Native T1 Mapping as a Biomarker of Myocardial Fibrosis in a Translational Model of Infarct Healing

Presenting Author(s)

• 

  David C. Wendell, PhD

  Senior Research Scientist
  Duke University Medical Center
  Durham, North Carolina, United States

Primary Author(s)

• 

  David C. Wendell, PhD

  Senior Research Scientist
  Duke University Medical Center
  Durham, North Carolina, United States

Co-Author(s)

• SA

  Satya Achanta, PhD

  Assistant Professor
  Duke University Medical Center, United States
• CC

  Céleste Chevalier, MD

  Postdoctoral fellow
  Duke University Medical Center
  Durham, North Carolina, United States
• 

  Wolfgang Rehwald, PhD

  Staff Scientist
  Siemens Healthineers
  Chapel Hill, North Carolina, United States
• HK

  Han Kim, MD

  Associate Professor of Medicine
  Duke University Medical Center
  Durham, North Carolina, United States
• MP

  Michele Parker, MSc

  Statistician / Business Manager
  Duke Cardiovascular Magnetic Resonance Center, North Carolina, United States
• EC

  Enn-Ling Chen, PhD

  Research Professor
  Duke Cardiovascular Magnetic Resonance Center, North Carolina, United States
• 

  Raymond Kim, MD

  Professor
  Duke Cardiovascular Magnetic Resonance Center
  Durham, North Carolina, United States

Background: Myocardial fibrosis is a fundamental process in cardiac injury. Following acute myocardial infarction (MI), the infarcted tissue undergoes a sequence of pathophysiological changes including necrosis, inflammation, and subsequent healing with the development of replacement fibrosis. Native T1 mapping has been purported to diagnose myocardial fibrosis¹, identify remote myocardial remodeling, and peri-infarct myocardial changes, without the need for Gadolinium-based contrast agents. However, recent studies^2,3 have shown T1 mapping values can be artifactually elevated in chronic MI due to fat. Therefore, we tested native T1-mapping’s ability to detect myocardial fibrosis in a translational animal model of healing MI using a pathology-based reference standard for myocardial fibrosis.

Methods: A canine model of acute myocardial infarction was used as previously described⁴. MI was induced in 8 animals by 90-minute occlusion of left anterior descending (LAD) coronary artery followed by reperfusion. Cardiac Magnetic Resonance (CMR) imaging was performed on 1-, 3-, 6-, and 8-weeks post-MI induction. Native T1 mapping and delayed-enhancement imaging were obtained at each time point. Following euthanasia, the heart was harvested for histopathologic processing including Masson-Trichrome stain for fibrosis. Hydroxyproline levels within normal and infarcted myocardium were measured using mass spectrometry (MS). Native T1 values within infarcted and normal myocardium were compared against tissue levels of collagen hydroxyproline in these regions.

Results: CMR imaging results are presented for animals at each studied time point (1-week: n=2; 3-weeks: n=3; 6-weeks: n=3; 8-weeks: n=2). Figure 1 shows representative imaging for native T1, DE-CMR, and Masson-trichome stain at each time point. Native T1 values were presented as a ratio between MI and normal regions. MI/normal T1 ratios were elevated acutely (i.e. >1.1) with the infarcted myocardium native T1=1400ms (< 1289ms established normal range). At 3-, 6-, and 8-weeks post-MI, native T1 mapping ratios were ~1.0 (i.e. no difference between infarcted and remote myocardium) (Figure 2A). Collagen content progressively increased over the course of infarct healing within the infarcted myocardium (Figure 2B) but did not increase significantly for remote myocardium. Thus there was an inverse relationship between T1 ratio and levels of fibrosis by pathology (i.e. as fibrosis level increased infarcted-to-normal native T1 ratio decreased).

Conclusion: CMR has been instrumental in the evaluation of acute MI. However, relying on T1 mapping for accurate fibrosis detection remains problematic. The results of this study did not show correlation between native T1 and fibrosis levels. Additionally, minimal to no changes were observed in fibrosis burden or T1 values in remote myocardium. Therefore, it remains clear that DE-CMR remains the in vivo reference standard for imaging myocardial fibrosis.

Figure 1: Representative images for each time point with Native T1 (top), Delayed-enhancement Cardiac Magnetic Resonance (DE-CMR) images, and Masson-Trichrome stain for fibrosis (bottom). At 1 week post-MI Native T1 images show elevation in T1 values within the infarcted myocardium representing edema and acute necrosis (red arrow). DE-CMR shows enhancement in the same area (red arrow). Masson-Trichrome stain does not show any replacement fibrosis at the acute timepoint. At 3 weeks post-MI Native T1 may have some residual edema, DE-CMR shows clear infarction, and Masson-Trichrome stain shows the beginnings of replacement fibrosis (blue areas within the myocardium, yellow arrow). At 6 weeks post-MI Native T1 is normal in the infarcted region, DE-CMR shows clear enhancement, and Masson-Trichrome stain now shows dense replacement fibrosis within the infarcted region (yellow arrow). At 8 weeks post-MI Native T1 again appears within normal range, clear enhancement on DE-CMR, and dense replacement fibrosis (blue areas, yellow arrow) via Masson-Trichrome stain.
Figure 2: Tissue and image analysis in these animals shows (A) Native T1 ratio between infarcted and normal myocardium is elevated in acutely and approaches a ratio of 1.0 over the subsequent weeks (i.e. no difference between infarct and remote). (B) Fibrosis burden (as represented by hydroxyproline concentration) within the infarcted territory progressively increases over the course of weeks following MI. Remote myocardium does not show any increase in fibrosis over the healing process.