Vitamin D and Cardiovascular Disease: An Updated Narrative Review

During the last two decades, the potential impact of vitamin D on the risk of cardiovascular disease (CVD) has been rigorously studied. Data regarding the effect of vitamin D on CVD risk are puzzling: observational data indicate an inverse nonlinear association between vitamin D status and CVD events, with the highest CVD risk at severe vitamin D deficiency; however, preclinical data and randomized controlled trials (RCTs) show several beneficial effects of vitamin D on the surrogate parameters of vascular and cardiac function. By contrast, Mendelian randomization studies and large RCTs in the general population and in patients with chronic kidney disease, a high-risk group for CVD events, largely report no significant beneficial effect of vitamin D treatment on CVD events. In patients with rickets and osteomalacia, cardiovascular complications are infrequently reported, except for an increased risk of heart failure. In conclusion, there is no strong evidence for beneficial vitamin D effects on CVD risk, either in the general population or in high-risk groups. Whether some subgroups such as individuals with severe vitamin D deficiency or a combination of low vitamin D status with specific gene variants and/or certain nutrition/lifestyle factors would benefit from vitamin D (metabolite) administration, remains to be studied.

[1]  J. Manson,et al.  Effect of Vitamin D Supplementation, Omega-3 Fatty Acid Supplementation, or a Strength-Training Exercise Program on Clinical Outcomes in Older Adults: The DO-HEALTH Randomized Clinical Trial. , 2020, JAMA.

[2]  R. Erben,et al.  Vitamin D and Cardiovascular Disease, with Emphasis on Hypertension, Atherosclerosis, and Heart Failure , 2020, International journal of molecular sciences.

[3]  A. Saba,et al.  An Update on Vitamin D Metabolism , 2020, International journal of molecular sciences.

[4]  S. Pilz,et al.  The effect of vitamin D on fibroblast growth factor 23: a systematic review and meta-analysis of randomized controlled trials , 2020, European Journal of Clinical Nutrition.

[5]  R. Jorde,et al.  Vitamin D Supplementation for Prevention of Type 2 Diabetes Mellitus: To D or Not to D? , 2020, The Journal of clinical endocrinology and metabolism.

[6]  M. Holick,et al.  Immunologic Effects of Vitamin D on Human Health and Disease , 2020, Nutrients.

[7]  J. Linseisen,et al.  Role of Vitamin D in Preventing and Treating Selected Extraskeletal Diseases—An Umbrella Review , 2020, Nutrients.

[8]  Dongdong Zhang,et al.  Effect of Vitamin D on Blood Pressure and Hypertension in the General Population: An Update Meta-Analysis of Cohort Studies and Randomized Controlled Trials , 2020, Preventing chronic disease.

[9]  Chih-Yang Hsu,et al.  The effects of correction of vitamin D deficiency on arterial stiffness: A systematic review and updated meta-analysis of randomized controlled trials , 2019, The Journal of Steroid Biochemistry and Molecular Biology.

[10]  M. Holick Sunlight, UV Radiation, Vitamin D, and Skin Cancer: How Much Sunlight Do We Need? , 2020, Advances in experimental medicine and biology.

[11]  D. Dibaba,et al.  Effect of vitamin D supplementation on serum lipid profiles: a systematic review and meta-analysis. , 2019, Nutrition reviews.

[12]  J. Manson,et al.  Effect of Vitamin D and Omega-3 Fatty Acid Supplementation on Kidney Function in Patients With Type 2 Diabetes: A Randomized Clinical Trial. , 2019, JAMA.

[13]  G. Moradi,et al.  The association between circulating 25-hydroxyvitamin D and cardiovascular diseases: a meta-analysis of prospective cohort studies , 2019, BMC Cardiovascular Disorders.

[14]  H-L Yi,et al.  The association between vitamin D receptor gene polymorphism and susceptibility to hypertension: a meta-analysis. , 2019, European review for medical and pharmacological sciences.

[15]  N. Smart,et al.  Effect of vitamin D supplementation on endothelial function - An updated systematic review with meta-analysis and meta-regression. , 2019, Nutrition, metabolism, and cardiovascular diseases : NMCD.

[16]  R. Bouillon,et al.  Vitamin D and cardiovascular disorders , 2019, Osteoporosis International.

[17]  S. Vettoretti,et al.  Native Hypovitaminosis D in CKD Patients: From Experimental Evidence to Clinical Practice , 2019, Nutrients.

[18]  Juan Ou-Yang,et al.  Low serum vitamin D levels increase the mortality of cardiovascular disease in older adults , 2019, Medicine.

[19]  Shi-kun Yang,et al.  The Impact of Vitamin D Receptor Gene Polymorphisms on the Susceptibility of Diabetic Vascular Complications: A Meta-Analysis. , 2019, Genetic testing and molecular biomarkers.

[20]  J. Manson,et al.  Vitamin D Supplementation and Cardiovascular Disease Risks in More Than 83 000 Individuals in 21 Randomized Clinical Trials: A Meta-analysis. , 2019, JAMA cardiology.

[21]  J. Ware,et al.  Vitamin D Supplementation and Prevention of Type 2 Diabetes. , 2019, The New England journal of medicine.

[22]  Marc A Pfeffer,et al.  Heart Failure With Preserved Ejection Fraction In Perspective. , 2019, Circulation research.

[23]  Zhiqian Min,et al.  Meta-analysis of vitamin D supplementation in the treatment of chronic heart failure , 2019, Scandinavian cardiovascular journal : SCJ.

[24]  J. Gummert,et al.  Vitamin D supplementation of 4000 IU daily and cardiac function in patients with advanced heart failure: The EVITA trial. , 2019, International journal of cardiology.

[25]  M. Petkovich,et al.  Rationale for Raising Current Clinical Practice Guideline Target for Serum 25-Hydroxyvitamin D in Chronic Kidney Disease , 2019, American Journal of Nephrology.

[26]  Naijing Ye,et al.  Vitamin D supplementation for the improvement of vascular function in patients with chronic kidney disease: a meta-analysis of randomized controlled trials , 2019, International Urology and Nephrology.

[27]  A. Slominski,et al.  The serum vitamin D metabolome: What we know and what is still to discover , 2019, The Journal of Steroid Biochemistry and Molecular Biology.

[28]  W. März,et al.  Vitamin D testing and treatment: a narrative review of current evidence , 2019, Endocrine connections.

[29]  J. Manson,et al.  Vitamin D Supplements and Prevention of Cancer and Cardiovascular Disease , 2019, The New England journal of medicine.

[30]  K. Cashman,et al.  Is vitamin D deficiency a public health concern for low middle income countries? A systematic literature review , 2019, European Journal of Nutrition.

[31]  N. Yorioka,et al.  Effect of Oral Alfacalcidol on Clinical Outcomes in Patients Without Secondary Hyperparathyroidism Receiving Maintenance Hemodialysis: The J-DAVID Randomized Clinical Trial , 2018, JAMA.

[32]  David W. Johnson,et al.  Vitamin D status and mortality risk among patients on dialysis: a systematic review and meta-analysis of observational studies , 2018, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[33]  P. Dong,et al.  Effect of vitamin D on ventricular remodelling in heart failure: a meta-analysis of randomised controlled trials , 2018, BMJ Open.

[34]  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.

[35]  M. Hiligsmann,et al.  Rationale and Plan for Vitamin D Food Fortification: A Review and Guidance Paper , 2018, Front. Endocrinol..

[36]  N. Mirhosseini,et al.  Vitamin D Supplementation, Serum 25(OH)D Concentrations and Cardiovascular Disease Risk Factors: A Systematic Review and Meta-Analysis , 2018, Front. Cardiovasc. Med..

[37]  G. Davey Smith,et al.  Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians , 2018, British Medical Journal.

[38]  E. Giovannucci,et al.  Supplemental Vitamins and Minerals for CVD Prevention and Treatment. , 2018, Journal of the American College of Cardiology.

[39]  Ryan A. Harris,et al.  Effect of Vitamin D Supplementation on Markers of Vascular Function: A Systematic Review and Individual Participant Meta‐Analysis , 2018, Journal of the American Heart Association.

[40]  R. Jorde,et al.  Serum cholecalciferol may be a better marker of vitamin D status than 25-hydroxyvitamin D. , 2018, Medical hypotheses.

[41]  P. Lips,et al.  Global Overview of Vitamin D Status. , 2017, Endocrinology and metabolism clinics of North America.

[42]  Yufei Shi,et al.  Genetic Causes of Rickets , 2017, Journal of clinical research in pediatric endocrinology.

[43]  R. Jorde,et al.  Vitamin D Stored in Fat Tissue During a 5-Year Intervention Affects Serum 25-Hydroxyvitamin D Levels the Following Year , 2017, The Journal of clinical endocrinology and metabolism.

[44]  J. Gummert,et al.  Effect of vitamin D on all-cause mortality in heart failure (EVITA): a 3-year randomized clinical trial with 4000 IU vitamin D daily , 2017, European heart journal.

[45]  V. Gudnason,et al.  Non-skeletal health effects of vitamin D supplementation: A systematic review on findings from meta-analyses summarizing trial data , 2017, PloS one.

[46]  Kay-Tee Khaw,et al.  Effect of Monthly High-Dose Vitamin D Supplementation on Cardiovascular Disease in the Vitamin D Assessment Study: A Randomized Clinical Trial , 2017, JAMA cardiology.

[47]  G. Wang,et al.  Effects of vitamin D or its analogues on the mortality of patients with chronic kidney disease: an updated systematic review and meta-analysis , 2017, European Journal of Clinical Nutrition.

[48]  Yilong Wang,et al.  Serum 25-hydroxyvitamin D and the risk of cardiovascular disease: dose-response meta-analysis of prospective studies. , 2017, The American journal of clinical nutrition.

[49]  Shouling Wu,et al.  Vitamin D and hypertension: Prospective study and meta-analysis , 2017, PloS one.

[50]  K. Djafarian,et al.  Common Variants of Vitamin D Receptor Gene Polymorphisms and Susceptibility to Coronary Artery Disease: A Systematic Review and Meta-Analysis , 2017, Lifestyle Genomics.

[51]  A. Zittermann,et al.  Calciotropic and phosphaturic hormones in heart failure. , 2016, Nutrition, metabolism, and cardiovascular diseases : NMCD.

[52]  J. Brent Richards,et al.  Mendelian Randomization Studies Do Not Support a Role for Vitamin D in Coronary Artery Disease , 2016, Circulation. Cardiovascular genetics.

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

[54]  Fen Hu,et al.  The Associations Between the Polymorphisms of Vitamin D Receptor and Coronary Artery Disease , 2016, Medicine.

[55]  V. Srikanth,et al.  Effect of vitamin D supplementation on measures of arterial stiffness: a systematic review and meta‐analysis of randomized controlled trials , 2016, Clinical endocrinology.

[56]  Wei-Long Jiang,et al.  Vitamin D Supplementation in the Treatment of Chronic Heart Failure: A Meta‐analysis of Randomized Controlled Trials , 2016, Clinical cardiology.

[57]  L. Liao,et al.  Association of chemokine ligand 5/chemokine receptor 5 gene promoter polymorphisms with diabetic microvascular complications: A meta‐analysis , 2015, Journal of diabetes investigation.

[58]  C. Mølgaard,et al.  Vitamin D deficiency in Europe: pandemic? , 2016 .

[59]  M. Stojanović,et al.  Vitamin D versus placebo in improvement of endothelial dysfunction: a meta-analysis of randomized clinical trials. , 2015, Cardiovascular therapeutics.

[60]  R. Jorde,et al.  Effect of Vitamin D Supplementation on Blood Pressure: A Systematic Review and Meta-analysis Incorporating Individual Patient Data. , 2015, JAMA internal medicine.

[61]  Shoaib Afzal,et al.  No evidence that genetically reduced 25-hydroxyvitamin D is associated with increased risk of ischaemic heart disease or myocardial infarction: a Mendelian randomization study. , 2015, International journal of epidemiology.

[62]  S. Bojesen,et al.  Genetically low vitamin D concentrations and increased mortality: mendelian randomisation analysis in three large cohorts , 2014, BMJ : British Medical Journal.

[63]  C. Greenwood,et al.  The Causal Effect of Vitamin D Binding Protein (DBP) Levels on Calcemic and Cardiometabolic Diseases: A Mendelian Randomization Study , 2014, PLoS medicine.

[64]  A. Folsom,et al.  Serum magnesium, phosphorus, and calcium are associated with risk of incident heart failure: the Atherosclerosis Risk in Communities (ARIC) Study. , 2014, The American journal of clinical nutrition.

[65]  Xuefeng Yu,et al.  Associations study of vitamin D receptor gene polymorphisms with diabetic microvascular complications: a meta-analysis. , 2014, Gene.

[66]  Ross M. Fraser,et al.  Association of vitamin D status with arterial blood pressure and hypertension risk: a mendelian randomisation study , 2014, The lancet. Diabetes & endocrinology.

[67]  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.

[68]  F. Hirche,et al.  Dietary vitamin D inadequacy accelerates calcification and osteoblast-like cell formation in the vascular system of LDL receptor knockout and wild-type mice. , 2014, The Journal of nutrition.

[69]  M. Wolf,et al.  Roles of phosphate and fibroblast growth factor 23 in cardiovascular disease , 2014, Nature Reviews Nephrology.

[70]  I. Reid,et al.  The effect of vitamin D supplementation on skeletal, vascular, or cancer outcomes: a trial sequential meta-analysis. , 2014, The lancet. Diabetes & endocrinology.

[71]  O. Franco,et al.  Vitamin D and risk of cause specific death: systematic review and meta-analysis of observational cohort and randomised intervention studies , 2014, BMJ : British Medical Journal.

[72]  J. Powell,et al.  Vitamin D and cardiovascular disease. , 2014, Circulation research.

[73]  P. Autier,et al.  Vitamin D status and ill health: a systematic review. , 2014, The lancet. Diabetes & endocrinology.

[74]  Efsa Panel on Dietetic Products Scientific Opinion on Dietary Reference Values for vitamin A , 2015 .

[75]  H. Armbrecht,et al.  FGF-23 Regulates CYP27B1 Transcription in the Kidney and in Extra-Renal Tissues , 2013, PloS one.

[76]  B. Nordestgaard,et al.  25‐Hydroxyvitamin D and symptomatic ischemic stroke: An Original Study and Meta‐Analysis , 2013, Annals of neurology.

[77]  Khalid M. Alharbi,et al.  Hypocalcemic rachitic cardiomyopathy in infants. , 2013, Journal of the Saudi Heart Association.

[78]  J. Bacchetta,et al.  Beyond mineral metabolism, is there an interplay between FGF23 and vitamin D in innate immunity? , 2013, Pediatric Nephrology.

[79]  D. Viswanath,et al.  Dietary Reference Intakes for Calcium and Vitamin D , 2012, Pediatrics.

[80]  J. Manson,et al.  Circulating 25-Hydroxy-Vitamin D and Risk of Cardiovascular Disease: A Meta-Analysis of Prospective Studies , 2012, Circulation. Cardiovascular quality and outcomes.

[81]  F. Hirche,et al.  Vitamin D Receptor Deficiency and Low Vitamin D Diet Stimulate Aortic Calcification and Osteogenic Key Factor Expression in Mice , 2012, PloS one.

[82]  S. Shedeed Vitamin D Supplementation in Infants With Chronic Congestive Heart Failure , 2012, Pediatric Cardiology.

[83]  EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA); Scientific Opinion on the substantiation of a health claim related to isolated soy protein and reduction of blood LDL-cholesterol concentrations pursuant to Article 14 of Regulation (EC) No 1924/2006 , 2012 .

[84]  Christopher S. Law,et al.  Cardiomyocyte-Specific Deletion of the Vitamin D Receptor Gene Results in Cardiac Hypertrophy , 2011, Circulation.

[85]  V. Montori,et al.  Vitamin D and cardiovascular outcomes: a systematic review and meta-analysis. , 2011, The Journal of clinical endocrinology and metabolism.

[86]  Daniel L. Koller,et al.  Association of the Vitamin D Metabolism Gene CYP24A1 With Coronary Artery Calcification , 2010, Arteriosclerosis, thrombosis, and vascular biology.

[87]  R. Koerfer,et al.  Protective and toxic effects of vitamin D on vascular calcification: clinical implications. , 2008, Molecular aspects of medicine.

[88]  Christopher S. Law,et al.  Expression of the Vitamin D Receptor Is Increased in the Hypertrophic Heart , 2008, Hypertension.

[89]  K. Cao,et al.  Calcium-independent and 1,25(OH)2D3-dependent regulation of the renin-angiotensin system in 1alpha-hydroxylase knockout mice. , 2008, Kidney international.

[90]  M. Holick Sunlight, UV-radiation, vitamin D and skin cancer: how much sunlight do we need? , 2008, Advances in experimental medicine and biology.

[91]  K. Nanjo,et al.  Tumor-induced hypophosphatemic osteomalacia diagnosed by the combinatory procedures of magnetic resonance imaging and venous sampling for FGF23. , 2008, Internal medicine.

[92]  Y. Zorbas,et al.  Phosphate homeotasis in healthy subjects during prolonged periodic and continuous hypokinesia. , 2007, Clinical biochemistry.

[93]  Mikael Fogelholm,et al.  [Nordic nutrition recommendations]. , 2006, Ugeskrift for laeger.

[94]  N. Stern,et al.  25-Hydroxyvitamin D3-1α-Hydroxylase Is Expressed in Human Vascular Smooth Muscle Cells and Is Upregulated by Parathyroid Hormone and Estrogenic Compounds , 2005, Circulation.

[95]  Guilin Qiao,et al.  Cardiac hypertrophy in vitamin D receptor knockout mice: role of the systemic and cardiac renin-angiotensin systems. , 2005, American journal of physiology. Endocrinology and metabolism.

[96]  S. Jan de Beur Tumor-induced osteomalacia. , 2005, JAMA.

[97]  Yoko Yamamoto,et al.  Disruption of Nuclear Vitamin D Receptor Gene Causes Enhanced Thrombogenicity in Mice* , 2004, Journal of Biological Chemistry.

[98]  Kozo Nakamura,et al.  Venous sampling for fibroblast growth factor-23 confirms preoperative diagnosis of tumor-induced osteomalacia. , 2004, The Journal of clinical endocrinology and metabolism.

[99]  Guilin Qiao,et al.  Vitamin D: a negative endocrine regulator of the renin–angiotensin system and blood pressure , 2004, The Journal of Steroid Biochemistry and Molecular Biology.

[100]  G. Tenderich,et al.  Low vitamin D status: a contributing factor in the pathogenesis of congestive heart failure? , 2003, Journal of the American College of Cardiology.

[101]  Shu Q. Liu,et al.  1,25-Dihydroxyvitamin D(3) is a negative endocrine regulator of the renin-angiotensin system. , 2002, The Journal of clinical investigation.

[102]  M. Välimäki,et al.  Does it make a difference how and when you take your calcium? The acute effects of calcium on calcium and bone metabolism. , 2001, The American journal of clinical nutrition.

[103]  R. Foley,et al.  Clinical epidemiology of cardiovascular disease in chronic renal disease. , 1998, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[104]  P. Avery,et al.  Cardiac failure secondary to hypocalcaemia of nutritional osteomalacia. , 1992, European heart journal.

[105]  G. Jahreis,et al.  [Vitamin D-induced tissue calcinosis and arteriosclerosis changes. I: A contribution to the 60 year history of vitamin D research with special reference to childhood]. , 1990, Padiatrie und Grenzgebiete.

[106]  F. Singer,et al.  Pharmacokinetics and biologic effects of calcitriol in normal humans. , 1985, The Journal of laboratory and clinical medicine.

[107]  R. Francis,et al.  Plasma total and ionised calcium, albumin and globulin concentrations in pre- and post-menopausal women and the effects of oestrogen administration. , 1982, Clinica chimica acta; international journal of clinical chemistry.

[108]  E. Mawer,et al.  The distribution and storage of vitamin D and its metabolites in human tissues. , 1972, Clinical science.