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Indoxyl sulfate (IS), a protein-bound uremic toxin, induces chronic kidney disease (CKD) and atrial fibrillation (AF). Catheter ablation (CA) of AF improves the renal function. However, the transition of uremic toxins is unclear. This study aimed to investigate the transition of the serum IS level in AF patients with and without CKD after CA. A total of 138 consecutive AF patients who underwent CA and maintained sinus rhythm were prospectively enrolled (paroxysmal AF 67.4%). The patients were divided into 4 groups (non-CKD/low-IS:68, non-CKD/high-IS:28, CKD/low-IS:13, and CKD/high-IS:29). The plasma IS levels and estimated glomerular filtration rate (eGFR) were determined before and 1-year after CA. CKD was defined as CKD stage III and a high-IS according to the mean IS (IS ≥ 1.1 μg/ml). CA significantly improved the eGFR in CKD patients (p < 0.001). The serum IS level in the non-CKD/high-IS group was significantly decreased (from 1.7 ± 0.7 to 1.1 ± 0.6 μg/ml, p < 0.001). However, the serum IS level in the CKD/high-IS group did not improve (from 1.9 ± 0.9 to 1.7 ± 0.7 μg/ml, p = 0.22). The change in the IS in the CKD patients significantly differed from that in those without CKD. In the CKD patients, CA did not significantly decrease the IS, a risk factor of CKD, regardless of an improved eGFR.

Indoxyl sulfate (IS), a protein-bound uremic toxin, induces renal disorders and atrial fibrillation (AF). It is well known that renal dysfunction is a risk factor for AF and radiofrequency catheter ablation (RFCA) improves the renal function. However, the improvement in the renal function after RFCA in patients with early stage chronic kidney disease (CKD) and the serial changes in the IS level have not been fully elucidated. This study aimed to investigate whether IS affects the improvement in the renal function. A total of 91 consecutive patients with mild kidney dysfunction (CKD stage I–II) who underwent RFCA and maintained sinus rhythm were prospectively enrolled. The plasma IS level and estimated glomerular filtration rate (eGFR) were determined before, 3 months, and 1 year after RFCA. The patients were divided according to the IS quartiles (Q1–4; < 0.4, 0.4–0.7, 0.7–1.2, and > 1.2 μg/ml). There was no significant difference in the eGFR among the IS quartiles. A significantly higher eGFR improvement rate was obtained for IS-Q4 than the other quartiles ( p  = 0.039). The IS-Q4 IS level significantly decreased at 1 year after RFCA (1.8 ± 0.8 to 1.2 ± 0.7 μg/ml, p  < 0.01). The multivariable logistic model revealed that a high-IS level (IS-Q4) was an independent predictor of an eGFR improvement (OR 3.33; 95% CI 1.16–9.59; p  = 0.026). A high-IS level reduction after RFCA improved the renal function in AF patients with mild kidney dysfunction.

Background The clinical evaluation of a direct oral anticoagulant (DOAC) treatment for atrial fibrillation (AF) patients with renal dysfunction has not been sufficiently studied. This study aimed to evaluate the safety and efficacy of DOACs for patients with a severely impaired renal function. Methods This was a retrospective and observational study in a single center. We enrolled 894 consecutive AF patients who were prescribed DOACs, and divided them into three groups based on their creatinine clearance (CrCl) value: CrCl ≥ 50 mL/min group (n = 634), CrCl 30‐49 mL/min group (n = 207), and CrCl 15‐29 mL/min group (n = 53). We evaluated the occurrence of major bleeding (MB) as the safety outcome and thromboembolic events (TEs) as the efficacy outcome during the follow‐up. Results The incidence of MB in the CrCl 15‐29 mL/min group was significantly higher than in the other groups (CrCl ≥ 50 mL/min group, 0.8/100 person‐years; CrCl 30‐49 mL/min group, 1.2/100 person‐years; CrCl 15‐29 mL/min group, 9.0/100 person‐years, log rank test, P < .001). On the other hand, there was no significant difference in the incidence of TEs among the three groups. A multivariate analysis using a Cox proportional hazard model adjusted for the age revealed that the CrCl 15‐29 mL/min group was significantly associated with increased MB compared to the CrCl ≥ 50 mL/min group (hazard ratio: 9.76, 95% confidence interval: 2.69‐35.5, P < .001). Similar results were observed when adjusting for other multiple clinical factors. Conclusion This study demonstrated that the degree of renal dysfunction was a significant prognostic factor for MB in AF patients receiving DOACs. We evaluated the outcomes of AF patients with renal dysfunction receiving DOACs. A severely impaired renal function was associated with increased risk in MB. Apixaban might be safe in AF patients with a severely impaired renal function.

Background The safety and efficacy of an oral anticoagulant (OAC) treatment and the difference between direct OACs (DOACs) and warfarin in nonsevere frail elderly patients with AF are unclear. Methods This was a retrospective and observational study of 354 patients over 80 years of age with nonsevere frailty who were diagnosed with AF and treated with OACs. Nonsevere frailty was defined as a clinical frailty scale score of <7. Bleeding and thromboembolic events during the OAC treatment were followed up. Results Of 354 patients enrolled, 273 (77.1%) received DOACs and 81 (22.9%) received warfarin. Of 273 patients receiving DOACs, there were 210 (76.9%) prescribed with appropriate doses of DOACs. Of 81 warfarin‐treated patients, 53 (65.4%) were prescribed an appropriate dose of warfarin. During a follow‐up of 33.1 (14.0‐51.0) months, 15 patients (1.5/100 person‐years) had bleeding events and 10 (1.0/100 person‐years) had thromboembolic events while on an OAC treatment. The incidence ratio of bleeding events in patients receiving DOACs was lower than that in those receiving warfarin (1.0/100 person‐years vs 2.9/100 person‐years, hazard ratio [HR]: 0.26, 95% confidence interval [CI]: 0.07‐0.91, P = .036). There was no significant difference in the incidence of thromboembolic events between the DOAC and warfarin treatment groups (0.88/100 person‐years vs 1.4/100 person‐years, HR: 0.63, 95% CI: 0.16‐2.57, P = .52). Conclusions OACs are substantially safe and effective for preventing thromboembolic events in nonsevere frail patients over 80 years of age. Particularly, DOACs can be used more safely than warfarin. Oral anticoagulants (OACs) are substantially safe and effective for preventing thromboembolic events in non‐severe frail patients over 80 years of age. Particularly, direct OACs can be used more safely than warfarin.

Abstract Background Pilsicainide, a pure Na+ channel blocker, is a popular antiarrhythmic drug for the management of atrial tachyarrhythmias (AT), in Japan. However, serious drug-induced proarrhythmias (DIPs) may unexpectedly occur. We assessed the clinical background of AT patients presenting with DIPs caused by pilsicainide. Methods This study retrospectively enrolled 874 consecutive patients (543 men, 63.6±15.3 years old, and 57.9±16.5 kg of body weight), who were orally administered pilsicainide for AT management. We evaluated the relationship between DIPs and serum pilsicainide concentration, renal dysfunction (estimate glomerular filtration rate, eGFR), and electrocardiogram (ECG) parameters. Results Among the patients, 154 (17.6%) had renal dysfunction (eGFR<50 mL/min), including 12 (1.4%) on hemodialysis. DIPs were present in 10 patients (1.1%): all had renal dysfunction, and one was on hemodialysis. The eGFR in DIP patients was significantly lower than that in the non-DIP patients (32.2±15.1 vs. 68.4±22.1 mL/min, p <0.001). Among the clinical factors measured, only renal dysfunction (eGFR<50 mL/min) was significantly associated with DIPs (OR 44.6; 95% CI 5.61–335.0, p <0.001). Interestingly, among the ECG parameters, the corrected QT (QTc) intervals in DIP patients were longer than those in non-DIP patients (555.8±37.6 vs. 430.7±32.6 ms, p <0.001). As pilsicainide concentration increased, both QRS and QTc intervals prolonged. The latter were improved by discontinuing pilsicainide administration, and additional treatments. Conclusions DIPs caused by pilsicainide administration were strongly associated with renal dysfunction. Hence, confirmation of renal function would be necessary prior to and/or during the pilsicainide administration.

The aim of this study was to examine cancer and bleeding in atrial fibrillation patients administered with dabigatran. This study enrolled 509 consecutive nonvalvular atrial fibrillation patients who received dabigatran. The mean administration period was 14.8 ± 15.7 months. We investigated the prevalence and new development of cancers. Further, the relation between cancer and adverse events was evaluated. In the 509 patients, major bleeding occurred in 2.6% and dyspepsia in 8.4%. Further, 16.9% patients had a history of cancer and 3.9% developed new cancers. These adverse events developed in 45% patients who developed new cancers. The cancer (hazard ratio: 6.30; p = 0.003) was a significant predictor of major bleeding. Bleeding was associated with the presence of cancer.

Although the ε2 allele of apolipoprotein E ( APOE2 ) benefits longevity, its mechanism is not understood. The protective effects of the APOE 2 on Alzheimer’s disease (AD) risk, particularly through their effects on amyloid or tau accumulation, may confound APOE2 effects on longevity. Herein, we showed that the association between APOE2 and longer lifespan persisted irrespective of AD status, including its neuropathology, by analyzing clinical datasets as well as animal models. Notably, APOE2 was associated with preserved activity during aging, which also associated with lifespan. In animal models, distinct apoE isoform levels, where APOE2 has the highest, were correlated with activity levels, while some forms of cholesterol and triglycerides were associated with apoE and activity levels. These results indicate that APOE2 can contribute to longevity independent of AD. Preserved activity would be an early-observable feature of APOE2 -mediated longevity, where higher levels of apoE2 and its-associated lipid metabolism might be involved.

Cerebral amyloid angiopathy (CAA) often coexists with Alzheimer’s disease (AD). APOE4 is a strong genetic risk factor for both AD and CAA. Sex-dependent differences have been shown in AD as well as in cerebrovascular diseases. Therefore, we examined the effects of APOE4 , sex, and pathological components on CAA in AD subjects. A total of 428 autopsied brain samples from pathologically confirmed AD cases were analyzed. CAA severity was histologically scored in inferior parietal, middle frontal, motor, superior temporal and visual cortexes. In addition, subgroups with severe CAA ( n  = 60) or without CAA ( n  = 39) were subjected to biochemical analysis of amyloid-β (Aβ) and apolipoprotein E (apoE) by ELISA in the temporal cortex. After adjusting for age, Braak neurofibrillary tangle stage and Thal amyloid phase, we found that overall CAA scores were higher in males than females. Furthermore, carrying one or more APOE4 alleles was associated with higher overall CAA scores. Biochemical analysis revealed that the levels of detergent-soluble and detergent-insoluble Aβ40, and insoluble apoE were significantly elevated in individuals with severe CAA or APOE4 . The ratio of Aβ40/Aβ42 in insoluble fractions was also increased in the presence of CAA or APOE4 , although it was negatively associated with male sex. Levels of insoluble Aβ40 were positively associated with those of insoluble apoE, which were strongly influenced by CAA status. Pertaining to insoluble Aβ42, the levels of apoE correlated regardless of CAA status. Our results indicate that sex and APOE genotypes differentially influence the presence and severity of CAA in AD, likely by affecting interaction and aggregation of Aβ40 and apoE.