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J Thorac Cardiovasc Surg 2002;124:1054-1055
© 2002 The American Association for Thoracic Surgery
Letters to the Editor |
Research Department, Kokura Memorial Hospital, Kitakyushu-City, Japana, Assistant Professor II, Department of Physiology, The University of the Ryukyus School of Medicine, Okinawa, Japanb
To the Editor:
Motoyoshi and associates
1 are to be congratulated for their provocative article, titled "Establishment of a Local Cooling Model Against Spinal Cord Ischemia Representing Prolonged Induction of Heat Shock Protein." Their method seems reliable as a model to study heat shock protein (Hsp) problems unrelated to temperature, but it seems less reliable as a method to study spinal cord protection from which temperature cannot be unlinked. The explanation of how and why Hsp was induced consistently, in our opinion, is inadequate.
We do not contest that modest hypothermia exerts protective effects. 2 However, to claim that it is better not to do anything before ischemia to maximize the beneficial effects of ischemic stress before inducing hypothermia is contradictory to conventional hypothermic and/or pharmacologic protection concepts/approaches.
Systemic hypothermia induced by surface cooling in rabbits was used in studies of spinal cord protection. We found that esophageal temperature measured 3 cm above the gastroesophageal junction before aortic clamping correlated with that of the spinal cord, within 0.1°C to 0.2°C, and therefore was usable as a surrogate site, but rectal temperature was not usable. An esophageal temperature of 29.4°C ± 0.07°C allowed full functional recovery within 5.5 hours of reperfusion after 60 minutes of ischemia in all rabbits, which yielded 6 to 6.2 minutes of ischemic protection for each 1°C, decreased by surface cooling after eucapnic ventilation, equivalent to pH-stat perfusion hypothermia, and rewarmed over a 90-minute period to 34°C to 35°C; however, only 0.5°C higher hypothermia uniformly failed. 3,4 The proposed cooling method that results in spinal cord temperature with variability as large as 2°C is unacceptable for investigation or clinical use. Because it lacks other surrogate sites, without measuring actual spinal cord temperature, the exact role or degree of hypothermia required to achieve the reported effect could not be elucidated.
As illustrated in their Figure 1, the model was one of ischemia at 37°C to 36°C during the first 5 minutes and at 35°C to 33°C during the last 10 of the 15 minutes. Fifteen minutes of ischemia could theoretically be protective at 35.8°C induced by surface cooling.
Use of a normothermic group seems inappropriate to support their contention that local cooling is the key element. Instead, rabbits surface-cooled systemically to 36.1°C to 36.3°C before ischemia should have been used. Two rewarming rates should have been studied: a relatively fast rate, using conventional total body rewarming sources, and a rate similar to that of the locally cooled spinal cord. Although the authors did not mention how quickly the animals were rewarmed, in our opinion this information is needed to justify their conclusion, for the rate of rewarming could be the definitive and advantageous feature of local hypothermia.
Whether ischemia-injured neurons die by apoptosis or necrosis depends on the extent of depletion of high-energy
P 5; apoptosis-necrosis is a continuum, 6 necrosis occurring when depletion is maximal, but in either situation sustained Hsp70 synthesis cannot be supported, as in their normothermic rabbits.
Hsp70 is produced under stressful conditions for protection. If reduced stress was the mechanism of the prolonged induction of Hsp70, as the authors explain, the immunoreactivity should decrease, not increase. In our opinion, timely hypothermia spared enough high-energyP to preserve the metabolic machinery that enabled continuing synthesis of sufficient Hsp70 for 2 days, but not enough to restore normal function immediately after reperfusion. Two days later, normal function was restored and the presence of Hsp70 was no longer required, thus disappearing by 7 days; apoptosis was averted, as in their hypothermic group.
The proposed strategy is applicable to only short ischemic periods. Ischemic periods lasting long enough to exhaust the high-energyP store before implementation of systemic or local hypothermia commensurate to the ischemic time will induce a degree of metabolic machinery derangement that could not be protected by the then scarcely available Hsp70, resulting in irreversible injury as either apoptosis or necrosis. To protect the spinal cord during such long ischemic times necessitates implementation of hypothermic and/or pharmacologic preischemic protective means. The question is not how the hypothermia was induced, but whether it was timely and commensurate with the duration of ischemia. In our opinion, lasting Hsp production would occur with a barely effective degree of preischemic systemic hypothermia as part of the protective mechanism. If the ischemic duration is short, or the protective strategy results in effective sparing of enough high-energyP to sustain normal function until aerobic metabolism is reestablished after reperfusion, production of Hsp is not induced. We believe that is what happened in the study by Kumar and associates, 7 who described 10 minutes of ischemia at 30°C in the gerbil brain, although the authors' interpretation was different.
References
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