Prevention Of Cardiovascular Disease

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The association between vitamin C and cardiovascular disease prevention is still unclear, although several themes are emerging as evidence accumulates. In general, laboratory, epidemiological and observational follow-up studies suggest that vitamin C is associated with reduced incidence of cardiovascular disease although not all studies are positive (Houston 2005). Studies have looked at blood levels, dietary intake and supplemental vitamin C and in some studies, vitamin C is co-administered with other nutrients (often vitamin E) making it difficult to assess the contribution of vitamin C alone (Carr & Frei 1999, Khaw et al 2001, Knekt et al 2004, Kushi et al 1996, Lopes et al 1998, MRC/BHF 2002, Ness et al 1996, Nyyssonen et al 1997, Osganian et al 2003). It appears that if a protective effect is observed with supplementation, it is most likely with doses above RDI, long-term use and in populations with a substantial proportion of persons who have low or deficient intakes of vitamin C. Ideally, future human clinical trials will focus on subjects with increased oxidative stress rather than the general population to see whether this variable also influences study outcomes.

Possible mechanisms According to a 2001 review, ascorbic acid is inversely related to several risk factors and indicators of atherosclerotic cardiovascular disease, © 2007 Elsevier Australia

including hypertension and elevated concentrations of LDL, acute phase proteins, and haemostatic factors (Price et al 2001). More specifically, vitamin C inhibits oxidative modification of LDL-cholesterol directly through free radical scavenging activity, according to in vitro data, and indirectly by increasing glutathione and vitamin E concentrations within cell membranes. This has been demonstrated against the pro-oxidant combination of homocysteine and iron (Alul et al 2003) and may have implications for other diseases such as Alzheimer's dementia.

More recently, evidence suggests that other mechanisms are also likely to be involved. Vitamin C is linked to endothelial function and glucose metabolism. It improves endothelial dysfunction in smokers, renal transplant recipients, in patients with cardiovascular disease after a fatty meal, or intermittent claudication diabetes and those with hypertension (Kaufmann et al 2000, Ling et al 2002, Silvestro et al 2002, Solzbach et al 1997, Williams et al 2001), but not in healthy elderly people (Singh et al 2002). It is also required for collagen synthesis and metabolism, and has been shown to reduce arterial stiffness and platelet aggregation in healthy male volunteers, smokers and non-smokers, and diabetics (Schindler et al 2002, Wilkinson et al 1999). These effects are often observed in doses several times higher than current RDI levels. In vivo studies further indicate that vitamin C decreases carotid wall thickness, downregulates iNOS expression, normalises gene expression of antioxidant enzymes and inhibits plaque maturation (Kaliora et al 2006). Clinical studies involving vitamin C supplementation In the recent pooled analysis from the Pooling Project of Cohort Studies on Diet and Coronary Disease, those subjects with higher supplemental vitamin C intake (median intake of 756 mg/day) had a 24% reduced risk of coronary heart disease than those in the lowest quintile, whereas dietary vitamin C had no significant protective effect (Knekt et al 2004). The lower risk was independent of non-dietary risk factors and related to dose.

The researchers also adjusted for many relevant constituents of foods (e.g. dietary fibre and saturated fat) and found this adjustment had no effect on the association. Effects on blood pressure Although epidemiological evidence and prospective clinical trials point strongly to a role of vitamin C in reducing blood pressure in hypertensive and normotensive subjects, controlled studies have been inconsistent (Houston 2005). Interpretation of these results is difficult as some studies lack a control group, have no baseline readings, use variable vitamin C doses and population characteristics and do not report serum vitamin C or oxidative stress status. Overall, it appears that doses between 100 and 1000 mg of vitamin C daily are

required for a reduction in blood pressure, with greater reduction in SBP than DBP and greater response in people with higher initial value.

A 1997 review of epidemiological studies showed some inverse associations between SBP, DBP or both, and vitamin C plasma concentration or intake (Ness et al

1997). Three more recent studies have supported this finding (Bates et al 1998, Block 2002, Block et al 2001). Over the past 10 years, four intervention studies investigated the effects of vitamin C supplementation, with three producing positive results (Duffy et al 1999, Fotherby et al 2000, Galley et al 1997, Ghosh et al 1994). The doses used were typically 250 mg twice daily for a period of 6-8 weeks, although effects have been reported after 4 weeks' treatment.

The negative study by Ghosh et al showed a significant reduction in both SBP and DBP with ascorbic acid. This became non-significant when compared with the placebo responses, although the placebo and ascorbic acid groups were not evenly matched for baseline plasma ascorbate concentration.

Additionally, plasma ascorbate concentrations have been shown to be inversely correlated to pulse rate in one cross-sectional study involving 500 subjects (Bates et al

Nitrate tolerance Preliminary studies seem to support the role of vitamin C in attenuating the development of nitrate tolerance. Three human studies have found that vitamin C administration prevents the development of nitrate tolerance (Bassenge et al 1998, Watanabe et al 1998a,b). Although the mechanism responsible is not yet known, results from a double-blind study using an acute dose of 2 g have suggested that vitamin C is likely to protect NO from inactivation by oxygen free radicals (Wilkinson et al 1999), which could in part explain its observed effects. Myocardial infarction (Ml) Two prospective studies in men have suggested that ascorbic acid deficiency (Nyyssonen et al 1997) and marginal deficiency (Gey et al 1993) predict subsequent Ml independent of classical risk factors.

The first, a 5-year prospective population study of 1605 middle-aged Finnish men, free of coronary disease at baseline, found that a significantly higher percentage (13.2%) of the 91 men with baseline plasma vitamin C concentrations less than 11.4 micromol/L (2.0 mg/L) experienced Ml compared with men with higher plasma vitamin C levels (Nyyssonen et al 1997). These results are particularly impressive because low plasma ascorbate was the strongest risk factor of all the measured factors. The second, a 12-year follow-up study, revealed a significantly increased relative risk of ischaemic heart disease and stroke at initially low plasma levels of vitamin C (<22.7 micromol/L), independently of vitamin E and of the classical Vitamin C 1284

cardiovascular risk factors (Gey et al 1993).

In contrast, one smaller study Involving 180 male patients with a first acute Ml, but no recent angina, failed to detect an association between low plasma concentration of vitamin C and the risk of acute myocardial infarction (Riemersma et al 2000).

There is a large body of evidence that reactive oxygen species produced during myocardial ischaemia and reperfusion play a crucial role in myocardial damage and endothelial dysfunction. As a result, there has been some investigation to determine whether antioxidant supplementation (chiefly vitamins C and E) may improve the clinical outcome of patients with acute AMI and limit the size of the infarct.

According to a large randomised, double-blind, multicentre trial of 800 patients (mean age 62 years) with acute AMI and receiving standard care, co-treatment with vitamin C (1000 mg/12 h infusion) followed by 1200 mg/day orally and vitamin E (600 mg/day) for 30 days resulted in significantly less frequent incidence of re-infarction and other post-MI complications compared to placebo (14%vs 19% respectively) (Jaxa-Chamiec et al 2005). Another randomised, double-blind, placebo-controlled study of 37 patients with acute Ml investigated the effects of starting supplementation with vitamins C and E (600 mg/day each) on the first day of symptoms and for a further 14 days (Bednarz et al 2003). Active treatment resulted in significantly lower exercise-induced QT interval dispersion compared to placebo, although baseline QTd was similar in both groups. A prospective, randomised study of 61 patients further suggests that oral vitamin C administration (1 g/day) could be beneficial for patients at higher thrombotic risk post-MI, such as those with diabetes (Morel et al 2003).

CANCER: PREVENTION AND TREATMENT

Several consensus conferences have evaluated the biological effect of vitamin C, and more than 500 published articles have examined the association of vitamin C and cancer.

Prevention Epidemiological evidence of a protective effect of dietary vitamin C for non-hormone-dependent cancers is strong (Block 1991a,b). The majority of studies in which a dietary vitamin C intake was calculated have identified a statistically significant protective effect, with high intake conferring approximately a twofold protective effect compared with low intake. In general, most have shown that higher intakes of vitamin C are associated with decreased incidence of cancers of the mouth, throat and vocal chords, oesophagus and stomach, pancreas, colon, rectum, renal cell and lung (Cohen & Bhagavan 1995, FAO/WHO 2002, Jenab et al 2006, Negri et al 2000, You et al 2000). More recently, a case control study of men in New York found

that a higher intake of vitamin C was associated with reduced risk of prostate cancer (McCann etal 2005).

Two other large studies have identified inverse associations between dietary vitamin C and breast cancer risk (Michels et al 2001, Zhang et al 1999). More specifically, the Nurses' Health Study, which involved 83,234 women, detected a strong inverse association between total vitamin C from foods and breast cancer risk among pre-menopausal women with a positive family history of breast cancer (Zhang et al 1999). Those who consumed an average of 205 mg/day of vitamin C from foods had a 63% lower risk of breast cancer than those who consumed an average of 70 mg/day. A large, Swedish population-based prospective study that comprised 59,036 women identified high dietary intakes of ascorbic acid (mean intake 110 mg/day) as reducing the risk of breast cancer among women who are overweight and/or have a high intake of linoleic acid (Michels et al 2001).

More recently, a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) identified an inverse risk of gastric cancer in the highest versus lowest quartile of plasma vitamin C (Jenab et al 2006). The inverse association was more pronounced in subjects consuming higher levels of red and processed meats, a factor that may increase endogenous N-nitroso compound production. It has been proposed that vitamin C protects against gastric cancer because it inhibits carcinogenic N-nitroso compound production in the stomach and acts as a free radical scavenger.

Overall, it appears that the effect is dose-dependent, with studies finding significant cancer risk reductions in people consuming at least 80-110 mg of vitamin C daily long term (Carr & Frei 1999). Clinical studies

Clinical note — Vitamin C for cancer: a historical perspective

The well-known team of Ewan Cameron and Linus Pauling started investigating the effects of high doses of continuous intravenous vitamin C and oral supplements to treat advanced, incurable cancer over three decades ago. The idea of using vitamin C was born out of the recognition that the outcome of every cancer is determined to a significant extent by the individual's inherent resistance, which in turn is influenced by the availability of certain nutritional factors such as ascorbic acid (Cameron 1982). They have published the results of several trials that have shown enhanced QOL for some terminal patients and also improvements in objective markers. As a result, a protocol for the use of vitamin C in the treatment of cancer has been developed at the Vale of Leven Hospital, the chief site of their investigations (Cameron 1991). The protocol emphasises the importance of using © 2007 Elsevier Australia an initial course of intravenous ascorbate followed by a maintenance oral dose. Although their results are encouraging, they have been criticised because randomised double-blind principles were not adopted.

One of the first published studies by Cameron and Pauling (1974) was a Phase HI study in 50 patients with advanced, untreatable malignancies in which both subjective and objective markers were evaluated. They observed that 27 patients failed to respond to treatment; however, 3 patients experienced stabilisation of disease, tumour regression occurred in 5 patients and tumour haemorrhage and necrosis occurred in 4 patients. Two years later, the same research team published a report that compared the survival rates of 100 terminal cancer patients given supplemental ascorbate as part of their routine management with 1000 patients who were not, and observed the mean survival time to be more than 4.2-fold as great for the ascorbate subjects (>210 days) as for the controls (50 days) (Cameron & Pauling 1976).

In subsequent years, two randomised, placebo-controlled studies investigating the effects of oral vitamin C supplementation (10 g/day) in terminal cancer patients failed to detect a significant difference in outcome (Creagan et al 1979, Moertel et al 1985). These two studies are often cited as evidence disproving the benefits of vitamin C in cancer treatment; however, the different routes of administration investigated in these studies is an important factor central to the discrepant results (Padayatty & Levine 2000), as only intravenous ascorbate can produce millimolar plasma concentrations, which are toxic to many cancer cell lines.

Intravenous vitamin C Intravenous administration of vitamin C achieves much higher plasma and urine concentrations than oral dosing and has been proposed as the only viable means of achieving the high concentrations required to induce the antitumour effects exhibited by the vitamin (Padayatty et al 2004). Currently, there are case studies that suggest this approach can improve patient wellbeing and, in some cases, reduce tumour size and improve survival (Padayatty et al 2006, Riordan et al 2005).

A recent safety study involved 24 late-stage terminal cancer patients who were administered continuous vitamin C infusions of 1 50-710 mg/kg/day for up to 8 weeks (Riordan et al 2005). This treatment regimen increased plasma ascorbate concentrations to a mean of 1.1 mmol/L and was considered relatively safe. The most common side-effects reported were nausea, oedema and dry mouth or skin, and two 'possible' adverse events occurred. One was a patient with a history of renal calculi who developed a kidney stone after 13 days of treatment and another was a patient

who experienced hypokalemia after 6 weeks. Interestingly, the majority of patients were vitamin C deficient prior to treatment.

Based on the available evidence of antitumour mechanisms and these case reports, further research into this approach is clearly warranted. Adjunct to oncology treatments Whether vitamin C improves or hinders responses to standard oncology treatment has been the focus of intense debate for many decades. There are in vitro studies showing that vitamin C can enhance the antitumour activity of cisplatin and doxorubicin (Abdel-Latif et al 2005, Kurbacher et al 1996, Reddy et al 2001, Sarna & Bhola 1993). In vivo evidence shows vitamin C enhances the effectiveness of 5-fluorouracil, doxorubicin, cyclophosphamide and vincristine (Lamson & Brig nail 2000, Nagy et al 2003), whereas other studies find no change in drug effect. Although these results are promising, no large randomised studies are available to confirm their significance in humans.

Most recently, vitamin C inactivated the effects of bortezomib, a new proteasome inhibitor approved by the US FDA for the treatment of patients with relapsed multiple myeloma (Zou et al 2006). Interestingly, drug inactivation was not achieved through antioxidative mechanisms.

Evidence from experimental models suggests that vitamin C may also reduce drug toxicity in a dose-dependent manner (Giri et al 1998, Greggi Antunes et al 2000).

Clinical note — The debate continues ... to Vitamin C or not?

One research group based at the University of Colorado has produced evidence that suggests that vitamin C and other antioxidant nutrients may not only protect healthy cells from damage but also improve the antitumour effects of standard treatment (Gottlieb 1999). They are currently conducting further research to identify how cell selectivity occurs but propose that cancer cells may have lost the normal homeostatic regulatory mechanism that stops excessive concentrations of antioxidants from entering the cell. As intracellular levels rise, a series of reactions occurs resulting in growth inhibition and cell death. Another group at Memorial Sloan Kettering Cancer Centre (Gottlieb 1999) argues that tumours already contain higher levels of ascorbic acid than normal cells and have identified a mechanism to explain this observation. As such, they advocate against the use of vitamin C when cytotoxic agents that rely on free radical production are being used (see Chapter 10 for further discussion).

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