(Circulation. 2000;101:e16.)
© 2000 American Heart Association, Inc.
AHA Scientific Statement |
Prevention Conference V
Beyond Secondary Prevention : Identifying the High-Risk Patient for Primary Prevention : Noninvasive Tests of Atherosclerotic Burden : Writing Group III
Key Words: AHA Conference Proceedings • atherosclerosis • tests • prevention • risk factors • prognosis • risk assessment
Writing Group I of Prevention Conference V
considered the role of routine office-based measures for assessing
global risk in asymptomatic persons. With the
physician-directed office risk assessment as a foundation, further risk
stratification may be valuable, especially when the risk estimate is
neither clearly low risk nor high risk (intermediate risk). For the
intermediate-risk patient, further testing might include 
1
noninvasive measure of atherosclerotic burden.
Pathology studies have documented that levels of traditional risk factors are associated with the extent and severity of atherosclerosis. However, at every level of risk factor exposure, there is substantial variation in the amount of atherosclerosis. This variation in disease is probably due to genetic susceptibility; combinations and interactions with other risk factors, including life habits; duration of exposure to the specific level of the risk factors; and such factors as biological and laboratory variability. Thus, subclinical disease measurements, representing the end result of risk exposures, may be useful for improving coronary heart disease (CHD) risk prediction.
Noninvasive tests such as carotid artery duplex scanning, electron beam–computed tomography (EBCT), ultrasound-based endothelial function studies, ankle/brachial blood pressure ratios, and magnetic resonance imaging (MRI) techniques offer the potential for directly or indirectly measuring and monitoring atherosclerosis in asymptomatic persons. High-sensitivity testing for C-reactive protein (hs-CRP) may also represent a measure of atherosclerosis "burden" and may therefore be considered another potential marker of atherosclerosis disease risk. The Prevention Conference V participants considered the status of several measures of subclinical disease in CHD risk assessment. The discussion that follows is a summary of the data reviewed and discussed at Prevention Conference V.
Ankle-Brachial Blood Pressure Index
During the discussion groups at Prevention Conference V, the
ankle-brachial blood pressure index (ABI) was considered as a means of
predicting CHD events. The ABI is a simple, inexpensive
diagnostic test for lower-extremity peripheral
arterial disease (PAD). Among well-trained operators,
test-retest reliability is excellent, and the validity of the test for
stenosis 50% in leg arteries is high (sensitivity 
90%
and specificity 98%).1 2
The ABI can be measured in a vascular laboratory or physician’s office
with inexpensive equipment, which consists of an ordinary blood
pressure cuff and a Doppler ultrasonic sensor.3 The
blood pressure cuff is used to measure systolic blood pressure
in the brachial artery in both arms by use of the Doppler detector
in the antecubital fossa. The blood pressure cuff is then applied to
the ankle, and the Doppler probe is used to determine
systolic blood pressure at the left and right posterior tibial
arteries and dorsalis pedis arteries. The ABI for each leg equals the
ratio of the higher of the 2 systolic pressures (posterior
tibial or dorsalis pedis) in the leg and the average of the right and
left brachial artery pressures, unless there is a discrepancy 10
mm Hg in blood pressure values between the 2 arms. In such a case, the
higher reading is used for the ABI. Pressures in each leg should also
be measured and ABI calculated separately for each leg. An ABI <0.90
in either leg is considered evidence of PAD, and progressively lower
ABI values indicate more severe obstruction.
There is a considerable overlap of persons with ABI-detectable PAD and clinical cardiovascular disease. In population studies, persons with a low ABI have been found to have considerably higher prevalence of cardiovascular disease (CVD) (defined as history of myocardial infarction [MI], coronary artery bypass graft, stroke, or stroke surgery, or other measures of clinical CVD such as angina or congestive heart failure) than persons with a normal ABI.4 These data confirm that atherosclerosis is a diffuse (ie, systemic) disease and that an abnormal ABI test (ie, low ratio) will often indicate significant atherosclerosis in other vascular beds.
At least 3 studies5 6 7 have reported a combined incidence
of CVD morbidity and mortality in persons with PAD detected by ABI.
Several other studies have reported on the ability of ABI to predict
future coronary, total CVD, and all-cause
mortality.8 9 10 In 1 study, Criqui et al9
found that ABI-detected PAD in men and women with an average age of 66
years had a markedly increased risk of CVD mortality (relative risk
[RR] 6.3), CHD mortality (RR 4.8), and all-cause mortality (RR 3.1).
High relative risks were found even after excluding persons with known
CVD at baseline and after adjustment for other CVD risk factors such as
cholesterol, age, sex, smoking, glucose level, and high
body mass index. An abnormal ABI is generally, but not exclusively,
found in men and women >50 years of age11 ; therefore,
consideration of ABI for risk assessment should be restricted to
persons 50 years old.
Conclusions
The ABI is a simple, inexpensive, noninvasive measure of PAD. Many
asymptomatic persons 50 years of age will have abnormal
ABI values. Follow-up studies have shown that an abnormal ABI provides
incremental coronary and all-CVD risk assessment information
over and above that provided by traditional risk factors. The writing
group concluded that the ABI might be a useful addition to the
assessment of CHD risk in selected populations, especially in persons
50 years old or those who appear to be at intermediate or higher risk
of CVD on the basis of traditional risk factor assessment, such as
smokers or persons with diabetes, who have a particularly high risk of
PAD. If a patient is found to have an abnormal ABI, he or she can be
elevated to a higher risk category. The high relative risk in patients
with an abnormal ABI is similar to that of patients qualifying for the
AHA Secondary Prevention regimen.12
B-Mode Ultrasound
B-mode ultrasound is a relatively inexpensive and safe technique
that can noninvasively visualize the lumen and walls of selected
arteries, including the carotid, aorta, and femoral. B-mode ultrasound
has been validated for measuring intima-media thickness (IMT) in
several independent laboratories, and its reliability has been
established in single- and multicenter studies.13 Current
ultrasound instrumentation with transducers 8 MHz are most capable of
identifying the 2 arterial interfaces (lumen-intima and
media-adventitia) necessary for measuring IMT. The screening
examination is performed bilaterally on the extracranial carotid artery
segments. These segments are the distal straight 1 cm of the common
carotid arteries, the carotid bifurcations, and the proximal 1 cm of
the internal carotid arteries. Circumferential longitudinal scans can
identify IMTs that are >1.3 mm on the near and far walls of each
segment (total of 6 walls per side). A template can be used to identify
these IMT values. If the IMT value is >1.3 mm, the actual
thickness of each lesion is measured with ultrasound instrument
calipers. IMT is an operational measurement definition of a single
characteristic of atherosclerosis based on considerable
information documenting that both the intima and media are involved in
atherogenesis and the anatomical progression of lesions. Several
pathological studies have demonstrated that increases in intimal
thickness (fibromuscular hyperplasia) are associated with aging and
that medial thickness (smooth muscle hypertrophy) is
associated with hypertension, even in the absence of atherosclerotic
plaque.
Cross-sectional associations between common carotid artery IMT and
cardiovascular risk factors have been demonstrated in
several studies.14 15 16 Similarly, common carotid IMT has
been associated with prevalent cardiovascular disease
in cross-sectional studies.15 16 17 18 Furthermore, 5
published studies found that carotid IMT measurement is a viable
predictor of the presence of coronary
atherosclerosis and its clinical
sequelae.19 20 21 22 23 Thus, carotid IMT defined by noninvasive
B-mode ultrasound has been shown to be an independent risk factor for
CHD events and stroke. The strongest data relating IMT measurement with
incident cardiovascular events derive from the
Atherosclerosis Risk in Communities (ARIC)
Study.21 In this study, the relation of carotid IMT to CHD
incidence was studied over 4 to 7 years of follow-up in 4 US
communities from samples of 7289 women and 5552 men aged 45 to 64 years
who were free of clinical CHD at baseline. The hazard rate ratio
comparing extreme mean IMT (1 mm) to not extreme IMT (<1
mm) was 5.07 for women (95% confidence interval [CI], 3.08 to 8.36)
and 1.85 for men (95% CI, 1.28 to 2.69). The relation was graded
(monotonic), and although the strength of the association was reduced
by including major CHD risk factors, it remained elevated at a higher
IMT.21
In the Cardiovascular Health Study,23
associations between the thickness of the carotid-artery intima and
media and the incidence of new MI or stroke in persons without clinical
CVD were studied in 5858 subjects 65 years of age. The relative risk
of MI or stroke increased linearly with IMT. The relative risk of MI or
stroke (adjusted for age and sex) for the quintile with the highest
thickness compared with the lowest was 3.87 (95% CI, 2.72 to 5.51).
The association between cardiovascular events and IMT
remained significant after adjustment for traditional risk factors,
showing increasing risk for each quintile of combined IMT, from the
second quintile (RR 1.54; 95% CI, 1.04 to 2.28), to the third (RR
1.84; 95% CI, 1.26 to 2.67), fourth (RR 2.01; 95% CI, 1.38 to 2.91),
and fifth (RR 3.15; 95% CI, 2.19 to 4.52).
Several clinical intervention or prevention trials have illustrated the
ability of carotid B-mode ultrasound imaging to monitor changes in IMT
over time.24 25 26 Many epidemiological and clinical studies
have documented that the average annual IMT progression rates are
0.03 mm. In such plaque monitoring studies, quantitative quality
control of sonographers who perform the examinations and readers who
make the measurements was found to be critical. Although serial
measurements can be standardized in well-controlled research settings,
protocols for sonographers to monitor IMT over time in a valid and
reliable manner have not yet been implemented in clinical practice
environments. This represents a barrier to routine use of IMT
for serial assessment of plaque progression/regression in medical
practice. Provided that technical issues of this type can be resolved
by using standardized protocols for scanning and monitoring of IMT,
this method would be useful in follow-up of patients treated for plaque
progression or regression.
A further issue is whether B-mode ultrasound can provide information about individual plaques that are susceptible to rupture, with subsequent thrombosis and/or embolization. Several reports have indicated that B-mode densitometric evaluation gray scale intensity of plaques is feasible and valid when compared with the anatomic pathology of lesions. Although such information may not be specific for chemical components or metabolic byproducts within the arterial wall, gray scale intensity tissue characteristics are known within reasonable limits. Highly echogenic structures include fibrous connective tissue such as collagen and minerals, cholesterol monohydrate crystals, etc. Hypoechoic tissue includes necrotic regions of the plaque, recent hemorrhage into lesions, lipid filled cores, etc. Hypoechoic plaques, particularly those with thin fibromuscular caps, in combination with carotid IMT measurements, have the potential to identify unstable plaques prone to rupture. Further research is needed to establish this role for B-mode ultrasound.
Conclusions
Carotid artery B-mode ultrasound imaging is a safe, noninvasive,
and relatively inexpensive means of assessing subclinical
atherosclerosis. The technique is a valid and reliable
means of measuring IMT, an operational measure of
atherosclerosis. The severity of carotid IMT is an
independent predictor of transient cerebral ischemia, stroke,
and coronary events such as MI. Writing Group III concluded
that in asymptomatic persons >45 years old, carefully
performed carotid ultrasound examination with IMT measurement can add
incremental information to traditional risk factor assessment. In
experienced laboratories, this test can now be considered for further
clarification of CHD risk assessment at the request of a physician.
Coronary Calcium Scores in Assessment of Coronary Artery Disease Risk
Calcification within the coronary arterial
wall is a recognized marker of
atherosclerosis.27 EBCT and helical CT are
highly sensitive methods of detecting coronary
calcium28 and are being intensively evaluated as a
noninvasive means of defining coronary atherosclerotic disease
and identifying the asymptomatic but high-risk coronary
artery disease (CAD) patient. EBCT uses an electron sweep of stationary
tungsten target rings to generate x-ray images that can detect small
amounts of calcium with considerable accuracy,28 whereas
helical CT uses a continuously rotating x-ray source. Both allow
quantification of calcium area and density, and both are relatively
high cost. Histologic studies support the association of tissue
densities 130 Hounsfield units with calcified plaque.29
EBCT calcium scores correlate with pathological examination of the
atherosclerotic plaque.30 Importantly, however, vulnerable
plaque can be present in the absence of calcium.
EBCT calcium correlates with coronary angiographic findings. Studies have compared EBCT findings with coronary angiographic obstruction31 32 33 and have confirmed high sensitivity of EBCT calcium scores for detecting obstructive CAD, at least in some patient populations. EBCT calcium scores appear to add to the prediction of angiographic CAD findings over and above associations with conventional risk factors.33 Although EBCT is extremely sensitive for defining coronary calcium, the extent and site of calcium deposition do not equate with site-specific stenosis.34 Sex differences appear to play a role in the development of coronary calcium. In 1 study, the prevalence of coronary calcium in women was half that of men until age 60, when the difference diminished. Several studies have documented that reliability of coronary calcium scores is high. Limited recent data suggest that EBCT calcium scores may be of value in follow-up of patients for progression or regression of atherosclerosis, including patients on 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors.35
Relatively few prospective data link coronary calcium scores
with risk of subsequent CHD events. A multicenter EBCT calcium study by
Detrano et al36 reviewed event data in 491 patients
who underwent both an EBCT calcium study and coronary
angiography. Most patients were symptomatic and were
referred for angiography because of suspected CAD.36 A
calcium score 100 was useful for separating patients with cardiac
events from those without events. A logistic regression model, which
included calcium score, age, sex, and coronary angiographic
findings as independent variables, was used in EBCT calcium scores,
which were a better predictor of heart disease events than the number
of arteries with lumenal diameter stenosis 50%.
Risk-prediction data in asymptomatic persons (the primary focus of Prevention Conference V) are sparse. Arad et al37 reported a strong correlation between coronary calcium and prediction of cardiac events in asymptomatic persons who underwent coronary calcium screening by EBCT in response to advertisements and physician referrals. In the most recent follow-up from this group,38 1136 asymptomatic persons were monitored for 3.6 years (mean). There were 40 cardiovascular events, including 2 deaths, 14 MIs, 14 coronary bypass operations, and 10 coronary angioplasties. For a coronary artery calcium score of 600, sensitivity was 80% and specificity 85% for predicting cardiac events. Other risk factors measured or reported at the time of EBCT, such as the presence of hypercholesterolemia, high-density lipoprotein (HDL) cholesterol, hypertension, diabetes mellitus, and family history, did not predict CAD events.38 Reports from other groups suggest that the coronary calcium score adds to CAD risk prediction but may not be as strongly additive to traditional risk factors as suggested by the data of Arad et al. In the Arad study, physicians were aware of the calcium score and may have preferentially recommended intervention on that basis; therefore, these data are subject to referral bias. After the Prevention Conference V ended, a further report suggested that the EBCT calcium score was about equal to the Framingham risk score for predicting future coronary events.39
Conclusions
The presence of coronary calcium correlates strongly with
coronary atherosclerosis. Because the severity
of coronary atherosclerosis is well known (from
pathological or angiographic studies) to be associated with risk of
coronary events, coronary calcium scores likewise
should correlate with risk for coronary events. However, the
extent to which coronary calcium scores predict
coronary events independent of the traditional coronary
risk factors needs further study. This latter uncertainty must be
weighed against the costs of measurement and the risk that the test
results may create enough concern for patients and their physicians to
lead to inappropriate and invasive coronary evaluation. Because
of these uncertainties and concerns, Writing Group III was reluctant to
advocate the use of EBCT for routine risk assessment despite its
promise. The greatest potential for coronary calcium scores
appears to be in the detection of advanced coronary
atherosclerosis in patients who are apparently at
intermediate risk. Conversely, low or absent coronary calcium
scores may prove valuable in determining a low risk for CAD events.
Some clinicians and researchers currently recommend the use of the
coronary calcium score in risk assessment in these ways.
However, the majority opinion of Writing Group III was that until there
is more definitive information about the additive value of calcium
scores in asymptomatic persons, coronary calcium
measurement should not be recommended for routine risk assessment in
asymptomatic populations. Selected use of the
coronary calcium scores in a patient with intermediate
coronary disease risk may be appropriate. The Prevention
Conference V participants look forward to further research on
coronary calcium screening and its relation to future clinical
events. Such studies should be performed in as unbiased a manner as
possible so that use of the calcium score does not confound occurrence
of subsequent clinical events. Further studies of the role of calcium
scores in patient follow-up for assessing clinically relevant
progression or regression of CAD are also needed.
MRI and Atherosclerotic Disease
There has been increasing awareness of the importance of composition of atherosclerotic plaque as a major risk factor for acute coronary syndromes. However, some current imaging modalities such as angiography, although useful for evaluating lumenal narrowing and the consequences of reduced flow, are poor for evaluation of the vessel wall and characterization of plaque. MRI has been shown to characterize tissue noninvasively in many different study systems.40 41 42 Therefore, research has begun to focus on the use of in vivo MRI to evaluate the vessel wall in several animal models and humans. A combination of MR techniques was used to image in vitro carotid, aortic, and coronary artery specimens obtained at autopsy; all the different components of plaque were identified.43 44 45 Subsequent work imaging carotid arteries in vivo in patients referred for endarterectomy showed a high correlation with pathology.46
A recent study of patients with plaques in the thoracic aorta showed that in comparison with transesophageal echocardiography, plaque composition and size are accurately characterized and measured with MRI.47 Carotid and aortic atherosclerotic assessment with MRI may lead to its use as a screening tool for predicting future cardiovascular events and evaluating therapeutic interventions. These techniques have already been adapted for the study of plaques in different animal models.48 49 A goal for MRI is imaging plaque in vivo in coronary arteries, which is difficult because of their size and cardiorespiratory motion. Studies in an in vivo pig model50 51 and normal human subjects suggest that the MRI technique may eventually be applicable to the study of human coronary arteries in vivo.
Conclusions
MRI is a promising research tool, but its use appears to be
limited to only a small number of research laboratories at this time.
With further development, MRI may provide a means of understanding the
progression and prevention of atherosclerosis and
coronary disease. Writing Group III concluded that MRI is not
yet appropriate for use in identifying patients at high risk for CAD.
The Prevention Conference V participants have recommended that more
studies of MRI in CHD risk prediction should be encouraged. Additional
technical development in this area is expected and should be of
considerable value in the application of this emerging technology.
Endothelial Function Studies and Risk for CAD
Endothelial cells play a central role in inhibiting the development of atherosclerosis and its thrombotic consequences. Endothelial cell production of nitric oxide inhibits monocyte, leukocyte, and platelet adhesion to the vessel wall; decreases permeability to low-density lipoprotein; and inhibits smooth muscle cell proliferation. High-resolution ultrasound techniques can noninvasively study endothelial function by measuring endothelium-dependent vasodilator responses to various stimuli and can be used in clinical as well as population-based settings.
The most frequently used endothelial-directed vasodilator stimulus is an increase in blood flow. Increases in fluid shear stress stimulate endothelial cell release of nitric oxide, causing prompt dilation of the artery. To produce this stimulus, most investigators use ischemia-induced hyperemia in the distal forearm, resulting in a 2- to 5-fold increase in brachial blood flow. High-resolution 2D ultrasound measures the diameter of the artery before and after the flow stimulus.52 53 Responses to other vasomotor stimuli, such as the cold pressor test or mental stress, have also been examined. Clinical studies, generally each with a small number of subjects, found that brachial flow-mediated vasodilator responses may reflect an important element of the vascular health state. For example, patients with risk factors for CHD54 55 as well as those with established CHD56 have impaired vasodilator responses. Lipid-lowering therapy,57 antioxidants, and estrogen replacement have each been shown to improve these responses, and in some studies, changes are evident in as little as 4 to 6 weeks.
Investigators are still seeking to improve the methods for ultrasonographic analysis of brachial artery vasomotion. Progress has been made on methodological issues such as duration of ischemia required for an appropriate flow stimulus and characterization of the time course of the vasodilator response. However, lower-frequency ultrasound images have hampered accurate quantification of brachial artery diameter, and inter-reader variability has led to difficulties in replicating data and quantifying the real magnitude of response. To achieve optimal results, careful attention must be paid to details such as minimizing the patient’s stress or discomfort, recent fat intake, cigarette smoking, and other transient exposures that may alter sympathetic tone. More precise analysis techniques are now available in the form of automated continuous estimation of brachial artery responses. The technique is skill- and labor-intensive and not yet easily used in routine clinical practice.
Conclusions
Although the assessment of endothelial function,
as measured most typically by flow-mediated brachial artery
vasodilation, is a promising technique that may reflect an independent
measure of CVD risk, additional prospective research is needed to
demonstrate that this technique can truly add to standard CVD risk
prediction. In addition, standardization and improvement of the
measurement technique are needed before this modality can become a part
of routine clinical assessment of CVD risk.
High-Sensitivity C-Reactive Protein as a Marker of Risk for CAD
A number of blood factors have received attention as potential new markers of CAD and all-CVD risk. The list of potential candidates includes total plasma homocysteine [tHcy], lipoprotein(a) [Lp(a)], fibrinolytic function as assessed by tPA and plasminogen activator inhibitor-1 (PAI-1) antigens, and inflammatory parameters such as fibrinogen and C-reactive protein (CRP). Many of these markers are not yet considered applicable for routine clinical CVD risk assessment because of (1) lack of measurement standardization [eg, Lp(a) testing, fibrinogen, and total plasma homocysteine]; (2) lack of consistency in epidemiological findings from prospective studies with CVD end points [eg, data for Lp(a) and tHcy are inconsistent]; and (3) lack of evidence that the novel marker adds to risk prediction above that already achievable by use of established cardiovascular risk factors.58 Regarding the latter point, the demonstration that a given marker has predictive value in univariate analysis is not sufficiently compelling because the observed association may be the result of confounding by traditional risk factors [eg, this is a problem for fibrinolytic markers such as tPA and PAI-1; data on the additive value of Lp(a) and homocysteine are also inconsistent].
Laboratory evidence and findings from pathology studies suggest that the inflammatory process plays an important part in the atherosclerotic process.59 CRP is a sensitive marker for vascular inflammation, and it has been suggested that hs-CRP may provide a novel method to assess CVD risk that is additive to that of traditional CVD risk factors. Several prospective studies60 61 62 63 64 65 of hs-CRP have shown a consistent relation between baseline concentration of CRP and future CVD events. Perhaps the most intriguing data are those from the Physicians’ Health Study,60 63 which found that healthy male physicians in the highest CRP quartile at baseline had a 2-fold higher risk of stroke, a 3-fold higher risk of MI, and a 4-fold higher risk of severe PAD. Furthermore, these increased risks were independent of all other measured CVD risk factors and were not modified by smoking status. Similar findings have also been reported for initially healthy women in the Women’s Health Study64 as well as in a population-based prospective cohort from the Monitoring Trends and Determinants in Cardiovascular Disease (MONICA) Augsburg Cohort.65 Thus, hs-CRP shows promise as a new test for improving CVD risk assessment. Standardized commercial tests for hs-CRP should soon be available so that risk assessment with hs-CRP can be considered outside of research settings. In this regard, CRP could be considered a marker of existing arterial disease, as opposed to a primary risk factor leading to future disease.
Conclusions
hs-CRP has been shown to predict future coronary events in
several prospective studies and may add to the predictive value of
lipid testing alone.66 Commercially available hs-CRP may
become available in the near future. Writing Group III concluded that
further studies of this approach to risk prediction are warranted and
should be undertaken before this measurement can be recommended as an
addition to the routine assessment of coronary risk.
Footnotes
In connection with Prevention Conference V, Writing Group I has published a complete report on "Medical Office Assessment" (Circulation. 2000;101:e3–e11), and Writing Group II has published a complete report on "Tests for Silent and Inducible Ischemia" (Circulation. 2000;101:e12–e15). In addition, the Executive Summary of "Prevention Conference V: Beyond Secondary Prevention: Identifying the High-Risk Patient for Primary Prevention" has been published in Circulation (Circulation. 2000;101:111–116).
References
1. Yao ST, Hobbs JT, Irvine WT. Ankle systolic pressure measurements in arterial disease affecting the lower extremities. Br J Surg. 1969;56:676–679.[Medline] [Order article via Infotrieve]
2. Ouriel K, McDonnell AE, Metz CE, Zarins CK. Critical evaluation of stress testing in the diagnosis of peripheral vascular disease. Surgery. 1982;91:686–693.[Medline] [Order article via Infotrieve]
3.
Orchard TJ, Strandness DE Jr. Assessment of
peripheral vascular disease in diabetes: report and
recommendations of an international workshop sponsored by the American
Diabetes Association and the American Heart Association September
18–20, 1992 New Orleans, Louisiana. Circulation. 1993;88:819–828.
4. Criqui MH, Denenberg JO, Langer RD, Fronek A. The epidemiology of peripheral arterial disease: importance of identifying the population at risk. Vasc Med. 1997;2:221–226.[Medline] [Order article via Infotrieve]
5. Criqui MH, Langer RD, Fronek A, Feigelson HS. Coronary disease and stroke in patients with large vessel peripheral arterial disease. Drugs. 1991;42(suppl 5):16–21.
6. Ogren M, Hedblad B, Jungquist G, Isacsson SO, Lindell SE, Janzon L. Low ankle-brachial pressure index in 68-year-old men: prevalence, risk factors and prognosis: results from prospective population study "Men born in 1914," Malmo, Sweden. Eur J Vasc Surg. 1993;7:500–506.[Medline] [Order article via Infotrieve]
7.
Newman AB, Sutton-Tyrrell K, Vogt MT, Kuller LH.
Morbidity and mortality in hypertensive adults with a low ankle/arm
blood pressure index. JAMA. 1993;270:487–489.
8. McKenna M, Wolfson S, Kuller L. The ratio of ankle and arm arterial pressure as an independent predictor of mortality. Atherosclerosis. 1991;87:119–128.[Medline] [Order article via Infotrieve]
9. Criqui MH, Langer RD, Fronek A, Feigelson HS, Klauber MR, McCann TJ, Browner D. Mortality over a period of 10 years in patients with peripheral arterial disease. N Engl J Med. 1992;326:381–386.[Abstract]
10.
Vogt MT, Cauley JA, Newman AB, Kuller LH, Hulley SB.
Decreased ankle/arm blood pressure index and mortality in elderly
women. JAMA. 1993;270:465–469.
11.
Criqui MH, Fronek A, Barrett-Connor E, Klauber MR,
Gabriel S, Goodman D. The prevalence of peripheral
arterial disease in a defined population.
Circulation. 1985;71:510–515.
12. Smith SC Jr, Blair SN, Criqui MH, Fletcher GF, Fuster V, Gersh BJ, Gotto AM, Gould KL, Greenland P, Grundy SM, et al. Preventing heart attack and death in patients with coronary disease. Circulation. 1995;92:2–4.
13. Chambless LE, Zhong MM, Arnett D, Folsom AR, Riley WA, Heiss G. Variability in B-mode ultrasound measurements in the atherosclerosis risk in communities (ARIC) study. Ultrasound Med Biol. 1996;22:545–554.[Medline] [Order article via Infotrieve]
14. Poli A, Tremoli E, Colombo A, Sirtori M, Pignoli P, Paoletti R. Ultrasonographic measurement of the common carotid artery wall thickness in hypercholesterolemic patients: a new model for the quantitation and follow-up of preclinical atherosclerosis in living human subjects. Atherosclerosis. 1988;70:253–261.[Medline] [Order article via Infotrieve]
15.
O’Leary DH, Polak JF, Kronmal RA, Kittner SJ, Bond MG,
Wolfson SK Jr, Bommer W, Price TR, Gardin JM, Savage PJ. Distribution
and correlates of sonographically detected carotid artery disease in
the Cardiovascular Health Study: the CHS Collaborative
Research Group. Stroke. 1992;23:1752–1760.
16.
Mannami T, Konishi M, Baba S, Nishi N, Terao A.
Prevalence of asymptomatic carotid atherosclerotic lesions
detected by high-resolution ultrasonography and its relation to
cardiovascular risk factors in the general population
of a Japanese city: the Suita study. Stroke. 1997;28:518–525.
17.
Bots ML, Breslau PJ, Briet E, de Bruyn AM, von Vliet
HH, vanden Ouweland FA, de Jong PT, Hofman H, Grobbee DE.
Cardiovascular determinants of carotid artery disease:
the Rotterdam Elderly Study. Hypertension. 1992;19:717–720.
18.
Burke GL, Evans GW, Riley WA, Sharrett AR, Howard G,
Barnes RW, Rosamond W, Crow RS, Rautaharju PM, Heiss G.
Arterial wall thickness is associated with prevalent
cardiovascular disease in middle-aged adults: the
Atherosclerosis Risk in Communities (ARIC) Study.
Stroke. 1995;26:386–391.
19.
Salonen JT, Salonen R. Ultrasonographically assessed
carotid morphology and the risk of coronary heart disease.
Arterioscler Thromb. 1991;11:1245–1249.
20.
Bots ML, Hoes AW, Koudstaal PJ, Hofman A, Grobbee DE.
Common carotid intima-media thickness and risk of stroke and myocardial
infarction: the Rotterdam Study. Circulation. 1997;96:1432–1437.
21.
Chambless LE, Heiss G, Folsom AR, Rosamond W, Szklo M,
Sharrett AR, Clegg LX. Association of coronary heart disease
incidence with carotid arterial wall thickness and major
risk factors: the Atherosclerosis Risk in Communities
(ARIC) Study, 1987–1993. Am J Epidemiol. 1997;146:483–494.
22.
Hodis HN, Mack WJ, LaBree L, Selzer RH, Liu CR, Liu CH,
Azen SP. The role of carotid arterial intima-media
thickness in predicting clinical coronary events. Ann
Intern Med. 1998;128:262–269.
23.
O’Leary DH, Polak JF, Kronmal RA, Manolio TA, Burke
GL, Wolfson SK Jr. Carotid-artery intima and media thickness as a risk
factor for myocardial infarction and stroke in older adults:
Cardiovascular Health Study. N Engl J
Med. 1999;340:14–22.
24.
Blankenhorn DH, Selzer RH, Crawford DW, Barth JD, Liu
CR, Liu CH, Mack WJ, Alaupovic P. Beneficial effects of
colestipol-niacin therapy on the common carotid artery: two- and
four-year reduction of intima-media thickness measured by ultrasound.
Circulation. 1993;88:20–28.
25.
Furberg CD, Adams HP Jr, Applegate WB, Byington RP,
Espeland MA, Hartwell T, Hunninghake DB, Lefkowitz DS, Probstfield
J, Riley WA, et al. Effect of lovastatin on early carotid
atherosclerosis and cardiovascular
events: Asymptomatic Carotid Artery Progression Study
(ACAPS) Research Group. Circulation. 1994;90:1679–1687.
26.
Hodis HN, Mack WJ, LaBree L, Selzer RH, Liu C,
Alaupovic P, Kwong-Fu H, Azen SP. Reduction in carotid
arterial wall thickness using lovastatin and
dietary therapy: a randomized controlled clinical trial. Ann
Intern Med. 1996;124:548–556.
27.
Wexler L, Brundage B, Crouse J, Detrano R, Fuster V,
Maddahi J, Rumberger J, Stanford W, White R, Taubert K.
Coronary artery calcification: pathophysiology,
epidemiology, imaging methods, and clinical
implications: a statement for health professionals from the American
Heart Association: writing group. Circulation. 1996;94:1175–1192.
28.
Stanford W, Thompson BH, Weiss RM. Coronary
artery calcification: clinical significance and current methods of
detection. AJR Am J Roentgenol. 1993;161:1139–1146.
29.
Mautner GC, Mautner SL, Froehlich J, Feuerstein IM,
Proschan MA, Roberts WC, Doppman JL. Coronary artery
calcification: assessment with electron beam CT and histomorphometric
correlation. Radiology. 1994;192:619–623.
30.
Rumberger JA, Simons DB, Fitzpatrick LA, Sheedy PF,
Schwartz RS. Coronary artery calcium area by electron-beam
computed tomography and coronary atherosclerotic plaque area: a
histopathologic correlative study. Circulation. 1995;92:2157–2162.
31. Agatston AS, Janowitz WR, Hildner FJ, Zusmer NR, Viamonte M Jr, Detrano R. Quantification of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol. 1990;15:827–832.[Abstract]
32.
Budoff MJ, Georgiou D, Brody A, Agatston AS, Kennedy J,
Wolfkiel C, Stanford W, Shields P, Lewis RJ, Janowitz WR, Rich S,
Brundage BH. Ultrafast computed tomography as a diagnostic
modality in the detection of coronary artery disease: a
multicenter study. Circulation. 1996;93:898–904.
33.
Guerci AD, Spadaro LA, Goodman KJ, Lledo-Perez A,
Newstein D, Lerner G, Arad Y. Comparison of electron beam computed
tomography scanning and conventional risk factor assessment for the
prediction of angiographic coronary artery disease.
J Am Coll Cardiol. 1998;32:673–679.
34. Rumberger JA, Sheedy PF II, Breen JF, Fitzpatrick LA, Schwartz RS. Electron beam computed tomography and coronary artery disease: scanning for coronary artery calcification. Mayo Clin Proc. 1996;71:369–377.[Abstract]
35.
Callister TQ, Raggi P, Cooil B, Lippolis NJ, Russo DJ.
Effect of HMG-CoA reductase inhibitors on coronary
artery disease as assessed by electron-beam computed tomography.
N Engl J Med. 1998;339:1972–1978.
36. Detrano R, Hsiai T, Wang S, Puentes G, Fallavolita J, Shields P, Stanford W, Wolfkiel C, Georgiou D, Budoff M, Reed J. Prognostic value of coronary calcification and angiographic stenoses in patients undergoing coronary angiography. J Am Coll Cardiol. 1996;27:285–290.[Abstract]
37.
Arad Y, Spadaro LA, Goodman K, Lledo-Perez A, Sherman
S, Lerner G, Guerci AD. Predictive value of electron beam computed
tomography of the coronary arteries: 19-month follow-up of 1173
asymptomatic subjects. Circulation. 1996;93:1951–1953.
38. Arad Y, Spadaro LA, Goodman K, Lledo A, Sherman S, Guerci AD. 3.6 years follow-up of 1136 asymptomatic adults undergoing electron beam CT (EBCT) of the coronary arteries. J Am Coll Cardiol. 1998;31(suppl A):210A. Abstract.
39.
Detrano RC, Wong ND, Doherty TM, Shavelle RM, Tang W,
Ginzton LE, Budoff MJ, Narahara KA. Coronary calcium does not
accurately predict near-term future coronary events in
high-risk adults. Circulation. 1999;99:2633–2638.
40. Fuster V, Fayad ZA, Badimon JJ. Acute coronary syndromes: biology. Lancet. 1999;353(suppl 2):SII5–SII9.
41. Shinnar M, Fayad ZA, Fallon JT, Fuster V. Magnetic resonance imaging of the vessel wall in carotids and coronaries. In: Fuster V, ed. The Vulnerable Atherosclerotic Plaque: Understanding, Identification, and Modification. Armonk, NY: Futura Publishing, 1999:155–162.
42. Fayad ZA, Fuster V. Characterization of atherosclerotic plaques by magnetic resonance imaging. Ann N Y Acad Sci. 1999. In press.
43. Toussaint JF, Southern JF, Fuster V, Kantor HL. T2-weighted contrast for NMR characterization of human atherosclerosis. Arterioscler Thromb Vasc Biol. 1995;15:1533–1542.
44.
Toussaint JF, Southern JF, Fuster V, Kantor HL. Water
diffusion properties of human atherosclerosis and
thrombosis measured by pulse field gradient nuclear magnetic resonance.
Arterioscler Thromb Vasc Biol. 1997;17:542–546.
45. Shinnar M, Fallon JT, Wehrli S, Levin M, Dalmacy D, Fayad ZA, Badimon JJ, Harrington M, Harrington E, Fuster V. The diagnostic accuracy of ex vivo magnetic resonance imaging for human atherosclerotic plaque characterization. Arterioscler Thromb Vasc Biol. 1999. In press.
46.
Toussaint JF, LaMuraglia GM, Southern JF, Fuster V,
Kantor HL. Magnetic resonance images lipid, fibrous, calcified,
hemorrhagic, and thrombotic components of human
atherosclerosis in vivo. Circulation. 1996;94:932–938.
47. Fayad ZA, Nahar T, Badimon JJ, Goldman M, Weinberger J, Fallon JT, Aguinaldo G, Shinnar M, Chesebro JH, Fuster V. In-vivo MR characterization of plaques in the thoracic aorta. Circulation. 1998;98(suppl I):I-515. Abstract.
48. Skinner MP, Yuan C, Mitsumori L, Hayes CE, Raines EW, Nelson JA, Ross R. Serial magnetic resonance imaging of experimental atherosclerosis detects lesion fine structure, progression and complications in vivo. Nat Med. 1995;1:69–73.[Medline] [Order article via Infotrieve]
49.
Fayad ZA, Fallon JT, Shinnar M, Wehrli S, Dansky HM,
Poon M, Badimon JJ, Charlton SA, Fisher EA, Breslow JL, Fuster V.
Noninvasive in vivo high-resolution magnetic resonance imaging of
atherosclerotic lesions in genetically engineered mice.
Circulation. 1998;98:1541–1547.
50. Shinnar M, Gallo R, Fayad ZA, Fallon JT, Padurean A, Konstadt SN, Moskowitz D, Abela J, Badimon JJ, Fuster VF. In vivo magnetic resonance imaging of post angioplasty coronary vessel wall lesion in pigs. J Am Coll Cardiol. 1998;33:339A. Abstract.
51. Worsthley SG, Heft G, Fayad ZA, Osende JI, Fallon JT, Aguinaldo G, Roque M, Shinnar M, Fuster V, Badimon JJ. High-resolution ex-vivo MR imaging of in-situ coronary wall components in porcine model of atherosclerosis. Soc Magn Reson. 1999; 102.
52. Corretti MC, Plotnick GD, Vogel RA. Technical aspects of evaluating brachial artery vasodilatation using high-frequency ultrasound. Am J Physiol. 1995;268(4 pt 2):H1397–H1404.
53. Uehata A, Lieberman EH, Gerhard MD, Anderson TJ, Ganz P, Polak JF, Creager MA, Yeung AC. Noninvasive assessment of endothelium-dependent flow-mediated dilation of the brachial artery. Vasc Med. 1997;2:87–92.[Medline] [Order article via Infotrieve]
54. Stadler RW, Ibrahim SF, Lees RS. Measurement of the time course of peripheral vasoactivity: results in cigarette smokers. Atherosclerosis. 1998;138:197–205.[Medline] [Order article via Infotrieve]
55. Celermajer DS, Sorensen KE, Gooch VM, Spiegelhalter DJ, Miller OI, Sullivan ID, Lloyd JK, Deanfield JE. Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet. 1992;340:1111–1115.[Medline] [Order article via Infotrieve]
56.
Sorensen KE, Celemajer DS, Spiegelhalter DJ,
Georgakopoulos D, Robinson J, Thomas O, Deanfield JE. Non-invasive
measurement of human endothelium dependent
arterial responses: accuracy and reproducibility. Br
Heart J. 1995;74:247–253.
57. Vogel RA, Corretti MC, Plotnick GD. Changes in flow-mediated brachial artery vasoactivity with lowering of desirable cholesterol levels in healthy middle-aged men. Am J Cardiol. 1996;77:37–40.[Medline] [Order article via Infotrieve]
58.
Ridker PM. Evaluating novel
cardiovascular risk factors: can we better predict
heart attacks? Ann Intern Med.. 1999;130:933–937.
59.
Ross R. Atherosclerosis: an
inflammatory disease. N Engl J Med. 1999;340:115–126.
60.
Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens
CH. Inflammation, aspirin, and risk of cardiovascular
disease in apparently healthy men. N Engl J Med. 1997;336:973–979.
61.
Kuller LH, Tracy RP, Shaten J, Meilahn EN. Relation of
C-reactive protein and coronary heart disease in the MRFIT
nested case-control study: Multiple Risk Factor Intervention Trial.
Am J Epidemiol. 1996;144:537–547.
62.
Tracy RP, Lemaitre RN, Psaty BM, Ives DG, Evans RW,
Cushman M, Meilahn EN, Kuller LH. Relationship of C-reactive protein to
risk of cardiovascular disease in the elderly: results
from the Cardiovascular Health Study and the Rural
Health Promotion Project. Arterioscler Thromb Vasc Biol. 1997;17:1121–1127.
63.
Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens
CH. Plasma concentration of C-reactive protein and risk of developing
peripheral vascular disease. Circulation. 1998;97:425–428.
64.
Ridker PM, Buring JE, Shih J, Matias M, Hennekens CH.
Prospective study of C-reactive protein and the risk of future
cardiovascular events among apparently healthy women.
Circulation. 1998;98:731–733.
65.
Koenig W, Sund M, Froelich M, Fischer HG, Lowel H,
Doring A, Hutchinson WL, Pepys MB. C-reactive protein, a sensitive
marker of inflammation, predicts future risk of coronary heart
disease in initially healthy middle-aged men: results from the MONICA
(Monitoring Trends and Determinants in Cardiovascular
Disease) Augsburg Cohort Study, 1984 to 1992. Circulation. 1999;99:237–242.
66.
Ridker PM, Glynn RJ, Hennekens CH. C-reactive protein
adds to the predictive value of total and HDL cholesterol
in determining risk of first myocardial infarction.
Circulation. 1998;97:2007–2011.
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