P3099Lymphatic insufficiency increases cardiac edema after myocardial infarction as assessed by novel magnetic resonance TRAFFn and T2 relaxation times
Authors: Yla-Herttuala E , Vuorio T , Laidinen S , Yla-Herttuala S , Liimatainen T 
Published: October 2019

Abstract

Introduction
The role of cardiac lymphatic system in myocardial infarction (MI) is still unclear. A new method to detect and characterize MI without contrast agent is a relaxation along a fictitious field in nth rotating frame (RAFFn). The RAFFn takes advantage of the fictitious magnetic field, which is produced by a fast sweep of an effective radio frequency field, to increase a spin locking field strength without increasing the specific absorption rate. MI is detected as increased RAFFn relaxation times and cardiac edema by an increased T2 relaxation time. We have shown earlier that MI size can be accurately measured by the RAFFn relaxation times.

Purpose
To study the effects of the lack of cardiac lymphatic system on MI and cardiac edema in a mouse model.

Methods
Transgenic (TG) mice expressing soluble decoy VEGF receptor 3 (sVEGFR3) thus blocking lymphatic vessel formation in the heart and wild type (WT) control mice were used. MI was induced in 13–17 week old TG (n=11) and WT (n=14) mice by ligating the left anterior descending coronary artery. The RAFFn (TRAFF2 and TRAFF4), a continuous wave T1ρ and a T2 relaxation times were acquired at time points 0, 3, 7 and 21 days after the MI at 9.4 T. Histological sections were stained with hematoxylin eosin and Sirius red to assess cellularity and MI area. An Area of difference (AOD) was determined by subtracting MI areas based on TRAFF2, TRAFF4 and T1ρ maps from MI area based on T2 maps.

Results
MI size based on the TRAFF4 and T2 relaxation time maps were larger at early time points 3 and 7 days post MI in the WT group compared to the TG group (Figure 1A-B, p<0.05). However, the MI size was significantly larger in the T2 relaxation time map in the TG group compared to the WT group at the last time point and interaction between the groups were significant as a function of time (Figure 1A-B, p<0.05). The AOD values, which reflect cardiac edema, increased in the TG group as a function of time (Figure 1C, p<0.001). TRAFF2, TRAFF4 (Figure 1D), T1ρ and T2 relaxation times increased significantly (≈50%, p<0.001) after the MI compared to remote areas in both groups. In the WT group, the lymphatic vessel network is fully functional and removes edema efficiently between days 3 and 21 after the MI, while in the TG group the MI area in T2 map is relative stable indicating insufficient edema removal, caused by the lymphatic deficiency and insufficient lymphangiogenesis in the TG group. The MIs were also verified based on Sirius red stained histology (Figure 1E).
Figure 1

Conclusion
Lymphatic deficiency increases cardiac edema (AOD values) 7–21 days after MI as compared to the WT group. Results support the importance of cardiac lymphatic vessels for healing after MI. Effects of the lymphatics on MI can be detected based on the MI size difference based on the TRAFFn and the T2 relaxation times.

Acknowledgement/Funding
Doctoral Programme of Molecular Medicine