Atorvastatin, but not pravastatin, inhibits cardiac Akt/mTOR signaling and disturbs mitochondrial ultrastructure in cardiac myocytes.

Statins, which reduce LDL-cholesterol by inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, are among the most widely prescribed drugs. Skeletal myopathy is a known statin-induced adverse effect associated with mitochondrial changes. We hypothesized that similar effects would occur in cardiac myocytes in a lipophilicity-dependent manner between 2 common statins: atorvastatin (lipophilic) and pravastatin (hydrophilic). Neonatal cardiac ventricular myocytes were treated with atorvastatin and pravastatin for 48 h. Both statins induced endoplasmic reticular (ER) stress, but only atorvastatin inhibited ERK1/2T202/Y204, AktSer473, and mammalian target of rapamycin signaling; reduced protein abundance of caveolin-1, dystrophin, epidermal growth factor receptor, and insulin receptor-ß; decreased Ras homolog gene family member A activation; and induced apoptosis. In cardiomyocyte-equivalent HL-1 cells, atorvastatin, but not pravastatin, reduced mitochondrial oxygen consumption. When male mice underwent atorvastatin and pravastatin administration per os for up to 7 mo, only long-term atorvastatin, but not pravastatin, induced elevated serum creatine kinase; swollen, misaligned, size-variable, and disconnected cardiac mitochondria; alteration of ER structure; repression of mitochondria- and endoplasmic reticulum-related genes; and a 21% increase in mortality in cardiac-specific vinculin-knockout mice during the first 2 months of administration. To our knowledge, we are the first to demonstrate in vivo that long-term atorvastatin administration alters cardiac ultrastructure, a finding with important clinical implications.-Godoy, J. C., Niesman, I. R., Busija, A. R., Kassan, A., Schilling, J. M., Schwarz, A., Alvarez, E. A., Dalton, N. D., Drummond, J. C., Roth, D. M., Kararigas, G., Patel, H. H., Zemljic-Harpf, A. E. Atorvastatin, but not pravastatin, inhibits cardiac Akt/mTOR signaling and disturbs mitochondrial ultrastructure in cardiac myocytes.

An Observational Study of Cerebral Blood Flow Velocity During Hypotensive Epidural Anesthesia.

BACKGROUND: Hypotensive epidural anesthesia (HEA), as practiced at our institution, uses sympathetic blockade to achieve mean arterial blood pressure (MAP) of ≤50 mm Hg while administering epinephrine by infusion to support the circulation. HEA has not been associated with gross adverse effects on neurologic outcome or cognitive function in the postoperative period, suggesting adequate cerebral blood flow (CBF). However, the use of MAPs well below the commonly accepted lower limit of CBF autoregulation suggests that CBF should be significantly reduced below normal levels. To examine these conflicting hypotheses, we performed a prospective investigation of the effects of HEA on CBF velocity (CBFV), an accepted index of cerebral perfusion. METHODS: Fifty-two hip replacement patients were studied. HEA was induced by lumbar epidural injection of local anesthetic and infusion of epinephrine to achieve an MAP of ≤50 mm Hg. Propofol/midazolam sedation was administered. Baseline CBFV was recorded pre-HEA (after sedation and before local anesthetic injection) and continuously thereafter. RESULTS: During HEA, MAP decreased by 40% and was stable throughout. The CBFVmean at baseline and at 3 HEA intervals during surgery was 46 ± 12 (SD), 45 ± 12, 47 ± 14, and 47 ± 14 cm·s, respectively. Although mean CBFVmean did not vary, there was considerable heterogeneity among patients. Twelve patients (23%) experienced reductions of CBFVmean of >20% during HEA intervals (99% lower confidence limit: 9%) and 6 (12%) reductions of >30% (99% lower confidence limit: 1%). There was no correlation between CBFVmean and MAP for MAPs between 100 and 40 mm Hg (R = 0.0015, P = 0.44). There were no instances of gross postoperative neurologic injury. CONCLUSIONS: Both hypotheses proved partially correct. CBFV was sometimes well maintained during HEA, despite MAPs well below the commonly accepted lower limit of autoregulation. However, there was considerable interindividual heterogeneity with 23% of subjects having CBFV reductions >20% (99% lower confidence limit: 9%), with some reductions approaching the threshold for ischemic injury. The present data do not allow us to determine whether hypotension would be similarly tolerated in other circumstances.

Paraplegia after epidural-general anesthesia in a Morquio patient with moderate thoracic spinal stenosis.

PURPOSE: We describe an instance in which complete paraplegia was evident immediately postoperatively after apparently uneventful lumbar epidural-general anesthesia in a patient with Morquio Type A syndrome (Morquio A) with moderate thoracic spinal stenosis. CLINICAL FEATURES: A 16-yr-old male with Morquio A received lumbar epidural-general anesthesia for bilateral distal femoral osteotomies. Preoperative imaging had revealed a stable cervical spine and moderate thoracic spinal stenosis with a mild degree of spinal cord compression. Systolic blood pressure (BP) was maintained within 20% of the pre-anesthetic baseline value. The patient sustained a severe thoracic spinal cord infarction. The epidural anesthetic contributed to considerable delay in the recognition of the diagnosis of paraplegia. CONCLUSION: This experience leads us to suggest that, in patients with Morquio A, it may be prudent to avoid the use of epidural anesthesia without very firm indication, to support BP at or near baseline levels in the presence of even moderate spinal stenosis, and to avoid flexion or extension of the spinal column in intraoperative positioning. If the spinal cord/column status is unknown or if the patient is known to have any degree of spinal stenosis, we suggest that the same rigorous BP support practices that are typically applied in other patients with severe spinal stenosis, especially stenosis with myelomalacia, should apply to patients with Morquio A and that spinal cord neurophysiological monitoring should be employed. In the event that cord imaging is not available, e.g., emergency procedures, it would be prudent to assume the presence of spinal stenosis.

Direct pressure on a pseudomeningocele resulting in intraoperative cerebral ischemia.

PURPOSE: When positioning patients with meningocele and meningomyelocele, it is standard practice to avoid direct pressure on the lesions. That caution is intended to prevent injury to neural elements within the lesion and violation of the cerebrospinal fluid space. We herein report an additional hazard of direct intraoperative pressure on such lesions. An adult patient with a lumbosacral pseudomeningocele sustained a cerebral ischemic injury as a consequence of direct pressure on the lesion during general anesthesia. CLINICAL FEATURES: A 32-yr-old male with spina bifida and a pseudomeningocele related to recent lumbar surgery underwent a urologic procedure in the lithotomy position. Because the lesion was recognized to lie to the left of the midline, cushioning was placed under the patient's left hip and buttock. The patient was slow to awaken and has sustained significant long-term cognitive deficits. Imaging is consistent with a diffuse cerebral ischemic insult. CONCLUSION: In retrospect, the size and leftward extent of the pseudomeningocele were not appreciated preoperatively, and in spite of the care taken, intraoperative pressure was placed on the lesion. This report cautions that intraoperative pressure related to positioning patients with extra-axial lesions containing cerebrospinal fluid (CSF), e.g., meningoceles and pseudomeningoceles, can result in increases in CSF pressure and thereby a reduction in cerebral perfusion pressure sufficient to result in cerebral ischemia.

An observational study of the influence of "white-coat hypertension" on day-of-surgery blood pressure determinations.

BACKGROUND: Because decisions as to what range of intraoperative blood pressure (BP) is consistent with cerebral well-being are often made in reference to "baseline BP," we sought to determine whether day-of-surgery BPs accurately reflect baseline BP, as defined by ambulatory clinic BPs over the preceding 7 months. METHODS: Consecutive patients (n=101) who were severely hypertensive (Severe-HTN), systolic (S)>160 mm Hg, or diastolic (D)>100 at first operating room BP (1st OR-BP) were identified retrospectively. Two additional groups were formed from patients whose 1st OR-BP was moderately hypertensive (Mod-HTN, systolic BP=140 to 159 and/or diastolic BP=90 to 99; and normotensive, SBP=110 to 139 and DBP<89). 1st OR-BP was compared with: (1) BP before transfer to the OR (Pre-OR-BP); (2) BP during ambulatory evaluation 1 to 30 days preoperatively (Preop-Eval-BP); and (3) Baseline-BP (average of at least 3 ambulatory clinic BPs during the preceding 7 months). Comorbidity data were collected. RESULTS: For Severe-HTNs, 1st OR-BP, and Pre-OR-BP (expressed as mean arterial pressure) exceeded Baseline-BP by 16.4±11.6 (SD) and 5.2±11.6 (SD), respectively (P<0.05). Preop-Eval-BP was not different from Baseline-BP. For Mod-HTNs, 1st OR-BP exceeded Baseline-BP by 7.4±8.1 (SD) (P<0.05). But, Pre-OR-BP and Preop-Eval-BP did not differ from Baseline-BP. Among normotensives, 1st OR-BP was not different from Preop-Eval-BP or Baseline-BP. Hypertension, number of antihypertensive medications, vascular diagnoses (peripheral, coronary, cerebral), diabetes, and renal disease were more common in the hypertensive groups. The number of antihypertensive medications, a history of coronary disease, and insulin administration were predictors of an increase in 1st OR-BP over Baseline-BP. CONCLUSIONS: For most patients whose 1st OR-BP is hypertensive, that BP is greater than ambulatory clinic BPs recorded during the preceding 7 months. For most patients with Severe-HTN at 1st OR-BP, day-of-surgery BPs overestimate Baseline-BP and reference to prehospitalization BPs is advisable. When 1st OR-BP is normotensive, that BP usually reflects Baseline-BP.

Focal cerebral ischemia after surgery in the "beach chair" position: the role of a congenital variation of circle of Willis anatomy.

A 50-year-old man underwent shoulder surgery in the beach chair position. His mean arterial blood pressure at arm level was approximately 65 mm Hg. Postoperatively, there was delayed awakening and a right hemiparesis. Radiologic evaluation revealed a congenital asymmetry of the circle of Willis that resulted in limited collateral flow to the left anterior and middle cerebral artery distributions. Similar anatomical variations are relatively common in the general population and may render some patients relatively and unpredictably more vulnerable to hypotension.

Spinal cord ischemia occurring in association with induced hypotension for colonic surgery.

A 19-year-old woman underwent an ileoanal pull-through. Intraoperatively, deepening of anesthesia was associated with reduced bleeding. Therefore, induced hypotension, mean arterial blood pressure 50 to 55 mm Hg, was maintained for 2.5 hours. Postoperatively, the patient was paraplegic with spinal cord infarction on magnetic resonance imaging from T9 to the tip of the conus medullaris. The collateralization of the anterior spinal artery is very variable and it seems likely that in this individual induced hypotension was associated with inadequate blood flow in the distribution of the artery of Adamkiewicz.

Caveolin-1 expression is essential for N-methyl-D-aspartate receptor-mediated Src and extracellular signal-regulated kinase 1/2 activation and protection of primary neurons from ischemic cell death.

N-Methyl-D-aspartate (NMDA) receptor (NMDAR) activation and downstream signaling are important for neuronal function. Activation of prosurvival Src family kinases and extracellular signal-regulated kinase (ERK) 1/2 is initiated by NMDAR activation, but the cellular organization of these kinases in relation to NMDARs is not entirely clear. We hypothesized that caveolin-1 scaffolds and coordinates protein complexes involved in NMDAR signaling and that this organization is necessary for neuronal preconditioning, whereby NMDAR activation protects neurons from subsequent ischemic cell death. We found that sublethal ischemia (SLI) or preconditioning via NMDA treatment of primary cortical neurons from neonatal rats or mice increases expression of phosphorylated (P) caveolin-1, P-Src, and P-ERK1/2. The NMDAR antagonist, MK801, or the Src inhibitor, PP2, attenuated SLI-induced preconditioning. NMDAR2B distributed to buoyant fractions and heavy fractions, partially colocalized with caveolin-1 and the membrane raft marker, cholera toxin B. Cultures of primary neurons treated with caveolin-1 small interfering RNA or from caveolin-1(-/-) mice lacked the NMDA-mediated increase in P-Src and P-ERK, as well as SLI- and NMDA-induced preconditioning. Adenovirally mediated expression of caveolin-1 in neurons from caveolin-1(-/-) mice restored NMDA-mediated enhancement of P-Src and P-ERK1/2, redistributed NMDAR2B to buoyant fractions, and enhanced NMDAR2B localization to membrane rafts. We conclude that caveolin-1, perhaps via its ability to scaffold key signaling components, is essential for NMDAR localization to neuronal membrane rafts, NMDAR/Src tyrosine kinase family/ERK signaling, and protection of neurons from ischemic injury and cell death.