Vascular Biomarkers in the Prediction of Clinical
Cardiovascular Disease
The Strong Heart Study
Mary J. Roman, Jorge R. Kizer, Lyle G. Best, Elisa T. Lee, Barbara V. Howard,
Nawar M. Shara, Richard B. Devereux
Abstract—We compared the ability of separately measured intimal-medial thickness and atherosclerotic plaque to predict
incident cardiovascular disease. American Indian men and women from the Strong Heart Study who were free of
cardiovascular disease were evaluated with carotid ultrasound and cardiovascular disease risk factor assessment.
End-diastolic intimal-medial thickness of the common carotid arteries was measured and averaged. Arterial mass
(cross-sectional area) was calculated from intimal-medial thickness and end-diastolic diameter. Atherosclerosis was
defined by focal plaque (discrete thickening 50% relative to the adjacent wall) and the number of carotid segments
containing plaque (plaque score); 2441 participants (age 638 years) were followed-up for a mean of 7.72.8 years,
during which time 495 experienced incident cardiovascular disease events. Time-to-event analyses were performed in
groups stratified according to diabetes and hypertension status. Cardiovascular disease events were predicted by
presence and extent of atherosclerosis in all groups; intima-medial thickness and arterial mass were only associated with
outcomes when neither hypertension nor diabetes was present. Unequivocal evidence of atherosclerosis (plaque)
and its extent (plaque score) are independently associated with incident cardiovascular disease events in
individuals without preexisting cardiovascular disease regardless of diabetes and hypertension status.
Hypertension-related increases in intima-media thickness and arterial mass appear to limit their use as measures
of early or diffuse atherosclerosis and, hence, association with cardiovascular disease outcomes. These findings
support the utility of separate assessment of focal atherosclerosis and intimal-medial thickness in epidemiological
studies, trials, and risk stratification protocols. (Hypertension. 2012;59:29-35.)
Key Words: cardiovascular disease prognosis
carotid arteries
epidemiological methods
D
uplex carotid ultrasonography traditionally has been
used as a clinical tool to evaluate the presence of
significant stenosis in the setting of asymptomatic carotid
bruit or clinical cerebrovascular disease. More recently, the
technique has been utilized in epidemiological studies to
detect subclinical vascular disease (intimal-medial thickness
[IMT] and nonobstructive plaque) and to assess its relation to
cardiovascular disease (CVD) risk factors and prevalent and
incident cardiovascular disease.
1
Studies examining the prog-
nostic value of carotid ultrasonography have varied in meth-
odology. Importantly, IMT and plaque have not always been
separately evaluated. Focal plaque is a direct manifestation of
atherosclerosis, whereas IMT has been considered a measure
of diffuse or early atherosclerosis. However, IMT is increased
by hypertension because of medial hypertrophy unrelated to
atherosclerosis
2
and is not increased in chronic inflammatory
diseases despite markedly premature subclinical (and clini-
cal) atherosclerosis manifest by focal plaque.
3–5
Thus proto-
cols reporting wall thicknesses that incorporate focal plaque
thickness conflate the 2 entities and thereby potentially
overstate the prognostic importance of IMT.
Although a number of studies have separately examined
IMT and plaque in relation to CVD outcomes, several
limitations are noteworthy. Multivariable analyses including
standard CVD risk factors have not always been performed to
examine the independent or additive associations of carotid
ultrasound findings.
6–8
Some studies have limited CVD
events to either myocardial infarction
6,9,10
or stroke.
11,12
Other
studies have examined combined carotid and femoral artery
IMT
7,8
or have used study-specific internal reference values
of multiple averaged IMT segments.
13
Thus, the present study
was designed to evaluate the separate prognostic associations
of definite carotid atherosclerosis (presence and extent of
plaque) and common carotid artery (CCA) wall thickness
Received August 28, 2011; first decision September 16, 2011; revision accepted October 11, 2011.
From the Division of Cardiology (M.J.R., J.R.K., R.B.D.), Weill Cornell Medical College, New York, NY; Missouri Breaks Industries Research
(L.G.B.), Timber Lake, SD; Center for American Indian Health Research (E.T.L.), University of Oklahoma Health Sciences Center, Oklahoma City, OK;
Medstar Health Research Institute (B.V.H., N.M.S.), Washington, DC.
Correspondence to Mary J. Roman, Division of Cardiology, Weill Cornell Medical College, 525 East 68th Street, New York, NY 10021. E-mail
mroman@med.cornell.edu
© 2011 American Heart Association, Inc.
Hypertension is available at http://hyper.ahajournals.org DOI: 10.1161/HYPERTENSIONAHA.111.181925
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