The protective effect of vagus nerve stimulation against myocardial ischemia/reperfusion injury: pooled review from preclinical studies.

Aims: Myocardial ischemia-reperfusion (I/R) injury markedly undermines the protective benefits of revascularization, contributing to ventricular dysfunction and mortality. Due to complex mechanisms, no efficient ways exist to prevent cardiomyocyte reperfusion damage. Vagus nerve stimulation (VNS) appears as a potential therapeutic intervention to alleviate myocardial I/R injury. Hence, this meta-analysis intends to elucidate the potential cellular and molecular mechanisms underpinning the beneficial impact of VNS, along with its prospective clinical implications. Methods and Results: A literature search of MEDLINE, PubMed, Embase, and Cochrane Database yielded 10 articles that satisfied the inclusion criteria. VNS was significantly correlated with a reduced infarct size following myocardial I/R injury [Weighed mean difference (WMD): 25.24, 95% confidence interval (CI): 32.24 to 18.23, p < 0.001] when compared to the control group. Despite high heterogeneity (I2 = 95.3%, p < 0.001), sensitivity and subgroup analyses corroborated the robust efficacy of VNS in limiting infarct expansion. Moreover, meta-regression failed to identify significant influences of pre-specified covariates (i.e., stimulation type or site, VNS duration, condition, and species) on the primary estimates. Notably, VNS considerably impeded ventricular remodeling and cardiac dysfunction, as evidenced by improved left ventricular ejection fraction (LVEF) (WMD: 10.12, 95% CI: 4.28; 15.97, p = 0.001) and end-diastolic pressure (EDP) (WMD: 5.79, 95% CI: 9.84; -1.74, p = 0.005) during the reperfusion phase. Conclusion: VNS offers a protective role against myocardial I/R injury and emerges as a promising therapeutic strategy for future clinical application.

Discerning the Role of Blood Brain Barrier Dysfunction in Alzheimer's Disease.

Alzheimer's disease (AD) is the most common form of neurodegenerative disease. The predominant characteristics of AD are the accumulation of amyloid-ß (Aß) and hyperphosphorylated tau in the brain. Blood brain barrier (BBB) dysfunction as one of the causative factors of cognitive impairment is increasingly recognized in the last decades. However, the role of BBB dysfunction in AD pathogenesis is still not fully understood. It remains elusive whether BBB dysfunction is a consequence or causative fact of Aß pathology, tau pathology, neuroinflammation, or other conditions. In this review, we summarized the major findings of BBB dysfunction in AD and the reciprocal relationships between BBB dysfunction, Aß pathology, tau pathology, and neuroinflammation. In addition, the implications of BBB dysfunction in AD for delivering therapeutic drugs were presented. Finally, we discussed how to better determine the underlying mechanisms between BBB dysfunction and AD, as well as how to explore new therapies for BBB regulation to treat AD in the future.

Microglial Activation, Tau Pathology, and Neurodegeneration Biomarkers Predict Longitudinal Cognitive Decline in Alzheimer's Disease Continuum.

Purpose: Biomarkers used for predicting longitudinal cognitive change in Alzheimer's disease (AD) continuum are still elusive. Tau pathology, neuroinflammation, and neurodegeneration are the leading candidate predictors. We aimed to determine these three aspects of biomarkers in cerebrospinal fluid (CSF) and plasma to predict longitudinal cognition status using Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. Patients and Methods: A total of 430 subjects including, 96 cognitive normal (CN) with amyloid ß (Aß)-negative, 54 CN with Aß-positive, 195 mild cognitive impairment (MCI) with Aß-positive, and 85 AD with amyloid-positive (Aß-positive are identified by CSF Aß42/Aß40 < 0.138). Aß burden was evaluated by CSF and plasma Aß42/Aß40 ratio; tau pathology was evaluated by CSF and plasma phosphorylated-tau (p-tau181); microglial activation was measured by CSF soluble TREM2 (sTREM2) and progranulin (PGRN); neurodegeneration was measured by CSF and plasma t-tau and structural magnetic resonance imaging (MRI); cognition was examined annually over the subsequent 8 years using the Alzheimer's Disease Assessment Scale Cognition 13-item scale (ADAS13) and Mini-Mental State Exam (MMSE). Linear mixed-effects models (LME) were applied to assess the correlation between biomarkers and longitudinal cognition decline, as well as their effect size on the prediction of longitudinal cognitive decline. Results: Baseline CSF Aß42/Aß40 ratio was decreased in MCI and AD compared to CN, while CSF p-tau181 and t-tau increased. Baseline CSF sTREM2 and PGRN did not show any differences in MCI and AD compared to CN. Baseline brain volumes (including the hippocampal, entorhinal, middle temporal lobe, and whole-brain) decreased in MCI and AD groups. For the longitudinal study, there were significant interaction effects of CSF p-tau181 × time, plasma p-tau181 × time, CSF sTREM2 × time, and brain volumes × time, indicating CSF, and plasma p-tau181, CSF sTREM2, and brain volumes could predict longitudinal cognition deterioration rate. CSF sTREM2, CSF, and plasma p-tau181 had similar medium prediction effects, while brain volumes showed stronger effects in predicting cognition decline. Conclusion: Our study reported that baseline CSF sTREM2, CSF, and plasma p-tau181, as well as structural MRI, could predict longitudinal cognitive decline in subjects with positive AD pathology. Plasma p-tau181 can be used as a relatively noninvasive reliable biomarker for AD longitudinal cognition decline prediction.

Outcome and safety of intracardiac echocardiography guided left atrial appendage closure within zero-fluoroscopy atrial fibrillation ablation procedures.

BACKGROUND: Simultaneous atrial fibrillation (AF) catheter ablation and left atrial appendage closure (LAAC) are sometimes recommended for both rhythm control and stroke prevention. However, the advantages of intracardiac echocardiography (ICE) guidance for this combined procedure have been scarcely reported. We aim to evaluate the clinical outcomes and safety of ICE-guided LAAC within a zero-fluoroscopy catheter ablation procedure. METHODS AND RESULTS: From April 2019 to April 2020, 56 patients with symptomatic AF underwent concomitant catheter ablation and LAAC. ICE with a multi-angled imaging protocol mimicking the TEE echo windows was used to guide LAAC. Successful radiofrequency catheter ablation and LAAC were achieved in all patients. Procedure-related adverse event rate was 3.6%. During the 12-month follow-up, 75.0% of patients became free of arrhythmia recurrences and oral anticoagulants were discontinued in 96.4% of patients. No ischemic stroke occurred despite two cases of device-related thrombosis versus an expected stroke rate of 4.8% based on the CHA2 DS2 -VASc score. The overall major bleeding events rate was 1.8%, which represented a relative reduction of 68% versus an expected bleeding rate of 5.7% based on the HAS-BLED score of the patient cohort. The incidence of iatrogenic atrial septal defect secondary to single transseptal access dropped from 57.9% at 2 months to 4.2% at 12 months TEE follow-up. CONCLUSION: The combination of catheter ablation and LAAC under ICE guidance was safe and effective in AF patients with high stroke risk. ICE with our novel protocol was technically feasible for comprehensive and systematic assessment of device implantation.

Alzheimer's disease susceptibility locus in CD2AP is associated with increased cerebrospinal fluid tau levels in mild cognitive impairment.

INTRODUCTION: Rs9296559 within CD2-associated protein (CD2AP) has been identified as a susceptibility locus for Alzheimer's disease (AD). Recent studies indicated that CD2AP functioned as a regulator of endocytic trafficking to modulate the ß-amyloid (Aß) generation in neurons. Moreover, knockdown of cindr, the Drosophila ortholog of CD2AP, enhanced tau-induced neurodegeneration, implying CD2AP also participated in tau pathology. However, the role of rs9296559 in regulating Aß and tau metabolism in AD was still unclear. METHODS: Here, the associations of rs9296559 with CSF Aß1-42, p-tau, and t-tau were performed using a linear regression model in a total of 543 cognitive normal (CN), mild cognitive impairment (MCI), and AD subjects from the Alzheimer's disease Neuroimaging Initiative (ADNI) cohort. The results were replicated in an independent cohort consisting of 198 Chinese subjects recruited from our hospital. RESULTS: In the ADNI cohort, CC + TC genotypes significantly increased CSF t-tau and p-tau levels in MCI patients but did not alter CSF tau levels in AD. This association was also observed in the replication cohort. Moreover, there was no association between rs9296559 and CSF Aß1-42 level at different disease statuses in the two cohorts. CONCLUSION: Our findings showed that rs9296559 was associated with higher CSF t-tau and p-tau levels in MCI, supporting that CD2AP modified AD risk by altering tau-related neurodegeneration in the early stage of the AD continuum. To the best of our knowledge, this is the first study to evaluate the association between CD2AP genotypes and AD CSF biomarkers.

Assessment of High-Power Catheter Ablation in Patients With Atrial Fibrillation: A Meta-Analysis.

Background: High-power radiofrequency (RF) catheter ablation was considered as a promising alternative strategy to conventional-power ablation in the treatment of patients with atrial fibrillation (AF). This study sought to compare the efficacy and safety of high-power energy delivery to that of conventional-power setting in AF catheter ablation. Methods: We performed a systematic review of relevant literature in Pubmed, Embase, Cochrane library, and Google Scholar database. Sixteen eligible studies totaling 3,307 patients (1,929 for high-power ablation; 1,378 for conventional-power ablation) met inclusion criteria. Results: During a median 12 month follow-up, high-power ablation showed a significantly higher AF/atrial tachycardia-free survival rate in comparison with conventional-power ablation (risk ratio [RR] 1.09, 95% CI 1.02 to 1.15, p = 0.008). Notably, a high-power strategy convincingly decreased the procedure time (weighted mean difference [WMD] -46.11 min, 95% CI -59.15 to -33.07, p < 0.001) and RF ablation time (WMD -19.19 min, 95% CI -24.47 to -13.90, p < 0.001), along with reduced fluoroscopy time (WMD -7.82 min, 95% CI -15.13 to -0.68, p = 0.036). In addition, there was no perceptible difference in the potential risk of procedure-related complications between these two approaches (RR 0.81, 95% CI 0.48 to 1.37, p = 0.428). Conclusions: High-power RF catheter ablation was associated with an improvement in long-term sinus rhythm maintenance for treatment of AF, without exacerbating the risk of adverse events during the procedure. Impressively, high-power pulmonary vein isolation had the potential to shorten the application duration and minimize fluoroscopic exposure.

Optimal Combinations of AT(N) Biomarkers to Determine Longitudinal Cognition in the Alzheimer's Disease.

Background: National Institute on Aging-Alzheimer's Association (NIA-AA) proposed the AT(N) system based on ß-amyloid deposition, pathologic tau, and neurodegeneration, which considered the definition of Alzheimer's disease (AD) as a biological construct. However, the associations between different AT(N) combinations and cognitive progression have been poorly explored systematically. The aim of this study is to compare different AT(N) combinations using recognized biomarkers within the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. Methods: A total of 341 participants were classified into cognitively unimpaired (CU; n = 200) and cognitively impaired (CI; n = 141) groups according to the clinical manifestations and neuropsychological tests. Cerebrospinal fluid (CSF) Aß42 and amyloid-PET ([18F]flutemetamol) were used as biomarkers for A; CSF phosphorylated tau (p-tau) and tau-PET ([18F]flortaucipir) were used as biomarkers for T; CSF total tau (t-tau), hippocampal volume, temporal cortical thickness, [18F]fluorodeoxyglucose (FDG) PET, and plasma neurofilament light (NfL) were used as biomarkers for (N). Binary biomarkers were obtained from the Youden index and publicly available cutoffs. Prevalence of AT(N) categories was compared between different biomarkers within the group using related independent sample non-parametric test. The relationship between AT(N) combinations and 12-year longitudinal cognition was assessed using linear mixed-effects modeling. Results: Among the CU participants, A-T-(N)- was most common. More T+ were detected using p-tau than tau PET (p < 0.05), and more (N)+ were observed using fluid biomarkers (p < 0.001). A+T+(N)+ was more common in the CI group. Tau PET combined with cortical thickness best predicted cognitive changes in the CI group and MRI predicted changes in the CU group. Conclusions: These findings suggest that optimal AT(N) combinations to determine longitudinal cognition differ by cognitive status. Different biomarkers within a specific component for defining AT(N) cannot be used identically. Furthermore, different strategies for discontinuous biomarkers will be an important area for future studies.

Platelet-rich plasma regulating the repair of ultraviolet B-induced acute tissue inflammation: adjusting macrophage polarization through the activin receptor-follistatin system.

Ultraviolet B (UVB) is one of the most common exogenous factors in skin aging, especially photoaging. Once a large amount of UVB accumulates within a short period of time, skin tissue can become inflamed. It has also been found in clinics that platelet-rich plasma (PRP) can promote wound repair; therefore, the aim of this study was to identify the mechanism by which PRP repairs UVB-induced skin photodamage. We used PRP of Sprague-Dawley rats with the two-spin technique in the established acute UVB radiation photodamage model and harvested the corresponding skin after 1, 7, and 28 d. Hematoxylin and eosin staining was used to observe tissue inflammation. We found that PRP reduces inflammation in the early stages of UVB-induced acute skin damage, and then promotes the proliferation of collagen in the middle and late stages. Moreover, PRP can stimulate Act A and M1 polarization in the early stage, while inhibiting activin A (Act A) and inducing M2 polarization in the middle and late stages. In conclusion, this study demonstrates that PRP plays an important regulatory role in helping reduce UVB-induced acute skin tissue inflammation by adjusting macrophage polarization, which alleviates skin inflammation and stimulates collagen regeneration.

The role of P2X7R in neuroinflammation and implications in Alzheimer's disease.

Alzheimer's disease (AD) is the most common cause of dementia and is set to rise in prevalence as the global trends in population aging. The extracellular deposition of amyloid protein (Aß) and the intracellular formation of neurofibrillary tangles in the brain have been recognized as the two core pathologies of AD. Over the past decades, the presence of neuroinflammation in the brain has been documented as the third core pathology of AD. In recent years, emerging evidence demonstrated that the purinergic receptor P2X7 (P2X7R) serves a critical role in microglia responses and neuroinflammation. Besides, targeting P2X7R by genetic or pharmacological strategies attenuates the symptoms and pathological changes of AD models, and P2X7R has been recognized as a promising therapeutic target for AD. In this review, we summarized the recent evidence concerning the roles of P2X7R in neuroinflammation and implications in AD pathogenesis.

Serum human epididymis protein 4 levels in the prediction of the recurrence of atrial fibrillation after catheter ablation.

The aim of this study is to assess serum human epididymis protein 4 (HE-4) levels as a biomarker for predicting the recurrence of atrial fibrillation (AF) after catheter ablation. This was a prospective observational study that enrolled one hundred eighty-four consecutive nonvalvular AF patients (65 persistent, 119 paroxysmal) who were eligible for their first ablation. Multiple Cox proportional hazards models and Kaplan-Meier curve analyses were used to test the association between serum HE-4 levels and AF recurrence after catheter ablation. During the 12-month follow-up, we observed that 47 patients (25.5%) experienced AF recurrence. Patients were divided into tertiles of HE-4 level (T1: < 50 pmol/L; T2: ≥ 50 pmol/L). The AF recurrence rate of higher serum HE-4 level patients was significantly increased (34.6% vs 13.8%, P < 0.001). Generalized additive models were used to visually assess functional relationships between the serum HE-4 levels and the risk of AF recurrence. When stratified with serum levels as the cut-off value, Kaplan-Meier analysis showed that patients with serum HE-4 levels (> 50 pmol/L) had a significantly increased risk of AF recurrence. In addition, multivariate Cox proportional hazard modelling revealed that HE-4 (≥ 50 pmol/L) (HR 2.65; 95% CI 1.34, 5.27, P = 0.005) was independent predictors of AF recurrence. Serum HE-4 levels in patients with AF are associated with postoperative recurrence of AF, and high HE-4 levels are an independent predictor of AF recurrence after ablation.

Melatonin against Myocardial Ischemia-Reperfusion Injury: A Meta-analysis and Mechanism Insight from Animal Studies.

AIMS: Myocardial reperfusion damage after severe ischemia was an important issue during a clinical practice. However, the exacted pathogenesis involved remained unclear and also lacks effective interventions. Melatonin was identified to exert protective effects for alleviating the myocardial I/R injury. This meta-analysis was determined to evaluate the efficacy of melatonin treatment against reperfusion insult and further summarize potential molecular and cellular mechanisms. METHODS AND RESULTS: 15 eligible studies with 211 animals (108 received melatonin and 103 received vehicle) were included after searching the databases of PubMed, MEDLINE, Embase, and Cochrane. Pretreatment with melatonin was associated with a significant lower infarct size in comparison with vehicle in myocardial I/R damage (WMD: -20.45, 95% CI: -25.43 to -15.47, p < 0.001; I 2 = 91.4%, p < 0.001). Evidence from subgroup analyses and sensitivity analysis indicated the robust and consistent cardioprotective effect of melatonin, while the metaregression also did not unmask any significant interactions between the pooled estimates and covariates (i.e., sample size, state, species, study type, route of administration, and duration of reperfusion, along with timing regimen of pretreatment). Accordingly, melatonin evidently increased EF (WMD: 17.19, 95% CI: 11.08 to 23.29, p < 0.001; I 2 = 77.0%, p < 0.001) and FS (WMD: 14.18, 95% CI: 11.22 to 17.15, p < 0.001; I 2 = 3.5%, p = 0.387) in the setting of reperfusion damage. CONCLUSIONS: Melatonin preadministration conferred a profound cardioprotection against myocardial I/R injury in preclinical studies.

Protective role of silibinin against myocardial ischemia/reperfusion injury-induced cardiac dysfunction.

Silibinin is a traditional medicine and utilized for liver protection with antioxidant, anti-inflammation and anti-apoptosis properties. However, its role in myocardial I/R injury and the mechanism involved is currently unknown. In the present study, Silibinin treatment improves cardiac function and limits infarct size, and subsequently inhibits fibrotic remodeling in mice with myocardial I/R injury. Mechanistically, silibinin reduces cardiomyocytes apoptosis, attenuates mitochondrial impairment and endoplasmic reticulum (ER) stress, alleviates ROS generation, neutrophil infiltration and cytokines release. Consistently, silibinin prevents H9C2 cells from hypoxia/reperfusion-induced cell death, oxidative stress and inflammation in vitro. Furthermore, H9C2 cells treated with silibinin blocks NF-κB signaling activation by inhibiting IKKα phosphorylation, IκBα degradation and p65 NF-κB nuclear translocation during hypoxia/ reperfusion. In addition, silibinin plus BAY 11-7082 (a selected NF-κB inhibitor) do not provide incremental benefits in improving myocytes apoptosis, oxidative stress and inflammation in comparison with NF-κB signaling inhibition only. Thus, silibinin-mediated cardioprotection in myocardial I/R injury is associated with decreased apoptosis, oxidative stress and inflammatory response through deactivation of NF-κB pathway.

Efficacy and Safety of Adjunctive Substrate Modification During Pulmonary Vein Isolation for Atrial Fibrillation: A Meta-Analysis.

BACKGROUND: The efficacy and safety of adjuvant substrate modification (SM; either linear ablation [LA] or complex fractionated atrial electrogram [CFAE] ablation) in addition to pulmonary vein isolation (PVI) for the treatment of symptomatic, drug-refractory atrial fibrillation (AF), have still not been clarified and need further assessment. METHOD: We systematically searched the PubMed, MEDLINE, and Cochrane databases for studies comparing PVI with adjunctive SM versus PVI alone for treatment of drug-refractory AF. RESULTS: Twenty-six (26) studies including 3,409 patients (1,975 PVI + SM; 1,434 PVI alone) were included for further analysis. Atrial fibrillation/atrial tachycardia-free survival of patients with PVI + SM was comparable with that of PVI alone (relative risk [RR], 1.06; 95% confidence interval [CI], 0.98-1.14; p = 0.143). In line with this, the primary clinical outcomes were robust, irrespective of additional LA (RR, 1.07; 95% CI, 0.97-1.18; p = 0.194) or CFAE ablation (RR, 1.04; 95% CI, 0.93-1.16; p = 0.534). Adjuvant SM is associated with longer procedural time (weighted mean difference, 20.72; 95% CI, 10.25-31.20; p = 0.0) and fluoroscopy time (weighted mean difference, 6.66; 95% CI, 1.74-11.58; p = 0.000); surprisingly, it presented similar procedure-related complications as PVI alone during AF catheter ablation (RR, 1.01; 95% CI, 0.68-1.50; p = 0.946). CONCLUSIONS: Adjuvant LA or CFAE ablation do not provide incremental benefit over PVI alone. Although substrate-based ablation markedly prolonged procedural and fluoroscopic duration, there was no evidence of increased risk of procedure-related complications.

Young Patients with Unknown Stroke and Little P Wave in ECG.

Here we report two young patients with atrial fibrillation/atrial flutter complicated with cardiogenic cerebral embolism. Electrophysiological study revealed a large area of low-voltage zone or area of electric silence in both sides of the atrium during restoration of sinus rhythm, and the echocardiogram showed loss of mechanical function of the atrium. The electrical-mechanical dysfunction of the atrium was considered to be the cause of embolic event in this type of patient who was "very low" stroke risk atrial fibrillation or atrial flutter. The idiopathic, fibrotic atrial cardiomyopathy may be underlying in these patients.

A Meta-Analysis of Resveratrol Protects against Myocardial Ischemia/Reperfusion Injury: Evidence from Small Animal Studies and Insight into Molecular Mechanisms.

AIMS: Myocardial ischemia/reperfusion (I/R) injury is a leading cause of cardiomyocyte loss and subsequent ventricular dysfunction after restoring the coronary blood flow and contributes to considerable increase in morbidity and mortality. Resveratrol has been declared to confer cardioprotection against in vivo and ex vivo myocardial I/R injury. Here, we have sought to investigate the effects of preconditioning with resveratrol on myocardial I/R damage across the small animal studies. METHODS AND RESULTS: The MEDLINE, Google Scholar, PubMed, and Cochrane databases were searched for preclinical studies investigating resveratrol vs. vehicle published from the inception to July 2018. Eventually, 10 in vivo and 7 ex vivo studies with 261 animals (130 for resveratrol; 131 for vehicle) were included for meta-analysis. Pooled estimates for primary outcomes demonstrated that pretreatment with resveratrol significantly reduced the infarct size after myocardial I/R injury irrespective of in vivo (weighted mean difference (WMD): -13.42, 95% CI: -16.63 to -10.21, P ≤ 0.001) or ex vivo (WMD: -15.05, 95% CI: -18.23 to -11.86, P ≤ 0.001) studies. Consistently, stratified analysis according to the reperfusion duration, route of administration, or timing regimen of pretreatment all showed the infarct-sparing benefit of resveratrol. Metaregression did not indicate any difference in infarct size based on species, sample size, state, route of administration, reperfusion duration, and timing regimen of pretreatment. Meanwhile, sensitivity analysis also identified the cardioprotection of resveratrol with robust results in spite of significant heterogeneity. CONCLUSIONS: Preconditioning with resveratrol appears to prevent the heart from I/R injury in comparison with vehicle, as evidenced by limited infarct size in a preclinical setting. Studies with large animals or randomized controlled trials will add more evidence and provide the rationale for clinical use.

Islet transplantation attenuates cardiac fibrosis in diabetic rats through inhibition of TGF-ß1/Smad3 pathway.

Although islet transplantation has been identified as a promising endocrine replacement treatment for patient with diabetes mellitus (DM), it still remains unclear whether islet transplantation can inhibit the diabetic-induced myocardial injury and subsequent adverse ventricular remodeling. Here, we sought to explore the molecular mechanism underlying the cardioprotective effect of islet transplantation. We established the diabetic rat model by intraperitoneal injection of STZ, which was followed by either islet transplantation or conventional insulin treatment. Compared with insulin treatment, islet transplantation further reduced the elevated blood glucose which was nearly restored to normoglycaemia. In addition, islet transplantation attenuated the increased levels of cTn-I and CK-MB, cleaved-caspase-3 in response to DM, and ameliorated diabetic-induced cardiac hypertrophy and interstitial fibrosis, along with improved extracellular matrix (ECM) deposition. Moreover, diabetic rats that underwent islet transplantation had lower expression of TGF-ß1 and lower phosphorylation levels of Smad3. Therefore, islet transplantation exerted protective effect against diabetic-induced myocardial injury and fibrotic remodeling through deactivation of TGF-ß1/Smad3 signaling pathway.

The transient receptor potential melastatin 4 channel inhibitor 9-phenanthrol modulates cardiac sodium channel.

BACKGROUND AND PURPOSE: 9-Phenanthrol, known as a specific inhibitor of the transient receptor potential melastatin 4 (TRMP4) channel, has been shown to modulate cardiac electrical activity and exert antiarrhythmic effects. However, its pharmacological effects remain to be fully explored. Here, we tested the hypothesis that cardiac sodium current inhibition contributes to the cardioprotective effect of 9-phenanthrol. EXPERIMENTAL APPROACH: Single ventricular myocytes (VMs) and Purkinje cells (PCs) were enzymatically isolated from rabbits. Arterially perfused rabbit wedge preparations were also used, and transmural electrocardiogram and endocardial action potentials (APs) were simultaneously recorded. Wild-type and mutated human recombinant SCN5A were expressed in HEK293 cells. Anemonia toxin II (ATX-II) was used to amplify the late sodium current (INaL ) and induce arrhythmias. Whole-cell patch clamp technique was used to record APs and ionic currents. KEY RESULTS: 9-Phenanthrol (10-50 µM) stabilized ventricular repolarization and abolished arrhythmias induced by ATX-II in both isolated VMs, PCs and wedge preparations. Further study revealed that 9-phenanthrol modulated the gating properties of cardiac sodium channels and dose-dependently inhibited INaL and peak sodium current (INaP ) in VMs with an IC50 of 18 and 71.5 µM respectively. Its ability to inhibit INaL was further confirmed in PCs and HEK293 cells expressing SCN5A mutations. CONCLUSIONS AND IMPLICATIONS: Our results indicate that 9-phenanthrol modulates the gating properties of cardiac sodium channels and inhibits INaL and INaP , which may contribute to its antiarrhythmic and cardioprotective effects.

ICaL and Ito mediate rate-dependent repolarization in rabbit atrial myocytes

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

ICaL and Ito mediate rate-dependent repolarization in rabbit atrial myocytes.

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.