Serum electrolyte concentrations and risk of atrial fibrillation: an observational and mendelian randomization study.

BACKGROUND: Atrial fibrillation (AF) is a prevalent arrhythmic condition resulting in increased stroke risk and is associated with high mortality. Electrolyte imbalance can increase the risk of AF, where the relationship between AF and serum electrolytes remains unclear. METHODS: A total of 15,792 individuals were included in the observational study, with incident AF ascertainment in the Atherosclerosis Risk in Communities (ARIC) study. The Cox regression models were applied to calculate the hazard ratio (HR) and 95% confidence interval (CI) for AF based on different serum electrolyte levels. Mendelian randomization (MR) analyses were performed to examine the causal association. RESULTS: In observational study, after a median 19.7 years of follow-up, a total of 2551 developed AF. After full adjustment, participants with serum potassium below the 5th percentile had a higher risk of AF relative to participants in the middle quintile. Serum magnesium was also inversely associated with the risk of AF. An increased incidence of AF was identified in individuals with higher serum phosphate percentiles. Serum calcium levels were not related to AF risk. Moreover, MR analysis indicated that genetically predicted serum electrolyte levels were not causally associated with AF risk. The odds ratio for AF were 0.999 for potassium, 1.044 for magnesium, 0.728 for phosphate, and 0.979 for calcium, respectively. CONCLUSIONS: Serum electrolyte disorders such as hypokalemia, hypomagnesemia and hyperphosphatemia were associated with an increased risk of AF and may also serve to be prognostic factors. However, the present study did not support serum electrolytes as causal mediators for AF development.

Rosiglitazone-induced myocardial protection against ischaemia-reperfusion injury is mediated via a phosphatidylinositol 3-kinase/Akt-dependent pathway.

1. Rosiglitazone is widely used in the treatment of Type 2 diabetes. However, in recent years it has become evident that the therapeutic effects of peroxisome proliferator-activated receptor gamma ligands reach far beyond their use as insulin sensitizers. Recently, the ability of rosiglitazone pretreatment to induce cardioprotection following ischaemia-reperfusion (I/R) has been well documented; however, the protective mechanisms have not been elucidated. In the present study, examined the role of the phosphatidylinositol 3-kinase (PI3-K)/Akt signalling pathway in rosiglitazone cardioprotection following I/R injury. 2. Mice were pretreated with 3 mg/kg per day rosiglitazone for 14 days before hearts were subjected to ischaemia (30 min) and reperfusion (2 h). Wortmannin (1.4 mg/kg, i.p.), an inhibitor of PI3-K, was administered 10 min prior to myocardial I/R. Then, activation of the PI3-K/Akt/glycogen synthase kinase (GSK)-3alpha signalling pathway was examined. The effects of PI3-K inhibition on rosiglitazone-induced cardioprotection were also evaluated. 3. Compared with control rats, the ratio of infarct size to ischaemic area (area at risk) and the occurrence of sustained ventricular fibrillation in rosiglitazone-pretreated rats was significantly reduced (P < 0.05). Rosiglitazone pretreatment attenuated cardiac apoptosis, as assessed by ELISA to determine cardiomyocyte DNA fragmentation. Rosiglitazone pretreatment significantly increased levels of phosphorylated (p-) Akt and p-GSK-3alpha in the rat myocardium. Pharmacological inhibition of PI3-K by wortmannin markedly abolished the cardioprotection induced by rosiglitazone. 4. These results indicate that rosiglitazone-induced cardioprotection in I/R injury is mediated via a PI3-K/Akt/GSK-3alpha-dependent pathway. The data also suggest that modulation of PI3-K/Akt/GSK-3alpha-dependent signalling pathways may be a viable strategy to reduce myocardial I/R injury.

[Fluid shear stress upregulated endothelial nitric oxide synthase gene expression and nitric oxide formation in human endothelial progenitor cells].

OBJECTIVE: To observe the effect of fluid shear stress on the eNOS gene expression and NO production in endothelial progenitor cells (EPCs). METHODS: The peripheral blood mononuclear cells from healthy volunteers were inducted into EPCs and divided into stationary group (0 dyn/cm(2), 1 dyn/cm(2) = 0.1 Pa), low-flow shear stress group (5 dyn/cm(2)), medium-flow shear stress group (15 dyn/cm(2)) and high-flow shear stress group (25 dyn/cm(2)). The effects of shear stress on the endothelial nitric oxide synthase (eNOS) gene expression and nitric oxide (NO) production in human EPCs were measured. RESULTS: Typical "spindle-shaped" appearance was shown in EPCs derived from peripheral blood mononuclear cells and were positively labeled by acetylated-LDL, lectin, FLK-1 and vWF. After 4 hours treatment with various shear stresses, the ratio of eNOS/beta-actin mRNA expression by human EPCs in low, medium and high-flow shear stress group was 0.364, 0.505 and 0.548 respectively, which was significantly higher than that in stationary group (0.183, all P < 0.05) and the NO secretion in human EPCs in low, medium and high-flow shear stress group was also significantly higher than that in stationary group (all P < 0.05). CONCLUSION: Fluid shear stress enhances the eNOS mRNA expression and NO secretion in human EPCs, therefore, shear stress could potentiate the repair efficacy of EPCs for endothelial injury.

Effect of angiotensin converting enzyme inhibitor on the calcium transients and calcium handling proteins in ventricular myocytes from rats with heart failure.

BACKGROUND: Chronic heart failure (CHF) is associated with calcium transients and calcium handling proteins. Angiotensin converting enzyme (ACE) inhibitor has been demonstrated to have beneficial effect on CHF. Yet studies addressed to the relationship between ACE inhibitor and calcium transients in CHF are rare. The aim of this study was to investigate the influence of ACE inhibitor (perindopril) on the contractility and calcium transients and calcium handling proteins in ventricular myocytes from rats with experimental heart failure. METHODS: Male Wistar rats were randomized to heart failure group treated with perindopril [CHF-T, 3 mg.kg(-1).d(-1)], heart failure group without treatment (CHF-C) and sham-operated group (PS). Heart failure was induced by abdominal aortic constriction. All groups were further followed up for 12 weeks. Left ventricular myocytes were then isolated. Single cell shortening fraction and [Ca(2+)]i were simultaneously measured by laser scanning confocal microscope under the field stimulation (1.0 Hz). Reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blot were performed to evaluate the changes of mRNA and protein of Na(+)-Ca(2+) exchanger (NCX1), sarcoplasmic reticulum Ca(2+)-ATPase (SERCA2) and phospholamban (PLB). RESULTS: The fraction of cell shortening (FS%) and [Ca(2+)]imax (nmol/L) were significantly reduced in group CHF-C compared with group PS (FS%: 7.51 +/- 1.15 vs 13.21 +/- 1.49; [Ca(2+)]i max: 330.85 +/- 50.05 vs 498.16 +/- 14.07; both P < 0.01), and restored at least partially in CHF-T group. In CHF-C group, the left ventricular mRNA of NCX1 and PLB were significantly upregulated in comparing with PS group (RNCX1/beta-Actin: 0.51 +/- 0.12 vs 0.19 +/- 0.06, P < 0.01; RPLB/beta-Actin: 0.26 +/- 0.12 vs 0.20 +/- 0.08, P < 0.05), while SERCA2 mRNA was downregulated (0.48 +/- 0.10 vs 0.80 +/- 0.11, P < 0.01). The mRNA levels of NCX1 and SERCA2 in CHF-T group were between the CHF-C and PS group, and the differences of the latter two groups were significant (all P < 0.05). In CHF-C and CHF-T groups, the protein expression of NCX1 were 1.141 +/- 0.047 and 1.074 +/- 0.081 times of that in PS group respectively (both P < 0.05), and SERCA2 protein levels were 0.803 +/- 0.100 and 0.893 +/- 0.084 times of that in PS group respectively (both P < 0.05). The protein expression of NCX1 and SERCA2 in the CHF-C and CHF-T groups is significantly different (both P < 0.05). CONCLUSION: ACE inhibitor could improve cardiac function of failing heart through directly enhancing the contractility of single cardiomyocyte, and these effects are probably mediated by its roles in preventing the deleterious changes of calcium transients and calcium handling proteins in CHF.

[Effects of ACE inhibitor on the calcium transient and calcium handling proteins in ventricular myocytes from rats with heart failure].

OBJECTIVE: To investigate the influence of ACE inhibitor (perindopril) on the contractility and calcium transient and calcium handling proteins in ventricular myocytes from rats with experimental heart failure. METHODS: Male Wistar rats were randomized to heart failure group treated with perindopril (CHF-T, 3 mg.kg(-1).d(-1)), heart failure group without treatment (CHF-C) and sham-operated group (PS) after heart failure was induced by constricting abdominal aorta for 16 weeks. All groups were further followed up for 12 weeks. Left ventricular myocytes were isolated, and single cell shortening fraction and [Ca(2+)](i) were simultaneously measured through laser scanning confocal microscope under the field stimulation (1.0 Hz). RT-PCR and Western blot were performed to evaluate the level of mRNA and protein of Na(+)-Ca(2+) exchanger (NCX(1)), sarcoplasmic Ca(2+)-ATPase (SERCA(2)) and phospholamban (PLB). RESULTS: The fraction of cell shortening (FS%) and [Ca(2+)](i max) (nmol/L) were significantly smaller in group CHF-C than group PS (FS%: 7.51 +/- 1.15 vs 13.21 +/- 1.49; [Ca(2+)](i max): 330.85 +/- 50.05 vs 498.16 +/- 14.07; both P < 0.01). And in CHF-T group, FS and [Ca(2+)](i max) were greater than those in CHF-C group. In CHF-C group, the left ventricular mRNA of NCX(1) and PLB were significantly higher than those in PS group (R(NCX)(1)/beta-Actin: 0.51 +/- 0.12 vs 0.19 +/- 0.06, P < 0.01; R(PLB)/beta-Actin: 0.26 +/- 0.12 vs 0.20 +/- 0.08, P = 0.045), yet SERCA(2) mRNA was lower than PS group (0.48 +/- 0.10 vs 0.80 +/- 0.11, P < 0.01). In CHF-T group, the mRNA levels of NCX(1) and SERCA(2) were just in the midst of the CHF-C and PS group, and had statistical significance respectively (all P < 0.05). In CHF - C and CHF - T group, the protein levels of NCX(1) were 1.141 +/- 0.047 and 1.074 +/- 0.081 times PS group, respectively (both P < 0.05), and SERCA(2) protein levels were respectively 0.803 +/- 0.100 and 0.893 +/- 0.084 times as high as in PS group (both P < 0.05). The protein expression of NCX(1) and SERCA(2) were also different between CHF-C and CHF-T groups (both P < 0.05). CONCLUSION: ACE inhibitor could improve cardiac function in CHF through directly enhancing the contractility of single myocardial cell, and these effects were probably mediated by its role in preventing the deleterious changes of calcium transient and calcium handling proteins in CHF.

More favorable response to cardiac resynchronization therapy in women than in men.

BACKGROUND: Data on sex difference in response to cardiac resynchronization therapy (CRT) remain controversial. We conducted a meta-analysis to summarize all published studies to determine whether sex-based differences in response to CRT exist. METHODS AND RESULTS: We performed a literature search using MEDLINE (source PubMed; January 1966 to March 2014) and EMBASE (January 1980 to March 2014) with no restrictions. Pooled effect estimates were obtained by using random-effects meta-analysis. Seventy-two studies involving 33 434 patients were identified. Overall, female patients had better outcomes from CRT compared with male patients, with a significant 33% reduction in the risk of death from any cause (hazard ratio, 0.67; 95% confidence interval, 0.61-0.74; P<0.001), 20% reduction in death or hospitalization for heart failure (hazard ratio, 0.80; 95% confidence interval, 0.71-0.90; P<0.001), 41% reduction in cardiac death (hazard ratio, 0.59; 95% confidence interval, 0.42-0.84; P<0.001), and 41% reduction in ventricular arrhythmias or sudden cardiac death (hazard ratio, 0.59; 95% confidence interval, 0.49-0.70; P<0.001). These more favorable responses to CRT in women were consistently associated with greater echocardiographic evidence of reverse cardiac remodeling in women than in men. CONCLUSIONS: Women obtained greater reductions in the risk of death from any cause, cardiac cause, death or hospitalization for heart failure, and ventricular arrhythmias or sudden cardiac death with CRT therapy compared with men, with consistently greater echocardiographic evidence of reverse cardiac remodeling in women than in men. Further studies are needed to investigate the exact reasons for these results and determine whether indications for CRT in women should be different from men.

C-Reactive protein-induced endothelial microparticle generation in HUVECs is related to BH4-dependent NO formation.

BACKGROUND: C-reactive protein (CRP) has been proven to facilitate endothelial injury via reduced NO production. Endothelial microparticles (EMPs) have emerged as a novel marker of endothelial injury. METHODS: In vitro cultured human umbilical vein endothelial cells (HUVECs) were incubated with CRP (20 mg/l) for 24 h. The numbers of EMPs with CD31- and CD51-positive staining were assessed flow-cytometrically, and NO production was measured using the Griess reaction in the presence or absence of tetrahydrobiopterin (BH(4)), respectively. RESULTS: The number of EMPs was significantly increased in HUVECs stimulated by CRP compared with the control group and, in parallel, NO production was decreased (p < 0.05). In the presence of CRP, pretreatment with BH(4) decreased EMP counts and restored NO production to baseline levels (p < 0.05) while pretreatment with 2,4-diamino-6-hydroxypyrimidine (DAHP), a BH(4) synthesis inhibitor, further prompted EMP formation and decreased NO production (p < 0.05). However, adding exogenous BH(4) after pretreatment with DAHP suppressed EMP formation and restored NO production (p < 0.05). CONCLUSIONS: This study demonstrates that CRP induces EMP generation in HUVECs and this effect is, at least in part, related to impaired BH(4)-dependent NO production. Augmented EMP generation in HUVECs is suggested as a novel potential mechanism contributing to the pathogenesis of vascular injury related to CRP.

In vitro shear stress modulates antithrombogenic potentials of human endothelial progenitor cells.

BACKGROUND: Recent study suggested that endothelial progenitor cells (EPCs), a novel therapeutic approach for endothelial dysfunction, present limited antithrombogenic potentials. However, few attempts have been done to improve the antithrombogenic potentials of EPCs. Our previous study proved that in vitro shear stress contributes to the increase in t-PA production by human EPCs. Here, we further investigated whether in vitro shear stress contributes to the secretion of antithrombogenic substances including plasminogen activator inhibitor-1 (PAI-1) and prostaglandin I(2) (PGI(2)) by human EPCs. METHODS: The peripheral blood mononuclear cells of healthy subjects were induced into EPCs. Then the human EPCs were treated with four levels of shear stress including stationary condition low media and high flow shear stress. The production of PAI-1 and 6-keto-prostaglandin F1(1alpha)(6-Keto-PGF(1alpha)) by human EPCs with shear stress treatment were measured. RESULTS: In vitro medium and high flow shear stress inhibited PAI-1 secretion by human EPCs, but low flow shear stress had no effect on PAI-1 secretion by human EPCs. All levels of shear stress significantly increased 6-Keto-PGF(1alpha )production by human EPCs in a dose-dependent manner. CONCLUSIONS: The present study demonstrates that in vitro shear stress can promote PGI(2 )secretion and inhibit PAI-1 secretion by human EPCs, which improves the antithrombogenic potentials of human EPCs.