title: Low-intensity pulsed ultrasound induces angiogenesis and ameliorates left ventricular dysfunction in a porcine model of chronic myocardial ischemia.
abstract: BACKGROUND
  Although a significant progress has been made in the management of ischemic heart disease (IHD), the number of severe IHD patients is increasing. Thus, it is crucial to develop new, non-invasive therapeutic strategies. In the present study, we aimed to develop low-intensity pulsed ultrasound (LIPUS) therapy for the treatment of IHD.
  
  
  RESULTS
  We first confirmed that in cultured human endothelial cells, LIPUS significantly up-regulated mRNA expression of vascular endothelial growth factor (VEGF) with a peak at 32-cycle (P<0.05). Then, we examined the in vivo effects of LIPUS in a porcine model of chronic myocardial ischemia with reduced left ventricular ejection fraction (LVEF) (n = 28). The heart was treated with either sham (n = 14) or LIPUS (32-cycle with 193 mW/cm2 for 20 min, n = 14) at 3 different short axis levels. Four weeks after the treatment, LVEF was significantly improved in the LIPUS group (46±4 to 57±5%, P<0.05) without any adverse effects, whereas it remained unchanged in the sham group (46±5 to 47±6%, P = 0.33). Capillary density in the ischemic region was significantly increased in the LIPUS group compared with the control group (1084±175 vs. 858±151/mm2, P<0.05). Regional myocardial blood flow was also significantly improved in the LIPUS group (0.78±0.2 to 1.39±0.4 ml/min/g, P<0.05), but not in the control group (0.84±0.3 to 0.97±0.4 ml/min/g). Western blot analysis showed that VEGF, eNOS and bFGF were all significantly up-regulated only in the LIPUS group.
  
  
  CONCLUSIONS
  These results suggest that the LIPUS therapy is promising as a new, non-invasive therapy for IHD.
authors.affiliation: Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Hanawa
authors.affiliation: Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Kenta
authors.initials: K
authors.lastname: Ito
authors.affiliation: Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Aizawa
authors.affiliation: Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Shindo
authors.affiliation: Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Nishimiya
authors.affiliation: Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Yuhi
authors.initials: Y
authors.lastname: Hasebe
authors.affiliation: Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Ryuji
authors.initials: R
authors.lastname: Tuburaya
authors.affiliation: Division of Biomedical Measurements and Diagnostics, Graduate School of Biomedical Engineering, Tohoku University, Sendai, Japan; Department of Electronic Engineering, Graduate School of Engineering, Tohoku University, Sendai, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Hasegawa
authors.affiliation: National Cerebral and Cardiovascular Center, Osaka, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yasuda
authors.affiliation: Division of Biomedical Measurements and Diagnostics, Graduate School of Biomedical Engineering, Tohoku University, Sendai, Japan; Department of Electronic Engineering, Graduate School of Engineering, Tohoku University, Sendai, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kanai
authors.affiliation: Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shimokawa
mesh_terms: D000818:Animals; D002460:Cell Line; D004452:Echocardiography; D016222:Fibroblast Growth Factor 2 / Q000096:biosynthesis; D019220:High-Energy Shock Waves / Q000627:therapeutic use*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D017202:Myocardial Ischemia / Q000000981:diagnostic imaging / Q000628:therapy*; D009206:Myocardium / Q000473:pathology; D018919:Neovascularization, Physiologic; D052250:Nitric Oxide Synthase Type III / Q000096:biosynthesis; D012039:Regional Blood Flow; D013552:Swine; D000069453:Ultrasonic Waves; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000096:biosynthesis; D018487:Ventricular Dysfunction, Left / Q000000981:diagnostic imaging / Q000628:therapy*
chemical_list: C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D040301:Vascular Endothelial Growth Factor Receptor-2
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