Table 1.
The major experimental studies investigating the effect of CsA on myocardial infarct size
| Study | IRI Model | CsA dose and timing | Effect | Notes |
|---|---|---|---|---|
| CsA administered prior to or after the onset of myocardial ischaemia | ||||
| Weinbrenner et al., 1998 | Ex vivo rabbit heart LAD 30 min I 2 h R | 100 nM or 750 nM CsA either 10 min prior or 10 or 20 min after onset of I | ↓IS from 29 to 10% of area at risk except when CsA given 20 min after onset of I | Tacrolimus administered prior to I similarly cardioprotective |
| Squadrito et al., 1999 | In vivo rat heart LAD 30 min I 48 h R | 0.25, 0.5 or 1 mg·kg−1 CsA given 5 min after onset of I | The most effective dose was 1 mg·kg−1 with ↓IS from 57 to 12% of area at risk. | Less leucocyte accumulation, and reduces TNF-α, ICAM-1 and myocardial myeloperoxidase expression. |
| Niemann et al., 2002 | In vivo rat heart LAD 30 min I 24 h R | Daily pretreatment with CsA for 3 days (5, 10, 15, 25 mg·day−1) prior to I | The most effective dose was 15 mg·kg−1 with ↓IS from 29 to 7% of LV area. | Cardioprotective effect associated with reduced oxidative phosphorylation and ATP content. |
| Di Lisa et al., 2001 | Ex vivo rat heart LAD 30 min I 2 h R | 200 nM CsA present throughout perfusion protocol. | ↓myocardial necrosis as measured by LDH in coronary effluent | Associated preservation of mitochondrial NAD+ content. |
| Xie and Yu, 2007 | In vivo rat heart LAD 30 min I 180 min R | 10 mg·kg−1 CsA given 10 min prior to I | ↓IS from 49 to 30% of area at risk. | |
| CsA administered at the onset of myocardial reperfusion | ||||
| Hausenloy et al., 2002 | Ex vivo rat heart LAD 35 min I 2 h R | 200 nM CsA for the first 15 min of reperfusion | ↓IS from 45 to 25% of the area at risk. | Tacrolimus administered at R not cardioprotective |
| Hausenloy et al., 2003 | Ex vivo rat heart LAD 35 min I 2 h R | 1 µM SfA for the first 15 min of R | ↓IS from 44 to 24% of the area at risk. | No cardioprotection when SfA administered after 15 min of R |
| Argaud et al., 2005a | In vivo rabbit heart LAD 35 min I 2 h R | 10 mg·kg−1 of CsA or NIM811 given 1 min prior to R | ↓IS from 60 to 24% with CsA and 25% with NIM811 of the area at risk. | NIM811 a CsA derivative which does not inhibit calcineurin was equally cardioprotective |
| Lim et al., 2007 | In vivo murine heart LAD 30 min I 2 h R | 10 mg·kg−1 CsA or 25 mg·kg−1 SfA given 5 min prior to R | ↓IS from 48 to 32% and 29%, respectively, of area at risk. | |
| Skyschally et al., 2010 | In vivo pig heart LAD 90 min hypoperfusion 2 h R | 5 mg·kg−1 CsA given 5 min prior to R | ↓IS from 34 to 24% of area at risk. | Note this study using myocardial hypoperfusion as opposed to complete regional myocardial ischaemia. |
| Karlsson et al., 2010 | In vivo pig heart LAD 45 min I 2 h R | 10 mg·kg−1 CsA | No difference in IS | Potential worsening of IS when CsA administered with isoflurane. |
| Huhn et al., 2010 | In vivo rat heart (Zucker obese) LAD 25 min I 2 h R | 5 or 10 mg·kg−1 CsA given 1 min prior to R | No difference in IS | However, CsA not demonstrated to be effective in Zucker lean rat. |
IRI, ischaemia–reperfusion injury; I, ischaemia; R, reperfusion; CsA, cyclosporin A; SfA, Sanglifehrin A; LAD, left anterior descending coronary artery; IS, infarct size; NIM811, N-methyl-4-isoleucine cyclosporin.