Ultrasmall Superparamagnetic Particles of Iron Oxide in Patients With Acute Myocardial Infarction: Early Clinical Experience

Background—Inflammation following acute myocardial infarction (MI) has detrimental effects on reperfusion, myocardial remodelling, and ventricular function. Magnetic resonance imaging using ultrasmall superparamagnetic particles of iron oxide can detect cellular inflammation in tissues, and we therefore explored their role in acute MI in humans. Methods and Results—Sixteen patients with acute ST-segment elevation MI were recruited to undergo 3 sequential magnetic resonance scans within 5 days of admission at baseline, 24 and 48 hours following no infusion (controls; n=6) or intravenous infusion of ultrasmall superparamagnetic particles of iron oxide (n=10; 4 mg/kg). T2*-weighted multigradient-echo sequences were acquired and R2* values were calculated for specific regions of interest. In the control group, R2* values remained constant in all tissues across all scans with excellent repeatability (bias of −0.208 s−1, coefficient of repeatability of 26.96 s−1; intraclass coefficient 0.989). Consistent with uptake by the reticuloendothelial system, R2* value increased in the liver (84±49.5 to 319±70.0 s−1; P<0.001) but was unchanged in skeletal muscle (54±8.4 to 67.0±9.5 s−1; P>0.05) 24 hours after administration of ultrasmall superparamagnetic particles of iron oxide. In the myocardial infarct, R2* value increased from 41.0±12.0 s−1 (baseline) to 155±45.0 s−1 (P<0.001) and 124±35.0 s−1 (P<0.05) at 24 and 48 hours, respectively. A similar but lower magnitude response was seen in the remote myocardium, where it increased from 39±3.2 s−1 (baseline) to 80±14.9 s−1 (P<0.001) and 67.0±15.7 s−1 (P<0.05) at 24 and 48 hours, respectively. Conclusions—Following acute MI, uptake of ultrasmall superparamagnetic particles of iron oxide occurs with the infarcted and remote myocardium. This technique holds major promise as a potential method for assessing cellular myocardial inflammation and left ventricular remodelling, which may have a range of applications in patients with MI and other inflammatory cardiac conditions. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT01323296.

[1]  P. Libby,et al.  Identification of Splenic Reservoir Monocytes and Their Deployment to Inflammatory Sites , 2009, Science.

[2]  M. Matsuzaki,et al.  Induction of left ventricular remodeling and dysfunction in the recipient heart after donor heart myocardial infarction: new insights into the pathologic role of tumor necrosis factor-alpha from a novel heterotopic transplant-coronary ligation rat model. , 2003, Journal of the American College of Cardiology.

[3]  Ahmed Tawakol,et al.  PET/MRI of inflammation in myocardial infarction. , 2012, Journal of the American College of Cardiology.

[4]  Vasilis Ntziachristos,et al.  Fluorescence Tomography and Magnetic Resonance Imaging of Myocardial Macrophage Infiltration in Infarcted Myocardium In Vivo , 2007, Circulation.

[5]  J. Gili,et al.  Analysis of myocardial oedema by magnetic resonance imaging early after coronary artery occlusion with or without reperfusion. , 1993, Cardiovascular research.

[6]  D. Altman,et al.  STATISTICAL METHODS FOR ASSESSING AGREEMENT BETWEEN TWO METHODS OF CLINICAL MEASUREMENT , 1986, The Lancet.

[7]  J. Alpert,et al.  Joint ESC/ACCF/AHA/WHF Task Force for the Redefinition of Myocardial Infarction , 2008 .

[8]  P. Croisille,et al.  T2‐weighted cardiac MR assessment of the myocardial area‐at‐risk and salvage area in acute reperfused myocardial infarction: Comparison of state‐of‐the‐art dark blood and bright blood T2‐weighted sequences , 2012, Journal of magnetic resonance imaging : JMRI.

[9]  M. Pittet,et al.  Monocytes: protagonists of infarct inflammation and repair after myocardial infarction. , 2010, Circulation.

[10]  P. Libby,et al.  Rapid monocyte kinetics in acute myocardial infarction are sustained by extramedullary monocytopoiesis , 2012, The Journal of experimental medicine.

[11]  B Hamm,et al.  Magnetic resonance imaging of atherosclerotic plaques using superparamagnetic iron oxide particles , 2001, Journal of magnetic resonance imaging : JMRI.

[12]  N. Frangogiannis Targeting the inflammatory response in healing myocardial infarcts. , 2006, Current medicinal chemistry.

[13]  J. Debatin,et al.  Magnetic Resonance Imaging of Atherosclerotic Plaque With Ultrasmall Superparamagnetic Particles of Iron Oxide in Hyperlipidemic Rabbits , 2001, Circulation.

[14]  Wei Liu,et al.  Susceptibility gradient mapping (SGM): A new postprocessing method for positive contrast generation applied to superparamagnetic iron oxide particle (SPIO)‐labeled cells , 2008, Magnetic resonance in medicine.

[15]  Arantxa González,et al.  New targets to treat the structural remodeling of the myocardium. , 2011, Journal of the American College of Cardiology.

[16]  G. Schuler,et al.  Prognostic significance and determinants of myocardial salvage assessed by cardiovascular magnetic resonance in acute reperfused myocardial infarction. , 2010, Journal of the American College of Cardiology.

[17]  B Quesson,et al.  In vivo macrophage activity imaging in the central nervous system detected by magnetic resonance , 1999, Magnetic resonance in medicine.

[18]  D. Mann,et al.  Tissue expression and immunolocalization of tumor necrosis factor-alpha in postinfarction dysfunctional myocardium. , 1999, Circulation.

[19]  R. Willette,et al.  Differential uptake of ferumoxtran‐10 and ferumoxytol, ultrasmall superparamagnetic iron oxide contrast agents in rabbit: Critical determinants of atherosclerotic plaque labeling , 2005, Journal of magnetic resonance imaging : JMRI.

[20]  Fred S Apple,et al.  Universal definition of myocardial infarction. , 2007, Journal of the American College of Cardiology.

[21]  A. Prescher,et al.  Extra- and intracellular accumulation of ultrasmall superparamagnetic iron oxides (USPIO) in experimentally induced abscesses of the peripheral soft tissues and their effects on magnetic resonance imaging. , 1999, Magnetic resonance imaging.

[22]  David N. Firmin,et al.  Intercentre Reproducibility of Magnetic Resonance T2* Measurements of Myocardial Iron in Thalassaemia , 2005, The International Journal of Cardiovascular Imaging.

[23]  P. Pibarot,et al.  Predicting late myocardial recovery and outcomes in the early hours of ST-segment elevation myocardial infarction traditional measures compared with microvascular obstruction, salvaged myocardium, and necrosis characteristics by cardiovascular magnetic resonance. , 2010, Journal of the American College of Cardiology.

[24]  J. Gillard,et al.  Identifying Inflamed Carotid Plaques Using In Vivo USPIO-Enhanced MR Imaging to Label Plaque Macrophages , 2006, Arteriosclerosis, thrombosis, and vascular biology.

[25]  Calum Gray,et al.  Abdominal Aortic Aneurysm Growth Predicted by Uptake of Ultrasmall Superparamagnetic Particles of Iron Oxide: A Pilot Study , 2011, Circulation. Cardiovascular imaging.

[26]  M. E. Kooi,et al.  Accumulation of Ultrasmall Superparamagnetic Particles of Iron Oxide in Human Atherosclerotic Plaques Can Be Detected by In Vivo Magnetic Resonance Imaging , 2003, Circulation.

[27]  E. Camenzind,et al.  Inflammatory response post-myocardial infarction and reperfusion: a new therapeutic target? , 2005 .

[28]  F. Mach,et al.  The inflammatory response as a target to reduce myocardial ischaemia and reperfusion injury , 2009, Thrombosis and Haemostasis.

[29]  D N Firmin,et al.  Cardiovascular T2-star (T2*) magnetic resonance for the early diagnosis of myocardial iron overload. , 2001, European heart journal.