TY - JOUR
T1 - Plasma Methylglyoxal Levels Are Associated With Amputations and Mortality in Severe Limb Ischemia Patients With and Without Diabetes
AU - Hanssen, Nordin M. J.
AU - Teraa, Martin
AU - Scheijen, Jean L. J. M.
AU - Van de Waarenburg, Marjo
AU - Gremmels, Hendrik
AU - Stehouwer, Coen D. A.
AU - Verhaar, Marianne C.
AU - Schalkwijk, Casper G.
N1 - Funding Information:
The work was done with the financial support from a collaborative project with Central Council for Research in Homeopathy (CCRH), Under Ministry of AYUSH, Govt. of India (F. No. 6-01/14-15/CCRH/cash/11515)
Publisher Copyright:
© 2020 by the American Diabetes Association.
PY - 2021/1
Y1 - 2021/1
N2 - OBJECTIVE 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 end products (AGEs) and a potential driver of cardiovascular disease. We investigated whether plasma MGO levels are associated with poor outcomes in SLI. RESEARCH DESIGN AND METHODS We measured plasma levels of MGO, free AGEs, and d-lactate, the detoxification end product of MGO, with ultraperformance liquid chromatography-tandem mass spectrometry at baseline in 160 patients (64.8 +/- 13.3 years, 67.5% male, 37.5% with diabetes) with no-option SLI and recorded major adverse outcomes (n = 86, comprising n = 53 deaths and n = 49 amputations [first event counted]) over the 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, estimated glomerular filtration rate, systolic blood pressure, cholesterol levels, and BMI. Associations are reported per 1 SD plasma marker. RESULTS Higher plasma MGO levels were associated with more adverse outcomes (relative risk 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 N-epsilon-(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. CONCLUSIONS Plasma MGO levels are associated with adverse outcomes in SLI. Future studies should investigate whether MGO-targeting therapies improve outcomes in SLI.
AB - OBJECTIVE 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 end products (AGEs) and a potential driver of cardiovascular disease. We investigated whether plasma MGO levels are associated with poor outcomes in SLI. RESEARCH DESIGN AND METHODS We measured plasma levels of MGO, free AGEs, and d-lactate, the detoxification end product of MGO, with ultraperformance liquid chromatography-tandem mass spectrometry at baseline in 160 patients (64.8 +/- 13.3 years, 67.5% male, 37.5% with diabetes) with no-option SLI and recorded major adverse outcomes (n = 86, comprising n = 53 deaths and n = 49 amputations [first event counted]) over the 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, estimated glomerular filtration rate, systolic blood pressure, cholesterol levels, and BMI. Associations are reported per 1 SD plasma marker. RESULTS Higher plasma MGO levels were associated with more adverse outcomes (relative risk 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 N-epsilon-(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. CONCLUSIONS Plasma MGO levels are associated with adverse outcomes in SLI. Future studies should investigate whether MGO-targeting therapies improve outcomes in SLI.
KW - ADVANCED GLYCATION ENDPRODUCTS
KW - INTRAARTERIAL INFUSION
KW - CARDIOVASCULAR-DISEASE
KW - MONONUCLEAR-CELLS
KW - GLYOXALASE-I
KW - INDIVIDUALS
U2 - 10.2337/dc20-0581
DO - 10.2337/dc20-0581
M3 - Article
C2 - 33144352
SN - 0149-5992
VL - 44
SP - 157
EP - 163
JO - Diabetes Care
JF - Diabetes Care
IS - 1
ER -