Low-intensity pulsed ultrasound induces angiogenesis and ameliorates left ventricular dysfunction in a porcine model of chronic myocardial ischemia.

Kenichiro Hanawa,Hiroaki Shimokawa,Kensuke Nishimiya,Tomohiko Shindo,Yuhi Hasebe,Ryuji Tuburaya,Satoshi Yasuda,Kentaro Aizawa,Hiroshi Kanai,Kenta Ito,Hideyuki Hasegawa,Costanza Emanueli

doi:10.1371/journal.pone.0104863

Kenichiro Hanawa, Hiroaki Shimokawa + Show 10 more

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https://doi.org/10.1371/journal.pone.0104863

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Abstract

BackgroundAlthough 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.Methods and ResultsWe 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.ConclusionsThese results suggest that the LIPUS therapy is promising as a new, non-invasive therapy for IHD.

Highlights

Ischemic heart disease (IHD) is one of the major causes of death in developed countries, and its morbidity is increasing in developing countries [1]–[3]
These results suggest that the low-intensity pulsed ultrasound (LIPUS) therapy is promising as a new, non-invasive therapy for ischemic heart disease (IHD)
In accordance with the preliminary data mentioned above (Table S1), the LIPUS treatment significantly up-regulated mRNA expression of vascular endothelial growth factor (VEGF) in human umbilical vein endothelial cells (HUVEC), with a maximum effect noted at 32 cycles (1.33-fold increase, P,0.05) (Figure 1) while the expression of its receptor Flk-1 was not enhanced (Control, 1.0060.06 vs. LIPUS, 1.0160.10; at 32 cycles)

Summary

Introduction

Ischemic heart disease (IHD) is one of the major causes of death in developed countries, and its morbidity is increasing in developing countries [1]–[3]. Non-invasive therapeutic strategies for severe IHD remain to be developed. We have previously demonstrated that low-energy extracorporeal cardiac shock wave (SW) therapy improves myocardial ischemia in a porcine model of chronic myocardial ischemia and patients with severe angina pectoris [4]–[8]. We examined whether lowintensity pulsed ultrasound (LIPUS) enhances endothelial regeneration in vitro and whether it ameliorates ischemia-induced myocardial dysfunction in a porcine model of chronic myocardial ischemia in vivo, and if so, what molecular mechanisms are involved. A significant progress has been made in the management of ischemic heart disease (IHD), the number of severe IHD patients is increasing. We aimed to develop low-intensity pulsed ultrasound (LIPUS) therapy for the treatment of IHD

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