Assessment of global and segmental strain in heterozygous APE1/Ref-1 transgenic mice using cardiac magnetic resonance imaging

Abstract

Abstract Background Apurinic/apyrimidinic-endonuclease1(APE1/Ref-1) is a redox factor necessary for DNA binding and transcription regulator in ROS generation. The association between APE1/Ref-1 and heart failure(HF) has been observed in previous studies. Heterozygous APE1/Ref-1 transgenic mice displayed endothelial cell dysfunction with systemic hypertension. Global strain(GS) measures the myocardium's deformation along its axis and is known to be a sensitive marker of subclinical HF in hypertensive patients with preserved ejection fraction. Purpose This study aims to investigate the functional dynamics and GS of the heart in heterozygous APE1/Ref-1 mice to help identify the association between APE1/Ref-1 and early signs of HF and translate to clinical applications. Methods A study was conducted to assess the functional parameters of both the left ventricle(LV) and right ventricle (RV) and perform LV global and segmental strain analysis using cardiac magnetic resonance imaging(CMR) in heterozygous APE1/Ref-1 transgenic mice(n=4) and wild type mice (n=4) of age 10-12 weeks. A 7T CMR scanner and FSE T1 sequence were used to acquire short-axis views of mouse cardiac images. LV and RV functional parameters including ejection fraction(EF), stroke volume(SV), cardiac output, peak filling rate, peak emptying rate and strain indices including global circumferential strain, global radial strain, segmental circumferential strain, and segmental radial strain were calculated with a software dedicated to analyzing CMR images. Global LV and RV function was quantified both manually and using an AI-based algorithm of LV and RV segmentation. The strain analysis was performed using the strain medical image tracking toolbox module. Additionally, reproducibility testing was done to validate the accuracy of AI-driven calculations. Results We found that heterozygous APE1/Ref-1 mice displayed a decrease in SV(8.00±0.01ul vs 9.75±0.96ul, p=0.01) and LVEF(58.75±2.63% vs 66.50±2.89%, p=0.007) compared to controls while the functional parameters of RV were similar. Interestingly, the circumferential strain rate of LV was significantly reduced in APE1/Ref-1 mice compared to controls(p<0.001), particularly in the systolic phase. In addition, the study showed that manually-calculated and AI-derived indices were within an acceptable margin of error, rendering the AI system reproducible and reliable in calculating volumetric parameters and strain of the mice's hearts. Conclusions This study demonstrated that LV global circumferential strain rate, along with SV and LVEF decreased in heterozygous APE1/Ref-1 transgenic mice. These parameters could serve as markers for assessing early functional changes of mice hearts in a non-invasive manner. Volumetric and strain indices measured by AI-based analysis of mouse CMR images are reproducible parameters for cardiovascular research in small animals.LV strain analysis of mice CMRTable of volumetric parameters