title: Repeated and targeted transfer of angiogenic plasmids into the infarcted rat heart via ultrasound targeted microbubble destruction enhances cardiac repair.
abstract: OBJECTIVE
  Ultrasound-targeted microbubble destruction (UTMD) uses ultrasound energy to selectively deliver genes into the myocardium using plasmids conjugated to microbubbles. We hypothesized that repeated delivery of stem cell-mobilizing genes could boost the ability of this therapy to enhance cardiac repair and ventricular function after a myocardial infarction.
  
  
  RESULTS
  Beginning 7 days after coronary artery ligation, stem cell factor (SCF) and stromal cell-derived factor (SDF)-1α genes were administered to adult rats using 1, 3, or 6 UTMD treatments (repeat 1, 3, and 6 groups) at 2-day intervals (control=6 treatments with empty plasmid). Cardiac function (echocardiography) and myocardial perfusion (myocardial contrast echocardiography) were assessed on Days -7, 0, and 24 relative to the first treatment. Histological and biochemical assessments were performed on Day 24. Multiple UTMD treatments were associated with an increased presence of myocardial SCF and SDF-1α proteins and their receptors (vs. control and Repeat 1). All UTMD recipients exhibited increased vascular densities and smaller infarct regions (vs. control), with the highest ventricular densities in response to multiple treatments. Myocardial perfusion and ventricular function at Day 24 also improved progressively (vs. control) with the number of UTMD treatments.
  
  
  CONCLUSIONS
  Targeted ultrasound delivery of SCF and SDF-1α genes to the infarcted myocardium recruited progenitor cells and increased vascular density. Multiple UTMD treatments enhanced tissue repair, perfusion, and cardiac function. Repeated UTMD therapy may be applied to tailor the number of interventions required to optimize cardiac regeneration after an infarction.
authors.affiliation: Division of Cardiovascular Surgery, Department of Surgery, University of Toronto, Toronto, ON, Canada.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Fujii
authors.forename: Shu-Hong
authors.initials: SH
authors.lastname: Li
authors.forename: Jun
authors.initials: J
authors.lastname: Wu
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Miyagi
authors.forename: Terrence M
authors.initials: TM
authors.lastname: Yau
authors.forename: Harry
authors.initials: H
authors.lastname: Rakowski
authors.forename: Kensuke
authors.initials: K
authors.lastname: Egashira
authors.forename: Jian
authors.initials: J
authors.lastname: Guo
authors.forename: Richard D
authors.initials: RD
authors.lastname: Weisel
authors.forename: Ren-Ke
authors.initials: RK
authors.lastname: Li
mesh_terms: D000818:Animals; D054377:Chemokine CXCL12 / Q000235:genetics*; D003097:Collateral Circulation / Q000502:physiology; D004452:Echocardiography; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D045423:Microbubbles / Q000627:therapeutic use*; D009203:Myocardial Infarction / Q000628:therapy*; D009204:Myocardial Revascularization / Q000379:methods*; D058628:Myofibroblasts / Q000502:physiology; D018919:Neovascularization, Physiologic / Q000502:physiology; D010957:Plasmids; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D019718:Receptors, CXCR4 / Q000378:metabolism; D033581:Stem Cell Transplantation / Q000379:methods; D013318:Stroke Volume / Q000502:physiology; D014162:Transfection; D019210:Troponin I / Q000097:blood; D014464:Ultrasonic Therapy / Q000379:methods*; D016277:Ventricular Function, Left
chemical_list: D054377:Chemokine CXCL12; C486264:Cxcr4 protein, rat; D019718:Receptors, CXCR4; D019210:Troponin I; D019009:Proto-Oncogene Proteins c-kit