RESUMO
AIMS: Interaction between dronedarone and digitalis has been discussed as a possible cause for increased mortality in the presence of dronedarone observed in the PALLAS trial. The aim of this study was to assess possible proarrhythmic effects of dronedarone in combination with digitalis in an experimental whole heart model. METHODS AND RESULTS: Twenty-six female rabbits underwent chronic oral treatment with dronedarone (50 mg/kg/day for 6 weeks). Twenty-four rabbits received placebo. Heart failure was induced by rapid ventricular pacing. Sham-operated rabbits received a right-ventricular pacing lead but were not paced. Thereafter, hearts were isolated and Langendorff-perfused. Monophasic action potentials and a 12 lead electrocardiogram showed a dose-dependent decrease of QT interval, APD90, effective refractory periods, and postrepolarization refractoriness in control hearts and dronedarone-pretreated hearts after application of ouabain (0.1 and 0.2 µM). After acute application of ouabain, ventricular fibrillation (VF) was inducible by programmed ventricular stimulation in 6 of 12 untreated sham hearts (38 episodes) as compared with 7 of 11 dronedarone-pretreated sham hearts (76 episodes). In untreated failing hearts, 6 of 12 hearts were inducible (47 episodes) as compared with 7 of 15 hearts dronedarone-pretreated failing hearts (93 episodes). CONCLUSION: In this study, ouabain treatment resulted in an increased ventricular vulnerability in chronically dronedarone-pretreated control and failing hearts. Ouabain led to a significant abbreviation of ventricular repolarization. This was more marked in dronedarone-pretreated hearts and resulted in an elevated incidence of VF. This may help to interpret the results of the PALLAS trial.
Assuntos
Amiodarona/análogos & derivados , Glicosídeos Digitálicos/administração & dosagem , Glicosídeos Digitálicos/efeitos adversos , Fibrilação Ventricular/induzido quimicamente , Fibrilação Ventricular/prevenção & controle , Amiodarona/administração & dosagem , Amiodarona/efeitos adversos , Animais , Antiarrítmicos/administração & dosagem , Antiarrítmicos/efeitos adversos , Dronedarona , Interações Medicamentosas , Sinergismo Farmacológico , Quimioterapia Combinada , Feminino , Coelhos , Fibrilação Ventricular/diagnósticoRESUMO
Owing to increased life expectancy, patients with grown-up congenital heart disease nowadays present various types of arrhythmias. We report treatment of a 27-year-old patient with tricuspid and pulmonary atresia who was referred to our department with symptomatic tachycardia. During electrophysiologic study, a diagnosis of typical AV-nodal re-entrant tachycardia was made, and he was successfully treated despite the described anatomic malformation.
Assuntos
Nó Atrioventricular/fisiopatologia , Ablação por Cateter/métodos , Sistema de Condução Cardíaco/cirurgia , Taquicardia por Reentrada no Nó Atrioventricular/cirurgia , Atresia Tricúspide/complicações , Adulto , Eletrocardiografia , Técnicas Eletrofisiológicas Cardíacas , Seguimentos , Sistema de Condução Cardíaco/fisiopatologia , Humanos , Masculino , Taquicardia por Reentrada no Nó Atrioventricular/etiologia , Taquicardia por Reentrada no Nó Atrioventricular/fisiopatologia , Atresia Tricúspide/fisiopatologia , Atresia Tricúspide/cirurgiaRESUMO
BACKGROUND: The present ESC guidelines on atrial fibrillation have introduced vernakalant (VER) for pharmacologic cardioversion of atrial fibrillation. The aim of the present study was to investigate possible proarrhythmic effects of vernakalant in an experimental model of heart failure (HF). METHODS AND RESULTS: In 12 female rabbits, HF was induced with the use of 4 weeks of rapid ventricular pacing. Twelve rabbits were sham operated. Isolated hearts demonstrated a significant prolongation of myocardial repolarization after induction of HF. Vernakalant caused a concentration-dependent (10 µmol/L and 30 µmol/L) increase of action potential duration (APD90) and QT interval without affecting spatial and temporal dispersion of repolarization. The increase in APD90 was accompanied by a greater increase in refractory period resulting in a significant increase in post-repolarization refractoriness. In control conditions, programmed ventricular stimulation and burst pacing led to ventricular fibrillation (VF) in 2 of the 12 sham (4 episodes) and in 3 of the 12 HF (24 episodes) subjects. In the presence of 30 µmol/L vernakalant, VF was no longer inducible in both groups (0 episodes). In the presence of low K+ concentration, neither sham nor HF vernakalant-treated subjects developed early after-depolarizations or ventricular tachyarrhythmias. CONCLUSION: In the present study, application of vernakalant led to a significant prolongation of myocardial repolarization and increased post-repolarization refractoriness but did not induce early after-depolarization and therefore did not cause proarrhythmia in failing hearts.
Assuntos
Anisóis/farmacologia , Fibrilação Atrial/tratamento farmacológico , Terapia de Ressincronização Cardíaca/efeitos adversos , Insuficiência Cardíaca/fisiopatologia , Pirrolidinas/farmacologia , Animais , Antiarrítmicos/farmacologia , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/etiologia , Modelos Animais de Doenças , Eletrocardiografia , Feminino , Sistema de Condução Cardíaco/efeitos dos fármacos , Insuficiência Cardíaca/etiologia , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , Modelos Cardiovasculares , CoelhosRESUMO
AIM: The most recent European Society of Cardiology (ESC) update on atrial fibrillation has introduced vernakalant (VER) for pharmacological cardioversion of atrial fibrillation. The aim of the present study was to investigate the safety profile of VER in a sensitive model of proarrhythmia. METHODS AND RESULTS: In 36 Langendorff-perfused rabbit hearts, VER (10, 30 µM, n = 12); ranolazine (RAN, 10, 30 µM, n = 12), or sotalol (SOT, 50; 100 µM, n = 12) were infused after obtaining baseline data. Monophasic action potentials and a 12-lead electrocardiogram showed a significant QT prolongation after application of VER as compared with baseline (10 µM: +25 ms, 30 µM: +50 ms, P < 0.05) accompanied by an increase of action potential duration (APD). The increase in APD90 was accompanied by a more marked increase in effective refractory period (ERP) leading to a significant increase in post-repolarization refractoriness (PRR, 10 µM: +30 ms, 30 µM: +36 ms, P < 0.05). Vernakalant did not affect the dispersion of repolarization. Lowered potassium concentration in bradycardic hearts did not provoke early afterdepolarizations (EADs) or polymorphic ventricular tachycardia (pVT). Comparable results were obtained with RAN. Hundred micromolars of SOT led to an increase in QT interval (+49 ms) and APD90 combined with an increased ERP and PRR (+23 ms). In contrast to VER, 100 µM SOT led to a significant increase in dispersion of repolarization and to the occurrence of EAD in 10 of 12 and pVT in 8 of 12 hearts. CONCLUSION: In the present study, application of VER and SOT led to a comparable prolongation of myocardial repolarization. Both drugs increased the PRR. However, VER neither affect the dispersion of repolarization nor induce EAD and therefore did not cause proarrhythmia.
Assuntos
Anisóis/toxicidade , Antiarrítmicos/toxicidade , Arritmias Cardíacas/induzido quimicamente , Técnicas Eletrofisiológicas Cardíacas , Sistema de Condução Cardíaco/efeitos dos fármacos , Pirrolidinas/toxicidade , Acetanilidas/toxicidade , Potenciais de Ação , Animais , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/fisiopatologia , Sistema de Condução Cardíaco/fisiopatologia , Técnicas In Vitro , Modelos Animais , Perfusão , Piperazinas/toxicidade , Bloqueadores dos Canais de Potássio/toxicidade , Coelhos , Ranolazina , Medição de Risco , Fatores de Risco , Bloqueadores dos Canais de Sódio/toxicidade , Sotalol/toxicidade , Fatores de TempoRESUMO
AIMS: Phased radiofrequency (RF) ablation for atrial fibrillation is associated with an increased number of silent cerebral lesions on magnetic resonance imaging and cerebral microembolic signals (MESs) on transcranial Doppler ultrasound imaging compared with irrigated RF. The increased rate of embolic events may be due to a specific electrical interference of ablation electrodes attributed to the catheter design. The purpose of this study was to elucidate the effect of deactivating the culprit electrodes on cerebral MESs. METHODS AND RESULTS: Twenty-nine consecutive patients (60 ± 11 years, 10 female) underwent their first pulmonary vein isolation using phased RF energy. Electrode pairs 1 or 5 were deactivated to avoid electrical interference between electrodes 1 and 10 ('modified'). Detection of MESs by transcranial Doppler ultrasound was performed throughout the procedure to assess cerebral microembolism. Results were compared with the numbers of MESs in 31 patients ablated using all available electrodes ('conventional') and to 30 patients undergoing irrigated RF ablation of a previous randomized study. Ablation with 'modified' phased RF was associated with a marked decrease in MESs when compared with 'conventional' phased RF (566 ± 332 vs. 1530 ± 980; P < 0.001). This difference was mainly triggered by the reduction of MES during delivery of phased RF energy, resulting in MES numbers comparable to irrigated RF ablation (646 ± 449; P = 0.7). Total procedure duration as well as time of RF delivery was comparable between phased RF groups. Both times, however, were significantly shorter compared with the irrigated RF group (123 ± 28 vs. 195 ± 38; 15 ± 4 vs. 30 ± 9; P < 0.001, respectively). CONCLUSION: Pulmonary vein isolation with 'modified' phased RF is associated with a decreased number of cerebral microembolism especially during the delivery of ablation impulses, supporting the significance of electrical interference between ablation electrodes 1 and 10. Deactivation of electrode pairs 1 or 5 might increase the safety of this approach without an increase in procedure duration or RF delivery time.
Assuntos
Fibrilação Atrial/complicações , Fibrilação Atrial/cirurgia , Ablação por Cateter/efeitos adversos , Ablação por Cateter/métodos , Embolia Intracraniana/etiologia , Embolia Intracraniana/prevenção & controle , Veias Pulmonares/cirurgia , Fibrilação Atrial/diagnóstico , Feminino , Humanos , Embolia Intracraniana/diagnóstico , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
AIMS: In several clinical and pre-clinical studies, application of ranolazine (RAN) led to suppression of atrial fibrillation (AF). The aim of the present study was to investigate whether RAN can suppress AF in an experimental rabbit whole heart model, in which acute haemodynamic changes trigger AF. Ranolazine was compared with flecainide and sotalol as established antiarrhythmic agents. METHODS AND RESULTS: In 60 Langendorff-perfused, isolated rabbit hearts, AF episodes were evoked by burst pacing with a fixed number of stimuli at baseline and following acute atrial stretch. Data were obtained in the absence and presence of acute dilatation of the left atrium (20 mmHg) at baseline and after drug application (RAN 10 µM, n = 10; flecainide 2 µM, n = 10; sotalol 50 µM, n = 10). Application of sotalol, but not RAN or flecainide increased the atrial action potential duration at 90% repolarization (aAPD90); however, both RAN (+8 ms) and flecainide (+13 ms) increased interatrial conduction time. All three drugs caused a significant increase in atrial effective refractory period (aERP) and, thus, an increase in atrial post-repolarization refractoriness (aPRR: +11 ms each, P < 0.05). Acute dilatation of the left atrium reduced aAPD90 and aERP. The described drug effects were preserved in the setting of acute atrial dilatation. Acute atrial dilatation significantly increased the incidence of AF. Ranolazine and flecainide, but not sotalol, decreased the number of responses. CONCLUSION: Ranolazine-related sodium channel block is preserved upon acute atrial stretch. Ranolazine suppresses stretch-induced AF by increasing interatrial conduction time and aPRR. These results shed further evidence on the potential role of RAN in the prevention of AF. This might also apply to clinical conditions that are associated with haemodynamic or mechanical disorders, leading to acute dilatation of the atria.
Assuntos
Acetanilidas/administração & dosagem , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/fisiopatologia , Sistema de Condução Cardíaco/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , Condução Nervosa/efeitos dos fármacos , Piperazinas/administração & dosagem , Período Refratário Eletrofisiológico/efeitos dos fármacos , Administração Oral , Animais , Antiarrítmicos/administração & dosagem , Fibrilação Atrial/diagnóstico , Feminino , Flecainida/administração & dosagem , Sistema de Condução Cardíaco/efeitos dos fármacos , Técnicas In Vitro , Coelhos , Ranolazina , Bloqueadores dos Canais de Sódio/administração & dosagem , Sotalol/administração & dosagem , Resultado do TratamentoRESUMO
The cardiac Na(+)/Ca(2+) exchanger (NCX) generates an inward electrical current during SR-Ca(2+) release, thus possibly promoting afterdepolarizations of the action potential (AP). We used transgenic mice 12.5 weeks or younger with cardiomyocyte-directed overexpression of NCX (NCX-Tg) to study the proarrhythmic potential and mechanisms of enhanced NCX activity. NCX-Tg exhibited normal echocardiographic left ventricular function and heart/body weight ratio, while the QT interval was prolonged in surface ECG recordings. Langendorff-perfused NCX-Tg, but not wild-type (WT) hearts, developed ventricular tachycardia. APs and ionic currents were measured in isolated cardiomyocytes. Cell capacitance was unaltered between groups. APs were prolonged in NCX-Tg versus WT myocytes along with voltage-activated K(+) currents (K(v)) not being reduced but even increased in amplitude. During abrupt changes in pacing cycle length, early afterdepolarizations (EADs) were frequently recorded in NCX-Tg but not in WT myocytes. Next to EADs, delayed afterdepolarizations (DAD) triggering spontaneous APs (sAPs) occurred in NCX-Tg but not in WT myocytes. To test whether sAPs were associated with spontaneous Ca(2+) release (sCR), Ca(2+) transients were recorded. Despite the absence of sAPs in WT, sCR was observed in myocytes of both genotypes suggesting a facilitated translation of sCR into DADs in NCX-Tg. Moreover, sCR was more frequent in NCX-Tg as compared to WT. Myocardial protein levels of Ca(2+)-handling proteins were not different between groups except the ryanodine receptor (RyR), which was increased in NCX-Tg versus WT. We conclude that NCX overexpression is proarrhythmic in a non-failing environment even in the absence of reduced K(V). The underlying mechanisms are: (1) occurrence of EADs due to delayed repolarization; (2) facilitated translation from sCR into DADs; (3) proneness to sCR possibly caused by altered Ca(2+) handling and/or increased RyR expression.
Assuntos
Potenciais de Ação/fisiologia , Arritmias Cardíacas/metabolismo , Coração/fisiologia , Proteínas de Homeodomínio/metabolismo , Miócitos Cardíacos/metabolismo , Animais , Arritmias Cardíacas/genética , Western Blotting , Modelos Animais de Doenças , Eletrocardiografia , Proteínas de Homeodomínio/genética , Camundongos , Técnicas de Cultura de ÓrgãosRESUMO
BACKGROUND: Ranolazine inhibits late Na(+) and K(+) currents. Earlier studies have reported an antiarrhythmic effect. The aim of the present study was to understand whether ranolazine could still preserve its antiarrhythmic properties in the settings of chronic heart failure (CHF). METHODS AND RESULTS: In 12 female rabbits, CHF was induced by 4 weeks of rapid ventricular pacing leading to a decrease in ejection fraction. Twelve rabbits underwent sham operation. Isolated hearts were Langendorff perfused and demonstrated a significant QT prolongation after induction of heart failure. Ranolazine caused a concentration-dependent (10 and 30 µmol/L) increase of action potential duration (APD(90)) in sham-operated and failing hearts. Eight endo- and epicardial monophasic action potentials revealed a nonsignificant increase in spatial and temporal dispersion of repolarization. The increase in APD(90) was accompanied by a greater increase in refractory period, resulting in a significant increase in postrepolarization refractoriness in sham-operated (+29 ms and +55 ms; P < .01) and failing (+22 ms and +30 ms; P < .05) hearts. In control conditions, programmed ventricular stimulation and a burst pacing protocol led to ventricular fibrillation (VF) in 5 of the 12 sham-operated (6 episodes) and in 7 of the 12 failing (18 episodes) hearts. In the presence of ranolazine, VF was inducible in only 2 of 12 failing hearts (5 episodes). In the presence of low [K(+)], only 1 ranolazine-treated sham-operated heart developed early afterdepolarizations and ventricular tachyarrhythmias despite significant QT prolongation. CONCLUSIONS: Ranolazine decreases inducibility of VF in the presence of a significant increase in postrepolarization refractoriness. This antiarrhythmic effect in the intact heart is preserved in CHF and is not associated with drug-induced proarrhythmia.
Assuntos
Acetanilidas/farmacologia , Antiarrítmicos/farmacologia , Piperazinas/farmacologia , Período Refratário Eletrofisiológico/efeitos dos fármacos , Fibrilação Ventricular/prevenção & controle , Potenciais de Ação/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Eletrocardiografia , Insuficiência Cardíaca/tratamento farmacológico , Coelhos , Ranolazina , Sotalol/farmacologiaRESUMO
BACKGROUND: Dronedarone (D) is developed to maintain sinus rhythm in patients suffering from atrial fibrillation. The aim of the present study was to investigate, whether dronedarone also has an antiarrhythmic potential in the ventricle and to elucidate the mechanisms for its low proarrhythmic potential in an experimental whole heart model. METHODS AND RESULTS: Thirty-five rabbits underwent chronic treatment with D (n = 15; 50 mg · kg(-1) · d(-1)) and amiodarone (A; n = 20; 50 mg · kg(-1) · d(-1)). Hearts were perfused on a Langendorff apparatus. Results were compared with hearts acutely treated with sotalol (S; 50-100 µM; n = 14). A 12-lead electrocardiogram and up to 8 ventricular epi- and endocardial monophasic action potentials showed a significant prolongation of QT interval (D: +24 milliseconds, A: +28 milliseconds, S: +35 milliseconds (50 µM), +56 milliseconds (100 µM); P < 0.02) compared with baseline. In contrast to D and A, S led to a significant increase in dispersion of repolarization and exhibited reverse use dependence. D, A, and S increased refractory period, resulting in a significant increase in postrepolarization refractoriness (effective refractory period minus action potential duration; D = +12 milliseconds; A = +14 milliseconds; S = +25 milliseconds; P < 0.05). S led to a triangular action potential configuration, whereas D and A caused a fast phase 3 prolongation. After lowering of potassium concentration, 50% of S-treated hearts showed torsade de pointes, in contrast to an absence of torsade de pointes in D and A. CONCLUSIONS: Prolongation of myocardial repolarization and postrepolarization refractoriness by D may act antiarrhythmic. A fast phase 3 repolarization in the absence of both increased dispersion of repolarization and reverse use dependence prevents proarrhythmia.
Assuntos
Potenciais de Ação/efeitos dos fármacos , Amiodarona/análogos & derivados , Antiarrítmicos/farmacologia , Ventrículos do Coração/efeitos dos fármacos , Período Refratário Eletrofisiológico/efeitos dos fármacos , Função Ventricular/efeitos dos fármacos , Amiodarona/administração & dosagem , Amiodarona/efeitos adversos , Amiodarona/farmacologia , Animais , Antiarrítmicos/administração & dosagem , Antiarrítmicos/efeitos adversos , Dronedarona , Eletrocardiografia , Técnicas Eletrofisiológicas Cardíacas , Feminino , Técnicas In Vitro , Síndrome do QT Longo/induzido quimicamente , Perfusão , Coelhos , Sotalol/administração & dosagem , Sotalol/efeitos adversos , Sotalol/farmacologia , Torsades de Pointes/induzido quimicamenteRESUMO
AIMS: The use of implantable cardioverter defibrillators (ICD) in patients with torsade de pointes (TdP) and ventricular fibrillation in the presence of acquired long QT syndrome (aLQTS) is under debate, partly due to the fact that aLQTS is potentially reversible and currently no long-term follow-up data are available. We aimed to evaluate the long-term follow-up of patients with acquired long QT syndrome (aLQTS) who had received an implantable cardioverter defibrillator (ICD) for secondary prevention of sudden cardiac arrest (SCA). METHOD AND RESULTS: Over a 10 year period, 43 patients with an ICD after survived cardiac arrest (SCA) due to an aLQTS were included [female n= 27 (63%); mean age 61 ± 16 years]. There was no clinical evidence for congenital LQTS (Schwartz score 1.25 ± 0.8). Structural heart disease was present in 29 patients (47%; ischaemic n= 13; dilated cardiomyopathy n= 9; mean EF 41%± 12). The most common proarrhythmic trigger happened to be antiarrhythmic drugs (n= 34; 79%). Other triggers included contrast agent (n= 1), haloperidol (n= 2), severe hypokalaemia (n= 2), drug abuse/alcohol (n= 2), and mere severe bradycardia (n= 2). Under trigger QTc interval measured 536 ± 58 vs. 438 ± 33 ms without trigger (P< 0.001). During a mean follow-up of 84 ± 55 months, appropriate shocks occurred in 19 patients (44%); inappropriate shocks in 13 patients (30%; only inappropriate n= 3). Appropriate shocks were almost as common in patients without as in those with structural heart disease (35 vs. 48%; P= 0.32). None of the patients were re-exposed to the initial trigger during the follow-up period. Beta-blocker medication did not prevent ICD shocks (12 of 19 vs. 11 of 24 on medication). CONCLUSION: Appropriate ICD shocks are a common finding in patients with aLQTS and SCA irrespective of the underlying cause or structural heart disease. Thus, even in the presence of relevant acquired proarrhythmia ICD may be beneficial.
Assuntos
Desfibriladores Implantáveis , Síndrome do QT Longo/terapia , Antagonistas Adrenérgicos beta/uso terapêutico , Adulto , Idoso , Antiarrítmicos/uso terapêutico , Morte Súbita Cardíaca/prevenção & controle , Feminino , Seguimentos , Cardiopatias/terapia , Humanos , Síndrome do QT Longo/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Estudos Retrospectivos , Resultado do TratamentoRESUMO
We report a case of postoperative acquired atrioventricular (AV) block and successful ablation of isthmus-dependent atrial flutter using "cryomapping" in combination with a mapping system preserving AV conduction via right infero-septal accessory pathway.
Assuntos
Feixe Acessório Atrioventricular/diagnóstico , Flutter Atrial/diagnóstico , Bloqueio Atrioventricular/diagnóstico , Complicações Pós-Operatórias/diagnóstico , Feixe Acessório Atrioventricular/etiologia , Feixe Acessório Atrioventricular/cirurgia , Adenosina , Adulto , Antiarrítmicos , Flutter Atrial/cirurgia , Bloqueio Atrioventricular/etiologia , Bloqueio Atrioventricular/cirurgia , Ablação por Cateter , Eletrodiagnóstico , Comunicação Interventricular/cirurgia , Humanos , Masculino , Complicações Pós-Operatórias/cirurgia , Taquicardia/diagnóstico , Taquicardia/cirurgia , Resultado do TratamentoRESUMO
Pharmacologic modification of cellular calcium handling recently moved into focus as an alternative for prevention and treatment of ventricular tachyarrhythmias. Calcium overload and spontaneous calcium release from the sarcoplasmatic reticulum are regarded as possible initiations of early and delayed afterdepolarization thereby triggering ventricular arrhythmias. In chronic heart failure, calcium overload is more likely to occur compared with healthy hearts, which is one explantation for the increased vulnerability in this condition. L-type calcium channel, sodium-calcium-exchanger (NCX), and ryanodine receptor are crucial for calcium homeostasis and therefore represent potential targets for antiarrhythmic drug therapy. Experimental studies have proven beneficial effects for all these three mechanisms in prevention and suppression of tachyarrhythmias. However, clinical data is mainly available for the L-type calcium channel inhibitor verapamil. Therefore, it is still a long way to clinical employment of drugs modifying cellular calcium handling for antiarrhythmic therapy.
Assuntos
Cálcio/metabolismo , Taquicardia Ventricular/fisiopatologia , Animais , Antiarrítmicos/uso terapêutico , Canais de Cálcio Tipo L/efeitos dos fármacos , Canais de Cálcio Tipo L/fisiologia , Eletrocardiografia , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/fisiopatologia , Homeostase/efeitos dos fármacos , Homeostase/fisiologia , Humanos , Contração Miocárdica/efeitos dos fármacos , Contração Miocárdica/fisiologia , Canal de Liberação de Cálcio do Receptor de Rianodina/efeitos dos fármacos , Canal de Liberação de Cálcio do Receptor de Rianodina/fisiologia , Retículo Sarcoplasmático/efeitos dos fármacos , Retículo Sarcoplasmático/fisiologia , Trocador de Sódio e Cálcio/efeitos dos fármacos , Trocador de Sódio e Cálcio/fisiologia , Taquicardia Ventricular/tratamento farmacológico , Verapamil/uso terapêuticoRESUMO
G-CSF (granulocyte colony-stimulating factor) treatment has been shown to cause beneficial effects including a reduction of inducible arrhythmias in rodent models of ischemic cardiomyopathy. The aim of the present study was to test whether these effects do also apply to pacing-induced non-ischemic heart failure. In 24 female rabbits, heart failure was induced by rapid ventricular pacing. 24 rabbits were sham operated. The paced rabbits developed a significant decrease of ejection fraction. 11 heart failure rabbits (CHF) and 11 sham-operated (S) rabbits served as controls, whereas 13 sham (S-G-CSF) and 13 heart failure rabbits (CHF-G-CSF) were treated with 10 µg/kg G-CSF s.c. over 17 ± 4 days. G-CSF treatment caused a ~25% increased arterial and capillary density and a ~60% increased connexin 43 expression in failing hearts. In isolated, Langendorff-perfused rabbit hearts eight monophasic action potential recordings showed prolongation of repolarization in CHF as compared with controls in the presence of the QT prolonging agent erythromycin (+33 ± 12 ms; p < 0.01). Moreover, a significant increase in dispersion of repolarization contributed to a significantly higher rate of ventricular tachyarrhythmias in CHF. G-CSF-pre-treated hearts showed a further increase in prolongation of repolarization as compared with S and CHF. The further increase in dispersion of repolarization [S-G-CSF: +23 ± 9 ms (spatial), +13 ± 7 ms (temporal); CHF-G-CSF: +38 ± 14 ms (spatial), +10 ± 4 ms (temporal); p < 0.05 as compared with S and CHF], increased the incidence of ventricular tachyarrhythmias. In summary, chronic G-CSF treatment has moderate beneficial effects on parameters potentially related to hemodynamic function in the non-ischemic rabbit CHF model. However, a significant reduction of repolarization reserve might seriously challenge its suitability as a therapeutic agent for chronic CHF therapy.
Assuntos
Conexina 43/biossíntese , Fator Estimulador de Colônias de Granulócitos/farmacologia , Insuficiência Cardíaca/tratamento farmacológico , Coração/efeitos dos fármacos , Miocárdio/metabolismo , Neovascularização Fisiológica/efeitos dos fármacos , Potenciais de Ação/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Eletrocardiografia , Feminino , Imunofluorescência , Coração/fisiopatologia , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Miocárdio/patologia , Neovascularização Fisiológica/fisiologia , Técnicas de Cultura de Órgãos , CoelhosRESUMO
AIMS: Pulmonary veins (PV) play a pivotal role in atrial fibrillation (AF). Anatomical variants of PV have been described and related to a higher arrhythmogenic potential. The aim of this study was to compare the prevalence of PV variants and diameters of PV ostia in AF patients and controls. METHODS AND RESULTS: Variants of PV were defined as right or left common ostia (RCO, LCO), a right middle or right top PV . A long common trunk (LCT) was defined as an LCO with a distance to the first branching ≥ 10 mm. Multislice contrast-enhanced thoracic computed tomography was performed prior to AF ablation in 166 consecutive patients, 47.6% with paroxysmal, 52.4% with persistent AF, as well as in a sex- and age-matched control group without AF, for non-cardiological indications. Images were evaluated by two independent observers. The mean age was 59 ± 10 years, 108 were men (65.1%). A higher prevalence of LCO was found in the AF group: 33.7 vs. 19.9% (P= 0.004), odds ratio (OR) 2.1; 15.4% in patients vs. 10.2% in controls had an LCT (P= 0.14). No differences in other PV variants were found. The ostial diameters were greater in AF-patients (P< 0.001). CONCLUSIONS: To the best of our knowledge, the present study shows for the first time a higher prevalence of an LCO in patients with AF as compared with controls, with an OR of 2.1. This suggests a pre-disposing role of LCO in the development of AF.
Assuntos
Fibrilação Atrial/epidemiologia , Veias Pulmonares/anormalidades , Veias Pulmonares/diagnóstico por imagem , Idoso , Estudos de Casos e Controles , Causalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Fatores de Risco , Tomografia Computadorizada EspiralRESUMO
Arrhythmogenic cardiomyopathy (AC) is a rare heart muscle disease with a genetic background and autosomal dominant mode of transmission. The clinical manifestation is characterized by ventricular arrhythmias (VA), heart failure (HF) and the risk of sudden cardiac death (SCD). Pregnancy in young female patients with AC represents a challenging condition for the life and family planning of young affected women. In addition to genetic mechanisms that influence the complex pathophysiology of AC, experimental and clinical data have confirmed the pathogenetic role of strenuous exercise and competitive sports in the early onset and rapid progression of AC symptoms and complications. Pregnancy and exercise share a number of physiological aspects of adaptation. In AC, both result in ventricular volume overload and myocardial stretch. Therefore, pregnancy has been postulated as a potential risk factor for HF, VA, SCD, and pregnancy-related obstetric complications in patients with AC. However, the available evidence on pregnancy in AC does not confirm this hypothesis. In most women with AC, pregnancies are well tolerated, uneventful, and follow a benign course. Pregnancy-related symptoms (VA, syncope, HF) and mortality, as well as obstetric complications, are uncommon in AC patients and range in the order of background populations and cohorts with AC and no pregnancy. The number of completed pregnancies is not associated with an acceleration of AC pathology or an increased risk of VA or HF during pregnancy and follow-up. Accordingly, there is no medical indication to advise against pregnancy in patients with AC. Preconditions include stability of rhythm and hemodynamics at baseline, as well as clinical follow-ups and the availability of multidisciplinary expert consultation during pregnancy and postpartum. Genetic counseling is recommended prior to pregnancy for all couples and their families affected by AC.
Assuntos
Displasia Arritmogênica Ventricular Direita , Cardiomiopatias , Arritmias Cardíacas , Displasia Arritmogênica Ventricular Direita/diagnóstico , Displasia Arritmogênica Ventricular Direita/genética , Morte Súbita Cardíaca/prevenção & controle , Feminino , Humanos , Gravidez , Fatores de RiscoRESUMO
BACKGROUND: Short QT syndrome (SQTS) is a newly described ion channelopathy, characterized by a short QT interval resulting from an accelerated cardiac repolarization, associated with syncope, atrial fibrillation, and sudden cardiac death due to ventricular fibrillation. As therapeutic options in SQTS are still controversial, we examined antiarrhythmic mechanisms in an experimental model of SQTS. METHODS AND RESULTS: Pinacidil, an I(K-ATP) channel opener, was administered in increasing concentrations (50-100 microM) in 48 Langendorff-perfused rabbit hearts and led to a significant reduction of action potential duration and QT interval, thereby mimicking SQTS. Eight simultaneously recorded monophasic action potentials demonstrated an increase in dispersion of repolarization, especially between the left and the right ventricle. During programmed ventricular stimulation with up to two extrastimuli, pinacidil significantly increased the inducibility of ventricular fibrillation (1 heart under baseline conditions, 29 hearts during pinacidil administration; P = 0.0001). Additional treatment with the I(Kr) blocker sotalol (100 microM) and the class I antiarrhythmic drugs flecainide (2 microM) and quinidine (0.5 microM) randomly assigned to three groups of 16 hearts led to prolongation of repolarization as well as refractory period. Sotalol or flecainide did not reduce the rate of inducibility of ventricular fibrillation significantly (P = 0.63; P = 0.219). However, quinidine reduced the inducibility of ventricular fibrillation by 73% (P = 0.008). The antiarrhythmic potential of quinidine was associated with a significantly greater prolongation of MAP duration, refractoriness, and postrepolarization refractoriness (PRR) as compared with sotalol and flecainide. Moreover, quinidine, in contrast to sotalol and flecainide, reduced dispersion of repolarization. CONCLUSION: Pinacidil mimics SQTS via increasing potassium outward currents, thereby facilitating inducibility of ventricular fibrillation. Quinidine demonstrates superior antiarrhythmic properties in the treatment of ventricular fibrillation in this model as compared with sotalol and flecainide because of its effects on refractoriness, PRR, and by reducing dispersion of repolarization.
Assuntos
Antiarrítmicos/farmacologia , Arritmias Cardíacas/tratamento farmacológico , Sistema de Condução Cardíaco/efeitos dos fármacos , Quinidina/farmacologia , Potenciais de Ação/efeitos dos fármacos , Animais , Arritmias Cardíacas/induzido quimicamente , Arritmias Cardíacas/diagnóstico , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Eletrocardiografia , Técnicas Eletrofisiológicas Cardíacas , Flecainida/farmacologia , Técnicas In Vitro , Pinacidil , Coelhos , Distribuição Aleatória , Período Refratário Eletrofisiológico/efeitos dos fármacos , Sotalol/farmacologia , VasodilatadoresRESUMO
BACKGROUND: Numerous noncardiovascular drugs prolong repolarization and thereby increase the risk for patients to develop life-threatening tachyarrhythmias of the torsade de pointes (TdP) type. The development of TdP is an individual, patient-specific response to a repolarization-prolonging drug, depending on the repolarization reserve. The aim of the present study was to analyze the underlying mechanisms that discriminate hearts that will develop TdP from hearts that will not develop TdP. We therefore investigated the group of quinolone antibiotics that reduce repolarization reserve via I(Kr) blockade in an intact heart model of proarrhythmia. METHODS AND RESULTS: In 47 Langendorff-perfused, AV-blocked rabbit hearts, ciprofloxacin (n = 10), ofloxacin (n = 14), levofloxacin (n = 10), and moxifloxacin (n = 13) in concentrations from 100 microM to 1,000 microM were infused. Eight monophasic action potentials (MAPs) and an ECG were recorded simultaneously. After incremental pacing at cycle lengths from 900 ms to 300 ms to compare the action potential duration, potassium concentration was lowered to provoke TdP. All antibiotics led to a significant increase in QT interval and MAP duration, and exhibited reverse-use dependence. Eight simultaneously recorded MAPs demonstrated an increase in dispersion of repolarization in the presence of all antibiotics. MAP triangulation (ratio: MAP(90/50)) and fluctuation of consecutive action potentials were increased for all tested drugs at high concentrations. In the presence of low potassium concentration, all quinolones led to TdP: ciprofloxacin, 4 out of 10 (40%); ofloxacin, 3 out of 14 (21%); moxifloxacin, 9 out of 13 (69%); and levofloxacin, 2 out of 10 (20%). Hearts that developed TdP demonstrated a significant greater influence on dispersion of repolarization and on triangulation as compared with hearts without TdP. CONCLUSION: Quinolone antibiotics may be proarrhythmic due to a significant effect on myocardial repolarization. The individual response of a heart to develop TdP in this experimental model is characterized by a greater effect on dispersion of repolarization and on triangulation of action potential as compared with hearts that do not develop TdP.
Assuntos
Potenciais de Ação , Sistema de Condução Cardíaco/fisiopatologia , Torsades de Pointes/induzido quimicamente , Torsades de Pointes/fisiopatologia , Potenciais de Ação/efeitos dos fármacos , Animais , Anti-Infecciosos/farmacologia , Compostos Aza/farmacologia , Ciprofloxacina/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Eletrocardiografia , Técnicas Eletrofisiológicas Cardíacas , Fluoroquinolonas , Sistema de Condução Cardíaco/efeitos dos fármacos , Técnicas In Vitro , Levofloxacino , Masculino , Moxifloxacina , Ofloxacino/farmacologia , Quinolinas/farmacologia , Quinolonas/farmacologia , Coelhos , Torsades de Pointes/diagnósticoRESUMO
INTRODUCTION: The antihistaminic antazoline (ANT) was reported to be highly effective and safe for rapid conversion of atrial fibrillation (AF). We therefore analyzed underlying mechanisms in an experimental whole-heart model. METHODS AND RESULTS: Isolated and retrogradely perfused rabbit hearts underwent a standardized protocol employing atrial burst pacing-induced AF in five of 20 hearts under baseline conditions (seven episodes). Thereafter, a combination of acetylcholine and isoproterenol was employed to enhance AF occurrence. Two monophasic action potential recordings on the left- and two on the right atrial epicardium showed a decrease in atrial action potential duration (aAPD, -25 msec, P<.05) and atrial effective refractory period (aERP; -52 msec, P<.01) after infusion of acetylcholine (1 µmol/L) and isoproterenol (1 µmol/L). This led to induction of AF in 14 of 20 hearts (145 episodes). Simultaneous infusion of ANT (20 µmol/L) led to a complete suppression of AF in all inducible hearts. Treatment with ANT also led to a significant increase in aAPD (+41 msec, P<.01) and aERP (+74 msec, P<.05), leading to a marked increase in atrial postrepolarization refractoriness (aPRR, +33 msec, P<.01). Results were compared to 13 rabbits treated with flecainide. Flecainide induced a significant increase in aPRR and resulted in induction of AF in seven of 13 hearts (51 episodes) while 11 of 13 hearts were inducible with acetylcholine and isoproterenol (93 episodes). CONCLUSION: Administration of ANT was highly effective in suppressing AF. The antiarrhythmic effect could be explained by a significant increase in postrepolarization refractoriness as a result of a more marked increase in aERP as compared with aAPD.
Assuntos
Antazolina/farmacologia , Antiarrítmicos/farmacologia , Fibrilação Atrial/prevenção & controle , Frequência Cardíaca/efeitos dos fármacos , Antagonistas dos Receptores Histamínicos H1/farmacologia , Acetilcolina , Potenciais de Ação , Animais , Fibrilação Atrial/induzido quimicamente , Fibrilação Atrial/fisiopatologia , Estimulação Cardíaca Artificial , Relação Dose-Resposta a Droga , Descoberta de Drogas , Eletrocardiografia , Técnicas Eletrofisiológicas Cardíacas , Flecainida/farmacologia , Preparação de Coração Isolado , Isoproterenol , Coelhos , Período Refratário Eletrofisiológico , Fatores de TempoRESUMO
BACKGROUND: Congenital and acquired long QT syndrome (LQTS) are caused by abnormalities of ionic currents underlying ventricular repolarization. For a better understanding of the mechanisms by which functional electrical instability at the level of the whole heart leads to torsade de pointes (TdP), a novel model of LQT3 was developed and the role of transmural dispersion of repolarization for the development of proarrhythmia was evaluated. METHODS AND RESULTS: In 11 Langendorff-perfused rabbit hearts, veratridine (0.1-0.5 microM), an inhibitor of sodium channel inactivation, led to a concentration-dependent increase in QT-interval and simultaneously recorded monophasic ventricular action potentials (MAPs) (p<0.05) and thereby mimicked LQT3. Veratridine reproducibly induced early afterdepolarizations (EADs) and TdP after lowering potassium concentration. In bradycardic (AV-blocked) hearts, the increase in MAP duration showed marked regional differences. It was significantly more pronounced on the left endocardium as compared to left or right epicardium. This resulted in a significant increase in dispersion of repolarization (24% at 0.1 microM, 92% at 0.25 microM, 208% at 0.5 microM; p<0.01). Left ventricular transmural dispersion of repolarization increased significantly more than interventricular dispersion (104 to 33 ms at 0.5 microM veratridine; p<0.05). CONCLUSION: By inhibition of sodium channel inactivation, veratridine mimics LQT3 in this intact heart model. In bradycardic, hypokalemic hearts, it reproducibly induced EADs and TdP in the setting of significantly increased left ventricular transmural dispersion of repolarization. Based on these experimental data, reduction of transmural dispersion of repolarization may be considered an important target for the prevention of TdP in patients with LQT3.
Assuntos
Síndrome do QT Longo/metabolismo , Miocárdio/metabolismo , Bloqueadores dos Canais de Sódio/farmacologia , Veratridina/farmacologia , Potenciais de Ação/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Eletrocardiografia/efeitos dos fármacos , Endocárdio/efeitos dos fármacos , Endocárdio/metabolismo , Síndrome do QT Longo/fisiopatologia , Masculino , Modelos Animais , Perfusão , Pericárdio/efeitos dos fármacos , Pericárdio/metabolismo , CoelhosRESUMO
In several case reports a prolongation of the QT-interval and even proarrhythmic effects of fluconazole and voriconazole were reported. The aim of the present study was to investigate if application of fluconazole or voriconazole has the potential to provoke polymorphic ventricular tachycardia in a sensitive model of proarrhythmia. In female rabbits, fluconazole (10, 30 and 50 µM, n=6) and voriconazole (10, 30 and 50 µM, n=6) were infused after obtaining baseline data. Eight endocardial and epicardial monophasic action potentials and a simultaneously recorded 12-lead ECG showed a significant QT prolongation after application of fluconazole as compared with baseline (10 µM:+12 ms, 30 µM:+22 ms, 50 µM:+37 ms; P<0.05) accompanied by an increase of action potential duration (APD90). Administration of voriconazole also induced QT prolongation (30 µM:+10 ms, 50 µM:+20 ms, P<0.05). Spatial dispersion of repolarization remained stable in voriconazole-treated hearts while fluconazole induced a significant increase (30 µM:+15 ms, 50 µM:+16 ms; P<0.05). Lowering of potassium concentration in bradycardic AV-blocked hearts did not provoke any early afterdepolarizations (EADs) or polymorphic ventricular tachycardia in voriconazole-treated hearts. Application of fluconazole led to the reproducible induction of EADs in 4 of 6 hearts and polymorphic ventricular tachycardia in 3 of 6 hearts (36 episodes). In the present study, voriconazole demonstrated a safe electrophysiologic profile despite significant QT prolongation. In contrast, fluconazole led to a more marked prolongation of myocardial repolarization combined with a more marked increase of dispersion of repolarization. These results imply that application of fluconazole might be torsadogenic and the QT-interval should be closely monitored.