Abstract P3125: Big Data Evaluation Of Cardiac Remodeling Trajectories After Myocardial Infarction In Male And Female Mice

Abstract

Female mice display higher survival rates by day (D) 7 after myocardial infarction (MI) compared to their male counterparts. We used big data analysis of the mouse Heart Attack Research Tool (mHART) 2.0 database to identify sex similarities and differences in cardiac wound healing after MI. The database includes echocardiogram and necropsy analysis from n=1,746 (1,146M and 600F) C57BL/6J wild-type adult mice (age 2-9 months). The extent of cardiac dilation over the first week after MI (calculated as fold-change of average D0 value) was parallel in males and females on all days except MI D5. At D5, males displayed 22% higher end systolic volume and 17% higher end diastolic volume than females (both p<0.0001). D5 infarct size did not explain the dilation or survival differences (53±1% in males and 50±2% in females, p>0.99). Analysis of extracellular matrix (ECM) gene expression data for 84 ECM genes (by Qiagen array) from no MI D0 left ventricle (n=40, 24M/16F) and MI D5 (n=28, 21M/7F) infarct tissue revealed molecular signaling differences by sex. Compared to D0, MI D5 showed 70 ECM genes differentially expressed (all p<0.05). MI D5 showed 38 genes differentially expressed by sex (all p<0.05 by t-test), of which 20 were higher and 18 were lower in males. The top 3 genes ranked by variable important scores were Timp3, Col4a2, and Mmp7 , and all were increased in males. The most enriched pathway represented was focal adhesion in males and matrix metalloproteinases in females. Focal adhesion was enriched in both males and females at MI D5, albeit through upregulation of different gene profiles; Itgb1, Col3a1, Col4a1/2 in males and Lamb3, Lama1, and Itgax in females. Overall, our results indicate that male and female mice show unique cardiac remodeling trajectories with notable divergence at D5, leading to higher early survival.