(Circulation. 1995;92:1947-1953.)
© 1995 American Heart Association, Inc.
Articles |
Trandolapril Decreases Prevalence of Ventricular Ectopic Activity in Middle-Aged SHR
From INSERM-U127, Hôpital Lariboisière (B.C., B.S.), Paris, France; INSERM-U28, Hôpital Broussais (D.H., A.B., T.D., P.B.), Paris, France; Département de Santé Publique, Faculté de Médecine (Y.B.), Rennes, France; Laboratoire Roussel-UCLAF (S.J., G.H.), Romainville, France; and Département de Physiologie, Faculté de Médecine (F.C.), Rennes, France.
Correspondence to Dr Brigitte Chevalier, INSERM-U127, Hôpital Lariboisière, 41 Bd de la Chapelle, 75010 Paris, France.
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Abstract |
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 Top Abstract IntroductionMethods Results Discussion References |
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Background Although severe arrhythmias are still a major problem in patients with left ventricular hypertrophy (LVH), the relationship between ventricular remodeling and its regression or prevention, and the prevalence of ventricular premature beats (VPB) or more sustained arrhythmias are still poorly explored in hypertensive heart disease.
Methods and Results Holter monitoring was used to quantify supraventricular premature beats and VPB and heart rate (HR) in middle-aged spontaneously hypertensive rats (SHR) and Wistar rats treated for 3 months with trandolapril (ACE inhibitor, 0.3 mg/kg per day). Hypertrophy and fibrosis were morphometrically determined. Statistical analysis was performed with the use of simple regression and multivariate data analysis (cluster and correspondence analysis). SHR have higher cardiac mass and fibrosis, more VPB, and a decreased HR. Cluster analysis demonstrated that trandolapril was only effective in SHR. Trandolapril significantly reduced cardiac hypertrophy, fibrosis, and VPB incidence and increased the HR. Simple regression analysis showed that VPB incidence correlated to both hypertrophy and fibrosis. Correspondence analysis evidenced a strong correlation between hypertrophy, fibrosis, and VPB, but only for severe hypertrophy, and the correlation disappeared for moderate hypertrophy.
Conclusions After trandolapril treatment, the regression of VPB incidence not only is linked to hypertrophy and fibrosis, but additional causal factors also are involved including the myocardial phenotype and new calcium metabolism. Our model of Holter monitoring in conscious middle-aged SHR and multivariate data analysis might be useful in correlating myocardial structural modifications and ectopic activity.
Key Words: arrhythmia • hypertrophy
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Clinical trials and experimental studies have repeatedly evidenced the beneficial effects of ACEI in hypertensive heart disease both in terms of survival and regression of LVH.
Epidemiological studies1 and clinical practice also have shown that the incidence of sustained arrhythmias, a major cause of sudden death, and ectopic beats were linked to the degree of LVH,2 3 even in patients without coronary insufficiency.4 Nevertheless, clinical trials showing the effects of ACEI and consecutive regression of LVH on the incidence of arrhythmias are still rather rare. VPB in hypertensive patients decreased after ACEI,5 whereas the same treatment may have a beneficial effect on the the prevalence of ventricular tachycardia and couplets in patients with congestive heart failure.6
For the moment, experimental data on the reduction of ectopic activity after ACEI are still rare. Only two studies showed that the ectopic activity, evaluated on an isolated rat heart preparation, decreased after ACEI.7 8
Our work is based on an original technique that involves the use of Holter monitoring in rats.9 Our purpose was to take advantage of experimental conditions to study the protective effects of ACEI in terms of arrhythmogenicity in an animal model, the rat, which is known to be resistant to atherosclerosis. The design of this study was achieved to analyze with the use of multivariate data analysis10 the different components at the origin of arrhythmias, namely fibrosis, hypertrophy, and changes in myocardial phenotype.11 The study was performed on middle-aged WST and SHR treated for 3 months with trandolapril, an ACEI.
For the first time, we have shown in conscious rats that the regression of ventricular arrhythmias not only is linked to hypertrophy and fibrosis, but additional causal factors also are involved. Our model of Holter monitoring in conscious senescent SHR might be useful in correlating the response in myocardial structure to ACEI treatment with ventricular ectopic activity.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Our laboratory complies with the requirements of the Ministry of Agriculture and has been authorized to experiment on living animals according to Executive Order No. 87-848 of October 19, 1987.
Protocol
Experiments were performed on 13-month-old male WST
and SHR
of the same origin (Iffa Credo). The rats were kept under similar
housing conditions with a diurnal light cycle (lights on from 6
AM to 6 PM), fed ad libitum with AO4C-10
pellets (Extra Labo, UAR), and divided into four experimental groups:
untreated rats used as controls (SHR-C and WST-C, n=32 and 20,
respectively) were given tap water containing the solvent for the ACEI
trandolapril (stored at 10 mg/mL in 0.004N NaOH), and treated rats
(SHR-T and WST-T, n=28 and 12, respectively) were given tap water
containing trandolapril (0.3 mg/kg per day) for 3 months. The rats were
16 months old at the time of Holter monitoring. SBP was indirectly
measured with use of the tail-cuff technique (Narco-Biosystems,
BSR) twice monthly. After Holter monitoring, rats were killed, and
blood samples were taken to measure plasma renin and ACE
activities.12
Holter Monitoring
Long-term ECG recording was carried out as
previously described.9 After anesthesia was
induced (50 mg sodium pentobarbital/kg body wt), three electrodes were
implanted in the back of the rat. The leads were tunneled
subcutaneously to the nape of the neck and then passed through a
swivel-tethering system (Harvard Bioscience-Earling) that allowed
the animal to move freely. After amplification, the one-channel ECG
was recorded by a conventional Holter tape recorder
(recorder model 2124, Ela Medical Inc) with a recording
speed of 2 mm · s-1 adapted to the high heart rate of
the rat. Monitoring procedure was started 24 hours later, the rat being
placed in a special cage and provided with food and water ad libitum.
During this protocol, 8 of 32, 6 of 28, and 4 of 20 of SHR-C, SHR-T,
and WST-C, respectively, died. None of the treated WST died.
Quantification of Arrhythmias and Heart Rate
Printed
recordings were used to quantify
arrhythmias and were always analyzed by the same
investigator in a blind manner. As previously described,9
the classic definition of arrhythmias in humans was used. The
total number of SVPB and VPB were counted over the 24-hour monitoring.
VPB were assigned to isolated ectopic beats, unifocal or multifocal; or
repeated ectopic beats, couplets (two consecutive VPB), or more. The
severity of ventricular arrhythmias then was
assessed with the use of previous
classifications13 14 and
adapted to the high heart rate of the rat. The following definition was
used: no VPB was class 0, infrequent isolated monofocal VPB (
30 per
hour), class 1; frequent monofocal VPB (>30 per hour), class 2;
multifocal ectopic beats, class 3; couplets of VPB, class 4; triplets
and nonsustained salvos of VPB (6 ectopic beats), class 5; and
ventricular tachycardia, class 6. Heart rate was
measured every 30 minutes over the 24-hour period. Each measurement was
made on eight consecutive beats, and the mean heart rate was the
average of all the measures in activity and the resting period. After
elimination of artifacts, 81% of the Holter recordings were
exploitable. The incidence of artifacts was the same in the four
groups.
Myocardial Hypertrophy and Fibrosis
Determination
After the rats were killed, the hearts were blotted and
weighed.
In a first group, the left and right ventricles and the two atria were
dissected and weighed separately. In a second group, the heart was
immersed in formalin for histomorphometric analysis of
hypertrophy and fibrosis, as previously
described.15 16 Briefly, two standardized transversal
biventricular sections were stained with sirius red in
the same bath and blindly studied by one investigator. Myocardial
collagen was quantified with the use of an automated image
analysis processor based on mathematical morphology software.
Each field was transmitted by a gray level camera mounted on a light
microscope or macroscope to the image analyzer and transformed
into a 512x512-pixel digital image with 256 gray levels. Three
sequential programs were used to study LVH and macroscopic,
interstitial, and pericoronary collagen.
LVH and macroscopic collagen were determined in one field (x15 macroscopic magnification, final resolution of 30 µm per pixel). The whole left ventricular (LV) section was analyzed: the LV thickness and perimeter and the macroscopic collagen quantity and density (ratio between macroscopic collagen and total LV surface area) were quantified.
For the quantification of the interstitial collagen fraction in the subepicardium and subendocardium (magnification x250 with a final calibration of 0.048 µm per pixel), only fields that did not contain pericoronary or scar collagen were analyzed. For each field, mathematical morphology sequence (top hat method) extracted all collagen structures and the corresponding myocardial surface area. The ratio between both measurements gave subepicardial and subendocardial collagen densities. In a second step, morphological operators (opening and closing functions) were allowed to transform all neighboring collagen structures as one object, whereas distant collagen structures stayed disconnected. Moreover, all small collagen objects in the field are "attracted" by the closer and bigger collagen object. These morphological transformations gave an underestimation of collagen component and could typically discriminate fields where the same collagen quantity was either widely distributed in tiny objects or poorly distributed in big objects. The ratio between collagen surface area and component number represented the interstitial collagen mean size.
For the quantification of pericoronary collagen, all coronary sections of the LV surface were analyzed at the same magnification as the interstitial collagen. The collagen components were extracted with the same image analysis sequence in the whole field, and the coronary lumen was extracted. The collagen was considered as pericoronary if it was related to a neighborhood degree, depending on the lumen dimension. The results were expressed as the pericoronary collagen surface area divided by the coronary lumen perimeter. Valuable data were obtained in 14 SHR-C, 12 SHR-T, 8 WST-C, and 12 WST-T. The third program was only performed on the two SHR groups.
Statistical Analysis
Results are expressed as
mean±SEM. In all cases, statistical
significance was set at 5%. All data were compared with use of the
nonpaired Scheffé's F test after variance analysis
except for nonparametric data (ie, incidence of premature
beats), which were analyzed with use of the Kruskal-Wallis
test. Simple correlations were performed by linear regression
analysis with the least squares method. These statistical
analyses were performed with the use of an analysis
software (STATVIEW, Abacus Concepts, Inc). The same
groups of rats (SHR-C, n=10; SHR-T, n=11) were used for all the
simple
correlations.
Subsequently multivariate data analysis (cluster and correspondence analysis) was performed.10 This analytical method is less restrictive than those previously used (with only one parameter studied in two groups) because it allows the simultaneous treatment of seven variables (SBP in mm Hg, HW in mg, SVPB and VPB number per 24 hours, and macroscopic, subendothelial, and subepicardial collagen densities) for four groups of rats (WST-C and WST-T, SHR-C and SHR-T). They were divided into classes corresponding to variable modalities in function of their repartition (median and quartiles). In this way, a final table was obtained for 34 rats and 29 classes (four for each parameter except for SVPB, which was divided into five classes). The specific data value of each rat was coded as being present or absent in the corresponding class. This final table was studied by hierarchical cluster and multiple correspondence analysis. The calculations created homogenous subpopulations of rats that were compared with use of the Mann-Whitney U test, and the correlation between the variables were studied with Spearman correlations. The calculations were carried out on BI software LOGINSERM 1979/1987.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Effect of Strain: SHR Versus WST
Fig 1
shows
that in SHR-C, the SBP was higher than
in WST-C during the 3-month period. In WST-C, a slight increase in SBP
was observed from 128±3 at day 0 to 132±5 mm Hg at day 90
(P<.05). At the time the rats were killed, anatomic
examination showed that neither WST-C nor SHR-C presented signs
of failure. Plasma ACE activity was lower in SHR-C than in WST-C (66±3
versus 107±7 U/L, P<.001), but plasma renin activity was
similar in both groups (13±1 versus 13±2 ng angiotensin
I/mL per hour, P=NS).
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) and WST-C (n=19, 
)
indicate controls; SHR-T (n=23, 
) and WST-T (n=12, 
),
rats
treated with trandolapril. At day 0, all the rats were 13 months old.
Scheffé's test for individual values;
***P<.001,
*P<.05 vs WST-C;
******P<.001 vs
SHR-C.
Cardiac Hypertrophy and
Fibrosis
Body weight of SHR was 70% of that of age-matched WST, but HW
was higher in the SHR than in the WST (Table 1). Both
the LV and RV weights were elevated in SHR and the LV weight to right
ventricular (RV) weight ratio did not change when compared
with age-matched WST. The morphometric analysis showed that
LVH was characterized by a thickening of the LV wall (from 2.23±0.08
mm in WST-C to 2.97±0.06 mm in SHR-C, P<.001) and an
increased LV perimeter (from 35±0.9 to 46±0.7 mm,
P<.001).
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In SHR, the macroscopic collagen was more abundant
than in WST (Fig 2a and 2b and Table
2.) In SHR, the
increase in fibrosis also was found for the subepicardial (+38%) and
subendocardial (+45%) interstitial collagen densities
(Table 2).
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Arrhythmias and Heart Rate
The incidence of SVPB was similar in both groups. VPB were nearly
absent in the WST-C, whereas they were more than 60-fold more frequent
in SHR-C (Table 3). One SHR-C with 13 291 VPB was
excluded from the calculations. In addition, as illustrated in Fig
3, VPB were more complex in SHR-C than in WST-C. All the
WST-C belonged to class 0, whereas 53% of the SHR-C belonged to class
3 or 4. No rats were found in classes 5 and 6.
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) and bifocal
ventricular premature beats (
A slight but significant
bradycardia also was observed in SHR-C as
compared with WST-C. This decrease in HR was similar whether the rats
were in activity or at rest (Table 3
). Results also showed that
in both
groups, the HR was reduced at rest as compared with the activity period
(P<.05 for WST-C and P<.01 for SHR-C).
Effects of Trandolapril
The slight increase of SBP observed
in the 16-month-old WST-C
was suppressed by trandolapril (Fig 1). In SHR-T, the reduction
in SBP
was significant after 2 weeks and averaged -17% after 3 months.
Nevertheless, at the end of treatment, SBP remained higher in the SHR-T
than in WST-T. As expected, the treatment reduced plasma ACE activity;
nevertheless, the reduction was more pronounced in WST-T (to 15±1 U/L,
-85%, P<.001) than in SHR-T (to 39±4 U/L, -40%,
P<.001). After ACEI, a significant increase in plasma renin
activity was observed only in WST (from 13±1 ng
angiotensin I/mL per hour in WST-C to 44±5 in WST-T,
P<.001).
Cardiac Hypertrophy and Fibrosis
Trandolapril had no effect on body weight in either group and
induced a significant regression of cardiac hypertrophy
only in SHR (Table 1). In SHR-T, the reduction of cardiac
hypertrophy was higher in the atria (-49%) than in the
right ventricle and left ventricle (-29% and -24%, respectively),
but the LV weight to RV weight ratio was unchanged. Trandolapril did
not affect the collagen content of the WST ventricles but significantly
reduced fibrosis in SHR ventricles (Fig 2c). In SHR-T, the
macroscopic
and pericoronary collagen densities (-39% and -28%) and
the subepicardial collagen mean size significantly decreased (Table
2).
Arrhythmias and Heart Rate
In
both groups, the incidence of SVPB was unsensitive to the
treatment. By contrast, one of the major results of this study was that
ACEI nearly suppressed VPB in SHR-T, ventricular
arrhythmias being ninefold less frequent than in SHR-C (Table
3). As a result of trandolapril administration, the percentage
of SHR
in the classes of high-severity arrhythmias (classes 3 and
4) decreased from 53% to 23%.
After administration of trandolapril,
mean HR did not change in the
WST. In SHR-T, mean HR remained unchanged at rest but returned to the
values similar to those recorded in WST during the activity period.
Consequently, the difference in HR between activity and resting periods
became higher in SHR-T than in SHR-C (Table 3).
Statistical Analysis
Simple Correlation Analysis in the
SHR Group
The HR variations were only correlated to SBP changes
(r=.59, P<.008, n=19). By contrast, the
regression of cardiac hypertrophy was highly correlated to
SBP reduction (r=.71, P<.001, n=21) and to
myocardial fibrosis. The VPB reduction was correlated both to
hypertrophy and fibrosis. The simple correlation
analysis suggested that the ventricular
arrhythmia regression was best correlated with the reduction of
fibrosis. The VPB number was too scattered to allow
covariance analysis (see Table 4).
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Multivariate Data Analysis
Such an analytical
method allows the global description of systems
that consist of many variables for sets of several groups of
individuals (four groups of rats). In our study, we used two components
of the multivariate data analysis: cluster
analysis to research subpopulations and correspondence
analysis to define the relationship among the variables in
the four groups. In fact, we used only the rats in which the seven
following parameters were available: SBP; HW; macroscopic,
endocardial, and epicardial collagen densities; SVPB; and VPB.
Using
cluster analysis, we found only three significantly
distinct subpopulations (Fig 4A): (1) SHR-C, (2) SHR-T,
and (3) WST-C and WST-T, since there was no statistical difference
between the parameters in WST-C and WST-T. This
analysis allows the conclusion that trandolapril treatment was
only effective in SHR (P<.001) and not in WST (except for
the SBP at day 90). It further shows that despite the dramatic effects
of trandolapril, the SHR-T remained different from WST-C
(P<.001).
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According to correspondence analysis (Fig
4B), the highest
values of most of the variables (SBP4, HW4, Coll4, VPB4, SVPB5; see
Fig 4 legend) were regrouped in the lower left quadrant. The
lowest
values (SBP1, HW1, Coll1 and Coll2, VPB1, and SVPB1) are in the right
lower quadrant. Intermediate values were localized in the two upper
quadrants. HW and Coll were strongly linked one to each other
(r=.77, P<.01) and nearly distributed as a
parabola, suggesting a linear relationship between both
parameters. The same distribution also was observed for
SBP. The subepicardial and subendocardial interstitial
collagen densities presented noncoherent distributions (not
shown). The highest incidence of both VPB (VPB4) was localized with the
highest cardiac mass (HW4, HW >1600 mg) and highest fibrosis (Coll4,
macroscopic collagen density >1.5%). Nevertheless, this relationship
disappeared for the intermediate values: VPB3 colocalized with HW2
(upper right quadrant) and VPB2 with HW3 and Coll3 (upper left
quadrant).
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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The main results of this study are the following. (1) The incidence of VPB as recorded for the first time in conscious rats is higher in middle-aged nonfailing SHR than in age-matched WST. (2) In SHR, long-term treatment with an ACEI reduces in a parallel manner ventricular arrhythmias, LVH, and fibrosis. (3) The reduction of ventricular arrhythmias is highly correlated with both myocardial hypertrophy and fibrosis in severe hypertrophy. Nevertheless, correspondence analysis suggests the role of additional factors, particularly during moderate hypertrophy.
Middle-Aged SHR
The SHR is a genetic model of chronic
overload with a lifetime
elevated SBP and evolves toward failure with aging.17 In
young adult SHR, myocardial hypertrophy consists mainly of
LVH, and failure is preceded by a decrease in the LV weight to RV
weight ratio and only occurs after 18 months.18 19
Middle-aged SHR used here were nonfailing hypertensive rats with no
anatomic signs of failure and an LV to RV weight ratio similar to that
of age-matched WST (Table 1).
Fibrosis increases with
age both in SHR and WST and is always greater
in SHR.20 21 In this study, we found more than a
twofold increase in the macroscopic collagen density in SHR as compared
with WST. Middle-aged SHR present an important
pericoronary and interstitial collagen density,
as in older SHR.15 16 The morphometric analysis
showed that the increase in the interstitial fibrosis
mainly was due to an increase in the mean size of collagen scars
in the subendocardium and to a multiplication of collagen scars in the
subepicardium (Table 2).
Recent evidence suggested an important role of peptide hormones, mainly angiotensin II (AII) and bradykinin, produced within the myocardium in regulating fibroblast collagen turnover.22 23 AII stimulates collagen synthesis and bradykinin decreases collagen synthesis and increases the collagenolytic activity. In vitro autoradiography studies showed a colocalization of ACE binding sites and areas of fibrosis and an association between AII-specific receptors and fibrosis extent.24 25
Several data suggest that in LVH, the intracardiac AII synthesis is activated.26 27 More recently, in renal or genetic hypertension in rats, an upregulation of AII-specific receptors also has been reported.28 Consequently, locally synthetized AII may contribute to the myocardial growth and fibrosis development that appeared in middle-aged SHR.
Our work was the first to show an
increased number of
ventricular arrhythmias in conscious
middle-aged SHR compared with age-matched WST. These results
confirm previous findings showing a higher propensity to
arrhythmogenesis of isolated rat hearts from 14-month-old
SHR.7 8 The information obtained with the use of
Holter
monitoring technique is more quantitative and closer to the in vivo
situation than that obtained from an isolated heart preparation. As for
clinical studies, arrhythmias can be quantified and classified
according to their severity.13 14 Middle-aged SHR
presented prognostic arrhythmias (Table 3 and Fig
3),
since 53% of the SHR-C belonged to class 3 or 4, whereas all the WST-C
belonged to class 0. According to the incidence of arrhythmias,
middle-aged SHR closely resemble patients with LVH at New York
Heart Association stage I. In a previous study, by using the same
technique, we found a higher ectopic activity in senescent WST (24
months old) than in middle-aged WST (this study), suggesting that
not only long duration of hypertension but also senescence increased
the incidence of arrhythmias, thus extending previous
conclusions of other clinical or experimental
studies.29 30
In both groups, HR was significantly lower at rest than in activity. In SHR, mainly in activity, the mean HR was decreased compared with WST, as previously reported in 18-month-old SHR.31
Effects of Trandolapril
Cluster analysis (Fig
4A) clearly showed that trandolapril
had significant effects in SHR. This result is in agreement with a
previous study showing that the interstitial collagen in
WST was not affected by lisinopril treatment, when the same
treatment normalized the fibrosis in SHR.32
In our study, trandolapril induced a significant but only partial regression of myocardial hypertrophy and fibrosis. Our protocol should be considered more as a treatment trial that prevents the worsening of LVH and fibrosis than as a prevention trial. Both hypertrophy and fibrosis were significantly reduced in SHR-T compared with SHR-C but remained higher than that observed in the WST groups.
In this study, ACEI reduced LVH by about 25% and fibrosis
by about
40%. Trandolapril reduced perivascular reactive fibrosis and
interstitial reparative fibrosis by decreasing the mean
size of the collagen structures in the subepicardial interstitium
(Table 3). Previous studies on the effects of ACEI on LVH and
fibrosis
in young and senescent SHR clearly show that
hemodynamic and hormonal factors are involved in the
response of the myocardial structure to such a
treatment.22 Treating SHR with a subhypotensive dose of
ACEI had no effect on the SBP but prevented perivascular and
interstitial fibrosis.33 These results suggest
that the reduction of LVH depends mainly on hemodynamic
factors, whereas that of the fibrosis has another origin.
We could speculate that in this study, the most likely mechanism for the reduction of fibrosis after trandolapril is a local inhibition of AII synthesis, since the middle-aged SHR have a lower plasma ACE activity that is less inhibited after trandolapril than in WST, whereas no effect on myocardial structure was observed in this group. Indeed, ACEI can inhibit the myocardial ACE activity and consequently decrease the intracardiac AII content.34 Since, as discussed above, the local synthesis and the effects of AII should be increased in SHR, it is not surprising that the effects of trandolapril were higher in SHR than in WST.
Trandolapril nearly suppressed ventricular arrhythmias but did not affect SVPB in SHR. The same treatment did not alter the electrophysiological phenomena of WST. A significant diminution of the incidence of ectopic beats has been observed in SHR after ACEI treatment.7 8 In a previous work, arrhythmias were quantified on isolated hearts, and the ACEI treatment was maintained for 11 months.7 In this case, the treatment could be considered more as prevention treatment compared with our protocol even if LVH and fibrosis were already present at 12 weeks.33 After trandolapril treatment, the percentage of SHR-T in class 0 increased from 47% to 77% and that in classes 3 and 4 decreased. Middle-aged SHR appear to closely resemble the clinical situation, ie, arterial hypertension in 60-year-old patients, and our results are similar to those observed in clinical protocols in moderate hypertension showing that an ACEI reverses the ectopic activity, reduces the severity of arrhythmias, and has no effect on the incidence of SVPB.5
Correspondence analysis
(Fig 4B) clearly shows that
hypertrophy, fibrosis, and ventricular ectopic
activity were highly correlated for severe hypertrophy
since HW4, Coll4, and VPB4 are in the same quadrant. In this case the
major determinant of ventricular arrhythmias is
clearly the structural changes involved in the remodeling of the
hypertrophied myocardium. For moderate
hypertrophy, this relationship disappears and strongly
suggests that the relationship between myocardial remodeling and
ectopic activity is not as simple as previously
discussed5 7 and that other factors could prevail in
the
genesis of ventricular arrhythmias.
Experimental evidence of a link between arrhythmias and a new myocardial phenoptype was recently provided in our laboratory.36 AII has several biological effects that could induce cardiac arrhythmias, at least in the LVH. It has been reported that AII increases the cytosolic calcium concentration,37 38 which may mediate cardiac arrhythmias.39
Conclusions
Our model of Holter monitoring in senescent SHR
associated with a
multivariate data analysis might be useful in
correlating modifications of the response of the
cardiovascular system to an ACEI treatment with
reduction of ventricular arrhythmias. We showed
that the relationship between LVH and fibrosis and
ventricular ectopic activity is not as simple as has been
suggested.5 We postulate that in severe
hypertrophy, the genesis of arrhythmias is mainly dependent
on structural alterations of LVH, while in moderate
hypertrophy other factors are predominantly involved.
Prevention of severe arrhythmias is becoming a difficult task since the CAST Study.40 Our results suggest that the reduction of LVH is in fact the first step in treating benign arrhythmias. In addition, such a treatment has no toxicity as compared with other more classic antidysrhythmic drugs.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported by INSERM, Roussel-UCLAF, Fondation pour la Recherche Médicale, and Fondation de France (grant BS 1993). Dr Chevalier is a recipient of grant No. 90059 from Roussel UCLAF. The authors wish to thank D. Charlemagne and L. Rappaport for helpful discussions and rereading the article. We also thank F. Dowell for kind help in preparing the manuscript and D. Minet for his technical assistance.
Received March 2, 1995; accepted April 1, 1995.
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References |
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TopAbstractIntroductionMethods Results Discussion References |
|---|
1. Levy D, Garrison DJ, Daniel MS, Savage DD, Kannel WB, Castelli WP. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med. 1990;22:1561-1565.
2. Malerba M, Muiesan ML, Zulli R, Rizzoni D, Calebich S, Agabitt-Rosen E. Ventricular arrhythmias and changes in blood pressure and left ventricular mass induced by antihypertensive treatment in hypertensive patients. J Hypertens. 1991;9(suppl 6):S162-S163.
3. Messerli FH, Ventura HD, Elizardia DJ, Dunn FG, Fröhlich ED. Hypertension and sudden death: increased ventricular ectopic activity in left ventricular hypertrophy. Am J Med. 1984;77:18-22. [Medline] [Order article via Infotrieve]
4. Ghali JK, Kadakia S, Cooper RS, Liao Y. Impact of left ventricular hypertrophy on ventricular arrhythmias in the absence of coronary artery disease. J Am Coll Cardiol.1989;14:1365-1373.
5. Gonzalez-Fernandez RA, Rivera M, Rodriguez PJ, Fernandez-Martinez J, Soltero LH, Diaz LM, Luggo JE. Prevalence of ectopic ventricular activity after ventricular mass regression. Am J Hypertens. 1993;6:308-313. [Medline] [Order article via Infotrieve]
6. Fletcher RD, Cintron GB, Johnson G, Orndorff J, Larson P, Cohn JN. Enalapril decreases prevalence of ventricular tachycardia in patients with congestive heart failure. Circulation. 1993;87(suppl VI):VI-49-VI-55.
7.
Pahor M, Bernabei R, Sgadari A, Gambassi G, Lo Guidice
PL, Pacifici L, Ramacci MT, Lagrasta C, Olivetti G, Carbonin P.
Enalapril prevents cardiac fibrosis and arrhythmias
in hypertensive rats. Hypertension. 1991;18:148-157.
8. Tisne-Versailles J, Verscheure Y, Le Kim A, Pourrias B. Comparison between the ventricular fibrillation thresholds of spontaneously hypertensive and normotensive rats: investigation of antidysrhythmic drugs. J Cardiovasc Pharmacol. 1982;4:430-435. [Medline] [Order article via Infotrieve]
9. Carré F, Lessard Y, Coumel P, Ollivier L, Besse S, Lecarpentier Y, Swynghedauw B. Spontaneous arrhythmias in various models of cardiac hypertrophy and senescence of rats: a Holter monitoring study. Cardiovasc Res. 1992;26:698-705. [Medline] [Order article via Infotrieve]
10.
Benigni R, Giuliani A. Quantitative modeling and
biology: the multivariate approach. Am J
Physiol. 1994;266:R1697-1704.
11. McLenachan JM, Dargie HJ. Determinants of ventricular arrhythmias in cardiac hypertrophy. J Cardiovasc Pharmacol. 1991;17(suppl 2):S46-S49.
12. Callens-El Amrani F, Cheaw SL, Chevalier B, Paolaggi F, Jouquey S, Hamon G, Swynghedauw B. Regression of left ventricular hypertrophy by converting enzyme inhibition in 12-15 month old spontaneously hypertensive rats: effects on coronary resistance and ventricular compliance in normoxia and anoxia. J Cardiovasc Pharmacol. 1994;23:155-165. [Medline] [Order article via Infotrieve]
13. Lown B, Wolf M. Approaches to sudden death from coronary heart disease. Circulation. 1971;46:130-139.
14. Myerburg RJ, Kessler KM, Luceri RM, Zaman L, Trohman RG, Esses D, Castellanos P. Classification of ventricular arrhythmias based on parallel hierarchies of frequency and form. Am J Cardiol. 1984;54:1355-1358. [Medline] [Order article via Infotrieve]
15. Michel JB, Salzman JL, Ossondo NM, Bruneval P, Barres D, Camilleri JP. Morphometric analysis of collagen network and plasma perfused capillary bed in the myocardium of rats during evolution of cardiac hypertrophy. Basic Res Cardiol. 1986;81:142-154. [Medline] [Order article via Infotrieve]
16. Hinglais N, Heudes D, Nicoletti A, Laurent M, Mandet C, Bariety J, Michel JB. Colocalization of myocardial fibrosis and inflammatory cells in rats. Lab Invest. 1994;70:286-294. [Medline] [Order article via Infotrieve]
17. Takatsu T, Kashiiand C. Cardiac hypertrophy in spontaneously hypertensive rats. In: Okamoto K, ed. Spontaneous Hypertensive Rats: Pathogenesis and Complications. Berlin, Germany: Springer-Verlag; 1972:166-172.
18.
Boluyt MO, O'Neill L, Meredith AL, Bing OHL, Brooks
WW, Conrad CH, Crow MT, Lakatta EG. Alterations in cardiac gene
expression during the transition from stable hypertrophy to
heart failure. Circ Res. 1994;75:23-32.
19.
Perreault CL, Bing OHL, Brooks WW, Ransil BL, Morgan
JP. Differential effects of cardiac hypertrophy and
failure on right versus left ventricular calcium
activation. Circ Res. 1990;67:707-712.
20.
Engelman GL, Vitullo JC, Gerrity RG.
Morphometric analysis of cardiac hypertrophy
during development, maturation, and senescence in spontaneously
hypertensive rats. Circ Res. 1987;60:487-494.
21. Eghbali M, Robinson TF, Seifer S, Blumenfeld OO. Collagen accumulation in heart ventricles as a function of growth and aging. Cardiovasc Res. 1990;67:871-885.
22. Weber KT, Sun Y, Tyagi SC, Cleutjens JPM. Collagen network of the myocardium: function, structural remodeling and regulatory mechanisms. J Mol Cell Cardiol. 1994;26:279-292. [Medline] [Order article via Infotrieve]
23. Brilla CG, Zhou G, Matsubara L, Weber KT. Collagen metabolism in cultured adult cardiac fibroblasts: response to angiotensin and aldosterone. J Mol Cell Cardiol. 1994;26:809-820. [Medline] [Order article via Infotrieve]
24. Sun Y, Ratajska A, Zhou G, Weber KT. Angiotensin converting enzyme and myocardial fibrosis in the rat receiving angiotensin II or aldosterone. J Lab Clin Med. 1993;122:395-403. [Medline] [Order article via Infotrieve]
25. Sun Y, Weber KT. Angiotensin II receptor binding following myocardial infarction in the rat. Circ Res. 1994;28:1623-1628.
26.
Baker KM, Chernin MI, Wixson SK, Aceto JF.
Renin-angiotensin system involvement in pressure
overload cardiac hypertrophy in rats. Am J
Physiol. 1990;259:H324-H332.
27. Schunkert H, Dzau VJ, Shih Tang S, Hirssch AT, Apstein CS, Lorell BH. Increased rat cardiac angiotensin converting enzyme activity and mRNA expression in pressure overload left ventricular hypertrophy. J Clin Invest. 1990;86:1913-1920.
28.
Suzuki J, Matsubara H, Urakami M, Inada M. Rat
angiotensin II (type 1A) receptor mRNA regulation and
subtype expression in myocardial growth and
hypertrophy. Circ Res. 1993;73:439-447.
29. Pahor M, Lo Giudicia P, Bernabei R, Di Gennaro M, Pacifici L, Ramacci MT, Carbonnin PU. Age related increase in the incidence of ventricular arrhythmias in isolated hearts from spontaneously hypertensive rats. Cardiovasc Drugs Ther. 1993;3:163-169.
30.
Fleg JL, Kennedy HL. Cardiac arrhythmias
in a healthy elderly population. Chest. 1982;81:302-307.
31. Friberg P, Karlsson B, Nordlanderand M. Autonomic control of the diurnal variation in arterial pressure and heart rate in spontaneously hypertensive and Wistar Kyoto rats. J Hypertens. 1989;7:799-807. [Medline] [Order article via Infotrieve]
32.
Brilla CG, Janicki JS, Weber KT.
Cardioreparative effects of lisinopril in rats with
genetic hypertension and left ventricular
hypertrophy. Circulation. 1991;83:1771-1779.
33.
Brilla CG, Janicki JS, Weber KT. Impaired
diastolic function and coronary reserve in genetic
hypertension. Circ Res. 1991;69:107-115.
34. Nagano M, Higaki J, Mikami H, Nakamaru M, Higashimori K, Katahira K, Tabuchi Y, Moriguchi A, Akamura F, Ogihara T. Converting enzyme inhibitors regressed cardiac hypertrophy and reduced tissue angiotensin II in spontaneously hypertensive rats. J Hypertens. 1991;9:595-599. [Medline] [Order article via Infotrieve]
35. McLenachan JM, Dargie HJ. Determinants of ventricular arrhythmias in cardiac hypertrophy. J Cardiovasc Pharmacol. 1991;17(suppl 2):S46-S49.
36. Carré F, Rannou F, Sainte-Beuve C, Chevalier B, Moalic JM, Swynghedauw B, Charlemagne D. Arrhythmogenicity of the hypertrophied and senescent heart and relationship to membrane proteins involved in the altered calcium handling. Cardiovasc Res. 1993;27:1784-1789. [Medline] [Order article via Infotrieve]
37.
Baker KM, Singer HA, Aceto JF.
Angiotensin receptor-mediated stimulation of
cytosolic free calcium and inositol phosphate in chick
myocytes. J Pharmacol Exp Ther. 1989;251:578-585.
38.
Allen IS, Cohen NH, Dhallan RS, Gaa ST, Lederer WJ,
Rogers TB. Angiotensin II increases spontaneous
contractile frequency and stimulates calcium current in cultured
neonatal rat heart myocytes: insights into the underlying biochemical
mechanisms. Circ Res. 1988;62:524-534.
39.
Thandroyen FT, Morris AC, Hagler HK, Ziman B, Pai L,
Willerson JT, Buja LM. Intracellular calcium transients and
arrhythmias in isolated heart cells.
Circ Res. 1991;69:810-819.
40. The Cardiac Arrhythmia Suppression Trial (CAST). Investigators preliminary report: effect of ecainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. N Engl J Med. 1989;321:406-412.[Abstract]
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