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EDITORIAL COMMENT

The Stress of Plaque Prognostication*

Renu Virmani, MD,a Sho Torii, MD,a Hiroyoshi Mori, MD,a Aloke V. Finn, MDa,b

P laque rupture is a predominant cause of acutecoronary syndromes and sudden coronarydeath (1). However, not all plaques progress

to cause clinical events (2). Many remain dormant forthe life of the individual and cause neither symptomsnor clinical events, whereas others progressivelynarrow but do not rupture, thus resulting in stableangina. However, only a few plaques become progres-sively unstable in morphology and eventually are thecause of serious clinical events (Figures 1A to 1G).Because we currently lack the understanding andtechnology to identify correctly which so-calledvulnerable plaques (thin-cap fibroatheromas) in theshort term will go on to cause symptoms, andespecially acute myocardial infarctions, our focustherefore has been on the development of techniquesthat restore blood flow in arteries possessing hemody-namically significant lesions that cause ischemia orinfarction. This reactive strategy has meant thatalthough death rates for heart disease have continuedto fall in recent decades, the number of people withcardiovascular disease is rising because many morepeople are living with the crippling aftereffects of

*Editorials published in JACC: Cardiovascular Imaging reflect the views of

the authors and do not necessarily represent the views of JACC:

Cardiovascular Imaging or the American College of Cardiology.

From the aCVPath Institute, Inc., Gaithersburg, Maryland; and thebUniversity of Maryland School of Medicine, Baltimore, Maryland. This

study was sponsored by CVPath Institute, a nonprofit organization

dedicated to cardiovascular research. CVPath Institute has research

grants from Abbott Vascular, Atrium Medical, Boston Scientific,

Biosensors International, Cordis–Johnson & Johnson, Medtronic

CardioVascular, OrbusNeich Medical, and Terumo Corporation. Dr.

Virmani has reported speaking engagements for Merck; has received

honoraria from Abbott Vascular, Boston Scientific, Lutonix, Medtronic,

and Terumo Corporation; and is a consultant for 480 Biomedical,

Abbott Vascular, Medtronic, and W.L. Gore. Dr. Mori has received

honoraria from Abbott Vascular Japan, Goodman, and Terumo

Corporation. Dr. Finn has sponsored research agreements with Boston

Scientific and Medtronic CardioVascular; has served on the advisory

board of Medtronic CardioVascular; and has received honoraria from

Abbott Vascular, Boston Scientific, and Medtronic. Dr. Torii has

reported that he has no relationships relevant to the contents of this

paper to disclose.

heart attacks (3). In addition to finding better thera-pies for those patients with heart disease, preventingfuture events remains a major priority for the cardiol-ogy community.

Because most acute coronary syndromes resultfrom plaques that are modest in severity (4,5), coro-nary angiography is of limited utility in distinguish-ing lesions with a high short-term risk of causingclinical events. Detailed pathological examination ofplaque ruptures has allowed us to define morpho-logical criteria that we believe characterize plaques athigh risk for rupture (1). These vulnerable plaqueshave a large lipid core, a thin fibrous cap, and in-flammatory cell infiltration, with calcification resem-bling plaque rupture lesions but with an intact fibrouscap (1). However, perhaps the greatest problem withthis paradigm is that we lack high predictive valuesfor in vivo evidence that these so-called vulnerableplaques actually do go on to rupture. In what wasarguably the most thorough attempt to examine therelationship between plaque morphology as identi-fied by intravascular ultrasound (IVUS) and clinicalevents in living patients, Stone et al. (2) conductedthe landmark PROSPECT (Providing Regional Obser-vations to Study Predictors of Events in the CoronaryTree [NCT00180466]) trial, a study of 697 patientspresenting with acute coronary syndromes who un-derwent 3-vessel coronary angiography and gray-scale and radiofrequency IVUS-virtual histology(IVUS-VH) imaging after percutaneous coronaryintervention (2). Subsequent major cardiac events(MACE) over a median of 3.4 years were recordedand adjudicated to be caused either by the originalculprit lesion or by untreated nonculprit lesions (2).Although this group was able to define criteriathat were associated with new nonculprit MACE(large plaque burden $70%, minimum luminal area4.0 mm2 or less, and the presence of what appeared tobe vulnerable plaque characteristics as defined bycomposition using IVUS-VH), the positive predictivevalue of these criteria was very low (2). Most patients(88.2%) with lesions consistent with these so-calledhigh-risk characteristics did not have MACE (2).

FIGURE 1 Why Plaque Rupture Occurs at One Site and Not at Other Sites With Similar Plaques Must Remain a Mystery, at Least for Now

A 77-year-old white man with no known medical history was found unresponsive in his house. (A and B) Histological sections showed healing

plaque rupture with a large, underlying necrotic core (NC) in the mid-left circumflex artery. Thin-cap fibroatheromas were seen in the distal

consecutive sections of the mid-left circumflex artery (C and D) and in the proximal left anterior descending artery (E). (F and G) High-power

images showing the thin cap at the 2 different sites. Ca2þ ¼ calcification; Th ¼ thrombus.

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These findings suggested that although such lesioncharacteristics are conducive to the occurrence of asubsequent event, they are not sufficient to predictwhich atheromas will undergo plaque progression ona per-patient basis.

In this issue of iJACC, Stone et al. (6) attempt torefine these criteria by adding low endothelial shearstress (ESS) as a potential predictor of nonculpritevents in the PROSPECT trial. Using the same datasetbut adding ESS values for nonculprit lesions usingcomputational fluid dynamics obtained from angiog-raphy and IVUS imaging, the investigators exploredwhether adding such data would provide additionalprognostic information about nonculprit lesions.

Maintenance of physiological laminar shearstress is essential for normal vascular function,which includes the regulation of vascular caliber

and the inhibition of proliferation, thrombosis,and inflammation of the vessel wall. Low flow andoscillatory flow are often seen opposite arterialflow dividers that have a predisposition to athero-sclerosis. Endothelial cells have different behavioralresponses to altered flow patterns that promoteatherosclerosis in combination with other well-defined systemic risk factors. Earlier work conduct-ed by Stone et al. (7) in the PREDICTION (Prediction ofProgression of Coronary Artery Disease and ClinicalOutcome Using Vascular Profiling of Shear Stress andWall Morphology [NCT01316159]) study demonstratedthat the positive predictive value for coronary arterydisease progression requiring percutaneous coronaryintervention during 1-year follow-up was 22% on thebasis of plaque anatomy alone (large plaque burdenand small minimal lumen area), but it increased to

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41% if low ESS was also present in that plaque. Stoneet al. (6) use the PROSPECT trial data to determine theadditive value of low ESS in plaque prognostication.By comparing baseline ESS in nonculprit lesionsleading to new MACE with randomly selected non-culprit lesions without MACE, a propensity score forESS was constructed for each lesion, and the rela-tionship between ESS and subsequent nonculpritMACE was examined. Low ESS was strongly associ-ated with MACE (hazard ratio: 4.34; 95% confidenceinterval: 1.89 to 10.00; p < 0.001). High anatomic riskdefined by large plaque burden ($70%, minimumluminal area 4.0 mm2 or less, the presence of whatappeared to be a vulnerable plaque by compositionusing IVUS-VH) and low ESS were prognostically syn-ergistic: 3-year nonculprit MACE rates were 52.1%versus 14.4% versus 0.0% in lesions with highanatomic risk/low ESS, low anatomic risk/low ESS, andphysiological/high ESS, respectively (p < 0.0001).Stone et al. (6) conclude by stating that local ESSprovides incremental risk stratification of untreatedcoronary lesions in high-risk patients beyond theirpreviously defined high-risk plaque criteria.

What, then, are we to make of these data? Does theaddition of low-ESS areas provide useful informationthat could be used clinically to define vulnerableplaques? The study design, in particular, deservesadditional comment. The pre-specified comparisonbetween event-causing lesions and non–event-causing lesions makes the results very difficult tointerpret on a per-patient basis. Clinically useful in-formation such as positive and negative predictivevalues could not be reliably assessed because of thesmall sample size. There were also too few events toallow construction of a comprehensive multivariablemodel predicting outcomes. Thus the true value ofassessing low ESS to predict nonculprit MACE cannotbe assessed from these data. What we can say fromthese data is that they confirm prior observations thatlesions with low ESS are generally at higher risk forprogression, but it remains unclear how predictiveESS, even when combined with previous measures ofhigh-risk plaque, is for event prediction. In ouropinion, it is unlikely that the use of ESS providessignificant prognostic value on a per-patient basis, anecessary requirement for prediction of future eventswith high positive predictive value. Alterations inshear are expected in normal bifurcations, yet not allgo on to develop high-risk plaques. Other patient-and lesion-specific factors undoubtedly are importantin the development of high-risk lesions.

The larger and perhaps more important question forcardiology is this: “Is the vulnerable plaque paradigmworth pursuing and, if so, how?” Although there have

been recent advances in in vivo imaging of coronaryplaques with the use of IVUS, optical coherencetomography (OCT), cardiac magnetic resonance, andcomputed tomography, their resolution is limited,leading to errors in what is being described. Werecently evaluated the ability of previously describedOCT imaging patterns to describe histological findingsreliably in an ex vivo study (8). Most OCT patterns didnot correlate with any single histological finding.Previous work has also suggested significant errors inthe interpretation of IVUS-VH for describing histolog-ical characteristics (9). In the PROSPECT trial only 51%of lesions occurred at sites of vulnerable plaques,whereas other events were associated with thick-capatheromas. Is this because thick-cap lesions causeevents, or is it rather an indicator of how poor IVUS-VHis for identifying high-risk morphological features?One must ask, “Have we been able to locate vulnerableplaques properly using today’s technology?” Patholo-gically defined criteria such as necrotic core size,extent of macrophage infiltration, and cap thicknessare still not able to be assessed reliably using eitherinvasive or noninvasive imaging. Thus we cannot saywith certainty that the vulnerable plaque paradigmdoes not exist.

To explore this issue properly, further investmentin technology that is able to assess plaque featureswith greater accuracy must continue. Recentadvances in multimodality imaging such as OCTcombined with IVUS or near-infrared imaging mayhold significant promise because findings can beconfirmed using more than 1 approach (10).

We need tools that can accurately assess thefollowing: the presence of positive remodeling;fibrous cap thickness and its circumferential andlongitudinal dimensions; necrotic core size, its loca-tion in relation to the lumen, and its eccentricity; thepresence of inflammatory cells and whether they areactivated; and, above all, the type, thickness, extent,and location of calcium. Beyond these morphologicalcharacteristics, we also need additional physiologicaland biological characteristics (e.g., endothelial shearstress, blood flow patterns, state of endothelialfunction) and more information about patientsthemselves, including genetics, as well as biomarkersindicative of systemic inflammation and hyper-coagulation. Only by creating a large array of dataincluding an accurate description of coronary plaquesin living patients can we properly explore thevulnerable plaque paradigm.

ADDRESS FOR CORRESPONDENCE: Dr. RenuVirmani,CVPath Institute, Inc., 19 Firstfield Road, Gaithersburg,Maryland 20878. E-mail: rvirmani@cvpath.org.

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6. Stone PH, Maehara A, Coskun AU, et al. Role oflow endothelial shear stress and plaque charac-teristics in the prediction of nonculprit majoradverse cardiac events: the PROSPECT study. J AmColl Cardiol Img 2017;10:xxx–x.

7. Stone PH, Saito S, Takahashi S, et al. Predictionof progression of coronary artery disease andclinical outcomes using vascular profiling ofendothelial shear stress and arterial plaque char-acteristics: the PREDICTION study. Circulation2012;126:172–81.

8. Lutter C, Mori H, Yahagi K, et al. Histopatho-logical differential diagnosis of optical coherence

tomographic image interpretation after stenting.J Am Coll Cardiol Intv 2016;9:2511–23.

9. Thim T, Hagensen MK, Wallace-Bradley D, et al.Unreliable assessment of necrotic core by virtualhistology intravascular ultrasound in porcine cor-onary artery disease. Circ Cardiovasc Imaging2010;3:384–91.

10. Yoo H, Kim JW, Shishkov M, et al. Intra-arterialcatheter for simultaneous microstructural andmolecular imaging in vivo. Nat Med 2011;17:1680–4.

KEY WORDS atherosclerosis, coronary arterydisease, inflammation, prevention, shear stress