Ischemic Preconditioning and Tolerance in Human Brain
To the Editor:
Weih and colleagues1 conducted a retrospective case-control study of 37 patients with a transient ischemic attack (TIA) before their ischemic stroke and compared the outcome with that of 111 control patients with no TIA before the cerebral infarction. Their results revealed that milder strokes and favorable outcome were associated with the presence of a prodromal TIA. I would raise the following issues for clarification and discussions by the authors.
First, I do not understand the rationale behind adopting some of the exclusion criteria. Patients with a Canadian Neurological Scale score of ≤4 or ≥10.5 were excluded.1 Why should patients with a milder stroke be excluded? Patients with a severe stroke and/or aphasia may be noncommunicative, but the prior history of TIA can be sought from the spouse or other relatives. The success of acute thrombolysis with tissue plasminogen activator and the conduct of multicenter trial on acute ischemic stroke have blurred the distinction between a TIA and an ischemic stroke.2 3 In addition, small cerebral infarction has been documented by MRI in patients with clinically defined TIA.4 Thus, excluding patients with previous infarction on CT within the same vascular territory is unnecessary. On the other hand, patients with TIA in a vascular territory other than that of the index stroke may represent a “positive” control group to show whether the induced “ischemic tolerance” is confined to the vascular territory of the prodromal TIA.
Second, patients who died before completion of follow-up were excluded from the outcome analysis, and patients had varying durations of follow-up.1 I think the cause of death is relevant, and excluding stroke-related deaths would bias toward a better outcome. In any case, death following stroke is the worst outcome. On the other hand, assessment of independence and favorable outcome should be made at a comparable time after the index stroke.
Finally, the interval between the prodromal TIA and the index stroke varied from 6 hours to 2 years.1 It is rather unconvincing that a prodromal TIA can induce immediate and long-lasting “ischemic tolerance.” I wonder if the authors would include more patients into the group with a prodromal TIA, subdivide the whole group into a subgroup with a recent TIA and another subgroup with a remote TIA, and repeat some of the analyses.
- Copyright © 2000 by American Heart Association
Weih M, Kallenberg K, Bergk A, Dirnagl U, Harms L, Wernecke KD, Einhäupl KM. Attenuated stroke severity after prodromal TIA: a role for ischemic tolerance in the brain? Stroke.. 1999;30:1851–1854.
Adams HP Jr, Brott TG, Furlan AJ, Gomez CR, Grotta J, Helgason CM, Kwiatkowski T, Lyden PD, Marler JR, Torner J, Feinberg W, Mayberg M, Thies W. Guidelines for thrombolytic therapy for acute stroke: a supplement to the guidelines for the management of patients with acute ischemic stroke. Stroke.. 1996;27:1711–1718.
Kidwell CS, Alger JR, Di Salle F, Starkman S, Villablanca P, Bentson J, Saver JL. Diffusion MRI in patients with transient ischemic attacks. Stroke.. 1999;30:1174–1180.
Dr Cheung raises the important issue that the results of our study might be biased by inadequate inclusion and exclusion criteria. We included only Canadian Neurological Scale (CNS) scores from 4 to 10.5 to adjust the presumed stroke severity to the experimental situation. In experimental models, focal ischemic tolerance has been consistently shown for hemispheric infarcts of reproducible size, whereas very small or very large infarcts have not been examined in detail. It is true that TIAs and strokes represent different manifestations of the same disease, but most TIAs last <1 hour,R1 whereas the majority of stroke patients presently reach the hospital only after several hours, as was the case in our study. We believe that a clear distinction can be made between TIA and stroke in most cases. We excluded patients with a visible infarction on CT, because the preconditioning stimulus per definition should cause no or only minimal damage. Probably 30% of TIAs <1 hour in duration show corresponding diffusion-weighted imaging (DWI) abnormalities on MRI, but the volumes are rather small.R2 In another study,R3 the MRI abnormalities were not related to the TIA symptoms. We agree that the power of our study would have been improved by an admission MRI (including DWI) and follow-up scans at fixed time points. Unfortunately, this is currently not the standard institutional diagnostic regimen of our and many other stroke units. We excluded patients with TIA in another vascular territory because we were concerned whether they would represent a “positive control.” In rat brainR4 and rabbit hearts,R5 “remote preconditioning” has been observed, which means that ischemia in the other hemisphere or even in another organ would induce ischemic tolerance. The death rate between the groups was not different. Because the follow-up time was up to 4 years and the cause of death often was unknown, we found it inappropriate to select this as a primary end point of our study. Finally, most patients had their qualifying TIA only several days before stroke, a time at which the “delayed window” of ischemic tolerance has been demonstrated in numerous experimental studies. When the cases with a very long interval between TIA and stroke are excluded, the results do not change. The mean CNS score of all TIA patients was 8.7; for the subgroup with a TIA within 7 days before stroke, the CNS was 8.9. In contrast, patients with unheralded strokes had a worse CNS score on admission (7.4). For the patients with TIAs that occurred long before stroke, other factors, such as collateral development, have to be taken into account. We were careful to point out that our results suggest but do not prove the existence of ischemic tolerance in the brain. A prospective study with strict MRI criteria is needed to further clarify this issue and is currently under way in our institution.
Kidwell CS, Alger JR, Di SF, Starkman S, Villablanca P, Bentson J, Saver JL. Diffusion MRI in patients with transient ischemic attacks. Stroke. 1999;30:1174–1180.
Bhadelia RA, Anderson M, Polak JF, Manolio TA, Beauchamp N, Knepper L, O’Leary DH. Prevalence and associations of MRI-demonstrated brain infarcts in elderly subjects with a history of transient ischemic attack: the Cardiovascular Health Study. Stroke.. 1999;30:383–388.
Takaoka A, Nakae I, Mitsunami K, Yabe T, Morikawa S, Inubushi T, Kinoshita M. Renal ischemia/reperfusion remotely improves myocardial energy metabolism during myocardial ischemia via adenosine receptors in rabbits: effects of “remote preconditioning.” J Am Coll Cardiol. 1999;33:556–564.