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Pathophysiology of Myocardial Infarction and Acute Management Strategies

Article in Cardiovascular & Hematological Agents in Medicinal Chemistry · December 2016

DOI: 10.2174/1871525714666161216100553

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Cardiovascular & Hematological Agents in Medicinal Chemistry, 2016, 14, 150-159

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ISSN: 1871-5257
eISSN: 1875-6182

Cardiovascular
& Hematological Agents
Pathophysiology of Myocardial Infarction and Acute Management Strate-
gies The journal for current and in-depth reviews
on Cardiovascular & Hematological Agents

Miha Tibaut1, Dušan Mekiš2 and Daniel Petrovič3,*

Cardiovascular & Hematological Agents in Medicinal Chemistry

1
General Hospital Rakičan, Murska Sobota, Slovenia; 2Department of Anaesthesiology, Intensive Care and Pain Man-
agement, University Medical Centre Maribor, Maribor, Slovenia and 3Institute of Histology and Embryology, Faculty of
Medicine, University of Ljubljana, Ljubljana, Slovenia

ARTICLE HISTORY
Received: October 23, 2016
Revised: November 29, 2016
Accepted: December 05, 2016
DOI:
10.2174/18715257146661612161005
53
Abstract: On an annual basis, 13.2% of all deaths are attributable to coronary artery disease (CAD),
which makes CAD - with 7.4 million deaths – the leading cause of death in the world. In this review, we
discuss current knowledge in the pathophysiology of atherosclerosis with its progression to stable CAD
and its destabilization and complication with thrombus formation – myocardial infarction (MI). Next,
we describe mechanisms of myocardial cell death in MI, the ischemia-reperfusion injury, left-
ventricular remodeling and complications of MI. Furthermore, we add acute management strategies
concentrating on medical therapy, a decision on the reperfusion strategy, timing and cardiac protection
by ischemic preconditioning, post-conditioning and remote ischemic conditioning.

Keywords: Atherosclerosis, coronary artery disease, management, medical therapy, myocardial conditioning, myocardial in-
farction, pathophysiology.

INTRODUCTION Stable CAD is generally characterized by episodes of re-

Coronary artery disease (CAD) is characterized by an
atherosclerotic process taking place on the coronary vascula-
ture. The first signs of atherosclerosis can be noticed in in-
fants, followed by a regression in childhood, reappearance in
puberty and progression over time [1]. Asymptomatic dis-
ease can become symptomatic anytime with angina, exer-
tional or at rest, myocardial infarction (MI) or sudden death.
The incidence and prevalence of CAD are difficult to as-
sess as different definitions are used and due to its detection
only upon symptom appearance. The prevalence of angina
increases with age and is higher in middle-aged females than
males. It seems like mortality from CAD is decreasing; how-
ever, prevalence is not, undoubtedly as a result of better sur-
vival [2]. On an annual basis, 13.2% of all deaths are at-
tributed to CAD, which makes CAD – with 7.4 million
deaths – the leading cause of death in the world [3]. In de-
veloped countries, the incidence of MI has been decreasing
in the last couple of years, and so is the incidence of ST-
segment elevation myocardial infarction (STEMI) patients.
In European countries, it occurs in approximately
66/100000/year. Nonetheless, the incidence of non-ST-
segment elevation myocardial infarction (NSTEMI) patients
is slightly increasing (132/100000/year) [4, 5].
*Address correspondence to this author at the Institute of Histology and
Embryology, Faculty of Medicine University of Ljubljana, Korytkova 2,
1105 Ljubljana, Slovenia; Tel +386 1 543 7367; Fax + 386 1 543 7361;
E-mail: daniel.petrovic@mf.uni-lj.si
versible myocardial demand/supply mismatch, related to
ischemia or hypoxia, which are usually inducible by exer-
cise, emotion or other types of stress and are commonly as-
sociated with transient chest discomfort [2]. Stable CAD can
manifest itself due to plaque-related obstruction of coronary
arteries, their spasms, microvascular dysfunction or left ven-
tricular dysfunction [2].
MI is defined as myocardial cell death due to prolonged
ischemia. Clinically, the term MI is used when there is evi-
dence of myocardial necrosis in a clinical setting, consistent
with acute myocardial ischemia and with a rise in cardiac
troponin [6]. We distinguish between two types of MI on
which clinical decision-making is based: STEMI and
NSTEMI. In contrast to NSTEMI patients, patients with
STEMI are referred to immediate reperfusion treatment
strategies. Furthermore, MI is classified into 5 types depend-
ing on its pathophysiology, clinics and prognostics [6]:
 Type I: Spontaneous MI:
o Atherosclerotic plaque disturbance resulting in
thrombus formation and decreased myocardial blood
flow or distal platelet emboli with ensuing myocyte
necrosis
 Type II: MI secondary to an ischemic imbalance:
o Imbalance between myocardial oxygen supply and/or
demand due to other conditions (not CAD), e.g. coro-
nary endothelial dysfunction, coronary artery spasm,
coronary embolism, tachy-/brady-arrhythmias, heart

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Myocardial Infarction and Treatment Cardiovascular & Hematological Agents in Medicinal Chemistry, 2016, Vol. 14, No. 3
failure, anemia, respiratory failure, hypotension, hy-
pertension, renal failure or major procedures
 Type III: Myocardial infarction resulting in death when
biomarker values are unavailable
 Type IVa: Myocardial infarction related to percutaneous
coronary intervention (PCI)
 Type IVb: Myocardial infarction related to stent throm-
bosis
 Type V: Myocardial infarction related to coronary artery
bypass grafting (CABG)
ATHEROSCLEROSIS
Atherosclerosis is a chronic, inflammatory, fibro-
proliferative disease of the intima of large and medium-sized
arteries. It encompasses many pathophysiological mecha-
nisms: retention and modification of lipoproteins, recruit-
ment of monocytes and T-lymphocytes, and the accumula-
tion of excessive fibrous tissue [1]. The development and
progression of atherosclerosis depends on many risk factors,
including male gender, hypertension, diabetes, sedentary
lifestyle, smoking, elevated cholesterol, and genetic poly-
morphisms [7].
Development of Atherosclerosis
In places with low shear stress (outer walls of vessel
branch points, vascular curvatures), the intima is thickened
presumably as a physiological adaptation. The subendotheli-
al proteoglycan-rich layer and a deeper musculoelastic layer
with elastic fibers and smooth muscle cells (SMC) start to
form. The so-called intimal thickenings are atherosclerosis-
prone regions [1].
Apo B-containing lipoproteins (e.g. LDL) accumulate in
the proteoglycan-rich layer. Fat droplets are then subject to
enzyme and oxidative radical modification and, when oxi-
dized, act as proinflammatory mediators that induce the syn-
thesis of endothelial adhesion molecules and chemokines
which, in turn, stimulate the recruitment of monocyte-
derived macrophages [8]. Macrophages phagocyte oxidized
LDL particles, giving them the appearance of foam cells.
Other cells that accumulate excess lipids are SMCs which
contribute to the total intimal foam cell population [9]. Foam
cells amass in the thickened intima and form yellow fatty
streaks. Fatty streaks are a harmless and fully reversible
stage of atherosclerosis present in infants during the first 6
months of life [1].
When lipoproteins are further accumulated in fatty
streaks, lipid pools start to form under the layer of foam
cells, but no disruption of vascular intimal structure is seen.
In coronary arteries, these so-called intermediate lesions are
apparent by 20 to 30 years of age [1].
An irreversible turning point in the process of atheroscle-
rosis is the progression of intermediate lesions to more ad-
vanced lesions, e.g. fibroatheromas. A necrotic, lipid-rich
core is formed by the degradation of the extracellular matrix,
death of local SMCs and apoptosis of foam cells promoting
lipid accumulation. Serum lipoproteins are thought to be a
major lipid source in advanced lesions. Another lipid source
151
is intraplaque hemorrhage from neovessels spreading from
the vasa vasorum. On the intravascular side, fibroatheromas
are covered with a fibrous cap, consisting mostly of colla-
gen-rich fibrotic tissue that is secreted by modulated synthet-
ic-type SMCs replacing contractile SMCs due to local modu-
lators. Additionally, fibroatheromas consist of microscopic
intra- and extracellular calcifications, facilitated by osteogen-
ic SMCs. Calcification volumes vary and can encompass
most of the plaque [1].
While fibroatheromas consist of fibrous and lipid tissue, fi-
brous plaques lack a lipid-rich core. Its formation is not yet
fully understood. A different type of lesions are complicated
plaques, defined by the presence of an occlusive or non-
occlusive thrombus. A thrombus can complicate intermediate
or advanced lesions and is a direct consequence of plaque rup-
ture (fibrous cap rupture – microscopic evidence of rupture) or
plaque erosion (no microscopic evidence of rupture) [1].
STABLE CORONARY ARTERY DISEASE
With aging, plaques can progress and grow to become so
capacious that coronary artery lumen is reduced beyond the
critical point at which blood flow to cardiomyocytes is not
sufficient, exposing them to anaerobic environment and
causing ischemia to set in. With the onset of ischemia, stable
angina pectoris develops. Conversely, certain plaques do not
reduce lumen/flow significantly and therefore do not cause
symptoms. The severity of flow obstruction depends on
plaque size, vasospasms and a phenomenon called arterial
remodeling, consisting of two instances, positive and nega-
tive remodeling [10]. Positive or expansive remodeling is
thought to be partly a consequence of homeostatic responses
of the adjacent preserved vessel wall to maintain normal
shear stress. Another theory suggests that it is predominantly
a pathophysiologic process in which proteolytic enzymes
degrade the media and the external elastic membrane which
consequently expands [10]. Non-stenotic plaque is clinically
silent and cannot be seen on angiography. Therefore, it can
only be managed by conservative therapy [11]. Negative or
constrictive remodeling has not been studied in detail, but is
thought to be a consequence of plaque rupture followed by
healing [10]. Stenotic lesions cause angina pectoris and are
managed not only with drug therapy, but often also call for
revascularization therapy. In affected individuals, plaques
with positive and negative remodeling often coexist. Moreo-
ver, they usually lie in between those extremes [11].
Flow though coronary arteries is limited when there is more
than an 80% reduction in the luminal area or more than a 50%
reduction in diameter as seen on coronary angiography. In low-
er grade stenosis, only flow reserve is decreased. In stable
CAD, plaques progress gradually in with the above mentioned
process of atherosclerosis, sometimes complicated by plaque
ruptures that are, in the vast majority, clinically silent, causing
non-occlusive thrombus formation. Many complicated plaques
have several plaque rupture sites. The non-occlusive thrombus
is partly removed by natural lysis; the remaining part is then
covered with natural heparinoids to neutralize the thrombo-
genicity of the exposed collagen. After 36 hours, SMCs mi-
grate to this area and cover the surface with newly produced
connective tissue, restoring plaque integrity. With the restora-
tion of the fibrous cap (thickening), the affected plaque in-
152 Cardiovascular & Hematological Agents in Medicinal Chemistry, 2016, Vol. 14, No. 3
creases in size and contracts by healing SMCs – negative re-
modeling. For this reason, plaque progression is often not line-
ar, but phasic [1, 11, 12].
ACUTE CORONARY SYNDROMES
In the vast majority of cases, MI and unstable angina are
caused by the formation of thrombus on ruptured or eroded
plaque with or without simultaneous vasospasm [12]. The
thrombus causing unstable angina and NSTEMI is usually non-
occlusive and dynamic, whereas on the other hand, an occlusive
and persistent thrombus is found in STEMI patients. Other rarer
causes of acute coronary syndromes are spasms, emboli, sponta-
neous coronary artery dissection, vasculitis, cocaine abuse, trau-
ma and compressions of the coronary artery by myocardial
bridges (fragments of myocardium crossing on top of the coro-
nary artery causing obstruction with physiological contraction).
Plaque rupture is the major cause of thrombosis in coro-
nary vasculature and is more frequent in men [1]. When
plaque ruptures, the fibrous cap tears and exposes the highly
thrombogenic lipid core to blood. The lipid core contains a
tissue factor, collagens and lipid microcrystals, all of which
accelerate thrombosis, which starts in the plaque itself and
extends intraluminally. When there is no sign of fibrous cap
rupture, term plaque erosion is used. In plaque erosion, sub-
endothelial tissue, such as the basal membrane, is exposed to
blood, and the thrombus that forms is therefore adherent to
the plaque surface. The underlying mechanism of both pro-
cesses is an enhanced vascular inflammatory activity within
the plaque itself. Macrophages within the plaque are highly
activated, causing endothelial and SMC cell inhibition and
death by apoptosis, secretion of a wide range of metallopro-
teinases degrading the connective tissue matrix including
collagen. Apoptosis of endothelial tissue with lysis of adhe-
sion proteins are basis of endothelial erosion. Apoptosis of
SMCs with fibrous cap lysis, on the other hand, causes endo-
thelial rupture [1, 12]. Metalloproteinase secretion by mac-
rophages is upregulated by inflammatory cytokines. Plaque
rupture/erosion is therefore seen as an auto-destructive pro-
cess related to the inflammation [12].
The development of thrombus and its extent is highly varia-
ble and depends on: local flow disturbances, blood coagulability
and thrombogenicity of the exposed tissue – the Virchow triad
[1]. The most important factor in plaque rupture seems to be the
thrombogenicity of the expelled tissue; however, in plaque ero-
sion, the exposed tissue is not as thrombogenic as the lipid core
or particles containing the tissue factor, thus the main mechanism
is probably the disturbance in systemic and local thrombogenic
factors. The thrombus may progress rapidly or can develop over
the course of days, with intermittent flow disturbances due to
dynamic processes: thrombosis, thrombolysis with or without
vasospasms. Furthermore, as thrombus starts to form, blood con-
tinues to flow through the plaque washing away tissue factor-rich
debris resulting in microembolisation. Microembolisation may
also occur with PCI. Microemboli then obstruct small coronary
arteries in the size range of 50-100 μm distal to the plaque and
prevent myocardial perfusion despite the potential recanalization
of the culprit artery [1, 12].
A thrombus can form predominantly intraluminally or in-
side the plaque. A large occlusive thrombotic mass can form
on a small ruptured plaque on the one hand, whereas on the
Tibaut et al.
other hand, a thrombus can expand the plaque from within
and, in extreme cases, cause is complete disintegration [12].
Plaque Vulnerability
Only 14% of occlusions leading to MI develop on high-
grade stenoses (more than 70% in diameter) and more than
two thirds of MI occur on non-obstructive lesions (<50% in
diameter) [13]. Therefore, the severity of stenoses on angi-
ography does not define the extent of one’s risk for the de-
velopment of MI, whereas on the other hand, an important
risk factor is the number of vulnerable plaques. Vulnerable
plaques are prone to rupture. Rupture tends to occur where
the fibrous cap is the thinnest, usually on the cap margin –
shoulder region. Only in the minority of cases we can identi-
fy a mechanical trigger, which causes an escalation of forces
on the fibrous cap and precipitates rupture. Some examples
of triggers are: extreme physical activity, severe emotional
stress, sexual activity, drug abuse, cold exposure, and acute
infections. Triggers only determine the exact timing of MI,
in the majority of cases plaque rupture would occur anyway
in the next couple of days due to plaque morphology [1].
Rupture-prone plaques (Table 1) are characterized by a
thin fibrous cap, of less than 65 μm [14]. Nowadays, such
plaques can be detected by modern intravascular imaging
devices, such as intravascular ultrasound, or more precisely
by means of optical coherence tomography. Plaque infiltra-
tion by macrophages and lymphocytes and the subsequent
production of inflammatory mediators cause apoptosis of
SMCs, which are the main source of fibrous cap fibers. Mac-
rophages also excrete proteolytic enzymes, such as plasmin-
ogen activators and matrix metalloproteinases (MMPs),
which are capable of degrading almost all extracellular com-
ponents including the fibrous cap. As a result of these two
mechanisms, the fibrous cap weakens over time. The exact
time frame of this occurrence is not yet known [1, 12].
The presence and size of the lipid-rich core is also related
to plaque vulnerability. A larger lipid-rich core means great-
er tensile forces to the overlying fibrous cap and higher
amounts of prothrombotic particles, its expansion can also
erode the cap from below, predisposing it to rupture [1, 12].
Rupture-prone plaques tend to develop on luminal sites
with positive remodeling; they have a higher rating of neo-
vascularization, adventitial inflammation and a higher tissue
factor content. Plaque size does not seem to play an im-
portant role by itself; nonetheless, bigger plaques have a big-
ger lipid-rich core and less fibrosis. As mentioned above, the
severity of stenosis does not confer a greater risk of MI.
Even if the thrombus severely occludes the stenotic segment,
it usually does not result in MI; in that case collateral circu-
lation is sufficiently developed [1].
Molecular Mechanisms of Plaque Disruption
On a microanatomic level, four different mechanisms can
precipitate ACS [15]. Plaque rupture is the most common
cause, followed by superficial erosion, erosion around calci-
um nodules, or intraplaque hemorrhage. The extent of
thrombosis on a molecular level depends on the balance be-
tween procoagulant/anticoagulant factors, profibrinolyt-
ic/antifibrinolytic factors and local regulatory factors at the
Myocardial Infarction and Treatment Cardiovascular & Hematological Agents in Medicinal Chemistry, 2016, Vol. 14, No. 3
level of the arterial wall. It is now widely accepted that in-
flammation in common initiating pathway in development of
ACS [15]. The immunoinflammatory system can balance the
process in either way. CD4+ T-lymphocytes, natural killer
cells, natural killer T-cells and macrophages with expression
of toll-like receptor 4 (and downstream signaling through
Myd-88) promote inflammation and therefore atherogenesis.
On the other hand, a fully functional spleen, B cells, com-
plement 3 and regulatory T-lymphocytes (CD4+/CD25+)
were found to inhibit atherogenesis. The overall process
probably depends on the complex interaction and balance
between all of these individual components [16].
Table 1. Characteristics of rupture-prone plaques [1].
Fragile Fibrous Cap
Thin (<65 Μm)
Macrophage Infiltration with Inflammation
Low SMC Number
Large Lipid Rich Core
Hemorrhage into The Core
Expansive Remodeling
Neovascularization
Adventitial Inflammation
High Tissue Factor Content
Plaque Rupture
In plaque rupture, the fibrous cap breaks and exposes its
contents to blood flow. The fibrous cap retains its integrity if
the balance between collagen synthesis and degradation is
maintained. This balance is threatened by the infiltration of
shoulder regions of the plaque with dendritic cells which se-
crete T-lymphocyte-recruiting chemokines. T-lymphocytes
migrate into the plaque where they are activated through the
antigen presentation from the dendritic cells, resulting in inter-
feron-γ (IFN-γ) and TNF-α (potent inflammatory cytokines)
secretion. This process results in the reduction of SMCs activi-
ty and survival, and it also activates macrophages. Collagen
synthesis by plaque SMCs is therefore almost halted. SMCs’
ability to repair the fibrous cap is therefore reduced. To contin-
ue, the number of SMCs directly correlate with collagen quan-
tity. Proinflammatory cytokines promote apoptosis of SMCs,
thus diminishing their numbers. Another important aspect in
this balance is increased collagen degradation. MMPs in rup-
ture-prone plaques are overexpressed and more active, again as
a consequence of proinflammatory mediators. In order for col-
lagen digestion to take place, MMPs’ activity must overpower
the activity of tissue inhibitors of MMPs. [15, 16].
Superficial Plaque Erosion
Molecular mechanisms of superficial plaque erosion are
not well researched. They are speculated to be a result of
degradation of type IV collagen connecting endothelial cells
to the basal membrane with MMPs. Interstitial MMPs are
activated by endothelial cells’ surface MMPs, the expression
153
of which is once again augmented by inflammation. Another
possible mechanism for plaque erosion is endothelial cell
death by apoptosis [15]. Since inflammatory mediators can
promote or inhibit the rate of apoptosis, an exact mechanism
is not yet clear, nonetheless it was suggested that
CD4+/CD28-KIR2DS2+ lyse endothelial cells in patients
with unstable angina [16].
Erosion from Calcium Nodules
Plaque calcium content is, as collagen content, dependent
on the balance between its synthesis and degradation. Mac-
rophages express enzymes involved in bone resorption, and
higher calcium content plaques consequently exhibit a lower
rate of macrophage infiltration. Calcium nodules as small as
10 μm cause local flow disturbances, affecting biomechani-
cal properties of the plaque. Next, erosion takes place, fol-
lowed by thrombosis [15].
Intraplaque Hemorrhage
Intraplaque hemorrhage can cause rapid plaque expan-
sion and ACS, nevertheless that is rarely the case. In most
cases, intraplaque hemorrhages lead to progressive stepwise
occlusion of coronary arteries. Firstly, neovessels develop
under the influence of many growth factors and angiogenic
proteins that are excessively present in lesions. Plaque hem-
orrhages develop with repeated neovessel rupture [15].
MYOCARDIAL CELL DEATH IN MI
After the onset of thrombosis, cardiomyocytes die rapidly
due to a number of factors: hypoxia and energy depletion in
the absence of aerobic reserve (supply-demand mismatch),
reoxygenation, acidosis, oxidative stress and cytokine stimu-
lation [17]. After the first 30-45 seconds, diastolic and sys-
tolic dysfunction sets in, followed by the appearance of elec-
trocardiographic changes. The first necrotic cells are seen
after 30 to 40 minutes of flow deprivation; from there on
cells die exponentially. If no reperfusion is achieved either
by PCI or pharmacologic thrombolysis in 6 hours, almost all
of the non-perfused myocardium is affected by necrosis [17].
Myocardium is affected in the wavefront pattern – initially,
myocardial damage affects the endocardial region and grad-
ually progresses to the epicardial region [18].
Due to a lack of anaerobic metabolic pathways, the myo-
cardium is very susceptible to ischemia, which therefore causes
rapid intramyocardial ATP depletion. Still, a complete deple-
tion of ATP usually takes 40–60 min. On the other hand, con-
tractile arrest occurs after several minutes and cellular swelling
with intracellular changes in microstructure start as quickly as
15 minutes after the onset of ischemia. These events are trig-
gered by the accumulation of H+ as a side product of ATP deg-
radation. Low pH inactivates troponin C (disabling contrac-
tion), causes influx of Na+ (swelling), and gradual loss of ATP
results in inactivation of Ca2+ ATPases (Ca2+ buildup and acti-
vation of apoptosis or oncosis). All processes occur within
minutes, but progress gradually because the acidic environment
slows down all pathways [19].
Cardiomyocyte death occurs either by oncotic or apoptotic
pathways. The exact ratio of contribution of each of the two is
not yet known. Oncosis is activated by events rapidly rising in-
154 Cardiovascular & Hematological Agents in Medicinal Chemistry, 2016, Vol. 14, No. 3
tracellular calcium ion concentration or because of a dysfunction
of the mitochondria’s respiratory chain which decreases ATP
production. Water and ions enter cardiomyocytes which uncon-
trollably swell and burst. Apoptosis, on the other hand, is a well-
controlled process of death occurring mainly in the histological
border zone of the MI [17, 19].
Cell death initiates a surge of neutrophil and monocyte in-
vasion causing acute exudative inflammation. Inflammation
activates fibroblasts and endothelial cells, developing vascular-
ized granulation tissue in place of dead cardiomyocytes with
the aim of tissue repair (24 hours to 7 days after occlusion).
Rate apoptosis in the border zone is enhanced with the purpose
of containing granulation tissue inside the infarcted area. The
inflammatory reaction gradually resolves, granulation tissue
matures into collagenous scar and inflammatory cells, fibro-
blasts and endothelial cells in the infarcted area undergo apop-
tosis. After 7 days – or a few weeks in the case of the previous-
ly affected myocardium, only acellular scar tissue persists. Fur-
thermore, due to its inability to contract, it can lead to compen-
satory remodeling of heart chambers [17].
ACUTE MECHANICAL COMPLICATIONS OF MI
AND LEFT VENTRICULAR (LV) REMODELING
When inflammation in the infarcted area is not sufficiently
contained, the infarcted area is vast, or there is excessive ven-
tricular wall stress, the infarcted area expands with consequent
low tensile strength scar formation. Before the scar is absolute
(in the first days to a few weeks after MI) complications can
occur with acute or subacute left ventricular free wall rupture,
ventricular septal rupture, acute mitral regurgitation, right ven-
tricular infarction, formation of LV wall aneurysm and heart
failure. On the other hand, neurohumural factors, cytokines,
oxidative stress and wall stress contribute to LV remodeling
through non-infarct related hypertrophy or dilatation and to
pericardial complications (e.g. peri-infarction pericarditis, peri-
cardial effusion, postcardiac injury (Dressler's) syndrome). The
incidence of all complications is now (reperfusion era) much
lower than before [20-22].
Left ventricular free wall rupture is almost always fatal,
non-fatal instances are usually due to existing pericardial
adhesions (e.g. after cardiac surgery). Death occurs basically
because of instantaneous pericardial tamponade. 50% of in-
stances of free wall rupture occur within the first 5 days after
MI and within 2 weeks in more than 90% of cases. If the
ventricular wall ruptures on the intraventricular septum, left
to right shunt occurs, often resulting in cardiogenic shock
and immediate surgical treatment is considered most suc-
cessful. Nevertheless, mortality remains high [20].
Acute mitral regurgitation is usually a complication of in-
ferior infarction that includes the posteromedial papillary
muscle. It can result from a complete or partial papillary
muscle rupture, its dysfunction, chordal rupture or can be a
result of LV dilatation. Clinically significant are those mod-
erate to severe or severe, which present with cardiogenic
shock often resulting in death if not recognized in timely
manner and surgically treated [20].
Right ventricular infarction complicates up to half of in-
ferior MI. The right ventricle is a low pressure system, if
infarcted it quickly dilates causing a rapid fall in LV preload
Tibaut et al.
and cardiac output. Patients therefore present with the triad
of hypotension, clear lung fields, and elevated jugular ve-
nous pressure. Besides timely reperfusion, treatment consists
of rapid fluid administration and use of inotropes to normal-
ize LV preload and cardiac output. Nitrates and morphine
should be avoided as they often cause drastic hypotension
[20].
Peri-infarction pericarditis typically occurs in the first few
days after MI and is characterized by pericardial friction rub and
slow regression of ST-segment elevations. It is usually a conse-
quence of larger MI and is self-limiting, rarely requiring anti-
inflammatory therapy with aspirin and colchicine. Pericardial
effusion itself, on the other hand, is quite common, occurring in
up to one third of patients, but is mostly asymptomatic and re-
solves spontaneously. When symptoms are present, pericardial
tamponade should be excluded. In contrast, postcardiac injury
syndrome (PCIS) develops weeks to months after MI or other
cardiac insult and is thought to be an immune-mediated process.
In contrast to peri-infarction pericarditis, it is characterized by
fever, pleuritic chest pain, pericardial friction rub and sometimes
pulmonary infiltrates or effusions. It usually responds well to
treatment with non-steroidal anti-inflammatory drugs (NSAIDs)
or in refractory cases to steroids or colchicine [22].
ISCHEMIA-REPERFUSION INJURY
Even though timely reperfusion of the culprit artery dra-
matically improves the outcomes of patients with acute cor-
onary syndromes, the procedure is often less effective than
expected even if implemented in a timely manner. This is
due to the reperfusion injury. When the infarcted area is
reperfused, all substrates essential for ATP generation are
again available and extracellular pH is promptly normalized.
An extreme H+ gradient is generated across the membrane
activating the Na+/H+ exchanger causing massive Na+ influx.
Subsequently, the Na+/Ca2+ exchanger is activated overload-
ing cells with Ca2+. Because of the normalization of pH, in-
tracellular processes are again accelerated. The sudden re-
covery of aerobic metabolism boosts the mitochondrial res-
piratory chain resulting in ROS overload and consequent
oxidative damage to all cellular structures [19]. ROS over-
load also stimulates the opening of the mitochondrial perme-
ability transition pore (MPTP), a mega-channel in the inner
mitochondrial membrane which, when opened for extended
periods, dissipates the inner mitochondrial membrane poten-
tial, mitochondria swell and rupture [23, 24]. Another mech-
anism of reperfusion injury is a contraction band necrosis, a
direct consequence of contractile machinery activation with
Ca2+ overload and consequential hypercontraction with myo-
cyte rupture [25]. All these events, together with increased
inflammation, result in accelerated myocardial damage by
apoptosis and oncosis, which reaches its top 30 minutes after
reperfusion and ameliorates after 1 hour with Ca2+ reuptake
by sarcoplasmic reticulum [19].
ACUTE MANAGEMENT AND MEDICAL THERAPY
OF MI
Initial Therapy upon Diagnosis
Patients should primarily be managed according to the
ALS algorithm (ABCDE) [26]. Upon diagnosis, manage-
Myocardial Infarction and Treatment Cardiovascular & Hematological Agents in Medicinal Chemistry, 2016, Vol. 14, No. 3
ment of MI and unstable angina should simultaneously focus
on hemodynamic stabilization, relieving the pain (angina
pectoris), decreasing myocardial oxygen consumption (by
decreasing heart rate, blood pressure, preload or myocardial
contractility), increasing myocardial oxygen supply (by ad-
ministration of oxygen or through coronary vasodilation) and
initiating antithrombotic therapy [4].
Oxygen
Oxygen supplementation should be initiated in patients
with arterial oxygen saturation below 94% (or <88% if
chronic obstructive pulmonary disease (COPD) is present) to
achieve normoxia. Hyperoxia should be avoided since it
causes coronary artery vasoconstriction, increases early my-
ocardial injury and infarct size [27, 28].
Nitrates
In the absence of hypotension (systolic blood pressure
< 90 mmHg) and signs of right ventricular infarction (up to
40% of inferior STEMI), patients should be given nitrates,
namely nitroglycerin 0.4 mg sublingually every 5 minutes up
to three times [27] with the intention of increasing coronary
blood flow by decreasing preload. This can also alleviate
angina. In monitored patients, intravenous nitroglycerin can
be used as continuous infusion. Before nitrates are given,
one has to make sure the patient did not take phosphodiester-
ase-5 inhibitors (e.g. sildenafil) in last the 24-48 hours, since
combined with nitrates they can cause severe hypotension.
Morphine
If pain persists, intravenous (i.v.) morphine of 3 to 5 mg
may be given and repeated every few minutes [27] until the
patient is pain-free. Morphine diminishes sympathetic stimu-
lation caused by pain and anxiety, and therefore reduces my-
ocardial oxygen consumption. Generally, morphine should
be used only in patients with extreme pain as it was shown to
reduce the antiplatelet effect of P2Y12 receptor blockers, pre-
sumably through slowing intestinal absorption [27-30].
Antithrombotic Therapy
Antiplatelet Therapy
Patients should chew non–enteric-coated aspirin (150 to
300 mg) which blocks further platelet aggregation as a cen-
tral pathophysiologic mechanism of MI after plaque disrup-
tion. Also, i.v. preparation of 150 mg can be given if the pa-
tient is unable to take medications orally [27, 29].
Additional inhibition of platelet aggregation is achieved
by P2Y12 receptor antagonists, normally stimulated by ADP.
Clopidogrel and prasugrel are irreversible, whereas ticagrelor
is a reversible P2Y12 inhibitor. Prasugrel and ticagrelor have
a more rapid and consistent action, while clopidogrel is
known to have hypo- and hyper-responders. Dual antiplatelet
therapy (DAPT) with clopidogrel therapy has been shown to
reduce ischemic events compared to aspirin alone. Studies
comparing clopidogrel to prasugrel or ticagrelor found a sig-
nificant MACE reduction (due to reduction in MI) with pra-
sugrel and ticagrelor and superiority in mortality reduction
with ticagrelor, making an allowance for higher bleeding
risks with both drugs. Prasugrel has also been shown to have
lowest incidences of in-stent thromboses and has had a great
benefit in T2DM patients. Because of a higher bleeding risk,
155
patients over 75 years of age, below 60 kg or history of
TIA/stroke should not receive prasugrel, whereas on the oth-
er hand, ticagrelor is contraindicated in patients with history
of intracranial hemorrhages, and caution is advised in pa-
tients with bradycardia (increased incidence of asymptomatic
ventricular pauses) [4, 27, 31].
 In STEMI patients with planed PCI, pretreatment with a
loading dose of 180 mg of ticagrelor or 60 mg of prasug-
rel or 600 mg of clopidogrel should be given, bearing in
mind the contraindications. The choice of P2Y12 antago-
nists should always be guided by local protocols or by
consultation with a PCI center. When thrombolysis is
planned, newer P2Y12 antagonists should be avoided as
there no data in this setting, and clopidogrel should be
used instead (300 mg loading dose up to an age of 75 and
75 mg without loading dose if >75 years of age) [27].
 In NSTE-ACS with planed PCI, pretreatment with a
loading dose of 180 mg of ticagrelor or 300 mg of
clopidogrel should be given taking into account their
contraindications [4, 27]. Before coronary anatomy is
known and patients are not proceeding to PCI, prasugrel
should not be given in NSTE-ACS situations, since it
was shown to increase major bleeding events without re-
ducing thrombotic events. Ticagrelor and clopidogrel
were not investigated in regard to the timing of the treat-
ment, nonetheless they are recommended soon after di-
agnosis, regardless of the management strategy [4, 27,
31].
 If conservative management is preferred, prompt initia-
tion of DAPT is warranted, preferably with ticagrelor in
the absence of contraindications in STEMI or NSTE-
ACS patients [4].
Anticoagulation Therapy
After initiation of DAPT, anticoagulants should also be
given. Anticoagulation in adjunct to DAPT was shown to
reduce ischemic events. Unfractionated heparin (UFH) (ini-
tial bolus 70–100 U/kg when no glycoprotein (GP) IIb/IIIa
inhibitor is planned or 50–60 U/kg when the use of GP
IIb/IIIa inhibitors is expected is mainly used in patients re-
quiring immediate PCI [32]. Recent studies suggest that
enoxaparin (0.5 mg/kg i.v. followed by s.c. treatment [32])
may be preferred over UFH since it was shown to reduce
MACE. Fondaparinux is considered the safest and as effec-
tive as others, and is therefore preferred if there is no imme-
diate PCI planned, whereas on the other hand, in the context
of primary PCI, it was associated with potential harm and is
therefore not recommended. Alternative to all three, bival-
irudin (0.1 mg/kg i.v. bolus followed by an infusion of 0.25
mg/kg/h) may be used. Glycoprotein IIb/IIIa inhibition is
usually used in peri-procedural settings as there is no differ-
ence in ischemic events if given pre-procedurally and no
increased risk of bleeding [32, 33].
Reperfusion Strategy
The timing of invasive strategy depends on the risk of
complications (Table 2) [4]. In STEMI and very high risk
NSTE-ACS patients, reperfusion should be initiated as soon as
possible in less than 120 min if the time from symptom onset is
less than 12 hours. Reperfusion can be achieved by percutane-
156 Cardiovascular & Hematological Agents in Medicinal Chemistry, 2016, Vol. 14, No. 3
ous coronary intervention (PCI), with a prompt initiation of
fibrinolysis, or with a combination of both. When PCI can be
performed within a time limit of 60–90 min, then direct
transport to the PCI center is indicated. Diagnosis to balloon
time should be less than 120 min. Patients presenting to a non-
PCI hospital with STEMI should be immediately transported to
a PCI center, provided that treatment delays for primary PCI
are less than 120 min. If transport times in a prehospital setting
are higher than 30-60 min, prehospital fibrinolysis is a superior
method, but must be followed by PCI within 3-24 hours after
its initiation. [4, 27].
High-risk NSTE-ACS patients require early PCI in the
first 24 hours, since immediate PCI did not result in any ma-
jor benefit, while longer times, on the other hand, were con-
nected with higher mortality rates. Intermediate risk patients
and patients with positive non-invasive ischemia tests should
be referred to coronary angiography in a 72-hour window. If
the patient does not meet any of the risk criteria in Table 2, it
is considered low-risk, and non-invasive tests are indicated
prior to the decision on invasive management [4].
Table 2. Risk groups in NSTE-ACS. Patients are classified to
the highest group in which they meet at least one cri-
teria. (adopted from [4])
Very-High-Risk Group (at least one criteria)
Hemodynamic instability or cardiogenic shock
Recurrent or ongoing chest pain refractory to medical treatment
Life-threatening arrhythmias or cardiac arrest
Mechanical complications of MI
Acute heart failure
Recurrent dynamic ST-T wave changes, particularly with intermittent
ST-elevation
High-Risk Group (at least one criteria)
Rise or fall in cardiac troponin compatible with MI
Dynamic ST- or T-wave changes (symptomatic or silent)
GRACE score >140
Intermediate-Risk Group (at least one criteria)
Diabetes mellitus
Renal insufficiency
LVEF <40% or congestive heart failure
Early post-infarction angina
Prior PCI
Prior CABG
GRACE risk score >109 and <140
Low-Risk Group
Any characteristics not mentioned above
Beta Blockers
Beta-blockers lower blood pressure, heart rate and myo-
cardial contractility, therefore decreasing myocardial oxygen
consumption. They should be administered universally in
Tibaut et al.
patients without contraindications early after MI (in 24
hours) because of an observed relative risk reduction in mor-
tality in the first week and in-hospital. Beta-blockers are con-
traindicated in heart failure (Killip class III or IV), high
grade aortic stenosis or other low-output state, bradycardia
or heart block [27, 29, 30].
Angiotensin Converting Enzyme Inhibitors (ACEI)
Early oral introduction of ACEI in the first 24 hours of
MI reduces mortality regardless of the reperfusion strategy,
especially in patients with anterior infarction, pulmonary
congestion or an LV ejection fraction of less than 40%. They
should not be given in presence of contraindications or if
systolic blood pressure is below 100 mmHg [27].
Statins
Statins are a recommended therapy in all ACS patients
after the initial stabilization. Intensive statin therapy is rec-
ommended. According to ESC guidelines [4], the use of
statins that lower LDL for more than 50% is recommended,
and according to ACCF/AHA guidelines [5], atorvastatin 80
mg should be used. High intensity statin therapy significant-
ly reduces cardiovascular death and MACE in the first
month after ACS. After two months, statin therapy should be
titrated to achieve target LDL levels in secondary prevention
[5, 30].
When target levels of LDL are not reached or there are
also elevated triglycerides or lipoprotein(a), other lipid low-
ering drugs (PCSK9 inhibitors, fibrates, ezetimibe, niacin or
others) may be needed.
Proton-Pump Inhibitors
Proton pump inhibitor (PPI) should be initiated in all pa-
tients receiving dual antiplatelet therapy because of ACS,
regardless of their bleeding tendency or history of bleeding
[4, 34]. The use of PPIs in combination with clopidogrel may
reduce its antiplatelet effect through competitive inhibition
of CYP2C19; nevertheless, compliance of DAPT use with
concomitant use of PPI is higher [34].
Myocardial Protection by Conditioning
With the purpose of minimizing ischemia-reperfusion in-
jury, many researchers are investigating ways of protecting
the myocardium after ACS to reduce infarct size. Depending
on the time frame and the site of intervention, three terms are
used: ischemic preconditioning (IPC), postconditioning
(POC) and remote ischemic preconditioning (RIPC). Nowa-
days, the term conditioning refers to the intervention of in-
creasing the heart’s general ability to withstand ischemia.
Ischemic Preconditioning
IPC is defined as a phenomenon where brief periods of
ischemia accompanied by reperfusion just before sustained
ischemia results in a delayed progression or reduction of
infarct size, despite an increase in the total ischemic period
[19]. Its positive effects are exerted through a delay in ATP
consumption, reduction in oxygen consumption, retention of
intracellular structures and a delay in cellular necrosis. Typi-
cally, it is experimentally achieved by applying several short
cycles (a few minutes) of ischemia followed by reperfusion
and finally sustained ischemia. IPC, performed through the
Myocardial Infarction and Treatment Cardiovascular & Hematological Agents in Medicinal Chemistry, 2016, Vol. 14, No. 3
mentioned experiment, displayed benefits only in animal
models of ACS, since it cannot be used in patients with MI
by its very nature. Protection by IPC happens in two phases,
early (< 3h) and late (24-72h). Early phase protection is
mainly attributed to the activation of ion channels, phos-
phorylation (activation) of existing enzymes or a rapid turn-
over or translocation of substances, whereas the late phase is
attributable to the changed genetic expression of receptors,
membrane channels, enzymes, chaperons or immunomodula-
tors [17, 19, 23].
Versatile mechanisms/agents have been reported to be
more or less successfully influenced/used to mimic protec-
tion by IPC [19, 23, 24, 35]. Mitochondria are the most im-
portant effector in conditioning pathways. Agonists like
adenosine, bradykinin, opioids, acetylcholine, catechola-
mines and oxygen radicals activate the protein kinase C
(PKC) pathway, which seems to be the first convergent step
in the cascade leading to the opening of mitochondrial ATP-
sensitive potassium (KATP) channel. The KATP channel is one
of the key mediators in IPC, its opening causes an increase in
ROS production which further activates PKC in a positive
feedback loop. Low amounts of KATP channel-mediated ROS
release can trigger cardioprotection by yet unknown mecha-
nisms. Mitochondria’s MPTP is another important mediator
of IPC. Cardioprotection is exerted with the prevention of its
opening upon reperfusion. It is hypostasized that with IPC,
the activation of prosurvival pathways prevents MPTP open-
ing, secondly its opening can be inhibited by KATP-mediated
ROS production and, thirdly, oxidative stress with IPC is
diminished, therefore preventing MPTP opening. IPC also
attenuates increases in Na+ and Ca2+ and therefore in the cel-
lular volume load. Other molecules and structures thought to
be implicated in IPC through various pathways are connex-
in43, STAT3, hexokinase, aldehyde dehydrogenase, nitric
oxide though protein nitrosylation, sarcoplasmic reticulum
and cytoskeleton. [19, 23, 24, 35].
In humans, IPC has been studied through unstable angi-
na, exercise-induced ischemia, coronary angioplasty and
cardiac surgery. Studies investigating unstable angina found
smaller infarct sizes, which cannot only be attributed to IPC,
but can also be a consequence of collateral flow and reperfu-
sion rate. Repeated exercise stress tests in less than 60
minutes showed improved performance by more than half
with oxygen consumption reduction in the second test, sug-
gesting improved metabolic efficiency – IPC. A good exper-
imental human model for IPC is elective coronary angioplas-
ty, where repeated balloon inflations are done, resulting in
less subjective anginal pain and ECG ST changes in subse-
quent occlusions. The role of IPC in the adaptation to ische-
mia has been proven by usage of specific antagonist of IPC
pathways [35].
Postconditioning
The biggest downside to IPC is the need to apply thera-
peutic intervention before an unpredictable ischemic event in
MI patients takes place. Postconditioning (POC), on the oth-
er hand, in readily achievable after coronary intervention,
cardiac surgery or cardiac transplantation. Most studies test-
ing the concept of POC in humans were done during PCI.
After reperfusion, several episodes of ischemia are elicited
by angioplasty balloon inflations for short periods followed
157
by balloon deflation. Recent studies found three conditions
to be optimal for beneficial POC. First, the duration of index
ischemia has to be greater than 45 minutes, the POC proce-
dure should start in a few minutes after reperfusion (<5 min,
optimal 10 s – 1 min) and it should be repeated several times
with a total duration of several minutes (at least 3 cycles).
With optimal conditions, studies showed a reduced infarct
size, increased ejection fracture, restored postischemic con-
tractile function, decreased edema in the risk area and less
no-reflow phenomenon. It seems that most benefit is gained
in patients with anterior STEMI presenting with a complete-
ly occluded artery in which direct stenting is followed by an
upstream POC protocol [19, 24, 35, 36].
Pathophysiologically, upon reperfusion, intracellular pH
quickly recovers and causes Ca2+ overload and excessive
ROS formation leading to reperfusion injury. POC is there-
fore achieved by preventing Ca2+ overload and inhibiting
ROS generation. Those protective pathways seem to con-
verge on the mitochondria through the inhibition of MPTP
opening. Owing to those mechanisms, oxidative stress, pro-
inflammatory cytokine release, proapoptotic pathways and
neutrophil function are attenuated. Mechanisms involved in
POC have same effectors as in IPC, but differ since POC is
only effective in a strict timeframe [19, 35].
In studies, cardioprotection by POC was also elicited
pharmacologically with adenosine, atrial-natriuretic peptide,
erythropoietin, atorvastatin, metoprolol, GLP-1 analogs and
cyclosporine [23, 35, 36].
Studies on POC (interventional or pharmacological) were
predominantly positive, nonetheless they have not yet been
translated to clinical praxis since they were inconsistent in
patient selection, cardioprotective therapy, patient comorbid-
ities, timing and study endpoints [23, 35, 36].
Remote Ischemic pre-, per- and Postconditioning
Applying short episodes of ischemia and reperfusion in
the arm or leg using repeated blood-pressure cuff inflations
has been shown to exert cardioprotection. The main ad-
vantage of remote ischemic conditioning is that intervention
does not need to be done on the heart itself. Because of its
noninvasive nature, it can also can be applied before the in-
dex event (preconditioning), during ischemia (percondition-
ing) or after reperfusion (postconditioning). Exact mecha-
nisms of remote ischemic conditioning remain unclear. In
recent years, this type of conditioning has become the most
popular in elective PCI, with good results, except in trials
using propofol anesthesia, which seems to interfere in its
mechanism. Infarct size reduction has also been demonstrat-
ed in patients with MI [24, 36].
CONCLUSION
To summarize, CAD is characterized by an atherosclerot-
ic process taking place in the coronary vasculature. LDL
molecules accumulate in the outer walls of vessel branch
points in subendothelial spaces where they are oxidized. Ox-
idized LDL acts as a proinflammatory molecule attracting
macrophages and further aggravating inflammation. Lesions
formed in this way progress over time from intimal thicken-
ing, fatty streaks and intermediate lesions to irreversible fi-
broatheromas. Fibroatheromas may importantly occlude cor-
158 Cardiovascular & Hematological Agents in Medicinal Chemistry, 2016, Vol. 14, No. 3
onary artery lumen, causing angina pectoris, or stay asymp-
tomatic due to coronary artery remodeling or development of
collateral circulation. Fibroatheromas covered with a fibrous
cap are most fragile in their shoulder regions where they are
infiltrated with macrophages and T-lymphocytes which,
through various mechanisms, cause the thinning of the fi-
brous cap and its rupture, sometimes triggered by mechani-
cal stress exerted on the vessel wall. Fibroatheroma contents
exposed to blood cause thrombus formation, leading to
downstream myocardial cell death called myocardial infarc-
tion. Myocardial tissue damage progresses exponentially
with time, leading to complete necrosis in 6 hours. Cardio-
myocytes swell and take on apoptosis or necrosis due to the
Na+ and Ca2+ influx. Necrotic tissue is infiltrated with in-
flammatory cells which stimulate the formation of granula-
tion tissue and ultimately acellular scar tissue.
Acute patient care should be directed to hemodynamic
stabilization using ALS algorithms and a prompt initiation of
DAPT followed by an anticoagulant. Owing to better out-
comes, newer P2Y12 antagonists are preferred. UFH should
be used if immediate PCI is planned, otherwise fondaparinux
is the treatment of choice. Oxygen should only be given if
the patient is hypoxic. Nitrates are the preferred therapy for
symptom control and for a better myocardial oxygen deliv-
ery. Morphine should be used if nitrates are not sufficient for
pain relief, keeping in mind that it decreases the P2Y12 an-
tiplatelet effect. Beta blockers and ACEI reduce mortality
after MI and should be started early. Statins should initially
be administered in high doses to stabilize plaques (mortality
reduction) and months later titrated to achieve target LDL
levels. All MI patients on DAPT should have PPI therapy
initiated due to lower bleeding risk. All mentioned medica-
tions should be used in the absence of contraindications.
Reperfusion should be achieved in STEMI patients in 2
hours from the presentation when symptoms last less than 12
hours, and in NSTE-ACS in regard to the clinical picture and
risk evaluation. PCI is the preferred reperfusion strategy in
countries with a well-established PCI network and quick
transport times. Prehospital fibrinolysis is a superior method
when transport times are high.
If timely reperfusion is achieved either by thrombolysis,
PCI or cardiac surgery, an appropriate amount of myocardi-
um is salvaged; however, due to a sudden normalization of
pH and aerobic conditions, reperfusion injury sets in. In the
attempt to minimize or diminish its effects, researchers ob-
served the conditioning phenomenon. Conditioning is ac-
complished by inducing cycles of ischemia-reperfusion ei-
ther on the remote organ (remote ischemic conditioning) or
coronary vasculature itself. In contrast to preconditioning,
postconditioning is readily achievable in humans directly
after the reperfusion procedure resulting in infarct size re-
duction. Large scale, well-established clinical trials are need-
ed to incorporate POC in clinical praxis.
CONFLICT OF INTEREST
The authors confirm that this article content has no con-
flict of interest.
ACKNOWLEDGEMENTS
Declared none.
Tibaut et al.
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