Pei Han1,2, Rui Zhang3,4, Anthony Christodoulou2, Shawn Wagner2, Yibin Xie2, Eugenio Cingolani3, Eduardo Marban3, and Debiao Li1,2,5
1Department of Bioengineering, UCLA, Los Angeles, CA, United States, 2Biomedical Imaging Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States, 3Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States, 4Department of Cardiology, Xin-Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China, 5Department of Medicine, UCLA, Los Angeles, CA, United States
Synopsis
CMR T1 and ECV quantification can
be used to characterize focal or diffuse myocardial fibrosis. However, it is
technically challenging to acquire high-quality maps in small animals for
preclinical research because of high heart rates and high respiration rates. In
this study, we developed an ECG-free, free-breathing MR Multitasking T1 mapping
method on a 9.4T small animal MRI system. The feasibility of characterizing diffuse
myocardial fibrosis was tested in a HFpEF rat model. Elevated ECV found in the
HFpEF group is consistent with previous human studies and shows strong
correlation with the histological data.
Introduction
Cardiac magnetic resonance (CMR) T1
mapping is a powerful diagnostic modality for various abnormalities of the
myocardium. Combined with gadolinium contrast enhancement, T1 mapping allows
extracellular volume fraction (ECV) quantification, which can be used to
characterize focal or diffuse myocardial fibrosis1-3. However, it is
technically challenging to acquire high-quality T1 and ECV maps in small
animals for preclinical research because of high heart rates (usually faster
than 300 bpm) and high respiration rates (around 60 cpm).
Several studies have been done to improve
CMR T1 mapping4 and ECV measurement5 in small animals. In previous works,
dual cardiac/respiratory gating or ECG-triggering only was used to reduce
motion artifact. In this study, we developed an ECG-free, free-breathing MR
Multitasking6,7 T1 mapping method on a 9.4T small animal MRI system. The
feasibility of characterizing diffuse myocardial fibrosis was tested and
histologically validated in a rat heart failure model with preserved ejection
fraction (HFpEF).Methods
Rat model
The Dahl salt-sensitive (DSS) rat model
was used8. In this model, male DSS rats (Charles River Laboratories,
MA) were normally fed (0.3% NaCl) until the age of 7 weeks. Rats were then
randomly assigned to a high-salt diet group (8% NaCl) to induce HFpEF or a
low-salt diet group (0.3% NaCl) to serve as controls, until the age of 14
weeks. Imaging experiments and all measurements were done between the age of 14
and 15 weeks.
Imaging protocol
Nine control rats (control group,
n=9) and nine high-salt fed rats diagnosed with HFpEF (HFpEF group, n=9) were
imaged. All MRI data were acquired on a 9.4 T Bruker BioSpec preclinical system
with a single-channel volume coil.
Fig. 1(a) shows the imaging
workflow of the study. The sequence design of Multitasking T1 mapping is
illustrated in Fig. 1(b), with the following imaging parameters: matrix size=128x128, FOV=40x40mm2, voxel size=0.31x0.31x1.5mm, flip angle=5°, TR/TE=7.0/2.4ms, recovery period (time between adjacent IR pulses) = 2.9
s. In each Multitasking T1 mapping module, 85 IR preparation pulses were
applied, resulting in a scan time of 4 min 10 s. The total exam time for one
rat was around 25 minutes. After the scan, hematocrit (HCT) was measured for
ECV calculation.
Image reconstruction and
analysis
The basic steps of Multitasking
image reconstruction were as follows7: First, real-time temporal basis and corresponding
spatial coefficient maps were reconstructed from the training data and imaging
data respectively; these images were used for cardiac and respiratory binning. Then,
low-rank tensor reconstruction was performed with a tensor subspace constraint
estimated from a dictionary of Bloch-simulated T1 recovery evolutions, 10
cardiac bins and 5 respiratory bins. A major novelty for this work is that pre-
and post-Gd data were reconstructed jointly by modeling the paired T1
recovery evolutions, ensuring co-registration and improving SNR. Finally,
pixel-wise T1 maps were fitted at the end-expiration and diastolic phase with a
joint pre- and post-Gd T1 recovery model.
ECV values were calculated as
(1-HCT) times the ratio of ΔR1 in the septal myocardium to ΔR1 in the aorta.
The signal from aorta rather than the LV was used for blood ΔR1, to avoid the
signal loss resulting from LV inflow in this single slice setup. Both image
reconstruction and analysis were done in MATLAB.
Histological analysis
Masson's trichrome stain was used
to measure the extent of fibrosis. The hearts from five rats (n=5) of the
control group and five rats (n=5) of the HFpEF group were sectioned. Fractional
myocardial fibrosis (blue-gray pixels divided by total pixels) was measured
with ImageJ. A quantitative fibrosis percentage was calculated for each rat
using an average of five different sections.Results
Fig. 2(a-c) shows representative T1
and ECV maps from the control group and HFpEF group. Welch’s t-test showed that
ECV was significantly higher in the HFpEF group (22.4%±2.5%) compared with
those in the control group (18.0%±2.1%), p < 0.005, as displayed in Fig.
2(d).
Fig. 3(a-b) shows representative Masson
trichrome-stained sections of the control and HFpEF rats. The myocardial fibrosis
can be clearly seen in Fig. 3(b). Fig. 3(c) shows the relationship between ECV
value and the extent of fibrosis, in which a strong correlation can be found (r2 = 0.73, p = 0.0017).Discussion
In this study, Multitasking ECV
measurements were higher in the HFpEF group and strongly correlated with
histological fibrosis measurements. Future work will include evaluating the use
of more cardiac bins; 10 bins here correspond to a cardiac temporal resolution
of 20 ms for a heart rate of 300 bpm. For higher heart rates, such as those in
mice (~450 bpm), more cardiac bins may be required. For use in other disease
models featuring focal fibrosis, future work may include expanded spatial
coverage with 3D volumetric imaging and sequence improvements to address
potential B1 and B0 issues affecting T1 homogeneity in the inferior and lateral
walls, as visible in Fig. 2.Conclusion
ECG-free, free-breathing CMR
Multitasking T1/ECV mapping produces T1 and ECV maps in a high heart rate rat
model. Elevated ECV found in the HFpEF group is consistent with previous human studies
and shows strong correlation with the histological data. This technique can be
a powerful tool for myocardial tissue characterization in small animal models.Acknowledgements
No acknowledgement found.References
- Moon JC, Messroghli DR, Kellman
P, Piechnik SK, Robson MD, Ugander M, Gatehouse PD, Arai AE, Friedrich MG,
Neubauer S, Schulz-Menger J. Myocardial T1 mapping and extracellular volume
quantification: A Society for Cardiovascular Magnetic Resonance (SCMR) and CMR
Working Group of the European Society of Cardiology consensus statement.
Journal of Cardiovascular Magnetic Resonance. 2013 Dec;15(1):92.
- Haaf P, Garg P, Messroghli DR,
Broadbent DA, Greenwood JP, Plein S. Cardiac T1 mapping and extracellular
volume (ECV) in clinical practice: a comprehensive review. Journal of
Cardiovascular Magnetic Resonance. 2017 Jan;18(1):89.
- Su MY, Lin LY, Tseng YH, Chang
CC, Wu CK, Lin JL, Tseng WY. CMR-verified diffuse myocardial fibrosis is
associated with diastolic dysfunction in HFpEF. JACC: Cardiovascular Imaging.
2014 Oct 1;7(10):991-7.
- Zhang H, Ye Q, Zheng J,
Schelbert EB, Hitchens TK, Ho C. Improve myocardial T1 measurement in rats with
a new regression model: application to myocardial infarction and beyond.
Magnetic resonance in medicine. 2014 Sep;72(3):737-48.
- Messroghli DR, Nordmeyer S,
Buehrer M, Kozerke S, Dietrich T, Kaschina E, Becher PM, Hucko T, Berger F,
Klein C, Kuehne T. Small animal Look-Locker Inversion Recovery (SALLI) for
simultaneous generation of cardiac T1 maps and cine and inversion
recovery–prepared images at high heart rates: initial experience. Radiology. 2011
Oct;261(1):258-65.
- Christodoulou AG, Shaw JL,
Nguyen C, Yang Q, Xie Y, Wang N, Li D. Magnetic resonance multitasking for
motion-resolved quantitative cardiovascular imaging. Nature biomedical
engineering. 2018 Apr;2(4):215.
- Shaw JL, Yang Q, Zhou Z, Deng
Z, Nguyen C, Li D, Christodoulou AG. Free-breathing, non-ECG, continuous
myocardial T1 mapping with cardiovascular magnetic resonance multitasking.
Magnetic resonance in medicine. 2019 Apr;81(4):2450-63.
- Gallet R, de Couto G, Simsolo
E, Valle J, Sun B, Liu W, Tseliou E, Zile MR, Marbán E. Cardiosphere-derived
cells reverse heart failure with preserved ejection fraction in rats by
decreasing fibrosis and inflammation. JACC: Basic to Translational Science.
2016 Mar 2;1(1-2):14-28.