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Roselli C, Chaffin MD, Weng LC, et al. Multi-ethnic genome-wide association study for atrial fibrillation. Nat Genet 2018; 50:1225. Topic 16402 Version 27.0 https://www.uptodate.com/contents/mechanisms-of-atrial-fibrillation/print 33/45 7/5/23, 10:46 AM Mechanisms of atrial fibrillation - UpToDate GRAPHICS AF mechanisms Overview of mechanisms of AF. Four different positive-feedback loops are proposed as 2 the main driving forces for the atrial remodeling process. Enhanced Ca + loading during AF is believed to underlie most of the cellular proarrhythmic mechanisms (trigger loop). The main process in the electrical loop is an altered contribution of ion channels to the 2 action potential configuration that protects atrial myocytes against excessive Ca + loading. Abbreviation of the action potential facilitates re-entry and thereby promotes AF. In the structural loop, chronic atrial stretch activates numerous signaling cascades that produce alterations of the extracellular matrix and conduction disturbances, also facilitating re-entrant mechanisms. The main changes of the contractile properties of the heart are loss of atrial contractility which increases atrial compliance and the development of a ventricular tachycardiomyopathy, both of which increase stretch in the atrial wall. The circular positive-feedback enhancement of these pathophysiological changes explains the general tendency of AF to become more stable with time. It should be noted that the different loops are interconnected by mechanisms that are part of more than one loop. For example, increased Ca + loading enhances trigger activity 2 (trigger loop) and also results in a change in the ion channel population and activity (electrical loop). Re-entrant mechanisms are promoted by both shortening of refractoriness (electrical loop) as well as by conduction disturbances resulting from https://www.uptodate.com/contents/mechanisms-of-atrial-fibrillation/print 34/45 7/5/23, 10:46 AM Mechanisms of atrial fibrillation - UpToDate tissue fibrosis (structural loop). Like in a system of meshing gear wheels, one loop will drive the other, leading to progression of the arrhythmia. However, the proposed system of gear wheels does not start to move spontaneously. Structural heart diseases, arrhythmias, aging, or inherited diseases are required to initiate movement of one or more of these wheels. When the pathophysiological alterations eventually reach a certain threshold, AF will ensue. Ulrich Schotten, Sander Verheule, Paulus Kirchhof, and Andreas Goette. Pathophysiological Mechanisms of Atrial Fibrillation: A Translational Appraisal. Physiol Rev January 2011 91:265-325 [PRV1/2011]. Reproduced with permission. Copyright 2011 The American Physiological Society. Graphic 63675 Version 5.0 https://www.uptodate.com/contents/mechanisms-of-atrial-fibrillation/print 35/45 7/5/23, 10:46 AM Mechanisms of atrial fibrillation - UpToDate AF remodeling 2+ Mechanisms underlying ATR. Rapid atrial rates increase potentially cytotoxic Ca loading. Autoprotective I changes (I reductions occur via rapidly developing functional Ca,L inactivation) and more slowly developing changes in gene and protein Ca,L expression. Decreased I shortens refractoriness and reduces the wavelength (WL), which allows for smaller and 2+ reduces Ca loading but decreases APD. Diminished APD Ca,L more atrial reentry circuits, thus making AF unlikely to terminate. Atrial tachycardia also increases inward-rectifier currents such as I APD and promotes AF. and I , which further reduces K1 K,ACh,c RP: refractory period; WL: wavelength. Reproduced with permission from: Nattel S, Burstein B, Dobrev D. Atrial Remodeling and Atrial Fibrillation: Mechanisms and Implications. Circ Arrhythm Electrophysiol 2008; 1:62. Copyright 2008 Lippincott Williams & Wilkins. Graphic 51670 Version 8.0 https://www.uptodate.com/contents/mechanisms-of-atrial-fibrillation/print 36/45 7/5/23, 10:46 AM Mechanisms of atrial fibrillation - UpToDate Signal averaged electrocardiogram predicts atrial fibrillation after coronary artery bypass graft (CABG) surgery The incidence of atrial fibrillation (AF) after coronary artery bypass graft surgery is directly related to the duration of the P wave on a signal averaged ECG. Data from Zaman AG, Archbold RA, Helft G, et al. Circulation 2000; 101:1403. Graphic 60431 Version 4.0 https://www.uptodate.com/contents/mechanisms-of-atrial-fibrillation/print 37/45 7/5/23, 10:46 AM Mechanisms of atrial fibrillation - UpToDate Atrial activation in atrial fibrillation Spread of activation through right (upper half) and left (lower half) atria during stable atrial fibrillation. These activation maps show propagation of impulse through the atria, as visualized by color isochrones of 10 milliseconds (ms). White arrows indicate general direction of wavelets. Asterisks represent sites of impulse fragmentation and development of new wavelets. Redrawn from Allissie MA, Lammers WJEP, Bonke FIM, et al. In: Cardiac Arrhythmias, Grane &Stratton, Orlando, 1985, p. 265. Graphic 59310 Version 2.0 https://www.uptodate.com/contents/mechanisms-of-atrial-fibrillation/print 38/45 7/5/23, 10:46 AM Mechanisms of atrial fibrillation - UpToDate Two types of reentry in atrial fibrillation The isochronal activation maps demonstrate two types of reentry in atrial fibrillation. Map A shows random reentry with three simultaneous wavefronts (black arrows) activating most of the recording area. Map B also shows three simultaneous wavefronts, but they are coming from different directions than those in map A. Maps C and D show two consecutive cycles of complete reentry. The wave of activation (black arrow) spreads clockwise in a circular fashion around a line of unexcited tissue. Reproduced with permission from Holm M, Johansson R, Brandt J, et al. Eur Heart J 1997; 18:290. Graphic 73931 Version 2.0 https://www.uptodate.com/contents/mechanisms-of-atrial-fibrillation/print 39/45 7/5/23, 10:46 AM Mechanisms of atrial fibrillation - UpToDate Atrial electogram morphology in atrial fibrillation The morphology of unipolar electrograms recorded during atrial fibrillation reflect different patterns of conduction, as demonstrated by the isochrone maps. Black arrows indicate the direction of activation. Single potentials are indicative of rapid uniform conduction. Short doubles result from collision of the wavefronts along a line of collision (map A). Long doubles are due to conduction block (Map B). Fragmented electrograms refect multiple discrete deflections that may result from impulse conduction around a pivotal point (map C) or from slow or delayed conduction (map D). Reproduced with permission from Konings KTS, Smeets JLRM, Penn OC, et al. Circulation 1997; 95:1231. Graphic 52152 Version 2.0 https://www.uptodate.com/contents/mechanisms-of-atrial-fibrillation/print 40/45 7/5/23, 10:46 AM Mechanisms of atrial fibrillation - UpToDate Schema of normal impulse conduction in the heart The sinoatrial node (SAN) generates an action potential that is conducted through the right and left atria, resulting in atrial contraction. The impulse is then conducted through the atrioventricular node (AVN), activating the ventricular myocardium, resulting in contraction of the right and left ventricle. SVC: superior vena cava; IVC: inferior vena cava; PV: pulmonary veins; LAA: left atrial appendage; RAA: right atrial appendage. Graphic 57781 Version 2.0 https://www.uptodate.com/contents/mechanisms-of-atrial-fibrillation/print 41/45 7/5/23, 10:46 AM Mechanisms of atrial fibrillation - UpToDate Electrical activity in atrial fibrillation During atrial fibrillation there are multiple reentrant circuits within the right and left atrium, resulting in nonuniform activitation of the atrial myocardium. These circuits, which produce multiple wavelets, often occur around the normal structures of the atrial including the orifices of the superior (SVC) and inferior (IVC) vena cavae, the orifice of the pulmonary veins (PVs), and the right (RAA) and left (LAA) atrial appendages. Graphic 58689 Version 1.0 https://www.uptodate.com/contents/mechanisms-of-atrial-fibrillation/print 42/45 7/5/23, 10:46 AM Mechanisms of atrial fibrillation - UpToDate Noncontact endocardial activation map of focal atrial fibrillation The noncontact endocardial activation map of the half-open left atrium shows that the initial depolarization from an ectopic focus spreads centrifugally from the ostium of the right upper pulmonary vein (RUP), indicated by the white-blue color. LUP: left upper pulmonary vein. Reproduced with permission from Schneider MA, Ndrepepa G, Zrenner B, et al. Noncontact mapping-guided catheter ablation of atrial brillation associated with left atrial ectopy. J Cardiovascular Electrophysiol 2000; 11:475. Copyright 2000 Futura Publishing Company, Inc. Graphic 55997 Version 2.0 https://www.uptodate.com/contents/mechanisms-of-atrial-fibrillation/print 43/45 7/5/23, 10:46 AM Mechanisms of atrial fibrillation - UpToDate Activation patterns in atrial fibrillation Isochronal activation maps obtained from the right atrial free wall during atrial fibrillation show four distinct patterns of myocardial activation, indicated by black arrows. Activation from a localizable site which spreads in all directions away from the site is termed focal atrial activation (upper left). Type I activation is a single broad wavefront that propagates without conduction delay (upper right). Type II activation is a single wavefront that is associated with conduction slowing or block, or with two wavefronts (lower left). Type III activation results from the presence of three or more wave fronts associated with areas of slow and blocked conduction (lower right). Reproduced with permission from Holm M, Johansson R, Brandt J, et al. Eur Heart J 1997; 18:290. Graphic 66498 Version 2.0 https://www.uptodate.com/contents/mechanisms-of-atrial-fibrillation/print 44/45 7/5/23, 10:46 AM Mechanisms of atrial fibrillation - UpToDate Contributor Disclosures Brian Olshansky, MD Other Financial Interest: AstraZeneca [Member of the DSMB for the DIALYZE trial]; Medtelligence [Cardiovascular disease]. All of the relevant financial relationships listed have been mitigated. Rishi Arora, MD No relevant financial relationship(s) with ineligible companies to disclose. Bradley P Knight, MD, FACC Grant/Research/Clinical Trial Support: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; MDT [Electrophysiology]; Philips [Electrophysiology]. Consultant/Advisory Boards: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; CVRx [Heart failure]; MDT [Electrophysiology]; Philips [Electrophysiology]; Sanofi [Arrhythmias]. Speaker's Bureau: Abbott [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Transeptal catheterization]; BSCI [Electrophysiology]; MDT [Electrophysiology]. All of the relevant financial relationships listed have been mitigated. Hugh Calkins, MD Grant/Research/Clinical Trial Support: Adagio Medical [Atrial fibrillation]; Boston Scientific [ARVC]; Farapulse [Atrial fibrillation]; Medtronic [Atrial fibrillation]. Consultant/Advisory Boards: Abbott [Atrial fibrillation]; Atricure [Atrial fibrillation]; Biosense Webster [Catheter ablation]; Boston Scientific [ARVC and atrial fibrillation]; Medtronic [Atrial fibrillation]; Sanofi [Atrial fibrillation]. Other Financial Interest: Atricure [Lecture honoraria]; Biosense Webster [Lecture honoraria]; Boston Scientific [Lecture honoraria]; Medtronic [Lecture honoraria]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. 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