Chojiro Yamashita

Role of endogenous endothelin in the development of graft arteriosclerosis in rat cardiac allografts: Antiproliferative effects of bosentan, a nonselective endothelin receptor antagonist

BACKGROUND The purpose of this study was to determine whether endothelin-1 (ET-1) contributes to the development of graft arteriosclerosis and whether the orally active nonpeptide endothelin receptor antagonist bosentan, which blocks both ETA and ETB receptors, can protect against this pathologic damage. METHODS AND RESULTS Recipient male Lewis rats were divided into three groups; group 1 received heterotopic heart transplantations from Lewis donors and groups 2 and 3 received transplantations from Brown-Norway donors; group 3 recipients also received bosentan orally at the dose of 20 mg/kg per day for 120 days. All recipients were given cyclosporine and were euthanized at examination 120 days after transplantation. Plasma ET-1 levels were significantly higher in group 2 than in group 1 (6.99+/-0.91 and 4.15+/-.83 pg/mL, respectively). Strong ET-1 immunoreactivity was seen in both the thickened neointima and the media of the coronary arteries in group 2 but not in group 1. The mean ratio of the coronary luminal area to the total vascular area in group 2 (19.0+/-11.7%) was significantly lower than that in group 1 (34.2+/-9.9%) and was significantly increased in group 3 (33.2+/-9.2%). CONCLUSIONS These results show that local upregulation of ET-1, mainly in the thickened neointima and the media of the coronary arteries, may play an important role in the pathogenesis of graft arteriosclerosis by stimulating ETA receptors, ETB receptors, or both. Orally active bosentan might be a useful agent for the clinical prevention of graft arteriosclerosis.

Role of Endothelin-1 in Beagles With Dehydromonocrotaline-Induced Pulmonary Hypertension

BACKGROUND Although plasma levels of endothelin-1 (ET-1) increase in patients with pulmonary hypertension (PH), its role in PH is unknown. We investigated the contribution of endogenous ET-1 to cardiopulmonary changes in beagles with dehydromonocrotaline (DMCT)-induced PH. METHODS AND RESULTS Eight 3-month-old beagles were given a single injection of 3 mg/kg DMCT via the right atrium. During the 8 weeks after injection, the mean pulmonary arterial pressure (PAP) and plasma ET-1 level increased significantly from 11.6 +/- 2.3 to 35.9 +/- 7.1 mm Hg and from 1.24 +/- 0.25 to 3.25 +/- 0.94 pg/mL, respectively. In controls, ET-1 infusion elevated the systemic arterial pressure (SAP) but did not alter PAP. In PH beagles, ET-1 infusion increased SAP, which was attenuated by FR139317 (an endothelin type [ET] A receptor antagonist), and produced a dose-dependent decrease in PAP, which was attenuated by RES-701-1 (an ETB receptor antagonist). In PH beagles, FR139317 infusion decreased PAP, and RES-701-1 infusion increased PAP. Sarafotoxin S6c (an ETB agonist) infusion decreased PAP in PH beagles. CONCLUSIONS These results suggest that endogenous ET-1 is elevated in PH disease and may mitigate PH by acting on ETB receptors.

Endothelin receptor antagonists in a beagle model of pulmonary hypertension: Contribution to possible potential therapy?

OBJECTIVES This study investigated the pharmacologic effect of endothelin receptor antagonists on cardiopulmonary hemodynamic variables in a beagle model of pulmonary hypertension. BACKGROUND We recently developed a beagle model of pulmonary hypertension that allows accurate determination of cardiopulmonary hemodynamic variables and is associated with elevated plasma endothelin-1 concentrations similar to those in pulmonary hypertension in humans. METHODS Twelve beagles (pulmonary hypertension, n = 6; control group, n = 6) were studied during baseline conditions and during right atrial infusion of FR139317 (an ETA receptor antagonist), RES-701-1 (an ETB receptor antagonist), nitroglycerin and prostaglandin E1. Pulmonary hypertension was induced in experimental beagles 8 weeks after injection with 3 mg/kg body weight of dehydromonocrotaline. RESULTS FR139317 lowered pulmonary artery and systemic arterial pressures in both pulmonary hypertensive and control beagles, with a significantly greater effect on pulmonary artery pressure in pulmonary hypertensive dogs. RES-701-1 tended to increase pulmonary artery pressure only in pulmonary hypertensive beagles. Nitroglycerin depressed pulmonary artery and systemic arterial tone equally well in control and pulmonary hypertensive animals. Prostaglandin E1 produced a greater decrease in systemic arterial pressure in pulmonary hypertensive than in normal beagles despite having the same effect on pulmonary artery pressure in both. CONCLUSIONS ETA receptor antagonists decrease pulmonary artery pressure in a beagle model and may therefore be clinically useful for treatment of pulmonary hypertension.

Retrograde cerebral perfusion with circulatory arrest in aortic arch aneurysms

Two surgical cases of aortic arch aneurysms are presented. Retrograde (venoarterial) cerebral perfusion during circulatory arrest under deep hypothermia was performed to evacuate air and debris in cerebral vessels and preserve cerebral tissue. On postoperative day 1, the patients were conscious and alert with no neurological deficit. This technique is simple and can be applied during standard cardiopulmonary bypass. The technique is useful to avoid cerebral air and thromboembolisms.

Intravenous Leiomyomatosis Extending into the Right Ventricular Cavity: One-Stage Radical Operation Using Cardiopulmonary Bypass: A Case Report

The authors describe a 47-year-old woman with intravenous leiomyomatosis (IVL) extending into the right ventricular cavity. This rare entity is a neoplasm originating from smooth muscle of the uterus, with vermiform extensions into the inferior vena cava. The patient underwent a one-stage operation under simultaneous sternotomy and laparo tomy, and radical excision of the tumor was successfully achieved with use of normoth ermic cardiopulmonary bypass. Although this tumor is histologically benign, it sometimes extends into the cardiac cavity and causes sudden death due to incarceration into the atri oventricular orifice. Moreover, recurrence or lung metastasis of IVL has been reported. The authors recommend a one stage-radical resection of the tumor or a two-staged operation within a short interval. In the literature, 24 surgical cases of the intravenous leiomyomatosis with intracardiac extension have been reported. The diagnosis and surgical treatment of this tumor are reviewed and discussed.

Right ventricular ejection fraction in the preoperative risk evaluation of candidates for pulmonary resection

The major determinants of postoperative morbidity and mortality after lung resection are the physiologic and functional statuses of the pulmonary and cardiac systems. In our previous study, serial measurements of right ventricular performance after pulmonary resection demonstrated significant right ventricular dysfunction in the postoperative period. This study evaluates the preoperative measurement of right ventricular ejection fraction as a predictor of postoperative complications. In addition to conventional cardiopulmonary functional tests, right ventricular function was assessed with a thermodilution technique at rest and during exercise in 18 patients before and 3 weeks after lobectomy or pneumonectomy. The patients were grouped according to severity of right ventricular functional defect: right ventricular ejection fraction of at least 45% (group Ia, n = 8), right ventricular ejection fraction less than 45% (group Ib, n = 10), exercise-induced increases in right ventricular ejection fraction (group IIa, n = 8), and exercise-induced decreases in right ventricular ejection fraction (group IIb, n = 10). Postoperative cardiopulmonary morbidity was recorded for two patients (25%) in group Ia, three patients (30%) in group Ib, no patients (0%) in group IIa, and five patients (50%) in group IIb. Postoperative hospital stay was 28.9 +/- 8.5 days in group Ia, 29.9 +/- 20.2 days in group Ib, 19.4 +/- 8.0 days in group IIa, and 37.5 +/- 15.9 days in group IIb (p < 0.05, group IIa vs group IIb). Although resection-induced changes in forced expiratory volume in 1 second did not differ significantly between group Ia and group Ib, these values appeared to be increased in groups IIa (not statistically significant) and IIb (significantly, p < 0.05). The measured postoperative values of forced expiratory volume in 1 second and vital capacity were significantly higher than the predicted postoperative values (p < 0.05) in group IIa, but not in groups Ia, Ib, and IIb. We conclude that evaluation of right ventricular performance is useful in determining which patients are at increased risk for medical complications after lung resection. Exercise-induced change in right ventricular ejection fraction may be a better indicator of high risk among candidates for pulmonary resection than the absolute value of this parameter.

Preoperative Computerized Tomography Detection of Extensive Invasion of the Inferior Vena Cava by Renal Cell Carcinoma: Possible Indication for Resection with Partial Cardiopulmonary Bypass and Patch Grafting

The relationship of the diameter of the inferior vena cava as measured by computerized tomography (CT) and tumor invasion of the inferior vena caval wall was determined in patients with renal cell carcinoma. In addition, the indications and usefulness of surgery using partial cardiopulmonary bypass and a polytetrafluoroethylene (Gore-Tex) patch graft are discussed. In all 7 patients with an inferior vena caval diameter of 40 mm. or larger on CT tumor had extensively invaded the vessel wall macroscopically and microscopically. Therefore, resection of the inferior vena caval wall and repair with a patch graft were necessary. Partial cardiopulmonary bypass was used in 6 of these 7 patients. On the other hand, of 11 patients with an inferior vena cava less than 40 mm. in diameter only 2 with extensive tumor invasion of the vessel wall underwent a patch graft procedure without partial cardiopulmonary bypass. One patient who had massive hemorrhage before bypass was started died while in a coma. The survival of the remaining patients ranged from 6 to 131 months (median 19 months). Blood loss in patients who underwent surgery with partial cardiopulmonary bypass was much less than that in patients without bypass. In our series, there were no complications related to the graft itself and graft patency was excellent. Our results indicate that an inferior vena caval diameter of 40 mm. or more on CT probably indicates extensive tumor invasion. Although further experience and observation are necessary to evaluate whether partial cardiopulmonary bypass and/or a patch graft improves the prognosis of patients with extensive inferior vena caval invasion by renal cell carcinoma, this method was relatively safe and decreased blood loss.

Surgical treatment for transvenous tumor extension into the heart: Four cases

From 1984 to 1996, four patients with transvenous intracardiac tumor extension underwent operations in the Kobe University Hospital. The primary tumors of two were intravenous leiomyomatoses originating from the uterus; a third patient had invasive thymoma, and the fourth patient had clear cell sarcoma of the kidney. In 1985, one patient had a curative, staged resection. One-stage operations were carried out in three patients, and all intracardiac tumors were successfully resected en bloc with the primary tumors under conditions of electrical ventricular fibrillation and mild hypothermia. Combined venous reconstructions were necessary for en bloc resection in three cases. Two patients with malignancy received postoperative chemoradiotherapy, and all four patients were discharged uneventfully from our hospital. We consider radical resection with curative intent only for patients with tumors extending into the heart. In these cases, a one-stage operation is preferable, and electrical ventricular fibrillation with mild hypothermia is a recommended method of circulatory assist because of its simplicity.

Successful 24-hour reabbit heart preservation by hypothermic continuous coronary microperfusion with oxygenated university of wisconsin solution

BACKGROUND This study assessed whether a combination of hypothermic continuous coronary microperfusion and oxygenated University of Wisconsin Solution (UWS) improves postischemic functional recovery and minimizes myocardial tissue edema. METHODS Isolated rabbit hearts were divided into four groups (n = 6 each): group I (immediate reperfusion), group II (simple cold storage in UWS), group III (hypothermic continuous coronary microperfusion with UWS), and group IV (hypothermic continuous coronary microperfusion with oxygenated UWS). Hearts in groups II, III, and IV were preserved for 24 hours. Preischemic and postischemic cardiac function was measured using a Langendorff apparatus. RESULTS Hearts in group I showed complete functional recovery, whereas cardiac output in group II was inadequate. In groups III and IV, the percentage recovery rate (post/pre) of cardiac output was 57.0% +/- 3.1% and 82.2% +/- 9.1%, respectively (p < 0.05). In groups III and IV, perfusion pressures at the end of 24-hour preservation increased from the initial 5 mm Hg to 12.3 +/- 2.7 and 8.3 +/- 1.4 mm Hg (p < 0.05), respectively. In groups I, III, and IV, the percentage tissue water content was 82.8 +/- 1.0, 86.7 +/- 1.7, and 83.8 +/- 1.6, respectively (p < 0.05 for group III versus groups I and IV). There was a significant correlation between the percentage tissue water content and coronary perfusion pressure at the end of the 24-hour preservation (r = 0.60, p = 0.040) and a significant inverse correlation between percentage tissue water content and percentage recovery rate of cardiac output (r = -0.69, p = 0.014). In ultrastructural examination, myocardial tissue edema was limited and mitochondria were well preserved in group IV. CONCLUSION We conclude that the combination of a hypothermic continuous coronary microperfusion technique and oxygenation of UWS was the procedure of choice for reducing tissue edema and improving both the coronary microcirculation and functional recovery during 24-hour heart preservation.

Usefulness of cardiopulmonary bypass in reconstruction of inferior vena cava occupied by renal cell carcinoma tumor thrombus

Aggressive surgical treatment in renal cell carcinoma is still controversial. The aim of this paper is to assess inferior vena caval (IVC) reconstruction for suprahepatic vena caval renal cell carcinoma (RCC) tumor thrombus. Twelve patients with suprahepatic vena caval thrombus from renal cell carcinoma who underwent surgical repair with cardiopulmonary bypass were evaluated. The vena caval defect was reconstructed by direct suture, patch repair, or graft replacement. Of 12 patients undergoing partial cardiopulmonary bypass, tumor thrombus extended to the junction of the hepatic vein in three patients and to the right atrium in one. Tumor thrombus was removed manually or with balloon catheter. Tumor thrombus in the right atrium was removed during electrical ventricular fibrillation. Repair of the IVC was performed by direct suture of the IVC wall in two patients, patch repair with expanded polytetrafluoroethylene (EPTFE) graft in seven, and graft replacement with an EPTFE graft in three. There were no operative deaths and the only postoperative complication was one patient death from pulmonary emboli. The four patients with nonlocalized disease died within 2 years, but four patients lived for more than 3 years postoperatively. Survival was 37.5% at 3 years and 18.8% at 5 years by the Kaplan-Meiers method. Conclusions: (1) Partial cardiopulmonary bypass is useful for the control of bleeding when tumor thrombus in the IVC extends to the junction of the hepatic vein. (2) Nephrectomy with tumor thrombectomy of the IVC is valuable, and long-term survival is possible in patients without distant metastases or regional lymph node metastases.