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iVIEWE D I T O R ’ S P A G E

The Myth of the Mild Vulnerable Plaques

Gregg W. Stone, MD,* Jagat Narula, MD, PHDy

ew core concepts introduced in the pastseveral decades have become more ingrained

in the psyche of the cardiologist such as thebelief that coronary occlusion and myocardial

infarction most frequently evolve from a mildlystenotic coronary artery disease (1). This perceptionowes its origin to the observations made 25 years agothat among patients in whom coronary angiographyhad been performed at some point, days to yearsbefore a myocardial infarction, the lesion responsiblefor the subsequent infarct was angiographically lessthan severe in the majority of cases (2,3). Over theyears, this hypothesis has been supported by otherangiographic studies, most convincingly from theNational Heart, Lung, and Blood Institute’s Dy-namic Registry (4), the PROSPECT (Predictors ofResponse to Cardiac Resynchronization Therapy)trial (5), and the COURAGE (Clinical OutcomesUtilizing Revascularization and Aggressive DrugEvaluation) trial (6), although notably challenged byCASS (Coronary Artery Surgery Study) (7). How-ever, all these studies do not take into account theinterval progression of lesion severity that may occurbefore coronary thrombosis. Angiographic studiesperformed during a myocardial infarction purportingto reveal underlying plaque severity after thrombol-ysis (8) or aspiration (9) are less compelling giventhe inability of these modalities to completelyremove thrombus. Although fraught with selectionbias, a pathologic study of patients recently dyingafter myocardial infarction or sudden cardiac deathhas suggested that the fateful plaques were almostalways at least moderately occlusive and that thevulnerable plaques probably expanded in size beforethey ruptured (10). PROSPECT (5), which reliedon intravascular imaging rather than angiography,suggested that the lesions responsible for future

From the *Columbia University Medical Center and the Cardiovascular

Research Foundation, New York, New York; and the yIcahn School of

Medicine at Mount Sinai, New York, New York.

acute coronary syndromes (ACS) were indeed notmild but rather were in all cases moderate or severe.

In this issue of iJACC, we posed the question “Arethe culprit lesions severely stenotic?” and received 2diametrically opposed opinions from Niccoli et al.(No!), and Ambrose and Berg (Yes!) (11). Bothgroups buttress their positions with detailed datafrom studies correlating imaging results with clinicalend points. Each treatise also discusses the limitationsof the published studies. Thus, how can we reconcilethese conflicting results? Or are both positions correct(and if so, how is this possible)? The answer lies inunderstanding the limitations of coronary angiog-raphy as an imaging method (12). First, the angio-gram is in fact a “luminogram,” incapable of revealingplaque that resides in the vascular tunica mediaand adventitia that does not narrow the innerdiameter of the coronary vessel (13). This is partic-ularly relevant because plaque accumulation results invessel expansion before luminal compromise (14).This compensatory mechanism is usually overcomewhen the plaque occupies approximately 40% ofcross-sectional vascular area (or plaque burden),with progressive atherosclerosis thereafter resultingin luminal encroachment. Thus, by the time a lesionin a coronary artery with a 3.0-mm reference vesseldiameter appears angiographically mild (e.g., 33%diameter stenosis), the external elastic membrane ofthe vessel may have swollen to 5.5 mm or greater, andthe plaque burden may in truth be>85%. Indeed, thefact that coronary angiography can markedly under-estimate the pathologic degree of atherosclerosis waselegantly demonstrated 40 years ago (15). Second,the angiogram is a 2-dimensional representationof a complex 3-dimensional structure. Given plaqueeccentricity (which is the rule rather than theexception), angiography may either overestimateor underestimate the true cross-sectional lesionseverity, depending on the incident angle of the x-ray beam as it transects the narrowed lumen(10,13). For all of these reasons, the angiogram is agold standard, which we should not rely uponfor lesion analysis. In this regard, tomographic

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imaging techniques are more accurate, using pa-thology as a gold standard (10).

When trying to weigh the strength of data fromconflicting sources, the strongest evidence usuallyresides in prospective studies formulated to answerthe issue in question. In this regard, the multicenterPROSPECT study was designed to overcome thelimitations of prior studies, prospectively enrolling697 patients in whom angiography and 3-vesselintravascular imaging with grayscale and radio-frequency ultrasound was performed to characterizethose untreated nonculprit lesions responsible forfuture ACS events (5). With median follow-up of3.4 years, the strongest predictor of future eventswas the intravascular ultrasound (IVUS)–derivedplaque burden at the nonculprit lesion. The perlesion event rate was 9.5% for the 298 untreatedlesions in which plaque burden was $70%, 2.5% forthe 798 lesions in which plaque burden was$60% to70%, and <0.5% for thousands of lesions with<60% plaque burden (16). Indeed, not a singleadverse event arose from a segment of the coronarytree with <40% plaque burden. The minimalluminal area was also an independent predictor offuture ACS events. And given the space occupyingnature of the measuring catheter, IVUS may un-derestimate the true severity of lesions with thegreatest luminal narrowing. Of note, although le-sions destined to cause future ACS were severe byIVUS, by quantitative coronary angiography, themean angiographic diameter stenosis of these lesionswas only 32.3%, although they did progress to 65.4%at the time of the future event, consistent with rapidlesion progression due to plaque rupture and/orcoronary thrombosis. The fact that plaque burdenwas the most powerful predictor of future ACS

events was subsequently confirmed in the single-center prospective VIVA (VH-IVUS in VulnerableAtherosclerosis) study, which was of similar designas PROSPECT (17). The information availablefrom the analyses of pathological specimens thatcompared the vulnerable plaques and ruptured pla-ques demonstrated that the plaque burden wassubstantially higher in the latter; this indirectlysuggested that the plaques expand further beforerupture.

PROSPECT (and VIVA) have thus demonstratedthat lesions responsible for future major adverse car-diac events are both mild and severe: mild by angi-ography (as defined by the luminal diameter stenosisrelative to the adjacent reference lumens) but severe byIVUS (as defined by large atheroma volume withsevere cross-sectional area narrowing), the latter moreaccurately reflecting the truth. These studies have alsosuggested that the lesions must further expand duringthe interval between the initial assessment of vulner-able lesion and the subsequent event (10). This ismechanistically credible, because studies have re-ported that the greater the volume of atheroma, thegreater the burden of lipid and necrotic core, thethinner the fibrous cap, the more severe the inflam-mation, the more deranged the vaso vasorum, and themore abnormal the stress-strain relationships (18,19).Should we then bury the myth that vulnerable plaquesare milddand stop relying on coronary angiographyfor sophisticated lesion analysis?

Address for correspondence: Dr. Jagat Narula, IcahnSchool of Medicine at Mount Sinai, Mount Sinai Heart,One Gustave L. Levy Place, Mail box 1030, New York,New York 10029. E-mail: jagat.narula@mountsinai.org.

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