Aortic valve stenosis due to calcification of the valve leaflets is the most common valve disease in the developed world. It is the third leading cause of cardiovascular disease.[1][1] Risk factors include male gender, smoking, diabetes mellitus, hypertension, high levels of circulating lipids, and

Desmin is the major intermediate filament (IF) protein of muscle. Recently, mutations of the desmin gene have been reported to cause familial or sporadic forms of human skeletal, as well as cardiac, myopathy, termed desmin-related myopathy (DRM). The impact of any of these mutations on filament assembly and integration into the cytoskeletal network of myocytes is currently not understood, despite the fact that all cause the same histopathological defect, i.e., desmin aggregation. To gain more insight into the molecular basis of this process, we investigated how mutations within the α-helical rod domain of desmin affect both the assembly of the recombinant protein in vitro as well as the filament-forming capacity in cDNA-transfected cells. Whereas 6 of 14 mutants assemble into seemingly normal IFs in the test tube, the other mutants interfere with the assembly process at distinct stages, i.e., tetramer formation, unit-length filament (ULF) formation, filament elongation, and IF maturation. Correspondingly, the mutants with in vitro assembly defects yield dot-like aggregates in transfected cells, whereas the mutants that form IFs constitute a seemingly normal IF cytoskeleton in the cellular context. At present, it is entirely unclear why the latter mutant proteins also lead to aggregate formation in myocytes. Hence, these findings may be a starting point to dissect the contribution of the individual subdomains for desmin pathology and, eventually, the development of therapeutic interventions.

Cardiomyopathies represent a rare group of disorders often of genetic origin. While approximately 50% of genetic causes are known for other types of cardiomyopathies, the genetic spectrum of restrictive cardiomyopathy (RCM) is largely unknown. The aim of the present study was to identify the genetic background of idiopathic RCM and to compile the obtained genetic variants to the novel signalling pathways using in silico protein network analysis. We used Illumina MiSeq setup to screen for 108 cardiomyopathy and arrhythmia-associated genes in 24 patients with idiopathic RCM. Pathogenicity of genetic variants was classified according to American College of Medical Genetics and Genomics classification. Pathogenic and likely-pathogenic variants were detected in 13 of 24 patients resulting in an overall genotype-positive rate of 54%. Half of the genotype-positive patients carried a combination of pathogenic, likely-pathogenic variants and variants of unknown significance. The most frequent combination included mutations in sarcomeric and cytoskeletal genes (38%). A bioinformatics approach underlined the mechanotransducing protein networks important for RCM pathogenesis. Multiple gene mutations were detected in half of the RCM cases, with a combination of sarcomeric and cytoskeletal gene mutations being the most common. Mutations of genes encoding sarcomeric, cytoskeletal, and Z-line-associated proteins appear to have a predominant role in the development of RCM.

To assess the cardiovascular health, markers of cardiovascular aging and telomere length in survivors of the siege of Leningrad, who were either born during the siege or lived in the besieged city in their early childhood. Survivors of the Leningrad siege (n = 305, 64-81 years) and a control group of age and sex-matched individuals (n = 51, 67-82 years) were examined in terms of a observational retrospective cohort study. All participants were interviewed regarding risk factors, cardiovascular diseases, and therapy. Blood pressure measurement, anthropometry, echocardiography, and electrocardiography were performed according to standard guidelines. Fasting lipids and glucose were measured. Relative telomere length was measured by quantitative PCR, and the ratio of telomere repeat copy number to single gene copy number (T/S) was calculated for each DNA sample. Survivors had lower anthropometric parameters (height, weight, and BMI) and higher high-density lipoprotein level. There were no significant differences in the prevalence of cardiovascular diseases and target organ damage between groups. However, survivors had shorter telomere length: T/S ratio 0.44 (0.25; 0.64) vs. controls 0.91 (0.47; 1.13) (P < 0.0001), both in men and women, with clear association with the period of famine in early life. Exposure to famine in childhood and intrauterine period of life was associated with a higher prevalence of hypertension and shorter telomere length. Early-life famine, especially started in the intrauterine period and late childhood, may contribute to accelerated aging with telomere shortening in both sexes, but has no direct effect on the prevalence of cardiovascular diseases and risk factors after seven decades since exposure.