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Department Introduction

Department Introduction

Ischemia Heart Disease Group

(2) Circulation Group

Each year the cardiac catherizations are performed (click here for details) on approximately 120 cases of pulmonary hypertension and 260 cases of chronic cardiac failure, and clinical research are conducted on these particular diseases.

Serial changes in the number of cardiac catheterization

1. Pulmonary Hypertension

Pulmonary hypertension is a disease witrh unfavorable prognosis that exhibits progressive increase in pulmonary vascular resistance and pulmonary arterial pressure. Various therapeutic agents have been developed recently and have achieved some success. However their effectiveness is still insufficient. We have been studying the role of the Rho-kinase pathway in pulmonary hypertension and have shown the Rho-kinase inhibitor Fasudil is effective in improving hemodynamics and histology in animal models (J Cardivasc Pharmacol 2006, 2007, etc). We also have shown that Fasudil demonstrates an acute effect of decreasing pulmonary vascular resistance in pulmonary hypertension patients (Heart 2005). The department has plans to study the chronic effect of Fasudil on pulmonary hypertension patients.

New Strategy for Pulmonary Hypertension

2. Cardiovascular Disease

The development of atherosclerosis is associated with risk factors including hypertension and hyperlipidemia. Atherosclerosis is not only a cause of ischemic heart and brain diseases such as myocardial infarction, angina pectoris, and cerebral infarction, but also induces vascular dysfunction which play a role of hermodynamic deterioration in chronic heart failure. Up to now we have performed basic and clinical research on atherosclerosis and inflammation (Circulation 1997, 2001; JACC 2003; etc.). Our strategy for treatment of atherosclerosis aims qualitative improvement as well as quantitative improvement. Improved vascular endothelium function and plaque stabilization for atherosclerosis are important for qualitative improvement. It has been shown that anti-inflammation, macrophage inactivation, and collagen metabolism improvement play an important role (Circulation 2001, 2004). It has also been demonstrated that the Rho-kinase pathway contributes to vascular dysfunction such as vasospasms (ATVB 2004, J Cardivasc Pharmacol 2004, 2007, etc).
It has been shown that risk factors includings hypertension, hyperlipidemia, and diabetes mellitus are significantly associated with chronic heart failure, but the role of metabolic syndrome has not been investigated yet. Currently, multicenter registry study is conducting for studying the role of metabolic syndrome in chronic cardiac failure (Ministry of Health, Labour and Welfare Scientific Research Grant Adoption Study). In addition, central sleep apnea is recognized in approximately 30 percent of chronic heart failure patients and oxygen therapy appears to be effective. Chronic heart failure recognized as the final stage of a variety of cardiovascular diseases. Vasodilating drugs and diuretics are often used to treat chronic heart failure. When neccessary, inotropic asents and mechanical supports are applied. At this time, protecting the organs should be kept in mind during treatment, and since the kidney function is an independent prognostic factor, clinical research that focuses on chronic kidney diseases is emerging.

Clinical Research on Cardiovascular Diseases



Publications (since 2000)
  1. Satoh K, Nigro P, Berk BC. Oxidative Stress and Vascular Smooth Muscle Cell Growth: A Mechanistic Linkage by Cyclophilin A. Antioxid Redox Signal. 2010 in press.
  2. Satoh K, Nigro P, Matoba T, O'Dell MR, Cui Z, Shi X, Mohan A, Yan C, Abe J, Illig KA, Berk BC. Cyclophilin A enhances vascular oxidative stress and the development of angiotensin II-induced aortic aneurysms. Nat Med. 2009;15:649-56.
  3. Do E Z, Fukumoto Y, Takaki A, Tawara S, Ohashi J, Nakano M, Tada T, Saji K, Sugimura K, Fujita H, Hoshikawa Y, Nawata J, Kondo T, Shimokawa H. Evidence for Rho-Kinase Activation in Patients With Pulmonary Arterial Hypertension. Circ J. 2009;73:1731-1739.
  4. Fukui S, Fukumoto Y, Suzuki J, Saji K, Nawata J, Shinozaki T, Kagaya Y, Watanabe J, Shimokawa H. Diabetes mellitus accelerates left ventricular diastolic dysfunction through activation of the renin-angiotensin system in hypertensive rats. Hypertens Res. 2009;32:472-80.
  5. Rashid M, Tawara S, Fukumoto Y, Seto M, Yano K, Shimokawa H. Importance of Rac1 Signaling Pathway Inhibition in the Pleiotropic Effects of HMG-CoA Reductase Inhibitors. Circ J. 2009;73:361-70.
  6. Satoh K, Fukumoto Y, Nakano M, Sugimura K, Nawata J, Demachi J, Karibe A, Kagaya Y, Ishii N, Sugamura K, Shimokawa H. Statin Ameliorates Hypoxia-Induced Pulmonary Hypertension Associated with Down-regulated Stromal Cell-Derived Factor-1. Cardiovasc Res. 2009;81:226-34.
  7. Kerwin WS, Liu F, Yarnykh V, Underhill H, Oikawa M, Yu W, Hatsukami TS, Yuan C. Signal features of the atherosclerotic plaque at 3.0 Tesla versus 1.5 Tesla: impact on automatic classification. J Magn Reson Imaging. 2008;28:987-95.
  8. Shimokawa H, Ito K, Fukumoto Y, Yasuda S. Extracorporeal cardiac shock wave therapy for ischemic heart disease. Shock Waves. 2008;17:449-455.
  9. Ichinose A, Otani H, Oikawa M, Takase K, Saito H, Shimokawa H, Takahashi S. MRI of cardiac sarcoidosis: basal and subepicardial localization of myocardial lesions and their effect on left ventricular function. AJR Am J Roentgenol. 2008;191:862-9.
  10. Tada T, Nawata J, Wang H, Onoue N, Zhulanqiqige D, Ito K, Sugimura K, Fukumoto Y, Shimokawa H. Enhanced Pulsatile Pressure Accelerates Vascular Smooth Muscle Migration -Implications for Atherogenesis of Hypertension-. Cardiovasc Res. 2008;80:346-53.
  11. Underhill HR, Yarnykh VL, Hatsukami TS, Wang J, Balu N, Hayes CE, Oikawa M, Yu W, Xu D, Chu B, Wyman BT, Polissar NL, Yuan C. Carotid plaque morphology and composition: initial comparison between 1.5- and 3.0-T magnetic field strengths. Radiology. 2008;248:550-60.
  12. Satoh K, Matoba T, Suzuki J, O'Dell MR, Nigro P, Cui Z, Mohan A, Pan S, Li L, Jin ZG, Yan C, Abe J, Berk BC. Cyclophilin A mediates vascular remodeling by promoting inflammation and vascular smooth muscle cell proliferation. Circulation. 2008;117:3088-98.
  13. Satoh K, Berk BC. Circulating smooth muscle progenitor cells: novel players in plaque stability. Cardiovasc Res. 2008;77:445-7.
  14. Underhill HR, Yuan C, Terry JG, Chen H, Espeland MA, Hatsukami TS, Saam T, Chu B, Yu W, Oikawa M, Takaya N, Yarnykh VL, Kraft R, Carr JJ, Maldjian J, Tang R, Crouse JR 3rd. Differences in carotid arterial morphology and composition between individuals with and without obstructive coronary artery disease: a cardiovascular magnetic resonance study. J Cardiovasc Magn Reson. 2008;10:31.
  15. Yuan C, Oikawa M, Miller Z, Hatsukami T. MRI of carotid atherosclerosis. J Nucl Cardiol. 2008;15:266-75. Review.
  16. Kerwin WS, Oikawa M, Yuan C, Jarvik GP, Hatsukami TS. MR imaging of adventitial vasa vasorum in carotid atherosclerosis. Magn Reson Med. 2008;59:507-14.
  17. Fukui S, Fukumoto Y, Suzuki J, Saji K, Nawata J, Tawara S, Shinozaki T, Kagaya Y, Shimokawa H. Long-term Inhibition of Rho-kinase Ameliorates Diastolic Heart Failure in Hypertensive Rats. J Cardiovasc Pharmacol. 2008 ;51:317-326
  18. Fukumoto Y, Yasuda S, Ito A, Shimokawa H. Prognostic Effects of Benidipine in Patients With Vasospastic Angina: Comparison With Diltiazem and Amlodipine. J Cardiovasc Pharmacol. 2008 ;51:253-257.
  19. Oi K, Fukumoto Y, Ito K, Uwatoku T, Abe K, Hizume T, Shimokawa H. Extracorporeal shock wave therapy ameliorates hindlimb ischemia in rabbits. Tohoku J Exp Med. 2008 ;214:151-8.
  20. Onoue N, Nawata J, Tada T, Zhulanqiqige D, Wang H, Sugimura K, Fukumoto Y, Shirato K, Shimokawa H. Increased Static Pressure Promotes Migration of Vascular Smooth Muscle Cells: Involvement of the Rho-kinase Pathway. J Cardiovasc Pharmacol. 2008 ;51:55-61.
  21. Fukumoto Y, Kishi T, Tsutsui H, Yamada A, Okamatsu S, Takeshita A. Elevated serum C-reactive protein levels as a predictive indicator for subsequent renal impairment in patients with acute heart failure. Tohoku J Exp Med. 2007 ;213:361-8
  22. Saji K, Fukumoto Y, Suzuki J, Fukui S, Nawata J, Shimokawa H. Colchicine, a microtubule depolymerizing agent, inhibits myocardial apoptosis in rats. Tohoku J Exp Med. 2007 ;213:139-48.
  23. Tawara S, Fukumoto Y, Shimokawa H. Effects of Combined Therapy With a Rho-Kinase Inhibitor and Prostacyclin on Monocrotaline-Induced Pulmonary Hypertension in Rats. J Cardiovasc Pharmacol. 2007 ;50:195-200.
  24. Yamawaki T, Yamada A, Fukumoto Y, Kishi T, Sobashima A, Kuwata K, Nakamura R, Sekiya M, Ando H, Okamatsu S. Statin therapy may prevent restenosis after successful coronary intervention, independent of lipid-lowering effect and CRP level. Fukuoka Igaku Zasshi. 2007 ;98:260-9.
  25. Fukumoto Y, Tawara S, Shimokawa H. Recent progress in the treatment of pulmonary arterial hypertension. Expectation for Rho-kinase inhibitors- Tohoku J Exp Med. 2007; 211:309-320.
  26. Fukumoto Y, Mohri M, Inokuchi K, Ito A, Hirakawa Y, Masumoto A, Hirooka Y, Takeshita A, Shimokawa H. Anti-ischemic effects of fasudil, a specific Rho-kinase inhibitor, in patients with stable effort angina. J Cardiovasc Pharmacol. 2007;49:117-121
  27. Jiang BH, Tawara S, Abe K, Takaki A, Fukumoto Y, Shimokawa H. Acute vasodilator effect of fasudil, a Rho-kinase inhibitor, in monocrotaline-induced pulmonary hypertension in rats. J Cardiovasc Pharmacol. 2007;49:85-89
  28. Nakano M, Satoh K, Fukumoto Y, Ito Y, Kagaya Y, Ishii N, Sugamura K, Shimokawa H. Important role of erythropoietin receptor to promote VEGF expression and angiogenesis in peripheral ischemia in mice. Circ Res. 2007;100: 662-669
  29. Satoh K, Kagaya Y, Nakano M, Ito Y, Ohta J, Tada H, Karibe A, Minegishi N, Suzuki N, Yamamoto M, Ono M, Watanabe J, Shirato K, Ishii N, Sugamura K, Shimokawa H. Important role of endogenous erythropoietin system in recruitment of endothelial progenitor cells in hypoxia-induced pulmonary hypertention in mice. Circulation. 2006;113:1142-1450
  30. Abe K, Tawara S, Oi K, Hizume T, Uwatoku T, Fukumoto Y, Kaibuchi K, Shimokawa H. Long-term inhibition of Rho-kinase ameliorates hypoxia-induced pulmonary hypertension in mice. J Cardiovasc Pharmacol. 2006;48:280-285
  31. Fukumoto Y, Ito A, Uwatoku T, Matoba T, Kishi T, Tanaka H, Takeshita A, Sunagawa K, Shimokawa H. Extracorporeal cardiac shock wave therapy ameliorates myocardial ischemia in patients with severe coronary artery disease. Coron Artery Dis. 2006;17:63-70
  32. Oikawa M, Kagaya Y, Otani H, Sakuma M, Demachi J, Suzuki J, Takahashi T, Nawata J, Ido T, Watanabe J, Shirato K. Increased [18F]fluorodeoxyglucose accumulation in right ventricular free wall in patients with pulmonary hypertension and the effect of epoprostenol. J Am Coll Cardiol. 2005;45:1849-1855
  33. Saji K, Sakuma M, Suzuki J, Takahashi T, Demachi J, Nawata J, Kitamukai O, Onoue N, Sugimura K, Tada T, Fukui S, Kagaya Y, Watanabe J, Shirato K. Efficacy of acute inhalation of nitric oxide in patients with primary pulmonary hypertension using chronic use of continuous epoprostenol infusion. Circ J. 2005;69:335-338
  34. Sun H, Fukumoto Y, Ito A, Shimokawa H, Sunagawa K. Coronary Microvascular Dysfunction in Patients With Microvascular Angina: Analysis by TIMI Frame Count. J Cardiovasc Pharmacol. 2005;46:622-626
  35. Eto Y, Shimokawa H, Fukumoto Y, Matsumoto Y, Morishige K, Kunihiro I, Kandabashi T, Takeshita A. Combination therapy with cerivastatin and nifedipine improves endothelial dysfunction after balloon injury in porcine coronary arteries. J Cardiovasc Pharmacol. 2005;46:1-6
  36. Zhao Y, Fukumoto Y, Mohri M, Shimokawa H, Takeshita A. Impact of Sex and Age on Coronary Basal Tone. Internal Medicine. 2005;44: 354-355
  37. Fukumoto Y, Matoba T, Ito A, Tanaka H, Kishi T, Hayashidani S, Abe K, Takeshita A, Shimokawa H. Acute vasodilator effects of a Rho-kinase inhibitor, fasudil, in patients with severe pulmonary hypertension. Heart. 2005;91:391-392
  38. Wang H, Nawata J, Kakudo N, Sugimura K, Suzuki J, Sakuma M, Ikeda J, Shirato K. The upregulation of ICAM-1 and P-selectin requires high blood pressure but not circulating rennin-angiotensin system in vivo. J Hypertens. 2004;22:1323-1332
  39. Inokuchi K, Ito A, Fukumoto Y, Matoba T, Shiose A, Nishida T, Masuda M, Morita S, Shimokawa H. Usefulness of fasudil, a Rho-kinase inhibitor, to treat intractable severe coronary spasm after coronary artery bypass surgery. J Cardiovasc Pharmacol. 2004;44:275-277
  40. Ito A, Fukumoto Y, Shimokawa H. Changing Characteristics of Patients with Vasospastic Angina in the Era of New Calcium Channel Blockers. J Cardiovasc Pharmacol. 2004;44:480-485
  41. Fukumoto Y, Deguchi JO, Libby P, Rabkin-Aikawa E, Sakata Y, Chin MT, Hill CC, Lawler PR, Varo N, Schoen FJ, Krane SM, Aikawa M. Genetically determined resistance to collagenase action augments interstitial collagen accumulation in atherosclerotic plaques. Circulation. 2004;110:1953-1959
  42. Furukawa Y, Cole SE, Shah RV, Fukumoto Y, Libby P, Mitchell RN. Wild-type but not interferon-gamma-deficient T cells induce graft arterial disease in the absence of B cells. Cardiovasc Res. 2004;63:347-356
  43. Matsumoto Y, Uwatoku T, Oi K, Abe K, Hattori T, Morishige K, Eto Y, Fukumoto Y, Nakamura KI, Shibata Y, Matsuda T, Takeshita A, Shimokawa H. Long-term inhibition of Rho-kinase suppresses neointimal formation after stent implantation in porcine coronary arteries: involvement of multiple mechanisms. Arterioscler Thromb Vasc Biol. 2004;24:181-186
  44. Miura S, Ohno I, Suzuki J, Suzuki K, Okada S, Okuyama A, Nawata J, Ikeda J, Shirato K. Inhibition of matrix metalloproteinases prevents cardiac hypertrophy induced by beta-adrenergic stimulation in rats. J Cardiovasc Pharmacol. 2003;42:174-181
  45. Fukumoto Y, Tsutsui H, Tsuchihashi M, Masumoto A, Takeshita A, Cholesterol Embolism Study(CHEST) Investigators. The incidence and risk factors of cholesterol embolization syndrome, a complication of cardiac catheterization: a prospective study. JACC. 2003;42: 211-216
  46. Aikawa M, Sugiyama S, Voglic SJ, Rabkin E, Fukumoto Y, Hill CC, Schoen FJ, Witztum JL, Libby P. Lipid lowering reduces oxidative stress and endothelial cell activation in rabbit atheroma. Circulation. 2002;106:1390-1396
  47. Fukumoto Y, Urabe Y, Kubo T, Kaku T, Egashira K, Shimokawa H, Takeshita A. Augmented vasodilator response to L-arginine after coronary angioplasty may attenuate restenosis. Heart Vessels. 2002;16:171-174
  48. Takahashi T, Sakuma M, Ikeda J, Nawata J, Demachi J, Kitamukai O, Shirato K. Effects and problems of continuous infusion of epoprostenol for patients with primary pulmonary hypertension. Intern Med. 2002;41:784-788
  49. Kitamukai O, Sakuma M, Takahashi T, Nawata J, Ikeda J, Shirato K. Hemodynamic effects of inhaled nitric oxide using pulse delivery and continuous delivery systems in pulmonary hypertension. Intern Med. 2002;41:429-434
  50. Rabkin E, Aikawa M, Stone JR, Fukumoto Y, Libby P, Schoen FJ. Activated interstitial myofibroblasts express catabolic enzymes and mediate matrix remodeling in myxomatous heart valves. Circulation. 2001;104: 2525-2532
  51. Shimizu K, Sugiyama S, Aikawa M, Fukumoto Y, Rabkin E, Libby P, Mitchell RN. Host bone-marrow cells are a source of donor intimal smooth- muscle-like cells in murine aortic transplant arteriopathy. Nat Med. 2001; 6:738-741
  52. Fukumoto Y, Libby P, Rabkin E, Hill CC, Enomoto M, Hirouchi Y, Shiommi M, Aikawa M. Statins alter smooth muscle cell accumulation and collagen content in established atheroma of Watanabe heritable hyperlipidemic rabbits. Circulation. 2001;103:993-999
  53. Aikawa M, Rabkin E, Sugiyama S, Voglic SJ, Fukumoto Y, Furukawa Y, Shiomi M, Schoen FJ, Libby P. Cerivastatin, an HMG-CoA reductase inhibitor, suppresses growth of macrophage expressing matrix metalloproteinases and tissue factor in vivo and in vitro. Circulation. 2001;103:276-283
  54. Kuga T, Shimokawa H, Hirakawa Y, Kadokami T, Arai Y, Fukumoto Y, Kuwata K, Kozai T, Egashira K, Takeshita A. Increased expression of L-type calcium channels in vascular smooth muscle cells at spastic site in a porcine model of coronary artery spasm. J Cardiovasc Pharmacol. 2000;35:822-828

( Text by Yoshihiro Fukumoto )

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