Antiarrhythmic drug therapy and catheter ablation in patients with paroxysmal or persistent atrial fibrillation: a systematic review and meta-analysis.

BACKGROUND: Catheter ablation and antiarrhythmic drug therapy are utilized for rhythm control in atrial fibrillation (AF), but their comparative effectiveness, especially with contemporary treatment modalities, remains undefined. We conducted a systematic review and meta-analysis contrasting current ablation techniques against antiarrhythmic medications for AF. METHODS: We searched PubMed, SCOPUS, Cochrane CENTRAL, and Web of Science until November 2023 for randomized trials comparing AF catheter ablation with antiarrhythmics, against antiarrhythmic drug therapy alone, reporting outcomes for > 6 months. Four investigators extracted data and appraised risk of bias (ROB) with ROB 2 tool. Meta-analyses estimated pooled efficacy and safety outcomes using R software. RESULTS: Twelve trials (n = 3977) met the inclusion criteria. Catheter ablation was associated with lower AF recurrence (relative risk (RR) = 0.44, 95%CI (0.33, 0.59), P ˂ 0.0001) and hospitalizations (RR = 0.44, 95%CI (0.23, 0.82), P = 0.009) than antiarrhythmic medications. Catheter ablation also improved the physical quality of life component score (assessed by a 36-item Short Form survey) by 7.61 points (95%CI -0.70-15.92, P = 0.07); but, due to high heterogeneity, it was not statistically significant. Ablation was significantly associated with higher procedural-related complications [RR = 15.70, 95%CI (4.53, 54.38), P < 0.0001] and cardiac tamponade [RR = 9.22, 95%CI (2.16, 39.40), P = 0.0027]. All-cause mortality was similar between the two groups. CONCLUSIONS: For symptomatic AF, upfront catheter ablation reduces arrhythmia and hospitalizations better than continued medical therapy alone, albeit with moderately more adverse events. Careful patient selection and risk-benefit assessment are warranted regarding the timing of ablation.

Structural characterization, in vivo toxicity and biological activity of two new pyro-type diterpenoid alkaloids derived from 3-acetylaconitine.

OBJECTIVE: The transformations that occur in diterpenoid alkaloids during the process of sand frying for Chinese herbal medicine preparation have yet to be clarified. This study investigated the structural changes that take place in 3-acetylaconitine during a simulation of heat-processing and evaluated the toxicity and biological activity of the pyrolysis products. METHODS: The diterpenoid alkaloid 3-acetylaconitine was heated at 180 °C for 15 min to simulate the process of sand frying. The pyrolysis products were separated using column chromatography, and their structures were investigated using high-resolution electrospray ionization mass spectroscopy and nuclear magnetic resonance spectroscopy. Further, in vivo cardiotoxicity and acute toxicity of 3-acetylaconitine and its pyrolysis products were compared, and the aconitine-induced arrhythmia model was employed to evaluate the antiarrhythmic effect of the pyrolysis products. RESULTS: Two new diterpenoid alkaloids, pyroacetylaconitine and 16-epi-pyroacetylaconitine, a pair of epimers at C-16, were isolated. After comparing the structures of these compounds, possible transformation pathways were proposed. Compared with the prototype compound, 3-acetylaconitine, the cardiotoxicity and acute toxicity of the heat-transformed products were significantly decreased. In the biological activity assay, the two pyrolysis products exhibited an effective increase in ventricular premature beat latency, a reduction in the occurrence of ventricular tachycardia, as well as an increase in the rate of arrhythmia inhibition, implying strong antiarrhythmic activity. CONCLUSION: Compared with 3-acetylaconitine, its pyrolysis products displayed lower toxicity and good antiarrhythmic effects; thus, they have potential for being developed into antiarrhythmic medicines. Please cite this article as: Wang YJ, Wang Y, Tao P. Structural characterization, in vivo toxicity and biological activity of two new pyro-type diterpenoid alkaloids derived from 3-acetylaconitine. J Integr Med. 2023; 21(3): 302-314.

Structural characterization, in vivo toxicity and biological activity of two new pyro-type diterpenoid alkaloids derived from 3-acetylaconitine / 中西医结合学报

OBJECTIVE@#The transformations that occur in diterpenoid alkaloids during the process of sand frying for Chinese herbal medicine preparation have yet to be clarified. This study investigated the structural changes that take place in 3-acetylaconitine during a simulation of heat-processing and evaluated the toxicity and biological activity of the pyrolysis products.@*METHODS@#The diterpenoid alkaloid 3-acetylaconitine was heated at 180 °C for 15 min to simulate the process of sand frying. The pyrolysis products were separated using column chromatography, and their structures were investigated using high-resolution electrospray ionization mass spectroscopy and nuclear magnetic resonance spectroscopy. Further, in vivo cardiotoxicity and acute toxicity of 3-acetylaconitine and its pyrolysis products were compared, and the aconitine-induced arrhythmia model was employed to evaluate the antiarrhythmic effect of the pyrolysis products.@*RESULTS@#Two new diterpenoid alkaloids, pyroacetylaconitine and 16-epi-pyroacetylaconitine, a pair of epimers at C-16, were isolated. After comparing the structures of these compounds, possible transformation pathways were proposed. Compared with the prototype compound, 3-acetylaconitine, the cardiotoxicity and acute toxicity of the heat-transformed products were significantly decreased. In the biological activity assay, the two pyrolysis products exhibited an effective increase in ventricular premature beat latency, a reduction in the occurrence of ventricular tachycardia, as well as an increase in the rate of arrhythmia inhibition, implying strong antiarrhythmic activity.@*CONCLUSION@#Compared with 3-acetylaconitine, its pyrolysis products displayed lower toxicity and good antiarrhythmic effects; thus, they have potential for being developed into antiarrhythmic medicines. Please cite this article as: Wang YJ, Wang Y, Tao P. Structural characterization, in vivo toxicity and biological activity of two new pyro-type diterpenoid alkaloids derived from 3-acetylaconitine. J Integr Med. 2023; 21(3): 302-314.

Mechanism-based targeting of cardiac arrhythmias by phytochemicals and medicinal herbs: A comprehensive review of preclinical and clinical evidence.

Cardiac arrhythmias, characterized by an irregular heartbeat, are associated with high mortality and morbidity. Because of the narrow therapeutic window of antiarrhythmic drugs (AADs), the management of arrhythmia is still challenging. Therefore, searching for new safe, and effective therapeutic options is unavoidable. In this study, the antiarrhythmic effects of medicinal plants and their active constituents were systematically reviewed to introduce some possible candidates for mechanism-based targeting of cardiac arrhythmias. PubMed, Embase, and Cochrane library were searched from inception to June 2021 to find the plant extracts, phytochemicals, and multi-component herbal preparations with antiarrhythmic activities. From 7337 identified results, 57 original studies consisting of 49 preclinical and eight clinical studies were finally included. Three plant extracts, eight multi-component herbal preparations, and 26 phytochemicals were found to have antiarrhythmic effects mostly mediated by affecting K+ channels, followed by modulating Ca2+ channels, upstream target pathways, Na v channels, gap junction channels, and autonomic receptors. The most investigated medicinal plants were Rhodiola crenulata and Vitis vinifera. Resveratrol, Oxymatrine, and Curcumin were the most studied phytochemicals found to have multiple mechanisms of antiarrhythmic action. This review emphasized the importance of research on the cardioprotective effect of medicinal plants and their bioactive compounds to guide the future development of new AADs. The most prevalent limitation of the studies was their unqualified methodology. Thus, future well-designed experimental and clinical studies are necessary to provide more reliable evidence.

Electrocardiographic marker of the cardiac action potential triangulation induced by antiarrhythmic drugs in perfused guinea-pig heart.

NEW FINDINGS: What is the central question of this study? Can the triangular appearance of ventricular action potential, indicating proarrhythmic profile of antiarrhythmic agent, be approximated by specific changes on an electrocardiogram (ECG)? What are the main finding and its importance? The triangulation of the ventricular action potential seen when antiarrhythmic drugs induce a greater lengthening of the late repolarization compared to the initial repolarization in epicardium is closely approximated by a greater prolongation of the T wave upslope relative to the interval between the J point and the start of the T wave (the JTstart interval) on the ECG. These findings may improve the power of ECG assessments in predicting the drug-induced arrhythmia resulting from slowed phase 3 repolarization. ABSTRACT: Antiarrhythmic drugs prescribed to treat atrial fibrillation can occasionally precipitate ventricular tachyarrhythmia through a prominent slowing of the phase 3 repolarization. The latter results in the triangular shape of ventricular action potential, indicating high arrhythmic risk. However, clinically, the utility of triangulation assessments for predicting arrhythmia is limited owing to the invasive nature of the ventricular action potential recordings. This study examined whether the triangulation effect can be detected indirectly from electrocardiogram (ECG) analysis. Epicardial monophasic action potentials and the ECG were simultaneously recorded in perfused guinea-pig hearts. With antiarrhythmics (dofetilide, quinidine, procainamide and flecainide), a prolongation of the initial repolarization seen in the action potential recordings was closely approximated by lengthening of the interval between the J point and the start of the T wave (the JTstart interval) on the ECG, whereas a prolongation of the late repolarization was paralleled by widening of the T wave upslope. Dofetilide, quinidine and procainamide induced a prominent slowing of the phase 3 repolarization in epicardium, leading to triangulation of the action potential. These effects were accompanied by a greater prolongation of the T wave upslope compared to the JTstart interval. Flecainide elicited a proportional prolongation of the initial and the late ventricular repolarization, and therefore failed to induce triangulation, based on analysis of both epicardial action potential and ECG profiles. Collectively, these findings suggest that the ratio between the durations of the T wave upslope and the JTstart interval may represent the ECG metric of the ventricular action potential triangulation induced by antiarrhythmic drugs.

Análisis del tratamiento para mantener el ritmo sinusal en pacientes con fibrilación auricular prescrito en los servicios de urgencias: subanálisis del estudio HERMES-AF / Emergency department prescription of sinus rhythm maintenance therapy for patients treated for atrial fibrillation: a secondary analysis of the HERMES-AF study

Objetivo. El mantenimiento del ritmo sinusal (RS) con fármacos antiarrítmicos (FAA) y/o tratamiento del remodelado (TRM) es parte fundamental en la estrategia de control del ritmo en la fibrilación auricular (FA). Este estudio analiza estas estrategias y su adecuación en los servicios de urgencias hospitalarios (SUH). Método. Análisis secundario del estudio multicéntrico observacional transversal HERMES-AF, desarrollado en 124 SUH representativos del sistema sanitario español en 2011. Se incluyeron pacientes consecutivos con FA que revirtieron a RS y fueron dados de alta desde urgencias. Resultados. Se incluyeron 449 pacientes: 204 (45,4%) ya realizaban tratamiento para mantenimiento del RS. De los 245 restantes se prescribió tratamiento en el SUH a 107 (43,7%): 41 con FAA, 19 TRM y en 47 ambas terapias. En 10 casos (11,8%) la selección del FAA no era acorde a las recomendaciones de las guías. La prescripción de FAA se asoció a FA previa [odds ratio (OR) 2,024, IC 95%: 1,196-3,424, p = 0,009], frecuencia cardiaca > 110 lpm (OR 2,147, IC 95%: 1,034-4,456, p = 0,040) y anticoagulación al alta (OR 1,862, IC 95%: 1,094-3,170, p = 0,022). El TRM se asoció a frecuencia cardiaca > 110 lpm (OR 2,187, IC 95%: 1,005-4,757, p = 0,018). En total, al alta del SUH 311 pacientes (69,2%) recibían tratamiento para mantenimiento del RS (87 con FAA, 117 con TRM y 107 con ambas terapias). Conclusiones. La prescripción de tratamiento para evitar las recurrencias de la FA es insuficiente en los SUH. Extender esta prescripción y mejorar la adecuación del tratamiento antiarrítmico son áreas de mejora de la estrategia de control del ritmo en los SUH.

Background and objective. The maintenance of sinus rhythm by means of antiarrhythmic drugs and/or upstream therapy to counter cardiac remodeling is fundamental to the management of atrial fibrillation (AF). This study aimed to analyze this approach and its appropriateness in the setting of hospital emergency departments. Methods. Secondary analysis of data from the multicenter observational cross-sectional HERMES-AF study carried out in 124 hospitals representative of the Spanish national health service in 2011. Included were consecutive patients with AF restored to sinus rhythm who were discharged home from emergency care. Results. A total of 449 patients were included; 204 (45.4%) were already on sinus rhythm maintenance therapy. Of the 245 remaining patients, 107 (43.67%) were prescribed maintenance treatment in the emergency department, as follows: 41, an antiarrhythmic drug; 19, upstream therapy; and 49, both treatments. The selection of an antiarrhythmic drug did not follow guideline recommendations in 10 patients (11.8%). Antiarrhythmic drug prescription was associated with having had a prior episode of AF (odds ratio [OR], 2.024; 95% CI, 1.196-3.424; P = .009); a heart rate of more than 110 beats/min (OR, 2.147; 95% CI, 1.034-4.456, P = 0.40); and prescription of anticoagulation on discharge (OR, 1.862; 95% CI, 1.094-3.170; P = .022). Upstream therapy prescription was associated only with a heart rate over 110 beats/min (OR, 2.187; 95% CI, 1.005-4.757; P = .018). In total, 311 patients (69.23%) were discharged from the emergency department with sinus rhythm maintenance therapy: 87 with an antiarrhythmic drug, 117 with an upstream therapy, and 107 with both. Conclusions. Treatment to prevent the recurrence of AF is underprescribed in emergency departments. Increasing such prescription and ensuring the appropriateness of antiarrhythmic therapy prescribed are points emergency departments can improve in the interest of better sinus rhythm maintenance.

Emergency department prescription of sinus rhythm maintenance therapy for patients treated for atrial fibrillation: a secondary analysis of the HERMES-AF study / Análisis del tratamiento para mantener el ritmo sinusal en pacientes con fibrilación auricular prescrito en los servicios de urgencias: subanálisis del estudio HERMES-AF

OBJECTIVES: The maintenance of sinus rhythm by means of antiarrhythmic drugs and/or upstream therapy to counter cardiac remodeling is fundamental to the management of atrial fibrillation (AF). This study aimed to analyze this approach and its appropriateness in the setting of hospital emergency departments. MATERIAL AND METHODS: Secondary analysis of data from the multicenter observational cross-sectional HERMES-AF study carried out in 124 hospitals representative of the Spanish national health service in 2011. Included were consecutive patients with AF restored to sinus rhythm who were discharged home from emergency care. RESULTS: A total of 449 patients were included; 204 (45.4%) were already on sinus rhythm maintenance therapy. Of ,the 245 remaining patients, 107 (43.67%) were prescribed maintenance treatment in the emergency department, as follows: 41, an antiarrhythmic drug; 19, upstream therapy; and 49, both treatments. The selection of an antiarrhythmic drug did not follow guideline recommendations in 10 patients (11.8%). Antiarrhythmic drug prescription was associated with having had a prior episode of AF (odds ratio [OR], 2.024; 95% CI, 1.196-3.424; P = .009); a heart rate of more than 110 beats/min (OR, 2.147; 95% CI, 1.034-4.456, P = 0.40); and prescription of anticoagulation on discharge (OR, 1.862; 95% CI, 1.094-3.170; P = .022). Upstream therapy prescription was associated only with a heart rate over 110 beats/min (OR, 2.187; 95% CI, 1.005-4.757; P = .018). In total, 311 patients (69.23%) were discharged from the emergency department with sinus rhythm maintenance therapy: 87 with an antiarrhythmic drug, 117 with an upstream therapy, and 107 with both. CONCLUSION: Treatment to prevent the recurrence of AF is underprescribed in emergency departments. Increasing such prescription and ensuring the appropriateness of antiarrhythmic therapy prescribed are points emergency departments can improve in the interest of better sinus rhythm maintenance.

OBJETIVO: El mantenimiento del ritmo sinusal (RS) con fármacos antiarrítmicos (FAA) y/o tratamiento del remodelado (TRM) es parte fundamental en la estrategia de control del ritmo en la fibrilación auricular (FA). Este estudio analiza estas estrategias y su adecuación en los servicios de urgencias hospitalarios (SUH). METODO: Análisis secundario del estudio multicéntrico observacional transversal HERMES-AF, desarrollado en 124 SUH representativos del sistema sanitario español en 2011. Se incluyeron pacientes consecutivos con FA que revirtieron a RS y fueron dados de alta desde urgencias. RESULTADOS: Se incluyeron 449 pacientes: 204 (45,4%) ya realizaban tratamiento para mantenimiento del RS. De los 245 restantes se prescribió tratamiento en el SUH a 107 (43,7%): 41 con FAA, 19 TRM y en 47 ambas terapias. En 10 casos (11,8%) la selección del FAA no era acorde a las recomendaciones de las guías. La prescripción de FAA se asoció a FA previa [odds ratio (OR) 2,024, IC 95%: 1,196-3,424, p = 0,009], frecuencia cardiaca > 110 lpm (OR 2,147, IC 95%: 1,034-4,456, p = 0,040) y anticoagulación al alta (OR 1,862, IC 95%: 1,094-3,170, p = 0,022). El TRM se asoció a frecuencia cardiaca > 110 lpm (OR 2,187, IC 95%: 1,005-4,757, p = 0,018). En total, al alta del SUH 311 pacientes (69,2%) recibían tratamiento para mantenimiento del RS (87 con FAA, 117 con TRM y 107 con ambas terapias). CONCLUSIONES: La prescripción de tratamiento para evitar las recurrencias de la FA es insuficiente en los SUH. Extender esta prescripción y mejorar la adecuación del tratamiento antiarrítmico son áreas de mejora de la estrategia de control del ritmo en los SUH.

Investigating the efficiency and tolerability of traditional Chinese formulas combined with antiarrhythmic agents for paroxysmal atrial fibrillation: A systematic review and Bayesian network meta-analysis.

BACKGROUND: The combination of antiarrhythmic drugs with traditional Chinese formulas are used treatments for the management of paroxysmal atrial fibrillation (PAF). However, the most effective treatment for PAF has yet to be been determined. A Bayesian network meta-analysis study was thus performed for comparing the relative efficacy and tolerability of different treatment alternatives. METHODS: A comprehensive literature review of randomized controlled trials (RCTs) is performed from eight database. Maintenance rate of sinus rhythm (MRSR), p-wave dispersion (Pd), left atrium diameter (LAD), left ventricular ejection fraction (LVEF), and adverse events (AEs) were used as outcomes. We also estimated treatment rank based on the surface under the cumulative ranking curve (SUCRA). This study was performed using a Bayesian network meta-analysis with a random-effects model. FINDINGS: After screening, 59 RCTs involving 5,543 patients and 16 treatments were included. The results showed that Shensong-Yangxin capsule (SSYX) plus amiodarone (81%) was the most effective treatment for MRSR according to the value of SUCRA, followed by Wenxin-Keli granules (WXKL) plus amiodarone (73%). Meanwhile, SSYX plus amiodarone (7%) was most likely to reduce Pd, followed by SSYX plus metoprolol (23%), WXKL plus amiodarone (26%), WXKL plus bisoprolol (27%). Furthermore, SSYX plus amiodarone (4%) was more effective in improving LAD. WXKL plus amiodarone was preferred because it had the lowest toxicity. For benefit-risk ratio, amiodarone combined with WXKL or SSYX appeared to be the best option. CONCLUSION: Antiarrhythmic agents combined with traditional Chinese formulas had higher efficacy and lower toxicity than other treatment alternatives. This study might provide reference to help find the better treatment options for PAF.

Novel Arylpiperazine Derivatives of Salicylamide with α1-Adrenolytic Properties Showed Antiarrhythmic and Hypotensive Properties in Rats.

Cardiovascular diseases remain one of the leading causes of death worldwide. Unfortunately, the available pharmacotherapeutic options have limited effectiveness. Therefore, developing new drug candidates remains very important. We selected six novel arylpiperazine alkyl derivatives of salicylamide to investigate their cardiovascular effects. Having in mind the beneficial role of α1-adrenergic receptors in restoring sinus rhythm and regulating blood pressure, first, using radioligand binding assays, we evaluated the affinity of the tested compounds for α-adrenergic receptors. Our experiments revealed their high to moderate affinity for α1- but not α2-adrenoceptors. Next, we aimed to determine the antiarrhythmic potential of novel derivatives in rat models of arrhythmia induced by adrenaline, calcium chloride, or aconitine. All compounds showed potent prophylactic antiarrhythmic activity in the adrenaline-induced arrhythmia model and no effects in calcium chloride- or aconitine-induced arrhythmias. Moreover, the tested compounds demonstrated therapeutic antiarrhythmic activity, restoring a normal sinus rhythm immediately after the administration of the arrhythmogen adrenaline. Notably, none of the tested derivatives affected the normal electrocardiogram (ECG) parameters in rodents, which excludes their proarrhythmic potential. Finally, all tested compounds decreased blood pressure in normotensive rats and reversed the pressor response to methoxamine, suggesting that their hypotensive mechanism of action is connected with the blockade of α1-adrenoceptors. Our results confirm the antiarrhythmic and hypotensive activities of novel arylpiperazine derivatives and encourage their further investigation as model structures for potential drugs.

Treatment of Permanent Junctional Reciprocating Tachycardia in a Preterm Neonate: Case Report.

Permanent junctional reciprocating tachycardia (PJRT) is most often observed in infants and children and can lead to incessant tachycardia. PJRT is usually refractory to medical treatment. Tachycardia may infrequently occur in the fetus in which case fetal tachycardia transplacental treatment should be started immediately. Term delivery is recommended for fetuses with tachycardia in the absence of significant clinical compromise to avoid complications of preterm birth. Herein, a 36-week preterm neonate presented with PJRT. He had tachycardia in the fetal period and was treated with digoxin, amiodaron, and esmolol therapy after birth without undergoing the catheter ablation procedure.

Recognition, Prevention, and Management of Arrhythmias and Autonomic Disorders in Cardio-Oncology: A Scientific Statement From the American Heart Association.

With the advent of novel cancer therapeutics and improved screening, more patients are surviving a cancer diagnosis or living longer with advanced disease. Many of these treatments have associated cardiovascular toxicities that can manifest in both an acute and a delayed fashion. Arrhythmias are an increasingly identified complication with unique management challenges in the cancer population. The purpose of this scientific statement is to summarize the current state of knowledge regarding arrhythmia identification and treatment in patients with cancer. Atrial tachyarrhythmias, particularly atrial fibrillation, are most common, but ventricular arrhythmias, including those related to treatment-induced QT prolongation, and bradyarrhythmias can also occur. Despite increased recognition, dedicated prospective studies evaluating true incidence are lacking. Moreover, few studies have addressed appropriate prevention and treatment strategies. As such, this scientific statement serves to mobilize the cardio-oncology, electrophysiology, and oncology communities to develop clinical and scientific collaborations that will improve the care of patients with cancer who have arrhythmias.

QT Dispersion and Drug-Induced Torsade de Pointes.

Background Amiodarone causes less drug-induced torsade de pointes (TdP) compared to other class III antiarrhythmics. Two theories proposed for this finding include that amiodarone has less repolarization heterogeneity, and/or decreases early after depolarization (EADs). Corrected QT (QTc) dispersion as measured on a surface electrocardiogram (ECG) represents spatial heterogeneity of ventricular repolarization. Objective The purpose of this study was to analyze the difference in QT dispersion between amiodarone and other class III antiarrhythmics and to determine the etiology of TdP. Methods This was a retrospective, observational study at Montefiore Medical Center between January 2005 and January 2015. Inclusion criteria were adults >18 years on amiodarone, dofetilide, or sotalol with prolonged QT interval on 12-lead ECG. ECGs were reviewed by three blinded observers. QTc was calculated using the Bazett and Framingham formulas. QTc dispersion was calculated by subtracting the shortest from the longest QTc. Analysis of variance (ANOVA) was applied for comparison between antiarrhythmic groups with Bonferroni correction for multiple comparisons. Results A total of 447 ECGs were reviewed and 77 ECGs met inclusion criteria. The average QT dispersion for amiodarone, dofetilide, and sotalol was 0.050, 0.037, and 0.034, respectively (p=0.006) and the average QTc dispersion by Bazett was 0.053, 0.038, and 0.037 (p=0.008) and by Framingham was 0.049, 0.036, and 0.035 (p=0.009), respectively. Conclusion Our results show that given the increase in QT dispersion seen with amiodarone, heterogeneous ventricular repolarization as measured by QTc dispersion likely does not account for the lower incidence of drug-induced TdP seen with amiodarone. The ability of amiodarone to decrease EADs via sodium-channel blockade is more likely the explanation for its lower incidence of drug-induced TdP.

Tachyarrhythmias and neurologic complications.

Tachyarrhythmias are abnormal heart rhythms with a ventricular rate of 100 or more beats per minute. These rhythms are classified as either narrow or wide-complex tachycardia with further subdivision into regular or irregular rhythm. Patients are frequently symptomatic presenting with palpitations, diaphoresis, dyspnea, chest pain, dizziness, and syncope. Sudden cardiac death may occur with certain arrhythmias. Recognizing tachyarrhythmia and understanding its management is important as a wide spectrum of neurologic complications have been associated with such arrhythmias. The purpose of this chapter is to provide a comprehensive overview on the neurologic complications of tachyarrhythmias, neurologic adverse events of antiarrhythmic interventions, and neurologic conditions that can precipitate tachyarrhythmia.

Voltage-Gated Sodium Channel Blockers: Synthesis of Mexiletine Analogues and Homologues.

Mexiletine is an antiarrhythmic drug belonging to IB class, acting as sodium channel blocker. Besides its well-known activity on arrhythmias, its usefulness in the treatment of myotonia, myotonic dystrophy and amyotrophic lateral sclerosis is now widely recognized. Nevertheless, it has been retired from the market in several countries because of its undesired effects. Thus, several papers were reported in the last years about analogues and homologues of mexiletine being endowed with a wider therapeutic ratio and a more selectivity of action. Some of them showed sodium channel blocking activity higher than the parent compound. It is noteworthy that mexiletine is used in therapy as a racemate even though a difference in the activities of the two enantiomers was widely demonstrated, with (-)-(R)-enantiomer being more active: this finding led several research groups to study mexiletine and its analogues and homologues in their optically active forms. This review summarizes the different synthetic routes used to obtain these compounds. They could represent an interesting starting point to new mexiletine-like compounds without common side effects related to the use of mexiletine.

Dantrolene reduces CaMKIIδC-mediated atrial arrhythmias.

AIMS: In atrial fibrillation (AF), an increased diastolic Ca2+ leak from the sarcoplasmic reticulum (SR) mediated by calcium/calmodulin-dependent-protein-kinaseIIδC (CaMKII) can serve as a substrate for arrhythmia induction and persistence. Dantrolene has been shown to stabilize the cardiac ryanodine-receptor. This study investigated the effects of dantrolene on arrhythmogenesis in human and mouse atria with enhanced CaMKII activity. METHODS AND RESULTS: Human atrial cardiomyocytes (CMs) were isolated from patients with AF. To investigate CaMKII-mediated arrhythmogenesis, atrial CMs from mice overexpressing CaMKIIδC (TG) and the respective wildtype (WT) were studied using confocal microscopy (Fluo-4), patch-clamp technique, and in vivo atrial catheter-based burst stimulations. Dantrolene potently reduced Ca2+ spark frequency (CaSpF) and diastolic SR Ca2+ leak in AF CMs. Additional CaMKII inhibition did not further reduce CaSpF or leak compared to dantrolene alone. While the increased SR CaSpF and leak in TG mice were reduced by dantrolene, no effects could be detected in WT. Dantrolene also potently reduced the pathologically enhanced frequency of diastolic SR Ca2+ waves in TG without having effects in WT. As an increased diastolic SR Ca2+ release can induce a depolarizing transient inward current, we could demonstrate that the incidence of afterdepolarizations in TG, but not in WT, mice was significantly diminished in the presence of dantrolene. To translate these findings into an in vivo situation we could show that dantrolene strongly suppressed the inducibility of AF in vivo in TG mice. CONCLUSION: Dantrolene reduces CaMKII-mediated atrial arrhythmogenesis and may therefore constitute an interesting antiarrhythmic drug for treating patients with atrial arrhythmias driven by an enhanced CaMKII activity, such as AF.

Atrial arrhythmias in chronic lung disease-associated pulmonary hypertension.

Atrial arrhythmias are common during episodes of acute respiratory failure in patients with chronic lung disease-associated pulmonary hypertension. Expert opinion suggests that management of atrial arrhythmias in patients with pulmonary hypertension should aim to restore sinus rhythm. This is clinically challenging in pulmonary hypertension patients with coexisting chronic lung disease, as there is controversy on the use of rhythm control agents; generally, in regard to either their pulmonary toxicity profile or the lack of evidence supporting their use. Rate control methods are largely focused on the use of beta blockers and calcium channel blockers. Concerns regarding their use involve their negative inotropic properties in cor pulmonale, the risk of bronchospasm associated with beta blockers, and the potential for ventilation/perfusion mismatching associated with calcium channel blockers. While digoxin has been associated with promising outcomes during acute right ventricular failure, there is limited evidence to suggest its routine use. Electrical cardioversion is associated with a high failure rate and it frequently requires multiple attempts. Radiofrequency catheter ablation is a more definitive approach, but concerns surrounding mechanical ventilation and sedation limit its applicability in decompensated pulmonary hypertension. Individual approaches are needed to address atrial arrhythmia management during acute episodes of respiratory failure.