August 2016
Melissa A. Moser and Ock K. Chun
Abstract
Vitamin C is a powerful dietary antioxidant that has received considerable attention in the literature related to its possible role in heart health. Although classical vitamin C deficiency, marked by scurvy, is rare in most parts of the world, some research has shown variable heart disease risks depending on plasma vitamin C concentration, even within the normal range.
Furthermore, other studies have suggested possible heart-related benefits to vitamin C taken in doses beyond the minimal amounts required to prevent classically defined deficiency.
The objective of this review is to systematically review the findings of existing epidemiologic research on vitamin C and its potential role in cardiovascular disease (CVD). It is well established that vitamin C inhibits oxidation of LDL-protein, thereby reducing atherosclerosis, but the cardiovascular outcomes related to this action and other actions of vitamin C are not fully understood.
Randomized controlled trials as well as observational cohort studies have investigated this topic with varying results. Vitamin C has been linked in some work to improvements in lipid profiles, arterial stiffness, and endothelial function. However, other studies have failed to confirm these results, and observational cohort studies are varied in their findings on the vitamin’s effect on CVD risk and mortality.
Overall, current research suggests that vitamin C deficiency is associated with a higher risk of mortality from CVD and that vitamin C may slightly improve endothelial function and lipid profiles in some groups, especially those with low plasma vitamin C levels. However, the current literature provides little support for the widespread use of vitamin C supplementation to reduce CVD risk or mortality.
Keywords: vitamin C, cardiovascular disease, observational cohort studies, clinical trials, meta-analyses
Introduction
In their 2004 Science Advisory Report, the American Heart Association stated that the current literature does not support the use of antioxidant vitamin supplements for the prevention or treatment of cardiovascular disease (CVD) [1]. Although the research conducted in this area is not uniformly positive, a substantial body of work has hinted at a possible reduction in CVD risk associated with antioxidant intake. Of particular interest to this review is the potential role of vitamin C in heart health. Vitamin C’s functions as an antioxidant and as an enzyme cofactor are well established, but the ways in which these functions may modify chronic disease risk are less well established.
The belief that vitamin C may benefit heart health has stemmed from multiple pieces of evidence and lines of reasoning. First, much work has documented the beneficial effects of fruit and vegetable consumption on heart health, which has led to the hypothesis that, among other nutrients, vitamin C may be partially responsible for this relationship. Importantly, the link between fruit and vegetable consumption and improved cardiovascular outcomes has primarily been established through cohort studies, as randomized controlled trials in this area are scarce. Nevertheless, the wealth of evidence accumulated from these epidemiological and cohort studies has consistently demonstrated the cardiovascular benefits of fruits and vegetables. For example, in the Nurse’s Health Study (NHS) and the Health Professionals Follow-Up Study (HPFS), which together looked at over 126,000 healthy adults, it was shown that individuals in the highest quintile of fruit and vegetable intake had a relative risk for coronary heart disease (CHD) of 0.8 (95% confidence interval [CI]: 0.69–0.93) compared to those in the lowest quintile of intake [2]. Of note, green leafy vegetables and vitamin C-rich fruits contributed most to the apparent protective effect of total fruit and vegetable intake. Another cohort of 1725 men in Sweden showed similar benefits of fruits and vegetables [3]. Further, a meta-analysis of 13 independent cohorts including 278,459 total participants showed that compared with individuals who had less than three servings per day of fruits and vegetables, the pooled relative risk of CHD was 0.93 (95% CI: 0.86–1.00) for those consuming three to five servings per day and 0.83 (95% CI: 0.77–0.89) for those consuming more than five servings per day. In this study, increased consumption of fruits and vegetables from less than three to more than five servings per day was related to a 17% reduction in CHD risk [4].
The hypothesis that vitamin C may play a role in CVD prevention also draws support from the vitamin’s antioxidant capabilities. The epidemiological evidence relating fruit and vegetable intake to reduced risk of CVD may be explained, at least in part, by antioxidant content, and especially the role of these antioxidants in preventing oxidative changes to LDL [5]. Oxidized LDL is a target for scavenger receptors, which incorporate it into plaque [6]. Therefore, the prevention of LDL oxidation by vitamin C may prevent atherosclerosis, thereby mediating a potential role in CVD risk reduction.
Various other functions of vitamin C may also bolster the hypothesis that vitamin C can reduce cardiovascular risk. For example, vitamin C has been shown to reduce monocyte adhesion to the endothelium [7]. Adhesion of circulating monocytes to endothelial cells is one key in the formation of atheromas, and is considered one of the early signs of the development of atherosclerosis [7]. Additionally, vitamin C has been shown to improve nitric oxide production of the endothelium, which, in turn, increases vasodilation, reducing blood pressure [8]. Furthermore, vitamin C may prevent apoptosis of vascular smooth muscle cells, which helps keep plaques more stable if atherosclerosis has developed [9].
The requirement for dietary vitamin C is based on its role as an antioxidant, and was determined by estimating the quantity of dietary vitamin C needed to maximize its concentration in neutrophils, where it reduces reactive oxygen species produced during phagocytosis [10]. Given that vitamin C may relate to heart disease risk through more than one mechanism, it is possible that the recommended or typical levels of vitamin C intake are incongruous with the intake levels needed to provide protection against CVD. Therefore, even the Recommended Dietary Allowances (RDA) for vitamin C of 75 mg for women and 90 mg for men may be inadequate to obtain potential benefits. Based on a recent analysis of US adults in the National Health and Nutrition Examination Survey (NHANES) data, the mean intake of vitamin C from food alone is above the RDA for both men and women (104.6 ± 3.4 mg and 86.6 ± 2.7 mg, respectively) [11]. Many of the clinical trials testing hypotheses related to vitamin C and CVD have used supplemental vitamin C in doses of 500–1000 mg per day. Therefore, if vitamin C does alter cardiovascular risk, questions still remain regarding the relevant mechanisms, the differential effects of supplemental and naturally occurring vitamin C, and the recommended intakes of vitamin C to minimize heart disease risk. This review examines key pieces of literature seeking to answer these questions.
Methods
This review covers the cardiovascular effects of vitamin C in human studies and attempts to explain the underlying mechanisms involved. A literature search was conducted using three databases: PubMed, Web of Science, and Scopus. Articles were identified in these databases using the search “vitamin C cardiovascular disease”, and additionally using a MeSH search in PubMed: (“Ascorbic Acid” (Mesh)) AND “Cardiovascular Diseases” (Mesh). Other key words added to this search were myocardial infarction, low-density lipoprotein, hypertension, and endothelial function. The reference lists of relevant articles identified in this systematic review were searched manually for additional inclusions. Articles chosen for this review were published by May 2016. Publications identified by these methods were then limited to only those meeting all of the following criteria: (1) randomized controlled trials, observational studies, or meta-analyses examining vitamin C intake (dietary or supplemental) or plasma vitamin C concentrations; (2) studies involving adults aged ≥18 years; (3) studies reporting changes in cardiovascular outcomes or risk factors as an endpoint (mortality, CVD or CHD incidence, lipid profile, endothelial function, blood pressure).
Conclusions
The current literature provides little support for the use of vitamin C supplementation to reduce heart disease risk. Many cohort studies and randomized trials have shown no relationship between vitamin C intake and heart disease risk, while few have suggested moderate benefits, and some have even suggested slight increases in risk. Importantly, multiple studies have documented increases in cardiovascular risk associated with the use of supplemental vitamin C, even when taken in doses of about 1000 mg per day, which is half of the established Tolerable Upper Intake Level (UL) of 2000 mg [19,23]. Although several studies have shown similar absorption of vitamin C from supplements and from food sources [30,31], the mechanisms behind the apparent differential effects of supplemental and dietary vitamin C require further examination.
Interestingly, meta-analyses examining particular risk factors of heart disease show that vitamin C may favorably affect blood pressure and endothelial function. While these are only single elements of CVD, they do lend support to the hypothesis that vitamin C may play a role in heart disease. Additionally, multiple observational studies have confirmed that CVD risk and mortality are increased in those with the lowest plasma concentrations of vitamin C, even if they are not classified as deficient in this vitamin. All of these studies, however, are limited in several ways, including the use of only supplemental vitamin C, limited follow-up or intervention time, and reliance on self-reported diet or self-reported compliance with interventions.
The lack of consistency within the body of research on this topic has called into question the roles of antioxidants in the human body, and has even cast doubt on the LDL oxidative hypothesis [32,33,34]. A key limitation in understanding the relationship between vitamin C and CVD is the lack of mechanistic studies in humans.
Most evidence supporting this link is based on animal studies and observational studies in humans, which both may fail to capture other factors that could play an important mediating role in this relationship. Despite these issues, there is still compelling evidence that warrants continued investigation of the role of vitamin C and other antioxidants in CVD.
