RESUMO
Isolation of the pulmonary veins may be an effective treatment modality for eliminating atrial fibrillation (AF) episodes but unfortunately not for all patients. When ablative therapy fails, it is assumed that AF has progressed from a trigger-driven to a substrate-mediated arrhythmia. The effect of radiofrequency ablation on persistent AF can be attributed to various mechanisms, including elimination of the trigger, modification of the arrhythmogenic substrate, interruption of crucial pathways of conduction, atrial debulking, or atrial denervation. This review discusses the possible effects of pulmonary vein isolation on the fibrillatory process and the necessity of cardiac mapping in order to comprehend the mechanisms of AF in the individual patient and to select the optimal treatment modality.
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Cardiac experimental electrophysiology is in need of a well-defined Minimum Information Standard for recording, annotating, and reporting experimental data. As a step towards establishing this, we present a draft standard, called Minimum Information about a Cardiac Electrophysiology Experiment (MICEE). The ultimate goal is to develop a useful tool for cardiac electrophysiologists which facilitates and improves dissemination of the minimum information necessary for reproduction of cardiac electrophysiology research, allowing for easier comparison and utilisation of findings by others. It is hoped that this will enhance the integration of individual results into experimental, computational, and conceptual models. In its present form, this draft is intended for assessment and development by the research community. We invite the reader to join this effort, and, if deemed productive, implement the Minimum Information about a Cardiac Electrophysiology Experiment standard in their own work.
Assuntos
Fenômenos Eletrofisiológicos , Coração/fisiologia , Disseminação de Informação/métodos , Modelos Biológicos , Projetos de Pesquisa/normas , Animais , Humanos , Padrões de Referência , Reprodutibilidade dos TestesRESUMO
OBJECTIVE: In electrically remodeled atria the effect of blockers of the delayed rectifier K+ current I(Kr) on repolarization is reduced, whereas the efficacy of 'early' class III drugs (I(Kur)/I(to)/I(Kach) blockers) is enhanced. We evaluated the electrophysiological and antifibrillatory effects of AVE0118, dofetilide, and ibutilide (alone and in combination) on persistent atrial fibrillation (AF) in the goat. METHODS AND RESULTS: The effects of separate and combined administration of AVE0118, dofetilide, and ibutilide were determined before and after 48 h of AF. AVE0118 alone markedly prolonged the atrial refractory period (400 ms cycle length) (AERP400) before and after 48 h of AF. The prolongation of AERP(400) by dofetilide and ibutilide, respectively, was reduced by AF from 22+/-2 to 7+/-2 ms (p<0.01) and 25+/-5 to 5+/-2 ms (p=0.01). Pre-treatment with AVE0118 restored the prolongation of AERP400 by dofetilide or ibutilide (to 20+/-3 and 30+/-6 ms; p<0.01). This effect was atrial specific since the QT-interval was not changed. The antifibrillatory action was evaluated in 10 goats that were in persistent AF for 57+/-7 days. Dofetilide (20 microg/kg/h) or ibutilide (4 mg/h) alone restored sinus rhythm in only 20% of the animals. AVE0118 (1, 3 and 10 mg/kg/h) [DOSAGE ERROR CORRECTED] terminated AF in 11, 30, and 60%, respectively. Additional infusion of I(Kr) blockers caused an additional number of cardioversions, resulting in a final cardioversion rate of 56, 80, and 100%, respectively. AVE0118 alone prolonged the AF cycle length (AFCL) while the conduction velocity during AF (CV(AF)) remained unchanged (70+/-1 vs. 68+/-2 cm/s; p=0.3). Addition of dofetilide or ibutilide caused a synergistic increase in AFCL and a slight increase in CV(AF) to 74+/-1 cm/s (p<0.001). The length of the reentrant trajectories increased from 7.6+/-0.3 (control) to 11.6+/-0.5 cm after AVE0118 alone (p<0.001) and 14.8+/-0.8 cm after addition of dofetilide or ibutilide (p<0.001). CONCLUSIONS: In electrically remodeled atria, blockade of I(Kur)/I(to)/I(KAch) restored the class III action of I(Kr) blockers. Persistent AF could be effectively cardioverted by infusion of a combination of AVE0118 and dofetilide or ibutilide. This antifibrillatory action was associated with an almost twofold lengthening of the intra-atrial pathways for reentry.
Assuntos
Antiarrítmicos/uso terapêutico , Fibrilação Atrial/terapia , Cardioversão Elétrica , Potenciais de Ação/efeitos dos fármacos , Animais , Fibrilação Atrial/tratamento farmacológico , Compostos de Bifenilo/uso terapêutico , Terapia Combinada , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Eletrocardiografia/efeitos dos fármacos , Feminino , Cabras , Fenetilaminas/uso terapêutico , Sulfonamidas/uso terapêuticoRESUMO
Isolation of the pulmonary veins has been used as surgical treatment for atrial fibrillation (AF) from the early 90s, as it was incorporated in the Maze procedure. With the evidence that triggers form this area can induce AF, the Maze III procedure has been adapted and modified towards a single lesion around the pulmonary veins for the treatment of paroxysmal and chronic AF in some centers. New ablation techniques with a diversity of energy sources further paved the way for less invasive procedures. Minimal invasive techniques to prevent major surgery may potentially make the treatment available for a patient population that do not have to undergo cardiac surgery for other reasons. Besides these technical developments, high density mapping can be used to identify the AF substrate in the individual patient and optimization of the treatment by local substrate guided ablation. This review aims to summarize the robotic and thoracoscopic techniques to isolate the pulmonary veins. Furthermore, it is discussed why pulmonary veins isolation may be effective in patients with chronic AF, and whether there is a role for mapping guided minimal invasive surgical treatment of AF in the near future.
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OBJECTIVE: Atrial fibrillation (AF) induces electrical and ionic remodeling of the atria. We investigated whether AF-induced remodeling alters the electrophysiological and anti-fibrillatory effects of class I (flecainide) and class III (d-sotalol, ibutilide) anti-arrhythmic drugs. METHODS: In 9 goats, the effects of flecainide (6 mg/kg) and d-sotalol (6 mg/kg) on atrial electrophysiology were measured both before and after 48 h of electrically induced AF. During a 1-h infusion period the atrial effective refractory period (AERP) and conduction velocity (CV) were measured both during slow and rapid pacing (interval 400 and 200 ms). In 8 other goats, the rate-dependent effects of ibutilide (0.12 mg/kg) on AERP were determined. RESULTS: The effects of flecainide on atrial conduction and refractoriness were not altered after 48 h of AF. At a dose of 6 mg/kg flecainide reduced the CV200 by 19+/-5% in normal atria and by 21+/-9% after 48 h of AF (p=0.20). The AERP200 was prolonged by 10+/-6% and 8+/-7%, respectively (p=0.40). In contrast, the effect of d-sotalol on atrial refractoriness was markedly diminished. During control d-sotalol prolonged the AERP400 by 17+/-6% compared to only 6+/-5% after 2 days of AF (p<0.01). Also ibutilide lost much of its class III effect on the AERP by electrical remodeling (from 15 to 5%; p<0.05). The loss of class III action was less pronounced at rapid heart rates. CONCLUSIONS: AF-induced atrial electrical remodeling in the goat did not modulate the action of flecainide on atrial conduction and refractoriness. In contrast, the class III effects of d-sotalol and ibutilide on the atria were strongly reduced after 2 days of AF. The prolongation of QT-duration was not affected.
Assuntos
Antiarrítmicos/uso terapêutico , Fibrilação Atrial/prevenção & controle , Flecainida/uso terapêutico , Sotalol/uso terapêutico , Animais , Fibrilação Atrial/fisiopatologia , Função Atrial , Cardioversão Elétrica , Eletrofisiologia , Cabras , Modelos Animais , Distribuição Aleatória , Período Refratário Eletrofisiológico , Sulfonamidas/uso terapêutico , Falha de Tratamento , Remodelação VentricularRESUMO
BACKGROUND: Currently available antiarrhythmic drugs are only moderately effective against atrial fibrillation (AF) and may cause ventricular proarrhythmia. AVE0118 is a blocker of atrium-specific early K+ currents (I(Kur)/I(to)). METHODS AND RESULTS: Effects of intravenous AVE0118 and dofetilide on atrial effective refractory period (AERP) and inducibility of AF were measured before and after 48-hours of AF-induced electrical remodeling in the goat. During persistent AF (53+/-19 days), the cardioversion efficacy and effects on atrial wavelength of AVE0118, dofetilide, and ibutilide were evaluated. QT durations were measured during atrial pacing and persistent AF. After 48 hours of AF, the effect of dofetilide on AERP was reduced, and induction of AF was not prevented. In contrast, the class III action of AVE0118 was enhanced, and AF inducibility decreased from 100% to 32% (P<0.001). At 1, 3, and 10 mg x kg(-1) x h(-1), AVE0118 terminated persistent AF in 1 of 8, 3 of 8, and 5 of 8 goats, respectively. Dofetilide and ibutilide terminated AF in 1 of 5 and 2 of 7 goats. AVE0118 0.5, 1.5, and 5 mg/kg prolonged the AERP during AF and increased the fibrillation wavelength from 6.7+/-0.6 to 8.5+/-0.5, 9.7+/-0.5, and 11.2+/-0.9 cm (P<0.01). Whereas dofetilide and ibutilide prolonged QT duration, AVE0118 had no appreciable effect. CONCLUSIONS: AVE0118 markedly prolongs the AERP during AF without affecting QT duration. Cardioversion of AF was due to an approximately 2-fold increase in fibrillation wavelength. Atrium-selective class III drugs like AVE0118 may be a promising new option for safe and effective cardioversion of AF.
Assuntos
Antiarrítmicos/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Átrios do Coração/efeitos dos fármacos , Bloqueadores dos Canais de Potássio/uso terapêutico , Canais de Potássio de Abertura Dependente da Tensão da Membrana/efeitos dos fármacos , Potenciais de Ação/efeitos dos fármacos , Animais , Antiarrítmicos/farmacologia , Fibrilação Atrial/fisiopatologia , Fibrilação Atrial/terapia , Estimulação Cardíaca Artificial/efeitos adversos , Canais de Potássio de Retificação Tardia , Avaliação Pré-Clínica de Medicamentos , Cardioversão Elétrica , Feminino , Cabras , Átrios do Coração/fisiopatologia , Sistema de Condução Cardíaco/efeitos dos fármacos , Sistema de Condução Cardíaco/fisiopatologia , Infusões Intravenosas , Transporte de Íons/efeitos dos fármacos , Condução Nervosa/efeitos dos fármacos , Fenetilaminas/farmacologia , Fenetilaminas/uso terapêutico , Potássio/metabolismo , Bloqueadores dos Canais de Potássio/farmacologia , Canais de Potássio de Abertura Dependente da Tensão da Membrana/fisiologia , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêuticoRESUMO
BACKGROUND: Previously we documented cellular structural changes of a non-degenerative nature in atrial myocytes after atrial fibrillation (AF) in the goat. The time course of these changes was not studied. METHODS AND RESULTS: Cellular structural changes were studied by light- and electron microscopy and immunohistochemistry in goat atria after 0-16 weeks AF. The first sign of cellular structural remodeling was a more homogeneous chromatin distribution, at 1 week of AF. Sub-structural changes in mitochondria and sarcoplasmic reticulum occurred gradually. Cellular degeneration was absent. The degree of myolysis and glycogen accumulation increased till 8 weeks of AF and did not increase further from thereon. After 16 weeks of AF, 42% of the myocytes in the right atrial free wall were affected by myolysis. The diameter of the atrial myocytes increased. Dedifferentiation of the atrial myocytes was suggested by altered expression patterns of structural proteins, such as the disappearance of cardiotin (1 week), the A-I junctional part of titin (4 weeks), desmin at the intercalated disk (ID) (8 weeks) and a gradual re-expression of alpha-smooth muscle actin. CONCLUSION: Remodeling of the cellular ultrastructure in atrial myocardium of the goat develops progressively during AF. Re-expression of fetal proteins indicate dedifferentiation of atrial myocytes, analogous to observations in hibernating myocardium of the ventricle.
Assuntos
Fibrilação Atrial/fisiopatologia , Átrios do Coração/diagnóstico por imagem , Átrios do Coração/metabolismo , Proteínas/metabolismo , Actinina/metabolismo , Actinas/metabolismo , Animais , Fibrilação Atrial/metabolismo , Moléculas de Adesão Celular/metabolismo , Tamanho Celular , Conectina , Tecido Conjuntivo/diagnóstico por imagem , Modelos Animais de Doenças , Cabras , Átrios do Coração/patologia , Proteínas Musculares/metabolismo , Músculo Liso Vascular/metabolismo , Proteínas Quinases/metabolismo , Fatores de Tempo , UltrassonografiaRESUMO
INTRODUCTION: The mechanisms by which Class IC drugs slow the rate of functional reentrant arrhythmias are not completely understood. We hypothesized that flecainide widens the excitable gap beyond the pivot point of premature turning wavefronts. METHODS AND RESULTS: In eight perfused subepicardial layers of rabbit left ventricle, a linear lesion was made by radiofrequency (RF) ablation parallel to the fiber orientation. One end of the RF lesion was extended by a short incision. Pacing next to the lesion induced a wavefront propagating with a sharp U-turn around the end of the lesion in either the clockwise or counterclockwise direction. A high-density mapping electrode (240 electrodes, 350-microm resolution) was used to record unipolar electrograms at the pivot point. During control, the shortest V1-V2 interval proximal to the pivot point was 162 +/- 12 msec compared with 173 +/- 13 msec distal to the pivot point (difference 11 +/- 8 msec; P < 0.01). After infusion of flecainide 2 mg/L, the shortest V1-V2 interval proximal and distal to the pivot point were 217 +/- 29 msec and 244 +/- 36 msec (difference 27 +/- 16 msec; P < 0.01). Due to the increase in V1-V2 interval at the pivot point, flecainide widened the temporal excitable gap in the returning limb of the turning wavefront from 30 +/- 11 msec to 55 +/- 22 msec (P < 0.01). High-density mapping at the pivot point revealed that this widening of the excitable gap was due to both macroscopic discontinuous conduction and functional conduction block at the pivot point. CONCLUSION: Flecainide widens the excitable gap in the returning limb of premature U-turning wavefronts by causing macroscopic discontinuous conduction and functional conduction block at the pivot point.
Assuntos
Antiarrítmicos/farmacologia , Arritmias Cardíacas/tratamento farmacológico , Flecainida/farmacologia , Sistema de Condução Cardíaco/efeitos dos fármacos , Animais , Arritmias Cardíacas/fisiopatologia , Ablação por Cateter , Eletrocardiografia , Feminino , Sistema de Condução Cardíaco/fisiologia , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/fisiopatologia , Masculino , CoelhosRESUMO
BACKGROUND: Recently, the temporal excitable gap during atrial fibrillation (AF) has been identified as a vulnerable parameter for cardioversion of AF. In this study, we evaluated 5 methods to measure the refractory period (RP(AF)) and the excitable period (EP(AF)) during persistent AF. METHODS AND RESULTS: In 11 goats instrumented with 83 epicardial atrial electrodes, persistent AF (43+/-34 days) was induced with a median AF cycle length (CL) of 98+/-14 ms. To measure RP(AF), premature stimuli were applied to the center of the electrode array on the right or left atrium. The RP(AF) measured by mapping of premature stimuli was 70+/-12 ms ("gold standard"). The RP(AF) determined during entrainment of AF was 77+/-17 ms (R(2)=0.88, P<0.01). Statistical analysis of the effects of synchronized stimuli (each coupling interval x100) on the AFCL histogram yielded an RP(AF) of 70+/-13 ms (R(2)=0.94, P<0.01). A further simplification was to apply slow fixed-rate pacing (1 Hz) during AF. For each stimulus (n=250 to 500), the paced AFCL was plotted against its coupling interval, and capture was determined by statistical shortening of the AFCL (RP(AF) 71+/-17 ms, R(2)=0.84, P<0.01). The 5th percentile of the AFCL histogram as an index of RP(AF) was 77+/-12 ms (R(2)=0.90, P<0.01). CONCLUSIONS: During persistent AF with an AFCL of 98+/-14 ms, the RP(AF) determined by mapping of synchronized premature stimuli (gold standard) was 70+/-12 ms, with an excitable period of 28+/-8 ms. Although the indirect methods to measure RP(AF) all correlated well with the gold standard, slow fixed-rate pacing seems to be the most attractive technique because of the ease of acquiring the data and the clear graphic result.
Assuntos
Fibrilação Atrial/fisiopatologia , Técnicas Eletrofisiológicas Cardíacas/métodos , Animais , Mapeamento Potencial de Superfície Corporal , Estimulação Cardíaca Artificial/métodos , Modelos Animais de Doenças , Eletrodos Implantados , Cabras , Átrios do Coração/fisiopatologia , Sistema de Condução Cardíaco/fisiopatologia , Reprodutibilidade dos Testes , Limiar Sensorial , Fatores de TempoRESUMO
BACKGROUND: After cardioversion of atrial fibrillation (AF), the contractile function of the atria is temporarily impaired. Although this has significant clinical implications, the underlying cellular mechanisms are poorly understood. METHODS AND RESULTS: Forty-nine consecutive patients submitted for mitral valve surgery were investigated. Twenty-three were in persistent AF (>/=3 months); the others were in sinus rhythm. Before extracorporal circulation, the right atrial appendage was excised. ss-Adrenoceptors were quantified by radioligand binding, and G proteins were quantified by Western blot analysis. The isometric contractile response to Ca(2+), isoproterenol, Bay K8644, and the postrest potentiation of contractile force were investigated in thin atrial trabeculae, which were also examined histologically. The contractile force of the atrial preparations obtained from AF patients was 75% less than that in preparations from patients in sinus rhythm. Also, the positive inotropic effect of isoproterenol was impaired, and Bay K8644 failed to increase atrial contractile force. In contrast, the response to extracellular Ca(2+) was maintained, and the postrest potentiation was preserved. Beta-adrenoceptor density and G-protein expression were unchanged. Histological examination revealed 14% more myolysis in the atria of AF patients. CONCLUSIONS: After prolonged AF, atrial contractility was reduced by 75%. The impairment of beta-adrenergic modulation of contractile force cannot be explained by downregulation of ss-adrenoceptors or changes in G proteins. Dysfunction of the sarcoplasmic reticulum does not occur after prolonged AF. Failure of Bay K8644 to restore contractility suggests that the L-type Ca(2+) channel is responsible for the contractile dysfunction. The restoration of contractile force by high extracellular Ca(2+) shows that the contractile apparatus itself is nearly completely preserved after prolonged AF.
Assuntos
Fibrilação Atrial/fisiopatologia , Contração Miocárdica , Éster Metílico do Ácido 3-Piridinacarboxílico, 1,4-Di-Hidro-2,6-Dimetil-5-Nitro-4-(2-(Trifluormetil)fenil)/farmacologia , Fibrilação Atrial/metabolismo , Western Blotting , Agonistas dos Canais de Cálcio/farmacologia , Doença Crônica , Feminino , Humanos , Masculino , Microscopia , Pessoa de Meia-Idade , Contração Miocárdica/efeitos dos fármacos , Receptores Adrenérgicos beta/metabolismo , Transdução de SinaisRESUMO
INTRODUCTION: Atrial fibrillation (AF) and congestive heart failure (CHF) are two clinical entities that often coincide. Our aim was to establish the influence of concomitant high ventricular rate and consequent development of CHF on electrical remodeling and dilation during atrial tachycardia. METHODS AND RESULTS: A total of 14 goats was studied. Five goats were subjected to 3:1 AV pacing (A-paced group, atrial rate 240 beats/min, ventricular rate 80 beats/min). Nine goats were subjected to rapid 1:1 AV pacing (AV-paced group, atrial and ventricular rates 240 beats/min). During 4 weeks, right atrial (RA) and left ventricular (LV) diameters were measured during sinus rhythm. Atrial effective refractory periods (AERP) and inducibility of AF were assessed at three basic cycle lengths (BCL). After 4 weeks of rapid AV pacing, RA and LV diameters had increased to 151% and 113% of baseline, whereas after rapid atrial pacing alone, these parameters were unchanged. Right AERP (157+/-10 msec vs 144+/-16 msec at baseline with BCL of 400 msec in the A-paced and AV-paced group, respectively) initially decreased in both groups, reaching minimum values within 1 week. Subsequently, AERP partially recovered in AV-paced goats, whereas AERP remained short in A-paced goats (79+/-7 msec vs 102+/-12 msec after 4 weeks; P < 0.05). Left AERP demonstrated a similar time course. Inducibility of AF increased in both groups and reached a maximum during the first week in both groups, being 20% and 48% in the A-paced and AV-paced group, respectively. CONCLUSION: Nature and time course of atrial electrical remodeling and dilation during atrial tachycardia are influenced by concurrent high ventricular rate and consequent development of CHF.
Assuntos
Fibrilação Atrial/complicações , Fibrilação Atrial/etiologia , Cardiomegalia/etiologia , Insuficiência Cardíaca/etiologia , Frequência Cardíaca/fisiologia , Taquicardia/complicações , Animais , Cardiomegalia/fisiopatologia , Modelos Animais de Doenças , Eletrofisiologia , Feminino , Cabras , Átrios do Coração/fisiopatologia , Hemodinâmica , Taquicardia/fisiopatologiaRESUMO
We apply methods from non-linear statistical time series analysis to characterize electrograms of atrial fibrillation. These are based on concepts originating from the theory of non-linear dynamical systems and use the empirical reconstruction density in reconstructed phase space. Application of these methods is not restricted to deterministic chaos but is valid in a general time series context. We illustrate this by applying three recently proposed non-linear time series methods to fibrillation electrograms: 1) a test for time reversibility in atrial electrograms during paroxysmal atrial fibrillation in patients; 2) a test to detect differences in the dynamical behaviour during the pharmacological conversion of sustained atrial fibrillation in instrumented conscious goats; 3) a test for general Granger causality to identify couplings and information transport in the atria during fibrillation. We conclude that a characterization of the dynamics via the reconstruction density offers a useful framework for the non-linear analysis of electrograms of atrial fibrillation.
Assuntos
Fibrilação Atrial/diagnóstico , Animais , Eletrofisiologia , Cabras , Humanos , Matemática , Estatística como Assunto , Fatores de TempoRESUMO
Cardiac mapping has been defined as: "a method by which cardiac signals are recorded from multiple sites of the heart and spatially depicted as a function of time in an integrated manner". It requires determination of the local activation time at each electrode and the creation of activation maps which provide a spatial model of the activation sequence. With respect to atrial fibrillation, mapping is useful to gain insight into the underlying mechanism of atrial fibrillation. In this review, we will discuss the mapping studies of experimental and clinical atrial fibrillation.
Assuntos
Fibrilação Atrial/patologia , Fibrilação Atrial/fisiopatologia , Fenômenos Biofísicos , Biofísica , Eletrofisiologia , HumanosRESUMO
INTRODUCTION: Sustained atrial fibrillation (AF) is characterized by a marked shortening of the atrial effective refractory period (AERP) and a decrease or reversal of its physiologic adaptation to heart rate. The aim of the present study was to investigate whether the AF-induced changes in AERP in the goat are associated with changes in the atrial monophasic action potential (MAP) and whether an abnormal expression of specific ion channels underlies such changes. METHODS AND RESULTS: Following thoracotomy, MAPs were recorded from the free wall of the right atrium both before induction of AF (control) and after cardioversion of sustained AF (>2 months) in chronically instrumented goats. In control goats, MAP duration at 80% repolarization (MAPD80) shortened (P < 0.01) from 132+/-4 msec during slow pacing (400-msec interval) to 86+/-10 msec during fast pacing (180 msec). After cardioversion of sustained AF, the MAPD80 during slow pacing was as short as 67+/-5 msec (electrical remodeling). Increasing the pacing rate resulted in prolongation (P = 0.02) of the MAPD80 to 91+/-6 msec. Also, MAPD20 (20% repolarization) shortened (P = 0.05) from 32+/-4 msec (400 msec) to 14+/-7 msec (180 msec) in the control goats, whereas it prolonged (P = 0.03) from 20+/-3 msec (400 msec) to 33+/-5 msec (180 msec) in sustained AF. mRNA expression of the L-type Ca2+ channel alpha1c gene and Kv1.5 potassium channel gene, which underlie ICa and IKur, respectively, was reduced in sustained AF compared with sinus rhythm by 32% (P = 0.01) and 45% (P < 0.01), respectively. No significant changes were found in the mRNA levels of the rapid Na+ channel, the Na+/Ca2+ exchanger, or the Kv4.2/4.3 channels responsible for Ito. CONCLUSION: AF-induced electrical remodeling in the goat comprises shortening of MAPD and reversal of its physiologic rate adaptation. Changes in the time course of repolarization of the action potential are associated with changes in mRNA expression of the alpha subunit genes of the L-type Ca2+ channel and the Kv1.5 potassium channel.
Assuntos
Fibrilação Atrial/fisiopatologia , Cabras/fisiologia , Canais Iônicos/fisiologia , Canais de Potássio de Abertura Dependente da Tensão da Membrana , RNA Mensageiro/metabolismo , Potenciais de Ação , Animais , Função Atrial , Canais de Cálcio Tipo L/genética , Eletrofisiologia , Sistema de Condução Cardíaco/fisiopatologia , Canais Iônicos/genética , Canal de Potássio Kv1.5 , Miocárdio/metabolismo , Canais de Potássio/genética , Tempo de Reação , Período Refratário EletrofisiológicoRESUMO
BACKGROUND: Anisotropy creates nonuniformity in electrical propagation and may contribute to the occurrence of unidirectional conduction block and reentry. We describe the characteristics of reentrant tachycardia in a 2D layer of anisotropic ventricular myocardium. METHODS AND RESULTS: A Langendorff-perfused epicardial sheet (1.0+/-0.4 mm, n=35) was created by freezing the intramural layers of the rabbit left ventricle. Epicardial activation maps were constructed by use of different high-resolution mapping arrays connected to a mapping system. In 5 experiments, monophasic action potentials were recorded. In the intact left ventricle, no arrhythmias except VF could be induced. After freezing, programmed electrical stimulation or rapid pacing led to the induction of sustained VT (cycle length 130+/-11 ms). VT was caused by reentry around a functional line of block oriented parallel to the epicardial fiber direction. Action potential recordings demonstrated that the central line of block was kept refractory by electrotonic currents generated by the depolarization waves propagating at either side of the line of block. At the pivot points of the line of block, the pronounced curvature of the turning wave and abrupt loading changes created an excitable gap of 30 ms in the reentrant pathway. CONCLUSIONS: In uniform anisotropic myocardium, reentry around a functional Z-shaped line of block may occur. The core of the circuit is kept refractory by electrotonic currents. The pronounced wave-front curvature and abrupt loading changes at the pivot points cause local conduction delay and create a small excitable gap.
Assuntos
Sistema de Condução Cardíaco/fisiopatologia , Ventrículos do Coração/fisiopatologia , Miocárdio/metabolismo , Taquicardia Ventricular/fisiopatologia , Potenciais de Ação/fisiologia , Animais , Anisotropia , Estimulação Cardíaca Artificial , Estimulação Elétrica , Técnicas Eletrofisiológicas Cardíacas , Sistema de Condução Cardíaco/metabolismo , Ventrículos do Coração/metabolismo , Técnicas In Vitro , Coelhos , Tempo de Reação/fisiologia , Processamento de Sinais Assistido por Computador , Taquicardia Ventricular/etiologia , Taquicardia Ventricular/metabolismoRESUMO
In this study we applied both linear and nonlinear spatial correlation measures to characterize epicardial activation patterns of sustained atrial fibrillation in instrumented conscious goats. It was investigated if nonlinearity was involved in the spatial coupling of atrial regions and to what extent fibrillation was organized in the experimental model of sustained atrial fibrillation (AF) in instrumented goats. Data were collected in five goats during experiments to convert AF by continuous infusion of cibenzoline. Spatial organization during AF was quantified with the linear spatial cross correlation function and the nonlinear spatial cross redundancy which was calculated using the Grassberger-Procaccia correlation integral. Two different types of correlation were evaluated to distinguish simultaneous interaction from non-simultaneous interaction, for instance resulting from propagation of fibrillation waves. The nonlinear association length and the linear correlation length were estimated along the principal axes of iso-correlation contours in two-dimensional correlation maps of the nonlinear spatial redundancy and the linear spatial correlation function, respectively. To quantitatively assess the degree of nonlinearity, the association length was also estimated from the linearized spatial redundancy using multivariate surrogate data. The differences between the nonlinear and linearized association lengths indicated that a nonlinear component in the spatial organization of AF predominantly existed in the right atrium. The degree of organization characterized by association length along the short principal axis was higher in the right atrium (15 +/- 7 mm) than in the left atrium (8 +/- 4 mm). The spatial extension of coherent atrial patches was estimated from a surface of association equal to the area spanned by the principal axes of iso-correlation contours from the redundancy, including the effects from non-simultaneous interaction. Interpreting this area as the spatial domain of a fibrillation wavelet, the results suggest that the mapped region was activated on average by two wavelets in the left atrium and by one wavelet in the right atrium. Therefore, the activation pattern of sustained AF in goats was relatively organized, consistent with type II of AF. It is suggested that the surface of association is a measure of the number of independent wavelets present in the atria during sustained AF, and that larger association lengths result from fewer and larger reentrant circuits.
Assuntos
Fibrilação Atrial/fisiopatologia , Átrios do Coração/fisiopatologia , Animais , Antiarrítmicos/farmacologia , Antiarrítmicos/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Estado de Consciência , Cabras , Átrios do Coração/efeitos dos fármacos , Sistema de Condução Cardíaco/efeitos dos fármacos , Sistema de Condução Cardíaco/fisiopatologia , Imidazóis/farmacologia , Imidazóis/uso terapêutico , Modelos Biológicos , Dinâmica não LinearRESUMO
The nonlinear spatial redundancy and the linear spatial correlation function were used to investigate to what extent non-linearity was involved in the coupling of atrial regions and how organization in activation patterns of sustained atrial fibrillation (AF) had been modified by administration of the class IC agent cibenzoline in the experimental model of sustained AF in instrumented conscious goats. Electrograms were measured in five goats during sustained AF and when the fibrillation interval had been prolonged to about 25%, 50% and 85% (CIB25, CIB50, CIB85) with respect to control. The nonlinear association length and linear correlation length were estimated along the principal axes of two-dimensional correlation maps estimated from the spatial redundancy and the spatial correlation function, respectively. The estimated short axis association length in the right atrium increased already shortly after the start of infusion (CIB25, +61%), and remained significantly different from control during the experiment, including the effects of non-simultaneous interaction. At CIB85 the association length had almost become twice as long with respect to control (increase from 16 to 29 mm, 89%), while in the left atrium changes were less pronounced (increase from 9 to 12 mm, +32%). The linearized association length which was estimated using multivariate surrogate data increased more gradually and was less sensitive to changes in spatial organization. The results of the spatial correlation analysis suggest that the drug-induced nonlinearity in the spatio-temporal dynamics of sustained AF is related to activation patterns which are characterized by extended uniformly propagating fibrillation wavefronts (AF type I). We conclude that cibenzoline enhanced the spatial organization of sustained AF associated with a transition from type II to type I AF activation patterns. This may destabilize the perpetuation of AF since an increase in association length is equivalent to a reduction of atrial tissue mass available to support reentrant circuits. The results are consistent with the hypothesis that larger association lengths result from fewer and larger reentrant circuits. It is argued that effects of diminished curvature of fibrillation wavefronts are anti-arrhythmic under conditions of suppressed excitability imposed by cibenzoline. Termination of AF may be mediated by a mechanism resembling a bifurcation of the dynamics which sets in when the ends of fractionated wavefronts cannot sufficiently curve anymore to maintain a positive balance of newly generated wavelets needed to sustain AF.
Assuntos
Fibrilação Atrial/fisiopatologia , Átrios do Coração/fisiopatologia , Animais , Antiarrítmicos/farmacologia , Antiarrítmicos/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Estado de Consciência , Cabras , Átrios do Coração/efeitos dos fármacos , Átrios do Coração/ultraestrutura , Sistema de Condução Cardíaco/efeitos dos fármacos , Sistema de Condução Cardíaco/fisiopatologia , Imidazóis/farmacologia , Imidazóis/uso terapêutico , Modelos Biológicos , Dinâmica não LinearRESUMO
OBJECTIVE: Prolonged atrial fibrillation (AF) results in (ultra)structural remodelling of atrial cardiomyocytes resembling alterations seen in ischemia-induced ventricular hibernation. The mechanisms underlying these changes are incompletely understood. In the present study we explored the hypothesis that a profound imbalance in energy status during chronic AF acts as a stimulus for structural remodelling. METHODS AND RESULTS: The content of high energy-phosphates and related compounds together with a selected number of mitochondrial enzymes, known to be altered under ischemic conditions, were determined in tissue samples taken from atria of goats in sinus rhythm (SR) and after 1, 2, 4, 8 and 16 weeks of AF maintained by burst pacing. Atrial remodelling was quantified by counting the percentage of cells with >10% myolysis. During AF structural remodelling developed progressively, after 8 weeks about 40% of the atrial myocytes were affected. The concentration of adenine nucleotides and their degradation products did not change significantly during AF. Also the activity of mitochondrial cytochrome c oxidase activity was similar during AF and SR. Mitochondrial NADH-oxidase and proton-translocating ATPase activities were not induced by AF. The tissue content of phosphocreatine decreased during the first week by 60%, but completely recovered between 8 and 16 weeks of AF. CONCLUSIONS: The analysis of adenine nucleotides during AF provided no indication for the development of severe atrial ischemia. This notion is supported by enzyme cytochemical findings. However, AF-induced atrial remodelling was associated with a transient lowering of phosphocreatine content, suggesting an increase in energy demand during the early phase of AF. The subsequent recovery of the phosphocreatine pool indicates restoration of the balance between energy demand and supply in chronically fibrillating atria.
Assuntos
Adenosina Trifosfatases/análise , Apêndice Atrial/metabolismo , Fibrilação Atrial/metabolismo , Mitocôndrias Cardíacas/enzimologia , Fosfatos/metabolismo , Animais , Fibrilação Atrial/patologia , Estimulação Cardíaca Artificial , Doença Crônica , Creatina/análise , Cães , Feminino , Cabras , Átrios do Coração , Imuno-Histoquímica , Microscopia Eletrônica , Complexos Multienzimáticos/análise , Miocárdio/metabolismo , Miocárdio/ultraestrutura , NADH NADPH Oxirredutases/análise , Fosfocreatina/análise , Estatísticas não ParamétricasRESUMO
OBJECTIVE: It has been postulated that high atrial rate induced changes at the level of the gap junctions ('gap junctional remodeling', i.e. changes in distribution, intercellular orientation and expression of gap junction proteins), could be part of the vicious circle of electrophysiologic and structural changes leading to sustained atrial fibrillation (AF). To obtain experimental evidence in favour of such a postulate the timing of this remodeling process was studied in relation to the development of sustained AF in a goat model. METHODS AND RESULTS: Thin sections from the left (LAA) and right atrial appendage (RAA) from goats in sinus rhythm (SR) or AF, induced through programmed endocardial burst pacing for time periods between 0 and 16 weeks, were immunolabeled with antibodies against connexin(Cx)40 and Cx43 and analysed by immunofluorescence and confocal laser scanning microscopy. During SR the distribution pattern for Cx43 was completely homogeneous (LAA and RAA) and for Cx40 mostly homogeneous (LAA: all five goats, RAA: three out of five goats). The distribution pattern for Cx43 remained stable during AF, while the Cx40 distribution pattern became increasingly heterogeneous, both in the LAA and RAA, with increasing duration of pacing. This increase in heterogeneity in Cx40 distribution correlated (Spearman rank order) with an increase in stability of AF and the occurrence of structural changes (myolysis) in atrial myocytes. The Cx40/Cx43 immunofluorescence signal ratio in both the LAA and RAA appeared to be significantly lower in AF (1-16 weeks) as compared to SR (0 weeks); going from 0 to 16 weeks average ratios decreased 54.5% (n=5; P=0.026) in the LAA and 35.8 (n=5; P=0.034) in the RAA. Western blot analyses revealed similar decreases in the total Cx40/Cx43 protein ratio, on average 50.0% (n=5; P=0.008) and 47.8% (n=5; P=0.02) in the LAA and RAA, respectively. No changes were measured in the levels of Cx40 or Cx43 mRNA, as was assessed through RT-PCR. CONCLUSION: The time course of changes in the distribution and content of Cx40 gap junctions as observed during endocardial burst pacing of the goat atrium suggests that Cx40 gap junctional remodeling might be involved in the pathogenesis of sustained atrial fibrillation.