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. 2010 Feb 25;24(1):85–87. doi: 10.1007/s10557-010-6219-y

Cyclosporine A at Reperfusion Reduces Infarct Size in Pigs

Andreas Skyschally 1, Rainer Schulz 1, Gerd Heusch 1,✉
PMCID: PMC2855028  PMID: 20182781

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].

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*
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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.

Fig. 1

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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.

Acknowledgments

Open Access

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.

Footnotes

Supported by the German Research Foundation (He 1320/18-1).

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