WJ C World Journal of

Cardiology
Online Submissions: http://www.wjgnet.com/esps/ World J Cardiol 2014 March 26; 6(3): 100-106
bpgoffice@wjgnet.com ISSN 1949-8462 (online)
doi:10.4330/wjc.v6.i3.100 2014 Baishideng Publishing Group Co., Limited. All rights reserved.

MINIREVIEWS

Cardioprotection and pharmacological therapies in acute

myocardial infarction: Challenges in the current era

Alberto Dominguez-Rodriguez, Pedro Abreu-Gonzalez, Russel J Reiter

Alberto Dominguez-Rodriguez, Department of Cardiology, several promising pharmacological (cyclosporin-A, ex-

Complejo Hospitalario Universitario de Canarias, 38320 Tener- enatide, glucose-insulin-potassium, atrial natriuretic
ife, Spain peptide, adenosine, abciximab, erythropoietin, meto-
Alberto Dominguez-Rodriguez, Pedro Abreu-Gonzalez, In- prolol and melatonin) therapeutic strategies for reduc-
stituto Universitario de Tecnologas Biomdicas, 38320 Tenerife, ing the severity of myocardial reperfusion injury. Many
Spain of these agents have shown promise in initial proof-
Pedro Abreu-Gonzalez, Department of Physiology, University
of-principle clinical studies. In this article, we review
of La Laguna, 38320 Tenerife, Spain
the pathophysiology underlying myocardial reperfusion
Russel J Reiter, Department of Cellular and Structural Biology,
The University of Texas Health Science Center at San Antonio, injury and highlight the potential pharmacological inter-
San Antonio, TX 78229, United States ventions which could be used in the future to prevent
Author contributions: Dominguez-Rodriguez A, Abreu-Gon- reperfusion injury and improve clinical outcomes in pa-
zalez P and Reiter RJ substantially contributed to the concep- tients with coronary heart disease.
tion, design, acquisition, analysis and interpretation of data, and
drafted the article, revised it critically for important intellectual 2014 Baishideng Publishing Group Co., Limited. All rights
content, and gave final approval of the version to be published. reserved.
Supported by Framework of one research project of the Spanish
Society of Cardiology for Clinical Research in Cardiology 2012 Key words: ST-elevation myocardial infarction; Cardio-
Correspondence to: Alberto Dominguez-Rodriguez, MD, protection; Myocardial reperfusion injury; Infarct size;
PhD, Department of Cardiology, Complejo Hospitalario Univer- Adjunctive therapy
sitario de Canarias, Ofra s/n La Cuesta E-, 38320 Tenerife,
Spain. adrvdg@hotmail.com Core tip: As therapeutic interventions administered at
Telephone: + 34-922-679040 Fax: + 34-922-678460 the time myocardial reperfusion have been proven to
Received: November 28, 2013 Revised: December 17, 2013
reduce infarct size in both experimental and clinical
Accepted: January 17, 2014
models, the existence of a lethal reperfusion injury and
Published online: March 26, 2014
its contribution to ischemic cardiac cell death can no
longer be ignored. Patients presenting with an acute
ST-segment elevation myocardial infarction will likely
benefit from therapy aimed at the timely administration
Abstract of drugs, most likely via primary percutaneous coronary
In patients with an acute ST-segment elevation myo- intervention, for the reduction/prevention of lethal re-
cardial infarction, timely myocardial reperfusion using perfusion injury. This approach will ensure that patients
primary percutaneous coronary intervention is the most maximally benefit from the myocardial salvage that re-
effective therapy for limiting myocardial infarct size, sults from these therapies.
preserving left-ventricular systolic function and reduc-
ing the onset of heart failure. Within minutes after the
restoration of blood flow, however, reperfusion itself Dominguez-Rodriguez A, Abreu-Gonzalez P, Reiter RJ. Car-
results in additional damage, also known as myocardial dioprotection and pharmacological therapies in acute myocar-
ischemia-reperfusion injury. An improved understand- dial infarction: Challenges in the current era. World J Cardiol
ing of the pathophysiological mechanisms underlying 2014; 6(3): 100-106 Available from: URL: http://www.wjg-
reperfusion injury has resulted in the identification of net.com/1949-8462/full/v6/i3/100.htm DOI: http://dx.doi.
org/10.4330/wjc.v6.i3.100

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 Dominguez-Rodriguez A et al . Cardioprotective agents for myocardial infarction

Figure 1 Scheme of mechanism of myo-

INTRODUCTION MPTP
cardial injury by a reperfusion process.
ROS
Acute myocardial infarction (AMI) is a major cause of 2+ MPTP: Mitochondrial permeability transi-
Intracellular Ca overload
tion pore; ROS: Reactive oxygen species;
mortality and morbidity worldwide. Each year, an esti- RAS
RAS: Renin-Angiotensin system; NPS:
mated 785000 persons will have a new AMI in the United NPS
Neutrophil-Platelet system; CS: Comple-
CS
States alone and approximately every minute an American ment system; MI: Myocardial infarction;
will succumb to one[1]. In addition, AMI has major psy- MACE: Major adverse cardiac events.
chological and legal implications for patients and society
and is an important outcome measure in research studies. Microvascular dysfunction
The prevalence of AMI provides useful data regarding
the burden of coronary artery disease and offers insight
into health care planning, policy and resource allocation[1]. Cell death
The rapid time course of AMI and the temporal Left ventricular remodeling
Non-reflow
limitation on the maximal effectiveness of reperfusion
constitute the pathobiological basis for the contemporary
clinical strategies that emphasize early intervention within
MI size
1-2 h after the onset of symptoms[2]. Currently, timely
myocardial reperfusion using either thrombolytic therapy
or primary percutaneous coronary intervention forms MACE
the cornerstone of treatment for acute ST-segment eleva-
tion myocardial infarction (STEMI) patients[3]. However,
mortality remains substantial in these patients, with in- complement activation[8,9] (Figure 1).
hospital mortality ranging between 6% and 14%[4].
Reperfusion profoundly alters the outcome of an Mitochondrial permeability transition pore opening
evolving AMI. If instituted in a timely manner, a poten- Multiple lines of evidence have converged to show that
tial transmural AMI can be prevented and the extent of the mitochondria have a central role in the pathogenesis
necrosis greatly reduced and limited to the subendocar- of cell injury[10,11]. In stressed cells, deleterious and salu-
dium. However, some injured cardiomyocytes at the edge tary effects acting on mitochondria are mediated by death
of the wavefront become irreversibly injured during the channels and salvage pathways, respectively[12]. The mito-
reperfusion phenomenon, producing a component of chondrial death channels include the mitochondrial per-
lethal reperfusion injury[5]. After reperfusion, the salvaged meability transition pore and the mitochondrial apoptosis
myocardium exhibits impaired contractile function, a channel.
form of nonlethal reperfusion injury referred to as myo- The mitochondrial permeability transition pore is a
cardial stunning. The earlier the reperfusion, the less total voltage-dependent channel that is regulated by calcium
necrosis that occurs (including both the ischemia-induced and oxidative stress[13]. The opening in the first few min-
and reperfusion-induced component), as well as the earli- utes of reperfusion of the mitochondrial permeability
er the recovery of contractile function from the transient transition pore, a non-selective channel of the inner
stunning. Conversely, reperfusion can be rendered less ef- mitochondrial membrane, in response to mitochondrial
fective by the microvascular damage and obstruction that Ca2+ overload, oxidative stress, restoration of a physio-
develop during the ischemic phase; this is known as the logical pH and ATP depletion, induces the cardiomyocyte
no-reflow phenomenon[6,7]. death by uncoupling the biochemistry route of oxidative
In this minireview, we provide an overview of myo- phosphorylation[14], which leads to a reduction in ATP
cardial reperfusion injury and highlight potential phar- production.
macological interventions for preventing it in reperfused-
STEMI patients. Overproduction of oxygen-derived free radicals
Cell membranes are composed mostly of phospholipids
PATHOPHYSIOLOGICAL MECHANISMS and proteins. Alterations in membrane proteins by free
radicals are among the important factors in the evolution
OF MYOCARDIAL REPERFUSION INJURY of myocardial ischemia reperfusion damage. Large quan-
There are various pathophysiological mechanisms in- tities of oxygen-derived free radicals lead to overwhelm-
volved in myocardial injury reperfusion. It has been sug- ing of the cellular endogenous antioxidant defences. This
gested that mitochondrial permeability transition pore causes, among other effects, the peroxidation of lipid
opening, overproduction of oxygen-derived free radicals membranes and loss of membrane integrity which results
and intracellular calcium overload might be candidates in necrosis and cell death[15].
responsible for reperfusion injury. However, other fac- Re-introduction of abundant oxygen at the onset of
tors of importance in the pathogenesis of reperfusion reperfusion evokes a burst of additional toxic oxygen de-
injury must be included, such as platelet and neutrophil- rivatives, including superoxide anion, hydroxyl radical and
mediated injury, the renin-angiotensin system and the peroxynitrite, within the first few minutes of reflow. More-

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 Dominguez-Rodriguez A et al . Cardioprotective agents for myocardial infarction

Table 1 Pharmacological cardioprotective strategies for sluggish coronary flow[8,20].

preventing myocardial injury in reperfused-ST-segment
elevation myocardial infarction patients Renin-angiotensin system-mediated reperfusion injury
The key product of the renin-angiotensin system, angio-
Mitochondrial Overproduction Intracellular Neutrophil- Platelet-
permeability of oxygen- calcium mediated mediated
tensin , increases intracellular calcium levels of cardio-
transition derived free overload injury injury myocytes and smooth muscle cells, leading to positive in-
pore opening radicals otropism, impairment of diastolic function and coronary
Cyclosporin A Adenosine Glucose- Adenosine Abciximab vasoconstriction. At pathophysiological levels, angioten-
insulin-
sin is cardiotoxic and induces myocyte necrosis[8,21].
potassium
Melatonin Metoprolol Atrial Abciximab Melatonin
natriuretic
peptide
POTENTIAL PHARMACOLOGICAL
Erythropoietin
Glucose-insulin
Erythropoietin
Melatonin
THERAPIES FOR PREVENTING
-potassium MYOCARDIAL REPERFUSION INJURY
Exenatide
Melatonin Progress in understanding the basic pathobiology of
ischemic heart disease has led to many years of research
aimed at developing pharmacological approaches for lim-
over, oxidative stress also reduces the bioavailability of iting myocardial ischemic damage. Although myocardial
nitric oxide (vasodilator compound) during reperfusion[16]. ischemia-reperfusion injury is clearly mediated by several
elements (Figure 1), agents aimed against these compo-
Intracellular calcium overload nents of ischemic injury have not been consistently ef-
Changes in intracellular calcium homeostasis play an fective in different clinical trials[2,22]. A number of reasons
important role in the development of reperfusion injury. for the situation have been brought to light[2,7,23,24].
Intracellular calcium release at the time of myocardial A number of pharmacological interventions have
reperfusion is mediated by damage to the sarcolemmal been tried in the clinical setting to prevent myocardial re-
membrane and oxidative stress-induced dysfunction perfusion injury in reperfused-STEMI patients, although
of the sarcoplasmic reticulum. These changes result in the results have been largely disappointing. Moreover,
cardiomyocyte hypercontracture, mitochondrial calcium several pharmacological agents for preventing myocardial
overload and the opening of the mitochondrial perme- reperfusion injury in reperfused-STEMI patients are cur-
ability transition pore[17]. rently being tested in proof-of-principal clinical studies
(Table 1)[9,24].
Complement system
The complement system is activated during reperfusion in- Cyclosporin-A
jury. This contributes to the formation of the anaphylatox- Cyclosporine is known to inhibit the formation and open-
ins C3a, C4a and C5a, as well as the terminal complement ing of the mitochondrial permeability transition pore.
complex, the membrane attack complex, which is depos- In a proof-of-concept clinical trial involving 58 patients,
ited in cell membranes. The complement factors induce cyclosporine administered as a 2.5 mg/kg intravenous
direct cell injury by increasing cell permeability and release bolus at the time of percutaneous coronary intervention
of histamine and platelet activating factor. In addition, was found to reduce the size of the myocardial infarct
complement factors, especially C5a, are potent stimulators compared with placebo. Infarct size was reduced by 40%,
of neutrophil adherence and superoxide production[8]. as measured by creatine kinase release. Evaluation by
magnetic resonance imaging also showed less myocardial
Platelet and neutrophil-mediated injury damage[25,26]. The ongoing CIRCUS study (NCT01502774)
Neutrophils are important for the development of reper- is investigating whether this therapeutic approach can re-
fusion injury by releasing oxygen free radicals, proteases duce patient death, hospitalization for heart failure and a
and pro-inflammatory mediators that further amplify the 15% increase in left ventricular end-diastolic volume.
infiltration of neutrophils into the jeopardized myocar-
dium[18]. Additionally, the hemorrheologic properties of Exenatide
neutrophils contribute to leukocyte entrapment in the Exenatide a new antidiabetic drug, has been shown to
capillaries, leading to microvascular plugging[19]. reduce myocardial infarct size by 23% of area at risk at
Local platelet aggregation and deposition and also mi- 90 d, as assessed by magnetic resonance imaging, when
croembolization are partially responsible for reperfusion given as an intravenous infusion started 15 min prior to
injury, especially in relation to microvascular dysfunc- primary percutaneous coronary intervention and contin-
tion. Reperfusion injury induces platelet activation and ued for 6 h[27,28].
this exacerbates the damage to the myocardium. Platelet
products may exacerbate microcirculatory spasm, lead- Glucose-insulin-potassium
ing to further microvascular congestion, thrombosis and Of all the agents that have been tested reduce myocardial

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 Dominguez-Rodriguez A et al . Cardioprotective agents for myocardial infarction

infarct size or improve acute clinical outcome of STEMI, lus during primary percutaneous coronary intervention
perhaps none is more controversial than glucose-insulin- with an intravenous bolus in patients with STEMI. This
potassium regimen. In the CREATE-ECLA trial, in- large open-label, multicenter trial randomized > 2000
travenous glucose-insulin-potassium infusion for 24 h patients to intracoronary vs intravenous bolus abciximab
was initiated after reperfusion of AMI. This trial had a followed by a 12 h intravenous infusion. The primary
negative outcome since it showed a difference in mortal- composite end point at 90 d (all-cause mortality, recurrent
ity at 30 d[29]. The IMMEDIATE trial has been recently myocardial infarction or new congestive heart failure) was
published. In this trial, the intravenous glucose-insulin- similar in the intracoronary group versus the intravenous
potassium infusion for 12 h was started by paramedics in group. Whereas the incidence of death and reinfarction
the ambulance prior to reperfusion. The composite of did not differ between groups, fewer patients in the intra-
cardiac arrest or in-hospital mortality was lower in 4.4% coronary group developed new congestive heart failure.
of glucose-insulin-potassium patients compared to 8.7% The authors concluded that intracoronary abciximab
in the placebo patients (P = 0.01)[30]. Thus, the use of bolus is safe and might be considered to reduce the rates
glucose-insulin-potassium for AMI remains controversial of congestive heart failure. However, other secondary
and requires further studies. end points in this study, including enzymatic myocardial
infarct size, were negative.
Atrial natriuretic peptide
Kitakaze et al[31] demonstrated that an infusion of car- Erythropoietin
peritide (an atrial natriuretic peptide analogue) during 72 The large REVEAL study showed no reduction of in-
h after reperfusion reduced myocardial infarct size and farct size[38] and several other recent trials were negative
preserved left ventricular ejection fraction in reperfused- for infarct size reduction[39,40].
STEMI patients.
Metoprolol
Adenosine The capacity of -blockers to reduce infarct size was
Two large multicenter studies, AMI Study of Adenosine evaluated extensively in the pre-reperfusion era, with
(AMISTAD) 1 and AMISTAD 2, showed that a high- inconsistent results[41]. In the context of reperfusion as
dose 3-h intravenous infusion of adenosine started near the treatment of choice for STEMI, this has been poorly
the time of reperfusion significantly reduced anterior wall investigated. Experimental data suggest that the -blocker
myocardial infarct size, as determined by nuclear imag- metoprolol may reduce infarct size only when adminis-
ing[32,33]. Other studies, however, were negative. A total tered intravenously before reperfusion[42,43].
of 112 patients with STEMI were randomized to 4 mg Recently, the results have been demonstrated of the
intracoronary adenosine or placebo. There was no benefit Effect of Metoprolol in Cardioprotection During an
of adenosine on myocardial infarct size assessed by mag- AMI trial, the first randomized, clinical trial prospectively
netic resonance imaging at 4 mo[34]. Fokkema et al[35] also evaluating the effect of early intravenous -blockade on
studied the effect of high-dose intracoronary adenosine infarct size in conjunction with primary angioplasty. A
boluses on myocardial infarct size and parameters of total of 270 patients with anterior STEMI (Killip class
myocardial reperfusion. Four hundred and forty-eight pa- or less) revascularized within 6 h after symptom onset
tients with acute STEMI were randomized to placebo or were randomized to receive intravenous metoprolol or
2 bolus injections of intracoronary adenosine. Adenosine not before reperfusion. All patients received oral meto-
did not improve the myocardial infarct size. Thus, the prolol according to clinical guidelines (first dose, 12-24
efficacy of the use of adenosine for AMI remains un- h after infarction). Infarct size, evaluated by magnetic
proven and requires further studies. resonance imaging and creatine kinase release, was signifi-
cantly reduced in the intravenous metoprolol group with
Abciximab no excess side effects. The left ventricular ejection frac-
In a recent study by Stone et al[36], 452 patients presenting tion was higher in the intravenous metoprolol group[44].
within 4 h of STEMI with proximal or mid-left anterior
descending coronary artery occlusion and undergoing Melatonin
percutaneous coronary intervention plus bivalirudin as Melatonin, a circadian endocrine product of the pineal
an anticoagulant were randomized to bolus intracoro- gland, is formed and released predominantly during night
nary abciximab, no abciximab, and to manual aspiration time. Melatonin has a diverse functional repertoire with
thrombectomy versus no thrombectomy in a 2 2 facto- actions in essentially all organs, including the heart and
rial design. The authors concluded that in patients with other portions of the cardiovascular system[45-47]. Melato-
large STEMI undergoing percutaneous coronary inter- nin reduces the pathophysiological mechanisms that are
vention with bivalirudin, the addition of intracoronary involved in these benefits, in part due to the detoxifica-
abciximab bolus significantly reduced myocardial infarct tion myocardial reperfusion injury, with respect to radical
size. Not all recent clinical trials with abciximab have oxygen species and radical of oxygen and nitrogen-based
been positive. reactants melatonin and its metabolites[48,49]. Moreover,
Thiele et al[37] compared intracoronary abciximab bo- melatonin has indirect beneficial effects by increasing the

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 Dominguez-Rodriguez A et al . Cardioprotective agents for myocardial infarction

activity of principal antioxidant enzymes[50]. Recent data failure, particular attention must be paid to proper selec-
also suggest that the mechanism of protection of mela- tion of patients (who will benefit the most), application
tonin appears to involve, at least in part, the inhibition (relevant concentration in the early phase of reperfusion)
of mitochondrial permeability transition pore opening and hard end points.
via prevention of cardiolipin peroxidation[51]. The lack of
these cardioprotective effects due to insufficient high en-
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P- Reviewers: Berenguer AB, Izawa KB S- Editor: Qi Y

L- Editor: Roemmele A E- Editor: Liu SQ

WJC|www.wjgnet.com 106 March 26, 2014|Volume 6|Issue 3|