The blood contribution to early myocardial reperfusion injury is amplified in diabetes.

Cardiovascular disease is excessive in diabetes, and blood cell function is altered. It is not clear, however, if alterations in the blood contribute to the excessive cardiovascular complications of this disease. In this study, we compared the contribution of nondiabetic and diabetic blood to myocardial reperfusion injury. The recovery of cardiac contractile function following no-flow ischemia was studied in isolated diabetic and nondiabetic rat hearts perfused with diabetic or nondiabetic diluted whole blood. Hearts were isolated from 10- to 12-week-old diabetic (streptozotocin, 65 mg/kg, i.v.) and nondiabetic rats and perfused with a Krebs-albumin-red cell solution (K2RBC, Hct 20%). After a 30-min pre-ischemic control period, during which cardiac pump function was evaluated, diabetic and nondiabetic hearts were perfused for 5 min with diluted whole blood (DWB; Hct 20%) collected from either diabetic or nondiabetic donor animals. Coronary flow was then stopped and the hearts subjected to 30 min of no-flow ischemia. Following ischemia, the hearts were reperfused with the K2RBC perfusate. Cardiac contractile function was evaluated throughout the 60-min reperfusion period. Six groups were studied: diabetic and nondiabetic hearts perfused before ischemia with either K2RBC, nondiabetic DWB (NDDWB), or diabetic DWB (DDWB). Perfusion with DWB prior to ischemia impaired the recovery of contractile function in all cases. The impairment to recovery was greater with DDWB than with NDDWB. Although diabetic hearts perfused with K2RBC throughout recovered quite well, the effect of DDWB perfusion in the diabetic hearts was dramatic. In an effort to determine why diabetic blood impaired functional recovery, measures of blood filterability and the generation of reactive oxygen species (ROS) were made. We found that diabetic blood was less filterable than nondiabetic blood; that is, the diabetic blood cells tended to plug the 5-microm filter pores more readily than the nondiabetic blood cells. Also, we found that the diabetic blood was capable of generating significantly greater ROS (oxygen free radicals) than nondiabetic blood (P < 0.05). These findings suggest that the blood contribution to myocardial reperfusion injury is amplified in diabetes. A tendency for diabetic blood cells to plug capillary-sized pores and show enhanced oxygen free radical production may account for the excessive contribution of diabetic blood to reperfusion injury in the heart.

Implications of preoperative administration of aspirin in patients undergoing coronary artery bypass grafting. Department of Veterans Affairs Cooperative Study on Antiplatelet Therapy.

The perioperative consequences of preoperative aspirin administration were assessed in a large prospective cooperative study of 772 patients undergoing coronary artery bypass grafting. The 772 patients were randomized to receive either aspirin (325 mg once a day), aspirin (325 mg three times a day), aspirin plus dipyridamole (325 and 75 mg together three times a day) (aspirin group), sulfinpyrazone (267 mg three times a day) or placebo (nonaspirin group). The therapy, except in the aspirin group, was started 48 h before the operation. In all aspirin subgroups, one 325 mg aspirin dose was given 12 h before surgery and maintained thereafter according to the assigned regimen. Patients in the aspirin group had significantly more postoperative bleeding and received more packed blood cells and blood products than did patients in the nonaspirin group. Although total operative duration and cardiopulmonary bypass duration were not different, the interval between completion of cardiopulmonary bypass and wound closure was significantly longer (p = 0.035) in the aspirin group. Thirty-one (6.6%) of 471 patients in the aspirin group and 5 (1.7%) of 301 patients in the nonaspirin group also required reoperation for control of postoperative bleeding (p = 0.002). The site of bleeding found at reoperation was not different between the two groups. There was no difference in operative mortality rates, incidence of other bleeding complications or occurrence of other post-operative complications between the two groups. Thus, antiplatelet regimens involving preoperative initiation of aspirin therapy, which has been shown to improve graft patency, increase the risk of abnormal postoperative bleeding and the need for reoperation.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiac transplantation in patients over 50 years of age.

Sixty-two patients underwent cardiac transplantation at the University of Arizona from March 1979 to March 1985. Thirteen patients (11 men and 2 women) were over 50 years of age at the time of transplantation and 49 were under the age of 50. The mean age (+/- SEM) of the patients over 50 was 53 +/- 1 years. Eight of these patients were treated with conventional immunosuppressive therapy (azathioprine, prednisone and rabbit antithymocyte globulin) and five, beginning in January 1983, were treated with cyclosporine, prednisone and rabbit antithymocyte globulin. Early mortality (0 to 90 days) was 16% in the group over 50 versus 18% for those under 50. The late mortality (greater than 90 days) was 36 and 33%, respectively. In both groups, rejection and infection were the principal causes of death. The incidence of infection was 1.9 +/- 0.5 episodes per patient in those patients over 50 and 1.9 +/- 0.4 in those under 50. The incidence of rejection was 1.3 episodes per patient-year in patients over 50 and 1.7 episodes per patient-year in those under 50. Actuarial survival at 1 year was 72 +/- 14% in the group over 50 and 66 +/- 7% in the group under 50 years of age. These data indicate that the results of cardiac transplantation for patients over 50 do not differ significantly from those for patients under 50. Therefore, it is concluded that a rigidly defined age criterion for cardiac transplant recipients is not acceptable. Each potential recipient must be evaluated in terms of individual risk and benefit from the procedure.

Anatomic-ultrasound correlations for intraoperative open chest imaging of coronary artery atherosclerotic lesions in human beings.

This study was performed to further validate a method for intraoperative ultrasound imaging of coronary arteries. Ultrasound images of coronary atherosclerotic lesions were compared with anatomic specimens of the coronary arteries obtained from open chest human subjects. The anatomic specimens were derived from four cardiac transplant recipients, accepted as candidates for transplantation because they had severe diffuse atherosclerotic disease, and one patient who died in the early postoperative period after a coronary artery bypass procedure. Twenty-six ultrasonically imaged atherosclerotic areas of the coronary arteries in these patients were compared with formalin-fixed and decalcified anatomic specimens. Specific ultrasound appearances for atherosclerotic lesions were observed, including 1) discrete (focal) stenosing fibrous/atheromatous plaques; 2) diffuse nonobstructive fibrous/atheromatous disease (detectable even in anatomically small vessels); 3) complete occlusion by fibrous/atheromatous lesions or organizing thrombus; and 4) "shadowing," an ultrasound pattern characteristic of significant calcification within atherosclerotic plaques. As part of this study, a new 12 MHz water path probe was evaluated for coronary artery scanning. The new probe allowed improved access to coronary arteries and increased detail of anatomic visualization. Both the performance of the new high resolution probe and the knowledge gained by the anatomic correlations obtained in this study should aid the development of intraoperative coronary artery scanning for surgical localization of atherosclerotic disease during coronary bypass surgery.

Detection of deterioration or infection of homograft and porcine xenograft bioprosthetic valves in mitral and aortic positions by two-dimensional echocardiographic examination.

Results of two-dimensional echocardiographic examinations were compared with angiographic, hemodynamic and surgical results in 44 patients with bioprosthetic valves in mitral and aortic positions who were undergoing elective or urgent reinvestigation 24 to 87 months (mean 34) after implantation. In these patients, there were 18 homograft aortic valves in the aortic position, 9 stent-mounted homograft aortic valves in the mitral position, 13 porcine xenograft valves in the mitral position and 12 in the aortic position. Poor cusp support, gross fluttering and prolapse of cusps behind or below the anulus identified aortic insufficiency by two-dimensional echocardiography in six patients with an aortic homograft and four patients were identified with insufficiency of a stent-mounted aortic homograft in the mitral position. Two-dimensional echocardiographic examination revealed mitral stenosis in three patients with a porcine xenograft valve in the mitral position and suggested mitral insufficiency in two others. Bacterial endocarditis on homograft or porcine xenograft valves was associated with easily imaged vegetations by two-dimensional echocardiography in 10 patients. Despite difficulties in imaging valve cusps, and the skill required to obtain good echocardiographic images of bioprosthetic valves, significant valve deterioration or infected prostheses were quite effectively imaged by two-dimensional echocardiography in this study.

Bilateral chylothorax complicating Mustard repair of transposition of the great vessels.

Less than 60 cases of bilateral chylothorax have been previously reported, and only two of these involve complicated Mustard procedures. We describe herein a patient in whom severe bilateral chylothorax developed three weeks after Mustard repair of D transposition. Complete reversal of this condition was obtained with revision of the constricted interatrial baffle and ligation of the thoracic duct. This cases is compared clinically with previously reported instances of chylothorax, and the role of played by obstruction of the superior vena cava after a Mustard procedure for transposition of the great vessels is emphasized.

Gastrointestinal cytomegalovirus infection in heart and heart-lung transplant recipients.

Cytomegalovirus (CMV) causes major morbidity in organ transplant recipients. Gastrointestinal disease was the most prominent manifestation of CMV infection in a population of heart and heart-lung transplant patients, with an incidence of 9.9%, compared with pneumonitis (4.0%) and retinitis (0%), and occurred most frequently in CMV-seronegative recipients of organs from CMV-seropositive donors. Clinical manifestations included gastritis (nine patients), gastric ulceration (four patients), duodenitis (three patients), esophagitis (one patient), pyloric perforation (one patient), and colonic hemorrhage (one patient). Patients with gastrointestinal CMV infection were treated with intravenous ganciclovir sodium therapy, 5 mg/kg twice daily, for 2 to 8 weeks, with positive clinical, endoscopic, histologic, and virologic responses. Relapses occurred in four of nine patients who were followed up for a median period of 18 months. Retreatment resulted in healing of endoscopic lesions and in viral clearing. We conclude that early endoscopic evaluation for CMV is indicated in heart and heart-lung transplant patients with gastrointestinal symptoms. This study further suggests that intravenous ganciclovir therapy is effective for the treatment of gastrointestinal CMV in these patients.

Plasma propranolol before, during, and after cardiopulmonary bypass.

We evaluated changes in propranolol plasma levels before, during, and after cardiopulmonary bypass (CPB). Two groups of patients were studied, all of whom had been on long-term propranolol and had received their last oral dose 10 to 15 hr before surgery. Approximately 100 min before CPB began group 1 patients (n = 7) received 0.1 mg/kg propranolol intravenously while group II patients (n = 7) received a placebo. Before CPB the plasma propranolol levels fell in accordance with published descriptions for nonsurgical patients receiving oral and intravenous propranolol. Thereafter, the changes in the plasma levels were much the same in both groups. With the onset of CPB, the plasma levels decreased by approximately 50%. There was an insignificant fall in plasma levels during CPB, but the most interesting observation was made after : in each patient, the plasma levels obtained 5, 60, 120, and 240 min after CPB were higher than the last level during CPB. Mean plasma levels did not decline in either group during the 4-hr period. Although the reason for the sustained rise in the propranolol levels after CPB is not known, we suggest that it is due to the redistribution of propranolol from the lungs of the plasma coupled with reduction in hepatic elimination.

A comprehensive immunotopographic map of human thymus.

We have achieved a comprehensive immunotopographic mapping of human thymus by using a large battery of monoclonal antibodies and the methodological refinement of comparative serial tissue section immunohistochemistry, allowing analysis of multiple phenotypes in the same tissue site. Previous immunohistochemical studies of thymus have concentrated on the majority T-cell and epithelial cell populations. Besides demonstrating the complexity of T-cell antigenic expression (e.g., simultaneous cortical expression of Leu 2, Leu 3, CALLA, Tdt, and Leu 6), we delineate surprisingly complex B-cell zones (e.g., septal B-follicles with DRC+C3d+ dendritic cells and zonal maturation of B-cells). Whereas septal B-follicles were found in 25% of cases, medullary B-cells were universally present as a substantial minority component. This expanded immunotopographic knowledge of the complex T-, B-, epithelial, and reticulum cell neighborhoods suggests that the thymus is an organ capable of a broad repertoire of immunological responses, not limited to T-cell development.

One heart, two bodies: insight from the transplanted heart and its new electrocardiogram.

Cardiac transplantation provides a unique opportunity to record the electric field generated by a human heart in a new somatic environment. By examining pre- and posttransplantation electrocardiograms (ECGs), it is possible to address questions on the effect of rotation of the heart on its long axis on the surface ECG, the effect of thoracic anatomy on ECG voltage and predisposing factors for conduction defects observed after transplant surgery. To examine these questions, we reviewed a series of 35 matched donor and recipient ECGs. There were no differences in the mean height of the donors and recipients, but age, weight and body surface area were higher in the recipients (p less than 0.025). We found no significant differences in the mean heart rate or precordial voltage but the PR and QT intervals were shorter (p less than 0.025), and the precordial transitional zone was more to the left after transplantation (p less than 0.0005). New evidence of right bundle branch delay was found in 11 recipients and this was not related to pretransplantation hemodynamic factors or the period of ischemic arrest. Thus, there is indeed an anatomic basis for the ECG determination of clockwise rotation of the heart when the precordial transition zone is to the left. Age and body habitus, per se, do not appear to affect precordial voltage and evidence of right bundle delay in the transplant recipient appears to be related to the altered position of the heart and not to injury or changes in right ventricular hemodynamics.

Frequency of left atrioventricular regurgitation postoperatively after repair of complete atrioventricular defect.

Experience with 43 consecutive cases of isolated (except for patent ductus) atrioventricular (AV) defects treated surgically at University Medical Center in Tucson, Arizona, were reviewed to determine occurrence and amount of postoperative left AV valve regurgitation. Patients initially evaluated at ages 1 day to 59 months were included, 32 of whom had Down's syndrome and 11 of whom had normal chromosomes. Age at repair ranged from 1 month to 171 months; 70% of patients had repair at < 16 months of age. Mean follow up was 7.1 years. Nine patients died, 8 of whom had Down's syndrome. Left AV valve regurgitation was absent or mild in 69% of patients who survived the perioperative period; however, very early repair (age < or = 4 months) was associated with significantly greater probability of moderate or severe left AV valve regurgitation than that seen in patients who had repair after that age. These data suggest that left AV valve regurgitation after repair of AV defects is usually not clinically significant, but patients in this series who underwent operation very early (age < or = 4 months) were at the highest risk for significant left AV valve regurgitation.

Two dimensional Doppler echocardiographic/M mode echocardiographic and phonocardiographic method for study of extracardiac heterograft valved conduits in the right ventricular outflow tract position.

Significant concern exists over the long-term results of right ventricular outflow tract repair using heterograft valved conduits. Because these conduits and valves are difficult to image using ultrasound, a serially applicable two dimensional Doppler echocardiographic, M mode echocardiographic and phonocardiographic method for noninvasive investigation was developed and applied in 15 children. The method provides two dimensional echocardiographic imaging of valve contour and motion, as well as M mode and phonocardiographic analysis and quantitative range-gated Doppler information about the timing of flow through the conduit. Conduit diameter in two dimensional echocardiographic images correlated well with known conduit size (r = +0.96). A thickened and stenosed heterograft valve was predicted in two patients before hemodynamic investigation. This new method provides serially obtainable information to aid in the management of children and infants with a valved conduit placed for repair of congenital heart malformations and aids in planning the timing of hemodynamic follow-up studies.

Two dimensional echocardiography and intravenous digital video subtraction angiography for diagnosis and evaluation of double aortic arch.

Two infants and one 7 year old child with double aortic arch are described in whom subcostal two dimensional echocardiography identified the bifurcation of the aorta high within the thorax and imaged the proximal portions of the right and left aortic arches. In one of the infants and in the 7 year old child, the diagnosis was confirmed using intravenous digital video subtraction angiography, thus avoiding aortography and permitting accurate evaluation of the anatomic features. All cases were confirmed surgically. If X-ray examination after barium swallow and clinical history are suggestive of double aortic arch, two dimensional echocardiography is useful in verifying this possibility. Intravenous digital video subtraction angiography provides the capability for precise documentation of the anatomic features.

beta 2-Adrenoceptors regulate induction of myocardial ornithine decarboxylase in mice in vivo.

The pharmacological characteristics of the myocardial adrenoceptor of the mouse have been examined during embryogenesis by measuring ornithine decarboxylase (ODC, EC 4.1.1.17) induction. 2 A four fold elevation of ODC activity was observed after isoprenaline (10 mg/kg, s.c.), and enzyme activity was increased two to three fold following adrenaline (1 mg/kg, s.c.) or terbutaline given by direct injection to the foetus (10 microgram/500 mg). 3 Pretreatment with the beta-adrenoceptor antagonist, propranolol (10 mg/kg), totally blocked the increase in ODC activity. 4 Elevation of myocardial ODC activity was not inhibited by metoprolol, a relatively specific beta-adrenoceptor antagonist, at a dose of 10 mg/kg. 5 Since the increase in ODC activity was blocked by a beta-adrenoceptor antagonist (propranolol) and enzyme activity was stimulated by terbutaline, a beta 2-agonist, we conclude that beta 2-adrenoceptors are selectively coupled to the regulation of murine cardiac ODC activity following catecholamine stimulation.

Cyclosporine inhibits prolactin induction of ornithine decarboxylase in rat tissues.

Cyclosporine (CyA), formerly cyclosporin A, significantly inhibited the ability of prolactin (PRL) to elevate ornithine decarboxylase (ODC) activity in a variety of rat tissues. Administration of PRL to hypophysectomized rats also resulted in an induction of ODC activity which was inhibited markedly in all tissues studied in the presence of CyA. Transglutaminase ( TGase ) activity was not affected in any significant manner by PRL or CyA in most tissues studied. However, it was elevated in the adrenal by 10(-8) M PRL. Bromocryptine, which selectively antagonizes pituitary PRL release, decreased the kidney ODC basal levels to 30% of vehicle control and serum PRL level to 4.3 +/- 1.4 compared to 28 +/- 10 in controls, suggestive of PRL maintenance of steady-state ODC activity in the kidney. CyA administration did not affect the action of glucagon, a known cyclic AMP-mediated hormone, or 8-bromo-cyclic AMP on kidney ODC activity. The elevation of rat kidney ODC activity by dexamethasone and triiodothyronine (T3), compounds which elevated serum prolactin levels in all cases, was also blocked by administration of CyA. Epidermal growth factor (EGF), which did not induce rat kidney ODC activity by itself, was capable of producing a small increment in ODC activity in the presence of CyA. The marked effect of CyA to selectively block ODC induction by PRL may be due to the ability of CyA to interact with receptor-required phospholipids in membranes and thus to antagonize hormone-receptor interaction.

Myocardial function after preservation for 24 hours.

The orthotopically transplanted heart undergoes several steps between harvest from the donor and reperfusion in the recipient: cardioplegic arrest and cooling, ischemia during the operation, in most cases a preservation or storage period of varying duration, and reperfusion. Each of these steps represents a period during which damage to the heart can occur. In this study we have quantified the degree of damage sustained by a donor heart during each of these steps. This objective was achieved by evaluating the function of rabbit hearts via Langendorff procedures following (Group 1) cooling and reperfusion; (Group 2) cardioplegic arrest, cooling, and reperfusion; (Group 3) arrest, cooling, 1 hour of ischemia (5 degrees or 25 degrees C), and reperfusion; (Group 4) arrest, cooling, 24 hours of preservation, and reperfusion; and (Group 5) arrest, cooling, 24 hours of preservation, 1 hour of ischemia (25 degrees C), and reperfusion. Comparisons were made between groups and to control hearts. Cooling and reperfusing the heart (Group 1) led to no loss of function, although recovery to precooling function levels required approximately 25 minutes. Hearts that were arrested before cooling (Group 2) regained full function without the slow recovery time. Hearts that were arrested, cooled, and made ischemic at 5 degrees C (Group 3) recovered 95% of preischemic contractile function: maximum systolic pressure and the maximum positive derivative of the systolic pressure curve. No change in diastolic compliance was detected. Hearts that were arrested, cooled, and made ischemic at 25 degrees C (Group 3) recovered 89% of preischemic contractile function (maximum systolic pressure and the maximum positive derivative of the systolic pressure curve). Again, no change in diastolic compliance was detected. Hearts that were arrested, cooled, preserved for 24 hours, and reperfused (Group 4) recovered 84% of control contractile function (maximum systolic pressure and the maximum positive derivative of the systolic pressure curve), whereas hearts that had the additional hour of ischemia at 25 degrees C (Group 5) recovered only 75% of control contractile function. In the latter two groups diastolic compliance was also compromised. Group 4 had a 20% decrease in the volume required to reach 10 mm Hg, and Group 5 had a 26% decrease. Pressure-volume curves suggest a loss of contractility and a loss of compliance in these hearts. These data indicate that while significant damage occurred as a result of ischemia and reperfusion, this damage was masked by the larger decrease in function occurring as a result of the preservation period.

Lipid peroxidation results in compromised functional recovery of isolated rabbit hearts after low-pressure, hypothermic, perfused preservation for 24 hours.

Low-pressure, hypothermic perfusion of isolated rabbit hearts for 24 hours compromises contractile function. This occurs despite continuous recirculation of an oxygenated solution. This investigation tested the hypothesis that such functional impairment results from irreversible tissue damage consequent to ischemia-induced lipid peroxidation. Decreases in coronary flow were measured during preservation and related to concentrations of thiobarbituric acid reactive species (TBA+, primarily malondialdehyde, a by-product of lipid peroxidation) in the tissue after preservation. The concentration of TBA+ species and the percent decrease in coronary flow rates at 30 minutes and 24 hours were positively correlated (r = 0.591 and r = 0.646, respectively). India ink was used as a marker of microvascular perfusion. Hearts showing the greatest magnitude of ischemia (evidenced by decreased percentages of perfused microvessels) had the highest levels of TBA+ species (r = 0.924). Moreover, hearts that had the highest levels of TBA+ species in the tissue exhibited the lowest levels of left ventricular function (as measured on a modified Langendorff apparatus; r = 0.767). We conclude that impaired coronary flow rates during perfused preservation portend compromised myocardial contractility. Furthermore, these changes occur largely within the first 30 minutes of perfusion. It is likely that early decrements in microvascular perfusion and consequent tissue injury owing to lipid peroxidation underlie impaired myocardial function after preservation.

A technique to simplify and improve exposure in heart-lung transplantation.

Heart-lung transplantation is associated with high perioperative mortality rates. A modified operative technique was used by one surgeon operating on 17 patients at the University of Arizona, Tucson, and the Inland Northwest Thoracic Organ Transplant Program, Spokane, Washington. This technique gives greater exposure to the area of dissection behind the heart-lung block after implantation and makes maintaining hemostasis easier. No deaths from bleeding complications occurred and no reoperations for bleeding were required with this technique. The Kaplan-Meier survival was 82% at 1 year. This technique simplifies a difficult technical procedure and may reduce mortality rate.

Combined aortic and mitral valve replacement in an adult with Scheie's disease.

Mitral, aortic, and coronary arterial disease have been described in the various mucopolysaccharidoses. We report the first successful combined aortic and mitral valve replacement in an adult female patient with severe aortic and mitral stenosis due to Scheie's syndrome, a mucopolysaccharide storage disease. Both annulae were of sufficient integrity for good prosthetic placement, and the patient had an uneventful postoperative recovery.

Acoustic analysis of the closing sounds of bileaflet prosthetic valves in a sheep model.

Previous investigations of mechanical valve sounds have shown that (1) frequency spectra of sounds produced by abnormal valves differ from those of properly functioning valves and (2) leaflets of normally functioning bileaflet valves do not close synchronously. This investigation studied effects of mechanical valve size, environment, and hemodynamic state on closing sounds. A single 25 mm bileaflet mitral mechanical valve was implanted in six sheep and a single 27 mm valve in four sheep. With digital signal processing, asynchronous leaflet closure and frequency spectra were assessed after alterations in animal position, respiratory phase, heart rate, afterload, contractility, and preload. Both asynchronous leaflet closure and frequency spectra varied among animals, and, except for a decrease in asynchrony with increasing contractility, were largely independent of valve size and hemodynamics. Baseline asynchrony ranged from 0.5 to 4.2 msec. Frequency spectra were characterized by the first three resonant peaks. Lowest resonant peaks ranged from 2.5 to 3.4 kHz, middle from 4.7 to 6.8 kHz, and highest from 7.2 to 9.6 kHz. These results indicate that accurate assessment of mechanical valve function with acoustic analysis requires baseline studies in all patients by means of a system with a frequency response of more than 10 kHz.