Relationship between Impairment of the Vascular Endothelial Function and the CHA2DS2-VASc Score in Patients with Sinus Rhythm and Non-valvular Atrial Fibrillation.

Objective and methods There is little information concerning the influence of the heart rhythm on the vascular endothelial function in patients with non-valvular atrial fibrillation (AF) compared with studies concerning sinus rhythm (SR). The present study included paroxysmal (n=184) or chronic (n=53) AF patients without heart failure and control subjects with SR (n=79) matched for age, gender and the CHA2DS2-VASc score. Paroxysmal AF was defined as episodes that terminated spontaneously within 7 days, while chronic AF was defined as longstanding AF that was refractory to cardioversion for 12 months or longer. There were no significant differences in the numbers of patients receiving renin-angiotension-aldosterone system inhibitors or statins among the three groups. Results Among the 237 AF patients (155 men, mean age 64±9 years, mean CHA2DS2-VASc score 1.8±1.4), the flow-mediated dilatation (FMD) was 5.4%±2.6% in the paroxysmal AF group, 4.3%±2.1% in the chronic AF group and 6.5%±3.5% in the SR group. There were significant differences among the 3 groups (all, p<0.05). Nitroglycerin-induced dilatation (NMD) was noted in 14.6%±6.5% of the paroxysmal AF group, 16.5%±9.1% of the chronic AF group and 12.7%±5.9% of the SR group, with no significant differences among the 3 groups. There was a significant negative correlation between the CHA2DS2-VASc scores and the FMDs value in all 3 groups (paroxysmal AF group:r=-0.322, p<0.01; chronic AF group:r=-0.291, p<0.05; SR group:r=-0.326, p<0.01). Conclusion In comparison with SR, the frequency and duration of AF episodes appear to cause deterioration of the vascular endothelial function.

Comparison of the CHADS2, CHA2DS2-VASc and R2CHADS2 Scores in Japanese Patients with Non-valvular Paroxysmal Atrial Fibrillation Not Receiving Anticoagulation Therapy.

Objective It remains unclear whether the CHADS2, CHA2DS2-VASc, or R2CHADS2 score is the most useful for the risk stratification of ischemic stroke/systemic thromboembolism (IS/SE) in Japanese patients with paroxysmal non-valvular atrial fibrillation (PNVAF). Methods We investigated the incidence of IS/SE on the basis of the CHADS2, CHA2DS2-VASc, and R2CHADS2 scores in 332 consecutive PNVAF patients (224 men, mean age: 65±13 years) who had not been administered anticoagulation therapy but who were administered antiarrhythmic drug therapy to maintain sinus rhythm between August 1995 and July 2008 before the 2008 Japanese Circulation Society guideline was issued (mean follow-up period: 53±35 months). Results The annual rates of IS/SE without underlying antiarrhythmic drug therapy are shown in the table included in this article. Higher CHADS2, CHA2DS2-VASc, and R2CHADS2 scores were associated with greater annual rates of IS/SE (p<0.001). In a multivariate logistic regression analysis adjusted for potentially confounding variables, the CHADS2 scores [odds ratio (OR): 4.74, 95% confidence interval (CI): 2.80-8.00, p<0.001], CHA2DS2-VASc scores (OR: 4.15, 95% CI: 2.57-6.71, p<0.001), and R2CHADS2 scores (OR: 1.94, 95% CI: 1.48-2.53, p<0.001) were significant independent predictors of IS/SE. The area under the receiver-operator characteristic curve for predicting IS/SE was 0.89 for CHA2DS2-VASc scores, 0.87 for CHADS2 scores, and 0.85 for R2CHADS2 scores (all, p<0.001), with no significant difference among the three scores. Conclusion In Japanese patients with PNVAF, the CHADS2, CHA2DS2-VASc, and R2CHADS2 scores are all useful for the risk stratification of IS/SE cases.

A model to evaluate toxic factors influencing islets during collagenase digestion: the role of serine protease inhibitor in the protection of islets.

The recovery of all of the islets contained in a pancreas is the goal of islet isolation for transplantation. This study reveals an environment that injures the isolated islets during digestion and proposes a new model for optimal islet isolation. Islets were isolated from Wistar rat pancreases by stationary collagenase digestion while the digestion time was varied at 15, 30, 60, and 120 min. The digested pancreas and islets were analyzed histologically and adenosine nucleotides were measured. Overnight cultured islets (40 islets) were cocultured for 30 min with the supernatants obtained from pancreatic collagenase digestion at different digestion periods in order to assess the toxic environment. The peak yields of islets were obtained at 30 min of digestion. The histological study of digested pancreas showed that the exocrine cells lost their cellular integrity at 120 min of digestion, but the islet cells were left intact. Accordingly, the ATP levels of the pancreatic tissue decreased during the digestion period. The coculture experiment demonstrated that the islets cultured with the supernatants from the collagenase digestion showed digestion time-dependent disruption of the cellular integrity of islets in accordance with a rapid decrease of ATP levels in the islets. The addition of serine protease inhibitors into this coculture clearly showed protection of islets, which maintained high ATP levels in association with intact membrane integrity as assessed by AO/PI staining. Morphological deterioration of islets as well as a marked ATP decrease was evident in the entire digested pancreas as well as in islets cocultured in the supernatants from the collagenase digestion. Various factors toxic to the islets can therefore be analyzed in future experiments using this coculture model for obtaining a good yield of viable islets.

Mizoribine as sole immunosuppressive agent in islet xenotransplantation models: a candidate immunosuppressant causing no adverse effects on islets.

Mizoribine (MZ) inhibits the differentiation and proliferation of helper T and B cells after antigen recognition by suppressing the purine biosynthesis pathway and nucleic acid synthesis. MZ has been used in kidney transplantation, but distinct data are unavailable for islet transplantation. The present study investigated the efficacy of MZ for islet xenotransplantation. Immunosuppressive effects of MZ were determined by mixed lymphocyte reaction (MLR) assay in vitro. Toxicities for Wistar rat islets were determined by adenosine triphosphate (ATP) contents of islets during 3-day culture and stimulation index in response to glucose after culture. Immunosuppressive effects in vivo were tested in a Wistar-to-B6 islet xenotransplantation model. MZ was administered continuously for 28 days subcutaneously or intramuscularly. MZ inhibited MLR response by approximately 50% at 0.1 µg/ml. ATP contents decreased with MZ >100 µg/ml, while stimulation index was maintained. Continuous infusion of MZ at 10 mg/kg maintained blood concentrations at 0.13-0.19 µg/ml, while intramuscular injection of MZ at 100 mg/kg/day (peak 520 µg/ml at 1 h postinjection) resulted in below measurable levels (<0.03 µg/ml) within 24 h. Graft survival was significantly prolonged following continuous infusion of 10 mg/kg/day compared to controls (31.0 ± 9.5 vs. 13.2 ± 5.2 days; p = 0.002). Furthermore, animals with intramuscular injection at doses of 3.2, 10, or 100 mg/kg/day showed significantly longer graft survival (20.0 ± 7.5, 22.0 ± 7.31, and 24.5 ± 8.1 days, respectively; p < 0.05 each). Histological examination showed significant suppression of lymphocyte infiltration by MZ administration. MZ showed immunosuppressive effects in an experimental islet xenotransplantation model without adverse effects on endocrine function of islet grafts.

Relationship between CHA(2)DS(2)-VASc scores and ischemic stroke/cardiovascular events in Japanese patients with paroxysmal atrial fibrillation not receiving anticoagulant therapy.

BACKGROUND AND METHODS: The CHA(2)DS(2)-VASc score has been newly proposed for stratifying patients with nonvalvular atrial fibrillation (AF) according to the risk of ischemic stroke in the 2010 European Society of Cardiology guideline. However, there is little information about its usefulness for predicting long-term prognosis of cardiovascular events in Japanese patients with paroxysmal AF. This study retrospectively included 332 paroxysmal AF patients (224 men, mean age 65±13 years, mean follow-up period 53±35 months) without receiving anticoagulant therapy between June 1995 and August 2008 who were categorized into risk stratification on the basis of CHA(2)DS(2)-VASc score. RESULTS: The distribution of CHA(2)DS(2)-VASc scores was 0, 1, 2, 3, 4, 5, 6, and 7 points in 76 (23%), 60 (18%), 69 (21%), 69 (21%), 28 (8%), 23 (7%), 6 (2%), and 1 (0.3%) patients, respectively. The annual rates of symptomatic ischemic stroke were 0%, 0.60%, 0.95%, 1.96%, 5.45%, 9.06%, and 13.7% when the CHA(2)DS(2)-VASc score was 0, 1, 2, 3, 4, 5, and ≥6 points, respectively (p<0.001) and those of cardiovascular events including hospitalization for thromboembolism, heart failure and cardiovascular death were 0%, 1.43%, 1.50%, 2.52%, 10.14%, 12.85%, and 17.13% when the CHA(2)DS(2)-VASc score was 0, 1, 2, 3, 4, 5 and ≥6 points, respectively (p<0.001). Higher CHA(2)DS(2)-VASc scores were associated with greater annual rates of ischemic stroke and cardiovascular events. In a multivariate logistic regression analysis adjusted for the potentially confounding variables, the CHA(2)DS(2)-VASc score was associated with symptomatic ischemic stroke (odds ratio 7.051, 95% confidence interval 3.76-13.22, p<0.001) and cardiovascular events (odds ratio 3.448, 95% confidence interval 2.33-5.11, p<0.001). CONCLUSION: In Japanese patients with paroxysmal AF, the CHA(2)DS(2)-VASc score is a useful scheme for risk stratification of ischemic stroke and cardiovascular events.

Clinical profiles, efficacy of antiarrhythmic drug therapy, and cardiovascular prognosis in patients with first detected paroxysmal atrial fibrillation.

Little information is available concerning clinical profiles and outcomes of treatment in Japanese patients with first detected atrial fibrillation (AF). In the present study, 459 patients with paroxysmal AF (309 males, mean age, 66 ± 12 years) were divided into a first detected AF group (group A, n = 143) and a non-first detected AF group (group B, n = 316). Clinical profiles, prophylactic efficacy of antiarrhythmic drug therapy (AAD), and cardiovascular prognosis during a mean follow-up period of 50 ± 35 months were compared between the two groups. The number of AF recurrences in the individual patients regardless of AAD were significantly lower in group A than in group B (0.8 ± 1.4 versus 1.7 ± 1.9)(P < 0.05). The percentages of patients free from conversion to chronic AF at 12, 36, 60, and 120 months were significantly higher in group A (98%, 96%, 93%, and 91%, respectively) than in group B (95%, 86%, 83%, and 79%, respectively)(P < 0.01). The annual rates of hospitalization for thromboembolism, heart failure, and cardiovascular death did not differ between group A (2.2%, 1.1% and 1.0%, respectively) and group B (2.2%, 1.9% and 1.1%, respectively). In multivariate logistic regression analysis, a CHADS2 score ≥ 2 points (odds ratio 13.1, 95% confidence interval 3.36-51.0, P = 0.001), nocturnal AF onset (OR 0.201, 95% CI 0.050-0.815, P = 0.025), left ventricular diastolic dimension (LVDd) ≥ 50 mm (OR 3.845, 95% CI 1.078-13.71, P = 0.038), and conversion to chronic AF (OR 3.547, 95% CI 1.002-13.64, P = 0.048) were associated with cardiovascular events in group A. Rhythm control therapy with antiarrhythmic drugs was shown to be more effective for patients in group A than in group B. It is particularly important to prevent cardiovascular events in first detected AF patients with a CHADS2 score ≥ 2 points, LVDd ≥ 50 mm, and conversion to chronic AF.

Relationship between the long-term preventive effect of combined treatment with antiarrhythmic drugs plus angiotensin-converting enzyme inhibitors and circadian variation in the onset of paroxysmal atrial fibrillation.

We examined the relationship between the efficacy of combined treatment with antiarrhythmic drugs (AAD) plus enalapril for maintaining sinus rhythm and circadian variation in the onset of paroxysmal AF.Three hundred and forty-four patients with paroxysmal AF (239 men, mean age, 69 ± 11 years) who could be followed up ≥ 12 months were divided into 3 groups on the basis of circadian variation in the onset of AF: a diurnal group (7:00 AM-5:00 PM, n = 57), a nocturnal group (5:00 PM-7:00 AM, n = 108), and a mixed group (onset during both periods, n = 169). The maintenance rate of sinus rhythm during the follow-up period was compared between combined therapy (AAD plus enalapril) and AAD alone.In the diurnal group, the maintenance rates of sinus rhythm at 12, 36, 60, and 90 months were 100%, 100%, 100%, and 100%, respectively, for patients treated with AAD plus enalapril (n = 22) versus 97%, 91%, 89%, and 80% for patients treated with AAD alone (n = 35, P < 0.05). In the nocturnal group, the maintenance rates of sinus rhythm at 12, 36, 60, and 90 months were 96%, 96%, 96%, and 92%, respectively, in patients treated with AAD plus enalapril (n = 24) versus 100%, 100%, 100%, and 100% in patients treated with AAD alone (n = 84, P = NS). In the mixed group, maintenance rates of sinus rhythm at 12, 36, 60, and 90 months were 90%, 71%, 61%, and 57%, respectively, in patients treated with AAD plus enalapril (n = 49) versus 88%, 78%, 68%, and 61% in patients treated with AAD alone (n = 120, P = NS). Our findings suggest that the preventive efficacy of combined therapy with AAD plus enalapril is dependent on the timing of onset of paroxysmal AF, and this regimen seems to be most beneficial for the diurnal type of paroxysmal AF.

Prospective comparative study of intravenous cibenzoline and disopyramide therapy in the treatment of paroxysmal atrial fibrillation after cardiovascular surgery.

BACKGROUND: It has been reported that approximately one-third of patients undergoing cardiovascular surgery experience paroxysmal atrial fibrillation (AF) during the postoperative period. There is, however, little information on the selection of anti-arrhythmic drugs for terminating postoperative paroxysmal AF. METHODS AND RESULTS: Between April 2007 and March 2009, 118 patients (76 men, 42 women, mean age 68+/-10 years) who had postoperative paroxysmal AF lasting > or =30 min were randomly assigned to receive either iv cibenzoline (70 mg, n=60) or disopyramide (50 mg, n=58) for terminating postoperative paroxysmal AF. The success rate of iv cibenzoline therapy (47%) was significantly greater than that of iv disopyramide therapy (24%; P<0.05). To identify clinical factors to increase the termination efficacy of iv cibenzoline, multivariate logistic regression was used to adjust for several covariates and to generate adjusted odds ratios (OR). The significant variables for the termination of paroxysmal AF after iv cibenzoline therapy were pretreatment with oral beta-adrenergic blockers (OR =8.224, P=0.030) and smaller left atrial dimensions (OR =0.879, P=0.039). CONCLUSIONS: The efficacy of iv cibenzoline for the termination of postoperative paroxysmal AF was significantly better than that of disopyramide, especially in patients with pre-administration of oral beta-adrenergic blockers and those with smaller left atrium.

Sequential magnetic resonance imaging for evaluation of Kupffer cell function.

BACKGROUND/AIMS: Kupffer cells play an important role in liver regeneration and depression of their function is associated with poor outcome. However, there is no clinically safe and reliable method for evaluating Kupffer cell function. METHODOLOGY: We used magnetic resonance imaging following injection of superparamagnetic iron oxide, which is trapped by Kupffer cells, to evaluate Kupffer cell function in 14 patients, including 6 with normal liver and 8 with obstructive jaundice T1-weighed signal intensity of the liver parenchyma was examined every 4 minutes for 60 min after superparamagnetic iron oxide injection. RESULTS: Signal intensity values gradually decreased in both groups after accumulation of iron in the liver. Serum iron levels equally and significantly increased in both groups. In contrast, the values of relative enhancement, percentage of signal intensity of precontrast to postcontrast, between 8-20 minutes after superparamagnetic iron oxide injection were significantly higher in obstructive jaundice group than in the control, indicating Kupffer cell dysfunction in obstructive jaundiced liver. CONCLUSIONS: These results indicate that chronological magnetic resonance imaging with superparamagnetic iron oxide is a suitable method for assessment of Kupffer cell function in patients with obstructive jaundice.

Beneficial effects of protein-bound polysaccharide K plus tegafur/uracil in patients with stage II or III colorectal cancer: analysis of immunological parameters.

Protein-bound polysaccharide K (PSK) increased the 5-year disease-free survival rate and reduced the risk of recurrence in a randomised, controlled study for stage II and III colorectal cancer. In order to elucidate the disease-free survival benefits with PSK and what immunological markers could indicate a PSK responder, serial changes in immunological parameters were monitored in the study. PSK decreased the mean serum immunosuppressive acidic protein (IAP) level, and increased the mean population of natural killer (NK) cells compared with the controls. The 5-year disease-free and overall survival rate for patients with serum IAP values or=8% at 3 months after surgery, PSK conferred a significantly better (p=0.038) 5-year disease-free survival (86.7%; 95% CI: 74.5-98.8%) compared to the control group (60.0%; 95% CI: 29.6-90.4%). In the proportional hazards model, the presence of regional metastases (relative risk, 3.595; 95% CI: 1.518 to 8.518; p=0.004) and omission of PSK treatment (relative risk, 3.099; 95% CI: 1.202 to 7.990; p=0.019) were significant indicators of recurrence. PSK acts as an immunomodulatory activity and biochemical modulator in stage II or III colorectal cancer. Pre-operative serum IAP values or=8% at 3 months after surgery are possible PSK response predictors.