Fibrosis-related biomarkers and large and small vessel disease: the Cardiovascular Health Study.
OBJECTIVE
Fibrosis has been implicated in a number of pathological, organ-based conditions of the liver, kidney, heart, and lungs. The objective of this study was to determine whether biomarkers of fibrosis are associated with vascular disease in the large and/or small vessels.


METHODS
We evaluated the associations of two circulating biomarkers of fibrosis, transforming growth factor-β (TGF-β) and procollagen type III N-terminal propeptide (PIIINP), with incident peripheral artery disease (PAD) and subclinical macrovascular (carotid intima-media thickness, flow-mediated vasodilation, ankle-brachial index, retinal vein diameter), and microvascular (retinal artery diameter and retinopathy) disease among older adults in the Cardiovascular Health Study. We measured TGF-β and PIIINP from samples collected in 1996 and ascertained clinical PAD through 2011. Measurements of large and small vessels were collected between 1996 and 1998.


RESULTS
After adjustment for sociodemographic, clinical, and biochemical risk factors, TGF-β was associated with incident PAD (hazard ratio [HR] = 1.36 per doubling of TGF-β, 95% confidence interval [CI] = 1.04, 1.78) and retinal venular diameter (1.63 μm per doubling of TGF-β, CI = 0.23, 3.02). PIIINP was not associated with incident PAD, but was associated with carotid intima-media thickness (0.102 mm per doubling of PIIINP, CI = 0.029, 0.174) and impaired brachial artery reactivity (-0.20% change per doubling of PIIINP, CI = -0.39, -0.02). Neither TGF-β nor PIIINP were associated with retinal arteriolar diameter or retinopathy.


CONCLUSIONS
Serum concentrations of fibrosis-related biomarkers were associated with several measures of large vessel disease, including incident PAD, but not with small vessel disease. Fibrosis may contribute to large vessel atherosclerosis in older adults.
Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA. Electronic address: Isha_Agarwal@hms.harvard.edu.
Isha
I
Agarwal
Department of Biostatistics, University of Washington, Seattle, WA, USA.
Alice
A
Arnold
Department of Medicine, Boston University, Boston, MA, USA.
Nicole L
NL
Glazer
Department of Research and Education, St. Francis Hospital/SUNY at Stony Brook, Stony Brook, NY, USA.
Eddy
E
Barasch
Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA; Boston Veterans Healthcare System, Boston, MA, USA.
Luc
L
Djousse
Department of Epidemiology, University of Washington, Seattle, WA, USA.
Annette L
AL
Fitzpatrick
Department of Medicine, University of Maryland Medical School, Baltimore, MD, USA.
John S
JS
Gottdiener
Department of Medicine, University of California San Diego and Veterans Affairs San Diego Healthcare System, San Diego, CA, USA.
Joachim H
JH
Ix
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
Richard A
RA
Jensen
Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA; Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA.
Jorge R
JR
Kizer
Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA; Department of Nutrition, Harvard School of Public Health, Boston, MA, USA; Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA.
Eric B
EB
Rimm
Department of Epidemiology, University of Washington, Seattle, WA, USA; Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
David S
DS
Siscovick
Department of Biochemistry, University of Vermont, Burlington, VT, USA.
Russell P
RP
Tracy
Department of Ophthalmology, Singapore Eye Research Institute, National University of Singapore, Singapore.
Tien Y
TY
Wong
Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.
Kenneth J
KJ
Mukamal
D000368:Aged; D055109:Ankle Brachial Index; D015415:Biomarkers / Q000097:blood*; D001916:Brachial Artery / Q000503:physiopathology; D002340:Carotid Artery Diseases / Q000097:blood* / Q000175:diagnosis / Q000453:epidemiology / Q000503:physiopathology; D059168:Carotid Intima-Media Thickness; D003430:Cross-Sectional Studies; D005260:Female; D005355:Fibrosis; D006801:Humans; D015994:Incidence; D008297:Male; D010446:Peptide Fragments / Q000097:blood*; D058729:Peripheral Arterial Disease / Q000097:blood* / Q000175:diagnosis / Q000453:epidemiology / Q000503:physiopathology; D011237:Predictive Value of Tests; D011347:Procollagen / Q000097:blood*; D011379:Prognosis; D011446:Prospective Studies; D012164:Retinal Diseases / Q000097:blood* / Q000175:diagnosis / Q000453:epidemiology / Q000503:physiopathology; D012307:Risk Factors; D016212:Transforming Growth Factor beta / Q000097:blood*; D014481:United States / Q000453:epidemiology; D014664:Vasodilation
D015415:Biomarkers; D010446:Peptide Fragments; D011347:Procollagen; D016212:Transforming Growth Factor beta; C041876:procollagen Type III-N-terminal peptide
Atherosclerosis; Fibrosis; Peripheral artery disease