Body mass-normalized moderate dose of dietary nitrate intake improves endothelial function and walking capacity in patients with peripheral artery disease.

Peripheral artery disease (PAD) is characterized by the accumulation of atherosclerotic plaques in the lower extremity conduit arteries, which impairs blood flow and walking capacity. Dietary nitrate has been used to reduce blood pressure (BP) and improve walking capacity in PAD. However, a standardized dose for PAD has not been determined. Therefore, we sought to determine the effects of a body mass-normalized moderate dose of nitrate (0.11 mmol nitrate/kg) as beetroot juice on serum nitrate/nitrite, vascular function, walking capacity, and tissue oxygen utilization capacity in patients with PAD. A total of 11 patients with PAD received either nitrate supplement or placebo in a randomized crossover design. Total serum nitrate/nitrite, resting BP, brachial and popliteal artery endothelial function (flow-mediated dilation, FMD), arterial stiffness (pulse-wave velocity, PWV), augmentation index (AIx), maximal walking distance and time, claudication onset time, and skeletal muscle oxygen utilization were measured pre- and postnitrate and placebo intake. There were significant group × time interactions (P < 0.05) for serum nitrate/nitrite, FMD, BP, walking distance and time, and skeletal muscle oxygen utilization. The nitrate group showed significantly increased serum nitrate/nitrite (Δ1.32 µM), increased brachial and popliteal FMD (Δ1.3% and Δ1.7%, respectively), reduced peripheral and central systolic BP (Δ-4.7 mmHg and Δ-8.2 mmHg, respectively), increased maximal walking distance (Δ92.7 m) and time (Δ56.3 s), and reduced deoxygenated hemoglobin during walking. There were no changes in PWV, AIx, or claudication (P > 0.05). These results indicate that a body-mass normalized moderate dose of nitrate may be effective and safe for reducing BP, improving endothelial function, and improving walking capacity in patients with PAD.

Omega-3 fatty acids for intermittent claudication.

BACKGROUND: Omega-3 fatty acids have been used in the treatment and prevention of coronary artery disease although current evidence suggests they may be of limited benefit. Peripheral arterial disease and coronary artery disease share a similar pathogenesis so omega-3 fatty acids may have a similar effect on both conditions. This is an update of a review first published in 2004 and updated in 2007. OBJECTIVES: To determine the clinical and haematological effects of omega-3 supplementation in people with intermittent claudication. SEARCH METHODS: For this update the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched September 2012) and the Cochrane Central Register of Controlled Trials (CENTRAL) (2012, Issue 9). SELECTION CRITERIA: Randomised controlled trials of omega-3 fatty acids versus placebo or non-omega-3 fatty acids in people with intermittent claudication. DATA COLLECTION AND ANALYSIS: One review author identified potential trials. Two review authors independently assessed trial quality and extracted data. We contacted study authors for additional information if necessary. MAIN RESULTS: Nine studies were included representing 425 participants. All studies compared omega-3 fatty acid supplementation with placebo lasting from four weeks to two years. Three studies with long treatment periods administered additional substances, making any observed effects impossible to attribute to omega-3 fatty acids and were excluded from the statistical analyses. One study did not express any mean values and, therefore, could not be included in statistical analyses.No significant differences between intervention and control groups were observed in pain-free walking distance (mean difference (MD) 11.62 m, 95% confidence interval (CI) -67.74 to 90.98), maximal walking distance (MD 16.99 m, 95% CI -72.14 to 106.11), ankle brachial pressure index (MD -0.02, 95% CI -0.09 to 0.05), total cholesterol levels (MD 0.27 mmol/L, 95% CI -0.48 to 1.01), high-density lipoprotein cholesterol levels (MD 0.00 mmol/L, 95% CI -0.16 to 0.15), low-density lipoprotein cholesterol levels (MD 0.44 mmol/L, 95% CI -0.31 to 1.19), triglyceride levels (MD -0.39 mmol/L, 95% CI -1.10 to 0.33), systolic blood pressure (MD 5.00 mmHg, 95% CI -11.59 to 21.59) or plasma viscosity (MD 0.03 mPa/s, 95% CI -0.02 to 0.08).There was some limited evidence that blood but not plasma viscosity levels decreased with treatment and gastrointestinal side effects such as nausea, diarrhoea and flatulence were observed in two studies. AUTHORS' CONCLUSIONS: Omega-3 fatty acids appear to have little haematological benefit in people with intermittent claudication and there is no evidence of consistently improved clinical outcomes (quality of life, walking distance, ankle brachial pressure index or angiographic findings). Supplementation may also cause adverse effects such as nausea, diarrhoea and flatulence. Further research is needed to evaluate fully short- and long-term effects of omega-3 fatty acids on the most clinically relevant outcomes in people with intermittent claudication before they can be recommended for routine use.

Effect of niacin ER/lovastatin on claudication symptoms in patients with peripheral artery disease.

In patients with peripheral artery disease (PAD), statins may improve the symptoms of claudication. The Intermittent Claudication Proof of Principle (ICPOP) study tested the hypothesis that the combination of extended release niacin plus lovastatin would improve exercise performance in patients with PAD and claudication compared with a diet intervention. A phase 3 double-blind, parallel-group, multi-center, 28-week multi-national study evaluated subjects with a history of claudication who had an ankle-brachial index (ABI) < or = 0.90, a reproducible peak treadmill walking time (PWT) of 1-20 minutes, and a low-density lipoprotein (LDL)-cholesterol level < 160 mg/dl (< 4.1 mmol/l). Subjects were randomly assigned to low-dose niacin 1000 mg plus lovastatin 40 mg (low niacin-statin), high-dose niacin 2000 mg plus lovastatin 40 mg (high niacin-statin), or diet intervention (diet). The co-primary efficacy endpoint of percent change in PWT and claudication onset time (COT) at 28 weeks was assessed using a graded treadmill protocol. At completion, 385 subjects were analyzed for safety and 370 subjects were analyzed for efficacy. The primary efficacy analysis showed no statistical significance for overall treatment effect at week 28 for the co-primary endpoint of PWT and COT. The PWT component of the primary endpoint increased 26.5% on diet, 37.8% on high niacin-statin (p = 0.137) and 38.6% on low niacin-statin (p = 0.096). Flushing as the most common event leading to discontinuation and treatment was associated with increases in liver enzymes, fasting blood glucose concentration and a decrease in platelet count.

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

BACKGROUND: The aim was to determine whether folate supplementation improved arterial function in patients with peripheral arterial disease (PAD). METHODS: Individuals with PAD were randomly assigned to receive 400 microg folic acid (45 patients) or 5-methyltetrahydrofolate (5-MTHF) (48) daily, or placebo (40) for 16 weeks. Primary endpoints were changes in plasma total homocysteine (tHcy), ankle : brachial pressure index (ABPI) and pulse wave velocity (PWV). Secondary outcomes were changes in plasma inflammatory markers. RESULTS: Plasma tHcy was significantly reduced in folic acid and 5-MTHF groups compared with controls: median difference: - 2.12 (95 per cent confidence interval - 3.70 to - 0.75) micromol/l (P = 0.002) and - 2.07 (-3.48 to - 0.54) micromol/l (P = 0.007) respectively. ABPI improved significantly: median difference 0.07 (0.04 to 0.11) (P < 0.001) and 0.05 (0.01 to 0.10) (P = 0.009) respectively. Brachial-knee PWV (bk-PWV) decreased significantly in individuals receiving 5-MTHF and tended to be reduced in those taking folic acid compared with controls: median difference: - 1.10 (-2.20 to - 0.20) m/s (P = 0.011) and - 0.90 (-2.10 to 0.00) m/s (P = 0.051) respectively. Plasma levels of inflammatory markers were not affected. CONCLUSION: Folate administration reduced plasma homocysteine, and slightly improved ABPI and bk-PWV.

Omega-3 fatty acids for intermittent claudication.

BACKGROUND: Omega-3 fatty acids are established as being effective in the treatment and prevention of coronary artery disease. It is possible that they may also benefit people with peripheral arterial disease, since the pathogenesis of the two conditions is similar. OBJECTIVES: To determine the clinical and haematological effects of omega-3 supplementation in people with intermittent claudication. SEARCH STRATEGY: Trials were identified from the Cochrane Peripheral Vascular Diseases Group trials register (last searched August 2007), and the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (last searched Issue 3, 2007). In addition, we searched literature from pharmaceutical companies, manufacturers of omega-3 rich foods and web sites of nutritional organisations dedicated to omega-3 fatty acids. SELECTION CRITERIA: Randomised controlled trials of omega-3 fatty acids versus placebo or non-omega-3 fatty acids in people with intermittent claudication. DATA COLLECTION AND ANALYSIS: One author identified potential trials. Two authors independently assessed trial quality and extracted data. We contacted study authors for additional information if necessary. MAIN RESULTS: Six studies were included representing 313 participants. All studies compared omega-3 fatty acid supplementation with placebo lasting from 4 weeks to 2 years. Two studies with long treatment periods administered additional substances, making any observed effects impossible to attribute to omega-3 fatty acids and were therefore excluded from the statistical analyses. No significant differences between intervention and control groups were observed in ankle brachial pressure index (ABPI) (weighted mean difference (WMD) -0.02; 95% CI -0.09 to 0.05), systolic blood pressure (WMD 5.00 mmHg; 95% CI -11.59 to 21.59), plasma viscosity (WMD 0.03 mPa/s; 95% CI -0.02 to 0.08), pain-free walking distance (PFWD) (WMD 7.46 m; 95% CI -25.47 to 40.39), or maximal walking distance (MWD) (WMD 0.27 m; 95% CI -39.59 to 40.13). Blood viscosity levels decreased. Gastrointestinal side effects were observed in two studies. Omega-3 fatty acid supplementation increased (low-density lipoprotein) LDL cholesterol levels (WMD 0.80 mmol/litre; 95% CI 0.34 to 1.26) and total cholesterol levels (WMD 0.64 mmol/litre; 95% CI 0.08 to 1.20). AUTHORS' CONCLUSIONS: Omega-3 fatty acids appear to have limited haematological benefits in people with intermittent claudication but there is no evidence of consistent improved clinical outcomes which are the primary outcomes of this review (quality of life, PFWD, MWD, ABPI, angiographic findings). Supplementation may also cause adverse effects such as increased total and LDL cholesterol levels. Further research is needed in this area, to evaluate short- and long-term effects on more clinically relevant outcomes.

Estudio de las repercusiones clínicas y analíticas de una intervención nutricional en pacientes no hospitalizados con claudicación intermitente. Estudio aleatorio controlado / A study of the clinical and analytical repercussions of a nutritional intervention in non-hospitalised patients with intermittent claudication. A controlled randomised study

Introducción. La dieta es un pilar fundamental, a veces olvidado, en el control y tratamiento de la enfermedad vascular periférica (EVP). Objetivo. Estudiar los efectos de la ingesta de ciertos nutrientes con probado efecto beneficioso en la prevención de la enfermedad coronaria en la clínica y el perfil bioquímico de enfermos claudicantes. Pacientes y métodos. Estudio longitudinal, descriptivo, aleatorio y doble ciego, con 60 varones claudicantes (grado IIB de Fontaine), distribuidos en dos grupos. Grupo I (n = 30): además de su dieta habitual consumieron 500 mL/día de leche semidesnatada adicionada de ácidos eicosapentanoico, docoxahexanoico, oleico y fólico y vitaminas A, D, E y B6. Grupo C (n = 26): además de su dieta habitual consumieron 500 mL/día de leche semidesnatada. Ambos grupos obtuvieron los mismos consejos higienicodietéticos, un antiagregante plaquetario (triflusal) y un hemorreológico (pentoxifilina). Con control trimestral, la intervención duró 12 meses. En cada control se realizó una exploración clínica vascular, claudicometría, índice de Yao, placetismografía y analítica. Resultados. La concentración plasmática de los nutrientes suministrados aumentó en el grupo I (p < 0,05), seguido de un descenso en colesterol total y la concentración de apolipoproteína B. La homocisteína total disminuyó en aquellos pacientes con hiperhomocisteinemia (p < 0,01). Paralelamente, la distancia de claudicación triplicó su valor (p < 0,001) y el índice de Yao aumentó de manera gradual (p < 0,05). Conclusiones. La inclusión diaria en la dieta de ciertos nutrientes cardiosaludables produjo, junto con otras recomendaciones dietéticas y hábitos de vida, una mejora significativa en los parámetros clínicos y analíticos de este grupo de claudicantes. La nutrición puede desempeñar un papel importante en el tratamiento y control de la EVP

INTRODUCTION. Diet is a sometimes neglected cornerstone in the control and treatment of peripheral vascular disease (PVD). AIMS. To study how the intake of certain nutrients with a proven beneficial effect in the prevention of heart disease affects the clinical symptoms and biochemical profile of patients with claudication. PATIENTS AND METHODS. A longitudinal, descriptive, randomised, double-blind study was conducted with 60 males with claudication (Fontaine grade IIB), distributed in two groups. Group I (n = 30): in addition to their usual diet, subjects consumed 500 ml/day of semi-skimmed milk with added eicosapentaenoic, docosahexaenoic, oleic and folic acids, as well as vitamins A, D, E and B6. Group C (n = 26): in addition to their usual diet, subjects consumed 500 mL/day of semi-skimmed milk. Both groups received the same hygienic-dietary guidelines, an antiplatelet drug (triflusal) and a haemorrheologic agent (pentoxifylline). Including a three-monthly control, the intervention lasted 12 months. At each control the following tests were carried out: vascular clinical examination, treadmill exercise testing, Yao index, plethysmography and analyses. RESULTS. The plasma concentration of the nutrients given to patients increased in group I (p < 0.05), followed by a decrease in total cholesterol and apolipoprotein B concentration. The total homocysteine level dropped in patients with hyperhomocysteinemia (p < 0.01). In a parallel fashion, the claudication distance become three times longer (p < 0.001) and the Yao index gradually increased (p < 0.05). CONCLUSIONS. Including certain nutrients that are good for the heart in the daily diet, along with other guidelines concerning nutrition and lifestyle, led to a significant improvement in the clinical and analytical parameters of this group of patients with claudication. Nutrition can play an important role in the treatment and control of PVD

Effect of carbohydrate supplementation on walking performance in peripheral arterial disease: a preliminary physiologic study.

OBJECTIVE: In this preliminary study we tested the effect of short-term carbohydrate supplementation on carbohydrate oxidation and walking performance in peripheral arterial disease. METHODS: Eleven patients with peripheral arterial disease and intermittent claudication and 8 healthy control subjects completed several weeks of baseline exercise testing, then were given supplementation for 3 days with a carbohydrate solution and placebo. Maximal walking time was assessed with a graded treadmill test. Carbohydrate oxidation during a submaximal phase of this test was measured with indirect calorimetry. At the end of baseline testing a biopsy specimen was taken from the gastrocnemius muscle, and the active fraction of pyruvate dehydrogenase complex activity was determined. RESULTS: Carbohydrate supplementation resulted in a significant increase in body weight and carbohydrate oxidation during exercise in patients with intermittent claudication and control subjects. Maximal walking time decreased by 3% in control subjects, whereas it increased by 6% in patients with intermittent claudication (group x treatment interaction, P < .05). There was a wide range of performance responses to carbohydrate supplementation among patients with claudication (-3%-37%). This effect was greater in poorer performers, and was negatively correlated (P < .05) with muscle pyruvate dehydrogenase complex activity. CONCLUSION: Preliminary data suggest that carbohydrate oxidation during exercise might contribute to exercise intolerance in more dysfunctional patients with intermittent claudication and that carbohydrate supplementation might be an effective therapeutic intervention in these patients.

Omega-3 fatty acids for intermittent claudication.

BACKGROUND: Omega-3 fatty acids are established as being effective in the treatment and prevention of coronary artery disease. It is possible that they may also benefit people with peripheral arterial disease, since the pathogenesis of the two conditions is similar. OBJECTIVES: To determine the effects of omega-3 supplementation in people with intermittent claudication. SEARCH STRATEGY: Trials were identified from the Cochrane Peripheral Vascular Diseases Group trials register (last searched April 2004), and the Cochrane Central Register of Controlled Trials (CENTRAL) (last searched Issue 1, 2004). In addition, literature from pharmaceutical companies (Roche Pharmaceuticals and Seven Seas), manufacturers of omega-3 rich foods (Columbus Eggs) and web sites of nutritional organisations dedicated to omega-3 fatty acids (Omega-3 information and the Fish Foundation) were searched. SELECTION CRITERIA: Randomised controlled trials of omega-3 fatty acids versus placebo or non-omega-3 fatty acids in people with intermittent claudication. DATA COLLECTION AND ANALYSIS: One reviewer (TS) identified potential trials, assessed study quality and extracted data. The other reviewer (WH) assessed study quality and checked data extraction. MAIN RESULTS: Four studies were included involving a total of 203 participants. The overall methodological quality of studies was good. All studies compared omega-3 fatty acid supplementation with placebo. Two studies used an omega-6 fatty acid as the placebo preparation, one used a monounsaturated fatty acid and one used a combination of omega-6 and monounsaturated fatty acids.Omega-3 fatty acid supplementation reduced triglyceride levels (weighted mean difference (WMD) -0.66 mmol/litre; 95% confidence interval (CI) -1.24 to -0.09) and diastolic blood pressure (WMD -1.94 mmHg; 95% CI -3.58 to -0.29) in the treatment group, but increased total cholesterol levels (WMD 0.41 mmol/litre; 95% CI 0.03 to 0.80) and LDL cholesterol levels (WMD 0.43 mmol/litre; 95% CI 0.12 to 0.74). Gastrointestinal side-effects were observed in one study. No significant changes were observed in pain-free walking distance (WMD -17 m; 95% CI -51 to 17 m), maximal walking distance (WMD -21 m; 95% CI -59 to 17 m) or ankle brachial pressure index (WMD -0.03; 95% CI -0.1 to 0.04). REVIEWERS' CONCLUSIONS: Omega-3 fatty acids appear to have some beneficial biochemical and haemodynamic effects in people with intermittent claudication but there is no evidence of improved clinical outcomes. It should be noted that no consistent effect on primary outcome measures was detected. Further research is needed in this area, to evaluate short- and long-term effects on more clinically relevant outcomes.

Nutritional therapy for peripheral arterial disease: a double-blind, placebo-controlled, randomized trial of HeartBar.

We investigated the clinical effects of a food bar enriched with L-arginine and a combination of other nutrients known to enhance the activity of endothelium-derived nitric oxide (EDNO) in individuals with claudication from atherosclerotic peripheral arterial disease. The study was a 2-week, double-blind, placebo-controlled trial of subjects randomized to three groups (two active bars, one active and one placebo bar, and two placebo bars per day) followed by an 8-week open-label period. Subjects (n=41) were outpatient volunteers with intermittent claudication. Pain-free and total walking distances were measured by variable-grade, treadmill exercise testing. Quality of life was assessed using the Medical Outcome Survey (SF-36). After 2 weeks of treatment, the pain-free walking distance increased 66% while the total walking distance increased 23% in the group taking two active bars/day. The general and emotional/social functioning components of the SF-36 also improved. These effects were not observed in the one active bar/day and placebo groups. The effects were maintained after 10 weeks and, in addition, an improvement in walking distance was observed in the group taking one active bar. These findings reveal that use of a nutrient bar designed to enhance EDNO activity improves pain-free and total walking distance as well as quality of life in individuals with intermittent claudication.

Olive oil- and fish oil-enriched diets modify plasma lipids and susceptibility of LDL to oxidative modification in free-living male patients with peripheral vascular disease: the Spanish Nutrition Study.

The present study describes a clinical trial in which Spanish patients suffering from peripheral vascular disease (Fontaine stage II) were given specific lipid supplements. Designed as a longitudinal intervention study, patients were provided with olive oil for 3 months, followed by a 3 month wash-out period, then supplemented with a combination of fish oil and olive oil for the final 3 months. Changes in plasma and lipoprotein fatty acid composition and susceptibility of LDL to in vitro oxidation were examined. Furthermore, lipid-supplement-induced changes in LDL properties were measured as relative electrophoretic mobility and macrophage uptake. In addition, thirteen patients not provided with olive oil and fish oil were included as a control group and twenty healthy age-matched individuals were used as a reference group. A complete clinical study and a nutritional survey concerning food habits and lifestyle were performed every 3 months. Yao indices and claudicometry did not change significantly with dietary intervention although changes in plasma lipid composition suggested an improvement in the condition of the patients. The intake of the fish-oil supplement resulted in significantly increased plasma levels of eicosapentaenoic acid (20:5n-3) and docosahexaenoic acid (22:6n-3) in comparison with baseline concentrations, olive-oil and control groups. Fish-oil consumption significantly decreased plasma triacylglycerol levels compared with the olive-oil period, control and reference groups. The susceptibility of LDL to Cu-mediated oxidation was lower in the patients consuming olive oil and the fish-oil supplement than in the control group, and the uptake of LDL by macrophages was significantly lower in the group supplemented with fish oil. In conclusion, consumption of olive oil together with a dietary supplement of fish oil may be useful in the nutritional management of patients suffering from peripheral vascular disease in terms of increasing plasma n-3 long-chain polyunsaturated fatty acids and decreasing susceptibility of LDL to oxidation.

Randomized controlled trial of gamma-linolenic acid and eicosapentaenoic acid in peripheral arterial disease.

BACKGROUND AND AIMS: epidemiological studies suggest polyunsaturated fatty acids protect against the development of atherosclerosis. The aim of this study was to perform a randomized controlled trial of gamma-linolenic and eicosapentaenoic acids in patients with lower limb atherosclerosis. Main outcome measures were: cholesterol and lipoprotein concentrations; haemostatic and rheological variables; the ankle brachial pressure index; walking distance; and cardiovascular events and death. METHODS: 120 men and women with stable intermittent claudication were randomized to 2 years treatment with either a combination of gamma-linolenic and eicosapentaenoic acids, or placebo. RESULTS: 39 (65.0 cent) of those taking fatty acids and 36 (60.0 cent) of those taking placebo completed the trial. Lipid concentrations did not differ significantly during the trial. In those taking fatty acids, haematocrit was significantly higher than in the placebo group after 6 months (46.1 cent compared with 44.6 cent, P 0.05). CONCLUSIONS: a combination of polyunsaturated fatty acids produced a statistically significant reduction in systolic blood pressure, but no other significant benefits on risk factors. The trend towards fewer coronary events in those taking fatty acids warrants further investigation.

Fish oil supplementation in patients with stable claudication.

Increased blood viscosity occurs in patients with claudication. This increase in viscosity, which is mainly due to elevated fibrinogen levels and a decreased red cell deformability, adversely influences blood flow. In addition to a positive effect on blood pressure, blood lipids, and platelet responsiveness, fish oil may improve blood flow due to a favorable influence on hemorrheology. In a prospective, randomized, double-blind study, we evaluated the effect of six capsules of fish oil (1.8 g eicosapentaenoic acid and 1.2 g docosahexaenoic acid) versus six capsules of corn oil (3 g linoleic acid), administered for 4 months, on walking distances, pressure indices during rest and after exercise, blood pressure, red cell deformability, fibrinogen, and lipid levels in 32 patients with stable claudication. No significant changes in walking distances and pressure indices during rest and after exercise occurred, despite a significant increase in red cell deformability in the fish oil group. Fibrinogen levels did not change in either group. In the fish oil group, a favorable change in blood lipids was noted; high-density cholesterol increased and triglycerides decreased. Mean arterial blood pressure declined to a similar extent in both groups. Thus, short-term supplementation with fish oil does not lead to clinically significant improvement of symptoms in patients with stable claudication. This suggests that red cell deformability is of minor importance in the arterial blood flow in the legs of these patients.