Thorac Cardiovasc Surg 2004; 52
DOI: 10.1055/s-2004-816583

Cardiac apoptosis inhibition is an effective new strategy to improve myocardial protection

O Klass 1, UM Fischer 1, P Tossios 1, D Pfriem 2, M Probst 1, GR Kanani 1, M Steinhoff 3, JH Fischer 3, W Bloch 2, ER de Vivie 1, U Mehlhorn 1
  • 1Klinik f�r Herz- und Thoraxchirurgie, Uniklinik K�ln
  • 2Institut I f�r Anatomie, Uni K�ln
  • 3Institut f�r Experimentelle Medizin, Uni K�ln, Germany

Objectives: As cardioplegic arrest (CPA) has been shown to induce cardiac apoptosis, pharmacological inhibition of CPA-induced apoptosis activation may represent a new strategy to improve myocardial protection. Therefore, we studied the effect of two apoptosis inhibitors on myocardial apoptosis signal-pathway and regulatory proteins in a pig model of cardiopulmonary bypass (CPB) and CPA.

Material and Methods: Eigtheen pigs instrumented with LV sonomicrometry and micromanometry for cardiac performance determination were subjected to 1h CPA on CPB. LV biopsies were collected before CPB (Baseline), at 15 and 60min CPA, at 30min reperfusion on CPB, and at 120min post-CPB. In two treatment groups (n=6 each) we administered either the specific caspase-3 inhibitor DEVD or the non-specific apoptosis inhibitor YVAD-cmk. Six additional animals served as controls. LV specimen were immuno-cytochemically stained against activated caspase-3, apoptosis inducing factor (AIF), and TNF-α. Cardiomyocytes were then quantitatively investigated using TV densitometry (gray units: U).

Results: In controls, active caspase-3 significantly increased over time; in YVAD-cmk, caspase-3 was increased at 15 and 60min CPA, but decreased during reperfusion to reach baseline values at 120min post-CPB; in DEVD, caspase-3 was not activated. AIF increased significantly over time in controls, but remained unchanged in both DEVD and YVAD-cmk. TNF-α increased over time in controls and in DEVD, but remained unchanged in YVAD-cmk. Post-CPB LV contractility as measured by preload recruitable stroke work as well as cardiac output were significantly better preserved in both DEVD and YVAD-cmk as compared to controls.

Conclusions: Our data show that both specific and non-specific apoptosis inhibitors effectively block cardiac myocyte apoptosis signal cascade; this is associated with better preserved post-cardioplegia cardiac function.