Treatment of ischemic heart failure through ultrasound-targeted microbubble destruction and it's mechanism

Abstract Background The cavitation effect mediated by ultrasonic-targeted microbubble destruction (UTMD) can regulate the microenvironment and circulation of ischemic myocardium. The UTMD cavitation effect can rapidly enhance blood perfusion and improve cardiac function in patients with ischemic heart failure. However, the internal mechanism of this treatment has yet to be reported. Objective The objective of this study was to explore the underlying mechanism of UTMD-mediated cavitation effect to rapidly improve cardiac function in rats with ischemic heart failure. Methods In the first part of the study, the ischemic heart failure model was induced by ligation of the left anterior descending branch coronary in Sprague-Dawley rats, the rats were randomly divided into 7 groups: sham group, HF group, HF+MB(microbubble) group, HF+US(ultrasound) group, HF+UTMD group, HF+UTMD+LY294002(PI3K inhibitor) group, and HF+LY294002 group. Serum BNP level and echocardiographic parameters were measured to evaluate cardiac function. Thereafter, SD rats were treated with UTMD by specific ultrasonic parameters and microbubble concentration, cardiac function should be reassessed after treatment. Finally, the myocardial tissues were extracted for Western Blot and immunohistochemical analysis to detect the protein expression of the PI3K/Akt/eNOS signaling pathway, and the contents of serum nitric oxide(NO) and myocardial ATP were detected by Elisa. Results The application of UTMD resulted in significant improvements in ejection fraction (EF) and fractional shortening (FS) in rats with ischemic heart failure, as compared to the HF group (EF: 37.16 ± 1.21% vs. HF+UTMD: 46.31 ± 3.00%, P=0.0057; FS: 18.53 ± 0.58% vs. HF+UTMD: 24.05 ± 1.84%, P=0.0089). Additionally, UTMD treatment led to the activation of the PI3K/Akt/eNOS signaling pathway (HF vs. HF+UTMD, P < 0.01), and promoted the production of NO and ATP (HF vs. HF+UTMD, both, P< 0.05). However, when a PI3K inhibitor was used, the cardiac protective effects of UTMD treatment were largely eliminated. EF and FS deteriorated significantly (EF: HF+UTMD+LY294002: 42.84±2.88% vs. HF+LY294002: 32.73±3.05%, P<0.0001; FS: HF+UTMD+LY294002: 21.94±1.69% vs. HF+LY294002: 16.36±1.76%, P<0.0001), and the production of NO and ATP decreased significantly (HF+UTMD+LY294002 vs. HF+LY294002, both, P< 0.05). Conclusion The UTMD-mediated cavitation effect can rapidly improve the cardiac function of ischemic heart failure rats by activating PI3K/Akt/eNOS signaling pathway and promoting the release of NO and ATP.