Академический Документы
Профессиональный Документы
Культура Документы
REVIEW
Mechanisms of disease
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
* 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.
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
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
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.
Page 3 of 17
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.
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
Cardioprotection by local
postconditioning, remote
conditioning, drugs, and other
interventions in patients with ST
segment elevation myocardial
infarction
G. Heusch et al.
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.
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
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
*
n.s.
Hahn et al.132
POST
350/350
PoCo
ST segment resolution
n.s.
Limalanathan
et al.133
POSTEMI
136/136
PoCo
n.s
Mortality at 4 months
Eitel et al.134
LIPSIA CONDITIONING
160/173
PoCo
n.s.
n.s.
44/43
PoCo
n.s.
Luz et al.131
*
n.s.
Sloth et al.141
Crimi et al.137
CONDI
69/73
48/48
RIC
RIC
*
*
*
Eitel et al.134
LIPSIA CONDITIONING
160/158
RIC (+PoCo)
n.s.
n.s.
107/108
Aspiration thrombectomy
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
*
*
*
*
De Carlo et al.152
MACE at 1 year
Stone et al.153
Lagerqvist et al.143
INFUSE-AMI
TASTE
179/174
3623 /3621
Aspiration thrombectomy
Aspiration thrombectomy
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
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.
*
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
n.s.
*
Nichol et al.161
VELOCITY
26/28
Hypothermia
n.s.
*
AMIHOT
122/121
Hyperoxemia
n.s.
MACCE at 30 days
n.s.
AMIHOT II
CRISP-AMI
124/258
142/133
Hyperoxemia
Ballon counterpulsation
*
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
*
*
n.s.
n.s.
G. Heusch et al.
ONeill et al.162
Stone et al.163
Patel et al.157
HALT-MI
Granger et al.172
Mahaffey et al.173
153/159
LeukArrest
COMMA
271/281
Pexelizumab
Mortality at 6 months
*
COMPLY
307/309
Pexelizumab
APEX-AMI174
APEX-AMI
2885/2860
Pexelizumab
Mortality at 30 days
Atar et al.175
FIRE
104/94
FX06
n.s.
n.s.
ODonoghue
et al.176
LATITUDE-TIMI 60
1758/1731
Losmapimod
n.s.
Mahaffey et al.177
AMISTAD
117/119
Adenosine i.v.
*
n.s.
27/27
Adenosine i.c.
n.s.
*
703/1414
Adenosine i.v.
n.s.
n.s.
207/208
Adenosine i.c.
ST segment resolution
n.s.
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.
n.s.
*
Mortality at 1 year
MACE at 30 days
n.s.
Zeymer et al.185
ESCAMI
322/316
Eniporide
n.s
Ott et al.186
REVIVAL
52/52
Erythropoietin
Voors et al.187
HEBE III
235/213
Erythropoietin
*
Najjar et al.188
REVEAL
68/68
Erythropoietin
n.s.
*
Kitakaze et al.189
Kitakaze et al.189
J-WIND
J-WIND
280/255
260/269
ANP
Nicorandil
*
*
n.s.
40/40
Nitrite i.c.
n.s.
MACE at 1 year
*
228/227
d PKC inhibition
n.s.
n.s.
Lonborg et al.200
51/54
Exenatide
*
Ghaffari et al.197
51/50
Cyclosporine A
Lincoff et al.
193
PROTECTION AMI
n.s.
Page 7 of 17
n.s.
Continued
Jones et al.191
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
Cyclosporine A
n.s.
60/57
MTP-131
n.s.
n.s.
MITOCARE
80/83
TRO40303
n.s.
Safety events
*
METOCARD-CNIC
114/1106
Metoprolol
*
n.s.
Roolvink et al.203
EARLY-BAMI
347/336
Metoprolol
n.s.
MACE at 30 days
n.s.
Er et al.202
BEAT-AMI
50/50
Esmolol
*
Safety events
G. Heusch et al.
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.
Page 9 of 17
Page 10 of 17
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.
G. Heusch et al.
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.
References
1. Moran AE, Forouzanfar MH, Roth GA, Mensah GA, Ezzati M, Flaxman A,
Murray CJ, Naghavi M. The global burden of ischemic heart disease in 1990 and
2010: the global burden of disease 2010 study. Circulation 2014;129:1493 1501.
2. Roe MT, Messenger JC, Weintraub WS, Cannon CP, Fonarow GC, Dai D,
Chen AY, Klein LW, Masoudi FA, McKay C, Hewitt K, Brindis RG, Peterson ED,
Rumsfeld JS. Treatments, trends, and outcomes of acute myocardial infarction and
percutaneous coronary intervention. J Am Coll Cardiol 2010;56:254 263.
3. Jernberg T, Johanson P, Held C, Svennblad B, Lindback J, Wallentin L, SWEDEHEART/RIKS-HIA. Association between adoption of evidence-based treatment
and survival for patients with ST-elevation myocardial infarction. J Am Med Assoc
2011;305:1677 1684.
4. Puymirat E, Simon T, Steg PG, Schiele F, Gueret P, Blanchard D, Khalife K,
Goldstein P, Cattan S, Vaur L, Cambou JP, Ferrieres J, Danchin N, USIK USIC
2000 Investigators, FAST MI Investigators. Association of changes in clinical characteristics and management with improvement in survival among patients with
ST-elevation myocardial infarction. J Am Med Assoc 2012;308:998 1006.
5. Kristensen SD, Laut KG, Fajadet J, Kaifoszova Z, Kala P, Di Mario C, Wijns W,
Clemmensen P, Agladze V, Antoniades L, Alhabib KF, de Boer MJ, Claeys MJ,
Deleanu D, Dudek D, Erglis A, Gilard M, Goktekin O, Guagliumi G,
Gudnason T, Hansen KW, Huber K, James S, Janota T, Jennings S, Kajander O,
Kanakakis J, Karamfiloff KK, Kedev S, Kornowski R, Ludman PF, Merkely B,
Milicic D, Najafov R, Nicolini FA, Noc M, Ostojic M, Pereira H, Radovanovic D,
Sabate M, Sobhy M, Sokolov M, Studencan M, Terzic I, Wahler S, Widimsky P. Reperfusion therapy for ST elevation acute myocardial infarction 2010/2011: current
status in 37 ESC countries. Eur Heart J 2014;35:1957 1970.
6. Menees DS, Peterson ED, Wang Y, Curtis JP, Messenger JC, Rumsfeld JS,
Gurm HS. Door-to-balloon time and mortality among patients undergoing primary PCI. N Engl J Med 2013;369:901909.
7. Nallamothu BK, Normand SL, Wang Y, Hofer TP, Brush JE Jr, Messenger JC,
Bradley EH, Rumsfeld JS, Krumholz HM. Relation between door-to-balloon times
and mortality after primary percutaneous coronary intervention over time: a
retrospective study. Lancet 2015;385:1114 1122.
8. Stone GW, Selker HP, Thiele H, Patel MR, Udelson JE, Ohman EM, Maehara A,
Eitel I, Granger CB, Jenkins PL, Nichols M, Ben-Yehuda O. Relationship between
infarct size and outcomes following Primary PCI: patient-level analysis from 10
randomized trials. J Am Coll Cardiol 2016;67:1674 1683.
9. Heusch G, Libby P, Gersh B, Yellon D, Bohm M, Lopaschuk G, Opie L. Cardiovascular remodeling in coronary artery disease and heart failure. Lancet 2014;383:
1933 1943.
10. Heusch G. Postconditioning. Old wine in a new bottle? J Am Coll Cardiol 2004;44:
1111 1112.
11. Yellon DM, Hausenloy DJ. Myocardial reperfusion injury. N Engl J Med 2007;357:
1121 1135.
12. Schwartz Longacre L, Kloner RA, Arai AE, Baines CP, Bolli R, Braunwald E,
Downey J, Gibbons RJ, Gottlieb RA, Heusch G, Jennings RB, Lefer DJ,
Mentzer RM, Murphy E, Ovize M, Ping P, Przyklenk K, Sack MN, Van der
Heide RS, Vinten-Johansen J, Yellon DM. New horizons in cardioprotection: recommendations from the 2010 National Heart, Lung, and Blood Institute Workshop. Circulation 2011;124:1172 1179.
13. Heusch G. Cardioprotection: chances and challenges of its translation to the clinic. Lancet 2013;381:166 175.
14. Kloner RA. Current state of clinical translation of cardioprotective agents for
acute myocardial infarction. Circ Res 2013;113:451 463.
15. Ovize M, Thibault H, Przyklenk K. Myocardial conditioning: opportunities for clinical translation. Circ Res 2013;113:439 450.
16. Bulluck H, Yellon DM, Hausenloy DJ. Reducing myocardial infarct size: challenges
and future opportunities. Heart 2015;102:341 348.
17. Ibanez B, Heusch G, Ovize M, Van de Werf F. Evolving therapies for myocardial
ischemia/reperfusion injury. J Am Coll Cardiol 2015;65:1454 1471.
18. DeWood MA, Spores J, Notske R, Mouser LT, Burroughs R, Golden MS, Lang HT.
Prevalence of total coronary occlusion during the early hours of the transmural
myocardial infarction. N Engl J Med 1980;303:897 902.
19. Reimer KA, Jennings RB, Cobb FR, Murdock RH, Greenfield JC Jr, Becker LC,
Bulkley BH, Hutchins GM, Schwartz RP Jr, Bailey KR, Passamani ER. Animal models for protecting ischemic myocardium: results of the NHLBI cooperative study.
Comparison of unconscious and conscious dog models. Circ Res 1985;56:
651 665.
20. Skyschally A, Schulz R, Heusch G. Pathophysiology of myocardial infarction: protection by ischemic pre- and postconditioning. Herz 2008;33:88 100.
21. Reimer KA, Lowe JE, Rasmussen MM, Jennings RB. The wavefront phenomenon of
ischemic cell death. 1. Myocardial infarct size vs duration of coronary occlusion in
dogs. Circulation 1977;56:786 794.
22. Reimer KA, Jennings RB. The wavefront phenomenon of myocardial ischemic
cell death. II. Transmural progression of necrosis within the framework of ischemic bed size (myocardium at risk) and collateral flow. Lab Invest 1979;40:
633 644.
23. Jennings RB. Historical perspective on the pathology of myocardial ischemia/reperfusion injury. Circ Res 2013;113:428 438.
24. Schomig A, Mehilli J, Antoniucci D, Ndrepepa G, Markwardt C, Di Pede F,
Nekolla SG, Schlotterbeck K, Schu hlen H, Pache J, Seyfarth M, Martinoff S,
Benzer W, Schmitt C, Dirschinger J, Schwaiger M, Kastrati A. Mechanical reperfusion in patients with acute myocardial infarction presenting more than 12 hours
surgery, thus entailing greater surgical trauma from which, in contrast to myocardial ischaemia/reperfusion injury, remote ischaemic
conditioning does not protect.227 Therefore, with hopefully better
understanding of the protective transfer and of the activation of
myocardial protective signal transduction, remote ischaemic conditioning may indeed become the future of cardioprotection.228 It is
also certainly worthwhile to pursue further the drugs for which
positive clinical trials in patients with STEMI exist, i.e. atrial natriuretic peptide,189 the glucagon-like peptide 1 analogue exenatide200,229
and the b-blockers metoprolol201 and esmolol.202 As for remote ischaemic conditioning, a better understanding of the protective signal transduction by these agents is needed. Clearly, mitochondria
are critical subcellular target organelles for cardioprotection.99 Despite recent disappointing trials which targeted specific mitochondrial molecules, i.e. cyclophilin D,195 cardiolipin,199 or the
translocator protein 18 kDa198,230 with the aim of improving respiration and to inhibit opening of the MPTP, further investigation of
mitochondria with identification of novel targets, such as the release
of mitochondrial DNA,231 or better approaches at established targets, such as connexin 43,104 ATP-dependent K+-channels,106,232
STAT 3,102 and GSK-3b,233 appears worthwhile. Also, combinations
of cardioprotective manoeuvers and drugs appear to be a logical target for further investigation.234
As pointed out before12,204,205 embarking on phase III clinical
trials with longer-term clinical outcome as primary endpoint, solid
experimental data from large animal models and preferably confirmed by other laboratories and positive proof-of-concept trials
with infarct size (biomarker, imaging) and microvascular obstruction
as primary endpoints are mandatory. Patients with larger, preferably
anterior infarcts and with an occluded coronary artery at the time of
the protective intervention will benefit more than patients with
smaller infarcts and with already partial reperfusion at the time of
the protective intervention.235 Clearly, additional protection beyond timely reperfusion is still needed, as more and more patients
who have survived an acute myocardial infarction develop heart failure.9 So, despite the challenges and the disappointments the goal of
cardioprotection in patients undergoing reperfusion for STEMI remains the last frontier of reperfusion and a worthwhile target for
translation from the experimental model to the bedside. It has
been a long and bumpy road but the end is not yet in sight.
Page 11 of 17
Page 12 of 17
25.
26.
27.
28.
29.
30.
31.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
32.
G. Heusch et al.
95. Andreotti F, Pasceri V, Hackett DR, Davies GJ, Haider AW, Maseri A. Preinfarction
as a predictor of more rapid coronary thrombolysis in patients with acute myocardial infarction. N Engl J Med 1996;334:7 12.
96. Btker HE, Kharbanda R, Schmidt MR, Bottcher M, Kaltoft AK, Terkelsen CJ,
Munk K, Andersen NH, Hansen TM, Trautner S, Lassen JF, Christiansen EH,
Krusell LR, Kristensen SD, Thuesen L, Nielsen SS, Rehling M, Sorensen HT,
Redington AN, Nielsen TT. Remote ischaemic conditioning before hospital admission, as a complement to angioplasty, and effect on myocardial salvage in patients with acute myocardial infarction: a randomised trial. Lancet 2010;375:
727 734.
97. Yellon DM, Downey JM. Preconditioning the myocardium: from cellular physiology to clinical cardiology. Physiol Rev 2003;83:1113 1151.
98. Heusch G, Boengler K, Schulz R. Cardioprotection: nitric oxide, protein kinases,
and mitochondria. Circulation 2008;118:1915 1919.
99. Heusch G. Molecular basis of cardioprotection: signal transduction in ischemic
pre-, post- and remote conditioning. Circ Res 2015;116:674 699.
100. Hausenloy DJ, Tsang A, Yellon DM. The reperfusion injury salvage kinase pathway:
a common target for both ischemic preconditioning and postconditioning. Trends
Cardiovasc Med. 2005;15:6975.
101. Lecour S. Multiple protective pathways against reperfusion injury: a SAFE path
without aktion? J Mol.Cell Cardiol 2009;46:607609.
102. Heusch G, Musiolik J, Gedik N, Skyschally A. Mitochondrial STAT3 activation and
cardioprotection by ischemic postconditioning in pigs with regional myocardial ischemia/reperfusion. Circ Res 2011;109:1302 1308.
103. Boengler K, Dodoni G, Rodriguez-Sinovas A, Cabestrero A, Ruiz-Meana M,
Gres P, Konietzka I, Lopez-Iglesias C, Garca-Dorado D, Di Lisa F, Heusch G,
Schulz R. Connexin 43 in cardiomyocyte mitochondria and its increase by ischemic preconditioning. Cardiovasc Res 2005;67:234 244.
104. Schulz R, Gorge PM, Gorbe A, Ferdinandy P, Lampe PD, Leybaert L. Connexin 43
is an emerging therapeutic target in ischemia/reperfusion injury, cardioprotection
and neuroprotection. Pharmacol Ther 2015;153:90 106.
105. Grover GJ, Garlid KD. ATP-sensitive potassium channels: a review of their cardioprotective pharmacology. J Mol Cell Cardiol 2000;32:677695.
106. Heinzel FR, Luo Y, Li X, Boengler K, Buechert A, Garca-Dorado D, Di Lisa F,
Schulz R, Heusch G. Impairment of diazoxide-induced formation of reactive oxygen species and loss of cardioprotection in connexin 43 deficient mice. Circ Res
2005;97:583 586.
107. Bernardi P, Di Lisa F. The mitochondrial permeability transition pore: molecular
nature and role as a target in cardioprotection. J Mol Cell Cardiol 2015;78:
100 106.
108. Heusch G, Botker HE, Przyklenk K, Redington A, Yellon DM. Remote ischemic
conditioning. J Am Coll Cardiol 2015;65:177 195.
109. Heusch G, Musiolik J, Kottenberg E, Peters J, Jakob H, Thielmann M. STAT5 activation and cardioprotection by remote ischemic preconditioning in humans. Circ
Res 2012;110:111115.
110. Kleinbongard P, Heusch G. Extracellular signalling molecules in the ischaemic/reperfused heartdruggable and translatable for cardioprotection? Br J Pharmacol
2015;172:2010 2025.
111. Staat P, Rioufol G, Piot C, Cottin Y, Cung TT, LHuillier I, Aupetit J-F, Bonnefoy E,
Finet G, Andre-Fouet X, Ovize M. Postconditioning the human heart. Circulation
2005;112:2143 2148.
112. Ma XJ, Zhang XH, Li CM, Luo M. Effect of postconditioning on coronary blood
flow velocity and endothelial function in patients with acute myocardial infarction.
Scand Cardiovasc J 2006;40:327 333.
113. Yang XC, Liu Y, Wang LF, Cui L, Wang T, Ge YG, Wang HS, Li WM, Xu L, Ni ZH,
Liu SH, Zhang L, Jia HM, Vinten-Johansen J, Zhao ZQ. Reduction in myocardial
infarct size by postconditioning in patients after percutaneous coronary intervention. J Invasive Cardiol 2007;19:424 430.
114. Laskey WK, Yoon S, Calzada N, Ricciardi MJ. Concordant improvements in coronary flow reserve and ST-segment resolution during percutaneous coronary
intervention for acute myocardial infarction: a benefit of postconditioning. Catheter Cardiovasc Interv 2008;72:212 220.
115. Thibault H, Piot C, Staat P, Bontemps L, Sportouch C, Rioufol G, Cung TT,
Bonnefoy E, Angoulvant D, Aupetit JF, Finet G, Andre-Fouet X, Macia JC,
Raczka F, Rossi R, Itti R, Kirkorian G, Derumeaux G, Ovize M. Long-term benefit
of postconditioning. Circulation 2008;117:1037 1044.
116. Zhao WS, Xu L, Wang LF, Zhang L, Zhang ZY, Liu Y, Liu XL, Yang XC, Cui L,
Zhang L. A 60-s postconditioning protocol by percutaneous coronary intervention inhibits myocardial apoptosis in patients with acute myocardial infarction.
Apoptosis 2009;14:1204 1211.
117. Lonborg J, Kelbaek H, Vejlstrup N, Jorgensen E, Helqvist S, Saunamaki K,
Clemmensen P, Holmvang L, Treiman M, Jensen JS, Engstrom T. Cardioprotective
effects of ischemic postconditioning in patients treated with primary percutaneous coronary intervention, evaluated by magnetic resonance. Circ Cardiovasc Interv 2010;3:34 41.
Page 13 of 17
Page 14 of 17
137.
138.
139.
140.
141.
142.
143.
144.
145.
146.
147.
148.
149.
150.
151.
G. Heusch et al.
152.
153.
154.
155.
157.
158.
159.
160.
161.
162.
163.
164.
156.
stenting alone in patients with acute myocardial infarction. The JETSTENT trial.
J Am Coll Cardiol 2010;56:1298 1306.
De Carlo M, Aquaro GD, Palmieri C, Guerra E, Misuraca L, Giannini C,
Lombardi M, Berti S, Petronio AS. A prospective randomized trial of thrombectomy versus no thrombectomy in patients with ST-segment elevation myocardial
infarction and thrombus-rich lesions: MUSTELA (MUltidevice Thrombectomy in
Acute ST-Segment ELevation Acute Myocardial Infarction) trial. J Am Coll Cardiol
Cardiovasc Interv 2012;5:1223 1230.
Stone GW, Maehara A, Witzenbichler B, Godlewski J, Parise H, Dambrink JH,
Ochala A, Carlton TW, Cristea E, Wolff SD, Brener SJ, Chowdhary S,
El-Omar M, Neunteufl T, Metzger DC, Karwoski T, Dizon JM, Mehran R,
Gibson CM. Intracoronary abciximab and aspiration thrombectomy in patients
with large anterior myocardial infarction: the INFUSE-AMI randomized trial.
J Am Med Assoc 2012;307:1817 1826.
Desch S, Stiermaier T, de Waha S, Lurz P, Gutberlet M, Sandri M, Mangner N,
Boudriot E, Woinke M, Erbs S, Schuler G, Fuernau G, Eitel I, Thiele H. Thrombus
aspiration in patients with ST-segment elevation myocardial infarction presenting
late after symptom onset. J Am Coll Cardiol Cardiovasc Interv 2016;9:113122.
Sardella G, Mancone M, Bucciarelli-Ducci C, Agati L, Scardala R, Carbone I,
Francone M, Di RA, Benedetti G, Conti G, Fedele F. Thrombus aspiration during
primary percutaneous coronary intervention improves myocardial reperfusion
and reduces infarct size: the EXPIRA (thrombectomy with export catheter in
infarct-related artery during primary percutaneous coronary intervention) prospective, randomized trial. J Am Coll Cardiol 2009;53:309 315.
Kelbaek H, Hofsten DE, Kober L, Helqvist S, Klovgaard L, Holmvang L,
Jorgensen E, Pedersen F, Saunamaki K, De Backer O, Bang LE, Kofoed KF,
Lonborg J, Ahtarovski K, Vejlstrup N, Botker HE, Terkelsen CJ,
Christiansen EH, Ravkilde J, Tilsted HH, Villadsen AB, Aaroe J, Jensen SE,
Raungaard B, Jensen LO, Clemmensen P, Grande P, Madsen JK,
Torp-Pedersen C, Engstrom T. Deferred versus conventional stent implantation
in patients with ST-segment elevation myocardial infarction (DANAMI 3-DEFER):
an open-label, randomised controlled trial. Lancet 2016;doi:10.1016/
S0140-6736(16)30072-1.
Patel MR, Smalling RW, Thiele H, Barnhart HX, Zhou Y, Chandra P, Chew D,
Cohen M, French J, Perera D, Ohman EM. Intra-aortic balloon counterpulsation
and infarct size in patients with acute anterior myocardial infarction without
shock: the CRISP AMI randomized trial. J Am Med Assoc 2011;306:1329 1337.
Dixon SR, Whitbourn RJ, Dae MW, Grube E, Sherman W, Schaer GL, Jenkins JS,
Baim DS, Gibbons RJ, Kuntz RE, Popma JJ, Nguyen TT, ONeill WW. Induction of
mild systemic hypothermia with endovascular cooling during primary percutaneous coronary intervention for acute myocardial infarction. J Am Coll Cardiol
2002;40:1928 1934.
Gotberg M, Olivecrona GK, Koul S, Carlsson M, Engblom H, Ugander M, van der
Pals J, Algotsson L, Arheden H, Erlinge D. A pilot study of rapid cooling by cold
saline and endovascular cooling before reperfusion in patients with ST-elevation
myocardial infarction. Circ Cardiovasc Interv 2010;3:400407.
Erlinge D, Gotberg M, Lang I, Holzer M, Noc M, Clemmensen P, Jensen U,
Metzler B, James S, Btker HE, Omerovic E, Engblom H, Carlsson M,
Arheden H, Ostlund O, Wallentin L, Harnek J, Olivecrona GK. Rapid endovascular catheter core cooling combined with cold saline as an adjunct to percutaneous
coronary intervention for the treatment of acute myocardial infarction (The
CHILL-MI trial). J Am Coll Cardiol 2014;63:1857 1865.
Nichol G, Strickland W, Shavelle D, Maehara A, Ben-Yehuda O, Genereux P,
Dressler O, Parvataneni R, Nichols M, McPherson J, Barbeau G, Laddu A,
Elrod JA, Tully GW, Ivanhoe R, Stone GW, Investigators V. Prospective, multicenter, randomized, controlled pilot trial of peritoneal hypothermia in patients with
ST-segment- elevation myocardial infarction. Circ Cardiovasc Interv 2015;8:
e001965.
ONeill WW, Martin JL, Dixon SR, Bartorelli AL, Trabattoni D, Oemrawsingh PV,
Atsma DE, Chang M, Marquardt W, Oh JK, Krucoff MW, Gibbons RJ, Spears JR.
Acute myocardial infarction with hyperoxemic therapy (AMIHOT): a prospective,
randomized trial of intracoronary hyperoxemic reperfusion after percutaneous
coronary intervention. J Am Coll Cardiol 2007;50:397405.
Stone GW, Martin JL, de Boer MJ, Margheri M, Bramucci E, Blankenship JC,
Metzger DC, Gibbons RJ, Lindsay BS, Weiner BH, Lansky AJ, Krucoff MW,
Fahy M, Boscardin WJ. Effect of supersaturated oxygen delivery on infarct size
after percutaneous coronary intervention in acute myocardial infarction. Circ Cardiovasc Interv 2009;2:366375.
Selker HP, Beshansky JR, Sheehan PR, Massaro JM, Griffith JL, DAgostino RB,
Ruthazer R, Atkins JM, Sayah AJ, Levy MK, Richards ME, Aufderheide TP,
Braude DA, Pirrallo RG, Doyle DD, Frascone RJ, Kosiak DJ, Leaming JM, Van
Gelder CM, Walter GP, Wayne MA, Woolard RH, Opie LH, Rackley CE,
Apstein CS, Udelson JE. Out-of-hospital administration of intravenous
glucose-insulin-potassium in patients with suspected acute coronary syndromes:
the IMMEDIATE Randomized Controlled Trial. JAMA 2012;107:1925 1933.
Page 15 of 17
Page 16 of 17
G. Heusch et al.
224. Hausenloy DJ, Kharbanda R, Rahbek Schmidt M, Moller UK, Ravkilde J, Okkels
Jensen L, Engstrom T, Garcia Ruiz JM, Radovanovic N, Christensen EF,
Sorensen HT, Ramlall M, Bulluck H, Evans R, Nicholas J, Knight R, Clayton T,
Yellon DM, Botker HE. Effect of remote ischaemic conditioning on clinical outcomes in patients presenting with an ST-segment elevation myocardial infarction
undergoing primary percutaneous coronary intervention. Eur Heart J 2015;36:
1846 1848.
225. Hausenloy DJ, Candilio L, Evans R, Ariti C, Jenkins DP, Kolvekar S, Knight R,
Kunst G, Laing C, Nicholas J, Pepper J, Robertson S, Xenou M, Clayton T,
Yellon DM, Investigators ET. Remote ischemic preconditioning and outcomes
of cardiac surgery. N Engl J Med 2015;373:1408 1417.
226. Meybohm P, Bein B, Brosteanu O, Cremer J, Gruenewald M, Stoppe C, Coburn M,
Schaelte G, Boning A, Niemann B, Roesner J, Kletzin F, Strouhal U, Reyher C,
Laufenberg-Feldmann R, Ferner M, Brandes IF, Bauer M, Stehr SN, Kortgen A,
Wittmann M, Baumgarten G, Meyer-Treschan T, Kienbaum P, Heringlake M,
Schon J, Sander M, Treskatsch S, Smul T, Wolwender E, Schilling T, Fuernau G,
Hasenclever D, Zacharowski K, Collaborators RIS. A multicenter trial of remote
ischemic preconditioning for heart surgery. N Engl J Med 2015;373:1397 1407.
227. Heusch G, Gersh BJ. ERICCA and RIPHeart: two nails in the coffin for cardioprotection by remote ischemic conditioning? Probably not! Eur Heart J 2015;37:
200 201.
228. Heusch G. Remote conditioning: the future of cardioprotection? J Cardiovasc Med
(Hagerstown) 2013;14:176 179.
229. Woo JS, Kim W, Ha SJ, Kim JB, Kim SJ, Kim WS, Seon HJ, Kim KS. Cardioprotective
effects of exenatide in patients with ST-segment-elevation myocardial infarction
undergoing primary percutaneous coronary intervention: results of exenatide
myocardial protection in revascularization study. Arterioscler Thromb Vasc Biol
2013;33:2252 2260.
230. Schaller S, Paradis S, Ngoh GA, Assaly R, Buisson B, Drouot C, Ostuni MA,
Lacapere JJ, Bassissi F, Bordet T, Berdeaux A, Jones SP, Morin D, Pruss RM.
TRO40303, a new cardioprotective compound, inhibits mitochondrial permeability transition. J Pharmacol Exp Ther 2010;333:696 706.
231. Yang XM, Cui L, White J, Kuck J, Ruchko MV, Wilson GL, Alexeyev M,
Gillespie MN, Downey JM, Cohen MV. Mitochondrially targeted Endonuclease
III has a powerful anti-infarct effect in an in vivo rat model of myocardial ischemia/reperfusion. Basic Res Cardiol 2015;110:3.
232. Garlid KD, Costa ADT, Quinlan CL, Pierre SV, Dos Santos P. Cardioprotective
signaling to mitochondria. J Mol Cell Cardiol 2009;46:858 866.
233. Juhaszova M, Zorov DB, Kim S-H, Pepe S, Fu Q, Fishbein KW, Ziman BD, Wang S,
Ytrehus K, Antos CL, Olson EN, Sollott SJ. Glycogen synthase kinase-3b mediates
convergence of protection signaling to inhibit the mitochondrial permeability
transition pore. J Clin Invest 2004;113:1535 1549.
234. Alburquerque-Bejar JJ, Barba I, Inserte J, Miro-Casas E, Ruiz-Meana M, Poncelas M,
Vilardosa U, Valls-Lacalle L, Rodriguez-Sinovas A, Garcia-Dorado D. Combination therapy with remote ischaemic conditioning and insulin or exenatide enhances infarct size limitation in pigs. Cardiovasc Res 2015;107:246 254.
235. Roubille F, Mewton N, Elbaz M, Roth O, Prunier F, Cung TT, Piot C, Roncalli J,
Rioufol G, Bonnefoy-Cudraz E, Wiedemann JY, Furber A, Jacquemin L,
Willoteaux S, Abi-Khallil W, Sanchez I, Finet G, Sibellas F, Ranc S, Boussaha I,
Croisille P, Ovize M. No post-conditioning in the human heart with thrombolysis
in myocardial infarction flow 23 on admission. Eur Heart J 2014;35:1675 1682.
Page 17 of 17