Phosphorylation of transcriptional factors and cell-cycle-dependent proteins by casein kinase II.

Casein kinase II is involved in the phosphorylation of several proto-oncogenes, anti-oncogenes, and oncogenes that are nuclear transcriptional regulatory factors. The potential functions of the phosphorylations in each of these proteins are evaluated. New findings indicate that casein kinase II is a critical component of the mechanisms regulating the cell cycle.

Interactions of Cbl with Grb2 and phosphatidylinositol 3'-kinase in activated Jurkat cells.

T-cell receptor (TCR) cross-linking increases tyrosine phosphorylation of multiple proteins, only a few of which have been identified. One of the most rapidly tyrosine-phosphorylated polypeptides is the 120-kDa product of the proto-oncogene c-cbl, a cytosolic and cytoskeletal protein containing multiple proline-rich motifs that are potential binding sites for proteins containing Src homology 3 (SH3) domains. We report here that in cultured Jurkat T cells, Cbl is coprecipitated with antibody against the adapter protein Grb2. Upon activation of Jurkat T cells via the TCR-CD3 complex, we find that high-affinity binding of Cbl requires the N-terminal SH3 domain of GST-Grb2 fusion protein but after cross-linking of the TCR-CD3 and CD4 receptors, Cbl binds equally to its SH2 domain. Grb2 antisera also precipitated p85 from serum-starved cells, while TCR activation increased p85 and tyrosine-phosphorylated Cbl but not Cbl protein in Grb2 immunocomplexes. Phosphatidylinositol (PI) 3-kinase activity was immunoprecipitated from serum-starved cells with Cbl and to a lesser extent with Grb2 antisera, and TCR cross-linking increased this activity severalfold. The PI 3-kinase activity associated with Cbl amounted to 5 to 10% of the total cellular activity that could be precipitated by p85 antisera. The Ras exchange factor Son-of-sevenless 1 (Sos-1) was not found in anti-Cbl immunoprecipitates from activated cells, and Cbl was not detectable in anti-Sos-1 precipitates, supporting the likelihood that Sos-Grb2 and Cbl-Grb2 are present as distinct complexes. Taken together, these data suggest that Cbl function in Jurkat T cells involves its constitutive association with Grb2 and its recruitment of PI 3-kinase in response to TCR activation.

Interactions of Drosophila Cbl with epidermal growth factor receptors and role of Cbl in R7 photoreceptor cell development.

The human proto-oncogene product c-Cbl and a similar protein in Caenorhabditis elegans (Sli-1) contain a proline-rich COOH-terminal region that binds Src homology 3 (SH3) domains of proteins such as the adapter Grb2. Cb1-Grb2 complexes can be recruited to tyrosine-phosphorylated epidermal growth factor (EGF) receptors through the SH2 domain of Grb2. Here we identify by molecular cloning a Drosophila cDNA encoding a protein (Drosophila Cbl [D-Cbl]) that shows high sequence similarity to the N-terminal region of human c-Cbl but lacks proline-rich sequences and fails to bind Grb2. Nonetheless, in COS-1 cells, expression of hemagglutinin epitope-tagged D-Cbl results in its coimmunoprecipitation with EGF receptors in response to EGF. EGF also caused tyrosine phosphorylation of D-Cbl in such cells, but no association of phosphatidylinositol 3-kinase was detected in assays using anti-p85 antibody. A point mutation in D-Cbl (G305E) that suppresses the negative regulation of LET-23 by the Cbl homolog Sli-1 in C. elegans prevented tyrosine phosphorylation of D-Cbl as well as binding to the liganded EGF receptor in COS-1 cells. Colocalization of EGF receptors with both endogenous c-Cbl or expressed D-Cbl in endosomes of EGF-treated COS-1 cells is also demonstrated by immunofluorescence microscopy. In lysates of adult transgenic Drosophila melanogaster, GST-DCbl binds to the tyrosine-phosphorylated 150-kDa torso-DER chimeric receptor. Expression of D-Cbl directed by the sevenless enhancer in intact Drosophila compromises severely the development of the R7 photoreceptor neuron. These data suggest that despite the lack of Grb2 binding sites, D-Cbl functions as a negative regulator of receptor tyrosine kinase signaling in the Drosophila eye by a mechanism that involves its association with EGF receptors or other tyrosine kinases.

Preoperative positron emission tomographic viability assessment and perioperative and postoperative risk in patients with advanced ischemic heart disease.

OBJECTIVES: This study sought to investigate whether determination of tissue viability by means of positron emission tomography (PET) before coronary artery bypass graft surgery (CABG) affects clinical outcome with respect to both in-hospital mortality and 1-year survival rate. BACKGROUND: Patients with coronary artery disease (CAD) and severe left ventricular (LV) dysfunction are at higher risk for perioperative complications associated with CABG. Therefore, the selection of patients who will benefit from CABG is an important clinical issue. METHODS: This study retrospectively evaluated 76 patients with advanced CAD and LV dysfunction (LV ejection fraction < or = 0.35) who were considered candidates for CABG. Thirty-five patients were selected for CABG on the basis of clinical presentation and angiographic data (group A), and 34 of 41 patients were selected according to extent of viable tissue determined by PET (group B) in addition to clinical presentation and angiographic data. RESULTS: There were four in-hospital deaths (11.4%) in group A and none in group B (p = 0.04). After 12 months, the survival rate was 79% in group A and 97% in group B (p = 0.01). Postoperatively, group B patients had a less complicated recovery (p = 0.05). They required lower doses of catecholamines (p = 0.002) and demonstrated a significantly decreased incidence of low output syndrome (p = 0.05). CONCLUSIONS: This retrospective data analysis suggests that selection of patients with impaired LV function on the basis of extent of viability supplementary to clinical and angiographic data may lead to postoperative recovery with a low early mortality and promising short-term survival. Therefore, viability studies permit selection of patients who are at low risk for serious perioperative complications.

Time course and extent of improvement of dysfunctioning myocardium in patients with coronary artery disease and severely depressed left ventricular function after revascularization: correlation with positron emission tomographic findings.

OBJECTIVES: This study was performed to evaluate the prevalence, time course of recovery and extent of improvement of segments with a positron emission tomographic (PET) flow-metabolism mismatch and match pattern, as well as of PET segments with normal perfusion but with impaired myocardial function. BACKGROUND: Previous studies have shown that scintigraphic techniques evaluating myocardial viability provide predictive information about the improvement of regional wall motion. However, there are little data concerning the time course and extent of improvement of segments according to preoperative scintigraphic patterns. METHODS: Twenty-nine patients with ischemic cardiomyopathy (ejection fraction 18% to 35%) underwent preoperative PET viability assessment and were functionally assessed by two-dimensional echocardiography preoperatively and at 11 days, 14 weeks and >12 months after coronary artery bypass graft surgery. RESULTS: In 168 (70%) of 240 dysfunctional segments, a "normal" scintigraphic pattern was present, whereas a "mismatch" pattern was observed in 24% (p<0.01). Mismatch areas were associated with more severe preoperative wall motion abnormalities and incomplete postoperative recovery. After one year, 31% of normal scintigraphic segments, compared with only 18% of mismatch segments, showed complete functional restoration (p<0.05). CONCLUSIONS: These data suggest that in patients with severe left ventricular dysfunction, a scintigraphic pattern of normal perfusion and normal metabolism is more prevalent than a flow-metabolism mismatch pattern. Functional recovery is more frequent in normal scintigraphic segments, whereas in mismatch segments, postoperative recovery remains incomplete even after one year.

Acute cardiac inflammatory responses to postischemic reperfusion during cardiopulmonary bypass.

OBJECTIVES: The investigation centers on whether there is a reperfusion-induced specific cardiac inflammatory reaction after bypass surgery. BACKGROUND: Cardiopulmonary bypass (CPB) leads to systemic inflammation. Additionally, cardiac inflammation due to reperfusion could occur. Knowledge about nature and time course of this reaction might help to develop cardioprotective interventions. METHODS: In 12 patients receiving coronary bypass grafts, arterial and coronary venous blood was obtained before onset of CPB, and 1, 5, 10, 25, 35 and 75 min after cardiac reperfusion. Plasma levels of IL6 and IL8 were measured by immunoassay. CD11b, CD41, and CD62 on blood cells were quantified by flow cytometry. Measurement of CD41, a platelet marker, on neutrophils and monocytes allowed detection of leukocyte-platelet microaggregates. RESULTS: Transcardiac veno-arterial difference of IL6 rose in the 10th and 25th min of reperfusion (from 0 to 7 pg/ml; p < 0.05), and after 75 min (15 pg/ml). IL8 did not change. CD11b on neutrophils (PMN) decreased transcardially to 95, 88 and 82% of the initial level in the 5th, 10th, and 75th min, respectively, suggesting sequestration of activated neutrophils. CD62 on platelets rose about 30% in the 75th min. Initially, leukocyte-platelet microaggregates were formed during coronary passage (+31% of the arterial level for PMN, +23% for monocytes). During reperfusion, coaggregates were retained (PMN: -1% and -7% in the 5th and 10th min, monocytes: -22%, -13% and -12% in the 1st, 5th and 10th min. CONCLUSIONS: During early reperfusion after aortic declamping, the coronary bed is already a source of proinflammatory stimuli and target for activated leukocytes, partly in conjunction with platelets. Mitigation of these phenomena might help to improve cardiac function after CPB especially in patients at risk.

Changes of renal mRNA species abundance by ochratoxin A.

Ochratoxin A is a nephrotoxin produced by certain species of Aspergillus and Penicillium. We have found previously that renal but not hepatic P-enolpyruvate carboxykinase, and the mRNA for this enzyme, are rapidly decreased in rats and swine fed 0.1 to 1 mg/kg body weight for a few days. In the present study, we isolated kidney mRNA from rats fed ochratoxin A for 2-5 days. By screening a rat kidney cDNA library with [32P]RNA, we have identified several renal mRNAs whose concentration is changed within 2 days by the toxin. The transcription rate of each mRNA was measured in nuclei isolated from kidneys of rats fed ochratoxin A. The incorporation of [32P]UMP into P-enolpyruvate carboxykinase mRNA and the synthesis of other RNAs were not affected. Therefore, the toxin changes mRNA abundance at the post-transcriptional level.

Risk factors for perioperative mortality in children with anomalous origin of the left coronary artery from the pulmonary artery.

The present study was conducted on 33 children (median age at initial cardiac catheterization 0.4 years [0.1 to 11.8]) with anomalous origin of the left coronary artery from the pulmonary artery, without associated hemodynamically significant cardiovascular anomalies, who were treated throughout a period of 18 years in our hospital. A two coronary artery circulation was reestablished in 31 of 33 children. One child died before the intended operation, and in one child the left coronary artery was ligated. There were six operative deaths, five intraoperative and one 12 hours after operation. The purpose of the study was to assess which preoperative clinical and angiographic features were associated with a higher perioperative mortality. The following preoperative factors were associated with a statistically significant higher perioperative mortality: young age at operation (p less than 0.03), left and balanced type of coronary circulation (p less than 0.01), and electrocardiographic signs of extensive acute myocardial infarction, namely, marked ST elevation (greater than or equal to 0.2 mV in at least two leads) (p less than 0.03). Left axis deviation on the electrocardiogram was associated with an extreme right dominant type of coronary circulation (p less than 0.005). The latter was also linked with adequate perfusion of the posterolateral left ventricular wall (p less than 0.005). At autopsy, severe increase of heart weight to two or three times the normal heart weight was established in six of seven children. Thus the perioperative mortality was determined primarily by the extent of myocardial ischemia. This in turn is decisively influenced by the dominant type of coronary circulation and the extent of inter-arterial collateralization. Young age, in addition, proved to be a risk factor for mortality at corrective surgery.

Intracardiac thrombus formation after the Fontan operation.

OBJECTIVES: Intracardiac thrombus formation is suspected to be a specific sequela after the Fontan operation and is difficult to determine by means of routine transthoracic echocardiography. The aim of our study was to evaluate the occurrence of intracardiac thrombi in the different types of Fontan modifications and to identify predisposing risk factors. METHODS: We evaluated 52 patients who had undergone a Fontan-type operation and were free of symptoms regarding thrombosis as determined by transesophageal echocardiography. RESULTS: In 17 (33%) patients thrombus formation could be found without clinical evidence of thromboembolic complications. Neither underlying morphologic disease nor age at operation, type of Fontan operation, sex, follow-up interval, arrhythmias, or laboratory or hemodynamic findings could be identified as predisposing risk factors. CONCLUSION: In patients having had a Fontan operation with inadequate or without anticoagulation medication, we would recommend routine transesophageal echocardiography to exclude eventual thrombi. Because of the high incidence of thrombi, we suggest oral anticoagulation therapy in all patients.

Left ventricular function assessed with echocardiography and myocardial perfusion assessed with scintigraphy under dipyridamole stress in pediatric patients after repair for anomalous origin of the left coronary artery from the pulmonary artery.

Twenty-three patients who underwent operation for anomalous origin of the left coronary artery from the pulmonary artery were reexamined with two-dimensional echocardiography and thallium 201 perfusion imaging. Follow-up studies were performed 0.6 to 16.2 years (median 2.9 years) after operation. In 22 of 23 patients, a two coronary artery system had been established by implantation of the left coronary artery into the aorta (n = 8) or by anastomosis of the left subclavian artery with the left coronary artery (n = 14). The left coronary artery had been ligated in only one patient. For stress testing, 0.8 mg dipyridamole per kilogram body weight was infused in a 10-minute period in 20 of the 23 patients. High-dose dipyridamole infusion increased mean heart rate (98.1 +/- 27.1 to 122.3 +/- 19.2 beats/min, p < 0.001) and mean left ventricular ejection fraction (54.8% +/- 11.8% to 61.3% +/- 12.5%, p < 0.05) and decreased left ventricular end-diastolic volume index (38.8 +/- 26.7 to 29.9 +/- 8.3 ml/m2, p < 0.005). At rest, left ventricular dimensions were abnormal in only one patient, in whom the anastomosis with the left coronary artery proved to be occluded, as seen with subsequent angiography. Left ventricular function seen with two-dimensional echocardiography was normal in 19 patients and was compromised in 3 (all of whom had major structural anomalies of the left ventricle, such as left ventricular aneurysm, occlusion of the anastomosis, or mitral valve prosthesis). Patients with R-wave loss as seen with preoperative electrocardiography tended to have larger left ventricular volumes at follow-up (69.2 +/- 56.5 ml/m2 versus 32.4 +/- 9.6 ml/m2, p < 0.07). Ten of 20 patients had normal thallium 201-perfusion scans. In 9 of 20 patients defects revealed by permanent thallium 201-perfusion were observed and determined to be myocardial scars. Transient perfusion defects under dipyridamole stress with redistribution at rest occurred in three children, two of whom also had permanent thallium 201 defects. None of the three patients had angina-like symptoms or S-T segment changes during dipyridamole stress. Left ventricular ejection fraction, however, decreased severely during dipyridamole infusion in the single patient with ligature of the left coronary artery. The two remaining patients had normal echocardiographic left ventricular function under stress, and the diagnosis of myocardial ischemia as seen with scintigraphy must be questioned.(ABSTRACT TRUNCATED AT 400 WORDS)

Evidence for inflammatory responses of the lungs during coronary artery bypass grafting with cardiopulmonary bypass.

OBJECTIVE: The occurrence of a systemic inflammatory reaction during cardiac surgery with cardiopulmonary bypass (CPB) has been well established, and the heart itself has been shown to release inflammatory mediators after ischemia. The hypothesis of the present study was that the lungs are also a site of inflammatory responses during early reperfusion. METHODS: In 20 consecutive patients undergoing coronary artery bypass grafting, blood was simultaneously drawn from the right atrium (RA) and the pulmonary vein (PV) before CPB and at 1 min, 10 min, and 20 min of reperfusion. The levels of interleukin (IL)-6, IL-8, IL-10, and tumor necrosis factor (TNF)-alpha were determined, as well as the adhesion molecules CD41 and CD62 on platelets and CD11b and CD41 on leukocytes. As a measure of the pulmonary release, ratios of PV and RA levels were calculated. RESULTS: Before CPB, the concentrations of cytokines tended to be lower in the PV compared with the RA. At 1 min of reperfusion, no significant concentration increases were found in the PV. At 10 min of reperfusion, the PV/RA ratio (mean +/- SEM) for IL-6 was 2.06 +/- 0.37 and 1.24 +/- 0.15 for IL-8 (p = 0.02 and p = 0.04, respectively, compared with the pre-CPB ratios of 0.89 +/- 0.4 and 0.99 +/- 0.2). At 20 min of reperfusion, PV/RA ratios for IL-6 (1.95 +/- 0.37) and IL-10 (0.99 +/- 0.4) were higher than before CPB (0.89 +/- 0.04, p = 0.05 and 0.85 +/- 0.06, p = 0.03, respectively). Adhesion molecule counts on platelets and polymorphonuclear neutrophils (PMNs) tended to be higher in the PV than in the RA before CPB. At 1 min of reperfusion, the PV/RA ratio of CD41 on monocytes (0.89 +/- 0.04) and of CD41 on PMNs (1.05 +/- 0.05) was less than before CPB (1.24 +/- 0.08, p = 0.0002 and 1.55 +/- 0.14, p = 0.0002). At 10 min and 20 min of reperfusion, similar changes were found. CONCLUSIONS: The observed changes indicate an inflammatory response of the lungs. Proinflammatory cytokines are increased in pulmonary venous blood. At the same time, activated blood cells are retained in the pulmonary circulation. This may contribute to pulmonary dysfunction almost routinely observed after CPB.

Sodium nitroprusside in patients with compromised left ventricular function undergoing coronary bypass: reduction of cardiac proinflammatory substances.

OBJECTIVE: The aim of the present study was to investigate whether the nitric oxide donor sodium nitroprusside can reduce the cardiac inflammatory response during coronary artery bypass grafting in patients with severely compromised left ventricular function. METHODS: Patients (n = 30) were assigned to receive placebo or sodium nitroprusside (0.5 microg. kg(-1). min(-1)) for the first 60 minutes of reperfusion. Interleukin 6, interleukin 8, and tumor necrosis factor alpha levels; platelet adhesion molecule CD41 and CD62 levels; and CD11b on leukocytes were determined in the radial artery and coronary sinus before cardiopulmonary bypass and during reperfusion (1, 5, 10, 35, and 75 minutes). RESULTS: At 1 minute of reperfusion, coronary venous levels of CD41-positive polymorphonuclear leukocytes were 8% lower than arterial levels in the placebo group and 18% higher in the sodium nitroprusside group (P =.021). At 5 minutes of reperfusion, the respective levels were 29% and 1% for interleukin 6 (P =.015), -5% and 20% for CD41-positive monocytes (P =.032), and -2% and 16% for CD11b-positive monocytes (P =.038). At 10 minutes of reperfusion, these levels were -14% and 21% for CD41-positive monocytes (P =.006). At 35 minutes of reperfusion, these levels were -13% and 7% for CD41-positive monocytes (P =.017), -41% and 23% for CD11b-positive monocytes (P =.001), and 7% and 25% for CD62-positive platelets (P =. 041). At 75 minutes of reperfusion, the levels were 15% and -7% for tumor necrosis factor alpha (P =.025) and -10% and 10% for CD62-positive platelets (P =.041). CONCLUSIONS: Transcardiac production of proinflammatory cytokines is reduced in patients undergoing coronary artery bypass grafting treated with the nitric oxide donor sodium nitroprusside. At the same time, less activated leukocytes and platelets are retained in the coronary circulation.

Hemostatic activation during cardiopulmonary bypass with different aprotinin dosages in pediatric patients having cardiac operations.

The effect of high-dose aprotinin treatment on hemostatic activation during cardiopulmonary bypass in pediatric patients having cardiac operations was investigated. Sixty patients weighing less than 10 kg undergoing cardiac operations for different types of congenital heart diseases were studied: 20 patients were treated with aprotinin 2 x 15,000 KIU/kg, 20 patients with 2 x 30,000 KIU/kg, and 20 patients without aprotinin treatment served as the control group. Different split products of fibrinogen and/or fibrin and the fibrinolytic activity on fibrin plates were measured to assess fibrinolytic activation. F1/F2 prothrombin fragments, thrombin-antithrombin III-complex, and fibrin monomers were measured to estimate thrombin activation. There was a significant dose-dependent reduction in fibrin-fibrinogen split product formation during cardiopulmonary bypass: In the high-dose aprotinin group the concentration of the split products at the end of bypass was 1.5 +/- 0.6 micrograms/ml, compared with 3.4 +/- 3.0 micrograms/ml in the low-dose aprotinin group and 6.7 +/- 3.5 micrograms/ml in the control group (p < 00.5). Fibrinolytic activation on fibrin plates was also significantly reduced by aprotinin. Fibrin monomer formation was significantly diminished at the end of cardiopulmonary bypass in the high-dose group: 9.2 +/- 5.2 micrograms/ml compared with 21.6 +/- 14 micrograms/ml in the control group (p < 00.5). Elastase in complex with alpha 1-protease inhibitor at the end of bypass was increased to the same amount in the three groups: 784 +/- 278 ng/mL (control group), 693 +/- 189 ng/ml (low-dose aprotinin), and 719 +/- 270 ng/mL (high dose aprotinin) (no significant difference). Blood loss 6 hours postoperatively was significantly (p < 00.5) less in the high-dose group (99 +/- 32 ml/m2) than in the control group (164 +/- 87 ml/m2; low-dose group: 160 +/- 106 ml/m2). These observations suggest an attenuation of hemostatic activation during cardiopulmonary bypass with less plasmin formation and, because of inhibition of contact activation, less thrombin generation with aprotinin treatment. Thus the thrombotic-thrombolytic equilibrium is kept more balanced after cardiopulmonary bypass. High-dose aprotinin treatment is recommended for pediatric patients undergoing cardiac operations.

Long-term survival and functional follow-up in patients after the arterial switch operation.

BACKGROUND: For many years, the arterial switch operation (ASO) has been the therapy of choice for patients with transposition of the great arteries (TGA). Although excellent short- and mid-term results were reported, long-term results are rare. METHODS: Between May 1983 and September 1997, ASO was performed on 285 patients with simple TGA (n = 171), TGA with ventricular septal defect (VSD) (n = 85), and Taussig-Bing (TB) anomaly (n = 29). This retrospective study describes long-term morbidity and mortality over a 15-year period. RESULTS: Hospital mortality was 3.5% for simple TGA, 9.4% for TGA with VSD, and 13.8% for TB anomaly. Late death occured in 2 patients, 1 with simple TGA and 1 with TGA and VSD. The cumulative survival for all patients at 5 and 10 years is 93%, and at 15 years is 86%. Reoperations were required in 31 patients and were most common for stenosis of the right ventricular outflow tract (RVOT). However, no correlation was found between technical variations on pulmonary artery reconstruction and this type of complication. Forty-six patients underwent follow-up angiography, which revealed five cases with coronary occlusion or stenosis. Follow-up is complete in 96% of the patients from 1 to 15.2 years. Sinus rhythm is present in 97%; 88% of the patients show no limitations on exertion. CONCLUSIONS: The ASO can be performed with low early mortality, almost absent late mortality, and infrequent need for reoperation. The favorable long-term results demonstrate that the ASO can be considered as the optimal approach for patients with TGA and special forms of double-outlet right ventricle.

Acute effects of aortocoronary bypass surgery on left ventricular function and regional myocardial mechanics: a clinical study.

The acute effects of myocardial revascularization on overall left ventricular performance and on myocardial segmental wall motion were assessed intraoperatively in 22 patients who had unstable (11 patients) or stable angina pectoris (11 patients). Segmental contraction patterns were evaluated using an ultrasonic transit-time method. In 9 patients with unstable angina pectoris, notable improvement in segmental wall motion was observed as the short-term response to coronary bypass grafting. Hypokinetic patterns were rendered normal after revascularization. Despite marked changes in segmental myocardial function, overall left ventricular performance was not altered notably. In contrast, reperfusion did not lead to acute effects on either segmental wall motion or total left ventricular function in patients with stable angina pectoris. The results indicate that aortocoronary bypass grafting may improve segmental wall motion in patients with unstable angina.

Results after surgical repair of Ebstein's anomaly.

BACKGROUND: Ebstein's anomaly of the tricuspid valve is a complex malformation. Various operations have been undertaken with varying results. Because valve replacement yielded poor results, surgical treatment has focused on valvuloplasties. METHODS: Between April 1974 and February 1995, 60 patients with Ebstein's anomaly underwent surgical repair. Age ranged from 5 months to 54 years. In 56 patients (93.3%), tricuspid valvuloplasty was feasible, mainly by creating a monocusp valve with the single-stitch technique. The other 4 patients had valve replacement with a bioprosthesis. Six reoperations were necessary (10.0%): four valve replacements and two repeat valvuloplasties. RESULTS: There were two hospital deaths (3.3%) and a late mortality rate of 10.0% (6 patients). Forty-nine (94.2%) of 52 survivors were followed for 5 months to 18.6 years (median follow-up, 5.0 years; mean follow-up, 6.9 years). The actuarial survival rate (Kaplan-Meier) was 96.5% +/- 2.4% at 1 year and 83.3% +/- 5.6% at 18 years. At follow-up evaluation, nearly all patients showed substantial improvement (93.9% were in functional class I or II) compared with their preoperative status. Doppler echocardiographic studies demonstrated good tricuspid valve function in most patients. CONCLUSIONS: Valvuloplasty using the single-stitch technique is a rewarding operation. It yields good long-term results with substantial improvement in functional performance and clinical status.

Drew-Anderson technique attenuates systemic inflammatory response syndrome and improves respiratory function after coronary artery bypass grafting.

BACKGROUND: Cardiopulmonary bypass causes inflammatory reactions leading to organ dysfunction postoperatively. This study was undertaken to determine whether using patients' own lungs as oxygenator in a bilateral circuit (Drew-Anderson Technique) could reduce systemic inflammatory response to cardiopulmonary bypass, improving patients clinical outcome following coronary artery bypass grafting. METHODS: A prospective randomized controlled trial involving 30 patients, divided in two groups of 15 patients each, undergoing elective coronary artery bypass grafting, was undertaken. In the Drew-group bilateral extracorporeal circulation using patient's lung as oxygenator was performed. The other patients served as control group, where standard cardiopulmonary bypass procedure was used. RESULTS: Pro-inflammatory and anti-inflammatory mediators were measured. Peak concentrations of proinflammatory interleukin-6, interleukin-8, were significantly lower in 15 patients undergoing Drew-Anderson Technique compared with the concentrations measured in 15 patients treated with standard cardiopulmonary bypass technique. Differences in patient recovery were analyzed with respect to time of intubation, blood loss, intrapulmonary shunting, oxygenation, and respiratory index. In patients undergoing uncomplicated coronary artery bypass grafting procedures bilateral extracorporeal circulation using the patients' own lung as oxygenator provided significant biochemical and clinical benefit in comparison to the standard cardiopulmonary bypass procedure. CONCLUSIONS: This prospective randomized clinical study has demonstrated that exclusion of an artificial oxygenator from cardiopulmonary bypass circuit significantly decreases the activation of inflammatory reaction, and that interventions that attenuate this response may result in more favorable clinical outcome.

Performance of allografts and xenografts for right ventricular outflow tract reconstruction.

BACKGROUND: We compared the long-term durability of allografts and xenografts implanted for reconstruction of the right ventricular outflow tract. METHODS: A total of 401 patients were studied from January 1974 to June 2000 (145 xeno- and 256 allografts), follow-up being 98% complete. We analyzed freedom from reoperation and allograft specific factors that may indicate degeneration. RESULTS: The age at implantation was 2 days to 31 years (median 4.0 years). Conduit exchange rate was similar (p = 0.2) for conduit diameters less than 15 mm (41%+/-9% for allografts, 30%+/-6% for xenografts), but significantly different (p = 0.02) for diameters of 15 mm or larger (60%+/-8% for allografts, 30%+/-10% for xenografts). Diagnosis-related 20-year survival analysis showed a significantly (p = 0.01) better survival of patients with tetralogy of Fallot/pulmonary atresia (83%+/-5%) and Rastelli-type surgery (81%+/-8%) compared with patients with truncus arteriosus communis (69%+/-8%). ABO-compatibility, preservation method, and aortic or pulmonary allograft could not be identified as risk factors for allograft longevity. CONCLUSIONS: For smaller diameters (less than 15 mm), allografts exhibit no advantage over xenografts, whereas in larger diameters (15 mm or larger) allografts are the conduit of choice for the right ventricular outflow tract.

Influence of high- and low-dose aprotinin on activation of hemostasis in open heart operations.

BACKGROUND: The protease inhibitor aprotinin reduces hemostatic activation and blood loss after cardiac operations. The aim of the present study was to investigate the influence of two different aprotinin doses on hemostatic activation and to identify the most effective dose to reduce the postoperative bleeding tendency. METHODS: In a prospective, randomized, double-blind clinical trial, 230 patients scheduled for routine open heart operations received either high-dose (group H) or low-dose (group L) aprotinin. Primary outcome measures were the level of F(1+2) prothrombin fragments as a marker of thrombin generation, the level of D-dimers as an indicator of fibrinolysis, and the amount of postoperative blood loss. Allogeneic blood transfusion was recorded as a secondary outcome measure. RESULTS: Aprotinin plasma concentrations 5 minutes after the onset of cardiopulmonary bypass were 166 +/- 45 kallikrein inactivator units per milliliter in group H and 118 +/- 30 kallikrein inactivator units per milliliter in group L (p < 0.05). Fibrinolytic activation was reduced significantly in group H compared with group L: the level of D-dimers at the end of CPB was 1,027 +/- 781 ng/mL and 1,977 +/- 1,001 ng/mL, respectively, in the two groups (p < 0.05). However, thrombin generation (F(1+2) fragments) did not differ between the two groups (7.4 +/- 3.5 nmol/L in group H and 8.6 +/- 4.3 nmol/L in group L). Twenty-four-hour postoperative blood loss was 663 +/- 461 mL in group H compared with 877 +/- 513 mL in group L (p < 0.05), and the corresponding allogeneic blood requirement was 1.3 +/- 1.9 U in group H and 1.9 +/- 2.3 U in group L (p < 0.05). CONCLUSIONS: A high-dose aprotinin regimen was significantly more effective than a low-dose regimen in attenuating fibrinolysis and reducing the bleeding tendency and allogeneic blood requirements, but not in reducing F(1+2) prothrombin fragments. High-dose aprotinin therapy appears to be superior to low-dose therapy.

Long-term results after repair of complete atrioventricular septal defects: analysis of risk factors.

BACKGROUND: We analyzed data from 320 patients to evaluate the impact of different preoperative, operative, and postoperative factors on the outcome after repair of complete atrioventricular septal defect. METHODS: Between October 1974 and December 1995, 320 patients with complete atrioventricular septal defect not associated with major cardiac anomalies were operated on. Two hundred seventy-four patients underwent total repair. Sixty-three patients (23%) were less than 6 months old. One hundred ninety-eight (72.2%) underwent primary repair. Seventy-six patients (27.7%) had a previous palliative operation. RESULTS: Operative mortality in patients who underwent primary repair decreased from 17.6% (1974 to 1979) to 5.0% (1990 to 1995) despite an increase in the number of patients younger than 6 months. In patients undergoing a two-stage procedure operative mortality was 3.9% (late mortality, 7.9%). Young age (<6 months) was an incremental risk factor (p = 0.008) for operative mortality in the early study period. Coarctation of the aorta (p = 0.02) and severe dysplastic left atrioventricular valve (p = 0.001) were associated with a higher risk for operative mortality. Freedom from reoperation at 10 years was 82.5% +/- 3.8%. CONCLUSIONS: In patients with complete atrioventricular septal defect, primary repair is the treatment of choice and can be accomplished with good results. In our experience over a period of more than 20 years, earlier date of operation, young age (<6 months), dysplastic left atrioventricular valve, and coexisting coarctation were incremental risk factors for hospital death. The presence of a previously placed pulmonary artery band did not alter the outcome of repair. The reconstructed atrioventricular valve shows a good and long-lasting performance.