Abstract
BACKGROUND: Advanced glycation end-products result from chemical modification of proteins under conditions of hyperglycemia or oxidative stress common with advancing age. Advanced glycation end-product (AGE) formation alters vascular and cardiac structure and function, yet the prospective associations of circulating AGEs with heart failure (HF) and atrial fibrillation (AF) have not been studied. METHODS: We evaluated the associations of serum N(ε)-carboxymethyl-lysine (CML), a major AGE in tissue proteins, and incident HF and AF in the CHS (Cardiovascular Health Study), a population-based cohort of older adults. HF subtypes were examined secondarily, as were prevalent echocardiographic phenotypes. CML was measured by immunoassay. RESULTS: Among 2685 eligible participants (age 77±5; 63% women; 17% with diabetes), 832 HF and 1016 AF events occurred over a median follow-up of 9 years. After adjustment for potential confounders, serum CML was associated with a higher risk of incident HF and AF (hazard ratio per SD, 1.10 and 1.09 [95% CI, 1.02-1.17 and 1.02-1.16], respectively). The association with AF was attenuated and nonsignificant after adjusting for estimated glomerular filtration rate and urine albumin-creatinine ratio. The CML-HF relation was similarly attenuated after adjusting for time-updated myocardial infarction. Both associations were nonsignificant after adjusting for natriuretic peptides or excluding those with elevated levels at baseline. Secondary analyses of incident HF subtypes or baseline cardiac mechanics showed no significant associations. CONCLUSIONS: In older adults, serum CML was prospectively associated with higher risk of HF and AF independent of potential confounders, with evidence of attenuation by certain putative mediators. AGEs and AGE-countering therapies merit additional evaluation in this high-risk population.