卡维地洛对心房肌细胞电生理的影响

心房颤动（房颤）是临床最常见的持续性心律失常，其发生率随年龄增加而升高。房颤不仅影响患者的生活质量，还增加患者的致残、致死率。最近研究表明卡维地洛可减少心胸外科手术后房颤的发生并可防止电复律后房颤的复发，但其机制尚不清楚。本研究的目的是观察长期应用卡维地洛对兔心房肌细胞电生理的影响，以阐明其抗心律失常效应的离子机制。[第一段]     

Electrocardiographic evidence of ventricular repolarization remodelling during atrial fibrillation.

AIMS: Some atrial fibrillation (AF) patients develop excessive QTc prolongation and torsade de pointes when they take QTc-prolonging antiarrhythmic drugs (class IA/III) immediately after termination of AF. We hypothesized that this is caused by changes in ventricular repolarization during AF. We aimed to establish whether such 'ventricular repolarization remodelling' occurs. METHODS AND RESULTS: We studied all patients who visited our cardiac emergency room with AF and converted to sinus rhythm (SR) in a 30 months' period. We defined four groups: (i) no antiarrhythmic drugs, electrical cardioversion (n = 30), (ii) no antiarrhythmic drugs, spontaneous AF termination (n = 19), (iii) antiarrhythmic drugs, electrical cardioversion (n = 29), and (iv) antiarrhythmic drugs, spontaneous AF termination (n = 9). We studied QTc duration at SR before AF (SR(baseline)), immediately after termination of AF (SR(postAF)), and at follow-up (SR(followup): > or =7 days after SR(postAF)). Moreover, we studied determinants of QTc prolongation at SR(postAF). We found that, in all groups, QTc at SR(postAF) was significantly and transiently prolonged compared with SR(baseline). Although of limited magnitude on average (approximately 5%), the increase was substantial (approximately 15%) in some individuals. The only independent predictor of the magnitude of QTc prolongation was QTc duration at SR(baseline); this relation had a negative correlation. CONCLUSION: AF causes ventricular repolarization remodelling, resulting in QTc prolongation. QTc prolongation is substantial in some patients and may render these patients vulnerable to pro-arrhythmia from class IA/III antiarrhythmic drugs immediately after termination of AF.     

G-protein-coupled receptor kinase activity in human heart failure: effects of beta-adrenoceptor blockade

OBJECTIVES: In human end-stage heart failure as well as in experimental animal models of heart failure, G-protein-coupled receptor kinase activity (GRK) is increased while beta-adrenoceptor responsiveness is diminished. In animal studies, beta-adrenoceptor blockers reverse the GRK-mediated desensitization and down-regulation of myocardial beta-adrenoceptors. The aim of this study was to investigate whether alterations in GRK activity are an early or late accompaniment of human heart failure and whether also in humans beta-adrenoceptor blocker treatment is able to influence myocardial GRK activity. METHODS: We assessed in right atria, obtained from patients at different stages of heart failure, treated with or not treated with beta-adrenoceptor blockers, and in the four chambers of explanted hearts, obtained from patients with end-stage heart failure, beta-adrenoceptor density (by (-)-[(125)I]-iodocyanopindolol binding) and GRK activity (by an in vitro rhodopsin phosphorylation assay). RESULTS: With increasing severity of heart failure, plasma noradrenaline levels increased while myocardial beta-adrenoceptor density decreased with a maximum in GRK activity in end-stage heart failure. However, in relation to the progression of heart failure, we found that GRK activity transiently increased at an early stage of heart failure (NYHA I and II) but decreased back to control values in patients at NYHA III and IV. beta-Adrenoceptor blockers were able to reduce the early increase in GRK activity at NYHA I and II to control levels, whereas in those patients who did not have increased GRK activity (NYHA III and IV), they had only a marginal effect. CONCLUSION: According to our results, an increase in GRK activity is an early and transient event in the course of heart failure that can be prevented by beta-adrenoceptor blocker treatment.     

Structural remodelling during chronic atrial fibrillation: act of programmed cell survival

Atrial fibrillation is the most common cardiac arrhythmia with an overall prevalence of almost 1%. Increasing prevalence and associated risks such as stroke and mortality have increased the need for better and more reliable therapeutic treatment. This has stimulated research to elucidate the pathophysiological mechanisms underlying atrial fibrillation. Atrial fibrillation is primarily characterised by electrical remodelling and functional deterioration. Both phenomena are reversible but after prolonged duration of atrial fibrillation, a discrepancy occurs between rapid electrical remodelling and slow recovery of contractile function. Recent studies have indicated that morphological remodelling might underlie this incongruity. In experimental models of lone atrial fibrillation, the remodelling involves cellular changes that are reminiscent of dedifferentiation and are characterised by cellular volume increase, myolysis, glycogen accumulation, mitochondrial changes and chromatin redistribution. The absence of clear signs of degeneration in these models points towards cardiomyocyte adaptation or a mechanism of programmed cell survival. In patients with atrial fibrillation cardiomyocyte degeneration does occur along with dedifferentiation which might be the result of underlying cardiac pathologies or longer duration of atrial fibrillation. In this review we focus on structural remodelling during atrial fibrillation. The different aspects of histological and ultrastructural changes as well as their role in atrial dysfunction and cardiomyocyte survival are discussed. We briefly describe the underlying molecular remodelling. and possible mechanisms responsible for remodelling involving calcium overload and stretch are presented.     

The relationship of human atrial cellular electrophysiology to clinical function and ultrastructure

Although previous studies have described the electrophysiological and ultrastructural characteristics of human cardiac fibers, no attempt has been made as yet to describe quantitatively the relationship between the ultrastructural and cellular electrophysiological derangements occurring with cardiac disease, and their clinical manifestations. In this study, we used standard microelectrode techniques to record the action potential characteristics of human atrial fibers obtained during cardiac surgery and correlated the electrophysiological parameters with clinical and ultrastructural data. Ultrastructure was studied by optical and electron microscopy. We found a multiple linear regression among maximum diastolic potential, atrial size and pressure, P wave duration and ultrastructure changes. Proliferations of Z band material, widening of intercalated discs, and degenerative changes were quantified and correlated with electrophysiological and clinical data. These studies emphasize the relationship between hemodynamic anomalies and resultant changes in both human atrial fiber structure and electrical function. Finally, the likelihood of occurrence of arrhythmias can be predicted using the analytic method described.     

Acute beta-adrenoceptor blockade improves efficacy of ibutilide in conversion of atrial fibrillation with a rapid ventricular rate

Aims: Activation of beta-adrenoceptors attenuates prolongation ofaction potential duration induced by blockade of the delayedrectifier potassium current. We examined whether acute administrationof beta-blocker could enhance ibutilide (IB) efficacy in conversionof atrial fibrillation (AF) with a rapid ventricular rate. Methods and results: Ninety patients (aged 63 ± 13.5 years) with rapidly conductingAF were randomized in to two groups. Group A (n = 44) receivedesmolol titrated to achieve a heart rate of <100 bpm followedby IB co-administration, while Group B (n = 46) were treatedwith IB as monotherapy. In Group A, 29 patients (67%) convertedto sinus rhythm (SR) compared with 21 (46%) in Group B (P =0.04). The use of esmolol was the most important predictor forcardioversion (P = 0.009). The slower the heart rate at thetime of IB initiation, the higher the likelihood for cardioversion(P = 0.015). Patients in Group A had significantly shorter correctedQT interval (QTc) at the time of conversion than those in GroupB (433 vs. 501 ms, P = 0.003). Two patients in Group A developedsevere bradycardia, whereas three patients in Group B developedsevere ventricular tachycardia (VT). Conclusion: Compared with IB monotherapy, the combination therapy of esmololand IB appears to be more effective in conversion of rapidlyconducting AF back to SR. The addition of beta-blocker reducesQTc prolongation and diminishes the risk of VT at the expense,however, of increased bradycardic events.     

Suppression of ethanol-induced cardiac hypertrophy by beta-adrenoceptor blockade

The effects of D,L-propranolol and its resolved epimers on cardiac size in rats given ethanol, or a control diet containing maltose-dextrin, every 8 h by gavage, for 48 h were assessed. Co-treatment with ethanol plus saline for 48 h resulted in increases of approximately 10% in wet and dry heart weights, and in their proportional measures (g/kg body wt). Cardiac protein content was increased similarly. Administration of D,L-propranolol (10, 20 mg/kg), or L-propranolol (5, 10, 20 mg/kg), suppressed the increases in response to ethanol, D-Propranolol (10, 20 mg/kg) was ineffective in attenuating ethanol-induced increases in heart weights and protein content. Values of total cardiac DNA and fractional water content were unaffected by any of the treatments. Adrenaline and noradrenaline levels in urine were elevated during 48 h of intoxication in all rats given ethanol. The results suggest that severe, subacute intoxication with ethanol induces cardiac hypertrophy. Further, the data implies that the hypertrophy is mediated through activation of cardiac beta-adrenoceptors.     

The pharmacological response of ischemia-related atrial fibrillation in dogs: evidence for substrate-specific efficacy

OBJECTIVE: Acute atrial ischemia produces a substrate for atrial fibrillation (AF) maintenance, but the response of this substrate to antiarrhythmic-drugs has not been defined. The present study assessed the effects of class 1-4 antiarrhythmic-drugs on the electrophysiological consequences of acute atrial ischemia, and compared effects in ischemic AF with those in vagal AF. METHODS AND RESULTS: Isolated atrial ischemia was created by ligating a right coronary artery branch perfusing the right atrial free wall. Experiments were performed in dogs treated with loading and maintenance doses of flecainide (class 1; n=5), nadolol (class 2, n=7), dofetilide (class 3, n=5), or diltiazem (class 4, n=7) prior to coronary artery occlusion. Dogs subjected to coronary occlusion without pre-treatment (n=10) served as controls. Coronary artery occlusion substantially increased AF duration, e.g. from 7+/-4 s (pre-ischemic baseline) to 876+/-245 s at 3 h of ischemia, and caused substantial ischemic zone conduction slowing. Diltiazem and nadolol prevented AF promotion (AF durations 12+/-8 s and 4+/-1 s at 3 h of ischemia respectively; each p<0.001 vs control) and suppressed ischemic conduction slowing. Flecainide and dofetilide failed to prevent ischemia-induced AF promotion (e.g. AF duration at 3-hour ischemia 779+/-417 and 801+/-414 respectively, p=NS vs control) and failed to alter ischemia-induced conduction slowing. A different pattern of response occurred with vagal AF: flecainide was highly effective in reducing vagal AF duration; dofetilide, diltiazem, and nadolol were ineffective. CONCLUSIONS: Beta-blockade and Ca(2+) antagonism suppress the arrhythmic consequences of acute atrial ischemia, whereas Na(+) channel or K(+)-channel block are ineffective. These results are relevant to understanding the effects of different classes of antiarrhythmic-drugs on AF occurring in coronary disease patients.     

迷走神经性房颤大鼠模型的建立及心房电生理学研究

目的 探索房颤（AF）模型发生维持机制的关键病理环节建立稳定AF模型。 方法 选取健康雄性SD大鼠40只，将体质量均衡大鼠随机分为对照组、模型1组、模型2组及模型3组，每组10只（n=10）共4组，分别以不同浓度和天数尾静脉给予乙酰胆碱-氯化钙（ACh-CaCl₂）溶液，进行造模条件优选。以Langendorff恒温恒流灌流系统，描记离体心电图，同时以S1S2程控刺激检测各组大鼠心房有效不应期（AERP）。运用Western blot方法检测AF模型大鼠心房肌Cav1.2蛋白表达程度。 结果 大鼠AF造模不同条件成功率分别为:模型1组为100%，模型2组70%，模型3组0；大鼠不同造模条件35 d后，AF维持时间比较:模型1组与模型2组，模型1组与模型3组，模型1组与对照组，模型2组与对照组差异均显著（P<0.05），大鼠造模后，各组AERP相比较，对照组>模型1组，模型2组>模型1组（P<0.05）；使用Western blot 检测，模型组大鼠及对照组大鼠心房肌Cav1.2表达量有变化。 结论 运用ACh（99 μg/mL），CaCl₂（10 mg/mL）这一给药浓度，持续尾静脉给药35 d，造模成功率较高，可诱发大鼠稳定AF模型。      

Adipocytes modulate the electrophysiology of atrial myocytes: implications in obesity-induced atrial fibrillation

Obesity is an important risk factor for atrial fibrillation (AF). Increased epicardial adipose tissue in obesity can enhance inflammation and plays an important role in the pathophysiology of AF. However, it is not clear whether epicardial adipocytes directly modulate the electrophysiological characteristics of atrial myocytes. Whole-cell patch clamp was used to record the action potentials (APs) and ionic currents in isolated rabbit left atrium (LA) myocytes incubated with and without (control) isolated adipocytes from epicardial, retrosternal, or abdominal adipose tissues, or adipocytes-conditioned supernatant for 2-4?h. Compared to control LA myocytes (n?=?22), LA myocytes incubated with epicardial (n?=?17), retrosternal (n?=?18), or abdominal adipocytes (n?=?22) had longer (80?±?3, 109?±?6, 109?±?6, and 110?±?7?ms, p??0.05) in comparison to control myocytes. Epicardial adipocyte-incubated LA myocytes had larger late sodium currents, L-type calcium currents, and transient outward potassium currents, but smaller delayed rectifier potassium and inward rectifier potassium currents than control LA myocytes. Moreover, isoproterenol (10?nM) induced a higher incidence (67 vs. 22?%, p?相似文献   

Blood coagulation and platelet function following maximal exercise: effects of beta-adrenoceptor blockade

Alterations of platelet function and blood coagulation may occur with exercise or beta-adrenoceptor blockade. To determine if beta-blockade could modify exercise-induced changes in haemostatic factors we performed a double-blind study of acute strenuous exercise in normal males with and without beta-blockade. Exercise increased prostacyclin and plasminogen activator levels but there was no evidence of thrombin generation as indicated by unchanged platelet aggregation responses, beta-thromboglobulin and fibrinopeptide A levels. The only alteration in coagulation by beta-blockade was a reduction in the factor VIII:C and VIII:RAg rise after exercise and this modification may be relevant to the protective effect of these drugs in patients with coronary artery disease.     

Gender differences in the long QT syndrome: effects of beta-adrenoceptor blockade

BACKGROUND: Gender differences have been reported in patients with the congenital long QT syndrome (LQTS). We analyzed whether electrocardiographic differences existed in females, males, girls and boys in response to beta-adrenoceptor blockade. METHODS: 12-lead ECGs before and during beta-adrenoceptor blockade were collected in 87 genotyped LQTS patients (48 women, 14 men, 12 girls and 13 boys). Up to three QTc intervals were determined in each lead of the ECG. V4 was used for QT/QTc analysis. Difference between longest and shortest QT interval was taken as a measure for dispersion of QT intervals. RESULTS: (1) Adult males had the greatest shortening of the QTc interval upon treatment with beta-adrenoceptor blockade. During treatment, adult males with LQTS(1) (mutation in the KCNQ1 gene, affecting I(Ks) current) were found to have shorter QTc intervals than adult females; this difference did not exist in LQTS(2) patients (mutation in the HERG gene, affecting I(Kr) current). (2) Female LQTS(2) patients had a 50% larger dispersion than female LQTS(1) patients both before and during treatment. (3) Adult male LQTS(1) patients constitute the only patient group with a marked decrease in QTc intervals and dispersion associated with a 100% efficacy of treatment in response to beta-adrenoceptor blockade. CONCLUSIONS: These findings indicate that, in addition to underlying differences in repolarization between men and women, cardiac electrophysiological responses to beta-adrenoceptor blockade can be modulated by gender-related factors.     

Chronic beta-adrenoceptor blockade prevents the development of beta-adrenergic subsensitivity in experimental right-sided congestive heart failure in dogs.

BACKGROUND. The reductions of myocardial beta-adrenergic receptor density and responsiveness to catecholamines in congestive heart failure are associated with excessive sympathetic stimulation. The purpose of this study was to determine whether the myocardial changes could be prevented by beta-receptor blockade. METHODS AND RESULTS. We administered the oral beta-receptor blocking agent nadolol (40 mg/day) to dogs during an early stage of experimental right heart failure and to sham-operated dogs for 5 weeks. Animals receiving no nadolol were studied concurrently. Nadolol treatment did not prevent right ventricular hypertrophy or elevated concentrations of plasma norepinephrine that occurred in right heart failure, nor did it affect the decrease in myocardial norepinephrine content and norepinephrine uptake activity, suggesting that the hemodynamic stress imposed on the right ventricle of dogs with right heart failure was similar regardless of the presence or absence of beta-receptor blockade. Resting heart rate, right atrial pressure, aortic pressure, cardiac output, right ventricular dP/dt, and left ventricular dP/dt and dP/dt/P measured 5 days after discontinuation of nadolol did not differ significantly from those without nadolol treatment in either right heart failure or sham-operated animals. Sham-operated dogs also showed no changes in myocardial beta-receptor or adenylate cyclase activity after nadolol treatment. However, nadolol treatment prevented the reduction of myocardial beta-receptor density and attenuated the decrease in the cardiac beta-adrenergic sensitivity that occurred in right heart failure. CONCLUSIONS. Excessive sympathetic stimulation may play an important role in the development of beta-receptor downregulation and beta-adrenergic subsensitivity in right heart failure.     

Acute effects of alpha- and beta-adrenoceptor blockade on plasma atrial natriuretic peptides during exercise in elderly patients with mild hypertension.

In a randomized study in 26 elderly patients with mild essential hypertension, acute effects of alpha- and beta-adrenoceptor blockade on plasma ANP levels were examined at rest and during ergometric exercise. Plasma ANP level and LVEF were measured before and after administration of prazosin (an alpha 1-adrenergic blocker), atenolol (a cardioselective beta-adrenergic blocker), or carteolol (a nonselective beta-adrenergic blocker). Plasma ANP level was increased by exercise. Carteolol and atenolol increased plasma ANP levels at rest and during exercise, but the effect of atenolol was not statistically significant. Prazosin significantly suppressed the ANP values at rest and during exercise. The LVEF was increased by prazosin and decreased by beta-blockers, especially by carteolol. Multivariate regression analysis showed that LVEF was the most significant predictor of the plasma ANP level at maximal exercise; the resting blood pressure and heart rate were not predictors of this value. The results showed that single administrations of an alpha-blocker and a nonselective beta-blocker had opposite effects on the plasma ANP level both at rest and during exercise in elderly patients with mild essential hypertension. The observed difference in the ANP response seems to be related to changes in left ventricular function rather than changes in blood pressure or heart rate.     

Microparticles in atrial fibrillation: A link between cell activation or apoptosis,tissue remodelling and thrombogenicity

Microparticles (MPs) are small membrane vesicles that are shed from virtually all cells in response to stress. Widely described in atherothrombotic diseases, recent data suggest a role for circulating MPs in the hypercoagulable state associated with supraventricular tachyarrhythmia. During atrial fibrillation, several mechanisms, such as high ventricular heart rate, low or oscillatory shear stress, stretch, hypoxia, inflammation and oxidative stress, are potent inducers of apoptotic cell death, which leads to the shedding of procoagulant MPs within the vasculature. As key regulators of cell–cell cross-talk and important mediators of inflammatory, thrombogenic and proteolytic pathways, MPs directly or indirectly contribute to the amplification loops involved in atrial fibrillation. Because high levels of platelets and endothelial-derived MPs are identified during stroke and are associated with infarct size and clinical outcome, they are proposed to be a potent marker of ischaemic risk. During pulmonary vein isolation, the additional increases of platelet and leukocyte MP levels suggest the extent of tissue damage and reflect a transient activation of the coagulation cascade that could favour ischaemic stroke. Conversely, the observed decreases of several apoptotic markers some months after the restoration of sinus rhythm suggest that the extent of apoptotic processes is reversible and might enable restoration of haemostasis. In this review, we will summarise the current evidence supporting the roles of apoptosis and cell activation in the development of the prothrombotic state observed in atrial fibrillation, with a particular focus on procoagulant MPs.     

Progestin-specific markers in human cell lines: biological and pharmacological applications

We review the progestin-specific responses (induced proteins, increased enzymatic activity) described in uterus, mammary tumours and human breast cancer cell lines established from pleural effusions. Recent data from our laboratory using the T47D breast cancer cell line are then given. They include: (a) a general methodology for evaluating the specific effects of steroids on the production of [35S]methionine-labelled proteins released into the culture medium; (b) results concerning the specificity of regulation by the progestins of a 48 000 dalton protein secreted by T47D cells; (c) the evidence for androgen-specific proteins in the same cells; (d) A discussion of the criteria required to define the receptor responsible for a particular effect of steroids. Lastly, we consider the general interest of progestin-regulated proteins in cell culture for pharmacology and biology.     

心房肌急性电重构的临床研究

目的探讨快速心房激动对心房电生理特性的影响.方法以150～200ms起搏周长(PCL)对21例射频消融术后患者右心房进行S1S1刺激诱发心房颤动,心房快速刺激前、后均以400ms周长分别对高位右心房(HRA)、低位右心房(LRA)、希氏束周围(HB)、右心耳(RAA)等多部位进行S1S2扫描,测定心房有效不应期(ERP)、有效不应期空间离散度(ERPd)、右心房内及心房间传导时间(CT)的变化;以350ms、400ms和450ms3个不同周长随机对RAA进行S1S2扫描,观察有效不应期频率自适应性(ERPA)的变化.结果快速心房激动后ERP较刺激前有明显缩短,HRA的ERP[(193.2±25.5)msvs(179.7±23.3)ms,P=0.001、LRA的ERP [(198.0±30.8)msvs(182.0±22.5)ms,P=0.026]、HB的ERP[(195.0±26.6)ms vs(182.0±16.8)ms,P=0.018]、RAA的ERP(194.0±20.1)msvs(180.0±29.0)ms,P=0.014].而ERPd则无明显变化[(25.0±17.8)ms vs(28.0±16.9)ms,P=0.576];3个不同周长下RAA的ERP均较心房快速激动前有显著缩短,S1S1为350ms、400ms和450ms.心房快速激动前后ERP分别为[(186.2±24.4)ms vs(168.7±30.9)ms,P=0.006]、[(194.0±20.1)ms vs(180.0±29.0)ms,P=0.014]和[(191.2±33.1)ms vs(170.0±28.3)ms,P=0.0001];心房快速激动前、后ERP与PCL相关系数分别为(rb=0.998,P=0.041;ra=0.397,P=0.74),心房激动前斜率接近正常0.058,激动后斜率为0.015.房内房间CT无明显变化,HRA-HB[(46.5±12.5)msvs(48.4±12.0)ms,P=0.125]、HB-CSD[(47.0±14.2)ms vs(49.6±14.8)ms,P=0.153].结论快速心房激动使右心房同一周长不同部位、同一部位不同起搏周长下ERP缩短,ERPA下降;ERPd及右心房内房间传导速度无明显改变.快速心房刺激使人心房肌发生电重构,ERP缩短、ERPA下降可能是心房颤动发生、维持和发展的重要原因.