Patients with type 2 diabetes have a high risk for early and extensive development of peripheral arterial disease (PAD) and this excess risk is not explained by increased burden of traditional atherosclerotic risk factors. Activation of the receptor for advanced glycation end products (RAGE) could be one additional mechanism for accelerated PAD and increased risk for amputation and death. We investigated the association between RAGE plasma components and the risk for PAD, amputation and death in patients with type 2 diabetes. We also estimated the rate of amputation-free survival and survival without PAD.
We investigated if plasma levels of carboxymethyl-lysine, S100A12 and endosecretory RAGE (esRAGE) were associated with two endpoints: survival without development of PAD and survival without amputation in a 12 years prospective population-based cohort of 146 patients with type 2 diabetes, free from PAD at inclusion. Influence of baseline plasma levels of RAGE ligands (individually and combined by a RAGE-score) were evaluated for both endpoints in the Cox-regression analysis.
106 patients survived without amputation and 93 survived without signs of PAD during follow up. Higher levels of S100A12 and RAGE-score were associated with increased risk for amputation or death, hazard ratios (HR) 1.29; 95% confidence interval (CI) [1.04, 1.59] and 1.79; 95% CI [1.07, 2.99] and with increased risk for PAD or death, HR 1.22; 95% CI [1.00, 1.49] and 1.56; [1.00, 2.44] after adjustment for age and sex. The effect was decreased after adjustment for Framingham cardiovascular disease score: risk for amputation or death, HR 1.17; 95% CI [0.94, 1.46] and 1.54; [0.95, 2.49], and risk for PAD or death, HR 1.12; 95% CI [0.91, 1.38] and 1.38; [0.91, 2.11] for S100A12 and RAGE-score respectively. The incidence for amputation or death was 2.8 per 100 person-years; 95% CI [2.0, 3.7] and the incidence rate for PAD or death was 3.6 per 100 person-years; 95% CI [2.7, 4.8].
Higher plasma levels of S100A12 and the combined effect (RAGE-score) of esRAGE, carboxymethyl-lysine and S100A12 seem to be associated with shorter PAD- and amputation-free survival in patients with type 2 diabetes. This may indicate a role for S100A12 in PAD by activation of the RAGE system.
Cites: J Biol Chem. 1999 Oct 29;274(44):31740-910531386
Ruptured abdominal aortic aneurysms (AAA) cause 600 deaths per year in Sweden. As most patients are without symptoms prior to rupture, and about half the patients with a ruptured AAA die before arrival to hospital, the only way to reduce mortality substantially would be by screening and prophylactic treatment. The article reviews experience of screening for AAA from other European countries, data from the Swedish vascular registry (Swedvasc) and from the official registry of the causes of death in Sweden. With these data as input, a theoretical model of inviting all 65-year-old men in Sweden to take part in a screening programme for AAA is created. When the programme is fully developed after ten years, assuming an attendance rate of 75%, mortality in AAA would decrease from 630 to 346 per year. The total cost would increase from 154 to 161 million SEK (9 SEK = 1 Euro). The reason for the relatively minor increase in cost is explained by the fact that expensive emergency operations for ruptured AAA decrease by 50%. The cost per life saved would be 3,000-4,000 SEK. In conclusion, available data suggest that screening for AAA in Sweden would save many lives at a low cost.
Comment In: Lakartidningen. 2003 May 22;100(21):1874-612815871
The prevalence of abdominal aortic aneurysms (AAAs) differs considerably between the sexes, illustrated by the male/female ratio 4-6:1. Women are also reported to have a higher risk of rupture, and a poorer outcome compared with men. The primary aim of this study was to investigate if women with AAA have a different reproductive history compared with other women. The secondary aim was to study if women with a larger AAA differ in their reproductive history from women with a smaller AAA.
This case-control study was performed in October 2009 and included 140 consecutively monitored women with AAA and 140 with peripheral arterial disease (PAD) at the Department of Vascular Surgery at Karolinska University Hospital, Stockholm. AAA was defined as AAA diameter >3 cm, and women with AAA were subdivided into groups with AAA diameter =5 cm and diameter
The most commonly used predictor of rupture of an abdominal aortic aneurysm (AAA) is the diameter; however, this does not estimate the true risk for each patient. Why women with AAAs have an increased growth rate, weaker aortic wall, and increased risk for rupture is yet unclear. It is likely that geometrical and biomechanical properties contribute to found gender differences. Several studies have shown that peak wall stress (PWS) and peak wall rupture risk (PWRR), predicted by a finite element (FE) analysis of AAAs derived from computed tomography (CT), is a better predictor of rupture than maximum diameter. The purpose of this study was to investigate if women with AAAs have an increased PWS and PWRR using an FE model compared to men.
Fifteen men and 15 women (AAAs 4-6 cm) were included. AAA geometry was derived from CT scans, and PWS and PWRR were estimated using the FE method. Comparisons were made by t test and Mann-Whitney test.
Mean age (women 73 years old vs men 71 years old) and mean AAA diameter was similar (49.7 mm vs 50.1 mm) for women and men. PWS did not differ for women 184 and men 198 kPa. PWRR was 0.54 (0.28-0.85) for women and 0.43 (0.24-0.66) for men, P = .06.
This is the first analysis of stress and strength of the aneurysm wall with a gender perspective. The reported higher rupture risk for women has previously not been tested with geometrical and biomechanical properties. PWS did not differ, but the PWRR was slightly higher in women. However, the difference did not reach statistical significance, probably due to the small sample size. In summary, the results in the present study suggest that differences in biomechanical properties could be a contributing explanation for the higher rupture risk reported for female patients with AAAs.
BACKGROUND: The contribution of hereditary and environmental factors to the development of abdominal aortic aneurysms (AAAs) is still partly unknown. The aim of this study was to analyze the role of these factors in a large population-based sample of twins. METHODS: The Swedish Twin Registry, containing data on twins born in the country since 1886, was cross-linked with the Inpatient Registry, providing national coverage of discharge diagnoses coded according to the International Classification of Diseases (ICD). All twins with an infrarenal AAA were identified. Concordance rates and tetrachoric correlations were calculated for monozygotic (MZ) and dizygotic (DZ) twins. Tetrachoric correlations were calculated assuming an underlying normal distribution of liability, with multiple factors contributing additively and a threshold value that discriminates between AAA and no AAA. Higher concordance rates and correlations of liability in MZ twins than in DZ twins suggest that genetic factors influence disease development. Structural equation modeling techniques, Mx-analyses, were used to estimate the contributions of genetic effects as well as shared and nonshared environmental factors for development of AAA. RESULTS: There were 172,890 twins registered at the time of the study including 265 twins (81% men; mean age 72 years; range, 48-94) with AAA. There were 7 MZ and 5 DZ concordant pairs as well as 44 MZ and 197 DZ discordant pairs with AAA. The probandwise concordance rates for MZ and DZ pairs were 24% and 4.8%, respectively. The tetrachoric correlations were 0.71 in MZ pairs and 0.31 in DZ pairs. The odds ratio (OR) was 71 (95% confidence interval [CI] 27-183) for MZ twins and 7.6 (95% CI 3.0-19) for DZ twins. In the structural equation models, genetic effects accounted for 70% (95% CI 0.33-0.83), shared environmental effects for 0% (95% CI 0-0.27), and nonshared environmental effects for 30% (95% CI 0.17-0.46) of the phenotypic variance among twins. CONCLUSION: These data provide robust epidemiologic evidence that heritability contributes to aneurysm formation. Concordances and correlations were higher in MZ compared with DZ twins, indicating genetic effects. There was a 24% probability that an MZ twin of a person with AAA will have the disease. The twin of an MZ twin with AAA had a risk of AAA that was 71 times that of the MZ twin of a person without AAA. A heritability of 70% of the total trait variance was estimated. The remaining variance was explained by nonshared environmental factors with no support for a role of shared environmental influences.