Elaine E. Tseng

Barrett’s esophagus with high grade dysplasia: Surgical results and long-term outcome— An update

We updated our surgical results and long-term outcome for prophylactic esophagectomy in patients with Barrett’s esophagus and high-grade dysplasia (HGD) and determined the incidence of occult adenocarcinoma. Sixty consecutive patients with HGD who underwent esophagectomy had pre- and postoperative pathology examined at our institution from 1982 to 2001. We reviewed medical records to determine patient characteristics, surgical approach, operative morbidity and mortality, pathology, and length of stay. Patients and/or referring physicians were contacted to determine long-term outcome. Fifty-three men (88%) and 7 women (12%) were followed up for a median of 4.6 years. Transhiatal esophagectomy was performed in the majority of patients (82%). There was one operative death (1.7%) and 15 complications (29%). Median length of stay was 9 days. In 18 patients (30%), invasive adenocarcinoma was detected in the resected specimen. When examined by time periods, 43% (13/30) of patients were diagnosed with occult cancer from 1982–1994, whereas 17% (5/30) harbored occult malignancy from 1994–2001. All patients with adenocarcinoma in the recent interval had stage I disease, as opposed to only 61.5% of patients from the earlier study. Operative mortality declined from 3.3% to 0% over the two intervals as did mean length of stay from 14 days to 10 days. Five-year survival was excellent at 88%. Age and amount of preoperative weight loss were preoperative predictors of survival, whereas major postoperative complications and stage were postoperative predictors of outcome. Barrett’s esophagus with high-grade dysplasia continues to be an indication for prophylactic esophagectomy. Overall prevalence of occult adenocarcinoma remains high. We have demonstrated a declining incidence of occult cancer and treatment of earlier stage adenocarcinoma when found in this population of patients treated with esophagectomy.

Aortic valve replacement in the elderly. Risk factors and long-term results.

OBJECTIVE The current study was undertaken to determine long-term results of aortic valve replacement (AVR) in the elderly, to ascertain predictors of poor outcome, and to assess quality of life. SUMMARY BACKGROUND DATA Aortic valve replacement is the procedure of choice for elderly patients with aortic valve disease. The number of patients aged 70 and older requiring AVR continues to increase. However, controversy exists as to whether surgery devoted to this subset reflect a cost-effective approach to attaining a meaningful quality of life. METHODS This study reviews data on 247 patients aged 70 to 89 years who underwent isolated AVR between 1980 and 1995; there were 126 men (51%) and 121 women (49%). Follow-up was 97% complete (239/247 patients) for a total of 974.9 patient-years. Mean age was 76.2 +/- 4.8 years. Operative mortality and actuarial survival were determined. Patient age, gender, symptoms, associated diseases, prior conditions, New York Health Association class congestive heart failure, native valve disease, prosthetic valve type, preoperative catheterization data, and early postoperative conditions were analyzed as possible predictors of outcome. Functional recovery was evaluated using the SF-36 quality assessment tool. RESULTS Operative mortality was 6.1% (15/247). Multivariate logistic regression showed that poor left ventricular function and preoperative pacemaker insertion were independent predictors of early mortality. After surgery, infection was predictive of early mortality. Overall actuarial survival at 1, 5, and 10 years was 89.5 +/- 2% (198 patients at risk), 69.3 +/- 3.4% (89 patients at risk), and 41.2 +/- 6% (13 patients at risk), respectively. Cox proportional hazards model showed that chronic obstructive pulmonary disease and urgency of operation were independent predictors of poor long-term survival. Postoperative renal failure also was predictive of poor outcome. Using the SF-36 quality assessment tool, elderly patients who underwent AVR scored comparably to their age-matched population norms in seven of eight dimensions of overall health. The exception is mental health. CONCLUSIONS Aortic valve replacement in the elderly can be performed with acceptable mortality. Significant preoperative risk factors for early mortality include poor left ventricular function and preoperative pacemaker insertion. Predictors of late mortality include chronic obstructive pulmonary disease and urgency of operation. These results stress the importance of operating on the elderly with aortic valve disease; both long-term survival and functional recovery are excellent.

A Computationally Efficient Formal Optimization of Regional Myocardial Contractility in a Sheep With Left Ventricular Aneurysm

A non-invasive method for estimating regional myocardial contractility in vivo would be of great value in the design and evaluation of new surgical and medical strategies to treat and/or prevent infarction-induced heart failure. As a first step towards developing such a method, an explicit finite element (FE) model-based formal optimization of regional myocardial contractility in a sheep with left ventricular (LV) aneurysm was performed using tagged magnetic resonance (MR) images and cardiac catheterization pressures. From the tagged MR images, 3-dimensional (3D) myocardial strains, LV volumes and geometry for the animal-specific 3D FE model of the LV were calculated, while the LV pressures provided physiological loading conditions. Active material parameters (T(max_B) and T(max_R)) in the non-infarcted myocardium adjacent to the aneurysm (borderzone) and in myocardium remote from the aneurysm were estimated by minimizing the errors between FE model-predicted and measured systolic strains and LV volumes using the successive response surface method for optimization. The significant depression in optimized T(max_B) relative to T(max_R) was confirmed by direct ex vivo force measurements from skinned fiber preparations. The optimized values of T(max_B) and T(max_R) were not overly sensitive to the passive material parameters specified. The computation time of less than 5 hours associated with our proposed method for estimating regional myocardial contractility in vivo makes it a potentially very useful clinical tool.

Reversal of direct thrombin inhibition after cardiopulmonary bypass in a patient with heparin-induced thrombocytopenia.

UNLABELLED We treated persistent hemorrhage after cardiopulmonary bypass in a heart transplant recipient who had received anticoagulation with the direct thrombin inhibitor bivalirudin by a combination therapy aimed at reducing the plasma concentration of the thrombin antagonist (hemodialysis and modified ultrafiltration), increasing the concentration of thrombin at bleeding sites (recombinant factor VIIa), and increasing the plasma concentration of other coagulation factors (fresh frozen plasma and cryoprecipitate). The bleeding was controlled, and there was no thrombotic complication. IMPLICATIONS A combination of modified ultrafiltration, hemodialysis, and the administration of recombinant factor VIIa, fresh frozen plasma, and cryoprecipitate may reverse the anticoagulant effect of bivalirudin.

Patient-Specific Multiscale Modeling of Blood Flow for Coronary Artery Bypass Graft Surgery

We present a computational framework for multiscale modeling and simulation of blood flow in coronary artery bypass graft (CABG) patients. Using this framework, only CT and non-invasive clinical measurements are required without the need to assume pressure and/or flow waveforms in the coronaries and we can capture global circulatory dynamics. We demonstrate this methodology in a case study of a patient with multiple CABGs. A patient-specific model of the blood vessels is constructed from CT image data to include the aorta, aortic branch vessels (brachiocephalic artery and carotids), the coronary arteries and multiple bypass grafts. The rest of the circulatory system is modeled using a lumped parameter network (LPN) 0 dimensional (0D) system comprised of resistances, capacitors (compliance), inductors (inertance), elastance and diodes (valves) that are tuned to match patient-specific clinical data. A finite element solver is used to compute blood flow and pressure in the 3D (3 dimensional) model, and this solver is implicitly coupled to the 0D LPN code at all inlets and outlets. By systematically parameterizing the graft geometry, we evaluate the influence of graft shape on the local hemodynamics, and global circulatory dynamics. Virtual manipulation of graft geometry is automated using Bezier splines and control points along the pathlines. Using this framework, we quantify wall shear stress, wall shear stress gradients and oscillatory shear index for different surgical geometries. We also compare pressures, flow rates and ventricular pressure–volume loops pre- and post-bypass graft surgery. We observe that PV loops do not change significantly after CABG but that both coronary perfusion and local hemodynamic parameters near the anastomosis region change substantially. Implications for future patient-specific optimization of CABG are discussed.

Neuronal nitric oxide synthase inhibition reduces neuronal apoptosis after hypothermic circulatory arrest

BACKGROUND Neurologic injury, including choreoathetosis and learning and memory deficits, occurs after prolonged hypothermic circulatory arrest (HCA). Apoptosis, or programmed cell death, is a possible cause of the neurologic injury seen after HCA. However, the mechanism of apoptosis is unknown. Hypothermic circulatory arrest causes glutamate excitotoxicity, resulting in increased nitric oxide production. We therefore hypothesized that nitric oxide mediates apoptosis. The purpose of this study was to determine if neuronal nitric oxide synthase inhibition reduces neuronal apoptosis in an established canine model of HCA. METHODS Fourteen male hound dogs (weight, 20 to 27 kg) were placed on closed-chest cardiopulmonary bypass, subjected to 2 hours of HCA at 18 degrees C, rewarmed to normothermia, and sacrificed 8 hours after HCA. Group 1 (n = 7) dogs were treated with the neuronal nitric oxide inhibitor 7-nitroindazole, 25 mg/kg intraperitoneally, before arrest and every 2 hours until sacrifice. Group 2 (n = 7) dogs received vehicle only. The brains were analyzed histopathologically. Apoptosis, identified by hematoxylin-eosin staining, was confirmed by DNA terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end-labeling assay and electron microscopy. Apoptosis was scored by a blinded neuropathologist from 0 (normal) to 100 (severe injury). RESULTS Apoptosis occurred early after HCA in select neuronal populations, including the hippocampus, stria terminalis, neocortex, and entorhinal cortex. Apoptotic neurons showed a characteristic shrunken cytoplasm and nuclear chromatin condensation. 7-Nitroindazole significantly inhibited apoptosis (group 1 versus 2: 19.17 +/- 14.39 versus 61.11 +/- 5.41; p < .001). CONCLUSIONS Our results provide evidence that apoptosis is associated with the neurologic injury that occurs after HCA and that nitric oxide mediates the apoptosis that occurs after HCA. Strategies for cerebral protection during HCA may include the inhibition of neuronal nitric oxide synthase.

Magnetic Resonance Measurement of Turbulent Kinetic Energy for the Estimation of Irreversible Pressure Loss in Aortic Stenosis

OBJECTIVES The authors sought to measure the turbulent kinetic energy (TKE) in the ascending aorta of patients with aortic stenosis and to assess its relationship to irreversible pressure loss. BACKGROUND Irreversible pressure loss caused by energy dissipation in post-stenotic flow is an important determinant of the hemodynamic significance of aortic stenosis. The simplified Bernoulli equation used to estimate pressure gradients often misclassifies the ventricular overload caused by aortic stenosis. The current gold standard for estimation of irreversible pressure loss is catheterization, but this method is rarely used due to its invasiveness. Post-stenotic pressure loss is largely caused by dissipation of turbulent kinetic energy into heat. Recent developments in magnetic resonance flow imaging permit noninvasive estimation of TKE. METHODS The study was approved by the local ethics review board and all subjects gave written informed consent. Three-dimensional cine magnetic resonance flow imaging was used to measure TKE in 18 subjects (4 normal volunteers, 14 patients with aortic stenosis with and without dilation). For each subject, the peak total TKE in the ascending aorta was compared with a pressure loss index. The pressure loss index was based on a previously validated theory relating pressure loss to measures obtainable by echocardiography. RESULTS The total TKE did not appear to be related to global flow patterns visualized based on magnetic resonance-measured velocity fields. The TKE was significantly higher in patients with aortic stenosis than in normal volunteers (p < 0.001). The peak total TKE in the ascending aorta was strongly correlated to index pressure loss (R(2) = 0.91). CONCLUSIONS Peak total TKE in the ascending aorta correlated strongly with irreversible pressure loss estimated by a well-established method. Direct measurement of TKE by magnetic resonance flow imaging may, with further validation, be used to estimate irreversible pressure loss in aortic stenosis.

Assessing the impact of cerebral injury after cardiac surgery: will determining the mechanism reduce this injury?

BACKGROUND Central nervous system dysfunction continues to produce significant morbidity and associated mortality in patients undergoing cardiac surgery. Using a closed-chest canine cardiopulmonary bypass model, dogs underwent 2 h of hypothermic circulatory arrest (HCA) at 18 degrees C, followed by resuscitation and recovery for 3 days. Animals were assessed functionally by a species-specific behavioral scale, histologically for patterns of selective neuronal necrosis, biochemically by analysis of microdialysis effluent, and by receptor autoradiography for N-methyl-D-aspartate (NMDA) glutamate receptor subtype expression. RESULTS Using a selective NMDA (glutamate) receptor antagonist (MK801) and an AMPA antagonist (NBQX), glutamate excitotoxicity in the development of HCA-induced brain injury was documented and validated. A microdialysis technique was employed to evaluate the role of nitric oxide (NO) in neuronal cell death. Arginine plus oxygen is converted to NO plus citrulline (CIT) by the action of NO synthase (nNOS). CIT recovery in the cerebrospinal fluid and from canine cortical homogenates increased during HCA and reperfusion. These studies demonstrated that neurotoxicity after HCA involves a significant and early induction of nNOS expression, and neuronal processes leading to widespread augmentation of NO production in the brain. To further investigate the production of excitatory amino acids in the brain, we hypothesized the following scenario: HCA--> increased glutamate, increased aspartate, increased glycine--> increased intracellular Ca2+--> increased NO + CIT. Using the same animal preparation, we demonstrated that HCA caused increased intracerebral glutamate and aspartate that persists up to 20 h post-HCA. HCA also resulted in CIT (NO) production, causing a continued and delayed neurologic injury. Confirmatory evidence of the role of NO was demonstrated by a further experiment using a specific nNOS inhibitor, 7-nitroindazole. Animals underwent 2 h of HCA, and then were evaluated both physiologically and for NO production. 7-Nitroindazole reduced CIT (NO) production by 58.4 +/- 28.3%. In addition, dogs treated with this drug had superior neurologic function compared with untreated HCA controls. CONCLUSIONS These experiments have documented the role of glutamate excitotoxicity in neurologic injury and have implicated NO as a significant neurotoxin causing necrosis and apoptosis. Continued research into the pathophysiologic mechanisms involved in cerebral injury will eventually yield a safe and reliable neuroprotectant strategy. Specific interventional agents will include glutamate receptor antagonists and specific neuronal NO synthase inhibitors.

Transcatheter aortic valves inadequately relieve stenosis in small degenerated bioprostheses

OBJECTIVES Transcatheter aortic valves (TAVs) are a promising treatment for high risk surgical patients suffering from degeneration of previously implanted bioprostheses (valve-in-valve therapy). However, unlike native stenosed aortic valves which have accommodated Edwards SAPIEN transcatheter valves after valvuloplasty, rigid bioprostheses may prevent full TAV stent expansion and disrupt leaflet function. We hypothesized that current 23 mm TAVs would not completely relieve severe stenosis in small bioprosthetic valves. The objective of this study was to study the hemodynamics of TAVs in degenerated bioprostheses. METHODS Twelve TAVs designed to mimic the 23 mm SAPIEN valve were created. Using a pulse duplicator, hemodynamics of valve-in-valve implantation were measured within 19, 21, and 23 mm Carpentier-Edwards PERIMOUNT degenerated bioprostheses (n=6 each). Bioprosthetic degeneration was simulated using BioGlue to achieve a mean pressure gradient of 50 mmHg. RESULTS TAVs significantly reduced the mean pressure gradient (50.9+/-4.7-9.1+/-4.1 mmHg, P<0.001) and total energy loss (870.3+/-157.4-307.8+/-87.3 mJ, P<0.001) in 23 mm degenerated bioprostheses. In 21 mm bioprostheses, the pressure gradient (52.3+/-7.0-19.5+/-5.0 mmHg, P<0.001) and energy loss (785.5+/-128.1-477.8+/-123.2 mJ, P=0.007) were reduced significantly. However, no significant changes in the pressure gradient (57.1+/-4.3-46.5+/-9.3 mmHg, P=0.086) or energy loss (839.3+/-49.3-960.5+/-158.1 mJ, P=0.144) were obtained after TAVI implantation in 19 mm bioprostheses. Incomplete stent expansion resulted in leaflet distortion and central regurgitation when implanted in 19 and 21 mm bioprostheses. CONCLUSIONS The bioprosthetic annulus and stent posts offered a suitable landing zone for TAVs. However, oversized transcatheter valves were constrained by the rigid bioprostheses resulting in inadequate resolution of bioprosthetic stenosis. Hemodynamics of valve-in-valve intervention was worse than comparable size surgical valve replacements, particularly in 19 and 21 mm valves. Small degenerated bioprostheses require modification of current TAV design to yield acceptable hemodynamics.

Imaging Biomarkers of Aortic Disease: Increased Growth Rates With Eccentric Systolic Flow

To the Editor: Is the aortic dilation that is commonly seen with bicuspid aortic valve (BAV) related to intrinsic aortic wall fragility or altered systolic hemodynamics? Recent publications on the topic favor the intrinsic fragility hypothesis. But recent advancements in imaging show very abnormal