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Plasma methylglyoxal levels are associated with amputations and mortality in severe limb ischemia patients with and without diabetes

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posted on 03.11.2020, 21:41 by Nordin MJ Hanssen, Martin Teraa, Jean LJM Scheijen, Marjo Van de Waarenburg, Hendrik Gremmels, Coen DA Stehouwer, Marianne C Verhaar, Casper G Schalkwijk
Introduction

Diabetes is a risk factor for severe limb ischemia (SLI), a condition associated with high mortality, morbidity and limb loss. The reactive glucose-derived dicarbonyl methylglyoxal (MGO) is a major precursor for advanced glycation endproducts (AGEs) and potential driver of cardiovascular disease. We investigated whether plasma MGO levels are associated with poor outcomes in SLI.

Methods

We measured plasma levels of MGO, free AGEs, and D-lactate, the detoxification endproduct of MGO, with ultra-performance liquid chromatography tandem mass spectrometry at baseline in 160 patients (64.8±13.3years, 67.5% male, 37.5% diabetes) with no-option SLI and recorded major adverse outcomes (n=86, containing death n=53 or amputations n=49 (First event counted)) over 5-year follow-up. Data were analyzed with linear or Cox regression, after Ln-transformation of the independent variables, adjusted for sex, age, trial arm, diabetes, eGFR, systolic blood pressure, cholesterol levels and BMI. Associations are reported per 1SD plasma marker.

Results

Higher plasma MGO levels were associated with more adverse outcomes (RR: 1.44; 95%CI: 1.11-1.86) and amputations separately (1.55; 1.13-2.21). We observed a similar, but weaker trend for mortality (1.28; 0.93-1.77). The MGO derived AGE Nε-(carboxyethyl)lysine was also associated with more adverse outcomes (1.46; 1.00-2.15) and amputations (1.71; 1.04-2.79). D-lactate was not associated with adverse incident outcomes. Higher plasma MGO levels were also associated with more inflammation and white blood cells and fewer progenitor cells.

Conclusion

Plasma MGO levels are associated with adverse outcomes in SLI. Future studies should investigate whether MGO-targeting therapies improve outcomes in SLI.

Funding

NMJH is supported by a Dr E. Dekker grant by the Dutch Heart Foundation (2017T039) and a junior post-doc grant from the Dutch Diabetes Foundation (2017.85.005). The Juventas Study was supported by the “Stichting Vrienden UMC Utrecht” on behalf of the Dirkzwager-Assink foundation (The Netherlands, grant CS 06.007), the Dutch Heart Foundation (grant 2008B094), The Netherlands Organization for Scientific Research (ZonMw-TAS grant 116001026), and foundation “Stichting De Drie Lichten” (The Netherlands, grant 10/06).

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