Response to Letters by Hsieh and Chen, and by Tang et al
We appreciate Hsieh and Chen’s interest in our study. We agree that understanding the pathomechansim of the development of intraplaque hemorrhage (IPH) is of key importance that may help to develop therapeutic strategies to arrest or reverse the processes of atherosclerosis. Although no direct causal relationship between IPH and embolic stroke has been established, a number of studies have highlighted IPH as a marker of plaque rupture.1–3 The noninvasive detection of MR IPH will prove very useful for future in vivo pathophysiological studies.
We also thank Tang and colleagues for their interest in our work and the opportunity to clarify their misunderstanding. It was our study aim to evaluate the clinical relevance of a previously described and histologically validated MRI surrogate marker of the unstable plaque.4 From a clinical practice perspective it is desirable to identify patients at high or low risk of subsequent events, within a group of patients with symptomatic carotid stenosis. For this reason, we tested whether MRI signs of intraplaque hemorrhage predict subsequent clinical events. We found that 14/44 patients with MR IPH developed symptoms while awaiting carotid endarterectomy, whereas only 2/22 without MR IPH did so (hazard ratio, 4.8). We also showed that MR IPH was an independent risk factor and had additional value beyond existing risk factors, such as the presence of IHD. In this regard, the raised concerns are irrelevant.
We certainly agree that our observation does not provide evidence for a direct cause and effect relationship, and as mentioned in the reply to Hsieh and Chen, we agree that interrogation of the pathomechanism that leads to IPH and its potential causal relationships to embolic events will be of key interest for future studies. Nevertheless, absence of such proof does not invalidate our findings using MR IPH as surrogate marker.
We also cannot share Tang and colleagues concerns regarding the contralateral asymptomatic carotid artery. The fact that high-grade stenosis predicts stroke more strongly in symptomatic carotid disease compared with asymptomatic carotid disease does not invalidate the risk prediction. Tang and colleagues are incorrect to imply that if IPH is found in the contralateral carotid artery and then remains asymptomatic (for the study duration of 1 month), then IPH cannot be a risk factor for recurrence in the ipsilateral, symptomatic side. It is, however, an interesting question whether IPH predicts clinical events in asymptomatic carotids, and this has been shown by Takaya et al.5 The request to study contralateral events in the context of our study is, however, ill posed because it overlooks the expected incidence of ischemic events in patients with asymptomatic carotid stenosis over a period of 1 month.
Tang and colleagues propose to look into the predictive value of MR IPH in patients with mild to moderate degree carotid stenosis who will not undergo carotid endarterectomy. We have undertaken exactly this study design and were able to show that ipsilateral MR IPH also predicts subsequent neurological events in symptomatic patients with symptomatic mild and moderate degree stenosis.6
Tang and colleagues question the reliability of the MR IPH detection. The chosen MR sequence uses a water selected pulse effectively suppressing fat and lipids. Furthermore, high accuracy in predicting the unstable plaque has been previously demonstrated.7 Other groups independently tested the prediction of IPH using T1-weighted MR sequences showing that gradient-echo sequences (such as ours) outperform spin-echo sequences.8 Assessing presence or absence of MR IPH signal requires very little training, is easy and previously published κ values of blinded assessors show high interrater reliability.7,9 We chose 2 assessors as part of good research practice to ensure that human errors in coding and reporting were avoided.
We wish to maintain our statement about the clinical importance of our findings, simply because we feel it is important for these findings to be available to clinicians. It is well recognized that the benefit from carotid endarterectomy is directly related to the absolute risk of the patients in whom it is used: in patient groups with a very low risk of a stroke then a carotid endarterectomy is of little use, but in patient groups at very high risk then the benefits of the procedure are large. MR IPH is one step toward identifying such groups. We certainly agree that more, replicating, data from other centers are required.
Virmani R, Kolodgie FD, Burke AP, Finn AV, Gold HK, Tulenko TN, Wrenn SP, Narula J. Atherosclerotic plaque progression and vulnerability to rupture: angiogenesis as a source of intraplaque hemorrhage. Arterioscler Thromb Vasc Bio. 2005; 25: 2054–2061.
Redgrave JN, Lovett JK, Gallagher PJ, Rothwell PM. 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.
Altaf N, MacSweeney ST, Gladman J, Auer DP. Carotid intraplaque hemorrhage predicts recurrent symptoms in patients with high-grade carotid stenosis. Stroke. 2007; 38: 1633–1635.
Takaya N, Yuan C, Chu B, Saam T, Underhill H, Cai J, Tran N, Polissar NL, Isaac C, Ferguson MS, Garden GA, Cramer SC, Maravilla KR, Hashimoto B, Hatsukami TS. Association between carotid plaque characteristics and subsequent ischemic cerebrovascular events: a prospective assessment with MRI—initial results. Stroke. 2006; 37: 818–823.
Altaf N, Daniels LR, Morgan PS, Auer DP, MacSweeney ST, Moody AR, Gladman JR. Detection of intraplaque hemorrhage by magnetic resonance imaging in symptomatic patients with mild to moderate carotid stenosis predicts recurrent neurological events. J Vasc Surg. 2007;In press.
Moody AR, Murphy RE, Morgan PS, Martel AL, Delay GS, Allder S, MacSweeney ST, Tennant WG, Gladman J, Lowe J, Hunt BJ. Characterization of complicated carotid plaque with magnetic resonance direct thrombus imaging in patients with cerebral ischemia. Circulation. 2003; 107: 3047–3052.