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Knowledge of the role of advanced glycation end products (AGE), their receptor (RAGE), and the receptor's soluble form (sRAGE), in heart failure (HF) is very limited. We evaluated the clinical role of the AGE–RAGE system in HF and in particular any association it might have with ischaemic aetiology.We measured fluorescent AGE, glycated albumin and sRAGE in 103 patients with chronic HF. We showed that sRAGE but not AGE was related to ischaemic aetiology (1638.3 ± 207.4 ischaemic vs. 1065.1 ± 94.2 pg/mL non-ischaemic group; P =0.016) independent of age, sex, diabetes, renal function, clinical severity, or other variables (OR: 1.091; 95% CI (confidence interval): 1.032–1.153; P =0.007). Moreover, sRAGE was directly associated with extent of coronary disease (OR for three vessel disease compared with non-coronary lesions: 1.186; 95% CI: 1.065–1.322; P =0.002). We also found a correlation between sRAGE and severity of HF, which increased with New York Heart Association (NYHA) class (741.9 ± 88.9 pg/mL in class 1, 1195.9 ± 113.2 pg/mL in class II, and 1724.8 ± 245.7 pg/mL in class III (P < 0.05)) and brain natriuretic peptide (BNP) levels (667.4 ± 68.0 vs. 1344.5 ± 126.0 pg/mL for BNP < and ≥400 pg/mL, respectively).sRAGE is an indicator of chronic heart failure severity and an independent marker of coronary artery disease and its severity in patients with CHF.