University of Groningen

Towards prevention of AF progressionHobbelt, Anne

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Chapter 1Introduction

Chapter 1 11

Today atrial fibrillation (AF) is known as one of the cardiovascular epidemics of the west-

ern world.1 Millions of Europeans suffer from AF and this number will continue to rise

during the next years, mainly due to ageing of the population.2,3 Not 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.1,4-6 As a consequence, AF has an enormous impact on public health.7

The 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,8,9 but

also as a consequence of AF itself (AF begets AF).10 This 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 mortality, among others due to heart failure, stroke, or

myocardial infarction.8,11

Multiple 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.12-15 The 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.4,16 Structural remodeling results in electrical dissociation of the cardiac muscle

bundles and local conduction heterogeneities, facilitating the initiation and perpetuation

of AF.10,12,13,17,18 This 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).19 Once AF is present, the remodeling processes in the

atria progress further to constitute a vicious circle.10,16,20,21

The 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.22 Quantifying 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.23-25 The 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.11,17,22,26-28 This 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.17,29,30 So 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.31-33 For 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).4,34 Especially underlying

(heart) conditions may be a more important determinant of prognosis than rhythm con-

trol.35 However, results of the rate versus rhythm control trials may have been influenced

by failure of pharmacological rhythm control strategies.36 Nevertheless, 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 AFHypothetical 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.

Chapter 1 13

Identification of those patients who will respond to rhythm control therapy or alteration

of substrate remodeling is challenging.22 In 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.37 It 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.12 It 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, with permission.

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.17,37,38

Therapies 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.39-41 Also 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.42 The 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 careAll patients with AF should receive care directed at these five domains. Adapted from Kirchhof et al.4 , with permission.

Chapter 1 15

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.43

This 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.44

aim 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

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