Animal Models of Dyssynchrony

Article (PDF Available)inJournal of Cardiovascular Translational Research 5(2):135-45 · December 2011with36 Reads
DOI: 10.1007/s12265-011-9336-5 · Source: PubMed
Abstract
Cardiac resynchronization therapy (CRT) is an important therapy for patients with heart failure and conduction pathology, but the benefits are heterogeneous between patients and approximately a third of patients do not show signs of clinical or echocardiographic response. This calls for a better understanding of the underlying conduction disease and resynchronization. In this review, we discuss to what extent established and novel animal models can help to better understand the pathophysiology of dyssynchrony and the benefits of CRT. Electronic supplementary material The online version of this article (doi:10.1007/s12265-011-9336-5) contains supplementary material, which is available to authorized users.

Figures

Animal Models of Dyssynchrony
Marc Strik & Lars B. van Middendorp & Kevin Vernooy
Received: 27 October 2011 / Accepted: 17 November 2011 / Published online: 1 December 2011
#
The Author(s) 2011. This article is published with open access at Springerlink.com
Abstract Cardiac resynchronization therapy (CR T) is an im-
portant therapy for patients with heart failure and conduction
pathology, but the benefits are heterogeneous between patients
and approximately a third of patients do not show signs of
clinical or echocardiographic response. This calls for a better
understanding of the underlying conduction disease and resyn-
chronization. In this review, we discuss to what extent estab-
lished and novel animal models can help to better understand
the pathophysiology of dyssynchrony and the benefits of CRT.
Keywords Left bundle branch block
.
Dyssynchrony
.
Animal research
.
Cardiac resynchronization therapy
Introduction
To maintain normal cardiac pump function, a near synchro-
nous electrical activation sequence of both ventricles is
imperative. This synchronous activation applies to multiple
anatomic levels: within atria, between atria and ventricles,
between ventricles, and especially within the left ventricle
(LV). Right-sided pre-excitation, such as during left bundle
branch block (LBBB) and right ventricular (RV) pacing ,
induces dyssynchrony, which instantly decreases cardiac
pump function and is a risk factor for development of heart
failure [1]. Cardiac resynchronization therapy (CRT)
attempts to treat dyssynchrony by simultaneous or sequen-
tial stimulation of both ventricles in patients with symptom-
atic heart failure, LV systolic dysfunction, and increased
QRS complex durat ion. Even though large clinical trials
clearly show the efficacy of CRT at the population level,
in this heterogeneous group of patients, approximately one
third does not show evidence of clinical or echocardiograph-
ic response after device implantation [24]. In addition, the
range of response is highly variable, raising the question
whether CRT is optimally performed in every patient or
whether each patient can benefit equally from CRT. There-
fore, a better understanding concerning the effects of dys-
synchrony and resynchronization on cardiac pump function
is required. The goal of the present article is to revie w how
animal models of dyssynchrony can help clarify the patho-
physiology of dyssynchrony and further improve the treat-
ment of dyssynchrony by CRT.
Animal Models of Dyssynchrony
Over one century ago, Eppinger and Tothberger discovered
large and specific changes in QRS morphology after making
a small incision in the left or right surface of the interven-
tricular septum in canine hearts [5]. The first dyssynchro-
nous animal model was established and was in fact a
dyssynchrony model by a proximal lesion of the bundle
branches. Since then, LBBB has been described in humans
but also in monkeys and pigs [6, 7]. Investigating LBBB in
other animals may apply less to the human situation, as there
are inter-species differences in anatomy of the left bundle
branch. For example, in hearts from ox and sheep, the
Electronic supplementary material The online version of this article
(doi:10.1007/s12265-011-9336-5) contains supplementary material,
which is available to authorized users.
M. Strik (*)
:
L. B. van Middendorp
Department of Physiology, Cardiovascular Research Institute
Maastricht, Maastricht University,
P.O. Box 616, 6200 MD Maastricht, The Netherlands
e-mail: m.strik@maastrichtuniversity.nl
K. Vernooy
Department of Cardiology, Maastricht University Medical Center,
Maastricht, The Netherlands
J. of Cardiovasc. Trans. Res. (2012) 5:135145
DOI 10.1007/s12265-011-9336-5
bundles are significantly thicker and thei r branches extend
much more towards the epicardium [8]. In rabbit hearts, the
left bundle is composed of groups of fine sheets covering
the subendocardial tissue [9]. Since the extent of elect rical
asynchrony in dogs is comparable to humans (where a
doubling of QRS duration is seen), the canine heart is
considered the most suitable animal model for investigating
LBBB. In contrast, RV pacing and LBBB increases QRS
duration by only 50% in pigs [7] and even less in goats
(unpublished observ ations).
For obvious reasons, animal experiments have presented
more detailed information than clinical studies, but they
suffer from limitations such as the fact that most animal
studies are performed in (initially) young and healthy ani-
mals and that various preparations have been used, which
differ from the clinical and intact human situation. Because
an animal model based on intraventricular incisions was not
suitable to investigate the hemodynamic effects of LBBB,
later research focused on dyssynchrony based on ventricular
pacing. In 1925, Wiggers described that artificial stimula-
tion of the canine left ventricle (1) slows down the rise of
intraventricular pressure, (2) lengthens the isometric con-
traction phase, (3) low ers the maxi mal systolic pressure, and
(4) increases the duration of systole [10]. Even though it was
clear that dyssynchrony has adverse effects on cardiac pump
function, major inte rest in the pathophysiology of dyssyn-
chrony developed only after these effects were revealed in
large groups of patients who underwent permanent RV
pacing [8]. Similar to LBBB, RV pacing induces delays in
transseptal and intraventricular conduction which explains
why the hemodynamic effects of altered ventricular activa-
tion during RV pacing and LBBB are comparable. How ever,
there are important differences between the two situations.
RV apex pacing disturbs RV activation since pacing induces
slow intramyocardial conduction instead of fast conduction
through the Purkinje fibers. Secondly, the site of stimulation-
induced breakthrough differs from the site of intrinsic break-
through. Therefore, LV depolarization through the interven-
tricular septum is also different from that during LBBB.
To investigate the effects of LBBB and CRT, a LBBB
model was developed in canine hearts [1113]. Through the
aortic valve, an ablation catheter is positioned against the
basal septum. Guided by the local endocardial electrogram
derived from the tip of the catheter, the left bundle branch is
located as evidenced by a sharp deflection between A-wave
and V-wave and subsequently ablated (Fig. 1)[13]. Electri-
cal mapping during dyssynchronous activation is discussed
more extensively elsewhere in this edition. In short, in the
healthy canine heart electrical activation is very synchro-
nous but ablation of the proximal left bundle branch causes
a severe delay in the electrical activation of the LV postero-
lateral wall (Fig. 2). As shown in Fig. 3, the morphology and
duration of the QRS complex change and in agreement to
the observations of Wiggers, dyssynchronous contraction
causes reduction in ejection time and slows rates of rise
and fall of LV and aortic pressure and increases duration of
isovolumic contraction and relaxation [14, 15]. For animat-
ed echocardiographic short-axis LV examples of normal
conduction and left bundle branch block, see Online Re-
source 1 and 2.
Electromechanical Delay
Myocardial contraction does not immediately follow depo-
larization, and the delay between local electrical activation
and shortening, or electro-mechanical delay, was found to
be approximately 30 ms in normal canine hearts [16]. More
advanced measurements (MRI tagging) at many sites in
asynchronous ventricles showed that timing differences in
Fig. 1 Creation of left bundle branch through radiofrequency ablation:
on the electrogram derived from a standard ablation catheter, intro-
duced through the aortic valve into the LV, the left bundle branch
potential is observed as a sharp deflection between the A-wave and
V-wave in the local electrograms (bottom tracing). Subsequently, ab-
lation is started at this location, which results in a proximal LBBB. The
top tracing shows a simultaneously recorded surface electrocardiogram
136 J. of Cardiovasc. Trans. Res. (2012) 5:135145
shortening are larger than in electrical activation [17]. This
larger mechanical asynchrony is presumably explained com-
pletely by its definition: the onset of shortening. Recent
studies in canine hearts indicate that when the onset of
active force generation rather than the onset of shortening
is used to define mechanical activation, electro-mechanical
delay is equal throughout the asynchronous heart and directly
reflects the timing of electrical activation [18]. This discrep-
ancy between onset of active force generation and onset of
shortening is explained by the fact that early-activated
regions can start to shorten immediately upon activation,
because cavity pressure is low and all other muscle fibers
are passive, while this is not valid for late activated regions
(see also the short-axis echocardiography; Online Resource 2).
The prolonged electro-mechanical delay in the later activated
region could not be explained by increased excitationcon-
traction coupling time or increased pressure at the time of local
depolarization. However, the higher rate of rise of LV pressure
(dP/dt) that late activated regions have to oppose prolongs
the interval when force generation is accelerated to a rate
superior to load rise, resulting in delayed onset of shortening
[19]. Moreover, the septum contracts against a reduced load
resulting in a faster than normal shortening during the iso-
volumic phase. This phenomenon can be used as an echo-
cardiographic marker for dyssynchrony and is possibly able
to predict response to CRT [20]. Additionally, early septal
Fig. 2 Typical examples of 3D electrical activation in canine hearts
during normal conduction (left panel) and after creation of LBBB
(right panel). Plotted activation times were derived from 110
epicardial and endocardial contact electrodes and referenced to the
onset of the Q wave. In the right panel, the ablation catheter is shown
with the approximate location of ablation after which a LBBB pattern
occurred
Fig. 3 Effects of synchronous (top) and asynchronous (bottom) ven-
tricular activation. Asynchronous electromechanical activation induces
increased QRS duration (a) mechanical interventricular assynchrony
(b) and onset of LV shortening (strain) is regionally delayed (negative
deflection of curve) (c). Adapted with permission from Verbeek et al.
[13]
J. of Cardiovasc. Trans. Res. (2012) 5:135145 137
contraction pre-stretches the left ventricular free wall and
when this region starts to contract after its delayed onset
of shortening will stretch the septum again [21]. This
combination of delayed onset of shortening, early septal
shortening, and reciprocated stretching causes a less effec-
tive contraction and reduces the rate in rise of pressure. The
early fiber shortening in early-activated regions and pro-
nounced shortening in late activated regions found in canine
dyssynchrony models was also found in LBBB patients [19,
22, 23]. Since LV dP/dt reflects LV function and contractility,
the magnitude of mechanical dyssynchrony may vary over
time in a given patient when there are changes in LV function
[19].
Structural Remodeling
The ventricular wall is capable of adapting to changes in
workload by changing the extracellular matrix composition
and by hypertrophy of cardiomyocytes. It is not entirely
clear which mechanisms are responsible for initiating these
changes, but neurohumoral and cardiac load have been
ascribed to play an important role. Within the LV wall, an
asynchronous electrical activation causes a redistribution of
mechanical work, perfusion and oxygen demand [22, 24].
Ventricular pacing results in reductions in regional myocar-
dial perfusion and oxygen consumption near the pacing site.
Moreover, the larger mechanical load in late activated
regions leads, in the long run, to increased wall thickness
in regions opposing the site of pacing, while early-activated
wall segments tend to become thinner [21, 22, 25]. The latter
is even more the case in canine hearts, which were paced at the
RV, while pressure overload was induced by aortic banding. In
this model, no added hypertrophy was seen in the late-
activated wall, but a clear inhibition of hypertrophy in the
early-activated septum [26]. The generally more pronounced
hypertrophy in the pre-stretched regions indicates that the
local mechanical load is an important stimulus in this
remodeling process [25]. On top of abnormal contraction,
premature relaxation in early-activated regions and delayed
contraction in others cause abnormal relaxation [8].
Myocardial Perfusion and Metabol ism
To investigate regional myocardial blood flow, the micro-
sphere deposition method can be used, the gold standard for
regional blood flow measurements. After injection of radio-
active or fluorescent microspheres, deposition is measured
and thereby provides information on regional perfusion
[27]. During sinus rhythm, blood flow is homogeneous
and equally distributed. However, in the dyssynchronous
heart, early-activated regions consistently show a reduced
myocardial blood flow, while higher flow is observed in
late-activated region s [22 , 28]. Closely related to myocardial
blood flow is myocardial oxygen consumption (MVO
2
).
Not surprisingly, MVO
2
shows a similar distribution as
myocardial blood flow, where early-activated regions show
a reduction in MVO
2
and a near normal oxygen consump-
tion is observed in the latest activated regions [28 ]. Oxygen
extraction from the blood is not altered in the different
regions and remains stable over a wide physiological range.
Therefore, it is speculated that the local changes in work-
load, due to dyssynchronous contraction, changes the local
oxygen demand and thereby local perfusion. In humans,
dyssynchrony has usually a silent onset and is often first
diagnosed when patients present themselves with other car-
diovascular problems. Frequently non-invasive myocardial im-
aging is performed to diagnose perfusion defects due to
coronary artery disease (CAD). However , septal perfusion
defects are frequently found in patients with LBBB in the
absence of any significant CAD [29, 30]. As argued above,
the data from animal studies suggest that this effect in
patients is probably due to reduced oxygen demand, caused
by the underlying electrical substrate. An alternative hypothe sis
of the septal underperfusion in dyssynchronous hearts is that
perfusion is hampered by the abnormal contraction, which
augments intramyocardial pressure and shortens the diastolic
period, where coronary perfusion occurs [3133].
Changes in myocardial blood flow and workload are
paralleled by changes in metabolism. In dogs with dyssyn-
chronous hearts, glucose uptake in the septum is markedly
reduced in a similar fashion as the redistribution in myocar-
dial blood flow [31]. In patients with dyssynchrony, a rela-
tive reduction of glucose uptake in the septum compared to
the lateral wall is observed as assessed by fluorodeoxyglu-
cose positron emission tomography imaging. However, the
perceived reduction in glucose uptake in the septum may
also be due to an increase in absolute glucose uptake in the
lateral wall, caused by an increase in work load and higher
energy demand in that wall [34].
Cardiac Resynchronization Therapy in Animal Models
Immediately upon inducing LBBB in the canine hearts, LV
dP/dt
max
decreased by 22% and adverse effects as described
in earlier animal models of pacing induced dyssyn chrony
are reproduced [35]. Interestingly, biventricular pacing in
the LBBB heart immediately causes an almost normaliza-
tion of the strain pattern (Fig. 4) and increases LV d P/dt
max
to 86±5% of pre-LBBB followed by a slight further im-
provement to 89±5% of pre-LBBB values after 8 weeks of
CRT. Therefore, the data from this animal study indicate that
CRT clearly improves cardiac pump function in the LBBB
hearts, but does not return it completely to pre-LBBB values.
138 J. of Cardiovasc. Trans. Res. (2012) 5:135145
This could be explained by the fact that the physiological
sequence of activation and contraction are never completely
restore d during CRT, remaining less efficient than through
the Purkinje system [36]. Asymmetric hypertrophy, as seen
during chronic LV pacing, also applies to the situation of
LBBB [37]. Eight weeks after creation of LBBB, wall mass
of the lateral wall and LV cavity size increased by 30%,
whereas mass of the septum barely changed [37]. After
8 weeks of CRT, LV cavity size and regional differences
in hypertrophy normalized to pre-LBBB levels. The obser-
vations made in these dog models are readily translatable to
the human situation. In patients with LBBB, the effect of
asynchronous activation on regional hypertrophy was com-
parable to that observed in dogs. Nonetheless, the effects of
CRT are less pronounced in patients possibly due to the
large heterogeneity and confoun ding factors such as hyper-
trophy, fibrosis, infarction, and dilatation that are so often
present in these patient groups [34, 38].
The aforementioned findings give rise to the notion that
dyssynchronous ventricular activation by LBBB on its own
is sufficient for CRT to be efficient. The described animal
models contain dyssynchronous activation either by ventricu-
lar pacing or by proximal ablation of the left bundle branch
and, unlike CRT candidates, these models do not suffer from
co-morbidities complicating their conduction defect. It is
important t o understand the effects of additional factors
such as LV systolic dysfunction for better selection of
CRT candidates and to improve response to treatment. In
healthy canine hearts, isolated LBBB induces electrical and
mechanical dyssynchrony that eventually will lead to loss of
LV pump function and ventricular remodeling. In these hearts,
CRT largely reversed global and regional function and struc-
tural abnormalities, indicating that LBBB as electrical
substrate is sufficient for acute and long-term response to
CRT [39]. Recently, multiple clinical trials have indeed
shown high CRT efficacy in heart failure patients who were
not severely symptomatic (NYHA class I and II) [2, 4043].
Role of Infarction in CRT
While, based on these studies, inclusion criteria for CRT
may be extended to patients without severe symptomatic
heart failure, still a significant number of patients complying
with the curren t guidelines do not respond to CRT. To this
regard, most clinical studies show that the number of non-
responders is highest in patients who suffer from ischemic
cardiomyopathy (ICM). One possible mechanism is that
there is insufficient viable tissue to allow an increase in
contractility by CRT. Another possible mechanism lies in
modification of the electrical substrate where the extent of
resynchronization would be limited as a result of slow-
conducting or non-conducting regions. This would mean
that a go od response to CRT in ICM patients not only
requires clear conduction disease, but also the capability to
properly resynchronize the heart . An important feature in
this regard is the site of pacing as pacing in the vicinity of
scar tissue is considered to compromise conduction.
To investigate this idea, an animal model was developed
where asynchronous activation by proximal left bundle
branch ablation was combined with myocardial infar ction
[44]. Transmural myocardial infarction was created by em-
bolization of the left anterior descending (LAD) or circum-
flex (LCX) artery using a suspension of polyvinyl alcohol
foam particles. Four weeks later, LBBB was induced and
another week later measurements on electrical activation
Fig. 4 Typical example of myo-
cardial circumferential shorten-
ing (%) tracings in eight regions
along the mid-basal LV circum-
ference. Please note the abnor-
mal shortening patterns during
LBBB and the normalization
during CRT (LBBB+CRT)
J. of Cardiovasc. Trans. Res. (2012) 5:135145 139
and hemodynamics were performed. TTC staining showed
that all infarctions were transmural with an infarct size of
19.9±6.0% (range 1432%) of LV mass (see typical exam-
ple in Fig. 5)[44]. In LBBB hearts with myocardial infarc-
tion, pacing remote from the infarcted regions resulted in a
similar CRT response as in non-infarcted ca nine LBBB
hearts. Achieving the maximal benefit in infarcted dyssyn-
chronous hearts, however, required accurate positioning of
the LV pacing lead and more precise timing of LV stimula-
tion. In infarcted hearts, the optimal pacing site did not
coincide with the region of latest activation but rather a
region dist ant from the infarction and more basal or apical
than the preferred pacing site in non-infarcted hearts. The
optimal LV pacing position in infarcted dyssynchronous
hearts appears to be determined by the fastest pathway of
activation wavefront from LV and RV electrodes. This study
[44] indicated that in heart s with LAD occlusion, the infarc-
tion is located apically and basal pacing allows the activa-
tion wavefront to bypass the infarcted area. In contrast, the
midlateral position is best in case of LCX infarctions since
the activation wavefront can easily propagate over the lateral
wall and apex. The preclinical data indicate that it is important
to know the location of the infarction but in many CRT
candidates, this is not known since scar imaging before device
implantation is not regularly performed. Even if scar imaging
is not feasible, acute hemodynamic or electrocardiographic
testing during pacemaker implantation could help to optimize
CR T response in patients with underlying ischemic disease.
Role of Dilation on Benefit of (Endocardial) CRT
Besides ventricular conduction delay and possibly myocar-
dial infarction, many CRT candidates suffer from dilated
cardiomyopathy. Even though dyssynchrony alone is
sufficient for CRT to be successful, inducing heart failure
in addition to electrical asynchrony can be essential to test
certain hypotheses. For example, it was found that in canine
hearts with isolated LBBB, endocardial LV pacing during
CRT consistently improved systolic LV pump function,
reduced electrical asynchrony, and decreased dispersion of
repolarization, as compared to epicardial LV pacing at the
same site [45]. Three possible mechanisms explaining the
more rapid electrical activation during endocardial CRT in
this model were proposed: (1) shorter path length of con-
duction, (2) faster endocardial than epicardial conduction as
well as (3) faster conduction from endocardium to epicardium
than vice versa. While all three factors may contribute in the
setting of LBBB in otherwise healthy canine hearts, ventricu-
lar dilatation and wall thinning would reduce the difference in
conduction pathlength between endocardium and epicardium,
potentially reducing the advantages of endocardial CRT in
patients with dilated cardiomyopathy. Better understanding
of the various factors determining the benefits of endocardial
CRT in animal models with compromised hearts can also be
used to propose explanations to ambivalent results reported
from the few small clinical studies on endocardial CRT [46
48]. For this purpose, we performed a study to investigate
the efficacy of endocardial CRT in canine LBBB hearts
combined with dilated cardiomyopathy [49]. The results
were compared with endocardial CRT in dogs with acute
LBBB and in dogs with chronic LBBB and infarction (model
as described above). To obtain dilated cardiomyopathy, the
apex of the right ventricle was paced at a rate of
220 beats per minute for 4 weeks, as described earlier by other
groups [50, 51].
As compared to the acute LBBB group, LV function was
depressed in the myocardial infarction group as indicated by
decreased stroke work and elevated LV and RV end-diastolic
pressures. Echocardiographically, LV end-diastolic diameter
remained constant while wall thickness increased. The ratio
of LV end-diastolic radius with wall thickness (outer) to LV
end-diastolic radius (inner) signifies the type of remodeling,
and this ratio was higher in the infarcted dyssynchronous
hearts as compared with the acute LBBB hearts (1.88 versus
1.61, respectively) indicati ng hypertrophic remodeling. In
the failing LBBB group, 4 weeks of rapid pacing induced an
increase in LV end-diastolic diameter and a decrease in LV
wall thickness. In this model, the ratio of outer LV radius
and inner LV radius decreased to 1.36, reflecting dilatation,
which was accompanied by severe systolic dysfunction as
evidenced by an LV ejection fraction of 15% in combina-
tion with 50% reduction of LV dP/dt
max
and elevation of
LV EDP. The differences in pathlength between various
dyssynchrony models indeed influenced the effect of (con-
ventional) epicardial or endocardial CRT on electrical
resynchronization (as determined by LV electrical mapping).
As depicted in Fig. 6, the added benefit of endocardial over
Fig. 5 Short-axis slice at the mid-level of LV demonstrating trans-
mural myocardial infarction of the canine LV lateral wall in the LBBB
+infarction model (for details see text)
140 J. of Cardiovasc. Trans. Res. (2012) 5:135145
epicardial CRT on electrical resynchronization was greater
in hyperthropic than dilated hearts. It was interesting to
observe that despite these differences between the three
models, CRT resulted in a similar a bsolute increase in LV
dP/dt
max
(150 mmHg/s with epicardial CRT and
250 mmHg/s with endocardial CRT). Because baseline
LV dP/dt
max
was considerably lower in the failing LBBB
group, this translated to higher relative increases in LV dP/
dt
max
during CRT, relative increases that are similar to those
found in patients [52]. Therefore, the extent of additional
electrical resynchronization by endocardial CRT is
dependent on cardiac remodeling but the functional re-
sponse is not, which could be related to higher subendocar-
dial conduction velocities, faster transmural depola rization,
and a shorter pathlength towards the various wall regions.
These data further emphasize the benefits of endocardial LV
stimulation in CRT patients.
Pacing-induced tachycardia results in severe LV dilata-
tion and decreases LV systolic function to levels similar to
those found in heart failure patients. However, evaluating
chronic effects of CRT in this model is only possible when
tachycardia is maintained during resynchronization as the
Fig. 6 Percent change in LV
electrical asynchrony during
epicardial versus endocardial
CRT as a function of the ratio of
outer LV radius to inner LV
radius in the three experimental
groups. P values signify a
statistical significant difference
in ENDO-EPI CRT between
groups
Fig. 7 Examples of echocardiog-
raphy, fluoroscopy, and cardiac
MRI in canine hearts before and
after creation of mitral regurgita-
tion. The cardiac MRI was per-
formed 5 months after creating
mitral regurgitation. Arrows point
to the regurgitative blood flow
into the left atrium
J. of Cardiovasc. Trans. Res. (2012) 5:135145 141
heart would recover independently from therapy. This mod-
el has been used to exp lore genetic alterations induced by
dyssynchrony and the capability of CRT (at the same high
rate) to restore these alterations [53]. This model provided
some interesting data, showing that even though heart rate
remained high and hemodynamics hardly improved, electrical
resynchronization and mechanical recoordination resulted in
extensive cellular and molecular recovery [54, 55].
To investigate chronic effects of CRT under physiological
heart rates in LBBB and dilated cardiomyopathy, an alter-
native heart failure model is necessary. Therefore, we have
recently commenced the development of a chronic model of
heart failure and dyssynchrony in our laboratory by inducing
LBBB and mitral regurgitation in canine hearts. The model is
based on a known canine mitral regurgitation model in ab-
sence of LBBB which was used to investigate atrial fibrilla-
tion [56]. Mitral regurgitation was induced using a
customized electrophysiology catheter with a hook at the
distal tip which was introduced into the left ventricle via the
aortic valve. After grasping one or more chorda(e), the hook
was withdrawn into a sheet and cauterized to partially obliterate
the mitral suspension. This process was repeated until
echocardiographic and fluoroscopic evaluation indicated se-
vere mitral regurgitation. Figure 7 shows typical examples of
mitral regurgitation on echocardiography, fluoroscopy, and
cardiac MRI in canine hearts. For animated examples of
cardiac MRI and long-axis echocardiography during one
cardiac cycle in a dog with mitral regurgitation, see Online
Resource 3 and 4, respectively. One month after the proce-
dure, LBBB was induced by radiofrequency ablation of the
left bundle branch. Upon creation of mitral regurgitation,
heart rate and LV end-diastolic pressure increased, accom-
panied by a modest decrease in maximal LV pressure. LV
contractility decreased more gradually and after 5 months
(including creation of LBBB after 1 month) ultimately de-
creased to 57% of baseline. Clearly left atrial dilatation and
pericardial fluid are seen on the cardiac MRI, indicating
heart failure. Signs and symptoms of heart failure were also
clinically present in the dogs. Meanwhile, LV end-diastolic
pressure doubled compared to baseline values and peak
systolic pressure decreased to 83% of baseline (preliminary
data). Figure 8 shows an example of left ventricular dilata-
tion over time in a dog with mitral regurgitation and LBBB.
Note the rather steep increase in the first weeks after
Table 1 Canine models of dyssynchrony and associated left ventricular changes in hypertrophy, dilatation, EF, and dP/dt
max
Heart rate Wall thickening Dilatation Ejection fraction LV dP/dt
max
LV pacing [25, 57] 0 Septal wall 0/+ 0/ 0/
LBBB/RV pacing [26, 37] 0 Lateral wall + −−
added AoS [58] 0 ++ 0 ++
added MI [44, 59] 0 ++−−
added MR [35, 60] 0/+ ++ +
a
added atrial tachypacing [53]++ −− ++ −− −−
LBBB left bundle branch block, AoS aortic stenosis, MI myocardial infarction, MR mitral regurgitation
a
Gross EF, including backflow towards the left atrium
Fig. 8 Bi-weekly echocardio-
graphic follow-up of left ventricu-
lar internal diameters of a dog with
mitral regurgitation at week 4. At
day 0, the left bundle bran ch is
ablated. Note the steep increase in
end-diastolic and end-systolic in-
ternal diameter of the left ventricle
after superimposing LBBB upon
mitral regurgitation
142 J. of Cardiovasc. Trans. Res. (2012) 5:135145
superimposing LBBB upon mitral regurgitation. We expect
that this model will be useful to compare effects of isolated
dyssynchrony with dyssynchrony complicated by heart failure.
Of particular interest are biomarkers sensitive to dyssynchrony
and regional differences in wall structure and protein synthesis.
As delineated in an overview of discussed canine models of
dyssynchrony and their effects on left ventricular character-
istics (Table 1), we believe that this novel dyssynchrony
model is the animal model which resembles the pathophys-
iology of CRT patients the closest, especially since mitral
regurgitation is also an important component of the dyssyn-
chronous heart.
Conclusion
Animal models are of great importance in understanding the
events and consequences of dyssynchrony and resynchroni-
zation. Depending on the hypothesis to be tested, multiple
well-established and novel animal models of dyssynchrony
exist. Detailed animal experiments demonstrate that ventricu-
lar dyssynchrony is a complex disease, which can and needs to
be treated in a better way than it is often performed today.
Acknowledgments This research was performed within the frame-
work of CTMM, the Center for Translational Molecular Medicine
(www.ctmm.nl), project COHFAR (grant 01C-203), and supported by
the Dutch Heart Foundation.
Open Access This article is distributed under the terms of the Crea-
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    • "LBBB is considered the hallmark conduction disturbance that is associated with delayed LV activation. In canine hearts where proximal ablation of the left bundle-branch was performed , electrical mapping showed that earliest electrical activation occurs inside the right ventricle and that the electrical wave front then slowly propagates through the interventricular septum towards the lateral wall of the LV [36]. Induction of LBBB in healthy canine hearts leads to electrical and mechanical dyssynchrony that in turn causes loss of LV pump function and ventricular remodelling [37]. "
    [Show abstract] [Hide abstract] ABSTRACT: Cardiac resynchronization therapy (CRT) is a well-known treatment modality for patients with a reduced left ventricular ejection fraction accompanied by a ventricular conduction delay. However, a large proportion of patients does not benefit from this therapy. Better patient selection may importantly reduce the number of non-responders. Here, we review the strengths and weaknesses of the electrocardiogram (ECG) markers currently being used in guidelines for patient selection, e.g., QRS duration and morphology. We shed light on the current knowledge on the underlying electrical substrate and the mechanism of action of CRT. Finally, we discuss potentially better ECG-based biomarkers for CRT candidate selection, of which the vectorcardiogram may have high potential.
    Full-text · Article · May 2016
    • "This disorder has been widely associated with intra-ventricular dyssynchrony [34]. The close link between LBBB (electrical defect) and intraventricular dyssynchrony (mechanical defect) has been studied in animal models [43], clinical subjects [19], and, more recently in computational models [24]. However, the respective influence of one defect on the other remains an open issue. "
    [Show abstract] [Hide abstract] ABSTRACT: This manuscript describes our recent developments towards better understanding of the mechanisms amenable to cardiac resynchronization therapy response. We report the results from a full multimodal dataset corresponding to eight patients from the euHeart project. The datasets include echocardiography, MRI and electrophysiological studies. We investigate two aspects. The first one focuses on pre-operative multimodal image data. From 2D echocardiography and 3D tagged MRI images, we compute atlas based dyssynchrony indices. We complement these indices with presence and extent of scar tissue and correlate them with CRT response. The second one focuses on computational models. We use pre-operative imaging to generate a patient-specific computational model. We show results of a fully automatic personalized electromechanical simulation. By case-per-case discussion of the results, we highlight the potential and key issues of this multimodal pipeline for the understanding of the mechanisms of CRT response and a better patient selection.
    Full-text · Article · Feb 2013
    • "Early activated regions are indicated by a red color (close to 0 ms) and late activation regions are indicated by a dark blue color (over 100 ms), see color bar. Reproduced with permission [8] a LBBB-like QRS morphology [14] . The heterogeneous activation patterns seen in heart failure patients with LBBB might in part explain why CRT leads to varying amount of response. "
    [Show abstract] [Hide abstract] ABSTRACT: Cardiac resynchronization therapy (CRT) aims to treat selected heart failure patients suffering from conduction abnormalities with left bundle branch block (LBBB) as the culprit disease. LBBB remained largely underinvestigated until it became apparent that the amount of response to CRT was heterogeneous and that the therapy and underlying pathology were thus incompletely understood. In this review, current knowledge concerning activation in LBBB and during biventricular pacing will be explored and applied to current CRT practice, highlighting novel ways to better measure and treat the electrical substrate.
    Full-text · Article · Apr 2012
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