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European Heart Journal Advance Access published June 26, 2016

REVIEW

European Heart Journal


doi:10.1093/eurheartj/ehw224

Mechanisms of disease

The pathophysiology of acute myocardial


infarction and strategies of protection beyond
reperfusion: a continual challenge
Gerd Heusch 1* and Bernard J. Gersh 2
1
Institute for Pathophysiology, West German Heart and Vascular Center, University of Essen Medical School, Hufelandstr. 55, 45122 Essen, Germany; and 2Division of Cardiovascular
Diseases, Mayo Clinic and Mayo Clinic College of Medicine, Rochester, MN, USA

The incidence of ST segment elevation myocardial infarction (STEMI) has decreased over the last two decades in developed countries, but
mortality from STEMI despite widespread access to reperfusion therapy is still substantial as is the development of heart failure, particularly
among an expanding older population. In developing countries, the incidence of STEMI is increasing and interventional reperfusion is often
not available. We here review the pathophysiology of acute myocardial infarction and reperfusion, notably the temporal and spatial
evolution of ischaemic and reperfusion injury, the different modes of cell death, and the resulting coronary microvascular dysfunction.
We then go on to briefly characterize the cardioprotective phenomena of ischaemic preconditioning, ischaemic postconditioning, and remote ischaemic conditioning and their underlying signal transduction pathways. We discuss in detail the attempts to translate conditioning
strategies and drug therapy into the clinical setting. Most attempts have failed so far to reduce infarct size and improve clinical outcomes in
STEMI patients, and we discuss potential reasons for such failure. Currently, it appears that remote ischaemic conditioning and a few drugs
(atrial natriuretic peptide, exenatide, metoprolol, and esmolol) reduce infarct size, but studies with clinical outcome as primary endpoint are
still underway.

----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords

Acute myocardial infarction Cardioprotection Coronary microvascular dysfunction Infarct size


Postconditioning Preconditioning Remote conditioning Reperfusion Reperfusion injury

The changing epidemiology of


ST segment elevation myocardial
infarction
The incidence of acute ST segment elevation myocardial infarction
(STEMI) has decreased over the last decades, mostly in developed
higher-income countries. However, in developing lower-income
countries the incidence of acute myocardial infarction (both STEMI and Non-STEMI) has increased, as has the incidence of ischaemic heart failure globally.1 The mortality from acute myocardial
infarction has also decreased from 20% in the late 1980s to
5 7% in routine practice in the USA2 and Europe,3 5 however
with large regional variations largely secondary to differences in
use and mode of reperfusion, e.g. by primary percutaneous coronary intervention (PPCI) or thrombolysis, and the efficacy of its

delivery. Although door-to-balloon time in patients with STEMI


undergoing PPCI has consistently declined in the USA, overall inhospital mortality has not decreased further,6 perhaps in part due
to changes in the patient population, i.e. increased number of sicker patients.7 A recent patient-level meta-analysis emphasized the
pivotal importance of infarct size within 1 month after PPCI as a
determinant of all-cause mortality and hospitalization for heart failure at 1 year,8 supporting the use of infarct size as a useful surrogate endpoint in clinical trials. Although timely and complete
reperfusion is the most effective way of limiting infarct size and
subsequent ventricular remodelling,9 reperfusion per se adds an
additional component of irreversible injury to the myocardium
and the coronary circulation and it contributes to final infarct
size.10,11 The prevention and treatment of lethal reperfusion injury
and coronary microvascular dysfunction pose a continued and formidable barrier to successful myocardial perfusion as opposed to

* Corresponding author. Tel: +49 201 723 4480, Fax: +49 201 723 4481, Email: gerd.heusch@uk-essen.de
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2016. For permissions please email: journals.permissions@oup.com.

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Received 23 February 2016; revised 12 April 2016; accepted 12 May 2016

Page 2 of 17
establishing patency of the epicardial infarct-related artery, and in
this context the need for additional cardioprotective strategies to
reduce infarct size and coronary microvascular dysfunction remains the last frontier of reperfusion therapy.12 17

The pathophysiology of myocardial


ischaemia/reperfusion injury and
coronary microvascular
dysfunction

modification of reperfusion attenuates such injury.10,37 Staccato reperfusion, as in ischaemic postconditioning36 and gentle, more gradual reperfusion at reduced coronary blood flow rates38 reduce
infarct size in the experimental animal model.
In order to better understand the discordance between the
many positive animal studies and the difficult translation to the
clinical arena, a discussion of pathophysiological concepts underlying myocardial ischaemia/reperfusion injury is clinically relevant.
Figure 1 displays a schematic diagram of mechanisms contributing
to myocardial ischaemia/reperfusion injury to the cardiomyocyte
and coronary vascular compartment. Morphologically, the infarcted
myocardium is characterized by myofibrillar contraction bands,
swollen and/or ruptured mitochondria, sarcolemmal rupture,
microvascular destruction, haemorrhage, and infiltrating leukocytes.
These histological signs reflect necrosis which typically becomes
more manifest and is perhaps accelerated during reperfusion.21 23
Cellular calcium overload through reverse mode Na+/Ca2+exchange after sodium overload through the Na+/H+-exchanger,39,40
oscillatory release from and re-uptake of Ca2+ into the sarcoplasmic
reticulum with resulting uncoordinated and excessive myofibrillar
contractions,41 digestion of cytoskeleton and sarcolemma by calpains,42 and excess formation of reactive oxygen species (ROS)43 all
contribute to necrotic cell death.17
Whereas necrosis is considered as an unregulated mode of cell
death, more regulated modes of cell death also occur in infarcting
myocardium, but their quantitative contribution to final infarct
size is not really clear.17,44,45 Apoptosis is an energy-dependent
mode of cell death with typical DNA fragmentation but lack of an
inflammatory response, and is initiated extrinsically through sarcolemmal receptors and intrinsically by release of cytochrome C
from damaged mitochondria.46,47 Opening of the mitochondrial
permeability transition pore (MPTP) is of major importance for necrotic and apoptotic cardiomyocyte death.48 51 Autophagy is the
process of lysosomal protein degradation, particularly of mitochondrial proteins (mitophagy) and serves for recycling of proteins; its
role in human myocardial ischaemia/reperfusion and cardioprotection is less clear.52,53 Necroptosis is initiated by activation of specific
receptor-interacting kinases and otherwise shares features with necrosis and apoptosis.54 56 Whereas the quantitative contribution of
the different modes of cell death to infarction or cardioprotection
(autophagy) is not clear, a role for mitochondria is decisive in all
of them; the regulated modes of cell death may present specific targets for pharmacological cardioprotection.17
The coronary circulation with atherosclerotic plaque rupture and
superimposed thrombosis is not only the culprit of myocardial ischemia but after restoration of coronary blood flow it is also the target of ischaemia/reperfusion injury.57 Ischaemia/reperfusion injury in
the coronary circulation manifests as microvascular dysfunction, primarily by increased capillary permeability and oedema,58,59 coronary microembolization of atherosclerotic particular debris,60
impaired vasomotion secondary to endothelial and vascular smooth
muscle damage61 63 and release of vasoconstrictor substances
from the atherosclerotic lesion,64 66 stasis, i.e. platelet, leukocyte
and erythrocyte aggregates in the microcirculation,67 69 and finally
capillary destruction and haemorrhage.70,71 Impaired myocardial
blood flow despite restoration of epicardial coronary patency was
first reported by Krug et al.,72 and Kloner et al.73 subsequently

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ST segment elevation myocardial infarction reflects acute myocardial infarction resulting from the rupture or erosion of an atherosclerotic plaque with thrombotic occlusion of an epicardial
coronary artery18 and transmural ischaemia. The size of the resulting infarction depends on (i) the size of the ischaemic area at risk, (ii)
the duration and intermittency of coronary occlusion, and (iii) the
magnitude of residual collateral blood flow and the extent of coronary microvascular dysfunction. In the experimental animal, temperature also impacts on infarct size, whereas, contrary to previously
held notions, the haemodynamic situation and myocardial oxygen
demands are only of relatively minor importance for infarct
size.19,20 The infarct develops in a typical wavefront manner, starting
in the subendocardial layers in the centre of the area at risk and
progressing into subepicardial layers and to the border zones of
area at risk with ongoing duration of coronary occlusion.21 23
The progressive development of myocardial infarction with the
duration of coronary occlusion is largely species-dependent, due
to differences in the innate collateral circulation but also in the
innate resistance to myocardial ischemia. In humans, 30 50% of
the area at risk is still viable and therefore salvageable by reperfusion
after 46 h from the onset of anginal symptoms, as estimated from
magnetic resonance imaging (MRI) and biomarker analysis of
myocardial salvage.17 Even after 12 h of coronary occlusion, there
is viable myocardium and interventional reperfusion can limit
infarct size.24
Seminal studies by Ross and co-workers in 1972 demonstrated
that reperfusion after 3 h coronary occlusion reduces infarct size
in dogs,25,26 and this was the start of the reperfusion era.27 After pilot reports by Chazov and Rentrop, a number of trials with intracoronary thrombolysis confirmed the feasibility of thrombolytic
reperfusion28,29 before the definitive GISSI and ISIS-2 trials demonstrated improved outcome in STEMI patients with intravenous
thrombolysis.30,31 Almost in parallel, PPCI was introduced32 and is
now the preferred mode of reperfusion in countries and regions
in which the procedure can be performed expeditiously,33 whereas
the pharmacoinvasive strategy is the only realistic option in many
parts of the developing world.
Whereas reperfusion is mandatory in order to salvage ischaemic
myocardium from impending infarction, reperfusion also inflicts
additional injury which is not only reversible, as in stunning,34 but
also irreversible and manifests in increased infarct size and microvascular dysfunction. The existence of lethal reperfusion injury has
long been debated35 but with the recognition of the postconditioning phenomenon36 it has become unequivocally clear
that reperfusion as such causes irreversible injury and that

G. Heusch et al.

Cardioprotection beyond reperfusion

Page 3 of 17

versible ischemia/reperfusion injury.

characterized the no-reflow phenomenon as the most severe form


of coronary microvascular ischaemia/reperfusion injury. No-reflow
is observed in 35% of patients after STEMI,74 and the frequency of
its diagnosis depends upon the technique of measurement, ranging
from 10% using angiography to 60% using MRI or contrast echocardiography.75 The incidence of no-reflow increases with the delay
to reperfusion,76 and both, no-reflow and intramyocardial haemorrhage, are powerful and clinically important adverse prognostic
factors.74,77 79 The causal relationship between myocardial and
coronary microvascular ischaemia/reperfusion injury is largely unclear, although they are closely associated.80,81 Delayed hypothermia after 30 min reperfusion reduces no-reflow, but not infarct
size in rabbits.82 In contrast, ischaemic postconditioning in pigs reduces infarct size, but not no-reflow.83 Possibly, there is a common
pathophysiologic mechanism such as formation of ROS84 that underlies myocardial and coronary microvascular ischaemia/reperfusion injury, but with a distinct impact on both compartments.
Clearly, better coronary microvascular function, as reflected by a
better angiographic perfusion score, is associated with better left

ventricular function and less remodelling following percutaneous


coronary intervention.85

The pathophysiological impact


of pre-infarction angina
Since the occurrence and onset of acute myocardial infarction is unpredictable, controlled randomized trials on the impact of local or
remote ischaemic preconditioning on infarct size and clinical outcome are difficult to execute. Pre-infarction angina is considered a
clinical correlate of ischaemic preconditioning,86,87 and by the very
nature of this phenomenon only retrospective, observational
studies are available. Nonetheless, the evidence is persuasive that
pre-infarction angina is associated with reduced infarct size,86,88 90
reduced coronary microvascular injury,91,92 and better clinical outcome.86,89,93 However, it is unclear whether these benefits are
mechanistically related to acute or delayed ischaemic preconditioning87 or, alternatively, to reduced platelet aggregation94 or more

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Figure 1 Schematic diagram of mechanisms in the cardiomyocyte and coronary vascular compartment which interact and contribute to irrer-

Page 4 of 17
rapid thrombolysis,95 or a combination of all three factors. Moreover, a recent population-based analysis suggested that preceding ischaemic symptoms from peripheral arterial disease also reduced
mortality from acute myocardial infarction, a potential correlate
of remote ischaemic preconditioning.93 Remote ischaemic perconditioning, i.e. a remote ischaemic conditioning manoeuvre after the
onset of ischaemic symptoms but before interventional reperfusion,
can be performed in the ambulance and reduces infarct size,96 and as
such is a potentially valuable strategy particularly for networks utilizing the pharmaco-invasive strategy.

Experimental studies over the last three decades have identified


complex signal transduction processes underlying the cardioprotection by ischaemic preconditioning, ischaemic postconditioning, and
remote ischaemic conditioning.97 99 The local ischaemic pre- and
postconditioning phenomena are initiated by the release of autacoids, e.g. adenosine and bradykinin, of neurohormones, e.g. catecholamines and opioids, and cytokines, e.g. interleukins and
tumour necrosis factor alpha (TNFa) in response to brief episodes
of myocardial ischaemia/reperfusion before or after the episode of
sustained myocardial ischaemia which eventually causes infarction.
These trigger molecules then act on sarcolemmal receptors and initiate intracellular signal cascades, which for the most part involves
the phosphorylation/activation of protein kinases and involve converge on the mitochondria. Conceptually, three major signal transduction cascades can be identified, i.e. the nitric oxide/protein
kinase G system, the reperfusion injury salvage kinase system,100
which includes phosphatidylinositol (4,5)-bisphosphate 3 kinase,
protein kinase B (Akt) and extracellular regulated kinases, and the
salvage activating factor enhancement system,101 which includes
TNFa and signal transducer and activator of transcription 3. These
signal transduction cascades target the mitochondria where they
interact with the respiratory chain,102 connexin 43,103,104 and ATPdependent K-channels105,106 to inhibit ROS formation and opening
of the MPTP. Opening of the MPTP initiates cell death through collapse of the mitochondrial membrane potential, failure of ATP production, and release of cytochrome C into the cytosol where it
activates proteolytic caspases.47,107 Remote ischaemic conditioning
shares largely the intracellular signal transduction pathways with the
local conditioning phenomena, but involves in addition the transfer
of a cardioprotective signal from the ischaemic/reperfused remote
tissue or organ to the heart, through both neuronal and humoral
pathways.108 The signal transduction pathways of the conditioning
phenomena in the human heart are still largely unknown; in remote
ischaemic conditioning, the activation of STAT 5 appears to play a
role.109 Despite this uncertainty, not only the conditioning phenomena per se but also single signalling steps of conditioning have been

the focus of attempts to translate to the clinical setting of STEMI.99,110 The forest plots display changes in infarct size, as estimated
from biomarkers (creatine kinase, creatine kinase-muscle brain,
troponin I or T) or imaging (SPECT, MRI) (Figures 1 3). The table
displays clinical outcome data (Table 1).

Conditioning strategies
Ischaemic postconditioning reduced infarct size in most smaller
proof-of-concept studies,111 131 but did not so in recent larger
trials in patients with STEMI undergoing PPCI.132 134 In contrast, remote ischaemic conditioning reduced infarct size in all available
studies, no matter whether patients underwent reperfusion by
PPCI96,134 139 or thrombolysis140 (Figure 2). Only one small study
on ischaemic postconditioning reported improved clinical outcome
in terms of a reduced incidence of heart failure development.117
Only a single retrospective analysis reported reduced all-cause mortality and less MACCE with remote ischaemic conditioning141
(Table 1).

Mechanical/non-pharmacological
strategies
Neither aspiration nor mechanical thrombectomy reduced infarct
size in a meta-analysis of patients with STEMI undergoing PPCI,142
and 1 year-mortality was not reduced by aspiration thrombectomy
in the TASTE trial.143 Also, 1 year-mortality was not reduced by
thrombectomy in the FAST-MI144 and BCIS-NICOR145 registries.
Some studies reported reduced infarct size, 146,147 others did
not148 154 (Figure 3). Some studies reported attenuated coronary
microvascular injury146,152,155 and improved clinical outcome151,155
(Table 1). The recent DANAMI 3-DEFER trial of delayed stenting in
an attempt to reduce distal thromboembolism from a larger clot
burden was entirely neutral: disappointing in some ways but the results obviate the need for patients to routinely undergo two procedures.156 Intra-aortic balloon counterpulsation also did not reduce
infarct size in patients with anterior STEMI.157 One small study with
endovascular cooling in patients with acute myocardial infarction
undergoing PPCI reported no serious adverse events and a trend
for reduced infarct size by SPECT,158 and another small study in
20 STEMI patients (RAPID-ICE) even reported reduced infarct
size (MRI, troponin release) with hypothermia by endovascular
cooling.159 However, in the larger CHILL-MI trial in 120 STEMI patients infarct size (MRI, creatine kinase-muscle brain, troponin) was
not reduced.160 In the very recent VELOCITY trial, peritoneal hypothermia in patients with STEMI before and for 3 h after PPCI did not
reduce infarct size or microvascular obstruction (MRI), but even increased the rate of adverse events.161 Data on hyperoxemic reperfusion are controversial. Final infarct size (SPECT) 2 weeks after
PPCI in STEMI patients was not reduced in AMIHOT I,162 but was
reduced in AMIHOT II;163 clinical outcome was not affected by hyperoxemic reperfusion.

Pharmacological strategies
Glucose-insulin-potassium (started in the ambulance) reduced infarct size in a small subgroup of the IMMEDIATE trial, and in-hospital
mortality/cardiac arrest was reduced in the entire trial.164 However,
chronic anti-diabetic therapy also impacts the clinical outcome from

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Cardioprotection by local
postconditioning, remote
conditioning, drugs, and other
interventions in patients with ST
segment elevation myocardial
infarction

G. Heusch et al.

Cardioprotection beyond reperfusion

Page 5 of 17

endpoint. CK, creatine kinase; CK-MB, creatine kinase muscle brain; MRI, magnetic resonance imaging; PLA, placebo; PoCo, postconditioning; RIC,
remote ischemic conditioning; SPECT, single photon emission computed tomography; TnI, troponin I; TnT, troponin T.

Figure 3 Forest plot of clinical studies on thrombectomy, hypothermia, hyperoxemia, and balloon counterpulsation in STEMI patients with
infarct size as endpoint. CK, creatine kinase; CK-MB, creatine kinase muscle brain; INT, intervention; MRI, magnetic resonance imaging; PLA, placebo; SPECT, single photon emission computed tomography.

acute myocardial infarction, as patients receiving gliclazide or


glimepiride had lower in hospital-mortality than those receiving glibenclamide,165 possibly because of lack of interference with

conditioning.166 A variety of pharmacological approaches to cardioprotection have been tried, many of them attempting to recruit signalling steps of local or remote ischaemic pre-, per-, and

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Figure 2 Forest plot of clinical studies on ischaemic postconditioning and remote ischaemic conditioning in STEMI patients with infarct size as

Clinical outcomes in trials of ST segment elevation myocardial infarction patients undergoing reperfusion therapy together with an adjunct intervention

Authors

Acronym

Placebo/
intervention

Intervention

Primary endpoint

Secondary endpoint

.............................................................................................................................................................................................................................................
Lonborg et al.117
Tarantini et al.123

POST-AMI

59/59
39/39

PoCo
PoCo

Myocardial salvage at 3 months (MRI)


Infarct size (MRI)

*
 n.s.

Hahn et al.132

POST

350/350

PoCo

ST segment resolution

MACE over 1 month

 n.s.

Limalanathan
et al.133

POSTEMI

136/136

PoCo

Infarct size (MRI)

 n.s

Mortality at 4 months

Eitel et al.134

LIPSIA CONDITIONING

160/173

PoCo

Myocardial salvage within 3 days (MRI)

 n.s.

Combined death, reinfarction, new heart


failure within 6 months

 n.s.

44/43

PoCo

Infarct size (TnT)

 n.s.

New myocardial infarction or cardac


death at 14 months

Luz et al.131

No. of patients developing heart failure


MACE over 6 months

*
 n.s.

Sloth et al.141
Crimi et al.137

CONDI

69/73
48/48

RIC
RIC

Myocardial salvage at 30 day (SPECT)


Infarct size (CK-MB)

*
*

Mortality, MACCE over 3.8 years


MACE at 12 months

*

Eitel et al.134

LIPSIA CONDITIONING

160/158

RIC (+PoCo)

Myocardial salvage within 3 days (MRI)

 n.s.

Combined death, reinfarction, new heart


failure within 6 months

 n.s.

107/108

Aspiration thrombectomy

Myocardial salvage (SPECT)

 n.s.

MACE at 30 days

Vlaar et al.149
Sardella et al.155

TAPAS
EXPIRA

536/535
87/88

Aspiration thrombectomy
Aspiration thrombectomy

 n.s.
*

MUSTELA

104/104
75/79

Aspiration thrombectomy

*
*
*
*

Infarct size (CK)


Mortality at 9 months

De Carlo et al.152

Myocardial blush grade


Myocardial blush grade
ST segment resolution
ST segment resolution
Infarct size (MRI)

MACE at 1 year

Stone et al.153
Lagerqvist et al.143

INFUSE-AMI
TASTE

179/174
3623 /3621

Aspiration thrombectomy
Aspiration thrombectomy

Infarct size at 30 days (MRI)


Mortality at 30 days

 n.s.
 n.s.
 n.s.

MACCE at 30 days
Rehospitalization for infarction
Stent thrombosis
MACCE at 30 days

 n.s.

Kaltoft et al.148

Desch et al.154

55/56

Aspiration thrombectomy

Microvascular obstruction (MRI)

Antoniucci et al.146

50/50

Rheolytic thrombectomy

ST segment resolution

*

MACCE at 1 month

240/246
208/217

Rheolytic thrombectomy

ST segment resolution
Infarct size (SPECT)

*
 n.s.

MACE at 1 year

*

21/21
9/9

Hypothermia
Hypothermia

MACE at 30 days
Infarct size (MRI)

 n.s.
*

Infarct size (SPECT)


MACE at 30 days

 n.s.

Migliorini et al.151

JETSTENT

Dixon et al.158
Gotberg et al.159

Page 6 of 17

Table 1

Erlinge et al.160

CHILL-MI

47/49

Hypothermia

Infarct size (MRI)

 n.s.

Death and heart failure at 45 days

*

Nichol et al.161

VELOCITY

26/28

Hypothermia

Infarct size (MRI)

 n.s.

Composite of death, reinfarction, target


vessel revascularization, bleeding,
tachycardia, sepsis, stent thrombosis

*

AMIHOT

122/121

Hyperoxemia

Infarct size (SPECT)

 n.s.

MACCE at 30 days

 n.s.

AMIHOT II
CRISP-AMI

124/258
142/133

Hyperoxemia
Ballon counterpulsation

Infarct size (SPECT)


Infarct size (MRI)

*
 n.s.

MACCE at 30 days
Mortality at 6 months

 n.s.
 n.s.

Selker et al.164

IMMEDIATE

242/200

GIK

Progression to infarction

 n.s.

Stone et al.153

INFUSE-AMI

172/181

Abciximab

Infarct size (MRI)

*

In-hospital mortality and cardiac arrest,


mortality at 30 days
MACE at 30 days

*
 n.s.
 n.s.

G. Heusch et al.

ONeill et al.162
Stone et al.163
Patel et al.157

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HALT-MI

Granger et al.172
Mahaffey et al.173

153/159

LeukArrest

Infarct size (SPECT)

Composite of death, new infarction,


rehospitalization for heart failure

COMMA

271/281

Pexelizumab

Infarct size (CK-MB)

Mortality at 6 months

*

COMPLY

307/309

Pexelizumab

Infarct size (CK-MB)

Composite of death, new/worsening


heart failure, shock or stroke

APEX-AMI174

APEX-AMI

2885/2860

Pexelizumab

Mortality at 30 days

Composite of death, shock or heart


failure

Atar et al.175

FIRE

104/94

FX06

Infarct size (MRI)

 n.s.

Composite of cardiac death and new


onset heart failure/pulmonary oedema

 n.s.

ODonoghue
et al.176

LATITUDE-TIMI 60

1758/1731

Losmapimod

 n.s.

Mahaffey et al.177

AMISTAD

117/119

Adenosine i.v.

Composite of cardiovascular death,


myocardial infarction, recurrent
ischaemia at 12 weeks
Infarct size (SPECT)

*

Composite of in-hospital death,


reinfarction, stroke, heart failure, and
cardiogenic shock

 n.s.

27/27

Adenosine i.c.

Infarct size (CK)

 n.s.

Composite of recurrent ischaemia,


non-fatal infarction, heart failure, and
cardiac death

*

703/1414

Adenosine i.v.

Composite of death, new heart failure, or


re-hospitalization for heart failure
within 6 months

 n.s.

Infarct size (SPECT)

 n.s.

207/208

Adenosine i.c.

ST segment resolution

 n.s.

Mortality, reinfarction, target vessel


revascularization at 30 days

 n.s.

Marzilli et al.178

Ross et al.179

AMISTAD II

Fokkema et al.180

Desmet et al.182
Niccoli et al. 181

REOPEN-AMI

49/51
80/80

Adenosine i.c.
Adenosine i.c.

Myocardial salvage (MRI)


ST segment resolution

 n.s.
*

Mortality at 1 year
MACE at 30 days

 n.s.

Zeymer et al.185

ESCAMI

322/316

Eniporide

Infarct size (a-HBDH)

 n.s

Ott et al.186

REVIVAL

52/52

Erythropoietin

Ejection fraction at 6 months (MRI)

Composite of death, cardiogenic shock,


heart failure, and sustained ventricular
arrhythmias at 6 weeks
Event-free survival at 6 months

Voors et al.187

HEBE III

235/213

Erythropoietin

Ejection fraction at 6 weeks (scintigraphy)

Event-free survival at 6 weeks

*

Najjar et al.188

REVEAL

68/68

Erythropoietin

Infarct size (MRI)

 n.s.

Death, infarction, stroke, or stent


thrombosis

*

Kitakaze et al.189
Kitakaze et al.189

J-WIND
J-WIND

280/255
260/269

ANP
Nicorandil

Infarct size (CK)


Infarct size (CK)

*

Cardiac death, heart failure


Cardiac death, heart failure

*
 n.s.

40/40

Nitrite i.c.

Infarct size (CK)

 n.s.

MACE at 1 year

*

228/227

d PKC inhibition

Infarct size (CK-MB)

 n.s.

 n.s.

Lonborg et al.200

51/54

Exenatide

Myocardial salvage (MRI)

*

Ghaffari et al.197

51/50

Cyclosporine A

Composite of in-hospital heart failure,


sustained arrhythmias and death at
6 months

Composite of death, cardiogenic shock,


heart failure, and ventricular
arrhythmias at 3 months
Composite of cardiac death, infarction,
stent thrombosis, and stroke at 30 days
Infarct size (CK-MB)

Lincoff et al.

193

PROTECTION AMI

 n.s.

Page 7 of 17

 n.s.

Continued

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Jones et al.191

Cardioprotection beyond reperfusion

Faxon et al.171

Page 8 of 17

Table 1

Continued

Authors

Acronym

Placebo/
intervention

Intervention

Primary endpoint

Secondary endpoint

.............................................................................................................................................................................................................................................
Cung et al.195

CIRCUS

396/395

Cyclosporine A

Ottani et al.196

CYCLE

192/199

Gibson et al.199

EMBRACE-AMI

Atar et al.198
Ibanez et al.17

Infarct size (CK)

Cyclosporine A

Composite of death, worsening of heart


failure in-hospital, rehospitalization for
heart failure, remodelling at 1 year
ST segment resolution

 n.s.

Composite of death, heart failure, and


cardiogenic shock at 6 month

60/57

MTP-131

Infarct size (CK-MB)

 n.s.

Composite of death, new onset of heart


failure, heart failure rehospitalization at
30 days

 n.s.

MITOCARE

80/83

TRO40303

Infarct size (TnI)

 n.s.

Safety events

*

METOCARD-CNIC

114/1106

Metoprolol

Infarct size (MRI)

*

Composite of death, malignant


arrhythmias, cardiogenic shock,
reinfarction at 24 h

 n.s.

Roolvink et al.203

EARLY-BAMI

347/336

Metoprolol

Infarct size (MRI)

 n.s.

MACE at 30 days

 n.s.

Er et al.202

BEAT-AMI

50/50

Esmolol

Infarct size (TnT)

*

Safety events

The n-values refer to the primary endpoint.


CK, creatine kinase; CK-MB, creatine kinase muscle brain; a-HBDH, a-hydroxy-butyrate dehydrogenase; MRI, magnetic resonance imaging; PoCo, postconditioning; RIC, remote ischaemic conditioning; SPECT, single photon emission
computed tomography; Tn, troponin.

G. Heusch et al.

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Cardioprotection beyond reperfusion

reperfused myocardial infarctions also revealed no benefit from


cyclosporine A just before reperfusion on peak troponin T on day
4, LV remodelling and clinical outcome at 6 months.196 These neutral results are also consistent with a lack of effect of prethrombolytic cyclosporine A on peak troponin I and creatine kinasemuscle brain.197 Two other recent trials targeting the mitochondria
also did not report reduced infarct size or better clinical outcome;198,199 in fact, in one trial the agent increased the safety
events.198
Agents which have reduced infarct size and are still promising are
atrial natriuretic peptide in J-WIND,189 exenatide,200 metoprolol,201
and esmolol.202 However, the promising results with metoprolol in
the METOCARD trial were not confirmed in the recent larger
EARLY-BAMI trial.203

Potential reasons for failure of


translation from experimental and
proof-of-concept trials to clinical
practice
As pointed out before12,13,17,204,205 the translation of cardioprotectionon top of early reperfusionfrom animal experiments and/
or early proof-of-concept studies in humans with acute myocardial
infarction to clinical practice has been difficult, and it remains a challenge and perhaps a source of frustration as the gap between the
bench and the bedside appears to be wide and to date unbridged.

Figure 4 Forest plot of clinical studies on drugs in STEMI patients with infarct size as endpoint. CK, creatine kinase; CK-MB, creatine kinase
muscle brain; MRI, magnetic resonance imaging; PLA, placebo; SPECT, single photon emission computed tomography; TnI, troponin I; TnT, troponin T; VER, verum.

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postconditioning.99 The results are for the most part disappointing.


Platelet inhibition by intracoronary abciximab, a glycoprotein IIb/IIIa
receptor antagonist, reduced infarct size but did not improve clinical
outcomes at 30 days in the INFUSE-AMI trial.153 Despite prior encouraging studies,167 170 anti-inflammatory interventions (integrin
receptor-antibodies, 171 complement C5 antibodies,172 174 and
cadherin-antibodies175) neither consistently reduced infarct size
(Figure 4) nor improved clinical outcomes (Table 1). Also, the recent
LATITUDE-TIMI 60 trial reported no reduction of major cardiovascular events by the anti-inflammatory p38 mitogen-activated protein
kinase inhibitor losmapimod in patients with acute myocardial infarction.176 No consistent benefit was observed for adenosine on
infarct size and clinical outcomes,177 183 and a meta-analysis found
less microvascular injury and heart failure outcome only with intracoronary adenosine.184 The sodium-proton-exchange inhibitor eniporide had no significant effect on infarct size and clinical
outcome.185 Erythropoietin did not reduce infarct size,186 188 improved event-free survival at 6 weeks in HEBE III,187 but increased
MACCE rates in the REVEAL trial.188 Nicorandil, intravenous nitrite,
and intracoronary nitrite did not reduce infarct size,189 191 but intracoronary nitrite reduced MACCE rate at 1 year.191 Inhibition of
the protein kinase C delta isoform with delcasertib did not reduce
infarct size or improve clinical outcome.192,193 After a pilot
proof-of-concept study on the use of intravenous cyclosporine A
immediately prior to reperfusion in STEMI patients had shown reduced infarct size,194 the larger follow-up CIRCUS trial did not confirm such protection, both in terms of infarct size and clinical
outcome.195 The recent CYCLE trial in patients with large

Page 9 of 17

Page 10 of 17

Figure 5 Myocardial salvage as a function of time from symptom


onset to reperfusion. With rapid reperfusion, reperfusion per se
salvages most of the myocardium so that there is little room for
an additional intervention or drug to protect. On the other
hand, when reperfusion is late there is little salvageable myocardium left. From Gersh et al.215 (with permission).

Some of the drugs used in trials may simply not work at all. The
infarct size reduction by adenosine was contentious in the animal
experiments,110,218 220 and it is therefore not surprising that the human data are contentious, too. A recent study in pigs with reperfused anterior myocardial infarction suggested that high-dose,
prolonged intracoronary infusion of adenosine is needed to reduce
infarct size and no-reflow.221 The pilot trial on d-PKC inhibition had
not revealed an infarct size reduction,192 and it is therefore not surprising that the PROTECTION-AMI trial also failed to find an infarct
size reduction.193 The most disappointing lack of translation relates
to cyclosporine A which in a pilot phase II trial had reduced infarct
size in patients with STEMI undergoing PPCI,194 but failed to reduce
infarct size and improve clinical outcome in two recent larger phase
III trials (CIRCUS, CYCLE).195,196 The reasons for this discrepancy
may relate to differences in P2Y12 antagonist treatment and use of
direct stenting, as discussed above, but also in differences in time
from symptom onset to reperfusion (within 12 h in the CIRCUS
trial) and a different vehicle for cyclosporine A in the CIRCUS,222
but not in the CYCLE trial.

On what targets should we focus?


Remote ischaemic conditioning is a simple, effective, safe, and inexpensive intervention, and infarct size reduction has been evidenced
by all trials in STEMI patients, no matter whether undergoing primary PCI96,134 139 or thrombolysis140 for reperfusion. The results
of the still ongoing RIC-STEMI and CONDI-2/ERIC-PPCI trials will
tell whether remote ischaemic conditioning in STEMI patients improves clinical outcome.223,224 The lack of protection, in terms of
biomarker release and clinical outcomes, in two recent larger-scale
trials not in patients with STEMI but in patients undergoing cardiovascular surgery is at first glance somewhat discouraging and surprising.225,226 In both these trials, however, the potential protection
by remote ischaemic conditioning was obviated by use of propofol
in almost all patients, and in both trials a large number of patients
underwent not only bypass surgery but additional valve or vascular

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An appreciation of the differences between the human patient and


the animal models is integral to understanding these disappointing
results in the clinical arena and perhaps will serve as a basis for
the design of future trials. The mechanistic animal experiments
have for the most part been performed in young and healthy animals
with a virgin (without endothelial dysfunction and atherosclerosis)
coronary circulation; sometimes before going to human trials, infarct size reduction has not even been demonstrated in larger mammals with acute myocardial infarction which are closer to humans
than rodents.198,206
In contrast to such young and healthy animal models, humans
with acute myocardial infarction regularly have a number of risk factors and co-morbidities, such as advanced age, diabetes, hypertension, and hypercholesterolaemia which all interfere with
cardioprotective interventions and attenuate or abrogate an infarct
size reduction by conditioning strategies or drugs.166 On the other
hand, patients with acute myocardial infarction are regularly under
treatment with a number of medications which per se may reduce
infarct size, such as ACE inhibitors/AT1 blockers, b-blockers, statins,
and anti-diabetics.110,166,207 In particular, the novel P2Y12 antagonists not only reduce platelet aggregation but also induce direct cardioprotection through a similar signal transduction pathway as
ischaemic postconditioning.208,209 Therefore, conditioning strategies may become redundant with use of the novel P2Y12 antagonists, as emphasized by Cohen and Downey210,211 and suggested
by a retrospective analysis on infarct size reduction by ischaemic
postconditioning.212 Use of opioids for pain management during
acute myocardial infarction may also initiate direct cardioprotection.166,213 Thus the potential to ascertain an infarct size reduction
by comparison of patients with STEMI undergoing optimal therapy
to patients who additionally undergo a cardioprotective intervention may be limited by the reduced efficiency of the intervention
secondary to the patients comorbidities and the redundant nature
of the intervention with several medications which in themselves elicit direct cardioprotection. Interestingly, however, in the CONDI
trial only smoking was associated with a reduced efficacy and statin
use with an increased efficacy of remote ischaemic conditioning to
reduce infarct size.214
Apart from interference of co-morbidities and co-medications,
the temporal evolution of myocardial infarction in interaction with
the logistics of interventional reperfusion poses a major problem
(Figure 5). If reperfusion is rapid, e.g. within 30 min, after the onset
of symptoms, no intervention or drug will make a difference in terms
of infarct size or clinical outcomes because reperfusion per se is so
successful. On the other hand, if reperfusion is late, e.g. after 4 h or
more, there remains only little salvageable myocardium.215 During
the window of opportunity between 1 and 2/3 h, an intervention
may be able to affect infarct size but demonstrating a difference in
outcomes statistically will be very difficult as successful reperfusion
per se in this time window is associated with a low mortality.
Then there are specific reasons for potential failure of translation.
Ischaemic postconditioning entails further manipulation of the culprit lesion and may induce coronary microembolization which
may offset the cardioprotective effect;207,216 it may therefore be
mandatory to use direct stenting and inflate the balloon upstream
of the stent217 to recruit the full potential of ischaemic
postconditioning.111

G. Heusch et al.

Cardioprotection beyond reperfusion

Authors contributions
G.H. and B.J.G. drafted the manuscript.

Funding
G.H. was supported by the German Research Foundation (He 1320/
18-3; SFB 1116/B8).
Conflict of interest: none declared.

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