Substrate for the myocardial inflammation–heart failure hypothesis identified using novel USPIO methodology

Research output: Contribution to journalArticlepeer-review

  • External authors:
  • Jakub Lagan
  • Kara Simpson
  • Philip Foden
  • Julie Morris
  • David Clark
  • Lindsay Birchall
  • Jessica Caldwell
  • Christien Fortune
  • Michael H. Cullen
  • Nazia Chaudhuri
  • Jaydeep Sarma
  • Erik B Schelbert
  • Matthias Schmitt
  • Karen Piper Hanley
  • Christopher Miller

Abstract

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

Objectives: 1.Identify where USPIO locate to in myocardium; 2.Develop a methodology that differentiates active macrophage uptake of USPIO from passive tissue distribution; 3.Investigate myocardial inflammation in cardiovascular diseases.

Methods: 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 ischaemic cardiomyopathy (n=7), myocarditis (n=6), dilated cardiomyopathy (n=5) and chronic sarcoidosis (n=5).

Results: 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* behaviour and R2*/R1 ratio were higher in infarcted (p=0.001) and remote (p=0.033) myocardium in acute MI and in chronic ischaemic 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.

Conclusions: USPIO are phagocytised 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 ischaemic cardiomyopathy, providing a substrate for HF.

Bibliographical metadata

Original languageEnglish
JournalJACC: Cardiovascular Imaging
Publication statusAccepted/In press - 3 Feb 2020