The non-synonymous coding IKr-channel variant KCNH2-K897T is associated with atrial fibrillation: results from a systematic candidate gene-based analysis of KCNH2 (HERG)

Aims: Atrial fibrillation (AF) is the most frequent arrhythmia inhumans. Rare familial forms exist. Recent evidence indicatesa genetic susceptibility to common forms of AF. The -subunitof the myocardial I_Kr-channel, encoded by the KCNH2 gene, iscrucial to ventricular and atrial repolarization. Patients withmutations in KCNH2 present with higher incidence of AF. Commonvariants in KCNH2 have been shown to modify ventricular repolarization.We intended to investigate, whether such variants may also modulateatrial repolarization and predispose to AF. Methods and results: In a two-stage association study we analysed 1207 AF-cases and2475 controls. In stage I 40 tagSNPs (single nucleotide polymorphisms)from the KCNH2 genomic region were genotyped in 671 AF-casesand 694 controls. Of five associated variants, the common K897-alleleof the KCNH2-K897T variant was replicated in n = 536 independentAF cases and n = 1781 controls in stage II [overall odds ratio1.25, 95% confidence interval 1.11–1.41, P = 0.00033].This association remained significant after adjustment for genderand age. Conclusion: We report a genetic association finding including positive replicationbetween the K897-allele and higher incidence of AF. This providesa molecular correlate for complex genetic predispositions toAF. The consequences of the K897T variant at the atrial levelwill require further functional investigations.     

Factor V Leiden and Risk of Ischemic Stroke in Nonvalvular Atrial Fibrillation: The AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study

Background: Atrial fibrillation is a major cause of cardioembolic stroke. Since atrial and venous pressures are similar, genetic variants that promote venous thromboembolism may increase the risk of atrial thrombi and subsequent stroke in atrial fibrillation. Methods: We conducted a nested case-control study of the association between the presence of factor V Leiden polymorphism and incident ischemic stroke within a prospective cohort of 13,559 adult patients with diagnosed nonvalvular atrial fibrillation between July 1, 1996 and December 31, 1997. Incident cases with ischemic strokes were identified through August 31, 1999 and matching stroke-free controls were enrolled. Results: One hundred thirty-seven case patients with incident stroke and 214 controls were enrolled. Cases were older, more likely to be women, and more likely to have a prior stroke, heart failure, hypertension, diabetes, and coronary disease. The factor V Leiden polymorphism was present in 5.8% of cases and 3.7% of controls (P = 0.36). Among non-anticoagulated patients, 7/96 (7.3%) case patients and 3/81 (3.6%) control subjects were heterozygous for factor V Leiden (Odds Ratio 2.1 [95% CI: 0.5–8.4]). Adjustment for known stroke risk factors did not significantly change the observed association in non-anticoagulated patients (adjusted OR 1.9 [0.5–8.0]). Conclusions: Within a large nested case-control sample of patients with atrial fibrillation, factor V Leiden was not significantly associated with risk of stroke. However, given the suggestive nature of our findings, further study in even larger numbers of patients is needed to clarify the impact of factor V Leiden on stroke risk in atrial fibrillation.     

Amiodarone in Atrial Fibrillation

ABSTRACT Twenty-seven patients with atrial fibrillation without any concomitant conduction abnormality have been treated with oral amiodarone in a daily maintenance dose of 200 mg. The drug has been used for three purposes: 1) to block atrioventricular conduction, thereby decreasing the ventricular rate during atrial fibrillation (9 patients), 2) as prophylaxis against paroxysmal atrial fibrillation (8 patients), 3) as prophylaxis against recurrence of atrial fibrillation after DC conversion to sinus rhythm (13 patients). All patients were considered refractory to other antiarrhythmic drugs in these respects. In the second group, 4 of the 8 patients reported complete cessation of attacks and the others a marked reduction of the attack rate. In the third group, 10 of the 13 patients have maintained sinus rhythm for a longer period on treatment with amiodarone than with other drugs, resulting more than a triple prolongation of the time in sinus rhythm. In 3 patients the drug has been discontinued because of side-effects. In conclusion, amiodarone affords protection from episodes of paroxysmal atrial fibrillation, as well as from recurrence of atrial fibrillation after DC conversion to sinus rhythm. If the drug is ineffective in either of these respects, it may still be useful as a means of moderating the ventricular response in atrial fibrillation.     

心房颤动的治疗进展

心房颤动是临床最常见的持续性心律失常,也是目前的研究热点。其治疗的方法包括药物、导管消融及外科手术等。对于其方式的选择也有争论。现就心房颤动的当前相关治疗进行综述。     

Echocardiography in Lone Atrial Fibrillation

Twenty-seven consecutive patients with suspected lone atrial fibrillation were studied by M-mode echocardiography. Echocardiography disclosed structural or functional cardiac abnormalities in only two (12%) of 17 patients without any sign of underlying heart disease by history or physical examination, whereas an accompanying or underlying cardiac disorder was found in 6 (60 %) of 10 patients with ambiguous clinical findings. It is concluded that echocardiography is of minor value in patients with lone atrial fibrillation if symptoms and signs of other cardiac disorders are totally absent, but the presence of even minor or ambiguous clinical abnormalities seems to be a clear indication for echocardiography in these patients. It is, however, emphasized that echocardiography appears to guide the clinical management in less than 20% of patients with clinically suspected lone atrial fibrillation.     

Immediate Reinitiation of Atrial Fibrillation Following Internal Atrial Defibrillation

Immediate Reinitiation of AF. Introduction: Although the recurrence rate of atrial fibrillation has been reported to be similar to that after external and internal cardioversion, little is known about immediate reinitiation of atrial fibrillation (IRAF) following internal cardioversion. Methods and Results: Thirty-eight patients (24 men; mean age 63 ± 13 years) underwent internal atrial defibrillation. Catheter-based defibrillation electrodes were positioned in the anterolateral right atrium and the coronary sinus. All patients were cardioverted at a mean threshold of 4.6 ± 3.4 J. Five of 38 patients (13%) had 1 to 4 episodes of IRAF. No difference in clinical and echocardiographic characteristics were observed when patients with and without IRAF were compared. Atrial fibrillation was always reinitiated by an atrial premature beat. When the earliest atrial endocardial activation time on the defibrillation catheters was analyzed, these atrial premature heats did not seem to originate from the defibrillation catheters. Twenty-one patients had atrial premature heats without IRAF. When the coupling intervals of the first atrial premature heat in patients without and with IRAF after conversion were compared, a significant difference was found (661 ± 229 vs 418 ± 79 msec, P < 0.05). IRAF was successfully treated with repeated shock delivery after the administration of atropine in 1 patient and intravenous flecainide in 2. Only repeated shock delivery was sufficient to treat IRAF in another 2 patients. Late recurrences of atrial fibrillation occurred in 3 of 5 with IRAK and in 19 of 33 patients without IRAF (P = NS). Conclusion: IRAF after internal atrial defibrillation occurred in 13% of patients, was always initiated by an atrial premature heat having a short coupling interval not originating from the defibrillation catheters, and was prevented by repeated shock delivery with or without preceding administration of pharmacologic agents. IRAF did not predict early recurrences of the arrhythmia after discharge from the hospital, emphasizing the necessity to treat immediate reinitiation promptly to achieve a successful cardioversion.     

A Contemporary Review on the Genetic Basis of Atrial Fibrillation

Atrial fibrillation is the most common sustained cardiac arrhythmia, and affected individuals suffer from increased rates of heart failure, stroke, and death. Despite the enormous clinical burden that it exerts on patients and health care systems, contemporary treatment strategies have only modest efficacy that likely stems from our limited understanding of its underlying pathophysiology. Epidemiological studies have provided unequivocal evidence that the arrhythmia has a substantial heritable component. Subsequent investigations into the genetics underlying atrial fibrillation have suggested that there is considerable interindividual variability in the pathophysiology characterizing the arrhythmia. This heterogeneity may partly account for the poor treatment efficacy of current therapies. Subdividing atrial fibrillation into mechanistic subtypes on the basis of genotype illustrates the heterogeneous nature of the arrhythmia and may ultimately help guide treatment strategies. A pharmacogenetic approach to the management of atrial fibrillation may lead to dramatic improvements in treatment efficacy and improved patient outcomes     

心房颤动患者心房纤维化研究进展

心房颤动的发生和维持与心房重构有关。心房纤维化是心房颤动患者心房结构重构最突出的表现,目前被认为是发生心房颤动的结构基础,是心房颤动发生、维持的一个重要因素。现综述心房颤动患者心房纤维化及其发生机制。通过对心房颤动患者心房纤维化结构改变及肾素-血管紧张素系统、转化生长因子、基质金属蛋白酶等在心房纤维化的发生和心房颤动发生、维持中的作用等的全面阐述,,探讨了心房颤动患者心房纤维化的研究进展。防治心房颤动新的策略取决于对心房纤维化机制更好的理解。     

心房颤动与白细胞介素的相关性研究进展

心房颤动是临床最常见的心律失常之一,并且有很高的致残率和致死率。随着心脏病抢救成功率的提高和病死率的下降,社会人口的老龄化,心房颤动的发病率呈明显上升趋势。近年来越来越多的临床研究表明了白细胞介素参与了心房颤动的发生和持续。心房颤动的发生和持续与白细胞介素及其基因型明显相关。现就心房颤动与白细胞介素与其基因多态性的关系进行综述。     

心房颤动的基础研究和临床治疗新进展

近年来,心房颤动的基础研究和临床治疗有很多新的进展,现对此作一综述。     

Maintenance of Sinus Rhythm after Cardioversion of Atrial Fibrillation in Patients with Lone Atrial Fibrillation and Patients with Hypertension

Background: The success rate and prognosis of cardioversion of atrial fibrillation (AF) in patients with organic heart disease is well known. In contrast, little data exist about cardioversion success and maintenance of sinus rhythm (SR) in patients with lone AF and in patients with hypertension as the only underlying cardiovascular disease. Methods: In a prospective cardioversion registry 148 of 181 patients (81.8%) with lone AF (age 58 ± 13 years, duration of AF 7.6 ± 19 weeks) and 120 of 148 patients (81.1%) with hypertension (age 62 ± 10 years, duration of AF 6.6 ± 21 weeks) had successful cardioversion and were followed for 7.7 ± 1.9 months. Results: At follow-up, 120 patients (81.1%) with lone AF were in SR, and 18 of these patients had had repeated cardioversion during follow-up (AF total recurrence rate 31.1%). In stepwise regression analysis, the number of previous cardioversions was predictive of rhythm at follow-up (P = 0.0453). Rhythm at follow-up did not differ between patients who were or were not on antiarrhythmic drugs. At follow-up 96 patients (80%) with hypertension were in SR, and 9 of these had had repeated cardioversion during follow-up (AF total recurrence rate 27.5%). As in lone AF, the recurrence rate of AF did not differ between patients with or without antiarrhythmic drug treatment, and in multivariate regression analysis, the number of previous cardioversions was the only clinical predictor of rhythm at follow-up (P = 0.0284). Conclusions: Even in patients with such benign conditions as lone AF or hypertension as the only underlying disease, the prognosis of cardioversion in terms of maintenance of SR is poor. Future studies of rhythm control versus rate control need to include not only patients with organic heart disease but also patients with lone AF and patients with hypertension, since the long-term benefits of these two strategies remain unclear even in these subsets of patients.     

Effects of High-Frequency Atrial Pacing in Atypical Atrial Flutter and Atrial Fibrillation

Atypical atrial flutter has, hitherto, been relatively refractory totermination by rapid atrial pacing. High-frequency pacing (HFP) in theatrium, for termination of atrial flutter or atrial fibrillation (AF), andthe electrophysiologic effects related to it have not been examined. Weexamined the clinical efficacy, safety, and electrophysiologic mechanisms ofHFP using 50-Hz bursts at 10 mA applied at the high right atrium in patientswith atypical atrial flutter (group 1) or AF (group 2), using a prospectiverandomized study protocol. Four burst durations (500, 1000, 2000, and 4000ms) were applied at the high right atrium repetitively in random sequence in22 patients with spontaneous atrial flutter or AF. Local and distant rightand left atrial electrogram recordings were analyzed during and after HFP.HFP resulted in local and distant right and left atrial electrogramacceleration in 8 of 10 patients (80%) in group 1 but caused lessfrequent local atrial electrogram acceleration (6 of 12 patients) and nodistant atrial electrogram effects in group 2 (p < .05 versus group 1).The HFP protocol was effective in arrhythmia termination in 6 of 10patients in group 1 but in no patient in group 2 (p < .05 versus group1). Standard HFP protocol applied at the high right atrium can frequentlyalter atrial activation in both atria and can terminate atypical atrialflutter. Efficacy in AF is limited, probably due to limitedelectrophysiologic actions beyond the local pacing site.     

Atrial Electrograms and Activation Sequences in the Transition Between Atrial Fibrillation and Atrial Flutter

Transition Between Atrial Fibrillation and Flutter. Introduction: The eletrophysiologic mechanism of atrial fibrillation (AF) has a wide spectrum, and it seems that some atrial regions are essential for the occurrence of a particular type of AF. We focused on one type of AF: AF associated with typical atrial flutter (AFI), which was right atrial (RA) arrhythmia, and sought to investigate intra-atrial electrograms and activation sequences in the transition between AF and AFL.
Methods and Results: Intra-atrial electrograms and activation sequences in the R.A free wall and the septum were evaluated in the transition between AF and AFL in seven patients without organic heart disease (all men; mean age 57 ± 11 years). In five episodes of the conversion of AFL into AF, the AFL cycle length was shortened (from 211 ± 6 msec in stable AFL to 190 ± 15 msec before the conversion, P, 0.001). Interruption of the AFL wavefront and an abrupt activation sequential change induced by a premature atrial impulse resulted in fractionation and disorganization of the septal electrograms. During sustained AF, septal electrograms were persistently fractionated with disorganized activation sequences. However, the RA free-wall electrograms were organized, and the activation sequence was predominantly craniocaudal rather than caudocranial throughout AF. In 12 episodes of the conversion of AF into AFL, the AF cycle length measured in the RA free wall increased (from 165 ± 26 msec at the onset of AF to 180 ± 24 msec before the conversion, P, 0.001). AFL resumed when fractionated septal electrograms were separated and organized to the caudocranial direction, despite the RA free-wall electrograms remaining discrete and sharp with an isoelectric line.
Conclusion: Changes of the electrogram and activation sequence in the atrial septum played an important role in the transition between AF and AFL.