Maisa Kivistö & Katharine Wilding
Introduction
Coronary artery disease (CAD) is the most common national disease in Finland among cancers according to Duodecim (2016). It is a cardiovascular disease which are most burdening the health care. That is why we wanted to focus on the early diagnosis of CAD with non-invasive heart imaging. Furthermore, as using non-invasive imaging methods the patients do not need to undergo invasive procedures which always have greater risks of complications and side-effects. Usually non-invasive methods cost less and are not so risky for the patient.
A good example of an invasive imaging method for the coronary arteries in coronary angiography. In that a catheter is inserted from the groin or radial artery to the coronary artery and meanwhile contract agent is injected to the vein to make the vessels visible. The blood flow in the arteries are observed with x-ray imaging. This exposes the patient to a high radiation dose. However, this procedure is good since the quality of imaging is high-resolution and a possible blockage can be treated right away with a balloon catheter or stent.
Non-invasive methods are different functional imaging methods such as myocardial perfusion imaging with radio-isotopes (nuclear technique) or with contrast agents. Myocardial perfusion imaging is functional imaging which means that the function of organs and tissues (e.g. blood flow, metabolism, structure) can be demonstrated.
The MR contrast agents can have mild side-effects but the radio-isotopes have a rather short half-life so they have hardly any side-effects. Nuclear techniques are for example SPECT (single photon emission computed tomography) and PET (positron emission tomography). In magnetic resolution imaging (MRI) is used contrast agents and this is also the imaging method we are focusing on. These methods are convenient and almost as accurate as the invasive methods and they are constantly developing to become more accurate.
How does it work?
Cardiac Magnetic Resonance Imaging (CMRI) is a well-established form of clinical and functional molecular imaging which is safer for the patient as it is non-invasive and avoids the use of ionizing radiation. Patient lies inside the magnetic resonance tube as the imaging is started. Images are obtained by using a very strong magnetic field, which makes all the hydrogen nuclei (i.e. all protons in the body) react and regulate themselves like tiny magnets. When the protons emit a signal, it is transformed into a visible image with the simultaneous use of radiofrequency pulsations.
A Contrast Agent (CA) can be used to highlight areas of interest. The CA is a fluid containing gadolinium, (an easily magnetized rare metal), which is injected intravenously. Different levels of diffusion of the CA into the cardiac tissue show different areas and stages of damage.
Usability and Safety
This technology enables the professionals to see minute structural changes of the heart (eg. inflammatory changes) which aid in the diagnosis. It can be seen if there is an old fibrosis or an ongoing inflammation. In addition to the heart muscle structure the CMRI shows also the condition of heart valves and coronary vessels. As a good image of the heart is seen, the need for an invasive procedure can be re-assessed.
Cardiac Magnetic Resonance Imaging (CMRI) is a relatively safe and reliable method of obtaining cardiac structural and functional information, but it does have some particular drawbacks.
· Cannot be scanned if patient has a pacemaker, ICD, implanted drug infusion pump, some types of dental implants, metal or shrapnel in the body
· Other situations such as kidney problems, pregnancy, recent open -heart surgery and tattoos may affect the patient’s safety in the scanner
· Expensive technique and currently limited availability
· Demands skilled technician (different skills than normal MRI)
· No biological harm, but possible geno-toxicity (i.e. damaging genetic information in cells which may lead to cancer)
· Noisy and possible claustrophobia for the patient
If iron oxide nanoparticles are added to the equation, then further complications are obvious. Dissanayake et al. (2015) showed in their research that iron oxide nanoparticles exposure could cause mutagenic effects. The results of their work show that DNA alteration was seen post-iron oxide nanoparticle exposure which potentially damages an organism’s (in this case, the patient) development and ability to reproduce. Yarjanli et al. (2017) speculated on the potential for iron oxide nanoparticles to cross the blood-brain barrier and accumulate in the nervous system, causing toxicity and neural damage of the same type as neurodegenerative diseases. Alam et al. (2015) noted that different types of macrophages have different activity levels and may take the iron oxide nanoparticles into the targeted tissue at different rates, causing false positive/negative enhancement and possibility of clinical misjudgment.
As mentioned previously, one type of iron oxide nanoparticle, Ferumoxytol, (trade name-Feraheme in America, Rienso in Europe) is used as a treatment for anemia in Chronic Kidney Disease and it is thought to be potentially valuable in Cardiac Magnetic Resonance Imaging. However, despite being licensed for use in Europe as Rienso, it was withdrawn from medical use by its manufacturer (Takeda) in 2015, following several serious adverse effects and some deaths. It continues to be administered in America, as Feraheme in its capacity to treat anemia only, but has been subjected to rigorous testing and strongly worded warnings on its packaging.
Future views and prospects
The MRI is based on molecular imaging, where even individual cells or components can be seen. One such cell of interest in cardiac magnetic resonance imaging is the macrophage. Inflammation is found in many cardiovascular conditions such as atherosclerosis, myocardial infarction and heart failure. Macrophages (a type of white blood cell that engulfs and digests anything unrelated to the body in its path) are very important to the inflammatory process, as macrophages both destroy foreign matter in the body and then clear the way for repair work. By imaging macrophages at work, doctors can understand more fully how cardiovascular diseases start, and can also evaluate how severe the condition is in real time. This can aid in diagnostics, prognosis and evaluate efficiency of treatments.
An advanced level of Cardiac Magnetic Resonance Imaging would be to use iron oxide nanoparticles. The contrast agent would carry the nanoparticles to the macrophages, rendering the macrophages highly visible. Magnetizing these nanoparticles would show enhanced images of the heart’s structure, as the nanoparticles aggregate with the macrophages. The superparamagnetic iron oxide nanoparticles (SPIONP) are made from either magnetite or maghemite and covered with a polymer coat. The size and thickness of both iron and polymer determine in what structures the particles can be used. One type of iron oxide nanoparticle, Ferumoxytol, is used as a treatment for anemia in Chronic Kidney Disease.
Different areas of medicine had shown great interest in the promise and potential of nanoparticles. The concept that medication and cell grafts could be directly targeted and transported to body areas of need has garnered interest in the fields of oncology and neurology, amongst others. But despite these potentially game-changing treatments, nanoparticle development is still slow and steady, with as many researchers finding pitfalls and hazards as finding novel applications.
In relation to cardiac diagnostics and treatment, nanoparticles have several different prospective uses. With the MRI, a large magnetic field can be created which would use the iron oxide nanoparticles to “pull” medication into the cells, a process known as magnetofection. Magnetic targeting, on the other hand, would use the magnetized nanoparticles to break up thrombi (blood clots). The imaging aspect could also make it possible to “track” magnetized cells in the heart in still non-invasive manner and even evaluate cell grafts and cell based therapies. It is also hoped that the medication, Ferumoxytol, may be used to differentiate between acute myocardial inflammation from old myocardial damage, which opens up the possibilities of observing early stages of heart transplant rejection and cardiac tumors.
References
Alam, S.R., Stirrat, C., Richards, J., Mirsadraee, S., Semple, S.I., Tse, G., Henriksen, P., Newby, D.E. 2015. Vascular and plaque imaging with ultrasmall superparamagnetic particles of iron oxide. [Review] Journal of Cardiovascular Magnetic Resonance. 17:83, 2015 Sep 18.
Dissanayake, N.M., Current, K.M., Obare, S.O. 2015. Mutagenic Effects of Iron Oxide Nanoparticles on Biological Cells. [Review]. International Journal of Molecular Sciences. 16(10):23 482-516, 2015 Sep 30.
Frommann, B. 2017a. Coronary heart disease: non-invasive imaging reduces catheter examinations. Interview with Prof. Riemer H. J. A. Slart. Medica Magazine 01.09.2017. Available online <https://www.medica-tradefair.com/cgi-bin/md_medica/lib/pub/tt.cgi/Coronary_heart_disease_non-invasive_imaging_reduces_catheter_examinations.html?oid=85851&lang=2&ticket=g_u_e_s_t >
Frommann, B. 2017b. Imaging techniques: ultrasound, MRI, CT, catheters and other procedures to keep a healthy heart. Medica Magazine 09/01/2017. Available online <https://www.medica-tradefair.com/cgi-bin/md_medica/lib/pub/tt.cgi/Imaging_techniques_ultrasound_MRI_CT_catheters_and_other_procedures_to_keep_a_healthy_heart.html?oid=85849&lang=2&ticket=g_u_e_s_t>
Frommann, B. 2017c. Myocarditis: more specific diagnosis thanks to molecular imaging. Interview with Prof. Ali Yilmaz. Medica Maganize, September 2017, 09/01/2017. Available online < https://www.medica-tradefair.com/cgi bin/md_medica/lib/pub/tt.cgi/Myocarditis_more_specific_diagnosis_thanks_to_molecular_imaging.html?oid=85853&lang=2&ticket=g_u_e_s_t>