Authors
Duane S Pinto, MD, MPH
C Michael Gibson, MS, MD
Joanna J Wykrzykowska, MD
Section Editor
Bernard J Gersh, MB, ChB, DPhil, FRCP, MACC
Deputy Editor
Gordon M Saperia, MD, FACC
Disclosures
All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Mar 2013. | This topic last updated: Apr 22, 2012.
Effective therapies to reduce or prevent reperfusion injury have proven elusive. Despite an
improved understanding of the pathophysiology of this process and encouraging preclinical
trials of multiple agents, most of the clinical trials to prevent reperfusion injury have been
disappointing [ 4,5 ]. Despite these problems, adjunctive therapies to limit reperfusion injury
remain an active area of investigation.
This card will discuss the pathophysiology and manifestations of reperfusion injury, as well as
potential therapeutic strategies. More general discussions of the clinical use of primary PCI and
thrombolytic therapy in acute myocardial infarction are presented separately. (See "Primary
percutaneous coronary intervention in acute ST elevation myocardial infarction: Determinants
of outcome" and "Fibrinolytic therapy in acute ST elevation myocardial infarction: Initiation of
therapy" .)
Reperfusion arrhythmias
Endothelial cell damage leading to microvascular dysfunction
Myocardial stunning
Reduced intracellular pH
Prior to cell death there is a period during which the ischemic myocyte is viable, but vulnerable
to further injury if blood flow is restored (ie, reperfusion injury). During this period, the
reintroduction of oxygen and energy into an abnormal cellular environment triggers additional
events that produce further myocyte damage.
Myocyte hypercontracture
Platelet activation [ 7 ]
Complement activation [ 8 ]
The increased osmotic load induced by the flow of constituents into the mitochondrial
body causes the mitochondrion to swell and ultimately forces rupture of the outer
membrane. The subsequent release of mitochondrial proteins stimulates apoptosis.
(See 'Apoptosis' below.)
Myocyte hypercontracture Restoration of blood flow to previously ischemic cells can result
in myocyte hypercontracture [ 15 ]. Factors that contribute to hypercontracture include:
Mechanisms by which hypercontracture can result in additional cardiac injury include the
following [ 18 ]:
Myocytes tearing away from the tight intercellular junctions during hypercontracture
can cause damage to the sarcolemma of adjacent cells.
Oxygen and other free radicals Free radicals are produced within minutes of reperfusion
and continue to be generated for hours after the restoration of blood flow to ischemic tissue
[ 19 ]. These include:
Several mechanisms have been proposed for the development of these free radicals including
xanthine oxidase, activated neutrophils, electron leakage from ischemic mitochondrion,
catecholamine oxidation, as well as cyclooxygenase and lipoxygenase enzymes [ 20 ]. The
relative importance of each of these pathways is not clear, but they are probably interrelated
and may potentiate one another.
Free radicals damage myocytes directly by altering membrane proteins and phospholipids
[ 21 ]. Because these membrane constituents play crucial roles as receptors, enzymes, and ion
channels, free radical injury can lead to fatal metabolic and structural derangements. As an
example, oxygen radicals injure the sarcolemma and may impair contractile function of the
myocyte on this basis [ 20 ]. The role for free radicals as a source of significant myocardial
damage is further supported by studies showing that free radical scavengers, such as
superoxide dismutase, administered during thrombolytic therapy help preserve myocardial
function [ 22 ]. Finally, reactive oxygen species stimulate leukocyte activation, chemotaxis, and
leukocyte-endothelial adherence [ 21].
New expression of adhesion molecules, diminished release of nitric oxide (NO), and
changes in the actin cytoskeleton allow greater vascular permeability, giving
neutrophils access to vulnerable myocytes [ 26 ].
Platelet activation Circulating platelets become activated early during reperfusion, and
their degree of activation is related to the duration of preceding ischemia. Furthermore, the
degree of platelet activation was related to the extent of reperfusion injury. These
observations support the possibility of an important role for activated platelets in reperfusion
injury.
Complement activation Complement activation appears to play a role in the "no-reflow"
phenomenon and possibly reperfusion injury [ 8 ]. Terminal complement cascade species
directly injure the endothelium, rendering it incapable of elaborating vasodilatory compounds
such as NO. This perpetuates a cycle of vasoconstriction and reduction in microvascular
perfusion leading to apoptosis not only within the infarct area, but also in the border zone
[ 10 ].
Apoptosis Apoptosis, or programmed cell death, has a number of features that distinguish
it from necrosis:
Apoptosis can occur in response limited molecular damage that is otherwise not
sufficient to cause a fatal loss of cellular integrity.
While ischemic damage occurs principally through necrosis, reperfusion injury may also act
through apoptosis [ 30-32 ]. In a rabbit model, markers of apoptosis found in reperfused tissue
were not present in normal tissue or tissue injured solely by ischemia [ 31 ]. Others have
reported the appearance of apoptotic cells in the peri-necrotic zone during reperfusion [ 33 ]
and suggested that understanding the different contributions of necrosis and apoptosis to
reperfusion injury may help identify novel treatment strategies [ 34 ].
A link between reperfusion and apoptosis is supported by studies demonstrating the role of
magnesium-dependent superoxide dismutase and oxygen radical formation in the activation of
pro-apoptotic factors. An apoptosis repressor is capable of inhibiting this process and reducing
the extent of myocardial infarction [ 35,36 ].
Ventricular tachycardia and ventricular fibrillation can also occur after thrombolytic therapy,
however these arrhythmias are more likely to reflect persistent occlusion and infarction than a
reperfused infarct-related artery [ 38 ]. The pathogenesis of reperfusion arrhythmias is
discussed extensively elsewhere. (See "Pathogenesis of ventricular tachycardia and ventricular
fibrillation during acute myocardial infarction" .)
Features associated with reperfusion injury that may contribute to microvascular dysfunction
include:
Platelet activation, which has been shown to contribute to microvascular injury and
reperfusion injury [ 7 ]. Thus, the beneficial effects of aggressive antiplatelet therapies,
including glycoprotein IIbIIIa inhibitors, may be due in part to prevention of
microvascular dysfunction [ 41-44 ]. (See 'Platelet activation' above.)
Because stunning can recover with time, inotropic agents can be used in the short-term to
improve cardiac function and organ perfusion. Several agents that may prevent its occurrence
are being investigated. (See 'Potential therapies' below.)
Myocyte death The most concerning consequence of reperfusion injury is myocyte death.
Animal data suggest that up to 50 percent of an infarct size may be attributable to reperfusion
injury [ 48,49 ]. This observation highlights the potential value of therapies that reduce or
eliminate reperfusion injury. Despite an improved understanding of the processes associated
with reperfusion injury, there is still uncertainty regarding the magnitude and significance of
myocyte death associated with reperfusion.
Potential reasons for the ultimate failure of agents that appeared promising in preclinical trials
include the following:
It may not be possible to administer a therapy at the optimal time in clinical practice
(eg, some agents may perform best if patients are pretreated).
Vasodilation
Based upon these properties, adenosine has been tested in both preclinical and clinical
studies. The demonstration of cardioprotective effects of adenosine in animal models [ 55-57 ]
provided the rationale for randomized clinical trials. The following are representative studies
that have shown mixed results:
In the AMISTAD trial, 236 patients with an acute MI treated with fibrinolysis were
randomly assigned to adenosine or placebo [ 58 ]. At a follow-up of six days, infarction
size was significantly smaller in patients assigned to adenosine treatment, a benefit
that was limited to those with anterior infarctions.
In the PREVENT-ICARUS trial, 260 patients undergoing elective PCI were randomly
assigned to either intracoronary adenosine or placebo [ 61 ]. There was no significant
difference between the two groups in the primary end point of a periprocedural
increase in troponin I > three times the upper limit of normal.
In summary, the administration of either intravenous or intracoronary adenosine has not been
established as an effective therapy to reduce the risk of clinical events after PCI in either stable
patients or those with acute coronary syndromes. Adequately powered studies to evaluate
whether intracoronary adenosine leads to improved clinical outcomes are unlikely to be
performed
Several members of the sydnonimine class of NO donors have reduced infarct size in
an animal model [ 63,64 ]. These compounds spontaneously decompose to form NO.
ACE inhibitors may have several beneficial actions in reperfusion, including the
scavenging of free radicals, vasodilation of the coronary bed, and elevation of
prostacyclin and bradykinin levels [ 65 ]. In an animal model, ACE inhibitors enhanced
coronary blood flow, but failed to produce any improvement in regional ventricular
function [ 66 ].
Ion channel modulation Changes in intracellular and extracellular ion concentrations and
pH play a role in some of the processes involved in reperfusion injury. Thus, ion channels are
an attractive target for novel treatments of reperfusion injury. (See 'Mitochondrial
dysfunction' above and'Myocyte hypercontracture' above.)
The potential role of ion channel modulation in the treatment of reperfusion injury is
illustrated by the following observations:
GIK solution Glucose-insulin-potassium (GIK) therapy has been tested as a potential way to
stimulate anaerobic glycolysis, increase ATP levels, and decrease the free fatty acid release.
Although initial trials suggested a benefit with this therapy, larger trials including CREATE-ECLA
and DIGAMI 2 showed no benefit with GIK.
Similarly disappointing were results reported for the complement inhibitor pexelizumab [ 86-
88 ]. This may be due to the complexity and the multiple steps of immune activation involved
in reperfusion injury. Part of the success of the intracoronary glycoprotein IIb/IIIa inhibitor
administration in PCI may be also due to its effect on leukocyte integrin receptors [ 89 ].
(See 'Glycoprotein IIb/IIIa inhibitors' above.)
The results have been mixed [ 90 ] and investigation remains focused at the animal level.
Erythropoietin [ 25,91-94 ], estrogen [ 95,96 ], heme oxygenase1 [ 97 ], and hypoxia induced
factor1 (HIF-1) [ 98 ] have all been shown to reduce reperfusion injury, and investigation is
ongoing.
Magnesium The role of magnesium in minimizing reperfusion injury was first evaluated in a
large placebo controlled trial in the Fourth International Study of Infarct Survival (ISIS-4) [ 99 ].
Magnesium infusions were administered for 24 hours to patients presenting with suspected
acute myocardial infarction, but failed to show any benefit. However, controversy over the
role of magnesium has persisted because the infusion was not started until after the time of
reperfusion. The subsequent MAGIC trial showed that magnesium infusion has no effect on
mortality even when administered at the time of reperfusion [ 100 ]. (See "Intravenous
magnesium sulfate in acute myocardial infarction" .)
Cyclosporine In addition to its well know immunosuppressive effects, cyclosporine can limit
reperfusion injury by potently inhibiting opening of the mitochondrial permeability-transition
pore [ 101 ]. A pilot study of 58 patients showed that a single intravenous bolus of cyclosporine
administered before primary PCI results in a reduction of Creatinine kinase by 44 percent and
in a subset of 27 patients, this translated into a 20 percent reduction in infarct size as
measured by delayed enhancement cardiac MR [ 102 ].
Ischemic postconditioning Ischemic postconditioning refers to the ability of a series of brief
coronary artery occlusions after a severe ischemic insult to protect against ischemic-
reperfusion injury of the myocardium. In animal models, ischemic postconditioning is almost
as effective as ischemic preconditioning and involves similar pathogenetic mechanisms
[ 103,104 ]. (See "Definition and pathogenesis of ischemic preconditioning", section on
'Ischemic preconditioning' .)
When applied to patients with ST-segment elevation myocardial infarction, this interventional
technique involves repeated short balloon inflations at low pressure to temporarily occlude
the infarct-related artery after patency has been achieved.
Forearm studies Initial insights into the potential timing of ischemic postconditioning in
humans were provided by a forearm model of ischemic postconditioning [ 108 ]. After 20
minutes of sustained forearm ischemia, and at the onset of 20 minutes of reperfusion, an
ischemic postconditioning protocol was applied comprising three 10 or 30 second cycles of
alternate ischemia and reperfusion. The following findings were observed:
Primary PCI The potential efficacy of ischemic postconditioning in humans has been
illustrated in three randomized, pilot trials of (17, 30 and 38) patients who received successful
primary PCI for ST-segment elevation myocardial infarction. Patients who received ischemic
post conditioning, as opposed to usual care, were seen to derive the following benefits in
these studies:
Greater attenuation of ST-segment elevation and improved distal coronary artery flow
[ 110 ].
Ischemic postconditioning has potential clinical applications since it might be performed at the
time of reperfusion by percutaneous coronary intervention for acute myocardial infarction or
at the time of coronary artery bypass graft surgery.
Another mechanical solution that has shown some effectiveness in animal models, in surgical
patients and patients treated with thrombolysis is a Percutaneous Intermittent Coronary Sinus
Occlusion device that may work by improving collateral recruitment, increased NO production
and wash-out of oxidative radicals [ 114 ].
The etiology of reperfusion injury is complex, involving abnormalities in energy production and
utilization, disturbance of cellular architecture, and possibly leukocyte, platelet, and
complement activation. (See 'Pathophysiology' above.)
Therapies specifically targeted to the prevention reperfusion injury are not available for clinical
use. Despite ongoing improvements in the understanding of the underlying mechanisms and a
wide range of potential treatments under investigation, effective therapies remain elusive.
(See 'Potential therapies'above.)