The Pivotal Role of Thiamine Supplementation in Counteracting Cardiometabolic Dysfunctions Associated with Thiamine Deficiency
Abstract
1. Introduction
2. Thiamine Accumulation
3. Thiamine Deficiency
3.1. Causes of Thiamine Deficiency
3.2. Diagnosis of Thiamine Deficiency
3.3. Effects of Thiamine Deficiency on Metabolism
3.4. Effects of Thiamine Deficiency on Cardiovascular System
3.5. Effects of Thiamine Deficiency on HF
3.6. Nutritional Intervention to Improve Thiamine Status and Prevent Thiamine Deficiency
3.7. The Impact of Thiamine Deficiency: Molecular Mechanisms
3.8. The Impact of Thiamine Deficiency and Furosemide Treatment on Cardiac Health
3.9. The Role of Thiamine in Diabetes Mellitus: Implications of Deficiency for Metabolic Dysfunction
4. The Benefits and Risks of Thiamine Supplementation
4.1. Thiamine Supplementation in Heart Failure
4.2. The Potential Benefits of Thiamine Supplementation in Diabetes Management
4.3. The Beneficial Effects of Thiamine Supplementation in Atherosclerosis Development and Progression
4.4. Supplementation of Lipophilic Derivatives of Thiamine and Their Therapeutic Potential
4.4.1. Thiamine Pyrophosphate (TPP) Supplementation
4.4.2. Allithiamine Supplementation
4.5. The Role of Thiamine in Cancer Therapy and Cardiotoxicity Prevention
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
AGEs | Advanced glycosylation end products |
ATP | Adenosine triphosphate |
B1 | Vitamin B1 |
BAVA | Attenuated brachial artery vasoactivity |
BBB | Blood–brain barrier |
BCAAs | Branched-chain amino acids |
CALR | Calreticulin |
CF | Coronary flow |
CI | Confidence interval |
CPT1/2 | Carnitine palmitoyltransferase 1 and 2 |
CVD | Cardiovascular disease |
DLVP | Diastolic left ventricular development |
DM | Diabetes mellitus |
DOX | Doxorubicin |
dp/dt max | Maximum rate of left ventricular development |
dp/dt min | Minimum rate of left ventricular development |
EAR | Estimated average requirement |
EDV | Endothelium-dependent vasodilation |
EF | Ejection fraction |
eNOS | Endothelial nitric oxide synthase |
ETK | Erythrocyte transketolase |
ETKA | Erythrocyte transketolase activation assay |
FAD | Flavin adenine dinucleotide |
FADH2 | Flavin adenine dinucleotide |
FBS | Fasting blood sugar |
FDA | Food and Drug Administration |
FS | Fractional shortening |
GDM | Gestational diabetes mellitus |
GSH | Glutathione |
HACL1 | 2-hydroxyacyl-CoA lyase 1 |
HbA1c | Glycated hemoglobin |
HDLs | High-density lipoproteins |
HF | Heart failure |
HFpEF | Heart failure with preserved ejection fraction |
HO• | Hydroxyl radicals |
HO-1 | Heme oxygenase 1 |
HOO• | Hydroperoxyl radicals |
HPLC | High-performance liquid chromatography |
HPLC–MS/MS | High-performance liquid chromatography–tandem mass spectrometry |
HR | Heart rate |
hs-CRP | High-sensitivity C-reactive protein |
hTHTR-1 | Human thiamine transporter-1 |
hTHTR-2 | Human thiamine transporter-2 |
hTPPT | Human thiamine pyrophosphate transporter |
HUVECs | Human umbilical vein endothelial cells |
IC50 | Half-maximal inhibitory concentration |
ICAM-1 | Intercellular adhesion molecule 1 |
IGT | Impaired glucose tolerance |
iNOS | Nitric oxide inducible synthase |
JAK2 | Janus kinase 2 |
KGDHC | Alpha-ketoglutarate dehydrogenase complex |
LDL | Low-density lipoprotein |
LDLc | Low-density lipoprotein cholesterol |
L-NAME | NG-nitro-L-arginine-methyl-ester |
LV | Left ventricle |
LVEF | Left ventricular ejection fraction |
LVIDd | Left ventricle internal dimension at end-diastole |
LVIDs | Left ventricle internal dimension at end-systole |
LVPWd | Left ventricle internal dimension at end-diastole |
LVPWs | Left ventricular posterior wall thickness at end-systole |
MALDI-MS | Matrix-assisted laser desorption/ionization mass spectrometry |
MDA | Malondialdehyde |
MI | Myocardial infarction |
MTPP-1 | Mitochondrial thiamin pyrophosphate transporter 1 |
NADH | Nicotinamide adenine dinucleotide |
NADPH | Nicotinamide adenine dinucleotide phosphate |
NF-k B | Nuclear factor kappa B |
NF-KB | Nuclear factor kappa-light-chain-enhancer of activated B cells |
NIDDM | Non-insulin-dependent diabetes mellitus |
NO | Nitric oxide |
NOS | Nitric oxide synthase |
OCT1 | Organic cation transporter 1 |
OCT2/3 | Organic cation transporter 2 and 3 |
OR | Odds ratio |
P2Y6 | Pyrimidinergic receptor P2Y6 |
PAD | Peripheral arterial disease |
PARP | Poly (ADP-ribose) polymerase |
PDH | Pyruvate dehydrogenase |
PDK | Pyruvate dehydrogenase kinase |
PPP | Pentose phosphate pathway |
RBCs | Red blood cells |
RBS | Random blood sugar |
RDA | Recommended daily allowance |
RF | Renal failure |
ROS | Reactive oxygen species |
SAM | Severe acute malnutrition |
SLC19A1 | Solute carrier family 19 member 1 |
SLC19A2 | Solute carrier family 19 member 2 |
SLC19A3 | Solute carrier family 19 member 3 |
SLC22A1 | Solute carrier family 22 member 1 |
SLC25A19 | Solute carrier family 25 member 19 |
SLC35F3 | Solute carrier family 35 member F3 |
SLC44A4 | Solute carrier family 44 member 4 |
SLVP | Systolic left ventricular development |
SOD | Superoxide dismutase |
Sp1 | Transcription factor specificity protein-1 |
STIM1 | Stromal Interaction Molecule 1 |
T1D | Type 1 diabetes |
T2D | Type 2 diabetes |
T2DM | Type 2 diabetes mellitus |
TCA | Tricarboxylic citric acid |
TD | Thiamine deficiency |
TDDs | Thiamine deficiency disorders |
ThDP | Thiamine diphosphate |
THIA | Thiamine |
THTR1 | Thiamine transporter-1 |
THTR2 | Thiamine transporter-2 |
TK | Transketolase enzyme |
TMP | Thiamine monophosphate |
TNF-α | Tumor necrosis factor-alpha |
TPK1 | Thiamine pyrophosphokinase 1 |
TPP | Thiamine pyrophosphate |
TPPE | Effect of thiamine pyrophosphate |
TPPT-1 | Thiamine pyrophosphate transporter 1 |
TRMA | Thiamine-responsive megaloblastic anemia |
TSH | Thyroid-stimulating hormone |
US | United States |
UTP | Uridine 5′-triphosphate |
Vo2 | Oxygen consumption |
References
- Polegato, B.F.; Pereira, A.G.; Azevedo, P.S.; Costa, N.A.; Zornoff, L.A.M.; Paiva, S.A.R.; Minicucci, M.F. Role of Thiamin in Health and Disease. Nutr. Clin. Pract. 2019, 34, 558–564. [Google Scholar] [CrossRef] [PubMed]
- Ysphaneendramallimoggala; Biswas, M.; Anburaj, S.E.; Iqbal, F.; Shrikiran, A.; Suryakanth, V.B.; Lewis, L.E.S. Thiamine: An indispensable regulator of paediatric neuro-cardiovascular health and diseases. Eur. J. Pediatr. 2024, 183, 4597–4610. [Google Scholar] [CrossRef] [PubMed]
- Prajapati, S.; Rabe von Pappenheim, F.; Tittmann, K. Frontiers in the enzymology of thiamin diphosphate-dependent enzymes. Curr. Opin. Struct. Biol. 2022, 76, 102441. [Google Scholar] [CrossRef]
- Tylicki, A.; Łotowski, Z.; Siemieniuk, M.; Ratkiewicz, A. Thiamine and selected thiamine antivitamins—Biological activity and methods of synthesis. Biosci Rep. 2018, 38, BSR20171148. [Google Scholar] [CrossRef]
- Kattoor, A.J.; Goel, A.; Mehta, J.L. Thiamine Therapy for Heart Failure: A Promise or Fiction? Cardiovasc. Drugs. 2018, 32, 313–317. [Google Scholar] [CrossRef] [PubMed]
- Ahmed, M.; Azizi-Namini, P.; Yan, A.T.; Keith, M. Thiamin deficiency and heart failure: The current knowledge and gaps in literature. Heart Fail. Rev. 2015, 20, 1–11. [Google Scholar] [CrossRef]
- Marrs, C.; Lonsdale, D. Hiding in Plain Sight: Modern Thiamine Deficiency. Cells 2021, 10, 2595. [Google Scholar] [CrossRef]
- Marcé-Grau, A.; Martí-Sánchez, L.; Baide-Mairena, H.; Ortigoza-Escobar, J.D.; Pérez-Dueñas, B. Genetic defects of thiamine transport and metabolism: A review of clinical phenotypes, genetics, and functional studies. J. Inherit. Metab. Dis. 2019, 42, 581–597. [Google Scholar] [CrossRef]
- Hrubša, M.; Siatka, T.; Nejmanová, I.; Vopršalová, M.; Kujovská Krčmová, L.; Matoušová, K.; Javorská, L.; Macáková, K.; Mercolini, L.; Remião, F.; et al. Biological Properties of Vitamins of the B-Complex, Part 1: Vitamins B1, B2, B3, and B5. Nutrients 2022, 14, 484. [Google Scholar] [CrossRef]
- Wiley, K.D.; Gupta, M. Vitamin B1 (Thiamine) Deficiency; StatPearls Publishing: Treasure Island, FL, USA, 2025. Available online: https://www.ncbi.nlm.nih.gov/books/NBK537204/ (accessed on 1 January 2025).
- Eshak, E.S.; Arafa, A.E. Thiamine deficiency and cardiovascular disorders. Nutr. Metab. Cardiovasc. Dis. 2018, 28, 965–972. [Google Scholar] [CrossRef]
- Mrowicka, M.; Mrowicki, J.; Dragan, G.; Majsterek, I. The importance of thiamine (vitamin B1) in humans. Biosci Rep. 2023, 43, BSR20230374. [Google Scholar] [CrossRef] [PubMed]
- Johnson, C.R.; Fischer, P.R.; Thacher, T.D.; Topazian, M.D.; Bourassa, M.W.; Combs, G.F., Jr. Thiamin deficiency in low- and middle-income countries: Disorders, prevalences, previous interventions and current recommendations. Nutr. Health 2019, 25, 127–151. [Google Scholar] [CrossRef]
- Whitfield, K.C.; Smith, T.J.; Rohner, F.; Wieringa, F.T.; Green, T.J. Thiamine fortification strategies in low- and middle-income settings: A review. Ann. N. Y. Acad. Sci. 2021, 1498, 29–45. [Google Scholar] [CrossRef]
- Yue, S.; Wang, J.; Zhao, Y.; Ye, E.; Niu, D.; Huang, J.; Li, X.; Hu, Y.; Hou, X.; Wu, J. Thiamine administration may increase survival benefit in critically ill patients with myocardial infarction. Front. Nutr. 2023, 10, 1227974. [Google Scholar] [CrossRef]
- Kareem, O.; Nisar, S.; Tanvir, M.; Muzaffer, U.; Bader, G.N. Thiamine deficiency in pregnancy and lactation: Implications and present perspectives. Front. Nutr. 2023, 10, 1080611. [Google Scholar] [CrossRef]
- Ott, M.; Werneke, U. Wernicke’s encephalopathy—From basic science to clinical practice. Part 1: Understanding the role of thiamine. Ther. Adv. Psychopharmacol. 2020, 10, 2045125320978106. [Google Scholar] [CrossRef] [PubMed]
- Polat, B.; Suleyman, H.; Sener, E.; Akcay, F. Examination of the Effects of Thiamine and Thiamine Pyrophosphate on Doxorubicin-Induced Experimental Cardiotoxicity. J. Cardiovasc. Pharmacol. Ther. 2015, 20, 221–229. [Google Scholar] [CrossRef]
- DiNicolantonio, J.J.; Liu, J.; O’Keefe, J.H. Thiamine and Cardiovascular Disease: A Literature Review. Prog. Cardiovasc. Dis. 2018, 61, 27–32. [Google Scholar] [CrossRef]
- Liu, X.; Montissol, S.; Uber, A.; Ganley, S.; Grossestreuer, A.V.; Berg, K.; Heydrick, S.; Donnino, M.W. The Effects of Thiamine on Breast Cancer Cells. Molecules 2018, 23, 1464. [Google Scholar] [CrossRef]
- Smith, T.J.; Hess, S.Y. Infantile thiamine deficiency in South and Southeast Asia: An age-old problem needing new solutions. Nutr. Bull. 2021, 46, 12–25. [Google Scholar] [CrossRef]
- Bozic, I.; Lavrnja, I. Thiamine and benfotiamine: Focus on their therapeutic potential. Heliyon 2023, 9, e21839. [Google Scholar] [CrossRef]
- Whitfield, K.C.; Bourassa, M.W.; Adamolekun, B.; Bergeron, G.; Bettendorff, L.; Brown, K.H.; Cox, L.; Fattal-Valevski, A.; Fischer, P.R.; Frank, E.L.; et al. Thiamine deficiency disorders: Diagnosis, prevalence, and a roadmap for global control programs. Ann. N. Y. Acad. Sci. 2018, 1430, 3–43. [Google Scholar] [CrossRef] [PubMed]
- Coats, D.; Shelton-Dodge, K.; Ou, K.; Khun, V.; Seab, S.; Sok, K.; Prou, C.; Tortorelli, S.; Moyer, T.P.; Cooper, L.E.; et al. Thiamine deficiency in Cambodian infants with and without beriberi. J. Pediatr. 2012, 161, 843–847. [Google Scholar] [CrossRef] [PubMed]
- Abdou, E.; Hazell, A.S. Thiamine deficiency: An update of pathophysiologic mechanisms and future therapeutic considerations. Neurochem. Res. 2015, 40, 353–361. [Google Scholar] [CrossRef]
- Smith, T.J.; Johnson, C.R.; Koshy, R.; Hess, S.Y.; Qureshi, U.A.; Mynak, M.L.; Fischer, P.R. Thiamine deficiency disorders: A clinical perspective. Ann. N. Y. Acad. Sci. 2021, 1498, 9–28. [Google Scholar] [CrossRef] [PubMed]
- Wijnia, J.W. A Clinician’s View of Wernicke-Korsakoff Syndrome. J. Clin. Med. 2022, 11, 6755. [Google Scholar] [CrossRef]
- Edwards, K.A.; Randall, E.A.; Wolfe, P.C.; Angert, E.R.; Kraft, C.E. Dietary factors potentially impacting thiaminase I-mediated thiamine deficiency. Sci. Rep. 2023, 13, 7008. [Google Scholar] [CrossRef]
- Schostak, T.; San Millan, I.; Jani, A.; Johnson, R.J. Thiamine deficiency: A commonly unrecognised but easily treatable condition. Postgrad. Med. J. 2023, 99, 844–848. [Google Scholar] [CrossRef]
- Martin, P.R.; Singleton, C.K.; Hiller-Sturmhöfel, S. The role of thiamine deficiency in alcoholic brain disease. Alcohol Res. Health 2003, 27, 134–142. [Google Scholar]
- Iso, T.; Kurabayashi, M. Cardiac Metabolism and Contractile Function in Mice with Reduced Trans-Endothelial Fatty Acid Transport. Metabolites 2021, 11, 889. [Google Scholar] [CrossRef]
- Han, X.; Qu, L.; Yu, M.; Ye, L.; Shi, L.; Ye, G.; Yang, J.; Wang, Y.; Fan, H.; Wang, Y.; et al. Thiamine-modified metabolic reprogramming of human pluripotent stem cell-derived cardiomyocyte under space microgravity. Signal. Transduct. Target Ther. 2024, 9, 86. [Google Scholar] [CrossRef] [PubMed]
- Nguyen, B.Y.; Ruiz-Velasco, A.; Bui, T.; Collins, L.; Wang, X.; Liu, W. Mitochondrial function in the heart: The insight into mechanisms and therapeutic potentials. Br. J. Pharmacol. 2019, 176, 4302–4318. [Google Scholar] [CrossRef] [PubMed]
- Gioda, C.R.; Capettini, L.S.; Cruz, J.S.; Lemos, V.S. Thiamine deficiency leads to reduced nitric oxide production and vascular dysfunction in rats. Nutr. Metab. Cardiovasc. Dis. 2014, 24, 183–188. [Google Scholar] [CrossRef]
- Chen, J.Y.; Ye, Z.X.; Wang, X.F.; Chang, J.; Yang, M.W.; Zhong, H.H.; Hong, F.F.; Yang, S.L. Nitric oxide bioavailability dysfunction involves in atherosclerosis. Biomed. Pharmacother. 2018, 97, 423–428. [Google Scholar] [CrossRef]
- Mitu, O.; Cirneala, I.A.; Lupsan, A.I.; Iurciuc, M.; Mitu, I.; Dimitriu, D.C.; Costache, A.D.; Petris, A.O.; Costache, I.I. The Effect of Vitamin Supplementation on Subclinical Atherosclerosis in Patients without Manifest Cardiovascular Diseases: Never-ending Hope or Underestimated Effect? Molecules 2020, 25, 1717. [Google Scholar] [CrossRef]
- Helali, J.; Park, S.; Ziaeian, B.; Han, J.K.; Lankarani-Fard, A. Thiamine and Heart Failure: Challenging Cases of Modern-Day Cardiac Beriberi. Mayo. Clin. Proc. Innov. Qual. Outcomes 2019, 3, 221–225. [Google Scholar] [CrossRef] [PubMed]
- Jain, A.; Mehta, R.; Al-Ani, M.; Hill, J.A.; Winchester, D.E. Determining the Role of Thiamine Deficiency in Systolic Heart Failure: A Meta-Analysis and Systematic Review. J. Card. Fail. 2015, 21, 1000–1007. [Google Scholar] [CrossRef]
- Schwinger, R.H.G. Pathophysiology of heart failure. Cardiovasc. Diagn. Ther. 2021, 11, 263–276. [Google Scholar] [CrossRef]
- Yang, R.; Huang, J.; Zhao, Y.; Wang, J.; Niu, D.; Ye, E.; Yue, S.; Hou, X.; Cui, L.; Wu, J. Association of thiamine administration and prognosis in critically ill patients with heart failure. Front Pharmacol. 2023, 14, 1162797. [Google Scholar] [CrossRef]
- Smithline, H.A.; Donnino, M.; Blank, F.S.J.; Barus, R.; Coute, R.A.; Knee, A.B.; Visintainer, P. Supplemental thiamine for the treatment of acute heart failure syndrome: A randomized controlled trial. BMC Complement. Altern. Med. 2019, 19, 96. [Google Scholar] [CrossRef]
- Anderson, S.H.; Charles, T.J.; Nicol, A.D. Thiamine Deficiency at a District General Hospital: Report of Five Cases. QJM Int. J. Med. 1985, 55, 15–32. [Google Scholar] [CrossRef]
- Keith, M.; Quach, S.; Ahmed, M.; Azizi-Namini, P.; Al-Hesayen, A.; Azevedo, E.; James, R.; Leong-Poi, H.; Ong, G.; Desjardins, S.; et al. Thiamin supplementation does not improve left ventricular ejection fraction in ambulatory heart failure patients: A randomized controlled trial. Am. J. Clin. Nutr. 2019, 110, 1287–1295. [Google Scholar] [CrossRef]
- Yamada, Y.; Kusakari, Y.; Akaoka, M.; Watanabe, M.; Tanihata, J.; Nishioka, N.; Bochimoto, H.; Akaike, T.; Tachibana, T.; Minamisawa, S. Thiamine treatment preserves cardiac function against ischemia injury via maintaining mitochondrial size and ATP levels. J. Appl. Physiol. 2021, 130, 26–35. [Google Scholar] [CrossRef] [PubMed]
- Bicer, I.; Dizdar, O.S.; Dondurmacı, E.; Ozcetin, M.; Yılmaz, R.; Gundogan, K.; Gunal, A.I. Furosemide-related thiamine deficiency in hospitalized hypervolemic patients with renal failure and heart failure. Nefrologia 2023, 43, 111–119. [Google Scholar] [CrossRef]
- Mazzeo, A.; Barutta, F.; Bellucci, L.; Trento, M.; Gruden, G.; Porta, M.; Beltramo, E. Reduced Thiamine Availability and Hyperglycemia Impair Thiamine Transport in Renal Glomerular Cells through Modulation of Thiamine Transporter 2. Biomedicines 2021, 9, 385. [Google Scholar] [CrossRef] [PubMed]
- Nix, W.A.; Zirwes, R.; Bangert, V.; Kaiser, R.P.; Schilling, M.; Hostalek, U.; Obeid, R. Vitamin B status in patients with type 2 diabetes mellitus with and without incipient nephropathy. Diabetes Res. Clin. Pract. 2015, 107, 157–165. [Google Scholar] [CrossRef] [PubMed]
- Al-Daghri, N.M.; Alharbi, M.; Wani, K.; Abd-Alrahman, S.H.; Sheshah, E.; Alokail, M.S. Biochemical changes correlated with blood thiamine and its phosphate esters levels in patients with diabetes type 1 (DMT1). Int. J. Clin. Exp. Pathol. 2015, 8, 13483–13488. [Google Scholar] [PubMed]
- Duc, H.N.; Oh, H.; Yoon, I.M.; Kim, M.S. Association between levels of thiamine intake, diabetes, cardiovascular diseases and depression in Korea: A national cross-sectional study. J. Nutr. Sci. 2021, 10, e31. [Google Scholar] [CrossRef]
- Dong, Z.; Wang, Q. L-shaped association of thiamine intake and risk for peripheral artery disease in US adults: A cross-sectional study. Front. Nutr. 2024, 11, 1437930. [Google Scholar] [CrossRef]
- Berg, K.M.; Grossestreuer, A.V.; Balaji, L.; Moskowitz, A.; Berlin, N.; Cocchi, M.N.; Morton, A.C.; Li, F.; Mehta, S.; Peradze, N.; et al. Thiamine as a metabolic resuscitator after in-hospital cardiac arrest. Resuscitation 2024, 198, 110160. [Google Scholar] [CrossRef]
- Andersen, L.W.; Holmberg, M.J.; Berg, K.M.; Chase, M.; Cocchi, M.N.; Sulmonte, C.; Balkema, J.; MacDonald, M.; Montissol, S.; Senthilnathan, V.; et al. Thiamine as an adjunctive therapy in cardiac surgery: A randomized, double-blind, placebo-controlled, phase II trial. Crit. Care 2016, 20, 92. [Google Scholar] [CrossRef] [PubMed]
- Datt, V.; Wadhhwa, R.; Sharma, V.; Virmani, S.; Minhas, H.S.; Malik, S. Vasoplegic syndrome after cardiovascular surgery: A review of pathophysiology and outcome-oriented therapeutic management. J. Card. Surg. 2021, 36, 3749–3760. [Google Scholar] [CrossRef] [PubMed]
- Al-Attas, O.; Al-Daghri, N.; Alokail, M.; Abd-Alrahman, S.; Vinodson, B.; Sabico, S. Metabolic Benefits of Six-month Thiamine Supplementation in Patients with and Without Diabetes Mellitus Type 2. Clin. Med. Insights Endocrinol. Diabetes 2014, 7, 1–6. [Google Scholar] [CrossRef]
- Amirani, E.; Aghadavod, E.; Shafabakhsh, R.; Asemi, Z.; Tabassi, Z.; Panahandeh, I.; Naderi, F.; Abed, A. Anti-inflammatory and antioxidative effects of thiamin supplements in patients with gestational diabetes mellitus. J. Matern. Fetal. Neonatal. Med. 2022, 35, 2085–2090. [Google Scholar] [CrossRef]
- Veetil, V.M.; Pachat, D.; Nikitha, K.; Kutty, J.M. Thiamine-responsive megaloblastic anaemia. Natl. Med. J. India 2023, 36, 314–315. [Google Scholar] [CrossRef] [PubMed]
- Arora, S.; Lidor, A.; Abularrage, C.J.; Weiswasser, J.M.; Nylen, E.; Kellicut, D.; Sidawy, A.N. Thiamine (vitamin B1) improves endothelium-dependent vasodilatation in the presence of hyperglycemia. Ann. Vasc. Surg. 2006, 20, 653–658. [Google Scholar] [CrossRef]
- Stirban, A.; Pop, A.; Tschoepe, D. A randomized, double-blind, crossover, placebo-controlled trial of 6 weeks benfotiamine treatment on postprandial vascular function and variables of autonomic nerve function in Type 2 diabetes. Diabet. Med. 2013, 30, 1204–1208. [Google Scholar] [CrossRef]
- Berg, K.M.; Gautam, S.; Salciccioli, J.D.; Giberson, T.; Saindon, B.; Donnino, M.W. Intravenous thiamine is associated with increased oxygen consumption in critically ill patients with preserved cardiac index. Ann. Am. Thorac. Soc. 2014, 11, 1597–1601. [Google Scholar] [CrossRef]
- Bhat, J.I.; Rather, H.A.; Ahangar, A.A.; Qureshi, U.A.; Dar, P.; Ahmed, Q.I.; Charoo, B.A.; Ali, S.W. Shoshin beriberi-thiamine responsive pulmonary hypertension in exclusively breastfed infants: A study from northern India. Indian Heart J. 2017, 69, 24–27. [Google Scholar] [CrossRef]
- Liu, D.; Ke, Z.; Luo, J. Thiamine Deficiency and Neurodegeneration: The Interplay Among Oxidative Stress, Endoplasmic Reticulum Stress, and Autophagy. Mol. Neurobiol. 2017, 54, 5440–5448. [Google Scholar] [CrossRef]
- Scorza, F.A.; de Almeida, A.C.; Scorza, C.A. Thiamine deficiency to ward off cardiovascular dysfunction and SUDEP: Yay or nay? Epilepsy Behav. 2016, 56, 48–49. [Google Scholar] [CrossRef]
- Roman-Campos, D.; Cruz, J.S. Current aspects of thiamine deficiency on heart function. Life Sci. 2014, 98, 1–5. [Google Scholar] [CrossRef] [PubMed]
- McMahon, B.A.; Chawla, L.S. The furosemide stress test: Current use and future potential. Ren. Fail. 2021, 43, 830–839. [Google Scholar] [CrossRef]
- Zhang, K.; Huentelman, M.J.; Rao, F.; Sun, E.I.; Corneveaux, J.J.; Schork, A.J.; Wei, Z.; Waalen, J.; Miramontes-Gonzalez, J.P.; Hightower, C.M.; et al. Genetic implication of a novel thiamine transporter in human hypertension. J. Am. Coll. Cardiol. 2014, 63, 1542–1555. [Google Scholar] [CrossRef]
- Page, G.L.; Laight, D.; Cummings, M.H. Thiamine deficiency in diabetes mellitus and the impact of thiamine replacement on glucose metabolism and vascular disease. Int. J. Clin. Pract. 2011, 65, 684–690. [Google Scholar] [CrossRef] [PubMed]
- Bíró, A.; Remenyik, J. Effect of allithiamine on the level of hyperglycaemia-induced advanced glycation end products. Acta Agrar. Debreceniensis 2019, 2, 41–44. [Google Scholar] [CrossRef]
- Wong, E.K.C.; Lee, J.Y.; Leong, D.P.; Mbuagbaw, L.; Yousuf, H.; Keen, S.; Straus, S.E.; Patterson, C.J.; Demers, C. Thiamine versus placebo in older heart failure patients: Study protocol for a randomized controlled crossover feasibility trial (THIAMINE-HF). Pilot Feasibility Stud. 2018, 4, 149. [Google Scholar] [CrossRef] [PubMed]
- Nordanstig, J.; Behrendt, C.A.; Bradbury, A.W.; de Borst, G.J.; Fowkes, F.; Golledge, J.; Gottsater, A.; Hinchliffe, R.J.; Nikol, S.; Norgren, L. Peripheral arterial disease (PAD)—A challenging manifestation of atherosclerosis. Prev. Med. 2023, 171, 107489. [Google Scholar] [CrossRef] [PubMed]
- Issa, M.S.; Grossestreuer, A.V.; Patel, H.; Ntshinga, L.; Coker, A.; Yankama, T.; Donnino, M.W.; Berg, K.M. Lactate and hypotension as predictors of mortality after in-hospital cardiac arrest. Resuscitation 2021, 158, 208–214. [Google Scholar] [CrossRef]
- Coffey, S.; Dixit, P.; Saw, E.L.; Babakr, A.A.; van Hout, I.; Galvin, I.F.; Saxena, P.; Bunton, R.W.; Davis, P.J.; Lamberts, R.R.; et al. Thiamine increases resident endoglin positive cardiac progenitor cells and atrial contractile force in humans: A randomised controlled trial. Int. J. Cardiol. 2021, 341, 70–73. [Google Scholar] [CrossRef]
- DeFronzo, R.; Fleming, G.A.; Chen, K.; Bicsak, T.A. Metformin-associated lactic acidosis: Current perspectives on causes and risk. Metabolism 2016, 65, 20–29. [Google Scholar] [CrossRef]
- Fadden, E.J.; Longley, C.; Mahambrey, T. Metformin-associated lactic acidosis. BMJ Case Rep. 2021, 14, e239154. [Google Scholar] [CrossRef]
- Tamaki, H.; Tsushima, H.; Kachi, N.; Jimura, F. Cardiac Dysfunction Due to Thiamine Deficiency after Hemodialysis for Biguanide-related Lactic Acidosis. Intern. Med. 2022, 61, 2905–2909. [Google Scholar] [CrossRef] [PubMed]
- Poznyak, A.; Grechko, A.V.; Poggio, P.; Myasoedova, V.A.; Alfieri, V.; Orekhov, A.N. The Diabetes Mellitus-Atherosclerosis Connection: The Role of Lipid and Glucose Metabolism and Chronic Inflammation. Int. J. Mol. Sci. 2020, 21, 1835. [Google Scholar] [CrossRef] [PubMed]
- Xu, S.; Ilyas, I.; Little, P.J.; Li, H.; Kamato, D.; Zheng, X.; Luo, S.; Li, Z.; Liu, P.; Han, J.; et al. Endothelial Dysfunction in Atherosclerotic Cardiovascular Diseases and Beyond: From Mechanism to Pharmacotherapies. Pharmacol. Rev. 2021, 73, 924–967. [Google Scholar] [CrossRef] [PubMed]
- Li, Y.; Zhou, M.; Li, H.; Dai, C.; Yin, L.; Liu, C.; Li, Y.; Zhang, E.; Dong, X.; Ji, H.; et al. Macrophage P2Y6 receptor deletion attenuates atherosclerosis by limiting foam cell formation through phospholipase Cβ/store-operated calcium entry/calreticulin/scavenger receptor A pathways. Eur. Heart J. 2024, 45, 268–283. [Google Scholar] [CrossRef]
- Starling-Soares, B.; Carrera-Bastos, P.; Bettendorff, L. Role of the Synthetic B1 Vitamin Sulbutiamine on Health. J. Nutr. Metab. 2020, 2020, 9349063. [Google Scholar] [CrossRef]
- Alcázar-Leyva, S.; Zapata, E.; Bernal-Alcántara, D.; Gorocica, P.; Alvarado-Vásquez, N. Thiamine pyrophosphate diminishes nitric oxide synthesis in endothelial cells. Int. J. Vitam. Nutr. Res. 2021, 91, 491–499. [Google Scholar] [CrossRef]
- Biró, A.; Markovics, A.; Fazekas, M.É.; Fidler, G.; Szalóki, G.; Paholcsek, M.; Lukács, J.; Stündl, L.; Remenyik, J. Allithiamine Alleviates Hyperglycaemia-Induced Endothelial Dysfunction. Nutrients 2020, 12, 1690. [Google Scholar] [CrossRef]
- Jonus, H.C.; Byrnes, C.C.; Kim, J.; Valle, M.L.; Bartlett, M.G.; Said, H.M.; Zastre, J.A. Thiamine mimetics sulbutiamine and benfotiamine as a nutraceutical approach to anticancer therapy. Biomed. Pharmacother. 2020, 121, 109648. [Google Scholar] [CrossRef]
- Rankovic, M.; Draginic, N.; Jeremic, J.; Samanovic, A.M.; Stojkov, S.; Mitrovic, S.; Jeremic, N.; Radonjic, T.; Srejovic, I.; Bolevich, S.; et al. Protective Role of Vitamin B1 in Doxorubicin-Induced Cardiotoxicity in Rats: Focus on Hemodynamic, Redox, and Apoptotic Markers in Heart. Front. Physiol. 2021, 12, 690619. [Google Scholar] [CrossRef]
- Radonjic, T.; Rankovic, M.; Ravic, M.; Zivkovic, V.; Srejovic, I.; Jeremic, J.; Jeremic, N.; Sretenovic, J.; Matic, S.; Jakovljevic, V.; et al. The Effects of Thiamine Hydrochloride on Cardiac Function, Redox Status and Morphometric Alterations in Doxorubicin-Treated Rats. Cardiovasc. Toxicol. 2020, 20, 111–120. [Google Scholar] [CrossRef] [PubMed]
- Cinici, E.; Dilekmen, N.; Senol, O.; Arpalı, E.; Cinici, O.; Tanas, S. Blood thiamine pyrophosphate concentration and its correlation with the stage of diabetic retinopathy. Int. Ophthalmol. 2020, 40, 3279–3284. [Google Scholar] [CrossRef] [PubMed]
- Sahu, U.; Villa, E.; Reczek, C.R.; Zhao, Z.; O’Hara, B.P.; Torno, M.D.; Mishra, R.; Shannon, W.D.; Asara, J.M.; Gao, P.; et al. Pyrimidines maintain mitochondrial pyruvate oxidation to support de novo lipogenesis. Science 2024, 383, 1484–1492. [Google Scholar] [CrossRef]
- Kim, J.; Jonus, H.C.; Zastre, J.A.; Bartlett, M.G. Development of an IPRP-LC-MS/MS method to determine the fate of intracellular thiamine in cancer cells. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 2019, 1124, 247–255. [Google Scholar] [CrossRef] [PubMed]
- Ichikawa, Y.; Ghanefar, M.; Bayeva, M.; Wu, R.; Khechaduri, A.; Naga Prasad, S.V.; Mutharasan, R.K.; Naik, T.J.; Ardehali, H. Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation. J. Clin. Invest. 2014, 124, 617–630. [Google Scholar] [CrossRef]
- Wen, H.; Niu, X.; Zhao, R.; Wang, Q.; Sun, N.; Ma, L.; Li, Y.; Zhang, W. Association of vitamin B1 with cardiovascular diseases, all-cause and cardiovascular mortality in US adults. Front. Nutr. 2023, 10, 1175961. [Google Scholar] [CrossRef]
The Impact of Thiamine Deficiency: Molecular Mechanisms | |||
---|---|---|---|
Author, Year | Clinical Trials | Properties | Ref. |
Keith M. et al., 2019 Yamada Y. et al., 2021 | Depletion of mitochondrial ATP resulting from thiamine deficiency | Negatively impacts myocardial contractility and LVEF; Contributes to heart hypertrophy, HFpEF cardiac insufficiency, and lactic acidosis. | [43,44] |
Gioda C.R. et al., 2014 | Thiamine deficiency induces significant endothelial dysfunction and a reduction in the contractility of cardiomyocytes | Decreases expression levels of eNOS in highly conductive blood vessels; Development of cardiac hypotrophy, bradycardia, and the onset of heart failure. | [34] |
Gioda C.R. et al., 2014 | NO measurements in a thiamine deficiency study | Decrease in the activity of aortic valves, associated with a reduction in acetylcholine-induced vascular relaxation. The results demonstrated a heightened contractile response in aortas from rats with thiamine deficiency, which reverted to control response levels when the endothelium was removed or NOS was inhibited with L-NAME. | [34] |
The Impact of Thiamine Deficiency and Furosemide Treatment on Cardiac Health | |||
Author, Year | Clinical Trials | Properties | Ref. |
Bicer I. et al., 2023 | The investigation aimed to delineate thiamine status in hospitalized patients with hypervolemic HF and/or RF receiving furosemide treatment | Thiamine levels in hypervolemic patients showed a significant decline during hospitalization, despite continued furosemide treatment (p = 0.029); A significant decrease in thiamine levels was observed specifically in patients with HF (p = 0.026). | [45] |
The Role of Thiamine in Diabetes Mellitus: Implications of Deficiency for Metabolic Dysfunction | |||
Clinical Trials | Properties | Ref. | |
Mazzeo A. et al., 2021 | Clinical study about the association of hyperglycemia and thiamine deficiency | Reduction in the expression of THTR2 and Sp1, thereby impairing the transport of thiamine into glomerular cells. | [46] |
Nix W.A. et al., 2015 | Study involving 120 adults with T2D, including 46 individuals with microalbuminuria | Thiamine deficiency was highly prevalent, occurring in 98% of patients with microalbuminuria and in 100% of those without it. | [47] |
Eshak E.S. et al., 2018 Al-Daghri N.M. et al., 2015 | Investigation into individuals with T1D | Presented lower blood levels of thiamine compared to healthy controls, with thiamine levels inversely correlating with glucose levels. | [11,48] |
Al-Daghri N.M. et al., 2015 | Blood thiamine levels in patients with type 1 and type 2 diabetes were evaluated, comparing them to a healthy control group | Increased levels of FBS, RBS, HbA1c, triglycerides, and total cholesterol compared to controls; Notably lower serum thiamine and HDL levels than the controls. | [48] |
Supplementation in Heart Failure | |||
Author, Year | Clinical Trials | Properties | Ref. |
Duc H.N. et al., 2021 | According to research, daily intake of thiamine | Reduce risks of hypertension (OR 0.95; 95% CI 0.90, 0.99), myocardial infarction, angina (OR 0.84; 95% CI 0.74, 0.95), type 2 diabetes (OR 0.86; 95% CI 0.81, 0.93), depression (OR 0.90; 95% CI 0.83, 0.97), and dyslipidemia (OR 0.90; 95% C0.86, 0.95); HbA1c and fasting glucose levels were lower in participants with adequate thiamine intake than those with insufficient intake. | [49] |
Smithline H.A. et al., 2019 | The study included hospitalized patients with acute heart failure, supplementing thiamine with the standard of care to improve dyspnea | Thiamine levels increased significantly in the treatment group, while they remained unchanged in the control group; A significant difference between groups over time of breath measured in the upright sitting position with oxygen; No changes were observed for other measures of dyspnea and for all secondary measures. | [41] |
Dong Z. et al., 2024 | Dong and Wang’s study included over 6000 participants and aimed to examine the relationship between thiamin intake and PAD risk among US adults | Thiamine intake below 0.65 mg/day was found to be associated with an increased risk of developing PAD; Insufficient levels of thiamine may contribute to an increased vulnerability to this condition. | [50] |
Berg K.M. et al., 2024 | The clinical study investigated thiamine as a potential metabolic resuscitator for in-hospital cardiac arrest to determine if thiamine could lower elevated lactate levels and enhance oxygen consumption in patients | Existing research indicates that thiamine may significantly improve outcomes for cardiac arrest survivors, although the study was halted after enrolling 36 patients due to safety concerns. | [51] |
Andersen L.W. et al., 2016 | Andersen et al.’s research analyzed post-operative lactate levels at the time of arrival in intensive care | Thiamine administration could improve aerobic metabolism and decrease post-operative lactate levels; The study looked at secondary endpoints like PDH activity, post-operative complications, duration of intensive care and hospital stay, and mortality. | [52] |
Datt V. et al., 2021 | The study investigates vasoplegic syndrome following vascular surgery, administering thiamine (400 mg/day) in combination with ascorbic acid (6 g) and hydrocortisone (200 mg/day) | Significant reduction in the need for vasopressors and offers benefits in terms of both mortality and morbidity; Thiamine decreased the conversion of ascorbic acid to oxalate, preventing hyperoxaluria, and improved the clearance of lactate by serving as a cofactor in the metabolism of lactate-by-lactate dehydrogenase. | [53] |
Thiamine Supplementation in Diabetes Management | |||
Author, Year | Clinical Trials | Properties | Ref. |
Al-Attas O. et al., 2014 | Interventional follow-up study based on supplementing with 100 mg of thiamine for six months for patients with T2DM | Increased serum thiamine levels and its derivatives, as well as enhancements in lipid and creatinine levels; A significant decrease in serum creatinine levels was noted over time, which is a reliable indicator of kidney function. | [54] |
Amirani E. et al., 2022 | A small clinical trial that involved patients with gestational diabetes who received thiamine supplementation for a period of 6 weeks | Decreased levels of specific markers of inflammation and oxidative stress, including serum C-reactive protein, TNF-α gene expression, and plasma MDA levels. | [55] |
Amirani E. et al., 2022 | A clinical investigation was carried out to evaluate the effects of thiamin supplementation on biomarkers of inflammation and oxidative stress in patients with gestational diabetes mellitus (GDM) | Significantly decreased serum hs-CRP (β—0.98 mg/L; 95% CI, −1.54, −0.42; p = 0.001) and plasma MDA levels (β—0.86 µmol/L; 95% CI, −1.15, −0.57; p < 0.001) when compared with the placebo; downregulation of gene expression of tumor necrosis factor-alpha (TNF-α) (p = 0.002) in peripheral blood mononuclear cells of patients with GDM; Not affecting other biomarkers of inflammation and oxidative stress. | [55] |
Veetil V.M. et al., 2023 | A clinical case of thiamine-responsive megaloblastic anemia (TRMA) in a 26-year-old woman who was diagnosed with diabetes mellitus in childhood | The patient showed significant improvement in hemoglobin levels and glycemic control; The study emphasizes the importance of thiamine treatment to improve the quality of life for patients with TRMA, while noting that thiamine cannot prevent hearing loss. | [56] |
Thiamine Supplementation in Atherosclerosis | |||
Author, Year | Clinical Trials | Properties | Ref. |
Arora S. et al., 2006 | The study has been proposed to evaluate the impact of thiamine on BAVA when there is acute hyperglycemia | Thiamine would protect against impaired glucose tolerance in healthy individuals, those with reduced glucose tolerance, and those with early NIDDM in hyperglycemic conditions. | [57] |
Al-Attas O. et al., 2014 | Evaluation of vitamin B1 supplementation and related hypolipidemic effect | Significant effect on reducing vascular inflammation, and there are negative correlations between high levels of thiamine and LDLc, as well as triglycerides; The progression of atherosclerosis can be slowed down through chronic vitamin B1 administration. | [54] |
Supplementation of Lipophilic Derivatives of Thiamine and Their Therapeutic Potential | |||
Author, Year | Clinical Trials | Properties | Ref. |
Stirban A. et al., 2013 | In a placebo-controlled randomized double-blind crossover trial, 31 individuals with type 2 diabetes were given either 900 mg/day benfotiamine or a placebo for a 6-week period | The basal flow-mediated dilation was impaired (2.63 ± 2.49%) in participants; After placebo treatment, postprandial flow-mediated dilation decreased significantly in patients with the highest flow-mediated dilation but benfotiamine pre-treatment mitigated this effect. | [58] |
The Role of Thiamine in Preventing Cardiac Inflammation | |||
Author, Year | Clinical Trials | Properties | Ref. |
Berg K.M. et al., 2014 | In a pilot, open-label, prospective study, patients with different diagnoses—including endocarditis, pancreatitis, pleural effusion, and cardiac arrest—were injected intravenously with 200 mg of thiamine | No effects were observed in patients with reduced cardiac index (< 2.4 L/min/m2). No association was observed between initial thiamine level and change in Vo2 after thiamine administration. An increase in Vo2 in critically ill patients and a considerable increase in Vo2 in patients with preserved or elevated cardiac index were observed. | [59] |
Supplementation of Lipophilic Derivatives of Thiamine and Their Therapeutic Potential | ||
---|---|---|
In Vitro and In Vivo Studies | Properties | Ref. |
Some researchers have evaluated the synthesis of NO in endothelial cells incubated with TPP and high concentrations of glucose, considering their family history since a history of diabetes or hypertension has been linked to endothelium response. | According to the results, 0.625 mg/mL of TPP in the presence of 5 mmol/L of glucose does not affect the viability or proliferation of endothelial cells; However, incubating endothelial cells with TPP and a high glucose concentration increased their viability and proliferation, the presence of TPP regulates the consumption of glucose and the synthesis of NO, which would explain its protective effect in the endothelium of diabetic patients. | [79] |
The study examines the effects of garlic-derived allithiamine, a derivative of thiamine (B1) with less polarity, on hyperglycemic-induced endothelial dysfunction using HUVECs as a model for hyperglycemia. | Allithiamine has significant antioxidant effects, reducing the production of ROS and suppressing the increase in AGEs induced by hyperglycemia; It also negatively affected the activation of NF-κ B. | [80] |
The Role of Thiamine in Cancer Therapy and Cardiotoxicity Prevention | ||
In Vitro and In Vivo Studies | Properties | Ref. |
The study evaluated the antitumor effect of thiamine in vitro, taking advantage of commercially available lipophilic thiamine analogs, such as sulbutiamine and benfotiamine, which enhance the antitumor effect. | Neither sulbutiamine nor benfotiamine decreased thiamine’s millimolar IC50 value to micromolar equivalents; According to HPLC analysis, sulbutiamine and benfotiamine had a significant effect on the intracellular concentrations of thiamine and TPP in vitro, leading to a reduction in PDH’s phosphorylation levels. | [81] |
The study investigated the protective role of thiamine (25 mg/kg i.p.) against DOX-induced cardiotoxicity in rats. | Thiamine pre-treatment preserved cardiac structure after DOX application in terms of lowering LV dimensions LVIDs, LVIDd, LVPWs, and LVPWd; The DOX+THIA group presented an improvement in EF and FS relative to the DOX group of rats; a 7-day thiamine administration induced a significant increase in antioxidant values SOD and GSH in heart tissue compared to its activity in DOX rats. | [82] |
The study by Radonjic et al. focused on the effect of thiamine hydrochloride on the reversal of DOX-induced cardiotoxicity and compared it with the reversal in the absence of thiamine pre-treatment. | Cardiac contractility was significantly altered after DOX treatment and diminished by thiamine pre-treatment; Pre-treatment with thiamine hydrochloride before doxorubicin administration could decrease oxidative stress production, increase myocardial contractility, and enhance the antioxidant defense system. | [83] |
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Ritorto, G.; Ussia, S.; Mollace, R.; Serra, M.; Tavernese, A.; Palma, E.; Muscoli, C.; Mollace, V.; Macrì, R. The Pivotal Role of Thiamine Supplementation in Counteracting Cardiometabolic Dysfunctions Associated with Thiamine Deficiency. Int. J. Mol. Sci. 2025, 26, 3090. https://doi.org/10.3390/ijms26073090
Ritorto G, Ussia S, Mollace R, Serra M, Tavernese A, Palma E, Muscoli C, Mollace V, Macrì R. The Pivotal Role of Thiamine Supplementation in Counteracting Cardiometabolic Dysfunctions Associated with Thiamine Deficiency. International Journal of Molecular Sciences. 2025; 26(7):3090. https://doi.org/10.3390/ijms26073090
Chicago/Turabian StyleRitorto, Giovanna, Sara Ussia, Rocco Mollace, Maria Serra, Annamaria Tavernese, Ernesto Palma, Carolina Muscoli, Vincenzo Mollace, and Roberta Macrì. 2025. "The Pivotal Role of Thiamine Supplementation in Counteracting Cardiometabolic Dysfunctions Associated with Thiamine Deficiency" International Journal of Molecular Sciences 26, no. 7: 3090. https://doi.org/10.3390/ijms26073090
APA StyleRitorto, G., Ussia, S., Mollace, R., Serra, M., Tavernese, A., Palma, E., Muscoli, C., Mollace, V., & Macrì, R. (2025). The Pivotal Role of Thiamine Supplementation in Counteracting Cardiometabolic Dysfunctions Associated with Thiamine Deficiency. International Journal of Molecular Sciences, 26(7), 3090. https://doi.org/10.3390/ijms26073090