Inhibition of oxidative stress by testosterone improves synaptic plasticity in senescence accelerated mice.

It is well known that synaptic plasticity is associated with cognitive performance in Alzheimer's disease (AD). Testosterone (T) is known to exert protective effects on cognitive deficits in AD, but the underlying mechanisms of androgenic action on synaptic plasticity remain unclear. Thus, the aim of this study was to examine the protective mechanism attributed to T on synaptic plasticity in an AD senescence accelerated mouse prone 8 (SAMP8) model. The following parameters were measured: (1) number of intact pyramidal cells in hippocampal CA1 region (2) phosphorylated N-methyl-D-aspartate receptor-1 (p-NMDAR1) and (3) phosphorylated calmodulin-dependent protein kinase II (p-CaMKII). In addition, the content of whole brain malondialdehyde (MDA) as well as activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) were determined. Treatment with T significantly elevated the number of intact pyramidal cells in hippocampal CA1 region and markedly increased hippocampal protein and mRNA expression levels of p-NMDAR1 and p-CaMK II. Further, T significantly decreased whole brain MDA levels accompanied by elevated activities of SOD and GSH-Px. Data suggest that the protective effects of T on synaptic plasticity in a mouse AD model may be associated with reduction of oxidant stress.

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.

Clinical characteristics and long-term prognosis in patients with chronic heart failure and reduced ejection fraction in China.

AIMS: Chronic heart failure with reduced ejection fraction (CHF-REF) remains a major public health problem with high morbidity and mortality, but the data on current treatment status and long-term prognosis in China were still missing. METHODS: Among prospectively recruited 2368 patients with CHF-REF in 10 hospitals, 2154 patients provided complete followed data. Two aetiology subgroups (dilated cardiomyopathy, DCM and ischaemic cardiomyopathy, ICM) were classified. Clinical data and long-term prognosis were analysed. RESULTS: After a median follow-up of 52 months, 850 (39.46%) patients died, of whom 302 (35.53%) were sudden cardiac death (SCD). Unadjusted rates of all-cause mortality and SCD were higher in DCM than those in ICM (p<0.001 for both modes of death), but mortalities were comparable after adjustment for co-variables (p=0.387 and p=0.483 respectively). ACEIs/ARBs, aldosterone receptor antagonists, ß-blockers and diuretics were dominant prescribed drugs with the prescription rates of 65.97%, 74.61%, 68.29% and 74.37% respectively. Multivariable analysis identified co-morbidities (eg, hypertension), NHYA class, ventricular tachycardia/fibrillation (VT/VF), QRS duration, left ventricular EF and creatinine as independent predictors of mortalities, whereas ACEIs/ARB, ß-blockers and statins were associated with better prognosis. Survived from sustained VT/VF episodes had the highest predictive value for SCD (HR, 4.230; 95% CI, 2.500-7.157; p<0.001). The predictors for mortalities in DCM and ICM were different. CONCLUSIONS: Patients with CHF-REF had a poor prognosis in China despite being under current standard therapies, especially patients with DCM. Predictors for all-cause mortality and SCD might be identified for evaluating the prognosis of these patients.

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.

A common NOS1AP genetic polymorphism, rs12567209 G>A, is associated with sudden cardiac death in patients with chronic heart failure in the Chinese Han population.

BACKGROUND: Variants in NOS1AP associated with cardiac repolarization and sudden cardiac death (SCD) in coronary artery disease have been reported. Whether they are related to mortality and QTc interval in chronic heart failure (CHF) has not been investigated. METHODS AND RESULTS: A total of 1,428 patients with CHF and 480 control subjects were genotyped for 6 SNPs of NOS1AP, and the genetic associations with mortality as well as QTc interval were analyzed. During a median follow-up period of 52 months, 467 patients (32.70%) died, of which deaths 169 (36.19%) were SCD. The A allele of rs12567209 was associated with greater risk of all-cause death and SCD (hazard ratio [HR] 1.381, 95% confidence interval [CI] 1.124-1.698 [P = .002], and HR 1.645, 95% CI 1.184-2.287 [P = .003], respectively). After adjusting for other risk factors, significant differences remained (HR 1.309, 95% CI 1.054-1.624 [P = .015], and HR 1.601, 95% CI 1.129-2.271 [P = .008]). The A allele was also associated with prolongation of QTc interval by 4.04 ms in the entire population (P = .026). CONCLUSIONS: The A allele of rs12567209 in NOS1AP may serve as an independent predictor of all-cause death and SCD in patients with CHF, it is also associated with prolonged QTc interval in the Chinese Han population.

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

AIMS: 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. METHODS AND RESULTS: A total of 2062 patients with CHF and 824 control subjects were recruited. Beta1-AAbs and M2-AAbs were detected by the enzyme-linked immunosorbent assay (ELISA) method, and the correlation between these autoantibodies and the prognosis of CHF was analysed. During a median follow-up period of 36 months (0.40 ± 65 months), 379 (21.56%) cases died-164 had dilated cardiomyopathy (DCM) and 215 had ischaemic cardiomyopathy (ICM). Of these, SCD occurred in 69 cases (40.37%) of DCM and in 84 cases (39.07%) of ICM. Positivity for beta1-AAbs in DCM and ICM was significantly higher than for the controls (8.1% and 8.25% v.s 2.2%, both P < 0.01). However, positive M2-AAbs did not show any statistical difference between the three groups. Cox regression analysis revealed that positive beta1-AAbs were associated with higher mortality in CHF and that it predicted SCD for DCM [hazard ratio (HR) 4.51, 95% confidence interval (CI) 2.405-8.471] and ICM (HR 3.749, 95% CI 2.389-5.884) patients, but not non-SCD (NSCD) patients. CONCLUSIONS: The rates of positive beta1-AAbs were higher in CHF patients than in the controls. Positive beta1-AAbs might serve as an independent predictor for SCD in patients with CHF.

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.