Imaging to Assess the Effect of Anti-Inflammatory Therapy in Aortic and Carotid Atherosclerosis∗

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY

VOL. 68, NO. 16, 2016

ª 2016 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

ISSN 0735-1097/$36.00

PUBLISHED BY ELSEVIER

http://dx.doi.org/10.1016/j.jacc.2016.08.011

EDITORIAL COMMENT

Imaging to Assess the Effect of Anti-Inflammatory Therapy in Aortic and Carotid Atherosclerosis* Xue-Qiao Zhao, MD,a Chun Yuan, PHD,b Prediman K. Shah, MDc

A

considerable body of experimental and clin-

canakinumab did not reduce atherosclerotic burden

ical evidence has implicated inflammation

nor improve arterial function significantly compared

in the pathogenesis of atherosclerosis and

to placebo during a 12-month period, even though the

its complications, such as plaque disruption and

drug did significantly decrease circulating levels

thrombosis (1,2). Because elevated levels of athero-

of

genic (containing apolipoprotein B-100) lipoproteins

C-reactive protein (hsCRP) and IL-6.

inflammatory

markers,

both

high-sensitivity

play a major role in initiation and progression of

These results are disappointing in view of IL-1b ’s

inflammation and atherosclerosis, the primary thera-

previously established role in inflammation and

peutic target for atherosclerosis involves interven-

atherogenesis and its favorable effects on inhibiting

tions such as statins that reduce circulating levels of

IL-1 b signaling in animal models of atherosclerosis

atherogenic lipoproteins. Although attractive, inter-

(4,5). What could explain the lack of effect on athero-

ventions directly targeting inflammatory pathways

sclerosis burden and vascular function despite a

remain largely unproven.

compelling hypothesis? Among the possible explana-

SEE PAGE 1769

In this issue of the Journal, Choudhury et al. (3) presented the results of a multicenter investigation of the effects of the anti-inflammatory agent canakinumab, an interleukin (IL)-1 b inhibitor, on arterial

tions are poor subject selection; limits of the imaging methodology;

suboptimal

endpoints,

suboptimal

dosing, and inadequate duration of treatment; and even the possibility of an incorrect hypothesis.

SUBJECT AND ENDPOINT SELECTION

structure and function as assessed by magnetic resonance imaging (MRI) in patients with clinical

Enrolled patients had clinically high-risk atheroscle-

evidence of atherosclerosis and either type 2 diabetes

rotic vascular disease, with 90% having coronary

or impaired glucose tolerance. We congratulate the

artery disease, 22% a history of stroke, and 69% dia-

investigators for this international MRI study of

betes of $5 years’ duration. They were also treated

both carotid arteries and aorta in 189 qualified sub-

with standard-of-care medications for cardiovascular

jects. The collaborative effort demonstrated that

disease and diabetes: 95% were on antiplatelet agents, 98% were on a statin, and 73% were on an angiotensinconverting enzyme inhibitor; 63% had a glycosylated

*Editorials published in the Journal of the American College of Cardiology

hemoglobin #7%, and the average hsCRP was 1.8 mg/l.

reflect the views of the authors and do not necessarily represent the

The problem is that aggressive standard therapies

views of JACC or the American College of Cardiology. From the aDepartment of Cardiology, University of Washington, Seattle, Washington;

b

Department of Radiology, University of Washington,

may have made it difficult to demonstrate effectiveness of incremental therapy with canakinumab.

Seattle, Washington; and the Department of Medicine, Cedars-Sinai

It is unclear in the current study how many sub-

Heart Institute, West Hollywood, California. Dr. Zhao has received

jects had carotid lesions with advanced plaque

research grant support from AstraZeneca and KOWA; and consulting fees

features, such as a lipid-rich necrotic core (LRNC).

c

from Amgen and Sanofi. Dr. Yuan has received research grant support from Philips Healthcare; and has served as a member of the Philips

In a similar population in the AIM-HIGH (Athero-

Radiology Advisory Medical Network. Dr. Shah has reported that he has

thrombosis Intervention in Metabolic Syndrome

no relationships relevant to the contents of this paper to disclose.

with Low HDL/High Triglycerides: Impact on Global

Zhao et al.

JACC VOL. 68, NO. 16, 2016 OCTOBER 18, 2016:1781–4

Imaging of AI Therapy in Atherosclerosis

F I G U R E 1 Percent Wall Volume Change Over 2 Years

50 45 40 Percent Wall Volume (%)

1782

P<0.001 46.6

Baseline 2 years

44.5 P=NS

35

36.7 36.3

30

associated with clinical cerebrovascular and coronary events. Previous MRI studies involving lipid-altering therapy

provided

valuable

insights

on

plaque

burden reduction in relation to plaque LRNC and fibrous tissue changes. The CPC (Carotid Plaque Composition by MRI during Lipid Lowering) study showed that plaque LRNC reduction preceded plaque regression during intensive lipid-lowering therapy, and plaques containing

25

LRNC had significantly more plaque volume regression

20

than those without (16). The differential plaque volume regression in plaques with and without LRNC was

15

subsequently confirmed in a subject-based analysis of

10

the CPC study, with a larger sample size. Percent of

5

wall volume (PWV) decreased significantly from

0

46.6
1.1% to 44.5
1.0% (p < 0.001) over 2 years of LRNC(+) (n=46)

LRNC(-) (n=67)

lipid therapy in 46 subjects with LRNC at baseline, but did not change (36.7
0.6% vs. 36.3
0.5%) in 67 subjects without LRNC (Figure 1).

Among a subset of 113 participants in the CPC (Carotid Plaque Composition by MRI during Lipid Lowering) study, 46 were identified to have lipid-rich necrotic core (LRNC) at baseline and 67 were without. Percent wall volume

Furthermore, Du et al. (17) recently showed that 4 years of statin therapy resulted in continued decrease

decreased significantly over 2 years of intensive lipid therapy in LRNC(þ)

in LRNC and an increase in fibrous tissue without

subjects, but did not change in subjects without LRNC. LRNC(þ) ¼ had

significant change in PWV. These data suggested that

lipid-rich necrotic core; LRNC(-) ¼ did not have lipid-rich necrotic core.

plaque burden measurement alone is unable to reveal complex tissue composition changes, including LRNC reduction and increase of fibrous tissue and calcium

Health Outcomes) carotid MRI substudy (6), 52% of

content during extended statin therapy.

AIM-HIGH study patients had LRNC and 11% had advanced, American Heart Association type VI lesions with possible surface defects, intraplaque hemor-

NEOVASCULARIZATION, PERMEABILITY, AND INFLAMMATION

rhage (IPH), or mural thrombus. Conversely, it is highly likely that some of the current study partici-

Inflammatory cells, such as monocyte macrophages,

pants did not have atherosclerotic plaques with these

appear to enter plaques from the luminal side as

high-risk features. Beyond selecting subjects with an

well as from the adventitial vasa vasorum via

increased inflammatory state—as Choudhury et al. (3)

neovascularization. Studies have shown that neo-

recognized—it may be important, too, to include pa-

vasculature and macrophage content are topographi-

tients with high-risk plaque features to examine

cally

effects of newer treatments. The presence of plaques

microvessels are immature, fragile, and leaky, and

with LRNC seems to determine plaque regression in

express cellular adhesion molecules, resulting in the

lipid-lowering therapy (discussed in detail later).

accumulation of inflammatory cells, local extravasa-

A screening MRI to identify subjects with high-risk

tion of plasma proteins, and ultimately the accumu-

and

statistically

associated

(18,19).

New

plaques could be helpful, particularly in phase 2

lation of erythrocytes, an indication of IPH (20).

proof-of-concept studies, for the best chance of

Several studies have suggested the association of vasa

proving the proposed hypothesis. Had Choudhury

vasorum neovascularization with plaque instability

et al. used this approach for subject inclusion, the

(9,21–23). In addition to 18fluorodeoxyglucose positron

results might have been different.

emission tomography, as the authors have suggested,

MRI has emerged as a precise, highly reproducible,

dynamic contrast-enhanced (DCE) MRI using gadolin-

and versatile tool to assess both vascular structure

ium agents can assess plaque perfusion arising from

and function. Importantly, MRI can discriminate and

the adventitial vasa vasorum. Kinetic modeling of

quantify plaque tissue components validated by his-

DCE-MRI can assess elevated vascularity (Vp ¼ partial

tological studies (7,8). Prospective MRI studies of

plasma volume) and vascular permeability (Ktrans ).

carotid lesions (9–15) demonstrated compelling evi-

Because V p and K trans also associate with inflamma-

dence that high-risk plaque features—including IPH, a

tion, DCE-MRI has been used to characterize plaque

large LRNC, and thin or ruptured cap—are strongly

inflammation (24,25). Kerwin et al. (19) reported a

Zhao et al.

JACC VOL. 68, NO. 16, 2016 OCTOBER 18, 2016:1781–4

Imaging of AI Therapy in Atherosclerosis

correlation of 0.8 between Vp estimated by kinetic

3 years (16). The heterogeneity of changes in LRNC

modeling of DCE-MRI and histological measurements

during intensive lipid therapy suggested an individu-

of neovessel areas in subjects undergoing carotid

alized vascular response to a given therapy, which is

endarterectomy. Both Vp and Ktrans correlated with

consistent with findings in recent clinical trials with

plaque macrophage content. DCE-MRI also has been

low-density lipoprotein cholesterol (LDL-C) lowering

shown in multicenter studies to have excellent repro-

(29–31) showing that not everyone benefits equally for

ducibility across scanner platforms (26).

any given reduced LDL-C level. For example, in the

DCE-MRI was used to investigate changes in vasa

IMPROVE-IT (Improved Reduction of Outcomes:

vasorum in the CPC subjects. Dong et al. (27) reported

Vytorin Efficacy International Trial) trial (29), overall,

a drop in adventitial K trans from 0.085 to 0.067 min 1

the lower levels of LDL-C achieved on therapy were

(p ¼ 0.02) after 1 year of intensive lipid therapy. This

associated with better outcomes; however, 33% of

decrease in K trans was independent of LRNC and PWV

subjects treated with simvastatin plus ezetimibe to a

reduction (27). Longer duration of statin therapy was

mean LDL-C level of 54 mg/dl continued to develop

associated with decreased carotid plaque vascularity

cardiovascular events over 7 years. Identifying in-

in the AIM-HIGH carotid MRI substudy (28). Given

dividuals with increased residual cardiovascular risk,

that both fluorodeoxyglucose positron emission to-

despite intensive statin therapy, remains an unmet

mography and K trans are indirect measures of plaque

clinical need.

inflammation, it might be interesting to consider a

Future imaging studies are warranted to evaluate

study that uses both to better understand their role in

the link between individualized vascular response to

vascular inflammation. Thus, measurement of these

therapy, in addition to clinical risk factors and bio-

indexes of inflammation could have provided addi-

markers, and subsequent vascular events. If verified,

tional insights into the effects of anti-inflammatory

this link might improve residual cardiovascular risk

therapy in atherosclerosis.

prediction and potentially guide further therapy.

The authors discussed some of the possible reasons

Notwithstanding these negative results, we eagerly

for the observed discordance between changes in

await the results of the ongoing event-based CANTOS

circulating inflammatory markers (hsCRP and IL-6

(Canakinumab Anti-inflammatory Thrombosis Out-

levels) and vascular response (no significant reduc-

comes Study) trial, which is also evaluating targeted

tion in carotid and aorta wall areas or improvement of

IL-1b inhibition with canakinumab (32).

aorta distensibility). In the CPC study, we found that LRNC regression varied during lipid-altering therapy.

REPRINT REQUESTS AND CORRESPONDENCE: Dr.

LRNC can be partially depleted after 3 years in some,

Chun Yuan, Department of Radiology, University of

but not all, subjects on intensive lipid therapy. Five

Washington, 850 Republican Street, P.O. Box 358050,

subjects developed new measurable LRNC during the

Seattle,

3 years, but only 1 of these 5 had measurable LRNC at

u.washington.edu.

Washington

98109.

E-mail:

cyuan@

REFERENCES 1. Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation 2002;105:1135–43. 2. Ross R. Atherosclerosis – an inflammatory disease. N Engl J Med 2003;340:115–26. 3. Choudhury RP, Birks JS, Mani V, et al. Arterial effects of canakinumab in patients with atherosclerosis and type 2 diabetes or glucose intolerance. J Am Coll Cardiol 2016;68:1769–80. 4. Robinson JG, Farnier M, Krempf M, et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 2010; 464:1357–61. 5. Merhi-Soussi F, Kwak BR, Magne D, et al. Interleukin-1 plays a major role in vascular inflammation and atherosclerosis in male apolipoprotein E-knockout mice. Cardiovasc Res 2005; 66:583–93. 6. Zhao XQ, Hatsukami TS, Hippe DS, et al., AIM-HIGH Carotid MRI Sub-study Investigators. Clinical factors associated with high-risk carotid

plaque features as assessed by magnetic resonance imaging in patients with established vascular disease (from the AIM-HIGH Study). Am J Cardiol 2014;114:1412–9. 7. Cai JM, Hatsukami TS, Ferguson MS, et al. Classification of human carotid atherosclerotic lesions with in vivo multicontrast magnetic resonance imaging. Circulation 2002;106:1368–73. 8. Cai J, Hatsukami TS, Ferguson MS, et al. In vivo quantitative measurement of intact fibrous cap and lipid rich necrotic core size in atherosclerotic carotid plaque: a comparison of high resolution contrast enhanced MRI and histology. Circulation 2005;112:3437–44. 9. Hellings WE, Peeters W, Moll FL, et al. Composition of carotid atherosclerotic plaque is associated with cardiovascular outcome: a prognostic study. Circulation 2010;121:1941–50. 10. Takaya N, Yuan C, Chu B, Saam T, et al. Association between carotid plaque characteristics

and subsequent ischemic cerebrovascular events: a prospective assessment with MRI— initial results. Stroke 2006;37:818–23. 11. Singh N, Moody AR, Gladstone DJ, et al. Moderate carotid artery stenosis: MR imaging-depicted intraplaque hemorrhage predicts risk of cerebrovascular ischemic events in asymptomatic men. Radiology 2009;252: 502–8. 12. Sadat U, Teng Z, Young VE, et al. Association between biomechanical structural stresses of atherosclerotic carotid plaques and subsequent ischaemic cerebrovascular events–a longitudinal in vivo magnetic resonance imaging-based finite element study. Eur J Vasc Endovasc Surg 2010; 40:485–91. 13. Kwee RM, van Oostenbrugge RJ, Mess WH, et al. MRI of carotid atherosclerosis to identify TIA and stroke patients who are at risk of a recurrence. J Magn Reson Imaging 2013;37: 1189–94.

1783

1784

Zhao et al.

JACC VOL. 68, NO. 16, 2016 OCTOBER 18, 2016:1781–4

Imaging of AI Therapy in Atherosclerosis

14. Hosseini AA, Kandiyil N, Macsweeney ST, et al. Carotid plaque hemorrhage on magnetic resonance imaging strongly predicts recurrent ischemia and stroke. Ann Neurol 2013;73:774–84.

21. Moreno PR, Falk E, Palacios IF, et al. Macrophage infiltration in acute coronary syndromes. Implications for plaque rupture. Circulation 1994; 90:775–8.

15. Sun Jie, Zhao Xue-Qiao, Balu Niranjan, et al. Magnetic resonance imaging-detected carotid plaque characteristics predict systemic cardiovascular outcomes in patients with clinically established atherosclerosis in the AIM-HIGH study. J Am Coll Cardiol Img 2016; in press.

22. 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;25:2054–61.

16. Zhao XQ, Dong L, Hatsukami T, et al. MR Imaging of Carotid Plaque Composition During LipidLowering Therapy A Prospective Assessment of Effect and Time Course. J Am Coll Cardiol Img 2011;4:977–86. 17. Du R, Zhao XQ, Cai J, et al. Changes in carotid plaque tissue composition in subjects who continued and discontinued statin therapy. J Clin Lipidol 2016;10:587–93. 18. O’Brien KD, McDonald TO, Chait A, et al. Neovascular expression of E-selectin, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 in human atherosclerosis and their relation to intimal leukocyte content. Circulation 1996;93:672–82.

23. Moulton KS, Vakili K, Zurakowski D, et al. Inhibition of plaque neovascularization reduces macrophage accumulation and progression of advanced atherosclerosis. Proc Natl Acad Sci U S A 2003;100:4736–41. 24. Gaffney K, Cookson J, Blake D, et al. Quantification of rheumatoid synovitis by magnetic resonance imaging. Arthritis Rheum 1995;38: 1610–7. 25. Semelka RC, Chung JJ, Hussain SM. Chronic hepatitis: Correlation of early patchy and late linear enhancement patterns on gadoliniumenhanced MR images with histophathology initial experience. J Magn Reson Imaging 2001;13: 385–91.

dynamic contrast-enhanced MR imaging. Radiology 2011;260:224–31. 28. O’Brien KD, Hippe DS, Chen H, et al. Longer duration of statin therapy is associated with decreased carotid plaque vascularity by magnetic resonance imaging. Atherosclerosis 2016;245: 74–81. 29. Cannon CP, Blazing MA, Giugliano RP, et al., IMPROVE-IT Investigators. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med 2015;372:2387–97. 30. Robinson JG, Farnier M, Krempf M, et al., ODYSSEY LONG TERM Investigators. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372: 1489–99. 31. Sabatine MS, Giugliano RP, Wiviott SD, et al., Open-Label Study of Long-Term Evaluation against LDL Cholesterol (OSLER) Investigators. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372:1500–9. 32. Ridker PM, Thuren T, Zalewski A, Libby P. Interleukin-1beta inhibition and the prevention of recurrent cardiovascular events: rationale and

19. Kerwin WS, O’Brien KD, Ferguson MS, et al. Inflammation in carotid atherosclerotic plaque: a dynamic contrast-enhanced MR imaging study. Radiology 2006;241:459–68.

26. Chen H, Sun J, Kerwin WS, et al. Scan-rescan reproducibility of quantitative assessment of inflammatory carotid atherosclerotic plaque using dynamic contrast-enhanced 3T CMR in a multicenter study. J Cardiovasc Magn Reson 2014;16:51.

20. Kolodgie FD, Gold HK, Burke AP, et al. Intra-

27. Dong L, Kerwin WS, Chen H, et al. Carotid

KEY WORDS interleukin, lipid lowering,

plaque hemorrhage and progression of coronary atheroma. N Engl J Med 2003;349:2316–25.

artery atherosclerosis: effect of intensive lipid therapy on the vasa vasorum—evaluation by using

lipid-rich necrotic core, magnetic resonance imaging

design of the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS). Am Heart J 2011;162:597–605.