Advances in the Understanding of Plaque Composition and Treatment Options · 2016-11-13 ·...

Journal of the American College of Cardiology Vol. 63, No. 16, 2014� 2014 by the American College of Cardiology Foundation ISSN 0735-1097/$36.00Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jacc.2014.01.042

Advances in the Understanding ofPlaque Composition and Treatment Options
Year in Review
Matthew I. Tomey, MD, Jagat Narula, MD, PHD, Jason C. Kovacic, MD, PHD

New York, New York

A

From the Zena an

Research Center, I

Dr. Narula has rec

Dr. Kovacic has r

(K08HL111330),

Award), and Astr

relevant to the con

Manuscript rece

2014, accepted Jan

therosclerosis research has classically followed 2 intertwining lines of investigation concerning atherosclerosis as alocal process (the “high-risk plaque”) and as a systemic disease (the “high-risk patient”). Over time, the weight ofattention has swung, like a pendulum, between these 2 related foci. With optimal medical therapy and attention torisk factors firmly established as fundamental aspects of management, in the past year, we have neverthelessperceived a shift in the pendulum toward renewed focus on the local plaque. We contend that this shift results froma convergence of major advances in understanding the biology of plaque progression, novel sophisticated invasiveand noninvasive imaging modalities for the in vivo characterization of plaque composition and inflammation, andemerging data and technologies that have renewed interest in locally targeted interventions. Here, we review thedynamic and exciting progress that has occurred over the last 12 months in this arena, while acknowledging futurework that remains to be done to refine and validate new imaging modalities and therapies. (J Am Coll Cardiol2014;63:1604–16) ª 2014 by the American College of Cardiology Foundation

Atherosclerotic plaque is the local manifestation of a sys-temic disease. As such, research in this field has generallyfollowed 2 intertwining lines of investigation, focused eitheron the local process (the “high-risk plaque”) or the systemicdisease (the “high-risk patient”) (1). Over time, the weightof collective attention has swung like a pendulum betweenthese related foci. Two decades ago, observations on thenatural history of coronary plaque (2) and newly availableintravascular tools such as intravascular ultrasound (IVUS),virtual histology, palpography, and thermography fueledinterest in the local plaque. Emphasis on understanding,diagnosing, and treating atherosclerosis as a systemic diseasethen took hold as medications, rather than locally targetedtherapies, demonstrated efficacy in reducing myocardialinfarction (MI) and death. In the last decade, this shift waspunctuated by results of the COURAGE (Clinical Out-comes Utilizing Revascularization and Aggressive druGEvaluation) trial in which an initial strategy of local therapy(revascularization) conferred no advantage for prevention ofthe composite of death or nonfatal MI above and beyondoptimal medical therapy (3).

d Michael A. Wiener Cardiovascular Institute and Cardiovascular

cahn School of Medicine at Mount Sinai, New York, New York.

eived research grants from GE Healthcare and Phillips Healthcare.

eceived research support from the National Institutes of Health

The Leducq Foundation (Transatlantic Network of Excellence

aZeneca. Dr. Tomey has reported that he has no relationships

tents of this paper to disclose.

ived September 30, 2013; revised manuscript received January 2,

uary 28, 2014.

On this backdrop of optimal medical therapy and riskfactor modification, now established as the bedrock ofatherosclerosis management, efforts over the past year tounderstand, diagnose, and treat the local atheroscleroticplaque have gained momentum (Fig. 1). Central to thisresurgence of interest in the high-risk plaque is the arrival ofdiverse new tools for invasive and noninvasive plaque im-aging. Informed by advances in our understanding of boththe pathology of the local plaque and the molecular mech-anisms of systemic atherosclerosis, these novel imagingapproaches provide opportunities to describe, not only theanatomy, but also the biology of the plaque in vivo. In thisnarrative review, we aim to synthesize key findings over thepast year in atherosclerosis, plaque biology, plaque imaging,and emerging therapies.

Defining the High-Risk Plaque

Pathological observations. Core insights informing ourparadigm of the plaque at high risk of rupture have tradi-tionally derived from pathological observations of rupturedand nonruptured plaques post-mortem (4). Adding to thisbody of published data, a recent analysis of 295 plaques in213 sudden cardiac death victims identified aspects of plaquecomposition and burden as markers of risk. In this study,Narula et al. (5) compared 105 stable plaques, 88 thin-capfibroatheromas (TCFA), and 102 ruptured plaques withrespect to features of plaque morphology: fibrous capthickness, percent luminal stenosis, plaque area, necroticcore area, macrophage area, and calcification. Fibrous cap

http://crossmark.crossref.org/dialog/?doi=10.1016/j.jacc.2014.01.042&domain=pdf

http://dx.doi.org/10.1016/j.jacc.2014.01.042

Abbreviationsand Acronyms

ACS = acute coronary

syndrome(s)

CAD = coronary artery

disease

CI = confidence interval

HDL-C = high-density

lipoprotein-cholesterol

IL = interleukin

IVUS = intravascular

ultrasound

LDL-C = low-density

lipoprotein-cholesterol

MACE = major adverse

cardiac event(s)

MI = myocardial infarction

ROS = reactive oxygen

species

TCFA = thin-cap

fibroatheroma

JACC Vol. 63, No. 16, 2014 Tomey et al.April 29, 2014:1604–16 Plaque Composition and Treatment Options: Year in Review

1605

thickness was the best discriminator of plaque type,measuring <54 mm in ruptured plaques, 54 to 84 mm inmost TCFA, and >84 mm in stable plaques. Uponexclusion of cap thickness, the best discriminators ofTCFA were macrophage infiltration and necrotic core.

In seeming contradistinction to the earlier observation byAmbrose et al. (2) that incident MI tended to emerge frompreviously nonobstructive plaque, the majority of TCFAin this pathological study exhibited >50% stenosis, and70% of ruptured plaques showed >75% stenosis. This patho-logical observation is consistent with angiographic findingsin a substudy of the COURAGE trial in which non-revascularized, �50% lesions predicted subsequent acute cor-onary syndromes (ACS) (6) and IVUS findings in thePROSPECT (ProspectiveNatural-History Study of CoronaryAtherosclerosis) in which nonculprit lesions responsible forsubsequent ischemic events were associated with large plaqueburden and reduced minimal luminal area despite apparentlymild luminal narrowing at angiography (7).

Reconciling these observations may be important todefining the high-risk plaque, as reviewed recently by Puriet al. (8). It is possible that seemingly nonobstructive plaqueat initial angiography represents the “tip of the iceberg,” withsignificant plaque burden not detected by angiographybecause of positive (outward) remodeling. Alternatively, MImay be associated with rapid plaque progression in thepreceding weeks to months, with acceleration of plaqueprogression mediated by subclinical cycles of plaque ruptureand healing (9) or intraplaque hemorrhage (as seen in carotidplaque) (10).Molecular and cellular basis of plaque progression.Advances in understanding of the cellular and molecularbasis for plaque progression have helped to define markersof plaque vulnerability with potential application to bothimaging and therapy.

A first theme has been refinement of our understanding ofthe role of macrophages, monocytes and inflammation inplaque progression. Macrophages and monocytes have beenunderstood classically to contribute to plaque progressionthrough phagocytosis of cholesterol droplets and debris,yielding a sequence of foam cell generation, foam cell death,and formation of the necrotic core, as well as contributingto inflammation and plaque rupture (11). In mouse models,monocytosis develops after MI or stroke in a sympatheticnervous system–dependent manner, a potential mechanismfor accelerated atherosclerosis (12). Whether plaque accu-mulation of macrophages and monocytes results from infil-tration has now become the subject of controversy followingrecent surprising results suggesting that local proliferation(rather than infiltration) accounts for the majority of thesecells within plaques (13,14). There is also suggestion thatneutrophils may precede monocytes at sites of vascularinflammation, on the basis of the finding in a mouse modelthat neutrophil-derived cathelicidins induce adhesion ofcirculating monocytes (15). Circulating leukocyte mem-brane microparticles that become elevated in humans with

unstable carotid plaque may befootprints of this process (16).Furthermore, there is growingevidence that molecular inflam-matory mediators associated withleukocyte activation may relate torisk of atherosclerosis disease pro-gression. A key example is inter-leukin (IL)-6, an inflammatorycytokine associated with increasedC-reactive protein production thatis released by activated leukocytesand vascular smooth muscle cellsat sites of vascular injury. The po-tential role of IL-6 signaling inatherosclerosis progression wasbolstered by recent observationsof significant variation in coronaryartery disease (CAD) risk withthe Asp358Ala allelic variant ofthe IL-6 receptor (17,18).

A second key theme of publi-
cations has been the role of free hemoglobin and oxidativestress in plaque progression. When free hemoglobin isreleased into plaque as a consequence of intraplaque hem-orrhage, heme iron is a potent generator of reactive oxygenspecies (ROS). Binding of free hemoglobin by circulatinghaptoglobin attenuates oxidative activity and promotesclearance of hemoglobin by macrophages via the CD163scavenger receptor. Unchecked, oxidative activity related tofree hemoglobin may contribute to plaque progression. In astudy of human aortic plaques, a genetic polymorphism atthe haptoglobin locus (Hp2-2) linked to defective attenua-tion of heme iron–mediated oxidation was associated with asignificant increase in apoptotic macrophages, oxidizedphospholipid, and malondialdehyde-like oxidation-specificepitopes (19). In addition, among patients with diabetesmellitus in the Nurses’ Health Study, the Hp2-2 genotypewas associated with a significantly increased risk of coronaryheart disease (relative risk 7.90, 95% confidence interval[CI]: 4.43 to 14.10, p ¼ 0.004) (20).
Free hemoglobin within plaque may influence differen-tiation of macrophages into different subtypes and theircapacity to engage in reverse cholesterol transport. Evalu-ating pathological specimens of human atheroscleroticplaque, Finn et al. (21) demonstrated that macrophageswith high expression of mannose and CD163 receptors,devoid of neutral lipids typical of foam cells, preferentiallyexist at sites of intraplaque hemorrhage and that intracel-lular hemoglobin in a rabbit model is necessary to drivedifferentiation of this macrophage subtype, M(Hb).Whereas M(Hb) was associated with increased ferroportinexpression, reduced intracellular iron, reduced ROS,increased liver X receptor alpha (LXRa) activation andcholesterol efflux via ATP binding cassette (ABC) trans-porters, degradation of ferroportin using hepcidin increased

Figure 1 Swinging Focus of Interest in Atherosclerosis

Concept of a swinging focus of interest in atherosclerosis and high-risk plaques, and potential factors driving this changing interest.

Tomey et al. JACC Vol. 63, No. 16, 2014Plaque Composition and Treatment Options: Year in Review April 29, 2014:1604–16

1606

ROS and reduced ABCA1 expression, LXRa activation,and cholesterol efflux.

Emerging evidence suggests that, in addition to and inde-pendent of ROS, damage to mitochondrial DNA (mtDNA)may promote atherosclerotic plaque progression (22). Inapolipoprotein E-null mice, mtDNA damage was observedearly in the vessel wall preceding significant atherosclerosis.Mice bred for deficiency in mitochondrial polymerase-gproofreading activity, yielding extensive mtDNA damage,demonstrated impaired oxidative phosphorylation withoutincrease in ROS, along with hyperlipidemia, vascular smoothmuscle cell apoptosis, and atherosclerosis. In humans,mtDNA damage in leukocytes was associated with plaquehigh-risk features on radiofrequency (“virtual histology”)intravascular ultrasound (RF-IVUS).

A third key theme was the role of lipid mediators, inparticular, high-density lipoprotein (HDL), in plaquebiology. Classical hypotheses as to the role of HDL inplaque progression have centered on cholesterol efflux fromfoam cells or reverse cholesterol transport, yielding reductionin lesion size or inflammation (23). Despite a consistentobservation of an inverse relationship between high-densitylipoprotein cholesterol (HDL-C) and CAD risk in epide-miological studies; however, the mechanistic role of HDL-Cin plaque progression has become increasingly controversial(24), fueled by successive negative trials of HDL-C–raisingtherapies, most recently dalcetrapib (25–27). Controversywas further stoked this year by results of a Mendelianrandomization study showing no association between anallelic variant of the endothelial lipase gene (LIPGAsn396Ser) and risk of MI despite a significant associatedincrease in HDL-C (28). As a possible explanation for thesefindings, it is plausible that the level of HDL-C is merely

the wrong metric of HDL functionality. Recent evidencehas highlighted the importance rather of HDL particlenumber (29,30) and the HDL proteome in predicting riskand plaque progression (31), as well as additional candidatemediators such as HDL-associated lipoprotein-associatedphospholipase A2 (32). New data on apolipoprotein A1further underscore the importance of taking caution ininterpretation of investigations on the basis of lipoproteinparticles isolated from plasma or serum, because the distri-bution and function of these circulating particles may differsubstantially from those found in atherosclerotic plaque (33).Use of collagen-specific peptide conjugated HDL nano-particles as cardiac magnetic resonance imaging (CMR)contrast agents is under active investigation for the study ofplaque regression (34) and may provide new insights intoHDL distribution and function in vivo.

Although diverse, these molecular advances in our un-derstanding of plaque biology represent a major step forward(Fig. 2), and we predict that several of these insights mayshape translational and pre-clinical efforts to therapeuticallymodulate plaque biology in the coming years. Selectedadditional important new papers are summarized in Table 1(35–45).

Identifying the High-Risk Plaque In Vivo

By translating features of high-risk plaque and plaque pro-gression from pathological, molecular, and cellular investi-gations into imaging, there is the potential to characterizethe risk profile of plaque in vivo. Putative benefits of iden-tifying high-risk plaque include prediction of atheroscleroticevents, monitoring response to therapy, and targeting ther-apies to patients and even to specific lesions. To the extent

Figure 2 Recent Advances in Atherosclerosis

Selected advances in 2012 to 2013 in understanding of local atherosclerotic plaque progression. CAD ¼ coronary artery disease; DNA ¼ deoxyribonucleic acid; HDL ¼ high-

density lipoprotein; IL ¼ interleukin; Lp-PLA2 ¼ lipoprotein-associated phospholipase A2; miRNA ¼ microinhibitory RNA. The figure was created using Servier medical art

(Servier, Suresnes, France).


1607

that we have witnessed a rebirth of interest in plaque im-aging, with a proliferation of papers over the past year(Table 2) (46–52), this field remains in its infancy, withsignificant progress needed to overcome shortcomings ofolder technologies and to refine new tools. Here, we high-light key contributions in the past year.Grayscale and RF-IVUS. Expanding on the findings ofthe PROSPECT study, additional analyses of RF-IVUSdata from that study have offered insight into differencesin plaque morphology in patient subsets. Patients withchronic kidney disease, who were more likely to be older,female, and diabetic, had more extensive, severe athero-sclerosis than patients without chronic kidney disease,exhibiting a greater necrotic core burden and less fibroustissue (53). Women, despite being older and with greaterprevalence of comorbidities, exhibited less extensiveatherosclerosis than men with fewer nonculprit lesions, lessnecrotic core and calcium, and less plaque rupture (6.6% vs.16.3%, p ¼ 0.002) (54). In women, predictors of majoradverse cardiac events (MACE) at 3 years related to anonculprit lesion included plaque burden �70% and TCFA.Patients with diabetes and metabolic syndrome tended toexhibit lesions that were longer with greater plaque burden,smaller luminal area, and greater necrotic core and calcifi-cation, of which necrotic core and calcification were signif-icantly associated with future nonculprit MACE (55).

A separate analysis of RF-IVUS in a subset of 63 patientsin the HORIZONS-AMI (Harmonizing Outcomes withRevascularization and Stents in Acute Myocardial Infarc-tion) study provided parallel insights in patients after

ST-segment elevation MI (56). Of 99 untreated nonculpritlesions, 41 were TCFA at baseline; at 13-month follow-up,32 of 41 lesions (78%) remained classified as TCFA, and anadditional 21 lesions were newly classified as TCFA,reclassified from pathological intimal thickening or thick-cap fibroatheroma. Lesions categorized as TCFA at base-line exhibited a decrease in minimal lumen area and anincrease in percent necrotic core at 13-month follow-up.

IVUS has been used to study the relationship betweendifferent patterns of calcification and plaque progression.Whereas extensively calcified plaques have been consideredto be less vulnerable to rupture, so-called “spotty” calcifi-cation has been associated with ischemic events. In a serialIVUS study, Kataoka et al. (57) found that spotty calcifi-cation, defined by lesions 1 to 4 mm in length with an arcof calcium <90�, was associated with male sex, diabetesmellitus, prior MI, lower on-treatment HDL-C level,greater percent and total atheroma volume, and greaterprogression of percent atheroma volume on subsequentIVUS examination, despite medical therapy. Conversely,calcified nodules, defined by IVUS as distinct calcificationswith an irregular, protruding, and convex luminal surface,may confer a lower risk of ischemic events. In a substudy ofthe PROSPECT study, calcified nodules were associatedwith older patient age, greater plaque burden, more thick-cap fibroatheromas, and a lower rate of nonculpritMACE (58).

Although RF-IVUS–determined TCFA were indepen-dent predictors of subsequent ischemic events in thePROSPECT and VIVA (Virtual Histology-IVUS in

Table 1 Selected Additional Studies Exploring the Molecular Basis of Plaque Progression

First Author (Ref. #) Design Methods Findings Implications

Bonaca et al. (35) Randomizedclinical trial,substudy

Measured PAPP-A, a zinc-bindingmetalloproteinase associated with high-risk plaque, in 3,782 patients with NSTE-ACS randomized to ranolazine orplacebo.

PAPP-A >6.0 mIU/ml at presentation wasassociated with doubling in risk of MI orCV death at 30 days.

Supports investigation intoPAPP-A as a prognosticmarker, mediator of plaqueprogression, and possibletherapeutic target.

Chan et al. (36) Meta-analysis Analyzed 33,673 subjects in 21 studieswith data on angiographic CAD, MI, and9p21 genotype.

Increased risk of angiographic CAD andmultivessel CAD with 9p21 risk allele,but not MI.

Implicates 9p21 locus inatherosclerotic phenotype.

Ganda et al. (37) Cross-sectional Measured cystatin C, blood counts, lipids,cIMT, and amino acid metabolitesassociated with low HDL-C and insulinresistance.

Monocyte count was associated with cIMT.High cystatin C, low HDL-C andmetabolites associated with metabolicsyndrome predicted higher monocytecounts.

Implicates increasing monocytelevels in atherogenesis in mildrenal dysfunction.

Gupta et al. (38) Cross-sectional Measured CRP, CAC, AWT, and APB in amultiethnic, population-basedprobability sample of adults age 30 to65 yrs in Dallas County and comparedassociations across BMI strata.

C-statistics of CRP for CAC, AWT, and APBwere higher for normal weight thanobese patients.

CRP may be less useful forprediction of atheroscleroticburden in obese patients.

Khan et al. (39) Animal model Studied atherosclerosis in LDL-receptor,GGTase-I knockout mouse model.

GGTase-I deficiency was associated withincreased plaque inflammation butdecreased plaque area and increasedreverse cholesterol transport.

Contributes to understanding ofmechanisms involvinggeranylgeranylation inatherogenesis and the effectsof statins.

Le et al. (40) Animal model Studied atherosclerosis in an endothelialcell specific ERK5 knockout (ERK5-EKO)mouse.

ERK5-EKO mice showed increasedleukocyte rolling and vascular reactivity,and increased atherogenesis with LDL-receptor knockout. P90RSK, increasedin diabetic mouse vessels, inhibitedERK5 transcriptional activity, reducedendothelial nitric oxide synthaseexpression and increased leukocyterecruitment.

Implicates P90RSK/ERK5complex in endothelialdysfunction andatherogenesis in diabetes.

Mahabadi et al. (41) Prospectivecohort

Measured EAT by CT and incident coronaryevents over 8 yrs follow-up in 4,093subjects from general population.

Increased risk of fatal and nonfatalcoronary events with doubling of EAT,independent of clinical risk factors andCAC.

Identifies EAT as a novelpredictor of coronary eventsand raises interest in EAT as amarkerdor mediatordofcoronary atherogenesis.

Mani et al. (42) Animal model CSE knockout mouse. CSE knockout mice experienced earlyatherogenesis, which was inhibited byexogenous hydrogen sulfide.

Implicates CSE/H2S pathway inatherogenesis.

Tang et al. (43) Controlledexperiment;prospectivecohort

Measured levels of TMAO in humansubjects after a phosphatidylcholinechallenge, before and after broad-spectrum antibiotics. Measured TMAO in4,007 patients undergoing electivecoronary angiography.

Antibiotics suppressed TMAO levels.Plasma TMAO predicted death/MI/stroke at 3-year follow-up.

Implicates intestinal microbiotain TMAO generation andatherosclerosis diseaseprogression. See also Koethet al. (44).

Xiao et al. (45) Animal model Evaluated relationship between disturbedblood flow patterns, inflammasomeinduction and atherogenesis in mouseaorta.

Oscillatory flow induced SREBP2 andNLRP3 inflammasome in endothelialcells. SREBP2 and NLRP3 were elevatedin atheroprone areas of aorta andoverexpression of SREBP2 increasedatherosclerosis in atheroresistant areas.

Suggests a molecularmechanism for focaldistribution of atherosclerosis.

APB¼ aortic plaque burden; AWT¼ aortic wall thickness; BMI¼ bodymass index; CAC¼ coronary artery calcium score; CAD¼ coronary artery disease; cIMT¼ carotid intimamedia thickness; CRP¼ C-reactiveprotein; CSE¼ cystathionine g-lyase; CT¼ computed tomography; CV¼ cardiovascular; EAT¼ epicardial adipose tissue; ERK5¼ extracellular-signal-regulated kinase 5; GGTase-I¼ geranylgeranyltransferase-I;HDL-C ¼ high-density lipoprotein cholesterol; LDL ¼ low-density lipoprotein; NLRP3 ¼ NOD-like receptor family, pyrin domain containing 3; NSTE-ACS ¼ non–ST-segment elevation acute coronary syndromes;MI ¼ myocardial infarction; PAPP-A ¼ pregnancy-associated plasma protein-A; SREBP2 ¼ sterol regulatory element binding protein 2; TMAO ¼ trimethylamine-N-oxide.


1608

Vulnerable Atherosclerosis) (59) studies, limitations to RF-IVUS must be acknowledged (60). Because the axial reso-lution of RF-IVUS is insufficient to accurately measurefibrous cap thickness, RF-IVUS defines TCFA on the basisof the presence of a necrotic core abutting the lumen,without evident overlying fibrous tissue, and plaque volumeof �40% on at least 3 consecutive images (61). The accuracyof necrotic core determination itself has been challenged,

albeit in a miniswine model (62). Proper acquisition andanalysis of RF-IVUS is also technically challenging. Inparticular, this poses challenges for serial imaging of specificlesions.Optical coherence tomography. Optical coherence to-mography (OCT), which measures depth-resolved back-reflection of infrared light, provides axial (5 to 20 mm) andtransverse resolution (30 mm) that is far superior to IVUS

Table 2 Selected Additional Studies Exploring Plaque Imaging, Disease Progression, and Risk Prediction

First Author (Ref. #) Design Methods Findings Implications

Baldassarre et al. (46) Prospective cohort Performed carotid ultrasonography in3,703 subjects with at least 3 riskfactors, with a median 36.2-monthfollow-up, and compared thepredictive value of differentapproaches to cIMT measurement.

Average of 8 maximal cIMTmeasurements, alone or incombination with interadventitiacommon carotid diameter, wassuperior for prediction of incidentcardiovascular events comparedwith common carotid mean IMT.All methods provided incrementalimprovement over Framinghamscoring.

Reaffirmed utility of cIMT inreclassifying patients atintermediate (if not high) risk andraised the question of how toproceed when cIMT measurementresults in downwardreclassification of patients judgedhigh risk on the basis of clinicalrisk factors.

Budoff et al. (47) Prospective cohort Measured CAC at baseline and at amedian 2.5 yrs in 5,682 patientsin the Multi-Ethnic Study ofAtherosclerosis, with a medianclinical follow-up of 7.6 yrs.

CAC progression independentlypredicted coronary events afteradjustment for age, sex, ethnicity,baseline CAC, and other riskfactors.

Provided evidence for CACprogression as a marker of diseaseprogression and risk.

Naya et al. (48) Retrospective cohort Evaluated CAC and CFR with respectto clinical outcomes in 901consecutive patients undergoingmyocardial perfusion PET (withnormal perfusion) and CT, with amedian 1.53 yrs follow-up.

CFR was inversely related to CAC.CFR, but not CAC, improvedprediction of MACE.

Provided evidence for CFR as a riskmarker in patients with normalperfusion.

Rifkin et al. (49) Prospective cohort Examined renal artery calcification onscreening whole-body computedtomography in 4,950 community-dwelling healthy subjects inrelation to all-cause mortality, witha median 8.2 yrs follow-up.

Renal artery calcification significantlyadded to a model incorporatingFramingham risk factors and CACin predicting mortality.

Identified renal artery calcification asa novel predictor of all-causedeath.

Sillesen et al. (50) Cross-sectional Measured carotid plaque burden by3D ultrasound and compared withCAC, cIMT, abdominal aorticdiameter, and ABI in 6,101asymptomatic patients.

Carotid plaque burden correlatedwith CAC more strongly than didcIMT, AAD, or ABI.

Identified carotid plaque burden as asuperior noninvasive predictor ofcoronary calcification, raisinginterest in its utility in riskprediction.

Stone et al. (51) Prospective cohort Performed invasive vascular profilingatbaseline and, in74%of cases,6 to10months later in 506 patientswithACS, with 1-yr clinical follow-up.

Large plaque burden and low localendothelial shear stress predictedlocal plaque progression.

Provided evidence for differences inendothelial shear stress as a driverof local plaque progression.

Toutouzas et al. (52) Observational Measured carotid plaquetemperature in vivo usingmicrowave radiometry in 34patients before endarterectomyand controls, and compared withex vivo plaque histopathology.

Plaque temperature was higher incases versus controls, and higherin plaques with thin fibrous capsand high expression of CD3, CD68,and VEGF.

Identified plaque temperature, asmeasured by microwaveradiometry, as a novel marker forhigh-risk plaque.

3D ¼ 3-dimensional; AAD ¼ abdominal aortic diameter; ABI ¼ ankle brachial index; ACS ¼ acute coronary syndrome(s); CFR ¼ coronary flow reserve; MACE ¼ major adverse cardiovascular event(s);PET ¼ positron emission tomography; VEGF ¼ vascular endothelial growth factor; other abbreviations as in Table 1.


1609

(63). With respect to discrimination of high-risk plaque,OCT permits evaluation of lipid content and macrophageinfiltration, and measurement of fibrous cap thickness.Limitations include inconsistent accuracy in discriminatinglipid plaque, similar optical properties between macrophageaccumulation and lipid plaque, artifacts, and lack of stan-dardization of analysis of fibrous cap thickness (64). Recentpublication of consensus standards for acquisition, mea-surement, and reporting for OCT will facilitate its use forboth research and potential clinical applications (65).

Registries of patients undergoing 3-vessel OCT havepermitted observations about plaque composition indifferent patient subsets. Key recent publications haveexplored plaque morphology in the settings of diabetes andACS. In an analysis of 98 patients with 230 nonculpritplaques, diabetes was associated with larger lipid volumeindex and higher prevalence of calcification and thrombus,with fibrous cap thickness being inversely related to

glycosylated hemoglobin (HbA1c) (66). TCFA and macro-phage infiltration were most common in patients withHbA1c �8%. In an analysis of 17 ACS patients with 45nonculprit plaques, and 87 non-ACS patients with 203nonculprit plaques, plaques in ACS patients were associatedwith larger lipid volume index, thinner fibrous cap (mean70.2 � 20.2 mm vs. 103.3 � 46.8 mm, p < 0.001), andgreater frequency of TCFA (64.7% vs. 14.9%, p < 0.001),macrophage infiltration (82.4% vs. 37.9%, p ¼ 0.001), andthrombus (29.4% vs. 1.1%, p < 0.001) (67). OCT innonobstructive plaques has revealed imaging predictors ofplaque progression, including intimal laceration, micro-channels, lipid pools, TCFA, macrophage content, andintramural thrombi (68).

Perhaps most remarkably, OCT that is performed pre-intervention in the setting of ACS has permitted in vivocharacterization of the mechanisms of plaque disruption.Jia et al. (69), evaluating pre-intervention OCT findings of


1610

culprit lesions in 126 patients with ACS, demonstratedOCT evidence of plaque rupture in 43.7%, plaque erosion in31.0%, and calcified nodules in 7.9%. Compared with pla-que rupture, plaque erosion was associated with younger age,lower frequency of lipid plaque, and thicker fibrous cap,whereas calcified nodules, as observed with IVUS, wereassociated with older age.

In summary, although OCT still lacks a clinical indicationfor use (and therefore reimbursement), this burgeoning bodyof published data attests to the power of OCT as an imagingtool. Our understanding of plaque biology has grownthrough these OCT-based studies, and it will be interestingto see whether OCT can challenge IVUS as a clinicallyindicated imaging tool and as the preferred imaging mo-dality for clinical studies using lesion- and vessel-basedendpoints.Computed tomography. Several publications over the pastyear have evaluated the utility of cardiac computed tomogra-phy (CT) to describe high-risk plaque features and delineateindividual plaque components. Although CT identifies pla-que components with similar accuracy to RF-IVUS (70), animportant limitation of CT is that its spatial resolution doesnot permit measurement of fibrous cap thickness, preventingits use for the identification of TCFA.

A notable advance has been the identification of thenapkin-ring sign, defined as a ring-like attenuation patternof coronary atherosclerotic plaques on CT. Validated againsthistological sections in an investigation of 21 coronaryarteries in 7 donor hearts, the napkin-ring sign identifiedadvanced atherosclerotic lesions with high specificity andpositive predictive value (71). In a subsequent prospectivestudy of 12,727 analyzed coronary segments and 1,174plaques in 895 patients with more than 1-year follow-up(mean 2.3 � 0.8 years), low-attenuation plaque, positivearterial remodeling, and the napkin-ring sign emerged assignificant, independent predictors of ACS (72).CMR and molecular imaging. Previously used extensivelyin the evaluation of carotid plaque, recent studies have movedto describing the utility of CMR in characterizing coronaryplaque. In a study ofT1, T2, and ultrashort echo timeCMR in28 plaques from fixed post-mortem human coronary arteries,CMR demonstrated high specificity and sensitivity fordetection of calcification (100% and 90%, respectively) andlipid-rich necrotic core (90% and 75%, respectively), withcomplete agreement in plaque histological classification in 22of 28 cases (weightedK¼ 0.6945, p< 0.0001) (73). Althoughstill experimental, these data are tantalizing and hopefully are aglimpse of what the future may hold in terms of CMR andin vivo coronary plaque imaging.

Imaging of molecular markers associated with plaque pro-gression is among the most exciting emerging developmentsin identification of high-risk plaque (74,75). In general, theseapproaches pair a probe designed to target cells or moleculesimplicated in plaque progression with an imaging modality.There are numerous pathways of interest that may be targetedby molecular imaging such as cellular activation, phagocytosis,

lipoproteins, metabolic activity, cell death, oxidative stress,neovascularization, matrix metalloproteinase activity, intra-plaque hemorrhage and thrombosis, and microcalcification(76). The growing list of targets for molecular imaging nowincludes macrophages, matrix metalloproteinases, cysteineproteases, avb3 integrins, glucose transporter 1, and HDLnanoparticles.

There are several imaging possibilities under investigationfor the detection of molecular markers, the most promisingcurrently being positron emission tomography (PET),CMR, single-photon emission CT, spectral CT, and near-infrared fluorescence, each with relative advantages anddisadvantages, as reviewed previously (77). Of these,18F-fluorodeoxyglucose (FDG) PET has high sensitivity,high availability, and perhaps the greatest promise in thenear term (78), but suffers from limited spatial resolutionand the need for radioactive isotopes. Use of 18F-FDG forthe purpose of coronary plaque–specific imaging is furtherlimited by uptake by neighboring cells, including car-diomyocytes and smooth muscle cells, motivating the searchfor more specific probes (79). 18F-sodium fluoride may beuseful for this purpose. In a study of 37 patients with acutemyocardial infarction, Joshi et al. (80) demonstrated differ-ential uptake of 18F-sodium fluoride, but not 18F-FDG, inruptured (culprit) plaques compared with nonculprit plaques(Fig. 3). Furthermore, in patients with stable angina, plaqueswith high 18F-sodium fluoride uptake were associated with ahigher likelihood of high-risk features on RF-IVUS thanwere plaques without 18F-sodium fluoride uptake. CMRprovides high spatial resolution without radiation exposureto the patient, but has lower sensitivity and longer imagingtimes (77); and recent questions have also been raised con-cerning effects on lymphocyte DNA integrity (81).

Hybrid approaches incorporating both PET and CMRare increasingly being used. This was nicely demonstratedthis year by Majmudar et al. (79) using zirconium-89–radi-olabeled dextran nanoparticles for the purpose of macrophageimaging. Using a mouse model, the investigators demon-strated specific uptake of probe by macrophages rather thanother leukocytes, and increased uptake of probe in the aorticroots of atherogenic mice compared with controls. Anti-inflammatory therapy with a short interfering RNA–basedsilencer of the monocyte-recruiting receptor CCR2 yielded adecrease in probe signal. These findings provide an excellentexample of the promise of molecular imaging to ultimatelyidentify high-risk plaque and measure its response to therapy,while at the same time highlighting the nascent state of playin this area, which has yet to be validated in the clinic.Certainly, it would seem fair to state that several more yearswill be required before these modalities become available forwidespread clinical use.

Measuring Plaque Response to Systemic Therapy

Statins and lipid plaque. HMG-CoA reductase inhibitors(statins) alter the natural history of CAD, as evident in their

Figure 3 Focal 18F-Sodium Fluoride Uptake in Patients With Acute MI

Patient with acute ST-segment elevation myocardial infarction (MI) with (A) proximal occlusion (red arrow) of the left anterior descending artery on invasive coronary angiography

and (B) intense focal 18F-sodium fluoride (tissue-to-background ratios, culprit 2.27 vs. reference segment 1.09 [108% increase]) uptake (yellow to red) at the site of the culprit

plaque (red arrow) on the combined positron emission and computed tomogram (PET-CT). Patient with anterior non–ST-segment elevation MI with (C) culprit (red arrow; left

anterior descending artery) and bystander nonculprit (white arrow; circumflex artery) lesions on invasive coronary angiography that were both stented during the index

admission. (D) After percutaneous coronary intervention, only the culprit lesion had increased 18F-sodium fluoride uptake on PET-CT (tissue-to-background ratios, culprit 2.03 vs.

reference segment 1.08 [88% increase]). The figure was generated using Servier medical art (Servier, Suresnes, France). Adapted with permission from Joshi et al. (80).


1611

reduction of MACE in both primary and secondary pre-vention cohorts (82,83). Helping elucidate the mechanismof benefit, key imaging studies over the past year haveillustrated changes in plaque composition with statintherapy.

In a prospective observational study of serial OCT,grayscale IVUS, and integrated backscatter IVUS fornontarget lesions in 42 patients undergoing percutaneouscoronary intervention (PCI) for stable CAD, Hattori et al.(84) demonstrated significant reductions in plaque volumeindex (IVUS) and lipid volume index (OCT), and increasein fibrous cap thickness at a mean follow-up of 9 months inpatients treated with pitavastatin 4 mg compared withcontrol patients who refused statin therapy.

The YELLOW (Reduction in Yellow Plaque by Aggres-sive Lipid Lowering Therapy) trial compared IVUS andnear-infrared spectroscopy findings in 87 patients undergoingPCI for multivessel CAD with at least 1 obstructive non-target lesion randomized to rosuvastatin 40 mg daily orstandard-of-care in 87 patients (85). Following 7 weeks of

drug therapy, intensive statin therapy was associated with asignificantly greater median reduction in maximal lipid coreburden index in 4 mm that remained significant afteradjustment for baseline differences. Gross changes in plaquemorphology were not evident on IVUS, as has been re-ported previously with intensive statin therapy after longerfollow-up (86). Nonetheless, the findings of the YELLOWtrial were notable in showing that even at this early time point,changes consistent with plaque regression were evident(Fig. 4). The ongoing YELLOW II trial seeks to identifymolecular mechanisms of these early plaque changes,including the contribution of HDL functionality.

In an important IVUS subanalysis of SATURN (Studyof Coronary Atheroma by Intravascular Ultrasound: Effectof Rosuvastatin vs. Atorvastatin), Puri et al. (87). examinedthe effect of baseline atheroma volume on clinical outcomesafter 2 years of high-intensity statin therapy in 1,039 pa-tients. Three provocative findings emerged. First, low-density lipoprotein cholesterol (LDL-C) levels were similarbetween patients with a higher versus a lower baseline

Figure 4 Plaque Lipid Core Burden Before and After Intensive Statin Therapy

Panels illustrate findings on coronary angiography, intravascular ultrasound (IVUS), and near-infrared spectroscopy for an atherosclerotic plaque in the mid left anterior

descending artery before (A) and 7 weeks after (B) initiation of intensive statin therapy. Images demonstrate reduction in total lipid core burden index (LCBI) and maximal LCBI

in a given 4 mm segment with no significant change in angiographic diameter stenosis or plaque area as measured by IVUS. Reprinted with permission from Kini et al. (85).


1612

percent atheroma volume (above vs. below the median).Second, despite achieving LDL-C levels <70 mg/dl withhigh-intensity statin therapy, baseline coronary atheromavolume remained strongly predictive of subsequent MACE,with increasing baseline atheroma volume being associatedwith greater cumulative MACE. These associationsremained significant despite adjustment for LDL-C levels.Third, and despite their increased MACE, patients with ahigher baseline coronary atheroma volume experiencedgreater plaque regression and lumen expansion with potentstatin therapy, compared with patients with lesser atheromavolume at baseline. In summary, it would appear that LDL-Ccan account only partially for plaque volume, and thatalthough statins induce plaque regression, they do not nullifythe baseline burden of atherosclerotic disease. This studyspeaks to the need to continue to seek novel ways to reduceatherosclerotic disease burden, because there remains anunmet need for further plaque and risk reduction in thosewith more advanced disease.Therapies for vascular inflammation. Several recentmanuscripts have described application of noninvasiveimaging, and in particular 18F-FDG-PET/CT, to evaluate

effects of statins and other more novel therapies on vascularinflammation in human subjects.

Tawakol et al. (88) randomized 67 adults with establishedatherosclerosis, who were not yet on statin therapy, toatorvastatin 80 mg or 10 mg daily and measured the target-to-background ratio of 18F-FDG uptake in the ascendingthoracic aorta at baseline, 4 and 12 weeks. With intensivetherapy, there was significant reduction in target-to-background ratio as early as 4 weeks.

Vucic et al. (89) reported the effects of a novelLXRa agonist,R211945, on 18F-FDG PET/CT and dynamic contrast-enhanced CMR inflammation and neovascularization in rab-bit atherosclerotic plaques. Rabbits treated with the LXRaagonist exhibited decreased plaque mean and maximum stan-dard uptake values on 18F-FDG-PET/CT over time, sug-gesting regression of inflammation, whereas rabbits treatedwith atorvastatin showed no change and control subjectsshowed increased standard uptake values. The LXRa agonistwas also associated with a decrease in macrophage, apolipo-protein B, and oxidized phospholipid immunoreactivity.

A second study evaluated losmapimod, an inhibitor ofp38 mitogen-associated kinase, which has been associated


1613

with initiation and progression of inflammation in athero-sclerosis (90). Elkhawad et al. (90) randomized 99 patientson stable doses of statin therapy to losmapimod 7.5 mg onceor twice daily or placebo for 12 weeks, with serial imaging ofvascular inflammation by 18F-FDG-PET/CT. There wasno difference in the primary endpoint of change frombaseline in average tissue-to-background ratio across allvessel segments; however, there was a significant reductionin tissue-to-background ratio in active segments.

As an aside, within the last year, an old anti-inflammatoryagent, colchicine, was shown to significantly reduce ischemicevents in patients with stable CAD (91). It is striking tocompare the wealth of imaging data with statins and otheragents against the paucity of data with colchicine. We flagcolchicine as “low-hanging fruit” for plaque imaging studiesin the hope of stimulating mechanistic research exploringthe beneficial effects of this agent.A new frontier: PCSK9 inhibition. Perhaps the mostexciting therapeutic advance over the past year has been withthe inhibitors of proprotein convertase subtilisin/kexin type 9(PCSK9), reviewed recently in the Journal (92).

The primary expected mechanism of PCSK9 inhibitionfor modulation of atherosclerotic plaque is a dramaticreduction in LDL-C. Interest in PCSK9 developed fromobservations of subjects with loss-of-function mutations inPCSK9 and extremely low levels of LDL-C, without sig-nificant adverse effects. Subsequent work has elucidated themechanism of PCSK9’s role in lipoprotein homeostasis,leading to the development of several candidate monoclonalantibodies and other agents to inhibit PCSK9. In the pastyear, 4 phase 2 studies of a PCSK9 inhibitor, in patientswith hyperlipidemia on or off lipid-lowering therapy(93,94), familial hyperlipidemia (95), and statin intolerance(96), demonstrated consistent, large, sustained reductions inLDL-C. Phase 3 studies are now being conducted to eval-uate the effect of PCSK9 inhibition on clinical outcomes.

Of interest, beyond LDL-C reduction, it is evident thatPCSK9 is expressed in atherosclerotic plaques (97), and path-ways are being explored connecting PCSK9 to vascularinflammation and apoptosis. As clinical investigations ofPCSK9 inhibitors proceed, itwill be valuable to assess the impactof these agents on the composition and behavior of stable andvulnerable plaque. Insights in this regard may come from theGLAGOV (GLobal Assessment of Plaque reGression With aPCSK9 antibOdy as Measured by intraVascular Ultrasound)study, which is currently in active enrollment (NCT01813422).

Targeting Local Therapy to High-Risk Plaque?

With the recent publication of positive results of thePRAMI (Randomized Trial of Preventive Angioplasty inMyocardial Infarction) (98), the question has resurfaced: isthere a role for preventive PCI? In the PRAMI trial, whichrandomized patients with ST-segment elevation MI toculprit lesion PCI with or without additional revasculariza-tion of all nonculprit stenosis associated with �50%

reduction in luminal diameter, the strategy of preventivePCI was associated with a significant reduction in thecomposite primary endpoint of cardiac death, nonfatal MI,or refractory angina (hazard ratio: 0.35, 95% CI: 0.21 to0.58, p < 0.001) as well as the individual endpoint ofnonfatal MI (hazard ratio: 0.32, 95% CI: 0.13 to 0.75).

The results of the PRAMI trial and its effect size haveengendered significant debate. Important unanswered sci-entific questions include what proportion of ischemicendpoint events in the PRAMI control group were derivedfrom unrevascularized nonculprit plaques. Also, as lesions inPRAMI were defined angiographically, we do not know thenature of their composition. Nevertheless, although PRAMIis unlikely to unilaterally change clinical practice, it hasopened what seemed a closed door to reconsider the role oflocal therapies in cardiovascular prevention.

As another novel interventional strategy, investigatorshave also begun to consider whether a preventive approachof performing selective PCI on plaques assessed by imagingto be high risk would improve clinical outcomes. However, aselective approach of only performing PCI on high-risk le-sions may be more challenging than expected, because pla-ques at high risk of rupture may also be more likely to causecomplications when treated in the catheterization laboratory.For example, by CT, target lesion low-attenuation plaque,positive remodeling, and spotty calcification predict post-PCI troponin elevation (99), and low-attenuation plaque,positive remodeling, and circumferential plaque calcificationpredict intraprocedural slow-flow (100). Invasive identifica-tion of necrotic core and TCFA, by RF-IVUS and OCT,similarly predicts distal microembolization and slow-flow(101). These findings have motivated interest in potentialtechniques to limit these complications of PCI, such as distalprotection devices and mesh-covered stents designed to trapand exclude thrombus and friable atheromatous debris dis-rupted during PCI, as has been studied in the context ofprimary angioplasty for acute ST-segment elevationMI (102).

With respect to selective PCI of high-risk lesions, andalthough yet to be explored for this indication, newer bio-logically resorbable stents are an intuitively attractive platformfor potential preventive PCI of high-risk lesions. There is aperception that these devices may permit the interventionaltreatment of offending lesions with many of the upsides, butfewer of the permanent downsides, of current metallic stents.Although it remains to be seenwhether this will be efficacious,we suspect that the field is poised to embark on an era ofintense investigation of targeted local therapies for athero-sclerosis founded upon sensitive and specific imaging mo-dalities to detect vulnerable and high-risk lesions, combinedwith “biologically friendly” resorbable stents that may beloaded with targeted biological agents to prevent restenosis.

Conclusions

Although it will only become clear with the passage oftime, we believe 2012 to 2013 may prove to be a pivotal

http://www.clinicaltrials.gov/ct2/show/NCT01813422?term=NCT01813422&rank=1


1614

period in the field of atherosclerosis. To the extent that thepast year saw a shift in interest back toward the high-riskplaque (Fig. 1), this reflects the culmination of many yearsof translational research and growing synergy between ad-vances in molecular and cellular biology and plaque imaging.It is critical to recognize that plaque composition imagingremains in its infancy, still requiring much validation,technological refinement, and standardization of analysis. Astools for discrimination of high-risk plaque graduallyimprove, the central question will become: to what end? Weforesee utility for these technologies in investigating thebiology of plaque progression and regression in vivo that weexpect will eclipse simple imaging of plaque burden via CT(103,104) or IVUS (87,105). Large, well-designed pro-spective human trials powered to measure clinical outcomesare now required to define the precise role of these advancedimaging modalities in predicting risk, measuring response tosystemic therapy, and targeting local intervention. With thisexcitement, it will be important in the coming years toperiodically check the momentum of the pendulum, main-taining a balance between management of atherosclerosis asa systemic disease and, where appropriate, understandingand treating individually concerning lesions.

Reprint requests and correspondence: Dr. Jason C. Kovacic,Division of Cardiology, Mount Sinai Medical Center, OneGustave L. Levy Place, Box 1030, New York, New York 10029.E-mail: [email protected].

REFERENCES

1. Naghavi M, Libby P, Falk E, et al. From vulnerable plaque tovulnerable patient: a call for new definitions and risk assessmentstrategies: part I. Circulation 2003;108:1664–72.

2. Ambrose JA, Tannenbaum MA, Alexopoulos D, et al. Angiographicprogression of coronary artery disease and the development ofmyocardial infarction. J Am Coll Cardiol 1988;12:56–62.

3. Boden WE, O’Rourke RA, Teo KK, et al. Optimal medical therapywith or without PCI for stable coronary disease. N Engl J Med 2007;356:1503–16.

4. Stary HC, Chandler AB, Dinsmore RE, et al. A definition ofadvanced types of atherosclerotic lesions and a histological classifica-tion of atherosclerosis. A report from the Committee on VascularLesions of the Council on Arteriosclerosis, American Heart Associ-ation. Circulation 1995;92:1355–74.

5. Narula J, Nakano M, Virmani R, et al. Histopathologic characteristicsof atherosclerotic coronary disease and implications of the findings forthe invasive and noninvasive detection of vulnerable plaques. J AmColl Cardiol 2013;61:1041–51.

6. Mancini GB, Hartigan PM, Bates ER, et al. Angiographic diseaseprogression and residual risk of cardiovascular events while on optimalmedical therapy: observations from the COURAGE trial. Circ Car-diovasc Interv 2011;4:545–52.

7. Stone GW,Maehara A, Lansky AJ, et al. A prospective natural-historystudy of coronary atherosclerosis. N Engl J Med 2011;364:226–35.

8. Puri R, Nicholls SJ, Ellis SG, Tuzcu EM, Kapadia SR. High-riskcoronary atheroma: the interplay between ischemia, plaque burden,and disease progression. J Am Coll Cardiol 2014;63:1134–40.

9. Mann J, Davies MJ. Mechanisms of progression in native coronaryartery disease: role of healed plaque disruption. Heart 1999;82:265–8.

10. Sun J, Underhill HR, Hippe DS, Xue Y, Yuan C, Hatsukami TS.Sustained acceleration in carotid atherosclerotic plaque progression

with intraplaque hemorrhage: a long-term time course study. J AmColl Cardiol Img 2012;5:798–804.

11. Ghattas A, Griffiths HR, Devitt A, Lip GY, Shantsila E. Monocytesin coronary artery disease and atherosclerosis: where are we now? J AmColl Cardiol 2013;62:1541–5.

12. Dutta P, Courties G, Wei Y, et al. Myocardial infarction acceleratesatherosclerosis. Nature 2012;487:325–9.

13. Robbins CS, Hilgendorf I, Weber GF, et al. Local proliferationdominates lesional macrophage accumulation in atherosclerosis. NatMed 2013;19:1166–72.

14. Randolph GJ. Proliferating macrophages prevail in atherosclerosis.Nat Med 2013;19:1094–5.

15. Wantha S, Alard JE, Megens RT, et al. Neutrophil-derived cath-elicidin promotes adhesion of classical monocytes. Circ Res 2013;112:792–801.

16. Sarlon-Bartoli G, Bennis Y, Lacroix R, et al. Plasmatic level ofleukocyte-derived microparticles is associated with unstable plaque inasymptomatic patients with high-grade carotid stenosis. J Am CollCardiol 2013;62:1436–41.

17. Sarwar N, Butterworth AS, Freitag DF, et al. Interleukin-6 receptorpathways in coronary heart disease: a collaborative meta-analysis of82 studies. Lancet 2012;379:1205–13.

18. Hingorani AD, Casas JP. The interleukin-6 receptor as a target forprevention of coronary heart disease: a Mendelian randomisationanalysis. Lancet 2012;379:1214–24.

19. Purushothaman KR, Purushothaman M, Levy AP, et al. Increasedexpression of oxidation-specific epitopes and apoptosis are associatedwith haptoglobin genotype: possible implications for plaque progres-sion in human atherosclerosis. J Am Coll Cardiol 2012;60:112–9.

20. Cahill LE, Levy AP, Chiuve SE, et al. Haptoglobin genotype is aconsistent marker of coronary heart disease risk among individualswith elevated glycosylated hemoglobin. J Am Coll Cardiol 2013;61:728–37.

21. Finn AV, Nakano M, Polavarapu R, et al. Hemoglobin directsmacrophage differentiation and prevents foam cell formation in hu-man atherosclerotic plaques. J Am Coll Cardiol 2012;59:166–77.

22. Yu E, Calvert PA, Mercer JR, et al. Mitochondrial DNA damage canpromote atherosclerosis independently of reactive oxygen speciesthrough effects on smooth muscle cells and monocytes and correlateswith higher-risk plaques in humans. Circulation 2013;128:702–12.

23. Rader DJ, Tall AR. The not-so-simple HDL story: is it time to revisethe HDL cholesterol hypothesis? Nat Med 2012;18:1344–6.

24. Hewing B, Moore KJ, Fisher EA. HDL and cardiovascular risk: timeto call the plumber? Circ Res 2012;111:1117–20.

25. Barter PJ, Caulfield M, Eriksson M, et al. Effects of torcetrapib inpatients at high risk for coronary events. N Engl J Med 2007;357:2109–22.

26. Schwartz GG, Olsson AG, Abt M, et al. Effects of dalcetrapib inpatients with a recent acute coronary syndrome. N Engl J Med 2012;367:2089–99.

27. AIM-HIGH Investigators, Boden WE, Probstfield JL, Anderson T,et al. Niacin in patients with low HDL cholesterol levels receivingintensive statin therapy. N Engl J Med 2011;365:2255–67.

28. Voight BF, Peloso GM, Orho-Melander M, et al. Plasma HDLcholesterol and risk of myocardial infarction: a Mendelian random-isation study. Lancet 2012;380:572–80.

29. Mackey RH, Greenland P, Goff DC Jr., Lloyd-Jones D, Sibley CT,Mora S. High-density lipoprotein cholesterol and particle concen-trations, carotid atherosclerosis, and coronary events: MESA (Multi-Ethnic Study of Atherosclerosis). J Am Coll Cardiol 2012;60:508–16.

30. Mora S, Glynn RJ, Ridker PM. High-density lipoprotein cholesterol,size, particle number, and residual vascular risk after potent statintherapy. Circulation 2013;128:1189–97.

31. Riwanto M, Rohrer L, Roschitzki B, et al. Altered activation ofendothelial anti- and proapoptotic pathways by high-density lipo-protein from patients with coronary artery disease: role of high-densitylipoprotein-proteome remodeling. Circulation 2013;127:891–904.

32. Rallidis LS, Tellis CC, Lekakis J, et al. Lipoprotein-associatedphospholipase A(2) bound on high-density lipoprotein is associatedwith lower risk for cardiac death in stable coronary artery diseasepatients: a 3-year follow-up. J Am Coll Cardiol 2012;60:2053–60.

33. DiDonato JA, Huang Y, Aulak KS, et al. Function and distribution ofapolipoprotein A1 in the artery wall are markedly distinct from thosein plasma. Circulation 2013;128:1644–55.

mailto:[email protected]

http://refhub.elsevier.com/S0735-1097(14)01088-2/sref1










































































































1615

34. Chen W, Cormode DP, Vengrenyuk Y, et al. Collagen-specificpeptide conjugated HDL nanoparticles as MRI contrast agent toevaluate compositional changes in atherosclerotic plaque regression.J Am Coll Cardiol Img 2013;6:373–84.

35. Bonaca MP, Scirica BM, Sabatine MS, et al. Prospective evaluation ofpregnancy-associated plasma protein-a and outcomes in patients withacute coronary syndromes. J Am Coll Cardiol 2012;60:332–8.

36. Chan K, Patel RS, Newcombe P, et al. Association between thechromosome 9p21 locus and angiographic coronary artery diseaseburden: a collaborative meta-analysis. J Am Coll Cardiol 2013;61:957–70.

37. Ganda A, Magnusson M, Yvan-Charvet L, et al. Mild renaldysfunction and metabolites tied to lowHDL cholesterol are associatedwith monocytosis and atherosclerosis. Circulation 2013;127:988–96.

38. Gupta NK, de Lemos JA, Ayers CR, Abdullah SM, McGuire DK,Khera A. The relationship between C-reactive protein and athero-sclerosis differs on the basis of body mass index: the Dallas HeartStudy. J Am Coll Cardiol 2012;60:1148–55.

39. Khan OM, Akula MK, Skalen K, et al. Targeting GGTase-I activatesRHOA, increases macrophage reverse cholesterol transport, and re-duces atherosclerosis in mice. Circulation 2013;127:782–90.

40. Le NT, Heo KS, Takei Y, et al. A crucial role for p90RSK-mediatedreduction of ERK5 transcriptional activity in endothelial dysfunctionand atherosclerosis. Circulation 2013;127:486–99.

41. Mahabadi AA, Berg MH, Lehmann N, et al. Association of epicar-dial fat with cardiovascular risk factors and incident myocardialinfarction in the general population: the Heinz Nixdorf Recall study.J Am Coll Cardiol 2013;61:1388–95.

42. Mani S, Li H, Untereiner A, et al. Decreased endogenous productionof hydrogen sulfide accelerates atherosclerosis. Circulation 2013;127:2523–34.

43. Tang WH, Wang Z, Levison BS, et al. Intestinal microbial meta-bolism of phosphatidylcholine and cardiovascular risk. N Engl J Med2013;368:1575–84.

44. Koeth RA, Wang Z, Levison BS, et al. Intestinal microbiota meta-bolism of L-carnitine, a nutrient in red meat, promotes atheroscle-rosis. Nat Med 2013;19:576–85.

45. Xiao H, Lu M, Lin TY, et al. Sterol Regulatory Element BindingProtein 2 activation of NLRP3 inflammasome in endotheliummediates hemodynamic-induced atherosclerosis susceptibility. Circu-lation 2013;128:632–42.

46. Baldassarre D, Hamsten A, Veglia F, et al. Measurements of carotidintima-media thickness and of interadventitia common carotiddiameter improve prediction of cardiovascular events: results ofthe IMPROVE (Carotid Intima Media Thickness [IMT] andIMT-Progression as Predictors of Vascular Events in a High RiskEuropean Population) study. J Am Coll Cardiol 2012;60:1489–99.

47. Budoff MJ, Young R, Lopez VA, et al. Progression of coronary cal-cium and incident coronary heart disease events: MESA (Multi-Ethnic Study of Atherosclerosis). J Am Coll Cardiol 2013;61:1231–9.

48. Naya M, Murthy VL, Foster CR, et al. Prognostic interplay of cor-onary artery calcification and underlying vascular dysfunction inpatients with suspected coronary artery disease. J Am Coll Cardiol2013;61:2098–106.

49. Rifkin DE, Ix JH, Wassel CL, Criqui MH, Allison MA. Renal arterycalcification and mortality among clinically asymptomatic adults. J AmColl Cardiol 2012;60:1079–85.

50. Sillesen H, Muntendam P, Adourian A, et al. Carotid plaque burdenas a measure of subclinical atherosclerosis: comparison with other testsfor subclinical arterial disease in the High Risk Plaque BioImagestudy. J Am Coll Cardiol Img 2012;5:681–9.

51. Stone PH, Saito S, Takahashi S, et al. Prediction of progression ofcoronary artery disease and clinical outcomes using vascular profilingof endothelial shear stress and arterial plaque characteristics: thePREDICTION study. Circulation 2012;126:172–81.

52. Toutouzas K, Grassos C, Drakopoulou M, et al. First in vivo appli-cation of microwave radiometry in human carotids: a new noninvasivemethod for detection of local inflammatory activation. J Am CollCardiol 2012;59:1645–53.

53. Baber U, Stone GW, Weisz G, et al. Coronary plaque composition,morphology, and outcomes in patients with and without chronickidney disease presenting with acute coronary syndromes. J Am CollCardiol Img 2012;5:S53–61.

54. Lansky AJ, Ng VG, Maehara A, et al. Gender and the extent ofcoronary atherosclerosis, plaque composition, and clinical outcomes inacute coronary syndromes. J Am Coll Cardiol Img 2012;5:S62–72.

55. Marso SP, Mercado N, Maehara A, et al. Plaque composition andclinical outcomes in acute coronary syndrome patients with metabolicsyndrome or diabetes. J Am Coll Cardiol Img 2012;5:S42–52.

56. Zhao Z, Witzenbichler B, Mintz GS, et al. Dynamic nature ofnonculprit coronary artery lesion morphology in STEMI: a serialIVUS analysis from the HORIZONS-AMI trial. J Am Coll CardiolImg 2013;6:86–95.

57. Kataoka Y, Wolski K, Uno K, et al. Spotty calcification as a marker ofaccelerated progression of coronary atherosclerosis: insights from serialintravascular ultrasound. J Am Coll Cardiol 2012;59:1592–7.

58. Xu Y, Mintz GS, Tam A, et al. Prevalence, distribution, predictors,and outcomes of patients with calcified nodules in native coronaryarteries: a 3-vessel intravascular ultrasound analysis from ProvidingRegional Observations to Study Predictors of Events in the CoronaryTree (PROSPECT). Circulation 2012;126:537–45.

59. Calvert PA, Obaid DR, O’Sullivan M, et al. Association betweenIVUS findings and adverse outcomes in patients with coronary arterydisease: the VIVA (VH-IVUS in Vulnerable Atherosclerosis) study.J Am Coll Cardiol Img 2011;4:894–901.

60. Falk E, Wilensky RL. Prediction of coronary events by intravascularimaging. J Am Coll Cardiol Img 2012;5:S38–41.

61. Suh WM, Seto AH, Margey RJ, Cruz-Gonzalez I, Jang IK. Intra-vascular detection of the vulnerable plaque. Circ Cardiovasc Imaging2011;4:169–78.

62. Thim T, Hagensen MK, Wallace-Bradley D, et al. Unreliableassessment of necrotic core by virtual histology intravascular ultra-sound in porcine coronary artery disease. Circ Cardiovasc Imaging2010;3:384–91.

63. Fleg JL, Stone GW, Fayad ZA, et al. Detection of high-riskatherosclerotic plaque: report of the NHLBI Working Group oncurrent status and future directions. J Am Coll Cardiol Imaging 2012;5:941–55.

64. Radu MD, Falk E. In search of vulnerable features of coronary plaqueswith optical coherence tomography: is it time to rethink the currentmethodological concepts? Eur Heart J 2012;33:9–12.

65. Tearney GJ, Regar E, Akasaka T, et al. Consensus standards foracquisition, measurement, and reporting of intravascular opticalcoherence tomography studies: a report from the InternationalWorking Group for Intravascular Optical Coherence TomographyStandardization and Validation. J Am Coll Cardiol 2012;59:1058–72.

66. Kato K, Yonetsu T, Kim SJ, et al. Comparison of nonculprit coronaryplaque characteristics between patients with and without diabetes: a3-vessel optical coherence tomography study. J Am Coll Cardiol Intv2012;5:1150–8.

67. Kato K, Yonetsu T, Kim SJ, et al. Nonculprit plaques in patients withacute coronary syndromes havemore vulnerable features compared withthose with non-acute coronary syndromes: a 3-vessel optical coherencetomography study. Circ Cardiovasc Imaging 2012;5:433–40.

68. Uemura S, Ishigami K, Soeda T, et al. Thin-cap fibroatheroma andmicrochannel findings in optical coherence tomography correlate withsubsequent progression of coronary atheromatous plaques. Eur Heart J2012;33:78–85.

69. Jia H, Abtahian F, Aguirre AD, et al. In vivo diagnosis of plaqueerosion and calcified nodule in patients with acute coronary syndromeby intravascular optical coherence tomography. J Am Coll Cardiol2013;62:1748–58.

70. Obaid DR, Calvert PA, Gopalan D, et al. Atherosclerotic plaquecomposition and classification identified by coronary computed to-mography: assessment of computed tomography-generated plaquemaps compared with virtual histology intravascular ultrasound andhistology. Circ Cardiovasc Imaging 2013;6:655–64.

71. Maurovich-Horvat P, Schlett CL, Alkadhi H, et al. The napkin-ringsign indicates advanced atherosclerotic lesions in coronary CT angio-graphy. J Am Coll Cardiol Img 2012;5:1243–52.

72. Otsuka K, Fukuda S, Tanaka A, et al. Napkin-ring sign on coronaryCT angiography for the prediction of acute coronary syndrome. J AmColl Cardiol Img 2013;6:448–57.

73. Karolyi M, Seifarth H, Liew G, et al. Classification of coronaryatherosclerotic plaques ex vivo with T1, T2, and ultrashort echo timeCMR. J Am Coll Cardiol Img 2013;6:466–74.




















































































































































1616

74. Briley-Saebo KC, Nguyen TH, Saeboe AM, et al. In vivo detection ofoxidation-specific epitopes in atherosclerotic lesions using biocom-patible manganese molecular magnetic imaging probes. J Am CollCardiol 2012;59:616–26.

75. Osborn EA, Jaffer FA. The year in molecular imaging. J Am CollCardiol Img 2012;5:317–28.

76. Quillard T, Libby P. Molecular imaging of atherosclerosis forimproving diagnostic and therapeutic development. Circ Res 2012;111:231–44.

77. Sanz J, Fayad ZA. Imaging of atherosclerotic cardiovascular disease.Nature 2008;451:953–7.

78. Dweck MR, Chow MW, Joshi NV, et al. Coronary arterial 18F-sodium fluoride uptake: a novel marker of plaque biology. J Am CollCardiol 2012;59:1539–48.

79. Majmudar MD, Yoo J, Keliher EJ, et al. Polymeric nanoparticle PET/MR imaging allows macrophage detection in atherosclerotic plaques.Circ Res 2013;112:755–61.

80. Joshi NV, Vesey AT, Williams MC, et al. 18F-fluoride positronemission tomography for identification of ruptured and high-riskcoronary atherosclerotic plaques: a prospective clinical trial. Lancet2014;383:705–13.

81. Fiechter M, Stehli J, Fuchs TA, Dougoud S, Gaemperli O,Kaufmann PA. Impact of cardiac magnetic resonance imaging onhuman lymphocyte DNA integrity. Eur Heart J 2013;34:2340–5.

82. Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to preventvascular events in men and women with elevated C-reactive protein.N Engl J Med 2008;359:2195–207.

83. Randomised trial of cholesterol lowering in 4444 patients with cor-onary heart disease: the Scandinavian Simvastatin Survival Study (4S).Lancet 1994;344:1383–9.

84. Hattori K, Ozaki Y, Ismail TF, et al. Impact of statin therapy onplaque characteristics as assessed by serial OCT, grayscale and inte-grated backscatter-IVUS. J Am Coll Cardiol Img 2012;5:169–77.

85. Kini AS, Baber U, Kovacic JC, et al. Changes in plaque lipidcontent after short-term intensive versus standard statin therapy: theYELLOW trial (Reduction in YEllow Plaque by Aggressive LipidLOWering Therapy). J Am Coll Cardiol 2013;62:21–9.

86. Nissen SE, Nicholls SJ, Sipahi I, et al. Effect of very high-intensitystatin therapy on regression of coronary atherosclerosis: theASTEROID trial. JAMA 2006;295:1556–65.

87. Puri R, Nissen SE, Shao M, et al. Coronary atheroma volume andcardiovascular events during maximally intensive statin therapy. EurHeart J 2013;34:3182–90.

88. Tawakol A, Fayad ZA, Mogg R, et al. Intensification of statin therapyresults in a rapid reduction in atherosclerotic inflammation: results of amulticenter fluorodeoxyglucose-positron emission tomography/com-puted tomography feasibility study. J AmCollCardiol 2013;62:909–17.

89. Vucic E, Calcagno C, Dickson SD, et al. Regression of inflammationin atherosclerosis by the LXR agonist R211945: a noninvasiveassessment and comparison with atorvastatin. J Am Coll Cardiol Img2012;5:819–28.

90. Elkhawad M, Rudd JH, Sarov-Blat L, et al. Effects of p38 mitogen-activated protein kinase inhibition on vascular and systemic inflam-mation in patients with atherosclerosis. J Am Coll Cardiol Img 2012;5:911–22.

91. Nidorf SM, Eikelboom JW, Budgeon CA, Thompson PL. Low-dosecolchicine for secondary prevention of cardiovascular disease. J AmColl Cardiol 2013;61:404–10.

92. Urban D, Poss J, Bohm M, Laufs U. Targeting the proprotein con-vertase subtilisin/kexin type 9 (PCSK9) for the treatment of dyslipi-demia and atherosclerosis. J Am Coll Cardiol 2013;62:1401–8.

93. Giugliano RP, Desai NR, Kohli P, et al. Efficacy, safety, and toler-ability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 in combination with a statin in patients with hyper-cholesterolaemia (LAPLACE-TIMI 57): a randomised, placebo-controlled, dose-ranging, phase 2 study. Lancet 2012;380:2007–17.

94. Koren MJ, Scott R, Kim JB, et al. Efficacy, safety, and tolerabilityof a monoclonal antibody to proprotein convertase subtilisin/kexintype 9 as monotherapy in patients with hypercholesterolaemia(MENDEL): a randomised, double-blind, placebo-controlled, phase2 study. Lancet 2012;380:1995–2006.

95. Raal F, Scott R, Somaratne R, et al. Low-density lipoproteincholesterol-lowering effects of AMG 145, a monoclonal antibodyto proprotein convertase subtilisin/kexin type 9 serine protease inpatients with heterozygous familial hypercholesterolemia: the Re-duction of LDL-C with PCSK9 Inhibition in Heterozygous FamilialHypercholesterolemia Disorder (RUTHERFORD) randomized trial.Circulation 2012;126:2408–17.

96. Sullivan D, Olsson AG, Scott R, et al. Effect of a monoclonal anti-body to PCSK9 on low-density lipoprotein cholesterol levels in statin-intolerant patients: the GAUSS randomized trial. JAMA 2012;308:2497–506.

97. Ferri N, Tibolla G, Pirillo A, et al. Proprotein convertase subtilisinkexin type 9 (PCSK9) secreted by cultured smooth muscle cellsreduces macrophages LDLR levels. Atherosclerosis 2012;220:381–6.

98. Wald DS, Morris JK, Wald NJ, et al. Randomized trial of preventiveangioplasty in myocardial infarction. N Engl J Med 2013;369:1115–23.

99. Watabe H, Sato A, Akiyama D, et al. Impact of coronary plaquecomposition on cardiac troponin elevation after percutaneous coronaryintervention in stable angina pectoris: a computed tomography anal-ysis. J Am Coll Cardiol 2012;59:1881–8.

100. Kodama T, Kondo T, Oida A, Fujimoto S, Narula J. Computedtomographic angiography-verified plaque characteristics and slow-flow phenomenon during percutaneous coronary intervention. J AmColl Cardiol Intv 2012;5:636–43.

101. Claessen BE, Maehara A, Fahy M, Xu K, Stone GW, Mintz GS.Plaque composition by intravascular ultrasound and distal emboliza-tion after percutaneous coronary intervention. J Am Coll Cardiol Img2012;5:S111–8.

102. Stone GW, Abizaid A, Silber S, et al. Prospective, randomized,multicenter evaluation of a polyethylene terephthalate micronetmesh-covered stent (MGuard) in ST-Segment elevation myocardialinfarction: the MASTER trial. J Am Coll Cardiol 2012;60:1975–84.

103. Kristensen TS, Kofoed KF, Kuhl JT, Nielsen WB, Nielsen MB,Kelbaek H. Prognostic implications of nonobstructive coronary pla-ques in patients with non-ST-segment elevation myocardial infarc-tion: a multidetector computed tomography study. J Am Coll Cardiol2011;58:502–9.

104. Lin FY, Shaw LJ, Dunning AM, et al. Mortality risk in symptomaticpatients with nonobstructive coronary artery disease: a prospective2-center study of 2,583 patients undergoing 64-detector row coronarycomputed tomographic angiography. J Am Coll Cardiol 2011;58:510–9.

105. Nicholls SJ, Hsu A, Wolski K, et al. Intravascular ultrasound-derivedmeasures of coronary atherosclerotic plaque burden and clinicaloutcome. J Am Coll Cardiol 2010;55:2399–407.

Key Words: atherosclerotic plaque - imaging - inflammation -

PCSK9 - statins.























































































































Advances in the Understanding of Plaque Composition and Treatment Options · 2016-11-13 ·...

Documents

Transcript of Advances in the Understanding of Plaque Composition and Treatment Options · 2016-11-13 ·...