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Detection of cardiac inflammation using ultrasmall superparamagnetic particles of iron oxide-enhanced magnetic resonance imaging
Background Ultrasmall superparamagnetic particles of iron oxide (USPIO)-
enhanced magnetic resonance imaging (MRI) can detect tissue-resident
inflammatory macrophages and identify cellular inflammation. Clinical studies using
this non-invasive technique are now emerging.
Objectives The aims of this thesis were (i) to determine whether USPIO-enhanced
MRI can detect and serially monitor myocardial inflammation after myocardial
infarction (MI) using single and repeated USPIO administration, (ii) to report a range
of normal R2* (1/T2*) values at 1.5 tesla (T) and 3 T in healthy myocardium and
other tissues before and after USPIO administration, (iii) to determine whether
USPIO-enhanced MRI can detect myocardial inflammation in acute myocarditis, and
(iv) to determine whether USPIO-enhanced MRI can detect myocardial inflammation
in patients with a prior cardiac transplant.
Methods Thirty-one patients were recruited following acute MI and followed up for
3 months with repeated T2 and USPIO-enhanced T2* mapping 3 T MRI. Twenty
healthy volunteers were recruited: 10 imaged each at 1.5 T and 3 T. T2 and USPIO-enhanced
T2* mapping MRI was conducted. Fourteen patients with suspected acute
myocarditis underwent T2 and USPIO-enhanced T2* mapping 3 T MRI, with further
imaging at 3 months. Eleven patients with prior cardiac transplant underwent T2 and
USPIO-enhanced T2* mapping 1.5 T MRI with further imaging at 3 months.
Regions of interest within the myocardium, along with other tissues, were selected
for analysis. Pre-contrast T2 values, and the change in R2* due to USPIO from
baseline to 24 hours after USPIO were compared for each region of interest.
Results In patients with MI, USPIO uptake in the infarct zone peaked at days 2-3,
and greater USPIO uptake was detected in the infarct zone compared to remote
myocardium in the first 2 weeks after myocardial infarction. In contrast, T2-defined
myocardial oedema peaked at days 3-9 and remained increased in the infarct zone
throughout the 3-month follow up period. Histology confirmed colocalisation of iron
and macrophages within the infarcted, but not the non-infarcted, myocardium.
In healthy volunteers, we reported a range of normal myocardial and tissue R2*
values at baseline, and following USPIO. Tissues showing greatest USPIO
enhancement were organs of the reticuloendothelial system: the liver, spleen and
bone marrow.
Myocarditis was confirmed in 9 of the 14 suspected cases of myocarditis. There was
greater myocardial oedema, but no demonstrable difference in USPIO enhancement,
in inflamed myocardial regions in patients with myocarditis when compared to
healthy myocardium. We recorded an improvement in cardiac function and reduced
imaging measures of inflammation after 3 months.
Ten patients with cardiac transplant were retained for analysis. Measures of
myocardial oedema were greater in patients with cardiac transplant than healthy
volunteers. There was no difference in the change in R2* due to USPIO between
patients with transplantation and healthy volunteers. Imaging recordings did not
change when repeated at 3 months.
Conclusions Myocardial macrophage activity can be detected using USPIO-enhanced
MRI in the first 2 weeks following acute MI. This observed pattern of
cellular inflammation is distinct, and provides complementary information to, the
more prolonged myocardial oedema detectable using T2 mapping.
In patients with acute myocarditis, USPIO-enhanced MRI does not provide
additional clinically relevant information to standard clinical MRI sequences. This
suggests that tissue-resident macrophages do not provide a substantial contribution to
the myocardial inflammation in this condition.
Stable patients with cardiac transplantation have increased myocardial T2 values,
consistent with resting myocardial oedema or fibrosis. In contrast, USPIO-enhanced
MRI is normal and stable over time suggesting the absence of chronic macrophage-driven
cellular inflammation.
In conclusion, this imaging technique holds promise as a non-invasive method of
assessing and monitoring macrophage-driven myocardial inflammation after
myocardial infarction with potential application to diagnosis, risk stratification and
assessment of novel anti-inflammatory therapeutic interventions. It remains to be
determined whether USPIO-enhanced MRI may be able to identify myocardial
inflammation in other myocardial inflammatory conditions including acute cardiac
transplant rejection