Plasma matrix metalloproteinases are associated with incident cardiovascular disease and all-cause mortality in patients with type 1 diabetes: a 12-year follow-up study

TY - JOUR

T1 - Plasma matrix metalloproteinases are associated with incident cardiovascular disease and all-cause mortality in patients with type 1 diabetes

T2 - a 12-year follow-up study

AU - Peeters, S A

AU - Engelen, L

AU - Buijs, J

AU - Jorsal, A

AU - Parving, H-H

AU - Tarnow, L

AU - Rossing, P

AU - Schalkwijk, C G

AU - Stehouwer, C D A

PY - 2017/4/26

Y1 - 2017/4/26

N2 - BACKGROUND: Altered regulation of extracellular matrix remodeling by matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinase (TIMP) may contribute to vascular complications in type 1 diabetes. We investigated associations between plasma MMP-1, -2, -3, -9, -10 and TIMP-1, and cardiovascular events and all-cause mortality in type 1 diabetic patients.METHODS: We prospectively followed 337 type 1 diabetic patients [mean age 41.4 years (9.6), 39% female], 170 with and 167 without diabetic nephropathy, with median follow-up of 12.3 years. Survival analyses were applied to investigate differences in plasma MMP-1, -2, -3, -9, -10, and TIMP-1-levels in patients with and without a cardiovascular event and in those who died vs survivors. All analyses were adjusted for age, sex, duration of diabetes, HbA1c, nephropathy and for other conventional cardiovascular risk factors.RESULTS: After adjustment for potential confounders, higher MMP-2 plasma levels were significantly associated with higher incidence of cardiovascular events [HR 1.49 (95% CI 1.11; 1.99)], and higher plasma levels of MMP-1 [1.38 (1.07; 1.78)], MMP-2 [1.60 (1.19; 2.15)] and MMP-3 [1.39 (1.05; 1.85)] were associated with all-cause mortality. All associations were independent of low-grade inflammation and endothelial dysfunction as estimated by plasma markers. Associations between MMP-2 and cardiovascular events and between MMP-3 and mortality were attenuated after further adjustment for eGFR and changes in eGFR.CONCLUSIONS: Higher levels of MMP-2 are associated with CVD and higher MMP-1, -2 and -3 with all-cause mortality. In addition, associations between MMP-2 and CVD, and MMP-3 and mortality were attenuated after adjustment for eGFR while both MMPs were associated with eGFR decline, indicating a possible mediating role of eGFR.

AB - BACKGROUND: Altered regulation of extracellular matrix remodeling by matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinase (TIMP) may contribute to vascular complications in type 1 diabetes. We investigated associations between plasma MMP-1, -2, -3, -9, -10 and TIMP-1, and cardiovascular events and all-cause mortality in type 1 diabetic patients.METHODS: We prospectively followed 337 type 1 diabetic patients [mean age 41.4 years (9.6), 39% female], 170 with and 167 without diabetic nephropathy, with median follow-up of 12.3 years. Survival analyses were applied to investigate differences in plasma MMP-1, -2, -3, -9, -10, and TIMP-1-levels in patients with and without a cardiovascular event and in those who died vs survivors. All analyses were adjusted for age, sex, duration of diabetes, HbA1c, nephropathy and for other conventional cardiovascular risk factors.RESULTS: After adjustment for potential confounders, higher MMP-2 plasma levels were significantly associated with higher incidence of cardiovascular events [HR 1.49 (95% CI 1.11; 1.99)], and higher plasma levels of MMP-1 [1.38 (1.07; 1.78)], MMP-2 [1.60 (1.19; 2.15)] and MMP-3 [1.39 (1.05; 1.85)] were associated with all-cause mortality. All associations were independent of low-grade inflammation and endothelial dysfunction as estimated by plasma markers. Associations between MMP-2 and cardiovascular events and between MMP-3 and mortality were attenuated after further adjustment for eGFR and changes in eGFR.CONCLUSIONS: Higher levels of MMP-2 are associated with CVD and higher MMP-1, -2 and -3 with all-cause mortality. In addition, associations between MMP-2 and CVD, and MMP-3 and mortality were attenuated after adjustment for eGFR while both MMPs were associated with eGFR decline, indicating a possible mediating role of eGFR.

KW - Adult

KW - Biomarkers/blood

KW - Cardiovascular Diseases/blood

KW - Cause of Death

KW - Diabetes Mellitus, Type 1/blood

KW - Female

KW - Follow-Up Studies

KW - Glomerular Filtration Rate

KW - Humans

KW - Incidence

KW - Kidney/physiopathology

KW - Male

KW - Matrix Metalloproteinases, Secreted/blood

KW - Middle Aged

KW - Netherlands/epidemiology

KW - Predictive Value of Tests

KW - Prognosis

KW - Proportional Hazards Models

KW - Prospective Studies

KW - Risk Assessment

KW - Risk Factors

KW - Time Factors

KW - Tissue Inhibitor of Metalloproteinase-1/blood

U2 - 10.1186/s12933-017-0539-1

DO - 10.1186/s12933-017-0539-1

M3 - Journal article

C2 - 28446168

SN - 1475-2840

VL - 16

JO - Cardiovascular Diabetology

JF - Cardiovascular Diabetology

IS - 1

M1 - 55

ER -