Introduction

T1 mapping is a popular method use in myocardial fobrosis assessment. Extracellular volume fraction (ECV) derived from T1 mapping correlated well with collagen volume fraction (CVF) histological. Endogenous contrast T1ρ mapping for detecting collagen content has been used more and more often recently, although it was used first in regional fibrosis. ECV reflects myocardial fibrosis through extracellular expansion measurements while myocardial fibrosis index (mFI), which is a new non-contrast myocardial fibrosis index calculated based on the dispersion characteristics of T1ρ, derived from T1ρ detects collagen content, so it worth well to investigate the difference. A type 2 diabetes mellitus (T2DM) rehsus monkey model with different diastolic dysfunction (DD) was used.

Methods

A total of 27 male rhesus monkeys were studied. Eighteen (14.33±2.24years, 10.89±1.48kg) of them were spontaneous T2DM (T2DM, FPG: 6.43 (6.08 6.58)mmol/L, HbA1c: 4.90 (4.75 5.10)%). The other nine (13.33years±1.11years, 10.15kg±0.84kg) healthy controls (HC, FPG: 4.24 (4.05 4.48)mmol/L, HbA1c: 4.35 (4.30 4.45)%) are matched in age, weight and gender. There was a four-week acclimation for blood biochemical examination. Echocardiography was performed for diastolic function classification (normal, mild, and moderate DD) on all monkeys 48h after the last blood collection. Cardiac magnetic resonance (CMR) was performed sequentially on all of the monkeys. CMR whole-heart cine was used for cardiac function evaluation, T1 mapping for ECV calulation, T1ρ mapping at two different spin-locking frequencies for mFI and absooute T1ρ values mesurements and late gadolinium enhancement (LGE) imaging for regional fobrosis detection. One heart of a T2DM monkey with moderate DD was harvested for histopathology. Masson staining were performed to confirm diffuse myocardial fibrosis. According to the classification of DD, we further assigned T2DM with HFpEF into different groups: T2DM with mild DD, T2DM with moderate DD. The comparisons were processed among three groups.

Results

Echocardiographic results showed mild DD in 9 T2DM monkeys (E/A < 1,E’/A’ > 1 or < 1, E’ > 7, E/E’ < 11) and moderate DD in the other 9 T2DM monkeys (E/A > 1,E’/A’ < 1, E’ < 7, E/E’ > 11). The mFI increased progressively from healthy to mild DD, and then to moderate DD (2.90 ± 1.41 vs. 4.91 ± 2.09 vs. 7.74 ± 2.48). The differences between healthy and the mild (p = 0.049) or between the mild and the moderate (p = 0.007) were all significant. The corresponding global ECV was significantly different between three groups (24.61 (22.96 to 25.88) vs. 26.34 (25.39 to 26.97) vs. 29.02 (27.46 to 34.48)), but there was no significant different in ECV between healthy and the mild. Meanwhile, there was a positive correlation between mFI and ECV (r = 0.603, p = 0.001). For focal fibrosis, there was no evidence of regional late contrast enhancement in all animals. E’ correlated with mFI (r = -0.465) and ECV(r = -0.715). Histopathology showed that the myocardial extracellular space was widened with diffuse fibrosis (ECV = 37.46% and mFI =5.85) in T2DM with moderate DD.

Discussion

Collagen deposition around intramural cardiac vessels and between myofibres, as well as expanded extracellular space are thought to be important contributors to DD in T2DM (1). While a good correlation between mFI and ECV was found, there still difference. The precise mechanisms to account for the different behaviors of ECV and mFI to differentiate HC from T2DM with mild DD remain unknown. One reason may be that increased ECV reflects the expansion of extracellular volume while increased mFI reflects the deposition of excessive collagen. Based on chemical exchange theory (2), an increased concentration of water protons bound to macromolecules (e.g., collagen) leads to increases in mFI. The magnitude of the increase is modulated by the chemical shifts and exchange rates of macromolecules. Although ECV correlated well with histologically quantified CVF, it theoretically delineates histological extracellular space. In a recent study by Shiro et al (3) showed ECV strongly correlated (r = 0.86) with histological extracellular space component but only modestly correlated (r = 0.66) with histological CVF in patients with dilated cardiomyopathy.

Conclusion

From the results of our study, at the very early stage of DD, diffuse myocardial fibrosis still play an important role, meanwhile, ECV is not sensitive enough in ECM remodeling detection while mFI assess the changes in collagen contents. The nature between collagen deposition and extracellular volume expansion is still need further investigated. Future study to systematical validate mFI method by histologically defined collagen volume is warranted with sufficient sample size.

Acknowledgements

No acknowledgement found.