Experimental Treatment for Preservation of Mechanically Competent Cardiac Activity Following Cardiac Arrest

  • I. M. Ayoub
  • J. Radhakrishnan
  • R. J. Gazmuri
Conference paper


It has been suggested that sudden cardiac arrest may affect as many as 6.8 million individuals annually (~1:1,000 people) [1, 2]. In the United States, every year approximately 300,000 individuals suffer an episode of out-of-hospital sudden cardiac arrest [3]. Efforts to reestablish life are formidably challenging, requiring not only that cardiac activity be reestablished but that injury to vital organs be prevented, minimised, or reversed. Resuscitation methods yield an average survival and hospital discharge rate with intact neurological function that approaches 7.9% in the United States [4], 10.7% in Europe [5], and only 1.0% in the rest of the world [6]. In the United States, efficient emergency medical service systems can initially reestablish cardiac activity in approximately 30% of individuals [7–9] with >40% dying before hospital admission [10]. Of those admitted to hospital, nearly 75% die before hospital discharge due to variable degrees of myocardial or neurological dysfunction, systemic inflammation, intercurrent illnesses, or a combination thereof [10–12]. Thus, initial reestablishment of cardiac activity using available resuscitation treatments does not ensure ultimate survival.


Cardiac Arrest Ventricular Fibrillation Chest Compression Cardiac Activity Spontaneous Circulation 
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.


  1. 1.
    Smith TW, Cain ME (2006) Sudden cardiac death: epidemiologic and financial worldwide perspective. J Interv Card Electrophysiol 17 (3): 199–203PubMedCrossRefGoogle Scholar
  2. 2.
    U.S. Census Bureau (2010) U.S. and World Population Clocks Available at Accessed 9 Dec 2010Google Scholar
  3. 3.
    Lloyd-Jones D, Adams R, Carnethon M et al (2009) Heart disease and stroke statistics — 2009 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 119: e21–e181PubMedCrossRefGoogle Scholar
  4. 4.
    Nichol G, Thomas E, Callaway CW et al (2008) Regional variation in out-of- hospital cardiac arrest incidence and outcome. JAMA 300 (12): 1423–1431PubMedCrossRefGoogle Scholar
  5. 5.
    Atwood C, Eisenberg MS, Herlitz J, Rea TD (2005) Incidence of EMS-treated out-of-hospital cardiac arrest in Europe. Resuscitation 6–7 (1): 75–80PubMedCrossRefGoogle Scholar
  6. 6.
    Seidl K, Senges J (2003) Worldwide utilization of implantable cardioverter/defibrillators now and in the future. Card Electrophysiol Rev 7 (1): 5–13PubMedCrossRefGoogle Scholar
  7. 7.
    Brown CG, Martin DR, Pepe PE et al (1992) A comparison of standard-dose and high-dose epinephrine in cardiac arrest outside the hospital. N Engl J Med 327: 1051–1055PubMedCrossRefGoogle Scholar
  8. 8.
    Kellermann AL, Hackman BB, Somes G (1993) Predicting the outcome of unsuccessful prehospital advanced cardiac life support. JAMA 270: 1433–1436PubMedCrossRefGoogle Scholar
  9. 9.
    Lombardi G, Gallagher J, Gennis P (1994) Outcome of out-of-hospital cardiac arrest in New York City. The pre-hospital arrest survival evaluation ( PHASE) study. JAMA 271: 678–683PubMedCrossRefGoogle Scholar
  10. 10.
    Laurent I, Monchi M, Chiche JD et al (2002) Reversible myocardial dysfunction in survivors of out-of-hospital cardiac arrest. J Am Coll Cardiol 40 (12): 2110–2116PubMedCrossRefGoogle Scholar
  11. 11.
    Checchia PA, Sehra R, Moynihan J et al (2003) Myocardial injury in children following resuscitation after cardiac arrest. Resuscitation 57 (2): 131–137PubMedCrossRefGoogle Scholar
  12. 12.
    Laver S, Farrow C, Turner D, Nolan J (2004) Mode of death after admission to an intensive care unit following cardiac arrest. Intensive Care Med 30 (11): 2126–2128PubMedCrossRefGoogle Scholar
  13. 13.
    van Alem AP, Post J, Koster RW (2003) VF recurrence: characteristics and patient outcome in out-of-hospital cardiac arrest. Resuscitation 59 (2): 181–188PubMedCrossRefGoogle Scholar
  14. 14.
    Kuo CS, Munakata K, Reddy CP, Surawicz B (1983) Characteristics and possible mechanism of ventricular arrhythmia dependent on the dispersion of action potential durations. Circulation 67 (6): 1356–1367PubMedCrossRefGoogle Scholar
  15. 15.
    Mandapati R, Asano Y, Baxter WT et al (1998) Quantification of effects of global ischemia on dynamics of ventricular fibrillation in isolated rabbit heart. Circulation 98 (16): 1688–1696PubMedGoogle Scholar
  16. 16.
    Jardetzky O, Greene EA, Lorber V (1956) Oxygen consumption of the completely isolated dog heart in fibrillation. Circ Res 4 (2): 144–147PubMedGoogle Scholar
  17. 17.
    Hashimoto K, Shigei T, Imai S et al (1960) Oxygen consumption and coronary vascular tone in the isolated fibrillating dog heart. Am J Physiol 198: 965–970PubMedGoogle Scholar
  18. 18.
    Kusuoka H, Chacko VP, Marban E (1992) Myocardial energetics during ventricular fibrillation investigated by magnetization transfer nuclear magnetic resonance spectroscopy. Circ Res 71 (5): 1111–1122PubMedGoogle Scholar
  19. 19.
    Luqman N, Sung RJ, Wang CL, Kuo CT (2007) Myocardial ischemia and ventricular fibrillation: pathophysiology and clinical implications. Int J Cardiol 119 (3): 283–290PubMedCrossRefGoogle Scholar
  20. 20.
    Trenor B, Romero L, Ferrero JM Jr et al (2007) Vulnerability to reentry in a regionally ischemic tissue: a simulation study. Ann Biomed Eng 35 (10): 1756–1770PubMedCrossRefGoogle Scholar
  21. 21.
    Karmazyn M, Sawyer M, Fliegel L (2005) The na(+)/h(+) exchanger: a target for cardiac therapeutic intervention. Curr Drug Targets Cardiovasc Haematol Disord 5 (4): 323–335PubMedCrossRefGoogle Scholar
  22. 22.
    Imahashi K, Kusuoka H, Hashimoto K et al (1999) Intracellular sodium accumulation during ischemia as the substrate for reperfusion injury. Circ Res 84 (12): 1401–1406PubMedGoogle Scholar
  23. 23.
    Gazmuri RJ, Hoffner E, Kalcheim J et al (2001) Myocardial protection during ventricular fibrillation by reduction of proton-driven sarcolemmal sodium influx. J Lab Clin Med 137 (1): 43–55PubMedCrossRefGoogle Scholar
  24. 24.
    Avkiran M, Ibuki C, Shimada Y, Haddock PS (1996) Effects of acidic reperfusion on arrhythmias and Na(+)-K(+)-ATPase activity in regionally ischemic rat hearts. Am J Physiol 270 (3 Pt 2): H957–H964PubMedGoogle Scholar
  25. 25.
    An J, Varadarajan SG, Camara A et al (2001) Blocking Na(+)/H(+) exchange reduces [Na(+)](i) and [Ca(2+)](i) load after ischemia and improves function in intact hearts. Am J Physiol 281 (6): H2398–H2409Google Scholar
  26. 26.
    Gunter TE, Buntinas L, Sparagna G et al (2000) Mitochondrial calcium transport: mechanisms and functions. Cell Calcium 28 (5–6): 285–296PubMedCrossRefGoogle Scholar
  27. 27.
    Yamamoto S, Matsui K, Ohashi N (2002) Protective effect of Na+ /H+ exchange inhibitor, SM-20550, on impaired mitochondrial respiratory function and mitochondrial Ca2+ overload in ischemic/reperfused rat hearts. J Cardiovasc Pharmacol 39 (4): 569–575PubMedCrossRefGoogle Scholar
  28. 28.
    Borutaite V, Brown GC (2003) Mitochondria in apoptosis of ischemic heart. FEBS Lett 541 (1–3): 1–5PubMedCrossRefGoogle Scholar
  29. 29.
    Karmazyn M (1998) The myocardial sodium-hydrogen exchanger (NHE) and its role in mediating ischemic and reperfusion injury. Keio J Med 47 (2): 65–72PubMedCrossRefGoogle Scholar
  30. 30.
    Kusumoto K, Haist JV, Karmazyn M (2001) Na(+)/H(+) exchange inhibition reduces hypertrophy and heart failure after myocardial infarction in rats. Am J Physiol 280 (2): H738–H745Google Scholar
  31. 31.
    Teshima Y, Akao M, Jones SP, Marban E (2003) Cariporide (HOE642), a selective Na+-H+ exchange inhibitor, inhibits the mitochondrial death pathway. Circulation 108 (18): 2275–2281PubMedCrossRefGoogle Scholar
  32. 32.
    Wang S, Radhakrishnan J, Ayoub IM et al (2007) Limiting sarcolemmal Na+ entry during resuscitation from VF prevents excess mitochondrial Ca2+ accumulation and attenuates myocardial injury. J Appl Physiol 103: 55–65PubMedCrossRefGoogle Scholar
  33. 33.
    Kolarova JD, Ayoub IM, Gazmuri RJ (2005) Cariporide enables hemodynamically more effective chest compression by leftward shift of its flow-depth relationship. Am J Physiol Heart Circ Physiol 288: H2904–H2911PubMedCrossRefGoogle Scholar
  34. 34.
    Ayoub IM, Kolarova J, Kantola R et al (2007) Zoniporide preserves left ventricular compliance during ventricular fibrillation and minimizes post-resuscitation myocardial dysfunction through benefits on energy metabolism. Crit Care Med 35: 2329–2336PubMedCrossRefGoogle Scholar
  35. 35.
    Ayoub IM, Kolarova J, Gazmuri RJ (2010) Cariporide given during resuscitation promotes return of electrically stable and mechanically competent cardiac activity. Resuscitation 81 (1): 106–110PubMedCrossRefGoogle Scholar
  36. 36.
    Klouche K, Weil MH, Sun S et al (2002) Evolution of the stone heart after prolonged cardiac arrest. Chest 122 (3): 1006–1011PubMedCrossRefGoogle Scholar
  37. 37.
    Ayoub IM, Kolarova JD, Yi Z et al (2003) Sodium-hydrogen exchange inhibition during ventricular fibrillation: Beneficial effects on ischemic contracture, action potential duration, reperfusion arrhythmias, myocardial function, and resuscitability. Circulation 107: 1804–1809PubMedCrossRefGoogle Scholar
  38. 38.
    White RD, Russell JK (2002) Refibrillation, resuscitation and survival in out-of-hospital sudden cardiac arrest victims treated with biphasic automated external defibrillators. Resuscitation 55 (1): 17–23PubMedCrossRefGoogle Scholar
  39. 39.
    Hess EP, White RD (2004) Recurrent ventricular fibrillation in out-of-hospital cardiac arrest after defibrillation by police and firefighters: implications for automated external defibrillator users. Crit Care Med 32 (9 Suppl): S436–S439PubMedCrossRefGoogle Scholar
  40. 40.
    Gazmuri RJ, Weil MH, Bisera J et al (1996) Myocardial dysfunction after successful resuscitation from cardiac arrest. Crit Care Med 24 (6): 992–1000PubMedCrossRefGoogle Scholar
  41. 41.
    Kern KB, Hilwig RW, Rhee KH, Berg RA (1996) Myocardial dysfunction after resuscitation from cardiac arrest: An example of global myocardial stunning. J Am Coll Cardiol 28: 232–240PubMedCrossRefGoogle Scholar
  42. 42.
    Ruiz-Bailen M, Aguayo dH, Ruiz-Navarro S et al (2005) Reversible myocardial dysfunction after cardiopulmonary resuscitation. Resuscitation 66 (2): 175–181PubMedCrossRefGoogle Scholar
  43. 43.
    Schlesinger PH, Gross A, Yin XM et al (1997) Comparison of the ion channel characteristics of proapoptotic BAX and antiapoptotic BCL-2. Proc Natl Acad Sci USA 94 (21): 11357–11362PubMedCrossRefGoogle Scholar
  44. 44.
    Korsmeyer SJ, Wei MC, Saito M et al (2000) Pro-apoptotic cascade activates BID, which oligomerizes BAK or BAX into pores that result in the release of cytochrome c. Cell Death Differ 7 (12): 1166–1173PubMedCrossRefGoogle Scholar
  45. 45.
    Opie LH, Clusin WT (1990) Cellular mechanism for ischemic ventricular arrhythmias. Annu Rev Med 41: 231–238PubMedCrossRefGoogle Scholar
  46. 46.
    Shivkumar K, Deutsch NA, Lamp ST et al (1997) Mechanism of hypoxic K loss in rabbit ventricle. J Clin Invest 100 (7): 1782–1788PubMedCrossRefGoogle Scholar
  47. 47.
    Franz MR (1999) Current status of monophasic action potential recording: theories, measurements and interpretations. Cardiovasc Res 41 (1): 25–40PubMedCrossRefGoogle Scholar
  48. 48.
    Ayoub IM, Kolarova JD, Sehgal MA et al (2003) Sodium-hydrogen exchange inhibition minimizes adverse effects of epinephrine during cardiac resuscitation. Circulation 108: IV–420Google Scholar
  49. 49.
    Wirth KJ, Maier T, Busch AE (2001) NHE1-inhibitor cariporide prevents the transient reperfusion-induced shortening of the monophasic action potential after coronary ischemia in pigs. Basic Res Cardiol 96 (2): 192–197PubMedCrossRefGoogle Scholar
  50. 50.
    Gazmuri RJ, Ayoub IM, Hoffner E, Kolarova JD (2001) Successful ventricular defibrillation by the selective sodium-hydrogen exchanger isoform-1 inhibitor cariporide. Circulation 104: 234–239PubMedGoogle Scholar
  51. 51.
    Ayoub IM, Kolarova J, Kantola RL et al (2005) Cariporide minimizes adverse myocardial effects of epinephrine during resuscitation from ventricular fibrillation. Crit Care Med 33 (11): 2599–2605PubMedCrossRefGoogle Scholar
  52. 52.
    Xu T, Tang W, Ristagno G et al (2008) Postresuscitation myocardial diastolic dysfunction following prolonged ventricular fibrillation and cardiopulmonary resuscitation. Crit Care Med 36 (1): 188–192PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Italia 2011

Authors and Affiliations

  • I. M. Ayoub
  • J. Radhakrishnan
  • R. J. Gazmuri

There are no affiliations available

Personalised recommendations