Left atrial enlargement and high uric acid level are risk factors for left atrial thrombus or dense spontaneous echo contrast in atrial fibrillation patients with low to moderate embolic risk assessed by CHA2DS2-VASC score.

Aims: To investigate the correlation and predictive value of left atrial diameter and blood uric acid levels with the occurrence of left atrial thrombus or dense spontaneous echo contrast in atrial fibrillation patients with low to moderate CHA2DS2-VASc scores. Methods and results: A total of 849 inpatients diagnosed with atrial fibrillation who had low to moderate CHA2DS2-VASc scores and complete transesophageal echocardiography were included in this study. Among them, 66 patients had left atrial thrombus or dense spontaneous echo contrast. When different models were used to correct other known risk factors, acid levels and abnormal left atrial diameter were identified as additional risk factors for left atrial thrombus or dense spontaneous echo contrast. The incidence of left atrial thrombus or dense spontaneous echo contrast was higher in patients with abnormal serum uric acid levels than in the control group (12.4% vs. 5.6%, p < 0.05), and this difference persisted after correcting the baseline data with propensity score matching (10.6% vs. 4.1%, p < 0.05). Abnormal left atrial diameter was another risk factor suggested by regression analysis, with an increased incidence of left atrial thrombus or dense spontaneous echo contrast in the abnormal left atrial diameter group compared to the control group, both before (18.0% vs. 3.5%, p < 0.05) and after (15.5% vs. 5.2%, p < 0.05) propensity score matching. The best predictive value was obtained by adding both abnormal serum uric acid levels and abnormal left atrial diameter. Conclusion: Left atrial enlargement and high uric acid levels increase the risk of left atrial thrombus or dense spontaneous echo contrast in atrial fibrillation patients with low to moderate CHA2DS2-VASc scores.

Amino acids downregulate SIRT4 to detoxify ammonia through the urea cycle.

Ammonia production via glutamate dehydrogenase is inhibited by SIRT4, a sirtuin that displays both amidase and non-amidase activities. The processes underlying the regulation of ammonia removal by amino acids remain unclear. Here, we report that SIRT4 acts as a decarbamylase that responds to amino acid sufficiency and regulates ammonia removal. Amino acids promote lysine 307 carbamylation (OTCCP-K307) of ornithine transcarbamylase (OTC), which activates OTC and the urea cycle. Proteomic and interactome screening identified OTC as a substrate of SIRT4. SIRT4 decarbamylates OTCCP-K307 and inactivates OTC in an NAD+-dependent manner. SIRT4 expression was transcriptionally upregulated by the amino acid insufficiency-activated GCN2-eIF2α-ATF4 axis. SIRT4 knockout in cultured cells caused higher OTCCP-K307 levels, activated OTC, elevated urea cycle intermediates and urea production via amino acid catabolism. Sirt4 ablation decreased male mouse blood ammonia levels and ameliorated CCl4-induced hepatic encephalopathy phenotypes. We reveal that SIRT4 safeguards cellular ammonia toxicity during amino acid catabolism.

Methylene-bridge tryptophan fatty acylation regulates PI3K-AKT signaling and glucose uptake.

Protein fatty acylation regulates numerous cell signaling pathways. Polyunsaturated fatty acids (PUFAs) exert a plethora of physiological effects, including cell signaling regulation, with underlying mechanisms to be fully understood. Herein, we report that docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) regulate PI3K-AKT signaling by modifying PDK1 and AKT2. DHA-administered mice exhibit altered phosphorylation of proteins in signaling pathways. Methylene bridge-containing DHA/EPA acylate δ1 carbon of tryptophan 448/543 in PDK1 and tryptophan 414 in AKT2 via free radical pathway, recruit both the proteins to the cytoplasmic membrane, and activate PI3K signaling and glucose uptake in a tryptophan acylation-dependent but insulin-independent manner in cultured cells and in mice. DHA/EPA deplete cytosolic PDK1 and AKT2 and induce insulin resistance. Akt2 knockout in mice abrogates DHA/EPA-induced PI3K-AKT signaling. Our results identify PUFA's methylene bridge tryptophan acylation, a protein fatty acylation that regulates cell signaling and may underlie multifaceted effects of methylene-bridge-containing PUFAs.

Inactivation of the AMPK-GATA3-ECHS1 Pathway Induces Fatty Acid Synthesis That Promotes Clear Cell Renal Cell Carcinoma Growth.

The tumorigenic role and underlying mechanisms of lipid accumulation, commonly observed in many cancers, remain insufficiently understood. In this study, we identified an AMP-activated protein kinase (AMPK)-GATA-binding protein 3 (GATA3)-enoyl-CoA hydratase short-chain 1 (ECHS1) pathway that induces lipid accumulation and promotes cell proliferation in clear cell renal cell carcinoma (ccRCC). Decreased expression of ECHS1, which is responsible for inactivation of fatty acid (FA) oxidation and activation of de novo FA synthesis, positively associated with ccRCC progression and predicted poor patient survival. Mechanistically, ECHS1 downregulation induced FA and branched-chain amino acid (BCAA) accumulation, which inhibited AMPK-promoted expression of GATA3, a transcriptional activator of ECHS1. BCAA accumulation induced activation of mTORC1 and de novo FA synthesis, and promoted cell proliferation. Furthermore, GATA3 expression phenocopied ECHS1 in predicting ccRCC progression and patient survival. The AMPK-GATA3-ECHS1 pathway may offer new therapeutic approaches and prognostic assessment for ccRCC in the clinic. SIGNIFICANCE: These findings uncover molecular mechanisms underlying lipid accumulation in ccRCC, suggesting the AMPK-GATA3-ECHS1 pathway as a potential therapeutic target and prognostic biomarker.

The Prognostic Value of Programmed Death-Ligand 1 in a Chinese Cohort With Clear Cell Renal Cell Carcinoma.

Objective: To investigate the association between tumor PD-L1 expression and patient survival to determine whether PD-L1 represents an independent prognostic feature for patients with non-metastatic clear cell renal cell carcinoma (RCC). Patients and Methods: The tissue bank of the Fudan University Shanghai Cancer Center was queried to identity tissue samples of patients treated with radical nephrectomy, for non-metastatic sporadic clear cell RCC (ccRCC) between 2008 and 2015. Real-time polymerase chain reaction and immunohistochemistry staining was performed to detect the expression level of PD-L1 in paired cancer tissue and paracancerous tissue. Results: Three-hundred-and-thirty patients were enrolled in this study, with a mean age of 55.0 years at surgery and a mean tumor size of 5.2 cm. Two-hundred-and-forty-two (73.3%) and 88 (26.7%) patients showed a high and low expression of PD-L1 mRNA, respectively, while 254 patients had positive PD-L1 immunohistochemistry staining. Two-hundred-and-ninety-two patients had consistent results for mRNA and the PD-L1 protein based on these different detection methods. Patients with high PD-L1 expression were more likely to exhibit adverse pathologic features including an advanced T stage (P = 0.002) and lymph node metastasis (P = 0.044). The Kaplan-Meier curves of PFS and OS stratified by PD-L1 expression had a statistically significant difference. PD-L1 expression maintained a significant predictive role for PFS and OS in the multivariate cox model. Conclusions: Our data suggests that PD-L1 correlates with prognosis in RCC and targeting the PD-1/PD-L1 pathway should be considered in the treatment of RCC patients.

PLD4 promotes M1 macrophages to perform antitumor effects in colon cancer cells.

Phospholipase D4 (PLD4) is a newly identified protein expressed in microglia. However, the function of PLD4 in tumor-associated macrophages (TAMs) is unknown. In the present study, we revealed that the expression of PLD4 was located in macrophages in the colon cancer mesenchymal and lymph nodes as shown by immunohistochemical analysis. furthermore, its expression was associated with clinical staging of colon cancer. Then, THP-1 as a cell model induced into TAMs. Western blot and RT-PCR analysis showed that PLD4 was mainly presented in M1 phenotype TAMs. The secretion of pro-inflammatory cytokines in M1 macrophages was significantly reduced after the expression of PLD4 inhibited by PLD4-siRNA. Furthermore, co-cultured with condition-medium from control or PLD4-siRNA M1 macrophages for 24 h, cell apoptosis, cycle and proliferation of cancer cells improved compared to control. These results indicated that PLD4 could be involved in the activation process of M1 phenotype macrophages.

MTHFR c.677C>T Inhibits Cell Proliferation and Decreases Prostate Cancer Susceptibility in the Han Chinese Population in Shanghai.

Methylenetetrahydrofolate reductase (MTHFR) c.677C>T and c.1298A>C variants were known to be associated with prostate cancer (PCa) risk with conflicting results, because of MTHFR and nutrient status interaction in the prostate development. In this large-scale, hospital-based, case-control study of 1817 PCa cases and 2026 cancer-free controls, we aimed to clarify the association between these two MTHFR variants and PCa risk in Shanghai and to explore the underlying molecular mechanisms. We found that both the heterozygous CT (adjusted OR = 0.78, 95% CI: 0.67-0.92) and the homozygous TT genotypes (adjusted OR = 0.68, 95% CI: 0.55-0.83) of c.677C>T were associated with a significantly decreased risk of PCa compared with homozygous wild-type CC genotype, respectively, using multivariate logistic regression. Furthermore, we confirmed that MTHFR c.677T allele was related to an increased serum homocysteine level in the Han Chinese population in Shanghai. In the cultured PCa cell lines, we observed that MTHFR c.677T could elevate the cellular homocysteine level and cause DNA damage, thus increasing cell apoptosis and finally inhibiting cell proliferation. In conclusion, MTHFR c.677T was a protective factor of PCa risk in ethnic Han Chinese males by inducing DNA damage and cell apoptosis.

Functional variants of the 5-methyltetrahydrofolate-homocysteine methyltransferase gene significantly increase susceptibility to prostate cancer: Results from an ethnic Han Chinese population.

Aberrant DNA methylation has been implicated in prostate carcinogenesis. The one-carbon metabolism pathway and related metabolites determine cellular DNA methylation and thus is thought to play a pivotal role in PCa occurrence. This study aimed to investigate the contribution of genetic variants in one-carbon metabolism genes to prostate cancer (PCa) risk and the underlying biological mechanisms. In this hospital-based case-control study of 1817 PCa cases and 2026 cancer-free controls, we genotyped six polymorphisms in three one-carbon metabolism genes and assessed their association with the risk of PCa. We found two noncoding MTR variants, rs28372871 T > G and rs1131450 G > A, were independently associated with a significantly increased risk of PCa. The rs28372871 GG genotype (adjusted OR = 1.40, P = 0.004) and rs1131450 AA genotype (adjusted OR = 1.64, P = 0.007) exhibited 1.40-fold and 1.64-fold higher risk of PCa, respectively, compared with their respective homozygous wild-type genotypes. Further functional analyses revealed these two variants contribute to reducing MTR expression, elevating homocysteine and SAH levels, reducing methionine and SAM levels, increasing SAH/SAM ratio, and promoting the invasion of PCa cells in vitro. Collectively, our data suggest regulatory variants of the MTR gene significantly increase the PCa risk via decreasing methylation potential. These findings provide a novel molecular mechanism for the prostate carcinogenesis.

CC-Chemokine Ligand 2 (CCL2) Suppresses High Density Lipoprotein (HDL) Internalization and Cholesterol Efflux via CC-Chemokine Receptor 2 (CCR2) Induction and p42/44 Mitogen-activated Protein Kinase (MAPK) Activation in Human Endothelial Cells.

High density lipoprotein (HDL) has been proposed to be internalized and to promote reverse cholesterol transport in endothelial cells (ECs). However, the mechanism underlying these processes has not been studied. In this study, we aim to characterize HDL internalization and cholesterol efflux in ECs and regulatory mechanisms. We found mature HDL particles were reduced in patients with coronary artery disease (CAD), which was associated with an increase in CC-chemokine ligand 2 (CCL2). In cultured primary human coronary artery endothelial cells and human umbilical vein endothelial cells, we determined that CCL2 suppressed the binding (4 °C) and association (37 °C) of HDL to/with ECs and HDL cellular internalization. Furthermore, CCL2 inhibited [(3)H]cholesterol efflux to HDL/apoA1 in ECs. We further found that CCL2 induced CC-chemokine receptor 2 (CCR2) expression and siRNA-CCR2 reversed CCL2 suppression on HDL binding, association, internalization, and on cholesterol efflux in ECs. Moreover, CCL2 induced p42/44 mitogen-activated protein kinase (MAPK) phosphorylation via CCR2, and p42/44 MAPK inhibition reversed the suppression of CCL2 on HDL metabolism in ECs. Our study suggests that CCL2 was elevated in CAD patients. CCL2 suppressed HDL internalization and cholesterol efflux via CCR2 induction and p42/44 MAPK activation in ECs. CCL2 induction may contribute to impair HDL function and form atherosclerosis in CAD.

Regulation of CD40 signaling in colon cancer cells and its implications in clinical tissues.

CD40 is a member of the tumor necrosis factor receptor family. We reveal here a correlation between CD40 expression and colon cancer differentiation. Upon CD40 ligand (CD40L) binding, CD40/CD40L signaling inhibited colon cancer proliferation, induced apoptosis, stalled cells at G0/G1, and influenced cell adhesion and metastasis. Clustering analysis identified the elevation of aryl hydrocarbon receptor repressor (AHRR) expression along with activation of CD40/CD40L signaling. Examination of clinical specimens revealed that both AHR and AHRR levels correlated with colon cancer histological grade. In addition, high expression of AHRR was associated with high expression of CD40 in tumor cells, with CD40L expression being particularly high in the tumor interstitium. Real-time PCR and western blotting analysis showed that AHRR expression in colon cancer cells was up-regulated by CD40L binding. The likely mediating signaling pathways for the effects of CD40 are described herein.

Stromal interaction molecule 1 plays an important role in gastric cancer progression.

Studies have shown that stromal interaction molecule 1 (STIM1) is expressed in a variety of cancers and is related to tumor growth. The present study aimed to investigate the expression and roles of STIM1 in gastric carcinoma. Immunohistochemistry and western blotting revealed that STIM1 was expressed at higher levels in gastric cancer tissues (82%) than these levels in normal gastric tissues (42%). In addition, STIM1 was also expressed in tumor vascular endothelial cells. The effects of STIM1 on proliferation, apoptosis, adhesion, invasion and migration of gastric cancer cells were detected by MTT assay, flow cytometry, cell adhesion assay and Transwell assay, respectively. The results shown that STIM1 knockdown did not alter proliferation or apoptosis, but promoted cell adhesion and inhibited migration and invasion in the gastric cancer cells. In addition, STIM1 knockdown did not alter the expression or phosphorylation of mitogen-activated protein kinase (MEK) or extracellular signal-regulated kinase (ERK), implying that STIM1 affected gastric cancer cell migration through a pathway independent of the MEK/ERK pathway.

Fully human HER2/cluster of differentiation 3 bispecific antibody triggers potent and specific cytotoxicity of T lymphocytes against breast cancer.

The use of a bispecific antibody (BsAb) is a promising and highly specific approach to cancer therapy. In the present study, a fully human recombinant single chain variable fragment BsAb against human epidermal growth factor receptor (HER)2 and cluster of differentiation (CD)3 was constructed with the aim of developing an effective treatment for breast cancer. HER2/CD3 BsAb was expressed in Chinese hamster ovary cells and purified via nickel column chromatography. Flow cytometry revealed that the HER2/CD3 BsAb was able to specifically bind to HER2 and CD3­positive cells. HER2/CD3 BsAb was able to stimulate T-cell activation and induce the lysis of cultured SKBR­3 and BT474 cells in the presence of unstimulated T lymphocytes. HER2/CD3 BsAb efficiently inhibited the growth of breast cancer tissue by activating and inducing the proliferation of tumor tissue infiltrating lymphocytes. Therefore, HER2/CD3 BsAb is a potent tool which may be a suitable candidate for the treatment of breast cancer.

Effect of fosinopril on the transient outward potassium current of hypertrophied left ventricular myocardium in the spontaneously hypertensive rat.

To investigate fosinopril's effect on the transient outward potassium current (Ito) of differing degrees of hypertrophied myocytes in the spontaneously hypertensive rat (SHR). Ten- and 24-week-old SHRs were used as models for cardiac hypertrophy. Hypertrophied ventricular myocytes were exposed to 1, 10, and 100 µmol/L fosinopril; the whole-cell patch-clamp technique was used to study the effects on the transient outward potassium current. Ito current density was decreased in SHR myocytes relative to controls (14.17 ± 0.31 and 11.62 ± 0.08 pA/pF in 10- and 24-week-old SHR versus 16.73 ± 0.15 pA/pF, p < 0.01). Higher concentrations of fosinopril (10 and 100 µmol/L) increased Ito peak current density in 10-week-old SHR myocytes compared with controls (14.92 ± 0.14 and 15.27 ± 0.13 pA/pF versus 14.17 ± 0.31 pA/pF, p < 0.01). Fosinopril increased Ito peak current density in 24-week-old SHR myocytes at all doses (12.70 ± 0.07, 13.74 ± 0.10, and 14.53 ± 0.13 versus 11.62 ± 0.08 pA/pF for controls, p < 0.01). Fosinopril had a greater Ito elevation potential on hypertrophied myocytes in 24-week-old compared with 10-week-old SHR for each dose (1.08 ± 0.09 versus 0.37 ± 0.26 pA/pF, p < 0.01; 2.13 ± 0.05 versus 0.75 ± 0.35 pA/pF, p < 0.01; 2.92 ± 0.07 versus 1.10 ± 0.40 pA/pF, p < 0.01). Fosinopril increased Ito current density in hypertrophied myocytes. This effect was more pronounced in myocytes with a greater degree of hypertrophy.

Association of higher resistin levels with inflammatory activation and endothelial dysfunction in patients with essential hypertension.

BACKGROUND: Some studies have shown that serum resistin levels increase in hypertensive patients. Whether the increase of resistin is related to inflammatory or vascular endothelial function is still unknown. We investigated the relationship of increased resistin levels to inflammatory factors and circulating biomarkers of vascular endothelial function in hypertensive patients. METHODS: One hundred and forty-four nondiabetic patients with new onset, hypertension were recruited. Blood pressure, blood glucose, insulin, resistin, tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6), von Willebrand factor (vWF), endothelin-1 (ET-1) and nitric oxide (NO) were measured. The homeostasis model assessment, insulin resistance index (HOMA-IR) was calculated. Patients were divided into two groups according to the median level of resistin. Cytokine levels and indicators of vascular endothelial function were compared. Multiple linear regression was used to determine factors influencing resistin. RESULTS: Serum resistin ranged from 2.57 ng/ml to 20.18 ng/ml in hypertensive patients. High resistin group (> 8.36 ng/ml) had higher levels of TNF-α, IL-6, vWF and ET-1 but lower level of NO compared with low resistin group (P < 0.01). Resistin was positively correlated with body mass index, systolic blood pressure, HOMA-IR, low-density lipoprotein cholesterol, TNF-α and ET-1 but negatively correlated with NO (all P < 0.05). Multiple linear regression analysis revealed that HOMA-IR, TNF-α, NO and ET-1 are independent predictors of resistin with standardized regression coefficients of 0.625, 0.368, -0.260 and 0.222, respectively (all P < 0.01). CONCLUSIONS: We conclude that higher resistin levels are associated with inflammatory activation and endothelial dysfunction, because patients with essential hypertension have increased TNF-α, IL-6, vWF and ET-1 and decreased NO. Moreover, the statistical association of resistin with TNF-α, NO and ET-1 suggests involvement of resistin in the progression of hypertension by influencing inflammation and endothelial function.

Effect of amiodarone on dispersion of ventricular repolarization in a canine congestive heart failure model.

The effects of amiodarone on ventricular electrophysiological parameters, especially the dispersion of ventricular repolarization, were investigated in a canine model of congestive heart failure (CHF). Dogs were randomized to either a control, amiodarone, CHF, or CHF+amiodarone group. Dogs in the CHF and CHF+amiodarone groups underwent 4-5 weeks of rapid ventricular pacing; dogs in the control and amiodarone groups underwent sham operation only. Amiodarone (20 mg/kg per day) was administered orally, beginning on postoperative Day 1, in the treatment groups; ventricular electrophysiological variables were evaluated 4-5 weeks after rapid pacing or sham operation. In CHF dogs, the transmural dispersion ventricular repolarization time (TDVRT) increased significantly. Amiodarone significantly decreased the TDVRT in CHF dogs. The ventricular fibrillation threshold (VFT) decreased in the CHF group. Amiodarone increased the VFT in CHF dogs. The TDVRT increased in CHF dogs, but amiodarone decreased TDVRT and increased VFT in these dogs. These results suggest a beneficial effect of amiodarone on malignant arrhythmias and may provide the basis for its use in CHF patients.

Increased level of soluble syndecan-1 in serum correlates with myocardial expression in a rat model of myocardial infarction.

A candidate marker for ventricular remodeling after myocardial infarction (MI), syndecan-1 (Sdc1), has been shown to be upregulated in myocardial tissues. However, the clinical potential of this marker depends on the ability to obtain samples safely and noninvasively. Therefore, we investigated the expression of soluble Sdc1 in the serum of rats after MI. Anterior descending coronary arteries of Sprague-Dawley rats were ligated, and MI was confirmed by morphologic and physiologic methods. Rats that underwent surgery without ligation served as the control group. We analyzed the expression of Sdc1 mRNA by quantitative reverse-transcription polymerase chain reaction and that of Sdc1 protein by western blot in heart tissue from the MI border and compared it to the expression of soluble Sdc1 in serum. The myocardial levels of expression of Sdc1 mRNA and protein were very low in the sham group but increased significantly in the MI group (P<0.01). The expression of myocardial Sdc1 reached a peak at day 3 and declined gradually thereafter, although the levels at 14 days remained significantly higher than those in the sham group. The expression of soluble Sdc1 in the sera of the rats in the MI group followed a similar pattern and was linearly correlated with the expression of Sdc1 protein in the MI border zone (r=0.952, P<0.01). Soluble Sdc1 was also detected at low levels in normal rat serum. These results may facilitate additional exploration of the utility of serum Sdc1 as a biomarker for MI in humans.

Potential proarrhythmic effect of cardiac resynchronization therapy during perioperative period: data from a single cardiac center.

BACKGROUND: Cardiac resynchronization therapy (CRT) could improve heart function, symptom status, quality of life and reduce hospitalization and mortality in patients with severe heart failure (HF) with optimal medical management. However, the possible adverse effects of CRT are often ignored by clinicians. METHOD: A retrospective analysis of CRT over a 6-year period was made in a single cardiac center. RESULTS: Fifty-four patients were treated with CRT(D) device, aged (57 ± 11) years, with left ventricular ejection fraction of (32.1 ± 9.8)%, of which 4 (7%) developed ventricular tachycardia/ventricular fibrillation (VT/VF) or junctional tachycardia after operation. Except for one with frequent ventricular premature beat before operation, the others had no previous history of ventricular arrhythmia. Of the 4 patients, 3 had dilated cardiomyopathy and 1 had ischemic cardiomyopathy, and tachycardia occurred within 3 days after operation. Sustained, refractory VT and subsequent VF occurred in one patient, frequent nonsustained VT in two patients and nonparoxysmal atrioventricular junctional tachycardia in one patient. VT was managed by amiodarone in two patients, amiodarone together with beta-blocker in one patient, and junctional tachycardia was terminated by overdrive pacing. During over 12-month follow-up, except for one patient's death due to refractory heart and respiratory failure in hospital, the others remain alive and arrhythmia-free. CONCLUSIONS: New-onset VT/VF or junctional tachycardia may occur in a minority of patients with or without prior history of tachycardia after biventricular pacing. Arrhythmia can be managed by conventional therapy, but may require temporary discontinuation of pacing. More observational studies should be performed to determine the potential proarrhythmic effect of CRT.

Antioxidant probucol attenuates myocardial oxidative stress and collagen expressions in post-myocardial infarction rats.

This study was designed to evaluate the effects of the antioxidant probucol on myocardial oxidative stress and collagen remodeling by determining type I and III collagen together with relevant collagen mRNA expressions in both the infarcted and noninfarcted myocardium in post-myocardial infarction (MI) rats. Acute myocardial infarction was induced by ligation of the left anterior coronary artery in rats. Rats surviving 24 h after MI were randomly assigned to the group treated with vehicle or probucol. Sham-operated rats served as controls. Cardiac hemodynamics, parameters of oxidative stress in noninfarcted myocardium, collagen content, collagen volume density fraction, collagen type I and III together with the ratio, type I and III collagen mRNA were evaluated after 6 weeks. Probucol decreased oxidative stress as assessed by increased myocardial total antioxidative capacity, superoxide dismutase (SOD) activity, and SOD-to-myocardial malondialdehyde (MDA) ratio accompanied by decreased MDA level, decreased left ventricular end diastolic pressure and LV -dP/dtmax, and decreased collagen content and CVF in the noninfarcted area accompanied by decrease of type I and III mRNA expressions. The increase of collagen type I/III ratio in noninfarcted area was suppressed by probucol accompanied by inhibition of the increase in type I/III collagen mRNA ratio. Probucol did not affect collagen type I/III ratio and the corresponding mRNA ratio in the infarcted area. These results suggest that suppression of oxidative stress by probucol may attenuate collagen synthesis by inhibition of collagen mRNA expressions and improve diastolic function.

[Clinical analysis of inappropriate shock of implantable cardioverter defibrillators].

OBJECTIVE: Implantable cardioverter defibrillator (ICD) can effectively treat life-threatening ventricular arrhythmias. The most common side effect is inappropriate discharge. This study analyzes the incidence and causes of inappropriate discharges of ICD in our hospital. METHODS: Forty-three patients implanted with ICD in our hospital from November 2001 to October 2007 were involved in our study. Patients were followed-up regularly. All episodes recorded and stored in the ICD were analyzed. RESULTS: Seven of the 43 patients underwent ninety-six inappropriate discharges. Inappropriate discharges in six patients were caused by supraventricular tachyarrhythmias (SVT). In one patient the discharge was caused by noise. Most inappropriate discharges occurred in the first year after implantation. The history of atrial fibrillation before implantation is an independent predictor of inappropriate discharges. CONCLUSIONS: The incidence of inappropriate discharge is 16.3% in our study and the most common cause is SVT. Most inappropriate discharges occur in the first year after implantation. Patients with atrial fibrillation history have a higher risk of inappropriate discharges.

[PPAR gamma agonist rosiglitazone alleviates hypoxia/reoxygenation-induced oxidative stress and apoptosis in rat cardiac myocytes].

OBJECTIVE: To observe the effects of different concentrations of PPAR gamma agonist rosiglitazone on hypoxia/reoxygenation-induced oxidative stress, cell viability and apoptosis in rat cardiac myocytes. METHODS: Cultured rat cardiac myocytes were divided into 5 groups, namely group I (normal group), group II (20 micromo/L ROS group), group III (I/R group), group IV (I/R+20 micromo/L ROS group), and group V (I/R+80 micromo/L ROS group). Group IV and group V were treated with rosiglitazone 12 h before hypoxia/reoxygenation. The changes in cell morphology were observed under optical and transmission electron microscopy, and levels of malondialdehyde (MDA), superoxide dismutase (SOD) activity, and lactate dehydrogenase (LDH) content were determined after the treatment. MTT assay was performed to assess the cell viability and flow cytometry was used to analyze the cell apoptosis. RESULTS: Hypoxia/reoxygenation resulted in significantly increased MDA and LDH contents and apoptosis of the cardiac myocytes (P<0.05), but lowered SOD activity and the cell viability (P<0.05). The MDA and LDH contents and apoptotic rate were significantly lower but SOD content and cell vitality significantly higher in groups IV and V than in group III (P<0.05). Group V showed significantly lower MDA and LDH contents and apoptotic rate but higher but SOD content and cell vitality than group IV (P<0.05). Electron microscopy revealed obvious apoptotic changes in group III, and only mild changes were found in group V. CONCLUSION: Rosiglitazone can significantly reduce hypoxia/reoxygenation-induced oxidative stress in cardiac myocytes, improve the cell viability and dose-dependently reduce the apoptotic rate of the cardiac myocytes.