Display options
Share it on

Physiol Rep. 2021 Sep;9(17):e15004. doi: 10.14814/phy2.15004.

Differential inflammatory responses of the native left and right ventricle associated with donor heart preservation.

Physiological reports

Ienglam Lei, Wei Huang, Peter A Ward, Jordan S Pober, George Tellides, Gorav Ailawadi, Francis D Pagani, Andrew P Landstrom, Zhong Wang, Richard M Mortensen, Marilia Cascalho, Jeffrey Platt, Yuqing Eugene Chen, Hugo Yu Kor Lam, Paul C Tang

Affiliations

  1. Department of Cardiac Surgery, University of Michigan Frankel Cardiovascular Center, Ann Arbor, Michigan, USA.
  2. Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
  3. Department of Immunobiology, Yale University, New Haven, Connecticut, USA.
  4. Department of Surgery, Yale University, New Haven, Connecticut, USA.
  5. Department of Pediatrics, Duke University, Durham, North Carolina, USA.
  6. Department of Internal Medicine, University of Michigan Frankel Cardiovascular Center, Ann Arbor, Michigan, USA.
  7. Department of Surgery, University of Michigan Medical School, Ann Arbor, Michigan, USA.
  8. Hypahub Inc, San Jose, California, USA.

PMID: 34435466 PMCID: PMC8387788 DOI: 10.14814/phy2.15004

Abstract

BACKGROUND: Dysfunction and inflammation of hearts subjected to cold ischemic preservation may differ between left and right ventricles, suggesting distinct strategies for amelioration.

METHODS AND RESULTS: Explanted murine hearts subjected to cold ischemia for 0, 4, or 8 h in preservation solution were assessed for function during 60 min of warm perfusion and then analyzed for cell death and inflammation by immunohistochemistry and western blotting and total RNA sequencing. Increased cold ischemic times led to greater left ventricle (LV) dysfunction compared to right ventricle (RV). The LV experienced greater cell death assessed by TUNEL

CONCLUSIONS: Mouse hearts subjected to cold ischemia showed time-dependent contractile dysfunction and increased cell death, inflammatory cytokine expression and inflammasome expression that are greater in the LV than RV. However, IL-6 protein elevations and altered transcriptional profiles were similar in both ventricles. Similar changes are observed in human hearts.

© 2021 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.

Keywords: contractile function; inflammation; ischemia; myocardial biology; transplantation

References

  1. Arslan, F., de Kleijn, D. P., & Pasterkamp, G. (2011). Innate immune signaling in cardiac ischemia. Nature Reviews Cardiology, 8, 292-300. https://doi.org/10.1038/nrcardio.2011.38 - PubMed
  2. Barklin, A. (2009). Systemic inflammation in the brain-dead organ donor. Acta Anaesthesiologica Scandinavica, 53, 425-435. https://doi.org/10.1111/j.1399-6576.2008.01879.x - PubMed
  3. Benichou, G., & Thomson, A. W. (2009). Direct versus indirect allorecognition pathways: On the right track. American Journal of Transplantation, 9, 655-656. https://doi.org/10.1111/j.1600-6143.2009.02572.x - PubMed
  4. Birks, E. J., Burton, P. B., Owen, V., Mullen, A. J., Hunt, D., Banner, N. R., Barton, P. J., & Yacoub, M. H. (2000). Elevated tumor necrosis factor-alpha and interleukin-6 in myocardium and serum of malfunctioning donor hearts. Circulation, 102:III352-III358. - PubMed
  5. Birks, E. J., Owen, V. J., Burton, P. B., Bishop, A. E., Banner, N. R., Khaghani, A., Polak, J. M., & Yacoub, M. H. (2000). Tumor necrosis factor-alpha is expressed in donor heart and predicts right ventricular failure after human heart transplantation. Circulation, 102, 326-331. - PubMed
  6. Bracey, N. A., Beck, P. L., Muruve, D. A., Hirota, S. A., Guo, J., Jabagi, H., Wright, J. R. Jr, Macdonald, J. A., Lees-Miller, J. P., Roach, D., Semeniuk, L. M., & Duff, H. J. (2013). The Nlrp3 inflammasome promotes myocardial dysfunction in structural cardiomyopathy through interleukin-1beta. Experimental Physiology, 98, 462-472. - PubMed
  7. Chilton, P. M., Embry, C. A., & Mitchell, T. C. (2012). Effects of differences in lipid A structure on TLR4 pro-inflammatory signaling and inflammasome activation. Frontiers in Immunology, 3, 154. - PubMed
  8. Choi, M. E., Price, D. R., Ryter, S. W., & Choi, A. M. K. (2019). Necroptosis: A crucial pathogenic mediator of human disease. JCI Insight, 4(15), https://doi.org/10.1172/jci.insight.128834 - PubMed
  9. de Groot-Kruseman, H. A., Baan, C. C., Loonen, E. H., Mol, W. M., Niesters, H. G., Maat, A. P., Balk, A. H., & Weimar, W. (2001). Failure to down-regulate intragraft cytokine mRNA expression shortly after clinical heart transplantation is associated with high incidence of acute rejection. Journal of Heart and Lung Transplantation, 20, 503-510. https://doi.org/10.1016/S1053-2498(00)00325-9 - PubMed
  10. Dell'Italia, L. J., & Walsh, R. A. (1988). Acute determinants of the hangout interval in the pulmonary circulation. American Heart Journal, 116, 1289-1297. https://doi.org/10.1016/0002-8703(88)90454-1. - PubMed
  11. DeWitt, E. S., Black, K. J., & Kheir, J. N. (2016). Rodent working heart model for the study of myocardial performance and oxygen consumption. Journal of Visualized Experiments. https://doi.org/10.3791/54149 - PubMed
  12. Fattahi, F., Frydrych, L. M., Bian, G., Kalbitz, M., Herron, T. J., Malan, E. A., Delano, M. J., & Ward, P. A. (2018). Role of complement C5a and histones in septic cardiomyopathy. Molecular Immunology, 102, 32-41. https://doi.org/10.1016/j.molimm.2018.06.006 - PubMed
  13. Fattahi, F., & Ward, P. A. (2017). Complement and sepsis-induced heart dysfunction. Molecular Immunology, 84, 57-64. https://doi.org/10.1016/j.molimm.2016.11.012 - PubMed
  14. Goldhaber, J. I., Kim, K. H., Natterson, P. D., Lawrence, T., Yang, P., & Weiss, J. N. (1996). Effects of TNF-alpha on [Ca2+]i and contractility in isolated adult rabbit ventricular myocytes. American Journal of Physiology, 271, H1449-H1455. https://doi.org/10.1152/ajpheart.1996.271.4.H1449 - PubMed
  15. Kalbitz, M., Fattahi, F., Grailer, J. J., Jajou, L., Malan, E. A., Zetoune, F. S., Huber-Lang, M., Russell, M. W., & Ward, P. A. (2016). Complement-induced activation of the cardiac NLRP3 inflammasome in sepsis. The FASEB Journal, 30, 3997-4006. https://doi.org/10.1096/fj.201600728R - PubMed
  16. Kalbitz, M., Fattahi, F., Herron, T. J., Grailer, J. J., Jajou, L., Lu, H., Huber-Lang, M., Zetoune, F. S., Sarma, J. V., Day, S. M., Russell, M. W., Jalife, J., & Ward, P. A. (2016). Complement destabilizes cardiomyocyte function in vivo after polymicrobial sepsis and in vitro. The Journal of Immunology, 197, 2353-2361. https://doi.org/10.4049/jimmunol.1600091 - PubMed
  17. Kobashigawa, J., Zuckermann, A., Macdonald, P., Leprince, P., Esmailian, F., Luu, M., Mancini, D., Patel, J., Razi, R., Reichenspurner, H., Russell, S., Segovia, J., Smedira, N., Stehlik, J., & Wagner, F. (2014). Report from a consensus conference on primary graft dysfunction after cardiac transplantation. The Journal of Heart and Lung Transplantation, 33(4), 327-340. https://doi.org/10.1016/j.healun.2014.02.027 - PubMed
  18. Kondo, R. P., Dederko, D. A., Teutsch, C., Chrast, J., Catalucci, D., Chien, K. R., & Giles, W. R. (2006). Comparison of contraction and calcium handling between right and left ventricular myocytes from adult mouse heart: A role for repolarization waveform. Journal of Physiology, 571, 131-146. https://doi.org/10.1113/jphysiol.2005.101428 - PubMed
  19. Krishnamurthy, P., Rajasingh, J., Lambers, E., Qin, G., Losordo, D. W., & Kishore, R. (2009). IL-10 inhibits inflammation and attenuates left ventricular remodeling after myocardial infarction via activation of STAT3 and suppression of HuR. Circulation Research, 104, e9-e18. https://doi.org/10.1161/CIRCRESAHA.108.188243 - PubMed
  20. Lei, I., Wang, Z., Chen, Y. E., Ma, P. X., Huang, W., Kim, E., Lam, H. Y. K., Goldstein, D. R., Aaronson, K. D., Pagani, F. D., & Tang, P. C. (2020). "The secret life of human donor hearts": An examination of transcriptomic events during cold storage. Circulation: Heart Failure, 13, e006409. https://doi.org/10.1161/CIRCHEARTFAILURE.119.006409 - PubMed
  21. Li, T., Zhang, Z., Kolwicz, S. C. Jr, Abell, L., Roe, N. D., Kim, M., Zhou, B., Cao, Y., Ritterhoff, J., Gu, H., Raftery, D., Sun, H., & Tian, R. (2017). Defective branched-chain amino acid catabolism disrupts glucose metabolism and sensitizes the heart to ischemia-reperfusion injury. Cell Metabolism, 25, 374-385. https://doi.org/10.1016/j.cmet.2016.11.005 - PubMed
  22. Liu, X., Zhang, Z., Ruan, J., Pan, Y., Magupalli, V. G., Wu, H., & Lieberman, J. (2016). Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores. Nature, 535, 153-158. https://doi.org/10.1038/nature18629 - PubMed
  23. MacNee, W. (1994). Pathophysiology of cor pulmonale in chronic obstructive pulmonary disease. Part One. American Journal of Respiratory and Critical Care Medicine, 150, 833-852. https://doi.org/10.1164/ajrccm.150.3.8087359 - PubMed
  24. McGeough, M. D., Wree, A., Inzaugarat, M. E., Haimovich, A., Johnson, C. D., Pena, C. A., Goldbach-Mansky, R., Broderick, L., Feldstein, A. E., & Hoffman, H. M. (2017). TNF regulates transcription of NLRP3 inflammasome components and inflammatory molecules in cryopyrinopathies. Journal of Clinical Investigation, 127, 4488-4497. https://doi.org/10.1172/JCI90699 - PubMed
  25. Miller, A., & Wright, G. L. (2011). Fabrication of murine ventricular balloons for the langendorff heart preparation. Journal of Biotechnology & Biomaterials, 1. https://doi.org/10.4172/2155-952X.1000101 - PubMed
  26. Modesti, P. A., Vanni, S., Bertolozzi, I., Cecioni, I., Lumachi, C., Perna, A. M., Boddi, M., & Gensini, G. F. (2004). Different growth factor activation in the right and left ventricles in experimental volume overload. Hypertension, 43, 101-108. https://doi.org/10.1161/01.HYP.0000104720.76179.18 - PubMed
  27. Plenz, G., Eschert, H., Erren, M., Wichter, T., Bohm, M., Flesch, M., Scheld, H. H., & Deng, M. C. (2002). The interleukin-6/interleukin-6-receptor system is activated in donor hearts. Journal of the American College of Cardiology, 39, 1508-1512. https://doi.org/10.1016/S0735-1097(02)01791-6 - PubMed
  28. Rollins, B. J. (1996). Monocyte chemoattractant protein 1: A potential regulator of monocyte recruitment in inflammatory disease. Molecular Medicine Today, 2, 198-204. https://doi.org/10.1016/1357-4310(96)88772-7 - PubMed
  29. Schroeder, L. W., Chowdhury, S. M., Burnette, A. L., Kavarana, M. N., Hamilton Baker, G., Savage, A. J., Atz, A. M., & Butts, R. J. (2018). Longer ischemic time is associated with increased ventricular stiffness as measured by pressure-volume loop analysis in pediatric heart transplant recipients. Pediatric Cardiology, 39, 324-328. https://doi.org/10.1007/s00246-017-1758-7 - PubMed
  30. Singh, S. S. A., Dalzell, J. R., Berry, C., & Al-Attar, N. (2019). Primary graft dysfunction after heart transplantation: A thorn amongst the roses. Heart Failure Reviews. https://doi.org/10.1007/s10741-019-09794-1 - PubMed
  31. Vilahur, G., & Badimon, L. (2014). Ischemia/reperfusion activates myocardial innate immune response: The key role of the toll-like receptor. Frontiers in Physiology, 5, 496. https://doi.org/10.3389/fphys.2014.00496 - PubMed
  32. Voelkel, N. F., Natarajan, R., Drake, J. I., & Bogaard, H. J. (2011). Right ventricle in pulmonary hypertension. Comprehensive Physiology, 1, 525-540. - PubMed
  33. Wajant, H., Pfizenmaier, K., & Scheurich, P. (2003). Tumor necrosis factor signaling. Cell Death and Differentiation, 10, 45-65. https://doi.org/10.1038/sj.cdd.4401189 - PubMed
  34. Yang, Z., Zingarelli, B., & Szabo, C. (2000). Crucial role of endogenous interleukin-10 production in myocardial ischemia/reperfusion injury. Circulation, 101, 1019-1026. https://doi.org/10.1161/01.CIR.101.9.1019 - PubMed
  35. Zhang, M., Xu, Y. J., Saini, H. K., Turan, B., Liu, P. P., & Dhalla, N. S. (2005). TNF-alpha as a potential mediator of cardiac dysfunction due to intracellular Ca2+-overload. Biochemical and Biophysical Research Communications, 327, 57-63. - PubMed
  36. Zhang, W., Xu, X., Kao, R., Mele, T., Kvietys, P., Martin, C. M., & Rui, T. (2014). Cardiac fibroblasts contribute to myocardial dysfunction in mice with sepsis: The role of NLRP3 inflammasome activation. PLoS One, 9, e107639. https://doi.org/10.1371/journal.pone.0107639 - PubMed

Publication Types

Grant support