USPIO-Enhanced CMR of Myocardial Inflammation

Inflammation is a key underlying mechanism of many ischemic, infectious, and inflammatory myocardial diseases. However, the diagnostic, prognostic, and predictive value of myocardial inflammation for specific conditions and for their progression to heart failure remains unclear.

A rich array of established and novel noninvasive imaging methods allow visualizing, characterizing, and quantifying cardiovascular inflammation in vivo in both animal models and patients. Ultra-small particles of iron oxide (USPIO)–enhanced magnetic resonance imaging (MRI) has been employed in several cardiovascular imaging studies as a marker of vascular and myocardial inflammation (1). USPIO are nanoparticles containing an iron oxide core. When injected intravenously, they passively extravasate in tissues, where they are then actively internalized by phagocytic cells, such as inflammatory macrophages. USPIO accumulation increases R1 and R2(*) tissue relaxation rates proportionally to their concentration, and their uptake can be visualized using appropriately weighted T₁/T₂(*) magnetic resonance (MR) sequences or relaxation mapping.

In atherosclerosis, USPIO have been shown to colocalize with plaque macrophages in carotid endarterectomy specimens (2), and USPIO-enhanced MRI has been used as a noninvasive imaging readout of antiatherosclerotic interventions (atorvastatin) (3). USPIO-enhanced cardiac magnetic resonance (CMR) has also been used to quantify myocardial inflammation. In acute ST-segment elevation myocardial infarction (MI), USPIO preferentially accumulated in the infarct and peri-infarct area, with lower accumulation in the remote myocardium (4,5). Another study found that USPIO infarct accumulation changed over time, with R2* peaking at 2 to 3 days after MI and remaining high up to 2 weeks after the event (6). In patients with stable coronary artery disease after coronary artery bypass graft (CABG) surgery, USPIO-enhanced CMR showed increased myocardial R2* (7). Studies in patients with myocarditis (8) and heart transplantation (9) showed no difference in USPIO-enhanced CMR between subjects and controls.

Although some of these studies showed USPIO uptake by (5) or colocalization with (6) macrophages, how much active cellular uptake versus passive tissue accumulation contribute to USPIO myocardial signal and the time course of these 2 phenomena have yet to be fully elucidated.

In this issue of iJACC, Lekarz et al. (10) attempt to answer these questions by establishing a novel image acquisition and analysis methodology for USPIO-enhanced CMR. Preliminary histological analysis in mice with and without myocardial infarction confirmed colocalization of cardiac MAC-3+ macrophages and USPIO, as well as USPIO infiltration in the interstitium. In healthy human volunteers, R1 and R2* increased and then declined in the heart within a few days after USPIO injection. However, USPIO temporal signal modulation was very different in the spleen and liver, where R2* (but not R1) increased and then remained elevated over the course of the experiment. The authors suggest that this behavior may reflect the different mechanisms underlying changes in R1 and R2* upon USPIO injection. In the healthy heart, where inflammatory/phagocytic cells are scarce, USPIO uptake is most likely predominantly passive, with USPIO being homogeneously distributed in the interstitium, thereby equally affecting R1 and R2*. However, in the spleen and liver, organs rich in phagocytic cells, R1 most likely reflects USPIO passive organ accumulation, whereas R2* is dependent on USPIO compartmentalization into phagocytic cells. Based on these observations, the authors propose and apply a novel metric based on both R2* and R1 mapping (R2*/R1 ratio) to characterize the relative contributions of passive versus active uptake to the USPIO CMR signal as a marker of myocardial inflammation in an array of cardiac diseases. In both acute MI and ischemic cardiomyopathy, they find R2* and the R2*/R1 ratio to be higher with respect to healthy in the infarct and remote myocardium over the course of several days (with infarct R2*/R1 ratio not reaching statistical significance in the infarct in ischemic cardiomyopathy). No difference in both parameters between cases and control subjects was found for acute myocarditis, dilated cardiomyopathy, and sarcoidosis.

Through their methodological advancements, Lekarz et al. (10) bring some clarity to the processes responsible for generating USPIO MR signal in tissues. However, in-depth preclinical and clinical work is still needed to establish USPIO and the R2*/R1 ratio as robust markers of cardiac inflammation, especially in light of potential safety concerns with USPIO usage in humans (11). A comparison with other imaging approaches, most notably positron emission tomography (PET) with the well-established metabolic tracer ¹⁸F fluorodeoxyglucose, is surely warranted (12), along with other emerging PET inflammation tracers (12,13). We foresee that the advent and expanding use of hybrid clinical PET/MR dual-imaging systems (14) will facilitate investigation of the respective benefits, challenges, and added value of USPIO-enhanced CMR of cardiovascular inflammation with respect to these other methodologies.