SpringerLink
Log in

East Asian variant aldehyde dehydrogenase type 2 genotype exacerbates ischemia/reperfusion injury with ST-elevation myocardial infarction in men: possible sex differences

  • Original Article
  • Published:
Heart and Vessels Aims and scope Submit manuscript

Abstract

Mitochondrial aldehyde dehydrogenase 2 (ALDH2) detoxifies toxic aldehydes generated during ischemia/reperfusion (I/R) injury in ST-elevation myocardial infarction (STEMI). The deficient variant ALDH2 genotype (ALDH2*2) is prevalent among East Asians. Whether ALDH2*2 exacerbates I/R injury of in patients with STEMI is not known. The study subjects comprised 218 Japanese patients with STEMI (158 men and 60 women, mean age 67.9 ± 11.9) who underwent successful percutaneous coronary intervention. Of these, 120 (55.0%) were the carriers of variant ALDH2*2 and 98 (45.0%) those of wild ALDH2*1/*1 on genoty**. There were no differences in clinical characteristics between the ALDH2*2 and ALDH2*1/*1 group except lower alcohol habit (14.2% vs 46.3%, P < 0.001) in the ALDH2*2 group. The peak plasma levels of creatine phosphokinase myocardial binding (CKMB), a marker of myocardial injury, however, were significantly higher in the patients with ALDH2*2 than in those with ALDH2*1/*1 [a median 275.0 (175.8–407.5) vs 177.5 (126.9–344.3) U/L, P = 0.001] among men but not among women (P = 0.811). There was a significant interaction between men (male sex) and ALDH2*2 for I/R injury (χ2 = 4.425, P = 0.040). The variant ALDH2*2 was associated with more severe I/R injury than the wild ALDH2*1/*1 in STEMI patients in men with possible sex differences.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. O’Gara PT, Kushner FG, Ascheim DD, Casey DE Jr, Chung MK, de Lemos JA, Ettinger SM, Fang JC, Fesmire FM, Franklin BA, Granger CB, Krumholz HM, Linderbaum JA, Morrow DA, Newby LK, Ornato JP, Ou N, Radford MJ, Tamis-Holland JE, Tommaso CL, Tracy CM, Woo YJ, Zhao DX, Anderson JL, Jacobs AK, Halperin JL, Albert NM, Brindis RG, Creager MA, DeMets D, Guyton RA, Hochman JS, Kovacs RJ, Kushner FG, Ohman EM, Stevenson WG, Yancy CW, American College of Cardiology Foundation/American Heart Association Task Force on Practice G (2013) 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines. Circulation 127(4):e362-425

    PubMed  Google Scholar 

  2. Heusch G, Gersh BJ (2017) The pathophysiology of acute myocardial infarction and strategies of protection beyond reperfusion: a continual challenge. Eur Heart J 38(11):774–784

    CAS  PubMed  Google Scholar 

  3. Hausenloy DJ, Barrabes JA, Botker HE, Davidson SM, Di Lisa F, Downey J, Engstrom T, Ferdinandy P, Carbrera-Fuentes HA, Heusch G, Ibanez B, Iliodromitis EK, Inserte J, Jennings R, Kalia N, Kharbanda R, Lecour S, Marber M, Miura T, Ovize M, Perez-Pinzon MA, Piper HM, Przyklenk K, Schmidt MR, Redington A, Ruiz-Meana M, Vilahur G, Vinten-Johansen J, Yellon DM, Garcia-Dorado D (2016) Ischaemic conditioning and targeting reperfusion injury: a 30 year voyage of discovery. Basic Res Cardiol 111(6):70

    Article  Google Scholar 

  4. Eaton P, Li JM, Hearse DJ, Shattock MJ (1999) Formation of 4-hydroxy-2-nonenal-modified proteins in ischemic rat heart. Am J Physiol 276(3):H935-943

    CAS  PubMed  Google Scholar 

  5. Singh S, Brocker C, Koppaka V, Chen Y, Jackson BC, Matsumoto A, Thompson DC, Vasiliou V (2013) Aldehyde dehydrogenases in cellular responses to oxidative/electrophilic stress. Free Radic Biol Med 56:89–101

    Article  CAS  Google Scholar 

  6. Chen CH, Budas GR, Churchill EN, Disatnik MH, Hurley TD, Mochly-Rosen D (2008) Activation of aldehyde dehydrogenase-2 reduces ischemic damage to the heart. Science 321(5895):1493–1495

    Article  CAS  Google Scholar 

  7. Ma H, Guo R, Yu L, Zhang Y, Ren J (2011) Aldehyde dehydrogenase 2 (ALDH2) rescues myocardial ischaemia/reperfusion injury: role of autophagy paradox and toxic aldehyde. Eur Heart J 32(8):1025–1038

    Article  CAS  Google Scholar 

  8. Chen CH, Ferreira JC, Gross ER, Mochly-Rosen D (2014) Targeting aldehyde dehydrogenase 2: new therapeutic opportunities. Physiol Rev 94(1):1–34

    Article  Google Scholar 

  9. Sun A, Zou Y, Wang P, Xu D, Gong H, Wang S, Qin Y, Zhang P, Chen Y, Harada M, Isse T, Kawamoto T, Fan H, Yang P, Akazawa H, Nagai T, Takano H, ** P, Komuro I, Ge J (2014) Mitochondrial aldehyde dehydrogenase 2 plays protective roles in heart failure after myocardial infarction via suppression of the cytosolic JNK/p53 pathway in mice. J Am Heart Assoc 3(5):e000779

    Article  Google Scholar 

  10. Li H, Borinskaya S, Yoshimura K, Kal’ina N, Marusin A, Stepanov VA, Qin Z, Khaliq S, Lee MY, Yang Y, Mohyuddin A, Gurwitz D, Mehdi SQ, Rogaev E, ** L, Yankovsky NK, Kidd JR, Kidd KK (2009) Refined geographic distribution of the oriental ALDH2*504Lys (nee 487Lys) variant. Ann Hum Genet 73(Pt 3):335–345

    Article  CAS  Google Scholar 

  11. Lagranha CJ, Deschamps A, Aponte A, Steenbergen C, Murphy E (2010) Sex differences in the phosphorylation of mitochondrial proteins result in reduced production of reactive oxygen species and cardioprotection in females. Circ Res 106(11):1681–1691

    Article  CAS  Google Scholar 

  12. Casin KM, Fallica J, Mackowski N, Veenema RJ, Chan A, St Paul A, Zhu G, Bedja D, Biswal S, Kohr MJ (2018) S-Nitrosoglutathione reductase is essential for protecting the female heart from ischemia-reperfusion injury. Circ Res 123(11):1232–1243

    Article  CAS  Google Scholar 

  13. Hayashida M, Ota T, Ishii M, Iwao-Koizumi K, Murata S, Kinoshita K (2014) 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. Anal Sci 30(3):427–429

    Article  CAS  Google Scholar 

  14. Mizuno Y, Harada E, Morita S, Kinoshita K, Hayashida M, Shono M, Morikawa Y, Murohara T, Nakayama M, Yoshimura M, Yasue H (2015) East asian variant of aldehyde dehydrogenase 2 is associated with coronary spastic angina: possible roles of reactive aldehydes and implications of alcohol flushing syndrome. Circulation 131(19):1665–1673

    Article  CAS  Google Scholar 

  15. Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, Picard MH, Roman MJ, Seward J, Shanewise JS, Solomon SD, Spencer KT, Sutton MS, Stewart WJ, Chamber Quantification Writing G, American Society of Echocardiography’s G, Standards C, European Association of E (2005) Recommendations for chamber quantification: a report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr 18(12):1440–1463

    Article  Google Scholar 

  16. Lim CC, van Gaal WJ, Testa L, Cuculi F, Arnold JR, Karamitsos T, Francis JM, Petersen SE, Digby JE, Westaby S, Antoniades C, Kharbanda RK, Burrell LM, Neubauer S, Banning AP (2011) With the “universal definition,” measurement of creatine kinase-myocardial band rather than troponin allows more accurate diagnosis of periprocedural necrosis and infarction after coronary intervention. J Am Coll Cardiol 57(6):653–661

    Article  CAS  Google Scholar 

  17. Moussa ID, Klein LW, Shah B, Mehran R, Mack MJ, Brilakis ES, Reilly JP, Zoghbi G, Holper E, Stone GW (2013) Consideration of a new definition of clinically relevant myocardial infarction after coronary revascularization: an expert consensus document from the Society for Cardiovascular Angiography and Interventions (SCAI). J Am Coll Cardiol 62(17):1563–1570

    Article  Google Scholar 

  18. Hartman MHT, Ep**a RN, Vlaar PJJ, Lexis CPH, Lipsic E, Haeck JDE, van Veldhuisen DJ, van der Horst ICC, van der Harst P (2017) The contemporary value of peak creatine kinase-MB after ST-segment elevation myocardial infarction above other clinical and angiographic characteristics in predicting infarct size, left ventricular ejection fraction, and mortality. Clin Cardiol 40(5):322–328

    Article  Google Scholar 

  19. Katz MH (2011) Multivariable analysis: a practical guide for clinicians and public health researchers. Cambridge University Press, Cambridge, pp 118–124

    Book  Google Scholar 

  20. Ota M, Hisada A, Lu X, Nakashita C, Masuda S, Katoh T (2016) Associations between aldehyde dehydrogenase 2 (ALDH2) genetic polymorphisms, drinking status, and hypertension risk in Japanese adult male workers: a case-control study. Environ Health Prev Med 21(1):1–8

    Article  CAS  Google Scholar 

  21. Takagi S, Iwai N, Yamauchi R, Kojima S, Yasuno S, Baba T, Terashima M, Tsutsumi Y, Suzuki S, Morii I, Hanai S, Ono K, Baba S, Tomoike H, Kawamura A, Miyazaki S, Nonogi H, Goto Y (2002) Aldehyde dehydrogenase 2 gene is a risk factor for myocardial infarction in Japanese men. Hypertens Res 25(5):677–681

    Article  CAS  Google Scholar 

  22. Jo SA, Kim EK, Park MH, Han C, Park HY, Jang Y, Song BJ, Jo I (2007) A Glu487Lys polymorphism in the gene for mitochondrial aldehyde dehydrogenase 2 is associated with myocardial infarction in elderly Korean men. Clin Chim Acta 382(1–2):43–47

    Article  CAS  Google Scholar 

  23. Xu F, Chen YG, Xue L, Li RJ, Zhang H, Bian Y, Zhang C, Lv RJ, Feng JB, Zhang Y (2011) Role of aldehyde dehydrogenase 2 Glu504lys polymorphism in acute coronary syndrome. J Cell Mol Med 15(9):1955–1962

    Article  CAS  Google Scholar 

  24. Takeuchi F, Yokota M, Yamamoto K, Nakashima E, Katsuya T, Asano H, Isono M, Nabika T, Sugiyama T, Fujioka A, Awata N, Ohnaka K, Nakatochi M, Kitajima H, Rakugi H, Nakamura J, Ohkubo T, Imai Y, Shimamoto K, Yamori Y, Yamaguchi S, Kobayashi S, Takayanagi R, Ogihara T, Kato N (2012) Genome-wide association study of coronary artery disease in the Japanese. Eur J Hum Genet 20(3):333–340

    Article  CAS  Google Scholar 

  25. Mizuno Y, Hokimoto S, Harada E, Kinoshita K, Nakagawa K, Yoshimura M, Ogawa H, Yasue H (2016) Variant aldehyde dehydrogenase 2 (ALDH2*2) is a risk factor for coronary spasm and ST-segment elevation myocardial infarction. J Am Heart Assoc 5(5):e003247

    Article  Google Scholar 

  26. Lewis SJ (2010) Mendelian randomization as applied to coronary heart disease, including recent advances incorporating new technology. Circ Cardiovasc Genet 3(1):109–117

    Article  Google Scholar 

  27. Jansen H, Samani NJ, Schunkert H (2014) Mendelian randomization studies in coronary artery disease. Eur Heart J 35(29):1917–1924

    Article  CAS  Google Scholar 

  28. Casin KM, Kohr MJ (2020) An emerging perspective on sex differences: intersecting S-nitrosothiol and aldehyde signaling in the heart. Redox Biol 31:101441

    Article  CAS  Google Scholar 

  29. Sun X, Briel M, Busse JW, You JJ, Akl EA, Mejza F, Bala MM, Bassler D, Mertz D, Diaz-Granados N, Vandvik PO, Malaga G, Srinathan SK, Dahm P, Johnston BC, Alonso-Coello P, Hassouneh B, Walter SD, Heels-Ansdell D, Bhatnagar N, Altman DG, Guyatt GH (2012) Credibility of claims of subgroup effects in randomised controlled trials: systematic review. BMJ 344:e1553

    Article  Google Scholar 

  30. Lemoine S, Tritapepe L, Hanouz JL, Puddu PE (2016) The mechanisms of cardio-protective effects of desflurane and sevoflurane at the time of reperfusion: anaesthetic post-conditioning potentially translatable to humans? Br J Anaesth 116(4):456–475

    Article  CAS  Google Scholar 

  31. OECD(2013) (2013) Mortality following acute myocardial infarction (AMI). In Health at a Glance 2013. OECD Indicators, OECD Publishing, Paris, pp 112–113

    Google Scholar 

  32. Qian F, Ling FS, Deedwania P, Hernandez AF, Fonarow GC, Cannon CP, Peterson ED, Peacock WF, Kaltenbach LA, Laskey WK, Schwamm LH, Bhatt DL, Get With The Guidelines Steering C, Investigators (2012) Care and outcomes of Asian-American acute myocardial infarction patients: findings from the American Heart Association get with the guidelines-coronary artery disease program. Circ Cardiovasc Qual Outcomes 5(1):126–133

    Article  Google Scholar 

  33. Kim EJ, Kressin NR, Paasche-Orlow MK, Lopez L, Rosen JE, Lin M, Hanchate AD (2018) Racial/ethnic disparities among Asian Americans in inpatient acute myocardial infarction mortality in the United States. BMC Health Serv Res 18(1):370

    Article  Google Scholar 

  34. Wang R, Lagakos SW, Ware JH, Hunter DJ, Drazen JM (2007) Statistics in medicine–reporting of subgroup analyses in clinical trials. N Engl J Med 357(21):2189–2194

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We appreciate prof. Makoto Futatsuka, MD, PhD, an epidemiologist, for consultation on statistical analysis in this study. We also acknowledge all the paramedical staff and clinical secretaries for their kind support for this work.

Author information

Authors and Affiliations

  1. Department of Cardiovascular Medicine, Faculty of Life Science, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan

    Toshifumi Ishida, Yuichiro Arima, Takayoshi Yamashita, Daisuke Sueta, Kenji Sakamoto, Satoru Suzuki, Koichi Kaikita & Kenichi Tsujita

  2. Division of Cardiovascular Medicine, Kumamoto Kinoh Hospital Kumamoto Aging Research Institute, Kumamoto, Japan

    Toshifumi Ishida, Yuji Mizuno, Eisaku Harada & Hirofumi Yasue

  3. Division of Cardiovascular Medicine, Fukuoka Tokushukai Hospital, Kasuga, Japan

    Yoshihiro Yamada & Hideki Shimomura

  4. Division of Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan

    Kentaro Oniki & Junji Saruwatari

  5. Division of Cardiovascular Medicine, Kumamoto City Ueki Hospital, Kumamoto, Japan

    Seiji Hokimoto

Authors
  1. Toshifumi Ishida
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yuichiro Arima
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yuji Mizuno
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Eisaku Harada
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Takayoshi Yamashita
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Daisuke Sueta
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kenji Sakamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Satoru Suzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Koichi Kaikita
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yoshihiro Yamada
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Hideki Shimomura
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Kentaro Oniki
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Junji Saruwatari
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Seiji Hokimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Hirofumi Yasue
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Kenichi Tsujita
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kenichi Tsujita.

Ethics declarations

Conflict of interest

Sources of grants: This study was supported in part by grants-in-aid for scientific research from the Ministry of Education, Culture, Sports, Science and Technology, Japan, the Japan Heart Foundation, Tokyo, and the Japan Vascular Disease Research Foundation, Kyoto, Japan.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ishida, T., Arima, Y., Mizuno, Y. et al. East Asian variant aldehyde dehydrogenase type 2 genotype exacerbates ischemia/reperfusion injury with ST-elevation myocardial infarction in men: possible sex differences. Heart Vessels 37, 184–193 (2022). https://doi.org/10.1007/s00380-021-01907-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00380-021-01907-x

Keywords

Search

Navigation