Introduction

Creatine (Cr) plays a critical role in the buffering and transport of chemical energy to maintain the dynamic demands of the heart [1]. Measurement of Cr may provide useful information for evaluating myocardial metabolic state. Superior over ¹H MRS, chemical exchange saturation transfer (CEST) MRI enables Cr imaging with better spatial resolution and higher detection sensitivity [2]. The present study aims to investigate dynamic change of myocardium Cr in infarct heart remodeling process using CEST MRI, which may provide complementary information for better understanding of heart remodeling at the molecular level.

Materials and Methods

MRI study: The study was approved by the local Institutional Animal Care and Use Committee. Seven adult Bama pigs underwent MRI studies on a 3T scanner (uMR 790, Shanghai United Imaging Healthcare, Shanghai, China) 3 (D3) and 14 days (D14) after myocardium infarction (MI) induction, respectively. Cardiac quiescent period was identified from cine imaging (0.95×0.95×8.0 mm³, TR/TE=3.1/1.5 ms, 25 retrospectively reconstructed cardiac phases, flip angle=50°). ECG-triggered and respiration-navigated single-slice CEST scans were performed at the short-axis plane covering infarction (1.1×1.1×8.0 mm³, matrix size=270×288, TE=1.2 ms, flip angle=50°, iPAT=2). The CEST pulse sequence was illustrated in Fig. 1. In brief, six Gaussian-shaped saturation pulses with equivalent B₁ of 3.8 μT were applied in the CEST preparation module (pulse duration=40 ms, inter-pulse delay=40 ms, flip angle=2700°), as optimized previously [3]. Data was acquired using a bSSFP readout at cardiac quiescent period. In addition to a reference scan without RF irradiation, 31 CEST-weighted images were collected with saturation frequency offsets equally distributed between ± 4.5 ppm. Finally, LGE imaging was completed 5-10 minutes after the contrast agent injection (0.1 mmol/kg, gadopentetate, Kangchen, Guangzhou, China) using PSIR technique (0.63×0.63×8.0 mm³, TR/TE/TI=4.37/1.78/350 ms, flip angle=25°).
Data analysis: Cines on the slice of CEST imaging were loaded into Medis Suite 3.2 (Medis Medical Imaging Systems, Leiden, Netherlands) for LV structure and function measurements, including myocardium mass (MM), end-diastolic volume (EDV), end-systolic volume (ESV), stroke volume (SV), and ejection fraction (EF). CEST data was processed using custom-written MATLAB codes. The algorithm of minimizing residual complexity [4] was employed to co-register CEST-weighted images and manual adjustment was conducted if necessary. Pixel-wised Z-spectrum (M_Z) was normalized by the signal without RF irradiation (M₀), interpolated by smoothing splines, and centered to the water resonance [5]. Then, the normalized Z-spectrum was fitted using a probabilistic combination of three-pool Lorentzian functions to resolve saturation transfer effects of magnetization transfer (MT), direct water saturation (DWS) and Cr pool with their chemical shifts at -1.5, 0 and 1.8 ppm, respectively [6]. The amplitude of the Cr pool is defined as the Cr CEST. Infarcted myocardium was identified as hyperintense in the LGE T₁w images, with infarct angle recorded. The remaining myocardium was circumferentially divided into six equiangular radial segments. The two segments immediately adjacent to infarction were classified as the adjacent region, and the remaining four segments were categorized as the remote region [7]. Cr CEST signal was measured in each region and global myocardium. Student’s t-test was employed with P<0.05 considered statistically significant.

Results and Discussion

Figure 2 compares multiparametric MR images of a representative infarct porcine at D3 and D14 after MI induction. Pronounced scar compaction was observed at D14, resulting in smaller infarct angle compared to that at D3. Noticeably lower Cr CEST signal was found to be largely consistent with the scar region shown on the LGE T₁w images at both time points. Additionally, substantially higher Cr CEST contrast was exhibited at D14 than that at D3, especially in the infarct myocardium and its adjacent areas.
Cardiac structural and functional indices on the slice of CEST imaging were compared between D3 and D14 after MI induction (Fig. 3). The changes of myocardium mass, EDV, and ESV were not statistically significant between the two time points. In contrast, significant increase of SV and EF, and decrease of infarct angle were observed at D14 compared to that at D3.
Figure 4 displays the Cr CEST signal change in the infarct, adjacent and remote regions as well as the entire myocardium over the studied period. Statistically significant increase of Cr CEST signal was found in the infarct, adjacent, and entire myocardium. Meanwhile, alteration of Cr CEST signal in the remote region was insignificant.
Quantitatively, none of LV mass, EDV, ESV, SV or EF exhibited significant correlation with global or regional Cr CEST signals (Table 1). Whereas, significantly negative correlations of Cr CEST signals with infarct angle were observed in the infarct, adjacent, and entire myocardium. The results demonstrated that the larger the infarct angle, the lower the Cr CEST signal, implying the extent of CK metabolic abnormality to be likely associated with infarct size.

Conclusion

Significant increase of Cr CEST signals was observed in infarct and its adjacent myocardium from day 3 to day 14 after MI injury. The indicated metabolic acitivity improvement may be associated with cardiac structural and functional recovery. The study shows that Cr CEST MRI is promising to provide complementary information for better understanding of heart remodeling at the molecular level.

References

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