Intraoperative Echocardiography: Guide to Decision-Making.

PURPOSE OF REVIEW: This review aims to provide a concise overview of key recommendations, with a specific focus on common challenges faced by intraoperative echocardiographers when dealing with frequently encountered valvular pathologies and mechanical circulatory support. It offers valuable insights for medical practitioners in this field. RECENT FINDINGS: The American Society of Echocardiography (ASE) and the American College of Cardiology/American Heart Association (ACC/AHA) have released updated comprehensive guidelines for the use of transesophageal echocardiography (TEE) for the assessment of cardiac structures and implanted devices to help guide intraoperative decision-making. Transesophageal echocardiography (TEE) is a regularly employed intraoperative diagnostic and monitoring tool, offering various modalities for the rapid evaluation of valvular and aortic pathology, hemodynamic disturbances, and cardiac function. It is particularly valuable in assessing and placing mechanical circulatory support (MCS) devices, providing views often challenging to obtain through transthoracic echocardiography. Additionally, intraoperative TEE can be used for decision-making in patients with valvular disease allowing incorporation of patient-specific and situational factors. Echocardiographers can employ this information in real-time to help guide surgical treatment selection such as repair, replacement, or deferral of intervention.

Pharmacological effects of ex vivo mesenchymal stem cell immunotherapy in patients with acute kidney injury and underlying systemic inflammation.

Mesenchymal stem cells (MSCs) have natural immunoregulatory functions that have been explored for medicinal use as a cell therapy with limited success. A phase Ib study was conducted to evaluate the safety and immunoregulatory mechanism of action of MSCs using a novel ex vivo product (SBI-101) to preserve cell activity in patients with severe acute kidney injury. Pharmacological data demonstrated MSC-secreted factor activity that was associated with anti-inflammatory signatures in the molecular and cellular profiling of patient blood. Systems biology analysis captured multicompartment effects consistent with immune reprogramming and kidney tissue repair. Although the study was not powered for clinical efficacy, these results are supportive of the therapeutic hypothesis, namely, that treatment with SBI-101 elicits an immunotherapeutic response that triggers an accelerated phenotypic switch from tissue injury to tissue repair. Ex vivo administration of MSCs, with increased power of testing, is a potential new biological delivery paradigm that assures sustained MSC activity and immunomodulation.

Teprasiran, a Small Interfering RNA, for the Prevention of Acute Kidney Injury in High-Risk Patients Undergoing Cardiac Surgery: A Randomized Clinical Study.

BACKGROUND: Acute kidney injury (AKI) affects up to 30% of patients undergoing cardiac surgery, leading to increased in-hospital and long-term morbidity and mortality. Teprasiran is a novel small interfering RNA that temporarily inhibits p53-mediated cell death that underlies AKI. METHODS: This prospective, multicenter, double-blind, randomized, controlled phase 2 trial evaluated the efficacy and safety of a single 10 mg/kg dose of teprasiran versus placebo (1:1), in reducing the incidence, severity, and duration of AKI after cardiac surgery in high-risk patients. The primary end point was the proportion of patients who developed AKI determined by serum creatinine by postoperative day 5. Other end points included AKI severity and duration using various prespecified criteria. To inform future clinical development, a composite end point of major adverse kidney events at day 90, including death, renal replacement therapy, and ≥25% reduction of estimated glomerular filtration rate was assessed. Both serum creatinine and serum cystatin-C were used for estimated glomerular filtration rate assessments. RESULTS: A total of 360 patients were randomly assigned in 41 centers; 341 dosed patients were 73±7.5 years of age (mean±SD), 72% were men, and median European System for Cardiac Operative Risk Evaluation score was 2.6%. Demographics and surgical parameters were similar between groups. AKI incidence was 37% for teprasiran- versus 50% for placebo-treated patients, a 12.8% absolute risk reduction, P=0.02; odds ratio, 0.58 (95% CI, 0.37-0.92). AKI severity and duration were also improved with teprasiran: 2.5% of teprasiran- versus 6.7% of placebo-treated patients had grade 3 AKI; 7% teprasiran- versus 13% placebo-treated patients had AKI lasting for 5 days. No significant difference was observed for the major adverse kidney events at day 90 composite in the overall population. No safety issues were identified with teprasiran treatment. CONCLUSIONS: The incidence, severity, and duration of early AKI in high-risk patients undergoing cardiac surgery were significantly reduced after teprasiran administration. A phase 3 study with a major adverse kidney event at day 90 primary outcome that has recently completed enrollment was designed on the basis of these findings (NCT03510897). Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02610283.

Conventional Ultrafiltration During Elective Cardiac Surgery and Postoperative Acute Kidney Injury.

OBJECTIVE: Conventional ultrafiltration (CUF) during cardiopulmonary bypass (CPB) serves to hemoconcentrate blood volume to avoid allogeneic blood transfusions. Previous studies have determined CUF volumes as a continuous variable are associated with postoperative acute kidney injury (AKI) after cardiac surgery, but optimal weight-indexed volumes that predict AKI have not been described. DESIGN: Retrospective cohort. SETTING: Single-center university hospital. PARTICIPANTS: A total of 1,641 consecutive patients who underwent elective cardiac surgery between June 2013 and December 2015. INTERVENTIONS: The CUF volume was removed during CPB in all participants as part of routine practice. The authors investigated the association of dichotomized weight-indexed CUF volume removal with postoperative AKI development to provide pragmatic guidance for clinical practice at the authors' institution. MEASUREMENTS AND MAIN RESULTS: Primary outcomes of postoperative AKI were defined by the Kidney Disease: Improving Global Outcomes staging criteria and dichotomized, weight-indexed CUF volumes (mL/kg) were defined by (1) extreme quartiles (Q3) and (2) Youden's criterion that best predicted AKI development. Multivariate logistic regression models were developed to test the association of these dichotomized indices with AKI status. Postoperative AKI occurred in 827 patients (50.4%). Higher CUF volumes were associated with AKI development by quartiles (CUF >Q3 = 32.6 v CUF < Q1 = 10.4 mL/kg; odds ratio [OR] = 1.68, 95% CI: 1.19-2.3) and Youden's criterion (CUF ≥ 32.9 v CUF <32.9 mL/kg; OR = 1.60, 95% CI: 1.21-2.13). Despite similar intraoperative nadir hematocrits among groups (p = 0.8), higher CUF volumes were associated with more allogeneic blood transfusions (p = 0.002) and longer lengths of stay (p < 0.001). CONCLUSIONS: Removal of weight-indexed CUF volumes > 32 mL/kg increased the risk for postoperative AKI development. Importantly, CUF volume removal of any amount did not mitigate allogeneic blood transfusion during elective cardiac surgery. Prospective studies are needed to validate these findings.

Hepatocyte Growth Factor Mimetic ANG-3777 for Cardiac Surgery-Associated Acute Kidney Injury.

INTRODUCTION: Nearly one-third of patients undergoing cardiac surgery involving cardiopulmonary bypass (CPB) experience cardiac surgery-associated (CSA) acute kidney injury (AKI); 5% require renal replacement therapy. ANG-3777 is a hepatocyte growth factor mimetic. In vitro, ANG-3777 reduces apoptosis and increases cell proliferation, migration, morphogenesis, and angiogenesis in injured kidneys. In animal models, ANG-3777 mitigates the effects of renal damage secondary to ischemia reperfusion injury and nephrotoxic chemicals. Phase 2 data in AKI of renal transplantation have shown improved renal function and comparable safety relative to placebo. The Guard Against Renal Damage (GUARD) study is a phase 2 proof of concept trial of ANG-3777 in CSA-AKI. METHODS: GUARD is a 240-patient, multicenter, double-blind, randomized placebo-controlled trial to assess the efficacy and safety of ANG-3777 in patients at elevated pre-surgery risk for AKI undergoing coronary artery bypass graft (CABG) or heart valve repair/replacement requiring CPB. Subjects are randomized 1:1 to receive ANG-3777 (2 mg/kg) or placebo. Study drug is dosed via 4 daily intravenous 30-minute infusions. The first dose is administered less than 4 hours after completing CPB, second at 24 ± 2 hours post-CPB, with two subsequent doses at 24 ± 2 hours after the previous dose. RESULTS: The primary efficacy endpoint is percent change from baseline serum creatinine to mean area under the curve from days 2 through 6. Secondary endpoints include change in estimated glomerular filtration rate from baseline to day 30, the proportion of patients diagnosed with AKI by stage through day 5, and the length of CSA-AKI hospitalization. Safety will include adverse events and laboratory measures. CONCLUSION: This phase 2 study of ANG-3777 provides data to develop a phase 3 registrational study in this medically complex condition.

Guidelines for the Use of Transesophageal Echocardiography to Assist with Surgical Decision-Making in the Operating Room: A Surgery-Based Approach: From the American Society of Echocardiography in Collaboration with the Society of Cardiovascular Anesthesiologists and the Society of Thoracic Surgeons.

Intraoperative transesophageal echocardiography is a standard diagnostic and monitoring tool employed in the management of patients undergoing an entire spectrum of cardiac surgical procedures, ranging from "routine" surgical coronary revascularization to complex valve repair, combined procedures, and organ transplantation. Utilizing a protocol as a starting point for imaging in all procedures and all patients enables standardization of image acquisition, reduction in variability in quality of imaging and reporting, and ultimately better patient care. Clear communication of the echocardiographic findings to the surgical team, as well as understanding the impact of new findings on the surgical plan, are paramount. Equally important is the need for complete understanding of the technical steps of the surgical procedures being performed and the complications that may occur, in order to direct the postprocedure evaluation toward aspects directly related to the surgical procedure and to provide pertinent echocardiographic information. The rationale for this document is to outline a systematic approach describing how to apply the existing guidelines to questions on cardiac structure and function specific to the intraoperative environment in open, minimally invasive, or hybrid cardiac surgery procedures.

Differences in Two- and Three-Dimensional Assessment of the Mitral Valve by Novices and Experts, Illustrated Using Anterior Mitral Valve Leaflet Length.

OBJECTIVES: In this measurement validation study, the authors evaluated agreement between 2-dimensional (2D) and three-dimensional (3D) transesophageal echocardiography (TEE), measuring anterior mitral valve leaflet length by both novice and experienced echocardiographers. DESIGN: This was a retrospective, observational study. SETTING: Single university hospital. PARTICIPANTS: Analyses on datasets from 44 patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Fifty datasets from 44 patients with mitral regurgitation were analyzed by 4 observers (2 novices, 2 experts). All observers measured the anterior mitral valve leaflet length from end-systolic 2D TEE images from the midesophageal longitudinal axis view and 3D software-augmented TEE images. The overall mean anterior mitral valve leaflet length was significantly shorter with 3D versus 2D TEE measurements (24.6 ± 4.5 mm v 26.2 ± 5.3 mm; p < 0.001), with novices measuring shorter leaflets than experts for both techniques (p < 0.001 and p = 0.005, respectively). Bland-Altman plots of 3D and 2D TEE measurements showed mean biases (95% limits of agreement) of -1.6 mm (-9.0 to 5.9 mm), -1.8 mm (-9.6 to 6.0 mm), and -1.3 mm (-8.4 to 5.7 mm) for all observers, novices, and experts, respectively. For 2D measurements, interobserver reliability was very strong among experts and strong among novices (Pearson's r = 0.83 v 0.66; p = 0.055). For 3D measurements, interobserver reliability was strong in experts and moderate in novices (Pearson's r = 0.69 v 0.51; p = 0.168). CONCLUSION: For both novices and experts, 3D TEE measurements of the anterior mitral valve leaflet were significantly shorter than 2D measurements. Interobserver reliability was lowest for novices making 3D TEE measurements, indicating that reliable, quantitative evaluation of 3D TEE may require a greater amount of practice.

Renal Angina Is a Sensitive, but Nonspecific Identifier of Postcardiac Surgery Acute Kidney Injury.

OBJECTIVES: Acute kidney injury (AKI) is a common complication of cardiac surgery, and early detection is difficult. This study was performed to determine the sensitivity, specificity, positive predictive value, negative predictive value, and statistical performance of renal angina (RA) as an early predictor of AKI in an adult cardiac surgical patient population. DESIGN: Retrospective, nonrandomized, observational study. SETTING: A single, university-affiliated, quaternary medical center. PARTICIPANTS: The study comprised 324 consecutive patients undergoing coronary artery bypass grafting or cardiac valvular surgery from February 1 through July 30, 2014. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: One hundred-seven patients at moderate or high risk of developing postoperative renal injury were identified, 82 of whom met criteria for RA. The occurrence of RA was found to have an 80.9% sensitivity and 30.8% specificity for the prediction of AKI using Acute Kidney Injury Network criteria and 89.3% sensitivity and 27.8% specificity when paired with the Risk, Injury, Failure, Loss, End Stage Renal Disease criteria. A receiver operating characteristic area under the curve analysis revealed a nonsignificant predictive ability of 55.8% (95% confidence interval 0.47-0.65) when RA was paired with Acute Kidney Injury Network criteria; however, the receiver operating characteristic area under the curve was significant when paired with Risk, Injury, Failure, Loss, End Stage Renal Disease criteria, with a predictive ability of 0.586 (0.509-0.662). CONCLUSIONS: RA is a sensitive, but nonspecific, predictor of postcardiac surgery AKI, with clinical utility most suited as a screening tool.

Tricuspid Valve Regurgitation Immediately After Heart Transplant and Long-Term Outcomes.

BACKGROUND: Tricuspid valve regurgitation (TR) is a common finding immediately after cardiac transplantation. However, there is a scarcity of data regarding its implication if left untreated on long-term outcomes and the role of early surgical repair. METHODS: We retrospectively reviewed the Duke University Medical Center transplant database from January 2000 to June 2012 and identified 542 patients who underwent orthotropic heart transplantation. Patients were excluded if they underwent surgical repair for TR during the transplant or if the transplant was part of a multiorgan transplant or redo heart transplantation. TR was assessed intraoperatively after weaning from cardiopulmonary bypass. Independent variables were grade of TR and changes in TR grade during follow-up. TR grades were classified as insignificant (none or mild) versus significant (moderate or severe). Survival and need for posttransplant valve repair during follow-up were assessed. RESULTS: Significant TR was detected in 114 patients (21%) after weaning from cardiopulmonary bypass, with no significant difference in preoperative recipient pulmonary vascular resistance. Significant TR was associated with increased maximum postoperative plasma creatinine (median [interquartile range], 2.2 [1.5 to 3.2] mg/dL vs 1.8 [1.4 to 2.6] mg/dL, p = 0.008), prolonged postoperative stay (median [interquartile range], 12 [9 to 21] days vs 10 [8 to 14] days; p < 0.001), and decreased adjusted survival. Significant TR regressed to insignificant in 91% of recipients by 1 year after transplant. Six recipients (1%) who had significant TR after cardiopulmonary bypass underwent delayed tricuspid valve repair for significant TR during follow-up. CONCLUSIONS: Significant TR is a common finding immediately after transplant and is associated with early morbidity and reduced adjusted survival. Most significant TR resolves by 1 year after transplant. Optimal algorithms for follow-up and treatment of significant TR after heart transplantation need to be defined.

Development and validation of machine learning models to identify high-risk surgical patients using automatically curated electronic health record data (Pythia): A retrospective, single-site study.

BACKGROUND: Pythia is an automated, clinically curated surgical data pipeline and repository housing all surgical patient electronic health record (EHR) data from a large, quaternary, multisite health institute for data science initiatives. In an effort to better identify high-risk surgical patients from complex data, a machine learning project trained on Pythia was built to predict postoperative complication risk. METHODS AND FINDINGS: A curated data repository of surgical outcomes was created using automated SQL and R code that extracted and processed patient clinical and surgical data across 37 million clinical encounters from the EHRs. A total of 194 clinical features including patient demographics (e.g., age, sex, race), smoking status, medications, comorbidities, procedure information, and proxies for surgical complexity were constructed and aggregated. A cohort of 66,370 patients that had undergone 99,755 invasive procedural encounters between January 1, 2014, and January 31, 2017, was studied further for the purpose of predicting postoperative complications. The average complication and 30-day postoperative mortality rates of this cohort were 16.0% and 0.51%, respectively. Least absolute shrinkage and selection operator (lasso) penalized logistic regression, random forest models, and extreme gradient boosted decision trees were trained on this surgical cohort with cross-validation on 14 specific postoperative outcome groupings. Resulting models had area under the receiver operator characteristic curve (AUC) values ranging between 0.747 and 0.924, calculated on an out-of-sample test set from the last 5 months of data. Lasso penalized regression was identified as a high-performing model, providing clinically interpretable actionable insights. Highest and lowest performing lasso models predicted postoperative shock and genitourinary outcomes with AUCs of 0.924 (95% CI: 0.901, 0.946) and 0.780 (95% CI: 0.752, 0.810), respectively. A calculator requiring input of 9 data fields was created to produce a risk assessment for the 14 groupings of postoperative outcomes. A high-risk threshold (15% risk of any complication) was determined to identify high-risk surgical patients. The model sensitivity was 76%, with a specificity of 76%. Compared to heuristics that identify high-risk patients developed by clinical experts and the ACS NSQIP calculator, this tool performed superiorly, providing an improved approach for clinicians to estimate postoperative risk for patients. Limitations of this study include the missingness of data that were removed for analysis. CONCLUSIONS: Extracting and curating a large, local institution's EHR data for machine learning purposes resulted in models with strong predictive performance. These models can be used in clinical settings as decision support tools for identification of high-risk patients as well as patient evaluation and care management. Further work is necessary to evaluate the impact of the Pythia risk calculator within the clinical workflow on postoperative outcomes and to optimize this data flow for future machine learning efforts.

The Association of Aortic Valve Pathology With Renal Resistive Index as a Kidney Injury Biomarker.

BACKGROUND: Acute kidney injury (AKI) is a common serious complication after cardiac surgery. Doppler-determined renal resistive index (RRI) is a promising early AKI biomarker in this population. However, the relationship between aortic valve pathology (insufficiency and/or stenosis) and RRI is unknown. This study aimed to investigate RRI variability related to aortic valve pathology. METHODS: In a retrospective review of cardiac surgery patients, RRI and aortic valve pathology were assessed prior to cardiopulmonary bypass using transesophageal echocardiography. Aortic valve status was categorized into four subgroups: normal (insufficiency and stenosis, none/trace/mild), insufficiency (insufficiency, moderate/severe; stenosis, none/trace/mild), combined insufficiency/stenosis (insufficiency and stenosis, moderate/severe), or stenosis (insufficiency, none/trace/mild; stenosis, moderate/severe). RRI and time-matched hemodynamic and Doppler measurements were compared among subgroups. RESULTS: Of 175 patients, 60 had aortic valve pathology (16 insufficiency, 18 insufficiency/stenosis, 26 stenosis). Compared with the normal subgroup, patients with aortic insufficiency had lower diastolic blood pressure and trough renal Doppler velocities, and higher RRI (0.77 versus 0.69; p < 0.001); patients with combined insufficiency/stenosis also had higher RRI (0.72 versus 0.69, p = 0.042). CONCLUSIONS: Patients with aortic insufficiency and combined insufficiency/stenosis had higher median RRI values compared with normal patients. For these individuals, diastolic flow differences related to aortic insufficiency may explain why their presurgery RRI values often exceeded postoperative thresholds typically associated with AKI. Strategies to account for the potentially confounding effects of aortic insufficiency on renal flow patterns, independent of renal injury, may add to the value of RRI as an early AKI biomarker.

Allogeneic Mesenchymal Stem Cells for Treatment of AKI after Cardiac Surgery.

AKI after cardiac surgery remains strongly associated with mortality and lacks effective treatment or prevention. Preclinical studies suggest that cell-based interventions may influence functional recovery. We conducted a phase 2, randomized, double-blind, placebo-controlled trial in 27 centers across North America to determine the safety and efficacy of allogeneic human mesenchymal stem cells (MSCs) in reducing the time to recovery from AKI after cardiac surgery. We randomized 156 adult subjects undergoing cardiac surgery with evidence of early AKI to receive intra-aortic MSCs (AC607; n=67) or placebo (n=68). The primary outcome was the time to recovery of kidney function defined as return of postintervention creatinine level to baseline. The median time to recovery of kidney function was 15 days with AC607 and 12 days with placebo (25th, 75th percentile range, 10-29 versus 6-21, respectively; hazard ratio, 0.81; 95% confidence interval, 0.53 to 1.24; P=0.32). We did not detect a significant difference between groups in 30-day all-cause mortality (16.7% with AC607; 11.8% with placebo) or dialysis (10.6% with AC607; 7.4% with placebo). At follow-up, 12 patients who received AC607 and six patients who received placebo had died. Rates of other adverse events did not differ between groups. In these patients with AKI after cardiac surgery, administration of allogeneic MSCs did not decrease the time to recovery of kidney function. Our results contrast with those in preclinical studies and provide important information regarding the potential effects of MSCs in this setting.

Neuroendocrine stress response: implications for cardiac surgery-associated acute kidney injury.

Surgical stress causes biochemical and physiologic perturbations of every homeostatic axis. These alterations include volume/baroreceptor regulation, sympathetic activation, parasympathetic suppression, neuroendocrine activation, acute phase response protein synthesis and secretion, immune response modulation and long-term behavioral adaptation. The kidney is central to the stress response because of its main role in the maintenance of water, electrolyte balance and hence, intracellular and extracellular compartments, including the intravascular volume. Acute kidney injury after cardiac surgery occurs as a result of numerous factors including ischemia-reperfusion, inflammation, oxidative stress, neurohormonal activation, metabolic factors, and nephrotoxicity or pigment nephropathy. The neuroendocrine stress response has a central role in initiating renal injury during cardiac surgery through an increased release of arginine-vasopressin and activation of the sympathetic nervous system and the intrarenal and systemic renin-angiotensin-aldosterone system. The contribution of an exaggerated neuroendocrine stress response to cardiac surgery and cardiopulmonary bypass as key pathophysiologic mechanism for acute kidney injury after cardiac surgery represents an opportunity for scientific exploration.

Management of 1-Lung Ventilation in a Patient With Failing Fontan Circulation.

The number of patients reaching adulthood after undergoing Fontan palliation for the repair of a congenital heart defect continues to increase. In this case report, we present the anesthetic management of a patient with a history of tricuspid atresia treated with palliative Fontan repair who had developed clinical evidence of Fontan failure. He presented with septic shock secondary to streptococcal toxic shock syndrome complicated by a loculated pleural effusion. He underwent open thoracic decortication under 1-lung ventilation. Discussion focuses on the management of volume status and pulmonary vascular resistance as well as surgical implications of Fontan physiology in thoracic surgery.

Discordance in Grading Methods of Aortic Stenosis by Pre-Cardiopulmonary Bypass Transesophageal Echocardiography.

BACKGROUND: Current guidelines define severe aortic valve stenosis (AS) as an aortic valve area (AVA) ≤1.0 cm by the continuity equation and mean gradient (ΔPm) ≥ 40 mm Hg. However, these measurements can be discordant when classifying AS severity. Approximately one-third of patients with normal ejection fraction and severe AS by AVA have nonsevere AS by ΔPm when measured by preoperative transthoracic echocardiography (TTE). Given the use of positive pressure ventilation and general anesthesia in the pre-cardiopulmonary bypass (pre-CPB) period, we hypothesized that discordance between ΔPm and AVA during pre-CPB transesophageal echocardiography (TEE) would be higher than previously reported by TTE. METHODS: We retrospectively examined pre-CPB TEE data for patients who had aortic valve replacement, with or without coronary artery bypass grafting, from 2000 to 2012. Patients were excluded if they had ejection fraction <55%, emergency surgery, repeat sternotomy, moderate or severe mitral regurgitation, or severe aortic regurgitation. Only patients with both pre-CPB AVA and ΔPm measurements were included. Patients were grouped according to severity (mild, moderate, and severe) by AVA or ΔPm. Discordance was defined as disagreement between severities based on either parameter. RESULTS: A total of 277 patients met inclusion criteria. There were 227 patients with AVA ≤ 1.0 cm. The proportion of these patients with a ΔPm < 40 mm Hg was 54% (95% confidence interval, 47%-61%). The rate of discordance was significantly higher than the rate (37%; P < 0.001) found in previously reported analyses using TTE. Of the patients with a ΔPm ≥ 40 mm Hg, only 8% (n = 9/113) had a discordant AVA. In contrast, of the patients with ΔPm < 40 mm Hg, 80% (n = 131/164) had a discordant AVA. CONCLUSIONS: We confirmed our hypothesis that grading AS by ΔPm and AVA during pre-CPB TEE exhibits higher discordance than reported for TTE by others. It remains unclear whether these discrepancies reflect the effect of general anesthesia, imaging modality (TTE versus TEE) differences, inaccuracies in AS grading cutoffs when applied to pre-CPB TEE, or selection bias of the surgical population.