Associations between Myocardial Susceptibility and Reactive Oxygen Species in the Subacute and Chronic Period of Myocardial Infarction

Presenting Author(s)

• 

  Marina M. Awad, BSc

  PhD Student
  University of Pennsylvania
  Philadelphia, Pennsylvania, United States

Primary Author(s)

• 

  Marina M. Awad, BSc

  PhD Student
  University of Pennsylvania
  Philadelphia, Pennsylvania, United States

Co-Author(s)

• SS

  Sophia Swago

  PhD student
  University of Pennsylvania
  Philadelphia, Pennsylvania, United States
• CC

  Chiara Camillo, PhD

  Associate Research Scientist
  Columbia University
  New York, New York, United States
• ET

  Elizabeth Thompson, PhD

  MD-PhD Student
  University of Pennsylvania, United States
• GF

  Giovanni Ferrari, PhD

  Associate Professor
  Columbia University
  New York, New York, United States
• EC

  Estibaliz Castillero, PhD

  Associate Research Scientist
  Columbia University
  New York, New York, United States
• EG

  Evan Gallagher, BSc

  PhD Student
  The Children’s Hospital of Philadelphia
  Philadelphia, Pennsylvania, United States
• MM

  Meagan McManus, PhD

  Associate Research Scientist
  The Children’s Hospital of Philadelphia
  Philadelphia, Pennsylvania, United States
• 

  Victor A. Ferrari, MD

  Professor of Medicine and Radiology
  University of PA Medical Center
  Phila., Pennsylvania, United States
• RG

  Robert Gorman, MD

  Professor
  University of Pennsylvania
  Philadelphia, Pennsylvania, United States
• CT

  Cory Tschabrunn, PhD

  Assistant Professor
  University of Pennsylvania, Massachusetts, United States
• RM

  Robert Mach, PhD

  Professor of Radiology
  University of Pennsylvania, United States
• JK

  Joel Karp, PhD

  Professor of Radiologic Physics
  University of Pennsylvania, United States
• 

  Paco E. Bravo, MD

  Director of Nuclear Cardiology and Cardiovascular Molecular Imaging
  Hospital of the University of Pennsylvania
  Philadelphia, Pennsylvania, United States
• WW

  Walter R. Witschey, PhD

  Associate Professor of Radiology
  Perelman Center for Advanced Medicine
  Philadelphia, Pennsylvania, United States

Background: Reperfusion injury after myocardial infarction (MI) has been reported in 41-54% of patients. The presence of this ischemia-reperfusion injury (IRI) plays a catalytic role in reactive oxygen species (ROS) production, initiated by coronary artery extravasation (hemorrhage). These patients develop adverse left ventricular remodeling and have an increased risk of heart failure. However, associations of ROS with reperfusion injury and with infarct remodeling have not been studied before due to limitations in measuring ROS noninvasively. In this study, we used novel PET radiotracer [18F]ROStrace to image ROS and quantitative susceptibility mapping to image iron in a swine model of IRI within 3-7 days (subacute) and 8 weeks of reperfusion (chronic).

Methods: The mid left anterior descending coronary artery was occluded in eight swine (Fig. 1), followed by reperfusion. At ~6.1±1.2 days and eight weeks following IRI, swine underwent CMR (1.5 T Siemens Avanto) and whole-body PET (Penn PET Explorer). [18F]ROStrace myocardial perfusion was calibrated using [82]Rb fractional uptake rate (FUR) to compute the myocardial blood flow corrected ROStrace FUR in the infarct and remote regions. We computed the difference in ROS activity between the infarct and remote regions (ΔROS). Hemorrhage was determined based on T2* thresholding less than 25 ms in the myocardium. The protocol included LGE, cine, and gradient echo imaging to acquire T2*w images and QSMs. Susceptibility of the myocardium was measured from the QSM. The relationship between susceptibility and ΔROS was computed using repeated-measures correlation. Infarct size and MVO were quantified from LGE using QMass 8.1. Cine MRI was used to calculate hemodynamics such as cardiac output (CO).

Results: Three swine were excluded from QSM analysis due to image quality, and one was excluded from PET due to missing data. Images at the subacute and chronic time point are shown in Fig. 2. Seven of eight swine had hemorrhage in the infarct at the subacute period, but not at the chronic time point (Fig. 2). There was increased myocardium susceptibility at subacute (0.001 ± 0.014 ppm) compared to chronic (-0.015 ± 0.015 ppm). ΔROS was significantly higher at the subacute period (0.07 ± 0.03 mL/g) compared to chronic (-0.03 ± 0.05 mL/g), p=0.0003. There was a significant positive correlation between susceptibility and ΔROS (r=0.9, p=0.02) (Fig. 3). Infarct size was significantly higher at the subacute period (7.9 ± 3.7 g) compared to chronic (5.4 ± 1.9 g), p=0.03. MVO size was significantly higher at the subacute period (0.9 ± 0.9 g) compared to chronic (0.2 ± 0.3 g), p=0.04. CO was significantly higher at the chronic period compared to subacute (p=0.005). The CO was 5.2 ± 1.3 L/min at subacute and 6.2 ± 1.4 L/min at chronic.

Conclusion: Using CMR and PET, increased susceptibility, ROS activity, infarct and MVO size were found at the subacute period compared to chronic, and a strong positive correlation between ROS and susceptibility was observed.

Figure 1: Experimental procedures. MI was induced percutaneously (Day 0) and CMR and whole-body [18F] ROStrace PET were performed at subacute (Day 3-7) and chronic (Week 8) IRI period. Icons are from BioRender.
Figure 2: Data analysis. Example of LGE, T2*w, and QSM in a swine imaged at the sub-acute and chronic MI time points.
Figure 3: Boxplots of myocardium susceptibility, difference in ROStrace FUR between infarct and remote regions, and cardiac output at the subacute and chronic period. A graph on the relationship between ROS and susceptibility of four swine (had CMR QSM and PET complete).