Vol. 284, Issue 1, H241-H248, January 2003
Time course of right ventricular remodeling in rats with
experimental myocardial infarction
Matthias
Nahrendorf1,
Kai
Hu1,
Daniela
Fraccarollo1,
Karl-Heinz
Hiller2,
Axel
Haase2,
Wolfgang R.
Bauer1, and
Georg
Ertl1
1 Department of Internal Medicine, 97080 Würzburg; and 2 Department of Biophysics
Experimentelle Physik, University of Würzburg, 97074 Würzburg, Germany
 |
ABSTRACT |
Right ventricular (RV) weight increases
dependent on time after myocardial infarction (MI) and on MI size. The
sequential changes in RV volume and hemodynamics and their relations to
left ventricular (LV) remodeling after MI are unknown. We therefore examined the time course of RV remodeling in rats with LV MI. MI was
produced by left coronary artery ligation. Four, eight, and sixteen
weeks later, LV and RV hemodynamic measurements were performed and
pressure-volume curves were obtained. For serial measurement of RV
volumes and performance, cine-MRI was performed 2 and 8 wk after MI.
The ratios of 
-myosin heavy chain (MHC) to 
-MHC and skeletal to
cardiac -actin were determined for the RV and LV after large MI or
sham operation. RV weight increased in rats with MI, as did RV volume.
RV pressure-volume curves were shifted toward larger volumes 16 wk
after large MI. RV systolic pressure increased gradually over time;
however, the gain in RV weight was always in excess of RV systolic
pressure. The ratios of skeletal to cardiac -actin and -MHC to
-MHC were increased after MI in both ventricles in a similar
fashion. Because RV wall stress was not increased after infarction,
mechanical factors may not conclusively explain hypertrophy, which
maintained balanced loading conditions for the RV even after large LV infarction.
rat heart; magnetic resonance imaging
| |
INTRODUCTION |
MYOCARDIAL
INFARCTION (MI) may induce hypertrophy, dysfunction, and
dilatation of the left ventricle (LV) (2, 20, 24). Previous studies showed that left coronary artery ligation in the rat
produced a broad spectrum of LV dysfunction ranging from minimal
impairment to overt heart failure, depending on infarct size and time
after MI (19, 23). LV and right ventricular (RV)
hypertrophy is observed after large MI in rats (2, 23). RV
dilatation after LV MI was also reported in a clinical setting (9). Little is known about the time course and magnitude
of RV remodeling and its determinants after LV infarction. RV
remodeling might be triggered by changes of LV hemodynamics, but there
may be influences of other factors such as humoral activation as well. The purpose of the present study was therefore to test the hypothesis that RV changes after LV MI are not solely due to RV volume overload caused by LV backward failure. In addition, the value of cine-MRI for
assessment of the RV was tested for the rat MI model. Furthermore, passive pressure-volume curves, which are an established technique for
the LV, were acquired for the RV.
| |
METHODS |
Animals and experimental MI.
Adult male Wistar rats were used, which weighed 269 ± 3 g at
the beginning of the study. Coronary artery ligation was performed as
described previously under ventilation and ether anesthesia (7,
10, 22). The left anterior descending branch was ligated between
the pulmonary outflow tract and the left atrium. A total of 134 rats
were subjected to coronary ligation; 19 rats were sham operated. The
mortality of this procedure was 50%. All procedures were approved by
the institutional animal research committee.
MRI.
MRI was performed 2 and 8 wk after MI on a 7-T BIOSPEC (Bruker) under
inhalation anesthesia applied by nose cone (1.5 vol% isoflurane
supplemented by 0.5 l/min oxygen). An ECG-triggered fast-gradient echo
sequence (FLASH) (8) was used with the following parameters: flip angle 30°, echo time 1.1 ms, repetition time 3.2 ms,
and 12 frames/heart cycle. Eighteen to twenty-two contiguous ventricular short-axis slices of 1 mm thickness with no interslice gap
were acquired to cover the entire range of the ventricles. With a field
of view of 50 mm and an image matrix of 128 × 128, the in-plane
resolution was 390 µm. Data analysis was performed with an
operator-interactive threshold technique by one trained observer as
described previously (18). In all slices, myocardial and
ventricular volumes were determined from end-diastolic and end-systolic
images by multiplication of compartment area and slice thickness (1 mm). Total volumes were calculated as the sum of all slice volumes. LV
mass was calculated as LV end-diastolic myocardial volume multiplied by
the myocardial-specific gravity (1.05 g/cm3). Stroke volume
(SV) and ejection fraction (EF) were calculated with the end-diastolic
(EDV) and end-systolic (ESV) volumes (SV = EDV 
ESV;
EF = SV/EDV). For cardiac output, SV was multiplied by heart rate
(HR). For calculation of time-volume curves to characterize filling
dynamics, all 12 time frames of a single midventricular slice were used
for segmentation of RV and LV slice volume.
RV mass was not determined because the spatial resolution was deemed
insufficient for reliable segmentation of the thin RV wall. However, RV
wall thickness was measured in a midventricular slice and used for
estimation of hypertrophy. Wall thickness was measured in three
segments of the RV wall, and mean wall thickness was measured from
end-diastolic and end-systolic frames and used for calculation of wall thickening.
MI size was determined for every slice as the myocardial portion of the
LV with significant thinning and akinesia or dyskinesia during systole
(18). Relative MI size was calculated by taking the sum of
the endocardial and epicardial circumferences of end-systolic frames
occupied by the MI and dividing by the sum of the total endocardial and
epicardial circumferences (18).
Hemodynamic measurements and pressure-volume curves.
Four, eight, and sixteen weeks after MI, rats were anesthetized with
ether. Cannulas were inserted into the trachea for artificial ventilation, into the right carotid artery and jugular vein, and into a
femoral vein. Pressures were measured through a short segment of
fluid-filled polyethylene (PE)-50 tubing connected to a microtip manometer (Millar). The carotid cannula was advanced into the LV and
then withdrawn to the aortic arch while pressures were recorded. The
jugular vein cannula was advanced into the RV. LV and RV systolic (LVSP
and RVSP) and end-diastolic pressures (LVEDP and RVEDP), the maximum
rate of rise of LVSP and RVSP (LV dP/dtmax and
RV dP/dtmax), mean arterial pressure (MAP), and
HR were measured under light ether anesthesia and spontaneous
respiration. Mean right atrial pressure (RAP) was measured after the
right jugular vein catheter was withdrawn to the right atrium. A flow
probe (2.5 or 3.0 mm; Statham) was placed around the ascending aorta for measurement of aortic blood flow, which was taken as the cardiac index (CI) (22). Systemic vascular resistance index was
calculated as (MAP RAP)/CI and was expressed as millimeters of
mercury per milliliter per minute per kilogram of body weight.
Thereafter, warmed (39-40°C) Tyrode solution was infused into a
femoral vein at a rate of 40 ml · kg
1 · min1
for 45 s (22). Maximum cardiac performance was
defined as peak values of cardiac output and SV during Tyrode infusion.
Ten to fifteen minutes after the volume load, the arterial catheter was advanced into the LV. A second volume loading was applied to determine the peak LVEDP and RVEDP. Passive pressure-volume curves of the LV were
obtained as previously described (6). The heart was arrested by potassium chloride, and a double-lumen catheter (PE-50 inside PE-200) was inserted into the LV via the ascending aorta. The
atrioventricular groove was ligated, and isotonic saline was infused at
a rate of 0.76 ml/min via one lumen while intraventricular pressure was
recorded through the other lumen from negative pressure to 30 mmHg
while the double-lumen catheter in the RV was open. Operating LVEDV was
derived from the LV pressure-volume curve (22, 25) defined
as the volume on the pressure-volume curve corresponding to a filling
pressure equal to in vivo end-diastolic pressure.
For the RV passive pressure-volume curves, a double-lumen catheter was
inserted into the RV via the pulmonary trunk. To isolate the RV from
the venous vessels, the right atrium was excluded by a ligation around
the superior and inferior venae cavas following the right part of the
atrioventricular groove. This procedure results in a sealed tricuspid
valve. Isotonic saline was infused at a rate of 1.55 ml/min via one
lumen while intraventricular pressure was recorded through the other
with an open catheter in the LV. Two pressure-volume curves were
recorded for both ventricles.
PCR.
Total RNA was isolated from surviving LV myocardium (septum) and the RV
free wall of rats with large MI with TRIzol reagent (Invitrogen). After
reverse transcription (SuperScript II, Invitrogen), - and -myosin
heavy chain (MHC) iso-mRNAs and skeletal and cardiac -actin
iso-mRNAs were amplified by PCR as previously described (13) with digoxigenin-labeled forward primers.
After digestion with the restriction enzyme Tru9I for MHC
and SacI for -actin (Roche), fragments of the PCR
amplification product were separated on 8% and 6% polyacrylamide
gels, respectively (lengths: 309 bp for -MHC and 259 bp for -MHC;
202 bp for skeletal and 161 bp for cardiac -actin). DNA fragments
were transferred onto a nylon membrane positively charged (Roche) and
exposed to film suitable for detection of chemiluminescence (Kodak
BioMax Light). The resultant bands on the autoradiograms were then
quantified with NIH Image (version 1.61, National Institutes of Health,
Bethesda, MD), and results were expressed as ratios of - to -MHC
mRNA and skeletal to cardiac -actin mRNA.
Infarct size.
Histological measurement of MI size was performed as previously
described in the hemodynamic groups (22, 31). The hearts were fixed in formalin, embedded in paraffin, sliced in serial sections
from apex to base, mounted, and stained with Sirius red. Infarct size
was determined by planimetric measurement with a digital image system
(Mocha computer digitizing program) and calculated by dividing the sum
of endocardial and epicardial circumferences occupied by the infarct by
the sum of the total endocardial and epicardial circumferences.
Data analysis.
Results are expressed as means ± SD unless otherwise indicated.
Infarcts were classified as small (<35%) and large (>35%). In a
previous serial MR study, 35% has been shown to be the cutoff value
between large MI progressing into heart failure and small MI without
progressive dilatation (19). Total pulmonary vascular resistance (PVR) was calculated as RVSP divided by CI. Precapillary PVR
was defined by (RVSP LVEDP) divided by CI, because pulmonary arterial pressure was not measured. An estimate of RV end-diastolic wall stress was calculated from hemodynamic data as (RVEDP × RV operating volume)/RV weight and from MRI data as RVEDV/RV end-diastolic wall thickness. An estimate of RV systolic wall stress was calculated as RVSP/RV weight.
Statistical comparisons among various groups over time were evaluated
by ANOVA, followed by Duncan test to isolate significance of
differences between individual means. P < 0.05 was
considered to indicate statistical significance.
| |
RESULTS |
Animal numbers, infarct size, body weights, and ventricular
weights.
Histological infarct size was similar 4, 8, and 16 wk after MI, and
therefore comparisons between time points are feasible. The RV
weight-to-body weight ratio (RV/BW) was unchanged in rats with small MI
but significantly increased in rats with large MI over time (Table
1).
MRI.
With cine-FLASH MRI, RV volumes were determined in serial measurements.
LV infarct size was 36% at 2 and 8 wk after MI as measured by MRI. In
a previous study (18), we found the following relation
between MRI and histological determination of MI size: MIhist = 1.1MIMRI + 0.55. With this
equation, a MRI infarct size of 36% as found in the MRI group yields a
theoretical histological MI size of 40% and is therefore in the range
of large infarcts seen in the hemodynamic group.
Typical MR images are shown in Fig. 1. To
cover the entire RV, three to five additional short-axis slices in the
superior direction had to be acquired because the roof of the RV is
shifted cranially compared with the LV (Fig. 1). To prove that the
quality of RV MRI is sufficient for volumetry, LV (LCO) and RV output (RCO) were compared. LCO was not significantly different from RCO (LCO:
118.5 ± 35.3 ml/min, RCO: 127.9 ± 35.7 ml/min; 8 wk after
surgery, n = 21) with significant correlation (LCO = 27.6 + 0.71RCO; R2 = 0.52, P < 0.05).
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Fig. 1.
A and B: long-axis view of a rat
heart 8 wk after large myocardial infarction (MI) in diastole
(A) and systole (B). Note closed aortic valve in
diastolic frame. Arrows indicate thinned scar area. The cranial end of
the right ventricle (RV) is higher than the aortic valve. C
and D: long-axis views of the RV 8 wk after large MI in
diastole (C) and systole (D). E and
F: diastolic (E) and systolic (F)
short-axis slices at the level of the tricuspid valve in a rat 8 wk
after MI. Note closed tricuspid valve in systolic image. G
and H: diastolic short-axis slices at the level of the
papillary muscles in a rat 8 wk after MI (G) and a
sham-operated rat (H).
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|
As shown in Fig. 2, LVEDV and RVEDV
increased from 2 to 8 wk after myocardial infarction. The increase of
RVEDV between 2 and 8 wk was significantly higher in the MI group
[sham: +68.3 ± 39.1 µl (n = 9), MI:
+175.9 ± 65.2 µl (n = 12); P < 0.05] and correlated to infarct size (r = 0.72, P = 0.004). RV end-diastolic wall thickness was
significantly increased only in the MI group (Table
2). Compared with sham-operated rats, RV
EF was lower at 2 wk (Table 2). At 2 wk after MI, RCO was lower than in
sham rats but returned to normal 8 wk after MI. RV wall thickening was
impaired 8 wk after MI.
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Fig. 2.
Left ventricular (LV) and RV end-diastolic volumes (LEDV
and REDV) 2 and 8 wk after MI measured by MRI. Values are means ± SE; n = 9 for sham-operated group and 12 for MI
group.
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|
In rats with large infarction, maximal RV and LV volumes did not occur
at the same time point of the cardiac cycle. Maximal LV and RV slice
volumes were found to be one to two image frames apart from each other
(example shown in Fig. 3). These frames were recalculated into time (individual sampling time for cardiac cycle
divided by number of frames), and the result was a mean delay of peak
RV filling of 11 ± 14 ms at 2 wk and 16 ± 17.5 ms at 8 wk
after MI. In infarcted rats this delay was found to be correlated to
infarct size at 2 and 8 wk (2 wk: r = 0.54; 8 wk: r = 0.66; both P < 0.05) and inversely
correlated to RV EF at 8 wk only (r = 0.54;
P < 0.05, both n = 12). Despite the
desynchronization of RV and LV diastolic filling, end systole was
always coincident. In sham-operated rats no RV delay was observed
(example shown in Fig. 3). MRI parameters of LV remodeling consisting
of LV dilatation and hypertrophy are displayed in Table 2.
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Fig. 3.
Time-volume curves of the midventricular slice in a rat 8 wk after large MI (top) with corresponding cine frames and a
sham-operated rat (bottom). y-Axis is the volume
of the midventricular slice; x-axis is the time after end
systole. In the MI rat, maximal RV filling occurs later than LV maximal
filling. In the sham-operated rat, RV and LV peak filling coincide.
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Hemodynamic measurements.
LVSP and MAP tended to decrease after MI (data not shown). LVEDP
substantially increased in rats with large MI. RAP tended to increase
in rats with MI. In rats with large MI, RVSP increased at 16 wk and RV
dP/dtmax increased at 4 wk after operation but remained unchanged in other groups. RVEDP also did not change in MI
rats (Table 1). Peak LVEDP during volume loading increased in rats with
large MI 8 and 16 wk after operation (not shown), whereas peak RVEDP
remained unchanged (Table 3).
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Table 3.
Peak cardiac performance, total and precapillary PVR, operating
volume/ventricular weight ratios, and RV end-diastolic wall stress
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RV passive pressure-volume curves of rats with small MI remained
unchanged (not shown). A rightward shift toward larger volumes occurred
in rats with large MI at 16 wk (Fig. 4).
Total PVR was increased in rats with large MI 16 wk after operation,
but precapillary PVR did not change after MI (Table 3). RV
volume-to-mass ratio was normal in rats with small MI (not shown) and
shifted to the right 4 wk after large MI but was back to normal 8 wk
after MI (Fig. 5). RV operating volume
increased by trend after large MI. RV end-diastolic wall stress
remained unchanged after MI (Table 3). RV systolic
pressure-to-weight ratio was decreased in rats with large MI 16 wk
after operation (Table 3).
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Fig. 4.
RV passive pressure-volume curves in rats with large MI.
Area between the 2 dotted lines represents the mean ± 2SE of
sham-operated rats (n = 10). Vertical arrows indicate
the baseline RV operating volumes (n = 8 for every time
point). *P < 0.05 vs. sham-operated rats.
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Fig. 5.
RV volume-to-RV weight ratio in rats with large MI
(n = 8 for every time point). Area between the 2 dotted
lines represents the mean ± 2SE of sham-operated rats.
*P < 0.05 vs. sham-operated rats (n = 10).
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LV passive pressure-volume curves showed a rightward shift toward
larger volumes in proportion to MI size and time after MI (not shown).
These data were in good accordance with LV dilatation detected by MRI
(Fig. 2). In contrast to RV volume-to-mass ratio, LV volume-to-mass
ratio was shifted toward larger volumes in proportion to MI size and
over time after MI.
Hypertrophic markers.
The ratio of -MHC to -MHC was significantly higher in rats 12 wk
after large MI in the RV as well as in the LV (sham LV: 0.28 ± 0.02, MI LV: 1.13 ± 0.26, sham RV: 0.17 ± 0.16, MI RV: 1.43 ± 0.34; P < 0.001 MI vs. respective
sham-operated rat). The ratio of skeletal to cardiac -actin was
changed in a similar fashion by myocardial infarction (sham LV:
0.12 ± 0.02, MI LV: 0.41 ± 0.22, sham RV: 0.24 ± 0.05, MI RV: 0.58 ± 0.12; P < 0.001 MI vs.
respective sham-operated rat). There were no significant differences
between the RV and the LV in either ratios. RV -MHC/-MHC correlated to RV/BW (r = 0.96, P = 0.0002) and RV skeletal/cardiac -actin correlated to RV/BW
(r = 0.85, P < 0.005).
| |
DISCUSSION |
In this study, the time course of changes in RV morphology,
function, and hemodynamics after LV MI have been followed for the first
time. Even in rats after large MI, hypertrophy and dilatation remained
balanced, with no increase in wall stress or chronic decline of RV
function. RV volume overload was also not detected. RV diastolic peak
filling was found to be delayed. RV MR volumetry in the rat model of MI
and application of pressure-volume curves for assessment of RV
remodeling proved feasible.
Validity of RV MRI.
MRI, the gold standard for RV volumetry in humans (3, 21,
29), was used for the first time to assess RV changes in a LV
infarct rat model. In this study, RV data were measured from LV
short-axis slices, because a study by Jauhiainen et al.
(12) showed no advantage of different slice angulations in
human cardiac casts for RV volumetry. As shown in RESULTS,
RCO correlates reasonably with LCO. This may serve as evidence that the
quality of RV MRI is sufficient for reliable volumetry in this model. A
higher correlation of RCO to LCO might be achieved in an experimental
setting with more scattering of cardiac output values, for instance, in
a study using rats of different ages.
RV remodeling.
The present study documents a remarkable ability of the RV to
compensate for increased afterload due to LV infarction and dysfunction. RV weight was increased in rats with large MI compared with sham-operated rats and rats with small MI after 8 wk, as was RV
wall thickness shown by MRI. These observations are in good accordance
with previous studies in this model (7, 10, 22, 32).
Consistent with the increase of RV mass, increased ratios of -MHC to
-MHC and skeletal to cardiac -actin were found. Although the
initial injury by ischemia was imposed on the LV, the changes
of hypertrophic markers occurred equally in both ventricles.
Dilatation of the RV was detected by a shift of pressure-volume curves
toward larger volumes. This dilatation was confirmed by serial MRI. In
contrast to LV remodeling (19), RV dilatation seen in rats
with large MI did not result in increased wall stress. The increase in
RV weight over time was greater than the increase in volume. For the
LV, a progressive increase in volume-to-mass ratio was seen, which
stabilized between 8 and 16 wk after MI as previously reported for rats
with this MI size (19). For the RV, this ratio instead
decreased over time. At in vivo RVEDP ("operating volume"), it was
in a normal range for all groups of MI rats at all times (Fig. 4). From
MRI data, an estimation of RV wall stress was calculated by the
quotient RVEDV/RV wall thickness, which was not significantly different
from that in sham-operated rats and did not change from 2 to 8 wk
(Table 2). These data suggest that diastolic wall stress was not
increased and RV volume overload did not occur. This observation is in
accordance with previous reports on regional biochemical changes in the
heart after MI (1, 11, 15). Total creatine kinase was
reduced in the surviving myocardium of the rat LV 8 wk after MI but
normal in RV myocardium (15). It has been suggested that
decreased creatine kinase activity indicates pump failure
(11). Calcium uptake was reduced in the LV 4 and 8 wk
after MI but increased in the RV (1). In contrast,
reprogramming of the isoenzyme pattern of creatine kinase and myosin
and reexpression of atrial natriuretic peptide occurred homogeneously
in both ventricles (15, 17).
Because RV systolic volume, which is sensitive to pulmonary arterial
pressure, was not measured in the hemodynamic group, assumptions about
systolic wall stress remain uncertain (14). RVSP was
increased in rats with large MI 16 wk after operation. Nevertheless,
markedly increased RV weight maintained RVSP-to-weight ratio in the
range of that in sham-operated animals. In addition, at the time when
RV hypertrophy developed, 4 and 8 wk after MI, RVSP was not elevated.
Despite hypertrophy, RV chamber stiffness constants also remained
within a normal range after MI (data not shown), most likely because
changes of mass were in proportion to changes of volume. Accordingly,
RV function was depressed 2 wk after MI (decreased RCO in MRI) but
later returned to adequate levels as suggested by the normal RVSP,
RVEDP, and RV dP/dtmax at baseline and during
volume loading and normal RCO and improved EF at 8 wk after MRI.
Total and precapillary pulmonary vascular resistance [RVSP/CI and
(RVSP LVEDP)/CI] were estimated with RVSP because mean pulmonary artery pressure was not available. The data suggest that an
increase in precapillary PVR was small even in rats with large MI
because RVSP increased by 5 mmHg versus sham-operated rats, whereas
LVEDP increased by 10 mmHg. RVSP was significantly (P = 0.00067) correlated with LVEDP (r = 0.558) at 16 wk
after MI. Thus increased load of the RV was primarily due to increased LVEDP rather than morphological or functional changes of the pulmonary vascular bed. This is somewhat in conflict with previous observations of more or less severe morphological changes of the pulmonary vasculature in rats with MI (5, 32). However, either those observations were made in the presence of excessively high LVEDP (32 ± 2 mmHg; Ref. 32), compared with a rather
chronically compensated LV dysfunction with LVEDP of 14-21 mmHg in
this study, or LVEDP was not measured (5).
LV remodeling.
The ability of the RV to remain in a structural and functional
compensated state was documented in the presence of severe LV
remodeling and dysfunction. MI induced hypertrophy of surviving LV
myocardium, as suggested by the increase of LV mass by 27% from 2 to 8 wk measured in MRI (Table 2). LV dysfunction was characterized by
decreased CI and EF and increased LV filling pressure (LVEDP).
Delay of RV peak diastolic filling.
The capability of high temporal and spatial resolution of MRI enabled
the detection of a delay in RV filling in large MI. It has been found
that there is RV and LV interaction (4, 27, 28) and that
RV diastolic function is affected by LV failure (26, 30),
but a delay of peak filling compared with LV peak filling has, to our
knowledge, not been reported. Some temporal uncertainty is inherent in
our method, because the cardiac cycle was sampled by only 12 frames and
because of timing requirements that limit the acquisition period to
being 5-10 ms shorter than the heart cycle. This led to delays of
peak RV filling of one to two image frames, which were converted into
an actual time delay with the individual interframe spacing of every MR
measurement, which depends on HR. We ensured that this imaging period
always contained both the end-systolic and end-diastolic phases. An
additional problem is that the shape of the ECG signal is regularly
distorted by the high magnetic fields and can therefore not serve as a
landmark. This made further exact interindividual comparison of timing
difficult. However, the described delay could clearly be identified.
Because the delay is correlated to MI size, one could speculate that
high LV filling pressures far exceeding RV diastolic pressures
interfere with RV filling in rats with large MI. Maximal filling might
only be achieved after LV isovolumetric contraction has started.
Whether this phenomenon has a role in the impairment of RV function (as indicated by inverse correlation to RV EF) remains speculative. However, prolongation of diastole with constant HR results in shortening of systole.
In conclusion, the present study shows both LV and RV hypertrophy after
MI. RV diastolic wall stress always remained normal. There was a
correlation between RV weight and RVSP at 16 wk after MI. However, it
is difficult to explain RV hypertrophy by pressure overload alone,
because RVSP was normal during development of hypertrophy. The
inconsistency between hypertrophy and relatively normal RV hemodynamics
suggests that factor(s) independent of volume and pressure overload
contribute to RV hypertrophy in this model, such as activated systemic
and local renin-angiotensin system (16).
| |
ACKNOWLEDGEMENTS |
This work was supported by Deutsche Forschungsgemeinschaft,
Sonderforschungsbereich "Pathophysiologie der Herzinsuffizienz" SFB
355/A8 and B1.
| |
FOOTNOTES |
Address for reprint requests and other correspondence: M. Nahrendorf, Medizinische Universitätsklinik, Universität
Würzburg, Josef Schneider-Strasse 2, 97080 Würzburg, Germany (E-mail:
M.Nahrendorf{at}medizin.uni-wuerzburg.de).
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
First published September 12, 2002;10.1152/ajpheart.00537.2002
Received 28 June 2002; accepted in final form 9 September 2002.
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