Conditioning Strategies Limit Cellular Injury?

DOI: 10.4236/wjcd.2014.411065   PDF   HTML   XML   2,520 Downloads   2,899 Views   Citations


Evaluation of multiorgan protection strategies against ischemic injury in humans is essential to improve quality of life and reduce mortality. Over the past 40 years a host of pharmacologic and non-pharmacologic interventions have been evaluated with the aim of limiting cell damage produced by ischemia-reperfusion injury. Different conditioning strategies, such as remote conditioning, are documented to mitigate ischemic injury in animal and human studies and may have remarkable clinical promise. However, successful clinical application of these interventions remains questionable since protection is known to be compromised in humans with comorbidities either with or without medications. Regardless, ongoing studies continue to examine the underlying mechanisms involved in this endogenous cytoprotective phenomenon to further its successful implementation in the clinical setting. In this review, we examine recent findings in support of remote conditioning stratagems for organ protection and their relevance for translation to clinical use.

Share and Cite:

Kingma, J. (2014) Conditioning Strategies Limit Cellular Injury?. World Journal of Cardiovascular Diseases, 4, 539-547. doi: 10.4236/wjcd.2014.411065.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Kloner, R.A. (2013) Current State of Clinical Translation of Cardioprotective Agents for Acute Myocardial Infarction. Circulation Research, 113, 451-463.
[2] Hausenloy, D.J., Baxter, G., Bell, R., Botker, H.E., Davidson, S.M., Downey, J., Heusch, G., Kitakaze, M., Lecour, S., Mentzer, R., Mocanu, M.M., Ovize, M., Schulz, R., Shannon, R., Walker, M., Walkinshaw, G. and Yellon, D.M. (2010) Translating Novel Strategies for Cardioprotection: The Hatter Workshop Recommendations. Basic Research in Cardiology, 105, 677-686.
[3] Murry, C.E., Jennings, R.B. and Reimer, K.A. (1986) Preconditioning with Ischemia: A Delay of Lethal Cell Injury in Ischemic Myocardium. Circulation, 74, 1124-1136.
[4] Cohen, M.V., Liu, G.S. and Downey, J.M. (1991) Preconditioning Causes Improved Wall Motion as Well as Smaller Infarcts after Transient Coronary Occlusion in Rabbits. Circulation, 84, 341-349.
[5] Shiki, K. and Hearse, D.J. (1987) Preconditioning of Ischemic Myocardium: Reperfusion-Induced Arrhythmias. American Journal of Physiology, 253, H1470-H1476.
[6] Vegh, A., Komori, S., Szekeres, L. and Parratt, J.R. (1992) Antiarrhythmic Effects of Preconditioning in Anaesthetised Dogs and Rats. Cardiovascular Research, 26, 487-495.
[7] Asimakis, G.K., Inners-McBride, K., Conti, V.R. and Yang, C.J. (1994) Transient Beta Adrenergic Stimulation Can Precondition the Rat Heart against Postischaemic Contractile Dys-function. Cardiovascular Research, 28, 1726-1734.
[8] DeFily, D.V. and Chilian, W.M. (1993) Preconditioning Protects Coronary Arteriolar Endothelium from Ischemia-Reperfusion Injury. American Journal of Physiology, 265, H700-H706.
[9] Laude, K., Beauchamp, P., Thuillez, C. and Richard, V. (2002) Endothelial Protective Effects of Preconditioning. Cardiovascular Research, 55, 466-473.
[10] Ma, X.J., Zhang, X.H., Li, C.M. and Luo, M. (2006) Effect of Postconditioning on Coronary Blood Flow Velocity and Endothelial Function in Patients with Acute Myocardial Infarction. Scandinavian Cardiovascular Journal, 40, 327-333.
[11] Ambrosio, G., Weisman, H.F., Mannisi, J.A. and Becker, L.C. (1989) Progressive Impairment of Regional Myocardial Perfusion after Initial Restoration of Postischemic Blood Flow. Circulation, 80, 1846-1861.
[12] Schwartz, B.G. and Kloner, R.A. (2012) Coronary No Reflow. Journal of Molecular and Cellular Cardiology, 52, 873-882.
[13] Schaller, B. (2005) Ischemic Preconditioning as Induction of Ischemic Tolerance after Transient Ischemic Attacks in Human Brain: Its Clinical Relevance. Neuroscience Letters, 377, 206-211.
[14] Lee, H.T. and Emala, C.W. (2000) Protective Effects of Renal Ischemic Preconditioning and Adenosine Pretreatment: Role of A(1) and A(3) Receptors. American Journal of Physiology. Renal Physiology, 278, F380-F387.
[15] Liu, G.S., Thornton, J., Van Winkle, D.M., Stanley, A.W.H., Olsson, R.A. and Downey, J.M. (1991) Protection against Infarction Afforded by Preconditioning Is Mediated by A1 Adenosine Receptors in Rabbit Heart. Circulation, 84, 350-356.
[16] Dawn, B. and Bolli, R. (2002) Role of Nitric Oxide in Myocardial Preconditioning. Annals of the New York Academy of Sciences, 962, 18-41.
[17] Goto, M., Liu, Y., Yang, X.-M., Ardell, J.L., Cohen, M.V. and Downey, J.M. (1995) Role of Bradykinin in Protection of Ischemic Preconditioning in Rabbit Hearts. Circulation Research, 77, 611-621.
[18] Yellon, D.M. and Downey, J.M. (2003) Preconditioning the Myocardium: From Cellular Physiology to Clinical Cardiology. Physiological Reviews, 83, 1113-1151.
[19] Murphy, E. and Steenbergen, C. (2008) Mechanisms Underlying Acute Protection from Cardiac Ischemia-Reperfusion Injury. Physiological Reviews, 88, 581-609.
[20] Currie, R.W., Tanguay, R.M. and Kingma Jr., J.G. (1993) Heat-Shock Response and Limitation of Tissue Necrosis during Occlusion/Reperfusion in Rabbit Hearts. Circulation, 87, 963-971.
[21] Bolli, R. (2000) The Late Phase of Preconditioning. Circulation Research, 87, 972-983.
[22] Ovize, M., Kloner, R.A. and Przyklenk, K. (1994) Stretch Preconditions Canine Myocardium. American Journal of Physiology, 266, H137-H146.
[23] Gysembergh, A., Margonari, H., Loufoua, J., Ovize, A., Andre-Fouet, X., Minaire, Y. and Ovize, M. (1998) Stretch-Induced Protection Shares a Common Mechanism with Ischemic Preconditioning in Rabbit Heart. American Journal of Physiology, 274, H955-H964.
[24] Huang, C.H., Wang, J.S., Chiang, S.C., Wang, Y.Y., Lai, S.T. and Weng, Z.C. (2004) Brief Pressure Overload of the Left Ventricle Preconditions Rabbit Myocardium against Infarction. The Annals of Thoracic Surgery, 78, 628-633.
[25] Szekeres, L., Papp, J.G., Szilvassy, Z., Udvary, E. and Vegh, A. (1993) Moderate Stress by Cardiac Pacing May Induce both Short Term and Long Term Cardioprotection. Cardiovascular Research, 27, 593-596.
[26] Hearse, D.J., Ferrari, R. and Sutherland, F.J. (1999) Cardioprotection: Intermittent Ventricular Fibrillation and Rapid Pacing Can Induce Preconditioning in the Blood-Perfused Rat Heart. Journal of Molecular and Cellular Cardiology, 31, 1961-1973.
[27] Banerjee, A., Locke-Winter, C., Rogers, K.B., Mitchell, M.B., Brew, E.C., Cairns, C.B., Bensard, D.D. and Harken, A.H. (1993) Preconditioning against Myocardial Dysfunction after Ischemia and Reperfusion by an a1-Adrenergic Mechanism. Circulation Research, 73, 656-670.
[28] Ovize, M., Thibault, H. and Przyklenk, K. (2013) Myocardial Conditioning: Opportunities for Clinical Translation. Circulation Research, 113, 439-450.
[29] Heide, R.S.V. and Steenbergen, C. (2013) Cardio-protection and Myocardial Reperfusion: Pitfalls to Clinical Application. Circulation Research, 113, 464-477.
[30] Przyklenk, K., Bauer, B., Ovize, M., Kloner, R.A. and Whittaker, P. (1993) Regional Ischemic Preconditioning Protects Remote Virgin Myocardium from Subsequent Coronary Occlusion. Circulation, 87, 893-899.
[31] Konstantinov, I.E., Arab, S., Kharbanda, R.K., Li, J., Cheung, M.M., Cherepanov, V., Downey, G.P., Liu, P.P., Cukerman, E., Coles, J.G. and Redington, A.N. (2004) The Remote Ischemic Preconditioning Stimulus Modifies Inflammatory Gene Expression in Humans. Physiological Genomics, 19, 143-150.
[32] Konstantinov, I.E., Li, J., Cheung, M.M., Shimizu, M., Stokoe, J., Kharbanda, R.K. and Redington, A.N. (2005) Remote Ischemic Preconditioning of the Recipient Reduces Myocardial Ischemia-Reperfusion Injury of the Denervated Donor Heart via a Katp Channel-Dependent Mechanism. Transplantation, 79, 1691-1695.
[33] Shimizu, M., Konstantinov, I.E., Kharbanda, R.K., Cheung, M.H. and Redington, A.N. (2007) Effects of Intermittent Lower Limb Ischaemia on Coronary Blood Flow and Coronary Resistance in Pigs. Acta Physiologica, 190, 103-109.
[34] Kharbanda, R.K., Mortensen, U.M., White, P.A., Kristiansen, S.B., Schmidt, M.R., Hoschtitzky, J.A., Vogel, M., Sorensen, K., Redington, A.N. and MacAllister, R. (2002) Transient Limb Ischemia Induces Remote Ischemic Preconditioning in Vivo. Circulation, 106, 2881-2883.
[35] Vinten-Johansen, J. and Shi, W. (2011) Perconditioning and Postconditioning: Current Knowledge, Knowledge Gaps, Barriers to Adoption and Future Directions. Journal of Cardiovascular Pharmacology and Therapeutics, 16, 260-266.
[36] Przyklenk, K. (2013) Reduction of Myocardial Infarct Size with Ischemic “Conditioning”: Physiologic and Technical Considerations. Anesthesia Analgesia, 117, 891-901.
[37] Hausenloy, D.J. and Yellon, D.M. (2009) Preconditioning and Postconditioning: Underlying Mechanisms and Clinical Application. Atherosclerosis, 204, 334-341.
[38] Lim, S.Y. and Hausenloy, D.J. (2012) Remote Ischemic Conditioning: From Bench to Bedside. Frontiers in Physiology, 3, 27.
[39] Stowe, D.F. and Kevin, L.G. (2004) Cardiac Preconditioning by Volatile Anesthetic Agents: A Defining Role for Altered Mitochondrial Bioenergetics. Antioxidants Redox Signaling, 6, 439-448.
[40] Saxena, P., Newman, M.A., Shehatha, J.S., Redington, A.N. and Konstantinov, I.E. (2010) Remote Ischemic Conditioning: Evolution of the Concept, Mechanisms and Clinical Application. Journal of Cardiac Surgery, 25, 127-134.
[41] Weber, C. (2010) Far from the Heart: Receptor Cross-Talk in Remote Conditioning. Nature Medicine, 16, 760-762.
[42] Dickson, E.W., Lorbar, M., Porcaro, W.A., Fenton, R.A., Reinhardt, C.P., Gysembergh, A. and Przyklenk, K. (1999) Rabbit Heart Can Be “Preconditioned” via Transfer of Coronary Effluent. American Journal of Physiology, 277, H2451-H2457.
[43] Gho, B.C., Schoemaker, R.G., van den Doel, M.A., Duncker, D.J. and Verdouw, P.D. (1996) Myocardial Protection by Brief Ischemia in Noncardiac Tissue. Circulation, 94, 2193-2200.
[44] Weinbrenner, C., Nelles, M., Herzog, N., Sarvary, L. and Strasser, R.H. (2002) Remote Preconditioning by Infrarenal Occlusion of the Aorta Protects the Heart from Infarction: A Newly Identified Non-Neuronal but PKC-Dependent Pathway. Cardiovascular Research, 55, 590-601.
[45] Loukogeorgakis, S.P., Panagiotidou, A.T., Broadhead, M.W., Donald, A., Deanfield, J.E. and MacAllister, R.J. (2005) Remote Ischemic Preconditioning Provides Early and Late Protection against Endothelial Ischemia-Reperfusion Injury in Humans: Role of the Autonomic Nervous System. Journal of the American College of Cardiology, 46, 450-456.
[46] Manintveld, O.C., Te Lintel, H.M., Keijzer, E., Verdouw, P.D. and Duncker, D.J. (2005) Intravenous Adenosine Protects the Myocardium Primarily by Activation of a Neurogenic Pathway. British Journal of Pharmacology, 145, 703-711.
[47] Ding, Y.F., Zhang, M.M. and He, R.R. (2001) Role of Renal Nerve in Cardioprotection Provided by Renal Ischemic Preconditioning in Anesthetized Rabbits. Acta Physiologica, 53, 7-12.
[48] Ardell, J.L., Yang, X.-M., Barron, B.A., Downey, J.M. and Cohen, M.V. (1996) Endogenous Myocardial Norepinephrine Is Not Essential for Ischemic Preconditioning in Rabbit Heart. American Journal of Physiology, 270, H1078-H1084.
[49] Vander Heide, R.S., Schwartz, L.M., Jennings, R.B. and Reimer, K.A. (1995) Effect of Catecholamine Depletion on Myocardial Infarct Size in Dogs: Role of Catecholamines in Ischemic Preconditioning. Cardiovascular Research, 30, 656-662.
[50] Kingma, J.G., Simard, D., Voisine, P. and Rouleau, J.R. (2011) Role of the Autonomic Nervous System in Cardioprotection by Remote Preconditioning in Isoflurane-Anaesthetized Dogs. Cardiovascular Research, 89, 384-391.
[51] Ardell, J.L., Butler, C.K., Smith, F.M., Hopkins, D.A. and Armour, J.A. (1991) Activity of in Vivo Atrial and Ventricular Neurons in Chronically Decentralized Canine Hearts. American Journal of Physiology, 260, H713-H721.
[52] Ardell, J.L., Cardinal, R., Vermeulen, M. and Armour, J.A. (2009) Dorsal Spinal Cord Stimulation Obtunds the Capacity of Intrathoracic Extracardiac Neurons to Transduce Myocardial Ischemia. American Journal of Physiology, 297, R470-R477.
[53] Lavallee, M., Amano, J., Vatner, S.F., Manders, W.T., Randall, W.C. and Thomas Jr., J.X. (1985) Adverse Effects of Chronic Cardiac Denervation in Conscious Dogs with Myocardial Ischemia. Circulation Research, 57, 383-392.
[54] Vergroesen, I., Merkus, D., Van Teeffelen, J.W.G.E., Dankelman, J., Spaan, J.A.E., Van Wezel, H.B., Noble, M.I.M. and Drake-Holland, A.J. (1999) Chronic Cardiac Denervation Affects the Speed of Coronary Vascular Regulation. Cardiovascular Research, 44, 615-622.
[55] Acad, B.-A., Joselevitz-Goldman, J., Scholz, P.M. and Weiss, H.R. (1988) Improved Distribution of Regional Oxygenation in Denervated Ischemic Dog Myocardium. Circulation Research, 62, 1041-1048.
[56] Kudej, R.K., Shen, Y.T., Peppas, A.P., Huang, C.H., Chen, W., Yan, L., Vatner, D.E. and Vatner, S.F. (2006) Obligatory Role of Cardiac Nerves and Alpha1-Adrenergic Receptors for the Second Window of Ischemic Preconditioning in Conscious Pigs. Circulation Research, 99, 1270-1276.
[57] Haessler, R., Wolff, R.A., Chien, G.L., Davis, R.F. and Van Winkle, D.M. (1997) High Spinal Anesthesia Does Not Alter Experimental Myocardial Infarction Size or Ischemic Preconditioning. Journal of Cardiothoracic and Vascular Anesthesia, 11, 72-79.
[58] Heusch, G. (2013) Cardioprotection: Chances and Challenges of Its Translation to the Clinic. The Lancet, 381, 166-175.
[59] Ferdinandy, P., Schulz, R. and Baxter, G.F. (2007) Interaction of Cardiovascular Risk Factors with Myocardial Ischemia/Reperfusion Injury, Preconditioning and Postconditioning. Pharmacological Reviews, 59, 418-458.
[60] Ludman, A.J., Yellon, D.M. and Hausenloy, D.J. (2010) Cardiac Preconditioning for Ischaemia: Lost in Translation. Disease Models Mechanisms, 3, 35-38.
[61] Sack, M.N. and Murphy, E. (2011) The Role of Comorbidities in Cardioprotection. Journal of Cardiovascular Pharmacology and Therapeutics, 16, 267-272.
[62] Przyklenk, K. (2011) Efficacy of Cardioprotective “Conditioning” Strategies in Aging and Diabetic Cohorts: The Co-Morbidity Conundrum. Drugs Aging, 28, 331-343.
[63] Tsang, A., Hausenloy, D.J., Mocanu, M.M., Carr, R.D. and Yellon, D.M. (2005) Preconditioning the Diabetic Heart: The Importance of Akt Phosphorylation. Diabetes, 54, 2360-2364.
[64] Sivaraman, V., Hausenloy, D.J., Wynne, A.M. and Yellon, D.M. (2010) Preconditioning the Diabetic Human Myocardium. Journal of Cellular and Molecular Medicine, 14, 1740-1746.
[65] Przyklenk, K., Maynard, M., Darling, C.E. and Whittaker, P. (2008) Aging Mouse Hearts Are Refractory to Infarct Size Reduction with Post-Conditioning. Journal of Cellular and Molecular Medicine, 51, 1393-1398.
[66] Abete, P., Ferrara, N., Cioppa, A., Ferrara, P., Bianco, S., Calabrese, C., Cacciatore, F., Longobardi, G. and Rengo, F. (1996) Preconditioning Does Not Prevent Postischemic Dysfunction in Aging Heart. Journal of the American College of Cardiology, 27, 1777-1786.
[67] Dikow, R., Kihm, L.P., Zeier, M., Kapitza, J., Tornig, J., Amann, K., Tiefenbacher, C. and Ritz, E. (2004) Increased Infarct Size in Uremic Rats: Reduced Ischemia Tolerance? Journal of the American Society of Nephrology, 15, 1530-1536.
[68] Byrne, C.J., McCafferty, K., Kieswich, J., Harwood, S., Andrikopoulos, P., Raftery, M., Thiemermann, C. and Yaqoob, M.M. (2012) Ischemic Conditioning Protects the Uremic Heart in a Rodent Model of Myocardial Infarction. Circulation, 125, 1256-1265.
[69] Amann, K., Breitbach, M., Ritz, E. and Mall, G. (1998) Myocyte/Capillary Mismatch in the Heart of Uremic Patients. Journal of the American Society of Nephrology, 9, 1018-1022.
[70] Kocsis, G.F., Sarkozy, M., Bencsik, P., Pipicz, M., Varga, Z.V., Paloczi, J., Csonka, C., Ferdinandy, P. and Csont, T. (2012) Preconditioning Protects the Heart in a Prolonged Uremic Condition. Heart and Circulatory Physiology—American Journal of Physiology, 303, H1229-H1236.
[71] Herrick, J.B. (1912) Clinical Features of the Sudden Obstruction of the Coronary Arteries. The Journal of the American Medical Association, LIX, 2015-2022.
[72] Rouleau, J.R., Boerboom, L.E., Surjadhana, A. and Hoffman, J.I.E. (1979) The Role of Autoregulation and Tissue Diastolic Pressures in the Transmural Distribution of Left Ventricular Blood Flow in Anesthetized Dogs. Circulation Research, 45, 804-815.
[73] Surjadhana, A., Rouleau, J., Boerboom, L. and Hoffman, J.I. (1978) Myocardial Blood Flow and Its Distribution in Anesthetized Polycythemic Dogs. Circulation Research, 43, 619-631.
[74] Andrikou, E., Bafakis, I., Grassos, C., Papaspyropoulos, A. and Kranidis, A. (2012) J-Curve Phenomenon: A Matter of Debate. The Hellenic Journal of Cardiology, 53, 357-366.
[75] Madias, J.E. (2011) Effect of Serial Arm Ischemic Preconditioning Sessions on the Systemic Blood Pressure of a Normotensive Subject. Medical Hypotheses, 76, 503-506.
[76] Jones, H., Hopkins, N., Bailey, T.G., Green, D.J., Cable, N.T. and Thijssen, D.H. (2014) Seven-Day Remote Ischemic Preconditioning Improves Local and Systemic Endothelial Function and Microcirculation in Healthy Humans. American Journal of Hypertension, 27, 918-925.
[77] Agarwal, R. (2009) Blood Pressure Components and the Risk for End-Stage Renal Disease and Death in Chronic Kidney Disease. Clinical Journal of the American Society of Nephrology, 4, 830-837.
[78] Ivanovic, B. and Tadic, M. (2014) When Does Low Normal Blood Pressure Become Too Low? The J-Curve Phenomenon. Acta Cardiologica, 69, 121-129.
[79] Vatner, S.F. (1980) Correlation between Acute Reductions in Myocardial Blood Flow and Function in Conscious Dogs. Circulation Research, 47, 201-207.
[80] Kingma, J.G., Simard, D. and Rouleau, J.R. (2011) Modulation of Nitric Oxide Affects Myocardial Perfusion-Contraction Matching in Anesthetised Dogs with Recurrent No-Flow Ischemia. Experimental Physiology, 96, 1293-1301.
[81] Gallagher, K.P., Matsuzaki, M., Koziol, J.A., Kemper, W.S. and Ross Jr., J. (1984) Regional Myocardial Perfusion and Wall Thickening during Ischemia in Conscious Dogs. Heart and Circulatory Physiology—American Journal of Physiology, 247, H727-H738.
[82] Ross Jr., J., Gallagher, K.P., Matzusaki, M., Lee, J.D., Guth, B. and Goldfarb, R. (1986) Regional Myocardial Blood Flow and Function in Experimental Myocardial Ischemia. Canadian Journal of Cardiology, Supplement A, 9A-18A.
[83] Ross Jr., J. (1991) Myocardial Perfusion-Contraction Matching. Implications for Coronary Heart Disease and Hibernation. Circulation, 83, 1076-1083.
[84] Heusch, G. (2008) Heart Rate in the Pathophysiology of Coronary Blood Flow and Myocardial Ischaemia: Benefit from Selective Bradycardic Agents. British Journal of Pharmacology, 153, 1589-1601.
[85] Gall Jr., S.A., Maier, G.W., Glower, D.D., Gaynor, J.W., Cobb, F.R., Sabiston Jr., D.C. and Rankin, J.S. (1993) Recovery of Myocardial Function after Repetitive Episodes of Reversible Ischemia. Heart and Circulatory Physiology— American Journal of Physiology, 264, H1130-H1138.
[86] Heusch, G., Kleinbongard, P., Skyschally, A., Levkau, B., Schulz, R. and Erbel, R. (2012) The Coronary Circulation in Cardioprotection: More than Just One Confounder. Cardiovascular Research, 94, 237-245.
[87] Herrmann, J., Kaski, J.C. and Lerman, A. (2012) Coronary Microvascular Dysfunction in the Clinical Setting: From Mystery to Reality. European Heart Journal, 33, 2771-2781.
[88] Bolognese, L., Carrabba, N., Parodi, G., Santoro, G.M., Buonamici, P., Cerisano, G. and Antoniucci, D. (2004) Impact of Microvascular Dysfunction on Left Ventricular Remodelling and Long-Term Clinical Outcome after Primary Coronary Angioplasty for Acute Myocardial Infarction. Circulation, 109, 1121-1126.
[89] Dwivedi, G., Janardhanan, R., Hayat, S.A., Swinburn, J.M. and Senior, R. (2007) Prognostic Value of Myocardial Viability Detected by Myocardial Contrast Echocardiography Early after Acute Myocardial Infarction. Journal of the American College of Cardiology, 50, 327-334.

comments powered by Disqus

Copyright © 2020 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.