The Effect of Vitamin Supplementation on Subclinical Atherosclerosis in Patients without Manifest Cardiovascular Diseases: Never-ending Hope or Underestimated Effect?

Micronutrients, especially vitamins, play an important role in the evolution of cardiovascular diseases (CVD). It has been speculated that additional intake of vitamins may reduce the CVD burden by acting on the inflammatory and oxidative response starting from early stages of atherosclerosis, when the vascular impairment might still be reversible or, at least, slowed down. The current review assesses the role of major vitamins on subclinical atherosclerosis process and the potential clinical implications in patients without CVD. We have comprehensively examined the literature data for the major vitamins: A, B group, C, D, and E, respectively. Most data are based on vitamin E, D and C supplementation, while vitamins A and B have been scarcely examined for the subclinical atherosclerosis action. Though the fundamental premise was optimistic, the up-to-date trials with vitamin supplementation revealed divergent results on subclinical atherosclerosis improvement, both in healthy subjects and patients with CVD, while the long-term effect seems minimal. Thus, there are no conclusive data on the prevention and progression of atherosclerosis based on vitamin supplementation. However, given their enormous potential, future trials are certainly needed for a more tailored CVD prevention focusing on early stages as subclinical atherosclerosis.

[1]  David T. Smith Niacin , 1943, Reactions Weekly.

[2]  E. Andrès,et al.  Cobalamin (vitamin B12) malabsorption , 2020 .

[3]  N. Yanaka,et al.  Novel preventive mechanisms of vitamin B6 against inflammation, inflammasome, and chronic diseases , 2020 .

[4]  W. Schimetta,et al.  A Randomized Pilot Trial to Evaluate the Bioavailability of Natural versus Synthetic Vitamin B Complexes in Healthy Humans and Their Effects on Homocysteine, Oxidative Stress, and Antioxidant Levels , 2019, Oxidative medicine and cellular longevity.

[5]  M. Hancianu,et al.  Pharmacokinetic Interactions between Cardiovascular Medicines and Plant Products , 2019, Cardiovascular therapeutics.

[6]  R. Bowen,et al.  Best practices in mitigating the risk of biotin interference with laboratory testing. , 2019, Clinical biochemistry.

[7]  W. Blaner Vitamin A signaling and homeostasis in obesity, diabetes, and metabolic disorders. , 2019, Pharmacology & therapeutics.

[8]  C. Wagner,et al.  Association of circulating 25-hydroxyvitamin D and parathyroid hormone with carotid intima media thickness in children and adolescents with excess weight , 2019, The Journal of Steroid Biochemistry and Molecular Biology.

[9]  E. Goldberg,et al.  Gender differences in homocysteine concentrations, a population-based cross-sectional study. , 2019, Nutrition, metabolism, and cardiovascular diseases : NMCD.

[10]  G. Ferns,et al.  Serum vitamin E as a significant prognostic factor in patients with dyslipidemia disorders. , 2019, Diabetes & metabolic syndrome.

[11]  N. Viguerie,et al.  Niacin induces miR-502-3p expression which impairs insulin sensitivity in human adipocytes , 2018, International Journal of Obesity.

[12]  A. Arafa,et al.  Thiamine deficiency and cardiovascular disorders. , 2018, Nutrition, metabolism, and cardiovascular diseases : NMCD.

[13]  M. Adorni,et al.  Vitamin D replacement ameliorates serum lipoprotein functions, adipokine profile and subclinical atherosclerosis in pre-menopausal women. , 2018, Nutrition, metabolism, and cardiovascular diseases : NMCD.

[14]  S. Frisbee,et al.  Subclinical atherosclerosis, cardiovascular health, and disease risk: is there a case for the Cardiovascular Health Index in the primary prevention population? , 2018, BMC Public Health.

[15]  S. Costanzo,et al.  Serum vitamin D deficiency and risk of hospitalization for heart failure: Prospective results from the Moli-sani study. , 2017, Nutrition, metabolism, and cardiovascular diseases : NMCD.

[16]  V. M. Kodentsova,et al.  [Sex and line differences in biochemical indices and fat soluble vitamins sufficiency in rats on in vivo model of metabolic syndrome]. , 2018, Voprosy pitaniia.

[17]  D. Hougaard,et al.  Syddansk Universitet Associations between vitamin D status and atherosclerosis among Inuit in Greenland , 2017 .

[18]  Yanbin Dong,et al.  Dose responses of vitamin D3 supplementation on arterial stiffness in overweight African Americans with vitamin D deficiency: A placebo controlled randomized trial , 2017, PloS one.

[19]  A. Tajik,et al.  Vitamins for Cardiovascular Diseases: Is the Expense Justified? , 2017, Cardiology in review.

[20]  V. Jha,et al.  A Randomized Trial of Vitamin D Supplementation on Vascular Function in CKD. , 2017, Journal of the American Society of Nephrology : JASN.

[21]  U. Nöthlings,et al.  Association of Vitamin E Levels with Metabolic Syndrome, and MRI-Derived Body Fat Volumes and Liver Fat Content , 2017, Nutrients.

[22]  M. K. Kim,et al.  The long-term relationship between dietary pantothenic acid (vitamin B5) intake and C-reactive protein concentration in adults aged 40 years and older. , 2017, Nutrition, metabolism, and cardiovascular diseases : NMCD.

[23]  J. L. Napoli Cellular retinoid binding-proteins, CRBP, CRABP, FABP5: Effects on retinoid metabolism, function and related diseases. , 2017, Pharmacology & therapeutics.

[24]  J. Matte,et al.  Pyridoxine (Vitamin B6) and the Glutathione Peroxidase System; a Link between One-Carbon Metabolism and Antioxidation , 2017, Nutrients.

[25]  G. Curhan,et al.  Effect of Vitamin D on Endothelial Function: A Randomized, Double-Blind, Placebo-Controlled Trial , 2017, American journal of hypertension.

[26]  C. Luca,et al.  Crosstalk between Vitamins A, B12, D, K, C, and E Status and Arterial Stiffness , 2017, Disease markers.

[27]  A. Howard,et al.  Lutein and atherosclerosis: Belfast versus Toulouse revisited. , 2017, Medical hypotheses.

[28]  J. Fu,et al.  Biological Properties of Tocotrienols: Evidence in Human Studies , 2016, International journal of molecular sciences.

[29]  M. K. Kim,et al.  The cross-sectional relationships of dietary and serum vitamin D with cardiometabolic risk factors: Metabolic components, subclinical atherosclerosis, and arterial stiffness. , 2016, Nutrition.

[30]  M. Levine,et al.  Vitamin C: the known and the unknown and Goldilocks. , 2016, Oral diseases.

[31]  L. Brandi,et al.  The Effect of High Dose Cholecalciferol on Arterial Stiffness and Peripheral and Central Blood Pressure in Healthy Humans: A Randomized Controlled Trial , 2016, PloS one.

[32]  O. Chun,et al.  Vitamin C and Heart Health: A Review Based on Findings from Epidemiologic Studies , 2016, International journal of molecular sciences.

[33]  W. März,et al.  Vitamin D and cardiovascular disease prevention , 2016, Nature Reviews Cardiology.

[34]  F. Ilkhani Niacin and Oxidative Stress: A Mini-Review , 2016 .

[35]  B. D. Craft,et al.  Modeling the impact of residual fat-soluble vitamin (FSV) contents on the oxidative stability of commercially refined vegetable oils , 2016 .

[36]  A. Nègre-Salvayre,et al.  Oxidative theory of atherosclerosis and antioxidants. , 2016, Biochimie.

[37]  Stefan Lorkowski,et al.  Complexity of vitamin E metabolism. , 2016, World journal of biological chemistry.

[38]  J. Valdivielso,et al.  Predictors of Subclinical Atheromatosis Progression over 2 Years in Patients with Different Stages of CKD. , 2016, Clinical journal of the American Society of Nephrology : CJASN.

[39]  D. Kennedy B Vitamins and the Brain: Mechanisms, Dose and Efficacy—A Review , 2016, Nutrients.

[40]  G. Hitman,et al.  Effects of vitamin D2 or D3 supplementation on glycaemic control and cardiometabolic risk among people at risk of type 2 diabetes: results of a randomized double‐blind placebo‐controlled trial , 2016, Diabetes, obesity & metabolism.

[41]  K. Yadav,et al.  Role of Traditional Risk Factors, Inflammation and DMARDs in Cardiovascular Diseases in Rheumatoid Arthritis and Management of Lipid Profile , 2016 .

[42]  Eugenia G. Giannopoulou,et al.  Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH , 2015, Science.

[43]  E. Denova-Gutiérrez,et al.  The effect of vitamin D supplementation on serum lipids in postmenopausal women with diabetes: A randomized controlled trial. , 2015, Clinical nutrition.

[44]  Thomas J. Wang,et al.  High-Dose versus Low-Dose Vitamin D Supplementation and Arterial Stiffness among Individuals with Prehypertension and Vitamin D Deficiency , 2015, Disease markers.

[45]  Y. Abed,et al.  Effect of vitamin C on inflammation and metabolic markers in hypertensive and/or diabetic obese adults: a randomized controlled trial , 2015, Drug design, development and therapy.

[46]  I. Mozoș,et al.  Links between Vitamin D Deficiency and Cardiovascular Diseases , 2015, BioMed research international.

[47]  C. W. Wong,et al.  Vitamin B12 deficiency in the elderly: is it worth screening? , 2015, Hong Kong medical journal = Xianggang yi xue za zhi.

[48]  J. Mathers,et al.  Effect of vitamin C on endothelial function in health and disease: a systematic review and meta-analysis of randomised controlled trials. , 2014, Atherosclerosis.

[49]  W. Rathmann,et al.  Vitamin D and mortality: meta-analysis of individual participant data from a large consortium of cohort studies from Europe and the United States , 2014, BMJ : British Medical Journal.

[50]  K. Moreau,et al.  Oxidative stress contributes to large elastic arterial stiffening across the stages of the menopausal transition , 2014, Menopause.

[51]  Keith C. Norris,et al.  The Effect of Short Term Vitamin D Supplementation on the Inflammatory and Oxidative Mediators of Arterial Stiffness , 2014, Health.

[52]  M. Ashoori,et al.  Riboflavin (vitamin B2) and oxidative stress: a review , 2014, British Journal of Nutrition.

[53]  J. Rumberger,et al.  Pantethine, a derivative of vitamin B5, favorably alters total, LDL and non-HDL cholesterol in low to moderate cardiovascular risk subjects eligible for statin therapy: a triple-blinded placebo and diet-controlled investigation , 2014, Vascular health and risk management.

[54]  S. Lorkowski,et al.  Regulatory metabolites of vitamin E and their putative relevance for atherogenesis , 2014, Redox biology.

[55]  N. Al-Daghri,et al.  Metabolic Benefits of Six-month Thiamine Supplementation in Patients With and Without Diabetes Mellitus Type 2 , 2014, Clinical medicine insights. Endocrinology and diabetes.

[56]  M. Boaz,et al.  Effect of high doses of vitamin D on arterial properties, adiponectin, leptin and glucose homeostasis in type 2 diabetic patients. , 2013, Clinical nutrition.

[57]  K. Onodera,et al.  Linkage between coenzyme a metabolism and inflammation: roles of pantetheinase. , 2013, Journal of Pharmacological Sciences.

[58]  B. Cheung,et al.  Randomized controlled trial of vitamin D supplement on endothelial function in patients with type 2 diabetes. , 2013, Atherosclerosis.

[59]  L. Mahan,et al.  Krause's food, nutrition , 2012 .

[60]  J. Manson,et al.  Associations between retinol-binding protein 4 and cardiometabolic risk factors and subclinical atherosclerosis in recently postmenopausal women: cross-sectional analyses from the KEEPS study , 2012, Cardiovascular Diabetology.

[61]  G. Sesti,et al.  Oxidative stress impairs endothelial function in nondipper hypertensive patients. , 2012, Cardiovascular therapeutics.

[62]  U. Jeschke,et al.  Oxidative stress stimulates α-tocopherol transfer protein in human trophoblast tumor cells BeWo , 2012, Journal of perinatal medicine.

[63]  L. Mahan,et al.  Krause's Food & the Nutrition Care Process , 2011 .

[64]  Daniel Keeton,et al.  Vitamin D3 supplementation for 16 weeks improves flow-mediated dilation in overweight African-American adults. , 2011, American journal of hypertension.

[65]  C. Zechner,et al.  Vitamin D: Cardiovascular Effects and Vascular Calcification , 2011 .

[66]  A. Pfeiffer,et al.  Relation between retinol, retinol-binding protein 4, transthyretin and carotid intima media thickness. , 2010, Atherosclerosis.

[67]  N. Noy Between death and survival: retinoic acid in regulation of apoptosis. , 2010, Annual review of nutrition.

[68]  Pierre Amarenco,et al.  Meta-analysis of the effect of nicotinic acid alone or in combination on cardiovascular events and atherosclerosis. , 2010, Atherosclerosis.

[69]  H. Boeing,et al.  Vitamin E and Risk of Cardiovascular Diseases: A Review of Epidemiologic and Clinical Trial Studies , 2010, Critical reviews in food science and nutrition.

[70]  A. Floegel,et al.  Estimation of antioxidant intakes from diet and supplements in U.S. adults. , 2010, The Journal of nutrition.

[71]  J. M. May,et al.  Vitamin C function in the brain: vital role of the ascorbate transporter SVCT2. , 2009, Free radical biology & medicine.

[72]  R. Detrano,et al.  High-Dose B Vitamin Supplementation and Progression of Subclinical Atherosclerosis: A Randomized Controlled Trial , 2009, Stroke.

[73]  Bo George,et al.  Oxidative stress and the effect of riboflavin supplementation in individuals with uncomplicated malaria infection. , 2009 .

[74]  E. Andrès,et al.  An update on cobalamin deficiency in adults. , 2009, QJM : monthly journal of the Association of Physicians.

[75]  E. Ingelsson,et al.  Circulating Retinol-Binding Protein 4 and Subclinical Cardiovascular Disease in the Elderly , 2008, Diabetes Care.

[76]  J. Manson,et al.  Vitamins E and C in the prevention of cardiovascular disease in men: the Physicians' Health Study II randomized controlled trial. , 2008, JAMA.

[77]  K. Yuen,et al.  Arterial compliance and vitamin E blood levels with a self emulsifying preparation of tocotrienol rich vitamin E , 2008, Archives of pharmacal research.

[78]  J. Sugden,et al.  Vitamin D improves endothelial function in patients with Type 2 diabetes mellitus and low vitamin D levels , 2008, Diabetic medicine : a journal of the British Diabetic Association.

[79]  G. Umpierrez,et al.  The effects of extended‐release niacin on carotid intimal media thickness, endothelial function and inflammatory markers in patients with the metabolic syndrome , 2007, International journal of clinical practice.

[80]  J. Zingg,et al.  Cellular, molecular and clinical aspects of vitamin E on atherosclerosis prevention. , 2007, Molecular aspects of medicine.

[81]  S. Eichinger,et al.  Low vitamin B6 levels and the risk of recurrent venous thromboembolism , 2007, Haematologica.

[82]  H. Boeing,et al.  Plasma pyridoxal-5-phosphate and future risk of myocardial infarction in the European Prospective Investigation into Cancer and Nutrition Potsdam cohort. , 2007, The American journal of clinical nutrition.

[83]  V. Funanage,et al.  Reduction of elevated serum retinol binding protein in obese children by lifestyle intervention: association with subclinical inflammation. , 2007, The Journal of clinical endocrinology and metabolism.

[84]  M. Sivakumar,et al.  Niacin affects cell adhesion molecules and plasminogen activator inhibitor-1 in HepG2 cells. , 2007, Clinica chimica acta; international journal of clinical chemistry.

[85]  A. Sidawy,et al.  Thiamine (Vitamin B1) Improves Endothelium-Dependent Vasodilatation in the Presence of Hyperglycemia , 2006, Annals of vascular surgery.

[86]  A. Mangoni Folic acid, inflammation, and atherosclerosis: false hopes or the need for better trials? , 2006, Clinica chimica acta; international journal of clinical chemistry.

[87]  D. Lonsdale A Review of the Biochemistry, Metabolism and Clinical Benefits of Thiamin(e) and Its Derivatives , 2006, Evidence-based complementary and alternative medicine : eCAM.

[88]  G. Hansson,et al.  Inflammation and atherosclerosis. , 2006, Annual review of pathology.

[89]  J. Mehta,et al.  Oxidized LDL, a critical factor in atherogenesis. , 2005, Cardiovascular research.

[90]  P. Weinberg Analysis of the variable effect of dietary vitamin E supplements on experimental atherosclerosis. , 2005, Journal of plant physiology.

[91]  E. Schouten,et al.  Effect of lowering of homocysteine levels on inflammatory markers: a randomized controlled trial. , 2005, Archives of internal medicine.

[92]  Roberto Pastor-Barriuso,et al.  Meta-Analysis: High-Dosage Vitamin E Supplementation May Increase All-Cause Mortality , 2005, Annals of Internal Medicine.

[93]  D. Mock,et al.  Determination of the biotin content of select foods using accurate and sensitive HPLC/avidin binding. , 2004, Journal of food composition and analysis : an official publication of the United Nations University, International Network of Food Data Systems.

[94]  G. Lamas,et al.  Randomized Trials of Vitamin E in the Treatment and Prevention of Cardiovascular Disease , 2004 .

[95]  L. Wojtczak,et al.  Pantothenic acid and pantothenol increase biosynthesis of glutathione by boosting cell energetics , 2004, FEBS letters.

[96]  D. Seals,et al.  Ascorbic acid does not affect large elastic artery compliance or central blood pressure in young and older men. , 2004, American journal of physiology. Heart and circulatory physiology.

[97]  P. Libby,et al.  Inflammation and atherosclerosis: role of C-reactive protein in risk assessment. , 2004, The American journal of medicine.

[98]  Richard B Devereux,et al.  Relationship of High and Low Ankle Brachial Index to All-Cause and Cardiovascular Disease Mortality: The Strong Heart Study , 2004, Circulation.

[99]  J. Manson,et al.  Vitamin C and risk of coronary heart disease in women. , 2003, Journal of the American College of Cardiology.

[100]  A. Mangoni,et al.  Effects of folic acid supplementation on inflammatory and thrombogenic markers in chronic smokers. A randomised controlled trial. , 2003, Thrombosis research.

[101]  B. Rutkowski,et al.  Is there any relationship between lipids and vitamin B levels in persons with elevated risk of atherosclerosis? , 2003, Medical science monitor : international medical journal of experimental and clinical research.

[102]  Peter Eck,et al.  Vitamin C as an Antioxidant: Evaluation of Its Role in Disease Prevention , 2003, Journal of the American College of Nutrition.

[103]  Stephen H. D. Jackson,et al.  Folic acid enhances endothelial function and reduces blood pressure in smokers: a randomized controlled trial , 2002, Journal of internal medicine.

[104]  I. Young,et al.  Ascorbic Acid Reduces Blood Pressure and Arterial Stiffness in Type 2 Diabetes , 2002, Hypertension.

[105]  J. Deisenhofer,et al.  Structure of factor-inhibiting hypoxia-inducible factor 1: An asparaginyl hydroxylase involved in the hypoxic response pathway , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[106]  L. Rudel,et al.  α-Tocopherol protects against diet induced atherosclerosis in New Zealand white rabbits Published, JLR Papers in Press, August 16, 2002. DOI 10.1194/jlr.M200261-JLR200 , 2002, Journal of Lipid Research.

[107]  S. Azen,et al.  Alpha-Tocopherol Supplementation in Healthy Individuals Reduces Low-Density Lipoprotein Oxidation but Not Atherosclerosis: The Vitamin E Atherosclerosis Prevention Study (VEAPS) , 2002, Circulation.

[108]  M. Kurabayashi,et al.  Retinoids Induce the PAI-1 Gene Expression Through Tyrosine Kinase-Dependent Pathways in Vascular Smooth Muscle Cells , 2002, Journal of cardiovascular pharmacology.

[109]  Frank Hu,et al.  The Effect of Fruit and Vegetable Intake on Risk for Coronary Heart Disease , 2001, Annals of Internal Medicine.

[110]  D. Webb,et al.  Acute Methionine Loading Does not Alter Arterial Stiffness in Humans , 2001, Journal of cardiovascular pharmacology.

[111]  S. Brody,et al.  A randomized controlled trial of high dose ascorbic acid for reduction of blood pressure, cortisol, and subjective responses to psychological stress , 2001, Psychopharmacology.

[112]  T. Lakka,et al.  Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) study: a randomized trial of the effect of vitamins E and C on 3‐year progression of carotid atherosclerosis , 2000, Journal of internal medicine.

[113]  I. Meredith,et al.  Vitamin E supplementation improves endothelial function in type I diabetes mellitus: a randomized, placebo-controlled study. , 2000, Journal of the American College of Cardiology.

[114]  J. Twisk,et al.  Effect of homocysteine-lowering treatment with folic acid plus vitamin B6 on progression of subclinical atherosclerosis: a randomised, placebo-controlled trial , 2000, The Lancet.

[115]  A. Sidawy,et al.  Thiamine (Vitamin B1) Protects against Glucose- and Insulin-Mediated Proliferation of Human Infragenicular Arterial Smooth Muscle Cells , 2000, Annals of vascular surgery.

[116]  D. Leake,et al.  Vitamin C protects human vascular smooth muscle cells against apoptosis induced by moderately oxidized LDL containing high levels of lipid hydroperoxides. , 1999, Arteriosclerosis, thrombosis, and vascular biology.

[117]  G. Gabbiani,et al.  Retinoic acid regulates arterial smooth muscle cell proliferation and phenotypic features in vivo and in vitro through an RARalpha-dependent signaling pathway. , 1999, Arteriosclerosis, thrombosis, and vascular biology.

[118]  S. Srinivasan,et al.  Atherosclerosis: a nutritional disease of childhood. , 1998, The American journal of cardiology.

[119]  J. Heinecke Oxidants and antioxidants in the pathogenesis of atherosclerosis: implications for the oxidized low density lipoprotein hypothesis. , 1998, Atherosclerosis.

[120]  A. Chait,et al.  Dietary antioxidants inhibit development of fatty streak lesions in the LDL receptor-deficient mouse. , 1998, Arteriosclerosis, thrombosis, and vascular biology.

[121]  R. Winneker,et al.  TNF-alpha and 9-cis-retinoic acid synergistically induce ICAM-1 expression: evidence for interaction of retinoid receptors with NF-kappa B. , 1998, Experimental cell research.

[122]  F. Kok,et al.  Vitamin E supplementation in elderly lowers the oxidation rate of linoleic acid in LDL. , 1997, Atherosclerosis.

[123]  A. Zeiher,et al.  Oxidized low-density lipoprotein induces apoptosis of human endothelial cells by activation of CPP32-like proteases. A mechanistic clue to the 'response to injury' hypothesis. , 1997, Circulation.

[124]  W. Erl,et al.  Increased adhesiveness of isolated monocytes to endothelium is prevented by vitamin C intake in smokers. , 1996, Circulation.

[125]  H. Khor,et al.  Tocotrienols inhibit liver HMG CoA reductase activity in the guinea pig , 1995 .

[126]  R. Parker,et al.  Tocotrienols regulate cholesterol production in mammalian cells by post-transcriptional suppression of 3-hydroxy-3-methylglutaryl-coenzyme A reductase. , 1993, The Journal of biological chemistry.

[127]  M. Motro,et al.  Thiamine deficiency in patients with congestive heart failure receiving long-term furosemide therapy: a pilot study. , 1991, The American journal of medicine.

[128]  M. Motro,et al.  Thiamine deficiency in patients with congestive heart failure on long term furosemide therapy , 1991 .

[129]  R. Paroni,et al.  Modulation of HMG-CoA reductase activity by pantetheine/pantethine. , 1988, Biochimica et biophysica acta.

[130]  H. Powers,et al.  Riboflavin deficiency in man: effects on haemoglobin and reduced glutathione in erythrocytes of different ages , 1981, British Journal of Nutrition.

[131]  M. Sporn,et al.  Prevention of chemical carcinogenesis by vitamin A and its synthetic analogs (retinoids). , 1976, Federation proceedings.

[132]  H. Sauberlich,et al.  Clinical manifestations of ascorbic acid deficiency in man. , 1971, American Journal of Clinical Nutrition.