Identification of key genes involved in calcific aortic valve disease based on integrated bioinformatics analysis.

The calcific aortic valve disease (CAVD) develops as an aortic valve sclerosis and progresses to an advanced form of stenosis. In many biological fields, bioinformatics becomes a fundamental component. The key mechanisms involved in CAVD are discovered with the use of bioinformatics to investigate gene function and pathways. We downloaded the original data (GSE51472) from the Gene Expression Omnibus (GEO) database (http://www.ncbi.nlm.nih.gov/geo/). After standardization, 2978 differentially expressed genes (DEGs) were identified from the data sets GSE51472 containing samples from normal, calcified, and sclerotic aortic valves. Analysis of DEGs based on the series test of clusters (STCs) revealed the two most significant patterns. Based on the result of the STC, the functional enrichment analysis of gene ontology (GO) was conducted to investigate the molecular function (MF), biological process (BP), and cell compound (CC) of the DEGs. With a p value of 0.01, DEGs associated with "chronic inflammation," "T-cell receptor complexes," and "antigen binding" had the highest significance within BP, CC, and MF. DEG enrichment in signaling pathways was analyzed using KEGG pathway enrichment. Using a p < 0.05 level of significance, the most enriched biological pathways related to CAVD were "Chemokine signaling pathway," "Cytokine-cytokine receptor interaction," "Tuberculosis," "PI3K-Akt signaling pathway," and "Transcriptional misregulation in cancer." Finally, the construction of gene co-expression networks and pathway networks illustrated the pathogensis of CAVD. TLR2, CD86, and TYROBP were identified as hub genes for the development of CAVD. Moreover, "MAPK signaling pathway," "Apoptosis," and "Pathways in cancer" were regarded as the core pathways among the samples of normal, sclerotic and calcified aortic valve samples.

Clinical Relevance of Plasma Endogenous Tissue-Plasminogen Activator and Aortic Valve Sclerosis: Performance as a Diagnostic Biomarker.

Background: Aortic valve sclerosis (AVSc), a common precursor to calcific aortic valve disease, may progress into advanced aortic stenosis with hemodynamic instability. However, plasma biomarkers of such a subclinical condition remain lacking. Since impaired fibrinolysis featuring dysregulated tissue plasminogen activator (t-PA) is involved in several cardiovascular diseases, we investigated whether endogenous t-PA was also associated with AVSc. Methods: Plasma t-PA levels were measured in 295 consecutive patients undergoing standard echocardiography and Doppler flow imaging. Multiple logistic regression analyses were used to assess the association between t-PA and AVSc. Receiver operating characteristic curve analysis was performed for determining the diagnostic value of t-PA for AVSc. The performance of adding t-PA to clinical signatures of AVSc was evaluated. Concentration of t-PA was assessed in human sclerotic and non-sclerotic aortic valves by histology and immunohistochemistry analysis. Results: Plasma t-PA was higher in patients with AVSc than in non-AVSc counterparts (median, 2063.10 vs. 1403.17 pg/mL, p < 0.01). C-statistics of plasma t-PA for discriminating AVSc was 0.698 (95%CI: 0.639-0.758). The performance of t-PA for identifying AVSc was better among male and non-hypertensive patients [C-statistics (95%CI): 0.712 (0.634-0.790) and 0.805 (0.693-0.916), respectively]. Combination of t-PA and clinical factors improved classification of the patients (category-free NRI: 0.452, p < 0.001; IDI: 0.020, p = 0.012). The concentration of t-PA was three times higher in sclerotic compared to non-sclerotic aortic valves. Conclusion: Elevated circulating t-PA level confers an increased risk for AVSc. Further prospective studies with larger sample size are needed to examine if t-PA could serve as a diagnostic clinical marker for AVSc.

Clinical significance of pain in patients with chronic heart failure.

BACKGROUND: There is a paucity of studies investigating the clinical and biochemical characteristics of pain in chronic heart failure (CHF) patients. This study aimed to determine the clinical and biochemical characteristics and outcomes in Chinese patients with CHF and symptoms of pain. METHODS: Sociodemographics, serum levels of creatinine, NT-proBNP, high-sensitivity C-reactive protein (hs-CRP), tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-10, and two-dimensional echocardiographic left ventricular ejection fraction (LVEF) were determined in 305 patients with CHF. A questionnaire packet including the Brief Pain Inventory (BPI) and the Minnesota Living with Heart Failure Questionnaire (MLHFQ) was used to assess the degree of pain rated on a 0 - 10 scale and the quality of life (QOL). A six-minute walking test was performed during routine clinic visits. Major adverse cardiac events (MACE) were recorded; including all-cause or cardiac mortality and rehospitalization because of myocardial infarction, worsening heart failure or stroke at follow-up. RESULTS: Pain occurred in 25.6% of CHF patients, and was more common when the New York Heart Association (NYHA) functional class was worse. More patients with pain were female in gender, and had more co-morbidities, lower LVEF, and shorter distance during the 6-minute walking test. Despite similar serum levels of creatinine, N-terminal prohormone of brain natriuretic peptide (NT-proBNP), IL-6 and IL-10, the TNF-α levels were higher and MLHFQ scores were greater in CHF patients with pain. At follow-up, CHF patients with moderate to severe pain (≥ 4 scale) had higher rates of all-cause and cardiac mortality and rehospitalization because of myocardial infarction, worsening heart failure or stroke. Multivariate regression analysis revealed that the presence of pain was an independent risk factor for MACE and reduced QOL in CHF patients. CONCLUSIONS: Pain occurs in all stages of the CHF trajectory, and its incidence increases as clinical functional status is worsened. The presence of pain exerts a negative impact on clinical outcome and QOL in patients with CHF.

Impact of potentially lethal ventricular arrhythmias on long-term outcome in patients with chronic heart failure.

BACKGROUND: Potentially lethal ventricular arrhythmias (PLVAs) occur frequently in survivors after acute myocardial infarction and are increasingly recognized in other forms of structural heart diseases. This study investigated the prevalence and prognostic significance of PLVAs in patients with chronic heart failure (CHF). METHODS: Data concerning demographics, etiology of heart failure, NYHA functional class, biochemical variables, electrocardiographic and echocardiographic findings, and medical treatments were collected by reviewing hospital medical records from 1080 patients with NYHA II-IV and a left ventricular (LV) ejection fraction ≤ 45%. PLVAs were defined as multi-focal ventricular ectopy (> 30 beats/h on Holter monitoring), bursts of ventricular premature beats, and nonsustained ventricular tachycardia. All-cause mortality, sudden death, and rehospitalization due to worsening heart failure, or cardiac transplantation during 5-year follow-up after discharge were recorded. RESULTS: The occurrence rate of PLVAs in CHF was 30.2%, and increased with age; 23.4% in patients < 45 years old, 27.8% in those between 45 - 65 years old, and 33.5% in patients > 65 years old (P = 0.033). Patients with PLVAs had larger LV size and lower ejection fraction (both P < 0.01) and higher all-cause mortality (P = 0.014) during 5-year follow-up than those without PLVAs. Age (OR 1.041, 95%CI 1.004 - 1.079, P = 0.03) and LV end-diastolic dimension (OR 1.068, 95%CI 1.013 - 1.126, P = 0.015) independently predicted the occurrence of PLVAs. And PLVA was an independent factor for all-cause mortality (RR 1.702, 95%CI 1.017 - 2.848, P = 0.031) and sudden death (RR 1.937, 95%CI 1.068 - 3.516, P = 0.030) in patients with CHF. CONCLUSION: PLVAs are common and exert a negative impact on long-term clinical outcome in patients with CHF.