The value of imaging in subclinical coronary artery disease

    The value of imaging in subclinical coronary artery disease Marco Zimarino, Francesco Prati, Riccardo Marano, Francesca Angeramo, Irene Pescetelli, Laura Gatto, Valeria Marco, Isabella Bruno, Raffaele De Caterina PII: DOI: Reference:

S1537-1891(15)30067-7 doi: 10.1016/j.vph.2016.02.001 VPH 6292

To appear in:

Vascular Pharmacology

Received date: Revised date: Accepted date:

23 October 2015 28 January 2016 1 February 2016

Please cite this article as: Zimarino, Marco, Prati, Francesco, Marano, Riccardo, Angeramo, Francesca, Pescetelli, Irene, Gatto, Laura, Marco, Valeria, Bruno, Isabella, De Caterina, Raffaele, The value of imaging in subclinical coronary artery disease, Vascular Pharmacology (2016), doi: 10.1016/j.vph.2016.02.001

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 The value of imaging in subclinical coronary artery disease

T

Marco Zimarino1, MD; PhD, Francesco Prati2, MD; Riccardo Marano3, MD;

IP

Francesca Angeramo1, MD; Irene Pescetelli1, MD; Laura Gatto2, MD;

1

SC R

Valeria Marco2, RN; Isabella Bruno4, MD; Raffaele De Caterina1, MD, PhD.

Institute of Cardiology and Center of Excellence on Aging, “G. d’Annunzio” University – Chieti

NU

(Italy)

San Giovanni Addolorata Hospital; CLI-Foundation-Rome

3

Department of Radiological Sciences, Institute of Radiology "A. Gemelli" Hospital, Catholic

MA

2

University – Rome (Italy)

Institute of Nuclear Medicine, "A. Gemelli" Hospital, Catholic University – Rome (Italy)

TE

D

4

Short running title: Imaging of subclinical CAD

CE P

Word count: 4,843 words (text only)

Indexing words: coronary artery disease, angiography, IVUS, OCT, NIRS, coronary-CT

AC

angiography.

The authors state that there is no commercial associations that may pose a conflict of interest in connection with the submitted manuscript. Corresponding author: Marco Zimarino, MD, PhD Institute of Cardiology, "G. d'Annunzio" University – Chieti C/o Ospedale SS. Annunziata Via dei Vestini 66013 Chieti, Italy Tel. +39-0871-41512 FAX: +39-0871-402817 e-mail: [email protected] 1

ACCEPTED MANUSCRIPT ABSTRACT

Although the treatment of acute coronary syndromes (ACS) has advanced considerably, the ability

IP

T

to detect, predict, and prevent complications of atherosclerotic plaques, considered the main cause of ACS, remains elusive. Several imaging tools have therefore been developed to characterize

SC R

morphological determinants of plaque vulnerability, defined as the propensity or probability of plaques to complicate with coronary thrombosis, able to predict patients at risk. By utilizing both intravascular and noninvasive imaging tools, indeed prospective longitudinal studies have recently

formation, progression, and instabilization.

NU

provided considerable knowledge, increasing our understanding of determinants of plaque

MA

In the present review we aim at 1) critically analyzing the incremental utility of imaging tools over currently available “traditional” methods of risk stratification; 2) documenting the capacity of such modalities to monitor atherosclerosis progression and regression according to lifestyle

D

modifications and targeted therapy; and 3) evaluating the potential clinical relevance of advanced

TE

imaging, testing whether detection of such lesions may guide therapeutic decisions and changes in treatment strategy.

CE P

The current understanding of modes of progression of atherosclerotic vascular disease and the appropriate use of available diagnostic tools may already now gauge the selection of patients to be enrolled in primary and secondary prevention studies. Appropriate trials should now, however,

AC

evaluate the cost-effectiveness of an aggressive search of vulnerable plaques, favoring implementation of such diagnostic tools in daily practice.

Key words: atherosclerosis; plaque; inflammation; thin-cap fibroatheroma; imaging.

2

ACCEPTED MANUSCRIPT ABBREVIATIONS AND ACRONYMS

T

ACS = Acute Coronary Syndromes

IP

CAD = Coronary Artery Disease

SC R

CAD = Coronary Heart Disease CT = Computed Tomography

NU

IVUS = IntraVascular UltraSound MDCT = Multi-Detector Computed Tomography

MA

MDCT-CA = Multi-Detector Computed Tomography Coronary Angiography MRCA = Magnetic Resonance Coronary Angiography

D

NIRS = Near InfraRed Spectroscopy

TE

OCT = Optical Coherence Tomography

CE P

PET = Positron Emission Tomography

SPECT = Single Photon Emission Computed Tomography

AC

VH-IVUS = Virtual Histology IntraVascular UltraSound

3

ACCEPTED MANUSCRIPT 1. The rationale for assessing subclinical atherosclerosis

Atherosclerosis is a chronic progressive disease with sudden transitions from a stable status to life-

IP

T

threatening conditions, including acute coronary syndromes (ACS) and atherothrombotic ischemic stroke, usually attributed to plaque rupture or plaque erosion, with subsequent intimal denudation

SC R

and thrombosis. Prevention – rather than treatment – of acute events seems to be the only effective strategy to reduce the epidemiological burden of cardiovascular disease (CVD) in general and coronary heart disease (CHD) in particular, and significantly improve mortality and morbidity(1).

NU

We conventionally define coronary artery disease (CAD), the largely prevailing pathological substrate of CHD, as “subclinical” in the presence of non-obstructive coronary atherosclerotic plaques, because of their low probability to result in symptoms and signs related to decreased

MA

coronary reserve, resulting, for example, in exercise-induced ischemia. Such lesions are relatively common, occurring in 10% to 25% of patients undergoing coronary angiography(2). Historically,

D

most CHD prevention studies have included patients with either obstructive CAD or a previous clinical cardiovascular event, and such restrictive selection criteria have led to the unavailability of

TE

sufficient data to understand the prognostic implications (cardiovascular outcomes) of subclinical

CE P

CAD.

To identify factors that trigger the onset of ACS, Mueller et al.(3) originally identified still silent, not yet “culprit” lesions able to give a cardiac event at a later follow-up: such lesions, designated as

AC

“vulnerable plaques”, were characterized by a large lipid pool, a thin fibrous cap, and abundance of inflammatory macrophages(4,5). More recently, evidence has emerged that most plaque complications arise from non-obstructive “vulnerable” lesions, and that such lesions, much more abundant than obstructive lesions, are responsible for a number of adverse cardiovascular events at least comparable with that deriving from obstructive plaques(6-8), or from plaques already responsible for a previous ACS. It is also possible that we are now witnessing a change in the pathological substrate of ACS. The extensive use of statins, public policies banning smoking, the improved control of risk factors, as well as increased life expectancy, have likely produced a shift in the morphology of human culprit lesions over the last decade(9). Plaques obtained from recent patients with symptomatic carotid artery disease in contemporary practice reveal significantly more fibrous and non-inflammatory characteristics compared with plaques from previous patients(10). In parallel, and potentially linked to this, a change in the ACS presentation has been now documented, with increased prevalence of 4

ACCEPTED MANUSCRIPT non-ST elevation (NSTE) myocardial infarction (MI) versus ST-segment elevation MI (STEMI), and a higher proportion of women, younger individuals, and of subjects with obesity, insulin resistance or frank diabetes(11). Alongside with these features, studies performed with

T

intracoronary imaging tools have documented an increased prevalence of plaque erosion over

IP

rupture, with patients experiencing plaque erosion being more frequently female, younger, with a lower amount of lipid burden and a thicker fibrous cap(12). Despite such a shift in the proportion of

SC R

the underlying mechanisms of plaque instabilization may adversely affect the value of imaging technologies, the identification and monitoring over time of vulnerable plaques in non-obstructive CAD may have clinical relevance. Aside from coronary angiography, which depicts the lumen

NU

reduction caused by the presence of the plaque, an accurate imaging of the coronary wall and even of the plaque components can nowadays be accomplished with invasive and non-invasive imaging

MA

techniques. Such diagnostic tools have remarkable accuracy in the identification of plaque morphology and its changes following changes in lifestyle, as well as with medical or interventional therapy. However, strategic studies focusing on the use of such advanced diagnostic modalities

CE P

2. Localization of plaques

TE

D

have so far failed to document clinical benefit in primary and secondary prevention.

Although the entire vascular bed is constantly exposed to the same risk factors, atherosclerotic lesions present a distinct pattern of localization and progression, being consistently more frequent in

AC

specific segments of the arterial vascular bed. Both pathology(13) and in vivo studies have shown that such lesions preferentially localize at coronary artery bifurcations, with a prevalence of 15-20% among all coronary segments in patients undergoing percutaneous coronary interventions (PCI)(14). Typical localizations of vulnerable, thin-cap, lipid-rich plaques, are the outer walls of bifurcations and the inner wall of curvatures; conversely, the flow dividers of bifurcations are mostly spared(15,16) (Figure 1). Such a peculiar distribution may be related to endothelial shear stress(17) – the stress, tangential to the endothelial surface – derived from the friction of the flowing blood on the endothelial surface of arteries. The endothelial shear stress modulates endothelial function, acting on mechanoreceptors functionally demonstrated on the surface of endothelial cells(18), affecting gene expression and regulating the production of vasoactive substances and local inflammation factors(19). A low endothelial shear stress (<5 dyne/cm2) has been documented in regions prone to atherosclerosis, and has been associated with an aggressive inflammatory and proliferative pattern of endothelial gene expression that promotes atherosclerosis(20) (Figure 1). Regional differences have been reported in the adaptive mechanisms of vessel walls to 5

ACCEPTED MANUSCRIPT atherosclerotic progression, and in response to risk factor-modifying therapies. A positive remodeling – the outward enlargement of the vessel wall as a compensatory reaction to accommodate plaque growth and prevent lumen reduction – is associated with vulnerable plaques,

T

being present in >80% of cases identified in the proximal segments of the coronary vasculature(21).

IP

Conversely, a constrictive (“negative”) remodeling occurs more frequently in diabetic than in nondiabetic patients, is frequently localized in the distal epicardial coronary arteries, and is associated

SC R

with stable CAD(22). Currently considered ”optimal” medical therapy, aimed at correcting common cardiovascular risk factors – such as hypertension, dyslipidemia, diabetes mellitus – can limit the lumen impingement of atheromatous lesions, as is associated with positive remodeling in segments

NU

of large epicardial arteries – particularly the left main coronary artery –, while downstream

MA

segments feature a progressively more constrictive pattern of remodeling(23).

3. Invasive assessment (Table 1)

D

An invasive diagnostic evaluation is performed only when there is a strong suspicion of clinically

TE

relevant CAD, as in patients symptomatic for angina, with documented stress-induced ischemia or

CE P

in the setting of a high-to-intermediate risk ACS.

3.1. Although coronary angiography is still the gold standard for the assessment of CAD, it simply shows the coronary lumen, without depicting the vessel wall and atherosclerotic plaques.

AC

Myocardial ischemia may be provoked by abnormal epicardial and/or microvascular coronary dysfunction in patients without CAD as detected by angiography(24). Moreover, angiography may miss culprit lesions, and is unable to address plaque vulnerability or provide information on the extent and severity of atherosclerosis(25). Efforts have been done in the past few years to overcome such limitations of angiography by developing invasive imaging modalities capable of imaging coronary atherosclerosis and of providing a better understanding of coronary pathology. Intravascular imaging has broadened our knowledge of coronary atherosclerosis by providing detailed visualization of both the lumen and plaque morphology, and reliably quantifying the atheroma and its composition(26).

3.2. Intravascular ultrasound (IVUS) provides real-time, high resolution, tomographic images of the lumen, as well as atherosclerotic changes in the vessel wall. This imaging technique requires a selective interrogation of the vessel with an imaging catheter that incorporates a transducer emitting 6

ACCEPTED MANUSCRIPT high-frequency (20–45 MHz) ultrasounds. Detection of the contours of the lumen and of the media– adventitia interface permits a direct measurement of the lumen and of the total cross-sectional vessel area, and therefore allows calculation of the absolute and percent plaque area. In addition, severity,

and

composition

of

coronary

atherosclerotic

plaques

can

be

T

morphology,

IP

determined(27,28). With IVUS, atheromas have been classified in four grey-scale categories: (1) soft plaques, with lesion echogenicity less than the surrounding adventitia; (2) fibrous plaques, with

SC R

echogenicity intermediate between soft atheromas and highly echogenic calcified plaques; (3) calcified plaque, with echogenicity higher than the adventitia, and with acoustic shadowing; and (4) mixed plaques, with no single acoustical subtype, and representing >80% of the plaques(29).

NU

To overcome limitations of the qualitative visual interpretation of the IVUS images and to describe the coronary plaque morphology, several computer-assisted post-processing methods have been

MA

developed in recent years. A commonly used one is virtual histology (VH) IVUS, based not only on the amplitude but also on the underlying frequency of the reflected signals, to analyze tissue composition of the plaques. This combined information allows a classification into four basic

D

plaque tissue components(30): (1) fibrous tissue (usually depicted in dark green); (2) fibro-fatty

TE

tissue (in light green); (3) necrotic core (in red); and (4) dense calcium (in white). The Providing Regional Observations to Study Predictors of Events in the Coronary Tree

CE P

(PROSPECT) trial(6) evaluated the natural history of atherosclerosis by studying 697 patients presenting with an ACS and treated with PCI of the culprit lesion plus optimal medical therapy. All patients had 3-vessel grey scale and VH-IVUS imaging. The study showed that both culprit and non-culprit lesions were equally responsible for major adverse coronary events (MACE) over 3

AC

years. Most non-culprit lesions causing events during the follow-up had a mild angiographic narrowing at baseline. A multivariate analysis carried on with VH-IVUS data identified 3 independent predictors of adverse events: a plaque burden ≥70%, a minimal luminal area (MLA) ≤4.0 mm2, and the presence of a thin-cap fibroatheroma, identified as a lipid-rich atheroma with only a thin fibrous layer of intimal tissue covering the necrotic core. Likewise, in the VH-IVUS in Vulnerable Atherosclerosis (VIVA) study(31), 3-vessel VH-IVUS was performed in 170 patients with stable angina or ACS before and after a PCI. During 1.7 years of follow-up, 19 (13 non-culprit and 6 culprit) lesions led to death, myocardial infarction (MI) or unplanned revascularization. Factors of non-culprit lesions associated with later total major adverse events were again a plaque burden >70% and a MLA <4 mm2. Thus, IVUS studies positively identified features associated with the development of ACS. However, they also identified many plaques that, despite such morphologic characteristics associated with vulnerability, never caused a

7

ACCEPTED MANUSCRIPT fatal rupture. Such notion therefore somehow challenges the “vulnerable plaque” concept itself(11) and argues against the clinical utility of intravascular imaging.

T

3.3. Optical coherence tomography (OCT) is an imaging technique based on infrared light, able

IP

to study atherosclerotic plaques and stented segments with extreme spatial accuracy(32). Its currently used new version, the Frequency Domain-OCT(33), has replaced the former Time

SC R

Domain-OCT, providing images of improved quality due to the higher number of cross-sections per seconds and higher number of lines per cross-sections. OCT has a resolution much higher than IVUS (10-15 µm versus 100-150 µm)(34), but at the expenses of lesser tissue penetration, thereby

NU

limiting the assessment of vessel dimensions and of the overall plaque volume. OCT allows the identification of several plaque pathologic features, including an accurate detection

MA

of small extracellular lipid pools in “intermediate” (Stary type III) atherosclerotic lesions(35). It also allows a good assessment of PCI results and stent complications (dissection, thrombosis, tissue prolapse and strut malapposition/uncoverage)(36). With its ability to define the superficial vessel

D

wall structure, in addition to tissue elements characterizing vulnerable plaques, such as lipid pools,

TE

fibrous components and calcified nodules, OCT can directly measure fibrous cap thickness and lipid pool extension (Figure 2). OCT clearly identifies the underlying substrate in a patient presenting

CE P

with an ACS, with important prognostic information; for example, the identification of plaque rupture by OCT has been identified as an independent predictor of 3-year adverse cardiac events (HR 3.73, P=0.010) compared with the presence of an intact fibrous cap(37). Three-vessel OCT studies have shown a greater prevalence of lipid-rich plaques in patients with the

AC

metabolic syndrome(38) and in non-culprit vessels of patients with ACS(39), supporting the concept that, in unstable patients, cardiovascular risk factors and systemic inflammation apparently impact the entire coronary tree rather than only the culprit vessel. OCT has supported concepts derived from pathology studies, demonstrating that in ACS patients culprit ruptured plaques are not uniformly distributed throughout the coronary vessel, but mainly located in the proximal 30 mm arterial segment. OCT studies have also shown that the morphology of culprit lesions seems to differ throughout the coronary arteries, with proximal culprit lesions being more often associated with rupture and the occurrence of thin-cap fibroatheromas(40). Interestingly, diabetic patients, presenting with their first ACS, exhibit less lipid components and a greater number of calcified quadrants at the site of MLA in comparison with non-diabetic patients(41). In line with previous IVUS findings and with the evidence of a higher prevalence of negative remodeling in diabetic patients, OCT has documented a more advanced stage of atherosclerosis in such patients,

8

ACCEPTED MANUSCRIPT supporting the hypothesis that malfunctioning protective mechanisms have a role in plaque progression in the presence of diabetes(42). OCT can also identify plaque characteristics that predict accelerated atherosclerosis progression: the

T

presence of thin-cap fibroatheroma and intraplaque microvessels – identified by OCT as tubular

IP

structures without connection with the vessel lumen – highly correlates with subsequent CAD lumen reduction as assessed by coronary angiography at a 7-month follow-up(43). More recently,

SC R

the abundance of vasa vasorum has been correlated with the volume of fibrous plaques, and the presence of intra-plaque neovessels has been associated with plaque vulnerability(44). OCT has also allowed to document a time-shift in the paradigm of the “vulnerable plaque”, with a

NU

recently reduced incidence of plaque rupture as correlate of ACS, in favor of a growing proportion of plaque erosions, that occur more frequently in plaques with a limited lipid pool and thicker

MA

fibrous cap, notably in women and in diabetic patients(12).

Although OCT has the capacity to identify features related to plaque progression and instability already at a simple visual inspection, the use of dedicated softwares for post-processing has proven

D

to be very helpful in identifying and quantifying such features. The use of dedicated algorithms now

TE

allows to identify local signs of inflammation(45,46). Software-assisted post-processing also facilitates the serial comparison of the same segment at different time points: the “Carpet View” is a

CE P

software that allows to “unfold” the vessel, reconstructing it as an open 3-D structure, thus improving the off-line serial comparisons of both coronary plaques and stented segments, and enabling the matching of the imaged cross-section at different time points(47). This has a great potential in studies of atherosclerosis progression or regression, improving from the IVUS concept

AC

of total plaque volume changes to that of variations in plaque composition.

3.4. Near InfraRed Spectroscopy (NIRS). Lipid-rich atherosclerotic plaques are known for being responsible of most ACS(48) and have a specific chemical signature related to the presence of cholesterol esters in lipid cores. NIRS is a novel catheter-based imaging modality that allows to determine the chemical composition of the artery wall in vivo(49), and potentially to detect lipidrich atheromata. The NIRS system, consisting of a pullback and rotation device, a console and a catheter, utilizes changes in the reflection of emitted light to map the vessel wall in the form of a chemogram, where yellow regions are those with a higher probability of the presence of a lipid pool, while red regions have a lower probability (Figure 2). The chemogram enables the measurement of the lipid core burden index (LCBI), as the fraction of yellow pixels within a region(50); here culprit lesions were associated with significantly higher LCBI than non-culprit segments(51). 9

ACCEPTED MANUSCRIPT The accuracy of NIRS has been validated in coronary autopsy specimens(49) and subsequently in vivo(52). An assessment of the comparative prevalence and distribution of lipid plaques in patients with stable CAD and ACS(53) has shown that target lesions more frequently feature lipid plaques

T

by NIRS in ACS patients than in patients with stable angina (84% versus 53%, P=0.004), and that

IP

approximately one half of target lesions in stable patients contain lipid plaques. Moreover, at sites

than in stable patients (73% versus 18%, P=0.002).

SC R

anatomically remote from the target lesion, lipid-rich plaques appeared much more frequent in ACS

The prognostic implication of lipid-rich coronary plaques has been documented in the European Collaborative Project on Inflammation and Vascular Wall Remodeling in Atherosclerosis–Near-

NU

Infrared Spectroscopy (ATHEROREMO-NIRS) study(54), where a “high” LCBI in a single, nonstenotic segment of a non-culprit coronary artery was associated with a 4-fold risk of increased

D

4. Noninvasive assessment (Table 1)

MA

cardiovascular events during a 1-year follow-up.

TE

4.1. Multi-detector Computed Tomography Coronary Angiography. The remarkable technical evolution in Computed Tomography (CT) in the past 15 years with the development and

CE P

widespread use of the newest multi-detector CT (MDCT) scanners, characterized both by high temporal (66-175 ms) and spatial (240-600 μm) resolutions, as well as with a larger scan coverage, the availability of prospective or retrospective ECG-gating, and – above all – the dramatic reduction

AC

and better control of the radiation dose (now even <1 mSv(55)) have made the non-invasive CT imaging of the coronary arteries more and more practical, reliable, and affordable. The coronary calcium is a well-known biological marker of CAD. It can be detected by noncontrast CT and can be quantified with the coronary artery calcium score, which allows a better stratification of asymptomatic subjects classified in the uncertain category of intermediate risk for future events by the traditional clinical risk score(56). In the Multi-Ethnic Study of Atherosclerosis (MESA), the coronary calcium score has been documented to significantly improve the ability of prediction for cardiovascular events, mostly effective in primary prevention for the reclassification of patients judged at intermediate risk on the basis of traditional risk factors(57), and has been then proposed as a valuable tool to define the “ideal” target population that could benefit from preventive pharmacotherapy(58). Coronary calcium however fails to detect non-calcified plaques, which are considered more prone to complication and adverse events than calcified plaques(59).

10

ACCEPTED MANUSCRIPT MDCT-coronary angiography (MDCT-CA) is currently the only non-invasive diagnostic tool able to distinguish normal coronary artery segments, non-obstructive (Fig. 3) or obstructive atherosclerotic lesions (Fig. 4). The diagnostic accuracy of this technique has been extensively

T

documented in a patient-based meta-analysis of several studies, whereby 64-row MDCT has shown

IP

a pooled sensitivity of 97%, specificity of 90%, a positive predictive value of 93%, and a negative predictive value of 96% for detecting >50% diameter stenoses(60). Provided that the diagnostic

SC R

accuracy of MDCT-CA is strongly determined by the image quality, as well as the appropriate patient selection and preparation, current guidelines and appropriateness criteria recognize a role for MDCT-CA in patients with intermediate-to-low pre-test probability of CAD(61-63), mostly

NU

because of its high negative predictive value(64-66), useful to rule out the presence of CAD. Although MDCT-CA seems to be the optimal diagnostic tool to detect subclinical CAD, the clinical

MA

relevance of such information is still unclear. Indeed, in patients with suspected CAD, the MDCTCA recently failed to add any clinical benefit over non-invasive functional diagnostic tests: in the Prospective Multicenter Imaging Study for Evaluation of Chest Pain (PROMISE)(67), a strategy of

D

initial anatomical assessment with MDCT-CA compared with functional testing did not improve 2-

TE

year clinical outcomes in 10,003 patients. Compared with subjects undergoing a functional assessment, subjects in the MDCT-CA group underwent catheterization more frequently (12.2%

P<0.001).

CE P

versus 8.1%, P<0.001) and had a higher overall radiation exposure (12.0 mSv versus 10.1 mSv;

However, MDCT-CA likely provides incremental prognostic utility in predicting mortality and nonfatal MI in asymptomatic subjects selected for a moderately-high risk profile. The COronary CT

AC

Angiography EvaluatioN For Clinical Outcomes: an InteRnational Multicenter (CONFIRM) registry analyzed data on 27,125 consecutive patients. Among the 3,217 asymptomatic individuals without known CAD, the incremental value of MDCT-CA over the Framingham risk score could be demonstrated only in individuals with moderate-high calcium score (>100)(68). Among 10,418 patients with non-obstructive CAD, each additional segment with a non-obstructive plaque implied a 6% higher risk of 2-year death (P=0.021). Baseline statin therapy was associated with a 56% lower mortality (P=0.0003), and such benefit was apparent only for individuals with nonobstructive CAD (P<0.001), and not for those without the presence of a plaque (P=NS)(69). The sole presence of diabetes does not apparently identify a population of patients deriving a benefit from an initial non-invasive anatomic assessment. The Screening For Asymptomatic Obstructive Coronary Artery Disease Among High-Risk Diabetic Patients Using CT Angiography, Following Core-64: A Randomized Control Study (FACTOR-64)(70) recently failed to detect any benefit from a strategy of routine MDCT-CA as compared to standard care among 900 asymptomatic diabetic 11

ACCEPTED MANUSCRIPT patients: those aggressively screened experienced a non-significant (20%) relative risk reduction of death, MI or unstable angina. Although well-conducted, the trial resulted, however, to be underpowered, because patients in the control group had a much better outcome than anticipated,

T

the prevalence of severe CAD was low, the rate of increased revascularization was modest (5.8%),

IP

and the hypothetical benefit deriving from low-density lipoprotein (LDL) cholesterol reduction (only 2.6 mg/dL) was negligible in patients assigned to the aggressive screening(71).

SC R

Nevertheless, MDCT-CA is currently the sole non-invasive diagnostic modality capable of imaging the coronary wall, of evaluating and quantifying the plaque, and of effectively monitoring the progression and/or regression of atherosclerosis following statin therapy(72). To date, the CT

NU

spatial resolution is still inadequate to detect the thin-cap fibroatheroma, while a low attenuation density (<90 Hounsfield units [HU]) area already seems to be able to accurately detect a lipid-rich

MA

core. To identify vulnerable plaques(59) beyond plaque burden, positive remodeling (Fig. 4) and spotty calcifications (small, dense >130 HU plaque components surrounded by non-calcified plaque tissue), a new feature has been recently identified in the so called “napkin-ring” sign(73,74). This

D

refers to a thin ring-like rim of contrast enhancement surrounding the coronary plaque, mainly

TE

reflecting the neo-vascularization of the plaque through the vasa-vasorum with active inflammation(73), and has been documented as being extremely specific (>95%) for the detection

CE P

of a thin fibrous cap at OCT(75,76).

The next developments in MDCT-CA to improve detection of vulnerable plaques are aiming at better morphologic and functional assessments. A further increase in CT spatial/temporal resolution and/or the use of multiple energy scan data sets (80 kV and 140 kV) will reduce the overlap of

AC

density values of the various plaque components and improve the discriminating capacity. Recent advances in computational fluid dynamics now also permit the determination of endothelial shear stress distribution(77). More interestingly, MDCT-CA can identify the functional relevance of coronary lesions(78), and has been recently used to non-invasively compute the fractional flow reserve (FFR) – the ratio of maximal coronary blood flow through a stenotic artery to the blood flow in the hypothetical case the artery lumen were normal. In the Determination of Fractional Flow Reserve by Anatomic Computed Tomographic Angiography (DeFACTO) trial(79), CT-derived FFR has recently documented a better diagnostic performance than MDCT–CA alone for the assessment of clinically “significant” coronary lesions, i.e., those limiting the coronary reserve. Finally, the recent availability of new targeted iodinated nano-particulate contrast agents (as N1177) seems promising for the detection of inflammation within atherosclerotic plaques(80). In particular, the uptake of this new contrast agent has been tested in atherosclerotic rabbits for the CT detection of macrophages within aortic plaques, with a correlation with fluoro-deoxyglucose (FDG)-uptake at 12

ACCEPTED MANUSCRIPT positron-emission tomography, but the feasibility and clinical applicability of CT for the molecular imaging of plaque vulnerability still awaits testing in humans.

T

4.2. Magnetic Resonance Coronary Angiography (MRCA). MRCA has been extensively

IP

validated for the detection and characterization of atherosclerotic plaques(81,82), and the monitoring of their possible change under pharmacological treatment(83,84). MRCA is a promising

SC R

technology for the imaging of vulnerable plaques, but its application has always been limited to larger arteries (aorta and carotid arteries) due to its low spatial resolution. Major strengths of MR are the capability to visualize both the lumen and the wall of large vessels, the absence of radiation

NU

exposure – ensuring serial repeatability – and the excellent contrast resolution, useful to evaluate compositional and morphological features of atherosclerotic plaques. Multi-spectral-MR can

MA

identify the lipid-rich necrotic core in human carotid atherosclerosis(85), and characterize the state of the fibrous cap in vivo (81). The capability of MR to detect the presence of macrophages in the context of atherosclerotic plaques by using the ultra-small particles of iron oxide might play a

D

significant role in the detection and characterization of human vulnerable plaques(86), and be used

TE

in the serial assessment of the effects of statin therapy, but such imaging modality has been so far limited to human carotid plaques, devoid of motion artefacts(84). Despite the documented

CE P

continuous evolution of MR techniques for the non-invasive coronary artery imaging80,81, with improvements of lumen and vessel wall assessments and occasional exciting examples of coronary plaque assessment(87-89), MRCA still remains an investigational technique due to both limited spatial and temporal resolution, which strongly limit its use in the clinical setting. In fact, in

AC

comparison with MDCT-CA, MRCA is still a clunky diagnostic tool, with higher failure rates, exceedingly long scan times, and poor diagnostic performance due to a low positive predictive value(89), and has therefore currently a limited role in risk stratification of clinical and subclinical CAD.

4.3. Nuclear imaging (Table 1) Molecular radioisotopic imaging, with Single Photon Emission Computed Tomography (SPECT) and Positron Emission Tomography (PET), can assess perfusion and tissue metabolic activity, providing functional information on plaque activity and potentially assessing plaque stability(90,91). Currently, new hardware designs combining nuclear imaging techniques with others with better spatial resolution, such as SPECT-CT, PET-CT, and PET-RM dual-modality systems, and dedicated cardiac gamma cameras with optimal detector geometric arrays, linear count statistic and count rate response, allow for lower-radiation imaging, reduced scan time and 13

ACCEPTED MANUSCRIPT improved image quality. The high sensitivity of both SPECT and PET nuclear imaging techniques, together with the ability of CT to identify the anatomical burden of CAD, hold the promise to increase the low positive value of CT imaging alone distinguishing vulnerable from stable

IP

T

plaques(90,92).

4.3.1. Single Photon-Emission Computed Tomography (SPECT) imaging: Technetium-99m99m

Tc-sestamibi and

99m

Tc-tetrofosmin – are widely used in

SC R

labelled (99mTc) radiotracers – such as

clinical practice for the investigation of myocardial perfusion and viability.

99m

Tc-labelled annexin

A5, a new SPECT tracer, has been recently proposed to identify plaque apoptosis in a porcine CAD

NU

model(93), and – more recently – to detect unstable atherosclerotic lesions in vivo in a human study(94). Furthermore, dietary changes and simvastatin therapy have been recently associated with 99m

Tc-labelled-annexin A5 uptake in the plaque(95). However, despite

MA

a significant reduction of

initial promising results for the identification of vulnerable atherosclerotic plaques, most current studies using integrated SPECT/CT focus on myocardial perfusion imaging, while plaque imaging

D

is still limited because of resolution limits and insufficient specificity of the tracer. Moreover, this

TE

tracer is not yet commercially available for clinical use(96).

CE P

4.3.2. Positron Emission Tomography (PET) imaging may also be a powerful tool to detect vulnerable coronary plaques. PET imaging has several technical advantages over SPECT, including a better spatial resolution. Finally, with the dual PET-TC systems, investigation of both morphology and activity of the plaque could be easier to achieve. In addition to structural changes, the metabolic

AC

(and in particular inflammatory) activation of plaques is an important factor predisposing to the plaque rupture. Recent studies have suggested that FDG-PET has the potential to assess plaque metabolism and add to prediction of vascular risk(97). This molecular imaging modality is currently used for the identification of metabolic activity through the assessment of glucose utilization. Macrophages are dependent on external glucose for their metabolism because they are unable to store glycogen and have a glycolytic activity 5- to 20-fold higher than background tissues, increasing up to 50-fold when activated (Figure 5). Plaques with significant FDG uptake have been identified more often in patients with ACS than in stable patients. In addition to identifying metabolically active lesions, this tracer may have an important role in monitoring response of atherosclerosis to therapy(98). Future applications might include the prediction of plaque rupture and clinical events, thanks to the employment of hybrid systems, such as PET-CT and PET-MR, or through other tracers investigating pathophysiologic aspects of plaque activity, such as fatty acid synthesis and active mineral deposition(99,100). 14

ACCEPTED MANUSCRIPT

T

5. Conclusions and gaps in knowledge

IP

The clinical relevance of subclinical CAD is unquestionable: In the recent past, imaging has had a critical role in characterizing coronary atherosclerosis, with the identification of features associated

SC R

with plaque rupture and adverse coronary events – the presence of a thin fibrous cap, large plaque burden, positive remodeling, microcalcifications and microchannels. Coronary imaging is now giving us the opportunity to witness a change in the pathophysiology of coronary thrombosis

NU

concurrent with a shift in the demographics of ACS, a larger number of admitted female, obese and diabetic patients, paralleled by an increasing prevalence of plaque erosions, located in lesions with

MA

thick fibrous cap, fewer inflammatory cells, a smaller lipid pool and abundant extracellular matrix. However, the search for vulnerable plaques is predicated on the postulate that these are causal for ACS and that interventions directed at these plaques may prevent plaque instabilization and

D

thrombosis, thus ultimately preventing ACS. To date, randomized trials testing therapeutic choices

TE

based on plaque imaging assessment have failed to document these benefits. Currently, even the experimental implementation of an aggressive risk stratification strategy based on imaging tools

CE P

must be weighed against additional costs and patient’s exposure to unwarranted risks. This hypothesis will be however tested in the ongoing PROSPECT II trial(101), where NIRS imaging will aim at identifying vulnerable plaques, and the potential benefit of a subsequent plaque

AC

“passivation” with the implant of a bioresorbable scaffold technology stent will be explored. The continuous refinements of diagnostic tools – allowing a higher accuracy in the definition of morphologic components with safer imaging modalities – and the availability of more effective interventional and drug therapies should allow the design of strategy studies aimed at testing reasonable clinical hypotheses in selected high-risk subgroups of patients. Until such demonstrations are provided, the time is not yet ripe for the practical utilization of such imaging modalities to guide plaque-directed interventional strategies.

15

ACCEPTED MANUSCRIPT REFERENCES

7. 8.

9. 10.

11. 12.

13.

14. 15.

16.

17. 18. 19.

20.

T

IP

SC R

NU

6.

MA

5.

D

4.

TE

3.

CE P

2.

Braunwald E. Epilogue: what do clinicians expect from imagers? Journal of the American College of Cardiology 2006;47:C101-3. Patel MR, Peterson ED, Dai D et al. Low diagnostic yield of elective coronary angiography. The New England journal of medicine 2010;362:886-95. Muller JE, Abela GS, Nesto RW, Tofler GH. Triggers, acute risk factors and vulnerable plaques: the lexicon of a new frontier. Journal of the American College of Cardiology 1994;23:809-13. Virmani R, Kolodgie FD, Burke AP, Farb A, Schwartz SM. Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesions. Arteriosclerosis, thrombosis, and vascular biology 2000;20:1262-75. Davies MJ. The composition of coronary-artery plaques. The New England journal of medicine 1997;336:1312-4. Stone GW, Maehara A, Lansky AJ et al. A prospective natural-history study of coronary atherosclerosis. The New England journal of medicine 2011;364:226-35. Maddox TM, Stanislawski MA, Grunwald GK et al. Nonobstructive coronary artery disease and risk of myocardial infarction. JAMA 2014;312:1754-63. Dedic A, Kurata A, Lubbers M et al. Prognostic implications of non-culprit plaques in acute coronary syndrome: non-invasive assessment with coronary CT angiography. European heart journal cardiovascular Imaging 2014;15:1231-7. Zimarino M, Cappelletti L, Venarucci V et al. Age-dependence of risk factors for carotid stenosis: an observational study among candidates for coronary arteriography. Atherosclerosis 2001;159:165-73. van Lammeren GW, den Ruijter HM, Vrijenhoek JE et al. Time-dependent changes in atherosclerotic plaque composition in patients undergoing carotid surgery. Circulation 2014;129:2269-76. Libby P, Pasterkamp G. Requiem for the 'vulnerable plaque'. European heart journal 2015;36:29847. Jia H, Abtahian F, Aguirre AD et al. In vivo diagnosis of plaque erosion and calcified nodule in patients with acute coronary syndrome by intravascular optical coherence tomography. Journal of the American College of Cardiology 2013;62:1748-58. Nakazawa G, Yazdani SK, Finn AV, Vorpahl M, Kolodgie FD, Virmani R. Pathological findings at bifurcation lesions: the impact of flow distribution on atherosclerosis and arterial healing after stent implantation. Journal of the American College of Cardiology 2010;55:1679-87. Myler RK, Shaw RE, Stertzer SH et al. Lesion morphology and coronary angioplasty: current experience and analysis. Journal of the American College of Cardiology 1992;19:1641-52. Zimarino M, Corazzini A, Ricci F, Di Nicola M, De Caterina R. Late thrombosis after double versus single drug-eluting stent in the treatment of coronary bifurcations: a meta-analysis of randomized and observational Studies. JACC Cardiovascular interventions 2013;6:687-95. Oviedo C, Maehara A, Mintz GS et al. Intravascular ultrasound classification of plaque distribution in left main coronary artery bifurcations: where is the plaque really located? Circulation Cardiovascular interventions 2010;3:105-12. Caro CG, Fitz-Gerald JM, Schroter RC. Arterial wall shear and distribution of early atheroma in man. Nature 1969;223:1159-60. Li YS, Haga JH, Chien S. Molecular basis of the effects of shear stress on vascular endothelial cells. J Biomech 2005;38:1949-71. Chatzizisis YS, Coskun AU, Jonas M, Edelman ER, Feldman CL, Stone PH. Role of endothelial shear stress in the natural history of coronary atherosclerosis and vascular remodeling: molecular, cellular, and vascular behavior. Journal of the American College of Cardiology 2007;49:2379-93. Stone PH, Coskun AU, Kinlay S et al. Effect of endothelial shear stress on the progression of coronary artery disease, vascular remodeling, and in-stent restenosis in humans: in vivo 6-month follow-up study. Circulation 2003;108:438-44.

AC

1.

16

ACCEPTED MANUSCRIPT

28. 29.

30.

31.

32.

33.

34. 35.

36.

37.

38.

39.

T

IP

SC R

27.

NU

26.

MA

25.

D

24.

TE

23.

CE P

22.

Cheruvu PK, Finn AV, Gardner C et al. Frequency and distribution of thin-cap fibroatheroma and ruptured plaques in human coronary arteries: a pathologic study. Journal of the American College of Cardiology 2007;50:940-9. Kornowski R, Hong MK, Leon MB. Current perspectives on direct myocardial revascularization. The American journal of cardiology 1998;81:44E-48E. Puri R, Wolski K, Uno K et al. Left main coronary atherosclerosis progression, constrictive remodeling, and clinical events. JACC Cardiovascular interventions 2013;6:29-35. Radico F, Cicchitti V, Zimarino M, De Caterina R. Angina pectoris and myocardial ischemia in the absence of obstructive coronary artery disease: practical considerations for diagnostic tests. JACC Cardiovascular interventions 2014;7:453-63. Topol EJ, Nissen SE. Our preoccupation with coronary luminology. The dissociation between clinical and angiographic findings in ischemic heart disease. Circulation 1995;92:2333-42. Spaan JA, Piek JJ, Hoffman JI, Siebes M. Physiological basis of clinically used coronary hemodynamic indices. Circulation 2006;113:446-55. Di Mario C, Gorge G, Peters R et al. Clinical application and image interpretation in intracoronary ultrasound. Study Group on Intracoronary Imaging of the Working Group of Coronary Circulation and of the Subgroup on Intravascular Ultrasound of the Working Group of Echocardiography of the European Society of Cardiology. European heart journal 1998;19:207-29. Nissen SE, Yock P. Intravascular ultrasound: novel pathophysiological insights and current clinical applications. Circulation 2001;103:604-16. Mintz GS, Nissen SE, Anderson WD et al. American College of Cardiology Clinical Expert Consensus Document on Standards for Acquisition, Measurement and Reporting of Intravascular Ultrasound Studies (IVUS). A report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents. Journal of the American College of Cardiology 2001;37:1478-92. Nair A, Kuban BD, Tuzcu EM, Schoenhagen P, Nissen SE, Vince DG. Coronary plaque classification with intravascular ultrasound radiofrequency data analysis. Circulation 2002;106:22006. Calvert PA, Obaid DR, O'Sullivan M et al. Association between IVUS findings and adverse outcomes in patients with coronary artery disease: the VIVA (VH-IVUS in Vulnerable Atherosclerosis) Study. JACC Cardiovascular imaging 2011;4:894-901. Prati F, Guagliumi G, Mintz GS et al. Expert review document part 2: methodology, terminology and clinical applications of optical coherence tomography for the assessment of interventional procedures. European heart journal 2012;33:2513-20. Takarada S, Imanishi T, Liu Y et al. Advantage of next-generation frequency-domain optical coherence tomography compared with conventional time-domain system in the assessment of coronary lesion. Catheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography & Interventions 2010;75:202-6. Jang IK, Tearney GJ, MacNeill B et al. In vivo characterization of coronary atherosclerotic plaque by use of optical coherence tomography. Circulation 2005;111:1551-5. Zimarino M, Prati F, Stabile E et al. Optical coherence tomography accurately identifies intermediate atherosclerotic lesions--an in vivo evaluation in the rabbit carotid artery. Atherosclerosis 2007;193:94-101. Tearney GJ, Regar E, Akasaka T et al. Consensus standards for acquisition, measurement, and reporting of intravascular optical coherence tomography studies: a report from the International Working Group for Intravascular Optical Coherence Tomography Standardization and Validation. Journal of the American College of Cardiology 2012;59:1058-72. Niccoli G, Montone RA, Di Vito L et al. Plaque rupture and intact fibrous cap assessed by optical coherence tomography portend different outcomes in patients with acute coronary syndrome. European heart journal 2015;36:1377-84. Yonetsu T, Kato K, Uemura S et al. Features of coronary plaque in patients with metabolic syndrome and diabetes mellitus assessed by 3-vessel optical coherence tomography. Circulation Cardiovascular imaging 2013;6:665-73. Kato K, Yonetsu T, Kim SJ et al. Nonculprit plaques in patients with acute coronary syndromes have more vulnerable features compared with those with non-acute coronary syndromes: a 3-vessel optical coherence tomography study. Circulation Cardiovascular imaging 2012;5:433-40.

AC

21.

17

ACCEPTED MANUSCRIPT

46.

47.

48. 49.

50.

51.

52.

53.

54.

55. 56.

57. 58.

59.

T

IP

SC R

NU

45.

MA

44.

D

43.

TE

42.

CE P

41.

Toutouzas K, Karanasos A, Riga M et al. Optical coherence tomography assessment of the spatial distribution of culprit ruptured plaques and thin-cap fibroatheromas in acute coronary syndrome. EuroIntervention : journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology 2012;8:477-85. Niccoli G, Giubilato S, Di Vito L et al. Severity of coronary atherosclerosis in patients with a first acute coronary event: a diabetes paradox. European heart journal 2013;34:729-41. Kornowski R, Mintz GS, Abizaid A, Leon MB. Intravascular ultrasound observations of atherosclerotic lesion formation and restenosis in patients with diabetes mellitus. International journal of cardiovascular interventions 1999;2:13-20. Uemura S, Ishigami K, Soeda T et al. Thin-cap fibroatheroma and microchannel findings in optical coherence tomography correlate with subsequent progression of coronary atheromatous plaques. European heart journal 2012;33:78-85. Taruya A, Tanaka A, Nishiguchi T et al. Vasa Vasorum Restructuring in Human Atherosclerotic Plaque Vulnerability: A Clinical Optical Coherence Tomography Study. Journal of the American College of Cardiology 2015;65:2469-77. Tearney GJ, Yabushita H, Houser SL et al. Quantification of macrophage content in atherosclerotic plaques by optical coherence tomography. Circulation 2003;107:113-9. Di Vito L, Agozzino M, Marco V et al. Identification and quantification of macrophage presence in coronary atherosclerotic plaques by optical coherence tomography. European heart journal cardiovascular Imaging 2015;16:807-13. Gabriele A, Marco V, Gatto L et al. Reproducibility of the Carpet View system: a novel technical solution for display and off line analysis of OCT images. The international journal of cardiovascular imaging 2014;30:1225-33. Falk E, Fuster V. Angina pectoris and disease progression. Circulation 1995;92:2033-5. Gardner CM, Tan H, Hull EL et al. Detection of lipid core coronary plaques in autopsy specimens with a novel catheter-based near-infrared spectroscopy system. JACC Cardiovascular imaging 2008;1:638-48. Garg S, Serruys PW, van der Ent M et al. First use in patients of a combined near infra-red spectroscopy and intra-vascular ultrasound catheter to identify composition and structure of coronary plaque. EuroIntervention : journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology 2010;5:755-6. Madder RD, Goldstein JA, Madden SP et al. Detection by near-infrared spectroscopy of large lipid core plaques at culprit sites in patients with acute ST-segment elevation myocardial infarction. JACC Cardiovascular interventions 2013;6:838-46. Hong YJ, Mintz GS, Kim SW et al. Impact of plaque composition on cardiac troponin elevation after percutaneous coronary intervention: an ultrasound analysis. JACC Cardiovascular imaging 2009;2:458-68. Madder RD, Smith JL, Dixon SR, Goldstein JA. Composition of target lesions by near-infrared spectroscopy in patients with acute coronary syndrome versus stable angina. Circulation Cardiovascular interventions 2012;5:55-61. Oemrawsingh RM, Cheng JM, Garcia-Garcia HM et al. Near-infrared spectroscopy predicts cardiovascular outcome in patients with coronary artery disease. Journal of the American College of Cardiology 2014;64:2510-8. Halliburton S, Arbab-Zadeh A, Dey D et al. State-of-the-art in CT hardware and scan modes for cardiovascular CT. Journal of cardiovascular computed tomography 2012;6:154-63. Greenland P, LaBree L, Azen SP, Doherty TM, Detrano RC. Coronary artery calcium score combined with Framingham score for risk prediction in asymptomatic individuals. JAMA 2004;291:210-5. Polonsky TS, McClelland RL, Jorgensen NW et al. Coronary artery calcium score and risk classification for coronary heart disease prediction. JAMA 2010;303:1610-6. Nasir K, Bittencourt MS, Blaha MJ et al. Implications of Coronary Artery Calcium Testing Among Statin Candidates According to American College of Cardiology/American Heart Association Cholesterol Management Guidelines: MESA (Multi-Ethnic Study of Atherosclerosis). Journal of the American College of Cardiology 2015;66:1657-68. 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;108:1664-72. 18

AC

40.

ACCEPTED MANUSCRIPT 60.

64. 65.

69.

70.

71. 72.

73. 74. 75.

76.

CE P

68.

AC

67.

TE

D

66.

NU

63.

MA

62.

SC R

IP

T

61.

Hamon M, Morello R, Riddell JW, Hamon M. Coronary arteries: diagnostic performance of 16versus 64-section spiral CT compared with invasive coronary angiography--meta-analysis. Radiology 2007;245:720-31. Taylor AJ, Cerqueira M, Hodgson JM et al. ACCF/SCCT/ACR/AHA/ASE/ASNC/NASCI/SCAI/SCMR 2010 Appropriate Use Criteria for Cardiac Computed Tomography. A Report of the American College of Cardiology Foundation Appropriate Use Criteria Task Force, the Society of Cardiovascular Computed Tomography, the American College of Radiology, the American Heart Association, the American Society of Echocardiography, the American Society of Nuclear Cardiology, the North American Society for Cardiovascular Imaging, the Society for Cardiovascular Angiography and Interventions, and the Society for Cardiovascular Magnetic Resonance. Circulation 2010;122:e525-55. American College of Cardiology Foundation Task Force on Expert Consensus D, Mark DB, Berman DS et al. ACCF/ACR/AHA/NASCI/SAIP/SCAI/SCCT 2010 expert consensus document on coronary computed tomographic angiography: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents. Circulation 2010;121:2509-43. di Cesare E, Carbone I, Carriero A et al. Clinical indications for cardiac computed tomography. From the Working Group of the Cardiac Radiology Section of the Italian Society of Medical Radiology (SIRM). La Radiologia medica 2012;117:901-38. Miller JM, Rochitte CE, Dewey M et al. Diagnostic performance of coronary angiography by 64-row CT. The New England journal of medicine 2008;359:2324-36. Meijboom WB, Meijs MF, Schuijf JD et al. Diagnostic accuracy of 64-slice computed tomography coronary angiography: a prospective, multicenter, multivendor study. Journal of the American College of Cardiology 2008;52:2135-44. Budoff MJ, Dowe D, Jollis JG et al. Diagnostic performance of 64-multidetector row coronary computed tomographic angiography for evaluation of coronary artery stenosis in individuals without known coronary artery disease: results from the prospective multicenter ACCURACY (Assessment by Coronary Computed Tomographic Angiography of Individuals Undergoing Invasive Coronary Angiography) trial. Journal of the American College of Cardiology 2008;52:1724-32. Douglas PS, Hoffmann U, Patel MR et al. Outcomes of anatomical versus functional testing for coronary artery disease. The New England journal of medicine 2015;372:1291-300. Cho I, Chang HJ, B OH et al. Incremental prognostic utility of coronary CT angiography for asymptomatic patients based upon extent and severity of coronary artery calcium: results from the COronary CT Angiography EvaluatioN For Clinical Outcomes InteRnational Multicenter (CONFIRM) study. European heart journal 2015;36:501-8. Chow BJ, Small G, Yam Y et al. Prognostic and therapeutic implications of statin and aspirin therapy in individuals with nonobstructive coronary artery disease: results from the CONFIRM (COronary CT Angiography EvaluatioN For Clinical Outcomes: An InteRnational Multicenter registry) registry. Arteriosclerosis, thrombosis, and vascular biology 2015;35:981-9. Muhlestein JB, Lappe DL, Lima JA 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. Gibbons RJ. Optimal medical therapy vs CT angiography screening for patients with diabetes. JAMA 2014;312:2219-20. Inoue K, Motoyama S, Sarai M et al. Serial coronary CT angiography-verified changes in plaque characteristics as an end point: evaluation of effect of statin intervention. JACC Cardiovascular imaging 2010;3:691-8. Maurovich-Horvat P, Hoffmann U, Vorpahl M, Nakano M, Virmani R, Alkadhi H. The napkin-ring sign: CT signature of high-risk coronary plaques? JACC Cardiovascular imaging 2010;3:440-4. Maurovich-Horvat P, Ferencik M, Voros S, Merkely B, Hoffmann U. Comprehensive plaque assessment by coronary CT angiography. Nature reviews Cardiology 2014;11:390-402. Kashiwagi M, Tanaka A, Kitabata H et al. Feasibility of noninvasive assessment of thin-cap fibroatheroma by multidetector computed tomography. JACC Cardiovascular imaging 2009;2:14129. Voros S, Rinehart S, Qian Z et al. Coronary atherosclerosis imaging by coronary CT angiography: current status, correlation with intravascular interrogation and meta-analysis. JACC Cardiovascular imaging 2011;4:537-48. 19

ACCEPTED MANUSCRIPT 77. 78. 79.

86.

87. 88. 89. 90. 91. 92.

93.

94.

95.

96.

97.

SC R

NU

MA

85.

D

84.

TE

83.

CE P

82.

AC

81.

IP

T

80.

Gijsen FJ, Migliavacca F. Plaque mechanics. J Biomech 2014;47:763-4. Storto ML, Marano R, Maddestra N, Caputo M, Zimarino M, Bonomo L. Images in cardiovascular medicine. Multislice spiral computed tomography for in-stent restenosis. Circulation 2002;105:2005. Min JK, Leipsic J, Pencina MJ et al. Diagnostic accuracy of fractional flow reserve from anatomic CT angiography. JAMA 2012;308:1237-45. Hyafil F, Cornily JC, Rudd JH, Machac J, Feldman LJ, Fayad ZA. Quantification of inflammation within rabbit atherosclerotic plaques using the macrophage-specific CT contrast agent N1177: a comparison with 18F-FDG PET/CT and histology. Journal of nuclear medicine : official publication, Society of Nuclear Medicine 2009;50:959-65. Saam T, Hatsukami TS, Takaya N et al. The vulnerable, or high-risk, atherosclerotic plaque: noninvasive MR imaging for characterization and assessment. Radiology 2007;244:64-77. Demarco JK, Ota H, Underhill HR et al. MR carotid plaque imaging and contrast-enhanced MR angiography identifies lesions associated with recent ipsilateral thromboembolic symptoms: an in vivo study at 3T. AJNR American journal of neuroradiology 2010;31:1395-402. Corti R, Fayad ZA, Fuster V et al. Effects of lipid-lowering by simvastatin on human atherosclerotic lesions: a longitudinal study by high-resolution, noninvasive magnetic resonance imaging. Circulation 2001;104:249-52. Tang TY, Howarth SP, Miller SR et al. The ATHEROMA (Atorvastatin Therapy: Effects on Reduction of Macrophage Activity) Study. Evaluation using ultrasmall superparamagnetic iron oxide-enhanced magnetic resonance imaging in carotid disease. Journal of the American College of Cardiology 2009;53:2039-50. 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;104:2051-6. Trivedi RA, JM UK-I, Graves MJ et al. In vivo detection of macrophages in human carotid atheroma: temporal dependence of ultrasmall superparamagnetic particles of iron oxide-enhanced MRI. Stroke; a journal of cerebral circulation 2004;35:1631-5. Fayad ZA, Fuster V, Fallon JT et al. Noninvasive in vivo human coronary artery lumen and wall imaging using black-blood magnetic resonance imaging. Circulation 2000;102:506-10. Keegan J. Coronary artery wall imaging. Journal of magnetic resonance imaging : JMRI 2015;41:1190-202. Nagel E. Magnetic resonance coronary angiography: the condemned live longer. Journal of the American College of Cardiology 2010;56:992-4. Rahmim A, Zaidi H. PET versus SPECT: strengths, limitations and challenges. Nuclear medicine communications 2008;29:193-207. Sun ZH, Rashmizal H, Xu L. Molecular imaging of plaques in coronary arteries with PET and SPECT. Journal of geriatric cardiology : JGC 2014;11:259-73. Loeffelbein DJ, Souvatzoglou M, Wankerl V et al. PET-MRI fusion in head-and-neck oncology: current status and implications for hybrid PET/MRI. Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons 2012;70:473-83. Johnson LL, Schofield L, Donahay T, Narula N, Narula J. 99mTc-annexin V imaging for in vivo detection of atherosclerotic lesions in porcine coronary arteries. Journal of nuclear medicine : official publication, Society of Nuclear Medicine 2005;46:1186-93. Kietselaer BL, Hofstra L, Dumont EA, Reutelingsperger CP, Heidendal GA. The role of labeled Annexin A5 in imaging of programmed cell death. From animal to clinical imaging. The quarterly journal of nuclear medicine : official publication of the Italian Association of Nuclear Medicine 2003;47:349-61. Hartung D, Sarai M, Petrov A et al. Resolution of apoptosis in atherosclerotic plaque by dietary modification and statin therapy. Journal of nuclear medicine : official publication, Society of Nuclear Medicine 2005;46:2051-6. Ogawa M, Magata Y, Kato T et al. Application of 18F-FDG PET for monitoring the therapeutic effect of antiinflammatory drugs on stabilization of vulnerable atherosclerotic plaques. Journal of nuclear medicine : official publication, Society of Nuclear Medicine 2006;47:1845-50. Rudd JH, Narula J, Strauss HW et al. Imaging atherosclerotic plaque inflammation by fluorodeoxyglucose with positron emission tomography: ready for prime time? Journal of the American College of Cardiology 2010;55:2527-35. 20

ACCEPTED MANUSCRIPT

T

IP

SC R

NU MA D

101.

TE

100.

CE P

99.

Duivenvoorden R, Mani V, Woodward M et al. Relationship of serum inflammatory biomarkers with plaque inflammation assessed by FDG PET/CT: the dal-PLAQUE study. JACC Cardiovascular imaging 2013;6:1087-94. Derlin T, Richter U, Bannas P et al. Feasibility of 18F-sodium fluoride PET/CT for imaging of atherosclerotic plaque. Journal of nuclear medicine : official publication, Society of Nuclear Medicine 2010;51:862-5. Derlin T, Habermann CR, Lengyel Z et al. Feasibility of 11C-acetate PET/CT for imaging of fatty acid synthesis in the atherosclerotic vessel wall. Journal of nuclear medicine : official publication, Society of Nuclear Medicine 2011;52:1848-54. Erlinge D, Stone GW. A Multicentre Prospective Natural History Study Using Multimodality Imaging in Patients With Acute Coronary Syndromes - PROSPECT II (Natural History Study), Combined With a Randomized, Controlled, Intervention Study - PROSPECT ABSORB (Randomized Trial). https://clinicaltrialsgov/ct2/show/record/NCT02171065 (as assessed on January 27, 2016).

AC

98.

21

ACCEPTED MANUSCRIPT Table 1. Comparative features of imaging modalities in the detection of vulnerable plaque characteristics Angiography

IVUS

OCT

NIRS-

+

+++

Cap Thickness

+

+++

+

++

+++

+

++

+

++

+++

++

Thrombus

+

+

+++

+

NU

++

+++

++

MA

Inflammatory Cells

D

(Macrophages)

+++

+

TE

Plaque

CE P

remodeling

Abbreviations as in the text.

AC

*: non-coronary arteries (i.e.: carotid arteries, aorta)

22

+

+

+++

+++

PET/CT

++

++++

++

++

+++

+++

Calcification

Lipid Core

IP

+++

SC R

Plaque Burden

MR*

T

IVUS

MDCT

+

ACCEPTED MANUSCRIPT LEGEND TO FIGURES

Figure 1. Low and oscillatory vs pulsatile endothelial shear stress. A low time-average

IP

T

magnitude endothelial shear stress (<10-12 dyne/cm2) results in a bidirectional, oscillatory flow that contrasts with the unidirectional, pulsatile, laminar flow. While laminar flow results in a

SC R

physiologic stimulus for the endothelium, able to induce a quiescent, antiproliferative, antioxidant, and antithrombotic phenotype resulting in an atheroprotective gene expression profile; a low and an

AC

CE P

TE

D

MA

NU

oscillatory shear stress promotes atherosclerosis initiation and progression.

23

ACCEPTED MANUSCRIPT Figure 2: Intravascular coronary imaging: In a 59 male diabetic patient admitted for NSTEACS, coronary angiography documented the culprit lesion in the left anterior descending (LAD), where a drug-eluting stent (dashed lines) was deployed (A); an intermediate non-culprit lesion of

T

the proximal left circumflex artery (LCX, red arrow) was interrogated with optical coherence

IP

tomography (OCT). With this technique, a plaque extending for 161° was detected, with a large lipid necrotic pool, a thick fibrous cap of 98 µm (double-headed arrow in the magnified spot) and a

SC R

residual lumen area of 2.96 mm2 (B). Near-infrared spectroscopy with intravascular ultrasound (NIRS-IVUS) documented that the true lipid arc extension was 123° (C); the chemogram, showing the lipid areas in yellow (D), allowed the calculation of a lipid core burden index (LCBI) of 305,

NU

lower than the cut-off value (>400) used for the identification of a vulnerable plaque.

MA

Figure 3: Coronary-CT angiography of a normal and a non-obstructive atherosclerotic coronary artery.

D

A-D: In a hypertensive 56-year old male with an ECG stress test suggestive of ischemia, coronary

TE

CT-angiography with 3D volume-rendered images documented normal right coronary artery (RCA), left anterior descending (LAD) and left circumflex (LCX) arteries, with a large obtuse

CE P

marginal (OM) artery; E-H: A dyslipidemic 67-year old female smoker with repeated admissions to the emergency department for recurrent chest pain underwent coronary-CT angiography: sagittal multi-planar (E) and oblique (F) images documented a proximal LAD with a thin eccentric non-

AC

calcified atheroma without significant stenosis, as better demonstrated by the 2D orthogonal view to the long axis of the vessel (G); such findings were confirmed at coronary angiography (H);

Figure 4: Coronary-CT angiography of an obstructive coronary artery atherosclerotic lesion. A 72-year old smoker male underwent coronary CT-angiography before a percutaneous intervention for a critical internal carotid artery lesion; 3D volume rendered (A) and 2D multiplanar (B) images showed a significant stenosis of the distal LCX, due to an eccentric non-calcified plaque, as confirmed by coronary angiography (C). 2D oblique (D), 3D volume-rendered (E), and stretched (G) images documented a significant (>50%) mid-LAD stenosis due to an eccentric noncalcified plaque, as better shown by the 2D view orthogonal to the long axis of the vessel (G), and associated with positive remodeling of vessel wall (head arrows in D and F).

24

ACCEPTED MANUSCRIPT Figure 5: Transaxial 18F-FDG PET/CT 24 hours after PCI in a patient with an acute coronary syndrome. In a patient admitted for unstable angina,

18

F-FDG performed 24 hours after stent

deployment in the right coronary artery documented elevated tracer uptake in the coronary wall

T

(arrow). A) Computed Tomography (CT) image; B) Positron-Emission Tomography (PET) image;

AC

CE P

TE

D

MA

NU

SC R

IP

C) Coregistered and fused PET/CT image.

25

AC

Figure 1

CE P

TE

D

MA

NU

SC R

IP

T

ACCEPTED MANUSCRIPT

26

AC

Figure 2

CE P

TE

D

MA

NU

SC R

IP

T

ACCEPTED MANUSCRIPT

27

AC

Figure 3

CE P

TE

D

MA

NU

SC R

IP

T

ACCEPTED MANUSCRIPT

28

AC

Figure 4

CE P

TE

D

MA

NU

SC R

IP

T

ACCEPTED MANUSCRIPT

29

AC

Figure 5

CE P

TE

D

MA

NU

SC R

IP

T

ACCEPTED MANUSCRIPT

30

AC

Graphical abstract

CE P

TE

D

MA

NU

SC R

IP

T

ACCEPTED MANUSCRIPT

31