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Title: Reperfusion injury Pathogenesis and basis of treatment options
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Dr. Ashfaq Ul Hassan1, Dr. Sajjad Reshi2, Dr. Pervez Shah3, Dr Afeera Abida4, Dr. Zahida
Rasool5
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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
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Correspondence to:
Dr. Ashfaq Ul Hassan MBBS MS
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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
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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.
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 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
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Lucchesi, 1999; Agati, 1999).1, 2, 3
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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
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play a crucial role in the development of reperfusion injury (Bolli et al., 1989) In trials use of
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antioxidants have shown to be beneficial for reperfusion injury but the same experiments in animal
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models have not been encouraging to the level of therapeutic efficacy.
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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
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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
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incidence of reperfusion arrhythmias in this preparation (Klein et al., 1988).
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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
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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.,
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2005).7
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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
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et al., 2005). 8
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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
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intracellular energy generation, and protection of myocardial and endothelial cells (KAI, 2004).9
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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
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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)
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induction of generalized hypothermia is slow and the technique has encountered considerable side
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effects. The aim was to develop and validate a method for regional cooling during myocardial
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reperfusion using hypothermic autologous blood.
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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
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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.
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Results:
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The pathogenesis of reperfusion injury is complex and multiple pathways are involved. The concept of
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reperfusion injury is gaining recognition and different strategies are evolving ranging from simple
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high dose antioxidant therapy to complex induction of hypothermia with trials of a variety of drugs.
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Animal models have demonstrated therapeutic efficacy but in real clinical situations the drugs have
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not proven to be of clinical significance. However need for more effective drugs targeting multiple
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pathways of cell death and preventing apoptosis simultaneously s is the needand a path forwards from
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current levels of research is needed.
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References:
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1 Granger DN. Ischemia-reperfusion: mechanisms of microvascular dysfunction and the influence
of risk factors for cardiovascular disease. Microcirculation. 1999; 6: 167–178
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2 Park JL, Lucchesi BR. Mechanisms of myocardial reperfusion injury. Ann Thorac Surg. 1999;
68: 1905–1912
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3 Agati L. Microvascular integrity after reperfusion therapy. Am Heart J. 1999; 138(2 Pt 2): S76–
S78
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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
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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
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6 R.Gowda, and I.Khan, , 2004, Magnesium in treatment of acute myocardial infarction,
International Journal of Cardiology, 96(3):467-9.
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7 Journal of Molecular and Cellular Cardiology. 40(1), 2006, 35-46Kawahara, Koichi
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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.
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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
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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
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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
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12 Cyclosporine reduces reperfusion injury, ACUTE CORONARY SYNDROMES Sue Hughes
July 30, 2008 | Sue Hughes
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