Use of three-dimensional electroanatomic mapping for epicardial access: needle tracking, electrographic characteristics, and clinical application.

AIMS: Pericardiocentesis is usually completed under fluoroscopy. The electroanatomic mapping (EAM) system allows visualizing puncture needle tip (NT) while displaying the electrogram recorded from NT, making it possible to obtain epicardial access (EA) independent of fluoroscopy. This study was designed to establish and validate a technique by which EA is obtained under guidance of three-dimensional (3D) EAM combined with NT electrogram. METHODS AND RESULTS: 3D shell of the heart was generated, and the NT was made trackable in the EAM system. Unipolar NT electrogram was continuously monitored. Penetration into pericardial sac was determined by an increase in NT potential amplitude and an injury current. A long guidewire of which the tip was also visible in the EAM system was advanced to confirm EA. Epicardial access was successfully obtained without complication in 13 pigs and 22 patients. In the animals, NT potential amplitude was 3.2 ± 1.0 mV when it was located in mediastinum, 5.2 ± 1.6 mV when in contact with fibrous pericardium, and 9.8 ± 2.8 mV after penetrating into pericardial sac (all P ≤ 0.001). In human subjects, it measured 1.54 ± 0.40 mV, 3.61 ± 1.08 mV, and 7.15 ± 2.88 mV, respectively (all P < 0.001). Fluoroscopy time decreased in every 4-5 cases (64 ± 15, 23 ± 17, and 0 s for animals 1-4, 5-8, 9-13, respectively, P = 0.01; 44 ± 23, 31 ± 18, 4±7 s for patients 1-7, 8-14, 15-22, respectively, P < 0.001). In five pigs and seven patients, EA was obtained without X-ray exposure. CONCLUSION: By tracking NT in the 3D EAM system and continuously monitoring the NT electrogram, it is feasible and safe to obtain EA with minimum or no fluoroscopic guidance.

Risk Factors for Left Ventricular Thrombus Formation in Patients with Dilated Cardiomyopathy.

BACKGROUND: Left ventricular thrombus (LVT) is a common complication of dilated cardiomyopathy (DCM), causing morbidity and mortality. METHODS: This study retrospectively analyzed patients with DCM from January 2002 to August 2020 in Beijing Anzhen Hospital. Clinical characteristics were compared between the LVT group and the age and sex 1:4 matched with the LVT absent group. The receiver operator characteristic (ROC) curve was plotted to evaluate the diagnostic value of D-dimer predicting LVT occurrence in DCM. RESULTS: A total of 3,134 patients were screened, and LVT was detected in 72 (2.3%) patients on echocardiography. The patients with LVT had higher D-dimer, fibrinogen, and lower systolic blood pressure than those without LVT. The ejection fraction (EF) was lower and left ventricular end-systolic diameter was larger in the LVT group. Severe mitral regurgitation (MR) was more common in the LVT absent groups. The prevalence of atrial fibrillation was lower in the LVT group. The ROC curve analysis yielded an optimal cut-off value of 444 ng/mL DDU (D-dimer units) for D-dimer to predict the presence of LVT. Multivariable binary logistic regression analysis revealed that EF (OR = 0.90, 95% CI = 0.86-0.95), severe MR (OR = 0.19, 95% CI = 0.08-0.48), and D-dimer level (OR = 15.4, 95% CI = 7.58-31.4) were independently associated with LVT formation. CONCLUSION: This study suggested that elevated D-dimer levels (>444 ng/mL DDU) and reduced EF were independently associated with increased risk of LVT formation. Severe MR could decrease the incidence of LVT.

Visualization and mapping of the right phrenic nerve by intracardiac echocardiography during atrial fibrillation ablation.

OBJECTIVE: This study aimed to evaluate the feasibility of real-time visualization and mapping of the right phrenic nerve (RPN) by using intracardiac echocardiography (ICE) during atrial fibrillation (AF) ablation. BACKGROUND: RPN injury is a complication associated with the ablation of AF. Multiple approaches are currently being used to prevent and detect RPN injuries. However, none of these approaches can directly visualize the RPN in real-time during the ablation procedure. METHODS AND RESULTS: The RPN was detected using ICE. The RPN and its adjacent structures were analysed. The relationship between the RPN's distance from the superior vena cava (SVC) and its pacing capture threshold was quantified. The safety of SVC isolation guided by the ICE-visualized RPN was evaluated. Thirty-eight people were enrolled in this study. The RPN was visualized by ICE in 92% of patients. It ran through the space between the SVC and the mediastinal pleura and had a 'straw'-like appearance upon ICE imaging. The course of the RPN was close to the SVC (minimum 1.0 ± 0.4 mm) and the right superior pulmonary vein (minimum 14.1 ± 7.3 mm). There was a positive linear correlation between the RPN's capture threshold and its distance from the SVC (Spearman's correlation coefficient = 0.728, < 0.001). SVC isolation was guided by the RPN; none of the patients developed an RPN injury. CONCLUSIONS: RPN can be visualized by ICE in most patients, thus providing a novel approach for the real-time detection of RPN during AF ablation.

Empagliflozin Ameliorates Ouabain-Induced Na+ and Ca2+ Dysregulations in Ventricular Myocytes in an Na+-Dependent Manner.

PURPOSE: Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a novel class of glucose-lowering agents that have improved clinical outcomes in patients with heart failure; however, their therapeutic mechanisms remain elusive. Although contradictory results have been reported, it has been proposed that improving Na+ homeostasis may be the underlying mechanism of action of SGLT2 inhibitors in heart failure treatment. This study explored whether empagliflozin ameliorates Na+ and Ca2+ handling disorders induced by ouabain in an Na+-dependent manner. METHODS: Isolated ventricular myocytes of mice were incubated with ouabain to establish a cellular model of Na+ overload. Effects of empagliflozin on Na+ and Ca2+ handling were evaluated using an ionOptix system and a confocal microscope. Distinct cytosolic Na+ levels were established by incubating different ouabain concentrations (10, 50, and 100 µmol/L). RESULTS: In the absence of ouabain, 1 µmol/L empagliflozin had a negligible impact on Na+ and Ca2+ handling in ventricular myocytes. Ouabain (50 µmol/L) significantly enhanced cytosolic Na+ levels and dysregulated Ca2+ handling, including an increased Ca2+ transient amplitude, elevated Ca2+ content in the sarcoplasmic reticulum, and enhanced spontaneous Ca2+ release normalized by treatment with 1 µmol/L empagliflozin within 10 min. All Na+ and Ca2+ handling abnormalities induced by ouabain were reversed by 1 µmol/L empagliflozin. The efficacy of empagliflozin was more potent at higher cytosolic Na+ levels. Pretreatment with the Na+/H+ exchanger (NHE) inhibitor (1 µmol/L cariporide) abolished the effects of empagliflozin. CONCLUSION: Empagliflozin ameliorates ouabain-induced Na+ and Ca2+ handling disorders in a cytosolic Na+-dependent manner, potentially by inhibiting the NHE.

Outcome of cancer patients after atrial fibrillation ablation: Insights from the China-AF registry.

BACKGROUND: Cancer has become significant comorbidity in patients with atrial fibrillation (AF). However, little is known about the efficacy and safety of AF ablation, the first-line rhythm control strategy, in patients with cancer. This study aims to evaluate the incidence and risk of AF recurrence and safety endpoints in patients with cancer compared to the non-cancer group after ablation. METHODS: From August 2011 to December 2020, we consecutively enrolled cancer patients in the China-AF cohort. We used propensity score matching (1:3) to select the control group and assessed the risk of AF recurrence and adverse events after ablation in cancer patients using a multivariable Fine and Gray competing risk model. RESULTS: A total of 203 patients with cancer were enrolled and 21 of them were active cancer, with a median follow-up of 12.3 months. The cumulative incidence of AF recurrence was comparable between patients with and without cancer (43.8% vs. 51.1%; p = .88). No difference in the risk of AF recurrence, thromboembolism, major bleeding, and mortality was observed after adjusting confounders. Active cancer was not associated with an increased risk of AF recurrence compared to the stable disease (SHR = 1.32; 95% CI 0.72-2.43; p = .46). Cancer was associated with a low risk of cardiovascular hospitalization (SHR, 0.54; 95% CI, 0.36-0.81; p = .01). Subgroup analysis found that hematological malignancy was associated with a high risk of AF recurrence (SHR, 5.68; 95% CI, 3.00-10.8; p < .001). CONCLUSIONS: This study suggests that catheter ablation could be feasible for rhythm control of AF patients with concomitant cancer.

Association of shift work and dietary inflammatory potential with all-cause death among us hypertensive population: national health and nutrition examination study, 2005-2010.

BACKGROUND & AIMS: The individual effect of working schedule on survival in the hypertensive population has not been adequately studied. Shiftworkers are also prone to unhealthy lifestyles like pro-inflammatory diet. Therefore, we assessed the effect of shift work and its joint association with dietary inflammatory potential on mortality risk among the large US nationally representative sample of adult hypertensive population. METHODS: Data were from a nationally representative prospective cohort among US hypertensive population (n = 3680; weighted population, 54,192,988). The participants were linked to the 2019 public-access linked mortality archives. The working schedule were self-reported using the Occupation Questionnaire Section. Dietary inflammatory index (DII) scores were equally calculated using the 24-hour dietary recall (24 h) interviews. Multivariable Cox proportional hazards regression models were used to estimate hazard ratio and 95% confidence intervals (95%CI) for survival of hypertension individuals by work schedule and dietary inflammatory potential. The joint effect of work schedule and dietary inflammatory potential was then examined. RESULTS: Among the 3680 hypertension individuals (39.89% female [n = 1479] and 71.42% white [n = 1707]; weighted mean [SE] age, 47.35 [0.32] years), 592 individuals reported shift work status. 474 (10.76%) reported shift work status with pro-inflammatory dietary pattern (DII scores > 0). 118 (3.06%) reported shift work status with anti-inflammatory dietary pattern (DII scores < 0). 646 (19.64%) reported a non-shift working schedule with anti-inflammatory dietary pattern, while 2442 (66.54%) reported non-shift working schedule with pro-inflammatory dietary pattern. After a median follow-up of 11.67 years (140 months), 317 deaths (cardiovascular diseases (CVD), 65; cancer, 104) were registered. Cox regression analysis showed that shift work was associated with higher risk of all-cause mortality (hazard ratio [HR], 1.48; 95% CI, 1.07-2.06) compared with non-shift workers. In the joint analysis, shift work status combined with pro-inflammatory dietary pattern was associated with the highest all-cause mortality risk. Moreover, adopting the anti-inflammatory diet significantly attenuates the deleterious effect of shift work on mortality risk. CONCLUSIONS: In this large representative sample of adults with hypertension in the U.S., the combination of shift work status with pro-inflammatory dietary pattern was highly prevalent and was associated with the highest risks of death from all causes.

Sex Differences and Temporal Trends in Hospitalization for Catheter Ablation of Nonvalvular Atrial Fibrillation: A Single-Center Experience for 15 Years.

Background: There exist sex differences in the clinical profile, management, and outcome of atrial fibrillation (AF). Catheter ablation of AF has become a first-line therapy and has markedly made headway over the recent decades. Little is known about sex differences and temporal trends in hospitalization for catheter ablation of AF in the real-world setting. Methods: We retrospectively retrieved medical records of patients at Beijing Anzhen Hospital between January 2005 and December 2019. The patients undergoing catheter ablation of AF were enrolled. Demographical and clinical data were compared between sexes. The temporal trends of sex differences were evaluated. Results: We identified 13502 male patients (66.8%) and 6713 female patients (33.2%). The number of patients undergoing AF ablation had remarkably increased over time, but no sex differences were observed (p=0.17). The median age of women was five years older than that of men (p < 0.001). The median time of in-hospital stay for the women decreased from 11 days to 4 days and for the men from 9 to 4 days. In-hospital mortality was 0.03% and 0.01% for women and men, respectively, with no significant difference between sexes. The women were more likely to have a comorbid diagnosis of hypertension and heart failure than men (p < 0.001). The CHA2DS2-VA score was higher in women than in men (1.64 vs. 1.28, p < 0.001). The temporal trend in the score increased in women from 1.17 to 1.81 (p < 0.001) and in men from 0.91 to 1.41 (p < 0.001). The percentage of patients with CHA2DS2-VA score ≥2 was higher in women than in men (49.8% vs. 35.8%, p < 0.001), and the temporal trend of this sex gap was nearly doubled (8.0% in 2005-2007 vs. 15.5% in 2017-2019, p=0.03). Conclusions: Safety of catheter ablation for AF was comparable in both sexes. In contrast, the women showed a higher CHA2DS2-VA score than men. The percentage of patients with CHA2DS2-VA score ≥2 increased more quickly in women than in men. Furthermore, sex-specific research is warranted to reduce this sex disparity.

Effects of intensive blood pressure control on cardiovascular and cognitive outcomes in patients with atrial fibrillation: insights from the SPRINT trial.

AIMS: Patients with atrial fibrillation (AF) have an increased risk of cardiovascular events and dementia, even if anticoagulated. Hypertension is highly prevalent in AF population; however, the optimal blood pressure (BP) target for AF patients remains unknown. METHODS AND RESULTS: We conducted subgroup analysis of the Systolic Blood Pressure Intervention Trial (SPRINT) to examine whether AF modified the treatment effects of intensive BP control on cardiovascular and cognitive outcomes using Cox proportional hazards regression and likelihood ratio tests. Among 9361 randomized participants, 778 (8.3%) had baseline AF, and 695 (89.3%) completed at least one follow-up cognitive assessment. Intensive BP control reduced the similar relative risk of cardiovascular events irrespective of the presence of AF, with all interaction P-values > 0.05. Patients with AF experienced a greater absolute risk reduction in the composite primary cardiovascular outcome (12.3 vs. 5.6 events per 1000 person-years) with intensive treatment, compared with those without AF. However, intensive BP control increased the risk of probable dementia in patients with AF [hazard ratio (HR), 2.22; 95% confidence interval (CI), 1.03-4.80], while reducing the dementia risk in patients without AF (HR, 0.75; 95% CI, 0.60-0.95; P = 0.009 for interaction). There were no significant interactions between the presence of AF and intensive BP treatment for mild cognitive impairment. CONCLUSION: Patients with AF experienced greater absolute cardiovascular benefits with intensive BP treatment, but may need to be cautious of an increased risk of dementia. This post hoc analysis should be considered as hypothesis generating and merit further study. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01206062.

Sex differences in the association between green tea consumption and hypertension in elderly Chinese adults.

BACKGROUND: Green tea has been one of the most popular beverages in China since ancient times. Mixed results concerning the effect of green tea consumption on the incidence of hypertension have been published over the past decades. However, no previous studies have focused on longevous individuals in China and the sex differences in the association between habitual green tea intake and hypertension. METHODS: The data extracted from the database of the Chinese Longitudinal Healthy Longevity Survey (CLHLS) in 2018 were used for a secondary analysis. Logistic regression models were employed to examine the odds ratio (OR) of daily green tea consumption on the incidence of hypertension by sex. RESULTS: A total of 9277 individuals were included in the analysis (39.8% were men). The included individuals had a mean age of 80.9 and 84.8 years for those who drank green tea daily and those who had never, respectively (p <  0.001). The incidence of hypertension varied at baseline according to green tea drinking habit and sex. For women who had a habitual green tea intake or had never drunk green tea, the incidence of hypertension was 47.3 and 43.9%, respectively (p = 0.241), whereas it was 51.6 and 39.7% for men (p <  0.001). After adjusting for potential confounders, a 38% increase in the risk of hypertension was observed in men who consumed green tea daily (OR, 1.38; 95% CI, 1.15-1.67; p <  0.001). CONCLUSIONS: Chinese longevous men had a 38% higher risk of developing hypertension when drinking green tea daily. However, no effect of green tea consumption on the incidence of hypertension in women was found. More attention should be paid to the lifestyle of longevous individuals for health promotion, and a sex-specific approach to deliver care for very elderly people is warranted.

Retraction Note: Inhibition of miR-296-5p protects the heart from cardiac hypertrophy by targeting CACNG6.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Early versus delayed removal of the pericardial drain in patients with cardiac tamponade complicating radiofrequency ablation of atrial fibrillation.

INTRODUCTION: Cardiac tamponade is a common life-threatening complication during radiofrequency ablation of atrial fibrillation (RAAF) and is mostly managed by pericardiocentesis. Thus far, the optimal timing for drain removal has not been established. METHODS AND RESULTS: We retrospectively enrolled patients with cardiac tamponade complicating RAAF. The ablation was performed with interrupted novel oral anticoagulants, interrupted warfarin or uninterrupted warfarin protocols. An observation period of at least 30 minutes after the last aspiration via the drain was used to monitor the reaccumulation of pericardial fluid, and then, the patients were divided into an early removal (ER) group in the electrophysiology (EP) laboratory and a delayed removal (DR) group in the ward. A total of 51 patients were included: 25 patients in the ER group and 26 patients in the DR group. There were no significant differences in baseline demographics between the two groups, and no cardiac tamponade reoccurred in either group in the ward. Unlike the DR group, the ER group showed an association with a decreased rate of chest pain (P = .000), fever (P = .001), nausea (P = .000), in-hospital recurrent AF (P = .010), and antibiotic use (P = .012). Anticoagulation was earlier (P = .009), and the median in-hospital stay was shorter (P = .001) in the ER group than in the DR group. CONCLUSIONS: ER of the pericardial drain after no evidence of pericardial bleeding for at least 30 minutes in the EP laboratory is safe and associated with a better early hospital course.

Role of cardioprotective agents on chemotherapy-induced heart failure: A systematic review and network meta-analysis of randomized controlled trials.

BACKGROUND: Although previous clinical randomized controlled trials (RCTs) have tested the effect of a variety of cardioprotective agents on cancer therapy-induced cardiotoxicity, the number of included patients was limited, and the results remained controversial. In this study, we aimed to evaluate the preventive or therapeutic effects of cardioprotective agents on heart failure (HF) caused by cardiotoxicity induced by cancer therapy. METHODS: We included trials of the following cardioprotective drugs: Angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, beta-blockers, aldosterone antagonists and stains. We extracted the relevant information with predefined data extraction forms, and assessed the risk of bias in randomized controlled trials with the Cochrane risk of bias tool. The primary outcome was the left ventricular ejection fraction of patients after chemotherapy. We used the random-effects model to carry out pair-wise meta-analysis, and then carry out the random-effects network meta-analysis within the Bayesian framework. RESULTS: Twenty-two relevant RCTs, including 1 916 patients (79.6 % women) with a mean age of 48.4 years, were included. Based on the evaluation of all drug species from 20 studies (26 comparisons), the analysis found that 4 therapies, aldosterone antagonists (MD, 12.78 [95 % CI, 2.87-22.69] and MD, 13.75 [95 % CI, 2.21-25.30]), ACEIs (MD, 6.79 [95 % CI, 2.11-11.48] and MD, 7.76 [95 % CI, 2.64-12.88]), statin (MD, 8.35 [95 % CI, 1.11-15.59]), and beta-blockers (MD, 4.00 [95 % CI, 0.87-7.14]), had a higher efficacy than placebo and/or control, suggesting an LVEF protective effect of cardioprotective therapy. In the analysis classified by single drug or drug combination, based on 22 studies (31 comparisons), spironolactone (MD, 12.77 [95 % CI, 1.76-23.79] and MD, 14.62 [95 % CI, 1.70-27.55]), a combination of candesartan and carvedilol (MD, 12.40 [95 % CI, 0.99-23.81]), enalapril (MD, 7.35 [95 % CI, 1.16-13.54] and MD, 9.20 [95 % CI, 2.61-15.79]), and statin (MD, 8.36 [95 % CI, 0.36-16.36]) showed significant benefits in protecting left ventricular (LV) systolic function compared with the placebo and/or control. CONCLUSION: When classified according to drug type, aldosterone antagonists, ACEIs, statins, and beta-blockers could substantially improve the LV systolic function. In the analysis classified by single drug or drug combination, spironolactone, enalapril, and statin have a significant cardioprotective effect. However, ARBs have no cardioprotective effect and fail to improve the LVEF.

Pravastatin alleviates intracellular calcium dysregulation induced by Interleukin-6 via the mitochondrial ROS pathway in adult ventricular myocytes.

Acute inflammation often contributes to the increased arrhythmogenesis in the cardiomyocytes. We investigated the protective effects of pravastatin on calcium disorders induced by acute administration of pro-inflammatory cytokines in isolated ventricular myocytes and its underlying mechanisms. Wild-type mice were intraperitoneally injected for five days with either pravastatin 20 mg/kg per day or an equal volume of normal saline. Cytosol Ca2+ handling was studied in freshly isolated ventricular myocytes after acute exposure of interleukin-6 (IL-6) (1 ng/ml) for 120 min by Ionoptix and confocal microscopy. Acute administration of clinically relevant concentrations of IL-6 disturbed calcium handling in ventricular myocytes, which presented as decreased amplitudes, prolonged decay times of Ca2+ transients, and reduced sarcoplasmic reticulum (SR) calcium stores. The frequency of spontaneous Ca2+ release, including calcium sparks and spontaneous calcium waves, was dramatically enhanced in the setting of IL-6. Notably, the pretreatment of pravastatin alleviated disturbed Ca2+ cycling, reduced spontaneous Ca2+ leakage induced by IL-6. Mitochondrial ROS pathway may constitute the underlying mechanism of the protective effects of pravastatin. Pravastatin protected the cardiomyocytes against calcium disorders induced by IL-6 via the mitochondrial ROS pathway, which suggests that pravastatin may represent a promising auxiliary therapeutic strategy for cardiac injury under acute inflammation.

Depolarization and repolarization parameters on ECG predict recurrence after atrial fibrillation ablation in patients with hypertrophic cardiomyopathy.

INTRODUCTION: The outcomes of atrial fibrillation (AF) ablation remain suboptimal. It is important to identify which AF patients will most likely benefit from ablation and who are more likely to show treatment failure, especially in those with structural heart disease such as hypertrophic cardiomyopathy (HCM). METHODS AND RESULTS: We enrolled 120 HCM patients who underwent primary AF ablation (48 with persistent AF). Preprocedural QTc was measured and corrected using the Bazett's formula, and the distribution of fragmentation of the QRS complex (fQRS) was recorded. Arrhythmia recurrence was defined as any kind of documented atrial tachyarrhythmia of more than 30 seconds. Overall, arrhythmia recurrence occurred in 69 patients after 13.4 months' follow-up. fQRS was present in 71 (59.17%) patients and was most commonly (81.69%) observed in the inferior leads. QTc more than 448 ms could predict arrhythmia recurrence with a sensitivity of 68.1% and specificity of 68.6%. Patients with QTc more than 448 ms (hazard ratio [HR]: 1.982; 95% confidence interval [CI]: 1.155-3.402; P = .013) or those with fQRS+ (HR: 1.922; 95% CI: 1.151-3.210; P = .012) were at an increased risk of recurrence. A combination of fQRS+ and QTc more than 448 ms was superior to fQRS or QTc alone in predicting arrhythmia recurrence. CONCLUSION: In patients with HCM undergoing AF ablation, QTc prolongation, specifically >448 ms, and presence of fQRS are independent risk factors for arrhythmia recurrence at follow-up. The combination of these two parameters has greater predictive value and would help to identify patients who are at the highest risk of procedural failure.

Acute administration of tumour necrosis factor-α induces spontaneous calcium release via the reactive oxygen species pathway in atrial myocytes.

Aims: The arrhythmogenic mechanisms of atrial fibrillation (AF) that are induced by acute inflammation, such as postoperative AF, are not well understood. We investigated the acute effects of tumour necrosis factor-α (TNF-α) that mimic acute inflammation on Ca2+ handling in isolated atrial myocytes and its underlying mechanisms. Methods and results: Cytosol Ca2+ handling and mitochondrial reactive oxygen species (ROS) production were studied in freshly isolated atrial myocytes of wild-type mice that were exposed to TNF-α (0.05 ng/mL) for 2 h by Ionoptix and confocal microscopy. The acute effects of TNF-α on Ca2+ handling were decreased amplitudes and prolonged decay times of Ca2+ transients in isolated atrial myocytes. A significant reduction in the sarcoplasmic reticulum (SR) Ca2+ content was detected in TNF-α treated cells, which was associated with increased spontaneous Ca2+ release events. In particular, physiological concentrations of TNF-α dramatically promoted the frequency of spontaneous Ca2+ waves and Ca2+ sparks, while the spark mass presented with reduced amplitudes and prolonged durations. The underlying mechanisms of pro-arrhythmic effects of TNF-α were further investigated. Acute exposure to TNF-α rapidly promoted mitochondrial ROS production that was correlated with the acute effect of TNF-α on Ca2+ handling, and enhanced the oxidation of calcium/calmodulin-dependent protein kinase II (CaMKII) and the phosphorylation of RyR2. However, the performance of ROS inhibitor, DL-Dithiothreitol (DTT), reversed Ca2+ handling disorders induced by TNF-α. Conclusion: Tumour necrosis factor-α rapidly increases spontaneous Ca2+ release and promotes atrial arrhythmogenesis via the ROS pathway, which suggests that antioxidant therapy is a promising strategy for acute inflammation related AF.

Fluconazole-induced long QT syndrome via impaired human ether-a-go-go-related gene (hERG) protein trafficking in rabbits.

AIMS: hERG protein trafficking deficiency has long been known in drug-induced long QT syndrome (LQTS). However, validated evidence from in vivo data kept scanty. Our goal was to investigate the proarrhythmic action of fluconazole and its underlying mechanism in an animal model. METHODS AND RESULTS: Twenty female Japanese long-eared white rabbits were randomly distributed into a control group and a fluconazole group for a chronic 2-week treatment. The control group was treated with 0.5% sodium carboxymethylcellulose (CMCNa), and the fluconazole group was treated with fluconazole. Electrocardiograms (ECGs) were recorded during the experimental period. Isolated arterially perfused left ventricular wedge preparations from the rabbits were made 2 weeks after treatment, and the arrhythmia events, the transmural ECG, and action potential from both the endocardium and epicardium were recorded. The changes in hERG protein expression were measured by western blot. The fluconazole group showed a longer QT interval 1 week after treatment (P < 0.05) and a higher arrhythmia occurrence 2 weeks after treatment (P < 0.05) than the control group. The fluconazole group also showed a longer transmural dispersion of repolarization and a higher occurrence of life-threatening torsades de pointes in arterially perfused left ventricular preparations. Furthermore, western blot analysis showed that the density of mature hERG protein was lower in the fluconazole group than that in the control group. CONCLUSION: Fluconazole can prolong the QT interval and possess proarrhythmic activity due to its inhibition of hERG protein trafficking in our experimental model. These findings may impact the clinical potential of fluconazole in humans.

Genetically induced dysfunctions of Kir2.1 channels: implications for short QT3 syndrome and autism-epilepsy phenotype.

Short QT3 syndrome (SQT3S) is a cardiac disorder characterized by a high risk of mortality and associated with mutations in Kir2.1 (KCNJ2) channels. The molecular mechanisms leading to channel dysfunction, cardiac rhythm disturbances and neurodevelopmental disorders, potentially associated with SQT3S, remain incompletely understood. Here, we report on monozygotic twins displaying a short QT interval on electrocardiogram recordings and autism-epilepsy phenotype. Genetic screening identified a novel KCNJ2 variant in Kir2.1 that (i) enhanced the channel's surface expression and stability at the plasma membrane, (ii) reduced protein ubiquitylation and degradation, (iii) altered protein compartmentalization in lipid rafts by targeting more channels to cholesterol-poor domains and (iv) reduced interactions with caveolin 2. Importantly, our study reveals novel physiological mechanisms concerning wild-type Kir2.1 channel processing by the cell, such as binding to both caveolin 1 and 2, protein degradation through the ubiquitin-proteasome pathway; in addition, it uncovers a potential multifunctional site that controls Kir2.1 surface expression, protein half-life and partitioning to lipid rafts. The reported mechanisms emerge as crucial also for proper astrocyte function, suggesting the need for a neuropsychiatric evaluation in patients with SQT3S and offering new opportunities for disease management.

KCNJ2 mutation in short QT syndrome 3 results in atrial fibrillation and ventricular proarrhythmia.

We describe a mutation (E299V) in KCNJ2, the gene that encodes the strong inward rectifier K(+) channel protein (Kir2.1), in an 11-y-old boy. The unique short QT syndrome type-3 phenotype is associated with an extremely abbreviated QT interval (200 ms) on ECG and paroxysmal atrial fibrillation. Genetic screening identified an A896T substitution in a highly conserved region of KCNJ2 that resulted in a de novo mutation E299V. Whole-cell patch-clamp experiments showed that E299V presents an abnormally large outward IK1 at potentials above -55 mV (P < 0.001 versus wild type) due to a lack of inward rectification. Coexpression of wild-type and mutant channels to mimic the heterozygous condition still resulted in a large outward current. Coimmunoprecipitation and kinetic analysis showed that E299V and wild-type isoforms may heteromerize and that their interaction impairs function. The homomeric assembly of E299V mutant proteins actually results in gain of function. Computer simulations of ventricular excitation and propagation using both the homozygous and heterozygous conditions at three different levels of integration (single cell, 2D, and 3D) accurately reproduced the electrocardiographic phenotype of the proband, including an exceedingly short QT interval with merging of the QRS and the T wave, absence of ST segment, and peaked T waves. Numerical experiments predict that, in addition to the short QT interval, absence of inward rectification in the E299V mutation should result in atrial fibrillation. In addition, as predicted by simulations using a geometrically accurate three-dimensional ventricular model that included the His-Purkinje network, a slight reduction in ventricular excitability via 20% reduction of the sodium current should increase vulnerability to life-threatening ventricular tachyarrhythmia.

Incidence and clinical characteristics of transient ST-T elevation during transseptal catheterization for atrial fibrillation ablation.

AIMS: Transient ST-T elevation (STE) is a rare complication that occurs during transseptal catheterization. This study aims to delineate the incidence and characteristics of transient STE during transseptal catheterization for atrial fibrillation (AF) ablation. METHODS AND RESULTS: Consecutive patients who underwent fluoroscopy-guided transseptal catheterization for circumferential pulmonary vein radiofrequency ablation in Beijing An Zhen Hospital from January 2006 to January 2013 were enrolled in this study. Out of 2965 patients with a total of 3452 transseptal catheterization procedures, 13 patients (0.38%, mean age 57 ± 8, 6 female, 12 paroxysmal AF, mean left atrial diameter 35.4 ± 3.8 mm) had STE. ST-T elevation occurred after transseptal puncture in 10 patients and after pulmonary vein venography in three patients. Systolic blood pressure (129 ± 10 vs. 104 ± 20 mmHg, P < 0.001), diastolic blood pressure (78 ± 6 vs. 64 ± 11 mmHg, P < 0.001), and heart rate (83 ± 19 bpm vs. 64 ± 23 b.p.m., P = 0.022) significantly decreased when STE occurred. Eleven patients complained of chest pain, one patient complained of dizziness, and one patient had no symptoms. Patients recovered in about 4.6 min (2-10 min) with dopamine or fast saline drip. Catheter ablation of AF was completed in all the 13 patients without sequelae or other complications. Four of the 13 patients (30.8%) had recurrence of AF after a mean follow-up of 21.7 months. CONCLUSION: ST-T elevation is a rare complication associated with transseptal catheterization without sequelae. Catheter ablation of AF could be safely completed in these patients.