Postoperative stroke assessment inconsistencies in cardiac surgery: Contributors to higher stroke-related mortality?

OBJECTIVES: In-hospital stroke mortality is surprisingly much worse than for strokes occurring outside of the hospital. Cardiac surgery patients are amongst the highest risk groups for in-hospital stroke and experience high stroke-related mortality. Variability in institutional practices appears to play an important role in the diagnosis, management, and outcome of postoperative stroke. We therefore tested the hypothesis that variability in postoperative stroke management of cardiac surgical patients exists across institutions. MATERIALS AND METHODS: A 13 item survey was employed to determine postoperative stroke practice patterns for cardiac surgical patients across 45 academic institutions. RESULTS: Less than half (44%) reported any formal clinical effort to preoperatively identify patients at high risk for postoperative stroke. Epiaortic ultrasonography for the detection of aortic atheroma, a proven preventative measure, was routinely practiced in only 16% of institutions. Forty-four percent (44%) reported not knowing whether a validated stroke assessment tool was utilized for the detection of postoperative stroke, and 20% reported that validated tools were not routinely used. All responders, however, confirmed the availability of stroke intervention teams. CONCLUSIONS: Adoption of a best practices approach to the management of postoperative stroke is highly variable and may improve outcomes in postoperative stroke after cardiac surgery.

Impact of supervised exercise on skeletal muscle blood flow and vascular function measured with MRI in patients with peripheral artery disease.

Supervised exercise is a common therapeutic intervention for patients with peripheral artery disease (PAD), however, the mechanism underlying the improvement in claudication symptomatology is not completely understood. The hypothesis that exercise improves microvascular blood flow is herein tested via temporally resolved magnetic resonance imaging (MRI) measurement of blood flow and oxygenation dynamics during reactive hyperemia in the leg with the lower ankle-brachial index. One hundred and forty-eight subjects with PAD were prospectively assigned to standard medical care or 3 mo of supervised exercise therapy. Before and after the intervention period, subjects performed a graded treadmill walking test, and MRI data were collected with Perfusion, Intravascular Venous Oxygen saturation, and T2* (PIVOT), a method that simultaneously quantifies microvascular perfusion, as well as relative oxygenation changes in skeletal muscle and venous oxygen saturation in a large draining vein. The 3-mo exercise intervention was associated with an improvement in peak walking time (64% greater in those randomized to the exercise group at follow-up, P < 0.001). Significant differences were not observed in the MRI measures between the subjects randomized to exercise therapy versus standard medical care based on an intention-to-treat analysis. However, the peak postischemia perfusion averaged across the leg between baseline and follow-up visits increased by 10% (P = 0.021) in participants that were adherent to the exercise protocol (completed >80% of prescribed exercise visits). In this cohort of adherent exercisers, there was no difference in the time to peak perfusion or oxygenation metrics, suggesting that there was no improvement in microvascular function nor changes in tissue metabolism in response to the 3-mo exercise intervention.NEW & NOTEWORTHY Supervised exercise interventions can improve symptomatology in patients with peripheral artery disease, but the underlying mechanism remains unclear. Here, MRI was used to evaluate perfusion, relative tissue oxygenation, and venous oxygen saturation in response to cuff-induced ischemia. Reactive hyperemia responses were measured before and after 3 mo of randomized supervised exercise therapy or standard medical care. Those participants who were adherent to the exercise regimen had a significant improvement in peak perfusion.

Anesthesia and neurotoxicity study design, execution, and reporting in the nonhuman primate: A systematic review.

BACKGROUND: Concern for a role of anesthesia in neurotoxicity in children originated from neonatal rodent and nonhuman primate (NHP) models, yet prospective clinical studies have largely not supported this concern. The goal of this study was to conduct an objective assessment of published NHP study rigor in design, execution, and reporting. METHODS: A MEDLINE search from 2005 to December 2021 was performed. Inclusion criteria included full-length original studies published in English under peer-reviewed journals. We documented experimental parameters on anesthetic dosing, monitoring, vitals, and experimental outcomes. RESULTS: Twenty-three manuscripts were included. Critical issues identified in study design included: lack of blinding in data acquisition (57%) and analysis (100%), supratherapeutic (4-12 fold) maintenance dosing in 22% of studies, lack of sample size justification (91%) resulting in a mean (SD) sample size of 6 (3) animals per group. Critical items identified in the conduct and reporting of studies included: documentation of anesthesia provider (0%), electrocardiogram monitoring (35%), arterial monitoring (4%), spontaneous ventilation employed (35%), failed intubations resulting in comingling ventilated and unventilated animals in data analysis, inaccurate reporting of failed intubation, and only 50% reporting on survival. Inconsistencies were noted in drug-related induction of neuroapoptosis and region of occurrence. Further, 67%-100% of behavior outcomes were not significantly different from controls. CONCLUSIONS: Important deficits in study design, execution, and reporting were identified in neonatal NHP studies. These results raise concern for the validity and reliability of these studies and may explain in part the divergence from results obtained in human neonates.

Cerebral Hypoxia: Its Role in Age-Related Chronic and Acute Cognitive Dysfunction.

Postoperative cognitive dysfunction (POCD) has been reported with widely varying frequency but appears to be strongly associated with aging. Outside of the surgical arena, chronic and acute cerebral hypoxia may exist as a result of respiratory, cardiovascular, or anemic conditions. Hypoxia has been extensively implicated in cognitive impairment. Furthermore, disease states associated with hypoxia both accompany and progress with aging. Perioperative cerebral hypoxia is likely underdiagnosed, and its contribution to POCD is underappreciated. Herein, we discuss the various disease processes and forms in which hypoxia may contribute to POCD. Furthermore, we outline hypoxia-related mechanisms, such as hypoxia-inducible factor activation, cerebral ischemia, cerebrovascular reserve, excitotoxicity, and neuroinflammation, which may contribute to cognitive impairment and how these mechanisms interact with aging. Finally, we discuss opportunities to prevent and manage POCD related to hypoxia.

Hypoxia, hypercarbia, and mortality reporting in studies of anaesthesia-related neonatal neurodevelopmental delay in rodent models: A systematic review.

BACKGROUND: The concept of anaesthesia-related neonatal neurotoxicity originated in neonatal rodent models, yet prospective clinical studies have largely not supported this concern. OBJECTIVES: To determine the frequency and magnitude of hypercarbia, hypoxia and death in rodent models of neonatal anaesthetic toxicity and neurodevelopmental delay. DESIGN: Systematic review of published rodent studies of neonatal anaesthesia neurotoxicity. We documented anaesthetic, route, dose, frequency and duration of exposures. We further report ventilation method, documentation of adequacy of ventilation [arterial blood gas (ABG), other], mortality and the reporting of mortality. DATA SOURCES: A PubMed literature search from 2003 to 2017 was conducted to identify studies on neurotoxicity in neonatal rodent models. ELIGIBILITY: Studies were included when at least one group of animals fell within the postnatal age range of 3 to 15 days. Only English language original studies published as full-length articles in peer reviewed journals were included in the final analysis. RESULTS: One hundred and three manuscripts were included. Ninety-eight percent of studies were conducted using spontaneous ventilation (101/103), with ABG monitoring used in only 33% of studies and visual monitoring alone for respiratory distress or cyanosis was employed in 60%. Of the 33% who reported ABG results, there were widely divergent values, with most reporting modest-to-severe hypercarbia. Mortality (median 11%, range of 0 to 40%), which infers severe hypoxia, was documented in only 36/103 (35%) reports. CONCLUSION: Hypoxia and hypercarbia have known apoptotic effects on developing brains. Hence, the inadequate control of hypercarbia and hypoxia in neonatal rodent models of anaesthetic exposure during spontaneous ventilation suggests that the evidence for developmental delay and neurotoxicity attributed to anaesthesia may not be valid in humans.

Simultaneous measurement of macro- and microvascular blood flow and oxygen saturation for quantification of muscle oxygen consumption.

PURPOSE: To investigate the relationship between blood flow and oxygen consumption in skeletal muscle, a technique called "Velocity and Perfusion, Intravascular Venous Oxygen saturation and T2*" (vPIVOT) is presented. vPIVOT allows the quantification of feeding artery blood flow velocity, perfusion, draining vein oxygen saturation, and muscle T2*, all at 4-s temporal resolution. Together, the measurement of blood flow and oxygen extraction can yield muscle oxygen consumption ( V˙O2) via the Fick principle. METHODS: In five subjects, vPIVOT-derived results were compared with those obtained from stand-alone sequences during separate ischemia-reperfusion paradigms to investigate the presence of measurement bias. Subsequently, in 10 subjects, vPIVOT was applied to assess muscle hemodynamics and V˙O2 following a bout of dynamic plantar flexion contractions. RESULTS: From the ischemia-reperfusion paradigm, no significant differences were observed between data from vPIVOT and comparison sequences. After exercise, the macrovascular flow response reached a maximum 8 ± 3 s after relaxation; however, perfusion in the gastrocnemius muscle continued to rise for 101 ± 53 s. Peak V˙O2 calculated based on mass-normalized arterial blood flow or perfusion was 15.2 ± 6.7 mL O2 /min/100 g or 6.0 ± 1.9 mL O2 /min/100 g, respectively. CONCLUSIONS: vPIVOT is a new method to measure blood flow and oxygen saturation, and therefore to quantify muscle oxygen consumption. Magn Reson Med 79:846-855, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Pathogenesis and Risk Factors for Cerebral Infarct After Surgical Aortic Valve Replacement.

BACKGROUND AND PURPOSE: Stroke is a potentially devastating complication of cardiac surgery. Identifying predictors of radiographic infarct may lead to improved stroke prevention for surgical patients. METHODS: We reviewed 129 postoperative brain magnetic resonance imagings from a prospective study of patients undergoing surgical aortic valve replacement. Acute infarcts were classified as watershed or embolic using prespecified criteria. RESULTS: Acute infarct on magnetic resonance imaging was seen in 79 of 129 patients (61%), and interrater reliability for stroke pathogenesis was high (κ=0.93). Embolic infarcts only were identified in 60 patients (46%), watershed only in 2 (2%), and both in 17 (13%). In multivariable logistic regression, embolic infarct was associated with aortic arch atheroma (odds ratio [OR], 3.4; 95% confidence interval [CI], 1.0-12.0; P=0.055), old subcortical infarcts (OR, 5.5; 95% CI, 1.1-26.6; P=0.04), no history of percutaneous transluminal coronary angioplasty or coronary artery bypass graft (OR, 4.0; 95% CI, 1.2-13.7; P=0.03), and higher aortic valve gradient (OR, 1.3 per 5 mm Hg; 95% CI, 1.09-1.6; P=0.004). Watershed infarct was associated with internal carotid artery stenosis ≥70% (OR, 11.7; 95% CI, 1.8-76.8; P=0.01) and increased left ventricular ejection fraction (OR, 1.6 per 5% increase; 95% CI, 1.08-2.4; P=0.02). CONCLUSIONS: The principal mechanism of acute cerebral infarction after aortic valve replacement is embolism. There are distinct factors associated with watershed and embolic infarct, some of which may be modifiable.

Measurement of skeletal muscle perfusion dynamics with pseudo-continuous arterial spin labeling (pCASL): Assessment of relative labeling efficiency at rest and during hyperemia, and comparison to pulsed arterial spin labeling (PASL).

PURPOSE: To compare calf skeletal muscle perfusion measured with pulsed arterial spin labeling (PASL) and pseudo-continuous arterial spin labeling (pCASL) methods, and to assess the variability of pCASL labeling efficiency in the popliteal artery throughout an ischemia-reperfusion paradigm. MATERIALS AND METHODS: At 3T, relative pCASL labeling efficiency was experimentally assessed in five subjects by measuring the signal intensity of blood in the popliteal artery just distal to the labeling plane immediately following pCASL labeling or control preparation pulses, or without any preparation pulses throughout separate ischemia-reperfusion paradigms. The relative label and control efficiencies were determined during baseline, hyperemia, and recovery. In a separate cohort of 10 subjects, pCASL and PASL sequences were used to measure reactive hyperemia perfusion dynamics. RESULTS: Calculated pCASL labeling and control efficiencies did not differ significantly between baseline and hyperemia or between hyperemia and recovery periods. Relative to the average baseline, pCASL label efficiency was 2 ± 9% lower during hyperemia. Perfusion dynamics measured with pCASL and PASL did not differ significantly (P > 0.05). Average leg muscle peak perfusion was 47 ± 20 mL/min/100g or 50 ± 12 mL/min/100g, and time to peak perfusion was 25 ± 3 seconds and 25 ± 7 seconds from pCASL and PASL data, respectively. Differences of further metrics parameterizing the perfusion time course were not significant between pCASL and PASL measurements (P > 0.05). CONCLUSION: No change in pCASL labeling efficiency was detected despite the almost 10-fold increase in average blood flow velocity in the popliteal artery. pCASL and PASL provide precise and consistent measurement of skeletal muscle reactive hyperemia perfusion dynamics. J. MAGN. RESON. IMAGING 2016;44:929-939.

Stroke after aortic valve surgery: results from a prospective cohort.

BACKGROUND: The incidence and impact of clinical stroke and silent radiographic cerebral infarction complicating open surgical aortic valve replacement (AVR) are poorly characterized. METHODS AND RESULTS: We performed a prospective cohort study of subjects ≥65 years of age who were undergoing AVR for calcific aortic stenosis. Subjects were evaluated by neurologists preoperatively and postoperatively and underwent postoperative magnetic resonance imaging. Over a 4-year period, 196 subjects were enrolled at 2 sites (mean age, 75.8±6.2 years; 36% women; 6% nonwhite). Clinical strokes were detected in 17%, transient ischemic attack in 2%, and in-hospital mortality was 5%. The frequency of stroke in the Society for Thoracic Surgery database in this cohort was 7%. Most strokes were mild; the median National Institutes of Health Stroke Scale was 3 (interquartile range, 1-9). Clinical stroke was associated with increased length of stay (median, 12 versus 10 days; P=0.02). Moderate or severe stroke (National Institutes of Health Stroke Scale ≥10) occurred in 8 (4%) and was strongly associated with in-hospital mortality (38% versus 4%; P=0.005). Of the 109 stroke-free subjects with postoperative magnetic resonance imaging, silent infarct was identified in 59 (54%). Silent infarct was not associated with in-hospital mortality or increased length of stay. CONCLUSIONS: Clinical stroke after AVR was more common than reported previously, more than double for this same cohort in the Society for Thoracic Surgery database, and silent cerebral infarctions were detected in more than half of the patients undergoing AVR. Clinical stroke complicating AVR is associated with increased length of stay and mortality.

Fiber-optic Monitoring of Spinal Cord Hemodynamics in Experimental Aortic Occlusion.

BACKGROUND: Spinal cord ischemia occurs frequently during thoracic aneurysm repair. Current methods based on electrophysiology techniques to detect ischemia are indirect, non-specific, and temporally slow. In this article, the authors report the testing of a spinal cord blood flow and oxygenation monitor, based on diffuse correlation and optical spectroscopies, during aortic occlusion in a sheep model. METHODS: Testing was carried out in 16 Dorset sheep. Sensitivity in detecting spinal cord blood flow and oxygenation changes during aortic occlusion, pharmacologically induced hypotension and hypertension, and physiologically induced hypoxia/hypercarbia was assessed. Accuracy of the diffuse correlation spectroscopy measurements was determined via comparison with microsphere blood flow measurements. Precision was assessed through repeated measurements in response to pharmacologic interventions. RESULTS: The fiber-optic probe can be placed percutaneously and is capable of continuously measuring spinal cord blood flow and oxygenation preoperatively, intraoperatively, and postoperatively. The device is sensitive to spinal cord blood flow and oxygenation changes associated with aortic occlusion, immediately detecting a decrease in blood flow (-65 ± 32%; n = 32) and blood oxygenation (-17 ± 13%, n = 11) in 100% of trials. Comparison of spinal cord blood flow measurements by the device with microsphere measurements led to a correlation of R = 0.49, P < 0.01, and the within-sheep coefficient of variation was 9.69%. Finally, diffuse correlation spectroscopy is temporally more sensitive to ischemic interventions than motor-evoked potentials. CONCLUSION: The first-generation spinal fiber-optic monitoring device offers a novel and potentially important step forward in the monitoring of spinal cord ischemia.

Perioperative stroke.

Ischaemic or haemorrhagic perioperative stroke (that is, stroke occurring during or within 30 days following surgery) can be a devastating complication following surgery. Incidence is reported in the 0.1-0.7% range in adults undergoing non-cardiac and non-neurological surgery, in the 1-5% range in patients undergoing cardiac surgery and in the 1-10% range following neurological surgery. However, higher rates have been reported when patients are actively assessed and in high-risk populations. Prognosis is significantly worse than stroke occurring in the community, with double the 30-day mortality, greater disability and diminished quality of life among survivors. Considering the annual volume of surgeries performed worldwide, perioperative stroke represents a substantial burden. Despite notable differences in aetiology, patient populations and clinical settings, existing clinical recommendations for perioperative stroke are extrapolated mainly from stroke in the community. Perioperative in-hospital stroke is unique with respect to the stroke occurring in other settings, and it is essential to apply evidence from other settings with caution and to identify existing knowledge gaps in order to effectively guide patient care and future research.

Quantitative CMR markers of impaired vascular reactivity associated with age and peripheral artery disease.

BACKGROUND: The aim of this study was to develop and evaluate an integrated CMR method incorporating dynamic oximetry, blood flow and pulse-wave velocimetry to assess vascular reactivity in patients with peripheral artery disease (PAD) and healthy controls. METHODS AND RESULTS: The study population consisted of young healthy subjects (YH, 30 ± 7 yrs, N = 19),PAD (71 ± 9 yrs, N = 38), and older healthy controls (OHC, 68 ± 9 yrs, N = 43). Peripheral vascular reactivity was evaluated with two methods, time-resolved quantification of blood flow velocity and oxygenation level in the femoral artery and vein, respectively, performed simultaneously both at rest and hyperemia. Aortic stiffness was assessed via pulse-wave velocity. Oximetric data showed that compared to OHC, the time-course of the hemoglobin oxygen saturation in PAD patients had longer washout time (28.6 ± 1.2 vs 16.9 ± 1.1 s, p < 0.0001), reduced upslope (0.60 ± 0.1 vs 1.3 ± 0.08 HbO2/sec, p < 0.0001) and lower overshoot (8 ± 1.4 vs 14 ± 1.2 HbO2, p = 0.0064). PAD patients also had longer-lasting antegrade femoral artery flow during hyperemia (51 ± 2.1 vs 24 ± 1.8 s, p < 0.0001), and reduced peak-to-baseline flow rate (3.1 ± 0.5 vs 7.4 ± 0.4, p < 0.0001). Further, the pulsatility at rest was reduced (0.75 ± 0.32 vs 5.2 ± 0.3, p < 0.0001), and aortic PWV was elevated (10.2 ± 0.4 vs 8.1 ± 0.4 m/s, p = 0.0048). CONCLUSION: The proposed CMR protocol quantifies multiple aspects of vascular reactivity and represents an initial step toward development of a potential tool for evaluating interventions, extrapolating clinical outcomes and predicting functional endpoints based on quantitative parameters.

Combined measurement of perfusion, venous oxygen saturation, and skeletal muscle T2* during reactive hyperemia in the leg.

BACKGROUND: The function of the peripheral microvascular may be interrogated by measuring perfusion, tissue oxygen concentration, or venous oxygen saturation (SvO2) recovery dynamics following induced ischemia. The purpose of this work is to develop and evaluate a magnetic resonance (MR) technique for simultaneous measurement of perfusion, SvO2, and skeletal muscle T2*. METHODS: Perfusion, Intravascular Venous Oxygen saturation, and T2* (PIVOT) is comprised of interleaved pulsed arterial spin labeling (PASL) and multi-echo gradient-recalled echo (GRE) sequences. During the PASL post-labeling delay, images are acquired with a multi-echo GRE to quantify SvO2 and T2* at a downstream slice location. Thus time-courses of perfusion, SvO2, and T2* are quantified simultaneously within a single scan. The new sequence was compared to separately measured PASL or multi-echo GRE data during reactive hyperemia in five young healthy subjects. To explore the impairment present in peripheral artery disease patients, five patients were evaluated with PIVOT. RESULTS: Comparison of PIVOT-derived data to the standard techniques shows that there was no significant bias in any of the time-course-derived metrics. Preliminary data show that PAD patients exhibited alterations in perfusion, SvO2, and T2* time-courses compared to young healthy subjects. CONCLUSION: Simultaneous quantification of perfusion, SvO2, and T2* is possible with PIVOT. Kinetics of perfusion, SvO2, and T2* during reactive hyperemia may help to provide insight into the function of the peripheral microvasculature in patients with PAD.

Vessel-wall imaging and quantification of flow-mediated dilation using water-selective 3D SSFP-echo.

BACKGROUND: To introduce a new, efficient method for vessel-wall imaging of carotid and peripheral arteries by means of a flow-sensitive 3D water-selective SSFP-echo pulse sequence. METHODS: Periodic applications of RF pulses will generate two transverse steady states, immediately after and before an RF pulse; the latter being referred to as the SSFP-echo. The SSFP-echo signal for water protons in blood is spoiled as a result of moving spins losing phase coherence in the presence of a gradient pulse along the flow direction. Bloch equation simulations were performed over a wide range of velocities to evaluate the flow sensitivity of the SSFP-echo signal. Vessel walls of carotid and femoral and popliteal arteries were imaged at 3 T. In two patients with peripheral artery disease the femoral arteries were imaged bilaterally to demonstrate method's potential to visualize atherosclerotic plaques. The method was also evaluated as a means to measure femoral artery flow-mediated dilation (FMD) in response to cuff-induced ischemia in four subjects. RESULTS: The SSFP-echo pulse sequence, which does not have a dedicated blood signal suppression preparation, achieved low blood signal permitting discrimination of the carotid and peripheral arterial walls with in-plane spatial resolution ranging from 0.5 to 0.69 mm and slice thickness of 2 to 3 mm, i.e. comparable to conventional 2D vessel-wall imaging techniques. The results of the simulations were in good agreement with analytical solution and observations for both vascular territories examined. Scan time ranged from 2.5 to 5 s per slice yielding a contrast-to-noise ratio between the vessel wall and lumen from 3.5 to 17. Mean femoral FMD in the four subjects was 9%, in good qualitative agreement with literature values. CONCLUSIONS: Water-selective 3D SSFP-echo pulse sequence is a potential alternative to 2D vessel-wall imaging. The proposed method is fast, robust, applicable to a wide range of flow velocities, and straightforward to implement.

Aged Mouse Hippocampus Exhibits Signs of Chronic Hypoxia and an Impaired HIF-Controlled Response to Acute Hypoxic Exposures.

Altered hypoxia-inducible factor-alpha (HIF-α) activity may have significant consequences in the hippocampus, which mediates declarative memory, has limited vascularization, and is vulnerable to hypoxic insults. Previous studies have reported that neurovascular coupling is reduced in aged brains and that diseases which cause hypoxia increase with age, which may render the hippocampus susceptible to acute hypoxia. Most studies have investigated the actions of HIF-α in aging cortical structures, but few have focused on the role of HIF-α within aged hippocampus. This study tests the hypothesis that aging is associated with impaired hippocampal HIF-α activity. Dorsal hippocampal sections from mice aged 3, 9, 18, and 24 months were probed for the presence of HIF-α isoforms or their associated gene products using immunohistochemistry and fluorescent in situ hybridization (fISH). A subset of each age was exposed to acute hypoxia (8% oxygen) for 3 h to investigate changes in the responsiveness of HIF-α to hypoxia. Basal mean intensity of fluorescently labeled HIF-1α protein increases with age in the hippocampus, whereas HIF-2α intensity only increases in the 24-month group. Acute hypoxic elevation of HIF-1α is lost with aging and is reversed in the 24-month group. fISH reveals that glycolytic genes induced by HIF-1α (lactose dehydrogenase-a, phosphoglycerate kinase 1, and pyruvate dehydrogenase kinase 1) are lower in aged hippocampus than in 3-month hippocampus, and mRNA for monocarboxylate transporter 1, a lactose transporter, increases. These results indicate that lactate, used in neurotransmission, may be limited in aged hippocampus, concurrent with impaired HIF-α response to hypoxic events. Therefore, impaired HIF-α may contribute to age-associated cognitive decline during hypoxic events.

Preoperative cognition predicts clinical stroke/TIA and mortality after surgical aortic valve replacement in older adults.

Stroke and death remain risks of surgical aortic valve replacement (SAVR). Preoperative cognitive screeners repeatedly show that reduced scores predict postoperative outcome, but less is known about comprehensive neuropsychological measures predicting risk. This study had two aims: 1) investigate whether preoperative cognitive measures predicted postoperative clinical stroke/transient ischemic attack (TIA) and mortality in older adults undergoing SAVR, and 2) identify the best predictors within a comprehensive cognitive protocol. A total of 165 participants aged 65 + with moderate-to-severe aortic stenosis completed a comprehensive cognitive test battery preoperatively. Postoperative stroke evaluations were conducted by trained stroke neurologists preoperatively and postoperatively, and mortality outcomes were obtained by report and records. Logistic regressions were conducted to evaluate preoperative cognitive predictors of clinical stroke/TIA within 1 week of surgery and mortality within 1 year of surgery. Multivariate models showed measures of delayed verbal memory recall (OR = 0.86; 95% CI 0.74-0.99) and visuospatial skills (OR = 0.95; 95% CI 0.90-1.01) predicted clinical stroke/TIA within 1 week of surgery, R2 = .41, p < .001, ƒ2 = .69. Measures of naming ability (OR = 0.88; 95% CI 0.80-0.96), verbal memory recall (OR = 1.23; 95% CI 0.99-1.51), visual memory recall (OR = 0.90; 95% CI 0.80-1.00), medical comorbidities (OR = 1.71; 95% CI 1.22-2.65), and sex (OR = 2.39; 95% CI 0.90-7.04) were significant predictors of death within 1 year of surgery, R2 = .68, p < .001, ƒ2 = 2.12. Preoperative cognitive measures reflecting temporal and parietal lobe functions predicted postoperative clinical stroke/TIA within 1 week of SAVR and mortality within 1 year of SAVR. As such, cognitive measures may offer objective and timely indicators of preoperative health, specifically vulnerabilities in cerebral hypoperfusion, which may inform intervention and/or intensive postoperative monitoring and follow-up after SAVR.

Metabolite patterns associated with individual response to supervised exercise therapy in patients with intermittent claudication.

Objective: Supervised exercise therapy (SET) is the first line treatment for intermittent claudication owing to peripheral arterial disease. Despite multiple randomized controlled trials proving the efficacy of SET, there are large differences in individual patient's responses. We used plasma metabolomics to identify potential metabolic influences on the individual response to SET. Methods: Primary metabolites, complex lipids, and lipid mediators were measured on plasma samples taken at before and after Gardner graded treadmill walking tests that were administered before and after 12 weeks of SET. We used an ensemble modeling approach to identify metabolites or changes in metabolites at specific time points that associated with interindividual variability in the functional response to SET. Specific time points analyzed included baseline metabolite levels before SET, dynamic metabolomics changes before SET, the difference in pre- and post-SET baseline metabolomics, and the difference (pre- and post-SET) of the dynamic (pre- and post-treadmill). Results: High levels of baseline anandamide levels pre- and post-SET were associated with a worse response to SET. Increased arachidonic acid (AA) and decreased levels of the AA precursor dihomo-γ-linolenic acid across SET were associated with a worse response to SET. Participants who were able to tolerate large increases in AA during acute exercise had longer, or better, walking times both before and after SET. Conclusions: We identified two pathways of relevance to individual response to SET that warrant further study: anandamide synthesis may activate endocannabinoid receptors, resulting in worse treadmill test performance. SET may train patients to withstand higher levels of AA, and inflammatory signaling, resulting in longer walking times. Clinical Relevance: This manuscript describes the use of metabolomic techniques to measure the interindividual effects of SET in patients with peripheral artery disease (PAD). We identified high levels of AEA are linked to CB1 signaling and activation of inflammatory pathways. This alters energy expenditure in myoblasts by decreasing glucose uptake and may induce an acquired skeletal muscle myopathy. SET may also help participants tolerate increased levels of AA and inflammation produced during exercise, resulting in longer walking times. This data will enhance understanding of the pathophysiology of PAD and the mechanism by which SET improves walking intolerance.

Exercise Training Increases Resting Calf Muscle Oxygen Metabolism in Patients with Peripheral Artery Disease.

Exercise training can mitigate symptoms of claudication (walking-induced muscle pain) in patients with peripheral artery disease (PAD). One adaptive response enabling this improvement is enhanced muscle oxygen metabolism. To explore this issue, we used arterial-occlusion diffuse optical spectroscopy (AO-DOS) to measure the effects of exercise training on the metabolic rate of oxygen (MRO2) in resting calf muscle. Additionally, venous-occlusion DOS (VO-DOS) and frequency-domain DOS (FD-DOS) were used to measure muscle blood flow (F) and tissue oxygen saturation (StO2), and resting calf muscle oxygen extraction fraction (OEF) was calculated from MRO2, F, and blood hemoglobin. Lastly, the venous/arterial ratio (γ) of blood monitored by FD-DOS was calculated from OEF and StO2. PAD patients who experience claudication (n = 28) were randomly assigned to exercise and control groups. Patients in the exercise group received 3 months of supervised exercise training. Optical measurements were obtained at baseline and at 3 months in both groups. Resting MRO2, OEF, and F, respectively, increased by 30% (12%, 44%) (p < 0.001), 17% (6%, 45%) (p = 0.003), and 7% (0%, 16%) (p = 0.11), after exercise training (median (interquartile range)). The pre-exercise γ was 0.76 (0.61, 0.89); it decreased by 12% (35%, 6%) after exercise training (p = 0.011). Improvement in exercise performance was associated with a correlative increase in resting OEF (R = 0.45, p = 0.02).

Towards rapid intraoperative axial localization of spinal cord ischemia with epidural diffuse correlation monitoring.

Spinal cord ischemia leads to iatrogenic injury in multiple surgical fields, and the ability to immediately identify onset and anatomic origin of ischemia is critical to its management. Current clinical monitoring, however, does not directly measure spinal cord blood flow, resulting in poor sensitivity/specificity, delayed alerts, and delayed intervention. We have developed an epidural device employing diffuse correlation spectroscopy (DCS) to monitor spinal cord ischemia continuously at multiple positions. We investigate the ability of this device to localize spinal cord ischemia in a porcine model and validate DCS versus Laser Doppler Flowmetry (LDF). Specifically, we demonstrate continuous (>0.1Hz) spatially resolved (3 locations) monitoring of spinal cord blood flow in a purely ischemic model with an epidural DCS probe. Changes in blood flow measured by DCS and LDF were highly correlated (r = 0.83). Spinal cord blood flow measured by DCS caudal to aortic occlusion decreased 62%. This monitor demonstrated a sensitivity of 0.87 and specificity of 0.91 for detection of a 25% decrease in flow. This technology may enable early identification and critically important localization of spinal cord ischemia.

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

BACKGROUND: Postoperative cognitive dysfunction occurs frequently after cardiac, major vascular, and major orthopedic surgery. Aging and hypertensive cerebrovascular disease are leading risk factors for this disorder. Acute anemia, common to major surgery, has been identified as a possible contributor to postoperative cognitive dysfunction. The effect of hypoxia upon cognition and the cellular and molecular processes involved in learning and memory has been well described. Cerebrovascular changes related to chronic hypertension may expose cells to increased hypoxia with anemia. METHODS: Young to aged spontaneously hypertensive rats underwent testing for visuospatial memory and learning in the Morris water maze, measurement of cerebral tissue oxygenation via tissue oxygen probe, and measurement of hypoxia-sensitive genes and proteins, under conditions of sham and experimental isovolemic anemia. RESULTS: Acute isovolemic anemia elicited evidence of aging-dependent visuospatial working memory and learning impairment. Isovolemic anemia did not result in cerebral tissue hypoxia, when measured via tissue oxygen probe. Evidence of cellular hypoxia was, however, identified in response to the anemic challenge, as hypoxia-sensitive genes and proteins were up-regulated. Importantly, cellular hypoxic gene responses were increased with anemia in an age-dependent manner in this model of aging with chronic hypertension. CONCLUSIONS: In a translational model of chronic hypertension, clinically relevant levels of acute anemia were associated with an age-dependent visuospatial working memory and learning impairment that was matched by an age-dependent cellular sensitivity to anemic hypoxia. These data offer support for a possible link between anemic hypoxia and postoperative cognitive dysfunction in humans.