(Circulation. 1999;99:448-454.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Magnetic Resonance Imaging and Invasive Evaluation of Development of Heart Failure in Transgenic Mice With Myocardial Expression of Tumor Necrosis Factor-
From the Departments of Radiology (F.F., R.M.P.), Internal Medicine (G.D.T., R.G.V., R.M.P.), and Pediatrics (B.G., D.B., R.M.P.) at the University of Texas Southwestern Medical Center at Dallas and the Department of Electrical Engineering (M.C.B., M.C.C.), University of Texas at Arlington.
Correspondence to Ronald M. Peshock, MD, Mary Nell and Ralph B. Rogers Magnetic Resonance Center, University of Texas, Southwestern Medical Center, 5801 Forest Park, Dallas, TX 75235-9085. E-mail rpesho{at}mednet.swmed.edu
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Abstract |
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Background—Transgenic mice expressing tumor necrosis factor-
(TNF-) in cardiac myocytes
develop dilated cardiomyopathy, but the temporal
progression to cardiac dysfunction is not well characterized. We asked
(1) Does magnetic resonance imaging (MRI) provide a reproducible
assessment of cardiac output in mice that correlates with invasive
measurements obtained with thermodilution? (2) What is the time course
of left ventricular (LV) remodeling in transgenic mice with
myocardial expression of TNF-?
Methods and Results—Transgenic mice from 2 different lineages
with differing amounts of myocardial TNF- expression [lineage 1
(L1) and lineage 2 (L2)] and littermate controls (LC) were studied. In
protocol 1, cardiac output (CO) and stroke volume (SV) were measured by
MRI and thermodilution (TD) in 15 mice (3 L1, 4 L2, 8 LC). In protocol
2, 23 mice (7 L1, 8 L2, 8 LC) were scanned at 1 month of life and every
4 weeks thereafter. In both protocols, cine-MRI was performed with the
use of a 1.5-T clinical system (1.5-mm slices, 195x195 µm
in-plane resolution). MRI CO and SV correlated well with TD
[COTD (mL/min)=0.94*COMRI+0.72,
r=0.84;
SVTD(µL)=1.01*SVMRI-1.07,
r=0.94]. Serial MRI studies showed significant increase
in LV mass and volumes over time and a significant decrease in ejection
fraction in transgenic mice when compared with littermate controls.
Compared with lineage 2, lineage 1 showed significantly larger LV mass
and volumes and significantly lower ejection fraction.
Conclusions—MRI assessment of cardiac function in mice correlates
well with invasive measurements. Serial MRI studies in the TNF-
mouse model demonstrate that the rate of progression and severity of LV
dysfunction are dependent on the degree of TNF- overexpression.
Key Words: heart failure • systole • magnetic resonance imaging • cardiac output
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Tumor necrosis factor-
(TNF-) is a multifunctional
cytokine detected in several human cardiac-related conditions,
including congestive heart failure.1 2 There is increasing
evidence that cardiac expression of TNF- may be a common response to
different types of cardiac stress.3 4 5 However, the role
played by TNF- in the development and progression of
ventricular dilatation and cardiac decompensation is not
known.
Recently, a transgenic mouse model has been developed in which TNF-
is overexpressed specifically in the myocardium, resulting
in dilated cardiomyopathy and cardiac
failure.6 7 A method that permits longitudinal evaluation
of structure and function in individual animals would be of value to
define the phenotypic consequences of TNF- overexpression. However,
repeated, reproducible assessment of in vivo cardiac function in mice
remains a challenge. It requires a technique that is easily available
to the molecular biologist and accurate enough to detect minimal
changes.
Recently, magnetic resonance imaging (MRI) has emerged as a highly
accurate and quantitative tool for the evaluation of cardiac
function.8 However, the application of MRI to study
cardiac function in the mouse has been limited to very high-field
magnets with imaging gradients that are not widely
available.7 9 In addition, studies evaluating the accuracy
and reproducibility of MRI in the quantification of systolic
function in the mouse model are lacking. Recently, we developed and
validated a highly accurate and reproducible MRI technique at 1.5 T for
estimating left ventricular (LV) mass in a transgenic mouse
model of cardiac hypertrophy.10 In the
present study, we asked (1) Does MRI provide a reproducible
assessment of cardiac output in mice that correlates with invasive
measurements obtained by thermodilution? (2) What is the time course of
LV remodeling in transgenic mice with heart failure in the setting of
overexpression of TNF-?
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Study Population
Two groups of mice were studied. The first group consisted of 15 C57BL/6JXJL/J mice (7 transgenic and 8 wild-type). The second group consisted of 23 C57BL/6JXJL/J mice (15 transgenic and 8 littermate controls). The transgenic mouse model of heart failure was produced as previously described.6 From the initial founders, 2 lineages with different levels of transgene expression were created. Cardiac TNF levels were 4 times greater in lineage 1 than in lineage 2.6 Lineage 1 develops severe, rapidly progressive heart failure with near 100% of mortality by the fourth month of life and lineage 2 has only moderate impairment of cardiac function with survival up to 9 to 12 months. Transgenic animals were otherwise phenotypically normal at birth and remained so until the onset of heart failure. All animals were used in accordance with the guidelines of the University of Texas Southwestern Medical Center Animal Care and Research Advisory Committee and in compliance with the rules governing animal use, as published by the National Institutes of Health.
Study Design
Two separate studies were performed. In protocol 1, noninvasive
MRI and invasive thermodilution measurements of cardiac output and
stroke volume were compared in a cross-sectional study of 15 mice (3
from lineage 1, 4 from lineage 2, 8 wild-type controls). After surgery,
MRI was performed followed by thermodilution measurements.
In protocol 2, 23 mice (7 from lineage 1, 8 from lineage 2, and 8 littermate controls) had serial MRI studies for evaluation of LV function. All mice were imaged at 4 to 6 weeks of age and every 4 weeks thereafter. Animals were weighed before MRI and anesthetized with serial intraperitoneal injections of Avertin (2.5% tribromoethanol and 0.8% 2-methyl, 2-butanol in water). The end point for this longitudinal study was premature death or 6 months of follow-up. To test the reproducibility of the MRI technique, a subgroup of mice including 2 transgenic and 3 wild-type were imaged twice in the same day and during 2 consecutive days.
Cardiac Output Measurement by Thermodilution
Mice studied in protocol 1 were weighed and then
anesthetized with a combination of Telazol (a 1:1
combination of tiletamine HCl and zolazepam HCl; 7.5 mg/kg IM) and
xylazine (20 mg/kg IM) with atropine (0.5 mg/kg SC) to prevent
excessive tracheal secretion. Mice were placed on a heating pad
(temperature 35 to 37°C), and a PE-10 catheter was inserted into the
right external jugular vein and advanced to the right atrium. A
thermocouple in a 1F catheter (outer diameter 0.49 mm) was
inserted into the right carotid artery and advanced to the aortic arch.
The thermocouple was attached to a cardiac output computer (Cardiotherm
500, Columbus Instruments), and the venous catheter was attached to an
automatic injector (Micro-Injector 400, Columbus Instruments) primed
with 0.9% NaCl at 15°C. Probe placement was checked by a test
injection. The mice were allowed to stabilize for 15 to 20 minutes and
then were taken to the MRI scanner.
Immediately after MRI, the mouse was taken out of the scanner and thermodilution measurements were performed. Cardiac output was measured by monitoring the change in the temperature of the blood in the aortic arch after venous injection of cold (15°C) saline (18 to 25 µL). Dilution curves were recorded on a chart recorder, and cardiac output values were displayed automatically by the computer. For each mouse, 4 to 6 cardiac output measurements were performed at intervals of 1 minute. On completion of the experiment, the mice were euthanized with sodium pentobarbital. Venous catheter and thermocouple placements were verified after each study by postmortem examination.
Magnetic Resonance Imaging
The imaging sequences were the same for protocols 1 and 2. MRI
was performed with the use of a 1.5-T scanner (Philips NT). The mouse
was positioned supine on a Petri dish, and ECG leads were attached to
both front and hind paws. The leads from the standard clinical ECG
probe were attached to a home-built amplifier to amplify ECG signal for
detection by the clinical gating software on the magnetic resonance
system. A surface coil (4x8 cm) was placed over the animal's chest
and used for imaging. Multislice, multiphase, cine-MRI was performed as
previously described.10 Four or five slices perpendicular
to the long axis were obtained for each heart, spanning apex to base.
The slice thickness was 1.5 mm, with a 0.2 mm gap between
slices. The matrix was 256x256, with a field of view of 50 mm
(yielding voxel sizes of 0.19x0.19x1.5 mm), flip angle of
30 degrees, repetition time of 39 ms, and echo time of 14 ms.
Data Analysis
Image Analysis
The frame with the largest chamber dimensions was used as the
end-diastolic image and the smallest as
end-systolic image. For LV volume determinations, the
endocardial border was identified by hand and volumes calculated by
summation:8
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Stroke volume was calculated as (SV=LVEDV-LVESV) and ejection fraction as (EF=SV/LVEDV). Cardiac output was computed as (CO=SVxHR), where the HR was the average heart rate during the scan. LV mass was estimated as described previously.10
Thermodilution Analysis
Cardiac output by thermodilution was determined as the average
of the measurements obtained in each mouse. Stroke volume was
calculated as (SV=CO/HR), where HR was the average heart rate during
the thermodilution measurements.
Statistics
Data are expressed as mean±1 SD.
The cardiac output and stroke volume measurements obtained by thermodilution were compared with those measured by MRI with a 2-variable linear regression analysis. A Bland-Altman analysis was performed to examine the agreement between the thermodilution and MRI measurements methods.11
Interobserver, intraobserver, and interstudy variability were calculated as previously described.10 LV mass, volumes, and ejection fraction from transgenic and control mice were assessed for differences at each time point with a 2-tailed, unpaired t test. The changes in LV mass, volumes, and ejection fraction over time for each group were analyzed with a random-effects ANOVA test.12 A Bonferroni adjustment was used to account for multiple comparisons.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Protocol 1: Thermodilution and MRI Measurements of Cardiac Output and Stroke Volume
The mean age of the 15 mice was 5.1±2.0 months (range 1 to 10 months) and mean body weight was 29.9±4.9 g (range 19.8 to 38 g). The mean heart rate was 356±42 bpm (range 260 to 420 bpm) during MRI and 361±44 bpm (range 260 to 420 bpm) during the thermodilution measurements (P=NS).
Cardiac output by thermodilution ranged from 9.3 to 19.2 mL/min (mean
13.4±1.7 mL/min) and by MRI 10.8 to 17.5 mL/min (mean 13.5±1.5
mL/min). Stroke volume by thermodilution ranged from 22 to 58 µL
(mean 38±8 µL) and by MRI ranged from 26 to 58 µL (mean 39±8
µL). Figure 1
shows a typical
thermodilution curve obtained during the study. As shown in Figure 2, there was a good correlation between
thermodilution and MRI measurements of cardiac output
(r=0.84) and stroke volume (r=0.94). Bland-Altman
analysis also demonstrated good agreement between
thermodilution and MRI measurements of cardiac output and stroke
volume. The limits of agreement (defined as ±2 SD from the mean
difference) between the measurements obtained with the 2 methods are
shown in Figure 3.
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Protocol 2: Serial Evaluation of LV Systolic Function in
Transgenic Mice and Controls by MRI
MRI was performed in 23 mice at the first month of life and every
4 weeks thereafter. There was excellent reproducibility of magnetic
resonance measurements with low intraobserver (3±1%) and
interobserver (7±6%) variability. The interstudy variability for LV
end-diastolic volume (LVEDV), LV end-systolic
volume (LVESV), and LV ejection fraction (LVEF) was 6.1±3.6%,
5.2±3.2%, and 3±2.6%, respectively.
Figure 4 shows short-axis views in
diastole and systole in transgenic mice from lineages 1 and
2 and a littermate control at age 1 month and 3 months. Mean body
weight, heart rate, stroke volume, and cardiac output for all mice are
detailed in Table 1. The average
values for LV volumes, LVEF, and LV mass at each time point, in both
lineages and littermate controls, are given in Table 2.
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There was a significant increase in LVEDV and in LVESV in both lineage
1 and lineage 2 compared with controls (P<0.0001 for each
variable) over time. LVEF was significantly lower in both lineages
1 and 2 compared with controls (P<0.0001). LV mass was
significantly increased in lineage 1 but not in lineage 2 when compared
with controls (P<0.0001 versus P=0.18). There
were no significant differences in stroke volume over time in lineage 1
and lineage 2 versus control mice. However, there was a significant
decrease in cardiac output in mice from lineage 1 compared with
controls (P<0.02). Figure 5
illustrates the progression of LV volumes and ejection fraction for
transgenic and wild-type mice.
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), lineage 2 (
), and littermate
controls (
) are shown.There was a significant increase in LV mass and end-systolic volume over time in lineage 1 as compared with lineage 2 (P<0.0001 for each variable). There was also a decrease in ejection fraction over time in lineage 1 as compared with lineage 2 (P<0.0008).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The results of this study indicate that (1) there is a good correlation between MRI and the thermodilution method in measuring cardiac output and stroke volume, (2) MRI is an accurate technique with low interstudy variability and thus well suited for longitudinal studies of cardiac size and function; and (3) in the TNF-
transgenic
model of heart failure, the rate of progression and severity of LV
dysfunction are dependent on the degree of TNF- overexpression.
Noninvasive Assessment of LV Systolic Function in
Mice
Serial reliable measurements of LV function to noninvasively track
cardiac function would be useful in evaluating the development of heart
disease in transgenic mouse models.
Echocardiography has been used to evaluate LV
function in mice.13 14 However, these studies have not
been validated against an independent measurement. Further, the
quantification of LV volumes by 2-dimensional
echocardiography is generally based on geometric
models of the left ventricle.15 With congestive heart
failure geometry may change, limiting the applicability of a specific
model. Although Doppler techniques have been applied with some
success to evaluate LV function in mice,16 Doppler
measurements of cardiac output and stroke volume are highly dependent
on accurate measurements of aortic diameter and also require that the
Doppler beam is oriented parallel to flow.
MRI has proven to be a highly accurate and reproducible technique8 for evaluation of ventricular function and myocardial mass both in animal studies17 and in humans.18 19 MRI provides a volumetric, 3-dimensional evaluation of the LV and does not rely on geometric assumptions. Recently, using a widely available clinical MRI system (1.5 T), we developed an MRI method to estimate LV mass that was validated by necropsy.10 Our present study indicates that this approach can be extended to the quantification of LV volumes and ejection fraction in mice.
Independent Confirmation of MRI by Thermodilution Method
One problem in performing in vivo validation of MRI measurements
of LV volumes in mice is determining an appropriate reference standard.
Cardiac output measurements may be obtained in mice with open-chest
surgical techniques by placement of a flow probe on the ascending
aorta. However, the surgery is difficult and results in significantly
depressed hemodynamics and force-frequency relations
when compared with closed-chest preparations.20
Although microsphere techniques have been used to assess cardiovascular hemodynamics in conscious mice,21 studies with microspheres are technically demanding and permit only a limited number of measurements of cardiac output. This method requires a significant blood withdrawal, leading to eventual hemodynamic degradation and preventing an adequate comparison with the cardiac output measurements obtained from MRI.
The indicator-dilution method has been used as a reference for cardiac output measurements in humans, large animal models,22 and more recently in mice.23 The thermodilution method, in which a bolus of chilled water is the indicator, has been applied widely in patients and animal models including rats.24 25
Several features of thermodilution make it a reasonable approach for use in the setting of MRI. First, the surgery can be performed quickly (15 to 20 minutes) with minimal blood loss. Second, the venous catheter and thermoprobe can be inserted before the MRI and the mouse stabilized so that measurements by MRI and thermodilution can be done under similar hemodynamic conditions. Third, the measurements can be repeated as required without adverse effects.
Our results show an excellent correlation between MRI and thermodilution across a wide range of stroke volumes. In addition, the Bland-Altman analysis shows no major bias between the thermodilution and MRI methods. Furthermore, the values for cardiac output that we obtained both with MRI and thermodilution are within the ranges previously reported in mice by investigators using a variety of measurement techniques.23
Serial Evaluation of LV Systolic Function in TNF- Model
of Heart Failure by MRI
Multiple clinical observations have reported an increase in the
plasma levels of TNF- in patients with congestive
cardiomyopathy,1 2 3 and there appears
to be a direct relation between disease severity and circulating levels
of TNF-.26 Recently we have shown that myocyte
production of TNF- is sufficient to produce severe
myocarditis in mice that results in myocardial dysfunction and cardiac
failure.6 Survival in these transgenic animals in
2 different lineages was related to the amount of TNF- expressed in
the myocardium. However, the progression of
ventricular remodeling and dilatation related to the
overexpression of TNF- in the myocardium was not
examined.
The MRI assessment of LV volumes and ejection fraction over time
demonstrated the development of LV dysfunction in transgenic mice when
compared with littermate controls. Several lines of evidence support a
causal relation between the myocardial expression of TNF and
ventricular dilatation with pump dysfunction: First, the
secretion of TNF- in this mouse model begins
perinatally,6 and our data show that a significant
difference in LV ejection fraction is present in the first month of
life in both lineages compared with wild-type mice. Second, the degree
of overexpression of TNF in transgenic mice correlates with the
severity and rate of development of disease. In mice from lineage 1, in
which the amount of TNF determined in the myocardium is 4
times greater than in lineage 2,6 ventricular
dilatation and dysfunction were more severe. In addition, the serial
measurements of volumes and function in this study clearly show a
progressive increase in LV volumes and deterioration in
systolic function over time that is significantly different
between the 2 lineages. Also, interindividual variability observed in
LV volumes and ejection fraction was larger in the transgenic groups
than in the littermate controls, perhaps reflecting variability of
TNF- expression within each lineage.6 This is not
dissimilar from the clinical heterogeneity found in
patients with heart failure. Our results are also consistent
with a recent report describing the effects of TNF- infusion in
rats.27
Third, our study demonstrated evidence of remodeling in terms of an increase in myocardial mass that reached significance at 3 months in lineage 1 but not until 6 months in lineage 2. This suggests an ongoing process that occurs earlier if the level of TNF overexpression is higher. It is known that the animals in lineage 1 develop severe myocarditis with apoptosis of cardiac myocytes and fibrosis early in their life, resulting in 50% mortality rates by the 70th day of life. It has been proposed that myocardial TNF production might mediate compensatory hypertrophy.28 Our data could be interpreted as indicating that a high level of TNF leads to hypertrophy or that hypertrophy develops only after a certain level of dysfunction is present with result activation of compensatory mechanisms.
Last, the progressive increase in LV volumes and LV mass seen in this
study is similar to the ventricular remodeling that occurs
in patients with heart failure. Importantly, it appears that the amount
of TNF produced in the heart correlates well with the severity of the
disease that these animals develop. This is consistent with the
observation that in patients with cardiac failure, the plasmatic levels
of TNF- are directly correlated with the severity of the
disease26 and supports the hypothesis that TNF- may
play a role in myocardial damage, ventricular dilatation,
and cardiac decompensation observed in patients with congestive
cardiomyopathy.29
Limitations of the Study
First, the typical anesthetized mouse heart rate is 
450
bpm, with a typical duration of systole of 50 ms. Given the temporal
resolution of 39 ms used in this study, a trigger delay must be used to
ensure that images are obtained at both end-diastole and
end-systole for the assessment of function.
Second, a relatively limited number of slices was used, raising the possibility of partial volume effects. In our prior studies in which the myocardial wall volume was used to estimate the myocardial mass, there was good agreement with necropsy measurements.10 This suggests that effects of slice thickness on volume determinations are minimal.
Third, thermodilution has been successfully used to measure cardiac output in rats.24 25 However, the limitations of the thermodilution cardiac output in small animals have been well described.30 It has been argued that thermodilution measurements in small animals may be associated with greater errors than in larger animals. Heat diffusion across the wall of the vessel increases as its diameter decreases, and it is greater across a thin-walled vessel. This would lead to loss of "thermal bolus" as an indicator affecting measurements. Despite that concern, our data show good agreement between MRI and thermodilution, suggesting that a major bias is not present.
Fourth, anesthesia may affect cardiac output, and both the magnitude and direction of the effect vary with the anesthetic used.31 Ideally, the measurement of cardiac function in mouse models should be done in conscious animals. This may be possible with the use of restraint devices and should be examined in further work.
Conclusions
The present study demonstrates that MRI at 1.5 T, readily
accessible at most medical centers, provides accurate and reproducible
quantification of LV volumes and ejection fraction. Thus MRI can in 1
step measure LV mass, volumes, and ejection fraction accurately and
determine ventricular geometry in a mouse model of heart
failure. In addition, MRI is well suited for serial evaluation of the
LV size and function in living mice and can be used to track the
development of LV dilatation and failure. The comparison between normal
control littermates and the 2 lineages of mice overexpressing TNF-
showed a clear progressive increase in cardiac volumes that was related
to differing expression of TNF-.
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Acknowledgments |
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This study was supported by a grant from Luso-American Foundation (FLAD), Lisbon, Portugal (Dr Franco), by grants from the National Institutes of Health (POI-HL-06296, Dr Victor, and 5R29-GM-51822-04, Dr Giroir), and by a grant from the American Heart Association, Texas Affiliate (966-064, Dr Thomas). The authors wish to extend their appreciation to Dr Thomas J. Carmody for his expertise with the statistical analysis and to Dorothy E. Smith and Charles J. Storey for their technical assistance.
Received July 15, 1998; revision received August 28, 1998; accepted September 16, 1998.
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