{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T17:47:02Z","timestamp":1775065622607,"version":"3.50.1"},"reference-count":45,"publisher":"Japanese Circulation Society","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Circ J"],"published-print":{"date-parts":[[2020,2,25]]},"DOI":"10.1253\/circj.cj-19-0989","type":"journal-article","created":{"date-parts":[[2020,1,30]],"date-time":"2020-01-30T22:04:07Z","timestamp":1580421847000},"page":"479-486","source":"Crossref","is-referenced-by-count":12,"title":["East Asians Variant Mitochondrial Aldehyde Dehydrogenase 2 Genotype Exacerbates Nitrate Tolerance in Patients With Coronary Spastic Angina"],"prefix":"10.1253","volume":"84","author":[{"given":"Yuji","family":"Mizuno","sequence":"first","affiliation":[{"name":"Division of Cardiovascular Medicine, Kumamoto Kinoh Hospital, Kumamoto Aging Research Institute"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eisaku","family":"Harada","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Kumamoto Kinoh Hospital, Kumamoto Aging Research Institute"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fumihito","family":"Kugimiya","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Kumamoto Kinoh Hospital, Kumamoto Aging Research Institute"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Makoto","family":"Shono","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Kumamoto Kinoh Hospital, Kumamoto Aging Research Institute"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Izumi","family":"Kusumegi","sequence":"additional","affiliation":[{"name":"Cardiovascular Examination Room, Kumamoto Kinoh Hospital"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michihiro","family":"Yoshimura","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine, The Jikei University School of Medicine"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenji","family":"Kinoshita","sequence":"additional","affiliation":[{"name":"Bio Education Laboratory"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hirofumi","family":"Yasue","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Kumamoto Kinoh Hospital, Kumamoto Aging Research Institute"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"330","reference":[{"key":"1","doi-asserted-by":"crossref","unstructured":"1. Parker JD. Nitrate tolerance, oxidative stress, and mitochondrial function: Another worrisome chapter on the effects of organic nitrates. <i>J Clin Invest<\/i> 2004; 113: 352\u2013354.","DOI":"10.1172\/JCI21003"},{"key":"2","doi-asserted-by":"crossref","unstructured":"2. M\u00fcnzel T, Daiber A, Gori T. Nitrate therapy: New aspects concerning molecular action and tolerance. <i>Circulation<\/i> 2011; 123: 2132\u20132144.","DOI":"10.1161\/CIRCULATIONAHA.110.981407"},{"key":"3","doi-asserted-by":"crossref","unstructured":"3. Daiber A, M\u00fcnzel T. Organic nitrate therapy, nitrate tolerance, and nitrate-induced endothelial dysfunction: Emphasis on redox biology and oxidative stress. <i>Antioxid Redox Signal<\/i> 2015; 23: 899\u2013942.","DOI":"10.1089\/ars.2015.6376"},{"key":"4","doi-asserted-by":"crossref","unstructured":"4. Opelt M, W\u00f6lkart G, Eroglu E, Waldeck-Weiermair M, Malli R, Graier WF, et al. Sustained formation of nitroglycerin-derived nitric oxide by aldehyde dehydrogenase-2 in vascular smooth muscle without added reductants: Implications for the development of nitrate tolerance. <i>Mol Pharmacol<\/i> 2018; 93: 335\u2013343.","DOI":"10.1124\/mol.117.110783"},{"key":"5","doi-asserted-by":"crossref","unstructured":"5. Chen CH, Ferreira JC, Gross ER, Mochly-Rosen D. Targeting aldehyde dehydrogenase 2: New therapeutic opportunities. <i>Physiol Rev<\/i> 2014; 94: 1\u201334.","DOI":"10.1152\/physrev.00017.2013"},{"key":"6","doi-asserted-by":"crossref","unstructured":"6. Opelt M, Eroglu E, Waldeck-Weiermair M, Russwurm M, Koesling D, Malli R, et al. Formation of nitric oxide by aldehyde dehydrogenase-2 is necessary and sufficient for vascular bioactivation of nitroglycerin. <i>J Biol Chem<\/i> 2016; 291: 24076\u201324084.","DOI":"10.1074\/jbc.M116.752071"},{"key":"7","doi-asserted-by":"crossref","unstructured":"7. Li H, Borinskaya S, Yoshimura K, Kal\u2019ina N, Marusin A, Stepanov VA, et al. Refined geographic distribution of the oriental ALDH2*504Lys (nee 487Lys) variant. <i>Ann Hum Genet<\/i> 2009; 73: 335\u2013345.","DOI":"10.1111\/j.1469-1809.2009.00517.x"},{"key":"8","doi-asserted-by":"crossref","unstructured":"8. Yokoyama A, Omori T, Yokoyama T. Alcohol and aldehyde dehydrogenase polymorphisms and a new strategy for prevention and screening for cancer in the upper aerodigestive tract in East Asians. <i>Keio J Med<\/i> 2010; 59: 115\u2013130.","DOI":"10.2302\/kjm.59.115"},{"key":"9","doi-asserted-by":"crossref","unstructured":"9. Mizuno Y, Harada E, Morita S, Kinoshita K, Hayashida M, Shono M, et al. East Asian variant of aldehyde dehydrogenase 2 is associated with coronary spastic angina: Possible roles of reactive aldehydes and implications of alcohol flushing syndrome. <i>Circulation<\/i> 2015; 131: 1665\u20131673.","DOI":"10.1161\/CIRCULATIONAHA.114.013120"},{"key":"10","doi-asserted-by":"crossref","unstructured":"10. JCS Joint Working Group. Guidelines for diagnosis and treatment of patients with vasospastic angina (coronary spastic angina) (JCS 2013): Digest version. <i>Circ J<\/i> 2014; 78: 2779\u20132801.","DOI":"10.1253\/circj.CJ-66-0098"},{"key":"11","doi-asserted-by":"crossref","unstructured":"11. Yasue H, Mizuno Y, Harada E. Coronary artery spasm: Clinical features, pathogenesis and treatment. <i>Proc Jpn Acad Ser B Phys Biol Sci<\/i> 2019; 95: 53\u201366.","DOI":"10.2183\/pjab.95.005"},{"key":"12","doi-asserted-by":"crossref","unstructured":"12. Takeuchi F, Yokota M, Yamamoto K, Nakashima E, Katsuya T, Asano H, et al. Genome-wide association study of coronary artery disease in the Japanese. <i>Eur J Hum Genet<\/i> 2012; 20: 333\u2013340.","DOI":"10.1038\/ejhg.2011.184"},{"key":"13","doi-asserted-by":"crossref","unstructured":"13. Mizuno Y, Hokimoto S, Harada E, Kinoshita K, Nakagawa K, Yoshimura M, et al. Variant aldehyde dehydrogenase 2 (ALDH2*2) is a risk factor for coronary spasm and ST-segment elevation myocardial infarction. <i>J Am Heart Assoc<\/i> 2016; 5: pii: e003247.","DOI":"10.1161\/JAHA.116.003247"},{"key":"14","doi-asserted-by":"crossref","unstructured":"14. Corretti MC, Anderson TJ, Benjamin EJ, Celermajer D, Charbonneau F, Creager MA, et al. Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: A report of the International Brachial Artery Reactivity Task Force. <i>J Am Coll Cardiol<\/i> 2002; 39: 257\u2013265.","DOI":"10.1016\/S0735-1097(01)01746-6"},{"key":"15","doi-asserted-by":"crossref","unstructured":"15. Donald AE, Halcox JP, Charakida M, Storry C, Wallace SM, Cole TJ, et al. Methodological approaches to optimize reproducibility and power in clinical studies of flow-mediated dilation. <i>J Am Coll Cardiol<\/i> 2008; 51: 1959\u20131964.","DOI":"10.1016\/j.jacc.2008.02.044"},{"key":"16","doi-asserted-by":"crossref","unstructured":"16. Tomiyama H, Kohro T, Higashi Y, Takase B, Suzuki T, Ishizu T, et al. Reliability of measurement of endothelial function across multiple institutions and establishment of reference values in Japanese. <i>Atherosclerosis<\/i> 2015; 242: 433\u2013442.","DOI":"10.1016\/j.atherosclerosis.2015.08.001"},{"key":"17","doi-asserted-by":"crossref","unstructured":"17. Thijssen DHJ, Bruno RM, van Mil ACCM, Holder SM, Faita F, Greyling A, et al. Expert consensus and evidence-based recommendations for the assessment of flow-mediated dilation in humans. <i>Eur Heart J<\/i> 2019; 40: 2534\u20132547.","DOI":"10.1093\/eurheartj\/ehz350"},{"key":"18","doi-asserted-by":"crossref","unstructured":"18. Hayashida M, Ota T, Ishii M, Iwao-Koizumi K, Murata S, Kinoshita K. Direct detection of single nucleotide polymorphism (SNP) by the TaqMan PCR assay using dried saliva on water soluble paper and hair-roots without DNA extraction. <i>Anal Sci<\/i> 2014; 30: 427\u2013429.","DOI":"10.2116\/analsci.30.427"},{"key":"19","doi-asserted-by":"crossref","unstructured":"19. Lewis SJ. Mendelian randomization as applied to coronary heart disease, including recent advances incorporating new technology. <i>Circ Cardiovasc Genet<\/i> 2010; 3: 109\u2013117.","DOI":"10.1161\/CIRCGENETICS.109.880955"},{"key":"20","doi-asserted-by":"crossref","unstructured":"20. Jansen H, Samani NJ, Schunkert H. Mendelian randomization studies in coronary artery disease. <i>Eur Heart J<\/i> 2014; 35: 1917\u20131924.","DOI":"10.1093\/eurheartj\/ehu208"},{"key":"21","doi-asserted-by":"crossref","unstructured":"21. Li Y, Zhang D, Jin W, Shao C, Yan P, Xu C, et al. Mitochondrial aldehyde dehydrogenase-2 (ALDH2) Glu504Lys polymorphism contributes to the variation in efficacy of sublingual nitroglycerin. <i>J Clin Invest<\/i> 2006; 116: 506\u2013511.","DOI":"10.1172\/JCI26564"},{"key":"22","doi-asserted-by":"crossref","unstructured":"22. Sakata S, Yoshihara T, Arima H, Shiraishi F, Oniki H, Takahashi-Yanaga F, et al. Differential effects of organic nitrates on arterial diameter among healthy Japanese participants with different mitochondrial aldehyde dehydrogenase 2 genotypes: Randomised crossover trial. <i>BMJ Open<\/i> 2011; 1: e000133.","DOI":"10.1136\/bmjopen-2011-000133"},{"key":"23","doi-asserted-by":"crossref","unstructured":"23. Hink U, Daiber A, Kayhan N, Trischler J, Kraatz C, Oelze M, et al. Oxidative inhibition of the mitochondrial aldehyde dehydrogenase promotes nitroglycerin tolerance in human blood vessels. <i>J Am Coll Cardiol<\/i> 2007; 50: 2226\u20132232.","DOI":"10.1016\/j.jacc.2007.08.031"},{"key":"24","doi-asserted-by":"crossref","unstructured":"24. Schulz E, Tsilimingas N, Rinze R, Reiter B, Wendt M, Oelze M, et al. Functional and biochemical analysis of endothelial (dys)function and NO\/cGMP signaling in human blood vessels with and without nitroglycerin pretreatment. <i>Circulation<\/i> 2002; 105: 1170\u20131175.","DOI":"10.1161\/hc1002.105186"},{"key":"25","doi-asserted-by":"crossref","unstructured":"25. Yasue H, Matsuyama K, Matsuyama K, Okumura K, Morikami Y, Ogawa H. Responses of angiographically normal human coronary arteries to intracoronary injection of acetylcholine by age and segment: Possible role of early coronary atherosclerosis. <i>Circulation<\/i> 1990; 81: 482\u2013490.","DOI":"10.1161\/01.CIR.81.2.482"},{"key":"26","doi-asserted-by":"crossref","unstructured":"26. Kugiyama K, Yasue H, Okumura K, Ogawa H, Fujimoto K, Nakao K, et al. Nitric oxideactivity is deficient in spasm arteries of patients with coronary spastic angina. <i>Circulation<\/i> 1996; 94: 266\u2013271.","DOI":"10.1161\/01.CIR.94.3.266"},{"key":"27","doi-asserted-by":"crossref","unstructured":"27. Motoyama T, Kawano H, Kugiyama K, Hirashima O, Ohgushi M, Tsunoda R, et al. Vitamin E administration improves impairment of endothelium-dependent vasodilation in patients with coronary spastic angina. <i>J Am Coll Cardiol<\/i> 1998; 32: 1672\u20131679.","DOI":"10.1016\/S0735-1097(98)00447-1"},{"key":"28","doi-asserted-by":"crossref","unstructured":"28. Miyamoto S, Kawano H, Sakamoto T, Soejima H, Kajiwara I, Hokamaki J, et al. Increased plasma levels of thioredoxin in patients with coronary spastic angina. <i>Antioxid Redox Signal<\/i> 2004; 6: 75\u201380.","DOI":"10.1089\/152308604771978363"},{"key":"29","doi-asserted-by":"crossref","unstructured":"29. Maruhashi T, Soga J, Fujimura N, Idei N, Mikami S, Iwamoto Y, et al. Endothelial dysfunction, increased arterial stiffness, and cardiovascular risk prediction in patients with coronary artery disease: FMD-J (Flow-Mediated Dilation Japan) Study A. <i>J Am Heart Assoc<\/i> 2018; 7: e008588.","DOI":"10.1161\/JAHA.118.008588"},{"key":"30","doi-asserted-by":"crossref","unstructured":"30. Daiber A, Di Lisa F, Oelze M, Kr\u00f6ller-Sch\u00f6n S, Steven S, Schulz E, et al. Crosstalk of mitochondria with NADPH oxidase via reactive oxygen and nitrogen species signalling and its role for vascular function. <i>Br J Pharmacol<\/i> 2017; 174: 1670\u20131689.","DOI":"10.1111\/bph.13403"},{"key":"31","doi-asserted-by":"crossref","unstructured":"31. Mizuno Y, Hokimoto S, Harada E, Kinoshita K, Yoshimura M, Yasue H. Variant aldehyde dehydrogenase 2 (ALDH2*2) in East Asians interactively exacerbates tobacco smoking risk for coronary spasm- possible role of reactive aldehydes. <i>Circ J<\/i> 2016; 81: 96\u2013102.","DOI":"10.1253\/circj.CJ-16-0969"},{"key":"32","doi-asserted-by":"crossref","unstructured":"32. Beretta M, Gorren AC, Wenzl MV, Weis R, Russwurm M, Koesling D, et al. Characterization of the East Asian variant of aldehyde dehydrogenase-2: Bioactivation of nitroglycerin and effects of Alda-1. <i>J Biol Chem<\/i> 2010; 285: 943\u2013952.","DOI":"10.1074\/jbc.M109.014548"},{"key":"33","doi-asserted-by":"crossref","unstructured":"33. D\u2019Souza Y, Ji Y, Bennett BM. Effect of overexpression of human aldehyde dehydrogenase 2 in LLC-PK1 cells on glyceryl trinitrate biotransformation and cGMP accumulation. <i>Br J Pharmacol<\/i> 2013; 168: 978\u2013987.","DOI":"10.1111\/j.1476-5381.2012.02220.x"},{"key":"34","doi-asserted-by":"crossref","unstructured":"34. Neubauer R, W\u00f6lkart G, Opelt M, Schwarzenegger C, Hofinger M, Neubauer A, et al. Aldehyde dehydrogenase-independent bioactivation of nitroglycerin in porcine and bovine blood vessels. <i>Biochem Pharmacol<\/i> 2015; 93: 440\u2013448.","DOI":"10.1016\/j.bcp.2014.12.021"},{"key":"35","doi-asserted-by":"crossref","unstructured":"35. Kitta Y, Obata JE, Nakamura T, Hirano M, Kodama Y, Fujioka D, et al. Persistent impairment of endothelial vasomotor function has a negative impact on outcome in patients with coronary artery disease. <i>J Am Coll Cardiol<\/i> 2009; 53: 323\u2013330.","DOI":"10.1016\/j.jacc.2008.08.074"},{"key":"36","doi-asserted-by":"crossref","unstructured":"36. Nakamura Y, Moss AJ, Brown MW, Kinoshita M, Kawai C. Long-term nitrate use may be deleterious in ischemic heart disease: A study using the databases from two large-scale postinfarction studies. Multicenter Myocardial Ischemia Research Group. <i>Am Heart J<\/i> 1999; 138: 577\u2013585.","DOI":"10.1016\/S0002-8703(99)70163-8"},{"key":"37","doi-asserted-by":"crossref","unstructured":"37. Kojima S, Matsui K, Sakamoto T, Ishihara M, Kimura K, Miyazaki S, et al. Acute Coronary Syndrome Study (JACSS) Investigators. Long-term nitrate therapy after acute myocardial infarction does not improve or aggravate prognosis. <i>Circ J<\/i> 2007; 71: 301\u2013307.","DOI":"10.1253\/circj.71.301"},{"key":"38","doi-asserted-by":"crossref","unstructured":"38. Morikawa Y, Mizuno Y, Harada E, Kuboyama O, Yoshimura M, Yasue H. Nitrate tolerance as a possible cause of multidrug-resistant coronary artery spasm. <i>Int Heart J<\/i> 2010; 51: 211\u2013213.","DOI":"10.1536\/ihj.51.211"},{"key":"39","doi-asserted-by":"crossref","unstructured":"39. Kosugi M, Nakagomi A, Shibui T, Kato K, Kusama Y, Atarashi H, et al. Effect of long-term nitrate treatment on cardiac events in patients with vasospastic angina. <i>Circ J<\/i> 2011; 75: 2196\u20132205.","DOI":"10.1253\/circj.CJ-11-0056"},{"key":"40","doi-asserted-by":"crossref","unstructured":"40. Takahashi J, Nihei T, Takagi Y, Miyata S, Odaka Y, Tsunoda R, et al. Prognostic impact of chronic nitrate therapy in patients with vasospastic angina: Multicentre registry study of the Japanese coronary spasm association. <i>Eur Heart J<\/i> 2015; 36: 228\u2013237.","DOI":"10.1093\/eurheartj\/ehu313"},{"key":"41","doi-asserted-by":"crossref","unstructured":"41. Kim CH, Park TK, Cho SW, Oh MS, Lee DH, Seong CS, et al. Impact of different nitrate therapies on long-term clinical outcomes of patients with vasospastic angina: A propensity score-matched analysis. <i>Int J Cardiol<\/i> 2018; 252: 1\u20135.","DOI":"10.1016\/j.ijcard.2017.07.031"},{"key":"42","doi-asserted-by":"crossref","unstructured":"42. Steven S, Oelze M, Hausding M, Roohani S, Kashani F, Kr\u00f6ller-Sch\u00f6n S, et al. The Endothelin Receptor Antagonist Macitentan Improves Isosorbide-5-Mononitrate (ISMN) and Isosorbide Dinitrate (ISDN) induced endothelial dysfunction, oxidative stress, and vascular inflammation. <i>Oxid Med Cell Longev<\/i> 2018; 2018: 7845629.","DOI":"10.1155\/2018\/7845629"},{"key":"43","doi-asserted-by":"crossref","unstructured":"43. Murohara T, Tayama S, Tabuchi T, Sumida H, Honda T, Hayasaki K, et al. Effects of angiotensin-converting enzyme inhibitor alacepril in patients with stable effort angina during chronic isosorbide dinitrate treatment. <i>Am J Cardiol<\/i> 1996; 77: 1159\u20131163.","DOI":"10.1016\/S0002-9149(96)00155-5"},{"key":"44","doi-asserted-by":"crossref","unstructured":"44. Hirai N, Kawano H, Yasue H, Shimomura H, Miyamoto S, Soejima H, et al. Attenuation of nitrate tolerance and oxidative stress by an angiotensin II receptor blocker in patients with coronary spastic angina. <i>Circulation<\/i> 2003; 108: 1446\u20131450.","DOI":"10.1161\/01.CIR.0000089092.61590.A8"},{"key":"45","doi-asserted-by":"crossref","unstructured":"45. Knorr M, Hausding M, Kr\u00f6ller-Schuhmacher S, Steven S, Oelze M, Heeren T, et al. Nitroglycerin-induced endothelial dysfunction and tolerance involve adverse phosphorylation and S-Glutathionylation of endothelial nitric oxide synthase: Beneficial effects of therapy with the AT1 receptor blocker telmisartan. <i>Arterioscler Thromb Vasc Bio<\/i> 2011; 31: 2223\u20132231.","DOI":"10.1161\/ATVBAHA.111.232058"}],"container-title":["Circulation Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.jstage.jst.go.jp\/article\/circj\/84\/3\/84_CJ-19-0989\/_pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,2,29]],"date-time":"2020-02-29T03:21:32Z","timestamp":1582946492000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.jstage.jst.go.jp\/article\/circj\/84\/3\/84_CJ-19-0989\/_article"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,2,25]]},"references-count":45,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2020]]}},"URL":"https:\/\/doi.org\/10.1253\/circj.cj-19-0989","relation":{},"ISSN":["1346-9843","1347-4820"],"issn-type":[{"value":"1346-9843","type":"print"},{"value":"1347-4820","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,2,25]]}}}