Early and Delayed Protection Against Ventricular Arrhythmias Induced by Preconditioning

  • Agnes Vegh
  • Adrienn Kis
  • Julius Gy Papp
  • James R. Parratt
Part of the Progress in Experimental Cardiology book series (PREC, volume 1)


Ischemic preconditioning, induced by brief periods of coronary artery occlusion, results not only in a reduction in myocardial ischemic damage but also in suppression of those life-threatening ventricular arrhythmias that result from a subsequent, more prolonged ischemia-reperfusion insult. Although this protection is marked, the antiarrhythmic effect is transient and the protection wanes with time (e.g., 60 minutes after the preconditioning stimulus, the antiarrhythmic effect is almost lost). Protection against ventricular arrhythmias can also result from brief periods of cardiac pacing, which leads to both immediate and delayed protection, e.g., a marked reduction in the incidence of ischemia-induced ventricular fibrillation, five minutes after pacing and also 24 hours later. This delayed protection against arrhythmias is less marked 48 and 72 hours after the pacing stimulus but can be reinstated, and lasts for a more prolonged period, if dogs are repaced at a time when protection from the initial pacing stimulus begins to wane. Whether it is possible to protect the heart in the longer term by pacing is unknown but is under investigation. Although the precise mechanisms of both the early and delayed protection are not yet fully understood, there is some evidence that endogenous protective mediators derived from coronary vascular endothelium, such as bradykinin, nitric oxide, and prostanoids (most likely prostacyclin), are involved in both phases of this antiarrhythmic protection. These may then trigger the induction, during the late phase, of protective proteins.


Ventricular Tachycardia Ventricular Arrhythmia Ventricular Fibrillation Ischemic Precondition Coronary Artery Occlusion 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Parratt JR. 1982. Early Arrhythmias Resulting from Myocardial Ischaemia. London: Macmillan.Google Scholar
  2. 2.
    Goldstein S, Bayes-de-Luna A, Soldevila JE. 1994. Sudden Cardiac Death. New York: Futura.Google Scholar
  3. 3.
    Zehender M, Meinertz T, Just H. 1994. Myocardial Ischaemia and Arrhythmia. Darmstadt: Steinkopf.Google Scholar
  4. 4.
    Murry CE, Jennings RB, Reimer KA. 1986. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 74:1124–1136.PubMedGoogle Scholar
  5. 5.
    Shiki K, Hearse DJ. 1987. Preconditioning of ischemic myocardium: reperfusion-induced arrhythmias. Am J Physiol 253:H1470–H1476.PubMedGoogle Scholar
  6. 6.
    Vegh A, Szekeres L, Parratt JR. 1990. Protective effect of preconditioning of the ischaemic myocardium involves cyclooxygenase products. Cardiovasc Res 12:1020–1022.Google Scholar
  7. 7.
    Vegh A, Komori S, Szekeres L, Parratt JR. 1992. Antiarrhythmic effects of preconditioning in anaesthetised dogs and rats. Cardiovasc Res 26:487–495.PubMedGoogle Scholar
  8. 8.
    Cave AC, Hearse DJ. 1992. Ischaemic preconditioning and contractile function: studies with normothermic and hypothermic global ischaemia. J Mol Cell Cardiol 24:1113–1123.PubMedCrossRefGoogle Scholar
  9. 9.
    Schott RJ, Rohmann S, Braun ER, Schaper W. 1990. Ischemic preconditioning reduces infarct size in swine myocardium. Circulation Res 66:1133–1142.PubMedGoogle Scholar
  10. 10.
    Parratt JR. 1995. Possibilities for the pharmacological exploitation of ischaemic preconditioning. J Mol Cell Cardiol 27:991–1000.PubMedCrossRefGoogle Scholar
  11. 11.
    Parratt JR. 1993. Endogenous myocardial protective (antiarrhythmic) substances. Cardiovasc Res 27:693–702.PubMedGoogle Scholar
  12. 12.
    Harris AG. 1950. Delayed development of ventricular ectopic rhythms following experimental coronary occlusion. Circulation 1:1318–1326.PubMedGoogle Scholar
  13. 13.
    Gülker H, Kramer B, Stephan K, Meesmann W. 1977. Changes in ventricular fibrillation thseshold during repeated short-term coronary occlusion and release. Basic Res Cardiol 72:547–562.PubMedCrossRefGoogle Scholar
  14. 14.
    Barber MJ. 1983. Effect of time interval between repeated brief coronary artery occlusions on arrhythmias, electrical activity and myocardial blood flow. J Am Coll Cardiol 2:699–705.PubMedGoogle Scholar
  15. 15.
    Maroko PR, Kjekshus JK, Sobel BE, Watanabe T, Covell JW, Ross J, Braunwald E. 1971. Factors influencing infarct size following experimental coronary artery occlusions. Circulation 43:67–74.PubMedGoogle Scholar
  16. 16.
    Marshall RJ, Parratt JR. 1977. The haemodynamic and metabolic effects of MG8926, a prospective antidysrhythmic and antianginal agent. Br J Pharmacol 59:311–322.PubMedGoogle Scholar
  17. 17.
    Marshall RJ, Parratt JR. 1979. The effects of disopyramide phosphate on early post-coronary artery ligation dysrhythmias, and on epicardial ST-segment elevation, in anaesthetised dogs. Br J Pharmacol 66:241–250.PubMedGoogle Scholar
  18. 18.
    Komori S, Parratt JR, Szekeres L, Vegh A. 1990. Preconditioning reduces the severity of ischaemia and reperfusion-induced arrhythmias in both anaesthetised rats and dogs. J Physiol 423:16P.Google Scholar
  19. 19.
    Komori S, Fukimaki S, Ijili H, Asakawa T, Watanabe Y, Tamura Y, Parratt JR. 1990. Inhibitory effect of ischemic preconditioning on ischemic arrhythmias using a rat coronary artery ligation model. Jpn J Electrocardiol 10:774–782.Google Scholar
  20. 20.
    Kane KA, Parratt JR, Williams FM. 1984. An investigation into the characteristics of reperfusion-induced arrhythmias in the anaesthetised rat and their susceptibility to antiarrhythmic agents. Br J Pharmacol 82:349–357.PubMedGoogle Scholar
  21. 21.
    Meesmann W. 1982. Early arrhythmias and primary ventricular fibrillation after acute myocardial ischaemia in relation to pre-existing coronary collaterals. In Parratt JR (ed), Early Arrhythmias Resulting from Myocardial Ischaemia. London: Macmillan, pp. 93–112.Google Scholar
  22. 22.
    Parratt JR, Vegh A, Kaszala K, Papp JGy. 1996. Suppression of life-threatening ventricular arrhythmias by brief periods of ischaemia and by cardiac pacing with particular reference to delayed myocardial protection. In Marber MS, Yellon DM (eds), Ischaemia: Preconditioning and Adaptation. BIOS Scientific Publishers, pp. 85–111.Google Scholar
  23. 23.
    Vegh A, Parratt JR. 1996. Ischaemic preconditioning markedly reduces the severity of ischaemia and reperfusion-induced arrhythmias: role of endogenous myocardial protective substances. In Wainwright CL, Parratt JR (eds), Myocardial Preconditioning. Barlin: Springer, pp. 35–60.Google Scholar
  24. 24.
    Li Y, Kloner RA. 1992. Cardioprotective effects of ischaemic preconditioning is not mediated by prostanoids. Cardiovasc Res 26:226–231.PubMedGoogle Scholar
  25. 25.
    Lawson CS, Coltart DJ, Hearse DJ. 1993. Dose-dependency and temporal characteristics of protection by ischaemic preconditioning against ischaemia-induced arrhythmias in rat hearts. J Mol Cell Cardiol 25:1391–1402.PubMedCrossRefGoogle Scholar
  26. 26.
    Lawson CS, Avkiran M, Shattock MJ, Coltart DJ, Hearse DJ. 1993. Preconditioning and reperfusion arrhythmias in the isolated rat heart: true protection or temporal shift in vulnerability? Cardiovasc Res 27:2274–2281.PubMedCrossRefGoogle Scholar
  27. 27.
    Piacentini L, Wainwright CL, Parratt JR. 1993. The antiarrhythmic effect of ischaemic preconditioning in isolated rat hearts involves a pertussis toxin sensitive mechanism. Cardiovasc Res 27:674–680.PubMedGoogle Scholar
  28. 28.
    Li Y, Vasquez JA, Gallagher KP, Lucchesi BR. 1990. Myocardial protection with preconditioning. Circulation 82:609–619.PubMedGoogle Scholar
  29. 29.
    Przyklenk K, Kloner RA. 1995. Preconditioning: a balanced perspective. Br Heart J 74:575–577.PubMedCrossRefGoogle Scholar
  30. 30.
    Vander Heide RS, Schwartz LM, Jennings RB, Reimer KA. 1995. Effect of catecholamine depletion on myocardial infarct size in dogs: role of catecholamines in ischemic preconditioning. Cardiovasc Res 30:656–662.CrossRefGoogle Scholar
  31. 31.
    Wainwright CL, Parratt JR. 1990. Electrocardiographic and haemodynamic effects of myocardial preconditioning in pigs. J Mol Cell Cardiol 22(Suppl III):PF65.Google Scholar
  32. 32.
    Ovize M, Aupetit JF, Rioufol G, Laufona J, Andre-Fouet X, Minaire Y, Faucon G. 1995. Preconditioning reduces infarct size but accelerates time to ventricular fibrillation in ischemic pig heart. Am J Physiol 269:H72–H79.PubMedGoogle Scholar
  33. 33.
    Vegh A, Szekeres L, Parratt JR. 1991. Transient ischaemia induced by rapid cardiac pacing results in myocardial preconditioning. Cardiovasc Res 25:1051–1053.PubMedGoogle Scholar
  34. 34.
    Szekeres L, Papp JGy, Szilvassy Z, Udvary E, Vegh A. 1993. Moderate stress by cardiac pacing may induce both short term and long term cardioprotection. Cardiovasc Res 27:593–596.PubMedGoogle Scholar
  35. 35.
    Koning MMG, Simonis L, De Zeeuw S, Nieukoop S, Post S, Verdouw PD. 1994. Ischaemic preconditioning by partial occlusion without intermittent reperfusion. Cardiovasc Res 28:1146–1151.PubMedCrossRefGoogle Scholar
  36. 36.
    Ovize M, Przyklenk K, Kloner RA. 1992. Partial coronary stenosis is sufficient and complete reperfusion is mandatory for preconditioning the canine heart. Circulation Res 71:1165–1173.PubMedGoogle Scholar
  37. 37.
    Shizukuda Y, Maller RT, Lee SC, Downey HF. 1992. Hypoxic preconditioning of ischaemic canine myocardium. Cardiovasc Res 26:534–542.PubMedCrossRefGoogle Scholar
  38. 38.
    Ovize M, Kloner RA, Przyklenk K. 1994. Stretch preconditions canine myocardium. Am J Physiol 266:H137–H146.PubMedGoogle Scholar
  39. 39.
    Przyklenk K, Bauer B, Ovize M, Kloner RA, Whittaker P. 1993. Regional ischaemic “preconditioning” protects remote virgin myocardium from subsequent sustained coronary occlusion. Circulation 87:893–899.PubMedGoogle Scholar
  40. 40.
    McClanahan TB, Nao BS, Wolke LJ, Martin BJ, Metz TE, Gallagher KP. 1993. Brief renal occlusion and reperfusion reduces myocardial infarct size in rabbits. FASEB J 7:A176.Google Scholar
  41. 41.
    Gho BC, Shoemaker RG, Van der Lee C, Sharma HS, Verdouw PD. 1994. Myocardial infarct size limitation in rat by transient renal ischaemia. Circulation 90:4–2, 1–476.Google Scholar
  42. 42.
    Marshall RJ, Parratt JR. 1980. The early consequences of myocardial ischaemia and their modification. J Physiol (Paris) 76:699–715.Google Scholar
  43. 43.
    Kaszala K, Vegh A, Papp JGy, Parratt JR. 1996. Time-course of the protection against ischaemia and reperfusion-induced ventricular arrhythmias resulting from brief periods of cardiac pacing. J Mol Cell Cardiol 28:2085–2095.PubMedCrossRefGoogle Scholar
  44. 44.
    Kaszala K, Vegh A, Papp JGy, Parratt JR. 1995. The role of bradykinin in pacing-induced preconditioning. J Mol Cell Cardiol 28:A14.Google Scholar
  45. 45.
    Kuzuya T, Hoshida S, Yamashita N, Fuji H, Oe H, Hori M, Kamada T, Tada M. 1993. Delayed effects of sublethal ischemia on the acquisition of tolerance to ischemia. Circulation Res 72:1293–1299.PubMedGoogle Scholar
  46. 46.
    Marber MS, Latchman DS, Walker JM, Yellon DM. 1993. Cardiac stress protein elevation 24 hours after brief ischemia or heat stress is associated with resistance to myocardial infarction. Circulation 88:1264–1272.PubMedGoogle Scholar
  47. 47.
    Yellon DM, Baxter GF. 1995. A “second window of protection” or delayed preconditioning phenomenon: future horizons for myocardial protection? J Mol Cell Cardiol 27:1023–1034.PubMedCrossRefGoogle Scholar
  48. 48.
    Vegh A, Papp JGy, Kaszala K, Parratt JR. 1994. Cardiac pacing in anaesthetised dogs preconditions the heart against arrhythmias when ischaemia induced 24 h later. J Physiol (Lond) P480.Google Scholar
  49. 49.
    Vegh A, Papp JGy, Parratt JR. 1994. Prevention by dexamethasone of the marked antiarrhythmic effects of preconditioning induced 20h after rapid cardiac pacing. Br J Pharmacol 113:1081–1082.PubMedGoogle Scholar
  50. 50.
    Kis A, Vegh A, Papp JGy, Parratt JR. 1996. Repeated pacing widens the time window of delayed protection against ventricular arrhythmias in dogs (abstract 229). J Mol Cell Cardiol 28:A59.Google Scholar
  51. 51.
    Parratt JR. 1994. Protection of the heart by ischaemic preconditioning: mechanisms and possibilities for pharmacological exploitation. Trends Pharmacol Sci 15:19–25.PubMedCrossRefGoogle Scholar
  52. 52.
    Curtis MJ, Pugsley MK, Walker MJA. 1993. Endogenous chemical mediators of ventricular arrhythmias in ischaemic heart disease, Cardiovasc Res 27:703–719.PubMedGoogle Scholar
  53. 53.
    Cohen MV, Liu Y, Downey JM. 1996. Activation of protein kinase C is critical to the production of preconditioning. In Wainwright CL, Parratt JR (eds), Myocardial Preconditioning. Barlin: Springer, pp. 189–206.Google Scholar
  54. 54.
    Liu GS, Thornton J, Van Winkle DM, Stanley AWH, Olson RA, Downey JM. 1991. Protection against infarction afforded by preconditioning is madiated by A1 adenosine receptors in rabbit heart. Circulation 84:350–356.PubMedGoogle Scholar
  55. 55.
    Miura T. 1996. Preconditioning against myocardial infarction—its features and adenosine-mediated mechanism. In Wainwright CL, Parratt JR (eds), Myocardial Preconditioning. Barlin: Springer, pp. 1–17.Google Scholar
  56. 56.
    Piacentini L, Wainwright CL, Parratt JR. 1992. The antiarrhythmic effect of preconditioning in rat isolated hearts does not involve A1 receptors. Br J Pharmacol 107:137P.Google Scholar
  57. 57.
    Vegh A, Papp JGy, Parratt JR. 1995. Pronounced antiarrhythmic effects of preconditioning in anaesthetised dogs: is adenosine involved? J Mol Cell Cardiol 27:349–356.PubMedGoogle Scholar
  58. 58.
    Boachie-Ansah G, Kane KA, Parratt JR. 1993. Is adenosine an endogenous myocardial protective (antiarrhythmic) substance under conditions of ischaemia. Cardiovasc Res 27:77–83.PubMedGoogle Scholar
  59. 59.
    Parratt JR, Vegh A. 1996. Endothelial cells, nitric oxide and ischaemic preconditioning. Basic Res Cardiol 91:27–30.PubMedGoogle Scholar
  60. 60.
    Parratt JR, Vegh A, Zeitlin IJ, Ahmad M, Oldroyd K, Kaszala K, Papp JGy. 1997, Bradykinin and endothelial-myocyte interactions in ischaemic preconditioning: a review. Am J Cardiol 80:124–131A.CrossRefGoogle Scholar
  61. 61.
    Fatehi-Hassanabad Z, Furman BL, Parratt JR. 1996. The effect of the endothelium on coronary artery occlusion-induced arrhythmias in rat isolated perfused hearts. J Physiol 494:112–113P.Google Scholar
  62. 62.
    Vegh A, Szekeres L, Parratt JR. 1991. Local coronary infusions of bradykinin profoundly reduce the severity of ischaemia-induced arrhythmias in anaesthetised dogs. Br J Pharmacol 104:294–295.PubMedGoogle Scholar
  63. 63.
    Coker SJ, Parratt JR. 1983. Prostacyclin—antiarrhythmic or arrhythmogenic? Comparison of the effects of intravenous and intracoronary prostacyclin and ZK36374 during coronary artery occlusion and reperfusion in anaesthetised greyhounds. J Cardiovasc Pharmacol 5:557–567.PubMedCrossRefGoogle Scholar
  64. 64.
    Vegh A, Papp JGy, Szekeres L, Parratt JR. 1993. Prevention by an inhibitor of the L-arginine nitric oxide pathway of the antiarrhythmic effects of bradykinin in anaesthetised dogs. Br J Pharmacol 110:18–19.PubMedGoogle Scholar
  65. 65.
    Coker SJ, Parratt JR, Ledingham IMcA, Zeitlin IJ. 1981. Thromboxane and prostacyclin release from ischaemic myocardium in relation to arrhythmias. Nature 291:323–324.PubMedCrossRefGoogle Scholar
  66. 66.
    Coker SJ, Parratt JR. 1984. The effects of nafazatrom on arrhythmias and prostanoid release during coronary artery occlusion and reperfusion in anaesthetised greyhounds. J Mol Cell Cardiol 16:43–52.PubMedCrossRefGoogle Scholar
  67. 67.
    Pahor M, Ganbassi G, Carbonia P. 1994. Antiarrhythmic effects of ACE inhibitors: a matter of faith or reality. Cardiovasc Res 28:173–182.PubMedGoogle Scholar
  68. 68.
    Vegh A, Papp JGy, Parratt JR. 1994. Attenuation of the anti-arrhythmic effects of ischaemic preconditioning by blockade of bradykinin B2 receptors. Br J Pharmacol 113:1167–1172PubMedGoogle Scholar
  69. 69.
    Parratt JR, Vegh A, Papp JGy. 1995. Bradykinin as an endogenous myocardial protective substance with particular reference to ischemic preconditioning—a brief review of the evidence. Can J Physiol Pharmacol 73:837–842.PubMedGoogle Scholar
  70. 70.
    Kis A, Vegh A, Papp JGy, Parratt JR. 1997. Dual blockade of the cyclooxygenase and L-arginine nitric oxide pathways prevents the antiarrhythmic effect of preconditioning. Exp Clin Cordiol 2:112–118.Google Scholar
  71. 71.
    Parratt JR. 1989. Eicosanoids and arrhythmogenesis. In Vaughn-Williams EM (ed), Handbook of Experimental Pharmacology. Vol. 89, Antiarrhythmic Drugs. Barlin: Springer, pp. 569–589.Google Scholar
  72. 72.
    Parratt JR. 1987. Modification of the thromboxane/prostacyclin balance as an approach to antiarrhythmic therapy during myocardial ischaemia and reperfusion; the concept of endogenous antiarrhythmic substances. In Dhalla NS, Innes IR, Beamish RE (eds), Myocardial Ischaemia. Boston: Martinus Nijhoff, pp. 21–35.Google Scholar
  73. 73.
    Vegh A, Szekeres L, Parratt JR. 1992. Preconditioning of the ischaemic myocardium; involvement of the L-arginine nitric oxide pathway. Br J Pharmacol 107:648–652.PubMedGoogle Scholar
  74. 74.
    Vegh A, Papp JGy, Szekeres L, Parratt JR. 1992. The local intracoronary administration of methylene blue prevents the pronounced antiarrhythmic effect of ischaemic preconditioning. Br J Phamacol 107:910–911.Google Scholar
  75. 75.
    Kolar F, Parratt JR. 1997. Antiarrhythmic effect of ischaemic preconditioning in hearts of spontaneously hypertensive rats. Exp Clin Cardiol 2:124–127.Google Scholar
  76. 76.
    Yellon DM, Baxter GF. 1995. A “second window of protection” or delayed preconditioning phenomenon: future horizons for myocardial protection? J Mol Cell Cardiol 27:1023–1034.PubMedCrossRefGoogle Scholar
  77. 77.
    Vegh A, Kaszala K, Papp JGy, Parratt JR. 1995. Delayed myocardial protection by pacing-induced preconditioning: a possible role for bradykinin. Br J Pharmacol 116:288P.Google Scholar
  78. 78.
    Wu S, Furman BL, Parratt JR. 1994. Attenuation by dexamethasone of endotoxin protection against ischaemia-induced ventricular arrhythmias. Br J Pharmacol 113:1083–1084.Google Scholar
  79. 79.
    Wu Song, Furman BL, Parratt JR. 1996. Delayed protection by bacterial lipopolysaccharide (endotoxin) against ischaemia-induced myocardial damage and arrhythmias. Br J Phamacol 118:2157–2163.Google Scholar
  80. 80.
    Vegh A, Papp JGy, Parratt JR, Elliott GT. 1996. Pretreatment with monophosphoryl lipid-A (MPL-C) reduces ischaemia-induced ventricular arrhythmias (abstract 217). J Mol Cell Cardiol 28:A56.Google Scholar
  81. 81.
    Stein B, Frank P, Schmitz W, Scholz H, Thoenes M. 1996. Endotoxin and cytokines induce direct cardioprotective effects in mammalian cardiomyocytes via induction of nitric oxide synthase. J Mol Cell Cardiol 28:1631–1639.PubMedCrossRefGoogle Scholar

Copyright information

© Kluwer Academic Publishers 1998

Authors and Affiliations

  • Agnes Vegh
    • 1
  • Adrienn Kis
    • 1
  • Julius Gy Papp
    • 1
  • James R. Parratt
    • 2
  1. 1.Albert Szent-Györgyi Medical UniversityHungary
  2. 2.University of StrathclydeUSA

Personalised recommendations