Download The Effect of Ramipril on Left Ventricular Mass, Myocardial Fibrosis

J Vet Intern Med 2006;20:1093–1105
The Effect of Ramipril on Left Ventricular Mass, Myocardial
Fibrosis, Diastolic Function, and Plasma Neurohormones in Maine
Coon Cats with Familial Hypertrophic Cardiomyopathy without
Heart Failure
Kristin A. MacDonald, Mark D. Kittleson, Richard F. Larson, Philip Kass, Tyler Klose,
and Erik R. Wisner
Background: Hypertrophic cardiomyopathy (HCM) is the most common heart disease of cats, resulting in left ventricular
(LV) hypertrophy, myocardial fibrosis, and diastolic dysfunction.
Hypothesis: Ramipril will reduce LV mass, improve diastolic function, and reduce myocardial fibrosis in cats with HCM
without congestive heart failure (CHF).
Animals: This prospective, blinded, placebo-controlled study included 26 Maine Coon and Maine Coon cross-bred cats with
familial HCM but without CHF.
Methods: Cats were matched for LV mass index (LVMI) and were randomized to receive ramipril (0.5 mg/kg) or placebo
q24h for 1 year, with investigators blinded. Plasma brain natriuretic peptide (BNP) concentration, plasma aldosterone
concentration, Doppler tissue imaging (DTI), and systolic blood pressure were measured at baseline and every 3 months for
1 year. Cardiac magnetic resonance imaging (cMRI) was performed to quantify LV mass and myocardial fibrosis by delayed
enhancement (DE) cMRI at baseline and 6 and 12 months. Plasma angiotensin-converting enzyme (ACE) activity was
measured on 16 cats 1 hour after PO administration.
Results: Plasma ACE activity was adequately suppressed (97%) in cats treated with ramipril. LV mass, LVMI, DTI, DE,
blood pressure, plasma BNP, and plasma aldosterone were not different in cats treated with ramipril compared with placebo
(P 5 .85, P 5 .94, P 5 .91, P 5 .89, P 5 .28, P 5 .18, and P 5 .25, respectively).
Conclusion: Treatment of Maine Coon cats with HCM without CHF with ramipril did not change LV mass, improve
diastolic function, alter DE, or alter plasma BNP or aldosterone concentrations in a relevant manner.
Key words: Aldosterone; Angiotensin-converting enzyme inhibitor; Brain natriuretic peptide; Cardiac MRI; Delayed enhancement; Doppler tissue imaging; Hypertrophy.
ypertrophic cardiomyopathy (HCM) is the most
common cardiac disease in cats. HCM is defined
as concentric hypertrophy of the left ventricle (LV) in
the absence of other causes of concentric hypertrophy
including systemic hypertension, aortic stenosis, hyperthyroidism, and acromegaly. The initial phenotype in
HCM is thought to be a functional defect of the
sarcomere, and intermediary pathways are thought to
connect the initial defect to the final phenotype of
compensatory concentric LV hypertrophy, LV interstitial myocardial fibrosis, and myofiber disarray.1 LV
hypertrophy, myofiber disarray, and myocardial fibrosis
cause diastolic dysfunction.2 Severe diastolic dysfunction
may lead to left atrial (LA) dilation and to severe
consequences including congestive heart failure (CHF),
arterial thromboembolism, and sudden death.
HCM is inherited as an autosomal dominant trait
with incomplete penetrance in the colony of Maine
Coon cats used in this study.3 A missense mutation in
H
From the Departments of Veterinary Medicine and Epidemiology
(MacDonald, Kittleson), Surgical and Radiological Sciences (Wisner), Population Health and Reproduction (Kass), Veterinary
Medical Teaching Hospital (Larson), School of Veterinary Medicine (Klose), University of California, Davis, CA.
Reprint requests: Kristin MacDonald, DVM, Department of
Medicine and Epidemiology, University of California, Davis, 2108
Tupper Hall, 1 Shields Ave., Davis, CA 95616; e-mail: kamacdonald@
ucdavis.edu.
Submitted August 24, 2005; Revised November 23, 2005;
Accepted March 6, 2006.
Copyright E 2006 by the American College of Veterinary Internal
Medicine
0891-6640/06/2005-0006/$3.00/0
the sarcomeric protein myosin-binding protein C has
been identified in affected Maine Coon cats and results
in a change from the conserved amino acid alanine to
proline in exon 3, thus altering protein conformation.4
Affected cats develop concentric LV hypertrophy,
papillary muscle hypertrophy, and often systolic anterior motion (SAM) of the mitral valve and often LA
enlargement.3 Histopathologic myocardial lesions found
in cats from this colony include myocyte disarray,
interstitial and replacement fibrosis, concentric hypertrophy, and small coronary arteriosclerosis.3
Activation of the circulating and the cardiac reninangiotensin-aldosterone systems (RAAS) has been
shown in naturally occurring and experimental models
of heart disease.5–12 Renal renin concentration is increased in cats with HCM at postmortem examination.13
Similarly, plasma renin activity (PRA) and plasma
aldosterone concentrations may be increased in cats
with cardiomyopathy and are severely increased in cats
with CHF.14,a Tissue RAAS is activated earlier in the
course of cardiac disease than is circulating RAAS in
humans.9 Activation of RAAS causes vasoconstriction,
aldosterone-induced sodium and water retention, and
sympathetic activation. In addition to these wellrecognized systemic effects, angiotensin II (ATII) and
aldosterone also exert deleterious effects on the myocardium including myocyte hypertrophy and fibrosis,
which are independent of effects on blood pressure and
sympathetic activation.10–12,15
Angiotensin-converting enzyme inhibitors (ACEI) are
the current standard of care in humans with CHF, and
ACEI also are commonly administered to dogs with
CHF. Numerous studies have shown that ACEI reduce
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morbidity and mortality in humans with CHF and in
dogs with CHF secondary to dilated cardiomyopathy
and myxomatous mitral valve degeneration.16–21 Despite
these advances, investigators in veterinary and human
medicine alike have been in search of pharmacologic
therapy to decrease LV mass, limit myocardial fibrosis,
and improve diastolic dysfunction to slow or prevent
disease progression.22 Targeting the RAAS with pharmacologic inhibitors is a well-established practice for
treatment of hypertensive cardiomyopathy, ischemic
heart disease, and dilated cardiomyopathy in humans,
but not in patients with HCM.17,23,24 Avoidance of ACEI
in people with HCM may be because of fear of
worsening SAM of the mitral valve by afterload
reduction. Rationale for the use of RAAS antagonists
for treatment of HCM is supported by in vitro and in
vivo experimental evidence that ACEI and angiotensin
receptor blockers (ARB) prevent ATII- or aldosteroneinduced LV hypertrophy and myocardial fibrosis.25–29
Additionally, in a troponin T transgenic mouse model of
human HCM, treatment with an ATII receptor blocker
reversed myocardial fibrosis but had no effect on
myofiber disarray.30
Cats with CHF due to various cardiomyopathies
often are treated with ACEI, but there is no clear
evidence of their efficacy.b Treatment of cats with HCM
in CHF with ACEI is routine, but such practice is based
on personal experience and anecdotal evidence. Studies
in cats with HCM and no clinical signs are limited to
only 2 small uncontrolled or retrospective studies
evaluating the effects of ACEI on LV wall thickness.31,32
Studies have not quantified LV mass as an end point but
rather have relied upon 2-dimensional (2-D) measurements of the LV free wall and interventricular septal
thickness measured on echocardiography (ECHO). In 1
study, 2-D–guided M-mode was used, whereas wall
thickness was measured with 2-D ECHO in the other
investigation. Shortcomings of 2-D ECHO measurement
of interventricular septal thickness at end diastole
(IVSd) and LV free wall thickness at end diastole
(LVFWd) include high interobserver and intraobserver
variabilities in awake cats (18% and 20%, respectively).33
Additionally, wall thickness measurements vary according to region of the LV measured and hypertrophy often
is nonuniform. Therefore, serial quantification of LV
hypertrophy and assessment of changes in LV hypertrophy after pharmacologic therapy may be suboptimal
with ECHO measurements. Both studies reported that
ACEI reduced LV hypertrophy.31,32 No studies have
been undertaken to evaluate the effects of ACEI on LV
mass, diastolic function, and myocardial fibrosis in any
species with HCM.
Measurement of plasma brain natriuretic peptide
(BNP) concentration has emerged as a useful test to
evaluate the presence of LV hypertrophy and diastolic
dysfunction in humans.34,35 A rapid point of care assay is
useful to diagnose patients with diastolic heart failure
who have a moderately increased plasma BNP concentration in proportion to the degree of diastolic
dysfunction as determined by Doppler ECHO.34,36 In
one study patients with a spectral Doppler-derived
mitral valve restrictive inflow filling pattern or patients
with clinical signs with any diastolic filling pattern had
the highest plasma BNP concentrations when compared
with patients with diastolic dysfunction without a restrictive pattern or without clinical signs.34,36 Plasma
BNP concentration is increased in people and in cats
with severe HCM and increases further when CHF
develops.14,35,37,38,a BNP concentration has been shown to
decrease after neurohormonal antagonist treatment with
agents including spironolactone and ACEI in people
with various cardiac diseases.39,40 No studies have
evaluated plasma BNP concentrations during treatment
of HCM with an ACEI in any species.
This is the first study to investigate the effect of
ACE inhibition on LV mass, diastolic function, and
several neurohormones in any species with HCM. The
hypothesis of this prospective, blinded, placebocontrolled study was that ramipril would reduce LV
mass, improve diastolic function, reduce myocardial fibrosis, and reduce plasma aldosterone and
plasma BNP concentrations in Maine Coon cats
with mild to severe familial HCM but no evidence of
CHF. The primary end point of this study was
measurement of LV mass by cardiac magnetic resonance
imaging (cMRI) to assess whether regression of LV mass
occurred in cats with HCM treated with ramipril.
Specific aims included: quantification of LV mass by
gradient echo cMRI), assessment of diastolic function
by Doppler tissue imaging (DTI) ECHO, assessment of
myocardial fibrosis by delayed enhancement (DE)
cMRI, measurement of plasma aldosterone and plasma
BNP concentrations, and Doppler measurement of
systolic blood pressure, all at baseline and during a 1year treatment period.
Materials and Methods
The study included 26 adult research colony Maine Coon cats
or Maine Coon cross-bred cats with asymptomatic mild to severe
familial HCM. Animals were cared for according to the guidelines
in the National Institute of Health Guide for the Care and Use of
Laboratory Animals. HCM was diagnosed by a 2-D ECHO
measurement of LVFWd or IVSd of $6 mm with the right
parasternal short-axis view in the absence of systemic hypertension.c Only cats with stable concentric LV hypertrophy, defined as
unchanged measurements at a 3-month interval, were included in
the study. Two cats were examined for only 9 of the 12 months
because the study was stopped early.
Echocardiography
Cats were sedated with 0.1 mg/kg SC acepromazine and 0.1 mg/
kg SC hydromorphone. Standard ECHO measurements made on
all cats included LVFWd, IVSd, LA, and aortic (Ao) diameters by
2-D measurement from a right parasternal short-axis view. The
LA:Ao ratio was calculated. Mild, moderate, and severe cases of
concentric LV hypertrophy were defined as LVFWd or IVSd of 6–
7 mm, 7.1–8 mm, and .8 mm, respectively. LV mass was
calculated by means of the truncated ellipse formula with the right
parasternal long-axis and short-axis views at end-diastole, as
described previously.41 LV papillary muscles were included in the
measurement of LV mass. The right parasternal long-axis view was
chosen because the left apical view underestimated the long axis
Ramipril and Hypertrophic Cardiomyopathy in Cats
1095
investigator were determined from 20 normal domestic shorthair
cats and used as historical controls. A total of 64 measurements of
Em were recorded at different heart rates with an Acuson 128-XP
machine.42 Because Em is positively correlated with heart rate, 95%
prediction intervals were constructed for this study to determine
the upper and lower limits of normal Em depending on heart rate,
by the following formula:
vffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi
u
u
Þ2
1
ðX {X
SIND ~ SY: X u
P 2
t1z n z P
ð Xi Þ
Xi2 { n
Yc z={ tSIND
Y 5 predicted individual value of Em; X 5 heart rate; X 5 mean
heart rate; n 5 sample number; SIND 5 square root of variance of
Y; t 5 t multiple determined for n 2 2 degrees of freedom.
Cardiac Magnetic Resonance Imaging
Fig 1. Doppler tissue imaging (DTI) echocardiography (ECHO)
of a Maine Coon cat with severe familial hypertrophic cardiomyopathy. (A) A left-sided 4-chamber apical view is used for DTI
ECHO of the lateral mitral annulus. The white bars represent the
position of the pulsed-wave Doppler gate. (B) DTI myocardial
velocity of the lateral mitral annulus in a cat with severe
hypertrophic cardiomyopathy reveals reduced early diastolic mitral
annular velocity (Em), reduced systolic velocity (S), and E:A
reversal indicating diastolic dysfunction.
and there was poor visualization of the apex. The Simpson rule was
not used because of suboptimal visualization of the right
ventricular side of the interventricular septum and epicardial
surface near the apex. LV mass was indexed (LVMI) to body
weight (g/kg).
Doppler Tissue Imaging Echocardiography
DTI ECHO was performed 20 minutes after sedation to
examine diastolic function. Heart rate was recorded by ECG. With
a 12-mHz transducer,c DTI of the lateral mitral annulus was
performed from the left apical 4-chamber view, with the pulsed
Doppler gate placed perpendicular to myocardial movement
(Fig 1). Specific DTI settings included Nyquist limit, 10–15 cm/s;
sweep speed, 100 cm/s; gate width, 0.11 cm; and filter, 50 Hz. Five
nonconsecutive measurements of peak diastolic velocity (Em) were
recorded and averaged (Fig 1). Chosen tracings had the highest
velocities and minimal artifact. Peak diastolic velocity included
measurements of either early diastolic mitral annular velocity or
summated early and late diastolic mitral annular velocity,
depending on heart rate.
Normal lateral mitral annular Em velocities at different heart
rates that were obtained on an earlier date by a different
Cats were sedated as previously described, and anesthesia was
induced with up to 2 mg/kg IV propofol administered through
a cephalic vein catheter in 0.25-dose increments alternating with
0.1 mg/kg IV midazolam administered twice. A light plane of
anesthesia was maintained by a continuous-rate infusion of
0.15 mg/kg/minute of propofol. Cats were intubated with a cuffed
endotracheal tube and maintained with positive-pressure ventilation on 100% oxygen (peak inspired pressure, 9–12 mm Hg;
respiratory rate, 8–15 breaths/minute; tidal volume, 15 mL/kg;
end tidal carbon dioxide maintained between 35 and 42 mm Hg).
The ventrum of each cat was shaved over the region of the heart
and the caudal abdomen. Cats were placed in dorsal recumbency
with their hindlimbs placed toward the MRI gantry. MRIcompatible electrodesd were placed cranial to the heart (2
electrodes) and on the caudal-ventral abdomen (2 electrodes).
The lead with the tallest QRS complex was chosen for ECG gating.
If ECG gating was unsuccessful because of artifact, gating was
based on the peripheral pulse generated by an oximeter placed
on the ventral surface of the tongue. A respiratory belt was
placed just caudal to the costal arch to measure respiratory
excursions and was used to sort the phase-encoding data to
minimize respiratory ghosting artifacts. Two phased-array surface
coils, measuring 3 inches in diameter, were placed as close
together as possible on either side of the thorax at the level of
the heart. A 10-mL vial of dilute copper sulfate solution was placed
next to the chest parallel to the long axis of the heart and served as
an external standard for the gadolinium contrast-enhancement
studies.
T1-weighted cMRI images were acquired during multiple
phases of the cardiac cycle with a gradient echo sequence with
the following parameters: field of view, 12 cm2; echo time, 5.2 ms;
repetition time, 12.1 ms; flip angle, 30 degrees; number of
excitations, 1; matrix, 256 x 128 pixels. Initial sagittal, transverse, and frontal plane localizer images were acquired during
free breathing from which subsequent imaging planes were
prescribed. Long-axis images were obtained by placing the imaging plane from the LV apex to the center of the mitral annulus
on the sagittal localizer image and bisecting the LV on the
transverse localizer view at the 2–3 o’clock position, with a method
previously described.43 Short-axis images were acquired by obtaining 3-mm contiguous slices perpendicular to the long-axis images,
extending from the mitral annulus to the LV apex. Short-axis
images of each LV slice then were obtained during hyperventilation-induced apnea. For each LV slice, multiple images (15–25)
were acquired throughout the cardiac cycle depending on heart
rate.
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MacDonald et al
Fig 2. Left ventricular (LV) mass quantification by cardiac
magnetic resonance imaging. Epicardial (1) and endocardial (2)
borders were manually traced at end-systole on all slices from the
mitral annulus to the apex for LV mass quantification. This cat
with severe hypertrophic cardiomyopathy has nearly complete endsystolic cavity obliteration.
LV mass was calculated by the Simpson rule. The LV
endocardial and epicardial borders, including the papillary
muscles, were manually traced at end-systole on all slices extending
from the annulus to the apex (Fig 2).e End-systolic measurements
were used because they yielded the most accurate LV mass
measurements in a previous validation study with 7 normal
domestic shorthair cats.43 In areas where the endocardial surface
was indistinct because of partial volume averaging, half of the
indistinct area was included in the trace. Myocardial area of each
slice was the difference between epicardial and endocardial areas.
Myocardial volume of each slice was the product of slice thickness
(3 mm) and myocardial area. The myocardial volume of all slices
was summed and multiplied by the specific gravity of muscle
(1.05 g/mL) to obtain total LV mass (g). LV mass was indexed to
body weight (g/kg).
Delayed Enhancement Cardiac Magnetic
Resonance Imaging
Once precontrast short-axis images were acquired, 0.1 mmol/kg
gadolinium dimeglumine was administered as an IV bolus
and postcontrast short-axis images were acquired 7 minutes
later. Precontrast and postcontrast images were analyzed at endsystole. The LV was divided into 4 quadrants, including the
anterior free wall, interventricular septum, posterior free wall, and
lateral free wall. Out of a total of 9 to 13 slices, slices 5–8 were
analyzed because they represented the middle section of the LV and
included the greatest myocardial area. Operator-defined regions of
interest were manually drawn in each quadrant of all 4 LV slices to
obtain average signal intensity (SI) for each region (Fig 3).
Hyperintense blood pool or regions of intermediate myocardial
SI due to partial volume effect were avoided. Partial volume effect
occurs when there is nonuniform thickness of the myocardium
within the slice, which results in an intermediate SI between
myocardium and the blood pool. SI of the copper sulfate served as
an external standard to normalize the myocardial SI. Relative
intensity (RI) of the myocardium was defined as SImyocardium/
SIcopper and was used to correct for variation in magnetic field
intensity between images and studies. All images were evaluated for
gross evidence of increased regional SI of the myocardium (i.e.,
DE), which would indicate myocardial fibrosis. Myocardial
contrast enhancement (MCE) was defined as the percentage
Fig 3. Quantification of myocardial contrast enhancement
(MCE) and evaluation of delayed enhancement by cardiac
magnetic resonance imaging. The left ventricle is divided into 4
quadrants, and regions of interest (1–4) are manually drawn within
those quadrants at end-systole from 5 midventricular slices to
obtain average myocardial signal intensity (SI) within the regions.
Another region of interest is drawn within the copper sulfate
external standard (5) and is used to calculate myocardial relative
intensity (RI). MCE was calculated by myocardial RI before and
after contrast injection with the equation: MCE 5 ([RIpost 2
RIpre]/RIpre) 3 100; RI 5 SImyocardium/SIcopper.
change of myocardial RI between precontrast and postcontrast
images. MCE was calculated by myocardial RI before and after
contrast injection with the equation: MCE 5 ([RIpost 2 RIpre]/
RIpre) x 100.
Neurohormones
Eight mL whole blood was collected at baseline and every
3 months during the year of treatment for measurement of plasma
BNP and aldosterone concentrations. For plasma BNP concentrations, blood was collected into polypropylene tubes with EDTA
and 0.2 mL of aprotinin and immediately centrifuged. Aprotinin
was used to inhibit in vitro proteolysis of BNP. For aldosterone,
blood was collected into polypropylene tubes with EDTA. Plasma
was frozen at 270uC. At baseline, 6 months, and 1 year, samples
were collected immediately after induction of anesthesia with
propofol before cMRI examination. Most (,87%) of the baseline,
6-month, and 12-month samples were collected at 7:30 AM. Blood
collection at 3 and 9 months was done in sedated cats after they
had been lying in lateral recumbency for approximately 20 minutes, and more than half of the samples were collected between 7:00
and 9:30 AM. Cats were fed the same low-sodium diet of Purina Pro
Plan salmon and rice throughout the study.f
Plasma BNP concentration was measured in duplicate by
a competitive radioimmunoassay (RIA) specific for canine BNP32, which has been validated for use with cat plasma.g,14 There is
exact homology of the antigenic ring of canine and feline BNP, the
epitope to which the RIA kit is directed.44 All materials and buffers
were supplied with the kit and used in strict accordance with the kit
guidelines.g Plasma samples were stored for variable periods of time
before batched analysis. BNP was extracted from the plasma
samples with separator columns and buffers, and the samples were
dried with a centrifugal concentrator. A gamma counter was used
to determine the counts per minute of the pellets. A standard curve
Ramipril and Hypertrophic Cardiomyopathy in Cats
Table 1.
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Baseline characteristics of placebo and ramipril groups.
Parameter
Placebo group (n 5 13)
Age (years)
LVFWd (mm)
IVSd (mm)
LVMI (g/kg)
Em by DTI (cm/s)
BNP (pg/mL)
Aldosterone (pmol/L)
5.1
6.9
6.2
2.71
9.2
23
370
+/2
+/2
+/2
+/2
+/2
+/2
+/2
3.7 (0.8–11.6)
0.9 (6–8.4)
0.9 (4.5–7.5)
0.46 (1.97–3.23)
2.1 (6.3–11.7)
16 (6–66)
219 (64–816)
Ramipril group (n 5 13)
4.7
6.8
6.4
2.72
8.7
33
523
+/2
+/2
+/2
+/2
+/2
+/2
+/2
3.4 (0.8–11.4)
1.6 (5.5–11.1)
1.7 (3.6–10.1)
0.67 (1.91–4.36)
2.9 (4.6–14.8)
25 (10–108)
283 (134–990)
Data are represented as means, standard deviations, and ranges. LVFWd, end-diastolic left ventricular wall thickness by
echocardiography; IVSd, end-diastolic interventricular septal thickness by echocardiography; LVMI, left ventricular mass index by cardiac
magnetic resonance imaging; Em by DTI, early diastolic mitral annular velocity by Doppler tissue imaging; BNP, plasma brain natriuretic
peptide. Normal values: BNP, ,25 pg/mL; aldosterone, 194–388 pmol/L; LVFWd and IVSd , 5.5 mm; LVMI , 1.9, Em . 8.6 cm/s.
was established and used to determine the unknown BNP
concentrations. Interassay variation is reported by the company
to be ,15% and intra-assay variation to be ,5%.g The lower limit
of detection of plasma BNP concentration determined in our
laboratory was 10 pg/mL, and a value of 5 pg/mL was assigned to
any sample with a BNP concentration measuring ,10 pg/mL.
Plasma for aldosterone analysis was shipped on dry ice to the
Michigan State University Diagnostic Center for Population and
Animal Health, Endocrine Laboratory for analysis of plasma
aldosterone concentration by a competitive RIA kit.h Samples were
stored for a maximum of 1 month before RIA analysis. Plasma
aldosterone concentrations .388 pmol/L were considered abnormally high according to the reference range developed by the
laboratory.
Blood Pressure
Systolic blood pressure was measured with a Parks Doppler
blood pressure unit at baseline and every 3 months for the year of
study.i The metatarsal region of 1 hind limb of each cat was shaved,
and a 3-cm cuff placed above the tarsus. Serial blood pressure
measurements were made over 5 minutes, and the lowest consistent
value obtained over 3 measurements was recorded.
Randomization of Treatment Groups
Cats were paired based on similarity of LVMI at baseline and
then by age. With a random number generator, the first member of
the pair was randomized to be treated either with ramipril or
placebo (labeled treatment A or B during the study), and the
second member received the opposite.j Cats were given 0.5 mg/kg
ramipril or placebo PO q24h for 1 year. This dosage of ramipril
was chosen based on prior pharmacokinetic data indicating peak
plasma ACE inhibition of 100% and 24-hour plasma ACE
inhibition of 81% in normal cats.k Because ramipril is unaffected
by coadministration with food (unpublished data), it was
administered within a treat or a small amount of canned food,
with complete ingestion of the pill carefully witnessed by the
technician.
Plasma ACE Activity
After 6 months of treatment, plasma ACE activity was
measured 24 hours after pill administration (i.e., trough concentration) and 1 hour after PO drug administration to ensure the
administered dosage was adequate. Representative samples were
analyzed from cats in both groups. Blood samples were collected in
EDTA tubes, centrifuged for 15 minutes, and plasma immediately
separated and frozen at 270uC. Plasma ACE activity was
measured in duplicate with a colorimetric kit measuring conversion
of the synthetic substrate 3H-hippuryl-glycyl-glycine to 3H-hippuric
acid and a dipeptide by ACE.l The assay used has a coefficient of
variation of 2.7–7.6%.j
Statistical Analysis
All data were tested for normality by the Kolmogorov-Smirnov test, and homogeneity of variances was
assessed by the Levene median test. Parametric tests
were selected provided the data were normally distributed with equality of variance. Baseline variables were
compared between treatment groups by an unpaired 2tailed student’s t-test. Repeated measures analysis of
variance (RM-ANOVA) was performed with treatment
as a between-group variable and time as a within-group
variable. A significant difference was defined as P , .05.
A subgroup analysis was performed by RM-ANOVA in
cats with Em #8.6 cm/s at baseline. Simple linear
regression was used to assess whether plasma BNP or
plasma aldosterone concentrations were correlated with
LVMI or systemic blood pressure. For analysis of
plasma ACE activity, the student’s t-test was used to
compare 24-hour trough ACE activity between ramipril
and placebo groups and to compare ACE activity at the
trough and 1 hour after drug administration.
Results
Baseline
Data were normally distributed with equal variances.
Baseline characteristics of all variables were the same
between treatment groups (Table 1). Plasma aldosterone
concentrations were increased above the laboratory’s
reference range (.388 pmol/L) in 54% of cats (14/26) at
baseline (6 cats receiving placebo and 8 cats receiving
ramipril). Upper limit of normal plasma BNP concentration was calculated as the mean + 2 SD and was based
on a previous study of 32 normal domestic shorthair
cats, performed by another investigator with the same
RIA kit.a Concentrations .25 pg/mL were considered
high (mean plasma BNP concentration, 11.6 +/2 6 pg/
mL).a These normal reference values were similar to
normal plasma BNP concentrations measured in 7
domestic shorthair cats by the University of California,
Davis clinical endocrinology laboratory (mean plasma
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MacDonald et al
Fig 4. 95% prediction intervals of peak diastolic mitral annular
velocity (Em) depending on heart rate in 20 normal domestic
shorthair cats and in 26 Maine Coon cats with hypertrophic
cardiomyopathy (HCM). Em previously measured in 20 cats several
times at different heart rates (n 5 64). The 95% confidence intervals
were constructed to determine the upper and lower limits of normal
Em for a given heart rate (dark lines) (A) The lower limit of the 95%
prediction interval of Em for a given heart rate was used to identify
HCM cats with decreased Em and diastolic dysfunction (B) Em was
lower in Maine Coon cats with mild to severe HCM when
compared with normal domestic shorthair cats (P , .001). With the
lower limit of the 95% prediction intervals, 17 of 26 (65%) cats with
HCM had reduced Em at baseline and 9 cats had normal Em.
BNP concentration, 10 +/2 8 pg/mL).m Plasma BNP
concentrations were increased (.25 pg/mL) in 50% of
cats (4 cats treated with placebo and 9 cats treated with
ramipril). Four cats had only marginally increased
plasma BNP concentrations ranging from 26 to 28 pg/
mL. Plasma BNP concentrations were not measured
until 6 months after collection in 18 of the 26 cats, and
some degradation of the samples may have occurred
during optimal storage conditions at 270uC in the
presence of aprotinin.m Plasma BNP and aldosterone
concentrations were not correlated with LVMI, and
plasma BNP concentration was minimally correlated
with systolic blood pressure (r 5 .41, P 5 .05) although
systemic blood pressure was within the normal range for
all cats.
Data from 20 historically normal domestic shorthair
cats indicated that Em is heart rate dependent.42 The 95%
prediction intervals for Em are shown in Figure 4. To
obtain Em over a wide range of heart rates, Em was
measured 3 times in each cat, which may mildly narrow
the prediction interval. Heart rates of these normal
Fig 5. Discrete regional delayed enhancement in a Maine Coon
cat with severe hypertrophic cardiomyopathy (HCM). (A) Precontrast magnetic resonance imaging (MRI) of a cat with severe
HCM, with asymmetrical hypertrophy. (B) Postcontrast MRI
revealed a large, discrete region of delayed enhancement (arrow) at
the region of the anterior LV free wall. This region is consistent
with a large region of replacement fibrosis of the myocardium. LV,
left ventricular chamber; RV, right ventricular chamber.
domestic shorthair cats ranged from 115 to 242 beats per
minute, and mean Em was 12.6 +/2 2.1 cm/s.42 With the
95% prediction intervals, 65% (17/26) of cats with HCM
had decreased Em at baseline, with 6 of 12 cats in the
placebo group and 3 of 12 cats in the ramipril group
having normal baseline Em. Em of cats with HCM
treated with placebo or ramipril were 9.2 +/2 2.1 cm/s
and 8.7 +/2 2.9 cm/s, respectively (Table 1). Absolute
Em was not significantly different at baseline between
treatment groups. Only 1 cat had evidence of discrete
delayed-contrast enhancement on cMRI, which was
located in the anterior LV free wall within the region of
the most severe hypertrophy (Fig 5). This cat had been
treated with placebo.
Ramipril and Hypertrophic Cardiomyopathy in Cats
1099
changes were clinically insignificant and could be
accounted for by variability in measurements rather
than true physiologic changes.
Plasma aldosterone concentration was increased in
58–69% (depending on the time point at which the
measurement occurred) of cats treated with ramipril
during the year of treatment and 58–62% of cats treated
with placebo. Plasma aldosterone concentration was not
statistically different in cats treated with ramipril
compared with cats given placebo at any time point
(Table 2).
Fig 6. Plasma angiotensin-converting enzyme (ACE) activity at
the 24-hour trough and 1-hour post pill in cats treated with
ramipril or placebo. This box and whisker plot depicts median,
lower 25%, and upper 75% of ACE activity in 7 cats chronically
treated with ramipril and 9 cats treated with placebo. Cats treated
with ramipril had lower 24-hour trough ACE activity (t 5 0) than
cats treated with placebo (P , .0001). Plasma ACE activity 1 hour
after ramipril administration was markedly reduced to 97% of
baseline activity (P 5 .0002), whereas there was no change in cats
treated with placebo.
Plasma ACE Activity
Blood samples were analyzed for plasma ACE
activity in 9 cats given placebo and 7 cats treated with
ramipril for approximately 6 months. Cats in the
ramipril group had 60% lower 24-hour trough ACE
activity than cats in the placebo group (P , .0001)
(Fig 6). Ramipril reduced ACE activity by 97% 1 hour
after PO drug administration (P 5 .0002 trough vs
1 hour after drug administration), whereas no change in
ACE activity was observed in the placebo group.
The average dosage of ramipril over the 12-month
investigation was 0.52 mg/kg (range, 0.41–0.66 mg/kg;
SD, 0.05 mg/kg ). Cats were treated PO q24h for 1 year,
and compliance was 100%. Cats were subjectively
evaluated throughout the study, and none had clinical
evidence of CHF, other illnesses, or adverse effects.
Treatment Effects
There were no differences between treatment groups
or significant treatment-time interactions for LVMI by
cMRI and ECHO, Em by DTI, mean and maximum DE
by cMRI, systolic blood pressure, and plasma BNP and
aldosterone concentrations (Table 2, Figs 7–10). Subgroup analysis for DTI included 6 cats treated with
ramipril and 6 cats given placebo, all with baseline Em of
#8.6 cm/s. Within this subgroup, baseline Em was 6.3
+/2 1.46 cm/s and 7.2 +/2 1.46 cm/s in cats treated with
ramipril or placebo, respectively. The subgroup analysis
identified no significant differences in any of the
measured variables (LVMI, DTI, DEmin, DEmax, blood
pressure, BNP, and aldosterone) between treatment
groups. Because of technical problems with the last
BNP analysis, data from 6 cats at the 12-month time
point and from 2 cats at the 9-month time point were
not included in the data analysis. There was a statistically
significant change in LVMI by ECHO, Em, and plasma
BNP concentration over time in both groups, but
Discussion
This is the first study to evaluate the effect of ACEI
on the primary end point of LV mass and secondary end
points of diastolic function, blood pressure, plasma
aldosterone concentration, and plasma BNP concentration in any model of HCM. The study used cMRI,
a highly accurate technique in normal cats, to quantify
LVMI in cats with mild to severe HCM and no CHF.43
There was no statistically significant difference in any
measured variable (LV mass and LVMI by both cMRI
and ECHO, DE, Em, systolic blood pressure, plasma
BNP concentration, and plasma aldosterone concentration) in the cats examined in this study over 1 year,
whether they were treated with placebo or ramipril.
These data suggest that ramipril does not produce
significant differences in variables used to assess clinical
improvement in cats with HCM but without CHF. It is
possible that before development of CHF, RAAS is not
maximally activated, and therapeutic effects of ACEI
would not be identified at this early stage.
Although it is rational to treat HCM with ACEI,
only 2 small studies have evaluated the use of ACEI
in humans with HCM.n,45 Avoidance of ACEI in
patients with hypertrophic obstructive cardiomyopathy
(HOCM) is likely because of concern about reducing
systolic blood pressure and worsening SAM of the
mitral valve. In cats with SAM, enalapril did not worsen
the degree of LV outflow tract obstruction in 1 study.o
The only report of long-term clinical treatment of people
with HCM with ACEI was a 1995 study of 26 people
with HCM that was not subsequently published as
a peer-reviewed study.n Patients in this study were
treated with conventional therapy (calcium channel
blockers or beta blockers) and were randomized to
receive additional treatment with enalapril (n 5 13) or
no additional treatment. ECHO evaluation included 2-D
ECHO measurements of LV wall thickness and interventricular septal thickness, LV diastolic diameter,
and LA diameter. Cardiac mass and diastolic function
were not assessed. There was no effect of enalapril on
the 2-D ECHO measurements or exercise time in this
study.n These results are contradictory to those 2
veterinary studies which reported that enalapril or
benazepril decreased LV wall thickness in cats with
HCM when measured with a less precise technique
(ECHO) than used in the current study.31,32
Diastolic function assessed by DTI ECHO was not
different in cats treated with ramipril compared with
1100
MacDonald et al
Table 2. RM-ANOVA comparing measured variables in cats treated with ramipril vs placebo over 1 year.
Parameter
Body weight (kg)
LVMI by cMRI (g/kg)
LVMI by ECHO (g/kg)
Maximum DE by MRI (%)
Em by DTI (cm/s)
Systolic BP (mm Hg)
Plasma [BNP] (pg/mL)
Plasma [aldosterone]
(pmol/L)
Time (months)
Ramipril
(mean; SD)
0
3
6
9
12
0
6
12
0
3
6
12
0
6
12
0
3
6
9
12
0
3
6
9
12
0
3
6
9
12
0
3
6
9
12
4.4; 0.8
4.5; 0.8
4.4; 0.8
4.4; 0.8
4.4; 0.9
2.5; 0.8
2.4; 0.7
2.6; 0.8
2.5; 0.8
2.8; 1.1
2.6; 0.9
2.8; 1.1
47; 13
56; 24
47; 12
8.7; 2.9
7.8; 2.6
7.8; 1.8
8.1; 2.4
9.1; 2.7
128; 21
123; 17
129; 15
130; 17
132;18
32.7; 25.1
41.6; 33.3
23.6; 23.8
16.7; 8.5
40.7; 22.9
523; 283
469; 177
458; 193
445; 197
442; 204
Placebo
(mean; SD)
4.4;
4.4;
4.4;
4.5;
4.4;
2.5;
2.4;
2.5;
2.5;
2.6;
2.4;
2.7;
50;
44;
53;
9.2;
7.9;
8.5;
8.7;
8.5;
131;
128;
136;
139;
138;
23.1;
32.4;
11.9;
16.7;
36.6;
370;
405;
453;
329;
373;
0.6
0.6
0.6
0.6
0.7
0.6
0.5
0.4
0.6
0.5
0.6
0.7
12
13
17
2.1
1.8
2.1
2.7
2.0
14
13
15
21
21
16.4
17.2
9.2
8.5
24.4
219
117
218
164
124
Treatment
(P value)
Treatment-time interaction
(P value)
.91
.9
.94
.6
.79
.7
.89
.1
.91
.5
.28
.99
.35
.73
.25
.2
Level of significance defined as P , .05. LVMI, left ventricular mass index; cMRI, cardiac magnetic resonance imaging; ECHO,
echocardiography; DE, delayed-contrast enhancement; Em, early diastolic mitral annular velocity by Doppler tissue imaging; BP, blood
pressure; BNP, brain natriuretic peptide. BNP values missing for 1 cat in each treatment group at 6 and 9 months, and for 4 cats in each
treatment group at 12 months.
cats treated with placebo throughout the study. In
contrast, intracoronary but not sublingual administration of enalapril augmented coronary blood flow,
increased flow reserve, and improved diastolic dysfunction as evidenced by reduced tau and reduced LV enddiastolic pressure in 1 study of 20 people with HOCM.45
Peak plasma ACE activity was markedly inhibited by
ramipril (97% inhibition after 1 hour), illustrating that
an effective dose was used and that the drug was
adequately absorbed in the treated cats. Pharmacokinetic data from a previous study indicated excellent
ACE inhibition over 24 hours at the dose used in the
current study (0.5 mg/kg PO q24h).k However, measurement of tissue ACE activity in the myocardium was
not possible in the current study.
Suppression of tissue ACE is not synonymous with
suppression of circulating ACE and often requires much
higher doses of ACEI.46 In rats with myocardial
infarction, neither low- nor high-dose ACEI altered
LV ACE activity or ACE mRNA, despite strong plasma
ACE inhibition in 1 study.47 Despite this finding, the
high-dose ACEI decreased LV mass and mortality.
Similarly, ramipril caused less ACE inhibition in the
myocardium than in the arteries and kidneys in human
tissue samples.48 Potency and duration of ACE inhibition in the myocardium has been shown to depend
more on binding characteristics than on tissue-penetrating properties.26,49
Local myocardial effects of ATII and aldosterone are
very important and are independent of circulating
effects.10–12 Each component of the RAAS, with the
exception of renin, has been shown to be synthesized de
novo within the myocardium.50,51 The myocardium has
a much higher ATII concentration than does blood,
where it has several effects including producing hypertrophy and fibrosis.25,52 Myocardial ATII, mediated by
the ATI receptor subtype, induces myocyte hypertrophy,
mitogenesis of fibroblasts, increased collagen synthesis,
Ramipril and Hypertrophic Cardiomyopathy in Cats
Fig 7. Mean left ventricular mass index (LVMI) by cardiac
magnetic resonance imaging (cMRI) in cats treated with ramipril
compared with cats treated with placebo for 1 year. There was no
significant difference of group means of LVMI measured by
cardiac MRI between cats treated with ramipril versus those
administered placebo (P 5 .94).
and upregulation of the profibrotic cytokine transforming growth factor b1 (TGF-b1).25 Aldosterone exerts its
profibrotic effect indirectly by increasing ATI receptor
density, which potentiates the fibrinogenic and hypertrophic effects of ATII.16 Aldosterone also increases
endothelin I (ET-I) receptor density, which leads to
increased myocardial collagen synthesis. Complex interactions among RAAS, ET-I, and induction of profibrotic cytokines result in a network that promotes
myocardial fibrosis and hypertrophy.
The current study demonstrated that circulating
RAAS often is activated in cats with moderate to severe
HCM but without CHF, in which 58% of the cats had
increased plasma aldosterone concentrations at baseline.
Increased plasma aldosterone concentration was interpreted as evidence of RAAS activation, although Plasma
Renin Activity (PRA) and plasma ATII concentration
were not measured. Plasma aldosterone concentrations
were increased in a large percentage of cats treated with
ramipril (58–69%), and aldosterone concentrations were
not different between the ramipril and placebo groups.
Because PRA and ATII concentration were not
Fig 8. Scatter plot of the difference of left ventricular mass index
(LVMI) measured by cardiac magnetic resonance imaging (cMRI)
from baseline to 12 months in cats treated with placebo or ramipril.
There was a large amount of overlap of LVMI between groups,
resulting in no significant difference in LVMI between cats treated
with ramipril versus placebo (P 5 .94).
1101
Fig 9. Mean early mitral annular velocity (Em) in cats treated
with ramipril compared with cats treated with placebo for 1 year.
There was no significant difference in mean Em measured by
Doppler tissue imaging echocardiography in cats treated with
ramipril versus placebo (P 5 .91). There was no significant
treatment-time interaction (P 5 .5).
measured, the mechanism of persistent aldosterone
activation was undetermined.
The dilemma of persistent ACE activation and
increased aldosterone concentrations during ACE inhibition also is problematic in human medicine. In
people treated with ACEI, 15–50% have increased
plasma ATII concentrations compared with 40% of
people with increased plasma aldosterone concentrations.54,57 In 1 study people with increased plasma ATII
concentrations while on an ACEI had worse heart
failure and increased mortality. Conversion of ATI to
ATII in the presence of ACEI therapy is greater in
people with more severe CHF. Increased generation of
ATII over time in patients receiving ACEI can be
suppressed with higher doses of ACEI.55,56 Chronic
ACEI therapy may upregulate ACE production. Treatment of cultured human endothelial cells with captopril
was shown to induce ACE activity.57 Whether this plays
a role in ACE reactivation in vivo has yet to be
determined. The ACE DD genotype in patients with
CHF appears to play an important role in plasma ACE
Fig 10. Scatter plot of the difference of the early diastolic mitral
annular velocity (Em) measured by Doppler tissue imaging
echocardiography from baseline to 12 months in cats treated with
placebo or ramipril. There was no significant difference in Em
between cats treated with ramipril versus placebo (P 5 .91) and no
significant treatment-time interaction P 5 .5) in the 26 Maine Coon
cats with mild to severe hypertrophic cardiomyopathy.
1102
MacDonald et al
and aldosterone escape. The DD genotype results in
higher serum and tissue ACE concentrations and
activity compared with the ID or II genotypes and
requires higher ACEI doses for adequate inhibition.58
ACE polymorphisms have not been assessed in cats or
dogs.
Persistent increases of plasma aldosterone concentration in the face of low plasma ACE activity may have
been because of alternative tissue-dependent pathways
of ATI conversion to ATII. Alternative pathways have
been described in people in which plasma ATII
concentrations returned to baseline ,24 hours after
benazepril administration in normal people despite
significant inhibition of plasma ACE activity.59 Serine
proteases (cathepsins A, D, and G and tonin), chymase,
and ACE-2 also convert ATI to ATII.60 Ventricular
production of ATII in humans, dogs, and cats is due to
an increased ventricular a-chymase concentration,
which produces 90%, 81%, and 84%, respectively, of
the myocardial-derived ATII in myocardial extracts.62,63
During ACEI therapy, plasma renin and ATI are
increased because of removal of the negative feedback
by ATII.59 This effect provides greater substrate for
conversion to ATII by alternative pathways. In a study
of patients on chronic lisinopril therapy for CHF,
dissociation was observed between measurement of
plasma RAAS and in vivo physiologic activity of the
tissue RAAS system.55 Similarly, in rats with experimental myocardial infarction, although plasma aldosterone production was markedly inhibited by ACEI and
ARB, myocardial aldosterone concentration was increased in the group treated with ACEI and was
suppressed in the ARB group.64 A perplexing phenomenon is the increase in plasma aldosterone concentration
observed during combination ACEI and ARB treatment
in people.65 In 1 study after 17 weeks of treatment,
plasma aldosterone concentration was greatly decreased,
but by 43 weeks plasma aldosterone concentration
returned to baseline despite maximal doses of both
ACEI and ARB. Hyperkalemia or hyponatremia may
be factors contributing to persistent aldosterone increases in people with low ATII concentration.66,67
One therapeutic goal of antagonizing the RAAS in
cats with HCM is to reduce myocardial fibrosis. The
antifibrotic effects of losartan, an ARB, have been
evaluated in a transgenic TnT mouse HCM model.
Losartan normalized collagen volume fraction (decreased from 49% to 5%) and reduced TGF-b concentration by 50%, with no effect on myofiber disarray or
heart weight/body weight ratio.30 The current study
utilized noninvasive methods of contrast-enhancement
cMRI for quantification of myocardial fibrosis rather
than histopathologic quantification of fibrosis. This
study did not identify a difference in myocardial
contrast enhancement or DE in cats treated with
ramipril compared with cats treated with placebo.
However, detection of myocardial fibrosis by cMRI
appeared to be of limited value in the Maine Coon cats
with mild to severe HCM in the current study.
Myocardial fibrosis may not be present at this stage of
the disease. Only 1 of 26 cats had evidence of discrete
DE suggestive of myocardial fibrosis. When compared
with 7 normal domestic shorthair cats, cats with mild to
severe HCM in the current study did not have increased
myocardial contrast enhancement.68 Consequently, noninvasive quantification of myocardial fibrosis by contrast-enhancement cMRI may not be useful in cats with
mild to severe HCM without CHF. This finding is in
contrast to people with HCM who commonly (80%)
have discrete DE on cMRI.69 Detection of diffuse
interstitial fibrosis by DE is more limited because the
technique is sensitive to regional differences in gadolinium accumulation. DE is seen in ,50% of people with
dilated cardiomyopathy when there is diffuse interstitial
fibrosis.70,71 Unfortunately, no other noninvasive markers of myocardial fibrosis are available in cats.
Circulating markers of collagen synthesis and degradation such as hydroxyproline, procollagen I and III
propeptides, and collagen I degradation products are
not helpful to distinguish cats with HCM from normal
cats, and there is marked individual variability in these
measurements (authors’ unpublished data).
Limitations
A limitation of this study was lack of postmortem
quantification of myocardial fibrosis in these cats.
Additionally, serial measurement of plasma BNP with
RIA appears to be fraught with problems including
degradation of plasma BNP during storage and probable interassay variability, especially when measuring
low concentrations of BNP.m In addition, the study
included a small number of cats (n 5 26), with 6 having
mild HCM. However, use of cMRI for LV mass
quantification enables use of a smaller sample size given
the greater accuracy of the technique. For example, in 1
study the sample size necessary to demonstrate a 10-g
change in LV mass in people with LV hypertrophy was
15 people with cMRI vs 152 people with ECHO.72
Postmortem measurement of LV mass and histopathologic quantification of myocardial fibrosis were not
performed in the current study. DTI was abnormal in
65% (17/26) of the cats at baseline. Detection of
improved diastolic function is only relevant in the cats
with impaired diastolic function due to presumptive
myocardial fibrosis. When a subgroup analysis was
performed on 12 cats (6 treated with ramipril and 6
treated with placebo) with the lowest Em at baseline,
there was no statistically or clinically significant
difference in any measured variable between treatment
groups throughout the study. Although it is possible
that a larger number of cats could have resulted in
a statistical difference in the variables measured, the
empirical differences observed in this study were so
small as to be of negligible clinical importance.
Pretreatment ACE activity was not determined in the
cats treated with ramipril. Therefore, it is impossible to
assess the amount of decrease of ACE activity at the 24hour trough period compared with baseline before
treatment. Peak reduction in ACE activity after chronic
medication was assessed 1 hour after pill administration
compared with the 24-hour trough ACE activity, which
Ramipril and Hypertrophic Cardiomyopathy in Cats
demonstrated a 97% reduction in ACE activity. In
a pharmacokinetic study of normal cats, 81% reduction
of ACE activity occurred at the 24-hour trough when
chronically medicating cats with 0.5 mg/kg PO q24h.k
RAAS activation was assessed by plasma aldosterone
concentration. Plasma renin activity and plasma ATII
concentrations were not measured. Fifty-eight percent
of cats in this study had increased plasma aldosterone concentrations at baseline which was interpreted as
activation of the RAAS. Marked individual variability of plasma aldosterone concentrations was observed
over time. Efforts were made to reduce temporal and
positional changes in plasma aldosterone concentrations
by collecting the majority of plasma samples between
7:00 and 9:00 AM, and all samples were collected after
15–20 minutes of lateral recumbency. RAAS may not
be maximally activated in cats with mild to severe
HCM without CHF, which could result in the lack of
an observed effect of ramipril at the dose used in this
study.
1103
k
Coulet M, Burgaud S. Pharmacokinetics of ramipril and
ramiprilat and angiotensin converting enzyme activity after single
and repeated oral administration of ramipril to cats. 12th
Congress of the European College of Veterinary Internal
Medicine-Companion Animals, Munich, Germany, September
19–21, 2002. Abstract
l
Buhlmann Laboratories AG, Allschwil 1, Switzerland
m
MacDonald KA, Klose T, Munro C, Kittleson MD. The effect of
long term storage on the concentration of brain natriuretic
peptide in frozen plasma of cats. Proceedings of the 23rd Annual
American College of Veterinary Internal Medicine Forum,
Baltimore, MD, June 1–4, 2005. Abstract 184
n
Hartmann A, Putz A, Hopf R. Effect of long-term ACE-inhibitor
therapy in hypertrophic cardiomyopathy (HCM). J Am Coll
Cardiol 1995;25(Suppl 1):234A. Abstract
o
Oyama M, Gidlewski J, Sisson D. Effect of ACE-inhibition on
dynamic left ventricular obstruction in cats with hypertrophic
obstructive cardiomyopathy. Proceedings of the 21st Annual
American College of Veterinary Internal Medicine Forum,
Charlotte, NC, June 4–7, 2003. Abstract 84. J Vet Intern Med
2003;17:400
Conclusion
There were no statistically or clinically relevant
changes in LVMI, diastolic function, DE cMRI, plasma
aldosterone concentration, or plasma BNP concentration in Maine Coon and Maine Coon cross-bred cats
with mild to severe familial HCM and no CHF treated
with ramipril (0.5 mg/kg PO q24h) compared with
placebo. Given the lack of clinically relevant differences
in measurements between the treatment groups in the
current study, early use of ramipril to decrease LV mass
at the dose used in asymptomatic cats with HCM may
not be warranted. Additionally, lack of a reduction in
plasma aldosterone concentration appears to be a relatively common finding in cats treated long-term with
ramipril.
Footnotes
a
Sisson D, Oyama MA, Solter P. Plasma levels of ANP, BNP,
epinephrine, norepinephrine, serum aldosterone, and plasma
renin activity in healthy cats and cats with myocardial disease.
Proceedings of the 21st Annual American College of Veterinary
Internal Medicine Forum, Charlotte, NC, June 4–7, 2003.
Abstract 241. J Vet Intern Med 2003;17:438
b
Fox PR. Prospective, double-blinded, multicenter evaluation of
chronic therapies for feline diastolic heart failure: Interim
analysis. Proceedings of the 21st Annual American College of
Veterinary Internal Medicine Forum, Charlotte, NC, June 4–7,
2003. Abstract 952
c
HP Sonos 5500, Philips Medical Systems, Andover, MA
d
Quatrode, In Vivo Research, Inc, Orlando, FL
e
General Electric Advantage 3.1 workstation, GE Medical
Systems, Milwaukee, WI
f
Purina Pro Plan, Société des Produits Nestlé SA, Vevey,
Switzerland
g
Phoenix Pharmaceutical Inc, Belmont, CA
h
Michigan State University, Diagnostic Center for Population and
Animal Health, Endocrine Diagnostic Section, Lansing MI
i
Parks Medical Electronics, Inc, Aloha, OR
j
Intervet Pharma R & D, Beaucouze, France
Acknowledgments
The authors thank Intervet Pharma R & D, the Winn
Feline Foundation, and UC Davis Center for Animal
Health for funding this study, Coralie Munro for
performing the RIA for plasma BNP, and Purina for
donating the Pro Plan salmon and rice dry food.
Supported by the following grants: Intervet Pharma R&
D, Winn Feline Foundation, and University of California
at Davis Center for Companion Animal Health
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