J. Ian Spark

A systematic review to evaluate the effectiveness of carnitine supplementation in improving walking performance among individuals with intermittent claudication

OBJECTIVE To evaluate the evidence for the use of carnitine supplementation in improving walking performance among individuals with intermittent claudication. DESIGN Systematic review. METHODS An electronic search of the literature was performed using MEDLINE (PubMed), Scopus, Cochrane Central Register of Controlled Trials and The Cochrane Library from inception through to November 2012. Search terms included peripheral arterial disease, intermittent claudication and carnitine. Reference lists of review articles and primary studies were also examined. Full reports of published experimental studies including randomized controlled trials and pre-test/post-test trials were selected for inclusion. A quality assessment was undertaken according to the Jadad scale. RESULTS A total of 40 articles were retrieved, of which 23 did not meet the inclusion criteria. The 17 included articles reported on a total of 18 experimental studies of carnitine supplementation (5 pre-test/post-test; 8 parallel RCT; 5 cross-over RCT) for improving walking performance in adults with intermittent claudication. For pre-test/post-test studies, 300-2000 mg propionyl-L-carnitine (PLC) was administered orally or intravenously for a maximum of 90 days (7-42 participants) with statistically significant improvements of between 74 m and 157 m in pain free walking distance and between 71 m and 135 m in maximal walking distance across 3 out of 5 studies. Similarly, PLC (600 mg-3000 mg) was administered orally in 7 out of 8 parallel RCTs (22-485 participants), the longest duration being 12 months. All but one of the smallest trials demonstrated statistically significant improvements in walking performance between 31 and 54 m greater than placebo for pain free walking distance and between 9 and 86 m greater than placebo for maximal walking distance. A double-blind parallel RCT of cilostazol plus 2000 mg oral L-carnitine or placebo for 180 days (145 participants) did not demonstrate any significant improvement in walking performance. Of 5 cross-over RCTs (8-20 participants), 4 demonstrated significant improvements in walking performance following administration of 300-6000 mg L-carnitine or PLC. Compared to placebo, pain free walking distance and maximal walking distance improved by 23-132 m and 104 m respectively following carnitine intervention. CONCLUSIONS Most trials demonstrated a small or modest improvement in walking performance with administration of PLC or L-carnitine. These findings were largely independent of level or quality of evidence, while there was some evidence that intravenous administration was more effective than oral administration and those with severe claudication may achieve greater benefits than those with moderate claudication. Routine carnitine supplementation in the form of PLC may therefore be a useful adjunct therapy for management of intermittent claudication. Further research is warranted to determine the optimal form, duration, dose and safety of carnitine supplementation across the spectrum of peripheral arterial disease severity and its effect with concurrent supervised exercise programs and best medical therapy. These studies should be supplemented with cost effectiveness studies to ensure that the return on the investment is acceptable.

Neutrophil-lymphocyte ratio as a prognostic marker of outcome in infrapopliteal percutaneous interventions for critical limb ischemia

BACKGROUND Endovascular intervention has become a frequently used treatment of critical limb ischemia (CLI) in recent times. The recent Bypass vs Angioplasty in Severe Ischaemia of the Leg (BASIL) trial consensus recommended endovascular treatment as a first-line treatment in patients who have a life expectancy that was limited to <2 years. Despite these recommendations, there still remains limited data available to clinicians when seeking to risk stratify patients who present with CLI. The neutrophil-lymphocyte ratio (NLR) has been suggested to be a marker for predicting mortality and patency. This study aimed to investigate the use of the NLR as a prognostic marker for primary patency and mortality after an infrapopliteal endovascular intervention in patients with CLI. METHODS All patients who underwent tibial angioplasty for CLI were retrospectively analyzed. Demographics, degrees of stenosis, vessel patency rates, mortality, and comorbidities were recorded. NLRs were calculated from preoperative blood samples. Primary end points were all-cause mortality, primary patency, and amputation-free survival (AFS) within the follow-up period of 12 months. Multivariate Cox proportional hazard models were used to identify independent predictors. Overall survival, AFS, and the probability of a vessel remaining patent were evaluated by standard Kaplan-Meier survival curves and groups compared by the log-rank test. RESULTS Eighty-three patients were monitored for 12 months. Ninety limbs were identified, with 104 procedural events and 127 vessels undergoing successful angioplasty. The technical success rate was 86%, and patency at 1 year was 19%. Survival at 1 year was 76% and AFS was 61%. Patients with a NLR ≥5.25 had an increased risk of death (hazard ratio, 1.97; 95% confidence interval, 1.08-3.62; P = .03) compared with those with a NLR of <5.25. Furthermore, those with lymphocytes counts of <1.5 × 10(9)/L had higher mortality (hazard ratio, 1.88; 95% confidence interval, 1.02-3.70; P = .045) than those with lymphocyte counts >1.5 × 10(9)/L. CONCLUSIONS The NLR and absolute lymphocyte counts are potentially valuable prognostic indicators for risk stratification of patients presenting with CLI undergoing infrapopliteal angioplasty.

A Comparison of Measures of Endothelial Function in Patients with Peripheral Arterial Disease and Age and Gender Matched Controls

This study compared flow-mediated dilatation (FMD), peripheral artery tonometry (PAT), and serum nitric oxide (NO) measures of endothelial function in patients with peripheral artery disease (PAD) against age/gender matched controls. 25 patients (mean age: 72.4 years, M : F 18 : 7) with established PAD and an age/gender matched group of 25 healthy controls (mean age: 72.4 years, M : F 18 : 7) were studied. Endothelial function was measured using the % FMD, reactive hyperemia index (RHI) using PAT and serum NO (μmol). Difference for each method between PAD and control patients and correlation between the methods were investigated. FMD and RHI were lower in patients with PAD (median FMD for PAD = 2.16% versus control = 3.77%, p = 0.034 and median RHI in PAD = 1.64 versus control = 1.92, p = 0.005). NO levels were not significantly different between the groups (PAD median = 7.70 μmol, control median = 13.05 μmol, p = 0.662). These results were obtained in elderly patients and cannot be extrapolated to younger individuals. FMD and PAT both demonstrated a lower hyperaemic response in patients with PAD; however, FMD results in PAD patients were unequivocally reduced whereas half the PAD patients had RHI values above the established threshold for endothelial dysfunction. This suggests that FMD is a more appropriate method for the measurement of NO-mediated endothelial function.

Do Medications Commonly Prescribed to Patients with Peripheral Arterial Disease Have an Effect on Nutritional Status? A Review of the Literature.

BACKGROUND Polypharmacy is common among patients with peripheral arterial disease (PAD) with a combination of medications used for risk-factor modification and medical management of the disease itself. Interaction between commonly prescribed medications and nutritional status has not previously been well described. This review aims to critically appraise evidence exploring associations between medications commonly prescribed to patients with PAD and nutritional status and provide recommendations for practice. METHODS A comprehensive literature search was conducted to locate studies relating to nutrient interactions among lipid-lowering, antihypertensive, antiplatelet, and oral hypoglycemic drug classes. Quality of the evidence was rated on the basis of recommendations by the National Health and Medical Research Council. RESULTS A total of 25 articles were identified as suitable and included in the review. No studies were specific to patients with PAD, and hence findings highlighting risk of ubiquinone (coenzyme Q10 [CoQ10]) depletion with lipid-lowering medications, zinc depletion with antihypertensive medications, and vitamin B12 depletion with oral hypoglycemic medications are extrapolated from heterogeneous groups of patients and healthy adults. The body of evidence ranged in quality from satisfactory to poor. CONCLUSIONS High-quality research is required to confirm the interactions suggested by the included studies in patients with PAD specifically. It is, however, recommended that patients with PAD that are long-term consumers of the selected medications are monitored for CoQ10, zinc, and vitamin B12 to facilitate early identification of deficiencies and initiation of treatment. Treatment may involve dietary intervention and/or supplementation.

The impact of different supervised exercise regimens on endothelial function in patients with intermittent claudication

Background and objectives The impact of supervised exercise training on endothelial function in patients with intermittent claudication is unclear. This study assesses the impact of treadmill-based supervised exercise training alone or in combination with resistance training on pain free walking distance, flow-mediated dilatation, reactive hyperaemia index, nitric oxide and asymmetric dimethylarginine. Methods Thirty-five patients with intermittent claudication were randomised to 12 weeks of treadmill-only supervised exercise training (Group 1) or a combination of treadmill and lower-limb resistance supervised exercise training (Group 2). Pain free walking distance was assessed by six-minute walk test. Endothelial function was assessed by brachial artery flow-mediated dilatation, reactive hyperaemia index and serum analysis of asymmetric dimethylarginine and nitric oxide. Results Pain free walking distance improved within Group 1 (160 m to 204 m, p = 0.03) but not Group 2 (181 m to 188 m, p = 0.82), no between group difference. No significant change in flow-mediated dilatation or reactive hyperaemia index in either group. Nitric oxide decreased in Group 1 (15.0 µmol/L to 8.3 µmol/L, p = 0.003) but not Group 2 (11.2 µmol/L to 9.1 µmol/L, p = 0.14), p = 0.07 between groups. Asymmetric dimethylarginine decreased in Group 2 (0.61 µmol/L to 0.56 µmol/L, p = 0.03) but not Group 1 (0.58 µmol/l to 0.58 µmol/L, p = 0.776), no between group difference. Conclusion Supervised exercise training does not improve endothelial function as measured by flow-mediated dilatation, reactive hyperaemia index and nitric oxide bioavailability.

Can fish oil supplementation improve endothelial function in asymptomatic offspring of patients with peripheral arterial disease

Correspondence: J Ian Spark Department of Vascular Surgery, Flinders Medical Centre, Flinders Drive, Bedford Park, Adelaide, SA 5042, Australia Tel +618 8204 5445 Fax +618 8204 7106 Email ian.spark@health.sa.gov.au Background: Peripheral arterial disease affects 10%–25% of adults aged .55 years, and while a multitude of risk factors exist, one key influence is genetics. Rather than awaiting the onset of debilitating symptoms, interventions that target high-risk individuals and prevent or delay the onset of symptoms would have widespread impact. The aim of this study is to implement a 12-week fish oil intervention (10 mL/day containing approximately 1.5 g of eicosapentaenoic acid and 1 g of docosahexaenoic acid), with the intention of improving endothelial function, inflammation, and lipid status in a high-risk population, ie, those with impaired endothelial function and a parent with symptomatic peripheral arterial disease. Methods: This is a parallel-group, double-blind, randomized controlled trial involving administration of fish oil containing either about 1.5 g of docosahexaenoic acid and 1 g of docosahexaenoic acid (intervention) or about 0.15 g of eicosapentaenoic acid and about 0.1 g of docosahexaenoic acid for 12 consecutive weeks (control). The participants are 100 offspring of adults with diagnosed peripheral arterial disease who themselves have an ankle-brachial pressure index

Pathophysiology of Abdominal Aortic Aneurysm – Genetic Factors and Homocysteine Metabolism

0.9 but impaired endothelial function according to peripheral arterial tonometry. Measures performed at baseline and at 6 and 12 weeks include flow-mediated dilatation, Creactive protein, absolute neutrophil and lymphocyte counts, tumor necrosis factor-α, interleukin-1β, and interleukin-6 levels, thromboxane and prostacyclin, lipid status, and homocysteine, nitrite, and nitrate levels. Participants will be phoned fortnightly to monitor adherence and side effects, while participants will maintain a diary of fish oil consumption on a daily basis, and fish oil returned will be measured to confirm adherence. Participants will complete validated surveys to determine background diet and physical activity levels. Discussion: This study will examine the effectiveness of a moderate-dose fish oil intervention in reversing endothelial dysfunction in asymptomatic offspring of patients with peripheral arterial disease. It provides the opportunity to delay the progression of peripheral arterial disease using a cheap and readily available dietary supplement that has minimal side effects compared with synthetic vasoactive pharmacological medications.

Does Angioplasty Improve the Quality of Life for Claudicants?: A Prospective Study

Homocysteine (Hcy) is a non-protein amino acid resulting from the demethylation of the essential amino acid methionine. This is an important step in the metabolism of nucleic acids, fats and high-energy bonds and for this reason, the transmethylation reaction of Hcy back to methionine requiring Vitamin B12 and folic acid, is equally important. This pathway is dependent on a form of folate produced by methylenetetrahydrofolate reductase (MTHFR). Hcy can also be metabolised to cystathionine, an intermediate of the non-essential amino acid cysteine. Vitamin B6 is necessary for this transulphuration reaction to occur (Figure 1) (Warsi et al, 2004; Guilliams, 2004; Moroz et al, 2007; Castro et al, 2006) Excess levels of Hcy are excreted to the plasma where the liver and kidney are the organs achieving catabolism and excretion of Hcy. Despite this, mild hyperHcy is present in 5-7% of the general population, due to either inherited or acquired dietary deficiencies of vitamin B6, B12 and folic acid. Other causes include renal failure, malignancy, hypothyroidism and use of folate and vitamin B6 antagonists (Halazun et al, 2007).