J wave syndromes: a decade of progress.

OBJECTIVE: The objective was to provide a brief history of J wave syndromes and to summarize our current understanding of their molecular, ionic, cellular mechanisms, and clinical features. We will also discuss the existing debates and further direction in basic and clinical research for J wave syndromes. DATA SOURCES: The publications on key words of "J wave syndromes", "early repolarization syndrome (ERS)", "Brugada syndrome (BrS)" and "ST-segment elevation myocardial infarction (STEMI)" were comprehensively reviewed through search of the PubMed literatures without restriction on the publication date. STUDY SELECTION: Original articles, reviews and other literatures concerning J wave syndromes, ERS, BrS and STEMI were selected. RESULTS: J wave syndromes were firstly defined by Yan et al. in a Chinese journal a decade ago, which represent a spectrum of variable phenotypes characterized by appearance of prominent electrocardiographic J wave including ERS, BrS and ventricular fibrillation (VF) associated with hypothermia and acute STEMI. J wave syndromes can be inherited or acquired and are mechanistically linked to amplification of the transient outward current (I to )-mediated J waves that can lead to phase 2 reentry capable of initiating VF. CONCLUSIONS: J wave syndromes are a group of newly highlighted clinical entities that share similar molecular, ionic and cellular mechanism and marked by amplified J wave on the electrocardiogram and a risk of VF. The clinical challenge ahead is to identify the patients with J wave syndromes who are at risk for sudden cardiac death and determine the alternative therapeutic strategies to reduce mortality.

The pharmacological research of Tek-1 relevance to anti-neuroinflammation, a candidate compound based on Telmisartan.

In this paper, BV-2 mouse small glial cell inflammation model induced by LPS is established. The experiment used 0.1-10 µM of telmisartan and Tek-1 to incubate with small glial cell and used telmisartan and Tek-1 to incubate with PPAR gamma special heterosexual antagonistic anti-agent GW9662. The article used ELISA method to dectect TNF-a effect on small glial cell for telmisartan and Tek-1. The article used real-time quantitative PCR method to dectect mRNA level expression effect of CD11b, CD16 and iNOS on small glial cell for telmisartan and Tek-1 and used Western Blot method to dectect MAPKs signal pathway and NF-κb signal turned guide pathway effect on small glial cell for telmisartan and Tek-1. Results show that Tek-1 had high affinity with AT1 receptor and inhibited intracellular calcium ion activation which can be for the AT1 receptor antagonists. Meanwhile, Tek-1 can partially activate PPAR gamma compared with full agonists of rosiglitazone.

Vasorelaxant activities of Danhong injection and their differential effects on the rat abdominal aorta and mesenteric artery.

Previous studies have found that Danhong injection (DHI), an extensively used herbal extract preparation in China, might be a powerful vasodilator. The aims of this study were to determine the vascular activity of DHI and its effects on arteries of different sizes. The results showed that DHI significantly inhibited rat-hindquarters and rabbit-ear vasoconstriction elicited by norepinephrine (NE) perfusion and markedly relaxed KCl-contracted and NE-contracted rat abdominal aortic and mesenteric artery rings. The endothelium made only a minor contribution to the vasorelaxant effect of DHI on artery segments. The vasorelaxant effect of DHI varied with the artery size, with larger arteries exhibiting a more sensitive and potent vasodilator response. DHI relaxed NE-induced vasoconstriction probably through inhibition of the intracellular Ca2+ release through the inositol triphosphate receptor system in the abdominal aorta and mesenteric artery, along with blockage of extracellular Ca2+ influx through the receptor-linked Ca2+ channels in the mesenteric artery. In addition, DHI completely relaxed KCl-induced contraction in both of the arteries, suggesting that inhibition of Ca2+ influx through voltage-gated Ca2+ channels is involved in the vasorelaxant effect of DHI. This elucidation of the vascular effects of DHI and the underlying mechanisms could lead to improved clinical applications.

Imbalanced response of ATP-binding cassette transporter A1 and CD36 expression to increased oxidized low-density lipoprotein loading contributes to the development of THP-1 derived foam cells.

ATP-binding cassette transporter A1 (ABCA1) and CD36, type B scavenger receptor, function as the key mediators of macrophages cholesterol efflux and intake, respectively. However, their contribution to development of foam cells still remains uncertain. We here examined the effects of increased oxidized low-density lipoprotein (oxLDL) loading on the ABCA1 and CD36 expression, and lipid accumulation in THP-1 macrophages. The cultured THP-1 macrophages were treated with different copper-oxLDL concentrations. The intracellular lipid contents and cholesterol efflux were measured, and the ABCA1 and CD36 expression were assessed. We found that expression of ABCA1 and CD36 were coordinately induced upon low to moderate doses of oxLDL loading. However, higher doses of oxLDL stimulation resulted in the imbalanced expression of ABCA1 and CD36 proteins with more preferentially suppressed ABCA1 protein, attenuated cholesterol efflux and development of THP-1 derived foam cells. The PPAR-γ expression was remarkably induced, and PPAR-γ agonist, pioglitazone, significantly promoted the ABCA1 and CD36 expression. Additionally, ABCA1 and CD36 proteins were strong colocalized in THP-1 macrophages membrane. In conclusion, the more preferentially suppressed ABCA1 expression as compared with CD36 at higher doses of oxLDL stimulation may be the initiator for the formation of macrophage-derived foam cells.

[Mechanism of drug-induced torsade de pointes: an experimental study in dogs].

OBJECTIVE: To investigate the mechanism of drug-induced torsade de pointes (Tdp) in dogs. METHODS: In arterially perfused canine left ventricular wedge preparations, the action potential duration (APD) of the endocardial (Endo), midmyocardial (M) and epicardial (Epi) myocytes, and transmural electrocardiogram (ECG) were recorded simultaneously. The effects of different concentrations of D-Sotalol on APD, transmural dispersion of repolarization (TDR), early after depolarization (EAD) and Tdp were observed. RESULTS: D-Sotalol prolonged APD of the Endo, M and Epi cells in a concentration-dependent manner from 0-100 µmol/L, and increased TDR due to a preferential APD prolongation of the M cells relative to Epi and Endo cells. The application of D-Sotalol elicited EAD, R on T ventricular premature beats, transmural reentry and Tdp in the M cells. CONCLUSION: EAD and R on T ventricular premature beats induced by D-Sotalol in M cells triggers Tdp, which is maintained by TDR increment and transmural reentry.

L539 fs/47, a truncated mutation of human ether-a-go-go-related gene (hERG), decreases hERG ion channel currents in HEK 293 cells.

Mutations in the human ether-a-go-go-related gene (hERG) are responsible for congenital Type 2 long QT syndrome (LQT2). Previously, we reported a truncated mutation of hERG in a Chinese family with LQT2, namely L539 fs/47, which is composed of a 19 bp deletion mutation and an A1692G polymorphism. This mutation was found to cause an LQT2 phenotype. The aim of the present study was to investigate the functional role of L539 fs/47 at the cellular level and its potential contribution to the loss of function of hERG channels. The function of the truncated mutation L539 fs/47 was evaluated by constructing a mutated plasmid, transfection of the mutated cDNA into HEK 293 cells and subsequent patch-clamp, western blotting and immunostaining experiments. Homologous expression of L539 fs/47 in HEK 293 cells produced a non-functional protein that was detected in cell membranes. When L539 fs/47 was expressed simultaneously with wild-type hERG, it suppressed wild-type hERG currents in a dose-dependent manner and changed the gating properties of the channel. Although L539 fs/47 hERG proteins were detected on plasma membranes, they failed to generate hERG currents. In general, L539 fs/47 dose-dependently decreases hERG ion channel currents and suppresses the function of wild-type channels function. This may explain, in part, the clinical manifestations of LQT2 in the family with this mutation.

Transfection by eukaryotic expression vector pcDNA3-HERG inhibits the cultured neonatal rabbit ventricular myocyte hypertrophy induced by phenylephrine.

OBJECTIVE: Prolonged action potential and decreased outward K(+) currents are consistent findings in hypertrophic myocardium. The relation between action potential prolongation and myocyte hypertrophy has remained unclear. The present study investigated the temporal relation between action potential prolongation and myocyte hypertrophy, and the effect of enhancing repolarization on myocyte hypertrophy induced by phenylephrine. METHODS: Neonatal rabbit ventricular myocytes were cultured and treated with 10 µmol/l phenylephrine. At 6 and 48 h after phenylephrine stimulation, myocyte hypertrophic parameters (including myocyte volume, total protein content, and membrane capacitance), action potential duration (APD), and calcineurin activity were measured; meanwhile, the effect of human-ether-a-go-go-related gene (HERG; encoding the αsubunit of rapidly activating delayed rectifier potassium channel) transfection on the above parameters at 48 h of phenylephrine stimulation was also measured. RESULTS: At 6 h after phenylephrine treatment, APD at 90% repolarization of neonatal rabbit ventricular myocytes was prolonged by 14.3% (P<.05), but myocyte hypertrophy was not found. At 48 h after phenylephrine stimulation, APD at 90% repolarization of neonatal rabbit ventricular myocytes was furthermore prolonged by 18.8% (P<.05); at the same time, myocyte volume, total protein content, membrane capacitance, and calcineurin activity were increased by 40.0%, 41.8%, 36.4%, and 124.1%, respectively (P<.01). Neonatal rabbit ventricular myocytes transfected by pcDNA3-HERG overexpressed I(HERG,tail) current, which was about fourfold higher than I(Kr) (rapidly activating delayed rectifier K(+) current) of neonatal rabbit ventricular myocytes without transfection of HERG. HERG overexpression could accelerate repolarization and shorten APD at 90% repolarization prolonged by phenylephrine and partially inhibit myocyte hypertrophy and calcineurin activation. CONCLUSIONS: During the myocyte hypertrophy induced by phenylephrine, prolongation of APD at 90% repolarization is not secondary to but precedes myocyte hypertrophy. HERG overexpression could enhance the repolarization and inhibit the calcineurin activation and myocyte hypertrophy induced by phenylephrine.

Effects of electric stimulations applied during absolute refractory period on cardiac function of rabbits with heart failure.

The effects of electric currents applied during absolute refractory period (ARP) on the cardiac function of rabbits with heart failure due to myocardial infarction (MI), and the safety of this method were investigated. Thirty rabbits were randomly assigned equally to 3 groups: sham-operated group, LV-anterior wall cardiac contractility modulation (LV-CCM) group, and septum-CCM (S-CCM) group. A thoracotomy was performed on all the rabbits. Electric pulses were delivered during the ARP on the anterior wall of left ventricle in CCM group and in the septum in S-CCM group, respectively. The left ventricular systolic pressure (LVSP) and maximum positive left ventricular pressure change (+dp/dt(max)), heart rates, ventricular tachycardia, ventricular fibrillation were observed. It was found that, as compared with the baseline, LVSP, and +dp/dtmax were significantly increased, on average, by 15.2% and 19.5% in LV-CCM group (P<0.05), and by 8.5% and 10.8% in S-CCM group (P<0.05). LVEDP was significantly decreased and -dp/dt(max) increased both in LV-CCM group and S-CCM group (P<0.05). CCM had no effect on heart rate and induced no arrhythmia in short time. It is concluded that electric currents delivered during the ARP could significantly enhance the contractility of myocardium safely, suggesting that CCM stimulation is a novel potent method for contractility modulation.

Effects of Electric Stimulations Applied during Absolute Refractory Period on Cardiac Function of Rabbits with Heart Failure / 华中科技大学学报（医学）（英德文版）

The effects of electric currents applied during absolute refractory period(ARP)on the cardiac function of rabbits with heart failure due to myocardial infarction(MI),and the safety of this method were investigated.Thirty rabbits were randomly assigned equally to 3 groups: sham-operated group,LV-anterior wall cardiac contractility modulation(LV-CCM)group,and septum-CCM(S-CCM)group.A thoracotomy was performed on all the rabbits.Electric pulses were delivered during the ARP on the anterior wall of left ventricle in CCM group and in the septum in S-CCM group,respectively.The left ventricular systolic pressure(LVSP)and maximum positive left ventricular pressure change(+dp/dtmax),heart rates,ventricular tachycardia,ventricular fibrillation were observed.It was found that,as compared with the baseline,LVSP,and+dp/dtmax were significantly increased,on average,by 15.2% and 19.5% in LV-CCM group(P<0.05),and by 8.5% and 10.8% in S-CCM group(P<0.05).LVEDP was significantly decreased and-dp/dtmax increased both in LV-CCM group and S-CCM group(P<0.05).CCM had no effect on heart rate and induced no arrhythmia in short time.It is concluded that electric currents delivered during the ARP could significantly enhance the contractility of myocardium safely,suggesting that CCM stimulation is a novel potent method for contractility modulation.

Proteomic analysis of mitochondria reveals a metabolic switch from fatty acid oxidation to glycolysis in the failing heart.

This work characterizes the mitochondrial proteomic profile in the failing heart and elucidates the molecular basis of mitochondria in heart failure. Heart failure was induced in rats by myocardial infarction, and mitochondria were isolated from hearts by differential centrifugation. Using two-dimensional gel electrophoresis and matrix-assisted laser desorption/ionization-time of flight mass spectrometry, a system biology approach was employed to investigate differences in mitochondrial proteins between normal and failing hearts. Mass spectrometry identified 27 proteins differentially expressed that involved in energy metabolism. Among those, the up-regulated proteins included tricarboxylic acid cycle enzymes and pyruvate dehydrogenase complex subunits while the down-regulated proteins were involved in fatty acid oxidation and the OXPHOS complex. These results suggest a substantial metabolic switch from free fatty acid oxidation to glycolysis in heart failure and provide molecular evidence for alterations in the structural and functional parameters of mitochondria that may contribute to cardiac dysfunction during ischemic injury.

[Dynamic changes of electrical remodeling in midmyocardium of rabbit left ventricle during the early stage of chronic pressure-overload.].

In the previous study, we had found that the action potential duration (APD) of midmyocardial (M) cells was gradually prolonged and M cells were easier to produce early after-depolarization (EAD) in the rabbit left ventricle during the early stage of chronic pressure-overload. The present study was performed to investigate the dynamic changes and significance of ionic current remodeling in M cells of rabbit left ventricle during the early stage of chronic pressure-overload. Sixty-four New Zealand rabbits were randomly divided into constriction groups and sham groups. The rabbit models with chronic pressure-overload were prepared by partial constriction of suprarenal abdominal aorta at the site proximal 5-10 mm away from the left renal artery. At 2 and 8 weeks after operation, the single cardiomyocytes were isolated by enzymatic digestion method. The midmyocardium from the anterolateral free wall of left ventricle was obtained by removing the epicardial and endocardial surfaces. Whole-cell patch-clamp technique was used to record the slowly activating delayed rectifier potassium current (I(Ks)), transient outward potassium current (I(to)), L-type calcium current (I(Ca-L)) of M cells. At 2 weeks after the constriction operation, compared with the sham group, I(Ks) tail current (I(Ks,tail)) and I(to) densities of M cells from constriction group significantly decreased by 33.3% and 51.5%, respectively. There was no significant difference in I(Ca-L) density between the two groups. At 8 weeks after operation, compared with the sham group, I(Ks,tail) and I(to) densities of M cells from constriction group significantly decreased by 37.0% and 49.2%, respectively. There was still no significant difference in I(Ca-L) density between the two groups. These results suggest that during the early phase of chronic pressure-overload, the electrical remodeling of M cells in rabbit left ventricle has developed, representing as the down regulations of I(Ks) and I(to) that can lead to the prolongation of APD, which might be a risk factor for the occurrence of malignant arrhythmia.

[Bone marrow stem cell mobilization to the peripheral blood and tumor necrosis factor-alpha expression in ischemic myocardium in rabbit models of hibernating myocardium].

OBJECTIVE: To investigate the changes in peripheral blood bone marrow stem cells and tumor necrosis factor-alpha gene expression in the ischemic myocardium in rabbit models of hibernating myocardium. METHODS: Twenty-four male Japanese white rabbits were randomized into 4 groups, including a sham-operated group and 3 model groups with hibernating myocardium induced by partial ligation of the left anterior descending coronary artery. The percentage of CD34-positive cells in the peripheral blood was evaluated by flow cytometry, and TNF-alpha mRNA expression in the ischemic myocardium was determined by real-time RT-PCR in the 3 model groups (at 3, 7, or 28 days after the operation) and in the sham-operated group. RESULTS: In rabbits with partial ligation of the left anterior descending coronary artery, the percentage of CD34-positive cells in the peripheral blood and myocardial TNF-alpha mRNA expression were significantly increased at 3 and 7 days after the operation in comparison with those in the sham-operated group and those at 28 days postoperatively (P<0.01). No significant differences were found in the percentage of CD34 positive cells or myocardial TNF-alpha mRNA expression between the sham-operated group and the rabbits 28 days after the coronary artery ligation (P>0.05). CONCLUSION: Bone marrow stem cell can be mobilized into the peripheral blood in rabbit hibernating myocardium model possibly by increasing TNF-alpha gene expression in the ischemic myocardium.

HERG-F463L potassium channels linked to long QT syndrome reduce I(Kr) current by a trafficking-deficient mechanism.

1. Congenital long QT syndrome (LQTS) is a genetically heterogeneous disease. The aim of the present study was to identify the gene mutation in a Chinese family with LQTS and investigate the functional changes associated with the mutation. 2. Polymerase chain reaction and DNA sequencing were used to screen for the KCNH2 mutation in the proband. A mutant F463L HERG channel was expressed in HEK293 cells using a lipofectamine method. The IKr current was recorded using the whole-cell voltage clamp technique. Expression of HERG protein was detected by western blotting and the subcellular location of HERG channels in cell was analysed by confocal microscopy. 3. The novel heterozygous missense mutation F463L in KCNH2 was detected. We found that the F463L mutation did not lead to any expression of detectable I(Kr) current, which was consistent with western blotting analysis indicating that the F463L mutation only expressed a band at 135 kDa. When coexpressed with wild-type HERG, F463L HERG exhibited strong dominant-negative current suppression, resulting in a decrease in I(Kr) current density, and induced a positive shift in the voltage dependence of activation, as well as interference with trafficking of wild-type channel protein. The processing of the F463L channels was partly corrected in cells incubated in E4031. In addition, confocal microscopy demonstrated that F463L subunits could be inserted into the cell membrane when forming heteromultimeric channels with wild-type channel subunits. 4. The results of the present study suggest that the F463L mutation leads to loss of function in HERG through a dominant-negative effect caused by impaired trafficking of the channel.

[Eukaryotic expression vector pcDNA3-HERG transfection inhibits angiotensin II induced neonatal rabbit ventricular myocyte hypertrophy in vitro].

OBJECTIVE: To explore the effects of eukaryotic expression vector pcDNA3-HERG transfection on angiotensin II (Ang II) induced myocyte hypertrophy in cultured neonatal rabbit ventricular myocytes. METHODS: Neonatal rabbit ventricular myocytes and eukaryotic expression vector pcDNA3-HERG transfected ventricular myocytes were cultured in Dulbecco's-modified Eagle medium (DMEM), containing 1% fetal bovine serum (FBS) for 6 h, then stimulated with Ang II (10(-7) mol/L) for 48 h. Control ventricular myocytes were cultured in Dulbecco's-modified Eagle medium (DMEM), containing 1% fetal bovine serum (FBS) for 54 h. At 6 and 54 h, myocyte hypertrophic parameters including myocyte volume, total protein content and membrane capacitance, action potential duration (APD) and Calcineurin (CaN) activity were measured. RESULTS: Compared to control myocytes, APD at 90% repolarization (APD(90)) was prolonged by 19.8% (P < 0.01), without signs of myocyte hypertrophy at 6 h post Ang II stimulation, APD(90) was prolonged by 22.1% (P < 0.01), myocyte volume, total protein content and membrane capacitance and CaN activity were significantly increased by 40.4%, 40.4%, 38.2% and 114.7% respectively (all P < 0.01) at 48 h after Ang II stimulation. HERG gene transfection upregulated I(HERG) tail current (3.6-fold higher than I(Kr)-rapidly activating delayed rectifier potassium current, P < 0.01). HERG gene transfection also accelerated and repolarization and a shortened APD(90) and inhibited myocyte hypertrophy and CaN activation induced by Ang II. CONCLUSIONS: Ang II induced prolongation of APD(90) is directly associated with myocyte hypertrophy by increasing the Ca(2+) influx and resulting in the increment of intracellular Ca(2+) and activation of CaN reaction pathway.

[Identification of a novel KCNH2 mutation in a family with congenital long QT syndrome and prediction of the secondary structure of its encoding protein].

OBJECTIVE: To identify the gene mutation in a Chinese family with congenital long QT syndrome (LQTS) and predict the changes of the secondary structure of the protein. METHODS: Polymerase chain reaction and DNA sequencing were used to screen for KCNH2 mutation in the proband. After the mutation was identified, KCNH2 gene of the family members was screened by multiplex PCR with site-specific primers. Network analysis software was used to predict the secondary structure of the KCNH2 protein. RESULTS: A novel heterozygous missense mutation of F463L(GenBank accession no.EU218526) located at the transmembrane domain S2 of KCNH2 was detected. The mutation did not result in the change of the transmembrane domain, but altered the hydrophobicity and secondary structure of the protein. CONCLUSION: The novel mutation identified in this study has enriched the GenBank data of ion channel gene mutation in LQTS. The changes of the secondary structure caused by the gene mutation were analyzed by Mfold and TMHMM software, which may help to understand LQTS.

[Geographical characteristics of single nucleotide polymorphism of candidate genes associated with coronary artery disease in Chinese Han population].

OBJECTIVE: To investigate the geographical characteristics of single nucleotide polymorphism (SNP) of candidate genes associated with coronary artery disease in Chinese Han population. METHODS: Study population were Chinese Han nationality recruited from Xi'an, Shiyan and Ningbo districts. Patients with coronary artery disease were defined by coronary angiography with stenosis >or= 50% and control subjects with stenosis < 10%, respectively. The DNA was extracted from peripheral white blood cell by approach comprised proteinase K digestion, phenol and chloroform extraction as well as isopropanol precipitation. The SNP of ATP-binding cassette transporter (ABCA1)-G596A, cholesteryl ester transfer protein (CETP)-Taq1B, Lipoprotein lipase (LPL)-Hind III and LPL-Pvu II were genotyped by PCR-RFLPs, and verified by gene sequencing. RESULTS: A Total of 615 patients undertaken coronary angiography were recruited from cardiac center in Xi'an (220), Ningbo (209) and Shiyan district (186), China (mean age 60 +/- 10 years, 75.9% males). Diabetes mellitus was more prevalent in Xi'an Cohort population than Shiyan and Ningbo cohort (P < 0.01). Plasma total cholesterol, LDL cholesterol and triglyceride levels in Xi'an Cohort population were significantly higher, and HDL-C siginificantly lower than in Shiyan and Ningbo cohort population [HDL-C: (1.17 +/- 0.48) mmol/L vs. (1.25 +/- 0.33) mmol/L and (1.29 +/- 0.44) mmol/L, P < 0.05]. Distribution differences for ABCA1-G596A and CETP-Taq1B genotypes were found in Xi'an Cohort population compared to Ningbo and Shiyan cohorts (for ABCA1, Xi'an: 0.24, 0.53, 0.23 and Shiyan: 0.17, 0.62, 0.21 and Ningbo: 0.34, 0.37, 0.29, for GG, AG, AA, respectively, P < 0.01; and for CETP, Xi'an: 0.29, 0.54, 0.17 and Shiyan: 0.38, 0.40, 0.22 and Ningbo: 0.39, 0.49, 0.12 for B1B1, B1B2, B2B2, respectively, P < 0.01), but not for LPL variants. ABCA1-G596A variant predicted HDL-C [Xi'an: (1.2 +/- 0.3) mmol/L, (1.3 +/- 0.2) mmol/L and (1.4 +/- 0.4) mmol/L, P = 0.01; Shiyan: (1.1 +/- 0.4) mmol/L: (1.2 +/- 0.3) mmol/L and (1.3 +/- 0.4) mmol/L, P = 0.03; Ningbo, (1.2 +/- 0.3) mmol/L, (1.3 +/- 0.4) mmol/L and (1.4 +/- 0.3) mmol/L, across GG, GA to AA genotype, respectively, P = 0.01] and TG levels [Xi'an: (2.4 +/- 1.3) mmol/L, (1.9 +/- 0.9) mmol/L and (1.6 +/- 0.8) mmol/L, P < 0.01; Shiyan: (2.1 +/- 1.0) mmol/L, (1.9 +/- 0.8) mmol/L and (1.8 +/- 0.7) mmol/L, P = 0.03; Ningbo: (1.9 +/- 1.1) mmol/L, (1.8 +/- 0.9) mmol/L and (1.6 +/- 0.7) mmol/L, across GG, GA to AA genotype, P = 0.05] with dose-dependent relationship. LPL-Hind III (+) carriers had higher triglycerides in three cohort population [Xi'an: (2.2 +/- 1.0) mmol/L, (1.8 +/- 0.9) mmol/L, (1.6 +/- 0.7) mmol/L, P = 0.01; Shiyan: (2.1 +/- 0.7) mmol/L, (1.9 +/- 1.0) mmol/L, (1.7 +/- 0.6) mmol/L, P = 0.01; Ningbo: (1.8 +/- 1.0) mmol/L, (1.6 +/- 0.6) mmol/L and (1.4 +/- 0.5) mmol/L, for +/+, +/- and -/- genotypes, respectively, P = 0.001]. SNP of CETP-Taq1B, LPL-Hind III and LPL-Pvu II predicted HDL-C and/or TG levels in different cohort population with different manners. All these SNP were not significantly associated with the development of coronary artery disease (all P > 0.05). CONCLUSION: A geographical heterogeneity of environmental and genetic risk factors related to the development of coronary artery disease exists in Chinese Han population. Irrespective of the different geographical cohort of Chinese Han population, the SNP of candidate genes can partly predict the differences in risk-related plasma HDL-C and/or TG levels rather than angiographic coronary artery disease.

Preclinical assessment of drug-induced proarrhythmias: role of the arterially perfused rabbit left ventricular wedge preparation.

Drug-induced torsade de pointes (TdP) is a rare but lethal side effect of many cardiovascular and non-cardiovascular drugs. It has led to black box warnings or even withdrawal of many useful compounds from the market and is one of the major stumbling blocks for new drug development. The critical need for a better test that can predict the TdP liability of a candidate drug has led to the development of multiple preclinical models. Each of these models has it own merits and limitations in preclinical testing for TdP liability; however, most of these models have not been adequately validated, so their precise sensitivity and specificity remain largely unknown. Recent blinded validation studies have demonstrated that the rabbit left ventricular wedge preparation can predict drug-induced TdP with an extremely high sensitivity and specificity. As a matter of fact, the wedge technique was initially developed primarily for studying the electrical heterogeneity of myocardium and the cellular basis of QT prolongation and TdP. Naturally then, the electrophysiological data obtained from the wedge takes into account every critical factor associated with the development of TdP. The TdP scores generated using the wedge technique have been shown to assess the torsadogenic potential of the drugs in a predictable fashion. This review elaborates on the current and prospective role of the rabbit left ventricular wedge preparation in preclinical assessment of drug-induced proarrhythmias including but not limited to TdP.

[Effect of short-term intensive treatment with insulin pump on beta cell function and the mechanism of oxidative stress in newly diagnosed type 2 diabetic patients].

OBJECTIVE: To investigate the effect of short-term intensive treatment with insulin pump on beta cell function and the mechanism of oxidative stress in newly diagnosed type 2 diabetic patients. METHODS: Totally 120 newly diagnosed type 2 diabetic patients were treated with insulin pump for 2 weeks. The levels of fasting plasma glucose (FPG), 2-hour postprandial blood glucose (2hPG), homeostatic model assessment of the insulin secretion index and insulin resistance index (HOMA-beta and HOMAIR, respectively), blood malondialdehyde (MDA) and superoxide dismutase (SOD) were measured before and after insulin pump treatment. RESULTS: After insulin pump treatment, FPG, 2hPG, HOMAIR and blood MDA were significantly decreased (P<0.01), while HOMA-beta and blood SOD were significantly increased (P<0.01). CONCLUSION: Short-term intensive treatment with insulin pump can effectively improve beta cell function probably by decreasing oxidative stress in newly diagnosed type 2 diabetic patients.