Preconditioning of the Heart Following Transmyocardial Revascularization

  • Chartchai Kositprapa
  • On Topaz
  • Arun Samidurai
  • Shinji Okubo
  • Vigneshwar Kasirajan
  • Rakesh C. KukrejaEmail author


Transmyocardial Laser Revascularization (TMR) is an approved treatment of end stage coronary artery disease. Explanation on how TMR improves symptoms is currently unknown although myocardial angiogenesis and denervation are considered as possible mechanisms. In this study, we investigated the potential preconditioning effect of TMR in a model of myocardial ischemia/reperfusion injury. It has been suggested that laser phototherapy causes accumulation of safe levels of ROS, which may potentially trigger protective signaling leading to accelerated healing. Considering the essential role of reactive oxygen species (ROS) in ischemic preconditioning (IPC), we hypothesized that TMR procedure could potentially trigger cardioprotection via generation of ROS. The studies were performed in a rabbit model of myocardial ischemia/reperfusion injury. Our results showed that TMR triggered cardioprotective effect similar to IPC which was responsible for significant reduction of infarct size both acutely as well as 24 h after TMR. Interestingly, such infarct limiting effect was abolished when rabbits were treated with an intracellular antioxidant suggesting that ROS are important triggers of cardioprotection. These studies suggest that in addition to angina relief, TMR also helps in salvaging myocardial tissue following ischemia/reperfusion injury. Further studies are necessary to delineate the signaling mechanisms and cardioprotective target proteins that may be synthesized in response to TMR.


Preconditioning Ischemia Reperfusion Infarction Free radicals Antioxidants Transmyocardial revascularization 



This research was supported by the National Institutes of Health Grants R37 HL51045, R01 HL 59469 R01 HL79424, R01HL93685 and R01 HL118808 to RCK.


  1. 1.
    Bolli R, Becker L, Gross G, Mentzer Jr R, Balshaw D, Lathrop DA. Myocardial protection at a crossroads: the need for translation into clinical therapy. Circ Res. 2004;95(2):125–34.CrossRefPubMedGoogle Scholar
  2. 2.
    Sen PK, Udwadia TE, Kinare SG, Parulkar GB. Transmyocardial acupuncture: a new approach to myocardial revascularization. J Thorac Cardiovasc Surg. 1965;50:181–9.PubMedGoogle Scholar
  3. 3.
    Mirhoseini M, Cayton MM. Revascularization of the heart by laser. J Microsurg. 1981;2(4):253–60.CrossRefPubMedGoogle Scholar
  4. 4.
    Krabatsch T, Schaper F, Leder C, Tulsner J, Thalmann U, Hetzer R. Histological findings after transmyocardial laser revascularization. J Card Surg. 1996;11(5):326–31.CrossRefPubMedGoogle Scholar
  5. 5.
    Hardy RI, Bove KE, James FW, Kaplan S, Goldman L. A histologic study of laser-induced transmyocardial channels. Lasers Surg Med. 1987;6(6):563–73.CrossRefPubMedGoogle Scholar
  6. 6.
    Kindzelski BA, Zhou Y, Horvath KA. Transmyocardial revascularization devices: technology update. Med Devices (Auckl). 2015;8:11–9.Google Scholar
  7. 7.
    Shahzad U, Li G, Zhang Y, Yau TM. Transmyocardial revascularization induces mesenchymal stem cell engraftment in infarcted hearts. Ann Thorac Surg. 2012;94(2):556–62.CrossRefPubMedGoogle Scholar
  8. 8.
    Shahzad U, Li G, Zhang Y, Li RK, Rao V, Yau TM. Transmyocardial revascularization enhances bone marrow stem cell engraftment in infarcted hearts through SCF-C-kit and SDF-1-CXCR4 signaling axes. Stem Cell Rev. 2015;11:332–46.CrossRefPubMedGoogle Scholar
  9. 9.
    Reyes G, Allen KB, Alvarez P, et al. Mid term results after bone marrow laser revascularization for treating refractory angina. BMC Cardiovasc Disord. 2010;10:42.PubMedCentralCrossRefPubMedGoogle Scholar
  10. 10.
    Goodarzi AA, Jeggo P, Lobrich M. The influence of heterochromatin on DNA double strand break repair: getting the strong, silent type to relax. DNA Repair (Amst). 2010;9(12):1273–82.CrossRefGoogle Scholar
  11. 11.
    Gowdak LH, Schettert IT, Rochitte CE, et al. Cell therapy plus transmyocardial laser revascularization for refractory angina. Ann Thorac Surg. 2005;80(2):712–4.CrossRefPubMedGoogle Scholar
  12. 12.
    Horvath KA, Smith WJ, Laurence RG, Schoen FJ, Appleyard RF, Cohn LH. Recovery and viability of an acute myocardial infarct after transmyocardial laser revascularization. J Am Coll Cardiol. 1995;25(1):258–63.CrossRefPubMedGoogle Scholar
  13. 13.
    Kohmoto T, DeRosa CM, Yamamoto N, et al. Evidence of vascular growth associated with laser treatment of normal canine myocardium. Ann Thorac Surg. 1998;65(5):1360–7.CrossRefPubMedGoogle Scholar
  14. 14.
    Yamamoto N, Kohmoto T, Gu A, DeRosa C, Smith CR, Burkhoff D. Angiogenesis is enhanced in ischemic canine myocardium by transmyocardial laser revascularization. J Am Coll Cardiol. 1998;31(6):1426–33.CrossRefPubMedGoogle Scholar
  15. 15.
    Beek JF, van der Sloot JA, Huikeshoven M, et al. Cardiac denervation after clinical transmyocardial laser revascularization: short-term and long-term iodine 123-labeled meta-iodobenzylguanide scintigraphic evidence. J Thorac Cardiovasc Surg. 2004;127(2):517–24.CrossRefPubMedGoogle Scholar
  16. 16.
    Al-Sheikh T, Allen KB, Straka SP, et al. Cardiac sympathetic denervation after transmyocardial laser revascularization. Circulation. 1999;100(2):135–40.CrossRefPubMedGoogle Scholar
  17. 17.
    Hughes GC, Lowe JE, Kypson AP, et al. Neovascularization after transmyocardial laser revascularization in a model of chronic ischemia. Ann Thorac Surg. 1998;66(6):2029–36.CrossRefPubMedGoogle Scholar
  18. 18.
    Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation. 1986;74(5):1124–36.CrossRefPubMedGoogle Scholar
  19. 19.
    Gill R, Kuriakose R, Gertz ZM, Salloum FN, Xi L, Kukreja RC. Remote ischemic preconditioning for myocardial protection: update on mechanisms and clinical relevance. Mol Cell Biochem. 2015;402:41–9.CrossRefPubMedGoogle Scholar
  20. 20.
    Jones SP, Tang XL, Guo Y, et al. The NHLBI-sponsored consortium for preclinicAl assESsment of cARdioprotective therapies (CAESAR): a new paradigm for rigorous, accurate, and reproducible evaluation of putative infarct-sparing interventions in mice, rabbits, and pigs. Circ Res. 2015;116:572–86.CrossRefPubMedGoogle Scholar
  21. 21.
    Yang X, Cohen MV, Downey JM. Mechanism of cardioprotection by early ischemic preconditioning. Cardiovasc Drugs Ther. 2010;24(3):225–34.PubMedCentralCrossRefPubMedGoogle Scholar
  22. 22.
    Okubo S, Xi L, Bernardo NL, Yoshida K, Kukreja RC. Myocardial preconditioning: basic concepts and potential mechanisms. Mol Cell Biochem. 1999;196(1–2):3–12.CrossRefPubMedGoogle Scholar
  23. 23.
    Xi L, Tekin D, Bhargava P, Kukreja RC. Whole body hyperthermia and preconditioning of the heart: basic concepts, complexity, and potential mechanisms. Int J Hyperthermia. 2001;17(5):439–55.CrossRefPubMedGoogle Scholar
  24. 24.
    Bolli R. The late phase of preconditioning. Circ Res. 2000;87(11):972–83.CrossRefPubMedGoogle Scholar
  25. 25.
    Murry CE RVJRRKA. Preconditioning with ischemia: is the protective effect mediated by free radical-induced myocardial stunning? Circulation. 1988;78(Suppl II):II-77. (Abstract).Google Scholar
  26. 26.
    Baines CP, Goto M, Downey JM. Oxygen radicals released during ischemic preconditioning contribute to cardioprotection in the rabbit myocardium. J Mol Cell Cardiol. 1997;29(1):207–16.CrossRefPubMedGoogle Scholar
  27. 27.
    Tritto I, D’Andrea D, Eramo N, et al. Oxygen radicals can induce preconditioning in rabbit hearts. Circ Res. 1997;80(5):743–8.CrossRefPubMedGoogle Scholar
  28. 28.
    Bolli R, Jeroudi MO, Patel BS, et al. Marked reduction of free radical generation and contractile dysfunction by antioxidant therapy begun at the time of reperfusion. Evidence that myocardial “stunning” is a manifestation of reperfusion injury. Circ Res. 1989;65(3):607–22.CrossRefPubMedGoogle Scholar
  29. 29.
    Liu Y, Yang XM, Iliodromitis EK, et al. Redox signaling at reperfusion is required for protection from ischemic preconditioning but not from a direct PKC activator. Basic Res Cardiol. 2008;103(1):54–9.PubMedCentralCrossRefPubMedGoogle Scholar
  30. 30.
    Dillenburg CS, Almeida LO, Martins MD, Squarize CH, Castilho RM. Laser phototherapy triggers the production of reactive oxygen species in oral epithelial cells without inducing DNA damage. J Biomed Opt. 2014;19(4):048002.CrossRefPubMedGoogle Scholar
  31. 31.
    Bernardo NL, D’Angelo M, Okubo S, Joy A, Kukreja RC. Delayed ischemic preconditioning is mediated by opening of ATP-sensitive potassium channels in the rabbit heart. Am J Physiol. 1999; 276(4 Pt 2): H1323–30.PubMedGoogle Scholar
  32. 32.
    Kositprapa C, Ockaili RA, Kukreja RC. Bradykinin B2 receptor is involved in the late phase of preconditioning in rabbit heart. J Mol Cell Cardiol. 2001;33(7):1355–62.CrossRefPubMedGoogle Scholar
  33. 33.
    Okubo S, Wildner O, Shah MR, Chelliah JC, Hess ML, Kukreja RC. Gene transfer of heat-shock protein 70 reduces infarct size in vivo after ischemia/reperfusion in the rabbit heart. Circulation. 2001;103(6):877–81.CrossRefPubMedGoogle Scholar
  34. 34.
    Ytrehus K, Liu Y, Downey JM. Preconditioning protects ischemic rabbit heart by protein kinase C activation. Am J Physiol. 1994;266(3 Pt 2):H1145–52.PubMedGoogle Scholar
  35. 35.
    Kukreja RC, Hess ML. The oxygen free radical system: from equations through membrane-protein interactions to cardiovascular injury and protection. Cardiovasc Res. 1992;26(7):641–55.CrossRefPubMedGoogle Scholar
  36. 36.
    Kukreja RC, Janin Y. Reperfusion injury: basic concepts and protection strategies. J Thromb Thrombolysis. 1997;4(1):7–24.CrossRefPubMedGoogle Scholar
  37. 37.
    Chen W, Gabel S, Steenbergen C, Murphy E. A redox-based mechanism for cardioprotection induced by ischemic preconditioning in perfused rat heart. Circ Res. 1995;77(2):424–9.CrossRefPubMedGoogle Scholar
  38. 38.
    Skyschally A, Schulz R, Gres P, Korth HG, Heusch G. Attenuation of ischemic preconditioning in pigs by scavenging of free oxyradicals with ascorbic acid. Am J Physiol Heart Circ Physiol. 2003;284(2):H698–703.CrossRefPubMedGoogle Scholar
  39. 39.
    Tanaka K, Weihrauch D, Kehl F, et al. Mechanism of preconditioning by isoflurane in rabbits: a direct role for reactive oxygen species. Anesthesiology. 2002;97(6):1485–90.CrossRefPubMedGoogle Scholar
  40. 40.
    Ushio-Fukai M, Tang Y, Fukai T, et al. Novel role of gp91(phox)-containing NAD(P)H oxidase in vascular endothelial growth factor-induced signaling and angiogenesis. Circ Res. 2002; 91(12):1160–7.CrossRefPubMedGoogle Scholar
  41. 41.
    Colavitti R, Pani G, Bedogni B, et al. Reactive oxygen species as downstream mediators of angiogenic signaling by vascular endothelial growth factor receptor-2/KDR. J Biol Chem. 2002; 277(5):3101–8.CrossRefPubMedGoogle Scholar
  42. 42.
    Lelkes PI, Hahn KL, Sukovich DA, Karmiol S, Schmidt DH. On the possible role of reactive oxygen species in angiogenesis. Adv Exp Med Biol. 1998;454:295–310.CrossRefPubMedGoogle Scholar
  43. 43.
    Maulik N. Redox regulation of vascular angiogenesis. Antioxid Redox Signal. 2002;4(5):783–4.CrossRefPubMedGoogle Scholar
  44. 44.
    Garlid KD, Costa AD, Quinlan CL, Pierre SV, Dos SP. Cardioprotective signaling to mitochondria. J Mol Cell Cardiol. 2009;46(6):858–66.PubMedCentralCrossRefPubMedGoogle Scholar
  45. 45.
    Andrukhiv A, Costa AD, West IC, Garlid KD. Opening mitoKATP increases superoxide generation from complex I of the electron transport chain. Am J Physiol Heart Circ Physiol. 2006;291(5):H2067–74.CrossRefPubMedGoogle Scholar
  46. 46.
    Kukreja RC. Mechanism of reactive oxygen species generation after opening of mitochondrial KATP channels. Am J Physiol Heart Circ Physiol. 2006;291(5):H2041–3.CrossRefPubMedGoogle Scholar
  47. 47.
    Kukreja RC, Kontos MC, Loesser KE, et al. Oxidant stress increases heat shock protein 70 mRNA in isolated perfused rat heart. Am J Physiol. 1994;267(6 Pt 2):H2213–9.PubMedGoogle Scholar
  48. 48.
    Kukreja RC, Kontos MC, Hess ML. Free radicals and heat shock protein in the heart. Ann N Y Acad Sci. 1996;793:108–22.CrossRefPubMedGoogle Scholar
  49. 49.
    Yoshida K, Maaieh MM, Shipley JB, et al. Monophosphoryl lipid A induces pharmacologic ‘preconditioning’ in rabbit hearts without concomitant expression of 70-kDa heat shock protein. Mol Cell Biochem. 1996;156(1):1–8.CrossRefPubMedGoogle Scholar
  50. 50.
    Yin C, Salloum FN, Kukreja RC. A novel role of microRNA in late preconditioning: upregulation of endothelial nitric oxide synthase and heat shock protein 70. Circ Res. 2009;104(5):572–5.PubMedCentralCrossRefPubMedGoogle Scholar
  51. 51.
    Xi L, Salloum F, Tekin D, Jarrett NC, Kukreja RC. Glycolipid RC-552 induces delayed preconditioning-like effect via iNOS-dependent pathway in mice. Am J Physiol. 1999;277(6 Pt 2): H2418–24.PubMedGoogle Scholar
  52. 52.
    Xi L, Jarrett NC, Hess ML, Kukreja RC. Essential role of inducible nitric oxide synthase in monophosphoryl lipid A-induced late cardioprotection: evidence from pharmacological inhibition and gene knockout mice. Circulation. 1999;99(16):2157–63.CrossRefPubMedGoogle Scholar
  53. 53.
    Xi L, Kukreja RC. Pivotal role of nitric oxide in delayed pharmacological preconditioning against myocardial infarction. Toxicology. 2000;155(1–3):37–44.CrossRefPubMedGoogle Scholar
  54. 54.
    Xi L, Tekin D, Gursoy E, Salloum F, Levasseur JE, Kukreja RC. Evidence that NOS2 acts as a trigger and mediator of late preconditioning induced by acute systemic hypoxia. Am J Physiol Heart Circ Physiol. 2002;283(1):H5–12.CrossRefPubMedGoogle Scholar
  55. 55.
    Okubo S, Tanabe Y, Takeda K, et al. Ischemic preconditioning and morphine attenuate myocardial apoptosis and infarction after ischemia-reperfusion in rabbits: role of delta-opioid receptor. Am J Physiol Heart Circ Physiol. 2004;287(4):H1786–91.CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag London 2015

Authors and Affiliations

  • Chartchai Kositprapa
    • 1
    • 2
  • On Topaz
    • 3
  • Arun Samidurai
    • 1
    • 4
  • Shinji Okubo
    • 1
    • 5
  • Vigneshwar Kasirajan
    • 1
    • 6
  • Rakesh C. Kukreja
    • 1
    • 4
    Email author
  1. 1.Division of Cardiology, Department of MedicinePauley Heart Center, Virginia Commonwealth UniversityRichmondUSA
  2. 2.Division of Cardiology, Department of Internal MedicineVirginia Commonwealth University Medical CenterRichmondUSA
  3. 3.Duke University School of Medicine, Interventional Cardiology, Division of Cardiology, Charles George Veterans Affairs Medical CenterAshevilleUSA
  4. 4.Department of Internal MedicineVirginia Commonwealth University Medical Center, Pauley Heart CenterRichmondUSA
  5. 5.Tokyo Medical University, Ibaraki Medical CenterIbarakiJapan
  6. 6.Department of SurgeryVirginia Commonwealth University Medical CenterRichmondUSA

Personalised recommendations