Our laboratory highlights on the realization of cutting-edge findings of basic researches from collaborating world-leading facilities, or investigating novel therapeutic modalities or devices, for severe cardiovascular diseases resistant to conventional therapies. In the field of translational research, there is a phrase “The valley of death”, which indicates the situation that patients could not survive without having excellent therapies brought from basic researches because of the lack of personnel who transport the knowledge to suffering patients. We pursue to be the personnel who bridge the gap, making the best use of our surgical skill and point of view. We work for the patients.
1. ES/iPS cell-based regenerative medicine
We have collaborated with Center for iPS Cell Research and Application (CiRA), Kyoto University for the researches of ES/iPS cell-based regenerative medicine. Combining ES/iPS cell differentiation system to cardiovascular cell populations (Prof. Jun K Yamashita, CiRA) and cell sheet technology (Institute of Advanced Biomedical and Science, Tokyo Women’s Medical University), we have shown excellent therapeutic potential of ES/iPS cell-derived cardiac cell sheets1.
We are now investigating for the molecular and cellular mechanisms of cell-based cardiac regenerative therapy using this ES/iPS cell-derived cardiac sheet system, and expanding this technology to human iPS cells for future clinical application.
Mouse ES cell-derived cardiomyocytes (left, center)11, endothelial and vascular mural cells (right)1.
Mouse ES cell-derived cardiac cell sheets (left) and the transplantation to rat sub-acute myocardial infarction model (center, right)1.
Neovascularization induced from cell sheet transplantation. vWF-positive (green) endothelial cells prominently accumulated around the grafted area (left) leading to increased capillary density (right)1.
2. “Bridge-to-recovery” from left ventricular assist devices (LVAD) for failing hearts
We have investigated therapeutic methods for severe heart failure needed mechanical support such as left ventricular assist devices (LVAD). This theme is especially important for Japanese society because of limited opportunity for heart transplantation. We established novel rat heterotopic heart transplantation model which unload the volume of failing heart, simulating LVAD situation1,3,6,8. We are investigating effective multidisciplinary approach for this refractory pathophysiology, including sustained release of anti-fibrotic or anti-apoptotic cytokines (e.g. hepatocyte growth factor) using gelatin hydrogel.
3. Angiogenic approach for severe limb ischemia using sustained release of basic fibro
blast growth factor (bFGF) with gelatin hydrogel
We have investigated a novel angiogenic approach for severe peripheral arterial diseases (PAD) utilizing sustained release of basic fibroblast growth factor (bFGF),a potent angiogenic cytokine, incorporated to gelatin hydrogel (collaboration with Prof. Yasuhiko Tabata, Institute for Frontier Medical Sciences, Kyoto University)26,27,28,33,34.
Preclinical study of bFGF therapy for rabbit hind limb ischemia. Angiography of control (left) and bFGF-treated rabbit (right)27.
A representative result of bFGF therapy for severe PAD (phase I-IIa clinical study). Pre-treatment (left) and 12 weeks after treatment (right)26.
4. Development of new devices for endovascular surgery
We have developed new devices for safer endovascular surgery using large animal model (e.g. porcine, canine) such as detachable arterial filter to prevent thromboembolism during endovascular surgery2, or side-branched stent graft for the perfusion of the artery of Adamkiewicz to prevent paraplegia after thoracic aortic stenting10. The experimental setting is almost the same as human surgery, and we can fully apply our surgical technique in this experimental field.
Experimental procedure using canine model.
The attachment of detachable arterial filter into internal carotid artery (scheme) (left) and the angiography after attachment (right)2.
The Inoue stent graft with small caliber branch for the perfusion of the artery of Adamkiewicz10.
- 1.The application of novel biodegradable glue derived from food additives for prevention of retrosternal adhesion, the career for antiarrhythmic agents5, or antibiotics6.
- 2. The cardioprotective effects of statin or polyphenol3,35 using rat Langendorff apparatus.
- 3. Attenuation of LV remodeling after LV repair using rat OMI model8,17,18,36,41,42,43.
- 4. Organ protection during cardiopulmonary bypass (CPB) using rat CPB model.
- 5. Attenuation of reperfusion injury after recanalization of acute lower limb thromboembolism9.
- 6. The application of micro-RNAs for the treatment of cardiovascular diseases.
- 7. Angiogenic effect of platelet-rich plasma (PRP)4,13.
- 8. New operative technique for LV plasty40 or repair of mitral valve22,23,24,29,39 using canine CPB model.
- 9. RV function after surgical repair of congenital heart diseases using canine model.
- Kyoto University
- Center for iPS Cell Research and Application (CiRA)
Institute for Frontier Medical Sciences
Department of Cardiovascular medicine
Department of Nephrology
- Institute of Advanced Biomedical Engineering and Science, Tokyo Women’s Medical University
National Cerebral and Cardiocvascular Center
Kyoto Institute of Technology
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Selected Publication List
- 1. Masumoto H, Matsuo T, Yamamizu K, Uosaki H, Narazaki G, Katayama S, Marui A, Shimizu T, Ikeda T, Okano T, Sakata R, Yamashita JK. Pluripotent stem cell-engineered cell sheets reassembled with defined cardiovascular populations ameliorate reduction in infarct heart function through cardiomyocyte-mediated neovascularization. Stem Cells. 2012 30:1196-205.
- 2. Uehara K, Marui A, Nagata Y, Sato M, Takeda T, Ikeda T, Sakata R, Inoue K. A novel detachable filter to prevent thromboembolism during endovascular surgery. J Thorac Cardiovasc Surg. 2012 [Epub ahead of print]
- 3. Yanagi S, Matsumura K, Marui A, Morishima M, Hyon SH, Ikeda T, Sakata R. Oral pretreatment with a green tea polyphenol for cardioprotection against ischemia-reperfusion injury in an isolated rat heart model. J Thorac Cardiovasc Surg. 2011;141:511-7.
- 4. Bir SC, Esaki J, Marui A, Sakaguchi H, Kevil CG, Ikeda T, Komeda M, Tabata Y, Sakata R. Therapeutic treatment with sustained-release platelet-rich plasma restores blood perfusion by augmenting ischemia-induced angiogenesis and arteriogenesis in diabetic mice. J Vasc Res. 2011;48:195-205.
- 5. Takeda T, Shimamoto T, Marui A, Saito N, Uehara K, Minakata K, Miwa S, Nakajima N, Ikeda T, Hyon SH, Sakata R. Topical application of a biodegradable disc with amiodarone for atrial fibrillation. Ann Thorac Surg. 2011;91:734-9.
- 6. Morishima M, Marui A, Yanagi S, Nomura T, Nakajima N, Hyon SH, Ikeda T, Sakata R. Sustained release of vancomycin from a new biodegradable glue to prevent methicillin-resistant Staphylococcus aureus graft infection. Interact Cardiovasc Thorac Surg. 2010;11:52-5.
- 7. Muranaka H, Marui A, Tsukashita M, Wang J, Nakano J, Ikeda T, Sakata R. Prolonged mechanical unloading preserves myocardial contractility but impairs relaxation in rat heart of dilated cardiomyopathy accompanied by myocardial stiffness and apoptosis. J Thorac Cardiovasc Surg. 2010;140:916-22.
- 8. Yoshikawa E, Marui A, Tsukashita M, Nishina T, Wang J, Muranaka H, Ikeda T, Komeda M. Carvedilol may alleviate late cardiac remodelling following surgical ventricular restoration. Eur J Cardiothorac Surg. 2010;37:362-7.
- 9. Tsubota H, Marui A, Esaki J, Bir SC, Ikeda T, Sakata R. Remote postconditioning may attenuate ischaemia-reperfusion injury in the murine hindlimb through adenosine receptor activation. Eur J Vasc Endovasc Surg. 2010;40:804-9.
- 10. Shimamoto T, Marui A, Nagata Y, Sato M, Saito N, Takeda T, Ueda M, Ikeda T, Sakata R, Inoue K. A novel approach to prevent spinal cord ischemia: Inoue stent graft with a side branch of small caliber for the reconstruction of the artery of Adamkiewicz. J Thorac Cardiovasc Surg. 2010;139:655-9.
- 11. Yan P, Nagasawa A, Uosaki H, Sugimoto A, Yamamizu K, Teranishi M, Matsuda H, Matsuoka S, Ikeda T, Komeda M, Sakata R, Yamashita JK. Cyclosporin-A potently induces highly cardiogenic progenitors from embryonic stem cells. Biochem Biophys Res Commun. 2009;379:115-20.
- 12. Wang J, Tsukashita M, Nishina T, Marui A, Yoshikawa E, Muranaka H, Matsuoka S, Ikeda T. Chronic partial unloading restores beta-adrenergic responsiveness and reverses receptor downregulation in failing rat hearts. J Thorac Cardiovasc Surg. 2009;137:465-70.
- 13. Bir SC, Esaki J, Marui A, Yamahara K, Tsubota H, Ikeda T, Sakata R. Angiogenic properties of sustained release platelet-rich plasma: characterization in-vitro and in the ischemic hind limb of the mouse. J Vasc Surg. 2009;50:870-879.e2.
- 14. Esaki J, Sakaguchi H, Marui A, Bir SC, Arai Y, Huang Y, Tsubota H, Kanaji T, Ikeda T, Sakata R. Local sustained release of prostaglandin E1 induces neovascularization in murine hindlimb ischemia. Circ J. 2009;73:1330-6.
- 15. Marui A, Hirose K, Sakaguchi H, Arai Y, Doi K, Tsukashita M, Shimamoto T, Ikeda T, Komeda M. A potential of autologous pericardium for a sustained-release carrier of vancomycin: a pilot study in vitro. J Thorac Cardiovasc Surg. 2009;137:783-4.
- 16. Nakajima H, Sakakibara Y, Tambara K, Marui A, Yoshimoto M, Premaratne GU, Lin X, Kanemitsu N, Sakaguchi G, Ikeda T, Nishimura K, Nakahata T, Komeda M. Delivery route in bone marrow cell transplantation should be optimized according to the etiology of heart disease. Circ J. 2008;72:1528-35.
- 17. Tsukashita M, Marui A, Nishina T, Yoshikawa E, Kanemitsu H, Wang J, Ikeda T, Komeda M. Spironolactone alleviates late cardiac remodeling after left ventricular restoration surgery. J Thorac Cardiovasc Surg. 2008;136:58-64.
- 18. Kanemitsu H, Takai S, Tsuneyoshi H, Yoshikawa E, Nishina T, Miyazaki M, Ikeda T, Komeda M. Chronic chymase inhibition preserves cardiac function after left ventricular repair in rats. Eur J Cardiothorac Surg. 2008;33:25-31.
- 19. Wang J, Marui A, Ikeda T, Komeda M. Partial left ventricular unloading reverses contractile dysfunction and helps recover gene expressions in failing rat hearts. Interact Cardiovasc Thorac Surg. 2008;7:27-31.
- 20. Huang Y, Marui A, Sakaguchi H, Esaki J, Arai Y, Hirose K, Bir SC, Horiuchi H, Maruyama T, Ikeda T, Tabata Y, Komeda M. Sustained release of prostaglandin E1 potentiates the impaired therapeutic angiogenesis by basic fibroblast growth factor in diabetic murine hindlimb ischemia. Circ J. 2008;72:1693-9.
- 21.Sakaguchi H, Marui A, Hirose K, Nomura T, Arai Y, Bir SC, Huang Y, Esaki J, Tabata Y, Ikeda T, Komeda M. Less-invasive and highly effective method for preventing methicillin-resistant Staphylococcus aureus graft infection by local sustained release of vancomycin. J Thorac Cardiovasc Surg. 2008;135:25-31.
- 22. Masuyama S, Marui A, Shimamoto T, Komeda M. Reversed L-shaped deformity of the anterior mitral leaflet and its reparative technique. J Thorac Cardiovasc Surg. 2008;136:1599-601.
- 23. Masuyama S, Marui A, Shimamoto T, Nonaka M, Tsukiji M, Watanabe N, Ikeda T, Yoshida K, Komeda M. Chordal translocation for ischemic mitral regurgitation may ameliorate tethering of the posterior and anterior mitral leaflets. J Thorac Cardiovasc Surg. 2008;136:868-75.
- 24. Nonaka M, Marui A, Fukuoka M, Shimamoto T, Masuyama S, Ikeda T, Komeda M. Differences in mitral valve-left ventricle dimensions between a beating heart and during saline injection test. Eur J Cardiothorac Surg. 2008;34:755-9.
- 25. Lin X, Fujita M, Kanemitsu N, Kimura Y, Tambara K, Premaratne GU, Nagasawa A, Ikeda T, Tabata Y, Komeda M. Sustained-release erythropoietin ameliorates cardiac function in infarcted rat-heart without inducing polycythemia. Circ J. 2007;71:132-7.
- 26. Marui A, Tabata Y, Kojima S, Yamamoto M, Tambara K, Nishina T, Saji Y, Inui K, Hashida T, Yokoyama S, Onodera R, Ikeda T, Fukushima M, Komeda M. A novel approach to therapeutic angiogenesis for patients with critical limb ischemia by sustained release of basic fibroblast growth factor using biodegradable gelatin hydrogel: an initial report of the phase I-IIa study. Circ J. 2007;71:1181-6.
- 27. Doi K, Ikeda T, Marui A, Kushibiki T, Arai Y, Hirose K, Soga Y, Iwakura A, Ueyama K, Yamahara K, Itoh H, Nishimura K, Tabata Y, Komeda M. Enhanced angiogenesis by gelatin hydrogels incorporating basic fibroblast growth factor in rabbit model of hind limb ischemia. Heart Vessels. 2007;22:104-8.
- 28. Arai Y, Fujita M, Marui A, Hirose K, Sakaguchi H, Ikeda T, Tabata Y, Komeda M. Combined treatment with sustained-release basic fibroblast growth factor and heparin enhances neovascularization in hypercholesterolemic mouse hindlimb ischemia. Circ J. 2007;71:412-7.
- 29. Fukuoka M, Nonaka M, Masuyama S, Shimamoto T, Tambara K, Yoshida H, Ikeda T, Komeda M. Chordal "translocation" for functional mitral regurgitation with severe valve tenting: an effort to preserve left ventricular structure and function. J Thorac Cardiovasc Surg. 2007;133:1004-11.
- 30. Marui A, Hirose K, Maruyama T, Arai Y, Huang Y, Doi K, Ikeda T, Komeda M. Prostaglandin E2 EP4 receptor-selective agonist facilitates sternal healing after harvesting bilateral internal thoracic arteries in diabetic rats. J Thorac Cardiovasc Surg. 2006;131:587-93.
- 31. Tambara K, Premaratne GU, Sakaguchi G, Kanemitsu N, Lin X, Nakajima H, Sakakibara Y, Kimura Y, Yamamoto M, Tabata Y, Ikeda T, Komeda M. Administration of control-released hepatocyte growth factor enhances the efficacy of skeletal myoblast transplantation in rat infarcted hearts by greatly increasing both quantity and quality of the graft. Circulation. 2005;112:I129-34.
- 32. Tsuneyoshi H, Oriyanhan W, Kanemitsu H, Shiina R, Nishina T, Matsuoka S, Ikeda T, Komeda M. Does the beta2-agonist clenbuterol help to maintain myocardial potential to recover during mechanical unloading? Circulation. 2005;112:I51-6.
- 33. Hirose K, Marui A, Arai Y, Fujita M, Nomura T, Mitsuyama M, Tabata Y, Komeda M. Sustained-release form of basic fibroblast growth factor prevents catheter-related bacterial invasion in mice. Interact Cardiovasc Thorac Surg. 2005;4:526-30.
- 34. Marui A, Kanematsu A, Yamahara K, Doi K, Kushibiki T, Yamamoto M, Itoh H, Ikeda T, Tabata Y, Komeda M. Simultaneous application of basic fibroblast growth factor and hepatocyte growth factor to enhance the blood vessels formation. J Vasc Surg. 2005;41:82-90.
- 35. Miwa S, Yamazaki K, Hyon SH, Komeda M. A novel method of 'preparative' myocardial protection using green tea polyphenol in oral uptake. Interact Cardiovasc Thorac Surg. 2004;3:612-5.
- 36. Tsuneyoshi H, Nishina T, Nomoto T, Kanemitsu H, Kawakami R, Unimonh O, Nishimura K, Komeda M. Atrial natriuretic peptide helps prevent late remodeling after left ventricular aneurysm repair. Circulation. 2004;110:II174-9.
- 37. Tambara K, Sakakibara Y, Sakaguchi G, Lu F, Premaratne GU, Lin X, Nishimura K, Komeda M. Transplanted skeletal myoblasts can fully replace the infarcted myocardium when they survive in the host in large numbers. Circulation. 2003;108:II259-63.
- 38. Sakaguchi G, Sakakibara Y, Tambara K, Lu F, Premaratne G, Nishimura K, Komeda M. A pig model of chronic heart failure by intracoronary embolization with gelatin sponge. Ann Thorac Surg. 2003;75:1942-7.
- 39. Soga Y, Nishimura K, Yamazaki K, Komeda M. Simplified chordal reconstruction: 'oblique' placement of artificial chordae tendineae in mitral valve replacement. Eur J Cardiothorac Surg. 2003;24:653-5.
- 40. Koyama T, Nishimura K, Soga Y, Unimonh O, Ueyama K, Komeda M. Importance of preserving the apex and plication of the base in left ventricular volume reduction surgery. J Thorac Cardiovasc Surg. 2003;125:669-77.
- 41. Sakakibara Y, Tambara K, Lu F, Nishina T, Sakaguchi G, Nagaya N, Nishimura K, Li RK, Weisel RD, Komeda M. Combined procedure of surgical repair and cell transplantation for left ventricular aneurysm: an experimental study. Circulation. 2002;106:I193-7.
- 42. Nomoto T, Nishina T, Miwa S, Tsuneyoshi H, Maruyama I, Nishimura K, Komeda M. Angiotensin-converting enzyme inhibitor helps prevent late remodeling after left ventricular aneurysm repair in rats. Circulation. 2002;106:I115-9.
- 43. Nishina T, Nishimura K, Yuasa S, Miwa S, Nomoto T, Sakakibara Y, Handa N, Hamanaka I, Saito Y, Komeda M. Initial effects of the left ventricular repair by plication may not last long in a rat ischemic cardiomyopathy model. Circulation. 2001;104:I241-5.
- 44. Iwakura A, Tabata Y, Tamura N, Doi K, Nishimura K, Nakamura T, Shimizu Y, Fujita M, Komeda M. Gelatin sheet incorporating basic fibroblast growth factor enhances healing of devascularized sternum in diabetic rats. Circulation. 2001;104:I325-9.
- 45. Iwakura A, Tabata Y, Miyao M, Ozeki M, Tamura N, Ikai A, Nishimura K, Nakamura T, Shimizu Y, Fujita M, Komeda M. Novel method to enhance sternal healing after harvesting bilateral internal thoracic arteries with use of basic fibroblast growth factor. Circulation. 2000;102:III307-11.
- Hidetoshi Masumoto, M.D, Ph.D.
Department of Cardiovascular Surgery,
Kyoto University Hospital
54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, JAPAN.
Tel: +81-75-751-3784 Fax: +81-75-751-4960