Whole Exome Sequencing Uncovers the Genetic Complexity of Bicuspid Aortic Valve in Families with Early Onset Complications.

Bicuspid Aortic Valve (BAV) is the most common adult congenital heart lesion with an estimated population prevalence of 1%. We hypothesize that early onset complications of BAV (EBAV) are driven by specific impactful genetic variants. We analyzed whole exome sequences (WES) to identify rare coding variants that contribute to BAV disease in 215 EBAV families. Predicted pathogenic variants of causal genes were present in 111 EBAV families (51% of total), including genes that cause BAV (8%) or heritable thoracic aortic disease (HTAD, 17%). After appropriate filtration, we also identified 93 variants in 26 novel genes that are associated with autosomal dominant congenital heart phenotypes, including recurrent deleterious variation of FBN2, MYH6, channelopathy genes, and type 1 and 5 collagen genes. These findings confirm our hypothesis that unique rare genetic variants contribute to early onset complications of BAV disease.

Genetics of bicuspid aortic valve aortopathy.

PURPOSE OF REVIEW: The incidence of aortic dilation and acute complications (rupture and dissection) is higher in patients with a bicuspid aortic valve (BAV), the most frequent congenital heart defect.The present review focuses on the current knowledge in the genetics of BAV, emphasizing the clinical implications for early detection and personalized care. RECENT FINDINGS: BAV is a highly heritable trait, but the genetic causes remain largely elusive. NOTCH1 is the only proven candidate gene to be associated with both familial and sporadic BAV. Other genes have been reported to be associated with BAV, but some of these associations may result from coexisting disease.The application of modern high-throughput technologies (next generation sequencing, genome-wide copy number and genome-wide methylation arrays) have begun to dissect the genetic heterogeneity underlying BAV as well as the diverse molecular pathways involved in the progression of BAV aortopathy. SUMMARY: The clinical variability seen in BAV aortopathy, in terms of phenotype and natural/clinical history, suggests complex interactions between primary genetic defects, other modifier genes, epigenetic factors (DNA methylation or histone modifications, microRNA) and environmental factors (disturbed flow). Integrated, more comprehensive studies are needed for elucidating these connections to develop more individualized and accurate risk assessment methods.

Analysis of miRNAs Targeting 3'UTR of H2AFX Gene: a General in Silico Approach.

MiRNAs are gene (post-transcriptional) regulators that bind the 3'UTR of target genes. Single-nucleotide polymorphisms (SNPs) located within a miRNA binding site can impact miRNAdependent gene regulation by weakening or reinforcing the microRNA:mRNA bond. We present a general in silico approach enabling researchers to "predict" which of the several SNPs of 3'UTR of H2AFX gene can mainly affect its regulation. H2AFX gene encodes a member of the H2A histone family which is central in the detection of and response to DNA double-strand breaks. All the 17 common SNPs located within the 3'UTR of H2AFX gene were analyzed for putative miRNA-binding sites by using different databases (such as dbSNP and miRBase) and pre-existing algorithms (such as MicroSNiPer and RNAcofold) in order to calculate the minimum free energies of hybridization of the microRNA:mRNA duplex, for both the wild-type and mutant alleles. The difference in these energies was also calculated. Since in each tissue one target sequence can bind only one miRNA at a time, the sum of all the difference of energies can be considered a relevant parameter for predicting the importance of a SNP with respect to miRNA regulation. We used tertiles to classify the SNPs and provide a priority list based on their theoretically strongest impact on miRNA binding. By using the described approach, we provided the basis for a reasoned, user-friendly algorithm-driven selection of SNPs impacting miRNA biology. The proposed method is helpful for selecting SNPs having a more powerful (putative) biological function, minimizing workflow and costs for experimental and clinical investigations.

Mind injuries after cardiac surgery.

After cardiac surgery, delirium, cognitive dysfunction, depression, or anxiety disorders frequently occur, and profoundly affect patients' prognosis and quality of life. This narrative review focuses on the main clinical presentations of cognitive and psychological problems ('mind injuries') that occur postoperatively in absence of ascertainable focal neurologic deficits, exploring their pathophysiological mechanisms and possible strategies for prevention and treatment. Postoperative cognitive dysfunction is a potentially devastating complication that can involve several mechanisms and several predisposing, intraoperative, and postoperative risk factors, which can result in or be associated to cerebral microvascular damage. Postoperative depression is influenced by genetic or psychosocial predisposing factors, by neuroendocrine activation, and by the release of several pro-inflammatory factors. The net effect of these changes is neuroinflammation. These complex biochemical alterations, along with an aspecific response to stressful life events, might target the function of several brain areas, which are thought to represent a trigger factor for the onset of depression.

Stromal cell-derived factor-1-3'A polymorphism is associated with decreased risk of myocardial infarction and early endothelial disturbance.

AIM: Genome-wide association studies have identified single-nucleotide polymorphisms at the 10q11 locus as risk factors for myocardial infarction (MI). This locus lies upstream (∼80 kb) of the stromal cell-derived factor-1 (SDF1) gene that codify for a chemokine with protective atherogenetic effects and with a major role in the mobilization, homing, and differentiation of endothelial progenitor cells (EPCs). The purpose of this study was to investigate the possible association of SDF1-3'A polymorphism, that upregulates SDF1 protein expression, with MI and early endothelial dysfunction and atherosclerosis in young healthy subjects. METHODS: 200 patients (181 men age 57.3 ±â€Š7.7 years) and 230 healthy controls (96 men, age 52 ±â€Š11.9 years) were recruited to investigate the association between MI and SDF1-3'A polymorphism. The relationship between SDF1-3'A polymorphism and brachial artery flow-mediated dilation and the number of circulating EPCs was examined in 50 healthy young adults. RESULTS: A significant difference in SDF1-3'A genotype distribution was observed between patients and controls (P = 0.006). Patients carrying the A allele had a significantly reduced MI risk compared with subjects with GG genotype (odds ratio = 0.5, 95% CI = 0.3-0.9, P = 0.001). SDF1-3'A polymorphism presented a significant interaction with other cardiovascular risk factors (Pinteraction < 0. 0001). Controls carrying the A allele showed significantly higher flow-mediated dilation (13.9 ±â€Š4.9 vs 10.8 ±â€Š4.3, P = 0.03) and significantly higher values of EPCs (0.029 ±â€Š0.009 vs 0.022 ±â€Š0.008, P = 0.02) compared with GG homozygotes. CONCLUSION: SDF1-3'A polymorphism is associated with a decreased risk of MI and early endothelial dysfunction, strongly confirming the important atherogenic role of SDF1 gene at clinical level.

Correlation between vitamin D binding protein expression and angiographic-proven coronary artery disease.

AIM: Proteomics is considered a promising tool in the discovery of new biomarkers and/or therapeutic targets. The aim of this study was to identify proteins expressed in the plasma of survivors of myocardial infarction and possible correlations between expression of some proteins and the severity of coronary artery disease (CAD) in this population. METHODS: The study included 17 survivors (15 men; age=53±9 years) of myocardial infarction at young age (age<60 years) classified for the severity of CAD graded according to angiography and 10 healthy volunteers (nine men; age=54±9 years). Proteomic analysis was carried out using a high-throughput technology and MALDI TOF/TOF mass spectrometry. RESULTS: Compared with the healthy population, 14 proteins were differentially expressed in patients, and were classified in three principal categories: contraction, inflammation, and coagulation. Results show a correlation between the angiographic severity, the extension of CAD, and the expression of some proteins. In particular decreased levels of vitamin D binding protein (VDBP) in the plasma of patients statistically correlated with the number of affected coronary arteries. Enzyme-linked immunosorbent assay test confirmed modulation of VDBP. CONCLUSION: Our results suggest that some proteins are differentially expressed in atherosclerotic patients and their disregulation is strongly dependent on the severity of the artery disease. The down regulation of VDBP is confirmed and marked in multivessel disease patients.

Hormone replacement therapy and cardioprotection: a new dawn? A statement of the Study Group on Cardiovascular Disease in Women of the Italian Society of Cardiology on hormone replacement therapy in postmenopausal women.

Cardiovascular disease is the leading cause of death in women in Western countries. Despite preventive strategies, in the past decades the incidence of cardiovascular events has shown a decline in men but a rise in women, matching the growth of the population of postmenopausal women. Several epidemiological findings suggest the causative pathophysiological role of ovarian hormone deficiency in the development of cardiovascular disease in women. Observational and randomized studies have suggested that hormone replacement therapy in early postmenopause could be beneficial from a cardiovascular point of view. Conversely, aging, time since menopause and presence of cardiovascular risk factors or cardiovascular disease may decrease its efficacy and increase the risk of cardiovascular events. It is plausible that the unfavorable effects of the estrogen/progestin combination used in the randomized studies are not related to the hormone preparation per se but rather to the use of hormones in the less receptive group of women, older and with cardiovascular risk factors. Clinical judgment, choice of the right dose and estrogen/progestin combination are of pivotal importance to maximize the beneficial effect of estrogen replacement therapy/hormone replacement therapy, especially if given within a reasonable time after the menopause to women who need the therapy for the relief of menopausal symptoms.

Elevated levels of oxidative DNA damage in patients with coronary artery disease.

BACKGROUND: Somatic DNA damage has been suggested to contribute to the pathogenesis of atherosclerosis. However, little is known about the role of oxidative DNA damage in patients with coronary artery disease (CAD). METHODS: In this study, we used the comet assay to measure oxidative DNA damage (DNA strand breaks and enzyme-sensitive sites) in peripheral blood lymphocytes from 13 patients with angiographically documented CAD and 11 age- and sex-matched control participants. RESULTS: Mean values of DNA strand breaks, oxidized pyrimidines and altered purines were significantly higher in CAD patients than in the control group (11.9 +/- 1.4, 18.0 +/- 2.7 and 18.1 +/- 3.1 compared with 3.3 +/- 0.2, 2.7 +/- 0.5 and 4.5 +/- 1.1; P < 0.0001, P < 0.0001 and P = 0.0009, respectively). Moreover, oxidized purines (for example, 8-oxo-guanine) increased with the number of affected vessels and positively correlated with the extent of CAD measured by means of the number of the coronary lesions (P = 0.76, P = 0.003) and the Duke scoring system (P = 0.66, P = 0.01). Diabetic patients showed higher levels of oxidized pyrimidines (31.3 +/- 5.5 compared with 14.1 +/- 2.7; P = 0.013), while patients with dyslipidemia had elevated altered purines compared with normal patients (20.4 +/- 2.6 compared with 4.9 +/- 3.1; P = 0.03). CONCLUSIONS: These data indicate an overall elevation of oxidative DNA damage in CAD patients correlated with the severity of the disease and some atherogenic risk factors, suggesting a possible role of oxidative genetic damage in the pathogenesis of atherosclerosis.