Association between metformin prescription and growth rates of abdominal aortic aneurysms.

BACKGROUND: It has been suggested that diabetes medications, such as metformin, may have effects that inhibit abdominal aortic aneurysm (AAA) growth. The aim of this study was to examine the association of diabetes treatments with AAA growth in three patient cohorts. METHODS: AAA growth was studied using ultrasound surveillance in cohort 1, repeated CT in cohort 2 and more detailed repeat CT in cohort 3. Growth was estimated by the mean annual increase in maximum AAA diameter. RESULTS: A total of 1697 patients with an AAA were studied, of whom 118, 39 and 16 patients were prescribed metformin for the treatment of diabetes in cohorts 1, 2 and 3 respectively. Prescription of metformin was associated with a reduced likelihood of median or greater AAA growth in all three cohorts (cohort 1: adjusted odds ratio (OR) 0·59, 95 per cent c.i. 0·39 to 0·87, P = 0·008; cohort 2: adjusted OR 0·38, 0·18 to 0·80, P = 0·011; cohort 3: adjusted OR 0·13, 0·03 to 0·61, P = 0·010). No other diabetes treatment was significantly associated with AAA growth in any cohort. CONCLUSION: These findings suggest a potential role for metformin in limiting AAA growth.

Profile of diabetes in men aged 79-97 years: the Western Australian Health in Men Study.

AIMS: To investigate behavioural, physical and biochemical characteristics associated with diabetes in the oldest age group of elderly men. METHODS: We conducted a cross-sectional analysis of community-dwelling men aged 79-97 years from Perth, Western Australia. Lifestyle behaviours, self-rated health, physical function, and fasting glucose and HbA1c levels were assessed. RESULTS: Of 1426 men, 315 had diabetes (22%). Men with diabetes were of similar age to men without (84.9 vs 84.5 years; P = 0.14). Only 26.5% of men with diabetes self-rated their health as excellent or very good, compared with 40.6% of men without diabetes (P < 0.001). Diabetes was associated with less involvement with recreational walking (32.7 vs 41.0%; P < 0.01) and leisure activities (19.0 vs 26.5%; P < 0.01). Men with diabetes had poorer physical function on multiple measures, including longer times for the Timed Up-and-Go test (15.0 ± 6.9 s vs 13.4 ± 5.3 s; P < 0.001) and weaker knee extension (20.2 vs 21.9 kg; P < 0.001). In multivariate analyses, diabetes was associated with an increased prevalence of myocardial infarction (odds ratio 1.80, 95% CI 1.25-2.60; P < 0.001) and falls resulting in injury (odds ratio 1.55, 95% CI 1.06-2.26; P = 0.02). Average HbA1c was 49 ± 8 mmol/mol (6.6 ± 0.8%) in men with diabetes, with 90.6% of these men on diet or oral hypoglycaemic therapy. CONCLUSIONS: In older men, diabetes is associated with poorer self-perceived health, reduced healthy lifestyle behaviours and physical function, heart disease and injurious falls. The majority of these men with diabetes had good glycaemic control. Encouraging healthy lifestyle behaviours and improving physical function should be evaluated as interventions to improve quality-of-life and health outcomes.

Vitamin D and cardiovascular disease.

Vitamin D plays a classical hormonal role in skeletal health by regulating calcium and phosphorus metabolism. Vitamin D metabolites also have physiological functions in nonskeletal tissues, where local synthesis influences regulatory pathways via paracrine and autocrine mechanisms. The active metabolite of vitamin D, 1α,25-dihydroxyvitamin D, binds to the vitamin D receptor that regulates numerous genes involved in fundamental processes of potential relevance to cardiovascular disease, including cell proliferation and differentiation, apoptosis, oxidative stress, membrane transport, matrix homeostasis, and cell adhesion. Vitamin D receptors have been found in all the major cardiovascular cell types including cardiomyocytes, arterial wall cells, and immune cells. Experimental studies have established a role for vitamin D metabolites in pathways that are integral to cardiovascular function and disease, including inflammation, thrombosis, and the renin-angiotensin system. Clinical studies have generally demonstrated an independent association between vitamin D deficiency and various manifestations of degenerative cardiovascular disease including vascular calcification. However, the role of vitamin D supplementation in the management of cardiovascular disease remains to be established. This review summarizes the clinical studies showing associations between vitamin D status and cardiovascular disease and the experimental studies that explore the mechanistic basis for these associations.

Plasma Low-density Lipoprotein Receptor-related Protein 1 Concentration is not Associated with Human Abdominal Aortic Aneurysm Presence.

OBJECTIVE/BACKGROUND: Recent genetic data suggest that a polymorphism of LRP1 is an independent risk factor for abdominal aortic aneurysm (AAA). The aims of this study were to assess whether plasma and aortic concentrations of low-density lipoprotein receptor-related protein 1 (LRP1) are associated with AAA, and to investigate the possible relevance of LRP1 to AAA pathophysiology. METHODS: Three analyses were conducted. First, plasma LRP1 concentrations were measured in community-dwelling men with and without AAA (n = 189 and n = 309, respectively) using enzyme-linked immunosorbent assay. Second, Western blotting analyses were employed to compare the expression of LRP1 protein in aortic biopsies collected from patients with AAA and nonaneurysmal postmortem donors (n = 6/group). Finally, the effect of in vitro LRP1 blockade on matrix metalloprotease 9 (MMP9) clearance by vascular smooth muscle cells was assessed by zymography. RESULTS: Plasma LRP1 concentrations did not differ between groups of men with and without AAA (median concentration 4.56 µg/mL [interquartile range {IQR} (3.39-5.96)] and 4.43 µg/mL [IQR 3.44-5.84], respectively; p = .48), and were not associated with AAA after adjusting for other risk factors (odds ratio 1.10 [95% confidence interval: 0.91-1.32]; p = 0.35). In contrast, LRP1 expression was approximately 3.4-fold lower in aortic biopsies recovered from patients with AAA compared with controls (median [IQR] expression 1.72 [0.94-3.14] and 5.91 [4.63-6.94] relative density units, respectively; p < .01). In vitro LRP1 blockade significantly reduced the ability of vascular smooth muscle cells to internalize extracellular MMP9. CONCLUSIONS: These data suggest that aortic but not circulating LRP1 is downregulated in patients with AAA and indicates a possible role for this protein in clearing an aneurysm-relevant ligand.

Peripheral arterial disease increases the risk of subsequent hip fracture in older men: the Health in Men Study.

UNLABELLED: The aim of the present study was to assess whether peripheral arterial disease is associated with an increased risk of hip fracture in a cohort of 12,094 older men. There was no association between claudication and hip fracture, but there was a significant association with an ankle brachial index (ABI) <0.9. INTRODUCTION: It is uncertain whether peripheral arterial disease (PAD) is associated with an increased risk of subsequent hip fracture. The aim of the present study was to assess this in a large cohort of men aged 65 years and over. METHODS: Claudication was assessed by means of the Edinburgh Claudication Questionnaire in 12,094 men, and the ABI was measured in 4,321 of these men. Hospitalisations with hip fracture were identified by record linkage. The association between both claudication and an ABI <0.9 and subsequent hip fractures was assessed using survival curves and Cox regression models. RESULTS: Amongst the 12,094 men, the baseline prevalence of claudication according to the ECQ was 5.3 %. Amongst the 4,321 men with ABI results, the prevalence of an ABI <0.9 was 11.7 %. Of the 506 men with an ABI <0.9, 129 (25.5 %) also had claudication. Over a median (range) follow-up of 10.8 (0.3-12.7) years, 343 (2.8 %) of the 12,094 men were admitted to hospital with a hip fracture. There was no association between claudication and subsequent hip fractures (hazard ratio (HR) = 0.95; 95 % confidence interval (CI), 0.60, 1.52). Over a median (range) follow-up of 11.1 (0.06-12.3) years 135 (3.1 %) of the 4,321 men with ABI data were admitted to hospital with hip fractures. There was a significant association between an ABI <0.9 and subsequent hip fracture (HR = 1.69; 95 % CI, 1.08, 2.63). CONCLUSION: Older men with PAD defined as ABI < 0.9 are at increased risk of hip fracture, whereas the symptom of claudication is not an independent predictor of hip fracture.

Is hypovitaminosis D associated with abdominal aortic aneurysm, and is there a dose-response relationship?

OBJECTIVE: This study aims to investigate the association between plasma 25-hydroxyvitamin D (25(OH)D) concentrations with the presence of abdominal aortic aneurysm (AAA) and aortic diameter. DESIGN: An observational study of 4233 community-dwelling men aged 70-88 years, who participated in a randomised controlled trial of screening for AAA. METHODS: Infrarenal aortic diameter measured by ultrasound and 25(OH)D by immunoassay. RESULTS: A total of 311 men (7.4%) with AAA (defined as aortic diameter ≥ 30 mm) comprised the study. Multivariable models were adjusted for age, smoking, cardiovascular disease, hypertension, diabetes, dyslipidaemia, body mass index and serum creatinine concentration. Amongst men with the lowest 25(OH)D quartile of values compared with the highest quartile, the adjusted odds ratio of having an AAA increased in a graded fashion from 1.23 (95% confidence interval (CI) 0.87-1.73) for AAA ≥ 30 mm to 5.42 (95% CI 1.85-15.88) for AAA ≥ 40 mm. Similarly, there was a dose-response relationship between 25(OH)D concentrations and the size of the AAA: every 10-nmol l(-1) decrease in 25(OH)D levels was associated with 0.49 mm (95% CI 0.11-0.87) increase in mean aortic diameter. CONCLUSIONS: Low vitamin D status is associated with the presence of larger AAA in older men, and there is a graded inverse relationship between 25(OH)D concentrations and AAA diameter. Further research is needed to clarify the mechanisms underlying these associations.

Associations of total osteocalcin with all-cause and cardiovascular mortality in older men. The Health In Men Study.

SUMMARY: In older men, both lower and higher total osteocalcin levels predict increased all-cause mortality, with comparable associations for cardiovascular and non-cardiovascular deaths. Differences in osteocalcin levels might influence glucose metabolism and thereby cardiovascular risk, or reflect changes in bone turnover thus representing a marker for poorer health outcomes. INTRODUCTION: Reduced levels of total osteocalcin (TOC) are associated with adiposity, insulin resistance and type 2 diabetes, implying this bone-derived peptide might modulate cardiovascular risk. However, there are few longitudinal data relating TOC levels to survival. We examined associations of TOC level with all-cause and cardiovascular mortality in older men. METHODS: We conducted a prospective cohort study of community-dwelling men aged 70-89 years. Aliquots of plasma collected at baseline (2001-2004) were assayed for TOC. Incidence and causes of death to 31 December 2008 were ascertained using data linkage. Cox regression analyses were performed with adjustment for conventional cardiovascular risk factors. RESULTS: From 3,542 men followed for median 5.2 years there were 572 deaths (16.1%). Mortality was lowest in men with TOC levels in the second quintile (12.6%). In multivariate analyses, men with TOC in the lowest and highest quintiles of values had increased all-cause mortality (Q1 vs Q2: hazard ratio [HR], 1.36; 95% confidence interval 1.02-1.80 and Q5 vs Q2: HR, 1.53, 95% CI 1.18-1.98). Men with low TOC levels had similar HR for cardiovascular and non-cardiovascular deaths (Q1 vs Q2: HR, 1.35 and 1.30 respectively). Higher TOC levels predicted cardiovascular disease (CVD)-related mortality (Q5 vs Q2, HR, 1.69, 95% CI 1.09-2.64). CONCLUSIONS: TOC predicts all-cause and CVD-related mortality in community-dwelling older men. However, the relationship is U shaped with men at both ends of the distribution at increased risk. Further investigation is required to clarify whether the underlying mechanisms involve altered bone turnover or relate specifically to the biological activity of osteocalcin.

Meta-analysis of postoperative mortality after elective repair of abdominal aortic aneurysms detected by screening.

BACKGROUND: The aim of this study was to compare the mortality rate within 30 days of elective surgery for abdominal aortic aneurysm (AAA) in men randomized to an invitation for ultrasound screening with that of men in the control group, whose aneurysms were detected incidentally. METHODS: Relevant reports from randomized trials of screening were identified through a systematic search of MEDLINE. Four relevant trials were identified, and supplemented with data from the Viborg Vascular screening trial. Data were updated in two studies. Meta-analysis was undertaken with effects calculated as a fixed odds ratio (OR) with 95 per cent confidence interval. Heterogeneity between the studies was assessed by the χ(2) test. RESULTS: There were 25 deaths (2·9 per cent) following elective surgery in 858 men invited for screening compared with 21 (5·5 per cent) of 383 in the control group (OR 0·49, 0·27 to 0·88). There were 18 deaths (2·4 per cent) following elective surgery for 747 screen-detected AAAs compared with 28 (6·1 per cent) following elective repair of 459 incidentally detected aneurysms (OR 0·37, 0·20 to 0·68). CONCLUSION: The offer of screening identifies men whose early survival following elective AAA repair is better than that of men with an AAA detected incidentally.

Possible association between genetic polymorphisms in transforming growth factor beta receptors, serum transforming growth factor beta1 concentration and abdominal aortic aneurysm.

BACKGROUND: Previous studies have suggested a role for transforming growth factor (TGF) beta and its receptor in thoracic aortic aneurysm, but their role in abdominal aortic aneurysm (AAA) is unknown. This study examined the possible association between TGF-beta receptor 1 and 2 (TGFBR-1 and -2) single nucleotide polymorphisms (SNPs) and serum TGF-beta1 with AAA. METHODS: Serum concentrations of TGF-beta1 and 58 SNPs for TGFBR-1 and -2 were examined in 1003 and 1711 men respectively from the Health In Men Study. Validation of SNPs was examined in a second referral cohort of 1043 subjects from New Zealand, of whom 654 had an AAA. RESULTS: Serum TGF-beta1 was not associated with AAA. Only one SNP in TGFBR-2 was weakly associated with AAA; TGFBR2 g.42917C > T, SNP ID rs1078985CC; odds ratio 0.64 (95 per cent confidence interval (c.i.) 0.45 to 0.93); P = 0.020 uncorrected; but this association did not hold after adjusting for multiple testing and was not validated in the New Zealand cohort: odds ratio 0.98 (95 per cent c.i. 0.50 to 1.94); P = 0.960. CONCLUSION: These findings suggest there is no important role of genetic polymorphisms in the main receptors for TGF-beta and circulating TGF-beta1 in AAA in older individuals. (c) 2009 British Journal of Surgery Society Ltd.

Matrix metalloproteinase-2 gene variants and abdominal aortic aneurysm.

OBJECTIVE: To investigate associations between two polymorphisms of the matrix metalloproteinase-2 gene (MMP2) and the incidence and progression of abdominal aortic aneurysm (AAA). METHODS: Cases and controls were recruited from a trial of screening for AAAs. The association between two variants of MMP2 (-1360C>T, and +649C>T) in men with AAA (n=678) and in controls (n=659) was examined using multivariate analyses. The association with AAA expansion (n=638) was also assessed. RESULTS: In multivariate analyses with adjustments for multiple testing, no association between either SNP and AAA presence or expansion was detected. CONCLUSION: MMP2 -1360C>T and +649C>T variants are not risk factors for AAA.

A genetic polymorphism in transforming growth factor beta receptor-2 is associated with serum osteopontin.

Osteopontin (OPN) is a secreted glycoprotein demonstrated to play an important role in inflammation. Transforming growth factor beta and a related signalling pathway have been implicated in control of OPN secretion. We examined the relationship between transforming growth factor beta receptor-1 and -2 (TGFBR1 and 2) single nucleotide polymorphisms (SNP) and serum OPN in 296 men from the Health in Men Study. Serum concentrations of OPN and 58 SNPs for TGFBR1 and 2 were assessed. One SNP in TGFBR2 was associated with serum OPN (TGFBR2 g.20690C>T, SNP ID rs4522809, P = 0.0007) after adjusting for multiple testing. This study suggests that polymorphism in TGFBR2 are associated with altered secretion of OPN, supporting a role for transforming growth factor beta in OPN production.

Polymorphisms of the matrix metalloproteinase 9 gene and abdominal aortic aneurysm.

BACKGROUND: Increased matrix metalloproteinase (MMP) 9 activity has been implicated in the formation of abdominal aortic aneurysm (AAA). The aim was to explore the association between potentially functional variants of the MMP-9 gene and AAA. METHODS: The -1562C > T and -1811A > T variants of the MMP-9 gene were genotyped in 678 men with an AAA (at least 30 mm in diameter) and 659 control subjects (aortic diameter 19-22 mm) recruited from a population-based trial of screening for AAA. Levels of MMP-9 were measured in a random subset of 300 cases and 84 controls. The association between genetic variants (including haplotypes) and AAA was assessed by multivariable logistic regression. RESULTS: There was no association between the MMP-9-1562C > T (odds ratio (OR) 0.70 (95 per cent confidence interval (c.i.) 0.27 to 1.82)) or -1811A > T (OR 0.71 (95 per cent c.i. 0.28 to 1.85)) genotypes, or the most common haplotype (OR 0.81 (95 per cent c.i. 0.62 to 1.05)) and AAA. The serum MMP-9 concentration was higher in cases than controls, and in minor allele carriers in cases and controls, although the differences were not statistically significant. CONCLUSION: In this study, the genetic tendency to higher levels of circulating MMP-9 was not associated with AAA.

Polymorphisms of the interleukin-6 gene promoter and abdominal aortic aneurysm.

BACKGROUND: Elevated levels of circulating interleukin-6 (IL-6) have been reported in patients with abdominal aortic aneurysms (AAAs). Although this implicates inflammation as a cause of AAAs, there is also evidence that the aneurysmal aorta may secrete IL-6 into the circulation as a result of aortic proteolysis. Genetic association studies are one means of trying to clarify the role of specific mediators in the causal pathway. The aim of the present study was to examine the association between variants of the IL-6 gene and AAAs. METHODS: An association study involving 677 men with screen-detected AAAs and 656 age-matched controls was performed. Three variants in the IL-6 promoter region were analysed: IL-6-174G>C (rs1800795), IL-6-572G>C (rs1800796) and IL-6-597G>A (rs1800797). Univariate regression of SNP genotype on AAA as a binary outcome was initially performed under a range of genetic models (additive, dominant and recessive). This was followed by multivariate analyses, testing the same models but including risk factors known to be associated with AAAs. All analyses and haplotype estimation were performed under a generalized linear model framework. RESULTS: IL-6-572G>C polymorphism (frequency 1.5% in cases) was identified as an independent risk factor for AAA with an odds ratio (OR) of 6.00 (95%CI: 1.22, 29.41) when applied to the recessive model. No association was seen in the additive or dominant models. In a multivariate analysis using the most common haplotype (h.111, frequency 48.7%) as a reference, h.211 (frequency 4.4%) was an independent risk factor for AAA (OR 1.56, 95%CI: 1.02, 2.39). CONCLUSION: The IL-6 572G>C polymorphism (and h.211 haplotype) is associated with AAA, however it is too rare to be an important cause of most AAAs. This does not support the concept that the elevated level of IL-6 reported in patients with AAAs is a primary cause of the aneurysmal process.

Ankle brachial index combined with Framingham Risk Score to predict cardiovascular events and mortality: a meta-analysis.

CONTEXT: Prediction models to identify healthy individuals at high risk of cardiovascular disease have limited accuracy. A low ankle brachial index (ABI) is an indicator of atherosclerosis and has the potential to improve prediction. OBJECTIVE: To determine if the ABI provides information on the risk of cardiovascular events and mortality independently of the Framingham risk score (FRS) and can improve risk prediction. DATA SOURCES: Relevant studies were identified. A search of MEDLINE (1950 to February 2008) and EMBASE (1980 to February 2008) was conducted using common text words for the term ankle brachial index combined with text words and Medical Subject Headings to capture prospective cohort designs. Review of reference lists and conference proceedings, and correspondence with experts was conducted to identify additional published and unpublished studies. STUDY SELECTION: Studies were included if participants were derived from a general population, ABI was measured at baseline, and individuals were followed up to detect total and cardiovascular mortality. DATA EXTRACTION: Prespecified data on individuals in each selected study were extracted into a combined data set and an individual participant data meta-analysis was conducted on individuals who had no previous history of coronary heart disease. RESULTS: Sixteen population cohort studies fulfilling the inclusion criteria were included. During 480,325 person-years of follow-up of 24,955 men and 23,339 women, the risk of death by ABI had a reverse J-shaped distribution with a normal (low risk) ABI of 1.11 to 1.40. The 10-year cardiovascular mortality in men with a low ABI (< or = 0.90) was 18.7% (95% confidence interval [CI], 13.3%-24.1%) and with normal ABI (1.11-1.40) was 4.4% (95% CI, 3.2%-5.7%) (hazard ratio [HR], 4.2; 95% CI, 3.3-5.4). Corresponding mortalities in women were 12.6% (95% CI, 6.2%-19.0%) and 4.1% (95% CI, 2.2%-6.1%) (HR, 3.5; 95% CI, 2.4-5.1). The HRs remained elevated after adjusting for FRS (2.9 [95% CI, 2.3-3.7] for men vs 3.0 [95% CI, 2.0-4.4] for women). A low ABI (< or = 0.90) was associated with approximately twice the 10-year total mortality, cardiovascular mortality, and major coronary event rate compared with the overall rate in each FRS category. Inclusion of the ABI in cardiovascular risk stratification using the FRS would result in reclassification of the risk category and modification of treatment recommendations in approximately 19% of men and 36% of women. CONCLUSION: Measurement of the ABI may improve the accuracy of cardiovascular risk prediction beyond the FRS.

Vitamin D, shedding light on the development of disease in peripheral arteries.

Vitamin D is generally associated with calcium metabolism, especially in the context of uptake in the intestine and the formation and maintenance of bone. However, vitamin D influences a wide range of metabolic systems through both genomic and nongenomic pathways that have an impact on the properties of peripheral arteries. The genomic effects have wide importance for angiogenesis, elastogenesis, and immunomodulation; the nongenomic effects have mainly been observed in the presence of hypertension. Although some vitamin D is essential for cardiovascular health, excess may have detrimental effects, particularly on elastogenesis and inflammation of the arterial wall. Vitamin D is likely to have a role in the paradoxical association between arterial calcification and osteoporosis. This review explores the relationship between vitamin D and a range of physiological and pathological processes relevant to peripheral arteries.

Enhanced antiplatelet effect of clopidogrel in patients whose platelets are least inhibited by aspirin: a randomized crossover trial.

OBJECTIVE: We aimed to determine whether adding clopidogrel to aspirin in patients at high risk of future cardiovascular events would suppress laboratory measures of the antiplatelet effects of aspirin; and have greater platelet inhibitory effects in patients with the least inhibition of platelets by aspirin. METHODS: We performed a randomized, double-blind, placebo-controlled, crossover trial, comparing clopidogrel 75 mg day(-1) versus placebo, in 36 aspirin-treated patients with symptomatic objectively confirmed peripheral arterial disease. RESULTS: The addition of clopidogrel to aspirin did not suppress platelet aggregation induced by arachidonic acid, urinary 11 dehydro thromboxane B2 concentrations, or soluble markers of platelet activation markers (P-selectin, CD40-ligand) and inflammation (high sensitivity serum C-reactive protein, interleukin-6). Clopidogrel significantly inhibited platelet aggregation induced by ADP (reduction 26.2%; 95% CI: 21.3-31.1%, P < 0.0001) and collagen (reduction 6.2%; 95% CI: 3.2-9.3%, P = 0.0003). The greatest inhibition of collagen-induced platelet aggregation by clopidogrel was seen in patients with the least inhibition of arachidonic acid induced aggregation by aspirin [lower tertile of arachidonic acid-induced platelet aggregation: 2.8% (95% CI: -0.8 to 6.3%) reduction in mean collagen-induced aggregation by clopidogrel; middle tertile: 4.0% (95% CI: 0.4-7.6%); upper tertile 12.6% (95% CI: 4.5-20.8%); P-value for interaction 0.01]. CONCLUSIONS: The greatest platelet inhibitory effect of clopidogrel occurs in patients with the least inhibition of arachidonic acid-induced platelet aggregation by aspirin. This raises the possibility that the clinical benefits of adding clopidogrel to aspirin may be greatest in patients whose platelets are least inhibited by aspirin. Confirmation in clinical outcome studies may allow these patients to be targeted with antiplatelet drugs that inhibit the ADP receptor, thereby overcoming the problem of laboratory aspirin resistance.

Expression of transforming growth factor-beta1 (TGF-beta1) and urokinase-type plasminogen activator (u-PA) genes during arterial repair in the pig.

OBJECTIVE: The transition from quiescence to proliferation in vitro is accompanied by early expression of proliferation-associated genes encoding products including cytokines and enzymes. We aimed to investigate TGF-beta1, u-PA and PAI-1 gene expressions in relation to proliferation and extracellular matrix (ECM) protein gene expressions in porcine arteries following injury. METHODS: Right iliac arteries of juvenile pigs were de-endothelialised and harvested at fixed times after injury. RNA was then extracted and analysed by Northern blot analysis. RNA transcripts in thickened neointima of arteries were examined by in situ hybridisation using digoxygenin-labelled cDNA probes. RESULTS: TGF-beta1, u-PA and PAI-1 transcripts were rapidly elevated (2-8h) and preceded a peak in histone mRNA at 24h after arterial injury. A second prolonged rise in TGF-beta1 mRNA at 4d coincided with elevated ECM protein gene expression. TGF-beta1 gene expression was detected in neointimal cells lining the arterial lumen at 4wk after injury. CONCLUSIONS: The timings of increases in TGF-beta1, u-PA and PAI-1 mRNAs in injured arteries are consistent with contributions to processes prior to proliferation. The observation of a second protracted elevation in TGF-beta1 expression is supportive of an additional role in stimulation of ECM protein synthesis. Functional specialisation exists within the thickened intima of arteries late in repair.

Reported Amount of Salt Added to Food Is Associated with Increased All-Cause and Cancer-Related Mortality in Older Men in a Prospective Cohort Study.

BACKGROUND: The effect of dietary salt intake on important population outcomes such as mortality is controversial. The aim of this study was to examine the association between the dietary habit of adding salt to food and mortality in older men. Design, participants, setting and measurements: A risk factor questionnaire which contained a question about the dietary habit of adding salt to food was completed by 11742 community recruited older men between 1996 and 1999. The men were followed by means of the Western Australia Data Linkage System until November 30th 2010. Deaths due to cardiovascular diseases and cancers were identified using ICD-10 codes in the ranges I00-I99 and C00-D48, respectively. The association between the frequencies of adding salt to food and mortality was assessed using Kaplan Meier estimates and Cox proportional hazard analysis. RESULTS: Median follow-up for survivors was 12.5 years (inter-quartile range 8.3-13.2 years). A total of 5399 deaths occurred of which the primary cause registered was cancer and cardiovascular disease in 1962 (36.3%) and 1835 (34.0%) men, respectively. The reported frequency of adding salt to food was strongly positively associated with all-cause (p<0.001), cancer-related (p<0.001) but not cardiovascular-related (p=0.649) mortality. Men reporting adding salt to their food always had a 1.12-fold (95% CI 1.05-1.20, p<0.001) and a 1.20-fold (95% CI 1.07-1.34, p=0.001) increased risk of all-cause and cancer-related mortality, respectively, after adjusting for other risk factors. Men reporting adding salt to their food sometimes had a 1.16-fold (95% CI 1.04-1.29, p=0.007) increased risk of cancer-related mortality after adjusting for other risk factors. CONCLUSION: A history of adding salt to food is associated with increased cancer-related mortality in older men.

Does the Mediterranean paradox extend to abdominal aortic aneurysm?

BACKGROUND: We sought to test, in men undergoing ultrasound screening for abdominal aortic aneurysms (AAA) in Western Australia, clinical impressions that the prevalence of AAA is high in Dutch migrants and low in migrants from Mediterranean countries. METHODS: In a population-based trial, men undergoing screening for AAA completed a questionnaire covering their place of birth, smoking habits and consumption of alcohol, meat, fish, salt and milk. We examined the variation by place of birth in the mean, median, 95th and 99th centiles of infrarenal aortic diameter and the prevalences of AAA defined by criteria of 30 mm, 50 mm and by the 95th and 99th centiles, in men born in Australia, of aortic diameter adjusted for height. FINDINGS: Overall, 12,203 (70.5%) of the 19 583 men took up the invitation to undergo ultrasound screening. The prevalence of AAA defined by absolute diameter was higher than average in men born in The Netherlands or Scotland (more of whom had ever smoked or smoked currently) and lower in men of Mediterranean origin (more of whom drank alcohol currently). There were no consistent relationships with simple dietary data. Correction of aortic diameter for height eliminated the significant heterogeneity in prevalence of large AAA, although a threefold variation in prevalence of AAA exceeding the 95th centile of height-adjusted diameter in Australian men persisted. INTERPRETATION: In our cohort of men, which is subject to both 'healthy migrant' and 'survivor' effects, if it exists at all, any 'Mediterranean paradox' for AAA is more modest than that for coronary disease.