Diagnosis and Therapy of Atrial Fibrillation: the Past, the Present and the Future
Denise M.S. van Marion MSc1, Eva A.H. Lanters MD2, Marit Wiersma MSc1, Maurits A. Allessie MD, PhD3, Bianca B.J.J.M. Brundel, PhD,1,4, Natasja M.S. de Groot MD, PhD2
1Department of Clinical Pharmacy and Pharmacology, University Institute for Drug Exploration (GUIDE), University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.2Department of Cardiology, Erasmus Medical Center, Rotterdam, The Netherlands.3Cardiovascular Research Institute Maastricht, Maastricht, The Netherlands.4Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands.
Atrial fibrillation (AF) is the most common age-related cardiac arrhythmia. It is a progressive disease, which makes treatment difficult. The progression of AF is caused by the accumulation of damage in cardiomyocytes which makes the atria more vulnerable for AF. Especially structural remodeling and electrical remodeling, together called electropathology are sustainable in the atria and impair functional recovery to sinus rhythm after cardioversion.
Key Words : Atrial Fibrillation, Von Willebrand Factor, Biomarker..
Corresponding Address : N.M.S. de Groot, MD, PhDDepartment of CardiologyThoraxcenter-Room Ba 579Erasmus MC‘s Gravendijkwal 2303015 CE RotterdamThe Netherlandsl
The exact electropathological mechanisms underlying persistence of AF are at present unknown. High resolution wavemapping studies in patients with different types of AF showed that longitudinal dissociation in conduction and epicardial breakthrough were the key elements of the substrate of longstanding persistent AF. A double layer of electrically dissociated waves propagating transmurally can explain persistence of AF (Double Layer Hypothesis) but the molecular mechanism is unknown. Derailment of proteasis –defined as the homeostasis in protein synthesis, folding, assembly, trafficking, guided by chaperones, and clearance by protein degradation systems – may play an important role in remodeling of the cardiomyocyte. As current therapies are not effective in attenuating AF progression, step-by-step analysis of this process, in order to identify potential targets for drug therapy, is essential. In addition, novel mapping approaches enabling assessment of the degree of electropathology in the individual patient are mandatory to develop patient-tailored therapies. The aims of this review are to
1) summarize current knowledge of the electrical and molecular mechanisms underlying AF,
2) discuss the shortcomings of present diagnostic instruments and therapeutic options and
3) to present potential novel diagnostic tools and therapeutic targets.
The first electrocardiogram (ECG) of atrial fibrillation (AF) was recorded by Einthoven in 1906.1 Nowadays, AF is one of the most common arrhythmias with a prevalence varying from <0.1% to >12% in the elderly which is expected to be doubled in patients over 55 years by 2060.2,3 AF is originally known as a disease of the ageing population. However, an increasing prevalence is seen in young adults, especially in endurance athletes4 and patients with congenital heart disease.5 Hence, a continuous rise in the number of AF associated hospitalizations and healthcare costs is to be expected.6 Several treatment modalities have been developed, but all are associated with high recurrence rates or negative side effects. The aims of this review are to
1) summarize current knowledge of the electrical and molecular mechanisms underlying AF,
2) discuss the shortcomings of present diagnostic instruments and therapeutic options and
3) to present potential novel diagnostic tools and targets for future therapy.
Deficiencies in Diagnostic Tools of Atrial Fibrillation
AF is usually diagnosed by a surface ECG or Holter recording.However, diagnosis of new onset, paroxysmal or asymptomatic AF
can be challenging. An ECG only captures several seconds of the heart
rhythm and episodes of AF can therefore be easily missed. The use
of long-term ambulatory electrocardiography devices or implantable
loop recorders increases the chance of detecting AF paroxysms. In
addition, these devices also allow determination of the total duration
of all AF episodes within a specific time frame, the so-called AF
burden. However, electrocardiographic recordings do not provide any
information on the mechanism underlying AF. Recent studies7-10
suggest that body surface mapping arrays, containing 252 electrodes,
may be useful to identify driver regions in patients with AF. Yet,
none of the currently available recording techniques can determine
the degree and extensiveness of atrial electropathology. Hence, when
a patient presents with AF, we have no diagnostic tool available for
evaluating the mechanism underlying AF and determining the stage
of the disease at any time in the process.
Table 1. Novel therapeutic targets
Drug | Target | Phase | Indication | Ref (clinical trials.gov identifier) |
---|
GGA | HSP induction | Phase IV | Gastric ulcers
Gastritis
Gastric lesion | NCT01190657
NCT01547559
NCT01284647
NCT01397448 |
NYK9354 | HSP induction | Pre-clinical | Atrial Fibrillation
| (HoogstraBerends
et al., 2012) |
Leupeptin
ALLN
MDL-28170
A-705239
A-705253 | Calpain
induction | Pre-clinical | | reviewed in
Cardiovascular
Research (2012)
96, 23–31 |
Tubastatin | HDAC6 | Pre-clinical | Arthritis
Anti-inflammatory | (Vishwakarma et
al., 2013) |
ACY-1215 | HDAC6 | Phase I/II | Myeloma | NCT01323751
NCT01583283 |
Fasudil
Ezetimibe
AR-12286 | ROCK | Phase III
Phase II
Phase II
Phase IV
Phase II | Raynaud’s Phenomenon
Vascular function
study Atherosclerosis
Atherosclerosis
Glaucoma | NCT00498615
NCT00120718
NCT00670202
NCT00560170
NCT01936389 |
CCG-1423
Rhosin | Rho | Pre-clinical | | (Evelyn, et al.,
2007)
(Shang, et
al.,2012) |
Figure 1. Epicardial breakthrough Upper panel: beat-to-beat variation in spatiotemporal distribution of epicardial breakthrough waves (‘focal waves’) during 6 seconds of persistent AF in a small area of 1.25 X 1.25cm between the pulmonary veins. Each asterisk indicates a breakthrough site. The large map shows all 55 epicardial breakthroughs sites. The size of the asterisk is proportional to the number of epicardial breakthroughs occurring at that site. The breakthrough map demonstrates a wide distribution of these focal waves; none of these breakthrough waves occurred, however, repetitively. Lower panel: schematic presentation of excitation of the endoand epicardial layer explaining how transmural conduction from the endocardium to the epicardium gives rise to an epicardial breakthrough wave. Hence, the endocardial layer serves in this case as a source for ‘new’ fibrillation waves in the epicardial layer.22
Mechanisms Of Atrial Fibrillation: From Past To The Present
Experiments performed by Gordon Moe11 nearly 60 years ago,
provided the basis for the ongoing debate on the underlying cause
for AF. In isolated canine atria, he showed that AF could be due to
either fibrillatory conduction (AF caused by an ectopic focus with
a high frequency discharge resulting in non-uniform excitation of
the atria) or true fibrillation (AF persists independently from the
site where it was initiated). In 1959, Moe11 introduced the so-called
Multiple Wavelet Hypothesis which further described the features of
true fibrillation. In this hypothesis, Moe postulated that persistence
of AF depended on the average number of wavelets. With the total
number of wavelets being increased, the probability of extinguishment
and thus termination of AF would become smaller. Twenty-six years
later, Allessie et al.12 performed the first experimental evaluation of Moe’s multiple wavelet hypothesis. In a canine right atrium, during
0.5 second of acutely induced AF, he demonstrated in series of
consecutive excitation maps that there was a continuous beat-tobeat
change in activation pattern. The critical number of wavelets in
both right and left atria necessary to perpetuate AF was estimated
to be between three and six. Ever since, numerous experimental and
clinical mapping studies,11, 13-21 reporting on perpetuation of AF,
are supportive on either a focal (repetitive ectopic discharges) or
reentrant mechanism (mother-wave, rotor, multiple wavelets). In the
past years, most clinical studies reported on the presence of rotors in patients with various types of AF.20
Figure 2. Overview of AF-induced cardiomyocyte remodeling AF induces time-related progressive remodeling. First, AF causes a stressful cellular Ca2+ overload, which results in a direct inhibition of the L-type Ca2+ channel, shortening of action potential duration and contractile dysfunction. These changes have an early onset and are reversible. The early processes protect the cardiomyocyte against Ca2+ overload but at the expense of creating a substrate for persistent AF. When AF persists derailment of proteostasis occurs, which results in microtubule disruption, cytoskeletal changes and degradation of proteins. The targets involved in proteostasis are RhoA/ROCK, HDAC6 and calpain. In addition, HSP induction has been found to counteract these targets. Derailment of proteostasis results in structural remodeling, myolysis/ hibernation, and consequently impaired contractile function and AF persistence. Thus drugs that normalize proteostasis via inhibition of RhoA/ROCK, calpain, and HDAC6, but also via induction of cardioprotective HSPs are of therapeutic interest for future treatment of clinical AF.
Electropathology Associated With Persistence Of Atrial
Fibrillation
High-resolution wavemapping studies22 of AF in patients with
valvular heart disease and longlasting persistent AF, demonstrated
that a large proportion of fibrillation waves were so-called focal waves.
These waves appeared in the middle of the mapping area and could not
be explained by fibrillation waves propagating in the epicardial plane.
Focal fibrillation waves appeared scattered throughout the mapping
area and were not repetitive (Figure 1). The coupling interval was
longer than the dominant AF cycle length, and unipolar electrograms
at the epicardial origin of these waves exhibited R-waves.22 Hence,
characteristics of these focal fibrillation waves strongly suggest that
they originated from endo-epicardial breakthrough. These findings
were supported by a report from Lee et al.23 who observed that more
than one third of the fibrillation waves in patients with persistent AF were of ‘focal’ origin without any area sustaining focal activity.
Based on our observations, we recently introduced a new mechanism
explaining persistence of AF independently of the presence of foci or
re-entrant circuits in our Double Layer Hypothesis.22, 24 The “Double
Layer Hypothesis” states that the substrate of longstanding persistent
AF in humans is caused by progressive endo-epicardial dissociation,
transforming the atria into an electrical double layer of dissociated
waves that constantly ‘feed’ each other (Figure 1). Whereas in
patients with short-lasting episodes of AF, the endo- and epicardial
layers are still activated synchronously, in patients with longstanding
persistent AF, the endo- and epicardial layers of the atrial wall are
activated asynchronously. Over time, due to electrical and structural
remodeling of the atria, the atrial wall is gradually transformed into
a double layer of narrow anatomically delineated pathways. The
exact molecular mechanisms underlying electrical dissociation are,
however, unknown.
Figure 3. Intra-individual variation in electrogram morphology. Typical examples of unipolar fibrillation electrograms recorded from the middle of respectively the right atrial appendage (RA), Bachmann’s Bundle (BB) and the pulmonary vein area (PV) obtained from a patient with mitral valve disease and persistent AF. In the right atrium, the fibrillation potentials contain a single deflection whereas fibrillation potentials recorded from Bachmann’s Bundle and the pulmonary vein area contain multiple deflections.
Molecular Mechanisms Underlying Electropathology AF
As mentioned above, AF is a progressive disease, which can be
explained by the fact that AF itself induces alterations in both
function and structure of the cardiomyocyte. These alterations induce
an arrhythmogenic substrate which facilitates perpetuation of AF
episodes.25
During the last decennia, various researchers aimed to identify
the molecular mechanisms that underlie cardiomyocyte remodeling
and AF progression. Although several pathways, especially related
to ion channel remodeling, have been described, the exact molecular
mechanisms driving AF remodeling and progression are still
unidentified. The general concept is that during AF, cardiomyocytes
are subjected to rapid and irregular excitation causing calcium
overload in the cells which leads to fast and reversible electrical
remodeling and slower, irreversible structural remodeling (figure 2).
The cardiomyocyte responds to a calcium overload by the functional
downregulation of L-type Ca2+ current channels, which causes the shortening of action potential duration (APD) and electrical
remodeling, thereby providing a further substrate for AF.26-30
Also, several other ion channel currents are affected either on the expression level or phosphorylation and redox status.31-33 In addition,
various kinases and phosphatases become activated and regulate the
function of ion channels and other downstream target proteins, for
example transcriptions factors, various calcium handling proteins
(such as RyR2, Sarcoplasmic Reticulum Ca2+ ATPases (SERCA),
or Na+/Ca2+ exchanger) and the actin cytoskeleton.34-38
Figure 4. Inter-individual variation in characteristics of fibrillation waves. Examples of six consecutive wavemaps obtained from the right atrial free wall constructed during acute AF (upper panel) and persistent AF (lower panel); unipolar fibrillation electrograms recorded in the middle of the mapping area are shown on top. The mapping area activated by each individual fibrillation is represented by a color; every color indicates the moment of entrance in the mapping area (from red to purple); the arrows indicate the main trajectory of the fibrillation wave (black: peripheral fibrillation wave, white epicardial breakthrough wave). During acute AF, there are a fewer number of fibrillation waves and the patterns of activation are less complex, compared to persistent AF. In addition, ‘focal fibrillation waves’ occur more frequently during persistent AF.
When AF persists beyond a few days, irreversible structural
remodeling occurs, especially hibernation39 (figure 2). Various
research groups39-41 showed that hibernation is a form of tissue
adaptation. It is defined as the ability of the cardiomyocytes to turn
into a non-functional phenotype featuring irreversible degradation
of the myofibril structure (myolysis), which leads to loss of atrial contraction.
Figure 5. Atrial epicardial mapping Activation -, conduction block- and voltage maps constructed from Bachmann’s Bundle, right atrium, crista terminalis, pulmonary vein area, left atrioventricular groove, left atrial appendage during sinus rhythm, obtained from a patient with coronary artery disease. Electrograms recorded from the middle of the mapping area are shown on top. Arrows in the color-coded activation maps show the main trajectory of the excitation wave. Areas of slow conduction (<18cm/s) and conduction block (<30cm/s) are represented by respectively blue and red lines. Voltage maps show the peak-topeak amplitude of the atrial potentials.
While the early electrical remodeling is reversible30 a ‘second factor’
underlies the persistence of AF, having a time course comparable to
AF-induced structural changes (hibernation/myolysis) in the atrial
cardiomyocytes.42 Thus, the prevention of structural remodeling
represents a key target to attenuate cardiomyocyte remodeling
and dysfunction and may improve the outcome of (electrical)
cardioversion to normal sinus rhythm. We have strong indications
that derailment of proteostasis represents this ‘second factor’ that
underlies AF progression.38, 39, 43-46
Derailed Proteostasis Novel Concept Of Cardiomyocyte
Remodeling
Proteostasis is defined as the homeostasis in protein synthesis,
folding, assembly, trafficking, guided by chaperones, and clearance by
protein degradation systems.47-50 Healthy proteostasis is controlled
by an exquisitely regulated network of molecular components and cellular pathways, the protein quality control (PQC) system.47, 51
Cells, including cardiomyocytes, are very sensitive to changes in the
intra- and extracellular environment, induced by stressors, including
AF. Stressors can cause derailment in the proteostasis by altering
the stability of proteins, leading to protein damage, unfolding
and breakdown, as observed for cardiac troponins and structural
proteins.38, 43 In the heart, various chaperones, especially Heat Shock
Proteins (HSPs), are expressed to ensure a healthy cardiomyocyte
proteostasis and optimal function of the heart. For example HSP27,cvHSP, HSP20 and HSP22 are important members of the PQC
system and attenuate derailment of proteostasis in AF by assisting
in the refolding of unfolded proteins,38, 51 prevention of AF-induced
damage to contractile proteins44, 52 and attenuation of protein
breakdown.43 In this way, HSPs normalize the proteostasis and
protect the cardiomyocyte against remodeling and AF progression.
Molecular Pathways Underlying Derailed Proteostasis
Recently, several molecular pathways were found to induce
derailment of proteostasis. These pathways include the persistent
activation of calpain, activation of RhoA/ROCK pathway and the activation of HDAC6.
Investigators found proof for a role of persistent activation of the
calcium overload-induced protease calpain to underlie impairment of
proteostasis and AF progression in experimental cardiomyocyte, and
Drosophila model systems for AF,43, 52, 53 but also in human permanent
AF.39 In experimental studies it was observed that calpain activation
causes the degradation of contractile and structural proteins, and
subsequently contributes to structural cardiomyocyte remodeling
(myolysis) and dysfunction and AF progression.43, 53 The role of calpain
was confirmed in human AF. Here, a significant induction in calpain
activation was observed in patients with permanent AF, compared
to patients with paroxysmal AF and controls in sinus rhythm.39
Furthermore, patients with permanent AF revealed induced amounts
of myolysis which correlated significantly with calpain activity
levels, suggesting a role for calpain in derailment of cardiomyocyte
proteostasis, structural remodeling and AF progression.
Also, during AF, RhoA-GTPases are activated. RhoA-GTPases
represent a family of small GTP-binding proteins that are involved
in cell cytoskeleton organization, migration, transcription and
proliferation. They have an important role as regulators of the actin
cytoskeleton in cardiomyocytes54 and trigger the initiation of AF.55,
56 RhoA-GTPases activation results in conduction disturbances and
cardiac dysfunction.57, 58 Recent studies38 revealed that in AF, RhoAGTPase
become activated resulting in the activation of its downstream
effector ROCK and thereby stimulate the polymerization of G-actin
to filamentous F-actin stress bundles. These stress bundles impair
calcium homeostasis and contribute to contractile dysfunction,
cardiomyocyte remodeling and AF progression.38
Furthermore, recently it was found that histone deacetylases
(HDACs), such as HDAC6, are implicated in AF-induced
cardiomyocyte remodeling.43 HDACs affect cardiomyocyte
proteostasis by epigenetically regulating protein expression and
modulating various cytoplasmic proteins, including α-tubulin, a
structural protein from the microtubule network.59-61 By using
mutant constructs, AF-induced contractile dysfunction and
structural remodeling was proven to be driven by HDAC6 via deacetylation
of α-tubulin and finally breakdown of microtubules by
calpain. This effect of HDAC6 was observed in tachypaced HL-1
atrial cardiomyocytes, Drosophila, dogs and confirmed in patients
with permanent AF.43 HDAC6 inhibition by tubacin conserved the
microtubule homeostasis and prevented depolymerized α-tubulin
from calpain-mediated degradation. These results indicate a key
role for HDAC6 in the derailment of cardiomyocyte proteostasis in
experimental and clinical AF.
So, three key pathways in AF-induced structural and functional
remodeling have been identified, and all these pathways impair a
healthy proteostasis of the cardiomyocyte.
Induction Of HSPs Normalize Proteostasis
To maintain a good functioning PQC system, numerous chaperones
are expressed to ensure a healthy cardiomyocyte proteostasis.38 HSPs
are under the control of heat shock transcription factor 1 (HSF1), and
represent important chaperones in proteostatic control.47, 62 During
excessive stress situations such as AF, HSP levels were found to
become exhausted.44 This finding suggests that upregulation of HSP
levels might normalize proteostasis and improve cardiomyocyte
function in AF. In clinical studies, induced HSP levels showed
protection against AF initiation and progression. HSP70 atrial
expression levels were found to correlate with reduced incidence of
post-operative AF in patients in sinus rhythm undergoing cardiac
surgery.63, 64 In another clinical study,65 a potent Heat Shock Response
(HSR) and high HSP27 levels have been associated with restoration
of normal sinus rhythm in patients with permanent AF after mitral
valve surgery. Higher atrial HSP27 levels were found to be related to
shorter AF duration and less myolysis when comparing paroxysmal
versus persistent AF and sinus rhythm.44, 66 These findings suggest
that HSPs become activated after AF episodes, and exhaust in
time in a stress related manner.44 Consequently, PQC is lost and
incorrect/damaged proteins accumulate in cardiomyocytes, inducing
or accelerating remodeling, in turn resulting in AF progression and
recurrence. Next to AF, also a loss of PQC is recognized to contribute
to the deterioration of heart function, reduction of stress tolerance,
and the possibility of reducing the threshold for manifestation of
cardiac disease.67
Various in vitro and in vivo models for tachypacing-induced AF
identified HSPs to protect against AF initiation and against the
derailment of proteostasis and cardiomyocyte remodeling. HSPs
increase SERCA activity and stimulate both the reuptake of Ca2+
into the sarcoplasmic reticulum and the removal of Ca2+ out of
the cardiomyocyte via Na+/Ca2+ exchanger,68 suggesting that HSPs
attenuate AF progression by protecting against (tachypacing-induced)
changes in calcium handling proteins. Several HSPs (including
HSP27) were shown to reduce oxidative stress, thereby potentially
preventing or restoring the redox status of the ion channels69 and
preventing damage to the actin cytoskeleton. This protective effect
of HSP27 was found via direct binding to actin filaments and
indirectly by preserving the redox status.43, 44, 70-73 Reducing oxidative
stress preserves proteostasis and electrophysiological and contractile
function of the cardiomyocyte in AF. Moreover, HSPs prevent calpain
activation39, 53 and thereby attenuate contractile protein degradation
and conctractile dysfunction.
Deficiencies Of Present Therapy Of Atrial Fibrillation
Therapy of AF is aimed at either rhythm or rate control. Since
AF induces electrical, structural, and contractile remodeling, therapy
aimed at prevention or restoration of remodeling and consequently
restoration of sinus rhythm should be the strategy of first choice.74 The
different AF treatment modalities include pharmacological therapy,
electrical cardioversion (ECV), pacemaker implantation combined
with His bundle ablation or surgical isolation of the pulmonary
veins with or without additional linear lesions/substrate modification
(endovascular or surgical). According to the Multiple Wavelet Theory,
the stability of the fibrillatory process is determined by the number of
simultaneously circulating wavelets. Anti-fibrillatory effects of class
IA, IC and III drugs are based on widening of the excitable period
(difference between AF cycle length and refractory period). When the excitable period widens, it is less likely that a fibrillation wave
encounters atrial tissue, which is still refractory. This in turn decreases
the degree of fractionation of fibrillation waves and subsequently
also the number of fibrillation waves. It is most likely that when
patients with AF have a variable degree of remodeling due to e.g.
dissimilar underlying heart diseases or AF episodes of different
durations anti-arrhythmic drugs will also widen the excitable gap
to a variable degree. This in turn may explain differences in interindividual
responses to anti-arrhythmic drugs. The acute success rate
of intravenous chemical cardioversion (CCV) using various drugs
including amiodarone and flecainide is 58-75%75, 76 for patients with
paroxysmal or persistent AF and is highest when performed in AF
48 hours.76 Immediate (prior to discharge) AF recurrences were
observed in 3%76 and AF relapsed in 30-40% of patients within one
year with continuation of anti-arrhythmic drugs.76 When CCV is
unsuccessful, ECV is next treatment in line. Immediate restoration
of sinus rhythm is achieved in 88-97%.76-78 Comparable to CCV, AF
recurrences are common; sinus rhythm is maintained for one year in
only 40-60% of the patients.
Circumferential Pulmonary Vein Isolation (PVI), endovascular
or surgical, is aimed isolating ectopic foci within the myocardial
sleeves of the pulmonary veins. Endovascular PVI can be achieved
with radiofrequency current, laser or cryothermal energy. Navigation
of the ablation catheters can be performed either manually
guided by fluoroscopy or electroanatomical mapping systems, or
robotically using remote (non-) magnetic navigation systems.79-81
Despite the promising acute success rates, one year AF free
survival is approximately 40-50% and redo ablations are frequently
performed.79-82 This data is confirmed in a large meta-analysis by
Ganesan et al.83 In this study, the long-term success rate increased to
79,8%, however only after multiple ablation procedures. The overall
complication rate associated with endovascular AF ablation is 5%
including phrenic nerve palsy, pulmonary vein stenosis, pericardial
effusion and cardiac tamponade.82, 84 From a theoretical point of view,
PVI should be an effective treatment modality for patients with
paroxysms of AF triggered by ectopic foci within the pulmonary
veins. Recurrences of AF after pulmonary vein isolation can be due to
incompleteness of circular lesions, conduction or an arrhythmogenic
substrate located outside the pulmonary veins.85 In addition, an
arrhythmogenic substrate may also develop over time as a result
of a progressive cardiomyopathy. Different ablation approaches
targeting the assumed substrate of AF have therefore been developed
in the past years85 including ablation of ganglionated autonomic
plexuses in epicardial fat pads or disruption of dominant rotors in
the left or right atrium as recognized by high-frequency Complex
Fractionated Atrial Electrograms (CFAE).86 Wu et al.87 concluded
in a meta-analysis that CFAE ablation could reduce the recurrence
of atrial tachycardia in patients with nonparoxysmal AF after a single
procedure. This effect was not observed in patients with paroxysmal
AF. The reported one year AF free survival after the first CFAE
ablation is only 29% when performed as a standalone procedure86
and 74% in CFAE ablation additional to PVI.86, 88 Endovascular
ablation of the ganglionic plexi as a standalone procedure in
patients with paroxysmal AF is associated with a significantly lower
arrhythmia free survival when compared to the PVI.89, 90 When
performed additionally to (repeat) PVI in patients with persistent
AF, 16 months success rate rises to 59%.90 The recurrence rates of
these (concomitant) substrate modifications are thus high, indicating that the arrhythmogenic substrate underlying persistence of AF
was still not fully understood. Our Double Layer Hypothesis22, 24
provides the explanation why, in case the endo- and epicardial layers
are electrically dissociated, ablative therapy is not successful anymore.
As large numbers of disorders are associated with AF and patients
with AF reveal AF episodes of variable duration, it is most likely that
there is a large degree of variation in the degree of atrial remodeling.
In addition to this, within a patient, it is also likely that there is intraatrial
variation in the degree of remodeling. Examples of regional
differences in morphology of unipolar fibrillation potentials are
shown in Figure 3. Hence, knowledge of the degree and extensiveness
of the arrhythmogenic substrate in the individual patient is essential
in order to evaluate a patient-tailored therapy for AF. For this
purpose, we developed custom made mapping software (‘wave
mapping’) which enabled visualization of the individual fibrillation
waves and quantification of the fibrillatory process. By using this
software, we compared electrophysiological properties of fibrillation
waves recorded during induced AF in patients with normal atria
(physiological AF) with persistent AF in patients with valvular
heart disease (pathological AF) and demonstrated that electrical
dissociation of atrial muscle bundles and epicardial breakthrough of
fibrillation waves play a key role in development of the substrate of
persistent AF (figure 4).24 In order to diagnose the arrhythmogenic
substrate of AF in individual patients, we are currently evaluating
a real-time, high resolution, multi-site epicardial mapping approach
of the entire atria (figure 5) as a novel diagnostic tool which can be
applied as a routine procedure during cardiac surgery. An approach
like this allows quantification of electrophysiological properties of the
entire atria. In such manner, we study electropathology throughout
the entire atria in patients with and without AF and with a diversity
of underlying structural heart diseases. This novel mapping approach
will not only be used to gain further insights into the arrhythmogenic
substrate of AF, but will also be used to develop novel therapies or
to improve existing treatment modalities. For example, it may guide
ablative therapy when the arrhythmogenic substrate is confined to a
circumscribed region. In addition, data acquired with this mapping
approach will also provide the basis for development of less- or noninvasive
mapping techniques.
The Future Novel Therapeutic Targets
Current therapies are directed at suppression of AF symptoms, but
are not effective in attenuating AF remodeling , therefore there is a
high need to identify novel therapeutic targets which will improve the
clinical outcome. Novel targets include RhoA, calpain and HDAC6
inhibition, but also HSP induction. Recent studies revealed the
important role of the RhoA/ROCK pathway activation in structural
remodeling of cardiomyocytes during AF.38 To maintain proper
cardiac function, RhoA/ROCK inhibitors might be of therapeutic
interest. Several RhoA and ROCK inhibitors have been developed.
RhoA inhibitors CCG-1423 and Rhosin are studied in the preclinical
phase.91, 92 Fasudil, Ezetimibe and AR-12286 are ROCK inhibitors
currently studies in Phase II-IV trials for Raynaud’s phenomenon,
vascular function study, atherosclerosis and glaucoma (Table 1).
Calpain activation during AF causes the degradation of contractile
and structural proteins, resulting in myolysis.38, 39, 43 In vitro studies
showed that inhibitors of calpain conserve the cardiomyocyte
structure and function and therefore might have beneficial effects in the treatment of AF.43, 53 Various calpain inhibitors have been
developed and preclinically studied. Disadvantages of the current
developed inhibitors are that they show poor selectivity for subtypes
of calpain and often have a high LogP value and therefore are hard
to dissolve in aqueous solutions.93
HDAC6 inhibition, by tubacin, conserves-tubulin proteostasis, and
prevents its degradation by calpain 1 and thereby protects against loss
of calcium transient and cardiac remodeling in experimental model
systems for AF. As tubacin is not suitable for in vivo studies due
to low drug-likeness,94 other promising HDAC6 inhibitors, such as
tubastatin A and ACY-1215 have been recently developed94-96 (table
1). Interestingly, tubastatin A showed to protect against tachypacinginduced
cardiac remodeling in a canine model for AF,52 supporting
the use of HDAC6 inhibitors as a novel therapeutic approach in AF.
Promoting maintenance of proteostasis by revitalization of
the PQC system may prevent the derailment of proteostasis and
structural and functional remodeling in AF. Interestingly, the heat
shock response as part of the PQC system can be pharmacologically
boosted, and consequently cardiac remodeling may be prevented,
halted or even be restored. Indeed, as depicted earlier, increasing
HSP expression, by either pharmacologic compounds or molecular
biological means, displays cardioprotective effects in various
models for AF and in patients. HSP induction provided protection
against loss of actin proteostasis by reducing RhoA-GTPase-induced
remodeling38 and against activation of calpain.38, 43, 44, 46, 52, 53
Furthermore, in canine models for AF progression, treatment with
geranylgeranylacetone induced HSP expression and prevented AF
initiation and progression by inhibition of the prolongation of the
effective refractory period (ERP), shortening of APD and reductions
in L-type Ca2+ current and it revealed protective effects against
atrial conduction abnormalities.44, 97
Whether HSP induction also protects via HDAC inhibition
is currently unknown. Of all HSP inducing compounds, GGA
represents the most efficacious compound for the pharmacological
induction of HSPs. GGA has already been applied clinically in Japan
since 1984 as an antiulcer drug with no reported serious adverse
reactions.98-102 Due to high LogP value for GGA, high dosages
might be needed, therefore, GGA derivatives are developed with
improve pharmaco-chemical properties103 (table 1). Induction of
HSP is suggested to be the most promising therapeutic approach
with pleiotropic protective effects
Following stress, HSPs get expressed intracellular, but can also be
presented on the cell surface or released to the surroundings.104 HSPs
in serum may act as a biomarker to reveal the stage of AF. Elevated
serum HSP60 levels were found in patients with acute myocardial
infarction and seemed to be predictive for post-AMI adverse events.105
Elevated serum HSP70 and HSP60 have found to correlate to the
severity of metabolic syndrome-associated factors in postmenopausal
women.106 HSP60 and HSP70 were found to positively associate with
severity of cardiovascular disease.107-112 Patients with coronary artery
disease (CAD) have revealed antibodies to HSP27 in serum,113 but a
correlation between antibody titers to HSP27 and the extent of CAD
could not be found. Several studies have reported increased serum
levels for HSP27 several hours after myocardial infarction114, 115 In
another study, anti-HSP27 levels were found to be higher in patients
with more advanced cardiac artery disease, making the authors to conclude that serum anti-HSP27 titers may be associated with the
presence and severity of cardiac artery disease.116 Anti-HSP27 titers
measured in patients with stroke were found significantly elevated.117
These findings suggest that the measurement of HSP levels in serum,
may be useful as biomarkers of disease initiation, and progression.
AF naturally tends to progress from trigger dependent paroxysmal
AF to a more substrate mediated (longstanding) persistent or
permanent AF. Trigger focused treatments (endovascular or surgical
PVI) might be successful in patients with paroxysmal AF, however
this approach will not be sufficient for patients suffering from
more advanced types of AF, who require substrate modification.
Even treatments aimed at substrate modification, such as CFAE
ablation, Cox maze III and ganglion ablation, are associated with
AF recurrences. This implies insufficient understanding of the
electrophysiological and structural changes which form a substrate
underlying AF. Hence, as long as the electropathological substrate
remains poorly understood, and the stage of electropathology cannot
be evaluated, it is challenging to define the optimal approach per
individual patient. Therefore, research is focused on the dissection
of molecular mechanisms underlying electropathology. New findings
indicate a role for derailment of cardiomyocyte proteostasis in AF
progression and identified novel innovative targets for drug therapy.
These targets are directed at the attenuation of electropathology and
prevention of clinical AF progression. Since various drugs are already
on in clinical phase II/III for other indications, it seems worthwhile
to test some in clinical AF.
This work was supported by the LSH-Impulse grant (40-43100-98-008) and the Dutch Heart Foundation (2013T144, 2013T096 and 2011T046).