Acute anemia elicits cognitive dysfunction and evidence of cerebral cellular hypoxia in older rats with systemic hypertension

Postoperative cognitive dysfunction (POCD) primarily affects the working memory domains of attention, cognitive speed, and executive function, as well as hippocampal based memory acquisition or learning.1 POCD may occur in 40 – 60% of patients after cardiac surgery and somewhat less frequently after major vascular and orthopedic surgery.1,2 Aging3 appears to be the most important risk factor for its occurrence. Patients presenting for cardiac and noncardiac surgery often suffer from longstanding hypertension and preexisting hypertension-related cerebrovascular disease, also an important risk factor for cognitive impairment.4 Mechanisms potentially contributing to POCD remain poorly understood. Research has focused largely on processes related to the conduct of cardiopulmonary bypass in cardiac surgery. The “Off-Pump” approach for coronary artery bypass grafting, designed to avoid the presumed cerebral side effects associated with extracorporeal circulation, has failed to diminish the incidence of POCD.5 In light of this, and the parallel occurrence of POCD after major noncardiac surgery, it is plausible that POCD after both major cardiac and non-cardiac surgery shares common origins, at least in part unrelated to anesthetic exposure. Finally, although POCD occurs with high frequency postoperatively, it resolves in most cases over several weeks to months, and there is little evidence of permanent disability.6 Is there then a contributing process that shares such a time course? We propose that a role for anemic hypoxia be considered in the genesis of POCD. Acute anemia has been found by Weiskopf et al.7 to elicit cognitive impairment even in healthy nonsurgical subjects. Major surgery in all arenas frequently results in acute and severe anemia. Severe anemia during cardiopulmonary bypass has been shown to lead to developmental delay in infants after cardiac surgery.8 Kulier et al.9 and Karkouti et al.10 have demonstrated a correlation between adverse cerebral outcomes and lower preoperative hemoglobin levels. Mathew et al.11 randomized 108 elderly subjects to hematocrits of more than 27% or less than 18% during cardiopulmonary bypass, with subjects undergoing more profound hemodilution experiencing a greater degree of cognitive impairment. Finally, anemia is recoverable over a time course similar to recovery from POCD.12 Mild to moderate hypoxia associated with high-altitude exposure and intermittent hypoxia associated with sleep apnea have also been linked to working memory and learning impairment.13–15 It is not surprising then that mild to moderate hypoxia has also been found to impair neuronal protein synthesis and synaptic plasticity,16 key processes requisite for learning. Exposure to hypoxia triggers a cascade of events focused upon cell survival. The hypoxia-inducible factor (HIF) transcription system17 is the “master” regulator of this hypoxic response.18 The prolyl hydroxylases family of proteins (prolyl hydroxylases-1, -2, and -3), along with factor-inhibiting HIF, responsible for degrading ubiquitously present HIF during normoxia, are themselves inhibited during hypoxia, allowing levels of HIF to rise.19 This results in the transcription of hundreds of hypoxia-responsive genes20 involved in regulating a host of activities focused on cell survival, including glucose transport (glucose transporter-1, GLUT-1), glycolysis (phosphoglycerate kinase-1, PGK-1), oxygen transport (erythropoiesis-erythropoeitin), and angiogenesis (vascular endothelial growth factor, VGEF).21 Effective hypoxia sensing and adaptation to hypoxia are critical for cellular function in all organs, including the brain.22 HIF and related gene products are exquisitely sensitive biomarkers of cellular hypoxia. Critical to the management of our aging population, aging cells appear to have a diminished, putatively cytoprotective, hypoxic response.23 In this study, we test the hypothesis that acute isovolemic anemia leads to cognitive impairment with aging. We also test the hypothesis that aging with hypertension predisposes to cerebral tissue and cellular hypoxia with anemia. These experiments were conducted in a rodent model of chronic hypertension and cerebrovascular disease, the spontaneously hypertensive rat (SHR). We chose the SHR rat model in which to test these hypotheses because of the many similarities between this strain and humans with hypertensive cerebrovascular disease who present for cardiovascular, vascular, and major noncardiovascular surgery.