title: Ultrasound-mediated stimulation of microbubbles after acute myocardial infarction and reperfusion ameliorates left-ventricular remodelling in mice via improvement of borderzone vascularization.
abstract: OBJECTIVE
  Post-infarction remodelling (PIR) determines left-ventricular (LV) function and prognosis after myocardial infarction. The aim of this study was to evaluate transthoracic ultrasound-mediated microbubble stimulation (UMS) as a novel gene- and cell-free therapeutic option after acute myocardial infarction and reperfusion (AMI/R) in mice.
  
  
  RESULTS
  For myocardial delivery of UMS, a novel therapeutic ultrasound-system (TIPS, Philips Medical) and commercially available microbubbles (BR1, Bracco Suisse SA) were utilized in a closed-chest mouse model. UMS was performed as myocardial post-conditioning (PC) on day four after 30 minutes of coronary occlusion and reperfusion. LV-morphology, as well as global and regional function were measured repeatedly with reconstructive 3-dimensional echocardiography applying an additional low-dose dobutamine protocol after two weeks. Scar size was quantified by means of histomorphometry. A total of 41 mice were investigated; 17 received PC with UMS. Mean ejection fraction (EF) prior UMS was similar in both groups 53%±10 (w/o UMS) and 53%±14 (UMS, p = 0.5), reflecting comparable myocardial mass at risk 17%±8 (w/o UMS), 16%±13 (UMS, p = 0.5). Two weeks after AMI/R, mice undergoing UMS demonstrated significantly better global LV-function (EF = 53%±7) as compared to the group without PC (EF = 39%±11, p<0.01). The fraction of akinetic myocardial mass was significantly lower among mice undergoing UMS after AMI/R [27%±10 (w/o UMS), 13%±8 (UMS), p<0.001)]. Our experiments showed a fast onset of transient, UMS-induced upregulation of vascular-endothelial and insulin-like growth factor (VEGF-a, IGF-1), as well as caveolin-3 (Cav-3). The mice undergoing PC with UMS after AMI/R showed a significantly lower scar size. In addition, the microvascular density was significantly higher in the borderzone of UMS-treated animals.
  
  
  CONCLUSIONS
  UMS following AMI/R ameliorates PIR in mice via up-regulation of VEGF-a, IGF-1 and Cav-3, and consecutive improvement of myocardial borderzone vascularization.
authors: Department of Medicine/Cardiology, University of Bonn, Bonn, Germany.
authors: Jonas
authors: J
authors: Dörner
authors: Rafael
authors: R
authors: Struck
authors: Sebastian
authors: S
authors: Zimmer
authors: Christine
authors: C
authors: Peigney
authors: Georg Daniel
authors: GD
authors: Duerr
authors: Oliver
authors: O
authors: Dewald
authors: Se-Chan
authors: SC
authors: Kim
authors: Daniela
authors: D
authors: Malan
authors: Thierry
authors: T
authors: Bettinger
authors: Georg
authors: G
authors: Nickenig
authors: Alexander
authors: A
authors: Ghanem
mesh_terms: D000818:Animals; D006332:Cardiomegaly; D051244:Caveolin 3 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004452:Echocardiography; D005260:Female; D005786:Gene Expression Regulation; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D051379:Mice; D045423:Microbubbles / Q000627:therapeutic use*; D009203:Myocardial Infarction / Q000175:diagnosis / Q000503:physiopathology* / Q000628:therapy*; D015428:Myocardial Reperfusion Injury / Q000175:diagnosis / Q000503:physiopathology* / Q000628:therapy*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D020257:Ventricular Remodeling
chemical_list: D051244:Caveolin 3; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D007334:Insulin-Like Growth Factor I