Abstract 4143866: The Effect of S100A6 Gene Therapy on Cardiac Function in a Rat Model of Ischemic Cardiomyopathy

Background: S100A6 is a small calcium-binding protein that is important in managing calcium storage and myocyte contractility. This protein has a low basal cardiac expression and is upregulated following Myocardial Infarction (MI). Previous experiments have demonstrated that S100A6 gene transfer improves left ventricular function after acute ischemia/reperfusion injury. Hypothesis: Delivery of S100A6 by Ultrasound-Targeted Microbubble Destruction (UTMD) after established MI model results in improved left ventricular function and prevention of adverse ventricular remodeling. Aim: Assess the impact of UTMD delivery of S100A6 on cardiac function following experimental MI. Methods: MI was induced through permanent left anterior descending (LAD) coronary artery ligation in 8-week-Spragues Dawley (SD) male rats on day 0. On day 28, by using UTMD methods, we delivered microbubbles (1×109) coupled with either 200 μg of human S100A6 mini-circle DNA or empty minicircles to the left ventricle (LV), while control animals received no therapy. The three groups were monitored weekly for four weeks post-gene delivery using serial echocardiography to follow LV function, followed by tissue collection from various regions of the myocardium. Results: At day 28 post-MI, all groups showed reduced LV ejection fraction (LVEF) and fractional shortening (FS), with LVEF and FS values of 39.47±1.49% and 19.75±2.38%, respectively. Meanwhile, healthy animals showed LVEF and FS values of (63.75±2.38% and 36.20±1.29% (p<0.001). Four weeks after the UTMD delivery of the S100A6, LVEF increased to 51.14±3.7% and FS increased to 29.66±3.2% (p<0.05). In contrast, the empty minicircle and control groups showed no significant improvement (38.35±2.6% and 20.66±5.2%, p<0.05). The S100A6-treated group at 28 days post-treatment showed a 2.7±1.2-fold increase in the expression level of S100A6 in the border zones. Interestingly, the peri-infarct zone of S100A6-treated myocardium also had a lower expression level of the hypertrophic marker, β-MHC (0.77±0.7-fold), as compared to those of the control groups (2.48±1.63-fold). S100A6 transfection reduced infarct size (24.75±3.3%); vs control (36±4.58%), p<0.05 and decreased collagen content in viable myocardium compared to the control and empty minicircle group, p<0.01. Conclusion: S100A6 overexpression in the peri-infarct zone decreased both hypertrophy and fibrosis and was beneficial to the preservation of cardiac function in a model of chronic MI.