Observational studies suggest inverse associations between serum vitamin levels and the risk of heart failure (HF). However, the causal effects of vitamins on HF have not been fully elucidated. Here, we conducted a Mendelian randomization (MR) study to investigate the causal associations between genetically determined vitamin levels and HF.
Genetic instrumental variables for circulating vitamin levels, including vitamins A, B, C, D, and E, which were assessed as either absolute or metabolite levels were obtained from public genome-wide association studies. Summary statistics for single-nucleotide-polymorphisms and HF associations were retrieved from the HERMES Consortium (47,309 cases and 930,014 controls) and FinnGen Study (30,098 cases and 229,612 controls). Two-sample MR analyses were implemented to assess the causality between vitamin levels and HF per outcome database, and the results were subsequently combined by meta-analysis.
Our MR study did not find significant associations between genetically determined circulating vitamin levels and HF risk. For absolute vitamin levels, the odds ratio for HF ranged from 0.97 (95% confidence interval [CI]: 0.85–1.09, P = 0.41) for vitamin C to 1.05 (95% CI: 0.61–1.82, P = 0.85) for vitamin A. For vitamin metabolites, the odds ratio ranged between 0.94 (95% CI: 0.75–1.19, P = 0.62) for α-tocopherol and 1.11 (95% CI: 0.98–1.26, P = 0.09) for γ-tocopherol.
Evidence from our study does not support the causal effects of circulating vitamin levels on HF. Therefore, there may be no direct beneficial effects of vitamin intake on the prevention of primary HF.
McDonagh TA, Metra M, Adamo M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2021; 42: 3599−3726.
Roth GA, Forouzanfar MH, Moran AE, et al. Demographic and epidemiologic drivers of global cardiovascular mortality. N Engl J Med 2015; 372: 1333−1341.
de Boer RA, Nayor M, deFilippi CR, et al. Association of cardiovascular biomarkers with incident heart failure with preserved and reduced ejection fraction. JAMA Cardiol 2018; 3: 215−224.
van Oort S, Beulens JWJ, van Ballegooijen AJ, et al. Modifiable lifestyle factors and heart failure: A Mendelian randomization study. Am Heart J 2020; 227: 64−73.
Daiber A, Di Lisa F, Oelze M, et al. Crosstalk of mitochondria with NADPH oxidase via reactive oxygen and nitrogen species signalling and its role for vascular function. Br J Pharmacol 2017; 174: 1670−1689.
Cesari M, Penninx BW, Newman AB, et al. Inflammatory markers and onset of cardiovascular events: results from the health ABC study. Circulation 2003; 108: 2317−2322.
Vasan RS, Sullivan LM, Roubenoff R, et al. Inflammatory markers and risk of heart failure in elderly subjects without prior myocardial infarction: the Framingham Heart Study. Circulation 2003; 107: 1486−1491.
Shah AK, Dhalla NS. Effectiveness of some vitamins in the prevention of cardiovascular disease: a narrative review. Front Physiol 2021; 12: 729255.
van der Pol A, van Gilst WH, Voors AA, van der Meer P. Treating oxidative stress in heart failure: past, present and future. Eur J Heart Fail 2019; 21: 425−435.
Ahmed M, Azizi-Namini P, Yan AT, Keith M. Thiamin deficiency and heart failure: the current knowledge and gaps in literature. Heart Fail Rev 2015; 20: 1−11.
Hyppönen E, Läärä E, Reunanen A, et al. Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study. Lancet 2001; 358: 1500−3.
Eshak ES, Arafa AE. Thiamine deficiency and cardiovascular disorders. Nutr Metab Cardiovasc Dis 2018; 28: 965−72.
Song EK, Kang SM. Vitamin C deficiency, high-sensitivity C-reactive protein, and cardiac event-free survival in patients with heart failure. J Cardiovasc Nurs 2018; 33: 6−12.
Balasubramaniam S, Christodoulou J. Disorders of riboflavin metabolism. J Inherit Metab Dis 2019; 42: 608−619.
Keith ME, Walsh NA, Darling PB, et al. B-vitamin deficiency in hospitalized patients with heart failure. J Am Diet Assoc 2009; 109: 1406−1410.
Kheiri B, Abdalla A, Osman M, et al. Vitamin D deficiency and risk of cardiovascular diseases: a narrative review. Clin Hypertens 2018; 24: 9.
Barteková M, Adameová A, Görbe A, et al. Natural and synthetic antioxidants targeting cardiac oxidative stress and redox signaling in cardiometabolic diseases. Free Radic Biol Med 2021; 169: 446−477.
Gutierrez AD, de Serna DG, Robinson I, Schade DS. The response of gamma vitamin E to varying dosages of alpha vitamin E plus vitamin C. Metabolism 2009; 58: 469−478.
Khan MS, Khan F, Fonarow GC, et al. Dietary interventions and nutritional supplements for heart failure: a systematic appraisal and evidence map. Eur J Heart Fail 2021; 23: 1468−1476.
Lonn E, Bosch J, Yusuf S, et al. Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial. JAMA 2005; 293: 1338−1347.
Robinson T, Martin RM, Yarmolinsky J. Mendelian randomisation analysis of circulating adipokines and C-reactive protein on breast cancer risk. Int J Cancer 2020; 147: 1597−1603.
Burgess S, Scott RA, Timpson NJ, et al. Using published data in Mendelian randomization: a blueprint for efficient identification of causal risk factors. Eur J Epidemiol 2015; 30: 543−552.
Mondul AM, Yu K, Wheeler W, et al. Genome-wide association study of circulating retinol levels. Hum Mol Genet 2011; 20: 4724−4731.
Grarup N, Sulem P, Sandholt CH, et al. Genetic architecture of vitamin B12 and folate levels uncovered applying deeply sequenced large datasets. PLoS Genet 2013; 9: e1003530.
Zheng JS, Luan J, Sofianopoulou E, et al. Plasma vitamin C and type 2 diabetes: genome-wide association study and mendelian randomization analysis in European populations. Diabtes Care 2021; 44: 98−106.
Jiang X, O'Reilly PF, Aschard H. Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels. Nat Commun 2018; 9: 260.
Major JM, Yu K, Wheeler W, et al. Genome-wide association study identifies common variants associated with circulating vitamin E levels. Hum Mol Genet 2011; 20: 3876−3883.
Long T, Hicks M. Whole-genome sequencing identifies common-to-rare variants associated with human blood metabolites. Nat Genet 2017; 49: 568−578.
Shin SY, Fauman EB, Petersen AK, et al. An atlas of genetic influences on human blood metabolites. Nat Genet 2014; 46: 543−550.
Shah S, Henry A. Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure. Nat Commun 2020; 11: 163.
Willer CJ, Schmidt EM, Sengupta S, et al. Discovery and refinement of loci associated with lipid levels. Nat Genet 2013; 45: 1274−1283.
Howson JMM, Zhao W. Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms. Nat Genet 2017; 49: 1113−1119.
Luo J, le Cessie S, van Heemst D, Noordam R. Diet-derived circulating antioxidants and risk of coronary heart disease: a mendelian randomization study. J Am Coll Cardiol 2021; 77: 45−54.
Burgess S, Butterworth A, Thompson SG. Mendelian randomization analysis with multiple genetic variants using summarized data. Genet Epidemiol 2013; 37: 658−665.
Bowden J, Davey Smith G, Haycock PC, Burgess S. Consistent estimation in mendelian randomization with some invalid instruments using a weighted median estimator. Genet Epidemiol 2016; 40: 304−314.
Bowden J, Davey Smith G, Burgess S. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int J Epidemiol 2015; 44: 512−525.
Chen W, Cai X, Yan H, Pan Y. Causal effect of obstructive sleep apnea on atrial fibrillation: a mendelian randomization study. J Am Heart Assoc 2021; 10: e022560.
Verbanck M, Chen CY. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet 2018; 50: 693−698.
Ji X, Hong J, Qu Z, et al. HemoglobinA1c is a risk factor for changes of bone mineral density: a mendelian randomization study. Front Endocrinol (Lausanne) 2022; 13: 942878.
Nazarzadeh M, Pinho-Gomes AC, Bidel Z, et al. Plasma lipids and risk of aortic valve stenosis: a Mendelian randomization study. Eur Heart J 2020; 41: 3913−3920.
Tang Z, Wang P, Dong C, et al. Oxidative stress signaling mediated pathogenesis of diabetic cardiomyopathy. Oxid Med Cell Longev 2022; 2022: 5913374.
Ye C, Geng Z, Zhang LL, et al. Chronic infusion of ELABELA alleviates vascular remodeling in spontaneously hypertensive rats via anti-inflammatory, anti-oxidative and anti-proliferative effects. Acta Pharmacol Sin 2022; 43: 2573−2584.
Demaison L. Oxidative Stress and Obesity- and Type 2 Diabetes-Induced Heart Failure. Antioxidants (Basel) 2020; 9: 653.
Jiang M, Xie X, Cao F, Wang Y. Mitochondrial metabolism in myocardial remodeling and mechanical unloading: implications for ischemic heart disease. Front Cardiovasc Med 2021; 8: 789267.
Semba RD, Yuniar Y, Gamble MV, et al. Assessment of vitamin A status of preschool children in Indonesia using plasma retinol-binding protein. J Trop Pediatr 2002; 48: 84−87.
Tsutsui H, Kinugawa S, Matsushima S. Oxidative stress and heart failure. Am J Physiol Heart Circ Physiol 2011; 301: H2181−H2190.
Gao W, Wang H, Zhang L, et al. Retinol-binding protein 4 induces cardiomyocyte hypertrophy by activating TLR4/MyD88 pathway. Endocrinology 2016; 157: 2282−2293.
Eshak ES, Iso H, Yamagishi K, et al. Dietary intakes of fat soluble vitamins as predictors of mortality from heart failure in a large prospective cohort study. Nutrition 2018; 47: 50−55.
Wu JR, Song EK, Moser DK, Lennie TA. Dietary vitamin C deficiency is associated with health-related quality of life and cardiac event-free survival in adults with heart failure. J Cardiovasc Nurs 2019; 34: 29−35.
Ventura-Clapier R, Garnier A, Veksler V, Joubert F. Bioenergetics of the failing heart. Biochim Biophys Acta 2011; 1813: 1360−1372.
Azizi-Namini P, Ahmed M, Yan AT, Keith M. The role of B vitamins in the management of heart failure. Nutr Clin Pract 2012; 27: 363−374.
Lee KS, Moser DK, Park JH, Lennie TA. The association of deficiencies of water-soluble vitamin intake with health-related quality of life and prognosis in patients with heart failure. Qual Life Res 2021; 30: 1183−1190.
Lonn E, Yusuf S, Arnold MJ, et al. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med 2006; 354: 1567−1577.
Herrmann M, Stanger O, Paulweber B, et al. Effect of folate supplementation on N-terminal pro-brain natriuretic peptide. Int J Cardiol 2007; 118: 267−269.
Bouillon R, Marcocci C, Carmeliet G, et al. Skeletal and extraskeletal actions of vitamin D: current evidence and outstanding questions. Endocr Rev 2019; 40: 1109−1151.
Pilz S, März W, Wellnitz B, et al. Association of vitamin D deficiency with heart failure and sudden cardiac death in a large cross-sectional study of patients referred for coronary angiography. J Clin Endocrinol Metab 2008; 93: 3927−3935.
Boxer RS, Dauser DA, Walsh SJ, et al. The association between vitamin D and inflammation with the 6-minute walk and frailty in patients with heart failure. J Am Geriatr Soc 2008; 56: 454−461.
Virtanen JK, Nurmi T, Aro A, et al. Vitamin D supplementation and prevention of cardiovascular disease and cancer in the Finnish vitamin D trial-a randomized controlled trial. Am J Clin Nutr 2022; 115: 1300−1310.
Dahlen B, Müller F, Tröbs S-O, et al. Sex-specific relationship between parathyroid hormone and platelet indices in phenotypes of heart failure—results from the MyoVasc Study. Front Cardiovasc Med 2021; 8: 682521.
The authors thank the HERMES Consortium, SUNLIGHT consortium, ATBC Study, PLCO Cancer Screening Trial, TwinsUK cohort, InCHIANTI study, SardiNIA study, BLSA study, KORA study, Fenland study, EPIC-InterAct study, EPIC Norfolk study, EPIC-CVD study and other GWAS involved in our analysis for providing a publicly available GWAS dataset.