Published online before print October 14, 2002, doi: 10.1161/01.HYP.0000038340.95407.43
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(Hypertension. 2002;40:789.)
© 2002 American Heart Association, Inc.
Editorial Commentaries |
Blood Pressure Effects of Vitamin C
What’s the Key Question?
From the Duke Hypertension Center and the Sarah W. Stedman Center for Nutritional Studies, Duke University Medical Center (L.P.S.), Durham, NC; and the Division of Epidemiology and Clinical Applications, National Heart, Lung, and Blood Institute (C.M.L.), Bethesda, Md.
Correspondence to Laura P. Svetkey, Box 3075, Duke University Medical Center, Durham, NC 27710. E-mail svetk001{at}mc.duke.edu
Some, but not all, observational data concerning diet and health suggest an inverse relationship between dietary vitamin C and cardiovascular disease (CVD) morbidity and mortality.1 If such a relationship exists, vitamin C presumably protects against CVD through its antioxidant properties, possibly by preventing lipid peroxidation. Others have suggested that vitamin C might protect against CVD through effects on blood pressure (BP) and arterial stiffness.2–6 Such an effect is suggested by epidemiologic associations noted in some populations,7 but the role of this nutrient in BP regulation remains unclear, owing to design issues and/or confounding variables. For example, a recent analysis of the prospective Western Electric study2 suggests that low antioxidant intake is associated with the rise in BP with age. In that study, intake of both vitamin C and ß-carotene were combined to form an "antioxidant score," so the effect of vitamin C alone was not estimated. Even in studies that isolate vitamin C intake, results are inconclusive: not all studies demonstrate an inverse relationship between vitamin C and BP; key nutrients (eg, sodium) are not accurately measured by most diet survey methods; and more importantly, these observational studies are potentially confounded by intake of other nutrients that affect BP. For example, in the Western Electric study, the investigators did not adjust for intake of potassium, a nutrient with well-known BP-lowering effects,9 which is found in many antioxidant-rich foods. Thus, although a relationship between vitamin C intake and BP is suggested, the epidemiologic data are inconclusive.
Randomized controlled trials offer many advantages over prospective observational studies, including minimizing the effects of other confounding variables. Despite these advantages, a total of 7 previous trials examining BP effects of vitamin C have been inconclusive. Two of 4 randomized trials reviewed by Ness et al8 suggest no effect. The 2 positive studies in this review were methodologically flawed: one reported BP change only in the treatment group, and the other included only 20 individuals, most of whom did not have hypertension. Two subsequent trials were negative. A third study4 was difficult to interpret, likely because of its complex design: diastolic (but not systolic) BP was inversely related to plasma ascorbate level at the end of a preceding period of vitamin C depletion, but not to ascorbate level after vitamin C repletion. In aggregate, previous clinical trials do not convincingly demonstrate BP-lowering effects of vitamin C, and the question of whether vitamin C should be recommended for prevention or treatment of hypertension remains unanswered.
Unfortunately, the 2 papers in this issue5,6 do not resolve this question. Both studies are randomized controlled trials of 500 mg/day of supplemental vitamin C; yet, they have diametrically opposite results: one showing a decrease in BP6 and one showing no reduction (and perhaps an increase).5 Both studies included free-living, hypertensive and nonhypertensive adults who ate an uncontrolled diet during the study. However, these studies differed in several important ways that could have contributed to their discrepant results. The Mullan et al study,6 comparing 500 mg/day of vitamin C supplement to placebo for 1 month, showed a significant decrease in BP, of 9.9/4.4 mm Hg. This study was small (n=30) but used more precise (ie, triplicate) BP measurements. In contrast, the Kim et al study,5 comparing 500 mg/day of vitamin C to 50 mg/day of vitamin C for 5 years, showed no reduction in BP. The Kim study was larger (n=244) and therefore presumably had greater power, but it based BP estimates on a single (ie, less precise) measurement. In addition, there were differences in the prevalence of treated hypertension (
50% in the Mullan study versus 15% in the Kim study), inclusion and exclusion criteria that may affect absorption and turnover of vitamin C (eg, smoking status), and follow-up rates (100% in the Mullan study versus 80% in the Kim study). There were also potentially important differences in baseline mean BP (142/84 mm Hg in the Mullan study versus 127/77 mm Hg in the Kim study). The lower baseline BP and prevalence of treated hypertension in the Kim study could account in part for the lack of BP effect, given that nonpharmacologic interventions typically have greater effects on individuals with higher BP.
However, the 2 most important differences are the study populations and the duration of the treatment period. Mullan et al studied diabetics in Ireland, and Kim et al studied Japanese individuals with gastric atrophy. In addition to potential genetic differences between these 2 populations, the 2 clinical conditions may differ in vitamin C metabolism. For example, diabetes may be associated with higher vitamin C requirements for general health. In addition, neither population was selected specifically because of entry BP or the presence of hypertension. Therefore, it is difficult to know how to apply these results to the general population, to those with hypertension or high-normal BP, or to other at-risk groups.
An equally important difference between these 2 studies is the duration of treatment: 1 month in the Mullan study and 5 years in the Kim study. Disregarding other differences in study design, this difference might lead us to conclude that short-term treatment leads to BP reduction, but this effect either is not sustained or is overwhelmed by the typical rise in BP with aging. If vitamin C, or any intervention, is to be effective in preventing and/or controlling hypertension, a sustained effect is critically important. Either scenario—short-term treatment leading to long-term BP reduction or persistence of BP effects as long as treatment is continued—is acceptable, although the latter is biologically more likely to occur. We must keep in mind that the lack of a significant long-term effect in the Kim study could have been confounded by a relatively high dropout rate or by other factors such as changes in weight over time. It is not possible to determine whether there was a short-term effect in the Kim study or whether the BP effect observed in the Mullan study would have persisted if the treatment had been continued. In any case, at this time it is impossible to conclude that vitamin C has a sustained BP-lowering effect.
The discovery of a nutrient supplement that lowers BP would make widespread changes in dietary intake aimed at lowering BP unnecessary, but experience suggests that we are unlikely to find such a magic bullet. In fact, there appears to be little evidence that supplements of individual nutrients are sufficiently effective in preventing or controlling high BP. Despite a large body of epidemiologic literature suggesting that high intake of potassium, magnesium and calcium are protective against high BP, trials of these individual nutrients have generally been disappointing. A meta-analysis of potassium supplement studies suggests a reduction in SBP of 3/2 mm Hg.9 A meta-analysis of calcium supplement studies suggest an even smaller effect (<2 mm Hg).10 Even when combinations of 2 to 3 nutrient supplements are tested together, results are disappointing.11
Research on the health effects of diet has generally started with the most simplistic model, ie, testing the effect of a single nutrient. Perhaps we need to approach dietary research from the opposite direction, first testing which combinations of foods (ie, dietary patterns) lower BP or prevent the age-related rise in blood pressure. Once we know which dietary patterns have the desired effect, we can begin to disentangle the effects of individual nutrients or food components to enhance our understanding of the mechanisms through which diet affects BP. Nutrients are consumed in foods containing complex combinations of nutrients and other food components that may affect health. This complexity makes changes in food behaviors difficult to implement when goals are stated in terms of nutrients. Advice to increase or decrease consumption of individual foods as part of an overall dietary pattern may be more practical than messages to modify intakes of individual components.
The Dietary Approaches to Stop Hypertension (DASH) Study12 represents just such a practical approach. The minimal BP effects observed with individual nutrient supplements contrast sharply with the large BP effects noted when desirable nutrient combinations were tested in the DASH dietary pattern, which emphasizes fruits, vegetables, and low-fat dairy products. The DASH dietary pattern also includes whole grains, poultry, fish, and nuts, and it is reduced in fats, red meat, sweets, and sugar-containing beverages. Its nutrient content is increased in potassium, magnesium, calcium, and fiber; moderately increased in protein; and reduced in saturated fat, total fat, and cholesterol. In addition, the DASH diet is rich in vitamin C (266 mg/day compared with 133 mg/day in the control group) and other antioxidants. This dietary pattern led to BP reductions (net of control) of 5.5/3.0 mm Hg in a population with high-normal BP and stage 1 hypertension, and of 11.6/5.3 mm Hg in the subset with hypertension. The DASH study design does not allow us to identify the role of individual nutrients (with the exception of sodium in the DASH-Sodium study13). It is also impossible to determine which components of the DASH pattern are most important and what the dose-response relationship is—does one have to eat all 9 to 12 servings of fruits and vegetables and all 3 servings of low-fat dairy products to reap the BP benefits of the DASH diet? Additional research is needed to refine our understanding of dietary effects on BP and to perfect our dietary recommendations to the public.
The effect of vitamin C on BP may be important, but the clinical trials reported in this issue of Hypertension and others that have preceded them have asked a question that may be of secondary importance to public health. Although an understanding of the effect of individual nutrients on BP is important from a mechanistic point of view, the epidemic proportions of adverse BP levels in this country argue for a more practical approach. The majority of individuals age >60 years have high BP; those without high BP have an estimated 90% life-time risk of developing it; and individuals of any age with high-normal BP that would not currently be treated pharmacologically are at significant excess CVD risk from their above-optimal BP. From a public health and clinical perspective, the key question is how to optimize dietary patterns to prevent and treat high BP.
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
References
1. Loria CM. Vitamin C status and cardiovascular disease: a review of prospective studies. In: Frei B, Traber M, eds. The Antioxidant Vitamins C and E. Champaign, Ill: AOCS Press. In press.
2. Stamler J, Liu K, Ruth KJ, Pryer J, Greenland P. Eight-year blood pressure change in middle-aged men: relationship to multiple nutrients. Hypertension. 2002; 39: 1000–1006.
3. Duffy SJ, Gokce N, Holbrook M, Huang A, Frei B, Keaney JF Jr, Vita JA. Treatment of hypertension with ascorbic acid. Lancet. 1999; 354: 2048–2049.[CrossRef][Medline] [Order article via Infotrieve]
4. Block G, Mangel AR, Norkus EP, Patterson BH, Levander OA, Taylor PR. Ascorbic acid status and subsequent diastolic and systolic blood pressure. Hypertension. 2001; 37: 261–267.
5. Kim MK, Sasaki S, Okubo S, Hayashi M, Tsugane S. Lack of long-term effect of vitamin C supplementation on blood pressure. Hypertension. 2002; 40: 797–803.
6. Mullan BA, Young IS, Fee H, McCance DR. Ascorbic acid reduces blood pressure and arterial stiffness in type 2 diabetes. Hypertension. 2002; 40: 804–809.
7. Bates CJ, Walmsley CM, Prentice A, Finch S. Does vitamin C reduce blood pressure? Results of a large study of people aged 65 or older. J Hypertens. 1998; 16: 925–932.[CrossRef][Medline] [Order article via Infotrieve]
8. Ness AR, Chee D, Elliott P. Vitamin C and blood pressure: an overview. J Hum Hypertens. 1997; 11: 343–350.[CrossRef][Medline] [Order article via Infotrieve]
9. Whelton P He J, Cutler JA, Brancati FL, Appel LJ, Follmann D, Klag MJ. Effects of oral potassium on blood pressure: meta-analysis of randomized controlled clinical trials. JAMA. 1997; 277: 1624–1632.
10. Allender PS, Cutler JA, Follmann D, Cappuccio FP, Pryer J, Elliott P. dietary calcium and blood pressure: a meta-analysis of randomized clinical trials. Ann Intern Med. 1996; 124: 825–831.
11. The effects of nonpharmacologic interventions on blood pressure of persons with high normal levels: results of the Trials of Hypertension Prevention, phase I. JAMA. 1992; 267: 1213–1220.
12. Appel LJ, Moore TJ, Obarzanek E, Vollmer WM, Svetkey LP, Sacks FM, Bray GA, Vogt TM, Cutler JA, Windhauser MM, Lin P-H, Karanja N, for the DASH Collaborative Research Group. A clinical trial of the effects of dietary patterns on blood pressure. N Engl J Med. 1997; 336: 1117–1124.
13. Sacks FM, Svetkey LP, Vollmer WM, Appel LJ, Bray GA, Harsha D, Obarzanek E, Conlin PR, Miller ER III, Simons Morton DG, Karanja N, Lin P-H, for the DASH-Sodium Collaborative Research Group. Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet. N Engl J Med. 2001; 344: 3–10.
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