University of Groningen
Towards prevention of AF progression
Hobbelt, Anne
IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from
it. Please check the document version below.
Document Version
Publisher's PDF, also known as Version of record
Publication date:
2019
Link to publication in University of Groningen/UMCG research database
Citation for published version (APA):
Hobbelt, A. (2019). Towards prevention of AF progression. Rijksuniversiteit Groningen.
Copyright
Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).
Take-down policy
If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.
Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum.
Chapter 1
Today atrial fibrillation (AF) is known as one of the cardiovascular epidemics of the
west-ern world.
1Millions of Europeans suffer from AF and this number will continue to rise
during the next years, mainly due to ageing of the population.
2,3Not only is AF the most
frequent cardiac arrhythmia, AF is not benign. AF is associated with significant morbidity
and mortality, due to an increased risk of stroke, heart failure, decreased quality of life,
dementia, and death.
1,4-6As a consequence, AF has an enormous impact on public health.
7The pathophysiologic processes which underlie AF are complex and poorly understood.
Atrial remodeling occurs as a consequence multiple interacting mechanisms caused by
underlying conditions such as hypertension, prevalent heart failure, and/or diabetes,
8,9but
also as a consequence of AF itself (AF begets AF).
10This is the main driver of a gradual
worsening of AF over time, which makes it challenging to maintain sinus rhythm in the
long term. Progression of AF to more sustained forms of the disease, as a consequence
of the process of atrial remodeling, is associated with significant cardiovascular
morbid-ity, increased hospitalization and mortalmorbid-ity, among others due to heart failure, stroke, or
myocardial infarction.
8,11Multiple interacting mechanisms, including electrical remodeling and continuous
structural remodeling of the atria are thought to play a key role in the pathophysiologic
processes that set the stage for AF and AF progression.
12-15The process of remodeling is
marked by activation of renin-angiotensin-aldosterone system, cellular calcium overload,
increased release of endothelin-1, heath shock proteins, natriuretic peptides, adipokines,
and inflammation and oxidative stress, leading to structural remodeling as a consequence
of fibrosis, cellular hypertrophy, dedifferentiation, apoptosis and myolysis, and enlarged
atria.
4,16Structural remodeling results in electrical dissociation of the cardiac muscle
bundles and local conduction heterogeneities, facilitating the initiation and perpetuation
of AF.
10,12,13,17,18This electro-anatomical substrate allows multiple small re-entry circuits to
occur, leading to stabilization of AF. The process of remodeling is initiated long before the
first episode of AF occurs (figure 1).
19Once AF is present, the remodeling processes in the
atria progress further to constitute a vicious circle.
10,16,20,21The degree of structural remodeling and subsequent substrate for initiation and
pro-gression of AF is time dependent and is influenced by the normal aging process as well
as underlying conditions.
22Quantifying the extent of atrial remodeling or atrial substrate
is difficult and challenging, but it is necessary to improve personalized AF therapy and
subsequently improve outcome. Quantification of atrial fibrosis may be possible with late
gadolinium enhancement magnetic resonance imaging (MRI). However, it is so far only
done by one center and not yet reproduced.
23-25The latter raises the question if MRI in the
future will be feasible to quantify the atrial substrate. As a consequence physicians are
obliged to use clinical and biological markers to evaluate the extent of the atrial substrate.
In this perspective clinically relevant considerations of the extent of atrial remodeling are
age, concomitant cardiovascular disease such as heart failure, hypertension, diabetes,
12 Chapter 1
renal function, obesity, unfitness, chronic obstructive pulmonary disease, and sleep apnea,
duration and burden of AF, echocardiographic parameters such as left atrial size and
func-tion, and circulating biomarkers.
11,17,22,26-28This is also described in chapter 3 and chapter
4 of this thesis.
Although rhythm control strategies are continuously improving, including AF ablation
techniques, the success of rhythm control is still limited.
17,29,30So far, in terms of
cardio-vascular outcome only in one specific patient category (heart failure with reduced ejection
fraction below 35%) benefit has been shown for rhythm control through catheter ablation
over a treatment strategy with antiarrhythmic drugs.
31-33For all other AF patient categories
only acute rate control and, if indicated, rhythm control to stabilize hemodynamics,
treat-ment of concomitant cardiovascular comorbidities, and oral anticoagulation therapy have
currently been proven to improve the prognosis of AF (figure 3).
4,34Especially underlying
(heart) conditions may be a more important determinant of prognosis than rhythm
con-trol.
35However, results of the rate versus rhythm control trials may have been influenced
by failure of pharmacological rhythm control strategies.
36Nevertheless, rhythm control
remains the therapy of choice for symptomatic patients. Therefore, there is a great need to
search for new developments in AF treatment, with therapies that significantly improve the
current treatment and prognosis of AF in a cost-effective way. Preferably, this are therapies
that are initiated early in the disease process, so that the remodeling process can be delayed
or, even better, stopped.
Figure 1. Time course of AF
Hypothetical representation of the time course of atrial substrate remodeling in relation to the clinical appear-ance of AF. Adapted from Cosio et al.17, with permission.
Identification of those patients who will respond to rhythm control therapy or alteration
of substrate remodeling is challenging.
22In modern practice the classification paroxysmal
(AF lasting no longer than 7 days, either self-terminating or terminated with electrical or
chemical cardioversion), persistent (AF lasting longer than 7 days, including episodes that
are terminated with electrical or chemical cardioversion), long-lasting AF (ongoing AF
lasting longer than 1 year in which a rhythm control strategy is retained) and permanent AF
(AF that is accepted by the patient and physician, which means that a rate control strategy
is adopted) as described in current guidelines is being used as a clinical tool to estimate
whether or not a patient will benefit from a rhythm control strategy or should be treated
with rate control. However, current categorization of AF fails to adequately describe
pa-tient groups and expected rhythm outcome.
37It is proposed that current classification does
insufficiently take the severity of the underlying substrate into consideration. As described
by Allessie et al. the pathological mechanisms causing AF can be divided into abnormally
high vulnerability, due to the possible presence of genetic predisposition and due to
electri-cal remodeling causing increased vulnerability and triggered activity, and abnormally high
substrate for AF, causing increased stability of AF and occurrence of re-entry circuits.
12It is
Figure 2. Flow chart showing the series of events caused by stretch.
Hypothetical scheme of stretch induced by hypertension, heart failure and possibly extreme endurance exer-cise leading to calcium overload, activation of the renin–angiotensin–aldosterone system (RAAS) and release of different factors, resulting in structural remodelling and finally in AF. Adapted from A.M. De Jong et al.16,
14 Chapter 1
proposed that perhaps it is time to focus on those mechanisms which underlie AF
occur-rence and identification of the extent of structural remodeling, rather than a classification
based on the duration of AF episodes.
17,37,38Therapies that interfere early in the structural remodeling process are promising and
become more and more applied in the treatment of AF. The terms “targeted therapy” or
“upstream therapy” refer to the use of non-antiarrhythmic drugs that modify the atrial
substrate and at the same time target underlying conditions or risk factors of AF to prevent
the occurrence or recurrence of the arrhythmia. Such agents include
renin–angiotensin–al-dosterone system (RAAS) modulators, statins, N-3 polyunsaturated fatty acids and
gluco-corticoids.
39-41Also interventions to promote physical activity, i.e. fitness, weight reduction
(i.e. reduction of fatness) and a varied low-calorie diet can be considered as targeted
therapies.
42The key targets of targeted therapy are reduction of structural changes in the
atria, such as fibrosis, hypertrophy, inflammation, and oxidative stress. In second instance
targeted therapy has also direct and indirect effects on atrial ion channels, gap junctions,
and calcium handling. These effects differ significantly from the effects of conventional
rhythm control strategies, such as antiarrhythmic drugs, which only targets direct effects
on atrial ion channels, gap junctions, and calcium handling without direct substrate
modification. As a consequence of these effects, targeted therapies may be more effective
in maintaining sinus rhythm then conventional rhythm control therapies, especially when
instituted early in the disease process and not late, when damage is already done. The
ef-fect of such therapies may be two-folded, on the one hand it treats the underlying risk
factor, for example hypertension or heart failure, and on the other hand it has effect on the
Figure 3. Five domains of integrated atrial fibrillation care
All patients with AF should receive care directed at these five domains. Adapted from Kirchhof et al.4 , with
remodeling process itself. However, their actual effect may vary within individual patients
and depends on presence and amount of risk factors and degree of structural remodeling.
43This emphasizes that more insight in the relation between AF, structural and electrical
remodeling, and hypercoagulability, may affect future therapeutic management of AF,
which might lead to better patient tailored therapy and potentially improve outcome.
44aim of This Thesis:
The aim of this thesis is to study clinical and therapeutic implications of prevention of
progression of AF. In Chapter 1 we describe the various mechanisms involved in
pro-gression of AF and the importance of interference in this process. In chapter 2 we start
off with low-risk patients with short-lasting paroxysmal AF and assess the presence of
elevated clotting factors as a marker of early coagulation activity. In chapter 3 and chapter
4 we study genetic, chemical and clinical characteristics of patients with various AF
pat-terns, and potential targets for future treatment strategies to prevent AF progression. In
chapter 5 we investigate the effects of risk factor driven targeted therapy in patients with
short-lasting persistent AF and heart failure on the maintenance of sinus rhythm and on
adverse events, results of the RACE 3 study. In Chapter 6 the results of the RACE 3 study are
summarized, reviewed, and put in perspective. Chapter 7 provides an overview of tailored
treatment strategies as a new approach for modern management of AF in order to reduce
AF progression and improve prognosis. Finally, in Chapter 8 the results depicted in the
previous chapters will be summarized and put in perspective.
16 Chapter 1
RefeRenCes
1. Vermond RA, Geelhoed B, Verweij N, et al. Incidence of atrial fibrillation and relationship with cardiovascular events, heart failure, and mortality: A community-based study from the netherlands. J Am Coll Cardiol. 2015;66(9):1000-1007.
2. Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed atrial fibrillation in adults: National implications for rhythm management and stroke prevention: The AnTicoagulation and risk factors in atrial fibrillation (ATRIA) study. JAMA. 2001;285(18):2370-2375.
3. Chugh SS, Roth GA, Gillum RF, Mensah GA. Global burden of atrial fibrillation in developed and developing nations. Glob Heart. 2014;9(1):113-119.
4. Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC guidelines for the management of atrial fibrillation developed in collaboration with EACTS: The task force for the management of atrial fibrillation of the european society of cardiology (ESC)developed with the special contribution of the european heart rhythm association (EHRA) of the ESCEndorsed by the european stroke organisation (ESO). Europace. 2016.
5. Kim EJ, Yin X, Fontes JD, et al. Atrial fibrillation without comorbidities: Prevalence, incidence and prognosis (from the framingham heart study). Am Heart J. 2016;177:138-144.
6. Andersson T, Magnuson A, Bryngelsson IL, et al. Patients without comorbidities at the time of diagnosis of atrial fibrillation: Causes of death during long-term follow-up compared to matched controls. Clin Cardiol. 2017.
7. Wattigney WA, Mensah GA, Croft JB. Increasing trends in hospitalization for atrial fibrillation in the united states, 1985 through 1999: Implications for primary prevention. Circulation. 2003;108(6):711-716.
8. Nieuwlaat R, Prins MH, Le Heuzey JY, et al. Prognosis, disease progression, and treatment of atrial fibrillation patients during 1 year: Follow-up of the euro heart survey on atrial fibrillation. Eur Heart J. 2008;29(9):1181-1189.
9. Chatterjee NA, Chae CU, Kim E, et al. Modifiable risk factors for incident heart failure in atrial fibrillation. JACC Heart Fail. 2017;5(8):552-560.
10. Wijffels MC, Kirchhof CJ, Dorland R, Allessie MA. Atrial fibrillation begets atrial fibrillation. A study in awake chronically instrumented goats. Circulation. 1995;92(7):1954-1968.
11. De Vos CB, Pisters R, Nieuwlaat R, et al. Progression from paroxysmal to persistent atrial fibrillation clinical correlates and prognosis. J Am Coll Cardiol. 2010;55(8):725-731.
12. Allessie MA, Konings K, Kirchhof CJ, Wijffels M. Electrophysiologic mechanisms of perpetuation of atrial fibrillation. Am J Cardiol. 1996;77(3):10A-23A.
13. Ausma J, van der Velden HM, Lenders MH, et al. Reverse structural and gap-junctional remodeling after prolonged atrial fibrillation in the goat. Circulation. 2003;107(15):2051-2058.
14. Nattel S, Guasch E, Savelieva I, et al. Early management of atrial fibrillation to prevent cardiovascu-lar complications. Eur Heart J. 2014;35(22):1448-1456.
15. Spronk HM, De Jong AM, Verheule S, et al. Hypercoagulability causes atrial fibrosis and promotes atrial fibrillation. Eur Heart J. 2017;38(1):38-50.
16. De Jong AM, Maass AH, Oberdorf-Maass SU, Van Veldhuisen DJ, Van Gilst WH, Van Gelder IC. Mechanisms of atrial structural changes caused by stretch occurring before and during early atrial fibrillation. Cardiovasc Res. 2011;89(4):754-765.
17. Cosio FG, Aliot E, Botto GL, et al. Delayed rhythm control of atrial fibrillation may be a cause of failure to prevent recurrences: Reasons for change to active antiarrhythmic treatment at the time of the first detected episode. Europace. 2008;10(1):21-27.
18. Schotten U, Verheule S, Kirchhof P, Goette A. Pathophysiological mechanisms of atrial fibrillation: A translational appraisal. Physiol Rev. 2011;91(1):265-325.
19. Asselbergs FW, Van den Berg MP, Diercks GF, Van Gilst WH, Van Veldhuisen DJ. C-reactive protein and microalbuminuria are associated with atrial fibrillation. Int J Cardiol. 2005;98(1):73-77. 20. Nattel S, Shiroshita-Takeshita A, Cardin S, Pelletier P. Mechanisms of atrial remodeling and clinical
relevance. Curr Opin Cardiol. 2005;20(1):21-25.
21. Healey JS, Israel CW, Connolly SJ, et al. Relevance of electrical remodeling in human atrial fibril-lation: Results of the asymptomatic atrial fibrillation and stroke evaluation in pacemaker patients and the atrial fibrillation reduction atrial pacing trial mechanisms of atrial fibrillation study. Circ Arrhythm Electrophysiol. 2012;5(4):626-631.
22. Guichard JB, Nattel S. Atrial cardiomyopathy: A useful notion in cardiac disease management or a passing fad? J Am Coll Cardiol. 2017;70(6):756-765.
23. Habibi M, Lima JA, Khurram IM, et al. Association of left atrial function and left atrial enhancement in patients with atrial fibrillation: Cardiac magnetic resonance study. Circ Cardiovasc Imaging. 2015;8(2):e002769.
24. Oakes RS, Badger TJ, Kholmovski EG, et al. Detection and quantification of left atrial structural remodeling with delayed-enhancement magnetic resonance imaging in patients with atrial fibrilla-tion. Circulafibrilla-tion. 2009;119(13):1758-1767.
25. Kuppahally SS, Akoum N, Burgon NS, et al. Left atrial strain and strain rate in patients with parox-ysmal and persistent atrial fibrillation: Relationship to left atrial structural remodeling detected by delayed-enhancement MRI. Circ Cardiovasc Imaging. 2010;3(3):231-239.
26. Schoonderwoerd BA, Smit MD, Pen L, Van Gelder IC. New risk factors for atrial fibrillation: Causes of ‘not-so-lone atrial fibrillation’. Europace. 2008;10(6):668-673.
27. Schnabel RB, Larson MG, Yamamoto JF, et al. Relations of biomarkers of distinct pathophysiologi-cal pathways and atrial fibrillation incidence in the community. Circulation. 2010;121(2):200-207. 28. Smit MD, Maass AH, De Jong AM, Muller Kobold AC, Van Veldhuisen DJ, Van Gelder IC. Role of
inflammation in early atrial fibrillation recurrence. Europace. 2012;14(6):810-817.
29. Singh BN, Singh SN, Reda DJ, et al. Amiodarone versus sotalol for atrial fibrillation. N Engl J Med. 2005;352(18):1861-1872.
30. Nyong J, Amit G, Adler AJ, et al. Efficacy and safety of ablation for people with non-paroxysmal atrial fibrillation. Cochrane Database Syst Rev. 2016;11:CD012088.
31. Van Gelder IC, Hagens VE, Bosker HA, et al. A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. N Engl J Med. 2002;347(23):1834-1840. 32. Pottier P, Fouassier M, Hardouin JB, Volteau C, Planchon B. D-dimers, thrombin-antithrombin
complexes, and risk factors for thromboembolism in hospitalized patient. Clin Appl Thromb Hemost. 2009;15(6):666-675.
33. Marrouche NF, Brachmann J, Andresen D, et al. Catheter ablation for atrial fibrillation with heart failure. N Engl J Med. 2018;378(5):417-427.
34. Hylek EM, Go AS, Chang Y, et al. Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation. N Engl J Med. 2003;349(11):1019-1026.
35. Rienstra M, Van Gelder IC, Hagens VE, Veeger NJ, Van Veldhuisen DJ, Crijns HJ. Mending the rhythm does not improve prognosis in patients with persistent atrial fibrillation: A subanalysis of the RACE study. Eur Heart J. 2006;27(3):357-364.
36. Bloom HL. Concise review of atrial fibrillation: Treatment update considerations in light of AFFIRM and RACE. Clin Cardiol. 2004;27(9):495-500.
18 Chapter 1
37. Charitos EI, Purerfellner H, Glotzer TV, Ziegler PD. Clinical classifications of atrial fibrillation poorly reflect its temporal persistence: Insights from 1,195 patients continuously monitored with implantable devices. J Am Coll Cardiol. 2014;63(25 Pt A):2840-2848.
38. Lau DH, Linz D, Schotten U, Mahajan R, Sanders P, Kalman JM. Pathophysiology of paroxysmal and persistent atrial fibrillation: Rotors, foci and fibrosis. Heart Lung Circ. 2017;26(9):887-893. 39. Savelieva I, Kakouros N, Kourliouros A, Camm AJ. Upstream therapies for management of atrial
fibrillation: Review of clinical evidence and implications for european society of cardiology guide-lines. part II: Secondary prevention. Europace. 2011;13(5):610-625.
40. Savelieva I, Kakouros N, Kourliouros A, Camm AJ. Upstream therapies for management of atrial fibrillation: Review of clinical evidence and implications for european society of cardiology guide-lines. part I: Primary prevention. Europace. 2011;13(3):308-328.
41. Gorenek B, Pelliccia A, Benjamin EJ, et al. European heart rhythm association (EHRA)/european as-sociation of cardiovascular prevention and rehabilitation (EACPR) position paper on how to prevent atrial fibrillation endorsed by the heart rhythm society (HRS) and asia pacific heart rhythm society (APHRS). Europace. 2017;19(2):190-225.
42. Yongjun Q, Huanzhang S, Wenxia Z, Hong T, Xijun X. From changes in local RAAS to structural remodeling of the left atrium: A beautiful cycle in atrial fibrillation. Herz. 2015;40(3):514-520. 43. Rienstra M, Hobbelt AH, Alings M, et al. Targeted therapy of underlying conditions improves sinus
rhythm maintenance in patients with persistent atrial fibrillation: Results of the RACE 3 trial. Eur Heart J. 2018;39(32):2987-2996.
44. Van Gelder IC, Hobbelt AH, Marcos EG, et al. Tailored treatment strategies: A new approach for modern management of atrial fibrillation. J Intern Med. 2016;279(5):457-466.
