A novel method for high precision aortic constriction that allows for generation of specific cardiac phenotypes in mice.

Aims: Generation of reproducible cardiac disease phenotypes in mice is instrumental for investigating mechanisms leading to heart failure. For decades, suture-based thoracic aortic constriction has been the preferred method for increasing left ventricular (LV) afterload in rodents, but the degree of stenosis resulting from this method is variable. In an effort to improve this methodology, we subjected mice to constriction of the ascending aorta using o-rings with fixed inner diameters (IDs).

Methods and Results: Mice of C57BL/6J and FVB/N background were subjected to constriction of the ascending aorta using o-rings with fixed IDs of 0.71, 0.66 and 0.61 mm. O-ring aortic banding (ORAB) resulted in 98.7% survival 2 weeks post-surgery, with very low intra- and inter-surgeon variation. When using the narrowest o-ring (0.61 mm), mice developed hypertrophy within one week. Over 20 weeks, the mice gradually developed reduced LV ejection fraction and dilatation with increased left atrial dimensions and lung weight, indicating congestion. When using o-rings with IDs of 0.66 mm and 0.71 mm, the mice developed hypertrophy, but maintained a compensated state with stabilized LV ejection fraction 8-20 weeks post-surgery. The up-regulation of signature genes associated with heart failure, hypertrophy, fibrosis and the level of activation of MAPK and NFAT signaling pathways corresponded to the degree of stenosis.

Conclusion: We here introduce a novel method for high precision aortic constriction in mice with high intra- and inter-surgeon reproducibility and low post-operative mortality that allows generation of specific cardiac disease phenotypes.