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This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Hermann Aebert Permission Requests Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Aebert, H. Search for Related Content PubMed Articles by Aebert, H. Related Collections Myocardial protection

Ann Thorac Surg 2004;77:1389-1390
© 2004 The Society of Thoracic Surgeons

Invited commentary

Department of Thoracic and Cardiovascular Surgery Eberhard Karls University Hoppe-Seyler-Strasse 3 D-72706 Tuebingen, Germany

e-mail: hermann.aebert{at}med.uni-tuebingen.de

This article exemplifies impressively how the combination of classic physiological methods and molecular biology can result in new knowledge. Doctor Feng and colleagues observed that the decline of myocardial contractility and endothelium-dependent coronary relaxation after cardioplegic arrest is related to increased caspase-3 activation and decreased Bad phosphorylation. Why are these findings important?

The concept of apoptosis or programmed cell death has revolutionized our understanding of multicellular organism development, tissue homeostasis under normal and pathological conditions, and therapeutic interventions. If a cell is exposed to limited injury not resulting in direct necrosis, the scale beam of cell survival is inclining to apoptosis. This may be counterbalanced by anti-apoptotic factors. However, when a point of no return is reached, the cell will execute a preformed suicide program. Depending on the cell type and the kind of injury or signaling, several pathways of apoptosis are possible. The molecules required for apoptosis as well as pro- and anti-apoptotic proteins are always present in a cell. Chemical modification or translocation to other cell compartments results in activation or blocking of their action. In the heart, apoptosis of relatively few myocytes may have a significant impact on cardiac contractility by impingement of the force-generating ability of neighboring cells [1].

Doctor Feng and colleagues have examined several proteins playing an important role in apoptosis. Activated caspase-3 is a major link of a protease cascade executing apoptosis. Bax, Bad, and other Bcl-2 protein family members determine the balance of the pro- and anti-apoptotic scale for the mitochondrial pathway ahead of caspase-3 activation. Phosphorylation of the amino acid serine at certain positions of Bad protein results in inactivation of this pro-apoptotic molecule and may delay or stop induction of programmed cell death. This has been shown in different cell types such as human neutrophils [2], oligodendrocytes [3], and colon cancer cells [4]. Spine tingling is the fact that Bad phosphorylation and cell survival can be promoted by external signals like cytokines [2–4]. Therefore, the article of Feng et al not only adds further evidence for an important role of the mitochondrial pathway of apoptosis in post-cardioplegia myocardial stunning but also paves the path for ameliorating this problem.

"Bright light casts strong shadows" [Goethe, Götz von Berlichingen, 1st act]. There are several limitations of this study, particularly relating to the unusual cardioplegia regimens. The composition of the cardioplegic solutions and the regimens are uncommon. Clinically, warm crystalloid cardioplegia is not used for good reasons. A flow of normothermic antegrade blood cardioplegia amounting to at least a third of the physiological coronary flow of the working heart is required in patients [5]. Compared to the normal coronary flow measured in the rabbit hearts of about 35 mL/min, a flow of 1.5 mL/min during the cardioplegia experiments under normothermia appears insufficient. It is remarkable that even continuous blood cardioplegia resulted in a highly significant increase of caspase-3 activation, whereas during Krebs-Henseleit perfusion, no such increase was observed. One has to assume that the observed changes of activated caspase-3 and phosphorylated Bad are somewhat due to warm ischemia and insufficient myocardial protection. There is a lot of evidence that blood cardioplegia is better than crystalloid cardioplegia but rarely warm potassium induced ischemic arrest has been used for comparison. Further, the rabbit hearts have not been examined for direct evidence of apoptosis and for the affected cell types.

Irrespective of these limitations, this article stands in the landscape of cardiac research as a signpost guiding further investigations for evaluation of ischemia/cardioplegia and improvement of myocardial protection.

References

1. Cheng W, Li B, Kajstura J, et al. Stretch-induced programmed myocyte cell death. J Clin Invest 1995;96:2247–59.
2. Cowburn AS, Cadwallader KA, Reed BJ, Farahi N, Chilvers ER. Role of PI3-kinase-dependent Bad phosphorylation and altered transcription in cytokine-mediated neutrophil survival. Blood 2002;100:2607–16.
3. Soane L, Cho HJ, Niculescu F, Rus H, Shin ML. C5b-9 terminal complement complex protects oligodendrocytes from death by regulating Bad through phosphatidylinositol 3-kinase/Akt pathway. J Immunol 2001;167:2305–11.
4. Rice PL, Washington M, Schleman S, Beard KS, Driggers LJ, Ahnen DJ. Sulindac sulfide inhibits epidermal growth factor-induced phosphorylation of extracellular-regulated kinase and Bad in human colon cancer cells. Cancer Res 2003;63:616–20.
5. Barner HB. Historical aspects and current review of myocardial protection. In: Salerno TA, ed. Warm heart surgery. London, Boston, Sydney, Auckland: Arnold, London, 1995:1–15.

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Hermann Aebert Permission Requests Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Aebert, H. Search for Related Content PubMed Articles by Aebert, H. Related Collections Myocardial protection