Blocking NaV1.8 regulates atrial fibrillation inducibility and cardiac conduction after myocardial infarction.

BACKGROUND: The role of NaV1.8 impacts in atrial fibrillation susceptibility after myocardial infarction remains only partially understood. We studied the effect of blocking NaV1.8 in the cardiac ganglionated plexi (GP) on the atrial fibrillation inducibility and cardiac conduction in the myocardial infarction model. METHODS: Eighteen male beagles were randomly enrolled. Left anterior descending coronary artery was ligated to created myocardial infarction model. Four weeks after surgery, NaV1.8 blocker A-803,467 (n = 9) or DMSO (n = 9, control) was injected into the four cardiac major GPs. Sinus rate, ventricular rate during atrial fibrillation, PR interval, atrial effective refractory period, atrial fibrillation duration and the cumulative window of atrial vulnerability were measured before and 60 min after A-803,467 injection. RESULTS: Administration of A-803,467 significantly increased sinus rate, shortened PR interval and increased ventricular rate during atrial fibrillation compared to control. A-803,467 also significantly shortened atrial effective refractory period, prolonged atrial fibrillation duration and increased the cumulative window of atrial vulnerability. A-803,467 suppressed the slowing of heart rate response to high-frequency electrical stimulation of the anterior right GP, which was used as the surrogate marker for GP function. Double staining of ChAT and NaV1.8 demonstrated colocalization of ChAT and NaV1.8 in canine GPs. CONCLUSIONS: Blocking NaV1.8 in the cardiac GP may modulate atrial fibrillation inducibility and cardiac conduction after myocardial infarction, and the underlying mechanism may be associated with the regulation of the neural activity of the cardiac GP.

Ablation for atrial fibrillation improves the outcomes in patients with heart failure with preserved ejection fraction.

AIMS: Patients with heart failure with preserved ejection fraction (HFpEF) and atrial fibrillation (AF) have worse clinical outcomes than those with sinus rhythm (SR). We aim to investigate whether maintaining SR in patients with HFpEF through a strategy such as AF ablation would improve outcomes. METHODS AND RESULTS: This is a cohort study that analysed 1034 patients (median age 69 [63-76] years, 46.2% [478/1034] female) with HFpEF and AF. Of these, 392 patients who underwent first-time AF ablation were assigned to the ablation group, and the remaining 642 patients, who received only medical therapy, were assigned to the no ablation group. The primary endpoint was a composite of all-cause death or rehospitalization for worsening heart failure. After a median follow-up of 39 months, the cumulative incidence of the primary endpoint was significantly lower in the ablation group compared to the no ablation group (adjusted hazard ratio [HR], 0.55 [95% CI, 0.37-0.82], P = 0.003) in the propensity score-matched model. Secondary endpoint analysis showed that the benefit of AF ablation was mainly driven by a reduction in rehospitalization for worsening heart failure (adjusted HR, 0.52 [95% CI, 0.34-0.80], P = 0.003). Patients in the ablation group showed a 33% relative decrease in atrial tachycardia/AF recurrence compared to the no ablation group (adjusted HR, 0.67 [95% CI, 0.54-0.84], P < 0.001). CONCLUSION: Among patients with HFpEF and AF, the strategy of AF ablation to maintain SR was associated with a lower risk of the composite outcome of all-cause death or rehospitalization for worsening heart failure.

Circular RNA Ttc3 regulates cardiac function after myocardial infarction by sponging miR-15b.

The apoptotic death of cardiomyocytes critically contributes to cardiac remodeling after myocardial infarction (MI). Circular RNAs (circRNAs) are important regulators for a variety of biological functions. Circ-Ttc3 represents one of the top highest expressed circRNAs in the heart; however, its role in MI remains unknown. Herein, we found that circ-Ttc3 was markedly upregulated in the ischemic myocardium and the cardiomyocytes subjected to hypoxic insult. Forced expression of circ-Ttc3 in cardiomyocytes counteracted hypoxia-induced ATP depletion and apoptotic death, in sharp contrast to circ-Ttc3 knockdown. Accordingly, experiments with AAV9-cTnt-mediated knockdown of cardiac circ-Ttc3 in a rat model of MI recapitulated the in vitro findings, and showed the deterioration of cardiac dysfunction after MI. Furthermore, we identified that circ-Ttc3 sponged an endogenous miR-15b-5p to sequester and inhibit its activity, leading to the increased Arl2 expression. Conversely, knockdown of Arl2 partially abolished the beneficial effects of circ-Ttc3 overexpression on ATP production and apoptosis of cardiomyocytes. Thus, our findings revealed the cardioprotective role of circ-Ttc3 in MI. The miR-15b-Arl2 regulatory cascade underlies the protection against MI-induced cardiomyocyte apoptosis by circ-Ttc3.

MicroRNA-30c suppresses the pro-fibrogenic effects of cardiac fibroblasts induced by TGF-ß1 and prevents atrial fibrosis by targeting TGFßRII.

Atrial fibrosis serves as an important contributor to atrial fibrillation (AF). Recent data have suggested that microRNA-30c (miR-30c) is involved in fibrotic remodelling and cancer development, but the specific role of miR-30c in atrial fibrosis remains unclear. The purpose of this study was to investigate the role of miR-30c in atrial fibrosis and its underlying mechanisms through in vivo and in vitro experiments. Our results indicate that miR-30c is significantly down-regulated in the rat abdominal aortic constriction (AAC) model and in the cellular model of fibrosis induced by transforming growth factor-ß1 (TGF-ß1). Overexpression of miR-30c in cardiac fibroblasts (CFs) markedly inhibits CF proliferation, differentiation, migration and collagen production, whereas decrease in miR-30c leads to the opposite results. Moreover, we identified TGFßRII as a target of miR-30c. Finally, transferring adeno-associated virus 9 (AAV9)-miR-30c into the inferior vena cava of rats attenuated fibrosis in the left atrium following AAC. These data indicate that miR-30c attenuates atrial fibrosis via inhibition of CF proliferation, differentiation, migration and collagen production by targeting TGFßRII, suggesting that miR-30c might be a novel potential therapeutic target for preventing atrial fibrosis.

The Role of Angle in the Evaluation of Ablation Accuracy in Pulmonary Vein Isolation Navigated by Image Integration.

BACKGROUND: The conventional index for ablation accuracy is to compare the distance between mapping points with and without treatment by using image integration. We attempted to quantitatively evaluate the role of angle as an index in the ablation accuracy in patients with atrial fibrillation (AF). METHODS: A total of 48 patients with AF were included in the present study. Virtual fluoroscopy planes were predicted by pulmonary vein (PV) angiography, and the standard image planes were defined on the basis of the computed tomography images. Ablations were performed, guided by image integration; and the ablation planes were defined by the actual ablation rings. The predicted angle (distance) was defined as the angle (distance) between the fluoroscopy (predicted) plane and image (standard) plane, whereas the actual angle (distance) was defined as the angle (distance) between the ablation (actual) planes and the image (standard) planes. RESULTS: We found that all actual angles were significantly smaller than the predicted angles (P <.05), but only the actual distances in the left PV, right inferior PV, right superior PV, and right PV were significantly smaller; the distances in the left inferior PV and left superior PV were not significantly different (P >.05). CONCLUSION: Our finding indicates that both the angle and the distance can be significantly reduced by navigation with image integration, but that the angle exhibited better sensitivity than the conventional index of distance. We suggest that the angle should be considered as a new index for ablation accuracy.

Accuracy and efficiency stereo matching network with adaptive feature modulation.

Feature enhancement plays a crucial role in improving the quality and discriminative power of features used in matching tasks. By enhancing the informative and invariant aspects of features, the matching process becomes more robust and reliable, enabling accurate predictions even in challenging scenarios, such as occlusion and reflection in stereo matching. In this paper, we propose an end-to-end dual-dimension feature modulation network called DFMNet to address the issue of mismatches in interference areas. DFMNet utilizes dual-dimension feature modulation (DFM) to capture spatial and channel information separately. This approach enables the adaptive combination of local features with more extensive contextual information, resulting in an enhanced feature representation that is more effective in dealing with challenging scenarios. Additionally, we introduce the concept of cost filter volume (CFV) by utilizing guide weights derived from group-wise correlation. CFV aids in filtering the concatenated volume adaptively, effectively discarding redundant information, and further improving matching accuracy. To enable real-time performance, we designed a fast version named Fast-GFM. Fast-GFM employs the global feature modulation (GFM) block to enhance the feature expression ability, improving the accuracy and stereo matching robustness. The accurate DFMNet and the real-time Fast-GFM achieve state-of-the-art performance across multiple benchmarks, including Scene Flow, KITTI, ETH3D, and Middlebury. These results demonstrate the effectiveness of our proposed methods in enhancing feature representation and significantly improving matching accuracy in various stereo matching scenarios.

Local ischemic postconditioning during primary percutaneous coronary intervention: a meta-analysis.

OBJECTIVES: To investigate current evidence linking ischemic postconditioning (IPC) to cardioprotection in patients receiving primary percutaneous coronary intervention (PCI). METHODS: We performed searches of PubMed, Embase, MEDLINE and Cochrane databases from January 1998 to May 2011 for identifying relevant studies comparing IPC with usual care in patients undergoing primary PCI. A meta-analysis of eligible studies was assessed by Review Manager 5.0. RESULTS: Thirteen studies were eligible. Compared to the control, observed outcomes such as peak creatine kinase [weighted mean difference (WMD) -537.48, 95% confidence interval (CI) -779.32 to -295.65 IU/l], peak creatine kinase-myocardial band (WMD -61.11, 95% CI -76.56 to -45.66 U/l), complete ST-segment resolution (risk ratio 1.38, 95% CI 1.07 to 1.77), blush grade during reflow (WMD 0.64, 95% CI 0.49 to 0.78), corrected TIMI frame count, single-photon emission computed tomography determining infarct size, long-term left ventricular ejection fraction and short-term and long-term wall motion score indexes were improved in IPC group, with less occurrence of heart failure during the 3-month to 3.4-year follow-up. CONCLUSIONS: Though current evidence indicates that IPC provides potential cardioprotection to patients receiving primary PCI, larger adequately powered studies should be undertaken to confirm its advantages.

Inferior Vena Cava as a Trigger for Paroxysmal Atrial Fibrillation: Incidence, Characteristics, and Implications.

BACKGROUND: Identifying nonpulmonary vein triggers during atrial fibrillation (AF) ablation is of great importance. Currently, there are limited data on AF triggered by the inferior vena cava (IVC). OBJECTIVES: This study was performed to investigate the incidence, characteristics, and implications of IVC triggers for AF. METHODS: A total of 661 patients who underwent initial paroxysmal AF ablation were included. After pulmonary vein isolation, ectopic beats that triggered AF were further studied. Activation mapping and angiography were performed to confirm the location of ectopic origin. Electrocardiographic analysis of the ectopic P-wave (P'-wave) was performed. RESULTS: Six patients (0.91%) with AF triggered by the IVC were confirmed. The mean distance from the earliest activation site to the IVC ostium was 6.8 ± 2.5 mm (5.2 to 11.2 mm). Furthermore, the arrhythmogenic foci within the IVC were all located at the apical hemisphere of the IVC (3 at the septal side and 3 at the anterior side). A total of 2.3 ± 0.5 applications of radiofrequency energy were delivered to eliminate IVC triggers. The mean duration of the P' wave was 91.2 ± 11.2 milliseconds (81 to 108 milliseconds), which was narrower than that of the sinus P-wave (115.2 ± 19.3 milliseconds [87 to 139 milliseconds]; P = 0.002). Moreover, the configuration of all P' waves in the inferior leads was negative. During a mean follow-up period of 25.5 ± 7.3 months, all 6 patients remained arrhythmia free without antiarrhythmic drugs. CONCLUSIONS: IVC trigger, a rare but latent source of paroxysmal AF, could be identified and safely eliminated by focal radiofrequency ablation. Ectopic beats originating from the IVC presented with narrow P'-wave duration and negative P' waves in all inferior leads.

Blockade of NaV1.8 Increases the Susceptibility to Ventricular Arrhythmias During Acute Myocardial Infarction.

SCN10A/NaV1.8 may be associated with a lower risk of ventricular fibrillation in the setting of acute myocardial infarction (AMI), but if and by which mechanism NaV1.8 impacts on ventricular electrophysiology is still a matter of debate. The purpose of this study was to elucidate the contribution of NaV1.8 in ganglionated plexi (GP) to ventricular arrhythmias in the AMI model. Twenty beagles were randomized to either the A-803467 group (n = 10) or the control group (n = 10). NaV1.8 blocker (A-803467, 1 µmol/0.5 mL per GP) or DMSO (0.5 mL per GP) was injected into four major GPs. Ventricular effective refractory period, APD90, ventricular fibrillation threshold, and the incidence of ventricular arrhythmias were measured 1 h after left anterior descending coronary artery occlusion. A-803467 significantly shortened ventricular effective refractory period, APD90, and ventricular fibrillation threshold compared to control. In the A-803467 group, the incidence of ventricular arrhythmias was significantly higher compared to control. A-803467 suppressed the slowing of heart rate response to high-frequency electrical stimulation of the anterior right GP, suggesting that A-803467 could inhibit GP activity. SCN10A/NaV1.8 was readily detected in GPs, but was not validated in ventricles by quantitative RT-PCR, western blot and immunohistochemistry. While SCN10A/NaV1.8 is detectible in canine GPs but not in ventricles, blockade of NaV1.8 in GP increases the incidence of ventricular arrhythmias in AMI hearts. Our study shows for the first time an influence of SCN10A/NaV1.8 on the regulation of ventricular arrhythmogenesis via modulating GP activity in the AMI model.

Association of Small Intestinal Bacterial Overgrowth With Heart Failure and Its Prediction for Short-Term Outcomes.

Background Small intestinal bacterial overgrowth (SIBO) is a common pathological condition of intestinal microbiota. The prevalence of SIBO and its prognostic value in patients with heart failure (HF) are unknown. Methods and Results A total of 287 patients tested for SIBO using lactulose hydrogen-methane breath test were evaluated. At least 1 of the following criteria fulfilled was SIBO positive: patients with fasting hydrogen level ≥20 parts per million (ppm) or a ≥20 ppm rise in hydrogen by 90 minutes were diagnosed with SIBO (H2) positive; and patients with methane levels ≥10 ppm at any test point were diagnosed with SIBO (CH4) positive. The association between SIBO and the composite of cardiovascular death and HF rehospitalization was investigated. In 287 consecutive patients with HF, 128 (45%) were positive for SIBO. Our result showed SIBO increased the risk of HF rehospitalization in patients with HF with reduced ejection fraction (P<0.001), and the risk of cardiovascular death in patients with HF with preserved EF (P=0.011). SIBO was an independent risk factor of primary end point in patients with HF (hazard ratio [HR], 2.13; 95% CI; 1.26-3.58; P=0.005). In addition, SIBO (CH4) showed a prognostic value on adverse outcomes (HR, 2.35; 95% CI, 1.38-4.02; P<0.001), whereas the association between SIBO (H2) and outcomes was not statistically significant. Conclusions There was high prevalence of SIBO in patients with HF, and SIBO was independently associated with poor outcomes. Proactive treatment for SIBO may provide extra benefit for patients with HF.

Activated CD4+ T cells-derived exosomal miR-142-3p boosts post-ischemic ventricular remodeling by activating myofibroblast.

Cardiac fibrosis is a primary phenotype of cardiac remodeling that contributes to cardiac dysfunction and heart failure. The expansion and activation of CD4+ T cells in the heart has been identified to facilitate pathological cardiac remodeling and dysfunction; however, the underlying mechanisms remained not well clarified. Herein, we found that exosomes derived from activated CD4+ T cells (CD4-activated Exos) evoked pro-fibrotic effects of cardiac fibroblasts, and their delivery into the heart aggravated cardiac fibrosis and dysfunction post-infarction. Mechanistically, miR-142-3p that was enriched in CD4-activated Exos recapitulated the pro-fibrotic effects of CD4-activated Exos in cardiac fibroblasts, and vice versa. Furthermore, miR-142-3p directly targeted and inhibited the expression of Adenomatous Polyposis Coli (APC), a negative WNT signaling pathway regulator, contributing to the activation of WNT signaling pathway and cardiac fibroblast activation. Thus, CD4-activated Exos promote post-ischemic cardiac fibrosis through exosomal miR-142-3p-WNT signaling cascade-mediated activation of myofibroblasts. Targeting miR-142-3p in CD4-activated Exos may hold promise for treating cardiac remodeling post-MI.

Association of SCN10A Polymorphisms with the Recurrence of Atrial Fibrillation after Catheter Ablation in a Chinese Han Population.

The nonsynonymous SCN10A single nucleotide polymorphism (SNP) rs6795970 has been reported to associate with PR interval and atrial fibrillation (AF) and in strong linkage disequilibrium (LD) with the AF-associated SNP rs6800541. In this study, we investigated whether rs6795970 polymorphisms are associated with AF recurrence after catheter ablation. A total of 502 consecutive patients with AF who underwent catheter ablation were included. AF recurrence was defined as a documented episode of any atrial arrhythmias lasting ≥30 s after a blanking period of 3 months. AF recurrence was observed between 3 and 12 months after catheter ablation in 24.5% of the patients. There was a significant difference in the allele distribution (p = 7.86 × 10-5) and genotype distribution (p = 1.42 × 10-5) of rs6795970 between the AF recurrence and no recurrence groups. In a multivariate analysis, we identified the following independent predictors of AF recurrence: the rs6795970 genotypes in an additive model (OR 0.36, 95%CI 0.22~0.60, p = 7.04 × 10-5), a history of AF ≥36 months (OR 3.57, 95%CI 2.26~5.63, p = 4.33 × 10-8) and left atrial diameter (LAD) ≥40 mm (OR 1.85, 95%CI 1.08~3.19, p = 0.026). These data suggest that genetic variation in SCN10A may play an important role in predicting AF recurrence after catheter ablation in the Chinese Han population.

Common variants predict recurrence after nonfamilial atrial fibrillation ablation in Chinese Han population.

BACKGROUND: Genome-wide association studies (GWAS) have identified several loci associated with atrial fibrillation (AF) and have been reportedly associated with response to catheter ablation for AF in patients of European ancestry; however, associations between susceptibility loci and clinical recurrence of AF after catheter ablation have not been examined in Chinese Han populations. To the personalization of catheter ablation for AF, we examined whether these single nucleotide polymorphisms (SNPs) can predict clinical outcomes after catheter ablation for AF in Chinese Han population. METHODS AND RESULTS: The association between 8 SNPs and AF was studied in 1418 AF patients and 1424 controls by the unconditional logistic regression analysis. The survival analyses were used to compare AT/AF recurrence differences among 438 AF patients, which were classified by the genotype of rs2200733. rs2200733 and rs6590357 were significantly associated with AF in Chinese Han population. In addition, rs2200733 was associated with clinical recurrence of AF after catheter ablation. In Kaplan-Meier survival analysis, the recurrence-free rates for AF with TT and with TC+CC were 35.5% and 61.9%, respectively (P=0.0009). In multivariate Cox regression analysis, rs2200733 was strong independent risk factor for recurrence. CONCLUSION: rs2200733 risk allele at the 4q25 predicted impaired clinical response to catheter ablation for AF in Chinese Han population. Our findings suggested rs2200733 polymorphism may be used as a clinical tool for selection of patients for AF catheter ablation.

Clinical implications of and factors influencing dissociated pulmonary vein potentials.

BACKGROUND: Factors influencing dissociated pulmonary vein (PV) potentials (DPVPs) in atrial fibrillation (AF) patients undergoing circumferential PV isolation have not been investigated. Furthermore, the clinical implications of such DPVPs remain controversial. METHODS: Circumferential PV isolation as a first ablation procedure was performed in 688 consecutive patients with AF (460 men; mean age, 58.9±10.5 years). The clinical implications of and factors influencing DPVPs were evaluated. RESULTS: Acute PV isolation was achieved in 679 (98.7%) patients. A total of 578 (42.6%) ipsilateral PVs with DPVPs were documented in 378 (55.7%) patients (DPVPs group). Multivariate analysis revealed that male gender [odds ratio (OR): 1.894; 95% confidence interval (CI): 1.344-2.667; p<0.001] and paroxysmal AF (OR: 1.715; 95% CI: 1.182-2.488; p=0.005) were independent factors for DPVPs. The incidence of acute and intraoperative PV reconnection (PVR) was higher in the DPVPs group than in the non-DPVPs group (33.1% vs. 17.9%; p<0.001 and 44.4% vs. 28.2%; p<0.001). After the first procedure, 244 (65.6%) DPVPs-group patients and 168 (56.4%; p=0.015) non-DPVPs group patients were free from AF recurrence. During repeat procedures, PVR incidence was similar in the DPVPs group (81.8%) and non-DPVPs groups (83.3%; p=0.863). CONCLUSION: Male gender and paroxysmal AF were independent risk factors for DPVPs in patients undergoing circumferential PV isolation. DPVPs had a significant impact on acute and intraoperative PVR. The outcomes of the first ablation procedure were better in patients with DPVPs.

Polymorphisms of renin-angiotensin-aldosterone system gene in chinese han patients with nonfamilial atrial fibrillation.

BACKGROUND: Atrial fibrillation(AF) is the most common arrhythmia in the adult population. The activated renin-angiotensin-aldosterone system (RAS) has been reported to play an important role in the pathogenesis of atrial fibrillation. The aim of this study was to investigate the association between nonfamilial AF and polymorphisms in RAS gene. METHODS: A total of 931 patients with nonfamilial AF, 663 non-AF heart disease patients and 727 healthy subjects were selected. 10 tagSNPs (tSNPs) (ACE gene rs8066114, AGT gene rs7539020, rs3789678, rs2478544, rs11568023, rs2478523, rs4762, rs699 and CYP11B2 rs3802230, rs3097) were chosen and genotyped in our study. Single-locus analysis and haplotype analysis were used in this study. RESULTS: In single-locus analysis, we found rs11568023 and rs3789678 in AGT gene were associated with nonfamilial AF in Chinese Han population. AF risk was associated with rs3789678 between the AF group and control groups. Under dominant model, the significant AF risk was observed in rs3789678 between the AF group and non AF heart control group; And the protective effect was found in rs11568023, compared with the non-AF heart disease control group. In multilocus haplotype analysis, the association between frequencies of the haplotypes and AF risk was showed in AGT gene (rs7539020-rs3789678), compared 'TT' haplotype with the common 'TC' haplotype, adjusted for age, gender, LVEF, LVEDD, LAD and frequency of hypertension and diabetes. The diplotype with 'TC', carrying rs3789678-C-allele, was associated with reduced risk of AF between the AF group and the healthy control group. The diplotype with 'TT' haplotype in the same block, carrying rs3789678-T-allele, was associated with increased risk of AF. CONCLUSIONS: Via a large-scale case-control study, we found that rs3789678 site was potential susceptible locus of AF whereas rs11568023 was protective factor.

Age- and sex-related difference in lipid profiles of patients hospitalized with acute myocardial infarction in East China.

BACKGROUND: It was not understood whether age- and sex-related differences were apparent in lipid profiles among acute myocardial infarction (AMI) patients in China. OBJECTIVES: To investigate lipid abnormalities in such AMI patients. METHODS: A retrospective analysis of 1213 patients hospitalized with a first AMI between May 2007 and July 2011. RESULTS: Our data indicated that, compared with the elderly, the nonelderly tended to have higher low-density lipoprotein cholesterol (LDL), total cholesterol (TC), and non-high-density lipoprotein cholesterol (N-HDL) for both males and females. There was significant difference in LDL among various age groups (P < .001): LDL levels in the 50-59 and 60-69 year age groups were higher than those in 70-79 and 80-89 year age groups. Compared with males, females tended to have higher LDL in both the 50-59 and 60-69 year age groups. There was no difference in HDL among various age groups for female AMI patients, but there was significance for males. Compared with males, females had higher HDL in 40-49, 50-59, 60-69, and 70-79 year age groups, respectively. Among various age groups, there was significant difference in triglycerides (TG) for male AMI patients, but no difference in TG for females. The levels of TG were higher in 40-49, 50-59, and 60-69 year age groups than those in 70-79, 80-89, and ≥90 year age groups, respectively, for males. Isolated low HDL (low HDL + normal LDL + normal TG) was the most common type of combined dyslipidemia for male elderly (31.4%), male nonelderly (22.9%), and female elderly (19.2%) patients. CONCLUSION: We concluded that there was age- and sex-related difference in lipid profiles among AMI patients, with more prevalent dyslipidemia in the nonelderly than the elderly. Perimenopausal women were prone to higher LDL, and low HDL was prevalent among AMI patients in East China.

Nav1.8 channels in ganglionated plexi modulate atrial fibrillation inducibility.

AIMS: Emerging evidences indicate that SCN10A/NaV1.8 is associated with cardiac conduction and atrial fibrillation, but the exact role of NaV1.8 in cardiac electrophysiology remains poorly understood. The present study was designed to investigate the effects of blocking NaV1.8 channels in cardiac ganglionated plexi (GP) on modulating cardiac conduction and atrial fibrillation inducibility in the canine model. METHODS AND RESULTS: Thirteen mongrel dogs were randomly enrolled. Right cervical vagus nerve stimulation (VNS) was applied to determine its effects on the sinus rate, ventricular rate during atrial fibrillation, PR interval, atrial effective refractory period, and the cumulative window of vulnerability. The NaV1.8 blocker A-803467 (1 µmol/0.5 mL per GP, n = 7) or 5% DMSO/95% polyethylene glycol (0.5 mL per GP, n = 6, control) was injected into the anterior right GP and the inferior right GP. The effects of VNS on the sinus rate, ventricular rate, PR interval, atrial effective refractory period, and the cumulative window of vulnerability were significantly eliminated at 10, 35, and 90 min after A-803467 injection. In separate experiments (n = 8), A-803467 blunted the slowing of sinus rate with increasing stimulation voltage of the anterior right GP at 10 min after local injection. CONCLUSIONS: Blockade of NaV1.8 channels suppresses the effects of VNS on cardiac conduction and atrial fibrillation inducibility, most likely by inhibiting the neural activity of the cardiac GP.

Lysophosphatidic acid increases the electrophysiological instability of adult rabbit ventricular myocardium by augmenting L-type calcium current.

Lysophosphatidic acid (LPA) has diverse actions on the cardiovascular system and is widely reported to modulate multiple ion currents in some cell types. However, little is known about its electrophysiological effects on cardiac myocytes. This study investigated whether LPA has electrophysiological effects on isolated rabbit myocardial preparations. The results indicate that LPA prolongs action potential duration at 90% repolarization (APD(90)) in a concentration- and frequency-dependent manner in isolated rabbit ventricular myocytes. The application of extracellular LPA significantly increases the coefficient of APD(90) variability. LPA increased L-type calcium current (I(Ca,L)) density without altering its activation or deactivation properties. In contrast, LPA has no effect on two other ventricular repolarizing currents, the transient outward potassium current (I(to)) and the delayed rectifier potassium current (I(K)). In arterially perfused rabbit left ventricular wedge preparations, the monophasic action potential duration, QT interval, and Tpeak-end are prolonged by LPA. LPA treatment also significantly increases the incidence of ventricular tachycardia induced by S(1)S(2) stimulation. Notably, the effects of LPA on action potentials and I(Ca,L) are PTX-sensitive, suggesting LPA action requires a G(i)-type G protein. In conclusion, LPA prolongs APD and increases electrophysiological instability in isolated rabbit myocardial preparations by increasing I(Ca,L) in a G(i) protein-dependent manner.