レニン・アンジオテンシン系 (RAS) の抑制は心室性不整脈を減少させると考えられているが, 心房細動 (AF) など心房性不整脈についての効果は未だ明らかでない, そこで今回我々はイヌを用い, 洞調律下, 薬理学的自律神経遮断下にアンジオテンシンII (Ang II) またはAng II1型受容体拮抗薬 (AT1A) を投与してこれらが心房電気生理学的特性に与える影響について検討した.生理学的に十分量のAng IIまたはAT1A投与にもかかわらず心房有効不応期 (AERP) には有意な変化は認められず, 全例で洞調律が維持され, AFを含む心房性不整脈発生や心房受攻性亢進を示唆する所見も認められなかった.RASの変化は生体位の正常心房電気生理学的特性に急性の影響を与えず, 臨床上のAF―次予防という点で, 正常心で急性にRASを抑制する重要性はさほどないものと思われた.

he twin epidemics of modern cardiovascular disease, atrial brillation (AF) and heart failure (HF), present terribly mportant management challenges. When these 2 condiions co-exist, an effective strategy to ameliorate symptoms, imit hospitalization, and improve prognosis is a critical bjective given their prevalence and clinical and economic onsequences (1,2). Although much recent, even remarkble, progress has been made, there remain major clinical ubgroups in which the application of new therapeutic tools s still poorly defined.

article i nfo This review summarizes progress in the fields of cardiac electrophysiology, arrhythmias and sudden death made in the 25-year interval between 1992 and 2016 during which time Cardiovascular Pathology has been published. Organized along clinical lines, it considers the major heart rhythm disorders underlying atrial, atrioventricular and ventricular arrhythmias, and sudden cardiac death. There is a strong focus on the remarkable advances in understanding the genetic basis for cardiac rhythm disturbances and elucidating fundamental mechanisms of abnormal conduction and impulse formation. During this 25-year period, our understanding of how altered tissue structure (classical pathology) contributes to arrhythmias and sudden death has undergone continuous refinementas new insights have beengainedaboutarrhythmiamechanisms and thedynamicinterplay between anatomic substrates and triggers of the major heart rhythm disorders.

Whether the increased atrial fibrillation (AF) risk in metabolic syndrome (MetS) patients is due to the syndrome as a whole or simply the sum of the risks of its individual component parts is still obscure. These two clinical entities share many pathophysiological links and thus distinction between a casual observation and a significant association is difficult. Biomarkers associated with pathogenesis of AF in the context of MetS have the ability to refine future risk prediction. In the present review we identify circulating substances that could be regarded as potential biomarkers for prediction of incident AF, or of cardiovascular events in the setting of AF in patients with MetS. Cardiac myocyte injury and stress markers (troponin and natriuretic peptides), markers of renal function (glomeral filtration rate, cystatin-C), and inflammation markers/mediators (interleukin- 6, CRP) are promising biomarkers of patients with AF and MetS.

We studied the extent and distribution of left atrial (LA) fibrosis on delayed‐enhanced (DE) MRI in a general cardiology population.

We hypothesized that partial cellular uncoupling produced by low concentrations of heptanol increases the vulnerability to inducible atrial fibrillation (AF). The epicardial surface of 12 isolated-perfused canine left atria was optically mapped before and after 1-50 microM heptanol infusion. At baseline, no sustained (>30 s) AF could be induced in any of the 12 tissues. However, after 2 microM heptanol infusion, sustained AF was induced in 9 of 12 tissues (P < 0.001). Heptanol >5 microM caused loss of 1:1 capture during rapid pacing, causing no AF to be induced. AF was initiated by conduction block across the fiber leading to reentry, which broke up after one to two rotations into two to four independent wavelets that sustained the AF. Heptanol at 2 microM had no effect on the cellular action potential duration restitution or on the maximal velocity rate over time of the upstroke. The effects of heptanol were reversible. We conclude that partial cellular uncoupling by heptanol without changing atrial active membrane properties promotes wavebreak, reentry, and AF during rapid pacing.

We devise a methodology to determine an optimal pattern of inputs to synchronize firing patterns of cardiac cells which only requires the ability to measure action potential durations in individual cells. In numerical bidomain simulations, the resulting synchronizing inputs are shown to terminate spiral waves with a higher probability than comparable inputs that do not synchronize the cells as strongly. These results suggest that designing stimuli which promote synchronization in cardiac tissue could improve the success rate of defibrillation, and point towards novel strategies for optimizing antifibrillation pacing.

WRITING COMMITTEE MEMBERS Valentin Fuster, MD, PhD, FACC, FAHA, FESC, Co-Chair; Lars E. Rydén, MD, PhD, FACC, FESC, FAHA, Co-Chair; David S. Cannom, MD, FACC; Harry J. Crijns, MD, FACC, FESC*; Anne B. Curtis, MD, FACC, FAHA; Kenneth A. Ellenbogen, MD, FACC†; Jonathan L. Halperin, MD, FACC, FAHA; Jean-Yves Le Heuzey, MD, FESC; G. Neal Kay, MD, FACC; James E. Lowe, MD, FACC; S. Bertil Olsson, MD, PhD, FESC; Eric N. Prystowsky, MD, FACC; Juan Luis Tamargo, MD, FESC; Samuel Wann, MD, FACC, FESC

Viewpoint Management of Atrial Fibrillation in the Year 2033: New Concepts, Tools, and Applications Leading to Personalized Medicine Anne M. Gillis, MD, FRCPC, FHRS, Andrew D. Krahn, MD, FRCPC, FHRS, Allan C. Skanes, MD, FRCPC, and Stanley Nattel, MD, FRCPC Department of Cardiac Sciences, University of Calgary, Libin Cardiovascular Institute of Alberta, Calgary, Alberta, Canada Division of Cardiology, Vancouver General Hospital, University of British Columbia, Vancouver, British Columbia, Canada Division of Cardiology, University of Western Ontario, London, Ontario, Canada Department of Medicine and Research Centre, Montreal Heart Institute, Universit e de Montr eal, Montreal, Qu ebec, Canada

Understanding of the mechanisms underlying atrial fibrillation (AF) remain limited. However, both persistent and paroxysmal AF likely initiate via the interaction of triggers such as premature atrial beats with 'substrate', that includes static components such as fibrosis and scar, as well as dynamic alterations that may include the rate-response of repolarization and conduction, autonomic modulation and stretch. This article attempts to synthesize concepts for AF initiation from in silico, in vitro and in vivo animal data and human studies and apply them to the spectrum of disease processes that comprise clinical AF. Further investigation is urgently needed to translate these discoveries into effective therapy.

Treatment of atrial fibrillation (AF), the most common arrhythmia in clinical practice, remains challenging. Improved understanding of underlying mechanisms is needed to improve therapy. Functional re-entry is central to AF maintenance. The first detailed, quantitative theory of functional re-entry, the 'leading circle' model, was developed 40 years ago. Subsequently, an alternative paradigm based on 'spiral waves' has evolved. Spiral-wave generators, or 'rotors', have been identified using advanced mapping methods in experimental and clinical AF. A central tool in the analysis of spiral-wave rotors is the phase transformation, allowing for easier visualization of rotors and tracking of 'phase singularity' points at the rotor tip. In contrast to leading circle theory, which is expressed in terms familiar to (and easily understood by) cardiologists, the ideas needed to understand rotors are much more theoretical and harder for clinicians to apply. In this Review, we summarize the basic notions of phase mapping and spiral-wave rotors, and the ways in which rotor sources might be involved in AF maintenance. We discuss competing observations about the role of spatially confined rotors, short-lived rotors clustered at the edge of fibrotic zones, endocardial–epicardial interactive breeder properties and transmural re-entry, as well as studies underway to resolve them. We conclude with consideration of the clinical relevance of the issues discussed and their potential implications for the management of patients with AF.

Tissue size has been considered an important determinant of atrial fibrillation (AF), but recent work has questioned the critical size hypothesis. Here, we use a previously developed mathematical model of the two-dimensional canine atrium with realistic action potential, ionic, and conduction properties to address substrate size effects on the maintenance of fibrillatory activity. Cholinergic AF was simulated at different acetylcholine (ACh) concentrations ([ACh]) and distributions, with substrate area varied 11.1-fold. Automated phase singularity detection was used to facilitate the analysis of arrhythmic activity. The duration of activity induced by a single extrastimulus increased with increasing substrate dimensions. Two general mechanisms underlying activity were observed and were differentially affected by substrate size. For large mean [ACh], single primary rotors anchored in low-[ACh] zones maintained activity and substrate dimensions were not critical. At lower mean [ACh], extensive spiral wave meander prevented the emergence of single stable rotors. Prolonged activity was favored when substrate size permitted a sufficiently large number of simultaneous longer-lasting rotors that extinction of all was unlikely. Thus either single dominant rotor or multiple reentrant spiral generator mechanisms could maintain fibrillatory activity in this model and were differentially dependent on substrate size. These results speak to recent debates about the role in AF of single driver rotors versus multiple reentrant circuit mechanisms by suggesting that either may maintain fibrillatory atrial activity depending on atrial size and electrophysiological properties.

Time for primary review 23 days. Atrial fibrillation (AF) is presently the most common cardiac arrhythmia in clinical practice. Its treatment is inadequate. Maintenance of normal sinus rhythm (SR) is obviously the optimal approach, but is difficult to achieve without drugs that have the potential to cause ventricular proarrhythmia and increase mortality. Non-pharmacological therapy is attractive, but to date has not reached the same level of efficacy as in the treatment of arrhythmias other than AF. In order to improve therapeutic approaches, it is important to understand the detailed pathophysiology of the arrhythmia. A key component to the pathophysiology of any cardiac arrhythmia is the cellular milieu in which it occurs. Changes in ion transport processes, including pumps, channels and exchangers, are central to alterations in action potential properties that govern the occurrence of arrhythmias like AF. Action potential duration (APD) determines the refractory period and is therefore a key determinant of the likelihood of reentry. Maximum Na+-current ( I Na) governs phase 0 upstroke velocity, determining conduction velocity (CV) and contributing to the likelihood of reentry. Delayed and early afterdepolarizations produce abnormal activity that can in themselves produce tachyarrhythmias and can trigger reentrant arrhythmia. This paper reviews these aspects of the cellular electrophysiology of AF, attempting to summarize what is known, what remains to be explored and what this information can teach us about why AF occurs and how to treat it. The identification of the molecular structure of many ion channels involved in cardiac excitability and their functional correlation with native ionic currents have made it possible to study the effects of pathophysiological conditions, like AF, at different levels from genes to ionic currents. The different steps underlying the expression of an ion channel are depicted in Fig. 1 and have recently been reviewed by Roden and … * Corresponding author. Tel.: +49-7071-298-3196; fax: +49-7071-294-121 ralph.bosch{at}uni-tuebingen.de

There is an important association between heart failure and the development of atrial arrhythmias. Although most often associated with atrial fibrillation, there is some evidence to suggest an association between heart failure and other atrial arrhythmias and, in particular, atrial flutter and atrial tachycardia. The mechanisms by which these common atrial arrhythmias may arise in patients with heart failure are discussed.

The renin–angiotensin–aldosterone system (RAAS) is a critical regulator of blood pressure and electrolyte homeostasis. While essential for normal homeostasis, excessive RAAS activation is implicated in the development of hypertension and may underlie the pathophysiology of heart failure (HF). Thus, current AHA/ACC treatment guidelines recommend treatment of heart failure patients with an ACE inhibitor or angiotensin II receptor antagonist and a beta-adrenergic receptor blocker.1 Atrial fibrillation (AF) is the most common arrhythmia and a common comorbidity, occurring frequently in heart failure patients.2 As in heart failure, activation of the RAAS has an important role in the etiology of AF.3 In human AF, tissue angiotensin converting enzyme (ACE) is upregulated, correlating with increased atrial angiotensin II production.4 ACE inhibition has been shown to attenuate atrial structural remodeling (interstitial fibrosis) in a canine rapid ventricular pacing (RVP) model5-7 and to reduce the prevalence of AF in patients with left ventricular dysfunction post-myocardial infarction (MI).8 Other studies in the canine RVP model emphasize the role of fibrosis as an important mediator of increased atrial arrhythmia persistence.5 In the canine RVP-induced heart failure model, AF duration was increased relative to controls both before and following recovery of pacing-induced atrial electrical remodeling. This suggests that tissue fibrosis creates a substrate for increased arrhythmia persistence that is independent of action potential duration. It is interesting to note that, while enalapril attenuated the development of interstitial fibrosis, it had no impact on the atrial effective refractory period, conduction velocity, or wavelength of conduction in the canine rapid ventricular pacing model.6 This suggests that, while angiotensin II may contribute to the development of atrial fibrosis, it is unlikely to have prominent electrophysiologic effects. Another key component of the RAAS axis is the mineralocorticoid aldosterone. Serum aldosterone levels have been reported to be elevated in AF patients, and aldosterone levels

The progressive nature of atrial fibrillation (AF) has been demonstrated in numerous experimental as well as clinical investigations. Electrical remodeling (shortening of atrial refractoriness) develops within the first days of AF and contributes to the increase in stability of the arrhythmia. However, "domestication of AF" must also depend on other mechanisms since the stability of AF continues to increase after electrical remodeling has been completed. Chronic atrial stretch induces activation of numerous signaling pathways leading to cellular hypertrophy, fibroblast proliferation and tissue fibrosis. The resulting electro-anatomical substrate is characterized by increased non-uniform anisotropy and local conduction heterogeneities facilitating reentry in the dilated atria. Atrial fibrosis may lead to disruption of the electrical side-to-side junctions between muscle bundles. This can result in electrical dissociation between neighboring muscle bundles, i.e. they become activated out-of-phase. Recent mapping studies in goats with persistent AF showed that electrical dissociation can not only occur between neighboring muscle bundles but also in the third dimension, i.e. between the epicardial layer and the endocardial bundle network. Such endo-epicardial dissociation will significantly increase the number of wavefronts which can simultaneously be present in the atrial wall. This article reviews data suggesting a role of endo-epicardial dissociation in dilated and fibrillating atria, for the self-perpetuating nature of AF as well as its possible implications for therapeutic interventions.

The past 3 decades have been characterized by an exponential growth in knowledge and advances in the clinical treatment of atrial fibrillation (AF). It is now known that AF genesis requires a vulnerable atrial substrate and that the formation and composition of this substrate may vary depending on comorbid conditions, genetics, sex, and other factors. Population-based studies have identified numerous factors that modify the atrial substrate and increase AF susceptibility. To date, genetic studies have reported 17 independent signals for AF at 14 genomic regions. Studies have established that advanced age, male sex, and European ancestry are prominent AF risk factors. Other modifiable risk factors include sedentary lifestyle, smoking, obesity, diabetes mellitus, obstructive sleep apnea, and elevated blood pressure predispose to AF, and each factor has been shown to induce structural and electric remodeling of the atria. Both heart failure and myocardial infarction increase risk of AF and vice versa creating a feed-forward loop that increases mortality. Other cardiovascular outcomes attributed to AF, including stroke and thromboembolism, are well established, and epidemiology studies have championed therapeutics that mitigate these adverse outcomes. However, the role of anticoagulation for preventing dementia attributed to AF is less established. Our review is a comprehensive examination of the epidemiological data associating unmodifiable and modifiable risk factors for AF and of the pathophysiological evidence supporting the mechanistic link between each risk factor and AF genesis. Our review also critically examines the epidemiological data on clinical outcomes attributed to AF and summarizes current evidence linking each outcome with AF.

The numerous nonmyocytes present within the myocardium may establish electrical connections with myocytes through gap junctions, formed naturally or as a result of a cell therapy. The strength of the coupling and its potential impact on action potential characteristics and conduction are not well understood. This study used computer simulation to investigate the load-induced electrophysiological consequences of the coupling of myocytes with fibroblasts, where the fibroblast resting potential, density, distribution, and coupling strength were varied. Conduction velocity (CV), upstroke velocity, and action potential duration (APD) were analyzed for longitudinal and transverse impulse propagation in a two-dimensional microstructure tissue model, developed to represent a monolayer culture of cardiac cells covered by a layer of fibroblasts. The results show that 1) at weak coupling (<0.25 nS), the myocyte resting potential was elevated, leading to CV up to 5% faster than control; 2) at intermediate coupling, the myocyte resting potential elevation saturated, whereas the current flowing from the myocyte to the fibroblast progressively slowed down both CV and upstroke velocity; 3) at strong couplings (>8 nS), all of the effects saturated; and 4) APD at 90% repolarization was usually prolonged by 0-20 ms (up to 60-80 ms for high fibroblast density and coupling) by the coupling to fibroblasts. The changes in APD depended on the fibroblast resting potential. This complex, coupling-dependent interaction of fibroblast and myocytes also has relevance to the integration of other nonmyocytes in the heart, such as those used in cellular therapies.

The mechanisms underlying atrial fibrillation (AF) remain poorly understood. In some patients, AF initiation often occurs from arrhythmogenic foci arising at muscular sleeves in a pulmonary vein (PV).Either direct radiofrequency ablation of these foci or, more recently, their disconnection from the left atrium by ablation at venous ostia is the basis for curative AF ablation procedures. However, it is likely that, in most cases, the mechanism of AF maintenance is different from that which initiates it. Isolated animal heart experiments suggest that some cases of AF may be maintained by the uninterrupted periodic activity of a small number of discrete reentrant sites (rotors) located in the posterior left atrial (LA) wall, near the PV/LA junction. During sustained AF, such sources activate at an exceedingly high rotation frequency. Thus rotors near the PV/LA junction dominate over any other slower sources that may form elsewhere and act as the drivers for the entire fibrillatory process. High resolution spectral analysis of the spatial distribution of activation frequencies reveals a hierarchy with appreciable frequency gradients across the atria. Here we briefly review our current understanding of the mechanisms and manifestations of AF and discuss the applicability of spectral analysis tools to the study of AF in patients, with the idea of helping to improve the efficacy of ablation therapies. We focus in part on recent clinical studies that provide justification for the combined use of spectral analysis and electroanatomical mapping to systematically correlate the spatial distribution of excitation frequency with cardiac anatomy, to provide mechanistic insight into different types of AF and to facilitate ablation procedures.

The mechanisms by which Na+-channel blocking antiarrhythmic drugs terminate atrial fibrillation (AF) remain unclear. Classical “leading-circle” theory suggests that Na+-channel blockade should, if anything, promote re-entry. We used an ionically-based mathematical model of vagotonic AF to evaluate the effects of applying pure Na+-current (INa) inhibition during sustained arrhythmia. Under control conditions, AF was maintained by 1 or 2 dominant spiral waves, with fibrillatory propagation at critical levels of action potential duration (APD) dispersion. INa inhibition terminated AF increasingly with increasing block, terminating all AF at 65% block. During 1:1 conduction, INa inhibition reduced APD (by 13% at 4 Hz and 60% block), conduction velocity (by 37%), and re-entry wavelength (by 24%). During AF, INa inhibition increased the size of primary rotors and reduced re-entry rate (eg, dominant frequency decreased by 33% at 60% INa inhibition) while decreasing generation of secondary wavelets by wavebreak. Three mechanisms contributed to INa block–induced AF termination in the model: (1) enlargement of the center of rotation beyond the capacity of the computational substrate; (2) decreased anchoring to functional obstacles, increasing meander and extinction at boundaries; and (3) reduction in the number of secondary wavelets that could provide new primary rotors. Optical mapping in isolated sheep hearts confirmed that tetrodotoxin dose-dependently terminates AF while producing effects qualitatively like those of INa inhibition in the mathematical model. We conclude that pure INa inhibition terminates AF, producing activation changes consistent with previous clinical and experimental observations. These results provide insights into previously enigmatic mechanisms of class I antiarrhythmic drug-induced AF termination. The full text of this article is available online at http://circres.ahajournals.org