Selenium, Selenoproteins, and Heart Failure: Current Knowledge and Future Perspective

Purpose of Review (Mal-)nutrition of micronutrients, like selenium, has great impact on the human heart and improper micronutrient intake was observed in 30–50% of patients with heart failure. Low selenium levels have been reported in Europe and Asia and thought to be causal for Keshan disease. Selenium is an essential micronutrient that is needed for enzymatic activity of the 25 so-called selenoproteins, which have a broad range of activities. In this review, we aim to summarize the current evidence about selenium in heart failure and to provide insights about the potential mechanisms that can be modulated by selenoproteins. Recent Findings Suboptimal selenium levels (<100 μg/L) are prevalent in more than 70% of patients with heart failure and were associated with lower exercise capacity, lower quality of life, and worse prognosis. Small clinical trials assessing selenium supplementation in patients with HF showed improvement of clinical symptoms (NYHA class), left ventricular ejection fraction, and lipid profile, while governmental interventional programs in endemic areas have significantly decreased the incidence of Keshan disease. In addition, several selenoproteins are found impaired in suboptimal selenium conditions, potentially aggravating underlying mechanisms like oxidative stress, inflammation, and thyroid hormone insufficiency. Summary While the current evidence is not sufficient to advocate selenium supplementation in patients with heart failure, there is a clear need for high level evidence to show whether treatment with selenium has a place in the contemporary treatment of patients with HF to improve meaningful clinical endpoints. Graphical abstract

Integrative analyses identify potential key genes and pathways in Keshan disease using whole-exome sequencing

Keshan disease (KD), an endemic heart disease with multifocal necrosis and replacement fibrosis of the myocardium,is still a nightmare situation for human health. However, molecular mechanism in the pathogenesis of KD remains unclear. Herein, blood samples were collected from 68 KD patients and 100 controls, and we systematically analyzed mutation profiles using whole-exome sequencing (WES). Causative genes of dilated cardiomyopathy (DCM), gene-based burden analysis, disease and pathway enrichment analysis, and protein-protein interaction (PPI) network analysis were performed. Of the 98 DCM-causative genes, 106 rare variants in 28 genes were detected in KD patients with minor allele frequency (MAF) < 0.001. Gene-based burden analysis, PPI network analysis, and automated Phenolyzer analysis were performed to prioritize 199 candidate genes, which combined with 98 DCM-causative genes, and reference genes from gene microarray or proteomics in KD. Then, 19 candidate pathogenic genes were selected, and 9 candidate genes were identified using PPI analysis, including HIF1A, GART, ALAD, VCL, DTNA, NEXN, INPPL1, NOS3, and JAK2. The 199 candidate genes were further analyzed using disease enrichment with CTD database and PPI analysis, and 21 candidate genes were identified. By combining with disease enrichment and PPI analysis, 7 Selenium (Se)-related genes were further identified, including ALAD, RBM10, GSN, GGT1, ADD1, PARP1, and NOS3. Based on the gene function and data validation, NEXN, TAF1C, FUT4, ALAD, ZNF608, and STX2 were the most likely pathogenic genes in KD. Notably, ALAD is the only candidate pathogenic gene identified by four different analyses, and its homozygous mutant mice could affect heart development and cause death.

Keshan Disease: A Potentially Fatal Endemic Cardiomyopathy in Remote Mountains of China

Keshan disease (KD) as an endemic, highly lethal cardiomyopathy, first reported in northeast China's Keshan County in 1935. The clinical manifestations of patients with KD include primarily congestive heart failure, acute heart failure, and cardiac arrhythmia. Even though some possible etiologies, such as viral infection, fungal infection, microelement deficiency, and malnutrition, have been reported, the exact causes of KD remain poorly known. The endemic areas where KD is found are remote and rural, and many are poor and mountainous places where people are the most socioeconomically disadvantaged in terms of housing, income, education, transportation, and utilization of health services. To date, KD is a huge burden to and severely restricts the economic development of the local residents and health systems of the endemic areas. Although efforts have been made by the government to control, treat, and interrupt disease transmission, the cure for or complete eradication of KD still requires global attention. For this reason, in this review, we systematically describe the etiological hypothesis, clinical manifestations, incidence characteristics, and treatment of KD, to facilitate the better understanding of and draw more attention to this non-representative cardiovascular disease, with the aim of accelerating its elimination.

Controversies about selenium supplementation

Introduction. Selenium (Se) is a trace element found mainly in meat, seafood, nuts and grains. Se is found in selenoproteins such as selenocystein or selenomethionin. A well balanced diet provides enough Se. Many regulatory and metabolic enzymes contain Se as their component, which is why Se supplementation is used in the treatment as well as prevention of multiple disorders. Se may, however, be toxic if overdosed. Aim. The aim of this review is to summarize the data about functions of Se in human body and to discuss its use in treatment and prevention of diseases. Materials and methods. The search was conducted using the PubMed and Google Scholar databases in March and April 2020. The key words used were: ‘selenium’, ‘cardiovascular disease’, ‘selenium supplementation’, ‘Keshan disease’, ‘source of selenium’. A total of 68 articles were analysed. Results. The first cases of chronic Se deficiency cases were documented 85 years ago in China. The patients with cardiomyopathy, extensive fibrosis and degenerative changes in the heart were diagnosed with Keshan disease. Human selenoproteonome consists of at least 25 selenoproteins. Se plays a role in immunity and metabolism via its role in functioning of numerous enzymes: glutathione peroxidase, thioredoxine and methionine sulfoxide reductase, methionine-sulfoxide reductase B1. Se plays a role in glucose homeostasis, Alzheimer’s disease, thyroid disorders, infectious, inflammatory diseases, vascular diseases and fertility. Conclusion. Se deficiency increases the risk of Keshan disease, but there is not enough evidence to recommend its supplementation for prevention of cardiovascular disease. However, Se status is important part of health assessment. Se supplementation should not exceed the dose of 55μg/day.

Risk factors for Keshan disease: a prospective cohort study protocol of gut flora

Background Keshan disease is an endemic cardiomyopathy of undefined causes. Being involved in the unclear pathogenesis of Keshan disease, a clear diagnosis, and effective treatment cannot be initiated. However, the rapid development of gut flora in cardiovascular disease combined with omics and big data platforms may promote the discovery of new diagnostic markers and provide new therapeutic options. This study aims to identify biomarkers for the early diagnosis and further explore new therapeutic targets for Keshan disease. Methods This cohort study consists of two parts. Though the first part includes 300 participants, however, recruiting will be continued for the eligible participants. After rigorous screening, the blood samples, stools, electrocardiograms, and ultrasonic cardiogram data would be collected from participants to elucidate the relationship between gut flora and host. The second part includes a prospective follow-up study for every 6 months within 2 years. Finally, deep mining of big data and rapid machine learning will be employed to analyze the baseline data, experimental data, and clinical data to seek out the new biomarkers to predict the pathogenesis of Keshan disease. Discussion Our study will clarify the distribution of gut flora in patients with Keshan disease and the abundance and population changes of gut flora in different stages of the disease. Through the big data platform analyze the relationship between environmental factors, clinical factors, and gut flora, the main factors affecting the occurrence of Keshan disease were identified, and the changed molecular pathways of gut flora were predicted. Finally, the specific gut flora and molecular pathways affecting Keshan disease were identified by metagenomics combined with metabonomic analysis. Trial registration: ChiCTR1900026639. Registered on 16 October 2019.