Genetic landscape in Russian patients with familial left ventricular noncompaction.

Background: Left ventricular noncompaction (LVNC) cardiomyopathy is a disorder that can be complicated by heart failure, arrhythmias, thromboembolism, and sudden cardiac death. The aim of this study is to clarify the genetic landscape of LVNC in a large cohort of well-phenotyped Russian patients with LVNC, including 48 families (n=214). Methods: All index patients underwent clinical examination and genetic analysis, as well as family members who agreed to participate in the clinical study and/or in the genetic testing. The genetic testing included next generation sequencing and genetic classification according to ACMG guidelines. Results: A total of 55 alleles of 54 pathogenic and likely pathogenic variants in 24 genes were identified, with the largest number in the MYH7 and TTN genes. A significant proportion of variants -8 of 54 (14.8%) -have not been described earlier in other populations and may be specific to LVNC patients in Russia. In LVNC patients, the presence of each subsequent variant is associated with increased odds of having more severe LVNC subtypes than isolated LVNC with preserved ejection fraction. The corresponding odds ratio is 2.77 (1.37 -7.37; p <0.001) per variant after adjustment for sex, age, and family. Conclusion: Overall, the genetic analysis of LVNC patients, accompanied by cardiomyopathy-related family history analysis, resulted in a high diagnostic yield of 89.6%. These results suggest that genetic screening should be applied to the diagnosis and prognosis of LVNC patients.

The Association of PLAUR Genotype and Soluble suPAR Serum Level with COVID-19-Related Lung Damage Severity.

Uncovering the risk factors for acute respiratory disease coronavirus 2019 (COVID-19) severity may help to provide a valuable tool for early patient stratification and proper treatment implementation, improving the patient outcome and lowering the burden on the healthcare system. Here we report the results of a single-center retrospective cohort study on 151 severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-infected symptomatic hospitalized adult patients. We assessed the association of several blood test measurements, soluble urokinase receptor (uPAR) serum level and specific single nucleotide polymorphisms of ACE (I/D), NOS3 (rs2070744, rs1799983), SERPINE1 (rs1799768), PLAU (rs2227564) and PLAUR (rs344781, rs2302524) genes, with the disease severity classified by the percentage of lung involvement on computerized tomography scans. Our findings reveal that the T/C genotype of PLAUR rs2302524 was independently associated with a less severe lung damage (odds ratio 0.258 [0.071-0.811]). Along with high C-reactive protein, fibrinogen and soluble uPAR serum levels turned out to be independently associated with more severe lung damage in COVID-19 patients. The identified factors may be further employed as predictors of a possibly severe COVID-19 clinical course.

A Splice Variant of the MYH7 Gene Is Causative in a Family with Isolated Left Ventricular Noncompaction Cardiomyopathy.

Variants of the MYH7 gene have been associated with a number of primary cardiac conditions, including left ventricular noncompaction cardiomyopathy (LVNC). Most cases of MYH7-related diseases are associated with such variant types as missense substitutions and in-frame indels. Thus, truncating variants in MYH7 (MYH7tv) and associated mechanism of haploinsufficiency are usually considered not pathogenic in these disorders. However, recent large-scale studies demonstrated evidence of the significance of MYH7tv for LVNC and gave rise to an assumption that haploinsufficiency may be the causal mechanism for LVNC. In this article, we present a family with isolated LVNC and a heterozygous splice variant of the MYH7 gene, analyze possible consequences of this variant and conclude that not all variants that are predicted truncating really act through haploinsufficiency. This study can highlight the importance of a precise assessment of MYH7 splicing variants and their participation in the development of LVNC.

Regional pericarditis following uncomplicated catheter ablation procedure: a case report.

BACKGROUND: Acute post-ablation pericarditis is the most common complication of epicardial ablation of ventricular arrhythmias, while regional pericarditis following an initially uneventful endocardial catheter ablation (CA) procedure is a rare and elusive diagnosis. CASE SUMMARY: We report a case of a 66-year-old Russian female who developed chest pain accompanied by electrocardiogram (ECG) changes-biphasic T waves in V1-V4 leads after an initially uncomplicated premature ventricular complex CA procedure. After examination and investigations, including transthoracic echocardiography (TTE), cardiac magnetic resonance imaging (CMR) and cardiac computed tomography (CCT), she was diagnosed with regional pericarditis, which occurred even though the ablation was uneventful with the limited number of radiofrequency applications. Furthermore, the diagnosis was difficult due to normal body temperature and the absence of pericardial effusion and myocardial abnormalities on TTE, findings that are not characteristic of pericarditis. The patient's last office visit was in 6 months after the procedure. Neither patient had any complaintsnor there were any changes on ECG and TTE. DISCUSSION: Regional post-ablation pericarditis is a relatively rare type of post-cardiac injury syndrome (PCIS). The varying severity of the PCIS clinical course makes the diagnosis of post-ablation pericarditis initially difficult, especially in patients undergoing an uneventful CA procedure. Non-invasive imaging modalities as CMR and CCT should be considered initially in elusive cases of PCIS.

Overlapping Phenotype of Adult-Onset ALPK3-Cardiomyopathy in the Setting of Two Novel Variants.

Inherited cardiomyopathies (CMPs) are fairly common causes of morbidity and mortality, particularly, in young individuals. In substantial number of cases, only morphological diagnostic criteria cannot distinguish one CMP from another because of incomplete penetrance, advanced stage of the disease, or overlapping phenotypes. Genetic testing has become a mandatory tool for definite diagnosis that is required for family screening, individual prognosis, and personalized treatment strategy in routine practice. In parallel, accumulation of genotype-phenotype correlations, especially for rare genes, promotes the deciphering of underling molecular mechanisms and the development of targeting treatment of CMPs. Here we present an adult-onset case comprised morphological features of several CMPs: asymmetric left ventricle (LV) hypertrophy, severe systolic dysfunction, LV hypertrabeculation and restrictive physiology. Using next-generation sequencing, two novel variants (NM_020778.5:c.1958C>G:p.Ser653* and c.3491G>A:p.Arg1164Gln) in alpha-protein kinase 3 (ALPK3) gene were identified and confirmed with Sanger sequencing. The trans-position (location on different alleles) of identified ALPK3 variants was established by plasmid cloning method. The ALPK3 gene, encoding nuclear alpha-protein kinase 3, has only recently been associated with CMPs and there are still few clinical data on ALPK3 variant carriers. To date, only five affected individuals with adult-onset CMPs in the setting of biallelic variants of ALPK3 gene have been reported.

Neural Correlates of Group Versus Individual Problem Solving Revealed by fMRI.

Group problem solving is a prototypical complex collective intellectual activity. Psychological research provides compelling evidence that problem solving in groups is both qualitatively and quantitatively different from doing so alone. However, the question of whether individual and collective problem solving involve the same neural substrate has not yet been addressed, mainly due to methodological limitations. In the current study, functional magnetic resonance imaging was performed to compare brain activation when participants solved Raven-like matrix problems in a small group and individually. In the group condition, the participant in the scanner was able to discuss the problem with other team members using a special communication device. In the individual condition, the participant was required to think aloud while solving the problem in the silent presence of the other team members. Greater activation was found in several brain regions during group problem solving, including the medial prefrontal cortex; lateral parietal, cingulate, precuneus and retrosplenial cortices; frontal and temporal poles. These areas have been identified as potential components of the so-called "social brain" on the basis of research using offline judgments of material related to socializing. Therefore, this study demonstrated the actual involvement of these regions in real-time social interactions, such as group problem solving. However, further connectivity analysis revealed that the social brain components are co-activated, but do not increase their coupling during cooperation as would be suggested for a holistic network. We suggest that the social mode of the brain may be described instead as a re-configuration of connectivity between basic networks, and we found decreased connectivity between the language and salience networks in the group compared to the individual condition. A control experiment showed that the findings from the main experiment cannot be entirely accounted for by discourse comprehension. Thus, the study demonstrates affordances provided by the presented new technique for neuroimaging the "group mind," implementing the single-brain version of the second-person neuroscience approach.

Modulation of Intrinsic Brain Connectivity by Implicit Electroencephalographic Neurofeedback.

Despite the increasing popularity of neurofeedback, its mechanisms of action are still poorly understood. This study aims to describe the processes underlying implicit electroencephalographic neurofeedback. Fifty-two healthy volunteers were randomly assigned to a single session of infra-low frequency neurofeedback or sham neurofeedback, with electrodes over the right middle temporal gyrus and the right inferior parietal lobule. They observed a moving rocket, the speed of which was modulated by the waveform derived from a band-limited infra-low frequency filter. Immediately before and after the session, the participants underwent a resting-state fMRI. Network-based statistical analysis was applied, comparing post- vs. pre-session and real vs. sham neurofeedback conditions. As a result, two phenomena were observed. First, we described a brain circuit related to the implicit neurofeedback process itself, consisting of the lateral occipital cortex, right dorsolateral prefrontal cortex, left orbitofrontal cortex, right ventral striatum, and bilateral dorsal striatum. Second, we found increased connectivity between key regions of the salience, language, and visual networks, which is indicative of integration in sensory processing. Thus, it appears that a single session of implicit infra-low frequency electroencephalographic neurofeedback leads to significant changes in intrinsic brain connectivity.

Noncompaction cardiomyopathy is caused by a novel in-frame desmin (DES) deletion mutation within the 1A coiled-coil rod segment leading to a severe filament assembly defect.

Mutations in DES, encoding desmin protein, are associated with different kinds of skeletal and/or cardiac myopathies. However, it is unknown, whether DES mutations are associated with left ventricular hypertrabeculation (LVHT). Here, we performed a clinical examination and subsequent genetic analysis in a family, with two individuals presenting LVHT with conduction disease and skeletal myopathy. The genetic analysis revealed a novel small in-frame deletion within the DES gene, p.Q113_L115del, affecting the α-helical rod domain. Immunohistochemistry analysis of explanted myocardial tissue from the index patient revealed an abnormal cytoplasmic accumulation of desmin and a degraded sarcomeric structure. Cell transfection experiments with wild-type and mutant desmin verified the cytoplasmic aggregation and accumulation of mutant desmin. Cotransfection experiments were performed to model the heterozygous state of the patients and revealed a dominant negative effect of the mutant desmin on filament assembly. DES:p.Q113_L115del is classified as a pathogenic mutation associated with dilated cardiomyopathy with prominent LVHT.