Abstract

We demonstrated that coronary adventitial inflammation plays important roles in the pathogenesis of drug-eluting stent (DES)-induced coronary hyperconstricting responses in pigs in vivo. However, no therapy is yet available to treat coronary adventitial inflammation. We thus developed the low-intensity pulsed ultrasound (LIPUS) therapy that ameliorates myocardial ischemia by enhancing angiogenesis. We aimed to examine whether our LIPUS therapy suppresses DES-induced coronary hyperconstricting responses in pigs in vivo, and if so, what mechanisms are involved. Sixteen normal male pigs were randomly assigned to the LIPUS or the sham therapy groups after DES implantation into the left anterior descending (LAD) coronary artery. In the LIPUS group, LIPUS (32 cycles, 193 mW/cm2) was applied to the heart at 3 different levels (segments proximal and distal to the stent edges and middle of the stent) for 20 min at each level for every other day for 2 weeks. The sham therapy group was treated in the same manner but without LIPUS. At 4 weeks after stent implantation, we performed coronary angiography, followed by immunohistological analysis. Coronary vasoconstricting responses to serotonin in LAD at DES edges were significantly suppressed in the LIPUS group compared with the sham group. Furthermore, lymph transport speed in vivo was significantly faster in the LIPUS group than in the sham group. Histological analysis at DES edges showed that inflammatory changes and Rho-kinase activity were significantly suppressed in the LIPUS group, associated with eNOS up-regulation and enhanced lymph-angiogenesis. These results suggest that our non-invasive LIPUS therapy is useful to treat coronary functional abnormalities caused by coronary adventitial inflammation, indicating its potential for the novel and safe therapeutic approach of coronary artery disease.

Highlights

  • Endothelial dysfunction and subsequent intimal thickening are thought to be an initial step for coronary artery disease (CAD) [1], it has been suggested that coronary adventitial inflammation play pivotal roles in the pathogenesis of the disorder [2]

  • Coronary vasoconstricting responses to serotonin in left anterior descending (LAD) at drug-eluting stents (DES) edges were significantly suppressed in the low-intensity pulsed ultrasound (LIPUS) group compared with the sham group

  • Histological analysis at DES edges showed that inflammatory changes and Rho-kinase activity were significantly suppressed in the LIPUS group, associated with endothelial nitric oxide synthase (eNOS) up-regulation and enhanced lymph-angiogenesis. These results suggest that our non-invasive LIPUS therapy is useful to treat coronary functional abnormalities caused by coronary adventitial inflammation, indicating its potential for the novel and safe therapeutic approach of coronary artery disease

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Summary

Introduction

Endothelial dysfunction and subsequent intimal thickening are thought to be an initial step for coronary artery disease (CAD) [1], it has been suggested that coronary adventitial inflammation play pivotal roles in the pathogenesis of the disorder [2]. Coronary adventitial inflammation plays an important role in the pathogenesis of acute coronary syndrome (ACS) [3]. The LIPUS therapy exerts antiinflammatory effects [12, 15]. It remains to be examined whether the LIPUS therapy is able to suppress coronary adventitial inflammation

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