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1.
Am J Physiol Heart Circ Physiol ; 292(1): H560-71, 2007 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16920806

RESUMO

The nature of electrical remodeling in a canine model of ischemic cardiomyopathy (ICM; induced by repetitive intracoronary microembolizations) that exhibits spontaneous ventricular tachycardia is not entirely clear. We used the patch-clamp technique to record action potentials and ionic currents of left ventricular myocytes isolated from the region affected by microembolizations. We also used the immunoblot technique to examine channel subunit expression in adjacent affected tissue. Ventricular myocytes and tissue isolated from the corresponding region of normal hearts served as control. ICM myocytes had prolonged action potential duration (APD) and more pronounced APD dispersion. Slow delayed rectifier current (I(Ks)) was reduced at voltages positive to 0 mV, along with a negative shift in its voltage dependence of activation. Immunoblots showed that there was no change in KCNQ1.1 (I(Ks) pore-forming or alpha-subunit), but KCNE1 (I(Ks) auxiliary or beta-subunit) was reduced, and KCNQ1.2 (a truncated KCNQ1 splice variant with a dominant-negative effect on I(Ks)) was increased. Transient outward current (I(to)) was reduced, along with an acceleration of the slow phase of recovery from inactivation. Immunoblots showed that there was no change in Kv4.3 (alpha-subunit of fast-recovering I(to) component), but KChIP2 (beta-subunit of fast-recovering component) and Kv1.4 (alpha-subunit of slow-recovering component) were reduced. Inward rectifier current was reduced. L-type Ca current was unaltered. The immunoblot data provide mechanistic insights into the observed changes in current amplitude and gating kinetics of I(Ks) and I(to). We suggest that these changes, along with the decrease in inward rectifier current, contribute to APD prolongation in ICM hearts.


Assuntos
Potenciais de Ação , Cardiomiopatias/fisiopatologia , Sistema de Condução Cardíaco/fisiopatologia , Isquemia Miocárdica/fisiopatologia , Miócitos Cardíacos , Canais de Potássio/metabolismo , Animais , Cardiomiopatias/etiologia , Células Cultivadas , Cães , Masculino , Potenciais da Membrana , Isquemia Miocárdica/complicações
2.
Circulation ; 109(14): 1783-8, 2004 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-15066947

RESUMO

BACKGROUND: Mutations in KCNE2 have been linked to long-QT syndrome (LQT6), yet KCNE2 protein expression in the ventricle and its functional role in native channels are not clear. METHODS AND RESULTS: We detected KCNE2 protein in human, dog, and rat ventricles in Western blot experiments. Immunocytochemistry confirmed KCNE2 protein expression in ventricular myocytes. To explore the functional role of KCNE2, we studied how its expression was altered in 2 models of cardiac pathology and whether these alterations could help explain observed changes in the function of native channels, for which KCNE2 is a putative auxiliary (beta) subunit. In canine ventricle injured by coronary microembolizations, the rapid delayed rectifier current (I(Kr)) density was increased. Although the protein level of ERG (I(Kr) pore-forming, alpha, subunit) was not altered, the KCNE2 protein level was markedly reduced. These data are consistent with the effect of heterologously expressed KCNE2 on ERG and suggest that in canine ventricle, KCNE2 may associate with ERG and suppress its current amplitude. In aging rat ventricle, the pacemaker current (I(f)) density was increased. There was a significant increase in the KCNE2 protein level, whereas changes in the alpha-subunit (HCN2) were not significant. These data are consistent with the effect of heterologously expressed KCNE2 on HCN2 and suggest that in aging rat ventricle, KCNE2 may associate with HCN2 and enhance its current amplitude. CONCLUSIONS: KCNE2 protein is expressed in ventricles, and it can play diverse roles in ventricular electrical activity under (patho)physiological conditions.


Assuntos
Ventrículos do Coração/metabolismo , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Canais de Potássio/fisiologia , Potássio/metabolismo , Remodelação Ventricular/fisiologia , Envelhecimento/metabolismo , Animais , Células COS , Chlorocebus aethiops , Modelos Animais de Doenças , Cães , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go , Sistema de Condução Cardíaco/fisiopatologia , Ventrículos do Coração/patologia , Humanos , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização , Canais Iônicos/metabolismo , Transporte de Íons , Síndrome do QT Longo/metabolismo , Substâncias Macromoleculares , Masculino , Proteínas Musculares/metabolismo , Isquemia Miocárdica/metabolismo , Miocárdio/metabolismo , Canais de Potássio/análise , Canais de Potássio/genética , Canais de Potássio/metabolismo , Subunidades Proteicas , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Especificidade da Espécie , Transfecção
3.
J Cardiovasc Electrophysiol ; 14(5): 499-507, 2003 May.
Artigo em Inglês | MEDLINE | ID: mdl-12776867

RESUMO

INTRODUCTION: Atrial arrhythmias often complicate congestive heart failure (CHF). We characterized inducible atrial tachyarrhythmias and electrophysiologic alterations in dogs with CHF and atrial enlargement produced by rapid ventricular pacing. METHODS AND RESULTS: Endocardial pacing leads were implanted in the right ventricle, right atrium, and coronary sinus in 18 dogs. The right ventricular lead was connected to an implanted pacemaker capable of rapid ventricular pacing. The atrial leads were used to perform electrophysiologic studies in conscious animals at baseline in all dogs, during CHF induced by rapid ventricular pacing at 235 beats/min in 15 dogs, and during recovery from CHF in 6 dogs. After 20 +/- 7 days of rapid ventricular pacing, inducibility of sustained atrial tachycardia (cycle length 120 +/- 12 msec) was enhanced in dogs with CHF. Atrial tachycardia required a critical decrease in atrial burst pacing cycle length (< or = 130 msec) for induction and often could be terminated by overdrive pacing. Calcium antagonists (verapamil, flunarizine, ryanodine) terminated atrial tachycardia and suppressed inducibility. Effective refractory periods at 400- and 300-msec cycle lengths in the right atrium and coronary sinus were prolonged in dogs with CHF. Atrial cells from dogs with CHF had prolonged action potential durations and reduced resting potentials and delayed afterdepolarizations (DADs). Mitochondria from atrial tissue from dogs with CHF were enlarged and had internal cristae disorganization. CONCLUSIONS: CHF promotes inducibility of sustained atrial tachycardia. Based on the mode of tachycardia induction, responses to pacing and calcium antagonists, and presence of DADs, atrial tachycardia in this CHF model has a mechanism most consistent with DAD-induced triggered activity resulting from intracellular calcium overload.


Assuntos
Estimulação Cardíaca Artificial/efeitos adversos , Insuficiência Cardíaca/etiologia , Taquicardia Atrial Ectópica/classificação , Taquicardia Atrial Ectópica/etiologia , Potenciais de Ação/fisiologia , Antagonistas Adrenérgicos beta/farmacologia , Animais , Antiarrítmicos/farmacologia , Fator Natriurético Atrial/sangue , Pressão Sanguínea/fisiologia , Modelos Animais de Doenças , Cães , Ecocardiografia , Eletrocardiografia , Técnicas Eletrofisiológicas Cardíacas , Átrios do Coração/diagnóstico por imagem , Átrios do Coração/efeitos dos fármacos , Átrios do Coração/fisiopatologia , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/fisiopatologia , Ventrículos do Coração/diagnóstico por imagem , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/fisiopatologia , Modelos Cardiovasculares , Recuperação de Função Fisiológica/fisiologia , Volume Sistólico/fisiologia , Análise de Sobrevida , Taquicardia Atrial Ectópica/fisiopatologia , Disfunção Ventricular Esquerda/etiologia , Disfunção Ventricular Esquerda/fisiopatologia
4.
Prog Biophys Mol Biol ; 82(1-3): 25-42, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-12732266

RESUMO

Characteristics and functions of the cardiac swelling-activated Cl current (I(Cl,swell)) are considered in physiologic and pathophysiologic settings. I(Cl,swell) is broadly distributed throughout the heart and is stimulated not only by osmotic and hydrostatic increases in cell volume, but also by agents that alter membrane tension and direct mechanical stretch. The current is outwardly rectifying, reverses between the plateau and resting potentials (E(m)), and is time-independent over the physiologic voltage range. Consequently, I(Cl,swell) shortens action potential duration, depolarizes E(m), and acts to decrease cell volume. Because it is activated by stimuli that also activate cation stretch-activated channels, I(Cl,swell) should be considered as a potential effector of mechanoelectrical feedback. I(Cl,swell) is activated in ischemic and non-ischemic dilated cardiomyopathies and perhaps during ischemia and reperfusion. I(Cl,swell) plays a role in arrhythmogenesis, myocardial injury, preconditioning, and apoptosis of myocytes. As a result, I(Cl,swell) potentially is a novel therapeutic target.


Assuntos
Canais de Cloreto/química , Cloretos/química , Coração/fisiologia , Miocárdio/patologia , Potenciais de Ação , Animais , Ânions , Apoptose , Arritmias Cardíacas/patologia , Fenômenos Biofísicos , Biofísica , Membrana Celular/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Eletrofisiologia , Precondicionamento Isquêmico Miocárdico , Sistema de Sinalização das MAP Quinases , Células Musculares/metabolismo , Isquemia Miocárdica , Fenótipo , Proteína Quinase C/metabolismo , Proteínas Tirosina Quinases/metabolismo , Coelhos , Estresse Mecânico , Fatores de Tempo
5.
Pacing Clin Electrophysiol ; 26(1 Pt 1): 53-8, 2003 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-12685140

RESUMO

The aim of the study was to determine the long-term freedom from atrial arrhythmias after radiofrequency ablation of atrial flutter and to determine the factors associated with recurrent arrhythmias. Radiofrequency ablation has emerged as the preferred treatment for recurrent, typical atrial flutter. Although the short-term results after radiofrequency ablation of atrial flutter have been widely reported, there is insufficient data on long-term outcome with respect to the occurrence of atrial arrhythmias in patients after successful ablation. The first 108 patients to undergo successful ablation for typical atrial flutter at the authors' institutions were followed prospectively until the occurrence of typical atrial flutter, atrial fibrillation, atypical atrial flutter, or death. Several prespecified clinical and procedural factors were tested using univariate and multivariate analysis as predictors of arrhythmia recurrence. Patients were followed for a minimum of 3 years and a maximum of 8 years, or until the first arrhythmia recurrence (average duration 17 +/- 17 months). Recurrences of typical atrial flutter were usually observed within the first 6 months (73%, n = 16), with the remainder (27%, n = 6) occurring between 6 months and 2 years, and none were observed later. Freedom from recurrence of typical atrial flutter was 80% at 1 year (95% CIs 72-89%), 73% at 2 years (CIs 63-83%), and 73% at 5 years (CIs 63-83%). By contrast, freedom from occurrence of atrial fibrillation or atypical atrial flutter progressively declined over time; 80% at 1 year (CIs 71-88%), 59% at 2 years (CIs 48-70%), and 33% at 5 years (CIs 19-48%). A history of atrial fibrillation or atypical atrial flutter prior to ablation was associated with an increased risk of occurrence during follow-up (relative risk 3.4, CIs 1.5-8.1, P < 0.05). Freedom from occurrence of any atrial arrhythmia was only 27% at 5 years (CIs 15-40%). After successful ablation of typical atrial flutter, recurrence of typical flutter is relatively uncommon and usually occurs early. However, there is a progressive occurrence of atrial fibrillation and/or atypical flutter during follow-up so that many patients require further antiarrhythmic or additional ablative therapy. Radiofrequency ablation of typical atrial flutter should be considered a palliative procedure for most patients and only one component of the long-term care of the patient with atrial tachyarrhythmias.


Assuntos
Flutter Atrial/cirurgia , Ablação por Cateter , Idoso , Fibrilação Atrial/cirurgia , Flutter Atrial/mortalidade , Flutter Atrial/fisiopatologia , Feminino , Seguimentos , Humanos , Masculino , Modelos de Riscos Proporcionais , Recidiva , Taxa de Sobrevida , Fatores de Tempo
6.
J Am Coll Cardiol ; 41(1): 73-80, 2003 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-12570948

RESUMO

OBJECTIVES: This study evaluated the long-term reliability of an implantable cardioverter defibrillator (ICD) lead to determine the incidence, clinical presentation, and management of lead failure. BACKGROUND: Despite recent advances in ICD technology, the long-term reliability of ICD leads remains a significant problem. METHODS: Concern about long-term reliability of coaxial polyurethane ICD leads caused us to systematically study all patients implanted with Medtronic (Minneapolis, Minnesota) 6936 lead at our institution. We performed follow-up of 74 patients with 76 ICD leads that were implanted from February 28, 1995 to September 8, 1997. Thirty-seven patients underwent routine clinical ICD follow-up testing and ventricular fibrillation induction to determine the status of their ICD lead after a mean follow-up of 68.6 +/- 8.2 months. RESULTS: The lead survival analysis shows a cumulative failure probability of 37% (confidence interval, 24% to 54%) at 68.6 months. Six patients demonstrated a previously undescribed mode of ICD lead failure: prolonged oversensing immediately after shock therapy. The use of short interval counters to monitor nonphysiologic R-R intervals and the measurement of ring-to-coil impedance detected early lead failures in five patients. CONCLUSIONS: This analysis shows: 1) problems with ICD leads may not become apparent until late during follow-up and may become a significant late problem, 2) a "signature" mode of lead failure for the 6936 consisting of oversensing of electrical noise following shocks, 3) early detection of lead failure with a short interval counter algorithm or measurement of ring-to-coil impedance may be clinically useful.


Assuntos
Desfibriladores Implantáveis/efeitos adversos , Idoso , Técnicas de Diagnóstico Cardiovascular , Eletrocardiografia , Técnicas Eletrofisiológicas Cardíacas/métodos , Falha de Equipamento/estatística & dados numéricos , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Poliuretanos/efeitos adversos , Valor Preditivo dos Testes , Taquicardia Ventricular/terapia , Fatores de Tempo
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