Yinhui Zhang

The J wave and fragmented QRS complexes in inferior leads associated with sudden cardiac death in patients with chronic heart failure

AIMS To investigate the relationship between electrocardiogram (ECG) parameters [J wave, fragmented QRS (fQRS), QTc, the peak-to-end interval of T wave (Tp-Te)], and sudden cardiac death (SCD) in chronic heart failure (CHF). METHODS AND RESULTS The ECGs of 1570 CHF patients, 572 cases with dilated cardiomyopathy (DCM) and 998 cases with ischaemic cardiomyopathy (ICM) were analysed with the endpoint being an SCD or non-SCD (NSCD). During a median follow-up period of 36 months (0.40-65 months), 438 (27.89%) patients died, of which 158 (35.84%) were SCD. Overall, the occurrence of J wave, fQRS, and long Tp-Te were greater in SCD patients than that of NSCD patients (all P< 0.01). For DCM cases, more SCD patients had J waves observed in the inferior leads than that in the NSCD group (26.78 vs. 13.07%, P<0.001). However, ICM cases with SCD did have more fQRS in the inferior leads than that with NSCD (42.16 vs. 26.67%, P= 0.01). After adjusting for other risk factors, Cox regression analysis revealed that presence of J wave or fQRS in the inferior leads predicted a higher risk for SCD in DCM [hazard ratio (HR), 4.095; 95% confidence interval (CI), 2.132-7.863] and ICM (HR, 2.714; 95% CI, 1.809-4.072) patients. A left ventricular ejection fraction ≤ 30% also predicted SCD and NSCD in DCM and ICM patients. In contrast, the predictive value of QTc and Tp-Te for SCD was not significant. CONCLUSIONS Presence of J wave or fQRS in the inferior leads predicted higher risk of SCD in DCM and ICM patients and might serve as independent predictors for SCD in patients with CHF.

Aminoglycoside antibiotics restore functional expression of truncated HERG channels produced by nonsense mutations

BACKGROUND Pharmacologic restoration of the trafficking defects of HERG missense mutations has been documented. However, whether correction of HERG nonsense mutations is possible is unknown. OBJECTIVE The purpose of this study was to investigate the effect of aminoglycoside antibiotics on the expression of nonsense mutants expected to produce truncated HERG channels. METHODS HERG channel and mutant currents were recorded by whole-cell patch clamp techniques. Pharmacologic rescue was applied by culturing the cells in 400 microg/mL G-418 or gentamicin for 24 hours. RESULTS Current densities were significantly reduced in cells expressing R1014X and W927X mutants compared to those of cells expressing wild-type (WT) HERG. R863X and E698X mutants failed to generate any typical HERG currents. Mean peak tail current density of R1014X mutant was significantly lower than that of WT (3.9 +/- 1.4 pA/pF, n = 8, vs 47.8 +/- 6.3 pA/pF, n = 12, P <.05) and increased to 12.7 +/- 3.3 pA/pF (n = 7, P <.05) and 18.3 +/- 3.7 pA/pF (n = 8, P <.05) after G-418 and gentamicin treatment. The voltage dependence of activation of R1014X was also restored after drug treatment. Furthermore, expression of full-length proteins for R1014X induced by drugs was detected by western blot and confocal imaging. Similar results were observed in W927X. For R863X and E698X, however, gentamicin treatment had no effect. In the cells cotransfected with WT/R1014X, gentamicin and G-418 demonstrated different results: gentamicin, but not G-418, increased the current density by 2.2-fold (n = 12, P <.05). CONCLUSION The study findings provide proof of principle that interventions designed to read through premature stop mutations may at least partially reverse the LQT2 phenotype in vitro.

The predictive values of beta1-adrenergic and M2 muscarinic receptor autoantibodies for sudden cardiac death in patients with chronic heart failure

Clinical and animal studies suggest that beta1‐adrenergic and M2 muscarinic receptor autoantibodies (beta1‐AAbs and M2‐AAbs) play important roles in the pathophysiological process of chronic heart failure (CHF). Removal of these autoantibodies improved haemodynamic parameters and left ventricular ejection fraction patients with CHF. The goal of this project is to evaluate whether beta1‐AAbs and M2‐AAbs predict prognosis and sudden cardiac death (SCD) in CHF.

Comparison of read-through effects of aminoglycosides and PTC124 on rescuing nonsense mutations of HERG gene associated with long QT syndrome.

Aminoglycosides promote the readthrough of premature stop codons introduced by nonsense mutations to produce full-length proteins in genetic disease models. The read-through effects of different aminoglycosides and PTC124 on HERG gene have yet to be adequately elucidated. The wild-type (WT) or mutant genes were transiently transfected in HEK293 cells. The read-through effect was examined by adding drugs into culture medium for 24 h. Western blot analysis and patch clamping were performed to evaluate the expression and function of the genes. The mRNA levels were determined using qPCR. The results showed that G418 and PTC124 significantly increased the protein expression of R1014X mutant in a dose-dependent manner and produced a full-length protein. The maximal protein levels after G418, gentamicin or PTC124 treatment were 39.1±2.4, 18.6±0.3 or 10.3±1.0%, respectively, of the WT level. Tobramycin did not exhibit a read-through effect. The mRNA levels, however, did not differ between WT and mutant gene. The tail current densities of R1014X channels at 40 mV were 22.57±2.26 pA/pF for G418, 16.21±1.49 pA/pF for gentamicin and 9.62±0.73 pA/pF for PTC124. The leftward shift of the activation curve was corrected only by G418 and gentamicin. The read-through effects of W927X, R863X and E698X revealed that as the mutation site approached the N-terminal, the rescue efficiency was decreased. The above results suggest that aminoglycosides and PTC124 induced different effects on rescue nonsense mutations of the HERG gene. The mutation site was a significant factor in determining the pharmacological rescue efficiency.

Common Variants in TRDN and CALM1 Are Associated with Risk of Sudden Cardiac Death in Chronic Heart Failure Patients in Chinese Han Population

Background Recent studies suggest that variants in two calcium handling genes (RyR2 and CASQ2) associated with sudden cardiac death (SCD) and non-sudden cardiac death (NSCD) in subjects with heart failure and coronary artery disease, respectively. The purpose of this study was to identify other calcium handling genes associated with SCD in the long-term of chronic heart failure (CHF) in Chinese Han population. Methods and Results We investigated 20 SNPs representing 10 genes that regulated calcium handling in 1429 patients with CHF, and the genetic association with SCD and all-cause death was analysed. During a median follow-up period of 63 months, 538 patients (37.65%) died from CHF, of whom 185 (34.38%) had SCD and the others were NSCD. SNPs that pass a P value cut-off of 0.0025 were considered as significant. We found that patients carrying the CC genotype of rs3814843 on CALM1 gene had greater risks of SCD (HR 5.542, 95% CI 2.054–14.948, P = .001) and all cause death (HR 3.484, 95% CI 1.651–7.350, P = .001). After adjusting for other risk factors, significant associations remained. Moreover, patients carrying G allele of rs361508 on TRDN gene also had increased risk of SCD. Conclusions Common variants in TRDN and CALM1 are associated with increased risk of SCD in patients with CHF. These findings provide further evidence for association of variants in calcium handling regulating proteins and SCD in chronic heart failure.

Calcium Channel Autoantibodies Predicted Sudden Cardiac Death and All-Cause Mortality in Patients with Ischemic and Nonischemic Chronic Heart Failure

The purpose of this study was to evaluate whether CC-AAbs levels could predict prognosis in CHF patients. A total of 2096 patients with CHF (841 DCM patients and 1255 ICM patients) and 834 control subjects were recruited. CC-AAbs were detected and the relationship between CC-AAbs and patient prognosis was analyzed. During a median follow-up time of 52 months, there were 578 deaths. Of these, sudden cardiac death (SCD) occurred in 102 cases of DCM and 121 cases of ICM. The presence of CC-AAbs in patients was significantly higher than that of controls (both P < 0.001). Multivariate analysis revealed that positive CC-AAbs could predict SCD (HR 3.191, 95% CI 1.598–6.369 for DCM; HR 2.805, 95% CI 1.488–5.288 for ICM) and all-cause mortality (HR 1.733, 95% CI 1.042–2.883 for DCM; HR 2.219, 95% CI 1.461–3.371 for ICM) in CHF patients. A significant association between CC-AAbs and non-SCD (NSCD) was found in ICM patients (HR = 1.887, 95% CI 1.081–3.293). Our results demonstrated that the presence of CC-AAbs was higher in CHF patients versus controls and corresponds to a higher incidence of all-cause death and SCD. Positive CC-AAbs may serve as an independent predictor for SCD and all-cause death in these patients.

Identification of Proteins Implicated in the Increased Heart Rate in ShenSongYangXin-Treated Bradycardia Rabbits by iTRAQ-Based Quantitative Proteomics

The present study tries to identify proteins implicated in bradycardia rabbits in hearts after ShenSongYangXin (SSYX, a traditional Chinese medicine) treatment. Eighteen adult rabbits were randomly assigned to three groups: sham, model, and SSYX treatment groups. Heart rate was recorded in rabbits and proteins were isolated from ventricular muscle. We used isobaric tags for elative and absolute quantitation (iTRAQ) coupled with two-dimensional liquid chromatography-tandem mass spectrometry to identify altered proteins after SSYX treatment. The heart rate decreased after six weeks due to the injury of the sinoatrial node in the model group. This effect was partially reversed by 4-week SSYX treatment. A total of a2988 proteins were quantified by performing the iTRAQ-based experiments. Of these, 86 proteins were differentially expressed according to our criteria (42 upregulated and 44 downregulated). The identification of key proteins implicated in the treatment of bradycardia could serve as a foundation to better understand and further explore the molecular mechanism of SSYX treatment.