Xiao-Qing Quan

A novel mutation in the KCNH2 gene associated with short QT syndrome

A gain of function mutation N588K in the KCNH2 gene that encodes HERG channels has been shown to underlie the SQT1 form of short QT syndrome (SQTS). We describe a different mutation in the KCNH2 gene in a Chinese family with clinical evidence of SQTS. A Chinese family with a markedly short QT interval (QTc=316 ± 9 ms, n=4) and a strong family history of sudden death was investigated. Analysis of candidate genes contributing to ventricular repolarization identified a C1853T mutation in the KCNH2 gene coding for the HERG channel, resulting in an amino acid change (T618I) that was found to 100% co-segregate with the SQTS phenotype (n=4). Whole cell voltage clamp studies of the T618I mutation in HEK-cells demonstrated a 6-fold increase in maximum steady state current (146.1 ± 16.7 vs 23.8 ± 5.5 pA/pF) that occurred at a 20 mV more positive potential compared to the wild type channels. The voltage dependence of inactivation was significantly shifted in the positive voltage direction (WT -78.6 ± 6.8 vs T618I -29.3 ± 1.7 mV). Kinetic analysis revealed slower inactivation rates of T618I but faster rates of recovery from inactivation. Quinidine (5 μM) and sotalol (500 μM) had similar inhibitory effects on steady currents measured at +20 mV in WT and T618I but were less effective in inhibiting tail currents of mutant channels. The altered function of T618I-HERG channels suggests that this mutation in the KCNH2 gene is responsible for the SQTS phenotype in this family. Both quinidine and sotalol may be therapeutic options for patients with the T618I HERG mutation.

Increasing gap junction coupling reduces transmural dispersion of repolarization and prevents torsade de pointes in rabbit LQT3 model.

Introduction: Increased transmural dispersion of repolarization (TDR) contributes importantly to the development of torsades de pointes (TdP) in long QT syndrome (LQTS). Intercellular electrical coupling via gap junctions plays an important role in maintaining TDR in both normal and diseased hearts. This study examined the effects of antiarrhythmic peptide AAP10, a gap junction enhancer, on TDR and induction of TdP in a rabbit LQT3 model.

FOXP3 demethylation as a means of identifying quantitative defects in regulatory T cells in acute coronary syndrome

OBJECTIVE The contribution of regulatory T cells (Tregs) to the pathogenesis of acute coronary syndrome (ACS) remains poorly understood. One core obstacle is the lack of Treg-specific markers. A highly conserved CpG enriched element in forkhead box P3 intron 1 (FOXP3 i l) is unmethylated only in Tregs, and measuring the unmethylation of FOXP3 i l can be used to identify the role of Tregs in clinical diseases. This study investigated whether analyzing the demethylation status of FOXP3 i 1 is a more reliable means than using Treg-specific surface markers in ACS. METHODS AND RESULTS We evaluated circulating Tregs percentages on different levels including cell frequencies (CD4(+)CD25(hi)FOXP3(+)Tregs and CD4(+)CD25(hi)CD45(+)naïve Tregs) or FOXP3 mRNA, FOXP3 i 1 demethylation status and related cytokine secretion in 89 patients with ACS and 35 controls. FOXP3 i 1 demethylation assay showed that the amount of Tregs in ACS patients was significantly reduced than that in controls (p = 0.0005). However, flow cytometry analysis did not identify any reduction of CD4(+)CD25(hi)FOXP3(+)Tregs in ACS patients. Notably, younger patients had higher percentage of CD4(+)CD25(hi)FOXP3(+)Tregs but decreased percentage of CD4(+)CD25(hi)CD45(+)naïve Tregs than either controls or older patients. Furthermore, a DNA hypomethylation agent increased the amount of CD4(+)CD25(hi)FOXP3(+)Tregs and Tregs related cytokine IL-10 and suppressed the production of pro-inflammatory cytokine interferon-γ by inducing FOXP3 i 1 demethylation in vitro. CONCLUSIONS A quantitative defect of Tregs, suggestive of decreased peripheral tolerance, could be a potential hallmark of ACS disease. Targeting FOXP3 i l demethylation might elevate the inhibitory activity of Tregs in ACS.

Kv1.3 channels as a potential target for immunomodulation of CD4+CD28null T cells in patients with acute coronary syndrome

Modulation of CD4(+)CD28null T cells through K+ channels could provide potential novel targets for the treatment acute coronary syndrome (ACS). However, the surface phenotype and K+ channel expression of CD4(+)CD28null T cells in patients with ACS is unclear. The aim of this study was to investigate the surface phenotype and K+ channel expression of CD4(+)CD28null T cells in patients with ACS. We found that more than 80% of CD4(+)CD28null T cells in patients with ACS showed a CD45RA(-)CD45RO(+)CCR7- surface phenotype. CD4(+)CD28(null) T expressed small numbers of the voltage-gated Kv1.3 and intermediate-conductance Ca2+-activated K+ channel KCa3.1 when quiescent, but increased Kv1.3 expression 4-fold with little change in KCa3.1 levels upon activation. Consistent with their channel phenotypes, the production of interferon-γ and perforin in CD4(+)CD28null T cells was suppressed by the specific Kv1.3 blocker 5-(4-phenoxybutoxy)psoralen PAP-1. Therefore, selective targeting of Kv1.3 in CD4(+)CD28null T cells may hold potential therapeutic promise for ACS.

Pharmacological enhancement of cardiac gap junction coupling prevents arrhythmias in canine LQT2 model.

Gap junctions contribute to the transmural heterogeneity of repolarization in the normal heart and under conditions of prolonged QT interval in the diseased heart. This study examined whether enhancing of gap junction coupling can reduce transmural dispersion of repolarization (TDR) and prevent torsade de pointes (TdP) in a canine LQT2 model. Canine left ventricular wedge preparations were perfused with delayed rectifier potassium current (IKr) blocker d-sotalol to mimic LQT2 and the antiarrhythmic peptide 10 (AAP10) was used as a gap junction coupling enhancer. As compared with the control group, the LQT2 group had significantly augmented TDR and higher incidence of TdP associated with increased nonphosphorylated connexin 43 (Cx43). AAP10 prevented augmentation of TDR and induction of TdP while rescuing Cx43 phosphorylation. There was no significant change in the quantity and spatial distribution of Cx43. These data indicate that gap junction enhancer AAP10 can prevent augmentation of TDR and suppress TdP by preventing dephosphorylation of Cx43 in a LQT2 model.

Ability of ambulatory ECG-based T-wave alternans to modify risk assessment of cardiac events: a systematic review

BackgroundExercise-based spectral T-wave alternans (TWA) has been proposed as a noninvasive tool-identifying patients at risk of sudden cardiac death (SCD) and cardiac mortality. Prior studies have indicated that ambulatory electrocardiogram (AECG)-based TWA is an important alternative platform to exercise for risk stratification of cardiac events. This study sought to review data regarding 24-hour AECG-based TWA and to discuss its potential role in risk stratification of fatal cardiac events across a series of patient risk profiles.MethodsProspective clinical studies of the predictive value of AECG-based TWA obtained with daily activity published between January 1990 and November 2014 were retrieved. Major endpoints included composite endpoint of SCD, cardiac mortality, and severe arrhythmic events.ResultsData were accumulated from 5 studies involving a total of 1,588 patients, including 317 positive and 1,271 negative TWA results. Compared with the negative group, positive group showed increased rates of SCD (hazard ratio [HR]: 7.49, 95% confidence interval [CI]: 2.65 to 21.15), cardiac mortality (HR: 4.75, 95% CI: 0.42 to 53.55), and composite endpoint (SCD, cardiac mortality, and severe arrhythmic events, HR: 5.94, 95% CI: 1.80 to 19.63). For the 4 studies evaluating TWA measured using the modified moving average method, the HR associated with a positive versus negative TWA result was 9.51 (95% CI: 4.99 to 18.11) for the composite endpoint.ConclusionsThe positive group of AECG-based TWA has a nearly six-fold risk of severe outcomes compared with the negative group. Therefore, AECG-based TWA provides an accurate means of predicting fatal cardiac events.

Increasing gap junction coupling suppresses ibutilide-induced torsades de pointes.

Drug-induced torsades de pointes (TdP) is common with class III antiarrhythmic drugs. Increased transmural dispersion of repolarization (TDR) contributes significantly to the development of TdP. Gap junctions play an important role in maintaining TDR in long QT syndrome. The present study examined the effect of a gap junction enhancer, antiarrhythmic peptide 10 (AAP10), on ibutilide-induced TdP. Coronary-perfused rabbit ventricular wedge preparations were used to evaluate the effect of AAP10 on ibutilide-induced arrhythmia. Transmural electrocardiograms and action potentials were recorded simultaneously. Early afterdepolarizations (EADs), R-on-T extrasystole, TdP and changes in Tpeak-end (Tp-e) and the Tp-e/QT ratio were observed. Changes in the levels of non-phosphorylated connexin 43 (Cx43) were measured by immunoblotting. Compared with those in the control group, the QT interval, Tp-e/QT and incidence rates of EAD and TdP increased with augmented dephosphorylation in the ventricular wedge preparations perfused with ibutilide under conditions of hypokalemia and hypomagnesemia. In the presence of AAP10, the incidence rates of EAD and TdP were reduced and the Tp-e/QT ratio decreased, with a parallel reduction in the level of non-phosphorylated Cx43. The results indicate that AAP10 suppressed ibutilide-induced TdP under conditions of hypokalemia and hypomagnesemia by decreasing TDR. AAP10 reduced TDR, possibly by preventing the dephosphorylation of Cx43 and thereby increasing myocardial cell gap junction coupling.

Effects of potassium aspartate and magnesium on ventricular arrhythmia in ischemia-reperfusion rabbit heart

SummaryThe aim of this study was to determine if the potassium aspartate and magnesium (PAM) prevent reperfusion-induced ventricular arrhythmias (RIVA) in ischemia-reperfusion (IR) rabbit heart. Thirty rabbits were randomly divided into control, ischemia and PAM groups. Arterially-perfused rabbit left ventricular preparations were made, and transmural ECG as well as action potentials from both endocardium and epicardium were simultaneously recorded in the whole process of all experiments. In control group rabbit ventricular wedge preparations were continuously perfused with Tyrode’s solution, and in ischemia group and PAM groups the perfusion of Tyrode’s solution was stopped for 30 min. Then the ischemia group was reperfused with Tyrode’s solution and the PAM group with Tyrode’s solution containing 2.42 mg/L PAM, respectively. ECG, QT interval, transmural repolarization dispersion (TDR) and action potentials from epicardium and endocardium were simultaneously recorded, and the RIVA of the wedge preparation was observed. Compared with control group, TDR and incidence of RIVA were significantly increased in ischemia group (P<0.05). The incidence of RIVA in control, ischemia and PAM group was 0/10, 9/10 and 1/10, respectively. Compared with ischemia group, TDR and incidence of RIVA were significantly reduced in PAM group (P<0.05). Potassium aspartate and magnesium significantly reduce TDR and prevent ventricular arrhythmia in ischemic rabbit heart.The aim of this study was to determine if the potassium aspartate and magnesium (PAM) prevent reperfusion-induced ventricular arrhythmias (RIVA) in ischemia-reperfusion (IR) rabbit heart. Thirty rabbits were randomly divided into control, ischemia and PAM groups. Arterially-perfused rabbit left ventricular preparations were made, and transmural ECG as well as action potentials from both endocardium and epicardium were simultaneously recorded in the whole process of all experiments. In control group rabbit ventricular wedge preparations were continuously perfused with Tyrode’s solution, and in ischemia group and PAM groups the perfusion of Tyrode’s solution was stopped for 30 min. Then the ischemia group was reperfused with Tyrode’s solution and the PAM group with Tyrode’s solution containing 2.42 mg/L PAM, respectively. ECG, QT interval, transmural repolarization dispersion (TDR) and action potentials from epicardium and endocardium were simultaneously recorded, and the RIVA of the wedge preparation was observed. Compared with control group, TDR and incidence of RIVA were significantly increased in ischemia group (P<0.05). The incidence of RIVA in control, ischemia and PAM group was 0/10, 9/10 and 1/10, respectively. Compared with ischemia group, TDR and incidence of RIVA were significantly reduced in PAM group (P<0.05). Potassium aspartate and magnesium significantly reduce TDR and prevent ventricular arrhythmia in ischemic rabbit heart.

A meta-analytic review of prevalence for Brugada ECG patterns and the risk for death

Background:The prevalence of Brugada ECG pattern (BrEP) is different in different regions, and its mean prevalence over the world is unknown. The risk of people with BrEP for death remains unknown. We performed a meta-analysis to determine the prevalence of BrEP and risk ratio (RR) for death. Methods:Relevant studies published between July 1, 2000 and August 20, 2016, which contain prevalence and RR for all-cause death and cardiac death, were included. The prevalence and RR are analyzed using meta-analysis. Results:We finally retrieved 24 studies of the prevalence for BrEP and 5 studies of the RR for all-cause death and cardiac death. The worldwide mean prevalence of BrEP is 0.4%, with highest in Asia (0.9%) and lowest in North America (0.2%). Additionally, the mean prevalence in male is 0.9%, whereas it is 0.1% in female. The RR of BrEP for all-cause death is 0.78 (95% confidence interval 0.45–1.37), and for cardiac death it is 0.92 (95% confidence interval 0.23–3.66). Conclusion:The prevalence of BrEP is about 0.4% around the world with different prevalence in region and sex. Our study shows that BrEP may not be taken as a predictor of all-cause death and cardiac death.

Use of humour in medical education: a survey of students and teachers at a medical school in China

Objective Humour is a powerful resource in medical education. The purpose of this study is to investigate what students and teachers think about the use of humour. What challenges do teachers face in using humour and how they address them are also the subject of the present study. Design Separate cross-sectional questionnaire surveys. Setting Tongji Medical College and Tongji Hospital in China. Participants 327 students at Tongji Medical College and 165 physician teachers at Tongji Hospital in China. Main outcome measures The primary study outcome was assessed by proportion. Results 87% of student and teacher respondents agreed with using humour in the didactic setting. They felt humour fostered a positive didactic atmosphere. Interesting clinical case was the most frequently used humour type by teachers and considered the most effective by students. Lack of humorous materials related to the lecture subject was the main challenge to humour use cited by teachers. Collecting humorous materials in teacher’s daily work and life, observing teachers with a reputation for successfully using humour, and efficiently using the internet-enhanced humour use ability. Conclusion The present study confirms that most medical students and physician teachers support the use of humour in medical didactics, with particular strategies aiding its use and positive impact.