
==== Front
J Cardiovasc Magn Reson
J Cardiovasc Magn Reson
Journal of Cardiovascular Magnetic Resonance
1097-6647
1532-429X
Elsevier

S1097-6647(24)01098-6
10.1016/j.jocmr.2024.101071
101071
Editorial
Unfinished debate: Why IPH-based metrics are still needed—An Editorial for “Signal intensity and volume of carotid intraplaque hemorrhage on magnetic resonance imaging and the risk of ipsilateral cerebrovascular events: the Plaque At RISK (PARISK) study”
Yuan Chun
Department of Radiology and Imaging Sciences, University of Utah, Salt Lake City, Utah, USA
Department of Radiology, University of Washington, Seattle, Washington, USA
Canton Gador
Department of Radiology, University of Washington, Seattle, Washington, USA
Hatsukami Thomas S.
Department of Surgery, University of Washington, Seattle, Washington, USA
08 8 2024
2024
08 8 2024
26 2 10107117 7 2024
26 7 2024
© 2024 The Author(s)
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Abbreviations

IPH intraplaque hemorrhage

SIR signal intensity ratio

MRI magnetic resonance imaging

TIA transient ischemic attack

IQR interquartile range
==== Body
pmcIntraplaque hemorrhage (IPH) has emerged as a marker of carotid plaque vulnerability [1], as its presence has been associated with both rapid plaque progression [2] and future ischemic cerebrovascular events [3], regardless of symptom status [4] or degree of stenosis [5], [6], [7], [8]. As the strongest imaging marker associated with the occurrence of stroke [5], IPH has been the focus of multiple studies aiming to better understand its etiology and underlying pathophysiology [9], [10], [11], and to identify the best IPH-based feature that could be used clinically as event predictor [6], [12], [13], [14]. With respect to the most clinically useful feature, cross-sectional studies have suggested IPH signal intensity ratio (SIR) and volume as potential predictors of future ipsilateral ischemic events [12], [14].

Nies et al. [15] have assessed whether IPH SIR and volume are associated with a higher risk of new or recurrent ipsilateral cerebrovascular events in the subset of 87 patients from the Plaque At Risk cohort that had IPH in the ipsilateral carotid artery. These patients underwent magnetic resonance (MR) brain and carotid imaging at baseline to characterize their carotid plaque features, a clinical follow-up after 3 months and yearly thereafter for up to 5 years to record any recurrent ipsilateral cerebrovascular event. Sixty-nine of the 87 patients underwent a follow-up brain magnetic resonance imaging (MRI) after 2 years to identify any new clinically silent ipsilateral ischemic events. At baseline, a cerebral stroke was identified in 53% of participants, transient ischemic attack (TIA) in 36%, and amaurosis fugax in the remaining 11%. The median degree of stenosis was 23 (interquartile range [IQR]: 5–36), the median IPH SIR was 2.6 (IQR: 2–4.5), and median IPH volume was 115 µL (IQR: 29–238). Throughout a median follow-up of 5.1 (IQR: 3.1–5.6) years, 21 (24.1%) patients experienced a total of 22 recurrent ipsilateral ischemic events (9 strokes, 11 TIAs, and 2 amaurosis fugax). At the 2-year brain MR scan, a new ipsilateral brain infarct was detected in 12 (17.4%) patients. Neither IPH SIR nor IPH volume was associated with recurrent clinical ipsilateral ischemic events nor silent infarction on follow-up MRI. These findings remained true after adjusting for different factors (such as age, sex, degree of stenosis, plaque features, or index event) and after excluding patients with amaurosis fugax. Nies et al. [15] concluded that measuring IPH SIR and volume did not provide additional prognostic value, but that the much simpler task of identifying the mere presence of IPH is sufficient for risk stratification, which would markedly streamline clinical workflow.

Why IPH-based metrics are still needed

Given the relevance of IPH presence, studies are still needed to understand the mechanisms linking IPH with events, as well as those behind IPH occurrence. It is already established that IPH leads to rapid plaque burden progression [2] and that it is associated with plaque surface disruption [16] and adventitial inflammation [17], factors that can lead to an increase in luminal stenosis and/or thrombus formation. However, IPH pathogenesis is less understood, though recent studies are shedding some light on IPH development, suggesting a potential interaction between plaque calcification, blood pressure, and new IPH [18]. For studies investigating factors associated with IPH progression or regression, quantitative IPH metrics will play a vital role.

Though the results from Nies et al. [15] may impact clinical practice, the clinical relevance is limited to symptomatic patients with ipsilateral, mildly stenotic (<50%), IPH carotid plaques. It is unknown whether IPH SIR and/or volume can predict events in patients with moderate-to-severe carotid stenosis, patients with asymptomatic carotid atherosclerosis, or which plaque may be at higher risk in symptomatic/asymptomatic patients with bilateral IPH. While analysis of the contralateral carotid plaque may provide some insight into this cohort, a much larger study will be required to address this question.

Another limitation of their study is the lack of repeat carotid vessel wall imaging after the recurrent ischemic event, as this may have shed light on whether increased IPH volume/SIR follows, rather than precedes plaque rupture events. If this is indeed the case, it may explain the discrepancy between Nies’ findings and those of previous studies [12], [14] that demonstrated greater IPH volume or higher IPH SIR in previously symptomatic plaques.

In summary, though IPH-based metrics may not be needed to identify patients at risk of recurrent ischemic events, quantification is still needed to 1) elucidate IPH pathophysiology, 2) determine whether symptomatic plaques demonstrate an increase IPH volume/SIR at the time of, or following recurrent carotid plaque rupture events, and 3) the event risk in asymptomatic patients, specifically when there is bilateral IPH.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
==== Refs
References

1 Saba L. Saam T. Jäger H.R. Yuan C. Hatsukami T.S. Saloner D. Imaging biomarkers of vulnerable carotid plaques for stroke risk prediction and their potential clinical implications Lancet Neurol 18 2019 559 572 30954372
2 Takaya N. Yuan C. Chu B.C. Saam T. Polissar N.L. Jarvik G.P. Presence of intraplaque hemorrhage stimulates progression of carotid atherosclerotic plaques - a high-resolution magnetic resonance imaging study Circulation 111 2005 2768 2775 15911695
3 Gupta A. Baradaran H. Schweitzer A.D. Kamel H. Pandya A. Delgado D. Carotid plaque MRI and stroke risk a systematic review and meta-analysis Stroke 44 2013 3071 3077 23988640
4 Takaya N. Yuan C. Chu B.C. Saam T. Underhill H. Cai J.M. Association between carotid plaque characteristics and subsequent ischemic cerebrovascular events - a prospective assessment with MRI - initial results Stroke 37 2006 818 823 16469957
5 Saam T. Hetterich H. Hoffmann V. Yuan C. Dichgans M. Poppert H. Meta-analysis and systematic review of the predictive value of carotid plaque hemorrhage on cerebrovascular events by magnetic resonance imaging J Am Coll Cardiol 62 2013 1081 1091 23850912
6 Larson A.S. Brinjikji W. Savastano L. Rabinstein A.A. Saba L. Huston J. Carotid intraplaque hemorrhage and stenosis: at what stage of plaque progression does intraplaque hemorrhage occur, and when is it most likely to be associated with symptoms? AJNR Am J Neuroradiol 42 2021 1285 1290 33888452
7 Underhill H.R. Yuan C. Yarnykh V. Chu B. Oikawa M. Polissar N.L. Arterial remodeling in the subclinical carotid artery disease J Am Coll Cardiol Imaging 2 2009 1381 1389
8 Schindler A. Schinner R. Altaf N. Hosseini A.A. Simpson R.J. Esposito-Bauer L. Prediction of stroke risk by detection of hemorrhage in carotid plaques meta-analysis of individual patient data JACC Cardiovasc Imaging 13 2020 395 406 31202755
9 Sun J. Canton G. Balu N. Hippe D.S. Xu D. Liu J. Blood pressure is a major modifiable risk factor implicated in pathogenesis of intraplaque hemorrhage an in vivo magnetic resonance imaging study Arterioscler Thromb Vasc Biol 36 2016 743 749 26848155
10 Daemen M.J. Ferguson M.S. Gijsen F.J. Hippe D.S. Kooi M.E. Demarco K. Carotid plaque fissure: an underestimated source of intraplaque hemorrhage Atherosclerosis 254 2016 102 108 27718372
11 Sun J. Underhill H.R. Hippe D.S. Xue Y.J. Yuan C. Hatsukami T.S. Sustained acceleration in carotid atherosclerotic plaque progression with intraplaque hemorrhage: a long-term time course study JACC Cardiovasc Imaging 5 2012 798 804 22897993
12 Saba L. Micheletti G. Brinjikji W. Garofalo P. Montisci R. Balestrieri A. Carotid intraplaque-hemorrhage volume and its association with cerebrovascular events AJNR Am J Neuroradiol 40 2019 1731 1737 31558503
13 Liu Y. Wang M.X. Zhang B. Wang W. Xu Y. Han Y.J. Size of carotid artery intraplaque hemorrhage and acute ischemic stroke: a cardiovascular magnetic resonance Chinese atherosclerosis risk evaluation study J Cardiovasc Magn Reson 21 2019 36
14 Wang X.L. Sun J. Zhao X.H. Hippe D.S. Hatsukami T.S. Liu J. Ipsilateral plaques display higher T1 signals than contralateral plaques in recently symptomatic patients with bilateral carotid intraplaque hemorrhage Atherosclerosis 257 2017 78 85 28110259
15 Nies K.P.H. Aizaz M. van Dam-Nolen D.H.K. Goring T.C.D. Schreuder T.A.H.C. van Orshoven N.P. Signal intensity and volume of carotid intraplaque hemorrhage on magnetic resonance imaging and the risk of ipsilateral cerebrovascular events: the Plaque At RISK (PARISK) study J Cardiovasc Magn Reson 26 2024 101049
16 van Dijk A.C. Truijman M.T. Hussain B. Zadi T. Saiedie G. de Rotte A.A. Intraplaque hemorrhage and the plaque surface in carotid atherosclerosis: the Plaque At RISK study (PARISK) AJNR Am J Neuroradiol 36 2015 2127 2133 26251429
17 Sun J. Song Y. Chen H. Kerwin W. Hippe D. Dong L. Adventitial perfusion and intraplaque hemorrhage a dynamic contrast-enhanced MRI study in the carotid artery Stroke 44 2013 1031 1036 23471271
18 Canton G. Baylam Geleri D. Hippe D.S. Sun J. Guo Y. Balu N. Chu B. Pimentel K. Akçiçek H. Yaman Akçiçek E. Tirschwell D. Tang G. Kohler T. Shibata D. Ferguson M.S. Yuan C. Hatsukami T.S. Pathophysiology of carotid atherosclerosis: Calcification, intraplaque haemorrhage and pulse pressure as key players Eur J Radiol 178 2024 111647 10.1016/j.ejrad.2024.111647 Epub ahead of print. PMID: 39068857. 39068857
