Diagnostic ultrasound‐mediated microbubble cavitation dose‐dependently improves diabetic cardiomyopathy through angiogenesis

Abstract

Ultrasound-mediated microbubble cavitation (UMMC) induces therapeutic angiogenesis to treat ischemic diseases. This study aimed to investigate whether diagnostic UMMC alleviates diabetic cardiomyopathy (DCM) and, if so, through which mechanisms. DCM model was established by injecting streptozocin into rats to induce hyperglycemia, followed by a high-fat diet.The combined therapy of cation microbubble with low-intensity diagnostic ultrasound (frequency = 4 MHz), with a pulse frequency of 20 Hz and pulse length (PL) of 8, 18, 26, or 36 cycles, was given to rats twice a week for 8 consecutive weeks. Diagnostic UMMC therapy with PL at 8, 18, and 26 cycles, but not 36 cycles, dramatically prevented myocardial fibrosis, improved heart functions, and increased angiogenesis, accompanied by increased levels of PI3K, Akt, and eNOS proteins in the DCM model of rats. In cultured endothelial cells, low-intensity UMMC treatment (PL = 3 cycles, sound pressure level = 50%, mechanical index = 0.82) increased cell viability and activated PI3K-Akt-eNOS signaling. The combination of diagnostic ultrasound with microbubble destruction dose-dependently promoted angiogenesis, thus improving heart function through PI3K-Akt-eNOS signaling in diabetes. Accordingly, diagnostic UMMC therapy should be considered to protect the heart in patients with diabetes.

Cardiac gene delivery using ultrasound: State of the field

“…With the concept of microbubble-induced angiogenesis as a basis, more recent work has demonstrated this technique toward reversing cardiac dysfunction in an animal model of diabetic cardiomyopathy. 113 , 114 Using clinical SonoVue agent, a commercial scanner (VINNO 70, 4 MHz, 8–36 cycles, DC = 60%, 20 min duration) aimed directly at the heart improved reparative neovascularization, and increased cardiac perfusion was observed in a rat model of this disease. 113 …”