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Pimobendan
and Mitral Regurgitation
Humana Press
© Copyright 2005 by Humana Press Inc. All rights of any nature whatsoever reserved.
43
1530-7905/01
Increased Mitral Valve Regurgitation
and Myocardial Hypertrophy in Two Dogs
With Long-Term Pimobendan Therapy
R. Tissier,2,4,* V. Chetboul,1,4 R. Moraillon,3 A. Nicolle,1
C. Carlos,1 B. Enriquez,2,4 and J-L. Pouchelon1,4
1
Unité de Cardiologie, 2Unité Pédagogique de Pharmacie-Toxicologie,
Unité Pédagogique de Médecine, Ecole Nationale Vétérinaire d’Alfort,
Maisons-Alfort, France; and 4INSERM E00-01, Faculté de Médecine
Paris XII, Créteil, France
3
Abstract
*Author to whom all
correspondence and
reprint requests should be
addressed: Renaud Tissier,
DVM, PhD, Unité
Pédagogique de PharmacieToxicologie, Ecole
Nationale Vétérinaire
d’Alfort, 7 Avenue du
Général de Gaulle, 94704
Maisons-Alfort cedex,
France. E-mail: rtissier@
vet-alfort.fr
Received: 03/06/04
Revised: 05/10/04
Accepted: 05/24/04
Cardiovascular Toxicology,
vol. 5, no. 1, 43–51, 2005
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43
The aim of this article is to describe original adverse effects in two dogs chronically treated with the inodilator pimobendan. We report a German shepherd
(i.e., dog 1) and a poodle (i.e., dog 2) that were referred to our cardiology unit
after receiving pimobendan for 10 and 5 mo, respectively. In both dogs, conventional echo-Doppler examination demonstrated mitral valve regurgitation
and myocardial hypertrophy. Tissue Doppler imaging (TDI) was performed in
the first case and revealed an abnormal relaxation phase. After the first examination, pimobendan administration was stopped in both cases and dogs were
re-examined 3 and 1 mo later, respectively. Mitral valve regurgitation assessed
by echocardiography decreased in both dogs, and the systolic heart murmur
disappeared in dog 1. Importantly, most echocardiographic and TDI parameters tended to normalize in dog 1, suggesting, at least partial reversal of both
myocardial hypertrophy and relaxation abnormality produced during inodilator
therapy. This is the first report to describe an increase in mitral regurgitation
under clinical conditions in dogs treated with pimobendan. We also suggest
that pimobendan may induce ventricular hypertrophy. However, prospective
studies are needed to confirm this observation.
Key Words: Dog; pimobendan; inodilator; inotrope; echocardiography; tissue
Doppler imaging; ventricular hypertrophy; mitral valve regurgitation.
Introduction
Inodilators are pharmacological compounds producing vasodilation and inotropic effects mediated by phosphodiesterase III inhibition and calcium-sensitizing
properties. Despite controversy, the principal inodilators (i.e., levosimendan and
pimobendan) were demonstrated to be beneficial in the treatment of left ventricular
systolic failure in both human (1–3) and veterinary cardiology (4). However, Schneider
et al. (5) demonstrated that repeated pimobendan administration can be cardiotoxic
in healthy dogs, for example, leading to mitral jet lesions after 4 wk even at close to
therapeutic dosages. These findings raised an important issue, that is, the potential
adverse effects of chronic treatment with pimobendan in dogs without systolic myocardial dysfunction (e.g., in myxomatous valvular disease). Indeed, the usefulness
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Tissier et al.
of inodilator therapy in canine valvular insufficiency
has been greatly debated and remains an important
issue in the absence of definitive data. A study was
recently initiated to obtain more information on the
subject (6).
During routine clinical work at our veterinary cardiology unit, we observed original adverse effects of
pimobendan in two dogs that had been treated chronically with this inodilator and did not show decreased
left ventricular systolic function. The aim of this short
article is to describe these effects (i.e., increased
mitral valve regurgitation, myocardial hypertrophy,
and alterations in left ventricular relaxation) and to
demonstrate that they were, at least in part, reversed
after cessation of pimobendan administration.
Materials and Methods
Two dogs were referred to the Cardiology Unit of
Alfort. They underwent complete clinical exams
followed by conventional echocardiography. Tissue
Doppler imaging (TDI) examination was also performed in the first case.
Conventional Echocardiography
Two-dimensional (2D) and M-mode echocardiography, color flow imaging, and spectral Doppler
examinations were performed by the same trained
observer with continuous ECG monitoring using a
Vingmed system 5 (General Electric Medical System, Waukesha, WI) equipped with a 2.5- to 3.5-MHz
phased-array transducer. Ventricular measurements
were taken from the right parasternal location (shortaxis view) using the 2D-guided M-mode, according
to the recommendations of the American Society of
Echocardiography (7). Measurements of the aorta and
the left atrial diameter were performed with a 2D
method (8), using a short-axis right-sided parasternal view obtained at the level of the aortic valve, where
the commissures of the cusps are visualized during
diastole. For all ultrasound examinations, dogs were
awake, gently restrained in the standing position.
This method has already been proven in our group to
have good repeatability and reproducibility (9). A
left parasternal apical four-chamber view was used
to record mitral inflow by pulsed wave Doppler. Peak
diastolic velocities were measured in early (Em) and
late (Am) diastole, and the Em/Am ratio was then calculated. Finally, mitral regurgitation was assessed
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semiquantitatively by measuring the size of the systolic color-flow jet originating from the mitral valve
and spreading into the left atrium using the left apical four-chamber view. As previously described in
dogs (10), images were carefully analyzed frame by
frame to determine the maximum area of the regurgitant jet signal.
2D Color TDI Examination
The same materials and procedures described in
“Conventional Echocardiography” were used for TDI
examinations. Real-time color Doppler was superimposed on the gray scale with a frame rate ³100
frames per second. The Doppler receive gain was
adjusted to maintain optimal coloring of the myocardium, and Doppler velocity range was set as low
as possible to avoid occurrence of aliasing. Left ventricular free wall (LVFW) velocities resulting from the
radial left ventricular motion were measured using the
right parasternal ventricular short-axis view between
the two papillary muscles, as previously described
(11). The angle of interrogation of the beam was
carefully aligned to be perpendicular to the LVFW.
Measurements were made on an endocardial and an
epicardial segment (2 ´ 2 mm) of the LVFW. Simultaneous endocardial and epicardial velocity profiles
were obtained using a stand-alone off-line measuring system (Echo Pac for Vingmed System 5, General
Electric Medical System). TDI parameters included
maximal systolic (S), early (E), and late (A) diastolic
LVFW velocities. This method has also been proved
in our group to have good repeatability and reproducibility (11).
Results
Case Report: Dog 1
First Visit
A 6-yr-old 30-kg female German shepherd was
referred to the Cardiology Unit for exercise intolerance and depression that had been increasing for several weeks. The owner reported that the animal was
anxious for no specific reason. The dog had been
treated with pimobendan for 10 mo (0.33 mg/kg PO
q12h) without any prior echocardiographic examination. Biochemical parameters, blood cell count,
and systemic blood pressure (145 mmHg, 75 mmHg)
were within normal ranges. Physical examination
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Table 1
Conventional M-Mode and Two-Dimensional Echocardiographic
Parameters of Dogs 1 and 2 During Two Exams, Before and After Stopping Pimobendan a
Second exam
after stopping
pimobendan
therapy
Normal rangesa
for corresponding
weight
Care report 1
Day 0
Left ventricular end-diastolic diameter (mm)
34.6
Left ventricular end-systolic diameter (mm)
15.4
Interventricular septal diastolic thickness (mm)
12.9
Interventricular septal systolic thickness (mm)
21.1
Left ventricular free-wall diastolic thickness (mm)
15.4
Left ventricular free-wall systolic thickness (mm)
18.6
Shortening fraction (%)
56
Left atrium size (mm)/aorta diameter (mm)
0.89
Maximal mitral regurgitation jet area (mm2)
232
Mitral E wave (m/s)
0.21
Mitral A wave (m/s)
0.60
Mitral E wave/mitral A wave
0.35
Time of mitral regurgitation
Whole systole
Day 0 + 3 mo
40.0
25.0
9.6
15.7
10.5
16.2
37.5
0.83
22
0.74
0.43
1.72
Early systole
German shepherd 30 kg
40.3–43.6
25.0–27.4
10.2–11.3
15.4–16.7
8.2–9.2
13.2–14.4
33.5–45.9
0.83–1.13
—
0.59–1.18
0.33–0.93
1.04–2.42
—
Case report 2
Day 0
Left ventricular end-diastolic diameter (mm)
26.3
Left ventricular end-systolic diameter (mm)
12.0
Interventricular septal diastolic thickness (mm)
7.8
Interventricular septal systolic thickness (mm)
11.4
Left ventricular free-wall diastolic thickness (mm)
7.5
Left ventricular free-wall systolic thickness (mm)
13.6
Shortening fraction (%)
54
Left atrium size (mm)/aorta diameter (mm)
0.84
95
Maximal mitral regurgitation jet area (mm2)
Mitral E wave (m/s)
0.64
Mitral A wave (m/s)
0.87
Mitral E wave/mitral A wave
0.74
Time of mitral regurgitation
Whole systole
Day 0 + 1 mo
25.4
14.5
8.0
11.9
8.1
12.3
43
0.84
34
1.18
0.87
1.36
Early systole
Poodle 8.5 kg
16–28
8–16
4–6
6–10
4–6
6–10
35–57
0.83–1.13
—
0.59–1.18
0.33–0.93
1.04–2.42
—
Echocardiographic parameters
aSee
First exam
before stopping
pimobendan
therapy
ref. 12–15. —, not applicable.
revealed a weak and a tachypneic animal with a left
apical systolic heart murmur (grade III/VI). Heart
rate averaged 95 beats per minute (BPM).
Conventional M-mode and 2D echocardiographic
parameters are shown in Table 1. Right ventricular
and atrial dimensions were normal. 2D echocardiography revealed irregular and thickened mitral
valve leaflets on the right and left parasternal fourchamber views (maximal thickness = 4.0 mm). A
systolic anterior motion of the mitral valve was not
observed on M-mode images. Echo-Doppler examination showed a severe symmetric myocardial hyperCardiovascular Toxicology
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trophy in which the ventricular septum and the LVFW
were both affected (Fig. 1). This hypertrophy was
associated with a marked elevation of the shortening
fraction, reduced systolic and diastolic left ventricular cavity, and significant systolic mitral regurgitation. However, no left atrial dilation was observed.
The reversed Em/Am ratio (0.35) on Doppler examination of mitral inflow suggested impaired left ventricular relaxation.
As shown in Table 2, TDI examination revealed
high systolic radial myocardial velocities and an impaired relaxation phase with a characteristic decrease
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Tissier et al.
complete exam was performed. The systolic murmur
had totally disappeared and heart rate averaged 97
BPM.
Color flow Doppler examination showed a nearly
total disappearance of the mitral regurgitation (Table
1). On Doppler examination of mitral inflow, Em/
Am ratio (1.72) returned to normal. Shortening fraction and interventricular septal systolic thickness
returned to normal ranges. Interventricular septal
diastolic thickness strongly decreased under normal
ranges. Both LVFW diastolic and systolic thickness
remains slightly elevated. As shown in Table 2, systolic and early diastolic myocardial velocities also
returned to normal ranges, despite a persistent slight
increase in A wave. Moreover, and as illustrated in
Fig. 2B, normalized E/A ratio was observed in both
epicardial and endocardial layers (1.18 and 1.21,
respectively).
Case Report: Dog 2
First Visit
Fig. 1. (A, B) Echocardiography of dog 1 at the first
visit. (A) Two-dimensional echocardiogram showing the
marked left ventricular hypertrophy (end-systolic frame of
the left ventricle obtained from the right parasternal shortaxis view at the level of the papillary muscles). (B) M-mode
echocardiogram showing the symmetric myocardial hypertrophy and the reduction of the left ventricular diameter.
LV, left ventricle; RV, right ventricle; IVS, interventricular septal wall; LVFW, left ventricular free wall.
in the E-to-A ratio (E/A < 1) in the endocardial as
well as in the epicardial layers (0.46 and 0.48, respectively). Figure 2A illustrates an example of the TDI
velocity profile.
Second Visit: Follow-Up
After the first visit, pimobendan therapy was stopped
and changed to benazepril (0.33 mg/kg/d). The owner
reported that the dog was less depressed and less
anxious during the week following the new treatment.
Three months later, the dog was alert and a second
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A 10-yr-old 8.5-kg male poodle was referred to the
Cardiology Unit for exercise intolerance, lethargy,
and cough with tachypnea that had been increasing
for several weeks. Like the owner of dog 1, the owner
of dog 2 reported that the animal was getting more
and more anxious and nervous, particularly at night.
The dog had a prior history of tracheal collapse and
chronic bronchitis for several years. The dog underwent pimobendan treatment for 5 mo (0.29 mg/kg
PO q12h) without any prior echocardiographic examination. On physical examination, a nonproductive
cough was easily elicited by palpation of the trachea,
but no heart murmur was detected. Heart rate averaged 120 BPM during this first visit.
2D echocardiography revealed irregular and thickened mitral valve leaflets on the right and left parasternal four-chamber views (maximal thickness =
5.2 mm). A systolic anterior motion of the mitral valve
was not observed on M-mode images. Right ventricular and atrial dimensions were normal. As shown in
Table 1, conventional echo-Doppler examination
demonstrated slight myocardial hypertrophy associated with an elevated shortening fraction and mitral
regurgitation during the whole systole. However, no
left atrial dilation was observed. Similar to the results for dog 1, the reversed Em/Am ratio (0.73) on
Doppler examination of mitral inflow suggested impaired left ventricular relaxation.
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Table 2
Radial Tissue Doppler Imaging Parameters Measured in Endocardial and Epicardial Layers
of the Left Ventricular Free Wall of Dog 1 During Two Exams, Before and After Stopping Pimobendana
Tissue Doppler
imaging parameters
S wave (cm/s)
Endocardial
Epicardial
E wave (cm/s)
Endocardial
Epicardial
A wave (cm/s)
Endocardial
Epicardial
First exam
before stopping
pimobendan therapy
Second exam
after stopping
pimobendan therapy
Day 0
Day 0 + 3 mo
9.7
7.4
5.9
3.8
4.7–9.0
1.9–4.7
4.1
2.5
6.7
4.5
5.2–12.0
1.5–5.2
9.0
5.2
5.7
3.7
1.9–5.8
0.5–2.9
Normal rangesa
aSee
ref. 16.
A, peak velocity of the left ventricular free wall during late diastole: E, peak velocity of the left ventricular free wall during early
diastole: S, peak velocity of the left ventricular free wall during systole.
Second Visit: Follow-Up
Pimobendan treatment was stopped after the first
visit and no other treatment was given. Like the owner
of dog 1, the owner of dog 2 reported that the dog was
more alert and less anxious and nervous 1 wk later
and that cough and tachypnea had markedly decreased. One month later, the dog was in good condition and a second echo-Doppler exam was performed.
As illustrated in Table 1, myocardial wall thicknesses
were still slightly elevated, but the shortening fraction had diminished. Mitral inflow profile returned
to normal (Em/Am ratio = 1.35). Finally, mitral regurgitation markedly diminished. Heart rate averaged
107 beats/min during this second visit.
Discussion
Our reports demonstrate original adverse effects
associated with chronic treatment with pimobendan
in two dogs. In both cases, mitral valve regurgitation
strongly decreased when pimobendan therapy was
stopped. Ventricular hypertrophy was also demonstrated and appeared to be at least partially reversible
in one dog after pimobendan treatment was replaced
with the angiotensin-converting enzyme inhibitor
benazepril. Relaxation abnormalities were characterized by TDI and pulsed wave Doppler (mitral inCardiovascular Toxicology
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47
flow) in dog 1 and by pulsed wave Doppler only in
dog 2. These diastolic alterations were reversed after
cessation of pimobendan administration. Because
heart rate was similar between the two visits for dog
1, and decreased slightly (-13 BPM) for dog 2, a variation of heart rate could not explain the abnormal
relaxation phase during pimobendan therapy or its
normalization after cessation of the treatment. To our
knowledge, this is the first study to report reversible
mitral valve regurgitation, myocardial hypertrophy,
and diastolic dysfunction in dogs under pimobendan
treatment and in clinical conditions. Importantly,
both dogs were treated with dosages (0.33 and 0.29
mg/kg PO q12h, respectively) close to those recommended in canine systolic heart failure (0.3–0.6 mg/
kg/d) (4). The described potential adverse effects
could not therefore be related to high dosage and
might be observed at the therapeutic level.
In our study, the first important finding is pimobendan-induced increase in mitral valve regurgitation.
The imputability of this phenomenon to pimobendan
is highly probable because regurgitation was strongly
reduced after stopping this therapy. Obviously, increased valve regurgitation might be explained by
ventricular hypercontractility, which was characterized by greater shortening fraction during pimobendan therapy (Table 1). In dog 1, increased magnitude
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Fig. 2. (A, B) Analysis of left ventricular free wall (LVFW) radial motion (right panels) of dog 1 at the first visit (A)
and second visit (B) (after stopping pimobendan treatment). Two-dimensional color tissue Doppler imaging mode
recording from the right parasternal short-axis view was used (left panels). The yellow and green curves correspond to
the endocardial and epicardial velocity profiles, respectively. LV, left ventricle; A, peak velocity of the LVFW during
late diastole; E, peak velocity of the LVFW during early diastole; IVCT, isovolumic contraction phase; IVRT, isovolumic
relaxation phase; S, peak velocity of the LVFW during systole.
of S waves (assessed by TDI) also reflects this hypercontractile state. These findings further support the
conclusion that pimobendan’s vasodilating properCardiovascular Toxicology
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ties might not permit avoidance of ventricular overload and a secondary increase in mitral regurgitation. Interestingly, previous experimental data in
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49
healthy dogs demonstrated that mitral jet lesions
could be induced, even with the lack of valvular disease, by pimobendan administration (5). One might,
however, argue that previous studies (17,18) demonstrated that inotropic therapies (i.e., dobutamine)
were able to decrease mitral regurgitation in humans.
However, the pathophysiology of such mitral insufficiency was completely different because it occurred
in dilated cardiomyopathies that induced mitral regurgitation by an initial increase in mitral orifice
area. In such a situation, some inotropes have been
demonstrated to be beneficial by a reduction of mitral
orifice area (19). In dogs with myxomatous valvular
disease, the regurgitation is triggered by a primitive
valvular degeneration, and the effect of inotropes
might be completely different because a worsening
of regurgitation could be induced by a higher pressure gradient between atria and ventricles. Indeed, a
previous clinical report in dogs demonstrated that
the acute administration of another inotrope (i.e.,
digoxin) increased mitral regurgitation in four of five
cases (20). These findings suggest that ventricular
function should always be assessed before initiating
inodilator therapy, especially in dogs with myxomatous valvular disease.
One can hypothesize that our conclusions could
be explained by inter-day variability of our echocardiographically assessed mitral regurgitation jet size.
However, we observed a total disappearance of systolic left apical murmur after stopping pimobendan
therapy in dog 1. It also supports a strong decrease
in mitral regurgitation because murmur intensity and
Doppler-assessed jet size were demonstrated to be
well-correlated (21). Finally, it should be noted that
exercise tolerance was rapidly better in both dogs
(several days) after stopping administration of pimobendan, even though this parameter was assessed
subjectively.
The second major finding of this short article is
the observation of myocardial hypertrophy in these
two pimobendan-treated dogs. Obviously, our first
hypothesis was that these morphological alterations
reflected hypertrophic cardiomyopathy. This disease remains rare, but is well described in dogs (22).
However, ventricular hypertrophy was strongly reversed 3 mo after stopping pimobendan therapy in
dog 1. This reversal could not be explained by interday variability in echocardiographic procedures. For
example, the inter-day variation coefficient for the
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LVFW diastolic thickness averaged 9% in our clinic
(9), whereas this parameter evolved from 15.4 to
10.5 mm (i.e., -32%) after cessation of pimobendan
administration. These findings strongly suggest that
pimobendan triggered concentric hypertrophy in this
dog, especially because reversal myocardial diastolic dysfunction was also observed (Fig. 2). Again,
this reverse could not be explained by inter-day variability of TDI measurements (inter-day variation
coefficient of endocardial E wave = 25% vs a 63%
observed variation between the two exams) (11). In
dog 2, ventricular hypertrophy decreased but was not
reversed 1 mo after stopping pimobendan administration. It is probable that a longer time is needed for
reversal of this change.
Moreover, it is obvious that diastolic left ventricular myocardial hypertrophy cannot be considered
as a usual alteration in canine myxomatous valvular
disease and that our observations could therefore not
reflect the natural history of this disease. Indeed,
such a diastolic myocardial hypertrophy was never
reported, to our knowledge, in the numerous studies
describing canine valvular insufficiency (23). Nevertheless, a large prospective study is needed to confirm our hypothesis of possible pimobendan-induced
hypertrophy and to evaluate its incidence (6). Some
mechanistic theories could be hypothesized in order
to explain the genesis of such a hypertrophy. Indeed,
although the potential hypertrophic effect of longterm administration of inodilators has not yet been
described, the ability of other inotropes (e.g., isoproterenol or dobutamine) to induce ventricular hypertrophy is well known (24,25). Whether such a morphological alteration might be caused by hemodynamic factors or by b-adrenergic receptor stimulation
is debatable (26–28). Chronic pimobendan administration entered the picture because it mimics hemodynamic changes mediated by b-receptor agonists and
is characterized by a similar molecular pathway, that
is, activation of the cyclic adenosine monophosphate
pathway (by inhibition of phosphodiesterase III).
In conclusion, we report increased mitral valve regurgitation and reversal myocardial hypertrophy in
two dogs after long-term pimobendan therapy. Reversal diastolic dysfunction was also observed by TDI
in dog 1. These results suggest that echocardiography
may be useful both before and during pimobendan
therapy in order to rule out prior or induced diastolic
myocardial dysfunction and myocardial hypertro-
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Tissier et al.
phy. Further prospective studies are needed to confirm the potential cardiovascular adverse effects of
pimobendan.
12.
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