Expression of coxsackievirus and adenovirus receptor in hearts of rats with experimental autoimmune myocarditis.

The expression of coxsackievirus and adenovirus receptor (CAR) was dominant in the brains and hearts of mice until the newborn phase. There is no detailed information concerning the relation between the expression of CAR and development of hearts. It is also uncertain whether CAR is able to be induced in adult hearts after cardiac injury. We demonstrated that CAR was abundant in the hearts of newborn rats but was barely detectable in the hearts of adult rats. The expression of CAR in rat hearts with experimental autoimmune myocarditis, which was induced by immunization of purified cardiac myosin, was serially investigated. Active myocarditis was observed from day 15 after immunization. By immunohistochemistry, cardiomyocytes were strongly stained for CAR antibody from days 24 to 42. CAR mRNA was also detected from days 18 to 30 by using reverse transcription-polymerase chain reaction. In the next experiment, the induction of CAR on isolated cardiomyocytes was investigated. CAR was barely detectable in cultured cardiomyocytes by Western blot analysis after isolation. This molecule gradually appeared along with the creation of clusters and beating of cardiomyocytes. Furthermore, the induction of CAR in cultured cardiomyocytes increased after supplement with conditioned medium of rat splenocytes activated by concanavalin A. In conclusion, rat CAR is expressed strongly in the hearts of newborn rats and is suppressed in those of adult rats. The expression of CAR is enhanced during the active phase of experimental autoimmune myocarditis and is induced by inflammatory mediators. CAR may play a role in cell-to-cell contact and adhesion of cardiomyocytes.

Recent insights into the role of host innate and acquired immunity responses.

Viral myocarditis can present as dramatic heart failure in the young, and chronic indolent cardiomyopathy in the older adult. The outcome of the disease is still poor, associated with high mortality during long-term follow-up. Enteroviral myocarditis serves as an excellent model to understand virus and host interactions. The virus enters the target cells via collaborating receptors, and this process triggers an inflammatory response in the host. The immune reaction is a two-edged sword, with appropriate activation of the immune system capable of clearing the virus, but excessive activation leads to a chronic inflammatory process that triggers the remodeling of the heart and consequent clinical heart failure. Through genetic dissection strategies, we have identified that the acquired immune system is activated through the T cell receptor and signaling amplification systems, such as the tyrosine kinase p56lck, phosphatase CD45 and downstream ERK1/2, and the family of cytokines. This signaling system not only promotes inflammatory cell clonal expansion but paradoxically also promotes viral proliferation. The innate immune system is now recognized as playing an ever-expanding role in coordinating the host immune response through the Toll-like receptors, triggering downstream signaling adaptors such as MyD88, IRAK, and TRIF/IRFs. These lead to activation of cytokines or interferons, depending on the balance of the signal contributions. The ongoing research in this area should help us to understand the immune response of the heart to viral infection, while identifying potential targets for therapy.

Predictors of disease course in patients with acute myocarditis.

BACKGROUND: Clinical manifestations of acute myocarditis, with distinct onset, vary from asymptomatic to fatal. The predictors of the course of the disease in patients with acute myocarditis at initial presentation have not yet been established. In this study, we examined the predictive values of various parameters in the disease course of patients with myocarditis. METHODS AND RESULTS: Twenty-one consecutive patients who had been diagnosed as having acute myocarditis by histological examinations were analyzed. The patients with myocarditis were divided into the survival group (n=13) and the fatal group (n=8). We examined the parameters of the clinical state, hemodynamic variables, required therapies, biochemical laboratory data, and cytokines. The control groups were composed of 23 patients with old myocardial infarction and 20 healthy volunteers. The fatal group had lower blood pressure and higher pulmonary capillary wedge pressure compared with those values in the survival group. Mechanical ventilation support was more frequently required in the fatal group. Serum levels of soluble Fas (sFas) and soluble Fas ligand (sFasL) were significantly higher in the myocarditis group than in the 2 control groups. Furthermore, levels were significantly higher in the fatal group than in the survival group for sFas (13.93+/-4.77 versus 3.77+/-0.52 ng/mL, respectively; P:<0.001) and sFasL (611.4+/-127.7 versus 269.5+/-37.3 pg/mL, respectively; P:<0.05). Other clinical states, hemodynamic variables, required therapies, and biochemical laboratory parameters were not different between the 2 groups. CONCLUSIONS: Elevation of sFas and sFasL levels at initial presentation appear to be a good serological marker to predict the prognosis of acute myocarditis.

Protection against autoimmune myocarditis by gene transfer of interleukin-10 by electroporation.

BACKGROUND: Although immunosuppressive therapy for myocarditis has attracted a great deal of attention, its effectiveness is controversial. Interleukin (IL)-10 has a variety of immunomodulatory properties. Among the nonviral techniques for gene transfer in vivo, the direct injection of plasmid DNA into muscle is simple, inexpensive, and safe. METHODS AND RESULTS: We examined the applicability of murine IL-10 (mIL-10) gene transfer to the treatment of rats with experimental autoimmune myocarditis. Nine-week-old Lewis rats were inoculated with pig myosin (day 0). A plasmid vector expressing mIL-10 cDNA (800 microgram per rat) was transferred into the tibialis anterior muscles by electroporation 3 times (5 days before immunization and at days 4 and 13); control rats received empty plasmid. Electroporation increased the serum mIL-10 levels to >250 pg/mL. The 21-day survival rate in rats treated with mIL-10 cDNA was higher (15 of 15; 100%) than that of the control group (9 of 15; 60%). Furthermore, mIL-10 treatment significantly attenuated myocardial lesions and improved hemodynamic parameters. CONCLUSIONS: These findings showed that gene transfer into muscle by electroporation in vivo is an effective means of delivery of IL-10 for the treatment of autoimmune myocarditis.

Usefulness of extracorporeal membrane oxygenation for treatment of fulminant myocarditis and circulatory collapse.

Prognosis for fulminant myocarditis with cardiogenic shock refractory to conventional therapy is poor. This report describes mechanical circulatory support with extracorporeal membrane oxygenation as an effective alternative for treating fulminant myocarditis with circulatory collapse.

Low dose carvedilol inhibits progression of heart failure in rats with dilated cardiomyopathy.

The cardioprotective properties of carvedilol (a vasodilating beta-adrenoceptor blocking agent) were studied in a rat model of dilated cardiomyopathy induced by autoimmune myocarditis. Twenty-eight days after immunization, surviving Lewis rats (32/43=74%) were divided into three groups to be given 2 mg kg(-1) day(-1) (Group-C2, n=10) or 20 mg kg(-1) day(-1) (Group-C20, n=10) of carvedilol, or vehicle (0.5% methylcellulose, Group-V, n=12). After oral administration for 2 months, body weight, heart weight (HW), heart rate (HR), rat alpha-atrial natriuretic peptide (r-ANP) in blood, central venous pressure (CVP), mean blood pressure (mean BP), peak left ventricular pressure (LVP), left ventricular end-diastolic pressure (LVEDP), +/-dP dt(-1) and area of myocardial fibrosis were measured. Values were compared with those for normal Lewis rats (Group-N, n=10). Two out of 12 (17%) rats in Group-V died from day 28 to day 42 after immunization. No rat died in Groups-C2, -C20 and -N. Although the CVP, mean BP, LVP and +/-dP dt(-1) did not differ among the three groups, the HW, HR and r-ANP in Group-C2 (1.14+/-0.03, 339+/-16 and 135+/-31) and Group-C20 (1.23+/-0.04, 305+/-8 and 156+/-24) were significantly lower than those in Group-V (1.36+/-0.04 g, 389+/-9 beats min(-1) and 375+/-31 pg ml(-1), respectively). The LVEDP in Group-C2 was significantly lower than that in Group-V (7.4+/-1.4 and 12.2+/-1.2 mmHg, respectively, P<0. 05). The area of myocardial fibrosis in Group-C2 was smaller than that in Group-V (12+/-1 and 31+/-2%, P<0.01). These results indicate that a low dose of carvedilol has beneficial effects on dilated cardiomyopathy.

Recovery from lymphocytopenia and prognosis after adult extracorporeal membrane oxygenation.

Extracorporeal circulation severely impairs the host immune system. Also decreases in circulatory lymphocytes correlate with greater degrees of surgical damage. In this study, the pattern of recovery from lymphocytopenia after extracorporeal membrane oxygenation was retrospectively evaluated from a prognostic viewpoint. The results showed that the circulatory lymphocyte count of survivors returned to normal levels within 5 days after their being weaned from extracorporeal membrane oxygenation, while the circulatory lymphocyte count of nonsurvivors remained at low levels. Because it is easy to measure the number of peripheral lymphocytes, the changing pattern of the circulatory lymphocytes might be a simple and reliable prognostic factor after extracorporeal membrane oxygenation.

Infectious mediastinitis after cardiac operations: computed tomographic findings.

BACKGROUND: Infectious mediastinitis after cardiac operations is of great concern to cardiac surgeons because of its poor prognosis. Prompt surgical interventions such as debridement and irrigation are the key to treatment of infectious mediastinitis. METHODS: We surveyed retrospectively the cases of 722 consecutive cardiac surgery patients at our hospital. Mediastinitis developed in 21 patients after the cardiac operation. We performed computed tomography in 11 of these patients before resternotomy and in 10 patients as the control 2 to 3 weeks after the cardiac operation. RESULTS: Mediastinal soft tissue swelling was seen in 7 patients, bilateral pleural effusion was found in 9 patients, sternal dehiscence or sternal erosion was observed in 8 patients, and subcutaneous fluid accumulation was found in 7 of the mediastinitis group. Unilateral pleural effusion was seen in 6 and bilateral effusion in 1, and mediastinal soft tissue swelling was seen in 1 patient of the control group. CONCLUSIONS: Our study showed that mediastinal soft tissue mass combined with bilateral pleural effusion can be a characteristic computed tomography finding in poststernotomy infectious mediastinitis, and that chest computed tomography is more sensitive to detecting sternal dehiscence, sternal erosion, and subcutaneous fluid accumulation.

Growth potential and left ventricular diastolic function in cardiomyoplasty.

BACKGROUND: Dynamic cardiomyoplasty is an experimental operation for advanced heart failure. Current clinical results bring the possibility of its application to children. This study was designed to obtain information about the relationship between cardiomyoplasty and growth of the heart. METHODS: Six beagles, 9 to 10 weeks old, underwent cardiomyoplasty without electric stimulation (cardiomyoplasty group), and another 5 beagles underwent median sternotomy and pericardiotomy (control group). Six months later, weights of hearts, wrapped latissimus dorsi muscles, and unwrapped right latissimus dorsi muscles and pressure-volume relationships were obtained. RESULTS: Wrapped latissimus dorsi muscles weighed 33 +/- 3 g (mean +/- standard deviation), and unwrapped muscles weighed 68 +/- 5 g. The heart weight was 82 +/- 3 g in the cardiomyoplasty group and 89 +/- 7 g in the control group. Left ventricular maximum elastance was 3.8 +/- 0.8 mm Hg/mL in the cardiomyoplasty group and 3.9 +/- 0.9 mm Hg/mL in the control group. End-diastolic pressure versus end-diastolic volume ratios were 0.52 +/- 0.03 and 0.54 +/- 0.05, respectively. Pathologic examination showed fat infiltration and muscle fiber atrophy in the cardiomyoplasty group. CONCLUSIONS: The wrapped latissimus dorsi muscle flaps were growing and the diastolic function was not impaired. This indicates a potentially safe clinical application of dynamic cardiomyoplasty for children.

Helical computed tomographic minimum-intensity projection of a slit in an airway obstruction.

We treated a 54-year-old man with an anastomotic obstruction after a right upper sleeve lobectomy. By using minimum intensity projection images that were generated from helical computed tomographic data sets that indicated a twisted slit enhanced with air a few millimeters in length, through anastomosis to the distal bronchus, we successfully treated the obstruction by bronchoscopic balloon dilatation.

Platelet aggregation during cardiopulmonary bypass evaluated by a laser light-scattering method.

BACKGROUND: In regard to postoperative bleeding, the most important consequence of cardiopulmonary bypass (CPB) is the loss of aggregability. However, the mechanism of platelet aggregation loss during CPB is unclear. Newly developed particle-counting methods that use light scattering can be used to quantify changes in the number of platelet aggregates of different sizes after application of an aggregating stimulus. Using a light-scattering method, we investigated changes in platelet aggregation during cardiac operation. METHODS: Nineteen patients undergoing CPB were evaluated. Blood samples were obtained before the operation, 1 hour after initiation of CPB, at the end of CPB, at the end of the operation, and on day 1 after the operation. Platelet aggregation after stimulation by 2.5 micromol/L adenosine diphosphate and 2.0 microg/mL collagen was determined; small (9 to 25 microm), medium (25 to 50 microm), and large (50 to 70 microm) aggregates were counted. RESULTS: Generation of medium and large aggregates after stimulation with adenosine diphosphate and collagen were significantly decreased with CPB, whereas, in spite of hemodilution, the quantity of the small aggregates was maintained at the elevated level. CONCLUSIONS: These results reflect the fact that CPB does not affect the first phase of aggregation. It suggests that platelet dysfunction associated with CPB is mainly caused by an inhibition in the development of small aggregates into larger aggregates.

Organized thrombus of the tricuspid valve mimicking valvular tumor.

We report on a case of organized thrombus of the tricuspid valve mimicking a valve tumor. Preoperative transesophageal echocardiography showed the mass to have originated from the septal leaflet of the tricuspid valve. A pouch of the tricuspid valve and a ventricular septal defect were observed perioperatively, with the mass attached to the septal leaflet. Histologic examination revealed the mass to be an organized thrombus without tumor components.

Conduction disturbances after superior septal approach for mitral valve repair.

BACKGROUND: The superior septal approach sacrifices the sinus node artery, and it requires more invasive incisions into the right and left atria. Therefore, postoperative rhythm disturbances could be troublesome in patients with SSA. In this study, we evaluated perioperative and midterm conduction disturbances in the cardiac rhythms of patients who had a SSA for mitral valve repair. METHODS: Fifty-two patients had mitral valve operations by the superior septal approach, and cardiac rhythm status was assessed. The mean follow-up period was 15 +/- 8 months. In patients with normal sinus rhythms preoperatively, serial changes in PR intervals were also assessed. Holter electrocardiograms were used 6 to 12 months postoperatively. Twelve patients who had mitral valve operations by conventional left atriotomy from the right side of the left atrium served as the control group. RESULTS: There were no operative deaths, but one patient in the experimental group died of cerebral hemorrhage 4 months postoperatively. No intractable arrhythmias occurred. Of the 25 patients who maintained sinus rhythms, preoperative PR interval on electrocardiogram was 155 +/- 20 milliseconds. Postoperative PR intervals increased for 1 week, had decreased within 2 weeks postoperatively, and returned to the normal range by 6 months postoperatively. Holter electrocardiograms of 17 patients did not show supraventricular arrhythmias exceeding 3% of the total beats. None of the patients needed pacemaker implantation. The PR intervals of 5 patients with normal sinus rhythms in the control group did not show significant changes perioperatively. CONCLUSIONS: The superior septal approach is excellent for mitral valve operations because it overcomes postoperative dysrhythmias.

Symptomatic accessory cardiac bronchus.

Symptomatic accessory cardiac bronchus is rare. A 52-year-old woman with an accessory bronchus, who had had frequent episodes of hemosputum for 6 years, suffered from empyema complicated by a right lower lung abscess infected with Pseudomonas aeruginosa. Resection of the anomalous cardiac bronchus after open drainage of the pleural cavity was successful.

Autologous blood transfusion with recombinant human erythropoietin in heart operations.

The effects of recombinant human erythropoietin (rHuEPO) on improving the anemia associated with autologous blood collection before open heart operations and on improving the postoperative anemia were studied. The study was carried out on 18 patients undergoing coronary artery bypass operations; 400 mL of autologous whole blood was taken from each patient 2 weeks before operation and was subsequently used in the operation, and rHuEPO (100 U.kg-1.day-1) was given intravenously for 2 weeks before operation and for 1 week after operation. The group in which iron preparations were also administered intravenously was designated as group I (10 patients), and the group in which rHuEPO was given alone was designated as group II (8 patients). In group III, as a control group, 11 past patients were used in whom 400 mL of autologous whole blood was collected 2 weeks before operation but neither rHuEPO nor iron preparations were given. After autologous blood collections, the hemoglobin levels improved in group I, group II, and group III, in that order, and with significant differences among them. It was shown that rHuEPO was effective in ameliorating the anemia associated with preoperative autologous blood collection, and the effect was further enhanced with intravenous supplementing iron preparations. After operation, the anemia markedly improved while rHuEPO was administered, but the hemoglobin levels decreased rapidly when the administration was terminated. Further studies are needed regarding the use of rHuEPO after operation.

Saphenous vein graft pseudoaneurysm rupture after coronary artery bypass grafting.

An elderly woman underwent coronary artery bypass grafting, which was followed 1 month later by pseudoaneurysmal rupture at the distal anastomosis of a saphenous vein graft. Emergency repair of the suture line dehiscence was made, and the postoperative course was uneventful. Pseudoaneurysm formation of a saphenous vein graft after coronary artery bypass grafting is a rare but potentially lethal complication requiring urgent operative intervention.

Successful surgical treatment of a complete traumatic tracheal disruption.

We report a case of a survivor who suffered a complete traumatic disruption of the cervical trachea associated with multiple organ injuries. She underwent an emergent operation including end-to-end anastomosis of the disrupted trachea with pedicled omental coverage to prevent dehiscence and mediastinitis. The postoperative course was uneventful, with hospital discharge on day 36. She returned to her previous lifestyle.

Three-channeled aortic dissection.

A 68-year-old woman in whom a thoracic aortic dissection (DeBakey type III) had been followed up for 6 years was admitted to our hospital with a complaint of chest pain. A graft replacement of the descending thoracic aorta was performed. A communication between the second and third channels was detected intraoperatively. Nine cases of three-channeled aortic dissection whose third dissection existed within the outer wall of the second one were previously reported, and 4 of them had a communication between the two false channels.

Subcutaneous use of erythropoietin in heart surgery.

The effect of subcutaneous administration of recombinant human erythropoietin (rHuEPO) in ameliorating anemia resulting from autologous blood donation was compared with intravenous administration of rHuEPO. Forty patients undergoing coronary artery bypass procedures were divided into three groups. Group I (12 patients) received intravenous administration of rHuEPO (100 U.kg-1.day-1) and intravenous iron preparations for 14 days before operation; group II (14 patients) had subcutaneous administration of rHuEPO (600 U/kg) on preoperative days 14 and 7 and oral iron preparations for 14 days; and group III (14 patients) received oral iron preparations alone and served as the controls. Each patient predonated 800 mL of blood in the 2 weeks before operation. The reticulocyte count increased significantly in groups I and II (p less than 0.01), but little in group III. The hemoglobin level just before operation was higher in groups I (p less than 0.01) and II (p less than 0.05) compared with group III. Four patients (29%) in group III required homologous blood transfusion versus none in groups I and II (p less than 0.05). Subcutaneous administration of rHuEPO once a week was as effective as daily intravenous administration. Preoperative autologous blood donation can be performed over a short period on an outpatient basis with subcutaneous administration of rHuEPO.

Polydextrose and activities of brush-border membrane enzymes of small intestine in rats and glucose absorption in humans.

We investigated the effect of polydextrose, one of the water-soluble non-digestible polysaccharides, on the activities of brush-border membrane enzymes of small intestine in rats and on glucose absorption with relation to the thickness of the unstirred water layer in humans. Rats were fed a 5% polydextrose-supplemented elemental diet for 2 or 4 wk. The mucosal alkaline phosphatase, maltase, and sucrase activities were measured in the upper, middle, and lower intestine. There was no significant difference between control and polydextrose groups. The potentiometric tube was inserted orally in the jejunum. Glucose absorption was measured by perfusion with the solutions with or without 5% polydextrose. There was no significant difference in the glucose absorption rate or the thickness of the unstirred water layer between control and polydextrose solutions. The increase in viscosity of the polydextrose solution was negligible. This study indicated that polydextrose had no effect on the thickness of the unstirred water layer and did not inhibit glucose absorption in humans.