Functional foods and nutraceuticals in the treatment of hypercholesterolemia: Statement of the Spanish Society of Arteriosclerosis 2023. / Alimentos funcionales y nutracéuticos en el tratamiento de la hipercolesterolemia: posicionamiento de la Sociedad Española de Arteriosclerosis 2023.

In the management of hypercholesterolemia, besides advising a healthy, plant-based diet, it may be useful to recommend functional foods or nutraceutical with cholesterol-lowering properties. Given the progressive increase in the number of these products and their rising use by the population, the Spanish Society of Arteriosclerosis (SEA) has considered it appropriate to review the available information, select the results of the scientifically more robust studies and take a position on their usefulness, to recommend to health professionals and the general population their potential utility in terms of efficacy and their possible benefits and limitations. The following clinical scenarios have been identified in which these products could be used and will be analyzed in more detail in this document: (1) Hypolipidemic treatment in subjects with statin intolerance. (2) Hypolipidemic treatment «a la carte¼ in individuals in primary prevention. (3) Long-term cardiovascular prevention in individuals with no indication for lipid-lowering therapy. (4) Patients with optimized lipid-lowering treatment who do not achieve therapeutic objectives.

Matcha Green Tea Powder does not Prevent Diet-Induced Arteriosclerosis in New Zealand White Rabbits Due to Impaired Reverse Cholesterol Transport.

INTRODUCTION: Green tea is associated with decreased risk for cardiovascular disease and stroke. Matcha is a special kind of powdered green tea known for its use in the Japanese tea ceremony. Due to its influence on lipoprotein parameters, it has been postulated to exert antiatherogenic effects. This study investigates whether it modulates the high-density lipoprotein (HDL) function and thereby influences the atherogenic process in an animal model with a strong influence on humans' situation. METHODS AND RESULTS: After a pretreatment phase based on a standard diet, 10 female New Zealand White (NZW) rabbits are fed a high-fat diet for 20 weeks. The treatment group is additionally administered 1% matcha during the whole experiment. Long-term matcha treatment leads to lowered HDL cholesterol, impaired cholesterol transport manifested by reduced in vitro cholesterol efflux capacity, reduced cholesteryl ester transfer protein (CETP)-mediated cholesterol ester (CE) transfer between HDL and triglyceride-rich particles, and reduced macrophage-specific in vivo transfer, where ian increased absorption of cholesterol in the liver but a decreased secretion into bile is observed. Pulse wave velocity, assessed by nuclear magnetic resonance, is increased in matcha-treated animals, and a similar trend is observed for atherosclerotic lesion formation. CONCLUSION: Long-term matcha green tea treatment of hypercholesterolemic rabbits cause impaired reverse cholesterol transport and increased vascular stiffness, and susceptibility for atherosclerotic lesion development.

Circulating odd-chain saturated fatty acids were associated with arteriosclerosis among patients with diabetes, dyslipidemia, or hypertension in Sri Lanka but not Japan.

The differences in the morbidity and mortality of cardiovascular diseases between Sri Lankan and Japanese populations might be explained by the differences in their diet, especially fat. To test the hypothesis that the fatty acid (FA) compositions differ between Sri Lankan and Japanese populations and that high concentrations of n-3 polyunsaturated FAs and linoleic acid are associated with a low level of arteriosclerosis, the authors compared the circulating FA compositions between Sri Lankan and Japanese populations and examined the association of the circulating FA composition with arterial stiffness in each population. The study participants were patients with diabetes, dyslipidemia, or hypertension in Sri Lanka (n = 100) or Japan (n = 236). Serum FA compositions were measured by gas chromatography. Arterial stiffness was measured using the cardio-ankle vascular index (CAVI). Analysis of covariance was used to compare the FA compositions between the populations. Multiple regression was used to assess the association between each FA and CAVI levels. The concentrations of myristic, γ-linolenic, dihomo-γ-linolenic, and arachidonic acids were higher in the Sri Lankan patients than in the Japanese patients. In contrast, the concentrations of linoleic, α-linolenic, and eicosapentaenoic acids were higher in the Japanese patients than in the Sri Lankan patients. Although no associations of n-3 polyunsaturated FAs and linoleic acid with CAVI were observed in both patient populations, odd-chain saturated FAs (pentadecanoic and heptadecanoic acids) were significantly inversely associated with CAVI levels in the Sri Lankan (P for trend = .03) but not the Japanese patients. The odd-chain saturated FAs might be inversely associated with atherosclerosis in this Sri Lankan population.

Effect of Monthly High-Dose Vitamin D Supplementation on Cardiovascular Disease in the Vitamin D Assessment Study : A Randomized Clinical Trial.

Importance: Cohort studies have reported increased incidence of cardiovascular disease (CVD) among individuals with low vitamin D status. To date, randomized clinical trials of vitamin D supplementation have not found an effect, possibly because of using too low a dose of vitamin D. Objective: To examine whether monthly high-dose vitamin D supplementation prevents CVD in the general population. Design, Setting, and Participants: The Vitamin D Assessment Study is a randomized, double-blind, placebo-controlled trial that recruited participants mostly from family practices in Auckland, New Zealand, from April 5, 2011, through November 6, 2012, with follow-up until July 2015. Participants were community-resident adults aged 50 to 84 years. Of 47 905 adults invited from family practices and 163 from community groups, 5110 participants were randomized to receive vitamin D3 (n = 2558) or placebo (n = 2552). Two participants retracted consent, and all others (n = 5108) were included in the primary analysis. Interventions: Oral vitamin D3 in an initial dose of 200 000 IU, followed a month later by monthly doses of 100 000 IU, or placebo for a median of 3.3 years (range, 2.5-4.2 years). Main Outcomes and Measures: The primary outcome was the number of participants with incident CVD and death, including a prespecified subgroup analysis in participants with vitamin D deficiency (baseline deseasonalized 25-hydroxyvitamin D [25(OH)D] levels <20 ng/mL). Secondary outcomes were myocardial infarction, angina, heart failure, hypertension, arrhythmias, arteriosclerosis, stroke, and venous thrombosis. Results: Of the 5108 participants included in the analysis, the mean (SD) age was 65.9 (8.3) years, 2969 (58.1%) were male, and 4253 (83.3%) were of European or other ethnicity, with the remainder being Polynesian or South Asian. Mean (SD) baseline deseasonalized 25(OH)D concentration was 26.5 (9.0) ng/mL, with 1270 participants (24.9%) being vitamin D deficient. In a random sample of 438 participants, the mean follow-up 25(OH)D level was greater than 20 ng/mL higher in the vitamin D group than in the placebo group. The primary outcome of CVD occurred in 303 participants (11.8%) in the vitamin D group and 293 participants (11.5%) in the placebo group, yielding an adjusted hazard ratio of 1.02 (95% CI, 0.87-1.20). Similar results were seen for participants with baseline vitamin D deficiency and for secondary outcomes. Conclusions and Relevance: Monthly high-dose vitamin D supplementation does not prevent CVD. This result does not support the use of monthly vitamin D supplementation for this purpose. The effects of daily or weekly dosing require further study. Trial Registration: clinicaltrials.gov Identifier: ACTRN12611000402943.

Allium sativum Compared to Cilostazol as an Inhibitor of Myointimal Hyperplasia.

Objective: Intimal hyperplasia is associated with graft failure and vascular sutures in the first year after surgery and in postangioplasty restenosis. Allium sativum (common garlic) lowers cholesterol and has antioxidant effects; it also has antiplatelet and antitumor properties and, therefore, has great potential to reduce or inhibit intimal hyperplasia of the arteries. Our objective is to determine if the garlic has an efficacy to inhibit myointimal hyperplasia compared to cilostazol. Methods: Female New Zealand rabbits were divided into the following groups (n=10 each) according to treatment: group A, garlic, 800 µg×kg-1×day-1, orally; group C, cilostazol, 50 mg.day-1, orally; group PS, 10 ml of 0.9% physiological saline solution, orally. Our primary is the difference of the mean of myointimal hyperplasia. Statistical analysis was performed by using ANOVA and Tukey tests, as well as the Chi-square test. We calculated the 95% confidence interval for each point estimate, and the P value was set as < 0.05. Results: Group PS had a mean hyperplasia rate of 35.74% (95% CI, 31.76-39.71%); group C, 16.21% (95% CI, 13.36-19.05%); and group A, 21.12% (95% CI, 17.26-25.01%); P < 0.0001. Conclusion: We conclude that Allium sativum had the same efficacy in inhibiting myointimal hyperplasia when compared to the positive control, cilostazol.

Allium sativum compared to cilostazol as an inhibitor of myointimal hyperplasia

Abstract Objective: Intimal hyperplasia is associated with graft failure and vascular sutures in the first year after surgery and in postangioplasty restenosis. Allium sativum (common garlic) lowers cholesterol and has antioxidant effects; it also has antiplatelet and antitumor properties and, therefore, has great potential to reduce or inhibit intimal hyperplasia of the arteries. Our objective is to determine if the garlic has an efficacy to inhibit myointimal hyperplasia compared to cilostazol. Methods: Female New Zealand rabbits were divided into the following groups (n=10 each) according to treatment: group A, garlic, 800 µg×kg-1×day-1, orally; group C, cilostazol, 50 mg.day-1, orally; group PS, 10 ml of 0.9% physiological saline solution, orally. Our primary is the difference of the mean of myointimal hyperplasia. Statistical analysis was performed by using ANOVA and Tukey tests, as well as the Chi-square test. We calculated the 95% confidence interval for each point estimate, and the P value was set as < 0.05. Results: Group PS had a mean hyperplasia rate of 35.74% (95% CI, 31.76–39.71%); group C, 16.21% (95% CI, 13.36–19.05%); and group A, 21.12% (95% CI, 17.26–25.01%); P<0.0001. Conclusion: We conclude that Allium sativum had the same efficacy in inhibiting myointimal hyperplasia when compared to the positive control, cilostazol.

Serum ß-cryptoxanthin and ß-carotene derived from Satsuma mandarin and brachial-ankle pulse wave velocity: The Mikkabi cohort study.

BACKGROUND AND AIMS: Findings of observational studies suggest cardioprotective effects of antioxidant vitamins and carotenoids. However, recent meta-analyses failed to show the beneficial effects of supplemental intake of antioxidants on cardiovascular disease (CVD). We aimed to assess the association between CVD risk and ß-cryptoxanthin in Japan, where Satsuma mandarin, a major source of ß-cryptoxanthin, is widely consumed. METHODS AND RESULTS: This was part of the Mikkabi cohort study. Surveys were conducted at baseline, in 2003 and 2005, and on follow-up in 2006, 2009, and 2013. We examined brachial-ankle pulse wave velocity (baPWV) with a high cut-off value set at 18.3 m s(-1). Hazard ratios (HR) and 95% confidence intervals for high baPWV were estimated using a Cox proportional hazards model with adjustment for potential confounders. A total of 635 participants with baPWV of less than 18.3 m s(-1) at baseline were included in the analysis. During the follow-up period of 57,921 person-months, 99 subjects developed high baPWV. After multivariate adjustment, the HR for high baPWV in the highest tertile compared with the lowest tertile was significantly low for ß-cryptoxanthin, ß-carotene, and total carotenoids. Serum concentrations of ß-cryptoxanthin and ß-carotene were higher in people who ate Satsuma mandarin frequently. Compared with <1/d intake of Satsuma mandarin, 3-4/d was associated with a low risk of high PWV. CONCLUSION: This study indicated that ß-cryptoxanthin and ß-carotene derived from Satsuma mandarin are candidate micronutrients for preventing arteriosclerosis development. Further longitudinal and interventional studies will be required to validate the effect on CVD.

Recent findings of long-chain n-3 polyunsaturated fatty acids (LCn-3 PUFAs) on atherosclerosis and coronary heart disease (CHD) contrasting studies in Western countries to Japan.

Recent long-term randomized clinical trials (RCTs) of long-chain n-3 polyunsaturated fatty acids (LCn-3 PUFAs) on coronary heart disease (CHD) among high-risk patients conducted in Western countries all failed to show their clinical benefits. In striking contrast, an RCT of LCn-3 PUFAs on CHD conducted in Japan, which is a combination of secondary and primary prevention, showed a significant 19% reduction. Potential reasons for this discrepancy are large differences in doses of LCn-3 PUFAs administered (300-900 mg/day in Western countries vs. 1800 mg/day in Japan) and background dietary intake of LCn-3 PUFAs (<300 mg/day in Western countries vs. >1000 mg/day in Japan). These observations suggest that higher doses of LCn-3 PUFAs than examined in RCTs in Western countries may be cardio-protective. Atherosclerosis is the major underlying cause of CHD. Recent observational studies and an RCT of LCn-3 PUFAs on atherosclerosis in Japan show that LCn-3 PUFAs are anti-atherogenic. In this brief review, we focus on recent epidemiological and clinical findings of LCn-3 PUFAs on atherosclerosis and CHD, contrasting studies in Western countries to those in Japan. We also discuss mechanisms of high-dose LCn-3 PUFAs on atherosclerosis.

A study on the effect of resveratrol on lipid metabolism in hyperlipidemic mice.

BACKGROUND: The content of resveratrol is relatively high in Polygonum cuspidatum Sieb. et Zucc., and the resveratrol has the effect of blood vessel dilating, microcirculation improving, platelet aggregation inhibiting and anti-cancer. The objective of this paper was to study the effect of resveratrol on lipid metabolism in hyperlipidemia mice. MATERIALS AND METHODS: Through the establishment of an experimental mouse model of hyperlipidemia, the effect of resveratrol on change in total cholesterol (TC), triglyceride (TG), high density lipoprotein cholesterol (HDL-c), and low-density lipoprotein cholesterol (LDL-c) levels in mouse serum were determined. RESULTS: Resveratrol group can apparently reduce TC, TG, LDL-c and AI of hyperlipidemic mice in a dose effect manner. CONCLUSION: We concluded that resveratrol can effectively reduce blood lipid levels of hyperlipidemic mice.

Antiobesity and vasoprotective effects of resveratrol in apoE-deficient mice.

This study was performed to investigate the hypolipidemic, antiobese, and antiatherogenic effects of resveratrol in apoE-deficient mice fed an atherogenic diet (20% fat and 1% cholesterol). These animals were fed an atherogenic diet containing 0.02% lovastatin (w/w) or 0.02% resveratrol (w/w) for 12 weeks. Resveratrol and lovastatin supplementation significantly reduced either the body weight or epididymal fat weight without altering the food intake and food efficiency ratio. Resveratrol significantly decreased the plasma total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C) concentrations, apoB/apoA-I ratio, hepatic cholesterol, and triglyceride (TG) contents, whereas significantly it increased the plasma HDL-C concentration compared with the control and lovastatin groups. Plasma and hepatic TG and plasma apoB levels were significantly lower in both the lovastatin and resveratrol groups than in the control group without altering the plasma apoA-I concentration. Both resveratrol and lovastatin significantly decreased hepatic fatty acid and TG synthesis, whereas they increased fatty acid oxidation (ß-oxidation) except for the carnitine palmitoyltransferase activity compared with the control group. However, there was no difference in hepatic 3-hydroxyl-3-methylglutaryl-CoA reductase activity among the groups, although hepatic acyl-CoA: cholesterol acyltransferase activity was significantly lower in the lovastatin groups than in the control group. In epididymal adipose tissue, resveratrol supplementation led to an increase in ß-oxidation and decrease in TG synthesis, compared with the control group. Tissue morphology revealed that there were dramatic decreases in hepatic lipid droplets and aortic fatty streaks by resveratrol and lovastatin supplementation. This study demonstrates that resveratrol exerts not only antiobesity and hypolipidemic effects, but also protective effects for the liver and aorta through the modulation of lipid metabolism in both the liver and white adipose tissues.

Effect of dietary Maitake (Grifola frondosa) mushrooms on plasma cholesterol and hepatic gene expression in cholesterol-fed mice.

To investigate the effects of dietary Grifola frondosa on cholesterol, normal mice were fed a diet containing 1% cholesterol (HC group) or 1% cholesterol and 10% freeze-dried G. frondosa powder (HC+G group) for 4 weeks and hepatic and plasma lipid levels were compared with those of a cholesterol-free diet-fed mice (N group). Hepatic total cholesterol (TC), triacylglycerol contents were considerably increased and plasma TC / phospholipid (PL) was also increased significantly in the HC group compared with the N group. However, plasma TC content decreased in the HC+G group compared with the HC group. To characterize the mechanisms responsible for lowered plasma cholesterol in G. frondosa-supplemented mice, hepatic gene expression was profiled using DNA microarray and gene ontology. Genome analyses revealed that de novo cholesterol synthesis genes were suppressed following cholesterol intake. However, expression of bile acid biosynthesis and low-density lipoprotein receptor genes showed little change. Scarb1, Abcg5, and Abcg8, involved in cholesterol transport and excretion, were slightly upregulated in the HC+G group compared with the HC group. These data indicate the plasma cholesterol-lowering effect of G. frondosa. Moreover, fatty acid (FA) ß-oxidation was promoted via adipocytokine signaling pathways, and Saa, encodes serum amyloid A related to arteriosclerosis, was suppressed in the HC+G group.

Quercetin-3-O-glucuronide induces ABCA1 expression by LXRα activation in murine macrophages.

Reverse cholesterol transport (RCT) removes excess cholesterol from macrophages to prevent atherosclerosis. ATP-binding cassette, subfamily A, member 1 (ABCA1) is a crucial cholesterol transporter involved in RCT to produce high density lipoprotein-cholesterol (HDLC), and is transcriptionally regulated by liver X receptor alpha (LXRα), a nuclear receptor. Quercetin is a widely distributed flavonoid in edible plants which prevented atherosclerosis in an animal model. We found that quercetin-3-O-glucuronide (Q3GA), a major quercetin metabolite after absorption from the digestive tract, enhanced ABCA1 expression, in vitro, via LXRα in macrophages. In addition, leaf extracts of a traditional Asian edible plant, Nelumbo nucifera (NNE), which contained abundant amounts of quercetin glycosides, significantly elevated plasma HDLC in mice. We are the first to present experimental evidence that Q3GA induced ABCA1 in macrophages, and to provide an alternative explanation to previous studies on arteriosclerosis prevention by quercetin.

Homocysteine lowering interventions for peripheral arterial disease and bypass grafts.

BACKGROUND: Elevated plasma levels of the amino acid homocysteine (hyperhomocysteinaemia) are associated with narrowing or blocking of the arteries (atherosclerosis). Treatment to lower homocysteine levels has been shown to be both effective and cheap in healthy volunteers. However, the impact of reducing homocysteine levels on the progression of atherosclerosis and patency of the vessels after treatment for atherosclerosis is still unknown and forms the basis for this review. This is the second update of a review first published in 2002. OBJECTIVES: To assess the effects of plasma homocysteine lowering therapy on the clinical progression of disease in people with peripheral arterial disease (PAD) and hyperhomocysteinaemia including, as a subset, those who have undergone surgical or radiological intervention. SEARCH METHODS: For this update, the Cochrane Peripheral Vascular Disease Group Trials Search Co-ordinator (TSC) searched the Specialised Register (last searched January 2013) and CENTRAL (2012, Issue 12). Trial databases were searched by the TSC (January 2013) for details of ongoing and unpublished studies. We also searched the reference lists of relevant articles. SELECTION CRITERIA: Randomised trials in which participants with PAD and hyperhomocysteinaemia were allocated to either homocysteine lowering therapy or no treatment, including participants before and after surgical or radiological interventions. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted the data. Information on adverse events was collected from the trials. MAIN RESULTS: Two randomised trials with a total of 161 participants were included in this review. The studies did not report on mortality and rate of limb loss. One randomised trial with a total of 133 participants showed that there was a significant improvement in ankle brachial index (ABI) in participants who received folic acid compared with placebo (mean difference (MD) 0.07, 95% confidence interval (CI) 0.04 to 0.11, P < 0.001) and in participants who received 5-methyltetrahydrofolate (5-MTHF) versus placebo (MD 0.05, 95% CI 0.01 to 0.10, P = 0.009). A second trial with a total of 18 participants showed that there was no difference (P non-significant) in ABI in participants who received a multivitamin B supplement (mean ± SEM: 0.7 ± 01) compared with placebo (mean ± SEM: 0.8 ± 0.1). No major events were reported. AUTHORS' CONCLUSIONS: Currently, no recommendation can be made regarding the value of treatment of hyperhomocysteinaemia in peripheral arterial disease. Further, well constructed trials are urgently required.

Hatha yoga and vascular function: results from cross-sectional and interventional studies.

The aim of this study was to determine the effect of hatha yoga on arterial elasticity and endothelial function. First, a cross-sectional study was performed to determine whether yoga practitioners would demonstrate greater arterial compliance and endothelium-dependent vasodilation than their sedentary peers. Second, an intervention study involving 13 sedentary middle-aged and older adults (51 ± 7 years) was performed to determine whether 12 weeks of hatha yoga would elicit increases in arterial compliance and endothelial function. In the cross-sectional study involving a total of 34 subjects, there were no group differences in body fatness, blood lipid and lipoprotein concentrations, carotid artery compliance or brachial artery flow-mediated dilation (FMD). Hemoglobin A1c was lower in yoga practitioners than in sedentary adults (P < 0.05). Total cholesterol and hemoglobin A1c decreased after the intervention (P < 0.05) while carotid artery compliance and brachial artery FMD did not change. The results of both cross-sectional and interventional studies indicate that regular practice of hatha yoga is not associated with improvements in vascular functions.

The role of dietary fats for preventing cardiovascular disease. A review.

At the present, there is a pandemic of chronic non-communicable disease (NCD) affecting most countries of the world. The World Health Organisation (WHO) has identified the main contributing determinants to be cardiovascular disease (CVD), diabetes, malignant cancer and chronic disease of the respiratory system. Unhealthy nutrition, as well as other adverse lifestyle health behaviour are recognised to be part of the prime factors responsible. According to WHO guidelines, a healthy lifestyle should include substituting saturated fatty acids (SFAs) with polyunsaturated fatty acids (PUFAs) together with eliminating trans-fatty acids from the diet and limiting the intake of refined carbohydrates in conjunction with increasing the consumption of fruit, vegetables, nuts and wholegrain cereal products. Recent studies on the relations between CVD prevention and dietary fats have been however unclear. The present study thus aims to provide a review of current evidence and opinion on the type of dietary fat most appropriate for preventing arteriosclerosis. The adoption of dated recommendations on the need to increase dietary PUFA in both Northern Europe and America has led to n-6 PUFAs being predominant in diets as compared to n-3 PUFAs. This disproportion may have caused mortality to rise, due to CVD, as a result of arteriosclerosis in these countries. In contrast, a traditional Mediterranean diet yields a PUFA n-6/n-3 ratio of 2:1, which is much lower than for the aforementioned northern countries. Some authors however consider that assessing this ratio is irrelevant and that decreasing n-6 PUFA may be harmful. Such differences of opinion leads to confusion in adopting an effective approach for arteriosclerosis management regarding dietary n-6/n-3 ratios. Moreover, recent studies have added much controversy to the notion that the characteristics of SFAs are responsible for arteriosclerosis. These found that replacing dietary SFAs with carbohydrates did not reduce the risk of ishaemic heart disease (IHD). Furthermore, changing to monounsaturated fatty acids (MUFAs) gave equivocal findings, but only changing to PUFAs reduced the risk of IHD. This last statement however requires qualification in that dietary n-6 PUFAs increases the risk of IHD. It is only the n-3 PUFAs that are beneficial. Up till now these controversies remain unsolved. It is however noteworthy that adopting a Mediterranean diet reduces IHD mortality. This is explained by a low consumption of SFAs but high intake of unsaturated fatty acids including n-3 PUFAs, and is linked to choosing the right vegetable fats. Oils that contain alpha-linoleic acid (ALA) are to be preferred in the diets of northern countries.

The reduction of allograft arteriosclerosis in intestinal transplant is associated with sphingosine kinase 1/sphingosine-1-phosphate signaling after fish oil treatment.

BACKGROUND: Transplant arteriosclerosis is a major cause of late intestinal allograft dysfunction. However, little is known about the immunologic and molecular mechanisms underlying it, and no effective treatment is available. This study aimed to investigate the role of sphingosine kinase 1 (SPHK1)/sphingosine-1-phosphate (S1P) in transplant arteriosclerosis and find out whether fish oil (FO) attenuates allograft arteriosclerosis through S1P signaling. METHODS: A rat model with orthotopic intestinal transplantation was conducted in this study. Animals received daily FO supplementation after intestinal transplant. The allogeneic recipients by phosphate-buffered saline or corn oil treatment served as controls. The allograft arteriosclerosis was characterized, and the expression of SPHK1 and S1P receptors (S1P1, S1P2, and S1P3) was determined on day 190 posttransplant. RESULTS: The allogeneic controls presented transplant vasculopathy in mesenteric vessels, including intimal thickening, fibrosis, and leukocyte infiltration. The transplant arteriosclerosis was markedly reduced in FO-fed animals. The pression of SPHK1 and its activity were significantly augmented, and the expression of S1P1 and S1P3 messenger RNA was up-regulated in the allogeneic controls. FO supplementation suppressed the activation of SPHK1 and led to a decrease in the expression of S1P1 and S1P3 in these tissues in transplant arteriosclerosis. CONCLUSIONS: These results demonstrate that the activation of SPHK1/S1P signaling plays a possible role in the pathogenesis of transplant arteriosclerosis. The reduction of allograft arteriosclerosis by FO may be associated with down-regulation of SPHK1/S1P signaling. Understanding the role of FO for SPHK1/S1P may help us to identify considerable therapeutic targets for transplant arteriosclerosis.

Effects of a catechin-free fraction derived from green tea on gene expression of enzymes related to lipid metabolism in the mouse liver.

Many biological activities of green tea have been attributed to a major constituent, (minus;)-epigallocatechin gallate (EGCG). We previously reported that EGCG and an EGCG-free fraction derived from green tea modulated the gene expression of gluconeogenic enzymes, glucose-6-phosphatase and phosphoenolpyruvate carboxykinase, in the mouse liver. EGCG is also known to affect the gene expression of enzymes related to lipid metabolism. However, it remains to be examined whether or not a constituent other than EGCG contributes to the change in gene expression of these enzymes. In this study, we prepared an EGCG-free water-soluble fraction (GT-W), and examined its effects on the hepatic gene expression of lipogenic enzymes in mice. The results of quantitative real-time PCR assays indicated that the dietary administration of GT-W for 4 weeks reduced the hepatic gene expression of lipogenic enzymes: fatty acid synthase, hydroxymethylglutaryl coenzyme A reductase, and acetyl-coenzyme A carboxylase alpha. Also, the gene expression of sterol regulatory element-binding transcription factor (Srebf)1 and/or Srebf2 was reduced, suggesting that the reduction of Srebfs contributed to the down-regulation of the lipogenic enzymes, since these transcription factors bind the promoter region to enhance their expression. The plasma levels of triglycerides and cholesterol were reduced with statistical significance in the group given a diet containing GT-W. These results suggest that in addition to EGCG, green tea contains some component(s) which may help to prevent arteriosclerosis and obesity.

Antioxidant and anti-atherogenic activities of three Piper species on atherogenic diet fed hamsters.

Atherogenic diet is known to induce high plasma lipid concentration, oxidative stress and early atherosclerosis. Antioxidants have potentials to counter the effect of atherogenic diet. The present research aims at evaluating the antioxidant and anti-atherosclerotic activities of three Piper species (Piper guineense, Piper nigrum and Piper umbellatum) on atherogenic diet fed hamsters. Hamsters divided into 8 groups: normal control, atherosclerotic control and six test groups. The normal animals fed normal rodent chow, the atherosclerotic control animals fed the same rodent chow supplemented with 0.2% cholesterol and 10% coconut oil (high cholesterol diet). The 6 test groups' animals fed same diet as the atherosclerotic control group but with additional supplementation of 2 graded doses (1 and 0.25 mg/kg body weight, o.p.) of plant extracts for 12 weeks. The atherogenic diet induced a collapse of the erythrocyte antioxidant defense system (significant decrease in superoxide dismutase, catalase and glutathione peroxidase activities). Atherogenic diet also induced an increase in plasma total cholesterol, triglyceride, thiobarbituric acid reactive substances (TBARS), oxidation of low density lipoprotein cholesterol (LDL) and accumulation of foam cells in the aorta a hall mark for atherosclerosis. Administration of the Piper species prevented the collapse of the antioxidant system and the increase of plasma parameters maintaining them towards normality. The Piper species also prevented LDL oxidation by increasing the time (lag time) for its oxidation. The results suggest that these Piper species have significant antioxidant and anti-atherogenic effect against atherogenic diet intoxication.

Homocysteine-lowering and cardiovascular disease outcomes in kidney transplant recipients: primary results from the Folic Acid for Vascular Outcome Reduction in Transplantation trial.

BACKGROUND: Kidney transplant recipients, like other patients with chronic kidney disease, experience excess risk of cardiovascular disease and elevated total homocysteine concentrations. Observational studies of patients with chronic kidney disease suggest increased homocysteine is a risk factor for cardiovascular disease. The impact of lowering total homocysteine levels in kidney transplant recipients is unknown. METHODS AND RESULTS: In a double-blind controlled trial, we randomized 4110 stable kidney transplant recipients to a multivitamin that included either a high dose (n=2056) or low dose (n=2054) of folic acid, vitamin B6, and vitamin B12 to determine whether decreasing total homocysteine concentrations reduced the rate of the primary composite arteriosclerotic cardiovascular disease outcome (myocardial infarction, stroke, cardiovascular disease death, resuscitated sudden death, coronary artery or renal artery revascularization, lower-extremity arterial disease, carotid endarterectomy or angioplasty, or abdominal aortic aneurysm repair). Mean follow-up was 4.0 years. Treatment with the high-dose multivitamin reduced homocysteine but did not reduce the rates of the primary outcome (n=547 total events; hazards ratio [95 confidence interval]=0.99 [0.84 to 1.17]), secondary outcomes of all-cause mortality (n=431 deaths; 1.04 [0.86 to 1.26]), or dialysis-dependent kidney failure (n=343 events; 1.15 [0.93 to 1.43]) compared to the low-dose multivitamin. CONCLUSIONS: Treatment with a high-dose folic acid, B6, and B12 multivitamin in kidney transplant recipients did not reduce a composite cardiovascular disease outcome, all-cause mortality, or dialysis-dependent kidney failure despite significant reduction in homocysteine level.

L-carnitine supplementation and adipokines in patients with end-stage renal disease on regular hemodialysis.

Chronic hemodialysis (HD) patients frequently encounter carnitine depletion, elevated adipose tissue-derived hormones/cytokines, that may contribute to accelerated arteriosclerosis. 10 non-diabetic HD patients were studied over 28 weeks. In the 12 weeks treatment period 1 g L-carnitine was given iv after each HD session. Measurements of plasma free- and acylcarnitines, insulin, leptin, adiponectin, resistin and ghrelin were performed at baseline, at weeks 2, 4, 8, 12 (treatment period) and at weeks 24-28 (post-treatment period). L-carnitine supplementation resulted in progressive increase of free- and acylcarnitine levels. Plasma levels of insulin, resistin, leptin and ghrelin remained at the already elevated baseline values. L-carnitine therapy induced a significant increase in plasma adiponectin from 20.2 ± 12.7 µg/ml (baseline) to 32.7 ± 20.2 µg/ml in week 2 (p<0.05) and 35.4 ± 19.6 µg/ml in week 12 (p < 0.03), which remained unchanged in the post-carnitine period. Plasma insulin levels correlated positively with leptin (r = 0.525, p<0.0001) and resistin (r = 0.284, p<0.005); adiponectin levels correlated inversely with leptin (r = -0.255, p<0.02) and resistin (r = -0.213, p<0.04) irrespective of carnitine status. Plasma levels of adipokines and related hormones are greatly elevated in patients on regular HD. L-carnitine administration further augmented the plasma levels of protective adiponectin, therefore it may have a role in preventing cardiovascular complications of uremia.