The Atherosclerosis Introduction
Risk in Communities
(ARK)
Study
and Objectives of the Hemostasis Component
A. Richey Sharrett,
MD, DrPH, and the ARIC
Investigators
The Arherosclerosis Risk in Communities (ARIC) Study is an observational epidemiologic study conducted in four communities. ARK has two major components: One records the occurrence of myocardial infarction resulting in hos@&ation and coronary heart disease death in adults aged 35 to 74 living in the communities; the other is a prospective study of representative cohorts aged 45 to 64. Measurement of hemostatic factors is part of the cohort study, whose major objectives include investigating etiologic factors associated with atherosclerosis and its clinical outcomes. Arterial intimal-medial wall thickness, an index of early atherosclerosis, is measured precisely from ultrasound images of carotid and popliteal arteries. Participants (n = 15,801) corn&ted their first examination, which included measurements offactors associated with coagulation (fibrinogen, f&or VII, factor VIII, and van W&brand factor) and coagulation inhibition (protein C and antithrombin III). Measures of coagulation activation, platelet activation, and jibrinolytic activity will be performed on stored plasma from selected case patients and control subjects. Ann Epidemiol 1992;2:467-469. KEY WORDS:
Cardiovascular
disease, hemostusis.
The Atherosclerosis
Risk in Communities
tional epidemiologic
study (1). The communities
Jackson,
Mississippi;
Maryland.
(ARIC)
suburbs of Minneapolis,
ARIC has two major components.
Study is a four-community
observa-
are Forsyth County, North Carolina; Minnesota;
and Washington
The surveillance component
County, records the
occurrence of myocardial infarction resulting in hospitalization and coronary heart disease death in adults aged 35 to 74 years living in the communities. The cohort component is a prospective study of representative residents aged 45 to 64. ARIC’s objectives are to investigate the etiology and natural history of atherosclerosis and the clinical atherosclerotic
diseases, and to measure variations in cardiovascular risk factors,
medical care, and disease by race, sex, place, disease are assessed by the surveillance component component
and time. Trends
in coronary
in each community,
heart
and the cohort
evaluates factors associated with community trends and with the incidence
in individuals of each of the major cardiovascular diseases, that is, the various manifestations of coronary disease and stroke. In three of the communities, regardless of race, but in Jackson, participant
the cohorts are selected to represent all residents Mississippi, only blacks are selected. Each cohort
received a baseline examination,
another examination
3 years later, and
annual telephone calls. In the first examination, completed in March participants, 59% of the estimated eligibles invited, were seen.
1990,
15,801
Each examination includes, in addition to standard elements of a research cardiovascular examination, ultrasound imaging of arteries in the neck and leg for measurements of wall thickness as an index of atherosclerosis.
From the Epidemiology and Biometry Program, National Heart, Lung, and Blood Institute, Nattonal Institutes of Health, Bethesda, MD. Address reprint requests to: A. Richey Sharrett, MD, DrPH, Epidemiology and Biometry Program, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892. Accepted September 4, 1991. 0 1992 Elsevier Science Publishing Co.. Inc.
1047.2797/92/$05.00
468
Sharrett ARK: HEMOSTASIS
The
AEP Vol. 2, No. 4 July 1992: 467-469
STUDY DESIGN
laboratory
work includes measurement
of lipids, hemostasis,
hematology,
chemistry, and storage of a number of aliquots of serum or plasma for future studies. Most of these determinations are made in specialized laboratories. The ARIC Central Hemostasis Laboratory
is located at the University of Texas Medical School
ton. The ultrasound images are interpreted at a reading center University in Winston-Salem, North Carolina.
in Hous-
at Bowman
Gray
A very precise method of measuring arterial wall thickness from ultrasound B-mode images was developed at the Ultrasound Reading Center (2, 3). Folsom and colleagues, in this issue of the Ann& of Epidemiology, discuss the relationships of cardiovascular and other risk factors to the hemostatic factors measured in the ARIC (4). Wu and coworkers, also in this issue (5)) describe relationships between hemostatic atherosclerosis found using a case-control analysis. Patients
with atherosclerosis,
as defined in the ARIC
factors and
study, have one or more
measurements of the combined intima and media thickness of at least 1.6 mm in carotid arteries on both sides of the neck, or of 2.5 mm on one side. Control subjects have no evidence
of thickening
at any arterial site. ARIC
investigators
that patients defined in this way have all the classic atherosclerotic
have shown
risk factors: elevated
levels of low-density lipoprotin (LDL) cholesterol and triglycerides and lowered levels of high-density lipoprotin (HDL), higher levels of blood pressure, and more cigarettes smoked (6). Hemostatic factors selected initially included coagulation factors, indicators of coagulation activation, indicators of platelet activation, fibrinolytic factors, and coagulation inhibitors.
Seven of these were measured in all examinees:
fibrinogen,
factor
VII, factor VIII, von Willebrand factor, antithrombin III, protein C, and activated partial thromboplastin time. More complex measurements are now being undertaken in the stored blood samples from patients and control subjects. These include betathromboglobulin, platelet factor 4, fibrinopeptide A, tissue plasminogen plasminogen activator inhibitor-l, protein S, and D-dimer. The ARIC
investigators
are currently
activator,
also testing the atherosclerotic
case and
control patients for postprandial lipemia, which requires drawing blood samples after the subjects have consumed a fatty test meal. The peak lipemia samples will be measured not only for lipoproteins, but also for factor VII, inhibitor-l, and other hemostatic factors.
plasminogen
The goal of ARIC’s hemostasis study relates to both atherosclerosis, by carotid wall thickness, and to clinical diseases caused by atherosclerosis.
activator
as measured Hemostatic
factors related to acute coronary thrombosis may differ from those related to the progression of mural atheromata. In designing ARIC’s hemostatic study, the investigators were aware of the large number of positive findings in the literature. There is support in the literature for every one of the factors selected (7). Much of the support in the literature is based on comparisons of persons with and those without overt clinical disease. Much of this is unconvincing, because alterations seen in a hemostatic factor in persons with overt disease may be the effect, rather than the cause, of the disease (7). Because of the wealth of a priori hypotheses, the ARIC study includes index measurements of many of the major pathways involved in hemostasis, coagulation factors, endogenous anticoagulants, fibrinolytic factors, platelet activation and in vivo fibrin formation, and others. It attempts to assess the associations of these factors with disease using an efficient mix of measurements on the whole population and population subsamples. ARIC’s focus on early atherosclerosis and its prospective design should help distinguish between hemostatic factors that contribute to the etiology of athero-
AEP Vol. 2, No. 4
Shmett ARK: HEMOSTASIS STUDY DESIGN
July 1992: 467-469
469
sclerosis and its clinical outcomes and those factors that are simply affected by these diseases without having a pathogenic role.
REFERENCES 1.
The ARIC
Investigators.
Design and objectives, 2. scanning
Bond MG, procedure
The Atherosclerosis
Am J Epidemiol. Riley WA,
Barnes RW,
in the Atherosclerosis
Risk in Communities
(ARIC)
Study:
1989;129:687-702. et al., and the ARIC
Risk in Communities
Study Group.
(ARIC)
Ultrasound
Study, Neuroimaging.
1991;1(2). 3. ultrasonic
Riley WA,
Barnes RW,
measurement
of carotid
Bond MG, et al., and the ARK artery wall thickness
Study Group.
in the ARIC
cohort,
Non-invasive Neuroimaging.
1991;1(3). 4.
Folsom AR, Conlan
cardiovascular
MG, Davis CE, et al. Relations
risk factors in middle-aged
between hemostasis
variables and
adults, Ann Epidemiol. 1992;2:00-00. 5. Wu KK, Folsom AR, Heiss G, et al. Association of coagulation factors and inhibitors with atherosclerosis: Early results of the Atherosclerosis Risk in Communities (ARIC) Study, Ann Epidemiol. 1992;2:00-00. 6. Heiss G, Sharrett AR, Barnes R, et al., and the ARIC Investigators. Carotid atherosclerosis measured by B-mode ultrasound in populations: Associations with cardiovascular risk factors in the ARIC study, Am J Epidemiol. (in press). 7. Breddin K. Detection of prethrombotic states in patients with atherosclerotic lesions, Semin Thromb Hemost. 1986;12:110-23.
Risk in Communities
(ARK)
Study
and Objectives of the Hemostasis Component
A. Richey Sharrett,
MD, DrPH, and the ARIC
Investigators
The Arherosclerosis Risk in Communities (ARIC) Study is an observational epidemiologic study conducted in four communities. ARK has two major components: One records the occurrence of myocardial infarction resulting in hos@&ation and coronary heart disease death in adults aged 35 to 74 living in the communities; the other is a prospective study of representative cohorts aged 45 to 64. Measurement of hemostatic factors is part of the cohort study, whose major objectives include investigating etiologic factors associated with atherosclerosis and its clinical outcomes. Arterial intimal-medial wall thickness, an index of early atherosclerosis, is measured precisely from ultrasound images of carotid and popliteal arteries. Participants (n = 15,801) corn&ted their first examination, which included measurements offactors associated with coagulation (fibrinogen, f&or VII, factor VIII, and van W&brand factor) and coagulation inhibition (protein C and antithrombin III). Measures of coagulation activation, platelet activation, and jibrinolytic activity will be performed on stored plasma from selected case patients and control subjects. Ann Epidemiol 1992;2:467-469. KEY WORDS:
Cardiovascular
disease, hemostusis.
The Atherosclerosis
Risk in Communities
tional epidemiologic
study (1). The communities
Jackson,
Mississippi;
Maryland.
(ARIC)
suburbs of Minneapolis,
ARIC has two major components.
Study is a four-community
observa-
are Forsyth County, North Carolina; Minnesota;
and Washington
The surveillance component
County, records the
occurrence of myocardial infarction resulting in hospitalization and coronary heart disease death in adults aged 35 to 74 years living in the communities. The cohort component is a prospective study of representative residents aged 45 to 64. ARIC’s objectives are to investigate the etiology and natural history of atherosclerosis and the clinical atherosclerotic
diseases, and to measure variations in cardiovascular risk factors,
medical care, and disease by race, sex, place, disease are assessed by the surveillance component component
and time. Trends
in coronary
in each community,
heart
and the cohort
evaluates factors associated with community trends and with the incidence
in individuals of each of the major cardiovascular diseases, that is, the various manifestations of coronary disease and stroke. In three of the communities, regardless of race, but in Jackson, participant
the cohorts are selected to represent all residents Mississippi, only blacks are selected. Each cohort
received a baseline examination,
another examination
3 years later, and
annual telephone calls. In the first examination, completed in March participants, 59% of the estimated eligibles invited, were seen.
1990,
15,801
Each examination includes, in addition to standard elements of a research cardiovascular examination, ultrasound imaging of arteries in the neck and leg for measurements of wall thickness as an index of atherosclerosis.
From the Epidemiology and Biometry Program, National Heart, Lung, and Blood Institute, Nattonal Institutes of Health, Bethesda, MD. Address reprint requests to: A. Richey Sharrett, MD, DrPH, Epidemiology and Biometry Program, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892. Accepted September 4, 1991. 0 1992 Elsevier Science Publishing Co.. Inc.
1047.2797/92/$05.00
468
Sharrett ARK: HEMOSTASIS
The
AEP Vol. 2, No. 4 July 1992: 467-469
STUDY DESIGN
laboratory
work includes measurement
of lipids, hemostasis,
hematology,
chemistry, and storage of a number of aliquots of serum or plasma for future studies. Most of these determinations are made in specialized laboratories. The ARIC Central Hemostasis Laboratory
is located at the University of Texas Medical School
ton. The ultrasound images are interpreted at a reading center University in Winston-Salem, North Carolina.
in Hous-
at Bowman
Gray
A very precise method of measuring arterial wall thickness from ultrasound B-mode images was developed at the Ultrasound Reading Center (2, 3). Folsom and colleagues, in this issue of the Ann& of Epidemiology, discuss the relationships of cardiovascular and other risk factors to the hemostatic factors measured in the ARIC (4). Wu and coworkers, also in this issue (5)) describe relationships between hemostatic atherosclerosis found using a case-control analysis. Patients
with atherosclerosis,
as defined in the ARIC
factors and
study, have one or more
measurements of the combined intima and media thickness of at least 1.6 mm in carotid arteries on both sides of the neck, or of 2.5 mm on one side. Control subjects have no evidence
of thickening
at any arterial site. ARIC
investigators
that patients defined in this way have all the classic atherosclerotic
have shown
risk factors: elevated
levels of low-density lipoprotin (LDL) cholesterol and triglycerides and lowered levels of high-density lipoprotin (HDL), higher levels of blood pressure, and more cigarettes smoked (6). Hemostatic factors selected initially included coagulation factors, indicators of coagulation activation, indicators of platelet activation, fibrinolytic factors, and coagulation inhibitors.
Seven of these were measured in all examinees:
fibrinogen,
factor
VII, factor VIII, von Willebrand factor, antithrombin III, protein C, and activated partial thromboplastin time. More complex measurements are now being undertaken in the stored blood samples from patients and control subjects. These include betathromboglobulin, platelet factor 4, fibrinopeptide A, tissue plasminogen plasminogen activator inhibitor-l, protein S, and D-dimer. The ARIC
investigators
are currently
activator,
also testing the atherosclerotic
case and
control patients for postprandial lipemia, which requires drawing blood samples after the subjects have consumed a fatty test meal. The peak lipemia samples will be measured not only for lipoproteins, but also for factor VII, inhibitor-l, and other hemostatic factors.
plasminogen
The goal of ARIC’s hemostasis study relates to both atherosclerosis, by carotid wall thickness, and to clinical diseases caused by atherosclerosis.
activator
as measured Hemostatic
factors related to acute coronary thrombosis may differ from those related to the progression of mural atheromata. In designing ARIC’s hemostatic study, the investigators were aware of the large number of positive findings in the literature. There is support in the literature for every one of the factors selected (7). Much of the support in the literature is based on comparisons of persons with and those without overt clinical disease. Much of this is unconvincing, because alterations seen in a hemostatic factor in persons with overt disease may be the effect, rather than the cause, of the disease (7). Because of the wealth of a priori hypotheses, the ARIC study includes index measurements of many of the major pathways involved in hemostasis, coagulation factors, endogenous anticoagulants, fibrinolytic factors, platelet activation and in vivo fibrin formation, and others. It attempts to assess the associations of these factors with disease using an efficient mix of measurements on the whole population and population subsamples. ARIC’s focus on early atherosclerosis and its prospective design should help distinguish between hemostatic factors that contribute to the etiology of athero-
AEP Vol. 2, No. 4
Shmett ARK: HEMOSTASIS STUDY DESIGN
July 1992: 467-469
469
sclerosis and its clinical outcomes and those factors that are simply affected by these diseases without having a pathogenic role.
REFERENCES 1.
The ARIC
Investigators.
Design and objectives, 2. scanning
Bond MG, procedure
The Atherosclerosis
Am J Epidemiol. Riley WA,
Barnes RW,
in the Atherosclerosis
Risk in Communities
(ARIC)
Study:
1989;129:687-702. et al., and the ARIC
Risk in Communities
Study Group.
(ARIC)
Ultrasound
Study, Neuroimaging.
1991;1(2). 3. ultrasonic
Riley WA,
Barnes RW,
measurement
of carotid
Bond MG, et al., and the ARK artery wall thickness
Study Group.
in the ARIC
cohort,
Non-invasive Neuroimaging.
1991;1(3). 4.
Folsom AR, Conlan
cardiovascular
MG, Davis CE, et al. Relations
risk factors in middle-aged
between hemostasis
variables and
adults, Ann Epidemiol. 1992;2:00-00. 5. Wu KK, Folsom AR, Heiss G, et al. Association of coagulation factors and inhibitors with atherosclerosis: Early results of the Atherosclerosis Risk in Communities (ARIC) Study, Ann Epidemiol. 1992;2:00-00. 6. Heiss G, Sharrett AR, Barnes R, et al., and the ARIC Investigators. Carotid atherosclerosis measured by B-mode ultrasound in populations: Associations with cardiovascular risk factors in the ARIC study, Am J Epidemiol. (in press). 7. Breddin K. Detection of prethrombotic states in patients with atherosclerotic lesions, Semin Thromb Hemost. 1986;12:110-23.
