Plaque rupture relationship to plaque composition in coronary arteries. A 320-slice CT angiographic analysis

Original Article

Plaque rupture relationship to plaque compositionin coronary arteries. A 320-slice CT angiographicanalysis

Rochita Venkata Ramanan *

Department of Radiology, Apollo Hospitals, Chennai, India

1. Introduction

Cardiovascular deaths account for 30% of all deaths world-wide.1 Coronary thrombosis leading to myocardial ischemia

is now recognized as a diverse process arising from rupture orerosion of atherosclerotic plaques or presence of calcifiednodules within them.2 Majority of acute coronary syndromesare caused by plaque rupture in segments with 50% orless stenosis, which are asymptomatic prior to the event.3

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a r t i c l e i n f o

Article history:

Received 8 April 2015

Accepted 6 May 2015

Available online 6 June 2015

Keywords:

Plaque rupture

Mixed plaque

Soft plaque

Vulnerable plaque

CT angiography

a b s t r a c t

Background: Coronary thrombosis leading to myocardial ischemia is now recognized as a

diverse process arising from plaque rupture, erosion, or calcified nodules. These vulnerable

plaquesmay not always cause significant stenosis of the artery, and therefore bemissed on an

invasive catheter angiogram(ICA). Theadventofmultidetector computed tomography (MDCT)

imaging of the walls of the coronary artery has opened a unique window to these vulnerable

plaques. Differentiation of calcified plaques from soft plaques presents no challenge on CT.

Further characterization of the plaque into a ruptured plaque is possible by demonstration of

discontinuity of the plaque surface and contrast pooling within the plaque substance.

Purpose: To study the relation between coronary artery plaque rupture and plaque compo-

sition.

Materials and methods: 500 patients referred for coronary CT angiogram between 2008 and

2013, who had plaque thicknesses of 2 mmormore, were included in the study. The plaques

were divided into totally calcified, mixed, and soft categories. The totally calcified plaques

were excluded from the study as none of these showed signs of plaque rupture. A total

number of 2667 mixed and soft plaques were included in the study.

Results: 52% of the total plaques were ruptured and 48% not ruptured. Of the ruptured

plaques, 96.9% were mixed type and only 3.7% were soft. And of the non-ruptured plaques,

96.3% were soft and only 3.1% mixed ( p < 0.0001).

Conclusion: This study reveals that plaque rupture is significantly associated with mixed

plaques containing soft and calcific areas rather than purely soft plaques.

# 2015 Indraprastha Medical Corporation Ltd. Published by Elsevier B.V. All rights

reserved.

* Correspondence to: No. 34, Srinivasa Murthy Avenue, Off LB Road, Adayar, Chennai 600020, Tamil Nadu, India. Tel.: +91 44 24417055;mobile: +91 9840024528.

E-mail address: rochitav@yahoo.com

Available online at www.sciencedirect.com

ScienceDirect

journal homepage: www.elsevier.com/locate/apme

http://dx.doi.org/10.1016/j.apme.2015.05.0080976-0016/# 2015 Indraprastha Medical Corporation Ltd. Published by Elsevier B.V. All rights reserved.

Patients with ST elevation myocardial infarction caused byplaque rupture show a higher incidence of no-reflow, highercreatine-kinase levels, and lower ejection fractions.4 Needlessto say, that the hunt for the vulnerable plaque, which causesacute coronary syndromes, is being passionately pursued allover the world.

However, this exercise has presented significant obstacles.Animal models have led to an incomplete understanding ofthe progression of a stable fibroatheroma to a ruptured plaque.This is because mouse models rarely progress to plaquerupture.5 Histologic processing of plaques in search of thevulnerable plaque has also been challenging. It requiresfixation, dehydration, and some degree of decalcificationbefore paraffin embedding to allow sectioning and therebyleads to distortion of morphology and loss of information. Italso causes mechanical and physiochemical artifacts, such asshrinkage of the specimen and does not allow obtainingadjacent sections.

Coronary Computed Tomographic Angiography (CCTA)with its non-invasive cross-sectional information has seenremarkable growth in recent years. The 320-slice CTA is a newgeneration scanner, which can scan thewhole heart in a singlebeat giving clear images of plaques and their morphology.Recent studies show that percent diameter stenosis deter-mined with the use of 320-slice CCTA shows good correlationwith invasive catheter angiogram (ICA) (p < 0.0001).6 Differen-tiation of calcified from soft plaques presents no challenge onCCTA. Further characterization of the plaque into a rupturedplaque is now possible by demonstration of intraluminalcontrast pooling into the plaque substance.7

The objective of this study is to evaluate the relationshipbetween coronary arterial plaque rupture and plaque compo-sition in an attempt to determine whether soft or mixedplaques are more prone to rupture.

2. Materials and methods

Between 2008 and 2013, five hundred patients with plaquethickness of 2 mm and above were included in the study.Plaques thinner than 2 mmwere excluded, as it was difficult todetermine presence of small calcium specks or ulcerationswithin them. 68% patients had chest pain with normal ECGand negative cardiac biomarkers, and hence a CCTA wasordered to rule out coronary artery disease (CAD). 32% patientswere asymptomatic, but had borderline treadmill tests.CCTA was ordered to rule out CAD. 87% were men and 13%were women. 58% were hypertensives, 43% were diabetics,41% dyslipidemics, 37% smokers, and 46% had a family historyof coronary artery disease. None of the patients had had anycardiac interventions or surgery. The CCTA was performedusing a 320-slice CT scanner (Aquilion One, Toshiba MedicalSystems, Tokyo, Japan). Intravenous contrast used wasOptiray 350 mg (Mallinckrodt, USA). Patients with heart ratesmore than 80 and no contraindication to beta-blockers wereadministered oral Metoprolol up to 100 mg to reduce the heartrate prior to the scan. A sublingual nitroglycerine tablet of 5 mgwas used 10 min prior to the scan. A plain ECG gated scan wasperformed for calcium score followed by a contrast enhancedscan through the heart after 65 ml of intravenous contrast

injection at the rate of 4.5 ml/s with a pressure injector chasedby a bolus of 30 ml of normal saline at the same rate. Theimages were interpreted by a senior radiologist on curvedreconstructions through the vessel lumen as well as the crosssections at a dedicated workstation.

The plaques were divided into totally calcified, mixed, andsoft. Plaques with no calcium were considered soft, andplaques with presence of calcium within a soft componentwere considered mixed. Plaque rupture was identified bydemonstration of discontinuity of the plaque surface andcontrast pooling within the plaque substance (Figs. 1 and 2).Completely calcified plaques were excluded, as none of themrevealed signs of plaque rupture. A total of 2667mixed and softplaques were included in the study.

2.1. Statistical analysis

The statistical analysis was performed per plaque and not perpatient. p-Values were calculated. In all tests, differences wereconsidered not significant when p > 0.05.

3. Results

52% of the total plaques were ruptured, and 48% were notruptured. It was observed that out of the ruptured plaques,96.9% were mixed type, and only 3.7% were soft. And of thenon-ruptured plaques, 96.3% were soft, and only 3.1% weremixed (p < 0.0001) (Fig. 3). This demonstrated that mixedplaques were more prone to rupture than soft plaques.

4. Discussion

4.1. Classification of atherosclerotic plaques

Human atherosclerotic lesions are classified based on theirhistological composition and structure8 (Fig. 4). The initial TypeI lesion contains enough atherogenic lipoprotein to elicit anincrease in macrophages and formation of scattered macro-phage foam cells. Type II lesions consist primarily of layers ofmacrophage foam cells and lipid-laden smooth musclecells and include lesions grossly designated as fatty streaks.Type I and II are early lesions. Type III is the intermediate lesion.In addition to the lipid-laden cells of Type II, Type III lesionscontain scattered collections of extracellular lipid droplets andparticles that disrupt the coherence of some intimal smoothmuscle cells. This extracellular lipid is the immediateprecursor of the larger, confluent, and more disruptive coreof extracellular lipid that characterizes Type IV lesions. Type IVlesions would be visible on CCTA as soft plaques withhomogeneous low-density focal thickenings of the arterialwall with a smooth convex surface towards the lumen. Type Ilesions would be too small to be visible on CTA, and Type II andIII lesionsmayappear as just a thin focal thickening of thewall.Types I–IV are clinically silent and cause no symptoms.

Beginning around the fourth decade of life, lesions thatusually have a lipid core may also contain thick layers offibrous connective tissue (Type V lesion) and/or fissure,hematoma, and thrombus (Type VI lesion). Some Type V

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lesions are largely calcified (Type Vb), and some consist mainlyof fibrous connective tissue and a little or no accumulated lipidor calcium (Type Vc). The Types IV–VI are advanced lesions. TheType VI lesions are the ruptured or ulcerated plaques thatwould reveal contrast pooling in their substance on CCTA(Fig. 5). These lesions are responsible for symptomatic CADconsisting of angina pectoris, unstable angina, myocardialinfarction, and ischemic sudden death.

4.2. Growth of atherosclerotic plaques to advancedlesions

Seymour Glagov et al. reported in 1987 that two processes areinvolved in the growth of advanced plaques: (1) outwardexpansion of the arterial wall with no luminal compromiseand (2) subclinical plaque rupture of hemodynamicallyinsignificant thin lesions,where the thrombus is incorporatedinto the lesion over years, resulting in greater luminalnarrowing. Luminal compromise only occurs once the plaque

advances beyond 40% narrowing of the arterial cross-sectional area, i.e., when positive remodeling stops. Thus,repeated silent plaque ruptures are the cause of luminalcompromise, which heal and eventually lead to severeluminal narrowing.9

Plaque rupture therefore can be silent and is the mostimportant event that leads not only to acute myocardialinfarction but also to the increase in plaque thickness andprogressive chronic narrowing of coronary arteries. Preventionof such ruptures would have a dramatic control over CAD.

Atherosclerotic plaques considered advanced by theirhistology may or may not narrow the arterial lumen. Thosethat do not narrow the lumen because of outward remodel-ing of the arterial wall are invisible on ICA, but are clearlyseen on CCTA. Furthermore, they may be clinically silent.Such lesions are dangerous because they may lead to acuteocclusion of the lumen by an intraluminal thrombus formingover a ruptured plaque and myocardial infarction maydevelop suddenly.8

[(Fig._1)TD$FIG]

Fig. 1 – Typical soft non-ruptured plaque. A case of mildly positive treadmill test (TMT) in a 56-year-old postmenopausal ladywith positive family history of CAD. The left half shows a volume rendered 3D reconstruction of the heart showing the leftanterior descending artery (LAD). The right half shows the long and cross sections through the LAD. The proximal LADshows a thick soft plaque within white dots. The plaque substance is homogeneous as well as of low density, and thesurface is smooth with no break in continuity to suggest a rupture.

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4.3. Causes of plaque rupture

What causes an atherosclerotic plaque to rupture is anunsolved mystery.

Plaque rupture refers to a lesion consisting of a necroticcore with an overlying thin torn fibrous cap that leads to

luminal thrombosis because of contact of flowing blood with ahighly thrombogenic necrotic core.

Several factors are thought to play a role in causing orfacilitating rupture. These include the presence of inflammato-ry cells in plaques, the release of toxic substances andproteolytic enzymes by macrophages within the plaques,

[(Fig._2)TD$FIG]

Fig. 2 – Typical mixed ruptured plaque. The left half shows a volume rendered 3D reconstruction of the heart showing the LADin a 45-year-old male smoker with atypical chest pain. The right half shows the long and cross sections through the LAD. Theproximal LAD shows a thick mixed plaque, which is made of predominantly soft components with a speck of calcificationjust beneath the cap near the inferior shoulder of the plaque. The plaque surface reveals a discontinuity marked asulceration with contrast from the opacified arterial lumen entering and pooling in the plaque substance.[(Fig._3)TD$FIG]

Fig. 3 – The left panel of the bar chart represents the mixed plaques, and shows that majority of the mixed plaques revealedplaque rupture. The right panel of the bar chart represents soft plaques, and shows that majority of the soft plaques did notreveal signs of plaque rupture.

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coronary spasm, structural weakness related to plaque compo-sition, and shear stress.

4.4. Plaque lipid core causing rupture

The lipid core inside the plaque has been considered to playan important role in rupture. Burke et al. found that 80% ofruptured plaques contained necrotic cores larger than 1.0 mm2,and in nearly 90% the lipid core comprised greater than 10% ofthe plaque area. However, the length of the necrotic coresunderlying fatal and non-fatal plaque ruptures was found tohave a range of as small as 3.5 mm to as long as 22 mm.10

Because of such awide variation of necrotic core size in relationto rupture, it is difficult to assign specific parameters as cut-offpoints for CAD risk prediction. It is not clear, if a large necroticcore in a patient causes plaque rupture, or if local inflammato-ry, hemodynamic shear stress, or other factors are moreimportant causative factors.

4.5. Plaque degradation by macrophages causingrupture

Stary et al. found that tears may occur more frequently inregions of the plaque with many macrophage foam cells.8

Other authors11 also suggested that proteolytic enzymesreleased from macrophages cause matrix degradation andplaque instability. Libby proposed that collagen synthesiswithin the fibrous capwas impaired and thatmatrix degrading

enzymes, amain component of the vast secretory repertoire ofthe macrophage, may ultimately be responsible for thedegradation of the fibrous cap.12

4.6. Hemodynamic shear stress causing rupture

Some authors believe that hemodynamic shear stress is thecausative factor in the destabilization of vulnerable pla-ques.13 It has been observed that plaque rupture occurs morefrequently at the proximal side of the stenosis near bifurca-tions, an area where secondary wall shear stress is assumedto be the highest. Shear stress may also present a significantinfluence on processes that govern fibrous cap morphologyand composition, where increased peak circumferentialstress is greater in thinner fibrous caps.14 Therefore, regionsof high shear stress typically exhibit high strain, thussupporting the notion that mechanical stress applied to aweakened fibrous cap may precipitate rupture. However, it isknown that 40%of ruptures occur in the central part of the caprather than regions of high curvature at the shoulders of thelipid core, where maximum tissue stresses are predicted15

(Fig. 6).

4.7. Plaque calcification causing rupture

Vengrenyuk et al. hypothesized that minute cellular-levelmicro calcifications of typically 10 mm in diameter derivedfrom dead macrophages or smooth muscle cells in the fibrous

[(Fig._4)TD$FIG]

Fig. 4 – Classification of human atherosclerotic lesions based on their histological composition and structure.

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cap can cause its rupture.15 This could explain the paradox asto why rupture does not always occur at the location of whatwas previously thought to be maximal tissue stress. Theyhypothesize that it is because minute spherical calcificationscan increase the local stress around the embedded particle.They also predict that this phenomenon is nearly independentof the size of the particle and relatively insensitive to itsposition in the fibrous cap.

The presence of a calcified cellular inclusion in the shoulderwould therefore be even more dangerous than in the centralportion of the cap, because the background stress here isgreater and its doubling would make this region especiallyvulnerable. They proposed that the site of cap rupture dependson the relative location of both the circumferential stressconcentration, and whether minute cellular-level microcalcification is present in the cap.

Their hypothesis for fibrous cap rupture is inspired by theclassical theoretical studies of Goodier, who examined theeffect of minute solid spherical impurities in rubber tires as acause of their failure. Failure will not occur unless there isdebonding (failure at the tissue–particle interface). The mostfrequent cause of debonding is the formation of a minutecavitation bubble at the interface, which then rapidly expands.

Debonding occurs at the interface between the solid impurityand rubber because of the large mismatch in hardness of thematerials and the local stress concentrations that develop atthe poles of the impurity along the tensile axis as a result ofthismismatch. Another example of the influence of inclusionson the strength ofmaterials is the reduction in fatigue strengthof steels due to the stress concentration introduced by aninclusion. In high-hardness steel, cracks often initiate prefer-entially from non-metallic inclusions either on or beneath afree surface of a specimen and lead to final fracture.15

Rambhia et al. confirmed the above theory by reconstruct-ing a detailed model from a post-mortem coronary specimenof a patient with an observed vulnerable plaque, using high-resolution micro-CT. The superior contrast resolution of thisCT captured the micro calcifications embedded in the fibrouscap, which would otherwise be missed, by the routine CTscanners and IVUS.16 Our findings that plaque rupture isstrongly associated with mixed plaque morphology, wherespecks of calcification are embedded in a background softmatrix, correlate with the above studies (Figs. 7 and 8). This isalso supported by Min et al. who found that the presence ofmixed plaque was associated with the highest likelihoodof major adverse cardiac events within a follow-up period of22 months compared with calcified or purely non-calcifiedplaque in symptomatic patients.17 Other studies confirm theseresults.18 Not only has CCTA shown to provide an additionalincremental prognostic value as compared with a baselineclinical risk model plus calcium scoring, but also plaquecomposition and the presence of soft or mixed plaques,regardless of lesion severity, have been now found to be thestrongest predictor of events as a potential marker of plaquevulnerability (p < 0.0001).19

[(Fig._6)TD$FIG]

Fig. 6 – Central rupture of mixed plaques. A curvedreconstruction through the left aortic sinus, LMCA, and theLAD of a 67-year-old male patient with multiple risk factorsand angina pectoris with negative cardiac biomarkersreveals diffuse plaques. A discrete plaque is seen withinwhite dots in the proximal LAD. There is a central rupturein the plaque surface with the edges marked by straightarrows. Contrast pools within the cavitated plaque belly(arrowhead). Another discrete plaque is seen a little distallywithin star markers. This too reveals a central rupture(curved arrow).

[(Fig._5)TD$FIG]

Fig. 5 – Advanced Type VI ruptured plaque. A curvedreconstruction through the left aortic sinus, left maincoronary artery (LMCA), and the left circumflex artery (LCX)of a 56-year-old male patient with diabetes mellitus,hypertension, unstable angina, and negative cardiacbiomarkers reveals a mixed plaque within white dots. Theplaque reveals soft components proximally and a smallspeck of calcification (arrowhead). At the lower shoulderthe plaque surface reveals a discontinuity (curved arrow)suggestive of rupture. Contrast from the opacified arteriallumen enters the plaque belly through the rupture anddistends it (straight arrow). There is a significant luminalnarrowing.

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[(Fig._7)TD$FIG]

Fig. 7 – Mixed ruptured vs. soft non-ruptured plaque. Curved reconstructions through the LCX (left panel) and LAD (rightpanel) of a 61-year-old male asymptomatic patient with a mildly positive TMT, dyslipidemia, and poorly controlled diabetesmellitus. The square insets show the cross sections through the plaque. The LCX shows twomixed plaques within dots withsurface rupture and intraplaque contrast. The LAD shows a very thick soft plaque with significant positive outwardremodeling (white markers). The plaque shows no calcification and no disruption of its surface. There is no contrast withinthe plaque substance.

[(Fig._8)TD$FIG]

Fig. 8 – Mixed ruptured vs. soft non-ruptured plaque. (A) A collage of curved reconstructions through different arteries ofseveral patients with soft plaques none showing plaque rupture. (B) A collage of mixed plaques all showing plaque rupture.

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However, computational analysis applied to typical stablehuman coronary atherosclerotic plaques reveals that largercalcifications deeper in the intima do not increase fibrous capstress, and bulk calcification does not seem to decrease themechanical stability of the plaque. This strengthening occursbecause the model does not allow for debonding and thecalcification ismore rigid than the surroundingmaterial.20 Ourfinding that none of the totally calcified plaques revealed signsof rupture is consistent with the above.

5. Conclusion

The practice of cardiology today predominantly involvesinterventional therapy in the form of stenting and coronaryartery bypass grafting in order to revascularize significantlynarrowed coronary arteries. While this is essential to treatdeveloping cardiac ischemia and infarction it does not halt theprogression of atherosclerotic plaques and future plaqueruptures. Our study proves that plaque rupture is stronglyassociated with mixed plaques, which have specks ofcalcification against a background of soft matrix. Detectionof these plaques by CCTA helps in better risk stratification ofpatients. Novel methods of prevention of formation of microcalcification could prevent ruptures of the plaque surface andthus arrest plaque progression.

6. Study limitation

In our study, plaques less than 2 mm in thickness wereexcluded. Plaque rupture in small sized plaques therefore couldnot be studied. Our study also did not include an intravascularultrasound,which couldhave confirmed thepresence of plaquerupture.

Conflicts of interest

The author has none to declare.

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