Monte Cuc Co 2015

European Heart Journal Advance Access published November 4, 2015
REVIEW
European Heart Journal

doi:10.1093/eurheartj/ehv592
Novel therapeutic concepts
Pathophysiology of ST-segment elevation

myocardial infarction: novel mechanisms and
treatments
Fabrizio Montecucco1,2*, Federico Carbone 2, and Thomas H. Schindler3
1
Received 24 August 2015; revised 28 September 2015; accepted 12 October 2015
Despite major advances in mechanical and pharmacological reperfusion strategies to improve acute myocardial infarction (MI) injury, substantial
mortality, morbidity, and socioeconomic burden still exists. To further reduce infarct size and thus ameliorate clinical outcome, the focus has
also shifted towards early detection of MI with high-sensitive troponin assays, imaging, cardioprotection against pathophysiological targets of
myocardial reperfusion injury with mechanical (ischaemic post-conditioning, remote ischaemic pre-conditioning, therapeutic hypothermia, and
hypoxemia) and newer pharmacological interventions (atrial natriuretic peptide, cyclosporine A, and exenatide). Evidence from animal models
of myocardial ischaemia and reperfusion also demonstrated promising results on more selective anti-inflammatory compounds that require
additional validation in humans. Cardiac stem cell treatment also hold promise to reduce infarct size and negative remodelling of the left ventricle that may further improves symptoms and prognosis in these patients. This review focuses on the pathophysiology, detection, and reperfusion strategies of ST-segment elevation MI as well as current and future challenges to reduce ischaemia/reperfusion injury and infarct size that
may result in a further improved outcome in these patients.
----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords
Acute myocardial infarction Pathophysiology Treatment
Introduction: definition of the

disease
Pathophysiologically, acute myocardial infarction (MI) is commonly
defined as a cardiomyocyte death due to a prolonged ischaemia resulting from an acute imbalance between oxygen supply and demand.1 The clinical definition of MI was recently updated,
focusing on the values of serum markers of cardiac necrosis, such
as cardiac troponin (cTn). Patients presenting with suspected acute
coronary syndrome (ACS) in the emergency department will undergo clinical evaluation, 12-lead electrocardiogram, and complemented by measurements of cTnI or T in order to directly identify
and quantify cardiomyocyte injury.2 An increase and/or decrease
in a patients plasma of cTn with at least one cTn measurement
.99th percentile of the upper normal reference signifies MI (ischaemic chest pain at rest with cardiomyocyte necrosis), while the absence of such high plasma levels in cTn refers to unstable angina
(ischaemic chest pain at rest or at minimal exertion without cardiomyocyte necrosis).3 The relatively low sensitivity of conventional
cTn assays at the time of patient presentation due to a delayed elevation in circulating cTn levels commonly requires serial sampling
for .6 h. Conversely, primary reperfusion therapy without troponin assessment is recommended in all patients with symptoms of
,12 h duration and persistent ST-segment elevation or (presumed)
new left bundle branch block. In addition, there is general agreement
that reperfusion therapy should be considered if there is clinical and/or
electrocardiographic evidence of ongoing ischaemia, even if, according to the patient, symptoms started .12 h before as the exact
onset of symptoms is often unclear.4 With the introduction of highsensitive cTn, however, 3 h rule-out protocols in the emergency department are commonly applied. Furthermore, large observational
multi-centre studies have demonstrated an excellent performance
of a 2 h rule-out protocol that combines hs-cTn values with clinical
information5,6 and a 1-h rule-out protocol only based on hs-cTn
* Corresponding author: Tel: +39 010 3537940, Fax: +39 010 3538686, Email: [email protected]
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2015. For permissions please email: [email protected].
Downloaded from http://eurheartj.oxfordjournals.org/ by guest on November 8, 2015
First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa IRCCS Azienda Ospedaliera Universitaria San Martino IST Istituto Nazionale per la Ricerca
sul Cancro, 6 Viale Benedetto XV, 16132 Genoa, Italy; 2Division of Cardiology, Foundation for Medical Researches, Faculty of Medicine, University of Geneva, 64 avenue de la Roseraie,
1211 Geneva, Switzerland; and 3Department of Radiology, Johns Hopkins University, JHOC 3225, 601 N. Caroline Street, 21287 Baltimore, MD, USA
Page 2 of 21
Pathophysiology of MI: from

vulnerable plaque to vulnerable
patient
The rupture or erosion of a coronary atherosclerotic plaque is
the more frequent underlying condition for MI occurrence. In the
last 20 years, a strong debate on the structural characteristics of a
vulnerable plaque (a plaque more prone to rupture) has been performed without a conclusive statement. In addition, the identification of a vulnerable plaque in animal models and human
atherogenesis remains controversial. More recently, the concept
of vulnerable patients, considering different entities (i.e. plaque
characteristics, circulating biomarkers, and the response of the injured myocardium), was recently suggested as a better strategy to
assess the risk of MI (Figure 1). In fact, as subclinical process characterized by dynamic, non-linear, and unpredictable course, the attempt to prospectively identify specific morphological features
predictive of plaque rupture, erosion, and clinical event are likely
to be unrealistic. Rather, current pathophysiological paradigm
considers MI as the result of a perfect storm scenario in which a
coronary arterial stimulus for clinically relevant thrombosis overlaps
a pro-thrombotic milieu at the site of plaque rupture or erosion
(Figure 1).11 The majority of scientists traditionally consider thin-cap
fibroatheroma (TCFA) as a lesion at higher risk of rupture but the
association with MI might be far less strong than generally assumed.
In the large prospective clinical study Providing Regional Observations to Study Predictors of Events in the Coronary Tree, which
followed-up 697 patients treated for ACS, nearly half of the 3 years
recurrent cardiovascular events observed was ascribed to TCFAs as
assessed at baseline by virtual histology intravascular ultrasound.12
Indeed, cycles of plaque rupture and healing have been recognized
as fairly frequent events that contribute to coronary narrowing and
changes of plaque morphology without clinical symptoms.13 On the
contrary, transition to symptomatic plaque rupture involves only a
small fraction of moderately severe vulnerable plaques that undergo

rapid progression in the weeks to months before MI.14 Since high luminal stenosis is likely to be associated with greater atherosclerotic
burden, this latter might explain the high rate of event rather than
stenosis itself. This consideration may also agree with recent investigation of Buffon and colleagues, challenging the concept of single
vulnerable plaque. By measuring neutrophil myeloperoxidase content in cardiac and femoral circulations, the authors demonstrated
that widespread coronary inflammation observed in patients with
unstable angina was independent of the location of the culprit lesion.15 However, also intraplaque inflammation was described as a
critical process in atherogenesis and plaque evolution.16 In addition
to macrophages, Th1 cells and smooth muscle cells, recently B
lymphocyte subsets, dendritic cells, and neutrophils were described
to actively influence plaque vulnerability in both human and animal
models.16
Recently, additional systemic mediators increasing the risk of
MI are identified in auto-antibodies.17 IgG (instead of IgM that
were considered as protective) against modified low-density lipoproteins, phosphorylcholine, apolipoprotein A-1 (apoA-1), heat
shock proteins, and phospholipids were associated with an increased cardiovascular risk. Notably, the anti-apoA-1 IgG were described as active mediators of plaque vulnerability that may be
proven useful for prognostication of MI.18
Pathophysiological mechanisms
of myocardial ischemic/reperfusion
injury
After the occlusion of an epicardial artery, mechanical or pharmacological re-establishment of the blood flow (reperfusion) may save
part of hypoperfused myocardial area. However, in the early phases,
reperfusion itself may cause injury. In fact, reperfusion might trigger
recruitment and activation of inflammatory cells in the systemic circulation and within the myocardial ischaemic area that might increase
myocardial injury. Few days later, these inflammatory mechanisms
are thought to become beneficial allowing scare formation and stabilization. Reperfusion-induced injury therefore might be a selective
target to improve post-infarction function and negative remodelling
of the left ventricle. The first inflammatory cells infiltrating the ischaemic myocardium are neutrophils. These cells are recruited in
the area at risk (AAR) very early after reperfusion (within 30 min),
while resident macrophages disappear. Although neutrophils are
needed to ensure an effective scar formation and to prevent adverse
remodelling, they may in turn accelerate and perpetuate myocardial
injury.19 Pro-inflammatory environment due to reactive oxygen species (ROS) generation and cytokines release induces a positive feedback loop that enhances neutrophil recruitment and prolongs their
life-span. However, 37 days after MI, neutrophil infiltrate resolves
and granulocytes undergo apoptosis. Timely resolution of neutrophil
inflammation is a critical step for optimal healing of the infarcted
heart and multiple inhibitory signals have evolved for negative regulation of the inflammatory cascade following tissue injury.20 Because
of their regulated recruitment and different functional properties,
monocyte subpopulations have been suggested as master regulators
of the inflammatory reaction, alongside regulatory T cells and dying
values,7 but needing further clinical validation. The need of a standardized definitions of ST-segment elevation myocardial infarction
(STEMI) and non-STEMI are critical for diagnosis, clinical triage,
and research purposes. A first consensus definition of MI stated
that any necrosis in the setting of myocardial ischaemia should be
labelled as MI.1 The second and third universal definitions updated
both clinical and pathophysiological aspects, including MI types8,9
that can be secondary to ischaemic imbalance (Type 2 MI, e.g. due
to vasospasm, endothelial dysfunction, coronary embolism, anaemia, respiratory failure, arrhythmias, hypertension, and hypotension) and the sudden cardiac death suggestive for MI but without
available biomarker values (Type 3 MI) (Table 1). In addition, novel
entities, such as the procedure-related MI, due to percutaneous coronary intervention (Type 4a), stent thrombosis (Type 4b), and coronary artery bypass grafting (Type 5), were considered (Table 1).
The universal definition of MI substantially impacted on the diagnosis and treatment of the disease. Conversely, the prevention of MI
requires a more comprehensive understanding of the pathophysiological aspects in vulnerable patients.10 The present review aims at
updating the relevance of a pathophysiological approach for imaging
and treatments in MI models and patients.
F. Montecucco et al.
Page 3 of 21
Novel mechanisms and treatments
Table 1 Classification of myocardial infarction according to clinical criteria and cardiac troponin raise/fall reported
in the third (2012) universal definition of myocardial infarction
Criteria
Classification
Troponin threshold
Type 1 spontaneous
Rise or fall, with at least one value above 99th percentile
Time frame
Not defined
Additional criteria
...............................................................................................................................................................................
Symptoms of ischaemia
ECG patterns
Imaging evidence
Angiographic evidence of coronary thrombus
...............................................................................................................................................................................
Type 2 MI secondary to ischemic imbalance
Not defined
Additional criteria
ECG patterns
Imaging evidence
...............................................................................................................................................................................
Type 3 Cardiac death due to MI
Troponin threshold
Not defined
Time frame
Additional criteria
Not defined
ECG patterns
Cardiac death
...............................................................................................................................................................................
Troponin threshold
Type 4a MI related to PCI

One value .3 the 99th percentile with the normal baseline value
Time frame
Within 48 h after PCI
Additional criteria
ECG patterns
Angiographic evidence of peri-procedural complication
Imaging evidence
...............................................................................................................................................................................
Type 4b MI related to stent thrombosis
Troponin threshold
Time frame

Not defined
Additional criteria
Stent thrombosis detected by coronary angiography in setting of myocardial ischaemia
...............................................................................................................................................................................
Type 4c MI related to restenosis
Troponin threshold
Time frame
Additional criteria
Not defined
No significant obstructive CAD following stent deployment
No stenosis dilatation after angioplasty
...............................................................................................................................................................................
Type 5 MI related to CABG
Troponin threshold
Time frame
One value .10 the 99th percentile with the normal baseline value
Within 48 h after CABG
Additional criteria
ECG patterns
Angiographic evidence of new graft or new coronary artery occlusion
Imaging evidence
MI, myocardial infarction; ECG, electrocardiography; PCI, percutaneous coronary intervention; cTn, cardiac troponin; CAD, coronary artery disease; CABG, coronary artery
bypass grafting.
neutrophils. Cytokines and growth factor-rich environment dynamically regulate monocyte polarization, fibroblast activity, matrix
metabolism, and angiogenesis, thus orchestrating reparative
response. The myocardial salvage is dependent on many other factors including total ischaemic time, extension of the AAR (the area
submitted to ischaemia), haemodynamic status during ischaemia,
Troponin threshold
Time frame
Page 4 of 21
and residual blood flow through collateral vessels. Interestingly, a

severe form of coronary microvascular dysfunction (known as
no-reflow) (NR) may also occur. It is defined as the ineffective reperfusion of previously ischaemic myocardial tissue despite a proper recanalization of corresponding epicardial artery.21 No-reflow has an
incidence of 550% after percutaneous coronary intervention and
accounts, at least in part, for the residual mortality observed in reperfused ST-segment elevation acute MI. No-reflow may be sustained by
structural and functional impairment of coronary microcirculation
and extravascular compression. Endothelial swelling induced by ischaemia may itself obstruct microcirculation. In addition, ischaemic
endothelium represents a pro-thrombogenic environment where
neutrophils and platelets generate obstructive micro-aggregates. Reduced amount of nitric oxide production from ischaemic endothelium, autonomic dysfunction mediated by a-adrenergic receptor,
and embolization of thrombus debris further worsen microvascular
obstruction. On the other hand, extravascular compression characterized by interstitial oedema and haemorrhages is due to the massive leukocyte extravasation secondary to the opening of endothelial
gaps and the overexpression of adhesion molecules. Also myocardial
cell swelling and myofibrillar hyper-contraction may contribute to
compression on intramural vessels (Figure 1). However, whether
cardiomyocyte damage is causal for coronary microvascular dysfunction or both are consequence of ischaemia/reperfusion (I/R) injury
remains unclear. Cardiomyocytes have traditionally been viewed as
target of I/R injury, with a prevalent necrotic cell death characterized
by unregulated pathophysiological mechanisms leading to microvascular destruction, haemorrhage, and sterile inflammation. Instead,
accumulating evidence suggests that necrotic process may be tightly
regulated by the activation of receptor-interacting protein kinases 1
and 3 (necroptosis), whereas apoptosis and autophagy further contribute to myocardial cell death in I/R injury. Although it is unclear to
what extent each kind of cell death contributes to the infarct size, a
crosstalk between necrosis, apoptosis, and autophagy requires further investigations. Nowadays, the damage-associated molecular patterns, toll-like receptors (TLRs), and nucleotide-binding domain
leucine-rich repeat containing receptors (NLRs) appear as hot-topic
regulators of reperfusion injury.22 Once activated, downstream signalling of TLRs (including My88- and TRIF-dependent pathways) promotes nuclear translocation of NF-kB thus inducing production of
pro-inflammatory cytokines and expression of co-stimulatory molecules. In particular, TLR4 has been demonstrated to promote immune response by stimulating neutrophil homing and recruitment
into injured myocardium.23 Similarly, among different NLRs, the
Figure 1 Critical determinants of myocardial infarction injury. The overlapping of vulnerable plaque and thrombogenic blood are critical determinants for myocardial infarction occurrence and extension. In addition, myocardium vulnerability, which is largely due to coronary microvascular dysfunction, contributes to extension and severity of ischaemic injury. In the most severe form (known as no-reflow), structural and
functional impairment sustain vascular obstruction. Endothelial dysfunction triggers leukocyte and platelet activation/interaction, whereas thrombus debris may worsen the obstruction. Furthermore, cardiomyocyte swelling, interstitial oedema, and tissue inflammation promote extravascular
compression.
Imaging of myocardial infarction

The non-invasive assessment of the infarct size in the post-infarct
period plays a central role in patient management and prognostication.27 Although electrocardiography, cardiac enzyme levels, and
non-contrast echocardiography are used in clinical routine in order
to identify and characterize acute MI.3,28 30 They do not directly
visualize the extent and severity of myocardial necrosis. While there
are profound advances in contrast echocardiography, strain, and
strain rate imaging in the assessment of the infarct size,31 it is not
yet widely used in clinical routine.32 Applying contrast echocardiography, however, affords a reliable evaluation of the myocardial flow
or perfusion that is increasingly used for an accurate visualization
and delineation of the extent of MI.33 35 Contrast agents carrying
gas-filled microbubbles are injected intravenously that results into
myocardial opacification as they pass through the coronary microcirculation. Myocardial necrosis again reflects ultrasound beams
more intensely than unaltered myocardium that is signified by a
hyperechoic signal. In addition, applying second-harmonic imaging
with the use of a mechanical index of 0.5 renders an optimal differentiation between myocardial necrotic and normal regions. The
gas-filled microbubbles also enable an improved delineation of
endo- and epicardial border of the myocardium enabling for the
quantification of the transmural extent of the scar tissue. For
more than a decade, myocardial perfusion scintigraphy with
99m
Tc-sestamibi SPECT has been used to quantify resting perfusion
defects as an estimate of non-reversible tissue injury after MI providing valuable incremental prognostic information in these patients.36
With the advent of delayed gadolinium enhancement magnetic resonance imaging (DE-MRI), a more direct visualization of myocardial
necrosis became feasible.37 The high spatial resolution of cardiac
MRI with up to 1.5 mm in-plane resolution when compared with
10 mm of SPECT perfusion imaging affords the direct visualization
of the transmural thickness of the scar tissue. Cardiac DE-MRI
therefore systematically detects small subendocardial infarcts

(85%) that are commonly missed by conventional SPECT perfusion imaging (Figure 2).38 Conversely, DE-MRI may overestimate
the infarct zone by 1020%.39 The latter observations may be related to gadolinium accumulation not only in the necrotic area but
also in surrounding myocardial oedema in particular in patients
with acute MI. An increase in volume for the contrast agent gadolinium due to myocyte necrosis, oedema, and inflammationinduced increases in capillary permeability may account for a
reported 1020% overestimation of acute MI.39,40 Acute infarctionrelated myocardial oedema may last between 4 weeks and 6 months
as characterized by T2-weighted cardiac MR imaging (Figure 3A).41 In
particular, myocardial oedema is maximal and constant over the first
week after MI. In this respect, DE-MRI imaging affords a stable window for the retrospective analysis of the area at risk, while the assessment of the infarct size may be hampered to some extent
(Figure 3B). Myocardial regions with high signal intensity in DE-MRI
in fact may regress over time associated with recovery in function
providing direct proof that DE detection with MRI in the acute setting does not necessarily conform to myocardial necrosis or irreversible injury and, at the same time, may underestimate salvaged
myocardium to some degree.41 T2-weighted MR images were reported to signify the initial area at risk for myocardial necrosis in occluded vessels, if no timely restoration of myocardial flow was
achieved, by delineating the peri-infarction oedema.42,43 Conceptually, by subtraction of T2 from T1-weighted DE-MRI images, the true
extent of myocardial necrosis in an ACS may be unravelled.41,43
More recent investigations, however, question this concept by outlining that a bright myocardial signal on T2-weighted MR images
does not only reflect only myocardial oedema but also necrosis as
described by DE-MRI.44,45 For the time being, DE-MRI may be seen
as gold standard for an accurate delineation and characterization of
chronic MI,37 while a bright signal on T1-weighted and DE-MR
images may reflect both the area at risk and/or myocardial necrosis
in the setting of an acute MI.44,46 Notably, first pass myocardial perfusion MRI with gadolinium contrast may provide additional important information on the severity of MI by visualizing the extent of
infarct-related microvascular obstruction after successful restoration of coronary flow. This so-called no-reflow phenomenon signifies either no or inadequate reperfusion in the area of MI that carries
independent and predictive information on subsequent cardiovascular outcome. Specifically, In patients with STEMI, the presence
and magnitude of microvascular obstruction was associated
with the occurrence of mayor adverse cardiovascular events (adjusted HR 3.74 [95% CI 2.21 6.34]; P , 0.001).47 Combining first
pass myocardial perfusion and DE-MRI is also a unique means
to visualize in one study session infarct size, myocardial salvage,
microvascular obstruction, and intra-myocardial haemorrhage as
it has been demonstrated in the AIDA STEMI (Abciximab i.v. vs.
i.c. in STEMI) cardiac magnetic resonance sub-study.48 Another modality to indirectly assess the extent and severity of myocardial
necrosis is 18F-fluorodeoxyglucose positron emission tomography
(18F-FDG-PET). 18F-FDG-PET evaluates the presence of myocardial
viability predominantly in myocardial regions with wall motion abnormalities such as akinesis and dyskinesis.49 By visualization of extent of glucose metabolism of myocytes with 18F-FDG uptake in
dysfunctional segments, 18F-FDG-PET provides indirect information
NLRP3 inflammasome has been identified as mediator of inflammatory response in reperfused myocardium.24 Danger signals such
as potassium efflux, lysosomal destabilization, or mitochondrial
ROS lead to assembly NLRP3 inflammasome that include NLRP3,
apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and the cysteine protease caspase-1. Activated NLRP3 inflammasome binds and activates caspase-1, known
as the enzyme which converts to the active form interleukin (IL)-b,
probably the most important signal amplifier due to its potent
ability to induce secretion of other cytokines.24 In addition,
inflammasome-mediated caspase-1 activation may induce a highinflammatory form of cell death, known as pyroptosis, characterized by both apoptotic and necrotic features. Caspase-1 and ASC
deletion in mice were shown to suppress inflammatory responses
to I/R injury, including leukocyte recruitment and cytokine/
chemokine expression. Finally, defective coronary blood flow
further contributes to cardiac injury even in patients with TIMI
Grade 3 flow after primary angioplasty or stenting. This phenomenon, identified through a partial or no ST-segment resolution,
may be the result of tissue and microvascular injury remodelling
and has been associated with adverse cardiac remodelling and
increased mortality rate.25,26
Page 5 of 21
Page 6 of 21
on the extent of myocardial necrosis.40 Since the uptake of 18F-FDG

should not be confounded by the presence of myocardial oedema, it
may be the more optimal approach to identify indirectly the extent
of myocardial necrosis by delineating the presence of myocardial
viability in acute MI.49 Nevertheless, 18F-FDG-PET has also been
apt to some criticism as 18F-FDG may not only be taken up by viable
myocardial cells but also by penetrating macrophages associated
with acute MI.50 With the introduction of PET/MRI, however, a further improvement of the identification and characterization of both,
area at risk and infarct size, in acute MI appears feasible but needing
further clinical validation.51 Similar to DE-MRI, delayed iodinated
contrast enhancement of myocardium can be acquired with multislice computed tomography (CT) with extracellular contrast retention as another approach to assess the infarct size in acute MI anatomical marker of nonviable myocardium.52 Although this approach
with CT and contrast enhancement may be useful for the identification of myocardial scar tissue, for the time being at least, it does not
appear to be accurate enough for clinical use to differentiate between scar and viable myocardium in ischaemic cardiomyopathy patients when compared with 18F-FDG-PET imaging.53 Taken
together, direct visualization of myocardial necrosis plays an important role in determining patient management and prognostic outcome. Although there are multiple imaging modalities to visualize
the extent and severity of MI DE-MRI is considered to be the

most accurate method by which to assess myocardial necrosis in
the chronic state. Assessment of the infarct size in the acute MI,
however, remains a challenge for DE-MRI, while 18F-FDG-PET imaging may be of help to provide an indirect estimation of the extent
of the infarct size. With the advent of PET/MRI, however, a further
refinement of area at risk and infarct size is likely to ensue.51
Targeting pathophysiological
pathways in myocardial infarction:
new therapeutic strategies
Promising treatments in animal models
Reasonable therapeutic targets in the early stages of reperfusion
injury may become essential for cardiac repair so that early report
on potential anti-inflammatory therapy were later challenged by
experimental studies on knockout mice. Also spatial activity of antiinflammatory intervention may have a critical role, considering that
distinct signals may occur within infarcted and border zone. Furthermore, translation from mouse model to human beings presents several limitations. In humans, MI is usually triggered by sudden plaque
Figure 2 (A) Top panel with short-axis view (apical, mid-ventricular, and basal) of a fluorodeoxyglucose positron emission tomography viability
study in a patient with old infarction. (B) Bottom panel with corresponding images of gadolinium-delayed enhancement magnetic resonance imaging signifying hyperenhancement of the subendocardial myocardial infarction. As can be seen, in the area of reduced fluorodeoxyglucose uptake
on positron emission tomography, there is delayed gadolinium enhancement on magnetic resonance imaging. Owing the higher spatial resolution
of magnetic resonance imaging, there is a distinction between widely transmural, subendocardial, and papillary defects can be performed. (With
kind permission from reference: Klein et al.40).
Page 7 of 21
erosion/rupture in subjects characterized by middle-advanced age,

comorbidities (diabetes, hypertension, and dyslipidaemia), gender
differences, poly-pharmacological treatments, and genetic background. All these factors contribute to final infarct size, in addition
to the ischaemic pre-conditioning, eventually due to previous episodes of angina or prior coronary microembolization. On the contrary, MI is experimentally induced in anesthetized, young, healthy
mice subjected to sudden coronary occlusion and reperfusion. Furthermore, the high heart rate and the small size of mouse heart ensure oxygen and nutrients supply by diffusion, so that no .70% of
the AAR is actually infarcted. Concerning clinical outcome, ventricular arrhythmias are a very common cause of death in humans,
whereas their incidence is very low in mice. Table 2 summarizes
the most recent animal studies investigating promising pathophysiological treatments to reduce reperfusion injury. Specifically, we included pre-clinical studies testing compounds not yet translated in
human beings.54 75 In this regard, CC and CXC chemokine inhibition has been largely investigated as potential strategy to reduce
reperfusion-related inflammation (Figure 4).76,77 However, although
the inhibitors of CCL5/CCR5 (Maraviroc) and CXCL12/CXCR4
(Plerixafor) have already been approved by EMEA for clinical use
in HIV infection and stem cell mobilization, respectively, the evidence in MI was disappointing. The greatest concerns arose from
immunological side effects, especially in prolonged treatment. On
the other hand, promising results are expected by non-selective
chemokine inhibitors. The activation of cannabinoid receptor 2
(CB2) showed cardioprotective effect, potentially related to a
down-regulation of chemokine expression, and suppression of oxidative stress and apoptosis.78 Reduction of infarct size has been described in mice treated with CB2 agonists, which were also effective
in preventing arterial restenosis after percutaneous intervention
(PCI) (Table 2).79 Similarly, also adipocytokines have been suggested
as potential target. By suppressing the enzymatic activity of intracellular and extracellular nicotinamide phosphoribosyltransferase
(Nampt, also called visfatin), acute treatment with the compound
FK866 reduced infarct size (Table 2).65 Treatment with antiinflammatory adipocytokines chemerin and omentin prevented
reperfusion injury by suppressing leukocyte recruitment and cardiomyocyte apoptosis.66,67 Finally, inhibitors of NADPH oxidase and
free radical scavenger have so far provided interesting result. As reported in Table 2, beneficial effects on reperfused myocardium
induced by Ebselen, Fasudil, and Edaravone seem to confirm
Figure 3 (A) Myocardial infarction and time course of oedema. Mean percentage of left ventricular volume positive for myocardial oedema at
each time point. The volume of oedema remained stable in the first week after the event with a significant decrease at 15 17 days with near
resolution by 6 months (with kind permission from reference DallArmellina et al.41). (B and C) Representative cardiac magnetic resonance images.
In the column B, T2-weighted image (upward row) shows oedema in the anterior wall; the acute late gadolinium enhancement shows compact
enhancement (middle row), which is reduced in size by 6 months (bottom row). In another example (column C), oedema imaging confirms acute
injury (upward row). Late gadolinium enhancement present in the acute phase persists without significant alteration to the 6-month time point
(middle and bottom row) (with kind permission from reference: DallArmellina et al.).
Page 8 of 21
Table 2
Experimental studies investigating new therapeutic strategies for treatments of myocardial infarction
Author
Year Animal
Model
Treatment
Outcome
...............................................................................................................................................................................
CB2 agonists and antagonists
2009
Mouse
Reperfusion after
30 min of
ischaemia
CB2 selective agonist JWH-133

(20 mg/kg) 5 min before
reperfusion
Treatment reduced the infarct size (P , 0.05).

Additional findings were reduction of
oxidative stress and neutrophil infiltration.
Treatment also inhibited TNF-a induced
chemotaxis and integrin CD18/CD11b
(Mac-1) upregulation on human
neutrophils
Defer et al.55
2009
Mouse
Reperfusion after 1 h
of ischaemia
JWH-133 (3 mg/kg) 5 min before

reperfusion
Treatment reduced infarct size (P , 0.05).

In vitro, CB2 activation was shown to inhibit
cardiomyocyte and fibroblast death
Wang et al.56
2012
Mouse
Reperfusion after
30 min of global
ischaemia
Permanent ligation
HU308 (2 mg/kg) and/or AM630

In both models, pre-treatment with HU308
(2 mg/kg) before ligation (1 and
reduced infarct size and serum levels of
2 h respectively)
ROS and TNF-a (P , 0.01 for all)
Li et al.57
2013
Mouse
Reperfusion after
30 min of
ischaemia
JWH-133 (1, 10 or 100 nmol/L)

and/or AM6301 (1 mmol/L)
5 min before ligation
Treatment with JWH-133 reduced infarct

size (P , 0.05) promoting LV function
recovery. Furthermore, treatment
prevented mPTP opening
Wang et al.58
2014
Mouse
Permanent ligation
AM1241 (20 mg/daily) for 7 days

after ligation
Feng et al.59
2015
Rabbit
Reperfusion after
90 min of
ischaemia
CBD (100 mg/kg) 2 doses before

reperfusion
Treatment increase CPC, enhancing

cardiomyocyte proliferation. In addition
AM1241 significantly decrease serum levels
of MDA, TNF-a and IL-6
After 24 h, treated group showed a marked
reduction of serum cTnI, cardiac leukocyte
infiltration, and myocellular apoptosis
(P , 0.05). In addition, treatment
decreased microvascular obstruction
(P , 0.05), thus reducing infarct size and
improving systolic wall thickening
(P , 0.05)
...............................................................................................................................................................................
DPP-4 inhibitors
Hocher et al.60
2013
Rat
Reperfusion after
30 min of
ischaemia
BI 14361 (3 mg/kg daily) for a week In both models, treatment significantly

or Linagliptin (3 mg/kg daily) 4
reduced infarct size (P , 0.05) without
weeks before to 8 weeks after
improving cardiac function but increasing
surgery
myocardial recruitment of CPC.
Hausenloy et al.61
2013
Rat
Sitagliptin (100 mg/kg/day) for 2

weeks before surgery
Treatment was effective in reducing infarct

size (P , 0.05)
Chinda et al.62
2014
Rat
Reperfusion after
30 min of
ischaemia
Reperfusion after
30 min of
ischaemia
Vildagliptin (2 mg/kg)
Vildagliptin was effective in reducing infarct

size (P , 0.05) also preventing cardiac
dysfunction. This effect was associated with
improved mitochondrial function and
reduced ROS generation (P , 0.05)
Inthachai et al.63
2015
Rat
Permanent ligation
Vildagliptin (3 mg/kg) for 8 weeks

starting 3 days after surgery
Connelly et al.64
2015
Diabetic
rat
Permanent ligation
At the end of treatment, vildagliptin

significantly reduced infarct size also
improving %FS as compared to non-treated
rats. This effects were also associated with
reduced oxidative stress and cardiac
fibrosis (P , 0.05 for all)
Saxagliptin (10 mg/kg/day) and/or Saxagliptin increased rat overall survival
(P 0.02), also improving LV systolic
AMD3100 (1 mg/kg/day) for the
dysfunction (assessed by %FS; P , 0.001)
2 weeks before surgery
and chamber dilatation (P , 0.05) at day 2
after surgery. Due to the cleavage activity
on CXCL12, Saxagliptin reduced
cardiomyocyte hypertrophy. Accordingly,
co-administration with AMD3100
abolished these beneficial effects
Continued
Montecucco et al.54
Page 9 of 21
Table 2
Continued
Author
Year Animal
Model
Treatment
Outcome
Montecucco et al.65
2013
Mouse
Reperfusion after
30 min of
ischaemia
Nampt inhibitor (FK866 30 mg/kg) FK866 was effective in reducing infarct size
(P , 0.01). As additional findings,
treatment inhibited neutrophil recruitment
within infarcted heart and serum levels of
CXCL2. In vitro, FK866 was shown to
suppress the release of CXCL2 by
peripheral monocyte and Jurkat cells
Chang et al.66
2015
Mouse
Reperfusion after
45 min of
ischaemia
Chemerin-15 (0.3 ng/kg)
Kataoka et al.67
2014
Mouse
Reperfusion after
60 min of
ischaemia
Omentin (0.1 mg/g)
...............................................................................................................................................................................
Adipocytokines
...............................................................................................................................................................................
Antioxidants
Baljinnyam et al.68
2006
Rabbit
Reperfusion after
30 min of
ischaemia
Ebselen (30 or 100 mg/kg) infusion Ebselen reduced infarct size as compared with
24 h before surgery + H2O2
control group, but also dose-dependently
during the first minute of
abolished the increasing in infarct size due
reperfusion
to H2O2 administration (P , 0.05 for both
models). These findings were associated
with preserved glutathione levels and
enhanced HSP72 expression
Fasudil (5 min infusion of
Compared with control group, treatment
500 mg/kg/min)
reduced cardiomyocyte apoptosis and the
infarct size (P , 0.05 for both). Fasudil was
shown to increase Bcl-2 expression and Akt
phosphorylation, whereas Bax and
caspase-3 expression were suppressed
Jiang et al.69
2013
Rat
Reperfusion after
60 min of
ischaemia
Zhang et al.70
2013
Rat
Reperfusion after
45 min of
ischaemia
Edaravone (60 mL) + lactic acid

(60 mL) during surgery
Fu et al.71
2013
Dog
Reperfusion after
60 min of
ischaemia
HLF low (5 mg/kg) or high

(10 mg/kg) dosage i.v.
Reduced perfusion
pressure in the
LAD to one-third
of the baseline
value
Reperfusion after
60 min of LAD
occlusion
Carperitide (0.025 0.2 mg/ kg/min At 10 min after treatment, an increase of

into the coronary artery
coronary blood flow was observed. This
change was also characterized by increased
FS, cardiac NO, and pH levels in coronary
venous blood flow
VNS (30 min after LAD occlusion VNS applied 30 min after LAD occlusion, but
or at reperfusion). associated to
not at reperfusion, markedly reduced
ischaemia + atropine or
ventricular fibrillation incidence and infarct
reperfusion
size, improved cardiac function; attenuated
cardiac mitochondrial depolarization,
swelling, and cytochrome c release; as well
as ROS generation. These beneficial effects
of VNS were abolished by atropine
After 24 h reperfusion, Edaravone reduced

infarct size in both models (P , 0.05).
Significant improvement also included
serum markers of myocardial injury,
oxidative stress, and apoptosis rate
(P , 0.05 for all)
Treatment was useful in reducing the activity
of MPO, IL-1 and TNF-a. HLF and also
increased GRK2 expression
...............................................................................................................................................................................
Other
Asanuma et al.72
2014
Dog
Shinlapawittayatorn
et al.73
2014
Pig
Continued
Treatment reduced the infarct size (P , 0.05).

Additional findings were reduction of
neutrophil infiltration and cardiomyocyte
apoptosis as well as prevalence of M2
macrophage polarization within infarcted
heart
Treatment reduced the infarct size (P , 0.01)
regardless of mouse sex. Omentin
administration also reduced cardiomyocyte
apoptosis (P , 0.01) via AMPK pathway
Page 10 of 21
Table 2
Continued
Author
Year Animal
Model
Treatment
Outcome
Uitterdijk et al.74
2015
Swine
Reperfusion after
45 min of LAD
occlusion
VNS started 5 min prior to

reperfusion and continued until
15 min of reperfusion
After 2 h, treated group had significantly

reduced infarct size. These effects were
accompanied by reductions in neutrophil
and macrophage infiltration (P , 0.05).
Interestingly, in the presence of
NO-synthase inhibitor, VNS no longer
attenuated infarct size and area of NR
Koudstaal et al.75
2015
Pig
reperfusion after
75 min of LCx
occlusion
Nec-1 (1.0 mg/kg or 3.3 mg/kg)

10 min prior to reperfusion
At dose of 3.3 mg/kg, Nec-1significantly

reduced infarct size (P 0.016). In line,
cardiac function was characterized by
significantly higher LVEF (P 0.015) and
preserved contractility at 24-h follow-up
(P 0.032)
...............................................................................................................................................................................
previous evidence from experimental models of cerebral reperfusion injury, but further studies are required.68 70
Evidence from clinical studies

Fibrinolytic therapy
Pre-hospital fibrinolytic therapy (FT) to primary PCI is an attractive
concept that has proofed to be safe and effective in several
trials.80,81 This reperfusion strategy decreases the time to treatment
by 60 min and may decrease mortality by 17%.82,83 Conversely,
one-third of patients may not necessarily respond FT and a relative
delay or reperfusion may occur with subsequent PCI. 84 The
STREAM trial emphasizes a reperfusion strategy combining prehospital FT with immediate transfer of the patient to a tertiary centre for rescue-PCI in non-responders to FT and for early diagnostic
angiography and secondary PCI within 624 h after initiation of FT.
Overall, early reperfusion strategy with pre-hospital FT followed by
PCI is regarded as the optimal reperfusion strategy as stated in recent guidelines.85,4 84 Current guidelines recommend that FT should
be initiated within 30 min of first medical contact when primary
PCI cannot be performed within 90 min or within an acceptable
period of delay.4,27 When primary PCI is not available, then FT is
a viable option. Fibrinolytic therapy cautiously applied within 12 h
of symptom onset substantially reduces mortality and morbidity.86
It is important to bear in mind that the reduction of mortality is
greater when FT begins within 1 2 h from the onset of symptoms,
whereas the benefits decrease by half for patients treated between 7
and 12 h.87 Fibrin-specific agents such as tenecteplase, alteplase, and
retaplase rather than a non-fibrinic agent like streptokinase are preferred for FT. When compared with streptokinase, these fibrinspecific agents are antigenic and achieve higher patency rates of
the infarct-related artery of 85% vs. 60 70%.88 90 Prior to FT aspirin and clopidogrel should be given to dissolve or inhibit thrombocyte aggregation. In this regard, the ISIS-2 trial reported similar
efficacy of aspirin and streptokinase alone, whereas combined therapy provided an additive effect.91 Later, the CLARITY-TIMI 28 trial
indicated the association of aspirin and clopidogrel to FT as the gold
standard to improve patency rate and reduce ischaemic complication in STEMI patients treated with FT.92 This dual antiplatelet therapy should be continued for a minimum of 1 year in order to avoid
late in-stent thrombosis with associated increase in mortality rate up
to 45% and non-fatal MI rate of another 3040%.93,94
The role of more recently introduced antiplatelet agents like prasugrel and ticagrelor, that both antagonize the P2Y12 receptor, as an
adjunct to thrombolytic therapy for fibrinolysis in STEMI holds
promise, but large-scale trials are still needed to draw more definite
conclusions (Table 3).95 117 Unfractionated heparin, and more recently low-molecular-weight heparins (LMWH), such as enoxaparin
and fondaparinux, are increasingly used. The OASIS trial signified a
relevant advantage of fondaparinux and unfractionated heparin over
placebo with regard to death or reinfarction at 30 days. However,
the use of fondaparinux in primary PCI appears not recommended
due to the higher rate of catheter thrombosis.118 The role of
LMWH in STEMI still needs to be better defined in upcoming research trials. More recently, the adjunct use of Bivalirudin in STEMI
patients with primary PCI was investigated the recent
HORIZON-AMI trial, and marked 30 days cardiovascular event outcome improvement for Bivalirudin over heparin plus clopidogrel
(9.2 vs. 22%) was noted (Table 3).100 Such observations may suggest
an emerging role of Bivalirudin in STEMI patients who are undergoing primary PCI. Failed FT may be indicated by ongoing chest pain,
lack of .50% ST segment resolution and the absence of reperfusion
arrhythmias at 6090 min after application of fibrinolytic agents. A
failure of FT is commonly associated with a TIMI flow , 3 in the infarct artery (R110) and rescue PCI have been demonstrated to be
beneficial.119 Six months event-free survival was 84.6% in the group
with rescue-PCI when compared with 70.1% among those patients
CB2, cannabinoid receptor 2; JWH-133, CB2 receptor agonist; TNF-a, tumour necrosis factor-a; CD, cluster of differentiation; Mac-1, integrin-1a; HU308, CB2 receptor agonist;
AM630, CB2 selective inverse agonist; ROS, reactive oxygen species; mPTP, mitochondrial permeability transition pore; CPC, circulating progenitor cells; AM1241, peripheral
cannabinoid CB2 receptor agonist; MDA, malondialdehyde; IL, interleukin; CBD, cannabidiol; cTnI, cardiac troponin I; AMPK, 5 adenosine monophosphate-activated protein
kinase; DPP-4, dipeptidyl peptidase-4; CPC, circulating progenitor cells; FS, fractional shortening; LV, left ventricular; CXCL, chemokine (C-X-C motif) ligand; AMD3100, plerixafor
(CXCR4 inhibitor); AMPK, 5 adenosine monophosphate-activated protein kinase; HSP, heat shock protein; HLF, Hawthorn leaves flavonoids; MPO, myeloperoxidase; GRK2,
G-protein-coupled receptor kinases; LAD, left anterior descending coronary artery; FS, fractional shortening; NO, nitric oxide; VNS, vagal nerve stimulation; LCx, left circumflex
coronary artery; Nec-1, necrostatin-1.
Page 11 of 21
that plays a critical role in reprefusion injury following myocardial infarction. Whereas antioxidants selectively reduce reactive oxygen species,
cannabinoid receptor 2 agonists, and dipeptidyl peptidase-4 inhibitors were shown to significantly reduce oxidative stress and chemokine expression. Selective inhibition of chemokine axes CXCR-4/CCL12 and CCR5/CCL5 have so far provided controversial results. Finally, targeting
adipokines may be a promising strategy, effective in reducing chemokine expression and cardiomyocyte apoptosis.
receiving conservative treatment, or 68.7% undergoing repeat

FT.119 Conversely, such rescue-PCI after failed FT may be associated
with relatively higher rates of stroke and peri-procedural bleeding.120 As regards STEMI patients who responded successfully to
FT, elective catheterization should be performed routinely or ischaemia guided between 3 and 24 h post-therapy.84,99,121 Fibrinolytic agents have also been used as adjunct to primary PCI with or
without glycoprotein IIb/IIIa inhibitor. This so-called facilitated PCI
was based on the consideration that combined treatment will promote higher and faster rates of reperfusion of the infarcted region.
The ASSENT-4 PCI randomized trial evaluated this at first sight attractive concept of a facilitated PCI that, however, did not proof to
be successful.122 The trial was ended prematurely as a marked increase in mortality rate in patients with facilitated PCI vs. primary
PCI was observed. In another randomized trial,123 neither
combination-facilitated PCI (reteplase + abciximab) nor abciximabfacilitated PCI proved to be superior to primary PCI in patients with
acute MI to improve 90 days outcome, but it was associated with increased rates of major bleedings. In view of these findings, facilitated
PCI at least for the time being is not pursued any more.27 As most
patients with STEMI have a large thrombus burden, it appears
intriguing that thrombectomy may improve coronary flow, prevent

distal embolization, reduce microvascular obstruction, no reflow
phenomenon and thereby should further improve PCI-related outcome. Recent, The Thrombus Aspiration in ST-elevation Myocardial
Infarction in Scandinavia124 and Trial of Routine Aspiration Thrombectomy with PCI vs. PCI Alone in Patients with STEMI Undergoing
Primary PCI125 trials could not demonstrate reduction in mortality
and morbidity if adjunct thrombus aspiration was performed during
primary PCI.
Advances in stent employment with primary
percutaneous intervention
Bare-metal stent (BMS) employment during primary PCI has become routine practice as it reduces the rates of reinfarction and target vessel revascularization but not mortality.86,126,127 In recent
years, drug-eluting stents (DES) have more and more outperformed
BMS for both elective and primary PCI as they significantly reduce
restenosis rates and the need for reintervention.128 Of note, the
first-generation DES like Taxus and Cypher, when compared with
BMS, has been reported to increase the risk of very late stent thrombosis with MI and fatal outcome, particular in patients with large
Figure 4 Anti-inflammatory therapy in myocardial infarction: pre-clinical evidence. Cardiomyocyte death triggers a massive inflammatory burst
Page 12 of 21
Table 3
Clinical trials investigating new therapeutic strategies for treatments of myocardial infarction
Author
Year Study design (number

of patients)
Treatment (follow-up)
Results
...............................................................................................................................................................................
Fibrinolytic therapy
2009
Double-blind, randomized trial

(18 624 patients with ACS)
Ticagrelor (180 mg loading dose, 90 mg

twice daily thereafter) or clopidogrel
(300 600 mg loading dose, 75 mg daily
thereafter)
When compared with clopidogrel, ticagrelor

significantly reduced vascular death risk [HR 0.84
(95% CI 0.770.92); P , 0.001), without
increasing the rate of overall major bleeding
Montalescot
et al.96
2009

(3534 patients with STEMI
undergoing PCI)
Prasugrel (60 mg loading, 10 mg

maintenance) or clopidogrel
(300 mg loading, 75 mg maintenance)
When compared with clopidogrel prasugrel is more

effective in preventing ischaemic events [HR 0.79
(95% CI 0.650.97); P 0.025], without an
apparent excess in bleeding
Morrow
et al.97
2009

(13 608 patients with STEMI
undergoing PCI)
Prasugrel (60 mg loading, 10 mg

maintenance) or clopidogrel
When compared with clopidogrel prasugrel is more

effective in reducing the overall risk of MI [HR
0.79 (95% CI 0.67 0.85); P , 0.001], and involve
both procedure-related and non-procedural MI
bleeding
Steg et al.98
2010

undergoing PCI)
Ticagrelor (180 mg loading, 90 mg twice

daily maintenance) or clopidogrel
When compared with clopidogrel ticagrelor is

more effective in reducing the risk of MI
(P 0.03), and stent thrombosis (P 0.03)
Bhmer
et al.99
2010
Double-blind, randomized trial Rescue-PCI or conservative treatment

(266 patients with STEMI and
.90 min delay to PCI)
Rescue-PCI did not improve the composite

outcome but significantly reduced the rate of
death, reinfarction, and stroke (P 0.01).
Stone et al.100
2015

(5800 patients with ACS)
Bivalirudin reduced rates of major bleeding [RR 0.53

([95% CI 0.430.66); P , 0.001],
thrombocytopenia [RR 0.48 (95% CI 0.330.71);
P 0.002], and cardiac mortality [RR 0.70 (95% CI
0.500.97); P 0.03]. However, bivalirudin was
associated with increased acute stent thrombosis
rates [RR: 6.04 (95% CI 2.5514.31); P , 0.001].
Bivalirudin (0.75 mg/kg i.v. bolus, followed

by 1.75 mg/kg/h infusion) or heparin
(60 IU/kg i.v. bolus) + GPI (30 days)
...............................................................................................................................................................................
Stent employment with primary PCI
Sabate
et al.101
2012
Double-blind, randomized trial Everolimus-eluting stent or bare-metal

stents
(1498 patients with STEMI up
to 48 h after the onset of
symptoms requiring PCI)
Dewilde
et al.102
2013

(573 patients receiving oral
anticoagulants and
undergoing PCI)
de Belder
et al.103
2014
Double-blind, randomized trial Drug-eluting stent or bare-metal stents

(800 patients 80 years with
STEMI undergoing stent
placement)
Both stents offer good clinical outcome.

Drug-eluting stents were associated with a lower
rate of MI (8.7 vs. 4.3%; P 0.01) and target
vessel revascularization (7.0 vs. 2.0%; P 0.001)
without increased risk of bleeding

undergoing PCI)
Bioresorbable vascular scaffold implantation has

been demonstrated to be feasible and safe.
However, event-free survival was not different
when compared with the control group
Kocka et al.104 2014
Clopidogrel alone (300 600 mg

loading dose, 75 mg daily thereafter)
or clopidogrel plus aspirin
(80 100 mg/day) in addition to
anticoagulant therapy (1 year)
Bioresorbable vascular scaffold

implantation
The use of everolimus-eluting stent in the setting of

STEMI did not reduce the risk of adverse events.
However, everolimus-eluting stent was associated
with higher procedure success rate (97.5 vs.
94.6%; P 0.005) and reduced risk of stent
thrombosis (0.5 vs. 1.9%; P 0.019)
Use of clopidogrel without aspirin was associated
with a significant reduction in bleeding
complications [HR: 0.36 (95% CI 0.26 0.50);
P , 0.001] without increase in the rate of
thrombotic events
...............................................................................................................................................................................
Pharmacological cardioprotection in STEMI
Atar et al.105
2009

undergoing PCI)
FX06 (two i.v. bolus administration of

200 mg each during PCI; the first
immediately before the guidewire
passed the occlusion and the second
10 later)
On Day 5, the necrotic zone was significantly

reduced in the FX06 group (P , 0.025) without
significant differences in TnI levels. After 4
months, there were no longer significant
differences in scar size
Continued
Wallentin
et al.95
Page 13 of 21
Table 3
Continued
Author
Year Study design (number

of patients)
Treatment (follow-up)
Results
Botker
et al.106
2010

undergoing PCI)
Remote conditioning (intermittent arm

ischaemia through four cycles of 5-min
inflation and 5-min deflation of a
blood-pressure cuff).
Lnborg
et al.107
2012

undergoing PCI)
Exenatide (0.12 mg/min for 15 min and then Exenatide induced a significantly larger salvage index
reduced to 0.043 mg/min for 6 h) or
as assessed by CMR (0.71 + 0.13 vs. 0.62 + 0.16;
placebo i.v. (90 + 21 days)
P 0.003). However, no difference was observed
in left ventricular function or 30-day clinical
events. No adverse effects were reported
Lincoff
et al.108
2014
Double-blind, randomized trial Placebo or delcasertib (i.v. infusion of 50,

150, or 450 mg/h initiated before PCI
(1176 patients with anterior
and continued for 2.5 h) (3 months)
or inferior STEMI undergoing
PCI)
Treatment failed to reduce biomarkers of

myocardial injury
Sloth et al.109
2014

undergoing PCI)
PCI with or without remote ischaemic

conditioning (intermittent arm
ischaemia through four cycles of 5-min
inflation) (3.8 years)
Ischaemic conditioning was associated with reduced

risk of MACCE [13.5 vs. 25.6%; HR 0.49 (95% CI
0.27 0.89); P 0.018) and all-cause mortality
[HR 0.32 (95% CI 0.12 0.88); P 0.027]
Atar et al.110
2015

undergoing PCI)
TRO40303 (i.v. bolus administration of

6 mg/kg each during PCI; before the
guidewire passage, prior to balloon
inflation and stenting)
There were no significant differences in the

biochemical evaluation and CMR-assessed
infarct size and cardiac function between
TRO40303 and placebo. However, a greater
number of adjudicated safety events occurred in
the TRO40303 group
Cung et al.111
2015

undergoing PCI)
Cyclosporine (i.v. bolus administration of

2.5 mg/kg before recanalization)
The rate of composite adverse CV events between

cyclosporine and control group was similar [59.0
vs. 58.1%; OR 1.04 ([95% CI 0.78 1.39);
P 0.77]. Moreover, cyclosporine did not
reduce the incidence of the separate outcomes
...............................................................................................................................................................................
Myocardial salvage was greater in the remote
conditioning group (P 0.033)
Stem cells
Traverse
et al.112
2011
Double-blind, randomized trial Intracoronary infusion of autologous BMCs Infusion of autologous BMCs did not improve global
(87 patients with LVEF 45%
(150 106) or placebo infused 2 3
or regional function, assessed as changes in
post-MI undergoing PCI)
weeks after PCI (6 months)
global (LVEF) and regional (wall motion) LV
function in the infarct and border zone
Traverse
et al.113
2012

(120 patients with
LVEF 45% post-MI
undergoing PCI)
Intracoronary infusion of autologous BMCs BMCs at either 3 or 7 days after the event failed to
(150 106) or placebo infused 3 or 7
improve recovery of global or regional left
days after PCI (6 months)
ventricular function
Chugh et al.114 2012
Double-blind, randomized trial Intracoronary infusion of autologous CSCs After infusion of autologous CSCs, CMR showed a
(33 patients with LVEF 40%
(1 106) or placebo infused a mean of
significant reduction of infarct size (230.2% at
before CABG)
113 days after surgery (12 months)
12 months; P 0.039), and increase of LV liable
mass (+31.5 + 11.0 g at 12 months; P 0.035)
Makkar
et al.115
2012

(31 patients with LVEF of 25
45% after AMI)
Intracoronary infusion of autologous CSCs Infusion of autologous CSCs was associated with
(12.5 25 106) or placebo infused
decreased scar size (P 0.004), increased viable
within 90 days after AMI (1 year)
myocardium (P , 0.05), and improved regional
function (P 0.036) of infarcted myocardium
without rising significant safety concerns
Nasseri
et al.116
2014

(60 patients with IHD and
LVEF , 35% undergoing
CABG)
Intracoronary infusion of autologous

By cardiac MRI, the CD133+ group showed
+
6
CD133 BMC (12.5 25 10 ) or
improved myocardial perfusion at rest
(P , 0.001), and scar mass decreased (P 0.05).
placebo infused within 90 days after AMI
(6 months)
Mathiasen
et al.117
2015

(55 patients with severe
ischaemic HF and
LVEF 50%)
Intra-myocardial injection of 10 15
injections of MSCs (0.2 mL) or placebo
(6 months)
Treatment with MSCs reduced LVESV (P 0.001)

also improving LVEF (P , 0.001), stroke volume
(P , 0.001), and myocardial mass (P 0.001)
ACS, acute coronary syndrome; HR, hazard ratio; CI, confidence interval; STEMI, ST-elevation myocardial infarction; PCI, percutaneous coronary intervention; MI, myocardial
infarction; i.v., intravenous; GPI, glycoprotein IIb/IIIa inhibitor; RR, relative risk; CV, cardiovascular; MACCE, major adverse cardiac and cerebrovascular events; CMR, cardiac
magnetic resonance; OR, odds ratio; LVEF, left ventricular ejection fraction; BMCs, bone marrow mononuclear cells; LV, left ventricular; CABG, coronary artery bypass grafting;
CSCs, cardiac stem cells; AMI, acute myocardial infarction; IHD, ischaemic heart disease; HF, heart failure; MSCs, mesenchymal stromal cells; LVESV, left ventricular end-systolic
volume.
...............................................................................................................................................................................
Page 14 of 21
DES.129,130 When the newer generation of DES like Xience,
Promeus, and Endeavour was compared with BMS, no risk increase
of acute or late stent thrombosis was noted any more
(Table 3).101,103,131 The further development of DES with bioresorbable vascular scaffolds may avoid permanent rigid metallic
structure in coronary arteries. Bioresorbable vascular scaffolds
have been demonstrated to be safe and effective in chronic stable
coronary artery disease as well as in STEMI (Table 3).104,132 134
Stent implantation in patients taking oral anticoagulation and presenting with STEMI constitutes a significant challenge as it results
in a triple therapy significantly increasing the risk of major bleedings.
A recent study puts forth that in primary PCI warfarin plus clopidogrel had lower bleeding complications than warfarin, clopidogrel,
plus aspirin, while the rate of stent thrombosis was not increased
(Table 3).102 The study, however, was not sufficiently powered to
investigate the risk of stent thrombosis, so that further large-scale
studies in this direction are warranted.
in reducing infarct size was suggested in two small pilot trials.145,146

However, the Cyclosporine and Prognosis in Acute MI Patients
(CIRCUS) trial that included 791 patients recently demonstrated
that cyclosporine did not improve 1-year clinical outcome after
STEMI. Specifically, the treatment failed to reduce incidence of
both single and composite outcome including recurrent infarction,
unstable angina, and stroke.111 Contrariwise, the results of the Cardiovascular Risk Reduction Study, which investigates the antiinflammatory properties of Canakinumab (a human monoclonal
antibody neutralizing IL-1b) might be associated with a significant
reduction of recurrent MI. Specifically, the purpose of this trial is
to test Canakinumab in patients undergone MI at least 1 month prior
to recruitment and having high serum levels of high-sensitivity
C-reactive protein (CRP).147 Also first promising results of the
IL-6 inhibitor tocilizumab was reported as a potential treatment
against reperfusion injury. In patients with MI, treatment with tocilizumab was correlated with a significant decrease in CRP and cTn release.148 Finally, many large trials supported the early start of therapy
with inhibitors of the reninangiotensin aldosterone system. The
ISIS-4 first showed a reduction of 5-week mortality in captopriltreated patients when compared with placebo. Furthermore, this
beneficial effect was greater in certain high-risk groups, such as those
presenting with a history of previous MI or with heart failure.149
Stems cells in clinical trials
Various approaches of stem cell treatment have been investigated to
confine myocardial damage and potentially regenerate myocardium
in acute MI.150,151 In general, the effects of two populations of stem
cells on regeneration and left ventricular function such as adult bone
marrow mononuclear cells (BMCs) and cardiac stem cells are being
investigated in patients with MI and/or ischaemic cardiomyopathy.
Adult BMCs from the bone marrow aspirates carry 0.5 3.0%
haematopoietic and mesenchymal progenitor cells. These progenitor cells from the bone marrow, when injected intracoronarily or
directly into the myocardium, release growth factors and cytokines
that appears to confine myocardial inflammation and infarct
size.150,151 These cells have some ability to replicate but they cannot
transform into myocytes. Conversely, they release mediators that
recruit endogenous stem cells from the patient for repair or
limitation of cardiac injury. Several non-randomized and small-sized
clinical investigation have reported that intracoronary injection
of autologous un fractionated BMCs in acute MI may lead to a
mild but statistically significant increase of 2 3% in LVEF associated with a reduction in the size of the infarction of 5.5%
(Table 3).112,113,150,152 154 These initial results raised questions
about the optimal cell for acute MI treatment, the optimal timing
of cell injection, the viability of stem cells prior and after injection
into patients, and the best parameter to monitor and guide the success of stem cell treatment for cardiac repair. In this direction, the
LateTIME trial112 investigated in a randomized double-blind;
placebo-controlled fashion whether the application of adult BMCs
23 weeks after anterior wall MI would be safe and effective in confining infarct size and increasing left ventricular function. The infarct
volume, global and regional left ventricular function were determined by gadolinium magnetic resonance imaging (MRI) prior to intracoronary injection and 6 months after injection. Alterations of
infarct size, LVEF, wall motion in the infarct zone, and wall motion
Pharmacological cardioprotection in ST-segment

elevation myocardial infarction
Pharmaceutical interventions have been put forth to mediate some
cardioprotection against reperfusion injury, including calcium-channel
blockers, antioxidants, and anti-inflammatory agents, while these
pharmaceutical approaches of cardioprotection did not translate
into a clinical benefit with improved clinical outcome.135 139 More
recently, much hope was projected into protein kinase C (PKC) isoenzyme modulated cardioprotection.140,141 In a multi-centre,
double-blinded trial the effect of Delcasertib a selective inhibitor of
delta-PKC on infarct size and clinical outcome in 1010 patients undergoing primary PCI for anterior STEMI (Table 3).108 No significant
differences among the treatment groups in secondary endpoints of
infarct size, electrocardiographic ST-segment and time to stable ST
recovery, or left ventricular ejection fraction (LVEF) at 3 months
were noted. Although the trial was not sufficiently powered for clinical
endpoints, there was no improved outcome as regards death, heart
failure, or serious ventricular arrhythmia.108 Similarly, the use of peptides has so far provided controversial results. In the F.I.R.E. (Efficacy
of FX06 in the Prevention of Myocardial Reperfusion Injury) trial,
the administration of FX06 (a cleavage product of human fibrin) substantially reduced infarct size early after STEMI, but no significant difference with placebo was observed in the scar size after 4 months.105
Similarly, inhibiting mitochondrial permeability transition pore by the
peptide TRO40303, as tested in the MITOCARE trial, failed to reduce
reperfusion injury also inducing a not negligible number of adjudicated
safety events.110 In this regard, there is great expectation for the results
of EMBRACE STEMI, Phase 2a, randomized, double-blind, placebocontrolled trial designed for testing the mitochondrial targeting
peptide Bendavia in patients undergoing primary PCI within 4 h
of symptom onset for a first-time anterior STEMI occluding
proximal or mid-left anterior descending artery.142 Conversely,
mechanical interventions such as ischaemic post-conditioning, remote ischaemic pre-conditioning, therapeutic hypothermia and
hypoxemia,106,109,137,143,144 but also more recently introduced
pharmacologic interventions with atrial natriuretic peptide and exenatide hold promise for cardioprotection against myocardial perfusion injury but require confirmation in larger clinical trials
(Table 3).107,136,144 With regard to cyclosporine, a potential role
Page 15 of 21
and scar tissue decreased by 20.4 g in the stem cell treatment group
of 12 individuals with ischaemic cardiomyopathy. It is thought that
C-kit cardiac stem cells chemoattracted patient native stem cells to
areas of myocardial injury and also to transdifferentiate to myocytes
for cardiac regeneration. Another viable option is the use of
cardiosphere-derived cells (CDCs).167 The effects of autologous
CDCs have been evaluated in the open-labelled Cardiospherederived Autologous Stem Cells to Reverse Ventricular Dysfunction
(CADUCEUS) trial.115,166 In 17 patients, after MI with LVEFs of
2545% underwent endomyocardial biopsies of the right ventricular
septum and CDCs were obtained from cultures of the endomyocardial biopsy and the cells were propagated. Subsequently, 12.525 million CDCs were injected into the infarct-related artery 1.53 months
after their MI. After a 1 year follow-up, MRI-determined scar tissue
decreased in the mean by 11.9 g in the CDC-treated patients but
only by 1.7 g in the control patients. While the LVEF in the
CDC-treated group did not increase significantly, regional wall function of the infarcted segments increased and correlated well with the
decrease in size of MI.115,166 Overall, the SCIPIO and CADUCEUS
trials114,115,165,166 outline that the intracoronary application of
CDCs may indeed reduce the size of MI associated with a significant
improvement of left ventricular function that, however, needs to be
further clinically tested in large-scale and randomized trials. New development in stem cell treatment of MI is on the horizon such as intramyocardial transplantation of CD133+ BMCs, or autologous culture
expanded mesenchymal stromal cells, and transplantation of embryogenic stem cells-derived cardiac progenitor cells within a tissue-engineered construct, that constitute a further enrichment of stem cell
treatment of acute MI to stimulate further advancements in this critical research field and clinical applications (Table 3).116,117,168
Conclusion
Over the past decade, major advances in the early detection and reperfusion strategies of acute MI have led to a substantial reduction in
morbidity and mortality. To further optimize the clinical outcome in
these patients, many efforts have been geared towards cardioprotection against myocardial reperfusion injury with mechanical (ischaemic post-conditioning, remote ischaemic pre-conditioning,
therapeutic hypothermia and hypoxemia) and pharmacologic interventions (atrial natriuretic peptide, cyclosporine A, and exenatide).
Although mechanical and pharmacologic cardioprotection in acute
MI in the animal models and initial observational trials hold promise,
these concepts of cardioprotection need to be further firmly tested
in randomized clinical trials. In addition, stem cell therapy with BMC
in acute and chronic MI have yielded promising results but still needing confirmation in larger randomized trials. The SCIPIO trial with
autologous C-kit-positive cardiac stem cells and the CADUCEUS
trials with cardiosphere-derived autologous stem cells application
in acute MI signify reduced infarct size and improved left ventricular
function that may shift the pendulum in favour of stem cell trials to
further improve outcome in these patients.
Authors contributions
F.M., F.C., T.H.S.: handled funding and supervision; F.M., F.C., T.H.S.:
acquired the data; F.M., F.C., T.H.S.: conceived and designed the
in the border zone of the infarction, did not differ significantly between treatment and placebo group. The following TIME trial113
again evaluated also in a double-blind, placebo-controlled design
the effect of intracoronary application of autologous BMCs or placebo in 120 patients 37 days after predominantly acute MI of the
anterior wall. This trial was based on a prior REPAIR AMI trial that
noted a 5.1% increase in LVEF after application of BMCs to patients
5 7 days after acute MI.155 The TIME trial,113 however, could not
confirm the observation REPAIR AMI trial. Magnetic resonance
imaging-determined changes of infarct size, LVEF, wall motion in
the infarct zone, and wall motion in the border zone of the infarction
after the 6 months follow-up were not significantly different between treatment and placebo group.155 Another randomized trial,
the SWISS study156 evaluated the impact of 140 160 million
autologous BMCs injected at a median of 6 days or in a delayed fashion 24 days after acute MI. Cardiac MRI in these patients was performed at baseline prior to cell infusion and 4 months after the
injection of BMCs into the infarct-related coronary artery. Magnetic
resonance imaging results were compared with control patients
treated with optimal medical care. At 4 months after intracoronary
application, no significant changes in infarct size, left ventricular wall
thickening, or increase in left ventricular function in patients treated
early with BMC at 5 7 days or delayed 3 4 weeks after acute MI
when compared with control patients, respectively. The reasons
for the failure of these randomized, double blind, and placebocontrolled clinical investigations112,113,156 assessing the effect of intracoronary administration of BMCs on myocardial infarct size and
left ventricular function in patients with acute MI remains uncertain
but are thought to be related, at least in part, to small size of the infarction and extent of remodelling at baseline, concomitant effect of
optimal conservative medical treatment and recovery of myocardial
stunning,157,158 heterogeneity and dose of BMC population, red
blood cell contamination of BMC affecting the viability, migration
ability, and efficacy of BMCs,159 inhibiting effects of heparin on migration and homing of BMCs,160,161 and substantial non-homing of
BMCs in the myocardium.162,163
On the other hand, cardiac stem cells constitute specific undifferentiated progenitor cells commonly located in the right atrial appendage and the ventricular apices of the heart. Such cardiac stem cells
have paracrine effects, while recruiting stem cells from the patient
and potentially trans-differentiating into myocytes for cardiac repair.
Cardiac stem cells are multipotent progenitor cells and add to the
physiological turnover of myocytes and vascular endothelial cells in
the heart. As there is one cardiac stem cell per 1000 cardiac myocytes,164 endogenous cardiac stem cells are not capable to repair
heart injury caused by MI. Two recent clinical trials have investigated
the effects of major autologous cardiac stem cells for myocardial repair and regeneration in acute MI (Table 3).114,115,165,166 The openlabelled Cardiac Stem Cell Infusion in Patients with Ischemic Cardiomyopathy (SCIPIO) trial assessed the effect of autologous
C-kit-positive cardiac stem cells on left ventricular function and infarct
size,114,165 C-kit-positive stem cells were isolated during coronary artery bypass surgery from the right atrial appendages of ischaemic cardiomyopathy patients with an LVEF , 40%. Following 4 months, a
maximum of 1 million cardiac stem cells were injected into the saphenous vein grafts and coronary arteries supplying the infarcted region.
After follow-up of 2 years, MRI-determined LVEF increased by 11.9%
Page 16 of 21
research; F.M., F.C., T.H.S.: drafted the manuscript; F.M., F.C., T.H.S.:
made critical revision of the manuscript for key intellectual content.
Funding
This work was supported by a Swiss National Science Foundation grant
(#310030_152639/1) to F.M. This study was supported by a grant from
the Foundation Gustave and Simone Prevot and the F4LabMed to F.C.
Conflict of interest: none declared.
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European Heart Journal Advance Access published November 4, 2015

European Heart Journal

Novel therapeutic concepts

Pathophysiology of ST-segment elevation

Received 24 August 2015; revised 28 September 2015; accepted 12 October 2015

Acute myocardial infarction Pathophysiology Treatment

Introduction: definition of the

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Pathophysiology of MI: from

small fraction of moderately severe vulnerable plaques that undergo

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Novel mechanisms and treatments

Type 4a MI related to PCI

Within 48 h after PCI

Rise or fall, with at least one value above 99th percentile

Stent thrombosis detected by coronary angiography in setting of myocardial ischaemia

Rise or fall, with at least one value above 99th percentile

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and residual blood flow through collateral vessels. Interestingly, a

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Novel mechanisms and treatments

Imaging of myocardial infarction

therefore systematically detects small subendocardial infarcts

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on the extent of myocardial necrosis.40 Since the uptake of 18F-FDG

the extent and severity of MI DE-MRI is considered to be the

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Novel mechanisms and treatments

erosion/rupture in subjects characterized by middle-advanced age,

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CB2 selective agonist JWH-133

Treatment reduced the infarct size (P , 0.05).

JWH-133 (3 mg/kg) 5 min before

Treatment reduced infarct size (P , 0.05).

HU308 (2 mg/kg) and/or AM630

JWH-133 (1, 10 or 100 nmol/L)

Treatment with JWH-133 reduced infarct

AM1241 (20 mg/daily) for 7 days

CBD (100 mg/kg) 2 doses before

Treatment increase CPC, enhancing

BI 14361 (3 mg/kg daily) for a week In both models, treatment significantly

Sitagliptin (100 mg/kg/day) for 2

Treatment was effective in reducing infarct

Vildagliptin was effective in reducing infarct

Vildagliptin (3 mg/kg) for 8 weeks

At the end of treatment, vildagliptin

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Novel mechanisms and treatments

Chemerin-15 (0.3 ng/kg)

Omentin (0.1 mg/g)

Edaravone (60 mL) + lactic acid

HLF low (5 mg/kg) or high

Carperitide (0.025 0.2 mg/ kg/min At 10 min after treatment, an increase of

After 24 h reperfusion, Edaravone reduced

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Treatment reduced the infarct size (P , 0.05).

VNS started 5 min prior to

After 2 h, treated group had significantly