Identification of Variants of Uncertain Significance in the Genes Associated with Thoracic Aortic Disease in Russian Patients with Nonsyndromic Sporadic Subtypes of the Disorder.

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.

The role of adrenergic and muscarinic receptors in stress-induced cardiac injury.

Takotsubo syndrome (TS) is a rare but dangerous disease that can be fatal. The pathogenesis of TS is not well understood because there is no animal model of TS that fully mimics TS. It has now been documented that stress exposure (24 h) of rats induced the state which is similar TS in human: contracture damage of myofibrils, elevation of the serum creatine kinase MB level, increased 99mTc-pyrophosphate (99mTc-PYP) accumulation in the heart, QTc interval prolongation, and contractility dysfunction of the heart. Immobilization stress resulted in an increase in coronary blood flow. Emotional stress increased the serum catecholamine level. Blockade of ß1-adrenergic receptor (AR) prevented stress-induced cardiac injury (SICI). Blockade of ß2-AR aggravated stress-induced cardiac injury. Stimulation of ß2-AR increased cardiac tolerance to stress. Inhibition of ß3-AR, α1-AR had no effect on SICI. Blockade of peripheral muscarinic receptors or α2-AR aggravated SICI. Pretreatment with the selective ß1-AR antagonist atenolol attenuates stress-induced cardiac contractility dysfunction, but recovery of cardiac contractility is not complete. There is indirect evidence that circulating catecholamines play an important role in SICI. Consequently, the activation of ß1-AR plays a significant role in SICI. However, there are other receptors which are also involved in SICI and require further investigation.

Insights into ascending aortic aneurysm: Interactions between biomechanical properties of the aortic wall and tissue biomarkers.

Background: It remains difficult to understand the association between the local mechanical properties of ascending thoracic aorta aneurysm (asTAA), its tissue, and its cellular and molecular changes. The purpose of our study was to investigate the relationship between biomechanical properties, histopathological findings, and tissue biomarkers of asTAA. Methods: Intraoperative asTAA samples from 30 patients were studied. All samples were examined histologically and underwent a tensile test. We determined the tensile strength (σв, MPa), the strain (ε, mm/mm˟%), and the area under the strength-strain curve (S) along with the concentrations of tissue matrix metalloproteinases (MMP-1 et al.) and their inhibitors, their interleukins (IL) -6 -10, and their tumor necrosis factor (TNF) -α. Results: It was found that 43.3 % of asTAA patients had atherosclerosis, 3.3 % had aortitis, and 53.3 % of patients had connective tissue dysplasia. Differences in the studied parameters between these subgroups were not found. Age correlated with ε (r = -0.49) and S (r = -0.54). ε was also associated with media fibrosis degree (r = -0.5), collagen/elastin ratio (r = -0.61), and IL-10 (r = 0.52). IL-10 correlated with collagen/elastin ratio (r = -0.58), TNF-α (r = 0.77), and MMP-1 (r = 0.71). Conclusion: Tissue IL-10 has a protective effect on the elastic structures of the aortic wall and is positively associated with the activity of MMP-1 and pro-inflammatory cytokines. IL-6 is associated with media fibrosis degree, and negatively affects strength-strain parameters of asTAA samples.

Cardiovascular abnormalities in patient with Williams-Beuren syndrome.

We present a case of a 42-year-old male patient with severe supravalvular aortic stenosis associated with aortic and mitral valve stenosis as well as an anomalous origin of the right coronary ostium caused by deletion in the q11.23 region of the human chromosome 7 in a patient with Williams-Beuren syndrome.