Download subacute echocardiographic effects of ace inhibitors in the dogs with

Bull Vet inst Pulawy 52, 471-475, 2008
SUBACUTE ECHOCARDIOGRAPHIC EFFECTS
OF ACE INHIBITORS IN THE DOGS
WITH SEVERE MITRAL REGURGITATION
UTKU BAKIREL, SINEM GUNES, YUCEL MERAL1, AND TULAY BAKIREL2
Department of Internal Medicine, 2Department of Pharmacology and Toxicology,
Faculty of Veterinary Medicine, Istanbul University, 34851 Avcılar-İstanbul, Turkey
1
Department of Internal Medicine, Faculty of Veterinary Medicine,
Ondokuz Mayis University, 55139 Kurupelit- Samsun, Turkey
[email protected]
Received for publication November 19, 2007
Abstract
The effects of the angiotensin converting enzyme
inhibitors benazepril (B), enalapril (E), and ramipril (R) on the
function, geometry, and dimensions of the left ventricle (LV)
in the dogs with naturally acquired severe mitral regurgitation
(MR) were evaluated by echocardiography. Thirty-two dogs,
aged 8-16 years and weighing 10-12 kg, with fractional
shortening (FS) >50% were included into the study. Benazepril
(0.5mg/kg/d),
enalapril
(0.5mg/kg/d),
and
ramipril
(0.5mg/kg/d) were administered orally to B, E, and R groups,
respectively. Furosemide (2mg/kg/d) was administered orally
for conventional heart failure therapy. Physical, radiographic,
electrocardiographic, and echocardiographic examinations
were performed before treatment and on day 7 after the
treatment. A decrease in the left ventricle end diastolic
diameter (LVEDd) in groups E and R and in end diastolic
volume (EDV) in group E was considerable during the
subacute period (P<0.05). The stroke volume (SV)
significantly decreased in groups E and R (P<0.01), whereas
group B dogs had a mild decrease (P<0.05). FS and ejection
fraction (EF) that were higher before treatment decreased
significantly in all groups after the treatment (P<0.001).
Differences in SV, FS, and EF were not statistically significant
between groups. It was detected that LV was remodelled as a
result of the effects of enalapril and ramipril on LVEDd and
also EDV was decreased by enalapril. Furthermore, it was
observed that these ACE inhibitors were effective on
geometry, dimensions, and functions on LV of the dogs with
severe MR, and enalapril was found to be the most effective
agent, followed by ramipril and benazepril.
Key words: dog,
benazepril, enalapril, ramipril.
mitral
regurgitation,
Mitral regurgitation (MR) caused by
myxomatous degeneration of the mitral valve leaflets
and associated structures, is the most common
cardiovascular disease identified in dogs (13, 24). The
disease is frequently found in older dogs and small
breeds (3). Although the aetiology of the disease is
ascertained, there is a substantial information concerning
factors influencing the disease development, such as
genetic factors, collagen abnormalities, breed
predilection, stress, hypertension, hypoxia, prior viral
and bacterial infections, and a variety of endocrine
abnormalities (13, 19, 24). The diagnosis of MR is
commonly based on case description, history, and
physical examination findings. Echocardiography
identifies the abnormal valve anatomy and ventricle
enlargement (16). Chronic degenerative mitral valve
disease (CVD) causes thickening of the mitral valve
leaflets and the subsequent volume load associated with
MR causes left ventricular (LV) and atrial dilatation, LV
wall and septal hypertrophy, elevated parameters of
function, and hyperkinetic LV wall and interventricular
septal motion (5, 8, 13).
Blockade of the renin-angiotensin system with
angiotensin converting enzyme (ACE) inhibitors has
showed to modulate adverse LV remodelling and
beneficially alter haemodynamic and clinical status in
dogs with heart failure (10, 20, 23). The studies in
humans and dogs with MR have suggested that therapy
with ACE inhibitors prevents progressive worsening of
MR and LV dilatation (10, 15, 17, 23). In addition, the
studies, which tested ACE inhibitors for the prevention
of MR or for the reduction of the severity of the existing
regurgitation, demonstrated acute or long-term effects
(11, 15, 21, 23). However, the effects of ACE inhibitors
in dogs with MR are controversial. Because some dogs
have a dramatic response or no response or mild to
moderate improvement, clinical impression to ACE
inhibitors can be quite various (7, 17, 27). The
hypothesis that subacute therapy with ACE inhibitors,
such as benazepril, enalapril, and ramipril have
beneficial effects on the function, geometry, and
dimensions of LV in the dogs with naturally acquired
MR, was tested in present study.
472
Material and Methods
Study design. The medical records of dogs
examined between January 2000 and April 2007 were
reviewed. Sixty-two dogs with chronic mitral
regurgitation diagnosed by echocardiography were
detected in these records. Their body weight was
between 10 and 12 kg. The presence of a cough or
exercise intolerance and systolic heart murmur (V/VI or
VI/VI), and the identification of a severe degree of MR
and LV fractional shortening (FS) more than 50% by 2D and M-mode echocardiographic examination were the
criteria that was considered as suitable for inclusion to
the study.
The criteria that excluded dogs from the study
were the presence of myocardial disease of any
aetiology; systemic or congenital disease, or both;
multivalvular disease, acquired cardiovascular disorders
that affect the mitral valve, FS less than 50% in
miniature, toy, or large breed dogs. According to the
criteria, 32 dogs were selected for this study. They
consisted of 25 males and 7 females and aged 8-16
years. The dogs were randomly divided into three
groups as benazepril-treated (B), enalapril-treated (E),
and ramipril-treated (R).
Study protocol and drug administration.
Within group B, 10 dogs received benazepril tablets at a
daily dose of 0.5 mg/kg b.w. Enalapril tablets at a dose
of 0.5 mg/kg/d were given to 20 dogs in group E and
ramipril tablets at a dose of 0.25 mg/kg/d were given to
10 dogs in group R. All the drugs were administered for
7 d. A conventional therapy for heart failure (furosemide
2 mg/kg/d) was applied to all the dogs. Before and after
the medication, the dogs underwent clinical
examination, 12-lead electrocardiography, chest X-ray,
and echocardiography (2-D and M-mode). The
examination and all the measurements and calculations
were evaluated by two observers.
Echocardiography and measurements. In
accordance with the techniques described, records of 2D and M-mode echocardiograms were obtained from
right parasternal short-axis and long-axis views at the
level of the chordae tendineae with the dogs positioned
in a right lateral recumbence (2, 26). The
echocardiographic images were obtained with SDU350A echocardiography device and micro-convex
transducer of 3.5-5.0 MHz. After a complete 2dimensional examination of the dogs, LV diastolic and
systolic diameters were assessed on M-mode
measurement as recommended by the American Society
of Echocardiography. The examinations were performed
in conscious, unsedated dogs. Left ventricular enddiastolic diameter (LVEDd) and left ventricular endsystolic diameter (LVEDs) were obtained according to
M-mode measurements as previously described (2, 22).
The FS percentage was calculated using the following
formula: [(LVEDd - LVEDs)/ LVEDd) x 100]. The enddiastolic volume (EDV) and end-systolic volume (ESV)
were calculated using the Teichholz method: EDV= [7x
(EDD)3]/(2.4+EDD) and ESV= [7x (EDS)3 ]/(2.4+EDS).
Stroke volume (SV) and ejection fraction (EF, %) were
calculated according to the formula: SV=(EDV–ESV)
and EF%=[(EDV-ESV)/EDV) x 100] (13, 24).
Statistical analysis. The student’s t-test was
used for a comparison of changes from a baseline of
such parameters as LVEDd, LEVDs, FS, EDV, ESV,
SV, and EF. The treatment effects were compared
between groups and within groups using a two-way
repeated–measures analysis of variance (ANOVA).
Values of P<0.05 were considered to be statistically
significant. Data were presented as mean ± SD.
Results
None of the dogs used in the study had other
disease associated with severe MR and all of them had a
systolic murmur (V/VI and/or VI/VI) obtained in the left
cardiac apex. Clinical characteristics and measurements
of the LV dimensions and functions at baseline were
similar in all the groups and the differences of baseline
data were not statistically significant. The comparison of
the results before and after ACE inhibitors therapy
performed in dogs with severe MR is presented in
Table 1.
At the end of the 7-d treatment, LVEDd and
LVEDs decreased in all groups. While the left ventricle
end diastolic diameters were markedly declined, there
were no significant differences between the left ventricle
end systolic diameters. The decline of LVEDd was
significant in the dogs receiving enalapril and ramipril
(P<0.05). FS (>53%), which was higher before the
treatment decreased significantly during the 7-d period
in three groups (P<0.001).
Although the left ventricle EDV and ESV
decreased in all the dogs after the treatment, a decrease
in EDV was statistically significant only in group E
(P<0.05). SV was markedly declined in three groups. E
and R dogs showed significant differences in SV
(P<0.01), whereas group B dogs showed a mild
difference (P<0.05). Ejection fraction decreased
significantly in all the groups after the treatment
(P<0.001). No significant differences in SV, FS%,, and
EF% were detected between the groups, but the drugs
induced a considerable effect on these parameters.
The left atrial volume equal or larger than left
ventricular volume, thickening of inferior and posterior
leaflets of the mitral valve, mitral posterior and inferior
leaflets moving towards the left atrial space during
systole, opening the leaflets during systole, contact of
inferior leaflet of the mitral valve to the interventricular
septum, and ineffective contraction of LVPW were
detected by a pre-treatment echocardiographic
examination. A decrease in myocardial contractibility of
LVPW was obvious in post-treatment echocardiographic
evaluation. There was no significant decrease in
myocardial contractibility of the interventricular septum
(Fig. 1). In addition, it was detected that the left
ventricle was remodelled as a result of the effects of
enalapril and ramipril on LVEDd and enalapril
decreased diastolic stroke volume.
473
Table 1
Echocardiographic measurements before and after ACE inhibitor therapy in dogs
with severe mitral regurgitation
Group B (n=10)
Group E (n=12)
Group R (n=10)
Before
After
Before
After
Before
After
LVEDd (mm)
41.7±2.2
33.2±2.4 ns
41.6±0.89
32.2±0.81*
41.4±1.7
31.6±1.9*
LVEDs (mm)
19.5±1.0
18.6±1.1 ns
18.8±0.41
18.1±0.56 ns
19.2±1.0
19.0±1 ns
FS (%)
53.1±0.58
39.8±1.4***
54.7±1.2
40.5±1.5***
53.7±1.1
40±0.93***
EDV (ml)
118.1±13.1
77.9±11.8 ns
115±5.1
67.7±3.7*
95.3±4.2
67.1±9.0 ns
ESV (ml)
26±3.8
24.5±9.0 ns
23.7±1.3
22±0.96 ns
23.7±2.8
23.2±2.8 ns
SV (ml)
93.6±10.4
51.9±8.1*
91±4.0
44.9±3.9**
91.6±8
43.9±6.3**
EF (%)
79±0.59
66±1.4***
80.8±1.3
65.1±3.3***
79.6±0.93
65±1.2***
* P<0.05, ** P<0.05, *** P<0.001; ns : non-significant
B - benazepril-treated dogs, E - enalapril-treated dogs, R - ramipril-treated dogs, LVEDd - left ventricular end-diastolic diameter,
LVEDs - left ventricular end-systolic diameter, FS - fractional shortening, EDV - end-diastolic volume, ESV - end-systolic volume,
SV - stroke volume, EF - ejection fraction.
IVS
IVS
IVS
MV
IVS
CT
LV
LV
LV
MV
MV
LA
LVPW
LVPW
LA
LVPW
A
B
IVS
IVS
IVS
CT
CT
LV
CT
MV
LA
LVPW
LVPW
C
LV
LVPW
D
Fig. 1. M-mode and 2D echocardiograms obtained from right parasternal long-axis views: A - 2-D image of thickening of the mitral
valve leaflet and M-mode image of no closure of the mitral valve leaflets during systole from an echocardiogram of a dog in group B.
B - M-mode images of hyperkinetic left ventricle and interventricular septal wall motion and 2D image of left atrial space more
echogenic than left ventricular space from an echocardiogram of a dog in group R. C - hyperkinetic wall motion and contact of
inferior leaflet of the mitral valve to the interventricular septum shown in pre-treatment echocardiogram of a dog in group E. D – a
decrease in left ventricular diameter and myocardial contractility of the left ventricular posterior wall shown in post-treatment
echocardiogram of a dog in group E. IVS - interventricular septum, CT - chordae tendineae, LV - left ventricle, LA - left atrium, MV
- mitral valve, LVPW - posterior wall of left ventricle.
474
Discussion
The valvular lesions characteristic for CVD are
caused by an acquired chronic structural degeneration of
the atrioventricular valves. The disease occurs also due
to disturbances of the heart muscle, destruction of
connective tissue, and consequently, an enlargement of
the left ventricle and cardiac infract. Most commonly,
the mitral leaflets and corresponding chordae tendineae
are affected (9). Small breed dogs are sensitive to mitral
regurgitation due to CVD. The prevalence of the illness
is 10% within an appropriate dog population of five- to
eight-year-old animals and increases with age (1, 3, 4).
The dogs included into this study were of small breeds.
Several studies have shown that the age is a major
determinant of prevalence of CVD in various dog
populations (4, 5, 9).
CVD of mitral valve regurgitation may lead to
left atrioventricular volume overload, pulmonary
oedema, atrial dilatation, arrhythmias, and occasionally
to myocardial failure and pulmonary hypertension in
advanced heart disease (1). In this study, pulmonary
oedema, and left atrioventricular volume overload,
severe systolic murmur, and atrial dilatation were found
in the dogs by clinical, radiographic, and
echocardiographic evaluations and also supraventricular
arrhythmias were detected in most of the dogs by
electrocardiography.
Echocardiography permits a confirmation of the
diagnosis, a statement of disease severity, the probable
cause, as well as an evaluation of the process.
Additionally, the size and pumping function of the left
ventricle can be reliably determined with the help of the
echocardiography. MR, to a lesser degree, does not
induce any apparent changes in the indices of cardiac
size or function. As the regurgitation increases due to
progressive valvular lesions, the left atrium expands to
buffer the regurgitant volume. The left ventricle
compensates the loss of forward stroke volume by
increasing its end diastolic volume. This causes an
increased force of contraction according to the FrankStarling mechanism. The resistance to ventricular
emptying is reduced in MR, causing a more complete
emptying of the chamber (12, 14). When compared to
healthy dogs with the same body weight (19), LVEDd,
LVEDs, EDV, ESV, and SF were calculated as higher
pre-treatment echocardiographic parameters of the dogs
in this study. There was also a severe MR detected
clinically and by echocardiography in the dogs
examined.
There were three major findings of this study.
First: benazepril, enalapril, and ramipril significantly
reduced cardiac contractility and ejection fraction after
treatment. Second: ACE inhibition reduced cardiac
sizes. While this reduce was insignificant in LVEDs,
LVEDd significantly decreased in the groups E and R.
Therefore, ACE inhibitors used in this study prevented
progressive ventricular dilatation and it was detected
that the left ventricle was remodelled in the short period.
Third: in spite of a significant reduction in cardiac
contractility and sizes in preload in group E, no
alteration were detected in the afterload. It could be
explained by ventricular wall stress. However, a
reduction in stroke volume was significant in all the
groups.
ACE inhibitors are potent vasodilators reducing
volume load to the heart, as shown in the previous
human and animal studies (15, 17, 23). The effects of
ACE inhibitors, such as benazepril, enalapril, and
ramipril were compared in the present study. It was
reported in a study performed on the dogs with
experimentally induced MR that Lisinoprilin had a
decreasing effect on preload but not afterload (17). It
was reported also that ibersertan, angiotensin receptor
blocker did not improve LV remodelling and functions
in the dogs with subacute MR induced by chordal
disruption (20). However, it was suggested that a
decrease in LV volume and volume overload occurred in
the children under long-term treatment with cilazapril
and enalapril (15). In this study, it was found that
enalapril had a decreasing effect on the preload and SV
without alteration occurring in the left ventricle ESV.
With the effect of angiotensin II, left ventricular end
diastolic volume increases by filling excessive amount
of blood in diastole. This leads to left ventricular
remodelling and destruction of the left ventricular
geometry resulting in left ventricular enlargement and
deposition of papillary muscles of mitral valve leaflets
from a closure line. Thus, the mitral valves cannot close
completely and mitral regurgitation occurs (3, 20).
Therapeutic effects of benazepril, enalapril, and ramipril
on decreasing left ventricular end diastolic dimensions
and left ventricular volume in the dogs with severe MR
were shown in this study. Another parameter playing a
role in mitral regurgitation, is the difference in the
pressures of the left ventricle and left atrium. This
potency helps complete closure of mitral valves during
systole (12). In this study, no alteration in left
ventricular ESV was detected.
These findings are the short-term effects of
benazepril, enalapril, and ramipril. Studies made on the
long-term effect of ACE inhibitors showed a therapeutic
effect on the left ventricular function by decreasing the
end systolic volume (7, 10, 15, 17, 23). It has been
shown that our findings are related with results of cited
above studies. However, the limitation of this study was
the small number of dogs in groups and the remodelling
of the heart using other techniques as doppler
echocardiography would be more helpful in the
evaluation.
In addition to the standard therapy in dogs with
heart failure caused by MR, ACE inhibitors had been
demonstrated to be both efficacious and safe (7, 10, 23,
25). Ramipril, enalapril, and benazepril are hydrolysed
by the liver. Maximum haemodynamic effect starts just
3, 6, 7, and 12 h after the application and this effect lasts
24 h in ramipril and enalapril, whereas effect of
benazepril lasts longer than 24 h (18). In this research,
the effect of ramipril, and enalapril on decreasing
LVEDd and EDV in subacute period could be due to
time of maximum haemodynamic effect. Similarly, a
mild decrease in SV occurred in group B and a
significant decrease occurred in groups E and R. FS and
475
EF that were higher before treatment, decreased
significantly in all the groups after the treatment with
ACE inhibitors. No significant differences in SV, FS,
and EF were detected between the groups and the drugs
showed considerable effects on these parameters. It was
found that LV was remodelled as a result of the effects
of enalapril and ramipril on LVEDd and also EDV was
decreased by enalapril. Furthermore, it was observed
that these ACE inhibitors were effective on geometry,
dimensions, and functions of LV of the dogs with severe
MR and enalapril was found to be the most effective
agent, followed by ramipril and benazepril.
Acknowledgments: This study was
supported by Research Fund of the Istanbul University.
(Project number UDP-2027).
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