Matthew P. Armon

Homocysteine and peripheral arterial disease: systematic review and meta-analysis.

OBJECTIVE To evaluate homocysteine (Hcy) levels in patients with peripheral arterial disease (PAD) as compared to unaffected controls, and to review the clinical effects of therapy aimed at lowering homocysteine in PAD patients. METHODS MEDLINE, EMBASE and Cochrane databases were searched from 1950 to December 2007. We selected observational studies and trials that evaluated Hcy levels in patients with PAD compared to unaffected controls. We also included trials on the effect of Hcy-lowering therapy (folate supplementation) in PAD patients. Continuous outcomes were pooled in a random effects meta-analysis of the weighted mean difference between comparator groups. RESULTS We retrieved 33 potentially suitable articles from our search. Meta-analysis of 14 relevant studies showed that Hcy was significantly elevated (pooled mean difference +4.31micromoll; 95% C.I. 1.71, 6.31, p<0.0001 with significant heterogeneity) in patients with PAD compared to controls. As all 14 studies consistently demonstrated raised plasma Hcy levels in PAD patients, the significant heterogeneity in this meta-analysis probably arises from differences in the degree of Hcy elevation. The effect of folate supplementation on PAD was tested in eight clinical trials but clinically important end points were inconsistently reported. CONCLUSION Patients with PAD have significantly higher Hcy levels than unaffected controls. However, we did not find any robust evidence on clinically beneficial effects of folate supplementation in PAD.

Peripheral arterial disease and methylenetetrahydrofolate reductase (MTHFR) C677T mutations: A case-control study and meta-analysis

OBJECTIVE Hyperhomocysteinaemia is associated with peripheral arterial disease (PAD). There are inter-individual variations in the metabolism of homocysteine because of genetic polymorphisms. This study analyzed the role of one polymorphism that is associated with raised homocysteine, as a risk factor for PAD. METHODS This study considered the association of methylenetetrahydrofolate reductase (MTHFR) C677T polymorphisms with the incidence of PAD by performing a case-control study and a cross sectional study of homocysteine levels. We recruited 133 patients with PAD in Norfolk and compared the MTHFR allele distribution with 457 healthy individuals. We also carried out a meta-analysis to place our data within the context of other published studies. We searched Medline, Embase, and Cochrane databases up to March 2008 for any studies on the association between MTHFR C677T polymorphism and PAD. RESULTS The MTHFR C677T allele frequencies in the cases and controls were 0.37 and 0.33, and the odds ratios for the association of the 677 T allele or TT genotype with PAD were 1.18 (95% Confidence Interval [CI] 0.89, 1.58) and 1.99 (95% CI 1.09, 3.63). Homozygotes for the MTHFR C677T mutation had higher concentrations of plasma total homocysteine, odds ratio 2.82 (95% CI 1.03, 7.77) compared to homozygotes for the MTHFR 677 CC genotype. Twelve of 72 articles retrieved from the database search reported the prevalence of mutations in PAD patients. A meta-analysis of 9 appropriate studies, including our own, showed that being homozygous for the C677T allele was associated with an increased risk of PAD, pooled odds ratio 1.36 (95% CI 1.09, 1.68). CONCLUSION We have found a strong association between raised homocysteine, the TT genotype, and PAD.

Anaesthetic specialisation leads to improved early- and medium-term survival following major vascular surgery.

OBJECTIVE Vascular surgical specialisation is associated with improved outcomes. We aimed to assess the effect of anaesthetic specialisation on outcome following major vascular surgery. DESIGN Retrospective cohort study. METHODS Patients undergoing major vascular surgery (lower limb revascularisation, elective and ruptured abdominal aortic aneurysm repair, endovascular aneurysm repair and carotid endarterectomy) over a five-year period were identified from a prospective database. The primary outcomes were death within 30 days and death within two years of surgery. Potential risk factors for mortality were assessed using multivariate logistic regression modelling. RESULTS The analysis cohort comprised 1155 patients followed up for a median of 583 days. Mortality within two years of surgery was 16%. For the overall cohort, care from vascular anaesthetists was independently associated with reduced 30-day (odds ratio 0.22; 95% CI 0.12-0.62) and medium-term mortality (0.31; 95% CI 0.18-0.55). For elective patients (n=851), vascular anaesthesia reduced two-year mortality (odds ratio 0.29; 95% CI 0.15-0.58; P=0.0004) though not 30-day mortality (odds ratio 0.55; 95% CI 0.15-1.95; P=0.35). For emergency patients, care by a vascular anaesthetist influenced neither 30-day mortality (odds ratio 0.33; 95% CI 0.08-1.41; P=0.13) nor medium-term mortality (odds ratio 0.45; 95% CI 0.17-1.21; P=0.11). CONCLUSIONS Anaesthetic specialisation reduced early- and medium-term mortality rates following major vascular surgery. If replicated by prospective studies, these results suggest that vascular surgery services would benefit from specialised anaesthetic support.

Randomized clinical trial of folate supplementation in patients with peripheral arterial disease.

The aim was to determine whether folate supplementation improved arterial function in patients with peripheral arterial disease (PAD).

The association between ankle brachial pressure index and pulse wave velocity: clinical implication of pulse wave velocity.

Objective: The aim of this study was to assess the relationship between ankle brachial pressure index and pulse wave velocity in patients with peripheral arterial disease. Methods: Brachial-knee and brachial-ankle pulse wave velocity were measured by pneumoplethysmography using cuffs in a standard technique. Correlation between pulse wave velocity and Doppler-ankle brachial pressure index was assessed by Spearman correlation and receiver operating curves. Results: A total of 133 claudicants were assessed. Analysis by developing receiver operating curves for ankle brachial pressure index and pulse wave velocity showed that patients with ankle brachial pressure index over 0.6 were more likely to have a bk-pulse wave velocity over 9.2 m/s and ba-pulse wave velocity over 9.5 m/s. Conclusion: These results show for the first time that nondiabetic vascular patients may have measurable significant arterial stiffness independent of an impaired ankle brachial pressure index. These data suggest that pulse wave velocity may be valuable in screening and evaluating the severity of peripheral arterial disease.

The Effects of Increasing Obesity on Outcomes of Vascular Surgery

The aim of this study was to determine whether vascular patients are becoming progressively more obese and whether morbid obesity affects outcomes from vascular surgery. Data for the index vascular procedures of infrainguinal bypass, carotid endarterectomy, and abdominal aortic aneurysm (AAA) repair were collected in a computer database for 1996-2006. Body mass index (BMI) was stratified into <18.5 kg/m2 as underweight, >35 kg/m2 as morbidly obese, and other as control (18.5 < BMI < 35). The data were analyzed with respect to operation duration, length of stay, complication rates, and mortality rates. Results were adjusted for potential confounding variables, including mode of admission, diabetes, cardiac history, renal function, and smoking. A total of 1,317 patients were reviewed, and 1,105 cases were deemed suitable for analysis. The incidence of morbid obesity increased in a linear manner from 1.3% to 9% over the 10-year period. The operation duration was longer for morbidly obese subjects compared with normals. This was only statistically significant for AAA repair category, with a mean operating time of 158.4 +/- 65.5 min for patients with BMI <35 kg/m2 vs. 189.8 +/- 92.2 min for morbidly obese patients (p < 0.014). Infection rates were consistently higher in the morbidly obese group; however, this reached a statistically significant rate among AAA repair cases (43.5% [n = 16] vs. 34.8% [n = 159], p < 0.004). There were no significant differences in other complications, graft failure, length of stay, or mortality. Vascular patients are becoming progressively more obese. Procedures performed on morbidly obese subjects take longer, and these patients have higher rates of infectious complications. This is mainly attributable to AAA. This did not translate into poorer final outcomes in this study, although significant differences might emerge from a larger sample.

Photoplethysmography, an easy and accurate method for measuring ankle brachial pressure index: Can photoplethysmography replace doppler.

Objective: To assess the accuracy of ankle brachial pressure index (ABPI) assessed by photoplethysmography (PPG) compared with continuous wave Doppler (CW-Doppler). Methods: Ankle brachial pressure index was measured in a standard manner using both PPG and Doppler probes. For PPG-ABPI, a PPG probe was placed on the index finger and great toe, and a microcomputer determined the ABPI. These values were compared with the ABPI measured manually using an 8-MHz Doppler probe. Correlation and agreement between PPG and Doppler ABPI were assessed by Lin’s correlation coefficient and Bland—Altman plots. Results: In all, 133 claudicants were assessed. There was a strong correlation between the 2 ABPI methods (β = .79 and 95% limits of agreement of —0.23 to 0.24). Conclusion: Measuring ABPI automatically using the PPG technique is an effective alternative for Doppler ABPI. PPG-ABPI is completely objective, fast, and accurate.

Do novel risk biomarkers reflect the severity of peripheral arterial disease

The association between novel atherosclerotic risk biomarkers and severity of peripheral arterial disease (PAD) was assessed. Patients (n = 133) with PAD were recruited. Established risk biomarkers including low- and high-density cholesterol, triglycerides, and blood pressure were measured. Novel risk biomarkers including plasma C-reactive protein, von Willebrand factor (vWF), interleukin 6, red cell folate (RCF), vitamin B12, total homocysteine (tHcy), and Hcy genotypes were also determined. The severity of PAD was evaluated, using ankle—brachial pressure index (ABPI), brachial—knee, and brachial—ankle pulse wave velocity (bk- and ba-PWV). Plasma tHcy and systolic blood pressure had a positive independent correlation with bk-PWV (β = +0.56, P = .02 and β = +0.38, P < .001, respectively). Red cell folate had an independent inverse correlation with bk-PWV (β = —0.01, P = .01). Systolic blood pressure showed an independent positive correlation with ba-PWV only after adjustment for other risk biomarkers (β = +0.1, P = .04). Novel markers, plasma tHcy, and RCF levels correlated with the severity of PAD.

Folate supplementation improves arterial function in patients with peripheral arterial disease: a randomised double-blind, placebo-controlled clinical trial

Objective: To determine whether folate supplementation improved arterial function in patients with peripheral arterial disease (PAD) in a randomised, double-blind, placebo-controlled trial. Method: Individuals with PAD were randomly assigned to receive 400 μg folic acid (n = 45), 400 μg methyl-tetrahydrofolate (5-MTHF) (n = 48) or placebo (n = 40) for 4 months. The primary endpoints were change in total plasma homocysteine (tHcy), ankle brachial pressure index (ABPI) and pulse wave velocity (PWV). The secondary outcomes were any change in plasma C-reactive protein (CRP), von Willebrand factor (vWF) or interleukin 6 (IL6) levels. Results: Plasma tHcy was significantly reduced in both the folic acid and 5-MTHF groups compared with controls (median difference: −2·12 μmol/l [95% CI −3·70, −0·75, p = 0·0024] and −2·07 μmol/l [95% CI 3·48, −0·54, p = 0·0072], respectively). ABPI improved significantly in the folic acid and 5-MTHF groups compared with the placebo group (median difference: 0·07 [95% CI 0·04, 0·10, p < 0·0003] and 0·04 [95% CI 0·00, 0·09, p = 0·0279], respectively). Brachial-knee PWV (bk-PWV) reduced significantly in the group receiving 5-MTHF and there was a reducing trend in the group taking 5MTHF compared with the controls (median difference: −1·10m/s [95% CI −2·20, −0·20, p = 0·0105] and −0·90m/s [95% CI −2·10, 0·00, p = 0·05], respectively). Plasma levels of CRP, IL6 and vWF were not affected (p > 0·5). None of the variables changed significantly in the placebo group. Conclusion: Folate administration effectively reduced homocysteine and improved ABPI and bk-PWV. This effect was independent of plasma inflammatory markers.