Substrate for the Myocardial Inflammation-Heart Failure Hypothesis Identified Using Novel USPIO Methodology

Jakub Lagan, Josephine Naish, Kara Simpson, Min Zi, Elizabeth Cartwright, Philip Foden, Julie Morris, David Clark, Lindsay Birchall, Jessica Caldwell, Andrew Trafford, Christien Fortune, Michael H. Cullen, Nazia Chaudhuri, James Fildes, Jaydeep Sarma, Erik B Schelbert, Matthias Schmitt, Karen Piper Hanley, Christopher Miller

Research output: Contribution to journalArticlepeer-review


The purpose of this study was to identify where ultrasmall superparamagnetic particles of iron oxide (USPIO) locate to in myocardium, develop a methodology that differentiates active macrophage uptake of USPIO from passive tissue distribution; and investigate myocardial inflammation in cardiovascular diseases.

Myocardial inflammation is hypothesized to be a key pathophysiological mechanism of heart failure (HF), but human evidence is limited, partly because evaluation is challenging. USPIO-magnetic resonance imaging (MRI) potentially allows specific identification of myocardial inflammation but it remains unclear what the USPIO-MRI signal represents.

Histological validation was performed using a murine acute myocardial infarction (MI) model. A multiparametric, multi-time-point MRI methodology was developed, which was applied in patients with acute MI (n = 12), chronic ischemic cardiomyopathy (n = 7), myocarditis (n = 6), dilated cardiomyopathy (n = 5), and chronic sarcoidosis (n = 5).

USPIO were identified in myocardial macrophages and myocardial interstitium. R1 time-course reflected passive interstitial distribution whereas multi-time-point R2* was also sensitive to active macrophage uptake. R2*/R1 ratio provided a quantitative measurement of myocardial macrophage infiltration. R2* behavior and R2*/R1 ratio were higher in infarcted (p = 0.001) and remote (p = 0.033) myocardium in acute MI and in chronic ischemic cardiomyopathy (infarct: p = 0.008; remote p = 0.010), and were borderline higher in DCM (p = 0.096), in comparison to healthy controls, but were no different in myocarditis or sarcoidosis. An R2*/R1 threshold of 25 had a sensitivity and specificity of 90% and 83%, respectively, for detecting active USPIO uptake.

USPIO are phagocytized by cardiac macrophages but are also passively present in myocardial interstitium. A multiparametric multi-time-point MRI methodology specifically identifies active myocardial macrophage infiltration. Persistent active macrophage infiltration is present in infarcted and remote myocardium in chronic ischemic cardiomyopathy, providing a substrate for HF.
Original languageEnglish
Pages (from-to)365-376
Number of pages12
JournalJACC: Cardiovascular Imaging
Issue number2
Early online date15 Apr 2020
Publication statusPublished - 1 Feb 2021


  • Myocardial inflammation
  • Heart failure
  • Ultrasmall superparamagnetic particles of iron oxide
  • Magnetic resonance imaging


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