A Skyschally

Andreas Skyschally

C Piot

DJ Hausenloy

G Heusch

Gerd Heusch

L Argaud

P Ferdinandy

P Staat

Rainer Schulz

SY Lim

English

PubMed

Crossref

Cyclosporine A at Reperfusion Reduces Infarct Size in Pigs

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LETTER TO THE EDITOR
Cyclosporine A at Reperfusion Reduces Infarct Size in Pigs
Andreas Skyschally & Rainer Schulz & Gerd Heusch
Published online: 25 February 2010
# The Author(s) 2010. This article is published with open access at Springerlink.com
Key words Cyclosporine A . Infarct size .
Ischemia/reperfusion . Ischemic postconditioning .
Myocardial infarction . Reperfusion injury
Timely reperfusion is mandatory for salvage of ischemic
myocardium from irreversible damage. However, reperfu-
sion induces damage per se, i.e. reperfusion injury contrib-
utes to final infarct size [1]. Ischemic postconditioning, i.e.
brief episodes of intermittent coronary re-occlusion during
early reperfusion, reduces infarct size. This protective effect
was confirmed in all species tested so far [2], including
humans [3], but common co-morbidities of ischemic heart
disease may interfere with cardioprotective mechanisms
including ischemic postconditioning [4].
The signal transduction of ischemic postconditioning is
still unclear in detail [5]. Activation of “reperfusion injury
salvage kinases” (RISK) is causal for ischemic postcondi-
tioning’s protection in rodents [6]. In pigs, in which
coronary anatomy and the spatial and temporal develop-
ment of myocardial infarction are closer to that of humans,
RISK activation is not mandatory for protection [7].
The mitochondrial permeability transition pore
(mPTP) is a potential end-effector of myocardial protec-
tion at reperfusion [8–10]. Cyclosporine A binds to
cyclophilin D, inhibits mPTP opening and reduces infarct
size [9, 11]. Apart from experiments in rodents, cyclo-
sporine A when given at reperfusion reduced infarct size
in a proof-of-concept study in patients with acute
myocardial infarction [12].
Protection by cyclosporine A at reperfusion was now
tested in pigs. Enflurane-anesthetized Göttinger minipigs
(20–40 kg body weight) of either sex were subjected to
90 min controlled hypoperfusion of the left anterior
descending coronary artery and 120 min reperfusion [7].
In four pigs cyclosporine A (5 mg/kg i.v.) was infused
5 min before reperfusion; in four pigs, ischemic postcondi-
tioning was induced with six cycles of 20 s re-occlusion/
reperfusion each; four pigs with immediate full reperfusion
served as controls. Systemic hemodynamics (Table 1) and
subendocardial blood flow during ischemia (microspheres)
were matched between groups (Fig. 1). Both, cyclosporine
A at reperfusion and ischemic postconditioning reduced
infarct size (TTC staining) to a similar extent compared to
controls (Fig. 1).
Whereas pigs differ from rodents with respect to the
causal role of RISK in ischemic postconditioning, they
share with both rodents and importantly also humans
protection by cyclosporine A at reperfusion, suggesting an
important role for mitochondrial permeability transition
pore opening across all species.
Supported by the German Research Foundation (He 1320/18-1).
A. Skyschally :R. Schulz :G. Heusch (*)
Institut für Pathophysiologie, Universitätsklinikum Essen,
Hufelandstraße 55,
45122 Essen, Germany
e-mail: gerd.heusch@uk-essen.de
Cardiovasc Drugs Ther (2010) 24:85–87
DOI 10.1007/s10557-010-6219-y
Table 1 Systemic hemodynamics
HR [1/min] LVPmax [mmHg] dPdtmax [mmHg/s] CAPmean [mmHg] CBFmean [ml/min]
Cyclosporine A Baseline 99±7 94±7 1330±68 112±5 22.5±2.8
Isch5 100±6 79±3 959±55 20±3* 1.9±0.1*
Isch85 97±5 77±6* 925±45 20±2* 1.9±0.1*
Rep10 91±4 68±7* 796±108 102±4 66.1±8.9*
Rep30 108±7 72±8* 1060±203 105±1 61.4±10.9*
Rep60 115±7 70±6* 946±117 105±3 54.8±7.2*
Rep120 119±10 65±7* 946±111 103±5 54.1±7.7*
Postconditioning Baseline 100±9 96±3 1446±36 122±6 24.6±3.1
Isch5 112±11 77±7* 997±59 22±2* 2.9±0.6*
Isch85 105±9 77±3* 1112±46 24±2* 2.9±0.6*
Rep10 109±8 76±5* 1383±103 109±6 74.2±9.3*
Rep30 113±8 76±3* 1377±79 111±4 66.1±8.0*
Rep60 113±11 69±12* 1380±416 122±4# 65.8±10.9*
Rep120 125±12 69±5* 1364±259 115±7 59.1±14.7*
Immediate full reperfusion Baseline 93±6 103±2 1294±52 122±5 24.3±2.6
Isch5 98±10 82±2* 1039±87 23±2* 2.8±0.4*
Isch85 94±7 85±4* 1178±45 23±1* 2.8±0.4*
Rep10 95±7 76±5* 1101±173 111±7 57.6±9.0*
Rep30 103±12 72±6* 1278±183 106±4* 53.5±7.9*
Rep60 118±16 73±2* 1432±111 110±1 55.1±9.4*
Rep120 116±15 61±3* 1222±174 118±9# 67.1±16.8*
Isch5/85: 5/85 min ischemia; Rep10/30/60/120: 10/30/60/120 min reperfusion; HR: heart rate; LVPmax: maximal left ventricular pressure;
dPdtmax: maximum in the first derivative of LVP; CAPmean: mean coronary arterial pressure; CBFmean: mean coronary blood flow; means±SEM;
*p<0.05 vs. Baseline; # p<0.05 vs. Cyclosporine A; two-way-ANOVA with Fisher’s LSD post-hoc tests.
0
10
20
30
40
In
fa
rc
ts
iz
e
(%
 A
AR
)
Immediate full
reperfusion
0.029±0.004
Subendocardial blood
flow during ischemia
[ml·min-1·g-1]
Cyclosporine A
0.029±0.003
Postconditioning
0.030±0.004
p < 0.05p < 0.05
Fig. 1 Infarct size with
cyclosporine A given at
reperfusion, postconditioning,
and immediate full reperfusion;
means±SEM; AAR: area at risk;
ANOVA with Fisher’s LSD
post-hoc tests
86 Cardiovasc Drugs Ther (2010) 24:85–87
Open Access This article is distributed under the terms of the
Creative Commons Attribution Noncommercial License which per-
mits any noncommercial use, distribution, and reproduction in any
medium, provided the original author(s) and source are credited.
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Cardioprotection: nitric oxide, protein kinases, and mitochondria.

Effect of cyclosporine on reperfusion injury in acute myocardial infarction.

Inhibition of mitochondrial permeability transition pore opening: the holy grail of cardioprotection. Basic Res Cardiol.

Interaction of cardiovascular risk factors with myocardial ischemia/reperfusion injury, preconditioning, and postconditioning. Pharmacol Rev.

Ischemic postconditioning in pigs: no causal role for RISK activation. Circ Res.

Ischemic postconditioning— experimental models and protocol algorithms. Basic Res Cardiol.

Old wine in a new bottle?

Postconditioning inhibits mitochondrial permeability transition.

Postconditioning the human heart.

Preconditioning and postconditioning: the essential role of the mitochondrial permeability transition pore. Cardiovasc Res.

Reperfusion injury salvage kinase signalling: taking a RISK for cardioprotection. Heart Fail Rev.

Specific inhibition of the mitochondrial permeability transition prevents lethal reperfusion injury.

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Cyclosporine A at Reperfusion Reduces Infarct Size in Pigs

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