Genetic association of inflammatory marker GlycA with lung function and respiratory diseases.

Association of circulating glycoprotein acetyls (GlycA), a systemic inflammation biomarker, with lung function and respiratory diseases remain to be investigated. We examined the genetic correlation, shared genetics, and potential causality of GlycA (N = 115,078) with lung function and respiratory diseases (N = 497,000). GlycA showed significant genetic correlation with FEV1 (rg = -0.14), FVC (rg = -0.18), asthma (rg = 0.21) and COPD (rg = 0.31). We consistently identified ten shared loci (including chr3p21.31 and chr8p23.1) at both SNP and gene level revealing potential shared biological mechanisms involving ubiquitination, immune response, Wnt/ß-catenin signaling, cell growth and differentiation in tissues or cells including blood, epithelium, fibroblast, fetal thymus, and fetal intestine. Genetically elevated GlycA was significantly correlated with lung function and asthma susceptibility (354.13 ml decrement of FEV1, 442.28 ml decrement of FVC, and 144% increased risk of asthma per SD increment of GlycA) from MR analyses. Our findings provide insights into biological mechanisms of GlycA in relating to lung function, asthma, and COPD.

Residual Risk of Coronary Atherosclerotic Heart Disease and Severity of Coronary Atherosclerosis Assessed by ApoB and LDL-C in Participants With Statin Treatment: A Retrospective Cohort Study.

Background: Low-density lipoprotein cholesterol (LDL-C) is the primary target of lipid-lowering therapy on the management of hypercholesterolemia in the United States and European guidelines, while apolipoprotein B (apoB) is the secondary target. The objective was to determine if elevated levels of apoB is superior to LDL-C in assessing residual risk of coronary atherosclerotic heart disease and severity of coronary atherosclerosis in participants with statin treatment. Methods: This study included 131 participants with statin treatment. The generalized linear model and relative risk regression (generalized linear Poisson model with robust error variance) were used to analyze the association of the levels of apoB and LDL-C with the severity of coronary atherosclerosis and residual risk of coronary atherosclerotic heart disease. Results: Categorizing apoB and LDL-C based on tertiles, higher levels of apoB were significantly associated with the severity of coronary atherosclerosis (Ptrend = 0.012), whereas no such associations were found for elevated levels of LDL-C (Ptrend = 0.585). After multivariate adjustment, higher levels of apoB were significantly associated with residual risk of coronary atherosclerotic heart disease. When compared with low-level apoB (≤0.66 g/L), the multivariate adjusted RR and 95% CI of intermediate-level apoB (0.67-0.89 g/L) and high-level apoB (≥0.90 g/L) were 1.16 (1.01, 1.33) and 1.31 (1.08, 1.60), respectively (Ptrend = 0.011). There was a 45% increased residual risk of coronary atherosclerotic heart disease per unit increment in natural log-transformed apoB (Ptrend <0.05). However, higher levels of LDL-C were not significantly associated with residual risk of coronary atherosclerotic heart disease. When compared with low-level LDL-C (≤1.56 mmol/L), the multivariate adjusted RR and 95% CI of intermediate-level LDL-C (1.57-2.30 mmol/L) and high-level LDL-C (≥2.31 mmol/L) were 0.99 (0.84, 1.15) and 1.10 (0.86, 1.42), respectively (Ptrend = 0.437). Similar results were observed in the stratified analyses and sensitivity analyses. No significant interactions were detected for both apoB and LDL-C (all Pinteraction>0.05). Conclusions: Elevated apoB are superior in assessing the residual risk of coronary atherosclerotic heart disease and severity of coronary atherosclerosis in participants with statin treatment.

Risk factors for cardiac events in patients with Brugada syndrome: A PRISMA-compliant meta-analysis and systematic review.

INTRODUCTION: Inconsistent results have been reported about the risk stratification of patients with Brugada syndrome. We have summarized the evidence regarding the strength of association between 6 risk factors (family history of sudden cardiac death [SCD] or syncope, inducible ventricular arrhythmias on electrophysiology study [EPS], spontaneous type 1 Brugada electrocardiogram [ECG], male sex, family history of SCD, and sodium voltage-gated channel alpha subunit 5 [SCN5A] gene mutation) and subsequent cardiac events in Brugada syndrome patients. METHODS: Pubmed, Ovid, Embase, and the Cochrane Library were searched for studies published between January 1992 and March 2016. Only prospective studies (27 studies, 4494 patients) that reported estimates with 95% confidence intervals (CIs) of cardiac events for the 6 risk factors were included. RESULTS: Family history of SCD or syncope (risk ratio [RR] 4.97, 95% CI 3.96-6.23, P < 0.001), inducible ventricular arrhythmia on EPS (RR 3.56, 95% CI 1.30-9.74, P = 0.01), and spontaneous type 1 Brugada ECG (RR 4.07, 95% CI 2.23-7.41, P < 0.001) were associated with an increased risk of future cardiac events. Spontaneous type 1 Brugada ECG was associated with an elevated risk of future cardiac events in patients without a family history of SCD. CONCLUSIONS: Inducible ventricular arrhythmias on EPS, spontaneous type 1 Brugada ECG, and family history of SCD or syncope indicate a high risk of future cardiac events in patients with Brugada syndrome. Spontaneous type 1 Brugada ECG significantly increased the risk of future cardiac events in patients without family history of SCD.

Role of voltage-gated potassium channels in pathogenesis of chronic pulmonary heart disease.

The influence of hypoxia on the activity of voltage-gated potassium channel in pulmonary artery smooth muscle cells (PASMCs) of rats and its roles in the pathogenesis of chronic pulmonary heart disease were investigated. Eighty male Sprague-Dawley rats were randomly allocated into control group (n=10), acute hypoxic group (n=10), and chronic hypoxic groups (n=60). The chronic hypoxic groups were randomly divided into 6 subgroups (n=10 each) according to the chronic hypoxic periods. The rats in the control group were kept in room air and those in acute hypoxic group in hypoxia environmental chamber for 8 h. The rats in chronic hypoxic subgroups were kept in hypoxia environmental chamber for 8 h per day for 5, 10, 15, 20, 25, and 30 days, respectively. The mean pulmonary arterial pressure (mPAP), right ventricular hypertrophy index (RVHI), and the current of voltage-gated potassium channel (I K) in PASMCs were measured. Results showed that both acute and chronic hypoxia could decrease the I K in PASMCs of rats and the I-V relationship downward shifted to the right. And the peak I K density at +60mV decreased with prolongation of hypoxia exposure. No significant difference was noted in the density of I K (at +60 mV) and I-V relationship between control group and chronic hypoxic subgroup exposed to hypoxia for 5 days (P>0.05), but there was a significant difference between control group and chronic hypoxic subgroup exposed to hypoxia for 10 days (P<0.05). Significant differences were noted in the I K density (at +60 mV) and I-V relationships between control group and chronic hypoxic subgroups exposed to hypoxia for 20 days and 30 days (P<0.01). Compared with control rats, the mPAP and RVHI were significantly increased after chronic exposure to hypoxia for 10 days (P<0.05), which were further increased with prolongation of hypoxia exposure, and there were significant differences between control group and chronic hypoxic subgroups exposed to hypoxia for 20 days and 30 days (P<0.01). Both the mPAP and the RVHI were negatively correlated with the density of I K (r=-0.89769 and -0.94476, respectively, both P<0.01). It is concluded that exposure to hypoxia may cause decreased activity of voltage-gated potassium channel, leading to hypoxia pulmonary vasoconstriction (HPV). Sustained HPV may result in chronic pulmonary hypertension, even chronic pulmonary heart disease, contributing to the pathogenesis of chronic pulmonary heart disease.

CD4+CD25+Foxp3+ regulatory T cells protect endothelial function impaired by oxidized low density lipoprotein via the KLF-2 transcription factor.

OBJECTIVE: To investigate the regulation of CD4(+)CD25(+) Regulatory T cells (Tregs) on pro-inflammatory adhesion molecules, Krüppel-Like Factor-2 (KLF-2) and its downstream transcriptional targets in human umbilical vein endothelial cells (HUVECs) impaired by ox-LDL and the mechanisms of it. METHODS AND RESULTS: HUVECs were cultured in the continuous presence of ox-LDL(0 mg/L,25 mg/L,50 mg/L,100 mg/L) for 4, 6, 12 and 24 hours to allow identification of early-and late-induced genes, respectively, whereas non-stimulated controls were taken at 0 hours. The expression of pro-inflammatory adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1), intracellular adhesion molecule-1 (ICAM-1), E-selectin, KLF-2 and its target genes eNOS, PAI-1 were determined by real time RT-PCR and/or western-blot analysis. Expression of pro-inflammatory adhesion molecules, KLF-2, eNOS and PAI-1 in HUVEC cultured alone or with anti-CD3 mAbs activated Tregs, followed by addition of ox-LDL (50 mg/L) for 6 hours, are compared to expression levels in control cultures. Ox-LDL treated HUVECs increased pro-inflammatory adhesion molecules expression, as well as increased PAI-1 but decreased eNOS expression accompanied with significant downregulating of KLF-2 at a dose and time dependent manner. Furthermore, ox-LDL increased pro-inflammatory adhesion molecules but inhibited KLF2 expression was reversed by addition of Tregs. Small interfering RNA reduced endogenous KLF-2 expression and partly reversed the suppressive effect of Tregs on HUVECs activation, which strongly implicate KLF-2 as a transcriptional regulator of the Tregs-mediated effects in endothelial cells. Mechanism studies reveal that Treg-mediated KLF2 expression in HUVECs impaired by ox-LDL requires cell contact as well as soluble factors. CONCLUSIONS: Tregs could protect endothelial function that is largely dependent on KLF2 and its downstream transcriptional targets regulation involving cell-to-cell contact and soluble factors.

Congenital long QT syndrome caused by the F275S KCNQ1 mutation: mechanism of impaired channel function.

Congenital long QT syndrome is characterized by a prolongation of ventricular repolarization and recurrent episodes of life-threatening ventricular tachyarrhythmias, often leading to sudden death. We previously identified a missense mutation F275S located within the S5 transmembrane domain of the KCNQ1 ion channel in a Chinese family with long QT syndrome. We used oocyte expression of the KCNQ1 polypeptide to study the effects of the F275S mutation on channel properties. Expression of the F275 mutant, or co-expression with the wild-type S275 polypeptide, significantly decreased channel current amplitudes. Moreover, the F275S substitution decreased the rates of channel activation and deactivation. In transfected HEK293 cells fluorescence microscopy revealed that the F275S mutation perturbed the subcelluar localization of the ion channel. These results indicate that the F275S KCNQ1 mutation leads to impaired polypeptide trafficking that in turn leads to reduction of channel ion currents and altered gating kinetics.

Effects of platelet activating factor on action potentials and potassium channels in guinea-pig ventricular myocytes.

This study was designed to investigate the effects of platelet activating factor (PAF) on the action potential and potassium currents in guinea-pig ventricular myocytes. Whole cell patch clamp techniques were used. With 5 mmol/L ATP in the pipette electrode(mimic normal condition), 1 micromol/L PAF increased APD(90) from 225.8+/-23.3 to 352.8+/-29.8 ms (n=5, P<0.05), decreased I(K1) and I(K) tail currents from -6.1+/-1.3 to -5.6+/-1.1 nA (n=5, P<0.05) at -120 mV and from 173.5+/-16.7 to 152.1+/-11.5 pA (P<0.05, n=4) at +30 mV, respectively. But PAF had no effect on I(K1) at potentials within the normal range of membrane potentials (between -90 mV and +20 mV). In the contrary, without ATP in the pipette electrode by which I(K.ATP) was activated (mimic ischemic condition), 1 micro mol/L PAF shortened APD(90) from 153+/-24.6 to 88.2+/-19.4 ms (n=5, P<0.01). Incubation of myocytes with 1 micro mol/L glibenclamide, a blocker of I(K.ATP ) could restore prolongation of APD induced by PAF. In conclusion, in guinea-pig ventricular myocytes, with 5 mmol/L ATP in the pipette PAF could prolong APD partly due to the inhibition of I(K); while with 0 mmol/L ATP in the pipette, PAF could induce an activation of I(K.ATP), hence a decrease in APD. It is suggested that PAF may amplify the heterogeneity between ischemic and normal cardiac myocytes during ischemia /reperfusion, which may play a vital role in the pathogenesis of the arrhythmias induced by ischemia /reperfusion.

Long-term administration of angiotension-converting enzyme inhibitor improves the outcome of chronic heart failure in senile patients.

One hundred and sixteen senile patients (older than 65 years) with chronic heart failure (CHF) were analyzed retrospectively in order to verify if old patients with CHF would benefit from long-term (one year) angiotension-converting enzyme inhibitor (ACEI) treatment. The frequency of drugs (including ACEI, digitalis and diuretic) used was stratified into four degrees accordingly. Development of the CHF was scored with regard to relapse rate and severity of this disease. Stepwise regression analysis was applied to explore the relationship between the scored outcome of CHF and the frequency of individual drug administration. A significant relationship of the scored outcome of CHF to the frequency of ACEI usage but not to digitalis nor to diuretics was found (partial coefficient of the correlation r = 0.42, P = 0.002). It was concluded that the long-term administration of ACEI improves the outcome of CHF in senile patients.