Skip to main content
SpringerLink
Log in

Acute Changes in Myocardial Expression of Heat Shock Proteins and Apoptotic Response Following Blood, delNido, or Custodiol Cardioplegia in Infants Undergoing Open-Heart Surgery

  • Original Article
  • Published:
Pediatric Cardiology Aims and scope Submit manuscript

Abstract

Stress caused by cardioplegic ischemic arrest was shown to alter the expression levels of heat shock proteins (Hsp), but little is known about their effects, particularly on pediatric hearts. This study aimed to investigate whether myocardial cellular stress and apoptotic response changes due to different cardioplegia (CP) solutions during cardiopulmonary bypass (CPB) in infants and to determine their influence on surgical/clinical outcomes. Therefore, twenty-seven infants for surgical closure of ventricular septal defect were randomly assigned to a CP solution: normothermic blood (BCP), delNido (dNCP), and Custodiol (CCP). Hsp levels and apoptosis were determined by immunoblotting in cardiac tissue from the right atrium before and after CP, and their correlations with cardiac parameters were evaluated. No significant change was observed in Hsp27 levels. Hsp60, Hsp70, and Hsp90 levels decreased significantly in the BCP-group but increased markedly in the CCP-group. Decreased Hsp60 and increased Hsp70 expression were detected in dNCP-group. Importantly, apoptosis was not observed in dNCP- and CCP-groups, whereas marked increases in cleaved caspase-3 and -8 were determined after BCP. Serum cardiac troponin-I (cTn-I), myocardial injury marker, was markedly lower in the BCP- and dNCP-groups than CCP. Additionally, Hsp60, Hsp70, and Hsp90 levels were positively correlated with aortic cross-clamp time, total perfusion time, and cTn-I release. Our findings show that dNCP provides the most effective myocardial preservation in pediatric open-heart surgery and indicate that an increase in Hsp70 expression may be associated with a cardioprotective effect, while an increase in Hsp60 and Hsp90 levels may be an indicator of myocardial damage during CPB.

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

Access this article

Log in via an institution

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
Fig. 4
Fig. 5

Similar content being viewed by others

Data Availability

Data available on request from the authors.

Abbreviations

ACCT:

Aortic cross-clamp time

BCP:

Blood cardioplegia

CCP:

Custodiol cardioplegia

CHD:

Congenital heart disease

CP:

Cardioplegia

CPB:

Cardiopulmonary bypass

cTn-I:

Cardiac troponin-I

dNCP:

DelNido cardioplegia

Hsp:

Heat shock protein

I/R:

Ischemia/reperfusion

ICU:

Intensive care unit

IS:

Inotropic score

TPT:

Total perfusion time

VIS:

Vasoactive-inotropic score

VSD:

Ventricular septal defect

References

  1. Kotani Y, Tweddell J, Gruber P, Pizarro C, Austin EH 3rd, Woods RK et al (2013) Current cardioplegia practice in pediatric cardiac surgery: a North American multiinstitutional survey. Ann Thorac Surg 96(3):923–929. https://doi.org/10.1016/j.athoracsur.2013.05.052

    Article  PubMed  Google Scholar 

  2. Drury NE, Horsburgh A, Bi R, Willetts RG, Jones TJ (2019) Cardioplegia practice in paediatric cardiac surgery: a UK & Ireland survey. Perfusion 34(2):125–129. https://doi.org/10.1177/0267659118794343

    Article  PubMed  Google Scholar 

  3. Santos-Junior VA, Lollo PCB, Cantero MA, Moura CS, Amaya-Farfan J, Morato PN (2018) Heat shock proteins: protection and potential biomarkers for ischemic injury of cardiomyocytes after surgery. Braz J Cardiovasc Surg 33(3):291–302. https://doi.org/10.21470/1678-9741-2017-0169

    Article  PubMed  PubMed Central  Google Scholar 

  4. Schmitt JP, Schunkert H, Birnbaum DE, Aebert H (2002) Kinetics of heat shock protein 70 synthesis in the human heart after cold cardioplegic arrest. Eur J Cardiothorac Surg 22(3):415–420. https://doi.org/10.1016/s1010-7940(02)00327-5

    Article  CAS  PubMed  Google Scholar 

  5. Chello M, Mastroroberto P, Patti G, D’Ambrosio A, Di Sciascio G, Covino E (2003) Intermittent warm blood cardioplegia induces the expression of heat shock protein-72 by ischemic myocardial preconditioning. Cardiovasc Surg 11(5):367–374. https://doi.org/10.1016/S0967-2109(03)00078-4

    Article  CAS  PubMed  Google Scholar 

  6. Giannessi D, Caselli C, Vitale RL, Crucean A, Murzi B, Del Ry S et al (2003) A possible cardioprotective effect of heat shock proteins during cardiac surgery in pediatric patients. Pharmacol Res 48(5):519–529. https://doi.org/10.1016/s1043-6618(03)00193-2

    Article  CAS  PubMed  Google Scholar 

  7. Vittorini S, Storti S, Andreani G, Giusti L, Murzi B, Furfori P et al (2007) Heat shock protein 70–1 gene expression in pediatric heart surgery using blood cardioplegia. Clin Chem Lab Med 45(2):244–248. https://doi.org/10.1515/CCLM.2007.030

    Article  CAS  PubMed  Google Scholar 

  8. Peng EW, McCaig D, Pollock JC, MacArthur K, Lyall F, Danton MH (2011) Myocardial expression of heat shock protein 70i protects early postoperative right ventricular function in cyanotic tetralogy of Fallot. J Thorac Cardiovasc Surg 141(5):1184–1191. https://doi.org/10.1016/j.jtcvs.2011.01.047

    Article  CAS  PubMed  Google Scholar 

  9. Yavuz S, Kasap M, Parlar H, Agirbas H, Torol S, Kanli A et al (2011) Heat shock proteins and myocardial protection during cardiopulmonary bypass. J Int Med Res 39(2):499–507. https://doi.org/10.1177/147323001103900217

    Article  CAS  PubMed  Google Scholar 

  10. Clements RT, Feng J, Cordeiro B, Bianchi C, Sellke FW (2011) p38 MAPK-dependent small HSP27 and αB-crystallin phosphorylation in regulation of myocardial function following cardioplegic arrest. Am J Physiol Heart Circ Physiol 300(5):H1669–H1677. https://doi.org/10.1152/ajpheart.00272.2010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Walker S, Danton M, Peng EW, Lyall F (2013) Heat shock protein 27 is increased in cyanotic tetralogy of Fallot myocardium and is associated with improved cardiac output and contraction. Cell Stress Chaperones 18(3):269–277. https://doi.org/10.1007/s12192-012-0379-6

    Article  CAS  PubMed  Google Scholar 

  12. Salameh A, Keller M, Dähnert I, Dhein S (2017) Olesoxime inhibits cardioplegia-induced ischemia/reperfusion injury. A study in langendorff-perfused rabbit hearts. Front Physiol 8:324. https://doi.org/10.3389/fphys.2017.00324

    Article  PubMed  PubMed Central  Google Scholar 

  13. Willis MS, Patterson C (2010) Hold me tight: role of the heat shock protein family of chaperones in cardiac disease. Circulation 122(17):1740–1751. https://doi.org/10.1161/CIRCULATIONAHA.110.942250

    Article  PubMed  PubMed Central  Google Scholar 

  14. Kwon JH, Kim JB, Lee KH, Kang SM, Chung N, Jang Y et al (2007) Protective effect of heat shock protein 27 using protein transduction domain-mediated delivery on ischemia/reperfusion heart injury. Biochem Biophys Res Commun 363(2):399–404. https://doi.org/10.1016/j.bbrc.2007.09.001

    Article  CAS  PubMed  Google Scholar 

  15. McGinley LM, McMahon J, Stocca A, Duffy A, Flynn A, O’Toole D et al (2013) Mesenchymal stem cell survival in the infarcted heart is enhanced by lentivirus vector-mediated heat shock protein 27 expression. Hum Gene Ther 24(10):840–851. https://doi.org/10.1089/hum.2011.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Suzuki K, Murtuza B, Sammut IA, Latif N, Jayakumar J, Smolenski RT et al (2002) Heat shock protein 72 enhances manganese superoxide dismutase activity during myocardial ischemia-reperfusion injury, associated with mitochondrial protection and apoptosis reduction. Circulation 106:I270–I276. https://doi.org/10.1161/01.cir.0000032880.55215.92

    Article  CAS  PubMed  Google Scholar 

  17. Kohno H, Takahashi N, Shinohara T, Ooie T, Yufu K, Nakagawa M et al (2007) Receptor-mediated suppression of cardiac heat-shock protein 72 expression by testosterone in male rat heart. Endocrinology 148(7):3148–3155. https://doi.org/10.1210/en.2006-1581

    Article  CAS  PubMed  Google Scholar 

  18. Song N, Ma J, Meng XW, Liu H, Wang H, Song SY et al (2020) Heat shock protein 70 protects the heart from ischemia/reperfusion injury through inhibition of p38 MAPK signaling. Oxid Med Cell Longev 2020:3908641. https://doi.org/10.1155/2020/3908641

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Önay Uçar E, Şengelen A (2019) Resveratrol and siRNA in combination reduces Hsp27 expression and induces caspase-3 activity in human glioblastoma cells. Cell Stress Chaperones 24(4):763–775. https://doi.org/10.1007/s12192-019-01004-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Brar BK, Stephanou A, Wagstaff MJ, Coffin RS, Marber MS, Engelmann G et al (1999) Heat shock proteins delivered with a virus vector can protect cardiac cells against apoptosis as well as against thermal or hypoxic stress. J Mol Cell Cardiol 31(1):135–1146. https://doi.org/10.1006/jmcc.1998.0857

    Article  CAS  PubMed  Google Scholar 

  21. Vander Heide RS (2002) Increased expression of HSP27 protects canine myocytes from simulated ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol 282(3):H935–H941. https://doi.org/10.1152/ajpheart.00660.2001

    Article  CAS  PubMed  Google Scholar 

  22. Lu XY, Chen L, Cai XL, Yang HT (2008) Overexpression of heat shock protein 27 protects against ischaemia/reperfusion-induced cardiac dysfunction via stabilization of troponin I and T. Cardiovasc Res 79(3):500–508. https://doi.org/10.1093/cvr/cvn091

    Article  CAS  PubMed  Google Scholar 

  23. Ferns G, Shams S, Shafi S (2006) Heat shock protein 27: its potential role in vascular disease. Int J Exp Pathol 87(4):253–274. https://doi.org/10.1111/j.1365-2613.2006.00484.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Toga W, Tanonaka K, Takeo S (2007) Changes in Hsp60 level of the failing heart following acute myocardial infarction and the effect of long-term treatment with trandolapril. Biol Pharm Bull 30:105–110. https://doi.org/10.1248/bpb.30.105

    Article  CAS  PubMed  Google Scholar 

  25. Giannessi D, Colotti C, Maltinti M, Del Ry S, Prontera C, Turchi S et al (2007) Circulating heat shock proteins and inflammatory markers in patients with idiopathic left ventricular dysfunction: their relationships with myocardial and microvascular impairment. Cell Stress Chaperones 12(3):265–274. https://doi.org/10.1379/csc-272.1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Dybdahl B, Slørdahl SA, Waage A, Kierulf P, Espevik T, Sundan A (2005) Myocardial ischaemia and the inflammatory response: release of heat shock protein 70 after myocardial infarction. Heart 91(3):299–304. https://doi.org/10.1136/hrt.2003.028092:299-304

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Li Z, Song Y, Xing R, Yu H, Zhang Y, Li Z et al (2013) Heat shock protein 70 acts as a potential biomarker for early diagnosis of heart failure. PLoS ONE 8(7):e67964. https://doi.org/10.1371/journal.pone.0067964

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Jenei ZM, Széplaki G, Merkely B, Karádi I, Zima E, Prohászka Z (2013) Persistently elevated extracellular HSP70 (HSPA1A) level as an independent prognostic marker in post-cardiac-arrest patients. Cell Stress Chaperones 18(4):447–454. https://doi.org/10.1007/s12192-012-0399-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Marunouchi T, Nishiumi C, Iinuma S, Yano E, Tanonaka K (2021) Effects of Hsp90 inhibitor on the RIP1-RIP3-MLKL pathway during the development of heart failure in mice. Eur J Pharmacol 898:173987. https://doi.org/10.1016/j.ejphar.2021.173987

    Article  CAS  PubMed  Google Scholar 

  30. Scarabelli TM, Pasini E, Ferrari G, Ferrari M, Stephanou A, Lawrence K et al (2004) Warm blood cardioplegic arrest induces mitochondrial-mediated cardiomyocyte apoptosis associated with increased urocortin expression in viable cells. J Thorac Cardiovasc Surg 128(3):364–371. https://doi.org/10.1016/j.jtcvs.2003.11.028

    Article  PubMed  Google Scholar 

  31. Ramlawi B, Feng J, Mieno S, Szabo C, Zsengeller Z, Clements R et al (2006) Indices of apoptosis activation after blood cardioplegia and cardiopulmonary bypass. Circulation 114:I257–I263. https://doi.org/10.1161/CIRCULATIONAHA.105.000828

    Article  PubMed  Google Scholar 

  32. Mylonas KS, Tzani A, Metaxas P, Schizas D, Boikou V, Economopoulos KP (2017) Blood versus crystalloid cardioplegia in pediatric cardiac surgery: a systematic review and meta-analysis. Pediatr Cardiol 38(8):1527–1539. https://doi.org/10.1007/s00246-017-1732-4

    Article  PubMed  Google Scholar 

  33. Matte GS, del Nido PJ (2012) History and use of del Nido cardioplegia solution at Boston Children’s Hospital. J Extra Corpor Technol 44:98–103

    PubMed  PubMed Central  Google Scholar 

  34. Lewandrowski KB (2014) Cardiac markers of myocardial necrosis: a history and discussion of milestones and emerging new trends. Clin Lab Med 34(1):31–41. https://doi.org/10.1016/j.cll.2013.11.001

    Article  PubMed  Google Scholar 

Download references

Funding

No funding was received for conducting this study.

Author information

Authors and Affiliations

  1. Pediatric Cardiovascular Surgery Clinic, Kartal Koşuyolu High Specialization Training and Research Hospital, Health Sciences University, Denizer Road No:2, 34846, Cevizli-Kartal/Istanbul, Turkey

    Eylem Yayla-Tunçer, Berra Zümrüt Tan-Recep, Abdullah Arif Yilmaz & Hakan Ceyran

  2. Department of Molecular Biology and Genetics, Institute of Graduate Studies in Sciences, Istanbul University, Istanbul, Turkey

    Aslıhan Şengelen

  3. Anesthesiology and Reanimation Clinic, Kartal Koşuyolu High Specialization Training and Research Hospital, Health Sciences University, Istanbul, Turkey

    Ömer Faruk Şavluk

  4. Department of Molecular Biology and Genetics, Faculty of Science, Istanbul University, Balabanağa, Şehzadebaşı Road, Vezneciler, 34134, Istanbul, Turkey

    Evren Önay-Uçar

  5. Pediatric Cardiovascular Surgery Clinic, Konya City Hospital, Health Sciences University, Konya, Turkey

    Berra Zümrüt Tan-Recep

Authors
  1. Eylem Yayla-Tunçer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Aslıhan Şengelen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Berra Zümrüt Tan-Recep
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ömer Faruk Şavluk
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Abdullah Arif Yilmaz
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hakan Ceyran
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Evren Önay-Uçar
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

EY-T, EÖ-U, and HC conceived the project. EY-T, BZT-R, and AAY collected and assembled the clinical data. AŞ and EÖ-U collected and assembled the molecular data. AŞ and ÖFŞ analyzed the data. EY-T, AŞ, and EÖ-U interpreted the data and wrote the manuscript. All authors read and approved the manuscript.

Corresponding authors

Correspondence to Eylem Yayla-Tunçer or Evren Önay-Uçar.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Ethical Approval

The study was approved by the ethics committee of Kartal Koşuyolu High Specialization Training and Research Hospital, Istanbul, Turkey (decision no: 2017/5/31, 19th June 2017).

Additional information

Publisher's Note

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

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 824 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yayla-Tunçer, E., Şengelen, A., Tan-Recep, B.Z. et al. Acute Changes in Myocardial Expression of Heat Shock Proteins and Apoptotic Response Following Blood, delNido, or Custodiol Cardioplegia in Infants Undergoing Open-Heart Surgery. Pediatr Cardiol 43, 567–579 (2022). https://doi.org/10.1007/s00246-021-02759-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00246-021-02759-y

Keywords

Search

Navigation