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.

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.

Existing and Emerging Approaches to Risk Assessment in Patients with Ascending Thoracic Aortic Dilatation.

Ascending thoracic aortic aneurysm is a life-threatening disease, which is difficult to detect prior to the occurrence of a catastrophe. Epidemiology patterns of ascending thoracic aortic dilations/aneurysms remain understudied, whereas the risk assessment of it may be improved. The electronic databases PubMed/Medline 1966-2022, Web of Science 1975-2022, Scopus 1975-2022, and RSCI 1994-2022 were searched. The current guidelines recommend a purely aortic diameter-based assessment of the thoracic aortic aneurysm risk, but over 80% of the ascending aorta dissections occur at a size that is lower than the recommended threshold of 55 mm. Moreover, a 55 mm diameter criterion could exclude a vast majority (up to 99%) of the patients from preventive surgery. The authors review several visualization-based and alternative approaches which are proposed to better predict the risk of dissection in patients with borderline dilated thoracic aorta. The imaging-based assessments of the biomechanical aortic properties, the Young's elastic modulus, the Windkessel function, compliance, distensibility, wall shear stress, pulse wave velocity, and some other parameters have been proposed to improve the risk assessment in patients with ascending thoracic aortic aneurysm. While the authors do not argue for shifting the diameter threshold to the left, they emphasize the need for more personalized solutions that integrate the imaging data with the patient's genotypes and phenotypes in this heterogeneous pathology.

Predictive potential of ACE phenotyping in extrapulmonary sarcoidosis.

Elevated ACE expression in tissues (reflected by blood ACE levels) is associated with increased risk of cardiovascular diseases and is also a marker for granulomatous diseases. We developed a new approach for characterization of ACE status in the blood-ACE phenotyping and established normal values of ACE levels 50-150% of control pooled plasma. ACE phenotyping was performed in citrated plasma of 120 patients with known interstitial lung diseases. In the 1st set of 100 patients we found 22 patients with ACE levels > 150%; ACE phenotyping also objectively identified the presence of ACE inhibitors in the plasma of 15 patients. After excluding these patients and patient with ACE mutation that increases ACE shedding, 17 patients were identified as a suspicious for systemic sarcoidosis based on elevation of blood ACE (> 150% of mean). A new parameter that we have established-ACE immunoreactivity (with mAb 9B9)-allowed us to detect 22 patients with decreased values (< 80%) of this parameter, which may indicate the presence of ACE in the blood that originates from macrophages/dendritic cells of granulomas. In the remaining 20 patients, this new parameter (mAbs binding/activity ratio) was calculated using 3 mAbs (9B9, 3A5 and i1A8-having overlapping epitopes), and 8 patients were identified as having decreases in this parameter, thus increasing dramatically the sensitivity for detection of patients with systemic sarcoidosis. Whole body PET scan confirmed extrapulmonary granulomas in some patients with lower immunoreactivity towards anti-ACE mAbs. ACE phenotyping has novel potential to noninvasively detect patients with systemic sarcoidosis.

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.

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.

Functional connectivity of the dorsolateral prefrontal cortex contributes to different components of executive functions.

OBJECTIVE: The dorsolateral prefrontal cortex (DLPFC) orchestrates other brain regions and plays a vital role for "the most uniquely human" executive functions (EFs), which are divided into distinct components. Components of EFs have been localized to different brain regions and at the same time the DLPFC was found to be involved in a majority of EF components. The possible mechanism of the DLPFC's contribution to EF components might be found in DLPFC functional connectivity (FC): this FC of the DLPFC with other brain regions contributes to different EF components. METHOD: To explore the DLPFC FC contribution to different EFs, we used an integrative approach involving analysis of fMRI and neuropsychological assessment of EFs. Fifty healthy adults (27 females and 23 males, mean age 34.5 ± 16.6 years) underwent neuropsychological assessment of EFs as well as task-based and resting-state fMRI. Task-based fMRI was applied as a functional localizer for individually defined DLPFC ROIs that were further used for the FC seed-based correlation analysis of the resting-state data. Then we looked for associations between individual scores of different EF components and the whole-brain resting-state FC of the DLPFC. RESULTS: Resting-state correlates of DLPFC FC were revealed for three out of the seven EF components derived from an extensive neuropsychological assessment: inhibition, switching, and the verbal EF component. CONCLUSIONS: Our study is the first to reveal the contribution of the DLPFC FC to several distinct EF components. The obtained results give insight into the brain mechanisms of EFs.

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.

Calcification of coronary arteries in early rheumatoid arthritis prior to anti-rheumatic therapy.

Accelerated coronary atherosclerosis is common in patients with rheumatoid arthritis (RA). To examine coronary artery calcification (CAC) frequency and severity, its correlation with traditional risk factors (TRF) of cardiovascular diseases (CVD) and inflammatory markers in patients with early RA prior to anti-rheumatic therapy. RA adult patients (ACR/EULAR criteria, 2010, duration ≤ 12 months, without prior administration of disease-modifying anti-rheumatic drugs, glucocorticoids) underwent 32-row scanning for CAC scoring. Agatston, volume and mass calcium scores were calculated. Additionally, we used calculators on the website of the Multi-Ethnic Study of Atherosclerosis. 74 RA patients (women n = 54 (73%), median age 56 years, median RA duration 6 months) with moderate/high RA activity (median DAS28 [ESR] 5.4) were enrolled within the framework of the observational study. Most of the patients had multiple TRFs of CVD and subclinical organ damage. CAC has been detected in 34 (46%) early RA patients. Calcification severity was significantly higher in men and in patients with ischemic heart disease (IHD). In patients younger than 45 years (n = 16) CAC was not detected. Among patients older than 45 years (n = 58), the frequency of CAC was 59%: asymptomatic patients-n = 46 (48%), IHD patients-n = 12 (100%). Among asymptomatic patients the presence of CAC associated with a significantly higher frequency of arterial hypertension (1.6 fold) compared with cases without CAC. Coronary age in asymptomatic patients with CAC and IHD patients was significantly greater than their actual age. More than half of early RA patients older 45 years had CAC. The presence and severity of CAC correlated positively with TRFs, but not with lipid levels and RA activity.