART l

CHAPTER 3 Asymptomatic carotid artery stenosis and the risk of ischemic stroke in patients with clinical manifest arterial disease

Stroke. 2013 Apr;44(4):1002-7.

A.G. den Hartog1 S. Achterberg2 F.L. Moll1 L.J. Kappelle2 F.L.J. Visseren3 Y. van der Graaf4 A. Algra2,4 G.J. de Borst1 on behalf of the SMART Study Group

Department of Vascular Surgery, University Medical Center Utrecht, Utrecht, The Netherlands Utrecht Stroke Center, Department of Neurology and Neurosurgery, University Medical Center Utrecht, Utrecht, the Netherlands 3 Department of Vascular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands 4 Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands 1 2

phd_anne.indb 33

16-5-2013 7:59:49

ABSTRACT Background and Purpose Because best medical treatment is improving, the risk of stroke in asymptomatic carotid artery stenosis (ACAS) may decline. We evaluated the risk of ischemic stroke and stratified it according to stroke subtype in patients with ACAS during long-term follow-up.

Methods In total, 4319 consecutive patients in the Second Manifestations of Arterial disease study with clinically manifest arterial disease or specific risk factors, but without a history of cerebrovascular disease, were included. Degree of stenosis was evaluated with duplex ultrasound scanning. Strokes during follow-up were classified according to subtype. Cox proportional hazard-regression models were used to evaluate the relationship between ACAS and future stroke.

34

Results We identified 293 (6.8%) patients with ACAS 50% to 99%, of whom 193 had 70% to 99% stenosis. In these subgroups, mean follow-up was 6.2 and 6.0 years, respectively. In total, 94 ischemic strokes occurred, of which 8 in ACAS 50% to 99% patients. The any territory annual ischemic stroke risk was 0.4% in 50% to 99% ACAS and 0.5% per year for 70% to 99% ACAS patients. The risk of ischemic stroke was not significantly increased in patients with ACAS 70% to 99% (hazard ratio, 1.5; 95% CI, 0.7–3.5). Patients with ACAS 50% to 99% and ACAS 70% to 99% tended to have non significantly more large vessel disease strokes (hazard ratio, 1.5; 95% CI, 0.5–4.2 and hazard ratio, 1.7; 95% CI, 0.5–5.6).

Conclusions Patients with clinically manifest arterial disease or type 2 diabetes mellitus have a low risk of developing ischemic stroke, irrespective of its subtype and independent of the degree of ACAS stenosis.

phd_anne.indb 34

16-5-2013 7:59:49

ACAS AND SUBTYPE OF STROKE | CHAPTER 3

INTRODUCTION Asymptomatic carotid artery stenosis (ACAS) is defined as a ≥50% narrowing of the carotid artery in the absence of retinal or cerebral ischemia in the preceding six months. In the general population, the prevalence of high degree ACAS (≥70%) ranges from 0% to 3.1%, and the annual stroke rate in patients with ACAS ranges from 1% up to 3%.1-5 Another report showed that ACAS is an independent risk factor for any vascular event, especially vascular death, in patients with clinical manifest arterial disease or type 2 diabetes mellitus, and extent of ACAS was also associated with a higher increased risk of stroke.6 Since then the Second Manifestations of Arterial (SMART) disease cohort increased inclusion and the follow-up was importantly prolonged. The SMART study provides the unique possibility to report in more detail on stroke during long-term follow-up in these truly asymptomatic patients. Besides this SMART cohort, the only other large and long-term follow-up study of asymptomatic patients is from 2002 and reported stroke rates of 9.3% and 16.6% in patients with 50% to 99% internal carotid artery stenosis after 5 and 10 years, respectively.4 However, the reported average annual stroke rate among patients with ≥50% ACAS receiving medical intervention alone has fallen significantly.7-9 This could possibly be attributed to improved efficacy and

35

implementation of medical intervention.7,9 Furthermore, it is increasingly important to assess the long-term risk of stroke in patients with ACAS as this influences the balance in benefit in overall stroke prevention between a conservative treatment as opposed to revascularization and is therefore helpful in optimal clinical decision making. Furthermore, management of stroke is highly dependent on stroke subtype as are prognosis and the risk of recurrence.10 The aim of the present analysis was to assess the relationship between ACAS and the risk of ischemic stroke, classified according to stroke subtype, during long-term follow-up.

METHODS Design A prospective analysis was performed on patients enrolled in SMART. The design of the SMART study has been reported in detail previously.11 In summary, this is a single-center prospective cohort study among patients, newly referred to the University Medical Center Utrecht with (1) clinically manifest atherosclerotic vessel disease (coronary heart disease, cerebrovascular disease, abdominal aortic aneurysm, or peripheral arterial disease, renal

phd_anne.indb 35

16-5-2013 7:59:49

artery stenosis, and diabetic foot), or (2) marked risk factors for atherosclerosis (diabetes mellitus, hypertension, and hyperlipidemia).11 All patients, 18 to 79 years, who gave written informed consent underwent a standardized vascular screening at baseline, including a health questionnaire, laboratory assessment, and duplex ultrasonography (DUS) to investigate the prevalence and incidence of additional vascular diseases. The Ethics Committee of the University Medical Center Utrecht approved the study.

Patient Population For the present analysis, a total of 5866 SMART patients with clinical manifestations of arterial disease (coronary heart disease, cerebrovascular disease, abdominal aortic aneurysm, or peripheral arterial disease) or risk factors for atherosclerosis (diabetes mellitus, hypertension, and hyperlipidemia) were available. From these 5866, 1473 patients with a history of cerebrovascular disease (defined as transient ischemic attack, stroke, cerebral ischemia, amaurosis fugax, or retinal infarction) before their inclusion in SMART, and 74 patients with missing DUS data were excluded. Therefore, 4319 patients remained available for analysis.

36

Carotid Artery Stenosis All patients included in SMART underwent color Doppler-assisted DUS of the carotid arteries at entry. Severity of carotid artery stenosis was based on the peak systolic velocity.12 The observed greatest degree of stenosis was scored for analysis.

Follow-up Biannually, patients completed a questionnaire on hospitalizations and outpatient clinic visits. Hospital discharge letters, investigations, or other correspondence were obtained to record a specific event. Subsequently, all events were audited by 3 members of the Outcome Event Committee.

Outcome Primary outcome was the first occurrence of any territory ischemic stroke subclassified according to laterality and subtypes. During follow-up, retinal events and hemispheric transient ischemic attack were not recorded. Stroke subtypes were determined according to the criteria summarized in Table 1 and primarily based on imaging13 (computed tomography or magnetic resonance imaging). If imaging was unavailable or uninformative, clinical symptoms were used to determine subtype. Stroke classification was done with knowledge on the presence of carotid stenosis. In case of multiple events or strokes, only the first event was used for

phd_anne.indb 36

16-5-2013 7:59:49

ACAS AND SUBTYPE OF STROKE | CHAPTER 3

analysis. This stroke subtype classification was performed by 2 independent observers (A.H. and S.A.). In case of disagreement regarding subtype, a third and fourth observer (A.A. and G.B.) were consulted to get consensus. In case of absence of imaging and unclear clinical cause, or in the absence of agreement, strokes were included in the undetermined group.

Statistical Analyses Univariable and multivariable Cox-proportional hazard-regression models were performed to estimate hazard ratio (HR) and 95% confidence interval (CI) for the occurrence of ischemic stroke or stroke subtypes. Patients with intervention on one of the carotid arteries during follow-up were censored from this analysis at the time of carotid endarterectomy, including perioperative events. In model I, the unadjusted HR of ACAS for stroke was calculated. In model II, the HR was adjusted for age and sex. Model III, also adjusted for systolic and diastolic blood pressure, current smoking, diabetes mellitus, use of antiplatelet agents, blood pressure-lowering agents, and lipid-lowering agents at baseline.

37

Table 1. Patient characteristics

phd_anne.indb 37

Subtypes of stroke

Definitions

Large artery atherosclerosis

Imaging: Cortical or cerebellar infarcts >15mm in diameter Clinical features: Cortical function disorder or motor or sensory deficit of one area of the face, arm or leg. Cerebellar syndromes were classified as LVD Retinal ischemia was classified LVD

Small artery atherosclerosis

Imaging: Infarcts of 10%: 10/19 versus 80/95, adjusted P=0.006) were independently associated with XRT plaque, compared to non-XRT plaques.

Conclusions Carotid stenotic lesions in patients with previous cervical radiation are less inflammatory and more fibrotic than carotid atherosclerotic lesions in non-radiated patients.

phd_anne.indb 118

16-5-2013 8:00:04

PLAQUE COMPOSITION OF RADIATION INDUCED STENOSIS | CHAPTER 8

INTRODUCTION Severe carotid stenosis after previous cervical radiation is considered a high-risk condition for revascularisation.1 A causal relationship of cervical radiation therapy (XRT) and development of carotid stenosis has been shown in previous studies.2,3 Furthermore, in patients with carotid stenosis following prior XRT for head and neck malignancy, an increased stroke rate was demonstrated as compared to patients without a history of XRT.4 The underlying physiopathological mechanism of carotid stenosis after cervical XRT resulting in higher stroke risk remains unclear, although different pathways have been suggested.5,6 Differences between atherosclerotic-induced stenosis (AIS) and carotid stenosis after XRT have mainly been based on description of macroscopic morphologic lesion components and clinical patient characteristics. Clinically, XRT patients are younger and have a lower incidence of other risk factors (except hyperlipidaemia) for atherosclerosis compared to non-XRT patients. Morphologically, XRT lesions have a higher degree of stenosis, are likely to be longer and appear on non-typical atherosclerotic sites (more frequent in the external and common carotid artery).7-9 In addition, lesions of XRT patients frequently demonstrated a hypoechoic focus and less often shadowing compared with plaques found in atherosclerotic patients.7

119

These findings indicate that lesions in previously irradiated patients might act as a different disease entity compared to atherosclerotic-induced stenosis (AIS). However, differences in histological plaque characteristics have not been reported to date. Phenotype of carotid plaque has proven to be clinically relevant, due to close associations with presenting primary cerebrovascular events.10 In addition, the local atherosclerotic plaque composition has been shown to be an independent predictor of both future cardiovascular events and restenosis.10,11 Thus far, only animal studies and high-resolution magnetic resonance imaging (MRI) studies have attempted to identify characteristics in carotid plaques after radiation. With help of our longstanding Athero-Express biobank,12 we aimed to study carotid plaques microscopically, to identify plaque phenotype of patients with prior cervical XRT.

phd_anne.indb 119

16-5-2013 8:00:04

METHODS Design This cross-sectional study was designed on patients who have been included in the AtheroExpress biobank (2002-2009). Athero-Express is an ongoing longitudinal prospective study that includes patients undergoing CEA in the participating centers St. Antonius Hospital Nieuwegein and University Medical Center Utrecht.12 After CEA, the carotid plaque is collected and subjected to histological examination. All patients were asked to participate and provided written informed consent. Data of patients were collected prospectively, except for specific radiation characteristics, which were gathered retrospectively. Baseline characteristics included (1) demographic data: gender, age (at time of surgery), preoperative clinical presentation (asymptomatic, transient ischaemic attack (TIA), stroke and ocular symptoms), time between last symptoms and CEA, degree of ipsilateral stenosis (diagnosed by carotid colour Dopplerassisted duplex ultrasound and in most cases confirmed by magnetic resonance angiography (MRA) or computed tomography angiography (CTA)); and (2) risk factors for atherosclerotic

120

disease: (current) smoking, hypertension, hypercholesterolaemia, diabetes mellitus (DM), coronary artery disease (CAD), peripheral artery disease of the lower limbs, renal function (expressed in glomerular filtration rate, GFR (ml min-1 1.73 m-2) and body mass index (BMI) (kg m-2)). Hypertension and hypercholesterolaemia were by definition restricted to those cases using blood pressurelowering drugs respectively statins. DM was defined as use of insulin or oral glucose inhibitors.

Patients All previously radiated patients (XRT group) underwent consecutively CEA with histological plaque analysis according to the Athero-Express protocol. All patients with previous cervical radiation and CEAwere selected out of the Athero-Express database. They were matched to patients (out of the same database) without a history of XRT (non-XRT group) for (1) gender, (2) age (at time of surgery) and (3) clinical presentation. A control group of non-XRT plaques (1:5 ratio) was selected per XRT plaque, based on previously recommended criteria for case control studies.13 In the total study period, 1250 CEAs were performed for 85% symptomatic and 15% asymptomatic patients. Of those, 19 carotid plaques (1.5% of total surgeries) from 17 consecutive patients (median age: 69 years (range 56-92),15 males) with previous cervical XRT were compared to 95 matched controls (median age: 69 years (range 56-90), 76 males) without a history of cervical XRT. The same treatment regimen was followed for radiated and non-radiated patients.

phd_anne.indb 120

16-5-2013 8:00:05

PLAQUE COMPOSITION OF RADIATION INDUCED STENOSIS | CHAPTER 8

Plaque assessment and outcome Conforming to a standardised protocol, the carotid plaque obtained during CEA was divided into segments of five mm thickness along the longitudinal axis.12 The segment with the greatest plaque burden, the culprit lesion, was subjected to histological examination. Outcome of plaque characteristics was analysed microscopically by observers of the Athero-Express blinded for XRT status. Histological outcome parameters were widely accepted measures for atherosclerotic plaque stability and included: calcification, collagen, macrophages, smooth muscle cells (SMCs), fat, microvessels and intraplaque haemorrhage (IPH). Semi-quantitative estimation of the plaque morphology was performed for calcification (haematoxylin and eosin (H&E)), collagen (picro Sirius red (PSR)), macrophages (CD 68) and SMC (alpha actin). Plaque characteristics were scored as (1) no/minor staining or (2) moderate/ heavy staining. In addition, atheroma (PSR and H&E) was analysed as the percentage of the plaque occupied by the lipid core (10%). Microvessels (CD 34) were determined by the average number of CD 34-immunopositive microvessels of three hot spots within every plaque. For multivariable analysis, amount of microvessels was dichotomised as either below or above the median. IPH (H&E and Elastin von Gieson stainings) was rated as being absent or present. Finally, overall plaque phenotype was established by overall appearance. A plaque is considered more active

121

and unstable when it reveals a strong staining for macrophages, a large atheroma and when it lacks collagen and SMCs.14 The more fibrous stable lesion typically lacks inflammatory cells and fat and reveals strong staining for collagen and SMCs. The Athero-Express defines this as: fibrous plaque (40% of the plaque hides atheroma with presence of macrophages).12

Statistical analysis Statistical Package for the Social Sciences (SPSS) 17.0 was used for all analyses (SPSS Inc., Chicago, IL, USA). For dichotomized factors, we used crosstabs and Chi-square tests to calculate absolute risks (%) and p-values. Continuous characteristics were analysed with non-parametric Mann-Whitney-U test since parameters were not normally distributed. P-values 10%. Marked infiltration of macrophages (moderate or heavy) was less frequently observed in XRT-plaques 31.6% (6/19) as compared with non-XRT plaques 63.8% (60/95) (P=0.009). More fibrous plaques were identified in the XRT group; XRT plaques were associated with a smaller lipid core size compared to non-XRT plaques. A total of 84.2%

phd_anne.indb 122

16-5-2013 8:00:05

PLAQUE COMPOSITION OF RADIATION INDUCED STENOSIS | CHAPTER 8

(80/95) of the control plaques contained more than 10% atheroma, compared to only 52.6% (10/19) in the XRT plaque (P=0.002) (Table 3). In multivariable logistic regression analysis, infiltration of macrophages and atheroma >10% were independently associated with XRT plaques after adjusting for time between event and surgery, ipsilateral degree of stenosis and BMI (Adjusted OR 0.094 (95% CI 0.020-0.455) resp. 0.129 (95% CI 0.030-0.553) adjusted P=0.003 resp. P=0.006). The figure represents the histologically visualised result (Figure 1). Other histological parameters, including calcification, collagen, SMC, microvessels and IPH were not significantly associated with XRT status (Table 4).

Table 1. Characteristics of previously radiated patients Age

Gender

Malignancy

Lesion side

Intervala (years)

Received dosis (cGy)

96

F

Glottis larynx ca

R

13.1

7000

86

M

Glottis larynx ca

R

20.0

n.a

70

F

Hypopharynx ca

R

1.8

n.a

78

M

Pharynx ca

L

8.0

n.a

68

M

Oropharynx ca

L

4.2

30

72

M

Larynx ca

L

18.0

n.a

77

M

Maligne lymphoma tongue base

R

10.0

40

60

M

Nasopharynx ca

R

9.0

n.a

*

*

*

L

11.0

n.a

64

M

Non Hodgkin Lymfoma

L

12.9

355

74

M

Sqaumouscell ca nose

L

3.5

70

66

M

Tongue base ca, metastasis lymfnode

R

24.0

n.a

85

M

Squamous cell metastase lymfnode

L

3.6

5000

73

F

Squamous cell metastase lymfnode

R

14.0

n.a 5000

64

M

Tongue base ca, squamous

L

8.2

75

M

Tongue base ca

R

6.0

n.a

*

*

*

L

6.0

n.a

69

F

Jaw bone ca

R

15.0

n.a

73

M

Larynx ca

R

21.0

n.a

123

cGy, centi-Gray; F, female; M, male; ca, carcinoma; R, right; L, left; n.a, no data available a Time between end of radiation therapy to carotid endartectomy * Same patient as 1 line above, bilateral stenosis

phd_anne.indb 123

16-5-2013 8:00:05

Table 2. Demographic and clinical characteristics of the study population a Demographic characteristics

Age, years (median, range)

XRT-plaque

Non-XRT plaque

(N = 19)

(N = 95)

69 (56-92)

69 (56-90)

Sex

P-value

.903 .917

Male

15 (78.9)

76 (80.0)

Clinical presentation Asymptomatic

1 (5.3)

5 (5.3)

Symptomatic

18 (94.7)

90 (94.7)

Stroke

4 (21.1)

20 (21.1)

TIA

11 (57.9)

60 (63.2)

Ocular Time between event and surgery, days (median, range)

3 (15.8)

10 (10.5)

35 (2-205)

66 (1-364)

Degree of ipsilateral stenosis

.929

.099 .091

70-90%

15 (73.7)

50 (52.6)

90-99%

5 (26.3)

45 (47.4)

7 (38.9)

33 (37.5)

Hypertension

17 (89.6)

84 (88.4)

.895

Hypercholesterolemia (statin use)

14 (82.4)

67 (71.3)

.344

Diabetes mellitus

3 (15.8)

22 (23.2)

.692

Coronary artery disease

3 (15.8)

19 (20.0)

.671

Risk factors

124

Current smoker

Peripheral artery disease

.912

4 (21.1)

26 (27.4)

.568

GFR (median, range)

66 (46-110)

67 (17-124)

.849

BMI (median, range)

24 (22-29)

27 (18-39)

.001

TIA, transient ischemic accident; GFR, glomural filtration rate in ml/min/1.73m2; BMI, body mass index calculated as weight in kilograms divided by height in meters squared a Data are presented as No (%) unless otherwise indicated

phd_anne.indb 124

16-5-2013 8:00:05

PLAQUE COMPOSITION OF RADIATION INDUCED STENOSIS | CHAPTER 8

Table 3. Histological outcome Histological characteristics

XRT plaque

Non-XRT plaque

(N = 19)

(N = 95)

P-value

Calcification, moderate/heavy

8 (42.1)

58 (61.1)

.127

Collagen, moderate/heavy

14 (73.7)

73 (86.8)

.768

6 (31.6)

60 (63.8)

.009

Macrophages, moderate/heavy SMC, moderate/heavy

11 (57.9)

59 (62.1)

.731

Atheroma > 10%

10 (52.6)

80 (84.2)

.002

4.3 (0.3- 25.0)

7.0 (1.3 – 40.3)

.060

5 (26.3)

31 (32.6)

.589

11 (57.9)

28 (29.5)

.058

Microvessels (median, range) IPH present Overall plaque phenotype Fibrous Fibro-atheromatous

3 (15.8)

27 (28.4)

Atheromatous

5 (26.3)

40 (42.1)

SMC, smooth muscle cells; IPH, intraplaque haemorrhage a Data are presented as No (%) unless otherwise indicated

Table 4. Histological outcome, adjusted Odds Ratios for the presence of plaque parameters in patients with previous XRT as compared with controls Histological characteristics

Adjusted Odds Ratio* (95%CI)

Adjusted P value*

Calcification

0.340 (0.087-1.328)

0.121

Collagen

0.612 (0.144 – 2.601)

0.506

0.094 (0.020-0.455)

0.003

0.595 (0.158 – 2.245)

0.443

Atheroma > 10%

0.129 (0.030-0.553)

0.006

Microvessels > median (number per hotspot)

0.480 (0.120-1.915)

0.299

1.074 (0.286 – 4.039)

0.916

Macrophage infiltration SMC

IPH present

125

CI, confidence interval; SMC, smooth muscle cells; IPH, intraplaque hemorrhage *Adjusted for time between last event and surgery, ipsilateral preoperative degree of stenose and body mass index (kg/m2)

phd_anne.indb 125

16-5-2013 8:00:05

Control

Cervical XRT

126

Figure 1. Carotid plaque histology of radiated and non-radiated patients. Histological analysis of carotid endarterectomy specimens. A and B, control plaque. A, Haematoxylin and eosin staining showing macrophages (left) at the border of an atheroma (right). Bar ¼ 200 mm. B, immunohistochemical detection of macrophages (in brown; CD68 immunostain) in the same plaque as A with heavy staining of macrophages. C and D, XRT plaque. C, Haematoxylin and eosin staining showing connective tissue and calcification in the plaque. Bar ¼ 200 mm. D, no macrophages are present in the macrophage staining (CD68 immunostain) of the same area as C.in 2 different patients

DISCUSSION In this study, we compared histological characteristics of carotid plaques of patients with prior XRT with plaques from non-radiated patients. A more fibrous and less inflammatory plaque was observed in XRT patients compared to plaques derived from non-XRT patients. Soon after the introduction of radiation therapy, around 1940 cardiovascular changes following radiation were recognised and discussed in animal studies.15,16 An experimental study on the large vessels of irradiated mice found progressive changes consisting of intimal proliferation, fragmentation of the elastic lamina, overproduction of elastic tissue, necrosis, hyaline thickening

phd_anne.indb 126

16-5-2013 8:00:06

PLAQUE COMPOSITION OF RADIATION INDUCED STENOSIS | CHAPTER 8

and production of collagen.16 Lindsey et al. irradiated localized segments of the abdominal aorta in dogs.15 They observed arteriosclerotic changes consisting of selective disruption of the internal elastic layer and the development of intimal thickening without histological demonstrable injury to other layers of the vessel wall. Although above described changes were all short to mid-term effects (50%) after CEA.11 Applying this evidence for XRT plaques, patients could hypothetically be more prone to develop restenosis after revascularisation following prior XRT. Although current literature is conflicting, some data suggest that previously radiated patients indeed have a higher risk for restenosis than non-XRT patients after CEA.26 Evidence is more clear for XRT patients treated with carotid angioplasty and stenting (CAS), since rate of restenosis or occlusion was calculated as 5.4 per 100 person-years (95% CI 4.3-6.6) compared to 2.8 per 100 person-years (95% CI 1.9-4.0) after CEA (P=0.0025) in a recent literature review.27 Possibly, high rates of restenosis after CAS can be partly attributed to previous XRT status besides endovascular technique.

128 Limitations In this study, we were able to perform analyses on 19 plaques of 17 patients. Small sample sizes are known for its lack of precision and thus over- and underestimation of the relations under study. Analysing a small number of patients is inevitable since incidence of patients with previous XRT who underwent CEA is low. However, we believe this is an important group to report on. Furthermore, despite the small sample size, we believe this data is valuable and sufficient to meet with our study goal. Ideally, our results need to be confirmed in a prospective and a preferable larger cohort. Because limited data on follow-up were available, we were not able to analyse the possible consequences for clinical outcome and restenosis. Also, we are not aware of the exact time course of the development of radiation-induced lesions. Consequently, findings on histological level only apply for plaques at a median time interval after radiation of 10 years. For some cases, poor information of radiation characteristics (site and dose) was reported. However, this seems to be a minor problem since radiation-induced stenosis was detected not only at the ipsilateral side, but also to a same severe amount at the contralateral side of irradiation for cervical malignancies by others.28,29 Findings can be explained by the so-called ‘bystander effect’, whereas radiation of cells damages not only the target cells, but also non-targeted bystander cells.30 Lastly, because of segments with the greatest plaque burden were histological analysed, different segments of the carotid artery

phd_anne.indb 128

16-5-2013 8:00:06

PLAQUE COMPOSITION OF RADIATION INDUCED STENOSIS | CHAPTER 8

could be analysed in the XRT group and in the non-XRT group. However, examination of a single culprit segment of the plaque is reasonably representative for the plaque as a whole.22 Because physiopathological pathways of initial lesion stay the same, histology will reflect either atherosclerotic or radiation origin.

CONCLUSION Lipid poor, non-inflammatory plaque is distinctive for carotid plaques of previously irradiated and symptomatic patients, compared to a non-irradiated atherosclerotic plaque. Consequences for clinical outcome and restenosis after CEA need to be objectified in larger cohorts with longer follow-up.

129

phd_anne.indb 129

16-5-2013 8:00:06

REFERENCES 1. 2. 3.

130

North American Symptomatic Carotid Endarterectomy Trial. Methods, patient characteristics, and progress. Stroke 1991; 22:711-720. Carmody BJ, Arora S, Avena R et al. Accelerated carotid artery disease after high-dose head and neck radiotherapy: is there a role for routine carotid duplex surveillance? J Vasc Surg 1999; 30:1045-1051. Cheng SW, Ting AC, Lam LK et al. Carotid stenosis after radiotherapy for nasopharyngeal carcinoma. Arch Otolaryngol Head Neck Surg 2000; 126:5175 21. 4. Scott AS, Parr LA, Johnstone PA. Risk of cerebrovascular events after neck and supraclavicular radiotherapy: a systematic review. Radiother Oncol 2009; 9 0:163-165. 5. Louis EL, McLoughlin MJ, Wortzman G. Chronic damage to medium and large arteries following irradiation. J Can Assoc Radiol 1974; 25:94-104. 6. Zidar N, Ferluga D, Hvala A et al. Contribution to the pathogenesis of radiation-induced injury to large arteries. J Laryngol Otol 1997; 111:988-990. 7. Lam WW, Liu KH, Leung SF et al. Sonographic characterisation of radiation-induced carotid artery stenosis. Cerebrovasc Dis 2002; 13:168-173. 8. McGuirt WF, Feehs RS, Bond G et al. Irradiation-induced atherosclerosis: a factor in therapeutic planning. Ann Otol Rhinol Laryngol 1992; 101:222-228. 9. Shichita T, Ogata T, Yasaka M et al. Angiographic characteristics of radiation-induced carotid arterial stenosis. Angiology 2009; 60:276-282. 10. Verhoeven B, Hellings WE, Moll FL et al. Carotid atherosclerotic plaques in patients with transient ischemic attacks and stroke have unstable characteristics compared with plaques in asymptomatic and amaurosis fugax patients. J Vasc Surg 2005; 42:1075-1081. 11. Hellings WE, Moll FL, de Vries JP et al. Atherosclerotic plaque composition and occurrence of restenosis after carotid endarterectomy. JAMA 2008; 299:547-554. 12. Verhoeven BA, Velema E, Schoneveld AH et al. Athero-express: differential atherosclerotic plaque expression of mRNA and protein in relation to cardiovascular events and patient characteristics. Rationale and design. Eur J Epidemiol 2004; 19:1127-1133. 13. Pang D. A relative power table for nested matched case-control studies. Occup Environ Med 1999; 56:67-69. 14. Davies MJ, Richardson PD, Woolf N et al. Risk of thrombosis in human atherosclerotic plaques: role of extracellular lipid, macrophage, and smooth muscle cell content. Br Heart J 1993; 69:377-381. 15. Lindsay S, KOHN HI, DAKIN RL et al. Aortic arteriosclerosis in the dog after localized aortic x-irradiation. Circ Res 1962; 10:51-60. 16. Sams.A. Histological changes in the larger blood vessels of the hind limb of the mouse after X-irradiation. Int J Radiat Biol Relat Stud Phys Chem Med 1965; 9:165-174. 17. Murros KE, Toole JF. The effect of radiation on carotid arteries. A review article. Arch Neurol 1989; 46:449-455. 18. Elerding SC, Fernandez RN, Grotta JC et al. Carotid artery disease following external cervical irradiation. Ann Surg 1981; 194:609-615. 19. Lam WW. Radiation-induced extracranial carotid stenosis. Vasc Dis Prev 2006; 3:27-32. 20. Silverberg GD, Britt RH, Goffinet DR. Radiation-induced carotid artery disease. Cancer 1978; 41:130-137. 21. Peeters W, Hellings WE, de Kleijn DP et al. Carotid atherosclerotic plaques stabilize after stroke: insights into the natural process of atherosclerotic plaque stabilization. Arterioscler Thromb Vasc Biol 2009; 29:128-133. 22. Redgrave JN, Lovett JK, Gallagher PJ et al. Histological assessment of 526 symptomatic carotid plaques in relation to the nature and timing of ischemic symptoms: the Oxford plaque study. Circulation 2006; 113:2320-2328. 23. Furie KL, Kasner SE, Adams RJ et al. Guidelines for the prevention of stroke in patients with stroke or transient ischemic attack: a guideline for healthcare professionals from the american heart association/american stroke association. Stroke 2011; 42:227-276. 24. Virmani R, Kolodgie FD, Burke AP et al. Atherosclerotic plaque progression and vulnerability to rupture: angiogenesis as a source of intraplaque hemorrhage. Arterioscler Thromb Vasc Biol 2005; 25:2054-2061. 25. Gianicolo ME, Gianicolo EA, Tramacere F et al. Effects of external irradiation of the neck region on intima media thickness of the common carotid artery. Cardiovasc Ultrasound 2010; 8:8. 26. Leseche G, Castier Y, Chataigner O et al. Carotid artery revascularization through a radiated field. J Vasc Surg 2003; 38:244-250. 27. Fokkema M, den Hartog AG, Bots ML et al. Stenting versus surgery in patients with carotid stenosis after previous cervical radiation therapy: systematic review and meta-analysis. Stroke 2012; 43:793-801. 28. Brown PD, Foote RL, McLaughlin MP et al. A historical prospective cohort study of carotid artery stenosis after radiotherapy for head and neck malignancies. Int J Radiat Oncol Biol Phys 2005; 63:1361-1367. 29. Martin JD, Buckley AR, Graeb D et al. Carotid artery stenosis in asymptomatic patients who have received unilateral head-and-neck irradiation. Int J Radiat Oncol Biol Phys 2005; 63:1197-1205. 30. Olsson MG, Nilsson EJ, Rutardottir S et al. Bystander cell death and stress response is inhibited by the radical scavenger alpha(1)-microglobulin in irradiated cell cultures. Radiat Res 2010; 174:590-600.

phd_anne.indb 130

16-5-2013 8:00:06

Part III Imaging of carotid artery stenosis

phd_anne.indb 131

16-5-2013 8:00:07

phd_anne.indb 132

16-5-2013 8:00:08

IMAGING OF CAROTID ARTERY STENOSIS | PART lll

CHAPTER 9 Current status of clinical magnetic resonance imaging for plaque characterization in patients with carotid artery stenosis

European Journal of Vascular and Endovascular Surgery. 2013 Jan;45(1):7-21.

A.G. den Hartog1 S.M. Bovens1,2 W. Koning4 J. Hendrikse4 P.R. Luijten4 F.L. Moll1 G. Pasterkamp2 G.J. de Borst1

Department of Vascular Surgery, University Medical Center Utrecht, Utrecht, The Netherlands Experimental Cardiology Laboratory, University Medical Center Utrecht, Utrecht, The Netherlands 3 Netherlands Heart Institute (ICIN), Utrecht, The Netherlands 4 Department of Radiology, University Medical Center Utrecht, Utrecht, The Netherlands

1

2

phd_anne.indb 133

16-5-2013 8:00:08

ABSTRACT Objective The article aims to provide an overview of the literature that assessed the agreement between magnetic resonance imaging (MRI) and histology for specific carotid plaque characteristics associated with vulnerability in terms of sensitivity and specificity.

Methods A systematic search strategy was conducted in MEDLINE and EMBASE databases resulting in 1084 articles. Finally, we included 17 papers. Due to variation in presentation, especially in MRI and histology methods, a pooled analysis could not be performed.

Results Two studies were performed on a 3.0-T MRI scanner; all other studies were performed on a 1.5-T scanner. Most performed sequences were two-dimensional (2D) and three-

134

dimensional (3D) T1-weighted and all histology protocols varied slightly. Our results indicate that calcification, fibrous cap, intraplaque haemorrhage and lipid-rich necrotic cores can be identified with moderate to good sensitivity and specificity.

Conclusions Based on current literature, it appears premature for routine application of MRI as an imaging modality to assess carotid plaque characteristics associated with plaque vulnerability. Although MRI still holds promise, clinical application for plaque characterisation would require consensus regarding MRI settings and confirmation by histology. Predefined protocols for histology and MR imaging need to be established.

phd_anne.indb 134

16-5-2013 8:00:08

MRI AND CAROTID PLAQUE CHARACTERISTICS | CHAPTER 9

INTRODUCTION Large randomised trials for symptomatic1,2 and asymptomatic3,4 patients with high-grade (≥70%) carotid artery stenosis have confirmed the benefit of carotid endarterectomy (CEA). Currently, patient selection for CEA still merely depends on symptoms and degree of stenosis.5 Several studies, however, have suggested the relative importance of plaque characteristics, rather than stenosis, in relation to the future risk for stroke on both the short and the long term.6-8 Furthermore, local atherosclerotic plaque composition in patients undergoing CEA has been shown to be an independent predictor of future cardiovascular events.9 Non-invasive imaging might become increasingly important for identifying plaque characteristics in vivo. Validated histological markers for plaque vulnerability are a thin fibrous cap (FC), a lipid-rich necrotic core (LRNC), intraplaque haemorrhage (IPH) or thrombus and, of less importance, calcification.10 Development of new imaging modalities, or adaptation of existing techniques to visualize carotid atherosclerotic plaque characteristics in more detail, is clearly needed and in progress.11 For non-invasive imaging, it is of eminent importance that the major characteristics associated with vulnerability, and especially clinical outcome, can be identified. Implementation of high-resolution magnetic resonance imaging MRI (hrMRI)

135

seems one of the most promising techniques to reliably determine degree of stenosis and in addition identify carotid plaque morphology and vessel wall structure more precisely.12 This review assessed the agreement between MRI and histology for specific carotid plaque characteristics associated with vulnerability in terms of sensitivity and specificity.

METHODS Search strategy MEDLINE and EMBASE databases were systematically searched on all studies relating carotid artery stenosis, MRI and endarterectomy-derived plaque histology to include all possible eligible studies (Table 1). This search was conducted in July 2012 according to the search strategy and data collection guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement.13 A manual search of the Cochrane Library yielded no relevant articles.

phd_anne.indb 135

16-5-2013 8:00:08

Table 1. Search terms*

Figure 1. S

(((carotid*[tiab] OR extracranial[tiab]) AND (artery[tiab] OR vessel[tiab] OR bifurcation[tiab]) AND (stenosis[tiab] OR stenoses[tiab] OR atherosclerosis[tiab] OR atheroscleroses[tiab] OR disease[tiab] OR diseases[tiab])) OR “carotid stenosis”[tiab] OR “carotid stenoses”[tiab] OR “carotid atherosclerosis”[tiab] OR “Carotid artery diseases”[MesH] OR “Carotid stenosis”[MesH]) AND (“magnetic resonance imaging”[tiab] OR MRI[tiab] OR MR[tiab] OR “MR-imaging”[tiab] OR “tesla”[tiab] OR 1,5T[tiab] OR “1,5 tesla”[tiab] OR 3T[tiab] OR “3 tesla”[tiab] OR 7T[tiab] OR “7 tesla”[tiab] OR “magnetic resonance angiography”[tiab] OR “MR angiography”[tiab] OR MRA[tiab] OR ((MR[tiab] AND DTI[tiab]) OR (MRDTI[tiab]))) AND (plaque[tiab] OR histolog*[tiab] OR patholog*[tiab]) * Search strategy for MedLine is shown; the same search strategy was used in EMBASE; only ‘‘[tiab]’’ had to be exchanged for ‘‘:ti,ab‘‘)

Study selection After disregarding duplicates, the title and the abstract of the remaining articles were independently screened by two observers (A.H. and S.B.) according to predefined criteria. Inclusion criteria were: (1) presenting data about patients with carotid artery stenosis, (2) reporting data on the diagnostic accuracy of MRI and (3) histology as a reference test.

136

Review articles, letters, comments, abstracts for conferences, case reports 0.7 indicated good agreement.

phd_anne.indb 137

16-5-2013 8:00:09

Data presentation All included articles were presented per individual study in a descriptive manner and are summarised systematically in the tables.

RESULTS Our search resulted in 1084 articles. After removing duplicates and screening references, a critical appraisal was performed (Table 2). This led to the exclusion of seven articles, because for these articles sufficient data extraction was not possible. Finally, 17 articles were included. Calcification was reported in four studies15-18, FC in five15,17,19-21, IPH in 1315-19,22-29 and LRNC in six16-18,29-31 (Figure 1 and Table 2).

MRI sequences MRI protocols were specified in all studies, and slightly different sequences or settings were used (Table 3). Two studies were performed on 3.0-T MRI scanner26,27; all other studies were performed on a 1.5-T scanner. Mostly two-dimensional (2D and three-dimensional (3D) T1-

138

weighted (T1W) sequences were performed.

Histological analysis Histology protocols were described in all studies. In general, all protocols varied slightly, but most were only roughly documented (Table 4). Within the qualified protocols to perform histologic analysis, the American Heart Association(AHA) classification using a numeric classification of eight histological defined lesion types was most often chosen.

Major carotid plaque components The main outcome measures of the included studies are summarised in Table 5.

Calcification Four studies (Figure 2 and 3) described the detection of calcification by MRI confirmed with histology.15-18 Calcifications are usually detected as hypointense areas on all contrast weightings or as hypointense areas on two of four sequences (T1W, T2W, proton-density weighted (PDW) and time of flight (TOF)). However, no standardised protocols were used. The AHA classification was used by Cai et al.15 to assess plaque status, and calcified plaques were scaled in class VII. Saam et al.18 determined the areas of calcifications with a hypointense signal on all four weightings, and considering all areas of calcifications, the sensitivity was

phd_anne.indb 138

16-5-2013 8:00:09

MRI AND CAROTID PLAQUE CHARACTERISTICS | CHAPTER 9

Hatsukami

Adequate outcome measurements reported

Sufficient data extraction possible

Number of patients

Withdrawals explained

Uninterpretable results reported

Adequate clinical information

Blinded/correct evaluation of reference test

Blinded/correct evaluation of index test

Description of reference test

Description of index test

Independent reference test

Similar reference tests

Verification

Time between test

Correct reference test

Year

Clear selection criteria

Study

Correct patient spectrum

Table 2. Critical appraisal with QUADAS13 tool

Inclusion

2000

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

Yes

Yuan29

2001

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

Yes

Cai15

2002

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

Yes

Mitsumori21

2003

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

Yes

Moody

2003

+

+

+

?

+

+

+

+

+

+

+

+

+

+

+

+

+

Yes

20

25

Cappendijk

2004

+

+

+

+

?

+

+

+

+

?

+

+

-

-

+

-

-

No

Chu23

2004

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

Yes

Kampschulte24

2004

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

Yes

Trivedi

2004

+

?

+

-

+

+

+

+

+

?

?

+

+

+

+

?

-

No

Cappendijk

2005

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

Yes

Saam18

2005

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

Yes

Cai

2005

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

-

-

No

Honda

2006

+

-

?

-

?

?

+

+

-

?

?

+

+

-

?

-

-

No

Puppini

2006

+

+

+

+

+

+

+

+

+

+

?

+

+

+

+

+

+

Yes

Liu

2006

+

-

+

?

?

+

+

+

+

?

?

+

-

?

+

-

-

No

Alberquerque

2007

+

+

+

?

+

+

+

+

+

+

+

+

+

+

+

+

+

Yes

Watanabe

2008

+

+

+

?

-

+

+

+

+

?

+

+

?

?

+

-

-

No

Cappendijk

2008

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

Yes

16

17

19

30

Yim

2008

+

+

+

+

+

+

+

+

+

?

+

+

+

+

+

+

+

Yes

Yoshida

2008

+

+

+

?

+

+

+

+

+

+

+

+

?

?

+

-

-

No

28

Bitar

2008

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

Yes

Young31

2010

+

+

+

?

+

+

+

+

?

+

+

+

+

+

+

+

+

Yes

Ota26

2010

+

+

+

?

+

+

+

+

+

+

+

+

+

+

+

+

+

Yes

Qiao27

2011

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

Yes

22

139

+: yes, -:no, ?=no results or results unclear We added 3 questions to the standard Quadas tool13. Are the number of patients reported? Was sufficient data extraction possible? Were adequate outcome measurements reported?

phd_anne.indb 139

16-5-2013 8:00:09

Table 3. Magnetic resonance sequences of all included studiesa First author

Year

Hatsukami114

2000 1.5T SIGNA, GE Health care 2001 1.5T SIGNA, GE Health care 2002 1.5T SIGNA, GE Health care 2003 1.5T SIGNA, GE Health care 2003 1.5T Siemens 2004 1.5T SIGNA, GE Health care

Yuan35 Cai115 Mitsumori22 Moody29 Chu116

140

Type MRI

Kampschulte117 2004 1.5T SIGNA, GE Health care Cappendijk118 2005 1.5T Intera, Philips 8.1.2

T1W

T2W

PDW

TOF

OTHER

NA

NA

NA

NA

3D MOTSA

DIR 2D FSE Cardiac gated, Shared echo FSE DIR 2D FSE Cardiac gated, Shared echo FSE DIR 2D FSE Cardiac gated, Shared echo FSE (SHARE) 3D GE NA (MRDTI) BB Cardiac gated, 2D FSE FSE (fat suppression) Yes, not Yes, not specified specified

Cardiac gated, Shared echo FSE Cardiac gated, Shared echo FSE Cardiac gated, Shared echo FSE (SHARE) NA

NA

NA

NA

NA

NA

NA

NA

NA

2D TSE 3D TFE

Cardiac gated, 3D NA FSE (fat suppression) Yes, not Yes, not NA specified specified

Saam119

2005

FSE

Puppini120

2006 1.5T Siemens 2007 1.5T Siemens 2008 1.5T Intera, Philips 8.1.2 2008 1.5T SIGNA, GE Health care

TSE

ECG- gated, TSE ECG gated partial T2 weighted TSE Yes, not specified TSE (shared)

FS 3D GE

No

No

3D TFE 2D TSE FSE FSE with FS CE FSE after gado 3D FS GE (IPH)

2D TSE, ECG gated FSE

2D TSE, ECG NA gated Yes, not 3D TOF specified MR angio

NA

No

No

No

NA

FSE

FSE shared

FSE shared

TOF

NA

2D FSE 3D TOF 3D MPRAGE 3D FFE

No

No

No

No cardiac gaiting

No

No

3D TOF MRA

NA

Albuquerque Cappendijk37 Yim121

Bitar122 Young40 Ota123

Qiao124

2008 1.5T SIGNA, GE Health care 2010 1.5T SIGNA, GE Health care 2010 3.0T SIGNA Excite, GE Health Care & Achieva,Philips 2011 3.0T Philips Health care

NA

NA Scout 3D TFE

NA

Yes, not specified TSE (shared)

Yes, not NA specified 3D NA 3D MRA NA

NA

MRI, magnetic resonance imaging; T1W, T1-weighted; T2W, T2-weighted; PDW, proton density weighted; TOF, time of flight; MOTSA, multiple overlapping thin slab angiography; NA, not available; T, Tesla; DIR, double inversion recovery; 2D, two-dimensional; CE, contrast enhancent; FS, fat suppressed; FSE, fast spin echo; 3D, three-dimensional; SHARE, shared echo-FSE ; BB, black blood; MRDTI, magnetic resonance direct thrombus imaging; GE, gradient echo; TFE, turbo field echo; TSE, turbo spin echo; IPH, intraplaque hemorrhage; MP, magnetization prepared; RAGE, rapid acquisition gradient echo; gado, gadolinium; IR, inversion recovery a TSE and FSE are comparable sequences but dependent of the manufacturer of the MRI scanner used

phd_anne.indb 140

16-5-2013 8:00:09

MRI AND CAROTID PLAQUE CHARACTERISTICS | CHAPTER 9

76% and the specificity was 86%. A higher sensitivity and specificity were achieved when only areas >2 mm2 were considered. The correlation of MRI and histology for calcification was good (R=0.74; P < 0.001). Cappendijk et al.16 used a random combination of two weightings (T1W, T2W and intermediate and partial T2W) to assess calcification and identified 100% of regions of interest. A standard examination protocol with four different weightings (TOF, T1, PDW and T2) was used by Puppini et al.17 to identify calcification. Histology identified 40 of 56 sections, whereas MRI detected them in 32 of 40.

Fibrous cap Five studies15,17,19-21 (Figure 2 and 4) reported the appearance of the intact or ruptured FC, and only one study19 stated that the MRI protocol was not suitable for detecting FC structure. Due to the limiting resolution of MRI and the (usually) thin FCs, several different methods have been evaluated. Hatsukami et al.20 used a 3D multiple overlapping thinslab angiography sequence to investigate the capability of MRI in identifying FC thickness in vivo. A thick FC appeared as a dark band between the bright lumen and grey plaque components. The absence of this dark band with a bright grey region directly adjacent to the lumen indicated a thin or ruptured FC. Despite limited case numbers and wide confidence intervals (CIs), the

141

observed sensitivity and specificity for the identification of FC rupture were promising. In 20

contrast, Albuquerque et al.19 did not find a significant association between the presence of a hyperintense MRI signal and FC thickness (P=0.38). Probably the semiquantitative analysis by histology, according to Hatsukami et al.,20 limited their results. The T1W images did not allow evaluation of FC structure, and were therefore only based on FC thickness. Cai et al.15 used TOF images to determine whether FC was thick (>0.25 mm) or ruptured. The analysis used a modified AHA classification that differentiated ruptured from intact FC.32,33 The modified AHA class IV/V indicates a thick or thin intact FC, whereas AHA class VI indicates FC rupture. Mitsumori et al.21 evaluated the accuracy of in vivo multisequence MRI in identifying the unstable FC. A strong relation was found between the presence and the intactness of the FC. For identification of unstable FC in vivo, good sensitivity (81%) and specificity (90%) were found.

IPH This characteristic was mostly positively associated with imaging profiles. However, between all studies there was no consistency in protocols used. Thirteen studies (Figure 2 and 5) investigated the presence of IPH in the carotid plaque in patients with carotid artery stenosis documented by 1.5-T MRI.15-19,22-29 Two studies used a 3.0-T MRI in identifying IPH.26,27 IPH is often diffuse and located in the LRNC, making it difficult to distinguish between these two.

phd_anne.indb 141

16-5-2013 8:00:09

Figure 2a. Forest plots showing sensitivity (all plaque characteristics)*

142

Study Sensitivity Hatsukami et al. FC rupture 89 Yuan et al. IPH & LRNC 85 Yuan et al. LRNC 98 Cai et al. Type lV/V 84 Cai et al. Type Vl 82 Cai et al. Type Vll 80 Mitsumori et al. Unstable FC 81 Moody et al. IPH Type Vl 84 Chu et al. IPH Reader 1 95 Chu et al. IPH Reader 2 85 Chu et al. IPH Overall 90 Kampschulte et al. Any hemorrhage 96 Kampschulte et al. JLH/T 88 Cappendijk et al. 2005 Qualitative IPH and/or LRNC 93 Cappendijk et al. 2005 Semiquantative IPH and/or LRNC 76 Puppini et al. Calcification 80 Puppini et al. IPH 92 Puppini et al. LRNC 92 Albuquerque et al. IPH 96 Cappendijk et al. 2008 LRNC Single sequence* 77 Cappendijk et al. 2008 LRNC Multi sequence* 84 Yim et al. IPH Halo alone 90 Yim et al. IPH Multisequence 93 Bitar et al. IPH Reader 1 100 Bitar et al. IPH Reader 2 94 Young et al. LRNC 86 Ota et al. IPH Overall RAGE 47 Ota et al. IPH Overall TOF 35 Ota et al. IPH Overall FSE 47 Ota et al. RAGE (IPH>2.81mm2) 66 46 Ota et al. TOF (IPH>2.81mm2) 59 Ota et al. FSE (IPH>2.81mm2) 79 Qiao et al. IPH TOF Reader 1 79 Qiao et al. IPH TOF Reader 1 90 Qiao et al. IPH CE-MASK Reader 1 84 Qiao et al. IPH CE-MASK Reader 2

CI [52;100] [74;92] [88;100] [72;92] [72;89] [66;91] [63;93] [70;93] [90;98] [78;90] [86;93] [91;98] [73;96] [77;99] [56;90] [64;91] [62;100] [78;98] [85;99] [61;88] [69;93] [77;97] [81;99] [84;100] [79;99] [57;98] [37;58] [26;45] [37;58] [52;77] [33;59] [46;71] [67;89] [67;89] [80;96] [73;92]

76 84 82 87 92 95 93 97 79

[NA;NA] [NA;NA] [NA;NA] [NA;NA] [NA;NA] [NA;NA] [NA;NA] [NA;NA] [NA;NA]

Saam et al. Calcification All areas Saam et al. Calcification Areas >2mm2 Saam et al. IPH All areas Saam et al. IPH Areas >2mm2 Saam et al. LRNC All areas Saam et al. LRNC Areas >2mm2 Yim et al. IPH Combined Bitar et al. IPH Mean (both readers) Qiao et al. Mean IPH

30

40

50

60

70

80

90 100

Sensitivity (%) FC, fibrous cap; IPH, intraplaque hemorrhage; LRNC, lipid rich necrotic core, JLH/T, juxtaluminal hemorrhage/thrombus; RAGE, rapid acquisition gradient echo; TOF, time of flight; FSE, fast spin echo. *Calculation of forest plots not statistically possible for all studies (e.g. Saam, Yim (combined), Bitar (mean), Qiao (mean)).

phd_anne.indb 142

16-5-2013 8:00:09

MRI AND CAROTID PLAQUE CHARACTERISTICS | CHAPTER 9

Figure 2b. Forest plots showing specificity (all plaque characteristics)* Study Specifity Hatsukami et al. FC rupture 96 Yuan et al. IPH & LRNC 92 Yuan et al. LRNC 100 Cai et al. Type lV/V 90 Cai et al. Type Vl 91 Cai et al. Type Vll 94 Mitsumori et al. Unstable FC 90 Moody et al. IPH Type Vl 84 Chu et al. IPH Reader 1 77 Chu et al. IPH Reader 2 70 Chu et al. IPH Overall 74 Kampschulte et al. Any hemorrhage 82 Kampschulte et al. JLH/T 98 Cappendijk et al. 2005 Qualitative IPH and/or LRNC 96 Cappendijk et al. 2005 Semiquantative IPH and/or LRNC 100 Puppini et al. Calcification 94 Puppini et al. IPH 100 Puppini et al. LRNC 95 Albuquerque et al. IPH 96 Cappendijk et al. 2008 LRNC Single sequence* 71 Cappendijk et al. 2008 LRNC Multi sequence* 29 Yim et al. IPH Halo alone 84 Yim et al. IPH Multisequence 85 Bitar et al. IPH Reader 1 80 Bitar et al. IPH Reader 2 88 Young et al. LRNC 40 Ota et al. IPH Overall RAGE 97 Ota et al. IPH Overall TOF 96 Ota et al. IPH Overall FSE 92 Ota et al. RAGE (IPH>2.81mm2) 97 96 Ota et al. TOF (IPH>2.81mm2) 92 Ota et al. FSE (IPH>2.81mm2) 86 Qiao et al. IPH TOF Reader 1 88 Qiao et al. IPH TOF Reader 1 98 Qiao et al. IPH CE-MASK Reader 1 100 Qiao et al. IPH CE-MASK Reader 2

CI [81;100] [73;99] [87;100] [85;94] [86;95] [89;97] [79;96] [60;97] [62;89] [55;83] [63;83] [69;91] [94;100] [86;100] [90;100] [70;100] [88;100] [74;100] [79;100] [29;96] [4;71] [75;91] [76;92] [69;89] [78,95] [5;85] [93,99] [91;98] [86,96] [93,99] [91;98] [86;96] [77;93] [78;94] [91;100] [93;100]

86 91 77 84 65 76 88 84 87

[NA;NA] [NA;NA] [NA;NA] [NA;NA] [NA;NA] [NA;NA] [NA;NA] [NA;NA] [NA;NA]

Saam et al. Calcification All areas Saam et al. Calcification Areas >2mm2 Saam et al. IPH All areas Saam et al. IPH Areas >2mm2 Saam et al. LRNC All areas Saam et al. LRNC Areas >2mm2 Yim et al. IPH Combined Bitar et al. IPH Mean (both readers) Qiao et al. Mean IPH

143

10 20 30 40 50 60 70 80 90 100

Specifity (%) FC, fibrous cap; IPH, intraplaque hemorrhage; LRNC, lipid rich necrotic core, JLH/T, juxtaluminal hemorrhage/thrombus; RAGE, rapid acquisition gradient echo; TOF, time of flight; FSE, fast spin echo. *Calculation of forest plots not statistically possible for all studies (e.g. Saam, Yim (combined), Bitar (mean), Qiao (mean)).

phd_anne.indb 143

16-5-2013 8:00:09

Several studies report the use of multicontrast MRI to solve this problem. Yuan et al.29 used a TOF sequence combined with a T1W sequence in which the IPH and LRNC were both seen as hyperintense, whereas on the TOF images, IPH was hyperintense while the LRNC was isointense.29 Because only 16 patients showed isolated IPH, no accurate assessment of MRI for IPH alone could be made. More authors studied the combined detection method of TOF and T1W sequences, sometimes with addition of T2W and PDW sequences.15,17,18,23,24,27,28,31 Chu et al.23 subdivided IPH into fresh (6 weeks) haemorrhage. To distinguish between the different stages, they used all contrast weightings. In fresh haemorrhage, the IPH was hyperintense on T1W and TOF images and hypointense or isointense on T2W and PDW images. Recent IPH was hyperintense on all contrast weightings and old IPH was hypointense on all contrast weightings. Furthermore, Saam et al.18 identified a moderate-to-strong correlation between MRI and histology (R=0.66, P2mm2 0

10

20

30

CI [66;91] [64;91]

76 [NA;NA] 84 [NA;NA] 40

50

60

70

80

90

100

90

100

Sensitivity (%)

Figure 3b. Forest plot showing specificity of calcification* Study Cai et al. Type Vll Puppini et al. Calcification

Specifity CI 94 [89;97] 94 [70;100]

Saam et al. Calcification All areas Saam et al. Calcification Areas >2mm2 0

10

20

30

86 [NA;NA] 91 [NA;NA] 40

50

60

70

80

Specifity (%) *Calculation of forest plots not statistically possible for all studies (e.g. Saam, Cappendijk 2005).

145

Figure 4a. Forest plot showing sensitivity of FC* Study Hatsukami et al. FC rupture Cai et al. Type lV/V Cai et al. Type Vl Mitsumori et al. Unstable FC

Sensitivity CI 89 [52;100] 84 [72;92] 82 [72;89] 81 [63;93]

0

10

20

30

40

50

60

70

80

90

100

Sensitivity (%)

Figure 4b. Forest plot showing specificity of FC* Study Hatsukami et al. FC rupture Cai et al. Type lV/V Cai et al. Type Vl Mitsumori et al. Unstable FC

20

30

40

Specifity CI 96 [81;100] 90 [85;94] 91 [86;95] 90 [79;96]

50

60

70

80

90

100

Specifity (%) *Calculation of forest plots not statistically possible for all studies (e.g. Puppini, Albuquerque).

phd_anne.indb 145

16-5-2013 8:00:10

Figure 5a. Forest plot showing sensitivity of IPH*

146

Study Sensitivity 85 Yuan et al. IPH & LRNC Cai et al. Type Vl 82 84 Moody et al. IPH Type Vl Chu et al. IPH Reader 1 95 85 Chu et al. IPH Reader 2 Chu et al. IPH Overall 90 96 Kampschulte et al. Any hemorrhage 88 Kampschulte et al. JLH/T 93 Cappendijk et al. 2005 Qualitative IPH and/or LRNC 76 Cappendijk et al. 2005 Semiquantative IPH and/or LRNC 92 Puppini et al. IPH 96 Albuquerque et al. IPH 90 Yim et al. IPH Halo alone 93 Yim et al. IPH Multisequence 100 Bitar et al. IPH Reader 1 94 Bitar et al. IPH Reader 2 47 Ota et al. IPH Overall RAGE 35 Ota et al. IPH Overall TOF 47 Ota et al. IPH Overall FSE 66 Ota et al. RAGE (IPH>2.81mm2) 46 Ota et al. TOF (IPH>2.81mm2) 59 Ota et al. FSE (IPH>2.81mm2) 79 Qiao et al. IPH TOF Reader 1 79 Qiao et al. IPH TOF Reader 1 90 Qiao et al. IPH CE-MASK Reader 1 84 Qiao et al. IPH CE-MASK Reader 2

CI [74;92] [72;89] [70;93] [90;98] [78;90] [86;93] [91;98] [73;96] [77;99] [56;90] [62;100] [85;99] [77;97] [81;99] [84;100] [79;99] [37;58] [26;45] [37;58] [52;77] [33;59] [46;71] [67;89] [67;89] [80;96] [73;92]

82 87 93 97 79

[NA;NA] [NA;NA] [NA;NA] [NA;NA] [NA;NA]

Saam et al. IPH All areas Saam et al. IPH Areas >2mm2 Yim et al. IPH Combined Bitar et al. IPH Mean (both readers) Qiao et al. Mean IPH

0

10

20

30

40

50

60

70

80

90 100

Sensitivity (%)

*Calculation of forest plots not statistically possible for all studies (e.g. Saam, Yim (combined), Bitar (mean), Qiao (mean)).

phd_anne.indb 146

16-5-2013 8:00:10

MRI AND CAROTID PLAQUE CHARACTERISTICS | CHAPTER 9

Figure 5b. Forest plot showing specificity of IPH*

Study Specifity 92 Yuan et al. IPH & LRNC Cai et al. Type Vl 91 84 Moody et al. IPH Type Vl Chu et al. IPH Reader 1 77 70 Chu et al. IPH Reader 2 Chu et al. IPH Overall 74 82 Kampschulte et al. Any hemorrhage 98 Kampschulte et al. JLH/T 96 Cappendijk et al. 2005 Qualitative IPH and/or LRNC Cappendijk et al. 2005 Semiquantative IPH and/or LRNC 100 100 Puppini et al. IPH 96 Albuquerque et al. IPH 84 Yim et al. IPH Halo alone 85 Yim et al. IPH Multisequence 80 Bitar et al. IPH Reader 1 88 Bitar et al. IPH Reader 2 97 Ota et al. IPH Overall RAGE 96 Ota et al. IPH Overall TOF 92 Ota et al. IPH Overall FSE 97 Ota et al. RAGE (IPH>2.81mm2) 96 Ota et al. TOF (IPH>2.81mm2) 92 Ota et al. FSE (IPH>2.81mm2) 86 Qiao et al. IPH TOF Reader 1 88 Qiao et al. IPH TOF Reader 1 98 Qiao et al. IPH CE-MASK Reader 1 100 Qiao et al. IPH CE-MASK Reader 2

CI [73;99] [86;95] [60;97] [62;89] [55;83] [63;83] [69;91] [94;100] [86;100] [90;100] [88;100] [79;100] [75;91] [76;92] [69;89] [78;95] [93;99] [91;98] [86;96] [93;99] [91;98] [86;96] [77;93] [78;94] [91;100] [93;100]

77 84 88 84 87

[NA;NA] [NA;NA] [NA;NA] [NA;NA] [NA;NA]

30

40

Saam et al. IPH All areas Saam et al. IPH Areas >2mm2 Yim et al. IPH Combined Bitar et al. IPH Mean (both readers) Qiao et al. Mean IPH

0

10

20

50

147

60

60

80

90

100

Specifity (%)

*Calculation of forest plots not statistically possible for all studies (e.g. Saam, Yim (combined), Bitar (mean), Qiao (mean)).

phd_anne.indb 147

16-5-2013 8:00:10

LRNC appeared hyperintense on the T1W scans and isointense on the TOF scans. Saam et al. used comparable sequences when considering LRNC areas >2 mm2, and the sensitivity and the specificity increased, with a good correlation between MRI and histology (R=0.75, P2 mm2

LRNC alone

IPHTOF Reader 1 IPHTOF Reader 2 IPHCE-MASK Reader 1 CE-MASK Reader 2 Mean

IPH RAGE IPH TOF IPH FSE RAGE (IPH>2.81 mm2) FSE (IPH>2.81 mm2) TOF (IPH>2.81 mm2)

IPHReader 1 IPHReader 2 Mean measures

IPHHalo alone IPHMultisequence IPHCombined

IPH

IPH alone

IPH All areas IPH Areas >2 mm2

NS

ĸ=0.85

NS

ĸ=0.73 (0.62-0.82)

ĸ=0.98 (0.93-100)

ĸ intra: 0.84 (0.73-0.95) ĸ inter: 0.77 (0.67-0.88) ĸ intra: 0.94 (0.87-1.0) ĸ inter: 0.91 (0.84-0.98)

0.53 (0.68 >3pixels) 0.33 0.42 0.80 0.63 0.57

0.73 (0.59-0.86) 0.77 (0.64-0.91) 0.75

0.76 (0.51-0.89) 0.79 (0.60-0.95) 0.78 (0.55-0.90)

ĸ=0.91 (0.81-1.00)

ĸ=0.95

ĸ=0.71 (0.61-0.80)

RAGE, rapid acquisition gradient echo; TOF, time of flight; FSE, fast spin echo; IPH, intraplaque hemorrhage; FC, fibrous cap; LRNC, lipid-rich-necrotic-core; T1W, T1-weighted; PDW, proton density weighted; T2W, T2-weighted

Young

18

2001

Yuan35

LRNC

155

Puppini

2006

40

2005

Albuquerque19

Saam154

MRI AND CAROTID PLAQUE CHARACTERISTICS | CHAPTER 9

153

16-5-2013 8:00:11

these two components. For example, one study showed that the presence of both these components indicated a higher risk for plaque vulnerability and therefore might result in more clinical events.42 On the other hand, in a larger cohort, Hellings et al.9 showed that patients with plaque haemorrhage or marked intraplaque vessel formation demonstrated an increased risk of a vascular event in follow-up, in contrast to large lipid-core presence, which was not associated with clinical outcome. Due to these conflicting results in the literature and their supposed clinical impact, we believe it might be valuable to study and distinguish these two components more precisely with MRI. Imaging of thrombus and microvessels needs to be improved to establish imaging of plaque composition more precisely and thereby predict the more hazardous plaque. Thrombus is still merely investigated in concordance with the IPH component.43 Unfortunately in our literature search, we were not able to identify hrMRI studies specifically focussing on thrombus or microvessels that used histology as a reference. Possibly ultrasmall superparamagnetic iron oxide contrast agent (USPIO)-enhanced MRI might be valuable in imaging vascularity or plaque inflammation in vivo.44 Currently this technique is subject of research, but did not fit the scope of our review. To take MR plaque characterisation out of the realm of pure research and into the realm of clinical utility, an algorithm or grading

154

scale would be helpful. Unfortunately, this review shows the multitude of available studies and thereby the lack of comparable studies on the accuracy of MRI in detecting major plaque characteristics. Large studies with corresponding methods to accurately identify MRI as a valuable tool are needed. Comparable sequences and clearly described definitions of these sequences must be investigated. Performed histology protocols need to be validated and comparable. These steps and the interpretation of in vivo MRI always in relation to ex vivo histology will lead to definite use of MRI in the clinical setting.

Limitations Our study has a few limitations. First, we chose in vivo imaging for the scope of this review. For ex vivo imaging, the radiofrequency coil is placed very close to the plaque, creating higher signal intensities and is performed without blood flow and the possibility of swallowing; therefore, no triggering is needed and no flow artefacts are seen. However, we believe in vivo imaging reflects the most realistic clinical setting. Second, we believe it is essential to use histology as reference test to make conclusions on the clinical application of MRI more valuable. Studies that perform histology can report their findings in diagnostic outcome parameters, making it possible to compare and extrapolate to the clinical setting. By retaining these conditions, many studies on MRI had to be excluded. These excluded studies might however still be valuable for contributing to the development in MRI research despite not

phd_anne.indb 154

16-5-2013 8:00:11

MRI AND CAROTID PLAQUE CHARACTERISTICS | CHAPTER 9

fulfilling our inclusion criteria. Furthermore, plaque composition, which may predict future events, and degree of stenosis must both be part of decision for a specific treatment. For example, the presence of IPH in all categories of stenosis and plaque burden suggests that direct characterisation of plaque composition and surface status is necessary to fully discriminate disease severity.45 Therefore, the identification of vulnerable plaque characteristics in combination with degree of carotid stenosis might be the most valuable. In our opinion, for a good comparison, it is necessary that authors use predefined histologic analysis and MR sequences in studies investigating accuracy of MRI in patients with carotid artery stenosis. This corresponds with an earlier review of Lovett et al.46 Our review found incomparable or poorly reported histologic or imaging protocols, creating a potential interpretational error. To standardise future reporting, it is advisable to use comparison with a validated histologic protocol. Moreover, the variety of methods in all included studies and the multitude of plaque characteristics we investigated in this review sometimes make it difficult to state all the detailed information. Despite these limitations, we believe it is still valuable to provide this overview of articles summarising the current state of MRI clinically. Besides, this review may serve as a ‘wake-up call’ for all investigators to use standardized imaging and histology protocols to allow comparison and pooling of studies investigating the diagnostic accuracy of

155

MRI in identifying carotid plaque characteristics.

Future perspectives This current review contributes to the knowledge of in vivo carotid MRI and comparison with histology for identification of the ‘vulnerable’ plaque. Future research concerning carotid artery imaging should benefit by the use of predefined, validated histologic and imaging protocols to make clinical interpretation more reliable. Furthermore, application of 3.0-T MRI and even advanced 7.0-T MRI will possibly further boost the non-invasive identification of more hazardous and complicated plaques.47

phd_anne.indb 155

16-5-2013 8:00:11

Figure 6a. Forest plot showing sensitivity of LRNC*.

Study Sensitivity Yuan et al. IPH & LRNC 85 Yuan et al. LRNC 98 Cappendijk et al. 2005 Qualitative IPH and/or LRNC 93 Cappendijk et al. 2005 Semiquantative IPH and/or LRNC 76 Puppini et al. LRNC 92 Cappendijk et al. 2008 LRNC Single sequence* 77 Cappendijk et al. 2008 LRNC Multi sequence* 84 Young et al. LRNC 86

CI [74;92] [88;100] [77;99] [56;90] [78;98] [61;88] [69;93] [57;98]

Saam et al. LRNC All areas Saam et al. LRNC Areas >2mm2

[NA;NA] [NA;NA]

92 95

0

10

20

30

40

50

60

70

80

90

100

Sensitivity (%)

156 Figure 6b. Forest plot showing specificity of LRNC*

Study Specifity Yuan et al. IPH & LRNC 92 Yuan et al. LRNC 100 Cappendijk et al. 2005 Qualitative IPH and/or LRNC 96 Cappendijk et al. 2005 Semiquantative IPH and/or LRNC 100 Puppini et al. LRNC 95 Cappendijk et al. 2008 LRNC Single sequence* 71 Cappendijk et al. 2008 LRNC Multi sequence* 29 Young et al. LRNC 40

CI [73;99] [87;100] [86;100] [90;100] [74;100] [29;96] [4;71] [5;85]

Saam et al. LRNC All areas Saam et al. LRNC Areas >2mm2

[NA;NA] [NA;NA]

65 76

0 10 20 30 40 50 60 70 80 90 100

Specifity (%) *Calculation of forest plots not statistically possible for all studies (Saam).

phd_anne.indb 156

16-5-2013 8:00:11

MRI AND CAROTID PLAQUE CHARACTERISTICS | CHAPTER 9

CONCLUSION In vivo carotid plaque morphology imaging using MRI demonstrates good agreement with ex vivo histological analysis of specific plaque components. Therefore, MRI might be valuable in diagnostic work-up of patients with carotid artery stenosis in addition to stenosis grade. However, although MRI still holds a promise, clinical application for plaque characterisation would require consensus regarding MRI settings. For this reason and based on current literature, it may be too early to routinely apply MRI as a diagnostic imaging modality to assess plaque characteristics that have been associated with plaque vulnerability. Predefined protocols for histology and imaging must be established to make outcomes more comparable and clinically useful.

ACKNOWLEDGEMENTS The authors would like to thank Iris C.R.M. Kolder (Wellcome Trust Sanger Institute Cambridge) for assistance in providing the figures.

157

CONFLICT OF INTEREST S.M. Bovens’ work was funded by the Netherlands Heart Foundation (2006T106 to SB).

phd_anne.indb 157

16-5-2013 8:00:11

REFERENCES 1. 2.

158

Randomised trial of endarterectomy for recently symptomatic carotid stenosis: final results of the MRC European Carotid Surgery Trial (ECST). Lancet 1998; 351:1379-1387. Barnett HJ, Taylor DW, Eliasziw M et al. Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis. N Engl J Med 1998; 3 39:1415-1425. 3. Endarterectomy for asymptomatic carotid artery stenosis. Executive Committee for the Asymptomatic Carotid Atherosclerosis Study. JAMA 1995; 273:1421-1428. 4. Halliday A, Harrison M, Hayter E et al. 10-year stroke prevention after successful carotid endarterectomy for asymptomatic stenosis (ACST-1): a multicentre randomised trial. Lancet 2010; 376:1074-1084. 5. Rothwell PM, Eliasziw M, Gutnikov SA et al. Analysis of pooled data from the randomised controlled trials of endarterectomy for symptomatic carotid stenosis. Lancet 2003; 361:107-116. 6. Dawkins AA, Evans AL, Wattam J et al. Complications of cerebral angiography: a prospective analysis of 2,924 consecutive procedures. Neuroradiology 2007; 49:753-759. 7. Rothwell PM, Gibson R, Warlow CP. Interrelation between plaque surface morphology and degree of stenosis on carotid angiograms and the risk of ischemic stroke in patients with symptomatic carotid stenosis. On behalf of the European Carotid Surgery Trialists' Collaborative Group. Stroke 2000; 31:615-621. 8. Verhoeven B, Hellings WE, Moll FL et al. Carotid atherosclerotic plaques in patients with transient ischemic attacks and stroke have unstable characteristics compared with plaques in asymptomatic and amaurosis fugax patients. J Vasc Surg 2005; 42:1075-1081. 9. Hellings WE, Peeters W, Moll FL et al. Composition of carotid atherosclerotic plaque is associated with cardiovascular outcome: a prognostic study. Circulation 2010; 121:1941-1950. 10. Naghavi M, Libby P, Falk E et al. From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part I. Circulation 2003; 108:1664-1672. 11. Hermus L, van Dam GM, Zeebregts CJ. Advanced carotid plaque imaging. Eur J Vasc Endovasc Surg 2010; 39:125-133. 12. Yuan C, Mitsumori LM, Beach KW et al. Carotid atherosclerotic plaque: noninvasive MR characterization and identification of vulnerable lesions. Radiology 2001; 221:285-299. 13. Liberati A, Altman DG, Tetzlaff J et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ 2009; 339:b2700. 14. Whiting P, Rutjes AW, Reitsma JB et al. The development of QUADAS: a tool for the quality assessment of studies of diagnostic accuracy included in systematic reviews. BMC Med Res Methodol 2003; 3:25. 15. Cai JM, Hatsukami TS, Ferguson MS et al. Classification of human carotid atherosclerotic lesions with in vivo multicontrast magnetic resonance imaging. Circulation 2002; 106:1368-1373. 16. Cappendijk VC, Cleutjens KB, Kessels AG et al. Assessment of human atherosclerotic carotid plaque components with multisequence MR imaging: initial experience. Radiology 2005; 234:487-492. 17. Puppini G, Furlan F, Cirota N et al. Characterisation of carotid atherosclerotic plaque: comparison between magnetic resonance imaging and histology. Radiol Med 2006; 111:921-930. 18. Saam T, Ferguson MS, Yarnykh VL et al. Quantitative evaluation of carotid plaque composition by in vivo MRI. Arterioscler Thromb Vasc Biol 2005; 25:234-239. 19. Albuquerque LC, Narvaes LB, Maciel AA et al. Intraplaque hemorrhage assessed by high-resolution magnetic resonance imaging and C-reactive protein in carotid atherosclerosis. Journal of Vascular Surgery 2007; 46:1130-1137. 20. Hatsukami TS, Ross R, Polissar NL et al. Visualization of fibrous cap thickness and rupture in human atherosclerotic carotid plaque in vivo with high- resolution magnetic resonance imaging. Circulation 2000; 102:959-964. 21. Mitsumori LM, Hatsukami TS, Ferguson MS et al. In vivo accuracy of multisequence MR imaging for identifying unstable fibrous caps in advanced human carotid plaques. J Magn Reson Imaging 2003; 17:410-420. 22. Bitar R, Moody AR, Leung G et al. In vivo 3D high-spatial-resolution MR imaging of intraplaque hemorrhage. Radiology 2008; 249:259-267. 23. Chu B, Kampschulte A, Ferguson MS et al. Hemorrhage in the atherosclerotic carotid plaque: a high-resolution MRI study. Stroke 2004; 35:1079-1084. 24. Kampschulte A, Ferguson MS, Kerwin WS et al. Differentiation of intraplaque versus juxtaluminal hemorrhage/thrombus in advanced human carotid atherosclerotic lesions by in vivo magnetic resonance imaging. Circulation 2004; 110:3239-3244. 25. Moody AR, Murphy RE, Morgan PS et al. Characterization of complicated carotid plaque with magnetic resonance direct thrombus imaging in patients with cerebral ischemia. Circulation 2003; 107:3047-3052. 26. Ota H, Yarnykh VL, Ferguson MS et al. Carotid intraplaque hemorrhage imaging at 3.0-T MR imaging: comparison of the diagnostic performance of three T1-weighted sequences. Radiology 2010; 254:551-563. 27. Qiao Y, Etesami M, Malhotra S et al. Identification of intraplaque hemorrhage on MR angiography images: a comparison of contrast-enhanced mask and time-of-flight techniques. AJNR Am J Neuroradiol 2011; 32:454-459.

phd_anne.indb 158

16-5-2013 8:00:12

MRI AND CAROTID PLAQUE CHARACTERISTICS | CHAPTER 9

28. Yim YJ, Choe YH, Ko Y et al. High signal intensity halo around the carotid artery on maximum intensity projection images of time-of-flight MR angiography: a new sign for intraplaque hemorrhage. J Magn Reson Imaging 2008; 27:1341-1346. 29. Yuan C, Mitsumori LM, Ferguson MS et al. In vivo accuracy of multispectral magnetic resonance imaging for identifying lipid-rich necrotic cores and intraplaque hemorrhage in advanced human carotid plaques. Circulation 2001; 104:2051-2056. 30. Cappendijk VC, Kessels AGH, Heeneman S et al. Comparison of lipid-rich necrotic core size in symptomatic and asymptomatic carotid atherosclerotic plaque: Initial results. J Magn Reson Imaging 2008; 27:1356-1361. 31. Young VE, Patterson AJ, Sadat U et al. Diffusion-weighted magnetic resonance imaging for the detection of lipid-rich necrotic core in carotid atheroma in vivo. Neuroradiology 2010; 52:929-936. 32. Stary HC, Chandler AB, Dinsmore RE et al. A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis. Circulation 1995; 92:1355-1374. 33. Stary HC. Natural history and histological classification of atherosclerotic lesions: an update. Arterioscler Thromb Vasc Biol 2000; 20:1177-1178. 34. Das M, Braunschweig T, Muhlenbruch G et al. Carotid plaque analysis: comparison of dual-source computed tomography (CT) findings and histopathological correlation. Eur J Vasc Endovasc Surg 2009; 38:14-19. 35. Jahromi AS, Cina CS, Liu Y et al. Sensitivity and specificity of color duplex ultrasound measurement in the estimation of internal carotid artery stenosis: a systematic review and meta-analysis. J Vasc Surg 2005; 41:962-972. 36. Walker LJ, Ismail A, McMeekin W et al. Computed tomography angiography for the evaluation of carotid atherosclerotic plaque: correlation with histopathology of endarterectomy specimens. Stroke 2002; 33:977-981. 37. Hatsukami TS, Yuan C. MRI in the early identification and classification of high-risk atherosclerotic carotid plaques. Imaging Med 2010; 2:63-75. 38. Watanabe Y, Nagayama M. MR plaque imaging of the carotid artery. Neuroradiology 2010; 52:253-274. 39. Yuan C, Kerwin WS. MRI of atherosclerosis. J Magn Reson Imaging 2004; 19:710-719. 40. Hayes CE, Mathis CM, Yuan C. Surface coil phased arrays for high-resolution imaging of the carotid arteries. J Magn Reson Imaging 1996; 6:109-112. 41. Cheung HM, Moody AR, Singh N et al. Late stage complicated atheroma in low-grade stenotic carotid disease: MR imaging depiction--prevalence and risk factors. Radiology 2011; 260:841-847. 42. Takaya N, Yuan C, Chu B et al. Association between carotid plaque characteristics and subsequent ischemic cerebrovascular events: a prospective assessment with MRI--initial results. Stroke 2006; 37:818-823. 43. Kerwin W, Hooker A, Spilker M et al. Quantitative magnetic resonance imaging analysis of neovasculature volume in carotid atherosclerotic plaque. Circulation 2003; 107:851-856. 44. Trivedi RA, Mallawarachi C, King-Im JM et al. Identifying inflamed carotid plaques using in vivo USPIO-enhanced MR imaging to label plaque macrophages. Arterioscler Thromb Vasc Biol 2006; 26:1601-1606. 45. Zhao X, Underhill HR, Zhao Q et al. Discriminating carotid atherosclerotic lesion severity by luminal stenosis and plaque burden: a comparison utilizing high-resolution magnetic resonance imaging at 3.0 Tesla. Stroke 2011; 42:347-353. 46. Lovett JK, Redgrave JN, Rothwell PM. A critical appraisal of the performance, reporting, and interpretation of studies comparing carotid plaque imaging with histology. Stroke 2005; 36:1091-1097. 47. den Hartog AG, Bovens SM, Koning W et al. PLACD-7T Study: Atherosclerotic Carotid Plaque Components Correlated with Cerebral Damage at 7 Tesla Magnetic Resonance Imaging. Curr Cardiol Rev 2011; 7:28-34.

phd_anne.indb 159

159

16-5-2013 8:00:12

phd_anne.indb 160

16-5-2013 8:00:13

PART lll | IMAGING OF CAROTID ARTERY STENOSIS

CHAPTER 10 PLACD-7T Study: Atherosclerotic Carotid Plaque Components Correlated with Cerebral Damage at 7 Tesla Magnetic Resonance Imaging

Published in part: Current Cardiology Reviews. 2011 Feb;7(1):28-34.

A.G. den Hartog1* S.M. Bovens2,3* W. Koning4 F.L. Moll1 J. Hendrikse4 G. Pasterkamp2 G.J. de Borst1

Department of Vascular Surgery, University Medical Center Utrecht, Utrecht, The Netherlands Experimental Cardiology Laboratory, University Medical Center Utrecht, Utrecht, The Netherlands 3 Netherlands Heart Institute (ICIN), Utrecht, The Netherlands 4 Department of Radiology, University Medical Center Utrecht, Utrecht, The Netherlands

1

2

*These authors equally contributed to this study.

phd_anne.indb 161

16-5-2013 8:00:13

ABSTRACT Introduction In patients with carotid artery stenosis plaque composition is associated with plaque stability and with presenting symptomatology. Vulnerable plaque phenotype, composed of inflammatory cell infiltrates, thin fibrous cap and intraplaque hemorrhage is related to higher event rates, due to an increased risk of rupture. Preferentially, plaque vulnerability should be taken into account in pre-operative work-up of patients with severe carotid artery stenosis, to stratify high and low risk plaques and their chance to cause events. However, currently no appropriate and conclusive (non-)invasive technique to differentiate between the high and low risk carotid artery plaque in vivo is available. We propose that 7 Tesla human high resolution MRI scanning will visualize carotid plaque characteristics more precisely and will enable correlation of these specific components with cerebral damage.

Study objective 162

The aim of the PlaCD-7T study is to correlate 7T imaging with carotid plaque histology (gold standard). In addition, we correlated plaque characteristics with cerebral damage, reflected by clinically silent cerebral (micro) infarcts or bleeds, on 7 Tesla high resolution (HR) MRI.

Design We propose a single center prospective study for either symptomatic or asymptomatic patients with haemodynamic significant (≥70%) stenosis of at least one of the carotid arteries. The Athero-Express (AE) biobank histological analysis will be derived according to standard protocol. Patients who are included undergo a pre-operative 7 Tesla HR-MRI scan of both the head and neck area.

Preliminary results In this ongoing study, we were able to visualize the plaques in the T2w images in the first included patients. T1w (FLAIR) brain images clearly depicted infarcted areas. Quantitative and semi-quantitative analysis have not been performed yet. Histology showed visualization of several plaque components, such as lipid-rich necrotic core (LRNC), collagen, calcifications, and thrombus. Correlation studies of histology and MR images have to be performed to evaluate the value of 7 Tesla MR imaging of atherosclerotic lesion.

phd_anne.indb 162

16-5-2013 8:00:13

PLACD-7T PROTOCOL | CHAPTER 10

Discussion We hypothesize that the 7 Tesla MRI scanner will allow early identification of high risk carotid plaques being associated with micro infarcted cerebral areas, and will thus be able to identify patients with a high risk of peri-procedural stroke, by identification of surrogate measures of increased cardiovascular risk.

163

phd_anne.indb 163

16-5-2013 8:00:14

INTRODUCTION Ipsilateral carotid stenosis of 50% or more is found in approximately 10% of carotid territory ischemic strokes and approximately 15% of transient ischemic attacks (TIAs). Additionally, it is associated with a high risk of recurrent stroke.1,2 Current treatment of symptomatic patients with carotid stenosis is based on stenosis grade alone, where stenosis ≥70% is an indication for carotid endarterectomy (CEA). Plaque morphology is not yet included in this clinical decision, although it plays an important role as it is found to be directly correlated with the risk of embolism and progression to occlusion, thus resulting in cerebral ischaemia.3 Patients with a stenosis 80% of the carotid artery and planned to be scheduled for a CEA will be eligible for inclusion in this study as well. Pre-operative (~1 day) the included patients are scheduled for an MRI scan of the brain and carotid artery in the 7 Tesla MRI scanner. Anatomical scans of the brain are evaluated for the presence of cerebral damage. In the carotid artery, MRI images with several contrast weightings are acquired for plaque visualization and characterization. A contrast agent (gadolinium (Gadovist®)) will be injected to assess neovascularisation, intraplaque hemorrhage and inflammation, In future patients, after the correct sequences have been evaluated. The investigation takes approximately 75 minutes. Images are stored and during off line analyses the bifurcation of the carotid artery is used as an anatomical landmark.

Patient Population All indications for surgery are reviewed by a multidisciplinary vascular team.10 All patients are examined by a neurologist pre-operatively and postoperatively to document cerebrovascular symptom status and to record any new neurological deficits after CEA. Percentage stenosis

phd_anne.indb 167

16-5-2013 8:00:14

of both carotid arteries is recorded with duplex ultrasound pre-operatively following internationally accepted guidelines.28 A flowchart of the study protocol is shown in Figure 2. Baseline characteristics of included patients is collected by the AE investigators and include standard baseline characteristics together with known risk factors of cardiovascular disease. It is important to state that besides one MRI scan, patients receive the regular work-up, treatment, and follow-up according to the current guidelines for treatment of carotid artery disease.

Figure 1. Imaging examples of the carotid artery on 7 Tesla MRI in a healthy individual, acquired with a 4 channel tranceive coil (Machnet B.V., Eelde, The Netherlands).Athero-Express

168

Biobank AE is an ongoing longitudinal study that includes patients undergoing CEA. The study design has been reported earlier.10 In our study gold standard for plaque characterization is the histopathological analysis of the removed carotid artery plaque according to the standardized AE protocol. The segment with the largest plaque burden (the culprit lesion) is located and fixated in formalin for histological analysis. This analysis is routinely performed and intraand inter-observer analyses are excellent and have been reported in international literature previously.29 After surgery, the patients undergo normal clinical follow-up with duplex to assess procedural restenosis and to fill out questionnaires addressing the occurrence of relevant cardiovascular symptoms. All patients undergoing CEA in one participating center (University Medical Center Utrecht) are asked to participate in this study. The medical ethics

phd_anne.indb 168

16-5-2013 8:00:14

PLACD-7T PROTOCOL | CHAPTER 10

board of the University Medical Center Utrecht approved the study, and all participants of this study must provide written informed consent.

Figure 2. Simplified flowchart of study protocol Patients eligible for CEA (symptomatic & asymptomatic)

Inclusion in Athero-Express (AE) study

30 Patients participating in PlaCD-7T

Patients not participating in PlaCD-7T

Normal AE protocol

Inclusion in PlaCD-7T

169 30 patients pre-operative 7T MRI (75 minutes) with:  

Plaque imaging Brain scans

CEA (mostly on Thursdays)  

Peri-operative TCD Plaque removal  histology

Analysis of all results

   

Scan protocol The total MRI examination including MR plaque imaging and anatomical MRI of the brain takes approximately 75 minutes. (Figure 3) A dedicated RF coil is used for imaging of the carotid bifurcation. This coil allows for sub-millimeter resolution imaging of the carotid lumen, vessel wall and atherosclerotic plaque. First, the carotid bifurcation is identified by means

phd_anne.indb 169

16-5-2013 8:00:14

of

MR

material

angiography

without

enhancement.

contrast

Figure 3. Procedural set-up in 7 Tesla scanner

Subsequently,

several transverse images are obtained from several millimeters caudal to several millimeters cranial of the carotid bifurcation, imaging the complete plaque. This area is imaged using specific sequences to obtain different contrast weightings for optimal discrimination of plaque components. Next, post-contrast images after intravenous injection of gadolinium will be obtained, in future patients, when the sequences are

evaluated.

Additionally,

anatomical

MR brain imaging of cerebral damage is performed; 3D FLAIR and T2w images are acquired using the head coil. Two MRI readers blinded to the histo-pathological results and

170

clinical data score the MRI plaque status independently.

Carotid Endarterectomy Pre-operatively, patients start with aspirin, except those patients taking already oral anticoagulants for other indications. For these patients dipyridamol 2dd200mg is be added. Patients with aspirin intolerance receive plavix 75mg. Before exposure of the carotid artery, patients receive 5000 U of heparin intravenously. With the use of a standardized CEA technique, the plaque is carefully dissected and removed in toto, without procedure-related complications. Immediately after dissection, the plaque will is transferred to the laboratory.

Histology The atherosclerotic plaque is first decalcified in an EDTA solution (2 weeks), sliced at several loci, embedded in paraffin, and stained for presence of collagen (Sirius red), macrophages (CD68), smooth muscle cells (α-actin), lipid, thrombus and endothelium (CD34, microvessels or neovasculature). This analysis is routinely performed and intra- and inter-observer analyses are excellent and have been reported in international literature previously.29 Histology is assessed by an experienced pathologist blinded to the MRI results.

phd_anne.indb 170

16-5-2013 8:00:14

PLACD-7T PROTOCOL | CHAPTER 10

Figure 4. Imaging examples of an atherosclerotic plaque (T2W) in a patient.

171

phd_anne.indb 171

16-5-2013 8:00:14

Sample size In a previous study we observed a >100% increase in peri-operative stroke when a lipid rich plaque was obtained compared to plaques that were fibrous.3 A major endpoint was reached in 9% when a lipid rich lesion was evident but 2.5% when a fibrous lesion was present. We expect to observe cerebral micro-infarcted areas in 33% of the patients. This data is based on the article of Verhoeven et al.10 In this study TCD was used to measure micro embolism. In 27% of the patients an event was registered before or during surgery. We expect the 7 Tesla system to be sensitive enough to find micro infarcts as a result of micro embolism. The power analysis is based on the calculation of the differences between two groups of a continuous variable. A 3-fold detection increase from 1 to 3 micro embolisms or 1 versus 3 micro infarcts with an SD of 2, an α of 0.05 and β of 0.80 we calculate that we will need 2 groups of 14 patients. Therefore we asked and received permission to include 30 patients. We do not expect a normal distribution.

Data analysis MR images are processed with dedicated software, with this software component size and

172

intensity on images can be calculated. Histology is semi-quantitatively scored as previously described.3,10 Cerebral damage ((clinically silent) cerebral (micro) infarcts or bleeds) are depicted as a semi-quantitative measure (no, small, major defects). Micro-embolisation are assessed as a continuous variable. The different identified plaque components are correlated with cerebral damage by calculating the regular parameters for diagnostic testing (positive predictive value, negative predictive value, sensitivity, specificity).

Ethical consideration This study has been approved by the local Medical Ethics Committee of the University Medical Center in Utrecht.

RESULTS (preliminary) So far, 15 patients have been included in this study and in all patients T1w 3D FLAIR brain scans as well as T2w/PDW carotid artery scans have been acquired. From patient 6 on, an additional T1w sequence for the carotid artery was included in the standard MR protocol. In figure 4 T2w scans of an atherosclerotic lesion in the left carotid artery are shown, figure 4A

phd_anne.indb 172

16-5-2013 8:00:14

PLACD-7T PROTOCOL | CHAPTER 10

illustrates the culprit lesion and from figure 4B to 4I the entire plaque is shown, proximal to distal. Figure 5 shows examples of 2 different patients with major (A+B) and minor (C+D) cerebral infarctions. This is an ongoing study and therefore cerebral damage has not been correlation with atherosclerotic plaque components yet.

Figure 5. Imaging examples of the brain in 2 different patients

173

phd_anne.indb 173

16-5-2013 8:00:15

DISCUSSION We present the protocol and first preliminary results of a single center, observational study to determine the relation of plaque characteristics with cerebral damage ((clinically silent) cerebral (micro) infarcts or bleeds) with 7 Tesla HR-MRI. As gold standard histology of the plaques is obtained according to the protocol of the AE biobank. The interpretation of outcome in earlier studies imaging the carotid plaque and using histology as reference standard is complicated by the differences in histology methods, difference in the magnetic field strength of the MRI scanners and in scanning protocols (sequences). In previous ex vivo studies some limitation are apparent when translation their results to in vivo MRI. First, there is no blood flow, thus no triggering is needed and no flow artifacts are seen. Additionally, artifacts caused by swallowing are also absent. Second, the RF coil is placed very close to the plaque, creating higher signal intensities compared to in vivo measurements. There are also some limitations in current in vivo MR studies, mostly performed on lower

174

field 1.5 Tesla and some on 3 Tesla scanners. First, it is difficult to discriminate between IPH and intraplaque lipid. Second, in vivo, the length of the neck and depth of the carotid artery are main determinants of image quality. Some sequences, which can give excellent contrast between components ex vivo, are not applicable in vivo, due to timing of the sequence or due to limited total scan time of the patient. Third, there are currently several studies performed, however, it is difficult to draw conclusions of all these studies together, mainly due to differences in MRI and histology protocols. Some of these limitation will still stand, however, we believe the 7 Tesla MR scanner has some distinct advantages compared to the lower field scanners. First, is has been shown that the 7 Tesla has superior brain imaging.25 Second, the possibility to increase the resolution when imaging the atherosclerotic plaque might reveal structures that are hidden by partial volume effects. Third, a higher sensitivity for certain contrast mechanisms (e.g. susceptibility weighted imaging or Ultra short TE imaging (UTE)) will possibly allow detection of plaque components that are hard to detect with lower field strengths, like IPH). Several studies have focused on the identification of atherosclerotic plaque components by means of MRI to identify patients at risk for strokes or TIAs.13,14,17-20 Components such as large lipid pools, thin fibrous caps, IPH are the main focus points due to the increased risk of plaque rupture. One of the components that is of importance and has been correlated with cardiovascular and cerebrovascular events is microvasculature in the plaque.3 However, this

phd_anne.indb 174

16-5-2013 8:00:15

PLACD-7T PROTOCOL | CHAPTER 10

component is very small (the same holds true for mild/moderate IPH) and needs an imaging modality with a high spatial resolution and anatomical detail such as the 7 Tesla scanner can provide. In addition, the 7 Tesla scanner is superior in the detection of micro-infacts and/ or bleeds in the brain.25 Combining this information with the HR-MRI of the atherosclerotic plaque, as described in this protocol, we believe this can give new insights and possibly lead to new standardized protocols for patient work-up before CEA.

CONCLUSION We hypothesize that 7 Tesla HR-MRI will allow more detailed visualization of the brain, and is expected to determine the carotid plaque components more precisely. Therefore, in our opinion, this is the right modality to correlate brain imaging with carotid plaque characteristics. The AE biobank allows us to use histology as a validated reference according to standardized Athero-Express protocol. The first patient was included on May 25th, 2011 in the University Medical Center in Utrecht.

175

TRIAL COLLABORATORS Collaborators of this study (all located in the University Medical Center Utrecht, The Netherlands) are: (in alphabetical order): G.J. de Borst, MD, PhD, vascular surgeon S.M. Bovens, MSc, PhD student A.G. den Hartog, MD, PhD student vascular surgery J. Hendrikse, MD, PhD, radiologist L.J. Kappelle MD, PhD, Professor Neurology D.J.W. Klomp, PhD, assistent professor Functional Medical Imaging W. Koning, MSc, PhD student P. Luijten, MD, PhD, Professor radiology F.L. Moll, MD, PhD, Professor vascular surgery G. Pasterkamp, MD, PhD, Professor experimental Cardiology A. Vink, MD, PhD, pathologist H.B. van der Worp, MD, PhD, neurologist

phd_anne.indb 175

16-5-2013 8:00:15

ABBREVEVIATIONS

176

CEA

carotid endarterectomy

HR

high resolution

AE

athero-express

DWI

diffusion weighted imaging

IPH

intra-plaque haemorrhage

FLAIR

fluid attenuation inversion recovery

MRI

magnetic resonance imaging

RF

radio frequency

SMC

smooth muscle cells

SWI

susceptibility weighted imaging

T1W

T1 weighted

TCD

Trans Cranial Doppler

ACKNOWLEDGMENTS S.M. Bovens’ work was funded by the Netherlands Heart Foundation (2006T106 to SB).

phd_anne.indb 176

16-5-2013 8:00:15

PLACD-7T PROTOCOL | CHAPTER 10

REFERENCES 1.

Fairhead JF, Mehta Z, Rothwell PM. Population-based study of delays in carotid imaging and surgery and the risk of recurrent stroke. Neurology 2005; 65:371-375. 2. Lovett JK, Coull AJ, Rothwell PM. Early risk of recurrence by subtype of ischemic stroke in population-based incidence studies. Neurology 2004; 62:569-573. 3. Hellings WE, Peeters W, Moll FL et al. Composition of carotid atherosclerotic plaque is associated with cardiovascular outcome: a prognostic study. Circulation 2010; 121:1941-1950. 4. Carr S, Farb A, Pearce WH et al. Atherosclerotic plaque rupture in symptomatic carotid artery stenosis. J Vasc Surg 1996; 23:755-765. 5. Hellings WE, Pasterkamp G, Verhoeven BA et al. Gender-associated differences in plaque phenotype of patients undergoing carotid endarterectomy. J Vasc Surg 2007; 45:289-296. 6. Peeters W, Hellings WE, de Kleijn DP et al. Carotid atherosclerotic plaques stabilize after stroke: insights into the natural process of atherosclerotic plaque stabilization. Arterioscler Thromb Vasc Biol 2009; 29:128-133. 7. Redgrave JN, Lovett JK, Gallagher PJ et al. Histological assessment of 526 symptomatic carotid plaques in relation to the nature and timing of ischemic symptoms: the Oxford plaque study. Circulation 2006; 113:2320-2328. 8. van OO, Velema E, Schoneveld AH et al. Age-related changes in plaque composition: a study in patients suffering from carotid artery stenosis. Cardiovasc Pathol 2005; 14:126-134. 9. Verhoeven B, Hellings WE, Moll FL et al. Carotid atherosclerotic plaques in patients with transient ischemic attacks and stroke have unstable characteristics compared with plaques in asymptomatic and amaurosis fugax patients. J Vasc Surg 2005; 42:1075-1081. 10. Verhoeven BA, Velema E, Schoneveld AH et al. Athero-express: differential atherosclerotic plaque expression of mRNA and protein in relation to cardiovascular events and patient characteristics. Rationale and design. Eur J Epidemiol 2004; 19:1127-1133. 11. Verhoeven BA, de Vries JP, Pasterkamp G et al. Carotid atherosclerotic plaque characteristics are associated with microembolization during carotid endarterectomy and procedural outcome. Stroke 2005; 36:1735-1740. 12. Verhoeven BA, Pasterkamp G, de Vries JP et al. Closure of the arteriotomy after carotid endarterectomy: patch type is related to intraoperative microemboli and restenosis rate. J Vasc Surg 2005; 42:1082-1088. 13. Alizadeh DR, Doornbos J, Tamsma JT et al. Assessment of the carotid artery by MRI at 3T: a study on reproducibility. J Magn Reson Imaging 2007; 25:1035-1043. 14. Cappendijk VC, Cleutjens KB, Kessels AG et al. Assessment of human atherosclerotic carotid plaque components with multisequence MR imaging: initial experience. Radiology 2005; 234:487-492. 15. Clarke SE, Hammond RR, Mitchell JR et al. Quantitative assessment of carotid plaque composition using multicontrast MRI and registered histology. Magn Reson Med 2003; 50:1199-1208. 16. Fabiano S, Mancino S, Stefanini M et al. High-resolution multicontrast-weighted MR imaging from human carotid endarterectomy specimens to assess carotid plaque components. Eur Radiol 2008; 18:2912-2921. 17. Kerwin W, Xu D, Liu F et al. Magnetic resonance imaging of carotid atherosclerosis: plaque analysis. Top Magn Reson Imaging 2007; 18:371-378. 18. Moody AR, Murphy RE, Morgan PS et al. Characterization of complicated carotid plaque with magnetic resonance direct thrombus imaging in patients with cerebral ischemia. Circulation 2003; 107:3047-3052. 19. Ota H, Yu W, Underhill HR et al. Hemorrhage and large lipid-rich necrotic cores are independently associated with thin or ruptured fibrous caps: an in vivo 3T MRI study. Arterioscler Thromb Vasc Biol 2009; 29:1696-1701. 20. Yuan C, Kerwin WS, Ferguson MS et al. Contrast-enhanced high resolution MRI for atherosclerotic carotid artery tissue characterization. J Magn Reson Imaging 2002; 15:62-67. 21. te Boekhorst BC, van 't KR, Bovens SM et al. Evaluation of multicontrast MRI including fat suppression and inversion recovery spin echo for identification of intra-plaque hemorrhage and lipid core in human carotid plaque using the mahalanobis distance measure. Magn Reson Med 2012; 67:1764-1775. 22. Snyder CJ, DelaBarre L, Metzger GJ et al. Initial results of cardiac imaging at 7 Tesla. Magn Reson Med 2009; 61:517-524. 23. Zwanenburg JJ, Hendrikse J, Visser F et al. Fluid attenuated inversion recovery (FLAIR) MRI at 7.0 Tesla: comparison with 1.5 and 3.0 Tesla. Eur Radiol 2010; 20:915-922. 24. Pfeuffer J, Adriany G, Shmuel A et al. Perfusion-based high-resolution functional imaging in the human brain at 7 Tesla. Magn Reson Med 2002; 47:903-911. 25. Pfeuffer J, Van De Moortele PF, Yacoub E et al. Zoomed functional imaging in the human brain at 7 Tesla with simultaneous high spatial and high temporal resolution. Neuroimage 2002; 17:272-286. 26. Vaughan JT, Garwood M, Collins CM et al. 7T vs. 4T: RF power, homogeneity, and signal-to-noise comparison in head images. Magn Reson Med 2001; 46:24-30. 27. Yacoub E, Shmuel A, Pfeuffer J et al. Imaging brain function in humans at 7 Tesla. Magn Reson Med 2001; 45:588-594. 28. Grant EG, Benson CB, Moneta GL et al. Carotid artery stenosis: gray-scale and Doppler US diagnosis--Society of Radiologists in Ultrasound Consensus Conference. Radiology 2003; 229:340-346. 29. Hellings WE, Pasterkamp G, Vollebregt A et al. Intraobserver and interobserver variability and spatial differences in histologic examination of carotid endarterectomy specimens. J Vasc Surg 2007; 46:1147-1154.

phd_anne.indb 177

177

16-5-2013 8:00:15

phd_anne.indb 178

16-5-2013 8:00:16

SUMMARY AND FUTURE PERSPECTIVES | PART lV

CHAPTER 11 Summary and Future Perspectives

phd_anne.indb 179

16-5-2013 8:00:16

SUMMARY In this concluding chapter, the findings as discussed in the previous chapters are summarized, pose some questions for debate and outline thoughts that may be useful for future discussion concerning the topic addressed. As mentioned in the Introduction, identifying the risks that patients with carotid artery stenosis are exposed to is highly warranted in order to address serious health issues. Atherosclerosis of the carotid artery is the underlying cause of 10-20% of the ischemic strokes and stroke is the second cause of long-term disability and death in high-income countries.1 Determining these risks may result in appropriate selection for specific therapies, which in turn will lower the risk of transient ischemic attack (TIA) or stroke, and will eventually help patients and decrease health care costs.

Part I: Risk in patients with asymptomatic carotid artery stenosis Part I of this thesis gives insight into the fact that treatment of patients with asymptomatic

180

carotid artery stenosis (ACAS) still remains a matter of debate. Although the ACST-1 study showed a lower risk of stroke for patients undergoing CEA compared to best medical treatment alone,2 since then best medical treatment has improved and other potential issues were identified which may influence outcome of earlier studies.3-5 Several mechanisms may play a role, of which the composition of the carotid plaque is a main issue to assess. Plaque composition is usually merely investigated in symptomatic patients, since these plaques are harvested during carotid endarterectomy (CEA), and are subject of large biobank studies.6 Fortunately, the Athero-Express biobank also collects CEA derived plaques of asymptomatic patients in which CEA was considered indicated by a multidisciplinary panel. In several trials and guidelines patients are considered asymptomatic if 1) the patient’s medical history did not reflect the occurrence of any ipsilateral symptoms, or 2) the patient suffered from ACAS, but only showed ipsilateral symptoms of the carotid territory longer than six months prior to the CEA taking place.7-9 The data discussed in Chapter 2 demonstrated that patients reflecting ipsilateral symptoms longer than six months prior to CEA have more unstable plaques than truly asymptomatic patients who never suffered from cerebrovascular events. This study defined histopathological subgroups within ACAS patients based on reported ipsilateral events over time. In future studies, it would be interesting to investigate if this truly asymptomatic cohort has a lower stroke risk compared to patients with ACAS whom had symptoms more than six months ago.

phd_anne.indb 180

16-5-2013 8:00:16

SUMMARY | CHAPTER 11

Chapter 3 set out how data was collected from a large prospective cohort, the Second Manifestations of Arterial (SMART) study. All patients newly referred to the UMC Utrecht with clinically manifest atherosclerotic vessel disease or marked risk factors for atherosclerosis have been included in this cohort and will be monitored during their lifetime. This study provided the unique possibility to investigate patients with ACAS during a long-term followup period. This study demonstrated that the presence of 50-99% ACAS detected in patients with clinically manifest arterial disease or type 2 diabetes mellitus was associated with an average annual stroke risk of approximately 0.4%. For patients with 70-99% ACAS this was approximately 0.5%. Although the risk of suffering from a stroke is relatively low compared to patients without ACAS, there was still a slightly, not statistically significant, higher risk of suffering from a stroke in patients with ACAS ≥50%. Compared to other studies the observed stroke risk in these patients with ACAS is low.2,10,11 One of the possible explanations for the fact that this risk turns out to below, might be highly influenced by the increasing number of patients on best medical treatment.12,13 In this cohort patients on best medical treatment increased over time. The results described in Chapters 2 and 3 demonstrate that it is doubtful whether revascularization in any patient with ACAS is an appropriate treatment. First, the risk of

181

suffering from a stroke is low in patients with ACAS during long-term follow-up. Second, the results reflected that truly asymptomatic patients have stable plaque characteristics as well. Therefore a plea for a slightly conservative approach with establishing treatment for ACAS is present, where revascularization should only be recommended based on individual risks or should be limited within the confines of well-designed randomized clinical trials only. A group of patients that might be recommended for revascularization are patients with multivessel stenosis or ipsilateral stenosis combined with (symptomatic) occlusion of the contralateral carotid artery. This is due to the fact that these patients might be exposed to a decreased perfusion state of the brain. Incidence numbers of patients with carotid artery occlusion are sparse, risk of stroke in patients with a carotid occlusion too. Chapter 4 demonstrated a sub-analysis of the Asymptomatic Carotid Surgery Trial (ACST)-1 trial to determine the risk of new carotid artery occlusion and the risk of subsequent stroke. At present, this is the first large study that aimed to evaluate the risk of occlusion and subsequent stroke in patients with tight asymptomatic carotid stenosis suitable for surgery. During a longterm follow-up period, the annual risk of occlusion was measured at 1.1%. Most of these patients did not have a stroke, either at the time of occlusion or during follow-up. However, although the risk of suffering from an overall stroke was low, occlusion could be identified as an independent risk factor for developing a stroke in this cohort. Finally, this study gives

phd_anne.indb 181

16-5-2013 8:00:17

clinicians reason for explaining the future risks of carotid artery occlusion and stroke more clearly to patients with severe stenosis. As stated before, despite the low stroke risks and presumably relatively stable plaques in patients with ACAS there is a group of patients with ACAS who might be considered for revascularization. This might be patients with multivessel disease, a complete circle of Willis or patients included in randomized clinical trials. Carotid revascularisation in these patients can improve cerebral perfusion through collateral circulation in the brain. Chapter 5 described ACAS patients included in the ASCT-2 trial.9 It set out the investigations into the question whether the cerebral perfusion state of the brain is altered after revascularization, either by CEA or CAS. Patients with impaired cerebral perfusion in the ipsilateral hemisphere have a higher risk of suffering from a stroke.14,15 In these patients cerebral blood flow increased three months after revascularization. As the risk of suffering from a stroke is influenced by perfusion of the brain, this result is clinically important. This is, because it shows, without taking other outcome parameters into account, that revascularization has a beneficial impact on cerebral perfusion state. Larger studies are necessary to confirm this improved perfusion and to investigate clinical consequences.

182 Part II: Risk in patients with symptomatic carotid artery stenosis Treatment of patients with symptomatic carotid artery stenosis has been investigated extensively and several trials have shown explicitly patients with a severe (≥70%) stenosis may benefit from CEA.16,17 Thus, since treatment of patients with symptomatic carotid artery stenosis is generally evident, alternatives for surgery or additional risk stratification for symptomatic patients are of interest in clinical research. To protect patients from a future stroke, surgery within two weeks has the most beneficial effect.18 Therefore several guidelines on treatment of carotid artery disease recommend CEA within two weeks from the index event.19,20 Chapter 6 investigated the delay between the index event and surgery in patients with symptomatic carotid artery stenosis in our large tertiary referral center. Furthermore, it initiated to start a discussion about the definition of the so called ‘index event’. In most studies investigating delay between symptom and surgery, the exact definition of the index event has been omitted. Our study showed that this definition influenced the reported delay times. For example, some patients do not recognize a short TIA or amaurosis fugax as an event and will attend the clinician after a second or more severe event. Clinically measuring the delay from this first event to surgery is the most relevant, but this will definitely result in longer time intervals compared to measuring from the most recent event before attending the hospital. However, it is doubtful if all earlier studies on delay have

phd_anne.indb 182

16-5-2013 8:00:17

SUMMARY | CHAPTER 11

implemented this fact. In studies investigating the timing of carotid artery stenosis a definition of the index event should be included. Like other countries, in our hospital the time from index event to CEA exceeded the two week threshold.21-23 Specific in-hospital measures shortened the delay, but still the number of patients operated within two weeks needs to be higher in future. In 2013, the publication of a national guideline on timing of carotid revascularization from the Dutch Society for Vascular Surgery will hopefully accelerate the process of further reducing this delay. Carotid artery stenting (CAS) has been introduced as an alternative treatment for CEA in symptomatic carotid artery stenosis. However, a recent meta-analysis showed that endovascular treatment is associated with an increased risk of peri-procedural stroke or death compared with endarterectomy, although the longer term efficacy and the risk of restenosis are still unclear.24 Yet, there might be a population of patients whom will have benefit from CAS, these patients do have surgically inaccessible lesions or are defined in literature as the so called ‘high-risk’ patients. “High risk” is generally defined as anatomic or clinical factors that increase the risk of complications with surgery, ranging from stroke to peripheral nerve injury.25,26 This definition is doubtful and multi-interpretable, either high risk for stroke or high risk for surgery should not be mixed up.27 In Chapter 7 a meta-analysis of current literature to

183

investigate peri-procedural and long-term outcome of CAS and CEA in patients with carotid artery stenosis and previous cervical radiotherapy (XRT) was performed. This meta-analysis showed no preferred revascularization therapy; both had low risk for cerebrovascular events. Based on this meta-analysis no preferred treatment for patients with previous cervical XRT is indicated. In our opinion type of revascularization should be considered on an individual basis. In patients with previous cervical XRT an increased stroke rate was demonstrated compared to patients without a history of XRT.28 Chapter 8 provided data of a cross-sectional analysis of a biobank study to identify plaque phenotype of patients with prior cervical XRT. Plaques of patients with previous XRT were less vulnerable, or more stable and less active compared to plaques from patients without previous cervical XRT. Consequences for clinical outcome and restenosis after CEA need to be objectified in larger cohorts with longer follow-up.

Part III: Imaging of carotid artery stenosis By optimal imaging of the carotid artery specific vulnerable plaque characteristics may be distinguished, which identifies patients with a higher risk for cerebrovascular events. Implementation of non-invasive high-resolution magnetic resonance imaging MRI (hrMRI) seems one of the most promising techniques to reliably visualize the carotid arteries and the brain. It has the ability to identify the carotid plaque and cerebral (small) infarcts or

phd_anne.indb 183

16-5-2013 8:00:17

emboli more precisely. Therefore non invasive MRI will be valuable in clinical decision making in future by differentiating low risk and high risk patients and thereby determining which patients benefit most from revascularization. Chapter 9 assessed the agreement between MRI and histology for specific carotid plaque characteristics associated with vulnerability in terms of sensitivity and specificity. This review showed clinical application of MRI as a purely diagnostic imaging modality for plaque characterization is maybe too early and would require consensus regarding MR settings and comparison with predefined histology protocols. Still, MRI is a promising non-invasive technique which in future will determine degree of stenosis, plaque composition, infarcts and perfusion of the brain simultaneously and therefore might be of great influence in clinical decision making for patients with carotid artery stenosis. From this point of view the PLACD-7T (Plaque Components Correlated with Cerebral Damage) study was designed. In Chapter 10 the protocol of this study was presented which aims to correlate 7Tesla imaging with carotid plaque histology. Furthermore, it will correlate plaque characteristics with cerebral damage on 7Tesla high resolution (HR) MRI.

184

phd_anne.indb 184

16-5-2013 8:00:17

FUTURE PERSPECTIVES | CHAPTER 11

FUTURE PERSPECTIVES For studies described in this thesis patients with asymptomatic or symptomatic carotid artery stenosis were investigated. Focussed on asymptomatic patients several important results were assessed. First, different plaque characteristics were identified for specific subgroups in asymptomatic patients. Second, the risk of stroke in general and from occlusion was low in asymptomatic patients. Furthermore, perfusion improved after revascularisation, although the clinical impact of this outcome still need to be evaluated. The low annual risk of ipsilateral stroke in asymptomatic patients receiving optimal medical treatment was the main finding which supports a conservative approach in these patients. For future research predictors of high-risk asymptomatic patients is warranted. For example, specific clinical patient characteristics, silent microemboli or unstable plaque characteristics need to be identified. A non-invasive diagnostic approach in which MRI and transcranial Doppler monitoring are included will improve identification of these risk factors. In addition, a risk stratification score and an observational study which investigates patients with severe asymptomatic carotid artery stenosis with imaging modalities over time is urgently needed. In this study patients must receive best medical therapy and should undergo several imaging

185

modalities. At baseline patients will undergo Transcranial Doppler monitoring and MRI to identify clinically silent emboli, to determine specific plaque characteristics and to investigate the relation between carotid plaque characteristics and cerebral damage. In this observational study, patients can be followed over time to identify the risk of transient ischemic attacks, silent emboli or stroke. This may eventually show whether imaging characteristics assessed at baseline can predict clinical events and will identify the patients whom will benefit from revascularisation most. This thesis focussed on the identification of specific risk profiles for symptomatic patients, as previous research already identified CEA is superior to CAS. CEA must be performed within two weeks from the cerebrovascular event, as this results in a lower risk of recurrent TIA or stroke and is clinically preferable. Previous cervical radiation therapy is not in any case a risk factor for CEA based on current literature. Besides, plaque characteristics in patients with previous cervical radiation therapy are less vulnerable. Future research in symptomatic patients should investigate which patients with symptomatic carotid artery stenosis might benefit from CAS instead of CEA and which specific groups are the so-called “high-risk” patients. Thus this means, identification of specific patients with a high risk of a recurrent stroke is warranted in patients with symptomatic carotid artery disease. For example, patients

phd_anne.indb 185

16-5-2013 8:00:17

with a mild symptomatic stenosis (30-69%) but with the risk of rupture plaque have a higher risk of recurrent stroke and these specific “high risk” patients need to be identified in future studies. Studies described in this thesis stratify risks for patients with asymptomatic and symptomatic carotid artery stenosis. Although this thesis has given more insight on the management of asymptomatic and symptomatic carotid artery stenosis, the optimal diagnostic approach and optimal treatment remains challenging. In our opinion, the most important question that remains is in which subgroups treating patients with carotid artery stenosis is justified and if treatment is justified which treatment is the best to perform. This thesis answers this question in part, but it must be considered a simplification to extrapolate these results to all patients with carotid artery stenosis. First, as previously mentioned, an observational study which follows patients with severe asymptomatic carotid stenosis on best medical treatment over time by performing important imaging modalities as MRI and transcranial Doppler is urgently needed. Second, studies establishing a prognostic risk model for patients with carotid artery stenosis or identifying patients most at risk for recurrent stroke must be performed. These suggested studies may result in more precise risk stratification for patients with carotid

186

artery stenosis. Vascular surgeons, neurologists and interventional radiologists need to be involved in managing the patient with carotid artery stenosis. Diagnosing and treating patients with carotid artery stenosis is a multidisciplinary, complex and ongoing process, which needs to be evaluated over time to keep up to date and sufficient. Results of an observational study or a risk prediction model will improve morbidity and mortality and thereby lowering health care costs.

phd_anne.indb 186

16-5-2013 8:00:17

SUMMARY AND FUTURE PERSPECTIVES | CHAPTER 11

REFERENCES 1. 2. 3. 4. 5.

Roger VL, Go AS, Lloyd-Jones DM et al. Heart disease and stroke statistics--2012 update: a report from the American Heart Association. Circulation 2012; 125:e2-e220. Halliday A, Harrison M, Hayter E et al. 10-year stroke prevention after successful carotid endarterectomy for asymptomatic stenosis (ACST-1): a multicentre randomised trial. Lancet 2010; 376:1074-1084. Abbott AL, Bladin CF, Levi CR et al. What should we do with asymptomatic carotid stenosis? Int J Stroke 2007; 2:27-39. Naylor AR, Gaines PA, Rothwell PM. Who benefits most from intervention for asymptomatic carotid stenosis: patients or professionals? Eur J Vasc Endovasc Surg 2009; 37:625-632. Rockman C, Riles T. Carotid artery disease: selecting the appropriate asymptomatic patient for intervention. Perspect Vasc Surg Endovasc Ther 2010; 22:30-37. 6. Verhoeven BA, Velema E, Schoneveld AH et al. Athero-express: differential atherosclerotic plaque expression of mRNA and protein in relation to cardiovascular events and patient characteristics. Rationale and design. Eur J Epidemiol 2004; 19:1127-1133. 7. Chambers BR, Donnan GA. Carotid endarterectomy for asymptomatic carotid stenosis. Cochrane Database Syst Rev 2005;CD001923. 8. Halliday AW, Thomas D, Mansfield A. The Asymptomatic Carotid Surgery Trial (ACST). Rationale and design. Steering Committee. Eur J Vasc Surg 1994; 8 :703-710. 9. Rudarakanchana N, Dialynas M, Halliday A. Asymptomatic Carotid Surgery Trial-2 (ACST-2): rationale for a randomised clinical trial comparing carotid endarterectomy with carotid artery stenting in patients with asymptomatic carotid artery stenosis. Eur J Vasc Endovasc Surg 2009; 38:239-242. 10. Abbott AL, Chambers BR, Stork JL et al. Embolic signals and prediction of ipsilateral stroke or transient ischemic attack in asymptomatic carotid stenosis: a multicenter prospective cohort study. Stroke 2005; 36:1128-1133. 11. Nadareishvili ZG, Rothwell PM, Beletsky V et al. Long-term risk of stroke and other vascular events in patients with asymptomatic carotid artery stenosis. Arch Neurol 2002; 59:1162-1166. 12. Abbott AL. Medical (nonsurgical) intervention alone is now best for prevention of stroke associated with asymptomatic severe carotid stenosis: results of a systematic review and analysis. Stroke 2009; 40:e573-e583. 13. Ridker PM, Danielson E, Fonseca FA et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008; 359:2195-2207. 14. Blaser T, Hofmann K, Buerger T et al. Risk of stroke, transient ischemic attack, and vessel occlusion before endarterectomy in patients with symptomatic severe carotid stenosis. Stroke 2002; 33:1057-1062. 15. Markus H, Cullinane M. Severely impaired cerebrovascular reactivity predicts stroke and TIA risk in patients with carotid artery stenosis and occlusion. Brain 2001; 124:457-467. 16. European Carotid Surgery Trialists' Collaborative Group. MRC European Carotid Surgery Trial: interim results for symptomatic patients with severe (70- 99%) or with mild (0-29%) carotid stenosis. European Carotid Surgery Trialists' Collaborative Group. Lancet 1991; 337:1235-1243. 17. North American Symptomatic Carotid Endarterectomy Trial Collaborators. Beneficial effect of carotid endarterectomy in symptomatic patients with high grade carotid stenosis. N Engl J Med 1991; 325:445-453. 18. Rothwell PM, Eliasziw M, Gutnikov SA et al. Endarterectomy for symptomatic carotid stenosis in relation to clinical subgroups and timing of surgery. Lancet 2004; 363:915-924. 19. Goldstein LB, Bushnell CD, Adams RJ et al. Guidelines for the primary prevention of stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2011; 42:517-584. 20. Kakisis JD, Avgerinos ED, Antonopoulos CN et al. The European Society for Vascular Surgery guidelines for carotid intervention: an updated independent assessment and literature review. Eur J Vasc Endovasc Surg 2012; 44:238-243. 21. Halliday AW, Lees T, Kamugasha D et al. Waiting times for carotid endarterectomy in UK: observational study. BMJ 2009; 338:b1847. 22. Jetty P, Husereau D, Kubelik D et al. Wait times among patients with symptomatic carotid artery stenosis requiring carotid endarterectomy for stroke prevention. J Vasc Surg 2012; 56:661-667. 23. Vikatmaa P, Sairanen T, Lindholm JM et al. Structure of delay in carotid surgery--an observational study. Eur J Vasc Endovasc Surg 2011; 42:273-279. 24. Bonati LH, Lyrer P, Ederle J et al. Percutaneous transluminal balloon angioplasty and stenting for carotid artery stenosis. Cochrane Database Syst Rev 2012; 9:CD000515. 25. Fokkema M, den Hartog AG, Bots ML et al. Stenting versus surgery in patients with carotid stenosis after previous cervical radiation therapy: systematic review and meta-analysis. Stroke 2012; 43:793-801. 26. Frego M, Bridda A, Ruffolo C et al. The hostile neck does not increase the risk of carotid endarterectomy. J Vasc Surg 2009; 50:40-47. 27. de Borst GJ, Moll FL. Regarding: "carotid angioplasty and stenting in anatomically high-risk patients: safe and durable except for radiation-induced stenosis". J Vasc Surg 2010; 51:1077-1078. 28. Scott AS, Parr LA, Johnstone PA. Risk of cerebrovascular events after neck and supraclavicular radiotherapy: a systematic review. Radiother Oncol 2009; 90:163-165.

phd_anne.indb 187

187

16-5-2013 8:00:17

phd_anne.indb 188

16-5-2013 8:00:18

PART lV | SUMMARY AND FUTURE PERSPECTIVES

CHAPTER 12 Summary in Dutch – Nederlandse Samenvatting

phd_anne.indb 189

16-5-2013 8:00:18

INLEIDING Atherosclerose De definitie van atherosclerose komt van het Griekse woord arteria, dat slagader en sclerose, dat ‘hard’ betekent. Atherosclerose is slagaderverkalking. Het exacte ontstaansmechanisme van atherosclerose is onbekend, maar globaal gezien treedt door een uitgebreid ontstekingsproces van de vaatwand verharding van de slagaders op, de zogenaamde slagaderverkalking. Dit kan optreden in alle slagaders van het lichaam, maar het meest in de grote en middelgrote lichaams slagaders; de aorta, de kransslagaders, de halsslagaders en de beenvaten. Slagaderverkalking kan leiden tot hart- en vaatziekten, doordat er zogenaamde plaques, ofwel ophopingen, in de slagaderwand ontstaan die de slagader vernauwen of soms geheel verstoppen. Tevens kan er ook een stuk van de plaque afscheuren en verderop in een kleiner vat een vernauwing of verstopping veroorzaken, waardoor bijvoorbeeld een beroerte of een TIA (Transient Ischemic Attack= voorbijgaande neurologische uitval die binnen 24 uur verdwenen is) kan ontstaan. Doordat bij vele ziekten atherosclerose de onderliggende oorzaak

190

is van de klachten, is atherosclerose een ziekte die wereldwijd het meest leidt tot een kortere levensduur en overlijden.

Cerebrovasculaire ziekten Cerebrovasculaire ziekten is een verzamelterm voor ziekten die ontstaan als de bloedvoorziening van de hersenen is aangetast. Het wordt ook wel een beroerte of een CVA (Cerebro Vasculair Accident) genoemd. Wanneer de bloedtoevoer naar de hersenen wordt verstoord, kunnen hersencellen door zuurstoftekort verloren gaan of beschadigd raken. De neurologische stoornissen die hiervan het gevolg zijn, worden cerebrovasculaire accidenten genoemd, omdat dit veroorzaakt wordt door problemen met de hersenen (cerebrum) en de bloedvaten (vasculair). Onvoldoende bloedtoevoer gedurende korte perioden veroorzaakt een transient ischemic attack (TIA), een tijdelijke verstoring van de hersenfunctie. Omdat de bloedtoevoer snel wordt hersteld, sterft het hersenweefsel niet af en kunnen de klachten weer geheel herstellen. Een beroerte is een ernstige en vaak voorkomende ziekte wereldwijd, waardoor deze ziekte grote sociaal-economische gevolgen heeft. In Westerse landen overlijdt ongeveer 10-20% van de mensen door een beroerte en 10% van deze patiënten is jonger dan 65 jaar. In Nederland nemen elk jaar het aantal ziekenhuisopnames als gevolg van een beroerte toe. Bij ongeveer 20% van de beroerten gaat het om een hersenbloeding. Dit wordt veroorzaakt door een scheurtje in een bloedvat in de hersenen en daardoor stroomt

phd_anne.indb 190

16-5-2013 8:00:18

NEDERLANDSE SAMENVATTING | CHAPTER 12

er bloed in of rond de hersenen. Hierdoor wordt het hersenweefsel beschadigd. Echter, in 80% van de beroerten gaat het om een herseninfarct en dit wordt bijna altijd veroorzaakt door atherosclerose. Een herseninfarct ontstaat doordat een bloedstolsel of een stuk los schiet van een (atherosclerotische) plaque en daardoor een bloedvat (in het hoofd) afsluit. Het hersenweefsel achter de blokkade krijgt daardoor geen zuurstof en voeding meer en hierdoor kan er uitval ontstaan van bepaalde lichaamsdelen, en daardoor kan ook neurologische schade optreden. Ongeveer 10-20% van de patiënten, die een herseninfarct krijgen, hebben een vernauwing van (één van) de halsslagaders. Deze vernauwing wordt vaak veroorzaakt door een atherosclerotische plaque die zich in de arterie carotis (halsslagader) bevindt. Dit wordt ook wel een carotis stenose (=vernauwing) genoemd. Deze plaque bevindt zich meestal ter hoogte van de splitsing van de halsslagader, waarbij de zogenaamde interne halsslagader de bloedvoorziening van de hersenen verzorgt en de externe halsslagader de doorbloeding van het aangezicht verzorgt. Als een vernauwing van de halsslagader gedeeltelijk losraakt, waarbij de plaque scheurt, kan dit leiden tot een herseninfarct, een TIA (voorbijgaande neurologische uitval die binnen 24 uur verdwenen is) of uitval van het gezichtsveld (amaurosis fugax). Zodra er klachten ontstaan als gevolg van de plaque in de halsslagader wordt het ook wel een

191

symptomatische halsslagader vernauwing genoemd (symptomatische carotis stenose). Indien de plaque in de halsslagader nog niet (=klachtenvrij) heeft geleid tot een herseninfarct of TIA wordt het een asymptomatische halsslagader vernauwing genoemd (asymptomatische carotis stenose). Een carotis stenose kan worden vastgesteld met behulp van een echo van de hals, een zogenaamd duplex onderzoek. De meeste patiënten met een carotis stenose worden behandeld met medicatie. Echter, er bestaan ook 2 behandelingen waarbij de vernauwing met een iets meer ingrijpende behandeling verholpen wordt. Enerzijds bestaat er de mogelijkheid om de vernauwing chirurgisch te verwijderen; dit is een operatie, die ook carotis endarteriëctomie (CEA) wordt genoemd. Hierbij wordt de halsslagader open gemaakt en de plaque verwijderd. Op deze manier wordt de halsslagader als het ware van binnen ‘schoon’ gemaakt. Anderzijds bestaat er sinds enkele jaren ook de mogelijkheid om een buisje (stent) in de halsslagader te plaatsen. Daarbij wordt een stent in de halsslagader geschoven en wordt de vernauwing als het ware opzij (tegen de vaatwand aan) gedrukt, waardoor het vat weer goed doorgankelijk wordt.

phd_anne.indb 191

16-5-2013 8:00:18

Asymptomatische carotis stenose Een ernstige asymptomatische vernauwing (>70% van de diameter van de halsslagader) is in 0-3% van de algemene populatie aanwezig. Het jaarlijkse risico op een herseninfarct voor patiënten met een asymptomatische carotis stenose ligt tussen de 1-3%. Grote, internationale wetenschappelijke onderzoeken hebben aangetoond dat het verwijderen van de vernauwing met behulp van een operatie betere uitkomsten heeft dan patiënten alleen met adequate medicijnen te behandelen. Toch blijft het verwijderen van de plaque uit de halsslagader bij patiënten die een vernauwing zonder klachten hebben aan discussie onderhevig. Aangezien de afgelopen jaren de medicatie voor hart en vaatziekten sterk verbeterd is en in de eerder uitgevoerde, grote wetenschappelijke studies niet alle patiënten deze (nieuwe) medicatie hebben gekregen, blijft deze discussie vooralsnog bestaan. Daarnaast is de absolute risico verlaging voor patiënten die een operatie ondergaan vrij klein. Kort samengevat is het eigenlijk noodzakelijk om te onderzoeken òf en op welke manier revascularisatie van de halsslagader, met behulp van een operatie of stentplaatsing, bij patiënten met een asymptomatische carotis stenose het risico op een herseninfarct of een TIA kan verlagen. Hiervoor is het belangrijk om te bepalen aan welke risico’s patiënten met een asymptomatische carotis stenose worden

192

blootgesteld. Hebben patiënten met een gevaarlijke, makkelijk scheurende plaque een hoger risico op een herseninfarct dan patiënten die een stabielere plaque hebben? Hoe groot is de kans dat patiënten met een asymptomatische carotis stenose een herseninfarct krijgen? Of wat is het risico op een herseninfarct als deze patiënten een plaque hebben die de gehele halsslagader afsluit? Daarnaast is het ook van belang om te onderzoeken of het openmaken of verwijderen van de plaque in de halsslagader bij deze patiënten de doorbloeding van de hersenen ook daadwerkelijk verbeterd. In dit proefschrift zijn bovenstaande factoren onderzocht en is getracht antwoord te krijgen op bovenstaande vragen.

Symptomatische carotis stenose Een vernauwing van de halsslagader, die resulteert in uitval van het gezichtsveld, een TIA of een herseninfarct, wordt een symptomatische carotis stenose genoemd. Grote wetenschappelijke studies hebben voor deze symptomatische patiënten met een vernauwing van >70% al aangetoond, dat een operatie waarbij de plaque uit de halsslagader verwijderd wordt, zinvol en tevens de behandeling van eerste keuze is. Een recent, groot vergelijkend onderzoek toont tevens aan dat operatieve therapie de voorkeur heeft ten opzichte van een stentplaatsing in de halsslagader bij deze symptomatische patiënten. Een stentplaatsing is waarschijnlijk alleen bij specifieke patiëntengroepen geïndiceerd. Echter, er bestaat nog veel onduidelijkheid en verschillende aannames voor welke groepen patiënten dit dan geldt. De mate van vernauwing,

phd_anne.indb 192

16-5-2013 8:00:19

NEDERLANDSE SAMENVATTING | CHAPTER 12

de plaque samenstelling, de timing van opereren en specifieke anatomische factoren zijn allemaal factoren waarvan verschillende onderzoeken hebben aangegeven dat die van belang kunnen zijn in het selecteren van patiënten voor een specifieke behandeling. Het hoogste risico op opnieuw een neurologisch symptoom (TIA of herseninfarct) is vaak binnen enkele dagen tot weken na de eerste klachten. Daarom is het belangrijk om zo snel mogelijk na de eerste klachten een patiënt met een symptomatische carotis stenose te opereren. Een van die specifieke anatomische risicofactoren is een zogenaamd niet toegankelijke nek door eerdere radiotherapie in de halsregio. In dit proefschrift zijn de timing van operatie en de gevolgen van radiotherapie voor de vernauwing van de halsslagader nader onderzocht.

Beeldvorming van een vernauwing van de arterie carotis Voor alle patiënten - asymptomatisch of symptomatisch, met een minimale stenose of een ernstige stenose - geldt dat de soort samenstelling van de plaque een indicatie kan geven over het toekomstige risico op een herseninfarct. Binnen het klinische proces waarbij een patiënt met een carotis stenose in kaart wordt gebracht, is daarom beeldvorming van cruciaal belang. Met name het steeds beter kunnen afbeelden van de specifieke plaque kenmerken gaat er in

193

de toekomst hopelijk voor zorgen, dat we vroegtijdig een risico inschatting kunnen maken bij patiënten met bepaalde maten van vernauwingen. Voor patiënten met een ernstige vernauwing is bewezen dat revascularisatie de beste behandeling is, maar voor patiënten met een milde of mild-ernstige stenose is dit minder duidelijk. Voor deze patiënten zal beeldvorming, zoals bijvoorbeeld de MRI-scan, in de toekomst mogelijk meer informatie kunnen geven. MRI is een makkelijk uitvoerbare beeldvormingstechniek waarbij geen schadelijke röntgenstraling wordt gebruikt, maar er gebruik gemaakt wordt van een magnetisch veld. Hierdoor is het een niet belastende manier van beeldvorming. Hopelijk kan de MRI in de toekomst meer inzicht geven welke patiënten een stabiele plaque hebben, ofwel mogelijk lager risico op een herseninfarct en welke patiënten een instabiele plaque hebben, ofwel een mogelijk hoger risico op een herseninfarct. In dit proefschrift hebben we gekeken naar de huidige ontwikkeling van de MRI en beschrijven we het protocol van een studie die wij in het UMCU hebben opgezet om de waarde van een MRI scan in het ontdekken en analyseren van patiënten met een vernauwing van de halsslagader te kunnen verbeteren.

phd_anne.indb 193

16-5-2013 8:00:19

Doelstellingen van dit proefschrift Dit proefschrift bestaat uit drie delen. Het eerste deel beschrijft patiënten met een asymptomatische carotis stenose en met name welke risico’s deze patiënten lopen. Het tweede deel van dit proefschrift gaat over specifieke risico’s bij patiënten met een symptomatische carotis stenose. In het laatste deel van dit proefschrift wordt de beeldvorming van de halsslagader en de hersenen bij patiënten met een carotis stenose nader beschreven.

194

phd_anne.indb 194

16-5-2013 8:00:19

NEDERLANDSE SAMENVATTING | CHAPTER 12

SAMENVATTING In dit proefschrift hebben wij getracht om de risico’s te identificeren waaraan patiënten met een carotis stenose worden blootgesteld, hopelijk krijgt men daardoor een beter inzicht in deze ziekte en kunnen daarmee ernstige gezondheidsproblemen worden verminderd. Het vaststellen van deze risico’s kan leiden tot het maken van de juiste keuze voor een specifieke therapie, waardoor het risico op een TIA of een herseninfarct individueel verkleind wordt. Uiteindelijk zal dit patiënten kunnen helpen, waardoor de daarmee gepaard gaande gezondheidskosten mogelijk verlaagd kunnen worden.

Deel 1: Risico’s voor patiënten met een asymptomatische carotis stenose Verschillende mechanismen kunnen een rol spelen in het bepalen van het risico op een herseninfarct bij patiënten met een asymptomatische carotis stenose. In ieder geval is het identificeren van hoog risico patiënten belangrijk om eventuele toekomstige herseninfarcten te kunnen voorkomen. De samenstelling van de plaque in de halsslagader lijkt hierin een cruciale rol te spelen. Een plaque die makkelijk scheurt (instabiele plaque) heeft vaak een dunne bindweefsel laag en

195

bestaat uit veel ontstekingscellen, terwijl een stabiele plaque vaak een dikke bindweefsel laag heeft en weinig ontstekingscellen. De plaque samenstelling is vaker onderzocht bij patiënten met een symptomatische carotis stenose, aangezien deze patiënten vaker geopereerd worden en die plaques tijdens een operatie verwijderd en geanalyseerd kunnen worden in grote, nog lopende studies. In het UMC Utrecht (UMCU) worden patiënten met een asymptomatische carotis stenose alleen geopereerd in uitzonderlijke gevallen en alleen nadat door een multidisciplinair team beoordeeld is dat dit de meest aangewezen behandeling is. Binnen de Athero-Express biobank worden deze plaques vervolgens verzameld en geanalyseerd, waardoor er toch gegevens bekend zijn over de plaque samenstelling van patiënten met een asymptomatische carotis stenose. De data die beschreven worden in Hoofdstuk 2 tonen aan dat patiënten die een asymptomatische vernauwing hebben, maar wel ooit symptomen hebben gehad (< dan 6 maanden geleden) een plaque hebben met onstabielere kenmerken dan patiënten die echt nog nooit klachten hebben gehad. In toekomstige studies met asymptomatische patiënten zal onderzocht moeten worden of deze onderverdeling ook invloed heeft op het toekomstige risico op een herseninfarct indien deze patiënten niet geopereerd worden. Hoofdstuk 3 beschrijft het risico op een herseninfarct bij patiënten met vaatlijden en een

phd_anne.indb 195

16-5-2013 8:00:19

asymptomatische vernauwing van de halsslagader. Hierin zijn data van de SMART trial (SMART=Second Manifestations of ARTerial study) geanalyseerd. Voor deze studie worden patiënten met vaatlijden (die al eerder een symptoom hiervan hebben gehad ergens in het lichaam) of risicofactoren voor vaatlijden binnen het UMCU gevraagd om mee te werken. Gedurende de rest van hun leven zullen zij vervolgd worden en zullen de symptomen die zij kunnen krijgen als het gevolg van hun vaatlijden nauwkeurig gedocumenteerd en geanalyseerd worden. Deze studie geeft de mogelijkheid om patiënten met een asymptomatische carotis stenose te vervolgen gedurende vele jaren, en dat is echt uniek voor deze moeilijk te identificeren patiënten groep. Immers, normaal gesproken weet een patiënt vaak niet dat hij/zij een asymptomatische carotis stenose heeft, aangezien hij/zij nog nooit neurologische klachten als gevolg van de vernauwing heeft ontwikkeld. Deze studie toont aan dat binnen een groep van patiënten met vaatlijden patiënten met een 50-99% asymptomatische vernauwing van de halsslagader een laag risico op een (toekomstig) herseninfarct hebben. Daarnaast laat deze studie zien dat het risico op een herseninfarct bij patiënten met een asymptomatische carotis stenose van ≥50% dan wel klein is, maar nog steeds wel iets hoger dan bij patiënten zonder een vernauwing in de halsslagader. Een verklaring voor het lage aantal gevonden

196

herseninfarcten bij patiënten met een asymptomatische carotis stenose kan zijn dat patiënten steeds vaker behandeld worden met adequate medicatie en dat deze medicatie de afgelopen jaren in werkingsspectrum ook nog sterk verbeterd is. Een voorzichtige conservatieve benadering in de behandeling van patiënten met een klachtenvrije vernauwing van de halsslagader is momenteel de aangewezen therapie van keuze. Revascularisatie (operatief of stenting) moet alleen aanbevolen worden gebaseerd op specifieke individuele risico’s en binnen goed opgezette gerandomiseerde wetenschappelijke studies. Dit blijkt ook uit de resultaten gevonden in Hoofdstuk 2 en 3. Een groep patiënten die mogelijk wel in aanmerking komt voor revascularisatie zijn patiënten waarbij meerdere of alle halsslagaders (in totaal heeft ieder mens 4 halsslagaders) vernauwd zijn of patiënten waarbij een van de halsslagaders in zijn geheel is afgesloten. Deze gehele afsluiting wordt een 100% stenose, dan wel occlusie genoemd. Deze patiënten hebben waarschijnlijk een veel slechtere doorbloeding van hun hersenen doordat er meerdere halsslagaders vernauwd of geheel afgesloten zijn. Aangezien er weinig patiënten zijn waarbij de halsslagader geheel dicht zit door aderverkalking, is er nog weinig onderzoek gedaan naar de risico’s van zo’n geheel afgesloten halsslagader. Hierdoor is het risico op een herseninfarct bij deze patiënten groep grotendeels onbekend. Hoofdstuk 4 beschrijft een sub-studie van de Asymptomatic Carotis Surgery Trial (ACST)-1 trial. Dit is een grote, internationale studie die van 2003-2010 heeft onderzocht of patiënten met een asymptomatische carotis stenose het

phd_anne.indb 196

16-5-2013 8:00:19

NEDERLANDSE SAMENVATTING | CHAPTER 12

beste af zijn met een operatie of beter conservatief met medicatie kunnen worden behandeld. In dit hoofdstuk wordt beschreven hoe vaak patiënten met een ernstige asymptomatische vernauwing een occlusie van de halsslagader ontwikkelen. Daarnaast wordt er uiteengezet hoe vaak deze patiënten een herseninfarct ontwikkelden tijdens de lange follow-up van de studie. Het jaarlijkse risico op een occlusie blijkt laag te zijn. De meeste patiënten die een occlusie ontwikkelden kregen geen herseninfarct, niet op het moment dat de halsslagader geheel vernauwd raakte en ook niet gedurende de lange follow-up. Hoewel het risico op een herseninfarct laag is, blijkt het krijgen van een occlusie wel een onafhankelijke risicofactor voor het ontwikkelen van een herseninfarct binnen deze groep patiënten. Uiteindelijk zal deze studie ons de mogelijkheid gaan bieden om duidelijker aan patiënten, met dan nog een ernstige vernauwing van de halsslagader, te kunnen uitleggen wat de risico’s zijn als een halsslagader volledig dicht gaat zitten door een plaque. In Hoofdstuk 5 hebben we patiënten onderzocht die meedoen aan de ACST-2 trial. Dit is een grote, internationale studie die onderzoekt of patiënten die om specifieke redenen wèl in aanmerking komen voor een revascularisatie met een asymptomatische carotis stenose beter een stentplaatsing of een operatie kunnen ondergaan. In onze sub-studie wordt bekeken of de doorbloeding van de hersenen verbeterd na behandeling van de vernauwde halsslagader

197

door operatie, dan wel stentplaatsing. Patiënten met een vernauwing van de halsslagader en daardoor een verminderde doorbloeding van dat deel van de hersenen hebben over het algemeen een groter risico om een herseninfarct te ontwikkelen. Uit deze studie is gebleken dat bij deze kleine groep van patiënten met een asymptomatische vernauwing de doorbloeding van de hersenen iets was toegenomen 3 maanden na de revascularisatie. Dit lijkt van belang aangezien het risico op een herseninfarct beïnvloed wordt door de doorbloeding van de hersenen. Grotere en langere studies zijn echter nodig om deze verbeterde perfusie na revascularisatie te bevestigen en de klinische consequenties van deze uitkomst verder te onderzoeken.

Deel II: Risico’s voor patiënten met een symptomatische carotis stenose Het tweede deel van dit proefschrift gaat over specifieke risico’s bij patiënten met een symptomatische carotis stenose. Inmiddels is bewezen dat het cruciaal is om een patiënt binnen 2 weken na het eerste symptoom te opereren, omdat dan de kans op een (nieuw) herseninfarct het minst groot is. In Hoofdstuk 6 wordt het proces van symptoom tot aan de operatie geëvalueerd bij patiënten met een symptomatische carotis stenose die in het UMCU zijn geopereerd. In deze studie wordt ook beschreven dat het zeer belangrijk is om de definitie van het eerste symptoom duidelijk vast te stellen en te beschrijven. Deze studie

phd_anne.indb 197

16-5-2013 8:00:19

laat zien dat patiënten binnen het UMCU steeds sneller na hun eerste symptoom geopereerd worden, maar dat er zeker nog ruimte is voor verbetering. Met name patiënten die via andere ziekenhuizen naar het UMCU worden verwezen, zullen in de toekomst sneller geopereerd moeten worden om de doelstelling, om alle patiënten binnen 2 weken te opereren, te kunnen halen. Radiotherapie in de halsregio in de voorgeschiedenis van de patiënt wordt beschouwd als een risico factor voor het krijgen van een carotis stenose en eventuele neurologische (TIA en herseninfarct) klachten en bovendien wordt om deze reden in de literatuur een operatie vaak afgeraden bij deze patiënten. Dit wordt afgeraden, omdat men suggereert dat de hals door de radiotherapie operatief zeer moeilijk toegankelijk is en daardoor zou het lastig zijn om een goede operatie uit te voeren. In Hoofdstuk 7 wordt de huidige literatuur over de behandeling van patiënten met een symptomatische carotis stenose en eerdere bestraling in de hals samen gevat. Uit onze uiteenzetting van de huidige literatuur blijkt dat een eerdere bestraling in het hals gebied geen risico factor is voor een operatie aan de halsslagader. Deze studie toont aan dat een patiënt die eerder bestraald is individueel beoordeeld zou moeten worden om te kijken of een operatie haalbaar is.

198

In Hoofdstuk 8 is onderzocht of patiënten die eerder bestraald zijn in de halsregio minder stabiele plaques hebben dan patiënten die niet eerder bestraald zijn. Patiënten die eerder bestraald waren blijken minder stabiele plaques te hebben dan patiënten zonder bestraling in het halsgebied. Nadere klinische consequenties van deze uitkomst zullen in grotere patiënten groepen met langere vervolg tijd moeten worden uitgezocht.

Deel III: Beeldvorming van een stenose van de arterie carotis (halsslagader) Het laatste deel van dit proefschrift gaat over beeldvorming van de halsslagader en de hersenen bij patiënten met een carotis stenose. Adequate beeldvorming van de plaque en daarbij ook het visualiseren van de plaque samenstelling zal in de toekomst steeds belangrijker gaan worden. Bovendien geeft beeldvorming van de specifieke plaque karakteristieken inzicht in de stabiliteit van de plaque en daarmee kan ook het risico op een herseninfarct of TIA mogelijk makkelijker voorspeld worden. Hoofdstuk 9 beschrijft de huidige literatuur, die onderzocht heeft of de MRI adequaat is in het identificeren van specifieke plaque karakteristieken en of de MRI daarmee toepasbaar is in de praktijk. Dit overzicht van de huidige literatuur laat zien dat MRI de plaque karakteristieken goed kan identificeren. Echter, het is nog wat te vroeg om MRI als een standaard onderzoek bij de standaard onderzoeken van patiënten met een carotis stenose te kunnen invoegen. Hiervoor zal er meer consensus moeten komen over welk type MRI en de gebruikte instellingen. Als afsluitend hoofdstuk beschrijft Hoofdstuk 10

phd_anne.indb 198

16-5-2013 8:00:19

NEDERLANDSE SAMENVATTING | CHAPTER 12

het protocol van een studie, die de waarde van de allernieuwste MRI (7Tesla) onderzoekt bij het identificeren van de verschillende plaque kenmerken. Op dit moment zijn er 15 patiënten die aan dit onderzoek mee doen. Het doel is om minimaal 30 patiënten toestemming te vragen om mee te doen. Vervolgens zal er bekeken worden of deze allernieuwste MRI in staat is om specifieke plaque kenmerken te herkennen en of de afwijkingen die daarbij in de hersenen worden gevonden met elkaar te correleren zijn.

Toekomst perspectieven In dit proefschrift zijn studies beschreven die patiënten met een asymptomatische of een symptomatische vernauwing van de halsslagader hebben onderzocht. Patiënten met een asymptomatische carotis stenose die al optimaal medicamenteus behandeld worden, hebben jaarlijks een laag risico op een herseninfarct. Dit is een van de belangrijkste redenen om een conservatieve behandeling te verdedigen bij deze patiënten. Daarnaast is het voor toekomstig onderzoek belangrijk om andere voorspellers voor hoog-risico patiënten met een asymptomatische stenose te ontdekken. Dit zouden verschillende factoren kunnen zijn; specifieke klinische patiënt kenmerken, of bijvoorbeeld “stille’ micro-embolieën (stukjes die van een plaque ‘scheuren’) of meer inzicht in de onstabiele plaque kenmerken. Het

199

ontdekken van deze risico factoren zou ook het best kunnen gebeuren met behulp van niet ingrijpende diagnostische technieken zoals een MRI-scan of met een transcraniële doppler. Dit is een soort bril op het hoofd dat de bloedstroom en eventuele stukjes los geraakte plaque (embolieën) kan meten. Daarbij is het belangrijk dat er een risico predictie score ontwikkeld gaat worden en lijkt het noodzakelijk om op korte termijn een goed opgezette observationele studie uit te voeren om nog beter de hoog-risico patiënten binnen deze groep patiënten te kunnen identificeren. In deze toekomstige studie zullen patiënten met een asymptomatische carotis stenose een transcraniële doppler ondergaan om micro-embolieën op te sporen en een MRI om de samenstelling van de plaque te kunnen analyseren. Uiteindelijk kan er dan een relatie gelegd worden tussen de mate van stenose, de samenstelling van de plaque en de eventuele gevolgen voor de hersenen. In deze studie kunnen patiënten gedurende enkele jaren gevolgd worden om het risico op een TIA, een stil infarct of een herseninfarct vast te kunnen stellen. Deze studie kan er in resulteren dat bepaalde karakteristieken gemeten aan het begin bepaalde klinische symptomen kunnen voorspellen. Met behulp van dit onderzoek kunnen mogelijk patiënten ontdekt worden die eigenlijk wel of het meeste baat hebben van een revascularisatie van de halsslagader. Daarnaast heeft dit proefschrift getracht bepaalde risico profielen weer te geven bij patiënten met een symptomatische carotis stenose. Voor deze patiënten is uit eerder wetenschappelijk

phd_anne.indb 199

16-5-2013 8:00:19

onderzoek al naar voren gekomen dat revascularisatie de behandeling van keuze is en dat daarbij een operatie superieur is aan stentplaatsing. Meer onderzoek zal moeten uitwijzen of er toch groepen patiënten met een symptomatische carotis stenose zijn die meer baat hebben bij een stentplaatsing dan bij een operatie en welke groepen de specifieke “hoogrisico” groepen voor operatie zijn. Hiervoor is het belangrijk om te ontdekken welke patiënten een zeer hoog risico hebben op een herseninfarct. Patiënten die een milde (30-69%) stenose hebben, maar wel een gevaarlijke plaque hebben, hebben uiteraard een hoger risico op een herseninfarct. Deze patiënten moeten door toekomstig onderzoek eerder en sneller ontdekt worden. Hoewel dit proefschrift meer inzicht geeft in het ontdekken en behandelen van patiënten met een asymptomatische en symptomatische vernauwing van de halsslagader, blijft de optimale diagnostische aanpak en optimale behandeling uitdagend. Het belangrijkste vraagstuk dat overblijft; voor welke specifieke subgroepen is een behandeling gerechtvaardigd en welke behandeling is vervolgens de juiste? Dit proefschrift beantwoordt deze vraag ten dele, maar het is helaas onmogelijk gebleken om deze resultaten direct te betrekken op alle patiënten met een halsslagader stenose. Ten eerste zal dus een observationele studie, zoals eerder

200

besproken, hieraan kunnen bijdragen. Ten tweede zou het vaststellen van een prognostisch risico model voor patiënten met een carotis stenose kunnen leiden tot het makkelijker voorspellen welke patiënten een hoger risico voor een herseninfarct hebben. Tot slot zal bij patiënten met een symptomatische carotis stenose ontdekt moeten worden welke patiënten daadwerkelijk een hoog risico hebben voor operatie en hoe we deze risico’s kunnen verlagen. Deze voorgestelde studies kunnen leiden tot een nauwkeurigere risico inschatting van patiënten met een asymptomatische en symptomatische vernauwing van de halsslagader. Vaatchirurgen, neurologen en interventie radiologen moeten betrokken zijn bij de diagnostische en klinische work-up van patiënten met een vernauwing van de halsslagader. Het diagnosticeren en behandelen van patiënten met een vernauwing van de halsslagader is een multidisciplinair, complex en continue proces, dat van tijd tot tijd geëvalueerd moet worden om de gekozen strategie actueel en accuraat te houden. Resultaten van een observationele studie of een specifiek risico model zal de morbiditeit en mortaliteit van patiënten met een asymptomatische en symptomatische carotis stenose kunnen verbeteren en daardoor de kosten voor de gezondheidszorg kunnen verlagen.

phd_anne.indb 200

16-5-2013 8:00:19

Part V Appendices

phd_anne.indb 201

16-5-2013 8:00:20

phd_anne.indb 202

16-5-2013 8:00:20

APPENDICES | PART V

CHAPTER 13 Review committee Acknowledgements List of publications Curriculum Vitae

phd_anne.indb 203

16-5-2013 8:00:21

phd_anne.indb 204

16-5-2013 8:00:21

REVIEW COMMITEE | CHAPTER 13

REVIEW COMMITTEE Prof. Dr. I.H.M. Borel Rinkes Department of Surgery University Medical Center Utrecht Utrecht, the Netherlands Prof. Dr. M.L. Bots Julius Center for Health Science and Primary Care University Medical Center Utrecht Utrecht, the Netherlands Prof. Dr. A.W. Halliday Nuffield Department of Surgical Sciences John Radcliffe Hospital, Oxford University Oxford, United Kingdom

205

Prof. Dr. L.J. Kappelle Department of Neurology University Medical Center Utrecht Utrecht, the Netherlands

phd_anne.indb 205

16-5-2013 8:00:21

phd_anne.indb 206

16-5-2013 8:00:21

ACKNOWLEDGEMENTS | CHAPTER 13

ACKNOWLEDGEMENT- DANKWOORD Ja eindelijk…het is klaar! Dit proefschrift is het resultaat van enkele jaren hard werken. Het zou niet tot stand gekomen zijn zonder de hulp van vele anderen. Een aantal wil ik hier in het bijzonder noemen en bedanken. Prof. dr. F.L. Moll, beste professor. Enkele jaren geleden hebben u en Gert Jan mij de kans geboden om onder jullie begeleiding te gaan promoveren. Ik ben u ongelooflijk dankbaar voor deze geboden kans en de mogelijkheid om enkele maanden naar Oxford te gaan. Uw kennis en kunde is wereldwijd gerenommeerd en ik ben trots dat ik enkele jaren onder uw hoede aan mijn onderzoek heb mogen werken. Ik waardeer uw tomeloze enthousiasme en betrokkenheid bij eigenlijk alles. Altijd was er even dat ene mailtje of dat ene bemoedigende woord precies wanneer dat nodig was. Heel hartelijk dank voor uw vertrouwen in mij. Dr. G.J. de Borst, beste GJ. Ik heb je leren kennen tijdens mijn eerste co-schap chirurgie in het Diak. Tijdens mijn semi-arts stage in het UMC kwamen we elkaar weer tegen en heb jij het onmogelijke bij mij voor elkaar gekregen; je hebt me enthousiast gemaakt voor wetenschappelijk onderzoek! Het heeft geresulteerd in een aantal jaren waarin we intensief

207

met elkaar hebben samen gewerkt en uiteindelijk heeft het geleid tot dit proefschrift. Jouw kennis van zaken en jouw enthousiasme zorgden ervoor dat ik het uiteindelijk altijd weer zag zitten. Met name de 3 (!) reviews die je me hebt laten schrijven, hebben me bijna tot wanhoop gedreven, maar goed aan alles komt een einde en in dit geval ook meerdere publicaties. Ik bewonder je gevoel voor de wetenschap; al je ideeën en voorstellen die we hebben uitgewerkt, zijn allemaal gepubliceerd. Dank voor al je ondersteuning de afgelopen jaren en ik kijk er naar uit om straks samen met je te mogen opereren in het UMC. Prof. A.W. Halliday, dear Alison, thank you very much for the opportunity to work on data of the ACST-1 and ACST-2 trial. Hopefully you can agree that it resulted in some good papers. Thank you very much for given me the opportunity to come and join your study group. These months in Oxford were marvellous and a wonderful educational experience. Leden van de Leescommissie, members of the review committee; Prof. Dr. M.L. Bots, Prof. Dr. I.H.M. Borel Rinkes, Prof. Dr. A.W. Halliday, Prof. Dr. L.J. Kappelle, thank you very much for your time and critical assessment of this thesis. Dr. J. Hendrikse, Dr. A.W. van Overbeeke, Dr. R.J. Toorop. Dank voor uw tijd, interesse en bereidheid zitting te nemen in de oppositie.

phd_anne.indb 207

16-5-2013 8:00:21

Dr. J. Hendrikse, beste Jeroen. Vanaf het begin van mijn onderzoekstijd zijn wij met elkaar in contact geweest. Eerst met enkele projecten die helaas nergens op uit zijn gelopen, maar uiteindelijk ook over studies en ideeën die allemaal nu nog uitgevoerd worden. De kans die jij me geboden hebt door deel te nemen aan het ParisK onderzoek heb ik altijd enorm gewaardeerd. Tevens hoop ik dat er nog mooie resultaten gaan komen uit onze studie over de 7Tesla MRI. Hopelijk blijft de samenwerking nog jaren bestaan tussen de vaatchirurgie en de radiologie, waarbij de wetenschap aan 2 kanten versterkt kan worden. Dank. Prof. Dr. A. Algra, beste Ale, heel hartelijk dank voor de prettige samenwerking tijdens enkele projecten die in dit proefschrift beschreven staan. Jouw punctualiteit en kritische blik hebben geleid tot mooie stukken waarvoor ik je erg dankbaar ben. Prof. Dr. L.J. van Kappelle. Heel veel dank voor het altijd snelle reviseren van mijn stukken met kritisch, maar ook opbouwend commentaar. Ik heb de samenwerking altijd zeer gewaardeerd. Co-auteurs. Anja van der Kolk, Boudewijn Reichmann, Guus van Lammeren, Margriet Fokkema, Nolan Hartkamp en Sandra Bovens. Vele uren heeft het gekost, veel data hebben

208

we met elkaar verzameld en veel mails zijn over en weer gegaan, maar naar mijn idee heeft het uiteindelijk altijd geleid tot een mooi artikel. Heel veel dank voor onze prettige samenwerking. Graag wil ik all secretaresses van de afdeling Heelkunde in het UMCU bedanken. In het bijzonder Susan en Coby. Super dat ik voor alles bij jullie terecht kon en ik heb altijd erg genoten van alle momenten ‘bij’ praten met een kop koffie of wat lekkers. Anneke Hamersma, trial coördinator voor de radiologie. Zonder jouw hulp was het nooit gelukt om alle patiënten in te plannen voor hun MRI. Heel hartelijk dank voor het snelle schakelen en al het regelen. Dear Steffi, Ally, Carol and Flora. Thank you for the great time I have had in Oxford. I really enjoyed your hospitality and all your interest in my work and life. Hopefully we will see each other again. Steffi, especially you made my visit warm and pleasant. We had a wonderful time and I hope to see you again soon. All other people in the Oxford office, thank you for making my visit unforgettable. Dr. A. van Overbeeke, beste Adriaan. Sinds juli 2012 ben ik in opleiding tot chirurg onder uw supervisie. Ik ben elke dag enorm blij dat ik een deel van mijn opleiding in het Meander mag genieten. Dank voor uw begeleiding en expertise. Mooi dat u in de oppositie plaats neemt.

phd_anne.indb 208

16-5-2013 8:00:21

ACKNOWLEDGEMENTS | CHAPTER 13

Dr. M.R. Vriens, beste Menno. Dank voor het gestelde vertrouwen als assistent in opleiding tot chirurg. Ik kijk uit naar de jaren die ik straks onder jouw supervisie in het UMCU zal doorbrengen. Alle stafleden en arts-assistenten van de afdeling Heelkunde in het Meander Medisch Centrum Amersfoort, dank voor jullie interesse in mijn proefschrift. Vanaf nu kan ik me volledig focussen op alle mooie dingen in het Meander. Ik verheug me op de aankomende jaren als arts-assistent chirurgie in Amersfoort. Alle stafleden, arts-assistenten en onderzoekers van de afdeling Heelkunde in het UMCU, dank voor jullie interesse in mijn proefschrift. Ik verheug me op mijn tijd als AIOS vanaf 2015 in het UMCU. Voor mijn (oud) kamergenoten: Char, Emily, Roy, Klaas, Pieter, Jakob en Maarten. Heerlijk om met jullie over werk te kunnen praten, maar met name het even afblazen was top. Er was altijd tijd om mooie muziekjes te luisteren en na werk de kroeg in te gaan of een feestje mee te pakken. In het bijzonder: lieve Jasper, ik heb genoten van alles wat we samen deden, de lol die we

209

samen hebben gehad en alle liedjes en voetbalmomenten die we deelden. Helaas was dit alles te snel voorbij! Mijn andere collega-onderzoekers: Claire Pennekamp, Benjamin Emmink, Ernst Steller, Lutske Lodewijk, Okan Bastian, Marjolein Heeres, Martin Teraa, Guus van Lammeren, Vincent Scholtes, Herman Zandvoort, Dave Koole, Kathelijne Groeneveld, Samira Fegrachi, Siegrid de Meer, Peter Paul Wisman, Frederik Hoogwater, Nikol Snoeren, Tjaakje Visser, Eline van Hattum, Stijn van Esser en Femke Mauritz. Dank voor alle inhoudelijke discussies en de leuke tijden bij alle borrels en feestjes. Myra Nijman. Heel veel dank voor het verwerken van mijn lay-out. Jouw perfectionisme en punctualiteit hebben ervoor gezorgd dat het er top uit ziet. Dank. Troy van der Lugt en Jeroen Fontein. Troy, dank voor het opzetten van de uitwerking van Jeroen zijn idee voor de voorkant van mijn proefschrift. Jeroen, heel speciaal dat jij de omslag van dit boek bedacht hebt. Voor al mijn vrienden: ja eindelijk het is af. Vanaf nu ben ik als vanouds weer overal (tot het einde) bij. Dank voor jullie onvoorwaardelijke support en begrip voor alles!

phd_anne.indb 209

16-5-2013 8:00:21

Lieve Char en Houwie, mijn paranimfen, fantastisch dat jullie mijn paranimfen willen zijn. Houwie, lieve Marijn, mooi en bijzonder dat je na zoveel jaren vriendschap vandaag naast mij staat. Ik ben blij dat je op tijd wakker bent geworden en toch voor het mooiste vak hebt gekozen, hopelijk mogen we later samen nog ergens aan tafel staan. Daarnaast geniet ik van alle andere dingen die we samen delen: nèt iets te grote mond, nèt iets te snel een mening, nèt iets te hard schreeuwen, voetbal en natuurlijk het hebben van een goed gesprek met een biertje erbij. Op naar nog vele mooie jaren. Lieve Char, eten, drinken en genieten…dit zijn 3 woorden die op ons allebei slaan en ook op onze vriendschap. Ik heb genoten van alle momenten op onze kamer; of het nou om statistiek ging of om eten, gezelligheid of serieuze zaken, het is eigenlijk altijd leuk. Mooi dat we de afgelopen jaren zo naar elkaar zijn toe gegroeid en ik kijk alleen maar uit naar de komende jaren van onze vriendschap. Dank ook voor alle logeerpartijtjes en hopelijk houden we alle cursussen er gezamenlijk in. Ik vind het fantastisch dat je vandaag naast mij staat en kijk er naar uit om ooit samen met je te mogen opereren. Lieve Maud, JB, Julie en Mees, leuk dat jullie nu ook bij ‘mijn’ familie horen. Maud en JB; het

210

is te gek om zo met elkaar om te kunnen gaan en zo dicht bij elkaar te wonen. Julie en Mees; toppertjes, ik hoop nog vaak op jullie te mogen passen! Lieve Frans en Anna, wat bof ik met zulke ‘schoonouders’. Dank voor al jullie interesse. De bezoekjes bij jullie in Curaçao en alle andere momenten zijn altijd gezellig, vol mooie gesprekken. Heel leuk en speciaal dat jullie er vandaag bij zijn, helemaal overgekomen uit Curaçao. Lieve Opa en Oma, wat ongelooflijk bijzonder dat jullie erbij zijn vandaag! Ik kan me geen betere opa en oma wensen. Ik geniet altijd van alle momenten met elkaar en hoop dat er nog velen zullen volgen; op naar nog vele jaren in een goede conditie! Lieve Koen en Joost, mijn broer en broertje. Dank voor jullie support en interesse, ook al vinden jullie het soms maar onbegrijpelijk wat ik doe. Nu heb ik eindelijk een keer de kans om openlijk te zeggen dat ik trots ben op jullie, heel erg trots zelfs! En jongens; geen doel is te ver als je plezier hebt in wat je doet. Keep on going ;)

phd_anne.indb 210

16-5-2013 8:00:21

ACKNOWLEDGEMENTS | CHAPTER 13

Lieve Papa en Mama, ja het is af, eindelijk. Dit boek draag ik op aan jullie! Jullie hebben me altijd de kans en ruimte gegeven om te zijn wie ik ben. Jullie hebben me altijd gesteund in alles wat ik doe en jullie vertrouwen en jullie onvoorwaardelijke steun hebben mede geleid tot dit proefschrift. Waarvoor heel veel dank! Mam, je hebt maar één dochter en die kan zich geen betere moeder wensen, onthoud dat goed! Trots ben ik er op hoe je het altijd allemaal regelt om ons bij elkaar te krijgen. Pap, fantastisch om, naast alle andere gedeelde passies en onze onvoorwaardelijke band, ook onze interesse in de medische wereld met elkaar te kunnen delen! Lieve Jeroen, jij bent onbeschrijflijk, dus ik houd het kort. Mijn rots in de branding, mijn rustpunt, mijn denker, mijn maatje, maar bovenal degene bij wie ik elke dag wil zijn en met wie ik elke dag van het leven geniet. Dank voor al je begrip, steun en support!

211

phd_anne.indb 211

16-5-2013 8:00:21

phd_anne.indb 212

16-5-2013 8:00:21

LIST OF PUBLICATIONS | CHAPTER 13

LIST OF PUBLICATIONS den Hartog AG, Halliday AW, Hayter E, Pan H, Kong X, Moll FL, de Borst GJ, on behalf of the Asymptomatic Carotid Surgery Trial (ACST) Collaborators*. The risk of stroke from new carotid artery occlusion during follow-up in the Asymptomatic Carotid Surgery Trial (ACST-1). Stroke. 2013 Apr 30. Epub ahead of print. Fokkema TM, Reichmann BL, den Hartog AG, Klijn CJM, Moll FL, de Borst GJ. Selective external endarterectomy in patients with symptomatic internal carotid artery occlusion. J Vasc Surg. 2013 Mar 9. Epub ahead of print. den Hartog AG, Achterberg S, Moll FL, Kappelle LJ, Visseren FLJ, van der Graaf Y, Algra A, de Borst GJ, on behalf of the SMART Study Group. Asymptomatic carotid artery stenosis and the risk of ischemic stroke in patients with clinical manifest arterial disease. Stroke. 2013 Apr;44(4):1002-7. den Hartog AG, Bovens SM, Koning W, Hendrikse J, Luijten PR, Moll FL, Pasterkamp G, de

213

Borst GJ. Current status of clinical magnetic resonance imaging for plaque characterization in patients with carotid artery stenosis. Eur J Vasc Endovasc Surg. 2013 Jan;45(1):7-21. den Hartog AG*, van Lammeren GW*, Pasterkamp G, Vink A, de Vries JPPM, Moll FL, de Borst GJ. Asymptomatic Carotid Artery Stenosis: Identification of Subgroups with Different Underlying Plaque Characteristics. Eur J Vasc Endovasc Surg. 2012 Apr 14. Fokkema TM, den Hartog AG, Bots ML, van der Tweel I, Moll FL, de Borst GJ. Stenting versus surgery in patients with carotid stenosis after previous cervical radiation therapy: systematic review and meta-analysis. Stroke. 2012 Mar;43(3):793-801.

phd_anne.indb 213

16-5-2013 8:00:22

Fokkema FM, den Hartog AG, van Lammeren GW, Bots ML, Pasterkamp G, Vink A, Moll FL, de Borst GJ. Radiation-induced Carotid Stenotic Lesions have a more Stable Phenotype than De Novo Atherosclerotic Plaques. Eur J Vasc Endovasc Surg. 2012 Jun;43(6):643-8. van der Kolk AG, de Borst GJ, Jongen LM, den Hartog AG, Moll FL, Mali WP, Hendrikse J. Prevalence and Clinical Consequences of Carotid Artery Residual Defects Following Endarterectomy: A Prospective CT Angiography Evaluation Study. Eur J Vasc Endovasc Surg. 2011 Apr 29. den Hartog AG, Bovens SM, Koning W, Hendrikse J, Pasterkamp G, Moll FL and de Borst GJ. PLACD-7T Study: Atherosclerotic Carotid Plaque Components Correlated with Cerebral Damage at 7 Tesla Magnetic Resonance Imaging. Curr Cardiol Rev. 2011 Feb;7(1):28-34. van der Kolk AG, de Borst GJ, den Hartog AG, Kooi ME, Mali WP, Hendrikse J. Hyperintense

214

carotid plaque on T(1)-weighted turbo-field echo MRI in symptomatic patients with low-grade carotid stenosis and carotid occlusion. Cerebrovasc Dis. 2010 Aug;30(3):221-9. den Hartog AG, Algra A, Moll FL, de Borst GJ. Mechanisms of gender-related outcome differences after carotid endarterectomy. J Vasc Surg. 2010 Oct;52(4):1062-71, 1071.e1-6. Halliday AW, Bulbulia R, Naughten A, den Hartog AG, Delmestri A, Wallis C, le Conte S, MacDonald S, on behalf of the Asymptomatic Carotid Surgery Trial (ACST) Collaborators. Is Carotid Intervention in Trials becoming safer? Some early results from the ACST-2 (Asymptomatic Carotid Surgery-2) Trial. Submitted. den Hartog AG, Hartkamp N, Moll FL, Hendrikse J, Halliday AW, de Borst GJ. The influence of revascularization on cerebral perfusion in patients with asymptomatic carotid artery stenosis. Submitted.

phd_anne.indb 214

16-5-2013 8:00:22

LIST OF PUBLICATIONS | CHAPTER 13

den Hartog AG, Moll FL, van der Worp B, Kapelle LJ, de Borst GJ. Delay to carotid endarterectomy in patients with symptomatic carotid artery stenosis. In preparation. Streifler JY, den Hartog AG, Pan S, Pan H, Bulbulia R, Thomas DJ, Halliday AW, on behalf of the ACST-1 trial collaborators. Importance of previous brain infarcts in patients with asymptomatic carotid stenosis and the impact of surgery from the Asymptomatic Carotid Surgery Trial (ACST-1) trial. In preparation.

215

phd_anne.indb 215

16-5-2013 8:00:22

phd_anne.indb 216

16-5-2013 8:00:22

CURRICULUM VITAE | CHAPTER 13

CURRICULUM VITAE Anne Geerte den Hartog was born on August 29th 1982 in Leiderdorp, the Netherlands. She graduated from the Katholiek Gelders Lyceum in Arnhem in 2001. The same year she started her medical school at the University of Utrecht, the Netherlands. In 2003 she interrupted her medical study for a period of 12 months to become a member of the board that organised the 105th anniversary of her student sorority. Her interest into Surgery began during a junior internship at the Surgical Department of the Diakonessen Hospital Utrecht in 2005. After graduation from Medical School in 2008 she started working as a surgical resident (ANIOS) at the surgical department of the Meander Medical Center in Amersfoort. She commenced working as a PhD-student from July 2009 at the Department of Vascular Surgery of the University Medical Center of Utrecht, under the supervision of Prof. Dr. F.L. Moll en Dr. G.J. de Borst. In January 2012 she attended the University of Oxford for a research fellowship at the Nuffield Department of Surgical Sciences in the John Radcliffe Hospital in Oxford, United Kingdom (Prof. A.W. Halliday). She started her official surgical residency in July 2012 at the Meander Medical Center in Amersfoort (Dr. A. van Overbeeke). In 2015 she will continue her surgical training in the UMC Utrecht (Dr. M.R. Vriens).

phd_anne.indb 217

217

16-5-2013 8:00:22

phd_anne.indb 218

16-5-2013 8:00:22

phd_anne.indb 219

16-5-2013 8:00:22

phd_anne.indb 220

16-5-2013 8:00:22