Jiagao Lv

β-AR blockers suppresses ER stress in cardiac hypertrophy and heart failure.

Background Long-term β-adrenergic receptor (β-AR) blockade reduces mortality in patients with heart failure. Chronic sympathetic hyperactivity in heart failure causes sustained β-AR activation, and this can deplete Ca2+ in endoplasmic reticulum (ER) leading to ER stress and subsequent apoptosis. We tested the effect of β-AR blockers on ER stress pathway in experimental model of heart failure. Methods and discussions ER chaperones were markedly increased in failing hearts of patients with end-stage heart failure. In Sprague-Dawley rats, cardiac hypertrophy and heart failure was induced by abdominal aortic constriction or isoproterenol subcutaneous injection. Oral β-AR blockers treatment was performed in therapy groups. Cardiac remodeling and left ventricular function were analyzed in rats failing hearts. After 4 or 8 weeks of banding, rats developed cardiac hypertrophy and failure. Cardiac expression of ER chaperones was significantly increased. Similar to the findings above, sustained isoproterenol infusion for 2 weeks induced cardiac hypertrophy and failure with increased ER chaperones and apoptosis in hearts. β-AR blockers treatment markedly attenuated these pathological changes and reduced ER stress and apoptosis in failing hearts. On the other hand, β-AR agonist isoproterenol induced ER stress and apoptosis in cultured cardiomyocytes. β-AR blockers largely prevented ER stress and protected myocytes against apoptosis. And β-AR blockade significantly suppressed the overactivation of CaMKII in isoproterenol-stimulated cardiomyocytes and failing hearts in rats. Conclusions Our results demonstrated that ER stress occurred in failing hearts and this could be reversed by β-AR blockade. Alleviation of ER stress may be an important mechanism underlying the therapeutic effect of β-AR blockers on heart failure.

Clinical Features of Severe Wasp Sting Patients with Dominantly Toxic Reaction: Analysis of 1091 Cases

Background Massive wasp stings have been greatly underestimated and have not been systematically studied. The aim of this study was to identify the clinical features and treatment strategies of severe wasp stings. Methods and Findings A multicenter retrospective study was undertaken in 35 hospitals and medical centers including 12 tertiary care hospitals and 23 secondary care hospitals in the Hubei Province, China. The detailed clinical data of 1091 hospitalized wasp sting patients were investigated. Over three-fourths (76.9%) of the cases had 10 or more stings and the in-hospital mortality of patients was 5.1%. Forty-eight patients died of organ injury following toxic reactions to the stings, whereas six died from anaphylactic shock. The in-hospital mortality in patients with >10 stings was higher than that of ≤10 stings (5.2% vs. 1.0%, p = 0.02). Acute kidney injury (AKI) was seen in 21.0% patients and most patients required blood purification therapy. Rhabdomyolysis was seen in 24.1% patients, hemolysis in 19.2% patients, liver injury in 30.1% patients, and coagulopathy in 22.5% patients. Regression analysis revealed that high creatinine level, shock, oliguria, and anemia were risk factors for death. Blood purification therapy was beneficial for patients with ≥20 stings and delayed hospital admission of patients (≥4 hours after sting). Conclusions In China, most patients with multiple wasp stings presented with toxic reactions and multiple organ dysfunction caused by the venom rather than an anaphylactic reaction. AKI is the prominent clinical manifestation of wasp stings with toxic reaction. High creatinine levels, shock, oliguria, and anemia were risk factors for death.

Diagnostic Power of Longitudinal Strain at Rest for the Detection of Obstructive Coronary Artery Disease in Patients with Type 2 Diabetes Mellitus

Global longitudinal strain (GLS) measured by 2-D speckle-tracking echocardiography (2-D STE) at rest has been recognized as a sensitive parameter in the detection of significant coronary artery disease (CAD). However, the diagnostic power of 2-D STE in the detection of significant CAD in patients with diabetes mellitus is unknown. Two-dimensional STE features were studied in total of 143 consecutive patients who underwent echocardiography and coronary angiography. Left ventricular global and segmental peak systolic longitudinal strains (PSLSs) were quantified by speckle-tracking imaging. In the presence of obstructive CAD (defined as stenosis ≥75%), global PSLS was significantly lower in patients with diabetes mellitus than in patients without (16.65 ± 2.29% vs. 17.32 ± 2.27%, p < 0.05). Receiver operating characteristic analysis revealed that global PSLS could effectively detect obstructive CAD in patients without diabetes mellitus (cutoff value: -18.35%, sensitivity: 78.8%, specificity: 77.5%). However, global PSLS could detect obstructive CAD in diabetic patients at a lower cutoff value with inadequate sensitivity and specificity (cutoff value: -17.15%; sensitivity: 61.1%, specificity: 52.9%). In addition, the results for segmental PSLS were similar to those for global PSLS. In conclusion, global and segmental PSLSs at rest were significantly lower in patients with both obstructive CAD and diabetes mellitus than in patients with obstructive CAD only; thus, PSLSs at rest might not be a useful parameter in the detection of obstructive CAD in patients with diabetes mellitus.

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.

The role of high-sensitivity C-reactive Protein, interleukin-6 and cystatin C in ischemic stroke complicating atrial fibrillation

SummaryThis study examined the role of high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6) and cystatin C in ischemic stroke complicating atrial fibrillation (AF) and the relationship of systemic inflammation with this disease in order to identify AF patients who are at high risk of stroke and need optimal anticoagulant therapy. A total of 103 AF patients, simple (n=75) or complicated by ischemic stroke (n=28), and 112 control subjects were recruited. IL-6 level was detected by using enzyme linked immunosorbent assay. Cystatin C and hsCRP levels were measured by means of a particle-enhanced immunonephelometric assay. The results showed that the AF patients had higher levels of hsCRP (P=0.004), IL-6 (P=0.000), and cystatin C (P=0.000) than control subjects. Plasma hsCRP level was increased in the AF patients with ischemic stroke as compared to the patients with simple AF (P=0.036). The AF patients who had the level of hsCRP exceeding 3.83 mg/L were at a higher risk than those with hsCRP level lower than 3.83 mg/L (P=0.030). After adjusting for other factors, cystatin C remained positively associated with IL-6 (r=0.613) and hsCRP (r=0.488). It was concluded that hsCRP is positively correlated with ischemic stroke complicating AF and may be a risk factor independent of other risk factors for AF. Elevated cystatin C level is also indicative of the increased risk of AF.

KN-93, A CaMKII inhibitor, suppresses ventricular arrhythmia induced by LQT2 without decreasing TDR

Abnormal enhanced transmural dispersion of repolarization (TDR) plays an important role in the maintaining of the severe ventricular arrhythmias such as torsades de pointes (TDP) which can be induced in long-QT (LQT) syndrome. Taking advantage of an in vitro rabbit model of LQT2, we detected the effects of KN-93, a CaM-dependent kinase (CaMK) II inhibitor on repolarization heterogeneity of ventricular myocardium. Using the monophasic action potential recording technique, the action potentials of epicardium and endocardium were recorded in rabbit cardiac wedge infused with hypokalemic, hypomagnesaemic Tyrode’s solution. At a basic length (BCL) of 2000 ms, LQT2 model was successfully mimicked with the perfusion of 0.5 μmol/L E-4031, QT intervals and the interval from the peak of T wave to the end of T wave (Tp-e) were prolonged, and Tp-e/QT increased. Besides, TDR was increased and the occurrence rate of arrhythmias like EAD, R-on-T extrasystole, and TDP increased under the above condition. Pretreatment with KN-93 (0.5 μmol/L) could inhibit EAD, R-on-T extrasystole, and TDP induced by E-4031 without affecting QT interval, Tp-e, and Tp-e/QT. This study demonstrated KN-93, a CaMKII inhibitor, can inhibit EADs which are the triggers of TDP, resulting in the suppression of TDP induced by LQT2 without affecting TDR.SummaryAbnormal enhanced transmural dispersion of repolarization (TDR) plays an important role in the maintaining of the severe ventricular arrhythmias such as torsades de pointes (TDP) which can be induced in long-QT (LQT) syndrome. Taking advantage of an in vitro rabbit model of LQT2, we detected the effects of KN-93, a CaM-dependent kinase (CaMK) II inhibitor on repolarization heterogeneity of ventricular myocardium. Using the monophasic action potential recording technique, the action potentials of epicardium and endocardium were recorded in rabbit cardiac wedge infused with hypokalemic, hypomagnesaemic Tyrode’s solution. At a basic length (BCL) of 2000 ms, LQT2 model was successfully mimicked with the perfusion of 0.5 μmol/L E-4031, QT intervals and the interval from the peak of T wave to the end of T wave (Tp-e) were prolonged, and Tp-e/QT increased. Besides, TDR was increased and the occurrence rate of arrhythmias like EAD, R-on-T extrasystole, and TDP increased under the above condition. Pretreatment with KN-93 (0.5 μmol/L) could inhibit EAD, R-on-T extrasystole, and TDP induced by E-4031 without affecting QT interval, Tp-e, and Tp-e/QT. This study demonstrated KN-93, a CaMKII inhibitor, can inhibit EADs which are the triggers of TDP, resulting in the suppression of TDP induced by LQT2 without affecting TDR.

Influence of silencing soluble epoxide hydrolase with RNA interference on cardiomyocytes apoptosis induced by doxorubicin

SummaryIn order to investigate the influence of silencing soluble epoxide hydrolase (sEH) with double-stranded small interfering RNA (siRNA) on cardiomyocytes apoptosis induced by doxorubicin (DOX), two plasmids containing siRNA sequences specific to sEH were constructed and transfected into the primary cultured cardiomyocytes by using FuGENE HD transfection agents. The mRNA and protein expression levels of sEH were detected by semiquantitative RT-PCR and Western blotting respectively, and the plasmids that silenced sEH most significantly were selected, and renamed EH-R. The plasmids carrying a nonspecific siRNA coding sequence (PCN) served as the negative control. Cardiomyocytes were divided into four groups: control group, DOX group, PCN+DOX group, and EH-R+DOX group. Apoptosis of cardiomyocytes was induced by DOX at a concentration of 1 μmol/L. Apoptosis rate of cardiomyocytes was determined by flow cytometery. The protein expression levels of Bcl-2 and Bax were detected by Western blotting. The results showed that the expression of sEH was down-regulated by EH-R plasmid. The expression levels of sEH mRNA and protein in the EH-R+DOX group were significantly decreased as compared with other groups (P<0.01). As compared with the control group, the apoptosis rate of cardiomyocytes in three DOX-treated groups was obviously increased, the expression levels of Bax increased, and those of Bcl-2 decreased (P<0.01). However, the expression levels of Bax were decreased, those of Bcl-2 increased and the apoptosis rate of cardiomyocytes obviously decreased in EH-R+DOX group when compared with those in the DOX group and the PCN+DOX group (P<0.01 for each). It was concluded that the recombinant plasmids could be successfully constructed, and transfected into the primary cultured cardiomyocytes. They could ameliorate the DOX-induced cardiomyocytes apoptosis by selectively inhibiting the expression of sEH with RNAi and increasing the expression of Bcl-2.In order to investigate the influence of silencing soluble epoxide hydrolase (sEH) with double-stranded small interfering RNA (siRNA) on cardiomyocytes apoptosis induced by doxorubicin (DOX), two plasmids containing siRNA sequences specific to sEH were constructed and transfected into the primary cultured cardiomyocytes by using FuGENE HD transfection agents. The mRNA and protein expression levels of sEH were detected by semiquantitative RT-PCR and Western blotting respectively, and the plasmids that silenced sEH most significantly were selected, and renamed EH-R. The plasmids carrying a nonspecific siRNA coding sequence (PCN) served as the negative control. Cardiomyocytes were divided into four groups: control group, DOX group, PCN+DOX group, and EH-R+DOX group. Apoptosis of cardiomyocytes was induced by DOX at a concentration of 1 μmol/L. Apoptosis rate of cardiomyocytes was determined by flow cytometery. The protein expression levels of Bcl-2 and Bax were detected by Western blotting. The results showed that the expression of sEH was down-regulated by EH-R plasmid. The expression levels of sEH mRNA and protein in the EH-R+DOX group were significantly decreased as compared with other groups (P<0.01). As compared with the control group, the apoptosis rate of cardiomyocytes in three DOX-treated groups was obviously increased, the expression levels of Bax increased, and those of Bcl-2 decreased (P<0.01). However, the expression levels of Bax were decreased, those of Bcl-2 increased and the apoptosis rate of cardiomyocytes obviously decreased in EH-R+DOX group when compared with those in the DOX group and the PCN+DOX group (P<0.01 for each). It was concluded that the recombinant plasmids could be successfully constructed, and transfected into the primary cultured cardiomyocytes. They could ameliorate the DOX-induced cardiomyocytes apoptosis by selectively inhibiting the expression of sEH with RNAi and increasing the expression of Bcl-2.

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.

Inhibitory effects of roscovitine on proliferation and migration of vascular smooth muscle cells in vitro

Abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) are the major cause of in-stent restenosis (ISR). Intervention proliferation and migration of VSMCs is an important strategy for antirestenotic therapy. Roscovitine, a second-generation cyclin-dependent kinase inhibitor, can inhibit cell cycle of multiple cell types. We studied the effects of roscovitine on cell cycle distribution, proliferation and migration of VSMCs in vitro by flow cytometry, BrdU incorporation and wound healing assay, respectively. Our results showed that roscovitine increased the proportion of G0/G1 phase cells after 12 h (69.57±3.65 vs. 92.50±1.68, P=0.000), 24 h (80.87±2.24 vs. 90.25±0.79, P=0.000) and 48 h (88.08±3.86 vs. 88.87±2.43, P=0.427) as compared with control group. Roscovitine inhibited proliferation and migration of VSMCs in a concentration-dependent way. With the increase of concentration, roscovitine showed increased capacity for growth and migration inhibition. Roscovitine (30 μmol/L) led to an almost complete VSMCs growth and migration arrest. Combined with its low toxicity and selective inhibition to ISR-VSMCs, roscovitine may be a potential drug in the treatment of vascular stenosis diseases and particularly useful in the prevention and treatment of ISR.SummaryAbnormal proliferation and migration of vascular smooth muscle cells (VSMCs) are the major cause of in-stent restenosis (ISR). Intervention proliferation and migration of VSMCs is an important strategy for antirestenotic therapy. Roscovitine, a second-generation cyclin-dependent kinase inhibitor, can inhibit cell cycle of multiple cell types. We studied the effects of roscovitine on cell cycle distribution, proliferation and migration of VSMCs in vitro by flow cytometry, BrdU incorporation and wound healing assay, respectively. Our results showed that roscovitine increased the proportion of G0/G1 phase cells after 12 h (69.57±3.65 vs. 92.50±1.68, P=0.000), 24 h (80.87±2.24 vs. 90.25±0.79, P=0.000) and 48 h (88.08±3.86 vs. 88.87±2.43, P=0.427) as compared with control group. Roscovitine inhibited proliferation and migration of VSMCs in a concentration-dependent way. With the increase of concentration, roscovitine showed increased capacity for growth and migration inhibition. Roscovitine (30 μmol/L) led to an almost complete VSMCs growth and migration arrest. Combined with its low toxicity and selective inhibition to ISR-VSMCs, roscovitine may be a potential drug in the treatment of vascular stenosis diseases and particularly useful in the prevention and treatment of ISR.

Anticancer drugs-related QTc prolongation, torsade de pointes and sudden death: current evidence and future research perspectives

Anticancer drugs may have proarrhythmic effects including drug-induced QT interval prolongation, which is of particular importance because it can lead to a fatal polymorphic ventricular tachycardia termed torsade de pointes (TdP). QT interval prolongation and TdP are rare life-threatening untoward effects of anticancer therapy, particularly with arsenic trioxides and anthracyclines, and even some novel molecular targeted drugs touted as ‘tumor specific’. Several factors that affect myocardial repolarization can further increase the risk of TdP. This article reviews the mechanism of QT interval prolongation, risk factors for TdP and the QT toxicity of anticancer drugs as well as its management. Specific attention should be paid to high-risk populations such as patients with underlying heart diseases, electrolyte imbalance and bradycardia. To minimize the occurrence of QT interval prolongation and TdP, it is advisable to conduct a careful risk factor assessment before antitumor therapy. To this end, several new biomarkers have been introduced to predict TdP triggering and recent studies have pointed out the potential clinical relevance of genetic testing.