Thorac Cardiovasc Surg 2004; 52
DOI: 10.1055/s-2004-816779

Cardiac myocyte regulatory proteins: Potential new targets for myocardial preservation in cardiac surgery?

UM Fischer 1, O Klass 1, U Stock 2, P Tossios 1, HJ Geissler 1, 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: Mitogen-activated protein (MAP)-kinase (ERK1/2) and Akt/protein kinase B (AKT/PKB) are involved in various cardiac pathophysiologies. One important mechanism is NO generation following endothelial NO-synthase (eNOS) activation by AKT/PKB. As cardioplegic arrest (CPA) affects myocardial metabolism, we sought to investigate the time courses of ERK1/2, AKT/PKB, and eNOS activation during CPA and reperfusion.

Material and Methods: In 13 pigs subjected to 1h CPA on cardiopulmonary bypass (CPB), LV biopsies were collected before CPB (Baseline), at 60min CPA, at 15 and 30min reperfusion on CPB, and at 120min post CPB. LV specimen were immuno-cytochemically stained against phosphorylated ERK1/2, AKT/PKB, and eNOS. Cardiomyocytes were then quantitatively assessed using TV densitometry (gray units: U). From LV sonomicrometry and micromanometry data we derived the preload recruitable stroke work (PRSW), a load independent LV contractility index.

Results: ERK1/2 activity was unchanged at 60min CPA compared to baseline (p=0.3), but increased by 5.2±9.6U (p=0.07) at 15min reperfusion, 4.8±6.1U (p=0.02) at 30min reperfusion, and 4.0±6.7U (p=0.05) at 120min post CPB. AKT/PKB activity was increased by 8.5±9.2U (p=0.006) at 60min CPA and decreased over time to reach baseline level at 120min CPB (-0.2±6.4U; p=0.9). Significant eNOS activation accompanied AKT/PKB activity (p<0.001). LV contractility as measured by PRSW decreased from 58.4±24.0mmHg at baseline to 45.2±9.9mmHg at 120min post CPB (p=0.03).

Conclusions: Our data show AKT/PKB activiation by CPA which results in increased eNOS activity. Reperfusion resulted in AKT/PKB inactivation accompanied by ERK1/2 activation and was associated with depressed LV contractility post CPB. Thus, AKT/PKB, ERK1/2, and eNOS are involved in CPA-induced myocardial alterations and may represent novel therapeutic targets.