(Circulation. 2001;103:1564.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Serial Magnetic Resonance Imaging of Microvascular Remodeling in the Infarcted Rat Heart
From the Medizinische Universitätsklinik (C.W., K.H., M.N., G.E., W.R.B.) and the Physikalisches Institut (K.-H.H., E.K., S.V., A.H.), Universität Würzburg, Würzburg, Germany.
Correspondence to Dr Wolfgang R. Bauer, Universitätsklinik Würzburg, Medizinische Klinik, Josef-Schneider-Strasse 2, 97080 Würzburg, Germany. E-mail w.bauer{at}medizin.uni-wuerzburg.de
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Abstract |
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Background—Alterations in the coronary circulation are important determinants of myocardial function. Few data are available, however, about microvascular changes in reactive hypertrophy. With MRI, serial determination of myocardial microcirculation after myocardial infarction (MI) is feasible.
Methods and Results—We quantitatively determined myocardial perfusion and relative intracapillary blood volume using an MRI technique. Infarct size, myocardial mass, and left ventricular volumes were determined with cine MRI. Rats were investigated at 8, 12, and 16 weeks after MI (mean MI size 24.1±2.0%) or sham operation. Vasodilation was induced by adenosine. In the infarcted group, maximum perfusion decreased significantly from 8 to 16 weeks (5.6±0.3 versus 3.5±0.2 mL · g-1 · min-1, P<0.01) compared with sham animals (5.5±0.3 versus 5.0±0.2 mL · g-1 · min-1, P=0.17). Myocardial mass increased significantly (559.1±20.8 mg at 8 weeks versus 690.9±42.7 mg at 16 weeks, P<0.05) compared with sham-operated animals (516.3±41.7 versus 549.2±32.3 mg). Basal relative intracapillary blood volume increased significantly to 15.7±0.5 vol% at 8 weeks after MI and remained elevated (16.8±0.6 vol%) at 16 weeks compared with 12.1±0.3 vol% (P<0.01) in sham-operated rats.
Conclusions—Our results indicate that significant microvascular changes occur during cardiac remodeling. Hypoperfusion in the hypertrophied myocardium is related to an increase in vascular capacity, suggesting a compensatory vasodilatory response at the capillary level. These microvascular changes may therefore contribute to the development of heart failure.
Key Words: remodeling • microcirculation • magnetic resonance imaging
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Introduction |
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Transmural myocardial infarction (MI) induces hypertrophy and remodeling of the noninfarcted myocardium.1 2 3 Alterations in the myocardial microcirculation are involved in post-MI reactive hypertrophy.4 5 Anatomic studies4 6 found a reduction in capillary surface with myocyte hypertrophy 4 weeks after MI. In vivo studies5 7 indicate that perfusion and vasodilator reserve are depressed in cardiac hypertrophy. The functional significance of these changes in the capillary network of infarcted hearts, however, remains unclear. Data about the simultaneous quantitative determination of myocardial perfusion and intracapillary blood volume in the heart in vivo and serial data evaluation of these parameters during cardiac remodeling are never given.
Recently, a new MRI technique was developed for quantitative determination of perfusion and relative intracapillary blood volume (RBV) in vivo.8 9 The principle of the technique is the detection of intrinsic changes in longitudinal relaxation (T1) during the inflow of arterial blood in the myocardial tissue. By use of this arterial spin-labeling technique, perfusion can be measured noninvasively. RBV is determined from steady-state measurements before and after intravascular contrast agent application. In combination with the MRI method for the measurement of left ventricular (LV) geometry and function,10 serial determination of these parameters is feasible. The aim of the present study was to quantify perfusion and RBV during LV remodeling from 8 to 16 weeks after MI. The parameters were measured in the rat heart at rest and during administration of intravenous adenosine.11
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Methods |
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Infarct Model and Experimental Preparation
Experiments were performed in adult female Wistar rats (Charles River, Sulzfeld, FRG) weighing 250 to 290 g. MIs were produced by left coronary artery ligation by a method described previously.2 Briefly, left thoracotomy was performed after intubation under ether anesthesia. After exposure of the heart, the anterior descending branch of the left coronary artery was ligated. The thorax was instantly closed after the heart was replaced. The mortality of this procedure was 38% within 24 hours after surgical intervention. Sham-operated rats underwent the same surgical procedure but without coronary ligation. For MR measurements, the animals were anesthetized with sodium pentobarbital (Narcoren, Rhone Merieux GmbH; 40 mg/kg IP) and were orally intubated with a home-built tracheal cannula. Artificial ventilation was established with a small-animal respirator (BAS-7025, FMI). The respirator was controlled by the pulse program of the MR spectrometer. Respiration of the animal was automatically stopped during image acquisition to avoid respiratory motion artifacts. The ECG trigger signal was received via foreleg electrodes connected to a home-built ECG unit. Gd-DTPA–albumin was used as intravascular contrast agent and was produced according to a method described by Ogan et al.12 Anesthesia (sodium pentobarbital, 10 to 30 mg/kg IV) and contrast agent were administered via a tail vein. For RBV measurement, each animal received a single bolus injection of Gd-DTPA–albumin in a dose of 0.75 µmol/kg (
0.3 mL). Animals awoke after MR measurement and were
remeasured at 8, 12, and 16 weeks after operation. All experimental
procedures with animals were in accordance with the European regulation
on care and use of laboratory animals.
Image Acquisition
All images were acquired on a 7.05-T Biospec 70/21
spectrometer (Bruker). A specially adapted double probe head for rat
heart measurements was used, including a whole-body coil for
transmission and a circular polarized surface coil as
receiver.13
Quantitative T1 Imaging
T1 images were obtained with an inversion recovery
snapshot fast, low-angle shot (FLASH)
sequence.14 Twenty-four
ECG-triggered snapshot FLASH images were recorded after global or
slice-selective spin inversion. Each snapshot FLASH image (TR=2.25 ms,
TE=1 ms, flip angle 3°, slice thickness 3 mm, field of view
50x50 mm) was acquired within a heart cycle (180 to 200 ms), with
a resulting spatial resolution in plane of 390x780
µm2. A special technique was used to
improve the time resolution of the T1 measurement and to measure T1
values smaller than a heart rate: Two successive ECG-triggered T1
experiments with different delays (varying in steps of 50 to 100 ms)
between the inversion pulse and the first FLASH image were
recorded. For one T1 experiment, 24 snapshot FLASH images were
recorded, so that the total acquisition time for one T1 image was
in the range of 2x24=48 FLASH images (1 to 2 minutes).
Images were obtained in a short-axis slice perpendicular to
the long axis of the heart, which was identified after axial and
long-axis scout views. Infarcted myocardium of the anterior
wall was regularly visible in the imaging slice. Quantification of
perfusion was performed with a slice-selective and a global T1
experiment according to Equation 1
8 :
 | (1) |
9 :
 | (2) |
is the blood-tissue partition coefficient of
water, which is assumed to be 0.95 mL/g for blood-perfused myocardial
tissue.15 Values for
T1blood were obtained from pixels in the LV
heart chamber of T1glob maps. The calculated RBV
has to be corrected by a factor that is determined by the ratio of
hematocrit (Hct) in the ventricle and the capillaries. Because Hct of
the capillary blood is 63% to 75% of the blood of larger vessels, the
ratio is found to be
(1-Hctcapillaries)/(1-Hctventricle)=1.34.16
The corrected RBVc is given
by
 | (3) |
MR Cine Imaging
Imaging was performed with an ECG-triggered fast
gradient echo (FLASH) cine sequence with the following imaging
parameters: flip angle 40°, TE 1.2 ms, TR 4.3 ms, field
of view 30 to 35 mm2, slice thickness
1 mm. The acquisition matrix was 128x128, resulting in a spatial
resolution in plane of 270x310 µm2.
Measurements were performed in the short-axis plane. Acquisition time
for 1 cine image was in the range of 40 to 50 seconds, depending on
heart rate. To increase the signal-to-noise ratio, the images were
averaged 4 times. MR data acquisition was performed in multiple
short-axis images from the apex to the base of the left ventricle with
no interslice gap. Typically, 16 cine images were performed to cover
the whole left ventricle, resulting in a total acquisition time of
15 to 20 minutes.
Image Analysis
Perfusion and RBV
Spatially resolved T1 maps were calculated from the
48 FLASH images of 2 successive inversion recovery snapshot FLASH
experiments. The procedure of this calculation is described in detail
by Deichmann et al.18
In sham-operated animals, a midmyocardial region of interest (ROI)
covering the whole left ventricle was manually delineated (170 to 200
pixels). In infarcted animals, the ROI covered the posterior, lateral,
and septal hypertrophied LV regions, excluding the transient zone
adjacent to the scar (140 to 180 pixels). Mean values for perfusion and
RBV were obtained by averaging the pixel data in the ROI. The right
ventricular wall was eliminated for further evaluation
because of the thin myocardial wall and consecutive partial-volume
effects.
Infarct Size, Myocardial Function, and
Myocardial Mass
Quantitative analysis of MR infarct size and
myocardial mass and function was performed by a method described by
Zierhut et al.19 Briefly,
infarct size was expressed as the ratio of scar length to total
circumference determined by manual delineation of epicardial and
endocardial borders of scar length and total circumference of each cine
image. Histological studies have reported that the
summation of these length measurements approximates the surface of the
infarcted area.2 Scar was
easily identified in the MR images by changes in myocardial wall
thickness from scar to hypertrophied tissue. For LV mass measurement,
epicardial and endocardial borders of all slices were delineated, and
the mass was defined as the volume within the borders multiplied by a
factor of 1.05, which represents the myocardial specific
density (g/mL). The papillary muscles were included in the traced area.
Absolute cavity volumes were calculated in end diastole
(EDV) and end systole (ESV) as the sum of all blood pool areas. Stroke
volume (SV) was calculated from
SV=EDV-ESV.
Experimental Protocol
MR perfusion, RBV, and cine imaging were performed on
12 infarcted animals (group 1). Ten sham-operated animals served as
controls (group 2). Animals were measured 3 times at 8, 12, and 16
weeks after operation. At each time point, a measurement protocol was
observed, as follows: (1) cine imaging, (2) perfusion at rest, (3)
adenosine, (4) perfusion under adenosine, (5) RBV under
adenosine, (6) withdrawal of adenosine, and (7) RBV at
rest. Animals received adenosine in a continuous dose of 2.5 to
3
mg · kg-1 · min-1.
It was recently shown that this dose leads to a maximum vasodilatory
response9 20
without critical bradycardia. At 16 weeks, a final
hemodynamic measurement of groups 1 and 2 was performed
after MR measurement. Because of the serial character of the study, 2
additional groups (groups 3a and 3b) were needed for
hemodynamic studies at 8 and 12
weeks.
Hemodynamic Studies
A terminal hemodynamic study was
performed 16 weeks after sham operation or coronary artery
ligation. In addition, hemodynamic studies were
performed in a group of 16 animals with 8-week-old MI (n=8, group 3a)
and 12-week-old MI (n=8, group 3b). Rats were prepared as described
above. A polyethylene catheter (Portex) connected to a Millar
micromanometer (Millar Instruments) was used to
measure mean aortic pressure and heart rate.
Hemodynamic data were recorded at rest and during
infusion of adenosine as in the experimental setup of groups 1
and 2. Coronary resistance (CR) was determined from the mean
aortic pressure of group 3 and perfusion data of group 1 according to
CR=mean aortic pressure/perfusion. Infarct size determination of the
additional group was determined histologically
according to the method described by Pfeffer et
al.2
Statistical Analysis
The data are expressed as mean±SEM. Statistical
tests were evaluated by ANOVA (InStat, GraphPad). Significant
difference was determined by the Bonferroni test. The probability level
of statistical significance was
P<0.05. Correlation
coefficients were computed by a least-squares linear regression
analysis.
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Results |
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Perfusion and RBV
Perfusion and RBV maps of a representative animal of group 1 (MI 22.4%) at rest and during administration of 3 mg · kg-1 · min-1 of adenosine are shown in Figure 1
, a through d. Corresponding maps of perfusion and
RBV of an animal of group 2 at rest are illustrated in
Figure 1, e and f. Images were generated 8 weeks after
induction of MI. The scar tissue, LV dilation, and
hypertrophy of the noninfarcted myocardium are
visible. All animals developed MI in the size range of 10% to 35%
(mean 24.1±2.0%) of the LV area. Data of myocardial perfusion and RBV
of the infarcted (group 1) and the sham-operated (group 2) animals
during this time are demonstrated in
Figures 2 and 3. Perfusion in surviving
myocardium decreased significantly
(P<0.01) from 8 to 16 weeks
compared with the sham-operated animals. Coronary reserve was
reduced significantly at 16 weeks after MI
(P<0.01) compared with 8 weeks
after MI
(Figure 2). Basal RBV in surviving myocardium was
increased significantly at 8 weeks after MI
(P<0.01) and remained elevated
during the observation time, whereas maximum RBV during
adenosine was the same in the MI and the sham-operated groups
(Figure 3).
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MR Myocardial Mass and Functional
Parameters
Data for LV mass and volumes of the infarcted group and
the sham-operated animals are summarized in
Table 1. There was no significant change in body
weight with time or with respect to the sham-operated animals at each
time point. LV mass of the infarcted animals of group 1 increased
significantly from 8 to 16 weeks after MI
(P<0.05). LV mass of the
sham-operated animals at 16 weeks was significantly lower
(P<0.01) than the values of
the infarcted animals. LV volumes remained elevated compared with their
respective noninfarcted controls
(P<0.001) and did not increase
further with time from 8 to 16 weeks. LV weight–to–body weight ratio
(mg/g) relative to changes in RBV and perfusion of group 1 are
illustrated in
Figure 4. Perfusion at rest and during adenosine
decreased significantly
(P<0.01) with increasing
relative LV heart weight, whereas RBV at rest and during
adenosine showed no significant change. LV weight–to–body
weight ratio of the sham-operated group was 1.66±0.09, 1.64±0.08, and
1.74±0.09 mg/g at 8, 12, and 16 weeks, respectively. Linear regression
analyses of relative heart weight and CR at rest and during
adenosine are shown in
Figure 5. A significant correlation
(P<0.001) was found between
the 2 parameters.
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Systemic Hemodynamics
Hemodynamic data of group 1 (16 weeks
after MI), group 2 (16 weeks after sham operation), group 3a (8 weeks
after MI), and group 3b (12 weeks after MI) at rest and during
adenosine are shown in
Table 2. In all groups, mean aortic pressure and heart rate
decreased significantly
(P<0.001) during
administration of adenosine and returned to resting values
after drug study. The decrease of arterial blood pressure
and heart rate remained constant during the observation
time.
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Discussion |
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Methods
Although hemodynamic and geometric parameters during LV remodeling have been studied extensively,21 22 only a few methods focus on alterations of the microcirculation during this process. The "gold standard" to determine perfusion in the heart is based on the application of microspheres. This method is invasive, however, and serial measurements during cardiac remodeling are not feasible. Myocardial blood volume may be determined by morphometric techniques or from radioactive labeling of red blood cells.23 24 Unfortunately, the 2 methods cannot be used for longitudinal studies in the same animal because of ex vivo data evaluation. By echocardiography25 or CT imaging,26 myocardial blood volume can be determined after bolus injection of a contrast agent. Because of the underlying first-pass imaging technique, however, repeated measurements under steady-state conditions are not possible.
We recently developed a non–contrast agent–based MR technique to measure myocardial perfusion.8 This method has been validated by the microsphere technique for the isolated rat heart and for in vivo studies.9 27 In addition, we evaluated MRI of the RBV with an intravascular contrast agent.13 These data showed a favorable correlation with data for RBV obtained by the MR first-pass technique.28
Because of the serial character of this study, simultaneous invasive determination of blood pressure is not possible at each time point. Therefore, we introduced reference groups with comparable infarct sizes for the measurement of blood pressure at baseline and after vasodilation at 8 and 12 weeks after the induction of MI. This allowed calculation of derived parameters as CR.
Perfusion During LV Remodeling
At 8 weeks after MI, baseline perfusion was slightly
elevated, whereas the maximum perfusion was comparable to control
animals. In the following period (12 and 16 weeks) of remodeling,
baseline and maximum perfusion declined significantly
(Figure 2
). Because blood pressure was not significantly
different between the sham-operated and the infarcted animals of group
1
(Table 2), this decrease is due to an increase in CR. In
contrast to our findings, Karam et
al4 observed an increase of
myocardial baseline perfusion, mainly due to a reduction of CR, whereas
maximum perfusion was lower and minimum CR higher than in control
animals. Those authors, however, performed measurements 4 weeks after
infarction, whereas the decrease of baseline perfusion in our study was
observed from 12 weeks on after MI. CR is affected by vascular and
extravascular factors.29
Karam et al4 found a
significant increase in minimum CR, which was related to reactive LV
hypertrophy. The positive correlation between CR and
relative heart weight
(Figure 5) and the time course of both parameters
in our study suggest that parameters that are related to
myocardial hypertrophy may explain the elevation of
baseline and minimum CR. Our values of an increase in LV diameter and
relative heart weight are in good accordance with data of Pfeffer et
al30 for animals with small
MI size. Structural alterations of the resistance vessels, eg,
increased total arteriolar length or arteriolar wall
thickening,31 may be
responsible for this increase in CR.
RBV During LV Remodeling
RBV at baseline is elevated in residual
myocardium of post-MI hearts, whereas the RBV after
vasodilation does not differ from that of control hearts. In contrast
to myocardial perfusion, baseline and maximum regional blood
volume (RBV) remain almost constant during the observation time.
This implies that the increase in baseline RBV must have occurred
earlier than 8 weeks after MI. This elevation of RBV may be considered
as a compensatory mechanism at the capillary level to an increased
workload of the residual myocardium due to LV dilation.
Olivetti et al3 found a
preservation of the volume percent of capillaries within the surviving
myocardium as a result of an increase in capillary diameter
that compensated for the reduction of capillary density. This was found
also for hearts with small MI size and is congruent with our
observation when we relate the morphometric RBV to our maximum RBV
data. Other
groups1 32 have
described that insufficient vascular growth relative to myocyte
hypertrophy results in a vasodilatory response of
microvessels to maintain tissue oxygen needs due to
hypertrophy. Our results indicate that the RBV is
independent of changes in CR during cardiac remodeling, because RBV at
rest and during hyperemia remains constant over time, whereas
CR increases.
Our study has shown that significant adaptation of the myocardial microcirculation in hearts with small MI size occurs during LV remodeling. We found significant hypoperfusion from 8 to 16 weeks after MI with increasing CR and an increase in vascular capacity, suggesting a compensatory vasodilation at the capillary level. Our results suggest that microvascular remodeling due to myocyte hypertrophy may play an important role in the development of heart failure also in patients with chronic MI.
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Acknowledgments |
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This work was supported by grant SFB 355 and Graduiertenkolleg 178 NMR 178 HA 1232/8-1 of the Deutsche Forschungsgemeinschaft and of the Forschungsfonds der Universitätsklinik Mannheim/Heidelberg (Projekt 42). The authors gratefully acknowledge the dedicated work of T. Lanz, A. Weisser, and E. Rommel. The authors also thank F. Wiesmann for help with the experimental preparation.
Received May 15, 2000; revision received September 8, 2000; accepted September 22, 2000.
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 M. Nahrendorf, K.-H. Hiller, D. Theisen, K. Hu, C. Waller, R. Kaiser, A. Haase, G. Ertl, R. Brinkmann, and W. R. Bauer Effect of Transmyocardial Laser Revascularization on Myocardial Perfusion and Left Ventricular Remodeling after Myocardial Infarction in Rats Radiology, November 1, 2002; 225(2): 487 - 493. [Abstract] [Full Text] [PDF]
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