Abstract

The endothelium is an active organ with paracrine-endocrine capabilities that directs a multitude of physiological actions both locally and remotely. Cardiac arrest and resuscitation is a model of whole body ischemia reperfusion injury, interventions that have their basis in cytoprotection, reduction of the inflammatory cascade, fibrinolysis and improvement of microvasculature blood flow target the endothelium. This presentation will review pharmacologic, cell targeted therapies and periodic acceleration (pGz) interventions that have the endothelium in part as the target organ. The clinical potential of such interventions as preconditioning, conditioning and postconditioning strategies associated with cardiac arrest will be defined.

Keywords: endothelium, periodic acceleration (pGz), cardiac arrest, cardiopulmonary resuscitation, ischemia reperfusion, nitric oxide, shear stress

Introduction

The vascular endothelium is composed on 1-6 x1013 cells and covers an area of 1-7m2 in humans. It is uniquely localized to be a sensor and an effecter. Its location on the luminal surface of every blood vessel and the heart allows these cells to respond to humoral factors and blood flow. The interaction of the endothelium with its neighbouring cells (vascular smooth muscle cells as well as cardiomyocytes) allows for the regulation of a host of functions. Prominent among those functions are vasomotor tone, local and systemic coagulation profiles, and inflammation. Endothelial regulation of critical functions and interactions with almost all organs of the body attest to its importance in homeostasis. (1)
The endothelial cell (EC) responds to local blood flow patterns. Laminar shear stress is the undisturbed tangential flow which runs across the upper surface of the EC and pulsatile shear stress is the stress generated perpendicular to the EC surface with each heart beat. The EC response to both laminar and pulsatile shear has been assessed in several publications. Both increased laminar shear stress and pulsatile shear stress elicit EC production of vasoactive substances such as endothelial derived nitric oxide (eNO), endothelial derived hyperpolarizing factor (EDHF), prostaglandins, adrenomedullin and tissue plasminogen activator (tPA). (2-7) Marked decrease of laminar shear stress and turbulent flow produces an EC response that increases endothelin-1 (a potent vasoconstrictor) and tips the balance of pro-coagulant / anti-coagulant to favour the former. (8-9)
Nitric Oxide (NO) is generated by NO synthases (NOS) which catalyze the conversion of l-arginine to NO and l-citrulline. It is important to differentiate the three nitric oxide synthase isoforms and their functional aspects. The endothelial derived nitric oxide synthase (eNOS) is constitutively expressed, calcium calmodulin dependent, and causes release of eNO in nanomolar quantities into the circulation. The release of NO occurs intermittently in these small amounts. eNO is a potent vasodilator as well as an important intracellular signalling molecule that can regulate sarcoplasmic reticulum calcium influx and decrease mitochondrial oxygen consumption. (10-13) Additionally, eNO has anti-inflammatory properties through suppression of nuclear factor kappa beta (NF-κβ) activity. The latter orchestrates the inflammatory cascade. (14,15) Inducible nitric oxide synthase (iNOS) mostly present in macrophages and neutrophils produces continuous release of iNO in micromolar quantities over protracted time periods in response to inflammatory cytokines. Large quantities of nitric oxide induce severe vasodilatation and are in part responsible for intractable hypotension during sepsis. Neuronal nitric oxide synthase (nNOS) constitutionally releases small quantities of NO and is found in central and peripheral neuronal tissue as well as cardiomyocytes. The function of nNO remains under investigation but in the heart it regulates chronotropicity and may play a protective role in the myocardial response to injury. (16-21)

Endothelium and Ischemia Reperfusion Injury

Ischemia reperfusion (I/R) injury occurs after partial or total cessation of blood flow to an organ followed by restoration of blood flow. The inflammatory and oxidative stress cascade elicited by these events is extensive and in large part the endothelium is a key player during and after I/R. Endothelial activation by leukocytes during reperfusion induces a pro-coagulant, pro-inflammatory and pro-oxidant status that ultimately leads to endothelial dysfunction and inability to regulate local blood flow to vital organs. The greatest effects of I/R injury to the endothelium takes place at the microvasculature level.

Cardiac Arrest and Resuscitation a Model of Whole Body Ischemia Reperfusion Injury

Cardiac arrest and resuscitation has been shown by our laboratory and others to be a model of whole body I/R injury. (22-24) Depending upon the etiology of cardiac arrest, there is a period of no flow (ventricular fibrillation or asystole) or low flow (asphyxial cardiac arrest or hemorrhage) followed by a period of partial restoration of flow (chest compression, fluid/blood administration), and if successful restoration of the intrinsic heart beat and blood flow. These events are similar to those that which occur during focal ischemia in heart, brain and other organs. The duration of each phase is variable and the extent and severity of the injury related in large part to the initial two phases (span of time in cardiac arrest or low blood flow and the response to resuscitation).
Analogous to focal I/R injury, there are interventions that promote an innate protective organ response which when initiated can reduce or ameliorate the injury. Interventions performed prior to focal ischemia or cardiac arrests are termed preconditioning strategies (24-25) while those initiated during the ischemia or resuscitation phase are termed conditioning or per-conditioning. (26-28) Interventions performed after restoration of organ blood flow are termed postconditioning strategies. (29-33) The latter can be performed immediately upon restoration of blood flow (early postconditioning) or minutes or hours after restoration of blood flow (delayed postconditioning). (34)
Preconditioning strategies to reduce injury from focal I/R, e.g., acute myocardial infarction, have been thoroughly investigated but rarely put into practice due to the inability to predict when such event might occur. However, for pre-planned I/R such as cardiac bypass surgery, preconditioning with anaesthetics is currently clinically utilized. Deciphering the biochemical and cellular mechanisms of protection has been important in understanding pharmacologic protective strategies. The outcomes from postconditioning strategies depend upon the intervention used. (35-41) Following the successful outcome of CPR, delayed postconditioning has the potential for clinical application. (27,28)

The Endothelium during Cardiac Arrest and Resuscitation

Evidence that the endothelium plays an important role during and after cardiac arrest comes from both animal models and clinical studies. In animal models of cardiac arrest, impaired microcirculation, endothelial leakage, (42) and elevated serum levels of TNF-α and intracellular adhesion molecule-1 (ICAM-1) occur. (43-45) Studies of human survivors and non-survivors of cardiac arrest reveal increased levels of endothelin-1,(46) pro-coagulant activities, soluble endothelial adhesion molecules, complement, leukocyte endothelial interaction, (47-48) soluble selectins, von Willebrand factor and evidence of a systemic inflammatory response. (49-50) These findings and others have led to the hypothesis that postresuscitation syndrome may be analogous to a ‘sepsis-like syndrome’. (51-53)

Methods for Stimulating and Interacting with the Endothelium

Pharmacologic Interventions

Pharmacologic interventions that induce endothelial production of eNO such as statins and type V phosphodiesterase inhibitors, (54-58) those which decrease or block endothelial leukocyte interactions (peroxisome proliferator-activated receptor beta/delta (PPAR-ß), (59-61) and thrombolysis (tissue plasminogen activator) (62-63) have been explored in myocardial I/R injury and cardiac arrest with variable results. These pharmacologic interventions for preconditioning and postconditioning have limited success in part due to the poor distribution of these compounds in pharmacological significant activity to the microvasculature, the largest and most adversely affected region during I/R. Erythropoietin (EPO) is a cytoprotective molecule which in addition to having well known hematopoietic effects also has non-erythropoietic effects. (64-66) EPO enhances eNO production by phosphorylation and activation of eNOS in the endothelium. (67) Additionally, EPO mobilizes endothelial progenitor cells, which are important in endothelial repair after I/R. (68,69) EPO has been used in animal models of both focal myocardial I/R and cardiac arrest during resuscitation as a conditioning strategy as well as in pre- and postconditioning. Animal studies have shown that cardio and neuro protection occur when EPO is administered for preconditioning strategy or administered during resuscitation from cardiac arrest as well as reduced prevalence of arrhythmias when given prior to focal I/R. (67,70-75) EPO administered during cardiac arrest and resuscitation in early human trials appears encouraging. (76-77)

Gene Interventions

Endothelium targeted gene therapies for several cardiovascular diseases are being explored in animal models. Overexpression of specific targets such as eNOS, antioxidants, inhibitors of cell adhesion molecules and NF-κβ form the basis for such therapies. (78-79) Inhibition of NF-κβ activity via gene decoy before coronary ligation reduces infarct size by inhibiting pro-inflammatory and cell adhesion molecule expression. (80) Such therapies will require both preclinical and clinical confirmation but their contribution to elucidating protective endothelial mechanisms is important.

Mechanical Intervention

Periodic Acceleration (pGz) is the application of repetitive sinusoidal motion of the body in a head to foot direction. It is imparted with a motion platform that passively sets the whole body into motion (http://www.floridaheart.org/pgzmotion/). (81-85) Our laboratory has shown that pGz increases pulsatile shear stress on the vascular endothelium that increases release of eNO, prostaglandins, tissue plasminogen activator (t-PA), and adrenomedullin into the circulation. These substances are cardio-, neuro and cytoprotective. (85-89) Pulsatile shear stress induced by pGz elicits a genomic response of up-regulation of eNOS in EC as well as nNOS in EC and cardiomyocytes. (7,87)
Using models of whole body ischemia reperfusion injury such as cardiac arrest, our laboratory has shown that pGz initiated one hour prior to cardiac arrest (preconditioning) decreases post resuscitation myocardial stunning and arrhythmias, and reduces biochemical indices of myocardial tissue injury and inflammation. (24) pGz serves as a delayed postconditioning strategy after asphyxial cardiac arrest that diminishes myocardial stunning, tissue damage and inflammation. (90) In another application of pGz, Martinez et al utilized postconditioning in a rodent model of ischemic stroke. This significantly decreased cerebral infarct size compared to control animals who did not receive pGz. (91) The per-conditioning or conditioning potential of pGz has also been investigated. pGz when used as a method of resuscitation from ventricular fibrillation or asphyxial cardiac arrest decreased myocardial stunning, ameliorates reperfusion injury to a much greater extent than closed chest cardiac massage. Further, pGz treated survivors had excellent neurological outcomes. (16, 92-95)
In contrast to pharmacologic strategies where drug distribution may be impaired in poorly perfused areas, pulsatile shear stress during pGz is independent of perfusion limitations and acts on the entire vasculature. Thus, it allows wide availability of endothelial derived cytoprotective substances. The investigations that have cited in this paper have been conducted in large animal models of cardiac arrest and confirmatory studies in humans with cardiac arrest are sorely needed. pGz is a safe non-invasive intervention which is well tolerated in healthy humans and diseased patients. (96-100) Also, pGz has the potential as complementary to pharmacologic or other interventions to improve microvasculature blood flow. This should aid in better distribution of drug availability. (82,97)

Conclusions

The endothelium and in particular the microvasculature is adversely affected by I/R injury. Therapeutic interventions targeted to the endothelium which can ameliorate or reverse such injury are vitally important. Pharmacologic, gene based therapies and whole body periodic acceleration (pGz) have their basis in stimulating eNOS for its vasodilator, anti inflammatory, and antioxidant properties Getting the right therapy/signal to the right place (microvasculature) at the right time (pre, per, post conditioning) will require tailoring the therapy to the specific I/R event. Understanding endothelial biology during ischemia reperfusion injury has potential to translate into successful life-saving, therapeutic strategies.

ACKNOWLEDGEMENTS

We gratefully acknowledge the editorial review of Marvin Sackner, M.D, Raul Gazmuri, M.D. and Stefek Grmec, M.D. This work has been funded by grants from the Florida Heart Research Institute, and the American Heart Association. The author is very grateful to the contributions of the research staff, fellows and collaborators over the last 15 yrs.

REFERENCES

  1. Adams JA. Therapeutic approaches to altering hemodynamic forces. In: Aird WC, edithor. Endothelial Biomedicine. New York: Cambridge University Press; 2007.p.1690-7.
  2. Balcells M, Fernandez Suarez M, Vazquez M, Edelman ER. Cells in fluidic environments are sensitive to flow frequency. J Cell Physiol 2005;204(1):329-35.
  3. Fisslthaler B, Dimmeler S, Hermann C, Busse R, Fleming I. Phosphorylation and activation of the endothelial nitric oxide synthase by fluid shear stress. Acta Physiol Scand 2000;168(1):81-8.
  4. Hutcheson IR, Griffith TM. Release of endothelium-derived relaxing factor is modulated both by frequency and amplitude of pulsatile flow. Am J Physiol 1991;261(1 Pt 2):H257-62.
  5. Li H, Wallerath T, Forstermann U. Physiological mechanisms regulating the expression of endothelial-type NO synthase. Nitric Oxide 2002;7(2):132-47.
  6. Li Y, Zheng J, Bird IM, Magness RR. Effects of pulsatile shear stress on signaling mechanisms controlling nitric oxide production, endothelial nitric oxide synthase phosphorylation, and expression in ovine fetoplacental artery endothelial cells. Endothelium 2005;12(1-2):21-39.
  7. Wu H, Jin Y, Arias J, Bassuk J, Uryash A, Kurlansky P,et al. In vivo upregulation of nitric oxide synthases in healthy rats. Nitric Oxide 2009;21(1):63-8.
  8. Malek A, Izumo S. Physiological fluid shear stress causes downregulation of endothelin-1 mRNA in bovine aortic endothelium. Am J Physiol 1992;263(2 Pt 1):C389-96.
  9. Ohura N, Yamamoto K, Ichioka S, Sokabe T, Nakatsuka H, Baba A, et al. Global analysis of shear stress-responsive genes in vascular endothelial cells. J Atheroscler Thromb 2003;10(5):304-13.
  10. Cabrales P, Tsai AG, Frangos JA, Intaglietta M. Role of endothelial nitric oxide in microvascular oxygen delivery and consumption. Free Radic Biol Med 2005;39(9):1229-37.
  11. Cooper CE, Giulivi C. Nitric oxide regulation of mitochondrial oxygen consumption II: Molecular mechanism and tissue physiology. Am J Physiol Cell Physiol 2007;292(6):C1993-2003.
  12. Loke KE, Laycock SK, Mital S, Wolin MS,Berstein R, Oz M, et al. Nitric oxide modulates mitochondrial respiration in failing human heart. Circulation. 1999;100(12):1291-7.
  13. Zhao X, He G, Chen YR, Pandian RP, Kuppusamy P, Zweier JL. Endothelium-derived nitric oxide regulates postischemic myocardial oxygenation and oxygen consumption by modulation of mitochondrial electron transport. Circulation 2005;111(22):2966-72.
  14. Dudzinski DM, Michel T. Life history of eNOS: partners and pathways. Cardiovasc Res 2007;75(2):247-60.
  15. Grumbach IM, Chen W, Mertens SA, Harrison DG. A negative feedback mechanism involving nitric oxide and nuclear factor kappa-B modulates endothelial nitric oxide synthase transcription. J Mol Cell Cardiol 2005;39(4):595-603.
  16. Adams JA. Endothelium and cardiopulmonary resuscitation. Crit Care Med 2006;34(12 Suppl):S458-65.
  17. Albrecht EW, Stegeman CA, Heeringa P, Henning RH, van Goor H. Protective role of endothelial nitric oxide synthase. J Pathol 2003;199(1):8-17.
  18. Dudzinski DM, Igarashi J, Greif D, Michel T. The regulation and pharmacology of endothelial nitric oxide synthase. Annu Rev Pharmacol Toxicol 2006;46:235-76.
  19. Schulz R, Kelm M, Heusch G. Nitric oxide in myocardial ischemia/reperfusion injury. Cardiovasc Res 2004;61(3):402-13.
  20. Burger DE, Lu X, Lei M, Xiang FL,Hammoud J, Jinag M, et al. Neuronal nitric oxide synthase protects against myocardial infarction-induced ventricular arrhythmia and mortality in mice. Circulation 2009;120(14):1345-54.
  21. Danson EJ, Choate JK, Paterson DJ. Cardiac nitric oxide: emerging role for nNOS in regulating physiological function. Pharmacol Ther 2005;106(1):57-74.
  22. Wiklund L, Sharma HS, Basu S. Circulatory arrest as a model for studies of global ischemic injury and neuroprotection. Ann N Y Acad Sci 2005;1053:205-19.
  23. Adams JA, Wu D, Bassuk J, Arias J, Lozano H, Lamas G, et al. Nitric oxide synthase isoform inhibition before whole body ischemia reperfusion in pigs: Vital or protective? Resuscitation 2007;74(3):516-25.
  24. Adams JA, Wu H, Bassuk JA, Arias J, Uryash A, Jorapur V, et al. Periodic acceleration (pGz) prior to whole body Ischemia reperfusion injury provides early cardioprotective preconditioning. Life Sci 6 2010;86:707-15.
  25. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 1986;74(5):1124-36.
  26. Saxena P, Newman MA, Shehatha JS, Redington AN, Konstantinov IE. Remote ischemic conditioning: evolution of the concept, mechanisms, and clinical application. J Card Surg 2010;25(1):127-34.
  27. Schmidt MR, Smerup M, Konstantinov IE, Shimizu M, Li J, Cheung M, et al. Intermittent peripheral tissue ischemia during coronary ischemia reduces myocardial infarction through a KATP-dependent mechanism: first demonstration of remote ischemic perconditioning. Am J Physiol Heart Circ Physiol 2007;292(4):H1883-90.
  28. Xin P, Zhu W, Li J, Ma S, Wang L, Liu M, et al. Combined local ischemic postconditioning and remote perconditioning recapitulate the cardioprotective effects of local ischemic preconditioning. Am J Physiol Heart Circ Physiol 2010;298:H1819 -31.
  29. Hausenloy DJ, Yellon DM. Preconditioning and postconditioning: united at reperfusion. Pharmacol Ther 2007;116(2):173-91.
  30. Vinten-Johansen J, Zhao ZQ, Jiang R, Zatta AJ, Dobson GP. Preconditioning and postconditioning: innate cardioprotection from ischemia-reperfusion injury. J Appl Physiol 2007;103(4):1441-8.
  31. Vinten-Johansen J, Zhao ZQ, Zatta AJ, Kin H, Halkos ME, Kerendi F. Postconditioning-A new link in nature’s armor against myocardial ischemia-reperfusion injury. Basic Res Cardiol Jul 2005;100(4):295-310.
  32. Zhao ZQ, Corvera JS, Halkos ME, Kerendi F, Wang NP, Gyton RA, et al. Inhibition of myocardial injury by ischemic postconditioning during reperfusion: comparison with ischemic preconditioning. Am J Physiol Heart Circ Physiol 2003;285(2):H579-88.
  33. Zhao ZQ, Vinten-Johansen J. Postconditioning: reduction of reperfusion-induced injury. Cardiovasc Res May 1 2006;70(2):200-11.
  34. Adams JA, Bassuk JA, Arias J, Wu H, Jorapur V, Lamas GA, et al. Acute effects of “delayed postconditioning” with periodic acceleration after asphyxia induced shock in pigs. Pediatr Res 2008;64(5):533-7.
  35. Argaud L, Gateau-Roesch O, Raisky O, Loufouat J, Robert D, Ovize M. Postconditioning inhibits mitochondrial permeability transition. Circulation 2005;111(2):194-7.
  36. Danielisova V, Nemethova M, Gottlieb M, Burda J. The changes in endogenous antioxidant enzyme activity after postconditioning. Cell Mol Neurobiol 2006;26(7-8):1181-91.
  37. Dosenko VE, Nagibin VS, Tumanovskaya LV, Zagoriy VY, Moibenko AA, Vaage J. Proteasomal proteolysis in anoxia-reoxygenation, preconditioning and postconditioning of isolated cardiomyocytes. Pathophysiology 2006;13(2):119-25.
  38. Hausenloy DJ, Yellon DM. Preconditioning and postconditioning: new strategies for cardioprotection. Diabetes Obes Metab 2008;10:451-9.
  39. Penna C, Mancardi D, Tullio F, Pagliaro P. Postconditioning and intermittent bradykinin induced cardioprotection require cyclooxygenase activation and prostacyclin release during reperfusion. Basic Res Cardiol 2009; 104:390-402.
  40. Vinten-Johansen J. Postconditioning: a mechanical maneuver that triggers biological and molecular cardioprotective responses to reperfusion. Heart Fail Rev 2007;12(3-4):235-44.
  41. Zhu M, Feng J, Lucchinetti E, Fischer G, Xu L, Pedrazzini T, et al. Ischemic postconditioning protects remodeled myocardium via the PI3K-PKB/Akt reperfusion injury salvage kinase pathway. Cardiovasc Res 2006;72(1):152-62.
  42. Teschendorf P, Padosch SA, Del Valle YFD, Peter C, Popp E, Scbneider A, et al. Effects of activated protein C on post cardiac arrest microcirculation: an in vivo microscopy study. Resuscitation 2009;80(8):940-5.
  43. Larmann J, Schmidt C, Gammelin H, Van Aken HK, Frenzel T,Lanckohr C, et al. Intercellular adhesion molecule-1 inhibition attenuates neurologic and hepatic damage after resuscitation in mice. Anesthesiology 2005;103(6):1149-55.
  44. Callaway CW, Rittenberger JC, Logue ES, McMichael MJ. Hypothermia after cardiac arrest does not alter serum inflammatory markers. Crit Care Med 2008;36(9):2607-12.
  45. Chen F, Kondo N, Sonobe M, Fujinaga T, Wada H, Bando T. Expression of endothelial cell-specific adhesion molecules in lungs after cardiac arrest. Interact Cardiovasc Thorac Surg 2008;7(3):437-40.
  46. Haynes WG, Hamer DW, Robertson CE, Webb DJ. Plasma endothelin following cardiac arrest: differences between survivors and non-survivors. Resuscitation 1994;27(2):117-22.
  47. Bottiger BW, Motsch J, Bohrer H, Motsch J, Soder M, Fleischer F,et al. Activation of blood coagulation after cardiac arrest is not balanced adequately by activation of endogenous fibrinolysis. Circulation 1995;92(9):2572-8.
  48. Bottiger BW, Motsch J, Braun V, Martin E, Kirschfink M. Marked activation of complement and leukocytes and an increase in the concentrations of soluble endothelial adhesion molecules during cardiopulmonary resuscitation and early reperfusion after cardiac arrest in humans. Crit Care Med 2002;30(11):2473-80.
  49. Geppert A, Zorn G, Delle-Karth G, Heinz G, Maurer G,Siostrzonek P, et al. Plasminogen activator inhibitor type 1 and outcome after successful cardiopulmonary resuscitation. Crit Care Med 2001;29(9):1670-7.
  50. Geppert A, Zorn G, Karth GD, Haumer M,Gwechenberger M, Koller-Strametz J,et al. Soluble selectins and the systemic inflammatory response syndrome after successful cardiopulmonary resuscitation. Crit Care Med 2000;28(7):2360-5.
  51. Adrie C, Adib-Conquy M, Laurent I, Monchi M, Vinsonneau C, Fitting C, et al. Successful cardiopulmonary resuscitation after cardiac arrest as a “sepsis-like” syndrome. Circulation 2002;106(5):562-8.
  52. Adrie C, Laurent I, Monchi M, Cariou A, Dhainaou JF, Spaulding C. Postresuscitation disease after cardiac arrest: a sepsis-like syndrome? Current Opinnion in Critical Care 2004;10(3):208-12.
  53. Adrie C, Monchi M, Laurent I, Um S, Yan SB, Thuong M,et al. Coagulopathy after successful cardiopulmonary resuscitation following cardiac arrest: implication of the protein C anticoagulant pathway. J Am CollCardiol 2005;46(1):21-8.
  54. Ye Y, Lin Y, Atar S, Huang MH, Perez-Polo JR, Uretsky BF,et al. Myocardial protection by pioglitazone, atorvastatin, and their combination: mechanisms and possible interactions. Am J Physiol Heart Circ Physiol 2006;291(3):H1158-69.
  55. Ludman A, Venugopal V, Yellon DM, Hausenloy DJ. Statins and cardioprotection–more than just lipid lowering? Pharmacol Ther 2009;122(1):30-43.
  56. Ye Y, Martinez JD, Perez-Polo RJ, Lin Y, Uretsky BF, Birnbaum Y. The role of eNOS, iNOS, and NF-kappaB in upregulation and activation of cyclooxygenase-2 and infarct size reduction by atorvastatin. Am J Physiol Heart Circ Physiol 2008;295(1):H343-51.
  57. Gori T, Sicuro S, Dragoni S, Donati G, Forconi S, Parker JD. Sildenafil prevents endothelial dysfunction induced by ischemia and reperfusion via opening of adenosine triphosphate-sensitive potassium channels: a human in vivo study. Circulation 15 2005;111(6):742-6.
  58. Szabo G, Radovits T, Veres G, Krieger N, Loganathan S, Sandner P,et al. Vardenafil protects against myocardial and endothelial injuries after cardiopulmonary bypass. Eur J Cardiothorac Surg 2009;36(4):657-4.
  59. Piqueras L, Sanz MJ, Perretti M, Morcillo E, Norling L, Mitchell JA, et al. Activation of PPARbeta/delta inhibits leukocyte recruitment, cell adhesion molecule expression, and chemokine release. J Leukoc Biol 2009;86(1):115-22.
  60. Yeh CH, Chen TP, Lee CH, Wu YC, Lin YM, Lin PJ. Cardiomyocytic apoptosis following global cardiac ischemia and reperfusion can be attenuated by peroxisome proliferator-activated receptor alpha but not gamma activators. Shock 2006;26(3):262-70.
  61. Touyz RM, Schiffrin EL. Peroxisome proliferator-activated receptors in vascular biology-molecular mechanisms and clinical implications. Vascul Pharmacol 2006;45(1):19-28.
  62. Bottiger BW, Arntz HR, Chamberlain DA, Bhlumki E,Belmans A, Danays T,et al. Thrombolysis during resuscitation for out-of-hospital cardiac arrest. N Engl J Med 2008;359(25):2651-62.
  63. Spohr F, Bottiger BW. Thrombolysis during cardiopulmonary resuscitation: a pilot randomised trial of thrombolysis in cardiac arrest (the TICA trial). Resuscitation 2005;64(3):389.
  64. Bogoyevitch MA. An update on the cardiac effects of erythropoietin cardioprotection by erythropoietin and the lessons learnt from studies in neuroprotection. Cardiovasc Res 2004;63(2):208-16.
  65. Brines M. The therapeutic potential of erythropoiesis-stimulating agents for tissue protection: a tale of two receptors. Blood Purif 2010;29(2):86-92.
  66. Peterson TE, Katusic ZS. EPO tecting the endothelium. Br J Pharmacol 2007;150(7):823-5.
  67. Mihov D, Bogdanov N, Grenacher B, Gassmann M, Zünd G, Bogdanova A, et al. Erythropoietin protects from reperfusion-induced myocardial injury by enhancing coronary endothelial nitric oxide production. Eur J Cardiothorac Surg 2009;35(5):839-46.
  68. Besler C, Doerries C, Giannotti G, Luscher TF, Landmesser U. Pharmacological approaches to improve endothelial repair mechanisms. Expert review of cardiovascular therapy. Expert Rev Cardiovasc Ther 2008;6(8):1071-82.
  69. Fliser D, Bahlmann FH. Erythropoietin and the endothelium – a promising link? Eur J Clin Invest 2008;38(7):457-61.
  70. Burger DE, Xiang FL, Hammoud L, Jones DL, Feng Q. Erythropoietin protects the heart from ventricular arrhythmia during ischemia and reperfusion via neuronal nitric-oxide synthase. J Pharmacol Exp Ther 2009;329(3):900-7.
  71. Incagnoli P, Ramond A, Joyeux-Faure M, Pepin JL, Levy P, Ribuot C. Erythropoietin improved initial resuscitation and increased survival after cardiac arrest in rats. Resuscitation 2009;80(6):696-700.
  72. Singh D, Kolarova JD, Wang S, Ayoub IM, Gazmuri RJ. Myocardial protection by erythropoietin during resuscitation from ventricular fibrillation. Am J Ther 2007;14(4):361-8.
  73. Givehchian M, Beschorner R, Ehmann C, Frauenlob L, Morgalla M, Hashemi B,et al. Neuroprotective effects of erythropoietin during deep hypothermic circulatory arrest. Eur J Cardiothorac Surg 2010;37(3):662-8.
  74. Popp E, Vogel P, Teschendorf P, Bottiger BW. Effects of the application of erythropoietin on cerebral recovery after cardiac arrest in rats. Resuscitation 2007;74(2):344-51.
  75. Huang CH, Hsu CY, Tsai MS, Wang TD, Chang WT, Chen WJ. Cardioprotective effects of erythropoietin on postresuscitation myocardial dysfunction in appropriate therapeutic windows. Crit Care Med Nov 2008;36(11 Suppl):S467-73.
  76. Cariou A, Claessens YE, Pene F, Marx JS, Spaulding C, Hababou C, et al. Early high-dose erythropoietin therapy and hypothermia after out-of-hospital cardiac arrest: a matched control study. Resuscitation 2008;76(3):397-404.
  77. Grmec S, Strnad M, Kupnik D, Sinkovic A, Gazmuri RJ. Erythropoietin facilitates the return of spontaneous circulation and survival in victims of out-of-hospital cardiac arrest. Resuscitation 2009;80(6):631-7.
  78. Janssens S, Pokreisz P, Schoonjans L,Pellens M, Vermeersch P, Tjwa M, et al. Cardiomyocyte-specific overexpression of nitric oxide synthase 3 improves left ventricular performance and reduces compensatory hypertrophy after myocardial infarction. Circ Res 14 2004;94(9):1256-62.
  79. Melo LG, Gnecchi M, Pachori AS, Kong D, wang K, Liu X,et al. Endothelium-targeted gene and cell-based therapies for cardiovascular disease. Arterioscler Thromb Vasc Biol 2004;24(10):1761-74.
  80. Morishita R, Sugimoto T, Aoki M, Kida I, Tomita N, Moriguchi A,et al. In vivo transfection of cis element “decoy” against nuclear factor-kappaB binding site prevents myocardial infarction. Nat Med 1997;3(8):894-9.
  81. Adams JA, Mangino MJ, Bassuk J, Inman DM, Sackner MA. Noninvasive motion ventilation (NIMV): a novel approach to ventilatory support. J Appl Physiol 2000;89(6):2438-46.
  82. Adams JA, Mangino MJ, Bassuk J, Kurlansky P, Sackner MA. Regional blood flow during periodic acceleration. Crit Care Med 2001;29(10):1983-8.
  83. Adams JA, Mangino MJ, Bassuk J, Kurlansky P, Sackner MA. Novel CPR with periodic Gz acceleration. Resuscitation 2001;51(1):55-62.
  84. Adams JA, Mangino MJ, Bassuk J, Sackner MA. Hemodynamic effects of periodic G(z) acceleration in meconium aspiration in pigs. J Appl Physiol 2000;89(6):2447-52.
  85. Adams JA, Moore JE, Jr., Moreno MR, Coelho J, Bassuk J, Wu D. Effects of periodic body acceleration on the in vivo vasoactive response to N-omega-nitro-L-arginine and the in vitro nitric oxide production. Ann Biomed Eng 2003;31(11):1337-46.
  86. Adams JA, Bassuk J, Wu D, Grana M, Kurlansky P, Sackner MA. Periodic acceleration: effects on vasoactive, fibrinolytic, and coagulation factors. J Appl Physiol 2005;98(3):1083-90.
  87. Adams JA, Wu H, Bassuk JA, Arias J, Uryash A, Kurlansky P. Periodic acceleration (pGz) acutely increases endothelial and neuronal nitric oxide synthase expression in endomyocardium of normal swine. Peptides 2009;30(2):373-7.
  88. Lozano H, Wu D, Bassuk J, Aria J, Kurlansky P, Lamas GA,et al. The effects of prostaglandin inhibition on whole-body ischemia-reperfusion in swine. Am J Emerg Med 2008;26(1):45-53.
  89. Martinez A, Arias J, Bassuk JA, Wu H, Kurlansky P, Adams JA. Adrenomedullin is increased by pulsatile shear stress on the vascular endothelium via periodic acceleration (pGz). Peptides 2008;29(1):73-8.
  90. Adams JA, Bassuk JA, Arias J, Wu H, Joarpur V, Lamas GA, et al. Acute Effects of “Delayed Postconditioning” with Periodic Acceleration (pGz) After Asphyxia Induced Shock in Pigs. Pediatr Res 2008;64:533-7.
  91. Martinez-Murillo R, Serrano J, Fernandez AP, Martinez A. Whole-body periodic acceleration reduces brain damage in a focal ischemia model. Neuroscience 2009;158(4):1390-6.
  92. Adams JA, Bassuk J, Wu D, Kurlansky P. Survival and normal neurological outcome after CPR with periodic Gz acceleration and vasopressin. Resuscitation 2003;56(2):215-21.
  93. Adams JA, Bassuk JA, Arias J. Periodic acceleration (pGz) CPR in a swine model of asphyxia induced cardiac arrest Short-term hemodynamic comparisons. Resuscitation 2008; 77:132-8.
  94. Nava G, Adams JA, Bassuk J, Wu D, Kurlansky P, Lamas GA. Echocardiographic comparison of cardiopulmonary resuscitation (CPR) using periodic acceleration (pGz) versus chest compression. Resuscitation 2005;66(1):91-7.
  95. Wu D, Bassuk J, Arias J, Peschiera I, Lamet A, Kurlansky P, et al. Post-resuscitation reperfusion injury: comparison of periodic Gz acceleration versus Thumper CPR. Resuscitation 2006;70(3):454-62.
  96. Fujita M, Tambara, K, Ikemoto, M, Sakamoto, S, Ogai, A. Periodic Acceleration Enhances Release of Nitric Oxide in Healthy Adults. Int J Angiol 2005;14:11-14.
  97. Fukuda S, Shimada K, Kawasaki T, Kono Y,Jissho S, Taguchi H,et al. “Passive exercise” using whole body periodic acceleration: effects on coronary microcirculation. Am Heart J Apr 2010;159(4):620-6.
  98. Kohler M, Amann-Vesti BR, Clarenbach CF, Vrack T, Noll G, Russi EW, et al. Periodic whole body acceleration: a novel therapy for cardiovascular disease. Vasa 2007;36(4):261-6.
  99. Sackner MA, Gummels E, Adams JA. Nitric oxide is released into circulation with whole-body, periodic acceleration. Chest 2005;127(1):30-9.
  100. Sackner MA, Gummels EM, Adams JA. Say NO to fibromyalgia and chronic fatigue syndrome: an alternative and complementary therapy to aerobic exercise. Med Hypotheses 2004;63(1):118-23.

Creative Commons LicenseThis work is licensed under a Creative Commons Attribution 4.0 International License