RESUMO
Endothelial nitric oxide synthase (eNOS) is a critical regulatory enzyme that controls vascular tone via the production of nitric oxide. Although thrombin also modulates vascular tone predominantly via the activation of protease-activated receptors (PARs), the time course and mechanisms involved in how thrombin controls eNOS enzymatic activity are unknown. eNOS enzymatic activity is enhanced by the phosphorylation of eNOS-Ser1177 and reduced by the phosphorylation of eNOS-Thr495. In this study, we hypothesized that thrombin regulates vascular tone through the differential phosphorylation of eNOS. Using rat descending aorta, we show that thrombin modulates vascular tone in an eNOS-dependent manner via activated PAR-1. We also show that thrombin causes a temporal biphasic response. Protein kinase C (PKC) is associated with second phase of thrombin-induced response. Western blot analysis demonstrated thrombin phosphorylated eNOS-Ser1177 and eNOS-Thr495 in human umbilical vein endothelial cells. A PKC inhibitor suppressed the thrombin-induced phosphorylation of eNOS-Thr495, but not that of eNOS-Ser1177. Our results suggest that thrombin induces a temporal biphasic vascular response through the differential phosphorylation of eNOS via activated PAR-1. Thrombin causes transient vasorelaxation by the phosphorylation of eNOS-Ser1177, and subsequent attenuation of vasorelaxation by the phosphorylation of eNOS-Thr495 via PKC, leading to the modulation of vascular tone.
Assuntos
Óxido Nítrico Sintase Tipo III , Proteína Quinase C , Receptor PAR-1 , Trombina , Vasodilatação , Animais , Células Endoteliais da Veia Umbilical Humana/enzimologia , Humanos , Óxido Nítrico Sintase Tipo III/metabolismo , Fosforilação , Proteína Quinase C/metabolismo , Ratos , Receptor PAR-1/metabolismo , Trombina/metabolismo , Trombina/farmacologia , Trombina/fisiologia , Vasodilatação/efeitos dos fármacosRESUMO
Association between pre-ablation levels of biomarkers of cardiac and endothelial dysfunctions, CHADS2, CHA2DS2-VASc, and APPLE scores and the recurrence of atrial fibrillation (AF) after radiofrequency catheter ablation has not been fully studied. A total of 254 patients with nonvalvular AF were prospectively followed for AF recurrence after a single ablation procedure. During a two-year follow-up period, AF recurred in 65 (25.6%) patients. Patients with AF recurrence had significantly greater baseline ln brain natriuretic peptide (BNP) than those without AF recurrence (P < 0.01), whereas there were no significant differences in the levels of biomarkers of endothelial dysfunction and points of scoring systems. In the Cox regression analyses, the baseline ln BNP was significantly independently associated with AF recurrence (adjusted HR =1.286, 95% CI =1.000-1.655, P < 0.05). The baseline levels of ln BNP were significantly associated with rhythm at blood collection, age, sex, and left atrial diameter, and left ventricular ejection fraction (P < 0.05).The subgroup analysis showed a significant interaction on the risk of AF recurrence between ln BNP, sex difference, and rhythm at blood collection (P for interaction < 0.05). In conclusion, the results suggest that the pre-ablation levels of ln BNP are useful to evaluate the risk of AF recurrence after ablation therapy; however, there is a need to be careful while using BNP as a biomarker for the risk of AF recurrence by taking account of the effects of rhythm status at blood collection and sex difference.
Assuntos
Fibrilação Atrial/cirurgia , Ablação por Cateter/métodos , Peptídeo Natriurético Encefálico/sangue , Idoso , Fibrilação Atrial/sangue , Fibrilação Atrial/fisiopatologia , Biomarcadores/sangue , Endotélio Vascular/fisiopatologia , Ensaio de Imunoadsorção Enzimática , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Período Pré-Operatório , Prognóstico , Recidiva , Estudos Retrospectivos , Fatores de Risco , VasodilataçãoRESUMO
The effect of restoring sinus rhythm by pulmonary vein isolation (PVI) on the quality of life (QOL) of patients with persistent atrial fibrillation (PerAF) has not been adequately investigated. This study was performed to compare the changes in QOL after extended PVI between patients with PerAF and paroxysmal AF (PAF).Patients with PAF (n = 38) and PerAF (n = 22) who underwent their first PVI and developed no AF recurrence 6 months after PVI were enrolled. QOL surveys were performed at baseline and 6 months post-ablation using Short Form-36 surveys.The mental component summary score (MCS) (53.4 ± 10.2 to 56.5 ± 7.1, P = 0.019) and physical component summary score (PCS) (46.1 ± 10.6 to 48.5 ± 8.3, P = 0.015) improved after PVI in the PAF group. The PCS, but not the MCS, improved after PVI in the PerAF group (45.8 ± 7.9 to 51.5 ± 6.2, P < 0.001). Changes in the PCS were greater in the PerAF group than in the PAF group (8.6 ± 6.9 versus 2.8 ± 5.2, P = 0.009). Multivariate regression analysis demonstrated that a low baseline MCS and the type of AF (PAF) were independent predictors of an increased MCS and that a low baseline PCS and the type of AF (PerAF) were independent predictors of an increased PCS.The changes in QOL differed between PAF and PerAF after PVI. Although most patients with PerAF were asymptomatic before PVI, their improvement in physical QOL was greater than that in patients with PAF. Such beneficial effects on physical QOL are likely expected in patients with PerAF with a low PCS before PVI.
Assuntos
Fibrilação Atrial/psicologia , Fibrilação Atrial/terapia , Ablação por Cateter , Veias Pulmonares , Qualidade de Vida , Idoso , Fibrilação Atrial/fisiopatologia , Feminino , Seguimentos , Frequência Cardíaca , Humanos , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/sangue , Recidiva , Análise de Regressão , Resultado do TratamentoAssuntos
Doenças das Valvas Cardíacas , Marca-Passo Artificial , Insuficiência da Valva Tricúspide , Cordas Tendinosas/diagnóstico por imagem , Humanos , Marca-Passo Artificial/efeitos adversos , Valva Tricúspide/diagnóstico por imagem , Valva Tricúspide/cirurgia , Insuficiência da Valva Tricúspide/diagnóstico por imagem , Insuficiência da Valva Tricúspide/etiologia , Insuficiência da Valva Tricúspide/cirurgiaAssuntos
Bloqueio Atrioventricular , Linfoma , Marca-Passo Artificial , Síndrome da Veia Cava Superior , Humanos , Linfoma/complicações , Marca-Passo Artificial/efeitos adversos , Síndrome da Veia Cava Superior/diagnóstico por imagem , Síndrome da Veia Cava Superior/etiologia , Síndrome da Veia Cava Superior/terapia , Veia Cava SuperiorRESUMO
BACKGROUND: Long QT syndrome 2 (LQT2) is caused by mutations in the human ether-a-go-go-related gene (hERG). Most of its mutations give rise to unstable hERG proteins degraded by the proteasome. Recently, carbachol was reported to stabilize the wild-type hERG-FLAG via activation of the muscarinic type 3 receptor (M3-mAChR). Its action on mutant hERG-FLAG, however, remains uninvestigated.MethodsâandâResults:A novel mutant hERG-FLAG carried 2 mutations: an amino acid substitution G572S and an in-frame insertion D1037_V1038insGD. When expressed in HEK293 cells, this mutant hERG-FLAG was degraded by the proteasome and failed to be transported to the cell surface. Carbachol restored stability of the mutant hERG-FLAG and facilitated cell-surface expression. Carbachol activated PKC, augmented phosphorylation of heat shock factor 1 (HSF1) and enhanced expression of heat shock proteins (hsps), hsp70 and hsp90. Both a M3-mAChR antagonist, 4-DAMP, and a PKC inhibitor, bisindolylmaleimide, abolished carbachol-induced stabilization of the mutant hERG-FLAG. CONCLUSIONS: M3-mAChR activation leads to enhancement of hsp expression via PKC-dependent phosphorylation of HSF1, thereby stabilizing the mutant hERG-FLAG protein. Thus, M3-mAChR activators may have a therapeutic value for patients with LQT2. (Circ J 2016; 80: 2443-2452).
Assuntos
Proteínas de Ligação a DNA/metabolismo , Canal de Potássio ERG1 , Síndrome do QT Longo , Mutação , Receptor Muscarínico M3/metabolismo , Transdução de Sinais , Fatores de Transcrição/metabolismo , Adolescente , Proteínas de Ligação a DNA/genética , Canal de Potássio ERG1/genética , Canal de Potássio ERG1/metabolismo , Células HEK293 , Fatores de Transcrição de Choque Térmico , Humanos , Síndrome do QT Longo/genética , Síndrome do QT Longo/metabolismo , Masculino , Fosforilação/genética , Estabilidade Proteica , Receptor Muscarínico M3/genética , Fatores de Transcrição/genética , TransfecçãoRESUMO
AIMS: Catheter ablation for persistent atrial fibrillation (AF) is currently performed with different procedural endpoints. When AF did not terminate during ablation procedure, electrical cardioversion was performed at different defibrillation threshold (DFT) according to AF characteristics and atrial electrophysiologic substrates. We sought to evaluate the impact of atrial DFT after catheter ablation for persistent AF on clinical outcome. METHODS AND RESULTS: We studied 128 patients with persistent AF (age 63±9 years, 106 men). After completion of circumferential pulmonary vein isolation, the left atrial substrate ablation was performed until AF terminated or all identified complex fractionated electrograms were eliminated. If AF did not terminate during ablation, an internal cardioversion protocol was started at 5J and was increased incrementally in 5 J steps until successful cardioversion was accomplished. Procedural AF termination was achieved in 50 patients (Group A). Atrial fibrillation was terminated by cardioversion with DFT≤10 J in 47 patients (Group B) and with DFT>10 J in 31 patients (Group C). At 14±7 follow-up months after 1.3±0.5 sessions, 47 (94%) Group A patients, 42 (89%) Group B patients, and 14 (45%) Group C patients remained in sinus rhythm. In multivariate analysis of Group B and Group C, DFT (hazard ratio 5.54, P<0.001) and AF duration (hazard ratio 3.74, P=0.011) were independent predictors of recurrent arrhythmia. CONCLUSION: When AF does not terminate after the completion of predetermined stepwise ablation, further extensive ablation to terminate AF might be unnecessary if the AF can be successfully terminated by electrical cardioversion at low DFT.
Assuntos
Fibrilação Atrial/fisiopatologia , Fibrilação Atrial/terapia , Ablação por Cateter/métodos , Cardioversão Elétrica/métodos , Adulto , Idoso , Fibrilação Atrial/prevenção & controle , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Valor Preditivo dos Testes , Estudos Retrospectivos , Prevenção Secundária , Resultado do TratamentoRESUMO
OBJECTIVES: This study sought to assess the performance of current diagnostic criteria and identify additional electrophysiological features differentiating orthodromic reciprocating tachycardia (ORT) with a concealed nodoventricular/nodofascicular (NV/NF) pathway from atrioventricular nodal re-entrant tachycardia (AVNRT). BACKGROUND: Diagnosing sustained supraventricular tachycardia (SVT) despite the occurrence of ventriculoatrial block (VAB) is challenging. METHODS: We analyzed electrograms of 25 sustained SVTs (9 NV/NF-ORTs [n = 7/2] and 16 AVNRTs) with VAB and 91 AVNRTs without VAB (for reference). RESULTS: More than 1 SVT, each with a different ventriculoatrial interval, was commonly induced in AVNRT cases (75%) but not in NV/NF-ORT cases (0%; p = 0.0005). Wenckebach VAB was common in NV/NF-ORTs (78%), but VAB patterns varied in AVNRTs. The His-His interval transiently prolonged in the following beat after the VAB in most AVNRTs but rarely did in NV/NF-ORTs (79% vs. 22%; p = 0.01). NV/NF-ORT was diagnosed by His-refractory premature ventricular contractions (n = 5) and the findings during right ventricular overdrive pacing showing an uncorrected/corrected post-pacing interval (PPI)-tachycardia cycle length (TCL) ≤115/110 ms (n = 5/5), orthodromic His capture (n = 6), and V-V-A (ventricle-ventricle-atrial response) response (n = 3). A single form of induced SVT (positive predictive value [PPV]: 69%; negative predictive value [NPV]: 100%), Wenckebach VAB (PPV: 70%; NPV: 87%), stable His-His interval despite VAB (PPV: 70%; NPV: 85%), orthodromic His capture (PPV: 100%; NPV: 97%), and V-V-A response (PPV: 100%; NPV: 95%) characterized NV/NF-ORT, and a PPI-TCL of ≤125 ms (PPV: 100%; NPV: 100%) characterized NV-ORT. CONCLUSIONS: Induction of a single SVT form, Wenckebach VAB, stable His-His interval despite VAB, orthodromic His capture, and V-V-A response appeared to discriminate NV/NF-ORT from AVNRT, with a PPI-TCL of ≤125 ms discriminating NV-ORT from NF-ORT and AVNRT.
Assuntos
Taquicardia por Reentrada no Nó Atrioventricular , Taquicardia Reciprocante , Taquicardia Ventricular , Estimulação Cardíaca Artificial , Eletrocardiografia , Sistema de Condução Cardíaco , Humanos , Taquicardia por Reentrada no Nó Atrioventricular/diagnósticoRESUMO
AIMS: The His bundle electrogram is believed to reflect the exact location of the His bundle. However, the distinction between distal His bundle potential and proximal right bundle branch potential is challenging. The aim of this study was to pinpoint the location of the branching point of the His bundle, and to compare that site with the site of recording of the largest His bundle electrogram (LH) during sinus rhythm. METHODS: We hypothesized that the site of earliest His activation (EH) during retrograde conduction via the left bundle branch is the branching point. We studied 15 nonconsecutive patients (mean age = 40 +/- 22 years; eight men). We performed a programmed stimulation from right ventricular apex until retrograde right bundle branch block appeared. At that point we measured (1) the distance between antegrade LH site and retrograde EH site and (2) the atrial-to-ventricular amplitude ratio (A/V ratio) at both sites. RESULTS: EH was recorded at the proximal electrode of the His bundle catheter in all patients. Mean distance between EH and LH was 9.8 +/- 2.5 mm. The mean A/V ratios at the EH site and the LH site were 1.01 +/- 0.42 and 0.08 +/- 0.06, respectively. DISCUSSION: This study showed that the EH site is located approximately 10-mm proximal to the LH site. The mean A/V ratio at the EH site during sinus rhythm is approximately 1.0. These observations suggest that the majority of His potentials reflect proximal right bundle activation. Before delivering radiofrequency energy in the para-Hisian area, attention should be paid to the presence of a His potential and to the A/V ratio, rather to the amplitude of the His electrogram.
Assuntos
Mapeamento Potencial de Superfície Corporal/métodos , Fascículo Atrioventricular/fisiopatologia , Bloqueio de Ramo/diagnóstico , Bloqueio de Ramo/fisiopatologia , Técnicas Eletrofisiológicas Cardíacas/métodos , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
AIMS: To compare the risk of atrioventricular (AV) conduction disturbance between patients with sinus node dysfunction on AAI pacing who had a low or high Wenckebach block rate (WBR). METHODS AND RESULTS: Patients with sinus node dysfunction and normal AV conduction those underwent an electrophysiological study were studied. The patients were classified into two groups: Group L was with the patients with a WBR of 100 to 129 per minute and Group H was with the patients with a WBR > or = 130 per minute. All patients followed up every 3-6 months after an AAI pacemaker implantation. A total of 102 patients, including 35 Group L and 67 Group H, were followed for 90 +/- 44 months. Six patients died from non-cardiac cause and five patients required a new atrial lead implantation due to lead failure during follow-up. Symptomatic bradycardia requiring a new ventricular lead implantation developed in four patients (annual incidence 0.5%). In Group L, two patients developed AV block (annual incidence 0.7%). In Group H, two patients developed bradycardic atrial fibrillation (annual incidence 0.4%). Kaplan-Meier analysis revealed no significant difference between the two groups (P = 0.2983). CONCLUSION: These results suggest that a long-term risk of developing AV conduction disturbance is low even in patients with a WBR of 100 to 129 per minute.
Assuntos
Bloqueio Atrioventricular/etiologia , Bloqueio Atrioventricular/terapia , Estimulação Cardíaca Artificial/métodos , Marca-Passo Artificial , Síndrome do Nó Sinusal/terapia , Idoso , Idoso de 80 Anos ou mais , Bradicardia/etiologia , Estimulação Cardíaca Artificial/efeitos adversos , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Fatores de Risco , Síndrome do Nó Sinusal/complicações , Fatores de Tempo , Resultado do TratamentoRESUMO
A 76-year-old man with two different sustained atrial arrhythmias that occurred after coronary artery bypass grafting underwent electrophysiological studies. Macroreentrant atrial tachycardias were detected with an isolated slow pathway mimicking focal activation on three-dimensional electroanatomical mapping. The slow conduction pathway in the right atrial free wall was assumed to represent tissue damaged by right atrial cannulation during previous coronary artery bypass grafting.
Assuntos
Mapeamento Potencial de Superfície Corporal/métodos , Ponte de Artéria Coronária/efeitos adversos , Sistema de Condução Cardíaco/lesões , Sistema de Condução Cardíaco/cirurgia , Imageamento Tridimensional/métodos , Taquicardia por Reentrada no Nó Atrioventricular/diagnóstico , Taquicardia por Reentrada no Nó Atrioventricular/cirurgia , Idoso , Ablação por Cateter , Diagnóstico Diferencial , Humanos , Masculino , Taquicardia por Reentrada no Nó Atrioventricular/etiologia , Resultado do TratamentoRESUMO
A 36-year-old woman presented with drug-refractory atrial tachycardia. During the tachycardia episodes, P waves were positive in leads II, III, aVF, and V1, while they were negative in leads I and aVL. It was hard to determine whether the origin was the left atrial appendage or left superior pulmonary vein on the surface electrocardiogram. Electrophysiologic evaluation revealed that the earliest endocardial activation occurred at the base of the left atrial appendage, preceding the onset of P waves by 38 ms. On initiation of the tachycardia, a warm-up phenomenon was observed. There was a fixed relation between the coupling interval of a single extrastimulus and the return cycle length during the tachycardia. These findings suggested that the mechanism of the tachycardia was automaticity. Application of radiofrequency energy at the left atrial appendage terminated the tachycardia and it was not inducible after ablation.
Assuntos
Apêndice Atrial/cirurgia , Ablação por Cateter , Taquicardia Atrial Ectópica/cirurgia , Adulto , Apêndice Atrial/fisiopatologia , Feminino , Sistema de Condução Cardíaco/fisiopatologia , Sistema de Condução Cardíaco/cirurgia , Humanos , Taquicardia Atrial Ectópica/fisiopatologiaRESUMO
BACKGROUND: The inferior vena cava (IVC) is obliquely connected to the right atrium (RA), and often a low-voltage area is observed in the posteroinferior RA. OBJECTIVES: The purpose of this study was investigate the size of the IVC extension into RA and its anatomic background. METHODS: We investigated 30 human hearts [11 men and 19 women; mean age 79 +/- 10 years; 7 cardiac deaths (group A) and 23 noncardiac deaths (group B)]. After obtaining macroscopic measurements around the RA-IVC junction, serial sections were cut and examined histologically. We defined a horizontal baseline at the level of the cavotricuspid isthmus and measured (1) the length of IVC extension, which was defined as the distance from the baseline to the top of the RA-IVC junction, and (2) the width of the RA-IVC junction at the baseline level. RESULTS: The top of the RA-IVC junction was always located in the posteroinferior RA. The mean length of the IVC extension was 17.6 +/- 6.6 mm, and the mean width was 29.6 +/- 7.5 mm. The IVC extension was wider in group A than in group B (35.8 +/- 9.0 mm vs 27.5 +/- 5.9 mm; P = .0277). The right and left borders of the RA-IVC junction corresponded to the reflection of the pericardium. Histologic examination showed no myocardium in the IVC extension. CONCLUSION: The IVC extension into the posteroinferior RA always exists and varies in size. Because this area lacks myocardium, it is important to consider when analyzing catheter mapping from this area.
Assuntos
Coração/anatomia & histologia , Miocárdio/citologia , Veia Cava Inferior/anatomia & histologia , Idoso , Idoso de 80 Anos ou mais , Morte , Eletrocardiografia , Feminino , Átrios do Coração/anatomia & histologia , Átrios do Coração/citologia , Humanos , Masculino , Pessoa de Meia-Idade , Valores de ReferênciaRESUMO
BACKGROUND: Although several studies have assessed the predictors of recurrent atrial fibrillation (AF) after catheter ablation for persistent AF, the impact of antiarrhythmic drug (AAD) therapy on maintaining sinus rhythm after catheter ablation for persistent AF has not been fully evaluated. This case-control study aimed to evaluate the effect of bepridil on maintaining sinus rhythm after catheter ablation for persistent AF. METHODS AND RESULTS: We enrolled 122 consecutive patients (87 men; mean age: 62.3 years) who underwent catheter ablation for persistent AF and were administered AAD therapy after the initial procedure. Restoration of sinus rhythm was achieved in all of the patients by catheter ablation and cardioversion after the initial procedure. After a median 12-month follow up, 51 of 122 (41.8%) patients had recurrence of AF. In Cox proportional hazard regression analysis, postprocedural AAD therapy with bepridil was a significantly correlated factor with freedom from recurrent AF after the initial ablation procedure (hazard ratio 0.446, 95% confidence interval 0.236-0.842, p=0.012). In Kaplan-Meier analysis, AF-free survival was significantly better with bepridil compared with amiodarone (AMD) and sodium channel blocker (SCB) (log-rank test, bepridil vs AMD, p=0.012; bepridil vs SCB, p=0.018). CONCLUSIONS: Bepridil reduced the recurrence of AF compared with AMD and SCB in patients who underwent catheter ablation for persistent AF.
Assuntos
Antiarrítmicos/uso terapêutico , Fibrilação Atrial/terapia , Bepridil/uso terapêutico , Ablação por Cateter , Amiodarona/uso terapêutico , Estudos de Casos e Controles , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva , Bloqueadores dos Canais de Sódio/uso terapêuticoRESUMO
BACKGROUND: The human ether-a-go-go-related gene (HERG) encodes the α-subunit of rapidly activating delayed-rectifier potassium channels. Mutations in this gene cause long QT syndrome type 2 (LQT2). In most cases, mutations reduce the stability of the channel protein, which can be restored by heat shock (HS). METHODS: We identified the novel mutant A78T-HERG in a patient with LQT2. The purpose of the current study was to characterize this mutant protein and test whether HS and heat shock factors (HSFs) could stabilize the mutant protein. A78T-HERG and wild-type HERG (WT-HERG) were expressed in HEK293 cells and analyzed by immunoblotting, immunoprecipitation, immunofluorescence, and whole-cell patch clamping. RESULTS: When expressed in HEK293 cells, WT-HERG gave rise to immature and mature forms of the protein at 135 and 155 kDa, respectively. A78T-HERG gave rise only to the immature form, which was heavily ubiquitinated. The proteasome inhibitor MG132 increased the expression of immature A78T-HERG and increased both the immature and mature forms of WT-HERG. WT-HERG, but not A78T-HERG, was expressed on the plasma membrane. In whole-cell patch clamping experiments, depolarizing pulses evoked E4031-sensitive HERG channel currents in cells transfected with WT-HERG, but not in cells transfected with A78T-HERG. The A78V mutant, but not A78G mutant, remained in the immature form similarly to A78T. Maturation of the A78T-HERG protein was facilitated by HS, expression of HSF-1, or exposure to geranyl geranyl acetone. CONCLUSIONS: A78T-HERG was characterized by protein instability and reduced expression on the plasma membrane. The stability of the mutant was partially restored by HSF-1, indicating that HSF-1 is a target for the treatment for LQT2 caused by the A78T mutation in HERG.
RESUMO
Olprinone is an inotropic agent that inhibits phosphodiesterase (PDE) III and causes vasodilation. Olprinone has been shown to be less proarrhythmic and possibly affect expression of functional Kv1.5 channels that confer the ultra-rapid delayed-rectifier K+ channel current (IKur) responsible for action potential repolarization. To reveal involvement of Kv1.5 channels in the less arrhythmic effect of olprinone, we examined effects of the agent on the stability of Kv1.5 channel proteins expressed in COS7 cells. Olprinone at 30-1000 nM increased the protein level of Kv1.5 channels in a concentration-dependent manner. Chase experiments showed that olprinone delayed degradation of Kv1.5 channels. Olprinone increased the immunofluorescent signal of Kv1.5 channels in the endoplasmic reticulum (ER) and Golgi apparatus as well as on the cell surface. Kv1.5-mediated membrane currents, measured as 4-aminopyridine-sensitive currents, were increased by olprinone without changes in their activation kinetics. A protein transporter inhibitor, colchicine, abolished the olprinone-induced increase of Kv.1.5-mediated currents. The action of olprinone was inhibited by 4-aminopyridine, and was not mimicked by the application of 8-Bromo-cAMP. Taken together, we conclude that olprinone stabilizes Kv1.5 proteins at the ER through an action as a chemical chaperone, and thereby increases the density of Kv1.5 channels on the cell membrane. The enhancement of Kv1.5 currents could underlie less arrhythmogenicity of olprinone.
Assuntos
Cardiotônicos/metabolismo , Cardiotônicos/farmacologia , Imidazóis/metabolismo , Imidazóis/farmacologia , Canal de Potássio Kv1.5/metabolismo , Piridonas/metabolismo , Piridonas/farmacologia , Animais , Células COS , Chlorocebus aethiops , Relação Dose-Resposta a Droga , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Estabilidade Proteica/efeitos dos fármacosRESUMO
PTHrP is produced in a wide variety of different cells, including cardiomyocytes. Its production is augmented by mechanical and neurohumoral stimulation, and PTHrP has positive chronotropic and vasodilatory effects. Thus, in the heart, PTHrP has the potential to serve as a mechano-sensitive regulatory molecule. We evaluated peripheral and central levels of PTHrP in patients with congestive heart failure (CHF) and tested the hypothesis that PTHrP is released from the heart in patients with CHF. Intact full-length PTHrP (i-PTHrP) and C-terminal PTHrP (c-PTHrP) levels were measured in the plasma of 64 patients with CHF and 12 controls. Plasma PTHrP concentrations in the coronary sinus and aortic root were also measured in 18 CHF patients and 10 controls. Both plasma i-PTHrP and c-PTHrP levels in CHF patients were significantly higher than control levels and increased as a function of New York Heart Association classification. There were significant correlations between c-PTHrP levels and plasma norepinephrine, brain natriuretic peptide, angiotensin II, and endothelin-1 levels. Plasma i-PTHrP was significantly correlated with left ventricular ejection fraction and end-diastolic and end-systolic dimensions. Plasma i-PTHrP levels were significantly higher in the coronary sinus than in the aortic root in CHF patients, but among controls concentrations of i-PTHrP were indistinguishable at these two sites. This is the first report demonstrating that PTHrP is produced in the myocardium and is increased in CHF; these findings suggest that PTHrPs levels might be modulated by cardiac performance in patients with CHF.
Assuntos
Insuficiência Cardíaca/metabolismo , Miocárdio/metabolismo , Biossíntese de Proteínas , Adulto , Angiotensina II/sangue , Aorta , Fator Natriurético Atrial/sangue , Vasos Coronários , Diástole , Ecocardiografia , Endotelina-1/sangue , Feminino , Insuficiência Cardíaca/fisiopatologia , Hemodinâmica , Humanos , Masculino , Peptídeo Natriurético Encefálico/sangue , Norepinefrina/sangue , Proteína Relacionada ao Hormônio Paratireóideo , Fragmentos de Peptídeos/sangue , Proteínas/metabolismo , Volume Sistólico , Sístole , Função Ventricular EsquerdaRESUMO
We present a case of a 54-year-old man with carcinoid heart disease and mitral valve involvement. He had hepatic carcinoid with an extremely elevated urinary excretion of 5-hydroxyindole acetic acid and was referred to our division for shortness of breath and leg edema. Transthoracic echocardiography showed the thickened and retracted tricuspid valve leaflets and severe tricuspid regurgitation. Moderate mitral regurgitation was observed, with the involvement of mitral valve leaflets. A patent foramen ovale was not detected on transesophageal echocardiography. The extremely high concentration of circulating serotonin and/or other vasoactive substances may have contributed to left- as well as right-sided carcinoid heart disease.
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It is unknown whether salicylate enhances the action of antiarrhythmic agents on human Na+ channels with state dependency and tissue specificity. We therefore investigated effects of salicylate on quinidine-induced block of human cardiac and skeletal muscle Na+ channels. Human cardiac wild-type (hH1), LQT3-related mutant (ΔKPQ), and skeletal muscle (hSkM1) Na+ channel α subunits were expressed in COS7 cells. Effects of salicylate on quinidine-induced tonic and use-dependent block of Na+ channel currents were examined by the whole-cell patch-clamp technique. Salicylate enhanced the quinidine-induced tonic and use-dependent block of both hH1 and hSkM1 currents at a holding potential (HP) of -100 mV but not at -140 mV. Salicylate decreased the IC50 value for the quinidine-induced tonic block of hH1 at an HP of -100 mV, and produced a negative shift in the steady-state inactivation curve of hH1 in the presence of quinidine. According to the modulated receptor theory, it is probable that salicylate decreases the dissociation constant for quinidine binding to inactivated-state channels. Furthermore, salicylate significantly enhanced the quinidine-induced tonic and use-dependent block of the peak and steady-state ΔKPQ channel currents. The results suggest that salicylate enhances quinidine-induced block of Na+ channels via increasing the affinity of quinidine to inactivated state channels.
Assuntos
Quinidina/farmacologia , Salicilatos/farmacologia , Bloqueadores dos Canais de Sódio/farmacologia , Canais de Sódio/genética , Canais de Sódio/metabolismo , Animais , Células COS , Chlorocebus aethiops , Coração/efeitos dos fármacos , Humanos , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/genética , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Mutação , Miocárdio/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.5 , Ligação Proteica , Quinidina/metabolismoRESUMO
BACKGROUND: Coronary artery damage has been reported during catheter ablation procedures. Recently, linear ablation of thin left atrial tissue has been performed for atrial fibrillation. OBJECTIVE AND METHODS: Because we have little information about the arteries in the left atrium, this study was performed to evaluate the anatomy of these arteries, and to compare them with previously reported ablation lines. Coronary angiography was performed in 262 patients. Atrial coronary arteries between the left atrial appendage and the left superior pulmonary vein (LAA-LSPV region), as well as between the left inferior pulmonary vein and the mitral annulus ("mitral isthmus" region) were examined. RESULTS: Atrial coronary arteries extending to the LAA-LSPV region were found in 92 subjects (35%), while arteries crossing the mitral isthmus region were found in 119 subjects (46%). Atrial coronary arteries crossed the ablation line in about 69% of subjects overall. CONCLUSION: These results might suggest a risk of acute complications due to left atrial ablation. Alternatively, recurrence of atrial fibrillation might be caused by protected myocardium around the atrial arteries. We should note that atrial coronary arteries cross the ablation line in many patients.