Ischemic reperfusion injury of the heart

Ischemic reperfusion injury of the heart

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.

INTRODUCTION Primary reperfusion therapies, including primary percutaneous coronary

intervention (PCI) and thrombolysis, are the standard of care for the treatment of acute
coronary syndromes. Prompt restoration of blood flow to ischemic myocardium limits infarct
size and reduces mortality. Paradoxically, however, the return of blood flow can also result in
additional cardiac damage and complications, referred to as reperfusion injury [ 1-3 ]. Such
damage is more likely when reperfusion therapy is delayed.

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" .)

DEFINITION Reperfusion injury refers to myocardial, vascular, or electrophysiological

dysfunction that is induced by the restoration of blood flow to previously ischemic tissue.
Manifestations include:

Reperfusion arrhythmias
 Endothelial cell damage leading to microvascular dysfunction

Myocardial stunning

Myocyte death and infarction

PATHOPHYSIOLOGY When blood flow to cardiac myocytes is disrupted by occlusion of a

coronary artery, a series of events is set in motion that results in cellular injury and death [ 6 ].
These processes are largely related to energy production and utilization and include the
following:

Reduced energy production with a fall in intracellular ATP levels

A transition from aerobic to anaerobic energy utilization

An accumulation of the products of anaerobic metabolism

Reduced intracellular pH

These phenomena lead to dramatic distortions in myocyte physiology and architecture,

including mitochondrial and sarcolemmal injury and alterations in intracellular calcium
handling. Initially, the damage is reversible, and restoration of blood flow during this period
will lead to recovery of normal structures and function. However, if ischemia persists for an
extended period of time, this damage becomes irreversible and cell death occurs.

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.

Factors that contribute to reperfusion injury include the following:

Damage to cellular and organelle membranes, including mitochondria

Myocyte hypercontracture

Free radical formation

Aggregation of leukocytes and inflammatory mediators

Platelet activation [ 7 ]

Complement activation [ 8 ]

Activation of the pro-apoptotic signaling cascade [ 9,10 ]

Endothelium damage and vasoconstriction

Mitochondrial dysfunction The mitochondrial membrane is ordinarily impermeable to

most ions and metabolites. During periods of ischemia, however, several changes alter
mitochondrial membrane permeability. These include:

Elevated intra-mitochondrial calcium concentrations

Reduced levels of adenine nucleotide concentrations

Oxidative stress induced by ischemia.

In combination, these factors prime a non-specific pore in the inner mitochondrial membrane
called the mitochondrial permeability transition pore (MPTP) [11 ]. At the time of reperfusion,
with the restoration of blood flow and the normalization of cellular pH, this pore opens and
allows proteins to move freely across the membrane, with two important consequences:

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.)

Disruption of the ionic gradient across the mitochondrial membrane uncouples

oxidative phosphorylation and results in the hydrolyzing of ATP instead of its synthesis.
The subsequent fall in ATP levels further disrupts ionic and metabolic homeostasis and
leads to the activation of degradative enzymes [ 11 ].

In addition, Poly(ADP-ribose) polymerase-1 (PARP-1) overactivation and its effect on

Mitochondrial Respiratory Chain Complex I may also play a role in reperfusion injury. Excessive
PARP-1 activation can impair the function of other cellular organelles, including mitochondria
and accelerate production of reactive oxygen species [ 12 ]. PARP inhibitors have been shown
to reduce infarct size in animal models [ 13,14 ].

Myocyte hypercontracture Restoration of blood flow to previously ischemic cells can result
in myocyte hypercontracture [ 15 ]. Factors that contribute to hypercontracture include:

Increased intracellular calcium During an ischemic period, intracellular calcium

increases due to impaired calcium cycling and sarcolemmal damage [ 16 ]. This process
can be exacerbated with reperfusion. The restoration of a normal extracellular pH
after reperfusion produces a hydrogen gradient across the cell membrane.
The sodium/hydrogen (Na/H) exchanger is activated and causes a net influx of sodium
into the cytosol. Under normal conditions, the resulting increase in intracellular
sodium would be corrected by the sodium/potassium (Na/K) ATPase. However, this
channel may not function normally after a period of ischemia due to a lack of energy
and structural damage. In this setting, the sodium excess causes
thesodium/calcium (Na/Ca) channel to run in reverse, producing an influx of calcium
into the already calcium-overloaded cell.

Reoxygenation and reenergization of the myocyte Return of blood flow provides

oxygen and energy that stimulates myofibrils, and, in the setting of increased calcium,
contraction is uncontrolled and excessive.

Restoration of normal acid-base status Reduced cytosolic pH during ischemia

inhibits myofibrillar contraction [ 17 ]. With restoration of blood flow, a normal pH is
rapidly restored in the extracellular and then the intracellular space, removing the
acidic inhibition to contraction.

Mechanisms by which hypercontracture can result in additional cardiac injury include the
following [ 18 ]:

Cytoskeletal elements can be significantly damaged, ultimately resulting in cell death.

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:

Superoxide anion (O2)

Hydrogen peroxide (H2O2)

Hypochlorous acid (HOCl)

Nitric oxide-derived peroxynitrite

Hydroxyl radical (OH)

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].

Leukocyte aggregation Multiple factors induced by ischemia and reperfusion trigger

leukocyte aggregation and activation:

Neutrophils are stimulated after plasma membrane phospholipase A2 is activated to

form arachidonic acid, which is an important precursor in the inflammation pathway
[ 21 ].

Cytokines and complement are released from damaged myocardium [ 23-25 ].

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 ].

Neutrophil accumulation in non-perfused microvessels may contribute to the "no-reflow"

phenomenon [ 27 ]. Once in the extravascular space, leukocytes can release proteases and
elastases that destroy the cell membrane and cause cell death [ 28,29 ]. However, the roles of
the various inflammatory mediators are complex and incompletely understood. Although they
play a role in reperfusion injury, some also appear to have cardioprotective effects [24,25 ].

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.

Apoptosis is an energy-dependent process.

Apoptosis is an organized sequence of events triggered by specific signals.

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 ].

CLINICAL MANIFESTATIONS Manifestations of ischemic reperfusion injury include

arrhythmias, microvascular dysfunction, myocardial stunning, and myocyte death.

Arrhythmias Reperfusion arrhythmias are common in patients treated with thrombolytic

therapy, primary PCI, and cardiac surgery. The arrhythmia that is most commonly associated
with reperfusion is an accelerated idioventricular rhythm (AIVR). (See "Pathogenesis of
ventricular tachycardia and ventricular fibrillation during acute myocardial infarction", section
on 'Reperfusion arrhythmias' .)

Reperfusion arrhythmias may be mediated by mitochondrial dysfunction. Following prolonged

ischemia, the mitochondrion may not be able to restore or maintain its inner membrane
potential, thereby destabilizing the action potential and increasing susceptibility to
arrhythmias [ 37 ]. (See 'Mitochondrial dysfunction' above.)

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" .)

Microvascular dysfunction Preservation of the coronary microvasculature is essential to

the ultimate recovery of myocardial function [ 39 ]. Microvascular dysfunction, or the "no
reflow" phenomenon, refers to the impairment of resting blood flow within the post-ischemic
vasculature. The clinical significance of microvascular dysfunction lies in its association with
worse cardiovascular outcomes [ 40 ]. (See "Suboptimal reperfusion after primary
percutaneous coronary intervention in acute ST elevation myocardial infarction", section on
'No-reflow phenomenon' .)

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.)

Complement activation (see 'Complement activation' above).

Myocardial stunning Myocardial stunning refers to transient, myocardial dysfunction that

occurs after reperfusion, as opposed to dysfunctional hibernating myocardium secondary to
ongoing ischemia. It is thought to result from persistent anaerobic metabolism that continues
after reperfusion [ 20]. Myocardial stunning is also associated with microvascular injury and
better levels of regional and global myocardial function are seen when the microvasculature is
structurally intact [ 39,45-47 ]. (See "Pathophysiology of stunned or hibernating
myocardium" .)

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.

If a substantial percentage of myocardial injury during an acute MI occurs after reperfusion, a

central question is whether reperfusion hastens the development of injury already incurred
during the preceding ischemic period, or does reperfusion cause additional damage beyond
that accounted for by the ischemia [ 50 ]. Because it is technically impossible to follow the
progression of injury in the myocardium before and after reperfusion, studies have focused on
modifying the conditions of reperfusion to see if there is any effect on the extent of end-
damage [ 51 ].

POTENTIAL THERAPIES Although the pathophysiology of reperfusion injury lends itself to

potential therapeutic strategies, few treatments have found their way into clinical practice.

Potential reasons for the ultimate failure of agents that appeared promising in preclinical trials
include the following:

Multiple mechanisms contribute to the consequences of myocardial infarction and

reperfusion injury. Thus, the impact of a therapy targeted to single component of the
pathophysiology may be diluted in clinical practice.

Some mechanisms, such as neutrophil stimulation, may be mediators of injury, but

also play important roles in the healing process [ 23 ]. Targeting such mechanisms
 would have complex and unpredictable implications on outcomes. (See 'Leukocyte
aggregation' above.)

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).

The presence of comorbidities, such as diabetes and hypercholesterolemia, may

impact the efficacy of a new treatment.

Identification of patients at highest risk of reperfusion injury may be an important component

of bringing therapies into clinical practice. As an example, myocardial blush grade has been
used as a tool to evaluate myocardial level perfusion, and low blush grades correlate with
myocardial dysfunction [ 52-54]. Such tools may also allow for better clinical assessment of
therapeutic effectiveness of drugs tested in clinical trials. (See "Fibrinolytic (thrombolytic)
agents in acute ST elevation myocardial infarction: Markers of efficacy", section on 'TIMI
myocardial perfusion grade' .)

Glycoprotein IIb/IIIa inhibitors Platelet activation contributes to microvascular injury and

reperfusion injury in acute MI [ 7 ]. (See 'Platelet activation' above.) Glycoprotein IIbIIIa
inhibitors are potent inhibitors of platelet activity that improve outcomes in acute MI [ 41-44 ].
It is not known if part of the benefit of glycoprotein IIb/IIa inhibitors is due to a reduction in
reperfusion injury. (See "Suboptimal reperfusion after primary percutaneous coronary
intervention in acute ST elevation myocardial infarction", section on 'No-reflow
phenomenon' .)

Adenosine Adenosine has several properties that make it an attractive candidate to

prevent reperfusion injury. These include:

It is a substrate for ATP replenishment

Vasodilation

Platelet and neutrophil inhibition

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.

AMISTAD 2 is the largest trial of intravenous adenosine as an adjunctive therapy

during primary reperfusion for an acute MI [ 59,60 ]. This study included 2118 patients
treated with primary PCI or fibrinolytic therapy for anterior ST elevation MI. Although
infarct size was reduced with adenosine, there was no reduction in a combined clinical
end point of heart failure or overall mortality at six months.

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

Vasodilators A number of vasodilators have been investigated as potential therapies for

reperfusion injury.

Human studies with papaverine have also demonstrated success in improving

angiographically documented TIMI flow grades in epicardial arteries, however its use is
limited by occurrence of ventricular arrhythmias, especially with intracoronary
administration [ 62 ].

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 ].

Endothelin is a potent vasoconstrictor and possible mediator of the vasospastic

component of reperfusion injury. Several studies have investigated the effects of
inhibiting endothelin-1 synthesis or blocking its receptor [ 67-70 ]. Although conflicting
results have been reported, further study is ongoing.

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:

Na/H exchange inhibition Sodium/hydrogen exchange is an important regulator of

intracellular pH and calcium concentration. Blockade of this exchange reduces calcium
uptake and helps to preserve cellular architecture [ 71 ]. Several in vitro and animal
studies have suggested that inhibition of sodium/hydrogen exchange is effective in
reducing reperfusion injury and infarct size [ 71-74 ]. However, in a two-stage
randomized trial including a total of 1389 patients, the sodium/hydrogen exchange
inhibitor eniporide did not improve infarct size or clinical outcome [ 75,76 ].

Ranolazine Ranolazine is effective in the treatment of chronic angina, and may be

effective in reperfusion injury and limit infarct size in acute myocardial infarction [ 77 ].
Ranolazine is an inhibitor of the late sodium channel, and via this mechanism
decreases sodium dependent intracellular calcium overload during ischemia and
 reperfusion [ 78,79 ]. (See "New therapies for angina pectoris", section on
'Ranolazine' .)

K-ATP-channel openers Potassium-ATP (K-ATP) channels are involved in ischemic

preconditioning and microvascular vasodilation. In small clinical trials, K-ATP channel
openers such as nicorandil, resulted in better perfusion and left ventricular wall
motion, as well as a reduction in adverse events [ 80,81 ]. Cardiac magnetic resonance
imaging data suggest that nicorandil may improve microvascular obstruction [ 82 ].

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.

Antineutrophil and anticomplement therapy Inhibition of the accumulation and activation

of neutrophils has been correlated with a reduced infarct size in some studies, although other
trials have failed to show a benefit [ 52,83-85 ]. Unfortunately, the prolonged time from the
onset of infarction to the delivery of antineutrophil therapy such as CD18 may reduce the
ability of these agents to mitigate neutrophil-mediated cell injury [ 52 ].

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.)

Antioxidant therapy The prominent role of oxygen radicals in the pathophysiology of

reperfusion injury has prompted several studies to evaluate the efficacy of antioxidants in
reducing the damage associated with reperfusion. (See 'Oxygen and other free
radicals' 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' .)

It appears to affect cardioprotection by activating survival protein kinases of the reperfusion-

injury salvage kinase pathway [ 105,106 ]. Postconditioning reduces the number of necrotic,
apoptotic, and autophagic cells [ 107 ].

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:

Ischemic postconditioning improved endothelial function.

Both 10 and 30 second postconditioning protocols were comparably effective.

No protection was observed if application of the postconditioning protocol was

delayed for one minute, a finding that supports preclinical studies in which the
postconditioning protocol needs to be instituted within one minute of full reflow
[ 109 ].

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 ].

A significant reduction of 36 percent compared to the control group in infarct size, as

estimated from total creatine kinase release over 72 hours and a significantly
increased (2.44 versus 1.95) myocardial blush grade, a marker of myocardial
reperfusion [ 111 ]. (See "Fibrinolytic (thrombolytic) agents in acute ST elevation
myocardial infarction: Markers of efficacy", section on 'Infarct size' and "Fibrinolytic
(thrombolytic) agents in acute ST elevation myocardial infarction: Markers of efficacy",
section on 'TIMI myocardial perfusion grade' .)

A reduction in infarct size on SPECT imaging at six months and a 7 percent

improvement in ejection fraction at one year in patients assigned to ischemic
postconditioning after stenting [ 112 ].

These observations should be considered preliminary. Before postconditioning can be

recommended in patients who undergo primary PCI, additional studies are needed to confirm
efficacy in a larger number of patients, to determine the optimal protocol, to assess treatment
effect using a more accepted measure of infarct size after reperfusion (eg, SPECT imaging), and
to determine long-term outcomes [ 113 ].

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 ].

Endovascular cooling The premise of endovascular cooling is that myocardial metabolism

will be decreased at lower temperatures and thus some cardioprotection will be afforded,
analogous to cold cardioplegia used by cardiac surgeons during coronary bypass grafting.
Endovascular coils and external cooling blankets are used to bring the core temperature of a
patient down to 33 degrees Celsius during PCI for acute myocardial infarction [ 115-117 ].
COOL MI, a trial in 356 patients undergoing primary PCI, showed reduction in infarct size in the
subgroup of patients with an anterior MI.

SUMMARY Ischemic reperfusion injury is an important limitation to the efficacy of primary

reperfusion therapies in acute MI. Clinical manifestations include arrhythmias, microvascular
dysfunction, and myocyte dysfunction and death. (See 'Clinical manifestations' above.)

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.)