14 research outputs found
Non-compaction and dilated cardiomyopathy: genotypic, phenotypic and prognostic differences
Aim. To study and compare genotypic and phenotypic signs in patients with non-compaction cardiomyopathy (NCM) and dilated cardiomyopathy (DCM), to conduct a comparative analysis of clinical outcomes and 5-year cumulative survival of patients with NCM and DCM.Material and methods. The study included 144 unrelated patients with cardiomyopathy: NCM (n=74) and DCM (n=70). Mean age was 39 [30; 49] years (men, 96 (66,7%); left ventricular ejection fraction (LVEF) was 30,5 [24; 46]%. A comprehensive clinical examination included electrocardiography, Holter monitoring, echocardiography, cardiac magnetic resonance imaging, coronary angiography, DNA diagnostics (NGS+Sanger), cascade screening, and cosegregation analysis. To assess clinical outcomes, the NCM group was divided into 2 subtypes according to baseline LV systolic function (NCM/DCM phenotype — 50 individuals with LVEF ≤49%; and isolated NCM — 24 patients with LVEF ≥50%). The following adverse events were assessed as the composite endpoint: cardiovascular death, heart transplantation (HT), sustained ventricular tachycardia, ventricular fibrillation, successful cardiopulmonary resuscitation, cerebral thromboembolism. The follow-up period was 62 months.Results. Among patients with LVEF ≤49% at a 5-year follow-up, 37 (74,0%) of 50 patients with the NCM/DCM phenotype and 41 (58,6%) of 70 patients with DCM achieved composite endpoint. Out of 24 patients with NCM with LVEF ≥50% (median LVEF, 56 [51; 61]%), 2 (8,3%) patients achieved composite endpoint (χ2=28,8; p=0,001). In the NCM/DCM group with LVEF ≤49%, a higher level of pathogenic genetic variants (64% vs 41,4%/DCM vs 29,2%/NCM; χ2=11,4; p=0,003), cerebral thromboembolism (χ2=11,8; p=0,003) and HT (χ2=10,6; p=0,005). The results of the 5-year survival analysis (Kaplan-Meier) showed a worse prognosis for NCM with LVEF ≤49% compared with DCM (log rang: χ2=11,5; p=0,001) and isolated NCM (log rang: χ2=17,02; p=0,0001). In the overall cohort (n=144), gene-positivity was also associated with worse prognosis (log rang: χ2=5,38; p=0,02).Conclusion. In the present study, patients with dilated subtype of NCM showed a worse prognosis compared with DCM and isolated NCM. Heart failure progression and cerebral thromboembolism were the most common complications in patients with NCM/DCM
Genetic risk factors for dilated cardiomyopathy
Aim. To study the diagnostic significance of genetic testing in patients with dilated cardiomyopathy (DCM), identify predictors of life-threatening ventricular tachyarrhythmias (VTAs) and assess adverse clinical outcomes in different genetic groups.Material and methods. The study included 126 unrelated patients with verified DCM as follows: 70 (55,6%) probands with criteria for familial DCM and 56 (44,4%) individuals with a probable hereditary component. All patients (age, 43,1±11,3 years; men, 92 (73%); left ventricular ejection fraction, 30,6±8,43%; left ventricular enddiastolic diameter, 68,3±8,36 mm; follow-up period — median, 49 months) receive a complex of diagnostic investigations, including genetic screening using nextgeneration sequencing, followed by verification of variants by the Sanger method.Results. Pathogenic and likely pathogenic genetic variants were found in 61 (48,4%) of 126 patients with DCM. The dominant mutations were titin-truncating variants (TTNtvs), identified in 16 individuals (12,7%), and variants of lamin A/C (LMNA), identified in 13 probands (10,3%). Mutations in the other 19 genes were found in 32 (25,4%) patients. The following primary endpoints were assessed: sudden cardiac death (SCD), episodes of VTA (sustained ventricular tachycardia/ventricular fibrillation) and appropriate shocks of implanted cardiac resynchronization therapy (CRT)/cardioverter defibrillators (CVD) devices. As a result of ROC analysis, the following independent risk factors for SCD were identified: mutations in the LMNA gene (AUC, 0,760; p=0,0001) and non-sustained ventricular tachycardia (cut-off heart rate ≥161 bpm: AUC, 0,788; p=0,0001). When comparing the phenotypes and genotypes of DCM, TTNtv genotype was associated with a lower prevalence of complete left bundle branch block (χ2=7,46; p=0,024), a lower need for CRT/CVD implantation (χ2=5,70; p=0,017) and more rare episodes of sustained ventricular tachycardia/ventricular fibrillation (χ2=30,1; p=0,0001) compared with LMNA carriers. Kaplan-Meier analysis showed the worst prognosis in carriers of LMNA mutations both in relation to life-threatening VTA (log rang χ2=88,5; p=0,0001) and in achieving all unfavorable outcomes (χ2=27,8; p=0,0001) compared with groups of genenegative individuals, carriers of TTNtv and other genotypes.Conclusion. The phenotypes of DCM with TTNtv did not significantly differ in the incidence of VTAs and adverse outcomes compared with the gene-negative group and other genotypes (with the exception of LMNA). The contribution of the associations of LMNA mutations with VTAs on prognosis was confirmed, which shows the important role of LMNA genotype diagnosis for SCD risk stratification in patients with DCM
Dividing into individual doses: maintaining the uniformity of dosing
The article discusses the possibility of maintaining the uniformity of dosage of a medicines when dividing into individual doses on the example of tabletsВ статье рассмотрена возможность сохранения равномерности дозирования лекарственного препарата при разделении на индивидуальные дозы на примере таблетированных лекарственных фор
Possibilities for diagnosing the genetic risk of developing obesity
The purpose of the study is to compare genetic risk factors for obesity and body mass index (BMI) in outpatient patient records using the Atlas genetic passport.Цель. С помощью генетического паспорта «Атлас» сопоставить генетические факторы риска ожирения и показатели индекса массы тела (ИМТ) в амбулаторных картах пациенток
Uniparental Genetic Heritage of Belarusians: Encounter of Rare Middle Eastern Matrilineages with a Central European Mitochondrial DNA Pool
Ethnic Belarusians make up more than 80% of the nine and half million people inhabiting the Republic of Belarus. Belarusians together with Ukrainians and Russians represent the East Slavic linguistic group, largest both in numbers and territory, inhabiting East Europe alongside Baltic-, Finno-Permic- and Turkic-speaking people. Till date, only a limited number of low resolution genetic studies have been performed on this population. Therefore, with the phylogeographic analysis of 565 Y-chromosomes and 267 mitochondrial DNAs from six well covered geographic sub-regions of Belarus we strove to complement the existing genetic profile of eastern Europeans. Our results reveal that around 80% of the paternal Belarusian gene pool is composed of R1a, I2a and N1c Y-chromosome haplogroups – a profile which is very similar to the two other eastern European populations – Ukrainians and Russians. The maternal Belarusian gene pool encompasses a full range of West Eurasian haplogroups and agrees well with the genetic structure of central-east European populations. Our data attest that latitudinal gradients characterize the variation of the uniparentally transmitted gene pools of modern Belarusians. In particular, the Y-chromosome reflects movements of people in central-east Europe, starting probably as early as the beginning of the Holocene. Furthermore, the matrilineal legacy of Belarusians retains two rare mitochondrial DNA haplogroups, N1a3 and N3, whose phylogeographies were explored in detail after de novo sequencing of 20 and 13 complete mitogenomes, respectively, from all over Eurasia. Our phylogeographic analyses reveal that two mitochondrial DNA lineages, N3 and N1a3, both of Middle Eastern origin, might mark distinct events of matrilineal gene flow to Europe: during the mid-Holocene period and around the Pleistocene-Holocene transition, respectively
Dilated cardiomyopathy: reconceptualization of the problem
Dilated cardiomyopathy (DCM) is a complex, etiologically heterogeneous myocardial disease, which is one of the main causes of heart failure and heart transplantation. In 2016, experts from the European working group proposed a new definition of cardiomyopathy, which includes intermediate variants with a change in phenotype in carriers of mutations from subclinical form to the full manifestations of the disease. The classification of DCM was supplemented with intermediate phenotypes with the inclusion of a hypokinetic form with reduced contractile function without ventricular dilatation and variants with predominant dilation or arrhythmogenicity. Pathological architectonics of DCM consists of many genetic determinants that interact with numerous environmental factors. Clinical manifestations depend not only on the malignancy and penetrance of the gene mutation, but also on a number of other causes — epigenomic factors, age, toxic effects, environmental aggressiveness, pregnancy, and the effects of other acquired diseases. The article summarizes the current epidemiological data and ideas about specific molecular changes with an unfavorable prognosis. For clarity, we present clinical observations of familial DCM with mutations in the RBM20 and LMNA genes
Carvajal syndrome: a brief overview and clinical case of cardiomyopathy, associated with compound heterozygous mutations of the desmoplakin gene
Mutations in the genes encoding desmosomal proteins cause a wide range of diseases associated with abnormalities of the skin, hair and heart. In 45-50% these mutations determine the development of arrhythmogenic right ventricular cardiomyopathy. Today, more than 120 autosomal dominant and autosomal recessive mutations of the desmoplakin (DSP) gene are known, causing skin and cardiac disorders. The article presents a rare clinical case of Carvajal syndrome (OMIM 605676), associated with compound heterozygous mutations, with the classic triad of symptoms (the phenotype of dilated cardiomyopathy, keratoderma, and woolly hair), which was first identified in Eastern Europe (Belarus). A brief literature review of the problems and issues of differential diagnosis are presented in the article in the form of a comparative analysis of Carvajal syndrome with phenotypically similar pathology - Naxos syndrome, caused by mutations in the gene encoding another desmosomal protein - Placoglobin (Naxos syndrome, OMIM 601214), and leading to the development of arrhythmogenic right ventricular cardiomyopathy
Restrictive cardiomyopathy: difficulties desminopathy diagnostics
The article provides a brief overview of the problems of diagnostics and etiological verification of restrictive cardiomyopathy (RCMP). Multiple causes lead to the restrictive phenotype of intracardiac hemodynamics and diastolic dysfunction of the heart: infiltrative (amyloidosis, sarcoidosis, elastoma, metabolic syndrome, tumor metastasis to the myocardium); endomyocardial (tropical endomyocardial fibrosis, hypereosinophilic syndrome, carcinoid, radiation damage); accumulation diseases (hemochromatosis, Pompe and Gaucher diseases, Fabry disease). RKMP is also characteristic for desminopathy — so-called desmin storage disease. This is a disease caused by mutations in the desmin gene (DES) that determine the development of cardiomyopathy or myofibrillar myopathy, and in some cases cause a combined phenotype of the disease. Desmin belongs to the group of intermediate filaments that maintain the structural and functional integrity of myofibrils. Mutations in DES lead to disruption of the assembly of filaments and a change in the myofibrillar cell lattice, which contributes to an increased vulnerability of myocytes to mechanical stress. The article presents a clinical case of familial desminopathy associated with a new missense R118P mutation of DES gene, characterized by dominant cardiac RCMP phenotype and subclinical manifestations of myofibrillar myopathy
Non-compaction cardiomyopathy. Part I: clinical and genetic heterogeneity and predictors of unfavorable prognosis
Non-compaction cardiomyopathy (NCM) is a rare heart disease characterized by a two-layered ventricular wall, comprising a thinner compact epicardial layer and an inner non-compacted layer. However, only structural and morphological data without a thorough clinical assessment does not determine the NCM (regardless of the diagnostic criterion used).Aim. To study the NCM-related genes, phenotypic and genetic correlations, predictors of life-threatening ventricular tachyarrhythmias (VTA) and adverse clinical outcomes.Material and methods. Of 93 individuals with identified morphological criteria of NCM (median follow-up, 5 years), the study included 60 unrelated patients (38,5±13,8 years of age; men, 33 (55%); left ventricular ejection fraction (LVEF), 42,1±12,9%) with clinical verification of NCM (>1 obligate phenotypic trait). Adverse cardiovascular events were taken as the composite end point: life-threatening VTA, death, heart transplantation.Results. Pathogenic (or probably pathogenic) mutations were detected in 33 (55%) patients with NCM. The most common variants (57,9%) were identified in the sarcomere protein genes (TTN, MYBPC3, MYH7); digenic mutations were found in 21,6% of patients. Digenic mutations were associated with low LVEF and the highest risk of systolic dysfunction (OR, 38; 95% CI, 4,74-305; p=0,0001). Multivariate regression provided a predictive model (R=0,90; R2=0,81; F (5,41) =34,8; p<0,0001) and independent predictors of adverse clinical outcomes of NCM (genetic cause of the disease (pathogenic mutation), LV systolic dysfunction, myocardial fibrosis in 2 or more ventricular segments, and QRS prolongation. Regression and ROC-analysis identified electrical predictors of life-threatening VTA (fragmented QRS, QT prolongation, spatial QRS-T angle increase) and morphofunctional markers (myocardial fibrosis, systolic dysfunction).Conclusion. The study revealed a significant clinical and genetic heterogeneity of NCM with predominant mutations in the sarcomeric protein genes and determined the criteria for identification and prognosis of NCM
Non-compaction cardiomyopathy. Part II: limitations of imaging techniques and genetic screening, clinical observations
Improvement of high-tech methods of cardiac imaging and new generation sequencing with their introduction into widespread practice has significantly expanded the potential of diagnosis of rare cardiomyopathies. Modern imaging methods make it easy to reveal the myocardial non-compaction. However, in clinical practice, significant difficulties remain in the differentiation of normal/borderline patterns of increased ventricular trabecularity, morphology of myocardial noncompaction and non-compaction cardiomyopathy (NCM). After three decades of research, verifying the NCM is still a major clinical challenge. A key aspect of this problem is the lack of generally accepted recommendations on the diagnostic criteria for NCM and low number of long-term multicenter studies with segregation analysis on familial NCMs. A promising solution is the development of a multistep algorithm for the diagnosis of NCM with the integration of familial, morphological, genetic and clinical data.The article presents a brief literary review on NCM diagnosis with a discussion of own research and comparative characteristics of clinical and genetic data. To confirm the clinical and molecular heterogeneity of NCM, there are brief clinical observations of mixed phenotypes with a detailed presentation of overlap NCMs in the MOGE(S) classification