Plasminogen activator inhibitor-1 (PAI-1) activity and retinal vascular calibre in type 2 diabetes

doi:10.1016/j.diabres.2009.11.007

Diabetes Research and Clinical Practice

Volume 87, Issue 2, February 2010, Pages 192-199

https://doi.org/10.1016/j.diabres.2009.11.007 Get rights and content

Abstract

Objective

To describe relationships of retinal vascular calibre with plasminogen activator inhibitor-1 (PAI-1) and other cardiovascular risk factors in people with type 2 diabetes.

Methods

We recruited 112 community-based persons aged 44–83 years with type 2 diabetes, photo-documented retinal status using a digital fundus camera, and measured traditional and novel vascular risk factors. Retinal arteriolar and venular calibre and the arterio–venous ratio (AVR) were determined from fundus photographs using a validated computer-assisted method.

Results

In adjusted linear regression models, PAI-1 activity was strongly associated with all measures of retinal vascular calibre: positively with arterioles (p = 0.005) and AVR (p = 0.001), and inversely with venules (p = 0.001). In addition, wider arterioles were independently associated with waist-hip ratio (p < 0.0001), HDL-C (p = 0.015), and lower systolic blood pressure (p = 0.042), whereas narrower venules were associated with older age and a higher albumin excretion rate. Neither arteriolar nor venular calibre was associated with plasma total homocysteine or C-reactive protein concentration.

Conclusion

Retinal vascular calibre is independently associated with PAI-1 activity in type 2 diabetes. This finding supports a role for PAI-1 activity in the microvasculature of persons with type 2 diabetes and may explain the link between retinal vascular calibre and cardiovascular disease.

Introduction

Changes in retinal vascular calibre predict the incidence of cardiovascular disease (CVD), as well as microvascular complications in diabetes [1]. Retinal arteriolar narrowing, for example, predicts incident coronary heart disease and stroke [2], while larger venular calibre predicts retinopathy and nephropathy progression in type 2 diabetes [3], independent of other risk factors. The exact mechanisms underlying these associations, however, remain unclear.

Previous studies have investigated relationships between retinal vascular calibre and traditional vascular risk factors to help explain the observed association between retinal vascular calibre and clinical CVD risk [4]. Reports from these studies have consistently show that higher blood pressure is a major determinant of arteriolar narrowing, while cigarette smoking, measures of obesity, and systemic inflammation are predictive of wider retinal venular calibre [1]. However, more recent studies indicate that traditional risk factors cannot account for all the observed changes in retinal vascular calibre [5], reflecting the contribution of other yet unknown risk factors.

PAI-1 protein, a key regulator of fibrinolysis, is a novel risk marker for CVD. Elevated levels of PAI-1 are found in people with insulin resistance and type 2 diabetes and more importantly, it also predicts incident coronary heart disease in type 2 diabetes [6]. The association of PAI-1 with retinal vascular calibre, however, has not been previously investigated.

Hence, the purpose of this study is to describe the relationship of retinal vascular calibre with PAI-1 and other novel vascular risk factors in persons with type 2 diabetes so as to clarify other systemic determinants of retinal vascular calibre.

Section snippets

Study population and subject selection

We recruited 112 community-based volunteers with type 2 diabetes from the Melbourne Collaborative Cohort Study (MCCS), divided equally between Greek-born and Australian-born men and women, in order to capture a wider range of exposures. MCCS study design and details of subject recruitment have been described elsewhere [7]. Ethics approval was obtained from the MCCS Scientific Committee and Monash University (Melbourne, Australia), and written informed consent was obtained from each participant.

Subject characteristics

Selected subject characteristics are shown in Table 1. The majority of participants were centrally obese, older adults with inadequate control of traditional risk factors. Mean (SD) retinal arteriolar calibre (CRAE) and venular calibre (CRVE) did not differ significantly between genders, nor by country of birth. The prevalence of diabetic retinopathy in this cohort of patients was 30.8%.

Univariate correlates of retinal vascular calibre

Table 2 shows the univariate associations of retinal vascular calibre with selected CVD risk factors. PAI-1

Discussion

There is interest in using retinal vascular calibre as a non-invasive method for predicting CVD risk and for examining associations with vascular risk factors as retinal vessels are the only part of the human microcirculation that can be visualised directly and non-invasively. Changes in retinal vascular calibre independently predict incident coronary heart disease, stroke and nephropathy [15], but underlying mechanisms of these associations are not fully elucidated.

In a community-based

Conflict of interest

There are no conflicts of interest.

Acknowledgements

This work would not have been possible without the Melbourne Collaborative Cohort Study and the infrastructure support provided by the Cancer Council Victoria. Additional funding was provided by the National Health and Medical Research Council (#124317), the National Heart Foundation, and the Centre for Clinical Research Excellence in Clinical Science in Diabetes.

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To our knowledge, this is the first study to report an association of flicker-induced retinal vessel dilation with PAI-1, a biomarker representative of endothelial dysfunction and inflammation. A limited number of studies have investigated the associations of static retinal vessel calibres with PAI-1, with diverse findings being reported (Brazionis et al., 2010; Lammertyn et al., 2015; Wong et al., 2006). No associations were found in a group of Black and White South Africans (mean ages 48 and 49 years, respectively) (Lammertyn et al., 2015), whilst a weak positive association between PAI-1 and retinal venular calibre was found in individuals (mean age 62 years) free from clinical CVD (Wong et al., 2006).
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In multivariate regression analyses, maximal retinal venular dilation associated independently and inversely with PAI-1_act (adj. R² = 0.11; β = −0.15; p = 0.001) in the total group. In exploratory subgroup analyses, this association remained in White women (adj. R² = 0.07; β = −0.23; p = 0.005), and was more robust with younger age and lower blood pressure and in non-smokers, but also with greater central adiposity, higher low-density lipoprotein cholesterol and inflammation (all p < 0.05).
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¹: These authors contributed equally.

View full text

Plasminogen activator inhibitor-1 (PAI-1) activity and retinal vascular calibre in type 2 diabetes

Abstract

Objective

Methods

Results

Conclusion

Introduction

Section snippets

Study population and subject selection

Subject characteristics

Univariate correlates of retinal vascular calibre

Discussion

Conflict of interest

Acknowledgements

Ophthalmology

Am. J. Ophthalmol.

Ophthalmology

Diabetes Res. Clin. Pract.

Diabetes Res. Clin. Pract.

Bioorg. Med. Chem. Lett.

Retinal vascular caliber, cardiovascular risk factors, and inflammation: the multi-ethnic study of atherosclerosis (MESA)

Invest. Ophthalmol. Vis. Sci.

Quantitative retinal venular caliber and risk of cardiovascular disease in older persons: the cardiovascular health study

Arch. Intern. Med.

The relation of retinal vessel caliber to the incidence and progression of diabetic retinopathy: XIX: the wisconsin epidemiologic study of diabetic retinopathy

Arch. Ophthalmol.

Retinal vascular caliber, blood pressure, and cardiovascular risk factors in an Asian population: the Singapore Malay eye study

Invest. Ophthalmol. Vis. Sci.

Low birthweight is associated with narrower arterioles in adults

Hypertension

Plasminogen activator inhibitor-1 activity in type 2 diabetes. A different relationship with coronary heart disease and diabetic retinopathy

Arterioscler. Thromb. Vasc. Biol.

Epidemiology of food and disease: the Melbourne cohort study

Asia Pac. J. Clin. Nutr.

Diabetes Mellitus: Report of a WHO Study Group.

Obesity

Public Health Rep.

Is retinal photography useful in the measurement of stroke risk?

Lancet Neurol

Facts and recommendations about total homocysteine determinations: an expert opinion

Clin. Chem.