Search

Cardiac fibroblasts (CFs) drive extracellular matrix remodeling after inflammatory injury, leading to cardiac fibrosis and diastolic dysfunction. Recent studies described the role of epigenetics in cardiac fibrosis. Nevertheless, detailed reports on epigenetics regulating CFs pyroptosis and describing their implication in cardiac fibrosis are still unclear. Here, we found that DNMT3A reduces the expression of lncRNA Neat1 and promotes the NLRP3 axis leading to CFs pyroptosis, using cultured cells, animal models, and clinical samples to shed light on the underlying mechanism. We report that pyroptosis-related genes are increased explicitly in cardiac fibrosis tissue and LPS-treated CFs, while lncRNA Neat1 decreased. Mechanistically, we show that loss of DNMT3A or overexpression of lncRNA Neat1 in CFs after LPS treatment significantly enhances CFs pyroptosis and the production of pyroptosis-related markers in vitro. It has been demonstrated that DNMT3A can decrease lncRNA Neat1, promoting NLRP3 axis activation in CFs treated with LPS. In sum, this study is the first to identify that DNMT3A methylation decreases the expression of lncRNA Neat1 and promotes CFs pyroptosis and cardiac fibrosis, suggesting that DNMT3A and NEAT1 may function as an anti-fibrotic therapy target in cardiac fibrosis.

Novel insights into epigenetic control of cardiac fibrosis are now emerging. Cardiac fibroblasts (CFs) activation into myofibroblasts and the production of extracellular matrix (ECM) is the key to cardiac fibrosis development, but the specific mechanism is not fully understood. In the present study, we found that DNMT1 hypermethylation reduces the expression of microRNA-152-3p (miR-152-3p) and promotes Wnt1/β-catenin signaling pathway leading to CFs proliferation and activation. Cardiac fibrosis was produced by ISO, and the ISO was carried out according to the method described. CFs were harvested and cultured from SD neonatal rats and stimulated with TGF-β1. Importantly, DNMT1 resulted in the inhibition of miR-152-3p in activated CFs and both DNMT1 and miR-152-3p altered Wnt/β-catenin downstream protein levels. Over expression of DNMT1 and miR-152-3p inhibitors promotes proliferation of activating CFs. In addition, decreased methylation levels and over expression of miR-152-3p inhibited CFs proliferation. We determined that DNMT1 can methylate to miR-152-3p and demonstrated that expression of miR-152-3p inhibits CFs proliferation by inhibiting the Wnt1/β-catenin pathway. Our results stand out together DNMT1 methylation regulates miR-152-3p to slow the progression of cardiac fibrosis by inhibiting the Wnt1/β-catenin pathway.

Cell death and inflammation play critical roles in cardiac fibrosis. During the fibrosis process, inflammation and tissue injury were triggered; however, the mechanisms initiating cardiac fibrosis and driving fibroblast pyroptosis remained largely unknown. In this study, we identified long non-coding RNA (LncRNA)-GAS5 as the key onset of cardiac fibroblast pyroptosis and cardiac fibrosis. Here, we detected ISO-induced cardiac fibrosis models and cardiac fibroblast pyroptosis model by stimulating with LPS. We found that the expression of pyroptosis-related proteins such as caspase 1, NLRP3, and DNMT1 was increased in cardiac fibrosis tissue, while the expression of GAS5 was decreased. The overexpressing of LncRNA GAS5 was shown to increase and inhibit cardiac fibroblast pyroptosis, as well as attenuate caspase 1 and NLRP3 expression in cardiac fibroblast. However, the silencing of GAS5 was also observed; it shows the opposite situation. Furthermore, further studies revealed that treatment of DNMT inhibitor, 5-aza-2-deoxycytidine, or downregulation of DNMT1 led to increased GAS5 expression by reversion of promoter hypermethylation in cardiac fibroblast. Importantly, we have demonstrated that DNMT1 methylation of LncRNA GAS5 leads to cardiac fibroblast pyroptosis via affecting NLRP3 axis. Our findings indicate a new regulatory mechanism for cardiac fibroblast pyroptosis under LPS stress, providing a novel therapeutic target for cardiac fibrosis. Graphical Abstract.

Diabetic cardiomyopathy (DCM) is a serious cardiac complication of diabetes, which further lead to heartfailure. It is known that diabetes-induced cardiac fibrosis is a key pathogenic factor contributing topathological changes in DCM. However, pathogenetic mechanisms underlying diabetes cardiac fibrosis arestill elusive. Recent studies have indicated that noncoding RNAs (ncRNAs) play a key role in diabetescardiac fibrosis. The increasing complexity of epigenetic regulator poses great challenges to ourconventional conceptions regarding how ncRNAs regulate diabetes cardiac fibrosis. We searched PubMed, Web of Science, and Scopus for manuscripts published prior to April 2018 using keywords "Diabetic cardiomyopathy" AND " diabetes cardiac fibrosis " OR " noncoding RNAs " OR " longnoncoding RNAs " OR " microRNAs " OR "epigenetic". Manuscripts were collated, studied and carriedforward for discussion where appropriate. Based on the view that during diabetic cardiac fibrosis, ncRNAs are able to regulate diabetic cardiac fibrosisby targeting genes involved in epigenetic pathways. Many studies have focused on ncRNAs, an epigeneticregulator deregulating protein-coding genes in diabetic cardiac fibrosis, to identify potential therapeutictargets. Recent advances and new perspectives have found that long noncoding RNAs and microRNAs,exert their own effects on the progression of diabetic cardiac fibrosis. We firstly examine the growing role of ncRNAs characteristics and ncRNAs-regulated genes involved indiabetic cardiac fibrosis. Then, we provide several possible therapeutic strategies and highlight the potentialof molecular mechanisms in which targeting epigenetic regulators are considered as an effective means of treating diabetic cardiac fibrosis.

Cardiac fibrosis is defined as excess deposition of extracellular matrix (ECM), resulting in tissue scarring and organ dysfunction. In recent years, despite the underlying mechanisms of cardiac fibrosis are still unknown, numerous studies suggest that epigenetic regulation of cardiac fibrosis. Cardiac fibrosis is regulated by a myriad of factors that converge on the transcription of genes encoding extracellular matrix protein, a process the epigenetic machinery plays a pivotal role. Epigenetic modifications contain three main processes: DNA methylation, histone modifications, and noncoding RNAs. Here, we review recent studies that have illustrated key roles for epigenetic events in the control of pro-fibrotic gene expression, and highlight the potential of molecule mechanisms that target epigenetic regulators as a means of treating cardiac fibrosis.

Xiao Zhou, Hui Tao, Kai-Hu Shi Department of Cardiothoracic Surgery, The Second Hospital of Anhui Medical University, Hefei, People’s Republic of China Abstract: The aim of this study was to develop PEGylation liposomes formulations of erlotinib and evaluate their characteristics, stability, and release characteristics. The average particle sizes and entrapment efficiency of PEGylation erlotinib liposomes are 102.4±3.1nm and 85.3%±1.8%, respectively. Transmission electron microscopy images showed that the liposomes dispersed well with a uniform shape and no changes during the storage. The invitro drug-release kinetic model of erlotinib release from the PEGylation liposomes in phosphate-buffered saline fit well with the Higuchi equation. In vitro anticancer activity assay showed that the blank liposomes had lower cellular cytotoxicity and that the cellular cytotoxicity of erlotinib liposomes increased significantly under the same incubation condition, which should contribute to the increase in intracellular drug concentration by the transportation of liposomes. The two liposomes of erlotinib (with and without PEGylation) exhibited similar cellular cytotoxicity with no significantly different concentrations. Pharmacokinetic results indicated that erlotinib-loaded PEGylation liposomes can significantly change the pharmacokinetic behavior of drugs and improve the drug bioavailability by nearly 2 times compared to ordinary liposomes. No sign of damages such as the appearance of epithelial necrosis or sloughing of epithelial cells was detected in histological studies. Keywords: cellular cytotoxicity, drug-release, erlotinib, PEGylation liposomes, pharmacokinetic

Long noncoding RNAs (LncRNAs) are aberrantly expressed in many diseases including cardiac fibrosis. LncRNA growth arrest-specific 5 (GAS5) is reported as a significant mediator in the control of cell proliferation and growth; however, the role and function in cardiac fibrosis remain unknown. In this study, we confirmed that GAS5 was lowly expressed in cardiac fibrosis tissues as well as activated cardiac fibroblast. Overexpression of GAS5 inhibited the proliferation of cardiac fibroblast. Moreover, microRNA-21 (miR-21) has been reported to be overexpressed in cardiac fibrosis tissues as well as activated cardiac fibroblast, which is responsible for the progression of cardiac fibrosis. We found that up-regulated GAS5 decreased the expression of miR-21 significantly. Furthermore, GAS5 that upregulated or downregulated the expression of PTEN through miR-21 in cardiac fibroblasts. Taken together, GAS5 plays a suppressive role in cardiac fibrosis via negative regulation of miR-21. These results indicated that GAS5 may be a novel therapeutic target for further research of cardiac fibrosis.

Aims/hypothesis MicroRNA-21 has been implicated in diabetic complication, including diabetic cardiomyopathy. However, there is limited information regarding the biological role of the miR-21 passenger strand (miR-21–3p) in diabetic cardiac fibrosis. The aim of this study was to investigate the role of miR-21–3p and its target androgen receptor in STZ-induced diabetic cardiac fibrosis. Methods The pathological changes and collagen depositions was analyzed by HE, Sirius Red staining and Masson's Trichrome Staining. MiR-21–3p, AR, NLRP3, caspase1 and collagen I expression were analyzed by western blotting, immunohistochemistry, immunofluorescence, qRT-PCR, miR one step qRT-PCR, respectively. A luciferase reporter assay was used to verify the interaction between miR-21 and the 3′ untranslated region (3′UTR) of AR. Results Our results indicated that miR-21–3p level was up-regulated, while AR was decreased in STZ-induced diabetic cardiac fibrosis tissues and cardiac fibroblast. High glucose triggers cardiac fibroblasts pyroptosis and collagen deposition. Gain-of-function and loss-of-function assays demonstrated that miR-21–3p mediated the crucial role in diabetic cardiac fibrosis. Our results show that miR-21–3p bound to the 3′UTR of AR post-transcriptionally repressed its expression. We also found AR, which regulates cardiac fibroblasts pyroptosis and collagen deposition through caspase1 signaling. Conclusions /interpretation: Taken together, our study showed that miR-21–3p aggravates STZ-induced diabetic cardiac fibrosis through the caspase1 pathways by suppressing AR expression.

Down-regulation of DUSP5 has been shown to increase cell proliferation. DUSP5 expression is regulated through epigenetic events involving LncRNA H19 human choriocarcinoma cell line. However, the molecular mechanisms of H19 modulating the DUSP5 expression in cardiac fibrosis remain largely unknown. Here, we identify H19 negatively regulation of DUSP5 gene expression in cardiac fibroblast and fibrosis tissues. In vivo, the expression levels of H19, DUSP5, α-SMA, p-ERK1/2, and ERK1/2 in cardiac fibrosis tissue were estimated by Western blotting, quantitative reverse transcription-polymerase chain reaction and immunohistochemistry. In vitro stimulation of freshly isolated rat cardiac fibroblasts with recombinant marine TGF-β1 was performed, followed by quantitative reverse transcription-polymerase chain reaction and Western blotting to detect changes in H19, DUSP5, p-ERK1/2, and ERK1/2 levels. Cardiac fibroblasts were transfected with pEX-3-H19 overexpressing, H19-RNAi down-regulating, or pEGFP-C1-DUSP5 overexpressing. Finally, cell proliferation was assessed by the MTT assay and cell cycle. H19 endogenous expression is overexpressed in cardiac fibroblast and fibrosis tissues, and an opposite pattern is observed for DUSP5. H19 ectopic overexpression reduces DUSP5 abundance and increases the proliferation of cardiac fibroblast, whereas H19 silencing causes the opposite effects. In a broader perspective, these results demonstrated that LncRNA H19 contributes to cardiac fibroblast proliferation and fibrosis, which act in part through repression of DUSP5/ERK1/2.

Cardiac fibrosis is an important pathological feature of cardiac remodeling in heart diseases. Methyl-CpG-binding protein 2 (MeCP2) is a transcription inhibitor, and plays a key role in the fibrotic diseases. However, the precise role of MeCP2 in cardiac fibrosis remains unclear. α-tubulin plays an essential role in cell function, whereby the acetylation state of α-Tubulin dictates the efficiency of cell proliferation and differentiation. This study was undertaken to investigate that MeCP2 dynamics affect the acetylation state of α-tubulin in the cardiac fibrosis. Forty adult male Sprague–Dawley (SD) rats were randomly divided into two groups, cardiac fibrosis was produced by common ISO. Cardiac fibroblasts (CFs) were harvested from SD neonate rats and cultured. The expression of HDAC6, MeCP2, α-SMA, collagen I was measured by western blotting and qRT-PCR. siRNA of HDAC6 and MeCP2 effect the proliferation of cardiac fibroblasts, and affect the acetylation state of α-tubulin. We have found the acetylation state of α-tubulin in cardiac fibroblasts as well as cardiac tissue from a ISO-induced rat cardiac fibrosis model and observed a reduction in acetylated α-tubulin and an increase in the α-tubulin-specific deacetylase, histone deacetylase 6 (HDAC6). Furthermore, we have shown that treatment of cardiac fibroblasts with HDAC6 inhibitor Tubastatin A and HDAC6-siRNA can restore α-tubulin acetylation levels. In addition, treatment of cardiac fibroblasts with MeCP2-siRNA blocked cell proliferation. Knockdown of MeCP2 suppresses HDAC6 expression in activated cardiac fibroblasts but increases the acetylation of α-tubulin. We demonstrated that MeCP2 may negatively control the acetylation of α-tubulin through HDAC6 in cardiac fibroblast proliferation and fibrosis. This study indicated that MeCP2 could be a potentially new therapeutic option for cardiac fibrosis.

Objective Wnt signaling pathway significantly participates in cardiac fibrosis and CFs activation. Therefore, we reviewed current evidence on the new perspectives and biological association between Wnt signaling pathway and cardiac fibrosis. Design and Methods A PubMed database search was performed for studies of Wnt signaling pathway in cardiac fibrosis and CFs activation. Results Numerous studies have shown that the Wnt signaling pathway significantly participates in cardiac fibrosis pathogenesis. The aim of this review is to describe the present knowledge about the Wnt signaling pathway significantly participating in cardiac fibrosis and CFs activation, and look ahead on new perspectives of Wnt signaling pathway research. Moreover, we will discuss the different insights that interact with the Wnt signaling pathway-regulated cardiac fibrosis. The Wnt proteins are glycoproteins that bind to the Fz receptors on the cell surface, which lead to several important biological functions, such as cell differentiation and proliferation. There are several signals among the characterized pathways of cardiac fibrosis, including Wnt/β-catenin signaling. In this review, new insight into the Wnt signaling pathway in cardiac fibrosis pathogenesis is discussed, with special emphasis on Wnt/β-catenin. Conclusion It seems reasonable to suggest the potential targets of Wnt signaling pathway and it can be developed as a therapeutic target for cardiac fibrosis.

Lung cancer is the leading cause of cancer-related death worldwide with a 5-year survival rate of less than 15%, despite significant advances in both diagnostic and therapeutic approaches. Combined genomic and transcriptomic sequencing studies have identified numerous genetic driver mutations that are responsible for the development of lung cancer. Importantly, these approaches have also uncovered the widespread expression of "noncoding RNAs" including long noncoding RNAs (LncRNAs), which impact biologic responses through the regulation of mRNA transcription or translation. To date, most studies of the role of noncoding RNAs have focused on LncRNAs, which regulate mRNA translation via the RNA interference pathway. Although many of their attributes, such as patterns of expression, remain largely unknown, LncRNAs have key functions in transcriptional, post-transcriptional, and epigenetic gene regulation. Recent research showed that LncRNAs regulate flowering time in the lung cancer. In this review, we discuss these investigations into long noncoding RNAs were performed almost exclusively in lung cancer. Future work will need to extend these into lung cancer and to analyze how LncRNAs interact to regulate mRNA expression. From a clinical perspective, the targeting of LncRNAs as a novel therapeutic approach will require a deeper understanding of their function and mechanism of action.

Cardiac fibrosis is a complex pathological process that includes the abnormal proliferation of cardiac fibroblasts and deposition of the extracellular matrix (ECM) proteins and collagens. Methyl-CpG-binding protein 2 (MeCP2) is a multifunctional nuclear protein, and plays a key role in the fibrotic diseases. However, the potential role of MeCP2 in cardiac fibrosis remains unclear. We report that MeCP2 modulates cardiac fibrosis via down-regulation of dual-specificity phosphatase 5 (DUSP5), a nuclear phosphatase that negatively regulates prohypertrophic signaling by ERK1/2. MeCP2 is a critical participant in the epigenetic silencing of regulatory genes. Here, we found that down-regulation of DUSP5 in cardiac fibrosis is associated with MeCP2 over-expression. Treatment of cardiac fibroblasts with MeCP2-siRNA blocked proliferation. Knockdown of MeCP2 elevated DUSP5 expression in activated cardiac fibroblasts. Moreover, we investigated the effect of DUSP5 on the ERK1/2 activation. Our results demonstrated that MeCP2 modulates DUSP5 mediated activation of ERK1/2 in cardiac fibrosis. Taken together, these results indicated that MeCP2 acts as a key regulator of pathological cardiac fibrosis, promotes cardiac fibroblasts proliferation and fibrosis by down-regulation of DUSP5.

Objective: This study aims to investigate the effect of miR-29a targeting the regulation of DNMT3A on the development of cardiac fibrosis in Sprague-Dawley (SD) rats. Methods: In vivo experiment: SD rats were randomly divided into model and control groups. The cardiac and left ventricular indices in each group were calculated. The pathological changes of the myocardium were observed. The expression levels of miR-29a, CollA1, α-SMA, and DNMT3A in the myocardium of each group were detected. In vitro experiment: The cardiac fibroblasts (CFs) of SD rats were isolated from the myocardial tissue of SD rats and cultured. The miR-29a mimics, inhibitors, DNMT3A-siRNA, and control-siRNA were transfected into CFs. The expression levels of miR-29a, DNMT3A, CollA1, and α-SMA were detected, and the proliferation of CFs after transfection was observed. Results: The heart weight index of the rats in the model group increased significantly compared with that in the control group. Obvious collagen deposition was observed in the myocardial tissue of the model group. The expression levels of CollA1, α-SMA, and DNMT3A in the model group were significantly higher than those in the control group (p

Modulation of epigenetic marks has promised efficacy for treating fibrosis. Cardiac fibroblast is the primary source of activated myofibroblasts that produce extracellular matrix (ECM) in cardiac fibrosis, but the mechanisms underlying this process are incompletely understood. Here we show that microRNA-369-5p (miR-369-5p) through DNMT3A hypermethylation and suppression of the Patched1 pathway leads to fibroblast proliferation in cardiac fibrosis. Forty adult male Sprague-Dawley (SD) rats were randomly divided into two groups (sham and AAC group), cardiac fibrosis was produced by abdominal aortic constriction, and the operation of abdominal aortic constriction was carried out according to the method described. Cardiac fibroblasts (CFs) were harvested from SD neonate rats and cultured. Importantly, miR-369-5p bind directly to DNMT3A with high affinity. MiR-369-5p leads to inhibition of DNMT3A enzyme activity. Exogenous miR-369-5p in cells induces aberrant DNA methylation of the Patched1, resulting in hypermethylation of low to moderately methylated regions. Moreover, Overexpression of miR-369-5p in cardiac fibroblast cells inhibits proliferation. We identify DNMT3A as miR-369-5p target genes and demonstrate that inhibition of miR-369-5p expression augments cell proliferation by activating DNMT3A and suppression of the Patched1 pathway. Together, our results highlight miR-369-5p mediated DNMT3A epigenetic silencing of Patched1 as a mechanism of fibroblast proliferation in cardiac fibrosis.

Regulation of microRNA gene expression by DNA methylation may represent a key mechanism to drive cardiac fibrosis progression. Cardiac fibroblast autophagy is the primary source of cardiac fibrosis, but the mechanisms underlying this process are incompletely understood. Here we found that DNMT3A suppression of the microRNA-200b (miR-200b) through pathway leads to cardiac fibroblast autophagy in cardiac fibrosis. To understand the impact of DNMT3A on miR-200b at cardiac fibrosis, the rat cardiac fibrosis model was established via the abdominal aortic coarctation. Cardiac fibroblasts (CFs) were harvested from SD neonate rats and cultured. The expression of DNMT3A, miR-200b, collagen I was measured by western blotting, immunohistochemistry and qRT-PCR. Gain- or loss-of-function approaches were used to manipulate DNMT3A and miR-200b. DNMT3A level was upregulated and negatively correlated with miR-200b expression in fibrosis tissues and cardiac fibroblast. We found that autophagy was activated by miR-200b inhibitor and inactivated by miR-200b mimic in the rat cardiac fibroblast. Knockdown of DNMT3A notably increased the expression of miR-200b. Taken together, these findings indicate that DNMT3A regulation of miR-200b controls cardiac fibroblast autophagy during cardiac fibrosis and provide a basis for the development of therapies for cardiac fibrosis.

Objective This study aims to investigate the effect of miR-29a targeting the regulation of DNMT3A on the development of cardiac fibrosis in Sprague-Dawley (SD) rats. Methods In vivo experiment: SD rats were randomly divided into model and control groups. The cardiac and left ventricular indices in each group were calculated. The pathological changes of the myocardium were observed. The expression levels of miR-29a, CollA1, α-SMA, and DNMT3A in the myocardium of each group were detected. In vitro experiment: The cardiac fibroblasts (CFs) of SD rats were isolated from the myocardial tissue of SD rats and cultured. The miR-29a mimics, inhibitors, DNMT3A-siRNA, and control-siRNA were transfected into CFs. The expression levels of miR-29a, DNMT3A, CollA1, and α-SMA were detected, and the proliferation of CFs after transfection was observed. Results The heart weight index of the rats in the model group increased significantly compared with that in the control group. Obvious collagen deposition was observed in the myocardial tissue of the model group. The expression levels of CollA1, α-SMA, and DNMT3A in the model group were significantly higher than those in the control group (p Conclusion miR-29a reduced the activation and proliferation of CFs to improve cardiac fibrosis probably by the downregulation of DNMT3A.

Hepatic fibrosis is a common final pathological process in the progression of liver disease, which is primarily due to oxidative stress. Nrf2 is known to coordinate induction of genes that encode antioxidant enzymes. Moreover, Nrf2 expression is largely regulated through the association of Nrf2 with Keap1, which results in cytoplasmic Nrf2 degradation. Conversely, little is known concerning the regulation of Keap1 expression. Although the function of miRNA-200a controls Keap1 gene expression has been discussed in many cancers and fibrotic diseases, its role in hepatic fibrosis is still poorly understood. By using miRNA mimic, we observed miRNA-200a silencing in activated hepatic stellate cell and demonstrated that upon re-expression, miRNA-200a targets the Keap1, and leading to Keap1 mRNA degradation. We find that treatment with miRNA-200a mimics, restored miRNA-200a expression and reduced Keap1 levels. This reduction in Keap1 levels corresponded with Nrf2 nuclear translocation and activation of Nrf2-dependent NQO1 gene transcription. Moreover, we found that Nrf2 activation inhibited the TGF-β1-independent growth of hepatic stellate cell. Finally, our study demonstrates that miRNA-200a regulates the Keap1/Nrf2 pathway in hepatic stellate cell and fibrosis, and we find that epigenetic therapy can restore miRNA-200a regulation of Keap1 expression, therefore reactivating the Nrf2-dependent antioxidant pathway in liver fibrosis.

Cardiac fibrosis is an important pathological feature of cardiac remodeling in heart diseases. The molecular mechanisms of cardiac fibrosis are unknown. Histone deacetylases (HDACs) are enzymes that balance the acetylation activities of histone acetyltransferases on chromatin remodeling and play essential roles in regulating gene transcription. In recent years, the role of HDACs in cardiac fibrosis initiation and progression, as well as the therapeutic effects of HDAC inhibitors, has been well studied. Moreover, numerous studies indicated that HDAC activity is associated with the development and progression of cardiac fibrosis. In this review, the innovative aspects of HDACs are discussed, with respect to biogenesis, their role in cardiac fibrosis. Furthermore, the potential applications of HDAC inhibitors in the treatment of cardiac fibrosis associated with fibroblast activation and proliferation.

MicroRNAs (miRNAs) are small non-coding RNA molecules that negatively regulate gene expression of their targets at the post-transcriptional levels. They typically affect the mRNA stability or translation finally leading to the repression of target gene expression. Notably, it is thought that miRNAs are crucial for regulating gene expression during heart diseases, such as atrial fibrillation (AF). Numerous studies identify specific miRNA expression profiles associated to different histological features of AF, both in animal models and in patients. Therefore, we review the latest experimental approaches from the perspective of understanding miRNA gene expression regulatory networks in AF. In addition, miRNAs have also emerged as possible therapeutic targets for the treatment of AF. In this review, we discuss the experimental evidence about miRNAs both as potential non-invasive early diagnostic markers and as novel therapeutic targets in AF.

Cardiac fibrosis is characterized by excessive extracellular matrix accumulation that ultimately destroys tissue architecture and eventually abolishes normal function. In recent years, despite the underlying mechanisms of cardiac fibrosis are still unknown, numerous studies suggest that epigenetic modifications impact on the development of cardiac fibrosis. Epigenetic modifications control cell proliferation, differentiation, migration, and so on. Epigenetic modifications contain three main processes: DNA methylation, histone modifications, and silencing by microRNAs. We here outline the recent work pertaining to epigenetic changes in cardiac fibrosis. This review focuses on the epigenetic regulation of cardiac fibrosis.

Background: Folate deficiency is an independent risk factor for congenital heart disease (CHD); however, the maternal plasma folate level is paradoxically not a good diagnostic marker. Genome-wide surveys have identified variants of nonfolate metabolic genes associated with the plasma folate level, suggesting that these genetic polymorphisms are potential risk factors for CHD. Methods: To examine the effects of folate concentration-related variations on CHD risk in the Han Chinese population, we performed 3 independent case-control studies including a total of 1489 patients with CHD and 1745 control subjects. The expression of the Fidgetin (FIGN) was detected in human cardiovascular and decidua tissue specimens with quantitative real-time polymerase chain reaction and Western blotting. The molecular mechanisms were investigated by luciferase reporter assays, surface plasmon resonance, and chromatin immunoprecipitation. FIGN-interacting proteins were confirmed by tandem affinity purification and coimmunoprecipitation. Proteasome activity and metabolite concentrations in the folate pathway were quantified with a commercial proteasome activity assay and immunoassays, respectively. Results: The +94762G>C (rs2119289) variant in intron 4 of the FIGN gene was associated with significant reduction in CHD susceptibility ( P =5.1×10 −14 for the allele, P =8.5×10 –−13 for the genotype). Analysis of combined samples indicated that CHD risks in individuals carrying heterozygous (GC) or homozygous (CC) genotypes were reduced by 44% (odds ratio [OR]=0.56; 95% confidence interval [CI]=0.47–0.67) and 66% (OR=0.34; 95% CI=0.23–0.50), respectively, compared with those with the major GG genotype. Minor C allele carriers who had decreased plasma folate levels exhibited significantly increased FIGN expression because the transcription suppressor CREB1 did not bind the alternative promoter of FIGN isoform X3. Mechanistically, increased FIGN expression led to the accumulation of both reduced folate carrier 1 and dihydrofolate reductase via inhibition of their proteasomal degradation, which promoted folate absorption and metabolism. Conclusions: We report a previously undocumented finding that decreased circulating folate levels induced by increased folate transmembrane transport and utilization, as determined by the FIGN intronic variant, serves as a protective mechanism against CHD. Our results may explain why circulating folate levels do not have a good diagnostic value.

Homocysteine is an independent risk factor for various cardiovascular diseases. There are two ways to remove homocysteine from embryonic cardiac cells: remethylation to form methionine or transsulfuration to form cysteine. Cystathionine β-synthase (CBS) catalyzes the first step of homocysteine transsulfuration as a rate-limiting enzyme. In this study, we identified a functional variant -4673CG (rs2850144) in the CBS gene promoter region that significantly reduces the susceptibility to congenital heart disease (CHD) in a Han Chinese population consisting of 2 340 CHD patients and 2 270 controls. Individuals carrying the heterozygous CG and homozygous GG genotypes had a 15% (odds ratio (OR) = 0.85, 95% confidence interval (CI) = 0.75-0.96, P = 0.011) and 40% (OR = 0.60, 95% CI = 0.49-0.73, P = 1.78 × 10(-7)) reduced risk to develop CHD than the wild-type CC genotype carriers in the combined samples, respectively. Additional stratified analyses demonstrated that CBS -4673CG is significantly related to septation defects and conotruncal defects. In vivo detection of CBS mRNA levels in human cardiac tissues and in vitro luciferase assays consistently showed that the minor G allele significantly increased CBS transcription. A functional analysis revealed that both the attenuated transcription suppressor SP1 binding affinity and the CBS promoter hypomethylation specifically linked with the minor G allele contributed to the remarkably upregulated CBS expression. Consequently, the carriers with genetically increased CBS expression would benefit from the protection due to the low homocysteine levels maintained by CBS in certain cells during the critical heart development stages. These results shed light on unexpected role of CBS and highlight the importance of homocysteine removal in cardiac development.Cell Research advance online publication 18 September 2012; doi:10.1038/cr.2012.135.

Cardiac fibroblasts proliferation is the most important pathophysiological character of cardiac fibrosis while the underlying mechanisms are still incompletely known. MicroRNAs (miRNAs) regulate gene expression by binding to specific sites. Studies have been indicated that miRNA-29a play a key role in cardiac fibrosis. VEGF-A carries out its functions through MAPK signaling pathway in cardiac fibrosis. Existing proofs predict that the VEGF-A is one of the potential targets of miRNA-29a. We therefore probe the role of miRNA-29a and its latent target VEGF-A during cardiac fibrosis. In our study, miRNA-29a was down-regulated while VEGF-A was up-regulated in cardiac fibrosis tissues. The rat cardiac fibroblasts that were transfected with miRNA-29a inhibitor exhibited low-expression of miRNA-29a, enhanced VEGF-A protein and mRNA expression. Nevertheless, the cardiac fibroblasts transfected with miRNA-29a mimics obtained the opposite expression result. Furthermore, over-expression of miRNA-29a suppresses cardiac fibroblasts proliferation. In conclusion, these results suggested that miRNA-29a suppresses cardiac fibrosis and fibroblasts proliferation via targeting VEGF-A/MAPK signal pathway implicating that miRNA-29a might play a role in the treatment of cardiac fibrosis.

Pulmonary sequestration is a rare congenital lung malformation that more commonly occurs in the left lung, mainly near the lower mediastinum. It is rarely observed in patients with extralobar sequestration in adulthood. We report the case of a 55-year-old man with recurrent fever and cough lasting for about 1 month, who was admitted to our hospital. His past history was unremarkable. The final diagnosis of extralobar sequestration was dependent on three-dimensional computed tomography angiography (3D CTA), which showed an abnormal blood supply vessel to the consolidation from the aortic arch. The patient underwent a left pulmonary sequestration resection, and the pathological examination also verified the diagnosis postoperatively. 3D CTA images can provide an aberrant vessel anatomy map for the surgeon and play a decisive role in the detection of pulmonary sequestration.

Background: As an increasing number of aging patients are being referred for coronary artery bypass grafting (CABG), the radial artery (RA) has gained increasing popularity as a conduit. The aim of this study was to investigate the effectiveness of RA in CABG for the elderly with coronary heart disease. Methods and Results: Three hundred and twenty-six elderly patients underwent CABG with RA harvesting between January 2000 and June 2008. A total of 377 RA as grafts were collected. The mean number of distal anastomoses per patient was 3.1 while the mean for RA was 1.1. The operative mortality was 3.1%. Twenty patients developed atrial fibrillation, 7 experienced acute renal failure, 9 had neurological accidents, and 4 had myocardial infarction. There was no ischemic complication on hand. Paresthesia in the donor hand was found in 2 patients. A complete follow up was obtained in 77.2% of patients, with a mean time of 53.5 ±35.9 months. RA patency displayed by coronary angiography was 95.83% after a mean time of 74 months of follow up. Conclusions: It was proven to be safe and effective to use RA as a secondary arterial graft after the left internal mammary artery in the elderly patients. (Circ J 2009; 73: 1049-1054)

BACKGROUND Patients presenting with severe left ventricular dysfunction (SLVD) undergoing conventional coronary artery bypass grafting (CCABG) are at an increased risk of perioperative mortality and morbidity. The aim of this study was to assess the risk factors responsible for mortality and morbidity among patients with SLVD by comparing CCABG and off-pump coronary artery bypass surgery (OPCAB). METHODS We retrospectively evaluated 186 consecutive patients with SLVD who underwent coronary artery bypass grafting (CABG), including 102 by CCABG and 84 by OPCAB. Registry database, medical notes, and charts were studied for preoperative and postoperative data of the patients. Different variables and risk factors (preoperative, intraoperative, and postoperative) were evaluated and compared. The morbidity and mortality outcomes were compared in the two groups. The follow-up results and quality of life were assessed after surgery. RESULTS The two groups had similar percentage of patients with preoperative high-risk profiles and no significant differences were found between groups in baseline variables such as age or comorbidities. There was a significant difference in the number of grafts used between the two groups. CCABG patients received (3.6 +/- 0.5) grafts per patient, while OPCAB patients had (2.7 +/- 0.6) grafts (P < 0.05). Completeness of revascularization was also significantly different between the two groups (CCABG 91.1% vs OPCAB 73.8%, P < 0.05). The hospital mortality was similar in the two groups (4.8% in OPCAB vs 5.9% in CCABG). The risk-adjusted mortality, according to the calculated propensity score, did not reach statistical significance in the two groups. In this study, OPCAB seemed to have a beneficial effect on reducing reoperation for bleeding, blood transfusion requirement, and the length of stay at ICU. But the incidence of perioperative myocardial infarction was more common in the off-pump group (P < 0.05). The degree of improvement in angina and quality of life did not differ significantly between the two groups. CONCLUSIONS Using cardiopulmonary bypass is not an independent predictor of mortality and morbidity in patients with SLVD. Isolated CABG can be safely performed in SLVD patients with acceptable postoperative morbidity and mortality in addition to encouraging home discharge rates and higher quality of life. Therefore, CCABG remains a viable option in selected patients with SLVD.

Objective To investigate the effect of MCP-1 on mesenchymal stem cells(MSCs) homing to injured myocardium in a rat myocardial infarction(MI) model. Methods Rat myocardial infarction model was established by permanent left anterior descending branch ligation. Mesenchymal stem cells from donor rats were cultured in IMDM and labeled with BrdU. The Rats were divided into two groups. Monocyte chemotactic protein 1(MCP-1) expression were measured by in situ hybridization and immunohistochemistry in the sham operated or infarcted hearts at 1, 2, 4, 7, 14 and 28 days post operation in MCP-1 detection group. The rats were injected with MCP-1, anti-MCP-1 antibody or saline 4 days after myocardial infarction in intervention group. Then, a total of 5 × 10 6 cells in 2.5 ml of PBS were injected through the tail vein. The number of the labeled MSCs in the infarcted hearts was counted 3 days post injection. Cardiac function and blood vessel density were assessed 28 days post injection. Results Self-generating MCP-1 expression was increased at the first day, peaked at the 7 th day and decreased thereafter post MI and remained unchanged in sham operated hearts. The MSCs enrichment in the host hearts were more abundant in the MI groups than that in the non-MI group( P = 0.000), the MSCs enrichment in the host hearts were more abundant in the MCP-1 injected group than that in the anti-MCP-1 antibody and saline injected groups ( P = 0.000). Cardiac function was improved more in MCP-1 injected group than anti-MCP-1 antibody and saline injected groups( P = 0.000). Neovascularization in MCP-1 injected group significantly increased compared with that of other groups( P =0.000). Conclusion Myocardial MCP-1 expression was increased only in the early phase post MI. MCP-1 may enhance MSCs homing to the injured heart and improve cardiac function by promoting neovascularization.

Background microRNAs (miRs) have been reported to regulate cell biological functions. To explore the underlying mechanism of miR-21 involvement in patients with atrial fibrosis and atrial fibrillation (AF). Methods In total, 49 patients (24 AF, sinus rhythm 25) aged 33–68 years old, including heart valve replacement surgery and cardiac catheterisation. The pathological changes and collagen depositions was analysed by Masson’s Trichrome Staining. miR-21, TGF-β1, Smad2, p-Smad2, WWP-1, collagen I and collagen III expression were analysed by Western blotting, qRT-PCR, miR one step qRT-PCR, respectively. Treatment human cardiac fibroblasts with TGF-β1, qRT-PCR and Western blotting to find changes in miR-21, Smad2 and WWP-1 levels. Transfected human cardiac fibroblasts with miR-21 mimic and miR-21 inhibitor. Finally, cell proliferation ability was assessed by the MTT assay and flow cytometry. Results Compared to sinus rhythm (SR) group, the collagen volume fraction was significantly increased in AF patients. The levels of the TGF-β1, collagen I and collagen III were significantly elevated in AF group. In AF patients, the expression of miR-21 was increased, while the expression of WWP-1 was decreased. Transfected cardiac fibroblasts with miR-21 mimic increased miR-21 expression and decreased WWP-1 expression, whereas miR-21 inhibitor causes the opposite effects. Additionally, we demonstrated that knockdown miR-21 targeted up-regulation of WWP-1 may suppress cardiac fibroblasts proliferation. Conclusion These indicated that miR-21 inhibits cardiac fibroblasts proliferation by inactivating the TGF-β1/Smad2 signaling pathway via up-regulation of WWP-1.

Atrial fibrillation (AF) is the most common sustained arrhythmia. AF is a complex disease that results from genetic and environmental factors and their interactions. In recent years, numerous studies have shown that epigenetic mechanisms significantly participate in AF pathogenesis. Even though a poor understanding of the molecular and electrophysiologic mechanisms of AF, accumulated evidence has suggested that the relevance of epigenetic changes in the development of AF. The aim of this review is to describe the present knowledge about the epigenetic regulatory features significantly participates in AF, and look ahead on new perspectives of epigenetic mechanisms research. Epigenetic regulatory features such as DNA methylation, histone modification, and microRNA influence gene expression by epigenetic mechanisms and by directly binding to various factor response elements in the target gene promoters. Given the role of epigenetic alterations in regulating genes, there is potential for the integration of factors-induced epigenetic alterations as informative factors in the risk assessment process. In this review, new insight into the epigenetic mechanisms in AF pathogenesis is discussed, with special emphasis on DNA methylation, histone modification, and microRNA. Further studies are needed to reveal the potential targets of epigenetic mechanisms, and it can be developed as a therapeutic target for AF.

Cardiac fibrosis is an important pathological feature of cardiac remodeling in heart diseases. The molecular mechanisms of cardiac fibrosis are unknown. Genomic analyses estimated that many noncoding DNA regions generate noncoding RNAs (ncRNAs). ncRNAs have emerged as key molecular players in the regulation of gene expression in different biological processes. Recent studies have started to reveal the importance of ncRNAs in heart development and suggest also an involvement in cardiac fibrosis. These molecules are emerging as important regulators of cellular process. Here, we review particularly focuses on the involvement of two large families of ncRNAs, namely microRNAs (miRNAs) and long noncoding RNAs (LncRNAs) in the regulation of cardiac fibrosis. Furthermore, we review the functions and role of ncRNAs in cardiac biology and discuss these reports and the therapeutic potential of ncRNAs for cardiac fibrosis associated with fibroblast activation and proliferation.

Nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) plays a key role in lung injury diseases regulation, and its expression is increased in lung injury diseases. NLRP3 may be a good therapeutic target for lung injury diseases. The molecular mechanisms of NLRP3 in lung injury diseases remain unclear. It is a key to study the potential mechanism of NLRP3 during lung injury diseases, so that to exploit it as a good target for lung injury diseases therapy.

Objectives: Cardiac fibrosis is characterized by net accumulation of extracellular matrix proteins in the cardiac interstitium, and contributes to both systolic and diastolic dysfunction in many cardiac pathophysiologic conditions. HDAC6 is a transcriptional regulator of the histone deacetylase family, subfamily 2. Previous studies have shown that HDAC6 plays critical roles in transcription regulation and proliferation events. However, the precise mechanisms of how HDAC is associated with cardiac fibrosis progression have not yet been elucidated. Methods: Fifty adult male Sprague-Dawley (SD) rats were randomly divided into two groups. Cardiac fibrosis was produced by common isoprenaline and cardiac fibroblasts were harvested from SD neonate rats and cultured. The expression of HDAC6, RASSF1A, α-SMA and collagen I were measured by Western blotting and qRT-PCR. Small interfering (si)RNA of HDAC6 affects the proliferation of cardiac fibroblasts and the regulation of RASSF1A/ERK1/2 signaling pathways. Results: In this study, we found that mRNA and protein levels of HDAC6 were upregulated in cardiac fibrosis tissues and activated cardiac fibroblast cells. Inhibition of HDAC6 by siRNA or the inhibitor tubacin attenuated the TGF-β1-induced myofibroblast markers. In contrast, HDAC6 knockdown using siRNA inhibited cardiac fibroblast cell proliferation. Furthermore, we demonstrated that knockdown of HDAC6 elevated RASSF1A expression in activated cardiac fibroblasts, and treatment of cardiac fibroblasts with the HDAC6 inhibitor tubacin also elevated RASSF1A expression. Conclusions: The results of this study suggest that a previously unknown mechanism of HDAC6 inactivation of RASSF1A controls cardiac fibroblast proliferation and fibrosis.

Cardiac fibroblast activation is a pivotal cellular event in cardiac fibrosis. Numerous studies have indicated that epigenetic modifications control cardiac fibroblast activation. Greater knowledge of the role of epigenetic modifications could improve understanding of the cardiac fibrosis pathogenesis.The aim of this review is to describe the present knowledge about the important role of non-coding RNA (ncRNA) transcripts in epigenetic gene regulation in cardiac fibrosis and looks ahead on new perspectives of epigenetic modification research. Furthermore, we will discuss examples of ncRNAs that interact with histone modification or DNA methylation to regulate gene expression.MicroRNAs (miRNAs) and long ncRNAs (lncRNAs) modulate several important aspects of function. Recently, some studies continue to find novel pathways, including the important role of ncRNA transcripts in epigenetic gene regulation. Targeting the miRNAs and lncRNAs can be a promising direction in cardiac fibrosis treatment. We discuss new perspectives of ncRNAs that interact with histone modification or DNA methylation to regulate gene expression, others that are targets of these epigenetic mechanisms. The emerging recognition of the diverse functions of ncRNAs in regulating gene expression by epigenetic mechanisms suggests that they may represent new targets for therapeutic intervention.

We present the case of a 51 years old female who experienced foreign body aspiration 3 years before. The foreign body, which should be removed by bronchoscopy before, was lodged at the bifurcation of the right inferior bronchus and could only be removed via right lower lobectomy. The patient experienced a swift recovery and was well at follow-up 8 months later.

Cardiac fibrosis is characterized by net accumulation of extracellular matrix (ECM) proteins in the cardiac interstitium, and contributes to both systolic and diastolic dysfunction in many cardiac pathophysiologic conditions. More specifically, cardiac fibroblasts are activated by a variety of pathological stimuli, thereby undergoing proliferation, differentiation to myofibroblasts, and production of various cytokines and ECM proteins. Thus, understanding the biological processes of cardiac fibroblasts will provide novel insights into the underlying mechanisms of cardiac fibrosis. DNA methylation is an important epigenetic mechanism, which often occurs in response to environmental stimuli and is crucial in regulating gene expression. The aberrant methylation of CpG island promoters of selected genes is the prominent epigenetic mechanism by which gene transcription can be effectively silenced. Aberrant hypermethylation of a few selected genes such as RASSF1A plays an important role in facilitating fibrotic fibroblast activation and in driving fibrosis. In this review we will discuss the mechanisms of DNA methylation and their implications for cardiac fibroblasts activation and fibrosis. Control of DNA methylation may serve as a new strategy for anti-fibrotic therapy.

Cardiac fibrosis contributes to the pathogenesis of atrial fibrillation (AF). The molecular mechanisms underlying the cardiac fibrosis remain unclear. However, Ras association domain family 1 isoform A (RASSF1A) is a regulatory tumor suppressor, which is important for pathogenesis of cardiac fibrosis and fibroblasts activation. Moreover, DNA methylation plays a central role in the maintenance of cardiac fibrosis. DNA methyltransferases 3A (DNMT3A) is a critical participant in the epigenetic silencing of regulatory genes. Here, we report that the downregulation of RASSF1A in cardiac fibrosis is associated with DNMT3A. Treatment of cardiac fibroblasts with DNMT3A inhibitor 5-AzadC blocked proliferation. 5-AzadC also prevented the loss of RASSF1A expression that occurs during activated cardiac fibroblasts. To determine the underlying molecular mechanisms, we hypothesized that cardiac fibrosis is controlled by DNMT3A. We demonstrated that downregulation of RASSF1A is associated with cardiac fibrosis and fibroblasts activation. Knockdown of DNMT3A elevated RASSF1A expression in activated cardiac fibroblasts. Moreover, we investigated the effect of RASSF1A on the Ras/ERK pathway. Upregulation of p-ERK1/2 was detected in activated cardiac fibroblasts with decreased RASSF1A expression. Our results have shown that DNMT3A likely plays an essential role in RASSF1A mediated upregulation of ERK1/2 in rat cardiac fibrosis. DNMT3A and RASSF1A may serve as a new mechanism for cardiac fibrosis.

Aortic-left ventricular tunnel is a rare congenital cardiac anomaly, which always arises from the right coronary sinus and enters the left ventricle, occasionally the right ventricle and right atrium. However, aortic and left ventricular tunnel associated with infective endocarditis is rarely seen in literatures. Here, we present a case of aortic and left ventricular tunnel associated with infective endocarditis in a 47-year-old man.

The aims of this review are to describe the present knowledge about YKL-40 protein, discuss its relation to liver fibrosis, and to look ahead at future perspectives of YKL-40 research. Liver fibrosis is characterized by excess collagen deposition, decreased extracellular matrix degradation and activation of hepatic stellate cells. Therefore, advancement in the identification of liver fibrosis biomarkers with diagnostic and prognostic values becomes an important tool for future molecular therapy. The molecular basis of YKL-40 in liver fibrosis is unknown. A PubMed database search was performed for studies of YKL-40 in liver injury and fibrosis. YKL-40 is an inflammatory glycoprotein involved in endothelial dysfunction by promoting chemotaxis, cell attachment and migration, reorganization, and tissue remodeling as a response to endothelial damage. Several studies demonstrate that elevated serum YKL-levels are independently associated with the presence of endothelial damage and even higher YKL-40 levels are documented in liver fibrosis. YKL-40 may play a key role in liver injury and fibrosis.

Hepatic stellate cell (HSC) activation plays an important role in liver fibrogenesis. Transdifferentiation of quiescent hepatic stellate cells into myofibroblastic-HSCs is a key event in liver fibrosis. The methyl-CpG-binding protein MeCP2 which promotes repressed chromatin structure is selectively detected in myofibroblasts of diseased liver. MeCP2 binds to methylated CpG dinucleotides, which are abundant in the promoters of many genes. Treatment of HSCs with DNA methylation inhibitor 5-aza-2'- deoxycytidine (5-azadC) prevented proliferation and activation. Treatment with 5-azadC prevented loss of Patched (PTCH1) expression that occurred during HSCs activation. In a search for underlying molecular medchanisms, we investigated whether the targeting of epigenetic silencing mechanisms could be useful in the treatment of PTCH1-associated fibrogenesis. It was indicated that hypermethylation of PTCH1 is associated with the perpetuation of fibroblast activation and fibrosis in the liver. siRNA knockdown of MeCP2 increased the expressions of PTCH1 mRNA and protein in hepatic myofibroblasts. These data suggest that DNA methylation and MeCP2 may provide molecular mechanisms for silencing of PTCH1.

Objectives: The purpose of this study was to evaluate the impact of moderate-or-less functional tricuspid regurgitation (TR) treatment on the clinical outcome of patients with mitral valve (MV) surgery.Methods: From October 2001 to January 2005, 167 patients in our hospital with MV surgery and without organic tricuspid valve (TV) disease or pulmonary hypertension (PH) showed moderate-or-less functional TR preoperatively, and 41.9% of these patients were treated with TR (group T), compared with 58.1% untreated with TR (group no-T). According to tricuspid annulus dimension (TAD)/body surface area (BSA), these 167 patients were further divided into another 2 groups (A and B): group A (70 patients) represented TAD/BSA ? 21 mm/m2 with 32 patients from group T and 38 from group no-T, and group B (97 patients) represented TAD/BSA > 21 mm/m2 with 38 patients from group T and 59 patients from group no-T. There was no statistical difference in preoperative and operative variables between the 2 groups. Meanwhile, among the 167 patients with MV surgery, 157 patients were replaced with MV and 10 patients were repaired with MV, and De Vega technique was constantly used for TR treatment. All the results were estimated by multivariate analysis.Results: The median follow-up time was 63 months (25th and 75th percentiles are 53 and 94 months, respectively); 30-day mortality was 3% (1.4% in group T versus 4.1% in group no-T; P = .31). Adjusted 5-year survival was 70.7% (66.6%-80.4%) with 85.3% (83.0%-93.4%) in group T and 64.7% (33.7%-58.3%) in group no-T, P = .001. Among the 70 patients with TAD/BSA ? 21 mm/m2, patients who received treatment of moderate-or-less TR and those who did not showed similar secondary TR grade at postoperative period (0.5 � 0.6 in group T versus 0.9 � 0.9 in group no-T; P = .2) and follow-up (1.3 � 1.1 in group T versus 1.8 � 1.1 in group no-T; P = .06). In subgroup B (TAD/BSA > 21 mm/m2), patients who received tricuspid valvoplasty manifested more significantly improved outcome than patients without functional TR at postoperative period (0.8 � 0.8 in group T versus 1.6 � 1.3 in group no-T; P = .03) and follow-up (2.0 � 1.2 in group T versus 3.0 � 1.1 in group no-T; P = .005). The multivariate analysis identified TAD/BSA > 21 mm/m2 and preoperative atrial fibrillation (AF) as the risk factors for lower survival at follow-up period.Conclusions: Patients with MV surgery have better midterm outcome when they receive either more aggressive and effective surgical treatment for functional TR or moderate-or-less TR preoperatively. Indexed TAD (TAD/BSA > 21 mm/m2) is a more reliable surgical guideline for the treatment of TR. Preoperative tricuspid annulus dilation and AF might be predictors of late lower survival.

Background— Homocysteine is known to be an independent risk factor for congenital heart disease (CHD). Methionine synthase reductase ( MTRR ) is essential for the adequate remethylation of homocysteine, which is the dominant pathway for homocysteine removal during early embryonic development. Methods and Results— Here, we report that the c.56+781 A>C (rs326119) variant of intron-1 of MTRR significantly increases the risk of CHD in the Han Chinese population. In 3 independent case-control studies involving a total of 2340 CHD patients and 2270 healthy control participants from different geographic areas, we observed that patients carrying the heterozygous AC and homozygous CC genotype had a 1.40-fold (odds ratio=1.40; P =2.32×10 −7 ) and 1.84-fold (odds ratio=1.84; P =2.3×10 −11 ) increased risk, respectively, of developing CHD than those carrying the wild-type AA genotype. Both in vivo quantitative real-time polymerase chain reaction analysis of MTRR mRNA in cardiac tissue samples from CHD patients and in vitro luciferase assays in transfected cells demonstrated that the c.56+781 C allele profoundly decreased MTRR transcription. Further analysis demonstrated that the c.56+781 C allele manifested reduced CCAAT/enhancer binding protein-α binding affinity. In addition, healthy individuals with the homozygous CC genotype had significantly elevated levels of plasma homocysteine compared with the wild-type AA carriers. Conclusions— We have demonstrated that the MTRR c.56+781 A>C variant is an important genetic marker for increased CHD risk because this variant results in functionally reduced MTRR expression at the transcriptional level. Our results accentuate the significance of functional single-nucleotide polymorphisms in noncoding regions of the homocysteine/folate metabolism pathway core genes for their potential contributions to the origin of CHD.

To summarize the clinical effect and experience of extracorporeal membrane oxygenation (ECMO) support for severe heart failure during peri-operative period of end-stage cardiopathy.From June 2007 to July 2010, 6 patients with severe heart failure during peri-operative period of end-stage cardiopathy received ECMO support. The changes in the hemodynamics and outcome of the patients during the use of ECMO were investigated.The duration of ECMO assistance ranged from 23 to 168 hours with a mean of 78 hours. The hemodynamics after using ECMO was much improved than before ECMO [mean arterial pressure (mm Hg, 1 mm Hg=0.133 kPa): 78.13±8.01 vs. 47.75±5.21, central venous pressure ( mm Hg ): 11.03±3.21 vs. 19.36±4.51, cardiac output (L/min): 4.93±1.01 vs. 3.50±0.81, cardiac index (L×min(-1)×m(-2)): 2.71±0.51 vs. 1.91±0.40, pulmonary artery wedge pressure ( mm Hg ): 12.72±6.52 vs. 20.22±6.91, venous oxygen saturation: 0.66±0.13 vs. 0.54±0.07], and the amount of using inotropic drug was significantly reduced compared with that before ECMO [dopamine (μg×kg(-1)×min(-1)): 5.05±0.85 vs. 14.20±5.05, epinephrine (μg×kg(-1) ×min(-1)): 0.05±0.01 vs. 0.24±0.04, all P0.05]. All patients were successfully weaned from ECMO. After weaning, 3 patients recovered and discharged, and the hospital discharge rate was 50%, while 3 patients died of multiple organ failure (MOF). Major complication was bleeding, disseminated intravascular coagulation, infection, embolism.ECMO is an important extracorporeal method to support life. ECMO is an effective measure of treatment for end-stage cardiopathy patients with peri-operative severe heart failure. It is important to properly select patients for ECMO.