Low-intensity pulsed ultrasound therapy suppresses coronary adventitial inflammatory changes and hyperconstricting responses after coronary stent implantation in pigs in vivo

Abstract

Backgrounds 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. Aims 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. Methods 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. Results 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. Conclusions 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.

Mechanisms of Coronary Artery Spasm

“…21,44,60 In brief, coronary adventitia harbours a wide range of cellular and subcellular components, such as nutrient blood vessels (termed vasa vasorum), perivascular adipose tissue (PVAT), autonomic nervous system, and lymphatic vessels that drain adventitial inflammatory cells. [87][88][89][90][91][92][93][94] We have demonstrated that these adventitial residents have interactions with each other, all of which are involved in coronary hyperconstricting responses after drug-eluting stent (DES) implantation in pigs in vivo (Figure 5). [87][88][89][90][91][92][93] The first observation was that inflammatory changes were potent in the histology of coronary adventitia isolated from the porcine coronary segment with first-generation DES implantation compared with baremetal stent implantation.…”

“…92 More recent studies underline that impairment of cardiac lymphatic drainage function after DES implantation contributes to sustained adventitial inflammation, medial VSMC hypercontraction and resultant coronary hyperconstriction through activation of Rho-kinase in pigs in vivo. 93,94 We further examined the role of coronary adventitial inflammation in the clinical settings by using a multimodality imaging approach with optical coherence tomography (OCT) and 18 FDG-PET. [98][99][100][101] OCT is capable of visualising coronary adventitial vasa vasorum in pigs and humans and OCT-delineated adventitial vasa vasorum (VV) formation was significantly enhanced at the spastic segments of VSA patients as compared with those of the control subjects (Figure 5).…”

“…[105][106][107][108][109][110][111][112] Our recent study has demonstrated that the LIPUS therapy suppresses DES-induced coronary hyperconstricting responses in pigs in vivo by suppressing Rho-kinase activity. 94 The detailed molecular mechanisms of the LIPUS are that it enhances cardiac lymphatic vessel formation associated with endothelial nitric oxide synthase upregulation with no effects on the vasa vasorum, and that the enhancement of lymphatic vessel formation improves inflammatory drainage function, helping abrogate adventitial inflammation and Rho-kinase activity. 94 In addition to coronary artery spasm, PVAT inflammation has been demonstrated in human coronary atherosclerotic lesions in vivo.…”

“…94 The detailed molecular mechanisms of the LIPUS are that it enhances cardiac lymphatic vessel formation associated with endothelial nitric oxide synthase upregulation with no effects on the vasa vasorum, and that the enhancement of lymphatic vessel formation improves inflammatory drainage function, helping abrogate adventitial inflammation and Rho-kinase activity. 94 In addition to coronary artery spasm, PVAT inflammation has been demonstrated in human coronary atherosclerotic lesions in vivo. 113 Taken together, the LIPUS therapy could be a novel and safe therapeutic approach for a broad spectrum of cardiovascular disease in clinical practice.…”

LIPUS as a potential strategy for periodontitis treatment: A review of the mechanisms

“…LIPUS is already widely used both in various clinical applications and fundamental research (Xin et al, 2016;Xie et al, 2019;Elvey et al, 2020). It has been acknowledged as a non-invasive physical stimulation for therapeutic purposes, delivering acoustic energy to the targeted tissue (de Lucas et al, 2021;Ichijo et al, 2021;Watanabe et al, 2021). Unlike high-intensity ultrasound, LIPUS has drawn attention for its minimal thermal effects (Xin et al, 2016).…”