In this study, we performed a continuous evaluation through histological verification, CMR T1 mapping, and echocardiography parameters at longitudinal multi-time points in the T1DM mouse model. Meanwhile, the main objective was to determine the accuracy of the qualitative and quantitative evaluation of early DMIF at early time points. Our study results revealed that (a) the ECV value gradually increased during diabetic progression. Notably, at the 12-week time point, the ECV value significantly differed between the T1DM and control group. (b) The ECV value was strongly correlated with the CVF and moderately correlated with precontrast and postcontrast T1 values, which could continuous reflect the degree of DMIF in the duration of diabetes.
Because the myocardial T1 value was obtained to indirectly determine the tissue characteristics of the normal or damaged myocardium in humans, endomyocardial biopsy has seldom been performed in most cases, and the accuracy was still unstable[18]. Meanwhile, the accuracy was easily affected by CMR equipment, hemodynamics condition, acquisition sequence, and time phase. In addition, it was difficult to dynamically monitor cardiac diseases at multiple time points in humans[19] due to time and space. Thus, the underlying mechanism of disease progression remains unclear. However, animal models can be used to evaluate the degree of myocardial fibrosis by changing the T1 mapping parameter duration of DCM. Notably, not only the diabetic mouse model had the advantages of simplicity, high consistency, and excellent repeatability but also the effects of age, disease progression, and concomitant disease were prevented including those of hypertension[16] and coronary heart disease[20]. In this study, a diabetic mouse model was used, and DMIF was continuously monitored using a 7.0 T MRI device by using the GRE look–locker sequence compared with histology and echocardiography results.
Because the heart and respiratory rates of diabetic mice are affected by various factors (such as the flow concentration of the gas anesthetic, the severity of the disease, and ambient temperature), the changes are substantial[21]. Thus, cardiac tissue features are challenging to be accurately described. Transthoracic echocardiography is the most common imaging method that can assess the morphology and function of the heart, complying with the merits of no radiation and economic efficiency[22]. In our study, high-resolution echocardiography exhibited that compared with the control group, the T1DM group showed a gradual decrease in the E/A ratio. FS and EF progressively decreased in the T1DM group from 4 to 24 weeks, whereas EF was preserved; FS and EF values significantly differed at 16 weeks, whereas the E/A ratio significantly differed at 12 weeks between the T1DM and control groups. Diastolic dysfunction occurred earlier than systolic dysfunction, and the diastolic function gradually deteriorated in the T1DM group; this finding is consistent with that of previous studies[14, 23]. Meanwhile, LV mass and LV mass (corrected) increased from 4 to 24 weeks in the T1DM group, possibly due to cardiac hypertrophy, which was also confirmed by the increased ratio of the heart weight to tibia length.
CMRI not only has the advantages of no radiation and excellent repeatability but also can better evaluate the characteristics of the myocardium compared with echocardiography[6, 24]. Although the imaging time is considerably long, it is widely used to assess ischemic cardiomyopathy and nonischemic cardiomyopathy[25, 26]. DCM is mainly manifested as DMIF in the early stage of DM[4, 27]. In our experimental study, no LGE regions were observed in the myocardium in the T1DM group. Meanwhile, Zhang[28] and Zeng[29] have reported the same result. Some studies have indicated the presence of LGE regions in some patients with DM. Other mixed factors may lead to focal MF including nondiagnosed coronary heart disease, valvular heart diseases, and myocardial metabolic diseases[30].
In recent years, ultra-high field MRI and T1 mapping parameters have been widely used to detect DMIF[31, 32]. In particular, ECV can exhibit pre- and post-contrast T1 values when myocardial cells and blood pool contrast agents reach an equilibrium state. In addition, ECV can reflect changes in the myocardial extracellular matrix and is a relatively stable imaging marker that has been used to quantitatively evaluate DMIF. ECV is not disturbed by the acquisition time window, HCT, renal excretion rate, and contrast agent wash in and wash out in pathological conditions[33, 34]. Meanwhile, ECV can serve as a sensitive noninvasive imaging tool to observe changes in the extracellular space of the myocardium during diabetes progression and can be used to dynamically monitor the characteristic of the early stage of DCM. In our study, the ECV value gradually increased during diabetes progression. The ECV value at 12 weeks significantly differed between the T1DM and control groups; this finding is in line with that obtained for CVF. Our study showed that the ECV value was strongly correlated with CVF, and the postcontrast T1 value was moderately associated with the CVF value. The main reason is likely that the gadolinium agent (as an extracellular contrast agent) could not pass through the cell membrane and enter the cell; therefore, the postcontrast T1 value was mainly associated with the contrast agent concentration in the extracellular matrix, which is consistent with the findings of our previous studies[23, 29] and another study[28]. In addition, our study showed that the ECV value was higher than CVF, possibly because the CVF value reflects only the extracellular collagen fiber content, whereas the ECV value can also indicate mucus matrix, lipid, and necrosis components outside cells. In the early stage of DCM, pathophysiological changes can occur including oxidative stress, inflammatory reaction, edema, fatty degeneration of the heart, lipid deposition, and mild myocardial fibrosis[2]. Thus, the combination of these pathological processes leads to changes in cardiac morphology and function.
Several recent studies have shown that collagen fibers can prolong the native T1 value; thus, native T1 mapping without injecting contrast agents can be used to detect DMIF[35, 36]. This method does not need injecting a gadolinium contrast agent and is more convenient than the acquisition of the ECV value. Native T1 mapping can be used in patients with severe renal dysfunction and allergic constitution. In our study, a moderate correlation was observed between the CVF value and native T1 value in the T1DM group (T1DM r = 0.557 and T2DM r = 0.538). However, pathophysiological changes in DCM are complex including edema, fatty degeneration, hemorrhage, and collagen deposition, which can prolong or shorten the native T1 value in the myocardium. Therefore, the application of the native T1 value in the evaluation of DCM still needs to be studied in the future. Meanwhile, native T1ρ mapping, as an endogenous contrast technique, has been used for detecting myocardial fibrosis[37]. This technique does not require exogenous contrast agents, and in some studies, a positive correlation between T1ρ and ECV was observed[28, 38]. Thus, in our next study, native T1ρ mapping may be applied in DCM.