Plasma levels of the arterial wall protein fibulin-1 are associated with carotid-femoral pulse wave velocity: a cross-sectional study

Esben Laugesen, Pernille Høyem, Jens Sandahl Christiansen, Søren Tang Knudsen, Klavs Würgler Hansen, W Scott Argraves, Troels Krarup Hansen, Per Løgstrup Poulsen, Lars Melholt Rasmussen, Esben Laugesen, Pernille Høyem, Jens Sandahl Christiansen, Søren Tang Knudsen, Klavs Würgler Hansen, W Scott Argraves, Troels Krarup Hansen, Per Løgstrup Poulsen, Lars Melholt Rasmussen

Abstract

Background: The arterial system in diabetic patients is characterized by generalized non-atherosclerotic alterations in the vascular extracellular matrix causing increased arterial stiffness compared with subjects without diabetes. The underlying pathophysiology remains elusive. The elastin-associated extracellular matrix protein, fibulin-1, was recently found in higher concentrations in the arterial wall and in plasma in patients with long duration type 2 diabetes. Furthermore, plasma fibulin-1 independently predicted total mortality and was associated with pulse pressure, an indirect measure of arterial stiffness. Whether plasma fibulin-1 is associated with arterial stiffness at earlier phases of type 2 diabetes has not been determined.

Methods: In this cross-sectional study, we examined 90 patients with recently diagnosed type 2 diabetes (< 5 years) and 90 gender- and age-matched controls. Plasma fibulin-1 was measured immunochemically. Arterial stiffness was assessed by carotid-femoral Pulse Wave Velocity (PWV). Differences in means were assessed by t-tests. Associations were assessed by multivariate regression analyses.

Results: Plasma fibulin-1 levels were lower in the diabetic group compared with the control group, 93 ± 28 vs 106 ± 30 μg/mL, p = 0.005. In unadjusted analysis of the total study sample, plasma fibulin-1 was not associated with PWV, p = 0.46. However, with adjustment for the confounders age, gender, mean blood pressure, heart rate, body mass index, diabetes and glomerular filtration rate, a 10 μg/mL increase in plasma fibulin was associated with 0.09 ± 0.04 m/s increase in PWV, p < 0.05. In subgroup analysis, plasma fibulin-1 was associated with PWV in the diabetes group, (0.16 ± 0.07 m/s increase in PWV per 10 μg/mL increase in plasma fibulin-1, p<0.05), but not controls, β = 0.021 ± 0.057 m/s per 10 μg/mL, p = 0.70. The association remained significant in the diabetes group after adjustment for covariates, p < 0.05.

Conclusions: Plasma fibulin-1 is independently associated with PWV. Yet, as the plasma level of fibulin-1 was lower in patients with recently diagnosed type 2 diabetes than in healthy controls, plasma fibulin-1 levels are not a simple marker of the degree of arterial stiffening. Further studies are needed to determine the exact role of fibulin-1 in arterial stiffness and cardiovascular risk in patients with type 2 diabetes.

Trial registration: ClinicalTrials.gov NCT00674271.

Figures

Figure 1
Figure 1
Plasma fibulin-1 in patients with type 2 diabetes and gender- and age-matched controls. Horizontal line indicates mean. Panel A: Plasma fibulin-1 in 90 patients with type 2 diabetes and 90 gender- and age-matched controls. Subgroup analyses in panel B and C: Panel B: Plasma fibulin-1 in the 34 diabetes patients not receiving metformin and their 34 gender- and age- matched controls. Panel C: Plasma fibulin-1 in the 56 diabetes patients receiving metformin and their 56 gender- and age- matched controls.
Figure 2
Figure 2
Scatter-plots of plasma fibulin-1 and carotid femoral pulse wave velocity. r = Pearson’s correlation coefficient.

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