Lack of correlation between coronary artery calcium and myocardial perfusion imaging

Lack of correlation between coronary artery calcium and myocardial perfusion imaging Jonathan Rosman, MD, Michael Shapiro, DO, Anuragini Pandey, MD, Andrew VanTosh, MD, and Steven R. Bergmann, MD, PhD Background. Coronary artery calcium (CAC) provides evidence of coronary atherosclerosis and has significant prognostic power. Although prior studies have documented a relationship between CAC and hemodynamically significant coronary artery stenosis, the results have not been conclusive. Methods and Results. We evaluated 126 consecutive patients who underwent electron beam computed tomography CAC scoring by use of the Agatston method and stress myocardial perfusion imaging (MPI) within 3 months of each other. The analysis revealed no correlation between absolute CAC score and age- and gender-adjusted CAC scores with MPI. Overall, 18% of patients had abnormal MPI results irrespective of their CAC. Conclusion. CAC scoring and stress MPI should be thus considered complementary approaches rather than exclusionary in the evaluation of the patient at risk for coronary artery disease. (J Nucl Cardiol 2006;13:333-7.) Key Words: Myocardial perfusion imaging • single photon emission computed tomography • atherosclerosis • coronary artery disease Atherosclerosis often manifests initially as myocardial infarction or sudden cardiac death.1,2 It is therefore important to identify patients with coronary artery disease before major adverse cardiac events develop. Studies have documented a close correlation between the extent of coronary artery calcium (CAC) and atherosclerotic plaque burden.3,4 Recently, studies have compared CAC with hemodynamically significant coronary artery stenosis as assessed by stress testing with myocardial perfusion imaging (MPI).5-8 Although some studies have suggested a correlation between CAC and MPI, this relationship is not clear. METHODS Accordingly, we evaluated 126 patients who underwent CAC scoring by electron beam computed tomography (EBCT) followed by rest-stress dual-isotope MPI at the Beth Israel Medical Center (New York, NY) within 3 months of each other. The mean age of the population study was 59 ⫾ 11 years (range, 38-91 years), and 85 patients (67%) were men (Table 1). Patients were referred by their primary medical doctor or self-

From Beth Israel Medical Center, Albert Einstein College of Medicine, New York, NY. Received for publication Sept 28, 2005; final revision accepted Jan 30, 2006. Reprint requests: Jonathan Rosman, MD, 350 E 17th St, Baird Hall, 20th Floor, New York, NY 10003; [email protected]. 1071-3581/$32.00 Copyright © 2006 by the American Society of Nuclear Cardiology. doi:10.1016/j.nuclcard.2006.01.023

referred for coronary artery disease risk assessment. Patients were without significant symptoms of ischemia. This research was approved by the Institutional Review Board of the Beth Israel Medical Center. EBCT scanning was performed with the GE Imatron C-150 scanner (GE Imatron, South San Francisco, Calif) with a reconstruction field of 26 cm. Approximately 30 to 40 contiguous 3-mm slices were acquired during a single breath hold beginning at the level of the right pulmonary artery (above the base of the heart) and extending below the apex. The scan time was 100 milliseconds for each image synchronized to the end-systolic phase of the cardiac cycle (approximately 40% of the R-R interval). To qualify as a calcified lesion, at least 3 contiguous pixels of 130 Hounsfield units had to be present. Calcium scoring was performed on the Aquarius workstation (Terarecon, South San Francisco, Calif) by use of the standard Agatston calcium scoring algorithm,9 as well as the revised calcium volume method.10 The Agatston calcium scoring method quantifies the calcium in an area multiplied by a scaling factor based on peak pixel attenuation. Total scores are the sum of each set of deposit scores. In patients referred for stress MPI, a symptom-limited, graded treadmill test was performed according to the Bruce protocol in all patients able to perform exercise. ␤-Blockers were discontinued for at least 12 hours before the stress test. Perfusion tracers were injected approximately 60 to 120 seconds before treadmill termination. Details of the stress protocols and image acquisition have been previously reported.11,12 Pharmacologic stress testing was performed on all patients who were unable to reach at least 85% of the predicted maximal heart rate or were unable to achieve age- and gendercorrected exercise time, as well as in those patients with left bundle branch block or ventricular pacemakers. Adenosine was 333

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Table 1. Demographics of subjects categorized by absolute CAC score

CAC score

Age (y) % Male % Diabetes % Hypertension % Hyperlipidemia % Smoking % Prior CAD % Taking ␤-blocker % Taking statin/niacin % Taking ACEI/ARB % Taking CCB

All patients (n ⴝ 126)

0-99 (n ⴝ 33)

100-399 (n ⴝ 46)

400-999 (n ⴝ 25)

>1000 (n ⴝ 22)

P value

59 ⫾ 11 67 10 39 72 18 10 14 52 29 5

52 ⫾ 9 52 6 39 60 15 6 15 24 21 3

58 ⫾ 9 67 11 26 78 26 4 4 59 22 4

63 ⫾ 11 64 8 48 72 12 16 20 64 48 8

65 ⫾ 11 95 18 55 77 14 23 27 64 36 5

⬍.0001 .009 NS NS NS NS NS .04 .004 NS NS

CAC score is higher in older, male subjects and those taking ␤-blocker. CAD, Coronary artery disease; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; CCB, calcium channel blocker; NS, not significant.

used as the primary pharmacologic stress agent and was administered intravenously at 0.14 mg · kg⫺1 · min⫺1 for 6 minutes. Perfusion tracers were injected 3 minutes after the start of the infusion, and the infusion continued for another 3 minutes. For patients with a contraindication to adenosine, an intravenous infusion of dobutamine was administered in a graded fashion consisting of 3 minute stages, starting at 5 ␮g · kg⫺1 · min⫺1 and increasing to 10, 20, 30, and 40 ␮g · kg⫺1 · min⫺1. If the patient did not reach the target heart rate, leg raises were added during the last stage of the infusion.12 The perfusion tracer was injected 1 minute before the termination of the dobutamine infusion in these patients. Stress electrocardiograms were evaluated by 2 physicians with extensive experience in stress testing. Electrocardiograms were considered positive for ischemia if there was development of horizontal or downsloping ST changes of greater than 0.1 mV 60 milliseconds after the J point or upsloping ST changes of greater than 0.15 mV after the J point. In patients with abnormal ST segments on the baseline electrocardiogram, additional horizontal or downsloping ST depression of 1.5 mV or greater was considered evidence of ischemia. Radionuclide perfusion imaging was performed via a dual-isotope protocol. Patients received 3.0 to 3.5 mCi of thallium 201 at rest and had rest MPI performed 30 minutes after injection. At peak stress, they received 25 to 30 mCi of technetium 99m tetrofosmin and were asked to exercise for an additional 60 to 120 seconds. Patients underwent stress imaging approximately 30 to 60 minutes later. MPI was performed on a dual-headed GE MyoSIGHT system (GE Healthcare, Waukesha, Wis) with a 180° acquisition (from 45° right anterior oblique to 225° left posterior oblique). All scans were collected in a gated mode, thus allowing interpretation of wall motion and ejection fraction from the gated myocardial perfusion images.13 No attenuation correction was used. MPI findings were interpreted by 3 physicians with extensive

experience in nuclear cardiology. Images were assessed in a blinded fashion without knowledge of clinical factors or calcium score. The images were classified as either normal or abnormal, with abnormal images being further classified as reflecting ischemia or infarction. Ischemia was defined as images revealing a perfusion defect during stress with resolution of the defect or a substantially smaller defect on the resting scans. Infarction was defined as those images with a match defect at rest and an associated wall motion abnormality. Semiquantitative summed stress scoring was performed as well but did not alter the results whatsoever and is not included herein. Analyses were conducted to compare patients with regard to the presence or absence of hemodynamically significant coronary artery stenosis as evaluated by stress MPI. Medians of absolute calcium scores in the 2 groups were compared by use of the Wilcoxon rank sum test. Absolute calcium scores were subsequently classified into 5 categories (0, 1-99, 100-399, 400-999, and ⱖ1000). The prevalence of abnormal stress MPI findings was compared across calcium score categories by use of the CochranArmitage test for trend and the Jonckheere-Terpstra test for ordered differences. Similar analyses were conducted across age- and gender-adjusted CAC score percentile levels (050th, 51st-75th, 76th-90th, and 91st-100th). P ⱕ .05 was considered statistically different. All analyses were conducted with SAS software, version 9.1 (SAS Institute, Inc, Cary, NC).

RESULTS Subject demographics are shown in Tables 1 and 2. As shown in Figure 1, 7 patients (6%) had an absolute CAC score of 0, 26 (21%) had a score of 1 to 99, 46 (37%)

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Table 2. Demographics of subjects categorized by normal and abnormal MPI findings

Age (y) % Male % Diabetes % Hypertension % Hyperlipidemia % Smoking % Prior CAD % Taking ␤-blocker % Taking statin/niacin % Taking ACEI/ARB % Taking CCB % Ejection fraction

All patients (n ⴝ 126)

Abnormal MPI findings (n ⴝ 23)

Normal MPI findings (n ⴝ 103)

P value

59 ⫾ 11 67 10 39 72 18 10 14 50 29 5 60 ⫾ 8

60 ⫾ 11 91 13 44 78 22 17 13 44 35 4 55 ⫾ 10

58 ⫾ 11 62 10 38 71 18 9 15 52 28 7 62 ⫾ 7

NS ⬍.02 NS NS NS NS NS NS NS NS NS ⬍.001

% Abnormal Myocardial Perfusion Imaging

More men hade abnormal scans. The average ejection fraction was also lower in patients with abnormal perfusion. CAD, Coronary artery disease; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; CCB, calcium channel blocker.

35 30

n=22

25 n=25 20 15

n=7

n=26

n=46

10 5 0 0

1--99

100-399

400-999

>1000

Coronary Artery Calcium Score

Figure 1. Percent of subjects with abnormal MPI findings compared with absolute CAC score. Although the absolute percentage does increase with increasing CAC, even patients with a CAC score of less than 100 have a small but important rate of abnormal perfusion scans.

had a score of 100 to 399, 25 (20%) had a score of 400 to 999, and 22 (17%) had a score of 1000 or greater. A CAC score of less than 400 was associated with an abnormal stress MPI finding in 15% of subjects, even in those with a CAC score of 0. Although a CAC score of 400 or greater was associated with a greater percentage of abnormal MPI findings compared with a CAC score lower than 400, this difference did not reach statistical significance. As shown in Table 1, there were some differences in patients with higher CAC scores, including age, percent male, percent taking a statin or niacin, and percent taking a ␤-blocker. Figure 2 compares the age- and gender-adjusted calcium percentile with the percent of patients who had

Figure 2. Percent of patients having abnormal MPI findings compared with age- and gender-adjusted calcium percentile. When CAC is adjusted in this way, there is no difference in the percent of patients having an abnormal perfusion scan.

an abnormal MPI finding. There were 14 patients in the 0% to 50% group, 27 in the 51% to 75% group, 32 in the 76% to 90% group, and 53 in the 91% to 100% group. Of 14 patients in the 0% to 50% group, 5 (36%) had an abnormal MPI finding, whereas 9 of 53 patients (17%) in the 91% to 100% group had an abnormal MPI finding. There were no statistically significant differences among the 4 quartiles. Table 2 stratifies patients based on either normal or abnormal MPI finding. Only age and ejection fraction were significantly different between the 2 groups. DISCUSSION This study compared patients who underwent both MPI and CAC scoring within a short period of time.

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Rosman et al Lack of correlation between coronary artery calcium and MPI

Our results revealed a small but important prevalence of abnormal MPI findings in patients with low absolute CAC scores or with a low age- and genderadjusted calcium percentile score. Patients with a high CAC score or age- and gender-adjusted calcium percentile did not demonstrate a significantly different percentage of abnormal MPI findings than that in patients with a low CAC score or age- and genderadjusted calcium percentile. Our studies differ significantly from prior studies comparing coronary calcium and MPI. For example, Berman et al5 compared 1195 patients who had both CAC scoring by EBCT and MPI within 6 months of each other. They found a very low incidence of abnormal MPI findings in patients with a CAC score of less than 100. In their study a CAC score of 400 or greater was associated with a significantly higher percentage of abnormal MPI findings. However, the patient population in the study of Berman et al5 differed from our cohort of patients. Only 6% of patients in their study had ischemia present on MPI, whereas more than 18% of patients in our study had ischemia on MPI. Patients with a history of cardiac disease were excluded from their study, whereas our study compared all patients who had both CAC scoring and MPI regardless of prior cardiac history (Table 1). The apparent discrepancy in results between these 2 studies is likely related to the different cohorts enrolled. Whereas prior investigations have suggested a correlation between CAC score and MPI, we did not find that to be the case in our population. In our study approximately 15% of patients with a low absolute calcium score (⬍100) had an abnormal MPI finding. It is possible that patients with low calcium scores and positive MPI findings had noncalcified plaques that were not detected by EBCT. Although there was a slightly greater percent of positive scans in patients with a “high” absolute calcium score (ⱖ400), it was not statistically different from that in those with less calcium. Thus, whereas both abnormal perfusion imaging and high absolute CAC scores are associated with an increased risk of major adverse coronary events,14,15 we did not find a direct correlation between these 2 diagnostic modalities. Although we would not advocate stress perfusion studies in all patients with low calcium scores, a stress perfusion study may be appropriate in patients with multiple risk factors or in patients who are symptomatic. Conversely, patients with a normal stress perfusion study do not require EBCT unless they have multiple risk factors or the stress study was inconclusive. Therefore CAC scoring and stress MPI should thus be considered complementary approaches rather than exclu-

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sionary in the evaluation of the patient at risk for coronary artery disease. Acknowledgment We thank Theresa Perlis, PhD, for her assistance with the statistical analysis. We also thank T. J. Matarazzo, RT, for his help with the EBCT studies. The authors have indicated they have no financial conflicts of interest.

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