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Ann Thorac Surg 2004;77:1689-1690
© 2004 The Society of Thoracic Surgeons

Invited commentary

^b UCI Medical Center, 101 The City Drive Bldg 53, Rt 81, Orange, CA 92868-4080 USA
^a Division of Cardiology, VA Medical Center and University of Minnesota, Minneapolis, MN 55417 USA

e-mail: shekh003{at}tc.umn.edu
e-mail: narula{at}uci.edu

This study by Mukherjee et al is provocative and has a high potential for therapeutic utility. Consistent with other Pdata, they found that myocytes exposed to simulated hypothermic hyperkalemic cardioplegic arrest (HCA) demonstrated contractile dysfunction. More interestingly, they also found that a significant portion of this dysfunction could be attenuated with nonspecific caspase inhibition. This paper adds to the growing body of evidence that caspases play a role in myocardial dysfunction. Caspase over expression results in cardiac dysfunction [1, 2], while inhibiting caspase activity ameliorates this dysfunction [2, 3]. While some of this relates to reduced apoptosis, there is evidence that caspases can cleave contractile proteins [3–6] (in absence of nuclear fragmentation), and that reduced contractile protein cleavage following caspase inhibition may also contribute to improved LV function [2, 3, 6]. The present study indicates that a similar mechanism may be operative after HCA.

Caspases are ubiquitous proteases that mediate cleavage of multiple cellular proteins. Most of the early data focused on their ability to dismantle crucial proteins resulting in cell death. It is now being realized that, depending on the substrate affected, they can have multiple consequences. We have previously demonstrated that caspases are active and induce cleavage of multiple substrates, including contractile proteins at a time when they are unable to cleave DNA (due to a reactive reduction in DNA fragmentation factors) in the failing human heart. This creates a conceptual paradox of cells that are resistant to caspase-mediated killing, but at the same time, suffer functionally due to caspase-mediated contractile dysfunction; such myocytes have been referred to as Zombie cells [7]. Such a change could account for myocardial depression with no reduction in cellular viability as confirmed in this study.

Some issues, however, remain to be addressed. It will be important to demonstrate caspase activation (preferably along with contractile apparatus cleavage) in the hypothermic HCA group as well as an attenuation of these changes in the HCA+zVAD group. Such data will exclude "non-caspase mediated" actions associated with caspase inhibitors. For example, some of the caspases have potent effects on cytokine maturation and this might influence cellular function. Caspase inhibition also influences calpain activation and this could play a role in myocyte dysfunction. Finally, the caspase pathways are only one of the many bad guys in the neighborhood; it is not known if a cell that shows improved function after caspase inhibition has permanently escaped death by apoptosis through other pathways. If a sufficient number of cells died after showing short-lasting functional improvement, the net result might still be cardiac dysfunction. Answers to some of these questions and in-vivo data will be a requisite before embarking on clinical studies of caspase inhibition. Nevertheless, this should not detract from the conclusion that caspase inhibition ameliorates myocyte dysfunction after HCA. We look forward with interest to the author's laboratory to provide further crucial information in their future experiments.

References

1. Condorelli G., Pisani A., Stassi G., et al. Targeted expression of caspase 3 in transgenic mice induces contractile dysfunction and cardiomyocyte degeneration which is prevented by Bclxl. Circulation 1998;98:I46.
2. Laugwitz K.L., Moretti A., Weig H.J., et al. Blocking caspase-activated apoptosis improves contractility in failing myocardium. Hum Gene Ther 2001;12:2051-2063.[Medline]
3. Chandrashekhar Y., Sen S., Anway R., Shuros A., Anand I.S. Long term caspase inhibition ameliorates apoptosis, reduces myocardial troponin-I cleavage, protects LV function and attenuates remodeling in rats with a MI. J Am Coll Cardiol 2004.
4. Haider N., Kharbanda S., Chandrashekhar Y., et al. Caspase 3 mediated cleavage of troponin C at evolutionarily conserved calcium binding site: Relevance of apoptosis in heart failure. Circulation 1999;100:I-283.
5. Communal C., Sumandea M., de Tombe P., et al. Functional consequences of caspase activation in cardiac myocytes. Proc Natl Acad Sci USA 2002;99:6252-6256.[Abstract/Free Full Text]
6. Moretti A., Weig H.J., Ott T., et al. Essential myosin light chain as a target for caspase-3 in failing myocardium. Proc Natl Acad Sci 2002;99:1860-1865.
7. Narula J., Arbustini E., Chandrashekhar Y., Schwaiger M. Apoptosis and systolic dysfunction in congestive heart failure. Cardiol Clin 2001;19:113-126.[Medline]

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 Permission Requests Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Chandrashekhar, Y. Articles by Narula, J. Search for Related Content PubMed Articles by Chandrashekhar, Y. Articles by Narula, J. Related Collections Myocardial protection