Mitsuhiro Yokoyama, MD, PhD　1943–2016

Mitsuhiro Yokoyama, MD, PhD, Professor Emeritus of Cardiovascular Medicine, Kobe University Graduate School of Medicine, Japan, passed away on November 10, 2016, at age 73. He was a recognized leader in cardiovascular medicine. His research spanned a wide range including coronary circulation, vascular biology, atherosclerosis and heart failure.

Dr. Yokoyama was born on November 2, 1943 at Niihama City in Ehime Prefecture. After he moved to Kobe and Osaka, he earned his MD degree from Kobe University School of Medicine in 1969, and his career as a physician and cardiologist started at Kobe Rosai Hospital. After his residency, he started his research concerning coronary circulation with Dr. Mizutani, and earned his PhD from Kobe University Graduate School of Medicine. During his research he met Mikiyo, who was working at Kobe University Hospital as a physician, and they married in 1977. Dr. Yokoyama and Mikiyo have helped each other as the best partners in the life for 39 years. Just after their marriage Dr. Yokoyama moved to the Cardiology Department of Washington University at St. Louis in 1977. He has carried out his research projects focusing on the regulation of vascular tone in atherosclerotic arteries with Professors Phillip D. Henry and Burton E. Sobel. He discovered the crucial and unique findings that atherosclerotic arteries were hypersensitive and hyperreactive for ergonovine and serotonin,¹ and contributed significantly to the field of coronary spasm.

He returned to Japan in 1980 and continued his research at Kobe University. He accumulated evidence² and proposed that the hyperreactivity of coronary arteries for specific agonists is the major cause of coronary spasm.^3,4 He was appointed Associate Professor in 1986, and promoted to Professor in 1990, at the Department of Cardiovascular Medicine, Kobe University Graduate School of Medicine where he served for 17 years until he retired in 2007.

Dr. Yokoyama was a highly motivated researcher and scientist, and he made great contributions to cardiovascular research. He incorporated the technology of biochemistry, and molecular biology into his research to clarify underlying mechanisms in cardiovascular diseases. He expanded his research fields into endothelial function, oxidative stress and atherosclerosis by using cell biology, biochemistry and molecular biology. He clarified the mechanisms of endothelial dysfunction^5,6 and the role of oxidative stress in the process of atherosclerosis,⁷ and published numerous papers. He developed endothelial cell-specific endothelial nitric oxide synthase (eNOS) transgenic mice⁸ and clarified the pathophysiological role of eNOS in cardiovascular diseases.^9,10 He also discovered that eNOS produces superoxide rather than NO through eNOS uncoupling in atherosclerosis.¹¹

Dr. Yokoyama was a hard worker, and a fair and sincere leader for young cardiologists and researchers. When the Great Hanshin-Awaji Earthquake with a magnitude of 7.2 occurred on January 17, 1995, and Kobe University Hospital and laboratories were severely damaged by the large-scale earthquake, he showed leadership in the reconstruction and recovery of Kobe University, and Kobe City. He taught us how a leader should behave.

As his final clinical research, Dr. Yokoyama and colleagues proposed that eicosapentaenoic acid (EPA) treatment with statin reduced cardiovascular events in Japanese hypercholesterolemic patients (JELIS study), and 18,645 patients were recruited. It was found that EPA treatment did reduce cardiovascular events and Dr. Yokoyama presented the results at the late-breaking clinical trials of the AHA Annual Meeting at Dallas, Texas, USA in 2005. The results were also reported in The Lancet,¹² and the JELIS study was recognized as the pioneer of large-scale clinical trials in Japan.

He was an outstanding researcher, clinician, and teacher. After his retirement from Kobe University, he served as Principal of the Hyogo Awaji Prefectural Hospital from 2011 to 2013, and then Principal and advisor at the Himeji Cardiovascular Center from 2013 to 2016. Even after retiring from Kobe University, he continued his passion for clinical research and education, and taught the importance of research thinking for young doctors. He always encouraged young doctors to “Strike while the iron is hot.” We learned a lot about the fun and excitement of science. Dr. Yokoyama will be remembered and beloved by his family, friends and colleagues.

References

• 1.   Henry PD, Yokoyama M. Supersensitivity of atherosclerotic rabbit aorta to ergonovine: Mediation by a serotonergic mechanism. J Clin Invest 1980; 66: 306–313.
• 2.   Yokoyama M, Akita H, Mizutani T, Fukuzaki H, Watanabe Y. Hyperreactivity of coronary arterial smooth muscles in response to ergonovine from rabbits with hereditary hyperlipidemia. Circ Res 1983; 53: 63–71.
• 3.   Yokoyama M, Akita H, Hirata K, Usuki S, Fukuzaki H, Itoh H, et al. Supersensitivity of isolated coronary artery to ergonovine in a patient with variant angina. Am J Med 1990; 89: 507–515.
• 4.   Ishida T, Hirata K, Sakoda T, Kanazawa K, Kawashima S, Akita H, et al. 5-HT1Dbeta receptor mediates the supersensitivity of isolated coronary artery to serotonin in variant angina. Chest 1998; 113: 243–244.
• 5.   Yokoyama M, Hirata K, Miyake R, Akita H, Ishikawa Y, Fukuzaki H. Lysophosphatidylcholine: Essential role in the inhibition of endothelium-dependent vasorelaxation by oxidized low density lipoprotein. Biochem Biophys Res Commun 1990; 168: 301–308.
• 6.   Inoue N, Hirata K, Yamada M, Hamamori Y, Matsuda Y, Akita H, et al. Lysophosphatidylcholine inhibits bradykinin-induced phosphoinositide hydrolysis and calcium transients in cultured bovine aortic endothelial cells. Circ Res 1992; 71: 1410–1421.
• 7.   Azumi H, Inoue N, Ohashi Y, Terashima M, Mori T, Fujita H, et al. Superoxide generation in directional coronary atherectomy specimens of patients with angina pectoris: Important role of NAD(P)H oxidase. Arterioscler Thromb Vasc Biol 2002; 22: 1838–1844.
• 8.   Ohashi Y, Kawashima S, Hirata K, Yamashita T, Ishida T, Inoue N, et al. Hypotension and reduced nitric oxide-elicited vasorelaxation in transgenic mice overexpressing endothelial nitric oxide synthase. J Clin Invest 1998; 102: 2061–2071.
• 9.   Ozaki M, Kawashima S, Yamashita T, Ohashi Y, Rikitake Y, Inoue N, et al. Reduced hypoxic pulmonary vascular remodeling by nitric oxide from the endothelium. Hypertension 2001; 37: 322–327.
• 10.   Yamashita T, Kawashima S, Ohashi Y, Ozaki M, Ueyama T, Ishida T, et al. Resistance to endotoxin shock in transgenic mice overexpressing endothelial nitric oxide synthase. Circulation 2000; 101: 931–937.
• 11.   Ozaki M, Kawashima S, Yamashita T, Hirase T, Namiki M, Inoue N, et al. Overexpression of endothelial nitric oxide synthase accelerates atherosclerotic lesion formation in apoE-deficient mice. J Clin Invest 2002; 110: 331–340.
• 12.   Yokoyama M, Origasa H, Matsuzaki M, Matsuzawa Y, Saito Y, Ishikawa Y, et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): A randomised open-label, blinded endpoint analysis. Lancet 2007; 369: 1090–1098.