BACKGROUND:TMEM43 (transmembrane protein 43) is a ubiquitously expressed 4-transmembrane-protein localized in the endoplasmic reticulum and nuclear lamina. The missense mutation TMEM43-p.S358L causes fully penetrant ARVC5 (arrhythmogenic right ventricular cardiomyopathy type 5) especially in males. The TMEM43 function of the protein and the pathomechanisms of TMEM43-p.S358L remain poorly understood. We analyzed carrier-derived human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), human myocardial tissue from TMEM43-wild-type, and TMEM43-p.S358L and identified differentially interacting proteins. Here we provide evidence for a novel pathomechanism contributing to the onset of ARVC5. METHODS:Microsomes of human wild-type myocardium were separated by sucrose-gradient ultracentrifugation and characterized by mass-spectrometry to identify potential interacting proteins. Proteome and metabolome analyses of a TMEM43-p.S358L explanted human myocardium were performed. hiPSC-derived cardiomyocytes of TMEM43-p.S358L carrier and a corresponding isogenic control were generated. A 3'-end HA-Tag was introduced in TMEM43 for pull-down experiments under optimized conditions. Lipidomics, proteomics, contractility, and ATP-content were measured in hiPSC-CMs. RESULTS:Pull-down analyses of TMEM43-WT and mutant showed altered interacting proteins involved in metabolic pathways. Lipidomics revealed the accumulation of lipids and decreased lipid metabolism capacity in mutant hiPSC-CMs. The ATP to ADP ratio was lower in mutant hiPSC-CMs and could be associated with diminished contraction frequency. The human TMEM43-p.S358L myocardial proteome revealed altered protein-expression of metabolic pathways comparable to mutant hiPSC-CMs. Metabolic remodeling was also found in the mutant human myocardium. Ultracentrifugation fraction with the highest protein amount of TMEM43 and pull-down experiments of hiPSC-CMs revealed differentially interacting proteins of TMEM43-p.S358L from endoplasmic reticulum and mitochondrial membranes. CONCLUSIONS:We suggest differential interaction of mutant TMEM43 with proteins of mitochondria and endoplasmic reticulum influences endoplasmic reticulum-mitochondrial contact sites. TMEM43-p.S358L primarily contributes to changes in mitochondrial function affecting lipid homeostasis and energy supply.

Changes in the vascular system associated with aging contribute to conditions such as hypertension and atherosclerosis. In this study, we explored the prevalence and survival effects of vascular aging phenotypes in a Russian population, a group with a very high cardiovascular risk according to the SCORE2 scale. A cohort of 618 participants from three metro areas underwent carotid-femoral pulse wave velocity (cfPWV) assessment between 2012 and 2018, with biannual follow-ups to record cardiovascular events and mortality. We compared our data with findings from previously published European cohorts to evaluate methods for classifying vascular aging phenotypes. Our findings indicate that definitions designed for low- and medium-risk populations are of limited use in high-risk groups. Moreover, the association between elevated cfPWV and increased overall mortality suggests a potential selection pressure on vascular aging phenotypes. These insights advance the development of predictive biomarkers for cardiovascular risk in populations with high rates of cardiovascular disease.

Idiopathic recurrent pericarditis (IRP) is a rare autoinflammatory disorder characterized by NLRP3 inflammasome overactivation, resulting in excessive IL-1β and IL-1α production. Although IL-1 blockade shows promise as a therapeutic strategy, the underlying molecular mechanisms remain incompletely understood. We investigated the effect of goflikicept, a novel heterodimeric fusion protein that inhibits both IL-1β and IL-1α, on peripheral blood mononuclear cell (PBMC) transcriptomes from patients with IRP. Single-cell RNA sequencing was used to analyze PBMC subsets and identify treatment response-related transcriptomic signatures. Goflikicept induced temporal transcriptional reprogramming, with a particularly pronounced downregulation of IL-1-related inflammatory pathways in classical monocytes by day 35 of treatment. Furthermore, goflikicept modulated the adaptive immune response, suppressing naïve B cell activity, enhancing circulating plasma cell precursor activity, and significantly altering γδ T cell and mucosal-associated invariant T cell populations. In conclusion, goflikicept effectively normalized dysregulated immune responses in IRP, suggesting a novel therapeutic approach for NLRP3-mediated diseases. This study provides the first single-cell resolution insights into the molecular mechanisms of IL-1 blockade, informing the development of targeted therapies for autoinflammatory conditions.

With many amyloidosis-associated missense mutations still unidentified and early diagnostic methods largely unavailable, there is an urgent need for a reliable computational approach to predict hereditary amyloidoses from gene sequencing data. Progress has been made in predicting amyloidosis-triggering sequences within intrinsically disordered regions. However, some diseases are caused by mutations in amyloidogenic regions within structured domains that must unfold for amyloid formation. Accurate prediction of amyloidogenic regions requires tools for detecting amyloidogenicity and assessing mutation effects on protein stability. We developed datasets of mutations linked to hereditary ATTR cardiomyopathy and others likely unrelated, evaluating TTR mutants with amyloidogenicity and stability predictors. Notably, the stability predictors consistently indicated that ATTR-related mutations tend to destabilize the TTR structure more than non-ATTR-associated mutations. Using these datasets and newly generated mutation features, we developed a machine learning model SDAM-TTR to predict mutations leading to ATTR cardiomyopathy.

Introduction Calcific aortic valve disease (CAVD) is the third most common type of heart disease in developed countries, and no medical treatment is currently available. The Notch signaling pathway is among the molecular pathways implicated in CAVD pathogenesis and may represent a potential therapeutic target. However, its exact role remains incompletely understood. Objective The study evaluated Notch-dependent regulatory mechanisms of cross-talk between aortic valve endothelial cells and aortic valve interstitial cells in pathological osteogenic differentiation. Methods Primary human aortic valve endothelial and interstitial cells (VEC and VIC) were isolated from patients with CAVD and healthy donors. Notch was activated by lentiviral transduction with Notch1 intercellular domain (NICD). shRNA-mediated knockdown of RBPJ (DNA-binding protein for NICD interaction) was employed to inhibit Notch activity. Osteogenic differentiation was induced by cultivating the cells in osteogenic medium. Results This report shows that activating Notch in VEC when co-culturing them with VIC leads to an increase in osteogenic differentiation, while inhibiting Notch by small hairpin RNA to the RBPJ gene (shRBPJ) suppresses osteogenic differentiation. VEC from CAVD patients, have dysregulated Notch signaling and significantly enhance osteogenic differentiation when co-cultured with VIC. Conclusion Notch signaling pathway is dysregulated in VEC from patients with CAVD. This contributes to disruption of normal cross-talk between endothelial and interstitial cells in the valve and increases sensitivity to pro-osteogenic stimuli. The effect on Notch in VEC may be a powerful target for treatment of CAVD.

Singleton-Merten syndrome (SMS) is a rare genetic condition associated with abnormal calcification and skeletal anomalies. To explore the underlying mechanisms of this disorder, we generated induced pluripotent stem cells (iPSCs) from the blood cells of a patient with SMS. The iPSCs retain the genetic mutation linked to the syndrome, making them a relevant model for studying disease-specific processes. These cells display all key features of pluripotent stem cells, including the expression of characteristic markers, the ability to differentiate into cell types from all three germ layers, and stable growth during passaging. These iPSCs provide a valuable tool for investigating the processes involved in SMS, particularly those leading to abnormal calcification. They also offer a platform for testing potential therapeutic strategies aimed at addressing SMS-related complications. Future work will focus on directing these cells into specific cell types to better understand the pathways involved in the disease and identify possible treatment targets. This study highlights the potential of patient-derived iPSCs for advancing research into rare genetic disorders.

Introduction. Hypertrophic cardiomyopathy (HCM) is the most common form of cardiomyopathy (CMP). Myocardial hypertrophy in children is associated with a large heterogeneous group of diseases with a high representation of non-sarcomeric causes. Purpose. The study compares diagnostic information from targeted next-generation sequencing (NGS) panels with different gene sets for HCM in children. Materials and methods. A molecular genetic study was conducted using two targeted panels (172 and 39 genes), followed by an assessment of their effectiveness. Results. The study included 53 children with HCM, the median age of which was 10 ± 3.5; 14.0 years. 13 children were examined using a large cardiac panel containing 172 genes. The remaining 40 patients were examined using a targeted panel for HCM containing 39 genes, while in 10 cases (25.0 %) genetic diagnostics was uninformative. Pathogenic and likely pathogenic variants in various genes were detected in 35 (66.0 %) patients. The informativeness of genetic diagnostics in the group of children under one year old was 60.7 %, in the group with onset at the age of over one year — 69.2 %. Conclusion. It is advisable to use an extended cardio panel for NGS for the purpose of genetic diagnosis of HCM in patients with the onset of the disease in the first year of life and small target panels for HCM in patients with the onset at an older age.

BACKGROUND:In this case report, we aimed to raise awareness regarding arrhythmogenic cardiomyopathy (ACM) with inflammatory "hot phase" episodes in pediatric patients, which is often misdiagnosed as myocarditis. This condition, caused by aseptic intracellular inflammation, can be misdiagnosed as acute coronary syndrome or myocardial viral infection, with the latter being particularly common in children. Here, we report two pediatric cases of ACM with "hot phase" episodes and discuss the molecular mechanisms leading to aseptic myocardial inflammation due to desmosome and cytoskeletal damage. CASE SUMMARY:The first patient (aged 13 years) was hospitalized after experiencing a single episode of syncope, chest pain, and palpitation. Clinical examination revealed elevated troponin levels, complete right bundle branch block, right ventricular dilation, and normal coronary arteries. Cardiac magnetic resonance imaging (MRI) revealed extensive fibrotic changes in the right ventricle, which was consistent with ACM, and a pathogenic variant in DSG2 confirmed the diagnosis. The second patient (aged 4 years) presented with chest pain and elevated troponin levels. Electrocardiography revealed a left bundle branch block, while echocardiography showed reduced left ventricular contractility. Cardiac MRI demonstrated left ventricular dilation and subepicardial fibrosis. The phenotypic features, such as curly-wool hair, hyperkeratosis, and onychodystrophy, suggested a genetic nature of the disease. Two mutations identified in DSP confirmed the diagnosis of Carvajal syndrome with intermittent "hot phase" episodes. CONCLUSION:ACM in children can present with nonspecific inflammatory symptoms, which may be misdiagnosed as myocarditis or coronary artery pathology.

The pathogenesis of NEC in term infants with critical congenital heart defects (CHD) is mainly associated with hypoxic-ischemic events that initiate an exaggerated systemic inflammatory response. Herein, we investigated the cumulative impact of the cytokine landscape and gut microbiota on the pathobiology leading to NEC onset in term newborns with CHD. This study involved 36 newborns who underwent surgical correction of CHD during the first two weeks of life; eight of them developed NEC within one week after cardiac surgery. Blood and fecal samples were collected at two time points: before and after surgery. Newborns without NEC exhibited significant changes in the levels of 22 cytokines, whereas newborns with NEC had changes in only 4 cytokines during the perioperative period. A panel including IL-1RA, IL-5, IL-18, and MCP-1 showed impressive test performance characteristics for diagnosing NEC at the preclinical stage with an AUC of 0.938, a sensitivity of 100.0%, and a specificity of 85.7%. Fifteen bacterial taxa were differentially abundant between feces samples of newborn groups. The pathobionts Collinsella and Mediterraneibacter gnavus group, known to be associated with increased intestinal permeability, were enriched in NEC newborns’ feces before cardiac surgery. Our study demonstrated that the gut microbiota mediates the equilibrium of cytokine network dynamics under a broad spectrum of “friend or foe” conditions, effectively suppressing excessive inflammatory responses during early postnatal adaptation. In contrast, under conditions of low microbial diversity, a strong imbalanced cytokine feedback loop formed, resulting in deviations from normal immune response maturation. These findings offer new insights into understanding the fine-tuning of gut microbiota-immune system interactions in the first days of life.

BACKGROUND:Hypertrophic cardiomyopathy (HCM) presents a wide range of clinical scenarios depending on the age of manifestation, with a less favorable prognosis in children. The genetic spectrum and clinical causes of HCM diagnosed before one year of age is rarely reported. METHODS:We analyzed the genetic causes and genotype-phenotype correlations in 68 children diagnosed with HCM during the first year of life. Genetic analysis was performed using targeted gene sequencing (39 HCM-related genes), followed by whole-exome sequencing for genotype-negative cases. The genetic data were correlated with clinical characteristics, disease progression, and prognosis. RESULTS:The overall genotype-positive rate was 81%, with an equal proportion of sarcomeric (29%) and RAS-related genetic cases (29%). Gestational diabetes in mothers was more frequently observed in children with variants in Z-disc-related genes. Overall, one year-survival rate from all causes was 91.2%, with the best survival outcomes associated with sarcomeric and Z-disk-related gene variants. CONCLUSION:HCM manifesting in children before one year of age showed an approximately equal proportion of sarcomeric and RAS cascade-related cases. A more favorable prognosis was associated with sarcomeric mutations; whereas metabolic gene-related HCM cases were characterized by the highest one-and five-year mortality due to heart failure. IMPACT:We analyzed the genetic causes and genotype-phenotype correlations in 68 children diagnosed with HCM during the first year of life. Patients with sarcomeric mutations demonstrated a more favorable prognosis, whereas metabolic gene-related HCM cases were the highest one- and five-year mortality rates due to HF. We identified several factors associated with unfavorable outcomes, including LV thickness, HF class, elevated troponin, increased NT-proBNP levels, and RV hypertrophy. We proposed several new and previously unreported genes, such as ROBO4 and KMT2D, as potentially causative for infantile HCM. The true role of these genes in this disease requires confirmation.

Hypertrophic cardiomyopathy (HCM) progressing to end-stage heart failure and heart transplantation (HT) is a rare clinical scenario with an insufficiently explored genetic background. In this single-center retrospective cohort study, we aimed to characterize the genetic spectrum, variants of HCM adverse remodeling, and aspects of molecular pathogenesis of this subgroup. The study included 14 patients (9 females), among whom 10 developed a dilated/hypokinetic phenotype and 4 a restrictive phenotype. In 13 patients (93%), at least one pathogenic or likely pathogenic genetic variant was identified. Dilated remodeling/hypokinesis was associated with loss-of-function variants in LAMP2 (3) in females, ALPK3homo (1), MYH7 (1), MYBPC3 (1), a heterozygous missense variant in TRIM63 (1), FLNCtv (1), TTNtv (2). For the latter two, electrophoretic analysis of titin isoform composition and protein content in myocardial fragments from explanted hearts confirmed the functional significance of TTN gene variants. The restrictive phenotype in the adult group was associated with carriage of multiple pathogenic sarcomere gene variants: MYL3homo (1), MYBPC3+TPM1 (1), an MYH7 converter domain variant (1), and, in one child, with a TNNT2 variant. This findings support HCM progressing to HT is characterized by a higher frequency of variants in non-sarcomeric genes and Danon disease compared to the general HCM cohort.

Several mutations of the uppermost arginine, R219, in the voltage-sensing sliding helix S4I of cardiac sodium channel Nav1.5 are reported in the ClinVar databases, but the clinical significance of the respective variants is unknown (VUSs). AlphaFold 3 models predicted a significant downshift of S4I in the R219C VUS. Analogous downshift S4I, upon its in silico deactivation, resulted in a salt bridge between R219 and the uppermost glutamate, E161, in helix S2I. To understand how salt bridge elimination affects biophysical characteristics, we generated mutant channel R219E, expressed it in the HEK293-T cells, and employed the patch-clamp method in a whole-cell configuration. Mutation R219E did not change the peak current density but shortened time to the peak current at several potentials, significantly enhanced activation, enhanced steady-state inactivation and steady-state fast inactivation, and slowed recovery from inactivation. Taken together, these data suggest that mutation R219E destabilized the resting state of Nav1.5. Cardiac syndromes associated with mutations R219P/H/C/P or E161Q/K are consistent with the observed changes of biophysical characteristics of mutant channel R219E suggesting pathogenicity of the respective VUSs, as well as ClinVar-reported VUSs involving arginine or glutamate in homologous positions of several Nav1.5 paralogs.

Aim . To investigate clinical manifestations, phenotypic variants, genetic features, and outcomes in children with arrhythmogenic cardiomyopathy (ACM). Methods . The study group consisted of 24 patients (< 18 years of age) with ACM, who were under observation from 2011 to 2024. The median age at ACM diagnosis was 13 years [12-15]. The following data were analyzed: complaints and medical history, laboratory parameters (biochemical markers of inflammation and serum myocardial damage mar­ kers, NT-proBNP levels), electrocardiogram, Holter monitoring, echocardiography results, cardiac magnetic resonance imaging, selective coronary angiography, histological and molecular genetic studies. The median follow-up duration for ACM patients was 27 months [16.5-38]. Results . All patients were unrelated probands. All children presented with asymptomatic ventricular arrhythmias (VA) as the initial manifestation of the disease, 23 (95.8%) patients had complaints: palpitations in 21 (87.5%) children, syncope in 14 (58.3%) children, heart failure symptoms in 12 (50.0%), and isolated chest pain in 4 (16.7%) patients. 5 (20.8%) children had a “hot” phase. Analysis of arrhythmic data revealed several features of ACM in childhood: VAs were polymorphic, daily VA density was less than 20% at the time of diagnosis, presence of late ventricular potentials in most patients, and several criteria from the «repolarization abnormalities» group had low informativeness. During follow-up, 9 (37.5%) children had the right-dominant ACM, 7 (29.9%) had ACM with left ventricle involvement, and 8 (33.3%) had biventricular form. Desmosomal mutations were found in 16 children (66.7%), non-desmosomal gene variants in 8 patients (33.3%). Conclusion . It has been shown that ACM can manifest at an early age and is associated with the development of arrhythmic events and/or severe heart failure. Increasing awareness among physicians about the early onset of ACM is crucial for timely treatment of heart failure, prevention of sudden cardiac death, and family screening.

Aim: to study the clinical characteristics and genetic spectrum of children with arrhythmogenic cardiomyopathy (ACM) who have undergone heart transplantation (HT) or are currently on the heart transplantation waiting list (HTWL) Materials and Methods: this study included 5 pediatric patients with 3 female patients (60%) diagnosed with ACM who had either undergone HT or were on the HTWL. The mean age of the cohort was 16 [7,5; 16]. Comprehensive assessments were performed for all participants, including evaluation of clinical complaints (palpitations, syncope, symptoms of heart failure (HF)), family history, electrocardiography (ECG), ambulatory ECG monitoring (AECGM), echocardiography, cardiac magnetic resonance imaging (MRI), and endomyocardial biopsy (EMB) of the right cardiac chambers with PCR analysis. Molecular genetic testing was also conducted. Patients were stratified according to the 2010 Task Force criteria and Padua criteria for arrhythmogenic cardiomyopathy diagnosis Results: all participants were diagnosed with ACM. Of these, 4 (80%) presented with a biventricular phenotype, while 1 (20%) had a left ventricular (LV)-dominant phenotype. Pathological LV involvement was observed in all patients (100%). The mean left ventricular ejection fraction was 24,0 [22,0; 34,5]%. The average time to HF progression from disease onset was 3±1.6 years. Genetic testing revealed pathogenic mutations in desmosomal genes in 4 patients (80%), while 1 patient (20%) carried non-desmosomal mutations. Additionally, compound mutations were identified in 3 patients (60%), a digenic mutation in non-desmosomal genes in 1 patient (20%), and a frameshift mutation in 1 patient (20%). Conclusion: this study highlights the clinical and genetic patterns of ACM in pediatric patients who have undergone HT or are on HTWL It underscores the importance of molecular genetic testing, not only as a diagnostic tool for ACM but also as a means of identifying patients at higher risk for adverse disease outcomes. KEYWORDS: arrhythmogenic cardiomyopathy, children, heart transplantation, heart failure. FOR CITATION: Alekseeva D.Yu., Kofeinikova O.A., Kostareva A.A., Vershinina T.L., Kovalchuk T.S., Fedotov P.A., Pervunina T.M., Peregudina O.L., Sitnikova M.Y., Simonenko M.A., Vasichkina E.S. Сlinical and genetic patterns of arrhythmogenic cardiomyopathy in children after heart transplant or on the heart transplant waiting list. Russian Journal of Woman and Child Health. 2025;8(1):56–62 (in Russ.). DOI: 10.32364/2618-8430-2025-8-1-9

Myocardial diseases take a significant place in the world of the modern science and practical medicine, which is confirmed by a large number of publications. Despite the fact that the problems of myocarditis and cardiomyopathies have been studied for many years, there are still gaps in the diagnosis and management of these conditions, especially in cases of their co-existence. The mechanisms of mutual influence of these nosologies are also insufficiently studied. In particular that clinical situation in young patients is a specific problem. Objective. To evaluate the features of the clinical course and outcome of genetically determined cardiomyopathies in association with myocarditis in children. Materials and methods. The study is retrospective. The case histories of 17 pediatric patients with severe cardiomyopathies with the development of terminal heart failure were analyzed. 8 (47.0%) patients (3 boys and 5 girls) had a combination of genetically determined cardiomyopathy and confirmed myocarditis. All patients underwent an assessment of their medical history, laboratory parameters and results of instrumental examination methods. Results. 7 (87.5%) patients out of 8 children with a combination of cardiomyopathy and myocarditis underwent orthotopic heart transplantation on average 7 years after the onset of the first symptoms of the disease. Of these, 2 (28.5%) children had auxiliary blood circulation systems installed as a “bridge to the heart transplantation” — LVAD in one case and ECMO with subsequent implantation of the Excor system in the other case. In one case, there was a fatal outcome (12.5%) due to the development of a refractory polymorphic ventricular tachycardia. Conclusion. This work demonstrates the need for additional vigilance and more active actions in relation to the management of patients with atypical, severe myocarditis, as well as in the case of rapid progression of genetically determined cardiomyopathy.

LMNA mutations causing classical familial partial lipodystrophy of Dunnigan type (FPLD2) usually affect residue R482. FPLD is a severe metabolic disorder that often leads to cardiovascular and skeletal muscle complications. How LMNA mutations affect the functional properties of skeletal muscles is still not well understood. In the present project, we investigated the LMNA-R482L mutation-specific alterations in a transgenic mouse C2C12 cell line of myoblasts. Using single-cell RNA sequencing we have studied transcriptional diversity of cultured in vitro C2C12 cells. The LMNA-R482L mutation induces changes in C2C12 cluster composition and increases the expression of genes related to connective tissue development, oxidative stress, stress defense, and autophagy in a population-specific manner. Bulk RNA-seq confirmed these results and revealed the dysregulation of carbohydrate metabolism in differentiated R482L myotubes that was supported by ATP production profile evaluation. The measurement of reactive oxygen species (ROS) levels and glutathione accumulation in myoblasts and myotubes indicates R482L mutation-related dysregulation in mechanisms that control ROS production and scavenging through antioxidant glutathione system. The increased accumulation of autophagy-related structures in R482L myoblasts was also shown. Overall, our experiments showed a connection between the redox status and metabolic alterations with skeletal muscle pathological phenotypes in cells bearing pathogenic LMNA mutation.

BACKGROUND:Primary ciliary dyskinesia (PCD) is a group of rare genetically heterogeneous disorders caused by defective cilia and flagella motility. The clinical phenotype of PCD patients commonly includes chronic oto-sino-pulmonary disease, infertility, and, in about half of cases, laterality defects due to randomization of left-right body asymmetry. To date, pathogenic variants in more than 50 genes responsible for motile cilia structure and assembly have been reported in such patients. While multiple population-specific mutations have been described in PCD cohorts from different countries, the data on genetic spectrum of PCD in Russian population are still extremely limited. RESULTS:The present study provides a comprehensive clinical and genetic characterization of 21 Russian families with PCD living in various country regions. Anomalies of ciliary beating in patients` respiratory epithelial cells were confirmed by high-speed video microscopy. In the most cases, custom-designed panel sequencing allowed to uncover causative variants in well-known or rarely mentioned PCD-related genes, including DNAH5, DNAH11, CFAP300, LRRC6, ZMYND10, CCDC103, HYDIN, ODAD4, DNAL1, and OFD1. The variations comprised common mutations, as well as novel genetic variants, some of which probably specific for Russian patients. Additional targeted analysis of mRNA transcripts from ciliated cells enabled us to specify functional effects of newly identified genetic variants in DNAH5 (c.2052+3G>T, c.3599-2A>G), HYDIN (c.10949-2A>G, c.1797C>G), and ZMYND10 (c.510+1G>C) on splicing process. In particular, the splice site variant c.2052+3G>T, detected in four unrelated families, resulted in skipping of exon 14 in DNAH5 transcripts and, according to haplotype analysis of affected probands, was proposed as an ancestral founder mutation in Udmurt population. CONCLUSIONS:The reported data provide a vital insight into genetic background of primary ciliary dyskinesia in the Russian population. The findings clearly illustrate the utility of gene panel sequencing coupled with transcriptional analysis in identification and clinical interpretation of novel genetic variants.

Tropical teleost fish Danio rerio is increasingly used as a model object for electrophysiological studies of human cardiac physiology and pathology. D. rerio is characterized by the similarity with humans in such functional parameters of the electrical activity of the heart as heart rate, action potential morphology, as well as in a set of ion currents depolarizing and repolarizing the cell membrane. D. rerio is easy to breed, easy to handle experimentally, and easy to genetically modify. This overview presents current data on the structural and functional organization of ion channels in D. rerio heart myocytes.

Cardiac contractility modulation (CCM) is based on electrical stimulation of the heart without alteration of action potential and mechanical activation, the data on its fundamental molecular mechanisms are limited. Here we demonstrate clinical and physiological effect of 12 months CCM in 29 patients along with transcriptomic molecular data. Based on the CCM effect the patients were divided into two groups: responders (n = 13) and non-responders (n = 16). RNA-seq data were collected for 6 patients before and after CCM including 3 responders and 3 non-responders. The overall effect of CCM on gene expression was mainly provided by samples from the responder group and included the upregulation of the genes involved in the maintenance of proteostasis and mitochondrial structure and function. Using pathway enrichment analysis, we found that baseline myocardial tissue samples from responder group were characterized by upregulation of mitochondrial matrix-related genes, Z disc-protein encoding genes and muscle contraction-related genes. In summary, twelve months of ССM led to changes in signaling pathways associated with cellular respiration, apoptosis, and autophagy. The pattern of myocardial remodeling after CCM is associated with initial expression level of myocardial contractile proteins, adaptation reserves associated with mitochondria and low expression level of inflammatory molecules.

Anderson–Fabry disease (AFD) results from decreased enzyme activity of lysosomal enzymes and intralysosomal storage of nonhydrolyzed forms. Cardiovascular complications, mainly in the form of HCM, contribute substantially to AFD patient mortality. Here, we report three new cases of obstructive HCM (HOCM) in nonclassical presentations of AFD and isolated cardiac involvement. In all three cases, the diagnosis of AFD was made postoperatively by routine genetic and morphological testing. Together with previously published cases, this report illustrates the potential safety and beneficial effect of septal surgical myectomy in patients with AFD-HOCM, as well as underlines the need for more thorough screening for clinical signs of AFD-associated cardiomyopathy and GLA variants among patients with HOCM.