[Upregulation of PLOD2 promotes invasion and metastasis of osteosarcoma cells].

Objective: To investigate the relationship of procollagen-lysine 2-oxoglutarate 5-dioxygenase 2 (PLOD2) expression and the clinical characteristics of osteosarcoma, and explore the potential mechanism of tumour metastasis promoted by PLOD2. Methods: The expression of PLOD2 in osteosarcoma tissues and paired adjacent tissues were detected by immunohistochemistry and qRT-PCR. Correlation of PLOD2 expression in osteosarcoma with the clinical pathologic features was analyzed by Chi square test and Kaplan-Meier analysis.Fibrillar collagen formation and collagen deposition in the tumor tissues were detected by picrosirius red staining. We transfected U-2OS cells with LV-vector, LV-over/PLOD2, sh-NC and sh-PLOD2. The expression of PLOD2 was detected by qRT-PCR. The impact of POLD2 on U-2OS cell invasion was determined by wound-healing assay and Transwell migration assay. The expressions of PLOD2/FAK/JAK2-STAT3 signal pathway related proteins were detected by western blotting. Results: The high expression level of PLOD2 in osteosarcoma tissues was 72.5%, significantly higher than 0% in paired adjacent noncancerous tissues (P<0.01), the expression of PLOD2 was positively correlated with lymph node metastasis, pulmonary metastasis and poor outcome (P<0.01). The same results were also observed in qRT-PCR assay. The median survival time of patients with high expression of PLOD2 protein was 13 months, significantly shorter than 32 months of patients with low expression of PLOD2 (P<0.05). The result of picrosirius red staining showed that the percentage of collagen fiber deposition in the osteosarcoma tissue with high level of PLOD2 was (74.43+ 9.63)%, significantly higher than (9.67±1.28)% in tissue with low expression of PLOD2 (P<0.001). The result of wound-healing and Transwell migration assay showed that over-expression of PLOD2 markedly promoted the invasion, however, knockdown of PLOD2 suppressed the invasion of U-2OS cells (both P<0.01). The result of western blotting showed that over-expression of PLOD2 significantly increased the expression levels of p-FAK, p-JAK2, p-STAT3, but knockdown PLOD2 decreased the levels of p-FAK, p-JAK2, p-STAT3 in U-2OS cells. Conclusions: Up-regulation of PLOD2 in osteosarcoma is correlated with lymphatic and distant metastasis. PLOD2 promotes invasion and metastasis of osteosarcoma might through FAK/JAK2-STAT3 signal pathway.

[Mechanism of MALAT1 induced osimertinib resistance in HCC827 lung cancer cells].

Objective: To test the effect of metastasis associated in lung adenocarcinoma transcript 1 (MALAT1) and/or osimertinib on the proliferation and apoptosis of HCC827 cells, and explore the potential mechanism of MALAT1 induced resistance to osimertinib. Methods: We transfected HCC827 cells with LV-vector or LV-over/MALAT1. Stable transfected cells (HCC827/Vector, HCC827/MALAT1) were selected by adding puromycin. HCC827/MALAT1 cells were further transfected with the shRNA-negative control (NC) or shRNA-human epidermal growth factor receptor 3 (ERBB3) plasmid. The effects of overexpression of MALAT1, knockdown of ERBB3 and/or osimertinib on the proliferation of HCC827 cells were evaluated by 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2H tetrazolium bromide (MTT) assay. Cell apoptosis induced by MALAT1 overexpression, knockdown of ERBB3 and/or osimertinib treatment were analyzed by flow cytometry analysis. The expressions of EGFR and ERBB3 signal pathway related proteins in HCC827 cells treated with overexpression of MALAT1, knockdown of ERBB3 and/or osimertinib treatment were detected by western blot. Results: The MTT assay showed that sensitivity to osimertinib of HCC827/MALAT1 cells were significantly repressed. The 50% inhibitive concentration (IC(50)) of osimertinib >4 000 nmol/L in HCC827/MALAT1 cells. However, knockdown of ERBB3 facilitated the anti-proliferation effect of osimertinib, and the IC(50) of osimertinib in shRNA-ERBB3 cells was (17.27±3.21) nmol/L. The results of flow cytometry analysis showed that the apoptotic rate of HCC827/MALAT1 cells induced by 10 nmol/L osimertinib was (8.38±0.92)%, significantly lower than (27.17±5.83)% of knockdown of ERBB3 (P<0.01). Western blotting showed that the expression of p-ERBB3, p-AKT and p-extracellular regulated protein kinases (ERK) in HCC827/MALAT1 cells was markedly up-regulated, while the expression of p-epithelial growth factor receptor (EGFR) was inhibited. The expressions of p-ERBB3, p-AKT and p-ERK were marginally affected by osimertinb. However, osimertinib downregulated the expressions of p-EGFR, p-ERBB3, p-AKT and p-ERK in ERBB3 deleted cells. Conclusions: MALAT1 confers resistance to osimertinb in HCC827 cells by activating of the ERBB3/PI3K/AKT and ERBB3/MAPK/ERK signaling pathways.

[Expression of PLOD2 in esophageal squamous cell carcinoma and its correlation with invasion and metastasis].

Objective: To investigate PLOD2 expression in esophageal squamous cell carcinoma, and to explore the potential mechanism by which PLOD2 promotes tumor metastasis. Methods: The expression of PLOD2 in 60 cases of esophageal squamous cell carcinoma (the patients were collected at the first Affiliated Hospital of Xinxiang Medical University, from January 2016 to December 2017) was investigated by immunohistochemistry. Fibrillar collagen formation and collagen deposition were detected by picrosirius red staining. Correlation of PLOD2 expression with clinical pathologic features of the patients was performed using χ(2) test and Kaplan-Meier analysis. After EC-109 cells were transfected with LV-vector and LV-over/PLOD2, the expression of PLOD2 was detected by real time PCR and the impact of POLD2 on invasion in EC-109 cells was determined by transwell migration and invasion assays. The expression of PLOD2/AKT epithelial-to-mesenchymal transition signal pathway related proteins was detected by Western blot. Results: The expression level of PLOD2 in esophageal squamous cell carcinoma was 81.7% (49/60 cases),higher than their paired noncancerous tissues(8.3%, 5/60; P<0.01), and correlated significantly with tumor depth of invasion and nodal metastasis (P<0.01). Picrosirius red staining showed that collagen deposition was increased and the degree of fibrillar organization was enhanced in carcinoma tissues that had higher PLOD2 expression. Transwell migration and invasion assays showed that PLOD2 significantly promoted the migration and invasion ability of EC-109 cells. Western blot showed that PLOD2 significantly increased the expression levels of p-FAK, p-AKT and vimentin in EC-109 cells. Conclusions: Esophageal squamous cell carcinoma has a high expression of PLOD2 that correlates with tumor invasion and lymph node metastasis. PLOD2 promotes invasion and metastasis of esophageal squamous cell carcinoma through epithelial-to-mesenchymal transition via FAK/AKT signal pathway.

[Mechanism of miR-221 contributes to gefitinib resistance in PC-9 cells].

Objective: To investigate the effect of microRNA-221 (miR-221) overexpression on gefitinib resistance in PC-9 cells and study its underlying mechanisms. Methods: PC-9 cells were transfected with LV-NC and LV-miR-221 to establish cell stabilizing strains (PC-9/NC and PC-9/miR-221), then they were used to detect the relative expression of miR-221 and apoptotic protease activating factor-1 (APAF-1) mRNA by real-time fluorescence quantitative PCR (qRT-PCR). The effects of gefitinib (0-4 µmol/L) on the growth and proliferation of cell stabilizing strains were detected by CCK-8 Assay. After gefitinib treatment, cell apoptosis was detected by Flow Cytometry Assays. The expression of epidermal growth factor receptor (EGFR), phosphorylated epidermal growth factor receptor (p-EGFR), APAF-1 and cleaved cysteinyl aspartate specific proteinase-3 (Cleaved-caspase-3) were detected by Western blot. Dual-Luciferase Reporter Assay was used to evaluate the relationship between APAF-1 and miR-221. Results: The relative expression of miR-221 in PC-9/NC cells was significantly lower than that in PC-9/miR-221 cells[(1.00±0.082) vs (40.24±0.017)](P<0.01). The half maximal inhibitory concentration (IC(50)) in PC-9/NC cells was significantly lower than that in PC-9/miR-221 cells[(IC(50)=0.1 µmol/L) vs (IC(50)>4 µmol/L)](P<0.05). Apoptosis rate of PC-9/NC cell was significantly higher than PC-9/miR-221[(33.42±4.28)% vs (10.27±1.12)%](P<0.05); APAF-1 mRNA expression was significantly higher in PC-9/NC cells than PC-9/miR-221[(1.000+ 0.069) vs (0.701±0.072)](P<0.05), and the expression of APAF-1 protein in PC-9/NC cells was significantly higher than that of PC-9/miR-221 cells. The dual luciferase reporter gene results showed that miR-221a inhibited luciferase activity significantly stronger than transfected miRNA negative control group after co-transfection of luciferase plasmids pmir-REPORT-APAF-1-wt and miR-221a mimics (P<0.01). p-EGFR was down-regulated in both PC-9/NC and PC-9/miR-221 cells after treatment with gefitinib. APAF-1 and Cleaved-caspase-3 proteins were significantly down-regulated in PC-9/miR-221 cells compared with PC-9/NC cells, while APAF-1 and Cleaved-caspase-3 proteins were up-regulated in PC-9/NC cells treated with gefitinib compared with PC-9/miR-221 cells (P<0.05). Conclusion: miR-221 induces resistance to gefitinib in PC-9 cells by downregulating APAF-1 expression.

[Mechanism of long non-coding RNA-metastasis associated lung adenocarcinoma transcript 1 induced invasion and metastasis of esophageal cancer cell EC-109].

Objective: To investigate the effect and mechanism of long non-coding RNA-metastasis associated lung adenocarcinoma transcript 1, (LncRNA-MALAT1) on invasion and metastasis of esophageal cancer cell EC-109. Methods: EC-109 cells were transfected with lentiviral vector carrying short hairpin RNA of MALAT1( shRNA-MALAT1) or a nonspecific shRNA control (shRNA-control). The expressions of MALAT1, microRNA-200a, ZEB1 and ZEB2 were detected by qRT-PCR. The effect of shRNA-MALAT1 on invasion of EC-109 cells was determined by transwell assay. The expressions of components of epithelial-msenchymal transition pathway in EC-109 cells were determined by immunofluorescence array and western blotting. The expression relationship between MALAT1 and miR-200a in EC-109 cells was detected by dual-luciferase reporter assay. Results: The result of qRT-PCR showed that the expressions levels of MALAT1, ZEB1 and ZEB2 in shRNA-MALAT1 group were 0.43±0.06, 0.64±0.04 and 0.51±0.04, respectively, significantly lower than 0.97±0.08, 1.06±0.07 and 0.98±0.05 in shRNA-control group and 1 in control group, respectively(all P<0.05). Transwell assay showed that the number of invaded cells in shRNA MALAT1 group was (96.81±10.43) per low-power field, markedly lower than that of (278.44±13.28) per low-power field in shRNA-control group (P<0.01). Immunofluorescence staining and Western blotting showed that MALAT1 downregulation significantly reduced the expressions of proteins related to EMT signal pathway in EC-109 cells.Dual luciferase reporter assay showed that compared to negative control, the activities of luciferase reporter in EC-109 cells co-transfected with pmirGLO-MALAT1-wt and miR-200a were significantly down-regulated. While co-transfected pmirGLO-MALAT1-mut with miR-200a mimics had no effect on the luciferase reporter activities of MALAT1. Conclusion: LncRNA MALAT1 functions as a competing endogenous RNA to regulate the expressions of ZEB1 and ZEB2 by sponging miR-200a and promotes invasion and migration of esophageal cancer cells through inducing epithelial-mesenchymal transition.

Impaired balance of Th17/Treg in patients with nasal polyposis.

Nasal polyposis (NP) is a chronic inflammatory disease of the nasal cavity and sinuses that is regulated by T lymphocyte subsets. Imbalance of Th17/Treg has been considered critical in the development of inflammation and atopic reactions. To assess whether the balance of Th17/Treg is disrupted in patients with NP, we evaluated the distribution of Th17 and Treg cells among peripheral blood mononuclear cells (PBMCs) in atopic patients with NP, non-atopic patients with NP and controls. We then determined mRNA levels of RORc and Foxp3 and protein levels of IL-17, TGF-ß and IL-10 in polyp tissue among the three groups. Finally, we investigated the correlation between Th17-, Treg- and Th1-, Th2-related cytokines (INF-γ, IL-4, IL-5). The results demonstrated that both atopic and non-atopic patients with NP revealed significantly increased Th17 proportion and decreased Treg proportion in PBMCs, as well as significantly increased RORc and IL-17 levels and decreased Foxp3 and TGF-ß levels in polyp tissue. Furthermore, these differences were significant between atopic and non-atopic groups. The frequency of Treg in PBMCs was found to be negatively correlated with Th1 and Th2 cytokines in polyps. These results indicated that an impaired balance of Th17/Treg existed in patients with NP and was more severe in atopic patients, suggesting that the imbalance of Treg/Th17 may play an important role in the development of NP and that atopy may aggravate NP by promoting the imbalance of Th17/Treg.

Fracture behaviour of zirconia FPDs substructures.

The purpose of this study was to evaluate the occurrence of superficial flaws after machining and to identify fracture initiation and propagation in three-unit heat-treated machined fixed partial dentures (FPDs) substructures made of hot isostatic pressed (HIPed) yttria-stabilized tetragonal zirconia polycrystal (Y-TZP) after loaded to fracture. Four three-unit HIPed Y-TZP-based FPDs substructures were examined. To evaluate the occurrence of superficial flaws after machining, the surfaces were studied utilizing a fluorescent penetrant method. After static loading to fracture, characteristic fracture features on both mating halves of the fractured specimens were studied using a stereomicroscope and a scanning electron microscope. Grinding grooves were clearly visible on the surfaces of the machined FPDs substructures, but no other flaws could be seen with the fluorescent penetrant method. After loading to fracture, the characteristic fracture features of arrest lines, compression curl, fracture mirror, fracture origin, hackle and twist hackle were detected. These findings indicated that the decisive fracture was initiated at the gingival embrasure of the pontic in association with a grinding groove. Thus, in three-unit heat-treated machined HIPed Y-TZP FPDs substructures, with the shape studied in this study, the gingival embrasure of the pontic seems to be a weak area providing a location for tensile stresses when they are occlusally loaded. In this area, fracture initiation may be located to a grinding groove.

Effects of Pretreatment, Specimen Thickness, and Artificial Aging on Biaxial Flexural Strength of Two Types of Y-TZP Ceramics.

OBJECTIVES: To evaluate the effects of surface treatment, specimen thickness, and aging on the biaxial flexural strength (BFS) of two types of yttria-stabilized, tetragonal zirconia polycrystal (Y-TZP) ceramics. METHODS AND MATERIALS: Disc-shaped specimens, 0.4 and 1.3 mm thick, made from hot isostatic pressed (Denzir) and non-hot isostatic pressed (ZirPlus) Y-TZP, were sandblasted, heat treated, and autoclaved. The surface topography was assessed in accordance with European Standard 623-624:2004 and the BFS tests in accordance with International Organization for Standardization Standard 6872:2008. For statistical analyses, one-way Shapiro-Wilk test, analysis of variance (post hoc: least significant differences), Mann-Whitney U-test, and Pearson correlation tests (p<0.05) were used. RESULTS: As delivered, the BFS of the 0.4-mm ZirPlus was >1.3-mm ZirPlus (p<0.01), and the BFS of the 0.4-mm Denzir was >1.3-mm Denzir (p<0.001). Sandblasting with 0.2 MPa reduced the BFS of the ZirPlus and Denzir discs (p<0.01), whereas sandblasting with 0.6 MPa increased the BFS of the 0.4-mm Denzir (p<0.001) and reduced the BFS of the 0.4-mm ZirPlus (p<0.05). Heat treatment significantly reduced the BFS of all the groups except for the 0.6 MPa sandblasted 0.4-mm ZirPlus. Autoclaving reduced the BFS of the as-delivered ZirPlus and Denzir specimens (p<0.001), whereas autoclaving the 0.6 MPa sandblasted and heat-treated specimens had no effect (p>0.05) on the BFS. The 0.6 MPa sandblasted, heat-treated, and autoclaved 0.4-mm Denzir exhibited higher BFS than the 0.6 MPa sandblasted, heat-treated, and autoclaved 0.4-mm ZirPlus (p<0.05). CONCLUSIONS: Thickness and surface treatment of Y-TZP-based ceramics should be considered since those factors could influence the BFS of the material.

Inter-rater agreement of novel high-resolution impedance manometry metrics: Bolus flow time and esophageal impedance integral ratio.

BACKGROUND: Novel high-resolution impedance manometry (HRIM) metrics of bolus flow time (BFT) and esophageal impedance integral (EII) ratio have demonstrated clinical utility, though the reliability of their analysis has not been assessed. We aimed to evaluate the inter-rater agreement of the BFT and EII ratio. METHODS: HRIM studies including five upright, liquid swallows from 40 adult patients were analyzed by two raters using a customized MATLAB program to generate the BFT and EII ratio. Inter-rater agreement was assessed using the intraclass correlation coefficient (ICC) for median values generated per patient and also for all 200 swallows. KEY RESULTS: The ICC (95% confidence interval, CI) for BFT was 0.873 (0.759-0.933) for median values and 0.838 (0.778-0.881) for all swallows. The ICC (95% CI) for EII ratio was 0.983 (0.968-0.991) for median values and 0.905 (0.875-0.928) for all swallows. Median values for both BFT and EII ratio were similar between the two raters (P-values .05). CONCLUSIONS AND INFERENCES: The BFT and EII ratio can be reliably calculated as supported by generally excellent inter-rater agreement. Thus, broader utilization of these measures appears feasible and would facilitate further evaluation of their clinical utility.

Could the peristaltic transition zone be caused by non-uniform esophageal muscle fiber architecture? A simulation study.

BACKGROUND: Based on a fully coupled computational model of esophageal transport, we analyzed how varied esophageal muscle fiber architecture and/or dual contraction waves (CWs) affect bolus transport. Specifically, we studied the luminal pressure profile in those cases to better understand possible origins of the peristaltic transition zone. METHODS: Two groups of studies were conducted using a computational model. The first studied esophageal transport with circumferential-longitudinal fiber architecture, helical fiber architecture and various combinations of the two. In the second group, cases with dual CWs and varied muscle fiber architecture were simulated. Overall transport characteristics were examined and the space-time profiles of luminal pressure were plotted and compared. KEY RESULTS: Helical muscle fiber architecture featured reduced circumferential wall stress, greater esophageal distensibility, and greater axial shortening. Non-uniform fiber architecture featured a peristaltic pressure trough between two high-pressure segments. The distal pressure segment showed greater amplitude than the proximal segment, consistent with experimental data. Dual CWs also featured a pressure trough between two high-pressure segments. However, the minimum pressure in the region of overlap was much lower, and the amplitudes of the two high-pressure segments were similar. CONCLUSIONS & INFERENCES: The efficacy of esophageal transport is greatly affected by muscle fiber architecture. The peristaltic transition zone may be attributable to non-uniform architecture of muscle fibers along the length of the esophagus and/or dual CWs. The difference in amplitude between the proximal and distal pressure segments may be attributable to non-uniform muscle fiber architecture.

[Prevalence and risk factors of allergic rhinitis: a Meta-analysis].

Objective:To clarify the morbidity and risk factors of allergic rhinitis (AR) in China so as to provide scientific basis for prevention of AR in the relevant populations.Method:Pubmed,Embase,Web of science,Cochrane Library,CNKI,VIP,Wanfang Data,CBM databases were searched for associated studies. The prevalence and risk factors of AR in China were retrieved from individual studies and the pooled estimates generated by R3.2.3 software.Result:Thirty-one cross-sectional studies were included in the Meta-analysis. The results indicated that the incidences of AR in Chinese children were 15.79%(95%CI 15.13-16.45).The highest prevalence is 17.20% in central China,the lowest is 13.94% in eastern China. The incidences of AR in Chinese adult were 13.26% (95%CI 12.05-14.47).The highest prevalence is 15.45% in southern China,the lowest is 10.93% in southwestern China. The pooled odds ratio (OR) values of family history (5.40),dust exposure history (2.04),drug allergy history (2.83),history of asthma(4.45),environmental tobacco smoking(ETS)(2.00),water damage (1.50),upholstering(1.41),pollen allergy(17.18),molds(1.31),keeping pets (1.29),cockroach (1.69).Conclusion:A study on the epidemic tendency of AR in China showed the morbidity of AR in Chinese children is higher than adult. Moreover,prevalence vary from region to region. Eleven kinds of risk factors mentioned above play imperative roles in the pathogenesis of AR. The early interventions which are associated with risk factors should be implemented in AR.

Association between polymorphisms in the APOB gene and hyperlipidemia in the Chinese Yugur population.

We investigated the influence of apolipoprotein B gene (APOB) variants on the risk of hyperlipidemia (HL) in 631 middle-aged and elderly members of the Chinese Yugur population (HL, n=336; normolipidemia, n=295). APOB polymorphisms were identified using mass spectrometry, and five single nucleotide polymorphisms (rs1042034, rs2163204, rs512535, rs676210, and rs679899) and serum lipids were further analyzed. rs1042034 and rs676210 were significantly associated with HL (P<0.05). Compared with the GG or AA genotype, individuals with AG and AG+AA in rs1042034 and with AG and AG+GG in rs676210 had a 1.67-fold (95%CI=1.20-2.33),1.63-fold (95%CI=1.19-2.24), 1.72-fold (95%CI=1.24-2.40), and 1.67-fold (95%CI=1.21-2.291) increased risk of high HL, respectively. rs2163204 was in strong linkage disequilibrium with rs1042034, rs676210, and rs679899, and strong disequilibrium was observed between rs1042034 and rs676210 (D'>0.9). Compared with the GTGAA haplotype, haplotypes ATGGA and ATAGG were more strongly associated with HL [odds ratio (OR)=1.46, 95%CI=0.02-2.11; OR=1.63, 95%CI=1.03-2.60, respectively]. The risk factors age (P=0.008), body mass index (P<0.0001), GA+GG genotype in rs676210 (P=0.009), and alcohol consumption (P=0.056) contributed strongly to HL development. The A allele of rs1042034 and the G allele of rs676210 may thus predispose middle-aged and elderly members of the Chinese Yugur population to HL in combination with other genetic or nutritional factors, and could be used as new genetic markers for HL screening.

[Meta-analysis of the morbidity of asthma in children with allergic rhinitis].

Objective: Pathogenesis of allergic rhinitis(AR) is thought to be related with asthma in children. However, lager scaled reports concerned on the co-morbidity of this two diseases in children are rare. In this meta-analysis, we aim to clarify the morbidity of asthma in children with AR.Method:Pubmed, Science, Springer, Elsevier, Embase, BMJ Journals, Wanfang data, VIP, CBM and CNKI were searched for relevant studies．The prevalences of asthma in children with AR were retrieved from individual studies and the pooled estimates generated by R3.2.3.Result:Fifteen cross-sectional studies were included in the meta-analysis. The results showed that the incidences of asthma in AR children were 35.01%(95％CI32.32%-37.70%) in China and 31.59%(95％CI28.02%-35.16%) in foreign countries.Conclusion:Comorbidity of AR and asthma was high in children. The incidence of asthma is higher in children with AR in China than that in foreign countries.

Determinants of the ventricular rate during atrial fibrillation.

Determinants of the ventricular cycle length during atrial fibrillation were examined in 52 patients. Thirty-three patients had structural heart disease and none had an accessory atrioventricular (AV) connection. The AV node effective and functional refractory periods, the shortest atrial pacing cycle length associated with 1:1 conduction, the AV node conduction time and indexes of concealed conduction in the AV node were measured in the baseline state (36 patients) and after modification of sympathetic tone by infusion of isoproterenol or propranolol (8 patients each). Atrial fibrillation was then induced with rapid atrial pacing, and the mean, shortest and longest ventricular cycle lengths were measured. Variables that correlated most strongly with the mean RR interval during atrial fibrillation were the AV node effective refractory period (r = 0.93; p less than 0.001), AV node functional refractory period (r = 0.87; p less than 0.001) and shortest atrial pacing cycle length associated with 1:1 conduction (r = 0.91; p less than 0.001). The AH interval during sinus rhythm (r = 0.74; p less than 0.001) and during atrial pacing at the shortest cycle length with 1:1 conduction (r = 0.52; p less than 0.001) had weaker correlations. Measures of concealed conduction did not improve the prediction of the mean or longest ventricular cycle length during atrial fibrillation. In conclusion, the refractory periods and conductivity of the AV node are the best indicators of the potential of the node to transmit atrial impulses to the ventricles during atrial fibrillation. The degree of concealed conduction in the AV node is a less important determinant of the mean ventricular rate during atrial fibrillation.

Natural history of patients with unexplained syncope and a nondiagnostic electrophysiologic study.

The purpose of this study was to define the natural history of 99 patients with unexplained syncope who underwent an electrophysiologic test that either was entirely normal or demonstrated nonspecific abnormalities that were nondiagnostic (inducible polymorphic ventricular tachycardia or ventricular fibrillation, a mildly prolonged sinus node recovery time of less than 2 s, a His-ventricular interval of 55 to 99 ms or supraventricular tachycardia not associated with hypotension). The mean age (+/- SD) of the patients was 56 +/- 19 years; structural heart disease was present in 47 patients and absent in 52. Complete follow-up was available in 95 patients. During 20 +/- 11 months of follow-up, 2 patients (2%) died suddenly, 19 patients (20%) had recurrent syncope and 74 patients (78%) had no further episodes of syncope. Among the 19 patients who continued to have syncope after the electrophysiologic testing, the cause of syncope was established clinically in 4 and was found to be high degree atrioventricular (AV) block (2 patients) or sinus node dysfunction (2 patients). No clinical or laboratory findings distinguished patients who had sudden death or syncope during follow-up from patients who did not. In conclusion, in patients with unexplained syncope who undergo an electrophysiologic test that is nondiagnostic 1) the incidence of sudden death is low (2%); 2) the remission rate of syncope is high (80%); 3) the electrophysiologic test may be documented to have been falsely negative in greater than or equal to 20% of patients who continue to have syncope, syncope in these patients being caused by AV block or sinus node dysfunction; and 4) patients at risk of sudden death or recurrent syncope, or both, cannot be readily identified prospectively.

Concealed anterograde accessory pathway conduction during the induction of orthodromic reciprocating tachycardia.

The purpose of this study was to determine whether concealed anterograde accessory pathway conduction occurs during the induction of orthodromic tachycardia by an atrial extrastimulus (S2). Sixteen patients with an overt (n = 9) or concealed (n = 7) accessory pathway had inducible orthodromic tachycardia by S2 during an atrial drive (S1) cycle length of 500 to 650 ms. A ventricular extrastimulus (S3) was introduced coincident with the His depolarization resulting from S2 during the longest S1S2 interval that reproducibly induced orthodromic tachycardia. The S1S3 interval was decreased in 10 ms steps until S3 reached ventricular refractoriness. Retrograde accessory pathway conduction of S3 in the presence and absence of S2 was compared at the same S1S3 intervals. In the absence of S2 there was retrograde accessory pathway conduction after S3 in each patient. In the presence of S2, in patients with overt pre-excitation, retrograde accessory pathway conduction after S3 was absent in one patient, prolonged in four patients and present only after long S1S3 intervals in three patients. Only one patient had unchanged retrograde conduction regardless of the presence or absence of S2. In patients with a concealed accessory pathway, retrograde accessory pathway conduction after S3 was absent in five patients and was prolonged in two. Thus, concealed anterograde accessory pathway conduction was present in 15 of 16 patients at the time of orthodromic tachycardia induction. In conclusion, concealed anterograde accessory pathway conduction occurs in a majority of patients with an overt or a concealed accessory pathway during induction of orthodromic tachycardia by an atrial extrastimulus.(ABSTRACT TRUNCATED AT 250 WORDS)

Determinants of QRS alternans during narrow QRS tachycardia.

This study was designed to prospectively determine the incidence of QRS alternans during various types of narrow QRS tachycardia and to clarify the determinants of QRS alternans. An electrophysiologic study was performed in 28 consecutive patients with a narrow QRS tachycardia. Persistent QRS alternans was observed in 6 (43%) of 14 patients during orthodromic reciprocating tachycardia, 5 (71%) of 7 patients during atrial tachycardia and 3 (43%) of 7 patients during atrioventricular (AV) node reentrant tachycardia. Incremental atrial pacing during sinus rhythm resulted in QRS alternans in patients who had QRS alternans during tachycardia, unless the shortest pacing cycle length associated with 1:1 AV conduction exceeded the tachycardia cycle length. In patients without QRS alternans during narrow QRS tachycardia, incremental atrial pacing during sinus rhythm resulted in persistent QRS alternans in five patients in whom the shortest pacing cycle length associated with 1:1 AV conduction was 60 to 180 ms less than the tachycardia cycle length. In an additional 20 patients without a narrow QRS tachycardia, persistent QRS alternans was observed during incremental atrial pacing in 11 (55%) of the patients. In six of six patients who had QRS alternans during abrupt rapid atrial pacing, QRS alternans was not observed when the same pacing rates were achieved gradually. Among the patients with narrow QRS tachycardia, the mean tachycardia cycle length in those who had QRS alternans (mean +/- SD 288 +/- 44 ms) was significantly shorter than in those who did not (369 +/- 52 ms, p less than 0.001). The presence of QRS alternans was not related to the tachycardia mechanism, relative or functional refractory period of the His-Purkinje system (at a drive cycle length of 500 ms), age, presence of structural heart disease, direction of input into the AV node or concealed retrograde conduction in the His-Purkinje system. In conclusion, QRS alternans during narrow QRS tachycardias is a rate-related phenomenon that depends on an abrupt increase to a critical rate and is independent of the tachycardia mechanism.

Concealed entrainment as a guide for catheter ablation of ventricular tachycardia in patients with prior myocardial infarction.

Fifteen consecutive patients with drug-refractory, recurrent, sustained, monomorphic ventricular tachycardia and a history of remote myocardial infarction underwent catheter ablation of ventricular tachycardia. Shocks of 100 to 300 J were delivered to sites at which pacing during ventricular tachycardia resulted in concealed entrainment, in which the ventricular tachycardia accelerated to the pacing rate, there was a long stimulus to QRS interval and there was no change in the configuration of the QRS complex during pacing at several rates compared with the configuration during ventricular tachycardia, thus identifying a zone of slow conduction in the reentrant circuit. Concealed entrainment was demonstrated in nine (60%) of 15 patients, and the stimulus to QRS intervals were 90 to 400 ms. At sites of concealed entrainment, the endocardial activation time relative to the QRS complex during ventricular tachycardia ranged from -125 to +50 ms, the timing of the local electrogram relative to the QRS complex was the same during entrainment as during ventricular tachycardia and the pace map during sinus rhythm was discordant with that of the ventricular tachycardia in seven patients. In the six patients in whom a site of concealed entrainment could not be identified, the target site for ablation was selected on the basis of identification of an isolated mid-diastolic potential, activation mapping and pace mapping. The mean (+/- SD) cumulative number of joules delivered to the target site was 306 +/- 140. A successful long-term clinical outcome was achieved in 9 of the 15 patients (mean follow-up 20 +/- 7 months). The clinical success rate was the same whether the target site was selected on the basis of concealed entrainment (five of nine, 56%) or on the basis of the other mapping techniques (four of six, 67%). In conclusion, the responses to pacing suggest that sites at which there is concealed entrainment may be located within a zone of slow conduction in the ventricular tachycardia reentry circuit, although not necessarily in an area critical for the maintenance of reentry. The long-term clinical efficacy of catheter ablation targeted to sites of concealed entrainment is about 60%, similar to the results achieved when conventional mapping techniques are used.

Significance of ST segment depression during paroxysmal supraventricular tachycardia.

During paroxysmal supraventricular tachycardia, patients frequently experience chest pain and marked ST segment depression suggesting acute myocardial ischemia. The purpose of this study was to assess whether ST depression during supraventricular tachycardia is caused by myocardial ischemia as reflected by net myocardial lactate production. Twenty-five patients (14 men, 11 women) who had a history of paroxysmal supraventricular tachycardia and a mean age (+/- SD) of 38 +/- 14 years underwent electrophysiologic testing. Twenty-four of these patients had no evidence of coronary disease, whereas one patient had undergone previous coronary bypass surgery. Nineteen patients had orthodromic and six patients had atrioventricular node reentrant tachycardias. A 12 lead electrocardiogram and simultaneous femoral artery and coronary sinus blood samples for lactate determinations were obtained at baseline and at 5 and 10 min of supraventricular tachycardia. Mean baseline heart rate of 83 +/- 12 beats/min increased to 180 +/- 25 beats/min during supraventricular tachycardia. All patients had 1 to 8 mm of ST segment depression in 1 to 9 of the 12 leads. Chest pain occurred in 64% of patients during supraventricular tachycardia. Baseline myocardial lactate extraction was 28 +/- 13% with no significant change at 5 or 10 min of tachycardia. In contrast, in a comparison group of seven patients with known coronary artery disease, atrial pacing at 168 +/- 26 beats/min in five patients resulted in greater than or equal to 1 mm ST depression in 2 to 7 of the 12 leads and a change in lactate extraction from a baseline of 29 +/- 13% to -27 +/- 20% (p less than 0.05) indicating net myocardial lactate production.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of flecainide acetate on prevention of electrical induction of ventricular tachycardia and occurrence of ischemic ventricular fibrillation during the early postmyocardial infarction period: evaluation in a conscious canine model of sudden death.

The antiarrhythmic and antifibrillatory effects of flecainide acetate during the early postinfarction period were evaluated in a conscious canine model of sudden cardiac death. Ventricular tachycardia remained inducible early after infarction in eight of nine dogs receiving an intravenous loading dose of flecainide (2.0 mg/kg body weight) and seven of eight dogs receiving saline vehicle. In both the drug and vehicle groups, there was no significant change in the ventricular refractory period or in the cycle length of the induced ventricular tachycardia. With a maintenance intravenous infusion of flecainide, 1.0 mg/kg per h for 4 hours, the subsequent occurrence of acute posterolateral ischemia resulted in the development of ventricular fibrillation and sudden death in seven of eight flecainide-treated and eight of eight vehicle-treated dogs. Seven additional postinfarction dogs with noninducible tachycardia during pretreatment programmed stimulation, and thereby considered to be at "low risk" for the development of ischemic ventricular fibrillation, were also given flecainide in an intravenous loading and maintenance dosing regimen. The subsequent occurrence of posterolateral ischemia resulted in the development of ventricular fibrillation in three of these seven dogs. These findings suggest that flecainide acetate may not possess pharmacologic properties useful in managing ventricular tachycardia or in preventing ischemic ventricular fibrillation in the presence of recent myocardial damage.