Rationale:
Targeted: Ultrasound targeted microbubble destruction (UTMD) delivers genes directly to the injured myocardium. Tailored: UTMD could permit recurrent treatment until recovery is complete. Hypothesis: Repeated UTMD is a novel strategy to induce tissue regeneration and improve ventricular function after a myocardial infarction.
Methods:
Microbubbles were mixed with plasmids containing stem cell factor (SCF) and stromal cell-derived factor (SDF)-1α genes. Seven days after coronary artery ligation, adult rats underwent UTMD either 1, 3 or 6 times at 2-day intervals in 4 randomly assigned groups: Control group: 6 UTMD treatments with empty plasmid (n=4); Repeat 1 (n=6), Repeat 3 (n=7), Repeat 6 (n=6) groups: 1, 3 or 6 treatments, respectively, of UTMD with SCF and SDF-1α plasmid DNA. Cardiac function (echocardiography) and myocardial perfusion (myocardial contrast echocardiography) were assessed on days 0, 10 and 24 after the first treatment. Biochemical assessments were performed on day 24.
Results:
Cardiac function was highest in the Repeat 6 group (p<0.05 vs. Repeat 1). Myocardial SCF levels were higher after multiple rather than single UTMD treatments (p<0.05 for Repeat 3 and Repeat 6 vs. Repeat 1), with the highest levels in the Repeat 6 group (p<0.05 vs. Repeat 3). Myocardial SDF-1α levels and c-kit-positive cell counts also increased with the maximum number of treatments (p<0.05 for Repeat 6 vs. Repeat 1). Myocardial CXCR4-positive cells were more numerous in the remote regions of both multiple UTMD groups (p<0.05 for Repeat 3 and Repeat 6 vs. Repeat 1). Both myocardial perfusion in the infarct region and vascular density (Factor VIII or alpha-smooth muscle actin staining) in the border zone increased with repeated treatments (p<0.05 for Repeat 3 and Repeat 6 vs. Repeat 1), with an additional increase in the Repeat 6 group (p<0.01 vs. Repeat 3).
Conclusions:
Targeted ultrasound delivery of SCF and SDF-1α genes to the myocardium induced angiogenesis, recruited progenitor cells and improved cardiac function. Multiple UTMD treatments further enhanced regeneration. Tailoring the treatment by providing the number of interventions required to restore function provides a new approach to cardiac regeneration following a myocardial infarction.
Thallium-201 is comparable to technetium-99m-sestamibi for estimating cardiac function in patients with abnormal myocardial perfusion imaging