Advanced glycation/glycoxidation endproduct carboxymethyl-lysine and incidence of coronary heart disease and stroke in older adults.
BACKGROUND
Advanced glycation/glycoxidation endproducts (AGEs) accumulate in settings of increased oxidative stress--such as diabetes, chronic kidney disease and aging--where they promote vascular stiffness and atherogenesis, but the prospective association between AGEs and cardiovascular events in elders has not been previously examined.


METHODS
To test the hypothesis that circulating levels of N(ɛ)-carboxymethyl-lysine (CML), a major AGE, increase the risk of incident coronary heart disease and stroke in older adults, we measured serum CML by immunoassay in 2111 individuals free of prevalent cardiovascular disease participating in a population-based study of U.S. adults ages 65 and older.


RESULTS
During median follow-up of 9.1 years, 625 cardiovascular events occurred. CML was positively associated with incident cardiovascular events after adjustment for age, sex, race, systolic blood pressure, anti-hypertensive treatment, diabetes, smoking status, triglycerides, albumin, and self-reported health status (hazard ratio [HR] per SD [0.99 pmol/l] increase=1.11, 95% confidence interval [CI]=1.03-1.19). This association was not materially attenuated by additional adjustment for C-reactive protein, estimated glomerular filtration rate (eGFR), and urine albumin/creatinine ratio. Findings were similar for the component endpoints of coronary heart disease and stroke.


CONCLUSIONS
In this large older cohort, CML was associated with an increased risk of cardiovascular events independent of a wide array of potential confounders and mediators. Although the moderate association limits CML's value for risk prediction, these community-based findings provide support for clinical trials to test AGE-lowering therapies for cardiovascular prevention in this population.
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. Electronic address: jorge.kizer@einstein.yu.edu.
Jorge R
JR
Kizer
Department of Biostatistics, University of Washington, Seattle, WA, USA.
David
D
Benkeser
Department of Biostatistics, University of Washington, Seattle, WA, USA.
Alice M
AM
Arnold
Nephrology Section, Veterans Affairs San Diego Healthcare System, San Diego, CA, USA; Division of Nephrology, Department of Medicine, San Diego, CA, USA; Division of Preventive Medicine, Department of Family and Preventive Medicine, University of California San Diego, San Diego, CA, USA.
Joachim H
JH
Ix
Division of General Medicine and Primary Care, Beth Israel Deaconess Medical Center, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
Kenneth J
KJ
Mukamal
Harvard Medical School, Boston, MA, USA; Division of Aging, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
Luc
L
Djousse
Department of Pathology, University of Vermont, Colchester, VT, USA; Department of Biochemistry, University of Vermont, Colchester, VT, USA.
Russell P
RP
Tracy
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA; Cardiovascular Health Research Unit, Department of Epidemiology, University of Washington, Seattle, WA, USA.
David S
DS
Siscovick
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA; Cardiovascular Health Research Unit, Department of Epidemiology, University of Washington, Seattle, WA, USA; Department of Health Services, University of Washington, Seattle, WA, USA; Group Health Research Institute, Group Health Cooperative, Seattle, WA, USA.
Bruce M
BM
Psaty
Division of Geriatrics and Clinical Gerontology, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
Susan J
SJ
Zieman
D000368:Aged; D000418:Albumins / Q000032:analysis; D000959:Antihypertensive Agents / Q000737:chemistry; D001794:Blood Pressure; D002318:Cardiovascular Diseases / Q000097:blood; D015331:Cohort Studies; D003327:Coronary Disease / Q000097:blood* / Q000175:diagnosis / Q000453:epidemiology; D003404:Creatinine / Q000652:urine; D005260:Female; D005919:Glomerular Filtration Rate; D017127:Glycation End Products, Advanced / Q000097:blood*; D006801:Humans; D007118:Immunoassay; D015994:Incidence; D008239:Lysine / Q000031:analogs & derivatives* / Q000097:blood; D008297:Male; D018384:Oxidative Stress; D016016:Proportional Hazards Models; D020521:Stroke / Q000097:blood* / Q000175:diagnosis / Q000453:epidemiology; D016896:Treatment Outcome
D000418:Albumins; D000959:Antihypertensive Agents; D017127:Glycation End Products, Advanced; C048496:N(6)-carboxymethyllysine; D003404:Creatinine; D008239:Lysine
Advanced glycation endproducts; Aging; Carboxymethyl-lysine; Coronary heart disease; Older adults; Stroke