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Catheter-based pulmonary artery denervation (PADN) has achieved promising outcomes to treat pulmonary hypertension (PH). We herein present stereotactic body radiotherapy (SBRT) as a novel noninvasive approach for PADN. A single fraction of 15 Gy, 20 Gy or 25 Gy was delivered for PADN in a thromboxane A2 (TxA2) - induced acute PH swine model. We demonstrated that PADN by 20-Gy SBRT reduced mean pulmonary artery (PA) pressure during the TxA2 challenge. All SBRT dosages led to a deeper denervation area compared with radiofrequency ablation (RFA) and reduced sympathetic neural norepinephrine synthesis in the ablation zone. Probable radiation related side effects were mostly found in animals treated with 25-Gy. In subsequent monocrotaline-induced chronic PH animals, PADN by 20-Gy SBRT resulted in more significant improvement in pulmonary hemodynamics and PA remodeling in comparison to RFA. In summary, our findings suggest that appropriate SBRT scheme could balance the efficacy and safety for PADN, potentiating to be a novel strategy to treat PH. Catheter-based pulmonary artery denervation (PADN) has achieved promising outcomes to treat pulmonary hypertension (PH). Here, the authors show stereotactic body radiotherapy is a novel noninvasive approach for PADN with improved pulmonary hemodynamics in both acute and chronic PH swine models. [ABSTRACT FROM AUTHOR]

This work considers the innovation-based attacks with side information under the energy constraint in cyber-physical systems where Kullback-Leibler (K-L) divergence is used as the stealthiness metric. Moreover, the attacker requires to decide when to launch attacks over a finite time horizon since the energy limitation. To cause the largest degradation to the estimation performance, the attack strategy and schedule require to be designed synergistically under the constraints. The terminal error (TE) and average error (AE) are respectively taken as attack performance indices. Then, the optimal attack policies for the TE and AE are obtained by solving a constrained optimization problem and a 0–1 programming problem. Finally, simulation examples are employed to demonstrate the results. [ABSTRACT FROM AUTHOR]

Atrial fibrillation (AF) is the most prevalent sustained cardiac arrhythmia, and recent epidemiological studies suggested type 2 diabetes mellitus (T2DM) is an independent risk factor for the development of AF. Zinc finger and BTB (broad-complex, tram-track and bric-a-brac) domain containing 16 (Zbtb16) serve as transcriptional factors to regulate many biological processes. However, the potential effects of Zbtb16 in AF under T2DM condition remain unclear. Here, we reported that db/db mice displayed higher AF vulnerability and Zbtb16 was identified as the most significantly enriched gene by RNA sequencing (RNA-seq) analysis in atrium. In addition, thioredoxin interacting protein (Txnip) was distinguished as the key downstream gene of Zbtb16 by Cleavage Under Targets and Tagmentation (CUT&Tag) assay. Mechanistically, increased Txnip combined with thioredoxin 2 (Trx2) in mitochondrion induced excess reactive oxygen species (ROS) release, calcium/calmodulin-dependent protein kinase II (CaMKII) overactivation, and spontaneous Ca2+ waves (SCWs) occurrence, which could be inhibited through atrial-specific knockdown (KD) of Zbtb16 or Txnip by adeno-associated virus 9 (AAV9) or Mito-TEMPO treatment. High glucose (HG)-treated HL-1 cells were used to mimic the setting of diabetic in vitro. Zbtb16-Txnip-Trx2 signaling-induced excess ROS release and CaMKII activation were also verified in HL-1 cells under HG condition. Furthermore, atrial-specific Zbtb16 or Txnip-KD reduced incidence and duration of AF in db/db mice. Altogether, we demonstrated that interrupting Zbtb16-Txnip-Trx2 signaling in atrium could decrease AF susceptibility via reducing ROS release and CaMKII activation in the setting of T2DM. [ABSTRACT FROM AUTHOR]

Apamin-sensitive small-conductance calcium-activated potassium (SK) current (IKAS) plays an important role in cardiac repolarization under a variety of physiological and pathological conditions. The regulation of cardiac IKAS relies on SK channel expression, intracellular Ca2+, and interaction between SK channel and intracellular Ca2+. IKAS activation participates in multiple types of arrhythmias, including atrial fibrillation, ventricular tachyarrhythmias, and automaticity and conduction abnormality. Recently, sex dimorphisms in autonomic control have been noticed in IKAS activation, resulting in sex-differentiated action potential morphology and arrhythmogenesis. This review provides an update on the Ca2+-dependent regulation of cardiac IKAS and the role of IKAS on arrhythmias, with a special focus on sex differences in IKAS activation. We propose that sex dimorphism in autonomic control of IKAS may play a role in J wave syndrome. [ABSTRACT FROM AUTHOR]

Patients with high-risk long QT syndrome (LQTS) mutations may experience life-threatening cardiac events. The present study sought to characterize a novel pathogenic mutation, KCNQ1p.Thr312del, in a Chinese LQT1 family. Clinical and genetic analyses were performed to identify this novel causative gene mutation in this LQTS family. Autosomal dominant inheritance of KCNQ1p.T312del was demonstrated in the three-generation pedigree. All mutation carriers presented with prolonged QT intervals and experienced recurrent syncope during exercise or emotional stress. The functional consequences of the mutant channel were investigated by computer homology modeling as well as whole-cell patch-clamp, western-blot and co-immunoprecipitation techniques using transfected mammalian cells. T312 is in the selectivity filter (SF) of the pore region of the KCNQ1-encoded channel. Homology modeling suggested that secondary structure was altered in the mutant SF compared with the wild-type (WT) SF. There were no significant differences in Kv7.1 expression, membrane trafficking or physical interactions with KCNE1-encoded subunits between the WT and mutant transfected channels. However, the KCNQ1p.T312del channels expressed in transfected cells were non-functional in the absence or presence of auxiliary KCNE1-subunits. Dominant-negative suppression of current density and decelerated activation kinetics were observed in cells expressing KCNQ1WT and KCNQ1p.T312del combined with KCNE1 (KCNQ1WT/p.T312del + KCNE1 channels). Those electrophysiological characteristics underlie the pathogenesis of this novel mutation and also suggest a high risk of cardiac events in patients carrying KCNQ1p.T312del. Although protein kinase A-dependent current increase was preserved, a significant suppression of rate-dependent current facilitation was noted in the KCNQ1WT/p.T312del + KCNE1 channels compared to the WT channels during 1- and 2-Hz stimulation, which was consistent with the patients' phenotype being triggered by exercise. Overall, KCNQ1p.Thr312del induces a loss of function in channel electrophysiology, and it is a high-risk mutation responsible for LQT1. [ABSTRACT FROM AUTHOR]

Rate-dependent repolarization (RDR) of action potential (AP) in cardiomyocyte plays a critical role in the genesis of arrhythmias and RDR in atrium has been linked with atrial fibrillation. However, detailed studies focusing on the role of RDR in rabbit atrium are scant. In this study, atrial cells were isolated from rabbit heart and rate-dependent property was explored in single atrial cell to elucidate the underlying mechanism. Our results indicated that rate-dependent prolongation was evident at the action potential duration at 20% (APD20) and 50% (APD50) repolarization but not at 90% repolarization (APD90) under control condition. Using transient outward potassium current (Ito) inhibitor 4-Aminopyridine (4-AP, 2 mM) effectively eliminated the changes in APD20 and APD50, and unmasked the rate-dependent reduction of APD90 which could be diminished by further adding L-type calcium current (ICaL) inhibitor nifedipine (30 μM). However, using the selective late sodium current (INaL) inhibitor GS-458967 (GS967, 1 μM) caused minimal effect on APD90 of atrial cells both in the absence and presence of 4-AP. In consistence with results from APs, Ito and ICaL displayed significant rate-dependent reduction because of their slow reactivation kinetics. In addition, the magnitude of INaL in rabbit atrium was so small that its rate-dependent changes were negligible. In conclusion, our study demonstrated that Ito and ICaL mediate RDR of AP in rabbit atrium, while minimal effect of INaL was seen. [ABSTRACT FROM AUTHOR]

Aim:Small GTPase Rac1 is a member of the Ras superfamily, which plays important roles in regulation of cytoskeleton reorganization, cell growth, proliferation, migration, etc. The aim of this study was to determine how a constitutively active Rac1b regulated cell proliferation and to investigate the effects of the Rac1b inhibitor sanguinarine.Methods:Three HEK293T cell lines stably overexpressing GFP, Rac1-GFP or Rac1b-GFP were constructed by lentiviral infection. The cells were treated with sanguinarine (1 μmol/L) or its analogue berberine (1 μmol/L) for 4 d. Cell proliferation was evaluated by counting cell numbers and with a BrdU incorporation assay. The levels of cleaved PARP-89 (an apoptosis marker) and cyclin-D1 (a proliferative index) were measured using Western blotting.Results:In 10% serum-containing media, overexpressing either Rac1 or Rac1b did not significantly change the cell proliferation. In the serum-starved media, however, the survival rate of Rac1b cells was significantly increased, whereas that of Rac1 cells was moderately increased. The level of cleaved PARP-89 was significantly increased in serum-starved Rac1 cells, but markedly reduced in serum-starved Rac1b cells. The level of cyclin-D1 was significantly increased in both serum-starved Rac1 and Rac1b cells. Treatment with sanguinarine, but not berberine, inhibited the proliferation of Rac1b cells, which was accompanied by significantly increased the level of PARP-89, and decreased both the level of cyclin-D1 and the percentage of BrdU positive cells.Conclusion:Rac1b enhances the cell proliferation under a growth-limiting condition via both anti-apoptotic and pro-proliferative mechanisms. Sanguinarine, as the specific inhibitor of Rac1b, is a potential therapeutic agent for malignant tumors with up-regulated Rac1b. [ABSTRACT FROM AUTHOR]

It has been shown that the elevated concentrations of oxidized low-density lipoprotein (Ox-LDL) or high-sensitivity C-reactive protein (hs-CRP) are predictive of future cardiovascular events for acute coronary syndrome (ACS) patients. But, the combined value of Ox-LDL and hs-CRP for predicting cardiovascular events is still unknown. Serum concentrations of Ox-LDL, hs-CRP, and cTnT were measured in a prospective cohort of 425 selective ACS patients followed 3-5 years for the occurrence of acute myocardial infarction (AMI) or death (AMI/death). Among 425 enrolled patients, 124 patients demonstrated AMI/death. Baseline levels of Ox-LDL, hs-CRP, and cTnT were significantly higher in AMI/death group than the event-free survival group. Kaplan-Meier survival analyses supported that elevations in Ox-LDL or hs-CRP predicted increased cardiovascular events risks. However, the strongest risk prediction was achieved by assessing Ox-LDL and hs-CRP together. Patients with high levels of Ox-LDL and hs-CRP were more likely to experience AMI or death than those with either Ox-LDL or hs-CRP elevated. Receiver-operating characteristic curves showed that Ox-LDL and hs-CRP have higher sensitivity and specificity than those of cTnT for predicting AMI or death. This was reflected by the AUC values for Ox-LDL, hs-CRP, and cTnT, which were 0.891, 0.834, and 0.626, respectively. The combined use of Ox-LDL and hs-CRP may improve prognosis after ACS with high-sensitivity and specificity. [ABSTRACT FROM AUTHOR]

Aim:To investigate whether resveratrol suppressed oxidative stress-induced arrhythmogenic activity and Ca2+ overload in ventricular myocytes and to explore the underlying mechanisms.Methods:Hydrogen peroxide (H2O2, 200 μmol/L)) was used to induce oxidative stress in rabbit ventricular myocytes. Cell shortening and calcium transients were simultaneously recorded to detect arrhythmogenic activity and to measure intracellular Ca2+ ([Ca2+]i). Ca2+/calmodulin-dependent protein kinases II (CaMKII) activity was measured using a CaMKII kit or Western blotting analysis. Voltage-activated Na+ and Ca2+ currents were examined using whole-cell recording in myocytes.Results:H2O2 markedly prolonged Ca2+ transient duration (CaTD), and induced early afterdepolarization (EAD)-like and delayed afterdepolarization (DAD)-like arrhythmogenic activity in myocytes paced at 0.16 Hz or 0.5 Hz. Application of resveratrol (30 or 50 μmol/L) dose-dependently suppressed H2O2-induced EAD-like arrhythmogenic activity and attenuated CaTD prolongation. Co-treatment with resveratrol (50 μmol/L) effectively prevented both EAD-like and DAD-like arrhythmogenic activity induced by H2O2. In addition, resveratrol markedly blunted H2O2-induced diastolic [Ca2+]i accumulation and prevented the myocytes from developing hypercontracture. In whole-cell recording studies, H2O2 significantly enhanced the late Na+ current (INa,L) and L-type Ca2+ current (ICa,L) in myocytes, which were dramatically suppressed or prevented by resveratrol. Furthermore, H2O2-induced ROS production and CaMKII activation were significantly prevented by resveratrol.Conclusion:Resveratrol protects ventricular myocytes against oxidative stress-induced arrhythmogenic activity and Ca2+ overload through inhibition of INa,L/ICa,L, reduction of ROS generation, and prevention of CaMKII activation. [ABSTRACT FROM AUTHOR]

Background: Critical sites within reentry circuits of postinfarction ventricular tachycardia (VT) were identified during sinus rhythm (SR) and VT to determine whether electrogram characteristics during SR may be helpful in identifying successful ablation sites. Methods: In 33 patients (mean age 67 ± 11 yrs) with prior infarction, mapping and radiofrequency (RF) catheter ablation of 57 hemodynamically-tolerated VT's (cycle length 478 ± 96) were performed. The morphologies of electrograms (EGM) at sites of concealed entrainment (CE) were compared during SR and VT. RF energy was delivered at 94 sites (51 successful and 43 unsuccessful ablation sites). Results: During SR, isolated potentials (IP), but not late potentials (LP) recorded via the mapping catheter, were associated with successful ablation. At 29/39 sites with an IP during sinus rhythm, an isolated diastolic potential (IDP) also was present during VT, whereas at 4 sites IP's were present only during SR ( p < 0.001). At 11/29 sites where isolated potentials were present during SR and VT, the morphology of the isolated potential during VT and SR was similar; and all but one of these sites were successful ablation sites ( p = 0.01). The EGM amplitude during VT correlated with the amplitude during SR ( R = 0.9, p < 0.001). An identical pacemap was present during SR at 33/94 sites; this was not associated with successful ablation. Conclusion: SR mapping may be helpful in identifying critical sites of reentry in postinfarction VT. At sites within the reentry circuit, characteristics of sinus rhythm EGM's that are associated with successful ablation include the presence of IP's, but not the presence of LP's. [ABSTRACT FROM AUTHOR]

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Objective: The mechanism by which pacing terminates ventricular tachycardia (VT) may depend on the location of the pacing site relative to the reentry circuit. The purpose of this study was to compare the mechanisms by which pacing terminates VT at left ventricular (LV) sites with and without concealed entrainment (CE) in patients with prior myocardial infarction. Methods and Results: LV mapping was performed in 29 patients (26 men, 3 women, mean age 67±11 years, ejection fraction 0.28±0.11) with 55 hemodynamically-tolerated VTs (mean cycle length 478±92 msec). A total of 408 pacing trains were delivered at 102 sites with CE. Radiofrequency catheter ablation was successful in 41 of 55 VT's. At sites with concealed entrainment, VT was terminated by pacing at 17/41 (41%) successful and at 4/61 (7%) unsuccessful ablation sites (p<0.01). Termination without global ventricular capture was the most frequent termination mode (10/21), followed by termination with orthodromic (4/21) and non-orthodromic capture (7/21). Conclusion: In patients with prior myocardial infarction, pacing at sites of CE during VT usually terminates VT either without global capture or by orthodromic capture. Termination of VT by pacing without global capture or with orthodromic capture at sites of CE suggests that the site is within a critical area of the reentry circuit. [ABSTRACT FROM AUTHOR]

Due to the heat pipes’ transient conduction, phase change and fluid dynamics during cooling/heating with high frequency charging/discharging of batteries, it is crucial to investigate in depth the experimental dynamic thermal characteristics in such complex heat transfer processes for more accurate thermal analysis and design of a BTMS. In this paper, the use of ultra-thin micro heat pipe (UMHP) for thermal management of a lithium-ion battery pack in EVs is explored by experiments to reveal the cooling/heating characteristics of the UMHP pack. The cooling performance is evaluated under different constant discharging and transient heat inputs conditions. And the heating efficiency is assessed under several sub-zero temperatures through heating films with/without UMHPs. Results show that the proposed UMHP BTMS with forced convection can keep the maximum temperature of the pack below 40 °C under 1 ~ 3C discharging, and effectively reduced the instant temperature increases and minimize the temperature fluctuation of the pack during transient federal urban driving schedule (FUDS) road conditions. Experimental data also indicate that heating films stuck on the fins of UMHPs brought about adequate high heating efficiency comparing with that stuck on the surface of cells under the same heating power, but has more convenient maintenance and less cost for the BTMS. The experimental dynamic temperature characteristics of UMHP which is found to be a high-efficient and low-energy consumption cooling/heating method for BTMSs, can be performed to guide thermal analysis and optimization of heat pipe BTMSs. [ABSTRACT FROM AUTHOR]

We perform this meta-analysis to compare the efficacy and safety of cryoablation versus radiofrequency ablation for patients with cavotricuspid valve isthmus dependent atrial flutter. By searching EMBASE, MEDLINE, PubMed and Cochrane electronic databases from March 1986 to September 2014, 7 randomized clinical trials were included. Acute (risk ratio[RR]: 0.93; P = 0.14) and long-term (RR: 0.94; P = 0.08) success rate were slightly lower in cryoablation group than in radiofrequency ablation group, but the difference was not statistically significant. Additionally, the fluoroscopy time was nonsignificantly reduced (weighted mean difference[WMD]: −2.83; P = 0.29), whereas procedure time was significantly longer (WMD: 25.95; P = 0.01) in cryoablation group compared with radiofrequency ablation group. Furthermore, Pain perception during the catheter ablation was substantially less in cryoabaltion group than in radiofrequency ablation group (standardized mean difference[SMD]: −2.36; P < 0.00001). Thus, our meta-analysis demonstrated that cryoablation and radiofrequency ablation produce comparable acute and long-term success rate for patients with cavotricuspid valve isthmus dependent atrial flutter. Meanwhile, cryoablation ablation tends to reduce the fluoroscopy time and significantly reduce pain perception in cost of significantly prolonged procedure time. [ABSTRACT FROM AUTHOR]