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Online Library: Atherosclerosis

The following pages provide an overview of the most recent research and clinical studies about the health benefits of micronutrients in fighting atherosclerosis. This collection of scientific facts proves that anyone who privately or publicly questions the health value of micronutrients does not serve YOUR health, or the health of the people, but rather the multi-billion dollar investment 'business with disease' based on patented pharmaceutical drugs.

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Carotenoids and asymptomatic carotid atherosclerosis.

Source: J Biol Regul Homeost Agents. 2010;24(4):447-52.

Author: Riccioni G, D'Orazio N, Speranza L, Di Ilio E, Glade M, Bucciarelli V, Scotti L, Martini F, Pennelli A, Bucciarelli T.

Affiliation: Cardiology Unit, San Camillo de Lellis Hospital, Manfredonia, Foggia, Italy.

Abstract: Participants with ultrasonic evidence of carotid atherosclerosis exhibited significantly greater body mass index, significantly higher serum concentrations of total cholesterol, LDL-associated cholesterol and triglycerides, and significantly higher plasma concentrations of uric acid, C-reactive protein and fibrinogen. In contrast, participants with ultrasonic evidence of carotid atherosclerosis exhibited significantly lower plasma concentrations of lycopene and beta-carotene. These results suggest that lycopene and beta-carotene may play important roles in delaying the development of the early asymptomatic stage of carotid atherosclerosis. Encouraging adequate intakes of antioxidant carotenoids may provide an important public health service.

Green Tea Catechins May Help Prevent Endothelial Dysfunction and Atherosclerosis in Smokers

Source: Intern Med 2010;49(23):2553-9.

Author: Oyama JI, Maeda T, et al

Affiliation: Department of Cardiovascular, Respiratory and Geriatric Medicine, Kyushu University Hospital at Beppu and Medical Institute of Bioregulation, Kyushu University

Abstract: In a study involving 30 healthy male smokers, supplementation with green tea catechins (GTC) was found to exert "anti-atherosclerotic effects on dysfunctional vessels" by "increasing the level of nitric oxide and reducing oxidative stress." These results suggest that consumption of green tea catechins in high doses such as those used in this study (580 mg/d) may be of benefit to smokers.

Effect of consumption of tomato juice enriched with n-3 polyunsaturated fatty acids on the lipid profile, antioxidant biomarker status, and cardiovascular disease risk in healthy women.

Source: European Journal of Nutrition 2011 Jul 14. [Epub ahead of print]

Author: García-Alonso FJ, Jorge-Vidal V, Ros G, Periago MJ.

Affiliation: Department of Food Science and Nutrition, University of Murcia, 30100, Murcia, Spain.

Abstract: In this study the scientist compared the effects of consumption of n-3 polyunsaturated fatty acids (PUFA)-enriched tomato juice versus plain tomato juice on the serum lipid profile and levels of biomarkers related to antioxidant status and cardiovascular disease (CVD) risk in women. They observed that intervention with the enriched juice had no effect on the lipid profile, and serum levels of triglycerides and cholesterol (total, LDL, and HDL) remained unchanged. The serum antioxidant status improved following juice intake, as revealed by an increase in total antioxidant capacity and a slight decrease in lipid peroxidation. The serum levels of homocysteine, a cardiovascular risk factor, decreased following n-3 PUFA-enriched juice consumption. A decrease in vascular adhesion molecule 1 (VCAM-1) levels was also noted after intake of either plain or enriched tomato juice, whereas intercellular adhesion molecule 1 (ICAM-1) levels only decreased following intake of the enriched juice. CONCLUSIONS: Overall, stronger positive amelioration of CVD risk factors was observed following the intake of n-3 PUFA-enriched juice than after plain tomato juice consumption, which suggested a possible synergistic action between n-3 PUFAs and tomato antioxidants.

Influence of n-3 polyunsaturated fatty acids on soluble cellular adhesion molecules as biomarkers of cardiovascular risk in young healthy subjects.

Source: Nutrition, metabolism, and cardiovascular diseases 2008;18(10):664-70. Epub 2008 Apr 16.

Author: Paulo MC, Andrade AM, Andrade ML, Morais MG, Kiely M, Parra D, Martinéz JA, Thorsdottir I, Bandarra NM.

Affiliation: The National Research Institute of Agriculture and Fisheries Research, Lisbon, Portugal.

Abstract: Serum levels of soluble cellular adhesion molecules (CAMs) and blood lipid parameters have been used as markers of inflammatory processes associated with cardiovascular disease (CVD) events. This study evaluated the effects of the intake of n-3 polyunsaturated fatty acids (PUFAs) in fish and fish oil within energy-restricted diets, on soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular adhesion molecule-1 (sVCAM-1). CONCLUSIONS: CAMs as inflammatory biomarkers in young and healthy subjects are not conclusive for the evaluation of CVD risk. Energy restriction in fish diets had a different effect on CAMs, being lean fish responsible for the highest decrease in ICAM-1. On the other hand, VCAM-1 results allow speculation that a low dose of n-3 PUFA may be anti-inflammatory contrarily to a high dose which can have a pro-inflammatory effect. CAMs mechanism is complex and affected by multiple factors such as lifestyle, gender, and n-3 dose and source.

Levels of vitamin D and cardiometabolic disorders: systematic review and meta-analysis.

Source: Maturitas 2010; 65(3): 225-36.

Author: Parker J, Hashmi O, Dutton D, Mavrodaris A, Stranges S, Kandala NB, Clarke A, Franco OH.

Affiliation: Health Sciences Research Institute, Warwick Medical School, University of Warwick, United Kingdom.

Abstract: Cardiometabolic disorders and vitamin D deficiency are becoming increasingly more prevalent across multiple populations. Different studies have suggested a potential association between abnormal vitamin D levels and multiple pathological conditions including cardiovascular diseases and diabetes. The authors aimed to evaluate the association between vitamin D levels, using 25-hydroxy vitamin D (25OHD) as an indicator of vitamin D status, and the presence of cardiometabolic disorders including cardiovascular disease, diabetes and metabolic syndrome. Therefore the authors performed a systematic review of the current literature on vitamin D and cardiometabolic disorders using the PubMed and Web of Knowledge databases in September 2009. Studies in adults looking at the effect of vitamin D levels on outcomes relating to cardiometabolic disorders were selected. We performed a meta-analysis to assess the risk of developing cardiometabolic disorders comparing the highest and lowest groups of serum 25OHD. From 6130 references we identified 28 studies that met our inclusion criteria, including 99,745 participants. There was moderate variation between the studies in their grouping of 25OHD levels, design and analytical approach. They found that the highest levels of serum 25OHD were associated with a 43% reduction in cardiometabolic disorders [OR 0.57, 95% (CI 0.48-0.68)]. Similar levels were observed, irrespective of the individual cardiometabolic outcome evaluated or study design. High levels of vitamin D among middle-age and elderly populations are associated with a substantial decrease in cardiovascular disease, type 2 diabetes and metabolic syndrome. If the relationship proves to be causal, interventions targeting vitamin D deficiency in adult populations could potentially slow the current epidemics of cardiometabolic disorders.

Omega-3 fatty acids for cardioprotection

Source: Mayo Clinic Proceedings 2008; 83(3):324-32

Author: Lee JH, O'Keefe JH, Lavie CJ, Marchioli R, Harris WS.

Affiliation: Mid America Heart Institute and University of Missouri-Kansas City, Kansas City, USA.

Abstract: The most compelling evidence for the cardiovascular benefit provided by omega-3 fatty acids comes from 3 large controlled trials of 32,000 participants randomized to receive omega-3 fatty acid supplements containing docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) or to act as controls. These trials showed reductions in cardiovascular events of 19% to 45%. These findings suggest that intake of omega-3 fatty acids, whether from dietary sources or fish oil supplements, should be increased, especially in those with or at risk for coronary artery disease. Patients should consume both DHA and EPA. The target DHA and EPA consumption levels are about 1 g/d for those with known coronary artery disease and at least 500 mg/d for those without disease. Patients with hypertriglyceridemia benefit from treatment with 3 to 4 g/d of DHA and EPA, a dosage that lowers triglyceride levels by 20% to 50%. Although 2 meals of oily fish per week can provide 400 to 500 mg/d of DHA and EPA, secondary prevention patients and those with hypertriglyceridemia must use fish oil supplements if they are to reach 1 g/d and 3 to 4 g/d of DHA and EPA, respectively. Combination therapy with omega-3 fatty acids and a statin is a safe and effective way to improve lipid levels and cardiovascular prognosis beyond the benefits provided by statin therapy alone. Blood DHA and EPA levels could one day be used to identify patients with deficient levels and to individualize therapeutic recommendations.

Coenzyme Q10 supplementation reduces oxidative stress and increases antioxidant enzyme activity in patients with coronary artery disease

Source: Nutrition 2012; 28(3): 250-255

Author: Bor-Jen Lee, Yi-Chia Huang, Shu-Ju Chen, Ping-Ting Lin

Affiliation: School of Nutrition, Chung Shan Medical University Hospital, Taiwan

Abstract: The purpose of this study was to investigate the effect of coenzyme Q10 supplementation on oxidative stress and antioxidant enzyme activity in patients with coronary artery disease (CAD). This was an intervention study. Patients who were identified by cardiac catheterization as having at least 50% stenosis of one major coronary artery or receiving percutaneous transluminal coronary angioplasty (n = 51) were randomly assigned to the placebo group (n = 14) or one of the two coenzyme Q10-supplemented groups (60 mg/d, n = 19; 150 mg/d, n = 18). Intervention was administered for 12 wk. Patients’ blood samples were analyzed every 4 wk for plasma coenzyme Q10 concentrations, malondialdehyde* (MDA), and antioxidant enzyme (catalase [CAT], superoxide dismutase [SOD], glutathione peroxidase) activity. Forty-three subjects with CAD completed intervention study. Plasma coenzyme Q10 concentration increased significantly. The MDA levels were significantly lower than baseline at week 4. The highest Q10-supplemented group had significantly lower MDA levels than the placebo group at week 8. With respect to antioxidant enzyme activity, subjects had significantly higher CAT and SOD activity than the placebo group at week 12. The plasma coenzyme Q10 concentration was significantly correlated with MDA levels and CAT and SOD activity. The ratio of plasma coenzyme Q10 to total cholesterol was significantly correlated with SOD activity. The ratio of plasma coenzyme Q10 to low-density lipoprotein was significantly correlated with CAT and SOD activity. However, there was no relation between coenzyme Q10 concentration and glutathione peroxidase activity. Conclusion: Coenzyme Q10 supplements at a dose of 150 mg can decrease oxidative stress and increase antioxidant enzyme activity in patients with CAD. A higher dose of coenzyme Q10 supplements (>150 mg/d) might promote rapid and sustainable antioxidation in patients with CAD.

* Malondialdehyde (MDA) is one of the most frequently used indicators of lipid peroxidation.

Coenzyme Q10 supplementation ameliorates inflammatory signaling and oxidative stress associated with strenuous exercise

Source: European Journal of Nutrition DOI: 10.1007/s00394-011-0257-5

Author: Díaz-Castro J, Guisado R, Kajarabille N, García C, Guisado IM, de Teresa C and Ochoa J

Affiliation: Department of Physiology, Granada, Spain, University of Granada, Spain

Abstract: Exhausting exercise induces muscle damage associated with high production of free radicals and pro-inflammatory mediators.The objective of this study was to determine for the first time and simultaneously whether oral coenzyme Q10 (CoQ10) supplementation can prevent over-expression of inflammatory mediators and oxidative stress associated with strenuous exercise. The participants were classified in two groups: CoQ10 group (CG) and placebo group (PG). The physical test consisted in a constant run (50 km) that combined several degrees of high effort (mountain run and ultra-endurance), in permanent climbing. Exercise was associated with an increase in TNF-α*, IL-6*, 8-hydroxy-2′-deoxyguanosine* (8-OHdG), and isoprostane* levels, revealing the degree of inflammation and oxidative stress induced. Oral supplementation of CoQ10 during exercise was efficient reducing oxidative stress (decreased membrane hydroperoxides, 8-OHdG and isoprostanes generation, increased catalase, and total antioxidant status), which would lead to the maintenance of the cell integrity. Data obtained also indicate that CoQ10 prevents over-expression of TNF-α after exercise, together with an increase in sTNF-RII that limits the pro-inflammatory actions of TNF. Moreover, CoQ10 supplementation reduced creatinine production. Conclusion: CoQ10 supplementation before strenuous exercise decreases the oxidative stress and modulates the inflammatory signaling, reducing the subsequent muscle damage.

* tumor necrosis factor alpha
* IL-6 is an interleukin that acts as both a pro-inflammatory and anti-inflammatory cytokine
*a biomarker of oxidative DNA damage
*The isoprostanes are prostaglandin-like compounds formed in vivo from the free radical-catalyzed peroxidation of essential fatty acids

Vitamin D3 and the risk of CVD in overweight and obese women: a randomised controlled trial.

Source: The British journal of nutrition 2012 Feb 9:1-8

Author: Salehpour A, Shidfar F, Hosseinpanah F, Vafa M, Razaghi M, Hoshiarrad A, Gohari M.

Affiliation: Department of Nutrition, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.

Abstract: Evidence indicates that vitamin D deficiency contributes to CVD. The authors investigated the effect of vitamin D3 supplementation on cardiovascular risk factors in women. Healthy premenopausal overweight and obese women (n 77; mean age 38 years) were randomly allocated to the vitamin D (25 μg/d as cholecalciferol) or the placebo group in a double-blind manner for 12 weeks. Blood pressure, serum lipoproteins, apolipoproteins and anthropometric parameters were recorded. Dietary intake was recorded using 24 h food recall and FFQ. Physical activity was assessed by the International Physical Activity Questionnaire. Mean total cholesterol concentrations increased in the vitamin D group but declined in the placebo group, and a significant effect was observed. In the vitamin D group, mean HDL-cholesterol concentration increased, whereas it decreased in the placebo group. Mean apoA-I concentration increased in the vitamin D group, although it decreased in the placebo group. Mean LDL-cholesterol:apoB-100 ratio augmented in the vitamin D group, while this ratio declined in the placebo group. Body fat mass was significantly decreased in the vitamin D group more than the placebo group.Conclusions: The findings showed that supplementation with vitamin D3 can significantly improve HDL-cholesterol, apoA-I concentrations and LDL-cholesterol:apoB-100 ratio, which remained significant in the multivariate model including anthropometric, dietary and physical activity measures.

Effect of folic acid supplementation on the progression of carotid intima-media thickness: a meta-analysis of randomized controlled trials.

Source: Atherosclerosis. 2012 Jun;222(2):307-13.

Author: Qin X, Xu M, Zhang Y, Li J, Xu X, Wang X, Xu X, Huo Y.

Affiliation: Institute of Biomedicine, Anhui Medical University, Hefei, China.

Abstract: The authors conducted a meta-analysis of relevant randomized trials to assess whether folic acid supplementation reduces the progression of atherosclerosis as measured by carotid intima-media thickness (CIMT). This analysis included 2052 subjects from ten folic acid randomized trials with the change in CIMT reported as one of the end points. The analysis showed that folic acid supplementation significantly reduces the progression of CIMT, particularly in subjects with chronic kidney disease (CKD) or high cardiovascular disease (CVD) risk but not in subjects who were generally healthy with only elevated homocysteine concentrations. Conclusion: The findings indicate that folic acid supplementation is effective in reducing the progression of CIMT, particularly in subjects with CKD or high CVD risk and among trials with higher baseline CIMT levels or a larger homocysteine reduction.

High-dose B vitamin supplementation and progression of subclinical atherosclerosis: a randomized controlled trial.

Source: Stroke. 2009 Mar;40(3):730-6.

Author: Hodis HN, Mack WJ, Dustin L, Mahrer PR, Azen SP, Detrano R, Selhub J, Alaupovic P, Liu CR, Liu CH, Hwang J, Wilcox AG, Selzer RH; BVAIT Research Group.

Affiliation: Atherosclerosis Research Unit, Department of Preventive Medicine, University of Southern California, Keck School of Medicine, Los Angeles, Calif. 90033, USA.

Abstract: Although plasma total homocysteine (tHcy) levels are associated with cardiovascular disease, it remains unclear whether homocysteine is a cause or a marker of atherosclerotic vascular disease. The authors determined whether reduction of tHcy levels with B vitamin supplementation reduces subclinical atherosclerosis progression. In this double-blind clinical trial, 506 participants 40 to 89 years of age with an initial tHcy >8.5 micromol/L without diabetes and cardiovascular disease were randomized to high-dose B vitamin supplementation (5 mg folic acid+0.4 mg vitamin B(12)+50 mg vitamin B(6)) or matching placebo for 3.1 years. Subclinical atherosclerosis progression across 3 vascular beds was assessed using high-resolution B-mode ultrasonography to measure carotid artery intima media thickness (primary outcome) and multi-detector spiral CT (Computed Tomography) to measure aortic and coronary artery calcium (secondary outcome). Although the overall carotid artery intima media thickness progression rate was lower with B vitamin supplementation than with placebo, statistically significant between-group differences were not found. However, among subjects with baseline tHcy >or=9.1 micromol/L, those randomized to B vitamin supplementation had a statistically significant lower average rate of carotid artery intima media thickness progression compared with placebo; among subjects with a baseline tHcy <9.1 micromol/L, there was no significant treatment effect. B vitamin supplementation had no effect on progression of aortic or coronary artery calcification overall or within subgroups. Conclusion: High-dose B vitamin supplementation significantly reduces progression of early-stage subclinical atherosclerosis (carotid artery intima media thickness) in well-nourished healthy B vitamin "replete" individuals at low risk for cardiovascular disease with a fasting tHcy >or=9.1 micromol/L.

High-dose resveratrol treatment for 2 weeks inhibits intestinal and hepatic lipoprotein production in overweight/obese men.

Source: http://www.ncbi.nlm.nih.gov/pubmed/24072699

Author: Dash S, Xiao C, Morgantini C, Szeto L, Lewis GF.

Affiliation: From the Department of Medicine, Physiology, and the Banting and Best Diabetes Centre, University of Toronto, Ontario, Canada

Abstract: Overproduction of hepatic apolipoprotein B (apoB)-100 containing very low-density lipoprotein particles and intestinal apoB-48 containing chylomicrons contributes to hypertriglyceridemia seen in conditions such as obesity and insulin resistance. Some, but not all, preclinical and clinical studies have demonstrated that the polyphenol resveratrol ameliorates insulin resistance and hypertriglyceridemia. Here, the authors assessed intestinal and hepatic lipoprotein turnover, in humans, after 2 weeks of treatment with resveratrol (1000 mg daily for week 1 followed by 2000 mg daily for week 2) or placebo. Eight overweight or obese individuals with mild hypertriglyceridemia were studied on 2 occasions, 4 to 6 weeks apart, after treatment with resveratrol or placebo in a randomized, double-blinded, crossover study. Steady-state lipoprotein kinetics was assessed in a constant fed state with a primed, constant infusion of deuterated leucine. Resveratrol treatment did not significantly affect insulin sensitivity (homeostasis model of assessment of insulin resistance), fasting or fed plasma triglyceride concentration. Resveratrol reduced apoB-48 production rate by 22% with no significant effect on fractional catabolic rate. Resveratrol reduced apoB-100 production rate by 27% and fractional catabolic rate by 26%. Conclusion: These results indicate that 2 weeks of high-dose resveratrol reduces intestinal and hepatic lipoprotein particle production.

A 3-year study shows that vitamin C consumption slows progression in thickening of coronary artery in elderly men.

Increase intakes of vitamin C and antioxidant rich fruits and vegetables in the diet of 233 elderly men over 3 years slowed the thickening of their carotid arteries as compared to 231 elderly men who did not increase their intake of antioxidant rich foods.

Vitamin C consumption is associated with less progression in carotid intima media thickness in elderly men: A 3-year intervention study.

Source: Nutr Metab Cardiovasc Dis. 2009 Jan;19(1):8-14.

Author: Ellingsen I, Seljeflot I, Arnesen H, Tonstad S.

Affiliation: Department of Preventive Cardiology, Ullevål University Hospital, Oslo, Norway. ingrid.ellingsen@uus.no

Abstract: BACKGROUND AND AIM: Plant foods may lower the risk of cardiovascular disease. METHODS AND RESULTS: We assessed changes in the intima media thickness (IMT) of the carotid artery and diet in elderly men. Men (n=563) aged 70+/-5 years were randomly assigned to 1 of 4 groups (dietary intervention, omega-3 supplementation, both or neither) using a 2 x 2 factorial design. B-mode ultrasound of the carotid arteries and calculation of dietary intake were performed at baseline and after 3 years. We previously showed that omega-3 supplementation did not influence the IMT, thus the dietary intervention (n=233) and no dietary intervention (n=231) groups were pooled. The dietary intervention group had less progression in the carotid IMT compared with the controls (0.044+/-0.091 mm versus 0.062+/-0.105 mm; P=0.047). This group increased their daily vitamin C intake (P=0.005) and intake of fruit, berries and vegetables (P<or=0.001). Increased intake of vitamin C and of fruit and berries was inversely associated with IMT progression (r=-0.181; P=0.006 and r=-0.125; P=0.056, respectively). Multivariate linear regression analysis showed that increased intakes of vitamin C and of fruit and berries were associated with less IMT progression in the intervention group and in the total study population, after adjustment for consumption of dietary cholesterol, cheese, saturated fat and group assignment. CONCLUSION: Vitamin C containing foods may protect against the progression of carotid atherosclerosis in elderly men.

A complex of antioxidant vitamins effectively inhibits free-radical oxidation of phospholipids in blood plasma, liver and myocardium.

This study suggests that supplements containing antioxidant vitamins ( Vitamin C, E, provitamin A) and selenium can be effective for prevention and complex therapy of atherosclerosis.

A complex of antioxidant vitamins effectively inhibits free-radical oxidation of LDL phospholipids in blood plasma and membrane structures of the liver and myocardium.

Source: Bull Exp Biol Med. 2003 Feb;135(2):143-6.

Author: Konovalova GG, Lisina MO, Tikhaze AK, Lankin VZ.

Affiliation: Laboratory of Biochemistry of Free-Radical Processes, A. L. Myasnikov Institute of Cardiology, Russian Cardiology Research-and-Production Center, Russian Ministry of Health, Moscow.

Abstract: Antioxidant effect of a complex preparation including antioxidant vitamins C, E, provitamin A and selenium was studied on the model of Cu(2+)-initiated free-radical oxidation of LDL isolated from human blood plasma. The antioxidant effect of combined administration of alpha-tocopherol+ascorbic acid and alpha-tocopherol+beta-carotene is far more pronounced that the antioxidant effect of individual components of these cocktails. Moreover, in the model system the combined action of all antioxidant components completely inhibited free-radical oxidation of LDL. A 30-day course of peroral administration of antioxidant vitamin cocktail and selenium to rats pronouncedly enhanced the antioxidant potential of liver and completely suppressed free-radical processes in the myocardium. It is suggested that preparations containing antioxidant vitamins and selenium can be perspective for prevention and complex therapy of atherosclerosis.

A component of hot peppers, Capsaicin, protects against lipid oxidation and protein damage in human red blood cells.

Capsaicin, responsible for the heat or spice properties of hot peppers can protect blood cells from the negative effects of oxidized fats and protein damage associated with too high glucose blood levels . This is just one example of the plethora of molecules found in common herbs that have powerful medicinal properties in respect to cardiovascular health that work with the same principles sought after by pharmaceutical industries.

Protection of lipid peroxidation and carbonyl formation in proteins by capsaicin in human erythrocytes subjected to oxidative stress.

Source: Phytother Res. 2006 Apr;20(4):303-6.

Author: Luqman S, Rizvi SI.

Affiliation: Department of Biochemistry, University of Allahabad, Allahabad 211002, India.

Abstract: Capsaicin (8-methyl-N-vanillyl-6-nonemide) is the major pungent principle found in hot peppers of the plant genus Capsicum. The present work was undertaken to investigate the antioxidative property of capsaicin on markers of oxidative stress; membrane lipid peroxidation (formation of malondialdehyde) and membrane carbonyl groups in human erythrocytes. The effect of capsaicin has been compared with l-ascorbic acid. Subjecting erythrocytes to oxidative stress by incubating them with t-BHP caused a significant increase in MDA level and protein carbonyl group content above the basal value. The presence of capsaicin (10 microm) in the incubation medium protected the erythrocytes from t-BHP-induced oxidative stress as evidenced by the decrease in MDA level and protein carbonyl group content, l-ascorbic acid also showed similar protective effect. The results conclusively prove the efficacy of the antioxidant property of capsaicin. This evidence suggests that dietary factors that act as antioxidants to decrease membrane lipid peroxidation and protein carbonyl formation may contribute to a protective effect against cancer, atherosclerosis and age related diseases. This antioxidant effect may, in part, explain the high consumption of capsicum in certain regions of the world.

Anti-inflammatory effects of Vitamin C

In people with elevated levels of C-reactive protein (CRP) which indicates inflammation, an intake of 1 gram of vitamin C and 800 IU vitamin E for 2 months reduced this marker as effectively as statins. Contrary to statins these nutrients do not trigger unwanted side effects. In addition, vitamin C supplementation did not lower CRP in those with normal CRP levels, suggesting that micronutrients alleviate pathology but do not disturb metabolic balance in healthy conditions.

Vitamin C treatment reduces elevated C-reactive protein.

Source: Free Radic Biol Med. 2009 Jan 1;46(1):70-7.

Author: Block G, Jensen CD, Dalvi TB, Norkus EP, Hudes M, Crawford PB, Holland N, Fung EB, Schumacher L, Harmatz P.

Affiliation: University of California, Berkeley, 94720, USA. gblock@berkeley.edu

Abstract: Plasma C-reactive protein (CRP) is an inflammatory biomarker that predicts cardiovascular disease. Lowering elevated CRP with statins has reduced the incidence of cardiovascular disease. We investigated whether vitamin C or E could reduce CRP. Healthy nonsmokers (N=396) were randomized to three groups, 1000 mg/day vitamin C, 800 IU/day vitamin E, or placebo, for 2 months. Median baseline CRP was low, 0.85 mg/L. No treatment effect was seen when all participants were included. However, a significant interaction was found, indicating that treatment effect depends on baseline CRP concentration. Among participants with CRP indicative of elevated cardiovascular risk (> or =1.0 mg/L), vitamin C reduced the median CRP by 25.3% vs placebo (p=0.02) (median reduction in the vitamin C group, 0.25 mg/L, 16.7%). These effects are similar to those of statins. The vitamin E effect was not significant. In summary, treatment with vitamin C but not vitamin E significantly reduced CRP among individuals with CRP > or =1.0 mg/L. Among the obese, 75% had CRP > or =1.0 mg/L. Research is needed to determine whether reducing this inflammatory biomarker with vitamin C could reduce diseases associated with obesity. But research on clinical benefits of antioxidants should limit participants to persons with elevations in the target biomarkers.

Antioxidant substances can prevent adhesion of white blood cells to inflamed endothelial vascular wall cells.

White blood cells attach to receptors exposed by inflamed cells of the artery lining. This accellerates formation of atherosclerotic lesion. This in vitro study identified compounds that can prevent this process. These compounds include vitamin C, E, and resveratrol.

Non-radioactive and colorimetric quantification of monocyte adhesion to endothelial cells in early atherogenesis.

Source: Biotechnol Lett. 2006 Nov;28(22):1805-10.

Author: Jun HJ, Chung MJ, Kim SY, Lee HJ, Lee SJ.

Affiliation: Division of Food Science, College of Life Science and Biotechnology, Institute of Biomedical Sciences and Safety, Korea University, Seoul, 136-713, Korea.

Abstract: Monocyte adhesion to vascular endothelium is an initial step in atherogenesis. To quantify this, we incubated monocytes with cultured endothelial cells, and quantified the adhered live monocytes using a colorimetric assay. Endothelium activated with lipopolysaccharide attracted monocytes in a dose-dependent manner and the adhesion was attenuated with post-treatments with L-ascorbic acid (53%), alpha- (40%) and gamma-tocopherol (39%), resveratrol (39%), and Lithospermum erythrorhizon root extract (45%). This non-radioactive, colorimetric assay may be useful for screening anti-atherogenic compounds in early atherogenesis.

Arterial Smooth Muscle Cells Produce Collagen in Response to Normal Levels of Ascorbic Acid.

Dr Rath’s scurvy-heart disease connection emphasizes the role of collagen for healthy structure and function of the vascular wall and its resistance to cholesterol accumulation and atherosclerotic plaque formation. . Arterial smooth muscle cells synthesize and attach themselves to a network of collagen, elastin, proteoglycans, and adhesive molecules that give arteries their unique properties of distending without tearing apart under high pressure, recoil back to its original shape, and the ability to change diameter in response to external chemical or nervous stimuli. Without collagen integrity, arteries are fragile and tear apart from blood pressure as in the Ehlers-Danlos Syndrome. On the other hand, stiff arteries with too much collagen are the result of metabolic compensation for abnormal conditions that impair artery functions. While basic, the fact that the artery requires vitamin C (ascorbic acid) for producing its internal collagen is still often ignored.

Ascorbic acid uptake and regulation of type I collagen synthesis in cultured vascular smooth muscle cells.

Source: J Vasc Res. 2009;46(1):15-24.

Author: Qiao H, Bell J, Juliao S, Li L, May JM.

Affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.

Abstract: BACKGROUND/AIMS: Vascular smooth muscle cells contribute both to the structure and function of arteries, but are also involved in pathologic changes that accompany inflammatory diseases such as atherosclerosis. Since inflammation is associated with oxidant stress, we examined the uptake and cellular effects of the antioxidant vitamin ascorbic acid in cultured A10 vascular smooth muscle cells. METHODS/RESULTS: A10 cells concentrated ascorbate against a gradient in a sodium-dependent manner, most likely on the sodium-dependent vitamin C transporter type 2 (SVCT2) ascorbate transporter, which was present in immunoblots of cell extracts. Although ascorbate did not affect A10 cell proliferation, it stimulated radiolabeled proline incorporation and type I collagen synthesis. The latter was evident in the cells as increases in proalpha1(I) collagen and conversion of proalpha1(I) and proalpha2(I) collagen to mature forms that were released from the cells and deposited as extracellular matrix. Intracellular type I procollagen maturation was optimal at intracellular ascorbate concentrations of 200 microM and below, which were readily achieved by culture of the cells at plasma physiologic ascorbate concentrations. CONCLUSION: These results show that the SVCT2 facilitates ascorbate uptake by vascular smooth muscle cells, which in turn increases both the synthesis and maturation of type I collagen.

Ascorbic acid restores arterial function in patients with Metabolic Syndrome.

Metabolic changes associated with diabetes negatively affect the cardiovascular system. Arteries of those with metabolic syndrome do not open normally in response to blood flow. This placebo-controlled, randomized, double-blind study shows that intravenous administration of 1 gram of ascorbic acid, allows to restore the function of arteries in patients with metabolic syndrome.

Oxidative stress-mediated arterial dysfunction in patients with metabolic syndrome: Effect of ascorbic acid.

Source: Free Radic Biol Med. 2007 Sep 1;43(5):853-9.

Author: Cangemi R, Angelico F, Loffredo L, Del Ben M, Pignatelli P, Martini A, Violi F.

Affiliation: Department of Experimental Medicine and Pathology, University of Rome La Sapienza, Rome 00161, Italy.

Abstract: Arterial dysfunction is a hallmark of early atherosclerosis; however, its behavior in patients with metabolic syndrome (MS) is still unclear. We investigated the role of oxidative stress on ischemia-induced flow-mediated dilatation (FMD) in patients with MS. FMD and oxidative stress, as assessed by serum levels of 8-hydroxy-2-deoxy-2-deoxyguanosine (8-OHdG), were studied in 18 MS and 30 control subjects. Thereafter, in the 18 MS patients, FMD was assessed after iv infusion of 1 g vitamin C or placebo in a randomized, double-blind, crossover design; serial blood samples were taken in peripheral circulation before and after FMD to analyze 8-OHdG. Compared to controls, MS patients had higher 8-OHdG (p<0.001) and lower FMD (p<0.001); 8-OHdG and FMD were inversely correlated (R=-0.74; p<0.01). In MS patients, placebo administration did not change FMD, whereas vitamin C significantly enhanced it (p<0.001). After placebo, ischemia-induced FMD was associated with a significant increase in 8-OHdG (p<0.001), an effect that was counteracted by vitamin C. Vitamin C infusion was associated with an inverse correlation between the changes in FMD and oxidative stress (R=-0.67; p<0.01). The present study shows that arterial dilatation is impaired and that enhanced oxidative stress may play a key role in patients with MS.

Atherosclerosis induced by high-cholesterol-diet in rabbits can be attenuated by supplementation with Citrulline, Arginine and Vitamin C and E

Amino acids supplementation in rabbits fed high cholesterol diets dramatically reverses atherosclerosis.

l-Citrulline and l-arginine supplementation retards the progression of high-cholesterol-diet-induced atherosclerosis in rabbits.

Source: Proc Natl Acad Sci U S A. 2005 Sep 20;102(38):13681-6.

Author: Hayashi T, Juliet PA, Matsui-Hirai H, Miyazaki A, Fukatsu A, Funami J, Iguchi A, Ignarro LJ.

Affiliation: Department of Geriatrics, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan. hayashi@med.nagoya-u.ac.jp

Abstract: The objective of this study was to evaluate the influence of ingested l-arginine, l-citrulline, and antioxidants (vitamins C and E) on the progression of atherosclerosis in rabbits fed a high-cholesterol diet. The fatty diet caused a marked impairment of endothelium-dependent vasorelaxation in isolated thoracic aorta and blood flow in rabbit ear artery in vivo, the development of atheromatous lesions and increased superoxide anion production in thoracic aorta, and increased oxidation-sensitive gene expression [Elk-1 and phosphorylated cAMP response element-binding protein]. Rabbits were treated orally for 12 weeks with l-arginine, l-citrulline, and/or antioxidants. l-arginine plus l-citrulline, either alone or in combination with antioxidants, caused a marked improvement in endothelium-dependent vasorelaxation and blood flow, dramatic regression in atheromatous lesions, and decrease in superoxide production and oxidation-sensitive gene expression. These therapeutic effects were associated with concomitant increases in aortic endothelial NO synthase expression and plasma NO(2)(-)+NO(3)(-) and cGMP levels. These observations indicate that ingestion of certain NO-boosting substances, including l-arginine, l-citrulline, and antioxidants, can abrogate the state of oxidative stress and reverse the progression of atherosclerosis. This approach may have clinical utility in the treatment of atherosclerosis in humans.

Beneficial role of vitamin C in protecting endothelial cell metabolism

Tumor necrosis alpha (TNF-a) has a damaging effect on the cells lining the artery, which when damaged elicits inflammation and clot formation. Vitamin C (Ascorbic acid) is able to counter the damaging effect of TNF-a on the endothelium.

Ascorbic acid blocks the growth inhibitory effect of tumor necrosis factor-alpha on endothelial cells.

Source: Exp Biol Med (Maywood). 2003 Jul;228(7):855-65.

Author: Saeed RW, Peng T, Metz CN.

Affiliation: Laboratory of Vascular Biology, Division of Medicinal Biochemistry, North Shore-Long Island Jewish Research Institute, Manhasset, New York 11030, USA.

Abstract: Impaired endothelial cell proliferation has been proposed to be an early, critical defect contributing to the development of atherosclerosis. Recent studies show that high plasma tumor necrosis factor (TNF)-alpha levels and low serum ascorbic acid (AA) levels correlate with atherosclerosis severity. Additionally, AA has been reported to have potential beneficial effects in preventing atherosclerosis. Based on these studies, we investigated the role of AA (< or =1mM) on TNF-alpha-mediated vascular endothelial cell growth inhibition in vitro. In accordance with previous reports, we found that TNF-alpha alone inhibited endothelial cell proliferation. Further studies revealed that AA alone enhanced endothelial cell proliferation and that AA blocked endothelial cell growth inhibition induced by TNF-alpha. By contrast, we observed no effect of AA on endothelial cell activation or nuclear entry of nuclear factor-kappaB in response to TNF-alpha. The protective effect of AA on endothelial cell proliferation was not simply the result of its antioxidant activity but did correlate with collagen IV expression by endothelial cells. AA pre-treatment of proliferating endothelial cells promoted retinoblastoma protein (Rb) phosphorylation and decreased p53 levels when compared to untreated cells. Furthermore, the addition of AA to TNF-alpha-treated proliferating endothelial cells blocked both the inhibition of retinoblastoma protein phosphorylation and enhanced p53 expression induced by TNF-alpha. Consistent with these results, we found that AA protects endothelial cells against TNF-alpha-induced apoptosis. These studies highlight the potential therapeutic role of AA in promoting endothelial cell proliferation during inflammatory conditions, such as atherosclerosis and cardiovascular disease.

Benefits of vitamin C in Type II Diabetes patients

2 grams oral ascorbic acid daily significantly increase forearm blood flow in patients with diabetes mellitus and coronary artery disease. Diabetes mellitus is known to have many consequences including atherosclerosis and higher oxidative damage.

Vascular endothelium and inflammatory process, in patients with combined Type 2 diabetes mellitus and coronary atherosclerosis: the effects of vitamin C.

Source: Diabet Med. 2004 Jun;21(6):552-8.

Author: Antoniades C, Tousoulis D, Tountas C, Tentolouris C, Toutouza M, Vasiliadou C, Tsioufis C, Toutouzas P, Stefanadis C.

Affiliation: Cardiology Department, Athens University Medical School, Greece.

Abstract: AIMS: Type 2 diabetes mellitus (DM) and coronary artery disease (CAD) are both associated with endothelial dysfunction and elevated oxidative and inflammatory state. We examined the effect of vitamin C on endothelial function and levels of soluble vascular cell adhesion molecule (sVCAM-1), interleukin-6 (IL-6) and tumour necrosis factor (TNF-alpha), in DM patients with or without CAD and in non-diabetic subjects. METHODS: Thirty-seven patients with DM + CAD, 17 patients with DM without CAD and 21 non-diabetic subjects were divided into groups receiving vitamin C 2 g/day or no anti-oxidant for 4 weeks. Forearm blood flow was determined using venous occlusion gauge-strain plethysmography. Forearm vasodilatory response to reactive hyperemia was considered as index of endothelium-dependent dilation. RESULTS: Baseline levels of IL-6 and TNF-alpha were significantly higher in patients with DM + CAD compared with patients with DM (P < 0.01) or non-diabetic subjects (P < 0.01). IL-6 and TNF-alpha levels were also higher in DM compared with non-diabetic subjects (P < 0.05). sVCAM-1 levels were lower in non-diabetic controls compared with DM + CAD (P < 0.05) or DM (P < 0.05). Reactive hyperaemia was higher in non-diabetic controls compared with DM + CAD (P < 0.001) or DM (P < 0.001). Vitamin C significantly increased reactive hyperaemia only in the DM + CAD group, while it had no effect on serum levels of sVCAM-1, TNF-alpha and IL-6 in any of the groups. CONCLUSIONS: Type 2 diabetes mellitus is associated with impaired endothelial function and increased levels of TNF-alpha, IL-6 and sVCAM-1, especially in patients with DM and CAD. Vitamin C significantly increased forearm vasodilatory response to reactive hyperaemia only in patients with combined DM and CAD.

Benefits of vitamins E and C in the vascular system are associated with their effects on extracellular matrix

This scientific review summarizes the role of vitamins E and C on the synthesis and structure of connective tissue of the blood vessel walls, essential for Optimum vascular wall function as well as in the repair of atherosclerotic lesions during disease development.

Regulatory role of vitamins E and C on extracellular matrix components of the vascular system.

Source: Mol Aspects Med. 2007 Oct-Dec;28(5-6):507-37.

Author: Villacorta L, Azzi A, Zingg JM.

Affiliation: Cardiovascular Research Center, University of Michigan Medical Center, Ann Arbor, MI 48109, USA.

Abstract: The protective effect of vitamins E (alpha-tocopherol) and C (L-ascorbic acid) in the prevention of cardiovascular disease (CVD) has been shown in a number of situations but a secure correlation is not universally accepted. Under certain conditions, both, L-ascorbic acid and alpha-tocopherol can exhibit antioxidant properties and thus may reduce the formation of oxidized small molecules, proteins and lipids, which are a possible cause of cellular de-regulation. However, non-antioxidant effects have also been suggested to play a role in the prevention of atherosclerosis. Vitamin E and C can modulate signal transduction and gene expression and thus affect many cellular reactions such as the proliferation of smooth muscle cells, the expression of cell adhesion and extracellular matrix molecules, the production of O(2)(-) by NADPH-oxidase, the aggregation of platelets and the inflammatory response. Vitamins E and C may modulate the extracellular matrix environment by affecting VSMC differentiation and the expression of connective tissue proteins involved in vascular remodeling as well as the maintenance of vascular wall integrity. This review summarizes individually the molecular activities of vitamins E and C on the cells within the connective tissue of the vasculature, which are centrally involved in the maintenance of an intact vascular wall as well as in the repair of atherosclerotic lesions during disease development.

Clinical study indicates that vitamin C can prevent vascular injury caused by oxidative stress

Ischemia-reperfusion (obstructing blood flow and restoring it) is an event that is very damaging in the case of heart attack, in which interrupted blood flow by a blood clot or a plaque is restored by surgical or chemical means. Ironically, restoring vital blood flow after a period of blood starvation causes further cellular and tissue damage, and whole fields of study are dedicated to preventing it. This clinical study shows that vitamin C (Ascorbic acid) is able to reverse the damage done to the dilation function of arteries exposed to ischemia-reperfusion injury.

Intra-arterial vitamin C prevents endothelial dysfunction caused by ischemia-reperfusion

Source: Atherosclerosis. 2008 Mar;197(1):383-91.

Author: Pleiner J, Schaller G, Mittermayer F, Marsik C, MacAllister RJ, Kapiotis S, Ziegler S, Ferlitsch A, Wolzt M.

Affiliation: Department of Clinical Pharmacology, Medical University of Vienna, Austria.

Abstract: OBJECTIVE: Ischemia-reperfusion (IR) injury causes tissue injury and endothelial dysfunction. There is evidence that oxidative stress plays an important role. METHODS: We tested if IR-induced endothelial dysfunction could be prevented by administration of the antioxidant vitamin C. Twenty-six healthy male subjects and eight male patients with peripheral arterial disease (PAD) were enrolled in this randomised placebo-controlled study. Forearm blood flow (FBF) measurements in response to the vasodilators acetylcholine (ACh; endothelium-dependent agonist) or nitroglycerin (NTG; endothelium-independent) were performed before and after forearm ischemia for 20 min. FBF responses were reassessed during reperfusion with intra-arterial co-administration of 24 mg/min vitamin C or placebo. In six volunteers responses to the NO-synthase inhibitor N-monomethyl-L-arginine (L-NMMA) were also assessed before and after ischemia with and without vitamin C. RESULTS: ACh-induced vasodilation was blunted in subjects receiving placebo after reperfusion (p<0.05 versus baseline). Administration of vitamin C completely prevented impaired responsiveness. NTG-induced vasodilation was not affected by reperfusion or vitamin C. This finding was consistent in patients with PAD and impaired endothelial function, where local vitamin C infusion restored FBF reactivity to ACh before and after IR injury (p<0.05 versus baseline). Again, NTG-induced vasodilation was not affected. Blunted L-NMMA responses seen during reperfusion could be completely reversed by vitamin C. CONCLUSIONS: Our data indicate that IR-induced vascular injury can be prevented by administration of antioxidants.

Clinical trial indicates that intake of vitamins C and E improves endothelial function in children with hyperlipidemia.

A randomized, double-blind, placebo-controlled trial in 15 children with high cholesterol (familial hypercholesterolemia) and lipid disorders shows that daily intake of vitamin C (500mg/d) and E (400 IU/d) for 6 weeks improves endothelial function thereby decreasing a risk for atherosclerosis.

Antioxidant vitamins C and E improve endothelial function in children with hyperlipidemia: Endothelial Assessment of Risk from Lipids in Youth (EARLY) Trial.

Source: Circulation. 2003 Sep 2;108(9):1059-63.

Author: Engler MM, Engler MB, Malloy MJ, Chiu EY, Schloetter MC, Paul SM, Stuehlinger M, Lin KY, Cooke JP, Morrow JD, Ridker PM, Rifai N, Miller E, Witztum JL, Mietus-Snyder M.

Affiliation: University of California, San Francisco, 2 Koret Way, Rm N631, San Francisco, Calif 94143-0610, USA. marguerite.engler@nursing.ucsf.edu

Abstract: BACKGROUND: Hyperlipidemia is associated with endothelial dysfunction, an early event in atherosclerosis and predictor of risk for future coronary artery disease. Epidemiological studies suggest that increased dietary intake of antioxidants reduces the risk of coronary artery disease. The purpose of this study was to determine whether antioxidant vitamin therapy improves endothelial function and affects surrogate biomarkers for oxidative stress and inflammation in hyperlipidemic children. METHODS AND RESULTS: In a randomized, double-blind, placebo-controlled trial, the effects of antioxidant vitamins C (500 mg/d) and E (400 IU/d) for 6 weeks and the National Cholesterol Education Program Step II (NCEP-II) diet for 6 months on endothelium-dependent flow-mediated dilation (FMD) of the brachial artery were examined in 15 children with familial hypercholesterolemia (FH) or the phenotype of familial combined hyperlipidemia (FCH). Antioxidant vitamin therapy improved FMD of the brachial artery compared with baseline (P<0.001) without an effect on biomarkers for oxidative stress (autoantibodies to epitopes of oxidized LDL, F2-isoprostanes, 8-hydroxy-2'-deoxyguanosine), inflammation (C-reactive protein), or levels of asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide. CONCLUSIONS: Antioxidant therapy with vitamins C and E restores endothelial function in hyperlipidemic children. Early detection and treatment of endothelial dysfunction in high-risk children may retard the progression of atherosclerosis.

EGCG from green tea improves various metabolic factors associated with atherosclerosis in high fat diets

This study conduced in rats fed of a diet extremely high in atherosclerotic lipids show that intraperitoneal administration of EGCG, a powerful polyphenol in green tea was able to reduce the blood lipid levels and lower oxidative stress in red blood cells and heart muscle despite of pro-atherogenic diet.

Epigallocatechin gallate improves serum lipid profile and erythrocyte and cardiac tissue antioxidant parameters in Wistar rats fed an atherogenic diet.

Source: Fundam Clin Pharmacol. 2008 Jun;22(3):275-84.

Author: Ramesh E, Elanchezhian R, Sakthivel M, Jayakumar T, Senthil Kumar RS, Geraldine P, Thomas PA.

Affiliation: Department of Animal Science, School of Life Sciences, Bharathidasan University, Tiruchirappalli 620 024, Tamil Nadu, India.

Abstract: Oxidative stress is believed to contribute to the pathogenesis of hypercholesterolaemic atherosclerosis; hence, various antioxidant compounds are being evaluated for potential anti-atherogenic effects. The present study assessed the efficacy of epigallocatechin gallate (EGCG), an antioxidant component of the plant Camellia sinensis, in improving serum lipid profile and antioxidant parameters in erythrocytes and cardiac tissue in rats fed an atherogenic diet. In male albino Wistar rats fed an atherogenic diet for 30 days, significantly increased serum levels of total cholesterol, triglycerides and lipoprotein cholesterol fractions and cardiac risk ratio were noted, compared with levels in rats fed a normal diet. Intraperitoneal administration of EGCG (100 mg/kg) for 7 or 15 days to the atherogenic diet-fed rats resulted in significantly lower serum levels of total cholesterol, triglycerides, low-density and very low density lipoprotein cholesterol fractions and a significantly higher serum level of high-density lipoprotein cholesterol compared with levels in atherogenic diet-fed, saline-treated rats. Significantly higher mean malondialdehyde levels and significantly lower mean activities of antioxidant enzymes and mean levels of non-enzymatic antioxidants occurred in atherogenic diet-fed rats compared with those fed a normal diet. When atherogenic diet-fed rats received EGCG treatment for 7 or 15 days, significantly lower mean levels of MDA, higher mean levels of non-enzymatic antioxidants and higher mean activities of enzymatic antioxidants occurred, compared with those in saline-treated rats. Thus, EGCG appears to ameliorate disruptions of serum lipid profile and of antioxidant parameters in erythrocyte and cardiac tissue of Wistar rats fed an atherogenic diet; these results may be relevant to treating human atherosclerosis.

Folic Acid, Omega-3 Fatty Acids, Arginine and antioxidant vitamins enhance positive function of Nitric oxide.

This study shows that the benefits of these micronutrients in cardiovascular health relate to cellular mechanism of enhancing endogenous NO, a vasodilatory molecule. The author suggest using a combination of these nutrients to enhance their positive effects.

Folic acid says NO to vascular diseases.

Source: Nutrition. 2003 Jul-Aug;19(7-8):686-92.

Author: Das UN.

Affiliation: EFA Sciences LLC, Norwood, Massachusetts, USA. undurti@hotmail.com

Abstract: OBJECTIVES: The possible link between folic acid or folate and tetrahydrobiopterin (H(4)B), vitamin C, polyunsaturated fatty acids (PUFAs), and nitric oxide (NO), which may explain the beneficial actions of these nutrients in various vascular conditions, was investigated. METHODS: The literature pertaining to the actions of folic acid/folate, H(4)B, vitamin C, PUFAs, and NO was reviewed. RESULTS: Impaired endothelial NO (eNO) activity is an early marker for cardiovascular disease. Most risk factors for atherosclerosis are associated with impaired endothelium-dependent vasodilatation due to reduced NO production. Folate not only reduces plasma homocysteine levels but also enhances eNO synthesis and shows anti-inflammatory actions. It stimulates endogenous H(4)B regeneration, a cofactor necessary for eNO synthesis, inhibits intracellular superoxide generation, and thus enhances the half-life of NO. H(4)B in turn enhances NO generation and augments arginine transport into the cells. Folic acid increases the concentration of omega-3 PUFAs, which also enhance eNO synthesis. Vitamin C augments eNO synthesis by increasing intracellular H(4)B and stabilization of H(4)B. Insulin stimulates H(4)B synthesis and PUFA metabolism, suppresses the production of proinflammatory cytokine tumor necrosis factor-alpha and superoxide anion, and enhances NO generation. The ability of folate to augment eNO generation is independent of its capacity to lower plasma homocysteine levels. CONCLUSIONS: The common mechanism by which folic acid, H(4)B, vitamin C, omega-3 fatty acids, and L-arginine bring about their beneficial actions in various vascular diseases is by enhancing eNO production. Hence, it remains to be determined whether a judicious combination of folic acid, vitamins B12, B6, and C, H(4)B, L-arginine, and omega-3 fatty acids in appropriate amounts may form a novel approach in the prevention and management of various conditions such as hyperlipidemias, coronary heart disease, atherosclerosis, peripheral vascular disease, and some neurodegenerative conditions.

Intravenous Vitamin C and Vitamin E coated hemodialysis membrane reduce oxidative damage and inflammation in patients undergoing hemodialysis.

Hemodialysis prolongs the life of those with life-threatening renal failure. Unfortunately, blood dialysis patients consequently suffer anemia and atherosclerosis from the procedure which causes a huge 14-times increase in free radicals in the blood. By administering intravenous vitamin C and coating the dialysis membrane with vitamin E, oxidative compounds in the plasma and oxidative damage in the blood were significantly reduced.

Effects of vitamin C infusion and vitamin E-coated membrane on hemodialysis-induced oxidative stress.

Source: Kidney Int. 2006 Feb;69(4):706-14.

Author: Yang CC, Hsu SP, Wu MS, Hsu SM, Chien CT.

Affiliation: Taipei City Hospital, Heping Branch, and Department of Physiology, National Taiwan University College of Medicine, Taipei, Taiwan.

Abstract: Chronic hemodialysis (HD) patients manifest anemia and atherosclerosis with associated oxidative stress. We explored whether intravenous infusion of vitamin C (VC) and/or use of vitamin E (VE)-coated dialysis membrane could palliate HD-evoked oxidative stress. Eighty patients undergoing chronic HD were enrolled and randomly assigned into four groups: HD with intravenous VC (n=20), HD with VE-coated dialyzer (n=20), HD with both (n=20), and HD with neither (n=20). We evaluated oxidative stress in blood and plasma, erythrocyte methemoglobin/ferricyanide reductase (red blood cells (RBC)-MFR) activity, plasma methemoglobin, and pro-inflammatory cytokines in these patients. All patients showed marked increases (14-fold) in blood reactive oxygen species (ROS) after HD. The types of ROS were mostly hydrogen peroxide, and in lesser amounts, O2*- and HOCl. HD resulted in decreased plasma VC, total antioxidant status, and RBC-MFR activity and increased plasma and erythrocyte levels of phosphatidylcholine hydroperoxide (PCOOH) and methemoglobin. Intravenous VC significantly palliated HD-induced oxidative stress, plasma and RBC levels of PCOOH, and plasma methemoglobin levels and preserved RBC-MFR activity. The VE-coated dialyzer effectively prevented RBCs from oxidative stress, although it showed a partial effect on the reduction of total ROS activity in whole blood. In conclusion, intravenous VC plus a VE-coated dialyzer is effective in palliating HD-evoked oxidative stress, as indicated by hemolysis and lipid peroxidation, and by overexpression of proinflammation cytokines in HD patients. Using VE-coated dialyzer per se is, however, effective in reducing lipid peroxidation and oxidative damage to RBCs.

Long-term low intake of vitamin C increases the risk of cardiovascular diseases

One of the pioneers of vitamin C research, Dr Emil Ginter reviews and discusses the role and cellular mechanisms of vitamin C in prevention of atherosclerosis.

Chronic vitamin C deficiency increases the risk of cardiovascular diseases.

Source: Bratisl Lek Listy. 2007;108(9):417-21.

Author: Ginter E.

Affiliation: Public Health Authority of the Slovak Republic, Bratislava, Slovakia. ginter.emil@mail.t-com.sk

Abstract: The studies on experimental animals (guinea pigs, monkeys, fish) have confirmed the important role of ascorbic acid deficiency in the development of hypercholesterolemia and atherosclerosis, but the clinical experience is not quite uniform. Metaanalyses of randomized controlled trials performed on subjects without established vitamin C-deficiency conclud that the evidence of the presence or absence of benefits derived from the ability of ascorbic acid to prevent cardiovascular diseases is not sufficient. This review is an outline of numerous clinical, epidemiological and prospective studies that have found a positive role of vitamin C in the prevention of atherosclerosis. If we admit the possibility that vitamin C deficiency is a significant risk factor of atherogenesis, due to ethical reasons it is impossible to perform long-term controlled trials on subjects with proved vitamin C deficiency, to recommend them not to change their nutrition and lifestyle, and to administer placebo to the control group. Therefore the proof of atherogenic effect of chronic vitamin C deficiency is limited to indirect evidence only. In this review many new data on the positive effects of ascorbic acid on human cardiovascular system are summarized and the mechanisms of its protective influence on blood vessels are discussed (Fig.5, Ref. 45).

Low dietary intake of beta-carotene, alpha-tocopherol and ascorbic acid is associated with increased inflammatory and oxidative stress

Study conducted among Swedish men (average 70 years old) over 7 years indicate that various metabolic markers associated with atherosclerosis and heart disease were lower in those with a higher dietary intake of antioxidant vitamins including vitamin C over a long period of time.

Low dietary intake of beta-carotene, alpha-tocopherol and ascorbic acid is associated with increased inflammatory and oxidative stress status in a Swedish cohort.

Source: Br J Nutr. 2009 Jun;101(12):1775-82.

Author: Helmersson J, Arnlöv J, Larsson A, Basu S.

Affiliation: Department of Research and Development, County Council of Gävleborg/Uppsala University, Gävle Hospital, Gävle SE-801 87, Sweden.

Abstract: Fruit and vegetable consumption has been associated with a reduced risk of several diseases including CVD. A part of these effects seen could be linked to anti-inflammatory and antioxidative effects, although this has not been thoroughly investigated. The present study was designed to investigate the effects of the dietary intake of beta-carotene, alpha-tocopherol and ascorbic acid on in vivo biomarkers of inflammation (PGF2alpha, high-sensitive C-reactive protein (hsCRP) and IL-6 formation) and oxidative stress (F2-isoprostane formation), the two important factors associated with accelerated atherosclerosis. The dietary intake of 704 participants in the Uppsala Longitudinal Study of Adult Men (ULSAM) at age 70 years was registered and inflammatory and oxidative stress biomarkers were quantified 7 years later. The registered dietary intakes of ascorbic acid and alpha-tocopherol were negatively associated linearly and in quartiles with both PGF2alpha, hsCRP, IL-6 and F2-isoprostanes, where ascorbic acid intake generally was more strongly associated. Dietary intake of beta-carotene was only significantly negatively associated with F2-isoprostanes. In conclusion, the present study is the first to suggest that the intake of food rich in antioxidants is associated with reduced cyclo-oxygenase- and cytokine-mediated inflammation and oxidative stress at 7 years of follow-up. These associations could be linked to the beneficial effects of fruit and vegetables observed on CVD.

Lower antioxidant vitamin levels indicate higher inflammation in coronary artery disease patients.

There is an association between atherosclerosis, oxidation damage, and lower levels of antioxidant vitamins in the bloodstream. This study also shows higher level of immune cell activation in coronar artery disease patients. Because oxidative stress is increased with chronic immune cell activation of any kind, it is important to replenish these antioxidant vitamins in order to prevent additional oxidative damage and keep the immune system functioning effectively.

Inverse association between serum concentrations of neopterin and antioxidants in patients with and without angiographic coronary artery disease.

Source: Atherosclerosis. 2009 Feb;202(2):543-9.

Author: Murr C, Winklhofer-Roob BM, Schroecksnadel K, Maritschnegg M, Mangge H, Böhm BO, Winkelmann BR, März W, Fuchs D.

Affiliation: Division of Biological Chemistry, Biocenter, Innsbruck Medical University, Innsbruck, Austria.

Abstract: Neopterin is released from human monocyte-derived macrophages upon stimulation with interferon-gamma and is a sensitive indicator for cellular immune activation. Furthermore, reactive oxygen species (ROS) are produced in case of immune activation and inflammation. In a cross-sectional approach, plasma concentrations of neopterin and of antioxidant compounds and vitamins were compared in 1463 patients investigated by coronary angiography, which were recruited within the LUdwigshafen RIsk and Cardiovascular Health (LURIC) study. Serum neopterin concentrations were higher in patients with coronary artery disease (CAD; mean+/-S.D.: 8.7+/-7.3 nmol/L) compared to controls (7.4+/-5.0 nmol/L; Welch's t-test: p<0.001). Mean concentrations of ascorbic acid (p<0.0001), gamma-tocopherol (p<0.05), lycopene (p<0.001), lutein+zeaxanthin (p<0.05), alpha-carotene (p<0.05) and beta-carotene (p<0.05) were lower in CAD than in controls. Neopterin concentrations correlated with CAD-score (r(s)=0.156; p<0.0001) and inversely with antioxidants lycopene (r(s)=-0.277; p<0.0001) and lutein+zeaxanthin (r(s)=-0.175; p<0.0001) levels and with vitamins ascorbic acid (r(s)=-0.207; p<0.0001) and alpha-tocopherol (r(s)=-0.105; p<0.0001). The study demonstrates that higher neopterin production is associated with lower concentrations of antioxidant compounds in patients at risk for atherosclerosis. Results suggest that lower concentrations of antioxidant compounds may relate to higher grade of chronic immune activation in patients.

Oral Vitamin C and E reduce stickiness of LDL to artery walls.

In addition to “Teflon-coating” effects of lysine and proline proposed by Dr Rath as a way to prevent stickiness of lipoproteins and their accumulation in the artery wall there are other nutritional approaches to combat other “sticky molecules” that cause lipoprotein infiltration and accumulation inside the artery. In this case, vitamin C and E diminish the affinity of LDL to vascular wall components in both smokers and non-smokers.

[Decrease of affinity between arterial proteoglycans and LDL isolated from smokers and non-smokers with vitamin E and C administration]

Source: Invest Clin. 2004 Jun;45(2):159-74.

Author: Barón L, Romero-Vecchione E, López F.

Affiliation: Cátedra de Bioquímica, Laboratorio de Lipoproteínas, Escuela de Medicina José María Vargas, Facultad de Medicina, Universidad Central de Venezuela, Caracas, Venezuela. publique@cantv.net

Abstract: LDL interaction with arterial proteoglycans and its oxidative modification is closely related to atherosclerosis. The objective of the present study was to examine the effect of the individual administration of vitamin E and a combination of vitamin E and C on LDL affinity for arterial proteoglycans in smokers and non-smokers subjects. Twenty smokers and ten non-smokers healthy subjects received by the oral route placebos of vitamins E and C for 15 days; then vitamin E (400 mg/d) for 30 days and finally vitamin E plus vitamin C (1000 mg/d) during the following 30 days. During the vitamin E supplementation period, the affinity of LDL for arterial proteoglycans decreased 19.3% in smokers and 25.2% in non-smokers. When the subjects received vitamin E plus vitamin C, the affinity of LDL for arterial proteoglycans decreased 25.6% and 30.1% in smokers and non-smokers respectively. In conclusion, simultaneous administration of vitamins E and C showed a synergistic effect to diminish the affinity of the LDL by arterial proteoglycans, that was greater than caused by the administration of vitamin E alone. These finding suggest a potential antiatherogenic effect of both antioxidant vitamins.

Plant components combined with vitamins C and E decrease insulin resistance and atherosclerotic changes in aged rats with chronic kidney failure

This animal study conducted on aging rats with chronic kidney failure has implications for human health. The authors of the study conclude that plant components (Catechin) and vitamins E and C supplementation can decrease oxidative stress associated with kidneyl failure, and counteract insulin resistance, elevated blood pressure and other changes associated with atherosclerosis in the elderly.

Catechin combined with vitamins C and E ameliorates insulin resistance (IR) and atherosclerotic changes in aged rats with chronic renal failure (CRF).

Source: Arch Gerontol Geriatr. 2008 Jan-Feb;46(1):25-39.

Author: Korish AA, Arafah MM.

Affiliation: Department of Physiology (29), Faculty of Medicine, King Saud University, PO Box 2925, Riyadh 11461, Saudi Arabia. iaidakorish@hotmail.com

Abstract: Aging is an inevitable biological process associated with increased oxidative stress and accumulation of asymmetric dimethylarginine (ADMA) a known endogenous inhibitor of nitric oxide synthase. Atherosclerosis and IR constitute major risk factors for cardiovascular mortality in elderly with chronic kidney disease (CKD). We investigated the impact of catechin, vitamins E and C supplementation on insulin sensitivity, redox state, ADMA, nitrate and nitrite (NO(2)(-)/NO(3)(-)) levels and histological picture of heart and large blood vessels of aged rats with CRF. Findings of the present study revealed that aging in rats is associated with hyperinsulinemia, hyperlipidemia, IR indicated by higher homeostasis model assessment (HOMA)-index, increased lipid peroxidation product malondialdehyde (MDA), ADMA, and blood pressure (BP), but decreased antioxidant capacity and NO(2)(-)/NO(3)(-) levels. CRF exaggerated all these findings and caused thickened intima of carotid arteries and myocardial hypertrophy. Treatment with catechin, vitamins E and C increases the antioxidant capacity and NO(2)(-)/NO(3)(-) production but, decreases MDA, ADMA and BP levels. Also it keeps insulin sensitivity and normal intima/media thickness of carotid arteries. We conclude that decreased nitric oxide (NO) availability due to ADMA accumulation may be responsible for IR and associated atherosclerotic changes in aged rats with CRF. Catechin, vitamins E and C supplementation may moderate oxidative stress of renal failure, prevent ADMA accumulation, and counteract IR and atherosclerotic changes in the elderly.

Study conducted among young adults shows increased risk of coronary calcifications with low vitamin C levels.

Analysis of the data from 2,637 African-American and White men and women aged 18-30 showed that low to marginally low vitamin C levels in men but not women predict coronary artery calcification. Calcification of the coronary arteries is an indicator of the advancement of atherosclerosis. Sites of calcification in the coronary arteries are prone to generation of thrombosis and consequent heart attack.

Relation of ascorbic acid to coronary artery calcium: the Coronary Artery Risk Development in Young Adults Study.

Source: Am J Epidemiol. 2004 Mar 15;159(6):581-8.

Author: Simon JA, Murtaugh MA, Gross MD, Loria CM, Hulley SB, Jacobs DR Jr.

Affiliation: General Internal Medicine Section (111A1), Medical Service, Veterans Affairs Medical Center and University of California, 4150 Clement Street, San Francisco, CA 94121, USA. jasimon@itsa.ucsf.edu

Abstract: Ascorbic acid is an antioxidant nutrient possibly related to the development of atherosclerosis. To examine the relation between ascorbic acid and coronary artery calcium, an indicator of subclinical coronary disease, the authors analyzed data from 2,637 African-American and White men and women aged 18-30 years at baseline who were enrolled in the Coronary Artery Risk Development in Young Adults (CARDIA) Study (1985-2001). Participants completed diet histories at enrollment and year 7, and plasma ascorbic acid levels were obtained at year 10. Coronary artery computed tomography was performed at year 15. The authors calculated odds ratios in four biologically relevant plasma ascorbic acid categories, adjusting for possible confounding variables. When compared with men with high plasma ascorbic acid levels, men with low levels to marginally low levels had an increased prevalence of coronary artery calcium (multivariate odds ratio = 2.68, 95% confidence interval: 1.31, 5.48). Among women, the association was attenuated and nonsignificant (multivariate odds ratio = 1.50, 95% confidence interval: 0.58, 3.85). Ascorbic acid intakes from diet alone and diet plus supplements were not associated with coronary artery calcium. Low to marginally low plasma ascorbic acid levels were associated with a higher prevalence of coronary artery calcium among men but not among women.

Supplementation with vitamins C and E improves arterial flexibility and function in patients with high blood pressure

This randomized, double-blind, placebo-controlled study in 30 men suffering from high blood pressure revealed that supplementation with vitamin C (1 g) and vitamin E (400 IU) for 8 weeks decrease oxidative stress and blood vessel stiffness a hallmark of high blood pressure.

Supplementation with vitamins C and E improves arterial stiffness and endothelial function in essential hypertensive patients.

Source: Am J Hypertens. 2007 Apr;20(4):392-7.

Author: Plantinga Y, Ghiadoni L, Magagna A, Giannarelli C, Franzoni F, Taddei S, Salvetti A.

Affiliation: Department of Internal Medicine, University of Pisa, Pisa, Italy.

Abstract: BACKGROUND: Essential hypertension is characterized by endothelial dysfunction, arterial stiffness, and increased oxidative stress. We evaluated the effect of short-term combined treatment with the antioxidants vitamins C and E on endothelial function, arterial stiffness, and oxidative stress in untreated essential hypertensive patients. METHODS: A randomized, double-blind, placebo-controlled, crossover study design was used to assign 30 male essential hypertensive patients to either vitamin C (1 g) and vitamin E (400 IU) or placebo for 8 weeks. Endothelium-dependent response was assessed as flow-mediated dilation (FMD) of the brachial artery. Arterial stiffness was assessed as central pulse wave velocity (PWV) and augmentation index (AIx). Plasma markers of oxidative stress and antioxidant status were measured. RESULTS: After vitamin supplementation, FMD was significantly improved. Central PWV was significantly reduced, while AIx tended to decrease. Plasma vitamin levels and antioxidant capacity increased significantly. Levels of oxidative stress decreased. Changes in central PWV were related to changes in levels of oxidative stress. CONCLUSIONS: Combined treatment with vitamins C and E has beneficial effects on endothelium-dependent vasodilation and arterial stiffness in untreated, essential hypertensive patients. This effect is associated with changes in plasma markers of oxidative stress.

Synergistic effect of N-acetylcysteine, Ascorbic acid, and Resveratrol can protect macrophage death

The combination of these nutrients had much higher effectiveness than their individual compounds in preventing the death of macrophages by a toxic substance, triacylglycerol. Healthy macrophage function is important in reducing atherosclerosis and arterial inflammation. This study confirms nutrient synergy approach pioneered by Dr Rath Research Institute is allowing to achieve superior physiological effects with moderate nutrient doses and preserve metabolic cellular balance.

Mechanism underlying oxidative stress-mediated lipotoxicity: exposure of J774.2 macrophages to triacylglycerols facilitates mitochondrial reactive oxygen species production and cellular necrosis.

Source: Free Radic Biol Med. 2005 May 1;38(9):1221-30.

Author: Aronis A, Madar Z, Tirosh O.

Affiliation: School of Nutritional Sciences, Institute of Biochemistry, Food Science and Nutrition, Faculty of Agricultural, Food and Environmental Quality Sciences, The Hebrew University of Jerusalem, Rehovot 76100, Israel.

Abstract: The aim of this study was to elucidate death pathways in macrophages resulting from exposure to triacylglycerols (TG), mechanisms which may be relevant to the development of atherosclerosis. A commercial TG emulsion (lipid emulsion, LE; 0.1-1.5 mg lipids/ml) was added to J774.2 cells in culture. Within the first 24 h after TG treatment, cellular reactive oxygen species (ROS) levels were strongly elevated and basal caspase-3 activity was attenuated. In contrast, after 48 h, ROS production was arrested. TG-mediated ROS production was demonstrated to be via mitochondrial complex 1 of the electron-transfer chain since the inhibitor of complex 1 rotenone significantly attenuated the cellular ROS levels in TG-treated cells. The TG effect culminated in cell death, with no caspase-3 activation. We therefore evaluated the effect of TG on apoptotic cells showing high caspase activity. TG induced elevated ROS levels and suppressed caspase-3 in apoptotic cells pretreated for 24 h with cycloheximide. Dual staining with propidium iodide and Annexin V followed by flow cytometric analysis showed that TG facilitated cell death with clear necrotic characteristics. To elucidate whether the necrotic cell death process is indeed oxidant dependent, antioxidant protection was studied. Treatment with N-acetylcysteine (NAC) (0.5 mM), ascorbic acid (0.5 mM), and resveratrol (0.2 mM) protected against the TG lipotoxic effect, while, surprisingly, lipophilic antioxidants did not. The combination of NAC, ascorbic acid, and resveratrol, each at much lower concentrations, had a synergistic protective effect. In conclusion, we show here for the first time that exposure to TG can directly regulate lipotoxicity in macrophages by inducing mitochondria-mediated prolonged oxidative stress; this, in turn, can inactivate the apoptotic caspase system, resulting in necrotic cell death which can be prevented by specific antioxidants.

The derivative of a flavonoid, Quercetin, and Vitamin C reduce blood viscosity and have other positive effects in patients with atherosclerosis.

An age-related changes that come with atherosclerosis of the branching arteries of the neck and brain is the combination of headaches, fatigue, confusion, and dizziness. This can lead to stroke. This Russian group uses a simple combination of dihydroquercetin and vitamin C to significantly improve this condition.

[Clinical efficacy of a novel hemorheological drug ascovertin in patients with vascular encephalopathy]

Source: Zh Nevrol Psikhiatr Im S S Korsakova. 2004;104(12):33-7.

Author: Plotnikov MB, Plotnikov DM, Alifirova VM, Aliev OI, Maslov MIu, Vasil'ev AS, Tiukavkina NA.

Affiliation:

Abstract: Patients with stages I and II of vascular encephalopathy developing on the background of atherosclerosis were treated with ascovertin during 21 days. Ascovertin is a complex of flavonoid dihydroquercetin and ascorbic acid. The study group included 21 patients aged 45-65 years and a comparison group consisted of 10 age-matched patients un treated with ascovertin. The ascovertin treatment relieved headache, reduced vertigo and fatigability, improved cognitive functions. The reliable diminishing of whole blood viscosity due to improvement of cellular rheology indices (decrease of aggregation and increase of erythrocyte deformability as well as decrease of indices of lipid peroxidation in erythrocyte membrane and blood plasma) was observed in the study group but not in the comparison one.

Vitamin C and E may decrease risk of arterial plaques rupture and consequent thrombosis

The existence of atherosclerotic plaque alone does not predict death by heart attack or stroke. If the atherosclerotic occlusion is not too severe, and inflammatory cytokines kept in check, plaque rupture and thrombosis will not occur, and nearly normal functioning will continue. Vitamin C and Vitamin E are important in plaque stability by increasing collagen integrity and decreasing its enzymatic degradation.

Antioxidant vitamins increase the collagen content and reduce MMP-1 in a porcine model of atherosclerosis: implications for plaque stabilization.

Source: Atherosclerosis. 2003 Mar;167(1):45-53.

Author: Orbe J, Rodríguez JA, Arias R, Belzunce M, Nespereira B, Pérez-Ilzarbe M, Roncal C, Páramo JA.

Affiliation: Atherosclerosis Research Laboratory, Division of Cardiovascular Pathophysiology, School of Medicine, University of Navarra, C/Irunlarrea 1, CIFA, E-31008 Pamplona, Spain.

Abstract: Degradation of extracellular matrix, particularly interstitial collagen, promotes plaque instability and contributes to restenosis after vascular injury. We have explored the effects of vitamins C and E on the collagen content and metalloproteinase-1 (MMP-1) expression after angioplasty in hypercholesterolemic pigs. Iliac angioplasty was performed on 18 minipigs divided into three diet groups: a normal-cholesterol (NC), a high-cholesterol (HC) and a high-cholesterol plus vitamins C+E (HCV). Four weeks later, after sacrifice, the vascular collagen content and MMP-1 protein expression, along with the plasma caseinolytic activity and lipid peroxidation, were measured. MMP-1 was also determined in arterial rings stimulated with native low-density lipoproteins (LDL) isolated from experimental groups. Cholesterol-rich diet augmented plasma lipid peroxidation (P<0.05), reduced the collagen content and increased vascular MMP-1 expression after injury (P<0.05). Enhanced caseinolytic activity (identified as MMP-1) was also observed in HC plasma samples and in supernatants from arterial rings incubated with HC-LDL. Vitamins C and E markedly increased neointimal collagen content (P<0.01), reduced the hypercholesterolemia-induced changes in vascular MMP-1 (P<0.05) and diminished plasma and ex vivo caseinolytic activity. Vitamins C and E may help stabilize atherosclerotic plaque after angioplasty and favor vascular remodeling by increasing collagen content and reducing vascular MMP-1 expression in porcine hypercholesterolemia.

Vitamin C and E prevent death of the arterial lining by factors released into the bloodstream by heart attack.

After myocardial infarction (heart attack), neutrophils and other inflammatory factors are released that can damage the arteries in other locations, literally adding insult to injury. Vitamin C and E among other substances prevents the inner lining of the artery, the endothelium, from death during this situation.

Prevention of endothelial cell apoptosis induced by neutrophils and sera from patients with acute myocardial infarction.

Source: Int J Cardiol. 2009 Feb 2. [Epub ahead of print]

Author: Frimmel S, Hemmer CJ, Kenzler J, Unverricht M, Ince H, Nienaber CA, Reisinger EC.

Affiliation: Division of Tropical Medicine and Infectious Diseases, Department of Medicine, University of Rostock Medical School, Germany.

Abstract: Apoptosis of cardiomyocytes and vascular endothelial cells has been shown to contribute to disease progression in coronary atherosclerosis, in myocardial infarction and in ischemia-reperfusion injury. Sera were obtained from 13 patients with acute ST elevation myocardial infarction and successful primary percutaneous coronary intervention. Human umbilical venous endothelial cells (HUVECs) were incubated with sera from these patients with or without addition of neutrophil granulocytes. TUNEL staining was performed, and apoptotic cells were quantified with immunofluorescence microscopy. To reduce apoptotic damage, ascorbic acid, vitamin E, ulinastatin, or activated protein C were added to patients' sera, with or without neutrophils, before incubation with endothelial cells. Incubation of endothelial cells with sera from patients increased the apoptosis rate significantly, compared to sera from 7 healthy controls (p<0.001). Co-incubation of endothelial cells with patients' sera and neutrophils led to a further significant increase of apoptosis. The addition of ascorbic acid, vitamin E, or activated protein C significantly decreased apoptosis rates of endothelial cells in the presence of neutrophils in vitro. Antiapoptotic strategies may be relevant for the therapy of acute coronary syndromes, since elevated leukocyte counts have been shown to be associated with increased morbidity and mortality in coronary heart disease.

Vitamin C Counteracts Arterial Dysfunction Caused by Free Fatty Acids.

Various studies indicate that elevated levels of non-esterified fatty acids impair endothelium-dependent dilation of blood vessels. This study shows that this effect can be alleviated by vitamin C and Arginine.

Vitamin C, diclophenac, and L-arginine protect endothelium-dependent vasodilation against elevated circulating fatty acid levels in humans.

Source: Atherosclerosis. 2003 May;168(1):65-72.

Author: Steer P, Millgård J, Basu S, Lithell H, Vessby B, Berne C, Lind L.

Affiliation: Department of Medical Sciences/Internal Medicine, University Hospital, SE-75185 Uppsala, Sweden. Peter.Steer@medsci.uu.se

Abstract: An acute elevation of circulating non-esterified fatty acids (NEFAs) has previously been shown to impair endothelium-dependent vasodilation (EDV). In this study, we investigated if local administration of vitamin C (n=8, 18 mg/min), L-arginine (n=8, 12.5 mg/min), or the cyclooxygenase (COX) inhibitor diclophenac (n=8, 0.5 mg/min) can counteract the endothelial dysfunction seen during infusion of Intralipid plus heparin (n=10). EDV and endothelium-independent vasodilation (EIDV) were studied in the forearm after local administration of methacholine chloride (Mch; 2 and 4 microg/min) and sodium nitroprusside (SNP; 5 and 10 microg/min). Forearm blood flow (FBF) was determined with venous occlusion plethysmography. Intralipid and heparin increased circulating NEFA levels sevenfold and impaired EDV (P<0.001 vs baseline). Concomitant administration of L-arginine or diclophenac abolished the NEFA-induced impairment in EDV. Concomitant vitamin C administration actually improved EDV (P<0.05 vs baseline). NEFA elevation increased EIDV (P<0.01), but this effect was not significant after L-arginine or diclophenac infusions. In conclusion, an acute elevation of circulating NEFAs led to impaired EDV. Administration of L-arginine, vitamin C or COX inhibition abolished this effect, suggesting that NEFAs might interact with endothelial vasodilatory function through multiple mechanisms.

Vitamin C effective in reducing inflammation in active and passive smokers

This randomized, double-blind, placebo-controlled, study in 160 active and passive smokers showed that 2 months intake of Vitamin C was superior to the antioxidant mixture in reducing C-reactive proteins (CRP) which is a marker of inflammation. Interestingly, these benefits of vitamin C supplementation were observed in people consuming more than 4 servings of fruits and vegetables daily.

Plasma C-reactive protein concentrations in active and passive smokers: influence of antioxidant supplementation.

Source: J Am Coll Nutr. 2004 Apr;23(2):141-7.

Author: Block G, Jensen C, Dietrich M, Norkus EP, Hudes M, Packer L.

Affiliation: Division of Community Health and Human Development, School of Public Health, University of California, Berkeley, California 94720, USA. Gblock@berkeley.edu

Abstract: OBJECTIVE: C-reactive protein (CRP) may directly affect the progression of atherosclerosis, and therefore, may be a target for reducing disease risk. The objective was to determine whether antioxidant supplementation reduces plasma CRP in active and passive smokers. DESIGN: Randomized, double-blind, placebo-controlled, parallel group trial with 2 months exposure to study supplements. SETTING: Berkeley and Oakland, California. SUBJECTS: Healthy adult men and women, consuming <4 daily servings of fruits and vegetables, and who were actively or passively exposed to cigarette smoke. Analysis was limited to participants with detectable baseline CRP concentrations and no evidence of inflammation associated with acute illness at baseline or follow-up as reflected in CRP elevations (> or =10.0 mg/L). A total of 1393 individuals were screened, 216 randomized, 203 completed the study, and 160 were included in the analysis. INTERVENTIONS: Participants were randomized to receive a placebo or vitamin C (515 mg/day) or antioxidant mixture (per day: 515 mg vitamin C, 371 mg alpha-tocopherol, 171 mg gamma-tocopherol, 252 mg mixed tocotrienols, and 95 mg alpha-lipoic acid). Measures of Outcome: Change in plasma CRP concentration. RESULTS: Vitamin C supplementation yielded a 24.0% reduction (95% confidence interval, -38.9% to -5.5%, p = 0.036 compared to control) in plasma CRP, whereas the antioxidant mixture and placebo produced a nonsignificant 4.7% reduction (-23.9% to 19.3%) and 4.3% increase (-15.1% to 28.2%), respectively. Results were adjusted for baseline body mass index and CRP concentrations. CONCLUSIONS: Plasma CRP itself may serve as a potential target for reducing the risk of atherosclerosis, and antioxidants, including vitamin C, should be investigated further to confirm their CRP-lowering and anti-inflammatory effects.

Vitamin C in protecting white blood cells (macrophages) against oxidative stress and triggering their death cycle (apoptosis)

Atherosclerotic plaques are associated with the recruitment of white blood cells to the site of arterial inflammation. This inflammation can be caused by several insults including oxidative damage to cholesterol carrying lipoproteins-LDL. This in vitro study indicates that vitamin C (Ascorbic acid) contributes to the survival of macrophages as they attempt to clear out and resolve oxidized-LDL. If the macrophages function normally, they have a chance to decrease inflammation, allowing the artery to heal.

Oxidized lipoprotein induces the macrophage ascorbate transporter (SVCT2): protection by intracellular ascorbate against oxidant stress and apoptosis.

Source: Arch Biochem Biophys. 2009 May 15;485(2):174-82.

Author: Chi X, May JM.

Affiliation: Department of Medicine, Vanderbilt University School of Medicine, 7465 Medical Research Building IV, Nashville, TN 37232-6303, USA.

Abstract: To assess whether ascorbic acid decreases the cytotoxicity of oxidized human low density lipoprotein (oxLDL) in cells involved in atherosclerosis, its interaction with oxLDL was studied in murine RAW264.7 macrophages. Macrophages took up ascorbate to millimolar intracellular concentrations and retained it with little loss over 18h in culture. Culture of the macrophages with oxLDL enhanced ascorbate uptake. This was associated with increased expression of the ascorbate transporter (SVCT2), which was prevented by ascorbate and by inhibiting the NF-kappaB pathway. Culture of RAW264.7 macrophages with oxLDL increased intracellular dihydrofluorescein oxidation and lipid peroxidation, both of which were decreased by intracellular ascorbate. Ascorbate also protected the cells against oxLDL-induced cytotoxicity and apoptosis, but it did not affect macrophage accumulation of lipid from oxLDL or oxLDL-induced increases in macrophage cytokine secretion. These results suggest that ascorbate protects macrophages against oxLDL-induced oxidant stress and subsequent apoptotic death without impairing their function.

Vitamin E and C reduce atherosclerotic progression in patients with high cholesterol levels.

This clinical study in 520 patients (smokers and nonsmokers) with high cholesterol blood levels shows that supplementation vith 500 mg of vitamin C daily for 6 years reduced the thickening of the carotid artery walls in men and women by 26% on average.

Six-year effect of combined vitamin C and E supplementation on atherosclerotic progression: the Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) Study.

Source: Circulation. 2003 Feb 25;107(7):947-53.

Author: Salonen RM, Nyyssönen K, Kaikkonen J, Porkkala-Sarataho E, Voutilainen S, Rissanen TH, Tuomainen TP, Valkonen VP, Ristonmaa U, Lakka HM, Vanharanta M, Salonen JT, Poulsen HE; Antioxidant Supplementation in Atherosclerosis Prevention Study.

Affiliation: Research Institute of Public Health, University of Kuopio, Finland. jukka.salonen@uku.fi

Abstract: BACKGROUND: Self-selected supplementation of vitamin E has been associated with reduced coronary events and atherosclerotic progression, but the evidence from clinical trials is controversial. In the first 3 years of the ASAP trial, the supplementation with 136 IU of vitamin E plus 250 mg of slow-release vitamin C twice daily slowed down the progression of carotid atherosclerosis in men but not women. This article examines the 6-year effect of supplementation on common carotid artery (CCA) intima-media thickness (IMT). METHODS AND RESULTS: The subjects were 520 smoking and nonsmoking men and postmenopausal women aged 45 to 69 years with serum cholesterol > or =5.0 mmol/L (193 mg/dL), 440 (84.6%) of whom completed the study. Atherosclerotic progression was assessed ultrasonographically. In covariance analysis in both sexes, supplementation reduced the main study outcome, the slope of mean CCA-IMT, by 26% (95% CI, 5 to 46, P=0.014), in men by 33% (95% CI, 4 to 62, P=0.024) and in women by 14% (not significant). In both sexes combined, the average annual increase of the mean CCA-IMT was 0.014 mm in the unsupplemented and 0.010 mm in the supplemented group (25% treatment effect, 95% CI, 2 to 49, P=0.034). In men, this treatment effect was 37% (95 CI, 4 to 69, P=0.028). The effect was larger in subjects with either low baseline plasma vitamin C levels or CCA plaques. Vitamin E had no effect on HDL cholesterol. CONCLUSIONS: These data replicate our 3-year findings confirming that the supplementation with combination of vitamin E and slow-release vitamin C slows down atherosclerotic progression in hypercholesterolemic persons.

Heart Disease and Taurine

The potential protective effects of taurine on coronary heart disease

Source: Atherosclerosis. 2010; 208(1): 19-25

Author: Wójcik OP, Koenig KL, Zeleniuch-Jacquotte A, Costa M, Chen Y

Affiliation: Department of Environmental Medicine, New York University School of Medicine, USA.

Abstract: In humans, taurine (2-aminoethanesulfonic acid) is mainly obtained from diet. Despite the fact that the health effects of taurine are largely unknown, taurine has become a popular supplement and ingredient in energy drinks in recent years. Evidence from mechanistic and animal studies has shown that the main biological actions of taurine include its ability to conjugate bile acids, regulate blood pressure (BP), and act as a potent antioxidant and anti-inflammatory agent. These actions suggest that high levels of taurine may be protective against coronary heart disease (CHD). However, data from epidemiologic and intervention studies in humans are limited. The authors review what is known about taurine’s metabolism, its transportation in the body, its food sources, and evidence of its effect on cardiovascular health from in vitro, animal, and epidemiologic studies. They also discuss shortcomings of the human studies that need to be addressed in the future. The identification of taurine as a preventive factor for CHD may be of great public health importance.

Is there any cardioprotective role of Taurine during cold ischemic period following global myocardial ischemia?

Source: Journal of cardiothoracic surgery 2011; 6: 31

Author: Mehmet A Sahin, Orhan Yucel, Adem Guler, et al

Affiliation: Gülhane Military Medical Academy, Department of Cardiovascular Surgery and the Department of Thoracic Surgery, Ankara, Turkey

Abstract: The aim of the present study was to investigate the cardioprotective effect of Taurine on the donor hearts during cold ischemic period. 32 rats were divided into 4 groups (sham*, taurine, ischemia, treatment group, 8 rats in each). All rats were fed with rat food for three weeks. Taurine and treatment groups were given a 200 mg/kg/day dose of Taurine by oral gavage besides rat feed. Cardiectomy was performed in all rats after three weeks. In ischemia and treatment groups, harvested hearts were kept in 0.9% sodium chloride at +4 degrees C for 5 hours. Tissue samples were taken from left ventricle in all groups. These samples were evaluated by histopathologic and biochemical examination. In the present study results of the biochemical and histopathological examination reveals the protective effects of Taurine. As a marker of lipid peroxidation, Malondialdehyde (MDA) levels in ischemia group were significantly higher than both Sham and Taurine groups. MDA levels decreased in treatment group. In accordance with MDA findings, while superoxide dismutase and glutathione peroxidase levels decreased in ischemia group, they increased in treatment group. There was no difference in Catalase (CAT) enzyme level between treatment and ischemia group. Less intracellular edema and inflammatory cell reaction were observed in histologic examination in favor of treatment group. Conclusion: Taurine decreased myocardial damage during cold ischemic period following global myocardial ischemia.

* Control group

Serum taurine and risk of coronary heart disease: a prospective, nested case-control study.

Source: European journal of nutrition 2012 Feb 10. [Epub ahead of print]

Author: Wójcik OP, Koenig KL, Zeleniuch-Jacquotte A, Pearte C, Costa M, Chen Y.

Affiliation: Department of Environmental Medicine, New York University School of Medicine, New York, USA.

Abstract: Taurine (2-aminoethanesulfonic acid), a molecule obtained from diet, is involved in bile acid conjugation, blood pressure regulation, anti-oxidation and anti-inflammation. The authors performed the first prospective study of taurine and CHD risk. The authors conducted a case-control study nested in the New York University Women's Health Study to evaluate the association between circulating taurine levels and risk of coronary heart disease (CHD). Taurine was measured in two yearly pre-diagnostic serum samples of 223 CHD cases and 223 matched controls and averaged for a more reliable measurement of long-term taurine levels. Mean serum taurine was positively related to age and dietary intake of poultry, niacin, vitamin B1, fiber and iron, and negatively related to dietary intake of saturated fat. There was no statistically significant association between serum taurine levels and the risk of CHD in the overall study population. There was a significant inverse association between serum taurine and CHD risk among women with high total serum cholesterol (>250 mg/dL) but not among those with low total serum cholesterol. The data suggest a possible inverse association of serum taurine with diabetes and hypertension risk. Conclusions: The findings suggest that high levels of taurine may be protective against CHD among individuals with high serum cholesterol levels.

Effect of conjugated linoleic acid and omega-3 fatty acid supplementation on inflammatory and oxidative stress markers in atherosclerotic patients.

Source: http://www.ncbi.nlm.nih.gov/pubmed/24575132

Author: Hassan Eftekhari M, et al.

Affiliation: Associate Professor, Department of Nutrition, School of Health and Nutrition, Shiraz University of Medical Sciences, Shiraz, Iran

Abstract: Cardiovascular disease is the major cause of morbidity, mortality, and disability in Iranian people. Inflammation and oxidative processes are key components of cardiovascular disease. The aim of this study was to evaluate the effect of conjugated linoleic acids (CLA) and omega-3 fatty acid (ů-3 fatty acids) supplementation on inflammation markers and oxidative stress in atherosclerotic patients. This study was a two-month clinical, randomized trial. 90 volunteers who referred to Emam Reza Heart Clinic of Shiraz University of Medical Sciences (Shiraz, Iran) from February to March 2011 and had the inclusion criteria of this study were selected. Participants were classified into 3 groups receiving 3 g/d CLA, 1920 mg/d ů-3, or placebo for 2 months. C-reactive protein (CRP), interleukin-6 (IL-6), malondialdehyde (MDA), and glutathione peroxidase (GPx) were measured before and after supplementation. The hs-CRP level decreased significantly in both the omega-3 and CLA group. IL-6 reduced significantly in the ů-3 group, but the reduction of IL-6 levels in the CLA group was not significant. GPx increased in the CLA and omega-3 group. MDA level decreased significantly in both omega-3 and CLA groups. Comparison between the groups indicates a significant change in CRP levels in the ů-3 group relative to the control group. However, other indices did not cause any significant change in the ů-3 and CLA groups in comparison to the control group. Diet supplementation with CLA and ů-3 can have a beneficial effect on some indices of inflammatory and oxidative stress.