Biologic effects of radiation from cardiac imaging: New insights from proteomic and genomic analyses

Abstract

An ongoing debate exists in the literature about the risk of carcinogenesis from radiation associated with medical imaging tests. Some position papers and societal guidelines advocate that the choice of a diagnostic imaging modality for any clinical indication be influenced by whether the test is associated with ionizing radiation. However, there is sparse scientific evidence underlying the current estimates of cancer risk from lowlevel (doses\100 mSv) radiation, which are based on the linear no-threshold (LNT) model. Although the Biological Effects of Ionizing Radiation (BEIR) VII report from the US National Academies recommends the use of the LNT model as the best simple model for purposes of radiation protection, as do reports from the United Nations as well as the leading international and US radiological protection organizations, several other widely divergent models have also been posited, including the theory of hormesis (protective effect of low dose radiation) on one extreme to a theory of hypersensitivity (to low dose compared to high dose) to the other. A major confounding factor in analyzing the observational data on this subject is the high population incidence of cancer, which makes it difficult to identify any small additional risk attributable to radiation from medical tests. Figure 1 from the BEIR VII report illustrates this point. A complementary approach to exploring the association between radiation and carcinogenesis is to determine whether exposure results in the activation of DNA repair pathways (activation of protein and genes involved in DNA repair, apoptosis, cell cycle regulation, and chromatic remodeling), indicating that DNA damage has occurred. Lobrich and colleagues have demonstrated proof of principle and validation of enumerating c-H2AX foci on peripheral blood lymphocytes as a marker of double-stranded DNA damage after a chest or abdominal CT scan, and the loss of these foci as a marker of DNA damage repair. The near-simultaneous publication of three recent articles using these surrogate markers of DNA damage to determine the genotoxic effects of radiation from cardiac imaging provides new and valuable insights on the subject. Won He Lee and colleagues from the laboratory of Joseph Wu at Stanford University, prospectively determined the activation of DNA response pathways in 63 patients having standard dose (average rest and stress activity 6.9 ± 0.5 and 23.8 ± 1.8 mCi, respectively; average rest, stress, and total effective dose 2.7 ± 0.6, 8.1 ± 0.4, and 10.7 ± 0.4 mSv, respectively) Tc-99m SPECT myocardial perfusion imaging. Notably, radiation doses to the peripheral lymphocytes were not determined. Twelve patients undergoing cardiac x-ray fluoroscopy (mean effective doses 18.2 ± 10.6 mSv) for coronary angiography and 15 undergoing echocardiography were used as positive and negative controls, respectively. Makers of DNA damage evaluated in peripheral blood T-lymphocytes collected before and after imaging were phosphorylation of DNA damagemarker proteins (H2AX, P53 and ATM) by flow cytometry and immunohistochemistry, and serial changes (up to 48 hours) in mRNA expression of DNA damage response genes (Bax, Mdm2, Ddb2, and Tp53). As expected, patients undergoing echocardiography had no changes in protein phosphorylation or gene expression after the procedure, compared to baseline. This control group served to mitigate against the possibility of chance or circadian variation being the explanation Reprint requests: Prem Soman MD, PhD, Division of Cardiology, University of Pittsburgh Medical Center, A-429 Scaife Hall, 200 Lothrop Street, Pittsburgh, PA 15213; somanp@upmc.edu J Nucl Cardiol 2016;23;754–7. 1071-3581/$34.00 Copyright 2016 American Society of Nuclear Cardiology.