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1.
J Atr Fibrillation ; 8(5): 1341, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27909474

RESUMO

BACKGROUND: Cryoballoon (CB) ablation is successful in eliminating atrial fibrillation (AF). PURPOSE: The purpose of this study was to assess procedural efficacy and safety of CB ablation performed by a newly trained operator. METHODS: Forty patients with documented paroxysmal AF (58 ± 11 years, 26 male) undergoing CB catheter ablation were prospectively enrolled. RESULTS: Electrical pulmonary vein (PV) isolation was achieved in all patients (156 PVs). The primary end point (PV isolation using CB only) was reached in 31 patients (92% PV isolation, 144/156 PVs). In the remaining 9 patients (12 PVs), additional single point cryofocal ablations were required to achieve isolation of all veins (LSPV, n = 5; LIPV, n = 3; LCPV, n = 2; RSPV, n = 1; RIPV, n = 1). There was no vascular access complication, pericardial effusion/tamponade, stroke/transient ischemic attack, phrenic nerve palsy, acute PV stenosis, or atrioesophageal fistula. The procedure duration decreased with experience by 30% from 155 min during the first 10 procedures to 108 min (final 10 treatments). Similar effects were observed with fluoroscopy time (-57%; from 28 min to 12 min), dose area product (-66%; from 22 Gy x cm2 to 8 Gy x cm2), CB time in the left atrium (-24%; from 99 min to 75 min), and cryoenergy delivery time (-19%; from 83 min to 67 min), when comparing cases #1-10 to cases #30-40. CONCLUSIONS: CB ablation of AF is effective and safe in the hands of a new operator. Procedure and fluoroscopy times decrease with user experience.

2.
Clin Res Cardiol ; 104(3): 241-9, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25331160

RESUMO

Left ventricular noncompaction (LVNC) is a cardiomyopathy with hypertrabeculation of the LV, often complicated by heart failure, arrhythmia and thromboembolic events. The features of LVNC are still incompletely characterized due to its late recognition as clinically relevant condition. The aims of this study were to describe echocardiographic and electrophysiologic characteristics of LVNC patients and to assess the effects of chronic ß-blocker treatment. Study patients (n = 20; 42.5 [36.3; 52.5] years; 12 men) exhibited reduced LV ejection fraction (median LVEF = 32 %) and an increased LV mass of 210 g. Sinus rhythm was present in 19 patients, whereas one patient was in atrial fibrillation. Baseline heart rate was 77.5 beats per minute. Left bundle branch block was detected in five cases. In a subgroup of patients receiving ß-blocker therapy (n = 17), LV mass was reduced from 226 [178; 306] g to 220 [169; 254] g (p = 0.007) at 13 ± 6 months follow-up. By contrast, a subgroup of three patients that were not treated with an anti-ß-adrenergic agent showed LV mass increase from 180 [169; 197] g to 199 [185; 213] g (p = 0.023). LVEF and electrocardiographic parameters were not significantly modulated during chronic ß-blocker treatment. There was no sustained symptomatic ventricular tachyarrhythmia, thromboembolic event or death in either group. In conclusion, this study reveals reduction of LV mass among LVNC patients during ß-blocker therapy. Effects of ß-blocker treatment in LVNC require validation in prospective controlled studies.


Assuntos
Antagonistas Adrenérgicos beta/uso terapêutico , Ecocardiografia Doppler em Cores , Eletrocardiografia , Miocárdio Ventricular não Compactado Isolado/tratamento farmacológico , Adulto , Feminino , Bloqueio Cardíaco/diagnóstico , Bloqueio Cardíaco/tratamento farmacológico , Bloqueio Cardíaco/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , Humanos , Hipertrofia Ventricular Esquerda/diagnóstico , Hipertrofia Ventricular Esquerda/tratamento farmacológico , Hipertrofia Ventricular Esquerda/fisiopatologia , Miocárdio Ventricular não Compactado Isolado/diagnóstico , Miocárdio Ventricular não Compactado Isolado/fisiopatologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Retrospectivos , Volume Sistólico/efeitos dos fármacos , Resultado do Tratamento , Função Ventricular Esquerda/efeitos dos fármacos
3.
Pacing Clin Electrophysiol ; 37(9): 1198-209, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24665992

RESUMO

BACKGROUND: Implantable defibrillators (ICD) are highly effective in reducing arrhythmia-related mortality. ICD shock therapy has been shown to increase psychological distress, health care utilization, and is associated with increased mortality. The Protecta ICDs (Medtronic Inc., Minneapolis, MN, USA) have algorithms designed to reduce unnecessary and inappropriate shock therapy. METHODS AND RESULTS: The PainFree SmartShock™ Technology (PainFree SST) study is a prospective, multicenter, clinical trial with two consecutive phases, a premarket phase safety study and a postmarket phase effectiveness study. We report the results of the PainFree SST safety study. The premarket phase aimed to investigate safety in the first year postimplant, and to determine if the novel algorithms (T-wave discrimination, right ventricular lead noise discrimination and confirmation+) affect appropriate ventricular fibrillation (VF) detection. Patients (total: n = 246 [male 78%, mean age 63 year, primary prevention indication in 76%]) were implanted either with a Protecta XT dual-chamber ICD (n = 114 [46%]) or a defibrillator with cardiac resynchronization therapy (n = 132 [54%]). Appropriate VF detection was measured during VF induction at implantation when the novel algorithms were programmed ON. A two-second delay in VF detection was classified as clinically significant. No delay in VF detection was observed with all algorithms programmed ON. No unanticipated serious adverse device effects occurred during first year postimplant. CONCLUSION: The results of the premarket phase of the PainFree SST trial demonstrate the safety of the Protecta XT defibrillators. Detection of induced VF was not delayed with SmartShock™ algorithms ON.


Assuntos
Algoritmos , Arritmias Cardíacas/terapia , Desfibriladores Implantáveis , Idoso , Anticoagulantes/uso terapêutico , Arritmias Cardíacas/fisiopatologia , Eletrocardiografia Ambulatorial , Segurança de Equipamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Segurança do Paciente , Vigilância de Produtos Comercializados , Estudos Prospectivos , Fatores de Risco , Sensibilidade e Especificidade , Resultado do Tratamento
4.
PLoS One ; 9(2): e88164, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24516604

RESUMO

Glioblastoma (GB) is associated with poor patient survival owing to uncontrolled tumor proliferation and resistance to apoptosis. Human ether-a-go-go-related gene K(+) channels (hERG; Kv11.1, KCNH2) are expressed in multiple cancer cells including GB and control cell proliferation and death. We hypothesized that pharmacological targeting of hERG protein would inhibit tumor growth by inducing apoptosis of GB cells. The small molecule hERG ligand doxazosin induced concentration-dependent apoptosis of human LNT-229 (EC50 = 35 µM) and U87MG (EC50 = 29 µM) GB cells, accompanied by cell cycle arrest in the G0/G1 phase. Apoptosis was associated with 64% reduction of hERG protein. HERG suppression via siRNA-mediated knock down mimicked pro-apoptotic effects of doxazosin. Antagonism of doxazosin binding by the non-apoptotic hERG ligand terazosin resulted in rescue of protein expression and in increased survival of GB cells. At the molecular level doxazosin-dependent apoptosis was characterized by activation of pro-apoptotic factors (phospho-erythropoietin-producing human hepatocellular carcinoma receptor tyrosine kinase A2, phospho-p38 mitogen-activated protein kinase, growth arrest and DNA damage inducible gene 153, cleaved caspases 9, 7, and 3), and by inactivation of anti-apoptotic poly-ADP-ribose-polymerase, respectively. In summary, this work identifies doxazosin as small molecule compound that promotes apoptosis and exerts anti-proliferative effects in human GB cells. Suppression of hERG protein is a crucial molecular event in GB cell apoptosis. Doxazosin and future derivatives are proposed as novel options for more effective GB treatment.


Assuntos
Apoptose , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Pontos de Checagem do Ciclo Celular , Canais de Potássio Éter-A-Go-Go/metabolismo , Glioblastoma/metabolismo , Glioblastoma/patologia , Apoptose/efeitos dos fármacos , Neoplasias Encefálicas/enzimologia , Caspase 9/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Citoproteção/efeitos dos fármacos , Desipramina/farmacologia , Doxazossina/farmacologia , Canal de Potássio ERG1 , Ativação Enzimática/efeitos dos fármacos , Fase G1/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Glioblastoma/enzimologia , Humanos , RNA Interferente Pequeno/metabolismo , Fase de Repouso do Ciclo Celular/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
5.
J Cardiovasc Electrophysiol ; 25(3): 242-9, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24237758

RESUMO

INTRODUCTION: Catheter ablation (CA) has emerged as a widespread therapeutic option in the treatment of atrial fibrillation (AF). Currently, no safety data with regard to the impact of the underlying structural heart diseases (SHD) are available. We sought to assess the risk for acute and long-term complications during CA of AF in relation to underlying SHD. METHODS AND RESULTS: We included 6,211 patients in a prospective registry undergoing CA of AF in 41 nationwide centers. All patients were divided into 4 groups according to the underlying heart disease: No SHD (69.4%), hypertensive heart disease (HHD) (12.0%), coronary artery disease (CAD) (15.1%), and cardiomyopathy (CM) (3.6%). In univariate analysis, patients with HHD had an overall complication rate of 7.28%, whereas patients without an SHD had a significantly lower rate of 6.01% (P < 0.01). Multivariate analysis revealed that HHD (adjusted odds ratio [OR]: 1.97 [95% confidence interval (CI): 1.02-3.83], P = 0.0442) and age (years; OR: 1.04 [95% CI: 1.01-1.07], P = 0.0155) were independent predictors of severe, nonfatal complications and death. Other SHD including CAD (OR: 1.48 (0.73-3.00), P = 0.2797) and CM (OR: 2.37 [0.70-7.99], P = 0.1630) failed to reach statistical significance. Male sex was protective (OR: 0.47 [95% CI: 0.27-0.81], P = 0.0062). CONCLUSION: In general, CA of AF has a low number of severe complications. In our prospective registry HHD emerged as an independent predictor of severe, nonfatal complications during AF ablation but other SHD including CAD and CM did not. The influence of HHD on the complication rate should be considered in patient selection.


Assuntos
Fibrilação Atrial/epidemiologia , Fibrilação Atrial/cirurgia , Ablação por Cateter/efeitos adversos , Complicações Pós-Operatórias/epidemiologia , Sistema de Registros , Idoso , Fibrilação Atrial/diagnóstico , Ablação por Cateter/tendências , Feminino , Seguimentos , Alemanha/epidemiologia , Cardiopatias/epidemiologia , Cardiopatias/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/diagnóstico , Estudos Prospectivos , Resultado do Tratamento
6.
Pacing Clin Electrophysiol ; 37(1): 35-47, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24102228

RESUMO

OBJECTIVES: To determine (1) the frequency and course of anxiety disorders in patients with implantable cardioverter defibrillators (ICDs), (2) the predictors of anxiety, (3) the treatment situation and patients' requests for therapy. METHODS: Quantitative and qualitative methods in a prospective design. At baseline, 327 ICD outpatients completed validated self-report questionnaires (participation rate = 77%). Five months later, a predefined subsample of patients (n = 108, participation rate = 81%) consisting of all patients with (n = 58) and a randomly selected subsample of patients without (n = 50) elevated symptoms of anxiety at baseline, was reassessed using a structured diagnostic interview, the baseline questionnaires, and open-ended questions. RESULTS: At baseline, 19.2% of patients suffered from at least some form of clinically relevant anxiety with an overall remission rate of 56.5% at follow-up. Predictive for anxiety at follow-up were higher levels of stress (odds ratio [OR], 1.52, P < 0.001), depression (OR, 1.26, P < 0.001), somatic symptom severity (OR, 1.25, P < 0.001), more perceived ICD-related constraints (OR, 2.4, P = 0.007), lower quality of life (physical health: OR, 0.91, P = 0.004; mental health: OR, 0.87, P = 0.001), and a higher New York Heart Association class (OR, 7.99, P = 0.002) at baseline. Only 35.3% of patients received an evidenced-based treatment for their anxiety disorder. A supervised ICD patient group was the most preferred treatment (51.1%). CONCLUSIONS: Most patients seemed to adapt well to ICD therapy. Patients suffering from additional psychological strains and reporting more negative ICD-related attitudes were at risk for developing an anxiety disorder. Special tailored interventions, such as a supervised ICD patient group, could reduce the gap between treatment needs and the treatment situation.


Assuntos
Transtornos de Ansiedade/psicologia , Transtornos de Ansiedade/terapia , Desfibriladores Implantáveis/psicologia , Desfibriladores Implantáveis/estatística & dados numéricos , Aceitação pelo Paciente de Cuidados de Saúde/psicologia , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Adulto , Transtornos de Ansiedade/epidemiologia , Atitude Frente a Saúde , Feminino , Alemanha/epidemiologia , Humanos , Incidência , Masculino , Participação do Paciente/psicologia , Participação do Paciente/estatística & dados numéricos , Prognóstico , Fatores de Risco , Inquéritos e Questionários , Resultado do Tratamento
7.
Naunyn Schmiedebergs Arch Pharmacol ; 387(3): 291-300, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24311292

RESUMO

The human KCNK18 gene is predominantly expressed in brain, spinal cord, and dorsal root ganglion neurons. Encoded K2P18.1K(+) channels are functionally implicated in migraine, pain and anesthesia. Data delineating the in vivo significance of K2P18.1 are still limited owing to a lack of model systems allowing for rapid, whole organism phenotypic analyses. We hypothesized that zebrafish (Danio rerio) might close this scientific gap. This work was designed to characterize the zebrafish ortholog of K2P18.1 in comparison to human K2P18.1 channels. The complete coding sequence of zKCNK18 was amplified from zebrafish cDNA. Zebrafish KCNK18 expression was assessed by in situ hybridization. Human and zebrafish K2P18.1 currents were functionally analyzed using two-electrode voltage clamp electrophysiology and the Xenopus oocyte expression system. KCNK18 mRNA is expressed in zebrafish brain and eyes. Human and zebrafish K2P18.1 proteins share 32 % identity. Zebrafish K2P18.1 channels mediate K(+)-selective background currents that stabilize the negative resting membrane potential. Functional similarities between human and zK2P18.1 currents include open rectification properties, inhibition by barium, and regulation by signaling molecules protein kinase (PK)C, PKA, and phospholipase C. In contrast to the human ortholog, zK2P18.1 exhibited reduced sensitivity to elevation of intracellular calcium levels by ionomycin and was virtually insensitive to inhibition by quinidine. Zebrafish and human K2P18.1 channels share functional and regulatory properties, indicating that the zebrafish may serve as model to assess K2P18.1 function in vivo. However, distinct differences in K2P18.1 current regulation require careful consideration when zebrafish data are extrapolated to human physiology.


Assuntos
Canais de Potássio de Domínios Poros em Tandem/metabolismo , Canais de Potássio/metabolismo , Animais , Cálcio/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , DNA Complementar/genética , Feminino , Humanos , Hibridização In Situ , Potenciais da Membrana/fisiologia , Oócitos , Técnicas de Patch-Clamp , Canais de Potássio/genética , Proteína Quinase C/metabolismo , Quinidina/farmacologia , Especificidade da Espécie , Fosfolipases Tipo C/metabolismo , Xenopus laevis , Peixe-Zebra
8.
Eur J Pharmacol ; 721(1-3): 237-48, 2013 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-24070813

RESUMO

Class IC antiarrhythmic drugs are commonly used for rhythm control in atrial fibrillation. In addition, class I drugs are administered to suppress ventricular tachyarrhythmia in selected cases. The multichannel blocking profile of class I compounds includes reduction of cardiac potassium currents in addition to their primary mechanism of action, sodium channel inhibition. Blockade of two-pore-domain potassium (K2P) channels in the heart causes action potential prolongation and may provide antiarrhythmic action in atrial fibrillation. This study was designed to elucidate inhibitory effects of class I antiarrhythmic drugs on K2P channels. Human K2P2.1 (TREK1) and hK2P3.1 (TASK1) channels were systematically tested for their sensitivity to clinically relevant class IA (ajmaline), class IB (mexiletine), and class IC (propafenone) antiarrhythmic compounds using whole-cell patch clamp and two-electrode voltage clamp electrophysiology in Chinese hamster ovary cells and in Xenopus oocytes. Mexiletine and propafenone inhibited hK2P2.1 (IC50,mexiletine=173µM; IC50,propafenone=7.6µM) and hK2P3.1 channels (IC50,mexiletine=97.3µM; IC50,propafenone=5.1µM) in mammalian cells. Ajmaline did not significantly reduce current amplitudes. K2P channels were blocked in open and closed states, resulting in resting membrane potential depolarization. Open rectification properties of the channels were not affected by class I drugs. In summary, class I antiarrhythmic drugs target cardiac K2P K(+) channels. Blockade of hK2P2.1 and hK2P3.1 potassium currents provides mechanistic evidence to establish cardiac K2P channels as antiarrhythmic drug targets.


Assuntos
Antiarrítmicos/farmacologia , Miocárdio/metabolismo , Bloqueadores dos Canais de Potássio/farmacologia , Canais de Potássio de Domínios Poros em Tandem/antagonistas & inibidores , Potenciais de Ação/efeitos dos fármacos , Animais , Células CHO , Cricetinae , Cricetulus , Humanos , Mexiletina/farmacologia , Miocárdio/citologia , Oócitos/metabolismo , Canais de Potássio de Domínios Poros em Tandem/genética , Propafenona/farmacologia , Xenopus laevis/genética
9.
Cardiovasc Res ; 98(3): 496-503, 2013 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-23447643

RESUMO

AIMS: Autoimmune-associated proarrhythmia in dilated cardiomyopathy (DCM) is poorly understood. Given the significance of KCNQ1 potassium channels in heart rhythm disorders, we hypothesized that circulating anti-KCNQ1 autoantibodies directly modulate cardiac electrophysiology in DCM patients. The purpose of this pilot study was to characterize ion channel autoantibodies in DCM targeting the cardiac repolarizing K(+) current, IKs, and the underlying KCNQ1 potassium channel. METHODS AND RESULTS: One hundred and fifty DCM patients were screened for anti-KCNQ1 autoantibodies using an enzyme-linked immunosorbent assay. Autoantibodies targeting the extracellular pore domain of the KCNQ1 channel were detected in 6% of study patients. Seropositive individuals exhibited significantly shorter corrected QT intervals when compared with seronegative patients (371 ± 39.9 ms vs. 408 ± 47.9 ms; P = 0.036). There was no difference in clinical severity of heart failure between groups. The functional significance of anti-KCNQ1 antibodies was determined in human embryonic kidney 293 cells expressing KCNQ1/KCNE1 using the whole-cell patch clamp technique. IKs recordings demonstrated a 2.7-fold increase in mean current density on exposure to patients' sera containing anti-KCNQ1 antibodies in contrast to seronegative controls (8.74 ± 1.44 pA/pF vs. 3.26 ± 0.36 pA/pF; P = 0.003). IKs enhancement was not associated with increased KCNQ1 protein levels or altered cell surface expression of the channel. CONCLUSION: Anti-KCNQ1 autoantibodies found in a subgroup of DCM patients are associated with QT interval shortening and increased IKs current.


Assuntos
Arritmias Cardíacas/imunologia , Autoanticorpos/sangue , Cardiomiopatia Dilatada/imunologia , Sistema de Condução Cardíaco/imunologia , Canal de Potássio KCNQ1/imunologia , Potenciais de Ação , Adulto , Idoso , Arritmias Cardíacas/sangue , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/fisiopatologia , Cardiomiopatia Dilatada/sangue , Cardiomiopatia Dilatada/complicações , Cardiomiopatia Dilatada/metabolismo , Cardiomiopatia Dilatada/fisiopatologia , Eletrocardiografia , Feminino , Células HEK293 , Sistema de Condução Cardíaco/metabolismo , Sistema de Condução Cardíaco/fisiopatologia , Humanos , Canal de Potássio KCNQ1/metabolismo , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Fatores de Tempo , Transfecção
10.
Eur Heart J ; 34(2): 147-57, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21785105

RESUMO

AIMS: Atrial fibrillation (AF) is linked to cardiomyocyte apoptosis, leading to atrial remodelling and reduction in electrical conduction velocity. We hypothesized that genetic suppression of an apoptotic key enzyme, caspase 3, would prevent the development of persistent AF by reducing apoptosis which may serve as an arrhythmogenic substrate. METHODS AND RESULTS: Atrial fibrillation was induced in domestic pigs by atrial burst pacing via an implanted cardiac pacemaker. Study animals were then assigned to receive either Ad-siRNA-Cas3 gene therapy to inactivate caspase 3 or green fluorescent protein (Ad-GFP) as a control. Adenoviruses were applied using a hybrid technique employing right and left atrial virus injection followed by epicardial electroporation to increase expression of plasmid DNA. In pigs treated with Ad-siRNA-Cas3, the onset of AF was suppressed or significantly delayed compared with controls (10.3 ± 1.2 days vs. 6.0 ± 1.6 days; P= 0.04). Electrical mapping revealed prolonged atrial conduction in the control group that was prevented by Ad-siRNA-Cas3 gene therapy. On the molecular level, Ad-siRNA-Cas3 application resulted in down-regulation of caspase 3 expression and suppression of apoptotic activity. CONCLUSION: Knockdown of caspase 3 by atrial Ad-siRNA-Cas3 gene transfer suppresses or delays the onset of persistent AF by reduction in apoptosis and prevention of intra-atrial conduction delay in a porcine model. These results highlight the significance of apoptosis in the pathophysiology of AF and demonstrate short-term efficacy of gene therapy for suppression of AF.


Assuntos
Fibrilação Atrial/terapia , Caspase 3/genética , Inibidores de Caspase/administração & dosagem , Técnicas de Silenciamento de Genes/métodos , Terapia Genética/métodos , RNA Interferente Pequeno/administração & dosagem , Adenoviridae , Animais , Apoptose/genética , Fibrilação Atrial/enzimologia , Fibrilação Atrial/patologia , Técnicas de Transferência de Genes , Vetores Genéticos , Miócitos Cardíacos/enzimologia , Miócitos Cardíacos/patologia , Marca-Passo Artificial , Sus scrofa
11.
J Cardiovasc Electrophysiol ; 24(1): 40-6, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23131063

RESUMO

BACKGROUND: Pulmonary vein isolation (PVI) has become the cornerstone procedure for the treatment of symptomatic drug-resistant atrial fibrillation (AF). At the present time, circumferential PVI (CPVI) using irrigated radiofrequency (RF) is the mostly used ablation technique. However, for CPVI, precise catheter navigation and excellent catheter stability is crucial thereby requiring experienced operators. Robotic navigation systems have been introduced to facilitate catheter navigation and to improve catheter stability, therefore potentially increasing procedural success and making CPVI accessible to less experienced operators. To date, no prospective randomized trial has evaluated the efficacy and safety of CPVI using RNS compared to manually performed ablation. METHODS: In this prospective international multicenter noninferiority trial, 258 patients with either paroxysmal or short-standing persistent AF will be randomized for comparison of PVI using either manual or robotic ablation. In all patients, CPVI will be performed using irrigated RF ablation in combination with a 3D mapping system. The primary endpoint of the trial is the absence of AF or atrial tachycardia without antiarrhythmic drug therapy during 12-month follow-up. Secondary endpoints will be evaluation of periprocedural complications and procedural data such as procedure time, fluoroscopy time, as well as the incidence of esophageal injury assessed by endoscopy within 48 hours after the procedure. CONCLUSION: The "Man and Machine Trial" is the first prospective international randomized controlled multicenter noninferiority trial to compare manually performed CPVI with robotically navigated CPVI, evaluating both the safety and efficacy of the 2 techniques during a 12-month follow-up period.


Assuntos
Fibrilação Atrial/cirurgia , Ablação por Cateter/métodos , Robótica/métodos , Cirurgia Assistida por Computador/métodos , Adulto , Idoso , Feminino , Humanos , Internacionalidade , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Projetos de Pesquisa , Resultado do Tratamento
12.
Eur Heart J ; 34(35): 2768-75, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23178648

RESUMO

AIMS: HCN4 channels are involved in generation, regulation, and stabilization of heart rhythm and channel dysfunction is associated with inherited sinus bradycardia. We asked whether dysfunctional HCN4 channels also contribute to the generation of cardiac tachyarrhythmias. METHODS AND RESULTS: In a candidate gene approach, we screened 422 patients with atrial and/or ventricular tachyarrhythmias and detected a novel HCN4 gene mutation that replaced the positively charged lysine 530 with an asparagine (HCN4-K530N) in a highly conserved region of the C-linker. The index patient developed tachycardia-bradycardia syndrome and persistent atrial fibrillation (AF) in an age-dependent fashion. Pedigree analysis identified eight affected family members with a similar course of disease. Whole-cell patch clamp electrophysiology of HEK293 cells showed that homomeric mutant channels almost are indistinguishable from wild-type channels. In contrast, heteromeric channels composed of mutant and wild-type subunits displayed a significant hyperpolarizing shift in the half-maximal activation voltage. This may be caused by a shift in the equilibrium between the tonically inhibited nucleotide-free state of the C-terminal domain of HCN4 believed to consist of a 'dimer of dimers' and the activated ligand-bound tetrameric form, leading to an increased inhibition of activity in heteromeric channels. CONCLUSION: Altered C-linker oligomerization in heteromeric channels is considered to promote familial tachycardia-bradycardia syndrome and persistent AF, indicating that f-channel dysfunction contributes to the development of atrial tachyarrhythmias.


Assuntos
Fibrilação Atrial/genética , Bradicardia/genética , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/genética , Mutação/genética , Taquicardia/genética , Adulto , Análise de Variância , Eletrocardiografia , Técnicas Eletrofisiológicas Cardíacas , Feminino , Células HEK293 , Humanos , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/química , Masculino , Pessoa de Meia-Idade , Linhagem
13.
J Am Heart Assoc ; 1(2)2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23130123

RESUMO

BACKGROUND: Elevated heart rate represents an independent risk factor for cardiovascular outcome in patients with heart disease. In the sinoatrial node, rate increase is mediated by ß(1) adrenoceptor mediated activation of the Gα(s) pathway. We hypothesized that genetic inactivation of the stimulatory Gα(s) protein in the sinoatrial node would provide sinus rate control and would prevent inappropriate heart rate acceleration during ß-adrenergic activation. METHODS AND RESULTS: Domestic pigs (n=10) were evenly assigned to receive either Ad-small interfering RNA (siRNA)-Gα(s) gene therapy to inactivate Gα(s) or adenovirus encoding for green fluorescent protein (Ad-GFP) as control. Adenoviruses were applied through virus injection into the sinoatrial node followed by epicardial electroporation, and heart rates were evaluated for 7 days. Genetic inhibition of Gα(s) protein significantly reduced mean heart rates on day 7 by 16.5% compared with control animals (110±8.8 vs 131±9.4 beats per minute; P<0.01). On ß-adrenergic stimulation with isoproterenol, we observed a tendency toward diminished rate response in the Ad-siRNA-Gα(s) group (Ad-siRNA-Gα(s), +79.3%; Ad-GFP, +61.7%; n=3 animals per group; P= 0.294). Adverse effects of gene transfer on left ventricular ejection fraction (LVEF) were not detected following treatment (LVEF(Ad-siRNA-Gαs), 66%; LVEF(Ad-GFP), 60%). CONCLUSIONS: In this preclinical proof-of-concept study targeted Ad-siRNA-Gα(s) gene therapy reduced heart rates during normal sinus rhythm compared with Ad-GFP treatment and prevented inappropriate rate increase after ß-adrenergic stimulation. Gene therapy may provide an additional therapeutic option for heart rate reduction in cardiac disease. (J Am Heart Assoc. 2012;1:jah3-e000372 doi: 10.1161/JAHA.111.000372).

14.
Acta Cardiol ; 67(4): 481-5, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22998007

RESUMO

We report a case of Anderson-Fabry disease in a young man presenting with cardiac hypertrophy and asymptomatic non-sustained ventricular tachycardia. The patient was referred for evaluation of implantable cardioverter/defibrillator therapy. Assessment of left ventricular ejection fraction is considered the gold standard for identifying patients at risk of sudden cardiac death. However, this patient's left ventricular function was preserved. Electrophysiological study did not reveal inducible arrhythmia or cardiac conduction abnormalities. Review of the literature indicates limited knowledge on the electrophysiology of Fabry cardiomyopathy and highlights the need for optimized risk stratification strategies.


Assuntos
Cardiomiopatias/fisiopatologia , Doença de Fabry/fisiopatologia , Adulto , Códon sem Sentido , Eletrocardiografia , Técnicas Eletrofisiológicas Cardíacas , Doença de Fabry/genética , Humanos , Masculino , Linhagem , Medição de Risco
15.
Gene ; 511(1): 26-33, 2012 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-23000022

RESUMO

Long QT syndrome (LQTS) 1 is the most common type of inherited LQTS and is linked to mutations in the KCNQ1 gene. We identified a KCNQ1 missense mutation, KCNQ1 G325R, in an asymptomatic patient presenting with significant QT prolongation (QTc, 448-600ms). Prior clinical reports revealed phenotypic variability ranging from the absence of symptoms to syncope among KCNQ1 G325R mutation carriers. The present study was designed to determine the G325R ion channel phenotype and its association with the clinical LQTS presentation. Electrophysiological testing was performed using the Xenopus oocyte expression system. KCNQ1 G325R channels were non-functional and suppressed wild type (WT) currents by 71.1%. In the presence of the native cardiac regulatory ß-subunit, KCNE1, currents conducted by G325R and WT KCNQ1 were reduced by 52.9%. Co-expression of G325R and WT KCNQ1 with KCNE1 shifted the voltage-dependence of I(Ks) activation by 12.0mV, indicating co-assembly of mutant and WT subunits. The dysfunctional biophysical phenotype validates the pathogenicity of the KCNQ1 G325R mutation and corresponds well with the severe clinical presentation revealed in some reports. However, the index patient and other mutation carriers were asymptomatic, highlighting potential limitations of risk assessment schemes based on ion channel data.


Assuntos
Canal de Potássio KCNQ1/genética , Canal de Potássio KCNQ1/metabolismo , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Síndrome de Romano-Ward/genética , Síndrome de Romano-Ward/metabolismo , Adulto , Sequência de Aminoácidos , Animais , Fenômenos Eletrofisiológicos , Feminino , Estudos de Associação Genética , Heterozigoto , Humanos , Técnicas In Vitro , Canal de Potássio KCNQ1/química , Dados de Sequência Molecular , Proteínas Mutantes/química , Mutação de Sentido Incorreto , Oócitos/metabolismo , Linhagem , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Fatores de Risco , Homologia de Sequência de Aminoácidos , Xenopus laevis
16.
Life Sci ; 91(11-12): 377-383, 2012 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-22910181

RESUMO

AIMS: K(2P)2.1 (TREK1) two-pore-domain potassium channels control electrical activity in the central nervous system (CNS) and in the heart. Auxiliary ß subunits (Kvß) increase functional K+ channel diversity in the CNS. Based on similar tissue distribution and common functional significance of Kvß2 protein and K(2P)2.1 channels in neuronal excitability, we hypothesized that Kvß2 subunits modulate K2P2.1 currents. MAIN METHODS: Rat K2P2.1 channels and rKvß subunits were expressed in Xenopus laevis oocytes, and two-electrode voltage clamp electrophysiology was used to assess K2P2.1 function. KEY FINDINGS: Kvß2 subunits increased K(2P)2.1 currents by 2.9-fold in concentration-dependent fashion (I(0mV,K2P2.1), 0.53±0.07µA; I(0mV,K2P2.1+Kvß2), 1.56±0.13µA; n=15). K2P2.1 channel stimulation resulted in resting membrane potential hyperpolarization by -10.7mV (n=15). Open rectification and current-voltage relationships of K(2P)2.1 channels were not markedly altered upon co-expression with Kvß2, and K2P2.1 membrane expression was not affected by Kvß2 subunits. Related subunits Kvß1 (1.7-fold; n=16), Kvß3 (2.2-fold; n=16), and Kvß4 (2.8-fold; n=16) similarly activated K2P2.1 currents, indicating a broader role for Kvß proteins in K2P2.1 regulation. SIGNIFICANCE: Kvß subunits stabilize the resting membrane potential through enhancement of K2P2.1K+ currents. The significance of this previously unappreciated biophysical mechanism in neuronal physiology remains to be investigated.


Assuntos
Oócitos/fisiologia , Canais de Potássio de Domínios Poros em Tandem/fisiologia , Canais de Potássio de Abertura Dependente da Tensão da Membrana/fisiologia , Proteínas de Xenopus/fisiologia , Animais , Western Blotting , Relação Dose-Resposta a Droga , Eletrodos , Eletrofisiologia , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Canais de Potássio de Abertura Dependente da Tensão da Membrana/farmacologia , Proteínas de Xenopus/farmacologia , Xenopus laevis
17.
Stroke ; 43(10): 2689-94, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22871678

RESUMO

BACKGROUND AND PURPOSE: Cardioembolism in paroxysmal atrial fibrillation (pxAF) is a frequent cause of ischemic stroke. Sensitive detection of pxAF after stroke is crucial for adequate secondary stroke prevention; the optimal diagnostic modality to detect pxAF on stroke units is unknown. We compared 24-hour Holter electrocardiography (ECG) with continuous stroke unit ECG monitoring (CEM) for pxAF detection. METHODS: Patients with acute ischemic stroke or transient ischemic attack were prospectively enrolled. After a 12-channel ECG on admission, all patients received 24-hour Holter ECG and CEM. Additionally, ECG monitoring data underwent automated analysis using dedicated software to identify pxAF. Patients with a history of atrial fibrillation or with atrial fibrillation on the admission ECG were excluded. RESULTS: Four hundred ninety-six patients (median age, 69 years; 61.5% male) fulfilled all inclusion criteria (ischemic stroke: 80.4%; transient ischemic attack: 19.6%). Median stroke unit stay lasted 88.8 hours (interquartile range, 65.0-122.0). ECG data for automated CEM analysis were available for a median time of 64.0 hours (43.0-89.8). Paroxysmal AF was documented in 41 of 496 patients (8.3%). Of these, Holter detected pxAF in 34.1%; CEM in 65.9%; and automated CEM in 92.7%. CEM and automated CEM detected significantly more patients with pxAF than Holter (P<0.001), and automated CEM detected more patients than CEM (P<0.001). CONCLUSIONS: Automated analysis of CEM improves pxAF detection in patients with stroke on stroke units compared with 24-hour Holter ECG. The comparative usefulness of prolonged or repetitive Holter ECG recordings requires further evaluation.


Assuntos
Fibrilação Atrial/diagnóstico , Eletrocardiografia Ambulatorial/métodos , Unidades Hospitalares , Monitorização Fisiológica/métodos , Acidente Vascular Cerebral/prevenção & controle , Idoso , Fibrilação Atrial/complicações , Fibrilação Atrial/fisiopatologia , Eletrocardiografia Ambulatorial/instrumentação , Humanos , Pacientes Internados , Ataque Isquêmico Transitório/etiologia , Ataque Isquêmico Transitório/prevenção & controle , Masculino , Pessoa de Meia-Idade , Monitorização Fisiológica/instrumentação , Pacientes Ambulatoriais , Estudos Prospectivos , Fatores de Risco , Prevenção Secundária , Acidente Vascular Cerebral/etiologia , Fatores de Tempo
18.
Naunyn Schmiedebergs Arch Pharmacol ; 385(10): 1003-16, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22790794

RESUMO

Dronedarone is currently used for the treatment of paroxysmal and persistent atrial fibrillation (AF). Pharmacological inhibition of cardiac two-pore-domain potassium (K(2P)) channels results in action potential prolongation and has recently been proposed as novel antiarrhythmic strategy. We hypothesized that blockade of human K(2P) channels contributes to the electrophysiological efficacy of dronedarone in AF. Two-electrode voltage clamp and whole-cell patch clamp electrophysiology was used to record K(2P) currents from Xenopus oocytes and Chinese hamster ovary cells. All functional human K(2P) channels were screened for dronedarone sensitivity, revealing significant and concentration-dependent inhibition of cardiac K(2P)2.1 (TREK1; IC(50) = 26.7 µM) and K(2P)3.1 channels (TASK1; IC(50) = 18.7 µM) with maximum current reduction of 60.3 and 65.5 % in oocytes. IC(50) values obtained from mammalian cells yielded 6.1 µM (K(2P)2.1) and 5.2 µM (K(2P)3.1). The molecular mechanism of action was studied in detail. Dronedarone block affected open and closed channels. K(2P)3.1 currents were reduced in frequency-dependent fashion in contrast to K(2P)2.1. Mutagenesis studies revealed that amino acid residues implicated in K(2P)3.1 drug interactions were not required for dronedarone blockade. The class III antiarrhythmic drug dronedarone targets multiple human cardiac two-pore-domain potassium channels, including atrial-selective K(2P)3.1 currents. K(2P) current inhibition by dronedarone represents a previously unrecognized mechanism of action that extends the multichannel blocking profile of the drug.


Assuntos
Amiodarona/análogos & derivados , Potenciais da Membrana/efeitos dos fármacos , Miocárdio/metabolismo , Bloqueadores dos Canais de Potássio/farmacologia , Canais de Potássio de Domínios Poros em Tandem/antagonistas & inibidores , Amiodarona/farmacologia , Amiodarona/uso terapêutico , Animais , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/metabolismo , Células CHO , Cricetinae , Cricetulus , Relação Dose-Resposta a Droga , Dronedarona , Ativação do Canal Iônico/efeitos dos fármacos , Oócitos/metabolismo , Técnicas de Patch-Clamp , Bloqueadores dos Canais de Potássio/uso terapêutico , Canais de Potássio de Domínios Poros em Tandem/genética , Transfecção , Xenopus laevis
19.
Biochem Biophys Res Commun ; 424(2): 315-20, 2012 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-22749993

RESUMO

Kir2.x channels form the molecular basis of cardiac I(K1) current and play a major role in cardiac electrophysiology. However, there is a substantial lack of selective Kir2 antagonists. We found the ß(3)-adrenoceptor antagonist SR59230A to be an inhibitor of Kir2.x channels. Therefore, we characterized the effects of SR59230A on Kir2.x and other relevant cardiac potassium channels. Cloned channels were expressed in the Xenopus oocyte expression system and measured with the double-microelectrode voltage clamp technique. SR59230A inhibited homomeric Kir2.1 channels with an IC(50) of 33µM. Homomeric Kir2.2 and Kir2.3 channels and Kir2.x heteromers were also inhibited by SR59230A with similar potency. In contrast, no relevant inhibitory effects of SR59230A were found in cardiac Kv1.5, Kv4.3 and KvLQT1/minK channels. In hERG channels, SR59230A only induced a weak inhibition at a high concentration. These findings establish SR59230A as a novel inhibitor of Kir2.1-2.3 channels with a favorable profile with respect to additional effects on other cardiac repolarizing potassium channels.


Assuntos
Antagonistas de Receptores Adrenérgicos beta 3/farmacologia , Canais de Potássio Corretores do Fluxo de Internalização/antagonistas & inibidores , Propanolaminas/farmacologia , Receptores Adrenérgicos beta 3/metabolismo , Animais , Oócitos , Xenopus laevis
20.
Basic Res Cardiol ; 107(3): 265, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22457123

RESUMO

Gene therapy-based modulation of atrioventricular (AV) conduction by overexpression of a constitutively active inhibitory Gα(i) protein effectively reduced heart rates in atrial fibrillation (AF). However, catecholamine stimulation caused an excessive increase in ventricular rate. We hypothesized that modest genetic suppression of a stimulatory G protein in the AV node would allow persistent rate control in acute AF and would prevent undesired heart rate acceleration during ß-adrenergic activation. Atrial fibrillation was induced in 12 pigs by atrial burst pacing via an implanted cardiac pacemaker. Study animals were then assigned to receive either Ad-siRNA-Gα(s) gene therapy to inactivate Gα(s) protein or Ad-ß-gal as control. Gα(s) protein inactivation resulted in a 20 % heart rate reduction (P < 0.01). AH and HV intervals were prolonged by 37 ms (P < 0.001) and 28 ms (P < 0.001), respectively, demonstrating atrioventricular conduction delay. Impairment of left ventricular ejection fraction (LVEF) during AF was attenuated by Gα(s) suppression (LVEF 49 %) compared with controls (LVEF 34 %; P = 0.03). Isoproterenol application accelerated ventricular heart rate from 233 to 281 bpm (P < 0.001) in control animals but did not significantly affect pigs treated with Ad-siRNA-Gα(s) (192 vs. 216 bpm; P = 0.19). In conclusion, genetic inhibition of Gα(s) protein in the AV node reduced heart rate and prevented AF-associated reduction of cardiac function in a porcine model. Rate control by gene therapy may provide an alternative to current pharmacological treatment of AF.


Assuntos
Fibrilação Atrial/terapia , Nó Atrioventricular/metabolismo , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Terapia Genética/métodos , Frequência Cardíaca/genética , Interferência de RNA , RNA Interferente Pequeno/administração & dosagem , Agonistas Adrenérgicos beta/administração & dosagem , Animais , Fibrilação Atrial/etiologia , Fibrilação Atrial/genética , Fibrilação Atrial/metabolismo , Fibrilação Atrial/patologia , Fibrilação Atrial/fisiopatologia , Nó Atrioventricular/patologia , Nó Atrioventricular/fisiopatologia , Estimulação Cardíaca Artificial , Modelos Animais de Doenças , Eletrocardiografia , Fibrose , Subunidades alfa Gs de Proteínas de Ligação ao GTP/metabolismo , Terapia Genética/efeitos adversos , Frequência Cardíaca/efeitos dos fármacos , Isoproterenol/administração & dosagem , Marca-Passo Artificial , Volume Sistólico , Sus scrofa , Fatores de Tempo , Função Ventricular Esquerda
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