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    Topic review

    Vitamin E and cardiovascular diseases

    Subjects: Nursing
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    Definition

    Cardiovascular diseases (CVD) cause about 1/3 of global deaths. Therefore, new strategies for the prevention and treatment of cardiovascular events are highly sought-after. Vitamin E is known for significant antioxidative and anti-inflammatory properties, and has been studied in the prevention of CVD, supported by findings that vitamin E deficiency is associated with increased risk of cardiovascular events. However, randomized controlled trials in humans reveal conflicting and ultimately disappointing results regarding the reduction of cardiovascular events with vitamin E supplementation. As we discuss in detail, this outcome is strongly affected by study design, cohort selection, co-morbidities, genetic variations, age, and gender. For effective chronic primary and secondary prevention by vitamin E, oxidative and inflammatory status might not have been sufficiently antagonized. In contrast, acute administration of vitamin E may be more translatable into positive clinical outcomes. In patients with myocardial infarction (MI), which is associated with severe oxidative and inflammatory reactions, decreased plasma levels of vitamin E have been found. The offsetting of this acute vitamin E deficiency via short-term treatment in MI has shown promising results, and, thus, acute medication, rather than chronic supplementation, with vitamin E might revitalize vitamin E therapy and even provide positive clinical outcomes.

    1. Introduction

    Cardiovascular diseases (CVD) such as atherosclerosis are a major cause of mortality and morbidity worldwide. Vitamin E is a very potent antioxidant, and shows anti-inflammatory properties . Therefore, vitamin E, particularly the α-tocopherol (α-TOH) form, has been suggested as a promising candidate in the prevention of CVD. However, enthusiastic research on vitamin E in large clinical trials has only resulted in controversial and mostly discouraging outcomes, and ultimately has not provided evidence for overall beneficial effects of vitamin E in CVD, with a few exceptions, as discussed below. The aim of the present review is to critically summarize the data available on vitamin E supplementation in CVD in general and systematically investigate potential reasons for the observed conflicting results, and we also provide a perspective on what we have learned from the past trials for future trials. We ultimately redirect the focus from chronic vitamin E supplementation to short-term vitamin E medication in acute clinical settings caused by high inflammatory and oxidative stress, such as MI.

    2. Vitamin E and Risk Factors for Cardiovascular Events

    The association between vitamin E and risk factors for cardiovascular events will be discussed in detail in the review “Cardiovascular and Metabolic Protection by Vitamin E: A Matter of Treatment Strategy?” by Melanie Ziegler, Maria Wallert, Stefan Lorkowski and Karlheinz Peter and is summarized in Table 1.

    Table 1. Vitamin E and Risk Factors for Cardiovascular Events.

    Risk Factor

    Type of Study

    Author

    Participants

    Endpoints

    Vitamin E Dosage

    Hypertension

     

     

     

     

     

    SBP (systolic blood pressure)

    DPB (diastolic blood pressure)

    Observational

    Kuwabara et al. [1]

    n = 3507

    Higher vitamin E intake is associated with a lower percentage of subjects with hypertension

     

     

    Interventional

    Boshtam et al. [2]

    n = 70
    mild hypertensive patients

    Significant decrease in SBP and DBP (mainly in SBP)

    134 mg per day (200 IU) for 27 weeks

     

    Interventional

    Tmj et al. [3]

    n = 60
    mild hypertensive subjects

    Decrease in blood pressure

    134 mg (200 IU) per day for 12 weeks

     

    Interventional

    Palumbo et al. [4]

    n = 142
    treated hypertensive patients

    No clinically relevant effect on blood pressure

    300 mg per day for 12 weeks

     

    Interventional

    Mihalj et al. [5]

    n = 57
    treated hypertensive patients

    No further effect of vitamin E/C supplementation

    720 mg vitamin E and 25 mg vitamin C per day for 8 weeks

     

    Interventional

    Barbagallo et al. [6]

    n = 12
    hypertensive patients

    No effect of vitamin E treatment on SBP or DBP

    600 mg vitamin E per day for 4 weeks

    Hyperlipidemia

     

     

     

     

     

    Hypercholesterolemic (HC)

    Observational

    Interventional

     

    Cangemi et al. [7]

    n = 30
    HC patients
    n = 20
    healthy subjects


    n = 30 HC patients

    Lower vitamin E plasma level in HC patients vs. healthy subjects

    Administration of atorvastatin restored vitamin E/TC plasma level

    10 mg atorvastatin per day for 30 days

     

    Observational

    Shin et al. [8]

    n = 76
    HC patients

    Increased α-TOH/lipid plasma level in HC patients

    20–40 mg simvastatin per day for 8 weeks

     

    Observational

    Blom et al. [9]

    n = 738
    HC patients

    Increased vitamin E/TC plasma level in evolocumab (anti- PCSK9 antibody)-treated patients from baseline to week 52,

    10 or 80 mg atorvastatin per day or 80 mg atorvastatin plus 10 mg ezetimibe per day for 52 weeks, 420 mg Evolocumab or placebo for 8 weeks

     

    Interventional

    Liu et al. [10]

    n = 19
    HC patients

    Increased vitamin E/LDL-C plasma level in atorvastatin-treated HC patients

    10 mg atorvastatin per day for 5 months

     

    Interventional

    Leonard et al. [11]

    n = 44
    HC patients

    Vitamin E supplementation did not alter cholesterol levels under statin therapy

    268 mg (400 IU)

    vitamin E per day or placebo for 12 weeks

    Thrombosis

     

     

     

     

     

     

    Interventional

    Glynn et al. [12]

    n = 39,876 women aged 45 and older

    Women taking vitamin E were 21% less likely to suffer a venous thromboembolism

    Vitamin E (540 mg) or a placebo on alternate days over a 10-year period.

     

    Interventional

    Vuckovic et al. [13]

    2506 patients with venous thrombosis, 2506 partner controls, and 2684 random-digit-dialing (RDD) controls

    n = 96 patients supplemented with vitamin E

    No association of vitamin E supplementation with a reduced venous thrombosis risk

    No information was obtained on the dosage of vitamin E intake

    Age

     

     

     

     

     

     

    Observational

    Ortega et al. [14]

    n= 120
    aged subjects (65–91 years)

    Lower vitamin E intake and α-TOH/TC plasma level correlates with cognitive impairment in elderly

    -

     

    Observational

    Vatassery et al. [15]

    48 healthy male volunteers aged 24–91 years

    α-TOH plasma level remained unchanged, decreased α-TOH level in platelets of elderly subjects

    -

     

    Observational

    Capuron et al. [16]

    n = 69
    aged subjects (73–86 years)

    Lower α-TOH plasma level in subjects with poor physical and mental health status

    -

     

    Observational

    Requejo et al. [17]

    n = 120
    aged subjects (65–91 years)

    95.2% are below recommendations of a-TOH intake

    -

     

    Observational

    Rudman et al. [18]

    n = 34 eating-dependent nursing home residents

    The vast majority did not receive micronutrient supplements

    -

     

    Interventional

    De la Fuente et al. [19]

    n = 33
    aged subjects (65–75 years)

    n= 30 controls (25–35 years)

    α-TOH improves immune functions and therefore health in aged people

    200 mg α-TOH per day for 3 months

    Obesity

     

     

     

     

     

     

    Observational

    Silva et al. [20]

    n = 33
    overweight adolescents
    n = 42
    obese adolescents
    n = 75
    healthy adolescents
    (10–15 years)

    Crude and energy-adjusted intake of vitamin E positively correlate with BMI, but not with plasma level of vitamin E; α-TOH/LDL-C and α-TOH/TC decrease in obese and overweight adolescents

    -

     

    Observational

    Mehmetoglu et al. [21]

    n = 98 obese patients
    n = 78 healthy subjects (18–65 years)

    Decreased α-TOH/TC + TG plasma level in obese subjects

    -

     

    Observational

    Kljno et al. [22]

    n = 17 obese girls
    n = 7 healthy girls
    (8–15 years)

    α-TOH/total lipids decreased in plasma and in LDL in obese subjects

    -

     

    Observational

    Strauss et al. [23]

    n = 6139 children (6–19 years) enrolled in the NHANES III

    Decreased α-TOH/TC + TG plasma level in obese subjects

    -

     

    Observational

    Molnar et al. [24]

    n = 15 obese adolescents
    n = 16 healthy adolescents
    (13–16 years)

    α-TOH/TC + TG plasma level remained unchanged in obese subjects

    -

     

    Observational

    Gunanti et al. [25]

    6139 children (8–15 years) enrolled in the 2001–2004 NHANES

    Adequate plasma level of α-TOH/TC are associated with reduced probability of overweight

    -

    Diabetes mellitus type 2 (DMT2)

     

     

     

     

     

    Observational

    Schneider et al. [26]

    n = 31 DMT2 patients (46–79 years)

    n = 31 control subjects (38–63 years)

    VLDLs and LDLs of DMT2 patients contained fewer vitamin E molecules compared to controls due to PLPT

    -

     

    Observational

    Galvan et al. [27]

    n = 12 male DMT2 patients (49–54 years)
    n = 19 control subjects (29–34 years)

    Insulin infusion decreased α-TOH/LDL-C plasma level

    -

     

    Observational (meta-analysis)

    Kollerits et al. [28]

    n = 20,136 subjects

    Vitamin E-binding protein afamin is an independent predictor for DMT2 incidence, increase in afamin is associated with prevalence DMT2

    -

     

    Observational/
    Interventional

    Mayer-Davis et al. [29]

    n = 895 non-diabetic adults (45–65 years)

    (n = 318 non-supplement users and n = 577 supplement users)

    α-TOH plasma level is decreased in DMT2 patients and correlates with diabetes incidence, but not the nutritional intake/use of supplements

    -/not defined

     

    Observational

    [30] et al.

    n = 62 DMT2 patients (49–64 years)

    n = 20 controls subjects

    Decreased α-TOH/TC, TG serum level in diabetic patients with macroangiopathy versus without vascular changes

    -

     

    Observational

    Salonen et al. [31]

    n = 944 male healthy subjects (42–60 years)

    Decreased α-TOH plasma levels associated with increase diabetes risk

    -

     

    Observational

    Eljaoudi et al. [32]

    n = 60 DMT2 patients
    n = 40 healthy subjects (31–76 years)

    Decreased α-TOH plasma level in DMT2

    -

     

    Observational

    Nourooz-Zadeh et al. [33]

    n = 87 DMT2 patients
    n = 41 healthy subjects (17–86 years)

    Decreased α-TOH/TC plasma level in DMT2

    -

     

    Observational

    Mehmetoglu et al. [21]

    n= 98 obese subjects
    n = 78 healthy subjects
    (18–65 years)

    no correlation of α-TOH/TC + TG plasma level and insulin resistance in obese subjects

    -

     

    Interventional

    Rafighi et al. [34]

    n = 170 DMT2 patients (30–60 years)

    Vitamin E supplementation decreased blood glucose level, antioxidative capacity, (increased SOD and GSH enzyme activity), oxidative stress and insulin resistance

    200 mg (300 IU) vitamin E (/day) and 267 mg vitamin C per day for 3 months

     

    Interventional

    Manning et al. [35]

    n = 80 healthy subjects (38–57 years)

    Vitamin E supplementation decreased inflammatory processes, fasting plasma glucose and improved insulin sensitivity in overweight subjects

    537 mg (800 IU) vitamin E per day or placebo for 3 months

     

    Interventional (Meta-analysis)

    Xu et al. [36]

    n = 714 subjects

    vitamin E supplementation did not change glycemic control (HbA1c, fasting glucose, fasting insulin)

    134–1074 mg (200–1600 IU) per day for 6–27 weeks

    Fatty Liver Disease

     

     

     

     

     

     

    Observational

    Erhardt et al. [37]

    n = 50 NASH patients
    n = 40 healthy controls
    (35–67 years)

    Decreased α-TOH plasma levels in NASH patients

    -

     

    Observational

    Machado et al. [38]

    n = 43 NASH patients
    n = 33 healthy controls
    (27–68 years)

    Increased α-TOH plasma levels in NASH patients

    -

     

    Interventional

    Violet et al. [39]

    n = 6 female NASH patients (33–53 years)
    n = 10 female healthy controls (19–35 years)

    Alteration of α-TOH kinetics in women with obesity-associated hepatosteatosis compared to healthy controls, decreased release of α-TOH from the liver, lower α-TOH plasma level

    2 mg α-TOH once

     

    Interventional

    Sanyal et al. [40]

    n = 167 NASH patients (n = 83 placebo, n = 84 α-TOH, 34–59 years)

    α-TOH supplementation improves ALT, AST, lobular inflammation and NASH compared to placebo treated group

    537 mg (800 IU) α-TOH per day or placebo for 2 years

     

    Interventional

    Lavine et al. [41]

    n = 11 NASH patients (<16 years)

    α-TOH supplementation decreased ALT, AST, ALP

    268–805 mg (400–1200 IU) α-TOH for 4–10 months

    Metabolic syndrome (MetS)

     

     

     

     

     

    Observational

    Ford et al. [42]

    MetS patients and healthy controls from NHANES III (≥20 years)

    Lower α-TOH plasma level in MetS patients

    -

     

    Observational

    Beydoun et al. [43]

    n = 3008–9099 participants from NHANES 2001–2006 (20–85 years)

    Higher α-TOH plasma level in MetS patients

    -

     

    Observational

    Yen et al. [44]

    n = 72 MetS patients
    n = 105 healthy controls

    α-TOH/TG plasma level remained unchanged

    -

     

    Interventional

    Mah et al. [45]

    n = 10 MetS patients
    n = 10 healthy controls

    MetS patients have lower α-TOH /lipid plasma level and lower α-TOH absorption and impaired hepatic trafficking compared to healthy subjects

    15 mg α-TOH once

     

    1. Cardiovascular Events, particularly MI

    An early study by Gey et al. [46] found a strong inverse association between plasma vitamin E level and mortality of ischemic heart disease. Furthermore, the risk of angina pectoris was inversely associated with the plasma concentration of vitamin E in a case-controlled population study of 110 cases of angina, even after adjustment for age, smoking habit, blood pressure, lipids, and relative weight [47].

    Recently, Huang et al. reported in a long-term prospective cohort study, including biochemical analysis of 29,092 participants, that higher baseline serum α-TOH was associated with lower risk of overall mortality and mortality from all major causes. This study supports the long-term health benefits of higher serum α-TOH for overall and disease-specific mortality such as CVD [48]. Several observational studies [49][50][51][52][53][54][55][56] have consistently shown that vitamin E supplementation and/or high vitamin E intake is associated with a decreased risk of CVD. To our knowledge, only one Mendelian randomization study in China showed that high vitamin E levels were associated with an increased risk of CVD [57]. Despite this study, the overall consistency in the other studies has led many to suggest that vitamin E supplements may reduce the risk of CVD and several interventional trials have begun to study the cardioprotective effect of vitamin E.

    Most studies have focused on vitamin E and the risk of CVD in general, while only a few have looked at the risk of major single causes of CVD like MI. A recent study from China stated that high vitamin E levels could increase the risk of MI [57]. A prospective study by Hak et al. [58] also reported that men without a history of CVD and with higher plasma vitamin E tended to have an increased MI risk. Hense and colleagues [59] found no association between serum vitamin E concentration and MI risk in their study population; however, they suggested that this might have been due to the high average levels of vitamin E in their study population.

    A high plasma level may not be associated with a lower risk of MI; nevertheless, an interesting observation is a decrease in vitamin E plasma level in MI patients [60]. Within the first 48 h after MI, the plasma level of vitamin E declines significantly by 26% [61], and remains low until the third day after the start of the catabolic response [62]. Following an infarct, Sood et al. [63] showed that reperfusion was associated with excessive oxidative stress and increased consumption of this antioxidant not only in the ischemic but also in the reperfused myocardium. Vitamin E can be suggested as a valid marker for reperfusion and supplementation of vitamin E could be a therapeutic option for antioxidative protection of the myocardium in the acute setting.

    Overall, numerous observational studies have consistently reported that high vitamin E intake or supplementation is associated with a decreased risk of CVD and overall mortality. However, no interventional trials in humans has shown, so far, the benefit of a supplementation of vitamin E to prevent any cardiovascular event. In contrast, promising preclinical data [64], the decrease in vitamin E plasma level within the first 48 h after MI and the high demand for vitamin E during reperfusion justify further investigations of a short-term vitamin E supplementation in patients presenting with acute MI.

    The entry is from 10.3390/antiox9100935

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