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Relation of Coronary Calcium

Progression and Control of Lipids


According to National Cholesterol
Education Program Guidelines
Nathan D. Wong, PhD, Miwa Kawakubo, MS, Laurie LaBree, MS, Stanley P. Azen, PhD,
Min Xiang, MS, and Robert Detrano, MD, PhD

Tracking of coronary artery calcium (CAC) has been examined in relation to progression of CAC. After ad-
suggested for monitoring the effects of lipid control, but justment for other risk factors and baseline CAC volume,
it is not known whether lipid control decreases progres- CAC progression was similar between those with ade-
sion of CAC. Seven hundred sixty-one subjects (mean quate and those with inadequate control of LDL choles-
age 64.5 ! 7.3 years; 91% men; 69% positive for CAC) terol (p " 0.68) and across categories of optimal, inter-
in an ongoing cohort study underwent baseline and mediate, and higher risk LDL cholesterol (p " 0.40).
follow-up (after 7.0 ! 0.5 years) computed tomography However, higher levels of HDL cholesterol (>1.5 mmol/L
for CAC. Subjects were stratified into low-risk (<2 risk [60 mg/dl]) were associated with less progression of
factors), intermediate-risk (>2 risk factors but <20% CAC volume (151 vs 203 mm3 in those with HDL cho-
risk of coronary heart disease over 10 years), or high- lesterol <1.0 mmol/L [40 mg/dl], p " 0.03). There was
risk (>2 risk factors and >20% risk of coronary heart
no relation between triglycerides and CAC progression
disease in 10 years or diabetes) groups. Lipid control
(p " 0.54). Our findings do not support the use of CAC
was defined according to criteria of the National Cho-
assessment for monitoring the control of LDL cholesterol,
lesterol Education Program. Two-way analysis of covari-
but greater progression of CAC may occur in those in
ance was used to examine the relation of low-density
lipoprotein (LDL) cholesterol and risk group to change in whom HDL cholesterol is not controlled. !2004 by
CAC volume score. Control of levels of high-density li- Excerpta Medica, Inc.
poprotein (HDL) cholesterol and triglycerides was also (Am J Cardiol 2004;94:431– 436)

C oronary artery calcium (CAC) scanning has been


proposed as a noninvasive means for following
atherosclerosis progression. It is currently accepted
1–5
METHODS
Study design: The study design of the South Bay
Heart Watch has been described elsewhere.8 Briefly,
that the quantity of coronary calcium roughly reflects the cohort comprised respondents to a community-
the extent of atherosclerosis,6,7 and several studies based mailing campaign of letters of invitation to
have documented the quantity of CAC to be associ- participate in a research project. The cohort initially
ated with an increased risk of future coronary heart consisted of 1,461 asymptomatic participants !45
disease events.8 –11 The South Bay Heart Watch is a years old without evidence of coronary heart disease
longitudinal cohort study designed to determine the at the time of enrollment but with multiple cardiac risk
relation between risk factors, CAC, and future events factors yielding a !10% 8-year risk of developing
and changes in CAC over time. We examined the coronary heart disease. Participants were initially
relation of control of lipids according to guidelines of screened and enrolled between December 1990 and
the National Cholesterol Education Program11 to de- December 1992. Participants with electrocardio-
gree of progression of CAC (calcium volume score) graphic evidence or a clinical history of myocardial
over 7 years. infarction, revascularization, or typical angina were
excluded. Thirty months after enrollment, 1,291 sur-
From the Heart Disease Prevention Program, Department of Medicine, viving participants who were free of intervening myo-
University of California, Irvine, California; the Statistical Consultation cardial infarction or symptoms requiring revascular-
Research Center, Department of Preventive Medicine, University of ization underwent a second evaluation of medical and
Southern California, Los Angeles, California; and the Division of Car-
diology, Harbor UCLA Research and Education Institute, Torrance,
risk factors, including fasting phlebotomy concurrent
California. This study was supported by grant 7RO1-HL-43277-02 with computed tomographic examinations for CAC.
from the National Heart, Lung, and Blood Institute, National Institutes All participants gave written informed consent at the
of Health, Bethesda, Maryland, and the Harbor UCLA General Clin- time of recruitment and at the time of repeat risk factor
ical Research Center, Torrance, California. Manuscript received assessment and computed tomography. The Harbor
February 20, 2004; revised manuscript received and accepted April
UCLA Research and Education Institute human sub-
30, 2004.
Address for reprints: Robert Detrano, MD, PhD, Harbor UCLA jects committee approved this study.
Research and Education Institute, 1124 West Carson Street, Bldg. CAC scanning: CAC scans were performed with an
E-5, Torrance, California 90502. E-mail: rdetrano@rei.edu. Imatron C-100 scanner (Imatron, South San Fran-

©2004 by Excerpta Medica, Inc. All rights reserved. 0002-9149/04/$–see front matter 431
The American Journal of Cardiology Vol. 94 August 15, 2004 doi:10.1016/j.amjcard.2004.05.003
cisco, California) within 2 ! 2 days after risk factor intermediate risk; or (3) LDL cholesterol $4.2
evaluation. All participants were scanned over a bone mmol/L [160 mg/dl] if low risk in risk-stratified anal-
mineral density phantom (Image Analysis, Columbia, yses. In analyses performed in the entire cohort (with-
Kentucky). The acquisition protocol consisted of out respect to risk category), optimal, intermediate,
6-mm image slices obtained at 80% of the electrocar- and higher risk levels of LDL cholesterol were defined
diographic RR interval during a single breath hold.12 as $100, 100 to 129, and !130 mg/dl, respectively.
Participants returned to the clinic for repeat evaluation HDL cholesterol categories were defined as !1.5
and scanning 85 ! 4.5 months after the initial scan. mmol/L [60 mg/dl], 1.0 to 1.5 mmol/L [40 to 59
During follow-up, we used an identical scanning pro- mg/dl], and $1.0 mmol/L [40 mg/dl], respectively;
tocol but with a C-150 Imatron scanner. and categories for triglycerides were defined as $1.7
CAC scoring: Although baseline calcium measures mmol/L [150 mg/dl], 1.7 to 2.3 mmol/L [150 to 199
were available for the entire cohort of 1,291 participants, mg/dl], and !2.3 mmol/L [200 mg/dl], respectively.
scans for 1,182 patients were recovered for re-reading The primary dependent variable was the absolute
and estimation of interpolated volume scores. Of these, change in the calcium volume score from the baseline
761 also had baseline and follow-up scans that could be scan to the follow-up scan 7 years later.
evaluated. Four hundred twenty-one subjects did not Statistical analysis: To evaluate follow-up bias,
return during the follow-up period, and 161 of the sub- baseline demographic variables, risk factors, and cal-
jects had died. Baseline demographic and clinical data cium volume scores were compared across the 761
from the 260 (421 minus 161) surviving participants who participants who returned for follow-up and had base-
did not return for a follow-up scan were used for assess- line and follow-up calcium volume data available
ing follow-up bias (see the following). compared with the 260 participants who did not return
A single cardiologist blinded to all clinical out- but were known to be alive at the time of follow-up.
come and serologic data interpreted the baseline and Statistical methods included Student’s t tests for con-
follow-up scans. The scoring software used was the tinuous variables and chi-square tests for categorical
same as that used for the Multi-Ethnic Study of Ath- variables. The primary calcium measure was the cal-
erosclerosis.13 This software includes a pixel adjust- cium volume score, which was normalized with a log
ment that uses the formula new pixel value"(old pixel transformation (loge[volume score &1]). The change
value#intercept)/slope, where slope and intercept re- in volume score was transformed in a similar fashion.
fer to the results of a least-squares linear fit relating The 11 patients with negative changes (decreases)
standard radiographic densities to the measured mean were excluded from these calculations. Two-way
brightness numbers in the calibration phantom analysis of variance was used to assess the interactive
scanned under the participants. The minimal calcific and independent effects of the 3 risk groups catego-
focus size was 4.1 mm3, chosen to be equivalent to rized according to the criteria of the National Choles-
that used previously.13 The Agatston coronary cal- terol Education Program (high, medium, and low) and
cium score was calculated according to the standard the 2 compliance groups with respect to LDL choles-
method.14 Calcium volume score was calculated by terol (LDL cholesterol controlled and not controlled)
the method of Callister and Raya.15 on the baseline calcium volume score. For progression
Risk factor determinations: Current smoking, blood in calcium volume score, 2-way analysis of covari-
pressure measurements (mean of 2 readings), fasting ance was used after adjusting for baseline calcium
lipoprotein measurements (which provided total cho- volume score and other risk factors (age, gender, race,
lesterol, high-density lipoprotein [HDL] cholesterol, diabetes, current smoker, hypertensive medication,
low-density lipoprotein [LDL] cholesterol and triglyc- cholesterol-lowering medication, baseline and fol-
erides), and electrocardiograms for left ventricular low-up averaged levels of HDL cholesterol, and tri-
hypertrophy were obtained within 2 days of scanning glycerides). In addition, 1-way analysis of variance
at baseline and at follow-up. Hypertension for pur- was used to compare the baseline volume score, and
poses of analysis was defined as a systolic blood analysis of covariance was used to compare the pro-
pressure !140 mm Hg, a diastolic blood pressure gression scores across LDL cholesterol, HDL choles-
!90 mm Hg, or a participant reporting use of antihy- terol, and triglyceride groups (optimal, borderline, and
pertensive therapy. Analysis for lipoproteins was per- high risk) for all risk groups combined. For these
formed as previously described.8 analyses, the lipid fraction being compared was not
We categorized participants into low-risk ($2 risk included as a covariate.
factors), intermediate-risk (!2 risk factors but $20% We also examined whether use of cholesterol-low-
risk of coronary heart disease over 10 years), or high- ering medication significantly affected these relations
risk (!2 risk factors and %20% risk of hard coronary (by using the presence of medication use at baseline
heart disease events in 10 years, or diabetes) groups and follow-up as interaction terms with LDL choles-
according to the National Cholesterol Education Pro- terol, HDL cholesterol, and triglyceride groups), and
gram.11 Compliance with control levels of LDL cho- whether the change in LDL cholesterol, HDL choles-
lesterol, HDL cholesterol, and triglycerides was based terol, and triglycerides from baseline added to the
on the mean of these parameters at baseline and 7 prediction of change in CAC volume. Further, given
years later. Control of LDL cholesterol was defined as the recent interest in C-reactive protein and findings
(1) LDL cholesterol $2.6 mmol/L [100 mg/dl] if high showing calcium score to stratify risk among C-reac-
risk; (2) LDL cholesterol $3.4 mmol/L [130 mg/dl] if tive protein groups,16 we examined whether our find-

432 THE AMERICAN JOURNAL OF CARDIOLOGY! VOL. 94 AUGUST 15, 2004


Progression of CAC by LDL choles-
TABLE 1 Baseline Demographic and Clinical Characteristics for Participants Who
Did and Did Not Return for Follow-up Scans terol group according to the National
Cholesterol Education Program: Table
Returned Did Not Return 2 presents the median and range of
Risk Factors* (n " 761) (n " 260) p Value†
controlled LDL cholesterol by the 3
Men 691 (91%) 216 (83%) 0.0006 risk groups according to the Adult
Age (yrs) 64.5 (7.3) 66.7 (8.1) 0.03 Treatment Panel III. Baseline calcium
Race
White 643 (85%) 200 (77%) 0.01‡ volume differed by risk group and
Black 31 (4%) 27 (10%) LDL cholesterol control status. Pair-
Asian 49 (6%) 13 (5%) wise comparison of the 3 risk groups
Hispanic 36 (5%) 20 (8%) showed that the average baseline cal-
Native American 2 (#1%) 0 (0%)
Current smoker 125 (16%) 41 (16%) 0.79
cium volume score in the high-risk
Diabetes 116 (15%) 67 (26%) 0.0001 group was much higher than that in the
Cholesterol-lowering medication 156 (21%) 57 (22%) 0.61 low-risk group (p " 0.01) and that
Hypertensive medication 291 (38%) 130 (50%) 0.001 baseline calcium volume score in the
Systolic blood pressure (mm Hg) 139.9 $ 17.9 145.5 $ 21.6 0.0001 controlled LDL cholesterol group was
Diastolic blood pressure (mm Hg) 79.5 $ 10.2 80.4 $ 11.4 0.25
LDL cholesterol significantly higher than that in the
(mmol/L) 3.9 $ 0.9 3.9 $ 1.0 0.40 noncontrolled LDL cholesterol group
mg/dl 150.3 $ 36.0 151.9 $ 40.4 (p " 0.02). After adjustment for age,
HDL cholesterol gender, race, other lipid and nonlipid
(mmol/L) 1.2 $ 0.4 1.2 $ 0.5 0.14
mg/dl 44.6 $ 14.6 46.4 $ 17.7
risk factors, and baseline calcium vol-
Triglyceride ume score, no significant differences
(mmol/L) 2.0 $ 1.7 2.2 $ 1.9 0.38 were found for progression in calcium
mg/dl 180.6 $ 151.1 190.5 $ 166.5 volume score across risk groups (p "
Positive calcium (!0) 522 (69%) 178 (68%) 0.97 0.11), LDL cholesterol control groups
Calcium volume (mm3) 27 (0–3,144) 34 (0–1,991) 0.44
(p " 0.68), or the interaction between
*Reported values are mean $ SD for continuous variables, frequency (percent) for categorical risk groups and LDL cholesterol con-
variables, and median (range) for the calcium volume score.

trol groups (p " 0.88). Findings re-
Statistical methods included the independent t test or Wilcoxon rank sum test for continuous variables,
and chi-square test or chi-square exact test for categorical variables.
mained similar after adjustment for

Across all races. measurement error when using base-
line information from the full cohort.
Progression of CAC according to
classification of LDL cholesterol, HDL
ings could be affected by C-reactive protein levels by cholesterol, and triglycerides: Table 3 lists significant
interaction terms of C-reactive protein status (!3 vs differences in baseline calcium volume score among
!3 mg/L) with each lipid group in separate analyses. LDL cholesterol groups, with baseline volume score
High-sensitivity measures of C-reactive protein at being highest in those with optimal control; the great-
baseline were measured as previously described.16 est change (increase) in volume score tended to occur
We also adjusted the calcium volume score for in this group, although differences across groups were
measurement error by using the methods proposed by not significant (p " 0.40) after adjusting for other
Yanez et al17 and using baseline information available covariates. HDL cholesterol ("1.5 mmol/L [60 mg/
from the full cohort. For our South Bay Heart Watch dl]) was significantly associated with less progression
cohort, replicate coronary calcium readings were of CAC volume (median change 151 mm3) compared
available for this analysis in 77 patients who had with those with low levels (#1.0 mmol/L [40 mg/dl];
repeat scans at baseline. All analyses were conducted median change 203 mm3; p " 0.03). Findings re-
at the 0.05 significance level and done with SAS
mained similar after adjustment for measurement
(version 2, SAS Institute, Cary, North Carolina).
error when using baseline information from the full
cohort. There were no significant differences in the
RESULTS degree of progression of CAC volume by triglycer-
Baseline characteristics: Table 1 presents baseline ide categories.
demographic variables, risk factors, and calcium vol- Effect of cholesterol-lowering medication: The prev-
ume scores for the 761 participants who returned for alence of cholesterol-lowering medication increased
follow-up and in comparison with the 260 participants from 20% (n " 154) at baseline to 48% (n " 363) at
who were alive at follow-up but did not return. Par- follow-up, with 16% of patients (n " 123) on therapy
ticipants who did not return tended to be older (p " at baseline and follow-up. There was no significant
0.03), were less likely to be men (p #0.001), and were difference in extent of progression of CAC by risk
more likely to have had diabetes or hypertension (p group, LDL cholesterol, HDL cholesterol, or triglyc-
#0.001). The distribution of ethnicity also differed eride control groups according to treatment status (as
among those who did not return (p " 0.01 vs those assessed by interaction terms with treatment defined
who did return), with larger proportions of blacks and as present at baseline only, follow-up only, or at both
Hispanics not returning. 2 time periods).

PREVENTIVE CARDIOLOGY/LIPID CONTROL AND PROGRESSION OF CORONARY CALCIUM 433


TABLE 2 Baseline and Change in Calcium Volume (in square millimeters) Stratified by National Cholesterol Education Program
Risk Groups and LDL Cholesterol Control Status Groups*
Patients Baseline Volume Change in Volume
Risk Group/LDL Cholesterol Control Level (n ! 753) Median (range) Median (range)

High/controlled "2.6 mmol/L (100 mg/dl) 42 83 (0–2,315) 326 (0–3,872)


High/uncontrolled "2.6 mmol/L (100 mg/dl) 270 36 (0–3,144) 217 ($123 to 3,592)
Intermediate/controlled "3.4 mmol/L (130 mg/dl) 131 37 (0–1,928) 239 ($4 to 2,987)
Intermediate/uncontrolled "3.4 mmol/L (130 mg/dl) 170 17 (0–1,552) 148 ($11 to 1,263)
Low/controlled "4.2 mmol/L (160 mg/dl) 96 12 (0–1,869) 77 ($93 to 2,213)
Low/uncontrolled "4.2 mmol/L (160 mg/dl) 44 13 (0–591) 97 ($27 to 1,183)
Risk group (p value) 0.01† 0.11
LDL cholesterol group (p value) 0.03‡ 0.68
Risk group % LDL cholesterol group (p value) 0.65 0.88

*LDL cholesterol was estimated averaging baseline and follow-up levels. Control of LDL cholesterol was defined as (1) "100 mg/dl if high risk, (2) "130 mg/dl
if intermediate risk, or (3) "160 mg/dl if low risk. Low-risk group: "2 risk factors; Intermediate-risk group: "2 risk factors but !20% calculated Framingham score
risk; high-risk group: diabetes or "2 risk factors and #20% calculated risk. Baseline score and change in volume score were log transformed to induce normality.
Baseline calcium volume score was analyzed by 2-way analysis of variance (3 risk groups [high, medium, and low] % 2 LDL cholesterol groups [controlled vs
noncontrolled]). Progression in calcium volume score was analyzed by 2-way analysis of covariance. Covariates were age, gender, race, diabetes, current smoker,
use of hypertensive medication use of cholesterol-lowering medication, systolic blood pressure, diastolic blood pressure, average of baseline and follow-up levels of
HDL cholesterol, and average level of triglycerides.

Average baseline volume score in high-risk group was higher than that for low-risk group (p ! 0.01).

Average baseline volume score in group with controlled LDL cholesterol was higher than that in the group with uncontrolled LDL cholesterol (p ! 0.02)

TABLE 3 Baseline and Change in Calcium Volume (in square millimeters) Stratified by LDL Cholesterol, HDL Cholesterol, and
Triglyceride Groups (NCEP Guideline)*
LDL Cholesterol Group HDL Cholesterol Group Triglyceride Group

Baseline Baseline Baseline


n Volume Change in Volume n Volume Change in Volume n Volume Change in Volume

Optimal 82 57 (0–2,315) 305 (0–3,872) 98 36 (0–2,664) 151 (0–2,213) 406 47 (0–2,664) 197 ($94 to 3,872)
Intermediate 240 34 (0–3,144) 232 ($52 to 3,592) 375 22 (0–3,144) 159 ($123 to 3,872) 140 9 (0–2,027) 106 ($123 to 2,828)
Higher risk 431 18 (0–2,027) 140 ($123 to 2,714) 288 28 (0–2,315) 203 ($52 to 2,828) 214 17 (0–3,144) 168 ($11 to 3,592)
p Value 0.001† 0.40 0.81 0.03‡ "0.0001§ 0.54

*Levels of LDL cholesterol, HDL cholesterol, and triglycerides were estimated by averaging levels at baseline and follow-up. Reported values are median (range).
Three lipids were categorized into 3 groups (optimal, intermediate, and higher risk) based on NCEP III guidelines ("100 mg/dl, 100 to "130 mg/dl, and "130
mg/dl for LDL cholesterol; "60 mg/dl, 40 to 59 mg/dl, and !40 mg/dl for HDL cholesterol; "150 mg/dl, 150 to 199 mg/dl, and "200 mg/dl for triglycerides).
Baseline score and change in volume score was log transformed to induce normality. Analysis of variance was used for baseline volume, and analysis of covariance
was used for volume changes in HDL cholesterol and triglycerides. Covariates were age, gender, race, diabetes, current smoking status; use of hypertensive
medication, use of cholesterol-lowering medication, systolic blood pressure, diastolic blood pressure, average levels of baseline and follow-up LDL cholesterol, and
average level of triglycerides.

Baseline volume score in the optimal LDL cholesterol group was higher than each of the intermediate and higher LDL cholesterol groups (p "0.05).

Change in volume score in the optimal HDL cholesterol group was significantly lower than that in the higher risk cholesterol group (p ! 0.03).
§
Baseline volume score in the optimal triglyceride group was higher than each of the intermediate and higher risk triglyceride groups (p ! 0.003).
NCEP ! National Cholesterol Education Program.

Effect of changes in lipid fractions, very low levels of terms of C-reactive protein with each lipid group
LDL cholesterol, and C-reactive protein on progression of were nonsignificant (p #0.5), indicating no effect
CAC: When the change in each lipid parameter was of baseline C-reactive protein on the relation of
included in a multiple regression model that in- lipid levels to progression of CAC.
cluded age, gender, race, other risk factors, and
baseline calcium volume and lipids, only a change DISCUSSION
in LDL cholesterol from baseline was indepen- We and others18,19 have previously documented
dently associated (inversely) with the degree of baseline levels of calcium volume or score to be, by
progression of calcium volume (p ! 0.003). In far, the strongest predictor of CAC progression, thus
addition, we examined, in a subanalysis, whether explaining most of the variation (#80% in our study)
progression of CAC might be different in those with in calcium progression. In this investigation, we found
very low levels of LDL cholesterol ("80 mg/dl); that, after adjustment for baseline calcium and other
there was no evidence of any trend of decreased risk factors, progression of CAC is inversely related to
progression of CAC in this group, although the the level of HDL cholesterol but not to control of
sample size was small (n ! 19). After examining levels of LDL cholesterol or triglycerides.
whether measurements of C-reactive protein (#3 vs Our relation of levels of HDL cholesterol to de-
!3 mg/L) affected the relation of control of each creased progression of CAC is consistent with the
lipid fraction on progression of CAC, interaction findings of others who reported decreased coronary

434 THE AMERICAN JOURNAL OF CARDIOLOGY! VOL. 94 AUGUST 15, 2004


angiographic progression in patients with low HDL those with optimal or borderline control when the
cholesterol20 and that carotid atherosclerosis is more lower of the 2 or follow-up LDL cholesterol values
common in those with low levels of HDL cholester- were used, respectively.
ol.21 The benefit of increasing levels of HDL choles- Our data provide observational evidence of a po-
terol on decreasing events of coronary heart disease tentially important benefit on progression of subclin-
has also been reported, although no relation of triglyc- ical atherosclerosis for maintaining optimal levels of
eride levels to clinical events has been observed,22 HDL cholesterol but do not support the use of com-
which is consistent with our finding of no relation of puted tomography for monitoring the effect that risk-
triglyceride control to progression of CAC. decreasing therapies, including cholesterol-lowering
Our failure to show a relation of LDL cholesterol medication, may have on this process.
or control of LDL cholesterol to decreased progres-
sion of CAC is consistent with a previous study19,23
that found no associations between calcium progres- Acknowledgment: The investigators acknowledge
sion and baseline hypercholesterolemia and another the editorial assistance of Eloisa Romero, MD, and
study24 that did not associate better control of LDL Linda Neese.
cholesterol to decreased progression of CAC. In con-
trast, other studies have reported less progression in
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