(Circulation. 1995;91:2642-2654.)
© 1995 American Heart Association, Inc.
Articles |
Serial Echocardiographic-Doppler Assessment of Left Ventricular Geometry and Function in Rats With Pressure-Overload Hypertrophy
Chronic Angiotensin-Converting Enzyme Inhibition Attenuates the Transition to Heart Failure
Presented in part at the American Heart Association 66th Scientific Sessions, Atlanta, Ga, November 1993.
From the Charles A. Dana Research Institute and the Harvard-Thorndike Laboratory, Department of Medicine (Cardiovascular Division), Beth Israel Hospital and Harvard Medical School, Boston, Mass, and University of Massachusetts Medical School (G.P.A.), Worcester, Mass.
Correspondence to Sheldon E. Litwin, MD, Division of Cardiology, University of Utah Medical Center, 50 N Medical Dr, Salt Lake City, UT 84132.
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Abstract |
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 Top Abstract IntroductionMethods Results Discussion References |
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Background Although chronic pressure overload may progress to left ventricular (LV) failure, the pathophysiology of this transition is not well understood. In addition, the effects of chronic angiotensin-converting enzyme (ACE) inhibition on this transition are largely undefined.
Methods and Results To examine changes in LV structure and function during the transition to heart failure, rats with LV hypertrophy due to banding of the ascending aorta (LVH, n=22) and age-matched sham-operated rats (n=6) were studied 6, 12, and 18 weeks after aortic banding. Two-dimensionally guided transthoracic M-mode echocardiograms and transmitral Doppler spectra were recorded for assessment of LV geometry and systolic and diastolic functions. LVH rats were randomized to no treatment (n=10) or treatment with the ACE inhibitor fosinopril (50 mg/kg per day, n=12) after the baseline echocardiogram. Six weeks after banding, LVH rats had increased LV wall thickness with normal cavity dimensions and supranormal endocardial systolic shortening. However, midwall shortening was mildly depressed, and a restrictive diastolic filling pattern was present. After 18 weeks of untreated pressure overload, LV wall thickness was unchanged, but cavity dilation, a fall in endocardial shortening, and further deterioration of diastolic filling were evident. In contrast to untreated LVH rats, the fosinopril-treated rats showed no change in LV diastolic cavity dimension, and systolic and diastolic functions did not deteriorate or improved. Closed chest LV systolic pressures at 18 weeks were not different in LVH or LVH-fosinopril rats (197 versus 198 mm Hg), although end-diastolic pressure was higher in the untreated rats (18 versus 11 mm Hg). Calculated LV systolic wall stress was lower in fosinopril-treated than untreated LVH rats. The severity of LV diastolic filling abnormalities correlated strongly with operating LV chamber stiffness (r=.88, P<.0001).
Conclusions This model of pressure overload is characterized initially by concentric LV hypertrophy with compensated LV chamber performance; however, markedly abnormal diastolic filling is present. The transition from compensated hypertrophy to early failure is heralded by LV dilation, impairment of systolic function, and progression of the abnormalities in LV filling. Chronic ACE inhibition in rats with supravalvular aortic banding (1) does not change in vivo LV systolic pressure but prevents increased LV cavity size and increased LV wall stress and (2) attenuates impairment of (or improves) both systolic and diastolic functions. The effects of fosinopril could be explained in part by inhibition of an intracardiac renin-angiotensin system.
Key Words: echocardiography • hypertrophy • diastole • angiotensin • heart failure, congestive
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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The development of left ventricular (LV) hypertrophy is an adaptive response to increased LV pressure because increased wall thickness may normalize LV wall stress.1 2 Even with the compensatory increase in LV mass, chronic pressure overload of the left ventricle is believed to eventually produce heart failure.3 4 Despite the wide acceptance of this concept, it has been difficult to produce animal models of pure LV pressure overload that show a clear evolution from compensated LV hypertrophy to heart failure.5 6 Likewise, documenting a transition to heart failure that results from pure LV pressure overload in patients has been limited by the difficulty of performing longitudinal studies and excluding obstructive coronary artery disease or age-related changes in cardiac structure as causes of deterioration in LV function. Thus, the pathophysiology of the postulated transition from compensated LV hypertrophy to heart failure is not well documented.
A growing body of data suggests that myocyte hypertrophy and myocyte function are modulated not only by loading conditions but also by systemic or local neurohumoral processes.7 Angiotensin II appears to be particularly important in this regard.8 9 There is a clear rationale for the administration of agents that inhibit the production of angiotensin II in subjects with systemic hypertension since these drugs will decrease afterload and as an adjunct may cause regression of LV hypertrophy. The validity of this strategy is controversial when the increased load is relatively fixed, as in the case of valvular aortic stenosis. In this circumstance, reduction of myocyte hypertrophy could be viewed as the loss of an adaptive mechanism that might result in afterload mismatch and decreased LV systolic function. Alternatively, since LV hypertrophy is thought to cause significant morbidity and mortality independent of other conditions,10 it may be that limiting the hypertrophic response in LV pressure overload has beneficial effects unrelated to improvement in hemodynamics.
The purpose of the current study was threefold: (1) to document in vivo the evolution to heart failure in a mammalian model of LV pressure overload, (2) to establish the nature and time course of changes in LV geometry and LV function (systolic and diastolic) in this process, and (3) to determine the effects of long-term angiotensin-converting enzyme (ACE) inhibition on LV geometry and function in the presence of a relatively fixed resistance to LV outflow. We used an anatomically validated transthoracic echocardiographic-Doppler technique to perform longitudinal studies in individual rats with pressure-overload LV hypertrophy (LVH) due to supravalvular aortic stenosis.11
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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All studies described herein were performed according to the guidelines of the American Physiological Society and with the approval of the institutional animal care committee.
Production of the Model
As previously described in our
laboratory, weanling male Wistar
rats (body weight, 60 to 70 g; age, 3 to 4 weeks; Charles River
Breeding Laboratories) were subjected to supravalvular aortic banding
with a 0.58-mm (internal diameter) tantalum clip
(n=74).12 13 14 Control rats
underwent similar surgery;
however, the clip was not placed on the aorta (n=57). Six weeks after
surgery, rats from the LVH cohort were randomized to no treatment or
treatment with fosinopril (50 mg/kg per day, courtesy of Bristol Myers
Squibb). This dose was chosen based on earlier studies showing 72%
inhibition of rabbit lung ACE activity by homogenates of left
ventricles from rats dosed orally for 3 days with
fosinopril.12 Treatment was continued weeks 6 through 18
after banding. Before beginning treatment, a subgroup of rats from each
treatment arm was randomly selected for inclusion in the
echocardiographic study (sham, n=6; LVH, n=10; LVH-fosinopril,
n=12).
Survival data, histological findings, and in vitro assessment of
cardiac function for the entire cohort have been reported
elsewhere.14 Immediately before initiating treatment,
baseline echocardiographic studies were performed.
Echocardiographic-Doppler studies were repeated 12 and 18 weeks after
surgery (after 6 and 12 weeks of treatment). These time intervals were
chosen because prior work showed that increased mortality and LV
dysfunction in the untreated LVH rats were evident by 18 weeks after
aortic banding.14 We were concerned that studies at later
time points would be complicated by the attrition of "sicker"
rats in the untreated group. We also believed that studies before 6
weeks would be difficult due to the small body size of the animals.
Echocardiographic-Doppler Studies
We have recently published
details of our methodology for
performing transthoracic echocardiographic-Doppler studies in
rats.11 This method was anatomically validated, and
intraobserver (2.8%) and interobserver (6.3%) variabilities
were acceptable. Other groups have recently reported similar
experience.15 16 Briefly, rats were lightly
anesthetized with intraperitoneal ketamine HCl (50 to 75
mg/kg) and xylazine (10 to 15 mg/kg). Using a commercially available
echocardiographic machine equipped with a 7.5-MHz transducer
(Hewlett-Packard), a two-dimensional short-axis view of the left
ventricle was obtained at the level of the papillary muscles. M-mode
tracings were recorded through the anterior and posterior LV walls at a
paper speed of 100 mm/s (Fig 1
). Anterior and posterior
wall thicknesses (end-diastolic and end-systolic) and LV
internal dimensions were measured using a modification of the American
Society for Echocardiography leading edge method from at least three
consecutive cardiac cycles on the M-mode tracings.17 The
leading edge of the anterior wall frequently was difficult to identify,
so the inner edge of this wall was used. The M-mode recordings were
analyzed using a commercially available off-line analysis system
(Cardiac Workstation, Freeland Systems) by one of two observers (S.E.K.
or S.E.L.) blinded to prior results.
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LV mass was calculated using a standard cube formula, which assumes a spherical LV geometry. According to this formulation
 | (1) |
where 1.04 is the specific gravity of muscle, EDD is LV end-diastolic dimension, PWT is diastolic posterior wall thickness, and AWT is diastolic anterior wall thickness. We have previously demonstrated a good correlation between LV mass calculated in this manner and postmortem LV mass in rats (r=.78, SEE=0.124, P<.0001).11
Endocardial shortening was calculated as
 | (2) |
where LVDD=LV internal diastolic dimension and LVSD= LV internal systolic dimension. In addition, since the inner half of the left ventricular wall contributes more to total left wall thickening than the outer half, we also calculated midwall shortening. Midwall shortening was calculated according to the two-shell cylindrical model of Shimizu et al.18 This model does not require the assumption that a theoretical midwall circumferential fiber maintains its relative midwall position throughout the cardiac cycle.
Pulsed-wave
Doppler spectra of mitral inflow were recorded from an
apical four-chamber view, with the sample volume placed near the tips
of the mitral leaflets and adjusted to the position where velocity was
maximal and the flow pattern was laminar (Fig 2). Sample
volume was adjusted to the smallest size available (0.6 mm). The left
atrium was then interrogated with pulsed-wave Doppler for the presence
of mitral regurgitation. All Doppler spectra were recorded on paper at
100 mm/s and analyzed off-line as described previously. Measurements
represent the mean of at least three consecutive cardiac
cycles.
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Hemodynamic Studies
Just before they were killed, rats were
anesthetized with
intraperitoneal sodium pentobarbital (50 mg/kg). After adequate
anesthesia was achieved, an incision was made in the midline of the
upper abdomen. The cardiac apex was palpated through the diaphragm, and
a 21-gauge needle attached to a short length of stiff, fluid-filled
catheter was inserted into the LV cavity through the apex. Hemodynamics
were allowed to stabilize for approximately 1 minute, and pressure
tracings were then recorded on a strip chart recorder at a paper speed
of 100 mm/s. Representative pressure tracings are shown in Fig
3. Rats were allowed to breathe spontaneously during the
pressure recordings.
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Estimation of LV Wall Stress
LV meridional wall stress was
estimated using a modification of
previously published methods.19 Briefly, LV pressure was
recorded within 48 hours of the final echocardiogram (as described in
the previous section). LV internal dimensions (end-systolic and
end-diastolic) and LV posterior wall thickness
(end-systolic and end-diastolic) were measured from the
M-mode echocardiogram. LV meridional wall stress was estimated as
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where LVID=LV internal dimension (end-systolic or end-diastolic) and PWT=posterior wall thickness (end-systolic or end-diastolic). This formulation assumes spherical LV geometry and uniform wall thickness.
Calculation of Chamber Stiffness
After in vivo hemodynamic
measurements were completed, hearts
were excised and perfused retrogradely via the aorta with an oxygenated
physiological saline solution maintained at 36°C as previously
described.12 13 14 Coronary flow rate was
adjusted to
achieve a mean coronary perfusion pressure of 110 mm Hg in LVH rats
and 75 mm Hg in sham-operated rats. Previous studies have shown that
this strategy achieves similar flow per gram of LV mass in both groups.
A compliant latex balloon was inserted into the LV cavity through the
mitral valve. After an initial stabilization period of 30 minutes,
during which hearts were paced at a rate of 240 beats per minute, LV
balloon volume was increased from 0.0 to 0.6 mL (in 0.05-mL increments)
or until a diastolic pressure of >35 mm Hg was reached. Two full
pressure-volume relations were recorded for each heart. The second
determination was used for calculation of chamber stiffness. LV chamber
stiffness constants were calculated using previously described
methods.20 21 Briefly, the pressure-volume relation
was
assumed to be monoexponential with the form of
 | (4) |
where P=LV diastolic pressure, A=a modeling constant, e=the base of the natural logarithm, k=the chamber stiffness constant, and v=LV cavity volume (assumed to be the same as balloon volume). Simplifying this equation yields
 | (5) |
and the chamber stiffness constant is the slope of the lnP versus volume relation, which was consistently linear (mean r2=.97±.01). Operating chamber stiffness (kO), or the slope of the pressure-volume relation at the in vivo LV diastolic pressure, was then calculated as
 | (6) |
where LVEDP=in vivo LV end-diastolic pressure.
Statistical Analysis
All values are shown as mean±SEM.
Main effects (group, time and
interaction of group, and time) were tested using a two-factor ANOVA
for repeated measures followed by Fisher's protected least significant
difference test for between-group comparisons. Differences at specific
time points (between groups and within groups) were assessed using
one-factor ANOVA with post hoc comparisons by Fisher's protected least
significant difference test. Correlation coefficients were
obtained using linear regression (the method of least squares). A
probability of <.05 was considered significant.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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No rats died during or within 48 hours of the echocardiographic studies. However, after randomization, 3 of 10 LVH rats and 2 of 12 LVH-fosinopril rats died. Survival data for the entire cohort have been reported elsewhere.14 Those data show improved survival in LVH rats receiving fosinopril compared with untreated LVH rats.
Hemodynamics
In vivo hemodynamic measurements showed
comparable elevations of
LV systolic pressure in untreated and fosinopril-treated LVH rats
compared with the sham group (Table 1). LV
end-diastolic pressure was significantly increased in
untreated LVH rats compared with sham-operated rats but was not
significantly different between fosinopril-treated LVH rats and
sham-operated rats (Table 1). Eighteen weeks after surgery,
estimated
LV systolic and diastolic wall stresses were significantly elevated in
untreated LVH rats compared with sham-operated rats. Systolic wall
stress was lower in fosinopril-treated LVH rats compared with untreated
LVH rats, and diastolic wall stress tended to be lower (Table
1).
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Effects of Untreated LV Pressure Overload
LV Geometry
Six weeks of untreated pressure overload caused concentric LV
hypertrophy characterized by increased wall thickness with normal LV
cavity dimensions (Table 2). Over time, LVH rats showed
progressive LV dilation compared with sham-operated rats, but LV wall
thickness did not change (Figs 1
and 4).
Relative wall
thickness (2xposterior wall thickness/LV diastolic dimension) is an
index relating changes in wall thickness to changes in cavity size. An
increase in relative wall thickness typically defines
"concentric" LVH, while chamber dilation out of proportion to
increases in wall thickness (decreased relative wall thickness) is
termed "eccentric" LVH. Relative wall thickness was markedly
elevated in rats with LVH at 6 weeks after aortic banding, suggesting
that the extent of LV hypertrophy was adequate to prevent chamber
dilation at this time. Relative wall thickness declined over time but
remained elevated even after 18 weeks of severe pressure
overload. LV mass calculated from the M-mode echocardiograms was
significantly increased at baseline and increased progressively over
the course of the study (Table 2).
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LV
Systolic Function
After 6 weeks of LVH, LV chamber function assessed
by conventional
endocardial shortening was hyperdynamic; however, midwall
shortening was mildly depressed at this time point (Table 3 and
Fig 5). With time, chamber function
deteriorated in untreated LVH rats as evidenced by an increase in LV
systolic dimension and a fall in endocardial shortening. Midwall
shortening remained depressed to a similar extent during the duration
of the study. Posterior wall thickening was also depressed after 18
weeks of untreated LVH compared with sham-operated rats (Table
3 and
Fig 1). LV systolic wall stress at 18 weeks was significantly
elevated
in untreated LVH rats compared with shams (Table 1). The linear
relation between endocardial shortening and systolic wall stress for
all three groups of rats (Fig 6) suggests that increased
wall stress contributed to the abnormalities in ejection performance in
the untreated LVH rats at the termination of the study.
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LV
Diastolic Function
At the time of the first echocardiographic-Doppler
study (6 weeks
after surgery), LVH rats already had abnormalities of diastolic filling
(Table 4 and Figs 2 and 7). The
transmitral flow profile revealed a "restrictive" filling pattern
with increased early (E wave) and decreased late (A wave) filling
velocities, an increased ratio of early to late filling velocities,
more rapid deceleration of the early filling wave, and a shortened
isovolumic relaxation time. These abnormalities became progressively
more exaggerated at 12 and 18 weeks (Table 4 and Figs
3 and 7). The
progression of changes occurred with no further increase in LV wall
thickness; however, LV dilation and worsening ejection performance
accompanied these abnormalities. After 18 weeks of untreated LVH, LV
end-diastolic pressure measured in vivo, estimated
diastolic wall stress (Table 1), and operating LV chamber
stiffness
(derived from in vivo LV end-diastolic pressure and the
pressure-volume relation of the isolated perfused hearts; Table
4) were
increased compared with sham-operated rats.
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Effects of Fosinopril Treatment
LV Geometry
LVH
rats were randomly assigned to no treatment or fosinopril
treatment before the first echocardiographic evaluation. Baseline
echocardiograms confirmed similar LV geometry for the two groups as a
whole (Table 2), although 2 rats with aortic banding that were
randomized to no treatment already showed signs of LV enlargement at
this point. Both of these rats survived through the entire 18-week
protocol and showed changes in geometry and function similar to the
rest of the group. Rats from both the untreated LVH and LVH-fosinopril
groups showed increases in LV dimensions between weeks 6 and 12;
however, LV dimension continued to increase in the untreated rats
between weeks 12 and 18, while the LV enlargement was arrested in the
fosinopril-treated rats (Table 2 and Fig 4).
Likewise, calculated LV
mass progressively increased in the untreated LVH rats but did not
increase between weeks 12 and 18 in the rats receiving fosinopril
(Table 2 and Fig 4). There was no change in wall
thickness during the
treatment period in either group. Therefore, the increased mass in the
untreated LVH rats compared with the fosinopril-treated rats resulted
from the greater increase in LV diameter in the untreated group.
LV Systolic Function
Baseline LV posterior wall
thickening was not different between
LVH and LVH-fosinopril rats (Table 3). Between weeks 12 and 18,
posterior wall thickening significantly decreased in the untreated LVH
rats, while this was not observed in the fosinopril-treated rats.
Similarly, LV systolic dimension increased and endocardial shortening
fell in the untreated rats, but these changes were largely prevented by
fosinopril. Midwall shortening was depressed after 6 weeks of pressure
overload in the untreated LVH rats compared with shams, and there was
no change in midwall shortening over time (Table 3 and Fig
5). In
contrast, midwall shortening increased during long-term fosinopril
treatment. Thus, all indexes of LV systolic function showed concordant,
favorable responses to fosinopril. Notably, the beneficial effects on
systolic performance occurred even though in vivo LV systolic pressures
remained elevated to similar levels in both the untreated and
fosinopril-treated LVH rats.
At 18 weeks, LV systolic wall stress was
significantly less in the
fosinopril-treated group relative to the untreated LVH group (Table
1).
The relation between LV wall stress and endocardial shortening for the
fosinopril-treated rats was shifted upward and to the left along the
same regression line determined for all three groups of rats (Fig
6).
LV Diastolic Function
Diastolic
filling abnormalities on the baseline echocardiogram
were more pronounced in the LVH rats randomized to no treatment than
those randomized to fosinopril treatment. These differences
probably occurred because the 2 rats in the untreated LVH group with
early LV dilation also had markedly restricted LV filling by 6 weeks of
pressure overload. The untreated group as a whole showed progressive
worsening of diastolic filling properties with increases in the ratio
of early to late filling velocities (E/A), more rapid E-wave
deceleration, and shortened isovolumic relaxation time. The progression
of diastolic dysfunction was almost completely prevented by
administration of fosinopril. These findings were very consistent with
the observed increase in LV end-diastolic pressure and
operating chamber stiffness in the untreated LVH rats and the
attenuation of these abnormalities in the treated group. LV diastolic
wall stress was not different between sham and fosinopril-treated LVH
rats. The favorable effects on diastolic filling occurred even though
wall thickness remained increased in the fosinopril-treated LVH rats.
For all of the rats, E/A measured on the final Doppler study showed a
strong correlation with calculated LV operating chamber stiffness
(r=.88, P<.0001; Fig 8).
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Discussion |
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The development of "compensatory" LVH in response to pressure overload has been clearly demonstrated by many investigators. Although clinical wisdom has long held that chronic pressure overload of the left ventricle may eventually result in "decompensation" with LV dilation and systolic dysfunction, this has been difficult to demonstrate in experimental models.5 6 Until recently, the lack of suitable animal models has hampered investigation of the events and mechanisms underlying the postulated transition to heart failure. In this study, we performed serial transthoracic echocardiographic-Doppler studies to evaluate LV geometry and function in rats with progressive pressure-overload LVH. Six weeks after aortic banding, we found concentric LVH with normal cavity size and abnormal diastolic filling. LV chamber function was initially hyperdynamic; however, subtle impairment of myocardial function was suggested by analysis of midwall shortening. With time, LV dilation and systolic dysfunction became more evident with abnormalities of both midwall and endocardial shortening. Stress-shortening relations imply that the development of afterload mismatch contributed to the impairment of endocardial shortening. Diastolic filling abnormalities also progressed with time. Long-term treatment with an ACE inhibitor, in a dose that did not lower LV systolic pressure, attenuated the development of LV dilation and improved both systolic and diastolic performance.
Early Pressure Overload
Six weeks after imposition of
supravalvular aortic banding, rats
had normal or enhanced LV chamber function as assessed by endocardial
shortening. However, analysis of midwall shortening suggested that
there was mild myocardial dysfunction at this time. Some investigators
have argued that midwall shortening is a better method than endocardial
shortening for comparing normal and hypertrophied hearts, since the
endocardial portion of the ventricular wall contributes more to wall
thickening than the epicardial portion, and midwall determinations are
less dependent on LV geometry.18 However, this point
remains controversial. A discrepancy between measurements of midwall
and endocardial shortening has been observed previously by Gaasch et
al,22 who reported that in dogs with chronic LV pressure
overload, depressed midwall shortening was detected earlier than
abnormalities of endocardial shortening. Preliminary data also suggest
similar pathophysiology in patients with hypertensive
LVH.23 Thus, the early state of concentric LVH that has
been classically described as "compensated" may in fact be
characterized by mild abnormalities of systolic function that are not
detected using conventional measures of endocardial shortening or
ejection performance. The increased myocardial mass may allow LV
chamber function to be preserved or hyperdynamic despite depressed
myocardial function.
The contribution of increased LV wall stress to the development of impaired shortening in these rats is difficult to determine. It is well known that ejection phase indexes of systolic function, such as endocardial shortening, are sensitive to changes in LV afterload.24 Whether the same holds true for midwall shortening is not clear. Measuring the relation between load and shortening is the best way to distinguish between decreased contractility and afterload mismatch. Unfortunately, it was not feasible to obtain invasive LV pressure recordings (for determination of wall stress) as part of a serial study. The findings of normal LV systolic dimension and preserved endocardial shortening at 6 weeks of untreated LVH suggest that wall stress was normal at that time.
Although abnormalities of LV systolic function were equivocal during the early stages of LV pressure overload (6 weeks), abnormalities of diastolic filling were definitely present. The diastolic filling pattern characterized by increased E/A, shortened isovolumic relaxation time, and rapid deceleration of the early filling wave has been referred to as a "restrictive" filling pattern.25 26 This filling pattern is believed to result in large part from elevation of left atrial pressure. Increased left atrial pressure will have several important effects on LV filling: (1) the mitral valve will open earlier, resulting in shortening of the isovolumic relaxation period; (2) the maximal left atrial–LV pressure gradient may increase, resulting in augmentation of the peak early filling velocity; and (3) LV operating chamber stiffness will increase due to an upward shift along the LV pressure-volume curve.27 The increased LV chamber stiffness will cause more rapid deceleration of the early filling wave and will also tend to reduce the volume of blood transported into the left ventricle for a given amount of pressure generated during atrial contraction. Changes in LV stiffness due to increased wall thickness and/or increased myocardial stiffness resulting from interstitial fibrosis also may contribute to the restrictive filling pattern.
Slowing of the rate of LV relaxation is thought to be the initial manifestation of many pathological states because of the large energetic requirements for transporting free calcium from the cytoplasm into the sarcoplasmic reticulum.4 28 However, an isolated change in LV relaxation has been predicted to result in a markedly different diastolic filling pattern than that observed in the rats with 6 weeks of untreated LVH.25 27 Impaired relaxation alone should cause a decrease in the peak left atrial–LV pressure gradient in early diastole, resulting in a diminution of the peak early filling velocity with compensatory enhancement of the atrial contribution to LV filling (decreased E to A ratio).27 In fact, such a pattern is seen very commonly but not universally in patients with a wide variety of cardiovascular disorders and may occur during normal aging.29 It is possible that a "slow relaxation" filling pattern was present in the rats with LVH at an earlier time point, but by 6 weeks of pressure overload, they had already evolved to a stage of more severe diastolic dysfunction with increased LV chamber stiffness and a resultant restrictive filling pattern.
Many investigators have compared the onset and development of changes in systolic and diastolic functions during LV pressure overload. Aoyagi et al6 found that adult sheep with 4 to 6 weeks of aortic constriction developed evidence of impaired contractility that was load independent. Interestingly, they found no abnormalities of intrinsic diastolic function (time constant of isovolumic relaxation or the myocardial stiffness constant). They therefore concluded that systolic dysfunction precedes any diastolic abnormalities in pressure-overload LVH. In contrast, other authors have reported abnormalities of diastolic function in patients18 30 or experimental animals21 22 31 with pressure-overload LVH. Our findings suggest that diastolic filling abnormalities develop in concert with mild abnormalities of midwall shortening but precede the development of impaired endocardial shortening and increased LV systolic dimension. We believe that there is no point in debating whether systolic or diastolic function changes first. Both systolic and diastolic performances are modulated by ventricular shape and loading conditions and in turn, changes in ventricular function certainly may alter LV geometry and load. The complex system of feedback loops linking myocardial function, reflex changes in the vasculature, neurohumoral activity, LV geometry, and LV load make it unlikely that any event occurs in isolation without constant adjustments in other factors.
Transition to Heart Failure
Between 12 and 18 weeks of
untreated pressure overload, LV
dilation became apparent, endocardial shortening decreased, and there
was progressive deterioration in all parameters of diastolic filling.
These findings provide support for the three-phase hypothetical
construct proposed over 100 years ago by Osler32 : namely,
a period of "development" of hypertrophy followed by a
period of "full compensation" and finally a phase of
deterioration or "broken compensation." In addition, the data
support the proposed evolution of changes in diastolic filling patterns
that may occur during progressive cardiac
decompensation.25
The concept of distinct phases of compensation is somewhat misleading. In the absence of acute insults, the disease progression probably occurs gradually. Even after 18 weeks of pressure overload, the depression of LV systolic function was fairly small. We think it is likely that these abnormalities would have become more dramatic with time. Our intent in this study was to characterize the pathophysiology of the period before there was profound LV dysfunction and myocyte dropout.
While it seems clear that decompensation does occur, the specific changes that initiate the cycle of worsening LV function are far less certain. It has been suggested that hypertrophied myocytes contract and relax abnormally because of altered expression of a variety of genes.4 Increased expression of several oncogenes occurs within minutes to hours after increasing LV load; however, gene expression may return to normal levels in a relatively short time as well.33 Thus, the role of these gene products in the late development of heart failure is tenuous. An abnormal pattern of cardiac gene expression, referred to as the "fetal gene program," is sustained in some models of LVH.13 This fetal phenotype may be characterized by abnormal cellular calcium homeostasis and contractile mechanisms. Accordingly, it is tempting to speculate that myocyte growth will invariably activate the expression of other genes that directly contribute to impaired contractile function. In fact, recent studies from our laboratory show that there is a 50% decrease in expression of sarcoplasmic reticulum calcium ATPase in rats with evidence of heart failure 20 weeks after aortic banding but not at 8 weeks after banding.13 Furthermore, preliminary data obtained using collagenase-dissociated myocytes from hearts 18 weeks after banding suggest depressed contractile function and impaired calcium responsiveness at the cellular level.34 However, it is certainly possible that the altered gene expression is a secondary or even an adaptive response to pressure overload rather than a primary cause of contractile dysfunction.
While depressed LV function may be directly related to myocyte hypertrophy and the associated changes in excitation-contraction coupling, a variety of other factors unrelated to myocyte growth may cause a decline in LV systolic function. For example, gradual changes in neuroendocrine activity (such as local production of angiotensin II, a hormone with potential negative inotropic and lusitropic effects in hypertrophied tissue) might contribute to the progressive alterations in chamber function independent of contractility at the level of the myocyte.12 35 Another possibility is that changes in the cardiac interstitium such as increased collagen deposition may negatively impact on either or both systolic and diastolic functions.36 Along similar lines, myocyte dropout with replacement fibrosis could explain a deterioration of LV function without changes in wall thickness. However, previous studies in our animal model show only trends toward increased interstitial collagen or LV hydroxyproline content.14 A third potential cause for deterioration of cardiac function is the appearance of impaired coronary vasomotor reserve with subendocardial ischemia.37 Endothelial function is abnormal in patients and experimental animals with hypertension or heart failure.38 Furthermore, there is increased susceptibility to ischemic dysfunction in this model of pressure-overload LVH.39
Considering all of the evidence, two major hypotheses to account for the transition to heart failure seem plausible. First, a primary abnormality of contractile function at the level of the myocyte could lead to a decrease in fiber shortening and an increase in LV end-systolic volume. The increased volume would tend to increase wall stress, which in turn might further impair LV ejection performance. Thus, a cycle of worsening systolic function and increasing afterload, each potentiating the other, could be initiated. In support of this theory are the gradual changes in endocardial shortening that were observed (normal at baseline and becoming abnormal between 12 and 18 weeks). In opposition is the reduction in midwall shortening, which appears early and does not change over the course of the study. If contractility does not change with time, a second hypothesis should be entertained, namely, that geometric or shape changes in the ventricle may be the more important determinant of progressive LV dysfunction. According to this alternate scheme, gradual LV dilation would increase wall stress and accordingly impair fiber shortening and ejection. The initial hemodynamic load might stimulate myocyte lengthening or side-to-side slippage, thus resulting in LV enlargement. The resultant increase in afterload might, therefore, be the dominant force causing further LV dilation and dysfunction rather than primary changes in contractility. It seems most likely that some combination of cellular dysfunction and afterload mismatch ultimately causes the deterioration in LV function.
Diastolic properties of the left ventricle also may be involved in the transition to heart failure. Although a restrictive LV filling pattern was noted at 6 weeks, all parameters of LV filling became progressively more abnormal with time. One might argue that this was simply the result of changing LV loading conditions, since E/A is known to be dependent on LV preload. However, our findings of a close correlation between the E/A and operating LV chamber stiffness at the termination of the study suggest that progressive alterations in the passive elastic properties of the left ventricle probably occurred between weeks 6 and 18.
Modification of the Process by ACE Inhibition
Our findings
expand on previous work in which Baker et
al40 reported that ACE inhibition initiated shortly after
abdominal aortic banding in rats blunted the development of LVH without
altering LV hemodynamics.40 Although systemic effects of
ACE inhibitors may be important, the data suggest that part of the
mechanism underlying the improvement in LV function with ACE inhibitors
relates to effects at the tissue level. The importance of a putative
tissue renin-angiotensin system is underscored by our previous
observation that cardiac ACE mRNA levels and ACE activity are
significantly increased in this model of heart failure.12
Further evidence that tissue effects of angiotensin II may be important
comes from recent work showing that AT1 receptor activation stimulated
a hypertrophic growth response in cultured ventricular myocytes where
loading conditions were not a factor.8 Angiotensin II also
may directly influence function at the tissue or cellular level.
Capasso et al35 reported that angiotensin II has
exaggerated negative inotropic effects in myocardium from rats with
postinfarction heart failure. These deleterious effects were blocked by
the specific angiotensin II antagonist losartan. Similarly, Schunkert
et al12 found increased conversion of angiotensin I to
angiotensin II and marked deterioration of diastolic function after
administration of angiotensin I to hypertrophied hearts from rats with
aortic banding. Thus, angiotensin II may stimulate cell growth and
modulate myocyte function. Furthermore, these direct myocardial effects
of angiotensin II appear to be enhanced in the setting of myocardial
hypertrophy or failure.
The beneficial effects of fosinopril on the pressure-overloaded hearts might be explained by mechanisms other than decreasing the intracardiac conversion of angiotensin I to angiotensin II. The reduction in LV end-diastolic pressure in the fosinopril-treated rats could be accounted for in part by a preload-reducing effect of this drug due to increased venous capacitance or decreased blood volume.41 Improvement of myocardial blood flow also could be a possible mechanism to explain the beneficial effects seen in this study.37 Inhibition of interstitial fibrosis by ACE inhibitors would be anticipated to lower LV filling pressures and chamber stiffness.36 Angiotensin II may have a direct toxic effect on myocytes that is prevented by ACE inhibition.42 And finally, chronic ACE inhibition has been reported to have favorable effects on excitation-contraction coupling in failing myocardium.43 Some of the effects of ACE inhibitors may be mediated by inhibiting the breakdown of bradykinin.44 For example, increased bradykinin levels might contribute to afterload reduction or improved myocardial blood flow. Furthermore, bradykinin, like angiotensin II, may directly modulate myocyte growth and function.
Clinical Implications
The findings in this model are
congruent with previous reports of
hemodynamic and echocardiographic assessments of LV structure and
function in patients with valvular aortic
stenosis30 45 46
and serve to confirm much that has been hypothesized based on such
cross-sectional observations. The evolution of changes in LV diastolic
filling observed in our rats is analogous to the changes that are
thought to occur in patients with LV damage or chronic LV
overload25 and documents the relation between LV chamber
stiffness and filling patterns.27 The transmitral Doppler
flow patterns in the untreated LVH rats are remarkably similar to those
described in patients with heart failure, even though rats have heart
rates of 250 to 350 beats per minute. The appearance of the restrictive
diastolic filling pattern has been reported in patients with aortic
stenosis and LV systolic dysfunction,45 has been observed
in virtually all of the patients in a cohort awaiting cardiac
transplantation,47 and has been shown to be a strong
predictor of mortality in patients with cardiac
amyloidosis.48 Thus, this filling pattern is a consistent
finding in heart failure or severe LV dysfunction. This is the first
study to show that chronic ACE inhibition retards the progression of
the restrictive filling abnormalities.
Even with these similarities, is it reasonable to extrapolate our results to patients with aortic stenosis? ACE inhibitors clearly improve survival and LV remodeling in patients with LV systolic dysfunction due to myocardial infarction or dilated cardiomyopathy.49 50 However, clinical wisdom dictates that vasodilating agents should be used with great caution, if at all, in patients with significant aortic stenosis. For this reason, patients with aortic stenosis generally have been excluded from clinical trials using ACE inhibitors, although there are data suggesting that acute systemic administration of nitroprusside is safe and may produce desirable hemodynamic effects in such a population.51 Furthermore, preliminary findings show that acute intracardiac ACE inhibition improves myocardial relaxation and lowers LV end-diastolic pressure in patients with aortic stenosis.52 One factor that may limit the applicability of findings in our rat model to patients with aortic stenosis is the location of the obstructive lesion. In patients with valvular aortic stenosis, peripheral vasodilation may result in coronary hypoperfusion with myocardial ischemia. In our rats, the supravalvular location of the clip may have protected against decreased myocardial perfusion caused by vasodilation. Clinical trials examining the cautious use of ACE inhibitors to prevent deterioration of LV function in normotensive patients with aortic stenosis will be required to address this issue.
The dose of fosinopril used in our study is significantly higher (on a mg/kg basis) than that which would typically be used in patients. However, the dosage of many medications required to produce a certain biological effect in rats is commonly much larger than that which would produce a comparable effect in humans. The dose of fosinopril used in this study resulted in modest (approximately 10 mm Hg) decreases in arterial systolic and diastolic pressures measured using the tail cuff method in our rats.14 Thus, we consider the dose to be roughly bioequivalent to clinically effective dosages in patients.
Recognizing that rats differ in many respects from humans, one may question whether findings in a rat model should be used as a basis for understanding the pathophysiology of or designing treatments for human ailments. In this regard, we note that earlier work describing the effects of ACE inhibitors in rats with postinfarction heart failure53 has subsequently been validated in a number of human trials.49 50
Study Limitations
The method used for estimating LV wall
stress may be limited by
the fact that pressure and chamber geometry were not measured
simultaneously and that peak LV systolic pressure may not coincide
temporally with peak posterior wall thickening measured by
echocardiography. Despite these problems, the comparisons between
the groups are of interest. Using peak LV systolic pressure
as an index of LV afterload is also problematic, since pressure alone
does not take into account the pulsatile components of afterload. It is
possible that the beneficial effects of fosinopril resulted from
dilatation of peripheral resistance vessels that act in series with the
fixed resistance imposed by the aortic clip. Decreased aortic impedance
due to alterations in pulse wave velocity or reflected pressure waves
could theoretically be significant, even with no change in peak
systolic pressure. Interestingly, the lower wall stress in the treated
rats appears to have resulted almost entirely from the prevention of LV
dilation rather than a decrease in LV systolic pressure, as might be
expected if fosinopril caused a significant decrease in resistance to
ejection.
Conclusions
First, our findings show that rats with ascending
aortic banding
imposed at an early age are an excellent model for examining the events
that characterize and the mechanisms responsible for the evolution of
compensated LVH to LV failure. Longitudinal noninvasive studies are
feasible in these animals and may be extremely useful in the assessment
of pharmacological interventions. Second, the early stage of pressure
overload in this model is characterized by preserved or hyperdynamic
chamber function, although there was a mild decrease in midwall
shortening. At that time, there were prominent diastolic filling
abnormalities. LV dilation and impaired endocardial shortening
characterized the later stages of untreated pressure overload. Finally,
the preservation (or lack of deterioration) in LV systolic and
diastolic function with ACE inhibition, despite persistent pressure
overload, suggests that this class of drugs is beneficial and may
function, at least in part, via mechanisms other than relief of
elevated LV systolic pressure. These findings are consistent with the
hypothesis that inhibition of a local renin-angiotensin system in the
heart may contribute to the various beneficial effects that have been
demonstrated with ACE inhibitors.
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Acknowledgments |
|---|
This work was done during the tenure of a Clinician Scientist Award from the American Heart Association to S.E.L. and was supported in part by National Heart, Lung, and Blood Institute Program project grant HL-38189, by an Established Investigatorship of the American Heart Association to B.H.L., by a National Grant-in-Aid from the American Heart Association (B.H.L.), and by an Educational Grant from Bristol Myers Squibb.
Received November 15, 1994; accepted December 13, 1994.
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