Современные клинико-фундаментальные аспекты в диагностике и лечении пациентов с ишемической кардиомиопатией (обзор)

Nonsyndromic sporadic thoracic aortic aneurysm (nssTAA) is characterized by diverse genetic variants that may vary in different populations. Our aim was to identify clinically relevant variants in genes implicated in hereditary aneurysms in Russian patients with nssTAA. Forty-one patients with nssTAA without dissection were analyzed. Using massive parallel sequencing, we searched for variants in exons of 53 known disease-causing genes. Patients were found to have no (likely) pathogenic variants in the genes of hereditary TAA. Six variants of uncertain significance (VUSs) were identified in four (9.8%) patients. Three VUSs [FBN1 c.7841C>T (p.Ala2614Val), COL3A1 c.2498A>T (p.Lys833Ile), and MYH11 c.4993C>T (p.Arg1665Cys)] are located in genes with “definitive” disease association (ClinGen). The remaining variants are in “potentially diagnostic” genes or genes with experimental evidence of disease association [NOTCH1 c.964G>A (p.Val322Met), COL4A5 c.953C>G (p.Pro318Arg), and PLOD3 c.833G>A (p.Gly278Asp)]. Russian patients with nssTAA without dissection examined in this study have ≥1 VUSs in six known genes of hereditary TAA (FBN1, COL3A1, MYH11, NOTCH1, COL4A5, or PLOD3). Experimental studies expanded genetic testing, and clinical examination of patients and first/second-degree relatives may shift VUSs to the pathogenic (benign) category or to a new class of rare “predisposing” low-penetrance variants causing the pathology if combined with other risk factors.

Lymphedema is a pathology caused by poor lymphatic flow which may lead to complete disability. Currently, precise, non-invasive techniques for quantifying lymphedema are lacking. In this paper, the results of an in vivo assessment of lymphedema via a developed small-animal model using the hindlimbs of rats and an optical coherence tomography (OCT) technique are presented. This model of lymphedema was based on a surgical lymph node resection and subsequent two-step X-ray exposure. The development of lymphedema was verified via the histological examination of tissue biopsies. The properties of the lymphedematous skin were analyzed in vivo and compared with healthy skin via OCT. The main differences observed were (1) a thickening of the stratum corneum layer, (2) a thinning of the viable epidermis layer, and (3) higher signal attenuation in the dermis layer of the lymphedematous skin. Based on the distribution of the OCT signal’s intensity in the skin, a machine learning algorithm was developed which allowed for a classification of normal and lymphedematous tissue sites with an accuracy of 90%. The obtained results pave the way for in vivo control over the development of lymphedema.

Aim. To analyze the comorbidity structure in patients with ascending thoracic aortic aneurysm (TAA) in the Siberian Federal District (SFD).Material and methods. The study included 163 patients (114 men (56,8±12,1 years) and 49 women (59,4±10,4 years)) with ascending TAA, who underwent open surgical treatment at the Cardiology Research Institute of the Tomsk National Research Medical Center. Concomitant pathologies were assessed on the basis of anamnesis and paraclinical investigations. Comparison of the prevalence of concomitant diseases in the group of patients with ascending TAA between men and women, as well as between patients ascending TAA in the SFD, other groups of patients with this pathology, population samples and patients with other cardiovascular diseases was performed using the χ² test or Fisher’s exact test in the Statistiсa 12 program.Results. In patients with ascending TAA, hypertension (67,5%), bicuspid aortic valve (44,2%), coronary artery disease (38,6%), arrhythmia (31,3%), and heart failure (27,6%). Atherosclerosis of the aorta, coronary and carotid arteries occur with a prevalence of 12,9%, 16,6% and 5,5%, respectively. Among other forms of pathologies, the most common are connective tissue dysplasia (65,6%), obesity (12,3%), and chronic obstructive bronchitis (9,8%). In men with ascending TAA, myocardial infarction and atrial fibrillation are detected more often than women (11,4% and 20,2% vs 2% and 6,1%; p<0,05), and in women — carotid atherosclerosis and impaired cerebral circulation (12,2% and 18,4% vs 2,6% and 5,3%, p<0,05). Compared to other compared groups, aortic, coronary and carotid atherosclerosis, myocardial infarction, stroke, and type 2 diabetes were less frequently recorded in patients with ascending TAA in the SFD.Conclusion. Patients with ascending TAA in the SFD are characterized by a complex structure of comorbidity, including both cardiovascular pathologies and related risk factors, and other pathologies, including diseases of the lungs, kidneys, gastrointestinal tract, infectious and cancer diseases. To confirm the presence of inverse comorbidity between ascending TAA, atherosclerosis of other location, and type 2 diabetes, large-scale epidemiological, morphological, and molecular genetic studies are needed, which will reveal the fundamental mechanisms underlying it.

Aim. To analyze the comorbidity structure in patients with ascending thoracic aortic aneurysm (TAA) in the Siberian Federal District (SFD).Material and methods. The study included 163 patients (114 men (56,8±12,1 years) and 49 women (59,4±10,4 years)) with ascending TAA, who underwent open surgical treatment at the Cardiology Research Institute of the Tomsk National Research Medical Center. Concomitant pathologies were assessed on the basis of anamnesis and paraclinical investigations. Comparison of the prevalence of concomitant diseases in the group of patients with ascending TAA between men and women, as well as between patients ascending TAA in the SFD, other groups of patients with this pathology, population samples and patients with other cardiovascular diseases was performed using the χ² test or Fisher’s exact test in the Statistiсa 12 program.Results. In patients with ascending TAA, hypertension (67,5%), bicuspid aortic valve (44,2%), coronary artery disease (38,6%), arrhythmia (31,3%), and heart failure (27,6%). Atherosclerosis of the aorta, coronary and carotid arteries occur with a prevalence of 12,9%, 16,6% and 5,5%, respectively. Among other forms of pathologies, the most common are connective tissue dysplasia (65,6%), obesity (12,3%), and chronic obstructive bronchitis (9,8%). In men with ascending TAA, myocardial infarction and atrial fibrillation are detected more often than women (11,4% and 20,2% vs 2% and 6,1%; p<0,05), and in women — carotid atherosclerosis and impaired cerebral circulation (12,2% and 18,4% vs 2,6% and 5,3%, p<0,05). Compared to other compared groups, aortic, coronary and carotid atherosclerosis, myocardial infarction, stroke, and type 2 diabetes were less frequently recorded in patients with ascending TAA in the SFD.Conclusion. Patients with ascending TAA in the SFD are characterized by a complex structure of comorbidity, including both cardiovascular pathologies and related risk factors, and other pathologies, including diseases of the lungs, kidneys, gastrointestinal tract, infectious and cancer diseases. To confirm the presence of inverse comorbidity between ascending TAA, atherosclerosis of other location, and type 2 diabetes, large-scale epidemiological, morphological, and molecular genetic studies are needed, which will reveal the fundamental mechanisms underlying it.

Introduction . Aortic arch anomalies, especially the “bovine arch”, can cause the development of an ascending aortic aneurysm. There is a high coefficient of heritability of this pathology, however, genetic studies are rare. Since the “bovine arch” is one of the variants of the development of the aortic arch and large vessels during embryogenesis, this pathology may be associated with genes encoding proteins involved in the embryonic development of the cardiovascular system. Aim: To identify rare, clinically significant variants of genes of cardiovascular embryonic development in patients with sporadic ascending aortic aneurysm and a “bovine arch”. Material and Methods . The study included 42 patients with a sporadic form of ascending aortic aneurysm, including 11 patients with a “bovine arch”. Analysis of the clinical exome was performed based on DNA sequencing data using Clinical Exome Solution (Sophia Genetics, Switzerland) and NextSeq 500 genetic sequencer (Illumina, USA). The search for rare, clinically significant variants (minor allele frequency G of the CCDC39 gene, which is a single-nucleotide substitution leading to the loss of the acceptor splice site (ΔScore = 0.97 Spliceailookup) and a variant of uncertain clinical significance (VUS) c.2564T>C in the ANKS6 gene, which has high pathogenicity rates on the CADD (Phred = 28.3) and AlphaMissense (0.972) scales. A likely pathogenic variant c.1151T>C of the ACVR2B gene was identified in the group of patients with aortic aneurysm without supraaortic vessels anomaly (AlphaMissense = 0.966). Among the 38 genes whose sequences revealed VUS in both groups of patients, the protein products of 17 (44.7%) are involved in the functioning of cilia and microtubules, and the proteins encoded by the genes MKS1, CCDC40, DNAAF1, ANKS6, CCDC39, DNAH5, DNAAF3 are also responsible for the development of the cardiovascular system. Conclusion . Rare, clinically significant variants in the CCDC39 and ANKS6 genes, which are crucial for primary cilia function, contribute to the development of sporadic ascending aortic aneurysm in combination with a “bull’s arch.” When a normal aortic arch is present, variants in the ACVR2B gene, belonging to the TGF-beta signaling protein superfamily, play an important role.