The two major derivates of vitamin B6 are the coenzyme species pyridoxamine 5′-phosphate and pyridoxal 5′-phosphate (PLP)(Reference Shane and Stipanuk1). PLP is both the major coenzyme form of vitamin B6 in plasma and the metabolically active coenzyme produced by the phosphorylation of the pyridoxal compound following the oxidation of other vitamin B6 vitamers in the liver. Plasma PLP is considered as the most sensitive indicator for tissue vitamin B6 status because it reflects liver PLP concentrations and stores(Reference Stickel, Choi and Kim2–Reference Lumeng, Lui and Li6), while other measures of vitamin B6 such as erythrocyte PLP, total plasma B6 and urinary excretion of 4-pyridoxic acid are also useful markers of human vitamin B6 status but are less commonly available in clinical practice(Reference Leklem7, Reference Mason8). Overt vitamin B6 deficiency is a rare condition and is mainly defined by the appearance of specific clinical signs or symptoms, nonetheless a suboptimal vitamin B6 status may influence the risk of development of several diseases. It has been previously suggested that vitamin B6 deficiency corresponds to plasma PLP concentrations below 20 nmol/l, while a borderline, marginal impairment of vitamin B6 status may be observed for plasma PLP levels below 30 nmol/l(Reference Leklem7, 9). However, there is no definite consensus for a value that unquestionably defines a deficient state of this nutrient. Vitamin B6 deficiency is rather a notion in evolution since novel at-risk pathological conditions seem, due to a grade of impairment that fails, to meet the magnitude of deficit classically defined as a clear vitamin B6-deficient status(Reference Mason8, 9).
Several reports have indicated a role of low plasma PLP concentrations in a number of pathological conditions. This suggests that not only does overt vitamin B6 deficiency increase the risk of certain chronic diseases, but even mild vitamin B6 deficiency could be associated with an increased risk of certain chronic diseases(Reference Pasceri and Yeh10–Reference Fairfield and Fletcher12).
Low plasma PLP concentrations have been reported to be inversely related to C-reactive protein (CRP), a major marker of inflammation and a risk factor for atherosclerotic disease(Reference Friso, Jacques and Wilson13, Reference Willerson and Ridker14). A number of studies have shown that low plasma vitamin B6 levels are associated with typical inflammatory chronic diseases, such as rheumatoid arthritis (RA)(Reference Chiang, Bagley and Roubenoff15) and inflammatory bowel diseases(Reference Saibeni, Cattaneo and Vecchi16), and are inversely related to the markers of inflammation(Reference Roubenoff, Roubenoff and Selhub17, Reference Chiang, Smith and Selhub18). These studies suggest that impaired vitamin B6 status in RA patients is not solely caused by either lower intake, malabsorption or excessive catabolism of the vitamin, but is rather the result of metabolic mechanisms caused by the inflammatory process(Reference Chiang, Smith and Selhub18, Reference Chiang, Bagley and Selhub19). Among other possible hypotheses, it has also been suggested that the underlying inflammatory condition itself may reduce circulating and hepatic concentrations of PLP by mobilising PLP from the liver and peripheral tissues to the sites of inflammation(Reference Chiang, Smith and Selhub18, Reference Chiang, Bagley and Selhub19). Chiang et al. (Reference Chiang, Smith and Selhub18) observed that plasma PLP concentrations in rats with adjuvant arthritis were about 53 % of the controls at acme of inflammation and related to the content of PLP in the liver, thus suggesting that the lower circulating PLP levels observed in RA could be a sign of a decrease in hepatic PLP pools, and that plasma PLP is a valuable indicator of liver vitamin B6 status during inflammation. Further data showed that PLP in plasma seems a more relevant metabolic marker than PLP in the erythrocytes during inflammation(Reference Chiang, Bagley and Selhub19) as also confirmed by the observation that plasma, but not erythrocyte PLP concentrations, inversely relates to both clinical and biochemical indices of disease activity and severity in patients affected by RA(Reference Chiang, Bagley and Selhub19).
For decades, several studies have demonstrated that patients with RA or other inflammatory diseases have a higher risk of developing premature coronary artery disease (CAD)(Reference Monson and Hall20, Reference Mikuls and Saag21) and traditional CVD risk factors did not, by themselves, clarify the increased prevalence of CAD in such patients(Reference del Rincon, Williams and Stern22). Through studying the relationship between RA, inflammation and CAD, some CVD prevention strategies in RA patients have been proposed, including anti-inflammatory therapy with cyclo-oxygenase-2-specific inhibitors and statins(Reference Snow and Mikuls23) as well as pyridoxine hydrochloride supplementation(Reference Chiang, Selhub and Bagley24). Several studies, moreover, have confirmed the theory of atherosclerosis as an inflammatory disease, thus demonstrating that the link between atherosclerosis, RA and other inflammatory chronic diseases is through inflammatory processes. Inflammation may therefore be considered as a major pathogenic mediator underlying atherosclerosis and its complications(Reference Ross25, Reference Libby, Ridker and Hansson26). The chronic inflammation in atherosclerotic-related disease, such as CAD and stroke, and its major clinical complications, namely myocardial infarction (MI), have also been associated with low plasma vitamin B6 concentrations(Reference Friso, Girelli and Martinelli11, Reference Robinson, Mayer and Miller27–Reference Kelly, Shih and Kistler29).
The relationship between atherosclerosis and vitamin B6-linked inflammatory mechanisms is indeed of great interest. Does low plasma PLP indicate the sole effect of inflammation? Or could it be a cofactor that promotes the development of inflammation, potentially contributing to a sustained chronic inflammatory response? The answer to these questions may open a way to novel and interesting approaches for dietary prevention and therapy.
Vitamin B6 and coronary artery disease, myocardial infarction and ischaemic stroke
Vitamin B6 and coronary artery disease
Table 1 summarises the human studies which addressed the relationship between vitamin B6 status and CAD. Low plasma vitamin B6 concentrations are not only associated with an increased risk for atherosclerotic diseases(Reference Robinson, Arheart and Refsum30) and more specifically with higher CAD incidence(Reference Robinson, Mayer and Miller27, Reference Folsom, Nieto and McGovern31, Reference Dalery, Lussier-Cacan and Selhub32) but the higher risk also appears to be independent of other recognised risk factors for CAD, including homocysteine(Reference Robinson, Mayer and Miller27). Moreover, adequate vitamin B6 levels emerged as a protective factor for CAD(Reference Folsom, Nieto and McGovern31). In a prospective design study, Folsom et al. (Reference Folsom, Chambless and Ballantyne33) demonstrated that the risk of developing CHD within 5 years significantly decreased in parallel with increasing concentrations of plasma PLP(Reference Folsom, Chambless and Ballantyne33). The association between low PLP and CAD was, however, not confirmed in all studies(Reference Verhoef, Kok and Kruyssen34, Reference Siri, Verhoef and Kok35) (Table 1).
CAD, coronary artery disease; PLP, pyridoxal 5′-phosphate; hs-CRP, high-sensitivity C-reactive protein; HR, hazard ratio; MI, myocardial infarction; RR, relative risk; tHcy, total homocysteine.
In addition to several epidemiological studies demonstrating a role for low PLP as an independent risk factor for CAD, some studies have shown that low PLP may be linked to CAD through inflammation. In an observational study conducted in an Italian population, a cohort of patients with angiography-defined, severe, multivessel CAD were compared with CAD-free subjects to evaluate the relationship between CAD risk and both plasma PLP concentrations and major markers of the acute-phase reaction(Reference Friso, Girelli and Martinelli11). An inverse relationship between plasma PLP and both high-sensitivity CRP (hs-CRP) and fibrinogen has been found, confirming previous findings of an inverse association between inflammatory markers and vitamin B6(Reference Friso, Jacques and Wilson13). The prevalence of low PLP (defined as PLP concentrations below 36·3 nmol/l, which was the median value in the control group) was significantly higher among CAD patients compared with controls(Reference Friso, Girelli and Martinelli11). The association between low plasma PLP concentrations and increased CAD risk was also independent of the major classical risk factors for atherosclerosis, including total plasma homocysteine. This association continued to be significant even when hs-CRP and fibrinogen were included in the multiple logistic regression models. The strength of this independent relationship was confirmed even after adjustments for a number of other conditions known to be associated with low concentrations of plasma PLP, including ageing, smoking status and impaired renal function. Results from the present study also showed that the combined presence of low PLP along with other major risk factors for CAD, such as higher hs-CRP and elevated LDL:HDL ratio, further increased the risk for CAD in a graded manner(Reference Friso, Girelli and Martinelli11).
These plasma PLP levels could be described as a mild PLP impairment compared with previous studies that had defined PLP impairment by concentrations as low as 20 nmol/l(Reference Robinson, Mayer and Miller27), suggesting that even a moderate impairment of this vitamin is sufficient to confer a higher risk for CAD. In a case–control study performed by Lin et al. (Reference Lin, Cheng and Liaw36), low PLP concentrations (defined as PLP below 30 nmol/l) were associated with a significantly increased risk of CAD for angiography-documented patients compared with healthy controls, even after adjustments for hs-CRP(Reference Lin, Cheng and Liaw36). In a case–control study evaluating whether plasma PLP exerts an independent or a synergic effect with inflammation in elevating the risk of CAD, Cheng et al. (Reference Cheng, Lin and Liaw37) confirmed that low PLP levels (below 20 nmol/l) are independently associated with higher CAD risk. The inverse relationship between PLP and hs-CRP was observed only within the control group.
Vitamin B6 and myocardial infarction
A specific association between low plasma PLP and incidence of MI, the main thrombotic complication of CAD, is supported by early reports(Reference Kok, Schrijver and Hofman38–Reference Vermaak, Barnard and Potgieter41) and by subsequent case–control and prospective studies(Reference Chasan-Taber, Selhub and Rosenberg42–Reference Gallant, Staszewski and Pozniak45), as listed in Table 2. Moreover, an association between lower dietary vitamin B6 intake and higher risk of MI has also been suggested(Reference Chasan-Taber, Selhub and Rosenberg42).
PLP, pyridoxal 5′-phosphate; RR, relative risk; HR, hazard ratio.
A number of studies have observed an inverse association between plasma concentrations of vitamin B6 and risk of MI, independent of known CAD risk factors(Reference Page, Ma and Chiuve44, Reference Verhoef, Stampfer and Buring46), though not all studies confirmed this independent association(Reference Dierkes, Weikert and Klipstein-Grobusch47). In a study evaluating heart transplant recipients, it has been observed that about 21 % of the patients showed lower PLP concentrations and that only 9 % of those with lower plasma PLP levels did not have CVD complications(Reference Nahlawi, Seshadri and Boparai48). Subjects in the highest quintile of PLP had a significantly reduced risk of MI but adjustment for either low-grade inflammation or smoking diminished this association(Reference Dierkes, Weikert and Klipstein-Grobusch47). With regard to the relationship between MI, vitamin B6 and major markers of inflammation, results from early studies have shown that low plasma PLP levels are related to acute-phase reactants in the initial phase of MI development(Reference Vermaak, Barnard and Potgieter41, Reference Vermaak, Barnard and Van Dalen49).
Vitamin B6 and stroke
In 1995, Selhub et al. (Reference Selhub, Jacques and Bostom28) described a relationship between lower vitamin B6 concentrations and extracranial carotid artery stenosis through its role in homocysteine metabolism. Moreover, recent case–control studies have described a possible relationship between low plasma vitamin B6 concentrations and the onset of cerebrovascular disease, specifically ischaemic stroke and transient ischaemic attack (TIA)(Reference Kelly, Shih and Kistler29, Reference Kelly, Kistler and Shih50). A strong association between stroke/TIA and low PLP (defined as levels less than 20 nmol/l) was independent of other well-established vascular risk factors, including total plasma homocysteine concentrations. Furthermore, results from that study identified a possible protective effect for higher PLP concentrations(Reference Kelly, Shih and Kistler29).
In the context of the Health Professional Follow-up Study, He et al. evaluated dietary intakes of vitamin B6 together with the intake of other B vitamins by a semiquantitative FFQ(Reference Willett51) in relation to the risk of ischaemic and haemorrhagic stroke(Reference He, Merchant and Rimm52). Unlike data related to other B vitamins, the intake of vitamin B6 was not associated with the risk of ischaemic stroke after adjustments for lifestyle and dietary factors(Reference He, Merchant and Rimm52).
Data from the Spanish National Nutrition Survey, which was designed to assess the association between dietary intake of B vitamins including vitamin B6 and coronary heart and cerebrovascular mortality, failed to prove a definite association between vitamin B6 impairment and cardiovascular mortality(Reference Medrano, Sierra and Almazan53) even though data on vitamin B6 supported a limited protective effect, only with respect to cerebrovascular mortality in men(Reference Medrano, Sierra and Almazan53).
Vitamin B6 and peripheral artery disease
Reports on the relationship between vitamin B6 and peripheral artery disease are few(Reference Wilmink, Welch and Quick54). Wilmink et al. (Reference Wilmink, Welch and Quick54) reported that daily vitamin B6 intake is lower in patients with peripheral artery disease, as defined by an ankle-brachial pressure index below 0·9, and appears as an independent predictor of peripheral artery occlusive disease. An increase in daily vitamin B6 intake by 1 standard deviation significantly decreased the risk of peripheral artery disease by 29 %.
Vitamin B6 supplementation, inflammation and CVD prevention
An early observation of patients given vitamin B6 for inflammatory diseases or degenerative diseases found that subjects supplemented with vitamin B6 had a lower risk of developing MI compared with patients who had not taken vitamin B6(Reference Ellis and McCully55). Table 3 summarises the main studies in which B vitamin supplementation, including supplementation with vitamin B6, has been performed. In the Nurses' Health Study, among women with no prior history of CAD, users of multivitamins containing folate and vitamin B6 had a reduced risk of CAD(Reference Rimm, Willett and Hu56).
WAFACS, Women's Antioxidant and Folic Acid Cardiovascular study; MI, myocardial infarction; RR, relative risk; WENBIT, Western Norway B Vitamin Intervention Trial; AMI, acute myocardial infarction; HR, hazard ratio; NORVIT, Norwegian Vitamin Trial; CAD, coronary artery disease; HOPE-2, Heart Outcomes Prevention Evaluation 2; VISP, Vitamin Intervention for Stroke Prevention randomised control trial; tHcy, total homocysteine; cIMT, carotid intima-media thickness; US, ultrasound; RTR, renal transplant recipients.
Very few human studies have been performed to evaluate the modifications of major markers of inflammation during supplementation with B vitamins, including vitamin B6, despite the association with either folate and/or vitamin B12(Reference Peeters, van Aken and Blom57, Reference Palmas58). Furthermore, results from these studies have shown that CRP and pro-inflammatory IL levels are unchanged after vitamin supplementation(Reference Peeters, van Aken and Blom57, Reference Palmas58). Antioxidant activity of vitamin B6 supplementation has been observed in a study performed on rats, but the exact mechanism is unclear(Reference Mahfouz and Kummerow59).
Several large, prospective trials have been conducted in recent years with the principal aim of studying the effects of lowering serum homocysteine concentrations with the use of B vitamins, including vitamin B6, on cardiovascular events(Reference Toole, Sane and Bettermann60, Reference Bønaa, Njolstad and Ueland61).
Overall, the most compelling data from vitamin supplementation studies have demonstrated that vitamin B6 is not effective for preventing the recurrence of cardiovascular events, including CAD, peripheral vascular disease and stroke(Reference Wilmink, Welch and Quick54, Reference Albert, Cook and Gaziano62, Reference Toole, Malinow and Chambless63).
Only a few small trials, performed with renal transplant patients that have hyperhomocysteinaemia and subjects at risk for cerebral ischaemia, have demonstrated the effectiveness of vitamin B6 supplementation with folate and vitamin B12 on carotid artery intima-media thickness progression(Reference Marcucci, Zanazzi and Bertoni64, Reference Till, Rohl and Jentsch65). This marker for subclinical atherosclerosis was also evaluated in another recent double-blind, placebo-controlled, randomised clinical trial(Reference Hodis, Mack and Dustin66). Vitamin supplementation significantly reduced subclinical atherosclerosis progression only in subjects at low risk for CVD, with total plasma homocysteine concentrations equal to or above 9·1 μmol/l(Reference Hodis, Mack and Dustin66). Other trials evaluated CAD patients for the effects of B vitamin supplementation, though the interpretation of the results was ambiguous. Supplementation with vitamin B6, folate and vitamin B12 after coronary angioplasty decreased the rate of restenosis and the need for revascularisation(Reference Schnyder, Roffi and Pin67), while supplementation after coronary stenting increased the risk of in-stent restenosis and the need for target-vessel revascularisation(Reference Lange, Suryapranata and De Luca68).
Despite the advantage of large randomised intervention studies, wisdom from the studies of cancer chemoprevention with folate clearly suggests that two critical factors should be taken into account in the aforementioned trials: time and dose of B vitamin supplementation. Nutritional intervention is indeed considered to be a two-edged sword, where a beneficial effect may be observed with nutritional support in the prevention phase and a disease-aggravating effect may be observed after the onset of illness, with nutritional support actually fuelling the disease process. This observation may certainly apply to folate supplementation, which can effectively prevent the onset or progression of disease in the early phase, while it may accelerate the progression of disease in the late phase. It can therefore be speculated that continuous supplementation with a single non-physiological form of vitamin supplements might contribute to unexpected or even harmful outcomes, even in the at-risk condition of having an impaired vitamin B6 status. Furthermore, the major endpoints of these studies were those of evaluating the effect of lowering plasma homocysteinaemia on the recurrence of established disease, mainly by the simultaneous use of various B vitamins that have many additional functions other than that of lowering total plasma homocysteine. Little information, however, is available regarding both the effects of vitamin B6 supplementation on inflammatory markers and the correct dose and timing to be followed to avoid the possible harmful effect of excessive or inappropriate vitamin B6 supplementation. This information that would be needed for a possible primary or secondary preventive approach using vitamin B6 is to be developed. Further specific studies are required to deepen our knowledge in this regard.
Even if there is consistently a lack of benefit in secondary prevention of CVD with B vitamin supplementation, with or without vitamin B6 (Western Norway B Vitamin Intervention Trial(Reference Ebbing, Bleie and Ueland69), Women's Antioxidant and Folic Acid Cardiovascular study(Reference Albert, Cook and Gaziano62), Vitamin Intervention for Stroke Prevention randomised controlled trial(Reference Toole, Malinow and Chambless63), Norwegian Vitamin Trial(Reference Bønaa, Njolstad and Ueland61), Heart Outcomes Prevention Evaluation 2(Reference Lonn, Yusuf and Arnold70)), it should also be considered that all the aforementioned studies are quite diverse from one another in terms of the time period of supplementation. In fact, one may raise the point that the time period of supplementation is especially critical to reach positive outcomes or avoid possible harmful effects in terms of the rate of CVD events(Reference Loscalzo71). However, despite the apparently clear outcomes(Reference Loscalzo71), it could be argued that a potential benefit that modifies secondary prevention outcomes may not be observed over a period of moderate duration (between 2 and 5 years for the Norwegian Vitamin Trial, Heart Outcomes Prevention Evaluation 2 and Vitamin Intervention for Stroke Prevention studies or of about 7 years for the Women's Antioxidant and Folic Acid Cardiovascular study).
Furthermore, the negative results of vitamin supplementation trials, including vitamin B6 use, do not preclude the possibility of a protective effect in primary prevention. It could be difficult, however, to demonstrate that vitamin B supplementation is ineffective in patients who have had a clinical vascular event, while effective in those without a clinical event or with subclinical atherosclerosis. Clinical trials for primary prevention may require a longer duration and larger populations in order to answer the key question on whether vitamin B6 supplementation is effective in preventing CAD before the first vascular event or in younger life.
Studies are needed to find the specific time and optimal dose of vitamin B6 in order to maximise efficacy, minimise adverse effects and identify targets for vitamin B6 interventions on the basis of genetic susceptibility and environmental factors. A better understanding of the mechanisms underlying the relationship between CVD and vitamin B6 may indeed be extremely helpful in designing the most accurate preventive strategies.
Inflammation and vitamin B6-related atherogenesis
PLP functions as a coenzyme in more than 100 reactions that are involved in the metabolic pathways of neurotransmitters as well as in the metabolism of amino acids, lipids and carbohydrates(Reference Endo, Nishiyama and Otsuka72). PLP also takes part in other significant pathways related to immune function(Reference Meydani, Hayek and Coleman73), thrombosis(74, Reference Schoene, Chanmugam and Reynolds75) and inflammation(Reference Roubenoff, Roubenoff and Selhub17), all of which are crucial mechanisms in every stage of the atherosclerotic process.
Furthermore, PLP is implicated in the synthesis and repair of both nucleic acids and proteins. Low vitamin B6 concentrations could thus reflect an increased consumption of PLP in the accelerated synthesis of cytokines(Reference Doke, Inagaki and Hayakawa76) and in the activation and proliferation of lymphocytes, both of which are key events in the inflammatory process(Reference Meydani, Ribaya-Mercado and Russell77, Reference Kwak, Hansen and Leklem78).
Considering the epidemiological evidence of a role of vitamin B6 in inflammatory-related diseases and the observed relationship with inflammatory markers(Reference Friso, Girelli and Martinelli11, Reference Saibeni, Cattaneo and Vecchi16, Reference Chiang, Smith and Selhub18, Reference Morris, Sakakeeny and Jacques79), it is plausible that vitamin B6 plays a role in CVD pathogenesis through mechanisms linked to inflammation (Table 4).
NHANES, National Health and Nutrition Examination Survey; CRP, C-reactive protein; PLP, pyridoxal 5′-phosphate; hs-CRP, high-sensitivity CRP; CAD, coronary artery disease; PL, pyridoxal; RA, rheumatoid arthritis; ESR, erythrocyte sedimentation rate; ARIC, Atherosclerosis Risk in Communities; IBD, inflammatory bowel disease; tHcy, total homocysteine.
Therefore, with the knowledge that systemic acute-phase markers are solid and independent risk factors for CAD(Reference Ridker80, Reference Ridker, Hennekens and Buring81), that inflammation exerts an essential role in all stages of the atherosclerotic process(Reference Grundy82) and the possibility that vitamin B6 has a role in inflammatory processes, several mechanisms were proposed linking low vitamin B6 and CVD using cell culture studies, animal studies(Reference Endo, Nishiyama and Otsuka72) and clinical trials.
Animal studies have reported that inflammation reduces circulating and hepatic concentrations of vitamin B6. Plasma PLP is considered as a sensitive indicator of tissue vitamin B6 status(Reference Parker, Marshall and Roberts3–Reference Leklem7, Reference Chiang, Bagley and Roubenoff15, Reference Chiang, Smith and Selhub18). As shown in Fig. 1, it is thus possible that, in patients in an inflammatory state, PLP is mobilised from the liver and peripheral tissues to the sites of inflammation(Reference Chiang, Bagley and Selhub19). Plasma PLP levels are known to be inversely related to TNF-α production and other inflammatory cytokines in RA(Reference Roubenoff, Roubenoff and Selhub17). It has also been reported that low plasma PLP concentrations are inversely related to both plasma fibrinogen(Reference James, Vorster and Venter83) and CRP(Reference Friso, Girelli and Martinelli11, Reference Friso, Jacques and Wilson13), with a robust and independent association of other major biomarkers related to vitamin B6 metabolism(Reference Friso, Girelli and Martinelli11). Moreover, inflammatory status increases oxidant stress, which results from an imbalance between oxidant production and antioxidant defences (Fig. 1). All these conditions characterised by the increase in inflammatory cytokines, fibrinogen, CRP and superoxide radicals may induce the consumption of vitamin B6, with a consequent reduction of PLP plasma levels and its antioxidant effect, and, at the same time, they may favour a thrombogenic effect, thus triggering an impairment of endothelial function which is a key event in the pathogenesis of atherosclerotic processes (Fig. 1)(Reference Heitzer, Schlinzig and Krohn84). PLP has also been described to have an inhibitory effect on endothelial cell proliferation(Reference Matsubara, Matsumoto and Mizushina85, Reference Matsubara, Mori and Akagi86). The persistence of a chronic inflammatory condition may result in the depletion of vitamin B6, which might then contribute to a sustained chronic inflammatory response (Fig. 1).
Most of the evidence demonstrates a potential role for vitamin B6 in inflammatory processes where the low vitamin B6 status in inflammation-related illnesses appears to result not from lower intake or excessive catabolism of PLP but from the inflammatory process underlying the disease itself(Reference Morris, Sakakeeny and Jacques79).
Although vitamin B6 represents an important coenzyme in the metabolism of homocysteine, a recognised risk factor for thrombosis, the role of PLP in atherosclerosis is only partly related to its function in the one-carbon pathway. Several studies have thus supported a role for vitamin B6 in the risk of CVD(Reference Robinson, Mayer and Miller27, Reference Folsom, Nieto and McGovern31, Reference Chasan-Taber, Selhub and Rosenberg42, Reference Verhoef, Stampfer and Buring46) and stroke(Reference Kelly, Shih and Kistler29), independent of homocysteine and other risk factors. A hypothesis is that vitamin B6 could be directly implicated as a cofactor in an anti-inflammatory mechanism where the utilisation of the vitamin results in its consumption, and the consequent low vitamin B6 concentrations could support and amplify the inflammatory process, thereby leading to chronic progression of inflammatory disease. Indeed, a mild deficiency of vitamin B6 may be associated with an increased risk, not only of atherosclerosis, but also of other chronic inflammatory diseases such as RA(Reference Chiang, Smith and Selhub18, Reference Woolf and Manore87) and inflammatory bowel diseases(Reference Saibeni, Cattaneo and Vecchi16). A number of studies have highlighted the relationship between PLP and inflammation, showing an inverse association between vitamin B6 and major markers of inflammation, including plasma fibrinogen concentration(Reference James, Vorster and Venter83), erythrocyte sedimentation rate and CRP(Reference Friso, Jacques and Wilson13). In the population-based Framingham Heart Study cohort, the association between PLP and CRP was strong and independent of other major biomarkers related to vitamin B6 metabolism(Reference Friso, Jacques and Wilson13), supporting a possible role for plasma PLP in inflammatory processes.
Some reports did not support this observation(Reference Folsom, Desvarieux and Nieto88), such as the study by Folsom et al. (Reference Folsom, Desvarieux and Nieto88), conducted among healthy middle-aged adults in the Atherosclerosis Risk in Communities Study, which did not find an inverse association between CRP and PLP. However, the authors did observe that lower plasma PLP and dietary vitamin B6 were associated with a higher leucocyte count, though this association was not found with the use of vitamin supplements(Reference Folsom, Desvarieux and Nieto88). It should also be taken into account that some diversity in the observations reported by the studies may be due to the different methods utilised to measure plasma PLP, although the methods used by most studies are considered highly reliable for the assessment of vitamin B6 status(Reference Friso, Girelli and Martinelli11, Reference Chiang, Bagley and Roubenoff15, Reference Folsom, Desvarieux and Nieto88–Reference Kimura, Kanehira and Yokoi90). The majority of studies, however, confirmed the inverse correlation between PLP and major markers of inflammation in various inflammation-related diseases. In subjects affected by RA(Reference Chiang, Bagley and Selhub19, Reference Chiang, Selhub and Bagley24), PLP was associated with erythrocyte sedimentation rate, CRP levels and other markers of disease activity and severity, suggesting that impaired vitamin B6 status is a result of inflammation. It also appeared that the relationship between lower vitamin B6 and increased inflammation in these RA patients could be tissue-specific(Reference Chiang, Selhub and Bagley24).
Plasma PLP concentrations are also altered in subjects who have acute diseases with an evident underlying inflammatory condition. Vasilaki et al. (Reference Vasilaki, McMillan and Kinsella91) observed that in patients admitted to an intensive therapy unit, high concentrations of CRP, PLP and intracellular pyridoxal levels were significantly lower in those critically ill patients than in the group of subjects taken as controls.
Further support for the hypothesis of a link between vitamin B6 and inflammation can be found in an analysis of data from a large population-based survey from participants in the 2003–4 National Health and Nutrition Examination Survey. Results showed that higher vitamin B6 intakes are protective against inflammation, as indicated by hs-CRP concentrations. Moreover, the level of vitamin B6 intake that was associated with maximum protection against vitamin B6 inadequacy was elevated in the presence of inflammation compared with its absence(Reference Morris, Sakakeeny and Jacques79).
A strong inverse association between vitamin B6 status, as measured by plasma PLP concentration, and the inflammatory marker CRP was also observed recently in a cohort of elderly Puerto Ricans living in Massachusetts(Reference Shen, Lai and Mattei92). In the present study, chronic inflammatory conditions, such as the metabolic syndrome, diabetes and obesity, were significantly associated with lower plasma PLP. The patients affected by such diseases were also significantly more likely to demonstrate vitamin B6 inadequacy. Furthermore, lower PLP plasma concentrations were associated with oxidative stress, as indicated by higher urinary concentrations of 8-hydroxydeoxyguanosine, a marker of DNA damage and oxidative stress(Reference Shen, Lai and Mattei92). Authors concluded that vitamin B6 status may influence CAD risk through mechanisms that link vitamin B6 to inflammatory processes rather than mechanisms related to the role of vitamin B6 in homocysteine metabolism(Reference Shen, Lai and Mattei92).
Several studies have demonstrated an association between mild vitamin B6 deficiency with inflammation-related diseases, including CVD(Reference Friso, Girelli and Martinelli11, Reference Saibeni, Cattaneo and Vecchi16, Reference Chiang, Smith and Selhub18, Reference Morris, Sakakeeny and Jacques79), by highlighting an inverse relationship between vitamin B6 and inflammatory markers(Reference Friso, Girelli and Martinelli11, Reference Chiang, Bagley and Selhub19, Reference Morris, Sakakeeny and Jacques79). In a consistent number of studies, this association between impaired vitamin B6 status and higher risk of CVD is independent of other major traditional atherosclerosis risk factors(Reference Friso, Jacques and Wilson13, Reference Robinson, Mayer and Miller27, Reference Cheng, Lin and Liaw37, Reference Verhoef, Stampfer and Buring46, Reference Page, Ma and Chiuve44) and is inversely related to the major markers of inflammation(Reference Friso, Girelli and Martinelli11). This evidence suggests a link between impaired vitamin B6 and CVD through inflammation. Because vitamin B6 is involved in a large number of physiological reactions, it could be essential to design appropriate studies to define the exact mechanisms underlying the inter-relationships among suboptimal vitamin B6 status, as defined by both plasma and tissue PLP concentrations, and biochemical–molecular alterations leading to the development of inflammation-related diseases. A research priority may be that of investigating the kinetics and regulation of B6 vitamers and enzymes in different body compartments during inflammatory processes.
Mild vitamin B6 deficiency is not a rare occurrence in population-based studies(Reference Fairfield and Fletcher12). This issue, therefore, deserves further investigation, especially in terms of prevention strategies, for the purpose of promoting specific public health policies. Current clinical trials have indicated that vitamin B6 supplementation seems not to be effective for the prevention of recurrence of CVD, although the appropriate dosage and timing for possible beneficial effects through the use of vitamin supplements still remains to be discussed. Other crucial issues pertain also to the evaluation of the actual effect of supplementation with vitamin B6 in synthetic form, as well as to whether such approach may be as effective as an adequate dietary vitamin B6 intake. The question of whether supplementation with vitamin B6 may be useful for primary prevention of CVD is yet another key issue to be defined. The importance of considering vitamin B6 status in relation to the risk for CVD may nevertheless open new insights for the potential identification of innovative preventive and therapeutic strategies. In order to help tailor an adequate nutritional approach on an individual basis, both dose and timing as well as the possible harmful effect of vitamin B6 supplementation should be carefully considered in the design of future ad hoc clinical trials that are aimed at identifying appropriate vitamin B6 supplementation.
The notion of a definite vitamin B6 deficiency is a concept to be considered in fieri since the risk of certain diseases seems to be associated with a degree of vitamin B6 impairment that falls short of the classical definition of a clear vitamin B6-deficient state.
The present review was supported by the National Funding of the Ministry of University, Scientific and Technologic Research (S. F., V. L.). The contribution of each author was as follows: S. F. and S.-W. C. identified the research question, the topic and main purposes of the present review and contributed to the critical analyses of the manuscript; V. L. designed the search strategy, carried out the literature searches, analysed the findings and drafted the text and tables. All authors contributed to synthesising the results and critical revision of the manuscript, and all approved the final version. The authors declare no conflict of interest related to this study.