Radhouane Bousselmi a,b,⇑, Mohamed Anis Lebbi a,b, Mustapha Ferjani a,b
a
b
Department of Cardiovascular Anaesthesia and Critical Care, Military Hospital of Tunis
Faculty of Medicine, University of Tunis, El Manar
a,b
Tunisia
Ischemia–reperfusion is a major determinant of myocardial impairment in patients undergoing cardiac surgery. The
main goal of research in cardioprotection is to develop effective techniques to avoid ischemia–reperfusion lesions.
Myocardial ischemic conditioning is a powerful endogenous cardioprotective phenomenon. First described in animals
in 1986, myocardial ischemic conditioning consists of applying increased tolerance of the myocardium to sustained
ischemia by exposing it to brief episodes of ischemia–reperfusion. Several studies have sought to demonstrate its
effective cardioprotective action in humans and to understand its underlying mechanisms. Myocardial ischemic
conditioning has two forms: ischemic preconditioning (IPC) when the conditioning stimulus is applied before the
index ischemia and ischemic postconditioning when the conditioning stimulus is applied after it. The cardioprotective
action of ischemic conditioning was reproduced by applying the ischemia–reperfusion stimulus to organs remote from
the heart. This non-invasive manner of applying ischemic conditioning has led to its application in clinical settings.
Clinical trials for the different forms of ischemic conditioning were mainly developed in cardiac surgery. Many studies
suggest that this phenomenon can represent an interesting adjuvant to classical cardioprotection during on-pump
cardiac surgery. Ischemic conditioning was also tested in interventional cardiology with interesting results. Finally,
advances made in the understanding of mechanisms that underlie the cardioprotective action of ischemic conditioning
have paved the way to a new form of myocardial conditioning which is pharmacological conditioning.
Ó 2013 King Saud University. Production and hosting by Elsevier B.V. All rights reserved.
Keywords: Ischemia–reperfusion injury, Ischemic preconditioning, Ischemic postconditioning, Remote ischemic
preconditioning, Cardiac surgery
Disclosure: Authors have nothing to disclose with regard to
commercial support.
Received 28 August 2013; revised 3 October 2013; accepted 3 November
2013.
Available online 13 November 2013
⇑ Corresponding author. Tel.: +216 22 622 495.
E-mail address: [email protected] (R. Bousselmi).
P.O. Box 2925 Riyadh – 11461KSA
Tel: +966 1 2520088 ext 40151
Fax: +966 1 2520718
Email: [email protected]
URL: www.sha.org.sa
1016–7315 Ó 2013 King Saud University. Production and hosting by Elsevier B.V. All rights reserved.
Peer review under responsibility of King Saud University.
URL: www.ksu.edu.sa
http://dx.doi.org/10.1016/j.jsha.2013.11.001
Production and hosting by Elsevier
REVIEW ARTICLE
Myocardial ischemic conditioning:
Physiological aspects and clinical
applications in cardiac surgery
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2014;26:93–100
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Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Physiological aspects of ischemic conditioning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Ischemic preconditioning (IPC) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Remote ischemic preconditioning (RIPC) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Ischemic postconditioning – remote ischemic postconditioning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Clinical applications of myocardial ischemic conditioning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Ischemic preconditioning (IPC) in cardiac surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Remote ischemic preconditioning (RIPC) in cardiac surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Ischemic postconditioning in cardiac surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Other clinical applications of myocardial ischemic conditioning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
From ischemic conditioning to pharmacological conditioning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Introduction
P
ostoperative myocardial dysfunction is still
common in patients undergoing cardiac surgery [1,2]. It is one of the leading causes of postoperative morbidity and mortality. Ischemia–
reperfusion injury is the most decisive factor in
myocardial impairment in such patients. Developing new strategies to reduce ischemia–reperfusion
injury is currently one of the main goals of research in cardioprotection. In this context, myocardial ischemic conditioning has recently been
proposed as an interesting adjuvant to classical
cardioprotection during cardiac surgery. Myocardial ischemic conditioning is a powerful endogenous cardioprotective phenomenon. It was first
described in animals in 1986 [3]. During the last
thirty years, myocardial ischemic conditioning
has been the subject of much research concerning
both its underlying mechanisms and its clinical
applications. Several clinical trials in cardiac surgery and interventional cardiology have therefore
sought to demonstrate its effectiveness in clinical
settings.
The aim of this article is to review the different
types of myocardial ischemic conditioning, its
underlying mechanisms, and its clinical applications in cardiac surgery.
Physiological aspects of ischemic
conditioning
Ischemic preconditioning (IPC)
In 1986, Murry et al. [3]. discovered that by applying 40 min of occlusion of the circumflex coronary
artery in dogs, the myocardial infarct size resulting
from this sustained ischemia was reduced by 75% if
the dogs were previously exposed to brief episodes
of ischemia–reperfusion. Ischemia–reperfusion
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Abbreviations
IPC
RIPC
mPTP
mKATP
ischemic preconditioning
remote ischemic preconditioning
mitochondrial permeability transition pore
mitochondrial ATP-dependent potassium
channels
consisted of four five-minute cycles of intermittent
occlusion of this same coronary artery. This ability
of the myocardium to tolerate sustained ischemia
after short episodes of ischemia–reperfusion was
named ischemic preconditioning (IPC). This
powerful cardioprotective phenomenon was found
thereafter in all species including humans [4].
During IPC, protection occurs in two phases. An
early phase of protection, known as classical ischemic preconditioning, begins immediately after the
preconditioning stimulus and lasts for 2–4 h. A delayed phase of protection begins after 12–24 h, lasts
2–3 days, and is known as the second window of
protection [5]. The classical ischemic preconditioning likely involves preformed factors. It has a powerful protective effect against myocardial necrosis
but does not protect against stunning [6]. The
second window of protection is likely related to
the synthesis of neoformed factors. It protects
against myocardial stunning but is less effective
against necrosis [6].
Ischemic preconditioning involves several factors that are usually divided into three groups:
triggers, mediators, and effectors. The signaling
pathways are complex and not yet fully understood. Brief episodes of ischemia result in the
release of initiating factors such as adenosine,
bradykinin, and endorphins [7].
During the early phase, these initiators bind to
their specific receptors coupled to G proteins
resulting in message transduction. Two signaling
BOUSSELMI ET AL
MYOCARDIAL ISCHEMIC CONDITIONING IN CARDIAC SURGERY
pathways have been identified. The RISK pathway
(Reperfusion-Induced Salvage Kinase) [8], involves the Phosphatidylinositol 3-Kinase (PI3-Kinase) [9,10], the protein kinase Akt [11], and the
extracellular signal-regulated kinase ½ (ERK ½)
[12]. These kinases activate glycogen synthetase
kinase 3b (GSK-3b), which leads to inhibiting
the opening of the mitochondrial permeability
transition pore (mPTP) [13]. The survivor activating factor enhancement (SAFE) pathway which involves the TNFa and the signal transducer and
activator of transcription-3 (STAT-3) [14], also
leads to inhibition of the mPTP opening. The
mPTP is the main effector of preconditioning. Its
opening causes the shutdown of ATP production,
mitochondrial swelling, and likely cell-membrane
rupture [15]. Other kinases are activated such as
the protein kinase C [16] and the protein kinase
G [17], and are responsible for the activation of
mitochondrial ATP-dependent potassium channels (mKATP) which are also likely effectors of
ischemic preconditioning [18,19].
During the second window of protection, mechanisms are different from those of the early phase
[20]. After the initial stages of receptor activation
coupled to G proteins and various signaling pathways (protein kinase C, protein kinase G, mKATP),
the activation of transcription factors occurs: specifically, the nuclear factor kb (NF-kb) [21]. This induces the expression of several proteins that
provide myocardial protection such as NO synthase (iNOS) [22], cyclooxygenase 2 (COX-2) [23],
and anti-apoptotic proteins [24].
Remote ischemic preconditioning (RIPC)
In 1993, Przyklenk et al. discovered a new form
of myocardial ischemic conditioning in dogs. They
demonstrated that prior application of four fiveminute cycles of ischemia–reperfusion on the circumflex coronary artery is able to significantly reduce the infarct size caused by sustained
occlusion of the left anterior descending coronary
artery [25]. It was subsequently shown that this
cardioprotective phenomenon is universal, and
can be provided by applying ischemia–reperfusion episodes in organs remote from the heart
such as the kidney [26], or the mesentery [27]. This
new form of myocardial ischemic conditioning
was called remote ischemic preconditioning
(RIPC). Applying this phenomenon to humans
was possible after discovering that the RIPC effect
is reproducible after inflating–deflating a cuff
placed around the limbs; in this case, a non-invasive method to trigger ischemia–reperfusion episodes in remote organs and muscles [28,29].
95
The mechanisms underlying cardioprotection induced by remote ischemic preconditioning are similar to those described for classical ischemic
preconditioning [30]. But the pathway that links remote organs, on which the preconditioning stimulus is applied, to the heart remains unclear. Three
theories were advanced. The first one involves
humoral factors, the second one involves a neural
pathway, and the third one a systemic response.
The humoral theory is supported by a study that
found that the blood taken from a previously
preconditioned rabbit can reduce the myocardial
infarct size when it is transferred to a non-preconditioned rabbit [31]. Another experimental study
showed that remote ischemic preconditioning applied to pigs with a denervated transplanted heart
can reduce myocardial infarct size [32]. The neural
theory was advanced after finding that hexamethonium, which is a ganglionic blocker, can cancel the
cardioprotective effect of ischemia–reperfusion
applied to the mesenteric artery [27]. Finally, the
systemic response theory is supported by studies
suggesting that RIPC promotes the transcription
of the anti-inflammatory gene [33].
Ischemic postconditioning – remote ischemic
postconditioning
In 2003, Zhao et al. found that applying brief
episodes of ischemia–reperfusion immediately
after a sustained occlusion of a coronary artery
in dogs is as cardioprotective as ischemic preconditioning [34]. The authors showed that the interruption of reperfusion for three 90-s cycles
immediately after a sustained occlusion of a coronary artery reduces myocardial infarct size by
50%. This phenomenon became known as ischemic postconditioning and was later found to occur
in all animal species [35–39]. Two years later,
Kerendi et al. demonstrated that ischemic postconditioning is reproducible by applying the postconditioning stimulus on organs remote from the
heart [40]. They were able to reduce the myocardial infarct size by nearly 50% in rats after a sustained occlusion of a coronary artery when 5 min
of ischemia–reperfusion was applied to the renal
artery at the time of reperfusion. This was called
remote ischemic postconditioning, and its reproducibility – by simple inflation–deflation of a cuff
placed around the limb – has been demonstrated
[41]. This paved the way for its non-invasive application in humans. The underlying mechanisms of
ischemic postconditioning are very similar to
those described for ischemic preconditioning.
After a sustained ischemia, sudden reperfusion
causes myocardial injuries by multiple mecha-
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nisms: generation of reactive oxygen species,
endothelium dysfunction, neutrophil accumulation, and loss of calcium homeostasis. Ischemic
postconditioning contributes to reducing these
injuries. It involves initiators (adenosine, bradykinin, opioids) and their receptors coupled to G proteins. Signaling pathways are complex and involve
at least the reperfusion-induced salvage kinase
pathway, protein kinase C and the JAK–STAT
pathway (Janus kinase–signal transducer and activator of transcription). Effectors are mainly represented by the mPTP (mitochondrial permeability
transition pore), the mKATP (mitochondrial ATPdependent potassium channel) and ROS (reactive
oxygen species) [42].
Clinical applications of myocardial ischemic
conditioning
Ischemic preconditioning (IPC) in cardiac surgery
Yellon et al. were the first to find a cardioprotective effect of IPC in humans [4]. In a randomized
controlled trial, they demonstrated that the application of two three-minute episodes of clamping
the ascending aorta, followed each time by 2 min
of declamping improves ATP levels in the myocardium after on-pump coronary artery bypass grafting. Many clinical trials were subsequently
performed in coronary artery bypass grafting and
valvular surgery. The preconditioning stimulus
was almost the same, consisting of brief episodes
of clamping–declamping the ascending aorta after
starting cardiopulmonary bypass and before any
other cardioprotection. The primary endpoint was
variable across studies, ranging between myocardial ATP levels [4,43], blood markers of myocardial
necrosis (CK-MB and troponin) [44–47], ventricular
arrhythmias [48] and the left ventricular contractile
function [49,50]. In 2008, a meta-analysis compiled
22 randomized controlled trials including 933 patients over 10 years. The conclusion was that ischemic preconditioning applied to cardiac surgery
significantly reduces postoperative ventricular
arrhythmias, the inotropic support, and the intensive care unit stay when it is associated with intraoperative myocardial protection by cardioplegia
[51]. But these studies were heterogeneous in relation to their endpoints, and most of them were
made to demonstrate the phenomenon of ischemic
preconditioning in humans and not to evaluate its
effects on prognosis. The high rate of neurologic
complications resulting from a risk increase in
embolic accidents during the manipulation of the
ascending aorta [52], and the emergence of RIPC,
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which is much less invasive than IPC, led to the
surrender of this technique.
Remote ischemic preconditioning (RIPC) in
cardiac surgery
The discovery that RIPC is reproducible after
application of ischemia–reperfusion by simple
inflation–deflation of a cuff placed around the
limbs was a turning point in the clinical application of this cardioprotective phenomenon [29].
The first clinical trial in humans was negative. In
2000, Gunaydin et al. found no difference in the
CK-MB levels between two groups of patients
undergoing CABG of which one was preconditioned with two cycles of ischemia–reperfusion
in the upper limb [53]. However, the size of groups
was very small (four patients in each group), and
ischemia–reperfusion cycles were very short (only
two episodes of three-minute ischemia followed
each time by 2 min of reperfusion). Thereafter, it
took 6 years for clinical trials to reappear with
Cheung et al. [54]. The authors randomized 37
children scheduled for surgical repair of congenital heart defects. Seventeen children were included in the RIPC group and received four fiveminute cycles of ischemia–reperfusion achieved
by inflation–deflation of a cuff placed on the lower
limb. Twenty children were included in the control group. The postoperative levels of troponin I
and the postoperative inotropic requirement were
significantly higher in the control group. It was the
first study to demonstrate the cardioprotective effect of RIPC in humans. RIPC has subsequently
been the subject of several clinical trials in cardiac
surgery. In 2011, a meta-analysis compiled nine
randomized controlled trials including 482 patients [55]. The conclusions were that RIPC reduces postoperative myocardial injury, but is not
associated with either a reduction in early postoperative mortality or with a reduction in the incidence of postoperative myocardial infarction.
However, large multicentre studies are needed
to determine the benefit of RIPC in clinical
settings.
Ischemic postconditioning in cardiac surgery
The possibility of administering the conditioning stimulus after the onset of index ischemia
has aroused a lot of interest, especially in interventional cardiology where the sudden installation of acute coronary syndromes leaves no time
to prior preconditioning. Ischemic postconditioning has therefore been more developed in interventional cardiology. In cardiac surgery, only
three clinical trials from the same team evaluated
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the interest of ischemic postconditioning on myocardial protection against ischemia–reperfusion
injury [56–58]. The first clinical trial was performed on children scheduled for surgical repair
of Tetralogy of Fallot [56]. The postconditioning
stimulus consisted of two 30-s cycles of clamping
the ascending aorta, followed each time by 30 s
of declamping it just before the cessation of cardiopulmonary bypass. The results were positive.
In fact, the levels of troponin I and CK-MB and
the postoperative inotropic requirement were significantly lower in the group that had postconditioning stimulus compared to the control group.
This was confirmed by a clinical trial performed
on adults undergoing valve replacement [57],
and also in another clinical trial on children
undergoing congenital heart disease repair [58].
But clamping–declamping the ascending aorta
was associated with a high risk of embolic accidents especially in adults with atherosclerotic lesions of the aortic wall. This partly explains the
paucity of clinical trials in cardiac surgery.
Other clinical applications of myocardial ischemic
conditioning
In some clinical trials, remote ischemic preconditioning was applied in interventional cardiology.
It was done in patients scheduled for elective percutaneous coronary intervention. Their results
were interesting [59,60]. Ischemic postconditioning, however, seems more suitable to interventional cardiology since it can be done without
predicting the occurrence of ischemia. Postconditioning stimulus consists of short cycles of inflation–deflation of a balloon in the occluded
coronary artery before removal of occlusion. In
2010, a meta-analysis compiled six randomized
controlled trials that evaluated the effect of ischemic postconditioning on 244 patients with ST-elevation acute coronary syndrome treated with
percutaneous coronary intervention [61]. The results demonstrated an effective cardioprotective
effect of ischemic postconditioning. The rates of
CK-MB were significantly lower and the left ventricular ejection fraction was significantly better
in patients who underwent postconditioning compared to control patients. The effect on prognosis
requires larger trials.
From ischemic conditioning to
pharmacological conditioning
Advances in the understanding of the physiological mechanisms underlying the cardioprotective action of different forms of myocardial
97
ischemic conditioning have led to numerous studies that seek to develop pharmacological agents
able to reproduce this action. Several animal studies have demonstrated the ability to mimic the effects of ischemic preconditioning by agonists of A1
and A3 adenosine receptors [62,63]. Other studies
were able to reproduce the cardioprotective action
by d opioids [64,65]. In humans, it has been demonstrated that nicorandil, acting on mitochondrial
KATP channel, is able to provide a cardioprotective
effect in patients with coronary artery disease
[66,67]. Also, several clinical trials in cardiac surgery showed that volatile anesthetics have a preconditioning effect on the myocardium [68–75]. A
recent meta-analysis compiled 22 clinical trials in
cardiac surgery including 1922 patients randomized into two groups, one receiving total intravenous anesthesia (TIVA) and the other volatile
anesthetics (sevoflurane or desflurane) [76]. The
use of volatile anesthetics resulted in a significant
reduction in the incidence of postoperative myocardial infarction and a significant reduction in
in-hospital mortality. Similarly, the troponin levels, the postoperative inotropic requirements, the
intensive care unit stay, and the duration of
mechanical ventilation were significantly lower
with volatile anesthetics.
Despite the existence of clinical trials that demonstrate the cardioprotective effect of several
molecules, the adoption of pharmacological conditioning in clinical practice requires larger studies
to better understand its underlying mechanisms
and validate its daily use.
Conclusion
Since its discovery in 1986, myocardial ischemic
conditioning has attracted much interest. Despite
the large number of studies related to this phenomenon, its underlying mechanisms remain
incompletely understood. Also, clinical trials in
humans are mostly proof-of-concept studies.
Large multicenter studies evaluating prognostic
data are necessary to validate the use of this cardioprotective method in clinical settings.
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