scholarly journals Genetic basis of anthracyclines cardiotoxicity: Literature review

2021 ◽  
Vol 6 (4) ◽  
pp. 27-38
Author(s):  
M. Yu. Sinitsky ◽  
A. V. Tsepokina ◽  
M. V. Khutornaya ◽  
A. V. Ponasenko ◽  
A. N. Sumin
Keyword(s):  
Candidate Genes ◽  
Translational Regulation ◽  
Myocardial Dysfunction ◽  
Molecular Genetic ◽  
Myocardial Damage ◽  
Malignant Neoplasms ◽  
Potential Candidate ◽  
Cardiotoxic Effect ◽  
Slc Transporters ◽  
Increased Risk

The purpose of this review was to systematize data on molecular genetic markers of increased risk of cardiotoxic effects, as well as to search for risk and protective variants of candidate genes. Today, the therapy of malignant neoplasms is based on the use of anthracyclines – drugs of the cytostatic mechanism of action. Along with their effectiveness, these drugs can have a cardiotoxic effect on cardiomyocytes by increasing the amount of reactive oxygen species and disrupting mitochondrial biogenesis. Pathological disorders lead to an increased risk of myocardial dysfunction and a number of other cardiovascular pathologies in patients receiving chemotherapy using anthracyclines. The cardiotoxic effect of anthracyclines leads to cardiomyopathy, heart failure, myocardial infarction, and thrombosis. Early detection of cardiotoxic damage leads to reducing the negative effects of these drugs due to changes in chemotherapy tactics. It is known that the risk of cardiotoxic myocardial damage is genetically determined and controlled by more than 80 genes. In this review, the description of basic molecules such as ATP-binding cassette transporters and solute carrier family (SLC transporters), carbonyl reductase, molecules of antioxidant defense, xenobiotic and iron metabolism was performed. In addition, a special attention is paid to the study of epigenetic and post-translational regulation. The available data are characterized by some inconsistency that may be explained by the ethnic differences of the studied populations. Thus, a more detailed research of various ethnic groups, gene-gene interactions between potential candidate genes and epigenetic regulation is necessary. Thus, understanding the contribution of genetic polymorphism to the development of cardiotoxicity will help to assess the individual risks of cardiovascular pathology in patients with various types of cancer, as well as reduce the risk of myocardial damage by developing individual preventive measures and correcting chemotherapy.

scholarly journals GENETICS OF PHOBIC DISORDERS

2021 ◽  
pp. 245-256
Author(s):  
V. Pomohaibo ◽  
O. Berezan ◽  
A. Petrushov
Keyword(s):  
Candidate Genes ◽  
Association Studies ◽  
Meta Analysis ◽  
Molecular Genetic ◽  
Genome Wide Association Studies ◽  
Potential Candidate ◽  
Social Phobias ◽  
Phobic Disorders ◽  
Multifactorial Diseases ◽  
Statistical Validity

At present time, on the basis of genome-wide association studies (GWAS), several authors found linkage of phobic disorders with certain regions of chromosomes – 3q26 (agoraphobia), 14q13 (specific phobias), 16q21 (social phobias), 16q22 (social phobias) and 4q31-q34 (phobic disorders). We propose 19 genes that are localized in these regions and are expressed in the brain: PRKCI, CLDN11, EIF5A2, TNIK, CLCN3, CPE, GLRB, GRIA2, NEK1, NPY2R, NPY5R, RAPGEF2,  TRIM2, SMAD1, ADGRG1, BEAN1, CDH8, DOK4 and KATNB1. Therefore, these genes may be investigated as candidate genes of phobic disorders. Various sources propose 26 potential candidate genes of phobic disorders. Finnish geneticist J. Donner carries out a meta-analysis to study the 8 most probable among them and corroborates statistical validity only for 4 genes: ALAD, CDH2, EPB41L4A and GAD1. First three genes are involved in the social phobias, and fourth is involved in whole phobic disorders. Phobias are heterogeneous and multifactorial diseases. To understand the biological mechanisms of such disorders, to create effective methods for their prevention and treatment, there are needed further intensive molecular genetic studies of these disorders on sufficiently large samples and corroborating these results by other authors.

scholarly journals Genetic characterization of Addison’s disease in Bearded Collies

BMC Genomics ◽  
2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Liza C. Gershony ◽  
Janelle M. Belanger ◽  
Marjo K. Hytönen ◽  
Hannes Lohi ◽  
Thomas R. Famula ◽  
...  
Keyword(s):  
Candidate Genes ◽  
Addison’S Disease ◽  
Genome Wide Association ◽  
Complex Nature ◽  
Addison's Disease ◽  
Regulatory Sequences ◽  
Potential Candidate ◽  
Genome Wide ◽  
A Genome ◽  
Increased Risk

Abstract Background Primary hypoadrenocorticism (or Addison’s disease, AD) is an autoimmune disease that results in destruction of the adrenal cortex and consequent adrenal insufficiency. The disease has been described in purebred and mixed breed dogs, although some breeds, including the Bearded Collie, are at increased risk for AD. Candidate gene approaches have yielded few associations that appear to be breed-specific. A single other genome-wide association study reported no significant regions of association for AD in Standard Poodles. The present study aimed to identify genomic regions of association for canine AD in Bearded Collies. Results Our study consists of the first genome-wide association analysis to identify a genome-wide significant region of association with canine AD (CFA18). Peaks of suggestive association were also noted on chromosomes 11, 16 and 29. Logistic regression analysis supported an additive effect of risk genotypes at these smaller effect loci on the probability of disease associated with carrying a risk genotype on CFA18. Potential candidate genes involved in adrenal steroidogenesis, regulation of immune responses and/or inflammation were identified within the associated regions of chromosomes 11 and 16. The gene-poor regions of chromosomes 18 and 29 may, however, harbor regulatory sequences that can modulate gene expression and contribute to disease susceptibility. Conclusion Our findings support the polygenic and complex nature of canine AD and identified a strongly associated locus on CFA18 that, when combined with three other smaller effect loci, was predictive of disease. The results offer progress in the identification of susceptibility loci for canine AD in the Bearded Collie. Further studies are needed to confirm association with the suggested candidate genes and identify actual causative mutations involved with AD susceptibility in this breed.

scholarly journals Role of the polymorphiс variants of immune response and inflammation genes in pathogenesis of ovarian cancer in women of different ethnic origin

2019 ◽  
pp. 10-20
Author(s):  
Э.Т. Мингажева ◽  
Д.С. Прокофьева ◽  
Я.В. Валова ◽  
А.Х. Нургалиева ◽  
Р.Р. Валиев ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Immune Response ◽  
Protective Factor ◽  
Molecular Genetic ◽  
Ethnic Origin ◽  
Malignant Neoplasms ◽  
Specific Pcr ◽  
Increased Risk ◽  
Il18 Gene

Рак яичников (РЯ) занимает одно из лидирующих мест среди онкопатологии репродуктивной сферы у женщин. Высокие показатели заболеваемости и смертности от данного вида рака свидетельствуют о необходимости более глубокого понимания молекулярно-генетических основ заболевания для разработки новых подходов к диагностике и лечению РЯ. В последнее время при исследовании патогенеза злокачественных новообразований яичников большой интерес ученых во всем мире вызывает изучение роли генов иммунного ответа и воспаления. В статье представлены результаты исследования роли аллельных вариантов генов NFKB1 (rs28362491), IL6 (rs1800795), IL18 (rs1946518) и IL23R (rs7517847, rs10889677) в патогенезе РЯ у женщин из Республики Башкортостан. Материалом для работы послужили образцы ДНК женщин с установленным диагнозом «рак яичников» (n=238) и здоровых индивидов (n=284). Генотипирование образцов ДНК проводили методами полимеразной цепной реакции (ПЦР) с последующим анализом полиморфизма длин рестрикционных фрагментов и аллель-специфичной ПЦР. Установлено, что генетическими маркерами риска развития рака яичников для женщин русской этнической принадлежности пременопаузального возраста являются генотипы rs28362491*ID в гене NFKB1 и rs1946518*СA в гене IL18. Носительство генотипов rs1800795*GG в гене IL6 и rs10889677*CС в гене IL23R для женщин татарской этнической принадлежности в постменопаузе является протективным фактором. Для татар с генотипом rs10889677*CА в гене IL23R в постменопаузе, напротив, было показано повышение риска развития заболевания. К маркерам пониженного риска развития РЯ у русских также можно отнести генотип rs1946518 *AA в гене IL18, который был отмечен как протективный фактор для женщин как в пре-, так и постменопаузе, а также у больных данной онкопатологией с начальными и запущенными стадиями заболевания. При сравнительном анализе распределения частот аллелей и генотипов полиморфного варианта rs7517847 в гене IL23R среди больных РЯ и здоровых доноров статистически значимых различий между исследуемыми группами не обнаружено. Ovarian cancer (OC) is one of the most common malignancyof the female reproductive system. High rates of morbidity and mortality from this type of cancer indicate the need for a deeper understanding of the molecular genetic basis of the disease, which in turn will contribute to the development of new approaches to the diagnosis and treatment of OC. Recently, when studying the pathogenesis of malignant neoplasms of the ovaries, a great interest of scientists around the world is directed to studying the role of the immune response and inflammation genes in the development of the OC. At this work presents the results of the study of the role of the polymorphic loci of the genes NFKB1 (rs28362491), IL6 (rs1800795), IL18 (rs1946518) and IL23R (rs7517847, rs10889677) in the pathogenesis of ovarian cancer in women from the Republic of Bashkortostan.The material for the work was the DNA samples of women with an established diagnosis of ovarian cancer (n = 238) and healthy individuals (n = 284). Genotyping of DNA samples was performed using polymerase chain reaction (PCR), followed by analysis of restriction fragment length polymorphism and allele-specific PCR. It has been established that the genetic markers of the risk of developing ovarian cancer for women of Russian ethnicity at premenopausal age are the genotypes rs28362491* ID in the NFKB1 gene and rs1946518 * CA in the IL18 gene. The carrier of the rs1800795 * GG genotypes in the IL6 gene and rs10889677 * CС in the IL23R gene for post-menopausal women of Tatar ethnicity is a protective factor. For Tatars with the rs10889677 * CA genotype in the IL23R postmenopausal gene, on the contrary, an increased risk of developing the disease was shown. Markers of a reduced risk of developing ovarian cancer in Russians can also include the rs1946518 * AA genotype in the IL18 gene, which was noted as a protective factor for women in both pre- and postmenopausal women, as well as in patients with this oncopathology with initial and advanced stages of the disease. A comparative analysis of the frequency distribution of alleles and genotypes of the polymorphic variant rs7517847 in the IL23R gene among patients with OC and healthy donors did not reveal statistically significant differences between the studied groups.

Clinical and Morphological Features of Myocardial Damage and the Course of Fulminant Myocarditis on the Background of СOVID-19, Diagnosis and Treatment Tactics

2020 ◽  
Vol 75 (5S) ◽  
pp. 414-425
Author(s):  
Olga S. Oynotkinova ◽  
Evgenii L. Nikonov ◽  
Oleg V. Zayratyants ◽  
Elena V. Rzhevskaya ◽  
Evgenii V. Krukov ◽  
...  
Keyword(s):  
Myocardial Dysfunction ◽  
Myocardial Damage ◽  
Heart Rhythm ◽  
Microvascular Dysfunction ◽  
Symptomatic Treatment ◽  
Clinical Situation ◽  
Diagnosis And Treatment ◽  
Screening Tests ◽  
Fulminant Myocarditis ◽  
Heart Rhythm Disorders

In a review article based on my own clinical experience of managing patients with acute myocardial injury and fulminant myocarditis, taking into account expert recommendations on the clinical treatment of myocardial damage associated with novel coronavirus infection a National clinical geriatric medical research center, division of cardiovascular diseases, the Chinese geriatrics society, Department of cardiology, Beijing Medical Association and European clinics discusses the pathogenesis, diagnosis and treatment of myocardial damage and FM patients, infected with SARS-CoV-2 in the context of the COVID-19 pandemic. Clinical features and diagnostic criteria are presented, including screening tests of markers of myocardial damage in the form of a highly sensitive troponin test, a natriuretic peptide. The article discusses in detail the pathogenesis and mechanisms of myocardial damage, including immune mechanisms, cytokine storm, systemic inflammation with macro- and microvascular dysfunction and the development of myocardial dysfunction with acute heart failure, hypotension, cardiogenic shock and/or life-threatening heart rhythm disorders caused by hypoxia and metabolic disorders at the cellular level. Features of the clinical course of fulminant myocarditis in infected patients (SARS-CoV-2) in the conditions of the COVID-19 pandemic are presented. For the first time, a detailed histo-morphological analysis of pathological myocardial injuries and complications is presented on the basis of unique autopsy material on post-mortem diagnostics of various pathoanatomic autopsies of those who died from COVID-19 in Moscow. Based on the clinical, functional and morphological material, the Protocol of etiopathogenetic treatment is presented. The basis of standard therapy is considered antiviral drugs, immunoglobulin G, the use of monoclonal antibodies to interleukin-6, anticoagulants, glucocorticoids, depending on the clinical situation, cardioprotectors and symptomatic treatment are recommended to maintain the heart, which in combination can achieve a certain clinical effectiveness. As adjuvant cardioprotective targeted therapy, the sodium salt of phosphocreatine is considered in order to preserve the myocardium, maintain its contractility and vital activity.

scholarly journals Cytoprotective Potential of Aged Garlic Extract (AGE) and Its Active Constituent, S-allyl-l-cysteine, in Presence of Carvedilol during Isoproterenol-Induced Myocardial Disturbance and Metabolic Derangements in Rats

Molecules ◽  
2021 ◽  
Vol 26 (11) ◽  
pp. 3203
Author(s):  
Syed Mohammed Basheeruddin Asdaq ◽  
Obulesu Challa ◽  
Abdulhakeem S. Alamri ◽  
Walaa F. Alsanie ◽  
Majid Alhomrani ◽  
...  
Keyword(s):  
Myocardial Dysfunction ◽  
Combined Therapy ◽  
Myocardial Damage ◽  
Thiobarbituric Acid ◽  
Significant Rise ◽  
Garlic Extract ◽  
High Dose ◽  
Aged Garlic Extract ◽  
Active Constituent ◽  
Aged Garlic

This study was conducted to determine the potential interaction of aged garlic extract (AGE) with carvedilol (CAR), as well as to investigate the role of S-allyl-l-cysteine (SAC), an active constituent of AGE, in rats with isoproterenol (ISO)-induced myocardial dysfunction. At the end of three weeks of treatment with AGE (2 and 5 mL/kg) or SAC (13.1 and 32.76 mg/kg), either alone or along with CAR (10 mg/kg) in the respective groups of animals, ISO was administered subcutaneously to induce myocardial damage. Myocardial infarction (MI) diagnostic predictor enzymes, lactate dehydrogenase (LDH) and creatinine kinase (CK-MB), were measured in both serum and heart tissue homogenates (HTH). Superoxide dismutase (SOD), catalase, and thiobarbituric acid reactive species (TBARS) were estimated in HTH. When compared with other groups, the combined therapy of high doses of AGE and SAC given alone or together with CAR caused a significant decrease in serum LDH and CK-MB activities. Further, significant rise in the LDH and CK-MB activities in HTH was noticed in the combined groups of AGE and SAC with CAR. It was also observed that both doses of AGE and SAC significantly increased endogenous antioxidants in HTH. Furthermore, histopathological observations corroborated the biochemical findings. The cytoprotective potential of SAC and AGE were dose-dependent, and SAC was more potent than AGE. The protection offered by aged garlic may be attributed to SAC. Overall, the results indicated that a high dose of AGE and its constituent SAC, when combined with carvedilol, has a synergistic effect in preventing morphological and physiological changes in the myocardium during ISO-induced myocardial damage.

scholarly journals Combination of GP88 Expression in Tumor Cells and Tumor-Infiltrating Immune Cells Is an Independent Prognostic Factor for Bladder Cancer Patients

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1796
Author(s):  
Markus Eckstein ◽  
Verena Lieb ◽  
Rudolf Jung ◽  
Danijel Sikic ◽  
Katrin Weigelt ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Prognostic Factor ◽  
Tumor Cells ◽  
Immune Cells ◽  
Potential Candidate ◽  
Poor Prognostic Factor ◽  
Risk Of Death ◽  
Increased Risk ◽  
Muscle Invasive ◽  
Disease Specific

Urothelial bladder cancer (BCa) is the ninth most commonly diagnosed cancer worldwide and accounts for approximately 3% of global cancer diagnoses. We are interested in prognostic markers that may characterize tumor cells (TCs) and immune cells (ICs) and their relationship in BCa. A potential candidate marker that meets these criteria is progranulin (GP88), which is expressed separately in TCs and ICs. We analyzed GP88 expression by immunohistochemistry (IHC) in 196 muscle-invasive BCa samples using a tissue microarray. The immunoreactive score for GP88 staining in TCs and the percentage of GP88-positive ICs was determined. An easy cutoff for the staining status of TCs (positive vs. negative) and ICs (0% vs. >0%) and, more generally, negative vs. positive GP88 staining could be applied. We detected 93 patients (47.4%) and 92 patients (46.9%) with GP88-positive TCs or ICs, respectively. The IHC results were correlated with clinicopathological and survival data. Positive GP88 staining in TCs appeared to be an independent poor prognostic factor for disease-specific survival (DSS) (RR (relative risk) = 1.74; p = 0.009) and recurrence-free survival (RFS) (RR = 1.92; p = 0.002). In contrast, negative GP88 staining in ICs was an independent negative predictor for overall survival (OS) (RR = 2.18; p < 0.001), DSS (RR = 2.84; p < 0.001) and RFS (RR = 2.91; p < 0.001) in multivariate Cox’s regression analysis. When combining GP88 staining in TCs and ICs, a specific combination of GP88-positive TCs and GP88-negative ICs was associated with a 2.54-fold increased risk of death, a 4.21-fold increased risk of disease-specific death and a 4.81-fold increased risk of recurrence compared to GP88-negative TCs and GP88-positive ICs. In summary, GP88 positivity in TCs is a negative prognostic factor for DSS and RFS. In addition, GP88 positivity can mark ICs that are associated with a good prognosis (OS, DSS and RFS). The combination of GP88 staining in TCs and ICs appears to be a significant independent prognostic biomarker in muscle-invasive BCa.

scholarly journals Genome-wide association study and gene network analyses reveal potential candidate genes for high night temperature tolerance in rice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Raju Bheemanahalli ◽  
Montana Knight ◽  
Cherryl Quinones ◽  
Colleen J. Doherty ◽  
S. V. Krishna Jagadish
Keyword(s):  
Grain Size ◽  
Candidate Genes ◽  
Gene Network ◽  
Genome Wide Association ◽  
Potential Candidate ◽  
Genetic Loci ◽  
Stay Green ◽  
Yield And Quality ◽  
Genome Wide ◽  
Wide Range

AbstractHigh night temperatures (HNT) are shown to significantly reduce rice (Oryza sativa L.) yield and quality. A better understanding of the genetic architecture of HNT tolerance will help rice breeders to develop varieties adapted to future warmer climates. In this study, a diverse indica rice panel displayed a wide range of phenotypic variability in yield and quality traits under control night (24 °C) and higher night (29 °C) temperatures. Genome-wide association analysis revealed 38 genetic loci associated across treatments (18 for control and 20 for HNT). Nineteen loci were detected with the relative changes in the traits between control and HNT. Positive phenotypic correlations and co-located genetic loci with previously cloned grain size genes revealed common genetic regulation between control and HNT, particularly grain size. Network-based predictive models prioritized 20 causal genes at the genetic loci based on known gene/s expression under HNT in rice. Our study provides important insights for future candidate gene validation and molecular marker development to enhance HNT tolerance in rice. Integrated physiological, genomic, and gene network-informed approaches indicate that the candidate genes for stay-green trait may be relevant to minimizing HNT-induced yield and quality losses during grain filling in rice by optimizing source-sink relationships.

scholarly journals Transcriptome profiling analysis of muscle tissue reveals potential candidate genes affecting water holding capacity in Chinese Simmental beef cattle

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Lili Du ◽  
Tianpeng Chang ◽  
Bingxing An ◽  
Mang Liang ◽  
Xinghai Duan ◽  
...  
Keyword(s):  
Beef Cattle ◽  
Candidate Genes ◽  
Molecular Mechanism ◽  
Meat Quality ◽  
Relevant Literature ◽  
Transcriptome Profiling ◽  
Water Holding Capacity ◽  
Potential Candidate ◽  
Protein Protein Interaction ◽  
Water Holding

AbstractWater holding capacity (WHC) is an important sensory attribute that greatly influences meat quality. However, the molecular mechanism that regulates the beef WHC remains to be elucidated. In this study, the longissimus dorsi (LD) muscles of 49 Chinese Simmental beef cattle were measured for meat quality traits and subjected to RNA sequencing. WHC had significant correlation with 35 kg water loss (r = − 0.99, p < 0.01) and IMF content (r = 0.31, p < 0.05), but not with SF (r = − 0.20, p = 0.18) and pH (r = 0.11, p = 0.44). Eight individuals with the highest WHC (H-WHC) and the lowest WHC (L-WHC) were selected for transcriptome analysis. A total of 865 genes were identified as differentially expressed genes (DEGs) between two groups, of which 633 genes were up-regulated and 232 genes were down-regulated. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment revealed that DEGs were significantly enriched in 15 GO terms and 96 pathways. Additionally, based on protein–protein interaction (PPI) network, animal QTL database (QTLdb), and relevant literature, the study not only confirmed seven genes (HSPA12A, HSPA13, PPARγ, MYL2, MYPN, TPI, and ATP2A1) influenced WHC in accordance with previous studies, but also identified ATP2B4, ACTN1, ITGAV, TGFBR1, THBS1, and TEK as the most promising novel candidate genes affecting the WHC. These findings could offer important insight for exploring the molecular mechanism underlying the WHC trait and facilitate the improvement of beef quality.

scholarly journals Current recommendations for clinical surveillance and genetic testing in rhabdoid tumor predisposition: a report from the SIOPE Host Genome Working Group

2021 ◽  
Author(s):  
M. C. Frühwald ◽  
K. Nemes ◽  
H. Boztug ◽  
M. C. A. Cornips ◽  
D. G. Evans ◽  
...  
Keyword(s):  
Working Group ◽  
Soft Part ◽  
Genetic Disorders ◽  
Panel Discussion ◽  
Rhabdoid Tumor ◽  
Host Genome ◽  
Cancer Surveillance ◽  
Malignant Neoplasms ◽  
Pathogenic Variants ◽  
Increased Risk

AbstractThe rhabdoid tumor (RT) predisposition syndromes 1 and 2 (RTPS1 and 2) are rare genetic conditions rendering young children vulnerable to an increased risk of RT, malignant neoplasms affecting the kidney, miscellaneous soft-part tissues, the liver and the central nervous system (Atypical Teratoid Rhabdoid Tumors, ATRT). Both, RTPS1&2 are due to pathogenic variants (PV) in genes encoding constituents of the BAF chromatin remodeling complex, i.e. SMARCB1 (RTPS1) and SMARCA4 (RTPS2). In contrast to other genetic disorders related to PVs in SMARCB1 and SMARCA4 such as Coffin-Siris Syndrome, RTPS1&2 are characterized by a predominance of truncating PVs, terminating transcription thus explaining a specific cancer risk. The penetrance of RTPS1 early in life is high and associated with a poor survival. However, few unaffected carriers may be encountered. Beyond RT, the tumor spectrum may be larger than initially suspected, and cancer surveillance offered to unaffected carriers (siblings or parents) and long-term survivors of RT is still a matter of discussion. RTPS2 exposes female carriers to an ill-defined risk of small cell carcinoma of the ovaries, hypercalcemic type (SCCOHT), which may appear in prepubertal females. RT surveillance protocols for these rare families have not been established. To address unresolved issues in the care of individuals with RTPS and to propose appropriate surveillance guidelines in childhood, the SIOPe Host Genome working group invited pediatric oncologists and geneticists to contribute to an expert meeting. The current manuscript summarizes conclusions of the panel discussion, including consented statements as well as non-evidence-based proposals for validation in the future.

Prevalence and prognostic impact of somatic mutations in patients with heart failure and reduced ejection fraction

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
D.J Vazquez Andres ◽  
A Hernandez Vicente ◽  
M Diez Diez ◽  
M Gomez Molina ◽  
A Quintas ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Somatic Mutations ◽  
Myocardial Dysfunction ◽  
Study Endpoint ◽  
Prognostic Impact ◽  
Reduced Ejection Fraction ◽  
Increased Risk ◽  
Patients With Heart Failure

Abstract Introduction Somatic mutations in hematopoietic cells are associated with age and have been associated with higher mortality in apparently healthy adults, especially due to atherosclerotic disease. In animal models, somatic mutations are associated with atherosclerosis progression and myocardial dysfunction, especially when gene TET2 is affected. Preliminary clinical data, referred to ischemic heart failure (HF), have associate the presence of these acquired mutations with impaired prognosis. Purpose To study the prevalence of somatic mutations in patients with heart failure with reduced ejection fraction (HFrEF) and their impact on long-term prognosis. Methods We studied a cohort of elderly patients (more than 60 years old) hospitalized with HFrEF (LVEF&lt;45%). The presence of somatic mutations was assessed using next generation sequencing (Illumina HiSeq 2500), with a mutated allelic fraction of at least 2% and a panel of 55 genes related with clonal hematopoiesis. Patients were followed-up for a median of three years. The study endpoint was a composite of death or readmission for worsening HF. Kaplan-Meier analysis (log-rank test) and Cox proportional hazards regression models were performed adjusting for age, sex and LVEF. Results A total of 62 patients (46 males (74.2%), age 74±7.5 years) with HFrEF (LVEF 29.7±7.8%) were enrolled in the study. The ischemic etiology was present in 54% of patients. Somatic mutations in Dnmt3a or Tet2 were present in 11 patients (17.7%). No differences existed in baseline characteristics except for a higher prevalence of atrial fibrillation in patients with somatic mutations (70% vs. 40%, p=0.007). During the follow-up period, 40 patients (64.5%) died and 38 (61.3%) had HF re-admission. The KM survival analysis for the combined event is shown in Figure 1. Compared with patients without somatic mutations and after adjusting for covariates, there was an increased risk of adverse outcomes when the somatic mutations were present (HR 3.6, 95% CI [1.6, 7.8], p=0.0014). This results remains considering death as a competing risk (Gray's test p=0.0097) and adjusting for covariates (HR = 2.21 95% CI [0.98, 5], p=0.0556). Conclusions Somatic mutation are present in patients with HFrEF and determine a higher risk of adverse events in the follow-up. Further studies are needed to assess the clinical implications of these findings. Figure 1 Funding Acknowledgement Type of funding source: None

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