Homocysteine metabolism as the target for predictive medical approach, disease prevention, prognosis, and treatments tailored to the person

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Abstract

Homocysteine (Hcy) metabolism is crucial for regulating methionine availability, protein homeostasis, and DNA-methylation presenting, therefore, key pathways in post-genomic and epigenetic regulation mechanisms. Consequently, impaired Hcy metabolism leading to elevated concentrations of Hcy in the blood plasma (hyperhomocysteinemia) is linked to the overproduction of free radicals, induced oxidative stress, mitochondrial impairments, systemic inflammation and increased risks of eye disorders, coronary artery diseases, atherosclerosis, myocardial infarction, ischemic stroke, thrombotic events, cancer development and progression, osteoporosis, neurodegenerative disorders, pregnancy complications, delayed healing processes, and poor COVID-19 outcomes, among others. This review focuses on the homocysteine metabolism impairments relevant for various pathological conditions. Innovative strategies in the framework of 3P medicine consider Hcy metabolic pathways as the specific target for in vitro diagnostics, predictive medical approaches, cost-effective preventive measures, and optimized treatments tailored to the individualized patient profiles in primary, secondary, and tertiary care.

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Global, Regional, and National Burden of Cardiovascular Diseases for 10 Causes, 1990 to 2015

Gregory A Roth, Catherine Johnson, Amanuel Abajobir … (2018)

Background The burden of cardiovascular diseases (CVDs) remains unclear in many regions of the world. Objectives The GBD (Global Burden of Disease) 2015 study integrated data on disease incidence, prevalence, and mortality to produce consistent, up-to-date estimates for cardiovascular burden. Methods CVD mortality was estimated from vital registration and verbal autopsy data. CVD prevalence was estimated using modeling software and data from health surveys, prospective cohorts, health system administrative data, and registries. Years lived with disability (YLD) were estimated by multiplying prevalence by disability weights. Years of life lost (YLL) were estimated by multiplying age-specific CVD deaths by a reference life expectancy. A sociodemographic index (SDI) was created for each location based on income per capita, educational attainment, and fertility. Results In 2015, there were an estimated 422.7 million cases of CVD (95% uncertainty interval: 415.53 to 427.87 million cases) and 17.92 million CVD deaths (95% uncertainty interval: 17.59 to 18.28 million CVD deaths). Declines in the age-standardized CVD death rate occurred between 1990 and 2015 in all high-income and some middle-income countries. Ischemic heart disease was the leading cause of CVD health lost globally, as well as in each world region, followed by stroke. As SDI increased beyond 0.25, the highest CVD mortality shifted from women to men. CVD mortality decreased sharply for both sexes in countries with an SDI >0.75. Conclusions CVDs remain a major cause of health loss for all regions of the world. Sociodemographic change over the past 25 years has been associated with dramatic declines in CVD in regions with very high SDI, but only a gradual decrease or no change in most regions. Future updates of the GBD study can be used to guide policymakers who are focused on reducing the overall burden of noncommunicable disease and achieving specific global health targets for CVD.

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Biomarkers associated with COVID-19 disease progression

Giovanni Ponti, Monia Maccaferri, Cristel Ruini … (2020)

Abstract The coronavirus disease 2019 (COVID-19) pandemic is a scientific, medical, and social challenge. The complexity of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is centered on the unpredictable clinical course of the disease that can rapidly develop, causing severe and deadly complications. The identification of effective laboratory biomarkers able to classify patients based on their risk is imperative in being able to guarantee prompt treatment. The analysis of recently published studies highlights the role of systemic vasculitis and cytokine mediated coagulation disorders as the principal actors of multi organ failure in patients with severe COVID-19 complications. The following biomarkers have been identified: hematological (lymphocyte count, neutrophil count, neutrophil–lymphocyte ratio (NLR)), inflammatory (C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), procalcitonin (PCT)), immunological (interleukin (IL)-6 and biochemical (D-dimer, troponin, creatine kinase (CK), aspartate aminotransferase (AST)), especially those related to coagulation cascades in disseminated intravascular coagulation (DIC) and acute respiratory distress syndrome (ARDS). New laboratory biomarkers could be identified through the accurate analysis of multicentric case series; in particular, homocysteine and angiotensin II could play a significant role.

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Homocysteine metabolism.

J Selhub (1999)

Homocysteine is a sulfur amino acid whose metabolism stands at the intersection of two pathways: remethylation to methionine, which requires folate and vitamin B12 (or betaine in an alternative reaction); and transsulfuration to cystathionine, which requires pyridoxal-5'-phosphate. The two pathways are coordinated by S-adenosylmethionine, which acts as an allosteric inhibitor of the methylenetetrahydrofolate reductase reaction and as an activator of cystathionine beta-synthase. Hyperhomocysteinemia, a condition that recent epidemiological studies have shown to be associated with increased risk of vascular disease, arises from disrupted homocysteine metabolism. Severe hyperhomocysteinemia is due to rare genetic defects resulting in deficiencies in cystathionine beta synthase, methylenetetrahydrofolate reductase, or in enzymes involved in methyl-B12 synthesis and homocysteine methylation. Mild hyperhomocysteinemia seen in fasting conditions is due to mild impairment in the methylation pathway (i.e. folate or B12 deficiencies or methylenetetrahydrofolate reductase thermolability). Post-methionine-load hyperhomocysteinemia may be due to heterozygous cystathionine beta-synthase defect or B6 deficiency. Early studies with nonphysiological high homocysteine levels showed a variety of deleterious effects on endothelial or smooth muscle cells in culture. More recent studies with human beings and animals with mild hyperhomocysteinemia provided encouraging results in the attempt to understand the mechanism that underlies this relationship between mild elevations of plasma homocysteine and vascular disease. The studies with animal models indicated the possibility that the effect of elevated homocysteine is multifactorial, affecting both the vascular wall structure and the blood coagulation system.

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Author and article information

Contributors

Peter Kubatka: peter.kubatka@uniba.sk

Olga Golubnitschaja: olga.golubnitschaja@ukbonn.de

Journal

Journal ID (nlm-ta): EPMA J

Journal ID (iso-abbrev): EPMA J

Title: The EPMA Journal

Publisher: Springer International Publishing (Cham )

ISSN (Print): 1878-5077

ISSN (Electronic): 1878-5085

Publication date (Electronic): 11 November 2021

Publication date PMC-release: 11 November 2021

Pages: 1-29

Affiliations

[1 ]GRID grid.7634.6, ISNI 0000000109409708, Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, , Comenius University in Bratislava, ; 036 01 Martin, Slovakia

[2 ]GRID grid.7634.6, ISNI 0000000109409708, Jessenius Faculty of Medicine in Martin, , Biomedical Centre Martin, Comenius University in Bratislava, ; Mala Hora 4D, 036 01 Martin, Slovakia

[3 ]GRID grid.418818.c, ISNI 0000 0001 0516 2170, Department of Physiology and Biophysics, , Weill Cornell Medicine in Qatar, Education City, Qatar Foundation, ; 24144 Doha, Qatar

[4 ]GRID grid.7634.6, ISNI 0000000109409708, Department of Medical Biology, Jessenius Faculty of Medicine, , Comenius University in Bratislava, ; 036 01 Martin, Slovakia

[5 ]GRID grid.15090.3d, ISNI 0000 0000 8786 803X, Predictive, Preventive, Personalised (3P) Medicine, Department of Radiation Oncology, , University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, ; 53127 Bonn, Germany

Article

Publisher ID: 263

DOI: 10.1007/s13167-021-00263-0

PMC ID: 8581606

PubMed ID: 34786033

SO-VID: 9aad0e2e-86c5-40e6-be58-2068a6beb60d

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 25 October 2021

Date accepted : 29 October 2021

Funding

Funded by: Rheinische Friedrich-Wilhelms-Universität Bonn (1040)

Open Access :

Open Access funding enabled and organized by Projekt DEAL.

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Homocysteine metabolism as the target for predictive medical approach, disease prevention, prognosis, and treatments tailored to the person

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Novel Coronavirus Disease COVID-19

Most cited references 225

Global, Regional, and National Burden of Cardiovascular Diseases for 10 Causes, 1990 to 2015

Biomarkers associated with COVID-19 disease progression

Homocysteine metabolism.

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