The Antiarrhythmic Action of the Na+/Ca2+ Exchanger Inhibitor SEA0400 on Drug-Induced Long QT Syndrome Depends on the Severity of Proarrhythmic Conditions in Anesthetized Atrioventricular Block Rabbits.

To clarify the pharmacological properties of the Na+/Ca2+ exchanger (NCX) inhibitor SEA0400 as an antiarrhythmic agent, we assessed its effects on rapid component of delayed rectifier K+ current (IKr) blocker-induced torsade de pointes (TdP) in isoflurane-anesthetized rabbits. Atrioventricular block was induced in rabbits using a catheter ablation technique, and the monophasic action potential (MAP) of the right ventricle was measured under electrical pacing at 60 beats/min. In non-treated control animals, intravenous administration of low-dose (0.3 mg/kg) or high-dose nifekalant (3 mg/kg) prolonged the MAP duration (MAP90) by 113 ± 11 ms (n = 5) and 237 ± 39 ms (n = 5), respectively, where TdP was induced in 1/5 animals treated with a low dose and in 3/5 animals treated with a high dose of nifekalant. In SEA0400-treated animals, low- and high-dose nifekalant prolonged the MAP90 by 65 ± 13 ms (n = 5) and 230 ± 20 ms (n = 5), respectively. No TdP was induced by the low dose but 1/5 animals treated with a high dose of nifekalant developed TdP. In verapamil-treated animals, low-dose and high-dose nifekalant prolonged MAP90 by 50 ± 12 ms (n = 5) and 147 ± 30 ms (n = 5), respectively, without inducing TdP. These results suggest that SEA0400 has the potential to inhibit low-dose nifekalant-induced TdP by suppressing the MAP-prolonging action of nifekalant, whereas the drug inhibited high-dose nifekalant-induced TdP without affecting the MAP-prolonging action of nifekalant. This may reveal that, in contrast to verapamil, the antiarrhythmic effects of SEA0400 on IKr blocker-induced TdP may be multifaceted, depending on the severity of the proarrhythmogenic conditions present.

Sophoridine manifests as a leading compound for anti-arrhythmia with multiple ion-channel blocking effects.

BACKGROUND: Sophoridine (SR) has shown the potential to be an antiarrhythmic agent. However, SR's electrophysiological properties and druggability research are relatively inadequate, which limits the development of SR as an antiarrhythmic candidate. PURPOSE: To facilitate the development process of SR as an antiarrhythmic candidate, we performed integrated studies on the electrophysiological properties of SR in vitro and ex vivo to gain more comprehensive insights into the multi-ion channel blocking effects of SR, which provided the foundation for the further drugability studies in antiarrhythmic and safety studies. Firstly, SR's electrophysiological properties and antiarrhythmic potentials were recorded and assessed at the cell and tissue levels by comprehensively integrating the patch clamp with the Electrical and Optical Mapping systems. Subsequently, the antiarrhythmic effects of SR were validated by aconitine and ouabain-induced arrhythmia in vivo. Finally, the safety of SR as an antiarrhythmic candidate compound was evaluated based on the guidelines of the Comprehensive in Vitro Proarrhythmia Assay (CiPA). STUDY DESIGN: The antiarrhythmic effect of SR was evaluated at the in vitro, ex vivo, and in vivo levels. METHODS: Isolated primary cardiomyocytes and stable cell lines were prepared to explore the electrophysiologic properties of being a multiple ion-channel blocker in vitro by whole-cell patch clamp. Using electrical and optical mapping, the negative chronotropic effect of SR was determined in langendorff-perfused rat or guinea-pig hearts.The antiarrhythmic activity of SR was assessed by the ex vivo tachyarrhythmia models induced by left coronary artery ligation (LCAL) and isoproterenol (ISO). Canonical models of aconitine and ouabain-induced arrhythmia were used to verify the antiarrhythmic effects in vivo. Finally, the pro-arrhythmic risk of SR was detected in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes (hSCCMs) using a Microelectrode array (MEA). RESULTS: Single-cell patch assay validated the multiple ion-channel blockers of SR in transient outward current potassium currents (Ito), l-type calcium currents (ICa-l), and rapid activation delayed rectifier potassium currents (IKr). SR ex vivo depressed heart rates (HR) and ventricular conduction velocity (CV) and prolonged Q-T intervals in a concentration-dependent manner. Consistent with the changes in HRs, SR extended the active time of hearts and increased the action potential duration measured at 90% repolarization (APD90). SR could also significantly lengthen the onset time and curtail the duration of spontaneous ventricular tachycardia (VT) in the ex vivo arrhythmic model induced by LCAL. Meanwhile, SR could also significantly upregulate the programmed electrical stimulation (PES) frequency after the ISO challenge in forming electrical alternans and re-entrant excitation. Furthermore, SR exerted antiarrhythmic effects in the tachyarrhythmia models induced by aconitine and ouabain in vivo. Notably, the pro-arrhythmic risk of SR was shallow for a moderate inhibition of the human ether-à-go-go-related gene (hERG) channel. Moreover, SR prolonged field potential duration (FPDc) of hSCCMs in a concentration-dependent manner without early after depolarization (EAD) and arrhythmia occurrence. CONCLUSION: Our results indicated that SR manifested as a multiple ion-channel blocker in the electrophysiological properties and exerts antiarrhythmic effects ex vivo and in vivo. Meanwhile, due to the low pro-arrhythmic risk in the hERG inhibition assay and the induction of EAD, SR has great potential as a leading candidate in the treatment of ventricular tachyarrhythmia.

Research Progress on Natural Products' Therapeutic Effects on Atrial Fibrillation by Regulating Ion Channels.

Antiarrhythmic drugs (AADs) have a therapeutic effect on atrial fibrillation (AF) by regulating the function of ion channels. However, several adverse effects and high recurrence rates after drug withdrawal seriously affect patients' medication compliance and clinical prognosis. Thus, safer and more effective drugs are urgently needed. Active components extracted from natural products are potential choices for AF therapy. Natural products like Panax notoginseng (Burk.) F.H. Chen, Sophora flavescens Ait., Stephania tetrandra S. Moore., Pueraria lobata (Willd.) Ohwi var. thomsonii (Benth.) Vaniot der Maesen., and Coptis chinensis Franch. have a long history in the treatment of arrhythmia, myocardial infarction, stroke, and heart failure in China. Based on the classification of chemical structures, this article discussed the natural product components' therapeutic effects on atrial fibrillation by regulating ion channels, connexins, and expression of related genes, in order to provide a reference for development of therapeutic drugs for atrial fibrillation.

Atrial Fibrillation Management: A Comprehensive Review with a Focus on Pharmacotherapy, Rate, and Rhythm Control Strategies.

Atrial fibrillation (AF) is an increasingly common arrhythmia encountered in clinical practice that leads to a substantial increase in utilization of healthcare services and a decrease in the quality of life of patients. The prevalence of AF will continue to increase as the population ages and develops cardiac comorbidities; thus, prompt and effective treatment is important to help mitigate systemic resource utilization. Treatment of AF involves two tenets: prevention of stroke and systemic embolism and symptom control with either a rate or a rhythm control strategy. Historically, due to the safe nature of medications like beta-blockers and non-dihydropyridine calcium channel blockers, used in rate control, it has been the initial strategy used for symptom control in AF. Newer data suggest that a rhythm control strategy with antiarrhythmic medications with or without catheter ablation may lead to a reduction in major adverse cardiovascular events, particularly in patients newly diagnosed with AF. Modulation of factors that promote AF or its complications is another important aspect of the overall holistic management of AF. This review provides a comprehensive focus on the management of patients with AF and an in-depth review of pharmacotherapy of AF in the rate and rhythm control strategies.

Screening for drugs potentially interfering with MCT8-mediated T3 transport in vitro identifies dexamethasone and some commonly used drugs as inhibitors of MCT8 activity.

BACKGROUND: Monocarboxylate transporter 8 (MCT8) is the first thyroid hormone transporter that has been linked to a human disease. Besides genetic alterations other factors might impair MCT8 activity. AIM: This study aimed at investigating whether some common drugs having a structural similarity with TH and/or whose treatment is associated with thyroid function test abnormalities, or which behave as antagonists of TH action can inhibit MCT8-mediated T3 transport. METHODS: [125I]T3 uptake and efflux were measured in COS-7 cells transiently transfected with hMCT8 before and after exposure to increasing concentrations of hydrocortisone, dexamethasone, prednisone, prednisolone, amiodarone, desethylamiodarone, dronedarone, buspirone, carbamazepine, valproic acid, and L-carnitine. The mode of inhibition was also determined. RESULTS: Dexamethasone significantly inhibited T3 uptake at 10 µM; hydrocortisone reduced T3 uptake only at high concentrations, i.e. at 500 and 1000 µM; prednisone and prednisolone were devoid of inhibitory potential. Amiodarone caused a reduction of T3 uptake by MCT8 only at the highest concentrations used (44% at 50 µM and 68% at 100 µM), and this effect was weaker than that produced by desethylamiodarone and dronedarone; buspirone resulted a potent inhibitor, reducing T3 uptake at 0.1-10 µM. L-Carnitine inhibited T3 uptake only at 500 mM and 1 M. Kinetic experiments revealed a noncompetitive mode of inhibition for all compounds. All drugs inhibiting T3 uptake did not affect T3 release. CONCLUSION: This study shows a novel effect of some common drugs, which is inhibition of T3 transport mediated by MCT8. Specifically, dexamethasone, buspirone, desethylamiodarone, and dronedarone behave as potent inhibitors of MCT8.

Neuroscientific therapies for atrial fibrillation.

The cardiac autonomic nervous system (ANS) plays an integral role in normal cardiac physiology as well as in disease states that cause cardiac arrhythmias. The cardiac ANS, comprised of a complex neural hierarchy in a nested series of interacting feedback loops, regulates atrial electrophysiology and is itself susceptible to remodelling by atrial rhythm. In light of the challenges of treating atrial fibrillation (AF) with conventional pharmacologic and myoablative techniques, increasingly interest has begun to focus on targeting the cardiac neuraxis for AF. Strong evidence from animal models and clinical patients demonstrates that parasympathetic and sympathetic activity within this neuraxis may trigger AF, and the ANS may either induce atrial remodelling or undergo remodelling itself to serve as a substrate for AF. Multiple nexus points within the cardiac neuraxis are therapeutic targets, and neuroablative and neuromodulatory therapies for AF include ganglionated plexus ablation, epicardial botulinum toxin injection, vagal nerve (tragus) stimulation, renal denervation, stellate ganglion block/resection, baroreceptor activation therapy, and spinal cord stimulation. Pre-clinical and clinical studies on these modalities have had promising results and are reviewed here.

Safety and Effectiveness of Rivaroxaban in Combination with Various Antiarrhythmic Drugs in Patients with Non-Permanent Atrial Fibrillation.

INTRODUCTION: Rivaroxaban reduces the risk of thromboembolism in atrial fibrillation (AF) patients, who often also receive antiarrhythmic drugs (AADs) to maintain sinus rhythm. Current guidelines contraindicate concomitant use of rivaroxaban with the popular AAD dronedarone, despite little data demonstrating interactions with AADs. This study investigates the outcomes of concomitant rivaroxaban and AAD drug use in a real-world cohort. METHODS: This retrospective study included 1777 non-permanent AF patients taking rivaroxaban for ≥ 1 month between 2011 and 2016 from a multicenter cohort in Taiwan, and compared concomitant AAD use against clinical outcome endpoints for safety, effectiveness, and major adverse cardiac events (MACE). Multivariate Cox proportional hazard analyses were used to evaluate the association between concomitant AAD use and outcomes. RESULTS: Patients were divided into rivaroxaban alone (n = 1205) and with concomitant amiodarone (n = 177), dronedarone (n = 231), or propafenone (n = 164) groups. The proportion of patients using rivaroxaban 10 mg was highest in the concomitant dronedarone group: rivaroxaban alone, 53.6%; with amiodarone, 57.6%; with dronedarone, 77.1%; and with propafenone, 46.3% (p < 0.001). The cumulative incidences of safety (p = 0.892), effectiveness (p = 0.336), and MACE (p = 0.674) were similar between the four groups; however, there were significantly fewer new systemic thromboembolisms in the dronedarone group: rivaroxaban alone, 2.5%; with amiodarone, 0.6%; with dronedarone, 0%; and with propafenone, 1.2% (p = 0.029). The all-cause death rate was also lowest in the dronedarone group: rivaroxaban alone, 9.0%; with amiodarone, 9.6%; with dronedarone, 3.0%; and with propafenone: 6.1% (p = 0.013). After covariate adjustment, there were no differences in the safety, effectiveness, and MACE endpoints between patients receiving or not receiving AADs. CONCLUSION: Concomitant use of rivaroxaban with AADs appears to be well tolerated, warranting further investigation into the apparent benefits of a reduced dose of rivaroxaban combined with dronedarone.

Guidance on Short-Term Management of Atrial Fibrillation in Coronavirus Disease 2019.

Atrial fibrillation is a common clinical manifestation in hospitalized patients with coronavirus disease 2019 (COVID-19). Medications used to treat atrial fibrillation, such as antiarrhythmic drugs and anticoagulants, may have significant drug interactions with emerging COVID-19 treatments. Common unintended nontherapeutic target effects of COVID-19 treatment include potassium channel blockade, cytochrome P 450 isoenzyme inhibition or activation, and P-glycoprotein inhibition. Drug-drug interactions with antiarrhythmic drugs and anticoagulants in these patients may lead to significant bradycardia, ventricular arrhythmias, or severe bleeding. It is important for clinicians to be aware of these interactions, drug metabolism changes, and clinical consequences when choosing antiarrhythmic drugs and anticoagulants for COVID-19 patients with atrial fibrillation. The objective of this review is to provide a practical guide for clinicians who are managing COVID-19 patients with concomitant atrial fibrillation.

Heart failure as a substrate and trigger for ventricular tachycardia.

Heart failure (HF) is a major cause of morbidity and mortality with more than 5.1 million individuals affected in the USA. Ventricular tachyarrhythmias (VAs) including ventricular tachycardia and ventricular fibrillation are common in patients with heart failure. The pathophysiology of these mechanisms as well as the contribution of heart failure to the genesis of these arrhythmias is complex and multifaceted. Myocardial hypertrophy and stretch with increased preload and afterload lead to shortening of the action potential at early repolarization and lengthening of the action potential at final repolarization which can result in re-entrant ventricular tachycardia. Myocardial fibrosis and scar can create the substrate for re-entrant ventricular tachycardia. Altered calcium handling in the failing heart can lead to the development of proarrhythmic early and delayed after depolarizations. Various medications used in the treatment of HF such as loop diuretics and angiotensin converting enzyme inhibitors have not demonstrated a reduction in sudden cardiac death (SCD); however, beta-blockers (BB) are effective in reducing mortality and SCD. Amongst patients who have HF with reduced ejection fraction, the angiotensin receptor-neprilysin inhibitor (sacubitril/valsartan) has been shown to reduce cardiovascular mortality, specifically by reducing SCD, as well as death due to worsening HF. Implantable cardioverter-defibrillator (ICD) implantation in HF patients reduces the risk of SCD; however, subsequent mortality is increased in those who receive ICD shocks. Prophylactic ICD implantation reduces death from arrhythmia but does not reduce overall mortality during the acute post-myocardial infarction (MI) period (less than 40 days), for those with reduced ejection fraction and impaired autonomic dysfunction. Furthermore, although death from arrhythmias is reduced, this is offset by an increase in the mortality from non-arrhythmic causes. This article provides a review of the aforementioned mechanisms of arrhythmogenesis in heart failure; the role and impact of HF therapy such as cardiac resynchronization therapy (CRT), including the role, if any, of CRT-P and CRT-D in preventing VAs; the utility of both non-invasive parameters as well as multiple implant-based parameters for telemonitoring in HF; and the effect of left ventricular assist device implantation on VAs.

Effect of Lidocaine Injection of Ganglionated Plexi in a Canine Model and Patients With Persistent and Long-Standing Persistent Atrial Fibrillation.

Background This study assessed the effect of blockading neural transmission in the ganglionated plexi by injecting lidocaine into fat pads in the vagal nerve stimulation canine model and patients with persistent atrial fibrillation ( AF ). Methods and Results An efficacy test of lidocaine injection was performed in 7 canines. During vagal nerve stimulation, AF was sustained for >5 minutes. The lidocaine was injected into ganglionated plexi during sinus rhythm and reinduction of AF was attempted. Six patients with persistent AF were studied at open heart surgery. Lidocaine was injected into ganglionated plexi. Atrial electrograms were recorded from 96 epicardial electrodes covering Bachmann's bundle and atrial appendages. In the canine vagal nerve stimulation AF model, AF was not inducible in 4 of 7 after lidocaine injection. In patients with persistent AF , during baseline AF , there was a left atrium ( LA )-to-right atrium ( RA ) frequency gradient ( LA , mean cycle length [ CL ] 175±17 ms; RA , mean CL 192±17 ms; P<0.01). After lidocaine injection, AF persisted in all patients, and the LA -to- RA frequency gradient disappeared ( LA , mean CL 186±13 ms; RA , mean CL 199±23 ms; P=0.08). Comparison of mean CL s before and after lidocaine demonstrated prolongation of LA CL s ( P<0.05) with no effect on RA CL s. Conclusions In the canine vagal nerve stimulation AF model, lidocaine injection decreased inducibility of AF . In patients with persistent AF , atrial electrograms from the LA had shorter CL s than RA , indicating an LA -to- RA frequency gradient. Lidocaine injection significantly prolonged only LA CL s, explaining disappearance of the LA -to- RA frequency gradient. The mechanism of localized atrial electrogram CL prolongation in patients with persistent AF is uncertain.

Effect of acupuncture at Neiguan point combined with amiodarone therapy on early recurrence after pulmonary vein electrical isolation in patients with persistent atrial fibrillation.

OBJECTIVE: Early atrial fibrillation (AF) recurrences are common and have been shown to predict AF recurrences late after AF ablation during follow-up. Neiguan point acupuncture has been recognized to be therapeutic in treating AF in clinical practice. METHODS AND RESULTS: Eighty-five patients were enrolled in succession due to persistent AF. All patients were randomized divided into control group and acupuncture group. In the control group (n = 45), amiodarone was orally taken from the first day after pulmonary vein isolation (PVI). In the acupuncture group (n = 40), patients were treated with Neiguan point acupuncture for 7 days and amiodarone was prescribed as same as the control group after PVI. The levels of inflammatory factors were analyzed before operation, 1 week after the operation and 3 months later. After 3 months, the acupuncture group had a lower rate of early recurrences than the control group (5/40 [12.5%] vs 15/45 [33.3%], P = 0.039). The inflammatory factors level in the two groups were significantly increased after ablation. However, compared with the control group, the levels of TNF-α, IL-6, CRP, TGF-ß1, MMP2 in the acupuncture group significantly lower (P < 0.05). In a multivariate analysis, acupuncture was an independent factor associated with a lower rate of early recurrences during the blanking period (odds ratio, 0.17; 95% confidence interval, 0.05-0.63; P = 0.008). CONCLUSION: Neiguan point acupuncture combined with amiodarone is superior to amiodarone alone in reducing early recurrences of patients with persistent AF after PVI. The efficacy of Neiguan acupuncture therapy on the early recurrence is associated with the decreased inflammation factors.

Amiodarone and acupuncture for cardiac arrhythmia: Study protocol for a systematic review.

BACKGROUND: Amiodarone and acupuncture (AA) are commonly used to treat cardiac arrhythmia (CA). The objective of this systematic review is to assess the efficacy and safety of AA for patients with CA. METHODS: Randomized controlled trials (RCTs) of AA for CC will be searched from 9 databases including PubMed, EMBASE, Cochrane Library, Web of Science, Scopus, Chinese Biomedical Literature Database, China National Knowledge Infrastructure, VIP Information, and Wanfang Data from inception to February 1, 2019 without any limitations. Two reviewers will independently screen the relevant papers, extract data, and evaluate the risk of bias for each included study. RevMan 5.3 software will be used for meta-analysis. The primary outcome includes arrhythmic episodes (including time and frequency domain parameters). The secondary outcomes consist of health-related quality of life, oxygen saturation, and safety. RESULTS: The protocol of this proposed study will provide evidence to judge whether AA is an effective treatment for patients with CA. CONCLUSION: The findings of this proposed study will summarize the up-to-date evidence of AA for CA. PROSPERO REGISTRATION NUMBER: PROSPERO CRD42019120962.

A Pilot Randomized Trial of Oral Magnesium Supplementation on Supraventricular Arrhythmias.

Low magnesium may increase the risk of atrial fibrillation. We conducted a double-blind pilot randomized trial to assess adherence to oral magnesium supplementation (400 mg of magnesium oxide daily) and a matching placebo, estimate the effect on circulating magnesium concentrations, and evaluate the feasibility of using an ambulatory heart rhythm monitoring device (ZioPatch) for assessing premature atrial contractions. A total of 59 participants were randomized; 73% were women, and the mean age was 62 years. A total of 98% of the participants completed the follow-up. In the magnesium supplement group, 75% of pills were taken, and in the placebo group, 83% were taken. The change in magnesium concentrations was significantly greater for those given the magnesium supplements than for those given the placebo (0.07; 95% confidence interval: 0.03, 0.12 mEq/L; p = 0.002). The ZioPatch wear time was approximately 13 of the requested 14 days at baseline and follow-up. There was no difference by intervention assignment in the change in log premature atrial contractions burden, glucose, or blood pressure. Gastrointestinal changes were more common among the participants assigned magnesium (50%) than among those assigned the placebo (7%), but only one person discontinued participation. In sum, compliance with the oral magnesium supplementation was very good, and acceptance of the ZioPatch monitoring was excellent. These findings support the feasibility of a larger trial for atrial fibrillation (AF) prevention with oral magnesium supplementation.

Evaluating the effect of magnesium supplementation and cardiac arrhythmias after acute coronary syndrome: a systematic review and meta-analysis.

BACKGROUND: Atrial and ventricular cardiac arrhythmias are one of the most common early complications after cardiac surgery and these serve as a major cause of mortality and morbidity after cardiac revascularization. We want to evaluate the effect of magnesium sulfate administration on the incidence of cardiac arrhythmias after cardiac revascularization by doing this systematic review and meta-analysis. METHODS: The search performed in several databases (SID, Magiran, IranDoc, IranMedex, MedLib, PubMed, EmBase, Web of Science, Scopus, the Cochrane Library and Google Scholar) for published Randomized controlled trials before December 2017 that have reported the association between Magnesium consumption and the incidence of cardiac arrhythmias. This relationship measured using odds ratios (ORs) with a confidence interval of 95% (CIs). Funnel plots and Egger test used to examine publication bias. STATA (version 11.1) used for all analyses. RESULTS: Twenty-two studies selected as eligible for this research and included in the final analysis. The total rate of ventricular arrhythmia was lower in the group receiving magnesium sulfate than placebo (11.88% versus 24.24%). The same trend obtained for the total incidence of supraventricular arrhythmia (10.36% in the magnesium versus 23.91% in the placebo group). In general the present meta-analysis showed that magnesium could decrease ventricular and supraventricular arrhythmias compared with placebo (OR = 0.32, 95% CI 0.16-0.49; p < 0.001 and OR = 0.42, 95% CI 0.22-0.65; p < 0.001, respectively). Subgroup analysis showed that the effect of magnesium on the incidence of cardiac arrhythmias was not affected by clinical settings and dosage of magnesium. Meta-regression analysis also showed that there was no significant association between the reduction of ventricular arrhythmias and sample size. CONCLUSION: The results of this meta-analysis study suggest that magnesium sulfate can be used safely and effectively and is a cost-effective way in the prevention of many of ventricular and supraventricular arrhythmias.

Sole and combined vitamin C supplementation can prevent postoperative atrial fibrillation after cardiac surgery: A systematic review and meta-analysis of randomized controlled trials.

We undertook a systematic review and meta-analysis to evaluate the effect of vitamin C supplementation (vitamin C solely or as adjunct to other therapy) on prevention of postoperative atrial fibrillation (POAF) in patients after cardiac surgery. PubMed, Embase, Web of Science, and Cochrane Library were systematically searched to identify randomized controlled trials assessing the effect of vitamin C supplementation in adult patients undergoing cardiac surgery, and the meta-analysis was performed with a random-effects model. Thirteen trials involving 1956 patients were included. Pooling estimate showed a significantly reduced incidence of POAF (relative risk [RR]: 0.68, 95% confidence interval [CI]: 0.54 to 0.87, P = 0.002) both in vitamin C alone (RR: 0.75, 95% CI: 0.63 to 0.90, P = 0.002) and as an adjunct to other therapy (RR: 0.32, 95% CI: 0.20 to 0.53, P < 0.001). The results remain stable and robust in subgroup and sensitivity analyses, and trial sequential analysis also confirmed that the evidence was sufficient and conclusive. Additionally, vitamin C could significantly decrease intensive care unit length of stay (weighted mean difference: -0.24 days, 95% CI: -0.45 to -0.03, P = 0.023), hospital length of stay (weighted mean difference: -0.95 days, 95% CI: -1.64 to -0.26, P = 0.007), and risk of adverse events (RR: 0.45, 95% CI: 0.21 to 0.96, P = 0.039). Use of vitamin C alone and as adjunct to other therapy can prevent POAF in patients undergoing cardiac surgery and should be recommended for patients receiving cardiac surgery for prevention of POAF.

Therapy Of Cardiac Arrhythmias In Children: An Emerging Role Of Electroanatomical Mapping Systems.

INTRODUCTION: Cardiac arrhythmias are challenging diseases in childhood. Most of them in pediatric subjects (90.2%) are atrioventricular reentrant tachycardias and atrioventricular nodal reentrant tachycardias. The standard 12-lead ECG is a highly accurate diagnostic tool but an invasive electrophysiological study is often required. The main concern about this kind of procedures is their invasive nature and the need of radiations, so antiarrhythmic agents are currently the first line therapy. However, they often show side effects and can be insufficient for the rate control. MATERIALS AND METHODS: We performed a systematic research on Embase and PubMed. We found 563 articles and selected the most representative 50. DISCUSSION: Management of cardiac arrhythmias could be very difficult in several scenarios, especially in children with body weight <15 kg and age <4 years. In general, pediatric subjects show a cumulative risk of malignancy greater than adults, having greater life expectancy. On this basis the guiding principle during radiation delivery in electrophysiological procedures is "as low as reasonably achievable" (acronym: ALARA). The development of 3-dimensional (3D) electroanatomical mapping systems allowed significant reduction of exposure. The most recently reported experiences demonstrate safety and feasibility of fluoroless ablation in the most common arrhythmias in children, even in challenging conditions. CONCLUSION: The first reasonable approach in cardiac arrhythmias involving younger patients seems to be pharmacological. However antiarrhythmic drugs pose problems both in terms of side effects and often have poor efficacy. Expertise in electrophysiological techniques is constantly increasing and the development of new technologies allow us to encourage the use of electroanatomical mapping systems in order to reduce the radiation exposure in children undergoing to catheter ablation, especially for accessory pathways.

Change in QRS morphology as a marker of spontaneous elimination in verapamil-sensitive idiopathic left ventricular tachycardia.

BACKGROUND: Verapamil-sensitive idiopathic left ventricular tachycardia (verapamil-ILVT) is thought to be due to a reentry within the LV fascicular system. Radiofrequency catheter ablation (RFCA) is effective for elimination of the VT; however, a long-term prognosis of patients with verapamil-ILVT is still unclear. METHODS AND RESULTS: Eighty consecutive verapamil-ILVT patients (62 men, 31 ± 12 years of age, LVEF: 65 ± 4%) were enrolled. Seventy-six (95%) cases of VT involved right bundle branch block and left axis deviation. We retrospectively analyzed changes in the QRS duration (ΔQRS-d) and QRS axis (ΔQRS-axis) during follow-up and compared them with recurrence of VT. During a mean follow-up period of 10 years (2-32 years), no sudden death or heart failure occurred. Fifty-one (64%) patients underwent RFCA, and 46 (90%) of them had no VT without any medication after RFCA. The ΔQRS-d (16 ± 2 vs. 8 ± 1 ms, P = 0.24) and ΔQRS-axis (20 ± 4 vs. 4 ± 3 degrees, P = 0.23) were not different in patients with no VT (VT[-]) and those with recurrence of VT (VT[+]). However, in the remaining 29 patients without RFCA, VT was spontaneously eliminated in 16 patients. The ΔQRS-d (30 ± 6 vs. 6 ± 1 ms, P = 0.002) and ΔQRS-axis (23 ± 4 vs. 5 ± 2 degrees, P = 0.001) were significantly larger in VT(-) patients compared to VT(+) patients during follow-up. CONCLUSIONS: Some verapamil-ILVT patients who show QRS morphology changes over the follow-up period may become free from VT without any invasive or pharmacological treatments, suggesting that further altered LV fascicular conduction might eliminate the reentry of verapamil-ILVT.

Computational modeling for cardiac safety pharmacology analysis: Contribution of fibroblasts.

INTRODUCTION: Drug-induced proarrhythmic potential is an important regulatory criterion in safety pharmacology. The application of in silico approaches to predict proarrhythmic potential of new compounds is under consideration as part of future guidelines. Current approaches simulate the electrophysiology of a single human adult ventricular cardiomyocyte. However, drug-induced proarrhythmic potential can be different when cardiomyocytes are surrounded by non-muscle cells. Incorporating fibroblasts in models of myocardium is important particularly for predicting a drugs cardiac liability in the aging population - a growing population who take more medications and exhibit increased cardiac fibrosis. In this study, we used computational models to investigate the effects of fibroblast coupling on the electrophysiology and response to drugs of cardiomyocytes. METHODS: A computational model of cardiomyocyte electrophysiology and ion handling (O'Hara, Virag, Varro, & Rudy, 2011) is coupled to a passive model of fibroblast electrophysiology to test the effects of three compounds that block cardiomyocyte ion channels. Results are compared to model results without fibroblast coupling to see how fibroblasts affect cardiomyocyte action potential duration at 90% repolarization (APD90) and propensity for early after depolarization (EAD). RESULTS: Simulation results show changes in cardiomyocyte APD90 with increasing concentration of three drugs that affect cardiac function (dofetilide, vardenafil and nebivolol) when no fibroblasts are coupled to the cardiomyocyte. Coupling fibroblasts to cardiomyocytes markedly shortens APD90. Moreover, increasing the number of fibroblasts can augment the shortening effect. DISCUSSION: Coupling cardiomyocytes and fibroblasts are predicted to decrease proarrhythmic susceptibility under dofetilide, vardenafil and nebivolol block. However, this result is sensitive to parameters which define the electrophysiological function of the fibroblast. Fibroblast membrane capacitance and conductance (CFB and GFB) have less of an effect on APD90 than the fibroblast resting membrane potential (EFB). This study suggests that in both theoretical models and experimental tissue constructs that represent cardiac tissue, both cardiomyocytes and non-muscle cells should be considered when testing cardiac pharmacological agents.

Intra-arterial verapamil post-thrombectomy is feasible, safe, and neuroprotective in stroke.

Large vessel ischemic stroke represents the most disabling subtype. While t-PA and endovascular thrombectomy can recanalize the occluded vessel, good clinical outcomes are not uniformly achieved. We propose that supplementing endovascular thrombectomy with superselective intra-arterial (IA) verapamil immediately following recanalization could be safe and effective. Verapamil, a calcium channel blocker, has been shown to be an effective IA adjunct in a pre-clinical mouse focal ischemia model. To demonstrate translational efficacy, mechanism, feasibility, and safety, we conducted a group of translational experiments. We performed in vivo IA dose-response evaluation in our animal stroke model with C57/Bl6 mice. We evaluated neuroprotective mechanism through in vitro primary cortical neuron (PCN) cultures. Finally, we performed a Phase I trial, SAVER-I, to evaluate feasibility and safety of administration in the human condition. IA verapamil has a likely plateau or inverted-U dose-response with a defined toxicity level in mice (LD50 16-17.5 mg/kg). Verapamil significantly prevented PCN death and deleterious ischemic effects. Finally, the SAVER-I clinical trial showed no evidence that IA verapamil increased the risk of intracranial hemorrhage or other adverse effect/procedural complication in human subjects. We conclude that superselective IA verapamil administration immediately following thrombectomy is safe and feasible, and has direct, dose-response-related benefits in ischemia.