Predictors of coronary heart disease events among asymptomatic persons with low low-density lipoprotein cholesterol MESA (Multi-Ethnic Study of Atherosclerosis).

Abstract

Our aim was to identify risk factors for coronary heart disease (CHD) events among asymptomatic persons with low (≤ 130 mg/dl) low-density lipoprotein cholesterol (LDL-C).
Even among persons with low LDL-C, some will still experience CHD events and may benefit from more aggressive pharmacologic and lifestyle therapies.
The MESA (Multi-Ethnic Study of Atherosclerosis) is a prospective cohort of 6,814 participants free of clinical cardiovascular disease. Of 5,627 participants who were not receiving any baseline lipid-lowering therapies, 3,714 (66%) had LDL-C ≤ 130 mg/dl and were included in the present study. Unadjusted and adjusted hazard ratios were calculated to assess the association of traditional risk factors and biomarkers with CHD events. To determine if subclinical atherosclerosis markers provided additional information beyond traditional risk factors, coronary artery calcium (CAC) and carotid intima media thickness were each separately added to the multivariable model.
During a median follow-up of 5.4 years, 120 (3.2%) CHD events were observed. In unadjusted analysis, age, male sex, hypertension, diabetes mellitus, low high-density lipoprotein cholesterol (HDL-C), high triglycerides, and subclinical atherosclerosis markers (CAC >0; carotid intima media thickness ≥1 mm) predicted CHD events. Independent predictors of CHD events included age, male sex, hypertension, diabetes, and low HDL-C. After accounting for all traditional risk factors, the predictive value of CAC was attenuated but remained highly significant. The relationship of all independent clinical predictors remained robust even after accounting for elevated CAC.
Among persons with low LDL-C, older age, male sex, hypertension, diabetes, and low HDL-C are associated with adverse CHD events. Even after accounting for all such variables, the presence of CAC provided incremental prognostic value. These results may serve as a basis for deciding which patients with low LDL-C may be considered for more aggressive therapies.

Full text

Page 1

doi:10.1016/j.jacc.2011.01.055
2011;58;364-374
J. Am. Coll. Cardiol.
Polak, Joao Lima, Roger S. Blumenthal, and Khurram Nasir
Ron Blankstein, Matthew J. Budoff, Leslee J. Shaw, David C. Goff, Jr, Joseph F.

Atherosclerosis)
ofWith Low Low-Density Lipoprotein Cholesterol: MESA (Multi-Ethnic Study
Predictors of Coronary Heart Disease Events Among Asymptomatic Persons
This information is current as of July 12, 2011
http://content.onlinejacc.org/cgi/content/full/58/4/364
located on the World Wide Web at:
The online version of this article, along with updated information and services, is
by guest on July 12, 2011 content.onlinejacc.orgDownloaded from

Page 2

Coronary Artery Disease
Predictors of Coronary Heart Disease Events
Among Asymptomatic Persons With Low
Low-Density Lipoprotein Cholesterol
MESA (Multi-Ethnic Study of Atherosclerosis)
Ron Blankstein, MD,* Matthew J. Budoff, MD,† Leslee J. Shaw, PHD,‡
David C. Goff, JR, MD, PHD,§ Joseph F. Polak, MD, MPH,? Joao Lima, MD,¶
Roger S. Blumenthal, MD,# Khurram Nasir, MD, MPH**
Boston, Massachusetts; Los Angeles, California; Atlanta, Georgia; Winston-Salem, North Carolina;
Baltimore, Maryland; and New Haven, Connecticut
Objectives
Our aim was to identify risk factors for coronary heart disease (CHD) events among asymptomatic persons with
low (?130 mg/dl) low-density lipoprotein cholesterol (LDL-C).
Background
Even among persons with low LDL-C, some will still experience CHD events and may benefit from more aggres-
sive pharmacologic and lifestyle therapies.
Methods
The MESA (Multi-Ethnic Study of Atherosclerosis) is a prospective cohort of 6,814 participants free of clinical cardio-
vascular disease. Of 5,627 participants who were not receiving any baseline lipid-lowering therapies, 3,714 (66%) had
LDL-C ?130 mg/dl and were included in the present study. Unadjusted and adjusted hazard ratios were calculated to
assess the association of traditional risk factors and biomarkers with CHD events. To determine if subclinical athero-
sclerosis markers provided additional information beyond traditional risk factors, coronary artery calcium (CAC) and
carotid intima media thickness were each separately added to the multivariable model.
Results
During a median follow-up of 5.4 years, 120 (3.2%) CHD events were observed. In unadjusted analysis, age, male sex,
hypertension, diabetes mellitus, low high-density lipoprotein cholesterol (HDL-C), high triglycerides, and subclinical
atherosclerosis markers (CAC ?0; carotid intima media thickness ?1 mm) predicted CHD events. Independent pre-
dictors of CHD events included age, male sex, hypertension, diabetes, and low HDL-C. After accounting for all tradi-
tional risk factors, the predictive value of CAC was attenuated but remained highly significant. The relationship of all
independent clinical predictors remained robust even after accounting for elevated CAC.
Conclusions
Among persons with low LDL-C, older age, male sex, hypertension, diabetes, and low HDL-C are associated with
adverse CHD events. Even after accounting for all such variables, the presence of CAC provided incremental
prognostic value. These results may serve as a basis for deciding which patients with low LDL-C may be consid-
ered for more aggressive therapies.(J Am Coll Cardiol 2011;58:364–74) © 2011 by the American College of
Cardiology Foundation
Low values of low-density lipoprotein cholesterol (LDL-C)
are known to be associated with fewer adverse cardiovascular
events in both primary and secondary prevention studies
than are normal or elevated LDL-C values. Given this
established relationship, the treatment guidelines of the
National Cholesterol Education Program (NCEP) have
From the *Non-invasive Cardiovascular Imaging Program, Department of Medicine
(Cardiovascular Division) and Radiology, Brigham and Women’s Hospital, Boston,
Massachusetts; †Division of Cardiology, Harbor-UCLA Medical Center, Los An-
geles, California; ‡Emory University School of Medicine, Atlanta, Georgia; §De-
partment of Public Health Sciences, Wake Forest University Health Sciences,
Winston-Salem, North Carolina; ?Department of Radiology, Tufts-New England
Medical Center, Boston, Massachusetts; ¶Departments of Medicine and Radiology,
Johns Hopkins University, Baltimore, Maryland; #Ciccarone Center for the Prevention
of Heart Disease, Johns Hopkins University, Baltimore, Maryland; and the **Section
of Cardiovascular Medicine, Yale University, New Haven, Connecticut. This
research was supported by contracts N01-HC-95159 through N01-HC-95167
and N01-HC-95169 from the National Heart, Lung, and Blood Institute. Dr.
Budoff is on the Speaker’s Bureau of GE Healthcare. Dr. Goff, Jr, has served as
an Operations Committee Member for a trial of glucose lowering medication by
Merck, and has served as a DSMB Member for a trial of glucose lowering
medication marketed by Takeda. All other authors have reported that they have
no relationships to disclose. Steven E. Nissen, MD, served as Guest Editor for
this paper.
Manuscript received October 7, 2010; revised manuscript received January 6, 2011,
accepted January 24, 2011.
by guest on July 12, 2011 content.onlinejacc.org
Journal of the American College of Cardiology
© 2011 by the American College of Cardiology Foundation
Published by Elsevier Inc.
Vol. 58, No. 4, 2011
ISSN 0735-1097/$36.00
doi:10.1016/j.jacc.2011.01.055
Downloaded from

Page 3

identified lowering LDL-C as the primary target of
cholesterol-lowering therapy (1). In light of multiple trials
that have confirmed the benefit of aggressive cholesterol-
lowering therapy, the NCEP amended its guidelines in
2004 and suggested that for high-risk persons, the LDL-C
goal is ?100 mg/dl, but when risk is very high, an LDL-C
goal of ?70 mg/dl is a reasonable therapeutic strategy (2).
The results of these guidelines have helped to shape a new
paradigm shift in which some have argued that when it
comes to LDL-C, the lower the better.
To date, there is no known threshold LDL-C level below
which no further reduction in risk occurs. A study by
Lepper et al. (3) demonstrated that even among patients
with very low LDL-C (?60 mg/dl), statin use was safe and
was associated with improved survival. The JUPITER (Justi-
fication for the Use of Statins in Primary Prevention: An
Intervention Trial Evaluating Rosuvastatin) study found that
among apparently healthy persons with LDL ?130 mg/dl and
high-sensitivity C-reactive protein (hsCRP) ?2 mg/l, treat-
ment with 20 mg of rosuvastatin significantly reduced the
incidence of major cardiovascular events. It is estimated that if
these so-called JUPITER criteria are applied to the U.S.
population, ?11 million new persons may be candidates for
statin therapy (4). Given the overall low event rate of most
primary prevention trials, many patients need to be treated to
prevent 1 cardiovascular event. Thus, identifying further risk
markers for cardiovascular events may allow a more precise
identification of persons who will benefit from statin therapy.
Given that even among patients with low LDL-C some will
still experience cardiovascular events, we sought to identify risk
factors for coronary heart disease (CHD) among patients with
no known coronary artery disease (CAD) and low LDL-C.
We hypothesized that both traditional risk factors (i.e., clinical
risk factors, inflammatory biomarkers, lipids) and imaging
biomarkers of pre-clinical atherosclerosis will predict CHD
events. Our secondary aim was, thus, to identify the incremen-
tal value of these imaging markers to the more traditional,
widely available clinical risk factors.
Methods
Study participants. Details of the design and organization
of the MESA trial have been reported previously (5–7).
Between July 2000 and September 2002, 6,814 persons were
selected to be members of the MESA cohort at 6 field
centers (Baltimore, Maryland; Chicago, Illinois; Forsyth
County, North Carolina; Los Angeles, California; New
York, New York; and St. Paul, Minnesota). The partici-
pants were required to be between 45 and 84 years of age
and to have no clinical cardiovascular disease at the time of
enrollment in the study. The participants were recruited at
each site from lists of residents, dwellings, and telephone
company customers. In the last few months of the recruit-
ment period, participants were also recruited from lists of
Medicare beneficiaries obtained from the Centers for Medi-
care and Medicaid Services and by referrals from other
participants, to ensure the enrollment of adequate numbers
of elderly participants and partic-
ipants from all 4 ethnic groups.
Participants identified them-
selves as white, black, Hispanic,
or Chinese at the time of enroll-
ment. The study was approved
by the institutional review boards
of each site, and all participants
gave written informed consent.
For the purposes of the pres-
ent study, 2,201 participants
(32%) with LDL-C ?130 mg/dl
were excluded. Of the remaining
4,613 participants, 899 (19%)
who were on lipid-lowering ther-
apies at baseline were excluded.
The resulting population thus
consisted of 3,714 subjects with
low LDL-C who were free of
cardiovascular disease and were
not receiving any lipid-lowering
therapies (Fig. 1). Among this
group, 1,511 (41%) participants
had LDL-C ?100 mg/dl and
the remaining 2,203 (59%) had
LDL-C between 101 and 130
mg/dl.
Computed tomography scan-
ning. Carr et al. (8) have reported details of the methods
used by the MESA trial for computed tomography (CT)
scanning and for interpretation of the scans. Each of the 6
MESA centers assessed the amount of coronary artery
calcium (CAC) with the use of either an electron-beam CT
scanner (at the Chicago, Los Angeles, and New York
centers) or a multidetector CT system (at the Baltimore,
Figure 1 Flowchart Illustrating Study Population
CHD ? coronary heart disease; LDL-C ? low-density lipoprotein cholesterol;
MESA ? Multi-Ethnic Study of Atherosclerosis.
Abbreviations
and Acronyms
CAC ? coronary artery
calcium
CAD ? coronary artery
disease
CHD ? coronary heart
disease
CI ? confidence interval
CIMT ? carotid intima
media thickness
CT ? computed
tomography
HDL-C ? high-density
lipoprotein cholesterol
HR ? hazard ratio
hsCRP ? high-sensitivity
C-reactive protein
IMT ? intima media
thickness
LDL-C ? low-density
lipoprotein cholesterol
NCEP ? National
Cholesterol Education
Program
ROC ? receiver-operating
characteristic
365
JACC Vol. 58, No. 4, 2011
July 19, 2011:364–74
Blankstein et al.
Cardiac Events Among Persons With Low LDL-C
by guest on July 12, 2011 content.onlinejacc.orgDownloaded from

Page 4

Forsyth County, and St. Paul centers). Certified technolo-
gists placed radiographic phantoms containing identical and
known concentrations of calcium beneath the thorax of each
participant and then scanned the participant 2 times.
A radiologist or cardiologist read all CT scans at a single
center (the Los Angeles Biomedical Research Institute at
Harbor–University of California Los Angeles Medical Cen-
ter, Torrance, California) and used an interactive scoring
system similar to that of Yaghoubi et al. (9). The reader–
work station interface calibrated each tomographic image
according to the estimated attenuation of the calcium
phantom and then identified and quantified the CAC in
each image. The coronary calcium score (Agatston score)
(10) was calculated for each scan, and the mean of the 2
scans was used in all analyses. Intraobserver and interob-
server agreement was excellent (kappa statistics 0.93 and
0.90, respectively).
Carotid intima media thickness. Trained technicians in
each center performed B-mode ultrasonography of the right
and left near and far walls of the internal carotid and
common carotid arteries (11). Images were recorded using
the Logiq 700 ultrasound device (General Electric Medical
Systems, Waukesha, Wisconsin). An ultrasound reading
center (Department of Radiology, Tufts Medical Center,
Boston, Massachusetts) measured maximal carotid intima
media thickness (CIMT) of the internal and common
carotid sites as the mean of the maximum intima media
thickness (IMT) of the near and far walls of the right and
left sides.
Risk factors. As part of the baseline examination, clinical
teams at each of the 6 centers collected information on
cardiovascular risk factors, including family history, history
of smoking, hypertension, and diabetes mellitus. Using a
Dinamap Pro 1000 automated oscillometric sphygmoma-
nometer (Critikon), resting blood pressure was measured 3
times with the participant in the seated position. A central
laboratory (University of Vermont, Burlington, Vermont)
measured levels of total and high-density lipoprotein cho-
lesterol (HDL-C), triglycerides, plasma glucose, and
hsCRP in blood samples obtained after a 12-h fast.
Diabetes was defined as a fasting plasma glucose level
?125 mg/dl or a history of medical treatment for diabetes.
The body mass index was calculated as the weight in
kilograms divided by the square of the height in meters.
Family history of CHD was obtained by asking the partic-
ipants whether any member of their immediate family
(parents, siblings, and children) had had a fatal or nonfatal
myocardial infarction, coronary angioplasty, or coronary
artery bypass graft surgery. The participants were classified
as current cigarette smokers, former smokers, or persons
who had never smoked.
Follow-up. New cardiovascular events were recorded for a
median of 5.4 years. At intervals of 9 to 12 months, an
interviewer contacted each participant or a family member
by telephone to inquire about interim hospital admissions,
outpatient diagnoses of cardiovascular disease, and deaths.
To verify self-reported diagnoses, medical records were
reviewed for participants who had been hospitalized or
received an outpatient diagnosis of cardiovascular disease.
Records were obtained for 98% of reported cardiovascular
events associated with hospitalization. For participants who
had died of cardiovascular causes outside the hospital,
interviews were conducted with the next of kin and copies of
death certificates were requested.
Trained personnel abstracted data from medical records
that reported possible cardiovascular events. Two physicians
who were members of the MESA trial mortality and
morbidity review committee independently classified events
and assigned incidence dates. If they disagreed, the full
committee made the final classification.
Coronary heart disease events consisted of myocardial
infarction, angina, resuscitated cardiac arrest, or CHD
death. The diagnosis of myocardial infarction was based on
a combination of symptoms, electrocardiographic findings,
and levels of cardiac biomarkers. Hospital records and
family interviews were used to determine whether deaths
were related to CHD. A death was considered related to
CHD if it occurred within 28 days after a myocardial
infarction, if the participant had chest pain within the 72 h
before death, or if the patient had a history of CHD and
there was no known nonatherosclerotic, noncardiac cause of
death.
The adjudicators graded angina as definite, probable, or
absent on the basis of their clinical judgment. A classifica-
tion of definite or probable angina required clear and
definite documentation of symptoms distinct from the
diagnosis of myocardial infarction. A classification of defi-
nite angina also required objective evidence of reversible
myocardial ischemia or obstructive CAD. A more detailed
description of the MESA trial follow-up methods is avail-
able online (12).
Statistical analysis. We used chi-square tests for categor-
ical variables and 1-way analysis of variance tests for
continuous variables to assess for differences among partic-
ipants with and without CHD events. Medians of
C-reactive protein were compared using the Kruskal-Wallis
equality of populations rank test.
We used unadjusted and adjusted Cox proportional
hazards regression analyses to estimate hazard ratio (HR)
for CHD events. The CAC score was examined as a binary
score (presence or absence of any CAC) and as a categorical
variable (0, 1 to 100, 101 to 400, and ?400). CIMT was
examined across a binary cutpoint (with ?1 mm considered
elevated) as well as across increasing quartiles of CIMT
thickness. Low HDL-C was defined as ?40 mg/dl for men
and ?50 mg/dl for women. Elevated triglycerides were
considered ?150 mg/dl.
All risk factors that have an established association with
CHD events were included in the multivariable model. To
isolate the effect of adding imaging markers (CAC and
CIMT) to clinical and biomarker data, which are more
readily available to clinicians, the multivariable model was
by guest on July 12, 2011 content.onlinejacc.org
366 Blankstein et al.
Cardiac Events Among Persons With Low LDL-C
JACC Vol. 58, No. 4, 2011
July 19, 2011:364–74
Downloaded from

Page 5

initially computed without any imaging markers. We then
separately added CAC (both as binary and categorical
variable) and CIMT to the multivariable model to deter-
mine the incremental predictive value of these markers. In
addition, CAC and CIMT were also added to a multivari-
able model that included the Framingham risk score (as a
continuous variable). We compared the area under the
receiver-operating characteristic (ROC) curve to identify
the incremental value of adding CAC to a multivariable
model that includes nonimaging clinical characteristics as
well as to the Framingham risk score.
To describe the frequency of coronary events according to
time, we constructed Nelson-Aalen cumulative hazard ra-
tios curves for CHD events among participants with
LDL-C ?130 mg/dl. The data were stratified according to
the presence or absence of CAC score. All analyses were
performed with Stata software version 11.0 (StataCorp,
College Station, Texas). Two-tailed p values ?0.05 were
considered significant.
Results
Baseline characteristics. The final study population con-
sisted of 3,714 participants (age 62 ? 11 years, 48% males).
Table 1 shows the baseline characteristics of the entire study
population.
CHD events. During the mean follow-up of 5.4 years
(range 0 to 7 years), 120 (3.2%) subjects experienced CHD
events, corresponding to 5.9 CHD events per 1,000 person-
years of follow-up. Table 2 shows the baseline characteris-
tics of the study population stratified by participants who
had and did not have CHD events. Participants experienc-
ing CHD events were more likely to be older males with
diabetes and hypertension and to have higher levels of
triglycerides but lower HDL-C. Correspondingly, they
were found to have a significantly higher Framingham risk
score (13.9% vs. 7.2% risk of a hard CHD event over the
next decade, p ? 0.001). Participants experiencing CHD
events during the follow-up period had a higher baseline
prevalence of CAC as well a higher baseline CIMT. There
was no difference in the CHD event rate for participants
with LDL-C ?100 mg/dl versus those with LDL-C
between 101 and 130 mg/dl (Fig. 2). Figure 3 illustrates the
relationship of CAC and CIMT with CHD events. There
was a stepwise increase in events rates across increasing
categories of CAC. Conversely, there was a less pronounced
relationship between CHD events across increasing quar-
tiles of CIMT.
Unadjusted predictors of CHD events. Among the 3,714
participants with LDL-C ?130 mg/dl, significant predic-
tors of CHD events included older age, male sex, diabetes,
hypertension, low HDL-C, and elevated triglycerides (Table 3).
However, family history of myocardial infarction, tobacco
use, and elevated hsCRP were not associated with an
increased risk.
Of the imaging markers evaluated, the presence of any
CAC was the most powerful predictor of events (HR: 13.5)
Baseline Characteristics of Study Participants
Table 1 Baseline Characteristics of Study Participants
VariableTotal Population
n 3,714
Age, yrs 61.6 ? 10.5
Sex, % male47.9
Race, %
Caucasian 36.9
Chinese13.0
African American 28.5
Hispanic 21.7
Cigarette smoking, %
Never49.5
Former 36.6
Current13.9
Hypertension, % 42.5
Diabetes mellitus, %12.8
Total cholesterol, mg/dl178.5.8 ? 24.6
HDL, mg/dl51.9 ? 16.1
LDL, mg/dl102.4 ? 19.8
TG, mg/dl103 (72–154)
Non-HDL, mg/dl126.6 ? 23.8
CRP, mg/l 1.87 (0.79–4.31)
IMT ?1 mm, % 31.1
CAC score ?0, %44.4
Framingham risk score7.45
Values are n, mean ? SD, %, or median (interquartile range).
CAC ? coronary artery calcium; CRP ? C-reactive protein; HDL ? high-density lipoprotein; IMT ?
intima media thickness; IQR ? interquartile range; LDL ? low-density lipoprotein; TG ?
triglycerides.
Baseline Characteristics Stratified byOccurrence of CHD Events During Follow-Up
Table 2
Occurrence of CHD Events During Follow-Up
Baseline Characteristics Stratified by
Variable No CHD CHDp Value
Age, yrs61.369.1
?0.001
Sex, % male 46.975.0
?0.001
Total cholesterol, mg/dl 178.6 176.10.27
Non-HDL cholesterol, mg/dl 126.4 131.00.04
HDL cholesterol, mg/dl52.2 45.1
?0.001
LDL cholesterol, mg/dl102.3 103.00.70
Triglycerides, mg/dl, median 102.0 125.50.002
Race, % 0.39
Caucasian36.643.3
Chinese13.1 9.2
African American28.627.5
Hispanic21.720.0
Hypertension, %41.570.8
?0.001
Diabetes mellitus, %12.329.2
?0.001
Cigarette smoking, % 0.15
Never49.8 42.5
Former 36.345.0
Current14.012.5
CRP, mg/l, median1.891.66 0.85*
CAC ?0, %42.9 89.2
?0.001
Carotid IMT ?1 mm, % 30.453.1
?0.001
Framingham risk score 7.2 13.9
?0.001
*By Kruskal-Wallis.
CHD ? coronary heart disease; other abbreviations as in Table 1.
by guest on July 12, 2011 content.onlinejacc.org
367
JACC Vol. 58, No. 4, 2011
July 19, 2011:364–74
Blankstein et al.
Cardiac Events Among Persons With Low LDL-C
Downloaded from