Role In Atrial Fibrillation Research Articles

Age-Dependent Prognostic Significance of Atrial Fibrillation in Outpatients with Chronic Heart Failure: Data from the Italian Network on Congestive Heart Failure Registry

Objectives: The role of atrial fibrillation (AF) in older patients with heart failure (HF) is controversial because many variables seem to influence their outcome. We investigated the predictivity of AF in 3 age groups of outpatients with HF. Methods: We analyzed 8,178 outpatients enrolled in the Italian Network on Congestive Heart Failure Registry with HF diagnosed according to the European Society of Cardiology criteria. A trained cardiologist established the diagnosis of AF and HF at the entry visit at each center. We stratified the population into 3 age groups, as follows: group A, ≤65 years; group B, 66–75 years, and group C, >75 years. Results: Group A was composed of 4,261 patients, 683 with AF (16.0%); in group B there were 2,651 patients, 638 with AF (24.1%), and group C was composed of 1,266 patients, 412 with AF (32.5%). The 1-year mortality rate was higher in AF patients in all groups. In a multivariate model, AF remained an independent risk factor for death in groups A and B, but not in group C [group A: hazard ratio (HR) 1.42, 95% confidence interval (CI) 1.10–1.81; group B: HR 1.29, 95% CI 1.00–1.67; group C: HR 1.05, 95% CI 0.78–1.43]. Conclusion: The prevalence of AF increased with age and was associated with a higher mortality rate. However, AF independently predicted all-cause mortality only in patients aged ≤75 years.

Natriuretic peptides and right atrial fibrosis in patients with paroxysmal versus persistent atrial fibrillation

Natriuretic peptides (NPs) are excellent diagnostic and prognostic markers of heart failure, but their roles in atrial fibrillation (AF), particularly of isolated cardiac valvular origin, are unclear. We assessed the mRNA and protein content of pro-atrial natriuretic peptide (pro-ANP) and pro-brain natriuretic peptide (pro-BNP) in right atrial appendages (RAAs) and their N-terminal fragments (nt-proANP and nt-proBNP) in the plasma of 30 patients with paroxysmal AF (PaAF) and 40 patients with persistent AF (PeAF) matched with 34 patients in sinus rhythm (SR) undergoing isolated valvular replacement. To explore the underlying mechanism, fibrosis related examinations were simultaneously carried out in RAAs. Unexpectedly, atrial expression of pro-NPs mRNA was notably augmented in the PaAF subgroup, but not so pronounced in the PeAF subgroup. Atrial content of pro-NPs proteins and plasma nt-proNPs, between which surprisingly strong positive correlations were found (pro-ANP and nt-proANP: r = 0.918, p < 0.001; pro-BNP and nt-proBNP: r = 0.913, p < 0.001), were increased analogously in PaAF and PeAF subgroups. We identified significantly increasing gradients of atrial collagen volume fraction (CVF), levels of collagen I and III in the SR, PaAF and PeAF groups, and convincing negative linear correlations between CVF, levels of collagen I and III, and atrial transcripts of pro-NPs. These findings suggest that the discordance between transcripts and protein contents of pro-NPs was possibly due to the more outstanding atrial fibrosis in PeAF, and that circulating nt-proNPs levels could reflect the corresponding atrial pro-NPs contents in this report.

Atrial electrophysiology is altered by acute hypercapnia but not hypoxemia: Implications for promotion of atrial fibrillation in pulmonary disease and sleep apnea

Chronic pulmonary disease and sleep apnea have been associated with the development of atrial fibrillation (AF). The purpose of this study was to characterize the atrial electrical changes that occur with hypercapnia and hypoxemia and to determine their role in AF development. Seventeen sheep (6 control, 5 hypercapnia, 6 hypoxemia) underwent open chest electrophysiologic evaluation under autonomic blockade. A 64-electrode endocardial basket catheter was positioned in the right atrium, and 2 x 128 electrode epicardial plaques were sutured to the right atrial and left atrial appendages to determine atrial refractoriness (effective refractory period [ERP]) at 9 sites and 5 cycle lengths, conduction time to fixed points on each plaque, and AF vulnerability. Hypercapnia was associated with a 152% lengthening of ERP from baseline and increased conduction time. ERPs rapidly returned to baseline, but recovery of conduction was delayed at least 117 +/- 24 minutes following resolution of hypercapnia. AF vulnerability was reduced during hypercapnia (with increased ERP) but increased significantly with subsequent return to eucapnia (when ERP normalized but conduction time remained prolonged). No significant changes in ERP, atrial conduction time, or AF vulnerability occurred in hypoxemic or control groups. Differential recovery of ERP and conduction that occurs following hypercapnia might account for the increased vulnerability to AF observed in the phase after return to eucapnia. This may explain in part the increased prevalence of AF in pulmonary disease and sleep apnea.

Atrial fibrillation is not just an artefact in the ICU

Atrial fibrillation (AF) is common in the intensive care unit (ICU) and is particularly frequent (46%) in septic shock patients. Inflammation favours AF in the general population, and there is a growing body of evidence that inflammation also plays a role in AF occurring after cardiac surgery but also in the general ICU. How such a finding could modify the therapeutic approach remains elusive. The impact of AF on mortality is not clearly demonstrated in the ICU, with AF reflecting essentially the severity of the underlying disease.

Role of atrial fibrillation after transcatheter closure of patent foramen ovale in patients with or without cryptogenic stroke

Atrial fibrillation (AF) after transcatheter closure of patent foramen ovale (PFO) is not a rare complication. However little is known about the effect of atrial septal device implantation on the occurrence of this arrhythmia. The aim of this study was to evaluate the occurrence of AF in two groups of patients who underwent transcatheter PFO closure: those with a previous cryptogenic stroke and those with other index events respectively. Patient population included 276 patients with documented PFO who underwent percutaneous closure at our institution. Patients were grouped on the basis of two distinct clinical presentations: a) 246 patients with history of previous cryptogenic cerebrovascular ischemic event (CIE) or b) 30 patients with other different index events. AF after PFO closure was detected by 12-lead electrocardiography or by 24-h-Holter monitoring. During a mean follow-up of 17 months, new-onset AF was documented in 10 patients (4%), all included in the group with a previous cryptogenic CIE, at a mean of 1.6 months post-procedure. Comparing patients with and without AF, age (mean 56 years vs 46 years, p = 0.012) and left atrial size (4.4 cm vs 3.7 cm, p = 0.001) resulted to differ significantly. The type and size of occluder devices do not seem to impact the occurrence of AF after PFO closure. In patients presenting with cryptogenic stroke, especially in those with slightly enlarged left atria and age above 50–55 years, detection of a PFO should prompt an extended monitoring for excluding AF.

Targeted G-protein inhibition as a novel approach to decrease vagal atrial fibrillation by selective parasympathetic attenuation

The parasympathetic nervous system is thought to play a key role in atrial fibrillation (AF). Since parasympathetic signalling is primarily mediated by the heterotrimeric G-protein, Galpha(i)betagamma, we hypothesized that targeted inhibition of Galpha(i) interactions in the posterior left atrium (PLA) would modify the substrate for vagal AF. Cell-penetrating(cp)-Galpha(i)1/2 and cp-Galpha(i)3 C-terminal peptides were assessed for their ability to attenuate cholinergic-parasympathetic signalling in isolated feline atrial myocytes and in canine left atrium (LA). Confocal fluorescence microscopy indicated that cp-Galpha(i)1/2 and/or cp-Galpha(i)3 peptides moderated carbachol attenuation of cellular Ca(2+) transients in isolated atrial myocytes. High-density epicardial mapping of dog PLA, left atrial pulmonary veins (PVs), and left atrial appendage (LAA) indicated that the delivery of cp-Galpha(i)1/2 peptide or cp-Galpha(i)3 peptide into the PLA prolonged effective refractory periods at baseline and during vagal stimulation in the PLA and to varying extents also in the LAA and PV regions. After delivery of cp-Galpha(i) peptides into the PLA, AF inducibility during vagal stimulation was significantly diminished. These results demonstrate the feasibility of using specific G(i)-protein inhibition to achieve selective parasympathetic denervation in the PLA, with a resulting change in vagal responsiveness across the entire LA.

S3-1 miRNAs and Cardiac Arrhythmogenesis: Role in Atrial Fibrillation

S3-1 miRNAs and Cardiac Arrhythmogenesis: Role in Atrial Fibrillation

Genetics and Sinus Node Dysfunction.

Sinus node dysfunction (SND) is commonly encountered in the clinic. The clinical phenotype ranges from asymptomatic sinus bradycardia to complete atrial standstill. In some cases, sinus bradycardia is associated with other myocardial conditions such as congenital abnormalities, myocarditis, dystrophies, cardiomyopathies as well as fibrosis or other structural remodeling of the SA node.1-8 Although there are many etiologies for symptomatic slow heart rates, the only effective treatment available today is the implantation of a pacemaker. The predominant ion channel currents contributing to the pacemaker activity in the sinoatrial node (SAN) include currents flowing through hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels,9 Ltype Ca, Ttype Ca,10 delayed rectifier K,11,12 and acetylcholine (ACh)-activated13,14 channels. However, their relative contribution remains a matter of debate and the cellular mechanisms contributing to abnormal sinus node function leading to bradycardia are not fully elucidated. Sodium channel current (INa), encoded by SCN5A, is responsible for the cardiac action potential (AP) upstroke and therefore has an important role in initiation and propagation of the cardiac action potential. Although it is largely absent in the sinus node, it plays an important role at the periphery of the sinus node in transmitting electrical activity from the sinus node to the rest of the atria. Mutations in genes encoding structural anchoring proteins (ANK2, Caveolin3, AKAP9) have been associated with the development of atrial as well as ventricular arrhythmias.15, 16, 17 Sinus node dysfunction has been associated with a variety of atrial tachyarrhythmias, atrial fibrillation (AF) in particular. In recent years, numerous publications have focused on the genetic basis for ion channels and structural protein remodeling, providing further insights in the mechanisms of sinus node dysfunction and its role in AF. In this review, we will focus on the genetic aspects of the various forms of sinus node dysfunction and their relation to AF.

Up‐regulation of the Ca2+ permeable TRPM7 channel in Atrial Fibrillation patients

Cardiac fibroblasts play an important role in cardiac fibrogenesis which associated with a variety of heart diseases including atrial fibrillation (AF). However, the Ca2+ permeable channels which are responsible for cellular functions of fibroblasts remain unknown. Here, we investigated the potential role of TRPM7‐mediated Ca2+ entry is involved in fibroblast differentiation. With consent, fibroblasts were obtained from patients undergoing cardiac surgery. The isolated fibroblast cells were used for patch‐clamp, Ca2+ image and immunostaining. TRPM7 siRNA was used to knock‐down TRPM7 expression when it was necessary. A typical TRPM7‐like current obtained from isolated fibroblasts by patch‐clamping. TRPM7 siRNA decreased the current density by 76%, confirming it was TRPM7. Interestingly, the current in AF patients were 3 folds bigger than those in control patients suggest that TRPM7 play a role in AF. Immunostaining results showed basal level of differentiation was much higher in cells from AF patients than those from control patients. TRPM7 siRNA significantly decreased TGF‐β1 induced fibroblast differentiation in both control and AF patients. To conclude, our study provided a novel molecule (TRPM7) as well as a novel mechanism for cardiac fibrogenesis: TRPM7‐mediated Ca2+ signal is important in cardiac fibroblast differentiation, which largely contributes to cardiac fibrogenesis cascade and related heart diseases. Project supported by NIH # HL 078960

Current controversies in using electrical devices

Current controversies in using electrical devices

Unique Histological Features of the Left Atrial Posterior Wall

The left atrial posterior wall (LAPW) plays a critical role in atrial fibrillation, but the underlying mechanism remains unclear. In the present study, we sought to characterize the histological features of the LAPW. Different atrial regions were dissected from hearts of normal Sprague-Dawley rats and humans. Haematoxylin/eosin and van Gieson staining were used to analyse atrial cardiomyocyte arrangement and collagen distribution, respectively. Intercellular junctions were evaluated by transmission electron microscopy. In contrast with other atrial regions, the LAPW exhibited more disorganized cardiomyocytes, larger intercellular spaces and variable myocardial fibre arrangement. The proportion of collagen was significantly higher in the LAPW than in other atrial regions. Interestingly, desmosomes were sparse along with intercellular gaps in the LAPW. In summary, distinct disarrangement of cardiomyocytes and an abundance of collagen exist in the LAPW. The sparsity of desmosomes in the LAPW may be related to the heterogeneous distribution and separation of atrial myocytes.

A POSSIBLE ROLE OF ATRIAL FIBRILLATION AS A RISK FACTOR FOR DEMENTIA

Atrial fibrillation (AF), which is a very common disease among the elderly, is already well known as a risk factor for arterial thromboembolism and stroke. The attention of medical research is now focused on establishing a possible role of AF in the development of cognitive impairment in order to include this arrhythmia among risk factors for dementia. The aim of this work was to investigate the relationship between AF and various types of dementia, such as vascular dementia (VaD), Alzheimer's disease (AD) and mixed dementia (MD). The study consisted of 71 VaD, AD or MD patients, 31 males and 40 females. The sample has been divided in 2 groups according to the sex, and these two groups have been analyzed separately. In females, a statistically significant association was found between mini mental state examination (MMSE) and clinical dementia rating (CDR) scores and AF occurrence (r = −0.32; p < 0.05; r = 0.33; p < 0.05). On the contrary, no significant linear correlation was found between AF and a lower activities if daily living (ADL) and instrumental activities if daily living (IADL) scores. In males, AF/MMSE, AF/CDR, AF/ADL and AF/IADL variables have not been found to be linearly related to each other. Unexpectedly, AF turned to be associated to AD more often than to VAD, becoming a possible risk factor for this neurodegenerative disease. Our results are supported by many studies in literature attributing a basic role of brain hypoperfusion in sporadic AD patho-genesis. More and more scientific data suggest that the already well known risk factors for AD could be considered just the top of an iceberg, providing powerful arguments for impaired cerebral perfusion as the primary trigger in the development of this disease. Moreover, the mildly favorable treatment response in patients with AD to therapy that improves cerebral blood flow is a consistent finding; the same cannot be said of antiamyloid treatments. This opens new possibilities to find an effective way to treat this dramatic pathology.

The influences of depression and venlafaxine use at therapeutic doses on atrial conduction

Patients with depression have increases risk of cardiac mortality. Overdose with venlafaxine has been accused of supraventricular tachycardia, atrial fibrillation and other cardiac effects. Discontinuous and inhomogeneous propagation of sinus impulses in atrium plays a major role in atrial fibrillation. We aimed to measure the effects of venlafaxine therapy on propagation of sinus impulses reflections in electrocardiography in depression. Eligible 19 participants were outpatients with depression. 75 mg/day dose of venlafaxine was administered to the patients. The patients were asked to complete both Beck Depression and Anxiety Inventories. 17 healthy participants enrolled in the study. The electrocardiography records were obtained while patients were drug naive and one week after treatment. The baseline durations of P(minimum) and P(maximum) in the patient group were significantly shorter than controls (p < 0,05). The differences between baseline and after venlafaxine therapy among electrocardiographical variables were statistically insignificant. There were no significant correlations between age, sex, body mass index, clinical inventories and electrocardiographical variables in both patients and controls. Autonomic dysregulation in myocardium is still inconclusive in depression. Venlafaxine at therapeutic dose of 75 mg/day does not seem to be associated with myocardial conduction dysregulation.

Atrial fibrillation subtypes, risk of stroke, and antithrombotic therapy

Despite a significant decline in the last 50 years, stroke remains the third leading cause of mortality in men and the second in women.1 Stroke also represents the leading cause of disability and the second of dementia, with a tremendous impact on the affected patients and their relatives. Approximately one-third of ischaemic strokes are caused by an embolus originating from the heart, and in the majority of these cases atrial fibrillation is responsible for the thromboembolic event. This proportion may be even higher, as the role of atrial fibrillation in the pathogenesis of stroke may be underestimated. In fact, the observation of sinus rhythm on the surface electrocardiogram at hospital admission for stroke, in the absence of clinical history of atrial fibrillation, does not rule out the possibility of a new-onset and self-terminating arrhythmic episode that preceded the occurrence of neurological symptoms. Close electrocardiographic monitoring may increase the detection of atrial fibrillation among stroke patients, but at present it can be performed only in the limited number of available stroke units. Atrial fibrillation is indeed one of the most important risk factors for stroke.2 The rate of ischaemic stroke among patients with atrial fibrillation averages 4.5% per year, which is 4–5 times more than in patients without atrial fibrillation, and the risk significantly increases with age.3 After 80 years of age, the annual rate of stroke in patients with atrial fibrillation reaches the staggering figure of 25%.4 Stroke due to atrial fibrillation is also associated with larger cerebral infarcts and a higher neurological impairment. As a consequence, the outcome of patients with atrial fibrillation who suffer a stroke is worse, as they show a greater degree of disability. The risk of stroke in … *Corresponding author. Tel: +39 02 619112850, Fax: +39 02 619112850, Email: stramba_badiale{at}auxologico.it

Dynamics factors preceding the initiation of atrial fibrillation in humans

Summary Several mechanisms may explain AF in animal models, but the extent to which they operatein human paroxysmal or persistent AF is undefined. AF may result from reentrant or focalmechanisms yet, in either case, the mechanisms enabling single beats or regular tachycardiasto cause fibrillation with regional organization are unclear. These questions are increasinglyrelevant as advances in imaging, mapping and ablation allow us to translate these concepts tothe bedside for improved therapies for AF. Acknowledgements This work was supported, in part, by grants from the National Institutes of Health (K23 HL70529, R01 HL83359) andDoris Duke Clinical Foundation to SMN, and by a grant from the American College of Cardiology Foundation/Merckto DEK. ReferencesTSC1 1. Calkins H, Brugada J, Packer D, et al. HRS/EHRA/ECAS expert Consensus Statement on catheter andsurgical ablation of atrial fibrillation: recommendations for personnel, policy, procedures and follow-up. A report of the Heart Rhythm Society (HRS) Task Force on catheter and surgical ablation of atrialfibrillation.European Heart Rhythm Association (EHRA); European Cardiac Arrhythmia Scoiety(ECAS); American College of Cardiology (ACC); American Heart Association (AHA); Society ofThoracic Surgeons (STS). Heart Rhythm 2007;4:816–861. [PubMed: 17556213]2. Haissaguerre M, Jais P, Shah DC, et al. Spontaneous Initiation of Atrial Fibrillation by Ectopic BeatsOriginating in the Pulmonary Veins. N Engl J Med 1998;339:659–666. [PubMed: 9725923]3. Scherlag BJ, Nakagawa H, Jackman WM, et al. Electrical Stimulation to Identify Neural Elements onthe Heart: Their Role in Atrial Fibrillation. Journal of Interventional Cardiac Electrophysiology2005;13:37–42. [PubMed: 16133854]4. Patterson E, Lazzara R, Szabo B, et al. Sodium-calcium exchange initiated by the Ca2+ transient: anarrhythmia trigger within pulmonary veins. J Am Coll Cardiol 2006;47:1196–1206. [PubMed:16545652]5. Arentz T, Haegeli L, Sanders P, et al. High-density mapping of spontaneous pulmonary vein activityinitiating atrial fibrillation in humans. J Cardiovasc Electrophys 2007;18:31–38.6. Verma A, Saliba W, Lakkireddy D, et al. Vagal responses induced by endocardial left atrial autonomicganglion stimulation before and after pulmonary vein antrum isolation for atrial fibrillation. HeartRhythm 2007;4:1177–1182. [PubMed: 17765618]

Adrenergic regulation of a key cardiac potassium channel can contribute to atrial fibrillation: evidence from an IKs transgenic mouse

Inherited gain-of-function mutations of genes coding for subunits of the heart slow potassium (I Ks) channel can cause familial atrial fibrillation (AF). Here we consider a potentially more prevalent mechanism and hypothesize that beta-adrenergic receptor (beta-AR)-mediated regulation of the I Ks channel, a natural gain-of-function pathway, can also lead to AF. Using a transgenic I Ks channel mouse model, we studied the role of the channel and its regulation by beta-AR stimulation on atrial arrhythmias. In vivo administration of isoprenaline (isoproterenol) predisposes I Ks channel transgenic mice but not wild-type (WT) littermates that lack I Ks to prolonged atrial arrhythmias. Patch-clamp analysis demonstrated expression and isoprenaline-mediated regulation of I Ks in atrial myocytes from transgenic but not WT littermates. Furthermore, computational modelling revealed that beta-AR stimulation-dependent accumulation of open I Ks channels accounts for the pro-arrhythmic substrate. Our results provide evidence that beta-AR-regulated I Ks channels can play a role in AF and imply that specific I Ks deregulation, perhaps through disruption of the I Ks macromolecular complex necessary for beta-AR-mediated I Ks channel regulation, may be a novel therapeutic strategy for treating this most common arrhythmia.

Newer Antiarrhythmic Agents for Atrial Fibrillation: Shall we Eventually do away with Proarrhythmia?

Despite advances in drug therapy for the treatment of atrial fibrillation (AF), there continues to be a need for antiarrhythmic agents that have improved safety and efficacy profile. Unfortunately, drugs that block the potassium channels or are multichannel blockers, although they may be effective antiarrhythmics, they delay repolarization and thus they confer a proarrhythmic effect by inducing torsade de pointes, a potentially lethal ventricular arrhythmia. Most newer antiarrhythmic drugs are potassium channel blockers and this limits their usefulness. A less toxic agent compared to amiodarone, the noniodinated analogue of amiodarone (dronedarone) is being investigated; however, it appears already unsafe in patients with heart failure. Future antiarrhythmic agents will probably be atrial-selective blocking agents without affecting repolarization in the ventricular myocardium and thus avoid ventricular proarrhythmia with its attendant life-threatening consequences. I N T R O D U C T I O N Despite advances in drug therapy for the treatment of atrial fibrillation (AF), there continues to be a need for antiarrhythmic agents that have improved safety and efficacy profile. The wavelength in the atrium plays a critical role in AF. The two fundamental mechanisms of antiarrhythmic drugs in terminating AF include slowing of conduction and lengthening of repolarization and refractoriness. In the wake of the CAST trial demonstrating the proarrhythmic properties of agents with selectivity for sodium channels, when used as antiarrhythmic drugs in patients with significant underlying structural heart disease, attention switched to drugs inhibiting potassium channels. They terminate and/or prevent AF by lengthening action potential duration and the effective refractory period. Unfortunately, drugs that delay repolarization can induce polymorphic ventricular tachycardia in the form of torsade de pointes, a potentially lethal proarrhythmic effect. RevIew 2 Department of Cardiology, Evagelismos General Hospital of Athens, Athens, Greece HOSPITAL CHRONICLES 2008, 3(1): 25–28 Correspondence to: Anthony Sideris, MD 2nd Department of Cardiology Evagelismos Hospital Athens, Greece E-mail: asideris@hol.gr Key wORDS: antiarrhythmic agents; atrial fibrillation; proarrhythmia; torsade de pointes; atrial selective

Atrial tachycardia induces remodelling of muscarinic receptors and their coupled potassium currents in canine left atrial and pulmonary vein cardiomyocytes

Both parasympathetic tone and atrial tachycardia (AT) remodelling of ion channels play important roles in atrial fibrillation (AF) pathophysiology. Different muscarinic cholinergic receptor (mAChR) subtypes (M2, M3, M4) in atrial cardiomyocytes are coupled to distinct K+-currents (called IKM2, IKM3, IKM4, respectively). Pulmonary veins (PVs) are important in AF and differential cholinergic current responses are a potential underlying mechanism. This study investigated AT-induced remodelling of mAChR subtypes and K+-currents in left-atrial (LA) and PV cardiomyocytes. Receptor expression was assayed by western blot. IKM2, IKM3 and IKM4 were recorded with whole-cell patch-clamp in LA and PV cardiomyocytes of nonpaced control dogs and dogs after 7 days of AT-pacing (400 bpm). Current densities of IKM2, IKM3 and IKM4 were significantly reduced by AT-pacing in LA and PV cardiomyocytes. PV cardiomyocyte current-voltage relations were similar to LA for all three cholinergic currents, both in control and AT remodelling. Membrane-protein expression levels corresponding to M2, M3 and M4 subtypes were decreased significantly (by about 50%) after AT pacing. Agonist concentration-response relations for all three currents were unaffected by AT pacing. AT downregulated all three mAChR-coupled K+-current subtypes, along with corresponding mAChR protein expression. These changes in cholinergic receptor-coupled function may play a role in AF pathophysiology. Cholinergic receptor-coupled K+-currents in PV cardiomyocytes were similar to those in LA under control and AT-pacing conditions, suggesting that differential cholinergic current properties do not explain the role of PVs in AF.

Pulmonary vein reentry—Properties and size matter: Insights from a computational analysis

Pulmonary vein (PV) ablation plays an important role in atrial fibrillation (AF) therapy but suffers from a limited mechanistic understanding of PV arrhythmogenicity. Rapid focal activation has been suggested, but some evidence points to underlying reentry. This study was performed to evaluate how the electrophysiological properties of PVs may make them a site for reentry and to analyze specifically the roles of PV dimensions and coupling properties. A computer model designed to efficiently reproduce electrophysiological behaviors was fit to action potentials from canine left atria (LA) and PVs. To assess structural and functional arrhythmogenic determinants, an idealized PV of varying length and circumference was attached to LA tissue, and 5 seconds of activity after extrastimulation were simulated. PV reentrant activity depended critically on vein size and coupling properties. With cumulative removal of transverse and longitudinal connections, sustained (n=23) or nonsustained (n=93) reentries could be observed (687 simulations) for veins 1-3 cm long and 1-2 cm in circumference. The prevalence of sustained reentry increased with PV length (8% for 1 cm vs. 22% and 31% for 2 and 3 cm, respectively; P<.05 for each). The PV circumference did not affect the incidence of sustained reentry (25%, 17%, and 21% for 1-, 1.5-, and 2-cm circumferences; P=NS), but the number of reentrant events increased from 12/201 simulations for PVs with a 1-cm circumference to 48/232 and 56/254 events for PVs with 1.5- and 2-cm circumferences, respectively (P<.05). Sustained reentry cycle lengths were approximately 200-250 ms (16/23), except for the longest PVs. Reentry occurs readily in PVs with realistic properties in the context of specific connection heterogeneities. Reentry properties and incidence depend on PV anisotropy and dimensions but could certainly contribute significantly to PV arrhythmogenesis.

The fibrosis and atrial fibrillation: Is the transforming growth factor-β 1 a candidate etiology of atrial fibrillation

Atrial fibrillation (AF) is the most commonly occurring arrhythmia in clinical practice, however, the mechanism of atrial fibrillation is not well explained. It has been considered that myocardial fibrosis plays a role in atrial fibrillation. Within the heart, this fibrosis is thought to be mediated by transforming growth factor-beta 1 (TGF-beta 1), a potent stimulator of collagen-producing cardiac fibroblasts. Recent studies indicate that atrial fibrillation is associated with elevated serum concentrations of TGF-beta 1 and C-terminal propeptide of procollagen type I (a marker of collagen type I synthesis). TGF-beta 1 was not only associated with the presence of atrial fibrillation but may also predict patients at increased risk for future development of atrial fibrillation. Why TGF-beta 1 in atrial fibrillation is high is a puzzling problem. We hypothesized that TGF-beta 1 is a possible cause of atrial fibrillation by initiating fibrosis response. Atrial interstitial fibrosis has been seen in patients with CHF and in animal models of pacing-induced heart failure. It was demonstrated that TGF-beta 1 levels were increased in the atria after the development of congestive heart failure in dogs. In a similar study, mice with increased expression of TGF-beta 1 were prone to atrial fibrillation development as a result of raised levels of atrial fibrosis. If the hypothesis is confirmed, administration of TGF-beta 1 monoclonal antibodies may be used to eliminate the etiology. It will be a new target point to treat atrial fibrillation.