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1 Title: Reperfusion injury Pathogenesis and basis of treatment options 2 3 Dr. Ashfaq Ul Hassan1, Dr. Sajjad Reshi2, Dr. Pervez Shah3, Dr Afeera Abida4, Dr. Zahida Rasool5 4 5 6 7 8 9 10 11 1. MBBS MS Lecturer , SKIMS Medical College Bemina, Srinagar, Kashmir, India. 2. MBBS, MRCP (Edin, London), Interventional Cardiologist, Khyber Heart Centre, Kashmir, India. 3. MBBS, MD, DM, Head of the Unit, Medicine, SMHS Hospital, Srinagar, Kashmir,India 4. MBBS, Resident Medicine, Ohio, USA 5. MBBS, Medical Consultant Islamic University of Science and Technology, Awantipora Kashmir India 12 13 14 15 Correspondence to: Dr. Ashfaq Ul Hassan MBBS MS 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 Abstract: E MAIL: [email protected] Myocardial reperfusion injury is defined as restoration of coronary blood flow after an ischemic episode, which can cause injury and death of cardiac myocyte that were considered viable before reperfusion. Due to increase in the cardiovascular accidents such as Myocardial infarction as well as increase in the number of procedures involved with effective restoration of blood supply to the myocardium, the phenomenon of reperfusion injury has gained greater recognition. The unexplained worsening condition of some patients in coronary care units can be explained by the reperfusion injury Reperfusion of coronary flow is necessary to resuscitate the ischemic or hypoxic myocardium. Timely reperfusion facilitates cardiomyocyte salvage and decreases cardiac morbidity and mortality. Reperfusion of an ischemic area may result, however, in paradoxical cardiomyocyte dysfunction, the pathogenesis of which has been tried to be simplified in this article along with some treatment options. This form of myocardial injury, which by itself can induce cardiomyocyte death and increase infarct size, may in part explain why, despite optimal myocardial reperfusion, the rate of death after an acute myocardial infarction approaches 10%, and the incidence of cardiac failure after an acute myocardial infarction is almost 25%." Myocardial reperfusion leads to 4 types of dangerous phenomenon: myocardial stunning, no-reflow phenomenon, reperfusion arrhythmias, and lethal reperfusion injury Aim: The aim of this article is to learn more about reperfusion injury, what pathophysiological effects it has upon the already unhealthy myocardium and how it can lead to more serious heart disease. The article also tries to outline some new treatment options available for this pathophysiological which is itself as a result of unavoidable treatment necessary for restoring the viability of myocardial tissue. Finally, every physician who has successfully resuscitated critically ill patients knows the frustration of a multiorgan failure syndrome in which reperfusion injury also plays a role. Key Words: Reperfusion, Myocardial infarction, Endothelial Dysfunction, Coronary 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 Discussion: Modalities for reperfusion that account for reperfusion injury are : Thrombolysis, Percutaneous coronary intervention (PCI), Coronary artery bypass grafting (CABG), Cardiac transplantation. Survival of Myocardium The myocardium can tolerate brief periods (up to 15 minutes) of severe and even total myocardial ischemia without resultant cardiomyocyte death. Although the cardiomyocytes suffer ischemic injury, the damage is reversible initially with prompt arterial reperfusion. With increasing duration and severity of ischemia, however, greater cardiomyocyte damage can develop, with a predisposition to a spectrum of reperfusion-associated pathologies, collectively called reperfusion injury. Reperfusion injury results in myocyte damage through Myocardial stunning, Micro vascular and endothelial injury, and Irreversible cell damage or necrosis Three theories have been put forward to explain reperfusion injury: Oxidative stress resulting in a burst of oxygen-radical formation, which can cause membrane damage; The energy paradox, which suggests that restarting energetic mitochondrial machinery results in myofibrillar hypercontracture, cytoskeleton fragility and membrane rupture The role of inflammation, which addresses the effects of leucocyte accumulation and activation. Manifestations of Reperfusion injury: Reperfusion causes marked endothelial cell dysfunction, which results in (1) Vasoconstriction, (2) Platelet and leukocyte activation, (3) Increased oxidant production (4) Increased fluid and protein extravasation (discussed below). (5) Limit adequate perfusion after reperfusion, a phenomenon termed “no-reflow”. Reperfusion injury of the myocardium is a complex phenomenon consisting of several independent etiologies. During the earliest phase (ie, minutes) of reperfusion, development of cardiomyocyte contracture seems to be the primary cause for necrotic cardiomyocyte injury. Thereafter (ie, minutes to hours), various additional causes can lead to a further increment of cell death either by necrosis or apoptosis, and vascular failure may further aggravate cardiomyocyte injury. When contracture affects the entire heart, as may occur after global ischemia, it has been termed as the “stone heart phenomenon”. Stone hearts are known to cardiac surgeons as a result of prolonged ischemia or unsatisfactory attempts to apply cardioplegic protection. Stone hearts may be caused by contracture developing either during ischemia or reperfusion. Major mediators of lethal reperfusion injury: Generation of reactive oxygen species. Intracellular Ca2+ overload. 94 95 96 97 Rapid restoration of physiologic pH. Inflammation. The most frequently cited include oxygen free radicals, intracellular calcium overload, endothelial and micro vascular dysfunction, and altered myocardial metabolism (Granger, 1999; Park and 98 Lucchesi, 1999; Agati, 1999).1, 2, 3 99 100 101 102 103 104 105 Oxygen Free Radicals: The production of excessive quantities of reactive oxygen species is an important mechanism of reperfusion injury. Molecular oxygen, when reintroduced into a previously ischemic myocardium, undergoes a sequential reduction leading to the formation of oxygen free radicals. A landmark study by Bolli and colleagues showed that potent oxidant radicals, such as superoxide anion, hydroxyl radical, and peroxynitrite, are produced within the first few minutes of reflow and 4. play a crucial role in the development of reperfusion injury (Bolli et al., 1989) In trials use of 106 antioxidants have shown to be beneficial for reperfusion injury but the same experiments in animal 107 models have not been encouraging to the level of therapeutic efficacy. 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 Endothelial Dysfunction and Micro vascular Injury Reperfusion results in marked endothelial cell dysfunction. Endothelium-dependent vasodilatation is impaired, whereas the responses to endothelium-dependent vasoconstrictors are exaggerated. Increased production of potent vasoconstrictors, such as endothelin-1 and oxygen free radicals, increases coronary vasoconstriction and reduces blood flow. Furthermore, endothelial dysfunction facilitates the expression of a prothrombotic phenotype characterized by platelet and neutrophil activation, important mediators of reperfusion injury 137 Changes in intracellular calcium Changes in intracellular calcium homeostasis play an important role in the development of reperfusion injury. Ischemia and reperfusion are associated with an increase in intracellular calcium; this effect may be related to increased sarcolemmal calcium entry through L-type calcium channels or may be secondary to alterations in sarcoplasmic reticulum calcium cycling. In addition to intracellular calcium overload, alterations in myofilament sensitivity to calcium have been implicated in reperfusion injury Altered Myocardial Metabolism Increased anaerobic metabolism with increased lactate release persists during reperfusion, suggesting a delayed recovery of normal aerobic metabolism. Increased lactate levels themselves have an adverse effect on recovery process as well as depletion of glutathione peroxidase. Glutathione peroxidase is an important enzyme in the degradative cascade of reactive oxygen free radicals, Proposed effective outcome strategies: 1.Superoxide dismutase : Superoxide dismutase is an endogenous free radical scavenger that converts toxic oxygen derived free radicals to hydrogen peroxide. Studies confirm the protective effects of superoxide dismutase against ischemia-reperfusion injury. In addition, its deficiency results in a dramatic susceptibility to ischemic injury. The incidence of reperfusion arrhythmias was not affected by (Superoxide dismutase) SOD treatment. It is concluded that. SOD treatment at the beginning of reperfusion neither significantly reduces infarct size nor diminishes the 5 incidence of reperfusion arrhythmias in this preparation (Klein et al., 1988). 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 2. Magnesium has properties of myocardial cytoprotection, the pathophysiological explanations of which in acute myocardial infarction include prevention of arrhythmia, antiplatelet effect, prevention of reperfusion injury, and coronary vasodilation. Although several studies have evaluated the role of magnesium administration in patients with acute myocardium infarction, the clinical impact of such a therapy in this condition has been controversial, largely as a result of conflicting data from randomized controlled trials. The data available to date do not favor the routine administration of intravenous magnesium in patients with myocardial infarction, but this should not preclude magnesium administration to replenish low serum magnesium concentrations or use of magnesium sulfate for treatment of torsade de pointes in patients with myocardial 6 infarction (Gowda and Khan, 2004). 3 Nitric oxide (NO) has been known to play various functional and pathological roles as an intracellular or intercellular messenger in the heart. In one study, was investigated whether NO produced during ischemia was involved in the coordination of ATP supply and demand, and also in protection from cell death using cultured cardiac myocytes. Unexpectedly, the survival rate of myocytes for 3 h simulated ischemia (SI) was increased as compared with that for 2 h SI at 24 h after reperfusion. Ischemia/reperfusion-induced death of cardiac myocytes: possible involvement of nitric oxide in the coordination of ATP supply and demand during ischemia (Davies et al., 157 2005).7 158 159 160 161 162 163 164 165 166 4 Combined use of controlled reperfusion, cariporide, and diazoxide decreases myocyte necrosis and loss of systolic function compared with an untreated control group. Combination treatment has the potential to improve the results of cardiac surgery, however further improvements are needed before clinical application. In one study, sodium-proton exchange inhibition with cariporide decreased infarct size and improved post-ischemic contractile function. This is similar to the effects noted in clinical trials; this was also an important component for the benefit from combination therapy at least in this experimental model. The beneficial effect of controlled reperfusion on contractile function was less than the benefit of cariporide, but controlled reperfusion has the advantage of being used after rather than before ischemia (Davies 167 et al., 2005). 8 168 169 170 171 172 173 174 175 5 KAI-9803 targets a specific Protein Kinase C isozyme, (delta-PKC), which has been found to activate a cascade of events causing cell injury and death during reperfusion injury. Reperfusion injury occurs when myocardial and endothelial cells undergo necrosis and apoptosis after the reintroduction of blood flow to the ischemic areas following heart attack.. Selective inhibition of the delta-PKC isozyme by KAI-9803 prevents damage to the mitochondria and inhibits both necrosis and apoptosis during reperfusion injury. In preclinical studies, treatment with KAI-9803 resulted in a 70 percent reduction in infarct size, an improvement in heart function, restoration of 176 intracellular energy generation, and protection of myocardial and endothelial cells (KAI, 2004).9 177 178 179 180 6 Therapeutic hypothermia: This method is emerging as a novel way to reduce final myocardial infarct size. Therapeutic cooling showed a significant ST-segment resolution in the group with anterior myocardial infarction .Patients with anterior-wall infarction and a core body temperature 181 182 of 35°C or less before angioplasty had a reduction in the final infarct size, as compared with 10. Because of the large human thermal mass, others with higher temperatures (Maeng et al., 2003) 183 induction of generalized hypothermia is slow and the technique has encountered considerable side 184 effects. The aim was to develop and validate a method for regional cooling during myocardial 185 reperfusion using hypothermic autologous blood. 186 187 188 189 190 191 192 193 194 195 196 197 198 7 Exochelins : A major cause of reperfusion injury is the iron-mediated generation of hydroxyl radical .In a study was explored the capacity of novel iron chelators called “exochelins” to prevent reperfusion injury. Exochelins , siderophores of Mycobacterium tuberculosis, are unique iron chelators because they are lipid soluble, and hence able to enter cells rapidly. Exochelins prevented ⋅OH formation. Desferri-exochelins prevented oxidative injury to cultured cardiac myocytes, and did so more rapidly and effectively than the nonlipid soluble iron chelator deferoxamine. The capacity of various desferri-exochelins to protect myocytes from oxidative injury varied directly with their solubility in lipid. Desferri-exochelins dramatically improved systolic and diastolic left ventricular function, preserved coronary flow, reduced release of the cardiac enzyme lactic dehydrogenase, and reduced myocardial concentrations of ⋅OH metabolites. Thus, highly diffusible desferri-exochelins block injury caused by ⋅OH production and have potential for the treatment of reperfusion injury (Horwitz et al., 1998). 11 199 200 201 202 203 204 205 206 207 208 209 210 8 Cyclosporine: The administration of cyclosporine at the time of reperfusion was associated with a reduction in infarct size in a small pilot study Although these data are preliminary and require confirmation in larger clinical trials, the results suggest that cyclosporine has the potential to become an effective treatment for reperfusion injury. A pore in the mitochondria of the myocyte opens during reperfusion, triggering a series of events that lead to cell death. Cyclosporine is a potent inhibitor of the opening of this pore, and experimental evidence from animal studies suggests that cyclosporine attenuates lethal myocardial injury that occurs at the time of reperfusion (http://www.theheart.org/article/885241.do). 12 The treatment options are not generalized and are patient specific and no one should adhere to any particular treatment without the consultation of a well qualified consultant. 211 Results: 212 The pathogenesis of reperfusion injury is complex and multiple pathways are involved. The concept of 213 reperfusion injury is gaining recognition and different strategies are evolving ranging from simple 214 high dose antioxidant therapy to complex induction of hypothermia with trials of a variety of drugs. 215 Animal models have demonstrated therapeutic efficacy but in real clinical situations the drugs have 216 not proven to be of clinical significance. However need for more effective drugs targeting multiple 217 pathways of cell death and preventing apoptosis simultaneously s is the needand a path forwards from 218 219 220 current levels of research is needed. 221 References: 222 223 1 Granger DN. Ischemia-reperfusion: mechanisms of microvascular dysfunction and the influence of risk factors for cardiovascular disease. Microcirculation. 1999; 6: 167–178 224 225 2 Park JL, Lucchesi BR. Mechanisms of myocardial reperfusion injury. Ann Thorac Surg. 1999; 68: 1905–1912 226 227 3 Agati L. Microvascular integrity after reperfusion therapy. Am Heart J. 1999; 138(2 Pt 2): S76– S78 228 229 230 4 Bolli R, Jeroudi MO, Patel BS, et al. Direct evidence that oxygen-derived free radicals contribute to postischemic myocardial dysfunction in the intact dog. Proc Natl Acad Sci U S A. 1989; 86: 4695–4699 231 232 233 234 5 Dr. H. H. Klein, S. Pich, S. Lindert, A. Buchwald, K. Nebendahl, H. Kreuzer, Intracoronary superoxide dismutase for the treatment of “reperfusion injury” A blind randomized placebocontrolled trial in ischemic, reperfused porcine hearts Journal Basic Research in Cardiology Issue Volume 83, Number 2 / March, 1988 235 236 6 R.Gowda, and I.Khan, , 2004, Magnesium in treatment of acute myocardial infarction, International Journal of Cardiology, 96(3):467-9. 237 7 Journal of Molecular and Cellular Cardiology. 40(1), 2006, 35-46Kawahara, Koichi 238 239 240 8 Davies JE, Digerness SB, Killingsworth CR, Zaragoza C, Katholi CR, Justice RK, Goldberg SP, Holman WL., 2005, Multiple Treatment Approach to Limit Cardiac Ischemia-Reperfusion Injury, Ann Thorac Surg 80(4):1408-16. 241 242 243 9 KAI Pharmaceuticals Initiates Phase I/II Clinical Trial for Treatment of Reperfusion Injury; Lead Drug Candidate KAI-9803 Receives 'Fast Track' Designation from the FDA, Business Wire, Sept 28, 2004 244 245 246 247 10 Maeng M, Kristiansen SB, Mortensen UM, Andersen HR., 2003, Myocardial cooling for reperfusion injury protection achieved by organ specific hypothermic autologous perfusion MAENG Michael ; KRISTIANSEN Steen Buus Scandinavian cardiovascular journal, 37(5): 297-303 248 249 250 11 Horwitz LD, Sherman NA, Kong Y, Pike AW, Gobin J, Fennessey PV, Horwitz MA., 1998, Lipophilic siderophores of Mycobacterium tuberculosis prevent cardiac reperfusion injury, Sherman PNAS April 28, vol. 95 no. 9 5263-5268 251 252 12 Cyclosporine reduces reperfusion injury, ACUTE CORONARY SYNDROMES Sue Hughes July 30, 2008 | Sue Hughes 253