| Co-Investigator(Kenkyū-buntansha) |
YOSHIDA Kiyoshi Kawasaki Medical School, the Medical Department, Professor (60322583)
KATSURA Masashi Kawasaki Medical School, the Medical Department, Associate Professor (80204452)
OKUMA Seitaro Kawasaki Medical School, the Medical Department, Professor (30152086)
NEISHI Yoji Kawasaki Medical School, the Medical Department, Lecturer (80319946)
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| Budget Amount *help |
¥3,950,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥150,000)
Fiscal Year 2007: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000)
Fiscal Year 2006: ¥3,300,000 (Direct Cost: ¥3,300,000)
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| Research Abstract |
This project was aimed to establish a novel therapeutic strategy fur the patient with ischemic cardiomyopathy using microbubbles and ultrasound irradiation to induce coronary angiogenesis and collateral growth. Since microbubbles irradiated by ultrasound is reported to induce sonoporadon phenomenon within blood stream in the perfused microvessel and this mechanical stimulation induces angiogenesis in ischemic hind limb of the experimental animals, we tested our working hypothesis that the sonoporation of microbbule by trans-thoracic (non-invasive) ultrasound irradiation would induce coronary angiogenesis and collateral growth in the territory of ischemic injury in the heart and this effect would be augmented by molecular targeted-microbubbles that are conjugated with antibody against inflammatory proteins specifically expressed in the territory of ischemic myocardial injury.
In the present project, we established a chronic rat model that demonstrated gradual progression of cardiac dysfu
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nction (=heart failure, but without scar formation in the heart) induced by repetitive ischemic protocol (30 min-ischemia, every 48 hrs) while conscious. A coronary endothelium in the territory of ischemic injury expressed some inflammatory proteins such as iNOS, MCP-1, and IL-6. Microbubbles were conjugated with antibody against these proteins and were intravenously injected and irradiated by trans-thoracic ultrasound during the repetitive ischemic protocol. Unfortunately, any advantageous effects were not observed by this procedure; i.e., improvement of a regression line of progression of cardiac dysfunction in the rat under the repetitive ischemic protocol was not observed. Although we succeeded in visualization of three-dimensional architecture of coronary microvessels, appearance of the coronary microvasculature was comparable between the heart of healthy subject and the heart under the repetitive ischemic protocol.
Accomplishment of the present project would be promised by overcoming some assignments that are found through the present experiments; such as i) requirement of filtering of the bubbles to unify the size of microbubbles, evaluation of reliability of conjugation of antibody to the microbubbles, evaluation of affinity of the antibody conjugated-microbubble to the coronary endothelium in the site of ischemic territory, and iv) evaluation of concentration of the microbubbles of retention at the targeted site. Furthermore, specificity of the ultrasound (energy, frequency, duty ratio, duration of irradiation etc.) should be improved to obtain effective sonoporation within the heart in-situ Because sonoporation was certainly observed in the isolated heart under Langendorff's-perfusion set-up, but that was not obscured in the closed chest condition under every conceivable conditions of ultrasound irradiation. Less
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