We have recently found in conscious pigs that a sequence of brief coronary occlusions induces severe myocardial stunning, but when the same sequence is repeated 24 hours later, the severity of stunning is markedly reduced (approximately 50%) ("late preconditioning against stunning"). As an initial step toward elucidating the mechanism and potential clinical significance of this powerful cardioprotective response, the present study was conducted to define the time course of late preconditioning against myocardial stunning. Conscious pigs underwent a sequence of ten 2-minute coronary occlusion/2-minute reperfusion cycles and then a second identical sequence at 6 hours (group I, n = 7), 12 hours (group II, n = 6), 24 hours (group III, n = 10), 3 days (group IV, n = 10), or 6 days (group V, n = 11) after the first. Systolic wall thickening (WTh) in the ischemic/reperfused region remained significantly depressed for at least 3 hours after the 10th reperfusion of the first sequence, indicating myocardial stunning. When the second sequence of coronary occlusions was performed 6 hours after the first (group I), the recovery of WTh was similar to the first. In contrast, when the second sequence was repeated 12 hours after the first (group II), the recovery of WTh was improved, though not consistently, and the total deficit of WTh decreased by 41% (P < .05) compared with the first sequence. When the second sequence was repeated 24 hours (group III) and 3 days (group IV) after the first, the recovery of WTh was substantially enhanced, with 52% and 49% reductions in the total deficit of WTh, respectively (P < .01 versus the first sequence). When the second sequence was repeated 6 days later (group V), the recovery of WTh was indistinguishable from the first sequence. Thus, late preconditioning against myocardial stunning requires > 6 hours to develop, lasts for at least 60 hours after its appearance (with the most effective protection present at 24 hours and 3 days), and disappears within 6 days after the preconditioning ischemia, a time course that is consistent with the synthesis and degradation of cardioprotective proteins. In view of its sustained duration, this endogenous cardioprotective mechanism is of potential clinical importance.
Antibody-mediated rejection (AMR) (humoral rejection) of cardiac allografts remains difficult to diagnose and treat. Interest in AMR of cardiac allografts has increased over the last decade as it has become apparent that untreated humoral rejection threatens graft and patient survival. An international and multidisciplinary consensus group has formulated guidelines for the diagnosis and treatment of AMR and established that identification of circulating or donor-specific antibodies is not required and that asymptomatic AMR, that is, biopsy-proven AMR without cardiac dysfunction is a real entity with worsened prognosis. Strict criteria for the diagnosis of cardiac AMR have not been firmly established, although the diagnosis relies heavily on tissue pathological findings. Therapy remains largely empirical. We review an unfortunate experience with one of our patients and summarize recommended criteria for the diagnosis of AMR and potential treatment schemes with a focus on current limitations and the need for future research and innovation.
The effectiveness of the late phase of ischemic preconditioning (PC) in protecting against myocardial infarction and the concomitant contractile dysfunction after sustained ischemia remains unclear. The early and late phases of PC have not been compared using the same protocol in the same experimental model; furthermore, the late phase of PC has not been assessed in the conscious state in a large animal preparation. The goal of this study was to directly compare the effects of early and late PC on myocardial infarct size and postischemic dysfunction in chronically instrumented, conscious pigs. Four groups of pigs were subjected to a 40-minute coronary occlusion followed by 3 days of reperfusion. Group 1 (n=7) served as control. Group 2 (n=6) was subjected to ten 2-minute occlusion/2-minute reperfusion cycles 25 minutes before the 40-minute occlusion (early PC). Groups 3 (n=7) and 4 (n=4) were subjected to 10 and 25 cycles, respectively, of 2-minute occlusion/2-minute reperfusion 24 hours before the 40-minute occlusion (late PC). Infarct size averaged 45.1+/-5.9% of the region at risk in control pigs, was reduced by 79% (to 9.4+/-3.2%) in group 2, but did not differ in groups 3 (33.3+/-4.8%) and 4 (38.8+/-8.2%) versus group 1. Power analysis demonstrated that there was an 80% probability of detecting a 40% decrease in infarct size in groups 3 and 4 versus group 1. The recovery of systolic wall thickening (measured with ultrasonic crystals) after the 40-minute occlusion was poor in groups 1, 3, and 4 but markedly enhanced in group 2 throughout the 3 days of reperfusion; this beneficial effect could have been due to limitation of infarct size, alleviation of stunning, or both. Thus, a series of ten 2-minute coronary occlusions had a profound (approximately 80%) early infarct-limiting effect, which was associated with a marked functional benefit. This protection, however, disappeared 24 hours later and could not be reinstituted by increasing the number of PC coronary occlusions to 25. The incidence and duration of ventricular tachycardia after reperfusion was not changed by either early or late PC; no conclusions could be drawn regarding ventricular fibrillation or ischemia-induced ventricular tachycardia, since these arrhythmias did not occur in control animals. Taken together, the present results demonstrate striking differences between the early and late effects of PC: In conscious swine subjected to a sustained coronary occlusion, a PC protocol that induces powerful protection during the early phase of PC fails to induce any protection during the late phase, indicating either that a late protective effect of PC does not exist or that, if it exists, it must be weaker than the early protective effect.
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