This editorial refers to ‘Impact of cardiac magnetic resonance imaging on human lymphocyte DNA integrity,’ by M. Fiechter et al., on page 2340

Cardiac imaging is increasingly used to detect heart diseases and to guide therapy. Along with the increased use of cardiac imaging at clinics there is increased attention to the potential risks related to the methods used. Currently imaging tests using ultrasound or magnetic fields have been regarded safer alternatives compared with the tests utilizing ionizing radiation such as X-rays, computed tomography (CT), and nuclear imaging.1

However, various sources of risks related to, for example, exercise testing, pharmacological stressors, contrast agents, the imaging procedures themselves, invasive procedures, and cumulative ionizing radiation should all be taken into account collectively and ultimately weighed against the risks related to undetected disease or delayed diagnosis.

Magnetic resonance (MR) imaging relies on three different types of low-frequency electromagnetic waves: a static magnetic field, radiofrequency (RF) pulses, and gradient magnetic fields. Potential risks associated with MR may derive from the effects of each component on biological tissues and mainly on ferromagnetic objects. The latter is a well-known limitation of MR that can be avoided by appropriate patient selection, i.e. exclusion of patients with any metal object in their body. A strong static magnetic field as such is unlikely to cause significant adverse biological effects, although sporadic and transient sensations of nausea and dizziness have been reported. The RF energy delivered to the body may cause heating of tissues.2 The amount of RF energy delivered is defined as the specific absorption rate (SAR). To avoid significant heating, clinical scanners are set to operate within defined SAR ranges. A gradient magnetic field can stimulate nerves and muscles, occasionally causing discomfort,3 but current MR systems typically operate below nerve stimulation levels. However, cardiac MR imaging requires some of the strongest and fastest switching electromagnetic gradients available in MR, exposing the patients to the highest accepted energy levels.4,5

DNA double-strand breaks (DSBs) in vivo have been used as a marker of biological damage and genotoxic effects induced by medical procedures especially in studying the effects of ionizing radiation. There are several approaches to measure the induction and repair of DSBs. A number of methods such as the Comet assay6,7 and measurement of gamma-H2AX phosphorylation (pH2AX)8,9 allow detection of low levels of DNA damage. The classical Comet assay is a simple and sensitive gel electrophoresis-based technique that can be used, with modifications, to measure DNA single-strand breaks (SSBs) and DSBs, as well as cross-links and apoptotic nuclei in individual eukaryotic cells. The pH2AX assay is methodologically more versatile as the phosphorylation event occurring on DNA DSBs can be measured using immunofluorescence microscopy, flow cytometry, and western blotting. Induction of pH2AX occurs within seconds, and maximal accumulation is reached ∼ 30 min after irradiation, followed by decay (epitope dephosphorylation), depending on the success of the repair processes.8 Both methods are also suitable for assessing the level of induced DNA damage in peripheral blood cells, but the high linearity of pH2AX signals with the radiation dose makes this biomarker the method of choice for indicating the exposure and monitoring the repair. No significant differences in the amount of pH2AX foci between lymphocyte subsets have been detected. However, the observed large interindividual variation in vitro10 and in vivo limits the usefulness of the pH2AX assay for radiation biodosimetry. Moreover, it should be noted that while microscope-based analysis of pH2AX foci allows detection of even a single DNA DSB in a cell, the accurate signal quantification by flow cytometric methods typically requires the presence of several foci per cell.

Fiechter et al.11 have now investigated the impact of cardiac MR on lymphocyte DNA. They analysed DSBs in blood lymphocytes before and after routine 1.5T cardiac MR examination using immunofluorescence microscopy and flow cytometric analysis for measurement of pH2AX signals. They found a significant increase in median numbers of DSBs in lymphocytes after cardiac MR examination. The authors concluded that cardiac MR should be used with caution, and restrictions may apply similar to those of other X-ray-based imaging techniques in order to avoid unnecessary damage of DNA integrity with a potential carcinogenic effect.

The results may sound surprising but are actually not completely new. In previous studies, in vitro and in vivo DNA damage in lymphocytes after cardiac MR has been demonstrated.4 Interestingly, previous studies with low-dose coronary CT angiography,12–14 nuclear imaging,15 and invasive X-ray angiography12 have documented DSBs with levels quite comparable with those detected after cardiac MR by Fiechter et al.,11 while the values have been somewhat higher after CT angiography performed with a higher radiation dose (Table 1). In addition, the studies have demonstrated a strong relationship between the amount of DSBs and the amount of ionizing irradiation in vitro.12,13 Based on serial measurements, repair of DSBs seems to be rapid as their number returns close to baseline in a few hours, but very limited data are available for the longer term existence of DSBs after scans. In the study by Simi etal.,4 DNA damage was detected up to 24 h after cardiac MR.

Table 1

Amount of excess DNA double strand breaks per lymphocyte induced by different diagnostic procedures

 Early measurements
 
Later measurements
 
Reference 
 DSB foci/lymphocytea Time of measurement DSB foci/lymphocyte Time of measurement  
[18F]FDG injection (5 mSv) 0.11 30 min post-injection 0.16 30 min post-PET/CT May et al. (2012)15 
CTA (∼2 mSv) 0.04 30 min post scan –  Kuefner et al. (2010)13 
CTA (∼8 mSv) 0.24 30 min post-scan 0.092 and 0.014 2 and 5 h post-scan Grudzenski et al. (2009)14 
CTA (∼17 mSv) 0.39 30 min post-scan –  Kuefner et al. (2010)13 
Invasive angiography 0.13b 15 min post-procedure –  Kuefner et al. (2009)12 
1.5T CMR 0.12 At the end of the scan –  Fiechter et al. (2013)11 
 Early measurements
 
Later measurements
 
Reference 
 DSB foci/lymphocytea Time of measurement DSB foci/lymphocyte Time of measurement  
[18F]FDG injection (5 mSv) 0.11 30 min post-injection 0.16 30 min post-PET/CT May et al. (2012)15 
CTA (∼2 mSv) 0.04 30 min post scan –  Kuefner et al. (2010)13 
CTA (∼8 mSv) 0.24 30 min post-scan 0.092 and 0.014 2 and 5 h post-scan Grudzenski et al. (2009)14 
CTA (∼17 mSv) 0.39 30 min post-scan –  Kuefner et al. (2010)13 
Invasive angiography 0.13b 15 min post-procedure –  Kuefner et al. (2009)12 
1.5T CMR 0.12 At the end of the scan –  Fiechter et al. (2013)11 

CMR, cardiac magnetic resonance; CTA, computed tomography angiography; DSB, doule-strand break; FDG, fluorodeoxyglucose; PET, positron emission tomography.

aBaseline level of DSBs is ∼0.06–0.08 DSB foci/lymphocyte.

bMedian of different non-cardiac dignostic and interventional procedures.

The long-term biological and clinical significance of DNA DSBs induced by MRI remains unknown. Mammalian cells respond rapidly to DNA damage caused by external agents such as ionizing radiation by rapidly activating the molecular machinery which aims at maintaining genomic integrity and thus preventing carcinogenic mutations. Repair of DSBs involves a complex series of finely orchestrated protein interactions which reverse the changes in the nucleotides in an extremely efficient way both qualitatively and quantitatively.16 The main mechanisms of DSB repair include non-homologous end-joining and homologous recombination. While they sometimes fail to restore genomic stability, the key question in the case of permanent DNA damage is the likelihood of a hazardous effect on the host.17 Of note, the risk from radiation-induced carcinogenesis is considered as a stochastic event. In other words, even an extremely low level of damage may result in a harmful effect since no threshold for mutational changes exists.

Some limitations in the study of Fiechter etal.11 need to be taken into account. The study population was small and the measured increase in DSBs relatively minute. Although the results are in agreement with an earlier comparable study,4 it is important to confirm the findings in a larger population. Fiechter et al.11 measured only one time point at the end of the MR scan. Temporal data about the dynamics of the DSB repair are needed. The effect of MR field strength (1.5T vs. 3T vs. 7T) needs to be studied, as well as the role of contrast agents which may enhance the biological effects of magnetic fields. It would also be important to determine if similar findings can be detected after MR imaging of other tissues such as the brain and abdominal organs. It is also pivotal to collect more data about DSBs for comparison of different imaging modalities including ultrasound or even sham imaging to better understand the usability of DSBs as a biomarker of cellular stress after various clinical procedures.

Assuming that DNA damage indeed occurs after cardiac MR imaging, what does that mean clinically? Unfortunately that information is not available, and will probably be very difficult to acquire. In the case of ionizing radiation, only extrapolation from larger radiation doses in population cohorts (e.g. atomic bomb survivors) has been able to document the increased risk of cancer after low-dose radiation. The Food and Drug Administration (FDA) has estimated that after 10 mSv of ionizing radiation, the excess incidence of fatal cancer would be 0.05%18 and, since the current population incidence of cancer is high (one in three women and one in two men in Western countries will develop cancer in his or her lifetime), the minute increase in cancer due to radiation is extremely difficult to detect. Thus, also in the case of cardiac MR one could anticipate that the potential risk is too low to be confirmed in clinical population studies. The cellular mechanism of how cardiac MR induces DNA damage is not known and may be different from that of radiation. The distribution of exposure locally and to the whole body is also different. Due to numerous open issues, it is obvious that further larger studies are warranted before any restrictions on the use of cardiac MR should be imposed.

Funding

The Academy of Finland Centre of Excellence in Molecular Imaging in Cardiovascular and Metabolic Research, Helsinki, Finland and Finnish Foundation for Cardiovascular Research.

Conflict of interest: J.K. received a grant from CardiRAd and fees from Lantheus. All other authors have no conflicts to declare.

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Author notes

This editorial was guest edited by Prof. Jeroen Bax, Leiden, The Netherlands.
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
doi:10.1093/eurheartj/eht184.

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