title: Mediation of cardiovascular risk factor effects through subclinical vascular disease: the Multi-Ethnic Study of Atherosclerosis.
abstract: OBJECTIVE
  It is unclear to what extent subclinical cardiovascular disease (CVD) such as coronary artery calcium (CAC), carotid intima-media thickness (CIMT), and brachial flow-mediated dilation (FMD) are mediators of the known associations between traditional cardiovascular risk factors and incident CVD events. We assessed the portion of the effects of risk factors on incident CVD events that are mediated through CAC, CIMT, and FMD.
  
  
  RESULTS
  Six thousand three hundred fifty-five of 6814 Multi-Ethnic Study of Atherosclerosis participants were included. Nonlinear implementation of structural equation modeling (STATA mediation package) was used to assess whether CAC, CIMT, or FMD are mediators of the association between traditional risk factors and incident CVD event. Mean age was 62 years, with 47% men, 12% diabetics, and 13% current smokers. After a mean follow-up of 7.5 years, there were 539 CVD adjudicated events. CAC showed the highest mediation while FMD showed the least. Age had the highest percent of total effect mediated via CAC for CVD outcomes, whereas current cigarette smoking had the least percent of total effect mediated via CAC (percent [95% confidence interval]: 80.2 [58.8-126.7] versus 10.6 [6.1-38.5], respectively). Body mass index showed the highest percent of total effect mediated via CIMT (17.7 [11.6-38.9]); only a negligible amount of the association between traditional risk factors and CVD was mediated via FMD.
  
  
  CONCLUSIONS
  Many of the risk factors for incident CVD (other than age, sex, and body mass index) showed a modest level of mediation via CAC, CIMT, and FMD, suggesting that current subclinical CVD markers may not be optimal intermediaries for gauging upstream risk factor modification.
authors.affiliation: From the Heart and Vascular Center of Excellence, Wake Forest University School of Medicine, Winston-Salem, NC (J.Y., D.M.H.); Department of Biostatistics, University of Washington, Seattle, WA (J.A.D., R.N., R.L.M.); Department of Radiology, Tufts Medical Center, Boston, MA (J.F.P.); National Institute of Health, Bethesda, MD (C.T.S.); Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC (A.B., G.L.B.); and Department of Radiology, Vanderbilt University School of Medicine, Nashville, TN (J.J.C.). jyeboah@wakehealth.edu.
authors.forename: Joseph
authors.initials: J
authors.lastname: Yeboah
authors.affiliation: From the Heart and Vascular Center of Excellence, Wake Forest University School of Medicine, Winston-Salem, NC (J.Y., D.M.H.); Department of Biostatistics, University of Washington, Seattle, WA (J.A.D., R.N., R.L.M.); Department of Radiology, Tufts Medical Center, Boston, MA (J.F.P.); National Institute of Health, Bethesda, MD (C.T.S.); Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC (A.B., G.L.B.); and Department of Radiology, Vanderbilt University School of Medicine, Nashville, TN (J.J.C.).
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Delaney
authors.affiliation: From the Heart and Vascular Center of Excellence, Wake Forest University School of Medicine, Winston-Salem, NC (J.Y., D.M.H.); Department of Biostatistics, University of Washington, Seattle, WA (J.A.D., R.N., R.L.M.); Department of Radiology, Tufts Medical Center, Boston, MA (J.F.P.); National Institute of Health, Bethesda, MD (C.T.S.); Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC (A.B., G.L.B.); and Department of Radiology, Vanderbilt University School of Medicine, Nashville, TN (J.J.C.).
authors.forename: Robin
authors.initials: R
authors.lastname: Nance
authors.affiliation: From the Heart and Vascular Center of Excellence, Wake Forest University School of Medicine, Winston-Salem, NC (J.Y., D.M.H.); Department of Biostatistics, University of Washington, Seattle, WA (J.A.D., R.N., R.L.M.); Department of Radiology, Tufts Medical Center, Boston, MA (J.F.P.); National Institute of Health, Bethesda, MD (C.T.S.); Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC (A.B., G.L.B.); and Department of Radiology, Vanderbilt University School of Medicine, Nashville, TN (J.J.C.).
authors.forename: Robyn L
authors.initials: RL
authors.lastname: McClelland
authors.affiliation: From the Heart and Vascular Center of Excellence, Wake Forest University School of Medicine, Winston-Salem, NC (J.Y., D.M.H.); Department of Biostatistics, University of Washington, Seattle, WA (J.A.D., R.N., R.L.M.); Department of Radiology, Tufts Medical Center, Boston, MA (J.F.P.); National Institute of Health, Bethesda, MD (C.T.S.); Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC (A.B., G.L.B.); and Department of Radiology, Vanderbilt University School of Medicine, Nashville, TN (J.J.C.).
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Polak
authors.affiliation: From the Heart and Vascular Center of Excellence, Wake Forest University School of Medicine, Winston-Salem, NC (J.Y., D.M.H.); Department of Biostatistics, University of Washington, Seattle, WA (J.A.D., R.N., R.L.M.); Department of Radiology, Tufts Medical Center, Boston, MA (J.F.P.); National Institute of Health, Bethesda, MD (C.T.S.); Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC (A.B., G.L.B.); and Department of Radiology, Vanderbilt University School of Medicine, Nashville, TN (J.J.C.).
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Sibley
authors.affiliation: From the Heart and Vascular Center of Excellence, Wake Forest University School of Medicine, Winston-Salem, NC (J.Y., D.M.H.); Department of Biostatistics, University of Washington, Seattle, WA (J.A.D., R.N., R.L.M.); Department of Radiology, Tufts Medical Center, Boston, MA (J.F.P.); National Institute of Health, Bethesda, MD (C.T.S.); Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC (A.B., G.L.B.); and Department of Radiology, Vanderbilt University School of Medicine, Nashville, TN (J.J.C.).
authors.forename: Alain
authors.initials: A
authors.lastname: Bertoni
authors.affiliation: From the Heart and Vascular Center of Excellence, Wake Forest University School of Medicine, Winston-Salem, NC (J.Y., D.M.H.); Department of Biostatistics, University of Washington, Seattle, WA (J.A.D., R.N., R.L.M.); Department of Radiology, Tufts Medical Center, Boston, MA (J.F.P.); National Institute of Health, Bethesda, MD (C.T.S.); Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC (A.B., G.L.B.); and Department of Radiology, Vanderbilt University School of Medicine, Nashville, TN (J.J.C.).
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Burke
authors.affiliation: From the Heart and Vascular Center of Excellence, Wake Forest University School of Medicine, Winston-Salem, NC (J.Y., D.M.H.); Department of Biostatistics, University of Washington, Seattle, WA (J.A.D., R.N., R.L.M.); Department of Radiology, Tufts Medical Center, Boston, MA (J.F.P.); National Institute of Health, Bethesda, MD (C.T.S.); Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC (A.B., G.L.B.); and Department of Radiology, Vanderbilt University School of Medicine, Nashville, TN (J.J.C.).
authors.forename: J Jeffery
authors.initials: JJ
authors.lastname: Carr
authors.affiliation: From the Heart and Vascular Center of Excellence, Wake Forest University School of Medicine, Winston-Salem, NC (J.Y., D.M.H.); Department of Biostatistics, University of Washington, Seattle, WA (J.A.D., R.N., R.L.M.); Department of Radiology, Tufts Medical Center, Boston, MA (J.F.P.); National Institute of Health, Bethesda, MD (C.T.S.); Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC (A.B., G.L.B.); and Department of Radiology, Vanderbilt University School of Medicine, Nashville, TN (J.J.C.).
authors.forename: David M
authors.initials: DM
authors.lastname: Herrington
mesh_terms: D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D058070:Asymptomatic Diseases; D050197:Atherosclerosis / Q000175:diagnosis / Q000453:epidemiology; D015992:Body Mass Index; D001916:Brachial Artery / Q000503:physiopathology; D002318:Cardiovascular Diseases / Q000175:diagnosis / Q000453:epidemiology* / Q000503:physiopathology; D002340:Carotid Artery Diseases / Q000175:diagnosis / Q000453:epidemiology; D059168:Carotid Intima-Media Thickness; D017023:Coronary Angiography / Q000379:methods; D003324:Coronary Artery Disease / Q000175:diagnosis / Q000453:epidemiology; D005006:Ethnicity; D005260:Female; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D017711:Nonlinear Dynamics; D009765:Obesity / Q000175:diagnosis / Q000453:epidemiology; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D011446:Prospective Studies; D012307:Risk Factors; D012737:Sex Factors; D012907:Smoking / Q000009:adverse effects / Q000453:epidemiology; D014057:Tomography, X-Ray Computed; D014481:United States / Q000453:epidemiology; D061205:Vascular Calcification / Q000175:diagnosis / Q000453:epidemiology; D014664:Vasodilation
keywords: cardiovascular events; carotid intima-media thickness; coronary artery calcium score; flow-mediated dilation; risk factors