23rd Annual NASA Space Radiation Investigators' Workshop (2012)
8042.pdf
Full Body Single Dose 0.5 Gy Proton is Beneficial Whereas Single 0.15Gy 56Fe Dose is Deleterious for Acute Myocardial
Infarct recovery up to 3 month post-IR
X. Yan1,3, S. P. Sasi1, Y. Yang1, J. Lee1, M, Peluso2, C. Coelho2, L. Hlatky2,3, J. Morgan1,3, J. Carrozza1,3,
R. Kishore4, D. A. Goukassian1,3
(1) CardioVascular Systems Biology and (2) Center of Cancer Systems Biology, Steward St Elizabeth’s Medical Center, (3) Tufts
University School of Medicine, Boston, MA, USA, (4) Feinberg Cardiovascular Institute, Northwestern University, Chicago, IL, USA
Background. Previous epidemiologic data in radiotherapy patients (breast, head and neck cancer), non-occupational exposure (Life
Span Study), occupational exposure (radiologists/technologists, radon-exposed miner, nuclear workers) for radiation-induced
circulatory diseases demonstrate that cardiovascular (CV) morbidity may occur within months or years, and CV mortality may occur
within decades, after initial radiation exposure. The effect of cosmic radiation during and after space flights on CV system is
unknown. The majority of space flight-associated risks identified for the CV system to date were determined shortly after International
Space Station (ISS) flight missions that include: serious cardiac dysrhytmias, compromised orthostatic CV response, and
manifestation of previously asymptomatic CV disease. These symptoms were determined to be a consequence of adaptation to
microgravity, and are not risk factors causatively related to space radiation that could be ameliorated by post-mission exercise
program. During the future Moon and Mars missions astronauts will be exposed to higher total doses of space radiation (~0.4-0.5Gy
from galactic cosmic rays (GCR), especially during Mars mission that is currently estimated to be 30 to 36 months. It was suggested
that due to GCR each cell in astronauts body will be traversed by a proton every three days, helium nuclei every few weeks, and high
charge and energy (HZE) nuclei (i.e. C, O, Si, Fe) every few months. In spite of the fact that only 1% of GCR is composed of ions
heavier than helium, approximately 41% of radiation dose equivalent is predicted to be HZE particles with 13% being from 56Fe
particles. During an exploration-class space mission to Mars, astronauts will not have access to comprehensive health care services for
periods of at least 2 years. Since the majority of experienced astronauts are middle-aged (average age is 46, and the range is 33 to 58
years), they are at risk for developing serious cardiovascular events, which may be life-threatening for the astronauts and missionthreatening for NASA. We hypothesized that: (1) low-dose space radiation-induced biological responses may be long-lasting and are
radiation type-dependent; and (2) radiation may increase CV risks of physiologic homeostasis in the aging heart
(Irradiation+Aging=IR+A) and affect processes of cardiac repair and regeneration due to acute myocardial infarct
(Iradiation+Aging+Acute Myocardial Infarct=IR+A+AMI).
Methods. 9-10 months old male C57Bl6 mice were irradiated once with 0.5Gy/1GeV/n of proton and 0.15Gy/1GeV/n 56Fe. One and 3
months later, hemodynamic measurements (HEMO) and echocardiography (ECHO) were performed in IR+A group. In a second set of
control, proton and 56Fe IR mice, we induced acute myocardial infarct (ligation of left anterior descending coronary artery, LAD) and
monitored AMI recovery over 4 weeks by ECHO and HEMO. Before, 7 and 14 days after AMI, hearts were harvested for evaluation
for post-AMI inflammation and cardiac apoptosis. Cardiac remodeling (heart tissue fibrosis) was evaluated 4 weeks post-AMI using
H&E and Masson’s trichrome staining.
Results. IR+A group – no significant difference was observed between non irradiated control and proton or 56Fe irradiated mice 1 and
3 months post-IR in cardiac function and remodeling as assessed by ECHO and HEMO [left ventricular ejection fraction (EF), LV
posterior wall thickness (PWth), LV systolic pressure (LVSP), LV end diastolic pressure (LVEDP), maximum and minimum pressure
change in LV (dP/dt max and dP/dtmin)]. There was a small but statistically significant (p<0.04) improvement of EF% in proton-IR
vs. control mice. IR+A+AMI group – there was no difference in post-AMI mortality (only one mouse/group died between days 4-6) in
any of the three groups. Compared to non-IR AMI mice (control-AMI), post-AMI inflammatory responses (CD68 staining) were
increased similarly in both proton-AMI and 56Fe-AMI mice up to day 7. Between day 7 and 14, post-AMI inflammation remained at
the same level in proton-AMI mice, whereas inflammation in the 56Fe-AMI mice was sharply decreased, most likely due to the
significant loss of cardiac muscle tissue to early fibrosis. Compared to control-AMI mice, by 14 days there was a significant (p<0.01)
increase in apoptosis in, both, proton-AMI and 56Fe-AMI mice, and cardiac apoptosis was significantly (p<0.03) higher in 56Fe-AMI
vs. proton-AMI mice. Four weeks after AMI, HEMO and ECHO revealed that proton-AMI mice had better cardiac functional
recovery compared to control-AMI and 56Fe-AMI mice; whereas EF %, an independent predictive factor for increased mortality after
AMI, was most decreased in 56Fe-AMI mice among the AMI groups (56Fe-AMI vs. proton-AMI: 18 vs. 48 %, p<0.007, pre-AMI EF%
was 60-65% for both ions). There was a 2-4-fold increase in LVEDP in 56Fe-AMI vs. Proton-AMI (p<0.04), suggesting that 56FeAMI hearts may have developed cardiac de-compensation and heart failure. Masson’s trichrome staining of mid-myocardial cross
sections revealed that AMI led to small transmural (full thickness of LV) infarct in control-AMI mice, large transmural infarct in 56FeAMI mice and small superficial infarct in proton AMI mice, suggesting that low dose proton IR may improve, whereas 56Fe IR is
deleterious for post-AMI recovery.
Summary. Our results reveal that low dose full body single proton or 56Fe IR-induced effects on myocardium are of long duration but
they do not affect CV homeostasis under normal conditions. Further, we found that a single proton IR 3 months prior to adverse CV
event (AMI) is beneficial, whereas 56Fe deleterious for AMI recovery, strongly suggesting that low dose HZE particle radiation have
long-lasting negative effect on degenerative CV risks in case of adverse CV event (e.g., AMI). Despite of possible “healthy worker
factor” for astronauts our findings necessitate further extensive studies of underlying molecular mechanisms of HZE particle radiation
in the heart and circulatory system that should include new studies with one or more combination of ions, as well as simulated SPE or
GCR cosmic rays, soon to be available at NSRL.