Objective: Measurements of oxidative stress biomarkers in patients with heart failure (HF) have yielded controversial results. This study aimed at testing the hypothesis that circulating levels of the lipid peroxidation product 4-hydroxynonenal bound to thiol proteins (4HNE-P) are strongly associated with those of its potential precursors, namely n-6 polyunsaturated fatty acids (PUFA).
Methods and results: Circulating levels of 4HNE-P were evaluated by gas chromatography-mass spectrometry in 71 control subjects and 61 ambulatory symptomatic HF patients along with various other clinically- and biochemically-relevant parameters, including other oxidative stress markers, and total levels of fatty acids from all classes, which reflect both free and bound to cholesterol, phospholipids and triglycerides. All HF patients had severe systolic functional impairment despite receiving optimal evidence-based therapies. Compared to controls, HF patients displayed markedly lower circulating levels of HDL- and LDL-cholesterol, which are major PUFA carriers, as well as of PUFA of the n-6 series, specifically linoleic acid (LA; P=0.001). Circulating 4HNE-P in HF patients was similar to controls, albeit multiple regression analysis revealed that LA was the only factor that was significantly associated with circulating 4HNE-P in the entire population (R (2)=0.086; P=0.02). In HF patients only, 4HNE-P was even more strongly associated with LA (P=0.003) and HDL-cholesterol (p<0.0002). Our results demonstrate that 4HNE-P levels, expressed relative to HDL-cholesterol, increase as HDL-cholesterol plasma levels decrease in the HF group only.
Conclusion: Results from this study emphasize the importance of considering changes in lipids and lipoproteins in the interpretation of measurements of lipid peroxidation products. Further studies appear warranted to explore the possibility that HDL-cholesterol particles may be a carrier of 4HNE adducts.
Keywords: 4-Hydroxynnonenal; 4HNE, 4-hydroxynonenal; 4HNE-P, 4-hydroxynonenal bound to circulating thiol proteins; AA, arachidonic acid; CRP, C-reactive protein; DHA, docosahexanaenoic acid; EPA, eicosapentaenoic acid; GSH, reduced glutathione; GSSG, oxidized glutathione; HF, heart failure; HFC-MHI, heart failure clinic of the Montreal Heart Institute; HOMA-IR, homeostatic model assessment of insulin resistance; Heart failure patients; LA, linoleic acid; Linoleic acid; Lipid peroxidation; MDA, malondialdehyde; MPO, myeloperoxidase; NT-pro-BNP, N-terminal proB-type natriuretic peptide; NYHA, New York Heart Association; Oxidative stress; PUFA, polyunsaturated fatty acids; Polyunsaturated fatty acids; RAS, renin-angiotensin system; TBARS, thiobarbituric acid-reactive substances; TNF, tumor necrosis factor; eGFR, estimated glomerular filtration rate.