Minimally Invasive Free-Breathing Gating-Free Extracellular Cellular Volume Quantification for Repetitive Myocardial Fibrosis Evaluation in Rodents

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Abstract
Background: Interstitial myocardial fibrosis is a crucial pathological feature of many cardiovascular disorders. Myocardial fibrosis resulting in extracellular volume (ECV) expansion can be quantified via cardiac MRI (CMR) with T1 mapping before and after minimally invasive gadolinium (Gd) contrast agent administration. However, longitudinal repetitive ECV measurements are challenging in rodents due to the prolonged scan time with cardiac and respiratory gating that is required for conventional T1 mapping and the invasive nature of the rodent intravenous lines. Methods: To address these challenges, the objective of this study is to establish a fast, free-breathing, and gating-free ECV procedure using a minimally invasive subcutaneous catheter for in-scanner Gd administration that can allow longitudinal repetitive ECV evaluations in rodent models. This is achieved by the (1) IntraGate sequence for free-breathing, gating-free cardiac imaging; (2) minimally invasive subcutaneous in-scanner Gd administration; and (3) fast T1 mapping with a varied flip angle (VFA) in conjunction with (4) triple jugular vein blood T1 normalization. Additionally, full cine CMR (multi-slice short-axis, long-axis 2-chamber, and long-axis 4-chamber) was acquired during the waiting period to assess comprehensive cardiac function and strain. Results: We successfully established a minimally invasive fast ECV quantification protocol to enable longitudinal repetitive ECV quantifications in rodents. Minimally invasive subcutaneous Gd bolus administration induced a reasonable dynamic contrast enhancement (DCE) time course, reaching a steady state in ~20 min for stable T1 quantification. The free-breathing gating-free VFA T1 quantification scheme allows for rapid cardiac (~2.5 min) and jugular vein (49 s) T1 quantification with no motion artifacts. The triple jugular vein T1 acquisitions (1 pre-contrast and 2 post-contrast) immediately flanking the heart T1 acquisitions enable accurate myocardial ECV quantification. Our data demonstrated that left-ventricular myocardial ECV quantification was highly reproducible with repeated scans, and the ECV values (0.25) are comparable to reported ranges among humans and rodents. This protocol was successfully applied to the ischemia–reperfusion injury model to detect myocardial fibrosis, which was validated by histopathology. Conclusions: We established a simple, fast, minimally invasive, and robust CMR protocol in rodents that can enable longitudinal repetitive ECV quantification for cardiovascular disease progression. It can be used to monitor disease regression with interventions.
Funding Information
  • American Heart Association (18CDA34140024)
  • National Institutes of Health (R21EB023507)
  • U.S. Department of War (W81XWH1810070)

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