Zusammenfassung
In der Kardiologie ist das schnelle interventionelle Wiedereröffnen akut verschlossener
Koronargefäße heute die wirksamste Therapie, um einen drohenden Herzinfarkt einzugrenzen.
Die Frühphase der Reperfusion ist als therapeutisches Fenster aber klinisch noch weitgehend
ungenutzt. Experimentell ist klar belegt, dass die Modalitäten der Reperfusion einen
wesentlichen Einfluss auf die Infarktgröße haben, da Reperfusion selbst auch Gewebsschädigung
herbeiführen kann (Reperfusionsschaden). Wichtigster Auslöser für den durch Reperfusion
akut ausgelösten Zellschaden ist die Hyperkontraktur der Herzmuskelzellen. Zytosolische
Ca2+-Überladung und Fehlfunktionen der Zellorganellen sarkoplasmatisches Retikulum und
Mitochondrien bestimmen die Pathophysiologie des Reperfusionsschadens. Diese Mechanismen
können in den ersten Minuten der Reperfusion durch Aktivierung protektiver zellulärer
Signalwege beeinflusst werden (Reperfusionstherapie). Erste klinische Studien belegen
die Wirksamkeit einer akuten Reperfusionstherapie.
Summary
Rapid interventional restoration of coronary blood flow is the most effective therapy
to limit infarct size in todayŽs cardiology. The early phase of reperfusion represents,
however, a window of therapeutic opportunities largely unused in the clinic. Experimentally
it has been clearly shown that the modalities of reperfusion have a substantial impact
on infarct size, since reperfusion itself can damage the myocardium (reperfusion injury).
The major cause for acute injury of the cardiomyocytes in reperfusion is their hypercontracture.
Cytosolic Ca2+ overload and malfunction of cell organelles, i. e. sarcoplasmic reticulum and mitochondria,
determine the pathophysiology of reperfusion injury. The underlying mechanisms can
be influenced in the first minutes of reperfusion by activation of protective signalling
pathways (reperfusion therapy). First clinical studies confirm the efficacy of acute
reperfusion therapy.
Schlüsselwörter
Myokardinfarkt - Reperfusionsschaden - Myokardprotektion - Mitochondrien - Calcium
Key words
myocardial infarction - reperfusion injury - myocardial protection - mitochondria
- calcium
Literatur
- 1
Abdallah Y, Gkatzoflia A, Pieper H. et al .
Mechanism of cGMP-mediated protection in a cellular model of myocardial reperfusion
injury.
Cardiovasc Res.
2005;
66
(1)
123-131
- 2
Abdallah Y, Gkatzoflia A, Gligorievski D. et al .
Insulin protects cardiomyocytes against reoxygenation-induced hypercontracture by
a survival pathway targeting SR Ca2+ storage.
Cardiovasc Res.
2006;
70
(2)
346-53
- 3
Argaud L, Gateau-Roesch O, Raisky O, Loufouat J, Robert D, Ovize M.
Postconditioning inhibits mitochondrial permeability transition.
Circulation.
2005;
111
194-197
- 4
Baines C P, Kaiser R A, Purcell N H. et al .
Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition
in cell death.
Nature.
2005;
434
658-662
- 5
Bernardi P, Krauskopf A, Basso E. et al .
The mitochondrial permeability transition from in vitro artifact to disease target.
FEBS J.
2006;
273
2077-2099
- 6 Bhamra G S, Hausenloy D J, Davidson S M. et al .Metformin protects the ischemic
heart by the Akt-mediated inhibition of mitochondrial permeability transition pore
opening. Basic Res Cardiol 2007 Dec 13 [Epub ahead of print]
- 7
Bopassa J C, Ferrera R, Gateau-Roesch O, Couture-Lepetit E, Ovize M.
PI 3-kinase regulates the mitochondrial transition pore in controlled reperfusion
and postconditioning.
Cardiovasc Res.
2006;
69
(1)
178-185
- 8
Di Lisa F, Menabo R, Canton M, Barile M, Bernardi P.
Opening of the mitochondrial permeability transition pore causes depletion of mitochondrial
and cytosolic NAD+ and is a causative event in the death of myocytes in postischemic
reperfusion of the heart.
J Biol Chem.
2001;
276
2571-2575
- 9
Ganote C E.
Contraction bands necrosis and irreversible myocardial injury.
J Mol Cell Cardiol.
1983;
15
67-73
- 10
Garcia-Dorado D, Theroux P, Desco M. et al .
Cell-to-cell interaction: a mechanism to explain wave-front progression of myocardial
necrosis.
Am J Physiol.
1989;
256
H1266-H1273
- 11
Garcia-Dorado D, Theroux P, Duran J M. et al .
Selective inhibition of the contractile apparatus. A new approach to modification
of infarct size, infarct composition, and infarct geometry during coronary artery
occlusion and reperfusion.
Circulation.
1992;
85
1160-1174
- 12
Garcia-Dorado D, Gonzalez M A, Barrabes J A. et al .
Prevention of ischemic rigor contracture during coronary occlusion by inhibition of
Na(+)-H+ exchange.
Cardiovasc Res.
1997;
35
80-89
- 13
Garcia-Dorado D, Inserte J, Ruiz-Meana M. et al .
Gap junction uncoupler heptanol prevents cell-to-cell progression of hypercontracture
and limits necrosis during myocardial reperfusion.
Circulation.
1997;
96
3579-3586
- 14
Gomez L, Thibault H, Gharib A. et al .
Inhibition of mitochondrial permeability transition improves functional recovery and
reduces mortality following acute myocardial infarction in mice.
Am J Physiol Heart Circ Physiol.
2007;
293
(3)
H1654-61
- 15
Griffiths E J, Halestrap A P.
Mitochondrial non-specific pores remain closed during cardiac ischaemia, but open
upon reperfusion.
Biochem J.
1995;
307
93-98
- 16
Halestrap A P, Clarke S J, Javadov S A.
Mitochondrial permeability transition pore opening during myocardial reperfusion -
a target for cardioprotection.
Cardiovasc Res.
2004;
61
372-385
- 17
Hausenloy D J, Yellon D M.
New directions for protecting the heart against ischaemia-reperfusion injury: targeting
the Reperfusion Injury Salvage Kinase (RISK)-pathway.
Cardiovasc Res.
2004;
61
(3)
448-460
- 18
Hausenloy D J, Tsang A, Yellon D M.
The reperfusion injury salvage kinase pathway: a common target for both ischemic preconditioning
and postconditioning.
Trends Cardiovasc Med.
2005;
15
69-75
- 19
Inserte J, Garcia-Dorado D, Ruiz-Meana M. et al .
Effect of inhibition of Na(+)/Ca(2+) exchanger at the time of myocardial reperfusion
on hypercontracture and cell death.
Cardiovasc Res.
2002;
55
739-748
- 20
Inserte J, Garcia-Dorado D, Hernando V, Soler-Soler J.
Calpain-mediated impairment of Na+/K+-ATPase activity during early reperfusion contributes
to cell death after myocardial ischemia.
Circ Res.
2005;
97
465-473
- 21
Juhaszova M, Zorov D B, Kim S H. et al .
Glycogen synthase kinase-3beta mediates convergence of protection signaling to inhibit
the mitochondrial permeability transition pore.
J Clin Invest.
2004;
113
(11)
1535-1549
- 22
Kin H, Zhao Z Q, Sun H Y. et al .
Postconditioning attenuates myocardial ischemia-reperfusion injury by inhibiting events
in the early minutes of reperfusion.
Cardiovasc Res.
2004;
62
74-85
- 23
Kitakaze M, Asakura M, Shintani Y. et al .
Large-scale trial using natriuretic peptide or nicorandil as an adjunct to percutaneous
coronary intervention for ST-segment elevation acute myocardial infarction.
Circulation.
2006;
114
2425-2426
- 24
Kitakaze M, Asakura M, Kim J. et al .
Human atrial natriuretic peptide and nicorandil as adjuncts to reperfusion treatment
for acute myocardial infarction (J-WIND): Two randomised trials.
Lancet.
2007;
370
(9597)
1483-1492
- 25
Klein H H, Pich S, Bohle R M. et al .
Na(+)/H(+) exchange inhibitor cariporide attenuates cell injury predominantly during
ischemia and not at onset of reperfusion in porcine hearts with low residual blood
flow.
Circulation.
2000;
102
1977-1982
- 26
Kuga H, Ogawa K, Oida A. et al .
Administration of atrial natriuretic peptide attenuates reperfusion phenomena and
preserves left ventricular regional wall motion after direct coronary angioplasty
for acute myocardial infarction.
Circ J.
2003;
67
443-448
- 27
Ladilov Y V, Siegmund B, Piper H M.
Protection of reoxygenated cardiomyocytes against hypercontracture by inhibition of
Na+/H+ exchange.
Am J Physiol.
1995;
268
H1531-H1539
- 28
Ladilov Y, Haffner S, Balser-Schäfer C, Maxeiner H, Piper H M.
Cardioprotective effects of KB-R7943: a novel inhibitor of the reverse mode of Na+/Ca2+
exchanger.
Am J Physiol.
1999;
276
H1868-76
- 29
Ladilov Y, Efe O, Schäfer C. et al .
Reoxygenation-induced rigor-type contracture.
J Mol Cell Cardiol.
2003;
35
1481-1490
- 30
Lim S Y, Davidson S M, Hausenloy D J, Yellon D M.
Preconditioning and postconditioning: the essential role of the mitochondrial permeability
transition pore.
Cardiovasc Res.
2007;
75
(3)
530-535
- 31
Liu J, Marchase R B, Chatham J C.
Increased O-GlcNAc levels during reperfusion lead to improved functional recovery
and reduced calpain proteolysis.
Am J Physiol Heart Circ Physiol.
2007;
293
(3)
H1391-9
- 32
Ma X, Zhang X, Li C, Luo M.
Effect of postconditioning on coronary blood flow velocity and endothelial function
and LV recovery after myocardial infarction.
J Interv Cardiol.
2006;
19
(5)
367-375
- 33
Nakagawa T, Shimizu S, Watanabe T. et al .
Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic
but not apoptotic cell death.
Nature.
2005;
434
652-658
- 34
Nichols C G, Lederer W J.
The role of ATP in energydeprivation contractures in unloaded rat ventricular myocytes.
Can J Physiol Pharmacol.
1990;
68
183-194
- 35
Park S S, Zhao H, Mueller R A, Xu Z.
Bradykinin prevents reperfusion injury by targeting mitochondrial permeability transition
pore through glycogen synthase kinase 3beta.
J Mol Cell Cardiol.
2006;
40
(5)
708-16
- 36
Piper H M, Kasseckert S, Abdallah Y.
The sarcoplasmic reticulum as the primary target of reperfusion protection.
Cardiovasc Res.
2006;
70
170-173
- 37 Piper H M, Abdallah Y, Kasseckert S, Schlüter K D. Sarcoplasmic reticulum mitochondrial
interaction in the mechanism of acute reperfusion injury. Cardiovasc Res 2007 Dec
18 [Epub ahead of print]
- 38
Rodriguez-Sinovas A, Abdallah Y, Piper H M, Garcia-Dorado D.
Reperfusion injury as a therapeutic challenge in patients with acute myocardial infarction.
Heart Fail Rev.
2007;
12
207-216
- 39
Ruiz-Meana M, Garcia-Dorado D, Hofstaetter B, Piper H M, Soler-Soler J.
Propagation of cardiomyocyte hypercontracture by passage of Na+ through gap junctions.
Circ Res.
1999;
85
280-287
- 40
Rupprecht H J, vom Dahl J, Terres W. et al .
Cardioprotective effects of the Na(+)/H(+) exchange inhibitor cariporide in patients
with acute anterior myocardial infarction undergoing direct PTCA.
Circulation.
2000;
101
2902-2908
- 41
Schäfer C, Ladilov Y, Inserte J. et al .
Role of the reverse mode of the Na+/Ca2+ exchanger in reoxygenation-induced cardiomyocyte
injury.
Cardiovasc Res.
2001;
51
241-250
- 42
Schinzel A C, Takeuchi O, Huang Z. et al .
Cyclophilin D is a component of mitochondrial permeability transition and mediates
neuronal cell death after focal cerebral ischemia.
Proc Natl Acad Sci USA.
2005;
102
12005-12010
- 43
Schlack W, Uebing A, Schäfer M. et al .
Regional contractile blockade at the onset of reperfusion reduces infarct size in
the dog heart.
Pflugers Arch.
1994;
428
134-141
- 44
Sebbag L, Verbinski S G, Reimer K A, Jennings R B.
Protection of ischemic myocardium in dogs using intracoronary 2,3-butanedione monoxime
(BDM).
J Mol Cell Cardiol.
2003;
35
165-176
- 45
Siegmund B, Klietz T, Schwartz P, Piper H M.
Temporary contractile blockade prevents hypercontracture in anoxic-reoxygenated cardiomyocytes.
Am J Physiol.
1991;
260
H426-H435
- 46
Siegmund B, Schlack W, Ladilov Y V, Balser C, Piper H M.
Halothane protects cardiomyocytes against reoxygenation-induced hypercontracture.
Circulation.
1997;
96
4372-4379
- 47
Staat P, Rioufol G, Piot C. et al .
Postconditioning the human heart.
Circulation.
2005;
112
2143-2148
- 48
Theroux P, Chaitman B R, Danchin N. et al .
Inhibition of the sodium-hydrogen exchanger with cariporide to prevent myocardial
infarction in high-risk ischemic situations. Main results of the GUARDIAN trial. Guard
during ischemia against necrosis (GUARDIAN) Investigators.
Circulation.
2000;
102
3032-3038
- 49
Yin H, Chao L, Chao J.
Adrenomedullin protects against myocardial apoptosis after ischemia/reperfusion through
activation of Akt-GSK signaling.
Hypertension.
2004;
43
(1)
109-116
- 50
Zeymer U, Suryapranata H, Monassier J P. et al .
The Na(+)/H(+) exchange inhibitor eniporide as an adjunct to early reperfusion therapy
for acute myocardial infarction. Results of the evaluation of the safety and cardioprotective
effects of eniporide in acute myocardial infarction (ESCAMI) trial.
J Am Coll Cardiol.
2001;
38
1644-1650
- 51
Zhao Z Q, Corvera J S, Halkos M E. et al .
Inhibition of myocardial injury by ischemic postconditioning during reperfusion: comparison
with ischemic preconditioning.
Am J Physiol Heart Circ Physiol.
2003;
285
(2)
H579-88
, Erratum in: Am J Physiol Heart Circ Physiol 2004 Jan; 286(1): H477
Prof. Dr. Dr. H. M. Piper
Physiologisches Institut, Justus-Liebig-Universität
Aulweg 129
35392 Gießen
Email: michael.piper@ugcvr.de
