Towards prevention of AF progression
Hobbelt, Anne
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Hobbelt, A. (2019). Towards prevention of AF progression. Rijksuniversiteit Groningen.
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Chapter 8
Discussion
findinGs
In this thesis we investigated clinical and therapeutic implications of prevention of AF pro-gression. We found that in very-low-risk patients (CHA2DS2-VASc score 0) with paroxysmal
AF elevated circulating levels of factor IXa-antithrombin were significant higher than in control patients without AF. This observation, may be interpreted as a first signal of hyper-coagulability, reflecting a prethrombotic state in very low risk patients (chapter 2). Clinical, biomarker and genetic predictors of specific types of AF in two different cohorts were then discussed and the possibility to allocate patients into different classifications depending on their vulnerability and triggers to AF, or the extent of the underlying substrate, as a tool to explore future intervention options (chapter 3 and chapter 4). We then assessed the influence of risk factor driven targeted therapy, including angiotensin converting enzyme inhibitors, angiotensin receptor blockers, aldosterone receptor antagonists, and statins, and a cardiac rehabilitation program aimed at improving fitness, fatness reduction and improving dietary habits, in the remodeling process in AF, in patients with early persistent AF and mild to moderate heart failure (chapter 5 and chapter 6). Last, we assessed the potential of patient tailored therapy to improve treatment outcomes and minimize adverse events (Chapter 7).
meChanisms of aTRial RemodelinG
Many patients with AF progress from short AF episodes to more frequent and longer forms of the arrhythmia and eventually persistence of AF. Atrial electrical and structural changes are the main promoter for initiation and progression of AF.1-4 Both mechanisms
are important and the underlying pathophysiologic mechanisms causing these changes are complex and are different in various patients. Atrial electrical remodeling occurs early and is the consequence of alterations in ion channels, ion pumps and ion exchangers.1-3,5
These processes cause alterations in refractory period, calcium hemostasis, autonomic activation, and early or delayed after depolarization’s setting the stage for occurrence of triggered or ectopic focal discharges that may trigger AF.1,2,6
Structural atrial changes play, an even more important, central role in initiation and progression of AF and occurs later. The mechanisms underlying structural remodeling are complex and are various. In par-ticular, underlying (cardiovascular) diseases play a key role in initiation and progression of structural remodeling. As soon as the underlying disease occurs, then already the re-modeling process starts. This means that atrial structural rere-modeling starts already (long) before the first occurrence of AF (figure 1).7 Underlying cardiovascular diseases cause
activation of several other processes leading to calcium overload, activation of the renin-angiotensin-aldosteron system (RAAS), increased levels of endotheline, natriuretic
pep-tides, transforming growth factor β, matrix metalloproteinases, and heath shock proteins, and it causes increased inflammation and oxidative stress.7 These processes are associated
with the occurrence of various types of structural remodeling causing atrial dilatation, car-diomyocyte hypertrophy, dedifferentiation, fibrosis, myolysis, and mitochondrial changes (figure 2).7 These changes in atrial structure cause disturbances in the atrial conduction
properties, which cause local electrical disturbances and re-entry, and eventually will lead to arrhythmogenesis, and subsequently AF initiation and progression.1-4,8
undeRlyinG CondiTions of aTRial RemodelinG
The amount of risk factors that are thought to be associated with an increased AF risk is enormous and varies over time.9 It is important to distinguish between non-modifiable
risk factors, such as advancing age, sex, inflammatory diseases, and genetic and ethnic background, and modifiable risk factors, for example the presence of hypertension, obe-sity and diabetes mellitus, because of the possibility to interfere in these modifiable risk factors creating a window for new treatment strategies.10,11 Presence of these associated
diseases, among others hypertension, heart failure and obesity, cause atrial stretch, leading to calcium overload, activation of RAAS, inflammation and oxidative stress and release of several other factors, which cause structural remodeling setting the stage for AF.7
Once AF eventually occurs, AF itself also increases the risk for AF to occur. A vicious circle is born.
Figure 1. Vulnerability for AF consists of genetic predisposition, a substrate and triggers
Vulnerability for AF, consisting of genetic predisposition, substrate, and triggers will ultimately lead to AF progression. Adapted from Chang et al.146, with permission.
age
As shown in chapter 3 and chapter 4, advancing age is an important non-modifiable risk factor of AF. Several mechanisms such as age-related conduction delay, vascular stiffen-ing and fibrosis, not necessarily accompanied by other cardiovascular diseases, make it easier for AF to occur.12-14
Although, advancing age as a risk factor is non-modifiable, in combination with the occurrence of cardiovascular diseases and decline in physical and cognitive functioning, it has a synergistic effect on negative outcome in terms of cardio-vascular morbidity, mortality, social wellbeing, and health care use.15-17 This underscores
the importance of pursuing healthy ageing in terms of improving cardiovascular health and fitness to prevent or delay occurrence of cardiovascular disease, improve physical and cognitive functioning, and reduce health care utilization.
sex
Male sex is another important non-modifiable risk factor in the occurrence of AF.9,18
Both the Rotterdam study and the Olmsted County Minnesota study describe higher incidence rates for men, 11.5 and 4.7 (per 1000 person-years), compared to women, 8.9 and 2.7 (per 1000 person-years)19,20
, which increases in both sexes substantially with increasing age with a incidence of 32.9 (per 1,000 person-years) in men and 30.4 (per 1,000 person-years)
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 remodeling and finally in AF. Adapted from De Jong et al.7, with
in women at the age of 85–89 year.21 This difference may be due to differences in phenotype
characteristics and prevalence of associated disease between men and women, for example in women hypertension18
and heart failure with a preserved ejection fraction22,23
are more prevalent, whereas coronary artery disease is more prevalent in men.24
Furthermore, physi-cal differences such as variation in stature, men are generally taller than women25-27, and
genetic or chromosomal differences28,29, may be another explanation for this difference
in incidence between men and women.18
Although the AF incidence in men is higher, due to a longer life expectancy in women the absolute number of AF patients and life time AF risk is similar between both sexes.19,30,31 Furthermore, female sex is associated with worse
symptoms, and subsequently more health care utilization and lower quality of life32-35, and
worse cardiovascular outcome. 36-38
hypertension
Hypertension is one of the main risk factors setting the stage for AF development. The prevalence of hypertension in AF cohorts ranges up to 80%, contributing to a significant proportion of AF risk.9,39 Several studies have shown that hypertension leads to atrial
stretch and subsequently causes atrial fibrosis, left atrium enlargement, slowed conduction and increased heterogeneity, influence on effective refractory periods, more fractionated AF episodes, and greater AF inducibility.40-42
However, not only hypertension is associ-ated with an increased AF risk, even a mildly elevassoci-ated blood pressure in young patients is already associated with an increased AF risk.43 This emphasizes early detection and early
intervention.
heart failure
Atrial fibrillation and heart failure frequently coexist, with a prevalence being as high as 50%.20,39
Both AF and heart failure are associated with increased morbidity and mortality. Besides sharing the same risk factors such as, ischemic heart disease, valvular disease, hypertension or diabetes mellitus, both diseases are inextricably linked to each other with each disease predisposing for the other. However, the pathophysiologic mechanisms which underlie both diseases are complex and not completely understood. Heart failure with reduced ejection fraction may cause AF due to neurohomormal activation, mechanical and hemodynamic factors, and electrophysiolical changes causing structural remodel-ing44, whereas heart failure with preserved ejection fraction, which is difficult to diagnose
and therefore often neglected, may give rise to AF because of occurrence of structural and functional remodeling of the left atrium, causing electrical remodeling and changes in re-fractoriness, also setting the stage for AF.45 Furthermore, in heart failure with an preserved
ejection fraction activation of neuroendocrine systems such as RAAS, and atrial natriuretic peptides, may contribute to the occurrence of AF.45
AF on the other hand may give rise to heart failure due to loss of AV synchronicity, rapid ventricular rate, and structural changes causing left ventricular myocardial fibrosis. 44,45
Furthermore, occurrence of atrioventricular remodeling causing mitral valve or tricuspid valve regurgitation may aggravate ongoing processes leading to heart failure.44
diabetes mellitus
Diabetes mellitus and AF frequently coexist and its prevalence is approximately 20% in the AF population.20
Data about the role of diabetes mellitus in atrial remodeling is sparse and its role is complex and not completely understood. Possible involved mechanisms are among others inflammation, including immunological alterations of the vasculature re-sulting in atherosclerosis as well as microvascular disease, oxidative stress, atrial fibrosis, and electrical vulnerability due to autonomic neuropathy and/or cardiac repolarization ab-normalities.11,46-48 These mechanisms may cause other cardiovascular disease, for example
peripheral and coronary artery disease, which also might play a role in the occurrence of AF.
obesity
Obesity is only recently recognized as an independent novel risk factor for AF. With an increasing BMI giving a higher AF risk.49,50
Obesity may cause increased sympathetic activ-ity, inflammation, left ventricular dysfunction and fatty infiltration of the atria.51,52
Further-more, obesity is associated with increased presence of epicardial adipose tissue. Through its biological activity, including metabolic activity, glycolysis, angiogenic factors, growth and remodeling factors, adipocytokines, and inflammatory cytokines and chemokines, epicardial adipose tissue is believed to be a possible important player in the formation of AF substrate, which is facilitated by the absence of facial barriers between the epicardial fat, cardiac musculature and blood vessels.51,53
Furthermore, obesity and subsequently an increase in epicardial adipose tissue has been associated with changes of the myocardial structure due to fatty infiltration, causing left atrial enlargement, conduction abnormal-ity, and interstitial fibrosis, resulting in structural remodeling and setting the stage for incident AF.53,54
sleep apnea syndrome
The numbers of patients with obstructive sleep apnea (OSA) is increasing over the last years and the rise in incidence, with or without presence of AF, may reflect its close association with obesity.55
Due to neurohormonal activation OSA can increase platelet aggregation and increase blood pressure subsequently causing cardiac hypertrophy, diastolic dysfunc-tion, left atrium dilatadysfunc-tion, and increase fibrosis and fat content.51,53,54,56 Furthermore
OSA causes increased vulnerability for AF due to increased expression in inflammatory cytokines57
, changes in refractory period58
fitness
Encouraging physical activity to increase cardiorespiratory fitness and to reduce weight is an important part of cardiac rehabilitation programs. There is increasing evidence that there is a dose dependent effect of weight loss and AF burden, improvement of blood pres-sure and blood glucose levels, improvement lipid management and alterations in cardiac structure.60-62 Furthermore there is increasing evidence that there is an inverse relationship
between an increase in physical activity and AF risk and it is associated with a reduced cardiovascular morbidity and mortality risk.63-66
High baseline cardiorespiratory fitness has been associated with almost 6-fold greater AF-free survival than those with low car-diorespiratory fitness. 60,61 On the other hand, vigorous exercise has been associated with
a higher risk of developing AF. However, data on this matter are conflicting.67
The mecha-nisms in which physical activity is believed to contribute to prevention of AF incidence and progression are various and concern indirect pathways.53,61 Regular exercise has important
effects on weight, blood pressure and blood glucose levels 60,61,68,69, inflammation and
subsequently vascular alterations, hemostasis, and prevention of neurodegeneration and other associated diseases such as heart failure.62,70-74 Therefore a sedentary life style should
be avoided at all costs.
lifestyle factors
Several modifiable lifestyle factor have been related to the occurrence of AF. Among others, excessive alcohol consumption, smoking, caffeine consumption, drug use and psycho-social factors and air pollution.10
However, data on the underlying mechanisms of these factors contributing to the occurrence of AF are sparse and the pathophysiologic processes are not completely understood.42,67
other risk factors
The above-mentioned risk factors are just a few of an enormous list of risk factors that may contribute to the occurrence of AF. Other factors contributing to AF occurrence are genetic predisposition75,76, clinical and subclinical hyperthyroidism77,78, clinical and subclinical
vascular disease79-81 , valvular disease9,24 , cholesterol levels67 , length25-27 , a high normal blood pressure43 , inflammation82
, and chronic kidney disease83
(table 1). Also psychologi-cal and psychosocial factors are a few of many factors contributing AF incidence.67 Beside
an important role in the onset of AF it is believed that these risk factors, through a continu-ous influence in the remodeling process, also play an important role in AF progression. However, clinical evidence so far is limited.
hyPeRCoaGulabiliTy in af – Cause oR ConsequenCe
As described previously, occurrence of ischemic stroke is one of the major complications of AF.39,84 The pathogenesis of thrombus formation is multifactorial and considered to
consist of a triad of events i.e. altered blood flow, endothelial dysfunction or damage, and abnormal hemostasis, known as Virchow’s triad.85
Although the role of stasis in a reduced contractility left atrium is well described, increasing evidence suggests that the
patho-Table 1. Overview of modifiable and non-modifiable risk factors, the list is not necessarily exhaustive.
Non-modifiable Modifiable
Conventional risk factors Conventional risk factors
Age Hypertension
Male Gender Heart failure
Genetic factors with reduced ejection fraction
Height with preserved ejection fraction
Less established risk factors Diabetes mellitus
Ethnic background Coronary artery disease
Valvular disease Hyperthyroidism Obesity
Less established risk factors
Chronic obstructive pulmonary disease Obstructive sleep apnea syndrome Left atrial dilatation
Atrial conduction delay/ PR interval Left ventricular diastolic function Left ventricular hypertrophy Subclinical atherosclerosis Borderline hypertension Chronic kidney disease Subclinical hyperthyroidism Inflammation
Pulse pressure Vigorous exercise Inactivity
Excessive alcohol intake Increased height Increased birth weight Smoking
genesis of thrombogenesis in AF is multifactorial and not only related to stasis in a poor contractility left atrium.85 Recent studies demonstrate that AF in itself confers additional
prothrombotic effects in low risk patients (CHA2DS2-VASc score 0), beyond the patient’s
comorbidities (chapter 2).85-87
This hypercoagulability might play an active role in the etiol-ogy and progression of AF.85 In recent years, a lot of research has been done on
biomark-ers that may predict AF and AF-related thromboembolic complications.88 For example,
biomarkers representing a prothrombotic state such as D-dimer, thrombin antithrombin complexes and fibrinogen have been related to AF.89,90
The origin of activated clotting in AF and other underlying conditions is thought to be multifactorial, however, firm evidence of causal factors and mechanisms is lacking. The following mechanistic factors have been proposed. Systemic pro-inflammatory mechanisms, a common pathophysiological mechanism of AF, can trigger systemic coagulation activity.91,92
Additional contributions to inflammation and coagulation stem from activated RAAS in patients with hypertension and heart failure and other (cardiovascular) diseases, which may activate pro-coagulant and anti-fibrinolytic mechanisms.85
Local factors are caused by endothelial perturbation in the left atrium. These include increased expression of tissue factor,93 reduced expression
of thrombomodulin,94 impairing protein C activation and increased concentration of
plas-minogen activator inhibitor 1 (PAI-1)95-97
as well as reduced nitrous oxide production.98-100
Even components of the contact system of coagulation may promote coagulation and/or inflammation mediated by platelets and plasma thrombin generation, and driven by an altered endothelial cell phenotype.99 With respect to the pathophysiology of AF-related
hypercoagulability the overall concept is that thrombin generation is the main process, while platelets and fibrinolysis contribute to an uncertain extent. Furthermore it was dem-onstrated that coagulation factors can activate protease-activated receptors (PARs), with a particular role for thrombin and factor Xa.101,102 PARs at their turn can cause inflammation,
endothelial dysfunction, vascular dysfunction, atherosclerosis, tissue fibrosis and cellular hypertrophy, as a consequence of their pro-inflammatory, profibrotic and prohypertrophic effects. 101,102 And therewith setting the stage for AF (figure 2). However, the precise
mecha-nisms in which hypercoagulability contributes to AF outcome, especially in combination with other underlying conditions, such as advancing age, sex, and cardiovascular comor-bidities are complex and have yet to be determined.
af ClassifiCaTion
A clinical tool to communicate the status of AF is to classify patients as having paroxysmal AF (AF lasting no longer than 7 days, either self-terminating or terminated with electri-cal or chemielectri-cal cardioversion), persistent AF (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), or permanent AF (AF that is accepted by the patient and physician, which means that a rate control strategy is adopted).11
However, previous studies have shown that this clinical classification of AF fails to adequately reflect the temporal persistence of AF and expected rhythm outcome. This may occur because the current clinical classification does not take the origin of AF, the severity of the underlying substrate, nor the actual AF burden, in consideration (figure 1).103
Therefore we investigated in chapter 3 and chapter 4 clinical, biomarker, and genetic predictors of specific AF types. In chapter 3 we showed that genetic background seems to play an important role in self-terminating AF. Furthermore, in mul-tivariate multinominal logistic regression advancing age was associated with all types of AF, male sex was associated with AF without 2-year recurrence, whereas male sex, higher BMI, higher mid-regional prohormone atrial natriuretic peptide (MR-proANP) levels, and antihypertensive medication were associated with self-terminating AF. Higher BMI, higher MR-proANP levels, lower heart rate, lipid lowering medication, and estimated glomerular filtration rate < 60ml/min/1.73m2
were associated with non-self-terminating AF.76
In ad-dition in chapter 4 we showed significant differences in clinical characteristics between patients with different AF patterns. Furthermore, patients with the non-selfterminating AF showed the highest progression rate to more persistent forms of AF. So, differences in underlying diseases and risk factors may lead to distinct AF patterns, possibly as a con-sequence of different underlying mechanisms causing atrial remodeling. This opens the door to more scientific evidence that classification derived from the presence of triggers and/or substrate is important for accurate patient classification.
measuRinG aTRial RemodelinG
The extent of atrial remodeling is pivotal for the success of rhythm control in AF.104,105
In ad-dition to clinical parameters like age and underlying disease, the extent of atrial remodeling is thought to be related to fibrosis, inflammation, hypercoagulability, genetic vulnerability to remodeling, and the duration of AF itself.85,106-109
A potent clinical marker of remodeling is left atrial (LA) size. LA size may correlate with the severity of structural remodeling. Furthermore LA size is a determinant of prognosis and an important and widely used clinical tool to predict rhythm control outcome.110,111 Nowadays other, more sophisticated,
echocardiographic methods are available to measure atrial function, such as strain and strain rate imaging, total atrial conduction time and left ventricular diastolic function.112,113
Beside echocardiographic markers, atrial remodeling also seems to be represented by circulating biomarkers. AF has been associated with markers54 of collagen/ collagen
metabolism (e.g. procollagens, matrix metalloproteinases),109
inflammatory mediators (e.g. white blood cell count, high-sensitive C-reactive protein, interleukins, tumor
necro-sis factor alpha, angiotensin II),106 neurohumoral factors (e.g. atrial natriuretic peptide,
brain-type natriuretic peptide, apelin),114,115 markers for atherosclerosis and endothelial
dysfunction (e.g. circulating endothelial progenitor cells, angiopoetin 2, nitric oxide),116
heat shock protein and thrombogenesis markers (e.g. P-selectin, von Willebrand factor, prothrombin fragment 1+2, fibrinopeptide A, d-dimer, tissue factor, β-thromboglobulin, thrombocytes, vascular endothelial growth factor),85,86,117 and fibrinolysis markers (PAI-1,
tissue plasminogen activator, plasmin-antiplasmin complex) 85,117-119
Other tools to evaluate atrial remodeling can be divided into non-invasive and invasive tools. Non-invasive tools to assess atrial remodeling include three-dimensional echocar-diography, multi-slice computed tomography and magnetic resonance imaging, although data on the accuracy are sparse and there use in clinical practice is limited.120-122
Invasive tools include electrophysiological mapping, a technique that can be performed during electrophysiological investigation or cardiac surgery, in which electrical potentials are recorded directly from the surface of the heart showing electrical disturbances reflecting presence of atrial remodeling.123
In addition, recent studies have been focusing on noninvasive imaging modalities for cardiac electrophysiology. This technique images potentials, electrograms and activation sequences (isochrones) by using a vest with electrodes. In combination with information collected during computed tomography and an mathematical algorithm a reconstruction of the electrical potentials on the heart’s surface is reproduced.124 However, this technique
is not widely used yet.
CliniCal imPliCaTions of PRoGRession of af and fuTuRe diReCTions
Although the knowledge about the pathophysiology of AF and pharmacological interven-tions, such as antiarrhythmic drugs, and therapeutically interventions such as ablation, has increased during the past decades, AF treatment is still cumbersome.125 In particular
the use of antiarrhythmic drugs has shown to have limited success on AF outcome.126 This
is due to the fact that present interventions do not target the underlying substrate contrib-uting to atrial remodeling that causes AF. We know for example, that current interventions such as ablation are especially effective in those patients with less remodeled atria, which are predominantly patients with paroxysmal AF.125 However, for the majority of patients
these interventions come too late and structural remodeling is already present and the damage is already done.127
In addition, inadequate treatment of underlying factors might be an important contribu-tor to failure of rhythm control.42 Therefore treatment strategies aiming at early
interven-tion on the underlying substrate to reduce atrial remodeling and subsequently prevent the occurrence of atrial fibrillation and progression are urgently needed. Previous studies
aiming at secondary prevention targeting a single risk factor showed conflicting, predomi-nantly negative, results on AF outcome.128-130 However, more recent studies highlighted
that intervening in a combination of risk factors and lifestyle to prevent AF development or improve AF outcome may be beneficial.42
For example, studies evaluating OSA treatment show possible benefits of accurate treatment on reverse remodeling and the risk of AF re-currences.131,132 However, the studied population was small and no conclusions regarding
cause effect relations may be drawn. Furthermore, echocardiographic measurements sug-gests reverse atrial remodeling in those patients successfully treated by CPAP.133,134
Recent studies have focused on the role of mild-moderate higher usual systolic blood pressure and hypertension and their role as a risk factor for atrial fibrillation, showing that even a 20mmHg higher usual systolic blood pressure in younger patients nearly doubled the risk of AF. Aggressive treatment of hypertension targeting a systolic blood pressure of less than 120 mmHg has been shown to result in a lower rate of fatal and nonfatal cardiovascular events and all-cause death and appear to be well tolerated by patients.135,136 Other studies
have focused on aggressive goal directed therapy in the care of overweight and obese AF patients and have shown that that weight reduction has a dose-dependent effect on AF out-come. 60 These studies also showed that weight reduction resulted in significant decrease
of systolic blood pressure, insulin resistance, inflammatory markers, cholesterol levels, and echocardiographic parameters such as left atrium volume, left ventricular end diastolic diameter, left ventricular hypertrophy, diastolic parameters, and symptom burden, as well as improvement of quality of life.60,137 Also cardiorespiratory fitness has been associated
with a beneficial effect on AF prevention and AF outcome. Improvement of cardiorespira-tory fitness within a certain range has been shown to be protective in prevention of AF.63
Furthermore baseline cardiorespiratory fitness in overweight and obese patients predicted long-term freedom of AF, with a significant dose-response relationship between baseline cardiorespiratory fitness with a 20% reduction in risk of AF recurrence for each metabolic equivalent of task increase in baseline cardiorespiratory fitness.61
It has also been shown that improvement of cardiorespiratory fitness on top of weight loss has an additive ef-fect in improving long term outcome of AF.61 In addition, the RACE 3 trial showed that
targeted upstream therapy consisting of an ACE-inhibitor or angiotensin receptor blocker, a mineralocorticoid receptor antagonist, a statin, cardiac rehabilitation consisting of a physiotherapist guided sports program three times a week, and 6-weekly counseling for dietary advice, to improve physical activity, and improve drug adherence, on top of usual AF an heart failure care according to current guidelines, resulted in a significantly lower systolic and diastolic blood pressure, a significant reduction in LDL cholesterol, and a greater decline in NT-proBNP levels compared to patients with a conventional treatment. In line with the effects on the underlying factors, patient in the targeted therapy group maintained sinus rhythm significantly more than patients in the conventional group
(chap-ter 5).138
cardiovascular hospitalizations were limited, showing no significant differences between both groups. This might be due to patient selection, severity of the underlying disease, the timing of intervention and the indirect effects of medication and lifestyle adjustments on cardiac, in specific atrial, function.
In this perspective an additional role may be reserved for the immediate and direct effects of antiarrhythmic drugs and/or an ablation procedure, as shown in the CABANA Trial and the CASLTE-AF study.139,140
In the CABANA Trial patients with new onset or undertreated AF, i.e. symptomatic AF despite treatment or incompletely treated AF that, in the opinion of the investigator, warranted therapy, were randomly assigned to undergo either catheter ablation or drug therapy to investigate the safety and efficacy of catheter ablation. Overall the study showed that ablation was not superior to drug therapy for the combined primary endpoint consisting of all-cause mortality, disabling stroke, serious bleeding or cardiac ar-rest. However, subgroup analysis indicates that specific patient categories might do benefit from ablation. Furthermore, the per protocol analysis indicated that there might be a re-duction in death or cardiovascular hospitalization with ablation compared to drug therapy. However, this was not the primary endpoint of the study and can only be interpreted as hypothesis-generating. In the CASTLE-AF study patients with symptomatic paroxysmal or persistent AF and heart failure were randomly assigned to undergo either catheter ablation or medical therapy. Although AF was not completely eliminated in all patients, this study suggests that the immediate and direct effects of these treatment strategies, on top of heart failure treatment, might further improve reverse remodeling and subsequently leads to a reduction in heart failure hospitalization and mortality in a predominantly (90% men) patient population with pre-existing heart failure, with a significant lower incidence rate in patients treated with ablation compared to medical therapy. Both studies suggest that combining both ‘upstream’ and ‘downstream’ treatment strategies may be the key to slow progression of AF and prevent adverse events, especially when started early in the disease process, which is investigated in the EAST trial.141-143
On top of that, an additional role may be reserved for the coagulation system. Besides the role of underlying risk factors, which also might cause activation of the coagulation system, also the coagulation system itself may play an important role in the occurrence of AF by activation of coagulation factors and subsequently prohypertrophic, pro-fibrotic and pro-inflammatory effects of PARs. Spronk et al. showed that hypercoagulability promotes the development of a substrate for AF in transgenic mice and in goats with persistent AF through activation of thrombin induced a pro-fibrotic and pro-inflammatory response by activation of the PAR1 receptors.102
Inhibition of coagulation with non-vitamin K an-tagonist oral anticoagulants (NOACs), who inhibit PAR stimulation, may not only prevent strokes but also inhibit the development of a substrate for AF.101 These findings suggest
there might be a potential role for the use of NOACs, not only as treatment for the adverse effects of AF such as stroke, but also as treatment of AF itself. However, no human studies
are published yet. Further research to elucidate the possible mechanisms and potential benefits of NOACs is therefore warranted, and will be performed within the RACE V study, as well as the role continuous rhythm monitoring in the treatment of AF by unraveling AF patterns and those at risk of AF progression. This emphasizes that more research needs to be done to examine the role of various interventions for prevention of incident and progression of AF.
It is evident that current knowledge opens the door to scientific evidence that lifestyle modification and risk factor management is effective in prevention of AF progression, and that we need adjust our model of care. To achieve lasting results in prevention of AF incidence and AF progression it is necessary to implement risk factor management and lifestyle changes on top of the current AF treatment strategies such as rate control, rhythm control and anticoagulation therapy.42
Beside risk factor management more insight in AF pattern and AF burden through continuous rhythm monitoring may improve risk predic-tion and subsequently optimize AF treatment. These invenpredic-tions should be tailored to the patients individual needs and underlying comorbidities to improve outcome and minimize adverse events (chapter 7).42,144,145
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