El-Sayed H Ibrahim1, Dhiraj Baruah1, Pierre Croisille2, Jadranka Stojanovska3, Jason Rubenstein1, Rachel Schlaak1, Anne Frei1, Elizabeth Gore1, and Carmen Bergom1
1Medical College of Wisconsin, Milwaukee, WI, United States, 2Jean-Monnet University, Lyon, France, 3University of Michigan, Ann Arbor, MI, United States
Synopsis
Lung cancer is the most frequently
diagnosed cancer worldwide. Radiation therapy (RT) is standard-of-care in one-third
of the patients, where the incidence of cardiac complications in lung cancer
patients after RT reaches 33%. The current paradigm for cardiotoxicity detection and management
relies primarily upon assessment of ejection fraction (EF). However, cardiac
injury can occur without a clear change in EF. In this study, we investigate
the effect of RT on global and regional cardiac function and myocardial T1/T2
values. The results show the capability of regional cardiac MRI for depicting early
changes in myocardial contractility pattern and tissue characterization
post-RT.
Introduction
Lung cancer is the leading cause of
cancer-related deaths, accounting for about 25% of all cancer deaths.1
About one-third of lung cancer patients are treated with radiation therapy (RT),
where the incidence of cardiac complications in lung cancer patients after RT
is as high as 33%.2
The current paradigm for cardiotoxicity detection and management
relies primarily upon the assessment of LV ejection fraction (EF), which may
not reflect the underlying advancement of subclinical cardiovascular disease.3
Therefore, there is a need for identifying new markers capable of early
detection of RT-induced cardiotoxicity in lung cancer. Myocardial strain, showed to be a sensitive measure for early
recognition of cardiac dysfunction and identification of patients at risk of heart
failure.3,4 Further, T1 and T2 mapping techniques showed
capabilities for myocardial tissue characterization in different cardiovascular
diseases.5
In this study, we investigate the capabilities of MRI strain
imaging and T1/T2 mapping techniques for identifying early development of
RT-induced subclinical cardiac dysfunction in a small-animal model of lung
cancer RT.Methods
A total of 22 salt-sensitive (SS) adult rats were divided into two
groups: control (n=7) and RT (n=15). The RT group received image-guided
localized whole-heart RT to 24 Gy using 3 equally-weighted fields, and then was
divided in two groups that were imaged at 8 weeks post-RT (n=6) and at 10 weeks
post-RT (n=9). All rats (control and RT) were imaged when they are around the
same age of 20 weeks on a Bruker 9.4T Biospec MRI scanner with 30-cm bore
diameter and equipped with 4-element surface coil.
The MRI scan included cine, tagging, and T1 (MOLLI) and T2
(spin-echo) mapping sequences. Total scan time was about one hour. The cine
images were analyzed to measure EF, end-diastolic volume (EDV), and myocardial
mass. The MOLLI and spin-echo images were analyzed to generate T1 and T2 maps,
respectively. The tagged images were analyzed using the Sinusoidal Modulation (SinMod)
technique to measure myocardial circumferential (Ecc) strain, radial (Err)
strain, and longitudinal (Ell) strains. Results
Global cardiac function was normal in all rats (Figure-1), with
increased EF and myocardial mass in the RT rats compared to controls. EF and
mass were 67±7%, 78±2, 79±3% and 0.38±0.04g, 0.49±0.04g, 0.56±0.04g in the
control, 8-week post-RT, and10-week post-RT rats, respectively. EDV values were
slightly smaller in the RT rats. EDV = 0.29±0.02ml, 0.26±0.03ml, and
0.26±0.02ml in the control, 8-week post-RT, and10-week post-RT rats,
respectively.
Despite normal global function, strain measurements showed reduced
(absolute) values in the RT rats compared to controls, where changes post-RT in
Ecc were more than changes in Err or Ell. Global Ecc = -14.1±2.2%, -10.2±0.7%,
and -8.4±0.5%; global Err = 23.3±4.0%, 21.7.2±3.7%, and 20.9.2±6.0%; and global
Ell = -15.6±1.8%, -12.3±1.0%, and -12.7±1.9% in the control, 8-week post-RT,
and10-week post-RT rats, respectively. The strain measurements showed larger
change between the control and the 8-week post-RT rats compared to the change
between the 8-week and 10-week post-RT rats. Err showed wider range of values,
especially at the basal and apical sites, compared to Ecc and Ell ranges of
values. On the regional basis, changes in strain values between different rat
groups showed different patterns, as shown in Figure-2.
Figure-3 shows representative T1 and T2 maps in a mid-ventricular
SAX slice in control and RT rats. T1 maps showed average myocardium T1 values
of 647±69ms, 619±41ms, and 655±46ms in the control, 8-week post-RT, and10-week
post-RT rats, respectively. In general, T1 values were slightly affected by RT
with no statistically significant differences between T1 values from different
rat groups, although T1 values in the 10-week post-RT rats were closer to those
in the control rats than to the values in the 8-week post-RT rats. The T2 maps
showed average myocardium T2 values of 12.7±0.8ms, 16.2±1.1ms, and14.7±1.8ms in
the control, 8-week post-RT, and10-week post-RT rats, respectively, where the
T2 values post-RT were elevated in the 8-week post-RT rat group compared to the
control rats, and then partially resolved in the 10-week post-RT rat group.Discussion
The
most interesting finding in this study is the increased EF post-RT, where EF
increased from 67% in the control rats to 78% and 79% in the 8-week and 10-week
post-RT rats. This was accompanied by significant ventricular hypertrophy: 29%
and 47% corresponding increases in myocardial mass, compared to control values.
This reflects the nature of cardiac remodeling to maintain global function in
the face of acute injuries from RT.
Despite
the normal global function, the MRI tagging-generated regional cardiac function
parameters revealed deteriorated myocardial contractility. Specifically, myocardial
strain showed to be a sensitive marker for detecting subclinical cardiac
dysfunction, where different strain components helped characterize the nature
of abnormal contractility patterns.
The
myocardial T1 and T2 values showed different changing pattern between different
rat groups. T1 and T2 values have previously been used for assessment of
changes in tissue composition, e.g. diffuse fibrosis (increased T1) and edema (increased
T2) formation, which could be part of acute cardiac response to RT. Conclusion
In conclusion, regional cardiac functional imaging and tissue
characterization by MRI provides detailed information about myocardial
contractility pattern post-RT and allows for early detection of induced
cardiotoxicity before global cardiac function is affected. Acknowledgements
Funding from Daniel M. Soref Charitable Trust,
MCW, USA.References
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