Keiko Kaneko

On the mechanism of termination and perpetuation of atrial fibrillation.

In an effort to further clarify the mechanism of termination and perpetuation of atrial fibrillation (AF), the intraatrial potentials during AF induced by programmable electrical stimulation were analyzed using the concept of wavelength which represents the size of a microreentrant circuit. Thirty patients with inducible AF were divided into 2 groups: 20 patients with AF that terminated spontaneously (group 1) and 10 patients with AF that did not terminate spontaneously (group 2). Wavelength is the product of refractory period and conduction velocity. During AF, the refractory period of the local atrial tissue was considered to correlate with the mean interval between each intraatrial potential (mean ff). An inverse relation was considered present between conduction velocity of the impulse and the width of intraatrial potentials (f width). Thus, the wavelength index was defined as (mean ff)/(mean f width). Ten intraatrial potentials at the high right atrium were sampled for measurement. Group 1 had higher wavelength indexes just after the induction of AF than did group 2 (1.33 +/- 0.31 vs 1.10 +/- 0.05, p less than 0.05). In group 1, the wavelength indexes were increased from the initial value to 1.49 +/- 0.36 just before termination of AF (p less than 0.001). In 3 group 2 patients, AF stopped after disopyramide was administered intravenously, whereas the wavelength indexes at the end of AF were higher than those before drug administration (1.27 +/- 0.08 vs 1.16 +/- 0.04, p less than 0.05). In conclusion, prolongation of the wavelength appears to be a major determinant for termination of AF, and shorter wavelengths are necessary for perpetuation of AF.

Comparison of the Effects of Angiotensin Receptor Antagonist, Angiotensin Converting Enzyme Inhibitor, and their Combination on Regression of Left Ventricular Hypertrophy of Diabetes Type 2 Patients on Recent Onset Hemodialysis Therapy

Abstract:  Left ventricular hypertrophy (LVH) is frequently found at the initiation of dialysis therapy of diabetic and hypertensive patients, and is highly predictive of future cardiac morbidity and mortality. In patients with hypertension and LVH, both an angiotensin converting enzyme (ACE) inhibitor and an angiotensin type 1 receptor (AT1) antagonist regress LVH. However, it remains controversial whether dual blockade of the renin–angiotensin system will regress LVH in these patients using a combination of ACE inhibitor and AT1 antagonist. Thirty‐three type II diabetic patients with end‐stage renal disease who had just entered into hemodialysis therapy and were diagnosed as having LVH evaluated by echocardiography were selected from three dialysis units staffed by the faculty of Saitama Medical School, Saitama, Japan between 1999 and 2001. The study was carried out for 1 year. All patients were assigned randomly to three groups with equal number: group I, an ACE inhibitor, enalapril 10 mg daily; group II, an AT1 antagonist, losartan 100 mg daily; group III, combination of enalapril 10 mg and losartan 100 mg daily. All antihypertensive drugs were given 30 min after the cessation of dialysis therapy. LVH was evaluated by echocardiography before the start of administration of drugs, at 6 months and 12 months after the start of drug therapy. Systolic blood pressure levels less than 140 mmHg were the target for the three groups. Using repeated measures analysis of variance, applied to those with four echocardiograms, there were progressive decreases over time in left ventricular mass index, posterior wall thickness and interventricular septum thickness. There were no significant differences in regression of LVH as well as blood pressure control between enalapril and losartan groups; however, dual blockade induced an additional 28% reduction in left ventricular mass index compared with any type of monotherapy. Both ACE inhibitors and AT1 antagonists benefit the regression of LVH in diabetic patients who start dialysis therapy. Moreover, combination therapy with ACE inhibitors and AT1 antagonists would provide more beneficial effects on LVH in these patients than monotherapy.

Angiotensin receptor antagonist regresses left ventricular hypertrophy associated with diabetic nephropathy in dialysis patients.

Background Left ventricular hypertrophy (LVH) is frequently found at the initiation of dialysis therapy for diabetic and hypertensive patients, and is highly predictive of future cardiac morbidity and mortality. Angiotensin type 1 receptor (AT1) antagonists may be able to regress LVH by mechanisms independent of their antihypertensive effects in diabetic patients. It is not known whether AT1 antagonists are able to reverse LVH in diabetic patients on dialysis therapy. Method Twenty-four type II diabetic patients with end-stage renal disease who had just entered into hemodialysis therapy, and were diagnosed as having LVH evaluated by echocardiography, were selected from 3 dialysis units staffed by the faculty of Saitama Medical School between 1998 and 2001. The study was carried out for 1 year. All patients were randomly assigned to 2 groups. One group received an AT 1 antagonist, losartan 100 mg daily 30 minutes after the cessation of dialysis therapy on dialysis days, or in the evening when dialysis therapy did not occur. The control group received placebo. LVH was evaluated by echocardiography before the start of administration of drugs, at 4 and 8 months, and again at 12 months after the start of drug therapy. A systolic blood pressure of less than 140 mm Hg was the target blood pressure in both groups. Results Using repeated measures analysis of variance, applied to those with 4 echocardiograms, there were progressive decreases over time in the left ventricular mass index (LVMi), posterior wall thickness, and intraventricular wall thickness in patients receiving losartan. The biggest changes in mass and the other parameters occurred between baseline and at month 6. Compared with these changes in the patients receiving losartan, left ventricular internal diameters and their derived parameters (e.g., ejection fraction) remained unchanged throughout the study. In spite of a similar reduction of bp in the patients receiving placebo, no significant changes in echocardiographic parameters were found in these patients. Conclusion An AT 1 antagonist, losartan, is beneficial for the regression of LVH in diabetic patients who started dialysis therapy under adequate blood pressure control.

Surgical resection of a solitary para-aortic lymph node metastasis from hepatocellular carcinoma

Lymph node (LN) metastases from hepatocellular carcinoma (HCC) are considered uncommon. We describe the surgical resection of a solitary para-aortic LN metastasis from HCC. A 65-year-old Japanese man with B-type liver cirrhosis was admitted for the evaluation of a liver tumor. He had already undergone radiofrequency ablation, transcatheter arterial chemoembolization, and percutaneous ethanol injection therapy for HCC. Despite treatment, viable regions remained in segments 4 and 8. We performed a right paramedian sectionectomy with partial resection of the left paramedian section of the liver. Six months later, serum concentrations of alpha-fetoprotein (189 ng/mL) and PIVKA-2 (507 mAU/mL) increased. Enhanced computed tomography of the abdomen revealed a tumor (20 mm in diameter) on the right side of the abdominal aorta. Fluorine-18 fluorodeoxyglucose positron emission tomography revealed an increased standard uptake value. There was no evidence of recurrence in other regions. Esophagogastroduodenoscopy and colonoscopy revealed no malignant tumor in the gastrointestinal tract. Para-aortic LN metastasis from HCC was thus diagnosed. We performed lymphadenectomy. Histopathological examination revealed that the tumor was largely necrotic, with poorly differentiated HCC on its surface, which confirmed the suspected diagnosis. After 6 mo tumor marker levels were normal, with no evidence of recurrence. Our experience suggests that a solitary para-aortic LN metastasis from HCC can be treated surgically.

Anti-CD137 monoclonal antibody enhances trastuzumab-induced, natural killer cell-mediated cytotoxicity against pancreatic cancer cell lines with low human epidermal growth factor-like receptor 2 expression

Background Because human epidermal growth factor-like receptor (HER) 2 is expressed on the surface of human pancreatic carcinoma cells to varying degrees, trastuzumab, an anti-HER2 monoclonal antibody (mAb), is expected to exert antibody-dependent, natural killer (NK) cell-mediated cytotoxicity (ADCC) against the cells. However, some reports found that the effect of trastuzumab against human pancreatic carcinoma cells was limited because most express only limited HER2. Methods We examined whether anti-CD137 stimulating mAb could enhance trastuzumab-mediated ADCC against Panc-1, a human pancreatic cancer cell line with low HER2 expression, in vitro. Results Supplementation of anti-CD137 mAb could improve trastuzumab-mediated ADCC against Panc-1 which was insufficient without this stimulating antibody. The ADCC differed in individual cells, and this was related to the expression of CD137 on the surface of NK cells after trastuzumab stimulation in association with the Fcγ-RIIIA polymorphism. NK cells with Fcγ-RIIIA-VV/VF showed high levels of ADCC against Panc-1, but those with Fcγ-RIIIA-FF did not show optimal ADCC. In addition, trastuzumab-mediated ADCC against the human pancreatic cancer cell line Capan-1 with high HER2 expression was generally high and not affected by the Fcγ-RIIIA polymorphism. Conclusions These results demonstrated that in Fcγ-RIIIA-VV/VF-carrying hosts, trastuzumab plus αCD137 mAb could induce effective ADCC against HER2-low-expressing pancreatic cancer cells. This also indicates the therapeutic potential for unresectable human pancreatic cancer, in which HER-2 expression is generally low.

Tu1037 Outflow of Hepatocytes Into the Hepatic Vein During Radiofrequency Ablation in Porcine Liver

[Background and Aims] Sporadic cases of unexpected recurrence, such as intrahepatic dissemination, extrahepatic seeding, and rapidly growing recurrence have been described following radiofrequency ablation (RFA). Some reports speculated that RFA during energy application may increase intratumoral pressure and favor intravascular spread of the tumor. Therefore, we examined the existence of hepatocytes in the hepatic vein during RFA. [Subjects and Methods] A total of 3 pigs with a mean body weight of 58.8 ± 5.7 kg were intubated and general anesthesia were maintained. Using the 8-Fr sheath inserted into the left jugular vein, a guidewire was used to guide a 4-Fr catheter to the hepatic vein. After median laparotomy, needle electrodes were inserted inside the liver, and RFA was performed near the catheter. A cooled-tip RF needle electrode was used for RFA. Ablation was performed by increasing output by 10 W/min, starting at 40 W. The duration of ablation was 6 min. The blood was collected by placing the catheter 10mm from the needle electrode tip. Fifteen RFA sessions of 3 animals were examined to detect exfoliated tissues. In every RFA session, 30 ml of the down-streaming blood in the vessel attached to the irradiated part was collected to a heparinized syringe and separated by using Ficoll-gradient method. Cell fractions were incubated with the culture medium for 15 hours. The number of cell clusters attached on culture dishes were counted and examined immunohistochemically for albumin as a hepatocyte marker. [Results] The results of immunohistochemistry showed that albumin-positive cells were found in cell clusters those were attaching and spreading on the culture dish. The margin of the cluster showed membrane ruffling. That means the live hepatocytes being trapped in the outbound vessel of RFA treated site. Various sizes of clusters were found. The clusters were classified in four as S-1 (5 to 10 cells), S-2 (11 to 20 cells), S-3 (21 to 50 cells), and S-4 (more than 50 cells) according to the constituted cell amount. The mean number of cell clusters found in every RFA was S-1; 9 ± 7.1, S-2; 5.1 ± 5.7, S-3; 0.6 ± 0.8, S-4; 0.5 ± 0.8, respectively. Smaller sizes of clusters (S-1 and S-2) were more frequently found (P, 0.01 vs. S-3 and S-4). These clusters were never found in the blood before RFA. Therefore, it should be concluded that the cell cluster was derived from the liver and was artificially exfoliated tissue masses by RFA. [Conclusions] The present results demonstrate that hepatocytes are pushed out alive into the hepatic vein from the hepatic lobules by RFA. These results suggested that a risk of dissemination due to RFA exists.

Su2030 Hepatocytes Migration Into Both Portal and Hepatic Vein During Radiofrequency Ablation in Porcine Liver

Introduction: Triphasic contrast-enhanced CT (CE-CT) demonstrating tumor hypervascularity on arterial phase (AP) followed by a washout pattern on portal venous phase (PVP) and/ or delayed phase (DP) is the characteristic feature underlying the imaging diagnosis of hepatocellular carcinomas (HCCs). However, this typical vascular feature is not always present, especially in small tumors of 200 ng/ml with a background of chronic liver disease. Mean attenuation in Hounsfield units (HU) were measured by placing regions of interest on tumors and surrounding liver. Hypervascularity of tumor were quantitatively defined by either AP(T-L) ,representing the conventional criteria that considers the attenuation difference between tumor (T) and surrounding liver (L) in AP, or T(AP-UE) ,representing the proposed criteria that compares the attenuation difference of tumor in AP to that of UE-CT. The cut-off criterion for tumor hypervascularity was quantitatively evaluated at 5 and 10HU. Result: T(AP-UE) identifiedmore tumor hypervascularity as compared to AP(T-L) at cut-off of 5HU (96% vs. 65%, p 2 to <4 cm (97/97% vs. 87/74%, p<0.001) and ≥ 4 cm (96/89% vs. 48/36%, p<0.001) when a cut-off of 5/10HU were used. Conclusion: UE-CT in combination with CE-CT can increase sensitivity of hypervascularity detection in HCC than CE-CT alone. A quantitative approach for the characterization of hypervascularity is feasible and may enhance detection and decrease operator-dependent variability. The use of UE-CT may enhance CECT detection of HCCs as per American Association for Study of Liver Disease (AASLD) / European Association for the Study of Liver (EASL) / Asian Pacific Association for the Study of the Liver (APASL) imaging criteria.

Effects of aprindine on monophasic action potentials

Using a catheter electrode developed by the authors for recording monophasic action potentials (MAPs), the atrial and ventricular MAPs of seven mongrel dogs were simultaneously recorded. The results were used to evaluate the effect of the new antiarrhythmic drug aprindine on MAPs. An electrophysiologic study was also carried out to evaluate the effect of aprindine on the conduction system. Aprindine caused a significant increase in both the AH interval (at a basic cycle length of 400 ms) and the HV interval (at basic cycle lengths of 400 and 500 ms). The effective refractory period increased in both the right atrium and the right ventricle. Although an increase in MAP duration at repolarizations to 90% MAP (MAPD90) was not observed in the right atrium, a significant increase was noted in MAPD90 in the right ventricle. There were no significant changes in the ratio between the effective refractory period and MAPD90 of the right ventricle before and after administration of aprindine. This result suggests that increases in MAPD90 contribute to an increase in the effective refractory period of the right ventricle.