Introduction

 Preliminary results from the Norwegian B-vitamin intervention study NORVIT, a study that investigates the secondary prevention effects of B-vitamin supplementation in patients suffering from acute myocardial infarction (MI), have recently been presented at the ESC congress in Stockholm.

 Mass media have reported and interpreted the preliminary results from NORVIT in a naive and unbalanced manner and concluded with a general statement that B-vitamins were generally harmful. This has resulted in considerable confusion, anxiety, scepticism not only in the general population, but also among doctors.

Insufficient statistical power

For several years before the first, preliminary results from the NORVIT study now are published, it has been estimated, based on earlier observational studies, that a reduction of homocysteine levels by about 25-30% (this reduction was achieved in NORVIT), would result in an about 10% reduced risk of coronary heart disease (CHD). In other words, this is a relatively modest risk reduction.

Power calculations showed that the majority of B-vitamin intervention studies, including NORVIT, would not have the statistical power to exclude especially false-negative results. Only large meta-analyses, which include the combined data and results of all ongoing intervention studies (that is a total number of about 60.000 patients) would allow to give definite answers whether or not homocysteine should be considered a causal risk factor. Results from these meta-analyses will be available in about 3-5 years.

For these reasons, the preliminary results from NORVIT should be treated with caution, and no firm conclusions can be drawn from this study.

Preliminary conclusions

So far, the results of NORVIT allow the following conclusion:

The complication rate during the first 6-12 months after an acute MI is generally quite high. These patients undergo intensive treatment and use potent drugs including ASA, cholesterol lowering drugs, blood pressure medicine and other cardiovascular medication. During these 6-12 months, treatment with folic acid combined with supra-physiologically doses of vitamin B6 (40 mg/d, that is about 15 times RDA-values) had no positive effects on the primary and secondary end-points in this study. Contrary, data from NORVIT indicate that patients receiving B-vitamins (in addition to standard cardiovascular therapy) had, compared to B-vitamin placebo, a slightly increased complication rate, 23% vs. 18%, respectively.

The potential influence of vitamin B6 on inflammation and microvascular re-modelling / angiogenesis is controversial

The potential negative influence of vitamin B6-folic acid-combinations in NORVIT is only demonstrated in patients in the acute phase after a MI (1-12 months) (secondary prevention), and not in healthy individuals before MI (primary prevention). During the acute phase after MI a number of reparative, inflammation-like processes happen, which include formation of reaction oxygen species (ROS), re-modelling of blood vessels and angiogenesis in connection with granulation tissue formation.

In contrast to vitamin B₁₂ and folic acid, the metabolic pathways of vitamin B6 are far more complex and not investigated in full depth. Vitamin B6 is involved in more than 150 metabolic reactions. It is thus self-evident that the metabolic consequences of high doses of vitamin B6 are far more complex than the homocysteine-lowering effects alone.

Moreover, vitamin B6 is the only vitamin among the water-soluble B-vitamins where serious, unwanted side-effects have been reported at high doses [1]. In most other B-vitamins, surplus amounts are renally excreted and are not harmful.

There are some indications that serum concentrations of vitamin B6 may be reduced as a result of prolonged inflammatory activity in CVD patients [2,3]. However, whether intake of very high doses of vitamin B6 may facilitate inflammatory response to an acute MI has not been investigated so far. Nevertheless, high doses of vitamin B6 can inhibit angiogenesis and endothelial cell proliferation at concentration in the range of magnitude that can be achieved in patients treated with 40 mg/d of vitamin B6 [4,5].

NORVIT results may only be valid to MI-patients in the acute phase of the disease

The NORVIT study investigated the effects of B-vitamins in the acute phase after MI. However, most of these patients have suffered from vascular disease and have been exposed to risk factors for many years, if not decades. It may thus be too late to study preventive effects of B-vitamins in this population. Furthermore, these patients are exposed to potent drugs that make it difficult to evaluate selective effects of B-vitamins. Thus, NORVIT results cannot counterproof the potential beneficial effects of B-vitamins in primary prevention of CVD in healthy people, or in MI patients after stabilisation of the disease.

In addition, it is difficult to evaluate whether use of more physiological vitamin B6 doses (2-4 mg/d) would have given different results. Interestingly, earlier B-vitamin intervention studies in patients undergoing PTCA without stenting have shown a reduced rate of restenosis when using only 10 mg B6/d (in addition to similar doses of folic acid and B₁₂ as in NORVIT) [6]. On the other hand, in another secondary intervention study using 48 mg/d of vitamin B6 (that is a dose similar to that used in NORVIT) patients undergoing PTCA with metal-stenting showed faster re-stenosis of the stent when receiving B-vitamins [7]. However, one has to bear in mind that a metal-stent has more traumatising effects on the endothelium and sub-endothelial structures than simple angioplasty without stenting, and is thus a more potent trigger for inflammatory responses.

The homocysteine hypothesis

Numerous publications of case-control studies and prospective cohort studies have demonstrated that elevated homocysteine – like cholesterol – is a predictor of CHD and stroke, and that this relationship is inversely correlated with folate [8] These observations constitute the basis of the hypothesis that homocysteine could represent a causal risk factor that can be alleviated or eliminated by B-vitamin supplementation.

Intake of high doses of B-vitamins had earlier been demonstrated to have dramatic positive effects on patients suffering from inherited homocystinuria. In these cases, B6-responsive homocystinurics, that are patients who responded with a substantial reduction of homocysteine upon vitamin B6-supplementation, had improved prognosis and reduced risk of premature CVD.

NORVIT results – an invitation to reassess former theories

The working hypothesis was that B-vitamin deficiency results in elevated homocysteine and that elevated homocysteine is responsible for increased CVD risk.

The preliminary NORVIT results seem to contradict our former theories on cause-effect-relationships in CVD. Could it be that inflammatory processes in connection with CVD development cause reduced B6-status and elevated homocysteine? Could intake of supra-physiological doses of vitamin B6 result in a disproportionate inflammatory response to an acute MI and could such doses inhibit angiogenesis? Angiogenesis and vascular remodeling are important components of wound healing and may limit the size of an infarction. Increased inflammatory responses and hampering of angiogenesis may thus have superseded the positive effects of homocysteine lowering.

It has to be admitted that the preliminary results from NORVIT may have weakened the homocysteine hypothesis, but they are not sufficient to reject the theory that homocysteine is a cardiovascular risk factor once and for all. Rather, NORVIT observations should be a stimulus for new and more discriminate assessment of the role of homocysteine and B-vitamins in acute MI, or in CVD in general.

Jörn Schneede, MD

Medical Bioscience, Clinical Chemistry
University Hospital of North Sweden
SE-901 85 Umeå, Sweden

E-mail: jorn.schneede@medbio.umu.se

References 

1.        Callizot N, Warter JM, Poindron P. Pyridoxine-induced neuropathy in rats: a sensory neuropathy that responds to 4-methylcatechol. Neurobiol Dis 2001;8:626-35.

2.         Kelly PJ, Kistler JP, Shih VE, Mandell R, Atassi N, Barron M, et al. Inflammation, homocysteine, and vitamin B6 status after ischemic stroke. Stroke 2004;35:12-5.

3.         Dierkes J, Hoffmann K, Klipstein-Grobusch K, Weikert C, Boeing H, Zyriax BC, et al. Low plasma pyridoxal-5'phosphate and cardiovascular disease risk in women: results from the Coronary Risk Factors for Atherosclerosis in Women Study. Am J Clin Nutr 2005;81:725-7; author reply 7-8.

4.         Bor MV, Refsum H, Bisp MR, Bleie O, Schneede J, Nordrehaug JE, et al. Plasma vitamin B6 vitamers before and after oral vitamin B6 treatment: a randomized placebo-controlled study. Clin Chem 2003;49:155-61.

5.         Matsubara K, Mori M, Matsuura Y, Kato N. Pyridoxal 5'-phosphate and pyridoxal inhibit angiogenesis in serum-free rat aortic ring assay. Int J Mol Med 2001;8:505-8.

6.         Schnyder G, Roffi M, Pin R, Flammer Y, Lange H, Eberli FR, et al. Decreased rate of coronary restenosis after lowering of plasma homocysteine levels. N Engl J Med 2001;345:1593-600.

7.         Lange H, Suryapranata H, De Luca G, Borner C, Dille J, Kallmayer K, et al. Folate therapy and in-stent restenosis after coronary stenting. N Engl J Med 2004;350:2673-81.

8.         Virtanen JK, Voutilainen S, Alfthan G, Korhonen MJ, Rissanen TH, Mursu J, et al. Homocysteine as a risk factor for CVD mortality in men with other CVD risk factors: the Kuopio Ischaemic Heart Disease Risk Factor (KIHD) Study. J Intern Med 2005;257:255-62.

Published September 30, 2005