Is Vitamin Supplementation Beneficial with Regards to Cardiovascular Disease?

Abstract

Cardiovascular diseases are the number one killer of humans worldwide according to the World Health Organization’s Statistics. Cardiovascular diseases are defined as diseases that affect the heart, arteries and veins. The most common reason for CVDs is atherosclerotic plaque buildup in the arteries. This can lead to complications such as Myocardial Infarction, strokes and Coronary Heart Disease. In the last two decades research has explored the effect of antioxidant vitamins in the prevention and treatment of CVDs. Observational and randomized control studies have explored the effect of Vitamin E, C and A through supplementation and dietary intake in the prevention and treatment of CVDs in humans and animals. The results are largely inconclusive and contradictory, this review explores research carried out in the last two decades and attempts to develop and consolidate the understanding of factors affecting the efficacy of vitamin treatment in prevention and treatment of CVDs. This review identifies methodological differences, additional factors and individual differences which all inversely and adversely affect the efficacy of vitamin treatment in preventing and treating CVDs.

Introduction

Cardiovascular diseases (CVDs) are diseases that affect the heart and the blood vessels i.e. the arteries and the veins; however they are generally associated with those caused by atherosclerosis. This includes Hypertension (high blood pressure), Coronary heart disease (heart attack), cerebrovascular disease (stroke), Peripheral vascular disease, Heart failure, Rheumatic heart disease, congenital heart disease and Cardiomyopathies; amongst others (WHO 2011).

Epidemiology

Figure 1

Figure 1 shows the Incidence of CVDs worldwide with the darker areas signifying higher prevalence; in 1999 the WHO stated that CVDs were responsible for a third of all deaths globally this escalated in 2010 to be the primary leading cause of death. The drastic increase in morbidity due to CVDs highlights the need for further knowledge and understanding around CVDs; their treatment and prevention. Gaining further understanding about treating and preventing CVDs can help decrease the current rate of morbidity. Improving the awareness and understanding of risk factors and preventative care will also aid a decrease in the expenditure by health services treating the diseases on a global scale. The latest figures from the Unites States of America and the European Union show that CVDs costs around €310.23 and €169 billion respectively in direct and indirect annual costs (Leal et al. 2006). CVDS is clearly a growing problem in today’s society that requires urgent attention.

Risk Factors

There are two types of risk factors, modifiable and non modifiable.
Modifiable risk factors are factors that can be controlled or treated. Non modifiable risk factors are factors that a person has no control over.

Modifiable risk factors, according to the World Heart Federation, include but are not limited to:

• Hypertension
• High levels of total cholesterol, high levels of triglycerides and high levels of low density lipoproteins combined with low levels of high density lypoproteins.
• Low physical activity
• Type II diabetes is classed as a major risk factor
• Left ventricular hypertrophy

Non modifiable risk factors include, but are not limited to:

• Age: Mackay and Mensah (2004) found that the risk of stroke doubles with every decade after the age of 55.
• Family history: If a first degree relative develops coronary heart disease before the age of 55 or 65 for males and females respectively then risk of CVDS increases (Mackay and Mensah 2004).
• Gender: Men have a higher risk of CVDs than pre menopausal women (Mackay and Mensah 2004).
• Ethnicity: People with African and Asian ancestry are deemed to have a higher risk of CVDs than other races. (Mackay and Mensah 2004)

Atherosclerosis

Atherosclerosis is caused by a buildup of fatty acids in the heart or blood vessels, leading to an atheromous plaque; which can then develop into cardiovascular disease.

Figure 2 The Pathogenesis of atherosclerosis.

As Figure 2 shows, the initial stage of atherosclerosis is a lesion which develops into a fatty streak; this fatty streak then becomes an intermediate lesion, as the fat further accumulates intracellularly. These early stages are clinically silent and symptoms only occur in the latter stages, if at all.

The origin of the fat deposits is the buildup of the “bad cholesterol” also known as low density lipoproteins.  When this is combined with the over production of Reactive Oxygen Species (ROS) it can lead to the peroxidation of the low density lipoproteins, which is a major cause of Atherosclerosis (Dusting and Triggle 2005). The oxidation of lipoproteins causes damage to endothelial lining and fibroblasts which can  result in severe atherosclerosis (Manson et al. 1995)

Anti-oxidants

Anti oxidants are species that can stabilize free radicals thus inhibiting oxidation of substances. They do this by counter-balancing the lone pair of electrons and thus sterically restricting the    -O- center from intermolecular reactions that could initiate free radical chain reactions (Finkel and Holbrook 2000).

“Antioxidants may slow or prevent atherosclerotic plaque formation by inhibiting low-density lipoprotein cholesterol oxidation, modifying platelet activity, reducing thrombotic potential, and modifying vascular reactivity. “ (Sesso et al, 2008) This has given precedence to researching an association between antioxidant intake, in the form of vitamin supplementation and dietary intake, and prevention and treatment of CVDs.

Figure 3-Molecular Structure Of Antioxidants

A wealth of studies have been conducted using a variety of methods to try and determine the effect vitamins have on pre existing and prevention of CVDs. 

Vitamin E

“Vitamin E is an important antioxidant vitamin, playing an essential protective role against free radical damage” (Riccioni, 2007).

Vitamin E is one, amongst many, of the antioxidant vitamins which have been explored in terms of their relationship with the development and prevention of CVDs. In the early 1990’s research began to consider the effect of Vitamin E on cardiovascular diseases. A series of early observational studies concluded that Vitamin E supplementation significantly reduced an individual’s risk of developing CVD in both men and women. Using self completion questionnaires as part of The Nurse Health Study Stampfer et al (1993) found that women with a higher intake of Vitamin E, through diet and supplementation, were at significantly lower risk of developing major coronary disease. They also found that women taking multi vitamin supplements were at a lower risk of developing major coronary disease, 0.66 relative risk at 95% confidence interval, 0.50 to 0.87, when compared to women taking no supplementation. When the study was extended to male health professionals, Rimm et al (1993) found that men with the highest intake of Vitamin E, through diet and supplementation, had the lowest risk of developing major coronary disease, 0.64 relative risk at 95% confidence interval, 0.49 to 0.83, compared with men consuming less Vitamin E or male participants not taking Vitamin E supplements. Although these studies cannot prove a causal relationship between Vitamin E consumption and risk of coronary disease they provide evidence of an association.

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This interesting new finding led to further research in the form of randomized control trials. However, the majority of recent randomized control trials failed to produce the same results as earlier observational studies. Eidelman et al (2004) evaluated seven randomized control trials and found vitamin E was neither statistically nor clinically significantly associated with any cardiovascular event. In the Cambridge Heart Antioxidant Study, (CHAOS), Stephens et al (1996) used a double – blind randomized placebo controlled study to test the effect of Vitamin E on patients with angiographically proven symptomatic coronary atherosclerosis. They found that patients receiving Vitamin E treatment had a significantly lower chance of developing non fatal myocardial infarction, 41 versus 64; relative risk 0.53 at 95% confidence interval, 0.34 to 0.83. This suggests Vitamin E intake may have a positive effect in the prevention of CVDs.

On the other hand, in the Physicians Health Study II, using a randomized, double – blind, placebo – controlled trial, with a mean follow up of 8 years, Sesso et al (2008) found that in healthy US male physicians Vitamin E supplementation had no effect on the incidence of major cardiovascular events, 10.9 events per 1000 person-years, compared to a placebo. Roberts et al (2007) examined the effect of dosage, and duration of supplementation, in participants with polygenic hypercholesterolemia and enhanced oxidative stress, a population deemed high at risk of developing CVDs              . Roberts et al (2007) firstly performed a time course study, where participants were supplemented with 3200 IU of Vitamin E daily for 20 weeks. A dose ranging study was then conducted, participants received 0, 100, 200, 400, 800, 1600, 3200 IU Vitamin E daily for 16 weeks. It was found that maximum suppression of plasma F2 –isoprostane concentrations, a biomarker of free radical– mediated lipid peroxidation, did not occur until 16 weeks of supplementation. Roberts et al (2007) reported a significant association between dosage of Vitamin E and percentage reduction in plasma F2 – isoprostane concentrations. This relationship reached significance at doses of 1600 IU (35 + 2%, p <0.035) and 3200IU (49 + 10%, p<0.005). The results from this study suggest that with the right dosage for the appropriate duration of time Vitamin E supplementation can significantly reduce risk of developing CVDs.

Research has also considered the effect of Vitamin E intake on cardio vascular health in animals. Animal studies can allow better control and more rigorous measures for lesion progression (Weinberg et al. 2005).Weinberg et al. (2005) reviewed previous trials using mice and rabbits to investigate the effect of Vitamin E intake. The majority of the mice trials showed significant vitamin E effects however, the rabbit trials however were not as conclusive with only 30% showing a significant effect of Vitamin E intake on cardiovascular health. Boger et al (1998) also investigated the effect of Vitamin E on the cardio vascular health of rabbits. Boger et al (1998) examined whether 300mg of Vitamin E, in the form of a – tocopherol, improved endothelium – dependent vasodilator function, reduced vascular oxidative stress and therefore reduced the progression of atherosclerosis in cholesterol –fed rabbits with pre existing hypercholesterolemia. It was discovered that a – tocopherol consumption reduced initial lesion formation by 41 + 11% and improved endothelium – dependent relaxation. They concluded that Vitamin E consumption reduced the progression of atherosclerotic plaques in cholesterol – fed rabbits. Whilst findings from animal studies cannot necessarily be applied to humans, the results from these studies give some indication of possible positive effects of Vitamin E consumption in reducing atherosclerotic plaque production.

Vitamin C

Vitamin C has the ability to reverse oxidation by acting as a hydrogen donor, leading to its classification as an antioxidant; it therefore facilitates the inactivation of free radicals before damage to proteins or lipids has occurred (Riccionni, 2007). This very nature of Vitamin C has driven research into the potential effect of Vitamin C in the prevention and treatment of  CVDs. Using a 20 year follow up study, Gale et al. (1995) investigated the effect of Vitamin C, through dietary intake and plasma ascorbic acid concentration, on mortality rates for CVDs in a group of elderly participants. Gale et al. (1995) established no association between Vitamin C intake and risk of death from coronary heart disease.

 Sesso et al (2008), as part of the Physicians Health Study II, also investigated the effect of Vitamin C on the prevention of CVDs in male health professionals. Vitamin C was found to have no significant effect on major cardiovascular events, total myocardial infarction or cardio vascular mortality.

On the other hand, Osganian et al. (2002) found an inverse relationship, 0.73 relative risk at 95% confidence interval; 0.57-0.9, between total vitamin C intake, through supplementation, and risk of developing CHD.   The same study also found a non significant association between dietary vitamin C intake and risk of developing CHD, relative risk 0.86 at 95% confidence interval; 0.59 to 1.26. Lee et al. (2004) investigated the relationship between Vitamin C intake, through supplementation and diet, and mortality from CVDs, coronary artery disease and stroke in diabetic post menopausal women. Lee et al (2004) established the relative risks of total  mortality from CVDs in participants were 1.0, 0.97, 1.11, 1.47, and 1.84 (P for trend < 0.01) across quintiles of total Vitamin C intake, from diet and supplementation. Adjusted relative risks of coronary artery disease were 1.0, 0.81, 0.99, 1.26, and 1.91 (P for trend = 0.01) and of stroke were 1.0, 0.52, 1.23, 2.22, and 2.57 (P for trend < 0.01) (Lee et al. 2004). The results from this study suggest that Vitamin C intake can increase risk of mortality from CVDs, including coronary artery disease and stroke. When the results were further analysed Lee et al. (2004) discovered only Vitamin C intake in the form of supplementation was positively associated with mortality from CVDs, coronary artery disease or stroke. This suggests that only Vitamin C intake from supplementation, rather than dietary, can be harmful to post menopausal women by increasing their risk of mortality from CVDs, including coronary artery disease or stroke. Interestingly Lee et al (2004) found no association between Vitamin C intake and mortality rates in non – diabetic participants.

Vitamin A

Rapola et al (1997) examined the effect of beta – carotene supplementation on the incidence of major coronary events in men with previous myocardial infarction. Using a randomized, double – blind, placebo – controlled study participants received daily supplements of beta – carotene (20 mg), a – tocopherol (50 mg daily), a combination of beta – carotene and a – tocopherol, or a placebo. Rapola et al (1997) then monitored and investigated any major coronary events occurring during follow up period, median follow up was 5.3 years. In participants receiving beta – carotene supplementation or combined beta – carotene and a – tocopherol supplementation there were significantly more deaths from fatal coronary heart disease reported (74/461, multivariate-adjusted relative risk 1.75 [95% CI 1.16-2.64], p=0.007 and 67/497, relative risk 1.58 [1.05-2.40], p=0.03 respectively) compared to the placebo group. However, there were no significant differences in the number of major coronary events reported between beta – carotene supplement group, a – tocopherol supplement group or the placebo group   (a-tocopherol 94/466; b-carotene 113/461; a-tocopherol and b-carotene 123/497; placebo 94/438 [log-rank test, p=0.25]). The results suggest that whilst beta – carotene supplementation may increase the risk of mortality due to fatal coronary heart disease, it appears that supplementation did not significantly increase the number of major coronary events reported overall.

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The Women’s Health Study Lee et al (1999) also used a randomized, double – blind, placebo – controlled trial to identify a potential relationship between beta – carotene and the prevention of cardio vascular disease in women over 45 years of age. The Women’s Health Study found, after a median follow up of 4.1 years, there were no statistically significant differences in incidence of CVDs or number of total deaths reported between women randomly assigned to the beta – carotene supplementation group and women randomly assigned to the placebo group.  The results from The Women’s Health Study (Lee et al, 1999) further suggest that beta – carotene supplementation has no significant effect, positive or adverse, on the prevention of CVDs.
Discussion

Research investigating the effect of Vitamin’s E, C and A on the prevention and treatment of CVDs in humans and animals has been largely inconclusive and in places contradictory. Further exploration of these findings is necessary to develop and consolidate our understanding of the effect of Vitamins E, C and A, through dietary intake and supplementation, on the development, prevention and treatment of CVDs.

The methodology used by studies is a key factor that must be considered when examining the validity of results.  It appears that there is inconsistency in results produced by observational and randomized control studies. For example, Investigating Vitamin E Stampfer et al (1993) & Rimm et al (1993), using an observational method of self completion dietary questionnaires, discovered that men and women with the highest dietary intake of Vitamin E had significantly lower risk of developing major coronary disease. However, when Eidelman et al (2004) evaluated results from seven randomized control trials a conclusion was drawn that Vitamin E was neither statistically or clinically significantly associated with any cardiovascular event.

 Dietrich et al (2009) argued that early observational studies tended to focus on primary prevention and excluded participants with pre existing CVDs. On the other hand, Dietrich et al (2009) argued, randomized control trials tended to consider secondary prevention and treatment thereby recruiting participants at high risk of developing CVDs , for example Roberts et al (2007), or participants with pre existing CVDs.  This fundamental difference in the design and approach could potentially explain part of the disparity of results. Dietrich et al. suspected that an underlying factor affecting the efficacy of Vitamin E in the prevention and treatment of CVDs was the existing health status of the participant. To further explore this consideration Dietrich et al (2009) carried out an observational study looking at primary and secondary prevention, and treatment, in individuals with no history of CVDs and a group of participants with pre existing CVDs; using participants from the Framingham Heart Study. They found no statistically significant relationship between Vitamin E supplementation, CVDs and all cause mortality in participants with and without pre existing CVDs. The results suggest that in this study Dietrich et al.’s hypothesis was incorrect; the health status of the participants at baseline had no affect on the efficacy of Vitamin E.  However, the validity of these findings is questionable due to the methodological approach adopted by the study.

The nature of observational studies means there may be several confounding variables that are not controlled for and therefore may affect the results. Gaziano (1996) discusses the problems encountered when using descriptive observational studies.  He notes several potential confounding variables which may affect the efficacy of Vitamin E treatment but are commonly not controlled for; these include other dietary factors, lifestyle characteristics, genetics and differences in access to health care.

Dietrich et al (2009) investigated potential confounding variables by exploring the relationship between dose and duration of supplementation and prevention and/or treatment of CVDs. Although they found no significant associations between dosage or duration of supplementation and CVDs age, diabetes and treatment for blood pressure were all identified as positive predictors of CVDs and all – cause mortality. This clearly indicates that there are confounding variables and individual differences which may affect the efficacy of Vitamin E treatment. For example, Lee et al (2004) found Vitamin C intake significantly increased the risk of mortality from CVDs, coronary artery disease and stroke in post menopausal diabetic women. However, they reported no association between Vitamin C intake and mortality in non diabetic post menopausal women. These results suggest that in this particular study the underlying health status of participants, diabetic or non diabetic, significantly affected the effect of Vitamin C intake. Roberts et al (2007) also investigated the effect of dosage and duration of supplementation on cardio vascular health in a population high at risk of developing CVDS, they found a significant relationship between dosage, duration and reduced risk of developing CVDs. The results suggest that the dosage and duration of supplementation are crucial factors that affect the overall effect of Vitamin intake. For example, studies which report no effect of Vitamin supplementation on cardiovascular health may not have been using a high enough dosage or for a long enough duration. The results from Roberts et al (2007) are directly clinically relevant as they indicate an appropriate dosage and duration of treatment to ensure a positive effect of Vitamin supplementation. It is important to consider that dosages and duration of treatment may vary between Vitamins and that whilst dosage and duration are important factors which evidently affect the efficacy of Vitamin intake they are not the only factors to consider. 

 Dietrich et al (2009) used self completion dietary questionnaires, an observational method, compared to Roberts et al (2007) who used a double – blind, randomized, placebo – controlled study; this further reiterates the argument that disparity in results may be partially explained by differences in methodological approach. Observational studies can only control for effects of known and measured or measurable potential confounding variables. However, unknown or un- measurable confounding variables cannot be taken into consideration. For example, levels of antioxidant and vitamin intake may not be the only protective factor for an individual, however when using a self completion dietary questionnaire antioxidant and vitamin intake is the only dietary factor that will be considered and measured (Gaziano, 1996).  For instance, Dietrich et al (2009) found that participants taking Vitamin E supplements were also more likely to be taking a multi vitamin than participants not taking Vitamin E supplement (63% versus 22%). Although when using multivariate models to investigate multi vitamin supplementation as a potential confounding variable the results were not changed, the fact that participants taking Vitamin E supplements were more likely to also take a multi vitamin suggests they may also be more likely to engage in other protective health or dietary behaviors which may, if investigated or controlled for, significantly affect the efficacy of Vitamin E intake.

 Therefore when considering whether Vitamin E adversely or inversely affects the prevention or treatment of pre exisiting CVDs there are several factors that need to be considered; including age, baseline health status, genetics, other dietary factors including additional supplementation (Gaziano, 1996).

Another important factor that needs to be considered when reviewing the findings of studies is whether participants received vitamin treatment through dietary intake or supplementation. The method of vitamin treatment, dietary and/ or supplementation, may also be partly responsible for some of the contradictions in findings. Osganian et al (2002) found an inverse relationship between Vitamin C supplementation and risk of developing coronary heart disease. However, no association was found between dietary intake of Vitamin C and risk of developing coronary heart disease. This suggests that the effect of vitamin treatment may depend upon the method of intake, although; results from Osganian et al (2002) indicate that only intake through supplementation is beneficial in reducing risk of CVDs. This closely links in with conclusions drawn from Roberts et al (1997) relating to dosage. Roberts et al (2004) found Vitamin E supplementation was only significantly associated with percentage reduction in plasma F2 – isoprostane concentrations at a dosage of 1600 IU (daily). The National Institute of Health’s (2011) daily recommended allowance (RDA) for Vitamin E is 22.4 IU (for men and women 14 years of age and older). This means to consume, through diet alone, the amount of Vitamin E Roberts et al (2007) found positively reduced risk of developing CVDs an individual would have to consume at least 71.4 times as much Vitamin E as the RDA for men and women over 14 years of age.

However, results from observational and double – blind, randomized, placebo – controlled studies are both useful and interesting. The results from Dietrich et al (2009)’s study highlights factors such as age, diabetes and treatment for blood pressure which potentially affect the efficacy of Vitamin treatment. Coupled with the results from Roberts et al (2007) study indicating that duration and dosage significantly affect the effect of Vitamin E supplementation; confounding variables and factors that inversely or adversely affect the effect of Vitamin intake have been identified.

Conclusion

It becomes apparent that when studying the effect of vitamins on CVDs there are several important factors that need to be considered. The Conclusion of this review is that there is not enough data that shows positive results for vitamin supplementation for the answer to the question “Is vitamin Supplementation beneficial with regard to Cardiovascular Disease.”  When reviewing research considering the effect of vitamins on the prevention and treatment of CVDs it is critical to consider the methodology adopted by a study. Whilst observational studies provide interesting and useful information, the lack of control for confounding variables must be taken into account. When considering the effect of vitamin intake, dietary and supplementation, on prevention and treatment of CVDs there are also several important factors that must be considered; these include, but are not limited to, age, menopausal status, sex, other dietary or protective factors, dosage, duration of treatment, form of intake (dietary or supplementation) and health status at baseline (diabetes, pre existing health problems and treatments).

Alternative further studies could focus on γ-Tocopherol as it is a common form of Vitamin E in certain countries and has not been researched as intensively as α-Tocopherol. Also if observational studies are to be used using younger study participants would better show effect of supplementation over a longer time period.

There is also the issue that as most studies use participants with pre existing CVDs or are at high risk of developing a CVD it may be that supplementation works better with people who have low levels of antioxidants but high oxidative stress. So further studies could focus on recruiting participants on a different basis.

Race of participants is another further study area as most vitamin supplementation studies with respect to CVDs use Caucasian participants which means the results cannot be extrapolated to a whole population as different Races have individual differences. So enrollment of all races would help the results to be more population relevant.

Another factor that may affect study results is that participants may be taking vitamin supplements but the dosing may be different if the source of the supplements is not the same for all participants and also if they are different stereoisomers this may have different effects on the body so future research should standardize dose, source and stereoisomers for all participants.

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