Role of new imaging modalities in pursuit of the vulnerable plaque and the vulnerable patient

    Role of new imaging modalities in pursuit of the vulnerable plaque and the vulnerable patient Paolo Raggi, Gianluca Pontone, Daniele Andreini PII: DOI: Reference:

S0167-5273(17)34906-9 doi:10.1016/j.ijcard.2017.10.046 IJCA 25555

To appear in:

International Journal of Cardiology

Received date: Revised date: Accepted date:

7 September 2017 8 October 2017 13 October 2017

Please cite this article as: Raggi Paolo, Pontone Gianluca, Andreini Daniele, Role of new imaging modalities in pursuit of the vulnerable plaque and the vulnerable patient, International Journal of Cardiology (2017), doi:10.1016/j.ijcard.2017.10.046

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT Role of new imaging modalities in pursuit of the vulnerable plaque and the vulnerable patient

Raggi, MD, 3,4Gianluca Pontone, MD, 3,5Daniele Andreini, MD

PT

1,2Paolo

NU

SC RI

From: 1 Mazankowski Alberta Heart Institute and 2University of Alberta, Edmonton, AB, Canada; 3Centro Cardiologico Monzino, IRCCS, University of Milan, Milan, Italy; 4 Yonsei University Health System, Seoul, South Korea; 5 Department of Clinical Sciences and Community Health, Cardiovascular Section, University of Milan, Milan, Italy

AC

CE

PT

ED

MA

Correspondence Paolo Raggi, MD Mazankowski Alberta Heart Institute, University of Alberta 4A7.050, 8440 – 112 Street Edmonton, AB T6G 2B7, Canada Tel 780 407-8006; Fax 780 407-7834 [email protected]

1

ACCEPTED MANUSCRIPT ABSTRACT Numerous biomarkers and imaging modalities were investigated during the past few decades to

PT

identify patients harboring plaques at high risk of rupturing and causing catastrophic events. The classical description of a vulnerable plaque included a large lipid core, covered by a thin fibrous cap

SC RI

and evidence of inflammation especially around the hinge points of the plaque. Unfortunately, the search has resulted to a large extent in a failure to accurately identify the site of a future event. In time the search focus switched to the vulnerable patient rather than the individual vulnerable

NU

plaques, but the debate continues as to the more appropriate approach to risk assessment. This

MA

review discusses the most recent developments in molecular, anatomical and functional imaging directed at identifying a patient at high-risk of coronary artery disease events.

ED

INTRODUCTION

PT

The desire to reduce the incidence of catastrophic cardiovascular events has taken many pathways over the past several decades. The implementation of aggressive preventive efforts, inclusive of life

CE

style changes and medical interventions with more effective drugs, has certainly contributed to the

AC

reported reduction in event rates. In another dimension, cardiovascular specialists have developed imaging modalities in pursuit of vulnerable atherosclerotic plaques hoping to be able to prognosticate an event. In view of the results that were often only partially successful, many investigators turned their attention to the search for the vulnerable patient. The latter is a patient that harbors vulnerable plaques but also a vulnerable milieu necessary and sufficient to promote an untoward event. In this invited review, we discuss some of the most recent developments in the field of plaque imaging that are getting us closer to identifying the vulnerable patient.

2

ACCEPTED MANUSCRIPT Molecular Imaging of High-Risk Plaques In the presence of a continuing epidemic of coronary artery disease in western countries, an

PT

accurate risk assessment of patients at potential risk of events is of paramount importance. The risk assessment tools in use for the past several decades have been focused on clinical characteristics,

SC RI

and are relatively inaccurate especially in subjects at low to intermediate risk, who constitute the majority of patients in danger of suffering an event. The description of the classic features of a vulnerable plaque (thin fibrous cap, large lipid core and inflammation) [1, 2] sparked an era of

NU

active search for the vulnerable plaque that unfortunately gave disappointing results. The concept of

MA

“vulnerable plaque” was replaced by that of “vulnerable patient” [3] and timid attempts were made to include atherosclerosis imaging in some of the risk scoring algorithms. [4-6] Disappointingly, efforts to prove the added value of imaging as a means to screen patients at high risk failed to

ED

deliver on the promise. The search for “vulnerable patients” among a high-risk population such as

PT

diabetic patients, for example, gave non-superior results both with nuclear stress testing [7] and CT angiography (CTA), [8] compared to more traditional approaches. Despite these unsatisfactory

CE

results, a recent international survey demonstrated a strong interest among physicians to utilize

AC

imaging information to more carefully assess risk and attain prevention goals. [9] As a result, there is still an animated debate between investigators supporting the importance of identifying vulnerable patients as opposed to vulnerable plaques. [10, 11] In this context molecular imaging with sodium-18fluoride (Na18F) holds promise as a method to identify vulnerable atherosclerotic lesions, if the encouraging results obtained so far are confirmed and expanded. Both fluoro-deoxy-glucose (FDG) and Na18F are 18F-based positron emission tomography (PET) tracers and have been employed to define the presence of vulnerable or high-risk arterial plaques in a variety of settings. It was initially believed that the uptake of FDG in the plaque was driven by macrophages responding to active inflammation within the plaque. [12] However, more recently it has been shown that macrophages up-take FDG in response to hypoxia within the plaque, while smooth muscle cells and endothelial cells show an increased uptake of FDG in 3

ACCEPTED MANUSCRIPT response to inflammatory stimuli. [13] On the other hand, Na18F is accumulated in plaques accruing calcium apatite. Numerous studies to date have highlighted the utility of coronary artery calcium

PT

(CAC) as the best marker of global risk since it represents the sum of all cumulative damage to the arterial tree over time. [14, 15] However, CAC provides static data and there is no information on

SC RI

the functional status of the plaque in CAC scoring. On the contrary, plaques actively accruing calcium are in development and potentially unstable (Figure 1). Na18F has been in use for some time to image bone metastases, [16] but investigators focused on Na18F as a potential

NU

atherosclerosis imaging agent only recently. Of interest, the uptake of Na18F in atherosclerotic

MA

plaques is proportional to the presence and number of traditional risk factors presented by the patient. [17, 18] In an initial study of 75 patients submitted to whole-body imaging in search of bone metastasis, about 12% of calcified sites seen in large arteries (aorta, carotid and femoral

ED

arteries) showed active Na18F uptake. [19] Similarly, Morbelli et al [20] described a poor

PT

correlation between large arteries calcification that correlated solely with age, and Na18F uptake that correlated with multiple risk factors for atherosclerosis. In a retrospective study Derlin et al [21]

CE

compared the uptake of FDG and Na18F in large arteries of 45 oncological patients submitted to

AC

whole-body imaging. The authors identified 503 calcified arterial sites; of 105 sites demonstrating Na18F uptake 77% were calcified, while 14.5% of the sites with FDG uptake showed calcification. Coincident uptake of Na18F and FDG was seen only in 6.5% of the cases. Hence, these 18F-based tracers clearly identify different arterial processes that do not necessarily co-exist and –as the authors pointed out- may constitute a novel way to investigate the pathophysiology of plaque growth. Dweck et al [22] published the first report on coronary artery imaging using Na18F and compared it with FDG uptake. They enlisted 119 volunteers of whom 40 had a history of prior cardiovascular or cerebrovascular events. To suppress myocardial uptake of FDG they asked the patients to observe a one-day carbohydrate-free, high fat diet. Despite this provision, they noted a large amount of myocardial contamination with poor coronary uptake of FDG that was not increased even in patients with prior cardiovascular disease. In 49% of the arterial territories 4

ACCEPTED MANUSCRIPT examined, coronary artery FDG uptake could not be accurately assessed due to myocardial spillover. On the contrary, Na18F uptake could be evaluated in 96% of the coronary artery territories

PT

and it showed a moderate correlation (p= 0.65) with CAC. Interestingly, 41% of patients with a CAC score >1000 showed no Na18F activity, which suggests that these large CAC scores may hide

SC RI

repaired and non-active atherosclerotic processes. In contrast, Na18F uptake was noted in areas adjacent to or even remote from visible CAC, suggesting that active atherosclerosis foci are developing in non-calcified areas and therefore remain hidden from CT imaging of CAC. Patients

NU

with increased Na18F (defined as a target-to-background ratio >1.6) were more often older, men and

MA

had suffered prior cardiovascular events. Finally, the Framingham risk score correlated with Na18F uptake but not with the CAC score. Fiz et al [23] reported that the attenuation (i.e density) of calcified plaques is inversely correlated with the uptake of Na18F, suggesting that nascent plaques

ED

accumulate calcium more avidly than older, more densely calcified and potentially more stable

PT

plaques. Similarly, Kitagawa et al, [24] showed that partially calcified plaques and plaques with positive remodeling, large lipid cores and micro-calcifications (that characterize an unstable plaque

CE

on CT angiography (CTA)) had the highest Na18F uptake. Hence, Na18F has the potential to identify

AC

patients harboring plaques on the verge of fissuring or rupturing causing an acute coronary event. Joshi et al [25] gave an initial demonstration of such concept in an investigation where they performed Na18F imaging in 40 patients with acute coronary syndromes, 40 patients with stable angina and 12 patients undergoing carotid endarterectomy because of recent cerebrovascular events. Na18F uptake was maximum in the culprit artery of patients with acute coronary syndromes, while in patients suffering from stable angina Na18F localized mostly in areas that showed remodeling, microcalcification and a large necrotic core on a simultaneously performed intravascular ultrasound study. In the patients with cerebrovascular symptoms, all ruptured carotid artery plaques showed an avid uptake of Na18F and on histology the plaques showed active calcification and inflammation, as well as apoptosis and necrosis. Similar findings in the carotid arteries of patients with stroke or TIAs were reported by Cocker et al. [26] Hence, these small and preliminary studies showed that 5

ACCEPTED MANUSCRIPT Na18F can effectively identify unstable plaques in patients with active cardio or cerebrovascular symptoms. The obvious limitation of these publications is that there is no prospective

PT

demonstration yet that finding plaques with increased Na18F uptake in asymptomatic patients helps predict the occurrence of future events. There are also several technical issues to be addressed

SC RI

before Na18F imaging can be implemented on a larger scale for prevention purposes. Although lower than the radiation dose of a single photon emission tomography (SPECT) study with 99technetium or 201-thallium (on average 10-18 mSv), a PET/CT scan with Na18F provides an

NU

ionizing dose of 4-6 mSv. The resolution of scanners currently on the market may not be sufficient

MA

to detect nascent but already active plaques. None of the studies published to date investigated the effect of treatment (such as statins and oral hypoglycemic agents for example) on the Na18F findings. Finally, an agreement needs to be reached between investigators on how to standardize

ED

reporting, in order to clearly define what represents an increased and potentially dangerous Na18F

PT

uptake. Standard uptake value (SUV), target-to-background (TBR) ratio and a combination of measurements have been used to gauge the extent of Na18F vascular activity, but there is no formal

CE

agreement on method and thresholds. As a result, this imaging modality is still in the early

AC

developmental phases although it appears very promising as a method to discover patients at risk of events due to the presence of vulnerable atherosclerotic plaques.

Coronary CT angiography: plaque features as predictors of adverse cardiac events A large body of literature has contributed to document the high sensitivity and excellent negative predictive value of coronary CT angiography (CCTA) to rule-out obstructive coronary artery disease (CAD).[27] In 2013, the European Society of Cardiology proposed CCTA as an alternative to stress imaging techniques as a first-line assessment of patients with chest pain and stable CAD.[28] In a recent update on the management of patients with new onset chest pain, the NICE Guidelines embraced CCTA for such purpose.[29] Beyond its utility to diagnose obstructive CAD, several publications demonstrated a robust prognostic value of CCTA based on the presence of non6

ACCEPTED MANUSCRIPT obstructive coronary lesions. [30, 31] Large studies showed an excellent long-term prognosis for patients without coronary plaques on CCTA and an intermediate prognostic value in patients with

PT

non-obstructive lesions, compared to patients with obstructive CAD. [32, 33] Non obstructive lesions of the left main coronary artery may be particularly dangerous in women compared to

SC RI

men.[34]

Non-invasive plaque characterization by CCTA imaging became a reality after the demonstration of the existence of a good correlation between plaque characteristics on CCTA and intravascular

NU

ultrasound findings. [35] Features that define a high-risk plaque (HRP) on CCTA include positive

MA

(i.e. outward) vessel remodeling (PR), low-attenuation plaques (LAP), spotty calcifications (SC) in the context of the plaque and napkin ring sign (Figure 2). These characteristics provide additional prognostic information beyond the degree of stenosis. [36-38] Positive remodeling, was reported

ED

40-years ago by Glagov et al [37] on histological preparations as a compensatory enlargement of

PT

coronary arteries accumulating atherosclerosis in the vessel wall, and it is associated with plaques with a large lipid core covered by a thin fibrous cap (thin cap fibroatheroma plaques: TCFA). TCFA

CE

is an important predictor of plaque rupture.[38, 39] The low attenuation within a plaque, defined as

AC

an attenuation (i.e density) below 30-50 Hounsfield Units, suggests a high lipid content, [39] while a napkin ring sign is typically due to the presence of a hypodense deposit of necrotic material in the center of the plaque. Finally, spotty calcifications are scattered calcified nodules within the context of a plaque with a diameter <3 mm. [40]39 Motoyama et al. [36]34 studied 1059 consecutive patients who underwent CCTA for suspected coronary disease and followed them for an average of 27+10 months for the development of acute coronary syndromes (ACS). They showed that PR>1.1 and/or LAP were independently associated with the development of future ACS. The same authors recently showed in 3158 patients undergoing CCTA that HRP provide incremental prognostic information beyond clinical characteristics and degree of luminal stenosis to predict the occurrence of ACS after an average follow-up of 3.9-years. [37]35 It is worth mentioning that only a portion (approximately 15-25%) of 7

ACCEPTED MANUSCRIPT patients with plaques presenting high-risk features will develop ACS, although a much smaller proportion of patients without such plaques will (0.5-1.5%).

PT

The ability of HRP to predict ACS in symptomatic patients was studied in the Rule Out Myocardial Infarction/Ischemia Using Computer-Assisted Tomography II (ROMICAT II) trial. [41] In this trial

SC RI

472 patients evaluated in the emergency room with acute chest pain and with no objective evidence of myocardial ischemia or infarction, were randomized to undergo a direct CCTA to exclude the presence of CAD. Of the 37 patients in whom an ACS was ultimately diagnosed, 75% had

NU

obstructive CAD on angiography, and 95% had at least one of the 4 characteristics of a HRP. In

MA

univariate analyses both >50% stenosis (relative risk of 34.4) and HRP features were associated with a significantly increased risk of ACS (relative risk of 32.0). The presence of HRP features remained independently associated with risk of ACS (odds ratio 8.9, CI 1.8 to 43.3; p = 0.006) after

ED

adjustment for stenosis >50% and cardiovascular risk factors (age, gender, number of risk factors).

PT

A recent meta-analysis compared the impact of high-risk and low-risk plaque features and culprit versus non-culprit lesions in patients with either ACS or stable angina. [40] The meta-analysis

CE

included 18 studies that provided data concerning coronary plaque type in ACS patients (n. 579)

AC

compared with stable angina patients (n. 1176) and 6 studies (n. 7482 patients) that investigated the outcome of ACS in high-risk (low-density or napkin-ring sign) versus low-risk (high-density or densely calcified) plaques. The main findings were that ACS patients had significantly higher number of non-calcified plaques (NCP) compared with stable angina patients (p= 0.0001). Although the total plaque volume in ACS was not larger than in stable angina (p= 0.32) patients, the NCP volume was significantly larger (p= 0.002) in the former than the latter. Finally, the remodeling index was higher in culprit lesions compared with non-culprit lesions in ACS patients, and in ACS compared with stable angina patients (p= 0.0001). HRP features were shown to be associated with an increased risk of events even in patients with isolated non-obstructive (<50%) CAD. [42] Conte et al [42] followed 245 patients for an average of

8

ACCEPTED MANUSCRIPT 8 years with non-obstructive CAD on CCTA and reported that the relative risk of cardiac death and/or ACS was 7.5 in the presence of at least two HRP features.

PT

Of interest, coronary atherosclerosis identified on CCTA has been associated with elevation in high-sensitivity cardiac troponin serum levels. Increasing circulating levels of high-sensitivity

SC RI

cardiac troponin were documented starting from individuals with no evidence of coronary artery atherosclerosis, to patients with calcified plaques, and patient with non-calcified or those with noncalcified and remodeled arteries. It is postulated that clinically silent micro-fractures and clot

NU

formation in the context of non-calcified and remodeled plaques causes microembolization and

MA

chronic troponin elevation. [43]

The implementation of dual-energy CT (DECT) may represent an important advancement in the ability to further characterize coronary artery plaques. In fact, the commonly used single-energy CT

ED

scanners are faced with a significant challenge in differentiating the various anatomical components

PT

of non-calcified plaques (e.g., lipid-rich vs. fibrous). Several studies showed considerable overlap in Hounsfield units between lipid-rich and fibrous non-calcified plaques; this is most likely

CE

attributable to the spatial resolution of single-energy CTs and to the interaction between plaque

AC

density and scanning or contrast parameters (i.e. tube voltage and current, iodine concentration, iodine delivery rate. [44] The utilization of 2 energy sources in DECTs makes them particularly apt at achieving material decomposition (i.e differentiation of different tissues), with improved plaque characterization.[44] Additionally, DECT seems very promising in limiting the artifacts caused by large calcified plaques.[44] In summary, CCTA is a non-invasive imaging tool with great potential to provide valuable prognostic information by leading to the identification of vulnerable patients based on the presence of plaques with vulnerable features.

Coronary artery plaque characteristics and their association with myocardial ischemia The classic view that progressive loss of coronary luminal diameter eventually results in reduced myocardial blood flow, and the reported benefit of intervening on patients with myocardial 9

ACCEPTED MANUSCRIPT ischemia on functional testing [45] led to the common practice of performing coronary artery revascularization after visual assessment of the severity of stenosis during invasive coronary

PT

angiography (ICA). However, the identification of obstructive CAD is only one aspect of the complex relationship

SC RI

between coronary stenosis and ischemia [46] and there is an increasing awareness that there is a disconnect between stenosis severity and inducibility of myocardial ischaemia. Several investigators reported that only about 50% of the patients with obstructive CAD on CCTA

NU

(diameter stenosis >50%) have inducible myocardial ischemia; on the other hand non-obstructive

MA

lesions can be associated with inducible ischaemia [47, 48]. To complicate matters, a large number of plaques causing acute coronary syndromes are non-obstructive [49]. As discussed above, CCTA provides helpful information on atherosclerotic plaque composition in addition to luminal diameter

ED

narrowing, and some plaque features have been shown to be independent predictors of adverse

PT

outcomes. Despite the ability to identify potentially vulnerable plaques with CCTA, there is no clear indication of which plaques and how many plaques with high-risk morphologic characteristics

CE

will eventually rupture and cause an untoward event. In the Providing Regional Observations to

AC

Study Predictors of Events in the Coronary Tree (PROSPECT) study only 5% of TCFA plaques identified by virtual histology caused coronary events [50]. Therefore, the consequences of a plaque disruption depend not only on the composition of the atheroma itself, but also on local rheological and hemodynamic phenomena [51]. How plaque composition (“the target”) and local phenomena (“the trigger”) interact is an important question and several investigators have tried to address it. In an early publication, Fay et al [52] showed that the number of plaques with mixed features (areas of calcification mixed with non-calcified areas) was associated with a higher incidence (OR 1.64, p = 0.01] of myocardial ischemia on single photon emission computed tomography (SPECT) imaging. In a subsequent publication in 49 patients with severe obstructive disease in a proximal coronary artery segment, low attenuation plaques (LAP) and positive remodelling (PR), but not spotty calcification were associated with a higher frequency of inducible ischemia [53]. 10

ACCEPTED MANUSCRIPT Diaz-Zamudio M et al. [54] reported that an abnormal invasive fractional flow reserve result (FFR<0.80, i.e pressure below the stenosis is less than 80% of pressure above the stenosis) can be

PT

expected in vessels with a large atheroma burden, especially in those with non-calcified plaques or LAP on CCTA. Similarly, Nakazato R et al [55] showed that the prevalence of PR, LAP and SC

SC RI

was three to five-fold higher in moderately stenotic vessels associated with downstream ischemia than in vessels perfusing non-ischaemic territories. In this case ischemia was investigated by both invasive FFR and non-invasive FFR measured by CT (Figure 3). Additionally, PR provided

NU

incremental predictive value for lesion-specific ischaemia over CCTA stenosis plus FFR (AUC 0.87

MA

vs. 0.83, p=0.002). Similar results were reported by Park H et al [48] who also showed that when adjusted for stenosis severity PR remained a predictor of ischemia for all degrees of stenosis. Dey D [56] showed that automatic measurement of non-calcified plaque burden in a coronary artery

ED

significantly improves prediction of impaired myocardial blood flow reserve in the corresponding

PT

coronary artery territory as measured by 13N-ammonia PET. In the report by Diaz-Zamudio M et al [57] HRP features were significantly associated with ischemia, whereas stenosis was not. Finally,

CE

Gaur S [58] showed that plaque tissue characterization and FFR by CT improve the ability to

AC

predict inducibility of ischemia in a myocardial territory dependent on a specific coronary lesion compared to mere luminal stenosis assessment. Although there is no known pathogenetic mechanism for the link between high-risk plaques and ischemia, it has been postulated that these plaques contain a sizeable necrotic core responsible for oxidative stress and local inflammation. These in turn may compromise the production and bioavailability of the vasodilator nitric oxide and increase the levels of vasoconstrictors such as isoprostanes. The latter along with local endothelial dysfunction could cause a focal ‘functional stenosis’ with inability of the vessel segment containing high-risk plaques to dilate adequately during stress [58, 59]. In this new optic, revascularization procedures should be reserved for patients with abnormal FFR (<0.80) in the presence of obstructive disease on invasive angiography, while high-intensity statin 11

ACCEPTED MANUSCRIPT therapy should be prescribed for patients with abnormal FFR in the setting of non-obstructive highrisk plaques with the aim to obtain plaque stabilization and, potentially, FFR normalization [46].

PT

Indeed, statin-mediated LDL-cholesterol lowering has been shown to limit the progression or even induce minimal regression of coronary atherosclerosis and lower the event rate.

SC RI

However, several questions remain open [60]. Is CCTA robust and reproducible enough to implement plaque characterization in real world clinical medicine? Is there a relationship between plaque characteristics and extent of ischaemic myocardium and therefore the need for

NU

revascularization? In this regard, studies have already been designed to investigate whether plaque

MA

characterization is a better approach to predict and detect myocardial ischemia compared to current standard of care [61]. A second aim of future studies is to assess the effect of various treatment

ED

strategies on plaque characteristics.

PT

In summary, the evidence of the existence of a relationship between plaque characteristics and ischemia as well as events, irrespective of the presence and severity of obstructive disease, suggests

CE

that there is a bidirectional interaction between target (plaque composition) and trigger (rheologic

AC

and hemodynamic factors), and that plaque imaging with CCTA may hold the key to cardiac events prediction. On the other hand, molecular imaging of plaque activity is also gaining ground and is poised to provide prognostically significant information if the current exciting results are expanded.

12

ACCEPTED MANUSCRIPT Figure legends

Figure 1. Example of patient with intense sodium-18fluoride uptake. Panel A: positron

PT

emission tomography (PET) scan showing a high signal emanating from the aortic root (yellow ring in the center of the picture) in the absence of any visible vascular calcification.

SC RI

Panel B: computed tomography (CT) scan of the chest obtained without iodine contrast injection showing dense calcification of the left main and left anterior descending coronary artery. Panel C: fusion image of PET and CT scans showing high uptake of sodium-18fluoride

NU

both in the non-calcified aortic root and the densely calcified coronary arteries (images courtesy of Dr. Jonathan Abele, Department of Diagnostic Imaging, University of Alberta,

MA

Edmonton, AB, Canada)

Figure 2. Plaque characterization by coronary computed tomography angiography

ED

Panels A: positive remodeling. Panel B: low attenuation plaque. The blue region inside the plaque represents the low attenuation part of the lesion. Panel C: spotty calcification (arrow).

PT

Panel D: napkin ring sign.

Figure 3. Example of perfusion defects correlating with abnormal fractional flow

CE

reserve measurements in a patient with single-vessel high-risk-plaque. Panels A-C: Coronary computed tomography angiography showing high-risk plaque features: in Panel A

AC

the arrow points at a non-calcified plaque in the middle left anterior descending coronary artery. In Panel B the arrow points at a calcified lesion (yellow area) next to the vessel lumen (green circle). Panel C shows a very low density (< 30 HU) plaque core. Panels D-F: Stress computed tomography perfusion images in short axis. Panel G: Stress computed tomography perfusion image in horizontal long-axis. Panels H-I: Stress computed tomography perfusion images in vertical long-axis. Subendocardial perfusion defects are visible in the mid to distal antero-septum and most of the apical segments. Panel J: non-invasive fractional flow reserve measured by computed tomography showing a significant pressure drop at the level of the high-risk plaque in the middle left anterior descending coronary artery. Panel K: invasive coronary angiography showing a moderate stenosis of the middle left anterior descending coronary artery and again a significant drop in fractional flow reserve at this level.

13

ACCEPTED MANUSCRIPT References

AC

CE

PT

ED

MA

NU

SC RI

PT

[1] Virmani R, Kolodgie FD, Burke AP, Farb A, Schwartz SM. Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesions. Arterioscler Thromb Vasc Biol. 2000;20:1262-75. [2] Kolodgie FD, Burke AP, Farb A, Gold HK, Yuan J, Narula J, et al. The thin-cap fibroatheroma: a type of vulnerable plaque: the major precursor lesion to acute coronary syndromes. Curr Opin Cardiol. 2001;16:285-92. [3] Naghavi M, Libby P, Falk E, Casscells SW, Litovsky S, Rumberger J, et al. From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part I. Circulation. 2003;108:1664-72. [4] Anderson TJ, Gregoire J, Pearson GJ, Barry AR, Couture P, Dawes M, et al. 2016 Canadian Cardiovascular Society Guidelines for the Management of Dyslipidemia for the Prevention of Cardiovascular Disease in the Adult. Can J Cardiol. 2016;32:1263-82. [5] Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;63:2889-934. [6] Authors/Task Force M, Piepoli MF, Hoes AW, Agewall S, Albus C, Brotons C, et al. 2016 European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts) Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Atherosclerosis. 2016;252:207-74. [7] Wackers FJ, Young LH, Inzucchi SE, Chyun DA, Davey JA, Barrett EJ, et al. Detection of silent myocardial ischemia in asymptomatic diabetic subjects: the DIAD study. Diabetes Care. 2004;27:1954-61. [8] Muhlestein JB, Lappe DL, Lima JA, Rosen BD, May HT, Knight S, et al. Effect of screening for coronary artery disease using CT angiography on mortality and cardiac events in high-risk patients with diabetes: the FACTOR-64 randomized clinical trial. JAMA. 2014;312:2234-43. [9] Mancini GBJ, Gupta M, Tsigoulis M, Cannon CP, Genest J, Ray KK, et al. Detection of atherosclerotic cardiovascular disease influences the perceived need for aggressive lipid management. Atherosclerosis. 2017;263:112-8. [10] Arbab-Zadeh A, Fuster V. The myth of the "vulnerable plaque": transitioning from a focus on individual lesions to atherosclerotic disease burden for coronary artery disease risk assessment. J Am Coll Cardiol. 2015;65:846-55. [11] Albaghdadi MS, Muse ED. Vulnerable Plaque: Absence of Evidence or Evidence of Absence. J Am Coll Cardiol. 2015;66:757-8. [12] Rudd JH, Warburton EA, Fryer TD, Jones HA, Clark JC, Antoun N, et al. Imaging atherosclerotic plaque inflammation with [18F]-fluorodeoxyglucose positron emission tomography. Circulation. 2002;105:2708-11. [13] Folco EJ, Sheikine Y, Rocha VZ, Christen T, Shvartz E, Sukhova GK, et al. Hypoxia but not inflammation augments glucose uptake in human macrophages: Implications for imaging atherosclerosis with 18fluorine-labeled 2-deoxy-D-glucose positron emission tomography. J Am Coll Cardiol. 2011;58:603-14. [14] Polonsky TS, McClelland RL, Jorgensen NW, Bild DE, Burke GL, Guerci AD, et al. Coronary artery calcium score and risk classification for coronary heart disease prediction. JAMA. 2010;303:1610-6. 14

ACCEPTED MANUSCRIPT

AC

CE

PT

ED

MA

NU

SC RI

PT

[15] Yeboah J, McClelland RL, Polonsky TS, Burke GL, Sibley CT, O'Leary D, et al. Comparison of novel risk markers for improvement in cardiovascular risk assessment in intermediate-risk individuals. JAMA. 2012;308:788-95. [16] Blau M, Ganatra R, Bender MA. 18 F-fluoride for bone imaging. Semin Nucl Med. 1972;2:31-7. [17] Oliveira-Santos M, Castelo-Branco M, Silva R, Gomes A, Chichorro N, Abrunhosa A, et al. Atherosclerotic plaque metabolism in high cardiovascular risk subjects - A subclinical atherosclerosis imaging study with 18F-NaF PET-CT. Atherosclerosis. 2017;260:41-6. [18] Derlin T, Wisotzki C, Richter U, Apostolova I, Bannas P, Weber C, et al. In vivo imaging of mineral deposition in carotid plaque using 18F-sodium fluoride PET/CT: correlation with atherogenic risk factors. J Nucl Med. 2011;52:362-8. [19] Derlin T, Richter U, Bannas P, Begemann P, Buchert R, Mester J, et al. Feasibility of 18Fsodium fluoride PET/CT for imaging of atherosclerotic plaque. J Nucl Med. 2010;51:862-5. [20] Morbelli S, Fiz F, Piccardo A, Picori L, Massollo M, Pestarino E, et al. Divergent determinants of 18F-NaF uptake and visible calcium deposition in large arteries: relationship with Framingham risk score. Int J Cardiovasc Imaging. 2014;30:439-47. [21] Derlin T, Toth Z, Papp L, Wisotzki C, Apostolova I, Habermann CR, et al. Correlation of inflammation assessed by 18F-FDG PET, active mineral deposition assessed by 18F-fluoride PET, and vascular calcification in atherosclerotic plaque: a dual-tracer PET/CT study. J Nucl Med. 2011;52:1020-7. [22] Dweck MR, Chow MW, Joshi NV, Williams MC, Jones C, Fletcher AM, et al. Coronary arterial 18F-sodium fluoride uptake: a novel marker of plaque biology. J Am Coll Cardiol. 2012;59:1539-48. [23] Fiz F, Morbelli S, Piccardo A, Bauckneht M, Ferrarazzo G, Pestarino E, et al. (1)(8)F-NaF Uptake by Atherosclerotic Plaque on PET/CT Imaging: Inverse Correlation Between Calcification Density and Mineral Metabolic Activity. J Nucl Med. 2015;56:1019-23. [24] Kitagawa T, Yamamoto H, Toshimitsu S, Sasaki K, Senoo A, Kubo Y, et al. 18F-sodium fluoride positron emission tomography for molecular imaging of coronary atherosclerosis based on computed tomography analysis. Atherosclerosis. 2017;263:385-92. [25] Joshi NV, Vesey AT, Williams MC, Shah AS, Calvert PA, Craighead FH, et al. 18F-fluoride positron emission tomography for identification of ruptured and high-risk coronary atherosclerotic plaques: a prospective clinical trial. Lancet. 2014;383:705-13. [26] Cocker MS, Spence JD, Hammond R, Wells G, deKemp RA, Lum C, et al. [18F]-NaF PET/CT Identifies Active Calcification in Carotid Plaque. JACC Cardiovasc Imaging. 2017;10:486-8. [27] Stein PD, Yaekoub AY, Matta F, Sostman HD. 64-slice CT for diagnosis of coronary artery disease: a systematic review. Am J Med. 2008;121:715-25. [28] Task Force M, Montalescot G, Sechtem U, Achenbach S, Andreotti F, Arden C, et al. 2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the management of stable coronary artery disease of the European Society of Cardiology. Eur Heart J. 2013;34:2949-3003. [29] NICE Guidelines. Chest pain of recent onset: assessment and diagnosis. https://www nice org uk/ guidance/ cg95 2016. [30] Min JK, Shaw LJ, Devereux RB, Okin PM, Weinsaft JW, Russo DJ, et al. Prognostic value of multidetector coronary computed tomographic angiography for prediction of all-cause mortality. J Am Coll Cardiol. 2007;50:1161-70. [31] Min JK, Dunning A, Lin FY, Achenbach S, Al-Mallah M, Budoff MJ, et al. Age- and sexrelated differences in all-cause mortality risk based on coronary computed tomography angiography findings results from the International Multicenter CONFIRM (Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter Registry) of 23,854 patients without known coronary artery disease. J Am Coll Cardiol. 2011;58:849-60. 15

ACCEPTED MANUSCRIPT

AC

CE

PT

ED

MA

NU

SC RI

PT

[32] Andreini D, Pontone G, Mushtaq S, Bertella E, Conte E, Baggiano A, et al. Prognostic value of multidetector computed tomography coronary angiography in diabetes: excellent longterm prognosis in patients with normal coronary arteries. Diabetes Care. 2013;36:1834-41. [33] Blanke P, Naoum C, Ahmadi A, Cheruvu C, Soon J, Arepalli C, et al. Long-Term Prognostic Utility of Coronary CT Angiography in Stable Patients With Diabetes Mellitus. JACC Cardiovasc Imaging. 2016;9:1280-8. [34] Xie JX, Eshtehardi P, Varghese T, Goyal A, Mehta PK, Kang W, et al. Prognostic Significance of Nonobstructive Left Main Coronary Artery Disease in Women Versus Men: Long-Term Outcomes From the CONFIRM (Coronary CT Angiography Evaluation For Clinical Outcomes: An International Multicenter) Registry. Circ Cardiovasc Imaging. 2017;10. [35] Pundziute G, Schuijf JD, Jukema JW, Decramer I, Sarno G, Vanhoenacker PK, et al. Head-tohead comparison of coronary plaque evaluation between multislice computed tomography and intravascular ultrasound radiofrequency data analysis. JACC Cardiovasc Interv. 2008;1:176-82. [36] Motoyama S, Sarai M, Harigaya H, Anno H, Inoue K, Hara T, et al. Computed tomographic angiography characteristics of atherosclerotic plaques subsequently resulting in acute coronary syndrome. J Am Coll Cardiol. 2009;54:49-57. [37] Glagov S, Weisenberg E, Zarins CK, Stankunavicius R, Kolettis GJ. Compensatory enlargement of human atherosclerotic coronary arteries. N Engl J Med. 1987;316:1371-5. [38] Virmani R, Burke AP, Farb A, Kolodgie FD. Pathology of the vulnerable plaque. J Am Coll Cardiol. 2006;47:C13-8. [39] Otsuka K, Fukuda S, Tanaka A, Nakanishi K, Taguchi H, Yoshikawa J, et al. Napkin-ring sign on coronary CT angiography for the prediction of acute coronary syndrome. JACC Cardiovasc Imaging. 2013;6:448-57. [40] Thomsen C, Abdulla J. Characteristics of high-risk coronary plaques identified by computed tomographic angiography and associated prognosis: a systematic review and metaanalysis. Eur Heart J Cardiovasc Imaging. 2016;17:120-9. [41] Puchner SB, Liu T, Mayrhofer T, Truong QA, Lee H, Fleg JL, et al. High-risk plaque detected on coronary CT angiography predicts acute coronary syndromes independent of significant stenosis in acute chest pain: results from the ROMICAT-II trial. J Am Coll Cardiol. 2014;64:684-92. [42] Conte E, Annoni A, Pontone G, Mushtaq S, Guglielmo M, Baggiano A, et al. Evaluation of coronary plaque characteristics with coronary computed tomography angiography in patients with non-obstructive coronary artery disease: a long-term follow-up study. Eur Heart J Cardiovasc Imaging. 2016. [43] Korosoglou G, Lehrke S, Mueller D, Hosch W, Kauczor HU, Humpert PM, et al. Determinants of troponin release in patients with stable coronary artery disease: insights from CT angiography characteristics of atherosclerotic plaque. Heart. 2011;97:823-31. [44] Andreini D. Dual Energy Coronary Computed Tomography Angiography for Detection and Quantification of Atherosclerotic Burden: Diagnostic and Prognostic Significance. Rev Esp Cardiol (Engl Ed). 2016;69:885-7. [45] Hachamovitch R, Hayes SW, Friedman JD, Cohen I, Berman DS. Comparison of the shortterm survival benefit associated with revascularization compared with medical therapy in patients with no prior coronary artery disease undergoing stress myocardial perfusion single photon emission computed tomography. Circulation. 2003;107:2900-7. [46] Pontone G. Anatomy and physiology in ischaemic heart disease: a second honeymoon? Eur Heart J. 2016;37:1228-31. [47] Schuijf JD, Wijns W, Jukema JW, Atsma DE, de Roos A, Lamb HJ, et al. Relationship between noninvasive coronary angiography with multi-slice computed tomography and myocardial perfusion imaging. J Am Coll Cardiol. 2006;48:2508-14. 16

ACCEPTED MANUSCRIPT

AC

CE

PT

ED

MA

NU

SC RI

PT

[48] Park HB, Heo R, o Hartaigh B, Cho I, Gransar H, Nakazato R, et al. Atherosclerotic plaque characteristics by CT angiography identify coronary lesions that cause ischemia: a direct comparison to fractional flow reserve. JACC Cardiovasc Imaging. 2015;8:1-10. [49] Falk E, Shah PK, Fuster V. Coronary plaque disruption. Circulation. 1995;92:657-71. [50] Stone GW, Maehara A, Lansky AJ, de Bruyne B, Cristea E, Mintz GS, et al. A prospective natural-history study of coronary atherosclerosis. N Engl J Med. 2011;364:226-35. [51] Libby P, Pasterkamp G. Requiem for the 'vulnerable plaque'. Eur Heart J. 2015;36:2984-7. [52] Lin F, Shaw LJ, Berman DS, Callister TQ, Weinsaft JW, Wong FJ, et al. Multidetector computed tomography coronary artery plaque predictors of stress-induced myocardial ischemia by SPECT. Atherosclerosis. 2008;197:700-9. [53] Shmilovich H, Cheng VY, Tamarappoo BK, Dey D, Nakazato R, Gransar H, et al. Vulnerable plaque features on coronary CT angiography as markers of inducible regional myocardial hypoperfusion from severe coronary artery stenoses. Atherosclerosis. 2011;219:588-95. [54] Diaz-Zamudio M, Dey D, Schuhbaeck A, Nakazato R, Gransar H, Slomka PJ, et al. Automated Quantitative Plaque Burden from Coronary CT Angiography Noninvasively Predicts Hemodynamic Significance by using Fractional Flow Reserve in Intermediate Coronary Lesions. Radiology. 2015;276:408-15. [55] Nakazato R, Park HB, Gransar H, Leipsic JA, Budoff MJ, Mancini GB, et al. Additive diagnostic value of atherosclerotic plaque characteristics to non-invasive FFR for identification of lesions causing ischaemia: results from a prospective international multicentre trial. EuroIntervention. 2016;12:473-81. [56] Dey D, Diaz Zamudio M, Schuhbaeck A, Juarez Orozco LE, Otaki Y, Gransar H, et al. Relationship Between Quantitative Adverse Plaque Features From Coronary Computed Tomography Angiography and Downstream Impaired Myocardial Flow Reserve by 13NAmmonia Positron Emission Tomography: A Pilot Study. Circ Cardiovasc Imaging. 2015;8:e003255. [57] Diaz-Zamudio M, Fuchs TA, Slomka P, Otaki Y, Arsanjani R, Gransar H, et al. Quantitative plaque features from coronary computed tomography angiography to identify regional ischemia by myocardial perfusion imaging. Eur Heart J Cardiovasc Imaging. 2017;18:499-507. [58] Gaur S, Ovrehus KA, Dey D, Leipsic J, Botker HE, Jensen JM, et al. Coronary plaque quantification and fractional flow reserve by coronary computed tomography angiography identify ischaemia-causing lesions. Eur Heart J. 2016;37:1220-7. [59] Lavi S, Yang EH, Prasad A, Mathew V, Barsness GW, Rihal CS, et al. The interaction between coronary endothelial dysfunction, local oxidative stress, and endogenous nitric oxide in humans. Hypertension. 2008;51:127-33. [60] Leipsic J, Blanke P, Norgaard BL. Defining the relationship between atherosclerotic plaque, ischaemia, and risk-the story unfolds. Eur Heart J Cardiovasc Imaging. 2017;18:508-9. [61] Rizvi A, Hartaigh BO, Knaapen P, Leipsic J, Shaw LJ, Andreini D, et al. Rationale and Design of the CREDENCE Trial: computed TomogRaphic evaluation of atherosclerotic DEtermiNants of myocardial IsChEmia. BMC Cardiovasc Disord. 2016;16:190.

17

SC RI

PT

ACCEPTED MANUSCRIPT

AC

CE

PT

ED

MA

NU

Figure 1

18

SC RI

PT

ACCEPTED MANUSCRIPT

AC

CE

PT

ED

MA

NU

Figure 2

19

NU

SC RI

PT

ACCEPTED MANUSCRIPT

AC

CE

PT

ED

MA

Figure 3

20