Refractory ventricular tachycardia and heart failure due to anti-mitochondrial antibody-positive inflammatory myopathy.

BACKGROUND: Anti-mitochondrial antibody (AMA)-positive inflammatory myopathy, a rare type of idiopathic inflammatory myopathy which was frequently difficult to diagnose, can affect muscles and the structure and electrical conduction of the heart. Early identification and treatment of this myopathy can prevent serious cardiovascular adverse events and improve cardiac function. CASE PRESENTATION: We report a patient who experienced repeated syncope, ventricular tachycardia (VT) and heart failure accompanied by weakness and muscle atrophy. He was initially diagnosed with dilated cardiomyopathy and received implantable cardioverter-defibrillator therapy. He was subsequently misdiagnosed as muscular dystrophy due to progressive muscular atrophy. However, the patient developed repeated and refractory VT storms that were not alleviated by conventional therapy. Finally, he was diagnosed with AMA-positive inflammatory myopathy with cardiac injuries. The patient was markedly recovered by being treated with immunosuppressive and immunomodulatory therapy. CONCLUSION: AMA could be screened when discovering myopathies accompanied by unexplained cardiac symptoms. Our findings provide insights into the diagnosis and therapy of this rare and severe disease.

Intensive vs non-intensive statin pretreatment before percutaneous coronary intervention in Chinese patients: A meta-analysis of randomized controlled trials.

BACKGROUND: The results of intensive statin pretreatment before percutaneous coronary intervention (PCI) is inconsistent between Chinese and Western populations, and there are no corresponding meta-analyses involving hard clinical endpoints in the available published literature. AIM: To evaluate the efficacy and safety of high-dose statin loading before PCI in Chinese patients through a meta-analysis. METHODS: Relevant studies were identified by searching the electronic databases of PubMed, Embase and Cochrane's Library to December 2019. The outcomes included an assessment of major adverse cardiovascular event (MACE), non-fatal myocardial infarction (MI), cardiac death, target vessel revascularization (TVR), myalgia /myasthenia and abnormal alanine aminotransferase (ALT) in all enrolled patients. Random effect model and fixed effect model were applied to combine the data, which were further analyzed by χ 2 test and I 2 test. The main outcomes were then analyzed through the use of relative risks (RR) and its 95% confidence interval (95%CI). RESULTS: Eleven studies involving 3123 individuals were included. Compared with patients receiving placebo or no statin treatment before surgery, intensive statin treatment was associated with a clear reduction of risk of MACE (RR = 0.44, 95%CI: 0.31-0.61, P < 0.00001). However, compared with the patients receiving moderate-intensity statin before surgery, no advantage to intensive statin treatment was seen (RR = 1.04, 95%CI: 0.82-1.31, P = 0.74). In addition, no significant difference was observed between intensive statin therapy and non-intensive statin therapy on the incidence of TVR (RR = 0.43, 95%CI: 0.18-1.02, P = 0.06) , myalgia /myasthenia (RR = 1.35, 95%CI: 0.30-5.95, P = 0.69) and abnormal alanine aminotransferase (RR = 1.47, 95%CI: 0.54-4.02, P = 0.45) except non-fatal MI (RR = 0.54, 95%CI: 0.33-0.88, P = 0.01). CONCLUSION: Compared with placebo or no statin pretreatment, intensive statin before PCI displayed reduced incidence of MACE. However, there was no significant benefit between high and moderate-intensity statin. In addition, no significant difference was observed between intensive statin therapy and non-intensive statin therapy on the incidence of TVR, myalgia/myasthenia and abnormal alanine aminotransferase except non-fatal MI.

Ripple mapping-guided atrial tachycardia ablation following open-heart surgery.

Ripple mapping can make the visualization of activation conduction on a 3-dimensional voltage map and is useful tool for scar-related organized atrial tachycardia (AT). This study sought to assess the efficacy of ripple mapping for interpreting reentrant circuits and critical isthmus in postoperative ATs. 34 consecutive patients with a history of mitral valve surgery (mean age, 54.5 ± 12.4 years) underwent high density (HD) RM during ATs with CARTO3v4 CONFIDENSE system. The voltage activation threshold was determined by RM over a bipolar voltage map. The identification of underlying mechanisms and ablation setting was based on RM without reviewing activation mapping. A total of 41 ATs (35 spontaneous, 6 induced) were characterized. 39 reentry circuits were successfully mapped (cycle length, 256 ± 43 ms). Of the 41 ATs, 28 were confirmed by ripple mapping alone (68%), and 12 (29%) by ripple mapping and entrainment mapping. Of 12 ATs in the left atrium, 9 (75%) needed entrainment to confirm, compared with 5 (17.8%) in the right atrium. Primary endpoint after initial ablation set was achieved in 32 of the 34 patients (94.1%). Freedom from atrial arrhythmias was 79.4% after the follow-up of 12 ± 5 months. Of the seven patients with recurrence, three underwent the repeated catheter ablation. Ripple mapping precisely delineated reentrant circuits in post-cardiac surgery AT resulting in a high success rate of ablation. Entrainment maneuvers remain useful for elucidation of complex AT circuits.

Human trophoblast-derived exosomes attenuate doxorubicin-induced cardiac injury by regulating miR-200b and downstream Zeb1.

Human trophoblast stem cells (TSCs) have been confirmed to play a cardioprotective role in heart failure. However, whether trophoblast stem cell-derived exosomes (TSC-Exos) can protect cardiomyocytes from doxorubicin (Dox)-induced injury remains unclear. In the present study, TSC-Exos were isolated from the supernatants of human trophoblasts using the ultracentrifugation method and characterized by transmission electron microscopy and western blotting. In vitro, primary cardiomyocytes were subjected to Dox and treated with TSC-Exos, miR-200b mimic or miR-200b inhibitor. Cellular apoptosis was observed by flow cytometry and immunoblotting. In vivo, mice were intraperitoneally injected into Dox to establish a heart failure model. Then, different groups of mice were administered either PBS, adeno-associated virus (AAV)-vector, AAV-miR-200b-inhibitor or TSC-Exos via tail vein injection. Then, the cardiac function, cardiac fibrosis and cardiomyocyte apoptosis in each group were evaluated, and the downstream molecular mechanism was explored. TSC-Exos and miR-200b inhibitor both decreased primary cardiomyocyte apoptosis. Similarly, mice receiving TSC-Exos and AAV-miR-200b inhibitor exhibited improved cardiac function, accompanied by reduced apoptosis and inflammation. The bioinformatic prediction and luciferase reporter results confirmed that Zeb1 was a downstream target of miR-200b and had an antiapoptotic effect. TSC-Exos attenuated doxorubicin-induced cardiac injury by playing antiapoptotic and anti-inflammatory roles. The underlying mechanism could be an increase in Zeb1 expression by the inhibition of miR-200b expression. In summary, this study sheds new light on the application of TSC-Exos as a potential therapeutic tool for heart failure.

Next-generation sequencing identifies a novel heterozygous I229T mutation on LMNA associated with familial cardiac conduction disease.

LMNA gene encodes Lamin A and C (Lamin A/C), which are intermediate filament protein implicating in DNA replication and transcription. Mutations in LMNA are validated to cause cardiac conduction disease (CCD) and cardiomyopathy.In a Chinese family, we identified 5 members harboring the identical heterozygous LMNA (c.686T>C, I229T) disease-causing mutation, which was not found in the 535 healthy controls. In silico analysis, we revealed structural alteration in Lamin A/C I229T mutant. Furthermore, molecular docking identified human polycomb repressive complex 2 and Lamin A/C interact with higher affinity in the presence of I229T, thus may downregulate Nav1.5 channel expression.Our findings expanded the spectrum of mutations associated with CCD and were valuable in the genetic diagnosis and clinical screening for CCD. Molecular docking analysis provided useful information of increased binding affinity between mutant Lamin A/C and polycomb repressive complex 2. However, the concrete mechanism of LMNA mutation (I229T) remains undetermined in our study, future genetics and molecular studies are still needed.

Inhibition of RAGE by FPS-ZM1 alleviates renal injury in spontaneously hypertensive rats.

The current study was designed to examine the protection of RAGE-specific inhibitor FPS-ZM1 against renal injury in spontaneously hypertensive rats (SHR) and investigate the underlying mechanism. The adult male SHR were treated with FPS-ZM1 via oral gavages for 12 weeks, and age-matched male Wistar-Kyoto rats (WKY) were used as control. Treatment of SHR with FPS-ZM1 slightly reduced blood pressure, and significantly improved baroreflex sensitivity in SHR. Treatment of SHR with FPS-ZM1 improved renal function, evidenced by increased glomerular filtration rate and renal blood flow, and reduced plasma creatinine, blood urea nitrogen and urine albumin excretion rate. Histology results revealed that treatment of SHR with FPS-ZM1 alleviated renal injury and reduced tubulointerstitial fibrosis. Treatment of SHR with FPS-ZM1 suppressed activation of NF-κB and reduced expression of pro-inflammatory cytokines including Tnf, Il6, and Il1b. Treatment of SHR with FPS-ZM1 abated oxidative stress and downregulated mRNA levels of components of NADPH oxidase (Nox) including Cyba, Nox1, Nox2, Nox4 and Ncf1 in kidneys. In addition, treatment of SHR with FPS-ZM1 reduced renal AngII levels, downregulated mRNA expression of Ace and upregulated expression of Agtr2. In conclusion, treatment with FPS-ZM1 alleviated hypertension-related renal dysfunction, possibly by suppressing NF-κB-mediated inflammation, abating Nox-mediated oxidative stress, and improving local renal renin-angiotensin system (RAS).

PDK1-AKT signaling pathway regulates the expression and function of cardiac hyperpolarization-activated cyclic nucleotide-modulated channels.

AIM: The enzyme 3-phosphoinositide-dependent protein kinase-1 (PDK1) is associated with cardiac and pathological remodeling and ion channel function regulation. However, whether it regulates hyperpolarization-activated cyclic nucleotide-modulated channels (HCNs) remains unclear. MAIN METHODS: In the atrial myocytes of heart-specific PDK1 "knockout" mouse model and neonatal mice, protein kinase B (AKT)-related inhibitors or agonists as well as knockdown or overexpression plasmids were used to study the relationship between PDK1 and HCNs. KEY FINDINGS: HCN1 expression and AKT phosphorylation at the Thr308 site were significantly decreased in atrial myocytes after PDK1 knockout or inhibition; in contrast, HCN2 and HCN4 levels were significantly increased. Also, a similar trend of HCNs expression has been observed in cultured atrial myocytes after PDK1 inhibition, as further demonstrated via immunofluorescence and patch-clamp experiments. Moreover, these results of PDK1 overexpression indicate an opposite trend compared with the previous experimental results. However, the results of PDK1 inhibition or overexpression could be reversed by activating or inhibiting AKT, respectively. SIGNIFICANCE: These results indicate that the PDK1-AKT signaling pathway is involved in the regulation of HCN mRNA transcription, protein expression, HCN current density, and cell membrane location.

Brugada Syndrome Caused by Sodium Channel Dysfunction Associated with a SCN1B Variant A197V.

OBJECTIVE: We aimed to identify and characterize a SCN1B variant, A197V, associated with Brugada Syndrome (BrS). METHODS: Whole-exome sequencing was employed to explore the potential causative genes in 8 unrelated clinically diagnosed BrS patients. A197V variant was only detected in exon 4 of SCN1B in a 46 year old patient, who was admitted due to syncope. Wild type (WT) and mutant (A197V) genes were co-expressed with SCN5A in human embryonic kidney cells (HEK293 cells) and studied using whole-cell patch clamp and immunodetection techniques. RESULTS: Coexpression of 5A/WT + 1B/A197V resulted in a marked decrease in current density compared to 5A/WT + 1B/WT. The activation velocity was decelerated by A197V mutation. No significant changes were observed in recovery from inactivation parameters. Cell surface protein analyses confirmed that Nav1.5 channel membrane distribution was affected by A197V mutation. CONCLUSIONS: The current study is the first to report the functional analysis of SCN1B/ A197V, serving as a substrate responsible for BrS.

Residual flow may increase the risk of adverse events in patients received combined catheter ablation and transcatheter left atrial appendage closure for nonvalvular atrial fibrillation: a meta-analysis.

BACKGROUND: Catheter ablation (CA) and left atrial appendage closure (LAAC) have been combined into a novel one-stop procedure for patients with atrial fibrillation (AF). However, postoperative complications are relatively common in patients undergoing LAAC; the complications, including residual flow, increase in the risk of bleeding, or other adverse events, are unknown in patients receiving one-stop therapy. Therefore, we tried to evaluate the adverse events of CA and LAAC hybrid therapy in patients with nonvalvular AF. METHODS: We performed a meta-analysis and computer-based literature search to identify publications listed in the PubMed, Embase, and Cochrane library databases. Studies were included if patients received CA and LAAC hybrid therapy and reported adverse events. RESULTS: Overall 13 studies involving 952 patients were eligible based on the inclusion criteria. In the periprocedural period, the pooled incidence of pericardial effusion was 3.15%. The rates of bleeding events and residual flow were 5.02 and 9.11%, respectively. During follow-up, the rates of all-cause mortality, embolism events, bleeding events, AF recurrence, and residual flow were 2.15, 5.24, 6.95, 32.89, and 15.35%, respectively. The maximum occurrence probability of residual flow events was 21.87%. Bleeding events were more common in patients with a higher procedural residual flow event rate (P = 0.03). A higher AF recurrence rate indicated higher rates of embolism events (P = 0.04) and residual flow (P = 0.03) during follow-up. CONCLUSIONS: Bleeding events were more common in patients with a higher procedural residual flow event rate. However, combined CA and LAAC therapy is reasonably safe and efficacious in patients with nonvalvular AF. Further studies on the safety and efficacy of CA or LAAC alone are necessary in future.

AMPK-mediated degradation of Nav1.5 through autophagy.

The voltage-gated cardiac sodium channel, Nav1.5, is the key component that controls cardiac excitative electrical impulse and propagation. However, the dynamic alterations of Nav1.5 during cardiac ischemia and reperfusion (I/R) are seldom reported. We found that the protein levels of rat cardiac Nav1.5 were significantly decreased in response to cardiac I/R injury. By simulating I/R injury in cells through activating AMPK by glucose deprivation, AMPK activator treatment, or hypoxia and reoxygenation (H/R), we found that Nav1.5 was down-regulated by AMPK-mediated autophagic degradation. Furthermore, AMPK was found to phosphorylate Nav1.5 at threonine (T) 101, which then regulates the interaction between Nav1.5 and the autophagic adaptor protein, microtubule-associated protein 1 light chain 3 (LC3), by exposing the LC3-interacting region adjacent to T101 in Nav1.5. This study highlights an instrumental role of AMPK in mediating the autophagic degradation of Nav1.5 during cardiac I/R injury.-Liu, X., Chen, Z., Han, Z., Liu, Y., Wu, X., Peng, Y., Di, W., Lan, R., Sun, B., Xu, B., Xu, W. AMPK-mediated degradation of Nav1.5 through autophagy.

Sex-specific mortality differences in heart failure patients with ischemia receiving cardiac resynchronization therapy.

BACKGROUND: Recent studies have reported prognosis differences between male and female heart failure patients following cardiac resynchronization therapy (CRT). However, the potential clinical factors that underpin these differences remain to be elucidated. METHODS: A meta-analysis was performed to investigate the factors that characterize sex-specific differences following CRT. This analysis involved searching the Medline (Pubmed source) and Embase databases in the period from January 1980 to September 2016. RESULTS: Fifty-eight studies involving 33445 patients (23.08% of whom were women) were analyzed as part of this study. Only patients receiving CRT with follow-up greater than six months were included in our analysis. Compared with males, females exhibited a reduction of 33% (hazard ratio, 0.67; 95% confidence interval, 0.62-0.73; P < 0.0001) and 42% (hazard ratio, 0.58; 95% confidence interval, 0.46-0.74; P = 0.003) in all-cause mortality and heart failure hospitalization or heart failure, respectively. Following a stratified analysis of all-cause mortality, we observed that ischemic causes (p = 0.03) were likely to account for most of the sex-specific differences in relation to CRT. CONCLUSION: These data suggest that women have a reduced risk of all-cause mortality and heart failure hospitalization or heart failure following CRT. Based on the results from the stratified analysis, we observed more optimal outcomes for females with ischemic heart disease. Thus, ischemia are likely to play a role in sex-related differences associated with CRT in heart failure patients. Further studies are required to determine other indications and the potential mechanisms that might be associated with sex-specific CRT outcomes.

CLOCK-BMAL1 regulate the cardiac L-type calcium channel subunit CACNA1C through PI3K-Akt signaling pathway.

The heterodimerized transcription factors CLOCK-BMAL1 regulate the cardiomyocyte circadian rhythms. The L-type calcium currents play important role in the cardiac electrogenesis and arrhythmogenesis. Whether and how the CLOCK-BMAL1 regulate the cardiac L-type calcium channels are yet to be determined. The functions of the L-type calcium channels were evaluated with patch clamping techniques. Recombinant adenoviruses of CLOCK and BMAL1 were used in the expression experiments. We reported that the expressions and functions of CACNA1C (the α-subunit of the L-type calcium channels) showed circadian rhythms, with the peak at zeitgeber time 3 (ZT3). The endocardial action potential durations 90 (APD90) were correspondingly longer at ZT3. The protein levels of the phosphorylated Akt at threonine 308 (pAkt T308) also showed circadian rhythms. Overexpressions of CLOCK-BMAL1 significantly reduced the levels of CACNA1C while increasing the levels of pAkt T308 and pik3r1. Furthermore, the inhibitory effects of CLOCK-BMAL1 on CACNA1C could be abolished by the Akt inhibitor MK2206 or the PDK1 inhibitor GSK2334470. Collectively, our findings suggested that the expressions of the cardiac CACNA1C were under the CLOCK-BMAL1 regulation, probably through the PI3K-Akt signal pathway.

Hemoptysis due to aspirin treatment alternative to warfarin therapy in a patient with atrial fibrillation.

An 80-year-old female with a history of hypertension and atrial fibrillation had been receiving warfarin anticoagulant therapy and had stably maintained an international normalized ratio (INR) within the 2.0-3.0 range. Due to dental extractions, she was prescribed aspirin (100 mg/day) as an alternative therapy to warfarin. Three days later, the patient complained of hemoptysis without obvious inducement and the INR was 3.51. The aspirin was immediately discontinued and intravenous vitamin K was administered. Hemoptysis did not reappear and the INR returned to the normal limits. According to the Drug Interaction Probability Scale, a causal relationship between aspirin and warfarin and an increased INR value is possible.

Prolonged action potential duration in cardiac ablation of PDK1 mice.

The involvement of the AGC protein kinase family in regulating arrhythmia has drawn considerable attention, but the underlying mechanisms are still not clear. The aim of this study is to explore the role of 3-phosphoinositide-dependent protein kinase-1 (PDK1), one of upstream protein kinases of the AGC protein kinase family, in the pathogenesis of dysregulated electrophysiological basis. PDK1(F/F) αMHC-Cre mice and PDK1(F/F) mice were divided into experiment group and control group. Using patch clamping technology, we explored action potential duration in both groups, and investigated the functions of transient outward potassium channel and L-type Ca(2+) channel to explain the abnormal action potential duration. Significant prolongation action potential duration was found in mice with PDK1 deletion. Further, the peak current of transient outward potassium current and L-type Ca(2+) current were decreased by 84% and 49% respectively. In addition, dysregulation of channel kinetics lead to action potential duration prolongation further. In conclusion, we have demonstrated that PDK1 participates in action potential prolongation in cardiac ablation of PDK1 mice. This effect is likely to be mediated largely through downregulation of transient outward potassium current. These findings indicate the modulation of the PDK1 pathway could provide a new mechanism for abnormal electrophysiological basis.

Deletion of PDK1 causes cardiac sodium current reduction in mice.

BACKGROUND: The AGC protein kinase family regulates multiple cellular functions. 3-phosphoinositide-dependent protein kinase-1 (PDK1) is involved in the pathogenesis of arrhythmia, and its downstream factor, Forkhead box O1 (Foxo1), negatively regulates the expression of the cardiac sodium channel, Nav1.5. Mice are known to die suddenly after PDK1 deletion within 11 weeks, but the underlying electrophysiological bases are unclear. Thus, the aim of this study was to investigate the potential mechanisms between PDK1 signaling pathway and cardiac sodium current. METHODS AND RESULTS: Using patch clamp and western blotting techniques, we investigated the role of the PDK1-Foxo1 pathway in PDK1 knockout mice and cultured cardiomyocytes. We found that PDK1 knockout mice undergo slower heart rate, prolonged QRS and QTc intervals and abnormal conduction within the first few weeks of birth. Furthermore, the peak sodium current is decreased by 33% in cells lacking PDK1. The phosphorylation of Akt (308T) and Foxo1 (24T) and the expression of Nav1.5 in the myocardium of PDK1-knockout mice are decreased, while the nuclear localization of Foxo1 is increased. The role of the PDK1-Foxo1 pathway in regulating Nav1.5 levels and sodium current density was verified using selective PDK1, Akt and Foxo1 inhibitors and isolated neonatal rat cardiomyocytes. CONCLUSION: These results indicate that PDK1 participates in the dysregulation of electrophysiological basis by regulating the PDK1-Foxo1 pathway, which in turn regulates the expression of Nav1.5 and cardiac sodium channel function.

The effects of A-803467 on cardiac Nav1.5 channels.

A-803467 is a selective Nav1.8 blocker, but its mechanism of action at cardiac sodium channels is uncertain. Thus, we investigated the mechanistic effects of A-803467 on cardiac sodium channels in isolated mouse ventricular myocytes and in human embryonic kidney 293 (HEK293) cell lines that transiently expressed Nav1.5/SCN5A, the predominant cardiac sodium channel. At 0.3µM and greater, A-803467 blocked cardiac sodium currents in a dose-dependent manner in both ventricular myocytes and in SCN5A-expressing HEK293 cell lines. In both models, the drug caused significant depolarizing shifts at the conductance voltage relationship midpoint, hyperpolarizing shifts in voltage-dependent channel inactivation, and slower recovery from inactivation. Also, the drug reduced sodium current amplitude in a frequency-dependent manner, and blocked late sodium currents, accelerated inactivation, and enhanced the intermediate inactivation state. Our results provide strong evidence that A-803467 affects multiple biophysical characteristics of the canonical cardiac Nav1.5 channel and our data can be used to study potential applications of A-803467 as an antiarrhythmic drug.

Cardiac ablation of Rheb1 reduces sodium currents in infant mice.

OBJECTIVE: The Ras homolog enriched in brain gene (Rheb) is a center player within the insulin/Rheb/Mammalian Target of Rapamycin (mTOR) pathway, and plays a critical role in regulating cellular growth. Rheb-/- embryos have been reported to die around midgestation, due to the defects of the development of the cardiovascular system. Recent studies from ours and another group consistently showed that Rheb1 was indispensable for the cardiac hypertrophic growth after early postnatal period. Besides that, we also found that Rheb1 a-MHC-Cre (cKO) mice exhibited ventricular tachycardia. However, the precise mechanism by which Rheb1 knockout causes ventricular arrhythmia in these mice is still unclear. METHODS: Mouse cardiomyocytes were isolated using 10 days suckling Rheb1 cKO and wide type mice using Collagenase Type II. Sodium currents and L-type calcium currents were recorded using the whole-cell patch clamping technique. RESULTS: The sodium current density of ventricular cardiomyocytes from Rheb1 cKO mice was decreased by about 60%. Significant left shift but no slope altered was observed in activation curve with V1/2 values of -35.35 ± 1.12 mV for Rheb1 cKO group and -40.72 ± 1.18 mV for the controls. In addition, the area of window current, which refers the overlap of normalized activation and inactivation, was larger in Rheb1 cKO mice. Moreover, the sodium current, in general, was recovered much slower in Rheb1 cKO mice than that of the controls. However, L-type calcium currents were preserved in Rheb1 cKO mice. CONCLUSION: Sodium currents are decreased in Rheb1 cKO mice, which might be responsible for the phenotype of arrhythima in Rheb1 cKO mice. Understanding the molecular composition of sodium ion channel complexes in the heart of these Rheb1 cKO mice will be critical to develop innovative and effective therapies for the treatment of cardiac arrhythmia.

Down-regulation of ATBF1 activates STAT3 signaling via PIAS3 in pacing-induced HL-1 atrial myocytes.

Atrial fibrillation (AF) is progressive and is the most common clinical arrhythmia. It is associated with inflammatory changes characterized by signal transducer and activator of transcription 3 (STAT3) signaling. A zinc finger homeobox 3 (ZFHX3, also named AT-motif binding factor 1, ATBF1) gene variant has been found in patients with AF. However, the mechanism by which the ATBF1 leads to inflammation in AF remains unknown. The aim of this study was to investigate whether tachypacing induces a decrease in ATBF1 expression and then activates STAT3 signaling via protein inhibitor of activated STAT3 (PIAS3). Atrial (HL-1 myocytes) cells were cultured in the presence of rapid electrical stimulations. In tachypaced HL-1 cells, we found that ATBF1 and PIAS3 protein levels were decreased, while the level of phosphorylated STAT3 (p-STAT3) was highly up-regulated compared with that of total STAT3. Knockdown of ATBF1 enhanced this trend, while the overexpression of ATBF1 had the opposite effect. A binary complex of ATBF1 and PIAS3 was formed and then the DNA-binding ability of activated STAT3 was enhanced in tachypaced HL-1 cells. These data indicate that tachypacing decreased ATBF1, leading to enhanced STAT3 DNA-binding activity due to the reduced formation of a binary complex of ATBF1 and PIAS3.

Cardiac ablation of Rheb1 induces impaired heart growth, endoplasmic reticulum-associated apoptosis and heart failure in infant mice.

Ras homologue enriched in brain 1 (Rheb1) plays an important role in a variety of cellular processes. In this study, we investigate the role of Rheb1 in the post-natal heart. We found that deletion of the gene responsible for production of Rheb1 from cardiomyocytes of post-natal mice resulted in malignant arrhythmias, heart failure, and premature death of these mice. In addition, heart growth impairment, aberrant metabolism relative gene expression, and increased cardiomyocyte apoptosis were observed in Rheb1-knockout mice prior to the development of heart failure and arrhythmias. Also, protein kinase B (PKB/Akt) signaling was enhanced in Rheb1-knockout mice, and removal of phosphatase and tensin homolog (Pten) significantly prolonged the survival of Rheb1-knockouts. Furthermore, signaling via the mammalian target of rapamycin complex 1 (mTORC1) was abolished and C/EBP homologous protein (CHOP) and phosphorylation levels of c-Jun N-terminal kinase (JNK) were increased in Rheb1 mutant mice. In conclusion, this study demonstrates that Rheb1 is important for maintaining cardiac function in post-natal mice via regulation of mTORC1 activity and stress on the endoplasmic reticulum. Moreover, activation of Akt signaling helps to improve the survival of mice with advanced heart failure. Thus, this study provides direct evidence that Rheb1 performs multiple important functions in the heart of the post-natal mouse. Enhancing Akt activity improves the survival of infant mice with advanced heart failure.