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Online Library: Stroke

The following pages provide an overview of the most recent research and clinical studies about the health benefits of micronutrients in fighting stroke. 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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Total Antioxidant Capacity of Diet and Risk of Stroke: A Population-Based Prospective Cohort of Women

Source: Stroke 2012 Feb; 43(2):335-40. Epub 2011 Dec 1

Author: Rautiainen S, Larsson S,Virtamo J, Wolk A

Affiliation: Division of Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; and the Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.

Abstract: Consumption of antioxidant-rich foods may reduce the risk of stroke by inhibition of oxidative stress and inflammation. Total antioxidant capacity (TAC) takes into account all antioxidants and the synergistic effects between them. The authors examined the association between dietary TAC and stroke incidence in cardiovascular disease (CVD)-free women and in women with CVD history at baseline. The study included women (31 035 CVD-free and 5680 with CVD history at baseline), aged 49 to 83 years, from the Swedish Mammography Cohort. Diet was assessed with a food frequency questionnaire. Dietary TAC was calculated using oxygen radical absorbance capacity values. Stroke cases were ascertained by linkage with the Swedish Hospital Discharge Registry. During follow-up (September 1997 to December 2009), the authors identified 1322 stroke cases (988 cerebral infarctions, 226 hemorrhagic strokes, and 108 unspecified strokes) among CVD-free women and 1007 stroke cases (796 cerebral infarctions, 100 hemorrhagic strokes, and 111 unspecified strokes) among women with a CVD history. The multivariable hazard ratio of total stroke comparing the highest with the lowest quintile of dietary TAC was 0.83 (95% CI, 0.70–0.99; P for trend=0.04) in CVD-free women. Among women with a CVD history, the hazard ratios for the highest versus lowest quartile of TAC were 0.90 (95% CI, 0.75–1.07; P for trend=0.30) for total stroke and 0.55 (95% CI, 0.32–0.95; P for trend=0.03) for hemorrhagic stroke. Conclusions: These findings suggest that dietary TAC is inversely associated with total stroke among CVD-free women and hemorrhagic stroke among women with CVD history.

Red meat consumption and risk of stroke in Swedish men

Source: The American journal of clinical nutrition 2011; 94(2):417-21.

Author: Larsson SC, Virtamo J, Wolk A.

Affiliation: Division of Nutritional Epidemiology, National Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.

Abstract: Red and processed meat consumption has been implicated in several diseases. However, data on meat consumption in relation to stroke incidence are sparse. The objective of this study was to examine the associations of red meat and processed meat consumption with stroke incidence in men. The authors prospectively followed 40,291 men aged 45-79 y who had no history of cardiovascular disease or cancer at baseline. Meat consumption was assessed with a self-administered questionnaire in 1997. During a mean follow-up of 10.1 y, 2409 incident cases of stroke (1849 cerebral infarctions, 350 hemorrhagic strokes, and 210 unspecified strokes) were identified from the Swedish Hospital Discharge Registry. Consumption of processed meat, but not of fresh red meat, was positively associated with risk of stroke. The multivariable relative risks (RRs) of total stroke for the highest compared with the lowest quintiles of consumption were 1.23 for processed meat and 1.07 for fresh red meat. Processed meat consumption was also positively associated with risk of cerebral infarction in a comparison of the highest with the lowest quintile. Conclusion: The findings from this prospective cohort of men indicate that processed meat consumption is positively associated with risk of stroke.

Dietary Flavonoids and Risk of Stroke in Women

Source: Stroke. 2012 Apr;43(4):946-51

Author: Cassidy A, Rimm EB, O'Reilly EJ et al

Affiliation: Department of Nutrition, Norwich Medical School, University of East Anglia, Norwich, UK; Departments of Nutrition and Epidemiology, Harvard School of Public Health, Boston, MA, US.

Abstract: To date, few studies have examined associations between the wide range of flavonoid subclasses and risk of ischemic, hemorrhagic, and total stroke. The authors conducted a prospective study among 69 622 women from the Nurses' Health Study. Total flavonoid and subclass intakes were calculated from semiquantitative food frequency questionnaires collected every 4 years using an updated and extended US Department of Agriculture flavonoid database. During 14 years of follow-up, 1803 incident strokes were confirmed. After adjusting for potential confounders, women in the highest compared with the lowest quintile of flavanone intake had a relative risk of ischemic stroke of 0.81. Citrus fruits/juices, the main dietary source of flavanones, tended to be associated with a reduced risk for ischemic stroke comparing extreme quintiles. Conclusions: Total flavonoid intake was not inversely associated with risk of stroke; however, increased intake of the flavanone subclass was associated with a reduction in the risk of ischemic stroke. Citrus fruit consumption may be associated with a reduction in stroke risk, and experimental data support these epidemiological associations that the flavanone content of citrus fruits may potentially be cardioprotective. Further prospective studies are needed to confirm these associations.


Intensive Nutritional Supplements Can Improve Outcomes in Stroke Rehabilitation

Source: Neurology 2008; 71(23): 1856-61

Author: Rabadi M.H., Coar P.L., Lukin M., Lesser M., Blass J.P.

Affiliation: VA Medical Center, 921 NE 13th Street, Oklahoma City, OK 73104, USA.

Abstract: This study tested whether intensive nutritional supplements given to undernourished patients from the time of their admission to a specialized stroke rehabilitation service would improve patient outcomes. This randomized, prospective, double-blind, single center study comparing intensive nutritional supplementation to routine nutritional supplementation in 116 undernourished patients admitted to a stroke service. The analysis included the 90% of patients who were not lost to follow-up due to acute or sub-acute hospitalization (n = 102; 51 in each group). The results show that patients receiving intensive nutritional supplementation improved more than those on standard nutritional supplements on measures of motor function (total FIM, FIM motor sub-score, 2-minute and 6-minute timed walk tests, all significant at p < 0.002). They did not, however, improve on measures of cognition (FIM cognition score). A higher proportion of patients who received the intensive nutritional supplementation went home compared to those on standard supplementation (p = 0.05). The study concludes that intensive nutritional supplementation, using readily available commercial preparations, improves motor recovery in previously undernourished patients receiving intensive in-patient rehabilitation after stroke.

Dietary Antioxidants as Potential Pharmacological Agents for Ischemic Stroke

Source: Current Medical Chemistry 2008; 15(12): 1236-48

Author: Cherubini A., Ruggiero C., Morand C., Lattanzio F., Dell'aquila G., Zuliani G., Di Iorio A., Andres-Lacueva C.

Affiliation: Department of Clinical and Experimental Medicine, Institute of Gerontology and Geriatrics, Policlinico Monteluce, Pad. E, Via Brunamonti, 51, 06100, Perugia, Italy.

Abstract: Acute ischemic stroke is a leading cause of death and severe disability in industrialized countries and also in many developing countries. This review examined the most relevant observational studies concerning the relationship between dietary antioxidants and ischemic stroke as well as clinical trials investigating the effects of single or multiple antioxidant supplementations in the prevention or treatment of acute ischemic stroke. Furthermore, this study reviewed the most promising antioxidant compounds, i.e. dehydroascorbic acid, alpha-tocotrienol, gamma-tocopherol, flavonoids, resveratrol and gingko biloba, tested in animal models of acute ischemic stroke. It also carefully evaluated the reasons for the discrepancy between experimental and clinical studies, and provided recommendations to improve the translation of the results obtained in animal models to patients with acute ischemic stroke.

Antioxidants and Free Radical Scavengers for the Treatment of Stroke, Traumatic Brain Injury and Aging

Source: Current Medical Chemistry 2008; 15(4): 404-14

Author: Slemmer J.E., Shacka J.J., Sweeney MI., Weber J.T.

Affiliation: Department of Biology, University of Prince Edward Island, Charlottetown, PE, Canada.

Abstract: The overproduction of reactive oxygen species (ROS) and reactive nitrogen species (RNS) is a common underlying mechanism of many neuropathologies, as they have been shown to damage various cellular components, including proteins, lipids and DNA. Free radicals, especially superoxide (O(2)*-), and non-radicals, such as hydrogen peroxide (H(2)O(2)), can be generated in quantities large enough to overwhelm endogenous protective enzyme systems, such as superoxide dismutase (SOD) and reduced glutathione (GSH). This study reviewed the mechanisms of ROS and RNS production, and their roles in ischemia, traumatic brain injury and aging. In particular, this study discusses several acute and chronic pharmacological therapies that have been extensively studied in order to reduce ROS/RNS loads in cells and the subsequent oxidative stress, so-called "free-radical scavengers." Although the overall aim has been to counteract the detrimental effects of ROS/RNS in these pathologies, success has been limited, especially in human clinical studies. This review highlights some of the recent successes and failures in animal and human studies by attempting to link a compound's chemical structure with its efficacy as a free radical scavenger. In particular, it demonstrates how antioxidants derived from natural products, as well as long-term dietary alterations, may prove to be effective scavengers of ROS and RNS.

Antioxidant Supplementation Enhances Antioxidant Capacity and Mitigates Oxidative Damage Following Acute Ischaemic Stroke

Source: European Journal of Clinical Nutrition 2005; 59(12): 1367-73

Author: Ullegaddi R., Powers H.J., Gariballa S.E.

Affiliation: Sheffield Institute for Studies on Ageing and Human Nutrition Unit, The University of Sheffield, Northern General Hospital, UK.

Abstract: The objective of this randomized controlled trial was to test whether supplementary antioxidants immediately following acute ischaemic stroke will enhance antioxidant capacity and mitigate oxidative damage. A total of 48 acute ischaemic stroke patients within 12 h of symptom onset were tested at a university teaching hospital. Daily oral 800 IU (727 mg) of alpha-tocopherol and 500 mg of vitamin C (n = 24), or no treatment (n = 24) for 14 days. Treatment group and controls were matched for stroke subtype and age. Alpha-tocopherol, ascorbic acid, total antioxidant capacity (TAOC), plasma malondialdehyde (MDA) and C-reactive protein (CRP) were measured before treatment, at day 7 and day 14 following recruitment. The study concludes that supplementation with antioxidant vitamins within 12 h of onset of acute ischaemic stroke increased antioxidant capacity, reduced lipid peroxidation products and may have an anti-inflammatory effect.

Antioxidant Strategies in the Treatment of Stroke

Source: Free Radical Biology & Medicine 2005; 39(4): 429-43

Author: Margaill I., Plotkine M., Lerouet D.

Affiliation: Faculte des Sciences Pharmaceutiques et Biologiques, Laboratoire de Pharmacologie (UPRES EA 2510), Universite Rene Descartes, 4 avenue de l'Observatoire, 75006 Paris, France.

Abstract: Excessive production of free radicals is known to lead to cell injury in a variety of diseases, such as cerebral ischemia. This review describes some of the numerous studies that have examined this oxidative stress and the efficiency of antioxidant strategies in focal cerebral ischemia. Besides using genetically modified mice, these strategies can be divided into three groups: (1) inhibition of free radical production, (2) scavenging of free radicals, and (3) increase of free radical degradation by using agents mimicking the enzymatic activity of endogenous antioxidants. Finally, the clinical trials that have tested or are currently testing the efficiency of antioxidants in patients suffering from stroke are reviewed. "The results presented here lead us to consider that antioxidants are very promising drugs for the treatment of ischemic stroke."

Dietary Antioxidants and the Risk of Ischemic Stroke: the Rotterdam Study

Source: Neurology 2003; 61(9): 1273-5

Author: Voko Z., Hollander M., Hofman A., Koudstaal P.J., Breteler M.M.

Affiliation: Department of Epidemiology & Biostatistics, Erasmus Medical Center Rotterdam, The Netherlands

Abstract: In the Rotterdam Study, the authors investigated whether high intake of antioxidants from food is associated with the risk of stroke. Among 5,197 participants who were followed on average for 6.4 years, 227 ischemic strokes occurred. Higher intake of antioxidants was associated with a lower risk of stroke. The relationship was dose-dependent, significant for vitamin C, and most pronounced in smokers. These results agree with the view that high dietary intake of antioxidants, in particular vitamin C and –in smokers–vitamin E, reduces the risk of stroke.

Antioxidant Capacity After Acute Ischaemic Stroke

Source: QJM 2002; 95(10): 685-90

Author: Gariballa S.E., Hutchin T.P., Sinclair A.J.

Affiliation: Sheffield Institute For Studies on Ageing, University of Sheffield, Northern General Hospital, Sheffield, UK.

Abstract: Experimental studies have reported a rapid increase in the production of markers of oxidative damage following acute stroke due to the reperfusion event following ischaemia, and that endogenous antioxidant defences are rapidly depleted, permitting further tissue damage. The aim of this observational cohort study was to measure changes in antioxidant capacity (individual and total) in stroke disease within a known time period post infarct. The study examined 31 acute ischaemic stroke patients; 26 hospitalized non-stroke patients and 23 community-based healthy controls. Non-fasting venous blood was obtained within 24 h, at 48-72 h and at 7 days after stroke onset (after hospitalization for non-stroke patients) and at baseline for community controls. Vitamins E and C, total plasma glutathione, total antioxidant capacity (TAC), uric acid, thiobarbituric-acid-reactive substances (TBARS), serum albumin, transferrin and C-reactive protein (CRP) were measured. The results show that serum vitamin C concentrations deteriorated significantly in stroke patients, and differences between the cumulative changes between strokes and hospital controls were also statistically significant (p=0.013). The study concludes that there was some evidence of reduction in TAC, despite increased uric acid concentrations, and deterioration in serum vitamin C levels in ischaemic stroke patients compared with controls.

Antioxidant Capacity After Acute Ischaemic Stroke

Source: QJM 2002; 95(10): 685-90

Author: Gariballa S.E., Hutchin T.P., Sinclair A.J.

Affiliation: Sheffield Institute For Studies on Ageing, University of Sheffield, Northern General Hospital, Sheffield, UK.

Abstract: Experimental studies have reported a rapid increase in the production of markers of oxidative damage following acute stroke due to the reperfusion event following ischaemia, and that endogenous antioxidant defences are rapidly depleted, permitting further tissue damage. The aim of this observational cohort study was to measure changes in antioxidant capacity (individual and total) in stroke disease within a known time period post infarct. The study examined 31 acute ischaemic stroke patients; 26 hospitalized non-stroke patients and 23 community-based healthy controls. Non-fasting venous blood was obtained within 24 h, at 48-72 h and at 7 days after stroke onset (after hospitalization for non-stroke patients) and at baseline for community controls. Vitamins E and C, total plasma glutathione, total antioxidant capacity (TAC), uric acid, thiobarbituric-acid-reactive substances (TBARS), serum albumin, transferrin and C-reactive protein (CRP) were measured. The results show that serum vitamin C concentrations deteriorated significantly in stroke patients, and differences between the cumulative changes between strokes and hospital controls were also statistically significant (p=0.013). The study concludes that there was some evidence of reduction in TAC, despite increased uric acid concentrations, and deterioration in serum vitamin C levels in ischaemic stroke patients compared with controls.

Low Plasma Antioxidant Activity is Associated with High Lesion Volume and Neurological Impairment in Stroke

Source: Stroke 2000; 31(1): 33-9

Author: Leinonen J.S., Ahonen J.P., Lonnrot K., Jehkonen M., Dastidar P., Molnar G., Alho H.

Affiliation: Department of Clinical Chemistry, Tampere University Hospital, Helsinki, Finland.

Abstract: Oxidative stress is probably involved in neuronal damage induced by ischemia-reperfusion. The purpose of this study was to assess the role of antioxidant activity in cerebral ischemic stroke. Antioxidant activity of blood plasma and cerebrospinal fluid was assessed in 22 patients with cerebral hemisphere infarction that was verified and quantified by MRI. The results show that low total peroxyl radical trapping potential of plasma, but not of cerebrospinal fluid, was associated with high lesion volume and high neurological impairment assessed by scores on NIH Stroke Scale, Barthel Index, and Hand Motor Score tests. The plasma concentrations of ascorbic acid, alpha-tocopherol, and protein thiols were also associated with the degree of neurological impairment. These data suggest that the antioxidant activity of plasma may be an important factor providing protection from neurological damage caused by stroke-associated oxidative stress.


Bioflavonoids Effectively Inhibit Smooth Muscle Cell-Mediated Contraction of Collagen Matrix Induced by Angiotensin II

Source: The Journal of Cardiovascular Pharmacology 2005; 46(5): 570-6

Author: V. Ivanov, M.W. Roomi, T. Kalinovsky, A. Niedzwiecki, M. Rath

Affiliation: Dr. Rath Research Institute, Santa Clara, CA, USA

Abstract: “Plant-derived bioflavonoids have been recognized to support arterial wall structural integrity and interfere with a variety of pro-atherosclerotic stimuli. In this study we tested the effects of bioflavonoids on the contractile activity of cultured human aortic smooth muscle cells (SMC) embedded in a three-dimensional type I collagen matrix. Results: Different classes of bioflavanoids showed variable efficiency in inhibiting angiotensin II (ATII)-dependent collagen gel contraction by SMCs. Catechin potencies in collagen inhibition were related to the number of gallate groups per catechin molecule and the potencies of phenolic-enriched plant-derived extracts were based on phenolic composition. Antioxidants (N-acetyl cysteine and ascorbic acid) did not inhibit collagen gel contraction. Bioflavonoid inhibition of collagen gel contraction by SMC correlated with inhibition of matrix metalloproteinase -2 expression. Conclusion: Bioflavonoids participate in the regulation of SMC-mediated contraction and have a strong potential in counteracting pathophysiological effects of ATII. Bioflavonoid activity depends on structural characteristics and can be related to extracellular matrix integrity.”

Cereal Grains

Cereal Grains and Legumes in the Prevention of Coronary Heart Disease and Stroke: a Review of the Literature

Source: European Journal of Clinical Nutrition 2006; 60(10): 1145-59

Author: Flight I., Clifton P.

Affiliation: CSIRO Human Nutrition, Adelaide, South Australia, Australia

Abstract: A number of reviewers have examined studies investigating the relationship between coronary heart disease and stroke prior to 2000. Since then, several key studies have been published. Five studies have examined the relationship between wholegrain consumption, coronary heart disease (CHD) and cardiovascular (CVD) disease and found protection for either or both diseases. The researchers concluded that a relationship between wholegrain intake and CHD is seen with at least a 20% and perhaps a 40% reduction in risk for those who eat wholegrain food habitually vs those who eat them rarely. Thus there are two messages: The intake of wholegrain foods clearly protects against heart disease and stroke but the exact mechanism is not clear. Fiber, magnesium, folate and vitamins B6 and vitamin E may be important. The intake of high GI carbohydrates (from both grain and non-grain sources) in large amounts is associated with an increased risk of heart disease in overweight and obese women even when fiber intake is high but this requires further confirmation in normal-weight women. The study’s recommendation: carbohydrate-rich foods should be wholegrain and if they are not, then the lowest GI product available should be consumed. Glycemic index is largely irrelevant for foods that contain small amounts of carbohydrate per serve (such as most vegetables).

Green Tea

Green and Black Tea Consumption and Risk of Stroke: a Meta-Analysis

Source: Stroke 2009; 40(5): 1786-92

Author: Arab L., Liu W., Elashoff D.

Affiliation: David Geffen School of Medicine, Los Angeles, CA 90095-1736, USA

Abstract: The objective of this study was to assess whether association of black or green tea consumption with reduced risk of stroke is evident in human populations. This study sought to identify and summarize all human clinical and observational data on tea and stroke and involved the search of PubMed and Web of Science for all studies on stroke and tea consumption in humans with original data, including estimation or measurement of tea consumption and outcomes of fatal or nonfatal stroke. Data from 9 studies involving 4378 strokes among 194 965 individuals were pooled. The main outcome was the occurrence of fatal or nonfatal stroke. This study tested for heterogeneity and calculated the summary effect estimate associated with consumption of >or=3 cups of tea (green or black) per day using random-effects and fixed-effects models for the homogeneous studies. Publication bias was also evaluated. The study concludes that although a randomized clinical trial would be necessary to confirm the effect, this meta-analysis suggests that daily consumption of either green or black tea equaling 3 cups per day could prevent the onset of ischemic stroke.

Tea Consumption and Ischemic Stroke Risk: a Case-Control Study in Southern China

Source: Stroke 2009; 40(7): 2480-5

Author: Liang W., Lee A.H., Binns C.W., Huang R., Hu D., Zhou Q.

Affiliation: School of Public Health, Curtin University of Technology, Perth, WA, Australia.

Abstract: This study aims to ascertain the relationship between tea drinking and ischemic stroke risk. A case-control study was conducted in southern China from 2007 to 2008. A total of 374 patients with incident ischemic stroke and 464 control subjects (mean age, 69 years) were recruited from 3 hospitals in Foshan. Information on frequency and duration of tea drinking, quantity of dried tea leaves, and types of tea consumed, together with habitual diet and lifestyle characteristics, was obtained from participants using a validated and reliable questionnaire. Logistic regression analyses were performed for tea consumption variables accounting for confounders that affect the ischemic stroke risk. The results show a significant decrease in ischemic stroke risk was observed for drinking at least one cup of tea weekly (P=0.015) when compared with infrequent or nondrinkers, the risk reduction being largest by drinking one to 2 cups of green or oolong tea daily. Significant inverse dose-response relationships were also found for years of drinking and the amount of dried tea leaves brewed. The adjusted ORs for the highest level of consumption in terms of frequency of intake, duration of drinking, and average tea leaves brewed were 0.61 (95% CI, 0.40 to 0.94), 0.40 (95% CI, 0.25 to 0.64), and 0.27 (95% CI, 0.16 to 0.46), respectively. The study concludes that long-term tea consumption is associated with reduced risk of ischemic stroke.

Consumption of Green and Roasted Teas and the Risk of Stroke Incidence: Results from the Tokamachi-Nakasato Cohort Study in Japan

Source: International Journal of Epidemiology 2008; 37(5): 1030-40

Author: Tanabe N., Suzuki H., Aizawa Y., Seki N.

Affiliation: Division of Health Promotion, Niigata University Graduate School of Medical and Dental Sciences, Japan.

Abstract: The purpose of the present study was to assess whether it is inversely associated with subsequent stroke incidence and whether this association is preserved even with roasted tea leaves. In 1998, 6358 Japanese adults (2087 men and 4271 women) aged 40-89 years without a history of stroke or heart disease completed a lifestyle questionnaire, including consumption of green tea or roasted tea. By the end of 2003, 110 stroke events (59 cerebral infarction events, 34 cerebral hemorrhage events, 15 subarachnoidal hemorrhage events and two stroke events of unspecified subtype) had been documented. Cox proportional hazards regression analysis was used to calculate the multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (95% CIs) for total stroke events, cerebral infarction events and cerebral hemorrhage events according to consumption categories of green tea and roasted tea. RESULTS: A considerably lower risk was observed for total stroke incidence in both the middle (multivariable HR, 0.43; 95% CI, 0.25-0.74; P = 0.002) and the high (multivariable HR, 0.41; 95% CI, 0.24-0.70; P = 0.001) categories of green tea consumption. This inverse association was consistent even when cerebral infarction and cerebral hemorrhage were analyzed separately. The consumption of roasted tea was not associated with stroke risk. The study concludes that green tea consumption is associated with a reduced risk of total stroke incidence, cerebral infarction and cerebral hemorrhage.

Green Tea and Stroke Prevention: Emerging Evidence

Source: Complementary Therapies in Medicine 2007; 15(1):46-53

Author: Fraser M.L., Mok G.S., Lee A.H.

Affiliation: School of Public Health, Curtin University of Technology, GPO Box U 1987, Perth, WA 6845, Australia.

Abstract: The objective of this study was to review the emerging evidence for green tea in stroke prevention. Published articles were located by searching the PubMed, ProQuest, CINAHL and other databases, using the keywords 'tea' and 'stroke' with no restriction on publication date. Reference lists of identified articles were also searched for relevant publications. Two published epidemiological studies on green tea reported positive findings. A large number of studies have also proposed biological mechanisms by which tea or tea components may reduce the stroke risk. Additional studies are required from a variety of populations, assessing duration and different types of tea consumption on subtypes of stroke to provide further evidence. This study concludes that green tea is a safe and cheap beverage. Its consumption should be encouraged because it could potentially serve as a practical method for stroke prevention.

Preventive Effects of Green Tea Catechins on Spontaneous Stroke in Rats

Source: Medical Science Monitor 2007; 13(2): BR40-5

Author: Ikeda M., Suzuki C., Umegaki K., Saito K., Tabuchi M., Tomita T.

Affiliation: College of Environment and Disaster Research, Fuji Tokoha University, Ohbuchi, Fuji, Shizuoka, Japan.

Abstract: This study has examined whether tea catechin intake decreases the incidence of spontaneous stroke in M-SHRSP. Male M-SHRSP ingested 0.5% green tea catechin extract (Polyphenon E) in their drinking water beginning at 5 weeks of age, and blood pressure, heart rate, and locomotor activity were continuously monitored from 8 weeks using a telemetry system. Stroke onset was assessed by the appearance of neurologic symptoms, body weight loss, and circadian rhythm disturbances in heart rate, blood pressure, and locomotor activity. The results show that tea catechin ingestion significantly delayed stroke onset by 10 days compared to the control group. Plasma EGCG concentration significantly decreased at post-stroke compared with that of pre-stroke. The study concludes that continuous ingestion of green tea catechins from an early age prevented the development of spontaneous stroke in M-SHRSP, probably by inhibiting the further development of high blood pressure at later ages.

Protective Effects of Green Tea Catechins on Cerebral Ischemic Damage

Source: Medical Science Monitor 2004; 10(6): BR166-74

Author: Suzuki M., Tabuchi M., Ikeda M., Umegaki K, Tomita T.

Affiliation: University of Shizuoka, Graduate School of Health Sciences, 52-1 Yada, Shizuoka 422-8526, Japan.

Abstract: The purpose of this study is to examine preventive and protective effects of green tea catechins on various deteriorative processes following stroke. Male Wistar rats were given ad libitum water with or without 0.25 and 0.5% tea catechin extract for 5 days prior to the operation and during the experiment. Right middle cerebral artery was occluded for 2 h, then reperfused for 22 h. Brain slices were stained with triphenyltetrazolim chloride to assess infarct area. Concentrations of plasma EGCg, and serum NOx were analyzed by HPLC. Detection of iNOS expression, neutrophil infiltration and peroxynitrite formation in the penumbra was performed by immunostain. Neurologic deficit was scored by posture reflex.Based on the results the study concludes that daily intake of green tea catechins efficiently protects the penumbra from irreversible damage due to cerebral ischemia, and consequent neurologic deficits.

Black and Green Tea Polyphenols Attenuate Blood Pressure Increases in Stroke-Prone Spontaneously Hypertensive Rats

Source: The Journal of Nutrition 2004; 134(1): 38-42

Author: Negishi H., Xu J.W., Ikeda K., Njelekela M., Nara Y., Yamori Y.

Affiliation: College of Human Life and Environment, Kinjo Gakuin University, Nagoya 463-8521, Japan.

Abstract: Two studies were conducted to determine whether black and green tea can lower blood pressure (BP) in stroke-prone spontaneously hypertensive rats (SHRSP). Male SHRSP (n=15) were allowed to recover for 2 wk after a transmitter for measuring BP was implanted in the peritoneal cavity. The rats were divided into three groups: the control group consumed tap water (30 mL/d); the black tea polyphenol group (BTP) consumed water containing 3.5 g/L thearubigins, 0.6 g/L theaflavins, 0.5 g/L flavonols and 0.4 g/L catechins; and the green tea polyphenol group (GTP) consumed water containing 3.5 g/L catechins, 0.5 g/L flavonols and 1 g/L polymetric flavonoids. The telemetry system was used to measure BP, which were recorded continuously every 5 min for 24 h. The data demonstrate that both black and green tea polyphenols attenuate blood pressure increases through their antioxidant properties in SHRSP. Furthermore, because the amounts of polyphenols used in this experiment correspond to those in approximately 1 L of tea, the regular consumption of black and green tea may also provide some protection against hypertension in humans.

Lipoprotein (a)

Lipoprotein(a) Concentration and the Risk of Coronary Heart Disease, Stroke, and Nonvascular Mortality

Source: The Journal of the American Medical Association 2009; 302(4): 412-23

Author: Emerging Risk Factors Collaboration, Erqou S., Kaptoge S., Perry P.L., Di Angelantonio E., Thompson A., White I.R., Marcovina S.M., Collins R., Thompson S.G., Danesh J.


Abstract: The objective of this study was to assess the relationship of Lp(a) concentration with risk of major vascular and nonvascular outcomes. Long-term prospective studies that recorded Lp(a) concentration and subsequent major vascular morbidity and/or cause-specific mortality published between January 1970 and March 2009 were identified through electronic searches of MEDLINE and other databases, manual searches of reference lists, and discussion with collaborators. Individual records were provided for each of 126,634 participants in 36 prospective studies. During 1.3 million person-years of follow-up, 22,076 first-ever fatal or nonfatal vascular disease outcomes or nonvascular deaths were recorded, including 9336 CHD outcomes, 1903 ischemic strokes, 338 hemorrhagic strokes, 751 unclassified strokes, 1091 other vascular deaths, 8114 nonvascular deaths, and 242 deaths of unknown cause. Within-study regression analyses were adjusted for within-person variation and combined using meta-analysis. Analyses excluded participants with known preexisting CHD or stroke at baseline. Lipoprotein(a) concentration was weakly correlated with several conventional vascular risk factors and it was highly consistent within individuals over several years. Associations of Lp(a) with CHD risk were broadly continuous in shape. The study concludes that under a wide range of circumstances, there are continuous, independent, and modest associations of Lp(a) concentration with risk of CHD and stroke that appear exclusive to vascular outcomes.

Major Lipids, Apolipoproteins, and Risk of Vascular Disease

Source: The Journal of the American Medical Association 2009; 302(18): 1993-2000

Author: Emerging Risk Factors Collaboration, Di Angelantonio E., Sarwar N., Perry P., Kaptoge S., Ray K.K., Thompson A., Wood A.M., Lewington S., Sattar N, Packard C.J., Collins R., Thompson SG., Danesh J.


Abstract: The objective of this study was to assess major lipids and apolipoproteins in vascular risk. Individual records were supplied on 302,430 people without initial vascular disease from 68 long-term prospective studies, mostly in Europe and North America. During 2.79 million person-years of follow-up, there were 8857 nonfatal myocardial infarctions, 3928 coronary heart disease [CHD] deaths, 2534 ischemic strokes, 513 hemorrhagic strokes, and 2536 unclassified strokes. Hazard ratios (HRs), adjusted for several conventional factors, were calculated for 1-SD higher values: 0.52 log(e) triglyceride, 15 mg/dL high-density lipoprotein cholesterol (HDL-C), 43 mg/dL non-HDL-C, 29 mg/dL apolipoprotein AI, 29 mg/dL apolipoprotein B, and 33 mg/dL directly measured low-density lipoprotein cholesterol (LDL-C). Within-study regression analyses were adjusted for within-person variation and combined using meta-analysis. The study concludes that lipid assessment in vascular disease can be simplified by measurement of either total and HDL cholesterol levels or apolipoproteins without the need to fast and without regard to triglyceride.

Lipoprotein(a) Levels and Risk of Future Coronary Heart Disease: Large-Scale Prospective Data

Source: Archives of Internal Medicine 2008; 168(6): 598-608

Author: Bennet A., Di Angelantonio E., Erqou S., Eiriksdottir G., Sigurdsson G., Woodward M., Rumley A., Lowe G.D., Danesh J., Gudnason V.

Affiliation: Department of Public Health and Primary Care, University of Cambridge, Cambridge, England.

Abstract: Large-scale prospective data are needed to determine whether associations between lipoprotein(a) (Lp[a]) and coronary heart disease (CHD) risk are independent of established risk factors, to characterize the shape of this relationship, and to quantify associations in relevant subgroups. In this study levels of Lp(a) were measured in samples obtained at baseline from 2047 patients who had first-ever nonfatal myocardial infarction or who died of CHD during the study and from 3921 control participants in the Reykjavik Study (n=18 569), as well as in paired samples obtained 12 years apart from 372 participants to quantify within-person fluctuations. The study concludes that there are independent, continuous associations between Lp(a) levels and risk of future CHD in a broad range of individuals. Levels of Lp(a) are highly stable within individuals across many years and are only weakly correlated with known risk factors. Further assessment of their possible role in CHD prevention is warranted.

Lipoprotein(a): a Unique Risk Factor for Cardiovascular Disease

Source: Clinics in Laboratory Medicine 2006; 26(4): pp.751-72

Author: Anuurad E., Boffa M.B., Koschinsky M.L., Berglund L.

Affiliation: Department of Medicine, VA Northern California Health Care System, UCD Medical Center, University of California-Davis, 4150 V Street, Suite G400, Sacramento, CA 95817, USA.

Abstract: Lipoprotein(a) (Lp(a)) is present in humans and primates. It has many properties in common with low-density lipoprotein, but contains a unique protein moiety designated apo(a), which is linked to apolipoprotein B-100 by a single disulfide bond. International standards for Lp(a) measurement and optimized Lp(a) assays insensitive to isoform size are not yet widely available. Lp(a) is a risk factor for coronary artery disease, and smaller size apo(a) is associated with coronary artery disease. The physiologic role of Lp(a) is unknown.

Lipoprotein(a) and Atherosclerosis: New Perspectives on the Mechanism of Action of an Enigmatic Lipoprotein

Source: Current Atherosclerosis Reports 2005; 7(5): 389-95

Author: Koschinsky M.L.

Affiliation: Department of Biochemistry, Queen's University, A208 Botterell Hall, Kingston, ON K7L 3N6, Canada.

Abstract: Although elevated plasma concentrations of lipoprotein(a) (Lp(a)) have been identified as a risk factor for coronary heart disease, the pathophysiologic and physiologic roles of Lp(a) continue to elude basic researchers and clinicians alike. Lp(a) is a challenging lipoprotein to study because it has a complex structure consisting of a low-density lipoprotein-like moiety to which is covalently attached the unique glycoprotein apolipoprotein(a) (apo(a)). Apo(a) contains multiply repeated kringle domains that are similar to a sequence found in the fibrinolytic proenzyme plasminogen; differing numbers of kringle sequences in apo(a) give rise to Lp(a) isoform size heterogeneity. In addition to elevated plasma concentrations of Lp(a), apo(a) isoform size has been identified as a risk factor for coronary heart disease, although studies addressing this relationship have been limited. The similarity of Lp(a) to low-density lipoprotein and plasminogen provides an enticing link between the processes of atherosclerosis and thrombosis, although a clear demonstration of this association in vivo has not been provided. Clearly, Lp(a) is a risk factor for both atherothrombotic and purely thrombotic events; a plethora of mechanisms to explain these clinical findings has been provided by both in vitro studies as well as animal models for Lp(a).

Lipoprotein(a) as a Risk Factor for Atherosclerosis and Thrombosis: Mechanistic Insights from Animal Models

Source: Clinical Biochemistry 2004; 37(5): 333-43

Author: Boffa M.B., Marcovina S.M., Koschinsky M.L.

Affiliation: Department of Biochemistry, Queen's University, Kingston, Ontario, Canada

Abstract: Evidence continues to accumulate from epidemiological studies that elevated plasma concentrations of lipoprotein(a) [Lp(a)] are a risk factor for a variety of atherosclerotic and thrombotic disorders. Lp(a) is a unique lipoprotein particle consisting of a moiety identical to low-density lipoprotein to which the glycoprotein apolipoprotein(a) [apo(a)] that is homologous to plasminogen is covalently attached. These features have suggested that Lp(a) may contribute to both proatherogenic and prothrombotic/antifibrinolytic processes and in vitro studies have identified many such candidate mechanisms. Establishment of animal models for Lp(a) has been hampered by the absence of this lipoprotein from common small laboratory animals. Transgenic mice and rabbits expressing human apo(a) have been developed and these have been used to: (i) examine regulation of apo(a) gene expression; (ii) study the mechanism and molecular determinants of Lp(a) assembly from LDL and apo(a); (iii) demonstrate that apo(a)/Lp(a) are indeed proatherogenic and antifibrinolytic; and (iv) identify structural domains in apo(a) that mediate its pathogenic effects. The recent construction of transgenic apo(a) rabbits is a particularly promising development in view of the excellent utility of the rabbit as a model of advanced atherosclerosis.


Myocardial Lysyl Oxidase Regulation of Cardiac Remodeling in a Murine Model of Diet-Induced Metabolic Syndrome

Source: American Journal of Physiology - Heart and circulatory physiology 2009; 297(3): H976-82

Author: Zibadi S., Vazquez R., Moore D., Larson D.F., Watson R.R.

Affiliation: Sarver Heart Center, College of Medicine, Mel and Enid Zuckerman Arizona College of Public Health, The University of Arizona, Tucson, Arizona 85724, USA.

Abstract: Metabolic syndrome (MetS) represents an increased risk of cardiovascular disease. Although its individual components adversely affect cardiac structure and function, the extent to which multiple components of MetS affect the cardiac extracellular matrix (ECM) has not been well characterized. Lysyl oxidase (LOX) is one of the cardiac ECM-modifying enzymes that catalyze the formation of collagen cross-linking. The objective of this study was to define the effect of diet-induced MetS on the LOX enzyme. MetS was induced in male C57BL/6 mice by administrating a high-fat, high-simple carbohydrate diet for 6 mo. Gene expression was determined by real-time PCR. The cardiac protein expression and enzymatic activity of LOX were measured. The severity of fibrosis was assessed by histology and hydroxylproline assay. Cardiac diastolic function was assessed by in vivo analysis of the pressure-volume relationship. The data signify that diet-induced MetS alters the remodeling enzymes, mainly LOX, thereby altering ECM structure by increasing the amount of cross-linking and inducing diastolic dysfunction.

Economic Assessment of the Secondary Prevention of Ischaemic Events with Lysine Acetylsalicylate

Source: PharmacoEconomics 2000; 18(2): 185-200

Author: Marissal J.P., Selke B., Lebrun T.

Affiliation: Department of Health Economics, Catholic University of Lille, France

Abstract: The objective of this study was to analyze the economic benefits, in comparison with placebo, of the secondary prevention of ischaemic stroke and myocardial infarction (MI) with lysine acetylsalicylate (Kardegic) in patients with a history of ischaemic stroke, MI or stable and unstable angina pectoris. This was a modeling study from the perspectives of direct medical costs, the social security system and society in France. METHODS: Efficacy data for the secondary prevention of ischaemic events were derived from the Antiplatelet Trialists' Collaboration meta-analysis on antithrombotics. The rates and costs of ischaemic disease and of serious gastrointestinal adverse affects arising from long term aspirin treatment, as well as the costs of treatment with lysine acetylsalicylate, were taken from published sources, using French data where possible. The results indicate that from the social security perspective, the estimated cost-effectiveness ratios show that the prevention of MI in patients with a history of unstable angina (with a 1-year follow-up) is a cost-saving strategy, with net benefits ranging from $US5703 (1996 prices) per avoided MI for lysine acetylsalicylate 300 mg/day to $US5761 per avoided MI for lysine acetylsalicylate 75 mg/day. Finally, a 4-year follow-up in patients with a history of stable angina pectoris shows that prophylactic treatment with lysine acetylsalicylate is associated with net costs per avoided MI, ranging from $US4375 to $US3608 per avoided event. Sensitivity analysis confirmed that prophylaxis with lysine acetylsalicylate in patients at high risk of cardiovascular and cerebrovascular events results in savings in social security expenditure. The results underline the high economic benefit of using lysine acetylsalicylate to prevent secondary ischaemic stroke and MI in patients at high risk of cardiovascular and/or cerebrovascular events, leading to savings for the social security system and society.

Neuroprotective Effect of L-lysine Monohydrochloride on Acute Iterative Anoxia in Rats with Quantitative Analysis of Electrocorticogram

Source: Life Sciences 1999; 65(2): PL19-25

Author: Hong-Ping G., Bao-Shan K.U.

Affiliation: Department of Pharmacology, Beijing Medical University, PR China.

Abstract: Lysine is one of the essential amino acids and L-lysine monohydrochloride (LMH) is widely available to public as a nonprescription oral supplement. Potential clinical usefulness of oral LMH supplements has been indicated in stroke, hypertension, and seizure induced by pentylenetetrazole (PTZ), etc. This study compared the effects of LMH and flunarizine on the Electrocorticogram (EcoG) of rats intragastrically administered 1 hour before anoxia. LMH dose-dependently prolonged the time reaching the lowest ECoG average amplitude after anoxia and decreased the recovery time after recirculation in both 0.63 g/kg and 1.26 g/kg groups. There was significant difference between the LMH- and saline-pretreated groups but no significant difference between the 1.26 g/kg LMH- and 2.5 mg/kg flunarizine-pretreated groups. The results tend to indicate that LMH can protect brain cells against anoxia by means of providing energy, reducing cerebral metabolic rate and inhibiting the effect of the excitable amino acids.

Nutrient Synergy

Plant-Derived Micronutrients Suppress Monocyte Adhesion to Cultured Human Aortic Endothelial Cell Layer by Modulating Its Extracellular Matrix Composition

Source: Journal of Cardiovascular Pharmacology 2008; 52(1): 55-65

Author: V. Ivanov, S. Ivanova, T. Kalinovsky, A. Niedzwiecki, M. Rath

Affiliation: Dr. Rath Research Institute, Santa Clara, CA

Abstract: This study investigated the effects of micronutrients on monocyte-binding properties of extracellular matrix (ECM) produced by human aortic endothelial cells (AoEC). Confluent cultures of AoEC were exposed to ascorbic acid, quercetin, gotu kola extract (10% asiatic acid), green tea extract (40% epigallocatechin gallate) or a mixture of these micronutrients for 48h. AoEC-produced ECM was exposed by differential treatment. U937 monocyte adhesion was assayed by fluorescence. ECM composition was assayed immunochemically and with radiolabeled metabolic precursors. AoEC exposure to micronutrients reduced ECM capacity to bind monocytes in a dose-dependent manner. This effect was accompanied by profound changes in the ECM composition. Correlation analysis revealed that changes in monocyte adhesion to ECM had the strongest positive correlation with ECM content for laminin (CC=0.9681, p <0.01), followed by fibronectin, collagens type III, I and IV, biglycan, heparan sulfate and elastin. The strongest negative correlation was with chondroitin sulfate (CC=-0.9623, p<0.01), followed by perlecan and versican. Individual micronutrients had diverse effects on ECM composition and binding properties while their mixture was the most effective treatment. In conclusion, micronutrient-dependent reduction of monocyte adhesion to endothelium is partly mediated through specific modulation of ECM composition and properties.

Anti-Atherogenic Effects of a Mixture of Ascorbic Acid, Lysine, Proline, Arginine, Cysteine and Green Tea Phenolics in Human Aortic Smooth Muscle Cells

Source: Journal of Cardiovascular Pharmacology 2007; 49(3): 140-5

Author: Ivanov V., Roomi M.W., Kalinovsky T., Niedzwiecki A, Rath M.

Affiliation: Dr. Rath Research Institute, Santa Clara, CA

Abstract: This study investigated the anti-atherogenic effects of a group of naturally occurring compounds (ascorbic acid, green tea extract, lysine, proline, arginine, and N-acetyl cysteine) using the model of cultured aortic smooth muscle cell. Cell growth was measured by DNA synthesis, cell invasiveness through matrix metalloproteinase-2 (MMP-2) expression by zymography, and SMC secretion of monocyte chemoattractant protein-1 (MCP-1) and interleukin-6 (IL-6) by immunochemistry. FBS-stimulated SMC growth was inhibited by the tested nutrient mixture (NM) with 85% inhibition at 100 g/ml. A corresponding concentration of EGCG (15 M), the most active tea phenolic, produced a significant, but lower effect than NM-inhibited aortic SMC Matrigel invasion in a dose-dependent manner and significantly decreased MMP-2 expression. Stimulation of SMC with TNF significantly increased autocrine production and secretion of such mediators of inflammation as IL-6 and MCP-1; addition of 100 g/ml NM inhibited secretion of MCP-1 and IL-6 by 65% and 47% respectively. From these data, the study concludes that the nutrient mixture of ascorbic acid, tea phenolics, and selected amino acids, has a potential in blocking the development of atherosclerotic lesions by inhibiting atherogenic responses of vascular SMC to pathological stimuli and warrants in vivo studies.

Extracellular Matrix-Mediated Control of Aortic Smooth Muscle Cell Growth and Migration by a Combination of Ascorbic Acid, Lysine, Proline and Catechins

Source: Journal of Cardiovascular Pharmacology 2007, 50(5): 541-547

Author: V. Ivanov, S. Ivanova, M.W. Roomi, T. Kalinovsky, A. Niedzwiecki, M. Rath

Affiliation: Dr. Rath Research Institute, Santa Clara, CA

Abstract: Extracellular matrix function and structure are severely compromised at atherosclerotic lesion sites, contributing to initiation and progression of the disease. We investigated whether ECM biological properties would be beneficially affected by exposure to nutrients essential for collagen synthesis and post-translational modification. Confluent layers of human aortic smooth muscle cells (SMC) grown on collagen substrate were cultured in the presence of the tested compounds for seven to ten days. Pre-treated cells were removed from the ECM surface by differential treatment and replaced with secondary innocent SMC cultures. Secondary SMC growth rate and invasiveness were assayed in standard growth medium. ECM protein composition was assayed immunochemically. ECM produced in the presence of ascorbic acid reduced SMC proliferation in a dose-dependent manner. Plant-derived phenolic extracts expressed different degrees of SMC growth inhibition when present during ECM production. A combination of selected nutrients had a greater effect than did individual components. The ECM deposited by SMC in the presence of ascorbate, lysine, proline and green tea catechins inhibited SMC migration rate up to 70%. The ECM produced under conditions of chronic essential nutrient deficiency can support pro-atherosclerotic SMC behavior. A combination of selected nutrients can counteract these adverse effects stronger than individual components.

A Nutrient Mixture Containing Ascorbic Acid, Lysine, Proline, Arginine, Cysteine, and Green Tea Extract Suppresses Autocrine Inflammatory Response in Cultured Human Aortic Smooth Muscle Cells

Source: Research Communications in Molecular Pathology and Pharmacology 2004; 9: 3–16

Author: V. Ivanov, S. Ivanova, M.W. Roomi, T. Kalinovsky, A. Niedzwiecki, M. Rath

Affiliation: Matthias Rath Research, 1260 Memorex Drive, Santa Clara, California, 95050 USA

Abstract: “Recognition of the involvement of inflammatory processes in atherosclerotic lesion initiation and development of pathological consequences initiated a search for an effective inhibitor. Naturally occurring compounds demonstrate a wider spectrum of biological activity and fewer side effects than synthetic drugs. Mixtures of natural compounds often produce synergistically enhanced therapeutic action. This prompted us to investigate whether a unique nutrient mixture (NS), containing ascorbic acid, lysine, proline, arginine, N-acetyl cysteine and tea phenolics, could reduce an autocrine response of human aortic smooth muscle cell (SMC) to inflammatory stimuli. Cultured SMC were challenged with tumor necrosis factor-alpha (TNF_) or lipopolysaccharide (LPS) in the presence or absence of NS. Expression of leading mediators of inflammatory reaction was assayed with ELISA (R&D Systems). The results of this study are important since multiple clinical studies support the significance of these inflammatory mediators in the pathogenesis of coronary atherosclerosis and unstable cardiac syndromes. This study makes an association between the presence and degree of inflammation and the presence of atherosclerosis. It further makes an association between the degree of inflammation and the instability of that atherosclerosis by noting an increase in inflammatory cytokines in the unstable angina group compared with the stable atherosclerosis group [Yamashita, Shimada et al. (2003)]. From these data, we conclude that the nutrient mixture of ascorbic acid, tea phenolics, and selected amino acids, has a strong inhibitory potential against vascular cell inflammatory responses to pathogenic stimuli. In view of these results and the experimental and clinical studies demonstrating the important role played by inflammatory mediators in the development of atherosclerosis and coronary complications, nutrient synergy is a promising therapeutic agent for atherosclerosis and its associated complications.”


Prolyl 4-Hydroxylases, Key Enzymes in the Synthesis of Collagens and Regulation of the Response to Hypoxia, and their Roles as Treatment Targets

Source: Annals of Medicine 2008; 40(6): pp.402-17

Author: Myllyharju J.

Affiliation: Oulu Centre for Cell-Matrix Research, Biocenter Oulu, Finland.

Abstract: Prolyl 4-hydroxylases (P4Hs) have central roles in the synthesis of collagens and the regulation of oxygen homeostasis. The 4-hydroxyproline residues generated by the endoplasmic reticulum (ER) luminal collagen P4Hs (C-P4Hs) are essential for the stability of the collagen triple helix. Vertebrate C-P4Hs are alpha2beta2 tetramers with three isoenzymes differing in their catalytic alpha subunits. Another P4H family, the HIF-P4Hs, hydroxylates specific prolines in the alpha subunit of the hypoxia-inducible transcription factor (HIF), a master regulator of hypoxia-inducible genes, and controls its stability in an oxygen-dependent manner. The HIF-P4Hs are cytoplasmic and nuclear enzymes, likewise with three isoenzymes in vertebrates. A third vertebrate P4H type is an ER transmembrane protein that can act on HIF-alpha but not on collagens. All P4Hs require Fe2+, 2-oxoglutarate, O2, and ascorbate. C-P4Hs are regarded as attractive targets for pharmacological inhibition to control excessive collagen accumulation in fibrotic diseases and severe scarring, while HIF-P4H inhibitors are believed to have beneficial effects in the treatment of diseases such as myocardial infarction, stroke, peripheral vascular disease, diabetes, and severe anemias. Studies with P4H inhibitors in various animal models of fibrosis, anemia, and ischemia and ongoing clinical trials with HIF-P4H inhibitors support this hypothesis by demonstrating efficacy in many applications.

Vitamin B Group

Riboflavin Status in Acute Ischaemic Stroke

Source: European Journal of Clinical Nutrition 2007; 61(10): 1237-40

Author: Gariballa S., Ullegaddi R.

Affiliation: Sheffield Institute for Studies on Ageing, Community Sciences Centre, The University of Sheffield, Sheffield, UK.

Abstract: There is experimental evidence that riboflavin (vitamin B2) supplementation reduces oxidative damage and cerebral oedema following acute stroke. The objective of this study was to measure riboflavin levels in acute stroke before and after supplementation with this vitamin. Ninety-six acute ischaemic stroke patients had their riboflavin status measured at baseline and then randomly assigned to receive 5 mg of oral riboflavin and other B-group vitamins within 12 h of the stroke onset and then daily or no B-vitamins for 14 days. Non-fasting venous blood was obtained at baseline, and at 7 and 14 days post-randomization for measurement of riboflavin status using erythrocyte glutathione reductase activity coefficient (EGRAC). EGRAC is a measure of riboflavin tissue saturation. This assay has the advantage of being extremely stable and sensitive. EGRAC values are inversely proportional to riboflavin status, so that values greater than 1.3 indicate biochemical deficiency. The results indicate that 51% of patients studied were riboflavin deficient at baseline. Fourteen days of riboflavin supplementation significantly improved the measure of vitamin B2 status compared with the control group. Seven out of 37 patients in the supplement group (19%) were riboflavin deficient compared with 22 out of 39 patients (56%) in the control group at the end of the treatment period (P=0.035 for the differences in cumulative changes between groups over 2 weeks). The study concludes that a high proportion of acute stroke patients were deficient in riboflavin immediately post-infarct. Supplementation with 5 mg of riboflavin for 2 weeks significantly improved riboflavin status; however, the clinical significance of these findings is not yet known.

Antioxidant Supplementation With or Without B-Group Vitamins after Acute Ischemic Stroke: a Randomized Controlled Trial

Source: JPEN - Journal of Parenteral and Enteral Nutrition 2006; 30(2): 108-14

Author: Ullegaddi R., Powers H.J., Gariballa S.E.

Affiliation: Sheffield Institute for Nutritional Studies on Ageing and the Human Nutrition Unit, University of Sheffield, Northern General Hospital, Sheffield S5 7AU, UK.

Abstract: Evidence shows that there is a rapid increase in the production of markers of oxidative damage immediately after acute ischemic stroke and that endogenous antioxidant defenses are rapidly depleted, thus permitting further tissue damage. Several studies point to an antioxidant effect of B-group vitamins and a pro-oxidant effect of elevated total plasma homocysteine (tHcy). METHODS: To test whether supplementary antioxidants with or without B-group vitamins during this critical period enhance antioxidant capacity or mitigate oxidative damage, ninety-six acute ischemic stroke patients within 12 hours of symptom onset were randomly assigned to receive either daily oral 800 IU (727 mg) vitamin E and 500 mg vitamin C (n = 24), or B-group vitamins (5 mg folic acid, 5 mg vitamin B(2), 50 mg vitamin B(6), and 0.4 mg of vitamin B(12); n = 24), both vitamins together (n = 24), or no supplementation (n = 24) for 14 days. Treatment groups and controls were matched for stroke subtype and age. Blood was obtained before treatment, at day 7, and day 14 for measurements of plasma or blood vitamin status, plasma total antioxidant capacity (TAOC), malondialdehyde (MDA), tHcy and C-reactive protein (CRP). The results indicate that antioxidants supplementation with or without B-group vitamins enhance antioxidant capacity, mitigates oxidative damage, and may have an anti-inflammatory effect immediately postinfarct in stroke disease.

B-Group Vitamin Supplementation Mitigates Oxidative Damage After Acute Ischaemic Stroke

Source: Clinical Science (London) 2004; 107(5): 477-84

Author: Ullegaddi R., Powers H.J., Gariballa S.E.

Affiliation: Sheffield Institute for Nutritional Studies on Ageing, The University of Sheffield, Northern General Hospital, Sheffield S5 7AU, UK.

Abstract: Evidence shows that there is a rapid increase in the production of markers of oxidative damage immediately following acute stroke and that endogenous antioxidant defenses are rapidly depleted, thus permitting further tissue damage. Several studies point to an antioxidant effect of B-group vitamins and a pro-oxidant effect of elevated plasma tHcy (total homocysteine). The present study assessed whether supplementary B-group vitamins during this critical period would enhance antioxidant capacity and mitigate oxidative damage. Forty-eight patients with acute ischaemic stroke within 12 h of symptom onset were assigned to receive daily oral supplements of B-group vitamins comprising 5 mg of folate, 5 mg of vitamin B2, 50 mg of vitamin B6 and 0.4 mg of vitamin B12 (n=24) or no supplements (n=24) for 14 days. The treatment group and controls were matched for stroke subtype and age. Supplementation for 14 days with B-group vitamins significantly increased the plasma concentrations of pyridoxal phosphate and red blood cell folate and improved a measure of B2 status compared with the control group (P<0.05). Plasma tHcy decreased in both groups albeit less in the control group, but differences in cumulative changes were not significant. In conclusion, B-group vitamin supplementation immediately post-infarct may have antioxidant and anti-inflammatory effects in stroke disease independent of a homocysteine-lowering effect.

Vitamin C

Prevention of Symptomatic Vasospasm by Continuous Cisternal Irrigation with Mock-CSF Containing Ascorbic Acid and Mg(2+)

Source: Acta Neurochirurgica - Supplement 2010; 107: 115-8

Author: Satoh A., Sugiyama T., Ooigawa H., Nakajima H., Ogura T., Neki H., Morikawa E.

Affiliation: Department of Neurosurgery, Stroke Center, International Medical Center, Saitama Medical University, 1397-1, Yamane, Hidaka City, Saitama, 350-1298, Japan.

Abstract: Symptomatic vasospasm (SVS) is still a major cause of poor outcome in cases undergoing early surgical intervention for ruptured intracranial aneurysm. Among the numbers of therapeutic trials to prevent and ameliorate neurological deterioration due to SVS, removal or quenching of oxy-hemoglobin (OxyHb) from subarachnoid colts and administration of Mg(2+) (Mg) have especially been expected to be effective. In this report the authors investigated the effect of continuous cisternal irrigation (CCI) with mock CSF containing ascorbic acid (ASA) and Mg, performed after early surgery for ruptured aneurysm. Sixty-three cases which had received CCI were retrospectively compared with 40 control cases as to the incidence of SVS and outcome. The study concludes that postoperative CCI with ASA and Mg was definitively effective in preventing SVS and in lessening severity of SVS if it occurs.

Vitamin C Function in the Brain: Vital Role of the Ascorbate Transporter SVCT2

Source: Free Radical Biology & Medicine 2009; 46(6): 719-30

Author: Harrison F.E., May J.M.

Affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232-6303, USA.

Abstract: Ascorbate (vitamin C) is a vital antioxidant molecule in the brain. However, it also has a number of other important functions, participating as a cofactor in several enzyme reactions, including catecholamine synthesis, collagen production, and regulation of HIF-1 alpha. Ascorbate is transported into the brain and neurons via the sodium-dependent vitamin C transporter 2 (SVCT2), which causes accumulation of ascorbate within cells against a concentration gradient. Dehydroascorbic acid, the oxidized form of ascorbate, is transported via glucose transporters of the GLUT family. Once in cells, it is rapidly reduced to ascorbate. The highest concentrations of ascorbate in the body are found in the brain and in neuroendocrine tissues such as adrenal, although the brain is the most difficult organ to deplete of ascorbate. Combined with regional asymmetry in ascorbate distribution within different brain areas, these facts suggest an important role for ascorbate in the brain. Ascorbate is proposed as a neuromodulator of glutamatergic, dopaminergic, cholinergic, and GABAergic transmission and related behaviors. Neurodegenerative diseases typically involve high levels of oxidative stress and thus ascorbate has been posited to have potential therapeutic roles against ischemic stroke, Alzheimer's disease, Parkinson's disease, and Huntington's disease.

Plasma Vitamin C Concentrations Predict Risk of Incident Stroke Over 10 y in 20,649 participants of the European Prospective Investigation into Cancer Norfolk Prospective Population Study

Source: The American Journal of Clinical Nutrition 2008; 87(1): 64-9

Author: Myint P.K., Luben R.N., Welch A.A., Bingham S.A., Wareham NJ., Khaw K.T.

Affiliation: Department of Public Health and Primary Care, University of Cambridge, United Kingdom.

Abstract: The relation between plasma vitamin C and risk of stroke remains unclear. Although clinical trials showed no significant benefit of vitamin C supplementation in reducing stroke risk, they were not able to examine the relation between plasma vitamin C concentrations and stroke risk in a general population. The objective was to examine the relation between baseline plasma vitamin C concentrations and risk of incident stroke in a British population. A population-based prospective study was conducted in 20,649 men and women aged 40-79 y without prevalent stroke at baseline and participating in the European Prospective Investigation into Cancer-Norfolk prospective population study. The participants completed a health questionnaire and attended a clinic during 1993-1997 and were followed up for incident strokes through March 2005.The study concludes that plasma vitamin C concentrations may serve as a biological marker of lifestyle or other factors associated with reduced stroke risk and may be useful in identifying those at high risk of stroke.

Oxidative Stress in Cerebral Stroke

Source: Polski merkuriusz lekarski 2008; 25(147): 205-8 [Article in Polish]

Author: Łagowska-Lenard M, Bielewicz J, Raszewski G, Stelmasiak Z, Bartosik-Psujek H.

Affiliation: Akademia Medyczna w Lublinie, Katedra i Klinika Neurologii.

Abstract: In systemic homeostasis, free radicals are inactivated by endo- and exogenous antioxidants and do not have destructive effects. The human organism possesses protective mechanisms, i.e. enzymatic systems (peroxide dismutase, glutathione peroxidase, catalase) and non-enzymatic systems (vitamin C and E selenium, coenzyme Q, lipoid acid, bilirubin). Recent studies demonstrated a significant role of inflammatory processes and oxidative stress in the pathomechanism of cerebral stroke. Increased production of free radicals was observed in both the ischaemic and haemorrhagic strokes and oxidative stress was shown to be one of the causative mechanisms of tissue damage in these diseases. This was confirmed by numerous studies assessing the concentration of oxidative stress biomarkers and levels of plasma antioxidants (enzymatic and non-enzymatic). At present, studies are being carried out about the use of antioxidative substances for the therapy of cerebral stroke. The present study reports current findings concerning oxidative stress issues in patients with stroke.

Source: Clinical Interventions in Aging 2007; 2(1): 147-51

Author: Rabadi M.H., Kristal B.S.

Affiliation: Burke Rehabilitation Hospital, an affiliate of Weill Medical College of Cornell Medical College, 785 Mamaroneck Avenue, White Plains, NY 10605, USA.

Abstract: Epidemiological studies have associated increased dietary intake of antioxidants (vitamin C, E, and beta-carotene) in preventing and decreasing the extent of ischemic brain injury. The effect of vitamin C supplementation on functional recovery after stroke has not been studied. In this retrospective, case-control study of 23 patients with ischemic stroke taking vitamin C were identified and matched for age, sex, onset to admission, and admission total functional independence measure (TFIM) with 23 patients with ischemic stroke not taking Vitamin C supplementation. Vitamin C 1000 mg daily was prescribed on admission to our unit mainly to patients who were undernourished (defined as significant weight loss and/or 90% or less ideal body weight for age and sex) and those with pressure sores. The outcome measures were: change in the TFIM, FIM-Cognition (FIM-Cog), and FIM-Motor sub-scores, discharge disposition, and length of stay (LOS). RESULTS: The change in TFIM (20 +/- 13 standard deviation [SD] vs. 26 +/- 6, p = 0.20), FIM-Cog (3 +/- 3 SD vs. 4 +/- 5, p = 0.41), FIM-Motor (15 +/- 11 SD vs. 20 +/- 13, p = 0.21) sub-scores were less in the vitamin C treated group, but these differences did not reach statistical significance.

Effects of Vitamin C and Aspirin in Ischemic Stroke-Related Lipid Peroxidation: Results of the AVASAS (Aspirin Versus Ascorbic Acid Plus Aspirin in Stroke). Study

Source: Biofactors 2005; 24(1-4): 265-74

Author: Polidori M.C., Pratico D., Ingegni T., Mariani E., Spazzafumo L., Del Sindaco P., Cecchetti R., Yao Y., Ricci S., Cherubini A., Stahl W., Sies H., Senin U., Mecocci P; AVASAS Study Group.

Affiliation: Institute of Biochemistry and Molecular Biology I, Heinrich-Heine University, Düsseldorf, Germany.

Abstract: A condition of oxidative stress is known to occur in ischemic stroke, the current therapeutic intervention of which is largely limited to thrombolysis. To assess the effect of vitamin C - in conjunction to aspirin - in ischemic stroke-related lipid peroxidation, this study measured plasma levels of ascorbate, of 8,12-isoprostanes F2alpha-VI (8,12-iPF2alpha-VI) and activities and levels of a broad spectrum of antioxidant enzymes and micronutrients in stroke patients randomized to receive, from stroke onset and up to three months, either vitamin C (200 mg/day) plus aspirin (300 mg/day) or only aspirin (300 mg/day). By the end of the first week, patients treated with vitamin C plus aspirin had higher vitamin C levels (p = 0.02) and lower 8,12-iPF2alpha-VI levels (p = 0.01) than patients treated with aspirin alone. The significance was maintained for the increase of vitamin C after three months of therapy (p < 0.01). The clinical functional outcome for both groups of patients similarly ameliorated after three months of treatment. The study concludes that vitamin C, at the dose of 200 mg/day and in conjunction with aspirin, significantly decreases ischemic stroke-related lipid peroxidation in humans. Further studies are warranted to clarify whether the use of vitamin C may add clinical long-term beneficial effects in patients with stroke.

Decreased Levels of Plasma Vitamin C and Increased Concentrations of Inflammatory and Oxidative Stress Markers After Stroke

Source: Stroke 2004; 35(1): 163-8

Author: Sanchez-Moreno C., Dashe J.F., Scott T., Thaler D., Folstein M.F., Martin A.

Affiliation: Nutrition and Neurocognition Laboratory, Jean Mayer USDA-Human Nutrition Research Center on Aging, Boston, Mass 02111, USA.

Abstract: Vitamin C has been shown to have important roles in cell performance and vascular function. This study compared the nutritional status and levels of inflammatory markers between stroke cases and controls and assessed which antioxidant was associated with levels of inflammatory markers and oxidative stress among cases and controls. The study evaluated the nutritional status and measured plasma levels of vitamins C and E, uric acid, serum levels of C-reactive protein (CRP), the cytokines tumor necrosis factor-alpha and interleukin-1beta, intercellular adhesion molecule-1 (ICAM-1) and chemokine monocyte chemoattractant protein-1 (MCP-1), prostaglandins PGE2 and PGI2, and 8-isoprostanes (8-epiPGF2alpha) for 15 patients with ischemic stroke within 2 to 5 days after stroke onset and for 24 control subjects. The study concludes that lower vitamin C concentration, higher serum levels of inflammatory (CRP, ICAM-1, MCP-1) and oxidative stress (8-epiPGF2alpha) markers, and lower PGI2 and PGE2 concentrations among stroke patients indicate the presence of an inflammatory response associated with stroke.

Vitamin C as an Antioxidant: Evaluation of Its Role in Disease Prevention

Source: Journal of the American College of Nutrition 2003; 22(1): 18-35

Author: Padayatty S.J., Katz A., Wang Y., Eck P., Kwon O., Lee J.H., Chen S., Corpe C, Dutta A., Dutta S.K., Levine M.

Affiliation: Molecular and Clinical Nutrition Section, Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.

Abstract: Vitamin C in humans must be ingested for survival. Vitamin C is an electron donor, and this property accounts for all its known functions. Epidemiological studies show that diets high in fruits and vegetables are associated with lower risk of cardiovascular disease, stroke and cancer, and with increased longevity. Whether these protective effects are directly attributable to vitamin C is not known. Intervention studies with vitamin C have shown no change in markers of oxidation or clinical benefit. Dose concentration studies of vitamin C in healthy people showed a sigmoidal relationship between oral dose and plasma and tissue vitamin C concentrations. Hence, optimal dosing is critical to intervention studies using vitamin C. Ideally, future studies of antioxidant actions of vitamin C should target selected patient groups. These groups should be known to have increased oxidative damage as assessed by a reliable biomarker or should have high morbidity and mortality due to diseases thought to be caused or exacerbated by oxidant damage.

Antioxidant [Including Vitamin C] Capacity After Acute Ischaemic Stroke

Source: QJM 2002; 95(10): 685-90

Author: Gariballa S.E., Hutchin T.P., Sinclair A.J.

Affiliation: Sheffield Institute For Studies on Ageing, University of Sheffield, Northern General Hospital, Sheffield, UK

Abstract: Experimental studies have reported a rapid increase in the production of markers of oxidative damage following acute stroke due to the reperfusion event following ischaemia, and that endogenous antioxidant defenses are rapidly depleted, permitting further tissue damage. The aim of this observational cohort study was to measure changes in antioxidant capacity (individual and total) in stroke disease within a known time period post infarct. The study examined 31 acute ischaemic stroke patients; 26 hospitalized non-stroke patients and 23 community-based healthy controls. Non-fasting venous blood was obtained within 24 h, at 48-72 h and at 7 days after stroke onset (after hospitalization for non-stroke patients) and at baseline for community controls. Vitamins E and C, total plasma glutathione, total antioxidant capacity (TAC), uric acid, thiobarbituric-acid-reactive substances (TBARS), serum albumin, transferrin and C-reactive protein (CRP) were measured. The results show that serum vitamin C concentrations deteriorated significantly in stroke patients, and differences between the cumulative changes between strokes and hospital controls were also statistically significant (p=0.013). The study concludes that there was some evidence of reduction in TAC, despite increased uric acid concentrations, and deterioration in serum vitamin C levels in ischaemic stroke patients compared with controls.

Plasma Vitamin C Modifies the Association Between Hypertension and Risk of Stroke

Source: Stroke 2002; 33(6): 1568-73

Author: Kurl S., Tuomainen T.P., Laukkanen J.A., Nyyssonen K., Lakka T, Sivenius J., Salonen JT.

Affiliation: Research Institute of Public Health, University of Kuopio, Kuopio, Finland.

Abstract: There are no prospective studies to determine whether plasma vitamin C modifies the risk of stroke among hypertensive and overweight individuals. This study examined whether plasma vitamin C modifies the association between overweight and hypertension and the risk of stroke in middle-aged men from eastern Finland. This a 10.4-year prospective population-based cohort study was conducted with 2419 randomly selected middle-aged men (42 to 60 years) with no history of stroke at baseline examination. A total of 120 men developed a stroke, of which 96 were ischemic and 24 hemorrhagic strokes. The results show that men with the lowest levels of plasma vitamin C (<28.4 micromol/L, lowest quarter) had a 2.4-fold (95% CI, 1.4 to 4.3; P=0.002) risk of any stroke compared with men with highest levels of plasma vitamin C (>64.96 micromol/L, highest quarter) after adjustment for age and examination months. An additional adjustment for body mass index, systolic blood pressure, smoking, alcohol consumption, serum total cholesterol, diabetes, and exercise-induced myocardial ischemia attenuated the association marginally (relative risk, 2.1; 95% CI, 1.2 to 3.8; P=0.01). Adjustment for prevalent coronary heart disease and atrial fibrillation did not attenuate the association any further. Furthermore, hypertensive men with the lowest vitamin C levels (<28.4 micromol/L) had a 2.6-fold risk (95% CI, 1.52 to 4.48; P<0.001), and overweight men (> or =25 kg/m2) with low plasma vitamin C had a 2.7-fold risk (95% CI, 1.48 to 4.90; P=0.001) for any stroke after adjustment for age, examination months, and other risk factors. The study concludes that low plasma vitamin C was associated with increased risk of stroke, especially among hypertensive and overweight men.

Dehydroascorbic Acid, a Blood-Brain Barrier Transportable Form of Vitamin C, Mediates Potent Cerebroprotection in Experimental Stroke

Source: Proceedings of the National Academy of Sciences USA 2001; 98(20): 11720-4

Author: Huang J., Agus D.B., Winfree C.J., Kiss S., Mack W.J., McTaggart RA., Choudhri T.F., Kim L.J., Mocco J., Pinsky D.J., Fox W.D., Israel R.J., Boyd T.A., Golde D.W., Connolly ES Jr.

Affiliation: Department of Neurological Surgery, College of Physicians and Surgeons, Columbia University, 710 West 168th Street, New York, NY 10032, USA.

Abstract: Although the antioxidant ascorbic acid (AA) or vitamin C does not penetrate the blood-brain barrier (BBB), its oxidized form, dehydroascorbic acid (DHA), enters the brain by means of facilitative transport. This study hypothesized that i.v. DHA would improve outcome after stroke because of its ability to cross the BBB and augment brain antioxidant levels. Reversible or permanent focal cerebral ischemia was created by intraluminal middle cerebral artery occlusion in mice treated with vehicle, AA, or DHA (40, 250, or 500 mg/kg), either before or after ischemia. Given before ischemia, DHA caused dose-dependent increases in postreperfusion cerebral blood flow, with reductions in neurological deficit and mortality. In reperfused cerebral ischemia, mean infarct volume was reduced from 53% and 59% in vehicle- and AA-treated animals, respectively, to 15% in 250 mg/kg DHA-treated animals (P < 0.05). Unlike exogenous AA, DHA confers in vivo, dose-dependent neuroprotection in reperfused and nonreperfused cerebral ischemia at clinically relevant times. As a naturally occurring interconvertible form of AA with BBB permeability, DHA represents a promising pharmacological therapy for stroke based on its effects in this model of cerebral ischemia.

Antioxidant Effects of Vitamins C and E are Associated with Altered Activation of Vascular NADPH Oxidase and Superoxide Dismutase in Stroke-Prone SHR

Source: Hypertension 2001; 38(3 Pt 2): 606-11

Author: Chen X., Touyz R.M., Park J.B., Schiffrin E.L.

Affiliation: Clinical Research Institute of Montreal, University of Montreal, Montreal, Quebec, Canada.

Abstract: Ascorbic acid (vitamin C) and alpha-tocopherol (vitamin E) have antioxidant properties that could improve redox-sensitive vascular changes associated with hypertension. This study determined whether vitamins C and E influence vascular function and structure in hypertension by modulating activity of NADPH oxidase and superoxide dismutase (SOD). Adult stroke-prone spontaneously hypertensive rats (SHRSP) were divided into 3 groups: control (C; n=6), vitamin C-treated (vit C, 1000 mg/day; n=7), and vitamin E-treated (vit E, 1000 IU/day; n=8). All rats were fed 4% NaCl. Blood pressure was measured weekly. After 6 weeks of treatment, the rats were killed, and mesenteric arteries were mounted as pressurized preparations. Vascular O(2)(-) generation and NADPH oxidase activity were measured by chemiluminescence. Vascular SOD activity and plasma total antioxidant status (TAS) were determined spectrophotometrically. The results demonstrate that vitamins C and E reduce oxidative stress, improve vascular function and structure, and prevent progression of hypertension in SHRSP. These effects may be mediated via modulation of enzyme systems that generate free radicals.

Serum Vitamin C Concentration was Inversely Associated with Subsequent 20-year Incidence of Stroke in a Japanese Rural Community. The Shibata Study

Source: Stroke 2000; 31(10): 2287-94

Author: Yokoyama T., Date C., Kokubo Y., Yoshiike N., Matsumura Y., Tanaka H.

Affiliation: Department of Epidemiology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.

Abstract: Epidemiological evidence suggests that vitamin C may decrease the risk of stroke. The purpose of the present study was to examine the association of serum vitamin C concentration with the subsequent incidence of stroke. In a Japanese rural community, a cohort of 880 men and 1241 women aged 40 years and older who were initially free of stroke was examined in 1977 and followed until 1997. The baseline examination included a measurement of serum vitamin C concentration. The incidence of stroke was determined by annual follow-up examinations and registry. During the 20-year observation period, 196 incident cases of all stroke, including 109 cerebral infarctions and 54 hemorrhagic strokes, were documented. Strong inverse associations were observed between serum vitamin C concentration and all stroke (sex- and age-adjusted hazard ratios were 0.93, 0.72, and 0.59, respectively, for the second, third, and fourth quartiles compared with the first quartile; P for trend=0.002), cerebral infarction (0.71, 0.59, and 0.51; P for trend=0.015), and hemorrhagic stroke (0.89, 0.75, and 0. 45; P for trend=0.013). The study concludes that serum vitamin C concentration was inversely related to the subsequent incidence of stroke. This relationship was significant for both cerebral infarction and hemorrhagic stroke. Additional mechanistic hypotheses may be required to explain our findings.

Vitamin E

Vitamin E and Cardiovascular Disease

Source: American Journal of Therapeutics 2009 May 15. [Epub ahead of print]

Author: Saremi A., Arora R.

Affiliation: Department of Medicine, Chicago Medical School, North Chicago, IL.

Abstract: The objective of this article is to review the role of vitamin E in cardiovascular disease. The study begins by describing the general characteristics and metabolism of vitamin E and the pathogenesis of atherosclerosis as it relates to oxidation. It also discusses key in vitro studies, animal studies, observational studies, and clinical trials regarding the potentially cardioprotective effect of vitamin E. Lastly, the study outlines the current recommendations regarding vitamin E in the prevention and treatment of cardiovascular disease as stated by the American Heart Association. Vitamin E has been shown to increase oxidative resistance in vitro and prevent atherosclerotic plaque formation in mouse models. Consumption of foods rich in vitamin E has been associated with lower risk of coronary heart disease in middle-aged to older men and women. The American Heart Association does not support the use of vitamin E supplements to prevent cardiovascular disease, but does recommend the consumption of foods abundant in antioxidant vitamins and other nutrients.

Vitamin E Suppresses Enhancement of Factor VIII-Dependent Thrombin Generation by Systemic Hypoxia

Source: Stroke 2009; 40(2): 656-9

Author: Wang J.S., Cheng M.L., Yen H.C., Lou B.S., Liu H.C.

Affiliation: Graduate Institute of Rehabilitation Science, Chang Gung University, Kwei-Shan, Tao-Yuan, Taiwan.

Abstract: This study elucidates how various hypoxic interventions impact endogenous thrombin generation (TG) after treatment with/without lipophilic antioxidant vitamin E. Twenty-four healthy sedentary men were randomly assigned to vitamin E (n=12) and placebo (n=12) groups. These subjects were randomly exposed to 12% (severe hypoxia), 15% (moderate hypoxia), 18% (light hypoxia), and 21% (normoxia) O(2) for 2 hours in a normobaric hypoxia chamber. A novel calibrated, automated thrombinography approach was used to measure TG in plasma. The study concludes that severe hypoxia promotes FVIII-dependent TG, likely by elevating oxidative stress; this hypoxic effect was ameliorated by pretreatment with vitamin E.

Cardioprotection [Against Stroke] with Palm Oil Tocotrienols: Comparision of Different Isomers

Source: American Journal of Physiology - Heart and Circulatory Physiology 2008; 294(2): H970-8.

Author: Das S., Lekli I., Das M., Szabo G., Varadi J., Juhasz B., Bak I., Nesaretam K., Tosaki A., Powell S.R., Das D.K.

Affiliation: Cardiovascular Research Center, University of Connecticut School of Medicine, Farmington, CT 06030-1110, USA.

Abstract: The present study compares cardioprotective abilities of different isomers of tocotrienol against TRF as recently tocotrienol has been found to function as a potent neuroprotective agent against stroke. Rats were randomly assigned to one of the following groups: animals were given, by gavage, either 0.35%, 1%, or 3.5% TRF for two different periods of time (2 or 4 wk) or 0.03, 0.3, and 3 mg/kg body wt of one of the isomers of tocotrienol (alpha, gamma, or delta) for 4 wk; control animals were given, by gavage, vehicle only. After 2 or 4 wk, rats were killed, and their hearts were then subjected to 30 min of global ischemia followed by 2 h of reperfusion. Dose-response and time-response experiments revealed that the optimal concentration for TRF was 3.5% TRF and 0.3 mg/kg body wt of tocotrienol given for 4 wk. TRF as well as all the isomers of tocotrienol used in the study provided cardioprotection, as evidenced by their ability to improve postischemic ventricular function and reduce myocardial infarct size. The gamma-isoform of tocotrienol was the most cardioprotective of all the isomers followed by the alpha- and delta-isoforms. The results demonstrate that tocotrienol isoforms reduced c-Src but increased the phosphorylation of Akt, thus generating a survival signal.

Vitamin E Supplementation Reduces Cardiovascular Events in a Subgroup of Middle-Aged Individuals with Both Type 2 diabetes Mellitus and the Haptoglobin 2-2 Genotype: a Prospective Double-Blinded Clinical Trial

Source: Arteriosclerosis, Thrombosis, and Vascular Biology 2008; 28(2): 341-7

Author: Milman U., Blum S., Shapira C., Aronson D., Miller-Lotan R., Anbinder Y., Alshiek J., Bennett L., Kostenko M., Landau M., Keidar S., Levy Y., Khemlin A, Radan A., Levy AP.

Affiliation: Clalit Health Services, Haifa, Israel.

Abstract: Clinical trials of vitamin E have failed to demonstrate a decrease in cardiovascular events. However, these studies did not address possible benefit to subgroups with increased oxidative stress. Haptoglobin (Hp), a major antioxidant protein, is a determinant of cardiovascular events in patients with Type 2 diabetes mellitus (DM). this study sought to test the hypothesis that vitamin E could reduce cardiovascular events in DM individuals with the Hp 2-2 genotype, a subgroup that comprises 2% to 3% of the general population. 1434 DM individuals > or = 55 years of age with the Hp 2-2 genotype were randomized to vitamin E (400 U/d) or placebo. The primary composite outcome was myocardial infarction, stroke, and cardiovascular death. At the first evaluation of events, 18 months after initiating the study, the primary outcome was significantly reduced in individuals receiving vitamin E (2.2%) compared with placebo (4.7%; P=0.01) and led to early termination of the study. The study concludes that vitamin E supplementation appears to reduce cardiovascular events in individuals with DM and the Hp 2-2 genotype.

The Effects of Vitamin E on Lipid Peroxidation, Nitric Oxide Production and Superoxide Dismutase Expression in Hyperglycemic Rats with Cerebral Ischemia-Reperfusion Injury

Source: Turkish Neurosurgery 2007; 17(2): 78-82

Author: Gumuştaş K., Meta Guzeyli F.M., Atukeren P., Sanus G.Z., Kemerdere R., Tanriverdi T., Kaynar M.Y.

Affiliation: Cerrahpasa Medical Faculty, Neurosurgery, Istanbul, Turkey.

Abstract: The purpose of this study was to investigate the effects of vitamin E (VE) on LP, NO production, and superoxide dismutase (SOD) expression in hyperglycemic rats after cerebral ischemia-reperfusion injury. Malondialdehyde (MA) (indicator of LP) in plasma and brain tissue, total nitrite/nitrate (metabolites of nitric oxide) in plasma, nitrite in brain tissue, and SOD in red blood cells were detected and the results were compared before and after VE administration in hyperglycemic rats with cerebral ischemia-reperfusion injury induced by two common carotid artery occlusions. The results indicate that ischemia-reperfusion injury together with hyperglycemia caused elevation in NO metabolites and MA levels and this elevation was more prominent in hyperglycemic rats. SOD was also increased in ischemia-reperfusion, and VE administration had positive effects on the SOD level. In addition, VE administration caused a significant decrease in NO metabolite levels after ischemia-reperfusion injury. These results suggest that prophylaxis with VE may have positive effects on reducing cerebral damage after stroke in patients with diabetes mellitus.

Risk of Mortality with Vitamin E supplements: the Cache County study

Source: The American Journal of Medicine 2007; 120(2): 180-4

Author: Hayden K.M., Welsh-Bohmer K.A., Wengreen HJ., Zandi P.P, Lyketsos C.G., Breitner J.C; Cache County Investigators.

Affiliation: Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA.

Abstract: A recent meta-analysis reported increased mortality in clinical trial participants randomized to high-dose vitamin E. This study sought to determine whether these mortality risks with vitamin E reflect adverse consequences of its use in the presence of cardiovascular disease. In a defined population aged 65 years or older, baseline interviews captured self- or proxy-reported history of cardiovascular illness. A medicine cabinet inventory verified nutritional supplement and medication use. Three sources identified subsequent deaths. Cox proportional hazards methods examined the association between vitamin E use and mortality. RESULTS: After adjustment for age and sex, there was no association in this population between vitamin E use and mortality (adjusted hazard ratio [aHR] 0.93; 95% confidence interval [CI], 0.74-1.15). Predictably, deaths were more frequent with a history of diabetes, stroke, coronary artery bypass graft surgery, or myocardial infarction, and with the use of warfarin, nitrates, or diuretics. The study concludes that in this population-based study, vitamin E use was unrelated to mortality, but this apparently null finding seems to represent a combination of increased mortality in those with severe cardiovascular disease and a possible protective effect in those without.

Vitamin E and Cardiovascular Disease: Observational Studies

Source: The Annals of the New York Academy of Sciences 2004; 1031: 280-91

Author: Gaziano J.M.

Affiliation: Brigham and Women's Hospital, Division of Aging, 1620 Tremont Street, Boston MA 02120, USA.

Abstract: This presentation summarizes data from the major observational studies. Overall, they support the possibility that vitamin E intake either from food or supplements may reduce risk of CVD; however, these studies have important limitations. Some are designed to test vitamin E alone as well as in combination with other antioxidant supplements because it is possible that antioxidants may be most effective if taken in particular combinations. Both case-control and prospective cohort studies have carefully explored the relationship between vitamin E intake and plasma and tissue vitamin E levels and the risk of CVD. In many, but not all, of these studies vitamin E intake over an extended period was associated with decreased risk of cardiovascular events. Currently, the American Heart Association maintains that there are insufficient efficacy data from completed randomized trials to justify population-wide recommendations for use of vitamin E supplements in disease prevention.

The Role of Vitamin E in the Prevention of Coronary Events and Stroke. Meta-Analysis of Randomized Controlled Trials

Source: Saudi Medical Journal 2004; 25(12): 1808-14

Author: Alkhenizan A.H., Al-Omran M.A.

Affiliation: Department of Family Medicine and Polyclinic, King Faisal Specialist Hospital and Research Centre, Riyadh, Kingdom of Saudi Arabia.

Abstract: This study did a meta-analysis, using the Cochrane Group Methodology, of all available randomized controlled trials (RCTs) to evaluate the role of vitamin E in the prevention of cardiovascular disease (CVD). Nine studies met inclusion criteria, including 80,645 participants. Vitamin E supplementation was not associated with a reduction in total mortality or total CVD mortality, but it was associated with a small statistically significant reduction in non-fatal myocardial infarction in patients with pre-existing coronary artery disease. Prophylactic use of vitamin E in doses ranging between 50-800 IU was not associated with any increase in the incidence of serious side effects.

Effects of Vitamin E and Sesamin on Hypertension and Cerebral Thrombogenesis in Stroke-Prone Spontaneously Hypertensive Rats

Source: Clinical and Experimental Pharmacology & Physiology 2004; 31 Suppl 2: S24-6

Author: Noguchi T., Ikeda K., Sasaki Y., Yamamoto J., Yamori Y.

Affiliation: Human Nutrition, Kobe Gakuin University, Nishi, Kobe, Japan.

Abstract: The preventive effects of sesamin, a lignan from sesame oil and vitamin E on hypertension and thrombosis were examined using stroke-prone spontaneously hypertensive rats (SHRSP). Animals at 5 weeks of age were separated into four groups: (i) control group; (ii) vitamin E group, which was given 1000 mg alpha-tocopherol/kg diet; (iii) sesamin group, given 1000 mg sesamin/kg diet; and (iv) vitamin E plus sesamin group, given 1000 mg alpha-tocopherol plus 1000 mg sesamin/kg diet for 5 weeks from 5 to 10 weeks of age. Resting blood pressure was measured by the tail-cuff method once weekly. A closed cranial window was created in the right parietal bone of the rat and platelet-rich thrombi were induced in vivo using a helium-neon laser technique. The number of laser pulses required for formation of an occlusive thrombus was used as an index of thrombotic tendency. The results of this study indicate that chronic ingestion of vitamin E and sesamin attenuated both elevation in blood pressure, oxidative stress and thrombotic tendency, suggesting that these treatments might be beneficial in the prevention of hypertension and stroke.

Anti-Atherosclerotic Effects of Vitamin E - Myth or Reality?

Source: Journal of Cellular and Molecular Medicine 2004; 8(1): 59-76

Author: Munteanu A., Zingg J.M., Azzi A.

Affiliation: Institute of Biochemistry and Molecular Biology, University of Bern, Bern, Switzerland.

Abstract: Several epidemiological studies and intervention trials have been performed with vitamin E, and some of them showed that it prevents atherosclerosis. For a long time, vitamin E was assumed to act by decreasing the oxidation of LDL, a key step in atherosclerosis initiation. However, at the cellular level, vitamin E acts by inhibition of smooth muscle cell proliferation, platelet aggregation, monocyte adhesion, oxLDL uptake and cytokine production, all reactions implied in the progression of atherosclerosis. Recent research revealed that these effects are not the result of the antioxidant activity of vitamin E, but rather of precise molecular actions of this compound. It is assumed that specific interactions of vitamin E with enzymes and proteins are at the basis of its non-antioxidant effects. Vitamin E influences the activity of several enzymes (e.g. PKC, PP2A, COX-2, 5-lipooxygenase, nitric oxide synthase, NADPH-oxidase, superoxide dismutase, phopholipase A2) and modulates the expression of genes that are involved in atherosclerosis (e.g. scavenger receptors, integrins, selectins, cytokines, cyclins). These interactions promise to reveal the biological properties of vitamin E and allow designing better strategies for the protection against atherosclerosis progression.

Vitamin E Isoforms, Alpha-Tocotrienol and Gamma-Tocopherol Prevent Cerebral Infarction in Mice

Source: Neuroscience Letters 2003; 337(1): 56-60

Author: Mishima K., Tanaka T., Pu F., Egashira N., Iwasaki K., Hidaka R., Matsunaga K., Takata J., Karube Y., Fujiwara M.

Affiliation: Department of Neuropharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Japan.

Abstract: Alpha-tocopherol and its derivatives have been shown to be effective in reducing cerebral ischemia-induced brain damage. However, the effects of other vitamin E isoforms have not been characterized. In the present study, we investigated the effects of six different isoforms of vitamin E on the ischemic brain damage in the mice middle cerebral artery (MCA) occlusion model. All vitamin E isoforms were injected i.v., twice, immediately before and 3 h after the occlusion. Alpha-tocopherol (2 mM), alpha-tocotrienol (0.2 and 2 mM) and gamma-tocopherol (0.2 and 2 mM) significantly decreased the size of the cerebral infarcts 1 day after the MCA occlusion, while gamma-tocotrienol, delta-tocopherol and delta-tocotrienol showed no effect on the cerebral infarcts. These results suggest that alpha-tocotrienol and gamma-tocopherol are potent and effective agents for preventing cerebral infarction induced by MCA occlusion.

Does Vitamin E Supplementation Prevent Cardiovascular Events?

Source: Journal of Women's Health 2003; 12(2): 123-36

Author: Manson J.E., Bassuk S.S., Stampfer M.J.

Affiliation: Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.

Abstract: In recent years, vitamin E has been investigated as a cardioprotective agent. Experimental studies have identified potential mechanisms by which vitamin E may inhibit the development of atherosclerosis, and observational studies of individuals without coronary disease suggest that vitamin E intake may prevent future cardiovascular events. Secondary prevention trials to date have demonstrated little benefit from vitamin E supplementation. It remains possible however, that supplementation may be useful among certain high-risk groups, including those with nutritional deficiencies. Limited data from completed primary prevention trials also indicate minimal cardioprotection from vitamin E, but large-scale trials now in progress may yet show benefit.