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Pathophysiology of Paroxysmal and Persistent Atrial Fibrillation: Rotors, Foci and Fibrosis
Accepted Manuscript Title: Pathophysiology of Paroxysmal and Persistent Atrial Fibrillation: Rotors, Foci and Fibrosis Authors: Dennis H. Lau MBBS, PhD, Dominik Linz, Ulrich Schotten, Rajiv Mahajan, Prashanthan Sanders MBBS, PhD, Jonathan M. Kalman MBBS, PhD PII: DOI: Reference:
S1443-9506(17)30483-3 http://dx.doi.org/doi:10.1016/j.hlc.2017.05.119 HLC 2389
To appear in: Please cite this article as: Lau Dennis H, Linz Dominik, Schotten Ulrich, Mahajan Rajiv, Sanders Prashanthan, Kalman Jonathan M.Pathophysiology of Paroxysmal and Persistent Atrial Fibrillation: Rotors, Foci and Fibrosis.Heart, Lung and Circulation http://dx.doi.org/10.1016/j.hlc.2017.05.119 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Pathophysiology of Paroxysmal and Persistent Atrial Fibrillation: Rotors, Foci and Fibrosis
Dennis H. Lau, MBBS, PhDa*, Dominik Linz,
ab,,
Ulrich Schotten, c, Rajiv Mahajan ,
Prashanthan Sanders, MBBS, PhDa, Jonathan M. Kalman, MBBS, PhDd
aCentre
for Heart Rhythm Disorders, South Australian Health and Medical Research Institute, University of Adelaide and Royal Adelaide Hospital, Adelaide, SA, Australia bDepartment of Cardiology, University Hospital of Saarland, Homburg/Saar, Germany cDepartment of Physiology, Maastricht University, Cardiovascular Research Institute Maastricht (CARIM), The Netherlands dDepartment of Cardiology, Royal Melbourne Hospital and Department of Medicine, The University of Melbourne, Melbourne, Vic, Australia *Corresponding author at: Centre for Heart Rhythm Disorders, Department of Cardiology, Royal Adelaide Hospital, Adelaide, 5000, AUSTRALIATel: +61882222723; Facsimile: +61882222722; Email: [email protected]
Abstract The current classification of atrial fibrillation (AF) is based mainly on the clinical presentations of the arthythmia, for example, whether it is paroxysmal or persistent; however, this may not sufficiently reflect the underlying severity of atrial disease. Novel electro-anatomical mapping studies and imaging technology, such as late gadolinium-enhanced MRI (LGE-MRI) could play a major role in guiding therapy, beyond simple clinical classification, by enabling individual patient evaluation of arrhythmic mechanisms such as rotational (“rotors”) and ectopic focal (“foci”) activations, and of the degree of atrial fibrosis. For example, in patients undergoing catheter ablation, increased LGE-MRI detected atrial fibrosis has been linked to higher AF recurrence. Keywords: Atrial fibrillation, Atrial fibrosis, Rotors, ectopic foci, Mapping studies, Imaging, atrial fibrosis
Introduction Research over the last several decades has led to significant advances in our understanding of the mechanisms underlying the initiation and maintenance of atrial fibrillation (AF). The
breadth and depth of these bench and bedside discoveries further highlights the complex pathophysiological basis of this arrhythmia. This further understanding can be broadly classified into ‘triggers’ and ‘substrate’ (Figure 1). In brief, alterations in atrial refractoriness, changes in cellular calcium homeostasis/handling, autonomic activation and delayed or early after-depolarisations can contribute to triggered activity or ectopic focal discharges that initiate AF. Further, structural abnormalities such as atrial dilatation/stretch, fibrosis, fatty infiltration and inflammation can contribute to local conduction disturbances and conduction block that are known to facilitate re-entry and AF sustenance. Several recent reviews provide in-depth coverage of the various fundamental mechanistic concepts that are beyond the scope of this review.[1-3] This review is focussed on the pathophysiological aspects of AF pertaining to atrial fibrosis and the two main arrhythmic mechanisms of rotational and ectopic focal activations that have emerged from recent mapping studies. Further, we undertake to delineate the differences of these two mechanisms in the paroxysmal (PAF) and persistent AF (PersAF) populations.
Clinical Classification of Atrial Fibrillation Atrial fibrillation is a progressive disease with many patients experiencing initial short and infrequent episodes (Figure 2, top left panel) to longer and more frequent ones (Figure 2, top right panel) while some may remain in permanent or chronic AF. However, AF will remain paroxysmal in a small proportion of patients (2–3%) or spontaneously regress from persistent to paroxysmal AF in some.[4, 5] The conventional method of AF classification is solely based on the clinical presentation in terms of episode duration and how it terminates. Current classification includes: newly diagnosed AF, PAF, PersAF, long-standing PersAF and permanent AF. Sometimes an overlap in presentation patterns will render this classification
difficult until a more predominant picture evolves. When correlated to AF recorded by an implantable device, current clinical AF classification has been shown to poorly reflect the temporal persistence of the arrhythmia.[6] In addition, patients with AF may be asymptomatic, rendering the classification irrelevant. Another major limitation of this classification is the lack of regard for the severity of the underlying atrial substrate or arrhythmia burden. As shown in Figure 2, the conventional AF classification would have failed to recognise the higher AF burden in the PAF patient (bottom left panel: AF burden: 37%) than the PersAF patient (bottom right panel: AF burden: 27%). Unfortunately, the distinction between PAF and PersAF has been used in most clinical trials and, therefore, still forms the basis of guideline recommendations.
The PersAF patients are more likely to have a higher number of concomitant AF risk factors and be exposed to longer durations of atrial remodelling (Figure 1).[7] In general, electroanatomical mapping studies have demonstrated the following atrial electro-structural differences in PersAF patients when compared to those with PAF: larger left atrial dimensions, lower atrial voltage, slower atrial conduction velocity, greater degree of electrogram fractionation and shorter AF cycle length.[8, 9] Several mapping studies have also demonstrated higher AF complexity in those with more persistent form of the arrhythmia to include higher number and narrower activation wavefronts, slower conduction, higher number of breakthrough waves, electrical dissociation, fractionation index and higher dominant frequencies.[10-13] However, the above is not always true given the variations in substrate complexity that may not be reflected in the conventional AF classification. While keeping the above limitations in mind, we aim to delineate the pathophysiological differences in fibrosis, rotors and foci between PAF and PersAF.
Atrial Remodelling and Fibrosis Atrial fibrosis has been recognised as a key structural change that underpins atrial conduction abnormalities and the perpetuation of AF by favouring re-entry, transmural conduction, preferential conduction and anchoring of AF drivers. Increased atrial fibrosis has been consistently demonstrated from histological analysis in different AF substrates using PicroSirius Red or Masson’s trichrome staining: sheep and rats with hypertension (induced by "one-kidney, one-clip” operation for up to 15 weeks, chronic hypertension following maternal exposure to corticosteroids for around 4 years and spontaneously hypertensive rats at 12–15 months old);[14-17] dogs or sheep with heart failure (induced by rapid ventricular pacing for 5 weeks and doxorubicin-induced non-ischaemic cardiomyopathy for 14 weeks);[18, 19] rats with type 2 diabetes (Zucker diabetic fatty rats, 38 weeks);[20] sheep with obesity (diet induced for up to 72 weeks); [21, 22] and, rats with simulated sleep apnoea (for 4 weeks).[23] Clinical observations suggest that certain combinations of risk factors may lead to more pronounced arrhythmogenic atrial remodelling, with AF progression seen more frequently in those with greater number of risk factors.[7] However, animal models investigating the effect of concomitant risk factors remain sparse.
Increased endomysial fibrosis (that is, increased transverse separation of atrial myocytes within bundles) and subsequent increased myocyte-myocyte distances in the atrial myocardium, as well as between the epicardial layer and the endocardial bundle network due to enhanced extracellular matrix formation, have been seen in experimental models of AF to result in more complex fibrillatory conduction and endo-epicardial electrical dissociation.[24, 25] Further, fat cell infiltration from the epicardium into the myocardium of
obese atria is a likely promoter of re-entry as this increases inert conduction barriers and potentiates atrial fibrosis.[22, 26] The above structural changes can result in altered connexin expression as well as spatial distribution from the polar to the lateral cell membrane of cardiomyocytes that are known to contribute to electrical disruption and AF perpetuation in both human and animal studies.[27, 28] All these changes can result in anisotropic conduction and increased three-dimensional (3D) functional surface available for fibrillation waves to coexist, and additional anchors that stabilise re-entrant fibrillatory activations.[29, 30] Such changes are more severe with the transition to more persistent forms of AF. For example, an increase in endomysial fibrosis, particularly in the outer millimetre of the atria, leads to a loss of continuity in the epicardial layer, and more complex fibrillatory conduction with longer duration of AF.[24] In addition, a 3D AF substrate has been documented in more persistent forms of the arrhythmia with rearrangement of atrial bundle architecture towards more perpendicular orientation of epicardial to endocardial bundles and increased endo-epicardial electrical dissociations.[30]
In humans, structural remodelling can be quantified and further characterised by electroanatomic mapping whereby increased fractionation of local atrial electrograms and areas of low voltage have been demonstrated in patients with chronic systemic hypertension,[31] long-term obstructive sleep apnoea,[32] and congestive heart failure.[33] Low-voltage areas (<0.5 mV) in the left atrium have been associated with endocardial scar and/or structural defects.[34, 35] Complex fractionated atrial electrograms (CFAEs) are defined as low voltage (≤0.15 mV) multiple potential signals with a very short cycle length (≤120 ms). CFAEs may occur at areas of diseased myocardium where the intercellular connectivity is poor, commonly because of fibrosis, slowed conduction or along a line of block.[36] Patients with
persistent AF have significantly lower LA voltage compared with patients with paroxysmal AF, even after adjustment for differences in indexed LA volume.[37] Another strategy to determine atrial tissue fibrosis is the use of late gadolinium-enhanced MRI (LGE-MRI), although this technique requires further refinement of imaging quality as well as analytical algorithms. The degree of atrial fibrosis detected by LGE-MRI has been shown to be higher in patients with PersAF as compared to PAF and in patients with more concomitant AF risk factors.[38] Additionally, novel high resolution mapping, imaging and modelling approaches in human PersAF demonstrated that intermittent and spatially unstable drivers anchor to structural heterogeneities and are preferentially clustered at the borders of fibrotic atrial regions.[39] Electro-anatomical mapping as well as LGE-MRI could play a major role in improved delineation of the underlying atrial substrate beyond the clinical classification of the arrhythmia to guide therapy. In patients undergoing catheter ablation, increased LGEMRI detected atrial fibrosis has been shown to be independently associated with higher AF recurrence.[40] Several studies have demonstrated improved AF ablation outcomes when additional targeting of areas with CFAEs and low atrial voltage were performed in select patient cohorts.[41, 42] Further prospective randomised clinical studies are necessary to clarify the role of substrate-based AF ablation in comparison to established strategies.
Rotors and Foci: Insights From Mapping Studies Recent advances in AF mapping to facilitate a ‘panoramic’ view of the electrical activations in the atria have identified two arrhythmic mechanisms of interest, namely, rotational (“rotors”) and ectopic focal (“foci”) activations as drivers of the arrhythmia. In brief, the endocardial contact mapping technique is known as focal impulse and rotor mapping (FIRM), which is facilitated by a 64-pole Basket catheter (Figure 3A) together with phase-
based signal processing.[43] The body surface potentials mapping technique utilises an inverse-solution electrocardiographic imaging (ECGI) system that consists of a non-invasive array of 252 body surface electrodes to derive virtual potentials on the epicardial atrial surface using thoracic computed tomography for bi-atrial geometric localisation followed by additional signal processing of wavelet transform and phase mapping (Figure 3B). Figure 3C and 3D depict examples of rotors in the left atrium detected by the FIRM and ECGI techniques respectively.
Both mapping techniques detected three to four rotors and ectopic foci in most AF patients with more sources seen in the left than right atrium (Figure 2, top panel).[44, 45] Notably, the FIRM basket-type technique yielded a higher proportion of rotors that lasted for thousands of cycles while the ECGI technique reported rotors that are transient and of several cycles only. The discrepancy between techniques can be due to the differences in the phase mapping algorithms used which remain proprietary and undisclosed. Several technical challenges in rotor detection have since been identified, including the need to consider electrode density, electrogram characteristics, and time-domain activation sequence when using the phase mapping algorithm.[46, 47] Activation mapping using a 128electrode epicardial plaque and a smaller field of field in long-lasting PersAF patients, suggests rotors to be transient with a median of three rotations.[48, 49] While data from the FIRM technique showed no significant differences in the electrophysiological characteristics of rotors and foci between PAF and PersAF patients, the ECGI data showed increased complexity of these drivers with prolonged AF duration.[50] Specifically, there were increased numbers of rotors and ectopic foci, increased number of regions with these AF drivers and extrapulmonary drivers, such as from the infero-posterior left atrium.[50]
Using the FIRM technique to guide additional ablation of rotors and focal sources to conventional wide area circumferential pulmonary vein isolation alone, Narayan and colleagues have demonstrated superior three-year outcome in an early report.[51] However, subsequent series on FIRM guided ablation have shown contradicting results on its efficacy while several randomised trials remain underway.[52-54] Further, Haissaguerre and co-workers used ECGI-guided ablation of rotors and focal sources to achieve similar success rates as conventional pulmonary vein and electrogram guided technique, albeit with shorter radiofrequency ablation time.[44] Results from this group demonstrate lower AF termination rate and shorter AF cycle length in those with longer duration of AF, suggesting a greater degree of electrical remodelling.[44, 50] Further advancements in mapping technologies along with our interpretation of these electrophysiological drivers of AF will be necessary to guide more mechanistic based therapies to improve outcomes for this complex arrhythmia. Additionally, standardisation of electrograms analysis with consensus on definitions for rotors, re-entry, fibrillation waves, conduction block and other phenomena is urgently needed for more meaningful analysis of the basic mechanisms of AF and to facilitate comparisons of different mapping techniques or algorithms.
Reversibility of the Atrial Remodelling Process and the Progression of AF Atrial fibrillation is a progressive disease that can be due to inadequately treated or unrecognised risk factors. For example, subclinical hypertension or aortic stiffness, alcohol excess and obstructive sleep apnoea may not be apparent without specific, targeted clinical attention.[55] Fortunately, the atrial remodelling is partially reversible when the underlying disease is treated. Blood pressure reduction after renal denervation is associated with
improvements in regional and global atrial conduction, and reduction in ventricular mass and fibrosis.[56, 57] Structured physician-directed risk factor and weight management programs have been shown to reduce AF burden and symptoms as well as improved sinus rhythm maintenance following catheter ablation.[58-60] Further, reverse atrial remodelling and reduced AF burden were also seen with improved cardiorespiratory fitness and aerobic interval training.[61, 62] Further studies are needed to determine if pharmacological upstream therapy targeting fibrosis, inflammation and the renin-angiotensin-aldosterone system may extend the benefits of treating the risk factors to modify the underlying atrial substrate.
Conclusions The current classification of AF is mainly based on the clinical presentation of the arrhythmia that may not reflect the underlying severity of the atrial disease. Novel mapping and imaging technologies to evaluate rotors, foci and fibrosis may help to improve AF characterisation and direct individualised mechanistic-based treatment of this complex arrhythmia.
Disclosures Dr Lau reports having received lecture and/or consulting fees from St Jude Medical and Boehringer Ingelheim. Dr Linz reports having received lecture and/or consulting fees from LivaNova, Pfizer, Sanofi Aventis, Boehringer Ingelheim and Medtronic. Dr. Schotten is cofounder and shareholder of YourRhythmics BV and received honoraria from the Università della Svizzera Italiana (USI, Switzerland), Universities of Utah and California (USA), Roche Diagnostics (Switzerland), Bayer Healthcare (Germany). Dr Schotten reports having received research grants from The Netherlands Heart Foundation, the European Union, Roche Diagnostics and Medtronic. Dr Mahajan reports having received lecture and/or consulting fees from St Jude Medical and Medtronic. Dr Mahajan reports having received research funding from Medtronic and St Jude Medical. Dr Sanders reports having served on the
advisory board of Biosense-Webster, Medtronic, and St Jude Medical. Dr Sanders reports having received lecture and/or consulting fees from Biosense-Webster, Medtronic, and St Jude Medical. Dr Sanders reports having received research funding from Medtronic, St Jude Medical, Boston Scientific, Biotronik and LivaNova.
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[62] Malmo V, Nes BM, Amundsen BH, Tjonna AE, Stoylen A, Rossvoll O, et al. Aerobic Interval Training Reduces the Burden of Atrial Fibrillation in the Short Term: A Randomized Trial. Circulation. 2016;133:466-73.
FIGURE LEGENDS: Figure 1: Interaction between different mechanisms underlying the initiation and maintenance of AF.
The mechanisms can be broadly classified into ‘triggers’ and ‘substrate’. Triggers are mainly represented by ectopic discharges originating in the pulmonary veins due to changes in calcium handling, autonomic activation, and triggered activity involving early afterdepolarisations and delayed after-depolarisations. These ectopic discharges can initiate AF by premature atrial electrical activations. Besides this, a substrate for AF is necessary to maintain the arrhythmia. The substrate is characterised by a structural remodelling process in the atrium (fibrosis, inflammation, fatty infiltration, etc.) and leads to local conduction disturbances and conduction block increasing the risk of re-entry circuits. The number of concomitant risk factors as well as the duration of the arrhythmia contribute to the progression of the atrial arrhythmogenic substrate which determines clinical AF burden. Treatment of modifiable risk factors like hypertension, heart failure, obesity or sleep apnoea can result in a regression of the substrate. Atrial fibrillation itself can further perpetuate the occurrence of triggers and the progression of the AF substrate.
Figure 2: Different representative atrial fibrillation (AF) histograms during 30 days are shown in patients with paroxysmal (PAF, left column) and persistent AF (PersAF, right column). Black bars represent daily percentage of time in AF. Additionally, AF-burden is indicated as percentage of recorded time in AF. Top left panel: Short self-terminating AF episodes (PAF, AF burden 20%). Top right panel: More sustained AF episodes requiring electrical cardioversions (PersAF, AF burden 53%). Of note, the conventional AF
classification of PAF and PersAF fails to recognise the higher AF burden in the PAF patient (bottom left panel, AF burden 37%) than in the PersAF patient (bottom right panel, AF burden 27%).
Figure 3: The table shows the fundamental electrophysiological characteristics of rotors and foci seen with the 2 different novel mapping techniques: FIRM using basket type mapping catheter (panel A)[45] vs. ECGI using 252-electrode vest (panel B)[44]. Panel C shows two consecutive clockwise rotors in the left atrium mapped using the FIRM technique. Panel D shows two consecutive counter-clockwise rotors near the right pulmonary veins mapped using the ECGI technique. Panels A-D are used with permission from Narayan et al [43] and Haissaguerre et al [44].
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S1443-9506(17)30483-3 http://dx.doi.org/doi:10.1016/j.hlc.2017.05.119 HLC 2389
To appear in: Please cite this article as: Lau Dennis H, Linz Dominik, Schotten Ulrich, Mahajan Rajiv, Sanders Prashanthan, Kalman Jonathan M.Pathophysiology of Paroxysmal and Persistent Atrial Fibrillation: Rotors, Foci and Fibrosis.Heart, Lung and Circulation http://dx.doi.org/10.1016/j.hlc.2017.05.119 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Pathophysiology of Paroxysmal and Persistent Atrial Fibrillation: Rotors, Foci and Fibrosis
Dennis H. Lau, MBBS, PhDa*, Dominik Linz,
ab,,
Ulrich Schotten, c, Rajiv Mahajan ,
Prashanthan Sanders, MBBS, PhDa, Jonathan M. Kalman, MBBS, PhDd
aCentre
for Heart Rhythm Disorders, South Australian Health and Medical Research Institute, University of Adelaide and Royal Adelaide Hospital, Adelaide, SA, Australia bDepartment of Cardiology, University Hospital of Saarland, Homburg/Saar, Germany cDepartment of Physiology, Maastricht University, Cardiovascular Research Institute Maastricht (CARIM), The Netherlands dDepartment of Cardiology, Royal Melbourne Hospital and Department of Medicine, The University of Melbourne, Melbourne, Vic, Australia *Corresponding author at: Centre for Heart Rhythm Disorders, Department of Cardiology, Royal Adelaide Hospital, Adelaide, 5000, AUSTRALIATel: +61882222723; Facsimile: +61882222722; Email: [email protected]
Abstract The current classification of atrial fibrillation (AF) is based mainly on the clinical presentations of the arthythmia, for example, whether it is paroxysmal or persistent; however, this may not sufficiently reflect the underlying severity of atrial disease. Novel electro-anatomical mapping studies and imaging technology, such as late gadolinium-enhanced MRI (LGE-MRI) could play a major role in guiding therapy, beyond simple clinical classification, by enabling individual patient evaluation of arrhythmic mechanisms such as rotational (“rotors”) and ectopic focal (“foci”) activations, and of the degree of atrial fibrosis. For example, in patients undergoing catheter ablation, increased LGE-MRI detected atrial fibrosis has been linked to higher AF recurrence. Keywords: Atrial fibrillation, Atrial fibrosis, Rotors, ectopic foci, Mapping studies, Imaging, atrial fibrosis
Introduction Research over the last several decades has led to significant advances in our understanding of the mechanisms underlying the initiation and maintenance of atrial fibrillation (AF). The
breadth and depth of these bench and bedside discoveries further highlights the complex pathophysiological basis of this arrhythmia. This further understanding can be broadly classified into ‘triggers’ and ‘substrate’ (Figure 1). In brief, alterations in atrial refractoriness, changes in cellular calcium homeostasis/handling, autonomic activation and delayed or early after-depolarisations can contribute to triggered activity or ectopic focal discharges that initiate AF. Further, structural abnormalities such as atrial dilatation/stretch, fibrosis, fatty infiltration and inflammation can contribute to local conduction disturbances and conduction block that are known to facilitate re-entry and AF sustenance. Several recent reviews provide in-depth coverage of the various fundamental mechanistic concepts that are beyond the scope of this review.[1-3] This review is focussed on the pathophysiological aspects of AF pertaining to atrial fibrosis and the two main arrhythmic mechanisms of rotational and ectopic focal activations that have emerged from recent mapping studies. Further, we undertake to delineate the differences of these two mechanisms in the paroxysmal (PAF) and persistent AF (PersAF) populations.
Clinical Classification of Atrial Fibrillation Atrial fibrillation is a progressive disease with many patients experiencing initial short and infrequent episodes (Figure 2, top left panel) to longer and more frequent ones (Figure 2, top right panel) while some may remain in permanent or chronic AF. However, AF will remain paroxysmal in a small proportion of patients (2–3%) or spontaneously regress from persistent to paroxysmal AF in some.[4, 5] The conventional method of AF classification is solely based on the clinical presentation in terms of episode duration and how it terminates. Current classification includes: newly diagnosed AF, PAF, PersAF, long-standing PersAF and permanent AF. Sometimes an overlap in presentation patterns will render this classification
difficult until a more predominant picture evolves. When correlated to AF recorded by an implantable device, current clinical AF classification has been shown to poorly reflect the temporal persistence of the arrhythmia.[6] In addition, patients with AF may be asymptomatic, rendering the classification irrelevant. Another major limitation of this classification is the lack of regard for the severity of the underlying atrial substrate or arrhythmia burden. As shown in Figure 2, the conventional AF classification would have failed to recognise the higher AF burden in the PAF patient (bottom left panel: AF burden: 37%) than the PersAF patient (bottom right panel: AF burden: 27%). Unfortunately, the distinction between PAF and PersAF has been used in most clinical trials and, therefore, still forms the basis of guideline recommendations.
The PersAF patients are more likely to have a higher number of concomitant AF risk factors and be exposed to longer durations of atrial remodelling (Figure 1).[7] In general, electroanatomical mapping studies have demonstrated the following atrial electro-structural differences in PersAF patients when compared to those with PAF: larger left atrial dimensions, lower atrial voltage, slower atrial conduction velocity, greater degree of electrogram fractionation and shorter AF cycle length.[8, 9] Several mapping studies have also demonstrated higher AF complexity in those with more persistent form of the arrhythmia to include higher number and narrower activation wavefronts, slower conduction, higher number of breakthrough waves, electrical dissociation, fractionation index and higher dominant frequencies.[10-13] However, the above is not always true given the variations in substrate complexity that may not be reflected in the conventional AF classification. While keeping the above limitations in mind, we aim to delineate the pathophysiological differences in fibrosis, rotors and foci between PAF and PersAF.
Atrial Remodelling and Fibrosis Atrial fibrosis has been recognised as a key structural change that underpins atrial conduction abnormalities and the perpetuation of AF by favouring re-entry, transmural conduction, preferential conduction and anchoring of AF drivers. Increased atrial fibrosis has been consistently demonstrated from histological analysis in different AF substrates using PicroSirius Red or Masson’s trichrome staining: sheep and rats with hypertension (induced by "one-kidney, one-clip” operation for up to 15 weeks, chronic hypertension following maternal exposure to corticosteroids for around 4 years and spontaneously hypertensive rats at 12–15 months old);[14-17] dogs or sheep with heart failure (induced by rapid ventricular pacing for 5 weeks and doxorubicin-induced non-ischaemic cardiomyopathy for 14 weeks);[18, 19] rats with type 2 diabetes (Zucker diabetic fatty rats, 38 weeks);[20] sheep with obesity (diet induced for up to 72 weeks); [21, 22] and, rats with simulated sleep apnoea (for 4 weeks).[23] Clinical observations suggest that certain combinations of risk factors may lead to more pronounced arrhythmogenic atrial remodelling, with AF progression seen more frequently in those with greater number of risk factors.[7] However, animal models investigating the effect of concomitant risk factors remain sparse.
Increased endomysial fibrosis (that is, increased transverse separation of atrial myocytes within bundles) and subsequent increased myocyte-myocyte distances in the atrial myocardium, as well as between the epicardial layer and the endocardial bundle network due to enhanced extracellular matrix formation, have been seen in experimental models of AF to result in more complex fibrillatory conduction and endo-epicardial electrical dissociation.[24, 25] Further, fat cell infiltration from the epicardium into the myocardium of
obese atria is a likely promoter of re-entry as this increases inert conduction barriers and potentiates atrial fibrosis.[22, 26] The above structural changes can result in altered connexin expression as well as spatial distribution from the polar to the lateral cell membrane of cardiomyocytes that are known to contribute to electrical disruption and AF perpetuation in both human and animal studies.[27, 28] All these changes can result in anisotropic conduction and increased three-dimensional (3D) functional surface available for fibrillation waves to coexist, and additional anchors that stabilise re-entrant fibrillatory activations.[29, 30] Such changes are more severe with the transition to more persistent forms of AF. For example, an increase in endomysial fibrosis, particularly in the outer millimetre of the atria, leads to a loss of continuity in the epicardial layer, and more complex fibrillatory conduction with longer duration of AF.[24] In addition, a 3D AF substrate has been documented in more persistent forms of the arrhythmia with rearrangement of atrial bundle architecture towards more perpendicular orientation of epicardial to endocardial bundles and increased endo-epicardial electrical dissociations.[30]
In humans, structural remodelling can be quantified and further characterised by electroanatomic mapping whereby increased fractionation of local atrial electrograms and areas of low voltage have been demonstrated in patients with chronic systemic hypertension,[31] long-term obstructive sleep apnoea,[32] and congestive heart failure.[33] Low-voltage areas (<0.5 mV) in the left atrium have been associated with endocardial scar and/or structural defects.[34, 35] Complex fractionated atrial electrograms (CFAEs) are defined as low voltage (≤0.15 mV) multiple potential signals with a very short cycle length (≤120 ms). CFAEs may occur at areas of diseased myocardium where the intercellular connectivity is poor, commonly because of fibrosis, slowed conduction or along a line of block.[36] Patients with
persistent AF have significantly lower LA voltage compared with patients with paroxysmal AF, even after adjustment for differences in indexed LA volume.[37] Another strategy to determine atrial tissue fibrosis is the use of late gadolinium-enhanced MRI (LGE-MRI), although this technique requires further refinement of imaging quality as well as analytical algorithms. The degree of atrial fibrosis detected by LGE-MRI has been shown to be higher in patients with PersAF as compared to PAF and in patients with more concomitant AF risk factors.[38] Additionally, novel high resolution mapping, imaging and modelling approaches in human PersAF demonstrated that intermittent and spatially unstable drivers anchor to structural heterogeneities and are preferentially clustered at the borders of fibrotic atrial regions.[39] Electro-anatomical mapping as well as LGE-MRI could play a major role in improved delineation of the underlying atrial substrate beyond the clinical classification of the arrhythmia to guide therapy. In patients undergoing catheter ablation, increased LGEMRI detected atrial fibrosis has been shown to be independently associated with higher AF recurrence.[40] Several studies have demonstrated improved AF ablation outcomes when additional targeting of areas with CFAEs and low atrial voltage were performed in select patient cohorts.[41, 42] Further prospective randomised clinical studies are necessary to clarify the role of substrate-based AF ablation in comparison to established strategies.
Rotors and Foci: Insights From Mapping Studies Recent advances in AF mapping to facilitate a ‘panoramic’ view of the electrical activations in the atria have identified two arrhythmic mechanisms of interest, namely, rotational (“rotors”) and ectopic focal (“foci”) activations as drivers of the arrhythmia. In brief, the endocardial contact mapping technique is known as focal impulse and rotor mapping (FIRM), which is facilitated by a 64-pole Basket catheter (Figure 3A) together with phase-
based signal processing.[43] The body surface potentials mapping technique utilises an inverse-solution electrocardiographic imaging (ECGI) system that consists of a non-invasive array of 252 body surface electrodes to derive virtual potentials on the epicardial atrial surface using thoracic computed tomography for bi-atrial geometric localisation followed by additional signal processing of wavelet transform and phase mapping (Figure 3B). Figure 3C and 3D depict examples of rotors in the left atrium detected by the FIRM and ECGI techniques respectively.
Both mapping techniques detected three to four rotors and ectopic foci in most AF patients with more sources seen in the left than right atrium (Figure 2, top panel).[44, 45] Notably, the FIRM basket-type technique yielded a higher proportion of rotors that lasted for thousands of cycles while the ECGI technique reported rotors that are transient and of several cycles only. The discrepancy between techniques can be due to the differences in the phase mapping algorithms used which remain proprietary and undisclosed. Several technical challenges in rotor detection have since been identified, including the need to consider electrode density, electrogram characteristics, and time-domain activation sequence when using the phase mapping algorithm.[46, 47] Activation mapping using a 128electrode epicardial plaque and a smaller field of field in long-lasting PersAF patients, suggests rotors to be transient with a median of three rotations.[48, 49] While data from the FIRM technique showed no significant differences in the electrophysiological characteristics of rotors and foci between PAF and PersAF patients, the ECGI data showed increased complexity of these drivers with prolonged AF duration.[50] Specifically, there were increased numbers of rotors and ectopic foci, increased number of regions with these AF drivers and extrapulmonary drivers, such as from the infero-posterior left atrium.[50]
Using the FIRM technique to guide additional ablation of rotors and focal sources to conventional wide area circumferential pulmonary vein isolation alone, Narayan and colleagues have demonstrated superior three-year outcome in an early report.[51] However, subsequent series on FIRM guided ablation have shown contradicting results on its efficacy while several randomised trials remain underway.[52-54] Further, Haissaguerre and co-workers used ECGI-guided ablation of rotors and focal sources to achieve similar success rates as conventional pulmonary vein and electrogram guided technique, albeit with shorter radiofrequency ablation time.[44] Results from this group demonstrate lower AF termination rate and shorter AF cycle length in those with longer duration of AF, suggesting a greater degree of electrical remodelling.[44, 50] Further advancements in mapping technologies along with our interpretation of these electrophysiological drivers of AF will be necessary to guide more mechanistic based therapies to improve outcomes for this complex arrhythmia. Additionally, standardisation of electrograms analysis with consensus on definitions for rotors, re-entry, fibrillation waves, conduction block and other phenomena is urgently needed for more meaningful analysis of the basic mechanisms of AF and to facilitate comparisons of different mapping techniques or algorithms.
Reversibility of the Atrial Remodelling Process and the Progression of AF Atrial fibrillation is a progressive disease that can be due to inadequately treated or unrecognised risk factors. For example, subclinical hypertension or aortic stiffness, alcohol excess and obstructive sleep apnoea may not be apparent without specific, targeted clinical attention.[55] Fortunately, the atrial remodelling is partially reversible when the underlying disease is treated. Blood pressure reduction after renal denervation is associated with
improvements in regional and global atrial conduction, and reduction in ventricular mass and fibrosis.[56, 57] Structured physician-directed risk factor and weight management programs have been shown to reduce AF burden and symptoms as well as improved sinus rhythm maintenance following catheter ablation.[58-60] Further, reverse atrial remodelling and reduced AF burden were also seen with improved cardiorespiratory fitness and aerobic interval training.[61, 62] Further studies are needed to determine if pharmacological upstream therapy targeting fibrosis, inflammation and the renin-angiotensin-aldosterone system may extend the benefits of treating the risk factors to modify the underlying atrial substrate.
Conclusions The current classification of AF is mainly based on the clinical presentation of the arrhythmia that may not reflect the underlying severity of the atrial disease. Novel mapping and imaging technologies to evaluate rotors, foci and fibrosis may help to improve AF characterisation and direct individualised mechanistic-based treatment of this complex arrhythmia.
Disclosures Dr Lau reports having received lecture and/or consulting fees from St Jude Medical and Boehringer Ingelheim. Dr Linz reports having received lecture and/or consulting fees from LivaNova, Pfizer, Sanofi Aventis, Boehringer Ingelheim and Medtronic. Dr. Schotten is cofounder and shareholder of YourRhythmics BV and received honoraria from the Università della Svizzera Italiana (USI, Switzerland), Universities of Utah and California (USA), Roche Diagnostics (Switzerland), Bayer Healthcare (Germany). Dr Schotten reports having received research grants from The Netherlands Heart Foundation, the European Union, Roche Diagnostics and Medtronic. Dr Mahajan reports having received lecture and/or consulting fees from St Jude Medical and Medtronic. Dr Mahajan reports having received research funding from Medtronic and St Jude Medical. Dr Sanders reports having served on the
advisory board of Biosense-Webster, Medtronic, and St Jude Medical. Dr Sanders reports having received lecture and/or consulting fees from Biosense-Webster, Medtronic, and St Jude Medical. Dr Sanders reports having received research funding from Medtronic, St Jude Medical, Boston Scientific, Biotronik and LivaNova.
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FIGURE LEGENDS: Figure 1: Interaction between different mechanisms underlying the initiation and maintenance of AF.
The mechanisms can be broadly classified into ‘triggers’ and ‘substrate’. Triggers are mainly represented by ectopic discharges originating in the pulmonary veins due to changes in calcium handling, autonomic activation, and triggered activity involving early afterdepolarisations and delayed after-depolarisations. These ectopic discharges can initiate AF by premature atrial electrical activations. Besides this, a substrate for AF is necessary to maintain the arrhythmia. The substrate is characterised by a structural remodelling process in the atrium (fibrosis, inflammation, fatty infiltration, etc.) and leads to local conduction disturbances and conduction block increasing the risk of re-entry circuits. The number of concomitant risk factors as well as the duration of the arrhythmia contribute to the progression of the atrial arrhythmogenic substrate which determines clinical AF burden. Treatment of modifiable risk factors like hypertension, heart failure, obesity or sleep apnoea can result in a regression of the substrate. Atrial fibrillation itself can further perpetuate the occurrence of triggers and the progression of the AF substrate.
Figure 2: Different representative atrial fibrillation (AF) histograms during 30 days are shown in patients with paroxysmal (PAF, left column) and persistent AF (PersAF, right column). Black bars represent daily percentage of time in AF. Additionally, AF-burden is indicated as percentage of recorded time in AF. Top left panel: Short self-terminating AF episodes (PAF, AF burden 20%). Top right panel: More sustained AF episodes requiring electrical cardioversions (PersAF, AF burden 53%). Of note, the conventional AF
classification of PAF and PersAF fails to recognise the higher AF burden in the PAF patient (bottom left panel, AF burden 37%) than in the PersAF patient (bottom right panel, AF burden 27%).
Figure 3: The table shows the fundamental electrophysiological characteristics of rotors and foci seen with the 2 different novel mapping techniques: FIRM using basket type mapping catheter (panel A)[45] vs. ECGI using 252-electrode vest (panel B)[44]. Panel C shows two consecutive clockwise rotors in the left atrium mapped using the FIRM technique. Panel D shows two consecutive counter-clockwise rotors near the right pulmonary veins mapped using the ECGI technique. Panels A-D are used with permission from Narayan et al [43] and Haissaguerre et al [44].
FIGURE 1:
[Insert space [-Replace “apnea” with “apnoea”]
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FIGURE 2:
FIGURE 3: