Supported by the German Research Foundation (He 1320/18-1).
Timely reperfusion is mandatory for salvage of ischemic myocardium from irreversible damage. However, reperfusion induces damage per se, i.e. reperfusion injury contributes 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 postconditioning’s protection in rodents [6]. In pigs, in which coronary anatomy and the spatial and temporal development of myocardial infarction are closer to that of humans, RISK activation is not mandatory for protection [7].
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The mitochondrial permeability transition pore (mPTP) is a potential end-effector of myocardial protection at reperfusion [8‐10]. Cyclosporine A binds to cyclophilin D, inhibits mPTP opening and reduces infarct size [9, 11]. Apart from experiments in rodents, cyclosporine 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 postconditioning 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).
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.
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
×
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.
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This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.
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Open AccessThis is an open access article distributed under the terms of the Creative Commons Attribution Noncommercial License (https://creativecommons.org/licenses/by-nc/2.0), which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.
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