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Orphan solute carrier (SLC) represents a group of membrane transporters whose exact functions and substrate specificities are not known. Elucidating the function and regulation of orphan SLC transporters is not only crucial for advancing our knowledge of cellular and molecular biology but can potentially lead to the development of new therapeutic strategies. Here, we provide evidence for the biological function of a ubiquitous orphan lysosomal SLC, the Major Facilitator Superfamily Domain-containing Protein 1 (MFSD1), which has remained phylogenetically unassigned. Targeted metabolomics revealed that dipeptides containing either lysine or arginine residues accumulate in lysosomes of cells lacking MFSD1. Whole-cell patch-clamp electrophysiological recordings of HEK293-cells expressing MFSD1 on the cell surface displayed transport affinities for positively charged dipeptides in the lower mM range, while dipeptides that carry a negative net charge were not transported. This was also true for single amino acids and tripeptides, which MFSD1 failed to transport. Our results identify MFSD1 as a highly selective lysosomal lysine/arginine/histidine-containing dipeptide exporter, which functions as a uniporter.

Dilated cardiomyopathy (DCM) is a leading cause of heart failure, sudden cardiac death, and heart transplantation in young patients. The causes of DCM are varied and include genetic factors and metabolic, infectious, toxic and others factors. Today it is known that germline mutations in more than 98 genes can be associated with the occurrence of DCM. However, the penetrance of these genes often depends on a combination of factors, including modifiable ones, i.e. those that change under the influence of the environment. About 20–25% of genetically determined forms of DCM are due to mutations in the titin gene (TTN). Titin is the largest protein in the body, which is an important component of the sarcomer. Although titin is the largest protein in the human body, its role in the physiology of heart and disease is not yet fully understood. However, a mutation in the TTN gene may later represent a potential therapeutic target for genetic and acquired cardiomyopathy. Thus, the analysis of clinical cases of cardiomyopathy in patients with identified mutations in the TTN gene is of great scientific interest. The article presents a clinical case of manifestation of DCM in patient with a revealed pathogenic variant of mutation in the gene TTN and reverse left ventricular remodeling of the against the background of optimal therapy of heart failure in a subsequent outpatient observation.

Aim. To analyze the experience of Chazov National Medical Research Center of Cardiology in patient selection for left ventricular assist device (LVAD) implantation. Materials and methods. 901 patients, whose documents were sent to Chazov National Medical Research Center of Cardiology from regional medical and prophylactic institutions, were screened as selection for LVAD implantation. Firstly, all patients underwent transthoracic echocardiography performed according to the extended protocol with a comprehensive assessment of the left and right ventricle size and function. Patients who underwent the screening procedure underwent further examination including both laboratory and instrumental diagnostic methods. In addition, the polyclinic database of patients diagnosed with chronic heart failure (CHF) and dilated cardiomyopathy was also analyzed. Results. Among 901 screened patients 7.9% were suitable candidates for LVAD implantation and only 23 (2.6%) patients underwent surgery. Among those not eligible for surgery: 208 (29%) patients were not on optimal medical therapy, 15% of patients had indications for other surgical treatment of CHF, 12% of patients had severe right ventricular failure, 9.8% had severe comorbidities, 6.8% of patients refused surgery. Conclusions. The main problems of selection for LVAD implantation were: low awareness of doctors about the introduction of new treatment methods, poor quality of transthoracic echocardiography, a large percentage of patients not receiving basic therapy for CHF, untimely referral of patients for other types of surgical treatment.

Aim. To evaluate the impact of a decrease in glomerular filtration rate (GFR) on the prognosis of patients with chronic heart failure (CHF), to analyze real clinical practice regarding the frequency of prescribing pathogenetic therapy for CHF, achieving target dosages depending on the gradation of GFR in patients included in the CHF Register of the Tyumen region. Materials and methods. The analysis included medical data of 4077 patients (1662 men and 2415 women) with NYHA class I–IV CHF who underwent examination and treatment in medical organizations of the Tyumen region for the period from January 2020 to May 2023. Criteria for inclusion in the register: proven heart failure. Chronic kidney disease (CKD) was assessed by GFR calculated using the CKD-EPI formula (ml/min/1.73 m2). The primary end point was defined as death from all causes. Results. GFR60 ml/min/1.73 m2 was recorded in 34.6% of patients, more common in women (40.2 and 26.6%, respectively; p0.001). When dividing patients into phenotypes according to LVEF, no statistically significant differences were found in the distribution of patients according to GFR. In patients with HFrEF and HFpEF GFR45 ml/min/1.73 m2 was associated with an increased risk of meeting the endpoint. Analysis of prescribed pathogenetic therapy showed that in patients with HFrEF, the frequency of prescription of ACE inhibitors, â-blockers and MRA decreased (p=0.023, 006 and 0.01, respectively), and ARNI, on the contrary, increased with a decrease in GFR (p=0.026). In patients with HFpEF, a similar trend towards a decrease in the frequency of prescription of ACEIs and MCBs with a decrease in GFR (p0.001) remained, but it was compensated by an inversely proportional increase in the frequency of prescription of ARBs (p0.001). 100% of the target dosage is achieved in more than 90% of patients taking MRA across the entire LVEF range. While for â-blockers and ARNI/ACE/ARB the percentage of patients receiving the full therapeutic dosage of drugs is significantly lower. When analyzing target dosages of pathogenetic drugs, gradations of achieved doses were distributed evenly throughout the entire range of GFR. Conclusion. GFR60 ml/min/1.73 m2 occurs in every 3 patients with CHF across the entire range of LVEF. A decrease in GFR worsens the prognosis of patients with both HFrEF and HFpEF, increasing in direct proportion with the severity of the stage of CKD. Inclusion of patients in the monitoring program within the framework of the CHF service allows the treatment to be significantly brought closer to optimal drug therapy, at the same time, certain efforts are required to overcome difficulties with titration to target dosages.

Aim. To evaluate the contribution of arterial hypertension (AH), high lowdensity lipoprotein cholesterol (LDL-C) level and their combination to the development of (myocardial infarction) MI and stroke.Material and methods. The analysis is based on data from 1 and 2 observations of ESSE-RF study (Epidemiology of cardiovascular diseases in various regions of the Russian Federation)". A multi-s tage cluster random sample was used, formed according to the territorial principle on the basis of medical and preventive institutions (health facilities). Socio-demographic data (gender, age, education, wealth), smoking status and medical history were determined. Blood pressure (BP) was measured twice, on the right arm, in a sitting position with an automatic blood pressure monitor. Blood samples and its derivatives (serum and plasma) were stored at a temperature of -70ºC. LDL-C value was also included into analysis (LDl- C ≥3 mmol/l). Prospective monitoring of new cases was carried out in the initial sample without patients with coronary artery disease, MI, and stroke. The median follow-up time is 7.5 years. The sample size was 19 794. 356 non-fatal cases were identified, including 222 cases of MI and 174 cases of stroke.Results. The average age was 44.7 years, in men — 43.2, and in women — 45.3. The prevalence of isolated forms of hypertension, high LDL-C level and its combination were 12.7%, 30.3% and 32%, respectively. It was revealed that the age was the lowest in healthy and those with an increased LDL-C, whereas those with hypertension and combined conditions were older. The risk of nonfatal cases of MI and stroke in the Cox models, was adjusted for gender, age and region. There was a significantly higher risk of new cases of nonfatal CVD in individuals with isolated hypertension compared with those with isolated LDL-C.Conclusion. The frequency of isolated AH and isolated LDL-C were 13% and 30%, respectively. The combined condition was detected in 30%. The presence of AH, isolated LDL-C and their combinations in the sample doubled the risk of new CVD events.

The serotonin transporter (SERT) removes synaptic serotonin and is the target of anti-depressant drugs. SERT adopts three conformations: outward-open, occluded, and inward-open. All known inhibitors target the outward-open state except ibogaine, which has unusual anti-depressant and substance-withdrawal effects, and stabilizes the inward-open conformation. Unfortunately, ibogaine's promiscuity and cardiotoxicity limit the understanding of inward-open state ligands. We docked over 200 million small molecules against the inward-open state of the SERT. Thirty-six top-ranking compounds were synthesized, and thirteen inhibited; further structure-based optimization led to the selection of two potent (low nanomolar) inhibitors. These stabilized an outward-closed state of the SERT with little activity against common off-targets. A cryo-EM structure of one of these bound to the SERT confirmed the predicted geometry. In mouse behavioral assays, both compounds had anxiolytic- and anti-depressant-like activity, with potencies up to 200-fold better than fluoxetine (Prozac), and one substantially reversed morphine withdrawal effects.

Despite the global trend towards a decrease in the prevalence of abdominal aortic aneurysm (AAA), this disease remains one of the sudden death causes in the elderly. This necessitates the need to conduct screening studies, the effectiveness and feasibility of which has been proven in large studies, including population-based ones, and meta-analyses. The traditional and most optimal screening method is ultrasound examination. According to the guidelines of different countries, the indications for abdominal aorta ultrasound vary. Today in Russia there is no accurate data on the prevalence of AAA, while the target group for screening has not been defined, and therefore the country needs to conduct large population studies to study its prevalence and risk factors, as well as to calculate indicators of the clinical and economic effectiveness of implementation AAA screening programs.

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IntroductionTo identify predictors of excessive daytime sleepiness we analyzed data from the ‘Epidemiology of cardiovascular diseases in regions of Russia (ESSE-RF)’ study.MethodsData from participants of the cohort study ESSE-RF (2012–2013), aged 25–64 years, from 13 regions of Russia were analyzed (2012–2013). The participants were interviewed regarding their sleep complaints, including difficulties with initiating and maintaining sleep, sleepiness, and use of sleeping pills. Sleepiness was considered significant if it occurred at least three times a week. The examination encompassed social, demographic, and anthropometric measures, lifestyle factors, self-reported diseases, and laboratory parameters. The final analysis included 13,255 respondents.ResultsFrequent (≥3 times/week) sleepiness was reported by 5,8%, and occasional sleepiness (1–2 times/week) by 10.8% of respondents. Multivariate regression analysis identified significant predictors of frequent sleepiness. Sleep complaints (insomnia, sleep apnea, snoring) and frequent use of sleep medication were prominent factors. Additionally, age, female gender, higher education, and retirement status were associated with sleepiness. Beyond demographics and sleep, the analysis revealed predictors: abnormal anxiety levels, low high-density lipoprotein, high salt intake and following medical conditions: arrhythmia, hypertension, myocardial infarction, other heart diseases, and renal disease.ConclusionThis study identified a significant prevalence of EDS in Russians, aligning with global trends. However, findings suggest potential regional variations. Analysis revealed a complex interplay of factors contributing to EDS, highlighting the importance of individualized treatment approaches for improved sleep health.

Aim. To evaluate the features of diagnosis of amyloid cardiomyopathy (ACMP), differential diagnosis of different types of amyloidosis and its clinical manifestations. Materials and methods. Were analyzed 150 cases of patients who consulted at the Expert Center for Amyloidosis with suspicion of the presence of ACMP. 63 patients were diagnosed with ACMP: 25 (39.7%) – women, 38 (60.3%) – men, with an average age of 64.1±1.5. 36 (57.1%) patients had AL-amyloidosis (immunoglobulin amyloid light-chain amyloidosis), 25 (39.7%) – ATTR-amyloidosis (transthyretin amyloidosis), 2 (3.2%) – AA-amyloidosis with heart failure (reactive systemic amyloidosis caused by hypersecretion of á-globulin). The analysis of clinical manifestations depending on the type of amyloidosis, data of laboratory and instrumental methods of diagnosis is carried out. Results. In most cases, 53 (84.1%) patients, amyloidosis manifested as signs of heart failure. Among cardiac manifestations, shortness of breath (95.2%), general weakness (93.7%), lower limb edema (76.2%) were the most common. To confirm the diagnosis, despite the high accuracy of the speckle-tracking echocardiography and magnetic resonance imaging of the heart with gadolinium, in rare cases a biopsy is required (e.g. there is a combination of clinical signs of several types of amyloidosis). Biopsy of the affected organ was performed in 31 (49.2%) patients. The strategy for further pathogenetic treatment depends on the determination of the type of amyloidosis. Free light chains of immunoglobulins were detected in 57.1% of cases, which allowed diagnosis of AL-amyloidosis. In 17 (38.6%) patients myocardial scintigraphy with 99mTc-pyrophosphate showed signs of ATTR-amyloidosis, which with a negative result of immunochemical studies allows non-invasive diagnosis of it. Conclusion. ACMP is a disease with an extremely adverse prognosis. Raising the awareness of specialists about ACMP is an important goal. With timely diagnosis, pathogenetic therapy can be started early, which will improve the quality of life and prognosis of patients with ACMP.

Aim. To study the inhospital outcomes of implantation of a centrifugal left ventricular assist device (LVAD) in patients with end-stage heart failure (HF).Material and methods. There were following inclusion criteria: estimated body surface area >1,2 m2, end-stage HF, LV ejection fraction

Unstable angina (UA) is a type of acute coronary syndrome (ACS) without ischemic myocardial damage. The main criterion for the diagnosis of UA in ACS is the absence of changes in the concentration of cardiac troponin in the patient’s blood. When the volume of myocardial damage is small, it may be difficult to detect myocardial infarction in a patient using low-sensitivity tests for determining of cardiac troponin in the blood. This issue may lead to overdiagnosis of UA in patients with non-STE ACS. Optimal drug therapy and revascularization of the coronary arteries significantly reduce the risk of death and the development of myocardial infarction both in the hospital and in the long-term period in patients with UA. Outpatient follow-up and provision of free of charge medications to patients may reduce long-term mortality after an episode of UA.

Ways for reducing mortality from cardiovascular diseases The article analyzes the possible ways to further reduce cardiovascular disease mortality in the Russian Federation by eliminating shortcomings and pitfalls, introducing known but not used opportunities, and new organizational and medical technologies based on the accumulated experience of "best practice".

The annual mortality of patients with clinically pronounced symptoms of chronic heart failure in the Russian Federation reaches 2629%, i.e., from 880 to 986 thousand patients with heart failure die in the country in one year, which is comparable to the population of a large city. Providing care for patients with heart failure places a heavy burden on the country's health care system, making a significant contribution to mortality rates, hospitalization rates, including readmissions, which in turn requires considerable costs. The article presents an overview of registry studies that are devoted to assessing the effectiveness of diagnostics, the completeness of examinations, as well as the adequacy of ongoing drug treatment.

Background. Comorbidity in patients with chronic heart failure (CHF) makes a major impact to the course of both the underlying and concomitant diseases, significantly worsens the prognosis and increases mortality from cardiovascular diseases. Improving specialized treatment within the framework of a three-tier model of providing medical care to patients with CHF is a healthcare priority. Aim. Analysis of the frequency of comorbid conditions in patients with CHF included in the CHF registry in the Tyumen region. Materials and methods. The study was conducted using the CHF register method, which has been operating in the Tyumen region since January 2020. Medical data from outpatient cards and discharge reports were entered by doctors from 9 polyclinics with an attached population, 1 consultative polyclinic, hospitals, on the basis of which there are outpatient CHF rooms in the structure of polyclinics in the city of Tobolsk, Zavodoukovsk, with. Nizhnyaya Tavda, Yalutorovsk, Tyumen Region, Ural Federal District. The study included medical data of 5741 patients with CHF I–IV functional classes (FC). Gender, clinical-instrumental and laboratory data, non-cardiac and cardiac diseases according to the International Classification of Diseases of the 10th revision were entered into a single map of the CHF registry. Results. In the study sample of patients with CHF, whose average age was 70.0±9.7 years, 2331 (40.6%) were men and 3410 (59.4%) were women. The most common cardiovascular diseases were: coronary artery disease – 55.4%, HD – 22.5% and HRT – 13.5% of cases. Among concomitant diseases of non-cardiac reasons, diabetes mellitus was most often noted – in 31.5% of cases, chronic kidney disease – in 31.1% and chronic obstructive pulmonary disease – in 10% of cases. Concomitant diseases were more common in patients with CHF of functional classes III–IV. Conclusion. Maintaining a register of CHF and analyzing register data makes it possible to assess the required volume of medical care, plan the necessary time, material, economic and organizational resources and take into account possible difficulties in diagnosis, treatment and outpatient monitoring.

Aim. To study the role of blood biomarkers in predicting death from cardiovascular events in patients with heart failure with reduced ejection fraction (HFrEF) within one year after cardioverter defibrillator (ICD) implantation.Material and methods. This one-center observation study included 384 HFrEF patients (men, 84%, NYHA class III – 74%, NYHA class IV – 7%), who underwent prospective observation for 1 year after ICD implantation. The study of the original panel of modern biomarkers (blood electrolytes, C-reactive protein, creatinine, soluble growth stimulation expressed gene 2 (sST2), N-terminal pro-brain natriuretic peptide (NT-proBNP), galectin-3), allowing to evaluate HF pathogenesis was conducted. Based on the blood creatinine concentration, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula was used to estimate the glomerular filtration rate (GFR).Results. In a one-year observation, the primary endpoint was recorded in 35 patients (11%). Single-factor logistic regression showed 3 biomarkers with the greatest predictive potential (p2000 pg/ml.Conclusion. The study of blood biomarkers is promising and in demand for the prediction of adverse outcomes of HF. According to the data obtained, the factors «GFR 2000 pg/ml» may be relevant for one-year mortality prediction.

Intraventricular septum rupture is a rare mechanic complication of myocardial infarction associated with high mortality. This case describes STEMI in recovered patient after COVID 19 associated pneumonia, which was complicated by ventricular septum rupture followed by cardiogenic shock. It was managed by percutaneous occluder implantation. The procedure was complicated by right ventricular wall rupture. Postmortem examination of myocardium showed the signs of inflammation infiltrate and myocyte necrosis, according to histopathological Dallas criteria diagnosis of COVID-19 associated myocarditis was established. The COVID-19 pandemic has contributed to increasing cardiovascular mortality. This is typically attributed to diminishing resources for timely and appropriate medical care, and patients late presentations for fear of contracting the infection. Cardiovascular complication of COVID-19 may be another contributing factor. Further research is needed to improve our understanding of the mechanisms and long-term sequelae of myocardium damage in COVID-19, to optimize treatment strategy and subsequent follow-up in such patients.

Aim. To characterize patients with acute non-ST elevation myocardial infarction (NSTEMI) hospitalized in Russian hospitals, study their anamnestic, demographic and clinical characteristics, treatment features and hospital outcomes, as well as compare data from previous Russian and foreign registries of acute coronary syndrome.Material and methods. Russian Registry of Acute Myocardial Infarction (REGION-IM) is a multicenter prospective observational study. The case report form contains demographic and anamnestic data, as well as the following information about the present MI: timing of symptom onset, first contact with medical personnel and admission to the hospital; data from coronary angiography (CAG) and percutaneous coronary intervention (PCI), therapy, hospitalization outcomes.Results. In total, for the period from November 1, 2020 to June 30, 2023, the study included 3253 patients with STEMI from 73 hospitals (30 vascular surgery departments, 17 of which are equipped with angiographic system, and 43 regional vascular surgery centers) from 45 constituent entities of the Russian Federation. There were 55% of high-risk patients. CAG was performed in 83,73% of patients. In 81%, CAG was performed ≤24 hours from hospitalization. PCI was performed in 62% of patients with NSTEMI. Median onset-to-balloon time was 27 hours [10;77]. The median door-to-balloon time was 5 hours [1;20]. Inhospital mortality was 3%. In the group with CAG, compared with the group without CAG, inhospital mortality was lower (2% and 6%, respectively; p

In modern Russia, the initiative budgeting mechanism has been developing systematically since 2015. The practice has been launched in 51 out of 85 constituent entities of the Russian Federation. This phenomenon is an urgent topic for research, in connection with its priority for the state as one of the important directions for the openness of the budget system development and degree of citizens’ satisfaction with the results of the budget policy improvement. The purpose of this study is to analyze the possibilities of the initiative budgeting practice development in the mobilization economy, which, apparently, for a certain time will become the main model of economic development in Russia. Such general scientific methods of research as comparison, analysis, statistics, and induction were used in the article. The study concludes that the initiative budgeting should be developed in the current state of the Russian economy as the social and managerial positive effects exceed the possible costs of the suspension of the practice.

Sequence variants in gene regulatory regions alter gene expression and contribute to phenotypes of individual cells and the whole organism, including disease susceptibility and progression. Single-nucleotide variants in enhancers or promoters may affect gene transcription by altering transcription factor binding sites. Differential transcription factor binding in heterozygous genomic loci provides a natural source of information on such regulatory variants. We present a novel approach to call the allele-specific transcription factor binding events at single-nucleotide variants in ChIP-Seq data, taking into account the joint contribution of aneuploidy and local copy number variation, that is estimated directly from variant calls. We have conducted a meta-analysis of more than 7 thousand ChIP-Seq experiments and assembled the database of allele-specific binding events listing more than half a million entries at nearly 270 thousand single-nucleotide polymorphisms for several hundred human transcription factors and cell types. These polymorphisms are enriched for associations with phenotypes of medical relevance and often overlap eQTLs, making candidates for causality by linking variants with molecular mechanisms. Specifically, there is a special class of switching sites, where different transcription factors preferably bind alternative alleles, thus revealing allele-specific rewiring of molecular circuitry.

Aim. To evaluate the information content of genetic risk scores (GRSs) for coronary artery disease (CAD), previously developed on European populations, in representatives of the Russian population.Material and methods. The work involved 1685 people from the ESSE-Ivanovo epidemiological study. CAD was verified in 3,1% of individuals. The coronary composite endpoint was assessed annually during 8-year follow-up. Next generation sequencing was performed using a targeted panel. Logistic regression analysis and area under the ROC curve (AUC) were used. Age, sex, and smoking status were taken into account in the multivariate model.Results. Of the 16 GRSs included in the analysis, only 2 GRSs demonstrated significance in the univariate analysis of association with CAD (highest AUC — 0,577). In a multivariate model, with an increase by 1 standard deviation (SD) for the 6 studied GRSs, a significant association with CAD was obtained — the odds ratio varied in the range of 1,31-1,47. The two GRSs demonstrated significant differences in the incidence of CAD between the groups corresponding to the upper and lower quintiles. Forty-five endpoints were registered. The risk ratio for the end point with an increase in GRS by 1 SD, taking into account cofactors, exceeded statistical significance for the 9 analyzed GRS and was in the range of 1,36-1,54.Conclusion. For the first time in Russia, 16 CAD GRSs, previously developed on European samples, was validated. The results were reproduced only for a few of the studied CAD SGRs.