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Relation of Aortic Valve Calcium to Myocardial Ischemic Perfusion in IndividualsWith a Low Coronary Artery Calcium Score

John Ho, MD*, Shannon FitzGerald, PhD, John Cannaday, MD, Lisa Stolfus, RN, Dana Weilbacher,Yvette Henderson, Tiffany Newman, Robin Whitehead, and Nina Radford, MD

The absence of coronary artery calcium (CAC) is associated with minimal atherosclerosis.Nonetheless, morbid and mortal cardiovascular events occur in patients with low CAC.This study attempts to identify whether calcific deposits outside the coronary arteries ortraditional cardiovascular risk variables are associated with myocardial ischemia in pa-tients with low CAC scores. From 1998 to 2006, a total of 605 patients with an AgatstonCAC score of 0 to 10 were referred for stress echocardiography or myocardial perfusionimaging. There was a low rate (1.2%) of myocardial ischemia. Seven of 303 patients (2.3%)had ischemia on perfusion imaging. Zero of 302 stress echocardiograms were abnormal.Traditional risk-factor analysis did not predict the presence of ischemia. No differences inage, gender, or self-reported hyperlipidemia, diabetes mellitus, tobacco use, hypertension,or family history of premature heart disease were noted. Contrary to previous belief,patients with myocardial ischemia were not younger or female. Aortic valve calcium (AVC)was associated with ischemia (p � 0.02), with a >10-fold likelihood of having ischemiadetected by MPS versus those without AVC (20.0% vs 1.7%). In conclusion, a CAC score<10 is associated with a low rate of myocardial ischemia. AVC may identify a subset ofpatients who may be at higher risk. © 2007 Elsevier Inc. All rights reserved. (Am J

Cardiol 2007;99:1535–1537)

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ow coronary artery calcium (CAC) scores are associatedith a low cardiovascular event rate.1–9 Nonetheless,orbid and mortal cardiovascular events occur in pa-

ients with low CAC scores. In this study, we endeavor todentify possible risk factors that would suggest the pres-nce of obstructive coronary artery disease in individualsith a low CAC score. Are traditional cardiovascular risk

actors related to inducible myocardial ischemia as de-ected by a myocardial perfusion study (MPS) in theseow-risk patients? Does the presence of extracoronaryalcium in the aortic valve or elsewhere suggest periph-ral vascular disease and thus an increased risk of coro-ary artery disease?

ethods and Results

rom 1998 to 2006, a total of 4,069 individuals underwentardiovascular risk assessment by their physician and cor-nary artery scoring using electron-beam computed tomog-aphy. Of these, 1,317 had a low CAC score, defined as angatston score of 0 to 10. Individuals with known cardio-ascular disease (n � 57) were eliminated from subsequentnalysis. Self-reported clinical and demographic data werenalyzed for the remaining 1,260 patients.

If their physician thought it clinically appropriate, pa-ients were referred for a stress imaging study to evaluateor the presence of ischemia. Clinical indications for furtherardiovascular evaluation in these patients with low CACcores included the presence of chest pain, multiple cardio-

Cooper Clinic, Dallas, Texas. Manuscript received November 6, 2006;evised manuscript received and accepted January 10, 2007.

*Corresponding author: Tel: 972-560-2741; fax: 972-560-2681.

ME-mail address: jsho@cooper-clinic.com (J. Ho).

002-9149/07/$ – see front matter © 2007 Elsevier Inc. All rights reserved.oi:10.1016/j.amjcard.2007.01.025

ascular risk factors, or an abnormal electrocardiogram. Ineneral, patients perceived to be low risk were not referredor testing (655 of 1,260, 52%). Patients perceived to be atow to intermediate risk were referred for stress echocardi-graphy, and those perceived to be intermediate or high riskere referred for nuclear stress testing.Approximately 1/4 of patients, or 302 of 1,260 (24%),

ere referred for stress echocardiography. An abnormaltress echocardiogram was defined as a stress-induced wallotion abnormality. The remaining patients (24%) were

eferred for an MPS. An abnormal MPS result was defineds a reversible perfusion defect on either thallium-201tress-delay reinjection or technetium-99m sestamibi or tet-afosmin rest-stress protocols.

Overall, 7 of 605 patients (1.2%) had an abnormal testesult. Despite a 30% prevalence of �1 risk factor, thereere no abnormal stress echocardiograms. Compared withatients referred for stress echocardiography, patients re-erred for MPS were a higher risk subgroup with a higherrevalence of hyperlipidemia and diabetes mellitus. In ad-ition, this group was older, more frequently men, moreverweight, and tended to have a family history of prema-ure heart disease (Table 1). Despite this higher risk profile,here was a low frequency of abnormal MPS results (2.3%,

of 303). Two of these 7 patients had a low ischemicurden, with a summed difference score (SDS) �4. Threef these 7 had a moderate ischemic burden (10 � SDS �5),hereas 2 had a high ischemic burden (SDS � 10). On

ollow-up, all patients with either a moderate or high ischemicurden underwent revascularization.

In the setting of a low CAC score, traditional cardiovas-ular risk factors were not associated with an abnormal

PS result (Table 2). No significant differences in age,

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1536 The American Journal of Cardiology (www.AJConline.org)

ender, or self-reported status for hypertension, hyperlipid-mia, diabetes mellitus, tobacco use, or family history ofremature heart disease were noted. The presence of chestain was more common in patients with an abnormal MPSesult compared with those with a normal MPS result71.4% vs 38.0%, respectively), but this did achieve statis-ical significance (p � 0.11).

In the subgroup referred for an MPS, the presence ofxtracoronary artery calcium was analyzed to assess itstility as a predictor of inducible ischemia in individualsith low CAC scores. Ten of 303 patients (3.3%) had aorticalve calcium (AVC), whereas 7 of 303 (2.3%) had mitralalve or mitral annular calcium. Calcium in the thoracicorta was much more prevalent (124 of 303, 40.9%). Cal-ium in the thoracic aorta or mitral valve/annulus was notssociated with an abnormal MPS result. However, AVCad a statistically significant association (Table 2). Patientsith AVC (10 of 303) had a �10-fold likelihood of having

schemia versus those without AVC (293 of 303, 20.0% vs.7%, p � 0.02). This finding, although statistically signif-cant, is based on only 2 individuals with AVC of 7 indi-iduals with an abnormal MPS result. Thus, the utility ofVC as a clinical risk prediction tool requires validation in

able 1verall characteristics of patients with a coronary artery calcium scoref 0 to 10 referred for a myocardial perfusion study (MPS) or stresschocardiogram

MPS(n � 303)

Stress Echocardiogram(n � 302)

p Value

ge (yrs) 54 � 8 53 � 9 0.24en 174 (57%) 109 (36%) �0.001yperlipidemia 158 (52%) 91 (30%) �0.001iabetes mellitus 13 (4%) 3 (1%) 0.01ypertension 102 (34%) 94 (31%) 0.50urrent-smoker 45 (15%) 44 (15%) 0.92besity 72 (24%) 34 (11%) �0.001amily history of coronary

artery disease122 (40%) 113 (37%) 0.50

Data presented as mean � SD or absolute number (percent).

able 2haracteristics of patients with low coronary artery calcium with normalersus abnormal myocardial perfusion study (MPS) results

Normal MPS(n � 296)

Abnormal MPS(n � 7)

p Value

ge (yrs) 55 � 8 56 � 10 0.62en 168 (57%) 6 (86%) 0.25yperlipidemia 155 (52%) 3 (43%) 0.71iabetes mellitus 13 (4%) 0 (0%) 1.0ypertension 100 (34%) 2 (29%) 1.0urrent smoker 45 (15%) 0 (0%) 0.60besity 70 (24%) 2 (29%) 0.67amily history of coronary

artery disease120 (41%) 2 (29%) 0.71

hest pain 110 (37%) 5 (71%) 0.11VC 8 (3%) 2 (29%) 0.02

Data presented as mean � SD or absolute number (percent).

larger study population. m

iscussion

ultiple studies have shown a strong graded relation withncreasing CAC and incident cardiovascular morbidity andortality. Conversely, the lower the CAC score, the more

avorable the prognosis.1–9 In the diabetic population, aroup with a high risk of cardiovascular events, the absencef CAC identifies a subgroup with a cardiovascular riskquivalent to that of patients without diabetes.10

Recent appropriateness guidelines and scientific state-ents recommended against the use of an MPS in patientsith a CAC score �100.11,12 The present study supports

hese guidelines, especially for those with a CAC score10. In this analysis, only 1.2% of patients with a CAC

core �10 had an abnormal myocardial stress imaging testesult, with none of the stress echocardiograms and only.3% of MPSs showing ischemia. This result comparesicely with the 1.6% frequency of an ischemic MPS resultoted by Berman et al13 in patients with no detectable CAC.n the same study, there were no ischemic MPS results inhose with a CAC score of 1 to 9 and a 2.4% frequency inhose with a CAC score of 10 to 99. In a previous study bye et al,14 there were no ischemic MPS results in patientsith a CAC score �10.Patients with obstructive heart disease with a low CAC

core are believed to represent fibrous or lipid-laden plaqueshat have yet to undergo calcification, presumably in youngemales. However, the results of this study do not supporthis notion. Compared with patients with normal perfusion,hose with an abnormal MPS result were of similar age andore likely to be male. In addition, no significant differ-

nces in self-reported hyperlipidemia, diabetes mellitus, to-acco use, hypertension, or family history of prematureeart disease were noted.

The low-risk nature of a low CAC score may not be asobust in patients with chest pain. Berman et al13 observedn increased frequency of ischemia in symptomatic versussymptomatic patients, but only in patients with a CACcore �10. In a study comparing CAC and stress echo-ardiography, there was a nonsignificant trend towardore abnormal stress echocardiographic results in pa-

ients with chest pain.15 In this study, chest pain alsohowed a favorable, but statistically insignificant, trendoward an ischemic MPS result (p � 0.11). This trenday explain the obstructive heart disease noted in symp-

omatic patients presenting to the emergency departmentespite a low CAC score.

A number of previous studies have shown an increasedisk of cardiovascular events in association withVC.16 –18 In the study by Barasch et al,16 aortic valve

clerosis was associated with a 1.13 hazard ratio of in-ident myocardial infarction. In another study by Otto etl,17 patients with aortic valve sclerosis had about a 50%ncreased risk of myocardial infarction and cardiovascu-ar death at a mean follow-up of 5 years. AVC may be aanifestation of peripheral vascular disease. The results

f this study suggest that the risk associated with AVCay also extend to patients with low CAC scores, al-

hough this association was based on a very small numberf cases. Identifying patients with low CAC scores who

ay warrant further cardiovascular risk stratification is

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1537Preventive Cardiology/AV Calcium in Low CAC Patients

hallenging. The clinical utility of AVC as a cardiovas-ular risk prediction tool in this setting warrants addi-ional investigation.

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7. Keelan P, Bielak L, Ashai K, Jamjourn L, Denktas A, Rumberger J,Sheedy P, Peyser P, Schwartz R. Long-term prognostic value ofcoronary calcification detected by electron-beam computed tomogra-phy in patients undergoing coronary angiography. Circulation 2001;104:412–417.

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