Review

The Coronary Circulation as a Target of Cardioprotection

Gerd Heusch

Abstract: The atherosclerotic coronary vasculature is not only the culprit but also a victim of myocardial ischemia/
reperfusion injury. Manifestations of such injury are increased vascular permeability and edema, endothelial
dysfunction and impaired vasomotion, microembolization of atherothrombotic debris, stasis with intravascular cell
aggregates, and finally, in its most severe form, capillary destruction with hemorrhage. In animal experiments, local
and remote ischemic pre- and postconditioning not only reduce infarct size but also these manifestations of coronary
vascular injury, as do drugs which recruit signal transduction steps of conditioning. Clinically, no-reflow is frequently
seen after interventional reperfusion, and it carries an adverse prognosis. The translation of cardioprotective
interventions to clinical practice has been difficult to date. Only 4 drugs (brain natriuretic peptide, exenatide,
metoprolol, and esmolol) stand unchallenged to date in reducing infarct size in patients with reperfused acute
myocardial infarction; unfortunately, for these drugs, no information on their impact on the ischemic/reperfused
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coronary circulation is available.   (Circ Res. 2016;118:1643-1658. DOI: 10.1161/CIRCRESAHA.116.308640.)

Key Words: coronary artery disease ■ coronary occlusion ■ hemorrhage
■ myocardial infarction ■ reperfusion injury

M yocardial ischemia/reperfusion injury affects not only

the cardiomyocyte compartment but also all other cel-
lular compartments, and the coronary circulation has a cen-
tral role in it.1,2 Acute myocardial infarction most often arises
from atherosclerotic plaque rupture/erosion with superim-
posed thrombosis (type 1 myocardial infarction). However, in
the absence of coronary atherosclerosis, coronary vasospasm
and endothelial dysfunction may also precipitate acute myo-
cardial infarction (type 2).3 Reperfusion of the occluded coro-
nary artery with restoration of coronary blood flow not only
terminates myocardial ischemia but also inflicts additional
injury,4–6 and interventional or surgical revascularization may
actually induce periprocedural myocardial infarction (types 4
and 5 myocardial infarction). The spatial and temporal evo-
lution of coronary occlusion and reperfusion determine not
only the size of the affected myocardial region but also the
nature of the outcome from myocardial ischemia/reperfusion,
that is, reversible (stunning) or irreversible (infarction) injury
and, vice versa, also protection from injury (hibernation and
conditioning).
Cardioprotective interventions reduce myocardial isch-
emia/reperfusion injury, notably infarct size, but also ar-
rhythmias, left ventricular dysfunction, and coronary vascular
impairment. A complex signal transduction cascade underlies
the cardioprotective effects of ischemic preconditioning, isch-
emic postconditioning, and remote ischemic conditioning.7
A variety of drugs that often recruit signaling steps of condi-
tioning strategies have been used to achieve cardioprotection.
The translation of cardioprotection from animal experiments
to clinical practice has been difficult and largely disappoint-
ing to date, despite several positive proof-of-concept studies
in humans.8 Neglect of the coronary circulation as a victim
of myocardial ischemia/reperfusion injury and as a target for
cardioprotection may have contributed to the lack of transla-
tion of cardioprotection to clinical practice.2
A particular problem is acute myocardial infarction in
women.9 On the one hand, the female heart is more resistant
to myocardial ischemia/reperfusion than the male heart.10 On
the other hand, women have nonobstructive coronary artery
disease more often than men, and coronary vasomotion (coro-
nary vasospasm, endothelial dysfunction, and microvascular
dysfunction) may play a greater role in precipitating acute
myocardial infarction in women.11
Coronary Circulation as a Determinant
of Myocardial Ischemic Injury
The perfusion territory of the coronary artery distal to the site
of the occlusion is the area at risk of infarction because the
coronary arteries are functional end arteries. Within a given
area at risk, both the duration and the severity of coronary
blood flow reduction determine the nature and amount of inju-
ry.12,13 A complete coronary occlusion of <20-minute duration
results in reversible injury, that is, contractile dysfunction with
a slow, but complete recovery during reperfusion, a phenom-
enon called myocardial stunning.14,15 The underlying mecha-
nisms of the prolonged contractile dysfunction relate to the

Original received March 1, 2016; revision received March 17, 2016; accepted March 22, 2016.
From the Institute for Pathophysiology, West German Heart and Vascular Center, University of Essen Medical School, University of Essen, Essen,
Germany.
Correspondence to Professor Dr. med. Dr. h.c. Gerd Heusch, Institut für Pathophysiologie, Westdeutsches Herz- und Gefässzentrum Essen,
Universitätsklinikum Essen, Hufelandstr. 55, 45122 Essen, Germany. E-mail gerd.heusch@uk-essen.de
© 2016 American Heart Association, Inc.
Circulation Research is available at http://circres.ahajournals.org DOI: 10.1161/CIRCRESAHA.116.308640

1643
 1644  Circulation Research  May 13, 2016
Nonstandard Abbreviations and Acronyms
MRI magnetic resonance imaging
PCI percutaneous coronary intervention
TIMI thrombolysis in myocardial infarction
enhanced formation of reactive oxygen species during early
reperfusion16 and impaired excitation–contraction coupling
after oxidative modification of the sarcoplasmic reticulum
and the contractile proteins.17 Repeated coronary occlusion of
short duration or prolonged moderate reduction in coronary
blood flow results in hibernating myocardium, a phenomenon
of reduced contractile function with retained viability and thus
eventual recovery after reperfusion. Hibernating myocardium
displays signs of both injury (loss of contractile proteins,
small doughnut-like mitochondria, and fibrosis) and adap-
tation (short-term energetic recovery, altered expression of
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mitochondrial proteins, and proteins related to cardioprotec-
tion).18,19 When the reduction in coronary blood flow is severe
and lasts longer than 20 to 40 minutes, infarction in larger
mammals develops first in the inner subendocardial layers of
the core of the area at risk and then spreads in a wavefront to
the outer subepicardial layers and the borders of the area at
risk over time. The wavefront of infarct development reflects
the lateral and transmural distribution of coronary blood flow,
which is less in the inner than in the outer layers of the myo-
cardium and less in the core than in the borders of the area at
risk.20,21 The evolution of infarction varies with species and de-
pends on the existence and extent of a collateral circulation.22
Rodents have a high heart rate and rapid development of in-
farction; only in guinea pigs there is such an extensive collater-
al circulation that no infarction develops for hours of coronary
occlusion.22 Dogs have a well-developed native collateral
circulation, and infarction starts after 40-minute coronary oc-
clusion and spreads to affect 70% of the area at risk after 6
hours20,21; in dogs, therefore, infarct size is best quantified as a
fraction of the area at risk and normalized to the residual blood
flow.12 Pigs have a negligible native collateral circulation, and
infarction starts after 15 to 35-minute coronary occlusion and
affects 80% of the area at risk after 60 to 180 minutes.23,24
Primates have few innate collaterals but are relatively resis-
tant to myocardial ischemia; there is no infarction after 40- to
60-minute coronary occlusion, and even after 90-minute coro-
nary occlusion, infarct size is smaller than that in pigs.25 Apart
from such species differences in the native collateral circu-
lation, coronary vasomotor mechanisms also differ between
species. Pigs, in contrast to dogs, respond to acetylcholine
with coronary vasoconstriction rather than vasodilation,26 and
pigs have only negligible α-adrenergic coronary vasoconstric-
tion.27 With respect to such coronary vasomotor mechanisms,
humans are closer to dogs than to pigs28; however, in the pres-
ence of coronary atherosclerosis in humans, the response to
acetylcholine may also be reversed from vasodilation to va-
soconstriction.29 Fortunately, infarct development in humans
is slower than that in the above-mentioned large mammals.
Even after 4 to 6 hours of coronary occlusion, 30% to 50% of
the area at risk remain viable and thus salvageable, as one can
estimate from magnetic resonance imaging (MRI) and from
the amount of salvage by reperfusion.30–32 Salvageable myo-
cardium remains even after 12 hours from symptom onset,33
and its salvage improves patients’ prognosis.34 It is unclear at
present to what extent the resistance of the diseased human
heart is attributable to a developed collateral circulation at
the time of infarction, as in the native dog heart, or reflects
an inherently greater resistance to ischemic injury, as in the
primate heart, or reflects preceding episodes of myocardial
ischemia/reperfusion with a preconditioning effect. Also, ef-
fective drug treatment (eg, by concomitant β-blockade, renin–
angiotensin system inhibition, statins, or P2Y12 antagonists)
may induce pre-existing cardioprotection and attenuate the
consequences of acute myocardial ischemia/reperfusion.35 In
contrast to previous notions, the hemodynamic situation has
little impact on the development of myocardial infarction;
only heart rate determines infarct progression to some ex-
tent.36 Variations in coronary blood flow not only determine
the nature and extent of myocardial injury but paradoxically
also protection from it. Repeated brief episodes of coronary
occlusion preceding a prolonged coronary occlusion with
reperfusion reduce infarct size, that is, there is ischemic pre-
conditioning.37 Likewise, repeated brief coronary occlusion
during early reperfusion reduces infarct size, that is, there is
ischemic postconditioning.38
Coronary Circulation as a Determinant
of Reperfusion and Reperfusion Injury
Although today it is unequivocally clear that timely reper-
fusion of an occluded coronary artery is the only way to
rescue myocardium from impending infarction, this notion
is a little more than 40 years old and goes back to the study
by Ross and collaborators39,40 who first reported that reper-
fusion after 180-minute coronary occlusion reduced infarct
size in dogs. These findings were quickly translated to hu-
mans with acute myocardial infarction who were reperfused
by thrombolysis or percutaneous coronary interventions
(PCIs).13,41–43 Even before the benefits of reperfusion were
established, the dark side of coronary reperfusion became
apparent, when Krug et al44 and then Kloner et al45 reported
the coronary no-reflow phenomenon. And again only a few
years later, Reimer et al20 and Reimer and Jennings21 report-
ed in a series of detailed dog studies that signs of irrevers-
ible myocardial injury, such as rupture of the sarcolemma,
became particularly manifest during reperfusion; at that
time, it was not clear whether the irreversible injury was
caused by reperfusion or only became better manifest dur-
ing reperfusion. The long debate on the existence of lethal
reperfusion injury46 was finally ended by the recognition of
the ischemic postconditioning phenomenon when Vinten-
Johansen and colleagues38 reported that repeated coronary
reocclusion during early reperfusion reduced infarct size in
dogs, and these findings were quickly confirmed in patients
with reperfused acute myocardial infarction.47,48 The fact
that a modified procedure of reperfusion could indeed at-
tenuate irreversible injury once again revived earlier studies
on gentle reperfusion,49 that is, the reduction of functional
and morphological signs of injury by reperfusion at reduced
perfusion pressure50 or reduced coronary blood flow.51 With
 Heusch   Cardioprotection and Coronary Circulation   1645
the unequivocal notion that reperfusion is both mandatory
for salvage from impending infarction and it causes irre-
versible injury per se, a complex picture arises in that both
ischemia and reperfusion contribute to the ultimate injury,
but their individual contribution to ultimate injury depends
on the duration and severity of coronary blood flow reduc-
tion.52 Whereas ischemic injury increases with the severity
and the duration of coronary blood flow reduction, there is a
maximum of reperfusion injury at more moderate ischemic
injury (Figure 1).
Technically, in the experiment, infarct size is best quan-
tified by triphenyl tetrazolium chloride staining after suffi-
cient reperfusion with washout of reductive equivalents.53,54
Infarct size is best normalized to the area at risk which is
delineated by a water-soluble dye injected into the left atri-
um after reocclusion of the coronary artery at its culprit site
(Figure 2). The area of no-reflow is delineated by injection
of thioflavin S into the left atrium, which stains endothelial
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cells, such that lack of thioflavin fluorescence reflects no-
reflow zones.55 In patients, infarct size can be estimated from
cardiac enzyme release or imaging, notably late gadolinium
enhancement in MRI. No-reflow is primarily an angiograph-
ic diagnosis immediately after reopening of the culprit coro-
nary occlusion, and it is quantified by reduced thrombolysis
in myocardial infarction (TIMI) flow grade, increased TIMI
frame count, and reduced myocardial blush grade.56–59 More
recently, microvascular obstruction is visualized by MRI as
lack of contrast within gadolinium-enhanced areas. Area of
risk can be best visualized by scintigraphy, and there are
problems in estimating area at risk with T2-weighted edema
imaging in MRI (see below).
Infarct size
[% Area at risk]
100
80
60
40
20
0 less is damaged by reperfusion. Reprinted
10
Residual
blood flow
[% of control]
Manifestations of Myocardial
Ischemia/Reperfusion Injury in the
Coronary Circulation
The manifestations of myocardial ischemia/reperfusion in the
coronary circulation go from mild and reversible functional
impairment to severe and irreversible destruction (Figure 3).
Vascular Permeability: Edema
Edema develops quickly within minutes of acute myocar-
dial ischemia60–64 and is both intracellular and interstitial.
Intracellular edema develops in cardiomyocytes and endothe-
lial cells largely as a consequence of the rapidly developing
energetic deficit and the reduced function of energy-dependent
ion pumps.65 Interstitial edema develops as a consequence of
increased interstitial osmolarity from increased ion and ca-
tabolite concentrations and a dysfunction of the endothelial
barrier function during myocardial ischemia.65 The endothelial
barrier function is made up by the glycocalyx,66 endothelial
cells, and pericytes (particularly at the postcapillary venules67).
Endothelial cytoskeletal derangement and hypercontracture
induce gap formation,68–71 which is enhanced by extracellular
adenosine but attenuated by extracellular ATP.72 Degradation of
the glycocalyx also contributes to reduced endothelial barrier
function and edema formation66,73,74; tumor necrosis factor α is
an important mediator of glycocalyx degradation,75 and glyco-
calyx degradation also promotes leukocyte76 and platelet adher-
ence.77 Exogenous nitric oxide preserves vascular integrity and
attenuates edema formation through protection of the glycoca-
lyx.78 On reperfusion, interstitial edema is greatly enhanced by
reactive hyperemia and the rapid washout of osmotically ac-
tive molecules from the intravascular space. The cellular (as a
Figure 1. Infarct size as a function of
duration of ischemia and residual/
collateral blood flow. With longer
ischemia duration and less blood flow,
ischemia-induced injury increases. The
greater the ischemia-induced injury, the
less myocardium is salvaged but also the
Time from Heusch.52 Copyright ©2013, American
Physiological Society.
 1646  Circulation Research  May 13, 2016
area at risk
infarction no-reflow
consequence of a reversed acidosis and intracellular sodium and
calcium overload) and interstitial edema development during
reperfusion follows a bimodal pattern where an initial maxi-
mum of water content after 120 minutes is associated with a
beginning leukocyte infiltration, and a secondary peak after 7
days is associated with enhanced collagen deposition.79 Edema
during reperfusion has been proposed to reflect the area at risk
on MRI,80 but edema may artifactually increase the area at
risk,81 and a bimodal pattern of edema further questions the
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use of T2-weighted edema measurement for area at risk delin-
eation.82 Myocardial edema not only is a consequence of sus-
tained myocardial ischemia/reperfusion but also contributes to
the impairment of microvascular perfusion by extravascular
compression.83,84
Vasomotion
The coronary microcirculation distal to a severe coronary ste-
nosis or coronary occlusion has traditionally been considered
as maximally dilated after exhaustion of autoregulatory reserve.
However, even during myocardial ischemia which limits region-
al contractile function, a pharmacologically recruitable vasodi-
lator reserve persists.85,86 Reactive oxygen species contributes
to the endothelial dysfunction and consequent impairment of
coronary vasomotion.87 The impairment of endothelium-medi-
ated vasodilation correlates to the severity of myocardial injury,
epicardial plaque
rupture
protection
devices
microembolization
vasomotion
IP, POCO, RIC
edema / capillary
obstruction adherence / infiltration
RIC
stasis capillary rupture /
hemorrhage
Figure 2. Typical example for delineation
of area at risk by Patent blue (left),
of infarction by triphenyl tetrazolium
chloride staining (middle), and of no-
reflow by thioflavin S fluorescence (right).
The no-reflow area was encircled by an
incision.
that is, it is greater in infarcted than in reversibly injured myo-
cardium (Figure 4).88 During myocardial ischemia/reperfusion,
the coronary microcirculation remains responsive to vasocon-
strictor mediators, notably α-adrenergic coronary vasocon-
striction.89,90 Such α-adrenergic coronary constrictor impact is
also seen in humans with chronic stable angina91 and during
PCIs.92,93 The release of vasoconstrictor substances, such as
thromboxane, serotonin,94,95 and endothelin96 from the ruptur-
ing culprit lesion into the microcirculation, in conjunction with
the impairment of endothelial function by ischemia/reperfusion
per se60,87,88,97,98 or by tumor necrosis factor α,95 can contribute
to such enhanced vasoconstrictor responsiveness during myo-
cardial ischemia/reperfusion. With more prolonged ischemia in
hibernating myocardium, there is structural remodeling of the
microvasculature with hypertrophy of smaller and atrophy of
larger vessels, reduced vascular distensibility, and increased
vasoconstriction in response to endothelin.99,100
Microembolization
Plaque fissure or rupture occur spontaneously and are induced
traumatically/iatrogenically by PCIs. Atherosclerotic debris
with superimposed thrombotic material is then dislodged and
embolized into the coronary microcirculation101 where it in-
duces patchy microinfarcts with an inflammatory reaction.102
Such microinfarcts add to the infarct size caused by sustained
Figure 3. Schematic diagram with the
different manifestations of coronary
vascular injury during acute myocardial
ischemia/reperfusion and the protective
IP, POCO, RIC interventions that attenuate these
impaired manifestations. IP indicates ischemic
preconditioning; POCO, ischemic
postconditioning; and RIC, remote ischemic
conditioning.
IP, RIC
leukocyte
 Heusch   Cardioprotection and Coronary Circulation   1647
Δ [% control]
subendocardium
150
midmyocardium
125
subepicardium
*# p<0.05 vs. 15 min occl.
p<0.05 vs. TTC positive
100
75
* tions. However, not for every manifestation of coronary vascular
50
* *#
25 * *#
0
15 min occlusion TTC positive TTC negative
60 min occlusion
Figure 4. Increase in regional myocardial blood flow in
response to intracoronary acetylcholine after 15- vs 60-minute
coronary occlusion in dogs, separately for subendocardial,
midmyocardial, and subepicardial layers. After 60-minute
coronary occlusion, the vasodilator response to acetylcholine is
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depressed, more in subendocardial than in subepicardial layers
and more in infarcted (triphenyl tetrazolium chloride [TTC] negative)
than in viable (TTC positive) myocardium. Reprinted from Ehring et
al.88 Copyright ©1995, the American Physiological Society.
coronary occlusion with reperfusion101,103,104 and impair cor-
onary dilator reserve.105,106 In patients, coronary microem-
bolization is particularly seen with PCIs in saphenous vein
bypass grafts, and it is here that protection devices are useful
to prevent atherothrombotic debris from embolizing into the
microcirculation.107,108
Stasis and Intravascular Cellular Aggregates
Myocardial ischemia and reperfusion increase the expres-
sion of adhesion molecules, such as intercellular adhesion
molecules, vascular cell adhesion molecules, and selectins,
on endothelium and circulating cells and thereby promote the
interaction of platelets, leukocytes, and endothelium and the
adherence of platelet aggregates and platelet–leukocyte ag-
gregates to the endothelium.109–115 Such aggregates are either
released from the epicardial atherosclerotic culprit lesion and
dislodged into the microcirculation or formed in the coronary
microcirculation. These cellular aggregates contribute to the
impairment of microvascular perfusion. In pronounced forms
of no-reflow, also typical erythrocyte aggregates are found
that block the capillaries.116
Capillary Destruction: Hemorrhage
The most severe forms of coronary microvascular injury
from myocardial ischemia/reperfusion, as already detailed
in the original reports of coronary no-reflow by Krug et al44
and Kloner et al,45 are the massive swelling of capillary en-
dothelial cells with consequent rupture of the vascular wall
and leakage of circulating cells into the interstitium, that is,
hemorrhage. Hemorrhage is associated with severe ischemia
during coronary occlusion and with severe myocardial necro-
sis.117,118 Hemorrhage in reperfused myocardial infarction has
received more attention by MRI because the hemoglobin ca-
tabolites are paramagnetic and attenuate the T2-weighted sig-
nal intensity within an otherwise high T2-weighted signal area
(edema).119–122 No-reflow is seen in ≈35% of patients with op-
timal reperfusion therapy, and its incidence increases with the
delay of reperfusion.123,124 No-reflow and hemorrhage carry
an adverse prognosis for patients with reperfused myocardial
infarction.124–126
The above manifestations of coronary vascular injury by
myocardial ischemia/reperfusion are attenuated by local isch-
emic pre- and postconditioning, as well as by remote ischemic
conditioning and by various cardioprotective drugs and interven-
injury information is available for every form of cardioprotec-
tion. Often, only the resulting no-reflow or the area of no-reflow
was assessed. In particular, data for patients with myocardial
ischemia/reperfusion are not systematically available.
Coronary Vascular Protection
by Ischemic Preconditioning
Ischemic preconditioning protects endothelial function and
structure from myocardial ischemia/reperfusion injury.127 In
Langendorff-perfused mouse hearts, ischemic preconditioning
by 1 cycle of 2-minute global ischemia/5-minute reperfusion
before 40-minute sustained global ischemia with reperfusion
preserved the ultrastructure of endothelial tight junctions and
attenuated edema.70 Similarly, ischemic preconditioning in
rats attenuated the increase in microvascular permeability and
edema development with sustained ischemia/reperfusion.128
Ischemic preconditioning with 5-minute coronary occlusion/10-
minute reperfusion before 60-minute coronary occlusion
and reperfusion in dogs reduced not only infarct size but also
edema.38 An early study in anesthetized dogs found no protec-
tion by ischemic preconditioning on endothelium-dependent
coronary vasodilation in response to acetylcholine and on low-
reflow after 60-minute coronary occlusion with reperfusion.129
Another study in dogs with 60-minute coronary occlusion and
reperfusion also reported no improvement in the coronary va-
sodilator response to acetylcholine but improved reflow with
ischemic preconditioning by 2 cycles of 5-minute myocardial
ischemia/5-minute reperfusion.130 However, the majority of
subsequent studies reported protection by ischemic precondi-
tioning on endothelial function, as assessed by endothelium-
dependent coronary vasodilation in response to acetylcholine,
serotonin, or ADP in rats,131–133 guinea pigs,134 dogs,135,136 pigs,137
and goats.138 Mechanistically, the preservation of endothelial
function by ischemic preconditioning was related to adenos-
ine,132,136 bradykinin,133 and nitric oxide.138,139 The preservation
of endothelial function by ischemic preconditioning became ap-
parent not only as improved endothelium-dependent coronary
vasodilation but also as reduced leukocyte adherence.134,135,139
Coronary endothelial function recovers only slowly after
myocardial ischemia/reperfusion and is still depressed after 1
month, but ischemic preconditioning also improves endotheli-
um-dependent coronary vasodilation in response to acetylcho-
line and endothelial ultrastructure after 1 month.140 Vice versa,
delayed ischemic preconditioning 24 hours before the sustained
myocardial ischemia/reperfusion increases the activity of en-
dothelial nitric oxide synthase, which mediates preservation of
coronary vasodilator response to acetylcholine, carbachol, and
bradykinin.141,142 Reactive oxygen species formation, although
detrimental acutely for endothelium-dependent coronary va-
sodilation in response to acetylcholine, is mandatory for the
delayed protection by ischemic preconditioning.143 Ischemic
preconditioning not only preserves endothelium-dependent
 1648  Circulation Research  May 13, 2016
coronary vasodilation but also attenuates the enhanced coro-
nary vasoconstrictor tone after hyperkalemic cardioplegia
through a ATP-dependent potassium channel–dependent mech-
anism in coronary vascular smooth muscle cells.144 Coronary
microembolization with release of adenosine into the coronary
vasculature does not induce acute preconditioning and reduce
infarct size or, conversely, interfere with protection by ischemic
preconditioning.103,145 Somewhat paradoxically, the increase
in tumor necrosis factor α expression secondary to coronary
microembolization can induce delayed protection and reduce
infarct size from subsequent coronary occlusion/reperfusion,146
such that the actual impact of coronary microembolization on
infarct size depends critically on timing and is difficult to pre-
dict. Preinfarction angina is considered a clinical correlate of
ischemic preconditioning.147,148 Patients with preinfarction an-
gina have reduced platelet reactivity, less monocyte–platelet ag-
gregates,149 and better reflow and coronary flow reserve during
reperfusion.150,151
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Coronary Vascular Protection
by Ischemic Postconditioning
The classical study by Vinten-Johansen and coworkers38 in
dogs undergoing an ischemic postconditioning protocol of 3
cycles of 30-second coronary reocclusion/30-second reperfu-
sion at immediate reperfusion after 60-minute coronary oc-
clusion reported not only reduced infarct size but also reduced
edema; both infarct size and edema were reduced to the same
extent as with ischemic preconditioning. Neither the reduction
of infarct size nor the reduction of no-reflow with ischemic
postconditioning was confirmed in a rabbit model,152 and no-
reflow reduction by ischemic postconditioning was also not
confirmed in pigs.153,154 In a mini-pig model of 3 hours of cor-
onary occlusion/reperfusion, ischemic postconditioning with
6 cycles of 10-second reocclusion/10-second reperfusion re-
duced infarct size and area of no-reflow, but hypercholesterol-
emia abrogated the protection by ischemic postconditioning.155
In patients with reperfused acute myocardial infarction, isch-
emic postconditioning protocols reduced infarct size,47,156–164
improved coronary blood flow47,156,160,161,164 and coronary flow
reserve,159 and reduced edema and no-reflow.163 However, nei-
ther the reduction of infarct size nor a reduction of microvas-
cular obstruction was confirmed in other trials.165–170 Reasons
for such discrepancy are not really clear but may relate to use
of direct stenting or lack of it48,171 and the increasing use of
P2Y12 antagonists which induce cardioprotection per se such
that the potential for further protection is diminished.172–174
Coronary Vascular Protection
by Remote Ischemic Conditioning
Remote ischemic conditioning was originally characterized
as an interaction between two coronary vascular territories175
and has now been established as a powerful cardioprotective
intervention which can be elicited from various vascular ter-
ritories, including noninvasive occlusion/reperfusion of the
limbs.176 Remote ischemic conditioning reduces infarct size
when performed before (preconditioning), during (percon-
ditioning), or after (postconditioning) sustained myocardial
ischemia/reperfusion, and it has been confirmed in various
species, including also proof-of-concept trials in humans un-
dergoing elective interventional or surgical coronary revascu-
larization or interventional/thrombolytic reperfusion of acute
myocardial infarction. In pigs, remote ischemic precondition-
ing improved coronary blood flow through an ATP-dependent
potassium channel–dependent mechanism.177 In healthy
young volunteers, repeated remote ischemic conditioning
twice a day for 1 week increased coronary flow reserve, and
it did so also in patients with heart failure.178 In patients un-
dergoing elective percutaneous coronary revascularization,
remote ischemic preconditioning did not reduce coronary mi-
crovascular resistance in a nontarget vessel.179 In the Effect
of Remote Ischemic Conditioning Before Hospital Admission
(CONDI) trial, in patients undergoing primary PCI for acute
myocardial infarction, remote ischemic perconditioning with
4 cycles of 5-minute arm ischemia/5-minute reperfusion dur-
ing transport in the ambulance reduced infarct size but did not
improve coronary blood flow.180 In patients with acute ST-
segment elevation myocardial infarction undergoing PCI, re-
mote ischemic perconditioning with 4 cycles of 5-minute arm
ischemia/5-minute reperfusion at hospital admission reduced
both infarct size and edema on MRI.181 Also in patients with
acute myocardial infarction undergoing PCI, remote ischemic
postconditioning by 3 cycles of lower limb ischemia/reperfu-
sion reduced edema (MRI) and infarct size (MRI, biomarker),
improved ST-segment resolution during reperfusion, but did
not improve TIMI frame count or myocardial blush grading.182
In the recent LIPSIA (from Leipzig) conditioning trial in pa-
tients undergoing primary PCI for acute ST-segment elevation
myocardial infarction, postconditioning alone with 4 cycles of
30-second reocclusion/reperfusion failed to improve myocar-
dial salvage and microvascular obstruction by MRI, but com-
bined postconditioning with remote ischemic perconditioning
by 3 cycles of 5-minute upper arm ischemia/5-minute reperfu-
sion improved myocardial salvage, albeit reduced microvas-
cular obstruction only nonsignificantly.169 Myocardial salvage
by remote ischemic preconditioning, in turn, is greater when
collateral blood flow is present, as evident from a retrospective
analysis of the CONDI trial and supporting the notion of a hu-
moral transfer of cardioprotective factors from the remote or-
gan to the heart.183 Remote ischemic preconditioning reduces
leukocyte adhesion and phagocytosis in healthy volunteers,184
and it attenuates the increased platelet reactivity and forma-
tion of monocyte–platelet aggregates in patients undergoing
ablation for atrial fibrillation185 and in patients undergoing
coronary procedures.186 Remote ischemic preconditioning ac-
tivates erythrocyte nitric oxide synthase187 and improves eryth-
rocyte deformability,188 thus potentially antagonizing stasis.
Coronary Vascular Protection by Drugs
and Cardioprotective Interventions
Experimental Studies
Most experimental studies on myocardial ischemia/reper-
fusion are performed in healthy and young animals which
have a virgin coronary circulation without atherosclerosis,
vascular remodeling, and endothelial dysfunction. Such
studies accordingly cannot account for the presence of ath-
erosclerosis with impaired endothelial function, exhaustion
 Heusch   Cardioprotection and Coronary Circulation   1649
of autoregulatory mechanisms and coronary vascular re-
modelling distal to coronary stenoses,189 the development
of a significant collateral circulation, and also pre-existing
myocardial disease (patchy microinfarcts and fibrosis) or
adaptation (hibernation). These limitations contribute to
the difficulties in translating data from animal studies to the
patient with acute myocardial infarction undergoing reper-
fusion therapy,8 apart from and in addition to confounding
comorbidities and comedications.190
Drugs
As reviewed in detail elsewhere,35,191,192 many exogenous
agents and drugs which often rely on the recruitment of sig-
nal transduction steps of conditioning maneuvers7 can reduce
infarct size in various experimental models and in different
species. In several such studies, the protection of the coro-
nary circulation was also addressed. Adenosine, only when
given at a high intracoronary dose for a prolonged period of
Downloaded from http://circres.ahajournals.org/ by guest on December 9, 2017
time, reduced infarct size, no-reflow, and leukocyte infiltra-
tion in pigs.193 Also in pigs, cyclosporine A that inhibits open-
ing of the mitochondrial permeability transition pore reduced
not only infarct size when given just before reperfusion but
also microvascular obstruction on MRI.194 Also, pretreatment
with high-density lipoproteins from normocholesterolemic
pigs which contain a load of sphingosine-1-phosphate195
reduced infarct size and the extent of no-reflow in pigs.196
Pretreatment with simvastatin reduced infarct size and the
area of no-reflow in pigs, and such protection was related to
activation of protein kinase A197 and of mitochondrial ATP-
dependent potassium channels.198 Glucagon-like peptide 1
when given just before reperfusion in rats decreased infarct
size and reduced the accumulation of leukocytes in the reper-
fused myocardium.199 Human recombinant angiopoietin-like
peptide 4 reduced infarct size and area of no-reflow in mice
and rabbits.69
Interventions
Hyperosmotic reperfusion with mannitol reduced edema and
infarct size in pigs.200 Electric vagal nerve stimulation in pigs
just before and into early reperfusion after 45-minute coro-
nary occlusion reduced infarct size, area of no-reflow, and
leukocyte accumulation, and the protective effects were re-
lated to nitric oxide synthase activity.201 Counterpulsation by
an intra-aortic balloon pump during reperfusion after 60-min-
ute coronary occlusion in pigs increased coronary blood flow
and reduced infarct size and area of no-reflow.202 In contrast,
partial clamping of the aorta to increase perfusion pressure
augmented infarct size and no-reflow in pigs.203 Hypothermia
(32°C) in rats and rabbits undergoing 30-minute coronary oc-
clusion and reperfusion reduced infarct size and no-reflow
area when initiated shortly after the onset of myocardial
ischemia.204 Of note, whereas in rabbits undergoing 30-min-
ute coronary occlusion with reperfusion, topical hypothermia
(32°C) when initiated at 5 minutes before versus at 5 min-
utes after reperfusion tended to reduce infarct size only with
hypothermia started before reperfusion, the area of no-reflow
was reduced in both cases. When hypothermia was initiated
no earlier than at 30-minute reperfusion, infarct size was not
affected at all, but the area of no-reflow was still reduced. This
particular study emphasizes the potential for a dissociation
of effects on infarct size from those on area of no-reflow.205
Finally, cellular postconditioning by intracoronary infusion of
allogeneic cardiosphere-derived cells in pigs at 30-minute re-
perfusion after 90-minute coronary occlusion reduced infarct
size and area of microvascular obstruction 48 hours later.206
Clinical Studies
As reviewed in detail elsewhere,13,191,207 many different inter-
ventions and drugs have been used, after successful preclini-
cal studies, as adjunct therapy to reperfusion with the aim to
reduce infarct size and possibly improve clinical outcome.
Most of these trials have failed to provide convincing evi-
dence for infarct size reduction. Hypothermia did not reduce
infarct size (single photon emission computed tomography)
or improve TIMI flow in patients with acute myocardial in-
farction undergoing primary PCI.208 Also, no reduction of
microvascular obstruction and infarct size was found with
MRI.209–211 Hyperoxemia,212,213 aspiration or mechanical
thrombectomy,214–221 and intra-aortic balloon counterpulsa-
tion222 did not reduce infarct size or improve coronary blood
flow. More recently, also the cardioprotection by cyclosporine
A which had been shown in a small-scale proof-of-concept
trial223 was not confirmed in another smaller study with pre-
thrombolytic cyclosporine A224 and, importantly, not in 2 larg-
er-scale phase III trials, Does Cyclosporine Improve Clinical
Outcome in ST Elevation Myocardial Infarction Patients
(CIRCUS) and CyclosporinE A in Reperfused Myocardial
Infarct (CYCLE).225,226 Many potential reasons for this dis-
crepancy have been discussed, such as lack of direct stenting
and greater use of P2Y12 antagonists, and also the use of a
different vehicle in CIRCUS, but not in CYCLE.227
In some of these studies, not only infarct size but also pa-
rameters reflecting coronary microvascular function were re-
ported, and the effects of cardioprotective drugs on infarct size
and coronary microvascular function were mostly concordant
(Figures 5–8). Intracoronary abciximab as compared with in-
travenous abciximab reduced infarct size (creatine kinase and
MRI) and microvascular obstruction (MRI).228 For intracoro-
nary adenosine, concordantly reduced infarct size (creatine
kinase and MRI) and less microvascular obstruction (TIMI
flow on angiography) were reported in patients undergoing
interventional reperfusion for acute myocardial infarction in
2229,230 but not in 3 other studies.31,231,232 Intravenous nitrite in
patients with ST-segment elevation myocardial infarction and
interventional reperfusion failed to reduce infarct size (bio-
marker and MRI) or to affect TIMI flow (angiography).233
Intracoronary nitrite in patients with ST-segment elevation
myocardial infarction and interventional reperfusion reduced
infarct size (creatine kinase and MRI) only in a subgroup of
patients with TIMI flow ≤1 at admission, and in this subgroup,
intracoronary nitrite also reduced the area of microvascular
obstruction (MRI).234 Erythropoietin in patients with ST-
segment elevation myocardial infarction and interventional
reperfusion neither reduced infarct size (creatine kinase and
MRI) nor improved TIMI flow.235 Two different mitochon-
dria-targeting drugs236,237 failed to reduce infarct size or to
improve coronary microvascular function. Currently, only 4
drugs stand unchallenged to provide cardioprotection in term
 1650  Circulation Research  May 13, 2016

Method PLA/INT Infarct size Intervention/Drug Acronym TIMI grade PLA/INT Authors

CK-MB 21/22 POCO 21/22 Garcia (2011)

MRI 168/181 POCO LIPSIA CONDITIONING 232/232 Eitel (2015)
MRI 55/56 POCO POST 55/56 Kim (2015)
CK-MB 48/48 RIC 48/48 Crimi (2013)
MRI 160/158 RIC LIPSIA CONDITIONING 232/232 Eitel (2015)
SPECT 20/20 Asp. Thromb. 24/20 Lipiecki (2009)
MRI 75/79 Asp. Thromb. MUSTELA 104/104 De Carlo (2012)
MRI 179/174 Asp. Thromb. INFUSE-AMI 223/229 Stone (2012)
SPECT 18/18 Hypothermia 21/21 Dixon (2002)
MRI 20/26 Hypothermia VELOCITY 25/26 Nichol (2015)
SPECT 122/121 Hyperoxemia AMIHOT 135/134 O'Neill (2007)
SPECT 124/258 Hyperoxemia pooled AMIHOT I+II 71/215 Stone (2009)
MRI 142/133 IABC CRISP AMI 169/156 Patel (2011)
MRI 172/188 abciximab INFUSE-AMI 223/229 Stone (2012)
SPECT 121/143 LeukArrest HALT-MI 150/134 Faxon (2002)
CK-MB 27/27 adenosine i.c. 27/27 Marzilli (2000)
MRI 49/51 adenosine i.c. 54/56 Desmet (2011)
TnT 80/80 adenosine i.c. REOPEN-AMI 80/80 Niccoli (2013)
MRI 86/91 adenosine i.c. 97/100 Garcia-Dorado (2014)
MRI 47/45 erythropoietin REVIVAL 70/68 Ott (2010)
MRI 88/85 sodium nitrite i.v. NIAMI 110/116 Siddiqi (2014)
CK-MB 51/50 cyclosporine 36/33 Ghaffari (2013)
CK 336/345 cyclosporine CIRCUS 487/466 Cung (2015)
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hsTnT 172/175 cyclosporine CYCLE 202/204 Ottani (2016)

-100 -80 -60 -40 -20 0 20 40 60 80 100 50 40 30 20 10 0 -10 -20 -30 -40 -50 [%]

Figure 5. Forest plot of infarct size and thrombolysis in myocardial infarction (TIMI) flow grade in clinical trials reporting on both
infarct size and microvascular dysfunction. The zero represents the mean value of the placebo group and gray bars the SEM of the
placebo group. ■, mean values with significant difference from placebo; □, mean values without significant difference from placebo. Asp.
Thromb indicates aspiration thrombectomy; CK, creatine kinase; CK-MB, creatine kinase muscle brain; hsTnT, high-sensitive troponin T;
IABC, intra-aortic balloon counterpulsation; INT, intervention; MRI, magnetic resonance imaging; PLA, placebo; POCO, postconditioning;
RIC, remote ischemic conditioning; SPECT, single photon emission computed tomography; and TnT, troponin T.

of infarct size reduction: atrial natriuretic peptide,238 metopro-
lol,32 esmolol,239 and exenatide,240–242 and no information on
coronary microvascular function is available for these drugs.
Coronary Microvascular Injury:
Cause or Consequence of Myocardial
Ischemia/Reperfusion
The available studies indicate a close correlation between infarct
size and that of no-reflow.243–245 Still, correlations cannot resolve
questions of causality, and the lack of adequate techniques to
make serial measurements of infarcted tissue and no-reflow with
reasonable spatial resolution is largely responsible that causal-
ity between myocardial infarction and coronary microvascular
no-reflow is not established.246 With microembolization of ath-
erosclerotic debris, plugging of platelet/leukocyte aggregates
and vasoconstriction in response to soluble mediators, the re-
sulting coronary microvascular obstruction could be cause to
myocardial infarction. With this rationale, thrombaspiration,
protection devices, and coronary vasodilators are used to re-
duce peri-interventional reperfusion injury.101 Also, recombinant
angiopoietin-like peptide 4 has been demonstrated to stabilize
the endothelial barrier and subsequently reduce infarct size and

Method PLA/INT Infarct size Intervention/Drug Acronym MBG PLA/INT Authors

CK 15/15 POCO 12/13 Staat (2005)

SPECT 18/23 POCO 18/23 Yang (2007)
CK 12/12 POCO 11/12 Laskey (2008)
MRI 38/37 POCO 39/39 Tarantini (2012)
CK-MB 350/350 POCO 348/349 Hahn (2013)
CK-MB 37/35 POCO 34/34 Araszkiewicz (2014)
MRI 55/56 POCO POST 55/56 Kim (2015)
CK-MB 48/48 RIC 47/44 Crimi (2013)
MRI 37/38 Asp. Thromb. 87/88 Sardella (2009)
MRI 179/174 Asp. Thromb. INFUSE-AMI 222/229 Stone (2012)
SPECT 208/217 Mech. Thromb. JETSTENT 211/215 Migliorini (2010)
MRI 172/188 abciximab INFUSE-AMI 223/228 Stone (2012)
CK 222/226 adenosine i.c. 222/226 Fokkema (2009)
TnT 80/80 adenosine i.c. REOPEN-AMI 80/80 Niccoli (2013)
MRI 86/91 adenosine i.c. 95/94 Garcia-Dorado (2014)

-100 -80 -60 -40 -20 0 20 40 60 80 100 50 40 30 20 10 0 -10 -20 -30 -40 -50 [%]

Figure 6. Forest plot of infarct size and myocardial blush grade (MBG) in clinical trials reporting on both infarct size and
microvascular dysfunction. The zero represents the mean value of the placebo group and gray bars the SEM of the placebo group. ■,
mean values with significant difference from placebo; □, mean values without significant difference from placebo. Asp. Thromb. indicates
aspiration thrombectomy; CK, creatine kinase; CK-MB, creatine kinase muscle brain; INT, intervention; Mech. Thromb., mechanical
thrombectomy; MRI, magnetic resonance imaging; PLA, placebo; POCO, postconditioning; RIC, remote ischemic conditioning; SPECT,
single photon emission computed tomography; and TnT, troponin T.
 Heusch   Cardioprotection and Coronary Circulation   1651

Method PLA/INT Infarct size Intervention/Drug Acronym cTFC PLA/INT Authors

CK-MB 47/47 POCO 47/47 Ma (2006)

CK-MB 34/30 POCO 34/30 Liu (2011)
CK-MB 42/37 POCO 42/37 Ugata (2012)
SPECT 69/73 RIC CONDI 125/126 Bøtker (2010)
SPECT 89/79 Asp. Thromb. 93/100 Kaltoft (2006)
SPECT 67/65 Asp. Thromb. 70/67 Ciszewski (2011)
MRI 75/79 Asp. Thromb. MUSTELA 104/104 De Carlo (2012)
MRI 179/174 Asp. Thromb. INFUSE-AMI 223/229 Stone (2012)
SPECT 50/50 Mech. Thromb. 50/50 Antoniucci (2004)
SPECT 208/217 Mech. Thromb. JETSTENT 216/228 Migliorini (2010)
MRI 172/188 abciximab INFUSE-AMI 223/229 Stone (2012)
SPECT 121/143 LeukArrest HALT-MI 153/139 Faxon (2002)
TnT 80/80 adenosine i.c. REOPEN-AMI 80/80 Niccoli (2013)
CK-MB 60/57 MTP-131 EMBRACE AMI 53/58 Gibson (2015)

-100 -80 -60 -40 -20 0 20 40 60 80 100 -50 -40 -30 -20 -10 0 10 20 30 40 50 [%]

Figure 7. Forest plot of infarct size and corrected thrombolysis in myocardial infarction frame count (cTFC) in clinical trials
reporting on both infarct size and microvascular dysfunction. The zero represents the mean value of the placebo group and
gray bars the SEM of the placebo group. ■, mean values with significant difference from placebo; □, mean values without significant
difference from placebo. Asp. Thromb. indicates aspiration thrombectomy; CK-MB, creatine kinase muscle brain; INT, intervention; Mech.
Downloaded from http://circres.ahajournals.org/ by guest on December 9, 2017

Thromb., mechanical thrombectomy; MRI, magnetic resonance imaging; PLA, placebo; POCO, postconditioning; RIC, remote ischemic
conditioning; SPECT, single photon emission computed tomography; and TnT, troponin T.

no-reflow in mice.69 However, vice versa there may be primary
damage to cardiomyocytes which only subsequently progresses
to coronary microvascular damage, as seen in animal models
with mechanical occlusion/reperfusion of virgin coronary arter-
ies without a culprit lesion.247 Of particular interest to resolve
a potential causality between infarct size and no-reflow are not
the vast majority of studies where effects on both infarct size
and no-reflow are concordant, but those few studies where they
are dissociated. In pigs, edema at reperfusion after 48-minute
coronary occlusion was reduced with both anoxic perfusion for
catabolite washout during coronary occlusion and ischemic pre-
conditioning by 2 cycles of 5-minute coronary occlusion/5-min-
ute reperfusion, but only ischemic preconditioning also reduced
infarct size.248 Delayed hypothermia starting no earlier than after
30-minute reperfusion following 30-minute coronary occlusion
in rabbits reduced no-reflow, but not infarct size.205 In contrast,
in a recent study in pigs with 60-minute coronary occlusion and
reperfusion, ischemic postconditioning reduced infarct size, but
not reflow.154 Although in most studies reduction of infarct size
and no-reflow or lack thereof went in parallel, these studies with
discordant effects on infarct size and no-reflow strongly argue
against a strictly causal role for one in the other. In fact, there
may rather be a common pathomechanism, such as damage by
reactive oxygen species249 but with somewhat different, at least
temporally different, impact on the myocardial and coronary mi-
crovascular compartment. Nothing is known on the signal trans-
duction in endothelial and vascular smooth muscle cells which
may confer protection from myocardial ischemia/reperfusion
injury to the coronary circulation, and much research is needed
here to help develop more effective and more specific therapeu-
tic approaches to target coronary microvascular injury. It seems
that mitochondrial dysfunction is central not only to myocardial

Method PLA/INT Infarct size Intervention/Drug Acronym MRI PLA/INT Param. Authors

MRI 25/25 POCO 25/25 edema Thuny (2012)

MRI 40/39 POCO 40/39 MVO Dwyer (2013)
MRI 25/25 POCO 25/25 MVO Mewton (2013)
MRI 168/181 POCO LIPSIA CONDITIONING 168/181 MVO Eitel (2015)
MRI 55/56 POCO POST 55/56 MVO Kim (2015)
CK-MB 48/48 RIC 42/35 edema Crimi (2013)
MRI 160/158 RIC LIPSIA CONDITIONING 168/166 MVO Eitel (2015)
MRI 43/40 RIC 40/43 edema White (2015)
MRI 55/56 Asp. Thromb. 55/56 MVO Desch (2016)
MRI 8/8 Hypothermia 8/8 MVO Götberg (2010)
MRI 47/49 Hypothermia CHILL-MI 47/49 MVO Erlinge (2014)
MRI 20/26 Hypothermia VELOCITY 20/26 MVO Nichol (2015)
MRI 142/133 IABC CRISP AMI 176/161 MVO Patel (2011)
MRI 49/51 adenosine i.c. 49/51 MVO Desmet (2011)
MRI 86/91 adenosine i.c. 86/91 MVO Garcia-Dorado (2014)
CK 40/40 sodium nitrite i.c. 35/33 MVO Jones (2015)
TnI 80/83 TRO40303 MITOCARE 43/50 MVO Atar (2015)

-100 -80 -60 -40 -20 0 20 40 60 80 100 -100 -80 -60 -40 -20 0 20 40 60 80 100 [%]

Figure 8. Forest plot of infarct size and edema and microvascular obstruction (MVO) on magnetic resonance imaging (MRI) in
clinical trials reporting on both infarct size and microvascular dysfunction. The zero represents the mean value of the placebo group
and gray bars the SEM of the placebo group. ■, mean values with significant difference from placebo; □, mean values without significant
difference from placebo. Asp. Thromb. indicates aspiration thrombectomy; CK, creatine kinase; CK-MB, creatine kinase muscle brain;
IABC, intra-aortic balloon counterpulsation; INT, intervention; PLA, placebo; POCO, postconditioning; RIC, remote ischemic conditioning;
and TnI, troponin I.
 1652  Circulation Research  May 13, 2016
ischemia/reperfusion injury but also to the impairment of meta-
bolic coronary vasodilation, rendering it as a target to not only
reduce infarct size but also improve coronary blood flow.250
Sources of Funding
G. Heusch was supported by the German Research Foundation (He
1320/18-3; SFB 1116/B8), the Hans and Gertie-Fischer Foundation,
and the Heinz Horst-Deichmann Foundation.
Disclosures
None.
References
1. Heusch G, Schulz R. Neglect of the coronary circulation: some critical
remarks on problems in the translation of cardioprotection. Cardiovasc
Res. 2009;84:11–14. doi: 10.1093/cvr/cvp210.
2. Heusch G, Kleinbongard P, Skyschally A, Levkau B, Schulz R, Erbel R.
The coronary circulation in cardioprotection: more than just one con-
founder. Cardiovasc Res. 2012;94:237–245. doi: 10.1093/cvr/cvr271.
Downloaded from http://circres.ahajournals.org/ by guest on December 9, 2017
3. Thygesen K, Alpert JS, Jaffe AS, et al; Writing Group on the Joint ESC/
ACCF/AHA/WHF Task Force for the Universal Definition of Myocardial
Infarction; ESC Committee for Practice Guidelines (CPG). Third univer-
sal definition of myocardial infarction. Eur Heart J. 2012;33:2551–2567.
doi: 10.1093/eurheartj/ehs184.
4. Heusch G. Postconditioning: old wine in a new bottle? J Am Coll Cardiol.
2004;44:1111–1112. doi: 10.1016/j.jacc.2004.06.013.
5. Yellon DM, Hausenloy DJ. Myocardial reperfusion injury. N Engl J Med.
2007;357:1121–1135. doi: 10.1056/NEJMra071667.
6. Hausenloy DJ, Yellon DM. Myocardial ischemia-reperfusion injury: a ne-
glected therapeutic target. J Clin Invest. 2013;123:92–100. doi: 10.1172/
JCI62874.
7. Heusch G. Molecular basis of cardioprotection: signal transduction in
ischemic pre-, post-, and remote conditioning. Circ Res. 2015;116:674–
699. doi: 10.1161/CIRCRESAHA.116.305348.
8. Heusch G. Cardioprotection: chances and challenges of its translation to the
clinic. Lancet. 2013;381:166–175. doi: 10.1016/S0140-6736(12)60916-7.
9. Mehta LS, Beckie TM, DeVon HA, Grines CL, Krumholz HM, Johnson MN,
Lindley KJ, Vaccarino V, Wang TY, Watson KE, Wenger NK; American
Heart Association Cardiovascular Disease in Women and Special Populations
Committee of the Council on Clinical Cardiology, Council on Epidemiology
and Prevention, Council on Cardiovascular and Stroke Nursing, and Council
on Quality of Care and Outcomes Research. Acute myocardial infarction
in women: a scientific statement from the American Heart Association.
Circulation. 2016;133:916–947. doi: 10.1161/CIR.0000000000000351.
10. Sack MN, Murphy E. The role of comorbidities in cardioprotec-
tion. J Cardiovasc Pharmacol Ther. 2011;16:267–272. doi: 10.1177/
1074248411408313.
11. Pepine CJ, Ferdinand KC, Shaw LJ, Light-McGroary KA, Shah RU,
Gulati M, Duvernoy C, Walsh MN, Bairey Merz CN; ACC CVD in
Women Committee. Emergence of nonobstructive coronary artery disease:
a woman’s problem and need for change in definition on angiography.
J Am Coll Cardiol. 2015;66:1918–1933. doi: 10.1016/j.jacc.2015.08.876.
12. Skyschally A, Schulz R, Heusch G. Pathophysiology of myocardial infarc-
tion: protection by ischemic pre- and postconditioning. Herz. 2008;33:88–
100. doi: 10.1007/s00059-008-3101-9.
13. Ibáñez B, Heusch G, Ovize M, Van de Werf F. Evolving therapies for myo-
cardial ischemia/reperfusion injury. J Am Coll Cardiol. 2015;65:1454–
1471. doi: 10.1016/j.jacc.2015.02.032.
14. Heyndrickx GR, Millard RW, McRitchie RJ, Maroko PR, Vatner SF.
Regional myocardial functional and electrophysiological alterations
after brief coronary artery occlusion in conscious dogs. J Clin Invest.
1975;56:978–985. doi: 10.1172/JCI108178.
15. Braunwald E, Kloner RA. The stunned myocardium: prolonged, postisch-
emic ventricular dysfunction. Circulation. 1982;66:1146–1149.
16. Bolli R. Mechanism of myocardial “stunning”. Circulation. 1990;82:723–738.
17. Bolli R, Marbán E. Molecular and cellular mechanisms of myocardial
stunning. Physiol Rev. 1999;79:609–634.
18. Heusch G. Hibernating myocardium. Physiol Rev. 1998;78:1055–1085.
19. Heusch G, Schulz R, Rahimtoola SH. Myocardial hibernation: a delicate
balance. Am J Physiol Heart Circ Physiol. 2005;288:H984–H999. doi:
10.1152/ajpheart.01109.2004.
20. Reimer KA, Lowe JE, Rasmussen MM, Jennings RB. The wavefront phe-
nomenon of ischemic cell death. 1. Myocardial infarct size vs duration of
coronary occlusion in dogs. Circulation. 1977;56:786–794.
21. 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.
22. Schaper W, Görge G, Winkler B, Schaper J. The collateral circulation of
the heart. Prog Cardiovasc Dis. 1988;31:57–77.
23. Horneffer PJ, Healy B, Gott VL, Gardner TJ. The rapid evolution of a
myocardial infarction in an end-artery coronary preparation. Circulation.
1987;76:V39–V42.
24. Pich S, Klein HH, Lindert S, Nebendahl K, Kreuzer H. Cell death in isch-
emic, reperfused porcine hearts: a histochemical and functional study.
Basic Res Cardiol. 1988;83:550–559.
25. Yang XM, Liu Y, Liu Y, Tandon N, Kambayashi J, Downey JM, Cohen
MV. Attenuation of infarction in cynomolgus monkeys: precondition-
ing and postconditioning. Basic Res Cardiol. 2010;105:119–128. doi:
10.1007/s00395-009-0050-2.
26. Cinca J, Carreño A, Mont L, Blanch P, Soler-Soler J. Neurally mediated
negative inotropic effect impairs myocardial function during cholinergic
coronary vasoconstriction in pigs. Circulation. 1996;94:1101–1108.
27. Oudiz R, Heusch G, Guth BD. Selective alpha1- and alpha2- ad-
renergic coronary vasoconstriction in anesthetized swine. Faseb J.
1989;3:A896-(abstr.).
28. Heusch G, Baumgart D, Camici P, Chilian W, Gregorini L, Hess O, Indolfi
C, Rimoldi O. Alpha-adrenergic coronary vasoconstriction and myocar-
dial ischemia in humans. Circulation. 2000;101:689–694.
29. Ludmer PL, Selwyn AP, Shook TL, Wayne RR, Mudge GH, Alexander
RW, Ganz P. Paradoxical vasoconstriction induced by acetylcholine in ath-
erosclerotic coronary arteries. N Engl J Med. 1986;315:1046–1051. doi:
10.1056/NEJM198610233151702.
30. Hedström E, Engblom H, Frogner F, Aström-Olsson K, Ohlin H, Jovinge
S, Arheden H. Infarct evolution in man studied in patients with first-time
coronary occlusion in comparison to different species - implications for
assessment of myocardial salvage. J Cardiovasc Magn Reson. 2009;11:38.
doi: 10.1186/1532-429X-11-38.
31. Desmet W, Bogaert J, Dubois C, Sinnaeve P, Adriaenssens T, Pappas C,
Ganame J, Dymarkowski S, Janssens S, Belmans A, Van de Werf F. High-
dose intracoronary adenosine for myocardial salvage in patients with acute
ST-segment elevation myocardial infarction. Eur Heart J. 2011;32:867–
877. doi: 10.1093/eurheartj/ehq492.
32. Ibanez B, Macaya C, Sánchez-Brunete V, et al. Effect of early metopro-
lol on infarct size in ST-segment-elevation myocardial infarction patients
undergoing primary percutaneous coronary intervention: the Effect of
Metoprolol in Cardioprotection During an Acute Myocardial Infarction
(METOCARD-CNIC) trial. Circulation. 2013;128:1495–1503. doi:
10.1161/CIRCULATIONAHA.113.003653.
33. Schömig A, Mehilli J, Antoniucci D, et al; Beyond 12 hours Reperfusion
AlternatiVe Evaluation (BRAVE-2) Trial Investigators. Mechanical re-
perfusion in patients with acute myocardial infarction presenting more
than 12 hours from symptom onset: a randomized controlled trial. JAMA.
2005;293:2865–2872. doi: 10.1001/jama.293.23.2865.
34. Ndrepepa G, Kastrati A, Mehilli J, Antoniucci D, Schömig A. Mechanical
reperfusion and long-term mortality in patients with acute myocardial
infarction presenting 12 to 48 hours from onset of symptoms. JAMA.
2009;301:487–488. doi: 10.1001/jama.2009.32.
35. Kleinbongard P, Heusch G. Extracellular signalling molecules in the isch-
aemic/reperfused heart - druggable and translatable for cardioprotection?
Br J Pharmacol. 2015;172:2010–2025. doi: 10.1111/bph.12902.
36. Heusch G. Heart rate in the pathophysiology of coronary blood flow and
myocardial ischaemia: benefit from selective bradycardic agents. Br J
Pharmacol. 2008;153:1589–1601. doi: 10.1038/sj.bjp.0707673.
37. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia:
a delay of lethal cell injury in ischemic myocardium. Circulation.
1986;74:1124–1136.
38. Zhao ZQ, Corvera JS, Halkos ME, Kerendi F, Wang NP, Guyton RA,
Vinten-Johansen J. Inhibition of myocardial injury by ischemic postcon-
ditioning during reperfusion: comparison with ischemic preconditioning.
Am J Physiol Heart Circ Physiol. 2003;285:H579–H588. doi: 10.1152/
ajpheart.01064.2002.
39. Maroko PR, Libby P, Ginks WR, Bloor CM, Shell WE, Sobel BE, Ross J
Jr. Coronary artery reperfusion. I. Early effects on local myocardial func-
tion and the extent of myocardial necrosis. J Clin Invest. 1972;51:2710–
2716. doi: 10.1172/JCI107090.
 Heusch   Cardioprotection and Coronary Circulation   1653
40. Ginks WR, Sybers HD, Maroko PR, Covell JW, Sobel BE, Ross J Jr.
Coronary artery reperfusion. II. Reduction of myocardial infarct size at 1
week after the coronary occlusion. J Clin Invest. 1972;51:2717–2723. doi:
10.1172/JCI107091.
41. Hartzler GO, Rutherford BD, McConahay DR, Johnson WL Jr, McCallister
BD, Gura GM Jr, Conn RC, Crockett JE. Percutaneous transluminal coro-
nary angioplasty with and without thrombolytic therapy for treatment of
acute myocardial infarction. Am Heart J. 1983;106:965–973.
42. Effectiveness of intravenous thrombolytic treatment in acute myocardial
infarction. Gruppo Italiano per lo Studio della Streptochinasi nell’Infarto
Miocardico (GISSI). Lancet. 1986;1:397–402.
43. Randomised trial of intravenous atenolol among 16 027 cases of suspected
acute mycardial infarction: ISIS-1. Lancet. 1986;2:57–69.
44. Krug A, Du Mesnil de Rochemont, Korb G. Blood supply of the myocar-
dium after temporary coronary occlusion. Circ Res. 1966;19:57–62.
45. Kloner RA, Ganote CE, Jennings RB. The “no-reflow” phenomenon after
temporary coronary occlusion in the dog. J Clin Invest. 1974;54:1496–
1508. doi: 10.1172/JCI107898.
46. Przyklenk K. Lethal myocardial “reperfusion injury”: The opinions of
good men. J Thromb Thrombolysis. 1997;4:5–6.
47. Staat P, Rioufol G, Piot C, Cottin Y, Cung TT, L’Huillier I, Aupetit JF,
Bonnefoy E, Finet G, André-Fouët X, Ovize M. Postconditioning
the human heart. Circulation. 2005;112:2143–2148. doi: 10.1161/
Downloaded from http://circres.ahajournals.org/ by guest on December 9, 2017
CIRCULATIONAHA.105.558122.
48. Heusch G. Reduction of infarct size by ischaemic post-conditioning in
humans: fact or fiction? Eur Heart J. 2012;33:13–15. doi: 10.1093/
eurheartj/ehr341.
49. Okamoto F, Allen BS, Buckberg GD, Bugyi H, Leaf J. Reperfusion con-
ditions: importance of ensuring gentle versus sudden reperfusion during
relief of coronary occlusion. J Thorac Cardiovasc Surg. 1986;92:613–620.
50. Ferrera R, Benhabbouche S, Da Silva CC, Alam MR, Ovize M. Delayed
low pressure at reperfusion: a new approach for cardioprotection. J Thorac
Cardiovasc Surg. 2015;150:1641–8.e2. doi: 10.1016/j.jtcvs.2015.08.053.
51. Musiolik J, van Caster P, Skyschally A, Boengler K, Gres P, Schulz R,
Heusch G. Reduction of infarct size by gentle reperfusion without acti-
vation of reperfusion injury salvage kinases in pigs. Cardiovasc Res.
2010;85:110–117. doi: 10.1093/cvr/cvp271.
52. Heusch G. Treatment of myocardial ischemia/reperfusion injury by
ischemic and pharmacological postconditioning. Compr Physiol.
2015;5:1123–1145. doi: 10.1002/cphy.c140075.
53. Schaper W, Frenzel H, Hort W. Experimental coronary artery occlusion. I.
Measurement of infarct size. Basic Res Cardiol. 1979;74:46–53.
54. Fishbein MC, Meerbaum S, Rit J, Lando U, Kanmatsuse K, Mercier JC,
Corday E, Ganz W. Early phase acute myocardial infarct size quantifica-
tion: validation of the triphenyl tetrazolium chloride tissue enzyme stain-
ing technique. Am Heart J. 1981;101:593–600.
55. Kloner RA. No-reflow phenomenon: maintaining vascular integ-
rity. J Cardiovasc Pharmacol Ther. 2011;16:244–250. doi: 10.1177/
1074248411405990.
56. Sheehan FH, Braunwald E, Canner P, Dodge HT, Gore J, Van Natta P,
Passamani ER, Williams DO, Zaret B. The effect of intravenous throm-
bolytic therapy on left ventricular function: a report on tissue-type plas-
minogen activator and streptokinase from the Thrombolysis in Myocardial
Infarction (TIMI Phase I) trial. Circulation. 1987;75:817–829.
57. Gibson CM, Cannon CP, Daley WL, Dodge JT Jr, Alexander B Jr, Marble
SJ, McCabe CH, Raymond L, Fortin T, Poole WK, Braunwald E. TIMI
frame count: a quantitative method of assessing coronary artery flow.
Circulation. 1996;93:879–888.
58. van ‘t Hof AW, Liem A, Suryapranata H, Hoorntje JC, de Boer MJ,
Zijlstra F. Angiographic assessment of myocardial reperfusion in patients
treated with primary angioplasty for acute myocardial infarction: myocar-
dial blush grade. Zwolle Myocardial Infarction Study Group. Circulation.
1998;97:2302–2306.
59. Niccoli G, Burzotta F, Galiuto L, Crea F. Myocardial no-reflow in humans.
J Am Coll Cardiol. 2009;54:281–292. doi: 10.1016/j.jacc.2009.03.054.
60. Dauber IM, VanBenthuysen KM, McMurtry IF, Wheeler GS, Lesnefsky
EJ, Horwitz LD, Weil JV. Functional coronary microvascular injury evi-
dent as increased permeability due to brief ischemia and reperfusion. Circ
Res. 1990;66:986–998.
61. García-Dorado D, Oliveras J, Gili J, Sanz E, Pérez-Villa F, Barrabés J,
Carreras MJ, Solares J, Soler-Soler J. Analysis of myocardial oedema by
magnetic resonance imaging early after coronary artery occlusion with or
without reperfusion. Cardiovasc Res. 1993;27:1462–1469.
62. Garcia-Dorado D, Oliveras J. Myocardial oedema: a preventable cause of
reperfusion injury? Cardiovasc Res. 1993;27:1555–1563.
63. Abdel-Aty H, Cocker M, Meek C, Tyberg JV, Friedrich MG. Edema
as a very early marker for acute myocardial ischemia: a cardiovascular
magnetic resonance study. J Am Coll Cardiol. 2009;53:1194–1201. doi:
10.1016/j.jacc.2008.10.065.
64. Garcia-Dorado D, Andres-Villarreal M, Ruiz-Meana M, Inserte J, Barba I.
Myocardial edema: a translational view. J Mol Cell Cardiol. 2012;52:931–
939. doi: 10.1016/j.yjmcc.2012.01.010.
65. Noll T, Muhs A, Besselmann M, Watanabe H, Piper HM. Initiation of hy-
perpermeability in energy-depleted coronary endothelial monolayers. Am
J Physiol. 1995;268:H1462–H1470.
66. Becker BF, Chappell D, Jacob M. Endothelial glycocalyx and coro-
nary vascular permeability: the fringe benefit. Basic Res Cardiol.
2010;105:687–701. doi: 10.1007/s00395-010-0118-z.
67. Juchem G, Weiss DR, Knott M, Senftl A, Förch S, Fischlein T, Kreuzer E,
Reichart B, Laufer S, Nees S. Regulation of coronary venular barrier func-
tion by blood borne inflammatory mediators and pharmacological tools:
insights from novel microvascular wall models. Am J Physiol Heart Circ
Physiol. 2012;302:H567–H581. doi: 10.1152/ajpheart.00360.2011.
68. Kuhne W, Besselmann M, Noll T, Muhs A, Watanabe H, Piper HM.
Disintegration of cytoskeletal structure of actin filaments in energy-de-
pleted endothelial cells. Am J Physiol. 1993;264:H1599–H1608.
69. Galaup A, Gomez E, Souktani R, et al. Protection against myocar-
dial infarction and no-reflow through preservation of vascular integrity
by angiopoietin-like 4. Circulation. 2012;125:140–149. doi: 10.1161/
CIRCULATIONAHA.111.049072.
70. Li Z, Jin ZQ. Ischemic preconditioning enhances integrity of coronary en-
dothelial tight junctions. Biochem Biophys Res Commun. 2012;425:630–
635. doi: 10.1016/j.bbrc.2012.07.130.
71. Aslam M, Schluter KD, Rohrbach S, Rafiq A, Nazli S, Piper HM, Noll
T, Schulz R, Gündüz D. Hypoxia-reoxygenation-induced endothelial bar-
rier failure: role of RhoA, Rac1 and myosin light chain kinase. J Physiol.
2013;591:461–473. doi: 10.1113/jphysiol.2012.237834.
72. Gündüz D, Aslam M, Krieger U, Becker L, Grebe M, Arshad M, Sedding
DG, Härtel FV, Abdallah Y, Piper HM, Voss RK, Noll T. Opposing
effects of ATP and adenosine on barrier function of rat coronary mi-
crovasculature. J Mol Cell Cardiol. 2012;52:962–970. doi: 10.1016/j.
yjmcc.2012.01.003.
73. van den Berg BM, Vink H, Spaan JA. The endothelial glycocalyx protects
against myocardial edema. Circ Res. 2003;92:592–594. doi: 10.1161/01.
RES.0000065917.53950.75.
74. Annecke T, Fischer J, Hartmann H, Tschoep J, Rehm M, Conzen P,
Sommerhoff CP, Becker BF. Shedding of the coronary endothelial gly-
cocalyx: effects of hypoxia/reoxygenation vs ischaemia/reperfusion. Br J
Anaesth. 2011;107:679–686. doi: 10.1093/bja/aer269.
75. Chappell D, Hofmann-Kiefer K, Jacob M, Rehm M, Briegel J, Welsch
U, Conzen P, Becker BF. TNF-alpha induced shedding of the endothelial
glycocalyx is prevented by hydrocortisone and antithrombin. Basic Res
Cardiol. 2009;104:78–89. doi: 10.1007/s00395-008-0749-5.
76. Chappell D, Dörfler N, Jacob M, Rehm M, Welsch U, Conzen P, Becker BF.
Glycocalyx protection reduces leukocyte adhesion after ischemia/reperfu-
sion. Shock. 2010;34:133–139. doi: 10.1097/SHK.0b013e3181cdc363.
77. Chappell D, Brettner F, Doerfler N, Jacob M, Rehm M, Bruegger D,
Conzen P, Jacob B, Becker BF. Protection of glycocalyx decreases platelet
adhesion after ischaemia/reperfusion: an animal study. Eur J Anaesthesiol.
2014;31:474–481. doi: 10.1097/EJA.0000000000000085.
78. Bruegger D, Rehm M, Jacob M, Chappell D, Stoeckelhuber M, Welsch
U, Conzen P, Becker BF. Exogenous nitric oxide requires an endothelial
glycocalyx to prevent postischemic coronary vascular leak in guinea pig
hearts. Crit Care. 2008;12:R73. doi: 10.1186/cc6913.
79. Fernández-Jiménez R, García-Prieto J, Sánchez-González J, Agüero J,
López-Martín GJ, Galán-Arriola C, Molina-Iracheta A, Doohan R, Fuster
V, Ibáñez B. Pathophysiology underlying the bimodal edema phenomenon
after myocardial ischemia/reperfusion. J Am Coll Cardiol. 2015;66:816–
828. doi: 10.1016/j.jacc.2015.06.023.
80. Aletras AH, Tilak GS, Natanzon A, Hsu LY, Gonzalez FM, Hoyt RF Jr,
Arai AE. Retrospective determination of the area at risk for reperfused
acute myocardial infarction with T2-weighted cardiac magnetic resonance
imaging: histopathological and displacement encoding with stimulated
echoes (DENSE) functional validations. Circulation. 2006;113:1865–
1870. doi: 10.1161/CIRCULATIONAHA.105.576025.
81. Mewton N, Rapacchi S, Augeul L, Ferrera R, Loufouat J, Boussel L,
Micolich A, Rioufol G, Revel D, Ovize M, Croisille P. Determination
of the myocardial area at risk with pre- versus post-reperfusion imaging
techniques in the pig model. Basic Res Cardiol. 2011;106:1247–1257.
doi: 10.1007/s00395-011-0214-8.
 1654  Circulation Research  May 13, 2016
82. Heusch P, Nensa F, Heusch G. Is MRI really the gold standard for
the quantification of salvage from myocardial infarction? Circ Res.
2015;117:222–224. doi: 10.1161/CIRCRESAHA.117.306929.
83. Frame LH, Powell WJ Jr. Progressive perfusion impairment during prolonged
low flow myocardial ischemia in dogs. Circ Res. 1976;39:269–276.
84. Manciet LH, Poole DC, McDonagh PF, Copeland JG, Mathieu-Costello
O. Microvascular compression during myocardial ischemia: mechanistic
basis for no-reflow phenomenon. Am J Physiol. 1994;266:H1541–H1550.
85. Aversano T, Becker LC. Persistence of coronary vasodilator re-
serve despite functionally significant flow reduction. Am J Physiol.
1985;248:H403–H411.
86. Canty JM Jr, Klocke FJ. Reduced regional myocardial perfusion
in the presence of pharmacologic vasodilator reserve. Circulation.
1985;71:370–377.
87. Gross GJ, O’Rourke ST, Pelc LR, Warltier DC. Myocardial and endothe-
lial dysfunction after multiple, brief coronary occlusions: role of oxygen
radicals. Am J Physiol. 1992;263:H1703–H1709.
88. Ehring T, Krajcar M, Baumgart D, Kompa S, Hümmelgen M, Heusch
G. Cholinergic and alpha-adrenergic coronary vasomotion [cor-
rected] with increasing ischemia-reperfusion injury. Am J Physiol.
1995;268:H886–H894.
89. Heusch G, Deussen A. The effects of cardiac sympathetic nerve stimu-
lation on perfusion of stenotic coronary arteries in the dog. Circ Res.
Downloaded from http://circres.ahajournals.org/ by guest on December 9, 2017
1983;53:8–15.
90. Heusch G, Deussen A, Thämer V. Cardiac sympathetic nerve activity and
progressive vasoconstriction distal to coronary stenoses: feed-back ag-
gravation of myocardial ischemia. J Auton Nerv Syst. 1985;13:311–326.
91. Baumgart D, Haude M, Görge G, Liu F, Ge J, Grosse-Eggebrecht C,
Erbel R, Heusch G. Augmented alpha-adrenergic constriction of athero-
sclerotic human coronary arteries. Circulation. 1999;99:2090–2097.
92. Gregorini L, Marco J, Kozàkovà M, Palombo C, Anguissola GB, Marco
I, Bernies M, Cassagneau B, Distante A, Bossi IM, Fajadet J, Heusch G.
Alpha-adrenergic blockade improves recovery of myocardial perfusion
and function after coronary stenting in patients with acute myocardial
infarction. Circulation. 1999;99:482–490.
93. Gregorini L, Marco J, Farah B, Bernies M, Palombo C, Kozàkovà M,
Bossi IM, Cassagneau B, Fajadet J, Di Mario C, Albiero R, Cugno M,
Grossi A, Heusch G. Effects of selective alpha1- and alpha2-adrenergic
blockade on coronary flow reserve after coronary stenting. Circulation.
2002;106:2901–2907.
94. Leineweber K, Böse D, Vogelsang M, Haude M, Erbel R, Heusch G.
Intense vasoconstriction in response to aspirate from stented saphenous
vein aortocoronary bypass grafts. J Am Coll Cardiol. 2006;47:981–986.
doi: 10.1016/j.jacc.2005.10.053.
95. Kleinbongard P, Böse D, Baars T, Möhlenkamp S, Konorza T, Schöner S,
Elter-Schulz M, Eggebrecht H, Degen H, Haude M, Levkau B, Schulz R,
Erbel R, Heusch G. Vasoconstrictor potential of coronary aspirate from
patients undergoing stenting of saphenous vein aortocoronary bypass
grafts and its pharmacological attenuation. Circ Res. 2011;108:344–352.
doi: 10.1161/CIRCRESAHA.110.235713.
96. Kleinbongard P, Baars T, Möhlenkamp S, Kahlert P, Erbel R, Heusch
G. Aspirate from human stented native coronary arteries vs. saphe-
nous vein grafts: more endothelin but less particulate debris. Am J
Physiol Heart Circ Physiol. 2013;305:H1222–H1229. doi: 10.1152/
ajpheart.00358.2013.
97. Ku DD. Coronary vascular reactivity after acute myocardial ischemia.
Science. 1982;218:576–578.
98. Bolli R, Triana JF, Jeroudi MO. Prolonged impairment of coronary va-
sodilation after reversible ischemia. Evidence for microvascular “stun-
ning”. Circ Res. 1990;67:332–343.
99. Mills I, Fallon JT, Wrenn D, Sasken H, Gray W, Bier J, Levine D, Berman
S, Gilson M, Gewirtz H. Adaptive responses of coronary circulation and
myocardium to chronic reduction in perfusion pressure and flow. Am J
Physiol. 1994;266:H447–H457.
100. Sorop O, Merkus D, de Beer VJ, Houweling B, Pistea A, McFalls EO,
Boomsma F, van Beusekom HM, van der Giessen WJ, VanBavel E,
Duncker DJ. Functional and structural adaptations of coronary microves-
sels distal to a chronic coronary artery stenosis. Circ Res. 2008;102:795–
803. doi: 10.1161/CIRCRESAHA.108.172528.
101. Heusch G, Kleinbongard P, Böse D, Levkau B, Haude M, Schulz R,
Erbel R. Coronary microembolization: from bedside to bench and
back to bedside. Circulation. 2009;120:1822–1836. doi: 10.1161/
CIRCULATIONAHA.109.888784.
102. Dörge H, Neumann T, Behrends M, Skyschally A, Schulz R, Kasper
C, Erbel R, Heusch G. Perfusion-contraction mismatch with coronary
microvascular obstruction: role of inflammation. Am J Physiol Heart
Circ Physiol. 2000;279:H2587–H2592.
103. Skyschally A, Gres P, Heusch P, Martin C, Haude M, Erbel R, Schulz
R, Heusch G. Preinfarction angina: no interference of coronary micro-
embolization with acute ischemic preconditioning. J Mol Cell Cardiol.
2005;39:355–361. doi: 10.1016/j.yjmcc.2005.04.003.
104. Skyschally A, Walter B, Heusch G. Coronary microembolization during
early reperfusion: infarct extension, but protection by ischaemic post-
conditioning. Eur Heart J. 2013;34:3314–3321. doi: 10.1093/eurheartj/
ehs434.
105. Herrmann J, Haude M, Lerman A, Schulz R, Volbracht L, Ge J,
Schmermund A, Wieneke H, von Birgelen C, Eggebrecht H, Baumgart
D, Heusch G, Erbel R. Abnormal coronary flow velocity reserve af-
ter coronary intervention is associated with cardiac marker elevation.
Circulation. 2001;103:2339–2345.
106. Skyschally A, Schulz R, Erbel R, Heusch G. Reduced coronary and ino-
tropic reserves with coronary microembolization. Am J Physiol Heart
Circ Physiol. 2002;282:H611–H614. doi: 10.1152/ajpheart.00797.2001.
107. Baim DS, Wahr D, George B, Leon MB, Greenberg J, Cutlip DE, Kaya
U, Popma JJ, Ho KK, Kuntz RE; Saphenous vein graft Angioplasty
Free of Emboli Randomized (SAFER) Trial Investigators. Randomized
trial of a distal embolic protection device during percutaneous inter-
vention of saphenous vein aorto-coronary bypass grafts. Circulation.
2002;105:1285–1290.
108. Lins M, Heuer H, Haude M, Braun P, Stahl F, Franz N, Simon R; FIRST
Trial Investigators. Distal embolic protection during percutaneous inter-
vention of aorto-coronary venous bypass grafts: the FIRST Trial. Clin
Res Cardiol. 2007;96:738–742. doi: 10.1007/s00392-007-0553-5.
109. Sheridan FM, Dauber IM, McMurtry IF, Lesnefsky EJ, Horwitz LD.
Role of leukocytes in coronary vascular endothelial injury due to isch-
emia and reperfusion. Circ Res. 1991;69:1566–1574.
110. Kogaki S, Sawa Y, Sano T, Matsushita T, Ohata T, Kurotobi S, Tojo SJ,
Matsuda H, Okada S. Selectin on activated platelets enhances neutrophil
endothelial adherence in myocardial reperfusion injury. Cardiovasc Res.
1999;43:968–973.
111. Kupatt C, Wichels R, Horstkotte J, Krombach F, Habazettl H, Boekstegers
P. Molecular mechanisms of platelet-mediated leukocyte recruitment
during myocardial reperfusion. J Leukoc Biol. 2002;72:455–461.
112. Barrabés JA, Garcia-Dorado D, Mirabet M, Inserte J, Agulló L, Soriano
B, Massaguer A, Padilla F, Lidón RM, Soler-Soler J. Antagonism of se-
lectin function attenuates microvascular platelet deposition and platelet-
mediated myocardial injury after transient ischemia. J Am Coll Cardiol.
2005;45:293–299. doi: 10.1016/j.jacc.2004.09.068.
113. Chukwuemeka AO, Brown KA, Venn GE, Chambers DJ. Changes in
P-selectin expression on cardiac microvessels in blood-perfused rat hearts
subjected to ischemia-reperfusion. Ann Thorac Surg. 2005;79:204–211.
doi: 10.1016/j.athoracsur.2004.06.105.
114. Barrabés JA, Mirabet M, Agulló L, Figueras J, Pizcueta P, Garcia-Dorado D.
Platelet deposition in remote cardiac regions after coronary occlusion. Eur J
Clin Invest. 2007;37:939–946. doi: 10.1111/j.1365-2362.2007.01883.x.
115. Barrabés JA, Inserte J, Agulló L, Alonso A, Mirabet M, Garcia-Dorado
D. Microvascular thrombosis: an exciting but elusive therapeutic target
in reperfused acute myocardial infarction. Cardiovasc Hematol Disord
Drug Targets. 2010;10:273–283.
116. Driesen RB, Zalewski J, Vanden Driessche N, Vermeulen K, Bogaert J,
Sipido KR, Van de Werf F, Claus P. Histological correlate of a cardiac
magnetic resonance imaged microvascular obstruction in a porcine mod-
el of ischemia-reperfusion. Cardiovasc Pathol. 2012;21:129–131. doi:
10.1016/j.carpath.2011.07.008.
117. Higginson LA, White F, Heggtveit HA, Sanders TM, Bloor CM, Covell
JW. Determinants of myocardial hemorrhage after coronary reperfusion
in the anesthetized dog. Circulation. 1982;65:62–69.
118. Higginson LA, Beanlands DS, Nair RC, Temple V, Sheldrick K. The time
course and characterization of myocardial hemorrhage after coronary re-
perfusion in the anesthetized dog. Circulation. 1983;67:1024–1031.
119. Beek AM, Nijveldt R, van Rossum AC. Intramyocardial hemorrhage
and microvascular obstruction after primary percutaneous coronary
intervention. Int J Cardiovasc Imaging. 2010;26:49–55. doi: 10.1007/
s10554-009-9499-1.
120. Marra MP, Cacciavillani L, Corbetti F, Tarantini G, Ramondo AB,
Napodano M, Basso C, Lacognata C, Marzari A, Maddalena F,
Iliceto S. The contribution of intramyocardial hemorrhage to the
“no-reflow phenomenon”: a study performed by cardiac magnetic
resonance. Echocardiography. 2010;27:1120–1129. doi: 10.1111/j.1540-
8175.2010.01213.x.
 Heusch   Cardioprotection and Coronary Circulation   1655
121. Bonanad C, Ruiz-Sauri A, Forteza MJ, et al. Microvascular obstruc-
tion in the right ventricle in reperfused anterior myocardial infarction.
Macroscopic and pathologic evidence in a swine model. Thromb Res.
2013;132:592–598. doi: 10.1016/j.thromres.2013.08.009.
122. Robbers LF, Eerenberg ES, Teunissen PF, Jansen MF, Hollander MR,
Horrevoets AJ, Knaapen P, Nijveldt R, Heymans MW, Levi MM,
van Rossum AC, Niessen HW, Marcu CB, Beek AM, van Royen N.
Magnetic resonance imaging-defined areas of microvascular obstruc-
tion after acute myocardial infarction represent microvascular de-
struction and haemorrhage. Eur Heart J. 2013;34:2346–2353. doi:
10.1093/eurheartj/eht100.
123. Prasad A, Gersh BJ, Mehran R, Brodie BR, Brener SJ, Dizon JM, Lansky
AJ, Witzenbichler B, Kornowski R, Guagliumi G, Dudek D, Stone GW.
Effect of ischemia duration and door-to-balloon time on myocardial per-
fusion in ST-segment elevation myocardial infarction: an analysis from
HORIZONS-AMI trial (Harmonizing Outcomes with Revascularization
and Stents in Acute Myocardial Infarction). JACC Cardiovasc Interv.
2015;8:1966–1974. doi: 10.1016/j.jcin.2015.08.031.
124. Niccoli G, Scalone G, Lerman A, Crea F. Coronary microvascular ob-
struction in acute myocardial infarction. Eur Heart J. 2016;37:1024–
1033. doi: 10.1093/eurheartj/ehv484.
125. Ndrepepa G, Tiroch K, Fusaro M, Keta D, Seyfarth M, Byrne RA,
Pache J, Alger P, Mehilli J, Schömig A, Kastrati A. 5-year prognostic
Downloaded from http://circres.ahajournals.org/ by guest on December 9, 2017
value of no-reflow phenomenon after percutaneous coronary interven-
tion in patients with acute myocardial infarction. J Am Coll Cardiol.
2010;55:2383–2389. doi: 10.1016/j.jacc.2009.12.054.
126. Betgem RP, de Waard GA, Nijveldt R, Beek AM, Escaned J, van Royen
N. Intramyocardial haemorrhage after acute myocardial infarction. Nat
Rev Cardiol. 2015;12:156–167. doi: 10.1038/nrcardio.2014.188.
127. Laude K, Beauchamp P, Thuillez C, Richard V. Endothelial protective
effects of preconditioning. Cardiovasc Res. 2002;55:466–473.
128. Di Napoli P, Di Muzio M, Contegiacomo G, Tiloca P, Spoletini L, Di
Crecchio A, Gallina S, Barsotti A. [Ischemic preconditioning of the myo-
cardium: the role of changes in the permeability of the coronary micro-
circulation]. Cardiologia. 1997;42:59–67.
129. Bauer B, Simkhovich BZ, Kloner RA, Przyklenk K. Does precondition-
ing protect the coronary vasculature from subsequent ischemia/reperfu-
sion injury? Circulation. 1993;88:659–672.
130. Loke KE, Woodman OL. Preconditioning improves myocardial function
and reflow, but not vasodilator reactivity, after ischaemia and reperfusion
in anaesthetized dogs. Clin Exp Pharmacol Physiol. 1998;25:552–558.
131. Richard V, Kaeffer N, Tron C, Thuillez C. Ischemic preconditioning pro-
tects against coronary endothelial dysfunction induced by ischemia and
reperfusion. Circulation. 1994;89:1254–1261.
132. Bouchard JF, Lamontagne D. Mechanisms of protection afforded by
preconditioning to endothelial function against ischemic injury. Am J
Physiol. 1996;271:H1801–H1806.
133. Bouchard JF, Chouinard J, Lamontagne D. Role of kinins in the endo-
thelial protective effect of ischaemic preconditioning. Br J Pharmacol.
1998;123:413–420. doi: 10.1038/sj.bjp.0701619.
134. Kurzelewski M, Czarnowska E, Maczewski M, Beresewicz A. Effect of
ischemic preconditioning on endothelial dysfunction and granulocyte ad-
hesion in isolated guinea-pig hearts subjected to ischemia/reperfusion. J
Physiol Pharmacol. 1999;50:617–628.
135. Thourani VH, Nakamura M, Duarte IG, Bufkin BL, Zhao ZQ, Jordan
JE, Shearer ST, Guyton RA, Vinten-Johansen J. Ischemic precondi-
tioning attenuates postischemic coronary artery endothelial dysfunc-
tion in a model of minimally invasive direct coronary artery bypass
grafting. J Thorac Cardiovasc Surg. 1999;117:383–389. doi: 10.1016/
S0022-5223(99)70437-X.
136. Merkus D, Stepp DW, Jones DW, Nishikawa Y, Chilian WM. Adenosine
preconditions against endothelin-induced constriction of coronary arteri-
oles. Am J Physiol Heart Circ Physiol. 2000;279:H2593–H2597.
137. Tofukuji M, Metais C, Li J, Hariawala MD, Franklin A, Vassileva C, Li
J, Simons M, Sellke FW. Effects of ischemic preconditioning on myo-
cardial perfusion, function, and microvascular regulation. Circulation.
1998;98:II-197–II-205.
138. Gattullo D, Linden RJ, Losano G, Pagliaro P, Westerhof N. Ischaemic
preconditioning changes the pattern of coronary reactive hyperae-
mia in the goat: role of adenosine and nitric oxide. Cardiovasc Res.
1999;42:57–64.
139. Posa A, Pavo N, Hemetsberger R, Csonka C, Csont T, Ferdinandy P, Petrási
Z, Varga C, Pavo IJ, Laszlo F Jr, Huber K, Gyöngyösi M. Protective ef-
fect of ischaemic preconditioning on ischaemia/reperfusion-induced mi-
crovascular obstruction determined by on-line measurements of coronary
pressure and blood flow in pigs. Thromb Haemost. 2010;103:450–460.
doi: 10.1160/TH09-03-0165.
140. Kaeffer N, Richard V, François A, Lallemand F, Henry JP, Thuillez C.
Preconditioning prevents chronic reperfusion-induced coronary endothe-
lial dysfunction in rats. Am J Physiol. 1996;271:H842–H849.
141. Laude K, Favre J, Thuillez C, Richard V. NO produced by endothelial
NO synthase is a mediator of delayed preconditioning-induced endo-
thelial protection. Am J Physiol Heart Circ Physiol. 2003;284:H2053–
H2060. doi: 10.1152/ajpheart.00627.2002.
142. Kim SJ, Zhang X, Xu X, Chen A, Gonzalez JB, Koul S, Vijayan K,
Crystal GJ, Vatner SF, Hintze TH. Evidence for enhanced eNOS function
in coronary microvessels during the second window of protection. Am
J Physiol Heart Circ Physiol. 2007;292:H2152–H2158. doi: 10.1152/
ajpheart.00326.2006.
143. Kaeffer N, Richard V, Thuillez C. Delayed coronary endothelial protec-
tion 24 hours after preconditioning: role of free radicals. Circulation.
1997;96:2311–2316.
144. Matsuda N, Morgan KG, Sellke FW. Preconditioning improves cardio-
plegia-related coronary microvascular smooth muscle hypercontractility:
role of KATP channels. J Thorac Cardiovasc Surg. 1999;118:438–445.
doi: 10.1016/S0022-5223(99)70180-7.
145. Skyschally A, Schulz R, Gres P, Konietzka I, Martin C, Haude M, Erbel
R, Heusch G. Coronary microembolization does not induce acute pre-
conditioning against infarction in pigs-the role of adenosine. Cardiovasc
Res. 2004;63:313–322. doi: 10.1016/j.cardiores.2004.04.003.
146. Skyschally A, Gres P, Hoffmann S, Haude M, Erbel R, Schulz R, Heusch
G. Bidirectional role of tumor necrosis factor-alpha in coronary micro-
embolization: progressive contractile dysfunction versus delayed protec-
tion against infarction. Circ Res. 2007;100:140–146. doi: 10.1161/01.
RES.0000255031.15793.86.
147. Heusch G. Nitroglycerin and delayed preconditioning in humans: yet an-
other new mechanism for an old drug? Circulation. 2001;103:2876–2878.
148. Rezkalla SH, Kloner RA. Ischemic preconditioning and preinfarction
angina in the clinical arena. Nat Clin Pract Cardiovasc Med. 2004;1:96–
102. doi: 10.1038/ncpcardio0047.
149. Scalone G, Aurigemma C, Tomai F, Corvo P, Battipaglia I, Lanza GA,
Crea F. Effect of pre-infarction angina on platelet reactivity in acute
myocardial infarction. Int J Cardiol. 2013;167:51–56. doi: 10.1016/j.
ijcard.2011.11.085.
150. Colonna P, Cadeddu C, Montisci R, Ruscazio M, Selem AH, Chen L,
Onnis E, Meloni L, Iliceto S. Reduced microvascular and myocardial
damage in patients with acute myocardial infarction and preinfarction
angina. Am Heart J. 2002;144:796–803.
151. Niccoli G, Scalone G, Cosentino N, Fabretti A, Mirizzi AM, Gramegna
M, Panebianco M, Roberto M, Crea F. Protective effect of pre-infarction
angina on microvascular obstruction after primary percutaneous coro-
nary intervention is blunted in humans by cardiovascular risk factors.
Circ J. 2014;78:1935–1941.
152. Hale SL, Mehra A, Leeka J, Kloner RA. Postconditioning fails to im-
prove no reflow or alter infarct size in an open-chest rabbit model of
myocardial ischemia-reperfusion. Am J Physiol Heart Circ Physiol.
2008;294:H421–H425. doi: 10.1152/ajpheart.00962.2007.
153. Bodi V, Ruiz-Nodar JM, Feliu E, et al. Effect of ischemic postcon-
ditioning on microvascular obstruction in reperfused myocardial
infarction. Results of a randomized study in patients and of an experi-
mental model in swine. Int J Cardiol. 2014;175:138–146. doi: 10.1016/j.
ijcard.2014.05.003.
154. Skyschally A, Kleinbongard P, Heusch G. Local and remote ischemic
preconditioning reduces myocardial infarct size and microvascular ob-
struction during reperfusion, whereas ischemic postconditioning only
reduces infarct size. Clin Res Cardiol. 2016;105 Suppl. 1:V845.
155. Zhao JL, Yang YJ, You SJ, Cui CJ, Gao RL. Different effects of post-
conditioning on myocardial no-reflow in the normal and hypercholester-
olemic mini-swines. Microvasc Res. 2007;73:137–142. doi: 10.1016/j.
mvr.2006.09.002.
156. Ma X, Zhang X, Li C, Luo M. Effect of postconditioning on coro-
nary blood flow velocity and endothelial function and LV recovery
after myocardial infarction. J Interv Cardiol. 2006;19:367–375. doi:
10.1111/j.1540-8183.2006.00191.x.
157. Ma XJ, Zhang XH, Li CM, Luo M. Effect of postconditioning on coro-
nary blood flow velocity and endothelial function in patients with acute
myocardial infarction. Scand Cardiovasc J. 2006;40:327–333. doi:
10.1080/14017430601047864.
158. 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
 1656  Circulation Research  May 13, 2016
ZQ. Reduction in myocardial infarct size by postconditioning in pa-
tients after percutaneous coronary intervention. J Invasive Cardiol.
2007;19:424–430.
159. Laskey WK, Yoon S, Calzada N, Ricciardi MJ. Concordant improve-
ments in coronary flow reserve and ST-segment resolution during percu-
taneous coronary intervention for acute myocardial infarction: a benefit
of postconditioning. Catheter Cardiovasc Interv. 2008;72:212–220. doi:
10.1002/ccd.21583.
160. Garcia S, Henry TD, Wang YL, Chavez IJ, Pedersen WR, Lesser
JR, Shroff GR, Moore L, Traverse JH. Long-term follow-up of pa-
tients undergoing postconditioning during ST-elevation myocardial
infarction. J Cardiovasc Transl Res. 2011;4:92–98. doi: 10.1007/
s12265-010-9252-0.
161. Liu TK, Mishra AK, Ding FX. [Protective effect of ischemia postcon-
ditioning on reperfusion injury in patients with ST-segment elevation
acute myocardial infarction]. Zhonghua Xin Xue Guan Bing Za Zhi.
2011;39:35–39.
162. Thuny F, Lairez O, Roubille F, et al. Post-conditioning reduces in-
farct size and edema in patients with ST-segment elevation myocar-
dial infarction. J Am Coll Cardiol. 2012;59:2175–2181. doi: 10.1016/j.
jacc.2012.03.026.
163. Mewton N, Thibault H, Roubille F, et al. Postconditioning attenuates
no-reflow in STEMI patients. Basic Res Cardiol. 2013;108:383. doi:
Downloaded from http://circres.ahajournals.org/ by guest on December 9, 2017
10.1007/s00395-013-0383-8.
164. Araszkiewicz A, Grygier M, Pyda M, Rajewska J, Michalak M, Lesiak
M, Grajek S. Postconditioning reduces enzymatic infarct size and
improves microvascular reperfusion in patients with ST-segment el-
evation myocardial infarction. Cardiology. 2014;129:250–257. doi:
10.1159/000367965.
165. Tarantini G, Favaretto E, Marra MP, Frigo AC, Napodano M,
Cacciavillani L, Giovagnoni A, Renda P, De Biasio V, Plebani M,
Mion M, Zaninotto M, Isabella G, Bilato C, Iliceto S. Postconditioning
during coronary angioplasty in acute myocardial infarction: the
POST-AMI trial. Int J Cardiol. 2012;162:33–38. doi: 10.1016/j.
ijcard.2012.03.136.
166. Ugata Y, Nakamura T, Taniguchi Y, Ako J, Momomura S. Effect of
postconditioning in patients with ST-elevation acute myocardial infarc-
tion. Cardiovasc Interv Ther. 2012;27:14–18. doi: 10.1007/s12928-
011-0077-9.
167. Dwyer NB, Mikami Y, Hilland D, Aljizeeri A, Friedrich MG, Traboulsi
M, Anderson TJ. No cardioprotective benefit of ischemic postcondition-
ing in patients with ST-segment elevation myocardial infarction. J Interv
Cardiol. 2013;26:482–490. doi: 10.1111/joic.12064.
168. Hahn JY, Song YB, Kim EK, et al. Ischemic postconditioning during pri-
mary percutaneous coronary intervention: the effects of postconditioning
on myocardial reperfusion in patients with ST-segment elevation myo-
cardial infarction (POST) randomized trial. Circulation. 2013;128:1889–
1896. doi: 10.1161/CIRCULATIONAHA.113.001690.
169. Eitel I, Stiermaier T, Rommel KP, Fuernau G, Sandri M, Mangner N,
Linke A, Erbs S, Lurz P, Boudriot E, Mende M, Desch S, Schuler G,
Thiele H. Cardioprotection by combined intrahospital remote ischaemic
perconditioning and postconditioning in ST-elevation myocardial in-
farction: the randomized LIPSIA CONDITIONING trial. Eur Heart J.
2015;36:3049–3057. doi: 10.1093/eurheartj/ehv463.
170. Kim EK, Hahn JY, Song YB, Lee SC, Choi JH, Choi SH, Lee SH, Choe
YH, Gwon HC. Effect of ischemic postconditioning on myocardial sal-
vage in patients undergoing primary percutaneous coronary intervention
for ST-segment elevation myocardial infarction: cardiac magnetic reso-
nance substudy of the POST randomized trial. Int J Cardiovasc Imaging.
2015;31:629–637. doi: 10.1007/s10554-015-0589-y.
171. Loubeyre C, Morice MC, Lefèvre T, Piéchaud JF, Louvard Y, Dumas
P. A randomized comparison of direct stenting with conventional stent
implantation in selected patients with acute myocardial infarction. J Am
Coll Cardiol. 2002;39:15–21.
172. Roubille F, Lairez O, Mewton N, Rioufol G, Ranc S, Sanchez I, Cung TT,
Elbaz M, Piot C, Ovize M. Cardioprotection by clopidogrel in acute ST-
elevated myocardial infarction patients: a retrospective analysis. Basic
Res Cardiol. 2012;107:275. doi: 10.1007/s00395-012-0275-3.
173. Cohen MV, Downey JM. Status of P2Y12 treatment must be considered
in evaluation of myocardial ischaemia/reperfusion injury. Cardiovasc
Res. 2015;106:8. doi: 10.1093/cvr/cvv051.
174. Iliodromitis EK, Cohen MV, Dagres N, Andreadou I, Kremastinos DT,
Downey JM. What is wrong with cardiac conditioning? We may be
shooting at moving targets. J Cardiovasc Pharmacol Ther. 2015;20:357–
369. doi: 10.1177/1074248414566459.
175. Przyklenk K, Bauer B, Ovize M, Kloner RA, Whittaker P. Regional isch-
emic ‘preconditioning’ protects remote virgin myocardium from subse-
quent sustained coronary occlusion. Circulation. 1993;87:893–899.
176. Heusch G, Bøtker HE, Przyklenk K, Redington A, Yellon D. Remote
ischemic conditioning. J Am Coll Cardiol. 2015;65:177–195. doi:
10.1016/j.jacc.2014.10.031.
177. Shimizu M, Konstantinov IE, Kharbanda RK, Cheung MH, Redington
AN. Effects of intermittent lower limb ischaemia on coronary blood flow
and coronary resistance in pigs. Acta Physiol (Oxf). 2007;190:103–109.
doi: 10.1111/j.1748-1716.2007.01667.x.
178. Kono Y, Fukuda S, Hanatani A, Nakanishi K, Otsuka K, Taguchi H,
Shimada K. Remote ischemic conditioning improves coronary microcir-
culation in healthy subjects and patients with heart failure. Drug Des
Devel Ther. 2014;8:1175–1181. doi: 10.2147/DDDT.S68715.
179. Hoole SP, Heck PM, White PA, Khan SN, O’Sullivan M, Clarke SC,
Dutka DP. Remote ischemic preconditioning stimulus does not reduce
microvascular resistance or improve myocardial blood flow in patients
undergoing elective percutaneous coronary intervention. Angiology.
2009;60:403–411. doi: 10.1177/0003319708328921.
180. Bøtker HE, Kharbanda R, Schmidt MR, et al. Remote ischaemic con-
ditioning before hospital admission, as a complement to angioplasty,
and effect on myocardial salvage in patients with acute myocardial in-
farction: a randomised trial. Lancet. 2010;375:727–734. doi: 10.1016/
S0140-6736(09)62001-8.
181. White SK, Frohlich GM, Sado DM, Maestrini V, Fontana M, Treibel
TA, Tehrani S, Flett AS, Meier P, Ariti C, Davies JR, Moon JC, Yellon
DM, Hausenloy DJ. Remote ischemic conditioning reduces myocardial
infarct size and edema in patients with ST-segment elevation myocardial
infarction. JACC Cardiovasc Interv. 2015;8:178–188. doi: 10.1016/j.
jcin.2014.05.015.
182. Crimi G, Pica S, Raineri C, et al. Remote ischemic post-conditioning of
the lower limb during primary percutaneous coronary intervention safely
reduces enzymatic infarct size in anterior myocardial infarction: a ran-
domized controlled trial. JACC Cardiovasc Interv. 2013;6:1055–1063.
doi: 10.1016/j.jcin.2013.05.011.
183. Pryds K, Botker HE. Influence of pre-infarction angina and coronary
collateral circulation on the efficacy of remote ischaemic condition-
ing in patients with ST-segment elevation myocardial infarction treated
with primary percutaneous coronary intervention. Eur Heart J Acute
Cardiovasc Care. In press.
184. Shimizu M, Saxena P, Konstantinov IE, Cherepanov V, Cheung MM,
Wearden P, Zhangdong H, Schmidt M, Downey GP, Redington AN.
Remote ischemic preconditioning decreases adhesion and selective-
ly modifies functional responses of human neutrophils. J Surg Res.
2010;158:155–161. doi: 10.1016/j.jss.2008.08.010.
185. Stazi A, Scalone G, Laurito M, Milo M, Pelargonio G, Narducci ML,
Parrinello R, Figliozzi S, Bencardino G, Perna F, Lanza GA, Crea
F. Effect of remote ischemic preconditioning on platelet activation
and reactivity induced by ablation for atrial fibrillation. Circulation.
2014;129:11–17. doi: 10.1161/CIRCULATIONAHA.113.005336.
186. Lanza GA, Stazi A, Villano A, Torrini F, Milo M, Laurito M, Flego D,
Aurigemma C, Liuzzo G, Crea F. Effect of remote ischemic precon-
ditioning on platelet activation induced by coronary procedures. Am J
Cardiol. 2016;117:359–365. doi: 10.1016/j.amjcard.2015.10.056.
187. Kleinbongard P, Schulz R, Rassaf T, et al. Red blood cells express a func-
tional endothelial nitric oxide synthase. Blood. 2006;107:2943–2951.
doi: 10.1182/blood-2005-10-3992.
188. Grau M, Kollikowski A, Bloch W. Remote ischemia preconditioning in-
creases red blood cell deformability through red blood cell-nitric oxide
synthase activation [published online ahead of print January 27, 2016].
Clin Hemorheol Microcirc. 2016.
189. Heusch G, Libby P, Gersh B, Yellon D, Böhm M, Lopaschuk G,
Opie L. Cardiovascular remodelling in coronary artery disease
and heart failure. Lancet. 2014;383:1933–1943. doi: 10.1016/
S0140-6736(14)60107-0.
190. Ferdinandy P, Hausenloy DJ, Heusch G, Baxter GF, Schulz R. Interaction
of risk factors, comorbidities, and comedications with ischemia/reperfu-
sion injury and cardioprotection by preconditioning, postconditioning,
and remote conditioning. Pharmacol Rev. 2014;66:1142–1174. doi:
10.1124/pr.113.008300.
191. Schwartz Longacre L, Kloner RA, Arai AE, et al; National Heart, Lung,
and Blood Institute, National Institutes of Health. New horizons in car-
dioprotection: recommendations from the 2010 National Heart, Lung,
and Blood Institute Workshop. Circulation. 2011;124:1172–1179. doi:
10.1161/CIRCULATIONAHA.111.032698.
 Heusch   Cardioprotection and Coronary Circulation   1657
192. Jones SP, Tang XL, Guo Y, et al. The NHLBI-sponsored Consortium
for preclinicAl assESsment of cARdioprotective therapies (CAESAR):
a new paradigm for rigorous, accurate, and reproducible evaluation of
putative infarct-sparing interventions in mice, rabbits, and pigs. Circ Res.
2015;116:572–586. doi: 10.1161/CIRCRESAHA.116.305462.
193. Yetgin T, Uitterdijk A, Te Lintel Hekkert M, Merkus D, Krabbendam-
Peters I, van Beusekom HM, Falotico R, Serruys PW, Manintveld OC,
van Geuns RJ, Zijlstra F, Duncker DJ. Limitation of infarct size and
no-reflow by intracoronary adenosine depends critically on dose and
duration. JACC Cardiovasc Interv. 2015;8:1990–1999. doi: 10.1016/j.
jcin.2015.08.033.
194. Zalewski J, Claus P, Bogaert J, Driessche NV, Driesen RB, Galan DT,
Sipido KR, Buszman P, Milewski K, Van de Werf F. Cyclosporine A re-
duces microvascular obstruction and preserves left ventricular function
deterioration following myocardial ischemia and reperfusion. Basic Res
Cardiol. 2015;110:18. doi: 10.1007/s00395-015-0475-8.
195. Sattler K, Gräler M, Keul P, Weske S, Reimann CM, Jindrová H,
Kleinbongard P, Sabbadini R, Bröcker-Preuss M, Erbel R, Heusch G,
Levkau B. Defects of high-density lipoproteins in coronary artery disease
caused by low sphingosine-1-phosphate content: correction by sphingo-
sine-1-phosphate-loading. J Am Coll Cardiol. 2015;66:1470–1485. doi:
10.1016/j.jacc.2015.07.057.
196. Vilahur G, Gutiérrez M, Casaní L, Cubedo J, Capdevila A, Pons-Llado
Downloaded from http://circres.ahajournals.org/ by guest on December 9, 2017
G, Carreras F, Hidalgo A, Badimon L. Hypercholesterolemia abolishes
high-density lipoprotein-related cardioprotective effects in the setting
of myocardial infarction. J Am Coll Cardiol. 2015;66:2469–2470. doi:
10.1016/j.jacc.2015.08.901.
197. Li XD, Yang YJ, Geng YJ, Cheng YT, Zhang HT, Zhao JL, Yuan JQ, Gao
RL. The cardioprotection of simvastatin in reperfused swine hearts re-
lates to the inhibition of myocardial edema by modulating aquaporins via
the PKA pathway. Int J Cardiol. 2013;167:2657–2666. doi: 10.1016/j.
ijcard.2012.06.121.
198. Zhao JL, Yang YJ, Cui CJ, You SJ, Gao RL. Pretreatment with simvastatin
reduces myocardial no-reflow by opening mitochondrial K(ATP) chan-
nel. Br J Pharmacol. 2006;149:243–249. doi: 10.1038/sj.bjp.0706862.
199. Dokken BB, La Bonte LR, Davis-Gorman G, Teachey MK, Seaver N,
McDonagh PF. Glucagon-like peptide-1 (GLP-1), immediately prior
to reperfusion, decreases neutrophil activation and reduces myocar-
dial infarct size in rodents. Horm Metab Res. 2011;43:300–305. doi:
10.1055/s-0031-1271777.
200. Garcia-Dorado D, Théroux P, Munoz R, Alonso J, Elizaga J, Fernandez-
Avilés F, Botas J, Solares J, Soriano J, Duran JM. Favorable effects of
hyperosmotic reperfusion on myocardial edema and infarct size. Am J
Physiol. 1992;262:H17–H22.
201. Uitterdijk A, Yetgin T, te Lintel Hekkert M, Sneep S, Krabbendam-
Peters I, van Beusekom HM, Fischer TM, Cornelussen RN, Manintveld
OC, Merkus D, Duncker DJ. Vagal nerve stimulation started just prior
to reperfusion limits infarct size and no-reflow. Basic Res Cardiol.
2015;110:508. doi: 10.1007/s00395-015-0508-3.
202. Pierrakos CN, Bonios MJ, Drakos SG, Charitos EI, Tsolakis EJ, Ntalianis
A, Nanas SN, Charitos CE, Nanas JN, Terrovitis JV. Mechanical as-
sistance by intra-aortic balloon pump counterpulsation during re-
perfusion increases coronary blood flow and mitigates the no-reflow
phenomenon: an experimental study. Artif Organs. 2011;35:867–874.
doi: 10.1111/j.1525-1594.2011.01241.x.
203. Pantsios C, Kapelios C, Vakrou S, Diakos N, Pozios I, Kontogiannis C,
Nanas J, Malliaras K. Effect of elevated reperfusion pressure on “no re-
flow” area and infarct size in a porcine model of ischemia-reperfusion
[published online ahead of print November 20, 2015]. J Cardiovasc
Pharmacol Ther. 2015.
204. Herring MJ, Dai W, Hale SL, Kloner RA. Rapid induction of hypo-
thermia by the ThermoSuit system profoundly reduces infarct size and
anatomic zone of no reflow following ischemia-reperfusion in rabbit
and rat hearts. J Cardiovasc Pharmacol Ther. 2015;20:193–202. doi:
10.1177/1074248414535664.
205. Hale SL, Herring MJ, Kloner RA. Delayed treatment with hypothermia pro-
tects against the no-reflow phenomenon despite failure to reduce infarct size.
J Am Heart Assoc. 2013;2:e004234. doi: 10.1161/JAHA.112.004234.
206. Kanazawa H, Tseliou E, Malliaras K, et al. Cellular postconditioning:
allogeneic cardiosphere-derived cells reduce infarct size and attenuate
microvascular obstruction when administered after reperfusion in pigs
with acute myocardial infarction. Circ Heart Fail. 2015;8:322–332. doi:
10.1161/CIRCHEARTFAILURE.114.001484.
207. Gerczuk PZ, Kloner RA. An update on cardioprotection: a review of
the latest adjunctive therapies to limit myocardial infarction size in
clinical trials. J Am Coll Cardiol. 2012;59:969–978. doi: 10.1016/j.
jacc.2011.07.054.
208. Dixon SR, Whitbourn RJ, Dae MW, Grube E, Sherman W, Schaer GL,
Jenkins JS, Baim DS, Gibbons RJ, Kuntz RE, Popma JJ, Nguyen TT,
O’Neill WW. Induction of mild systemic hypothermia with endovascu-
lar cooling during primary percutaneous coronary intervention for acute
myocardial infarction. J Am Coll Cardiol. 2002;40:1928–1934.
209. Götberg 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;3:400–407. doi: 10.1161/CIRCINTERVENTIONS.110.957902.
210. Erlinge D, Götberg M, Lang I, et al. Rapid endovascular catheter core
cooling combined with cold saline as an adjunct to percutaneous coro-
nary intervention for the treatment of acute myocardial infarction. The
CHILL-MI trial: a randomized controlled study of the use of central ve-
nous catheter core cooling combined with cold saline as an adjunct to
percutaneous coronary intervention for the treatment of acute myocar-
dial infarction. J Am Coll Cardiol. 2014;63:1857–1865. doi: 10.1016/j.
jacc.2013.12.027.
211. Nichol G, Strickland W, Shavelle D, et al; VELOCITY Investigators.
Prospective, multicenter, randomized, controlled pilot trial of peri-
toneal hypothermia in patients with ST-segment- elevation myocar-
dial infarction. Circ Cardiovasc Interv. 2015;8:e001965. doi: 10.1161/
CIRCINTERVENTIONS.114.001965.
212. O’Neill 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; AMIHOT Investigators. Acute Myocardial
Infarction with Hyperoxemic Therapy (AMIHOT): a prospective, ran-
domized trial of intracoronary hyperoxemic reperfusion after percuta-
neous coronary intervention. J Am Coll Cardiol. 2007;50:397–405. doi:
10.1016/j.jacc.2007.01.099.
213. 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; AMIHOT-II
Trial Investigators. Effect of supersaturated oxygen delivery on in-
farct size after percutaneous coronary intervention in acute myocar-
dial infarction. Circ Cardiovasc Interv. 2009;2:366–375. doi: 10.1161/
CIRCINTERVENTIONS.108.840066.
214. Antoniucci D, Valenti R, Migliorini A, Parodi G, Memisha G, Santoro
GM, Sciagrà R. Comparison of rheolytic thrombectomy before direct
infarct artery stenting versus direct stenting alone in patients undergoing
percutaneous coronary intervention for acute myocardial infarction. Am
J Cardiol. 2004;93:1033–1035. doi: 10.1016/j.amjcard.2004.01.011.
215. Kaltoft A, Bøttcher M, Nielsen SS, et al. Routine thrombectomy in
percutaneous coronary intervention for acute ST-segment-elevation
myocardial infarction: a randomized, controlled trial. Circulation.
2006;114:40–47. doi: 10.1161/CIRCULATIONAHA.105.595660.
216. Lipiecki J, Monzy S, Durel N, Cachin F, Chabrot P, Muliez A, Morand
D, Maublant J, Ponsonnaille J. Effect of thrombus aspiration on infarct
size and left ventricular function in high-risk patients with acute myocar-
dial infarction treated by percutaneous coronary intervention. Results of
a prospective controlled pilot study. Am Heart J. 2009;157:583.e1–583.
e7. doi: 10.1016/j.ahj.2008.11.017.
217. Sardella G, Mancone M, Bucciarelli-Ducci C, Agati L, Scardala R,
Carbone I, Francone M, Di Roma A, 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 pri-
mary percutaneous coronary intervention) prospective, randomized trial.
J Am Coll Cardiol. 2009;53:309–315. doi: 10.1016/j.jacc.2008.10.017.
218. Migliorini A, Stabile A, Rodriguez AE, Gandolfo C, Rodriguez Granillo
AM, Valenti R, Parodi G, Neumann FJ, Colombo A, Antoniucci D;
JETSTENT Trial Investigators. Comparison of AngioJet rheolytic throm-
bectomy before direct infarct artery stenting with direct stenting alone in
patients with acute myocardial infarction. The JETSTENT trial. J Am
Coll Cardiol. 2010;56:1298–1306. doi: 10.1016/j.jacc.2010.06.011.
219. Ciszewski M, Pregowski J, Teresińska A, Karcz M, Kalińczuk Ł, Pracon
R, Witkowski A, Rużyłło W. Aspiration coronary thrombectomy for
acute myocardial infarction increases myocardial salvage: single center
randomized study. Catheter Cardiovasc Interv. 2011;78:523–531. doi:
10.1002/ccd.22933.
220. 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
 1658  Circulation Research  May 13, 2016
elevation myocardial infarction and thrombus-rich lesions: MUSTELA
(MUltidevice Thrombectomy in Acute ST-Segment ELevation Acute
Myocardial Infarction) trial. JACC Cardiovasc Interv. 2012;5:1223–
1230. doi: 10.1016/j.jcin.2012.08.013.
221. Stone GW, Maehara A, Witzenbichler B, et al; INFUSE-AMI
Investigators. Intracoronary abciximab and aspiration thrombectomy
in patients with large anterior myocardial infarction: the INFUSE-
AMI randomized trial. JAMA. 2012;307:1817–1826. doi: 10.1001/
jama.2012.421.
222. 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 myocar-
dial infarction without shock: the CRISP AMI randomized trial. JAMA.
2011;306:1329–1337. doi: 10.1001/jama.2011.1280.
223. Piot C, Croisille P, Staat P, et al. Effect of cyclosporine on reperfusion
injury in acute myocardial infarction. N Engl J Med. 2008;359:473–481.
doi: 10.1056/NEJMoa071142.
224. Ghaffari S, Kazemi B, Toluey M, Sepehrvand N. The effect of prethrom-
bolytic cyclosporine-A injection on clinical outcome of acute anterior
ST-elevation myocardial infarction. Cardiovasc Ther. 2013;31:e34–e39.
doi: 10.1111/1755-5922.12010.
225. Cung TT, Morel O, Cayla G, et al. Cyclosporine before PCI in patients
with acute myocardial infarction. N Engl J Med. 2015;373:1021–1031.
Downloaded from http://circres.ahajournals.org/ by guest on December 9, 2017
doi: 10.1056/NEJMoa1505489.
226. Ottani F, Latini R, Staszewsky L, et al; CYCLE Investigators.
Cyclosporine A in reperfused myocardial infarction: the multicenter,
controlled, open-label CYCLE trial. J Am Coll Cardiol. 2016;67:365–
374. doi: 10.1016/j.jacc.2015.10.081.
227. Heusch G. CIRCUS: a kiss of death for cardioprotection? Cardiovasc
Res. 2015;108:215–216. doi: 10.1093/cvr/cvv225.
228. Thiele H, Schindler K, Friedenberger J, Eitel I, Fürnau G, Grebe E, Erbs
S, Linke A, Möbius-Winkler S, Kivelitz D, Schuler G. Intracoronary
compared with intravenous bolus abciximab application in patients
with ST-elevation myocardial infarction undergoing primary percutane-
ous coronary intervention: the randomized Leipzig immediate percu-
taneous coronary intervention abciximab IV versus IC in ST-elevation
myocardial infarction trial. Circulation. 2008;118:49–57. doi: 10.1161/
CIRCULATIONAHA.107.747642.
229. Marzilli M, Orsini E, Marraccini P, Testa R. Beneficial effects of intra-
coronary adenosine as an adjunct to primary angioplasty in acute myo-
cardial infarction. Circulation. 2000;101:2154–2159.
230. Niccoli G, Rigattieri S, De Vita MR, et al. Open-label, randomized, pla-
cebo-controlled evaluation of intracoronary adenosine or nitroprusside
after thrombus aspiration during primary percutaneous coronary inter-
vention for the prevention of microvascular obstruction in acute myo-
cardial infarction: the REOPEN-AMI study (Intracoronary Nitroprusside
Versus Adenosine in Acute Myocardial Infarction). JACC Cardiovasc
Interv. 2013;6:580–589. doi: 10.1016/j.jcin.2013.02.009.
231. Fokkema ML, Vlaar PJ, Vogelzang M, Gu YL, Kampinga MA, de Smet
BJ, Jessurun GA, Anthonio RL, van den Heuvel AF, Tan ES, Zijlstra F.
Effect of high-dose intracoronary adenosine administration during pri-
mary percutaneous coronary intervention in acute myocardial infarction:
a randomized controlled trial. Circ Cardiovasc Interv. 2009;2:323–329.
doi: 10.1161/CIRCINTERVENTIONS.109.858977.109.858977.
232. Garcia-Dorado D, García-del-Blanco B, Otaegui I, Rodríguez-Palomares
J, Pineda V, Gimeno F, Ruiz-Salmerón R, Elizaga J, Evangelista A,
Fernandez-Avilés F, San-Román A, Ferreira-González I. Intracoronary
injection of adenosine before reperfusion in patients with ST-segment
elevation myocardial infarction: a randomized controlled clinical trial.
Int J Cardiol. 2014;177:935–941. doi: 10.1016/j.ijcard.2014.09.203.
233. Siddiqi N, Neil C, Bruce M, et al; NIAMI investigators. Intravenous
sodium nitrite in acute ST-elevation myocardial infarction: a random-
ized controlled trial (NIAMI). Eur Heart J. 2014;35:1255–1262. doi:
10.1093/eurheartj/ehu096.
234. Jones DA, Pellaton C, Velmurugan S, Rathod KS, Andiapen M,
Antoniou S, van Eijl S, Webb AJ, Westwood MA, Parmar MK, Mathur
A, Ahluwalia A. Randomized phase 2 trial of intracoronary nitrite during
acute myocardial infarction. Circ Res. 2015;116:437–447. doi: 10.1161/
CIRCRESAHA.116.305082.
235. Ott I, Schulz S, Mehilli J, Fichtner S, Hadamitzky M, Hoppe K, Ibrahim
T, Martinoff S, Massberg S, Laugwitz KL, Dirschinger J, Schwaiger M,
Kastrati A, Schmig A; REVIVAL-3 Study Investigators. Erythropoietin
in patients with acute ST-segment elevation myocardial infarction under-
going primary percutaneous coronary intervention: a randomized, dou-
ble-blind trial. Circ Cardiovasc Interv. 2010;3:408–413. doi: 10.1161/
CIRCINTERVENTIONS.109.904425.
236. Atar D, Arheden H, Berdeaux A, et al. Effect of intravenous TRO40303
as an adjunct to primary percutaneous coronary intervention for acute
ST-elevation myocardial infarction: MITOCARE study results. Eur
Heart J. 2015;36:112–119. doi: 10.1093/eurheartj/ehu331.
237. Gibson CM, Giugliano RP, Kloner RA, et al. EMBRACE STEMI study:
a Phase 2a trial to evaluate the safety, tolerability, and efficacy of intrave-
nous MTP-131 on reperfusion injury in patients undergoing primary per-
cutaneous coronary intervention. Eur Heart J. 2015;10.1093/eurheartj/
ehv597
238. Kitakaze M, Asakura M, Kim J, et al; J-WIND investigators.
Human atrial natriuretic peptide and nicorandil as adjuncts to re-
perfusion treatment for acute myocardial infarction (J-WIND):
two randomised trials. Lancet. 2007;370:1483–1493. doi: 10.1016/
S0140-6736(07)61634-1.
239. Er F, Dahlem KM, Nia AM, et al. Randomized control of sympathetic
drive with continuous intravenous esmolol in patients with acute ST-
segment elevation myocardial infarction: The BEtA-Blocker Therapy
in Acute Myocardial Infarction (BEAT-AMI) trial. JACC Cardiovasc
Interv. 2016;9:231–240. doi: 10.1016/j.jcin.2015.10.035.
240. Lønborg J, Kelbæk H, Vejlstrup N, Bøtker HE, Kim WY, Holmvang L,
Jørgensen E, Helqvist S, Saunamäki K, Terkelsen CJ, Schoos MM, Køber
L, Clemmensen P, Treiman M, Engstrøm T. Exenatide reduces final in-
farct size in patients with ST-segment-elevation myocardial infarction
and short-duration of ischemia. Circ Cardiovasc Interv. 2012;5:288–295.
doi: 10.1161/CIRCINTERVENTIONS.112.968388.
241. Lønborg J, Vejlstrup N, Kelbæk H, et al. Exenatide reduces reperfusion
injury in patients with ST-segment elevation myocardial infarction. Eur
Heart J. 2012;33:1491–1499. doi: 10.1093/eurheartj/ehr309.
242. 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. doi: 10.1161/ATVBAHA.113.301586.
243. Reffelmann T, Hale SL, Li G, Kloner RA. Relationship between no re-
flow and infarct size as influenced by the duration of ischemia and re-
perfusion. Am J Physiol Heart Circ Physiol. 2002;282:H766–H772. doi:
10.1152/ajpheart.00767.2001.
244. Reffelmann T, Kloner RA. Microvascular reperfusion injury: rapid ex-
pansion of anatomic no reflow during reperfusion in the rabbit. Am J
Physiol Heart Circ Physiol. 2002;283:H1099–H1107. doi: 10.1152/
ajpheart.00270.2002.
245. Reffelmann T, Kloner RA. Is microvascular protection by cariporide and
ischemic preconditioning causally linked to myocardial salvage? Am J
Physiol Heart Circ Physiol. 2003;284:H1134–H1141. doi: 10.1152/
ajpheart.00563.2002.
246. Heusch G, Kleinbongard P, Skyschally A. Myocardial infarction
and coronary microvascular obstruction: an intimate, but compli-
cated relationship. Basic Res Cardiol. 2013;108:380. doi: 10.1007/
s00395-013-0380-y.
247. Kloner RA, Rude RE, Carlson N, Maroko PR, DeBoer LW, Braunwald
E. Ultrastructural evidence of microvascular damage and myocardial cell
injury after coronary artery occlusion: which comes first? Circulation.
1980;62:945–952.
248. Sanz E, García Dorado D, Oliveras J, Barrabés JA, Gonzalez MA,
Ruiz-Meana M, Solares J, Carreras MJ, García-Lafuente A, Desco M.
Dissociation between anti-infarct effect and anti-edema effect of isch-
emic preconditioning. Am J Physiol. 1995;268:H233–H241.
249. Hori M, Gotoh K, Kitakaze M, Iwai K, Iwakura K, Sato H, Koretsune Y,
Inoue M, Kitabatake A, Kamada T. Role of oxygen-derived free radicals
in myocardial edema and ischemia in coronary microvascular emboliza-
tion. Circulation. 1991;84:828–840.
250. Guarini G, Kiyooka T, Ohanyan V, et al. Impaired coronary metabolic
dilation in the metabolic syndrome is linked to mitochondrial dysfunc-
tion and mitochondrial DNA damage. Basic Res Cardiol. 2016;111:29.
doi: 10.1007/s00395-016-0547-4.
 The Coronary Circulation as a Target of Cardioprotection
Gerd Heusch
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Circ Res. 2016;118:1643-1658

doi: 10.1161/CIRCRESAHA.116.308640
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