European Heart Journal (2013) 34, 1714–1724 REVIEW

doi:10.1093/eurheartj/eht090

Novel therapeutic concepts

Myocardial reperfusion injury: looking beyond

primary PCI
Georg M. Fröhlich 1, Pascal Meier1, Steven K. White 1,2, Derek M. Yellon 2,

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and Derek J. Hausenloy 1,2*
1
The Heart Hospital, University College London Hospitals, 16-18 Westmoreland Street, W1G 8PH, London, UK; and 2The Hatter Cardiovascular Institute, 67 Chenies Mews,
WC1E 6HX, London, UK

Received 16 December 2012; revised 19 February 2013; accepted 26 February 2013; online publish-ahead-of-print 27 March 2013

Coronary heart disease (CHD) is the leading cause of death and disability in Europe. For patients presenting with an acute ST-segment ele-
vation myocardial infarction (STEMI), timely myocardial reperfusion using either thrombolytic therapy or primary percutaneous coronary
intervention (PPCI) is the most effective therapy for limiting myocardial infarct (MI) size, preserving left-ventricular systolic function and re-
ducing the onset of heart failure. Despite this, the morbidity and mortality of STEMI patients remain significant, and novel therapeutic inter-
ventions are required to improve clinical outcomes in this patient group. Paradoxically, the process of myocardial reperfusion can itself
induce cardiomyocyte death—a phenomenon which has been termed ‘myocardial reperfusion injury’ (RI), the irreversible consequences
of which include microvascular obstruction and myocardial infarction. Unfortunately, there is currently no effective therapy for preventing
myocardial RI in STEMI patients making it an important residual target for cardioprotection. Previous attempts to translate cardioprotective
therapies (antioxidants, calcium-channel blockers, and anti-inflammatory agents) for reducing RI into the clinic, have been unsuccessful. An
improved understanding of the pathophysiological mechanisms underlying RI has resulted in the identification of several promising mechan-
ical (ischaemic post-conditioning, remote ischaemic pre-conditioning, therapeutic hypothermia, and hyperoxaemia), and pharmacological
(atrial natriuretic peptide, cyclosporin-A, and exenatide) therapeutic strategies, for preventing myocardial RI, many of which have shown
promise in initial proof-of-principle clinical studies. In this article, we review the pathophysiology underlying myocardial RI, and highlight
the potential therapeutic interventions which may be used in the future to prevent RI and improve clinical outcomes in patients with CHD.
-----------------------------------------------------------------------------------------------------------------------------------------------------------
Keywords Myocardial reperfusion injury † ST-elevation myocardial infarction † Primary percutaneous coronary intervention
† Cardioprotection

reduce MI size, preserve left-ventricular (LV) systolic function,

Introduction
Coronary heart disease (CHD) is the leading cause of death in
Europe, accounting for 1.8 million deaths each year and costing
the European Union economy E60 billion per year. Seminal
experimental studies performed by Ginks et al.1 in 1972 first estab-
lished that myocardial reperfusion could reduce myocardial infarct
(MI) size following an acute coronary artery occlusion. Nowadays,
timely myocardial reperfusion using either thrombolytic therapy or
primary percutaneous coronary intervention (PPCI) forms the
cornerstone of therapy for acute ST-segment elevation myocardial
infarction (STEMI) patients. However, mortality remains substantial
in these patients with in-hospital mortality ranging between 6 and
14%.2 As such, novel therapeutic interventions are required to
and improve survival in reperfused-STEMI patients.
Paradoxically, although myocardial reperfusion is essential for
myocardial salvage, it comes at a price, as it can in itself induce
myocardial injury and cardiomyocyte death—a phenomenon
termed ‘myocardial reperfusion injury.’3,4 (Figure 1). There is cur-
rently no effective therapy for preventing myocardial reperfusion
injury (RI) in reperfused-STEMI patients, making it an important re-
sidual target for cardioprotection. In this review article, we provide
an overview of myocardial RI, and highlight potential therapeutic
interventions for preventing it in reperfused-STEMI patients.
We will not review those mechanical and pharmacological inter-
ventions which are used to optimize myocardial reperfusion
during PPCI such as thrombus aspiration, distal protection

* Corresponding author. Tel: +44 203 447 9894 or 9888, Fax: +44 203 447 9505, Email: d.hausenloy@ucl.ac.uk
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2013. For permissions please email: journals.permissions@oup.com
Myocardial reperfusion injury
Figure 1 This scheme illustrates the benefits of timely reperfusion and the addition of a therapeutic intervention for preventing myocardial
reperfusion injury (RI) on myocardial infarct size and myocardial salvage. Nearly 50% of the final myocardial infarct size is due to myocardial RI
and can therefore be reduced, thereby maximizing the benefits of myocardial reperfusion.
devices, anti-platelet, and anti-coagulant therapy—these are dealt
with in the recent ESC STEMI management guidelines.5
Types of myocardial reperfusion
injury
Reperfusion arrhythmias
Experimental animal studies from the 1980s by Hearse’s group
were among the first to describe ventricular arrhythmias specific-
ally induced by reperfusion.6 In reperfused-STEMI patients, the
most commonly encountered reperfusion arrhythmias are idioven-
tricular rhythm, ventricular tachycardia, and fibrillation,7 all of
which are easily dealt with.
Myocardial stunning
The reversible post-ischaemic contractile dysfunction which
occurs on reperfusing acute ischaemic myocardium is referred to
as ‘myocardial stunning’. This form of RI results from the detrimen-
tal effects of oxidative stress and intracellular calcium overload on
the myocardial contractile apparatus.8
Microvascular obstruction and
intramyocardial haemorrhage
Microvascular obstruction (MVO) is an irreversible form of myo-
cardial RI which results in the death of both endothelial cells and
cardiomyocytes. Microvascular obstruction was first described in
a feline heart as the ‘inability to reperfuse a previously ischemic
region’ by Krug et al.9 in 1966. The underlying aetiology of MVO
is unclear but a number of factors have been implicated
1715
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including10 – 12: (i) the embolization of particulate debris which
can be captured by protection devices; (ii) the release of vasocon-
strictor, thrombogenic, and inflammatory substances which can
also be captured by protection devices or the effects of which
can be attenuated by vasodilators; and (iii) structural collapse of
the capillary bed. It may manifest at the time of PPCI as persistent
ST-elevation, coronary ‘no-reflow‘ (TIMI flow ≤2), and reduced
myocardial blush grade. Even when post-PPCI coronary flow
appears normal (TIMI flow 3), 30– 40% of these patients actually
have evidence of MVO when imaged by myocardial contrast echo-
cardiography,13 myocardial perfusion nuclear scanning,14 or cardiac
MRI (Figure 2).15 The presence of MVO in reperfused-STEMI
patients is associated with a larger MI size, worse LV ejection frac-
tion, adverse LV remodelling, and worse short-term and long-term
clinical outcomes.13,15 In areas of severe MVO, extravasation of
blood may occur causing intramyocardial haemorrage within the
myocardial infarct, a feature which can be detected by cardiac
MRI (Figure 2) and portends to a worse prognosis.16 Importantly,
there is currently no effective therapy for preventing MVO and im-
proving clinical outcomes in reperfused-STEMI patients and so it
remains a neglected therapeutic target for cardioprotection.
Lethal myocardial reperfusion injury
In the 1960s, Jennings et al.17 first described the histological
features of myocardial reperfusion in the canine heart including ex-
plosive cardiomyocyte swelling, contraction bands, and intramito-
chondrial calcium phosphate granules. In the 1990s, controversy
surrounded the existence of myocardial RI as an independant me-
diator of cardiomyocyte death.3,18 It has been difficult to demon-
strate reperfusion-induced death of cardiomyocytes which were
1716 G.M. Fröhlich et al.

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Figure 2 (A) This representative figure illustrates a reperfused-STEMI patient with a relatively small myocardial infarct (MI). The left panel is a
T2 mapping sequence to delineate the area at risk (AAR). The central panel is a late-gadolinium-enhancement (LGE) sequence illustrating the
MI. The right panel is a T2 STIR sequence also delineating the AAR. (B) This representative figure illustrates a reperfused-STEMI patient with a
MI complicated by both microvascular obstruction (MVO) and intramyocardial haemorrhage and minimal myocardial salvage, features which
portend to a worse clinical outcome. The left panel is a T2 mapping sequence to delineate the AAR with a hypodense area corresponding
to the area of MVO. The central panel is a LGE sequence illustrating the MI and a hypodense area corresponding to the area of MVO. The
right panel is a T2* sequence delineating the area of intramyocardial haemorrhage.

viable or reversibly injured at the end of ischaemia. As such, the
evidence for the existence of myocardial RI as a distinct entity
has been indirect and relied upon the demonstration that a thera-
peutic intervention applied at the onset of myocardial reperfusion
can reduce MI size.4 These experimental studies have reported
reductions of 40 –50% in final MI size, suggesting that myocardial
RI may account for nearly half of the final infarct, making it an im-
portant target for cardioprotection (Figure 1).
Mediators of myocardial
reperfusion injury
Mitochondrial permeability transition
pore opening as a critical mediator
of myocardial reperfusion injury
Pioneering work by Crompton and Costi19 and Griffiths and Hale-
strap20 in the 1990s first implicated the mitochondrial permeability
transition pore (MPTP) as a critical mediator of lethal myocardial
RI. The opening of the MPTP, a non-selective channel of the
inner mitochondrial membrane, in the first few minutes of reperfu-
sion in response to mitochondrial Ca2+ overload, oxidative stress,
restoration of a physiological pH, and ATP depletion, induces car-
diomyocyte death by uncoupling oxidative phosphorylation21,22
(Figure 3). Mitochondrial permeability transition pore opening at
the time of reperfusion can be inhibited using either pharmaco-
logical (e.g. cyclosporin-A)23 – 25 or genetic inhibition26 of
cyclophilin-D (a regulatory component of the MPTP), resulting in
a 40–50% reduction in MI size. The role of the MPTP as a target
for clinical cardioprotection has been investigated in reperfused-
STEMI patients using CsA (discussed later). However, the discov-
ery of the molecular identity of the MPTP, which is currently
unknown, should allow more specific and potent MPTP inhibitors
to be developed as novel therapeutic agents for preventing myo-
cardial RI.
Calcium and myocardial reperfusion
injury
In 1972, Shen and Jennings27 were the first to demonstrate that
myocardial reperfusion resulted in cardiomyocyte calcium
Myocardial reperfusion injury
Figure 3 This scheme illustrates the major components of myocardial reperfusion injury (RI). These include oxidative stress, calcium over-
load, rapid restoration of physiological pH, and inflammation (neutrophil infiltration), factors which mediate cardiomyocyte death by inducing
cardiomyocyte hypercontracture and MPTP opening (details in text).
overload. Intracellular calcium entry at the time of myocardial
reperfusion is mediated by damage to the sarcolemmal membrane
and oxidative stress-induced dysfunction of the sarcoplasmic re-
ticulum,3 resulting in cardiomyocyte hypercontracture, mitochon-
drial calcium overload, and MPTP opening (Figure 3).
Experimental animal studies have demonstrated that pharmaco-
logically inhibiting intracellular and mitochondrial calcium overload
at the onset of myocardial reperfusion28,29 can reduce MI size by
40–50%. However, clinical studies investigating this therapeutic ap-
proach have been negative.30 – 32 It may well be that specific inhibi-
tors of the recently identified mitochondrial calcium uniporter may
be more effective.33
Oxidative stress, NO, and myocardial
reperfusion injury
Experimental animal studies have established that reperfusing is-
chaemic myocardium generates oxidative stress which contributes
to myocardial RI by inducing MPTP opening34 (Figure 3). Unfortu-
nately, both animal and clinical studies examining the cardioprotec-
tive potential of antioxidant reperfusion therapy have been
inconclusive.35,36 Oxidative stress also reduces the bioavailability
of nitric oxide (NO) at reperfusion, and the administration of
NO donors is cardioprotective.37 However, the NO donor,
Nicorandil, did not limit MI size when administered to reperfused-
STEMI patients.38 Other NO donors currently being investigated in
this clinical setting are sodium nitrite therapy (NIAMI trial:
NCT01388504 and NITRITE-AMI trial: NCT01584453) and
inhaled NO (NOMI trial: NCT01398384).
1717
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Inflammation and myocardial reperfusion
injury
The inflammatory response to myocardial RI is required for healing
and scar formation in the MI. However, the release of chemoattrac-
tants (cytokines, complement, ROS) from injured endothelial cells
and cardiomyocytes draw neutrophils into the infarct zone over
the first 6 h of myocardial reperfusion. Over the next 24 h, they
migrate into the myocardial tissue, a process which is facilitated by
cell-adhesion molecules, where they cause vascular plugging and
release degradative and proteolytic enzymes and reactive oxygen
species39 (Figure 3). Whether this acute inflammatory response
results in cardiomyocyte death or is it simply a response to the
infarct is unclear. Experimental animal studies have reported reduc-
tions in MI size by up to 50% with several interventions administered
at the time of myocardial reperfusion including leucocyte-depleted
blood,40 antibodies against the cell-adhesion molecules, P-selectin,41
CD11/CD18,42 and ICAM-1.43 However, clinical studies targeting
the inflammatory components of myocardial RI with anti-
inflammatory agents, adenosine, or atorvastatin have failed to dem-
onstrate any impact on clinical outcomes in reperfused-STEMI
patients.44 – 46 It is important to appreciate that both adenosine
and atorvastatin have been reported to cardioprotect via a
number of different mechanisms unrelated to inflammation.11,47,48
Intracellular pH changes and myocardial
reperfusion injury
Myocardial reperfusion results in a rapid restoration of physiologic-
al pH from the acidic conditions induced by acute myocardial
1718
ischaemia, resulting in cardiomyocyte death by releasing the inhibi-
tory effect of the acidosis on MPTP opening and cardiomyocyte
hypercontracture49 (Figure 3). Reperfusing ischaemic hearts with
acidic buffers and ischaemic post-conditioning can prevent lethal
myocardial RI by inhibiting MPTP opening and cardiomyocyte
hypercontracture.50 – 52
Cardiomyocyte hypercontracture
Cardiomyocyte hypercontracture at the time of myocardial reper-
fusion is induced by the recovery of energy production in the
presence of a high cytosolic calcium concentration53 (Figure 3).
Cytosolic calcium oscillations between the sarcoplasmic reticulum
and mitochondria can induce both cardiomyocyte hypercontrac-
ture and MPTP opening.54 Contractile inhibition at the time of
myocardial reperfusion can reduce MI size.55
Wavefront of myocardial reperfusion
injury
The current paradigm suggests that cardiomyocyte death induced
by myocardial RI occurs in the first few minutes of reflow (early
myocardial RI). However, a small number of therapeutic interven-
tions have been reported to reduce acute MI size even when
administered 30 min to 24 h into myocardial reperfusion,
suggesting that there may be an extended window of cardioprotec-
tion. These therapeutic interventions, which include erythropoi-
etin,56 PI3K-g/d inhibitors,57 and ischaemic post-conditioning58
may target the inflammatory and apoptotic components of
myocardial RI which generally manifest late into reperfusion (late
myocardial RI).
Consistent with a possible ‘wavefront of reperfusion injury’, MI
size has been reported to increase with reperfusion time,59
although not all studies have observed this finding.60 Whether
this therapeutic window exists in reperfused-STEMI patients is
not known, but it may allow one to target early myocardial RI
with one agent and late myocardial RI with another agent.
Evidence that lethal myocardial
reperfusion injury exists in man
Whether lethal myocardial reperfusion injury actually exists in man
has been intensely debated over the years.18 However, in 2005,
Staat et al. 61 provided the first clinical evidence that lethal myocar-
dial reperfusion injury actually exists in man. They demonstrated a
36% reduction in MI size in reperfused-STEMI patients randomized
to receive ischaemic post-conditioning (IPost, four-30 s inflations/
deflations of the angioplasty balloon following stent deployment).
The fact that a therapeutic intervention, applied at the onset
of myocardial reperfusion, could reduce MI size has provided con-
vincing evidence that myocardial RI exists in man and is a viable
target for cardioprotection.4 Whether preventing myocardial RI
in reperfused-STEMI patients can actually reduce major adverse
cardiac events (MACE) remains to be demonstrated.
G.M. Fröhlich et al.
Therapeutic interventions for
preventing myocardial
reperfusion injury
Improving the translation of
cardioprotection into clinic therapy
Over the years, a number of therapeutic interventions have been
tried in the clinical setting to prevent myocardial RI in reperfused-
STEMI patients although the results have been largely disappoint-
ing. The difficulties in translating cardioprotection from the
experimental animal studies into the clinical setting has been dis-
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cussed in relation to three main topics.62 – 65
The experimental animal model: The animal MI models which are
used to test potential cardioprotective strategies in the pre-clinical
setting do not adequately represent the typical MI patient, in terms
of patient age, co-morbidities, concomitant medication, and MI
pathophysiology, factors which are known to attenuate the
cardioprotective efficacy of many therapeutic interventions.66 An
important example of this are those patients with pre-infarct
angina67 and concomitant medication the patient may be on
(such as nitrates, statins, and so on),47,68 all of which may interfere
with the cardioprotective effect. Therefore, the use of more
clinically relevant animal MI models may result in more effective
cardioprotective interventions being tested in the clinical setting.
The cardioprotective intervention: Many of the cardioprotective
interventions which have failed in the clinical setting have relied
on targeting an individual component of myocardial RI. Combination
therapy aimed at multiple components of myocardial RI may be
more effective. Furthermore, many of the cardioprotective interven-
tions which have failed in the clinical setting had not been rigorously
or systematically tested in the experimental animal setting. The
NHLI-funded multicentre Consortium for preclinicAl assESsment
of cARdioprotective therapies (CAESAR) has been set-up to
perform systematic preclinical testing of novel cardioprotective
therapies using standardized protocols performed by blinded inves-
tigators.69 Hopefully, this will result in only the most robust cardio-
protective interventions being tested in the clinical setting.
The design of the clinical trial: The STEMI patients which are most
likely to benefit from a therapeutic intervention targeting myocar-
dial RI, are those with a complete occlusion (TIMI flow ,1) in a
large coronary artery (where the size of the AAR is .30%) and
in whom there is little coronary collateralization to the area at
risk (AAR). By including patients without these characteristics,
there is a risk of diluting any cardioprotective effect. Furthermore,
pre-existing coronary artery lesions in the infarct-related artery
may affect cardioprotection as gentle reperfusion through a re-
sidual stenosis is protective, although coronary microembolization
would be expected to add to the damage.70 – 72
Because lethal myocardial RI occurs in the first few minutes of
reflow, it is essential that the therapeutic intervention is applied
prior to or at the onset of myocardial reperfusion and failure to
do this may in part explain the negative findings of some clinical
cardioprotection studies. Finally, it is crucial to select clinical
endpoints which are relevant to cardioprotection such as MI
size, the extent of myocardial salvage, LV size and function,
Myocardial reperfusion injury
Figure 4 This representative figure illustrates the use of cardiac MRI to assess myocardial salvage in a reperfused-STEMI patient. The area of
late-gadolinium enhancement (dashed black outline on left panel) depicts the size of the myocardial infarct (MI) and the area at risk (AAR) is
delineated by the T2-weighted imaging (dashed black outline on right panel). Myocardial salvage equals the AAR subtract MI size.
cardiac death, and hospitalization for heart failure, as opposed to
coronary revascularization, re-infarction, and stroke.
Assessing the cardioprotective efficacy
of novel therapies
Assessing the cardioprotective efficacy of novel therapeutic inter-
ventions for preventing myocardial RI requires an estimation of the
size of AAR. This allows myocardial salvage (MI size subtract AAR
size) to be calculated, which can then be normalized to the AAR,
which varies greatly in man depending on the site of the coronary
artery occlusion (Figure 4). T2-weighted cardiac MRI imaging can
retrospectively delineate the AAR by detecting the extent of myo-
cardial oedema in reperfused-STEMI patients, thereby allowing the
estimation of myocardial salvage73,74 (Figure 4). However, its wide-
spread use has been hampered by difficulties with T2 imaging
sequences and concerns that the cardioprotective intervention
may actually reduce the extent of myocardial oedema thereby
leading to an underestimation of the AAR.75
Mechanical therapeutic interventions for
preventing myocardial reperfusion injury
Ischaemic post-conditioning: modifying myocardial
reperfusion
Ischaemic post-conditioning was first described in 2003 by Zhao
et al.,76 who demonstrated in canine hearts that interrupting myo-
cardial reperfusion with three-30 s cycles of LAD re-occlusion and
reflow prevented myocardial RI and reduced MI size by 44%. This
therapeutic approach was rapidly translated into the clinical setting
of PPCI by Staat et al. 61 in 2005 (Table 1). It is important to note
that modifying the process of myocardial reperfusion had already
been demonstrated to reduce myocardial RI in experimental
studies.77,78 A number of clinical studies have confirmed the effi-
cacy of IPost in reperfused-STEMI patients, although not all
studies have been positive79 (Table 1). The DANAMI-3 trial
1719
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(NCT01435408) is currently investigating whether IPost can
reduce cardiac death, re-infarction, and heart failure at 3 years.
Therapeutic hypothermia and hyperoxaemia
Two other mechanical therapeutic interventions which have been
reported in experimental animal studies to protect against myocar-
dial RI are therapeutic hyperoxaemia80 and therapeutic hypother-
mia.81 Hyperbaric oxygen reduces MI size by decreasing tissue
oedema, reducing formation of lipid peroxide radicals, altering
nitric oxide synthase expression, as well as inhibition of leucocyte
adherence and plugging in the microcirculation. Lowering myocar-
dial temperature during ischaemia to 32 –338C can limit MI size in
experimental studies by reducing metabolic demand, reducing the
inflammatory response, decreasing platelet aggregation, and in-
creasing myocardial efficiency. The results of proof-of-principal
clinical studies in reperfused-STEMI patients using these invasive
therapeutic interventions have shown some promise (Table 1).
The ongoing CHILL-MI study (NCT01379261) is investigating
whether this therapeutic approach can reduce acute MI size
(expressed as a percentage of the AAR) on cardiac MRI performed
at 4 days.
Remote ischaemic conditioning: give your right arm
to protect your heart
The phenomenon of remote ischaemic conditioning (RIC) allows
the therapeutic intervention to be applied to an organ or tissue
away from the heart, thereby facilitating its clinical application.82
Remote ischaemic conditioning refers to the cardioprotective
effect induced by non-invasively applying three-5 min cycles of
brief non-lethal ischaemia and reperfusion using a blood pressure
cuff applied to the upper arm.82 By applying this RIC protocol to
STEMI patients in the ambulance en route to the PPCI centre,
Botker et al.83 were able to demonstrate increased myocardial
salvage (Table 1). The actual mechanisms underlying RIC cardio-
protection remain unclear but have been attributed to a neuro-
hormonal pathway conveying the cardioprotective signal from
1720 G.M. Fröhlich et al.

Table 1 Mechanical therapeutic interventions for preventing myocardial reperfusion injury which have been reported
to have beneficial effects in reperfused-STEMI patients

Clinical study Therapeutic intervention n Outcome Notes

...............................................................................................................................................................................
Ischaemic post-conditioning
Staat et al.61 Four-60 s inflations/deflations 30 36% in 72 h AUC CK
34% in peak CK
MBG 1.7–2.4
Thibault et al.98 Four-60 s inflations/deflations 38 41% 72 h AUC CK-MB
39% MI size at 6 months by
SPECT
7% EF by echo at 1 year
Lonborg et al.99

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Four-30 s inflations/deflations 118 19% MI size at 3 months by CMR
31% in myocardial salvage index
Sorensson et al.100 Four-60 s inflations/deflations 76 No difference in 48 h AUC Increased myocardial salvage with
CK-MB/TnT or myocardial AAR .30% of LV
salvage by CMR at day 7 –9
Tarantini et al. 101 Four-60 s inflations/deflations 78 Non-significant increase in MI size IPost delivered within the stent
Hyeon-Cheol et al.,102 Four-60 s inflations/deflations 700 No difference in ST-segment IPost delivered within the stent, no
post trial resolution at 30 min post-PPCI measure of MI size
NCT00942500
Therapeutic hyperoxaemia
Stone et al.,103 IC hyperbaric hyperoxaemic reperfusion 281 No difference in 14-day MI size Invasive intervention
AMIHOT II started after PPCI and continued for 90 min on SPECT; Pooled analysis
suggested beneficial effects
on MI size
Therapeutic hypothermia
Gotberg et al.,104 IV infusion of 1–2 L of cold saline and central 20 Significant reduction in MI size Invasive intervention requiring
RAPID-MI-ICE venous catheter cooling with Philips as % of AAR on CMR at 4 days medication to prevent shivering
InnerCool RTx Endovascular System ‘prior’ 43% reduction in peak and
to PPCI to achieve 358C cumulative Trop T release
Remote ischaemic conditioning
Botker et al. 83 Four-5 min inflations/deflations of arm cuff 142 Increase in myocardial salvage Anterior STEMI subgroup had
delivered in ambulance index at 30 days. No difference greater myocardial salvage,
in MI size (SPECT or Peak smaller MI size, and better LV
Trop) function at 3 days105
Rentoukas et al.106 Three-4 min inflations/deflations of arm cuff 93 Better ST resolution and lower
delivered on arrival at the hospital ‘prior’ to peak Trop I. Synergistic effects
PPCI with morphine

AAR, area at risk; AUC, area under curve; CMR, cardiac MRI; LVESV, LV end-systolic volume.

the limb to the heart.82,84 A large multicentre study is now planned
in Europe to investigate whether RIC can actually reduce MACE in
reperfused-STEMI patients.
Pharmacological therapies for preventing
myocardial reperfusion injury
Atrial natriuretic peptide
Experimental studies have demonstrated that administering atrial
natriuretic peptide (ANP) at reperfusion reduced MI size
through the activation of pro-survival signalling pathways.85 In
2007, Kitakaze et al. 38 demonstrated that an infusion of carperitide
(an ANP analogue) reduced MI size and preserved LV ejection frac-
tion in reperfused-STEMI patients (Table 2).
Cyclosporin-A as an mitochondrial permeability transition
pore inhibitor
In 2008, Piot et al.86 were the first to translate MPTP inhibition at
reperfusion using cyclosporin-A as a therapeutic intervention into
the clinical setting (Table 2). The ongoing CIRCUS study
(NCT01502774) is investigating whether this therapeutic approach
can reduce death, hospitalization for heart failure, and a 15% in-
crease in LV end-diastolic volume. Two newly described indirect
MPTP inhibitors, TRO40303 (Mitocare study)87 and Bendavia
(EMBRACE study: NCT01572909) are currently being investigated
in this clinical setting.
Exenatide as a novel anti-diabetic cardioprotective agent
Exenatide, a glucagon-like peptide-1 (GLP-1) agonist, is a new anti-
diabetic drug, which has been shown in animal studies to reduce MI
Myocardial reperfusion injury 1721

Table 2 Pharmacological agents for preventing myocardial reperfusion injury which have been reported to have
beneficial effects in reperfused-STEMI patients

Clinical study Therapeutic intervention n Outcome Notes

...............................................................................................................................................................................
Atrial natriuretic peptide
Kitakaze et al.,38 IV carperitide 72 h infusion
J-WIND-ANP started ‘after’ reperfusion
Cyclosporin-A
Piot et al.,86 IV cyclosporin A (2.5 mg/kg)
10 min ‘prior’ to PPCI
569 15% reduction in 72 h AUC total CK and Only modest effect as all STEMI
2.0% increase in LVEF patients included and drug given
after reperfusion
58 44%MI size (72 h AUC total CK)
20% MI size (CMR in subset of 27
patients)
28%  MI size and smaller LVESV on CMR

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Exenatide
Lonborg et al., 89 IV infusion of exenatide started
15 min ‘prior’ to PPCI and
continued for 6 h
Glucose insulin potassium (GIK)
Mehta et al., 92 IV GIK infusion for 24 h started
CREATE-ECLA ‘after’ reperfusion in majority
of cases
Selker IV GIK infusion for 12 h started
et al.,93IMMEDIATE by paramedics in ambulance
‘prior’ to reperfusion
at 6 months107
107 Increase in myocardial salvage index (from
0.62 to 0.71) at 90 days by CMR.
Reduced MI size by 23% of AAR at 90
days by CMR
20,201 No difference in mortality at 30 days
357 Reduction in MI size and less in-hospital
mortality and cardiac arrest
Patients presenting with short
ischaemic times (≤132 min) had
greater myocardial salvage90
A significant proportion of patients
had GIK therapy administered after
the onset of myocardial
reperfusion

AAR, area at risk; AUC, area under curve; CMR, cardiac MRI; LVESV, LV end-systolic volume.

size when administered at the time of reperfusion.88 Lonborg
et al. 89,90 have successfully translated this therapeutic approach
into the clinical setting (Table 2).
Metabolic modulation using glucose– insulin –potassium
therapy
Experimental animal studies have shown that promoting glucose
metabolism using insulin during acute myocardial ischaemia is
beneficial for the heart.91 A large number of clinical trials have inves-
tigated the effect of this therapeutic approach using glucose–
insulin–potassium (GIK) therapy with mixed results. Although the
large CREATE-ECLA trial92 was negative, it appears that GIK
therapy may be more effective if administered in the ambulance
en route to the PPCI centre (when the myocardium was still
acutely ischaemic) as in the IMMEDIATE trial93(Table 2).
Other potential therapies for preventing myocardial
reperfusion injury
Several novel pharmacological agents for preventing myocardial RI
in reperfused-STEMI patients are currently being tested in
proof-of-principal clinical studies including intravenous metoprolol
in the ambulance (METOCARD-CNIC trial),94 melatonin (MARIA
trial; NCT00640094 and another trial; NCT01172171), RGN-352
(Thymosin Beta 4: NCT00378352), sevoflurane (a volatile anaes-
thetic agent; SIAMI trial: NCT00971607), and mecasermin (a re-
combinant human form of insulin-like growth factor-1)
(RESUS-AMI trial: NCT01438086). Interestingly, preliminary
experimental animal studies suggest that certain anti-platelet
agents (such as clopidogrel and cangrelor but not aspirin) may ac-
tually prevent myocardial RI and reduce MI size when administered
at the time of myocardial reperfusion,95,96 suggesting that anti-
platelet therapy given to STEMI patients undergoing PPCI may be
cardioprotective. A recent retrospective analysis has suggested
that clopidogrel may reduce MI size in STEMI patients treated by
PPCI.97
Conclusions
Although myocardial reperfusion is essential for myocardial
salvage, it can itself induce myocardial injury (reperfusion arryth-
mias and myocardial stunning) and cause cardiomyocyte death
(MVO and myocardial necrosis), a phenomenon which is termed
myocardial RI and which can contribute up to 50% of the final
MI size. Crucially, there are currently no effective therapies for
preventing myocardial RI in reperfused-STEMI patients, making it
a neglected target for cardioprotection. An improved understand-
ing of the pathophysiology of myocardial RI has resulted in the
identification of novel therapeutic strategies (such as IPost, RIC,
therapeutic hyperoxaemia and hypothermia, atrial natriuretic
peptide, cyclosporin-A, and exenatide) for potentially preventing
myocardial RI in reperfused-STEMI patients. Large multicentre
randomized clinical trials are now required to determine
whether preventing myocardial RI can actually reduce MACE in
this patient group.
1722
Acknowledgements
This study was carried out at the Heart Hospital/University
College London Hospital and University College London, which
received a proportion of funding from the Department of
Health’s NIHR Biomedical Research Centres funding scheme.
This research work was supported by the National Institute for
Health Research University College London Hospitals Biomedical
Research Centre.
Funding
This work was supported by British Heart Foundation (grant number
FS/06/023) and Swiss National Science Foundation Nr. PBZHP3_
143671.
Conflict of interest: none declared.
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