Validating scores predicting atrial fibrillation recurrence post catheter ablation in patients with concurrent atrial fibrillation and pulmonary diseases.

BACKGROUND: Several scores were available for predicting atrial fibrillation (AF) recurrence post radiofrequency ablation. However, the role of different scores predicting AF recurrence after ablation in patients with concurrent AF and pulmonary diseases (PDs) remained obscure. Herein, we aimed to investigate their predicting values and differences in patients with concurrent AF and PDs. METHODS: From January 2008 to April 2015, 304 patients with concurrent AF and PDs treated with catheter ablation were divided into 2 groups according to whether they experienced AF recurrence in our centers. Factors related with AF recurrence were explored using Cox regression and scores predicting recurrent AF were compared in these patients using ROC curves. RESULTS: During a median of 6-month of follow-up, factors correlating with late AF recurrence included heart failure (HF) history [hazard ratio (HR): 2.79; 95% confidence interval (CI): 1.49-5.22, P=0.001], current smoking (1.73; 1.13-2.68, P=0.01) and early AF recurrence (3.85; 95% CI: 2.62-5.66, P<0.001) according to univariate Cox regression analysis. When analyzed using multivariate Cox model, HF history (2.21; 1.12-4.37, P=0.02), hypertension history (1.54; 1.02-2.33, P=0.04) and early AF recurrence (3.90; 2.60-5.85, P<0.001) were related to late AF recurrence. The BASE-AF2 score had higher c-index than the MB-LATER, APPLE, CHADS2, CHA2DS2-VASc, CAAP-AF and HATCH scores when compared using ROC curves analysis (all P<0.05). The optimal point for predicting AF recurrence of the BASE-AF2 score in the ROC analysis was 1 point with sensitivity of 69.03% and specificity of 60.21%. CONCLUSIONS: The predicting AF recurrence value of BASE-AF2 score was superior to MB-LATER, APPLE, CHADS2, CHA2DS2-VASc, CAAP-AF and HATCH scores in patients with concurrent AF and PDs, which can be an effective and helpful score for making AF treatment decisions.

Network-based characterization and prediction of human DNA repair genes and pathways.

Network biology is a useful strategy to understand cell's functional organization. In this study, for the first time, we successfully introduced network approaches to study properties of human DNA repair genes. Compared with non-DNA repair genes, we found distinguishing features for DNA repair genes: (i) they tend to have higher degrees; (ii) they tend to be located at global network center; (iii) they tend to interact directly with each other. Based on these features, we developed the first algorithm to predict new DNA repair genes. We tested several machine-learning models and found that support vector machine with kernel function of radial basis function (RBF) achieve the best performance, with precision = 0.74 and area under curve (AUC) = 0.96. In the end, we applied the algorithm to predict new DNA repair genes and got 32 new candidates. Literature supporting four of the predictions was found. We believe the network approaches introduced here might open a new avenue to understand DNA repair genes and pathways. The suggested algorithm and the predicted genes might be helpful for scientists in the field.

Systematic Characterization and Prediction of Human Hypertension Genes.

Hypertension is a major cardiovascular risk factor and accounts for a large part of cardiovascular mortality. In this work, we analyzed the properties of hypertension genes and found that when compared with genes not yet known to be involved in hypertension regulation, known hypertension genes display distinguishing features: (1) hypertension genes tend to be located at network center; (2) hypertension genes tend to interact with each other; and (3) hypertension genes tend to enrich in certain biological processes and show certain phenotypes. Based on these features, we developed a machine-learning algorithm to predict new hypertension genes. One hundred and seventy-seven candidates were predicted with a posterior probability >0.9. Evidence supporting 17 of the predictions has been found.

Towards understanding the lifespan extension by reduced insulin signaling: bioinformatics analysis of DAF-16/FOXO direct targets in Caenorhabditis elegans.

DAF-16, the C. elegans FOXO transcription factor, is an important determinant in aging and longevity. In this work, we manually curated FOXODB http://lyh.pkmu.cn/foxodb/, a database of FOXO direct targets. It now covers 208 genes. Bioinformatics analysis on 109 DAF-16 direct targets in C. elegans found interesting results. (i) DAF-16 and transcription factor PQM-1 co-regulate some targets. (ii) Seventeen targets directly regulate lifespan. (iii) Four targets are involved in lifespan extension induced by dietary restriction. And (iv) DAF-16 direct targets might play global roles in lifespan regulation.

Ghrelin protects heart against ERS-induced injury and apoptosis by activating AMP-activated protein kinase.

Ghrelin, the endogenous ligand of growth hormone secretagogue receptor (GHS-R), is a cardioprotective peptide. In our previous work, we have revealed that ghrelin could protect heart against ischemia/reperfusion (I/R) injury by inhibiting endoplasmic reticulum stress (ERS), which contributes to many heart diseases. In current study, using both in vivo and in vitro models, we investigated how ghrelin inhibits myocardial ERS. In the in vivo rat heart injury model induced by isoproterenol (ISO), we found that exogenous ghrelin could alleviate heart dysfunction, reduce myocardial injury and apoptosis and inhibit the excessive myocardial ERS induced by ISO. More importantly, the activation of AMP-activated protein kinase (AMPK) was observed. To explore the role of AMPK activation in ERS inhibition by ghrelin, we set up two in vitro ERS models by exposing cultured rat cardiomyocytes to tunicamycin(Tm) or dithiothreitol (DTT). In both models, compared with Tm or DTT treatment alone, pre-incubation cardiomyocytes with ghrelin significantly activated AMPK, reversed the upregulation of the ERS markers, C/EBP-homologous protein (CHOP) and cleaved caspase-12, and reduced apoptosis of cardiomyocytes. Further, we found that the ERS inhibitory and anti-apoptotic actions induced by ghrelin were blocked by an AMPK inhibitor. To investigate how ghrelin activates AMPK, selective antagonist of GHS-R1a and inhibitor of Ca(2+)/Calmodulin-dependent protein kinase kinase (CaMKK) were added, respectively, before ghrelin pre-incubation, and we found that AMPK activation was prevented and the ERS inhibitory and anti-apoptotic actions of ghrelin were blocked. In conclusion, ghrelin could protect heart against ERS-induced injury and apoptosis, at least partially through a GHS-R1a/CaMKK/AMPK pathway.

Cortistatin attenuates vascular calcification in rats.

Cortistatin (CST) is a newly discovered polypeptide with multiple biological activities that plays a regulatory role in the nervous, endocrine and immune systems. However, the role of CST in the pathogenesis of cardiovascular diseases remains unclear. In this study, we investigated in rats whether CST inhibits vascular calcification induced by vitamin D3 and nicotine treatment in vivo and calcification of cultured rat vascular smooth muscular cells (VSMCs) induced by beta-glycerophosphate in vitro and the underlying mechanism. We measured rat hemodynamic variables, alkaline phosphatase (ALP) activity, calcium deposition and pathological changes in aortic tissues and cultured VSMCs. CST treatment significantly improved hemodynamic values and arterial compliance in rats with vascular calcification, by decreasing systolic blood pressure, pulse pressure, left ventricular end-systolic pressure and left ventricular end-diastolic pressure. CST also significantly decreased ALP activity and calcium deposition, alleviated pathological injury and down-regulated the mRNA expression of type III sodium-dependent phosphate co-transporter-1 (Pit-1) in aortic tissues. It dose-independently inhibited the calcification of VSMCs by decreasing ALP activity and calcium deposition, alleviating pathologic injury and down-regulating Pit-1 mRNA expression. As with CST treatment, ALP activation and calcium deposition were decreased significantly on treatment with ghrelin, the endogenous agonist of growth hormone secretagogue receptor 1a (GHSR1a), but not significantly with somatostatin-14 or proadrenomedullin N-terminal 20 peptide in VSMCs. Further, growth hormone-releasing peptide-6[D-lys], the endogenous antagonist of GHSR1a, markedly reversed the increased ALP activity and calcium deposition in VSMCs. CST could be a new target molecule for the prevention and therapy of vascular calcification, whose effects are mediated by GHSR1a rather than SSTRs or Mrg X2.

[Effect of adenovirus-mediated tissue factor pathway inhibitor gene transfer on apoptosis of rat vascular smooth muscle cells].

OBJECTIVE: Previous studies showed potential role of tissue factor pathway inhibitor (TFPI) on attenuating restenosis, we investigated the effect of TFPI gene transfer on vascular smooth muscle cells (VSMCs) apoptosis. METHODS: Human TFPI recombinant adenovirus or LacZ recombinant adenovirus or PBS were transferred to rat aortic VSMCs respectively in vitro. RT-PCR was used to detect the expression of exogenous TFPI gene. VSMCs were examined by cell counting and MTT. Apoptosis of VSMCs was detected by flow cytometry, TUNEL and electron microscope at different time after gene transfer. RESULTS: mRNA expression of TFPI was detected in VSMCs at the 3rd day after gene transfer. Cell numbers and absorbance value in Ad-TFPI group were similar as those in Ad-LacZ and PBS groups at the 1st, 3rd and 5th day but significantly lower at the 7th day (P<0.05) after gene transfer. The apoptosis rates in Ad-TFPI group tested by flow cytometry were all significant higher than those in Ad-lacZ groups at each time point. The positive rates in Ad-TFPI group determined by TUNEL were significant higher than those in Ad-LacZ groups at 3rd (10.82% +/- 1.57% vs. 3.46% +/- 0.93%), 5th and 7th (16.95% +/- 2.01% vs. 5.11% +/- 1.29%, all P<0.05) day post gene transfer. Electron microscope evidenced cell contracting, cytoplasm condensing, lightly swelled mitochondria, nucleus pyknosis and apoptotic body formation after gene transfer in Ad-TFPI group which were not shown in cells of LacZ and PBS groups. CONCLUSION: TFPI gene transfer could induce apoptosis in rat VSMCs which might be one of the mechanisms responsible for its beneficial effect on restenosis inhibition after angioplasty.

Inhibition of endoplasm reticulum stress by ghrelin protects against ischemia/reperfusion injury in rat heart.

Ghrelin is a multi-functional polypeptide with cardiovascular protective effects. We aimed to explore whether the cardioprotective effect of ghrelin is mediated by inhibiting myocardial endoplasmic reticulum stress (ERS). A Langendorff model of isolated rat heart was used with ischemia/reperfusion (I/R; 40/120 min). Cardiac function was monitored, and histomorphologic features, degree of myocardial injury, level of ERS markers, and number of apoptotic cardiomyocytes were determined. Compared with control group, the I/R group showed significantly decreased cardiac function, seriously damaged myocardial tissue, increased number of apoptotic cells, and overexpression of mRNA and protein of ERS markers. However, preadministration of ghrelin in vivo (10(-8)mol/kg, intraperitoneal injection, every 12h, twice in all) greatly ameliorated the damaged heart function, attenuated myocardial injury and apoptosis, and decreased the expression of ERS markers: it decreased the mRNA and protein levels of glucose-regulated protein78 (GRP78) and C/EBP homologous protein (CHOP), with reduced caspase-12 protein expression. Furthermore, in vitro, ghrelin directly inhibited the myocardial ERS response induced by tunicamycin or dithiothreitol in rat cardiac tissue. Ghrelin could protect the heart against I/R injury, at least in part, through inhibiting myocardial ERS.