Atrial remodeling in atrial fibrillation – independent rhythm evaluation

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Andreea Cuculici1, Eduard Apetrei1

1 „Prof. Dr. C. C. Iliescu” Emergency Institute for Cadiovascular Diseases, Bucharest, Romania

Abstract: Atrial fibrillation is the most prevalent rhythm disorder ,associated with electrical, structural and contractile remodeling of the atria.The progression of atrial fibrosis is the symbol of structural remodeling and considered the sub-strate of atrial fibrillation recurrence. Left atrial (LA) size is a marker of atrial structural remodeling and is associated with increased risk for atrial fibrillation and cardiovascular disease and has a prognostic importance. Left atrial function may be related to atrial fibrillation, irrespective of left atrium structure.Left atrium function index, an echocardiographic index of LA structure and function, rhythm independent measure, may predict and better characterize atrium remodeling and can be used for detecting arrhythmia recurrence.

Keywords: atrial fibrillation, atrial remodeling, echocardiography, left atrium, atrial function.

Atrial fibrillation (AF) is the most common type of car-diac arrhythmia. While signifi cant progress has been made in the last years to reduce the burden of AF on morbidity and mortality, this arrhythmia remains one of the leading causes of stroke, heart failure, sudden death worldwide1. With the ever-ageing population, the prevalence of AF is also increasing in the coming years and for effective care of patients with AF new information is continually generated and published2.
Similar to the increasing prevalence of AF, the inci-dence of AF is estimated to double with each passing decade of adult life3. Estimates suggest an AF preva-lence of approximately 3% in adults aged 20 years or older, with greater prevalence in older persons and in patients with conditions such as hypertension, heart failure, coronary artery disease (CAD), valvular heart disease, obesity, diabetes mellitus, or chronic kidney disease (CKD). While males have greater risk of de-veloping AF than females, the independent risk factor for death that the arrhythmia causes is lower in males (1.5 vs. 1.9 relative risk)4.

Changes in atrial structure and function that can act as a substrate for atrial arrhythmias are defined as ar-rhythmogenicatrial remodeling. Various diseases like underlying cardiac conditions, systemic processes, aging, or even AF itself can trigger atrial remodelling5. There are four main pathophysiological mechanisms  contributing to AF 1-4: electrical remodeling, struc-tural remodeling, autonomic nervous system changes, and Ca2+ handling abnormalities. Many forms of atrial remodeling promote the occu-rrence or maintenance of AF by acting on the funda-mental arrhythmia mechanisms illustrated in Figure 1.
Both rapid ectopic firing and reentry can maintain AF. Reentry requires a vulnerable substrate, as well as a trigger that acts on the substrate to initiate re-entry. Ectopic firing contributes to reentry by providing triggers for reentry induction. Atrial remodeling has the potential to increase the likelihood of ectopic or reentrant activity through a multitude of potential mechanisms6.
Electrical remodeling. Electrophysiological re-modelling is represented by the shortening of the du-ration of the action potential and refractory period. Evan a few minutes of rapid atrial rates can result in intracellular calcium overload, which decreases the L-type calcium current (ICaL) because of a decreased trans-sarcolemmal calcium gradient and calcium indu-ced inactivation of the L-type calcium channel, with consequent reduction in the IcaL7. This phenomenon was named „pseudo-remodelling”. The behaviour of L-type calcium channels can be influenced by sustai-ned high atrial rates – leading to downregulation and a subsequent decrease in ICaL favoring short atrial refractory periods. In long standing AF, atrial tissue (obtained during cardiac surgery) demostrated a similar reduction in ICaL and inactivation of calcium chan-nels7. Several studies have shown that this fall in the IcaL current is the cornerstone for electrical remodelling due to AF – while other currents play only a secondary role8.
Altered gene expression resulting in changes in ion channel density and function has lasting effects (from hours to days) over the ionic currents and is the real substrate for electrical remodelling8.
Autonomic Nervous SystemChanges. Dis-turbances in the autonomic nervous system can lead both to the initiation and to persistence of AF since it controls directly the atrial electrical activity. Increased adrenergic drive may play a critical role in AF due to promotion of ectopic activity favored by a suscepitble substrate secondary to atrial remodelling. Moreover, AF induced hyperinnervation is another consequence of remodeling and adds to the vulnerable AF substrate10.
Structural remodeling. Atrial structural remo-deling is due to increased interstitial fibrosis adding to cardiac structural alterations11, in the end leading to atrial enlargement and fibrosis. At the basis of atrial structural remodeling may be any process that favors the development of atrial fibrosis. Fibrosis promotes AF by interrupting fiber bundle continuity and causing local conduction disturbances12.
At cellular level, the process is initiated by vario-us profibrotic factors including Ang II, transforming growth factor beta, and platelet-derived growth fac-tor – that may act individually or synergistically13 to promote fibrosis.
Atrial fibrosis appears to be a common endpoint of a wide range of AF-promoting conditions and may predict recurrences14. Furthermore, the relation between AF and fi brosis is bidirectional, since AF ap-pears to promote atrial fibrosis15, which contributes importantly to therapeutic resistance in patients with long-standing arrhythmia16.
Functional remodeling. Atrial functional remo-deling results in decreased function independent of alteration in LA size. Atrial tachyarrhythmias, altera-tions in LA pressure may result in functional changes. LA functional remodeling may also be associated with
the development of LA fibrosis and consequent struc-tural changes.
The process in wich LA remodeling demonstrates the concept of improving or restoring atrial function is named Reverse remodeling. LA reverse remodeling has been more definitely described in the early sta-ges of LA structural and functional remodeling17. No-ninvasive imaging would be the most practical option to monitor LA reverse remodeling, but the extent of structural change, i.e., percentage reduction in LA vo-lume, and the specifi c functional parameter(s) to be utilized are poorly defined.
The left atrium is considered a biomarker for ad-verse cardiovascular outcomes, particularly in patients with left ventricular diastolic dysfunction and atrial fibrillation in whom left atrial enlargement is of pro-gnostic importance18.
LA remodeling is monitored in clinical practice using various noninvasive imaging modalities How-ever, specifi c monitoring of LA remodeling has not been incorporated into clinical decision-making. From the Framingham Heart study, LA remodeling, was de-fined as an encrease of LA diameter wich was 1 of 3 independent echocardiographic predictors for future development of AF19. Another reports have used a change in LA volume >15% compared with baseline, by echocardiographic assessment or cardiac magnetic resonance (CMR), as a result of LA remodeling. Alte-rations in LA function (LA strain) may precede chan-ges in LA volume, both in normal subjects20 as well as in diseased states21. More, a combination of structu-ral and functional remodeling may be more sensitive in monitoring diseased states. Yoon et al.22 evaluated LA volume and function by strain analysis demonstra-ting that LA indexed volume >34 ml/m2 and LA strain
<31% had increase for patients with paroxysmal AF to develop persistent AF.
Another echocardiographic parameters have been used to evaluate atrial function including the peak A wave velocity of transmitral flow in late diastole (obtained by pulsed wave Doppler and its velocity time integral (VTI). The fraction of atrial contribution (from transmitral flow)23 was estimated as the A wave VTI as a fraction of total mitral inflow VTI, has also been an established marker of atrial function. More recently the A0 velocity using Doppler tissue imaging has been used as a global measure of atrial function. The peak A0 velocity represents intrinsic atrial con-tractility and has been reduced in atrial dysfunction similar to the peak A wave velocity. The problem with these parameters is that they only can be be easily measured in sinus rhythm and are often not evaluated in AF and this makes the comparison of atrial function sinus rhythm vs atrial fibrillation, often difficult.
An echocardiographic evaluation of atrial function wich is rhythm independent was described to be LA function index (LAFI), a marker who incorporates ana-logues of cardiac output, LA size and atrial reservoir function.LAFI is inversely proportional to LA size and directly proportional to LA reservoir function and stroke volume. This marker is calculated as a ratio, LAFI=LAEF (LA emptying fraction) x LVOT-VTI (cm)/ LAESVI (and LAESVI is the largest LA volume mea-sure in ventricular systole (LAESV) in ml indexed to body surface area or ml/m)24.
LAFI was associated with AF and CVD and remained associated with them even among those with normal LA size, which persisted after adjustment for clinical prediction scores and echocardiographic measures. So, we have the hypothesis that LAFI, beyond LA structure can be a predictor of AF and CVD events25.
Left atrial function index was associated with an increased risk of developing incident atrial fi brillation independent of validated clinical risk prediction scores and echocardiographic measures of adverse cardiac remodeling. Left atrial function index can be measured using widely available 2-dimensional echocardiography and the studies demonstrated independent association of left atrial function index with adverse outcomes even in the presence of normal left atrial size25.

Figure 1. Fundamental arrhythmia mechanisms.

Figure 2. The modification of the calcium current by rapid atrial activation (AF atrial fibrillation, AP action potential, APD action potential duration) – modify by G.L. Botto26.

Figure 3. Speckle tracking 2D strain echocardiography- used to assess Left atrial reservoir function by [LA (left atrial systolic strain) and SSr (systolic strain rate)], LA conduit function by (ESr = Eary diastolic strain rate), LA booster pump by (ASr=Late diastole strain rate).

Figure 4. Pulsed wave doppler. Interrogation in LVOT used to measureVTI (Left ventricular outflow tract velocity time integral measure).

Figure 5. 2D echocardiography – LA maximum volume in the apical 4 chamber view.

The evaluation of LA size and function provides a marker of cardiovascular disease status that can be used to quantify the structural and functional remo-deling. LA remodeling represents a state of maladapti-ve deterioration whereas reverse remodeling reflects improvement in response to medical or nonmedical intervention, but clear definitions are required. There are some measure to evaluate atrial function and tra-ditional parameters are rhythm dependent. The LAFI is a rhythm independent measure of atrial function and may be a more sensitive marker of changes in atrial function such as in AF.
Conflict of interest: none declared.
1. Stefano BD, Kotecha A, Ahlsson D, Atar B, Casadei M, Castella H-C, Diener H,Heidbuchel J, Hendriks-2016 ESC Guidelines for the man-agement of atrial fibrillation developed in collaboration with EACTS-European Heart Journal, Volume 37, Issue 38, 7 October 2016.
2. Dang D, Arimie R, Haywood LJ. A review of atrial fibrillation. J Natl Med Assoc 2002;94:1036-48.
3. Piccini JP, Hammill BG, Sinner MF, et al. Incidence and prevalence of atrial fibrillation and associated mortality among Medicare benefi – ciaries, 1993-2007. Circ Cardiovasc Qual Outcomes 2012;5:85-93. 10.1161/Circoutcomes.111.962688.
4. Benjamin EJ, Wolf PA, D’Agostino RB, et al. Impact of atrial fibril-lation on the risk of death: the Framingham Heart Study. Circula-tion 1998;98:946-52. 10.1161/01.Cir.98.10.946].
5. Nattel S, Masahide H, Montreal, Quebec, Canada; and Hamamatsu, Japan -Atrial Remodeling and Atrial Fibrillation Recent Advances and Translational Perspectives
6. Nattel S, B Burstein, and D Dobrev- Atrial Remodeling and Atrial Fibrillation Mechanisms and Implications Originally published1 Apr
2008 Ar-rhythmia and Electrophysiology. 2008;1:62–73.
7. Pandozi C, Santini M. Update on atrial remodelling owing to rate; does atrial fibrillation always ‘beget’ atrial fibrillation? Eur Heart J 2001;22:541-53.
8. Nattel S. Atrial electrophysiological remodeling caused by rapid atri-al activation: underlying mechanisms and clinical relevance to atrial fibrillation. Cardiovasc Res 1999;42: 298—308.
9. Nishida K, Qi XY, Wakili R, et al. Mechanisms of atrial tachyarrhyth-mias associated with coronary artery occlusion in a chronic canine model. Circulation 2011;123:137–46.
10. Choi EK, Shen MJ, Han S, et al. Intrinsic cardiac nerve activity and paroxysmal atrial tachyarrhythmia in ambulatory dogs. Circulation 2010;121:2615–23.
11. Yoshihara F, Nishikimi T, Sasako Y, et al. Plasma atrial natriuretic peptide concentration inversely correlates with left atrial collagen volume fraction in patients with atrial fi brillation: plasma ANP as a possible biochemical marker to predict the outcome of the maze procedure. J Am Coll Cardiol 2002;39:288–94.
12. Burstein B, Comtois P, Michael G, et al. Changes in connexin expres-sion and the atrial fibrillation substrate in congestive heart failure. Circ Res 2009;105:1213–22.
13. Katz AM. Proliferative signaling and disease progression in heart fail-ure. Circ J 2002;66: 225–31.
14. Oakes RS, Badger TJ, Kholmovski EG, et al. Detection and quanti-fication of left atrial structural remodeling with delayed-enhanced magnetic resonance imaging in patients with atrial fibrillation. Circu-lation 2009;119:1758–67.
15. Burstein B, Qi XY, Yeh YH, Calderone A, Nattel S. Atrial cardio-myocyte tachycardia alters cardiac fibroblast function: a novel con-sideration in atrial remodeling. Cardiovasc Res 2007;76: 442–52.
16. Verheule S, Tuyls E, Gharaviri A, et al. Loss of continuity in the thin epicardial layer because of endomysial fibrosis increases the com-plexity of atrial fibrillatory conduction. Circ Arrhythm Electrophysi-ol 2013;6: 202–11.
17. Kumagai K, Nakashima H, Urata H, Gondo N, Arakawa K, Saku K. Effects of angiotensin II type 1 receptor antagonist on electri-cal and structural remodeling in atrial fibrillation. J Am Coll Cardiol 2003;41:2197–204.
18. Liza Thomas, Walter P. Abhayaratna- Left Atrial Reverse Remodel-ing Mechanisms, Evaluation, and Clinical Signifi cance ; JACC: Cardio-vascular Imaging VOL. 10, NO. 1, 2017.
19. Vaziri SM, Larson MG, Benjamin EJ, Levy D. Echocardiographic pre-dictors of nonrheumatic atrial fibrillation. The Framingham Heart Study. Circulation 1994;89:724–30.11
Andreea Cuculici et al. Romanian Journal of Cardiology Atrial remodeling in atrial fibrillation – independent rhythm evaluation Vol. 29, No. 1, 2019
20. Boyd AC, Richards DA, Marwick T, Thomas L. Atrial strain rate is a sensitive measure of alterations in atrial phasic function in healthy ageing. Heart 2011;97:1513–9.
21. Kojima T, Kawasaki M, Tanaka R, et al. Left atrial global and re-gional function in patients with paroxysmal atrial fibrillation has al-ready been impaired before enlargement of left atrium: velocity vec-tor imaging echocardiography study. Eur Heart J Cardiovasc Imaging 2012;13:227–34.
22. Yoon YE, Oh IY, Kim SA, et al. Echocardiographic predictors of pro-gression to persistent or permanent atrial fibrillation in patients with paroxysmal atrial fibrillation (E6P Study). J Am Soc Echocardiogr 2015;28:709–17.
23. Manning WJ, Leeman DE, Gotch PJ, Come PC. Pulsed Doppler eval-uation of atrial mechanical function after electrical cardioversion of atrial fibrillation. J Am Coll Cardiol 1989; 13:617–23.
24. Thomas L, Hoy M, Byth K, and Schiller N.B. – The left atrial func-tion index: a rhythm independent marker of atrial function ; Euro-pean Journal of Echocardiography (2008) 9, 356–362 doi:10.1016/j. euje.2007.06.002.
25. Sardana M, Lessard D,Tsao C.V.; Parikh N.V.; Barton B; et al Asso-ciation of Left Atrial Function Index with Atrial Fibrillation and Car-diovascular Disease: The Framingham Offspring Study; Journal of the American Heart Association Doi: 10.1161/Jaha.117.00843.
26. G.L. Botto, M. Luzi and A. Sagone- Atrial fi brillation: the remodelling phenomenon European Heart Journal Supplements (2003) 5 (Sup-plement H), H1—H7.

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