Silencing suppressor of cytokine signaling 3 induces apoptosis and activates the p-STAT3/NF-κB pathway in hypoxic cultivated H9c2 cells.

Suppressor of cytokine signaling 3 (SOCS3) plays a significant role in the process of myocardial adaptation to chronic hypoxia. SOCS3 finely regulates cell signaling cross-talk that occurs between NF-κB and STAT3 during the compensatory protective response. However, the role and mechanism of SOCS3 in hypoxic cardiomyocytes are not fully understood. In the study, we investigated the effect of SOCS3 on the p65 and STAT3 signaling pathways and further examined the potential molecular mechanism involved in regulating apoptosis. Our data showed that SOCS3 silencing could upregulate Ac-p65, p-p65, and p-STAT3 expression in nuclear extracts of H9c2 cells that received hypoxic treatment for 24, 48, and 72 h. SOCS3 silencing also remarkably increased the DNA-binding activity of the p65 motif in hypoxic cultivated H9c2 cells. We also found that SOCS3 knockdown increased cleaved-caspase-3, Bax, and PUMA expression and decreased cleaved PARP and Bcl-2 in expression in hypoxic H9c2 cells. Silencing of SOCS3 caused an increase in LDH leakage from injured cardiomyocytes and reduced cell viability under conditions of hypoxic stress. Furthermore, SOCS3 silencing enhanced the apoptosis of H9c2 cells at 72 h of hypoxia. These findings suggest that knockdown of SOCS3 leads to excessive activation of the NF-κB pathway, which, in turn, might promote apoptosis under conditions of chronic hypoxia.

AMPKα2 deficiency exacerbates hypoxia-induced pulmonary hypertension by promoting pulmonary arterial smooth muscle cell proliferation.

Increased evidence indicates that adenosine monophosphate-activated protein kinase (AMPK) plays a vital role in vascular homeostasis, especially under hypoxia, and protects against the progression of pulmonary hypertension (PH). However, the role of AMPK in the pathogenesis of PH remains to be clarified. In the present study, we confirmed that a loss of AMPKα2 exacerbated the development of PH by using hypoxia-induced PH model in AMPKα2 -/- mice. After a 4-week period of hypoxic exposure, AMPKα2 -/- mice exhibited more severe pulmonary vascular remodeling and pulmonary vascular smooth muscle cell (SMC) proliferation when compared with wild type (WT) mice. In vitro, AMPKα2 knockdown promoted the proliferation of pulmonary arterial smooth muscle cells (PASMCs) under hypoxia. This phenomenon was accompanied by upregulated Skp2 and downregulated p27kip1 expression and was abolished by rapamycin, an inhibitor of mTOR. These results indicate that AMPKα2 deficiency exacerbates hypoxia-induced PH by promoting PASMC proliferation via the mTOR/Skp2/p27kip1 signaling axis. Therefore, enhanced AMPKα2 activity might underlie a novel therapeutic strategy for the management of PH.

KLF15 is a protective regulatory factor of heart failure induced by pressure overload.

The aim of the present study was to investigate the protective effect of Kruppel­like factor 15 (KLF15) overexpression on heart failure (HF) induced by left ventricular (LV) pressure overload in mice. Wild­type (WT) mice and cardiac­specific KLF15­overexpressed transgenic (TG) mice were selected as research subjects, and an LV pressure overload model was constructed by ascending aortic constriction surgery. Changes in cardiac morphology and function, and ultrastructure and molecular expression were observed via M­mode echocardiography, histological and immunohistochemical staining, ELISA and western blotting at 2 and 6 weeks of LV overload. WT and TG mice subjected to 2 weeks of overload displayed adaptive LV hypertrophy characterized by ventricular thickness, cardiomyocyte size, ejection fraction and fractional shortening of heart­lung weight ratio and KLF15, and increases in vascular endothelial growth factor (VEGF) expression without other pathological changes. WT mice subjected to 6 weeks of overload displayed enlargement of the LV chamber, severe interstitial remodeling, and HW/LW, cardiac capillary and heart function decline, accompanied by downregulated expression of KLF15 and VEGF, and upregulated expression of connective tissue growth factor, phosphorylated p38 (p­p38) and phosphorylated Smad3 (p­Smad3). In contrast, TG mice exhibited improved resistance to 6 weeks of overload and a slighter molecular expression response compared with WT mice. KLF15 was revealed to be a critical factor regulating the expression of CTGF, VEGF, p­p38 and p­Smad3, and could alleviate the progression from adaptive LV hypertrophy to decompensatory cardiac insufficiency.

Multinucleated polyploid cardiomyocytes undergo an enhanced adaptability to hypoxia via mitophagy.

AIMS: There is a large subpopulation of multinucleated polyploid cardiomyocytes (M*Pc CMs) in the adult mammalian heart. However, the pathophysiological significance of increased M*Pc CMs in heart disease is poorly understood. We sought to determine the pathophysiological significance of increased M*Pc CMs during hypoxia adaptation. METHODS AND RESULTS: A model of hypoxia-induced cardiomyocyte (CM) multinucleation and polyploidization was established and found to be associated with less apoptosis and less reactive oxygen species (ROS) production. Compared to mononucleated diploid CMs (1*2c CMs), tetraploid CMs (4c CMs) exhibited better mitochondria quality control via increased mitochondrial autophagy (mitophagy). RNA-seq revealed Prkaa2, the gene for AMPKα2, was the most obviously up-regulated autophagy-related gene. Knockdown of AMPKα2 increased apoptosis and ROS production and suppressed mitophagy in 4c CMs compared to 1*2c CMs. Rapamycin, an autophagy activator, alleviated the adverse effect of AMPKα2 knockdown. Furthermore, silencing PINK1 also increased apoptosis and ROS in 4c CMs and weakened the adaptive superiority of 4c CMs. Finally, AMPKα2-/- mutant mice exhibited exacerbation of apoptosis and ROS production via decreases in AMPKα2-mediated mitophagy in 4c CMs compared to 1*2c CMs during hypoxia. CONCLUSIONS: Compared to 1*2c CMs, hypoxia-induced 4c CMs exhibited enhanced mitochondria quality control and less apoptosis via AMPKα2-mediated mitophagy. These results suggest that multinucleation and polyploidization allow CM to better adapt to stress via enhanced mitophagy. In addition, activation of AMPKα2 may be a promising target for myocardial hypoxia-related diseases.

Re-enforcing hypoxia-induced polyploid cardiomyocytes enter cytokinesis through activation of ß-catenin.

Cardiomyocyte (CM) loss is a characteristic of various heart diseases, including ischaemic heart disease. Cardiac regeneration has been suggested as a promising strategy to address CM loss. Although many studies of regeneration have focused mainly on mononucleated or diploid CM, the limitations associated with the cytokinesis of polyploid and multinucleated CMs remain less well known. Here, we show that ß-catenin, a key regulator in heart development, can increase cytokinesis in polyploid multinucleated CMs. The activation of ß-catenin increases the expression of the cytokinesis-related factor epithelial cell transforming 2 (ECT2), which regulates the actomyosin ring and thus leads to the completion of cytokinesis in polyploid CMs. In addition, hypoxia can induce polyploid and multinucleated CMs by increasing factors related to the G1-S-anaphase of the cell cycle, but not those related to cytokinesis. Our study therefore reveals that the ß-catenin can promote the cytokinesis of polyploid multinucleated CMs via upregulation of ECT2. These findings suggest a potential field of polyploid CM research that may be exploitable for cardiac regeneration therapy.

Effects of Preoperative Risk Stratification on Direct In-hospital Costs for Chinese Patients with Coronary Artery Bypass Graft: A Single Center Analysis.

The purpose of this study was to analyze the components of inpatient costs for coronary artery bypass graft (CABG) according to preoperative risk stratification and to provide evidence for improvement of diagnosis-related groups (DRGs) payment. All patients (n=458) receiving an isolated CABG between January 2014 and December 2016 in a tertiary referral center, in southwest China, were analyzed. Hospital mortality was predicted by the EuroSCORE II for each patient. The patients were subdivided into two groups according to the observed mortality (1.97%, 9/458): a high-risk group (group H, predicted mortality ≥1.97%) and a low-risk group (group L, predicted mortality <1.97%). Clinical outcomes, resource use, in-hospital direct costs, and reimbursement expenses were compared between the two groups. Significant differences existed between group L and group H in postoperative mortality (0.4% vs. 3.4%; P=0.02), postoperative complications (10.6% vs. 45.7%; P<0.001), postoperative length of hospital stay (17.5±4.9 days vs. 18.8±6.5 days, P=0.01), in-hospital costs ($20 256±3096 vs. $23 334±6332; P<0.001), and reimbursement expenses ($7775±2627 vs. $9639±3917; P<0.001). In general, a higher EuroSCORE II was significantly associated with a worse clinical outcome and increased costs. The CABG cost data provide evidence for improvement of DRGs payment.

Melatonin alleviates hypoxia-induced cardiac apoptosis through PI3K/Akt pathway.

Hypoxia-induced apoptosis is an inevitable problem in cyanotic congenital heart disease. In the present study, we investigated effects of melatonin on hypoxic cardiomyocytes in vitro and in vivo, and explored its underlying mechanism. H9C2 cells were subjected to hypoxia for 48 hours. Mice were subjected to hypoxia treatment (10% O2) for 4 weeks. Cell viability was detected by the cell counting kit-8 assay. Cellular apoptosis was assessed by Annexin V/7 AAD assay. Western blotting was employed to determine the expression of Bcl-2, Bax, cleaved caspase 3, phosphorylation of PI3K, and AKT. Melatonin increased cell viability and alleviated apoptosis in hypoxic H9C2 cells and cardiomyocytes of hypoxia-treated mice. Melatonin pretreatment increased Bcl-2 and decreased cleaved caspase 3 and Bax levels. Moreover, melatonin activated the PI3K/Akt pathway. The protective effects of melatonin were abolished by a PI3K/Akt-inhibitor, LY294002. Our results demonstrated that melatonin confers cardioprotection by inhibiting apoptosis through the activation of PI3K/Akt signaling pathway in hypoxic cardiomyocytes.

Downregulation of microRNA­199a­5p protects cardiomyocytes in cyanotic congenital heart disease by attenuating endoplasmic reticulum stress.

Chronic hypoxia is a key pathological change in patients with cyanotic congenital heart defect (CCHD). It has been demonstrated that enhanced myocardial unfolded protein response (UPR) increases the capacity to buffer endoplasmic reticulum (ER) stress and to avoid subsequent apoptosis caused by the hypoxia that underlies CCHD. The present study was performed to determine the regulatory role of microRNAs (miRNAs) in this cytoprotective UPR process. The results revealed that miR­199a­5p was markedly downregulated in the cardiac tissue of patients with CCHD and in human myocardial cells cultured in hypoxic conditions. The two major UPR modulators, 78 kDa glucose­regulated protein (GRP78) and activating transcription factor 6 (ATF6), were potential target genes of miR­199a­5p in CCHD myocardial specimens. In addition, the miR­199a­5p mimic and inhibitor were evidently able to change GRP78 and ATF6 gene expression and ER stress­associated apoptosis in hypoxia­treated cardiomyocytes. The interaction between miR­199a­5p and the ATF6 and GRP78 3'­UTR binding sites in myocardial cells was also confirmed by luciferase assay. Thus, it is concluded that myocardial downregulation of miR­199a­5p favors the UPR against hypoxia­induced ER stress in CCHD, which contributes to myocardial protection.

Cardiac resident macrophages are involved in hypoxia­induced postnatal cardiomyocyte proliferation.

Induction of cardiomyocyte proliferation, the most promising approach to reverse myocardial attrition, has been gaining importance as a therapy for cardiovascular disease. Hypoxia and macrophages were previously independently reported to promote cardiomyocyte proliferation in mice. However, whether hypoxia promotes cardiomyocyte proliferation in humans, and the association between hypoxia and macrophages in cardiomyocyte proliferation, have not to the best of our knowledge been previously investigated. The present study investigated the cardiomyocyte proliferation in 22 acyanotic and 29 cyanotic patients. Cardiomyocyte proliferation in a hypoxic mouse model (15% O2) was subsequently performed and the macrophage subsets were analyzed. A C­C chemokine receptor type 2 (CCR2) inhibitor was used to increase the number of resident macrophages in order to investigate the effect of macrophages on cardiomyocyte proliferation. The results demonstrated that cardiomyocyte proliferation in the cyanotic infant group was significantly increased compared with the acyanotic infant group and the hypoxia­treated C57BL/6J neonates confirmed the hypoxia­induced cardiomyocyte proliferation. However, hypoxia did not induce the proliferation of isolated cardiomyocytes. Notably, hypoxia treatment increased the number of cardiac resident macrophages in neonate hearts. Furthermore, increasing the number of resident macrophages significantly enhanced cardiomyocyte proliferation. In conclusion, postnatal hypoxia promoted cardiomyocyte proliferation in humans and animals, and cardiac resident macrophages may be involved in this process. Therefore, this novel mechanism may provide a promising strategy for cardiovascular disease treatment.

Macrophage migration inhibitory factor triggers vascular smooth muscle cell dedifferentiation by a p68-serum response factor axis.

AIMS: Macrophage migration inhibitory factor (MIF) is an important proinflammatory mediator linked to arterial diseases. Although its inflammatory property such as macrophage recruitment is known for contributing to vascular pathogenesis, the direct effects of MIF on homeostasis and biological function of vascular smooth muscle cell (VSMC) that are crucial for development of arterial abnormalities, are poorly understood. METHODS AND RESULTS: We show that MIF is able to directly induce VSMC dedifferentiation, a pathophysiological process fundamental for progression of various arterial diseases. Mechanistically, MIF suppresses p68 protein, a crucial regulator of cell growth and organ differentiation, via activation of JNK and p38 MAPKs. siRNA targeting of p68 facilitated dedifferentiation state in VSMCs, whereas p68 overexpression blocked MIF-elicited transition. In addition, MIF decreased the expression of serum response factor (SRF) that governs VSMC differentiation marker genes transcription, through repression of p68 protein. Furthermore, we showed a previously uncharacterized molecular interaction between p68 and SRF by co-immunoprecipitation assay. p68 attenuated MIF-elicited suppression of SRF recruitment to VSMC-specific promoter. Finally, anti-MIF treatment could reverse VSMC dedifferentiation, preserve vascular function, and inhibit remodelling due to vascular injury. CONCLUSIONS: Our results demonstrate a novel mechanism for the regulation of VSMC differentiation by MIF involving p68 and SRF. Strategy for targeting of MIF could inhibit aberrant transition of VSMC in cardiovascular pathogenesis, and may be of therapeutic benefit in phenotype-related arterial remodelling.

CUEDC2 modulates cardiomyocyte oxidative capacity by regulating GPX1 stability.

The irreversible loss of cardiomyocytes due to oxidative stress is the main cause of heart dysfunction following ischemia/reperfusion (I/R) injury and ageing-induced cardiomyopathy. Here, we report that CUEDC2, a CUE domain-containing protein, plays a critical role in oxidative stress-induced cardiac injury. Cuedc2(-/-) cardiomyocytes exhibited a greater resistance to oxidative stress-induced cell death. Loss of CUEDC2 enhanced the antioxidant capacity of cardiomyocytes, promoted reactive oxygen species (ROS) scavenging, and subsequently inhibited the redox-dependent activation of signaling pathways. Notably, CUEDC2 promoted E3 ubiquitin ligases tripartite motif-containing 33 (TRIM33)-mediated the antioxidant enzyme, glutathione peroxidase 1 (GPX1) ubiquitination, and proteasome-dependent degradation. Ablation of CUEDC2 upregulated the protein level of GPX1 in the heart significantly. Strikingly, in vivo, the infarct size of Cuedc2(-/-) heart was significantly decreased after I/R injury, and aged Cuedc2(-/-) mice preserved better heart function as the overall ROS levels in their hearts were significantly lower. Our results demonstrated a novel role of CUEDC2 in cardiomyocyte death regulation. Manipulating CUEDC2 level might be an attractive therapeutic strategy for promoting cardiomyocyte survival following oxidative stress-induced cardiac injury.

Risk Factors for Acute Kidney Injury after Cardiovascular Surgery: Evidence from 2,157 Cases and 49,777 Controls - A Meta-Analysis.

PURPOSE: Cardiovascular surgery-associated acute kidney injury (AKI-CS) contributes to mortality and morbidity. However, risk factors accelerating its development are unclear. We identified risk factors for AKI-CS in patients with cardiopulmonary bypass in the hospital surgical intensive care unit to predict and minimize renal complication in future cardiac surgery. METHODS: We analyzed data from 14 case-control studies published prior to June 2014 and indexed in Science Citation Index, PubMed, and other databases to determine the major risk factors for AKI-CS. RESULTS: Analyzed risk factors were divided into three groups: preoperative, intraoperative and postoperative. Preoperative factors included: age (OR, 4.87; 95% CI, 3.50-6.24), NYHA class III/IV (OR, 2.53; 95% CI, 1.32-4.86), hypertension (OR, 1.68; 95% CI, 1.44-1.97), preoperative creatinine (OR, 0.66; 95% CI, 0.18-1.14), peripheral vascular disease (OR, 1.31 95% CI, 1.09-1.57), respiratory system disease (OR, 1.29; 95% CI, 1.10-1.50), diabetes mellitus (OR, 1.52; 95% CI, 1.07-2.16), and cerebrovascular disease (OR, 2.13; 95% CI, 1.11-4.09). Intraoperative factors were: cardiopulmonary bypass time (OR, 33.78; 95% CI, 23.15-44.41), aortic clamping time (OR, 13.24; 95% CI, 7.78-18.69), use of intra-aortic balloon pump (OR, 4.44; 95% CI, 2.37-8.30), and type of surgery (OR, 1.01; 95% CI, 0.43-2.39). Postoperative factors were: infection (OR, 3.58; 95% CI, 1.43-8.97), redo operation (OR, 2.57; 95% CI, 1.75-3.78), emergency surgery (OR, 4.76; 95% CI, 3.05-7.43), and low cardiac output (OR, 2.30; 95% CI, 1.05-5.04). CONCLUSIONS: Our results support that preoperative, intraoperative, and postoperative factors are associated with AKI-CS. Ejection fraction, BMI, acute myocardial infarction, type of surgery, and congestive heart failure were not absolutely associated with AKI.

MicroRNA-146b inhibition augments hypoxia-induced cardiomyocyte apoptosis.

MicroRNAs (miRs) regulate a number of physiological and pathological processes, including myocardial chronic hypoxia. Previous studies revealed that the expression of miR-146b is increased in vitro and in vivo following the induction of hypoxia. In the present study, the role of miR­146b in hypoxic cardiomyocytes, and the mechanisms underlying its activity, were investigated. The expression of miR­146b was measured in tissue samples from patients with congenital heart disease by reverse transcription­quantitative polymerase chain reaction. The rat H9c2 cardiomyocyte cell line was transfected with an miR­146b inhibitor or the experimental controls, and the cells were maintained under hypoxic conditions for 72 h. The expression of miR­146b increased following the induction of hypoxia. Transfection with the miR­146b inhibitor enhanced the release of lactate dehydrogenase and increased hypoxia­induced apoptosis, as determined by terminal deoxynucleotidyl transferase dUTP nick­end labeling, Hoechst 33258 staining, JC­1 assay (measuring mitochondrial membrane permeability) and annexin V/propidium iodide analysis. A decreased expression of Bcl­2 was observed, whereas the expression levels of cleaved­caspase 3 and Bax were increased. Western blot analysis and a dual luciferase reporter assay confirmed that ribonuclease L is a direct target of miR­146b. Furthermore, inhibition of miR-146b increased the activation of nuclear factor-κB and signal transducer and activator of transcription 3. In conclusion, the inhibition of miR­146b may increase hypoxia-induced cardiomyocyte apoptosis.

rs10263935 and rs6045676 identified by genome-wide association study were associated with aortic dissection in a Chinese population.

Aortic dissection (AD) is a disease characterized by a tear in the aortic intimal layer and separation of the arterial wall. Some risk factors, such as hypertension and Marfan syndrome, are well known in AD, but the role of genetic factor is largely unknown. In this study, we investigated the relation between two single nucleotide polymorphisms (SNPs) identified by genome-wide association study and AD. Approximately 177 patients diagnosed with AD through clinical evaluation and imaging techniques and 183 age- and sex-matched control subjects who were suffering from chest pain but without AD were included in the study. Genotyping of rs10263935 and rs6045676 was performed in both patients and control subjects using the TaqMan(®) method [Life Technologies (AB & Invitrogen), Carlsbad, CA]. The frequency of the AA and AG genotype in rs10263935 was significantly higher in the AD patients (0.085 and 0.435, respectively) than in the control subjects (0.033 and 0.355, respectively). The rs10263935 A allele frequency in the AD patients was higher than that in the control subjects [0.302 vs 0.210, odds ratio (OR) = 1.62, 95% confidence interval (CI): 1.26-2.28, P = 0.005]. Similarly, the frequency of the GG genotype in rs6045676 was significantly higher in the AD patients than in the control subjects (0.107 vs 0.038, P = 0.015). The rs6045676 G allele frequency in the AD patients was higher than that in the control subjects (0.282 vs 0.191, OR = 1.67, 95% CI: 1.18-2.50, P = 0.004). After adjustment of the confounding factors, such as smoking, sex, and age, the differences remain significant in several models (rs10263935: GG vs AA: OR = 3.13, 95% CI: 1.15-8.33, P = 0.025; GG vs AG: OR = 1.57, 95% CI: 1.01-2.44, P = 0.045; rs6045676: GG vs CC: OR = 3.30, 95% CI: 1.32-8.25, P = 0.011). rs10263935 on chromosome 7 and rs6045676 on chromosome 20 are associated with AD. Further studies are warranted to elucidate the functional role of these two variants.

Association of gestational diabetes mellitus (GDM) with subclinical atherosclerosis: a systemic review and meta-analysis.

BACKGROUND: Gestational diabetes mellitus (GDM) is associated with an elevated risk of adverse health outcomes such as type 2 diabetes and cardiovascular diseases. Carotid intima-media thickness (cIMT) is increasingly used as a noninvasive marker for subclinical atherosclerosis. Whether there is a direct correlation between GDM and elevated cIMT is still controversial. METHODS: PubMed, Embase and reference lists of relevant papers were reviewed. Studies assessing the relationship between GDM and cIMT were included. Weighted Mean Difference (WMD) of cIMT was calculated using random-effect models. RESULTS: Fifteen studies with a total of 2247 subjects were included in our analysis, giving a pooled WMD of 0.05 (95% confidence interval [CI] 0.03 -0.07). Furthermore, meta regression and subgroup analysis found that the association between GDM and larger cIMT already existed during pregnancy, and this relation was stronger in obese GDM patients. CONCLUSIONS: GDM in and after pregnancy is associated with subclinical atherosclerosis. Weight control may be helpful to prevent cardiovascular diseases for GDM patients.

Liver X receptor activation protects against inflammation and enhances autophagy in myocardium of neonatal mouse challenged by lipopolysaccharides.

Liver X receptors (LXRs) has been emerged as negative regulators of cardiomyocytic inflammation. The cellular process of autophagy is believed to play a protective role in myocardium during the inflammatory status. In this study, we investigated the role of LXRs agonist TO901317 (TO) on lipopolysaccharides (LPS)-induced myocardial inflammation and autophagy. The results showed that TO pretreatment significantly reduced the LPS-induced infiltration of inflammatory cells, elevation of NF-κB protein, TNF-α, and IL-6 mRNA levels in the myocardium. Moreover, LPS stimulated autophagy in neonatal mice heart, and this effect was further enhanced by TO pretreatment as evidenced by increased LC3-II/GAPDH ratio increment. Furthermore, TUNEL assay revealed LPS stimulation also increased the number of apoptotic cells in the myocardium, and the increment was inhibited by TO pretreatment. Our findings suggested that attenuation of inflammation and apoptosis, and enhancement of autophagy by TO may contribute to the protection of myocardium under inflammatory condition.

Can serum levels of alkaline phosphatase and phosphate predict cardiovascular diseases and total mortality in individuals with preserved renal function? A systemic review and meta-analysis.

BACKGROUND: It is demonstrated that elevated serum levels of alkaline phosphatase (ALP) and phosphate indicate a higher risks of cardiovascular disease (CVD) and total mortality in population with chronic kidney disease (CKD), but it remains unclear whether this association exists in people with normal or preserved renal function. METHOD: Clinical trials were searched from Embase and PubMed from inception to 2013 December using the keywords "ALP", "phosphate", "CVD", "mortality" and so on, and finally 24 trials with a total of 147634 patients were included in this study. Dose-response and semi-parametric meta-analyses were performed. RESULTS: A linear association of serum levels of ALP and phosphate with risks of coronary heart disease (CHD) events, CVD events and deaths was identified. The relative risk (RR) of ALP for CVD deaths was 1.02 (95% confidence interval [CI], 1.01-1.04). The RR of phosphate for CVD deaths and events was 1.05 (95% CI, 1.02-1.09) and 1.04 (95% CI: 1.03-1.06), respectively. A non-linear association of ALP and phosphate with total mortality was identified. Compared with the reference category of ALP and phosphate, the pooled RR of ALP for total mortality was 1.57 (95% CI, 1.27-1.95) for the high ALP group, while the RR of phosphate for total mortality was 1.33 (95% CI, 1.21-1.46) for the high phosphate group. It was observed in subgroup analysis that higher levels of serum ALP and phosphate seemed to indicate a higher mortality rate in diabetic patients and those having previous CVD. The higher total mortality rate was more obvious in the men and Asians with high ALP. CONCLUSION: A non-linear relationship exists between serum levels of ALP and phosphate and risk of total mortality. There appears to be a positive association of serum levels of ALP/phosphate with total mortality in people with normal or preserved renal function, while the relationship between ALP and CVD is still ambiguous.

Serum phosphate concentration and incidence of stroke: a systemic review and meta-analysis.

Elevated serum phosphate is associated with cardiovascular and total mortality in patients with kidney diseases and healthy individuals. But whether serum phosphate is associated with stroke is controversial. We searched PubMed and Embase from January 1, 1970 to May 9, 2014 with keywords such as "serum phosphate", "serum phosphorus", and "stroke". Dose-response meta-analysis was conducted. A restricted cubic spline model was used, and then we estimated pooled RR using generalized least square regression taking into account the correlation among categories of each study. Five studies with a total of 32,608 patients were included. We identified a linear relationship between serum phosphate and risk of stroke (P for non-linearity = 0.5258). The RR of phosphate (1 mg/dL) for stroke was 1.00 (95 % CI 0.97-1.05), similar results were observed in subgroup analysis. A linear relationship between serum phosphate and risk of stroke is identified. There is no association between serum level of phosphate and stroke.

Emergent endovascular vs. open surgery repair for ruptured abdominal aortic aneurysms: a meta-analysis.

OBJECTIVES: To systematically review studies comparing peri-operative mortality and length of hospital stay in patients with ruptured abdominal aortic aneurysms (rAAAs) who underwent endovascular aneurysm repair (EVAR) to patients who underwent open surgical repair (OSR). METHODS: The Medline, Cochrane, EMBASE, and Google Scholar databases were searched until Apr 30, 2013 using keywords such as abdominal aortic aneurysm, emergent, emergency, rupture, leaking, acute, endovascular, stent, graft, and endoscopic. The primary outcome was peri-operative mortality and the secondary outcome was length of hospital stay. RESULTS: A total of 18 studies (2 randomized controlled trials, 5 prospective studies, and 11 retrospective studies) with a total of 135,734 rAAA patients were included. rAAA patients who underwent EVAR had significantly lower peri-operative mortality compared to those who underwent OSR (overall OR = 0.62, 95% CI = 0.58 to 0.67, P<0.001). rAAA patients with EVAR also had a significantly shorter mean length of hospital stay compared to those with OSR (difference in mean length of stay ranged from -2.00 to -19.10 days, with the overall estimate being -5.25 days (95% CI = -9.23 to -1.26, P = 0.010). There was no publication bias and sensitivity analysis showed good reliability. CONCLUSIONS: EVAR confers significant benefits in terms of peri-operative mortality and length of hospital stay. There is a need for more randomized controlled trials to compare outcomes of EVAR and OSR for rAAA.

Identification of differently expressed genes and small molecule drugs for Tetralogy of Fallot by bioinformatics strategy.

This study aimed to screen out differentially expressed genes (DEGs) and explore small molecule drugs for Tetralogy of Fallot (TOF). The gene expression profile of TOF GSE26125 was downloaded from the Gene Expression Omnibus database, including 16 idiopathic TOF samples and five healthy controls. The DEGs were identified by the Limma package in R language and underwent functional enrichment analysis via Database for Annotation, Visualization and Integrated Discovery tools. A protein-protein interaction (PPI) network of DEGs was then constructed and the significant clusters were selected for functional analysis. In addition, the DEGs were mapped to the connectivity map (CMap) database to identify potential small-molecule drugs. As a result, a total of 499 DEGs were selected between TOF and healthy controls. Meanwhile, the functional changes of DEGs related to TOF were mainly associated with cellular respiration and energy metabolism. Furthermore, in the PPI network, two clusters were identified via cluster 1 analysis. And only cluster 1 was significantly enriched into gene ontology terms, including respiratory chain, electron transport chain, and oxidation reduction. The hub gene of cluster 1 was NDUFAB1. Additionally, small molecules, such as harmine, solanine, and testosterone, may have the potential to repair the disordered metabolic pathways of TOF.