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Atrial remodeling due to atrial tachycardia and heart failure
Schoonderwoerd, Bas Arjan
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INTRODUCTION
Chapter 1
Introduction: Atrial Remodeling Due
to Atrial Tachycardia and Heart Failure
A Review of Experimental and Clinical Studies
Bas A. Schoonderwoerd, Dirk J. van Veldhuisen,
Maarten P. van den Berg, Harry J.G.M. Crijns (*)
and Isabelle C. van Gelder
From the Department of Cardiology, Thoraxcenter, University Hospital Groningen,
and the Department of Cardiology, University Hospital Maastricht (*), The Netherlands
9
CHAPTER 1
I. INTRODUCTION
Chronic heart failure (CHF) is a major health problem. With an incidence of 1.32%
and a prevalence of 3.0% in the Dutch population over 55 years of age, CHF was
responsible for more than 24.000 hospital admissions in the Netherlands in the year
2000.1 Atrial fibrillation (AF) is a frequently occurring arrhythmia and is often associated
with CHF. Improved treatment of acute cardiac conditions resulting in an improved
survival and an overall increase of the average age of the population has increased both
the incidence and prevalence of these two cardiac disorders. AF may occur as a
consequence of CHF2 due to hemodynamic and neurohormonal conditions caused by
CHF or due to a progressive common underlying condition. However, AF may also be
the cause of CHF due to rapid ventricular rates resulting in a tachycardia-induced
cardiomyopathy. Both AF and CHF are known to result in changes in atrial function
and/or structure, a series of processes known as atrial remodeling. This chapter provides
a review of experimental and clinical data on atrial remodeling due to these two frequently
occurring cardiac entities, discusses their reciprocal relationship and provides the rationale
of this thesis.
II. ATRIAL REMODELING
Atrial remodeling comprises a number of changes in atrial function and structure which
may occur due to different conditions including AF and CHF. Among these changes are
alterations in atrial electrophysiology, atrial dimensions, atrial contraction, atrial
ultrastructure and the secretion of atrial natriuretic peptides.
III. ATRIAL REMODELING DUE TO ATRIAL TACHYCARDIA AND FIBRILLATION
In recent years, atrial remodeling due to chronic high atrial rates has been the subject of
many experimental and clinical studies. It was well known from clinical practice that
AF is a progressive arrhythmia in terms of duration and frequency of episodes in patients
in which the arrhythmia is paroxysmal. Finally, in 14-24% of patients with paroxysmal
AF persistent AF will develop, also in the absence of progressive underlying heart disease.3,4
Furthermore, conversion of AF to sinus rhythm, either electrically5 or pharmacologically,6
becomes more difficult when the arrhythmia has been present for a longer period of
time. This indicates that the arrhythmia itself causes changes in the function and structure
of the atria which could explain its perpetuating character (“AF begets AF”).7
10
INTRODUCTION
III.A.1. Atrial electrical remodeling – experimental data
In 1972, Olsson et al. found short right atrial monophasic action potentials in patients
immediately after conversion of AF to sinus rhythm.8 Ten years later, Attuel et al. described
the loss of the physiological adaptation of the atrial refractory period to rate in patients
susceptible to atrial arrhythmia.9 Boutjdir et al.10 and Le Heuzey et al.11 found short
atrial refractory periods with loss of physiological adaptation to rate in atrial appendages
of patients with chronic AF undergoing surgery. At that time, these findings were
interpreted as an important cause of AF in these patients. However, in 1995 two
independent experimental studies first denominated changes in atrial electrophysiology
as a consequence of AF. Wijffels et al. demonstrated that repeated induction of AF in
goats resulted in progressive duration of the induced paroxysms together with shortening
of the atrial refractory period and loss or even reversal of its physiological adaptation to
rate.7 Similarly, Morillo et al. demonstrated that rapid atrial pacing during 6 weeks in
dogs resulted in shortening of atrial refractory periods, an increased inducibility and
stability of AF together with a increase in P wave duration and a decrease in atrial
conduction velocity.12 In addition, also other investigators found a decrease in atrial
conduction velocity after long term rapid atrial pacing.13,14
Shortening of refractoriness in combination with a decrease in conduction velocity
results in a shorter atrial wavelength which is the product of these two parameters. This
could be an explanation for the increased duration of AF since, according to the multiple wavelet theory, a short wavelength will result in smaller wavelets which would increase
the maximum number of wavelets, given a certain atrial surface. Furthermore, it was
demonstrated that chronic atrial tachycardia depresses sinus node function which may
reduce the stability of sinus rhythm and increase the stability of AF.13
Apart of these changes which may increase the stability of AF, changes in atrial
electrophysiology favoring an increased inducibility of AF have been described as a
consequence of long term pacing or repeated induction of the arrhythmia. An increased
heterogeneity of atrial conduction and atrial refractoriness which provides a substrate
for reentry have been described already after 24 hours of rapid atrial pacing.15
III.A.2. Atrial electrical remodeling – clinical data
Beside these experimental data, several studies have also investigated atrial electrical
remodeling in patients with AF. Short-term artificially induced AF in humans16 results
in shortening of atrial refractoriness. Additionally, in patients with persistent AF, atrial
refractoriness has been shown to be shorter when compared to controls17,18 and to prolong after conversion to sinus rhythm.19,20 However, despite these findings, a pivotal role
of atrial electrical remodeling in the progressive nature of clinical AF has never been
proven. Furthermore, experimental atrial electrical remodeling is complete within hours
to days while the development of sustained AF generally takes at least one week. This
indicates that other factors are involved.
11
CHAPTER 1
III.A.3. Atrial electrical remodeling – changes in ion currents and channels
Shortening of the atrial refractory period and the atrial action potential may be caused
by a net decrease of inward ionic currents (Na+ or Ca2+), a net increase in outward
currents (K+) or a combination of both. The changes of these currents and the expression
of the responsible channels in atrial electrical remodeling have been investigated both in
experimental and clinical studies.
In dogs subjected to 42 days of rapid atrial pacing, Yue et al. demonstrated a reduction
in the L-type calcium current (ICa,L) and the transient outward potassium current (Ito).
The inward rectifier K+ current (IK1) and the components of the delayed rectifier current
(IKur, IKr, IKs) were unchanged.21 In addition, they demonstrated a decrease of the mRNA
expression of the L-type calcium channel α1c-subunit, as well as Kv4.3 (encoding for
Ito).22 The decrease of ICa,L is responsible for shortening of the atrial action potential
whereas the decrease in Ito is considered to result in the loss of physiological rate adaptation
of the action potential. In humans, these findings have been largely confirmed. Several
studies demonstrated a decrease in ICa,L and Ito in patients with AF undergoing cardiac
surgery.23-26 The reduction in ICa,L may be explained by a decreased expression of the
reduction of the L-type calcium channel α1c-subunit.27-29 Brundel et al.18 additionally
reported a decreased protein expression of the L-type calcium channel, a finding that
could not be confirmed by others.30 Reduced mRNA and/or protein concentrations of
several potassium channels have also been reported.18,31,32
Changes in conduction velocity can in part be explained by changes in INa density.
In dogs subjected to rapid atrial pacing, INa was reduced by 52% after 42 days33 which
was associated with a decreased mRNA content of the Na+ channel α-subunit.22 In goats
with AF, however, the latter finding was not reproduced.34 In humans with AF, no change
in INa24 or mRNA of the Na+ channel α-subunit18 was found.
III.B. Changes in atrial diameter and contractility due to AF
In clinical practice there is a clear relationship between AF and atrial dilatation. However,
in individual patients it is often not recognizable whether the atria are dilated as a cause
or consequence of the arrhythmia. Atrial dilatation as a predictive factor for the
development of AF has been recognized since some decades.35,36 On the other hand,
atrial diameters have been shown to further increase when AF is present. In patients
with AF in the absence of structural heart disease Sanfillipo et al. demonstrated an
increase in atrial diameters of almost 40% during a mean follow up of 20.6 months.37
Additionally, it has been demonstrated that atrial diameters may decrease after conversion
of AF to sinus rhythm.38,39 Likewise, rapid atrial pacing during 6 weeks in healthy dogs
was shown to result in progressive bi-atrial enlargement.12
AF results in absence of atrial contraction which only reappears gradually after
conversion of long-term AF.40 This phenomenon is known as atrial stunning and is
considered to be one of the factors responsible for the occurrence of thromboembolic
complications during AF but also after a period of AF.41 Already after a few minutes of
12
INTRODUCTION
experimental AF, atrial contractility is impaired.42,43 In 1964 it was demonstrated that
the a-wave was missing in patients after conversion to sinus rhythm.44 Later, after the
introduction of echocardiography, the time course of restoration of atrial contractile
function after cardioversion could be monitored. It was demonstrated that the recovery
of the atrial contraction after AF can take weeks to even months and is related to the
duration of the previous episode of AF.40
III.C. Changes in atrial (ultra)structure due to high atrial rates
Chronic experimental AF leads to extensive changes in atrial (ultra)structure. The nature and time course of these alterations have been extensively investigated in goats by
Ausma and coworkers.45 After 9 to 23 weeks of artificially maintained AF, they found
marked changes in atrial cellular substructures, including loss of myofibrils, accumulation
of glycogen, changes in mitochondrial shape and size, fragmentation of sarcoplasmic
reticulum and dispersion of nuclear chromatin. These changes were present in up to
92% of studied atrial cells and are considered to be a sign of dedifferentiation rather
than degeneration i.e. the cells seemed to have changed to a fetal phenotype.
There are few data on changes in atrial ultrastructure in humans suffering from AF.
Bailey et al. reported the first study in which atrial myocardium of living patients with
AF was examined.46 They obtained atrial tissue from patients undergoing valve surgery
for rheumatic valve disease. Of the 44 patients included, 32 were in AF of whom 18 had
AF for more than 5 years at the time of surgery. They observed that long term AF was
characterized by loss of muscle mass which they described as diffuse atrophy. The presence
of rheumatic heart disease however may have importantly influenced the structural
abnormalities they saw. Mary-Rabine et al.47 described the relationship between atrial
cellular electrophysiology, function and ultrastructure in 121 patients undergoing cardiac
surgery of which 23 had AF. Atrial biopsies obtained from patients with AF showed
ultrastructural abnormalities such as loss of myofibrils and disorganization of sarcoplasmic
reticulum. However, interpretation of these changes is difficult since AF was associated
with higher patient age and atrial dilatation, factors independently associated with these
structural changes. One paper has been published describing atrial ultrastructural changes
in patients with lone AF (i.e. AF in the absence of a detectable underlying cause). These
included inflammatory infiltrates, myocyte hypertrophy, myocyte degeneration and
fibrosis.48 Brundel et al. evaluated atrial tissue of patients with a normal ventricular
function undergoing coronary artery bypass grafting and compared patients with persistent AF, paroxysmal AF and sinus rhythm.49 In patients with paroxysmal and persistent AF, contraction bands were observed which were virtually absent in patients with
sinus rhythm. In patients with AF, degenerative features such as clumping of nuclear
chromatin and the presence of lysosomelike bodies were present. Furthermore, only in
patients with persistent AF, hibernating atrial myocytes were found, characterized by
glycogen accumulation and the dispersion of nuclear chromatin.
13
CHAPTER 1
III.D. Neurohormonal changes: The natriuretic peptide system
Apart from the role in the electrophysiologic and hemodynamic function of the heart,
the atria also have an endocrinologic function. In situations in which there is an increased
hemodynamic burden on the heart, the atria secrete atrial natriuretic peptide (ANP).
Besides its diuretic effects, ANP reduces peripheral vascular resistance, reduces the
sympathetic tone and suppresses the renin-angiotensin-aldosteron axis.50 Thus, by
releasing ANP into the circulation, the preload is reduced and the atria protect themselves
against hemodynamic overload. AF is associated with elevated levels of plasma ANP in
the acute phase51 but also when the arrhythmia is chronic.52 The exact mechanism by
which atrial arrhythmia results in secretion of ANP is unknown, although it has been
demonstrated that atrial stretch is an important factor.53-55 Furthermore, the increased
atrial rate itself has been proposed to result in ANP release.56-58
IV. ATRIAL REMODELING IN HEART FAILURE AND/OR HEMODYNAMIC
OVERLOAD
IV.A.1. Experimental models of CHF induced atrial electrical remodeling
Increased ventricular and atrial pressures during the development of CHF may modulate
atrial electrophysiology by causing myocardial stretch. This phenomenon is called
mechanoelectric feedback or contraction-excitation coupling and has been demonstrated
in animal studies as well as in humans.
Several experimental studies have demonstrated changes in atrial refractoriness as a
result of an acute rise in atrial pressure. However, there is disagreement whether refractory
periods shorten or prolong. In dogs, an acute rise in atrial pressure caused by (near)
simultaneous atrioventricular pacing59 or by saline infusion60 resulted in prolongation
of AERP. In contrast, Solti et al.61 reported a decrease of AERP along with an increase of
atrial conduction velocity. Similarly, acute atrial volume overload in rabbits resulted in
shortening of AERP62 but in a decrease of atrial conduction velocity.63 Although the
results of these studies are conflicting, all report an enhanced susceptibility to AF during
an acute rise in atrial pressure.
The effects of chronic heart failure, resulting in long standing atrial hemodynamic
overload, on atrial electrophysiologic properties are even less well established. Li et al.64
evaluated the processes underlying the enhanced propensity to AF during the development
of pacing induced CHF in a dog model. They induced CHF by rapid ventricular pacing
during 5 weeks. When compared to control dogs, the dogs with CHF had a dramatically
increased duration of AF induced by burst pacing when compared to control dogs
(535±82 seconds versus 8±4 seconds). When comparing the atrial effective refractory
periods (AERP) between the groups, at longer basic cycle lengths AERP was comparable
14
INTRODUCTION
between both groups while at shorter cycle lengths AERP was slightly longer in the
CHF group. However, this prolongation of AERP is not likely responsible for the
enhanced inducibility and sustenance of AF during CHF. According to the multiple
wavelet theory, AF should be attenuated by a prolongation of AERP since the wavelength
(which equals conduction velocity x AERP) prolongs concurrently, resulting in a decreased
maximum number of wavelets during AF. However, they observed a dispersion of atrial
conduction in the CHF dogs, caused by extensive interstitial atrial fibrosis, resulting in
an environment vulnerable to reentry. Comparable results were obtained in sheep with
ventricular pacing induced CHF.65 During 6 weeks of pacing left atrial but not right
atrial AERP prolonged. The susceptibility to AF initially increased. However,
subsequently, the sheep became less susceptible to AF induced by an extrastimulus
although the duration of AF, when induced, was longer.
Boyden et al.66 found no differences in the action potential duration and shape in
the right atrium and only a slightly increased duration in the left atrium of cats with
cardiomyopathy when compared to controls. However, the diseased atria had a
substantially increased amount of inexcitable cells and showed structural abnormalities
including fibrosis, cellular hypertrophy and degeneration. In dogs with artificially induced
right atrial enlargement caused by tricuspid regurgitation they found no difference in
the right atrial action potential although the susceptibility to, and duration of AF was
significantly increased when compared to control dogs. However, there was no
spontaneously occurring AF.67 In contrast, Verheule et al. found prolonged atrial refractory
periods but unchanged atrial conduction velocity in dogs one month after the induction
of mitral regurgitation.68 Dogs with pacing induced CHF have an enhanced inducibility
of atrial tachycardia with foci located along the crista terminalis and pulmonary veins.
The focal nature of specific types of AF recently has gained a lot of interest. These
findings, although preliminary, indicate that the development of CHF may evoke atrial
foci, leading to AF.69
IV.A.2. The influence of hemodynamic overload on atrial electrophysiology in patients
There are few data on the influence of atrial disease, characterized by atrial dilatation, or
atrial mechanoelectric feedback in patients. Patients with dilated atria have been shown
to have a shorter atrial action potential with a lower amplitude than patients in whom
the atria have normal dimensions.70 However, this finding may partly be due to the
presence of AF in 25% of patients with the dilated atria, which, apart from underlying
heart disease, shortens AERP.7,16
Simultaneous atrioventricular pacing in patients has been reported to prolong AERP.71
In contrast, Calkins et al. found no change in AERP during simultaneous AV pacing.72
However, an acute increase of the atrial pressure by two simultaneous AV beats resulted
in a shortening of AERP.73 These results were not influenced by the presence or absence
of autonomic blockade. We previously reported a case of a patient who had exercise
15
CHAPTER 1
induced AF presumably caused by an acute increase of atrial pressure due to left ventricular
ischemia due to a coronary stenosis. After angioplasty, this patient had no recurrence of
AF.74 However, we did not prove this hypothesis by confirming changes in atrial
refractoriness.
Also chronic hemodynamic load may lead to changes in atrial electrophysiology.
Patients with AF and mitral valve regurgitation were shown to have an increased AERP.
This prolongation was not related to arrhythmia history, i.e. also patients with chronic
or paroxysmal AF and mitral regurgitation had longer AERP than patients suffering
from the same arrhythmia without valve disease.18,75 Sparks et al. investigated the effect
of VVI pacing in patients during sinus rhythm in the presence of an AV block. Chronic
AV dissociation also resulted in prolongation of AERP76 and an impairment of left atrial
contractility,77 processes which were reversible after reestablishing AV synchrony by DDD
pacing. In patients with an atrial septum defect, the chronic right atrial stretch results in
prolonged right AERP, conduction delay and sinus node dysfunction.78 Although these
studies provide evidence for mechanoelectric feedback in human atria, data on these
processes in patients with CHF are lacking.
IV.A.3. CHF induced atrial electrical remodeling – changes in ion currents and channels
Experimental CHF in dogs decreases the densities of atrial ICa,L, Ito and IKs. The net
result of the decrease of repolarizing potassium currents and the decrease of depolarizing
calcium current resulted in a slight prolongation of the atrial refractory period and
action potential duration but only at higher rates. Furthermore, the Na+/Ca2+ exchanger
(NCX) current was increased which may promote delayed afterdepolarization induced
ectopic activity.79
In humans with dilated atria, Le Grand et al.70 found a decrease in ICa,L while others80
found no change. Also, reported changes in Ito and other potassium currents are
conflicting. Some authors81 have reported an increase, others70,82 have found a decrease
of Ito in dilated atria. Additionally, the inward rectifier current IK1 was found to be
reduced83 or unchanged.70 The discrepancies of these findings may be explained by the
variety of underlying cardiac diseases, use of medication and the presence of AF in some
of these patients.
IV.B. Changes in atrial diameters and contractility due hemodynamic overload
Clinical CHF is associated with bi-atrial enlargement which is considered as an important factor in the genesis of atrial arrhythmias in patients with CHF. Although there are
numerous experimental ventricular pacing induced CHF studies, only few have evaluated
atrial dilatation during the development of pacing induced CHF. Five weeks of rapid
ventricular pacing (220-240 bpm) in dogs resulted in a 80.2% and 61.2% increase in
left and right atrial diastolic area, respectively, as measured by transthoracic
16
INTRODUCTION
echocardiography. This bi-atrial dilatation was associated with a decrease in atrial
contractile function which was reflected by a decrease in left and right fractional area
shortening of 41.8% and 33.7%, respectively.84 Similar results were found by Power et
al. who found a 100% increase of diastolic left atrial cross-sectional area after 6 weeks of
rapid ventricular pacing in sheep.65
In a study performed in 21 patients, loss of AV-synchrony due to VVI pacing during
sinus rhythm resulted in an increase of mean left atrial diameter from 3.96 to 4.40 cm.
Additionally, loss of atrial contractility was observed since the mitral A-wave velocity
decreased from 74.1 to 39.3 cm/s. Both atrial dilatation and loss of atrial contractility
were shown to be completely reversible after 3 months of reestablishment of AV-synchrony
by DDD pacing.77
IV.C. Changes in atrial ultrastructure due to hemodynamic overload
Atrial volume- or pressure overload results in atrial dilatation which is accompanied by
changes in atrial ultrastructure, also in the absence of atrial arrhythmia.
The development of rapid ventricular pacing induced heart failure in dogs is
associated with atrial interstitial fibrosis, cellular hypertrophy, loss of myofibrils, and
signs of necrosis,64 processes that were shown to be irreversible after cessation of pacing
and consequent recovery of the systolic ventricular function.85 Similarly, chronic atrial
dilatation in dogs due to experimental mitral regurgitation in the absence of overt CHF
results in atrial fibrosis, signs of chronic inflammation and increased accumulation of
glycogen. 68 Boyden et al. found marked structural abnormalities in cats with
spontaneously occurring cardiomyopathy. These abnormalities included large amounts
of interstitial fibrosis, cellular hypertrophy and degeneration, and thickened basement
membranes. The degree of structural pathology was related to the degree of left atrial
enlargement. However, part of the animals also suffered from AF which presence was
also related to the magnitude of atrial dilatation.66
The interpretation of changes in atrial ultrastructure in patients is hampered by the
often obscure arrhythmia history of an individual patient. Aimé-Sempé et al. investigated
human specimens of dilated right atrial myocardium and found signs of apoptosis and
myolysis in patients with AF as well as in patients with a decreased left ventricular
ejection fraction who were in sinus rhythm.86 These included a disrupted sarcomeric
apparatus with replacement by glycogen granules, the presence of large TUNEL positive
nuclei with condensed chromatin indicating the presence of DNA breakage and the
decreased expression of antiapoptotic proteins. Fenoglio et al. studied right atrial samples
of patients with an atrial septal defect. Although all patients had enlarged right atria,
structural abnormalities including hypertrophy and cell degeneration were only observed
in the presence of elevated right atrial pressures.87 Of note, all these 15 patients were in
sinus rhythm.
17
CHAPTER 1
IV.D. The natriuretic peptide system during CHF
Natriuretic peptides defend against excess salt and water retention, inhibit vasoconstrictor
peptides, promote vascular relaxation and inhibit the sympathetic neural system. These
neurohormones have been shown to be important markers in the assessment of clinical
severity and prognosis of CHF.88,89 Patients with CHF have high plasma concentrations
of both atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). These
concentrations are associated with the degree of left ventricular dysfunction and may
rise a factor 30 in patients with New York Heart Association class IV CHF.90 ANP is
mainly secreted from the cardiac atria but during CHF a proportion is also produced in
the ventricles.91 Several experimental pacing induced heart failure studies have demonstrated an increase in circulating ANP and BNP during the development of CHF.92-95
In conclusion, it has been established that both acute and chronic atrial stretch cause
changes in the electrophysiologic and structural substrate which may form an environment vulnerable to AF. However, the data are scarce and conflicting. Furthermore, other
mechanisms such as neurohormonal activation and medication in patients with structural
heart disease certainly will play a role. Therefore, the exact mechanisms by which CHF
causes AF still remain to be fully unraveled.
V. ATRIAL ARRHYTHMIA COMPLICATING CHRONIC HEART FAILURE
Atrial arrhythmias, in particular AF are often encountered in patients with CHF. The
prevalence of AF in the large CHF trials varies from 10% to 50% and increases with the
severity of CHF.96-99 Also there is an increased incidence of AF in CHF patients. The
presence of CHF increases the risk of developing AF by six times100 and even asymptomatic
LV dysfunction is associated with an increased risk of developing AF.101 However, relatively
little is known about the mechanisms by which CHF may cause AF. There may be an
underlying cardiac disease that may cause CHF and AF independently. Secondly, CHF
is associated with an altered neurohormonal status. The plasma level of circulating
catecholamines is increased and there is an increased activity of the sympathetic neural
system. Adrenergic stimulation is known to shorten atrial refractoriness which may form
a substrate for the initiation of atrial arrhythmia. Finally, CHF leads to altered
hemodynamic conditions which may result in atrial stretch. This atrial stretch in turn
may cause direct changes in atrial electrophysiologic properties but in time also in
structural changes such as atrial dilatation and fibrosis which favor the initiation and
perpetuation of AF.
The impact of the development of AF in patients suffering from CHF on survival
remains a subject of debate. Several studies did not show a independent prognostic
significance of AF in CHF patients.102-105 Conversely, in other studies there was a significant association between the development of AF and mortality.106-108 Some authors
18
INTRODUCTION
have suggested that the development of AF in patients with CHF, although associated
with a higher mortality, does not independently increase mortality but is merely a
reflection of general deterioration of the patients cardiac condition and rather is a
consequence than a cause. Others suggest that the impact of the development of AF
during CHF on mortality depends on the severity of CHF and is more significant when
the degree of CHF is relatively low.109,110
V I . H E A R T FA I LU R E C A U S E D BY AT R I A L A R R H Y T H M I A : TA C H YCARDIOMYOPATHY
Chronic incessant supraventricular tachycardia or AF may result in CHF. On one hand,
this is caused by the rapid irregular rhythm111,112 and the absence of the atrial contraction
(“atrial kick”).113 On the other hand, a tachycardia induced cardiomyopathy may be
induced during chronic fast atrial rhythms with a high concurrent ventricular rate. This
so-called tachycardiomyopathy contributes to the impaired ventricular function. A case
of a patient with AF who developed CHF suggesting a causal relationship was already
reported in 1913.114 However, not until the 1940’s this relationship was established.115,116
It may be difficult to recognize this form of CHF. The diagnosis is made when underlying
cardiac disease is absent and cardiac function improves after termination of the arrhythmia
or control of the ventricular rate.117-120 However, still a subset of patients who are thought
to have an idiopathic dilated cardiomyopathy in fact have tachycardiomyopathy. Left
ventricular dysfunction due to AF has even been reported in patients with normal heart
rates. A sustained improvement in LVEF from 30 to 39% after His bundle ablation has
been reported in these patients.121
VI.A. Experimental tachycardiomyopathy
The observation that chronic tachycardia may lead to CHF resulted in the development
of the first experimentally pacing induced CHF model in 1962.122 Since then, numerous
rapid atrial123-126 or ventricular127-136 pacing induced CHF models have been developed
in order to study CHF in general and tachycardiomyopathy in particular.137 Chronic
ventricular pacing or chronic atrial pacing with a high ventricular response results in a
dilating cardiomyopathy characterized by elevated filling pressures, ventricular dilatation,
a decreased ventricular endsystolic pressure and a decreased left ventricular ejection
fraction.138 Typically, the ventricular wall thickness reduces, which, together with
ventricular dilatation results in an unchanged ventricular mass.125 On a microscopic
level, ventricular tachycardiomyopathy is characterized by changes in ventricular myocyte
shape and alignment, destruction of the myocardial collagen matrix and an altered
orientation of contractile proteins.138 Termination of pacing results in a recovery of systolic
function and changes in the extracellular matrix.139 However, diastolic function remains
impaired and ventricular hypertrophy develops.
19
CHAPTER 1
VII. ATRIAL FIBRILLATION AND CHF: A CHICKEN-EGG RELATIONSHIP
As mentioned at the beginning of this chapter, AF and CHF frequently coincide and
have a reciprocal relationship which is schematically depicted in Figure 1.
In an individual patient, either CHF or AF may occur due to an underlying (cardiac)
disease. Subsequently, there are different ways in which one of these conditions may
result in the other. First, AF may cause CHF by an increased ventricular rate, eventually
resulting in tachycardiomyopathy. Second, CHF may be complicated by the development
of AF due to atrial remodeling depending on the altered hemodynamic and
neurohormonal conditions during CHF (CHF dependent atrial remodeling). A vicious
circle may thus develop. In addition, AF may stabilize due to atrial remodeling induced
by the arrhythmia itself (Rate dependent atrial remodeling). Finally, both CHF and AF
may be progressive due to deterioration of an underlying (heart) disease which may
cause CHF and AF independently. Due to these interacting processes, it may be difficult
to recognize which came first when a patient presents him/herself with both AF and
CHF.
Underlying Heart Disease
High
ventricular
rate
Progression of
underlying disease
CHF
AF
Atrial remodeling
(CHF dependent)
Figure 1.
20
Atrial remodeling
(Rate dependent)
INTRODUCTION
VIII. CONCLUSION AND AIM OF THE PRESENT STUDY
Atrial arrhythmia, in particular AF and CHF are two frequently encountered conditions
in clinical practice. Both lead to changes in atrial function and structure, an array of
processes known as atrial remodeling. In the recent past, many studies have evaluated
atrial remodeling due to either AF or CHF. However, AF and CHF often coexist in
patients. Furthermore, in most of the above mentioned experimental AF/rapid atrial
pacing studies, the ventricular rate was uncontrolled and therefore also high. This may
have resulted in hemodynamic changes and/or the development of tachycardiomyopathy
which could have influenced the results. In other words, apart of an increased atrial rate,
AF will also have had hemodynamic consequences for the atria with consequent atrial
remodeling in these experiments.
Therefore, the aim of the present study was to determine which processes in atrial
remodeling during a chronic atrial tachycardia with developing tachycardiomyopathy
are related to the high atrial rate (“rate dependent”) on one hand and which are related
to the high ventricular rate resulting in the development of tachycardiomyopathy (“CHF
dependent”) on the other.
For this purpose we developed an experimental animal model in which we could
investigate the processes involved in atrial remodeling during chronic atrial tachycardia
both in the presence and absence of a high ventricular rate, resulting in
tachycardiomyopathy.
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Murgatroyd FD, Camm AJ. Atrial arrhythmias. Lancet 1993;341:1317-1322.
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INTRODUCTION
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CHAPTER 1
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