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Usefulness of Echocardiographic Assessment of Cardiac andAscending Aorta Calcific Deposits to Predict Coronary ArteryCalcium and Presence and Severity of Obstructive Coronary

Artery Disease

Gaetano Nucifora, MDa,b, Joanne D. Schuijf, PhDa, Jacob M. van Werkhoven, MSca,J. Wouter Jukema, MD, PhDa,c, Nina Ajmone Marsan, MDa, Eduard R. Holman, MD, PhDa,

Ernst E. van der Wall, MD, PhDa,c, and Jeroen J. Bax, MD, PhDa,*

The presence of cardiac and aortic calcific deposits has been related to coronary arterydisease (CAD) and cardiovascular events. The present study aimed to evaluate whethercomprehensive echocardiographic assessment of cardiac and ascending aorta calcific de-posits could predict coronary calcium and obstructive CAD. A total of 140 outpatients (age61 � 11 years; 90 men) without a history of CAD were studied. Aortic valve sclerosis andmitral annular, papillary muscle, and ascending aorta calcific deposits were assessed usingechocardiography and semiquantified using an echocardiography-derived calcium score(ECS) ranging from 0 (no calcium visible) to 8 (severe calcific deposits). Coronary calciumscoring and noninvasive coronary angiography were performed using multislice computedtomography. Angiograms showing atherosclerosis were classified as having obstructive(>50% luminal narrowing) CAD or not. The relation between ECS and multislice com-puted tomographic findings was explored using multivariate and receiver-operator char-acteristic curve analyses. Only ECS was associated with coronary calcium score >400 (oddsratio [OR] 3.6, 95% confidence interval [CI] 2.4 to 5.5, p <0.001). Similarly, only ECS (OR1.8, 95% CI 1.4 to 2.4, p <0.001) and pretest likelihood of CAD (OR 1.7, 95% CI 1.0 to 2.8,p � 0.04) were associated with obstructive CAD. ECS >3 had high sensitivity andspecificity in identifying patients with coronary calcium score >400 (87% for both) andobstructive CAD (74% and 82%, respectively). In conclusion, echocardiographic assess-ment of cardiac and ascending aorta calcium may allow detection of patients with extensivecalcified coronary arterial atherosclerotic plaques. © 2009 Elsevier Inc. All rights reserved.

(Am J Cardiol 2009;103:1045–1050)

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The presence of cardiac and aortic calcium has beenelated to coronary artery disease (CAD) and cardiovascularvents.1–4 Moreover, it was suggested that mitral annularalcium and aortic valve sclerosis were not merely passivege-related degenerative processes. Rather, these phenom-na may be a form of atherosclerosis, sharing many riskactors and a similar cause with both systemic and coronarytherosclerosis.5–7 Possibly, recognition of cardiac and as-ending aorta calcific deposits using transthoracic echocar-

aDepartment of Cardiology, Leiden University Medical Center, Leiden,he Netherlands; bDepartment of Cardiopulmonary Sciences, Universityospital Santa Maria della Misericordia, Udine, Italy; and cThe Interuni-ersity Cardiology Institute of The Netherlands, Utrecht, The Netherlands.anuscript received October 6, 2008; revised manuscript received and

ccepted December 4, 2008.Dr. Nucifora was supported by a research grant from the European Asso-

iation of Percutaneous Cardiovascular Interventions, Sophia Antipolis,rance. Dr. Bax was supported by research grants from Biotronik, Berlin,ermany, BMS Medical Imaging, North Billerica, Massachusetts, Bostoncientific, Boston, Massachusetts, Edwards Lifesciences, Irvine, California,E Healthcare, Buckinghamshire, United Kingdom, Medtronic, Minneapolis,innesota, and St. Jude Medical, St. Paul, Minnesota.

*Corresponding author: Tel: �31-715-26-2020; fax: �31-715-26-6809.

sE-mail address: j.j.bax@lumc.nl (J.J. Bax).

002-9149/09/$ – see front matter © 2009 Elsevier Inc. All rights reserved.oi:10.1016/j.amjcard.2008.12.031

iography, a simple, noninvasive, and widely availableechnique, could be helpful for the identification of patientsith obstructive CAD. Therefore, the aim of the present

tudy was to determine whether an echocardiography-de-ived calcium score (ECS), obtained using comprehensivessessment of the burden of cardiac and ascending aortaalcium, was able to predict coronary artery calcium scoreCACS) and the presence of obstructive CAD, assessedsing multislice computed tomographic (MSCT) coronaryngiography.

ethods

A total of 140 consecutive outpatients referred for MSCTor coronary evaluation because of increased risk profilend/or stable chest pain symptoms were included. Trans-horacic echocardiography was performed in all patientsithin 1 month of MSCT coronary angiography. Patientsith aortic valve stenosis, rheumatic valvular disease, pros-

hetic valves, or bicuspid aortic valves were excluded. Also,atients with a history of CAD, cardiomyopathy, rhythmther than sinus, suboptimal echocardiographic studies (i.e.,nadequate visualization of the left ventricular endocardium,alves, and ascending aorta), or contraindications to multi-

lice computed tomography were excluded. History of CAD

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as defined as the presence of previous acute coronaryyndromes, percutaneous or surgical coronary revascular-zation, and/or �1 angiographically documented coronarytenosis �50% luminal diameter.8 Contraindications forultislice computed tomography were (1) known allergy to

odinated contrast agent, (2) renal insufficiency, and (3)regnancy.

MSCT coronary angiography was performed using a4-slice MSCT scanner (Aquilion 64; Toshiba Medical Sys-ems, Tokyo, Japan). Heart rate and blood pressure wereonitored before the examination in each patient. In the

bsence of contraindications, patients with a heart rate �65eats/min were administered oral � blockers (metoprolol 50r 100 mg, single dose, 1 hour before the examination).irst, a prospective coronary calcium scan without contrastnhancement was performed, followed by MSCT coronaryngiography performed according to the protocol describedlsewhere.9 Data were subsequently transferred to dedicated

able 1rading system of cardiac and ascending aortic calcium

rade AorticValve

Sclerosis

MitralAnnularCalcium

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Calcium

0 Absent Absent Absent Absent1 Mild �5 mm Present Present2 Moderate 5–10 mm3 Severe �10 mm

Aortic valve sclerosis was defined as focal areas of increased echoge-icity and thickening of the aortic valve leaflets with velocity �2.5 m/scross the aortic valve. Each aortic valve leaflet was graded on a scale of(normal) to 3 (severe) according to leaflet thickening and calcific depos-

ts. The highest score for a given cusp was assigned as the overall degreef aortic valve sclerosis. Mitral annular calcium was defined as an intensend bright echo-producing structure located at the junction of the atrioven-ricular groove and posterior mitral valve leaflet and was measured fromhe leading anterior to the trailing posterior edge and judged on a scale of

(normal) to 3 (severe). Papillary muscle calcium was defined as a brightcho involving the head of 1 or both papillary muscles. Ascending aortaalcium was defined as a focal or diffuse area of increased echoreflectancend thickening in the aortic root on the parasternal long-axis view.

able 2aseline characteristics of the study population (n � 140)

ariable

ge (yrs) 61 � 11en/women 90/50iabetes mellitus 54 (39%)ypertension 89 (64%)ypercholesterolemia (total cholesterol �240 mg/dl) 73 (52%)amily history of CAD 44 (31%)urrent or previous smoker 53 (38%)ody mass index (kg/m2) 27 � 4revious chest pain 65 (46%)Typical 31 (22%)Atypical 34 (24%)retest likelihood of CADLow 71 (51%)Intermediate 40 (28%)High 29 (21%)

orkstations for postprocessing and evaluation (Advantage; a

E Healthcare, Milwaukee, Wisconsin, and Vitrea 2; Vitalmages, Minnetonka, Minnesota). MSCT data analysis waserformed by 2 experienced observers who had no knowl-dge of the patient’s medical history and symptom status.isagreement was solved by consensus or evaluation by a

hird observer. Coronary artery calcium was identified as aense area in the coronary artery �130 Hounsfield units. Aotal CACS was recorded for each patient. According to theotal CACS, patients were subsequently categorized as hav-ng no calcium (total score � 0) or low (total score � 1 to00), moderate (total score � 101 to 400), and severe (totalcore �400) coronary artery calcium.10 MSCT coronaryngiograms were evaluated for the presence of CAD onatient, vessel, and segment levels. For this purpose, bothhe original axial data set and curved multiplanar recon-tructions were used. Coronary arteries were divided into 17egments according to the modified American Heart Asso-iation classification.11 Each segment was evaluated for theresence of atherosclerotic plaque, and 1 coronary plaqueas assigned per coronary segment. Subsequently, type oflaque was determined as (1) noncalcified plaques, plaquesith a lower density compared with the contrast-enhancedessel lumen; (2) calcified plaques, plaques with high den-ity; and (3) mixed plaques, plaques with noncalcified andalcified elements within a single plaque. Finally, plaquesere classified as obstructive (�50% luminal narrowing) oronobstructive.

Complete transthoracic echocardiographic studies wereerformed using a commercially available system (Vivid 7imension; GE Healthcare, Horten, Norway) equipped with

able 3esults of multislice computed tomographic (MSCT) coronaryngiography and transthoracic echocardiography (n � 140)

SCT Coronary Angiography

ACS 385 (29–967)No calcium 22 (16%)Low 27 (19%)Moderate 21 (15%)Severe 70 (50%)AD 123 (88%)bstructive CAD 80 (57%)Single-vessel disease 33 (24%)Multivessel disease 47 (34%)Left main/proximal left anterior descending CAD 37 (26%)egmentsNo. of diseased segments 7.3 � 4.0No. of segments with obstructive plaques 2.0 � 2.6No. of segments with nonobstructive plaques 5.3 � 3.4No. of segments with noncalcified plaques 1.9 � 2.3No. of segments with calcified plaques 3.7 � 3.5No. of segments with mixed plaques 1.6 � 1.9ransthoracic echocardiographyAortic valve sclerosis 77 (55%)Mitral annular calcium 55 (39%)Papillary muscle calcium 21 (15%)Ascending aorta calcium 61 (44%)ECS 2.5 � 2.0

�3 70 (50%)3–5 48 (34%)�5 22 (16%)

M3S phased-array transducer (3.5 MHz). A careful search

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1047Coronary Artery Disease/Cardiac Calcific Deposits and CAD

or cardiac calcific deposits was systematically performed.ll studies were digitally stored for off-line analysis. Off-

ine analysis was performed using dedicated softwareEchoPAC 7.0.0; GE Healthcare, Horten, Norway) by anbserver who had no knowledge of clinical data and MSCToronary angiography results. Criteria for judging aorticalve sclerosis, mitral annular calcium, and ascending aortand papillary muscle calcium were similar to grading sys-ems used in previous studies3,12–14 and are listed in Table 1.ccordingly, a final score was derived as the sum of all

dentified cardiac calcific deposits and was in the range of 0no calcium visible) to 8 (extensive cardiac and ascendingorta calcific deposits).

A total of 40 patients were randomly selected and analyzedgain 1 month later by a second observer to assess interob-erver agreement for the ECS. According to weighted � test,nterobserver agreement was good (weighted � � 0.84).

Continuous variables were expressed as mean � SD oredian and 25th to 75th percentile range when non-nor-ally distributed. Categorical variables were expressed as

bsolute number and percentage. Multivariable logistic re-ression analysis (backward stepwise with retention levelet at 0.1) was applied to evaluate the association betweenlinical and echocardiographic data and the presence of

igure 1. Relation between ECS and (A) severe coronary artery calciumnd (B) obstructive CAD. *p �0.001 in comparison to the other 2 groups.

evere coronary artery calcium and obstructive CAD at E

SCT coronary angiography. Variables entered in multiva-iable models were age, gender, diabetes mellitus, hyper-ension, hypercholesterolemia, positive family history,moking, pretest likelihood of CAD, mitral annular calcium,ortic valve sclerosis, papillary muscle calcium, ascendingorta calcium, and ECS. Odds ratios (ORs) and 95% con-dence intervals (CIs) were calculated. Relations between

igure 2. Relation between ECS and (A) number of vessels with obstructiveAD, (B) number of segments with obstructive CAD, and (C) number of

egments with calcified, noncalcified, and mixed plaque.

CS and the presence of severe coronary artery calcium,

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1048 The American Journal of Cardiology (www.AJConline.org)

resence of obstructive CAD, number of significantly dis-ased vessels, number of significantly diseased segments,nd numbers of segments with noncalcified, calcified, andixed plaques were also evaluated. The general populationas divided into 3 groups accordingly to ECS (group 1,CS �3; group 2, ECS 3 to 5; and group 3, ECS �5).omparison between continuous variables was performedsing 1-way analysis of variance test with polynomial con-rast to assess the presence of a linear trend across orderedevels of ECS. Chi-square test for �2 � 2 and Fisher’sxact test for 2 � 2 contingency tables were computed tossess differences in categorical variables. Receiver-opera-or characteristic (ROC) curves were used to evaluate thebility of the ECS to predict the presence of severe coronaryrtery calcium and the presence of obstructive CAD atSCT coronary angiography. In addition, ROC curve anal-

sis was performed to evaluate the ability of the CACS toredict the presence of obstructive CAD at MSCT coronaryngiography. A p value �0.05 was considered statisticallyignificant. Statistical analyses were performed using SPSSoftware (version 15.0; SPSS Inc., Chicago, Illinois).

esults

Table 2 lists baseline characteristics of the study popu-ation, and Table 3 lists results of MSCT coronary angiog-aphy and transthoracic echocardiography.

Multivariable logistic regression analysis identified ECSs the only variable among the clinical and echocardio-raphic variables with a significant association with severeoronary artery calcium (OR 3.6, 95% CI 2.4 to 5.5,�0.001). ECS (OR 1.8, 95% CI 1.4 to 2.4, p �0.001) and

retest likelihood of CAD (OR 1.7, 95% CI 1.0 to 2.8, p �.04) were identified as significantly associated with ob-tructive CAD.

As shown in Figure 1, patients with ECS of 3 to 5 and5 more frequently had severe coronary artery calcium and

bstructive CAD compared with the group with ECS �3p �0.001). Furthermore, a significant increasing linearrend in number of vessels with obstructive plaques, numberf segments with obstructive plaques, and number of seg-ents with calcified plaques was observed across the or-

ered levels of ECS (p �0.001, respectively; Figure 2).At ROC curve analysis (Figure 3), ECS �3 had the

ighest sensitivity and specificity for identification of pa-ients with severe coronary artery calcium (87% for both)nd obstructive CAD (74% and 82%, respectively). More-ver, the ability of ECS to predict obstructive CAD wasimilar to that shown by the CACS (Figure 3).

igure 3. ROC curve analyses. (A) Area under the ROC curve (AUC) ofhe ECS for the prediction of severe coronary artery calcium. The highestensitivity and specificity in identification of patients with severe coronaryrtery calcium (87% for both) was provided by ECS �3. (B) AUC of theCS for the prediction of obstructive CAD. The highest sensitivity andpecificity in the identification of patients with obstructive CAD (74% and2%, respectively) was provided by ECS �3. (C) AUC of CACS for therediction of obstructive CAD. The highest sensitivity and specificity in thedentification of patients with obstructive CAD (81% and 75%, respec-

ively) was provided by CACS �208.

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1049Coronary Artery Disease/Cardiac Calcific Deposits and CAD

iscussion

Results of the present study showed that an ECS obtainedhrough comprehensive assessment of cardiac and ascend-ng aorta calcium was able to predict the presence of exten-ive coronary calcium and obstructive CAD, assessed usingSCT coronary angiography. Furthermore, significant lin-

ar trends were observed between ECS and extent andeverity of coronary atherosclerosis and number of calcifiedoronary artery lesions.

Vascular deposition of mineral calcium is an organizednd regulated process that typically occurs in areas of ath-rosclerotic lipid accumulation, sharing many features withortical bone formation.7 In the last 2 decades, the clinicalelevance of vascular calcific deposits has emerged. Themount of calcium in both coronary arteries and the aortaorrelates with atherosclerotic plaque burden in each vas-ular bed15,16 and is associated with increased risk of car-iovascular events.4,17 Severe coronary calcific deposits aressociated with the presence of myocardial ischemia,18 andxtent of calcium in the aorta is related to coronary, carotid,nd peripheral artery disease.14

Mitral annular calcium and aortic valve sclerosis appearso be the result of similar pathologic processes. Both are notimple passive degenerative disorders influenced by me-hanical stress, but active inflammatory processes with his-opathologic features similar to atherosclerosis.5–7 Previouslinical studies have shown significant associations betweenitral annular calcium and aortic valve sclerosis with cardio-

ascular risk factors,12,19 impaired coronary microvascularunction,20,21 subclinical systemic calcified atherosclerosis,22

nducible myocardial ischemia,13 and obstructive CAD atonventional coronary angiography.23,24 Large populationohort studies showed that aortic valve sclerosis and mitralnnular calcium are associated with increased cardiovascu-ar morbidity and mortality.1–3 Because it is unlikely thatortic valve sclerosis and mitral annular calcium directlyead to adverse cardiovascular outcomes, their relation withoronary atherosclerosis most likely explains these obser-ations.

Calcific deposits of the papillary muscles are less com-only observed in the general population and usually lim-

ted to their apical portion. Similarly to mitral annular cal-ium and aortic valve sclerosis, papillary muscle calcium isssociated with the presence of CAD despite potentiallyifferent underlining mechanisms,5 more likely a conse-uence of necrosis or fibrosis caused by narrowing of theoronary arterial lumen by atherosclerosis.25

Noninvasive modalities for the diagnosis of CAD aremportant for both screening of asymptomatic subjects andisk stratification of symptomatic patients to identify thoseho could benefit from invasive coronary angiography.ecently, MSCT coronary angiography has emerged as a

easible and accurate technique allowing detection of coro-ary atherosclerosis by assessing the coronary artery cal-ium burden and performing noninvasive angiography.9

owever, it is expensive and not widely available. More-ver, it still carries high radiation exposure, which limits itsidespread use in asymptomatic patients, and a potential

ssociated risk of allergic reactions and nephrotoxicity re-

ated to the use of iodinated contrast agents.

According to the previously described association be-ween cardiovascular calcific deposits and coronary athero-clerosis, recognition of cardiac and ascending aorta cal-ium using transthoracic echocardiography could be helpfulo optimize the identification of patients with obstructiveAD. Transthoracic echocardiography has the advantage ofeing a simple, low-cost, radiation-free technique that isidely available and used in clinical practice. Based onrevious echocardiographic studies, sensitivity and speci-city of aortic valve sclerosis and mitral annular calcium for

he detection of obstructive CAD has been reported to ben the range of 38% to 64% and 60% to 86% and 57% to0% and 33% to 56%, respectively.23,26 –28 However,ost studies had drawbacks, such as (1) inclusion of

atients with a history of CAD; (2) use of invasiveoronary angiography for the diagnosis of CAD, possiblyntroducing a selection bias; (3) lack of information aboutoronary plaque composition; and (4) simple assessmentf the presence/absence of single cardiac calcific depos-ts, rather than a graded approach.

In the present study, in a consecutive group of patientsithout a history of CAD, comprehensive echocardio-raphic assessment of cardiac and ascending aorta calcificeposits was performed. Moreover, not only the presence/bsence of calcific deposits was assessed, but their burdenas also quantified, deriving a global score. MSCT coro-ary angiography was used to diagnose CAD. Use of thisechnique allowed us to show coronary atherosclerosis evenn patients asymptomatic or with low pretest likelihood andssess coronary plaque composition, thereby reducing (al-hough not completely obviating) the selection bias thatampered previous studies relying on invasive coronaryngiography.23,26–28 The derived global ECS was able toredict the presence of severe coronary artery calcium withensitivity and specificity of 87% for both and the presencef obstructive CAD with sensitivity of 74% and specificityf 82%. Furthermore, a linear trend between ECS and num-er of vessels and segments with obstructive CAD andumber of segments with calcified plaques was observed,trengthening the evidence of a relation between cardiac andortic calcific deposits and advanced calcified coronary ath-rosclerosis.

This study had some limitations that should be acknowl-dged. First, it is a single-center experience. Second, con-entional coronary angiography, the gold standard for diag-osing CAD, was not used. However, 64-slice MSCToronary angiography has been validated against invasivengiography and intravascular ultrasound, allowing detec-ion of significant stenoses and assessment of plaque com-osition with high accuracy.9,29 Moreover, the higher spa-ial resolution and lower voxel size of 64-slice MSCTompared with 16-slice MSCT decreased the blooming ar-ifacts related to coronary calcifications.30 Third, no fol-ow-up data were available. Therefore, it is unknownhether comprehensive assessment of cardiac and ascend-

ng aorta calcific deposits could provide incremental prog-ostic information.

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