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STATE-OF-THE-ART REVIEW

Physiological Predictors ofAcute Coronary SyndromesEmerging Insights From the Plaque to the Vulnerable Patient

Thomas J. Ford, MBCHB (HONS),a,b Colin Berry, MBCHB, PHD,a Bernard De Bruyne, MD, PHD,c

Andy S.C. Yong, MBBS, PHD,d,e Peter Barlis, MBBS, MPH, PHD,f William F. Fearon, MD,g

Martin K.C. Ng, MBBS (HONS), PHDe,h

ABSTRACT

FrobUdD

Au

Un

Au

au

Ma

In this review, the authors explore the evolving evidence linking physiological assessment of coronary artery disease with

plaque progression and vulnerability. Reducing adverse clinical events remains the ultimate goal for diagnostic tests, and

this review highlights evidence supporting the prognostic value of physiological metrics in predicting outcomes.

Historical and contemporary studies support synergy among lesion severity, ischemia, plaque vulnerability, and patient

prognosis. Ischemia contributes to clinical events through association with plaque burden, but this review addresses

the emerging concept that it associates with atherothrombosis via disturbed lesion hemodynamics. Biomechanical

pathophysiological forces including endothelial shear stress—the frictional force generated by blood flow on the

vessel wall—are increasingly linked with atherogenesis, vulnerable plaque morphology, and platelet and leukocyte

activation. The authors conclude by transitioning from the model of the vulnerable plaque to the concept of the

“vulnerable patient,” looking more broadly at physiological contributors to Virchow’s triad underpinning acute

coronary syndrome. (J Am Coll Cardiol Intv 2017;10:2539–47) © 2017 the American College of Cardiology Foundation.

Published by Elsevier. All rights reserved.

T he fractional flow reserve (FFR) reflects theextent to which maximal myocardial flow isdecreased because of the presence of an

epicardial narrowing (1,2). Revascularization decisionsbased on FFR improve prognosis in patients with coro-nary artery disease (3,4). Moving beyond flow limita-tion, the anatomic and physiological characteristicsof a plaque implicate a role for physiological factorsand biomechanical forces in the pathophysiology ofplaque rupture (5). Endothelial shear stress (ESS)—thefrictional force generated by blood flow on the vesselwall—is increasingly linked with atherogenesis and

m the aBritish Heart Foundation Cardiovascular Research Centre, U

niversity of New South Wales, Sydney, Australia; cCardiovascular Cent

epartment of Cardiology, Concord Hospital, Sydney, Australia; eSydney

stralia; fFaculty of Medicine, University of Melbourne, Melbourne, Australi

iversity Medical Center, Stanford, California; and the hDepartment of

stralia. Drs. Ford and Berry have received research support from the B

thors have reported that they have no relationships relevant to the conte

nuscript received April 13, 2017; revised manuscript received August 7, 2

plaque vulnerability in addition to platelet and leuko-cyte activation (6,7). Although coronary physiologicalindexes such as FFR have been proposed for interroga-tion of the ischemic potential of stable coronary steno-ses, lesion hemodynamic status is associated withatherosclerotic plaque biology and vulnerability (8).

Coronary physiological data may be integratedwith anatomic information from coronary angiog-raphy and intravascular imaging to provide novelinsights into lesion pathobiology with the potential tobetter inform the treatment of patients with coronarydisease. In this review, we explore the evolving

niversity of Glasgow, Glasgow, United Kingdom;

er Aalst, Onze-Lieve-Vrouw Clinic, Aalst, Belgium;

Medical School, The University of Sydney, Sydney,

a; gDepartment of Cardiovascular Medicine, Stanford

Cardiology, Royal Prince Alfred Hospital, Sydney,

ritish Heart Foundation (grant RE-13-5-30177). The

nts of this paper to disclose.

017, accepted August 15, 2017.

ABBR EV I A T I ON S

AND ACRONYMS

ACS = acute coronary

syndrome(s)

CTA = computed tomographic

angiography

DS = diameter stenosis

ESS = endothelial shear stress

FFR = fractional flow reserve

MACE = major adverse cardiac

event(s)

MI = myocardial infarction

PCI = percutaneous coronary

intervention

SPECT = single-photon

emission computed

tomography

TCFA = thin-cap fibroatheroma

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Physiological Predictors of Acute Coronary Syndromes D E C E M B E R 2 6 , 2 0 1 7 : 2 5 3 9 – 4 7

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evidence linking physiological assessment ofcoronary artery disease with plaque pro-gression and vulnerability.

ISCHEMIA BASED ON

ANATOMIC EVALUATION

(INVASIVE CORONARY ANGIOGRAPHY)

CORONARY ANGIOGRAPHY FOR DETECTING

PLAQUE AND ASSESSING VULNERABILITY.

Luminal changes demonstrable on coronaryangiography have traditionally been used todetermine whether a coronary stenosis is ofhemodynamic significance (i.e., associatedwith myocardial ischemia). However, x-rayangiography is merely a “luminogram,” andestimating physiological significance fromdiameter stenosis (DS) is fraught with many

pitfalls: the ratio of the minimal luminal diameter tothe adjacent normal segment ignores the facts thatatherosclerosis is a diffuse disease and angiographyalone is often unable to distinguish between normaland diseased segments (9). The Glagov phenomenonof positive vessel remodeling may obfuscate plaquewithin the vessel wall without causing luminalencroachment. Histopathologic studies show thatluminal narrowing typically occurs late after theatheroma expands to about 45% plaque burden bycross-sectional area (the limit of external elastic me-dia expansion) (10). Despite advances in quantitativecoronary angiographic techniques, there arewell-recognized limitations of angiography in deter-mining the hemodynamic significance of intermedi-ate coronary lesions (40% to 70% DS) (11).

THE RELATIONSHIP BETWEEN LESION SEVERITY

AND VULNERABILITY. Only a minority of earlyatherosclerotic plaques progress to high-risk thin-capfibroatheromas (TCFAs), which are thought to be themost common precursors to ruptured plaques (12).Nonobstructive plaques are more prevalent thanobstructive plaques, but the absolute risk for plaquerupture is higher with an obstructive lesion (8,13).Contemporary angiographic studies support that atthe time of myocardial infarction (MI), the underlyinglesion on angiography is usually severely stenotic(mean DS 66 � 12%) (14). Post-mortem data confirmsthe majority of lesions causing fatal infarction areobstructive when plaque burden is analyzed by his-topathologic cross-sectional area: more than 75%stenosis is seen in 70% of plaque ruptures (15). It islikely that rapid, though usually asymptomatic pro-gression and resultant stenosis or thrombosis occursin the days to weeks preceding acute MI such that

acute total vessel occlusion typically develops at thesite of an obstructive narrowing.

Studies of noninvasive angiography using coronarycomputed tomographic angiography (CTA) stronglysupport that larger plaque size associates with lesionvulnerability (16). Other high-risk atheroscleroticplaque features on coronary CTA include positivevessel remodeling, low-attenuation plaques, the“napkin ring” sign, and spotty calcification (17,18).

The PROSPECT (Providing Regional Observations toStudy Predictors of Events in the Coronary Tree) studyof the natural history of atherosclerosis using intra-vascular ultrasound is the single most important pieceof contemporary evidence supporting the notion thatlesion severity is associated with future risk of majoradverse cardiac events (MACE). Plaque burden $70%was the strongest predictor of future events (hazardratio: 5.03; p<0.001). Minimal luminal areawas also animportant independent predictor (13). Lesions withplaque burden $70% had event rates of almost 10%over a median follow-up duration of 3.4 years. Thesemay not always appear obstructive on conventionalangiography, in keeping with the Glagov phenomenonand the accepted limitations of angiography (10). Therewas not a single event arising from a coronary arterysegment with <40% plaque burden. Analysis of non-culprit lesions in PROSPECT that were responsible forfuture major adverse cardiac events (MACEs) showedthat the majority of these plaques were nonobstructiveon baseline angiography (mean DS 32.3 � 20.6%), butlater at the subsequent event, the angiographic severityin this subgroup had progressed to a mean DS of 65%.Importantly, the dominant driver of these events wasprogression of angina; the more robust clinicalendpoint of acute MI in a nonculprit vessel occurredin <1% of patients. Taken together, the most likelymodel of vulnerable plaques is that of stepwise accel-erated progression with subclinical plaque rupturesand increasing luminal encroachment, with a contin-uum of both obstructive and nonobstructive plaquesunderlying acute coronary syndrome (ACS) (19).

ISCHEMIA BASED ON

FUNCTIONAL EVALUATION

The adverse prognostic impact of ischemia has beenwell established using various imaging modalities fornoninvasive functional assessment. Myocardialischemia identified on single-photon emissioncomputed tomography (SPECT) is strongly predictiveof MACEs in both symptomatic and asymptomaticpatients (20,21). Comprehensive follow-up data fromalmost 70,000 myocardial perfusion scans highlightsthe high rates of MACEs with moderate- to high-risk

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ischemia on SPECT compared with low risk: up to8.5% per year versus 0.6% (22). Studies using stressperfusion cardiac magnetic resonance offer addi-tional insights due to superior spatial resolution andenhanced classification of inducible ischemia andmyocardial scar. Among 1,152 patients with anginafollowed up after stress perfusion cardiac magneticresonance, those with inducible ischemia experi-enced MACEs at 3.9% per year compared with only 1%in those with negative results. On multivariate anal-ysis, ischemia was the strongest independent pre-dictor of cardiac death, nonfatal MI, and stroke atmean follow-up of 4.2 years (hazard ratio: 3.21; 95%confidence interval: 2.06 to 5.00; p < 0.0001) (23).Furthermore recent cardiac magnetic resonance datasuggest the presence of an “ischemic threshold”whereby a burden of $1.5 ischemic segments wasindependently associated with nearly 9-foldincreased risk for cardiac death, MI, or late coronaryrevascularization during a mean follow-up durationof 2.5 years (24). Importantly, even when left ven-tricular function and myocardial scar burden wereaccounted for, this “ischemic threshold” remainedthe strongest independent predictor of “hard” clinicalendpoints: cardiac death and MI.

Ischemia may be a surrogate marker for anatomicplaque burden; indeed the COURAGE (Clinical Out-comes Utilizing Revascularization and AggressiveDrug Evaluation) trial highlighted the intuitiveinteraction between ischemia on SPECT and anatomicdisease burden on baseline angiography (p ¼ 0.03).Taken together, the COURAGE data showed anatomicdisease burden to be a more consistent predictor ofevents compared with ischemia (25,26). Importantly,this study overlooked the fact that the degree ofischemia was determined before treatment. The in-fluence of ischemia on outcome should be at leastpartly annulled following the initiation of treatmentsaimed at alleviating its existence; thus it is unsur-prising that plaque burden was more predictive ofevents. The COURAGE nuclear substudy did not showthat ischemia was associated with risk for futureevents, but it was not powered to perform this non-pre-specified analysis and may have been affectedby selection bias (27). Other contemporary cohortshave found ischemia on SPECT to be the strongestpredictor of events, providing complementary addi-tional information to the anatomic disease burdenassessed by coronary artery calcium score (28).Among patients with previous revascularization, theresidual ischemic burden is the strongest indepen-dent predictor of future events, consistently identi-fying high-risk patients in groups with similardegrees of anatomic plaque burden (29,30).

LESSONS FROM FAME: IS FFR A PREDICTOR OF

LESION VULNERABILITY? The FAME (FFR VersusAngiography for Multivessel Evaluation) 2 studyshowed that patients with functionally significantlesions (FFR #0.80) had superior outcomes withpercutaneous coronary intervention (PCI) and optimalmedical therapy compared with optimal medicaltherapy alone (3). Critics argue that urgent re-vascularizations were to be expected in this trial giventhat both patients and physicians were potentiallyaware of the significant lesions that were not stented.This may have lowered the threshold for urgentrevascularization in patients with FFR-positive steno-sis in the medical therapy group. Besides the fact thatthis phenomenon did not happen in the registry pa-tients (also aware of the presence of untreated lesions),one-half of the urgent revascularizations occurred inthe context of positive biomarkers or new electrocar-diographic (ECG) changes, while 80% occurred inpatients with these findings or rest angina. A blindedand independent clinical event committee adjudicatedall these events. In addition, it is very likely that thelarge number of unplanned revascularizations inpatients randomized to medical therapy actuallylimited the number of “hard endpoints” (death or MI).The 2-year follow-up data showed that after excludingthe potentially more benign periprocedural MIs, theincidence of death or MI was lower in the PCI groupthan in the medical therapy group (4.6% vs. 8.0%;p ¼ 0.04) (3). There was a significantly lower incidenceof revascularization procedures triggered by ECGchanges or MI in the PCI group than in the medicaltherapy group (3.4% vs. 7.0%; p ¼ 0.01).

Equally, FAME and now 15-year follow-up data fromthe DEFER study highlight the negative predictivevalue of FFR: nonischemic stenoses have an excellentprognosis on medical therapy, with a <1% annualizedincidence of MI (31). The DEFER study also reinforcesthe known adverse prognostic implications ofischemia: lower FFR values are associated with morethan double the rates of death and MI (Figure 1) (32).Moreover, the outcome in the FAME 2 registry group(FFR >0.8) at 2 years was identical to that observed inthe PCI group.

Further comprehensive evidence for the relation-ship between physiological lesion severity measuredby the FFR and clinical outcomes was demonstrated ina large meta-analysis: Johnson et al. (33) used study-level and individual patient-level data from studiesof FFR with follow-up for MACE. The authors demon-strated that lower FFR values have a continuous andindependent relationship with MACE and a larger ab-solute benefit from revascularization. Barbato et al.(34) recently provided further analysis from the FAME

FIGURE 2 Major A

Randomized to Med

This figure illustrates

follow-up by 0.05 s

increase in the rate o

FFR of 0.80 and pla

Barbato et al. (34).

FIGURE 1 Adverse Prognostic Implications of Ischemia

Cardiac death and acute myocardial infarction rate in the 3

groups of the DEFER study after a follow-up period of 5 years.

Pre-PCI patients with FFR $0.75 were randomly assigned to

deferral (DEFER group) or performance of PCI (PERFORM

group). If FFR was <0.75 then PCI was performed as planned

(REFERENCE). FFR ¼ fractional flow reserve. Reprinted with

permission from Pijls et al. (32).

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2 study showing the natural history of events accord-ing to FFR in patients who did not undergo revascu-larization. They showed a step-up increase in the ratesof MACEs by decreasing FFR values (Figure 2).

These findings are consistent with the hypothesisthat FFR assists in the prediction of plaque behavior:the ischemic potential of a lesion may be a surrogatemarker of plaque vulnerability with its attendant riskfor rupture. It is important to note that a lower

dverse Cardiac Event Rates at 2 Years in FAME 2 Patients

ical Therapy

the rate of major adverse cardiac events (MACEs) at 2 years of

trata of fractional flow reserve (FFR) values. There is a step-up

f MACEs by decreasing FFR values. This increase is steeper below an

teaus below an FFR of 0.60. Reprinted with permission from

absolute value of FFR corresponds with a higher riskfor events, but risk stratification using this approachdoes not necessarily detect which ischemia-producinglesion will drive events. Prospective studies haveshown that up to one-half of future MACE relate tonontarget vessels, but a large proportion of the futureMACE is attributable to the lesion’s FFR. Stentingthese hemodynamically significant vulnerable lesionsmay prevent future coronary events (33).HOW ISCHEMIA AFFECTS PLAQUE VULNERABILITY

AND PROPENSITY TO ACS. There are 2 main reasonswhy an ischemia-producing lesion is more likely tocause ACS than a nonischemia-producing lesion. First,an obstructive stenosis that limits blood flow is morelikely to become occlusive, leading to an acute MI asthe burden of plaque increases (plaque progression).Second, the increasing stenosis severity leads tochanges in flow dynamics and wall shear stress, whichin turn increase the likelihood of plaque rupture (8).Versteeg et al. (35) demonstrated that the responsesand expression of monocyte Toll-like receptors2 and 4, which are thought to be related to plaquevulnerability, are significantly greater in patients withFFR <0.75 compared with patients with FFR >0.80.

Recent data have shown that the fibrous capthickness of intermediate-grade lipid-rich plaquescorrelates with the physiological significance of thelesion (FFR <0.8) (36). A positive FFR is stronglypredictive of a thin-capped fibroatheroma (<80 mm).Histopathologic studies suggest that vulnerable pla-ques are those with cap thickness <65 mm; morerecent in vivo optical coherence tomographic datasupport the FFR-predicted critical cap thicknessvalue of <80 mm (37). Importantly, rupture of thesethin caps overlying vulnerable plaques is the causeof 75% of ACS (38). There is a wealth of evidencesupporting the role of more severe (and likelyischemia-producing lesions) to be more dangerous.ROMICAT-II (Rule Out Myocardial Infarction/Ischemia Using Computer-Assisted Tomography II)showed stenosis severity on coronary CTA to be thestrongest predictor of ACS in patients with acutechest pain (39). Multivariate analysis from a cohort ofmore than 3,000 patients undergoing coronary CTAshowed that although nonobstructive plaques werealmost 4 times more prevalent than obstructive ones,stenotic lesions were stronger predictors of ACS(hazard ratio: 3.2; 95% confidence interval: 2.11 to5.00; p < 0.0001) (40). In patients with ACS studiedwith intravascular ultrasound and optical coherencetomography, severely stenotic areas had TCFA withmore features of plaque vulnerability (41). Pathologystudies have shown that plaques are constantlyrupturing and healing, and when this happens over a

J A C C : C A R D I O V A S C U L A R I N T E R V E N T I O N S V O L . 1 0 , N O . 2 4 , 2 0 1 7 Ford et al.D E C E M B E R 2 6 , 2 0 1 7 : 2 5 3 9 – 4 7 Physiological Predictors of Acute Coronary Syndromes

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nonseverely obstructing lesion, it is more likely to besilent (42). Ruptured TCFA with thrombus formationsuperimposed on a severe stenosis is more likely tolimit the coronary blood flow (and lead to clinicalevents) than the same event superimposed on anonsevere stenosis.

BIOMECHANICAL PATHOPHYSIOLOGICAL

FORCES INCLUDING ESS

Blood flow within a conduit artery exerts 3 distincttypes of biomechanical strain on the vessel: axial,circumferential, and shear stress. Stress is a reflectionof force normalized per unit area (newtons per squaremeter or pascals or dyne per square centimeter;1 N/m2 ¼ 1 Pa ¼ 10 dyn/cm2). ESS is the most studied ofthese forces and appears to be the most fundamentaland robust predictor of atherosclerotic initiation anddevelopment (43). ESS is the tangential force exertedon the vessel wall attributable to the friction of bloodflow on the endothelial surface (Central Illustration).These endothelial cells are incredibly sensitive to ESSand regulate vascular function in health and diseasethrough mechanotransduction. Axial plaque stress is alongitudinalmechanical force applied along the lengthof plaque resulting from arterial blood pressure andstretching with phasic cardiac motion. Axial plaquestress occurs at force 103 to 105 times greater than ESSand thus may be the biomechanical factor more caus-ally related to plaque rupture. Challenges with in vivoestimation may partly explain a relative paucity ofresearch into its contribution to atherosclerotic plaquepathophysiology compared with ESS. Computerizedmodeling demonstrates that lesions with similarangiographic and hemodynamic severity can havehugely variable levels of axial plaque stress, poten-tially accounting for differences in vulnerabilityrelating to lesion geometry of the upstream ordownstream shoulder (radial gradient) (44).

HOW IS ESS ESTIMATED IN VIVO? The derivation ofESS depends on computational fluid dynamics,incorporating flow data (often obtained from invasiveDoppler wire) into 3-dimensional computerizedmodels of coronary arteries. These reconstructionsmay be created from biplane or 3-dimensional coro-nary angiography and even integrated with intravas-cular imaging for more accurate vascular profiling(45). Computational fluid dynamics has recentlybeen combined with coronary CTA, facilitating anoninvasive way of estimating shear stress (46,47).Fractional flow reserve from coronary CT angiographycan be obtained from 3-dimensional coronary re-constructions from coronary CTA using computational

fluid dynamics modeling and has been shown toreduce cost and unnecessary invasive procedures inpatients with stable angina (48).

HOW DOES SHEAR RELATE TO PLAQUE BIOLOGY

AND VULNERABILITY? Caro et al. (49) first describedthe pathological role of low and oscillatory ESS, form-ing the hypothesis that is now the consensus mecha-nism for the initiation of atherosclerosis (6,49,50).Coronary arteries with undisturbed flow and physio-logical ESS facilitate endothelial cell expression ofatheroprotective genes and the suppression of proa-therogenic genes leading to coronary plaque quies-cence and stability. However, in areas of disturbed lowflow with low ESS, atheroprotective genes are down-regulated and proatherogenic genes up-regulated,resulting in acceleration of atherogenesis (43,51).Mechanoreceptors on the endothelial cell surfacerespond to low-ESS, stimuli leading to mechano-sensitive gene expression promoting atherosclerosis(51). Reviewing the detailed nature of these mecha-nisms is outside the scope of this review, but there are anumber of complex molecular and cellular signalingpathways outlined in the Central Illustration.

THOMBOTIC MILIEU: EMERGING RELATIONSHIP BETWEEN

SHEAR STRESS AND PLATELET ACTIVATION. Plateletaggregation is a physiological prerequisite at sites ofarterial injury to arrest bleeding, allowing arterialrepair. Nevertheless, an exaggerated platelet responseat the site of a stenotic vulnerable plaque can lead toacute coronary syndrome. Platelets preferentiallyadhere to the low–shear stress zones (typically locatedat the downstream face), forming thrombi as aconsequence of disturbed blood flow hemodynamicstatus (52). Yong et al. (7) showed in humans thatcoronary artery stenosis severity correlates with shearstress and markers of platelet activation. Shear ap-pears to be a critical determinant of platelet activationand thus an important determinant of plaque vulner-ability and propensity to acute coronary syndrome.

RELATIONSHIP BETWEEN SHEAR STRESS, PLAQUE

PROGRESSION, AND RUPTURE. Depending on theplaque shape, a stenosis results in a concomitantspread of ESS, with relatively low ESS occurring inthe upstream shoulder of the plaque, high ESS atthemost stenotic site of the plaque, and low oscillatoryESS at the downstream shoulder (6,53). A sustainedlow ESS environment drives excessive inflammation,lipid accumulation, and matrix degradation, leadingto fragility and a propensity to rupture. Thesesites demonstrate augmented messenger ribonucleicacid expression with increased expression ofmatrix-degrading proteases, thereby shifting plaque

CENTRAL ILLUSTRATION Ischemic and Physiological Factors Contributing to Plaque Vulnerability

Ford, T.J. et al. J Am Coll Cardiol Intv. 2017;10(24):2539–47.

This schematic demonstrates the conceptual links among coronary physiology, hemodynamic sheer forces, and pathophysiology of plaque vulnerability.

ESS ¼ endothelial shear stress; FFR ¼ fractional flow reserve; IFN ¼ interferon; IL ¼ interleukin; LDL ¼ low-density lipoprotein cholesterol; MMP ¼ matrix

metalloproteinase; NO ¼ nitric oxide; PDGF ¼ platelet-derived growth factor; ROS ¼ reactive oxygen species; SMC ¼ smooth muscle cell; TGF ¼ transforming growth

factor; TNF ¼ tumor necrosis factor; VCAM ¼ vascular cell adhesion molecule; VEGF ¼ vascular endothelial growth factor.

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progression toward atheroma with a thin fibrous cap(54). Positive (expansive) remodeling maintainsluminal patency at the expense of perpetuating a low-ESS environment locally, allowing ongoing lipidaccumulation and inflammation and enhancing theplaque’s vulnerable characteristics (55). In vivo humanstudies using computed tomography–derived coro-nary artery reconstructions revealed lower averagewall shear stress to be a sensitive predictor of plaquelocation (56). More recently, optical coherence tomo-graphic vascular profiling after ACS showed that cor-onary regions exposed to low ESS are associated withlarger lipid burdens, thinner fibrous caps, and a higherprevalence of TCFA (57). Low ESS was associated withincreased plaque burden on longitudinal follow-up. Incontrast, high ESS at the site of maximal stenosis mayincrease the strain and erosion of the fibrous cap withincreased thrombogenicity and the potential for pla-que destabilization (58,59). In vivo imaging of culpritarteries using intravascular ultrasound supports a roleof high ESS in fibrous cap rupture (60).

Prospective in vivo studies of atherosclerosis haveonly limited accuracy in predicting future events onthe basis of anatomic plaque characteristics alone(13,61,62). The PREDICTION (Prediction of Progres-sion of Coronary Artery Disease and Clinical OutcomeUsing Vascular Profiling of Shear Stress and WallMorphology) study is the largest prospective obser-vational study of the impact of wall shear stress andmorphology on clinical outcomes, allowing insightsinto the natural history of coronary atherosclerosis.A combination of low local ESS, large plaque burden,and a large necrotic core had a positive predictivevalue of 53% for identifying coronary lesions leadingto cardiac events. Low ESS was an independent pre-dictor of worsening luminal obstruction both in thenatural history of CAD and in the development ofclinically relevant lesions treated with PCI (63).

In summary, low ESS is a pathophysiologicalparameter important in localization of plaque burdenand also correlates with features of vulnerability.High ESS may occur concurrently at the “neck” of a

FIGURE 3 Contemporary Premise on the Natural History of Coronary Plaques

Drivers toward acute coronary syndromes include local features of plaque vulnerability combined with systemic inflammatory factors and thrombotic milieu in the

vulnerable patient.

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stenosis, increasing in magnitude with progressiveluminal encroachment. This enhances local throm-bogenicity and triggers molecular pathways impli-cated in fibrous cap disruption, increasing theprobability of clinical manifestation as ACS.

FUTURE DIRECTIONS: NATURAL HISTORY OF

PLAQUES, INFLAMMATION, AND

PLAQUE VULNERABILITY

The pathobiology of atherosclerotic lesions is adynamic process (Figure 3).

TCFAs are common and can be found in themajorityof patients presenting with ACS (37,64). Nevertheless,the risk of an individual TCFA causing ACS is small,and the natural history of these lesions varies from anindolent course, transforming into more stable plaquetypes (65), or alternatively progressive luminalobstruction may occur in a stepwise fashion following

asymptomatic rupture (19,66). In vivo and patholog-ical studies support the concept that plaque rupturesare more likely to be symptomatic if they occur at thesite of a severe stenosis with resultant thrombuspotentiating abrupt vessel occlusion (15,67).

The translation of a “vulnerable plaque” to a“vulnerable patient” involves all 3 components ofVirchow’s triad: altered coagulation or thrombosis,endothelial dysfunction, and hemodynamic factors.This concept of the “vulnerable patient” is key; effortsto treat the entire diffuse atherosclerotic processmedically are paramount (68). Intravascular imagingtechniques allow detailed lesion characterization buthave not been proved to reduce events by directingpercutaneous treatment (e.g., PCI). This reflects thedynamic nature of intracoronary plaques and the lowspecificity of intravascular imaging in predictinglesion-specific future MACEs. FFR is currently themost robust tool in identifying lesions with ischemic

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potential (often correlating with markers of plaquevulnerability), allowing targeted intervention insymptomatic patients with the aim of reducing futureMACEs.

CONCLUSIONS

Plaque vulnerability may result from the hemody-namic perturbations and altered biomechanicalforces that associate with the functional significanceof a coronary artery stenosis (and downstreamischemia). There is interplay and synergy among thedegree of luminal obstruction, ischemia, shear stress,activation of blood cells, and subsequent vascular

remodeling. Plaque vulnerability is determined bymore than anatomy: coronary physiology is a pre-dictor of plaque behavior and complements infor-mation from angiography identifying high-risklesions and guiding revascularization to optimizepatient outcome. Future refinements in the use ofcoronary physiology may prove useful in the identi-fication and treatment of both the vulnerable plaqueand the vulnerable patient.

ADDRESS FOR CORRESPONDENCE: Prof. Martin K.C.Ng, Royal Prince Alfred Hospital, Department ofCardiology, Missenden Road, Camperdown, NSW2050, Australia. E-mail: mkcng@med.usyd.edu.au.

RE F E RENCE S

1. Pijls NH, van Son JA, Kirkeeide RL, De Bruyne B,Gould KL. Experimental basis of determiningmaximum coronary, myocardial, and collateralblood flow by pressure measurements for assess-ing functional stenosis severity before and afterpercutaneous transluminal coronary angioplasty.Circulation 1993;87:1354–67.

2. De Bruyne B, Baudhuin T, Melin JA, et al. Coro-nary flow reserve calculated from pressure mea-surements in humans. Validation with positronemission tomography. Circulation 1994;89:1013–22.

3. De Bruyne B, Fearon WF, Pijls NH, et al. Frac-tional flow reserve-guided PCI for stable coronaryartery disease. N Engl J Med 2014;371:1208–17.

4. Bech GJ, De Bruyne B, Pijls NH, et al.Fractional flow reserve to determine the appro-priateness of angioplasty in moderate coronarystenosis: a randomized trial. Circulation 2001;103:2928–34.

5. Johnson NP, Kirkeeide RL, Gould KL. Coronaryanatomy to predict physiology: fundamentallimits. Circ Cardiovasc Imaging 2013;6:817–32.

6. Wentzel JJ, Chatzizisis YS, Gijsen FJ,Giannoglou GD, Feldman CL, Stone PH. Endothe-lial shear stress in the evolution of coronaryatherosclerotic plaque and vascular remodelling:current understanding and remaining questions.Cardiovasc Res 2012;96:234–43.

7. Yong AS, Pennings GJ, Chang M, et al. Intra-coronary shear-related up-regulation of plateletP-selectin and platelet-monocyte aggregationdespite the use of aspirin and clopidogrel. Blood2011;117:11–20.

8. Fearon WF. Is a myocardial infarction morelikely to result from a mild coronary lesion or anischemia-producing one? Circ Cardiovasc Interv2011;4:539–41.

9. Topol EJ, Nissen SE. Our preoccupation withcoronary luminology: the dissociation betweenclinical and angiographic findings in ischemic heartdisease. Circulation 1995;92:2333–42.

10. Glagov S, Weisenberg E, Zarins CK,Stankunavicius R, Kolettis GJ. Compensatoryenlargement of human atherosclerotic coronaryarteries. N Engl J Med 1987;316:1371–5.

11. Tobis J, Azarbal B, Slavin L. Assessment of inter-mediate severity coronary lesions in the catheteriza-tion laboratory. J Am Coll Cardiol 2007;49:839–48.

12. Virmani R, Kolodgie FD, Burke AP, Farb A,Schwartz SM. Lessons from sudden coronarydeath: a comprehensive morphological classifica-tion scheme for atherosclerotic lesions. Arte-rioscler Thromb Vasc Biol 2000;20:1262–75.

13. Stone GW, Maehara A, Lansky AJ, et al.A prospective natural-history study of coronaryatherosclerosis. N Engl J Med 2011;364:226–35.

14. Manoharan G, Ntalianis A, Muller O, et al.Severity of coronary arterial stenoses responsiblefor acute coronary syndromes. Am J Cardiol 2009;103:1183–8.

15. Narula J, Nakano M, Virmani R, et al. Histo-pathologic characteristics of atherosclerotic coro-nary disease and implications of the findings forthe invasive and noninvasive detection of vulner-able plaques. J Am Coll Cardiol 2013;61:1041–51.

16. Motoyama S, Sarai M, Harigaya H, et al.Computed tomographic angiography characteris-tics of atherosclerotic plaques subsequentlyresulting in acute coronary syndrome. J Am CollCardiol 2009;54:49–57.

17. Otsuka K, Fukuda S, Tanaka A, et al. Napkin-ring sign on coronary CT angiography for theprediction of acute coronary syndrome. J Am CollCardiol Img 2013;6:448–57.

18. Motoyama S, Kondo T, Sarai M, et al. Multislicecomputed tomographic characteristics of coronarylesions in acute coronary syndromes. J Am CollCardiol 2007;50:319–26.

19. Burke AP, Kolodgie FD, Farb A, et al. Healedplaque ruptures and sudden coronary death: evi-dence that subclinical rupture has a role in plaqueprogression. Circulation 2001;103:934–40.

20. Pavin D, Delonca J, Siegenthaler M, Doat M,Rutishauser W, Righetti A. Long-term (10 years)prognostic value of a normal thallium-201myocardial exercise scintigraphy in patients withcoronary artery disease documented by angiog-raphy. Eur Heart J 1997;18:69–77.

21. Vanzetto G, Ormezzano O, Fagret D, Comet M,Denis B, Machecourt J. Long-term additive

prognostic value of thallium-201 myocardialperfusion imaging over clinical and exercise stresstest in low to intermediate risk patients: study in1137 patients with 6-year follow-up. Circulation1999;100:1521–7.

22. Shaw LJ, Iskandrian AE. Prognostic value ofgated myocardial perfusion SPECT. J Nucl Cardiol2004;11:171–85.

23. Buckert D, Dewes P, Walcher T, Rottbauer W,Bernhardt P. Intermediate-term prognostic valueof reversible perfusion deficit diagnosed byadenosine CMR: a prospective follow-up study in aconsecutive patient population. J Am Coll CardiolImg 2013;6:56–63.

24. Vincenti G, Masci PG, Monney P, et al. Stressperfusion CMR in patients with known and sus-pected CAD: prognostic value and optimalischemic threshold for revascularization. J Am CollCardiol Img 2017;10:526–37.

25. Mancini GB, Hartigan PM, Shaw LJ, et al. Pre-dicting outcome in the COURAGE trial (ClinicalOutcomes Utilizing Revascularization and Aggres-sive Drug Evaluation): coronary anatomy versusischemia. J Am Coll Cardiol Intv 2014;7:195–201.

26. Mancini GB, Hartigan PM, Bates ER, et al.Angiographic disease progression and residual riskof cardiovascular events while on optimal medicaltherapy: observations from the COURAGE trial.Circ Cardiovasc Interv 2011;4:545–52.

27. Shaw LJ, Weintraub WS, Maron DJ, et al. Base-line stressmyocardial perfusion imaging results andoutcomes in patients with stable ischemic heartdisease randomized to optimal medical therapywith or without percutaneous coronary interven-tion. Am Heart J 2012;164:243–50.

28. Chang SM, Nabi F, Xu J, et al. The coronaryartery calcium score and stress myocardial perfu-sion imaging provide independent and comple-mentary prediction of cardiac risk. J Am CollCardiol 2009;54:1872–82.

29. Schepis T, Benz K, Haldemann A,Kaufmann PA, Schmidhauser C, Frielingsdorf J.Prognostic value of stress-gated 99m-technetiumSPECT myocardial perfusion imaging: risk stratifi-cation of patients with multivessel coronary artery

J A C C : C A R D I O V A S C U L A R I N T E R V E N T I O N S V O L . 1 0 , N O . 2 4 , 2 0 1 7 Ford et al.D E C E M B E R 2 6 , 2 0 1 7 : 2 5 3 9 – 4 7 Physiological Predictors of Acute Coronary Syndromes

2547

disease and prior coronary revascularization.J Nucl Cardiol 2013;20:755–62.

30. Acampa W, Petretta M, Evangelista L, et al.Stress cardiac single-photon emission computedtomographic imaging late after coronary arterybypass surgery for risk stratification and estima-tion of time to cardiac events. J Thorac CardiovascSurg 2008;136:46–51.

31. Zimmermann FM, Ferrara A, Johnson NP, et al.Deferral vs. performance of percutaneous coro-nary intervention of functionally non-significantcoronary stenosis: 15-year follow-up of theDEFER trial. Eur Heart J 2015;36:3182–8.

32. Pijls NH, van Schaardenburgh P, Manoharan G,et al. Percutaneous coronary intervention offunctionally nonsignificant stenosis: 5-yearfollow-up of the DEFER Study. J Am Coll Cardiol2007;49:2105–11.

33. Johnson NP, Toth GG, Lai D, et al. Prognosticvalue of fractional flow reserve: linking physio-logic severity to clinical outcomes. J Am CollCardiol 2014;64:1641–54.

34. Barbato E, Toth GG, Johnson NP, et al.A prospective natural history study of coronaryatherosclerosis using fractional flow reserve. J AmColl Cardiol 2016;68:2247–55.

35. Versteeg D, Hoefer IE, Schoneveld AH, et al.Monocyte Toll-like receptor 2 and 4 responses andexpression following percutaneous coronaryintervention: association with lesion stenosis andfractional flow reserve. Heart 2008;94:770–6.

36. Reith S, Battermann S, Jaskolka A, et al.Relationship between optical coherence tomog-raphy derived intraluminal and intramural criteriaand haemodynamic relevance as determined byfractional flow reserve in intermediate coronarystenoses of patients with type 2 diabetes. Heart2013;99:700–7.

37. Yonetsu T, Kakuta T, Lee T, et al. In vivo criticalfibrous cap thickness for rupture-prone coronaryplaques assessed by optical coherence tomogra-phy. Eur Heart J 2011;32:1251–9.

38. Falk E, Nakano M, Bentzon JF, Finn AV,Virmani R. Update on acute coronary syndromes:the pathologists’ view. Eur Heart J 2013;34:719–28.

39. Puchner SB, Liu T, Mayrhofer T, et al. High-riskplaque detected on coronary CT angiography pre-dicts acute coronary syndromes independent of sig-nificant stenosis in acute chest pain: results from theROMICAT-II trial. J AmColl Cardiol 2014;64:684–92.

40. Motoyama S, Ito H, Sarai M, et al. Plaquecharacterization by coronary computed tomogra-phy angiography and the likelihood of acute cor-onary events in mid-term follow-up. J Am CollCardiol 2015;66:337–46.

41. Tian J, Dauerman H, Toma C, et al. Prevalenceand characteristics of TCFA and degree of coronaryartery stenosis: an OCT, IVUS, and angiographicstudy. J Am Coll Cardiol 2014;64:672–80.

42. Otsuka F, Joner M, Prati F, Virmani R, Narula J.Clinical classification of plaque morphology incoronary disease. Nat Rev Cardiol 2014;11:379–89.

43. Chatzizisis YS, Coskun AU, Jonas M,Edelman ER, Feldman CL, Stone PH. Role of

endothelial shear stress in the natural history ofcoronary atherosclerosis and vascular remodeling:molecular, cellular, and vascular behavior. J AmColl Cardiol 2007;49:2379–93.

44. Choi G, Lee JM, Kim HJ, et al. Coronary arteryaxial plaque stress and its relationship with lesiongeometry: application of computational fluid dy-namics to coronary CT angiography. J Am CollCardiol Img 2015;8:1156–66.

45. Li Y, Gutiérrez-Chico JL, Holm NR, et al.Impact of side branch modeling on computation ofendothelial shear stress in coronary artery disease.J Am Coll Cardiol 2015;66:125–35.

46. Maurovich-Horvat P, Ferencik M, Voros S,Merkely B, Hoffmann U. Comprehensive plaqueassessment by coronary CT angiography. Nat RevCardiol 2014;11:390–402.

47. Taylor CA, Fonte TA, Min JK. Computationalfluid dynamics applied to cardiac computed to-mography for noninvasive quantification of frac-tional flow reserve: scientific basis. J Am CollCardiol 2013;61:2233–41.

48. Douglas PS, De Bruyne B, Pontone G, et al.1-Year outcomes of FFRCT-guided care in patientswith suspected coronary disease: the PLATFORMstudy. J Am Coll Cardiol 2016;68:435–45.

49. Caro CG, Fitz-Gerald JM, Schroter RC.Atheroma and arterial wall shear. Observation,correlation and proposal of a shear dependentmass transfer mechanism for atherogenesis. ProcR Soc Lond B Biol Sci 1971;177:109–59.

50. Ku DN GD, Zarins CK, Glagov S. Pulsatile flowand atherosclerosis in the human carotid bifurca-tion. Positive correlation between plaque locationand low oscillating shear stress. ArteriosclerThromb Vasc Biol 1985;5:293–302.

51. Gimbrone MA Jr., Topper JN, Nagel T,Anderson KR, Garcia-Cardena G. Endothelialdysfunction, hemodynamic forces, and athero-genesis. Ann N Y Acad Sci 2000;902:230–9.

52. Nesbitt WS, Westein E, Tovar-Lopez FJ, et al.A shear gradient-dependent platelet aggregationmechanism drives thrombus formation. Nat Med2009;15:665–73.

53. Gijsen FJ, Wentzel JJ, Thury A, et al. Straindistribution over plaques in human coronary ar-teries relates to shear stress. Am J Physiol HeartCirc Physiol 2008;295:H1608–14.

54. Chatzizisis YS, Baker AB, Sukhova GK, et al.Augmented expression and activity of extracel-lular matrix-degrading enzymes in regions of lowendothelial shear stress colocalize with coronaryatheromata with thin fibrous caps in pigs. Circu-lation 2011;123:621–30.

55. Baker AB, Chatzizisis YS, Beigel R, et al.Regulation of heparanase expression in coronaryartery disease in diabetic, hyperlipidemic swine.Atherosclerosis 2010;213:436–42.

56. Rikhtegar F, Knight JA, Olgac U, et al.Choosing the optimal wall shear parameter for theprediction of plaque location—a patient-specificcomputational study in human left coronary ar-teries. Atherosclerosis 2012;221:432–7.

57. Vergallo R, Papafaklis MI, Yonetsu T, et al.Endothelial shear stress and coronary plaquecharacteristics in humans: combined frequency-domain optical coherence tomography andcomputational fluid dynamics study. Circ Car-diovasc Imaging 2014;7:905–11.

58. Kwak BR, Back M, Bochaton-Piallat ML, et al.Biomechanical factors in atherosclerosis: mecha-nisms and clinical implications. Eur Heart J 2014;35:3013–20.

59. Samady H, Eshtehardi P, McDaniel MC, et al.Coronary artery wall shear stress is associated withprogression and transformation of atheroscleroticplaque and arterial remodeling in patients withcoronary arterydisease. Circulation2011;124:779–88.

60. Fukumoto Y, Hiro T, Fujii T, et al. Localizedelevation of shear stress is related to coronaryplaque rupture. J Am Coll Cardiol 2008;51:645–50.

61. Cheng JM, Garcia-Garcia HM, de Boer SP, et al.In vivo detection of high-risk coronary plaques byradiofrequency intravascular ultrasound and car-diovascular outcome: results of the ATHEROREMO-IVUS study. Eur Heart J 2014;35:639–47.

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

63. Stone PH, Saito S, Takahashi S, et al. Predic-tion of 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.

64. KuboT, Imanishi T, Takarada S, et al. Assessmentof culprit lesion morphology in acute myocardialinfarction: ability of optical coherence tomographycompared with intravascular ultrasound and coro-nary angioscopy. J Am Coll Cardiol 2007;50:933–9.

65. Kubo T, Maehara A, Mintz GS, et al. The dy-namic nature of coronary artery lesionmorphology assessed by serial virtual histologyintravascular ultrasound tissue characterization.J Am Coll Cardiol 2010;55:1590–7.

66. Takano M, Murakami D, Yamamoto M, Seino Y,Mizuno K. Natural history of a thin-cap fibroa-theroma: serial observations by optical coherencetomography. Circ Cardiovasc Interv 2011;4:638–9.

67. Fujii K, Kobayashi Y, Mintz GS, et al. Intravas-cular ultrasound assessment of ulcerated rupturedplaques: a comparison of culprit and nonculprit le-sions of patients with acute coronary syndromesand lesions in patients without acute coronarysyndromes. Circulation 2003;108:2473–8.

68. Arbab-Zadeh A, Fuster V. The myth of the“vulnerable plaque”: transitioning from a focus onindividual lesions to atherosclerotic diseaseburden for coronary artery disease risk assess-ment. J Am Coll Cardiol 2015;65:846–55.

KEY WORDS acute coronary syndromes(s),coronary physiology, endothelial shearstress, mechanisms of atherosclerosis,plaque vulnerability