Ann Thorac Surg 2007;84:863
© 2007 The Society of Thoracic Surgeons
Original Articles: Cardiovascular
Invited commentary
Eliot R. Rosenkranz, MD
Division of Cardiovascular Surgery, University of Miami School of Medicine, JMH East Tower, Room 3072, PO Box 016960 (R-114), Miami, FL 33101-6960
(Email: erosenkr{at}med.miami.edu).
Of the many physiologic derangements imposed during open heart surgery, periods of ischemia followed by reperfusion result in the activation of endogenous cell mechanisms aimed at preventing permanent injury to the heart muscle. Despite decades of study, many of nature’s secrets concerning ischemia and reperfusion are as of yet unknown. The article by Al-Dadah and colleagues [1] is a continuation of their studies concerning the role that potassium-ATP (KATP) channel plays in the response of the myocyte to ischemia and raises more questions concerning the methods the heart uses to tolerate periods of ischemia.
A large body of literature suggests that KATP channels located on the sarcolemmal and mitochondrial membranes play critical roles in ischemia tolerance by coordinating vital cell functions with alterations in the energy state of the heart. The results of the study by Al-Dadah call into question the mechanism by which diazoxide, a pharmacologic opener of the KATP channel, improves post-ischemic myocardial function and suggest that there may be a role separate from that involving the KATP channel, such as inhibition of the enzyme succinate dehydrogenase (SDH).
It is likely that the response of the myocyte to ischemia and reperfusion results in the activation of complex molecular pathways all aimed at preserving myocyte survival if possible or in the orderly destruction of myocytes that have been irreversibly damaged (apoptosis). There are many unanswered questions concerning what these pathways are, how they function, and how they might be harnessed pharmacologically to prevent irreversible cell injury during elective periods of myocardial ischemia induced during heart surgery. Some of the unanswered questions include the following:
- 1 What role do KATP channels play in ischemia and reperfusion? Is it possible that the surrogate for ischemia used by Al-Dadah and colleagues [1], namely metabolic inhibition, affects the mechanism by which KATP channel opening might be protective in more traditional models of ischemia?
- 2 By what molecular mechanism(s) does diazoxide exert its beneficial function in this model? Pharmacologic mediators of channel activation and inhibition are notoriously nonspecific and dose-dependent, which is an inherent limitation of the model used. How does inhibition of SDH improve ischemia tolerance?
- 3 What does swelling do to myocytes? Could it be a mechanical means of adaptation to injury by activation of potentially beneficial molecular pathways regulated by changes in cell tension?
The article by Al-Dadah and colleagues [1] has served the role that all good research should be raising questions that result in new research that may unlock more of nature’s mysteries concerning myocardial ischemia tolerance.
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References
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- Al-Dadah AS, Voeller RK, Schuessler RB, Damiano Jr R, Lawton JS. Maintenance of myocyte volume homeostasis during stress by diazoxide is cardioprotective Ann Thorac Surg 2007;84:857-863.[Abstract/Free Full Text]
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