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Hydroxyl radical generation, levels of tumor necrosis factor-alpha, and progression to heart failure after acute myocardial infarction

Marco Valgimigli, MD^*,*, Elisa Merli, MD^*, Patrizia Malagutti, MD^*, Olga Soukhomovskaia, MD^*, Giordano Cicchitelli, MD^*, Alessandra Antelli, PhD, Donatella Canistro, PhD, Gloria Francolini, BSc, Gaetano Macrì, MD^*, Francesca Mastrorilli, MD^*, Moreno Paolini, PhD and Roberto Ferrari, MD, PhD^*

^* Chair of Cardiology, University of Ferrara, Ferrara, Italy
Cardiovascular Research Centre, Salvatore Maugeri Foundation, Gussago (Brescia), Italy
Department of Pharmacology, Alma Mater Studiorum, University of Bologna, Bologna, Italy

View larger version (19K): [in a new window]   Figure 1 Oxidative metabolism of salicylic acid: acetylsalicylic acid (ASA) is rapidly hydrolyzed to SA by esterases and for 60% remains unmodified and can undergo hydroxyl radical (·OH) attack to produce two derivates—namely, 2,3-dihydroxybenzoic acid (DHBA) and 2,5-DHBA. Enzymatic pathways through the cytochrome P-450 system can also produce the latter acid, whereas the former acid is solely formed by direct ·OH attack. Therefore, measurement of 2,3-DHBA or the 2,3-DHBA/SA ratio, after administration of ASA, is recognized as a sensitive and specific method to determine ·OH production in vivo.

View larger version (20K): [in a new window]   Figure 2 Hydroxyl radical generation during the hospital phase. (A) Time course of 2,3-dihydroxybenzoic acid (DHBA)/salicylic acid (SA) (expressed as molar ratio x 1,000) in 10 patients with myocardial infarction (Group 2), all patients with stable angina (Group 1), and 5 Controls. (B) Time course of 2,3-DHBA/SA (expressed as molar ratio x 1,000) in the remaining 65 patients with myocardial infarction (Group 2) and 25 Controls. Sampling was performed at entry (within 12 h from symptom onset), at 24, 48, and 72 h after symptom onset, and at discharge (10 ± 4 days). The insert shows the pattern of 2,3-DHBA/SA in patients without (Group 2Ai) and with (Group 2Bi) HF during hospitalization.

View larger version (16K): [in a new window]   Figure 3 Levels of vitamin E and coenzyme Q10 during the hospital phase. Time course of vitamin E (A) and coenzyme Q10 (B) levels in Controls (n = 30; open circles), patients with stable angina (Group 1, n = 12; inverted triangles), and patients with myocardial infarction (Group 2, n = 74; solid circles). Sampling times were at entry, 24, 48, and 72 h after symptom onset, and at discharge. *p < 0.05 versus Group 2. p < 0.01 versus Group 2.

View larger version (20K): [in a new window]   Figure 4 Levels of 2,3-dihydroxybenzoic acid (DHBA)/salicylic acid (SA) stratified by cytokine values. Group 2 patients showing high levels of tumor necrosis factor-alpha (TNF-a) and its soluble receptors (sTNFR-I and sTNFR-II) displayed significantly increased 2,3-DHBA/SA values at discharge, as compared with patients with low levels. Open bars = below median; solid bars = above median. *p < 0.05; p < 0.01. IL = interleukin.

View larger version (13K): [in a new window]   Figure 5 Levels of 2,3-dihydroxybenzoic acid (DHBA)/salicylic acid (SA) at six months, according to heart failure status. At month 6, 2,3-DHBA/SA (expressed as molar ratio x 1,000) in patients with heart failure (Group 2Bii) was significantly higher than that of patients without heart failure (Group 2Ai). *p < 0.0001.