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

S. A. Peeters, L. Engelen, J. Buijs, A. Jorsal, H. -H. Parving, L. Tarnow, P. Rossing, C. G. Schalkwijk, C. D. A. Stehouwer*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

34 Citations (Web of Science)

Abstract

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.

Original languageEnglish
Article number55
Number of pages12
JournalCardiovascular Diabetology
Volume16
DOIs
Publication statusPublished - 26 Apr 2017

Keywords

  • Type 1 diabetes
  • Cardiovascular disease
  • All-cause mortality
  • Matrix metalloproteinase
  • Tissue inhibitor of metalloproteinase
  • Estimated glomerular filtration rate
  • EURODIAB PROSPECTIVE COMPLICATIONS
  • TISSUE INHIBITOR
  • MYOCARDIAL-INFARCTION
  • HEART-FAILURE
  • MICROVASCULAR COMPLICATIONS
  • MATRIX-METALLOPROTEINASE-9
  • DYSFUNCTION
  • RETINOPATHY
  • MELLITUS
  • EVENTS

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