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Tissue plasminogen activator (tPA) activity is a novel and early marker of asymptomatic LEAD in type 2 diabetes
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. (AstraZeneca R&D, Mölndal, Sweden)
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. (Department of Medicine, Skellefteå Hospital, Skellefteå, Sweden)
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. (Department of Nephrology, Sahlgrenska University Hospital, Göteborg)
2009 (English)In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 123, no 5, 701-706 p.Article in journal (Refereed) Published
Abstract [en]

INTRODUCTION: Lower extremity arterial disease (LEAD) is often one of the first signs of a generalized atherosclerotic disease in type 1 and type 2 diabetic subjects.

MATERIALS AND METHODS: We studied 143 diabetic subjects at 30-70 years of age, M/F 69/74, 74 with type 1 and 69 with type 2 diabetes, without previously known or suspected lower extremity arterial disease. The relationship between early asymptomatic lower extremity arterial disease and blood levels of HbA1c, lipids and fibrinolysis markers (tPA-activity, tPA mass, PAI-1 activity, tPA-PAI-1 complex) was assessed. In parallel, a group with non-diabetic subjects (n=80) was studied.

RESULTS: 35 (24%) diabetic subjects were classified as having sign(s) of LEAD, defined as having at least one reduced peripheral blood pressure measurement, 28% in type 1 vs 20% in type 2 diabetic subjects (p=NS). In univariate logistic regression analyses age, glycemic level (HbA1c), male gender (only in type 1 diabetic subjects), hypertension and tPA activity (only in type 2 diabetic subjects) were positively associated with LEAD. When markers of fibrinolysis were entered into a multivariate model adjusting for age, hypertension, and HbA1c, only tPA activity remained independently associated with LEAD (p=0.01) and this was also found in type 2 diabetic subjects (p=0.05). In type 1 diabetic subjects the increase in odds ratio was non-significant.

CONCLUSIONS: Tissue plasminogen activator (tPA) activity may be an independent and early marker for asymptomatic lower extremity arterial disease in diabetic subjects, particularly in type 2 diabetes. Thus an altered fibrinolytic activity could be an early marker of atherosclerosis development in the lower extremities but the cause-effect relationship remains unclear.

Place, publisher, year, edition, pages
2009. Vol. 123, no 5, 701-706 p.
National Category
Family Medicine
Identifiers
URN: urn:nbn:se:umu:diva-22152DOI: 10.1016/j.thromres.2008.07.015PubMedID: 18945481OAI: oai:DiVA.org:umu-22152DiVA: diva2:212916
Available from: 2009-04-24 Created: 2009-04-24 Last updated: 2017-12-13Bibliographically approved
In thesis
1. Early arterial disease of the lower extremities in diabetes: diagnostic evaluation and risk markers
Open this publication in new window or tab >>Early arterial disease of the lower extremities in diabetes: diagnostic evaluation and risk markers
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The aim of the present thesis was to assess the occurrence of early lower extremity arterial disease (LEAD) in patients with diabetes and to assess novel potential risk markers for development or worsening of LEAD in the same patients. In parallel different measures of impaired peripheral circulation were evaluated.

The measurement of ankle-to- brachial blood pressure index (ABI) to screen for asymptomatic LEAD in diabetic subjects is unreliable since a large proportion of patients have stiff ankle arteries (mediasclerosis) and thus may display a too high ABI. We studied type 1-, type 2 diabetic and non-diabetic subjects without a previous history of LEAD and a composite variable of ankle – plus toe blood pressures and indices was compared to ABI alone in detecting LEAD. Significantly more subjects with reduced peripheral circulation were detected using the composite variable compared to ABI alone. This was particularly true in diabetic subjects, about 30% of whom had signs of impaired peripheral circulation. Thus, it was found that toe blood pressure measurements, alone or in combination with ankle blood pressure measurements, increase the sensitivity for finding early asymptomatic LEAD in diabetic subjects. No significant difference in reproducibility between measurements of absolute ankle- and toe blood pressure and indices was found, but a correlation between systemic (brachial) and toe blood pressure variations over time may suggest that indices are more correct in assessing peripheral arterial circulation.

Furthermore, toe blood pressure measurements can be performed using either the great toe or dig II and a strong concordance is found between these measurements. In addition, since the pole-test, another non-invasive method to measure peripheral blood pressure which is less sensitive to the presence of mediasclerosis compared to ABI, correlated significantly with toe blood pressure measurements this method may be used as an alternative screening method in subjects with previously known LEAD.

Age, hypertension and glycemic control are well known risk factors and, in addition, high tissue plasminogen activator (tPA) activity turned out to be a novel early marker for asymptomatic LEAD in diabetic subjects, particularly in patients with type 2 diabetes. Age and hyperglycemia are the most important risk factors for development and progression of subclinical lower extremity arterial disease in type 2 diabetic subjects. No independent associations between markers of inflammation, such as CRP, interleukin-6 and TNF-α and early asymptomatic LEAD were seen among non-diabetic or diabetic subjects.

In conclusion, impaired arterial circulation in the lower extremities is common in diabetic subjects even in the absence of symptoms. Including toe blood pressure measurement when screening for asymptomatic LEAD in diabetic subjects improves the ability to detect reduced peripheral circulation and this method avoids falsely elevated blood pressures readings due to mediasclerosis in the ankle arteries. Moreover, an altered fibrinolytic activity should be further evaluated as an early marker of atherosclerosis and LEAD.

Place, publisher, year, edition, pages
Umeå: Umeå university, 2009. 45 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1302
Keyword
diabetes mellitus, ankle blood pressure, toe blood pressure, screening, risk markers, mediasclerosis, macroangiopathy, fibrinolysis, inflammation
National Category
Medical and Health Sciences Endocrinology and Diabetes
Identifiers
urn:nbn:se:umu:diva-26711 (URN)978-91-7264-884-5 (ISBN)
Public defence
2009-11-13, Betula UnodL0, Umeå Universitet, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2009-10-26 Created: 2009-10-22 Last updated: 2012-08-15Bibliographically approved

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